Substituted anilinic piperidines as mch selective antagonists

专利摘要:
The present invention relates to compounds which are selective antagonists for melanin enriched hormone-1 (MCH1) receptor. The present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention and a pharmaceutically acceptable carrier. The present invention provides a pharmaceutical composition obtained by combining a therapeutically effective amount of a compound of the present invention with a pharmaceutically acceptable carrier. The present invention also provides a method of preparing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention and a pharmaceutically acceptable carrier.
公开号:KR20040027870A
申请号:KR10-2004-7000087
申请日:2002-07-03
公开日:2004-04-01
发明作者:모하매드 알 마자바디；존 웨트젤；존 이 델레온；장유；카이 루
申请人:시냅틱 파마세틱칼 코포레이션；
IPC主号:

专利说明:

SUBSTITUTED ANILINIC PIPERIDINES AS MCH SELECTIVE ANTAGONISTS}
[1] This application is part of US Application Serial No. 10 / 042,582, filed Jan. 9, 2002, and US Application Serial No. 09 / 899,794, filed Jul. 5, 2001, the contents of both applications. It is incorporated herein by reference in this application.
[2] Throughout this application, various publications are referenced by the author and year in parentheses. Full citations of these references may be found at the end of this specification immediately preceding the Sequence Listing and claims. The disclosures of these publications in their entirety are incorporated herein by reference to more fully describe the technical level to which the present invention pertains. Melanin enrichment hormone (MCH) is a cyclic peptide originally isolated from salmon and fish (tibia fish) (Kawauchi et al., 1983). In fish, 17 amino acid peptides cause agglomeration of melanin in melanocyte vesicles and act as functional antagonists of α-MSH to inhibit the release of ACTH. Mammalian MCH (19 amino acids) is highly conserved among rats, mice and humans, indicating 100% amino acid identity, but its physiological role is not clear. MCH has been reported to participate in a variety of procedures including feeding, water balance, energy metabolism, general arousal / attention status, memory and cognitive function, and mental disorders (Baker, 1991; Baker, 1994; Nahon, 1994; Knigge et al. , 1996). Its role in feeding or weight control is supported by a recent Nature publication (Qu et al., 1996), which overexpresses MCH in the hypothalamus of ob / ob mice compared to ob / + mice, and fasting obesity and Explained that MCH mRNA was further increased during fasting in all normal mice. MCH stimulated feeding even in normal rats when injected into the outer ventricle (Rossi et al., 1997). MCH has also 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 reduce preproMCH (ppMCH) mRNA levels, which are MCH precursors, while increasing POMC mRNA levels (Presse et al., 1992). Thus, MCH will serve as a cumulative neuropeptide involved in the response to stress as well as regulation of feeding and sexual activity (Baker, 1991; Knigge et al., 1996).
[3] Although the biological effects of MCH are thought to be mediated by specific receptors, the binding sites for MCH are not well described. It has been reported that tritium ligands ([ ³ H] -MCH) show specific binding to brain membranes but are not available for saturation analysis, so that neither affinity nor B _max can be determined (Drozdz and Eberle, 1995). . Radioiodination of tyrosine at position 13 results in ligands with dramatically reduced biological activity (see Drozdz and Eberle, 1995). In contrast, radioiodination of the MCH analog [Phe ¹³ , Tyr ¹⁹ ] -MCH was successful (Drozdz et al., 1995); The ligand retained biological activity and showed specific binding to various cell lines, including mouse melanoma (B16-F1, G4F, and G4F-7), PC12, and Cos cells. In G4F-7 cells, K _p = 0.118 nM and B _max was ˜1100 position / cell. Importantly, the binding was not inhibited by α-MSH but weakly inhibited by rat ANF (12 nM for native MCH, for Ki = 116 nM) (Drozdz et al., 1995). More recently, specific MCH binding has been reported in transformed keratinocytes (Burgaud et al., 1997) and melanoma cells (Drozdz et al., 1998), where photocrosslinking studies have shown that receptors have apparent molecular weights of 45-50 k Daltons. It is proposed to have a membrane protein that is compatible with the molecular weight range of the GPCR superfamily of the receptor. No radioautoradiographic studies of MCH receptor localization with this ligand have been reported yet.
[4] Localization and biological activity of MCH peptides suggest that modulation of MCH receptor activity will be available for many therapeutic applications. The role of MCH in feeding is best characterized by its potential clinical use. MCH is expressed in the lateral hypothalamus, a brain region involved in the control of thirst and hunger (Grillon et al., 1997); Recently, orexins A and B, strong orexin generating agents, have been shown to be localized very similarly to MCH in the lateral hypothalamus (Sakurai et al., 1998). MCH mRNA levels in this brain region were increased in rats after 24 hours of fasting (Herve and Fellman, 1997); After insulin injection, a marked increase in MCH immunoreactive perikarya and fiber abundance and staining intensity was observed with a significant increase in MCH mRNA levels (Bahjaoui-Bouhaddi et al., 1994). The ability of MCH to stimulate feeding in rats is that MCH mRNA levels are upregulated in the hypothalamus of obese ob / ob mice (Qu et al., 1996), decreased in the hypothalamus of rats treated with leptin, and leptinized rats. Consistent with the observation that the food intake and weight gain in the diet are also reduced (Sahu, 1998). MCH appears to act as a functional antagonist of the effects of melanocortin-based on food intake and hormone secretion in the HPA (hypothalamic pituitary / adrenal axis) (Ludwig et al., 1998). Together these data suggest the role of endogenous MCH in the regulation of energy balance and response to stress and provide a theoretical basis for the development of specific compounds that act on MCH receptors for use in the treatment of obesity and stress related disorders. to provide.
[5] In all species studied to date, neurons in most MCH cell populations occupy a somewhat constant position in their region of the lateral hypothalamus and hypothalamus, where they are located, and may be part of the so-called "extrapyramidal" motor circuit. have. These substantially include reciprocal connections to the striato and palidofugal pathways, hypothalamus regions, and the hypothalamus nucleus, medulla, and midbrain center associated with the thalamus and cerebral cortex (Bittencourt Et al., 1992). At these sites, the MCH cell population will provide a crosslinking or mechanism for expressing hypothalamic emotional activity with appropriate coordinated motor activity. Clinically, it would be of value to consider the involvement of the MCH system into motor disorders such as Parkinson's disease and Huntington's chorea, which are known to involve extracorporeal circuits.
[6] Human genetic association studies have placed the true hMCH locus on chromosome 12 (12q23-24) and the modified hMCH locus on chromosome 5 (5q12-13) (Pedeutour et al., 1994). The 12q23-24 locus is consistent with the locus mapped with the autosomal dominant cerebellar dyskinesia type II (SCA2) (Auburger et al., 1992; Twells et al., 1992). This disease includes neurodegenerative diseases including olive nucleus- glial- cerebellar atrophy. In addition, the gene for Darier's disease was mapped to the 12q23-24 locus (Craddock et al., 1993). Dariaire's disease is characterized by abnormal I keratinocyte adhesion and in some departments psychosis. In terms of functional and neuroanatomical patterns of the MCH nervous system in rat and human brains, the MCH gene may indicate that it is a good candidate for SCA2 or Dariaire disease. Interestingly, diseases with high social impacts have been mapped at this locus. Indeed, genes that cause chronic or acute spinal muscle atrophy have been assigned to chromosomes 5q12-13 using genetic association analysis (Melki et al., 1990; Westbook et al., 1992). It also supports the assignment of independent lines of evidence for major schizophrenia to chromosomes 5q11.2-13.3 (Sherrington et al., 1988; Bassett et al., 1988; Gilliam et al., 1989). The study suggests that MCH may play a role in neurodegenerative diseases and emotional disorders.
[7] The observed effects of MCH in other biological systems suggest further therapeutic applications for MCH related compounds. As an example, MCH may modulate reproductive function in male and female rats. MCH transcripts and MCH peptides are found in the testicular germ cells of rats that have grown, suggesting that MCH may participate in stem cell regeneration and / or early spermatogenesis (Hervieu et al., 1996). MCH injected directly into the medial visual cross-section (MPOA) or the dorsal nucleus (VMN) stimulated sexual activity in female rats (Gonzalez et al., 1996). In ovarian depleted rats given follicle hormone, MCH stimulated luteinizing hormone (LH) release, while anti-MCH antiserum inhibited LH release (Gonzalez et al., 1997). An indeterminate zone (zona incerta) containing multiple MCH cell bodies has already been identified as a regulatory site for pre-ovulation LH spikes (MacKenzie et al., 1984). MCH has been reported to affect the release of pituitary hormones, including ACTH and oxytocin. MCH analogs may also be useful for the treatment of epilepsy. In the PTZ seizure model, MCH injections prior to seizure induction prevented seizure activity in both rats and guinea pigs, suggesting that MCH-containing neurons may participate in neural circuit potential PTZ-induced seizures (Knigge and Wagner, 1997). MCH has also been observed to affect behavioral correlation of cognitive function. MCH treatment accelerates the loss of passive avoidance in rats (McBride et al., 1994), raising the possibility that MCH receptor antagonists may be beneficial for memory storage and / or retention. The possible role of MCH in the regulation or recognition of pain is supported by dense neurodistribution of periaqueductal grey (PAG) by MCH positive fibers. As a result, MCH may participate in the regulation of liquid intake. ICV infusion of MCH in conscious quantities produced changes in diuretic, sodium excretion and potassium excretion in response to increased plasma volume (Parkes, 1996). Together with anatomical data reporting the presence of MCH in the liquid regulatory region of the brain, the results indicate that MCH may be an important peptide involved in the central control of liquid homeostasis in mammals.
[8] The identification of G-protein coupled receptors for MCH has recently been published (Chambers et al., 1999; Saito et al., 1999). These groups identified MCH as an endogenous ligand for human orphan G-protein coupled receptor SLC-1 (Lakaye et al., 1998). Rat homologues of these receptors (now called MCH-1) have been reported to localize to the sites of the rat brain involved in feeding behavior (eg dorsal medial and dorsal hypothalamus). The association of MCH-1 and its effect on feeding of MCH has been confirmed by recent reports on the phenotype of MCH-1 knockout mice. In both groups independently (Marsh et al., 2002; Chen et al., 2002), the targeted disruption of the MCH-1 receptor gene in mice (MCH-1 knockout) shows anorexia nervosa but is identical to the wild type. It has been shown that this resulted in animals with reduced body mass compared to littermates. The decrease in body mass is due to an increase in metabolism. Each group demonstrated that MCH-1 knockout mice are resistant to diet-induced obesity and generally exhibit similar body weights to litters of the same embryos that maintained a constant diet.
[9] As a result, synthetic antagonist molecules for the MCH-1 receptor are now described in the literature. Bednarek et al. (2002) report on the synthesis of high affinity peptide antagonists of MCH-1. Small molecule antagonists of MCH-1 have also been described by Takekawa et al. (Takekawa et al., 2002). This compound, T-226296, showed high affinity for the MCH-1 receptor (about 5-9 nM for rat and human MCH-1) and inhibited food intake induced by ventricular application of MCH. These data demonstrate the strategy of using MCH-1 receptor antagonists for the treatment of obesity.
[10] In addition, in our own study, we tested MCH1 antagonists in some animal models that are well known for use in predicting compound efficacy in humans (Borowsky et al., Publication; unpublished data). These tests indicate that MCH1 antagonists are useful for treating obesity, depression, anxiety, as well as urinary disorders.
[11] As used herein, the term “antagonist” refers to a compound that binds to a receptor in the presence of an agonist, thereby reducing the activity of the receptor. For G-protein coupled receptors, activation may be measured using any suitable secondary delivery system coupled to the receptor in the cell or tissue in which the receptor is expressed. Some particular examples of well-known secondary delivery systems include adenyl cyclase, intracellular calcium mobilization, ion channel activation, guanyl cyclase, and inositol phospholipid hydrolysis. In contrast, the term "agonist" refers to a compound that binds to a receptor and increases its receptor activity relative to that of the receptor in the absence of any agonist.
[12] In one embodiment of the invention, compared to other cloned G-protein coupled receptors, it selectively binds to cloned human melanin enriched hormone-1 (MCH1) receptors and measures in vitro assays to activate the cloned receptors. The synthesis of novel compounds that inhibits is disclosed. In vitro receptor binding assays described below were performed using a variety of cultured cell lines, each transfected with monoclonal receptors to express only them.
[13] In addition, the compounds of the present invention may also be used to treat abnormalities such as eating disorders (obesity, dysregulation and anorexia nervosa), sexual / reproductive disorders, depression, anxiety, depression and anxiety, cerebral hemorrhage, congestive heart failure, sleep disorders, or MCH1 receptors. It can also be used to treat any condition in which antagonism may be beneficial. In addition, the compounds of the present invention can be used to reduce the body mass of a subject. In addition, the compounds of the present invention can be used to treat urinary disorders.
[14] Summary of the Invention
[15] The present invention provides a compound having the structure:
[16] .
[17] Wherein R ₁ is hydrogen, straight or branched C ₁ -C ₇ alkyl, monofluoroalkyl or polyfluoroalkyl, aryl or heteroaryl, wherein aryl or heteroaryl is one or more -F, -Cl, -Optionally substituted with -Br, -I, -CN, -N0 ₂ , -CH ₃ , -CF ₃ , -COR ₂ , C0 ₂ R ₂ , phenyl, phenoxy or straight or branched C ₁ -C ₇ alkyl;
[18] Wherein R ₂ is straight or branched C ₃ -C ₄ alkyl or cyclopropyl;
[19] Wherein R ₃ is aryl or heteroaryl, wherein aryl or heteroaryl is one or more -F, -Cl, -Br, -I, -CN, -N0 ₂ , straight or branched C ₁ -C ₇ alkyl Optionally substituted with;
[20] Wherein A is -H, -F, -Cl, -Br, -CN, -NO ₂ , -COR ₃ . -C0 ₂ R ₃ , straight or branched C ₁ -C ₇ alkyl, monofluoroalkyl or polyfluoroalkyl;
[21] Wherein x is 0 or NH; And
[22] In formula, n is an integer of 0-5 (including 0 and 5).
[23] In one embodiment, R ₁ is one or more —F, —Cl, —Br, —I, —CN, —NO ₂ , —COR ₂ , —C0 ₂ R ₂ , straight or branched C ₁ -C ₇ alkyl Optionally substituted aryl;
[24] Wherein R ₃ is phenyl;
[25] Wherein A is H; And
[26] In the formula, × is 0.
[27] In one embodiment, R ₂ is isopropyl.
[28] In one embodiment, the compound has the structure
[29] .
[30] In one embodiment, the compound has the structure
[31] .
[32] In one embodiment, R ₁ is hydrogen, straight or branched C ₁ -C ₇ alkyl; And
[33] In the formula, R ₃ is aryl.
[34] In one embodiment, R ₂ is isopropyl; And A is hydrogen.
[35] In one embodiment, the compound has the structure
[36] .
[37] In one embodiment, the compound has the structure
[38] .
[39] The present invention also provides a compound having the structure:
[40] ,
[41] Wherein R ₁ is at least one —F, —Cl, —Br, —I, —CN, —NO ₂ , —OCH ₃ , phenoxy, fused cyclopentanyl, straight or branched C ₁ -C ₇ alkyl, mono Aryl or heteroaryl optionally substituted with fluoroalkyl or polyfluoroalkyl;
[42] Wherein R ₂ is straight or branched C ₁ -C ₄ alkyl or cyclopropyl;
[43] Wherein A is —H, —F, —Cl, —Br, —CN, —NO ₂ , straight or branched C ₁ -C ₇ alkyl, monofluoroalkyl or polyfluoroalkyl; And
[44] In formula, n is an integer of 1-5 (including 1 and 5).
[45] In one embodiment, R ₁ is aryl optionally substituted with one or more —F, —Cl, —Br, —I, or straight or branched C ₁ -C ₄ alkyl; And
[46] In the formula, A is H.
[47] In one embodiment, R ₂ is isopropyl; And
[48] n is 2.
[49] In one embodiment, the compound has the structure
[50] .
[51] In one embodiment, the compound has the structure
[52] .
[53] In one embodiment, the compound has the structure
[54] .
[55] In one embodiment, R ₁ is thienyl; And wherein A is H.
[56] In one embodiment, R ₂ is isopropyl.
[57] In one embodiment, the compound has the structure
[58] .
[59] The present invention provides a compound having the structure:
[60] .
[61] Where W is
[62] or ego;
[63] Wherein, R ₁ are each independently, hydrogen, methyl or ethyl;
[64] Wherein R ₂ is straight or branched C ₃ -C ₄ alkyl or cyclopropyl;
[65] Wherein R ₃ is hydrogen, aryl or heteroaryl, wherein aryl or heteroaryl is one or more -H, -F, -C 1, -Br, -I, -CN, -NO ₂ , straight or branched C Optionally substituted with _1- C ₇ alkyl.
[66] Wherein A is each independently —H, —F, —Cl, —Br, —CN, —NO ₂ , —COR ₃ , —CO ₂ R ₃ , straight or branched C ₁ -C ₇ alkyl, monofluor Roalkyl or polyfluoroalkyl;
[67] Wherein x may be 0, NR ₃ , CO or absent; And
[68] Wherein Y is hydrogen, aryl or heteroaryl, where aryl or heteroaryl is one or more -F, -Cl, -Br, -I, -CN, -NO ₂ , straight or branched C ₁ -C ₇ alkyl Is optionally substituted.
[69] In one embodiment, W is
[70] ego,
[71] Wherein x may be 0 or absent.
[72] In one embodiment, R ₂ is isopropyl.
[73] In one embodiment, the compound has the structure
[74] .
[75] In one embodiment, the compound has the structure
[76] .
[77] In one embodiment, W is
[78]
[79] In one embodiment, A is —H, —F, —Cl, —Br.
[80] In one embodiment, R ₂ is isopropyl; And A is hydrogen.
[81] In one embodiment, the compound has the structure
[82] .
[83] The present invention provides compounds of the structure:
[84] ;
[85] Where W is
[86] or ego,
[87] Wherein R ₁ is hydrogen, straight or branched C ₁ -C ₇ alkyl, aryl or heteroaryl, wherein aryl or heteroaryl is one or more —F, —Cl, —Br, —CN, —NO ₂ , Optionally substituted with -OCH ₃ , -CO ₂ CH ₃ , -CF ₃ , phenyl, straight or branched C ₁ -C ₇ alkyl;
[88] Wherein R ₂ is straight or branched C ₃ -C ₄ alkyl or cyclopropyl;
[89] Wherein A is —H, —F, —Cl, —Br, —CN, —NO ₂ , —COR ₁ , —CO ₂ R ₁ , straight or branched C ₁ -C ₇ alkyl, monofluoroalkyl or Polyfluoroalkyl or phenyl,
[90] Wherein, B are each independently -H, -F, -Cl, -Br, -I, -CN, -N0 2, -COR 1, -CO 2 R 1, -OCH 3, -OCF 3, -CF ₃ , straight or branched C ₁ -C ₇ alkyl, monofluoroalkyl or polyfluoroalkyl or aryl, phenoxy or benzyloxy, wherein aryl, phenoxy or benzyloxy is one or more -F, -Cl, _{-Br, -CN, -NO 2, -COR} 1, -CO 2 R 1, -OCH 3, -OCF 3, -CF 3 or is optionally substituted by straight-chain or branched C ₁ -C ₃ alkyl.
[91] In one embodiment, W is
[92]
[93] In one embodiment, R ₁ is hydrogen or phenyl optionally substituted with one or more —F, —Cl, —Br, —CN, —NO ₂ , straight or branched C ₁ -C ₇ alkyl.
[94] In one embodiment, R ₂ is isopropyl.
[95] In one embodiment, the compound has the structure
[96] .
[97] In one embodiment, the compound has the structure
[98] .
[99] The present invention provides a compound having the structure:
[100] .
[101] Wherein R ₁ is hydrogen, straight or branched C ₁ -C ₇ alkyl, aryl or heteroaryl, wherein aryl or heteroaryl is one or more —F, —Cl, —Br, —CN, —NO ₂ , Optionally substituted with -CF ₃ , -OCH ₃ , straight or branched C ₁ -C ₃ alkyl;
[102] Wherein R ₂ is straight or branched C ₃ -C ₄ alkyl or cyclopropyl;
[103] Wherein R ₃ is —H, —F, —Cl, —Br, —I, —CN, —NO ₂ , —CF ₃ , —OCH ₃ or straight or branched C ₁ -C ₃ alkyl, monofluoro Alkyl or polyfluoroalkyl, or a phenyl ring fused to C ₆ and C ₇ of the indole moiety;
[104] Wherein R ₄ is hydrogen or aryl optionally substituted with one or more —F, —Cl, —Br, —I, —CN, —NO ₂ , —CF ₃ , straight or branched C ₁ -C ₃ alkyl;
[105] Wherein A is -H, -F, -Cl, -Br, -CN, -NO ₂ , straight or branched C ₁ -C ₇ alkyl, monofluoroalkyl or polyfluoroalkyl; And
[106] In formula, n is an integer of 2-4 (including 2 and 4).
[107] In one embodiment, R ₃ is -H, -F, -Cl, -Br, -I, -CN, -NO 2, -OCF 3 or -OCH _3, and; And
[108] Wherein R ₄ is hydrogen or phenyl optionally substituted with one or more -F, -Cl or -CF ₃ .
[109] In one embodiment, R ₁ is optionally substituted with hydrogen or one or more —F, —Cl, —Br, —CN, —NO ₂ , —CF ₃ , —OCH ₃ or straight or branched C ₁ -C ₃ alkyl Phenyl;
[110] In one embodiment, R ₂ is isopropyl.
[111] In one embodiment, the compound has the structure
[112] .
[113] In one embodiment, the compound has the structure
[114] .
[115] In one embodiment, the compound has the structure
[116] .
[117] The present invention provides a compound having the structure:
[118] .
[119] In which R ₁ is independently hydrogen or CH ₃ ;
[120] Wherein R ₂ is straight or branched C ₁ -C ₄ alkyl or cyclopropyl;
[121] Wherein R ₃ is benzyl or phenyl, wherein benzyl or phenyl is optionally substituted with one or more -F or -Cl or methylenedioxy groups;
[122] A is —H, —F, —Cl, —Br, —CN, —NO ₂ , straight or branched C ₁ -C ₇ alkyl, monofluoroalkyl or polyfluoroalkyl;
[123] Wherein X is (CH ₂ ) ₂ , COCH ₂ or CONH;
[124] In one embodiment, R ₃ is phenyl optionally substituted with one or more -F; And
[125] In the formula, A is hydrogen.
[126] In one embodiment, x is CONH.
[127] In one embodiment, R ₂ is methyl.
[128] In one embodiment, the compound has the structure
[129] .
[130] In one embodiment, the compound has the structure
[131] .
[132] In the formula, each Y is independently hydrogen or -F.
[133] In one embodiment, the compound has the structure
[134] .
[135] In one embodiment, the compound has the structure
[136] .
[137] In one embodiment, R ₃ is optionally substituted with one or more -F or -Cl or methylenedioxy groups.
[138] In one embodiment, the compound has the structure
[139]
[140] In the formula, each Y is independently hydrogen or -F.
[141] In one embodiment, the compound has the structure
[142] .
[143] In one embodiment, the compounds are enantiomerically pure.
[144] In one embodiment, the compounds are diastereomerically pure.
[145] In one embodiment, the compounds are enantiomerically and diastereoisomerically pure.
[146] The present invention also provides a pharmaceutical composition containing a therapeutically effective amount of a compound of the present invention and a pharmaceutically acceptable carrier.
[147] In one embodiment, the amount of the compound is about 0.01 mg to about 500 mg.
[148] In one embodiment, the amount of the compound is about 0.1 mg to about 60 mg.
[149] In one embodiment, the amount of the compound is about 1 mg to about 20 mg.
[150] In one embodiment, the pharmaceutical composition consists of a carrier that is a liquid and the composition is a solution.
[151] In one embodiment, the pharmaceutical composition consists of a carrier that is a solid and the composition is a tablet.
[152] In one embodiment, the pharmaceutical composition consists of a carrier which is a gel and the composition is a suppository.
[153] The invention also provides a process for the preparation of a pharmaceutical composition comprising mixing a therapeutically effective amount of any compound of the invention with a pharmaceutically acceptable carrier.
[154] The present invention also provides a method of treating a disorder comprising administering a therapeutically effective amount of a compound of the invention to a subject suffering from a disorder selected from the group consisting of depression, anxiety, urge incontinence, or obesity.
[155] In one embodiment, the therapeutically effective amount is about 0.03 to about 1000 mg per day.
[156] In one embodiment, the therapeutically effective amount is about 0.30 to 300 mg per day.
[157] In one embodiment, the therapeutically effective amount is about 1.0 to 100 mg per day.
[158] In one embodiment, the disorder is depression.
[159] In one embodiment, the disorder is anxiety.
[160] In one embodiment, the disorder is obesity.
[161] In one embodiment, the disorder is urge incontinence.
[162] The present invention provides a method for reducing body mass of a subject, comprising administering to the subject an effective amount of a compound of the present invention that reduces the body mass of the subject.
[163] The present invention provides a method of treating a subject suffering from depression comprising administering to the subject an amount of any compound of the claims of the invention effective to treat the subject's depression.
[164] The present invention provides a method for treating a subject suffering from anxiety, comprising administering to the subject an effective amount of a compound of the invention to treat the subject's anxiety.
[165] The present invention provides a method for alleviating urge incontinence in a subject suffering from overactive bladder, comprising administering to the subject an amount of a compound of the present invention effective to alleviate the subject's urge incontinence.
[166] The present invention provides a method for managing obesity in a subject in need of weight loss, comprising administering to the subject an effective amount of a compound of the invention to induce weight loss in the subject.
[167] The present invention provides a method of managing obesity in a subject who has experienced weight loss, comprising administering to the subject an amount of a compound of the invention effective to maintain such weight loss in the subject who has experienced weight loss.
[168] The present invention provides a method of treating overactive bladder in a subject comprising administering to the subject an amount of any compound of the invention effective to treat the overactive bladder in the subject.
[169] The present invention provides a method for treating a disorder in a subject, wherein the subject's symptoms can be alleviated by MCH1 antagonist treatment and the MCH1 antagonist is a compound of the invention.
[170] The present invention includes administering to a subject an amount of MCH1 antagonist effective to alleviate the condition, wherein MCH1 is a compound of the present invention, and provides a method for alleviating the symptoms of a disorder in a subject.
[171] The present invention provides a compound having the following structure or a pharmaceutically acceptable salt thereof:
[172]
[173] or
[174]
[175] Wherein each V is independently phthalimide, aryl, phenoxy or heteroaryl, where aryl, phenoxy or heteroaryl is one or more F; Cl; Br; I; COR ₅ ; C0 ₂ R ₅ ; -OCOR ₅ ; -CON (R ₅ ) ₂ ; -N (R ₅ ) COR ₅ ; CN; -NO ₂ ; -N (R ₅ ) ₂ ; -OR ₅ ; -SR ₅ ; (CH ₂ ) _q OR ₅ ; (CH ₂ ) _q R ₅ ; (CH ₂ ) _q SR ₅ ; Straight or branched C ₁ -C ₇ alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; Straight or branched C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl; Aryl; Phenoxy; Optionally substituted with C ₃ -C ₇ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
[176] Wherein each W is independently aryl or heteroaryl, wherein aryl or heteroaryl is one or more F; Cl; Br; I; COR ₃ ; -OCOR ₃ ; C0 ₂ R ₃ ; -CON (R ₃ ) ₂ ; -N (R) COR ₃ ; CN; -NO ₂ ; -N (R ₃ ) ₂ ; -OR ₃ ; -SR ₃ ; (CH ₂ ) _q OR ₃ ; (CH ₂ ) _q SR ₃ ; Straight or branched C ₁ -C ₇ alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; Straight or branched C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl; Aryl; Phenoxy; Optionally substituted with C ₃ -C ₇ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
[177] Wherein x is hydrogen or -OR ₃ , provided that when x is -OR ₃ , the V geminal to x cannot be phthalimide;
[178] Wherein Y is hydrogen, = 0 (carbonyl oxygen), OR ₃ , OV, COV, = NNHV, = NNR ₅ , NZR ₅ , NZV, NCONV (urea), NCONR ₅ , NR ₃ , carbazole, indole or Phthalimide; Wherein each R is independently -H; -F; Straight or branched C ₁ -C ₇ alkyl, monofluoroalkyl or polyfluoroalkyl; Straight or branched C ₂ -C ₇ alkenyl or alkynyl; -N (R ₃ ) ₂ ; -NO ₂ ; -CN; -CO ₂ R ₃ ; -OCOR ₃ ; -OR ₃ ; Or -N (R ₃ ) COR ₃ ; -CON (R ₃ ) ₂ ;
[179] In the formula, each R ₃ is independently -H; Straight or branched C ₁ -C ₇ alkyl, monofluoroalkyl or polyfluoroalkyl; Straight or branched C ₂ -C ₇ alkenyl or alkynyl; C ₃ -C ₇ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
[180] Wherein R ₅ is -H; -NO ₂ ; -N ₃ ; -CN; Straight or branched C ₁ -C ₇ alkyl, monofluoroalkyl or polyfluoroalkyl; Straight or branched C ₂ -C ₇ alkenyl or alkynyl; C ₃ -C ₇ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N (R ₃ ) ₂ ; -OR ₃ ; -(CH ₂ ) _p OR ₃ ; -COR ₃ ; -CO ₂ R ₃ ; -OCOR ₃ ; -CON (R ₃ ) ₂ ; -N (R ₃ ) COR ₃ ; Aryl or heteroaryl, wherein aryl or heteroaryl is one or more F; Cl; Br; I; COR ₆ ; C0 ₂ R ₃ ; -OCOR ₃ ; -CON (R ₃ ) ₂ ; -N (R ₃ ) COR ₃ ; CN; -NO ₂ ; -N (R ₃ ) ₂ ; -OR ₆ ; -SR ₆ ; (CH ₂ ) _q OR ₆ ; (CH ₂ ) _q SR ₆ ; Straight or branched C ₁ -C ₇ alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; Straight or branched C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl; Optionally substituted with C ₃ -C ₇ cycloalkyl, monofluoroalkyl, polyfluoroalkyl or cycloalkenyl;
[181] Wherein R ₆ is -H; Straight or branched C ₁ -C ₇ alkyl, monofluoroalkyl or polyfluoroalkyl; Straight or branched C ₂ -C ₇ alkenyl or alkynyl; C ₃ -C ₇ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N (R ₃ ) ₂ ; -OR ₃ ; -(CH ₂ ) _p OR ₃ ; -COR ₃ ; -CO ₂ R ₃ ; -OCOR ₃ ; -CON (R ₃ ) ₂ ; -N (R ₃ ) COR ₃ ; One or more F; Cl; Br; I; COR ₃ ; C0 ₂ R ₃ ; -OCOR ₃ ; -CON (R ₃ ) ₂ ; -N (R ₃ ) COR ₃ , CN; -NO ₂ ; -N (R ₃ ) ₂ ; -OR ₃ ; -SR ₃ ; (CH ₂ ) _q OR ₃ ; (CH ₂ ) _q SR ₃ ; Straight or branched C ₁ -C ₇ alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; Aryl; benzyl; Straight or branched C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl; Aryl, benzyl or heteroaryl optionally substituted with C ₃ -C ₇ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
[182] In which Z is CO, SO ₂ or SO ₂ NR ₆ ;
[183] Wherein m is each independently an integer from 0 to 3 (including 0 and 3);
[184] Wherein n is each independently an integer from 0 to 5 (including 0 and 5);
[185] Wherein p is each independently an integer from 1 to 7 (including 1 and 7); And
[186] In the formula, q is an integer of 1 to 3 (including 1 and 3).
[187] As used herein, the term "cycloalkyl" includes a C ₃ -C ₇ cycloalkyl moiety which may be substituted with one or more of the following: F; CN; -NO ₂ ; Straight or branched C ₁ -C ₇ alkyl, straight or branched C ₁ -C ₇ monofluoroalkyl, straight or branched C ₁ -C ₇ polyfluoroalkyl, straight or branched C ₂ -C ₇ alkenyl , Straight 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, -N (R ₃ ) ₂ ; -OR ₃ ; -NCOR ₃ ; -COR ₃ ; -CO ₂ R ₃ ; -CON (R ₃ ) ₂ or (CH ₂ ) _p -O- (CH ₃ ) _m -CH ₃ .
[188] In the present invention, the term "cycloalkenyl" includes a C ₅ -C ₇ cycloalkenyl moiety which may be substituted with one or more of the following: -F; -Cl; -Br, -I; CN; -NO ₂ ; Straight or branched C ₁ -C ₇ alkyl, straight or branched C ₃ -C ₇ monofluoroalkyl, straight or branched C ₁ -C ₇ polyfluoroalkyl, straight or branched C ₂ -C ₇ alkenyl , Straight 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, -N (R ₃ ) ₂ ; -OR ₃ ; -NCOR ₃ ; -COR ₃ ; -CO ₂ R ₃ ; -CON (R ₃ ) ₂ or (CH ₂ ) _P -O- (CH ₃ ) _m -CH ₃ .
[189] The term "heteroaryl" as used in the present invention is used to include 5 and 6 membered unsaturated rings which may contain one or more oxygen, sulfur or nitrogen atoms. Examples of heteroaryl groups include, but are not limited to, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, Thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.
[190] The term "heteroaryl" is also used to include fused bicyclic ring systems which may contain one or more heteroatoms such as oxygen, sulfur and nitrogen. Examples of such heteroaryl groups include, but are not limited to, indolinyl, indolyl, isoindoleyl, benzo [b] furanyl, benzo [b] thiophenyl, indazolyl, benzimidazolyl, furinyl, Benzoxazolyl, benzisoxazolyl, benzo [b] thiazolyl, imidazo [2,1-b] thiazolyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, putridinyl , Quinolinyl, isoquinolinyl, phthalimidyl and 2,1,3-benzothiazolyl.
[191] The term "heteroaryl" also includes the aforementioned chemical moieties which may be substituted with one or more of the following: -F; -Cl; -Br, -I; CN; -NO ₂ ; Straight or branched C ₁ -C ₇ alkyl, straight or branched C ₁ -C ₇ monofluoroalkyl, straight or branched C ₁ -C ₇ polyfluoroalkyl, straight or branched C ₂ -C ₇ alkenyl , Straight 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, -N (R ₃ ) ₂ ; -OR ₃ ; -NCOR ₃ ; -COR ₃ ; -CO ₂ R ₃ ; -CON (R ₃ ) ₂ or (CH ₂ ) _P- (CH ₃ ) _m -CH ₃ .
[192] In another embodiment of the invention described above, the compound has the structure:
[193]
[194] In a further embodiment of the invention, R ₆ is straight or branched C ₁ -C ₇ alkyl; C ₃ -C ₇ cycloalkyl; -N (R ₃ ) ₂ ; -OR ₃ ; -(CH ₂ ) _p OR ₃ ; One or more F; Cl; Br; I; -OR ₃ ; -(CH ₂ ) _q OR ₃ ; Or aryl, benzyl or heteroaryl optionally substituted with straight or branched C ₁ -C ₇ alkyl.
[195] In one embodiment of the invention, the compound has the structure
[196] or
[197] .
[198] In a further embodiment of the invention, at least one V is at least one F; Cl; Br; -OR ₃ ; -COR ₃ ; (CH ₂ ) _q OR ₃ ; Straight or branched C ₁ -C ₇ alkyl; C ₁ -C ₇ polyfluoroalkyl; Or phenyl optionally substituted with phenoxy.
[199] In one embodiment of the invention, the compound is the following compound:
[200] .
[201] In one embodiment, the compound is the following compound:
[202] .
[203] In one embodiment, the compound is the following compound:
[204] .
[205] In another embodiment of the invention, the compound has the structure
[206] or
[207] .
[208] In a further embodiment of the invention, at least one V is at least one F; Cl; Br; -OR ₃ ; (CH ₂ ) _q OR ₃ ; Straight or branched C ₁ -C ₇ alkyl; C ₁ -C ₇ polyfluoroalkyl; Or phenyl optionally substituted with phenoxy.
[209] In another embodiment of the invention, the compound is:
[210] .
[211] In one embodiment, the compound is:
[212] .
[213] In a further embodiment of the invention, the compound has the structure
[214] or
[215] .
[216] In another embodiment of the invention, at least one V is at least one F; Cl; Br; -OR ₃ ; (CH ₂ ) _q OR ₃ ; Straight or branched C ₁ -C ₇ alkyl; C ₁ -C ₇ polyfluoroalkyl; Phenyl optionally substituted with aryl or phenoxy.
[217] In another embodiment of the invention, the compound is:
[218] .
[219] In one embodiment, the compound is:
[220] .
[221] In one embodiment, the compound is:
[222] .
[223] In one embodiment, the compound is:
[224]
[225] In one embodiment the compound is:
[226]
[227] In one embodiment the compound is:
[228]
[229] In an embodiment of the invention the compound has the structure
[230]
[231] In a further embodiment of the invention, at least one V is at least one F; Cl; Br; -OR ₃ ; (CH ₂ ) _q OR ₃ ; Straight or branched C ₁ -C ₇ alkyl; C ₁ -C ₇ polyfluoroalkyl; Or phenyl optionally substituted with phenoxy.
[232] In a further embodiment of the invention the compounds are as follows:
[233]
[234] In one embodiment the compound has the structure
[235]
[236] In one embodiment the compound has the structure:
[237]
[238] In one embodiment the compound has the structure:
[239]
[240] In one embodiment the compound has the structure:
[241]
[242] In one embodiment the compound has the structure:
[243]
[244] In one embodiment the compound has the structure:
[245]
[246] In one embodiment the compound has the structure:
[247]
[248] In one embodiment the compound has the structure:
[249]
[250] In a further embodiment of the invention, Y is hydrogen and V is phthalimide.
[251] In a further embodiment of the invention, R ₆ is straight or branched C ₁ -C ₇ alkyl; C ₃ -C ₇ cycloalkyl; -N (R ₃ ) ₂ ; -OR ₃ ; -(CH ₂ ) _p OR ₃ ; One or more F; Cl; Br; I; -OR ₃ ; (CH ₂ ) _q OR ₃ ; Aryl, benzyl or heteroaryl optionally substituted with straight or branched C ₁ -C ₇ alkyl.
[252] In a further embodiment of the invention the compounds are as follows:
[253]
[254] In one embodiment, the compound has the structure:
[255]
[256] In one embodiment of the compound, at least one V is at least one F; Cl; Br; I; R ₅ ; -OR ₅ ; -(CH ₂ ) _q OR ₅ ; Straight or branched C ₁ -C ₇ alkyl; C ₁ -C ₇ monofluoroalkyl or polyfluoroalkyl; Or phenyl or heteroaryl optionally substituted with phenoxy.
[257] In one embodiment, the compound has the structure:
[258]
[259] In one embodiment, the compound has the structure:
[260]
[261] In one embodiment of the compound, V is one or more F; Cl; Br; -OR ₅ ; -(CH ₂ ) _q OR ₅ ; -(CH ₂ ) _q R ₅ ; Straight or branched C ₁ -C ₇ alkyl; C ₁ -C ₇ monofluoroalkyl or polyfluoroalkyl; Or phenyl optionally substituted with phenoxy.
[262] In one embodiment, the compound has the structure:
[263]
[264] In one embodiment, the compound has the structure:
[265]
[266] In one embodiment, the compound has the structure:
[267]
[268] In one embodiment, the compound has the structure:
[269]
[270] In one embodiment, the compound has the structure:
[271]
[272] In one embodiment of the compound, R ₅ is straight or branched C ₁ -C ₇ alkyl; C ₃ -C ₇ cycloalkyl; -N (R ₆ ) ₂ ; -OR ₆ ; -(CH ₂ ) _p OR ₆ ; -CH (R ₆ ) ₂ ; -(CH ₂ ) _q R ₆ ; Or aryl, benzyl or heteroaryl, wherein aryl, benzyl or heteroaryl is one or more F; Cl; I; R ₆ ; -N (R ₆ ) ₂ ; -OR ₆ ; -(CH ₂ ) _q OR ₆ ; -(CH ₂ ) _q R ₆ ; Or optionally substituted with straight or branched C ₁ -C ₇ alkyl.
[273] In one embodiment the compound has the structure:
[274]
[275] In one embodiment the compound has the structure:
[276]
[277] In one embodiment of the compound, X is hydrogen and Y is one or more F; Cl; Br; -OR ₅ ; -(CH ₂ ) _q OR ₅ ; -(CH ₂ ) _q R ₅ ; Straight or branched C ₁ -C ₇ alkyl; Or C ₁ -C ₇ monofluoroalkyl or polyfluoroalkyl; Or carbazole optionally substituted with phenoxy.
[278] In one embodiment the compound has the structure:
[279]
[280] In one embodiment the compound has the structure:
[281]
[282] In one embodiment of the compound, Y is hydrogen and V is at least one F; Cl; Br; R ₅ ; -CO ₂ R ₅ ; -OR ₅ ; -(CH ₂ ) _q OR ₅ ; -(CH ₂ ) _q R ₅ ; Straight or branched C ₁ -C ₇ alkyl; Or C ₁ -C ₇ monofluoroalkyl or polyfluoroalkyl; Or indole optionally substituted with phenoxy at the 1, 2, 3, 4, 5, 6, or 7 position.
[283] In one embodiment the compound has the structure:
[284]
[285] In one embodiment the compound has the structure:
[286]
[287] In one embodiment the compound has the structure:
[288]
[289] In one embodiment the compound has the structure:
[290]
[291] In one embodiment the compound has the structure:
[292]
[293] In one embodiment the compound has the structure:
[294]
[295] In one embodiment the compound has the structure:
[296]
[297] In one embodiment the compound has the structure:
[298]
[299] In one embodiment the compound has the structure:
[300]
[301] In one embodiment the compound has the structure:
[302]
[303] In one embodiment the compound has the structure:
[304]
[305] In one embodiment the compound has the structure:
[306]
[307] In one embodiment the compound has the structure:
[308]
[309] In one embodiment the compound has the structure:
[310]
[311] In one embodiment the compound has the structure:
[312]
[313] The present invention provides a compound having the following structure or a pharmaceutically acceptable salt thereof:
[314]
[315] Wherein each X is independently O or S;
[316] q is 1 or 2;
[317] Each R ₂ is independently H; — (CH ₂ ) _t C (X) N (R ₃ ) ₂ ; -(CH ₂ ) _t XR ₃ ; — (CH ₂ ) _t CO ₂ R ₃ ; -CO ₂ R ₃ ; Straight or branched C ₁ -C ₇ alkyl optionally substituted with —N (R ₃ ) ₂ ; -CON (R ₃ ) ₂ , or -N (R ₃ ) C (O) R ₃ ; Straight or branched C ₂ -C ₇ alkenyl or alkynyl; Or C ₃ -C ₇ cycloalkyl or C ₅ -C ₇ cycloalkenyl;
[318] Each t is an integer from 1-4 each;
[319] Each R ₃ is independently H; Straight or branched C ₁ -C ₇ alkyl; Straight or branched C ₂ -C ₇ alkenyl or alkynyl; Or C ₃ -C ₇ cycloalkyl or C ₅ -C ₇ cycloalkenyl;
[320] R ₄ is aryl, heteroaryl, and one or both of the aryl C ₁ -C ₇ alkyl or one or two of C ₁ -C ₇ alkyl substituted by a heteroaryl group substituted with, where the aryl and heteroaryl radicals, one or more F, Cl, Br, I, -CN, -NO ₂ , -N (R ₃ ) ₂ , -COR ₃ ,-(CH ₂ ) _n XR ₃ ,-(CH ₂ ) _n C (X) NR ₃ ,- (CH ₂ ) _n N (R ₃ ) C (X) R ₃ ,-(CH ₂ ) _n CO ₂ R _3, -(CH ₂ ) _n OCOR _3, straight or branched C ₁ -C ₇ alkyl, monofluor Roalkyl or polyfluoroalkyl, straight or branched C ₂ -C ₇ aminoalkyl, alkenyl or alkynyl; Or substituted with C ₃ -C ₇ cycloalkyl or C ₅ -C ₇ cycloalkenyl;
[321] Each n is independently an integer of 0-7;
[322] Each R ₅ is H; Aryl; Aryl, C ₁ -C ₇ alkyl substituted with heteroaryl, or C ₁ -C ₇ alkyl substituted with heteroaryl; Wherein aryl or heteroaryl is one or more of F, Cl, Br, I, -CN, -NO ₂ , -N (R ₃ ) ₂ , -COR ₃ ,-(CH ₂ ) _n XR ₃ ,-(CH ₂ ) _n C (X) NR ₃ ,-(CH ₂ ) _n CO ₂ R _3, straight or branched C ₁ -C ₇ alkyl, monofluoroalkyl or polyfluoroalkyl, or carboxamidoalkyl or straight chain or Branched C ₂ -C ₇ aminoalkyl, alkenyl or alkynyl; Or substituted with C ₃ -C ₇ cycloalkyl or C ₅ -C ₇ cycloalkenyl;
[323] R ₅ and one R ₂ on adjacent carbons may together form aryl, heteroaryl, indan or tetrahydronaphthyl, C ₃ -C ₇ cycloalkyl or heterocycloalkyl, wherein one or more hetero atoms is O , N, or S;
[324] R ₁ is as follows;
[325]
[326] Each V is independently aryl, phenoxy or heteroaryl, where aryl, phenoxy or heteroaryl is one or more of F, Cl, Br, I, -CN, -NO ₂ , -COR ₅ , -CO ₂ R ₅ , -OCOR ₅ , -CON (R ₅ ) _2, -N (R ₅ ) COR ₅ , -N (R ₅ ) _2, -OR ₅ , -SR ₅ ,-(CH ₂ ) _q -OR ₅ ,- (CH ₂ ) _q -SR ₅ ; Straight or branched C ₁ -C ₇ alkyl, monofluoroalkyl or polyfluoroalkyl, optionally substituted with -CON (R ₅ ) _2, -N (R ₅ ) COR ₃ , or -N (R ₃ ) ₂ , Straight or branched C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl; Phenoxy or optionally substituted with C ₃ -C ₇ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl,
[327] Each R ₆ is independently H; -(CH ₂ ) _t XR ₃ ; — (CH ₂ ) _t C (X) NR ₃ ; — (CH ₂ ) _t N (R ₃ ) C (X) R ₃ ;-( CH ₂ ) _t CO ₂ R ₃ ; -(CH ₂ ) _t OCOR ₃ ; Straight or branched C ₁ -C ₇ alkyl optionally substituted with —CON (R ₃ ) _2, or —NCOR ₃ , or straight or branched C ₂ -C ₇ alkyl substituted with —N (R ₃ ) ₂ ; Straight or branched C ₂ -C ₇ alkenyl or alkynyl; Or C ₃ -C ₇ cycloalkyl or C ₅ -C ₇ cycloalkenyl;
[328] Each R ₇ is independently H; F; Cl; Br; I; -CN; -NO ₂ ; -N (R ₃ ) ₂ ; -COR ₃ ; -CO ₂ R ₃ ; -(CH ₂ ) _n XR ₃ ; -(CH ₂ ) _n C (X) N (R ₃ ) ₂ ; — (CH ₂ ) _n N (R ₃ ) C (O) R ₃ ; — (CH ₂ ) _n CO ₂ R ₃ ; straight or branched C ₁ -C ₇ alkyl; Hydroxyalkyl, aminoalkyl, carboxamidoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; Straight or branched C ₂ -C ₇ alkenyl or alkynyl; C ₃ -C ₇ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl; Or C ₅ -C ₇ cycloalkenyl, wherein alkyl, aminoalkyl, carboxamidoalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl is one or more aryl or hetero Aryl or heteroaryl may be substituted with aryl, F, Cl, Br, I, -CN, -NO _2, -N (R ₃ ) _2, -SO ₂ R _3, -COR _3, -(CH ₂ ) _n XR _3, -(CH ₂ ) _n C (X) N (R ₃ ) _2, -(CH ₂ ) _n N (R ₃ ) C (O) R _3, -(CH ₂ ) _n CO ₂ R _3, Straight or branched C ₁ -C ₇ alkyl, monofluoroalkyl or polyfluoroalkyl, straight or branched C ₂ -C ₇ alkenyl or alkynyl or C ₃ -C ₇ cycloalkyl, monofluorocycloalkyl, Cycloaryl or heteroaryl substituted with polyfluorocycloalkyl or C ₅ -C ₇ cycloalkenyl, wherein the aryl or heteroaryl is one or more F, Cl, Br, I, -CN, -NO ₂ , -N ( R ₃ ) ₂ , -COR ₃ , -SO ₂ R _3, -(CH ₂ ) _n XR _3, -(CH ₂ ) _n C (X) N (R ₃ ) _2, -(CH ₂ ) _n N (R ₃ ) C (O) R _3, -(CH ₂ ) _n CO ₂ R _3, straight or branched C ₁ -C ₇ alkyl, straight or branched C ₁ -C ₇ monofluoroalkyl or polyfluoroalkyl, straight or Branched C ₂ -C ₇ alkenyl or alkynyl; Or substituted with C ₃ -C ₇ cycloalkyl or C ₅ -C ₇ cycloalkenyl;
[329] B is CO, SO ₂ , or SO ₂ NR ₆ ;
[330] Each R ₈ is -H; Straight or branched C ₁ -C ₇ alkyl, monofluoroalkyl or polyfluoroalkyl; Straight or branched C ₂ -C ₇ alkenyl or alkynyl; C ₃ -C ₇ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N (R ₃ ) ₂ ; -NR ₃ C (O) R ₃ ; -OR ₃ ; -(CH ₂ ) _p OR ₃ ; -COR ₃ ; -CO ₂ R ₃ ; -OCOR ₃ ; -CON (R ₃ ) ₂ ; Optionally F, Cl, Br, I, COR ₃ , CO ₂ R ₃ , -OCOR ₃ , OR ₃ , -SR ₃ , (CH ₂ ) _q OR ₃ , (CH ₂ ) _q SR _3, -CN, -NO ₂ , -N (R ₃ ) ₂ ; aryl or heteroaryl substituted with -NR ₃ C (O) R ₃ ; Straight or branched C ₁ -C ₇ alkyl optionally substituted with —CON (R ₃ ) _2, —NR ₃ C (O) R _3, or —N (R ₃ ) ₂ ; Straight or branched monofluoroalkyl or polyfluoroalkyl; Straight or branched C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl; C ₃ -C ₇ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl,
[331] m is independently an integer of 0 to 3,
[332] Z is as follows,
[333]
[334]
[335] Or C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkenyl is unsubstituted or substituted with one or more R ₉ groups;
[336] Each R ₉ is independently H; F; Cl; Br; I; -(CH ₂ ) _m XR ₃ ; -(CH ₂ ) _m C (X) NR ₃ ; — (CH ₂ ) _m CO ₂ R ₃ ; Straight or branched C ₁ -C ₇ alkyl, monofluoroalkyl or polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; Straight or branched C ₂ -C ₇ alkenyl or alkynyl; Or C ₃ -C ₇ cycloalkyl or C ₅ -C ₇ cycloalkenyl;
[337] R ₁₀ is H; -(CH ₂ ) _t XR ₃ ; — (CH ₂ ) _t C (X) NR ₃ ; — (CH ₂ ) _t CO ₂ R ₃ ; Straight or branched C ₁ -C ₇ alkyl, carboxamidoalkyl; Straight or branched C ₂ -C ₇ aminoalkyl, alkenyl or alkynyl; Or C ₃ -C ₇ cycloalkyl or C ₅ -C ₇ cycloalkenyl;
[338] Y is S, O, or NR ₁₀ ;
[339] p is independently an integer between 1 and 7.
[340] In a further embodiment of the invention, the compound has the structure:
[341]
[342] In a further embodiment of the invention, the compound has the structure:
[343]
[344] In a further embodiment of the invention, the compound has the structure:
[345]
[346] In one embodiment of the invention Z is as follows:
[347]
[348] In one embodiment of the invention Z is as follows:
[349]
[350] In a further embodiment of the invention, the compound has the structure:
[351]
[352] In a further embodiment of the invention, the compound has the structure:
[353]
[354] The present invention provides a compound having the structure:
[355]
[356] Wherein R ₁ is hydrogen, straight or branched C ₁ -C ₇ alkyl, monofluoroalkyl or polyfluoroalkyl, aryl or heteroaryl, aryl or heteroaryl is one or more -F, -Cl,- Optionally substituted with Br, -I, -CN, -NO ₂ , -CH ₃ , -CF ₃ , -COCH ₃ , -CO ₂ R ₂ , phenyl, phenoxy or straight or branched chain C ₁ -C ₇ alkyl;
[357] R ₂ is straight or branched C ₃ -C ₄ alkyl or cyclopropyl;
[358] R ₃ is aryl or heteroaryl, aryl or heteroaryl is optionally substituted with —F, —Cl, —Br, —I, —CN, —NO ₂ , or straight or branched C ₁ -C ₇ alkyl;
[359] A is —H, —F, —Cl, —Br, —I, —CN, —NO ₂ , —COR ₃ , —CO ₂ R ₃ , straight or branched C ₁ -C ₇ alkyl, monofluoroalkyl or Polyfluoroalkyl;
[360] X is O or NH;
[361] n is an integer of 0-5.
[362] In one embodiment, R ₁ is optionally one or more of -F, -Cl, -Br, -I, -CN, -NO ₂ , -COCH ₃ , -CO ₂ R ₂ , straight or branched C ₁ -C ₇ alkyl Substituted aryl;
[363] R ₃ is phenyl;
[364] A is H, and
[365] X is O.
[366] In one embodiment R ₂ is isopropyl.
[367] In a preferred embodiment, X is NH, R ₁ is alkyl and n is 1 or 2.
[368] In the most preferred embodiment, X is O, R ₁ is 3-acetyl phenyl, R ₂ is isopropyl, R ₃ is phenyl and n is 1.
[369] In one embodiment, the compound has the structure:
[370]
[371] In one embodiment, the compound has the structure:
[372]
[373] In one embodiment, R ₁ is hydrogen, straight or branched C ₁ -C ₇ alkyl, and R ₃ is aryl.
[374] In one embodiment R ₂ is isopropyl and A is hydrogen.
[375] In one embodiment, the compound has the structure:
[376]
[377] In one embodiment, the compound has the structure:
[378]
[379] The present invention also provides a compound having the structure:
[380]
[381] Wherein R ₁ is at least one —F, —Cl, —Br, —I, —CN, —NO ₂ , —OCH ₃ , phenoxy, fused cyclopentanyl, straight or branched C ₁ -C ₇ alkyl, mono Aryl or heteroaryl optionally substituted with fluoroalkyl or polyfluoroalkyl;
[382] R ₂ is straight or branched C ₁ -C ₄ alkyl or cyclopropyl;
[383] A is —H, —F, —Cl, —Br, —CN, —NO ₂ , straight or branched C ₁ -C ₇ alkyl, monofluoroalkyl or polyfluoroalkyl;
[384] n is an integer of 1-5.
[385] In one embodiment, R ₁ is aryl substituted with one or more —F, —Cl, —Br, —I, or straight or branched C ₁ -C ₄ alkyl,
[386] A is H.
[387] In one embodiment, R ₂ is isopropyl,
[388] n is 2.
[389] In a preferred embodiment, n is 2 and R ₂ is isopropyl.
[390] In one embodiment, the compound has the structure:
[391]
[392] In one embodiment, the compound has the structure:
[393]
[394] In one embodiment, the compound has the structure:
[395]
[396] In one embodiment, R ₁ is thienyl and A is H.
[397] In one embodiment, R ₂ is isopropyl.
[398] In one embodiment, the compound has the structure:
[399]
[400] The present invention provides compounds having the structure:
[401]
[402] Where W is
[403]
[404] to be.
[405] Wherein each R ₁ is independently hydrogen, methyl or ethyl;
[406] R ₂ is straight or branched C ₃ -C ₄ alkyl or cyclopropyl;
[407] R ₃ is hydrogen, aryl or heteroaryl, where aryl or heteroaryl is —H, —F, —Cl, —Br, —I, —CN, —NO ₂ , straight or branched C ₁ -C ₇ alkyl Optionally substituted with one or more,
[408] Each A is, independently, —H, —F, —Cl, —Br, —CN, —NO ₂ , —COR ₃ , —CO ₂ R ₃ , straight or branched C ₁ -C ₇ alkyl, monofluoroalkyl Or polyfluoroalkyl;
[409] X is O, NR ₃ , CO or absent; And
[410] Y is hydrogen, aryl, or heteroaryl, and aryl or heteroaryl is optionally substituted with -F, -Cl, -Br, -I, -CN, -NO ₂ , or straight or branched C ₁ -C ₇ alkyl do.
[411] In one implementation, W is as follows:
[412]
[413] Wherein X is O or deficient.
[414] In one embodiment, R ₂ is isopropyl.
[415] In one embodiment, the compound has the structure:
[416]
[417] In one embodiment, the compound has the structure:
[418]
[419] In one implementation, W is as follows:
[420]
[421] In one embodiment, A is -H, -F, -Cl, -Br.
[422] In one embodiment R ₂ is isopropyl and A is hydrogen.
[423] In one embodiment, the compound has the structure:
[424]
[425] The present invention provides compounds having the structure:
[426]
[427] Where W is
[428]
[429] to be.
[430] Wherein R ₁ is hydrogen, straight or branched C ₁ -C ₇ alkyl, aryl, or heteroaryl, and aryl or heteroaryl is —F, —Cl, —Br, —CN, —NO ₂ , —OCH Optionally substituted with one or more of ₃ , -CO ₂ CH ₃ , -CF ₃ , phenyl, or straight or branched C ₁ -C ₇ alkyl;
[431] R ₂ is straight or branched C ₃ -C ₄ alkyl or cyclopropyl;
[432] A is —H, —F, —Cl, —Br, —CN, —NO ₂ , —COR ₁ , —CO ₂ R ₁ , straight or branched C ₁ -C ₇ alkyl, monofluoroalkyl or polyfluoro Roalkyl or phenyl;
[433] Each B is independently -H, -F, -Cl, -Br, -I, -CN, -NO 2, -COR 1, -CO 2 R 1, -OCH 3, -OCF 3, -CF 3, straight-chain Or branched C ₁ -C ₇ alkyl, monofluoroalkyl or polyfluoroalkyl or aryl, phenoxy or benzyloxy, wherein aryl, phenoxy or benzyloxy is one or more -F, -Cl, -Br, -CN _{, -NO 2, -COR 1, -CO} 2 R 1, -OCH 3, -OCF 3, -CF 3, or straight-chain or branched-chain is optionally substituted by C ₁ -C ₃ alkyl.
[434] In one implementation, W is as follows:
[435]
[436] In one embodiment R ₁ is hydrogen, or phenyl, and phenyl is optionally substituted with -F, -Cl, -Br, -CN, -NO ₂ , straight or branched C ₁ -C ₇ alkyl.
[437] In one embodiment, R ₂ is isopropyl.
[438] In one embodiment, the compound has the structure:
[439]
[440] In one embodiment, the compound has the structure:
[441]
[442] The present invention provides compounds having the structure:
[443]
[444] Wherein R ₁ is hydrogen, straight or branched C ₁ -C ₇ alkyl, aryl, or heteroaryl, and aryl or heteroaryl is one or more —F, —Cl, —Br, —CN, —NO ₂ , Optionally substituted with -OCH ₃ , -CF ₃ , phenyl, or straight or branched C ₁ -C ₃ alkyl;
[445] R ₂ is straight or branched C ₃ -C ₄ alkyl or cyclopropyl;
[446] R ₃ is —H, —F, —Cl, —Br, —I, —CN, —NO ₂ , —OCH ₃ , —CF ₃ , or straight or branched C ₁ -C ₃ alkyl, monofluoroalkyl or Phenyl rings fused to C ₆ and C ₇ of the polyfluoroalkyl or indole groups;
[447] R ₄ is hydrogen or aryl optionally substituted with one or more —F, —Cl, —Br, —I, —CN, —NO ₂ , —CF ₃ , or straight or branched C ₁ -C ₃ alkyl;
[448] A is —H, —F, —Cl, —Br, —CN, —NO ₂ , straight or branched C ₁ -C ₇ alkyl, monofluoroalkyl or polyfluoroalkyl; And,
[449] n is an integer from 2 to 4.
[450] In one embodiment, R ₃ is -H, -F, -Cl, -Br, -I, -CN, -NO 2, -OCH 3, or -OCF _3, and;
[451] R ₄ is hydrogen or phenyl optionally substituted with one or more -F, -Cl, or -CF ₃ .
[452] In one embodiment, R ₁ is hydrogen or optionally substituted with one or more —F, —Cl, —Br, —CN, —NO ₂ , —OCH ₃ , —CF ₃ , or straight or branched C ₁ -C ₃ alkyl Phenyl.
[453] In one embodiment, R ₂ is isopropyl.
[454] In one embodiment, the compound has the structure:
[455]
[456] In one embodiment, the compound has the structure:
[457]
[458] In one embodiment, the compound has the structure:
[459]
[460] The present invention provides compounds having the structure:
[461]
[462] Wherein each R ₁ is independently hydrogen or methyl;
[463] R ₂ is straight or branched C ₁ -C ₄ alkyl or cyclopropyl;
[464] R ₃ is benzyl or phenyl, benzyl or phenyl is optionally substituted with one or more -F or -Cl, or methylenedioxy groups;
[465] A is —H, —F, —Cl, —Br, —CN, —NO ₂ , straight or branched C ₁ -C ₇ alkyl, monofluoroalkyl or polyfluoroalkyl;
[466] X is (CH ₂ ) ₂ , COCH ₂ or CONH.
[467] In one embodiment, R ₃ is phenyl optionally substituted with one or more -F; And,
[468] A is hydrogen.
[469] In one implementation, X is CONH.
[470] In one embodiment R ₂ is methyl.
[471] In one embodiment the compound has the structure:
[472]
[473] In one embodiment the compound has the structure:
[474]
[475] Wherein each Y is independently hydrogen or -F.
[476] In one embodiment the compound has the structure:
[477]
[478] In one embodiment the compound has the structure:
[479]
[480] In one embodiment, R ₃ is benzyl optionally substituted with one or more -F or -Cl, or methylenedioxy groups.
[481] In one embodiment the compound has the structure:
[482]
[483] Wherein each Y is independently hydrogen or -F.
[484] In one embodiment the compound has the structure:
[485]
[486] In one embodiment, the compound is pure in terms of enantiomers.
[487] In one embodiment, the compound is pure in terms of diastereoisomers.
[488] In one embodiment, the compound is pure in terms of enantiomers and diastereomers.
[489] The invention also provides a pharmaceutical composition comprising a mixture of a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier.
[490] In one embodiment, the amount of compound is about 0.01 mg to about 500 mg.
[491] In one embodiment, the amount of compound is about 0.1 mg to about 60 mg.
[492] In one embodiment, the amount of compound is about 1 mg to about 20 mg.
[493] In one embodiment, the pharmaceutical composition consists of a carrier that is a liquid and the composition is a solution.
[494] In one embodiment, the pharmaceutical composition consists of a carrier that is a solid and the composition is a tablet.
[495] In one embodiment, the pharmaceutical composition consists of a carrier which is a gel and the composition is a suppository.
[496] The invention also provides a method of preparing a pharmaceutical composition comprising mixing a therapeutically effective amount of any compound of the invention with a pharmaceutically acceptable carrier.
[497] The present invention also provides a method of treating a subject suffering from a disease selected from the group consisting of depression, nervous anxiety, hyper-urgency, or obesity, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention.
[498] In one embodiment, the therapeutically effective amount is about 0.03 mg to about 1000 mg per day.
[499] In one embodiment, the therapeutically effective amount is about 0.30 mg to about 300 mg per day.
[500] In one embodiment, the therapeutically effective amount is about 1.0 mg to about 100 mg per day.
[501] In one embodiment, the disease is depression.
[502] In one embodiment, the disease is neuroanxiety.
[503] In one embodiment, the disease is obesity.
[504] In one embodiment, the disease is hyper impulse.
[505] The present invention provides a method for weight loss of a subject, comprising administering to the subject an effective amount of a compound of the invention to reduce the weight of the subject.
[506] The present invention provides a method of treating a subject suffering from depression, comprising administering to the subject a compound of the invention that is an effective amount to treat the subject's depression.
[507] The present invention provides a method of treating a subject suffering from neuroanxiety, comprising administering to the subject an effective amount of a compound of the present invention to treat a neuroanxiety of the subject.
[508] The present invention provides a method for reducing urinary urge excess in a subject suffering from an overactive bladder, comprising administering to the subject an effective amount of the compound of the present invention to alleviate the urinary urge excessive in the subject.
[509] The present invention provides a method for treating obesity in a subject in need of weight loss, comprising administering to the subject an effective amount of a compound of the invention to induce weight loss in the subject.
[510] The present invention provides a method of controlling obesity in a subject suffering from weight loss, comprising administering to the subject a compound of the present invention that is effective to maintain the subject's weight loss.
[511] The present invention provides a method of treating a hyper-reactive bladder in a subject, comprising administering to the subject an effective amount of a compound of the invention to treat an excess of urination urge in the subject.
[512] The present invention provides a method of treating a subject's disease, wherein the subject's symptoms are alleviated by MCH1 antagonist treatment, and the MCH1 antagonist is a compound of the present invention.
[513] The present invention includes administering to a subject an effective amount of MCH1 antagonist capable of alleviating symptoms, wherein the MCH1 antagonist is a compound of the present invention, and provides a method for alleviating disease symptoms in a subject.
[514] The term 'heteroaryl' as used herein is used to include five or six membered unsaturated rings which may contain one or more oxygen, sulfur or nitrogen. Examples of non-limiting heteroaryls include carbazole, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxdiazolyl, triazolyl, thia Diazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl.
[515] The term 'heteroaryl' is also used to encompass fused bicyclic ring systems capable of containing one or more oxygen, sulfur or nitrogen. Examples of such heteroaryl without limitation include indolinyl, indolyl, isoindoleyl, benzo [b] furanyl, benzo [b] thiophenyl, indazolyl, benzimidazolyl, purinyl, benzoxazolyl, Benziaxazolyl, benzo [b] thiazolyl, imidazo [2,1-b] thiazolyl, cinnarinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, putridinyl, quinoliniryl , Isoquinolinyl, phthalimidyl and 2,1,3-benzothiazolyl.
[516] The term 'heteroaryl' also includes one or more of the aforementioned chemical moieties which may be substituted by: -F, -Cl, -Br, -I, -CN, -NO ₂ , straight or branched chain C ₁ -C ₇ Alkyl, straight or branched C ₁ -C ₇ monofluoroalkyl, straight or branched C ₁ -C ₇ polyfluoroalkyl, straight or branched C ₂ -C ₇ alkenyl, straight 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.
[517] The term “heteroaryl” includes N-oxides of the above-mentioned chemical residues having one or more nitrogen atoms.
[518] The term 'aryl' is, in the present invention, phenyl or naphthyl.
[519] The present invention provides each pure stereoisomer of any of the compounds described herein. Such stereoisomers include enantiomers, diastereomers, or E or Z alkene or imine isomers. The invention also provides stereoisomeric mixtures, including racemic mixtures, diastereomeric mixtures or E / Z isomer mixtures. Stereoisomers may be synthesized in pure form (Nogradi, M, Stereoselective Synthesis 1987, VCH Editor Ebel, H. and Asymetric Synthesis Vol3, B5, 1983, edited by Academic Press, Morrison J) or by various methods such as crystal and chromatographic techniques. Are separated (Jaques, J., Collet, A., Wilen, S. Enatiomer, Racemates and Resolutions, 1981, John Wiley and Sons, and Asymmetric Synthesis, Vol 2, 1983, Academic Press, Morrison J).
[520] The compounds of the present invention may also exist as enantiomers, diastereomers, and isomers, and two or more compounds may exist by forming racemic or diastereomeric mixtures.
[521] The compounds of the invention are preferably 80% pure, more preferably 90% pure and most pure 95% pure. Included in the present invention are pharmaceutically acceptable salts and complexes of all of the compounds described herein. Acids and bases from which these salts are prepared include, but are not limited to, acids and bases described herein. Non-limiting acids include the following inorganic acids: hydrochloric acid, bromic acid, iodic acid, sulfuric acid and boric acid. Non-limiting acids include 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. Non-limiting bases include: ammonia, methylamine, ethylamine, diethylamine, triethylamine, trimethylamine, propylamine, dimethylamine, ethylenediamine, hydroxyethylamine, morpholin, piperazine and Guanidine. The invention also provides hydrates and multiple forms of all compounds described herein.
[522] The present invention includes within its scope prodrugs of the compounds of the present invention. Generally such prodrugs are functional derivatives of the compounds of the invention, which are soon converted into the required compounds in vivo. Thus, the term 'administration' in the present invention encompasses both treatment of various conditions with especially the described compounds or treatment of various conditions with compounds which are not specifically described, but which are converted to specific compounds in vivo after administration to a patient. Conventional methods for the selection and preparation of suitable prodrug derivatives are, for example, Design of Prodrugs (H. Bundgaard et al., Elsevier, 1986).
[523] The invention also includes metabolites of the compounds of the invention. Metabolites include active species resulting from the introduction of a compound of the present invention in vivo.
[524] The invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier. In one embodiment, the amount of compound is about 0.01 mg to about 800 mg. In another embodiment, the amount of compound is about 0.01 mg to about 500 mg. In another embodiment, the amount of compound is about 0.1 mg to about 250 mg. In another embodiment, the amount of compound is about 0.1 mg to about 60 mg. In another embodiment, the amount of compound is about 1 mg to about 20 mg. In another 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 suppository, capsule or cream. In another embodiment, the compound is formulated as part of a pharmaceutically acceptable transdermal patch. In another embodiment, the compound is delivered to the subject by means of spray or inhalation.
[525] The invention also provides a pharmaceutical composition prepared by combining a therapeutically effective amount of a compound of the invention with a pharmaceutically acceptable carrier.
[526] The present invention provides a method for the preparation of a pharmaceutical composition comprising combining a therapeutically effective amount of a compound of the invention with a pharmaceutically acceptable carrier.
[527] Solid carriers include one or more substances that also act as internal carriers (ie, nutrient or micronutrient carriers), flavoring agents, lubricants, dissolving agents, suspending agents, fillers, glides, compression aids, binders, or tablet disintegrating agents. It may also be an encapsulating material. In powders, the carrier is a finely divided solid mixed with the finely divided active ingredient. In tablets, the active component is mixed with the carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. Powders and tablets contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, tar, sugar, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidone, low melting waxes and ion exchange resins.
[528] Liquid carriers are used in the preparation of solutions, suspensions, emulsions, syrups, elixirs, and compressed compositions. The active ingredient is dissolved or suspended in pharmaceutically acceptable liquid carriers such as water, organic solvents, mixtures thereof or pharmaceutically acceptable oils or fats. The liquid carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickeners, colorants, viscosity modifiers, stabilizers or inlet pressure regulators. Examples of suitable liquid carriers for oral or parenteral administration include water (preferably containing some of the above additives, such as cellulose derivatives, which are preferably sodium carboxymethyl cellulose solutions), alcohols (alcohols with one or more OH, eg Glycols) and derivatives and oils thereof (ie differentiated coconut oil and arachis oil). For parenteral administration, the carrier is also an oily ester such as ethyloleate or isopropyl myristate. Disinfection liquid carriers are useful for forming disinfection liquid compositions for parenteral administration. Liquid carriers for compression compositions are halogenated hydrocarbons or other pharmaceutically acceptable propellants.
[529] Liquid pharmaceutical compositions, which are disinfectant solutions or suspensions, can be used, for example, for intramuscular, endocardial, epidural, intraperitoneal or subcutaneous injection. Disinfection solutions are also injectable intravenously. The compounds may be prepared as sterile solid compositions that are dissolved or suspended upon administration with sterile water, saline or other suitable sterile injection media. Desired carriers include binders, suspending agents, lubricants, flavoring agents, sweetening agents, preservatives, dyes, and coatings, which are inert, if desired. Compounds are oleates of other solutes or suspending agents (e.g. saline or glucose sufficient for solution isotonicity), bile salts, acacia, gelatin, sorbitan monooleate, polysorbate 80 (sorbitol and anhydrides copolymerized with ethylene oxide Oral) in the form of a disinfectant solution or suspension, including).
[530] The compound is administered orally in the form of a pharmaceutical or solid composition. 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 for parenteral administration include antiseptic solutions, emulsions and suspensions.
[531] Optimal dosages are determined by those skilled in the art and vary depending on the particular compound employed, the strength of the formulation, the mode of administration, and the progression of the disease condition. Dosage is adjusted by including additional factors depending on the particular subject being treated, ie the subject's age, weight, sex, diet, and number of doses.
[532] In the present invention, a 'therapeutically effective amount' is any amount of a compound which, when administered to a subject with an effective disease, causes the reduction, decline or alleviation of the disease. In the present invention, the 'subject' is a vertebrate which is a human or mammal.
[533] The present invention is directed to a subject having an abnormality that reduces the abnormality by reducing the activity of the MCH1 receptor, comprising administering to the subject an amount of a compound of the invention that is an MCH1 receptor antagonist effective for treating the subject's abnormality. Provide a method of treatment.
[534] In a separate embodiment, the abnormalities may be steroid or pituitary hormone abnormalities, epinephrine secretion abnormalities, gastrointestinal abnormalities, cardiovascular abnormalities, electrolyte ratio abnormalities, hypotension, diabetes, respiratory disease, asthma, genital abnormalities, immune abnormalities, endocrine abnormalities, musculoskeletal abnormalities, Neurosecretory disorders, cognitive disorders, memory disorders such as Alzheimer's disease, sensory control and transmission disorders, motor coordination disorders, sensory total disorders, exercise total disorders, dopaminergic dysfunctions such as Parkinson's disease, sympathetic nerve control disorders, depression and anxiety It is the regulation of abnormalities such as emotional disorders, stress-related disorders, fluid coordination disorders, paralysis disorders, pain, mental disorders such as delirium, urinate abnormalities such as morphine tolerance, opioid addiction, migraine or urination urge.
[535] The following depressive and anxiety disease statements are intended to illustrate the usefulness of the compounds of the invention. The following definitions of depressive and anxiety diseases are described in the literature (DSM-IV; American Psychiatric Association, 1994a; Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, revised, DSM-III-R, American Psychiatric Association, 1987). . Additional information relating to these diseases is found in this document and the documents cited below, all of which are incorporated herein by reference.
[536] Depressive disorders include major depressive disorders and mood disorders (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. Major depressive episodes are generally defined as one major relatively persistent (almost every day for two weeks or more) depression or discomfort that interferes with daily functioning; This should include at least four of the following eight symptoms: changes in appetite, changes in sleep, fluctuations or delays in psychomotor activity, decreased interest or sexual desire in daily activities, increased fatigue, increased guilt or helplessness, slowed thinking or concentration Decay, and suicidal thoughts or longings for suicide (Medical Economics Company, 2002). Depressive disorder is not severe enough to be named as a major depressive episode, but involves a type of depression that lasts longer than the major depressive disorder without severe periods.
[537] Compounds of the invention are considered effective for treating depression in patients diagnosed with depression by any of the following test applications: Hamilton Depression Rating Scale (HDRS), Hamilton depressed mood item, Clinical Global Impressions (CGI) -Severity of Illness. In addition, the compounds of the present invention are effective in inducing improvements in CGI-degrees of HDRS subfactor scores and specific Illness ratings, including certain factors measured in the test, such as depression mood item sleep disorder factors and anxiety factors. Is considered. In addition, the compounds of the present invention are considered effective for preventing recurrence of major depressive episodes.
[538] Anxiety disorders include panic disorder, agoraphobia with or without a history of panic disorder, specific phobias, social phobia, obsessive compulsive disorder, post-traumatic stress disorder, acute stress disorder and general anxiety disorder. Compounds of the invention are considered effective in the treatment of any and all of the above disorders in a patient diagnosed with the disorder.
[539] Obsessive-compulsive disorder is characterized by recurrent persistent daydreaming, thinking, impulse, or imagination (urge), which is a child's cognitive and / or repetitive, deliberate and intensive behavior (obsession) that is perceived as an obsession (American Psychiatric Association). , 1994a). Obsessive compulsions or impulses cause significant pain and are time consuming or significantly disrupt social or professional functioning.
[540] The compounds of the present invention are considered to be effective for treating obsessive and impulsive treatment in patients diagnosed with OCD with appropriate test applications that may include, but are not limited to: Yale Brown Obsessive Compulsive Scale (YBOCS) ( Goodman, 1989) (for adults), National Institute of Mental Health Global OCD Scale (NIMH GOCS), CGI-Severity of Illness scale. In addition, the compounds of the present invention are considered effective at several point reductions in certain factors measured in the test, such as the YBOCS total score. In addition, the compounds of the present invention are considered effective for preventing relapse of obsessive-compulsive disorder.
[541] Anxiety disorders are characterized by recurrent unexpected panic attacks and concerns about further seizures, worries about consequences or a series of seizures, and / or significant changes in behavior associated with seizures (American Psychiatric Association, 1994a). Panic attacks are defined as the period of extreme fear or discomfort, in which four (or more) of the following symptoms occur suddenly or peak within 10 minutes: (1) palpitations, male strokes, or heart rate acceleration ; (2) sweating; (3) soothing or shaking; (4) detection of dyspnea or acetabular obstruction; (5) feeling of suffocation; (6) chest pain or discomfort; (7) nausea or abdominal pain; (8) feelings of dizziness, instability, dizziness, or fainting; (9) unreality (feeling unrealistic) or dichotomy (separation from self); (10) fear of loss of control; (11) fear of death; (12) paresthesia (anesthesia or pain); (13) intermittent hot flashes. Anxiety disorders may or may not be accompanied by agoraphobia, or an often unhelpful fear of being in the public.
[542] The compounds of the present invention are considered effective for treating anxiety disorders in patients diagnosed with anxiety disorders based on the incidence of panic attacks or using CGI-Severity on the Illness scale. Compounds of the present invention may also be used to improve the specific factors measured in the assessment, such as reducing or eliminating the frequency of panic attacks, improving CGI-Severity on the Illness scale, or CGI-Global Improvement Score 1 (very much improvement), 2 ( Much improvement) or 3 (minimum improvement) is considered effective. In addition, the compounds of the present invention are considered effective for preventing the recurrence of anxiety disorders.
[543] Social anxiety disorders, also known as social phobias, are characterized by unusual persistent fear in one or more social or functional situations subject to exposure to strangers or surveillance of others (American Psychiatric Association, 1994a). Exposure to fearful situations most of the time causes anxiety, which can be approached by the concentration of panic attacks. Fearful situations are avoided or endured with intensive worry or pain. Avoidance, anxious feelings, or pain in the feared situation (s) are a significant pain for having a significant disturbance or fear of an individual's daily, professional or academic function, or social activity or relationship. Lower levels of functional anxiety or shyness do not require psychopharmacological treatment.
[544] The compounds of the present invention are considered effective for treating social anxiety disorders in patients diagnosed with social anxiety disorders by any of the following trials: Liebowitz Social Anxiety Scale (LSAS), CGI-Severity on Illness Scale, Hamilton Rating Scale (HAM-A), Hamilton Rating Sacle for Depression (HAM-D), Axis of DSM-IV V Social and Occupational Funtioning Assessment Scale, Axis II (ICD-10) World Health Organization Disability Assessment, Schedule 2 ( DAS 2), Sheehan Disability Scale, Schneier Disability Profile, World Health Organization Quality of Life-100 (WHOQOL-100), or other tests such as those described in Bobes, 1998, incorporated herein by reference. In addition, the compounds of the present invention may also induce improvement as measured by the above tests, such as changes from baseline on the Liebowitz Social Anxiety Scale (LSAS), or CGI-Global Improvement Score 1 (very much improvement), 2 (many improvement). Or 3 (minimum improvement). In addition, the compounds of the present invention are considered effective for preventing the recurrence of social anxiety disorders.
[545] General anxiety disorders are characterized by excessive anxiety and anxiety (worry predictions) that last more than 6 months and prove to be difficult for the party to control (American Psychiatric Association, 1994a). It should be accompanied by three or more of the following six symptoms: feeling of hunger or dead end, fatigue, difficulty concentrating or emptiness, irritability, muscle tension, sleep disorders. Diagnostic criteria for such disorders are further described in the American Psychiatric Association, 1994a (DSM-IV), which is incorporated herein by reference.
[546] The compounds of the present invention are considered effective for treating general anxiety disorders in patients diagnosed with such disorders according to the diagnostic criteria described in DSM-IV. In addition, the compounds of the present invention are considered effective for reducing the pathology of such disorders, for example: excessive anxiety and anxiety, easily guided, difficult to control worry, easily guided, or feeling dead end, easily tired, difficult to concentrate Or emptiness, irritability, muscle tension, or sleep disorders. In addition, the compounds of the present invention are considered effective for preventing recurrence of anxiety disorders.
[547] In the diagnosis of post-traumatic stress disorder (PTSD) as defined in the DSM-III-R / IV (American Psychiatric Association, 1987, American Psychiatric Association, 1994a), the actual or confronted death or serious injury, or the physical shape of oneself or others Threats, and exposure to traumatic accidents with strong fear, helplessness or fear. Symptoms resulting from exposure to traumatic accidents include: strong psychological distress and psychological reactions to accidental reexperience in the form of compulsive thinking, flashbacks or dreams and exposure to clues about the accident; Avoiding situations suggestive of traumatic accidents, inability to recall details of accidents, and / or a general slowdown in responsiveness manifested as a loss of interest in significant activity, alienation from others, limited range of affect, or shortened sense of foreshortened future ); Autonomic arousal, including hyperboundary, excessive surprise reactions, sleep disorders, loss of concentration, and explosion of irritability or anger. In PTSD diagnosis, the condition is present for more than one month and requires that they cause clinically meaningful pain or a reduction in social, occupational, or other important functional areas.
[548] The compounds of the present invention are considered effective for the treatment of PTSD in patients diagnosed with PTSD with any of the following test applications: Clinician-Administered PTSD Scale Part 2 (CAPS), Patient Assessment Impact of Event Scale (IES) (Medical Economics Company) , 2002, p. 2752). In addition, the compounds of the present invention are considered effective for inducing improvement in CAPS, IES, CGI-Severity of Illness or CGI-Global Improvement tests. In addition, the compounds of the present invention are considered effective for preventing recurrence of PTSD.
[549] In a preferred embodiment, the subject invention provides methods for the treatment or management of the disorders shown below: depressive disorders, anxiety disorders, eating / weight disorders, and urinary disorders. Examples of depressive disorders are major depressive disorders or mood disorders. Examples of anxiety disorders are panic disorder, agoraphobia without history of panic disorder, specific phobias, social phobia, obsessive compulsive disorder, post traumatic stress disorder, acute stress disorder or general anxiety disorder. Examples of eating / 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, frequent urination, nocturia and nocturia. Irritable bladder and urge incontinence may or may not be associated with benign prostatic hyperplasia.
[550] The present invention provides a method of altering eating behavior in a subject, comprising administering to the subject an effective amount of a compound of the invention that reduces the subject's food consumption. The present invention also provides a method of treating an eating disorder in a subject comprising administering to the subject an effective amount of a compound of the invention. In an embodiment of the invention, the eating disorder is obesity, bulimia, bulimia nervosa or anorexia nervosa.
[551] The present invention also provides a method of reducing body mass of a patient, comprising administering to the patient a compound of the present invention in an amount effective to reduce the body mass of the patient. The invention also provides a method of managing obesity in a patient in need of weight loss, the method comprising administering to a patient a compound of the invention in an amount effective to induce weight loss in the patient. The invention also provides a method of managing obesity in a patient who has experienced weight loss, the method comprising administering to a patient a compound of the invention in an amount effective to maintain the weight loss of the patient.
[552] The invention also provides a method of treating depression in a patient comprising administering to a patient a compound of the invention in an amount effective to treat the depression in the patient. The invention also provides a method of treating anxiety in a patient comprising administering to a patient a compound of the invention in an amount effective to treat the anxiety in the patient. The invention also provides a method of treating depression and anxiety in a patient, comprising administering to a patient a compound of the invention in an amount effective to treat the depression and anxiety in the patient. The invention also provides a method of treating a major depressive disorder in a patient, comprising administering to the patient a compound of the invention in an amount effective to treat the major depressive disorder in the patient. The present invention also provides a method of treating a mood disorder in a patient comprising administering to a patient a compound of the invention in an amount effective to treat the mood disorder in the patient. The present invention also provides a method of treating obsessive compulsive and obsessive compulsive disorder in a patient with an obsessive compulsive disorder, comprising administering to the patient a compound of the present invention in an amount effective to treat the compulsive compulsive disorder and compulsive behavior of the patient. The present invention provides a method of treating a patient with or without panic disorder, comprising administering to a patient a compound of the present invention in an amount effective to treat the patient's panic disorder. The present invention also provides a method for treating a social anxiety disorder in a patient, comprising administering to a patient a compound of the present invention in an amount effective to treat the social anxiety disorder in the patient. The present invention also provides a method of treating a patient's generalized anxiety disorder, comprising administering to a patient a compound of the present invention in an amount effective to treat the patient's generalized anxiety disorder. The invention also provides a method of treating a patient with a post traumatic stress disorder, comprising administering to a patient a compound of the invention in an amount effective to treat a posttraumatic stress disorder in the subject.
[553] Compounds of the invention are believed to be effective in treating obesity, including weight loss and maintaining weight loss, in patients diagnosed with obesity by one or more of the following measures: increased body mass index, increased waist circumference (intraperitoneal fat index) ), Dual-energy X-ray absorption (DEXA) and resting (android) fat mass. It is also contemplated that the compounds of the present invention will be effective in inducing improvements in certain factors measured in these tests.
[554] The compounds of the present invention are urinary in patients with urge incontinence or mixed incontinence (dominant urinary incontinence), evidenced by the number of unnecessary episodes per week, the number of unnecessary urinations per day, and the release of small volumes per urination. It is thought to be effective in treating the disorder. It is also contemplated that the compounds of the present invention will be effective in inducing improvements in certain factors measured in these tests.
[555] The invention also treats patients suffering from bipolar I or II disorders, schizophrenic disorders, cognitive disorders with depression, personality disorders, insomnia, hypersleep, narcolepsy, rhythmic sleep disorders, nightmares, night terrors or sleepwalking Provide a way to.
[556] The invention also provides a method of treating bladder hypersensitivity with symptoms of urgency incontinence, urgency and / or urinary frequency of a patient, comprising administering to the patient a compound of the invention in an amount effective to treat the bladder hypersensitivity of the patient. To provide. The invention also provides a method of alleviating urge incontinence in a patient suffering from bladder hypersensitivity, the method comprising administering a compound of the invention in an amount effective to alleviate urge incontinence in a patient. The invention also provides a method of alleviating urinary urgency in a patient suffering from bladder hypersensitivity, the method comprising administering a compound of the invention in an amount effective to alleviate the urgent urine of the patient. to provide. In addition, the present invention provides a method of alleviating urinary frequency in a patient suffering from bladder hypersensitivity, the method comprising administering to a patient a compound of the present invention in an amount effective to alleviate the urinary frequency of the patient.
[557] The invention also provides a method of treating a patient suffering from a urinary disorder comprising administering to a patient a compound of the invention in an amount effective to treat the urinary disorder of the patient. In some embodiments, the urinary disorder is urinary incontinence, bladder hypersensitivity, urge incontinence, urinary frequency, urgent urine, nocturnal urination or urination.
[558] The present invention provides a method of alleviating a disorder symptom in a patient, the method comprising administering to the patient an MCH1 antagonist, any of the compounds of the present invention, in an amount effective to alleviate the condition.
[559] In an embodiment of the invention, the patient is a vertebrate, mammal, human or canine animal. In another embodiment, the compound is administered orally. Moreover, in another embodiment, the compound is administered in combination with food.
[560] The invention will be better understood from the experimental details of the preferred embodiments and the subject invention provides a method of treatment for the following presented: depression, anxiety, eating / weight disorders, urinary disorders. Examples of eating / weight disorders are obesity, hungry or neurotic hunger. Examples of urinary disorders include, but are not limited to, urinary incontinence, bladder hypersensitivity, urge urinary incontinence, frequent urination, urgent care, nocturia or urination. Bladder hypersensitivity and urgent cause may or may not be associated with benign prostatic hypertrophy.
[561] The present invention provides a method of controlling dietary behavior of a patient, the method comprising administering to the patient a compound of the present invention in an amount effective to reduce the food consumption of the patient.
[562] The invention also provides a method of treating a patient's eating disorder comprising administering to a patient a compound of the invention in an amount effective to reduce food consumption of the patient. In one embodiment of the invention, the eating disorder is hunger, obesity or neurotic hunger. In one embodiment of the invention, the patient is a vertebrate, mammal, human or canine animal. In another embodiment, the compound is administered in combination with food.
[563] The present invention also provides a method of reducing body mass of a patient, comprising administering to the patient a compound of the present invention in an amount effective to reduce the body mass of the patient.
[564] The invention also provides a method of treating a patient suffering from depression, the method comprising administering to a patient a compound of the invention in an amount effective to treat the depression of the patient. The invention also provides a method of treating a patient suffering from anxiety, comprising administering to a patient a compound of the invention in an amount effective to treat the patient's anxiety. The present invention also provides a method of treating a patient suffering from depression and anxiety, the method comprising administering to a patient a compound of the present invention in an amount effective to treat the depression and anxiety of the patient.
[565] The invention also includes major depressive disorders, mood disorders, bipolar I or II disorders, schizophrenic disorders, cognitive disorders with depression, personality disorders, insomnia, hypersomnia, narcolepsy, rhythmic sleep disorders, nightmares, night terrors, Provides a method for treating patients suffering from sleepwalking, obsessive compulsive disorder, panic disorder with or without agoraphobia, post traumatic stress disorder, social anxiety disorder, social phobia and general anxiety disorder.
[566] The invention also provides a method of treating a patient suffering from a urinary disorder comprising administering to a patient a compound of the invention in an amount effective to treat the urinary disorder of the patient. In some embodiments, the urinary disorder is urinary incontinence, bladder hypersensitivity, urge incontinence, urinary frequency, urgent urine, nocturnal urination or urination.
[567] The invention will be better understood from the following experimental details. However, those skilled in the art will readily appreciate that the specific methods and results of the discussion are merely illustrative of the invention described in more detail in the claims that follow.
[568] Experiment
[569] I. Synthetic Methods for Examples
[570] General method: All reactions (except those carried out in parallel synthetic reaction arrangements) were carried out under argon atmosphere and the appropriate reagents or pure reagents were transferred to the reaction vessel via syringe and cannula techniques. Parallel synthesis reaction arrangements were performed in vials (no inert atmosphere) using a J-KEM heated shaker (Saint Louis, MO). Anhydrous solvent was purchased from Aldrich Chemical Company and used as such. The examples described in this patent were named using the ACD / Name Program (Version 2.51, Advanced Chemistry Development Inc., Toronto, Ontario, M5H2L3, Canada). Unless otherwise stated, ¹ H spectra were reported at 300 and 400 MHz (QE Plus and Bruker, respectively) using tetramethylsilane as internal standard. s = singlet; d = doublet; t = triplet; q = quartet; p = pentet, hex; Seventh term (sept); br = broad; m = multiplet. Elemental analysis is performed by Robertson Microlit Laboratories, Inc. Was performed by. Unless otherwise noted, mass spectra were obtained using low-resolution electrospray (ESMS) and MH ⁺ was reported. Thin layer chromatography (TLC) was performed on glass plates (0.25 mm, EM Separations Tech.) Precoated with silica gel 60 F ₂₅₄ . Preparative thin layer chromatography was performed on glass sheets (2 mm, Analtech) precoated with silica gel GF. Flash column chromatography was performed on Merck silica gel 60 (230-400 mesh). Melting point (mp) was performed in the open capillary of the Mel-Temp apparatus and was not corrected.
[571] Piperidine Side Chain Intermediates
[572] tert-butyl 4-{[(trifluoromethyl) sulfonyl] oxy} -1,2,3,6-tetrahydro-1-pyridinecarboxylate: n-butyl lithium (17.6 mL, 44.2 mmol in hexane 2.5 M) was added to a solution of diisopropyl amine (96.2 mL, 44.2 mmol) in 40 mL of dry THF at 0 ° C. and stirred for 20 minutes. The reaction mixture is cooled to −78 ° C., tert-butyl 4-oxo-1-piperidinecarboxylate (Aldrich Chemical Company, 40.0 mmol) in THF (40 mL) is added dropwise to the reaction mixture and for 30 minutes Stirred. Tf ₂ NPh (42.0 mmol, 15.0 g) in THF (40 mL) was added dropwise to the reaction mixture, and stirred overnight at ° C. The reaction mixture was concentrated in vacuo, redissolved in hexanes: EtOAc (9: 1), passed through an alumina plug, and the alumina plug was washed with hexanes: EtOAc (9: 1). The combined extracts were concentrated to yield 16.5 g of the desired compound, which was contaminated with some starting Tf ₂ NPh.
[573]
[574] tert-butyl 4- [3- (amino) phenyl] -1,2,3,6-tetrahydro-1-pyridinecarboxylate: 2 M Na ₂ CO ₃ aqueous solution (4.2 mL), tert-butyl 4- { [(Trifluoromethyl) sulfonyl] oxy} -1,2,3,6-tetrahydro-1-pyridinecarboxylate (0.500 g, 1.51 mmol), 3-aminophenylboronic acid half sulfate (0.393 g, 2.11 mmol), a mixture of tetrakis-triphenylphosphine palladium (0) (0.080 g, 0.075 mmol) in lithium chloride (0.191 g, 4.50 mmol), and dimethoxyethane (5 mL) was inert The mixture was heated at reflux for 3 hours under an atmosphere (preferably to degas the mixture to prevent the formation of triphenylphosphine oxide). The organic layer of the cooled reaction mixture was separated and the aqueous layer was washed with ethyl acetate (3 ×). The combined organic extracts were dried and concentrated in vacuo. The crude product was chromatographed (silica, hexanes: EtOAc: dichloromethane (6: 1: 1) with 1% added isopropylamine to prevent hydrolysis of BOC groups) to give 0.330 g of the desired product. Obtained in% yield.
[575]
[576] tert-butyl 4- [3- (amino) phenyl] -1-piperidinecarboxylate: 3.10 g of tert-butyl 4- (3-aminophenyl) -1,2,3,6-tetrahydropyridine- A mixture of 1-carboxylate (11.3 mmol) and 1.0 g of 10% Pd / C in 200 mL ethanol was hydrogenated at room temperature for 2 days using the balloon method. The reaction mixture was filtered and washed with ethanol. The combined ethanol extracts were concentrated in vacuo and the residue was chromatographed on silica (dichloromethane: methanol 95: 5 with 1% added isopropylamine to prevent hydrolysis of BOC groups) to give 2.63 g of the desired product. (84%) was obtained.
[577]
[578] tert-butyl 4- [3- (acetylamino) phenyl] -1,2,3,6-tetrahydro-1-pyridinecarboxylate:
[579] Na ₂ CO ₃ saturated aqueous solution (25 mL), tert-butyl 4-{[((trifluoromethyl) sulfonyl] oxy} -1,2,3,6-tetrahydro-1-pyridinecarboxylate (20 mmol ), 3-acetamidophenylboronic acid (30 mmol) and a mixture of tetrakis-triphenylphosphine palladium (0) (1.15 g) in dimethoxyethane (40 mL) were heated at reflux overnight. The organic layer of the cooled reaction mixture was separated and the aqueous layer was washed with ethyl acetate (3 ×). The combined organic extracts were dried and concentrated in vacuo. The crude product was chromatographed to give the desired product:
[580]
[581] N1- [3- (1,2,3,6-tetrahydro-4-pyridinyl) phenyl] acetamide: A solution of 4M HCl in dioxane (10 mL) was added tert-butyl 4 in dichloromethane (30 mL). -[3- (acetylamino) phenyl] -1,2,3,6-tetrahydro-1-pyridinecarboxylate (8.25 mmol). The reaction mixture was stirred at rt overnight and concentrated in vacuo to afford the desired product as a hydrochloride salt (2.1 g):
[582]
[583] tert-butyl N- (3-bromopropyl) carbamate: Prepared from 3-bromopropylamine hydrobromide and BOC ₂ O in the presence of a base in 9.89 mmol dichloromethane.
[584]
[585] tert-butyl N- (3- {4- [3- (acetylamino) phenyl] -1,2,3,6-tetrahydro-1-pyridinyl} propyl) carbamate: dry dioxane (30 mL) N1- [3- (1,2,3,6-tetrahydro-4-pyridinyl) phenyl] acetamide. HCl (8.24 mmol), tert-butyl N- (3-bromopropyl) carbamate and The solution of potassium carbonate (33 mmol) was heated at reflux overnight. The solid was filtered off, the solution was concentrated in vacuo and the product was chromatographed to afford the desired product (110 mg).
[586]
[587] N1- {3- [1- (3-aminopropyl) -1,2,3,6-tetrahydro-4-pyridinyl] phenyl} acetamide: 1: 1 of TFA: CH ₂ Cl ₂ (5 mL) The solution was poured into tert-butyl N- (3- {4- [3- (acetylamino) phenyl] -1,2,3,6-tetrahydro-1-pyridinyl} propyl) carba in dichloromethane (5 mL). Added to mate. The resulting solution was stirred for 1 to 3 days at room temperature, saturated NaHCO ₃ was added to pH> 6 and the organic layer was separated and dried in vacuo to give the desired product (45 mg):
[588]
[589] tert-butyl 4- [3- (acetylamino) phenyl] -1-piperidinecarboxylate: 5% Pd / C (100 mg) and tert-butyl 4- [3- (acetyl in EtOH (10 mL) A mixture of amino) phenyl] -1,2,3,6-tetrahydro-1-pyridinecarboxylate (710 mg) was hydrogenated overnight at room temperature (balloon method). The reaction mixture was passed through a Celite 545 pad and the Celite pad was washed with ethanol. The combined ethanol extracts were concentrated and chromatographed to give the desired product (660 mg):
[590]
[591] N1- [3- (4-piperidyl) phenyl] acetamide: solution of HCl in dioxane (4N, 5 mL) was dried tert-butyl 4- [3- (acetylamino) in dichloromethane (15 mL) To phenyl] -1-piperidinecarboxylate (660 mg). The reaction mixture was stirred at rt overnight and concentrated in vacuo to afford the desired product (550 mg): melting point 102-104 ° C .;
[592]
[593] Tert-Butyl-N -(3- {4- [3- (acetylamino) phenyl] piperidino) propyl) carbamate:
[594] N1- [3- (4-piperidyl) phenyl] acetamide (550 mg, 0.210 mmol), tert-butyl N- (3-bromopropyl) carbamate (550 mg) in dioxane (20 mL) , 0.230 mmol), a solution of several crystals of K ₂ CO ₃ (1.10 g, 0.890 mmol), diisopropylethyl amine (1.50 mL) and KI was heated at reflux for 2 days. The precipitated salt was removed by filtration, concentrated in vacuo and the crude product was chromatographed to give the desired product (340 mg): ¹ H NMR (CDCl ₃ ) δ8.15 (s, 1H), 7.47 -7.44 (m, 2H), 7.22 (t, 1H, J = 7.8 Hz), 6.94 (d, 1H, J = 7.8 Hz), 5.53 (b, 1 H), 3.23 (b, 6 H), 2.80 -1.60 (m, 9 H), 2.20 (s, 3 H), 1.45 (s, 9 H).
[595] N1 -(3- [1- (3-aminopropyl) -4-piperidyl] phenyl} acetamide:
[596] To a solution of tert-butyl N- (3- {4- [3- (acetylamino) phenyl) piperidino} propyl) carbamate (340 mg) in dry dichloromethane (10 mL) add TFA (1.0 mL). Add and stir for 5 hours at room temperature. KOH 10% aqueous solution was added to the reaction mixture until pH> 6, and then dichloromethane was removed in vacuo. The aqueous layer was frozen and lyophilized to give a solid, which was extracted with methanol. Solvent was removed to afford the desired product (120 mg) as oil:^OneH NMR (CDCl₃) δ7.23-7.16 (obvious t, 1H, J = 7.5 Hz), 6.95-6.92 (m, 1H), 3.03-2.99 (m, 2H), 2.77-2.73 (t, 2H, J = 6.6 Hz), 2.50-1.60 (m, 10H), 2.13 (s, 3H).
[597] Tert-Butyl 4- (3-nitrophenyl) -3,6-dihydro-1 (2H) -pyridinecarboxylate:
[598] Na _{2 in} dimethoxyethane (5 mL) according to the procedure used for the synthesis of tert-butyl 4- [3- (amino) phenyl] -1,2,3,6-tetrahydro-l-pyridinecarboxylate. CO ₃ 2M aqueous solution (2.2 mL), tert-butyl 4-{[trifluoromethyl) sulfonyl) oxy} -1,2,3,6-tetrahydro-1-pyridine-carboxylate (0.500 g, 1.51 mmol), 3-nitrophenylboronic acid (0.353 g, 2.11 mmol), lithium chloride (0.191 g, 4.50 mmol) and tetrakis-triphenylphosphine palladium (0) (0.080 g, 0.075 mmol) 0.380 g of this desired product was provided.
[599] ¹ H NMR (400 MHz, CDCl ₃ ) δ8.23 (s, 1H), 8.11 (d, 1H, J = 8.0 Hz), 7.69 (d, 1H, J = 8.0 Hz), 7.51 (t, 1H, J = 8.0 Hz), 6.20 (m , 1H), 4.17-4.08 (m, 2H), 3.67 (t, 2H, J = 5.6 Hz), 2.61-2.52 (m, 2H), 1.50 (s, 9H); ESMS m / e: 249.1 (M + H -C ₄ H ₈ ) ⁺
[600] 1,2,3,6-tetrahydro-4- (3-nitrophenyl) pyridine:
[601] 5.00 g (16.0 mmol) of a stirred solution of tert-butyl 1,2,3,6-tetrahydro-4- (3-nitrophenyl) pyridine-1-carboxylate in 100 ml of 1,4-dioxane were 0 It was bubbled with HCl gas for 10 minutes at ℃. The reaction mixture was warmed to room temperature and bubbling with HCl gas was continued for 1 hour. The solvent was provided in vacuo and the residue was dissolved in 50 ml of water and neutralized by the addition of KOH pellets. The aqueous solution was extracted with 3 x 80 mL of dichloromethane and the combined organic extracts were dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 9: 1, dichloromethane: methanol + 1% isopropyl amine) to give 2.85 g (87.5% yield) of the desired product: ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.24 (s, 1H), 8.09 (d, 1H, J = 8.4 Hz), 7.71 (d, 1H, J = 8.0 Hz), 7.49 (t, 1H, J = 8.0 Hz), 6.35-6.25 (m , 1H), 3.58 (apparent q, 2H, J = 3.0 Hz), 3.14 (t, 2H, J = 5.6 Hz), 2.54-2.46 (m, 2H).
[602] Tert-Butyl 3- (4- (3-nitrophenyl) -3,6-dihydro-1 (2H) -pyridinyl) propylcarbamate:
[603] 2.80 g (14.0 mmol) of 1,2,3,6-tetrahydro-4- (3-nitrophenyl) pyridine in 250 ml of 1,4-dioxane, tert-butyl N- (3-bromopropyl) carb A mixture of 3.60 g (15.0 mmol) of bamate, 11.6 g (84.0 mmol) of K ₂ CO ₃ , 14.6 mL (84.0 mmol) of diisopropylethylamine and 0.78 g (2.00 mmol) of tetrabutylammonium iodide were refluxed Heat at temperature for 14 hours. The reaction mixture was filtered, the filtrate was dried (MgSO ₄ ), concentrated in vacuo and the residue was purified by column chromatography (silica, 9: 1, dichloromethane: methanol + 1% isopropyl amine) desired product 4.35 g (85.7% yield): ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.24 (t, 1H, J = 1.9 Hz), 8.09 (dd, 1H, J = 1.9, 8.0 Hz), 7.70 (obvious) d, 1H, J = 8.0 Hz), 7.49 (t, 1H, J = 8.0 Hz), 6.23 (m, 1H), 3.29-3.18 (m, 4H), 2.75 (t, 2H, J = 5.6 Hz), 2.64-2.54 (m, 1 H), 1.82-1.70 (m, 2 H), 1.44 (s, 9 H); ESMS m / e: 362.2 (M + H) ⁺
[604] 3- (4- (3-nitrophenyl) -3,6-dihydro-1 (2H) -pyridinyl) -1-propanamine:
[605] 4.35 g (12.0 mmol) tert-butyl3- (4- (3-nitrophenyl) -3,6-dihydro-1 (2H) -pyridinyl) propylcarbamate in 100 ml of 1,4-dioxane The stirred solution of was bubbled with HCl gas at 0 ° C. for 10 minutes. The reaction mixture was warmed to room temperature and bubbling continued for 1 hour. The solvent was removed in vacuo and the residue was dissolved in 50 mL of water and neutralized by addition of KOH pellets. The aqueous solution was extracted with 3 x 80 ml of dichloromethane, the combined organic extracts were dried (MgS0₄), Filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 9: 1, dichloromethane: methanol + 1% isopropyl amine) Provided 3.05 g (97.0% yield) of the desired product:^OneH NMR (400 MHz, CDCl₃) δ 8.24 (t, 1H, J = 1.8 Hz), 8.09 (dd, 1H, J = 1.8, 8.2 Hz), 7.69 (dd, 1H, J = 1.8, 8.2 Hz), 7.48 (t, 1H, J = 8.2 Hz), 6.24 (m, 1H), 3.21 (d, 2H, J = 3.6 Hz), 2.84 (t, 2H, J = 6.6 Hz), 2.75 (t, 2H, J = 5.8 Hz), 2.64- 2.54 (m, 4 H), 1.76 (m, 2 H); ESMS m / e: 262.2 (M + H)⁺; C₁₄H₁₉N₃0₂(0.06 CHCl₃), Calcd .: C, 62.90; H, 7. 16; N, 15.65.
[606] Found: C, 63.20; H, 7. 16; N, 15.65.
[607] Methyl (4S) -3-[({3- [4- (3-aminophenyl) -1-piperidinyl] propyl} amino) carbonyl] -4- (3,4-difluorophenyl) -6 -(Methoxymethyl) -2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate:
[608] 5-methyl 1- (4-nitrophenyl) (6S) -6- (3,4-difluorophenyl) -4- (methoxymethyl) -2-oxo-3 in 200 mL of dichloromethane (under argon) , 6-dihydro-1,5 (2H) -pyrimidinedicarboxylate 3.02 g (6.33 mmol), 3- (4- (3-nitrophenyl) -3,6-dihydro-1 (2H) -Pyridinyl) -1-propanamine 1.50 g (5.80 mmol), K₂CO₃A mixture of 7.94 g (75.5 mmol) and 1.00 mL of methanol was stirred at room temperature for 3 hours. The reaction mixture was filtered and concentrated in vacuo. The residue was dissolved in 100 ml of ethyl acetate and washed with 3 x 50 ml of NaOH 5% aqueous solution, the organic layer was dried (MgSO₄) Concentrated in vacuo. The residue was dissolved in 100 mL of absolute ethanol containing 0.50 g of 10% Pd / C and the reaction mixture was stirred for 24 h under a hydrogen balloon. The reaction mixture is passed through a column of Celite 545 filter, washed with ethanol, the filtrate is dried (MgSO₄) Concentrated in vacuo. The residue was purified by column chromatography (silica, 9.5: 0.5, dichloromethane: methanol + 1% isopropyl amine) to give 1.65 g (52.0% yield) of the desired product:^OneH NMR (400 MHz, CDCl₃) δ 7.80 (s, 1H), 7.22-7.02 (m, 2H), 6.95 (t, J = 8.70 Hz, 1H), 6.63-6.44 (m, 4H), 4.56 (Abq, 2H), 3.62 (s , 3H), 3.33 (s, 3H), 3.32-3.20 (m, 4H), 2.96 (br s, 2H), 2.33 (t, J = 7.50 Hz, 2H), 2.11-1.94 (m, 3H), 1.81 -1.64 (m, 4H); ESMS m / e: 572.3 (M + H)⁺;
[609] Tert-butyl-4- [3- (isobutyrylamino) phenyl] -3,6-dihydro-1 (2H) -pyridinecarboxylate:
[610] 4.00 g (16.0 mmol) of tert-butyl4- (3-aminophenyl) -3,6-dihydro-1 (2H) -pyridinecarboxylate in 100 ml of dichloromethane and 5.60 ml (32.0) of diisopropylethylamine 1.90 mL (19.0 mmol) of isobutyryl chloride was slowly added to the solution of mmol). The reaction mixture was stirred at rt for 2 h, washed with water, dried (MgSO₄), And concentrated in vacuo. The residue was purified by column chromatography (silica, 50: 46: 3: 1, Hexane: Dichloromethane: Methanol: Isopropyl amine) gave 2.90 g (52.0% yield) of the desired product:^OneH NMR (400 MHz, CDCl₃) δ 7.69 (s, 1 H), 7.34 (d, 1 H, J = 7.8 Hz), 7.27 (t, 1H, J = 7.8 Hz), 7.11 (d, 1H, J = 7.8 Hz), 6.04 ( s, 1H), 4.05 (s, 2H), 3.62 (apparent t, 2H, J = 4.9 Hz), 2.51 (m, 3H), 1.49 (s, 9H), 1.25 (d, 6H, J = 7.4 Hz ); ESMS m / e: 345.5 (M + H)⁺C₂₀H₂₈N₂0₃+0.175 CHCl₃Anal, calcd. C, 66.33; H, 7.77; N, 7.67.
[611] Found: C, 66.20; H, 7.41; N, 7.88
[612] Tert-Butyl 4- [3- (isobutyrylamino) phenyl] -1-piperidinecarboxylate:
[613] 2.90 g (8.40 mmol) of tert-butyl 4- [3- (isobutyrylamino) phenyl) -3,6-dihydro-1 (2H) -pyridinecarboxylate in 100 mL of ethanol and 10% yield Pd / A mixture of 0.80 g of C was stirred for 24 h under a hydrogen balloon. The reaction mixture is passed through a column of Celite 545 filter, the filtrate is dried (MgSO₄) Concentrated in vacuo. The residue was purified by column chromatography (silica, 9.5: 0.5, dichloromethane: Methanol + 1% isopropylamine) gave 2.40 g (84.0% yield) of the desired product:^OneH NMR (400 MHz, CDCl₃) δ 7.49-7.44 (m, 2H), 7.24 (t, 1H, J = 7.6 Hz), 6.93 (d, 1H, J = 7.6 Hz), 4.20-4.10 (m, 2H), 2.86-2.45 (m , 4H), 1.86-1.75 (m, 4H), 1.48 (s, 9H), 1.24 (d, 6H, J = 6.8 Hz); ESMS m / e: 345.2 (M + H)⁺; C₂₀H₃₀N₂0₃+ 0.3H₂Anal, calcd for 0: C, 68.27; H, 8. 77; N, 7.96.
[614] Found: C, 68.25; H, 8.54; N, 7.84.
[615] 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide:
[616] A stirred solution of tert-butyl 4- [3- (isobutyrylamino) phenyl] -1-piperidinecarboxylate in 100 mL of 1,4-dioxane was bubbled at 0 ° C. with HCl gas for 10 minutes. . The reaction mixture was warmed to room temperature and continued bubbling for 1 h with HCl gas. The solvent was removed in vacuo and the residue was dissolved in 50 mL of water and neutralized by addition of KOH pellets. The aqueous solution was extracted with 3 x 80 mL of dichloromethane, and the combined organic extracts were dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 9: 1, dichloromethane: methanol + 1% isopropyl amine) to give 0.700 g (46.0% yield) of the desired product: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.47 (s, 1H), 7.40 (d, 1H, J = 7.8 Hz), 7.24 (t, 1H, J = 7.8 Hz), 7.00 (d, 1H, J = 7.8 Hz), 3.23-3.14 (m , 5H), 2.82-2.57 (m, 4H), 1.20 (d, 6H, J = 6.8 Hz); ESMS m / e: 247.2 (M + H) ⁺ ; Hydrochloride was used for combustion analysis: C ₁₅ H ₂₂ N ₂ 0 + HCl + 0.15 CHCl ₃ Anal. Calcd: C, 60.51; H, 7.76; N, 9.32.
[617] Found: C, 60.57; H, 7.83; N, 8.88.
[618] 3- (4-piperidinyl) aniline:
[619] HCl 4M solution in dioxane (25 mL) was added to tert-butyl 4- [3- (amino) phenyl] -1-piperidinecarboxylate (2.60 g, 9.00 mmol) in dichloromethane (250 mL). It was. The reaction mixture was stirred at rt overnight, concentrated in vacuo and the residue dissolved in water (50 mL). The mixture was neutralized using KOH pellets and extracted with methylene chloride (3 x 50 mL). The combined organic extracts were dried (MgSO ₄ ), concentrated and chromatographed to give the desired product (1.03 g): ¹ H NMR (400 MHz, CDCl ₃ ) δ7.01 (t, 1H, J = 7.6 Hz) , 6.62-6.54 (m, 3H), 3.16 (br d, 2H, J = 10.3 Hz), 2.75 (dt, 2H, J = 2.7, 12.3 Hz), 2.56 (tt, 1H, J = 3.6, 12.3 Hz) , 1.81 (br d, 2H, J = 12.3 Hz), 1.65 (dq, 2H, J = 4.0, 12.3 Hz); ESMS m / e: 177.2 (M + H) ⁺
[620] Tert-butyl4- (4-Nitrophenyl) -3,6-dihydro-1 (2H) -pyridinecarboxylate:
[621] Tert-butyl4-{[(trifluoromethyl) sulfonyl] oxy} -3,6-dihydro-1 (2H) -pyridinecarboxylate (1.0 g), 4 in a 25 ml RB flask equipped with a condenser. Nitrophenylboronic acid (0.71 g), sodium carbonate (0.430 mL of 2 M solution), lithium chloride (0.382 g), tetrakis (triphenylphosphine) -palladium (0) (0.173 g) and ethylene glycol dimethyl ether (10 Ml) was added. The reaction mixture was washed three times with argon, after which the reaction mixture was heated to 100 ° C. for 3 hours. After cooling to room temperature, the reaction mixture was diluted with methylene chloride (30 mL) and water (30 mL) and the organic layer was separated. The aqueous layer was extracted with methylene chloride (3 × 20 mL) and the combined organic extracts were washed with saturated NH ₄ Cl (20 mL), brine (20 mL), dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by chromatography (6: 1 = hexanes: NH ₃ 1% ethyl acetate) to give the product (0.55 g, 59.9%) as a yellow oil. The compound is not stable at room temperature and is therefore effective for immediate use: ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.20 (d, 2H, J = 8.6 Hz), 7.51 (d, 2H, J = 8.6 Hz), 6.24 (m, 1H), 4.13 (m, 2H), 3.67 (apparent t, 2H, J = 5.5 Hz), 2.55 (m, 2H), 1.49 (s, 9H).
[622] 4- (4-nitrophenyl) -1,2,3,6-tetrahydropyridine:
[623] 4- (4-nitrophenyl) -1,2,3,6-tetrahydropyridine was reacted with HCl gas in dioxane (5.0 mL) and tert-butyl 4- (4-nitrophenyl) -3,6-di Prepared by a procedure similar to the procedure used to prepare 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide using hydro-1 (2H) -pyridinecarboxylate (130 mg). . The reaction mixture was concentrated in vacuo to afford crude product (69.8 mg), which was used in the next reaction without further purification.
[624] Oxazolidinone Intermediates:
[625] Amino- (3,4-difluorophenyl) -acetonitrile:
[626] A solution of 3,4-difluorobenzaldehyde (25.0 g, 0.176 mol) in MeOH (500 mL) in a round bottom flask was bubbled with ammonia gas at room temperature for 2 hours. The flask was then cooled to 0 ° C., after which trimethylsilylcyanide was added slowly. The reaction mixture was stirred for 2 hours, at which time TLC analysis indicated the reaction was complete (R _f = 0.35, 3: 2 hexanes / EtOAc). The solvent was removed in vacuo and the residue was flash column chromatography on silica gel to give the desired product which was used for next step without purification.
[627] Amino- (3,4-diruflophenyl) -acetic acid methyl ester:
[628] To a well-stirred solution of amino- (3,4-difluorophenyl) -acetonitrile (22.0 g, 0.130 mol), a solution of HCl in MeOH (200 mL) was added at room temperature. The resulting yellow solution was stirred at room temperature for 10 hours and heated at reflux for 1.5 hours. After cooling, the solvent was removed in vacuo and the resulting yellow solid was dissolved in water (200 mL). The aqueous solution was basified to pH 9 with NaOH 20% solution. The aqueous layer was extracted with CH ₂ Cl ₂ (3 × 100 mL). The organic layer was separated, dried over Na ₂ SO ₄ and filtered to remove the solvent in vacuo to afford the desired product, which was used in the next step without purification.
[629] 2-Amino-2- (3, 4-difluorophenyl) -ethanol:
[630] To a well-stirred LiAlH ₄ (4.7 g, 0.125 mol) suspension in THF (120 mL) in a three-neck round bottom flask equipped with a condenser and a dropping funnel, amino- (3,4-difluoro in THF (100 mL) Phenyl) -acetic acid methyl ester (10.0 g, 0.05 mmol) solution was added dropwise at 0 ° C. The resulting greenish brown suspension was heated at reflux for 2 hours. The reaction mixture was cooled to 0 ° C. and then quenched sequentially with 5 ml of water, 5 ml of 3N NaOH and 15 ml of water. The resulting suspension was filtered through a fritted glass funnel. 100 ml of Et ₂ 0 was added to the filter cake and the suspension was heated at reflux for 20 minutes. The suspension was filtered and the combined filtrates were dried over MgSO ₄ , filtered and the solvent removed in vacuo. 2-amino-2- (3,4-difluorophenyl) -ethanol was obtained as a yellow glassy syrup, which was used without further purification in the next step.
[631] [l- (3,4-Difluorophenyl) -2-hydroxy-ethyl] -carbamic acid-tert-butyl ester:
[632] CHCl ₃ (150 ㎖) 2- amino-2- (3,4-difluorophenyl) in ethanol (8.6 g, 49.7 m㏖) di -tert- butyl digital camera in CHCl ₃ (50 ㎖) carbonate To a solution Viterbo A portion of (11.4 g, 52.0 mmol) solution was added at 0 ° C. and the resulting solution was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was column chromatographed on silica gel (2: 1 hexanes-EtOAc, then EtOAc) [1- (3,4-difluorophenyl) -2-hydroxy-ethyl]- Carbamic acid-tert-butyl ester was obtained as a white solid (10.0 g, 74% yield).
[633] (+)-4- (3,4-difluorophenyl) -oxazolidin-2-one:
[634] To a well stirred suspension of NaH (1.1 g, 45.8 mmol) in THF (40 mL) was [1- (3,5-difluorophenyl) -2-hydroxy-ethyl] -carrha in THF (20 mL). A solution of cinnamic acid-tert-butylester (5.0 g, 18.3 mmol) was added via dropping funnel at room temperature. The resulting suspension was stirred for 3 hours and carefully quenched with 10 ml of water. The ideal mixture was extracted with 100 mL Et ₂ 0, washed with brine, filtered and the solvent removed in vacuo. The sticky residue thus obtained was subjected to column chromatography purification with silica gel (R _f = 0.15, 3: 2 hexane-EtOAc) to give 4- (3,5-difluorophenyl) -oxazolidin-2-one as white. Obtained as a flaky solid of (2.8 g, 77% yield). Melting point: 81-83 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) 67.23-7.03 (m, 3H), 6.08 (br s, 1H), 4.94 (dd, J = 6.6 Hz, J = 8.7 Hz, 1H), 4.73 (t , J = 8.7 Hz, 1H), 4.13 (dd, J = 6.6 Hz, J = 8.7 Hz, 1H). The enantiomers were separated by HPLC on a Chiralcel OD (20 x 250 mm) column using 80% hexanes / 20% isopropyl alcohol at 12.0 mL / min (254 nm) as the elution system. The retention times for both isomers were 16.19 and 20.08 minutes, respectively.
[635] 4-nitrophenyl (4S) -4- (3,4-difluorophenyl) -2-oxo-l, 3-oxazolidine-3-carboxylate:
[636] To a suspension of NaH (0.14 g, 5.30 mmol) in 20 ml of dry THF under argon gas, (+)-4- (3,4-difluorophenyl) -oxazolidin-2-one (0.88 g, 4.42 mmol) was added dropwise (dropping funnel). The resulting suspension was stirred at rt for 30 min. This suspension was then added via cannula to another round bottom flask containing a solution of 4-nitrophenylchloroformate (1.11 g, 5.30 mmol) in 25 ml THF and cooled to −78 ° C. for 15 minutes. . After removing the solvent, stirring was continued for 2 hours and the residue was purified by column chromatography on silica gel (1: 1 hexanes / CH ₂ Cl ₂ , then CH ₂ Cl ₂ ) (R _f = 0.4, CH ₂ Cl ₂ ) The desired product was obtained as a white solid (1.55 g, 86% yield).
[637] Similarly, according to the above procedure, in the first step, 4- (3,5) by substituting 3,4-difluorobenzaldehyde or 3,4,5-trifluorobenzaldehyde for 3,5-difluorobenzaldehyde, respectively -Difluorophenyl) -2-oxo-oxazolidine-3-carboxylic acid-4-nitro-phenyl ester and 4- (3,4,5-trifluorophenyl) -2-oxo-oxazolidine 3-carboxylic acid-4-nitro-phenyl ester was obtained. Oxazolidinone enantiomers were resolved by HPLC on a chiralcel OD column (as in the previous example) and 4-nitro-phenyl carbamate was prepared using 4-nitrophenylchloroformate.
[638] 4-nitrophenyl (4S) -4- (3,5-difluorophenyl) -2-oxo-1,3-oxazolidine-3-carboxylate:
[639] According to the synthesis procedure of 4- (3,4-difluorophenyl) -2-oxo-oxazolidine-3-carboxylic acid-4-nitro-phenyl ester, 3,5-difluorobenzaldehyde is the desired The product was calculated.
[640] ¹ H NMR (400 MHz, CDCl ₃ ) δ8.26 (d, 2H, J = 9.3 Hz), 7.33-6.81 (m, 5H), 5.41 (dd, 1H, J = 4.1, 8.7 Hz), 4.81 (t , 1H, J = 9.3 Hz), 4.33 (dd, 1H, J = 4.1, 9.3 Hz); Anal, Calcd for C ₁₆ H ₁₀ F ₂ N ₂ 0 ₆ + 0.2EtOAc: C, 52.84; H, 3.06; N, 7.34.
[641] Found: C, 53.26; H, 2.83; N, 7.73
[642] 4-nitrophenyl (4S) -2-oxo-4- (3,4,5-trifluorophenyl) -1,3-oxazolidine-3-carboxylate:
[643] According to the synthesis procedure of 4- (3,4-difluorophenyl) -2-oxo-oxazolidine-3-carboxylic acid-4-nitro-phenyl ester, 3,4,5-trifluorobenzaldehyde The desired product was calculated.
[644] ¹ H NMR (400 MHz, CDCl ₃ ) δ8.27 (d, 2H, J = 9.0 Hz), 7.31 (d, 2H, J = 9.0 Hz), 7.11-7.02 (m, 2H), 5.37 (dd, 1H , J = 4.1, 9.0 Hz), 4.81 (apparent t, 1H, J = 9.0 Hz), 4.33 (dd, 1H, J = 4.1, 9.0 Hz); Analysis for C ₁₆ H ₉ F ₃ N ₂ 0 ₆ , calcd. C, 50.27; H, 2. 37; N, 7.33.
[645] Found: C, 50.56; H, 2.50; N, 7.49.
[646] 1- (3,4-difluorophenyl) -2-methyl-2-hydroxypropylamine:
[647] To a well stirred solution of methyl 2-amino-2- (3,4-difluorophenyl) acetate (10.5 g, 52.19 mmol) in anhydrous ether (200 mL) methylmagnesium bromide (3 M, 87 mL in ether) , 261 mmol) was added at 0 ° C. over a period of 10 minutes. The reaction mixture was stirred at 0 ° C. for 2.5 h and warmed up to room temperature. After 12 hours, the reaction mixture was carefully poured into a mixture of ice (300 g) and saturated aqueous ammonium chloride (50 g). The ether layer was separated and the aqueous layer was extracted with more ether (4 x 200 mL). The combined extracts were dried over magnesium sulfate and the solvent was evaporated. The crude product was purified by column chromatography on silica gel using chloroform / methanol / 2M ammonia (1000: 20: 10, 1000: 40: 20, 1000: 80: 40) in methanol as eluent to afford the product as an oil. (6.5 g, 62% yield), which was used without further purification in the next step.
[648] 4- (3,4-Difluorophenyl) -5,5-dimethyl-2-oxo-oxazolidine:
[649] 1- (3,4-difluorophenyl) -2-methyl-2-hydroxypropylamine (3.00 g, 14.9 mmol) and carbonylimidazole (2.418 g, 14.9 m) in dichloromethane (150 mL) Mol)) was heated at reflux for 36 h and the solvent was evaporated. The residue was purified by column chromatography on silica gel using chloroform / ethyl acetate (9: 1) to give the product as a viscous oil, which solidified to stand (1.80 g, 50% yield) . The product was used in the next step without further characterization.
[650] 4-nitrophenyl 4- (3,4-difluorophenyl) -5,5-dimethyl-2-oxo-1,3-oxazolidine-3-carboxylate:
[651] To a stirred suspension of sodium hydride (60% suspension in paraffin 203 mg, 1.4 equiv) in THF (20 mL) 4- (3,4-difluorophenyl) -5,5-dimethyl-2 in THF (5 mL) An oxo-oxazolidine (870 mg, 3.622 mmol) solution was added at 0 ° C. and then stirred for 30 minutes. This suspension was added to a solution of 4-nitrophenyl chloroformate (950 mg, 4.71 mmol) in THF (20 mL) under argon gas and stirring was continued for 2 hours. It was slowly warmed up to room temperature and after 4 hours the solvent was evaporated. The residue was mixed with dichloromethane (150 mL), washed with 0.05 N sodium hydroxide (3 x 10 mL) and dried (sodium sulfate). The solvent was evaporated and the residue was purified by column chromatography on silica gel using chloroform / ethyl acetate (9: 1) as eluent to give the product as a white powder (860 mg, 59% yield).
[652] ¹ H NMR (400 MHz, CDC1 ₃ ) δ 8.24 (d, 2H, J = 9 Hz), 7.29-6.97 (m, 5H), 5.04 (s, 1H), 1.09 (s, 6H); C ₁₈ H ₁₄ F ₂ N ₂ 0 ₆ +0.2% Anal. Calcd. For H ₂ 0: C, 54.61; H, 3.67; N, 7.08.
[653] Found: C, 54.89; H, 3.59; N, 7.41.
[654] (3,4-difluorophenyl) -N (diphenylmethylene) methanamine:
[655] To a solution of 3,4-difluorobenzylamine (9.8 g, 69 mmol) and benzophenone (13.0 g, 71.0 mmol) in toluene (200 mL) was added a catalytic amount of BF ₃ .OEt ₂ and the resulting solution. Was heated at reflux for 12 h. The reaction mixture was concentrated in vacuo to yield an oil (21 g,> 95%), which was characterized by NMR analysis and used for the following reaction without further purification. ¹ H NMR (CDCl ₃ ) δ 4.57 (s, 2H), 7.80-6.80 (m, 13H).
[656] 1- (3,4-difluorophenyl) -1-[(diphenylmethylene) amino] propan-2-ol:
[657] To a solution of benzhydrylindene- (3,4-difluoro-benzyl) -amine (21 g, 69 mmol) in 250 ml of dry THF was added dropwise tert-butyllinium (1.7 M, 60 ml). The solution was stirred at -78 ° C for 0.5 h. Acetaldehyde (10 mL, 180 mmol) in 100 mL of THF was added to the solution and the solution was stirred at −78 ° C. for 2 hours and at 25 ° C. for 1 hour. The reaction mixture was quenched by addition of brine. The reaction mixture was diluted with 500 mL Et ₂ 0 and washed with brine. The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo to afford an oil, which was used without further purification in the next step.
[658] ¹ H NMR (CDCl ₃ ) δ1.04 (d, 3H), 2.77 (wide s, 1H), 4.08 (m, 1H), 4.15 (d, 1H), 7.80-6.80 (m, 13H)
[659] 1-amino-1- (3,4-difluoro-phenyl) -propan-2-ol:
[660] The crude product obtained in the previous procedure and a solution of MeONH ₂ .HCl (10 g, 120 mmol) were diluted with 200 mL of MeOH and stirred for 12 h. The reaction mixture was concentrated in vacuo to yield an oily residue, which was redissolved in 200 mL of EtOAc and washed with brine. The organic layer was concentrated in vacuo to give an oily mixture which was column chromatographed [5% NH _{3 in} CHCl ₃ (in MeOH 2.0 M)] to give the desired product as diastereomer (8.8 g, 3,4). 68% yield from difluorobenzylamine).
[661] ^OneH NMR (CDCl₃) (4: 1 mixture of diastereomers) δ1.02 (d, J = 6.0 Hz, 3H), 1.04 (d, J = 6.3 Hz, 3H), 2.10 (br, 6H), 3.56- 3.69 (m, 2H), 3.88-3.92 (m, 2
[662] H), 7.02-7.17 (m, 6H).
[663] [1- (3,4-Difluorophenyl) -2-hydroxy-propyl] -carbamic acid-Tert-butylester:
[664] CHCl₃CHCl at 0 ° C. in a solution of l-amino-1- (3,4-difluorophenyl) -propan-2-ol (13.1 g, 70.1 mmol) in (150 mL)₃A portion of di-tert-butyl dicarbonate (19.3 g, 87.6 mmol) solution in (50 mL) was added and the resulting solution was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was column chromatographed on silica gel (2: 1 hexanes-EtOAc, then EtOAc) to [l- (3,4-difluorophenyl) -2-hydroxy-propyl]- Carbamic acid-tert-butyl ester was obtained as a viscous oil (18.4 g, 91% yield).^OneH NMR (CDCl₃) (4: 1 mixture of diastereomers) δ1.05 (d, J = 6.6 Hz, 3H), 1.25 (d, J = 6.0 Hz, 3H), 1.41 (br, 20H), 3.92- 4.19 (br, 2H), 4.45-4.60 (m, 2H), 5.41-5.49 (br, 2H), 7.02-7.17 (m, 6H).
[665] 4- (3,4-Difluorophenyl) -5-methyl-oxazolidin-2-one:
[666] NaH 95 in a well stirred solution of [1- (3,4-difluorophenyl) -2-hydroxy-propyl] carbamic acid-tert-butyl ester (0.43 g, 1.5 mmol) in THF (20 mL). % (0.09 g, 3.8 mmol) was added at room temperature. If the reaction was carried out on a larger scale (> 5 g), 1.0 equivalent of KH and 1.5 equivalents of NaH were used as the base. The resulting suspension was stirred at about 35 ° C. for 3 hours (warm water bath) and then carefully quenched with ice. The biphasic mixture was extracted with 100 mL of EtOAc, washed with brine, dried over Na ₂ SO ₄ , filtered and the solvent was removed in vacuo. Two diastereomers were subjected to column chromatography on silica gel (first isomer: 0.16 g, R _f = 0.6, 3: 1 hexane-EtOAc; second isomer: 0.18 g, R _f = 0.5, 3: 1 hexane-EtOAc Separated by). NOE experiments suggest that the first diastereomer has a trans configuration of methyl and aryl groups while the second diastereomer has a cis relationship between the two groups. The ¹ H NMR spectrum for the trans diastereomer is as follows. ¹ H (CDCl ₃ ) δ 1.49 (d, J = 6.0 Hz, 3H), 4.37 (dq, J = 6.0 Hz, J = 7.2 Hz, 1H), 4.45 (d, J = 7.2 Hz, 1H), 6.63 (br s, 1 H), 7.08-7.28 (m, 3 H).
[667] The ¹ H NMR spectrum for the cis diastereomer is as follows. ¹ H (CDCl ₃ ) δ 0.96 (d, J = 6.6 Hz, 3H), 4.91 (d, J = 8.1 Hz, 1H), 4.99 (dq, J = 6.6 Hz, J = 8.1 Hz, 1H), 6.63 (br s, 1 H), 7.08-7.28 (m, 3 H).
[668] 4- (3,4-Difluorophenyl) -5-methyl-2-oxo-oxazolidine-3-carboxylic acid-4-nitro-phenyl ester
[669] Hexane (3.06 m) in a solution of one of the two diastereomers of 4- (3,4-difluorophenyl) -5-methyl-oxazolidin-2-one (0.97 g, 4.55 mmol) in 60 mL of THF. Mol, 4.9 mmol) was added dropwise with a syringe under an argon atmosphere at -78 ° C. The resulting yellow solution was stirred at −78 ° C. for 40 minutes. This solution was then added dropwise via cannula to another round bottom flask containing a solution of 4-nitrophenylchloroformate (1.03 g, 5.1 mmol) in 60 mL of THF and over a period of 15 minutes at −78 ° C. Cooled to. After 5 minutes, the flask was removed from the cold bath and stirring continued for 1 hour. The reaction mixture was quenched by addition of ice and extracted with EtOAc. The organic extract was washed with brine and the organic layer was dried over Na ₂ SO ₄ . After filtration the solvent was removed and the residue was purified by column chromatography on silica (1: 1 hexanes / CH ₂ Cl ₂ , then CH ₂ Cl ₂ ) to give the desired product.
[670] Relative arrangements of cis and trans isomers were assigned based on ¹ H NMR analysis of the respective p-nitrophenyloxycarbonyl derivatives. For the trans isomer, NOE was observed between the protons of the C-5 methyl group and the protons of C-4. No NOE was observed between the C-5 methyl group and the C-4 proton for the cis isomer. However, NOE was observed between protons at the C-4 and C-5 positions, which allowed us to assign this isomer to cis stereochemistry. Coupling constants of C-4 protons of cis (J = 7.8 Hz) and trans (J = 5.1 Hz) are also consistent with the values reported for similar oxazolidinones and are also useful for stereochemical assignments (Dondoni). , A .; Perrone, D .; Semola, T. Synthesis. 1995, 181).
[671] Enantiomers of diastereomers were subjected to isocratic conditions (UV 254) by HPLC using a Chiralcel OD column with 80% hexanes / 20% isopropyl alcohol / 0.1% diethylamine as the elution system (12 mL / min). Nm).
[672] In order to assign absolute arrangements to the stereogenic centers of oxazolidinone rings, new synthetic routes have been devised using enantiomerically pure substrates derived from chiral grasses. Commercially available (S)-(+)-methyl lactates are described by Martin et al. (Martin, R .; Pascual., 0 .; Romea, P .; Rovira, R .; Urpi, F .; Vilarrasa, J. Tetrahedron Lett And its pyrrolidine amides according to 1997, 38, 1633). Tert-butyl (dimethyl) silyl (1S) -1-methyl-2-oxo- as protected by the hydroxyl group of (2S) -1-oxo-1- (1-pyrrolidinyl) -2-propanol against TBDMS groups Treating 2- (1-pyrrolidinyl) ethyl ether with 3,4-difluorophenyllithium to give (2S) -2-{[tert-butyl (dimethyl) silyl] oxy} -1- (3,4- Difluorophenyl) -1-propanone was obtained as a single product, which was then (2S) -2- {tert-butyl (dimethyl) silyl] oxy} -1- (3,4-difluorophenyl ) -1-propanone oxime. (2S) -2- {tert-butyl (dimethyl) silyl] oxy} -1- (3,4-difluorophenyl) -1-propanone oxime is reduced with LiA1H ₄ to induce N-acylation and base induction Cyclization provided oxazolidinone diastereomers, which were separated by flash column chromatography. The purity of these isomers as enantiomers was confirmed by chiral HPLC analysis, and their absolute arrangements were assigned by comparing their racemic isomers with their ¹ H NMR spectra. Regarding the absolute configuration at C-5 of the lactic acid-derived oxazolidinones described above, the C-4 centers in the trans compounds have a (S) configuration. Thus, the absolute arrangements for the stereogenic centers in the cis compounds are appropriately assigned to (4R, 5S).
[673] 4-nitrophenyl (4S, 5R) -4- (3,4-difluorophenyl) -5-methyl-2-oxo-1,3-oxazolidine-3-carboxylate:
[674] ¹ H NMR (400 MHz, CDCl ₃ ) δ8.25 (d, 2H, J = 8.8 Hz), 7.30-6.99 (m, 5H), 5.35 (d, 1H, J. = 7.7 Hz), 5.07 (apparent OH Midline, 1H), 1.17 (d, 3H, J = 6.5 Hz); Anal, Calcd for C ₁₇ H ₁₂ F ₂ N ₂ 0 ₆ + 0.5H ₂ 0, C, 52.72; H, 3.38; N, 7.23.
[675] Found: C, 53.09; H, 3. 19; N, 7.50.
[676] (+)-2-Amino-3- (3,4-difluoro) -phenyl-propan-1-ol:
[677] 3,4-Difluorophenylalanine (1.0 g, 5.0 mmol) was added in portions to a stirred suspension of LiAlH ₄ (0.480 g, 12.5 mmol) in THF (30 mL) at 0 ° C. The resulting gray suspension was then heated at reflux for 2 hours. The reaction mixture was cooled to 0 ° C. and carefully quenched in the order of water (0.5 mL), 3 N NaOH (0.5 mL), and water (1.50 mL). The resulting suspension was filtered through a fritted glass funnel. Ether (50 mL) was added to the filter cake and the suspension was heated at reflux for 20 minutes.
[678] The suspension was filtered and combined with the previous filtrate. The combined organics were dried over MgSO ₄ , filtered and the solvent removed in vacuo. 2-Amino-3- (3,4-difluoro) -phenyl-propan-1-ol was obtained as a white solid (0.500 g, 100%), which was used without further purification in the next step.
[679] (+)-[1- (3,4-Difluorobenzyl) -2-hydroxy-ethyl] -carbamic acid-Tert-butyl ester:
[680] CHCl ₃ (10 ㎖) in di -tert- butyl dicarbonate (0.640 g, 2.90 m㏖) portion of CHCl ₃ (20 ㎖) in the (+) of a solution of - 2-amino-3- (3,4 To the solution of difluoro) -phenyl-propan-1-ol (0.500 g, 2.62 mmol) was added at 0 ° C. and the resulting solution was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was chromatographed (2: 1 hexanes-EtOAc, then EtOAc), (+)-[1- (3,4-difluorobenzyl) -2-hydroxy-ethyl] -Carbamic acid-tert-butyl] ester was provided as a white solid (0.640 g, 99%).
[681] (+)-4- (3,4-difluoro-benzyl) -oxazolidin-2-one:
[682] A solution of (+)-[1- (3,4-difluorobenzyl) -2-hydroxy-ethyl] -carbamic acid-tert-butyl ester (1.00 g, 4.00 mmol) in THF (10 mL) was prepared. At room temperature was added to a stirred suspension of 95% NaH (0.12 g, 5.0 mmol) in THF (20 mL) via a dropping funnel. The resulting suspension was stirred for 3 hours and then quenched carefully with water (10 mL). The ideal mixture was extracted with Et ₂ 0 (50 mL), washed with brine, filtered and the solvent removed in vacuo. The resulting sticky residue was purified by column chromatography (R _f = 0.25, 3: 2 hexanes-EtOAc) to afford the desired product as a white solid (0.320 g, 76%).
[683] (+)-4- (3,4-difluoro-benzyl) -oxazolidin-2-one-3-carboxylic acid-4-nitro-phenyl ester:
[684] A solution of (+)-4- (3,4-difluoro-benzyl) -oxazolidin-2-one (0.210 g, 1.0 mmol) in THF (10 mL) was added dropwise through anhydrous THF (10 ML) was added dropwise under argon gas to a stirred suspension of NaH (30.0 mg. 1.30 mmol). The resulting suspension was stirred for 30 minutes at room temperature. This suspension was then added dropwise via cannula to a solution of 4-nitrophenylchloroformate (0.300 g, 1.50 mmol) in THF (20 mL) at −78 ° C. over 15 minutes. After removing the solvent, stirring was continued for 2 hours and the residue was purified by column chromatography (1: 1 hexanes / CH ₂ Cl ₂ , then CH ₂ Cl ₂ ; R _f = 0.4, CH ₂ Cl ₂ ) to give the desired product. Was obtained as a yellow solid (0.350 g, 82%)
[685] Similarly, according to the above procedure, 4-nitrophenyl-4- (4-fluorobenzyl) -2-oxo- by replacing (+)-3,4-difluorophenyl alanine with p-fluorophenyl alanine. 1,3-oxazolidine-3-carboxylate was obtained.
[686] 4-nitrophenyl 4- (4-fluorobenzyl) -2-oxo-l, 3-oxazolidine-3-carboxylate:
[687] ¹ H NMR (400 MHz, CDCl ₃ ) δ8.32 (d, 2H, J = 9.3 Hz), 7.42 (d, 2H, J = 8.9 Hz), 7.24-6.99 (m, 4H), 4.69-4.59 (m , 1H), 4.35 (t, 1H, J = 8.6 Hz), 4.23 (dd, 1H, J = 2.7, 9.3 Hz), 3.37 (dd, 1H, J = 3.8, 13.6 Hz), 2.94 (dd, 1H, J = 9.3, 13.6 Hz); Anal, Calcd for C ₁₇ H ₁₃ FN ₂ 0 ₆ : C, 56.67; H, 3. 64; N, 7.77.
[688] Found: C, 56.94; H, 3.76; N, 7.71.
[689] 2- [6- (4-phenyl-1-piperidinyl) hexyl] -1 H-isoindole-1,3 (2H) -dione:
[690] 4-phenylpiperidine hydrochloric acid (5 g, 25 mmol), N- (6-bromohexyl) phthalimide (15.5 g, 50 mmol), N, N-diisopropyl in 500 ml round bottom flask Ethylamine (21.8 mL, 125 mmol), tetrabutylammonium iodide (0.2 g) and dioxane (250 mL) were added at room temperature. The reaction mixture was stirred at 100 ° C. for 72 hours. The solvent is removed in vacuo and the crude product is subjected to flash chromatography (98: 2 = chloroform: Purification with ammonia 2N in methanol) gave 7.67 g of the desired product (77% yield):^OneH NMR (400 MHz, CDCl₃) δ7.78-7.79 (m,2H), 7.74-7.65 (m, 2H), 7.32-7.14 (m, 5H), 3.69 (t, 2H, J = 7.35 Hz), 3.06 (d, 2H, J = 11.0 Hz), 2.49 (quintet, 1H, J = 7.6 Hz), 2.36 (t, 2H, J = 7.6 Hz), 2.02 (t, 2H, J = 12.5 Hz), 1.82 (br s, 4H), 1.69 (t, 2H, J = 6.3 Hz ), 1.54 (br s, 2H), 1.37 (br s, 4H); ESMS m / e: 391.3 (M + H)⁺ ;C₂₅H₃₀N₂0₂+ 0.2H₂Anal, calcd for 0: C, 76.19; H, 7.77; N, 7.11.
[691] Found: C, 76.14; H, 7. 38; N, 7.13.
[692] Method I. General preparation procedure of substituted 4- [4- (3-aminophenyl) -1-piperidinyl] -1- (phenyl) -1-butanone:
[693] 4- (3-aminophenyl) piperidine (2.0 mmol) in 5 ml of toluene, 2.4 mmol of appropriately substituted phenyl butyryl chloride (eg 4-chloro-4-phenoxybutylophenone, 4- Chloro-3 ', 4'-dimethylbutyrophenone, 4-chloro-4'-chlorobutyrophenone, γ-chlorobutyrophenone, 4-chloro-3', 4'-dimethoxybutyrophenone), K A mixture of ₂ CO ₃ 3.0 mmol and 18-crown-6 10 mg was heated at 110 ° C. for 2.5 days. The reaction mixture was concentrated and chromatographed on silica (5% methanol in dichloromethane) to afford the desired compound:
[694] 4- [4- (3-aminophenyl) -1-piperidinyl] -1- (4-phenoxyphenyl) -1-butanone:
[695] Using method I, the desired product was obtained. 305 mg; ESMS m / e: 415.4 (M + H) ⁺
[696] 4- [4- (3-aminophenyl) -1-piperidinyl] -1- (3,4-dimethylphenyl) -1-butanone:
[697] Using method I, the desired product was obtained. 320 mg; ESMS m / e: 351.3 (M + H) ⁺
[698] 4- [4- (3-aminophenyl) -1-piperidinyl] -1- (4-chlorophenyl) -1 - butanone:
[699] Using method I, the desired product was obtained. 500 mg; Anal, Calcd for C ₂₁ H ₂₅ ClN ₂ 0 + 0.3H ₂ 0: C, 69.62; H, 7. 12; N, 7.73.
[700] Found: C, 69.63; 11, 7.34; N, 7.60; ESMS m / e: 357.3 (M + H) ⁺
[701] 4- [4- (3-aminophenyl) -1-piperidinyl] -1-phenyl-1-butanone:
[702] Using method I, the desired product was obtained. 250 mg; Anal, Calcd for C ₂₁ H ₂₆ N ₂ 0 + 0.2H ₂ 0: C, 77.36; H, 8. 16; N, 8.59.
[703] Found: C, 77.55; H, 8.12; N, 8.75; ESMS m / e: 323.3 (M + H) ⁺
[704] 4- [4- (3-aminophenyl) -1-piperidinyl] -1- (2,4-dimethoxyphenyl) -l-butanone:
[705] Using Method 1, the desired product was obtained. 330 mg; Anal, Calcd for C ₂₃ H ₃₀ N ₂ 0 ₃ + 0.5H ₂ 0: C, 70.56; H, 7.98; N, 7.16.
[706] Found: C, 70.69; H, 7.87; N, 6.99; ESMS m / e: 383.3 (M + H) ⁺
[707] Method II. General acylation or sulfonylation procedure of substituted 4- (4- (3-aminophenyl) -1-piperidinyl] -l- (4-phenyl) -1-butanone:
[708] 1 equivalent of substituted 4- [4- (3-aminophenyl) -1-piperidinyl] -1- (4-phenyl) -1-butanone in dichloromethane, 1.5 equivalents of acid chloride or sulfonyl chloride, and di A mixture of 5 equivalents of isopropylethylamine was stirred at room temperature for 2 days. The reaction mixture was applied to a prepared TLC plate and eluted with dichloromethane: methanol (containing 15: 1, 1% isopropyl amine) to give the desired product.
[709] Method III. General preparation procedure of substituted 4-N- (3- {l- [4- (phenyl) -4-oxobutyl] -4-piperidinyl} phenyl) acetamide:
[710] N- [3- (4-piperidinyl) phenyl] acetamide (1.0 equiv) in dioxane (0.5-1.0 M) with aryl substituted chlorobutyrophenone (2.0 equiv), K ₂ CO ₃ (5.0 equiv) , A mixture of diisopropylethylamine (3.0 equiv) and tetrabutylammonium iodide (cat. 5-10%) was heated at reflux for 16 h. The reaction mixture was filtered and concentrated in vacuo. The crude product was chromatographed using silica prepared TLC (chloroform: methanol containing 0.5% isopropyl amine) to give the desired product.
[711] Example 1
[712] N- (3- {l- [4- (3,4-dimethylphenyl) -4-oxobutyl] -4-piperidinyl} phenyl) acetamide:
[713] Using method III, the desired product was obtained.^OneH NMR (CDC1₃) δ7.75 (s, 1H), 7.71 (d, 1H, J = 7.6 Hz), 7.45 (d, 2H, J = 7.2 Hz), 7.35 (s, 1H), 7.26-7.22 (m, 2H), 6.93 (d, 1H, J = 7.6 Hz), 3.24-3.21 (m, 2H), 3.04 (t, 2H, J = 7.0 Hz), 2.67-2.63 (m,2H), 2.59-2.48 (m, 1H), 2.32 (s, 6H), 2.30-2.27 (m,2H), 2.18 (s, 3H), 2.14-2.06 (m,2H), 2.00-1.80 (m, 4H); ESMS m / e: 393.3 (M + H)⁺
[714] Example 2
[715] N- (3- {l- [4- (3,4-dimethylphenyl) -4-oxobutyl] -4-piperidinyl} phenyl) -2-methylpropanamide:
[716] 0.0500 g (0.200 mmol) of 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide in 5 ml of DMF, 0.100 g (0.480) of 4-chloro-3 ', 4'-dimethylbutyrophenone mmol), K₂C0₃A mixture of 0.080 g (0.600 mmol) and 0.090 g (0.600 mmol) NaI was heated at reflux for 18 hours. The reaction mixture was filtered, the filtrate was poured into 5 ml of water and washed with 3 x 5 ml of ethyl acetate. Dry the combined organic extracts (MgSO₄), TLC prepared by concentrating in vacuo (silica; 9.5: 0.5, dichloromethane: methanol + Purification with 1% isopropyl amine) gave 0.067 g (80.0% yield) of the desired product:^OneH NMR (400 MHz, CDC1₃) δ 7.72 (d, 1H, J = 8.0 Hz), 7.44 (s, 1H), 7.38 (d, 1H, J = 8.0 Hz), 7.23-7.20 (m,2H), 7.16 (s, 1H), 6.95 (s, 1H, J = 6.8 Hz), 3.13-3.11 (m,2H), 3.02 (t, 2H, J = 7.0 Hz), 2.56-2.40 (m, 4H), 2.32 (s, 6H), 2.17-2.15 (m,2H), 2.04-1.78 (m, 6H), 1.25 (d, 6H, J = 6.8 Hz); ESMS m / e: 421.3 (M + H)⁺
[717] Example 3
[718] N- (3- {l- [4- (3,4-dimethylphenyl) -4-oxobutyl] -4-piperidinyl} phenyl) cyclohexanecarboxamide:
[719] Using Method II, the desired product was obtained. ¹ H NMR (400 MHz, CDC1 ₃ ) δ 7.80-6.81 (m, 7H), 3.41-3.00 (m, 4H), 2.95-2.41 (m, 4H), 2.32 (s, 6H), 2.22-1.05 ( m, 18 H); ESMS m / e: 461.4 (M + H) ⁺
[720] Example 4
[721] N- (3- {1- (4- (3,4-dimethylphenyl) -4-oxobutyl] -4-piperidinyl} phenyl) -2phenylacetamide:
[722] Using Method II, the desired product was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.85-7.65 (m, 2H), 7.45-6.92 (m , 10H), 3.76 (s, 2H), 3.10-2.90 (m, 4H), 2.50-2.35 ( m, 3H), 2.32 (s, 6H), 2.10-1.85 (m, 4H), 1.80-1.60 (m, 4H); ESMS m / e: 469.4 (M + H) ⁺
[723] Example 5
[724] N- (3- {l- [4- (3,4-dimethylphenyl) -4-oxobutyl] -4-piperidinyl} phenyl) -2- (3-methoxyphenyl) acetamide:
[725] Using Method II, the desired product was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ7.76-7.65 (m, 2H), 7.38-7.12 (m, 6H), 6.95-6.80 (m, 3H), 3.82 (s, 3H), 3.70 (s, 2H), 3.10-2.90 (m, 4H), 2.50-2.38 (m, 3H), 2.32 (s, 6H), 2.10-1.85 (m, 4H), 1.80-1.60 (m, 4H); ESMS m / e: 499.4 (M + H) ⁺
[726] Example 6
[727] N- (3- {l- [4- (3,4-dimethylphenyl) -4-oxobutyl] -4-piperidinyl} phenyl) -2-methoxyacetamide:
[728] Using Method II, the desired product was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.80-7.75 (m, 2H), 7.50-7.38 (m, 2H), 7.34-6.90 (m, 3H), 4.00 (s, 2H), 3.51 (s, 3H), 3.30-2.95 (m, 4H), 2.70-2.50 (m, 3H), 2.32 (s, 6H), 2.15-1.80 (m, 8H); ESMS m / e: 423.3 (M + H) ⁺
[729] Example 7
[730] N- (3- {l- [4- (3,4-dimethylphenyl) -4-oxobutyl] -4-piperidinyl} phenyl) methanesulfonamide:
[731] Using Method II, the desired product was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.82-7.10 (m, 7H), 3.41 (s, 3H), 3.40-2.85 (m, 4H), 2.82-2.35 (m, 5H), 2.32 (s, 6H), 2.22-1.80 (m, 6H); ESMS m / e: 429.3 (M + H) ⁺
[732] Example 8
[733] N- (3- {l- [4- (3,4-dimethylphenyl) -4-oxobutyl] -4-piperidinyl} phenyl) ethanesulfonamide:
[734] Using Method II, the desired product was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ7.75 (s, 1H), 7.71 (d, 1H, J = 7.6 Hz), 7.30-7.09 (m, 4H), 7.02 (d, 1H, J = 7.2 Hz ), 3.36-3.05 (m, 6H), 2.77-2.52 (m, 3H), 2.32 (s, 6H), 2.15-1.82 (m, 8H), 1.37 (t, 3H, J = 7.4 Hz); ESMS m / e: 443.3 (M + H) ⁺
[735] Example 9
[736] N- (3- {l- [4- (4-chlorophenyl) -4-oxobutyl] -4-piperidinyl} phenyl) acetamide:
[737] Using method III, the desired product was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ7.92 (d, 2H, J = 8.8 Hz), 7.55-7.40 (m, 3H), 7.35 (s, 1H), 7.22 (t, 1H, J = 8.0 Hz ), 6.92 (d, 1H, J = 8.0 Hz), 3.30-3.27 (m, 2H), 3.09 (t, 2H, J = 7.0 Hz), 2.76-2.39 (m, 5H), 2.20 (s, 3H) , 2.17-1.85 (m, 6 H); ESMS m / e: 399.3 (M + H) ⁺
[738] Example 10
[739] N- (3- {l- [4- (4-chlorophenyl) -4-oxobutyl] -4-piperidinyl} phenyl) -2-methylpropanamide:
[740] Using Method II, the desired product was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ7.93 (d, 2H, J = 8.6 Hz), 7.45 (d, 2H, J = 8.6 Hz), 7.39 (d, 1H, J = 7.2 Hz), 7.32 ( s, 1H), 7.24 (t, 1H, J = 7.8 Hz), 6.94 (d, 1H, J = 8.4 Hz), 3.21-3.18 (m, 2H), 3.05 (t, 2H, J = 7.0 Hz), 2.64-2.51 (m, 4H), 2.28-1.86 (m, 8H), 1.26 (d, 6H, J = 6.8 Hz); ESMS m / e: 427.3 (M + H) ⁺
[741] Example 11
[742] N- (3- {l- [4- (4-chlorophenyl) -4-oxobutyl] -4-piperidinyl} phenyl) cyclohexanecarboxamide:
[743] Using Method II, the desired product was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ7.93 (d, 2H, J = 8.4 Hz), 7.55-7.19 (m, 5H), 6.93 (d, 1H, J = 7.6 Hz), 3.25-3.00 (m , 4H), 2.65-2.45 (m, 4H), 2.30-1.50 (m, 18H); ESMS m / e: 467.3 (M + H) ⁺
[744] Example 12
[745] N- (3- {l- [4- (4-chlorophenyl) -4-oxobutyl] -4-piperidinyl) phenyl) -2-phenylacetamide:
[746] Using Method II, the desired product was obtained. ¹ H NMR (400 MHz, CDC1 ₃ ) δ7.92 (d, 2H, J = 8.4 Hz), 7.46-7.26 (m, 9H), 7.20 (t, 1H, J = 7.6 Hz), 6.92 (d, 1H , J = 7.6 Hz), 3.75 (s, 2H), 3.15-3.13 (m, 2H), 3.03 (t, 2H, J = 7.0 Hz), 2.64-2.46 (m, 3H), 2.22-1.60 (m, 8H); ESMS m / e: 475.3 (M + H) ⁺
[747] Example 13
[748] N- (3- {l- [4- (4-chlorophenyl) -4-oxobutyl] -4-piperidinyl} phenyl) -2- (3-methoxyphenyl) acetamide:
[749] Using Method II, the desired product was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ7.92 (d, 2H, J = 8.4 Hz), 7.44 (d, 2H, J = 8.4 Hz) 7.38 (s, 1H), 7.35-7.25 (m, 3H) , 7.19 (t, 1H, J = 7.8 Hz), 6.94-6.86 (m, 3H), 3.81 (s, 3H), 3.72 (s, 2H), 3.12-3.09 (m, 2H), 3.02 (t, 2H , J = 6.8 Hz), 2.57-2.44 (m, 3H), 2.20-1.60 (m, 8H); ESMS m / e: 505.3 (M + H) ⁺
[750] Example 14
[751] N- (3- {l- [4- (4-chlorophenyl) -4-oxobutyl] -4-piperidinyl} phenyl) -2-methoxyacetamide:
[752] Using Method II, the desired product was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ7.93 (d, 2H, J = 8.4 Hz), 7.50-7.25 (m, 5H), 6.98 (d, 1H, J = 7.8 Hz), 4.01 (s, 2H ), 3.57 (s, 3H), 3.30-3.15 (m, 2H), 3.06 (t, 2H, J = 6.8 Hz), 2.70-2.50 (m, 3H), 2.35-1.80 (m, 8H); ESMS m / e: 429.3 (M + H) ⁺
[753] Example 15
[754] N- (3- {l- [4- (4-chlorophenyl) -4-oxobutyl] -4-piperidinyl} phenyl) methanesulfonamide:
[755] Using Method II, the desired product was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.95-6.96 (m, 8H), 3.48 (s, 3H), 3.28-2.90 (m, 6H), 2.80-2.57 (m, 3H), 2.38-1.86 ( m, 6H); ESMS m / e: 435.2 (M + H) ⁺
[756] Example 16
[757] N- (3- {l- [4- (4-chlorophenyl) -4-oxobutyl] -4-piperidinyl} phenyl) ethanesulfonamide:
[758] Using Method II, the desired product was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ7.93 (d, 2H, J = 8.2 Hz), 7.45 (d, 2H, J = 8.2 Hz), 7.30-7.08 (m, 3H), 6.99 (d, 1H , J = 7.6 Hz), 3.26-3.02 (m, 6H), 2.69-2.45 (m, 3H), 2.32-1.75 (m, 8H),
[759] 1.36 (t, 3H, J = 7.4 Hz); ESMS m / e: 449.3 (M + H) ⁺
[760] Example 17
[761] N- {3- [l- (4-oxo-4-phenylbutyl) -4-piperidinyl] phenyl} acetamide:
[762] Using method III, the desired product was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ8.10-6.80 (m, 9H), 3.40-2.95 (m, 4H), 2.85-2.20 (m, 3H), 2.19 (s, 3H), 2.15-1.70 ( m, 8H); ESMS m / e: 365.3 (M + H) ⁺
[763] Example 18
[764] 2-methyl-N- {3- [1- (4-oxo-4-phenylbutyl) -4-piperidinyl] phenyl} propanamide:
[765] Using Method II, the desired product was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.99 (d, 2H, J = 7.4 Hz), 7.57 (t, 1H, J = 7.4 Hz), 7.48 (t, 2H, J = 7.4 Hz), 7.45- 7.20 (m, 2H), 7.24 (t, 1H, J = 8.0 Hz), 6.94 (d, 1H, 8.0 Hz), 3.24-3.21 (m, 2H), 3.09 (t, 2H, J = 7.0 Hz), 2.57-2.25 (m, 4H), 2.31-1.84 (m, 8H), 1.26 (d, 6H, J = 7.2 Hz); ESMS m / e: 393.3 (M + H) ⁺
[766] Example 19
[767] N- {3- [1- (4-oxo-4-phenylbutyl) -4-piperidinyl] phenyl} -2-phenylacetamide:
[768] Using Method II, the desired product was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (d, 2H, J = 7.6 Hz), 7.65-7.15 (m, 11H), 6.92 (d, 2H, J = 7.2 Hz), 3.74 (s, 2H ), 3.20-2.95 (m, 4H), 2.65-2.40 (m, 3H), 2.25-1.70 (m, 8H); ESMS m / e: 441.3 (M + H) ⁺
[769] Example 20
[770] 2- (3-methoxyphenyl) -N- {3- [l- (4-oxo-4-phenylbutyl) -4-piperidinyl] phenyl} acetamide:
[771] Using Method II, the desired product was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (d, 2H, J = 7.6 Hz), 7.56 (t, 1H, J = 7.62 Hz), 7.46 (t, 2H, J = 7.6 Hz), 7.40 ( s, 1H), 7.37-7.26 (m, 2H), 7.19 (t, 1H, J = 7.8 Hz), 6.94-6.86 (m, 3H), 3.81 (s, 3H), 3.71 (s, 3H), 3.12 -3.03 (m, 4H), 2.57-2.44 (m, 3H), 2.16-1.77 (m, 8H); ESMS m / e: 471.3 (M + H) ⁺
[772] Example 21
[773] N- (3- {l- [4- (2,4-dimethoxyphenyl) -4-oxobutyl] -4-piperidinyl} phenyl) acetamide:
[774] Using method III, the desired product was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.82 (d, 1H, J = 8.8 Hz), 7.54 (d, 1H, J = 7.6 Hz), 7.33 (s, lH), 7.22 (t, 1H, J = 7.6 Hz), 6.93 (d, 1H, J = 7.6 Hz), 6.53 (d, 1H, J = 8.8 Hz), 6.46 (s, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.48-3.27 (m, 2H), 3.05 (t, 2H, J = 6.8 Hz), 2.90-2.68 (m, 2H), 2.65-2.38 (m, 3H), 2.25 (s, 3H), 2.18-1.80 ( m, 6H); ESMS m / e: 425.3 (M + H) ⁺
[775] Example 22
[776] N- (3- {l- [4- (2,4-dimethoxyphenyl) -4-oxobutyl] -4-piperidinyl} phenyl) -2-methylpropanamide:
[777] Using Method II, the desired product was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (d, 1H, J = 8.6 Hz), 7.41-7.37 (m, 2H), 7.24 (t, 1H, J = 7.8 Hz), 6.96 (d, 1H , J = 7.8 Hz), 6.54 (d, 1H, J = 8.6 Hz), 6.46 (s, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 3.11-3.08 (m, 2H), 2.98 (t, 2H, J = 7.2 Hz), 2.53-2.46 (m, 4H), 2.13-1.79 (m, 8H), 1.25 (d, 6H, J = 6.8 Hz); ESMS m / e: 453.3 (M + H) ⁺
[778] Example 23
[779] N- (3- {l- [4- (2,4-dimethoxyphenyl) -4-oxobutyl] -4-piperidinyl} phenyl) -2-phenylacetamide:
[780] Using Method II, the desired product was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.85 (m, 12H), 3.89 (s, 3H), 3.86 (s, 3H), 3.74 (s, 2H), 3.22-2.90 (m, 4H), 2.64 -2.40 (m, 3 H), 2.25-1.70 (m, 8 H); ESMS m / e: 501.3 (M + H) ⁺
[781] Example 24
[782] N- (3- {l- [4- (2,4-dimethoxyphenyl) -4-oxobutyl] -4-piperidinyl} phenyl) -2- (3-methoxyphenyl) acetamide:
[783] Using Method II, the desired product was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ7.82 (d, 1H, J = 8.8 Hz), 7.48-7.15 (m, 5H), 6.95-6.80 (m, 3H), 6.58-6.45 (m, 2H) , 3.89 (s, 3H), 3.86 (s, 3H), 3.81 (s, 3H), 3.72 (s, 2H), 3.25-2.95 (m, 4H), 2.65-2.40 (m, 3H), 2.30-1.95 (m, 4H), 1.93-1.72 (m, 4H); ESMS m / e: 531.3 (M + H) ⁺
[784] Example 25
[785] N- (3- {1- [4-oxo-4- (4-phenoxyphenyl) butyl] -4-piperidinyl} phenyl) acetamide:
[786] Using method III, the desired product was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ8.15-6.75 (m, 13H), 3.30-2.80 (m, 4H), 2.75-2.10 (m, 5H), 2.03 (s, 3H), 2.00-1.60 ( m, 6H); ESMS m / e: 457.3 (M + H) ⁺
[787] Example 26
[788] 2-methyl-N- (3- {l- [4-oxo-4- (4-phenoxyphenyl) butyl] -4-piperidinyl} phenyl) propanamide:
[789] Using Method II, the desired product was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.96 (d, 2H, J = 8.8 Hz), 7.43-7.15 (m, 6H), 7.10-6.93 (m, 5H), 3.42-2.95 (m, 4H) , 2.80-2.45 (m, 4H), 2.20-1.80 (m, 8H), 1.14 (d, 6H, J = 6.8 Hz); ESMS m / e: 485.4 (M + H) ⁺
[790] Example 27
[791] 2- (3-methoxyphenyl) -N- (3- {l- [4-oxo-4- (4-phenoxyphenyl) butyl] -4-piperidinyl} phenyl) acetamide:
[792] Using Method II, the desired product was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.97 (d, 2H, J = 8.8 Hz), 7.41-7.18 (m, 7H), 7.08-6.99 (m, 5H), 6.94-6.87 (m, 3H) , 3.82 (s, 3H), 3.70 (s, 2H), 3.10-2.95 (m, 4H), 2.55-2.40 (m, 3H), 2.15-1.95 (m, 4H), 1.81-1.70 (m, 4H) ; ESMS m / e: 563.4 (M + H) ⁺
[793] Example 28
[794] N '-(3- {l- [4- (4-chlorophenyl) -4-oxobutyl] -4-piperidinyl} phenyl) N, N-dimethylsulfamide:
[795] Using Method II, the desired product was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ7.93 (d, 2H, J = 8.8 Hz), 7.44 (d, 2H, J = 8.8 Hz), 7.27 (s, 1H), 7.25-7.10 (m, 2H ), 6.94 (d, 1H, J = 7.6 Hz), 3.30-3.10 (m, 2H), 3.04 (t, 2H, J = 6.8 Hz), 2.83 (s, 6H), 2.68-2.45 (m, 3H) , 2.30-1.75 (m, 8 H); ESMS m / e: 464.3 (M + H) ⁺
[796] Example 29
[797] N- (3- {l- [4-oxo-4- (2-thienyl) butyl] -4-piperidinyl} phenyl) acetamide:
[798] Using method III, the desired product was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ7.90-6.78 (m, 7H), 3.22-2.88 (m, 4H), 2.69-2.25 (m, 5H), 2.02 (s, 3H), 2.00-1.64 ( m, 6H); ESMS m / e: 371.2 (M + H) ⁺
[799] Example 30
[800] N- (3- {l- [4- (4-isopropylphenyl) -4-oxobutyl] -4-piperidinyl} phenyl) acetamide:
[801] Using method III, the desired product was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ8.00-6.78 (m, 8H), 3.15-2.98 (m, 4H), 2.77-2.15 (m, 4H), 2.03 (s, 3H), 2.00-1.62 ( m, 8H), 0.927 (d, 6H, J = 6.0 Hz); ESMS m / e: 407.3 (M + H) ⁺
[802] Example 31
[803] N-(3- {l- [4- (4-methylphenyl) -4-oxobutyl] -4-piperidinyl} phenyl) acetamide:
[804] Using method III, the desired product was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ7.90-6.80 (m, 8H), 3.10-2.45 (m, 7H), 2.32 (s, 3H), 2.02 (s, 3H), 2.01-1.68 (m, 8H); ESMS m / e: 379.3 (M + H) ⁺
[805] Example 32
[806] N- (3- {1- [4- (4-bromophenyl) -4-oxobutyl] -4-piperidinyl} phenyl) acetamide:
[807] Using method III, the desired product was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ7.90-6.80 (m, 8H), 3.30-3.05 (m, 4H), 2.70-2.45 (m, 3H), 2.05 (s, 3H), 1.98-1.65 ( m, 8H); ESMS m / e: 444.0 (M + H) ⁺
[808] Example 33
[809] N- (3- {l- [4- (3,4-dimethylphenyl) -4-oxobutyl] -4-piperidinyl} phenyl) -2-propanesulfonamide:
[810] Using Method II, the desired product was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ7.75 (s, 1H), 7.71 (d, 1H, J = 7.6 Hz), 7.27-7.00 (m, 5H), 3.32-3.24 (m, 3H), 3.10 -3.02 (m, 2H), 2.78-2.50 (m, 3H), 2.32 (s, 6H), 2.19-1.84 (m, 8H), 1.39 (d, 6H, J = 6.8 Hz); ESMS m / e: 457.4 (M + H) ⁺
[811] Example 34
[812] N- (3- {l- [4-oxo-4- (4-phenoxyphenyl) butyl] -4-piperidinyl} phenyl) -2-propanesulfonamide:
[813] Using Method II, the desired product was obtained.
[814] ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.97 (d, 2H, J = 7.6 Hz), 7.44 (t, 2H, J = 7.6 Hz), 7.27-7.00 (m, 9H), 3.35-2.96 (m , 5H), 2.69-2.45 (m, 3H), 2.14-1.79 (m, 8H), 1.39 (d, 6H, J = 6.8 Hz); ESMS m / e: 521.4 (M + H) ⁺
[815] Example 35
[816] N- (3- {l- [3- (4-chlorophenyl) -3-methoxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide:
[817] 3-methoxy-3- (p-chlorophenyl) -1-chloropropane (27.4 mg, 0.125 mmol), 2-methyl-N- [3- (4-piperidinyl) phenyl in dioxane (2.0 mL) ] A mixture of propanamide (28.3 mg, 0.125 mmol), diisopropylethylamine (0.50 mL) and a catalytic amount of tetrabutylammonium iodide was stirred at 90 ° C. for 72 hours. The reaction mixture was concentrated to a small volume and chromatographed using a prepared TLC plate [NH ₃ 2.5% in CHCl ₃ (in methanol 2.0 M)] to N- (3- {l- [3- (4-chlorophenyl)- 3-methoxypropyl) -4-piperidinyl} phenyl) -2-methylpropanamide (39.5 mg, 73.8% yield) was provided as a thick oil: ¹ H NMR δ 7.48 (S, 1H), 7.34- 7.3 (m, 2H), 7.25 (m, 4H), 6.96 (d, 1H, J = 7.4 Hz), 4.20 (apparent dd, 1H, J = 5.9, 7.6 Hz), 3.2 (s, 3H), 3.04 ( d, 1H, J = 10.1 Hz), 2.99 (d, 1H, J = 10.l Hz), 2.49 (h, 4H, J = 6.6 Hz), 2.20-2.10 (m, 4H), 1.82 (m, 4H ), 1.25 (d, 6H, J = 7.1 Hz); ESMS m / e: 429.4 (M + H) ⁺
[818] Example 36
[819] N- (3- {1- [6- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) hexyl] -4-piperidinyl} phenyl) -2-methyl Propanamide:
[820] The synthesis method is as described for 2- [6- (4-phenyl-1-piperidinyl) hexyl] -1H-isoindole-1,3 (2H) -dione. N- (3- {1- [6- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) hexyl] -4-piperidinyl} phenyl) -2-methyl Propanamide: 506 mg (56% yield); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.86-7.80 (m, 2H), 7.73-7.68 (m, 2H), 7.44 (s, 1H), 7.37 (d, 1H, J = 8.3 Hz), 7.22 (t, 1H, J = 7.7 Hz), 6.96 (d, 1H, J = 7.7 Hz), 3.69 (t, 2H, J = 7.2 Hz), 3.01 (obvious d, 2H, J = ll.3 Hz), 2.58-2.40 (m, 2H), 2.33 (m, 2H) 1.98 (dt, 2H, J = 3.2, 11.3 Hz), 1.84-1.64 (m, 4H), 1.51 (q, 2H, J = 7.1 Hz), 1.43-1.30 (m, 6H), 1.24 (d, 6H, J = 6.8 Hz); ESMS m / e: 476.4 (M + H) ⁺
[821] Example 37
[822] N- {3- (1- (3-methoxy-3-phenylpropyl) -4-piperidinyl] phenyl} -2-methylpropanamide: methoxy-3-phenyl-1 in dioxane (2.0 mL) -Chloropropane (23.1 mg, 0.126 mmol), 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide (28.3 mg, 0.126 mmol), diisopropylethylamine (0.50 mL) and catalytic amount of tetrabutylammonium iodide mixture of beads and the mixture was stirred at 90 ℃ for 72 hours. chromatography using silica preparative TLC plates [CHCl ₃ in NH ₃ (methanol in 2.0 M) 2.5%] by performing, N- {3 -(1- (3-methoxy-3-phenylpropyl) -4-piperidinyl] phenyl} -2-methylpropanamide (45.4 mg, 91.2% yield) was obtained as a thick oil: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.45 (S, 1H), 7.34-7.25 (m, 5H), 7.25 (m, 2H), 6.96 (d, 1H, J = 7.4 Hz), 4.20 (apparent dd, 1H, J = 5.9, 7.6 Hz), 3.2 (s, 3H), 3.04 (d, 1H, J = 10.1 Hz), 2.99 (d, 1H, J = 10.l Hz), 2.49 (obvious sinter, partially hidden) , 4H, J = 6.6 Hz), 2.3-2.1 (m, 4H), 1.82 (m, 4H), 1.25 (d, 6H, J = 7.1 Hz); ESMS m / e: 395.4 (M + H) ⁺
[823] Example 38
[824] N- (3- {1- [4- (l, 3-dioxo-1,3-dihydro-2H-isoindol-2-yl) butyl] -4-piperidinyl} phenyl) -2-methyl Propanamide: The synthesis method is as described for 2- [6- (4-phenyl-1-piperidinyl) hexyl] -1H-isoindole-1,3 (2H) -dione. N- (3- {1- [4- (l, 3-dioxo-1,3-dihydro-2H-isoindol-2-yl) butyl] -4-piperidinyl} phenyl) -2-methyl Propanamide: 664 mg (74% yield); ¹ H NMR (400 MHZ, CDCl ₃ ) δ 7.87-7.78 (m, 2H), 7.76-7.64 (m, 2H), 7.47 (s, 1H), 7.39 (d, 1H, J = 7.6 Hz), 7.21 (t, 1H, J = 8.1 Hz), 6.94 (d, 1H, J = 7.6 Hz), 3.72 (t, 2H, J = 6.8 Hz), 3.37-3.22 (m, 2H), 3.0 (obvious d, 2H , J = 10.7 Hz), 2.75 (q, 2H, J = 7.0 Hz), 2.64-2.33 (m, 4H), 1.99 (dt, 2H, J = 2.6, 11.7 Hz), 1.86-1.65 (m, 2H) , 1.63-1.50 (m, 2H), 1.23 and 1.21 (two d, 6H, J = 5.5 Hz); ESMS m / e: 448.4 (M + H) ⁺ ; Analytical calculation for C ₂₇ H ₃₄ N ₃ ClO ₃ + 0.4H ₂ 0: C, 66.02; H, 7.14; N, 8.55. Found: C, 66.07; H, 6. 78; N, 8.65.
[825] Example 39
[826] N- (3- {1- [4- (l, 3-dioxo-1,3-dihydro-2H-isoindol-2-yl) butyl] -4-piperidinyl} phenyl) -2-methyl Propanamide: The synthesis method is as described for 2- [6- (4-phenyl-1-piperidinyl) hexyl] -1H-isoindole-1,3 (2H) -dione. N- (3- {1- [4- (l, 3-dioxo-1,3-dihydro-2H-isoindol-2-yl) butyl] -4-piperidinyl} phenyl) -2-methyl Propanamide: 614 mg (64% yield); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.87-7.8 (m, 2H), 7.76-7.68 (m, 2H), 7.48 (s, 1H), 7.41 (d, 1H, J = 7.6 Hz), 7.21 (t, 1H, J = 7.6 Hz), 6.95 (d, 1H, J = 7.6 Hz), 3.69 (t, 2H, J = 7.2 Hz), 3.39-3.28 (m, 2H), 3.02 (obvious d, 2H) , J = 11.6 Hz), 2.78 (q, 2H, J = 7.2 Hz), 2.64-2.52 (m, 1H), 2.52-2.40 (m, 1H), 2.40-2.31 (m, 2H), 2.01 (dt, 2H, J = 3.7, 11.1 Hz), 1.85-1.64 (m, 2H), 1.58 (q, 2H, J = 7.6 Hz), 1.45-1.32 (m, 2H), 1.23 (d, 6H, J = 6.9 Hz ); ESMS m / e: 462.4 (M + H) ⁺ ; Analytical calcd. For C ₂₈ H ₃₆ N ₃ ClO ₃ : C, 67.52; H, 7. 29; N, 8.44. Found: C, 67.04; H, 7.06; N, 8.38.
[827] Example 40
[828] 2-methyl-N- {3- [l- (4-phenylbutyl) -4-piperidinyl] phenyl} propanamide : N- [3- (4-piperidinyl) phenyl] propanamide (28.3 mg, 0.100 mmol), 4-phenyl-1-chlorobutane (21.1 mg, 0.125 mmol), diisopropylethylamine (0.50 mL), catalytic amount of tetrabutylammonium iodide and dioxane (2.0 mL) at reflux temperature Heated at for 3 days. The reaction mixture was concentrated and chromatographed using preparative TLC plate [NH _{3 in} CHCl ₃ (2.0 M in methanol) 2.5%] to give the product 2-methyl-N- {3- [l- (4-phenylbutyl ) -4-piperidinyl] phenyl} propanamide (9.50 mg, 25.1% yield) was obtained as a thick oil: ¹ H NMR δ7.37 (s, 1M), 7.29 (obvious d, 1H. J = 7.9 Hz) ), 7.18 (m, 3H), 7.11 (m, 3H), 6.90 (apparent d, 1H, J = 7.9 Hz), 3.02 (d, 2H, J = 6.8 Hz), 2.41 (m, 4H, partially hidden Load), 2.01 (m, 2H), 1.78 (m, 4H), 1.57 (m, 4H), 1.18 (d, 6H, J = 7.7 Hz); ESMS m / e: 379.4 (M + H) ⁺
[829] Example 41
[830] N- (3- {1- [3- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) propyl] -4-piperidinyl} phenyl) -2-methyl Propanamide: The synthesis method is as described for 2- [6- (4-phenyl-1-piperidinyl) hexyl] -1H-isoindole-1,3 (2H) -dione. N- (3- {1- [3- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) propyl] -4-piperidinyl} phenyl) -2-methyl Propanamide: 810 mg (93% yield); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.87-7.82 (m, 2H), 7.73-7.68 (m, 2H), 7.57 (s, 1H), 7.36 (d, 1H, J = 8.5 Hz), 7.18 (t, 1H, J = 7.7 Hz), 6.79 (d, 1H, J = 7.1 Hz), 3.78 (t, 2H, J = 6.8 Hz), 3.06 (quintet, 2H, J = 6 Hz), 2.95 ( Apparent d, 2H, J = 12.2 Hz, 2.58-2.31 (m, 4H), 1.96-1.83 (m, 2H), 1.70 (apparent d, 2H, J = 12.1 Hz), 1.52 (dt, 2H, J = 3.5, 12.5 Hz), 1.03 (d, 6H, J = 6.5 Hz); ESMS m / e: 434.4 (M + H) ⁺
[831] Example 42
[832] N- (3- {1-[(3S) -3-hydroxy-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: (S)-(-)-3-chloro -1-phenyl-1-propanol (0.426 g, 2.50 mmol, 99% ee), 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide (0.565 g, 2.00 mmol), diiso A mixture of propylethylamine (1.29 g, 10.0 mmol), dioxane (5.0 mL) and a catalytic amount of tetrabutylammonium iodide was stirred at 90 ° C. for 72 hours. Chromatography using silica preparative TLC plate [NH _{3 in} CHCl ₃ (2.0 M in methanol) 2.5%] afforded the desired product (306 mg, 39.3% yield) as a thick oil: ¹ H NMR (400 MHz , CDCl ₃ ) δ 7.46 (S, 1H), 7.42 (d, 4H, J = 8.1 Hz), 7.35 (m, 1H), 7.30 (d, 1H, J = 8.0 Hz), 7.23 (t, 1H, J = 8.1 Hz), 7.12 (s, 1H), 6.96 (apparent dd, 1H, J = 8.0 Hz), 5.0 (apparent dd, 1H, J = 4.4, 8.3 Hz), 3.18 (apparent dd, 2H, J = 2.5, 12.5 Hz), 2.74 (m, 2H), 2.50 (m, 2H), 2.3-2.1 (m, 6H), 1.8 (m, 2H), 1.25 (d, 6H, J = 7.1 Hz); ESMS m / e: 389.2 (M + H) ⁺
[833] Example 43
[834] N- (3- {1- [3-methoxy-3- (4-methylphenyl) propyl) -4-piperidinyl} phenyl) -2-methylpropanamide: 3-methoxy in dioxane (2.0 mL) -3- (p-tolyl) -1-chloropropane (24.9 mg, 0.126 mmol), 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide (28.3 mg, 0.126 mmol), di A mixture of isopropylethylamine (0.50 mL) and a catalytic amount of tetrabutylammonium iodide was stirred at 90 ° C. for 72 hours. Chromatography using silica preparative TLC plate [NH _{3 in} CHCl ₃ (2.0 M in methanol) 2.5%] afforded the desired product (10.9 mg, 21.2% yield) as a thick oil: ¹ H NMR (400 MHz). , CDCl ₃ ) δ 7.44 (s, 1H), 7.38 (m, 1H), 7.3-7.1 (m, 5H), 6.96 (d, 1H, J = 7.4 Hz), 4.18 (apparent dd, 1H, J = 5.6, 7.9 Hz), 3.24 (d, 1H, J = 8.2 Hz), 3.2 (s, 3H), 3.11 (m, 2H, J = 10.1 Hz), 2.49 (m, 4H), 2.35 (s, 3H) , 2.3-2.1 (m, 3H), 1.92 (d, 4H), 1.25 (d, 6H, J = 7.1 Hz); ESMS m / e: 409.4 (M + H) ⁺
[835] Example 44
[836] N- {3- [1- (3-isopropoxy-3-phenylpropyl) -4-piperidinyl] phenyl} -2-methylpropanamide: 3-isopropyl-3 'in dioxane (2.0 mL) -Phenyl-1-chloropropane (26.6 mg, 0.126 mmol), 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide (28.3 mg, 0.126 mmol), diisopropylethylamine (0.50 mL) and a catalytic amount of tetrabutylammonium iodide were stirred at 90 ° C. for 72 hours. Chromatography with silica preparative TLC plate [NH _{3 in} CHCl ₃ (2.0 M in methanol) 2.5%] afforded the desired product (14.1 mg, 26.5% yield) as a thick oil: ¹ H NMR (400 MHz , CDCl ₃ ) δ 7.46 (s, 1H), 7.43-7.37 (m, 2H), 7.33 (m, 3H), 7.23 (m, 2H), 6.95 (d, 1H, J = 8.4 Hz), 4.46 ( Obvious dd, 1H, J = 5.0, 8.3 Hz), 3.49 (apparent quintet, 1H, J = 7.1 Hz), 3.10 (s, 2H), 2.70 (m, 2H), 2.52 (apparent quintet, partially hidden Load, 4H, J = 6.6 Hz), 2.30-2.10 (m, 2H), 1.90-1.80 (d, 4H), 1.25 (d, 6H, J = 7.1 Hz), 1.15 (d, 3H, J = 6.4 Hz ), 1.08 (d, 3H, J = 6.4 Hz); ESMS m / e: 423.4 (M + H) ⁺
[837] Example 45
[838] N- (3- {1- [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl) phenyl) -2-methylpropanamide: 4,4- in dioxane (2.0 mL) Bis (4-fluoro-phenyl) -1-chloro-butane (39.0 mg, 0.126 mmol), 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide (28.3 mg, 0.126 mmol) , A mixture of diisopropylethylamine (0.50 mL) and a catalytic amount of tetrabutylammonium iodide was stirred at 90 ° C. for 72 hours. Chromatography using silica preparative TLC plate [NH _{3 in} CHCl ₃ (2.0 M in methanol) 2.5%] afforded the desired product (15.9 mg, 25.2% yield) as a thick oil: ¹ H NMR (400 MHz , CDCl ₃ ) δ 8.02 (s, 1H), 7.41 (s, 1H), 7.3-7.15 (m, 4H), 7.10 (m, 3H), 6.89 (obvious t, 5H), 3.81 (t, 1H, J = 7.8 Hz), 3.30 (s, 1H), 2.91 (d, 1H, J = 12.5 Hz), 2.80 (m, 1H), 2.40 (m, 2H), 2.31 (t, 1H, J = 8.0 Hz) , 1.93 (apparent q, 3H, J = 8.0 Hz), 1.72 (m, 3H), 1.40 (m, 2H), 1.20 (m, 2H), 1.15 (d, 6H, J = 8.1 Hz); ESMS m / e: 491.4 (M + H) ⁺
[839] Example 46
[840] N- {3- [l- (3-methoxybenzyl) -4-piperidinyl] phenyl} -2-methylpropanamide: 2-methyl-N- [3- (4-piperidinyl) phenyl] propane Amide (28.3 mg, 0.100 mmol), 3-methoxybenzyl chloride (19.6 mg, 0.125 mmol), diisopropylethylamine (0.50 mL), catalytic amount of tetrabutylammonium iodide and dioxane (2.0 mL) . Chromatography using silica preparative TLC plate [NH _{3 in} CHCl ₃ (2.0 M in methanol) 2.5%] afforded the desired product (10.2 mg, 27.9% yield) as a yellow solid: ¹ H NMR (400 MHz , CDCl ₃ ) δ 7.46 (s, 1H), 7.35 (apparent d, 1H, J = 8.3 Hz), 7.27-7.21 (m, 2H), 6.95 (apparent t, 3H, J = 6.9 Hz), 6.82 ( Apparent dd, 1H, J = 2.4, 8.3 Hz), 3.84 (m, 3H), 3.56 (s, 2H), 3.05 (d, 2H, J = 10.5 Hz), 2.51 (obvious sinter, partially hidden, 4H, J = 7.2 Hz), 2.13 (apparent t, 2H, J = 9,7 Hz), 1.88 (m, 2H), 1.25 (d, 6H, J = 6.7 Hz); ESMS m / e: 367.3 (M + H) ⁺
[841] Example 47
[842] N- (3- {1- [3,5-bis (trifluoromethyl) benzyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 2-methyl-N- [3- (4- Piperidinyl) phenyl] propanamide (28.3 mg, 0.100 mmol), 3,5-bis (trifluoromethyl) benzyl bromide (38.4 mg, 0.125 mmol), diisopropylethylamine (0.50 mL), catalytic amount of tetra A mixture of butylammonium iodide and dioxane (2.0 mL). Chromatography using silica preparative TLC plate [NH _{3 in} CHCl ₃ (2.0 M in methanol) 2.5%] afforded the desired product (12.2 mg, 25.8% yield) as a thick oil: ¹ H NMR (400 MHz , CDCl ₃ ) δ 7.83 (s, 2H), 7.77 (s, 1H), 7.53 (s, 1H), 7.30-7.21 (m, 2H), 7.16 (s, 1H), 6.98 (obvious d, 1H, J = 7.6 Hz), 3.62 (s, 2H), 2.94 (d, 2H, J = 9.4 Hz), 2.51 (apparent strait, partially hidden, 2H, J = 6.6 Hz), 2.14 (m, 2H) , 1.82 (m, 4H), 1.25 (d, 6H, J = 6.6 Hz); ESMS m / e: 473.2 (M + H) ⁺
[843] Example 48
[844] N- (3- {1-[(3R) -3- (3,4-dimethoxyphenoxy) -3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide
[845] Method A
[846] 4-{[(1R) -3-chloro-1-phenylpropyl] oxy} -1,2-dimethoxybenzene: 3,4-dimethoxyphenol (4.07 g, 26.4 mmol) in THF (110 mL), ( S)-(-)-3-chloro-phenyl-1-propanol (4.50 g, 26.4 mmol, 99% ee, Aldrich Chemical Co.), triphenylphosphine (6.92 g, 26.4 mmol) and diethyl azodicar A mixture of carboxylate (4.59 g, 26.4 mmol) was stirred at rt for 24 h. The reaction mixture was concentrated in vacuo. At this time, the residue can be washed with pentane (x3) and the combined pentane extracts are concentrated and chromatographed (silica with hexane-EtOAc 8: 1 as eluent) to give the desired product (Srebnik, M .; Ramachandran, PV; Brown, HCJ Org. Chem. 1988, 53, 2916-2920). This method was carried out in smaller amounts of reaction and the yield of product was only 40%.
[847] Alternatively, in larger amounts (26.4 mmol) the crude product (crude produ (t) was titrated with a small amount of dichloromethane and the precipitated triphenylphosphine oxide was filtered off. The filtrate was concentrated and the crude product was Chromatography gave the desired product as a dark yellow oil (7.30 g, 88.9% yield): ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.39-7.32 (m, 4H), 7.20 (m, 1H), 6.64 (d, 1H, J = 8.7 Hz), 6.51 (d, 1H, J = 2.7 Hz), 6.30 (dd, 1H, J = 2.7, 8.7 Hz), 5.27 (apparent dd, 1H, J = 4.5, 8.7 Hz ), 3.79 (s, 3H), 3.77 (s, 3H), 3.61 (m, 1H), 2.45 (m, 1H), 2.20 (m, 1H), 1.80 (s, 1H); ESMS m / e: 307.11 (M + H) ⁺
[848] N- (3- {1-[(3R) -3- (3,4-dimethoxyphenoxy) -3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide : DMF (5.0 ml) potassium carbonate (321 mg, 2.32 mmol), sodium iodide (522 mg, 3.48 mmol), 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide (570 mg, 2.32 mmol) And 4-{[(1R) -3-chloro-1-phenylpropyl] oxy} -1,2-dimethoxybenzene (712 mg, 2.32 mmol) was stirred at 100 ° C. for 3 hours at which time reaction was by TLC. I was able to know the dog. The reaction mixture was 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 magnesium sulfate and concentrated under reduced pressure. The crude product was purified by Prep-TLC plate [2.5% NH _{3 in} CHCl ₃ (2.0 M in methanol)] to give the product (970 mg, 90.1%) as a thick oil.
[849] Method B
[850] Triphenylphosphine (9.80 mg, 0.0375 mmol), diethyl azodicarboxylate (5.22 mg, 0.0300 mmol), N- (3- {l-[(3S) -3-hydroxy- in a 25 mL RB flask 3-phenylpropyl) -4-piperidinyl} phenyl) -2-methylpropanamide (9.53 mg, 0.0250 mmol), 3,4-dimethoxyphenol (7.70 mg, 0.O5O mmol) and THF (1.0 mL) Was added at room temperature. The reaction mixture was stirred at rt overnight (16 h). It was removed of solvent under reduced pressure, to afford the the residue purified by preparative TLC plates [CHCl ₃ in NH ₃ (methanol in 2.0 M) 2.5%], the desired product (4.4 mg, 34.1% yield) as a thick oil: ¹ H NMR (400 MHz, COCl ₃ ) δ 7.46 (s, 1H), 7.40-7.30 (m, 4H), 7.25 (m, 3H), 6.97 (d, 1H, J = 7.8 Hz), 6.64 (d , 1H, J = 9.1 Hz), 6.51 (d, 1H, J = 2.6 Hz), 6.29 (d, 1H, J = 2.6, 9.1 Hz), 5.20 (apparent dd, 1H, J = 4.4, 8.5 Hz), 3.80 (s, 3H), 3.77 (s, 3H), 3.23 (m, 2H), 2.77 (m, 2H), 2.5 (m, 2H), 2.3-2.1 (m, 6H), 1.80 (m, 2H) , 1.25 (d, 6H, J = 7.9 Hz); ESMS m / e: 517.4 (M + H) ⁺
[851] Example 49
[852] 2-methyl-N- (3- {l-[(3S) -3-phenoxy-3-phenylpropyl] -4-piperidinyl} phenyl) propanamide: N- (3- in THF (1.0 mL) {1-[(3R) -3-hydroxy-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide (9.53 mg, 0.0250 mmol), phenol (4.70 mg, 0.050 mmol), A mixture of triphenylphosphine (9.80 mg, 0.0375 mmol) and diethyl azodicarboxylate (5.22 mg, 0.0300 mmol) was stirred at rt for 3 days. Chromatography using silica preparative TLC plate [NH _{3 in} CHCl ₃ (2.0 M in methanol) 2.5%] afforded the desired product (2.7 mg, 23.6% yield) as a thick oil: ¹ H NMR δ 7.46 (s, 2H), 7.40-7.30 (m, 4H), 7.25 (m, 3H), 7.20 (m, 2H), 6.97 (apparent d, 1H, J = 7.4 Hz), 6.89 (apparent tt, 1H, J = 0.8, 7.6 Hz), 6.84 (apparent dt, 1H, J = 0.8, 8.0 Hz), 5.20 (apparent dd, 1H, J = 4.4, 8.5 Hz), 3.35 (m, 2H), 2.91 (m, 2H) , 2.60 (m, 2H), 2.30-2.10 (m, 6H), 1.90 (m, 2H), 1.25 (d, 6H, J = 7.9 Hz); ESMS m / e: 457.4 (M + H) ⁺
[853] Example 50
[854] N- (3- {1-[(3S) -3- (4-methoxyphenoxy) -3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: THF (1.0 mL) N- (3- {1-[(3R) -3-hydroxy-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide (9.53 mg, 0.0250 mmol) in 4-meth A mixture of oxyphenol (6.20 mg, 0.050 mmol), triphenylphosphine (9.80 mg, 0.0375 mmol) and diethyl azodicarboxylate (5.2 mg, 0.0300 mmol) was stirred at room temperature for 3 days. Silica Preparative TLC Chromatography with plate [NH _{3 in} CHCl ₃ (2.0 M in methanol) 2.5%] was carried out to give the desired product (4.6 mg, 37.9% yield) as a thick oil: ¹ H NMR (400 MHz, CDCl ₃ δ7.38-7.14 (m, 8H), 6.90 (apparent d, 1H, J = 7.7 Hz), 6.72-6.46 (m, 4H), 5.09 (apparent dd, 1H, J = 4.8, 8.1 Hz), 3.64 (s, 3H), 3.18 (m, 2H), 2.73 (m, 2H), 2.50 (m, 2H), 2.37-1.72 (m, 8H), 1.25 (d, 6H, J = 7.4 Hz); ESMS m / e: 487.4 (M + H) ⁺
[855] Example 51
[856] N- (3- {1-[(3S) -3- (3-chlorophenoxy) -3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: in THF (1.0 mL) N- (3- {1-[(3R) -3-hydroxy-3-phenylpropyl-4-piperidinyl} phenyl) -2-methylpropanamide (9.53 mg, 0.0250 mmol), 3-chlorophenol ( 6.40 mg, 0.050 mmol), triphenylphosphine (9.80 mg, 0.0375 mmol) and diethyl azodicarboxylate (5.22 mg, 0.0300 mmol) were stirred at room temperature for 3 days. Chromatography using silica preparative TLC plate [NH _{3 in} CHCl ₃ (2.0 M in methanol) 2.5%] afforded the desired product (4.9 mg, 40.0% yield) as a thick oil: ¹ H NMR (400 MHz , CDCl ₃ ) δ 7.39 (s, 1H), 7.35-7.10 (m, 7H), 7.02 (t, 1H, J = 8.0 Hz), 6.90 (d, 1H, J = 7.6 Hz), 6.84-6.75 ( m, 2H), 6.65 (m, 1H), 5.09 (apparent dd, 1H, J = 4.99, 8.1 Hz), 3.10 (m, 2H), 2.60 (m, 2H), 2.50 (m, 2H), 2.30- 1.70 (m, 8 H), 1.18 (d, 6 H, J = 6.8 Hz); ESMS m / e: 491.4 (M + H) ⁺
[857] Example 52
[858] N- (3- {1-[(3S) -3- (4-chlorophenoxy) -3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: in THF (1.0 mL) N- (3- {1-[(3R) -3-hydroxy-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide (9.53 mg, 0.0250 mmol), 4-chlorophenol (6.40 mg, 0.050 mmol), triphenylphosphine (9.80 mg, 0.0375 mmol) and diethyl azodicarboxylate (5.22 mg, 0.0300 mmol) were stirred at room temperature for 3 days. Chromatography using silica preparative TLC plate [NH _{3 in} CHCl ₃ (2.0 M in methanol) 2.5%] afforded the desired product (3.3 mg, 26.9% yield) as a thick oil: ¹ H NMR δ 7.36 (s, 1H), 7.35-7.22 (m, 7H), 7.12 (m, 2H), 6.97 (apparent d, 1H, J = 7.2 Hz), 6.77 (m, 2H), 5.23 (m, 1H), 3.18 (m, 2H), 2.70 (m, 2H), 2.50 (m, 2H), 2.40-1.80 (m, 8H), 1.25 (d, 6H, J = 6.8 Hz); ESMS m / e: 491.4 (M + H) ⁺
[859] Example 53
[860] 2-methyl-N- [3- (1-{(3S) -3-phenyl-3- [4- (trifluoromethyl) phenoxy] propyl} -4-piperidinyl) phenyl] propanamide: THF N- (3- {1-[(3R) -3-hydroxy-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide (9.53 mg, 0.0250 mmol) in (1.0 mL) , A mixture of 4-trifluoromethylphenol (8.100 mg, 0.050 mmol), triphenylphosphine (9.8 mg, 0.0375 mmol) and diethyl azodicarboxylate (5.22 mg, 0.0300 mmol) for 3 days at room temperature Stirred. Chromatography using silica preparative TLC plate [NH _{3 in} CHCl ₃ (2.0 M in methanol) 2.5%] afforded the desired product (5.10 mg, 38.9% yield) as a thick oil: ¹ H NMR δ8.06 (s, 1H), 7.49 (s, 1H), 7.44 (apparent d, 2H, J = .6 Hz), 7.38-7.30 (m, 4H), 7.30-7.20 (m, 3H), 6.96 (apparent d, 1H, J = 7.6 Hz), 6.91 (apparent d, 2H, J = 8.6 Hz), 5.34 (m, 1H), 3.19 (m, 2H), 2.72 (m, 2H), 2.53 (m, 2H), 2.40 -1.80 (m, 8H), 1.25 (d, 6H, J = 6.8 Hz); ESMS m / e: 525.4 (M + H) ⁺
[861] Example 54
[862] N- (3- {1-[(3R) -3- (2,5-difluorophenoxy) -3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: THF ( N- (3- {1-[(3R) -3-hydroxy-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide (9.53 mg, 0.0250 mmol) in 1.0 mL), A mixture of 2,5-difluorophenol (6.50 mg, 0.050 mmol), triphenylphosphine (9.80 mg, 0.0375 mmol) and diethyl azodicarboxylate (5.22 mg, 0.0300 mmol) was added at room temperature for 3 days. Stirred. Chromatography using silica preparative TLC plate [NH _{3 in} CHCl ₃ (2.0 M in methanol) 2.5%] afforded the desired product (3.60 mg, 29.3% yield) as a thick oil: ¹ H NMR δ 7.46 (s, 1H), 7.40-7.32 (m, 4H), 7.31-7.20 (m, 2H), 7.17 (s, 1H), 7.01-6.92 (m, 2H), 6.65-6.42 (m, 2H), 5.27 (m, 1H), 3.13 (m, 2H), 2.64 (m, 2H), 2.51 (m, 2H), 2.28-1.80 (m, 8H), 1.25 (d, 6H, J = 7.1 Hz); ESMS m / e: 493.4 (M + H) ⁺
[863] Example 55
[864] N- (3- {1-[(3R) -3- (3,4-dichlorophenoxy) -3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: THF (1.0 mL N- (3- {1-[(3S) -3-hydroxy-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide (9.53 mg, 0.0250 mmol) in 3), 3, A mixture of 4-dichlorophenol (8.20 mg, 0.050 mmol), triphenylphosphine (9.80 mg, 0.0375 mmol) and diethyl azodicarboxylate (5.22 mg, 0.0300 mmol) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plate [NH _{3 in} CHCl ₃ (2.0 M in methanol) 2.5%] afforded the desired product (5.20 mg, 39.7% yield) as a thick oil: ¹ H NMR (CDCl ₃ ) δ7.70-7.63 (m, 2H), 7.55 (m, 1H), 7.47-7.43 (m, 3H), 7.40-7.19 (m, 3H), 7.00-6.50 (m, 2H), 6.69 (dd, 1H, J = 2.2, 8.8 Hz), 5.25 (m, 1H), 3.20 (m, 2H), 2.70 (m, 2H), 2.53 (m, 2H), 2.40-2.20 (m, 4H), 2.10-1.80 (m, 4H), 1.25 (d, 6H, J = 7.1 Hz); ESMS m / e: 525.4 (M + H) ⁺
[865] Example 56
[866] 2-methyl-N- (3- {1-[(3R) -3-phenoxy-3-phenylpropyl] -4-piperidinyl} phenyl) propanamide: N- (3- in THF (1.0 mL) {1-[(3S) -3-hydroxy-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide (9.53 mg, 0.0250 mmol), phenol (4.70 mg, 0.050 mmol), A mixture of triphenylphosphine (9.80 mg, 0.0375 mmol) and diethyl azodicarboxylate (5.22 mg, 0.0300 mmol) was stirred at rt for 3 days. Chromatography with silica preparative TLC plate [NH _{3 in} CHCl ₃ (2.0 M in methanol) 2.5%] afforded the desired product (4.1 mg, 36.0% yield) as a thick oil: ¹ H NMR (400 MHz , CDCl ₃ ) δ 7.45 (s, 1H), 7.40-7.15 (m, lOH), 6.97 (d, 1H, J = 7.6 Hz), 6.88-6.82 (m, 2H), 5.26 (m, 1H), 3.18 (m, 2H), 2.75 (m, 2H), 2.53 (m, 2H), 2.40-2.10 (m, 4H), 2.10-1.80 (m, 4H), 1.25 (d, 6H, J = 6.9 Hz) ; ESMS m / e: 457.4 (M + H) ⁺
[867] Example 57
[868] N- (3- {1-[(3R) -3-hydroxy-3-phenylpropyl] -4-piperidyl} phenyl) -2-methylpropanamide
[869] Method A
[870] In a 25 mL RB flask, (R)-(+)-3-chloro-1-phenyl-1-propanol (0.545 g, 3.19 mmol, 99% ee, Aldrich Chemical Co.), 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide (0.748 g, 3.04 mmol), potassium carbonate (0.420 g, 3.04 mmol) and sodium iodide (0.684 g, 4.56 mmol) and DMF (6.0 mL) Was added. After stirring at 100 ° C. for 3 hours, TLC showed the reaction was complete. The reaction mixture was 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. The residue was purified by flash chromatography (1: 1 = hexanes: ethyl acetate with 1% isopropylamine) to afford the desired product (1.09 g, 94.3% yield) as a pale yellow solid: ¹ H NMR (400 MHz, CDCl ₃ ) 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) ⁺
[871] Hydrogen chloride salts were prepared by adding a slight excess of 1 N HCl in ether (1.2 equiv) to a free base solution in dichloromethane. The solvent was removed under reduced pressure, the residue was washed with ether and dried under reduced pressure: Analytical calculation for C ₂₄ H ₃₂ N ₂ O ₂ + HCl + 0.8H ₂ 0: C, 66.82; H, 8.08; N, 6.49; Cl, 8.22. Found: C, 66.90; H, 7.78; N, 6.63; Cl, 8.52.
[872] Method B
[873] In a 25 mL RB flask (R)-(+)-3-chloro-1-phenyl-1-propanol (0.426 g, 2.50 mmol), 2-methyl-N- [3- (4-piperidinyl) phenyl] Propanamide (0.565 g, 2.00 mmol), diisopropylethylamine (1.29 g, 10.0 mmol), dioxane (5.0 mL) and a catalytic amount of tetrabutylammonium iodide were added at room temperature. After stirring at 90 ° C. for 72 hours, the reaction mixture is poured into water (50 mL) and the aqueous layer is extracted with methylene chloride (3 × 20 mL). The combined organic extracts were washed with brine (20 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative TLC plate (1: 5: 100 = isopropylamine: methanol: ethyl acetate) to afford the desired product (0.260 g, 34.2% yield) as a pale yellow solid.
[874] Example 58
[875] N- (3- {1-[(3S) -3- (4-cyano-phenoxy) -3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: N- (3 -{1-[(3S) -3- (4-cyanophenoxy) -3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide
[876] N- (3- {l-[(3R) -3-hydroxy-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide (5.20 mg, 0.0137 mmol in THF (0.50 mL) ), 4-cyanophenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) were stirred at room temperature for 3 days. Chromatography using silica preparative TLC plate [NH _{3 in} CHCl ₃ (2.0 M in methanol) 2.5%] afforded the desired product (4.70 mg, 71.3% yield) as a thick oil: ¹ H NMR (400 MHz , CDCl ₃ ) δ 7.54 (m, 2H), 7.48 (d, 2H, J = 8.4 Hz), 7.30-7.20 (m, 3H), 7.20 (m, 3H), 6.97 (obvious d, 1H, J = 8.4 Hz), 6.92 (apparent d, 2H, J = 8.4 Hz), 5.36 (apparent dd, 1H, J = 3.9, 7.6 Hz), 3.12 (m, 2H), 2.61 (m, 2H), 2.53 (obvious 7 Midline, partially hidden, 2H, J = 7.6 Hz), 2.30-2.10 (m, 6H), 1.82 (m, 2H), 1.25 (d, 6H, J = 6.8 Hz); ESMS m / e: 482.2 (M + H) ⁺
[877] Example 59
[878] N- (3- {1-[(3S) -3- (4-fluorophenoxy) -3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: THF (0.50 mL) N- (3- {1-[(3R) -3-hydroxy-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide (5.20 mg, 0.0137 mmol) in 4-fluoro A mixture of rophenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plate [NH _{3 in} CHCl ₃ (2.0 M in methanol) 2.5%] afforded the desired product (4.20 mg, 64.7% yield) as a thick oil: ¹ H NMR (400 MHz , CDCl ₃ ) δ 7.40 (m, 2H), 7.30-7.20 (m, 5H), 7.20 (m, 3H), 6.97 (apparent d, 1H, J = 7.7 Hz), 6.87 (m, 1H), 6.76 (m, 1H), 5.26 (apparent dd, 1H, J = 4.0, 8.1 Hz), 3.09 (m, 2H), 2.66 (m, 2H), 2.51 (m, 2H), 2.3-2.1 (m, 6H) , 1.82 (m, 2 H), 1.25 (d, 6 H, overlapped); ESMS m / e: 475.2 (M + H) ⁺
[879] Example 60
[880] N- (3- {1-[(3S) -3- (4-fluorophenoxy) -3-phenylpropyl) -4-piperidinyl} phenyl) -2-methylpropanamide: THF (0.50 mL) N- (3- {1-[(3R) -3-hydroxy-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide (5.20 mg, 0.0137 mmol) in 4-fluoro A mixture of rophenol (100 mg), triphenylphosphine (30.0 mg. 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plate [NH _{3 in} CHCl ₃ (2.0 M in methanol) 2.5%] afforded the desired product (0.70 mg, 9.6% yield) as a thick oil: ¹ H NMR (400 MHz , CDCl ₃ ) δ 8.06 (s, 1H), 7.48 (m, 2H), 7.30-7.20 (m, 5H), 7.20 (m, 3H), 6.97 (obvious d, 1H, J = 8.5 Hz), 6.73 (Clear d, 2H, J = 8.5 Hz), 5.22 (Clear dd, 1H, J = 4.9, 7.8 Hz), 3.15 (m, 2H), 2.65 (m, 2H), 2.51 (Clear sinter, partially hidden Load, 2H, J = 7.6 Hz), 2.30-2.10 (m, 6H), 1.82 (m, 2H), 1.25 (d, 6H, J = 6.8 Hz); ESMS m / e: 535.1 (M + H) ⁺
[881] Example 61
[882] N- (3- {1-[(3S) -3- (3-methoxyphenoxy) -3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: THF (0.50 mL) N- (3- {1-[(3R) -3-hydroxy-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide (5.20 mg, 0.0137 mmol) in 3-meth A mixture of oxyphenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plate [NH _{3 in} CHCl ₃ (2.0 M in methanol) 2.5%] afforded the desired product (3.1 mg, 46.6% yield) as a thick oil: ¹ H NMR (400 MHz , CDCl ₃ ) δ 7.47 (d, 1H, J = 6.7 Hz), 7.42 (s, 1H), 7.3-7.20 (m, 3H), 7.20 (m, 3H), 7.07 (t, 1H, J = 8.4 Hz), 6.97 (apparent d, 1H, J = 6.7 Hz), 6.40 (m, 3H), 5.27 (apparent dd, 1H, J = 5.3, 8.0 Hz), 3.74 (s, 3H), 3.38 (m, 2H ), 2.93 (m, 2H), 2.61 (s, 1H), 2.53 (obvious sinter, partially hidden, 1H, J = 6.5 Hz), 2.30-2.10 (m, 6H), 1.82 (m, 2H) , 1.25 (d, 6H, J = 6.9 Hz); ESMS m / e: 487.3 (M + H) ⁺
[883] Example 62
[884] N- (3- {1-[(3S) -3- (4-cyano-2-methoxyphenoxy) -3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: N- (3- {1-[(3R) -3-hydroxy-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide (5.20 mg, 0.0137 mmol in THF (0.50 mL) ), A mixture of 2-methoxy-4-cyanophenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) at room temperature for 3 days Was stirred. Chromatography using silica preparative TLC plate [NH _{3 in} CHCl ₃ (2.0 M in methanol) 2.5%] afforded the desired product (5.50 mg, 76.5% yield) as a thick oil: ¹ H NMR (400 MHz , CDCl ₃ ) δ 7.51 (s, 1H), 7.38 (s, 1H), 7.37 (d, 2H, J = 2.4 Hz), 7.20 (m, 4H), 7.10 (d, 1H, J = 2.4 Hz) , 7.08 (s, 1H), 6.99 (apparent d, 1H, J = 8.3 Hz), 6.76 (apparent d, 1H, J = 8.3 Hz), 5.43 (apparent dd, 1H, J = 5.1, 8.0 Hz), 3.91 (s, 3H), 3.34 (m, 2H), 2.63 (m, 2H), 2.63 (s, 1H), 2.53 (apparent strait, partially hidden, 1H, J = 7.7 Hz), 2.30-2.10 ( m, 6H), 1.82 (m, 2H), 1.28 (d, 6H, J = 6.8 Hz); ESMS m / e: 512.2 (M + H) ⁺
[885] Example 63
[886] N- (3- {1-[(3S) -3- (5-acetyl-2-methoxyphenoxy) -3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: THF N- (3- {1-[(3R) -3-hydroxy-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide (5.20 mg, 0.0137 mmol) in (0.50 mL) , A mixture of 2-methoxy-5-acetylphenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) was stirred at room temperature for 3 days It was. Chromatography using silica preparative TLC plate [NH _{3 in} CHCl ₃ (2.0 M in methanol) 2.5%] afforded the desired product (1.60 mg, 22.2% yield) as a thick oil: ¹ H NMR (400 MHz , CDCl ₃ ) δ 7.52 (d, 2H, J = 2.4 Hz), 7.3-7.2 (m, 5H), 7.20 (m, 3H), 6.97 (obvious d, 1H, J = 6.7 Hz), 6.69 (obvious) d, 1H, J = 8.0 Hz), 5.47 (apparent dd, 1H, J = 4.3, 7.8 Hz), 3.95 (s, 3H), 3.38 (m, 2H), 2.93 (m, 2H), 2.61 (s, 1H), 2.53 (apparent saturation, partially hidden, 1H, J = 7.6 Hz), 2.50 (s, 3H), 2.30-2.10 (m, 6H), 1.82 (m, 2H), 1.25 (d, 6H , J = 6.8 Hz); ESMS m / e: 529.6 (M + H) ⁺
[887] Example 64
[888] N- (3- {1- (3R) -3- (2-acetylphenoxy) -3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: N in THF (0.50 mL) -(3- {1-[(3S) -3-hydroxy-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide (5.2 mg, 0.0137 mmol), 2-acetylphenol ( 100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and a mixture of diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) were stirred at room temperature for 3 days. Chromatography with silica preparative TLC plate [NH _{3 in} CHCl ₃ (2.0 M in methanol) 2.5%] afforded the desired product (1.70 mg, 24.9% yield) as a thick oil: ¹ H NMR (400 MHz , CDCl ₃ ) δ7.65 (m, 1H), 7.55 (s, 1H), 7.30-7.20 (m, 5H), 7.20 (m, 3H), 6.97 (m, 2H), 6.76 (obvious d, 1H) , 5.49 (apparent dd, 1H, J = 4.3, 8.0 Hz), 3.38 (m, 2H), 2.93 (m, 2H), 2.71 (s, 3H), 2.60 (s, 1H), 2.53 (apparent strait, Partially hidden, 1H, J = 7.6 Hz), 2.30-2.10 (m, 6H), 1.82 (m, 2H), 1.25 (d, 6H, J = 6.9 Hz); ESMS m / e: 498.8 (M ⁺ ).
[889] Example 65
[890] N- [3- (1-{(3R) -3- [2-fluoro-5- (trifluoromethyl) phenoxy] -3-phenylpropyl} -4-piperidinyl) phenyl] -2- Methylpropanamide: N- (3- {1-[(3S) -3-hydroxy-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide (5.20) in THF (0.50 ml) mg, 0.0137 mmol), 2-fluoro-5-trifluoromethylphenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) The mixture was stirred at rt for 3 days. Chromatography using silica preparative TLC plate [NH _{3 in} CHCl ₃ (2.0 M in methanol) 2.5%] afforded the desired product (2.50 mg, 33.7% yield) as a thick oil: ¹ H NMR (400 MHz , CDCl ₃ ) δ 8.07 (s, 1H), 7.67 (m, 1H), 7.54 (m, 1H), 7.45 (m, 2H), 7.30-7.10 (m, 6H), 7.14 (d, 1H, J = 7.4 Hz), 6.97 (apparent d, 1H, J = 7.7 Hz), 5.37 (apparent dd, 1H, J = 5.0, 8.5 Hz), 3.4 (m, 2H), 2.8 (m, 2H), 2.6 (s , 1H), 2.53 (apparent saturation, partially hidden, 1H, J = 7.4 Hz), 2.30-2.10 (m, 6H), 1.80 (m, 2H), 1.25 (d, 6H, J = 7.1 Hz, Overlap); ESMS m / e: 542.6 (M ⁺ ), 543.54 (M + H) ⁺
[891] Example 66
[892] N- [3- (1-{(3S) -3- [2-fluoro-5- (trifluoromethyl) phenoxy] -3-phenylpropyl} -4-piperidinyl) phenyl] -2- Methylpropanamide: N- (3- {1-[(3R) -3-hydroxy-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide (5.20) in THF (0.50 mL) mg, 0.0137 mmol), 2-fluoro-5-trifluoromethylphenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) The mixture was stirred at rt for 3 days. Chromatography using silica preparative TLC plate [NH _{3 in} CHCl ₃ (2.0 M in methanol) 2.5%] afforded the desired product (3.00 mg, 40.4% yield) as a thick oil: ¹ H NMR (400 MHz , CDCl ₃ ) δ 8.06 (s, 1H), 7.67 (m, 2H), 7.55 (m, 2H), 7.50-7.40 (m, 3H), 7.30-7.10 (m, 3H), 7.17 (d, 1H , J = 8.9 Hz), 7.07 (apparent d, 1H, J = 6.7 Hz), 6.97 (apparent d, 1H, J = 7.8 Hz), 5.37 (apparent dd, 1H, J = 4.2, 8.1 Hz), 3.37 ( m, 2H), 2.93 (m, 2H), 2.63 (s, 1H), 2.50 (obvious quintet, partially hidden, 1H, J = 7.9 Hz), 2.30-2.10 (m, 6H), 1.85 (m , 2H), 1.25 (d, 6H, J = 6.9 Hz); ESMS m / e: 542.7 (M + H) ⁺
[893] Example 67
[894] N- (3- {1-[(3S) -3- (2,5-difluorophenoxy) -3-phenylpropyl-4-piperidinyl} phenyl) -2-methylpropanamide: THF (0.50 N- (3- {1-[(3R) -3-hydroxy-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide (5.20 mg, 0.0137 mmol) in 2 mL), 2 A mixture of, 5-difluorophenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plate [NH _{3 in} CHCl ₃ (2.0 M in methanol) 2.5%] afforded the desired product (2.70 mg, 40.1% yield) as a thick oil: ¹ H NMR (400 MHz , CDCl ₃ ) δ 7.46 (s, 1H), 7.40-7.30 (m, 4H), 7.20 (m, 2H), 7.17 (s, 1H), 6.97 (m, 2H), 6.58 (m, 1H), 6.51 (m, 1H), 5.27 (apparent dd, 1H, J = 5.1, 8.2 Hz), 3.13 (apparent d, J = 9.7 Hz, 2H), 2.64 (m, 2H), 2.51 (m, 2H), 2.34 (Apparent quartet, partially hidden, J = 7.1 Hz, 1H), 2.17 (m, 3H), 1.90-1.80 (m, 4H), 1.25 (d, 6H, J = 7.1 Hz); ESMS m / e: 493.1 (M + H) ⁺
[895] Example 68
[896] N- (3- {1-[(3R) -3- (3-chlorophenoxy) -3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: in THF (0.50 mL) N- (3- {1-[(3S) -3-hydroxy-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide (5.20 mg, 0.0137 mmol), 3-chlorophenol (100 mg), a mixture of triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plate [NH _{3 in} CHCl ₃ (2.0 M in methanol) 2.5%] afforded the desired product (2.4 mg, 35.8% yield) as a thick oil: ¹ H NMR (400 MHz , CDCl ₃ ) δ7.30 (m, 2H), 7.30-7.20 (m, 3H), 7.20 (m, 3H), 6.90 (apparent d, 1H, J = 7.7 Hz), 6.71 (apparent d, 1H, J = 2.9 Hz), 6.69 (Clear t, 1H, J = 2.9 HZ), 6.67 (Clear t, 1H, J = 2.9 Hz), 6.65 (Clear d, 1H, J = 2.9 Hz), 5.09 (Clear dd, 1H , J = 4.8, 8.1 Hz), 3.18 (m, 2H), 2.73 (m, 2H), 2.50 (apparent strait, partially hidden, 2H, J = 7.1 Hz), 2.30-2.10 (m, 6H) , 1.89 (m, 2 H), 1.25 (d, 6 H, overlapped); ESMS m / e: 491.1 (M + H) ⁺
[897] Example 69
[898] (1S) -3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} -1-phenylpropyl 1-naphthoate: N in THF (0.50 mL) in a 25 mL RB flask -(3- {1-[(3S) -3-hydroxy-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide (5.20 mg, 0.0137 mmol), l-naphthalenecarbonyl Chloride (100 mg), diisopropylethylamine (0.30 mL) were added at room temperature. After stirring for 16 hours at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified using preparative TLC plate [NH _{3 in} CHCl ₃ (2.0 M in methanol) 2.5%] to afford the desired product (4.70 mg, 71.3% yield) as a thick oil: ¹ H NMR (400 MHz , CDCl ₃ ) δ8.90 (d, 1H, J = 8.9 Hz), 8.28 (apparent dd, 1H, J = 1.5, 7.2 Hz), 8.03 (d, 1H, J = 8.7 Hz), 7.88 (dm, 2H , J = 8.7 Hz), 7.60-7.48 (m, 7H), 7.40-7.32 (m, 3H), 7.25 (m, 1H), 6.90 (obvious d, 1H, J = 7.4 Hz), 6.18 (obvious dd, 1H, J = 5.7, 7.8 Hz), 3.42 (m, 2H), 2.84 (m, 2H), 2.53 (m, 2H), 2.44 (clear strait, partially hidden, 4H, J = 7.5 Hz), 2.30-2.10 (m, 2H), 1.82 (m, 2H), 1.25 (d, 6H, J = 6.8 Hz); ESMS m / e: 535.6 (M + H) ⁺
[899] Example 70
[900] N- (3- {1-[(3S) -3- (3-acetylphenoxy) -3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: in THF (0.50 mL) N- (3- {1-[(3R) -3-hydroxy-3-phenylpropyll-4-piperidinyl} phenyl) -2-methylpropanamide (5.20 mg, 0.0137 mmol), 2-acetylphenol (100 mg), a mixture of triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plate [NH _{3 in} CHCl ₃ (2.0 M in methanol) 2.5%] afforded the desired product (1.50 mg, 22.0% yield) as a thick oil: ¹ H NMR (400 MHz , CDCl ₃ ) δ7.65 (m, 1H), 7.55 (s, 1H), 7.30-7.20 (m, 5H), 7.20 (m, 3H), 6.97 (m, 2H), 6.76 (obvious d, 1H) , 5.49 (apparent dd, 1H, J = 4.3, 8.0 Hz), 3.38 (m, 2H), 2.93 (m, 2H), 2.75 (s, 3H), 2.53 (obvious sinter, partially hidden, 2H, J = 7.6 Hz), 2.30-2.10 (m, 6H), 1.92 (m, 2H), 1.25 (d, 6H, J = 6.9 Hz); ESMS m / e: 498.81 (M ⁺ ), 499.6 (M + H) ⁺
[901] Example 71
[902] N- (3- {1-[(3S) -3- (2-fluorophenoxy) -3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: THF (0.50 mL) N- (3- {l-[(3R) -3-hydroxy-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide (5.20 mg, 0.0137 mmol) in 2-fluoro A mixture of rophenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plate [NH _{3 in} CHCl ₃ (2.0 M in methanol) 2.5%] afforded the desired product (3.5 mg, 53.9% yield) as a thick oil: ¹ H NMR (400 MHz , CDCl ₃ ) δ 8.07 (s, 1H), 7.65 (m, 1H), 7.41 (s, 1H), 7.40-7.10 (m, 5H), 7.05 (m, 2H), 6.97 (obvious d, 1H, J = 8.7 Hz), 6.86 (m, 2H), 6.79 (apparent dt, 1H, J = 2.4, 7.9 Hz), 5.31 (apparent dd, 1H, J = 4.5, 8.0 Hz), 3.39 (m, 2H), 2.97 (m, 2H), 2.53 (obvious sinter, partially hidden, 2H, J = 7.5 Hz), 2.3-2.1 (m, 6H), 1.92 (m, 2H), 1.25 (d, 6H, J = 6.7 Hz); ESMS m / e: 475.7 (M + H) ⁺
[903] Example 72
[904] (4S) -N- (3- {4- [3- (acetylamino) phenyl] -1-piperidinyl} propyl) -4- (3,5-difluorophenyl) -2-oxo-1, 3-oxazolidine-3-carboxamide
[905] Method: N1- {3- [1- (3-aminopropyl) -4-piperidinyl] phenyl} acetamide (15 mg, 0.054 mmol), (4S) -4- (3,5 in a 20 mL glass bottle Dichloromethane (3 mL) together with -difluorophenyl) -2-oxo-oxazolidine-3-carboxylic acid-4-nitro-phenyl ester (39.3 mg, 1.08 mmol, 2 equiv) and 0.6% methanol Add at room temperature. After stirring at room temperature for 3 hours, the reaction mixture was filtered and purified by preparative silica TLC (19: 1 = chloroform: methanol) to give the desired product (18.3 mg, 68% yield): ¹ H NMR ( 400 MHz, CDCl ₃ ) δ 8.09 (br s, 1H), 7.40 (d, 1H, J = 8.0 Hz), 7.36-7.28 (m, 2H), 7.24 (t, 1H, J = 8.0 Hz), 6.99 (d, 1H, J = 8.0 Hz), 6.86-6.82 (m, 2H), 5.41 (dd, 1H, J = 4.1, 9.0 Hz), 4.72 (t, 1H, J = 9.0 Hz), 4.22 (dd, 1H, J = 3.9, 9.1 Hz), 3.42-3.29 (m, 2H); 3.02 (d, 2H, J = 11.1 Hz), 2.52-2.38 (m, 3H), 2.16 (s, 3H), 2.08-1.98 (m, 2H), 1.86-1.70 (m, 6H); ESMS m / e: 501.2 (M + H) ⁺ Analytical Calcd for C ₂₆ H ₃₀ F ₂ N ₄ 0 ₄ + 0.5H ₂ 0: C, 60.64; H, 6. 18; N, 10.88. Found: C, 60.67; H, 5.79; N, 10.86.
[906] Example 73
[907] The synthesis method is (4S) -N- (3- {4- [3- (acetylamino) phenyl] -1-piperidinyl} propyl) -4- (3,5-difluorophenyl) -2-oxo Same as described for -1,3-oxazolidine-3-carboxamide.
[908] (4S) -N- (3- {4- [3- (acetylamino) phenyl] -1-piperidinyl} propyl) -2-oxo-4- (3,4,5-trifluorophenyl)- 1,3-oxazolidine-3-carboxamide: 18.8 mg (67% yield); ¹ H NMR (400 MHz, CDCl ₃ ) δ8.09 (br s, 1H), 7.41-7.20 (m, 3H), 7.02-6.91 (m, 3H), 5.37 (dd, 1H, J = 3.8, 8.9 Hz ), 4.71 (t, 1H, J = 9 Hz), 4.21 (dd, 1H, J = 4, 9.3 Hz), 3.43-3.27 (m, 2H), 3.02 (d, 2H, J = 11.0 Hz), 2.53 -2.37 (m, 3H), 2.16 (s, 3H), 2.08-1.97 (m, 2H), 1.85-1.69 (m, 6H); ESMS m / e: 519.2 (M + H) ⁺ ; Analytical calcd. For C ₂₆ H ₂₉ F ₃ N ₄ O ₄ + 0.5H ₂ O: C, 59.20; H, 5.73; N, 10.62. Found: C, 59.40; H, 5. 35; N, 10.65.
[909] Example 74
[910] The synthesis method is (4S) -N- (3- {4- [3- (acetylamino) phenyl] -1-piperidinyl} propyl) -4- (3,5-difluorophenyl) -2-oxo Same as described for -1,3-oxazolidine-3-carboxamide.
[911] N- (3- {4- (3- (acetylamino) phenyl] -1-piperidinyl} propyl) -4- (3,4-difluorophenyl) -5,5-dimethyl-2-oxo- 1,3-oxazolidine-3-carboxamide: 19.6 mg (68% yield); ¹ H NMR (400 MHz, CDCl ₃ ) δ8.18 (t, 1H, J = 5.9 Hz), 7.41 (d, 1H, J = 8.8 Hz), 7.33 (s, 1H), 7.27-7.14 (m, 2H), 7.02-6.88 (m, 3H), 5.04 (s, 1H), 3.34 (qm, 2H, J = 6.3 Hz ), 3.02 (dm, 2H, J = 10.9 Hz), 2.53-2.38 (m, 3H), 2.16 (s, 3H), 2.07-1.96 (m, 2H), 1.87-1.69 (m, 6H), 1.62 ( s, 3H), 1.02 (s, 3H); ESMS m / e: 529.3 (M + H) ⁺ ; C ₂₈ H ₃₄ F ₂ N ₄ 0 ₄ : C, 63.62; H, 6.48; N, 10.60. C, 63.15; H, 6.27; N, 10.48.
[912] Example 75
[913] The synthesis method is (4S) -N- (3- {4- [3- (acetylamino) phenyl] -1-piperidinyl} propyl) -4- (3,5-difluorophenyl) -2-oxo Same as described for -1,3-oxazolidine-3-carboxamide.
[914] (4S, 5R) -N- (3- {4- [3- (acetylamino) phenyl] -1-piperidinyl} propyl) -4- (3,4-difluorophenyl) -5-methyl- 2-oxo-1,3-oxazolidine-3-carboxamide: 20.5 mg (74% yield); ¹ H NMR (400 MHz, CDCl ₃ ) δ8.14 (t, 1H, J = 5.5 Hz), 7.40 (d, 1H, J = 7.8 Hz), 7.37-6.89 (m, 6H), 5.35 (d, 1H , J = 7.5 Hz), 5.02-4.93 (m, 1H), 3.41-3.25 (m, 2H), 3.02 (d, 2H, J = 10.8 Hz), 2.53-2.37 (m, 3H), 2.16 (s, 3H), 2.07 (m, 2H), 1.89-1.68 (m, 6H), 1.04 (d, 3H, J = 6.4 Hz); ESMS m / e: 515.3 (M + H) ⁺ ; Analytical calcd. For C ₂₇ H ₃₂ F ₂ N ₄ 0 ₄ + 0.5H ₂ 0: C, 61.94; H, 6. 35; N, 10.70. Found: C, 61.90; H, 6. 13; N, 10.64.
[915] Example 76
[916] The synthesis method is (4S) -N- (3- {4- [3- (acetylamino) phenyl] -1-piperidinyl} propyl) -4- (3,5-difluorophenyl) -2-oxo Same as described for -1,3-oxazolidine-3-carboxamide.
[917] N- (3- {4- [3- (acetylamino) phenyl] -1-piperidinyl} propyl) -4- (4-fluorobenzyl) -2-oxo-1,3-oxazolidine-3 -Carboxamide: 17.4 mg (65% yield); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.08 (t, 1H, J = 5.6 Hz), 7.4 (d, 1H, J = 7.2 Hz), 7.34 (s, 1H), 7.28-7.14 (m, 3H ), 7.05-6.95 (m, 3H), 4.69-4.60 (m, 1H), 4.26 (t, 1H, J = 8.8 Hz), 4.15 (dd, 1H, J = 3.2, 9 Hz), 3.43 (q, 2H, J = 6.2 Hz), 3.3 (dm, 1H, J = 13.6 Hz), 3.04 (dm, 2H, J = 11 Hz), 2.87 (dd, 1H, J = 9.3, 14.4 Hz), 2.53-2.42 ( m, 3H), 2.16 (s, 3H), 2.09-1.99 (m, 2H), 1.87-1.65 (m, 6H); ESMS m / e: 497.3 (M + H) ⁺ ; Analytical calcd. For C ₂₇ H ₃₃ FN ₄ 0 ₄ + 0.5H ₂ O: C, 64.14; H, 6. 78; N, 11.08. Found: C, 64.26; H, 6.39; N, 11.12.
[918] Example 77
[919] 2-methyl-N- (3- {1-[(3R) -3- (2-nitrophenoxy) -3-phenylpropyl] -4-piperidinyl} phenyl) propanamide: in THF (0.50 mL) N- (3- {1-[(3S) -3-hydroxy-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide (5.20 mg, 0.0137 mmol), 2-nitrophenol (100 mg), a mixture of triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plate [NH _{3 in} CHCl ₃ (2.0 M in methanol) 2.5%] afforded the desired product (2.37 mg, 34.5% yield) as a thick oil: ¹ H NMR (400 MHz , CDCl ₃ ) δ 7.84 (d, 1H), 7.90 (m, 1H), 7.45 (m, 1H), 7.30-7.20 (m, 5H), 7.20 (m, 2H), 6.98 (m, 2H), 6.89 (apparent d, 1H, J = 7.7 Hz), 5.62 (apparent dd, 1H, J = 4.1, 8.9 Hz), 3.10 (m, 2H), 2.60 (m, 2H), 2.53 (m, 2H), 2.30 -2.10 (m, 6H), 1.90 (m, 2H), 1.25 (d, 6H, overlapped); ESMS m / e: 502.3 (M + H) ⁺
[920] Example 78
[921] N- (3- {1-[(3S) -3-([1,1'-biphenyl] -4-yloxy) -3-phenylpropyl-4-piperidinyl} phenyl) -2-methylpropane Amide: N- (3- {1-[(3R) -3-hydroxy-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide (5.20 mg, in THF (0.50 mL), 0.0137 mmol), 4-phenylphenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) were stirred at room temperature for 3 days. Chromatography using silica preparative TLC plate [NH _{3 in} CHCl ₃ (2.0 M in methanol) 2.5%] afforded the desired product (3.00 mg, 41.2% yield) as a thick oil: ¹ H NMR (400 MHz , CDCl ₃ ) δ 8.06 (s, 1H), 7.48 (m, 2H), 7.40-7.30 (m, 8H), 7.30-7.25 (m, 4H), 6.97 (obvious d, 1H, J = 7.6 Hz) , 6.91 (apparent d, 2H, J = 8.7 Hz), 5.34 (apparent dd, 1H, J = 4.4, 8.0 Hz), 3.40 (m, 2H), 2.98 (m, 2H), 2.53 (apparent sinter, partial Hidden by, 1H, J = 8.1 Hz), 2.44 (m, 1H), 2.30-2.10 (m, 6H), 1.93 (d, 2H), 1.26 (d, 6H, J = 6.9 Hz); ESMS m / e: 533.4 (M + H) ⁺
[922] Example 79
[923] 2-methyl-N- (3- {1-[(3R) -3- (3-nitrophenoxy) -3-phenylpropyl-4-piperidinyl} phenyl) propanamide: N in THF (0.50 mL) -(3- {1-[(3S) -3-hydroxy-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide (5.20 mg, 0.0137 mmol), 3-nitrophenol ( 100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) were stirred at room temperature for 3 days. Chromatography using silica preparative TLC plate [NH _{3 in} CHCl ₃ (2.0 M in methanol) 2.5%] afforded the desired product (2.80 mg, 40.8% yield) as a thick oil: ¹ H NMR (400 MHz , CDCl ₃ ) δ7.76 (dm, 1H), 7.71 (t, 1H, J = 1.8 Hz), 7.50-7.40 (m, 2H), 7.40-7.25 (m, 7H), 7.17 (obvious dd, 1H, J = 2.4, 8.2), 6.97 (apparent d, 1H, J = 7.7 Hz), 5.45 (apparent dd, 1H, J = 5.0, 8.1 Hz), 3.45 (m, 2H), 2.89 (m, 2H), 2.53 (Apparent quartet, partially hidden, 2H, J = 8.3 Hz), 2.30-2.10 (m, 6H), 1.92 (m, 2H), 1.25 (d, 6H, J = 6.8 Hz); ESMS m / e: 502.3 (M + H) ⁺
[924] Example 80
[925] N- (3- {1-[(3S) -3- (2-ethoxyphenoxy) -3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: THF (0.50 mL) N- (3- {1-[(3R) -3-hydroxy-3-phenylpropyl) -4-piperidinyl} phenyl-2-methylpropanamide (5.20 mg, 0.0137 mmol), 2-ethoxy in A mixture of phenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) was stirred at rt for 3 days. Chromatography with silica preparative TLC plate [NH _{3 in} CHCl ₃ (2.0 M in methanol) 2.5%] afforded the desired product (1.16 mg, 15.5% yield) as a thick oil: ¹ H NMR (400 MHz , CDCl ₃ ) δ 8.06 (s, 1H), 7.52 (s, 1H), 7.40-7.33 (m, 4H), 7.30-7.20 (m, 3H), 6.97 (obvious d, 1H, J = 7.7 Hz) , 6.88 (m, 2H), 6.68 (m, 2H), 5.21 (m, 1H), 4.11 (q, 2H, J = 7.3 Hz), 3.37 (m, 2H), 2.71 (m, 2H), 2.53 ( Obvious strait, partially hidden, 2H, J = 7.6 Hz), 2.30-2.10 (m, 6H), 1.89 (m, 2H), 1.49 (t, 3H, J = 7.3 Hz), 1.25 (d, 6H , J = 6.8 Hz); ESMS m / e: 501.4 (M + H) ⁺
[926] Example 81
[927] 2-methyl-N- (3- {1-[(3S) -3- (l-naphthyloxy) -3-phenylpropyl] -4-piperidinyl} phenyl) propanamide: in THF (0.50 mL) N- (3- {1-[(3R) -3-hydroxy-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide (5.20 mg, 0.0137 mmol), 1-naphthol ( 100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) were stirred at room temperature for 3 days. Chromatography using silica preparative TLC plate [NH _{3 in} CHCl ₃ (2.0 M in methanol) 2.5%] gave the desired product (4.30 mg, 66.2% yield) as a thick oil: ¹ H NMR (400 MHz , CDCl ₃ ) δ 8.06 (s, 1H), 7.72 (d, 1H, J = 8.5 Hz), 7.59 (d, 1H, J = 8.5 Hz), 7.5 (m, 2H), 7.45-7.30 (m, 6H), 7.25 (m, 3H), 7.17 (apparent dd, 1H, J = 2.6, 9.0 Hz), 7.01 (apparent d, 1H, J = 2.6 Hz), 6.97 (apparent d, 1H, J = 7.9 Hz) , 5.46 (apparent dd, 1H, J = 4.5, 8.1 Hz), 3.12 (m, 2H), 2.61 (m, 2H), 2.53 (apparent strait, partially hidden, 2H, J = 7.9 Hz), 2.30 -2.10 (m, 6H), 1.90 (m, 2H), 1.25 (d, 6H, J = 7.3 Hz, overlapped); ESMS m / e: 507.2 (M + H) ⁺
[928] Example 82
[929] N- (3- {1-[(3S) -3- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) -3-phenylpropyl] -4-piperidi Nyl} phenyl) -2-methylpropanamide
[930] Step 1:
[931] 2-[(1S) -3-chloro-1-phenylpropyl] -1H-isoindole-1,3 (2H) -dione: Srebnik, M .; Ramachandran, PV; Brown, HCJ Org. Chem. 1988, 53, 2916-2920, phthalimide (0.147 g, 1.0 mmol), (R)-(+)-3-chloro-phenyl-1-propanol (0.171 g, 1.0 mmol) in 5.0 mL of THF. , A mixture of triphenylphosphine (0.262 g, 1.0 mmol) and diethyl azodicarboxylate (0.174 g, 1.0 mmol) was stirred at rt for 24 h. The reaction mixture was concentrated in vacuo. The residue was washed with pentane (× 3), the combined pentane extracts were concentrated and chromatographed (performed on silica with hexane-EtOAc 8: 1 as eluent) to afford the desired product (0.121 g, 50.2%) as a yellow solid. Obtained as: ¹ H NMR (400 MHz, CDCl ₃ ) 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 (apparent saturation, 1H, J = 7.0 Hz) ; ESMS m / e: 300.13 (M + H) ⁺
[932] Step 2:
[933] N- (3- {1-[(3S) -3- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) -3-phenylpropyl] -4-piperidi Nil} phenyl) -2-methylpropanamide: potassium carbonate (29.2 mg, 0.211 mmol) in DMF (5.0 mL), sodium iodide (47.5 mg, 0.317 mmol), 2-methyl-N- [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) was stirred at 100 ° C. for 3 hours and by 3 hours TLC showed the reaction was complete. The reaction mixture was 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 Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by preparative TLC plate to give [NH _{3 in} CHCl ₃ (2.0 M in methanol) 2.5%], the desired product (74.1 mg, 77.1%) as a thick oil: ¹ H NMR (400 MHz, CDCl). ₃ ) 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, 1H, J = 7.8 Hz), 7.09 (s, 1H), 6.81 (apparent d, 1H, 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 (apparent saturation, 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: 510.37 (M + H) ⁺
[934] Example 83
[935] 2-methyl-N- (3- {1-[(3S) -3- (4-phenoxyphenoxy) -3-phenylpropyl] -4-piperidinyl} phenyl) propanamide
[936] Step 1:
[937] 4-{[(1S) -3-chloro-1-phenylpropyl] oxy}-(4-phenoxy) benzene: 4-phenoxyphenol (1.86 g, 10.0 mmol) in 5.0 mL of THF, (R)-( -)-3-chloro-phenyl-1-propanol (1.70 g, 10.0 mmol), triphenylphosphine (2.62 g, 10.0 mmol), diethyl azodicarboxylate (1.57 mL, 10.0 mmol) was stirred at room temperature. Stirred for 24 h. The reaction mixture was concentrated in vacuo. The residue was washed with pentane (× 3), the combined pentane extracts were concentrated and chromatographed (performed on silica with hexane-EtOAc 97: 3 as eluent) to continue solidifying the desired product (2.51 g, 75.7%). Obtained as a thick oil: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.4-7.23 (m, 7H), 7.03 (apparent t, 1H, J = 7.3 Hz), 6.91 (apparent dm, 2H, J = 7.8 Hz), 6.93 (Clear q, 4H, J = 7.8 Hz), 5.31 (Clear dd, 1H, J = 4.5, 8.6 Hz), 3.82 (m, 1H), 3.62 (Clear quintet, 1H, J = 5.6 Hz), 2.47 (m, 1 H), 2.20 (m, 1 H).
[938] Step 2:
[939] 2-methyl-N- (3- {1-[(3S) -3- (4-phenoxyphenoxy) -3-phenylpropyl] -4-piperidinyl} phenyl) propanamide: DMF (1.0 mL) 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide (65.5 mg, 0.266 mmol), 4-{[(1S) -3-chloro-1-phenylpropyl] oxy}-( A mixture of 4-phenoxy) benzene (0.100 mg, 0.296 mmol), potassium carbonate (40.9 mg, 0.296 mmol) and sodium iodide (67.0 mg, 0.444 mmol) was stirred at 100 ° C. for 3 hours. The reaction mixture was 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 Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by preparative TLC plate to give [NH _{3 in} CHCl ₃ (2.0 M in methanol) 2.5%], the desired product (0.109 g, 74.6%) as a thick oil: ¹ H NMR (400 MHz, CDCl). ₃ ) δ 7.48 (s, 1H), 7.40-7.30 (m, 4H), 7.20-7.10 (m, 6H), 7.09 (s, 1H), 6.99 (obvious d, 1H, J = 7.8 Hz), 6.98 (Apparent t, 1H, J = 7.8 Hz), 6.93 (apparent d, 2H, J = 8.4 Hz), 6.84 (m, 2H), 5.20 (apparent dd, 1H, J = 4.4, 8.5 Hz), 3.03 (m , 2H), 2.51 (m, 4H), 2.24 (apparent saturation, 1H, J = 7.8 Hz), 2.20-2.10 (m, 3H), 1.90 (m, 4H), 1.25 (d, 6H, J = 7.9 Hz); ESMS m / e: 549.41 (M + H) ⁺ ; Analytical Calcd for C ₃₆ H ₄₀ N ₂ O ₃ : C, 78.80; H, 7. 35; N, 5.11. Found: C, 78.58; H, 7. 48; N, 5.09.
[940] Example 84
[941] N- (4- {1-[(3R) -3- (3,4-dimethoxyphenoxy) -3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide
[942] Step 1:
[943] 1-[(3R) -3- (3,4-dimethoxyphenoxy) -3-phenylpropyl] -4- (4-nitrophenyl) -1,2,3,6-tetrahydropyridine: DMF (0.5 potassium carbonate (24.0 mg, 0.174 mmol), sodium iodide (39.0 mg, 0.260 mmol), 4- (4-nitrophenyl) -1,2,3,6-tetrahydropyridine (35.4 mg) , 0.174 mmol) and 4-{[(1R) -3-chloro-1-phenylpropyl] oxy} -1,2-dimethoxybenzene (53.4 mg, 0.174 mmol) were stirred at 100 ° C. for 3 hours. After that, TLC showed the reaction was complete. The reaction mixture was poured into water (5.0 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. The crude product was purified by preparative TLC plate to give [1: 1 = hexanes: ethyl acetate with 1% NH ₃ ], the desired product (63.1 mg, 76.6%) as a yellow oil. The product was used in the next reaction without further purification.
[944] Step 2:
[945] 4- {1-[(3R) -3- (3,4-dimethoxyphenoxy) -3-phenylpropyl] -4-piperidinyl} aniline in a 25 mL RB flask equipped with a hydrogen filled balloon at room temperature 1-[(3R) -3- (3,4-dimethoxyphenoxy) -3-phenylpropyl] -4- (4-nitrophenyl) -1,2,3,6-tetrahydropyridine (63.0 mg, 0.133 mmol), palladium on carbon (5.0 mol-eq%, 0.00665 mmol, 7.04 mg) and ethanol (2.0 mL). After 1 hour, the reaction mixture was charged through a Celite 545 plug and concentrated under reduced pressure. The crude product (54.1 mg, 89.4%) was used in the next reaction without further purification.
[946] Step 3:
[947] N- (4- {1-[(3R) -3- (3,4-dimethoxyphenoxy) -3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: methylene chloride ( 1.0 mL) 4- {1-[(3R) -3- (3,4-dimethoxyphenoxy) -3-phenylpropyl] -4-piperidinyl} aniline (5.31 mg, 0.0119 mmol), isobuty A mixture of reyl chloride (2.08 mg, 0.019 mmol), N, N-diisopropylethylamine (8.40 mg, 0.0650 mmol) was stirred at rt for 24 h. The reaction mixture was concentrated and chromatographed using preparative TLC plate to give [NH _{3 in} CHCl ₃ (2.0 M in methanol) 2.5%], product (3.5 mg, 56.5%) as a thick oil: ¹ H NMR ( 400 MHz, CDCl ₃ ) δ7.38 (d, 1H, J = 8.6 Hz), 7.30-7.20 (m, 4H), 7.20 (m, 1H), 7.11 (d, 2H, J = 8.6 Hz), 7.04 ( s, 1H), 6.57 (d, 1H, J = 8.3 Hz), 6.44 (d, 1H, J = 2.6 Hz), 6.22 (dd, 1H, J = 2.6, 8.3 Hz), 5.09 (obvious dd, 1H, J = 4.4, 8.1 Hz), 3.72 (s, 3H), 3.70 (s, 3H), 3.08 (m, 2H), 2.57 (m, 2H), 2.43 (obvious sinter, partially hidden, 2H, J = 6.8 Hz), 2.30-2.10 (m, 6H), 1.80 (m, 2H), 1.25 (d, 6H, J = 7.9 Hz); ESMS m / e: 517.3 (M + H) ⁺
[948] Example 85
[949] N- (3- {1-[(3S) -3- (3-acetylphenoxy) -3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: tree in 25 mL RB flask Phenylphosphine (9.80 mg, 0.0375 mmol), diethyl azodicarboxylate (5.22 mg, 0.0300 mmol), N- (3- {1-[(3R) -3-hydroxy-3-phenylpropyl)- 4-piperidinyl} phenyl) -2-methylpropanamide (9.53 mg, 0.0250 mmol), 3-hydroxyacetophenone (100 mg) and THF (1.0 mL) were added at room temperature. The reaction mixture was stirred at rt overnight (16 h). Was removed of solvent under reduced pressure, to afford the the residue purified by preparative TLC plates [CHCl ₃ in NH ₃ (methanol in 2.0 M) 2.5%], the desired product (2.73 mg, 39.9%) as a thick oil: ¹ H NMR (CDCl ₃ ) δ7.70-7.64 (m, 2H), 7.54 (m, 2H), 7.49-7.44 (m, 6H), 7.25 (m, 1H), 7.05 (d, 1H, J = 8.3 Hz ), 6.96 (apparent d, 1H, J = 7.7 Hz), 5.34 (apparent dd, 1H, J = 4.8, 8.2 Hz), 3.15 (m, 2H), 2.67 (m, 2H), 2.52 (s, 3H) , 2.53 (apparent quartet, partially hidden, 2H, J = 7.6 Hz), 2.30-2.10 (m, 6H), 1.89 (m, 2H), 1.25 (d, 6H, J = 6.9 Hz); ESMS m / e: 499.4 (M + H) ⁺
[950] Scheme A
[951] Synthesis of tert-butyl 4- (3-aminophenyl) -1-piperidinecarboxylate
[952]
[953] Scheme B1
[954] General Synthesis of MCH Antagonists
[955]
[956] Scheme B2
[957] General Synthesis of MCH Antagonists
[958]
[959] Scheme C1
[960] Specific examples of MCH antagonist synthesis
[961]
[962] Scheme C2
[963] Specific examples of MCH antagonist synthesis
[964]
[965] Scheme D1
[966] Specific examples of MCH antagonist synthesis
[967]
[968] Scheme D2
[969] Specific examples of MCH antagonist synthesis
[970]
[971] Scheme E
[972] General Synthesis of MCH Antagonists
[973]
[974] Scheme F
[975] General Synthesis of MCH Antagonists
[976]
[977] Scheme G
[978] General Synthesis of MCH Antagonists
[979]
[980] Scheme H
[981] Synthesis of oxazolidinone
[982]
[983] Scheme I
[984] Synthesis of gem-dialkyl substituted oxazolidinones
[985]
[986] Scheme J
[987] Synthesis and Chiral Splitting of Oxazolidinones
[988]
[989] Scheme K
[990]
[991] Scheme L
[992]
[993] Scheme M
[994]
[995] Scheme N
[996]
[997] Scheme O
[998]
[999] Scheme P
[1000]
[1001] Scheme Q
[1002]
[1003] Scheme R
[1004]
[1005] Reference section
[1006] The following additional symbols are used: HOAc, acetic acid; DMF, N, N-dimethylformamide; EtOAc, ethyl acetate; MeOH, methanol; NMP, 1-methyl-2-pyrrolidinone; TEA, triethylamine; THF, tetrahydrofuran; All solvent ratios are v / v unless stated otherwise.
[1007] 1- (4-methylphenyl) 1H-indole: 1-H-indole (58.5 mg, 0.500 mmol), 1- (iodo) -4-methylbenzene in 1-methyl-2-pyrrolidinone (1 mL) A mixture of 0.218 g, 1.00 mmol), copper powder (32.0 mg, 0.500 mmol) and K ₂ CO ₃ (0.138 g, 1.00 mmol) was heated at 150 ° C. under argon for 12 h. The resulting mixture was diluted with H ₂ 0 (6 mL). The aqueous layer was extracted with CH ₂ Cl ₂ (3 × 10 mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO ₄ and concentrated in vacuo. The residue was purified by preparative TLC using EtOAc / hexanes (1: 4) to afford the desired product (82 mg, 79%).
[1008]
[1009] Example 86
[1010] N- (3- {1-[(6-chloro-1H-indol-3-yl) methyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1 mL of HOAc: dioxane (1: 4) a solution of 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide (0.369 g, 1.50 mmol) and 37 wt% aqueous formaldehyde (30.0 mg, 1.50 mmol) in 6-chloro Was added to -1-H-indole (0.152 g, 1.00 mmol) and the reaction mixture was stirred at rt for 12 h. The resulting mixture was diluted with H ₂ 0 (10 mL). The aqueous layer was extracted with CH ₂ Cl ₂ (3 × 100 mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO ₄ and concentrated in vacuo. The residue was purified by preparative TLC on silica with 5% NH ₃ (2.0 M in methanol) in CH ₂ Cl ₂ to afford the desired product (79 mg, 42%).
[1011]
[1012] Example 87
[1013] 2-methyl-N- [3- (1-{[1- (4-methylphenyl) -1H-indol-3-yl] methyl} -4-piperidinyl) phenyl] propanamide: N- (3- { 1- (4-methylphenyl) -1H-indole (0.207 1.00, according to the procedure used for the synthesis of 1-[(6-chloro-1H-indol-3-yl) methyl] piperidinyl} phenyl) methylpropanamide mmol) as 2-methyl-N- [3- (1-{[1- (4-methylphenyl) -1H-indol-3-yl] methyl} -4-piperidinyl) phenyl] propanamide (0.441 g, 78%) was obtained.
[1014]
[1015] 2-[(1S) -3-chloro-1-phenylpropyl] -1H-isoindole-1,3 (2H) -dione: triphenylphosphine (5.25 g, 20.0 mmol) and diethyl azodicarboxylate (3.58 g, 20.0 mmol) was added to a solution of (1R) -3-chloro-1-phenyl-1-propanol (3.42 g, 20.0 mmol) and phthalimide (2.94 g, 20.0 mmol) in THF (100 mL). It was. The reaction mixture was stirred at rt for 4 h. The solvent was removed under reduced pressure and the residue triturated with pentane (3 x 50 mL). The combined pentane fractions were concentrated in vacuo and the crude product was purified by chromatography on silica using EtOAc / hexanes (3:97) to afford the desired product (4.40 g, 74%).
[1016]
[1017] N- (3- {1-[(3S) -3- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) -3-phenylpropyl] -4-piperidi Nyl} phenyl) -2-methylpropanamide: 2-[(1S) -3-chloro-1-phenylpropyl] -1H-isoindole-1,3 (2H) -dione (4.50 g in DMF (40 mL) , 15.0 mmol), 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide (4.26 g, 15.0 mmol), K ₂ CO ₃ (4.16 g, 30.0 mmol) and NaI (3.40 g, 20.0 mmol) was stirred at 90 ° C. for 12 h. The reaction mixture was diluted with water (50 mL), extracted with CH ₂ Cl ₂ (3 × 50 mL), and the combined organic extracts washed with brine (50 mL), dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by chromatography on silica with 5% NH ₃ (2.0 M in methanol) in CH ₂ Cl ₂ to afford the desired product (5.10 g, 74%).
[1018]
[1019] N- (3- {1-[(3S) -3-amino-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: N- (3- {in ethanol (150 mL) 1-[(3S) -3- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) -3-phenylpropyl] -4-piperidinyl} phenyl) -2 A mixture of methylpropanamide (4.60 g, 9.06 mmol) and hydrazine (3.62 g, 72.4 mmol) was refluxed for 12 h. The resulting white precipitate was filtered off and the precipitate was concentrated in vacuo. The residue was washed with CH ₂ Cl ₂ / EtOAc (1: 1, 3 × 50 mL) and the combined organic fractions were concentrated in vacuo to afford the desired product (2.90 g, 95%).
[1020]
[1021] Example 88
[1022] 2-methyl-N- (3- {1-[(3S) -3-phenyl-3- (propionylamino) propyl] -4-piperidinyl} phenyl) propanamide: N- (3- {1- According to the procedure used for the synthesis of [(3S) -3- (acetylamino) -3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide, N- (3- {1- [ 2-methyl with (3S) -3-amino-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide (11.0 mg, 0.0280 mmol) and propionyl chloride (3.80 mg, 0.0420 mmol) -N- (3- {1-[(3S) -3-phenyl-3- (propionylamino) propyl] -4-piperidinyl} phenyl) propanamide (12 mg, 97% yield) was obtained.
[1023]
[1024] Example 89
[1025] N- {3- [1-((3S) -3-{[(4-fluorophenyl) acetyl] amino) -3-phenylpropyl) -4-piperidinyl] phenyl} -2-methylpropanamide: N- (3- {1-[(3S) -3-amino-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide (11.0 mg, 0.0280 mmol) in THF (5 mL) And a mixture of (4-fluorophenyl) acetyl chloride (7.20 mg, 0.0420 mmol) was stirred at rt for 4 h. The solvent was removed under reduced pressure and the residue was purified by preparative TLC using hexanes: EtOAc (2: 1) to afford the desired product (13 mg, 90% yield).
[1026]
[1027] Example 90
[1028] N- (3- {1- [3- (1,2-diphenyl-1H-indol-3-yl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1,1-di Phenylhydrazine hydrochloride (10.3 mg, 0.0470 mmol), 2-methyl-N- (3- [1- (5-oxo-5-phenylpentyl) -4-piperidinyl] phenyl} propanamide (14.7 mg, 0.0362 mmol), ZnCl ₂ (14.85 mg, 0.109 mmol) and HOAc (0.5 mL) were heated for 4 h at 80 ° C. The resulting crude mixture was diluted with water (10 mL) and the aqueous layer was saturated K ₂ CO. Neutralized to ₃ and extracted with CH ₂ Cl ₂ (3 × 20 mL) The combined organic layers were concentrated in vacuo and the residue was aliquoted with 5% NH ₃ (2.0 M in methanol) in CH ₂ Cl ₂ . Purification by TLC gave the desired product N- (3- {1- [3- (1,2-diphenyl-1H-indol-3-yl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide (4.1 mg, 37%) was obtained.
[1029]
[1030] Example 91
[1031] N- (3- {1- [3- (5-methoxy-2-phenyl-1H-indol-3-yl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide: N- ( According to the procedure used for the synthesis of 3- {1- [3- (1,2-diphenyl-1H-indol-3-yl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide, 2-methyl-N- {3- [1- (5-oxo-5-phenylpentyl) -4-piperidinyl] phenyl} propanamide (15.6 mg, 38.2 mmol), and 1- (4-methoxyphenyl ) Hydrazine hydrochloride (8.00 mg, 0.0458 mmol) with N- (3- {1- [3- (5-methoxy-2-phenyl-1 H-indol-3-yl) propyl] -4-piperidinyl} Phenyl) -2-methylpropanamide (3.9 mg, 20%) was obtained.
[1032]
[1033] Example 92
[1034] N- (3- {1- [4- (5-methoxy-2-phenyl-1H-indol-3-yl) butyl] -4-piperidinyl} phenyl) -2-methylpropanamide: N- ( According to the procedure used for the synthesis of 3- {1- [3- (1,2-diphenyl-1H-indol-3-yl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide, 2-methyl-N- {3- [1- (6-oxo-6-phenylhexyl) -4-piperidinyl] phenyl} methylpropanamide (14.3 mg, 0.0339 mmol) and 1- (4-methoxyphenyl ) N- (3- {1- [4- (5-methoxy-2-phenyl-1H-indol-3-yl) butyl] -4-piperidinyl} with hydrazine hydrochloride (7.10 mg, 0.0407 mmol) Phenyl) -2-methylpropanamide (5.8 mg, 33%) was obtained.
[1035]
[1036] Example 93
[1037] 2-methyl-N- (3- {1-[(1-phenyl-1H-indol-3-yl) methyl] -4-piperidinyl} phenyl) propanamide: N- (3- {1- [3 N- {3- [1, according to the procedure used for the synthesis of-(1,2-diphenyl-1H-indol-3-yl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide -(3,3-dimethoxypropyl) -4-piperidinyl] phenyl} -2-methylpropanamide (15.2 mg, 0.0436 mmol) and 1,1-diphenylhydrazine hydrochloride (11.6 mg, 0.0524 mmol) 2-methyl-N- (3- {1-[(1-phenyl-1H-indol-3-yl) methyl] -4-piperidinyl} phenyl) propanamide (11 mg, 56%) was obtained.
[1038]
[1039] Example 94
[1040] 2-methyl-N- (3- {1-[(4E) -4-phenyl-4- (2-pyridinylhydrazono) butyl] -4-piperidinyl} phenyl) propanamide: N- (3- According to the procedure used for the synthesis of {1- [3- (1,2-diphenyl-1H-indol-3-yl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide, 2- Methyl-N- {3- [1- (4-oxo-4-phenylbutyl) -4-piperidinyl] phenyl} propanamide (8.70 mg, 0.0223 mmol) and 2-hydrazinopyridine (2.92 mg, 0.0268 mmol ) 2-methyl-N- (3- {1-[(4E) -4-phenyl-4- (2-pyridinylhydrazono) butyl] -4-piperidinyl} phenyl) propanamide (2.5 mg, 24%) was obtained.
[1041]
[1042] Example 95
[1043] N- (3- {1- [3- (5-methoxy-1H-indol-3-yl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide: N- (3- {1 N- (3, according to the procedure used for the synthesis of [3- (1,2-diphenyl-1H-indol-3-yl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide -{1- [4- (1,3-dioxolan-2-yl) butyl] -4-piperidinyl} phenyl) -2-methylpropanamide (23.5 mg, 0.0628 mmol) and 1- (4-meth Methoxyphenyl) hydrazine hydrochloride (13.2 mg, 0.0774 mmol) with N- (3- {1- [3- (5-methoxy-1H-indol-3-yl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide (11 mg, 42%) was obtained.
[1044]
[1045] tert-butyl 4- [3- (propionylamino) phenyl] -1-piperidinecarboxylate: Propionyl chloride (5.53 g, 0.0597 mol) was added to tert-butyl 4- (3- in THF (200 mL). To the solution of aminophenyl) -1-piperidinecarboxylate (15.0 g, 0.0543 mol) and TEA (16.5 g, 0.163 mol) was added dropwise and the mixture was stirred at room temperature for 3 h. Water (50 mL) is added to the reaction mixture, the aqueous layer is extracted with CH ₂ Cl ₂ (3 × 100 mL), the combined organic extracts are washed with brine (50 mL), dried over Na ₂ SO ₄ , and dried under reduced pressure. Concentration. The residue was purified by chromatography on silica using hexanes / EtOAc (10: 1) to give the product (18.8 g, 99%).
[1046]
[1047] N- [3- (4-piperidinyl) phenyl] propanamide: tert-butyl 4- [3- (propionylamino) phenyl] -1-piperidinecarboxyl in dioxane (100 mL) at 5 ° C HCl gas was bubbled for 2 h with a stirred solution of rate (18.8 g, 0.0543 mmol). The solvent was removed in vacuo and the residue was dissolved in water (100 mL) and neutralized by addition of an aqueous 10% KOH solution. The aqueous layer was extracted with a mixture of CHCl ₃ / isopropyl alcohol (3: 1) (3 × 200 mL) and the combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. I was. The residue was purified by column chromatography on silica using 5% NH ₃ (2.0 M in methanol) in CH ₂ Cl ₂ to afford the desired product (12.6 g, 99%).
[1048]
[1049] tert-butyl 4- {3-[(cyclopropylcarbonyl) amino] phenyl} -1-piperidinecarboxylate: tert-butyl 4- [3- (propionylamino) phenyl] -1-piperidine Tert-butyl 4- (3-aminophenyl) -1-piperidinecarboxylate (16.47 g 0.0596 mol) and cyclopropanecarbonyl chloride (6.27 g, 0.0597 mol) according to the procedure used for the synthesis of the carboxylate ) Tert-butyl 4- {3-[(cyclopropylcarbonyl) amino] phenyl} -1-piperidinecarboxylate (18.1 g, 100%).
[1050]
[1051] N- [3- (4-piperidinyl) phenyl] cyclopropanecarboxamide: tert-butyl 4-, according to the procedure used for the synthesis of N- [3- (4-piperidinyl) phenyl] propanamide {3-[(cyclopropylcarbonyl) amino] phenyl} -1-piperidinecarboxylate (18.9 g, 0.0543 mol) N- [3- (4-piperidinyl) phenyl] cyclopropanecarboxamide (13.2 g, 100%) was obtained.
[1052]
[1053] 1- (6-chlorohexyl) -1H-indole: To a mixture of NaH (0.249 g, 10.0 mmol) in DMF (5 mL) at 0 ° C. 1-H-indole (0.585 g, 5.00 mmol) in DMF (2 mL) ) Solution was added. The reaction mixture was stirred for 30 minutes and warmed to room temperature. Then 1-bromo-6-chlorohexane (0.998 g, 5.00 mmol) was added dropwise by syringe and the reaction mixture was stirred overnight. The reaction mixture is diluted with EtOAc (30 mL), washed with water (3 x 10 mL), dried over MgSO ₄ , concentrated in vacuo and purified by chromatography using hexanes / EtOAc (97.5: 2.5) to afford Obtained (0.900 g, 76%).
[1054]
[1055] 1- (5-chloropentyl) -1H-indole: 1-H-indole (0.585 g, 5.00 mmol) and 1-bro, following the procedure used for the synthesis of 1- (6-chlorohexyl) -1H-indole Mo-5-chloropentane (0.928 g, 5.00 mmol) gave the desired product (0.890 g, 80%).
[1056]
[1057] Example 96
[1058] N- (3- {1- [6- (1H-indol-1-yl) hexyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1- (6-chlorohexyl) -1H-indole (23.6 mg, 0.100 mmol), 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide (24.6 mg, 0.100 mmol), K ₂ CO ₃ (27.6 mg, 0.200 mmol), NaI ( 22.5 mg, 0.150 mmol) and DMF (1.00 mL) were combined and stirred at 100 ° C. overnight. The reaction mixture was cooled to room temperature and the crude was purified by preparative TLC using 5% NH ₃ (2.0M in methanol) in CH ₂ Cl ₂ to afford the desired product as a yellow solid (40 mg, 90%). .
[1059]
[1060] Example 97
[1061] N- (3- {1- [5- (1H-indol-1-yl) pentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1- (5-chloropentyl) -1H-indole (22.2 mg, 0.100 mmol), 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide (24.6 mg, 0.100 mmol), K ₂ CO ₃ (27.6 mg, 0.200 mmol), NaI ( Prepared as above using 23.0 mg, 0.150 mmol) and DMF (1.00 mL) to afford the desired product as a yellow oil (36 mg, 81%).
[1062]
[1063] Example 98
[1064] N- (4- {1-[(9-ethyl-9H-carbazol-3-yl) methyl] -4-piperidinyl} phenyl) -2-methylpropanamide: N- (3- {1- [ 4- (4-chlorophenoxy) benzyl] -4-piperidinyl} phenyl) -2-methylpropanamide (Example 108) N- (3- {1- [3- (1,2-diphenyl- 9-ethyl-9H-carbazole-3-carbaldehyde (22.3) according to the procedure used for the synthesis of 1H-indol-3-yl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide mg, 0.100 mmol) and 2-methyl-N- [4- (4-piperidinyl) phenyl] propanamide (24.6 mg, 0.100 mmol) in N- (4- {1-[(9-ethyl-9H- Carbazol-3-yl) methyl] -4-piperidinyl} phenyl) -2-methylpropanamide was obtained. This product was obtained as a white crystalline solid (20 mg, 44%).
[1065]
[1066] Example 99
[1067] N- (3- {1-[(9-ethyl-9H-carbazol-3-yl) methyl] -4-piperidinyl} phenyl) -2-methylpropanamide: N- (3- {1- [ 4- (4-chlorophenoxy) benzyl] -4-piperidinyl} phenyl) -2-methylpropanamide (Example 108) N- (4- {1-[(9-ethyl-9H-carbazole- 9-ethyl-9H-carbazole-3-carbaldehyde and 2-methyl-N, according to the procedure used for the synthesis of 3-yl) methyl] -4-piperidinyl} phenyl) -2-methylpropanamide -[3- (4-piperidinyl) phenyl] propanamide N- (3- {1-[(9-ethyl-9H-carbazol-3-yl) methyl] -4-piperidinyl} phenyl) -2-methylpropanamide (37 mg, 95%) was obtained.
[1068]
[1069] Example 100
[1070] N- [3- (1-{[1- (4-methoxyphenyl) -1H-indol-5-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: 1- (4 N- (3- [1- (1H-indol-5-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide (37.5) according to the procedure used for the synthesis of -methylphenyl) 1H-indole. mg, 0.100 mmol) and 1-iodo-4-methoxybenzene (46.8 mg, 0.200 mmol) gave the desired product (27 mg, 56%).
[1071]
[1072] Example 101
[1073] N- [3- (1-{[1- (4-fluorophenyl) -1H-indol-5-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: 1- (4 N- {3- [1- (1H-indol-5-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide (37.5, according to the procedure used for the synthesis of -methylphenyl) 1H-indole. mg, 0.100 mmol) and 1-fluoro-4-iodobenzene (44.4 mg, 0.200 mmol) gave the desired product (21 mg, 45%).
[1074]
[1075] Example 102
[1076] Methyl-4- [5-({4- [3- (isobutyrylamino) phenyl] -1-ifridinyl} methyl) -1H-indol-1-yl] benzoate: 1- (4-methylphenyl) N- {3- [1- (1H-indol-5-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide (37.5 mg, 0.100 according to the procedure used for the synthesis of 1H-indole) mmol) and methyl 4-iodobenzoate (52.4 mg, 0.200 mmol) gave the desired product (11 mg, 22%).
[1077]
[1078] Example 103
[1079] 2-methyl-N- [3- (1-{[1- (3-methylphenyl) -1H-indol-5-yl] methyl} -4-piperidinyl) phenyl] propanamide: 1- (4-methylphenyl N- {3- [1- (1H-indol-5-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide (37.5 mg, according to the procedure used for the synthesis of 1H-indole) 0.100 mmol) and 1-iodo-3-methylbenzene (43.6 mg, 0.200 mmol) gave the desired product (28 mg, 60%).
[1080]
[1081] Example 104
[1082] N- {3- [1- (3-{[(4-chloro-3-nitrophenyl) sulfonyl] amino} propyl) -4-piperidinyl] phenyl} -2-methylpropanamide: THF (2 mL N- {3 [1- (2-aminopropyl) -4-piperidinyl] phenyl} -2-methylpropanamide (10.0 mg, 0.0350 mmol), 4-chloro-3-nitrobenzenesulfonyl chloride ( 9.90 mg, 0.0380 mmol) and TEA (7.00 mg, 0.0700 mmol) were stirred at rt for 12 h. The crude product was purified by preparative TLC (CH ₂ Cl ₂ /MeOH/isopropylamine=19:1:0.2) to afford the desired product (16 mg, 86%).
[1083]
[1084] Example 105
[1085] N- [3- (1- {5- [4- (3,4-difluorophenyl) -2-oxo-1,3-oxazolidin-3-yl] pentyl} -4-piperidinyl) Phenyl] -2-methylpropanamide: 3- (5-bromopentyl) -4- (3,4-difluorophenyl) -1,3-oxazolidin-2-one in DMF (2 mL) 38.0 mg, 0.110 mmol), 2-methyl-N- [3- (4-piperidinyl) phenyl] -propanamide (26.0 mg, 0.100 mmol), NaI (23.0 mg, 0.150 mmol) and K ₂ CO ₃ ( 14.0 mg, 0.100 mmol) was heated at 50 ° C. for 1 hour. The crude product was purified by preparative TLC using CH ₂ Cl ₂ / MeOH / isopropyl amine (19: 1: 0.2) to afford the desired product (21 mg, 41%).
[1086]
[1087] Example 106
[1088] 3- (2,6-dichlorophenyl) -N- (5- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl) pentyl] -5-methyl-4-isoxazolecarbox Mid: 3- (2,6-dichlorophenyl) -4-formyl-5-isoxazolecarbonyl chloride (69.0 mg, 0.250 mmol) in THF (2 mL), N- {3- [1- (5- A mixture of aminopentyl) -4-piperidinyl] phenyl} -2-ethylpropanamide (44.0 mg, 0.150 mmol), TEA (30.0 mg, 0.300 mmol) was stirred at rt for 12 h. The crude product was purified by preparative TLC using CH ₂ Cl ₂ / MeOH / isopropyl amine (19: 1: 0.2) to afford the desired product (52 mg, 67%).
[1089]
[1090] Example 107
[1091] N- [3- (1- {2-[(diphenylacetyl) amino] ethyl} -4-piperidinyl) phenyl] -2-methylpropanamide: N- {3 [1- in THF (2 mL) (2-aminoethyl) -4-piperidinyl] phenyl} -2-methylpropanamide (20.0 mg, 0.0700 mmol), diphenylacetyl chloride (23.0 mg, 0.110 mmol), and TEA (20.0 mg, 0.140 mmol) The mixture was stirred at 23 ° C. overnight. The crude product was purified by preparative TLC using CH ₂ Cl ₂ / MeOH / isopropyl amine (19: 1: 0.2) to afford the desired product (8.0 mg, 47%).
[1092]
[1093] Example 108
[1094] N- (3- {1- [4- (4-chlorophenoxy) benzyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4- (4chlorophenoxy) benzaldehyde (0.119 g, 0.510 mmol) and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide (0.126 g, 0.510 mmol) were mixed in 1,2-dichloroethane (5 mL), followed by sodium triacetoxybo Treated with low hydride (0.424 g, 2.00 mmol) and HOAc (0.03 mL, 0.5 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was neutralized with saturated aqueous NaHCO ₃ solution and the aqueous layer was extracted with CH ₂ Cl ₂ (3 × 10 mL). The combined organic layers were washed with brine, dried over MgSO ₄ , concentrated in vacuo and purified by preparative TLC with 5% NH ₃ (2.0 M in methanol) in CH ₂ Cl ₂ to afford the desired product (53 mg, 23% ) Was obtained.
[1095]
[1096] Example 109
[1097] N- {3- [1-({2,5-dimethyl-1- [3- (trifluoromethyl) phenyl] -1H-pyrrol-3-yl} methyl) -4-piperidinyl] phenyl}- 2-methylpropanamide: 2,5-dimethyl-1- [3- (trifluoromethyl) phenyl] -1H-pyrrole-3-carbaldehyde (0.136 g, 0.510 mmol) in 4- (4-chlorophenoxy Prepared according to the procedure described in Example 108, using benzaldehyde instead.
[1098]
[1099] Example 110
[1100] N- (3- {1- [4- (3,4-difluorophenoxy) benzyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4- (3,4-difluoro Phenoxy) benzaldehyde (0.119 g, 0.510 mmol) was prepared according to the procedure described in Example 108, using 4- (4-chlorophenoxy) benzaldehyde instead of 4- (4-chlorophenoxy) benzaldehyde.
[1101]
[1102] Example 111
[1103] N- (3- {1-[(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl) methyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 5 -Chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (0.113 g, 0.510 mmol) was used instead of 4- (4chlorophenoxy) benzaldehyde according to the procedure described in Example 108. Produce.
[1104]
[1105] Example 112
[1106] N- (3- {1- [4- (3,4-dichlorophenoxy) benzyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4- (3,4-dichlorophenoxy) benzaldehyde (0.136 g, 0.510 mmol) using the procedure described in Example 108, using 4- (4-chlorophenoxy) benzaldehyde instead.
[1107]
[1108] Example 113
[1109] 2-methyl-N- (3- {1-[(2-phenyl-1H-imidazol-4-yl) methyl] -4-piperidinyl} phenyl) propanamide: 2-phenyl-1H-imidazole- Prepared according to the procedure described in Example 108, using 4-carbaldehyde (88.0 mg, 0.510 mmol) instead of 4- (4-chlorophenoxy) benzaldehyde.
[1110]
[1111] Example 114
[1112] N- (3- {1- [4- (diphenylamino) benzyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4- (diphenylamino) benzaldehyde (0.139 g, 0.510 mmol) Prepared according to the procedure described in Example 108, instead of 4- (4-chlorophenoxy) benzaldehyde.
[1113]
[1114] Example 115
[1115] N- [3- (1-{[4-bromo-1- (4-chlorobenzyl) -1H-pyrazol-5-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide In Example 108, using 4-bromo-1- (4-chlorobenzyl) -1H-pyrazole-5-carbaldehyde (0.153 g, 0.510 mmol) instead of 4- (4chlorophenoxy) benzaldehyde. Manufactured according to the described procedure.
[1116]
[1117] 1- (3-[{(1R) -3-chloro-phenylpropyl] oxy} phenyl) ethanone:
[1118] Azodicarboxylate (5.37 g, 0.0310 mol) was converted to triphenylphosphine (8.09 g, 0.0308 mol), 1S-3-chloro-1-phenyl-1-propanol (4.20 g, 0.031 mol) in THF (150 mL). ) And 1- (3-hydroxyphenyl) ethanone. The reaction mixture was stirred at 23 ° C. for 4 days. The solvent was removed under reduced pressure and the residue was triturated with ether / hexanes (1: 2) (3 × 100 mL). The combined organic fractions were concentrated in vacuo and the crude product was purified by chromatography using EtOAc / hexanes (1:14) to afford the desired product (6.55 g, 74%).
[1119]
[1120] Example 116
[1121] N- (3- {1-[(3R) -3- (3-acetylphenoxy) -3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide:In DMF (1 mL) 1- (3-{[(1R) -3-chloro-1-phenylpropyl] oxy} phenyl) ethanone (58.5 mg, 0.200 mmol), 2-methyl-N- [3- (4-piperidinyl) Phenyl] propanamide (56.8 mg, 0.200 mmol), NaI (34.0 mg, 0.200 mmol) and K₂CO₃(55.5 mg, 0.400 mmol) was stirred at 100 ° C. for 3 h. Remove solvent under reduced pressure, remove residue with CH₂Cl₂5% of NH₃Purification by chromatography on silica with (2.0 M in methanol) afforded the desired product (98 mg, 98%).
[1122]
[1123] step :
[1124] Procedure A (see also Example 48)
[1125] N- (3- {1-[(3R) -3- (3,4-dimethoxyphenoxy) -3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide:
[1126]
[1127] Method A
[1128] 4-{[(1R) -3-chloro-1-phenylpropyl] oxy} -1,2-dimethoxybenzene: 3,4-dimethoxyphenol (4.07 g, 26.4 mmol) in THF (110 mL), ( S)-(-)-3-chloro-phenyl-1-propanol (4.50 g, 26.4 mmol, 99% ee, Aldrich Chemical Co.), triphenylphosphine (6.92 g, 26.4 mmol) and diethyl azodicar A mixture of carboxylate (4.59 g, 26.4 mmol) was stirred at rt for 24 h. The reaction mixture was concentrated in vacuo. At this time, the residue was purified with pentane and the combined pentane extracts were concentrated and chromatographed with hexanes: EtOAc (8: 1) as eluent to give the desired product (Srebnik, M .; Ramachandran, PV; Brown, HCJ Org. Chem. 1988, 53, 2916-2920 as described in the usual procedure). The procedure was carried out on a smaller scale reaction, with only 40% yield of the product realized.
[1129] In contrast, on a larger scale (26.4 mmol), the crude product was triturated with a small amount of dichloromethane and the precipitated triphenylphosphine oxide was filtered off. The filtrate was concentrated and the crude product was chromatographed to give the desired product as a dark yellow oil (7.30 g, 88.9% yield):
[1130]
[1131] N- (3- {1-[(3R) -3- (3,4-dimethoxyphenoxy) -3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide:
[1132] Potassium carbonate (321 mg, 2.32 mmol), sodium iodide (522 mg, 3.48 mmol), 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide (570 mg, in DMF (5.00 mL) 2.32 mmol) and 4-{[(1R) -3-chloro-1-phenylpropyl] oxy} -1,2-dimethoxybenzene (712 mg, 2.32 mmol) were stirred at 100 ° C. for 3 h, TLC showed that the reaction was terminated. The reaction mixture was 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. The crude product preparative TLC [CHCl ₃ 2.5% of NH ₃ (2.0M in methanol) in] product as a thick oil to give (970 mg, 90.1%) was obtained.
[1133] Method B
[1134] Triphenylphosphine (9.80 mg, 0.0375 mmol), diethyl azodicarboxylate (5.22 mg, 0.0300 mmol), N- (3- {1-[(3S) -3-hydride in a 25-mL RB-flask Oxy-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide (9.53 mg, 0.0250 mmol), 3,4-dimethoxyphenol (7.70 mg, 0.0500 mmol) and THF (1.00 mL) Was added at room temperature. The reaction mixture was stirred at rt overnight (16 h). To remove the solvent under reduced pressure, and the residue was purified by preparative TLC plate [CHCl NH ₃ (2.0M in methanol) of 2.5% of ₃ to the desired product as a thick oil (4.40 mg, 34.1% yield):
[1135]
[1136] Procedure B(See also Example 49)
[1137] 2-Methyl-N- (3- {1-[(3S) -3-phenoxy-3-phenylpropyl] -4-piperidinyl} phenyl) propanamide: N- (3- in THF (1.00 mL) {1 [(3R) -3-hydroxy-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide (9.53 mg, 0.0250 mmol), phenol (4.70 mg, 0.050 mmol), tri A mixture of phenylphosphine (9.80 mg, 0.0375 mmol) and diethyl azodicarboxylate (5.22 mg, 0.0300 mmol) was stirred for 3 days at room temperature. Silica preparative TLC plate [2.5% in CHCl ₃ NH ₃ (2.0M in methanol)] by chromatography using a thick oil to give the desired product (2.70 mg, 23.6% yield):
[1138]
[1139] Procedure C
[1140] Scheme O
[1141]
[1142] 1- (4-methylphenyl) 1H-indole: 1-H-indole (58.5 mg, 0.500 mmol) in 1-methyl-2-pyrrolidinone (1.00 mL), 1-iodo-4-methylbenzene (0.218 g , 1.00 mmol), copper powder (32.0 mg, 0.500 mmol) and K ₂ CO ₃ (0.138 g, 1.00 mmol) were heated under argon at 150 ° C. for 12 h. The resulting mixture was diluted with H ₂ 0 (6 mL). The aqueous layer was extracted with CH ₂ Cl ₂ (3 × 10 mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO ₄ and concentrated in vacuo. The residue was purified by preparative TLC using EtOAc: hexanes (1: 4) to afford the desired product (82.0 mg, 79.0%):
[1143]
[1144] Procedure D ( see also Example 86 )
[1145] Scheme N
[1146]
[1147] N- (3- {1-[(6-chloro-lH-indol-3-yl) methyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1.00 mL of HOAc: dioxane (1: 4) a solution of 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide (O.369 g, 1.50 mmol) and 37 wt% aqueous formaldehyde (30.0 mg, 1.50 mmol) in 6) -Chloro-1-H-indole (0.152 g, 1.00 mmol). The reaction mixture was stirred at rt for 12 h. The resulting mixture was diluted with H ₂ 0 (10 mL). The aqueous layer was extracted with CH ₂ Cl ₂ (3 × 100 mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO ₄ and concentrated in vacuo. The residue was purified by preparative TLC plate with 5% NH ₃ (2.0 M in methanol) in CH ₂ Cl ₂ to afford the desired product (79.0 mg, 42.0%):
[1148]
[1149] Procedure E ( see also Example 90 )
[1150] Scheme M
[1151]
[1152] N- (3- {1- (3- {1,2-diphenyl-1H-indol-3-yl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1,1-di Phenylhydrazine hydrochloride (10.3 mg, 0.0470 mmol), 2-methyl-N- {3- [1- (5-oxo-5-phenylpentyl) -4-piperidinyl] phenyl} propanamide (14.7 mg, 0.0362 mmol), ZnCl ₂ (14.8 mg, 0.109 mmol) and HOAc (0.500 mL) were stirred at 80 ° C. for 4 h. The resulting crude mixture was diluted with water (10 mL) and the aqueous layer was neutralized with saturated K ₂ CO ₃ (10 mL) and extracted with CH ₂ Cl ₂ (3 × 20 mL). The combined organic layers were concentrated in vacuo and the residue was purified by preparative TLC plate with 5% NH ₃ (2.0 M in methanol) in CH ₂ Cl ₂ to give the desired product N- (3- {1- [3- (1 , 2-diphenyl-1H-indol-3-yl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide (4.10 mg, 37.0%) was obtained:
[1153]
[1154] Procedure F ( see also Example 108 )
[1155] Scheme R
[1156]
[1157] N- (3- {1- [4- (4-chlorophenoxy) benzyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4- (in 1,2-dichloroethane (5.00 mL) A solution of 4-chlorophenoxy) benzaldehyde (0.119 g, 0.510 mmol) and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide (0.126 g, 0.510 mmol) was dissolved in sodium triacetoxyboro Treated with hydride (0.424 g, 2.00 mmol) and HOAc (0.0300 mL, 0.500 mmol) at room temperature. The mixture was stirred overnight at room temperature. The reaction mixture was neutralized with saturated aqueous NaHCO ₃ (10 mL) and the aqueous layer was extracted with CH ₂ Cl ₂ (3 × 10 mL). The combined organic layers were washed with brine, dried over MgSO ₄ , concentrated in vacuo and purified by preparative TLC plate with 5% NH ₃ (2.0 M in methanol) in CH ₂ Cl ₂ to afford the desired product (53.0 mg, 23.0). %) Was obtained:
[1158]
[1159] Procedure G ( see also Example 116 )
[1160] Scheme F
[1161]
[1162] N- (3- {1-[(3R) -3- (3-acetylphenoxy) -3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: in DMF (1.00 mL) 1- (3-{[(1R) -3-chloro-1-phenylpropyl] oxy} phenyl) ethanone (58.5 mg, 0.200 mmol), 2-methyl-N- [3- (4-piperidinyl) A mixture of phenyl] propanamide (56.8 mg, 0.200 mmol), NaI (34.0 mg, 0.200 mmol) and K ₂ CO ₃ (55.5 mg, 0.400 mmol) was stirred at 100 ° C. for 3 h. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica using 5% NH ₃ (2.0 M in methanol) in CH ₂ Cl ₂ to afford the desired product (98.0 mg, 98.0%):
[1163]
[1164] Scheme S
[1165]
[1166] 2-methyl-N- (3- {1- [3- (1-methyl-1H-indol-3-yl) propyl] -4-piperidinyl} phenyl) propanamide: N- (3- {1- [4- (1,3-dioxolan-2-yl) butyl] -4-piperidinyl} phenyl) -2-methylpropanamide (100 mg, 0.270 mmol), 1-methyl-1-phenylhydrazine (106 mg, 0.870 mmol), ZnCl ₂ (119 mg, 0.870 mmol) and HOAc (1.00 mL) were heated at 80 ° C. for 12 h. The resulting crude mixture was diluted with water (20 mL) and the aqueous layer was neutralized with saturated K ₂ CO ₃ solution (10 mL) and extracted with CH ₂ Cl ₂ (3 × 20 mL). The combined organic layers were concentrated in vacuo and the residue was purified by preparative TLC using 3% NH ₃ (2.0 M in methanol) in CH ₂ Cl ₂ to afford the desired product 2-methyl-N- (3- {1- [3. -(1-methyl-1H-indol-3-yl) propyl] -4-piperidinyl} phenyl) propanamide (20.7 mg, 18.7%) was obtained.
[1167]
[1168] analysis. Theoretical for C ₂₇ H ₃₅ N ₃₀ + 0.225CHCl ₃ : C, 73.57; H, 7.99; N, 9.45. Found: C, 73.93; H, 7.90; N, 9.23; ESMS m / e: 418.2 (M + H) ⁺
[1169] Procedure I
[1170] Scheme T
[1171]
[1172] 7- (2-fluorophenyl) -1H-indole : 2-fluorophenylboronic acid (83.4 mg, 0.600 mmol), 7-bromo-1H-indole (98.0 mg, 0.500 mmol), LiCl (42.0 mg, 1.00 mmol), Na ₂ CO ₃ (2.0 M, 0.100 mL), Pd (PPh ₃ ) ₄ (115 mg, 0.100 mmol) and DME (2.00 mL) were heated under argon at 75 ° C. for 12 h. The resulting crude mixture was diluted with water (40 mL), the aqueous layer was extracted with CH ₂ Cl ₂ (3 × 20 mL), the combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered And concentrated in vacuo. The residue was purified by preparative TLC with hexanes: EtOAc (8: 1) to afford the desired product 7- (2-fluorophenyl) -1H-indole (108 mg, 100%):
[1173]
[1174] Procedure J
[1175] Scheme U
[1176]
[1177] 5- (4-methylphenoxy) -1H-indole: 5-bromo-1H-indole (98.0 mg, 0.500 mmol), p-cresol (108 mg, 1.00 mmol), Cu (32.0 mg, 0.500 mmol), A mixture of K ₂ CO ₃ (138 mg, 1.0 mL) and DMF (1.00 mL) was heated at 160 ° C. for 12 h. The resulting crude mixture was diluted with water (40 mL) and the aqueous layer was extracted with CH ₂ Cl ₂ (3 × 20 mL). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by preparative TLC with hexanes: EtOAc (4: 1) to afford the desired product 5- (4-methylphenoxy) -1H-indole (57.5 mg, 51.5%): ESMS m / e: 224.0 (M + H) ⁺
[1178] Procedure K
[1179]
[1180] Scheme AN
[1181]
[1182] N- (3- {1- [7- (2-fluorophenyl) -7-oxoheptyl] -4-piperidinyl} phenyl) -2-methylpropanamide: DMF (25.0) in a 50-mL round bottom flask 7-chloro-1-oxo-1 (2-fluorophenyl) heptane (2.42 g, 10.0 mmol), 2-methyl-N- [3- (4-piperidyl) phenyl] propanamide (2.46) in mL) g, 10.0 mmol), a solution of K ₂ CO ₃ (2.76 g, 20.0 mmol) and NaI (2.25 g, 15.0 mmol) were charged. The mixture was stirred at 25 ° C. for 10 minutes, then heated at 100 ° C. for 12 h, then cooled to 25 ° C. and diluted with EtOAc (100 mL). The reaction mixture was washed with water (4 x 50 mL) and the aqueous layer was extracted with EtOAc (100 mL). The organic layer was washed with brine (50 mL), dried over MgSO ₄ , concentrated in vacuo and the crude product was purified by chromatography (EtOAc: MeOH 97: 3) to afford the desired product (3.70 g, 82.0%). .
[1183] Procedure L
[1184]
[1185] Scheme AN
[1186]
[1187] N- (3- {1- [7- (2-fluorophenyl) -7-hydroxyheptyl] -4-piperidinyl] phenyl) -2-methylpropanamide: N- (3- {1- [ To a 50-mL round bottom flask filled with 7- (2-fluorophenyl) -7-oxoheptyl] -4-piperidinyl} phenyl) -2-methylpropanamide (5.0 mmol) and methanol (20 mL) NaBH ₄ (7.5 mmol) at 0 ° C. was added in an ice bath. The reaction mixture was raised to 25 ° C. and stirred for 2 h. The reaction was monitored by TLC (EtOAc: MeOH 95: 5). If necessary, 5.0 mmol of NaBH ₄ was added once more to the reaction mixture and the reaction mixture was refluxed for 1 h. The reaction was quenched with water (5.0 mL) and diluted with EtOAc (10 mL). The organic layer was separated, washed with saturated NaHCO ₃ solution (10 mL), dried over MgSO ₄ and concentrated in vacuo. The crude product was purified by chromatography (EtOAc: MeOH 97: 3) to afford the desired product (90%).
[1188] Procedure M
[1189] Scheme A
[1190]
[1191] Step 1: If reacted separately, a solution of amine or aniline (1.00 equiv), diisopropylethylamine or TEA (2.00 equiv) and electrophile (1.50 equiv) in CH ₂ Cl _{2 is} stirred at 23 ° C. for 24 h It was. The solvent was removed in vacuo and the crude product was chromatographed (silica) to give the final product.
[1192]
[1193] tert-Butyl 4- {3-[(4-chlorobutanoyl) amino] phenyl} -1-piperidinecarboxylate (3.32 g, 87.4%) was synthesized according to Scheme A and Procedure M:
[1194]
[1195]
[1196] Step B:
[1197] tert-butyl 4- [3- (2-oxo-1-pyrrolidinyl) phenyl] -1-piperidinecarboxylate: tert-butyl 4- [3- (2-oxo in dioxane (100 mL) To a solution of -1-pyrrolidinyl) phenyl] -1-piperidinecarboxylate (0.429 g, 16.9 mmol) was bubbled HCl gas at 25 ° C. for 1 h. The resulting crude mixture was basified with 10% KOH solution (100 mL) and the aqueous layer was extracted with 3: 1 CHCl ₃ : iso-propyl alcohol (3 × 150 mL). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by preparative TLC using 20% NH ₃ (in 2.0 M MeOH) in CH ₂ Cl ₂ solution to afford the desired product tert-butyl 4- [3- (2-oxo-1-pyrrolidinyl) phenyl]. -1-piperidinecarboxylate (245 mg, 78.7%) was obtained:
[1198]
[1199]
[1200] tert-butyl 4- (4-aminophenyl) -1-piperidinecarboxylate:
[1201] Arch Chemical Company, manufactured by NJ.
[1202] 2-methyl-N- [4- (4-piperidinyl) phenyl] propanamide: tert-butyl 4- (4-aminophenyl) -1-piperidinecarboxyl in dry THF (100 mL) at 0 ° C. To a solution of rate (8.20 g, 29.7 mmol) and triethylamine (8.4 mL, 60 mmol) was added slowly a solution of 2-methylpropanoyl chloride (3.84 g, 36.0 mmol) in THF (50 mL). The reaction mixture was then warmed to room temperature and stirred for 2 h. The solvent was removed in vacuo and the crude product was purified by recrystallization (hexane / THF) to give the desired amide, tert-butyl 4- [4- (isobutyrylamino) phenyl] -1-piperidinecarboxylate Was obtained as a white solid (8.60 g, 84%). tert-butyl 4- [4- (isobutyrylamino) phenyl] -1-piperidinecarboxylate is dissolved in CH ₂ Cl ₂ (50 mL) at room temperature and TFA (13.68 g, 120 mmol, 5 equiv. ) Was added by syringe. After the reaction mixture was stirred for 3 or 4 h, an additional 5 equivalents of TFA was added and the mixture was stirred for 2 or 3 h or more. The reaction solution was then basified to pH> 14 with KOH (aq, 2 M). This solution was extracted with CH ₂ Cl ₂ (8 × 200 mL). The combined organic layers were dried over K ₂ CO ₃ . Removal of solvent under reduced pressure gave free amine, 2-methyl-N- [4- (4-piperidinyl) phenyl] propanamide as a brown solid (5.99 g, 98%).
[1203]
[1204] N- [4- (4-piperidinyl) phenyl] propanamide: 2-methyl-N- using tert-butyl 4- (4-aminophenyl) -1-piperidinecarboxylate and propanoyl chloride Prepared by the procedure for [4- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 233.1 (M + H) ⁺
[1205] N- [4- (4-piperidinyl) phenyl] butanamide: 2-methyl-N- using tert-butyl 4- (4-aminophenyl) -1-piperidinecarboxylate and butanyl chloride Prepared by the procedure for [4- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 247.2 (M + H) ⁺
[1206] N- [3- (4-piperidinyl) phenyl] cyclopropanecarboxamide: 2 using tert-butyl 4- (3-aminophenyl) -1-piperidinecarboxylate and cyclopropanecarbonyl chloride Prepared by the procedure for -methyl-N- [4- (4-piperidinyl) phenyl] propanamide: analysis. Theoretical for C ₁₅ H ₂₀ N ₂ 0 + 0.15CH ₂ C _l2 : C, 70.8; H, 7.87; N, 10.9. Found: C, 70.9; H, 7.68; N, 11.1; ESMS m / e: 245.0 (M + H) ⁺
[1207] N- [3- (4-piperidinyl) phenyl] propanamide: 2-methyl-N- using tert-butyl 4- (3-aminophenyl) -1-piperidinecarboxylate and propanoyl chloride Prepared by the procedure for [4- (4-piperidinyl) phenyl] propanamide: assay. Theoretical for C ₁₄ H _{2 O} N ₂ 0: C, 72.2; H, 8.63; N, 12.1. Found: C, 72.4; H, 8.68; N, 12.1; ESMS m / e. 233.1.
[1208] Procedure N
[1209] [Reaction Scheme AV]
[1210]
[1211] The library was built on a polypropylene Robbins 46 well plate Reactor Block. On initial incubation, each well was charged with PS-TBD resin (Argonaut Technologies, 0.280 mmol, 2.50 eq, 200 mg) and piperidine (0.120 mmol, 1.10 equiv) in acetonitrile (0.500 mL) and stirred for 1 h. . A solution of benzyl iodide or bromide (0.110 mmol, 1.00 equiv) in acetonitrile (0.500 mL) was added to each well, followed by the addition of acetonitrile (1.00 mL) to a total volume of 2.00 mL. The mixture was spun in a Robbins rotary oven (room temperature, 16 h). AP-isocyanate resin (Argonaut Technologies, 250 mg, 0.430 mmol, 4.00 equiv) was then added to each well and further reacted for 12 h at room temperature. This mixture was filtered and the filtrate was concentrated in vacuo to give the desired product which was characterized by LC-MS.
[1212] Procedure 0
[1213] Alkylation of Piperidine with Alcohol and PS-TSCl in Robbins 48-well "Reactor Blocks"
[1214] Scheme W
[1215]
[1216] The library was constructed in polypropylene Robbins "Reactor Blocks", 46 well plates. PS-TSCl resin (100 mg, 1.00 eq, Argonaut Technologies) was charged to each well of a "Reactor Blocks" 46 well plate. To each well was added 3.00 mL of CH ₂ Cl ₂ and alcohol in pyridine (1: 1) (1.50 mmol). The mixture is stirred for 5 h, the resin is CH ₂ Cl ₂ (3 × 4 mL), DMF (5 × 4.0 mL), DMF / H ₂ O (3: 1, 5 × 4.0 mL), THF (3 × 4.0 mL ), CH ₂ Cl ₂ (3 × 4.0 mL), acetonitrile (2 × 4.0 mL), and dried under reduced pressure. A solution of amine (0.0750 mmol, 0.500 equiv) and NN-diisopropylethyl amine (19.0 mg, 0.150 mmol, 1.00 equiv) in acetonitrile (3.00 mL) was added to the well containing the derivatization resin and the mixture was 70 The reaction was carried out at 16 ° C. for 16 h. Finally, AP-isocyanate resin (120 mg, 0.150 mmol, 1.00 equiv) and THF (2.00 mL) were added to the reaction vessel, and further reacted at room temperature for 3 h. This solution was filtered through a Robbins receiving plate and concentrated in vacuo to give the desired tertiary amine, which was analyzed via LC-MS.
[1217] Procedure P
[1218] Scheme AB
[1219]
[1220] N- {3- [1- (3-{[(4-fluoroanilino) carbonyl] amino} propyl) -4-piperidinyl] phenyl} -methylpropanamide: N- in THF (1.00 mL) {3- [1- (3-aminopropyl) -4-piperidinyl] phenyl} -2-methylpropanamide (26.4 mg, 0.0870 mol), 1-fluoro-4-isocyanatobenzene (11.9 mg , 0.0870 mmol) was stirred at 25 ° C. for 12 h. The resulting crude mixture was diluted with water (10 mL) and the aqueous layer was extracted with CH ₂ Cl ₂ (3 × 20 mL). The combined organic layers were concentrated in vacuo and the residue was purified by preparative TLC using 2.5% NH ₃ (2.0 M in methanol) in CH ₂ Cl ₂ to give the desired product N- {3- [1- (3-{[( 4-fluoroanilino) carbonyl] amino} propyl) -4-piperidinyl] phenyl} -2-methylpropanamide (4.18 mg, 10.9%) was obtained:
[1221]
[1222] Procedure Q ₁
[1223] Scheme AT
[1224]
[1225] If reacted separately, a solution of amine (1.0 equiv), electrophile (1.5 equiv), diisopropylethylamine (2.0 equiv) in CH ₂ Cl ₂ was stirred for 1 day. The solvent was removed in vacuo and the crude product was chromatographed to give the final product.
[1226]
[1227] 2-methyl-N- {3- [1- (3-{[(4-methylphenyl) sulfonyl] amino} propyl) -4-piperidinyl] phenyl} propanamide: 4-methyl in THF (1.00 mL) Benzenesulfonyl chloride (16.6 mg, 0.0870 mmol), N- {3- [1- (3-aminopropyl) -4-piperidinyl] phenyl} -2-methylpropanamide (26.4 mg, 0.0870 mmol), TEA (10.0 mg, 0.174 mmol) was stirred at 25 ° C. for 12 h. The resulting crude mixture was diluted with water (20 mL) and the aqueous layer was extracted with CH ₂ Cl ₂ (2 × 20 mL). The combined organic layers were concentrated in vacuo and the residue was purified by preparative TLC with 2.5% NH ₃ (2.0 M in methanol) in CH ₂ Cl ₂ to afford the desired product 2-methyl-N- {3- [1- (3 -{[(4-methylphenyl) sulfonyl] amino} propyl) -4-piperidinyl} phenyl) propanamide (17.3 mg, 43.6%) was obtained:
[1228]
[1229] Procedure Q ₂
[1230] Capture and Release Methods for the Synthesis and Purification of Piperidine Libraries
[1231] A commercially available Amberlyst 15 exchange resin (Aldrich) was activated using the following procedure:
[1232] 1. The resin was shaken in methanol for 24 h.
[1233] 2. The resin was washed with methanol on filtration and a glass funnel.
[1234] 3. The resin was neutralized with 2N NH ₃ (pH checked) in MeOH and shaken for 1 h.
[1235] 4. The neutralized resin was acidified with 3M HCl (pH checked) in MeOH and shaken for 1 h.
[1236] 5. The resin was captured on a glassy funnel and washed with MeOH.
[1237] 6. The resin was dried under vacuum and stored.
[1238] Synthesis (acylation of amines):
[1239] The library was built in polypropylene Robbins 'Reactor Blocks', 46 well plates. Array of 5 amines (0.10 mmol) and 8 electrophiles (acid chloride, sulfonyl chloride, 1.5 equiv) in the presence of triethylamine (2.0 equiv) in THF / DCM 3: 1 (2,0 mL) in each plate Was reacted overnight to give 40 compounds / plate. The reaction was strictly monitored via TLC for depletion of starting amines due to the continued purification methodology through the acid Amberlyst 15 resin. After the disappearance of the starting amine, the desired product was captured and then released using the process outlined below.
[1240] Purification of Piperidine Product: Activated Amberlyst 15 ion-exchange resin (0.90 g, Aldrich) was added to each well and the plate was spun in a Robbins rotary oven for 2 h to capture the final product from the reaction mixture. The solvent was filtered off, and the resin was washed alternately with each solvent of CH ₃ 0H and CH ₂ Cl ₂ (x 3) (every 10 minutes). After final filtration, 2 N ammonia in methanol was added to the resin (2 mL in each well) and the reaction block was spun for 2 h to release the desired compound from the resin. The final compound was filtered through Robbins' “Receiving Blocks”, the solvent was removed and the compound analyzed via LC-MS.
[1241] Procedure R
[1242] Scheme Z
[1243]
[1244] [(3-Chloropropyl) sulfanyl ] benzene: benzenethiol (O.550 g, 5.00 mmol), 1-bromo chloropropane (106 mg, 5.50 mmol), TEA (1.01 g, 10.0 mmol) and THF (10.0) mL) was stirred at 25 ° C. for 12 h. The resulting crude mixture was diluted with water (40 mL) and the aqueous layer was extracted with CH ₂ Cl ₂ (3 × 30 mL). The combined organic layers were concentrated in vacuo and the residue was purified by preparative TLC using hexanes: EtOAc (10: 1) to afford the desired product [(3-chloropropyl) sulfanyl] benzene (1.05 g, 100%).
[1245] Scheme AA
[1246]
[1247] X = F, Cl, Br, I
[1248] Procedure S
[1249] 3-Chloropropyl 4-fluorophenyl sulfoxide: A solution of 3-chloropropyl 4-fluorophenyl sulfide (77.5 mg, 0.380 mmol) in CH ₂ Cl ₂ (2.00 mL) was cooled to 0 ° C. To this solution m-CPBA (78.7 mg, 0.460 mmol) was added. The reaction mixture was stirred at 0 ° C. for 30 minutes and then at 23 ° C. for 4 h. The resulting crude mixture was diluted with 10% aqueous Na ₂ SO ₃ (10 mL) and the aqueous layer was extracted with CH ₂ Cl ₂ (2 × 15 mL). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by preparative TLC using 2.5% NH ₃ (2.0M in methanol) in CH ₂ Cl ₂ to afford the desired product 3-chloropropyl 4-fluorophenyl sulfoxide (47.8 mg, 57.0%). .
[1250] Procedure T
[1251] Scheme AD
[1252]
[1253] N- (3- {1- [4- (3,4-dimethylphenyl) -4-oxobutyl] -4-piperidinyl} phenyl) -N, 2-dimethylpropanamide: N- (3- {1 -[4- (3,4-dimethylphenyl) -4-oxobutyl] -4-piperidinyl} phenyl) -2-methylpropanamide (15.0 mg, 0.0357 mmol), MeI (5.07 mg, 0.0357 mmol), A mixture of NaOtBu (6.86 mg, 0.0714 mmol) and THF (1.00 mL) was stirred at 25 ° C. for 5 h. The resulting crude mixture was diluted with water (10 mL) and the aqueous layer was extracted with CH ₂ Cl ₂ (3 × 20 mL). The combined organic layers were concentrated in vacuo and the residue was purified by preparative TLC using 4.0% NH ₃ (2.0 M in methanol) in CH ₂ Cl ₂ to give the desired product N- (3- {1- [4- (3, 4-Dimethylphenyl) -4-oxobutyl] -4-piperidinyl} phenyl) -N, 2-dimethylpropanamide (13.8 mg, 89.1%) was obtained:
[1254]
[1255] Procedure U
[1256] Scheme AK
[1257]
[1258] 1- [3- (3-chloropropoxy) phenyl] ethanone: 1- (3-hydroxyphenyl) ethanone (136 mg, 1.00) in a suspension of NaH (50.5 mg, 2.00 mmol) in DMF (1.00 mL). mmol) was added at 0 ° C. The reaction mixture was stirred for 1 h at room temperature. To this mixture was added a solution of 1-bromo-3-chloropropane (188 mg, 1.20 mmol) in DMF (0.500 mL). The reaction mixture was stirred at rt for 5 h. The resulting crude mixture was diluted with water (20 mL) and the aqueous layer was extracted with CH ₂ Cl ₂ (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by preparative TLC with hexanes: EtOAc (4: 1) to afford the desired product 1- [3- (3-chloropropoxy) phenyl] ethanone (235 mg, 55.2%):
[1259]
[1260] Procedure V
[1261] Scheme AE
[1262]
[1263] 1-[(2,2-dimethylpropanoyl) oxy] -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,2, 3,6-tetrahydropyridine:
[1264] 50 filled with bis (pinacolato) diboron (422 mg, 1.66 mmo1), KOAc (444 mg, 4.53 mmo1) and PdCl ₂ dppf (37.0 mg, 3.00 mol%), dppf (25.0 mg, 3.00 mol%) 1-[(2,2-dimethylpropaneyl) oxy] -1,2,3,6-tetrahydro-4-pyridinyl trifluoro in 1,4-dioxane (10.0 mL) in a -mL RB-flask A solution of methanesulfonate (500 mg, 1.51 mmol) was added at room temperature under argon. The mixture was heated at 80 ° C. overnight. After cooling to rt, the mixture was filtered through celite and the celite was washed with EtOAc (3 × 20 mL). The filtrate was concentrated in vacuo. The resulting residue was dissolved in EtOAc, washed with H ₂ O and brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The crude material was purified by flash chromatography (1: 9 EtOAc: hexane) to give 1-[(2,2-dimethylpropaneoyl) oxy] -4- (4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl) -1,2,3,6-tetrahydropyridine (355 mg, 76.0%) was obtained.
[1265] Procedure W
[1266] Reaction Scheme AF
[1267]
[1268] tert-butyl 4- [5- (isobutyrylamino) -2-methylphenyl] -3,6-dihydro-1 (2H) -pyridinecarboxylate: 1-[(2,2-dimethylpropanoyl) oxy ] -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,2-3,6-tetrahydropyridine (500 mg, 1.62 mmol ), N- (3-bromo-4-methylphenyl) -2 in DMF (10.0 mL) in a 50-mL RB flask containing K ₂ CO ₃ (670 mg, 4.86 mmol) and PdCl ₂ dppf (155 mg). A solution of -methylpropanamide (415 mg, 1.62 mmol) was added under argon at room temperature. This mixture was heated to 80 ° C. under argon overnight. After cooling to rt, the mixture was filtered through celite and the celite was washed with EtOAc (3 × 20 mL). The filtrate was washed with H ₂ 0 (20 mL), brine (20 mL), dried over MgSO ₄ , filtered and concentrated in vacuo. The crude material was flash chromatographed (20% EtOAc / hexanes) to give tert-butyl 4- [5- (isobutyrylamino) -2-methylphenyl] -3,6-dihydro-1 (2H) -pyridinecarboxylate (360 mg, 62.0%) was obtained.
[1269] Scheme AG
[1270]
[1271] Procedure X
[1272] tert-butyl 4- [5- (isobutyrylamino) -2-methylphenyl] -1-piperidinecarboxylate: tert-butyl 4- [5- (isobutyrylamino)-in EtOH (20.0 mL) A solution of 2-methylphenyl] -3,6-dihydro-1 (2H) -pyridinecarboxylate (335 mg, O.93 mmol) and 10% Pd / C (35.0 mg) was heated to room temperature using a hydrogen balloon method. Hydrogenated overnight at. The reaction mixture was filtered through celite and washed with ethanol (3 × 10 mL). The combined extracts were concentrated in vacuo to afford tert-butyl 4- [5- (isobutyrylamino) -2-methylphenyl] -1-piperidinecarboxylate (335 mg, 100%).
[1273] Procedure Y
[1274] Scheme AH
[1275]
[1276] 2-methyl-N- [4-methyl-3- (4-piperidinyl) phenyl] propanamide : tert-butyl 4- [5 (isobutyrylamino) -2- in CH ₂ C1 ₂ (10.0 mL) To a solution of methylphenyl] -l-piperidinecarboxylate (335 mg, 0.930 mmol) was added TFA (10.0 mL) at room temperature. The reaction mixture was stirred for 2 hours and concentrated in vacuo. The residue was dissolved in 20 mL of CHC1 ₃ / i-PrOH (3: 1) and basified with 5% KOH solution (10 mL). The aqueous phase was extracted with CHC1 ₃ / i-PrOH (3: 1, 3 × 10 mL). The combined organic extracts were washed with brine, dried over MgSO ₄ , filtered and concentrated in vacuo to give 2-methyl-N- [4-methyl-3- (4-piperidinyl) phenyl] propanamide (190 mg, 78.0%).
[1277] Procedure Z
[1278] Scheme AI
[1279]
[1280]
[1281] N- (3- {l- [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl} -4-methylphenyl) -2-methylpropanamide : 2- in DMF (10.0 mL) Methyl-N- [4-methyl-3- (4-piperidinyl) phenyl] propanamide (49.0 mg, 0.190 mmol), 1- [4-chloro-1- (4-fluorophenyl) butyl] -4 A solution of -fluorobenzene (58.0 mg, 0.210 mmol), NaI (42.0 mg, 0.280 mmol) and K ₂ CO ₃ (52.0 mg, 0.380 mmol) was heated at 95 ° C. overnight. The mixture was diluted with water (20 mL) and the aqueous phase extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine, dried over MgSO ₄ and concentrated in vacuo. The crude product was purified by flash chromatography [5% NH ₃ in CH ₂ C1 ₂ (2.0 M in MeOH)] to give N- (3- {l- [4,4-bis (4-fluorophenyl) butyl]- 4-piperidinyl} -4-methylphenyl) -2-methylpropanamide (37.0 mg, 38.0%) was obtained.
[1282] Procedure AA
[1283] Scheme AJ
[1284]
[1285] N- (3- {l- [4- (3,4-difluorophenoxy) benzyl] -4-piperidinyl} -4-methylphenyl) -2-methylpropanamide : 1,2-dichloroethane ( 5.00 mL) 4- (3,4-difluorophenoxy) benzaldehyde (41.0 mg, 0.170 mmol) and 2-methyl-N- [4-methyl-3- (4-piperidinyl) phenyl] propanamide To a (45.0 mg, 0.170 mmol) solution was added sodium triacetoxyborohydride (110 mg, 0.520 mmol) and AcOH (10.0 μl, 0.170 mmol) at room temperature. The mixture was stirred overnight. The reaction mixture was quenched with saturated NaHCO ₃ solution (10 ml) and extracted with CH ₂ Cl ₂ (3 × 10 ml). The combined organic layers were washed with brine, dried over MgSO ₄ and concentrated in vacuo. The crude product was purified by TLC using preparative 5% NH ₃ (2.0 M in MeOH) in CH ₂ C1 ₂ to afford the desired product N- (3- {1- [4- (3,4-difluorophenoxy). ) Benzyl] -4-piperidinyl} -4-methylphenyl) -2-methylpropanamide (44.0 mg, 54.0%) was obtained.
[1286] Procedure AC
[1287] Scheme AT: Synthesis of Amide Using PS-Carbodiimide Resin
[1288]
[1289] A mixture of carboxylic acid (0.0800 mmol) and PS-carbodiimide resin (2.00 eq, 80.0 mg, 1.34 mmol / g) in DCM: DMF (10: 1, 3.00 mL) was shaken for 30 minutes. Amine (0.0540 mmol) was added to the reaction mixture and the resulting mixture was shaken at room temperature for 12 hours. The reaction mixture was filtered and the resin washed with CH ₂ C1 ₂ . The combined organic extracts were concentrated to a small volume, applied to a preparative TLC plate and eluted with 6% NH ₃ (2.0 M in MeOH) in CH ₂ C1 ₂ to afford the desired product.
[1290] Procedure AD
[1291] Scheme X
[1292]
[1293] TERT-Butyl N- (3-bromopropyl) carbamate : Prepared from 3-bromopropylamine hydrobromide and BOC ₂ 0 in the presence of a base in CH ₂ C1 ₂ : ¹ H NMR (300 MHz) δ5. 07 (br, 1H), 3.31 (t, 2H, J = 6.6 Hz), 3.12 (apparent br q, 2H, J = 6.0 Hz), 1.92 (p, 2H, J = 6.6 Hz), 1.30 ( s, 9H).
[1294]
[1295] Step 1. A solution of piperidine (19.3 mmol) in dioxane (20.0 mL) was added N- (tert-butoxycarbonyl) -3-bromopropylamine (21.2 mmol) and potassium carbonate (38.7 mmol) at room temperature. Was added and the mixture was heated at reflux for 24 h. The reaction mixture was cooled to rt, concentrated in vacuo and partitioned between CHC1 ₃ (40 mL) and water (5 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (ethyl acetate: methanol 9: 1) to afford the desired product tert-butyl 3- {4- [3- (acetylamino) phenyl] piperidinyl] propylcarbamate as colorless oil. Was: ESMS m / e: 376.2 [M + H] ⁺
[1296] Step 2. HC1 gas was bubbled into a solution of boc-protected amine (12.1 mmol) in dioxane (5.00 mL) at 0-5 ° C. for 10-20 minutes. The resulting solution was stirred at 0-5 ° C. for 1 h, concentrated, neutralized with 10% KOH solution (10 mL) and extracted with CH ₂ C1 ₂ (25 mL). The organic extract was washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was chromatographed to give the desired product N- {3- [l- (3-aminopropyl) -4-piperidinyl] phenyl} acetamide: ESMS m / e: 276.1 [M + H] ⁺
[1297] Procedure AE
[1298] Scheme Y
[1299]
[1300] Step 1: piperidine (1.00 eq, 0.0226 mmol), N- (bromoalkyl) phthalimide (1.50 eq, 0.0338 mmol), BU ₄ NI (200 mg) and diisopropyl in dioxane (200 mL) The ethylamine (5.00 eq, 0.113 mmol) mixture was heated at 99 ° C. for 24 hours. The reaction was analyzed by TLC (95: 5 CH ₂ C1 ₂ : methanol). If necessary, additional 0.0113 mmol of appropriate bromoalkylphthalimide was added to each reaction mixture and heating was continued for an additional 48 hours. The reaction mixture was cooled to room temperature, the ammonium salt was filtered off and the solvent was removed under reduced pressure. The crude product was chromatographed to give the desired product.
[1301]
[1302] Step 2: Deprotection of the resulting phthalimide was carried out by heating the phthalimide protected amine solution at 90 ° C. for 4 hours using excess hydrazine hydrate (10 equiv) in ethanol (0.5-1.0 M). The reaction mixture was monitored by TLC until termination. At the end of the reaction, the mixture was cooled to room temperature, insoluble byproducts were removed by filtration through celite and the solvent was removed in vacuo. The crude product was chromatographed (dichloromethane-methanol-isopropylamine) to afford the desired product.
[1303]
[1304] Procedure AF
[1305]
[1306] Scheme H
[1307]
[1308] (4R) -4- (3,4-difluorophenyl) -N- (3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} propyl) -2-oxo- 1,3-oxazolidine-3-carboxamide was synthesized according to Scheme H and Procedure AF: (4R) -4- (3,4-difluorophenyl) -1,3 in THF (5.00 mL) -Oxazolidin-2-one (this compound and analogues prepared according to J. Med. Chem 2000, 43, 2775) (0.300 mol, 60.0 mg) in a solution LDA (2.0 M in THF, 0.390 mmol, 0.200 mL) ) Was added at 78 ° C. under argon. After 30 minutes at -78 ° C, the mixture was added a solution of 4-nitrophenyl chloroformate (0.330 mmol, 51.2 mg) in THF (0.500 mL) at -78 ° C. After stirring at −78 ° C. for 30 minutes, the reaction mixture was diluted with saturated Na ₂ CO ₃ solution (5.0 mL) and the aqueous phase was extracted with CH ₂ C1 ₂ (3 × 10 mL). The combined organic layers were washed with (10 mL), dried over Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by preparative TLC plate (10: 1 hexanes: ethyl acetate) to give 4-nitrophenyl (4R) -4- (3,4-difluorophenyl) -2-oxo-1,3-oxazolidine 3-carboxylate (51.5 mg, 54.0%) was obtained.
[1309] 4-nitrophenyl (4R) -4- (3,4-difluorophenyl) -2-oxo-1,3-oxazolidine-3-carboxylate (169 mg, 0.465 mmol), N- {3 -[1- (3-aminopropyl) -4-piperidinyl] phenyl} -2-methylpropanamide (141 mg, 0.465 mmol), K ₂ CO ₃ (0.193 g, 1.39 mmol), CH ₂ C1 ₂ ( 10 mL), and methanol (0.1 mL) were combined in the flask. The mixture is stirred overnight at room temperature, the solvent is removed in vacuo and the residue is chromatographed [2.5% NH ₃ in CH ₂ C1 ₂ (2.0 M in methanol)] to afford the desired product (26.1 mg, 10.6%). ¹ H NMR (400 MHz, CDC1 ₃ ) δ 8.08 (t, 1H, J = 5.5 Hz), 7.45 (S, 2H), 7.38 (d, 1H, J = 8.6 Hz), 7.24-7.12 (m , 3H), 7.06 (m, 1H), 6.97 (d, 1H, J = 8.6 Hz), 5.40 (dd, 1H, J = 3.9-8.8 Hz), 4.71 (t, 1H, J = 8.8 Hz), 4.23 (dd, 1H, J = 4.4, 9.1 Hz), 3.32 (qt, 2H, J = 6.1 Hz), 2.99 (d, 2H, J = 11.0 Hz), 2.49 (qt, 2H, J = 7.0 Hz), 2.41 (t, 2H, J = 7.0 Hz), 1.99-1.97 (m, 2H), 1.82-1.68 (m, 6H), 1.23 (d, 6H, J = 7.3 Hz); Analytical calcd. For C ₂₈ H ₃₄ F ₂ N ₄ 0 ₄ + HC1 + 0.185CHC1 ₃ : C, 57.6; H, 6.04; N, 9.54. Observation: C, 58.5; H, 6.08; N, 9.47; ESMS m / e: 529.1 (M + H) ⁺
[1310] Procedure AG
[1311] Scheme AR
[1312]
[1313] Step 1: A solution of ketoester (10 mmol), Meldrum acid (10 mmol), aldehyde (10 mmol) and ammonium acetate (11 mmol) in HOAc (10 mL) was heated at reflux for 18 h (MORALES, A). ; OCHOA, E .; SUAREZ, M .; VERDECIA, Y .; GONZALEZ, L .; MARTIN, N .; QUINTEIRO, M .; SEOANE, C .; SOTO, JL; J. Heterocycl. Chem. [JHTCAD] 1996 , 33 (1), 103-107). The cooled reaction mixture was poured onto ice (100 g). The precipitated oils were combined and dried under reduced pressure. Benzyl ester protected analogs solidified on trituration with ether / hexane mixtures.
[1314]
[1315] Step 2: Benzyl ester and 10% Pd / C mixture in methanol were hydrogenated at room temperature using the balloon method. The reaction mixture was monitored to completion (TLC), filtered through Celite 545, and the Celite filter cake was washed with methanol (3 x 10 mL).
[1316] The combined methanol extracts were concentrated in vacuo to afford the desired carboxylic acid used in the next step without any further purification.
[1317]
[1318] 4- (2,4-Difluorophenyl) -2-methyl-6-oxo-1,4,5,6-tetrahydro-3-pyridinecarboxylic acid was synthesized according to Procedure AG and Scheme AR: ¹ H NMR (CDC1 ₃ , 400 MHz) δ 7.82 (s, 1H), 7.00-6.72 (m, 3H), 4.51 (d, 1H, J = 8.4 Hz), 2.90 (dd, 1H, J = 8.4, 16.3 Hz), 2.68 (d, 1H, J = 16.3 Hz), 2.46 (s, 3H).
[1319]
[1320] 4- (3,4-Difluorophenyl) -2-methyl-6-oxo-1,4,5,6-tetrahydro-3-pyridinecarboxylic acid was synthesized according to Procedure AG and Scheme AR: ¹ H NMR (CDC1 ₃ , 300 MHz) δ 7.40-6.80 (m, 4H), 4.23 (d, 1H, J = 7.5 average Hz), 2.93 (dd, 1H, J = 16.8, 7.5 average Hz), 2.68 ( d, 1H, J = 16.5 average Hz), 2.45 (s, 3H)
[1321] Procedure AH
[1322]
[1323] 1- (6-chlorohexyl) -1H-indole : A solution of 1-H-indole (0.585 g, 5.00 mmol) in DMF (2.00 mL) was added to a mixture of NaH (0.249 g, 10.0 mmol) in DMF (5.00 mL). Add at ° C. The reaction mixture was stirred at 0 ° C. for 30 minutes and warmed to room temperature. To the reaction mixture was added dropwise 1-bromo-6-chlorohexane (0.998 g, 5.00 mmol) via dice and the reaction mixture was stirred overnight. The reaction mixture is diluted with EtOAc (30 mL), washed with water (3 x 10 mL), brine (10 mL), dried over MgSO ₄ , concentrated in vacuo and using hexanes: EtOAc (97.5: 2.5). Purification by chromatography gave the desired product (0.900 g, 76.0%): ¹ H NMR (400 MHz, CDC1 ₃ ) δ7.76-7.54 (m, 1H), 7.47-6.96 (m, 4H), 6.60- 6.34 (m, 1H), 4.13 (t, 2H, J = 6.8 Hz), 3.50 (t, 2H, J = 5.6 Hz), 1.98-1.79 (m, 2H), 1.79-1.64 (m, 2H), 1.54 -1.17 (m, 4H).
[1324] N- (3- {l- [6- (lH-indol-1-yl) hexyl] -4-piperidinyl} phenyl) -2-methylpropanamide : 1- (6-chlorohexyl) -1H-indole (23.6 mg, 0.100 mmol), 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide (24.6 mg, 0.100 mmol), K ₂ CO ₃ (27.6 mg, 0.200 mmol), NaI ( 22.5 mg, 0.150 mmol) and DMF (1.00 mL) were heated at 100 ° C. for 12 h. The reaction mixture was cooled to room temperature and the crude was purified by preparative TLC with NH ₃ in CH ₂ C1 ₂ (2.0 M in methanol) to afford the desired product as a yellow solid (40 mg, 90%): ¹ H NMR (400 MHz, CDC1 ₃ ) δ 8.08-6.52 (m, 11H), 4.17 (t, 2H, J = 7.2 Hz), 3.26 (d, 2H, J = 11.6 Hz), 2.74-2.52 (m, 4H) , 2.44-2.28 (m, 2H), 2.20-2.02 (m, 2H), 1.98-1.82 (m, 4H), l.78-1.62 (m, 2H), 1.43-1.28 (m, 4H), 1.28 ( d, 6H, J = 6.8 Hz); ESMS m / e: 446.5 (M + H) ⁺
[1325] Procedure AI :
[1326] Scheme AU : Preparation of tert-piperidine using PS-S02C1 resin
[1327]
[1328] The library was constructed in polypropylene robin “reactor block”, 48 well plates. PS-TSC1 resin (100 mg, 1.00 eq, purchased from Argonaut Technologies) was placed in each well of a "reactor block" 48 well plate. To each well was added 2-10 eq of alcohol in dichloromethane: pyridine (1: 1, 3.00 mL). The mixture was stirred at rt for 5 h, the resin was dichloromethane (3 x 4.00 mL), DMF (5 x 4.00 mL), DMF / H ₂ 0 (3: 1, 5 x 4.00 mL), THF (3 x 4.00 mL). mL), dichloromethane (3 x 4.00 mL), acetonitrile (2 x 4.00 mL), and dried under reduced pressure. A solution of amine (0.0750 mmol, 0.500 equiv) and N, N-diisopropylethylamine (19.0 mg, 0.150 mmol, 1.00 equiv) in acetonitrile (3.00 mL) was added to the well containing the derived resin and the mixture was added The reaction was carried out in a Robins rotary oven at 70 ° C. for 16 hours. After cooling, AP-isocyanate resin (120 mg, 0.150 mmol, 1.00 equiv) and THF (2.00 mL) were added to each reaction vessel and reacted for an additional 3 hours at room temperature. Robbins solution Filtration in a receiving plate and concentration in vacuo gave the desired tertiary amine analyzed via LC-MS.
[1329] Procedure AJ :
[1330] Scheme AV : Preparation of tert-piperidine using piperidine
[1331]
[1332] Polypropylene Robbins The library was built in a 48 well plate reactor block. During the initial incubation period, each well was filled with PS-TBD resin (Argonaut Technologies, 200 mg, 0.280 mmol, 2.50 equiv) and piperidine (0.120 mmol, 1.10 equiv) in acetonitrile (0.500 mL) for 1 hour. Stirred. Benzyl iodide or bromide (0.110 mmol, 1.00 equiv) in acetonitrile (0.500 mL) is added to each well, followed by the addition of additional acetonitrile (1.00 mL) to a total volume of 2 mL, and the mixture is robin rotated. Rotate in oven at room temperature for 16 hours. Subsequently, AP-isocyanate resin (Argonaut Technologies, 250 mg (0.430 mmol, 4.00 equiv)) was added to each well and reacted further for 12 hours at room temperature The mixture was filtered and the filtrate was concentrated in vacuo to LC The desired product identified via -MS.
[1333] Scheme AX
[1334]
[1335] Example 117
[1336] N- (3- {l- [3- (4-bromophenyl) -3-oxopropyl] -4-piperidinyl} phenyl) -2-methylpropanamide : 1- (4-bromophenyl)- Procedure K (KI) and Scheme E (K ₂ CO ₃ ) with 3-chloro-1-propanone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e : 457.1 (M + H) ⁺
[1337] Example 118
[1338] N- (3- {l- [3- (4-chlorophenyl) -3-oxopropyl] -4-piperidinyl} phenyl) -2-methylpropanamide : 3-chloro-l- (4-chlorophenyl Procedure K (KI) and Scheme E (K ₂ CO ₃ ): ESMS m / e: 413.1 with) -l-propaneone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide (M + H) ⁺
[1339] Example 119
[1340] N- (3- {1- [3- (4-methoxyphenyl) -3-oxopropyl] -4-piperidinyl} phenyl) -2-methylpropanamide : 3-chloro-l- (4- meth Procedure K (KI) and Scheme E (K ₂ CO ₃ ): ESMS m / e with methoxyphenyl) -1-propanone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide : 409.2 (M + H) ⁺
[1341] Example 120
[1342] N- (3- {1- [3- (2,3-dihydro-1H-inden-5-yl) -3-oxopropyl] -4-piperidinyl} phenyl) -2 -methylpropanamide : 3 Procedure with -chloro-l- (2,3-dihydro-1H-inden-5-yl) -l-propanone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide K (KI) and Scheme E (K ₂ CO ₃ ): ESMS m / e: 419.2 (M + H) ⁺
[1343] Example 121
[1344] 2-Methyl-N- {3- [l- (3-oxo-3-phenylpropyl) -4-piperidinyl] phenyl} propanamide : 3-chloro-l-phenyl-1 -propanone and 2-methyl Procedure K (KI) and Scheme E (K ₂ CO ₃ ): ESMS m / e: 379.2 (M + H) ⁺ using -N- [3- (4-piperidinyl) phenyl] propanamide
[1345] Example 122
[1346] 2-Methyl-N- (3- {l- [3- (4-methylphenyl) -3-oxopropyl] -4-piperidinyl} phenyl) propanamide : 3-chloro-l- (4-methylphenyl)- Procedure K (KI) and Scheme E (K ₂ CO ₃ ) with 1-Propanone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 393.2 (M + H) ⁺
[1347] Example 123
[1348] N- (3- {l- [3- (4-fluorophenyl) -3-oxopropyl] -4-piperidinyl} phenyl) -2-methylpropanamide : 3-chloro-l- (4-fluoro Procedure K (KI) and Scheme E (K ₂ CO ₃ ): ESMS m / e with Rophenyl) -1-Propanone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide : 397.2 (M + H) ⁺
[1349] Example 124
[1350] N- (3- {l- [3- (4-chlorophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide : N- (3- {1- [3 Prepared by Procedure L and Scheme AN using-(4-chlorophenyl) -3-oxopropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: ESMS m / e: 415.1 (M + H) ⁺
[1351] Example 125
[1352] N- (3- {l- [3- (4-chlorophenyl) -3- (3,4-difluorophenoxy) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide : N -(3- {1- [3- (4-chlorophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 3,4-difluorophenol Prepared by Procedure A and Scheme AN: ESMS m / e: 526.8 (M + H) ⁺
[1353] Example 126
[1354] N- (3- {l- [3- (4-chlorophenyl) -3- (2-methylphenoxy) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide : N- (3- Prepared by Procedure A and Scheme AN using {1- [3- (4-chlorophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and o-cresol ESMS m / e: 505.4 (M + H) ⁺
[1355] Example 127
[1356] N- (3- {l- [3- (4-fluorophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide : N- (3- {1- [ Prepared by Procedure L and Scheme AN using 3- (4-fluorophenyl) -3-oxopropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: ESMS m / e: 399.2 ( M + H) ⁺
[1357] Example 128
[1358] N- (3- {l- [3-hydroxy-3- (4-methoxyphenyl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide : N- (3- {l- [ Prepared by Procedure L and Scheme AN using 3- (4-methoxyphenyl) -3-oxopropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: ESMS m / e: 411.2 ( M + H) ⁺
[1359] Example 129
[1360] N- (3- {l- [3- (4-bromophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide : N- (3- {1- [ Prepared by Procedure L and Scheme AN using 3- (4-bromophenyl) -3-oxopropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: ESMS m / e: 459.1 ( M + H) ⁺
[1361] Example 130
[1362] N- (3- {l- [3- (4-chlorophenyl) -3- (4-methoxyphenoxy) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide : N- (3 -{1- [3- (4-chlorophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4-methoxyphenol in Procedure A and Scheme AN Manufactured by: ESMS m / e: 520.8 (M + H) ⁺
[1363] Example 131
[1364] N- (3- {l- [3- (4-chlorophenoxy) -3- (4-fluorophenyl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide : N- (3 -{1- [3- (4-fluorophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4-chlorophenol in Procedure A and Scheme AN Manufactured by: ESMS m / e: 509.1 (M + H) ⁺
[1365] Example 132
[1366] N- (3- {l- [3- (4-fluorophenyl) -3- (2,3,4,5,6-pentafluorophenoxy) propyl] -4-piperidinyl} phenyl)- 2-methylpropanamide : N- (3- {1- [3- (4-fluorophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 2,3 Prepared by Procedure A and Scheme AN using 4,5,6-pentafluorophenol: ESMS m / e: 564.7 (M + H) ⁺
[1367] Example 133
[1368] N- (3- {l- [3- (4-bromophenyl) -3- (2-methylphenoxy) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide : N- (3 -{1- [3- (4-bromophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 2-methylphenol in Procedure A and Scheme AN Manufactured by: ESMS m / e: 548.8 (M + H) ⁺
[1369] Example 134
[1370] N- (3- {l- [3- (3,4-difluorophenoxy) -3- (4-fluorophenyl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide : N- (3- {l- [3- (4-fluorophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 3,4-difluorophenol Prepared by Procedure A and Scheme AN using: ESMS m / e: 511.1 (M + H) ⁺
[1371] Example 135
[1372] N- (3- {l- [3- (4-bromophenoxy) -3- (4-fluorophenyl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide : N- ( Procedure A and Schemes Using 3- {1- [3- (4-fluorophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4-bromophenol Manufactured by AN: ESMS m / e: 553.0 (M + H) ⁺
[1373] Example 136
[1374] N- (3- {l- [3- (3,4-dichlorophenoxy) -3- (4-fluorophenyl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide : N- Procedure A using (3- {l- [3- (4-fluorophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 3,4-dichlorophenol And prepared by Scheme AN: ESMS m / e: 542.7 (M + H) ⁺
[1375] Example 137
[1376] N- [3- (l- {3- (4-fluorophenyl) -3- [4- (trifluoromethyl) phenoxy] propyl} -4-piperidinyl) phenyl] -2-methylpropanamide N- (3- {1- [3- (4-fluorophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4- (trifluoromethyl) Prepared by Procedure A and Scheme AN using phenol: ESMS m / e: 543.1 (M + H) ⁺
[1377] Example 138
[1378] N- (3- {1- [3- (3-bromophenoxy) -3- (4-fluorophenyl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide : N- ( Procedure A and Schemes Using 3- {1- [3- (4-fluorophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 3-bromophenol Manufactured by AN: ESMS m / e: 552.7 (M + H) ⁺
[1379] Example 139
[1380] N- (3- {l- [3- (4-fluorophenoxy) -3- (4-fluorophenyl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide : N- ( Procedure A and Schemes Using 3- {1- [3- (4-fluorophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4-fluorophenol Manufactured by AN: ESMS m / e: 493.2 (M + H) ⁺
[1381] Example 140
[1382] N- (3- {1- [3- (3-fluorophenoxy) -3- (4-fluorophenyl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide : N- ( Procedure A and Schemes Using 3- {1- [3- (4-fluorophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 3-fluorophenol Manufactured by AN: ESMS m / e: 492.9 (M + H) ⁺
[1383] Example 141
[1384] N- (3- {l- [3- (2,6-dichlorophenoxy) -3- (4-fluorophenyl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide : N- Procedure A using (3- {1- [3- (4-fluorophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 2,6-dichlorophenol And prepared by Scheme AN: ESMS m / e: 543.0 (M + H) ⁺
[1385] Example 142
[1386] N- (3- {1- [3- (2,5-difluorophenoxy) -3- (4-fluorophenyl) propyl] -4-piperidinyl) phenyl) -2-methylpropanamide : N- (3- {1- [3- (4-fluorophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 2,5-difluorophenol Prepared by Procedure A and Scheme AN using: ESMS m / e: 511.5 (M + H) ⁺
[1387] Example 143
[1388] N- (3- {l- [3- (3-chlorophenoxy) -3- (4-fluorophenyl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide : N- (3 -{1- [3- (4-fluorophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 3-chlorophenol in Procedure A and Scheme AN Manufactured by: ESMS m / e: 509.1 (M + H) ⁺
[1389] Example 144
[1390] N- (3- {l- [3- (4-bromophenyl) -3- (3-methylphenoxy) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide : N- (3 -{1- [3- (4-bromophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 3-methylphenol in Procedure A and Scheme AN Manufactured by: ESMS m / e: 549.1 (M + H) ⁺
[1391] Example 145
[1392] N- (3- {l- [3-([l, 1'-biphenyl] -4-yloxy) -3- (4-bromophenyl) propyl] -4-piperidinyl} phenyl) -2 -Methylpropanamide : N- (3- {1- [3- (4-bromophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4-phenylphenol Prepared by Procedure A and Scheme AN using ESMS m / e: 611.2 (M + H) ⁺
[1393] Example 146
[1394] N- (3- {l- [3- (2,4-difluorophenoxy) -3- (4-fluorophenyl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide : N- (3- {1- [3- (4-fluorophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 2,4-difluorophenol Prepared by Procedure A and Scheme AN using: ESMS m / e: 511.1 (M + H) ⁺
[1395] Example 147
[1396] N- (3- {1- [3- (4-bromophenyl) -3- (3-methoxyphenoxy) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide : N- ( Procedure A and Schemes Using 3- {1- [3- (4-bromophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 3-methoxyphenol Manufactured by AN: ESMS m / e: 564.6 (M + H) ⁺
[1397] Example 148
[1398] Methyl 4- (1- (4-bromophenyl) -3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} propoxy) benzoate: N- (3- {1 In Procedure A and Scheme AN using-[3- (4-bromophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and methyl 4-hydroxybenzoate Manufactured by: ESMS m / e: 593.0 (M + H) ⁺
[1399] Example 149
[1400] N- (3- {1- [3- (4-bromophenyl) -3- (4-phenoxyphenoxy) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide : N- ( Procedure A and Schemes Using 3- {1- [3- (4-bromophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4-phenoxyphenol Manufactured by AN: ESMS m / e: 626.6 (M + H) ⁺
[1401] Example 150
[1402] N- (3- {l- [3- (4-bromophenyl) -3- (2-chloro-4-methylphenoxy) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide : N- (3- {1- [3- (4-bromophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 2-chloro-4-methylphenol Prepared by Procedure A and Scheme AN using: ESMS m / e: 583.0 (M + H) ⁺
[1403] Example 151
[1404] N- (3- {l- [3- (4-bromophenyl) -3-phenoxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide : N- (3- {1- [ Prepared by Procedure A and Scheme AN using 3- (4-bromophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and phenol: ESMS m / e : 535.0 (M + H) ⁺
[1405] Example 152
[1406] N- [3- (l- {3- (4-bromophenyl) -3- [4- (trifluoromethyl) phenoxy] propyl} -4-piperidinyl) phenyl] -2-methylpropanamide N- (3- {1- [3- (4-bromophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4- (trifluoromethyl) Prepared by Procedure A and Scheme AN using phenol: ESMS m / e: 603.1 (M + H) ⁺
[1407] Example 153
[1408] N- (3- {l- [3- (2-acetylphenoxy) -3- (4-bromophenyl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide : N- (3 -{1- [3- (4-bromophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 2-acetylphenol in Procedure A and Scheme AN Manufactured by: ESMS m / e: 576.6 (M + H) ⁺
[1409] Example 154
[1410] N- (3- {l- [3- (3-acetylphenoxy) -3- (4-bromophenyl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide : N- (3 In Procedure A and Scheme AN using-{1- [3- (4-bromophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 3-acetylphenol Manufactured by: ESMS m / e: 576.9 (M + H) ⁺
[1411] Example 155
[1412] N- (3- {l- [3- (3-acetylphenoxy) -3- (2,3-dihydro-lH-inden-5-yl) propyl] -4-piperidinyl} phenyl) -2 -Methylpropanamide: N- (3- {l- [3- (2,3-dihydro-lH-inden-5-yl) -3-hydroxypropyl] piperidinyl} phenyl) -2-methylpropane Prepared by Procedure A and Scheme AN using amide and 3-acetylphenol: ESMS m / e: 539.2 (M + H) ⁺
[1413] Example 156
[1414] N- (3- {l- [3- (2,3-dihydro-1H-inden-5-yl) -3-phenoxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide : N- (3- {1- [3- (2,3-dihydro-1H-inden-5-yl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and Prepared by Procedure A and Scheme AN using phenol: ESMS m / e: 497.2 (M + H) ⁺
[1415] Example 157
[1416] N- (3- {l- [3- (2-acetylphenoxy) -3- (2,3-dihydro-1H-inden-5-yl) propyl] -4-piperidinyl} phenyl) -2 -Methylpropanamide: N- (3- {1- [3- (2,3-dihydro-lH-inden-5-yl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2 Prepared by Procedure A and Scheme AN using methylpropanamide 2-acetylphenol: ESMS m / e: 539.1 (M + H) ⁺
[1417] Example 158
[1418] N- (3- {l- [3- (4-bromophenoxy) -3- (4-bromophenyl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide: N- ( Procedure A and Schemes Using 3- {1- [3- (4-bromophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4-bromophenol Manufactured by AN: ESMS m / e: 612.7 (M + H) ⁺
[1419] Example 159
[1420] N- (3- {l- [3- (4-bromophenyl) -3- (4-chlorophenoxy) propyl] -4-piperidinyl] phenyl) -2-methylpropanamide: N- (3 -{1- [3- (4-bromophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4-chlorophenol in Procedure A and Scheme AN Manufactured by: ESMS m / e: 568.7 (M + H) ⁺
[1421] Example 160
[1422] N- (3- {l- [3- (4-bromophenyl) -3- (4-fluorophenoxy) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide: N- { Procedure A and Schemes Using 3- {1- [3- (4-bromophenyl) -3-hydroxypropyl] -4-piperidinyl) phenyl) -2-methylpropanamide and 4-fluorophenol Manufactured by AN: ESMS m / e: 552.8 (M + H) ⁺
[1423] Example 161
[1424] N- (3- {l- [3- (2,3-dihydro-1H-inden-5-yl) -3- (4-methoxyphenoxy) propyl] -4-piperidinyl} phenyl)- 2-methylpropanamide: N- (3 {1- [3- (2,3-dihydro-lH-inden-5-yl) hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropane Prepared by Procedure A and Scheme AN using amide and 4-methoxyphenol: ESMS m / e: 527.3 (M + H) ⁺
[1425] Example 162
[1426] N- (3- {l- [3- (2,3-dihydro-1H-inden-5-yl) -3- (4-fluorophenoxy) propyl] -4-piperidinyl} phenyl)- 2-methylpropanamide: N- (3- {1- [3- (2,3-dihydro-lH-inden-5-yl) hydroxypropyl] -4-piperidinyl} phenyl) -2-methyl Prepared by Procedure A and Scheme AN using propanamide and 4-fluorophenol: ESMS m / e: 515.2 (M + H) ⁺
[1427] Example 163
[1428] N- (3- {l- [3- (213-dihydro-1H-inden-5-yl) hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide
[1429] Using N- (3- {1- [3- (2,3-dihydro-lH-inden-5-yl) -3-oxopropyl] -4-piperidinyl} phenyl) -2-methylpropanamide Prepared by Procedure L and Scheme AN by : ESMS m / e: 421.2 (M + H) ⁺
[1430] Example 164
[1431] N- [3- (1- {3- (2,3-dihydro-1H-inden-5-yl) -3- [4- (trifluoromethyl) phenoxy] propyl} -4-piperidinyl ) Phenyl] -2-methylpropanamide: N- (3- {l- [3- (2,3-dihydro-lH-inden-5-yl) hydroxypropyl] -4-piperidinyl} phenyl) Prepared by Procedure A and Scheme AN using 2-methylpropanamide and 4-trifluoromethylphenol: ESMS m / e: 565.0 (M + H) ⁺
[1432] Example 165
[1433] N- (3- {l- [3- (4-bromophenoxy) -3- (2,3-dihydro-1H-inden-5-yl) propyl] -4-piperidinyl} phenyl)- 2-methylpropanamide: N- (3- {l- [3- (2,3-dihydro-lH-inden-5-yl) -3-hydroxypropyl] -4-piperidinyl} phenyl)- Prepared by Procedure A and Scheme AN using 2-methylpropanamide and 4-bromophenol: ESMS m / e: 577.4 (M + H) ⁺
[1434] Example 166
[1435] N- (3- {l- [3- (3-acetylphenoxy) -3- (4-chlorophenyl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide: N- (3- Prepared by Procedure A and Scheme AN using {1- [3- (4-chlorophenyl) -3-hydroxypropyl] -4-piperidinyl) phenyl) -2-methylpropanamide and 3-acetylphenol SMS: m / e: 533.1 (M + H) ⁺
[1436] Example 167
[1437] N- (3- {1- [3- (4-methoxyphenoxy) -3- (4-methoxyphenyl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide: N- ( Procedure A and Schemes Using 3- {l- [3-hydroxy-3- (4-methoxyphenyl) propyl} -4-piperidinyl} phenyl) -2-methylpropanamide and 4-methoxyphenol Manufactured by AN: ESMS m / e: 517.4 (M + H) ⁺
[1438] Example 168
[1439] N- (3- {l- [3- (4-chlorophenoxy) -3- (2,3-dihydro-1H-inden-5-yl) propyl] -4-piperidinyl} phenyl) -2 -Methylpropanamide: N- (3- {1- [3- (2,3-dihydro-1H-inden-5-yl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2 Prepared by Procedure A and Scheme AN using methylpropanamide and 4-chlorophenol: ESMS m / e: 531.1 (M + H) ⁺
[1440] Example 169
[1441] N- (3- {l- [3- (2-acetylphenoxy) -3- (4-chlorophenyl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide: N- (3- Prepared by Procedure A and Scheme AN using {1- [3- (4-chlorophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 2-acetylphenol ESMS m / e: 533.4 (M + H) ⁺
[1442] Example 170
[1443] N- (3- {l- [3- (4-bromophenyl) -3- (4-methoxyphenoxy) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide: N- ( Procedure A and Schemes Using 3- {1- [3- (4-bromophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4-methoxyphenol Manufactured by AN: ESMS M / e: 565.0 (M + H) ⁺
[1444] Example 171
[1445] N- (3- {l- [3- (4-bromophenoxy) -3- (4-chlorophenyl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide: N- (3 Procedure A and Scheme AN using-(1- [3- (4-chlorophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4-bromophenol Manufactured by: ESMS m / e: 568.8 (M + H) ⁺
[1446] Example 172
[1447] N- (3- {l- [3- (4-chlorophenoxy) -3- (4-chlorophenyl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide: N- (3- Prepared by Procedure A and Scheme AN using {1- [3- (4-chlorophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4-chlorophenol ESMS m / e: 525.0 (M + H) ⁺
[1448] Example 173
[1449] N- (3- {l- [3- (4-methoxyphenyl) -3-phenoxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: N- (3- {l- [ Prepared by Procedure A and Scheme AN using 3-hydroxy-3- (4-methoxyphenyl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide and phenol: ESMS m / e : 487.4 (M + H) ⁺
[1450] Example 174
[1451] N- (3- {l- [3- (4-fluorophenyl) -3-phenoxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: N- (3- {1- [ Prepared by Procedure A and Scheme AN using 3- (4-fluorophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and phenol: ESMS m / e : 475.6 (M + H) ⁺
[1452] Example 175
[1453] N- (3- {1- [3- (2-acetylphenoxy) -3- (4-fluorophenyl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide: N- (3 Procedure A and Scheme AN using {1- (3- (4-fluorophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 2-acetylphenol Manufactured by: ESMS m / e: 517.1 (M + H) ⁺
[1454] Example 176
[1455] N- (3- {l- [3- (3-acetylphenoxy) -3- (4-fluorophenyl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide:Procedure A using N- (3- {1- [3- (4-fluorophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 3-acetylphenol And prepared by Scheme AN: ESMS m / e: 516.9 (M + H)⁺
[1456] Example 177
[1457] N- (3- {l- [3- (4-fluorophenyl) -3- (4-methoxyphenoxy) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide: N- ( Procedure A and Schemes Using 3- {1- [3- (4-fluorophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4-methoxyphenol Manufactured by AN: ESMS m / e: 505.2 (M + H) ⁺
[1458] Example 178
[1459] N- (3- {l- [3- (4-chlorophenoxy) -3- (4-methoxyphenyl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide:Procedure A and Scheme AN using N- (3- {1- [3-hydroxy (4-methoxyphenyl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4-chlorophenol on Manufactured by:ESMS m / e: 521.5 (M + H)⁺
[1460] Example 179
[1461] N- (3- {l- [3- (3-acetylphenoxy) -3- (4-methoxyphenyl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide: N- (3 -{1- [3-hydroxy-3- (4-methoxyphenyl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 3-acetylphenol in Procedure A and Scheme AN Manufactured by : ESMS m / e: 529.0 (M + H) ⁺
[1462] Example 180
[1463] N- (3- {l- [3- (4-chlorophenyl) -3-phenoxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: N- (3- {1- [3 Prepared by Procedure A and Scheme AN using-(4-chlorophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and phenol: ESMS m / e: 490.9 (M + H) ⁺
[1464] Example 181
[1465] N- (3- {l- [3- (4-bromophenoxy) -3- (4-methoxyphenyl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide: N- ( By Procedure A and Scheme AN using 3- {1- [3-hydroxy (4-methoxyphenyl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4-bromophenol Prepared: ESMS m / e: 564.9 (M + H) ⁺
[1466] Example 182
[1467] N- [3- (l- {3- (4-methoxyphenyl) -3- [4- (trifluoromethyl) phenoxy] propyl} -4-piperidinyl} phenyl] -2-methylpropanamide : the N- methylphenol (3- {1- [3-hydroxy-3- (4-methoxyphenyl) propyl] -4-piperidinyl} phenyl) -2-methyl-propanamide, and 4-trifluoromethyl Prepared by Procedure A and Scheme AN using: ESMS m / e: 555.1 (M + H) ⁺
[1468] Example 183
[1469] N- (3- {l- [3- (4-chlorophenyl) -3- (4-fluorophenoxy) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide: N- (3 -{1- [3- (4-chlorophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4-fluorophenol in Procedure A and Scheme AN Manufactured by: ESMS m / e: 509.1 (M + H) ⁺
[1470] Example 184
[1471] N- (3- {l- [3- (4-fluorophenoxy) -3- (4-methoxyphenyl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide: N- ( Procedure A and Schemes Using 3- {1- [3-hydroxy-3- (4-methoxyphenyl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4-fluorophenol Manufactured by AN: ESMS m / e: 505.5 (M + H) ⁺
[1472] Example 185
[1473] N- (3- {l- [3- (2-acetylphenoxy) -3- (4-methoxyphenyl) propyl] -4-piperidinyl} phenyl ) -2-methylpropanamide: N- ( Procedure A and Scheme AN using 3- {1- [3-hydroxy-3- (4-methoxyphenyl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 2-acetylphenol Manufactured by: ESMS m / e: 529.2 (M + H) ⁺
[1474] Example 186
[1475] N- [3- {l- {3- (4-chlorophenyl) -3- [4- (trifluoromethyl) -3-phenoxy] propyl) piperidinyl} phenyl] 2-methylpropanamide: N -(3- {l- [3- (4-chlorophenyl) -3-hydroxypropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4-trifluoromethylphenol Prepared by A and Scheme AN: SMS m / e: 559.1 (M + H) ⁺
[1476] Example 187
[1477] N- (3- {l-[(3S) -3- (3-acetylphenoxy) -3-phenylpropyl] -4-piperidinyl] -4-methylphenyl) -2-methylpropanamide: 1- ( Using 3-{[(1S) -3-chloro-1-phenylpropyl] oxy} phenyl) ethanone and 2-methyl-N- [4-methyl-3- (4-piperidinyl} phenyl] propanamide Prepared by Procedure G and Scheme AI by: ESMS m / e: 513.0 (M + H) ⁺
[1478] 2- (isopentyloxy) -l - naphthaldehyde: 2-hydroxynaphthaldehyde (1.72 g, 10.0 mmol) and THF (50 ml) were combined in a flask. NaH (312 mg, 13 mmol) was added followed by 1-bromo methylbutane (1.20 mL, 10.0 mmol). The solution was stirred overnight at room temperature, the solvent was removed in vacuo and the residue was purified by chromatography (5-10% ethyl acetate / hexanes): ¹ HNMR (400 MHz, CDC1 ₃ ) δ 10.9 (s, 1H) , 9.28 (dd, 1H, J = 0.7 Hz, 8.6 Hz), 8.02 (d, 1H, J = 9.1 Hz), 7.75 (d, 1H, J = 8.1 Hz), 7.63-7.59 (m, 1H), 7.43 7.39 (m, 1H), 7.27 (d, 1H, J = 9.2 Hz), 4.25 (t, 2H, J = 6.5 Hz), 1.98-1.84 (m, 1H), 1.80-1.75 (m, 2H), 0.99 (d, 6H, J = 6.6 Hz); ESMS m / e: 242.8 (M + H) ⁺
[1479] Example 188
[1480] N- [3- (l-{[2- (isopentyloxy) -l-naphthyl] methyl} -4-piperidinyl} phenyl] 2-methylpropanamide: 2- (isopentyloxy) -1- Prepared by Procedure F and Scheme R using naphthaldehyde and 2-methyl-N- [3- (4-piperidinyl} phenyl] propanamide: ESMS m / e: 473.3 (M + H) ⁺
[1481] 2-propoxy-l - naphthaldehyde: Prepared according to the procedure for 2- (isopentyloxy) -1-naphthaldehyde using 2-hydroxy-l-naphthaldehyde and 1-bromopropane. .
[1482] Example 189
[1483] 2-methyl-N- (3- {1-[(2-propoxy-1-naphthyl) methyl] -4-piperidinyl} phenyl) propanamide: 2-propoxy- l-naphthaldehyde and 2 Prepared by Procedure F and Scheme R using -methyl-N- [3- (4-piperidinyl} phenyl] propanamide: ESMS m / e: 445.2 (M + H) ⁺
[1484] 4-{[(1-formyl-2-naphthyl) oxy] methyl} benzonitrile:
[1485] Prepared according to the procedure for 2- (isopentyloxy) -1-naphthaldehyde using 2-hydroxy-1-naphthaldehyde and 4- (bromomethyl) benzonitrile
[1486] Example 190
[1487] N- {3- [l-({2-[(4-cyanobenzyl) oxy] -1-naphthyl} methyl) -4-piperidinyl] phenyl} -2-methylpropanamide: 4-{[ Prepared by Procedure F and Scheme R using (1-formyl-2-naphthyl) oxy] methyl} benzonitrile and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide ESMS m / e: 518.2 (M + H) ⁺
[1488] [ (1-formyl-2-naphthyl) oxy] acetonitrile: for 2- (isopentyloxy) -1 -naphthaldehyde using 2-hydroxy- 1-naphthaldehyde and bromoacetonitrile Manufactured according to the procedure.
[1489] Example 191
[1490] N- [3- (l-{[2- (cyanomethoxy) -l-naphthyl] methyl} -4-piperidinyl} phenyl] -2-methylpropanamide: [(l-formyl-2- Prepared by Procedure F and Scheme R using naphthyl) oxy] acetonitrile and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 442.2 (M + H) ⁺
[1491] 2-[(3-chlorobenzyl) oxy] -1 -naphthaldehyde: 2- (isopentyloxy using 2-hydroxy-1-naphthaldehyde and 1- (bromomethyl) -3-chlorobenzene Prepared according to the procedure for) -l-naphthaldehyde.
[1492] Example 192
[1493] N- {3- [l-({2-[(3-chlorobenzyl) oxy] -1-naphthyl} methyl) -4-piperidinyl] phenyl} -2-methylpropanamide: 2-[(3 Prepared by Procedure F and Scheme R using -chlorobenzyl) oxy-1-naphthaldehyde and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 527.2 (M + H) ⁺
[1494] Example 193
[1495] N- (3- {l- [4- (4-chlorophenoxy) benzyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4- (4-chlorophenoxy) benzaldehyde and 2-methyl Prepared by Procedure F and Scheme R using -N- [3- (4-piperidinyl) phenyl] propanamide: ¹ HNMR (400 MHz, CDC1 ₃ ) δ 7.50 (s, 1H), 7.34-7.19 (m.7H), 6.98-6.87 (m, 5H), 3.50 (s, 2H), 2.98 (d, 2H, J = 11.8 Hz), 2.58-2.44 (m, 2H), 2.10-1.98 (m, 2H ), 1.83-1.76 (m, 4H), 1.24 (d, 6H, J = 6.8 Hz); ESMS m / e: 463.2 (M + H) ⁺
[1496] Example 194
[1497] N- (3- {1- [4- (3,4-difluorophenoxy) benzyl] -4-piperidinyl} phenyl) -2-methylpropanamide : 4- (3,4-difluoro Prepared by Procedure F and Scheme R using phenoxy) benzaldehyde and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 465.2 (M + H) ⁺
[1498] 4- (isopentyloxy) -l-naphthaldehyde: 2- (isopentyloxy) -1-naphthaldehyde using 4-hydroxy-l-naphthaldehyde and 1-bromo methylbutane.
[1499] Example 195
[1500] N- [3- (l-{[4- (isopentyloxy) -l-naphthyl] methyl} -4-piperidinyl} phenyl] -2-methylpropanamide: 4- (isopentyloxy) -1 Prepared by Procedure F and Scheme R using naphthaldehyde and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 473.3 (M + H) ⁺
[1501] Example 196
[1502] N- (3- {1- [4- (4-methoxyphenoxy) benzyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4- (4-methoxyphenoxy) benzaldehyde and 2 Prepared by Procedure F and Scheme R using -methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 459.2 (M + H) ⁺
[1503] 4-propoxy-1-naphthaldehyde: Prepared according to the procedure for 2- (isopentyloxy) -1-naphthaldehyde using 4-hydroxy-1-naphthaldehyde and 1-bromopropane. .
[1504] Example 197
[1505] 2-methyl-N- (3- {l-[(4-propoxy-1-naphthyl) methyl] -4-piperidinyl} phenyl) propanamide: 4-propoxy- l-naphthaldehyde and 2 Prepared by Procedure F and Scheme R using -methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 445.2 (M + H) ⁺
[1506] Example 198
[1507] N- (3- {l- [4- (3,4-dichlorophenoxy) benzyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4- (3,4-dichlorophenoxy) benzaldehyde And prepared by Procedure F and Scheme R using 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 497.1 (M + H) ⁺
[1508] Example 199
[1509] N- (3- {l- [4- (diphenylamino) benzyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4- (diphenylamino) benzaldehyde and 2-methyl-N- [ Prepared by Procedure F and Scheme R using 3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 504.2 (M + H) ⁺
[1510] Example 200
[1511] N- {3- [l-({2,5-dimethyl-1- [3- (trifluoromethyl) phenyl] -1H-pyrrole-3-yl} methyl) -4 - piperidinyl} phenyl)- 2-methylpropanamide: 2,5-dimethyl-l- [3- (trifluoromethyl) phenyl] -H-pyrrole-3-carbaldehyde and 2-methyl-N- [3- (4-piperidi Prepared by Procedure F and Scheme R using nil) phenyl] propanamide: ESMS m / e: 498.2 (M + H) ⁺
[1512] Example 201
[1513] 2-methyl-N- (3- {l- [l- (2-phenyl-1,3-thiazol-4-yl) ethyl] -4-piperidinyl} phenyl) propanamide: 1- (2- Prepared by Procedure F and Scheme R using phenyl-1,3-thiazol-4-yl) ethanone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 434.2 (M + H) ⁺
[1514] Example 202
[1515] N- (3- {1-[(5-chloro-3-methyl-1-phenyl-lH-pyrazol-4-yl) methyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 5 Procedure F and Scheme R using -chloro-3-methyl-l-phenyl-lH-pyrazole-4-carbaldehyde and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide Manufactured by: ESMS m / e: 451.2 (M + H) ⁺
[1516] Example 203
[1517] 2-Methyl-N- (3- {l-[(2-phenyl-1 H-imidazol-4-yl) methyl] -4-piperidinyl} phenyl) propanamide: 2-phenyl-lH-imidazole- Prepared by Procedure F and Scheme R using 4-carbaldehyde and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 403.2 (M + H) ⁺
[1518] Example 204
[1519] N- [3- (l-{[4-bromo-1- (4-chlorobenzyl) -lH-pyrazol-5-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide : 4-bromo-1- (4-chlorobenzyl) -lH- pyrazol-5-carbaldehyde and 2-methyl -N- [3- (4-piperidinyl) phenyl] propanamide the procedure using Prepared by F and Scheme R: ESMS m / e: 529.1 (M + H) ⁺
[1520] Example 205
[1521] 2-methyl-N- {3- [1- (3-phenoxybenzyl) -4-piperidinyl] phenyl} propanamide: 3-phenoxybenzaldehyde and 2-methyl-N- [3- (4-pipe Prepared by Procedure F and Scheme R using ridinyl) phenyl] propanamide: ESMS m / e: 429.2 (M + H) ⁺
[1522] Example 206
[1523] N- (3- {l- [3- (3,4-dichlorophenoxy) benzyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 3- (3,4-dichlorophenoxy) benzaldehyde And prepared by Procedure F and Scheme R using 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 497.15 (M + H) ⁺
[1524] Example 207
[1525] N- (3- {l- [3- (3,5-dichlorophenoxy) benzyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 3- (3,5-dichlorophenoxy) benzaldehyde And prepared by Procedure F and Scheme R using 2 -methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 497.2 (M + H) ⁺
[1526] Example 208
[1527] 2-methyl-N- (3- {l- [3- (4-methylphenoxy) benzyl] -4-piperidinyl} phenyl) propanamide: 3- (4-methylphenoxy) benzaldehyde and 2-methyl Prepared by Procedure F and Scheme R using -N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 443.2 (M + H) ⁺
[1528] Example 209
[1529] 2-methyl-N- [3- (1- {3- [3- (trifluoromethyl) phenoxy] benzyl} -4-piperidinyl) phenyl] propanamide: 3- [3- (trifluoro Prepared by Procedure F and Scheme R using methyl) phenoxy] benzaldehyde and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 497.2 (M + H ) ⁺
[1530] Example 210
[1531] N- (3- {l- [3- (4-chlorophenoxy) benzyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 3- (4-chlorophenoxy) benzaldehyde and 2-methyl Prepared by Procedure F and Scheme R using -N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 463.2 (M + H) ⁺
[1532] Example 211
[1533] N- (3- {l- [3- (dimethylamino) benzyl] -4-piperidinyl} phenyl) 2-methylpropanamide: 3- (dimethylamino) benzaldehyde and 2-methyl-N- [3- ( Prepared by Procedure F and Scheme R using 4-piperidinyl) phenyl] propanamide: ESMS m / e: 380.2 (M + H) ⁺
[1534] Example 212
[1535] N- (3- {l- [3- (4-methoxyphenoxy) benzyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 3- (4-methoxyphenoxy) benzaldehyde and 2 Prepared by Procedure F and Scheme R using -methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 459.2 (M + H) ⁺
[1536] Example 213
[1537] N- (3- {1- [3- (4-t-butylphenoxy) benzyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 3- (4-t-butylphenoxy) benzaldehyde And prepared by Procedure F and Scheme R using 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 485.3 (M + H) ⁺
[1538] Example 214
[1539] 2-methyl-N- (3- {l- [3-nitro (l-piperidinyl) benzyl] -4-piperidinyl} phenyl) propanamide: 3-nitro-4- (l-piperidinyl) Prepared by Procedure F and Scheme R using benzaldehyde and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 465.2 (M + H) ⁺
[1540] Example 215
[1541] N- (3- {1-[(3,4-dimethylthieno [2,3-B] thien-2-yl) methyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 3, Procedure F and Scheme R using 4-dimethylthieno [2,3-b] thiophene-2-carbaldehyde and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide Manufactured by: ESMS m / e: 427.1 (M + H) ⁺
[1542] Example 216
[1543] 2-methyl-N- {3- [l-({3- [4- (trifluoromethyl) phenyl] -1H-pyrazol-4-yl} methyl) -4-piperidinyl} phenyl) propanamide : 3- [4- (trifluoromethyl) phenyl] -lH- pyrazole-4-carbaldehyde and 2-methyl -N- [4- (4-piperidinyl) phenyl] propanamide the procedure using Prepared by F and Scheme R: ESMS m / e: 471.1 (M + H) ⁺
[1544] Example 217
[1545] 2-methyl-N- (3- {1- [4- (lH-1,2,4-triazol-1-yl) benzyl] -4-piperidinyl} phenyl) propanamide : 4- (1H- Prepared by Procedure F and Scheme R using 1,2,4-triazol-1-yl) benzaldehyde and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 404.1 (M + H) ⁺
[1546] Example 218
[1547] 2-methyl-N- (3- {l-[(5-methyl-1-phenyl-lH-pyrazol-4-yl) methyl] -4-piperidinyl} phenyl) propanamide: 5-methyl-1 Prepared by Procedure F and Scheme R using -phenyl-lH-pyrazole-4-carbaldehyde and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 417.1 (M + H) ⁺
[1548] Example 219
[1549] 2-methyl-N- (3- {l- [4- (4-morpholinyl) -3-nitrobenzyl] -4-piperidinyl} phenyl) propanamide: 4- (4-morpholinyl) nitro Prepared by Procedure F and Scheme R using benzaldehyde and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 467.1 (M + H) ⁺
[1550] Example 220
[1551] N- {3- [l-({5- [2-chloro-4- (trifluoromethyl) phenyl] -2-furyl} methyl) -4-piperidinyl] phenyl} -2-methylpropanamide: Procedure F and Schemes using 5- [2-chloro-4- (trifluoromethyl) phenyl] -2-furaldehyde and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide Manufactured by R: ESMS m / e: 505.0 (M + H) ⁺
[1552] Example 221
[1553] Ethyl 4-({4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} methyl) -2,5-dimethyl-1-phenyl-lH-pyrrole-3-carboxylate: ethyl 4 Procedure F using formyl-2,5-dimethyl-l-phenyl-lH-pyrrole-3-carboxylate and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide; and Prepared by Scheme R: ESMS m / e: 502.2 (M + H) ⁺
[1554] Example 222
[1555] Ethyl 5- (4-chlorophenyl) -2-({4- [3 (isobutyrylamino) phenyl] -1-piperidinyl} methyl) -3-furoate: ethyl 5- (4-chlorophenyl) Prepared by Procedure F and Scheme R using 2-formyl-3-furoate and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 509.0 (M + H) ⁺
[1556] Example 223
[1557] N- {3- [l- (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide: 2,3-di Prepared by Procedure F and Scheme R using hydro-1,4-benzodioxin-6-carbaldehyde and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 395.1 (M + H) ⁺
[1558] Example 224
[1559] 2-methyl-N- (3- {l-[(6-phenoxy-3-pyridinyl) methyl] -4-piperidinyl} phenyl) propanamide: 6-phenoxynicotinaldehyde and 2-methyl-N Prepared by Procedure F and Scheme R using [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 430.1 (M + H) ⁺
[1560] Example 225
[1561] 2-methyl-N- [3- (l-{[5- (2-pyridinyl) -2-thienyl] methyl} -4-piperidinyl) phenyl] propanamide: 5- (2-pyridinyl) Prepared by Procedure F and Scheme R using 2-thiophencarbaldehyde and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 420.1 (M + H) ⁺
[1562] Example 226
[1563] 2-methyl-N- {3- [l-({5- [1--methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl] -2-thienyl} methyl) -4 -Piperidinyl} phenyl] propanamide: 5- [l-methyl-3- (trifluoromethyl) -lH-pyrazol-5-yl] -2-thiophencarbaldehyde and 2-methyl-N- Prepared by Procedure F and Scheme R using [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 491.0 (M + H) ⁺
[1564] Example 227
[1565] 2-methyl-N- [3- (l-{[l- (phenylsulfonyl) -1H-indol-3-yl] methyl] -4-piperidinyl) phenyl] propanamide: 1- (phenylsulfonyl Prepared by Procedure F and Scheme R using) -lH-indole-3-carbaldehyde and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 516.1 (M + H) ⁺
[1566] Example 228
[1567] N- (3- {1-[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) methyl] -4-piperidinyl} phenyl ) -2-methylpropanamide: 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carbaldehyde and 2-methyl-N- [3- ( Prepared by Procedure F and Scheme R using 4-piperidinyl) phenyl] propanamide: ESMS m / e: 447.2 (M + H) ⁺
[1568] Example 229
[1569] N- (3- {1- [4- (4-t-butyl-l, 3-thiazol-2-yl) benzyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4- ( Prepared by Procedure F and Scheme R using 4-t-butyl-1,3-thiazol-2-yl) benzaldehyde and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide being.
[1570] Example 230
[1571] N- {3- {1- (2,3-dihydro-1-benzofuran-5-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide: 2,3-dihydro-1 Prepared by Procedure F and Scheme R using -benzofuran-5-carbaldehyde and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 379.1 ( M + H) ⁺
[1572] Example 231
[1573] 2-methyl-N- (3- {1-[(4-methyl-2-phenyl-5-pyrimidinyl) methyl] -4-piperidinyl} phenyl) propanamide: 4-methyl-2-phenyl- Prepared by Procedure F and Scheme R using 5-pyrimidinecarbaldehyde and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 429.2 (M + H) ⁺
[1574] Example 232
[1575] N- {3- [1- (2,1,3-benzothiadiazol-5-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide: 2,1,3-benzothiadia Prepared by Procedure F and Scheme R using sol-5-carbaldehyde and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 395.1 (M + H) ⁺
[1576] Example 233
[1577] 2-methyl-N- (3- {l-[(5-phenyl-2-thienyl) methyl] -4-piperidinyl} phenyl) propanamide: 5-phenyl-2-thiophencarbaldehyde and 2 Prepared by Procedure F and Scheme R using -methyl-N- [3- {4-piperidinyl) phenyl] propanamide: ESMS m / e: 419.1 (M + H) ⁺
[1578] Example 234
[1579] N- {3- [l- (3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide: 3,4 By Procedure F and Scheme R using dihydro-2H-1,5-benzodioxepin-7-carbaldehyde and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide Prepared: ESMS m / e: 409.2 (M + H) ⁺
[1580] Example 235
[1581] 2-methyl-N- [3- (l-{[3- (2-thienyl) -lH-pyrazol-4-yl] methyl} -4-piperidinyl) phenyl] propanamide: 3- (2 Prepared by Procedure F and Scheme R using Thienyl) -1H-pyrazole-4-carbaldehyde and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 409.1 (M + H) ⁺
[1582] Example 236
[1583] N- {3- [l-([1,1'-bithienyl] -4-ylmethyl) -4-piperidinyl] phenyl) -2-methylpropanamide: 2,2'-bithiophen-5 Prepared by Procedure F and Scheme R using carboxaldehyde and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 425.0 (M + H) ⁺
[1584] Example 237
[1585] N- (3- {l-[(2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl) methyl] -4-piperidinyl} phenyl) -2-methylpropanamide: Prepared by Procedure F and Scheme R using 2,2-dimethyl-6-chromancarbaldehyde and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 421.2 (M + H) ⁺
[1586] Example 238
[1587] 2-methyl-N- {3- [l-({5- [l-methyl-5- (trifluoromethyl) -1H-pyrazol-3-yl] -2-thienyl} methyl) -4- Piperidinyl] phenyl} propanamide: 5- [l-methyl-5- (trifluoromethyl) -lH-pyrazol-3-yl] -2-thiophencarbaldehyde and 2-methyl-N- [ Prepared by Procedure F and Scheme R using 3 (4-piperidinyl) phenyl] propanamide: ESMS m / e: 491.1 (M + H) ⁺
[1588] Example 239
[1589] 2-methyl-N- (3- {1-[(2-phenyl-1,3-thiazol-4-yl) methyl] -4-piperidinyl} phenyl) propanamide: 2-phenyl-1,3 Prepared by Procedure F and Scheme R using thiazole-4-carbaldehyde and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 420.0 ( M + H) ⁺
[1590] Example 240
[1591] 2-methyl-N- (3- {l-[(3-phenoxy-2-thienyl) methyl] -4-piperidinyl} phenyl) propanamide: 3-phenoxy-2-thiophencarbaldehyde And prepared by Procedure F and Scheme R using 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 435.0 (M + H) ⁺
[1592] Example 241
[1593] N- {3- [l-({2-[(4-chlorophenyl) sulfanyl] -3-thienyl} methyl) -4-piperidinyl] phenyl} -2-methylpropanamide: 2-[( Prepared by Procedure F and Scheme R using 4-chlorophenyl) sulfanyl] -3-thiophencarbaldehyde and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 485.0 (M + H) ⁺
[1594] Example 242
[1595] N- [3- (1-{[l- (4-chlorophenyl) -lH-pyrrol-2-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: 1- (4- Prepared by Procedure F and Scheme R using chlorophenyl) -1H-pyrrole-2-carbaldehyde and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 436.0 (M + H) ⁺
[1596] Example 243
[1597] 2-methyl-N- {3- [1-({5- [2- (trifluoromethoxy) phenyl] -2-furyl} methyl) -4-piperidinyl} phenyl) propanamide: 5- [2 Prepared by Procedure F and Scheme R using-(trifluoromethoxy) phenyl] -2-furaldehyde and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 487.1 (M + H) ⁺
[1598] Example 244
[1599] 2-methyl-N- (3- {1- [2- (4-morpholinyl) benzyl] -4-piperidinyl} phenyl) propanamide: 2- (4-morpholinyl) benzaldehyde and 2-methyl Prepared by Procedure F and Scheme R using -N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 422.2 (M + H) ⁺
[1600] Example 245
[1601] N- [3- (1-{[3- (4-methoxyphenyl) -1 H-pyrazol-4-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: 3- ( Prepared by Procedure F and Scheme R using 4-methoxyphenyl) -1H-pyrazole-4-carbaldehyde and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide ESMS m / e: 433.1 (M + H) ⁺
[1602] Example 246
[1603] 2-methyl-N- (3- {1- [4- (lH-pyrazol-1-yl) benzyl] -4-piperidinyl} phenyl) propanamide: 4- (1H-pyrazol-1-yl Prepared by Procedure F and Scheme R using benzaldehyde and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 402.8 (M + H) ⁺
[1604] Example 247
[1605] 2-methyl-N- {3- [1- (4-quinolinylmethyl) -4-piperidinyl} phenyl} propanamide: 4-quinolinecarbaldehyde and 2-methyl-N- [3- (4 Prepared by Procedure F and Scheme R using -piperidinyl) phenyl] propanamide: ESMS m / e: 388.1 (M + H) ⁺
[1606] Example 248
[1607] 2-methyl-N- (3- {l- [4- (4-morpholinyl) benzyl] -4-piperidinyl} phenyl) propanamide: 4- (4-morpholinyl) benzaldehyde and 2-methyl Prepared by Procedure F and Scheme R using -N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 422.5 (M + H) < + >
[1608] Example 249
[1609] 2-methyl-N- (3- {1- [4- (2-thienyl) benzyl] -4-piperidinyl) phenyl) propanamide: 4- (2-thienyl) benzaldehyde and 2-methyl-N Prepared by Procedure F and Scheme R using [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 419.1 (M + H) ⁺
[1610] Example 250
[1611] 2-methyl-N- (3- {l-[(2-methyl-5-phenyl-3-furyl) methyl] -4-piperidinyl} phenyl) propanamide: 2-methyl5-phenyl-3-fur Prepared by Procedure F and Scheme R using aldehyde and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 417.2 (M + H) ⁺
[1612] Example 251
[1613] N- (3- {l- [3- (cyclopentyloxy) -4-methoxybenzyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 3- (cyclopentyloxy) -4- meth Prepared by Procedure F and Scheme R using oxybenzaldehyde and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 451.1 (M + H) ⁺
[1614] Example 252
[1615] 2-methyl-N- {3- [l-({5- [4- (trifluoromethoxy) phenyl] -2-furyl} methyl) -4-piperidinyl] phenyl} propanamide: 5- [4 Prepared by Procedure F and Scheme R using-(trifluoromethoxy) phenyl] -2-furaldehyde and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 487.1 (M + H) ⁺
[1616] Example 253
[1617] N- {3- [l- (l-benzothien-2-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide: 1-benzothiophene-2-carbaldehyde and 2-methyl Prepared by Procedure F and Scheme R using -N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 393.2 (M + H) ⁺
[1618] Example 254
[1619] 2-methyl-N- {3- [l-({5- [3- (trifluoromethoxy) phenyl] -2-furyl} methyl) -4-piperidinyl] phenyl} propanamide: 5- [3 Prepared by Procedure F and Scheme R using-(trifluoromethoxy) phenyl] -2-furaldehyde and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 487.2 (M + H) ⁺
[1620] Example 255
[1621] 2-methyl-N- {3- [l- (2-quinolinylmethyl) -4-piperidinyl] phenyl} propanamide: 2-quinolinecarbaldehyde and 2-methyl-N- [3- (4 Prepared by Procedure F and Scheme R using -piperidinyl) phenyl] propanamide: ESMS m / e: 388.1 (M + H) ⁺
[1622] Example 256
[1623] N- (3- {l- [4- (lH-imidazol-1-yl) benzyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4- (lH-imidazol-1-yl Prepared by Procedure F and Scheme R using benzaldehyde and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 403.2 (M + H) ⁺
[1624] Example 257
[1625] N- {3- [l- (9H-fluoren-2-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide : 9H-fluorene-2-carbaldehyde and 2-methyl- Prepared by Procedure F and Scheme R using N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 425.1 (M + H) ⁺
[1626] Example 258
[1627] Methyl 3- [5-({4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} methyl) -2-furyl] -2-thiophenecarboxylate: methyl 3- (5- Prepared by Procedure F and Scheme R using formyl-2-furyl) -2-thiophenecarboxylate and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 467.1 (M + H) ⁺
[1628] Example 259
[1629] 2-methyl-N- {3- [l- (4-phenoxybenzyl) piperidinyl] phenyl} propanamide : 4-phenoxybenzaldehyde and 2-methyl-N- [3- (4-piperidinyl) Prepared by Procedure F and Scheme R using phenyl] propanamide: ESMS m / e: 429.2 (M + H) ⁺
[1630] Example 260
[1631] N- {3- [1-([1,1'-biphenyl] -4-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide: [1,1'-biphenyl]- Prepared by Procedure F and Scheme R using 4-carbaldehyde and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 413.2 (M + H) ⁺
[1632] Example 261
[1633] N- (3- {l- [4- (dibutylamino) benzyl] -4-piperidinyl) phenyl) -2-methylpropanamide: 4- (dibutylamino) benzaldehyde and 2-methyl-N- [ Prepared by Procedure F and Scheme R using 3 (4-piperidinyl) phenyl] propanamide: ESMS m / e: 464.6 (M + H) ⁺
[1634] Example 262
[1635] 2-methyl-N- [3- (l- {4-[(4-methylphenyl) sulfanyl] -3-nitrobenzyl] -4-piperidinyl) phenyl] propanamide: 4-[(4-methylphenyl) Prepared by Procedure F and Scheme R using sulfanyl] -3-nitrobenzaldehyde and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m /: e 504.2 (M + H) ⁺
[1636] Example 263
[1637] 2-methyl-N- (3- {l- [4- (1,2,3-thiadiazol-4-yl) benzyl] -4-piperidinyl} phenyl) propanamide: 4- (1,2 Prepared by Procedure F and Scheme R using, 3-thiadiazol-4-yl) benzaldehyde and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e : 421.1 (M + H) ⁺
[1638] 1- (3-{[(1S) -3-chloro-1-phenylpropynyl] oxy} phenyl) ethanone:
[1639] (lR) -3-chloro-l-phenyl-1-propanol (1.000 g, 5.86 mmol), 1- (3-hydroxyphenyl) ethanone (0.797 g, 5.86 mmol), triphenylphosphine (1.54 g, 5.86 mmol) and diethylazodicarboxylate (1.53 g, 8.79 mmol) were combined in a flask, which was immediately washed with argon. THF (20 mL) was added and the mixture was stirred under argon overnight. THF is removed in vacuo and the crude product is 50 mL of CH₂C1₂/ H₂0 (1: 1) and dissolved in organic layer, organic layer separated and MgSO₄ Dried over phase. After removal of solvent in vacuo, the residue was purified by flash chromatography using 10% ethyl acetate / hexanes to give the desired product (900 mg, 76.0%):^OneHNMR (400 MHz, CDC1₃δ 7.49-7.46 (m, 2H), 7.40-7.26 (m, 6H), 7.07-7.04 (m, 1H), 5.46-5.43 (dd, 1H, J = 4.4 Hz, 8.8 Hz), 3.84-3.78 ( m, 1H), 3.64-3.59 (m, 1H), 2.52 (s, 3H), 2.51-2.46 (m, 1H), 2.29-2.22 (m, 1H).
[1640] 4- (3,4-difluorophenoxy) benzaldehyde : 4-fluorobenzaldehyde (5.32 mL, 49.6 mmol), 3,4-difluorophenol (7.10 g, 54.6 mmol) and K ₂ CO ₃ (8.31 g, 60.1 mmol) were combined in a flask and this was immediately washed with argon. DMF (50.0 mL) was added and the mixture was heated to reflux for 6 h under argon. As soon as cooled to room temperature, EtOAc (100 mL) and H ₂ 0 (100 mL) were added; The ethyl acetate layer was separated and washed with H ₂ 0 (2 × 100 mL). The combined organic layers were washed with brine, dried over MgSO ₄ and the solvent removed in vacuo. The desired product was obtained (11.4 g, 98.0%): ¹ HNMR (400 MHz, CDC1 ₃ ) δ9.95 (s, 1H), 7.88 (dd, 2H J = 0.8 Hz, 8.8 Hz), 7.24-7.17 (m , 1H), 7.07 (d, 2H, J = 8.8 Hz), 6.97-6.92 (m, 1H), 6.86-6.82 (m, 1H); ESMS m / e: 235.0 (M + H) ⁺
[1641] t-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,6-dihydro-
[1642] 1 (2H) -pyridinecarboxylate : Bis (pinacolato) diboron (422 mg, 1.66 mmol), KOAc (444 mg, 4.53 mmol), PdCl ₂ dppf (37.0 mg, 3.00 mol%), dppf in flask (25.0 mg, 3.00 mol%) was added and the flask was washed with argon. T-butyl 4-{[(trifluoromethyl) sulfonyl] oxy} -1,2,3,6-tetrahydro-l-pyridinecarboxylate (500 mg) in 1,4-dioxane (10.0 ml) , 1.51 mmol) solution was added and the mixture was stirred at 80 ° C overnight. The mixture was filtered through celite and the filtrate was evaporated in vacuo. The resulting residue was dissolved in EtOAc and washed with H ₂ O and then brine. The organic layer was dried over MgSO _4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (10% EtOAC / hexane) to give t-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,6-dihydro-1 (2H) pyridinecarboxylate (355 mg, 76.0%) was obtained: ¹ HNMR (400 MHz, CDC1 ₃ ) δ6.44 (br s, 1H), 3.93 (br s , 2H), 3.42 (br s, 2H), 2.21 (br s, 2H), 1.45 (s, 9H), 1.25 (s, 12H); ESMS m / e: 310.4 (M + H) ⁺
[1643] N- (6-bromo-2-pyridinyl) -2-methylpropanamide : prepared by procedure Q1 using 2-methylpropaneoyl chloride and 6-bromo-2-pyridinamine: ESMS m / e : 242.8 (M + H) ⁺
[1644] t-butyl 4- [6- (isobutyrylamino) -2-pyridinyl] -3,6-dihydro-1 (2H) -pyridinecarboxylate: N- (6-bromo-2-pyridinyl ) -2-methylpropanamide and t-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,6-dihydro-1 (2H) -pyridinecarboxylate: ESMS m / e: 245.8 (M-100) ⁺
[1645] 2-methyl-N- [6- (4-piperidinyl) -2-pyridinyl] propanamide: t-butyl 4- [6- (isobutyrylamino) -2-pyridinyl] -3,6- Prepared by the procedure x and Y, schemes AG and AH, respectively, using dihydro-1 (2H) pyridinecarboxylate: ESMS m / e: 248.1 (M + H) ⁺
[1646] Example 264
[1647] M- (6- (l- [4- (3,4-dimethylphenyl) -4-oxobutyl] -4-piperidinyl} -2-pyridinyl) -2-methylpropanamide: 4-chloro-l Prepared by Procedure G and Scheme AI using-(3,4-dimethylphenyl) -1-butanone and 2-methyl-N- [6- (4-piperidinyl) -2-pyridinyl] propanamide ESMS m / e: 422.1 (M + H) ⁺
[1648] Example 265
[1649] N- (6- {l- [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl} -2-pyridinyl) -2-methylpropanamide: 1- [4-chloro- Procedure G and Scheme AI using 1- (4-fluorophenyl) butyl] -4-fluorobenzene and 2-methyl-N- [6 (4-piperidinyl) -2-pyridinyl] propanamide Manufactured by: ESMS m / e: 492.2 (M + H) ⁺
[1650] Example 266
[1651] N- (6- {l- [4- (3,4-difluorophenoxy) benzyl] -4-piperidinyl} -2-pyridinyl) -2-methylpropanamide: 4- (3,4 Prepared by Procedure AA and Scheme AJ using difluorophenoxy) benzaldehyde and 2-methyl-N- [6- (4-piperidinyl) -2-pyridinyl] propanamide: ESMS m / e : 466.0 (M + H) ⁺
[1652] N- (3-Bromo-4-methylphenyl) -2-methylpropanamide: Prepared by procedure Q1 using 2-methylpropanoyl chloride and 3-bromo-4-methylaniline: ESMS m / e: 255.9 (M + H) ⁺
[1653] t-butyl 4- [5- (isobutyrylamino) -2-methylphenyl] -3,6-dihydro-1 (2H) -pyridinecarboxylate: N- (3-bromo-4-methylphenyl)- 2-methylpropanamide and t-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,6-dihydro-1 (2H Prepared by Procedure W and Scheme AF using) -pyridinecarboxylate: ESMS m / e: 259.1 (M-1OO) ⁺
[1654] 2-methyl-N- [4-methyl-3- (4-piperidinyl) phenyl] propanamide: t-butyl 4- [5- (isobutyrylamino) -2-methylphenyl] -3,6-di Prepared by the procedure x and Y, schemes AG and AH, respectively, using hydro-1 (2H) -pyridinecarboxylate: ESMS m / e: 261.0 (M + H) ⁺
[1655] Example 267
[1656] N- (3- {1- [4- (3,4-difluorophenoxy) benzyl] -4-piperidinyl} -4-methylphenyl) -2-methylpropanamide: 4- (3,4- Prepared by Procedure AA and Scheme AJ using difluorophenoxy) benzaldehyde and 2-methyl-N- [4-methyl-3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 479.1 (M + H) ⁺
[1657] N- (5-Bromo-2-methylphenyl) -2-methylpropanamide: Prepared by procedure Q1 using 2-methylpropanoyl chloride and 5-bromo-2-methylaniline: ESMS m / e: 255.9 (M + H) ⁺
[1658] t-butyl 4- [3- (isobutyrylamino) -4-methylphenyl] -3,6-dihydro-1 (2H) -pyridinecarboxylate: N- (5-bromo-2-methylphenyl)- 2-methylpropanamide and t-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,6-dihydro-1 (2H Prepared by Procedure W and Scheme AF using) -pyridinecarboxylate: ESMS m / e: 259.1 (M-100) ⁺
[1659] 2-methyl-N- [2-methyl-5- (4-piperidinyl) phenyl] propanamide: t-butyl 4- [3- (isobutyrylamino) -4-methylphenyl] -3,6-di Prepared by the procedure x and Y, schemes AG and AH, respectively, using hydro-1 (2H) -pyridinecarboxylate: ESMS m / e: 261.0 (M + H) ⁺
[1660] Example 268
[1661] N- (5- {l-[(9-ethyl-9H-carbazol-3-yl) methyl] -4-piperidinyl} -2-methylphenyl) -2-methylpropanamide: 9-ethyl-9H- Prepared by Procedure AA and Scheme AJ using carbazole-3-carbaldehyde and 2-methyl-N- [2-methyl-5- (4-piperidinyl) phenyl] propanamide: ESMS m / e : 468.1 (M + H) ⁺
[1662] Example 269
[1663] N- (5- {l- [4- (3,4-difluorophenoxy) benzyl] -4-piperidinyl} -2-methylphenyl) -2-methylpropanamide: 4- (3,4- Prepared by Procedure AA and Scheme AJ using difluorophenoxy) benzaldehyde and 2-methyl-N- [2-methyl-5- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 479.2 (M + H) ⁺
[1664] Example 270
[1665] N- (3- {l-[(9-ethyl-9H-carbazol-3-yl) methyl] -4-piperidinyl} -4-methylphenyl) -2-methylpropanamide: 9-ethyl-9H- Prepared by Procedure AA and Scheme AJ using carbazole-3-carbaldehyde and 2-methyl-N- [4-methyl-3- (4-piperidinyl) phenyl] propanamide: ESMS m / e : 468.1 (M + H) ⁺
[1666] Example 271
[1667] 2-methyl-N- [2-methyl-5- (4-piperidinyl) phenyl] propanamide : 1- [4-chloro-1- (4-fluorophenyl) butyl] -4-fluorobenzene and Prepared by Procedure G and Scheme AI using 2-methyl-N- [2-methyl-5- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 505.1 (M + H) ⁺
[1668] Example 272
[1669] N- (3- {1-[(3S) -3- (3-acetylphenoxy) -3-phenylpropyl] -4-piperidinyl} -4-methylphenyl) -2-methylpropanamide: 1- ( 3-{[(1S) -3-chloro-1-phenylpropyl] oxy} phenyl) ethanone and 2-methyl-N- [4-methyl-3- (4-piperidinyl) phenyl] propanamide Prepared by Procedure G and Scheme AI by: ESMS m / e: 513.0 (M + H) ⁺
[1670] Example 273
[1671] N- (5- {1-[(3S) -3- (3-acetylphenoxy) -3-phenylpropyl] -4-piperidinyl} -2-methylphenyl) -2-methylpropanamide: 1- ( Using 3-{[(1S) -3-chloro-1-phenylpropyl] oxy} phenyl) ethanone and 2-methyl-N- [2-methyl-5- (4-piperidinyl) phenyl] propanamide Prepared by Procedure G and Scheme AI by: ESMS m / e: 512.9 (M + H) ⁺
[1672] N- (2-iodophenyl) -2-methylpropanamide: Prepared by Procedure Q1 using 2-methylpropaneoyl chloride and 2-iodoaniline. ESMS m / e: 289.9 (M + H) ⁺
[1673] t-butyl 4- [2- (isobutyrylamino) phenyl] -3,6-dihydro1 (2H) -pyridinecarboxylate: N- (2-iodophenyl) -2-methylpropanamide and tert -Butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,6-dihydro-1 (2H) -pyridinecarboxylate Prepared by Procedure W and Scheme AF using: ESMS m / e: 245.1 (M-100) ⁺
[1674] 2-methyl-N- [2- (4-piperidinyl) phenyl] propanamide:
[1675] tert-butyl 4- [2- (isobutyrylamino) phenyl] -3,6-dihydro-1 (2H) -pyridinecarboxylate using relative procedures X and Y, by Scheme AG and AH Prepared: ESMS m / e: 247.1 (M + H) ⁺
[1676] Example 274
[1677] N- (2- {1-[(9-ethyl-9H-carbazol-3-yl) methyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 9-ethyl-9H-carbazole- Prepared by procedure AA and Scheme AJ, using 3-carbaldehyde and 2-methyl-N- [2- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 454.1 (M + H ) ⁺
[1678] Example 275
[1679] N- (3- {1- [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl} -4-methylphenyl) -2-methylpropanamide: 1- [4-chloro-1 Procedure G and Scheme AI, using-(4-fluorophenyl) butyl] -4-fluorobenzene and 2-methyl-N- [4-methyl-3- (4-piperidinyl) phenyl] propanamide Manufactured by: ESMS m / e: 505.0 (M + H) ⁺
[1680] Example 276
[1681] N- (2- {1- [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1- [4-chloro-1- (4 Prepared by Procedure G and Scheme AI, using -fluorophenyl) butyl] -4-fluorobenzene and 2-methyl-N- [2- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 490.9 (M + H) ⁺
[1682] N- [2-bromo-4- (trifluoromethoxy) phenyl] -2-methylpropanamide: using 2-methylpropanoyl chloride and 2-bromo-4- (trifluoromethoxy) aniline, Prepared by procedure Q1: ESMS m / e: 325.9 (M + H) ⁺
[1683] TERT-Butyl 4- [2- (isobutyrylamino) -5- (trifluoromethoxy) phenyl] -3,6-dihydro-1 (2H) -pyridinecarboxylate: N- [2-bromo -4- (trifluoromethoxy) phenyl] -2-methylpropanamide and tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl Prepared by Procedure W and Scheme AF using) -3,6-dihydro-1 (2H) -pyridinecarboxylate: ESMS m / e: 329.0 (M-100) ⁺
[1684] 2-methyl-N- [2- (4-piperidinyl) -4- (trifluoromethoxy) phenyl] propanamide: tert-butyl 4- [2- (isobutyrylamino) -5- (trifluoro Prepared by Procedure x and Y, Schemes AG and AH, using methoxy) phenyl] -3,6-dihydro-1 (2H) -pyridinecarboxylate relative: ESMS m / e: 330.9 (M + H) ⁺
[1685] Example 277
[1686] N- [2- {1- [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl} -4- (trifluoromethoxy) phenyl] -2-methylpropanamide: 1- [4-Chloro-1- (4-fluorophenyl) butyl] -4-fluorobenzene and 2-methyl-N- [2- (4-piperidinyl) -4- (trifluoromethoxy) phenyl] Prepared by Procedure G and Scheme AI, using propanamide: ESMS m / e: 574.8 (M + H) ⁺
[1687] N- {3- [1- (4-hydroxybutyl) -4-piperidinyl] phenyl} -2-methylpropanamide: 4-chloro-1-butanol and 2-methyl-N- [3- ( Prepared by Procedure G and Scheme B1 using 4-piperidinyl) phenyl] propanamide: ESMS m / e: 319.3 (M + H) ⁺
[1688] N- {3- [1- (5-hydroxypentyl) -4-piperidinyl] phenyl} -2-methylpropanamide: 5-chloro-1-pentanol and 2-methyl-N- [3- ( Prepared by Procedure G and Scheme B1 using 4-piperidinyl) phenyl] propanamide: ESMS m / e: 333.3 (M + H) ⁺
[1689] N- {3- [1- (6-hydroxyhexyl) -4-piperidinyl] phenyl} -2-methylpropanamide: 6-chloro-1-hexanol and 2-methyl-N- [3- ( Prepared by Procedure G and Scheme B1 using 4-piperidinyl) phenyl] propanamide: ESMS m / e: 347.3 (M + H) ⁺
[1690] N- {3- [1- (3-hydroxypropyl) -4-piperidinyl] phenyl} -2-methylpropanamide: 3-chloro-1-propanol and 2-methyl-N- [3- (4 Prepared by Procedure G and Equation B1 using -piperidinyl) phenyl] propanamide: ESMS m / e: 305.3 (M + H) ⁺
[1691] N- (3- {1-[(2S) -2-hydroxy-2-phenylethyl] -4-piperidinyl} phenyl) -2-methylpropanamide: (1S) -2-chloro-1-phenyl Prepared by Procedure G and Scheme B1 using ethanol and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 367.2 (M + H) ⁺
[1692] N- (3- {1-[(2R) -2-hydroxy-2-phenylethyl] -4-piperidinyl} phenyl) -2-methylpropanamide: (1R) -2-chloro-1-phenyl Prepared by Procedure G and Scheme B1 using ethanol and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 367.2 (M + H) ⁺
[1693] N- (3- {1-[(2S) -3-hydroxy-2-methylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: (2R) -3-chloro-2-methyl Prepared by Procedure G and Scheme B1, using -1-propanol and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 319.2 (M + H) ⁺
[1694] N- (3- {1-[(2R) -3-hydroxy-2-methylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: (2S) -3-chloro-2-methyl Prepared by Procedure G and Scheme B1, using -1-propanol and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 319.2 (M + H) ⁺
[1695] Example 278
[1696] N- (3- {1-[(3R) -3-hydroxy-3-phenylpropyl] -4-piperidinyl} phenyl) cyclopropanecarboxamide: (1R) -3-chloro-1-phenyl- Prepared by Procedure G and Scheme B1, using 1-propanol and N- [3- (4-piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m / e: 379.2 (M + H) ⁺
[1697] Example 279
[1698] N- {3- [1- (4-hydroxy-4-phenylbutyl) -4-piperidinyl] phenyl} -2-methylpropanamide: prepared by Procedure L and Scheme AN, and step 1 is 2- Using methyl-N- {3- [1- (4-oxo-4-phenylbutyl) -4-piperidinyl] phenyl} propanamide: Anal. Calcd. For C25H34N202 + 0.08CHC1 ₃ : C, 74-5 ; H, 8.50; N, 6.93. Observation: C, 74-5; H, 8.63; N, 6.81; ESMS m / e: 395.2 (M + H) ⁺
[1699] Example 280
[1700] N- {3- [1- (5-hydroxy-5-phenylpentyl) -4-piperidinyl] phenyl} -2-methylpropanamide: prepared by Procedure L and Scheme AN, and step 1 is 2- Using methyl-N- {3- [1- (5-oxo-5-phenylpentyl) -4-piperidinyl] phenyl} propanamide: Anal. Calcd. For C26H36N202 + 0.25CHCl ₃ : C, 71-9 ; H, 8.33; N, 6.00. Observation: C, 71-3; H, 8.96; N, 6.86; ESMS m / e: 409.2 (M + H) ⁺
[1701] Example 281
[1702] N- {3- [1- (6-hydroxy-6-phenylhexyl) -4-piperidinyl] phenyl} -2-methylpropanamide: prepared by Procedure L and Scheme AN, and step 1 is 2- Using methyl-N- {3- [1- (6-oxo-6-phenylhexyl) -4-piperidinyl] phenyl} propanamide: Anal. Calcd. For C27H38N202 + 0.1CHC1 ₃ : C, 75.5; H, 8.93; N, 6.50. Observation: C, 75.3; H, 8.52; N, 6.00; ESMS m / e: 423.2 (M + H) ⁺
[1703] Example 282
[1704] N- {3- [1- (7-hydroxy-7-phenylheptyl) -4-piperidinyl] phenyl} -2-methylpropanamide: prepared by Procedure L and Scheme AN, and step 1 is 2- Using methyl-N- {3 [1- (7-oxo-7-phenylheptyl) -4-piperidinyl] phenyl} propanamide: Anal. Calcd. For C28H4ON202 + 0.1CHC1 ₃ : C, 75.8; H, 9. 10; N, 6.29. Observation: C, 75.1; H, 9.24; N, 6.51; ESMS m / e: 437.1 (M + H) ⁺
[1705] Example 283
[1706] N- (3- {1- [4- (4-fluorophenyl) -4-hydroxybutyl] -4-piperidinyl} phenyl) -2-methylpropanamide: prepared by Procedure L and Scheme AN , Step 1 uses N- (3- {1- [4- (4-fluorophenyl) -4-oxobutyl] -4-piperidinyl} phenyl) -2-methylpropanamide: ESMS m / e : 413.1 (M + H) ⁺
[1707] Example 284
[1708] 4- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} -1-phenylbutyl3- (2,6-dichlorophenyl) -5-methyl-4-isoxazolecarboxylate : N- {3- [1- (4- hydroxy-4-phenylbutyl) -4-piperidinyl] phenyl} -2-methyl-propanamide and 3- (2,6-dichlorophenyl) -5-methyl Prepared by procedure Q1 and scheme C2 (TEA), using 4-isoxazolcarbonyl chloride: ¹ HNMR (400 MHz, CDC1 ₃ ) δ7.56 (m, 1H), 7.47 (m, 2H), 7.44-7.39 (m, 3H), 7.25 (m, 2H), 7.09 (s, 1H), 7.03 (m, 2H), 6.95 (m, 1H), 6.83 (m, 1H), 5.75 (t, 1H, J = 7.1 Hz), 3.03 (t, 2H, J = 7.2 Hz), 2.93 (m, 2H), 2.78 (s, 3H), 2.48 (m, 3H), 2.25 (m, 2H), 1-48 ( m, 3H), 1-77 (m, 2H), 1-54 (m, 2H), 1-25 (d, 6H, J = 7.3 Hz); ESMS m / e: 647.7 (M + H) ⁺
[1709] Example 285
[1710] 4- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} -1-phenylbutyl (4-fluorophenyl) acetate: N- {3- [1- (4-hydroxy Prepared by Procedure Q1 and Scheme C2 (TEA), using -4-phenylbutyl) -4-piperidinyl] phenyl} -2-methylpropanamide and (4-fluorophenyl) acetyl chloride: ¹ HNMR (400 MHz, CDC1 ₃ ) δ 7.45 (s, 1H), 7.34-7.19 (m, 8H), 7.11 (m, 1H), 6.98 (m, 3H), 5.75 (t, 1H, J = 6.8 Hz) , 3.61 (s, 2H), 2.92 (d, 2H, J = 8.1 Hz), 2.48 (m, 2H), 2.31 (m, 2H), 1.99-1.84 (m, 4H), 1.84-1.67 (m, 5H ), 1.55-1.35 (m, 2H), 1.25 (d, 6H, J = 6.9 Hz); ESMS m / e: 531.1 (M + H) ⁺
[1711] Example 286
[1712] 3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} propyl (4-fluorophenyl) acetate: N- {3- [1- (3-hydroxypropyl) -4 Prepared by Procedure Q1 and Scheme C2 (TEA), using -piperidinyl] phenyl} -2-methylpropanamide and (4-fluorophenyl) acetyl chloride: ESMS m / e: 441.3 (M + H) ) ⁺
[1713] Example 287
[1714] 3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} propyl 3- (2-chloro-6-fluorophenyl) -5-methyl-4-isoxazolecarboxylate: N- {3- [1- (3-hydroxypropyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 3- (2-chloro-6-fluorophenyl) -5-methyl-4 Prepared by Procedure Q1 and Scheme C2 (TEA), using isoxazolecarbonyl chloride: ESMS m / e: 542.2 (M + H) ⁺
[1715] Example 288
[1716] 3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} propyl 3- (2,6-dichlorophenyl) -5-methyl-4-isoxazolecarboxylate: N- { 3- [1- (3-hydroxypropyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 3- (2,6-dichlorophenyl) -5-methyl-4-isoxazolecarbonyl chloride Using, prepared by procedure Q1 and scheme C2 (TEA): ESMS m / e: 558.2 (M + H) ⁺
[1717] Example 289
[1718] 3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} propyl 3- (2-chlorophenyl) -5-methyl-4-isoxazolecarboxylate: N- {3- [1- (3-hydroxypropyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 3- (2-chlorophenyl) -5-methyl-4-isoxazolcarbonyl chloride, Prepared by procedure Q1 and scheme C2 (TEA): ESMS m / e: 524.2 (M + H) ⁺
[1719] Example 290
[1720] (1S) -3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl] -1-phenylpropyl 3- (2,6-dichlorophenyl) -5-methyl-4-iso Solzolcarboxylates: N- (3- {1-[(3S) -3-hydroxy-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 3- (2,6 Prepared by Procedure Q1 and Scheme C2 (TEA) using -dichlorophenyl) -5-methyl-4-isoxazolcarbonyl chloride: ESMS m / e: 633.6 (M + H) ⁺
[1721] Example 291
[1722] 4- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} butyl 3- (2-chloro-6-fluorophenyl) -5-methyl-4-isoxazolecarboxylate: N- (3- [1- (4-hydroxybutyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 3- (2-chloro-6-fluorophenyl) -5-methyl-4 Prepared by Procedure Q1 and Scheme C2 (TEA), using isoxazolecarbonyl chloride: Anal. Calcd. For C3OH35ClFN304 + CH ₂ Cl ₂ : C, 63.3; H, 6.23; N, 7.33. , 63.0; H, 6.39; N, 7.03; ESMS m / e: 556.2 (M + H) ⁺
[1723] Example 292
[1724] 4- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} butyl 3- (2-chlorophenyl) -5-methyl-4-isoxazolecarboxylate: N- {3- [1- (4-hydroxybutyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 3- (2-chlorophenyl) -5-methyl-4-isoxazolcarbonyl chloride, Prepared by procedure Q1 and scheme C2 (TEA): ESMS m / e: 538.2 (M + H) ⁺
[1725] Example 293
[1726] 3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl) propyl 5-methyl-3-phenyl-4-isoxazolecarboxylate: N- {3- [1- (3 -Hydroxypropyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 5-methyl-3-phenyl-4-isoxazolcarbonyl chloride, by Procedure Q1 and Scheme C2 (TEA). Prepared: ESMS m / e: 490.3 (M + H) ⁺
[1727] Example 294
[1728] 4- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} butyl 3- (2,6-dichlorophenyl) -5-methyl-4-isoxazolecarboxylate: N- { 3- [1- (4-hydroxybutyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 3- (2,6-dichlorophenyl) -5-methyl-4-isoxazolecarbonyl chloride Using, prepared by procedure Q1 and scheme C2 (TEA): ESMS m / e: 572.2 (M + H) ⁺
[1729] Example 295
[1730] 4- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} -1-phenylbutyl 3- (2-chloro-6-fluorophenyl) -5-methyl-4-isoxazole Carboxylate: N- {3- [1- (4-hydroxy-4-phenylbutyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 3- (2-chloro-6-fluoro Prepared by Procedure Q1 and Scheme C2 (TEA), using phenyl) -5-methyl-4-isoxazolcarbonyl chloride: Anal. Calcd. For C36H39ClFN304 + 0.54CHC1 ₃ : C, 63.0; H, 5.72; N, 6.03. Observation: C, 63.0; H, 5.54; N, 6.05; ESMS m / e: 632.2 (M + H) ⁺
[1731] Example 296
[1732] 4- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} butyl 5-methyl-3-phenyl-4-isoxazolecarboxylate: N- {3- [1- (4 -Hydroxybutyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 5-methyl-3-phenyl-4-isoxazolcarbonyl chloride, by procedure Q1 and scheme C2 (TEA). Prepared: ESMS m / e: 504.3 (M + H) ⁺
[1733] Example 297
[1734] 6- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} hexyl 3- (2,6-dichlorophenyl) -5-methyl-4-isoxazolecarboxylate: N- { 3- [1- (6-hydroxyhexyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 3- (2,6-dichlorophenyl) -5-methyl-4-isoxazolecarbonyl chloride Using, prepared by procedure Q1 and scheme C2 (TEA): ESMS m / e: 600.0 (M + H) ⁺
[1735] Example 298
[1736] 6- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} hexyl 5-methyl-3-phenyl-4-isoxazolecarboxylate: N- {3- [1- (6 Prepared by Procedure Q1 and Scheme C2 (TEA), using hydroxyhexyl) -4-piperidinyl] phenyl} methylpropanamide and 5-methyl phenyl isoxazolcarbonyl chloride: ESMS m / e: 532.1 ( M + H) ⁺
[1737] Example 299
[1738] 4- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} butyl (4-fluorophenyl) acetate: N- {3- [1- (4-hydroxybutyl) -4 Prepared by Procedure Q1 and Scheme C2 (TEA), using -piperidinyl] phenyl} -2-methylpropanamide and (4-fluorophenyl) acetyl chloride: ESMS M / e: 455.3 (M + H) ) ⁺
[1739] Example 300
[1740] 4- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} -1-phenylbutyl 3- (2-chlorophenyl) -5-methyl-4-isoxazolecarboxylate: N -{3- [1- (4-hydroxy-4-phenylbutyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 3- (2-chlorophenyl) -5-methyl-4-iso Prepared by Procedure Q1 and Scheme C2 (TEA) using sazolcarbonyl chloride: ESMS m / e: 614.2 (M + H) ⁺
[1741] Example 301
[1742] 4- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} -1-phenylbutyl 5-methyl-3-phenyl-4-isoxazolecarboxylate: N- {3- [ Procedure Q1, using 1- (4-hydroxy-4-phenylbutyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 5-methyl-3-phenyl-4-isoxazolecarbonyl chloride And prepared by Scheme C2 (TEA): ESMS m / e: 580.0 (M + H) ⁺
[1743] Example 302
[1744] (1S) -3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} -1-phenylpropyl (4-fluorophenyl) acetate: N- (3- {1- [ Procedure Q1 and Scheme C2 (TEA) using (3S) -3-hydroxy-3-phenylpropyl] -4-piperidinyl} phenyl} -2-methylpropanamide and (4-fluorophenyl) acetyl chloride Prepared by: C32H37FN203 + 0.07CHC1 ₃ Anal. Calcd. For C, 73.4; H, 7.12; N, 5.35. Observations: C, 73.4; H, 6.96; N, 5.14; ESMS m / e: 517.1 ( M + H) ⁺
[1745] Example 303
[1746] N-((IS) -3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} -1-phenylpropyl) benzamide: N- (3- {1-[(3S ) -3-amino-3-phenylpropyl] -4-piperidinyl) phenyl] -2-methylpropanamide and benzoyl chloride, prepared by Procedure Q1 and Scheme AC: in C31H37N302 + 0.SSCHC1 ₃ Analyzed calcd for: C, 69.0; H, 6.89; N, 7.65. Observation: C, 69.7; H, 6.73; N, 6.03; ESMS m / e: 484.4 (M + H) ⁺
[1747] Example 304
[1748] N- [3- (1-{(3S) -3-[(diphenylacetyl) amino] -3-phenylpropyl} -4-piperidinyl) phenyl] -2-methylpropanamide: N- (3- Prepared by Procedure Q1 and Scheme AC, using {1-[(3S) -3-amino-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and diphenylacetyl chloride ESMS m / e: 574.3 (M + H) ⁺
[1749] Example 305
[1750] 3-chloro-N-((1S) -3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} -1-phenylpropyl) benzamide: N- (3- {1 Prepared by Procedure Q1 and Scheme AC, using-[(3S) -3-amino-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 3-chlorobenzoyl chloride: ESMS m / e: 518.3 (M + H) ⁺
[1751] Example 306
[1752] 3,5-dichloro-N-((1S) -3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} -1-phenylpropyl) benzamide: N- (3- Procedure Q1 and Scheme AC using {1-[(3S) -3-amino-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 3,5-dichlorobenzoyl chloride Manufactured by: ESMS m / e: 552.3 (M + H) ⁺
[1753] Example 307
[1754] 2- (ethylsulfanyl) -N-((1S) -3- {4- [3- (isobutyrylamino) phenyl] -1 - piperidinyl} -1 -phenylpropyl) nicotinamide: N- ( 3- {1-[(3S) -3-amino-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 2- (ethylsulfanyl) nicotinoyl chloride, Prepared by procedure Q1 and scheme AC: ESMS m / e: 545.3 (M + H) ⁺
[1755] Example 308
[1756] N-((1S) -3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} -1-phenylpropyl) [1,1'-biphenyl] -4-carbox Amides: N- (3- {1-[(3S) -3-amino-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and [1,1'-biphenyl]- Prepared by procedure Q1 and scheme AC using 4-carbonyl chloride: ESMS m / e: 560.3 (M + H) ⁺
[1757] Example 309
[1758] N-((1S) -3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} -1-phenylpropyl) -2-pyridinecarboxamide: N- (3- { Prepared by Procedure Q1 and Scheme AC, using 1-[(3S) -3-amino-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 2-pyridinecarbonyl chloride ESMS m / e: 484.6 (M + H) ⁺
[1759] Example 310
[1760] N-((1S) -3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} -1-phenylpropyl) -2-methoxybenzamide: N- (3- { Prepared by Procedure Q1 and Scheme AC, using 1-[(3S) -3-amino-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 2-methoxybenzoyl chloride ESMS M / e: 514.1 (M + H) ⁺
[1761] Example 311
[1762] N-((1S) -3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl) -1-phenylpropyl) -1-naphtamide: N- (3- {1- Prepared by Procedure Q1 and Scheme AC, using [(3S) -3-amino-3-phenylpropyl] -4-piperidinyl} phenyl) -2methylpropanamide and 1-naphthoyl chloride: ESMS m / e: 533.7 (M + H) ⁺
[1763] Example 312
[1764] 2,4-difluoro-N-((1S) -3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} -1-phenylpropyl) benzamide: N- ( Procedure Q1, using 3- {1-[(3S) -3-amino-3-phenylpropyl] -4-piperidinyl} phenyl} -2-methylpropanamide and 2,4-difluorobenzoyl chloride And prepared by scheme AC: ESMS m / e: 520.2 (M + H) ⁺
[1765] Example 313
[1766] 3- (2-chloro-6-fluorophenyl) -N-((1S) -3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} -1-phenylpropyl) -5-Methyl-4-isoxazolecarboxamide: N- (3- (1-[(3S) -3-amino-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide And prepared by Procedure Q1 and Scheme AC, using 3- (2-chloro-6-fluorophenyl) -5-methyl-4-isoxazolcarbonyl chloride: ESMS m / e: 617.2 (M + H) ) ⁺
[1767] Example 314
[1768] 3-chloro-N-((1S) -3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} -1-phenylpropyl) -2-thiophenecarboxamide: N -(3- {1-[(3S) -3-amino-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 3-chloro-2-thiophencarbonyl chloride Prepared by procedure Q1 and scheme AC by: ESMS m / e: 524.2 (M + H) ⁺
[1769] Example 315
[1770] N-((1S) -3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} -1-phenylpropyl) -2-phenoxynicotinamide: N- (3- { Procedure Q1 and Scheme AC, using 1-[(3S) -3-amino-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 2-phenoxynicotinoyl chloride Manufactured by: ESMS m / e: 577.3 (M + H) ⁺
[1771] Example 316
[1772] 1- (4-chlorophenyl) -N-((1S) -3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} -1-phenylpropyl) -3-propyl- 1H-pyrazole-4-carboxamide: N- (3- {1-[(3S) -3-amino-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1 Prepared by Procedure Q1 and Scheme AC, using-(4-chlorophenyl) -3-propyl-1H-pyrazole-4-carbonyl chloride: ESMS m / e: 626.3 (M + H) ⁺
[1773] Example 317
[1774] 4-chloro-N-((1S) -3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} -1-phenylpropyl) -1,3-dimethyl-1H-pyra Solo [3,4-B] pyridine-5-carboxamide: N- (3- {1-[(3S) -3-amino-3-phenylpropyl] -4-piperidinyl} phenyl) -2- Prepared by Procedure Q1 and Scheme AC, using methylpropanamide and 4-chloro-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbonyl chloride: ESMS m / e : 587.3 (M + H) ⁺
[1775] Example 318
[1776] 5- (3,5-dichlorophenoxy) -N-((1S) -3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} -1-phenylpropyl) -1H -Pyrrole-2-carboxamide: N- (3- {1-[(3S) -3-amino-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 5- ( Prepared by Procedure Q1 and Scheme AC, using 3,5-dichlorophenoxy) -1H-pyrrole-2-carbonyl chloride: ESMS m / e: 634.2 (M + H) ⁺
[1777] Example 319
[1778] N-((1S) -3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} -1-phenylpropyl) nicocotinamide: N- (3- {1-[( Prepared by Procedure Q1 and Scheme AC, using 3S) -3-amino-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and nicotinoyl chloride: ESMS m / e : 485.3 (M + H) ⁺
[1779] Example 320
[1780] 3,4-difluoro-N-((1S) -3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} -1-phenylpropyl) benzamide: N- ( Procedure Q1, using 3- {1-[(3S) -3-amino-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 3,4-difluorobenzoyl chloride And prepared by scheme AC: ESMS m / e: 520.3 (M + H) ⁺
[1781] Example 321
[1782] N-((1S) -3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} -1-phenylpropyl) -1-phenyl-3-propyl-1H-pyrazole- 4-carboxamides: N- (3- {1-[(3S) -3-amino-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1-phenyl-3- Prepared by procedure Q1 and scheme AC, using propyl-1H-pyrazole-4-carbonyl chloride: ESMS m / e: 592.2 (M + H) ⁺
[1783] Example 322
[1784] 4- (dimethylamino) -N-((1S) -3- {4- [3- (isobutylamino) phenyl] -1-piperidinyl} -1-phenylpropyl) benzamide: N- (3- Procedure Q1 and Scheme AC, using {1-[(3S) -3-amino-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4- (dimethylamino) benzoyl chloride Manufactured by: ESMS m / e: 527.3 (M + H) ⁺
[1785] Example 323
[1786] N-((1S) -3- {4- [3- (isobutylamino) phenyl] -1-piperidinyl} -1-phenylpropyl) -2-thiophenecarboxamide: N- (3- { By procedure Q1 and Scheme AC, using 1-[(3S) -3-amino-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 2-thiophencarbonyl chloride Prepared: ESMS m / e: 490.2 (M + H) ⁺
[1787] Example 324
[1788] N-((1S) -3- {4- [3- (isobutylamino) phenyl] -1-piperidinyl} -1-phenylpropyl) -5-nitro-2-furamide: N- (3- Procedure Q1 and Scheme using {1-[(3S) -3-amino-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 5-nitro-2-furoyl chloride Manufactured by AC: ESMS m / e: 519.2 (M + H) ⁺
[1789] Example 325
[1790] N- (3- {4- [3- (isobutylamino) phenyl] -1-piperidinyl} propyl) -5-methyl-3-phenyl-4-isoxazolecarboxamide: N- {3- [ 1- (3-aminopropyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 5-methyl-3-phenyl-4-isoxazolcarbonyl chloride, by Procedure Q1 and Scheme AC Prepared: ESMS m / e: 489.1 (M + H) ⁺
[1791] Example 326
[1792] N-((1S) -3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} -1-phenylpropyl) -2-furamide: N- {3- [1- Prepared by Procedure Q1 and Scheme AC, using (3-aminopropyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 2-furoyl chloride: ESMS m / e: 474-2 ( M + H) ⁺
[1793] Example 327
[1794] N-((1S) -3- {4- [3- (isobutylamino) phenyl] -1-piperidinyl} -1-phenylpropyl) -1- (4-nitrophenyl) -5- (trifluoro Rhomethyl) -1H-pyrazole-4-carboxamide: N- (3- {1-[(3S) -3-amino-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methyl Prepared by Procedure Q1 and Scheme AC, using propanamide and 1- (4-nitrophenyl) -5- (trifluoromethyl) -1H-pyrazole-4-carbonyl chloride: ESMS m / e: 663.2 (M + H) ⁺
[1795] Example 328
[1796] 3- (2-chloro-6-fluorophenyl) -N- (3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} propyl) -5-methyl-4-iso Solazolecarboxamides: N- {3- [1- (3-aminopropyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 3- (2-chloro-6-fluorophenyl) -5 Prepared by Procedure Q1 and Scheme AC, using -methyl-4-isoxazolcarbonyl chloride: ESMS m / e: 541.2 (M + H) ⁺
[1797] Example 329
[1798] N- [3- (1- {3-[(diphenylacetyl) amino] propyl} -4-piperidinyl) phenyl] -2-methylpropanamide: N- {3- [1- (3-aminopropyl Prepared by Procedure Q1 and Scheme AC, using) -4-piperidinyl] phenyl} -2-methylpropanamide and diphenylacetyl chloride: ¹ HNMR (400 MHz, CDC1 ₃ ) δ7.51 (s, 1H), 7.33-7.21 (m, 13H), 6.94 (m, 2H), 4.88 (s, 1H), 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 C ₃₂ H ₃₉ N ₃ 0 ₂ + HC1 + 0.19CHC1 ₃ : 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) ⁺
[1799] Example 330
[1800] N- (3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} propyl) -1-benzothiophene-3-carboxamide: N- {3- [1- ( Prepared by Procedure Q1 and Scheme AC, using 3-aminopropyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 1-benzothiophen-3-carbonyl chloride: ESMS m / e : 464.2 (M + H) ⁺
[1801] Example 331
[1802] 3- (2-Chlorophenyl) -N- (3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} propyl) -5-methyl-4-isoxazolecarboxamide: N- {3- [1- (3-aminopropyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 3- (2-chlorophenyl) -5-methyl-4-isoxazolecarbonyl chloride Using, prepared by Procedure Q1 and Scheme AC: ESMS m / e: 523.1 (M + H) ⁺
[1803] Example 332
[1804] 3- (2,6-dichlorophenyl) -N- (3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} propyl) -5-methyl-4-isoxazolecarbox Amides: N- {3- [1- (3-aminopropyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 3- (2,6-dichlorophenyl) -5-methyl-4-iso Prepared by Procedure Q1 and Scheme AC, using sazolcarbonyl chloride: ¹ HNMR (400 MHz, CDC1 ₃ ) δ7.50 (d, 1H, J = 2.3 Hz), 7.48 (s, 1H), 7.4 ( m, 1H), 7.39 (s, 1H), 7.37 (m, 2H), 7.24 (t, 1H, J = 7.2 Hz), 6.92 (d, 1H, J = 7.9 Hz), 6.06 (s, 1H), 3.31 (q, 2H, J = 6.4 Hz), 2.94 (d, 2H, J = 10.8 Hz), 2.79 (s, 3H), 2.53 (q, 1H, J = 6.1), 2.47 (tt, 1H, J = 4.2, 11-4 Hz), 2.29 (t, 2H, J = 7.2 Hz), 1.99 (t, 2H, J = 11.4 Hz), 1.81 (m, 2H), 1.69 (dt, 2H, J = 2.4, 11.6 ), 1-59 (q, 2H, J = 6.6 Hz), 1.24 (d, 6H, J = 6.5 Hz); ESMS m / e: 557.0 (M + H) ⁺
[1805] 1- [3- (3-chloropropoxy) phenyl] ethanone: prepared by Procedure U and Scheme AK, using 1- (3-hydroxyphenyl) ethanone and 1-bromo-3-chloropropane. being.
[1806] 1- (3-Chloropropoxy) -2-fluorobenzene: Prepared by Procedure U and Scheme AK, using 2-fluorophenol and 1-bromo-3-chloropropane.
[1807] 1-Chloro-3- (3-chloropropoxy) benzene: Prepared by Procedure U and Scheme AK, using 3-chlorophenol and 1-bromo-3-chloropropane.
[1808] 1-Chloro-4- (3-chloropropoxy) benzene: Prepared by Procedure U and Scheme AK, using 4-chlorophenol and 1-bromo-3-chloropropane.
[1809] 1- (3-Chloropropoxy) -3-fluorobenzene: Prepared by Procedure U and Scheme AK, using 3-fluorophenol and 1-bromo-3-chloropropane.
[1810] 1- (3-Chloropropoxy) -4-fluorobenzene: Prepared by Procedure U and Scheme AK, using 4-fluorophenol and 1-bromo-3-chloropropane.
[1811] 1-Chloro-2- (3-chloropropoxy) benzene: Prepared by Procedure U and Scheme AK, using 2-chlorophenol and 1-bromo-3-chloropropane.
[1812] 4- (3-Chloropropoxy) -1,2-dimethylbenzene: Prepared by Procedure U and Scheme AK, using 3,4-dimethylphenol and 1-bromo-3-chloropropane.
[1813] 1-Bromo-2- (3-chloropropoxy) benzene: Prepared by Procedure U and Scheme AK, using 2-bromophenol and 1-bromo-3-chloropropane.
[1814] 1-Bromo-3- (3-chloropropoxy) benzene: Prepared by Procedure U and Scheme AK, using 3-bromophenol and 1-bromo-3-chloropropane.
[1815] 1-Bromo-4- (3-chloropropoxy) benzene: Prepared by Procedure U and Scheme AK, using 4-bromophenol and 1-bromo-3-chloropropane.
[1816] 1- (3-Chloropropoxy) -4-methylbenzene: Prepared by Procedure U and Scheme AK, using ρ-cresol and 1-bromo-3-chloropropane.
[1817] 4-bromophenyl (2R) -3-chloro-2-methylpropyl ether: procedure U and reaction scheme using 4-bromophenol and (2S) -1-bromo-3-chloro-2-methylpropane Manufactured by AK.
[1818] 1-{[(2R) -3-chloro-2-methylpropyl] oxy} -2,4,5-trifluorobenzene: 2,4,5-trifluorophenol and (2S) -1-bromo Prepared by Procedure U and Scheme AK, using 3-chloro-2-methylpropane.
[1819] 1-chloro-3-{[(2R) -3-chloro-2-methylpropyl] oxy} benzene: using 3-chlorophenol and (2S) -1-bromo-3-chloro-2-methylpropane Prepared by Procedure U and Scheme AK.
[1820] 1-{[(2R) -3-chloro-2-methylpropyl] oxy} -4-fluorobenzene: 4-fluorophenol and (2S) -1-bromo-3-chloro-2-methylpropane Using, prepared by Procedure U and Scheme AK.
[1821] 1-{[(2R) -3-chloro-2-methylpropyl] oxy} -3-fluorobenzene: 3-fluorophenol and (2S) -1-bromo-3-chloro-2-methylpropane Using, prepared by Procedure U and Scheme AK.
[1822] 1-chloro-2-{[(2R) -3-chloro-2-methylpropyl] oxy} benzene: using 2-chlorophenol and (2S) -1-bromo-3-chloro-2-methylpropane Prepared by Procedure U and Scheme AK.
[1823] 1-{[(2R) -3-chloro-2-methylpropyl] oxy} -2-fluorobenzene: 2-fluorophenol and (2S) -1-bromo-3-chloro-2-methylpropane Using, prepared by Procedure U and Scheme AK.
[1824] 1-chloro-4-{[(2R) -3-chloro-2-methylpropyl] oxy} benzene: using 4-chlorophenol and (2S) -1-bromo-3-chloro-2-methylpropane Prepared by Procedure U and Scheme AK.
[1825] 3-bromophenyl (2R) -3-chloro-2-methylpropyl ether: procedure U and reaction scheme using 3-bromophenol and (2S) -1-bromo-3-chloro-2-methylpropane Manufactured by AK.
[1826] 2-bromophenyl (2R) -3-chloro-2-methylpropyl ether: procedure U and scheme using 2-bromophenol and (2S) -1-bromo-3-chloro-2-methylpropane Manufactured by AK.
[1827] 1-{[(2S) -3-chloro-2-methylpropyl] oxy} -3-fluorobenzene: 3-fluorophenol and (2R) -1-bromo-3-chloro-2-methylpropane Using, prepared by Procedure U and Scheme AK.
[1828] 1-{[(2S) -3-chloro-2-methylpropyl] oxy} -4-fluorobenzene: 4-fluorophenol and (2R) -1-bromo-3-chloro-2-methylpropane Using, prepared by Procedure U and Scheme AK.
[1829] 1-{[(2S) -3-chloro-2-methylpropyl] oxy} -2-fluorobenzene: 2-fluorophenol and (2R) -1-bromo-3-chloro-2-methylpropane Using, prepared by Procedure U and Scheme AK.
[1830] 1-chloro-2-{[(2S) -3-chloro-2-methylpropyl] oxy} benzene: using 2-chlorophenol and (2R) -1-bromo-3-chloro-2-methylpropane Prepared by Procedure U and Scheme AK.
[1831] 1-chloro-4-{[(2S) -3-chloro-2-methylpropyl] oxy} benzene: using 4-chlorophenol and (2R) -1-bromo-3-chloro-2-methylpropane Prepared by Procedure U and Scheme AK.
[1832] 4-bromophenyl (2S) -3-chloro-2-methylpropyl ether: procedure U and scheme using 4-bromophenol and (2R) -1-bromo-3-chloro-2-methylpropane Manufactured by AK.
[1833] 3-bromophenyl (2S) -3-chloro-2-methylpropyl ether: procedure U and reaction scheme using 3-bromophenol and (2R) -1-bromo-3-chloro-2-methylpropane Manufactured by AK.
[1834] 2-bromophenyl (2S) -3-chloro-2-methylpropyl ether: procedure U and scheme using 2-bromophenol and (2R) -1-bromo-3-chloro-2-methylpropane Manufactured by AK.
[1835] 1-chloro-3-{[(2S) -3-chloro-2-methylpropyl] oxy} benzene: using 3-chlorophenol and (2R) -1-bromo-3-chloro-2-methylpropane Manufactured by Procedure U and Scheme AK.
[1836] 1- [3- (4-chlorobutoxy) phenyl] ethanone: Prepared by Procedure U and Scheme AK, using 1- (3-hydroxyphenyl) ethanone and 1-bromo-4-chlorobutane being.
[1837] 1- [3- (4-chlorobutoxy) phenyl] ethanone: Prepared by Procedure U and Scheme AK, using 1- (3-hydroxyphenyl) ethanone and 1-bromo-4-chlorobutane being.
[1838] 1- (4-chlorobutoxy) -3-methoxybenzene: Prepared by Procedure U and Scheme AK, using 3-methoxyphenol and 1-bromo-4-chlorobutane.
[1839] 1- (4-chlorobutoxy) -4-methoxybenzene: Prepared by Procedure U and Scheme AK, using 4-methoxyphenol and 1-bromo-4-chlorobutane.
[1840] 1- (4-chlorobutoxy) -2-methoxybenzene: Prepared by Procedure U and Scheme AK, using 2-methoxyphenol and 1-bromo-4-chlorobutane.
[1841] 4- (4-Chlorobutoxy) -1,2-dimethylbenzene: Prepared by Procedure U and Scheme AK, using 3,4-dimethylphenol and 1-bromo-4-chlorobutane.
[1842] 1- {3-[(5-chloropentyl) oxy] phenyl} ethanone: Procedure U and Scheme AK, using 1- (3-hydroxyphenyl) ethanone and 1-bromo-5-chloropentane Manufactured by.
[1843] 1- {3-[(5-chloropentyl) oxy] phenyl} ethanone : Procedure U and Scheme AK, using 1- (3-hydroxyphenyl) ethanone and 1-bromo-5-chloropentane Manufactured by.
[1844] 1- {3-[(6-chlorohexyl) oxy] phenyl} ethanone: Procedure U and Scheme AK, using 1- (3-hydroxyphenyl) ethanone and 1-bromo-6-chlorohexane Manufactured by.
[1845] 1- {3-[(6-chlorohexyl) oxy] phenyl} ethanone: Procedure U and Scheme AK, using 1- (3-hydroxyphenyl) ethanone and 1-bromo-6-chlorohexane Manufactured by.
[1846] Example 333
[1847] N- (3- {1-[(2S) -2- (3-acetylphenoxy) -2-phenylethyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1- (3-hydrate Procedure B, using oxyphenyl) ethanone and N- (3- {1-[(2R) -2-hydroxy-2-phenylethyl] -4-piperidinyl} phenyl} -2-methylpropanamide And prepared by Scheme B1: ESMS m / e: 485.0 (M + H) ⁺
[1848] Example 334
[1849] N- (3- {1-[(2S) -2- (2-acetylphenoxy) -2-phenylethyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1- (2-hydrate Procedure B, using hydroxyphenyl) ethanone and N- (3- {1-[(2R) -2-hydroxy-2-phenylethyl] -4-piperidinyl} phenyl) -2-methylpropanamide And prepared by Scheme B1: ESMS m / e: 485.2 (M + H) ⁺
[1850] Example 335
[1851] N- (3- {1-[(2S) -2- (3-chlorophenoxy) -2-phenylethyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 3-chlorophenol and N Prepared by Procedure B and Scheme B1, using-(3- {1-[(2R) -2-hydroxy-2-phenylethyl] -4-piperidinyl} phenyl) -2-methylpropanamide ESMS m / e: 477.1 (M + H) ⁺
[1852] Example 336
[1853] N- (3- {1-[(2S) -2- (3,4-dimethoxyphenoxy) -2-phenylethyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 3,4 Procedure B and using dimethoxyphenol and N- (3- (1-[(2R) -2-hydroxy-2-phenylethyl] -4-piperidinyl} phenyl) -2-methylpropanamide Prepared by Scheme B1: ESMS m / e: 503.2 (M + H) ⁺
[1854] Example 337
[1855] N- (3- {1-[(2R) -2- (4-fluorophenoxy) -2-phenylethyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4-fluorophenol And by procedure B and Scheme B1, using N- (3- {1-[(2S) -2-hydroxy-2-phenylethyl] -4-piperidinyl} phenyl) -2-methylpropanamide. Prepared: ESMS m / e: 461.2 (M + H) ⁺
[1856] Example 338
[1857] N- (3- {1-[(2R) -2- (3-methoxyphenoxy) -2-phenylethyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 3-methoxyphenol And by procedure B and Scheme B1, using N- (3- {1-[(2S) -2-hydroxy-2-phenylethyl] -4-piperidinyl} phenyl) -2-methylpropanamide. Prepared: ESMS m / e: 472.9 (M + H) ⁺
[1858] Example 339
[1859] N- (3- {1-[(2R) -2- (3-chlorophenoxy) -2-phenylethyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 3-chlorophenol and N Prepared by Procedure B and Scheme B1 using-(3- {1-[(2S) -2-hydroxy-2-phenylethyl] piperidinyl} phenyl) -2-methylpropanamide: ESMS m / e: 478.5 (M + H) ⁺
[1860] N- {3- [1- (3,3-dimethoxypropyl) -4-piperidinyl] phenyl} -2-methylpropanamide: 3-bromo-1,1-dimethoxypropane and 2-methyl- Prepared by Procedure G and Scheme B1 using N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 349.2 (M + H) ⁺
[1861] Example 340
[1862] N- (3- {1-[(3S) -3- (3-acetylphenoxy) -3-phenylpropyl] -4-piperidinyl} phenyl) cyclopropanecarboxamide: 1- (3-hydroxy Procedure B and Schemes using phenyl) ethanone and N- (3- {1-[(3R) -3-hydroxy-3-phenylpropyl] -4-piperidinyl} phenyl) cyclopropanecarboxamide Manufactured by B1: ESMS m / e: 497.1 (M + H) ⁺
[1863] Example 341
[1864] N- (3- {1- [3- (3-acetylphenoxy) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1- [3- (3-chloropropoxy) phenyl] Prepared by Procedure G and Scheme B1, using ethanone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 423.2 (M + H) ⁺
[1865] Example 342
[1866] N- (3- {1- [3- (3-acetylphenoxy) propyl] -4-piperidinyl} phenyl) propanamide: 1- [3- (3-chloropropoxy) phenyl] ethanone and N Prepared by Procedure G and Scheme B1 using-[3- (4-piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m / e: 421.2 (M + H) ⁺
[1867] Example 343
[1868] N- (3- {1- [3- (2-fluorophenoxy) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1- (3-chloropropoxy) -2-fluor Prepared by Procedure G and Scheme B1, using robenzene and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 399.2 (M + H) ⁺
[1869] Example 344
[1870] N- (3- {1- [3- (3-chlorophenoxy) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1-chloro-3- (3-chloropropoxy) benzene And prepared by Procedure G and Scheme B1 using 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 415.2 (M + H) ⁺
[1871] Example 345
[1872] N- (3- {1- [3- (4-chlorophenoxy) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1-chloro-4- (3-chloropropoxy) benzene And prepared by Procedure G and Scheme B1 using 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ¹ HNMR (400 MHz, CDCl ₃ ) δ7.71 (dd, 1H, J = 3.2, 5.7 Hz), 7.53 (dd, 1H, J = 3.2, 5.7 Hz), 7.5O (m, 1H), 7.31 (m, 1H), 7.24-7.20 (m, 2H), 6.94 ( d, 1H, J = 7.9 Hz, 6.85-6.82 (m, 2H), 4.00 (t, 2H, J = 6.1 Hz), 3.07 (d, 2H, J = 10.9 Hz), 2.55 (m, 3H), 2.50 (sept, 1H, J = 6.2 Hz), 2.08 (dt, 2H, J = 3.1, 10.9 Hz), 2.00 (m, 2H), 1.83 (m, 3H), 1.69 (qt, 1H, J = 6.2 Hz ), 1.24 (d, 6H, J = 6.8 Hz); Anal. Calcd. For C2 ₄ H ₃₁ ClN ₂ 0 ₂ + HC1: C, 63.8; H, 7.09; N, 6.21. Observation: C, 63.3; H, 7.04; N, 6. 27; ESMS m / e: 415.2 (M + H) ⁺
[1873] Example 346
[1874] N- (3- {1- [3- (3-fluorophenoxy) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1- (3-chloropropoxy) -3-fluoro Prepared by Procedure G and Scheme B1, using robenzene and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 399.2 (M + H) ⁺
[1875] Example 347
[1876] N- (3- {1- [3- (4-fluorophenoxy) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1- (3-chloropropoxy) -4-fluor Prepared by Procedure G and Scheme B1, using robenzene and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 399.2 (M + H) ⁺
[1877] Example 348
[1878] N- (3- {1- [3- (2-chlorophenoxy) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1-chloro-2- (3-chloropropoxy) benzene And prepared by Procedure G and Scheme B1 using 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 415.2 (M + H) ⁺
[1879] Example 349
[1880] N- (3- {1- [3- (3,4-dimethylphenoxy) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4- (3-chloropropoxy) -1, Prepared by Procedure G and Scheme B1 using 2-dimethylbenzene and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 409.2 (M + H) ⁺
[1881] Example 350
[1882] N- (3- {1- [3- (2-bromophenoxy) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1-bromo-2- (3-chloropropoxy ) Prepared by Procedure G and Scheme B1 using benzene and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ¹ HNMR (400 MHz, CDC1 ₃ ) δ7.53 ( dd, 1H, J = 1.6, 7.9 Hz), 7.48 (s, 1H), 7.32 (m, 1H), 7.28-7.22 (m, 3H), 7.17 (s, 1H), 6.98 (d, 1H, J = 7.7 Hz), 6.93 (dd, 1H, J = 1.4, 8.4 Hz), 6.82 (dt, 1H, J = 7.6, 1.4 Hz), 4.11 (t, 2H, J = 6.3 Hz), 3.07 (d, 2H, J = 11.3 Hz), 2.61 (t, 2H, J = 6.9 Hz), 2.50 (m, 3H), 2.07 (m, 1H), 1.8-1.75 (m, 5H), 1.25 (d, 6H, J = 6.7 Hz); Anal. Calcd. For C ₂₄ H ₃₁ BrN ₂ 0 ₂ .HC1 + 0.2 CHC1 ₃ : C, 55.9; H, 6. 24; N, 5.39. Observation: C, 55.8; H, 6. 23; N, 5.47; ESMS m / e: 459.1 (M + H) ⁺
[1883] Example 351
[1884] N- (3- {1- [3- (3-bromophenoxy) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1-bromo-3- (3-chloropropoxy ) Prepared by Procedure G and Scheme B1 using benzene and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 459.1 (M + H) ⁺
[1885] Example 352
[1886] N- (3- {1- [3- (4-bromophenoxy) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1-bromo-4- (3-chloropropoxy ) Benzene and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ¹ HNMR (400 MHz, CDC1 ₃ ) δ7.51 (s, 1H), 7.37 (d, 2H, J = 7.6 Hz), 7.26 (m, 3H), 6.97 (d, 1H, J = 7.7 Hz), 6.79 (d, 2H, J = 7.7 Hz), 4.01 (t, 2H, J = 5.6 Hz), 3.08 (d , 2H, J = 9.4 Hz), 2.53 (m, 4H), 2.05 (m, 4H), 1.84 (m, 4H), 1.24 (d, 6H, J = 5.9 Hz); Anal. Calcd. For C ₂₄ H ₃₁ BrN ₂ 0 ₂ .HC1 + 0.34CHCl ₃ : C, 54.5; H, 6.08; N, 5 .22. Observation: C, 54-5; H, 6. 22; N, 5.22; ESMS m / e: 459.1 (M + H) ⁺
[1887] Example 353
[1888] N- (3- {1-[(3R) -3- (3,4-dimethoxyphenoxy) -3-phenylpropyl] -4-piperidinyl} phenyl) -N, 2-dimethylpropanamide: N -(3- {1-[(3R) -3- (3,4-dimethoxyphenoxy) -3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and methyl iodide Using, prepared by Procedure T and Scheme AD: ESMS m / e: 531.2 (M + H) ⁺
[1889] Example 354
[1890] N- (3- {1-[(3R) -3- (3-acetylphenoxy) -3-phenylpropyl] -4-piperidinyl} phenyl) -N, 2-dimethylpropanamide: N- (3 -T1-[(3R) -3- (3-acetylphenoxy) -3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and methyl iodide, using procedure T and Prepared by Scheme AD: ESMS m / e: 513.2 (M + H) ⁺
[1891] Example 355
[1892] N- (3- {1-[(3S) -3- (3-acetylphenoxy) -3-phenylpropyl] -4-piperidinyl} phenyl) -N, 2-dimethylpropanamide: N- (3 -T1-[(3S) -3- (3-acetylphenoxy) -3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide and methyl iodide, using procedure T and Prepared by Scheme AD: ESMS m / e: 513.2 (M + H) ⁺
[1893] Example 356
[1894] N- (3- {1-[(2S) -3- (4-bromophenoxy) -2-methylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4-bromophenyl Prepared by Procedure G and Scheme B1 using (2R) -3-chloro-2-methylpropyl ether and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 473.0 (M + H) ⁺
[1895] Example 357
[1896] 2-methyl-N- (3- {1-[(2S) -2-methyl-3- (2,4,5-trifluorophenoxy) propyl] -4-piperidinyl} phenyl) propanamide: 1-{[(2R) -3-chloro-2-methylpropyl] oxy} -2,4,5-trifluorobenzene and 2-methyl-N- [3- (4-piperidinyl) phenyl] propane Prepared by Procedure G and Scheme B1, using an amide: ESMS m / e: 449.2 (M + H) ⁺
[1897] Example 358
[1898] N- (3- {1-[(2S) -3- (3-chlorophenoxy) -2-methylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1-chloro-3- By Procedure G and Scheme B1 using {[(2R) -3-chloro-2-methylpropyl] oxy} benzene and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide Prepared: ESMS m / e: 429.2 (M + H) ⁺
[1899] Example 359
[1900] N- (3- {1-[(2S) -3- (4-fluorophenoxy) -2-methylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1-{[( Procedure G and Scheme B1, using 2R) -3-chloro-2-methylpropyl] oxy} -4-fluorobenzene and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide Manufactured by: ESMS m / e: 413.2 (M + H) ⁺
[1901] Example 360
[1902] N- (3- {1-[(2S) -3- (3-fluorophenoxy) -2-methylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1-{[( Procedure G and Scheme B1, using 2R) -3-chloro-2-methylpropyl] oxy} -3-fluorobenzene and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide Manufactured by: ESMS m / e: 413.2 (M + H) ⁺
[1903] Example 361
[1904] N- (3- {1-[(2S) -3- (2-chlorophenoxy) -2-methylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1-chloro-2- By Procedure G and Scheme B1 using {[(2R) -3-chloro-2-methylpropyl] oxy} benzene and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide Prepared: ESMS m / e: 429.1 (M + H) ⁺
[1905] Example 362
[1906] N- (3- {1-[(2S) -3- (2-fluorophenoxy) -2-methylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1-{[( Procedure G and Scheme B1, using 2R) -3-chloro-2-methylpropyl] oxy} -2-fluorobenzene and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide Manufactured by: ESMS m / e: 413.2 (M + H) ⁺
[1907] Example 363
[1908] N- (3- {1-[(2S) -3- (4-chlorophenoxy) -2-methylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1-chloro-4- By Procedure G and Scheme B1 using {[(2R) -3-chloro-2-methylpropyl] oxy} benzene and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide Prepared: ESMS m / e: 429.2 (M + H) ⁺
[1909] Example 364
[1910] N- (3- {1-[(2S) -3- (3-bromophenoxy) -2-methylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 3-bromophenyl Prepared by Procedure G and Scheme B1 using (2R) -3-chloro-2-methylpropyl ether and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 474.0 (M + H) ⁺
[1911] Example 365
[1912] N- (3- {1-[(2S) -3- (2-bromophenoxy) -2-methylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 2-bromophenyl Prepared by Procedure G and Scheme B1 using (2R) -3-chloro-2-methylpropyl ether and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 473.0 (M + H) ⁺
[1913] Example 366
[1914] N- (3- {1-[(2R) -3- (3-fluorophenoxy) -2-methylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1-{[( Procedure G and Scheme B1, using 2S) -3-chloro-2-methylpropyl] oxy} -3-fluorobenzene and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide Manufactured by: ESMS m / e: 413.2 (M + H) ⁺
[1915] Example 367
[1916] N- (3- {1-[(2R) -3- (4-fluorophenoxy) -2-methylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1-{[( Procedure G and Scheme B1, using 2S) -3-chloro-2-methylpropyl] oxy} -4-fluorobenzene and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide Manufactured by: ESMS m / e: 413.8 (M + H) ⁺
[1917] Example 368
[1918] N- (3- {1-[(2R) -3- (2-chlorophenoxy) -2-methylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1-chloro-2- By Procedure G and Scheme B1 using {[(2S) -3-chloro-2-methylpropyl] oxy} benzene and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide Prepared: ESMS m / e: 429.1 (M + H) ⁺
[1919] Example 369
[1920] N- (3- {1-[(2R) -3- (4-chlorophenoxy) -2-methylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1-chloro-4- By Procedure G and Scheme B1 using {[(2S) -3-chloro-2-methylpropyl] oxy} benzene and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide Prepared: ESMS m / e: 429.1 (M + H) ⁺
[1921] Example 370
[1922] N- (3- {1-[(2R) -3- (4-bromophenoxy) -2-methylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4-bromophenyl Prepared by Procedure G and Scheme B1 using (2S) -3-chloro-2-methylpropyl ether and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS M / e: 473.0 (M + H) ⁺
[1923] Example 371
[1924] N- (3- {1-[(2R) -3- (3-bromophenoxy) -2-methylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 3-bromophenyl Prepared by Procedure G and Scheme B1 using (2S) -3-chloro-2-methylpropyl ether and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 473.0 (M + H) ⁺
[1925] Example 372
[1926] N- (3- {1-[(2R) -3- (2-bromophenoxy) -2-methylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 2-bromophenyl Prepared by Procedure G and Scheme B1 using (2S) -3-chloro-2-methylpropyl ether and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 473.0 (M + H) ⁺
[1927] Example 373
[1928] N- (3- {1-[(2R) -3- (3-chlorophenoxy) -2-methylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1-chloro-3- By Procedure G and Scheme B1 using {[(2S) -3-chloro-2-methylpropyl] oxy} benzene and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide Prepared: ESMS m / e: 429.1 (M + H) ⁺
[1929] Example 374
[1930] N- (3- {1- [3- (5,5-dimethyl-l, 3-dioxan-2-yl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 2- ( Procedure G and Scheme B1 using 3-bromopropyl) -5,5-dimethyl-1,3-dioxane and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide Manufactured by: ESMS m / e: 403.2 (M + H) ⁺
[1931] Example 375
[1932] N- (3- {1- [4- (3-acetylphenoxy) butyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1- [3- (4-chlorobutoxy) phenyl] Prepared by Procedure G and Scheme B1, using ethanone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 437.2 (M + H) ⁺
[1933] Example 376
[1934] N- (3- {1- [4- (3-methoxyphenoxy) butyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1- (4-chlorobutoxy) -3- meth Prepared by Procedure G and Scheme B1, using oxybenzene and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 425.2 (M + H) ⁺
[1935] Example 377
[1936] N- (3- {1- [4- (4-methoxyphenoxy) butyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1- (4-chlorobutoxy) -4- meth Prepared by Procedure G and Scheme B1, using oxybenzene and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 425.2 (M + H) ⁺
[1937] Example 378
[1938] N- (3- {1- [4- (2-methoxyphenoxy) butyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1- (4-chlorobutoxy ) -2-meth Prepared by Procedure G and Scheme B1, using oxybenzene and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 425.2 (M + H) ⁺
[1939] Example 379
[1940] N- (3- {1- [4- (3,4-dimethylphenoxy) butyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4- (4-chlorobutoxy) -1, Prepared by Procedure G and Scheme B1 using 2-dimethylbenzene and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 423.2 (M + H) ⁺
[1941] Example 380
[1942] N- (3- {1- [4- (l, 3-dioxolan-2-yl) butyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 2- (4-chlorobutyl)- Prepared by Procedure G and Scheme B1 using 1,3-dioxolane and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 375.2 (M + H) ⁺
[1943] Example 381
[1944] N- (3- {1- [5- (3-acetylphenoxy) pentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1- {3-[(5-chloropentyl) oxy] Prepared by Procedure G and Scheme B1, using phenyl} ethanone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 451.3 (M + H) ⁺
[1945] Example 382
[1946] N- (3- {1- [5- (3-acetylphenoxy) pentyl] -4-piperidinyl} phenyl) cyclopropanecarboxamide: 1- {3-[(5chloropentyl) oxy] phenyl} Prepared by Procedure G and Scheme B1 using ethanone and N- [3- (4-piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m / e: 449.2 (M + H) ⁺
[1947] Example 383
[1948] N- (3- {1- [6- (3-acetylphenoxy) hexyl] -4-piperidinyl} pentyl) -2-methylpropanamide: 1- {3-[(6-chlorohexyl) oxy] Prepared by Procedure G and Scheme B1 using phenyl} ethanone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 465.3 (M + H) ⁺
[1949] Example 384
[1950] N- (3- {1- [6- (3-acetylphenoxy) hexyl] -4-piperidinyl} phenyl) cyclopropanecarboxamide: 1- {3-[(6-chlorohexyl) oxy] phenyl } Prepared by Procedure G and Scheme B1, using ethanone and N- [3- (4-piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m / e: 463.3 (M + H) ⁺
[1951] Example 385
[1952] N- (3- {1- [4- (4-chlorophenoxy) -4- (4-chlorophenyl) butyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4-chlorophenol and By Procedure B and Scheme AN, using N- (3- {1- [4- (4-chlorophenyl) -4-hydroxybutyl] -4-piperidinyl} phenyl} -2-methylpropanamide Prepared: ESMS m / e: 562.9 (M + 23) ⁺
[1953] Example 386
[1954] 2-methyl-N- (3- {1- [2- (1-methyl-2-phenyl-1H-indol-3-yl) ethyl] -4-piperidinyl} phenyl) propanamide: 2-methyl- Prepared by Procedure E and Scheme M, using N- {3- [1- (4-oxo-4-phenylbutyl) -4-piperidinyl] phenyl} propanamide and 1-methyl-l-phenylhydrazine. ESMS m / e: 480.3 (M + H) ⁺
[1955] Example 387
[1956] 2-methyl-N- (3- {1- [2- (2-phenyl-1H-benzo [G] indol-3-yl) ethyl] -4-piperidinyl} phenyl) propanamide: 2-methyl- Procedure E and Scheme M, using N- {3- [1- (4-oxo-4-phenylbutyl) -4-piperidinyl] phenyl} propanamide and 1- (1-naphthyl) hydrazine hydrochloride Manufactured by: ESMS m / e: 516.4 (M + H) ⁺
[1957] Example 388
[1958] 2-methyl-N- (3- {1- [3- (2-phenyl-1H-benzo [G) indol-3-yl) propyl] -4-piperidinyl} phenyl) propanamide: 2-methyl- Procedure E and Scheme M, using N- {3- [1- (5-oxo-5-phenylpentyl) -4-piperidinyl] phenyl} propanamide and 1- (1-naphthyl) hydrazine hydrochloride Manufactured by: ESMS m / e: 530.2 (M + H) ⁺
[1959] Example 389
[1960] 2-methyl-N- [3- (1- {3- [2-phenyl-5- (trifluoromethoxy) -1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] propanamide : 2-methyl-N- {3- [1- (5-oxo-5-phenylpentyl) -4-piperidinyl] phenyl} propanamide and 1- [4- (trifluoromethoxy) phenyl] hydrazine hydro Prepared by Procedure E and Scheme M, using chloride: ESMS m / e: 564.2 (M + H) ⁺
[1961] Example 390
[1962] 2-methyl-N- [3- (1- {4- [2-phenyl-5- (trifluoromethoxy) -1H-indol-3-yl] butyl} -4-piperidinyl) phenyl] propanamide : 2-methyl-N- {3- [1- (6-oxo-6-phenylhexyl) -4-piperidinyl] phenyl} propanamide and 1- [4- (trifluoromethoxy) phenyl] hydrazine hydro Prepared by Procedure E and Scheme M, using chloride: ESMS m / e: 578.2 (M + H) ⁺
[1963] Example 391
[1964] 2-methyl-N- (3- {1- [3- (1-methyl-2-phenyl-1H-indol-3-yl) propyl] -4-piperidinyl} phenyl) propanamide: 2-methyl- Prepared by Procedure E and Scheme M, using N- {3- [1- (5-oxo-5-phenylpentyl) -4-piperidinyl] phenyl} propanamide and 1-methyl-1-phenylhydrazine. ESMS m / e: 495.3 (M + H) ⁺
[1965] Example 392
[1966] N- (3- {1- [4- (1,2-diphenyl-1H-indol-3-yl) butyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 2-methyl-N Prepared by Procedure E and Scheme M, using-{3- [1- (6-oxo-6-phenylhexyl) -4-piperidinyl] phenyl} propanamide and 1,1-diphenylhydrazine hydrochloride ESMS m / e: 570.3 (M + H) ⁺
[1967] Example 393
[1968] 2-methyl-N- [3- (1- {5- [2-phenyl-5- (trifluoromethoxy) -1H-indol-3-yl] pentyl} -4-piperidinyl) phenyl] propanamide : 2-methyl-N- {3- [1- (7-oxo-7-phenylheptyl) -4-piperidinyl] phenyl} propanamide and 1- [4- (trifluoromethoxy) phenyl] hydrazine hydro Prepared by Procedure E and Scheme M, using chloride: ESMS m / e: 592.3 (M + H) ⁺
[1969] Example 394
[1970] N- (3- {1- [5- (1,2-diphenyl-1H-indol-3-yl) pentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 2-methyl-N Prepared by Procedure E and Scheme M, using-{3- [1- (7-oxo7-phenylheptyl) -4-piperidinyl] phenyl} propanamide and 1,1-diphenylhydrazine hydrochloride ESMS m / e: 584.3 (M + H) ⁺
[1971] Example 395
[1972] 2-methyl-N- (3- {1- [5- (1-methyl-2-phenyl-1H-indol-3-yl) pentyl] -4-piperidinyl} phenyl) propanamide: 2-methyl- Prepared by Procedure E and Scheme M, using N- {3- [1- (7-oxo-7-phenylheptyl) -4-piperidinyl] phenyl} propanamide and 1-methyl-1-phenylhydrazine. ESMS m / e: 522.3 (M + H) ⁺
[1973] Example 396
[1974] 2-methyl-N- (3- {1- [4- (2-phenyl-1H-benzo [G] indol-3-yl) butyl] -4-piperidinyl} phenyl) propanamide: 2-methyl- Procedure E and Scheme M using N- {3- [1- (6-oxo-6-phenylhexyl) -4-piperidinyl] phenyl} propanamide and 1- (1-naphthyl) hydrazine hydrochloride Manufactured by: ESMS m / e: 544.3 (M + H) ⁺
[1975] Example 397
[1976] 2-methyl-N- (3- {1- [4- (1-methyl-2-phenyl-1H-indol-3-yl) butyl] -4-piperidinyl} phenyl) propanamide: 2-methyl- Prepared by Procedure E and Scheme M, using N- {3- [1- (6-oxo-6-phenylhexyl) -4-piperidinyl] phenyl} propanamide and 1-methyl-1-phenylhydrazine. ESMS m / e: 508.3 (M. + H) ⁺
[1977] Example 398
[1978] 2-methyl-N- (3- {1- [5- (2-phenyl-1H-benzo [G] indol-3-yl) pentyl] -4-piperidinyl} phenyl) propanamide: 2-methyl- Procedure E and Scheme M using N- {3- [l- (7-oxo-7-phenylheptyl) -4-piperidinyl] phenyl} propanamide and 1- (1-naphthyl) hydrazine hydrochloride Manufactured by: ESMS m / e: 558.2 (M + H) ⁺ .9
[1979] Example 399
[1980] 2-Methyl-N- (3-Xl- [2- (5-methyl-2-phenyl-1 H-indol-3-yl) ethyl] -4-piperidinyl} phenyl) propanamide: 2-methyl- To procedure E and Scheme M, using N- {3- [1- (4-oxo-4-phenylbutyl) -4-piperidinyl] phenyl｝ propanamide and 1- (4-methylphenyl) hydrazine hydrochloride Prepared by: ESMS m / e: 480.2 (M + H) ⁺ .
[1981] Example 400
[1982] N- (3- {1- [2- (7-methoxy-2-phenyl-1H-indol-3-yl) ethyl] -4-piperidinyl] phenyl) -2-methylpropanamide: 2-methyl Procedure E and using 3-N- (3- [1- (4-oxo-4-phenylbutyl) -4-piperidinyl] phenyl} propanamide and 1- (2-methoxyphenyl) hydrazine hydrochloride Prepared by Scheme M: ESMS m / e: 496.2 (M + H) ⁺ .
[1983] Example 401
[1984] 2-Methyl-N- (3--3-l- [2- (7-methyl-2-phenyl-1 H-indol-3-yl) ethyl] -4-piperidinyl phenyl) propanamide: 2-methyl- Procedure E and Scheme M, using N-X3- [1- (4-oxo-4-phenylbutyl) -4-piperidinyl] phenyl} propanamide and 1- (2-methylphenyl) hydrazine hydrochloride Prepared by: ESMS m / e: 480.2 (M + H) ⁺ .9
[1985] Example 402
[1986] N- (3- {1- [3- (7-methoxy-2-phenyl-1H-indol-3-yl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 2-methyl -N- {3- [1- (5-oxo-5-phenylpentyl) -4-piperidinyl] phenyl} propanamide and 5-phenylpentyl) -4-piperidinyl] phenyl} propanamide and 1- Prepared by Procedure E and Scheme M, using (2-methoxyphenyl) hydrazine hydrochloride: ESMS m / e: 510.2 (M + H) ⁺ .
[1987] Example 403
[1988] 2-methyl-N- (3- {1- [4- (7-methyl-2-phenyl-1H-indol-3-yl) butyl] -4-piperidinyl} phenyl) propanamide: 2-methyl- Procedure E and Scheme M, using N- {3- [1- (6-oxo-6-phenylhexyl) -4-piperidinyl] phenyl} propanamide and 1- (2-methylphenyl) hydrazine hydrochloride Manufactured by: ESMS m / e: 508.3 (M + H) ⁺
[1989] Example 404
[1990] N- (3- {1- [2- (5-methoxy-2-phenyl-1H-indol-3-yl) ethyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 2-methyl Procedure E and, using -N- {3- [1- (4-oxo-4-phenylbutyl) -4-piperidinyl] phenyl} propanamide and 1- (4-methoxyphenyl) hydrazine hydrochloride Prepared by Scheme M: ESMS m / e: 496.2 (M + H) ⁺
[1991] Example 405
[1992] 2-methyl-N- (3- {1- [3- (5-methyl-2-phenyl-1H-indol-3-yl) propyl] -4-piperidinyl} phenyl) propanamide: 2-methyl- To Procedure E and Scheme M, using N- {3- [1- (5-oxo-5-phenylpentyl) -4-piperidinyl] phenyl} propanamide and 1- (4-methylphenyl) hydrazine hydrochloride Manufactured by: ESMS m / e: 494.3 (M + H) ⁺ ,
[1993] Example 406
[1994] N- (3- {1- [4- (7-methoxy-2-phenyl-1H-indol-3-yl) butyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 2-methyl Procedure E and, using -N- {3- [1- (6-oxo-6-phenylhexyl) -4-piperidinyl] phenyl} propanamide and 1- (2-methoxyphenyl) hydrazine hydrochloride Prepared by Scheme M: ESMS m / e: 524.3 (M + H) ⁺
[1995] Example 407
[1996] 2-methyl-N- (3- {1- [3- (1-phenyl-1H-indol-3-yl) propyl] -4-piperidinyl} phenyl) propanamide: N- (3- {1- Procedure H and reaction scheme using [4- (1,3-dioxolan-2-yl) butyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1,1-diphenylhydrazine hydrochloride Manufactured by S: ESMS m / e: 480.2 (M + H) ⁺
[1997] Example 408
[1998] 2-methyl-N- (3- {1- [2- (1-phenyl-1H-indol-3-yl) ethyl] -4-piperidinyl} phenyl) propanamide: N- (3- {1- By Procedure H and Scheme S, using [3- (1,3-dioxolan-2-yl) propyl] piperidinyl} phenyl} -2-methylpropanamide and 1,1-diphenylhydrazine hydrochloride Prepared: ESMS m / e: 466.2 (M + H) ⁺
[1999] Example 409
[2000] 2-methyl-N- (3- {1- [2- (7-methyl-1H-indol-3-yl) ethyl] -4-piperidinyl} phenyl) propanamide: N- (3- {1- Procedure H and [3- (1,3-dioxolan-2-yl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1- (2-methylphenyl) hydrazine hydrochloride using Prepared by Scheme S: ESMS m / e: 404.2 (M + H) ⁺
[2001] Example 410
[2002] 2-methyl-N- (3- {1- [2- (1-methyl-1H-indol-3-yl) ethyl] -4-piperidinyl} phenyl) propanamide: N- (3- {1- Procedure H and Scheme S, using [3- (1,3-dioxolan-2-yl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1-methyl-1-phenylhydrazine Manufactured by: ESMS m / e: 404.2 (M + H) ⁺
[2003] Example 411
[2004] 2-methyl-N- (3- {1- [2- (5-methyl-1H-indol-3-yl) ethyl] -4-piperidinyl} phenyl) propanamide: N- (3- {1- Procedure H and using [3- (1,3-dioxolan-2-yl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1- (4-methylphenyl) hydrazine hydrochloride Prepared by Scheme S: ESMS m / e: 404.2 (M + H) ⁺
[2005] Example 412
[2006] 2-methyl-N- [3- (1- {2- [5- (trifluoromethoxy) -1H-indol-3-yl] ethyl} -4-piperidinyl) phenyl] propanamide: N- ( 3- {1- [3- (1,3-dioxolan-2-yl) propyl] -4-piperidinyl} phenyl} -2-methylpropanamide and 1- [4- (trifluoromethoxy) phenyl ] Prepared by Procedure H and Scheme S, using hydrazine hydrochloride: ESMS m / e: 474.2 (M + H) ⁺
[2007] Example 413
[2008] N- (3- {1- [3- (1H-Benzo [G] indol-3-yl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide: N- (3- {1- Procedure H, using [4- (1,3-dioxolan-2-yl) butyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1- (1-naphthyl) hydrazine hydrochloride And prepared by Scheme S: ESMS 454.2 m / e: (M + H) ⁺
[2009] Example 414
[2010] 2-methyl-N- (3- {1- [3- (1-methyl-1H-indol-3-yl) propyl] -4-piperidinyl} phenyl) propanamide: prepared by Procedure H and Scheme S being. N- (3- {1- [4- (1,3-dioxolan-2-yl) butyl] -4-piperidinyl} phenyl) -2-methylpropanamide (100 mg, 0.270 mmol), 1- A mixture of methyl-1-phenylhydrazine (106 mg, 0.870 mmol), ZnC1 ₂ (119 mg, 0.870 mmol) and HOAc (1-00 mL) was heated to 80 ° C for 12 h. The resulting crude mixture was diluted with water (20 mL) and the aqueous layer was neutralized with saturated K ₂ CO ₃ solution (10 mL) and extracted with CH ₂ C1 ₂ (3 × 20 mL). The combined organic layers were concentrated in vacuo and the residue was purified by preparative TLC using 3% NH ₃ (2.0 M in methanol) in CH ₂ C1 ₂ to afford the desired product 2-methyl-N- (3 -{1- [3- (1-methyl-1H-indol-3-yl) propyl] -4-piperidinyl} phenyl} propanamide (20.7 mg, 18.7%) was provided: ¹ HNMR (400 MHz, CDC1 ₃ ) δ7.60 (d, 1H, J = 8.1 Hz), 7.45 (s, 1H), 7.35 (d, 1H, J = 7.4 Hz), 7.25 (m, 4H), 7.09 (t, 1H, J = 7.3 Hz), 6.97 (d, 1H, J = 7.3 Hz), 6.86 (s, 1H), 3.75 (s, 3H), 3.11 (d, 2H, J = 11.6 Hz), 2.79 (t, 2H, J = 7.3 Hz), 2.51 (m, 4H), 2.12-1.81 (m, 8H), 1.25 (d, 6H, J = 7.1 Hz); calcd for C ₂₇ H ₃₅ N ₃ O + 0.225 CHC1 ₃ : C, 73.57; H, 7.99; N, 9.45. Observation: C, 73.93; H, 7.90; N, 9.23; ESMS m / e: 418.2 (M + H) ⁺
[2011] Example 415
[2012] 2-methyl-N- (3- {1- [3- (5-methyl-1H-indol-3-yl) propyl] -4-piperidinyl} phenyl) propanamide: N- (3- {1- Procedure H and using [4- (1,3-dioxolan-2-yl) butyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1- (4-methylphenyl) hydrazine hydrochloride Prepared by Scheme S: ESMS m / e: 418.2 (M + H) ⁺
[2013] Example 416
[2014] 2-methyl-N- [3- (1- {3- [5- (trifluoromethoxy) -1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] propanamide: N- ( 3- {1- [4- (1,3-dioxolan-2-yl) butyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1- [4- (trifluoromethoxy) phenyl ] Prepared by Procedure H and Scheme S, using hydrazine hydrochloride: ESMS m / e: 488.2 (M + H) ⁺ .
[2015] Example 417
[2016] 2-methyl-N- (3- {1- [3- (7-methyl-1H-indol-3-yl) propyl] -4-piperidinyl} phenyl) propanamide: N- (3- {1- Procedure H and, using [4- (1,3-dioxolan-2-yl) butyl] -4-piperidinyl｝ phenyl) -2-methylpropanamide and 1- (2-methylphenyl) hydrazine hydrochloride Prepared by Scheme S: ESMS m / e: 418.2 (M + H) ⁺ .
[2017] Example 418
[2018] N- (3- {1- [3- (7-methoxy-1 H-indol-3-yl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide: N- (3- {1 Procedure H, using-[4- (1,3-dioxolane-2-yl) butyl] piperidinyl｝ phenyl) -2-methylpropanamide and 1- (2-methoxyphenyl) hydrazine hydrochloride Prepared by Scheme S: ESMS m / e: 434.0 (M + H) ⁺ .9
[2019] Example 419
[2020] N- (3- {1- [2- (7-methoxy-1H-indol-3-yl) ethyl] -4-piperidinyl} phenyl) -2-methylpropanamide: N- (3- {1 -[3- (1,3-dioxolan-2-yl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1- (2-methoxyphenyl) hydrazine hydrochloride, Prepared by Procedure H and Scheme S: ESMS m / e: 420.2 (M + H) ⁺ .
[2021] Example 420
[2022] N- (3- {1- [2- (5-methoxy-1H-indol-3-yl) ethyl] -4-piperidinyl｝ phenyl) -2-methylpropanamide: N- (3- {1 -[3- (1,3-dioxolan-2-yl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1- (4-methoxyphenyl) hydrazine hydrochloride, Prepared by Procedure H and Scheme S: ESMS m / e: 420.2 (M + H) ⁺ .
[2023] Example 421
[2024] 2-methyl-N- (3- {1- [4- (5-methyl-2-phenyl-1H-indol-3-yl) butyl] -4-piperidinyl} phenyl) propanamide: 2-methyl- Procedure E and Scheme M, using N- {3- [1- (6-oxo-6-phenylhexyl) -4-piperidinyl] phenyl} propanamide and 1- (4-methylphenyl) hydrazine hydrochloride Prepared by: ESMS m / e: 508.3 (M + H) ⁺ .
[2025] Example 422
[2026] 2-methyl-N- [4- (1-{[1- (4-methylphenyl) -1H-indol-3-yl] methyl--4-piperidinyl) phenyl] propanamide: 2-methyl-N- Prepared by Procedure D and Scheme N, using [4- (4-piperidinyl) phenyl] propanamide and 1- (4-methylphenyl) -1H-indole: ESMS m / e: 466.2 (M + H) ) ⁺ .
[2027] Example 423
[2028] N- [4- (1-{[1- (4-methylphenyl) -1H-indol-3-yl] methyl} -4-piperidinyl) phenyl] butanamide: N- [4- (4-piperidi Prepared by Procedure D and Scheme N, using nil) phenyl] butanamide and 1- (4-methylphenyl) -1H-indole: ESMS m / e: 466.2 (M + H) ⁺
[2029] Example 424
[2030] N- [3- (1-{[2- (2-aminophenyl) -1H-indol-3-yl] methyl) -4-piperidinyl) phenyl] -2-methylpropanamide: 2-methyl-N Prepared by Procedure D and Scheme N, using-[3- (4-piperidinyl) phenyl] propanamide and 2- (1H-indol- 2-yl) aniline: ESMS m / e: 467.2 (M + H) ⁺ .
[2031] Example 425
[2032] Ethyl 3-({4- [3- (isobutyrylamino) phenyl] 1-piperidinyl｝ methyl) -1H-indole-2-carboxylate: 2-methyl-N- [3- (4- Prepared by Procedure D and Scheme N, using piperidinyl) phenyl] propanamide and ethyl 1H-indole-2-carboxylate: ESMS m / e: 448.2 (M + H) ⁺ .
[2033] Example 426
[2034] 2-methyl-N- (3- ｛1-[(1-methyl-1H-indol-3-yl) methyl] -4-piperidinyl} phenyl) propanamide: 2-methyl-N- [3- ( Prepared by Procedure D and Scheme N, using 4-piperidinyl) phenyl] propanamide and 1-methyl-1H-indole: ESMS m / e: 390.2 (M + H) ⁺ .
[2035] Example 427
[2036] N- (3- {1-[(5-methoxy-2-methyl-1H-indol-3-yl) methyl] -4-piperidinyl｝ phenyl) -2-methylpropanamide: 2-methyl-N Prepared by Procedure D and Scheme N, using-[3- (4-piperidinyl) phenyl] propanamide and 5-methoxy-2-methyl-1H-indole: ESMS m / e: 420.2 (M + H) ⁺ .
[2037] Example 428
[2038] 2-methyl-N- (3- {1-[(1-methyl-2-phenyl-1H-indol-3-yl) methyl] -4-piperidinyl} phenyl) propanamide: 2-methyl-N- Prepared by Procedure D and Scheme N, using [3- (4-piperidinyl) phenyl] propanamide and 1-methyl-2-phenyl-1Hindole: ESMS m / e: 466.2 (M + H) ⁺ .
[2039] Example 429
[2040] 2-methyl-N- (3- {1-[(5-nitro-1H-indol-3-yl) methyl] -4-piperidinyl｝ phenyl) propanamide: 2-methyl-N- [3- ( Prepared by Procedure D and Scheme N, using 4-piperidinyl) phenyl] propanamide and 5-nitro-1H-indole: ESMS m / e: 421.1 (M + H) ⁺ .
[2041] Example 430
[2042] 2-methyl-N- (3- {1-[(2-methyl-1H-indol-3-yl) methyl] -4-piperidinyl｝ phenyl) propanamide: 2-methyl-N- [3- ( Prepared by Procedure D and Scheme N, using 4-piperidinyl) phenyl] propanamide and 2-methyl-1H-indole: ESMS m / e: 390.2 (M + H) ⁺ .
[2043] Example 431
[2044] N- (3- {1-[(4-bromo-1H-indol-3-yl) methyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 2-methyl-N- [3- Prepared by Procedure D and Scheme N, using (4-piperidinyl) phenyl] propanamide and 4-bromo-1H-indole: ESMS m / e: 455.0 (M + H) ⁺ .
[2045] Example 432
[2046] N- [3- (1-{[2- (4-fluorophenyl) -1H-indol-3-yl] methyl｝ -4-piperidinyl) phenyl] -2-methylpropanamide: 2-methyl- Prepared by Procedure D and Scheme N, using N- [3- (4-piperidinyl) phenyl] propanamide and 2- (4-fluorophenyl) -1H-indole: ESMS m / e: 470.0 (M + H) ⁺ .
[2047] Example 433
[2048] N- (3- {1-[(1,2-diphenyl-1H-indol-3-yl) methyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 2-methyl-N- [ Prepared by Procedure D and Scheme N, using 3- (4-piperidinyl) phenyl] propanamide and 1,2-diphenyl-1H-indole: ESMS m / e: 528.2 (M + H) ⁺ .
[2049] Example 434
[2050] N- [3- (1-{[2- (4-chlorophenyl) -1-ethyl-1H-indol-3-yl] methyl--4-piperidinyl) phenyl] -2-methylpropanamide: 2 Prepared by Procedure D and Scheme N, using -methyl-N- [3- (4-piperidinyl) phenyl] propanamide and 2- (4-chlorophenyl) -1-ethyl-1H-indole: ESMS m / e: 514.1 (M + H) ⁺ .
[2051] Example 435
[2052] N- (3- {1-[(5-chloro-2-methyl-1H-indol-3-yl) methyl] -4-piperidinyl｝ phenyl) -2-methylpropanamide: 2-methyl-N- Prepared by Procedure D and Scheme N, using [3- (4-piperidinyl) phenyl] propanamide and 5-chloro-2-methyl-1H-indole: ESMS m / e: 424.1 (M + H) ) ⁺ .
[2053] Example 436
[2054] N- (3- ｛1-[(5-cyano-1H-indol-3-yl) methyl] -4-piperidinyl｝ phenyl) -2-methylpropanamide: 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide and 1H-indole-5-carbonitrile: ESMS m / e: 401.1 (M + H) ⁺ .
[2055] Example 437
[2056] 2-Methyl-N- (3-methyl-1-((5-methyl-2-phenyl-1H-indol-3-yl) methyl] -4-piperidinyl phenyl) propanamide: 2-methyl-N- Prepared by Procedure D and Scheme N, using [3- (4-piperidinyl) phenyl] propanamide and 5-methyl-2-phenyl-1H-indole: ESMS m / e: 466.2 (M + H) ) ⁺ .
[2057] Example 438
[2058] 2-methyl-N- [3- (1-{[1- (4-nitrophenyl) -1H-indol-3-yl] methyl｝ -4-piperidinyl) phenyl] propanamide: 2-methyl-N Prepared by Procedure D and Scheme N, using-[3- (4-piperidinyl) phenyl] propanamide and 1- (4-nitrophenyl) -1H-indole: ESMS m / e: 497.2 (M + H) ⁺ .
[2059] Example 439
[2060] N- [3- (1-{[1- (2-fluorophenyl) -1H-indol-3-yl] methyl--4-piperidinyl) phenyl] -2-methylpropanamide: 2-methyl- Prepared by Procedure D and Scheme N, using N- [3- (4-piperidinyl) phenyl] propanamide and 1- (2-fluorophenyl) -1H-indole: ESMS m / e: 470.1 (M + H) ⁺ .
[2061] Example 440
[2062] N- (3- {1-[(5,6-dimethoxy-1H-indol-3-yl) methyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 2-methyl-N- [ Prepared by Procedure D and Scheme N, using 3- (4-piperidinyl) phenyl] propanamide and 5,6-dimethoxy-1H-indole: ESMS m / e: 436.2 (M + H) ⁺ .
[2063] Example 441
[2064] 2-methyl-N- [3- (1-{[1- (3-methylphenyl) -1H-indol-3-yl] methyl｝ -4-piperidinyl) phenyl] propanamide: 2-methyl-N- Prepared by Procedure D and Scheme N, using [3- (4-piperidinyl) phenyl] propanamide and 1- (3-methylphenyl) -1H-indole: ESMS m / e: 466.2 (M + H ) ⁺ .
[2065] Example 442
[2066] 2-methyl-N- {3- [1-({1- [3- (trifluoromethyl) phenyl] -1H-indol-3-yl｝ methyl) -4-piperidinyl] phenyl｝ propanamide: Prepared by Procedure D and Scheme N, using 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide and 1- [3- (trifluoromethyl) phenyl] -1H-indole. ESMS m / e: 520.2 (M + H) ⁺ .
[2067] Example 443
[2068] N- [3- (1-{[1- (4-methoxyphenyl) -1H-indol-3-yl] methyl] -4-piperidinyl) phenyl] -2-methylpropanamide: 2-methyl- Prepared by Procedure D and Scheme N, using N- [3- (4-piperidinyl) phenyl] propanamide and 5-methoxy-2-phenyl-1H-indole: ESMS m / e: 482.2 ( M + H) ⁺ .
[2069] Example 445
[2070] 2-Methyl-N- (3--3-l-[(5-methyl-1H-indol-3-yl) methyl] -4-piperidinyl} phenyl) propanamide: 2-methyl-N- [3- ( Prepared by Procedure D and Scheme N, using 4-piperidinyl) phenyl] propanamide and 5-methyl-1H-indole: ESMS m / e: 390.2 (M + H) ⁺ .9
[2071] Example 446
[2072] N- [3- (1-｛[1- (2-nitrophenyl) -1H-indol-3-yl] methyl｝ -4-piperidinyl) phenyl] -2-methylpropanamide: 1- (2- Prepared by Procedure D and Scheme N, using nitrophenyl) -1H-indole and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 497.2 (M + H) ⁺ .
[2073] Example 447
[2074] N- [3- (1-{[1- (2-methoxyphenyl) -1H-indol-3-yl] methyl) -4-piperidinyl) phenyl] -2-methylpropanamide: 1- (2 Prepared by Procedure D and Scheme N, using -methoxyphenyl) -1H-indole and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 482.2 (M + H) ⁺ .
[2075] Example 448
[2076] 2-methyl-N- {3- [1-({1- [2- (trifluoromethyl) phenyl] -1H-indol-3-yl｝ methyl) -4-piperidinyl] phenyl｝ propanamide: Prepared by Procedure D and Scheme N, using 1- [2- (trifluoromethyl) phenyl] -1H-indole and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide ESMS m / e: 520.2 (M + H) ⁺ .
[2077] Example 449
[2078] N- (3- {1-[(5-methoxy-1H-indol-3-yl) methyl] -4-piperidinyl｝ phenyl) -2-methylpropanamide: 1H-indol- 5-yl methyl ether And prepared by Procedure D and Scheme N, using 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 406.2 (M + H) ⁺ .
[2079] Example 450
[2080] N- [3- (1-{[1- (4-fluorophenyl) -1H-indol-3-yl] methyl｝ -4-piperidinyl) phenyl] -2-methylpropanamide: 1- (4 Prepared by Procedure D and Scheme N, using -fluorophenyl) -1H-indole and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 470.2 (M + H) ⁺ .
[2081] Example 451
[2082] N- [3- (1-{[1- (3-methoxyphenyl) -1H-indol-3-yl] methyl--4-piperidinyl) phenyl] -2-methylpropanamide: 1- (3 Prepared by Procedure D and Scheme N, using -methoxyphenyl) -1H-indole and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 482.2 (M + H) ⁺ .
[2083] Example 452
[2084] 2-methyl-N- [3- (1-{[1- (2-methylphenyl) -1H-indol-3-yl] methyl｝ -4-piperidinyl) phenyl] propanamide: 1- (2-methylphenyl Prepared by Procedure D and Scheme N, using) -1H-indole and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 466.2 (M + H ) ⁺ .
[2085] Example 453
[2086] Ethyl 3-({4- [3- (isobutyrylamino) phenyl] -1-piperidinyl｝ methyl) -5-methoxy-1H-indole-2-carboxylate: ethyl 5-methoxy-1H Prepared by Procedure D and Scheme N, using -indole-2-carboxylate and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 478.2 ( M + H) ⁺ .
[2087] Example 454
[2088] N- (3- {1-[(5-Fluoro-1H-indol-3-yl) methyl] -4-piperidinyl｝ phenyl) -2-methylpropanamide: 5-fluoro-1H-indole and Prepared by Procedure D and Scheme N, using 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 394.2 (M + H) ⁺ .
[2089] 1-phenyl-1H-indole: Prepared by Procedure C and Scheme 0 using 1H-indole and iodobenzene: ESMS m / e: 193.9 (M + H) ⁺ .
[2090] 1- (4-chlorophenyl) -1H-indole: Prepared by Procedure C and Scheme 0 using 1H-indole and 1-chloro-4-iodobenzene: ESMS m / e: 227.9 (M + H) ) ⁺
[2091] 1- (3-Chlorophenyl) -1H-indole: Prepared by Procedure C and Scheme 0, using 1H-indole and 1-chloro-3-iodobenzene: ESMS m / e: 227.9 (M + H) ) ⁺
[2092] 1- (2-chlorophenyl) -1H-indole: Prepared by Procedure C and Scheme 0, using 1H-indole and 1-chloro-2-iodobenzene: ESMS m / e: 227.9 (M + H) ) ⁺
[2093] 1- [2- (trifluoromethyl) phenyl] -1H-indole: Prepared by Procedure C and Scheme 0 using 1H-indole and 1-iodo-2- (trifluoromethyl) benzene: ESMS m / e: 262.0 (M + H) ⁺
[2094] 4- (1H-Indol-1-yl) benzonitrile: Prepared by Procedure C and Scheme 0, using 1H-indole and 4-iodobenzonitrile: ESMS m / e: 219.0 (M + H) ⁺
[2095] 1- (4-nitrophenyl) -1H-indole: Prepared by Procedure C and Scheme 0 using 1H-indole and 1-iodo-4-nitrobenzene: ESMS m / e: 238.2 (M + H ) ⁺
[2096] 1- (2-nitrophenyl) -1H-indole: Prepared by Procedure C and Scheme 0 using 1H-indole and 1-iodo-2-nitrobenzene: ESMS m / e: 238.2 (M + H ) ⁺
[2097] Example 455
[2098] N- [3- (1-{[1- (4-Chlorophenyl) -1H-indol-3-yl] methyl} -4-piperidinyl) phenyl] propanamide: 1- (4-chlorophenyl)- Prepared by Procedure D and Scheme N, using 1H-indole and N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 472.1 (M + H) ⁺
[2099] Example 456
[2100] N- [3- (1-{[1- (3-chlorophenyl) -1H-indol-3-yl] methyl} -4-piperidinyl) phenyl] propanamide: 1- (3-chlorophenyl)- Prepared by Procedure D and Scheme N, using 1H-indole and N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 472.1 (M + H) ⁺
[2101] Example 457
[2102] N- [3- (1-{[1- (2-chlorophenyl) -1H-indol-3-yl] methyl} -4-piperidinyl) phenyl] cyclopropanecarboxamide: 1- (2-chloro Prepared by Procedure D and Scheme N, using phenyl) -1H-indole and N- [3- (4-piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m / e: 484.1 (M + H ) ⁺
[2103] Example 458
[2104] N- [3- (1-{[1- (3-chlorophenyl) -1H-indol-3-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: 1- (3- Prepared by Procedure D and Scheme N, using chlorophenyl) -1H-indole and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 486.1 (M + H) ⁺
[2105] Example 459
[2106] N- [3- (1-{[1- (4-chlorophenyl) -1H-indol-3-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: 1- (4- Prepared by Procedure D and Scheme N, using chlorophenyl) -1H-indole and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 486.2 (M + H) ⁺
[2107] Example 460
[2108] N- [3- (1-{[1- (2-chlorophenyl) -1H-indol-3-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: 1- (2- Prepared by Procedure D and Scheme N, using chlorophenyl) -1H-indole and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 486.2 (M + H) ⁺
[2109] Example 461
[2110] N- [3- (1-{[1- (2-Chlorophenyl) -1H-indol-3-yl] methyl} -4-piperidinyl) phenyl] propanamide: 1- (2-chlorophenyl)- Prepared by Procedure D and Scheme N, using 1H-indole and N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 472.1 (M + H) ⁺
[2111] Example 462
[2112] N- [3- (1-{[1- (4-chlorophenyl) -1H-indol-3-yl] methyl} -4-piperidinyl) phenyl] cyclopropanecarboxamide: 1- (4-chloro Prepared by Procedure D and Scheme N, using phenyl) -1H-indole and N- [3- (4-piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m / e: 484.1 (M + H ) ⁺
[2113] Example 463
[2114] N- [3- (1-{[1- (3-chlorophenyl) -1H-indol-3-yl] methyl} -4-piperidinyl) phenyl] cyclopropanecarboxamide: 1- (3-chloro Prepared by Procedure D and Scheme N, using phenyl) -1H-indole and N- [3- (4-piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m / e: 484.1 (M + H ) ⁺ .
[2115] Example 464
[2116] N- (3- {1-[(1-phenyl-1H-indol-3-yl) methyl] -4-piperidinyl} phenyl) propanamide: 1-phenyl-1H-indole and N- [3- ( Prepared by Procedure D and Scheme N, using 4-piperidinyl) phenyl] propanamide: ESMS m / e: 438.2 (M + H) ⁺ .
[2117] Example 465
[2118] N- (3- {1-[(1-phenyl-1H-indol-3-yl) methyl] -4-piperidinyl｝ phenyl) cyclopropanecarboxamide: 1-phenyl-1H-indole and N- [ Prepared by Procedure D and Scheme N, using 3- (4-piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m / e: 450.2 (M + H) ⁺ .
[2119] 6-Chloro-1- (4-nitrophenyl) -1H-indole: Prepared by Procedure C and Scheme 0 using 6-chloro-1H-indole and 1-iodo-4-nitrobenzene: ESMS m / e: 272.6 (M + H) ⁺ .
[2120] 6-Chloro-1- (2,3-dichlorophenyl) -1H-indole: Prepared by Procedure C and Scheme 0 using 6-chloro-1H-indole and 1,2-dichloro-3-iodobenzene. ESMS m / e: 296.5 (M + H) ⁺ .
[2121] 6-Chloro-1- (3-methylphenyl) -1H-indole: Prepared by Procedure C and Scheme 0 using 6-chloro-1H-indole and 1-iodo-3-methylbenzene: ESMS m / e: 241.99 (M + H) ⁺ .
[2122] 6-Chloro-1- (2-methylphenyl) -1H-indole: Prepared by Procedure C and Scheme 0, using 6-chloro-1H-indole and 1-iodo-2-methylbenzene: ESMS m / e: 241.99 (M + H) ⁺ .
[2123] 2- (6-chloro-lH-indol-l-yl) phenyl methyl ether: prepared by procedure C and Scheme 0 using 6-chloro-lH-indole and 1-iodo-2-methoxybenzene : ESMS m / e: 257.9 (M + H) ⁺ .
[2124] 6-Chloro-l- [3- (trifluoromethyl) phenyl] -1H-indole: Procedure C using 6-chloro-lH-indole and 1-iodo-3- (trifluoromethyl) benzene. And prepared by Scheme 0: ESMS m / e: 295.6 (M + H) ⁺ .
[2125] 6-Chloro-l- (2-fluorophenyl) -lH-indole: Prepared by Procedure C and Scheme 0 using 6-chloro-lH-indole and 1-fluoro- 2-iodobenzene. ESMS m / e: 245.9 (M + H) ⁺ .
[2126] 6-Chloro-l- (3-chlorophenyl) -lH-indole: Prepared by Procedure C and Scheme 0 using 6-chloro-lH-indole and 1-chloro- 3-iodobenzene: ESMS m / e: 261.9 (M + H) ⁺ .
[2127] 6-Chloro-1- (4-chlorophenyl) -1H-indole: Prepared by Procedure C and Scheme 0 using 6-chloro-1H-indole and 1-chloro-4-iodobenzene: ESMS m / e: 262.9 (M + H) ⁺ .
[2128] 6-Chloro-l- (2-chlorophenyl) -lH-indole: Prepared by Procedure C and Scheme 0, using 6-chloro-lH-indole and 1-chloro- 2-iodobenzene: ESMS m / e: 262.9 (M + H) ⁺ .
[2129] 3- (6-Chloro-1H-indol-3-yl) phenyl methyl ether: Prepared by Procedure C and Scheme 0 using 6-chloro-1H-indole and 1-iodo-3-methoxybenzene. : ESMS m / e: 257.9 (M + H) ⁺ .
[2130] 6-Chloro-l- [4- (trifluoromethyl) phenyl] -1H-indole: Procedure C, using 6-chloro-lH-indole and 1-iodo-4- (trifluoromethyl) benzene. And prepared by Scheme 0: ESMS m / e: 295.6 (M + H) ⁺ .
[2131] 6-Chloro-1- (4-methylphenyl) -1H-indole: Prepared by Procedure C and Scheme 0 using 6-chloro-1H-indole and 1-iodo-4-methylbenzene: ESMS m / e: 241.9 (M + H) ⁺ .
[2132] 6-Chloro-l- (4-fluorophenyl) -lH-indole: Prepared by Procedure C and Scheme 0 using 6-chloro-lH-indole and 1-fluoro-4-iodobenzene. ESMS m / e: 245.9 (M + H) ⁺ .
[2133] Example 466
[2134] N- [3- (1-{[6-chloro-l- (4-fluorophenyl) -1H-indol-3-yl] methyl｝ -4-piperidinyl) phenyl] cyclopropanecarboxamide: 6 Prepared by Procedure D and Scheme N, using -chloro-l- (4-fluorophenyl) -lH-indole and N- [3- (4-piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m / e: 502.1 (M + H) ⁺ .
[2135] Example 467
[2136] N- [3- (1-｛[6-chloro-l- (4-fluorophenyl) -1 H-indol-3-yl] methyl--4--piperidinyl) phenyl] propanamide: 6-chloro- Prepared by Procedure D and Scheme N, using 1- (4-fluorophenyl) -1H-indole and N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 490.1 (M + H) ⁺ .
[2137] Example 468
[2138] N- (3- {1-[(6-fluoro-1H-indol-3-yl) methyl] -4-piperidinyl} phenyl) propanamide: 6-fluoro-1H-indole and N- [3 Prepared by Procedure D and Scheme N, using-(4-piperidinyl) phenyl] propanamide: ESMS m / e: 380.1 (M + H) ⁺ .
[2139] Example 469
[2140] N- (3- {1-[(6-fluoro-1H-indol-3-yl) methyl] -4-piperidinyl} phenyl) cyclopropanecarboxamide: 6-fluoro-1H-indole and N Prepared by Procedure D and Scheme N, using-[3- (4-piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m / e: 392.1 (M + H) ⁺ .9
[2141] Example 470
[2142] N- (3- {1-[(6-fluoro-1H-indol-3-yl) methyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 6-fluoro-1H-indole and Prepared by Procedure D and Scheme N, using 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 394.1 (M + H) ⁺ .
[2143] Example 471
[2144] N- [3- (1-{[6-chloro-l- (4-fluorophenyl) -lH-indol-3-yl] methyl--4--piperidinyl) phenyl] -2-methylpropanamide: Prepared by Procedure D and Scheme N, using 6-chloro-l- (4-fluorophenyl) -1H-indole and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide ESMS m / e: 504.1 (M + H) ⁺ .
[2145] Example 472
[2146] N- [3- (1-{[6-chloro-l- (2-fluorophenyl) -lH-indol-3-yl] methyl--4--piperazinyl) phenyl] propanamide: 6-chloro- Prepared by Procedure D and Scheme N, using 1- (2-fluorophenyl) -1H-indole and N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 490.1 (M + H) ⁺ .
[2147] Example 473
[2148] N- [3- (1-{[6-chloro-l- (2-fluorophenyl) -1 H-indol-3-yl] methyl--4--4-piperidinyl) phenyl] cyclopropanecarboxamide: 6 Prepared by Procedure D and Scheme N, using -chloro-l- (2-fluorophenyl) -1H-indole and N- [3- (4-piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m / e: 502.1 (M + H) ⁺ .
[2149] Example 474
[2150] N- [3- (1-{[6-chloro-l- (2-fluorophenyl) -1H-indol-3-yl] methyl--4-piperidinyl) phenyl] -2-methylpropanamide: Prepared by Procedure D and Scheme N, using 6-chloro-l- (2-fluorophenyl) -lH-indole and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide. ESMS m / e: 504.1 (M + H) ⁺ .
[2151] Example 475
[2152] N- [3- (1-{[6-chloro-l- (4-chlorophenyl) -1 H-indol-3-yl] methyl｝ -4-piperidinyl) phenyl] propanamide: 6-chloro-1 Prepared by Procedure D and Scheme N, using-(4-chlorophenyl) -1H-indole and N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 506.1 (M + H) ⁺ .
[2153] Example 476
[2154] N- [3- (1-{[6-chloro-l- (4-chlorophenyl) -1 H-indol-3-yl] methyl--4--4-piperidinyl) phenyl] cyclopropanecarboxamide: 6- Prepared by Procedure D and Scheme N, using Chloro-l- (4-chlorophenyl) -1H-indole and N- [3- (4-piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m / e: 518.1 (M + H) ⁺
[2155] Example 477
[2156] N- [3- (1-{[6-Chloro-1- (4-chlorophenyl) -1 H-indol-3-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: 6 Prepared by Procedure D and Scheme N, using -chloro-1- (4-chlorophenyl) -1H-indole and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 520.1 (M + H) ⁺
[2157] Example 478
[2158] N- [3- (1-{[6-Chloro-1- (3-chlorophenyl) -1 H-indol-3-yl] methyl} -4-piperidinyl) phenyl] propanamide: 6-chloro-1 Prepared by Procedure D and Scheme N, using-(3-chlorophenyl) -1H-indole and N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 506.1 (M + H) ⁺
[2159] Example 479
[2160] N- [3- (1-{[6-chloro-1- (3-chlorophenyl) -1H-indol-3-yl] methyl} -4-piperidinyl) phenyl] cyclopropanecarboxamide: 6- Prepared by Procedure D and Scheme N, using chloro-1- (3-chlorophenyl) -1H-indole and N- [3- (4-piperidinyl) phenyl] cyclopropanecarboxamide: ¹ HNMR (400 MHz, CDC1 ₃ ) δ7.72 (d, 1H, J = 8.4 Hz), 7.68 (s, 1H), 7.49 (m, 2H), 7.44 (d, 2H, J = 7.9 Hz), 7.49-7.25 (m, 4H), 7.21 (d, 1H, J = 7.9 Hz), 7.17 (d, 1H, J = 7.9 Hz), 6.93 (d, 1H, J = 7.9 Hz), 3.79 (s, 2H), 3.13 (d, 2H, J = 9.4 Hz), 2.48 (sept, 1H, J = 7.5 Hz), 2.16 (m, 2H), 1.80 (m, 4H), 1.51 (s, 1H), 1.06 (m, 2H) , 0.806 (m. 2 H); Anal. Calcd. For C ₃₀ H ₂₉ Cl ₂ N ₃ 0 + HC1 + 1.4H ₂ 0: C, 62.11; H, 5. 70; N, 7.24. Found: C, 62.19; H, 6. 21; N, 7.06; ESMS m / e: 519.2 (M + H) ⁺
[2161] Example 480
[2162] N- [3- (1-{[6-chloro-1- (3-chlorophenyl) -1H-indol-3-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: 6 Prepared by Procedure D and Scheme N, using -chloro-1- (3-chlorophenyl) -1H-indole and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 520.1 (M + H) ⁺
[2163] Example 481
[2164] N- (3- {1-[(5-fluoro-1H-indol-3-yl) methyl] -4-piperidinyl} phenyl) cyclopropanecarboxamide: 5-fluoro-1H-indole and N Prepared by Procedure D and Scheme N, using-[3- (4-piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m / e: 392.1 (M + H) ⁺
[2165] Example 482
[2166] N- [3- (1-{[6-Chloro-1- (2-chlorophenyl) -1 H-indol-3-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: 6 Prepared by Procedure D and Scheme N, using -chloro-1- (2-chlorophenyl) -1H-indole and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 520.2 (M + H) ⁺
[2167] Example 483
[2168] N- [3- (1-{[6-chloro-1- (3-methoxyphenyl) -1H-indol-3-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: By procedure D and Scheme N, using 3- (6-chloro-1H-indol-1-yl) phenyl methyl ether and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide Prepared: ESMS m / e: 516.2 (M + H) ⁺
[2169] Example 484
[2170] N- [3- (1-([6-chloro-1- (2-methoxyphenyl) -1H-indol-3-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: By Procedure D and Scheme N, using 2- (6-chloro-1H-indol-1-yl) phenyl methyl ether and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide Prepared: ESMS m / e: 516.2 (M + H) ⁺
[2171] Example 485
[2172] N- [3- (1-{[6-chloro-1- (2,3-dichlorophenyl) -1H-indol-3-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide : Procedure D and Scheme N using 6-chloro-1- (2,3-dichlorophenyl) -1H-indole and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide Manufactured by: ESMS m / e: 555.1 (M + H) ⁺
[2173] Example 486
[2174] N- [3- (1-{[6-chloro-1- (4-methylphenyl) -1H-indol-3-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: 6- Prepared by Procedure D and Scheme N, using chloro-1- (4-methylphenyl) -1H-indole and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 500.2 (M + H) ⁺
[2175] Example 487
[2176] N- {3- [1-({6-chloro-1- [3- (trifluoromethyl) phenyl] -1H-indol-3-yl) methyl) -4-piperidinyl] phenyl} -2- Methylpropanamide: 6-chloro-1- [3- (trifluoromethyl) phenyl] -1H-indole and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide, Prepared by Procedure D and Scheme N: ESMS m / e: 554.2 (M + H) ⁺
[2177] Example 488
[2178] N- {3- [1-({6-chloro-1- [4- (trifluoromethyl) phenyl] -1H-indol-3-yl} methyl) -4-piperidinyl] phenyl) -2- Methylpropanamide: 6-chloro-1- [4- (trifluoromethyl) phenyl] -1H-indole and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide, Prepared by Procedure D and Scheme N: ESMS m / e: 554.2 (M + H) ⁺
[2179] Example 489
[2180] N- [3- (1-{[6-chloro-1- (2-methylphenyl) -1H-indol-3-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: 6- Prepared by Procedure D and Scheme N, using chloro-1- (2-methylphenyl) -1H-indole and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 500.2 (M + H) ⁺
[2181] Example 490
[2182] N- [3- (1-{[6-chloro-1- (3-methylphenyl) -1H-indol-3-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: 6- Prepared by Procedure D and Scheme N, using chloro-1- (3-methylphenyl) -1H-indole and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 5OO.2 (M + H) ⁺
[2183] Example 491
[2184] N- (3- {1-[(7-chloro-1H-indol-3-yl) methyl] -4-piperidinyl} phenyl) cyclopropanecarboxamide: 7-chloro-1H-indole and N- [ Prepared by Procedure D and Scheme N, using 3- (4-piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m / e: 408.1 (M + H) ⁺
[2185] Example 492
[2186] N- (3- {1-[(7-chloro-1H-indol-3-yl) methyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 7-chloro-1H-indole and 2- Prepared by Procedure D and Scheme N, using methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 410.1 (M + H) ⁺
[2187] Example 493
[2188] N- (3- {1-[(4-fluoro-1H-indol-3-yl) methyl] -4-piperidinyl} phenyl) propanamide: 4-fluoro-1H-indole and N- [3 Prepared by Procedure D and Scheme N, using-(4-piperidinyl) phenyl] propanamide: ESMS m / e: 380.2 (M + H) ⁺
[2189] Example 494
[2190] N- (3- {1-[(7-chloro-1H-indol-3-yl) methyl] -4-piperidinyl} phenyl) propanamide: 7-chloro-1H-indole and N- [3- ( Prepared by Procedure D and Scheme N, using 4-piperidinyl) phenyl] propanamide: ESMS m / e: 396.1 (M + H) ⁺
[2191] Example 495
[2192] 2-methyl-N- (3- {1-[(6-methyl-1H-indol-3-yl) methyl] -4-piperidinyl} phenyl) propanamide: 6-methyl-1H-indole and 2- Prepared by Procedure D and Scheme N, using methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 390.2 (M + H) ⁺
[2193] Example 496
[2194] N- [3- (1-{[6- (benzyloxy) -1H-indol-3-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: 6- (benzyloxy)- Prepared by Procedure D and Scheme N, using 1H-indole and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 482.2 (M + H) ⁺
[2195] Example 497
[2196] N- (3- {1-[(6-methoxy-1H-indol-3-yl) methyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1H-indol-6-yl methyl ether And prepared by Procedure D and Scheme N, using 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 406.2 (M + H) ⁺
[2197] Example 498
[2198] Methyl 3-({4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} methyl) -1H-indole-6-carboxylate: methyl 1H-indole-6-carboxylate and 2 Prepared by Procedure D and Scheme N, using -methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 434.2 (M + H) ⁺
[2199] Example 499
[2200] 2-methyl-N- [3- (1-{[6- (trifluoromethyl) -1H-indol-3-yl] methyl} -4-piperidinyl) phenyl] propanamide: 6- (trifluoro Prepared by Procedure D and Scheme N, using rhomethyl) -1H-indole and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ¹ HNMR (400 MHz, CDC1 ₃ ) δ8.11 (s, 1H), 7.66 (s, 1H), 7.63 (sf 2H), 7.44 (d, 1H, J = 8.4 Hz), 7.39 (s, 2H), 7.32 (d, 1H, J = 8.4 Hz), 7.16 (t, 1H, J = 8.4 Hz), 6.84 (d, 1H, J = 8.4 Hz), 4.06 (s, 2H), 3.27 (d, 2H, J = 11.6 Hz), 2.56 (sept , 1H, J = 6.8 Hz, 2.37 (m, 3H), 1.93 (m, 2H), 1.75 (m, 2H), 1.22 (d, 6H, J = 6.8 Hz); C ₂₅ H ₂₈ F ₃ N ₃ Anal. Calcd. For 0 + 2HC1 + 0.5EtOAc: C, 57.8; H, 6. 11; N, 7.50. Observation: C, 56.5; H, 6. 46; N, 7.77; ESMS m / e: 444.2 (M + H) ⁺
[2201] 1- (2-pyridinyl) -1H-indole: Prepared by Procedure C and Scheme 0 using 2-iodopyridine and 1H-indole: ESMS m / e: 195.0 (M + H) ⁺
[2202] 1- (3-pyridinyl) -1H-indole: Prepared by Procedure C and Scheme 0 using 3-iodopyridine and 1H-indole: ESMS m / e: 195.0 (M + H) ⁺ .
[2203] Example 500
[2204] 2-methyl-N- [3- (1-{[1- (3-pyridinyl) -1H-indol-3-yl] methyl} -4-piperidinyl) phenyl] propanamide: 1- (3- Prepared by Procedure D and Scheme N, using pyridinyl) -1H-indole and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 453.2 (M + H) ⁺
[2205] Example 501
[2206] 2-methyl-N- [3- (1-{[1- (2-pyridinyl) -1H-indol-3-yl] methyl] -4-piperidinyl) phenyl] propanamide: 1- (2- Prepared by Procedure D and Scheme N, using pyridinyl) -1H-indole and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 453.2 (M + H) ⁺
[2207] Example 502
[2208] N- (3- {1-[(6-fluoro-1-phenyl-1H-indol-3-yl) methyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 6-fluoro- Prepared by Procedure D and Scheme N, using 1-phenyl-1H-indole and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 470.2 (M + H) ⁺
[2209] Example 503
[2210] N- (3- {1-[(6-chloro-1-phenyl-1H-indol-3-yl) methyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 6-chloro-1- Prepared by Procedure D and Scheme N, using phenyl-1H-indole and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 486.2 (M + H ) ⁺
[2211] 7-methyl-1-phenyl-1H-indole: Prepared by Procedure C and Scheme 0 using 7-methyl-1H-indole and iodobenzene: ESMS m / e: 208.1 (M + H) ⁺
[2212] Methyl 1-phenyl-1H-indole -6-carboxylate: Prepared by Procedure C and Scheme 0 using methyl 1H-indole-6-carboxylate and iodobenzene: ESMS m / e: 252.0 ( M + H) ⁺
[2213] 6-Methyl-1-phenyl-1H-indole: Prepared by Procedure C and Scheme 0, using 6-methyl-1H-indole and iodobenzene: ESMS m / e: 208.0 (M + H) ⁺
[2214] 7-chloro-1-phenyl-1H-indole: Prepared by Procedure C and Scheme 0, using 7-chloro-1H-indole and iodobenzene: ESMS m / e: 228.0 (M + H) ⁺
[2215] 6-nitro-1-phenyl-1H-indole: Prepared by Procedure C and Scheme 0, using 6-nitro-1H-indole and iodobenzene: ESMS m / e: 238.2 (M + H) ⁺
[2216] 6-methoxy-1-phenyl-1H-indole: Prepared by Procedure C and Scheme 0, using 1H- indol -6-yl methyl ether and iodobenzene: ESMS m / e: 224.0 (M + H ) ⁺
[2217] Benzyl 1-phenyl-1H-indol-6-yl ether: Prepared by Procedure C and Scheme 0 using 6- (benzyloxy) -1H-indole and iodobenzene: ESMS m / e: 300.0 (M + H) ⁺
[2218] 1-phenyl-1H-indol-3-yl trifluoromethyl ether: Prepared by Procedure C and Scheme 0 using 6- (trifluoromethoxy) -1H-indole and iodobenzene: ESMS m / e: 278.0 (M + H) ⁺
[2219] 7-methoxy-1-phenyl-1H-indole: Prepared by Procedure C and Scheme 0 using 1H- indol -7-yl methyl ether and iodobenzene: ESMS m / e: 224.0 (M + H ) ⁺
[2220] 1-phenyl-6- (trifluoromethyl) -1H-indole: Prepared by Procedure C and Scheme 0 using 6- (trifluoromethyl) -1H-indole and iodobenzene: ESMS m / e: 262.0 (M + H) ⁺
[2221] 1- (4-pyridinyl) -1H-indole: Prepared by Procedure C and Scheme 0, using 1H-indole and 4-iodopyridine: ESMS m / e: 195 (M + H) ⁺
[2222] Example 504
[2223] N- [3- (1-{[6- (benzyloxy) -1-phenyl-1H-indol-3-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: benzyl 1- Prepared by Procedure D and Scheme N, using phenyl-1H-indol-6-yl ether and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 558.0 (M + H) ⁺
[2224] Example 505
[2225] 2-methyl-N- (3- {1-[(6-methyl-1-phenyl-1H-indol-3-yl) methyl] -4-piperidinyl} phenyl) propanamide: 6-methyl-1- Prepared by Procedure D and Scheme N, using phenyl-1H-indole and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ¹ HNMR (400 MHz, CDC1 ₃ ) δ7 .66 (s, 1H), 7.64 (d, 1H, J = 7.8 Hz), 7.51 (d, 1H, J = 3.9 Hz), 7.50 (m, 3H), 7.4 (m, 2H), 7.36- 7.32 (m, 2H), 7.31 (s, 1H), 7.19 (t, 1H, J = 7.8 Hz), 7.04 (d, 1H, J = 7.8 Hz), 6.91 (d, 1H, J = 7.8 Hz), 3.94 (s, 2H), 3.25 (d, 2H, J = 9.2 Hz), 2.52 (sept, 1H, J = 6.4 Hz), 2.46 (s, 3H), 2.28 (dt, 2H, J = 11.8, 2.6 Hz ), 1.89 (dq, 2H, J = 2.9 Hz), 1.80 (m, 3H), 1.22 (d, 6H, J = 6.9 Hz); Anal. Calcd. For C ₃₁ H ₃₅ N ₃ 0 + HC1 + 0.6EtOAc: C, 72.2; H, 7.41; N, 7.57. Observation: C, 71.0; H, 7. 40; N, 7.66; ESMS m / e: 466. (M + H) ⁺
[2226] Example 506
[2227] Methyl 3-({4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} methyl) -1-phenyl-1H-indole-6-carboxylate: methyl 1-phenyl-1H-indole Prepared by Procedure D and Scheme N, using -6-carboxylate and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 510.0 (M + H) ⁺
[2228] Example 507
[2229] 2-methyl-N- (3- {1-[(6-nitro-1H-indol-3-yl) methyl] -4-piperidinyl} phenyl) propanamide: 6-nitro-1H-indole and 2- Prepared by Procedure D and Scheme N, using methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 421.0 (M + H) ⁺
[2230] Example 508
[2231] 2-methyl-N- [3- (l-{[1-phenyl-6- (trifluoromethyl) -1H-indol-3-yl] methyl} -4-piperidinyl) phenyl] propanamide: 1 Prepared by Procedure D and Scheme N, using -phenyl-6- (trifluoromethyl) -1H-indole and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 520.0 (M + H) ⁺
[2232] Example 509
[2233] 2-methyl-N- (3- {1-[(7-methyl-1-phenyl-1H-indol-3-yl) methyl] -4-piperidinyl} phenyl) propanamide: 7-methyl-1- Prepared by Procedure D and Scheme N, using phenyl-1H-indole and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 466.0 (M + H ) ⁺
[2234] Example 510
[2235] N- (3- {1-[(7-methoxy-1H-indol-3-yl) methyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1H-indol-7-yl methyl ether And prepared by Procedure D and Scheme N, using 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 406.0 (M + H) ⁺
[2236] Example 511
[2237] N- (3- {1-[(7-methoxy-1-phenyl-1H-indol-3-yl) methyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 7-methoxy- Prepared by Procedure D and Scheme N, using 1-phenyl-1H-indole and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 482.0 (M + H) ⁺
[2238] Example 512
[2239] N- (3- {1-[(7-chloro-1-phenyl-1H-indol-3-yl) methyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 7-chloro-1- Prepared by Procedure D and Scheme N, using phenyl-1H-indole and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 488.6 (M + H) ) ⁺
[2240] Example 513
[2241] 2-methyl-N- (3- {1-[(7-nitro-1H-indol-3-yl) methyl] -4-piperidinyl} phenyl) propanamide: 7-nitro-1H-indole and 2- Prepared by Procedure D and Scheme N, using methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 421.1 (M + H) ⁺
[2242] (4-piperidinyl) phenyl] propanamide: ESMS m / e: 421.1 (M + H) ⁺
[2243] Example 514
[2244] N- (3- {1-[(7-nitro-1H-indol-3-yl) methyl] -4-piperidinyl} phenyl) cyclopropanecarboxamide: 7-nitro-1H-indole and N- [ Prepared by Procedure D and Scheme N using 3- (4-piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m / e: 419.5 (M + H) ⁺
[2245] Example 515
[2246] N- (3- {1-[(7-nitro-1H-indol-3-yl) methyl] -4-piperidinyl} phenyl) propanamide: 7-nitro-1H-indole and N- [3- ( Prepared by Procedure D and Scheme N using 4-piperidinyl) phenyl] propanamide: ESMS m / e: 407.3 (M + H) ⁺
[2247] 7- (2-Fluorophenyl) -1H-indole: Prepared by Procedure I and Scheme T using 7-bromo-1H-indole and 2-fluorophenylboric acid: ESMS m / e: 211.9 (M + H) ⁺
[2248] Example 516
[2249] N- [3- (1-{[7- (2-fluorophenyl) -1H-indol-3-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: Procedure D and Scheme Manufactured by N. 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide (23.3 mg, 0.0948 mmol) in 1.00 mL HOAc: dioxane (1: 4) and 37 wt% aqueous formaldehyde (11.4 mg) , 0.142 mmol) was added 7- (2-fluorophenyl) -1H-indole (20.0 mg, 0.0948 mmol), and the reaction mixture was stirred at room temperature for 12 hours. The resulting mixture was diluted with H ₂ 0 (10 mL). The aqueous layer was extracted with CH ₂ Cl ₂ (3 × 10 mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO ₄ and concentrated in vacuo. The residue was purified by preparative TLC on silica with 4% NH ₃ in CH ₂ Cl ₂ (2.0 M in methanol) to give the desired product (56.1 mg, 100%): ¹ H NMR (400 MHz, CDCl ₃ ) δ8.58 (s, 1H), 7.73 (dd, 1H, J = 2.8, 6.3 Hz), 7.69 (s, 1H), 7.53 (dt, 1H, J = 1.8, 7.6 Hz), 7.44 (d , 1H, J = 8.1 Hz), 7.38 (m, 2H), 7.32 (s, 1H), 7.27-7.21 (m, 4H), 7.17 (t, 1H, J = 7.6 Hz), 6.88 (d, 1H, J = 7.6 Hz), 3.92 (s, 2 H); 3.20 (d, 1H, J = 11.6 Hz), 2.51 (qt, 1H, J = 6.7 Hz), 2.42 (m, 1H), 2.25 (dt, 2H, J = 2.2, 11.6 Hz), 1.89-1.72 (m , 5H), 1.22 (d, 6H, J = 7.3 Hz); ESMS m / e: 470.1 (M + H) ⁺
[2250] 7- (4-ethylphenyl) -1H-indole: Prepared by Procedure I and Scheme T using 7-bromo-1H-indole and 4-ethylphenylboric acid: ESMS m / e: 222.0 (M + H) ⁺
[2251] 7- (2-naphthyl) -1H-indole: Prepared by Procedure I and Scheme T using 7-bromo-1H-indole and 2-naphthylboric acid: ESMS m / e: 244.0 (M + H) ⁺
[2252] 7- (3-chlorophenyl) -1H-indole: Prepared by Procedure I and Scheme T using 7-bromo-1H-indole and 3-chlorophenylboric acid: ESMS m / e: 227.9 (M + H) ⁺
[2253] 6- (2-Fluorophenyl) -1H-indole: Prepared by Procedure I and Scheme T using 6-bromo-1H-indole and 2-fluorophenylboric acid: ESMS m / e: 211.9 (M + H) ⁺
[2254] 7- (3-nitrophenyl) -1H-indole: Prepared by Procedure I and Scheme T using 7-bromo-1H-indole and 3-nitrophenylboric acid: ESMS m / e: 238.9 (M + H) ⁺
[2255] 1- [4- (1H-Indol-7-yl) phenyl] ethanone: Prepared by Procedure I and Scheme T using 7-bromo-1H-indole and 4-acetylphenylboric acid: ESMS m / e: 235.2 (M + H) ⁺
[2256] 6- (2-Methylphenyl) -1H-indole: Prepared by Procedure I and Scheme T using 6-bromo-1H-indole and 2-methylphenylboric acid: ESMS m / e: 207.9 (M + H) ⁺
[2257] 6- (3-Chlorophenyl) -1H-indole: Prepared by Procedure I and Scheme T using 6-bromo-1H-indole and 3-chlorophenylboric acid: ESMS m / e: 227.9 (M + H) ⁺
[2258] 1- [4- (1H-Indol-6-yl) phenyl] ethanone: Prepared by Procedure I and Scheme T using 6-bromo-1H-indole and 4-acetylphenylboric acid: ESMS m / e: 235.8 (M + H) ⁺
[2259] 7- (2-Methylphenyl) -1H-indole: Prepared by Procedure I and Scheme T using 7-bromo-1H-indole and 2-methylphenylboric acid: ESMS m / e: 208 (M + H) ⁺
[2260] 6- (4-ethylphenyl) -1H-indole: Prepared by Procedure I and Scheme T using 6-bromo-1H-indole and 4-ethylphenylboric acid: ESMS m / e: 221.9 (M + H) ⁺
[2261] Example 517
[2262] 2-methyl-N- [3- (1-{[7- (2-naphthyl) -1H-indol-3-yl) methyl} -4-piperidinyl) phenyl] propanamide: 7- (2- Prepared by Procedure D and Scheme N using naphthyl) -1H-indole and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 502.2 (M + H ) ⁺
[2263] Example 518
[2264] N- [3- (1-{[7- (4-ethylphenyl) -1H-indol-3-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: 7- (4- Prepared by Procedure D and Scheme N using ethylphenyl) -1H-indole and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 480.2 (M + H ) ⁺
[2265] Example 519
[2266] 2-methyl-N- [3- (1-{[6- (2-methylphenyl) -1H-indol-3-yl] methyl} -4-piperidinyl) phenyl] propanamide: 6- (2-methylphenyl Prepared by Procedure D and Scheme N using) -1H-indole and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ¹ H NMR (400 MHz, CDCl ₃ ) δ8. 2 (s, 1H), 7.53 (m, 4H), 7.41 (d, 1H, J = 8.4 Hz), 7.34 (m, 2H), 7.27-7.12 (m, 5H), 6.81 (d, 1H, J = 8.4 Hz), 4.09 (s, 2H), 3.32 (d, 2H, J = 11.4 Hz), 2.57 (q, 2H, J = 7.6 Hz), 2.43 (m, 3H), 2.08 (s, 3H), 1.98 (m, 1 H), 1.75 (m, 2 H), 1.22 (d, 6H, J = 6.3 Hz); Anal calcd. For C ₃₁ H ₃₅ N ₃ 0 + CHC1 ₃ + DMF: C, 57.0; H, 6.09; N, 8.06. Found C, 56.5; H, 5.94; N, 7.76; ESMS m / e: 466.2 (M + H) ⁺
[2267] Example 520
[2268] N- [3- (1-{[7- (3-chlorophenyl) -1H-indol-3-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: 7- (3- Prepared by Procedure D and Scheme N using chlorophenyl) -1H-indole and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 486.1 (M + H ) ⁺
[2269] Example 521
[2270] 2-methyl-N- [3- (1-{[7- (3-nitrophenyl) -1H-indol-3-yl] methyl} -4-piperidinyl) phenyl] propanamide: 7- (3- Prepared by Procedure D and Scheme N using nitrophenyl) -1H-indole and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 497.0 (M + H ) ⁺
[2271] Example 522
[2272] N- [3- (1-{[7- (4-acetylphenyl) -1H-indol-3-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: 1- [4- Prepared by Procedure D and Scheme N using (1H-indol-7-yl) phenyl] ethanone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e : 493.6 (M + H) ⁺
[2273] Example 523
[2274] N- [3- (1-{[6- (4-ethylphenyl) -1H-indol-3-yl] methyl) -4-piperidinyl) phenyl] -2-methylpropanamide: 6- (4- Prepared by Procedure D and Scheme N using ethylphenyl) -1H-indole and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 480.1 (M + H ) ⁺
[2275] Example 524
[2276] 2-methyl-N- [3- (1-{[7- (2-methylphenyl) -1H-indol-3-yl] methyl} -4-piperidinyl) phenyl] propanamide: 7- (2-methylphenyl Prepared by Procedure D and Scheme N using) -1H-indole and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 466.1 (M + H) ⁺
[2277] Example 525
[2278] N- [3- (1-{[6- (2-fluorophenyl) -1H-indol-3-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: 6- (2 Prepared by Procedure D and Scheme N using -fluorophenyl) -1H-indole and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 470.2 (M + H) ⁺
[2279] 5- (4-Methylphenoxy) -1H-indole: Prepared by Procedure J and Scheme U using 5-bromo-1H-indole and p-cresol: ESMS m / e: 224.0 (M + H) ⁺
[2280] Example 526
[2281] N- (3- {1-[(5-bromo-1H-indol-3-yl) methyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 5-bromo-1H-indole and Prepared by Procedure D and Scheme N using 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS M / e: 454.0 (M + H) ⁺
[2282] 1- (4-pyridinyl) -6- (trifluoromethyl) -1H-indole: By Procedure C and Scheme O using 6- (trifluoromethyl) -1H-indole and 4-iodopyridine Preparation: ESMS m / e: 262.9 (M + H) ⁺
[2283] Example 527
[2284] 2-methyl-N- [3- (1-{[5- (4-methylphenoxy) -1H-indol-3-yl] methyl} -4-piperidinyl) phenyl] propanamide: 5- (4 Prepared by Procedure D and Scheme N using -methylphenoxy) -1H-indole and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 481.9 (M + H) ⁺
[2285] 1- (4-methylphenyl) -1H-indole: Prepared by Procedure C and Scheme O using 1H-indole and 1-iodo-4-methylbenzene. ESMS m / e: 208.0 (M + H) ⁺
[2286] 1- (3-methylphenyl) -1H-indole: Prepared by Procedure C and Scheme O using 1H-indole and 1-iodo-3-methylbenzene. ESMS m / e: 208.0 (M + H) ⁺
[2287] 1- [3- (trifluoromethyl) phenyl] -1H-indole: Prepared by Procedure C and Scheme O using 1H-indole and 1-iodo-3- (trifluoromethyl) benzene: ESMS m / e: 262.0 (M + H) ⁺
[2288] 1- (4-methoxyphenyl) -1H-indole: Prepared by Procedure C and Scheme O using 1H-indole and 1-iodo-4-methoxybenzene: ESMS m / e: 224.0 (M + H ) ⁺
[2289] 1- (2-methoxyphenyl) -1H-indole: Prepared by Procedure C and Scheme O using 1H-indole and 1-iodo-2-methoxybenzene: ESMS m / e: 224.0 (M + H ) ⁺
[2290] 1- (3-methoxyphenyl) -1H-indole: Prepared by Procedure C and Scheme O using 1H-indole and 1-iodo-3-methoxybenzene: ESMS m / e: 224.0 (M + H ) ⁺
[2291] 1- (2-methylphenyl) -1H-indole: Prepared by Procedure C and Scheme O using 1H-indole and 1-iodo-2-methylbenzene. is ESMS m / e: 208.0 (M + H) ⁺
[2292] 6-Fluoro-1-phenyl-1H-indole: Prepared by Procedure C and Scheme O using 6-fluoro-1H-indole and iodobenzene: ESMS m / e: 212.0 (M + H) ⁺
[2293] 6-Chloro-1-phenyl-1H-indole: Prepared by Procedure C and Scheme O using 6-chloro-1H-indole and iodobenzene: ESMS m / e: 228.0 (M + H) ⁺
[2294] 7-Chloro-1-phenyl-1H-indole: Prepared by Procedure C and Scheme O using 7-chloro-1H-indole and iodobenzene: ESMS m / e: 228.0 (M + H) ⁺
[2295] 6- (2-Fluorophenyl) -1H-indole: Prepared by Procedure I and Scheme T using 6-bromo-1H-indole and 2-fluorophenylboric acid: ESMS m / e: 211.9 (M + H) ⁺
[2296] Example 528
[2297] 2-methyl-N- {3- [1- (7-oxo-7-phenylheptyl) -4-piperidinyl] phenyl} propanamide: 7-chloro-1-phenyl-1-heptanone and 2-methyl Prepared by Procedure K and Scheme B1 using -N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 435.1 (M + H) ⁺
[2298] Example 529
[2299] 2-methyl-N- {3- [1- (6-oxo-6-phenylhexyl) -4-piperidinyl] phenyl} propanamide: 6-chloro-1-phenyl-1-hexanone and 2-methyl Prepared by Procedure K and Scheme B1 using -N- [3- (4-piperidinyl) phenyl] propanamide: Analytical calculation for C ₂₇ H ₃₆ N ₂ 0 ₂ + 0.1CHC1 ₃ : C, 75.3; H, 8.39; N, 6.46. Found C, 75.4; H, 7.89; N, 6.18; ESMS m / e: 421.1 (M + H) ⁺
[2300] Example 530
[2301] 2-methyl-N- {3- [1- (5-oxo-5-phenylpentyl) -4-piperidinyl] phenyl} propanamide: 5-chloro-1-phenyl-1-pentanone and 2-methyl Prepared by Procedure K and Scheme B1 using -N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 407.1 (M + H) ⁺
[2302] Example 531
[2303] N- (3- {1- [4- (4-methoxyphenyl) -4-oxobutyl] -4-piperidinyl} phenyl) propanamide: 4-chloro-1- (4-methoxyphenyl)- Prepared by Procedure K and Scheme B1 using 1-butanone and N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 409.2 (M + H) ⁺
[2304] Example 532
[2305] N- (3- {1- [4- (4-chlorophenyl) -4-oxobutyl] -4-piperidinyl} phenyl) propanamide: 4-chloro-1- (4-chlorophenyl) -1- Prepared by Procedure K and Scheme B1 using butanone and N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 413.1 (M + H) ⁺
[2306] Example 533
[2307] N- (3- {1- [4- (4-bromophenyl) -4-oxobutyl] -4-piperidinyl} phenyl) propanamide: 1- (4-bromophenyl) -4-chloro- Prepared by Procedure K and Scheme B1 using 1-butanone and N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 457.1 (M + H) ⁺
[2308] Example 534
[2309] N- (3- {1- [4- (4-TERT-butylphenyl) -4-oxobutyl] -4-piperidinyl} phenyl) propanamide: 1- (4-tert-butylphenyl) -4- Prepared by Procedure K and Scheme B1 using chloro-1-butanone and N- [3- (4--piperidinyl) phenyl] propanamide: ESMS m / e: 435.2 (M + H) ⁺
[2310] Example 535
[2311] N- (3- {1- [4- (4-fluorophenyl) -4-oxobutyl] -4-piperidinyl} phenyl) propanamide: 4-chloro-1- (4-fluorophenyl)- Prepared by Procedure K and Scheme B1 using 1-butanone and N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 397.2 (M + H) ⁺
[2312] Example 536
[2313] N- (3- (1- [4-oxo-4- (4-phenoxyphenyl) butyl] -4-piperidinyl} phenyl) propanamide: 4-chloro-1- (4-phenoxyphenyl)- Prepared by Procedure K and Scheme B1 using 1-butanone and N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 471.2 (M + H) ⁺
[2314] Example 537
[2315] N- (3- {1- [4- (4-isopropylphenyl) -4-oxobutyl] -4-piperidinyl} phenyl) cyclopropanecarboxamide: 4-chloro-1- (4-isopropyl Prepared by Procedure K and Scheme B1 using phenyl) -1-butanone and N- [3- (4-piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m / e: 433.2 (M + H) ⁺
[2316] Example 538
[2317] N- (3- {1- [4- (4-methoxyphenyl) -4-oxobutyl] -4-piperidinyl} phenyl) cyclopropanecarboxamide: 4-chloro-1- (4-methoxy Prepared by Procedure K and Scheme B1 using phenyl) -1-butanone and N- [3- (4-piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m / e: 421.2 (M + H) ⁺
[2318] Example 539
[2319] N- (3- {1- [4-oxo-4- (4-phenoxyphenyl) butyl] -4-piperidinyl} phenyl) cyclopropanecarboxamide: 4-chloro-1- (4-phenoxy Prepared by Procedure K and Scheme B1 using -phenyl) -1-butanone and N- [3- (4-piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m / e: 483.2 (M + H ) ⁺
[2320] Example 540
[2321] N- (3- {1- [4- (4-isopropylphenyl) -4-oxobutyl] -4-piperidinyl} phenyl) propanamide: 4-chloro-1- (4-isopropylphenyl)- Prepared by Procedure K and Scheme B1 using 1-butanone and N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 421.3 (M + H) ⁺
[2322] Example 541
[2323] N- (3- {1- [4- (4-TERT-butylphenyl) -4-oxobutyl] -4-piperidinyl} phenyl) cyclopropanecarboxamide: 1- (4-tert-butylphenyl) Prepared by Procedure K and Scheme B1 using 4-chloro-1-butanone and N- [3- (4-piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m / e: 447.2 (M + H) ⁺
[2324] Example 542
[2325] N- (3- {1- [4- (4-methylphenyl) -4-oxobutyl] -4-piperidinyl} phenyl) propanamide: 4-chloro-1- (4-methylphenyl) -1-butanone And prepared by Procedure K and Scheme B1 using N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 393.2 (M + H) ⁺
[2326] Example 543
[2327] N- (3- {1- [4- (3,4-dimethylphenyl) -4-oxobutyl] -4-piperidinyl} phenyl) propanamide: 4-chloro-1- (3,4-dimethylphenyl Prepared by Procedure K and Scheme B1 using) -1-butanone and N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 407.2 (M + H) ⁺
[2328] Example 544
[2329] N- (3- {1- [4- (4-bromophenyl) -4-oxobutyl] -4-piperidinyl} phenyl) cyclopropanecarboxamide: 1- (4-bromophenyl) -4 Prepared by Procedure K and Scheme B1 using -chloro-1-butanone and N- [3- (4-piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m / e: 469.1 (M + H) ⁺
[2330] Example 545
[2331] N- (3- {1- [5- (4-fluorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) propanamide: 5-chloro-1- (4-fluorophenyl)- Prepared by Procedure K and Scheme B1 using 1-pentanone and N- [3- (4-piperidinyl) phenyl] propanamide: ESMS M / e: 411.2 (M + H) ⁺
[2332] Example 546
[2333] N- (3- {1- [4- (3,4-dimethylphenyl) -4-oxobutyl] -4-piperidinyl} phenyl) cyclopropanecarboxamide: 4-chloro-1- (3,4 Prepared by Procedure K and Scheme B1 using -dimethylphenyl) -1-butanone and N- [3- (4-piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m / e: 419.2 (M + H) ⁺
[2334] Example 547
[2335] N- (3- {1- [4- (4-methylphenyl) -4-oxobutyl] -4-piperidinyl} phenyl) cyclopropanecarboxamide: 4-chloro-1- (4-methylphenyl) -1 Prepared by Procedure K and Scheme B1 using butanone and N- [3- (4-piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m / e: 405.2 (M + H) ⁺
[2336] Example 548
[2337] N- (3- {1- [4- (4-fluorophenyl) -4-oxobutyl] -4-piperidinyl} phenyl) cyclopropanecarboxamide: 4-chloro-1- (4-fluoro Prepared by Procedure K and Scheme B1 using Phenyl) -1-butanone and N- [3- (4-piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m / e: 409.2 (M + H) ⁺
[2338] Example 549
[2339] N- (3- {1- [5- (3-fluorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) cyclopropanecarboxamide: 5-chloro-1- (3-fluoro Prepared by Procedure K and Scheme B1 using Phenyl) -1-pentanone and N- [3- (4-piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m / e: 423.2 (M + H) ⁺
[2340] Example 550
[2341] N- [3- (1- {5-oxo-5- [4- (trifluoromethyl) phenyl] pentyl} -4-piperidinyl) phenyl] propanamide: 5-chloro-1- [4- ( Prepared by Procedure K and Scheme B1 using trifluoromethyl) phenyl] -1-pentanone and N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 461.2 (M + H) ⁺
[2342] Example 551
[2343] N- (3- {1- [5- (4-fluorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) cyclopropanecarboxamide: 5-chloro-1- (4-fluoro Prepared by Procedure K and Scheme B1 using Phenyl) -1-pentanone and N- [3- (4-piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m / e: 423.2 (M + H) ⁺
[2344] Example 552
[2345] N- (3- (1- [5- (3-nitrophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) propanamide: 5-chloro-1- (3-nitrophenyl) -1- Prepared by Procedure K and Scheme B1 using pentanone and N- [3- (4-piperidinyl) phenyl] propanamide ESMS m / e: 438.2 (M + H) ⁺
[2346] Example 553
[2347] N- (3- {1- [5- (3-nitrophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) cyclopropanecarboxamide: 5-chloro-1- (3-nitrophenyl) Prepared by Procedure K and Scheme B1 using -1-pentanone and N- [3- (4-piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m / e: 450.2 (M + H) ⁺
[2348] Example 554
[2349] N- (3- {1- [5- (2-fluorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) propanamide: 5-chloro-1- (2-fluorophenyl)- Prepared by Procedure K and Scheme B1 using 1-pentanone and N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 411.2 (M + H) ⁺
[2350] Example 555
[2351] N- (3- {1- [5- (3-fluorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) propanamide: 5-chloro-1- (3-fluorophenyl)- Prepared by Procedure K and Scheme B1 using 1-pentanone and N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 411.2 (M + H) ⁺
[2352] Example 556
[2353] N- (3- {1- [5- (4-nitrophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) propanamide: 5-chloro-1- (4-nitrophenyl) -1- Prepared by Procedure K and Scheme B1 using pentanone and N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 438.1 (M + H) ⁺
[2354] Example 557
[2355] N- (3- {1- [5- (4-nitrophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) cyclopropanecarboxamide: 5-chloro-1- (4-nitrophenyl) Prepared by Procedure K and Scheme B1 using -1-pentanone and N- [3- (4-piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m / e: 450.1 (M + H) ⁺
[2356] Example 558
[2357] N- (3- {1- [5- (4-chlorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) cyclopropanecarboxamide: 5-chloro-1- (4-chlorophenyl) Prepared by Procedure K and Scheme B1 using -1-pentanone and N- [3- (4-piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m / e: 439.1 (M + H) ⁺
[2358] Example 559
[2359] N- [3- (1- {5-oxo-5- [2- (trifluoromethyl) phenyl] pentyl} -4-piperidinyl) phenyl] propanamide: 5-chloro-1- [2- ( Prepared by Procedure K and Scheme B1 using trifluoromethyl) phenyl] -1-pentanone and N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 461.2 (M + H) ⁺
[2360] Example 560
[2361] N- [3- (1- {5-oxo-5- [2- (trifluoromethyl) phenyl] pentyl} -4-piperidinyl) phenyl] cyclopropanecarboxamide: 5-chloro-1- [ Prepared by Procedure K and Scheme B1 using 2- (trifluoromethyl) phenyl] -1-pentanone and N- [3- (4-piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m / e: 473.2 (M + H) ⁺
[2362] Example 561
[2363] N- (3- {1- [5- (4-chlorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) propanamide: 5-chloro-1- (4-chlorophenyl) -1- Prepared by Procedure K and Scheme B1 using pentanone and N- [3- (4-piperidinyl) phenyl] propanamide: RSMS m / e: 427.1 (M + H) ⁺
[2364] Example 562
[2365] N- (3- {1- [5- (3-chlorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) propanamide: 5-chloro-1- (3-chlorophenyl) -1- Prepared by Procedure K and Scheme B1 using pentanone and N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 427.1 (M + H) ⁺
[2366] Example 563
[2367] N- (3- {1- [5- (2-fluorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) cyclopropanecarboxamide: 5-chloro-1- (2-fluoro Prepared by Procedure K and Scheme B1 using Phenyl) -1-pentanone and N- [3- (4-piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m / e: 423.1 (M + H) ⁺
[2368] Example 564
[2369] N- (3- {1- [5- (3-chlorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) cyclopropanecarboxamide: 5-chloro-1- (3-chlorophenyl) Prepared by Procedure K and Scheme B1 using -1-pentanone and N- [3- (4-piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m / e: 439.1 (M + H) ⁺
[2370] Example 565
[2371] N- [3- (1- {5-oxo-5- [4- (trifluoromethyl) phenyl] pentyl} -4-piperidinyl) phenyl] cyclopropanecarboxamide: 5-chloro-1- [ Prepared by Procedure K and Scheme B1 using 4- (trifluoromethyl) phenyl] -1-pentanone and N- [3- (4-piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m / e: 473.2 (M + H) ⁺
[2372] Example 566
[2373] N- (3- {1- [5- (2-chlorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) propanamide: 5-chloro-1- (2-chlorophenyl) -1- Prepared by Procedure K and Scheme B1 using pentanone and N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 427.1 (M + H) ⁺
[2374] Example 567
[2375] N- (3- {1- [5- (2-chlorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) cyclopropanecarboxamide: 5-chloro-1- (2-chlorophenyl) Prepared by Procedure K and Scheme B1 using -1-pentanone and N- [3- (4-piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m / e: 439.1 (M + H) ⁺
[2376] Example 568
[2377] N- [3- (1- {5-oxo-5- [3- (trifluoromethyl) phenyl] pentyl} -4-piperidinyl) phenyl] cyclopropanecarboxamide: 5-chloro-1- [ Prepared by Procedure K and Scheme B1 using 3- (trifluoromethyl) phenyl] -1-pentanone and N- [3- (4-piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m / e: 473.2 (M + H) ⁺
[2378] Example 569
[2379] N- (3- {1- [4- (3,4-dimethylphenyl) -4-oxobutyl] -4-piperidinyl} phenyl) -N, 2-dimethylpropanamide: N- (3- {1 Prepared by Procedure T and Scheme AD using-[4- (3,4-dimethylphenyl) -4-oxobutyl] -4-piperidinyl} phenyl) -2-methylpropanamide and methyl iodide: ¹ H NMR (400 MHz, CDCl ₃ ) δ7.76 (s, 1H), 7.72 (dd, 1H, J = 1.8, 7.7 Hz), 7.33 (t, 1H, J = 8.8 Hz), 7.22 (d, 1H , J = 7.8 Hz), 7.18 (d, 1H, J = 8.8 Hz), 7.01 (m, 2H), 3.24 (s, 3H), 3.10 (d, 1H, J = 10.6 Hz), 3.00 (t, 1H , J = 7.6 Hz), 2.49 (m, 4H), 2.33 (s, 6H), 2.11 (m, 3H), 1.99 (m, 1H), 1.79 (m, 4H), 1.26 (t, 2H, J = 7.6 Hz), 1.02 (d, 6H, J = 7.6 Hz); ESMS m / e: 435.2 (M + H) ⁺
[2380] Example 570
[2381] 2-methyl-N- {3- [1- (1-methyl-4-oxo-4-phenylbutyl) -4-piperidinyl] phenyl} propanamide: 4-chloro-1-phenyl-1-pentanone And prepared by Procedure K and Scheme B1 using 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 407.2 (M + H) ⁺
[2382] Example 571
[2383] N- [3- (1- {5-oxo-5- [3- (trifluoromethyl) phenyl] pentyl} -4-piperidinyl) phenyl] propanamide: 5-chloro-1- [3- ( Prepared by Procedure K and Scheme B1 using trifluoromethyl) phenyl] -1-pentanone and N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 461.2 (M + H) ⁺
[2384] 3- (5-chloropentanoyl) -4- (3,4-difluorophenyl) -1,3-oxazolidin-2-one: 4- (3,4-difluorophenyl) -1, Prepared by Procedure AF and Scheme H using 3-oxazolidin-2-one and 5-chloropentanoyl chloride.
[2385] 3- (5-chloropentyl) -4- (3,4-difluorophenyl) -1,3-oxazolidin-2-one: 4- (3,4-difluorophenyl) -1,3 Prepared by Procedure G and Scheme C1 using oxazolidin-2-one and 1-bromo-5-chloropentane.
[2386] Example 572
[2387] N- [3- (1- {5-[(4R) -4- (3,4-difluorophenyl) -2-oxo-1,3-oxazolidin-3-yl] oxopentyl} -4 -Piperidinyl) phenyl] -2-methylpropanamide: (4R) -3- (5-chloropentanoyl) -4- (3,4-difluorophenyl) -1,3-oxazolidine-2 Prepared by Procedure G and Scheme B1 using -one and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 528.2 (M + H) ⁺
[2388] Example 573
[2389] (4R) -4- (3,4-difluorophenyl) -N- (3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} propyl) -2-oxo- 1,3-oxazolidine-3-carboxamide: 4-nitrophenyl (4R) -4- (3,4-difluorophenyl) -2-oxo-1,3-oxazolidine-3-car Prepared by Procedure AF and Scheme H, using carboxylate and N- {3- [1- (3-aminopropyl) -4-piperidinyl] phenyl} -2-methylpropanamide: ¹ H NMR (400 MHz , CDCl ₃ ) δ 8.08 (t, 1H, J = 5.5 Hz), 7.45 (S, 2H), 7.38 (d, 1H, J = 8.6 Hz), 7.24-7.12 (m, 3H), 7.06 (m, 1H), 6.97 (d, 1H, J = 8.6 Hz), 5.40 (dd, 1H, J = 3.9, 8.8 Hz), 4.71 (t, 1H, J = 8.8 Hz), 4.23 (dd, 1H, J = 4.4 , 9.1 Hz), 3.32 (qt, 2H, J = 6.1 Hz), 2.99 (d, 2H, J = 11.0 Hz), 2.49 (qt, 2H, J = 7.0 Hz), 2.41 (t, 2H, J = 7.0 Hz), 1.99 (m, 2H), 1.82-1.68 (m, 6H), 1.23 (d, 6H, J = 7.3 Hz); ESMS m / e: 529.1 (M + H) ⁺
[2390] (4S) -3- (5-chloropentyl) -4- (3,4-difluorophenyl) -1,3-oxazolidin-2-one: (4S) -4- (3,4-di Prepared by Procedure G and Scheme C1 using fluorophenyl) -1,3-oxazolidin-2-one and 1-bromo-5-chloropentane.
[2391] Example 574
[2392] N- [3- (1- {5-[(4S) -4- (3,4-difluorophenyl) -2-oxo-1,3-oxazolidin-3-yl] pentyl} -4- Piperidinyl) phenyl] -2-methylpropanamide: (4S) -3- (5-chloropentyl) -4- (3,4-difluorophenyl) -1,3-oxazolidin-2-one And prepared by Procedure G and Scheme B1 using 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.48 (s, 1H ), 7.32 (d, 1H, J = 8.6 Hz), 7.26-7.21 (m, 2H), 7.20-7.12 (m, 2H), 7.06 (m, 1H), 6.97 (d, 1H, J = 6.96 Hz) , 4.76 (dd, 1H, J = 6.3, 8.3 Hz), 4.62 (t, 1H, J = 9.0 Hz), 4.06 (dd, 1H, J = 6.4, 8.7 Hz), 3.46 (m, 1H), 3.0 ( d, 2H, J = 9.0 Hz), 2.77 (q, 1H, J = 6.8 Hz), 2.50 (q, 2H, J = 6.8 Hz), 2.31 (t, 2H, J = 6.8 Hz), 2.01 (m, 4H), 1.81 (m, 4H), 1.48 (m, 4H), 1.26 (d, 6H, J = 7.3 Hz); Analytical calcd. For C ₂₈ H ₃₇ F ₂ N ₃ 0 ₃ + HCl + 0.25CHCl ₃ : C, 60.6; H, 6.65; N, 7.25. Found: C, 60.7; H, 6.91; N, 7.05; ESMS m / e: 514.2 (M + H) ⁺
[2393] Example 575
[2394] N- [3- (1- {5-[(4S) -4- (3,4-difluorophenyl) -2-oxo-1,3-oxazolidin-3-yl] -5-oxopentyl } -4-piperidinyl) phenyl] -2-methylpropanamide: (4S) -3- (5-chloropentanoyl) -4- (3,4-difluorophenyl) -1,3-oxazoli Prepared by Procedure G and Scheme B1 using din-2-one and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 528.1 (M + H) ⁺
[2395] Example 576
[2396] (4S) -4- (3,4-difluorophenyl) -N- (3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} propyl) -2-oxo- 1,3-oxazolidine-3-carboxamide: 4-nitrophenyl (4S) -4- (3,4-difluorophenyl) -2-oxo-1,3-oxazolidine-3-car Prepared by Procedure AF and Scheme H, using carboxylate and N- {3- [1- (3-aminopropyl) -4-piperidinyl] phenyl} -2-methylpropanamide: ESMS m / e: 529.1 (M + H) ⁺
[2397] Example 577
[2398] (4S) -N- (3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} propyl) -2-oxo-4- (3,4,5-trifluorophenyl ) -1,3-oxazolidine-3-carboxamide: 4-nitrophenyl (4S) -4- (3,4-difluorophenyl) -2-oxo-1,3-oxazolidine-3 Prepared by Procedure AF and Scheme H using -carboxylate and N- {3- [1- (3-aminopropyl) -4-piperidinyl] phenyl} -2-methylpropanamide: ESMS m / e : 547.1 (M + H) ⁺
[2399] Example 578
[2400] (4S) -4- (3,5-difluorophenyl) -N- (3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} propyl) -2-oxo- 1,3-oxazolidine-3-carboxamide: 4-nitrophenyl (4S) -4- (3,4-difluorophenyl) -2-oxo-1,3-oxazolidine-3-car Prepared by Procedure AF and Scheme H, using carboxylate and N- {3- [1- (3-aminopropyl) -4-piperidinyl] phenyl} -2-methylpropanamide: ESMS m / e: 529.2 (M + H) ⁺
[2401] Example 579
[2402] N- (3- {1- [3- (phenylsulfanyl) propyl] -4-piperidinyl} phenyl) propanamide: [(3-chloropropyl) sulfanyl] benzene and N- [3- (4- Prepared by Procedure G and Scheme B1 using piperidinyl) phenyl] propanamide: ESMS m / e: 382.9 (M + H) ⁺
[2403] Example 580
[2404] N- (3- {1- [3- (phenylsulfanyl) propyl] -4-piperidinyl} phenyl) cyclopropanecarboxamide: [(3-chloropropyl) sulfanyl] benzene and N- [3- Prepared by Procedure G and Scheme B1 using (4-piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m / e: 395.1 (M + H) ⁺
[2405] Example 581
[2406] 2-methyl-N- (3- {1- [3- (phenylsulfanyl) propyl] -4-piperidinyl} phenyl) propanamide: [(3-chloropropyl) sulfanyl] benzene and 2-methyl- Prepared by Procedure G and Scheme B1 using N- [3- (4-piperidinyl) phenyl] propanamide: ¹ H NMR (400 MHz, CDCl ₃ ) δ7.63 (s, 1H), 7.48 (s , 1H), 7.33 (m, 3H), 7.27 (t, 2H, J = 7.5 Hz), 7.20 (t, 1H, J = 7.9 Hz), 7.15 (tt, 1H, J = 7.2, 1.4 Hz), 6.95 (d, 1H, J = 7.6 Hz), 2.97 (t, 4H, J = 7.3 Hz), 2.46 (m, 4H), 1.99 (dt, 2H, J = 11.4, 3.0 Hz), 1.84 (qt, 2H, J = 7.3 Hz), 1.77 (m, 4H), 1.21 (d, 6H, J = 6.8 Hz); ESMS m / e: 396.8 (M + H) ⁺
[2407] Example 582
[2408] N- (3- {1- [6- (phenylsulfanyl) hexyl] -4-piperidinyl} phenyl) cyclopropanecarboxamide: [(6-chlorohexyl) sulfanyl] benzene and N- [3- Prepared by Procedure G and Scheme B1 using (4-piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m / e: 437.4 (M + H) ⁺
[2409] Example 583
[2410] N- (3- {1- [4- (phenylsulfanyl) butyl] -4-piperidinyl} phenyl) propanamide: [(4-chlorobutyl) sulfanyl] benzene and N- [3- (4- Prepared by Procedure G and Scheme B1 using piperidinyl) phenyl] propanamide: ESMS m / e: 396.8 (M + H) ⁺
[2411] Example 584
[2412] N- (3- {1- [4- (phenylsulfanyl) butyl] -4-piperidinyl} phenyl) cyclopropanecarboxamide: [(4-chlorobutyl) sulfanyl] benzene and N- [3- Prepared by Procedure G and Scheme B1 using (4-piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m / e: 409.5 (M + H) ⁺
[2413] Example 585
[2414] 2-methyl-N- (3- {1- [4- (phenylsulfanyl) butyl] -4-piperidinyl} phenyl) propanamide: [(4-chlorobutyl) sulfanyl] benzene and 2-methyl- Prepared by Procedure G and Scheme B1 using N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 410.6 (M + H) ⁺
[2415] Example 586
[2416] 2-methyl-N- (3- {1- [5- (phenylsulfanyl) pentyl] -4-piperidinyl} phenyl) propanamide: [(5-chloropentyl) sulfanyl] benzene and 2-methyl- Prepared by Procedure G and Scheme B1 using N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 425.1 (M + H) ⁺
[2417] Example 587
[2418] N- (3- {1- [5- (phenylsulfanyl) pentyl] -4-piperidinyl] phenyl} cyclopropanecarboxamide: [(5-chloropentyl) sulfanyl] benzene and N- [3- Prepared by Procedure G and Scheme B1 using (4-piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m / e: 423.1 (M + H) ⁺
[2419] [(6-Chlorohexyl) sulfanyl] benzene: Prepared by Procedure R and Scheme Z using benzenethiol and 1-bromo-6-chlorohexane.
[2420] [(4-Chlorobutyl) sulfanyl] benzene: Prepared by Procedure R and Scheme Z using benzenethiol and 1-bromo-4-chlorobutane.
[2421] Example 588
[2422] N- (3- {1- [6- (phenylsulfanyl) hexyl] -4-piperidinyl} phenyl) propanamide: [(6-chlorohexyl) sulfanyl] benzene and N- [3- (4- Prepared by Procedure G and Scheme B1 using piperidinyl) phenyl] propanamide: ESMS m / e: 425.4 (M + H) ⁺
[2423] [(5-Chloropentyl) sulfanyl] benzene: Prepared by Procedure R and Scheme Z using benzenethiol and 1-bromo-5-chloropentane.
[2424] [(3-Chloropropyl) sulfanyl] benzene: Prepared by Procedure R and Scheme Z using benzenethiol and 1-bromo-3-chloropropane: ¹ H NMR (400 MHz, CDCl ₃ ) δ7.37-7.34 (m, 2H), 7.32-7.26 (m, 2H), 7.19 (tt, 1H, J = 1.4, 7.3 Hz), 3.67 (t, 2H, J = 6.6 Hz), 3.08 (t, 2H, J = 6.6 Hz), 2.06 (qt, 2H, J = 6.6 Hz).
[2425] Example 589
[2426] N- (3- {1- [5- (phenylsulfanyl) pentyl] -4-piperidinyl} phenyl) propanamide: [(5-chloropentyl) sulfanyl] benzene and N- [3- (4- Prepared by Procedure G and Scheme B1 using piperidinyl) phenyl] propanamide: ESMS m / e: 411.1 (M + H) ⁺
[2427] 3-Chloropropyl 4-fluorophenyl sulfide: Prepared by Procedure R and Scheme Z using 4-fluorobenzenethiol and 1-bromo-3-chloropropane.
[2428] 1-Bromo-2-[(3-chloropropyl) sulfanyl] benzene: Prepared by Procedure R and Scheme Z using 2-bromobenzenethiol and 1-bromo-3-chloropropane.
[2429] 3-Chloropropyl 4-fluorophenyl sulfoxide: Prepared by Procedure S and Scheme AA using 3-chloropropyl 4-fluorophenyl sulfide and 1 eq m-CPBA: ¹ H NMR (400 MHz, CDCl ₃ ) δ7.65-7.62 (m, 2H), 7.28-7.21 (m, 2H), 3.65 (m, 2H), 2.94 (m, 2H), 2.28 (m, 1H), 2.06 (m, 1H); ESMS m / e: 220.9 (M + H) ⁺
[2430] 3-Chloropropyl 3-fluorophenyl sulfide: Prepared by Procedure R and Scheme Z using 3-fluorobenzenethiol and 1-bromo-3-chloropropane.
[2431] 3-Chloropropyl 2-fluorophenyl sulfide: Prepared by Procedure R and Scheme Z using 2-fluorobenzenethiol and 1-bromo-3-chloropropane.
[2432] 1-bromo-2-[(3-chloropropyl) sulfinyl] benzene: procedure S and scheme using 1-bromo-2-[(3-chloropropyl) sulfanyl] benzene and 1 eq m-CPBA Manufactured by AA: ESMS m / e: 282.8 (M + H) ⁺
[2433] 1-chloro-2-[(3-chloropropyl) sulfanyl] benzene: Prepared by Procedure R and Scheme Z using 2-chlorobenzenethiol and 1-bromo-3-chloropropane.
[2434] 1-Chloro-3-[(3-chloropropyl) sulfanyl] benzene: Prepared by Procedure R and Scheme Z using 3-chlorobenzenethiol and 1-bromo-3-chloropropane.
[2435] 1-Chloro-4-[(3-chloropropyl) sulfanyl] benzene: Prepared by Procedure R and Scheme Z using 4-chlorobenzenethiol and 1-bromo-3-chloropropane.
[2436] 1-bromo-3-[(3-chloropropyl) sulfanyl] benzene: Prepared by Procedure R and Scheme Z using 3-bromobenzenethiol and 1-bromo-3-chloropropane.
[2437] 1-bromo-4-[(3-chloropropyl) sulfanyl] benzene: Prepared by Procedure R and Scheme Z using 4-bromobenzenethiol and 1-bromo-3-chloropropane.
[2438] 3-Chloropropyl 3,4-dimethylphenyl sulfide: Prepared by Procedure R and Scheme Z using 3,4-dimethylbenzenethiol and 1-bromo-3-chloropropane.
[2439] Example 590
[2440] N- [3- (1- {3-[(4-fluorophenyl) sulfinyl] propyl} -4-piperidinyl) phenyl] -2-methylpropanamide: 3-chloropropyl 4-fluorophenyl sulfoxide Prepared by Procedure G and Scheme B1 using seed and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ¹ H NMR (400 MHz, CDCl ₃ ) δ7.64 (m, 2H), 7.53 (s, 1H), 7.24 (m, 5H), 6.94 (d, 1H, J = 7.7 Hz), 2.89 (m, 4H), 2.45 (m, 4H) 1.99 (m, 3H), 1.77 (m, 5H), 1. 24 (d, 6H, J = 6.8 Hz); Analytical calcd. For C ₂₄ H ₃₁ FN ₂ 0 ₂ S + O.6EtOAc: C, 65.5; H, 7. 45; N, 5.79. Found: C, 65.4; H, 7. 30; N, 5.73; ESMS m / e: 431.1 (M + H) ⁺
[2441] Example 591
[2442] N- [3- (1- {3-[(2-bromophenyl) sulfinyl] propyl} -4-piperidinyl) phenyl] -2-methylpropanamide: 1-bromo-2-[(3 Prepared by Procedure G and Scheme B1 using -chloropropyl) sulfinyl] benzene and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: C ₂₄ H ₃₁ BrN ₂ 0 ₂ S Analytical calculation of + 0.3CHCl ₃ : ESMS m / e: 491.0 (M + H) ⁺
[2443] Example 592
[2444] N- {3- [1-((3S) -3-{[(3,4-difluorophenyl) sulfonyl] amino} -3-phenylpropyl) -4-piperidinyl] phenyl} -2- Methylpropanamide: 3,4-difluorobenzenesulfonyl chloride and N- (3-1-[(3S) -3-amino-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methyl Prepared by Procedure Q1 and Scheme AC using propanamide: ESMS m / e: 556.2 (M + H) ⁺
[2445] Example 593
[2446] 3-chloro-N-((1S) -3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} -1-phenylpropyl) -2-thiophenecarboxamide: 3 Using chloro-2-thiophencarbonyl chloride and N- (3- {1-[(3S) -3-amino-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide Manufactured by Procedure Q1 and Scheme AC by: ESMS m / e: 524.2 (M + H) ⁺
[2447] Example 594
[2448] N- (3- {1-[(3S) -3-({[5- (dimethylamino) -1-naphthyl] sulfonyl} amino) -3-phenylpropyl] -4-piperidinyl} phenyl) 2-methylpropanamide: 5- (dimethylamino) -1-naphthalenesulfonyl chloride and N- (3- (1-[(3S) -3-amino-3-phenylpropyl] -4-piperidinyl} Prepared by Procedure Q1 and Scheme AC using Phenyl) -2-methylpropanamide: ESMS m / e: 613.3 (M + H) ⁺
[2449] Example 595
[2450] 2-methyl-N- {3- [1-((3S) -3-{[(4-methylphenyl) sulfonyl] amino} -3-phenylpropyl) -4-piperidinyl] phenyl} propanamide: 4 Procedure Q1 and using methylbenzenesulfonyl chloride and N- (3- {1-[(3S) -3-amino-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide Manufactured by scheme AC: ESMS m / e: 534.2 (M + H) ⁺
[2451] Example 596
[2452] N- {3- [1-((3S) -3-{[(3,5-dichloro-2-hydroxyphenyl) sulfonyl] amino} -3-phenylpropyl) -4-piperidinyl] phenyl} 2-methylpropanamide: 3,5-dichloro-2-hydroxybenzenesulfonyl chloride and N- (3- {1-[(3S) -3-amino-3-phenylpropyl] -4-piperidinyl } Produced by Procedure Q1 and Scheme AC using phenyl) -2-methylpropanamide: ESMS m / e: 605.4 (M + H) ⁺
[2453] Example 597
[2454] 2-methyl-N- [3- (1-{(3S) -3-[(methylsulfonyl) amino] -3-phenylpropyl} -4-piperidinyl) phenyl] propanamide: methanesulfonyl chloride and Prepared by Procedure Q1 and Scheme AC using N- (3-1-[(3S) -3-amino-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: ESMS m / e: 458.6 (M + H) ⁺
[2455] Example 598
[2456] N- {3- [1-((3S) -3-{[(4-fluorophenyl) sulfonyl] amino} -3-phenylpropyl) -4-piperidinyl] phenyl) -2-methylpropanamide Procedure using 4-fluorobenzenesulfonyl chloride and N- (3- {1-[(3S) -3amino-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide Manufactured by Q1 and schematic AC: ESMS m / e: 538.1 (M + H) ⁺
[2457] Example 599
[2458] N- {3- [1-((3S) -3-{[(4-TERT-butylphenyl) sulfonyl] amino} -3-phenylpropyl) -4-piperidinyl] phenyl} -2-methylpropane Amides: 4-tert-butylbenzenesulfonyl chloride and N- (3- {1-[(3S) -3-amino-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide Manufactured by Procedure Q1 and Scheme AC using: ESMS m / e: 576.2 (M + H) ⁺
[2459] Example 600
[2460] N- {3- {1-((3S) -3-{[(2,5-dichlorophenyl) sulfonyl] amino} -3-phenylpropyl) -4-piperidinyl] phenyl} -2-methylpropane Amides: 2,5-dichlorobenzenesulfonyl chloride and N- (3- {1-[(3S) -3-amino-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide Prepared by Procedure Q1 and Scheme AC using: ESMS m / e: 588.0 (M + H) ⁺
[2461] Example 601
[2462] 2-methyl-N- [3- (1-{(3S) -3-phenyl-3-[(propylsulfonyl) amino] propyl} -4-piperidinyl) phenyl] propanamide: 1-propanesulfonyl Prepared by Procedure Q1 and Scheme AC using chloride and N (3- (1-[(3S) -3-amino-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide. ESMS m / e: 486.2 (M + H) ⁺
[2463] Example 602
[2464] N- {3- [1-((3S) -3-{[(3,5-dimethyl-4-isoxazolyl) sulfonyl] amino) -3-phenylpropyl) -4-piperidinyl] phenyl} 2-methylpropanamide: 3,5-dimethyl-4-isoxazolsulfonyl chloride and N- (3- {1-[(3S) -3-amino-3-phenylpropyl] -4-piperidinyl} Prepared by Procedure Q1 and Scheme AC using phenyl) -2-methylpropanamide: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.53 (s, 2H), 7.3-7.1 (m, 5H), 7.05 ( t, 2H, J = 6.5 Hz), 6.81 (d, 1H, J = 7.1 Hz), 4.65 (dd, 1H, J = 6.3, 2.2 Hz), 3.11 (t, 2H, J = 7.2 Hz), 2.4 ( m, 4H), 2.2 (s, 3H), 2.05 (m, 2H), 2.01 (s, 3H), 2.0-1.8 (m, 7H), 1.21 (d, 6H, J = 7.1 Hz); ESMS m / e: 539.5 (M + H) ⁺
[2465] Example 603
[2466] Methyl 3-{[(3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} propyl) amino] sulfonyl} -2-thiophenecarboxylate: methyl 3- (chloro Procedure Q1 and Scheme AC using Sulfonyl) -2-thiophenecarboxylate and N- (3- [1- (3-aminopropyl) -4-piperidinyl] phenyl} -2-methylpropanamide Prepared by: C ₂₄ H ₃₃ N ₃ 0 ₅ S.HCl calcd: C, 6.00; H, 5.30; N, 7.72 Found: C 52.9; H, 6.04; N, 7.59; ESMS m / e: 508.2 ( M + H) ⁺
[2467] Example 604
[2468] 2-methyl-N- {3- [1-((3S) -3-{[(4-phenoxynilino) carbonyl] amino} -3-phenylpropyl) -4-piperidinyl] phenyl} propane Amides: 1-isocyanato-4-phenoxybenzene and N- (3- {1-[(3S) -3-amino-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methyl Prepared by Procedure P and Scheme AB using propanamide: ESMS m / e: 591.3 (M + H) ⁺
[2469] Piperidinyl] phenyl} -2-methylpropanamide: 3,5-dimethyl-4-isoxazolesulfonyl chloride and N- (3- (1-[(3S) -3-amino-3-phenylpropyl]- Prepared by Procedure Q1 and Scheme AC using 4-piperidinyl} phenyl) -2-methylpropanamide: ¹ H NMR (400 MHz, CDCl ₃ ) δ7.53 (s, 2H), 7.3-7.1 (m , 5H), 7.05 (t, 2H, J = 6.5 Hz), 6.81 (d, 1H, J = 7.1 Hz), 4.65 (dd, 1H, J = 6.3, 2.2 Hz), 3.11 (t, 2H, J = 7.2 Hz), 2.4 (m, 4H), 2.2 (s, 3H), 2.05 (m, 2H), 2.01 (s, 3H), 2.0-1.8 (m, 7H), 1.21 (d, 6H, J = 7.1 Hz); ESMS m / e: 539.5 (M + H) ⁺
[2470] Example 603
[2471] Methyl 3-{[(3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} propyl) amino] sulfonyl} -2-thiophenecarboxylate: methyl 3- (chloro Sulfonyl) -2-thiophenecarboxylate and N- {3- [1- (3-aminopropyl) -4-piperidinyl] phenyl} -2-methylpropanamide were used in Procedure Q1 and Scheme AC. Prepared by: C ₂₄ H ₃₃ N ₃ 0 ₅ Analytical calcd. Of S.HCl: C, 6.00; H, 5. 30; N, 7.72. Found: C, 52.9; H, 6.04; N, 7.59; ESMS m / e: 508.2 (M + H) ⁺
[2472] Example 604
[2473] 2-methyl-N- {3- [1-((3S) -3-{[(4-phenoxynilino) carbonyl] amino} -3-phenylpropyl) -4-piperidinyl] phenyl} propane Amides: 1-isocyanato-4-phenoxybenzene and N- (3- {1-[(3S) -3-amino-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methyl Prepared by Procedure P and Scheme AB using propanamide: ESMS m / e: 591.3 (M + H) ⁺
[2474] Example 605
[2475] N- [3- (1-{(3S) -3-[(anilinocarbonyl) amino] -3-phenylpropyl} -4-piperidinyl) phenyl] -2-methylpropanamide: isocyanato Prepared by Procedure P and Scheme AB using benzene and N- (3- {1-[(3S) -3-amino-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide ESMS M / e: 499.2 (M + H) ⁺
[2476] Example 606
[2477] N- {3- [1-((3S) -3-{[(TERT-butylamino) carbothioyl] amino} -3-phenylpropyl) -4-piperidinyl] phenyl} -2-methylpropanamide : 2-isothiocyanato-2-methylpropane and N- (3- {1-[(3s) -3-amino-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropane Prepared by Procedure P and Scheme AB using amides: ESMS m / e: 495.1 (M + H) ⁺
[2478] Example 607
[2479] N- {3- [1-((3S) -3-{[(2-fluoroanilino) carbonyl] amino} -3-phenylpropyl) -4-piperidinyl] phenyl) -2-methylpropane Amides: 1-fluoro-2-isocyanatobenzene and N- (3- {1-[(3S) -3-amino-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methyl Prepared by Procedure P and Scheme AB using propanamide: ESMS m / e: 517.0 (M + H) ⁺
[2480] Example 608
[2481] 2-methyl-N- [3- (1-{(3S) -3-phenyl-3-[(2-toluidinocarbothionyl) amino] propyl} -4-piperidinyl) phenyl] propanamide: 1-isothiocyanato-2-methylbenzene and N- (3- {1-[(3S) -3-amino-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide Prepared by Procedure P and Scheme AB using: ESMS m / e: 529.1 (M + H) ⁺
[2482] Example 609
[2483] N- {3- [1-((3S) -3-{[(benzylamino) carbonyl] amino} -3-phenylpropyl) -4-piperidinyl] phenyl} -2-methylpropanamide: phenylpropyl ] -4-piperidinyl} phenyl) -2-methylpropanamide: ¹ H NMR (400 MHz, CDCl ₃ ) δ8.44 (s, 1H), 7.67 (d, 1H, J = 7.9 Hz), 7.31- 7.13 (m, 13H), 6.38 (s, 1H), 6.80 (d, 1H, J = 7.9 Hz), 5.54 (m, 1H), 4.81 (m, 1H), 4.41 (dd, 1H, J = 14.8, 6.2 Hz), 4.29 (dd, 1H, J = 14.9, 5.4 Hz), 2.99 (d, 1H, J = 11.2 Hz), 2.87 (d, 1H, J = 11.2 Hz), 2.67 (q, 1H, J = 6.2 Hz), 2.3 (m, 3H), 2.0-1.5 (m, 7H), 1.23 (d, 6H, J = 6.7 Hz); ESMS m / e: 513.2 (M + H) ⁺
[2484] Example 610
[2485] 2-methyl-N- {3- [1-((3S) -3-{[(2-nitroanilino) carbonyl] amino} -3-phenylpropyl) -4-piperidinyl] phenyl} propanamide : 1-isocyanato-2-nitrobenzene and N- (3- {1-[(3S) -3-amino-3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide Prepared by Procedure P and Scheme AB using: ESMS m / e: 543.6 (M + H) ⁺
[2486] Example 611
[2487] N- {3- [1-((3S) -3-{[(3,4-dichloroanilino) carbonyl] amino} -3-phenylpropyl) -4-piperidinyl] phenyl} -2-methyl Propanamide: 1,2-dichloro-4-isocyanatobenzene and N- (3- {1-[(3S) -3-amino-3-phenylpropyl] -4-piperidinyl} phenyl) -2 Prepared by Procedure P and Scheme AB using methylpropanamide: ESMS m / e: 567.1 (M + H) ⁺
[2488] Example 612
[2489] 2-methyl-N- (3- {1-[(3S) -3-({[2- (methylsulfanyl) anilino] carbonyl} amino) -3-phenylpropyl] -4-piperidinyl} Phenyl) propanamide: 1-isocyanato-2- (methylsulfanyl) benzene and N- (3- (1-[(3S) -3-amino-3-phenylpropyl} -4-piperidinyl} Prepared by Procedure P and Scheme AB using phenyl) -2-methylpropanamide: ESMS m / e: 545.0 (M + H) ⁺
[2490] Example 613
[2491] N-3- [1- (3-{[(4-fluoroanilino) carbonyl] amino} propyl) -4-piperidinyl] phenyl} -2-methylpropanamide: 1-fluoro-4- Isocyanatobenzene and N- {3- [1- (3-aminopropyl) -4-piperidinyl] phenyl} -2-methylpropanamide: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.45 ( q, 2H, J = 4.7 Hz), 7.23 (m, 4H), 7.05 (t, 4H, J = 7.8 Hz), 6.75 (m, 1H), 4.05 (m, 1H), 3.19 (s, 1H), 2.71 (m, 1H), 2.53 (m, 1H), 2.25 (m, 3H), 1.8 (m, 9H), 1.25 (d, 6H, J = 6.4 Hz); ESMS m / e: 441.1 (M + H) ⁺
[2492] Example 614
[2493] N- {3- [1- (3- (3,4-Dichloroanilino) carbonyl] amino} propyl) -4-piperidinyl] phenyl} -2-methylpropanamide: 1,2-dichloro-4 Prepared by Procedure P and Scheme AB using isocyanatobenzene and N- {3- [1- (3-aminopropyl) -4-piperidinyl] phenyl] -2-methylpropanamide: ESMS m / e: 493.2 (M + H) ⁺
[2494] Example 615
[2495] 2-methyl-N- [3- (1- {3-[(2-toluidinocarbothionyl) amino] propyl} -4-piperidinyl) phenyl] propanamide: 1-isothiocyanato- Prepared by Procedure P and Scheme AB using 2-methylbenzene and N- {3- [1- (3-aminopropyl) -4-piperidinyl} phenyl] -2-methylpropanamide: ESMS m / e : 453.2 (M + H) ⁺
[2496] Example 616
[2497] N- {3- [1- (3-{[(benzylamino) carbonyl] amino} propyl) -4-piperidinyl] phenyl} -2-methylpropanamide: (isocyanatomethyl) benzene and N Prepared by Procedure P and Scheme AB using-{3- [1- (3-aminopropyl) -4-piperidinyl] phenyl} -2-methylpropanamide: ESMS m / e: 437.2 (M + H ) ⁺
[2498] Example 617
[2499] N- {3- [1- (3-{[(4-ethoxyanilino) carbonyl] amino} propyl) -4-piperidinyl] phenyl} -2-methylpropanamide: 1-ethoxy-4 Prepared by Procedure P and Scheme AB using isocyanatobenzene and N- {3- [1- (3-aminopropyl) -4-piperidinyl] phenyl} -2-methylpropanamide: ESMS m / e: 467.2 (M + H) ⁺
[2500] Example 618
[2501] N- [3- (1- {3-[(anilinocarbonyl) amino] propyl} -4-piperidinyl) phenyl] -2-methylpropanamide: isocyanatobenzene and N- {3- [ Prepared by Procedure P and Scheme AB using 1- (3-aminopropyl) -4-piperidinyl] phenyl} -2-methylpropanamide: ESMS m / e: 422.9 (M + H) ⁺
[2502] Example 619
[2503] 2-methyl-N- (3- {1- [3-({[2- (methylsulfanyl) anilino] carbonyl} amino) propyl] -4-piperidinyl} phenyl) propanamide: 1-iso Procedure P and Scheme AB using cyanato-2- (methylsulfanyl) benzene and N- {3- [1- (3-aminopropyl) -4-piperidinyl] phenyl} -2-methylpropanamide Manufactured by: ESMS m / e: 469.1 (M + H) ⁺
[2504] Example 620
[2505] N- {3- [1- (3-{[(TERT-butylamino) carbothionyl] amino} propyl) -4-piperidinyl] phenyl} -2-methylpropanamide: 2-isothiocyanato Prepared by Procedure P and Scheme AB using -2-methylpropane and N- {3- [1- (3-aminopropyl) -4-piperidinyl] phenyl} -2-methylpropanamide: ESMS m / e: 419.0 (M + H) ⁺
[2506] Example 621
[2507] 2-methyl-N- {3- [1- (3-{[(4-phenoxyanilino) carbonyl] amino} propyl) -4-piperidinyl] phenyl) propanamide: 1-isocyanato Prepared by Procedure P and Scheme AB using 4-phenoxybenzene and N- {3- [1- (3-aminopropyl) -4-piperidinyl] phenyl} -2-methylpropanamide: ESMS m / e: 515.5 (M + H) ⁺
[2508] Example 622
[2509] N- (3- {4- [3- (acetylamino) phenyl] -1-piperidinyl} propyl) -4- (2,4-difluorophenyl) -2-methyl-6-oxo-1, 4,5,6-tetrahydro-3-pyridinecarboxamide: N- {3- [1- (3-aminopropyl) -4-piperidinyl] phenyl} acetamide and 4- (2,4-di Prepared by Procedure AC and Scheme AM using Fluorophenyl) -2-methyl-6-oxo-1,4,5,6-tetrahydro-3-pyridinecarboxylic acid: ESMS m / e: 525.2 (M + H) ⁺
[2510] Example 623
[2511] N- (3- {4- [3- (acetylamino) phenyl] -1-piperidinyl} propyl) -4- (3,4-difluorophenyl) -2-methyl-6-oxo-1, 4,5,6-tetrahydro-3-pyridinecarboxamide: N- {3- [1- (3-aminopropyl) -4-piperidinyl] phenyl} acetamide and 4- (3,4-di Prepared by Procedure AC and Scheme AM using Fluorophenyl) -2-methyl-6-oxo-1,4,5,6-tetrahydro-3-pyridinecarboxylic acid: ESMS m / e: 525.2 (M + H) ⁺
[2512] Example 624
[2513] N- (6- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} hexyl) -1- (4-nitrophenyl) -5- (trifluoromethyl) -1H-pyra Sol-4-carboxamides: N- {3- [1- (6-aminohexyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 1- (4-nitrophenyl) -5- ( Prepared by Procedure Q1 (THF) and Scheme AT using trifluoromethyl) -1H-pyrazole-4-carbonyl chloride: ESMS m / e: 629.2 (M + H) ⁺
[2514] Example 625
[2515] N- [3- (1- {6-[(diphenylacetyl) amino] hexyl} -4-piperidinyl) phenyl] -2-methylpropanamide: N- {3- [1- (6-aminohexyl ) -4-piperidinyl] phenyl} -2-methylpropanamide and diphenylacetyl chloride prepared by procedure Q1 (THF) and scheme AT: ESMS m / e: 540.3 (M + H) ⁺
[2516] Example 626
[2517] 5- (3,5-dichlorophenoxy) -N- (6- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} hexyl) -2-furamide: N- {3 Procedure Q1 (THF) using-[1- (6-aminohexyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 5- (3,5-dichlorophenoxy) -2-furoyl chloride ) And by the scheme AT: ESMS m / e: 600.2 (M + H) ⁺
[2518] Example 627
[2519] N- (6- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} hexyl) -2-phenoxynicotinamide: N- {3- [1- (6-aminohexyl) Prepared by procedure Q1 (THF) and scheme AT using -4-piperidinyl] phenyl} -2-methylpropanamide and 2-phenoxynicotinoyl chloride: ESMS m / e: 543.3 (M + H) ⁺
[2520] Example 628
[2521] N- (6- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} hexyl) -2-naphtamide: N- {3- [1- (6-aminohexyl) -4 Prepared by Procedure Q1 (THF) and Scheme AT using -piperidinyl] phenyl} -2-methylpropanamide and 2-naphthoyl chloride: ESMS m / e: 500.3 (M + H) ⁺
[2522] Example 629
[2523] 1-benzyl-3-TERT-butyl-N- (6- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} hexyl) -1H-pyrazole-5-carboxamide: N- {3- [1- (6-aminohexyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 1-benzyl-3-tert-butyl-1H-pyrazole-5-carbonyl chloride Prepared by procedure Q1 (THF) and scheme AT using: ESMS m / e: 586.3 (M + H) ⁺
[2524] Example 630
[2525] 3-Chloro-N- (6- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} hexyl) -4- (isopropylsulfonyl) -2-thiophenecarboxamide: N- {3- [1- (6-aminohexyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 3-chloro-4- (isopropylsulfonyl) -2-thiophencarbonyl chloride Prepared by procedure Q1 (THF) and scheme AT using: ESMS m / e: 596.2 (M + H) ⁺
[2526] Example 631
[2527] N- [3- (1- {6-[(anilinocarbonyl) amino] hexyl} -4-piperidinyl) phenyl] -2-methylpropanamide: N- {3- [1- (6-amino Prepared by procedure Q1 (THF) and scheme AT using hexyl) -4-piperidinyl] phenyl} -2-methylpropanamide and phenyl isocyanate: ESMS m / e: 465.2 (M + H) ⁺
[2528] Example 632
[2529] N- {3- [1- (6-{[(2,4-dichloroanilino) carbonyl] amino} hexyl) -4-piperidinyl] phenyl} -2-methylpropanamide: N- {3- Prepared by procedure Q1 (THF) and scheme AT using [1- (6-aminohexyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 2,4-dichlorophenyl isocyanate: ESMS m / e: 533.2 (M + H) ⁺
[2530] Example 633
[2531] N- (6- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} hexyl) -1-phenyl-5-propyl-1H-pyrazole-4-carboxamide: N- Procedure using {3- [1- (6-aminohexyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 1-phenyl-5-propyl-1H-pyrazole-4-carbonyl chloride Manufactured by Q1 (THF) and scheme AT: ESMS m / e: 558.3 (M + H) ⁺
[2532] Example 634
[2533] 2-methyl-N- {3- [1- (6-{[(1-naphthylamino) carbonyl] amino} hexyl) -4-piperidinyl] phenyl} propanamide: N- {3- [1 Prepared by Procedure Q1 (THF) and Scheme AT using-(6-aminohexyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 1-naphthyl isocyanate: ESMS m / e: 515.3 ( M + H) ⁺
[2534] Example 635
[2535] N- {3- [1- (6-{[([1,1'-biphenyl] -4-ylamino) carbonyl] amino} hexyl) -4-piperidinyl] phenyl} -2-methylpropane Amides: by procedure Q1 (THF) and Scheme AT using N- {3- [1- (6-aminohexyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 4-biphenyl isocyanate Preparation: ESMS m / e: 541.3 (M + H) ⁺
[2536] Example 636
[2537] 2-methyl-N- {3- [1- (6-{[(2-naphthylamino) carbonyl] amino} hexyl) -4-piperidinyl] phenyl} propanamide: N- {3- [1 Prepared by Procedure Q1 (THF) and Scheme AT using-(6-aminohexyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 2-naphthyl isocyanate: ESMS m / e: 515.3 ( M + H) ⁺
[2538] Example 637
[2539] N- {3- [1- (3-{[(3,4-dimethoxyphenyl) sulfonyl] amino} propyl) -4-piperidinyl] phenyl} -2-methylpropanamide: N- {3- Prepared by Procedure Q1 (THF) and Scheme AT using [1- (3-aminopropyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 3,4-dimethoxybenzenesulfonyl chloride: ESMS m / e: 504.2 (M + H) ⁺
[2540] Example 638
[2541] N- (3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} propyl) -5-methyl-3-phenyl-4-isoxazolecarboxamide: N- {3- Procedure Q1 (THF) and Scheme Using [1- (3-Aminopropyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 5-methyl-3-phenyl-4-isoxazolcarbonyl chloride Manufactured by AT: ESMS m / e: 489.3 (M + H) ⁺
[2542] Example 639
[2543] N- {3- [1- (3-{[(4-fluorophenyl) acetyl] amino} propyl) -4-piperidinyl] phenyl} -2-methylpropanamide: N- {3- [1- Prepared by procedure Q1 (THF) and scheme AT using (3-aminopropyl) -4-piperidinyl] phenyl} -2-methylpropanamide and (4-fluorophenyl) acetyl chloride: ESMS m / e : 440.3 (M + H) ⁺
[2544] Example 640
[2545] N- {3- [1- (3-{[(4-chloro-3-nitrophenyl) sulfonyl] amino} propyl) -4-piperidinyl] phenyl} -2-methylpropanamide: N- {3 -[1- (3-aminopropyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 4-chloro-3-nitrobenzenesulfonyl chloride by procedure Q1 (THF) and scheme AT Preparation: ESMS m / e: 523.1 (M + H) ⁺
[2546] Example 641
[2547] 2- (4-chlorophenoxy) -N- (3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} propyl) nicotinamide: N- {3- [1- ( Prepared by Procedure Q1 (THF) and Scheme AT using 3-aminopropyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 2- (4-chlorophenoxy) nicotinoyl chloride: ESMS m / e: 535.2 (M + H) ⁺
[2548] Example 642
[2549] 5- (3,5-Dichlorophenoxy) -N- (3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} propyl) -2-furamide: N- {3 Procedure Q1 (THF) using-[1- (3-aminopropyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 5- (3,5-dichlorophenoxy) -2-furoyl chloride ) And by the scheme AT: ESMS m / e: 558.2 (M + H) ⁺
[2550] Example 643
[2551] N- {3- [1- (3-{[(2-fluorophenyl) sulfonyl] amino} propyl) -4-piperidinyl] phenyl} -2-methylpropanamide: N- {3- [1 Prepared by Procedure Q1 (THF) and Scheme AT using-(3-aminopropyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 2-fluorobenzenesulfonyl chloride: ESMS m / e : 462.2 (M + H) ⁺
[2552] Example 644
[2553] N- {3- [1- (3-([(3,5-dimethyl-4-isoxazolyl) sulfonyl] amino} propyl) -4-piperidinyl] phenyl} -2-methylpropanamide: N Procedure Q1 (THF) using-{3- [1- (3-aminopropyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 3,5-dimethyl-4-isoxazolesulfonyl chloride And prepared by scheme AT: ESMS m / e: 463.2 (M + H) ⁺
[2554] Example 645
[2555] N- {3- [1- (3-{[(4-TERT-butylphenyl) sulfonyl] amino} propyl) -4-piperidinyl] phenyl} -2-methylpropanamide: N- {3- [ Prepared by Procedure Q1 (THF) and Scheme AT using 1- (3-aminopropyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 4-tert-butylbenzenesulfonyl chloride: ESMS m / e: 500.3 (M + H) ⁺
[2556] Example 646
[2557] N- {3- [1- (6-aminohexyl) -4-piperidinyl] phenyl} -2-methylpropanamide: N- (3- {1- [6- (1,3-dioxo-1 Prepared by Procedure AE and Scheme Y using, 3-dihydro-2H-isoindol-2-yl) hexyl] -4-piperidinyl} phenyl) -2-methylpropanamide and hydrazine hydrate: ESMS m / e: 346.2 (M + H) ⁺
[2558] Example 647
[2559] N- {3- [1- (2-{[([1,1'-biphenyl] -4-ylamino) carbonyl] amino} ethyl) -4-piperidinyl] phenyl) -2-methylpropane Amide: by procedure Q1 (THF) and Scheme AT using N- {3- [1- (2-aminoethyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 4-biphenyl isocyanate Preparation: ESMS m / e: 485.2 (M + H) ⁺
[2560] Example 648
[2561] 5- (3,5-dichlorophenoxy) -N- (2- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} ethyl) -3-furamide: N- {3 Procedure Q1 (THF) using-[1- (2-aminoethyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 5- (3,5-dichlorophenoxy) -3-furoyl chloride ) And by the scheme AT: ESMS m / e: 544.1 (M + H) ⁺
[2562] Example 649
[2563] N- [3- (1- {2-[(diphenylacetyl) amino] ethyl} -4-piperidinyl) phenyl] -2-methylpropanamide: N- {3- [1- (2-aminoethyl ) -4-piperidinyl] phenyl} -2-methylpropanamide and diphenylacetyl chloride prepared by procedure Q1 (THF) and scheme AT: ESMS m / e: 484.2 (M + H) ⁺
[2564] Example 650
[2565] N- (2- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} ethyl) -2-naphtamide: N- {3- [1- (2-aminoethyl) -4 -Prepared by procedure Q1 (THF) and scheme AT using piperidinyl] phenyl} -2-methylpropanamide and 2-naphthoyl chloride: ESMS m / e: 444.2 (M + H) ⁺
[2566] Example 651
[2567] 3- (2,6-dichlorophenyl) -N- (4- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} butyl) -5-methyl-4-isoxazolecarbox Amides: N- {3- [1- (4-aminobutyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 3- (2,6-dichlorophenyl) -5-methyl-4-iso Prepared by procedure Q1 (THF) and scheme AT using sazolcarbonyl chloride: ESMS m / e: 571.2 (M + H) ⁺
[2568] Example 652
[2569] 3- (2,6-dichlorophenyl) -N- (5- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} pentyl) -5-methyl-4-isoxazolecarbox Amides: N- {3- [1- (5-aminopentyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 3- (2,6-dichlorophenyl) -5-methyl-4-iso Prepared by procedure Q1 (THF) and scheme AT using sazolcarbonyl chloride: ESMS m / e: 585.2 (M + H) ⁺
[2570] Example 653
[2571] N- [3- (1- {4-[(diphenylacetyl) amino] butyl} -4-piperidinyl) phenyl] -2-methylpropanamide: N- {3- [1- (4-aminobutyl Prepared by Procedure Q2 (THF / DCM, 1: 3) and Scheme AT using) -4-piperidinyl] phenyl} -2-methylpropanamide and diphenylacetyl chloride: ESMS m / e: 512.0 (M + H) ⁺
[2572] Example 654
[2573] N- [3- (1- {5-[(diphenylacetyl) amino] pentyl} -4-piperidinyl) phenyl] -2-methylpropanamide: N- {3- [1- (5-aminopentyl Prepared by Procedure Q2 (THF / DCM, 1: 3) and Scheme AT using) -4-piperidinyl] phenyl} -2-methylpropanamide and diphenylacetyl chloride: ESMS m / e: 526.0 (M + H) ⁺
[2574] Example 655
[2575] 3,5-dichloro-N- (4- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} butyl) benzamide: N- {3- [1- (4-aminobutyl Prepared by Procedure Q2 (THF / DCM, 1: 3) and Scheme AT using) -4-piperidinyl] phenyl} -2-methylpropanamide and 3,5-dichlorobenzoyl chloride: ESMS m / e: 490.0 (M + H) ⁺
[2576] Example 656
[2577] 5- (3,5-dichlorophenoxy) -N- (4- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} butyl) -2-furamide: N- {3 Procedure Q2 (THF) using-[1- (4-aminobutyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 5- (3,5-dichlorophenoxy) -2-furoyl chloride / DCM, 1: 3) and prepared by the scheme AT: ESMS m / e: 572.0 (M + H) ⁺
[2578] Example 657
[2579] 3-Chloro-N- (4- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} butyl) benzamide: N- {3- [1- (4-aminobutyl)- Prepared by procedure Q2 (THF / DCM, 1: 3) and scheme AT using 4-piperidinyl] phenyl} -2-methylpropanamide and 3-chlorobenzoyl chloride: ESMS m / e: 456.0 (M + H) ⁺
[2580] Example 658
[2581] 3,4-difluoro-N- (4- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} butyl) benzamide: N- {3- [1- (4- Prepared by Procedure Q2 (THF / DCM, 1: 3) and Scheme AT using aminobutyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 3,4-difluorobenzoyl chloride: ESMS m / e: 458.0 (M + H) ⁺
[2582] Example 659
[2583] N- {3- [1- (4-{[(3,5-dichloroanilino) carbonyl] amino} butyl) -4-piperidinyl] phenyl} -2-methylpropanamide: N- (3- Procedure Q2 (THF / DCM, 1: 3) using {1- [4- (formylamino) butyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 3,5-dichlorophenyl isocyanate And prepared by scheme AT: ESMS m / e: 505.0 (M + H) ⁺
[2584] Example 660
[2585] N- {3- [1- (4-{[([1,1'-biphenyl] -4-ylamino) carbonyl] amino} butyl) -4-piperidinyl] phenyl} -2-methylpropane Amides: Procedure Q2 (THF / DCM, 1: 3) using N- {3- [1- (4-aminobutyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 4-biphenyl isocyanate ) And by the scheme AT: ESMS m / e: 513.0 (M + H) ⁺
[2586] Example 661
[2587] 2-methyl-N- (3- {1- [5- (4-nitrophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) propanamide: 5-chloro-1- (4-nitrophenyl Prepared by Procedure K and Scheme B1 (K ₂ CO ₃ ) using 1--1-pentanone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 452.2 (M + H) ⁺
[2588] Example 662
[2589] N- (3- {1- [5- (4-fluorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 5-chloro-1- (4-fluoro Prepared by Procedure K and Scheme B1 (K ₂ CO ₃ ) using rophenyl) -1-pentanone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 425.2 (M + H) ⁺
[2590] Example 663
[2591] 2-methyl-N- [3- (1- {5-oxo-5- [2- (trifluoromethyl) phenyl] pentyl} -4-piperidinyl) phenyl] propanamide: 5-chloro-1- Procedure K and Scheme B1 (K ₂ CO ₃ ) using [2- (trifluoromethyl) phenyl] -1-pentanone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide Manufactured by: ESMS m / e: 475.2 (M + H) ⁺
[2592] Example 664
[2593] N- (3- {1- [5- (3-bromophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1- (3-bromophenyl)- Prepared by Procedure K and Scheme B1 (K ₂ CO ₃ ) using 5-chloro-1-pentanone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 485.1 (M + H) ⁺
[2594] Example 665
[2595] 2-methyl-N- (3- {1- [5- (3-nitrophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) propanamide: 5-chloro-1- (3-nitrophenyl Prepared by Procedure K and Scheme B1 (K ₂ CO ₃ ) using 1--1-pentanone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 452.2 (M + H) ⁺
[2596] Example 666
[2597] N- (3- {1- [5- (3-chlorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1- (3-chlorophenyl) -5- Prepared by Procedure K and Scheme B1 (K ₂ CO ₃ ) using chloro-1-pentanone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 441.1 (M + H) ⁺
[2598] Example 667
[2599] N- (3- {1- [5- (4-bromophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1- (4-bromophenyl)- Prepared by Procedure K and Scheme B1 (K ₂ CO ₃ ) using 5-chloro-1-pentanone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 485.1 (M + H) ⁺
[2600] Example 668
[2601] N- (3- {1- [5- (2-iodophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1- (2-iodophenyl)- Prepared by Procedure K and Scheme B1 (K ₂ CO ₃ ) using 5-chloro-1-pentanone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 533.0 (M + H) ⁺
[2602] Example 669
[2603] N- (3- {1- [5- (3-fluorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1- (3-fluorophenyl)- Prepared by Procedure K and Scheme B1 (K ₂ CO ₃ ) using 5-chloro-1-pentanone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 425.2 (M + H) ⁺
[2604] Example 670
[2605] 2-methyl-N- [3- (1- {5-oxo-5- [3- (trifluoromethyl) phenyl] pentyl} -4-piperidinyl) phenyl] propanamide: 1- [3- ( Procedure K and Scheme B1 (K ₂ CO ₃ ) using trifluoromethyl) phenyl] -5-chloro-1-pentanone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide Manufactured by: ESMS m / e: 475.2 (M + H) ⁺
[2606] Example 671
[2607] N- (3- {1- [5- (2-fluorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1- (2-fluorophenyl)- Prepared by Procedure K and Scheme B1 (K ₂ CO ₃ ) using 5-chloro-1-pentanone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 425.2 (M + H) ⁺
[2608] Example 672
[2609] N- (3- {1- [5- (3-iodophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1- (3-iodophenyl)- Prepared by Procedure K and Scheme B1 (K ₂ CO ₃ ) using 5-chloro-1-pentanone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 533.0 (M + H) ⁺
[2610] Example 673
[2611] N- (3- {1- [5- (2-chlorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1- (2-chlorophenyl) -5- Prepared by Procedure K and Scheme B1 (K ₂ CO ₃ ) using chloro-1-pentanone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 441.1 (M + H) ⁺
[2612] Example 674
[2613] 2-methyl-N- [3- (1- {5-oxo-5- [4- (trifluoromethyl) phenyl] pentyl} -4-piperidinyl) phenyl] propanamide: 1- [4- ( Procedure K and Scheme B1 (K ₂ CO ₃ ) using trifluoromethyl) phenyl] -5-chloro-1-pentanone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide Manufactured by: ESMS m / e: 475.2 (M + H) ⁺
[2614] Example 675
[2615] N- (3- {1- [5- (4-chlorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1- (4-chlorophenyl) -5- Prepared by Procedure K and Scheme B1 (K ₂ CO ₃ ) using chloro-1-pentanone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 441.1 (M + H) ⁺
[2616] Example 676
[2617] N- (3- {1- [5- (4-iodophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1- (4-iodophenyl)- Prepared by Procedure K and Scheme B1 (K ₂ CO ₃ ) using 5-chloro-1-pentanone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 533 (M + H) ⁺
[2618] Example 677
[2619] N- (3- {1- [5- (2-bromophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1- (2-bromophenyl)- Prepared by Procedure K and Scheme B1 (K ₂ CO ₃ ) using 5-chloro-1-pentanone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 485.1 (M + H) ⁺
[2620] Example 678
[2621] 2- (4-chlorophenoxy) -N- (4- {4- [3- (isobutyrylamino) phenyl] 1-piperidinyl} butyl) nicotinamide: N- {3- [1- (4 -Aminobutyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 2- (4-chlorophenoxy) nicotinoyl chloride using procedure Q2 (THF / DCM, 1: 3) and Scheme AT Manufactured by: ESMS m / e: 549.0 (M + H) ⁺
[2622] Example 679
[2623] N- (4- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} butyl) -3,4-dimethoxybenzamide: N- {3- [1- (4-amino Butyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 3,4-dimethoxybenzoyl chloride prepared by procedure Q2 (THF / DCM, 1: 3) and scheme AT: ESMS m / e: 482.0 (M + H) ⁺
[2624] Example 680
[2625] 3- (2-Chlorophenyl) -N- (4- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} butyl) -5-methyl-4-isoxazolecarboxamide: N- {3- [1- (4-aminobutyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 3- (2-chlorophenyl) -5-methyl-4-isoxazolecarbonyl chloride Prepared by procedure Q2 (THF / DCM, 1: 3) and scheme AT using ESMS m / e: 537.0 (M + H) ⁺
[2626] Example 681
[2627] 3- (2-Chlorophenyl) -N- (5- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} pentyl) -5-methyl-4-isoxazolecarboxamide: N- {3- [1- (5-aminopentyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 3- (2-chlorophenyl) -5-methyl-4-isoxazolecarbonyl chloride Prepared by procedure Q2 (THF / DCM, 1: 3) and scheme AT using ESMS m / e: 551.0 (M + H) ⁺
[2628] Example 682
[2629] 2-methyl-N- {3- [1- (3- {1-methyl-2- [4- (trifluoromethyl) phenyl] -1H-indol-3-yl} propyl) -4-piperidinyl ] Phenyl} propanamide: 2-methyl-N- [3- (1- {5-oxo-5- [4- (trifluoromethyl) phenyl] pentyl} -4-piperidinyl) phenyl] propanamide and Prepared by Procedure E and Scheme M using 1-methyl-1-phenylhydrazine: ESMS m / e: 562.2 (M + H) ⁺
[2630] Example 683
[2631] 2-methyl-N- {3- [1- (3- {1-methyl-2- [4- (trifluoromethyl) phenyl] -1H-indol-3-yl} propyl) -4-piperidinyl ] Phenyl} propanamide: 2-methyl-N- [3- (1- {5-oxo-5- [4- (trifluoromethyl) phenyl] pentyl} -4-piperidinyl) phenyl] propanamide and Prepared by Procedure E and Scheme M using 4- (trifluoromethoxy) phenylhydrazine hydrochloride: ESMS m / e: 632.2 (M + H) ⁺
[2632] Example 684
[2633] 2-methyl-N- {3- [1- (3- {2- [4- (trifluoromethyl) phenyl] -1H-indol-3-yl} propyl) -4-piperidinyl] phenyl) propane Amides: 2-methyl-N- [3- (1- {5-oxo-5- [4- (trifluoromethyl) phenyl] pentyl} -4-piperidinyl) phenyl] propanamide and phenylhydrazine Prepared by procedure E and scheme M by: ESMS m / e: 548.2 (M + H) ⁺
[2634] Example 685
[2635] 2-methyl-N- {3- [1- (3- {1-phenyl-2- [4- (trifluoromethyl) phenyl] -1H-indol-3-yl} propyl) -4-piperidinyl ] Phenyl} propanamide: 2-methyl-N- [3- (1- (5-oxo-5- [4- (trifluoromethyl) phenyl] pentyl} -4-piperidinyl) phenyl] propanamide and Prepared by Procedure E and Scheme M using 1,1-diphenylhydrazine hydrochloride: ESMS m / e: 624.2 (M + H) ⁺
[2636] Example 686
[2637] 2-methyl-N- {3- [1- (3- {2- [4- (trifluoromethyl) phenyl] -1H-benzo [G] indol-3-yl} propyl) -4-piperidinyl ] Phenyl} propanamide: 2-methyl-N- [3- (1- {5-oxo-5- [4- (trifluoromethyl) phenyl] pentyl} -4-piperidinyl) phenyl] propanamide and Prepared by Procedure E and Scheme M using 1-naphthylhydrazine hydrochloride: ESMS m / e: 598.2 (M + H) ⁺
[2638] Example 687
[2639] 2-methyl-N- {3- [1- (3- {7-methyl-2- [4- (trifluoromethyl) phenyl] -1H-indol-3-yl} propyl) -4-piperidinyl ] Phenyl} propanamide: 2-methyl-N- [3- (1- {5-oxo-5- [4- (trifluoromethyl) phenyl] pentyl} -4-piperidinyl) phenyl] propanamide and Prepared by Procedure E and Scheme M using 1- (2-methylphenyl) hydrazine hydrochloride: ESMS m / e: 562.2 (M + H) ⁺
[2640] Example 688
[2641] 2-methyl-N- {3- [1- (3- {5-methyl-2- [4- (trifluoromethyl) phenyl] -1H-indol-3-yl} propyl) -4-piperidinyl ] Phenyl} propanamide: 2-methyl-N- [3- (1- {5-oxo-5- [4- (trifluoromethyl) phenyl] pentyl} -4-piperidinyl) phenyl] propanamide and Prepared by Procedure E and Scheme M using 4-methylphenylhydrazine hydrochloride: ESMS m / e: 562.2 (M + H) ⁺
[2642] Example 689
[2643] N- {3- [1- (3- {5-methoxy-2- [4- (trifluoromethyl) phenyl] -1H-indol-3-yl} propyl) -4-piperidinyl] phenyl} 2-methylpropanamide: 2-methyl-N- [3- (1- {5-oxo-5- [4- (trifluoromethyl) phenyl] pentyl} -4-piperidinyl) phenyl] propanamide And prepared by Procedure E and Scheme M using 4-methoxyphenylhydrazine hydrochloride: ESMS m / e: 578.2 (M + H) ⁺
[2644] Example 690
[2645] N- [3- (1- {3- [2- (3-fluorophenyl) -7-methyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: N- (3- {1- [5- (3-fluorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1- (2-methylphenyl) hydrazine Prepared by Procedure E and Scheme M using hydrochloride: ESMS m / e: 512.2 (M + H) ⁺
[2646] Example 691
[2647] N- [3- (1- {3- [2- (4-chlorophenyl) -1-methyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropanamide Using N- (3- {1- [5- (4-chlorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1-methyl-1-phenylhydrazine Prepared by procedure E and scheme M by: ESMS m / e: 528.2 (M + H) ⁺
[2648] Example 692
[2649] N- [3- (1- {3- [2- (4-fluorophenyl) -5-methoxy-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methyl Propanamide): N- (3- {1- [5- (4-fluorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4-methoxyphenylhydrazine Prepared by Procedure E and Scheme M using hydrochloride: ESMS m / e: 528.2 (M + H) ⁺
[2650] Example 693
[2651] N- [3- (1- {3- [2- (2-fluorophenyl) -1H-indol-3-yl] propyl} -4-piperidinyl] phenyl} -2-methylpropanamide: N- (3- {1- [5- (2-fluorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and phenylhydrazine by Procedure E and Scheme M Preparation: ESMS m / e: 498.2 (M + H) ⁺
[2652] Example 694
[2653] N- [3- (1- {3- [2- (3-fluorophenyl) -5- (trifluoromethoxy) -1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropanamide: N- (3- {1- [5- (3-fluorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4- ( Prepared by Procedure E and Scheme M using trifluoromethoxy) phenylhydrazine hydrochloride: ESMS m / e: 582.2 (M + H) ⁺
[2654] Example 695
[2655] N- [3- (1- {3- [2- (2-fluorophenyl) -5- (trifluoromethoxy) -1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropanamide: N- (3- {1- [5- (2-fluorophenyl) -5-oxopentyl] -4-piperidinyl] phenyl} -2-methylpropanamide and 4- ( Prepared by Procedure E and Scheme M using trifluoromethoxy) phenylhydrazine hydrochloride: ESMS m / e: 582.2 (M + H) ⁺
[2656] Example 696
[2657] N- [3- (1- {3- [2- (4-fluorophenyl) -1-phenyl-1H-indol-3-yl] propyl] -4-piperidinyl) phenyl] -2-methylpropane Amides: N- (3- {1- [5- (4-fluorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1,1-diphenylhydrazine hydrochloride Prepared by Procedure E and Scheme M using ESMS m / e: 548.2 (M + H) ⁺
[2658] Example 697
[2659] N- [3- (1- {3- [2- (2-fluorophenyl) -1H-benzo [G] indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: using N- (3- {1- [5- (2-fluorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1-naphthylhydrazine hydrochloride Prepared by procedure E and scheme M by: ESMS m / e: 547.7 (M + H) ⁺
[2660] Example 698
[2661] N- [3- (1- {3- [2- (2-fluorophenyl) -5-methyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: N- (3- (1- [5- (2-fluorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4-methylphenylhydrazine hydrochloride Prepared by procedure E and scheme M: ESMS m / e: 512.2 (M + H) ⁺
[2662] Example 699
[2663] N- [3- (1- {3- [2- (3-fluorophenyl) -1H-benzo [G] indol-3-yl) propyl] -4-piperidinyl} phenyl) -2-methylpropane Amides: using N- (3- {1- [5- (3-fluorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1-naphthylhydrazine hydrochloride Prepared by procedure E and scheme M by: ESMS m / e: 548.2 (M + H) ⁺
[2664] Example 700
[2665] N- [3- (1- {3- [2- (4-fluorophenyl) -1-methyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: N- (3- {1- [5- (4-fluorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1-methyl-1-phenylhydrazine Prepared by Procedure E and Scheme M using ESMS m / e: 512.2 (M + H) ⁺
[2666] Example 701
[2667] N- [3- (1- {3- [2- (3-fluorophenyl) -5-methoxy-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methyl Propanamides: N- (3- {1- [5- (3-fluorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4-methoxyphenylhydrazine hydrochloride Prepared by Procedure E and Scheme M using ESMS m / e: 528.2 (M + H) ⁺
[2668] Example 702
[2669] N- [3- (1- {3- [2- (3-fluorophenyl) -1-phenyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: N- (3- {1- [5- (3-fluorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1,1-diphenylhydrazine hydrochloride Prepared by Procedure E and Scheme M using ESMS m / e: 574.2 (M + H) ⁺
[2670] Example 703
[2671] N- [3- (1- {3- [2- (4-chlorophenyl) -5- (trifluoromethoxy) -1H-indol-3-yl] propyl} -4-piperidinyl) phenyl]- 2-methylpropanamide: N- (3- {1- [5- (4-chlorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4- (trifluor Prepared by Procedure E and Scheme M using romethoxy) phenylhydrazine hydrochloride: ESMS m / e: 598.2 (M + H) ⁺
[2672] Example 704
[2673] N- [3- (1- {3- [2- (3-fluorophenyl) -1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropanamide: N- (3- {1- [5- (3-fluorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and phenylhydrazine by Procedure E and Scheme M Preparation: ESMS m / e: 498.2 (M + H) ⁺
[2674] Example 705
[2675] N- [3- (1- {3- [2- (3-fluorophenyl) -1-methyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: N- (3- {1- [5- (3-fluorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1-methyl-1-phenylhydrazine Prepared by Procedure E and Scheme M using ESMS m / e: 512.2 (M + H) ⁺
[2676] Example 706
[2677] N- [3- (1- {3- [2- (3-fluorophenyl) -5-methyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: N- (3- (1- [5- (3-fluorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4-methylphenylhydrazine hydrochloride Prepared by procedure E and scheme M: ESMS m / e: 512.2 (M + H) ⁺
[2678] Example 707
[2679] N- [3- (1- {3- [2- (4-chlorophenyl) -1H-benzo [G] indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropanamide : Procedure using N- (3- {1- [5- (4-chlorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1-naphthylhydrazine hydrochloride Manufactured by E and Scheme M: ESMS m / e: 564.2 (M + H) ⁺
[2680] Example 708
[2681] N- [3- (1- {3- [2- (4-chlorophenyl) -1 H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropanamide: N- ( 3- {1- [5- (4-chlorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1-phenylhydrazine hydrochloride in Procedure E and Scheme M Manufactured by: ESMS m / e: 514.2 (M + H) ⁺
[2682] Example 709
[2683] N- [3- (1- {3- [2- (2-fluorophenyl) -1-methyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: N- (3- (1- [5- (2-fluorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1-methyl-1-phenylhydrazine Prepared by Procedure E and Scheme M using ESMS m / e: 512.2 (M + H) ⁺
[2684] Example 710
[2685] N- [3- (1- {3- [2- (2-fluorophenyl) -7-methyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: N- (3- (1- [5- (2-fluorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1- (2-methylphenyl) hydrazine Prepared by Procedure E and Scheme M using hydrochloride: ESMS m / e: 512.2 (M + H) ⁺
[2686] Example 711
[2687] N- [3- (1- {3- [2- (2-fluorophenyl) -1-phenyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: N- (3- {1- [5- (2-fluorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1,1-diphenylhydrazine hydrochloride Prepared by Procedure E and Scheme M using ESMS m / e: 574.2 (M + H) ⁺
[2688] Example 712
[2689] N- [3- (1- {3- [2- (2-fluorophenyl) -5-methoxy-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methyl Propanamides: N- (3- {1- [5- (2-fluorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4-methoxyphenylhydrazine hydrochloride Prepared by Procedure E and Scheme M using ESMS m / e: 528.2 (M + H) ⁺
[2690] Example 713
[2691] N- [3- (1- {3- [2- (4-chlorophenyl) -5-methoxy-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: using N- (3- {1- [5- (4-chlorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4-methoxyphenylhydrazine hydrochloride Prepared by Procedure E and Scheme M by: ESMS m / e: 544.2 (M + H) ⁺
[2692] Example 714
[2693] N- [3- (1- {3- [2- (4-fluorophenyl) -1H-benzo [G] indol-3-yl} propyl) -4-piperidinyl) phenyl] -2-methylpropane Amides: using N- (3- (1- [5- (4-fluorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1-naphthylhydrazine hydrochloride Prepared by Procedure E and Scheme M by: ESMS m / e: 548.2 (M + H) ⁺
[2694] Example 715
[2695] N- [3- (1- {3- [2- (4-fluorophenyl) -5- (trifluoromethoxy) -1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropanamide: N- (3- {1- [5- (4-fluorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4- ( Prepared by Procedure E and Scheme M using trifluoromethoxy) phenylhydrazine hydrochloride: ESMS m / e: 582.9 (M + H) ⁺
[2696] Example 716
[2697] N- [3- (1- {3- [2- (4-fluorophenyl) -7-methyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: N- (3- (1- [5- (4-fluorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1- (2-methylphenyl) hydrazine Prepared by Procedure E and Scheme M using hydrochloride: ESMS m / e: 512.2 (M + H) ⁺
[2698] Example 717
[2699] N- [3- (1- {3- [2- (4-fluorophenyl) -1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropanamide: N- (3- {1- [5- (4-fluorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and phenylhydrazine by Procedure E and Scheme M Preparation: ESMS m / e: 498.2 (M + H) ⁺
[2700] Example 718
[2701] N- [3- (1- {3- [2- (4-fluorophenyl) -5-methyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: N- (3- {1- [5- (4-fluorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4-methylphenylhydrazine hydrochloride Prepared by procedure E and scheme M: ESMS m / e: 512.2 (M + H) ⁺
[2702] Example 719
[2703] N- [3- (1- {3- [2- (4-chlorophenyl) -7-methyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropanamide : N- (3- {1- [5- (4-chlorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1- (2-methylphenyl) hydrazine hydrochloride Manufactured by Procedure E and Scheme M using: ESMS m / e: 528.2 (M + H) ⁺
[2704] Example 720
[2705] N- [3- (1- {3- [2- (4-chlorophenyl) -5-methyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropanamide Procedure E using N- (3- (1- [5- (4-chlorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4-methylphenylhydrazine hydrochloride And prepared by scheme M: ESMS m / e: 528.2 (M + H) ⁺
[2706] Example 721
[2707] N- [3- (1- {3- [2- (4-chlorophenyl) -1-phenyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropanamide Using N- (3- (1- [5- (4-chlorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1,1-diphenylhydrazine hydrochloride Prepared by Procedure E and Scheme M by: ESMS m / e: 590.2 (M + H) ⁺
[2708] Example 722
[2709] N- [3- (1- {3- [2- (3-chlorophenyl) -7-methyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropanamide : N- (3- {1- [5- (3-chlorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1- (2-methylphenyl) hydrazine hydrochloride Prepared by Procedure E and Scheme M using: ESMS m / e: 528.1 (M + H) ⁺
[2710] Example 723
[2711] N- [3- (1- {3- [2- (3-chlorophenyl) -5- (trifluoromethoxy) -1H-indol-3-yl] propyl} -4-piperidinyl) phenyl]- 2-methylpropanamide: N- (3- {1- [5- (3-chlorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4- (trifluoro Prepared by Procedure E and Scheme M using romethoxy) phenylhydrazine hydrochloride: ESMS m / e: 598.2 (M + H) ⁺
[2712] Example 724
[2713] N- [3- (1- {3- [2- (3-chlorophenyl) -1-methyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropanamide Using N- (3- {1- [5- (3-chlorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1-methyl-1-phenylhydrazine Prepared by procedure E and scheme M by: ESMS m / e: 528.2 (M + H) ⁺
[2714] Example 725
[2715] N- [3- (1- {3- [2- (3-chlorophenyl) -1-phenyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropanamide Using N- (3- {1- [5- (3-chlorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1,1-diphenylhydrazine hydrochloride Prepared by procedure E and scheme M by: ESMS m / e: 590.3 (M + H) ⁺
[2716] Example 726
[2717] N- [3- (1- {3- [2- (3-chlorophenyl) -5-methoxy-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: using N- (3- {1- [5- (3-chlorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4-methoxyphenylhydrazine hydrochloride Prepared by procedure E and scheme M by: ESMS m / e: 544.3 (M + H) ⁺
[2718] Example 727
[2719] N- [3- (1- {3- [2- (3-chlorophenyl) -5-methyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropanamide Procedure E using N- (3- {1- [5- (3-chlorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4-methylphenylhydrazine hydrochloride And prepared by scheme M: ESMS m / e: 528.2 (M + H) ⁺
[2720] Example 728
[2721] N- [3- (1- {3- [2- (3-chlorophenyl) -1H-benzo [G] indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropanamide : Procedure using N- (3- {1- [5- (3-chlorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1-naphthylhydrazine hydrochloride Manufactured by E and Scheme M: ESMS m / e: 564.2 (M + H) ⁺
[2722] Example 729
[2723] N- [3- (1- {3- [2- (3-chlorophenyl) -1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropanamide: N- ( Prepared by Procedure E and Scheme M using 3- {1- [5- (3-chlorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and phenylhydrazine: ESMS m / e: 514.2 (M + H) ⁺
[2724] Example 730
[2725] N- [3- (1- {3- [2- (2-chlorophenyl) -1 H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropanamide: N- ( Prepared by Procedure E and Scheme M using 3- {1- [5- (2-chlorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and phenylhydrazine: ESMS m / e: 514.2 (M + H) ⁺
[2726] Example 731
[2727] N- [3- (1- {3- [2- (2-chlorophenyl) -5- (trifluoromethoxy) -1H-indol-3-yl] propyl} -4-piperidinyl) phenyl]- 2-methylpropanamide: N- (3- {1- [5- (2-chlorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4- (trifluoro Prepared by Procedure E and Scheme M using romethoxy) phenylhydrazine hydrochloride: ESMS m / e: 598.2 (M + H) ⁺
[2728] Example 732
[2729] N- [3- (1- {3- [2- (2-chlorophenyl) -1H-benzo [G] indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropanamide : Procedure using N- (3- (1- [5- (2-chlorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1-naphthylhydrazine hydrochloride Manufactured by E and Scheme M: ESMS m / e: 564.2 (M + H) ⁺
[2730] Example 733
[2731] N- [3- (1- {3- [2- (2-chlorophenyl) -7-methyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropanamide : N- (3- {1- [5- (2-chlorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1- (2-methylphenyl) hydrazine hydrochloride Manufactured by Procedure E and Scheme M using: ESMS m / e: 528.2 (M + H) ⁺
[2732] Example 734
[2733] N- [3- (1- {3- [2- (2-chlorophenyl) -1-phenyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropanamide N- (3- {1- [5- (2-chlorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1,1-diphenylhydrazine hydrochloride are used. Prepared by Procedure E and Scheme M by: ESMS m / e: 590.2 (M + H) ⁺
[2734] Example 735
[2735] N- [3- (1- {3- [2- (2-chlorophenyl) -1-methyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropanamide Using N- (3- {1- [5- (2-chlorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1-methyl-1-phenylhydrazine Prepared by procedure E and scheme M by: ESMS m / e: 528.2 (M + H) ⁺
[2736] Example 736
[2737] N- [3- (1- {3- [2- (2-chlorophenyl) -5-methyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropanamide Procedure E using N- (3- {1- [5- (2-chlorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4-methylphenylhydrazine hydrochloride And prepared by scheme M: ESMS m / e: 528.2 (M + H) ⁺
[2738] Example 737
[2739] N- [3- (1- {3- [2- (3-iodophenyl) -1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropanamide: N- (3- {1- [5- (3-iodophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and phenylhydrazine by Procedure E and Scheme M Preparation: ESMS m / e: 606.2 (M + H) ⁺
[2740] Example 738
[2741] N- [3- (1- {3- [2- (3-iodophenyl) -1-methyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: N- (3- {1- [5- (3-iodophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1-methyl-1-phenylhydrazine Prepared by Procedure E and Scheme M using ESMS m / e: 620.2 (M + H) ⁺
[2742] Example 739
[2743] N- [3- (1- {3- [2- (3-iodophenyl) -1-phenyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: N- (3- {1- [5- (3-iodophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1,1-diphenylhydrazine hydrochloride Prepared by Procedure E and Scheme M using ESMS m / e: 682.2 (M + H) ⁺
[2744] Example 740
[2745] N- [3- (1- {3- [2- (3-iodophenyl) -1H-benzo [G] indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: using N- (3- (1- [5- (3-iodophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1-naphthylhydrazine hydrochloride Prepared by Procedure E and Scheme M by: ESMS m / e: 656.2 (M + H) ⁺
[2746] Example 741
[2747] N- [3- (1- {3- [2- (3-iodophenyl) -5- (trifluoromethoxy) -1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropanamide: N- (3- (1- [5- (3-iodophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4- ( Prepared by Procedure E and Scheme M using trifluoromethoxy) phenylhydrazine hydrochloride: ESMS m / e: 690.2 (M + H) ⁺
[2748] Example 742
[2749] N- [3- (1- {3- [2- (3-iophenyl) -5-methyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: Procedure E using N- (3- (1- [5- (3-iodophenyl) -5-oxopentyl] -piperidinyl} phenyl) -2-methylpropanamide and 4-methylphenylhydrazine hydrochloride And prepared by scheme M: ESMS m / e: 620.2 (M + H) ⁺
[2750] Example 743
[2751] N- [3- (1- {3- [2- (3-iodophenyl) -7-methyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: N- (3- {1- [5- (3-iodophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1- (2-methylphenyl) hydrazine Prepared by Procedure E and Scheme M using hydrochloride: ESMS m / e: 620.2 (M + H) ⁺
[2752] Example 744
[2753] N- [3- (1- {3- [2- (4-iodophenyl) -5- (trifluoromethoxy) -1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropanamide: N- (3- {1- [5- (4-iodophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4- ( Prepared by Procedure E and Scheme M using trifluoromethoxy) phenylhydrazine hydrochloride: ESMS m / e: 690.1 (M + H) ⁺
[2754] Example 745
[2755] N- [3- (1- {3- [2- (4-iodophenyl) -5-methyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: N- (3- {1- [5- (4-iodophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4-methylphenylhydrazine hydrochloride Prepared by procedure E and scheme M: ESMS m / e: 620.1 (M + H) ⁺
[2756] Example 746
[2757] N- [3- (1- {3- [2- (4-iodophenyl) -7-methyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: N- (3- {1- [5- (4-iodophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1- (2-methylphenyl) hydrazine Prepared by Procedure E and Scheme M using hydrochloride: ESMS m / e: 620.1 (M + H) ⁺
[2758] Example 747
[2759] N- [3- (1- {3- [2- (4-iodophenyl) -1-phenyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: N- (3- {1- [5- (4-iodophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1,1-diphenylhydrazine hydrochloride Prepared by Procedure E and Scheme M using ESMS m / e: 682.1 (M + H) ⁺
[2760] Example 748
[2761] N- [3- (1- {3- [2- (4-iodophenyl) -1-methyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: N- (3- {1- [5- (4-iodophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1-methyl-1-phenylhydrazine Prepared by Procedure E and Scheme M using ESMS m / e: 620.1 (M + H) ⁺
[2762] Example 749
[2763] N- [3- (1- {3- [2- (4-iodophenyl) -1H-benzo [G] indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: using N- (3- {1- [5- (4-iodophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1-naphthylhydrazine hydrochloride Prepared by procedure E and scheme M by: ESMS m / e: 656.1 (M + H) ⁺
[2764] Example 750
[2765] N- [3- (1- {3- [2- (4-iodophenyl) -1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropanamide: N- (3- {1- [5- (4-iodophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and phenylhydrazine by Procedure E and Scheme M Preparation: ESMS m / e: 606.1 (M + H) ⁺
[2766] Example 751
[2767] N- [3- (1- {3- [2- (3-bromophenyl) -5- (trifluoromethoxy) -1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropanamide: N- (3- {1- [5- (3-bromophenyl) -5-oxopentyl] -4-piperidinyl) phenyl} -2-methylpropanamide and 4- ( Prepared by Procedure E and Scheme M using trifluoromethoxy) phenylhydrazine hydrochloride: ESMS m / e: 642.0 (M + H) ⁺
[2768] Example 752
[2769] N- [3- (1- {3- [2- (4-bromophenyl) -1H-benzo [G] indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: using N- (3- {1- [5- (4-bromophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1-naphthylhydrazine hydrochloride Prepared by Procedure E and Scheme M by: ESMS m / e: 608.0 (M + H) ⁺
[2770] Example 753
[2771] N- [3- (1- {3- [2- (4-bromophenyl) -7-methyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: N- (3- {1- [5- (4-bromophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1- (2-methylphenyl) hydrazine Prepared by Procedure E and Scheme M using hydrochloride: ESMS m / e: 572 (M + H) ⁺
[2772] Example 754
[2773] N- [3- (1- {3- [2- (4-bromophenyl) -5- (trifluoromethoxy) -1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropanamide: N- (3- {1- [5- (4-bromophenyl) -5-oxopentyl] -4-piperidinyl] phenyl} -2-methylpropanamide and 4- ( Prepared by Procedure E and Scheme M using trifluoromethoxy) phenylhydrazine hydrochloride: ESMS m / e: 642 (M + H) ⁺
[2774] Example 755
[2775] N- [3- (1- {3- [2- (3-bromophenyl) -1H-benzo [G] indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: using N- (3- {1- [5- (3-bromophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1-naphthylhydrazine hydrochloride Prepared by Procedure E and Scheme M by: ESMS m / e: 608.0 (M + H) ⁺
[2776] Example 756
[2777] N- [3- (1- {3- [2- (4-bromophenyl) -1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropanamide: N- (3- {1- [5- (4-Bromophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and phenylhydrazine by Procedure E and Scheme M Preparation: ESMS m / e: 558.1 (M + H) ⁺
[2778] Example 757
[2779] N- [3- (1- {3- [2- (3-bromophenyl) -1-phenyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: N- (3- {1- [5- (3-bromophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1,1-diphenylhydrazine hydrochloride Prepared by Procedure E and Scheme M using ESMS m / e: 634.0 (M + H) ⁺
[2780] Example 758
[2781] N- [3- (1- {3- [2- (3-bromophenyl) -1-methyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: N- (3- {1- [5- (3-bromophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1-methyl-1-phenylhydrazine Prepared by Procedure E and Scheme M using ESMS m / e: 572.0 (M + H) ⁺
[2782] Example 759
[2783] N- [3- (1- {3- [2- (4-bromophenyl) -1-methyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: N- (3- {1- [5- (4-bromophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1-methyl-1-phenylhydrazine Prepared by Procedure E and Scheme M using ESMS m / e: 572.0 (M + H) ⁺
[2784] Example 760
[2785] N- [3- (1- {3- [2- (4-bromophenyl) -1-phenyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: N- (3- {1- [5- (4-bromophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1,1-diphenylhydrazine hydrochloride Prepared by Procedure E and Scheme M using ESMS m / e: 634.0 (M + H) ⁺
[2786] Example 761
[2787] N- [3- (1- {3- [2- (4-bromophenyl) -5-methoxy-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methyl Propanamides: N- (3- {1- [5- (4-bromophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4-methoxyphenylhydrazine hydrochloride Prepared by Procedure E and Scheme M using ESMS m / e: 588.1 (M + H) ⁺
[2788] Example 762
[2789] N- [3- (1- {3- [2- (3-bromophenyl) -7-methyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: N- (3- {1- [5- (3-bromophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1- (2-methylphenyl) hydrazine Prepared by Procedure E and Scheme M using hydrochloride: ESMS m / e: 572 (M + H) ⁺
[2790] Example 763
[2791] N- [3- (1- {3- [2- (3-bromophenyl) -5-methyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: N- (3- (1- [5- (3-bromophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4-methylphenylhydrazine hydrochloride Prepared by procedure E and scheme M: ESMS m / e: 572 (M + H) ⁺
[2792] Example 764
[2793] N- [3- (1- {3- [2- (4-bromophenyl) -5-methyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: N- (3- {1- [5- (4-bromophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4-methylphenylhydrazine hydrochloride Prepared by procedure E and scheme M: ESMS m / e: 572.0 (M + H) ⁺
[2794] Example 765
[2795] N- [3- (1- {3- [2- (3-bromophenyl) -5-methoxy-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methyl Propanamides: N- (3- {1- [5- (3-bromophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4-methoxyphenylhydrazine hydrochloride Prepared by Procedure E and Scheme M using ESMS m / e: 588.0 (M + H) ⁺
[2796] Example 766
[2797] 2-methyl-N- [3- (1- {3- [2- (3-nitrophenyl) -1H-indol-3-yl] propyl} -4-piperidinyl} phenyl] propanamide: 2-methyl Prepared by Procedure E and Scheme M using -N- (3- {1- [5- (3-nitrophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) propanamide and phenylhydrazine: ESMS m / e: 525.2 (M + H) ⁺
[2798] Example 767
[2799] 2-methyl-N- [3- (1- {3- [2- (3-nitrophenyl) -1H-benzo [G] indol-3-yl] propyl} -4-piperidinyl) phenyl] propanamide Procedure using 2-methyl-N- (3- (1- [5- (3-nitrophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) propanamide and 1-naphthylhydrazine hydrochloride Manufactured by E and Scheme M: ESMS m / e: 575.1 (M + H) ⁺
[2800] Example 768
[2801] 2-methyl-N- [3- (1- {3- [2- (3-nitrophenyl) -5- (trifluoromethoxy) -1H-indol-3-yl] propyl} -4-piperidinyl ) Phenyl] propanamide: 2-methyl-N- (3- {1- [5- (3-nitrophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) propanamide and 4- (trifluoro Prepared by Procedure E and Scheme M using methoxymethoxyphenylhydrazine hydrochloride: ESMS m / e: 609.1 (M + H) ⁺
[2802] Example 769
[2803] 2-methyl-N- [3- (1- {3- [5-methyl-2- (3-nitrophenyl) -1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] propanamide Procedure E using 2-methyl-N- (3- {1- [5- (3-nitrophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) propanamide and 4-methylphenylhydrazine hydrochloride And prepared by scheme M: ESMS m / e: 539.2 (M + H) ⁺
[2804] Example 770
[2805] N- [3- (1- {3- [5-methoxy-2- (3-nitrophenyl) -1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: using 2-methyl-N- (3- {1- [5- (3-nitrophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) propanamide and 4-methoxyphenylhydrazine hydrochloride Prepared by Procedure E and Scheme M by: ESMS m / e: 555.2 (M + H) ⁺
[2806] Example 771
[2807] 2-methyl-N- [3- (1- {3- [2- (3-nitrophenyl) -1-phenyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] propanamide : 2-methyl-N- (3- {1- [5- (3-nitrophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) propanamide and 1,1-diphenylhydrazine hydrochloride are used Prepared by Procedure E and Scheme M by: ESMS m / e: 601.1 (M + H) ⁺
[2808] Example 772
[2809] 2-methyl-N- [3- (1- {3- [1-methyl-2- (3-nitrophenyl) -1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] propanamide : 2-methyl-N- (3- {1- [5- (3-nitrophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) propanamide and 1-methyl-1-phenylhydrazine Prepared by Procedure E and Scheme M by: ESMS m / e: 539.2 (M + H) ⁺
[2810] Example 773
[2811] 2-methyl-N- [3- (1- {3- [7-methyl-2- (3-nitrophenyl) -1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] propanamide : 2-methyl-N- (3- {1- [5- (3-nitrophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) propanamide and 1- (2-methylphenyl) hydrazine hydrochloride Prepared by Procedure E and Scheme M using: ESMS m / e: 539.2 (M + H) ⁺
[2812] Example 774
[2813] N- [3- (1- {3- [5-methoxy-2- (4-nitrophenyl) -1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: 2-methyl-N- (3- {1- [5- (4-nitrophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) propanamide and 4-methoxyphenylhydrazine hydrochloride are used Prepared by procedure E and scheme M by: ESMS m / e: 555.6 (M + H) ⁺
[2814] Example 775
[2815] N- [3- (1- {3- [2- (2-bromophenyl) -1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropanamide: N- (3- {1- [5- (2-Bromophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and phenylhydrazine by Procedure E and Scheme M Preparation: ESMS m / e: 557.9 (M + H) ⁺
[2816] Example 776
[2817] 2-methyl-N- [3- (1- {3- [5-methyl-2- (4-nitrophenyl) -1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] propanamide Procedure E using 2-methyl-N- (3- {1- [5- (4-nitrophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) propanamide and 4-methylphenylhydrazine hydrochloride And prepared by scheme M: ESMS m / e: 539.1 (M + H) ⁺
[2818] Example 777
[2819] 2-methyl-N- [3- (1- {3- [2- (4-nitrophenyl) -1H-benzo [G] indol-3-yl] propyl} -4-piperidinyl) phenyl] propanamide Procedure using 2-methyl-N- (3- {1- [5- (4-nitrophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) propanamide and 1-naphthylhydrazine hydrochloride Manufactured by E and Scheme M: ESMS m / e: 574.7 (M + H) ⁺
[2820] Example 778
[2821] 2-methyl-N- (3- {1-[(5E) -5- (4-nitrophenyl) -5- (phenylhydrazono) pentyl] -4-piperidinyl} phenyl) propanamide: 2-methyl Prepared by Procedure E and Scheme AX using -N- (3- {1- [5- (4-nitrophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) propanamide and phenylhydrazine: ESMS m / e: 542.4 (M + H) ⁺
[2822] Example 779
[2823] 2-methyl-N- [3- (1- {3- [7-methyl-2- (4-nitrophenyl) -1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] propanamide : 2-methyl-N- (3- {1- [5- (4-nitrophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) propanamide and 1- (2-methylphenyl) hydrazine hydrochloride Prepared by Procedure E and Scheme M using: ESMS m / e: 538.8 (M + H) ⁺
[2824] Example 780
[2825] 2-methyl-N- {3- [1-((5E) -5- (4-nitrophenyl) -5-{[4- (trifluoromethoxy) phenyl] hydrazono} pentyl) -4-piperidi Nil] phenyl} propanamide: 2-methyl-N- (3- {1- [5- (4-nitrophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) propanamide and 4- (tri Prepared by Procedure E and Scheme M using fluoromethoxy) phenylhydrazine hydrochloride: ESMS m / e: 626.2 (M + H) ⁺
[2826] Example 781
[2827] N- [3- (1- {3- [2- (2-bromophenyl) -1H-benzo [G] indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: using N- (3- {1- [5- (2-bromophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1-naphthylhydrazine hydrochloride Prepared by Procedure E and Scheme M by: ESMS m / e: 608.0 (M + H) ⁺
[2828] Example 782
[2829] N- [3- (1- {3- [2- (2-bromophenyl) -5- (trifluoromethoxy) -1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropanamide: N- (3- {1- [5- (2-bromophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4- ( Prepared by Procedure E and Scheme M using trifluoromethoxy) phenylhydrazine hydrochloride: ESMS m / e: 641.9 (M + H) ⁺
[2830] Example 783
[2831] N- [3- (1- {3- [2- (2-bromophenyl) -7-methyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: N- (3- {1- [5- (2-bromophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1- (2-methylphenyl) hydrazine Prepared by Procedure E and Scheme M using hydrochloride: ESMS m / e: 572.0 (M + H) ⁺
[2832] Example 784
[2833] N- [3- (1- {3- [2- (2-bromophenyl) -1-phenyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: N- (3- {1- [5- (2-bromophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1,1-diphenylhydrazine hydrochloride Prepared by Procedure E and Scheme M using ESMS m / e: 634 (M + H) ⁺
[2834] Example 785
[2835] N- [3- (1- {3- [2- (2-bromophenyl) -5-methyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: N- (3- {1- [5- (2-bromophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4-methylphenylhydrazine hydrochloride Prepared by procedure E and scheme M: ESMS m / e: 572.0 (M + H) ⁺
[2836] Example 786
[2837] N- [3- (1- {3- [2- (2-iodophenyl) -5- (trifluoromethoxy) -1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropanamide: N- (3- {1- [5- (2-iodophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4- ( Prepared by Procedure E and Scheme M using trifluoromethoxy) phenylhydrazine hydrochloride: ESMS m / e: 690.0 (M + H) ⁺
[2838] Example 787
[2839] N- [3- (1- {3- [2- (2-iodophenyl) -5-methyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: N- (3- (1- [5- (2-iodophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 4-methylphenylhydrazine hydrochloride Prepared by Procedure E and Scheme M: ESMS m / e: 620.2 (M + H) ⁺
[2840] Example 788
[2841] 2-methyl-N- [3- (1- {3- [1-methyl-2- (4-nitrophenyl) -1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] propanamide : 2-methyl-N- (3- {1- [5- (4-nitrophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) propanamide and 1-methyl-1-phenylhydrazine Prepared by procedure E and scheme M by: ESMS m / e: 539.6 (M + H) ⁺
[2842] Example 789
[2843] 2-methyl-N- [3- (1- {3- [2- (4-nitrophenyl) -1-phenyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] propanamide : 2-methyl-N- (3- {1- [5- (4-nitrophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) propanamide and 1,1-diphenylhydrazine hydrochloride are used Prepared by procedure E and scheme M by: ESMS m / e: 601.6 (M + H) ⁺
[2844] Example 790
[2845] N- [3- (1- {3- [2- (2-iodophenyl) -1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropanamide: N- (3- {1- (5- (2-iodophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and phenylhydrazine by Procedure E and Scheme M Manufacture: ESMS m / e: 606.1 (M + H) ⁺
[2846] Example 791
[2847] N- [3- (1- {3- [2- (2-iodophenyl) -1H-benzo [G] indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: using N- (3- {1- [5- (2-iodophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1-naphthylhydrazine hydrochloride Prepared by procedure E and scheme M by: ESMS m / e: 656.1 (M + H) ⁺
[2848] Example 792
[2849] N- [3- (1- {3- [2- (2-iodophenyl) -1-phenyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: N- (3- {1- [5- (2-iodophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1,1-diphenylhydrazine hydrochloride Prepared by Procedure E and Scheme M using ESMS m / e: 682.1 (M + H) ⁺
[2850] Example 793
[2851] N- [3- (1- {3- [2- (2-iodophenyl) -7-methyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: N- (3- {1- [5- (2-iodophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1- (2-methylphenyl) hydrazine Prepared by Procedure E and Scheme M using hydrochloride: ESMS m / e: 619.6 (M + H) ⁺
[2852] Example 794
[2853] N- [3- (1- {3- [2- (2-bromophenyl) -1-methyl-1H-indol-3-yl] propyl} -4-piperidinyl) phenyl] -2-methylpropane Amides: N- (3- {1- [5- (2-bromophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide and 1-methyl-1-phenylhydrazine Prepared by Procedure E and Scheme M using ESMS m / e: 572 (M + H) ⁺
[2854] Example 795
[2855] 4- (3,4-difluorophenyl) -N- (3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} propyl) -2-methyl-6-oxo- 1,4,5,6-tetrahydro-3-pyridinecarboxamide: 4- (3,4-difluorophenyl) -2-methyl-6-oxo-1,4,5,6-tetrahydro- Prepared by Procedure AC and Scheme AM using 3-pyridinecarboxylic acid and N- {3- [1- (3-aminopropyl) -4-piperidinyl] phenyl} -2-methylpropanamide: ESMS m / e: 553.0 (M + H) ⁺
[2856] Example 796
[2857] 4- (2,4-difluorophenyl) -N- (3- {4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} propyl) -2-methyl-6-oxo- 1,4,5,6-tetrahydro-3-pyridinecarboxamide: 4- (2,4-difluorophenyl) -2-methyl-6-oxo-1,4,5,6-tetrahydro- Prepared by Procedure AC and Scheme AM using 3-pyridinecarboxylic acid and N- {3- [1- (3-aminopropyl) -4-piperidinyl] phenyl} -2-methylpropanamide: ESMS m / e: 553.0 (M + H) ⁺
[2858] Example 797
[2859] N- (3- {1- [4- (4-methoxyphenyl) butyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4- (4-methoxyphenyl) -1-butanol and Prepared by Procedure O and Scheme W using 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 409 (M + H) ⁺
[2860] Example 798
[2861] N- (4- {1- [3- (1,2-diphenyl-1H-indol-3-yl) propyl] -4-piperidinyl} phenyl) propanamide: 3- (1,2-diphenyl Prepared by Procedure O and Scheme W using -1H-indol-3-yl) -1-propanol and N- [4- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 542.0 (M + H) ⁺
[2862] Example 799
[2863] N- {4- [1- (3,3-diphenylpropyl) -4-piperidinyl] phenyl} propanamide: 3,3-diphenyl-1-propanol and N- [4- (4-piperidi Prepared by Procedure O and Scheme W using nil) phenyl] propanamide: ESMS m / e: 427.0 (M + H) ⁺
[2864] Example 800
[2865] 2-methyl-N- (3- {1- [4- (4-nitrophenyl) butyl] -4-piperidinyl} phenyl): 4- (4-nitrophenyl) -1-butanol and 2-methyl- Prepared by Procedure O and Scheme W using N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 424.2 (M + H) ⁺
[2866] Example 801
[2867] 2-methyl-N- (3- {1- [2- (1-naphthyl) ethyl] -4-piperidinyl} phenyl) propanamide: 2- (1-naphthyl) ethanol and 2-methyl-N Prepared by Procedure O and Scheme W using [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 401.2 (M + H) ⁺
[2868] Example 802
[2869] N- {3- [1- (3,3-diphenylpropyl) -4-piperidinyl] phenyl} -2-methylpropanamide: 3,3-diphenyl-1-propanol and 2-methyl-N- Prepared by Procedure O and Scheme W using [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 441.2 (M + H) ⁺
[2870] Example 803
[2871] N- (3- {1- [3- (3,4-dimethoxyphenyl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 3- (3,4-dimethoxyphenyl)- Prepared by Procedure O and Scheme W using 1-propanol and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 425.2 (M + H) ⁺
[2872] Example 804
[2873] 2-methyl-N- {3- [1- (3-phenylpropyl) -4-piperidinyl] phenyl} propanamide: 3-phenyl-1-propanol and 2-methyl-N- [3- (4- Prepared by Procedure O and Scheme W using piperidinyl) phenyl] propanamide: ESMS m / e: 365.2 (M + H) ⁺
[2874] Example 805
[2875] 2-methyl-N- (3- {1- [3- (4-pyridinyl) propyl] -4-piperidinyl} phenyl) propanamide: 3- (4-pyridinyl) -1-propanol and 2- Prepared by Procedure O and Scheme W using methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 366.2 (M + H) ⁺
[2876] Example 806
[2877] N- {3- [1- (4-TERT-butylbenzyl) -4-piperidinyl] phenyl} -2-methylpropanamide: 1-bromomethyl) -4-tert-butylbenzene and 2-methyl- Prepared by Procedure AJ and Scheme AV using N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 393.0 (M + H) ⁺
[2878] Example 807
[2879] N- {3- [1- (4-benzoylbenzyl) -4-piperidinyl] phenyl} -2-methylpropanamide: [4- (bromomethyl) phenyl] (phenyl) methanone and 2-methyl- Prepared by Procedure AJ and Scheme AV using N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 441.0 (M + H) ⁺
[2880] 1,2-dichloro-4-{[(1S) -3-chloro-1-phenylpropyl] oxy) benzene: 3,4-dichlorophenol and (1R) -3-chloro-1-phenyl-1-propanol Prepared by Procedure A using.
[2881] Example 808
[2882] N- (3- {1-[(3S) -3- (3,4-dichlorophenoxy) -3-phenylpropyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1,2- By Procedure A using dichloro-4-{[(1S) -3-chloro-1-phenylpropyl] oxy} benzene and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide Preparation: ESMS m / e: 525.3 (M + H) ⁺
[2883] Example 809
[2884] N- (3- {1- [6- (2-fluorophenyl) -6-hydroxyhexyl] -4-piperidinyl} phenyl) -2-methylpropanamide: N- (3- {1- [ Prepared by Procedure L and Scheme AN using 6- (2-fluorophenyl) -6-oxohexyl] -4-piperidinyl} phenyl) -2-methylpropanamide: ESMS m / e: 441.3 (M + H) ⁺
[2885] Example 810
[2886] N- [3- (1- {5-hydroxy-5- [4- (trifluoromethyl) phenyl] pentyl} -4-piperidinyl) phenyl] -2-methylpropanamide: 2-methyl-N Prepared by Procedure L and Scheme AN using-[3- (1- {5-oxo-5- [4- (trifluoromethyl) phenyl] pentyl} -4-piperidinyl) phenyl] propanamide: ESMS m / e: 477.2 (M + H) ⁺
[2887] Example 811
[2888] N- (3- {1- [5- (4-fluorophenyl) -5-hydroxypentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: N- (3- {1- [ Prepared by Procedure L and Scheme AN using 5- (4-fluorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: ESMS m / e: 427.2 (M + H) ⁺
[2889] Example 812
[2890] N- (3- {1- [7- (2-fluorophenyl) -7-hydroxyheptyl] -4-piperidinyl} phenyl) -2-methylpropanamide: N- (3- {1- [ Prepared by Procedure L and Scheme AN using 7- (2-fluorophenyl) -7-oxoheptyl] -4-piperidinyl} phenyl) -2-methylpropanamide: ESMS m / e: 455.2 (M + H) ⁺
[2891] Example 813
[2892] N- (3- {1- [6- (3-fluorophenyl) -6-hydroxyhexyl] -4-piperidinyl} phenyl) -2-methylpropanamide: N- (3- {1- [ Prepared by Procedure L and Scheme AN using 6- (3-fluorophenyl) -6-oxohexyl] -4-piperidinyl] phenyl) -2-methylpropanamide: ESMS m / e: 441.2 (M + H) ⁺
[2893] Example 814
[2894] N- (3- {1- [5- (2-fluorophenyl) -5-hydroxypentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: N- (3- {1- [ Prepared by Procedure L and Scheme AN using 5- (2-fluorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: ESMS m / e: 427.2 (M + H) ⁺
[2895] Example 815
[2896] N- (3- {1- [5- (3-fluorophenyl) -5-hydroxypentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: N- (3- [1- [ Prepared by Procedure L and Scheme AN using 5- (3-fluorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: ESMS m / e: 427.2 (M + H) ⁺
[2897] Example 816
[2898] N- (3- {1- [5- (3-chlorophenyl) -5-hydroxypentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: N- (3- {1- [5 Prepared by Procedure L and Scheme AN using-(3-chlorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: ESMS m / e: 443.1 (M + H ) ⁺
[2899] Example 817
[2900] N- (3- {1- [6- (4-fluorophenyl) -6-hydroxyhexyl] -4-piperidinyl} phenyl) -2-methylpropanamide: N- (3- {1- [ Prepared by Procedure L and Scheme AN using 6- (4-fluorophenyl) -6-oxohexyl] -4-piperidinyl} phenyl) -2-methylpropanamide: ESMS m / e: 441.2 (M + H) ⁺
[2901] Example 818
[2902] N- (3- {1- [6- (4-chlorophenyl) -6-hydroxyhexyl] -4-piperidinyl} phenyl) -2-methylpropanamide: N- (3- {1- [6 Prepared by Procedure L and Scheme AN using-(4-chlorophenyl) -6-oxohexyl] -4-piperidinyl] phenyl) -2-methylpropanamide: ESMS m / e: 456.9 (M + H ) ⁺
[2903] Example 819
[2904] N- (3- {1- [5- (4-chlorophenyl) -5-hydroxypentyl] -4-piperidinyl] phenyl) -2-methylpropanamide: N- (3- {1- [5 Prepared by Procedure L and Scheme AN using-(4-chlorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: ESMS m / e: 443.0 (M + H ) ⁺
[2905] Example 820
[2906] N- (4- {1-[(9-ethyl-9H-carbazol-3-yl) methyl] -4-piperidinyl} phenyl) butanamide: 9-ethyl-9H-carbazole-3, without HOAc Prepared by Procedure F and Scheme R using carbaaldehyde and N- [4- (4-piperidinyl) phenyl] butanamide: ESMS m / e: 454.2 (M + H) ⁺
[2907] Example 821
[2908] N- (3- {1-[(9-ethyl-9H-carbazol-3-yl) methyl] -4-piperidinyl} phenyl) propanamide: 9-ethyl-9H-carbazole-3, without HOAc Prepared by Procedure F and Scheme R using carbaaldehyde and N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 440.5 (M + H) ⁺
[2909] Example 822
[2910] N- (3- {1-[(1,9-dimethyl-9H-carbazol-3-yl) methyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1,9- without HOAc Prepared by Procedure F and Scheme R using dimethyl-9H-carbazole-3-carbaaldehyde and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.05-6.77 (m, 10H), 5.20-5.12 (m, 1H), 4.04 (s, 3H), 3.93 (s, 2H), 3.34-3.24 (m, 2H), 2.79 ( s, 3H), 2.56-2.38 (m, 2H), 2.38-2.26 (m, 2H), 2.08-1.88 (m, 2H), 1.82-1.70 (m, 2H), 1.16 (d, 6H, J = 6.8 Hz); ESMS m / e: 454.2 (M + H) ⁺
[2911] Example 823
[2912] N- (3- {1-[(9-ethyl-9H-carbazol-3-yl) methyl] -4-piperidinyl} phenyl) cyclopropanecarboxamide: 9-ethyl-9H-carbox, without HOAc Prepared by Procedure F and Scheme R using Bazol-3-carbaaldehyde and N- [3- (4-piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m / e: 452.6 (M + H) ⁺
[2913] Example 824
[2914] 1- (3- {1-[(9-ethyl-9H-carbazol-3-yl) methyl] -4-piperidinyl} phenyl) -2-pyrrolidinone: Prepared by Scheme R and Procedure F. 1- (9-ethyl-9H-carbazol-3-yl) ethanone (22.3 mg, 0.100 mmol) and 1- [3- (4-piperidinyl) phenyl in 1,2-dichloroethane (1.00 mL) ] -2-pyrrolidinone (27.2 mg, 0.100 mmol) solution was treated with sodium triacetoxyborohydride (63.6 mg, 0.300 mmol) and HOAc (5.70 uL, 0.100 mmol). The mixture was stirred at rt overnight. The reaction mixture was treated with saturated aqueous NaHCO ₃ (10 mL). The aqueous layer was extracted with CH ₂ Cl ₂ (3 × 10 mL) and the combined organic layers were washed with brine (10 mL), then dried over MgSO ₄ and concentrated in vacuo. The residue was purified by preparative TLC using 5% NH ₃ (2.0 M in methanol) in CH ₂ Cl ₂ to afford the desired product 1- (3- {1-[(9-ethyl-9H-carbazol-3-yl ) Methyl] -4-piperidinyl} phenyl) -2-pyrrolidinone (4.60 mg, 9.43%): ¹ H NMR (400 MHz, CDCl ₃ ) δ8.04 (d, 1H, J = 7.4 Hz), 7.99 (s, 1H), 7.43-7.28 (m, 5H), 6.96 (d, 1H, J = 7.4 Hz), 4.31 (q, 2H, J = 6.8 Hz), 3.77 (t, 2H, J = 7.3 Hz ), 3.70 (s, 2H), 3.06 (d, 2H, J = 10.6 Hz), 2.56-2.42 (m, 3H), 2.07 (m, 4H), 1.77 (m, 4H), 1.36 (m, 3H) ; ESMS m / e: 452.5 (M + H) ⁺
[2915] N- {3- [1- (1H-Indol-5-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide: 1H-indol-5-carbaaldehyde and 2-methyl without HOAc Prepared by Procedure F and Scheme R using -N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 376.2 (M + H) ⁺
[2916] 1- (4-Chlorobutyl) -1H-indole: Prepared by Procedure AH and Scheme P using 1H-indole and 1-bromo-4-chlorobutane: ¹ H NMR (400 MHz, CDCl ₃ ) δ7. 72-7.02 (m, 5H), 6.49 (d, 1H, J = 2.8 Hz), 4.13 (t, 2H, J = 6.8 Hz), 3.48 (t, 2H, J = 6.8 Hz), 2.06-1.92 (m , 2H), 1.80-1.70 (m, 2H).
[2917] 1- (3-Chloropropyl) -1H-indole: Prepared by Procedure AH and Scheme P using 1H-indole and 1-bromo-3-chloropropane: ¹ H NMR (400 MHz, CDCl ₃ ) δ7. 70-7.04 (m, 5H), 6.50 (d, 1H, J = 2.8 Hz), 4.31 (t, 2H, J = 6.8 Hz), 3.42 (t, 2H, J = 6.4 Hz), 2.28-2.20 (m , 2H).
[2918] Example 825
[2919] N- (4- {1- [5- (1H-indol-1-yl) pentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1- (5-chloropentyl) -1H-indole And prepared by Procedure AH and Scheme P using 2-methyl-N- [4- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 432.3 (M + H) ⁺
[2920] Example 826
[2921] N- (4- {1- [5- (1H-indol-1-yl) pentyl] -4-piperidinyl} phenyl) butanamide: 1- (5-chloropentyl) -1H-indole and N- [ Prepared by Procedure AH and Scheme P using 4- (4-piperidinyl) phenyl] butanamide: ESMS m / e: 432.3 (M + H) ⁺
[2922] Example 827
[2923] N- (4- {1- [5- (1H-indol-3-yl) pentyl] -4-piperidinyl} phenyl) propanamide: 1- (5-chloropentyl) -1H-indole and N- [ Prepared by Procedure AH and Scheme P using 4- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 418.2 (M + H) ⁺
[2924] Example 828
[2925] N- (4- {1- [6- (1H-indol-1-yl) hexyl] -4-piperidinyl} phenyl) propanamide: 1- (6-chlorohexyl) -1H-indole and N- [ Prepared by Procedure AH and Scheme P using 4- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 432.3 (M + H) ⁺
[2926] Example 829
[2927] 2-methyl-N- (3- {1-[(1-methyl-1H-indol-2-yl) methyl] -4-piperidinyl} phenyl) propanamide: 1-methyl-1H-indole, without HOAc Prepared by Procedure F and Scheme R using 2-carbaaldehyde and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 390.3 (M + H) ⁺
[2928] Example 830
[2929] N- {3- [1- (1H-indol-4-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide: 1H-indol-4-carbaaldehyde and 2-methyl without HOAc Prepared by Procedure F and Scheme R using -N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 376.2 (M + H) ⁺
[2930] Example 831
[2931] N- (4- {1- [6- (1H-indol-1-yl) hexyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1- (6-chlorohexyl) -1H-indole And prepared by Procedure AH and Scheme P using 2-methyl-N- [4- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 446.3 (M + H) ⁺
[2932] Example 832
[2933] N- {3- [1- (1H-Indol-7-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide: 1H-indol-7-carbaaldehyde and 2-methyl without HOAc Prepared by Procedure F and Scheme R using -N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 376.2 (M + H) ⁺
[2934] Example 833
[2935] N- [3- (1-{[1- (4-methoxyphenyl) -1H-indol-5-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: with CuBr instead of Cu Procedure C, using 1-iodo-4-methoxybenzene and N- {3- [1- (1H-indol-5-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide And prepared by scheme Q1: ESMS m / e: 482.O (M + H) ⁺
[2936] Example 834
[2937] Methyl 4- [4-({4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} methyl) -1H-indol-1-yl] benzoate: CuBr instead of Cu, methyl 4- Prepared by Procedure C and Scheme Q1 using iodobenzoate and N- {3- [1- (1H-indol-4-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide: ESMS m / e: 510.3 (M + H) ⁺
[2938] Example 835
[2939] 2-methyl-N- [3- (1-{[1- (3-methylphenyl) -1H-indol-5-yl] methyl} -4-piperidinyl) phenyl] propanamide: CuBr instead of Cu, 1 Procedure C and Scheme Q1 using iodo-3-methylbenzene and N- {3- [1- (1H-indol-5-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide Manufactured by: ESMS m / e: 466.3 (M + H) ⁺
[2940] Example 836
[2941] N- [3- (1-{[1- (4-fluorophenyl) -1H-indol-4-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: with CuBr instead of Cu Procedure C, using 1-fluoro-4-iodobenzene and N- {3- [1- (1H-indol-4-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide And prepared by scheme Q1: ¹ H NMR (400 MHz, CDCl ₃ ) δ7.66-6.92 (m, 12H), 6.65 (d, 1H, J = 3.2 Hz), 3.69 (s, 2H), 3.15-3.02 (m, 2H), 2.58-2.40 (m, 2H), 2.20-2.04 (m, 2H), 1.94-1.76 (m, 4H), 1.25 (d, 6H, J = 6.8 Hz); ESMS m / e: 470.6 (M + H) ⁺
[2942] Example 837
[2943] N- (3- {1- [4- (1H-indol-1-yl) butyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1- (4-chlorobutyl) -1H-indole And prepared by Procedure AH and Scheme P using 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 418.3 (M + H) ⁺
[2944] Example 838
[2945] N- [3- (1-{[1- (4-chlorophenyl) -1H-indol-5-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: with CuBr instead of Cu, Procedure C and Scheme Using 1-Chloro-4-iodobenzene and N- {3- [1- (1H-indol-5-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide Manufactured by Q1: ESMS m / e: 486.2 (M + H) ⁺
[2946] Example 839
[2947] N- [3- (1-{[1- (3-methoxyphenyl) -1H-indol-5-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: with CuBr instead of Cu Procedure C, using 1-iodo-3-methoxybenzene and N- (3- [1- (1H-indol-5-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide And prepared by scheme Q1: ESMS m / e: 482.2 (M + H) ⁺
[2948] Example 840
[2949] N- (4- {1- [4- (1H-indol-1-yl) butyl] -4-piperidinyl} phenyl) butanamide: 1- (4-chlorobutyl) -1H-indole and N- [ Prepared by Procedure AH and Scheme P using 4- (4-piperidinyl) phenyl] butanamide: ESMS m / e: 418.2 (M + H) ⁺
[2950] Example 841
[2951] N- [3- (1-{[1- (2-methoxyphenyl) -1H-indol-5-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: with CuBr instead of Cu Procedure C, using 1-iodo-2-methoxybenzene and N- {3- [1- (1H-indol-5-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide And prepared by scheme Q1: ESMS m / e: 482.2 (M + H) ⁺
[2952] Example 842
[2953] N- [3- (1-{[1- (3-chlorophenyl) -1H-indol-5-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: with CuBr instead of Cu, Procedure C and Scheme Using 1-Chloro-3-iodobenzene and N- {3- [1- (1H-Indol-5-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide Manufactured by Q1: ESMS m / e: 486.2 (M + H) ⁺
[2954] Example 843
[2955] Methyl 2- [5-({4- [3- (isobutyrylamino) phenyl] -1-piperidinyl} methyl) -1H-indol-1-yl] benzoate: CuBr instead of Cu, methyl 2- Prepared by Procedure C and Scheme Q1 using iodobenzoate and N- {3- [1- (1H-indol-5-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide: ESMS m / e: 510.2 (M + H) ⁺
[2956] Example 844
[2957] N- (3- {1- [3- (1H-indol-1-yl) propyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1- (3-chloropropyl) -1H-indole And prepared by Procedure AH and Scheme P using 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 404.2 (M + H) ⁺
[2958] Example 845
[2959] 2-methyl-N- {3- [1-({1- [4- (trifluoromethyl) phenyl] -1H-indol-5-yl} methyl) -4-piperidinyl] phenyl} propanamide: 1-iodo-4- (trifluoromethyl) benzene and N- {3- [1- (1H-indol-5-ylmethyl) -4-piperidinyl] phenyl} -2- with CuBr instead of Cu Prepared by Procedure C and Scheme Q1 using methylpropanamide: ESMS m / e: 520.2 (M + H) ⁺
[2960] Example 846
[2961] N- (3- {1-[(1- [1,1'-biphenyl] -2-yl-1H-indol-5-yl) methyl] -4-piperidinyl} phenyl) -2-methylpropane Amides: 2-iodo-1,1'-biphenyl and N- {3- [1- (1H-indol-5-ylmethyl) -4-piperidinyl] phenyl} -2- with CuBr instead of Cu Prepared by Procedure C and Scheme Q1 using methylpropanamide: ESMS m / e: 528.3 (M + H) ⁺
[2962] Example 847
[2963] 2-methyl-N- [3- (1-({1- (2-methylphenyl) -1H-indol-5-yl] methyl} -4-piperidinyl) phenyl] propanamide: with CuBr instead of Cu, 1 Procedure C and Scheme Q1 using iodo-2-methylbenzene and N- {3- [1- (1H-indol-5-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide Manufactured by: ESMS m / e: 466.2 (M + H) ⁺
[2964] Example 848
[2965] 2-methyl-N- [3- (1-{[1- (4-methylphenyl) -1H-indol-5-yl] methyl} -4-piperidinyl) phenyl] propanamide: CuBr instead of Cu, 1 Procedure C and Scheme Q1 using iodo-4-methylbenzene and N- {3- [1- (1H-indol-5-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide Manufactured by: ESMS m / e: 466.3 (M + H) ⁺
[2966] Example 849
[2967] N- [3- (1-{[1- (2-chlorophenyl) -1H-indol-5-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: with CuBr instead of Cu, Procedure C and Schemes Using 1-chloro-2-iodobenzene and N- {3- [1- (1H-indol-5-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide Manufactured by Q1: ESMS m / e: 486.2 (M + H) ⁺
[2968] Example 850
[2969] 2-methyl-N- {3- (1-({1- [3- (trifluoromethyl) phenyl] -1H-indol-5-yl} methyl) -4-piperidinyl] phenyl} propanamide: 1-iodo-3- (trifluoromethyl) benzene and N- {3- [1- (1H-indol-5-ylmethyl) -4-piperidinyl] phenyl} -2- with CuBr instead of Cu Prepared by Procedure C and Scheme Q1 using methylpropanamide: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.80-6.94 (m, 12H), 6.69 (d, 1H, J = 3.6 Hz), 3.36 ( s, 2H), 3.10-3.00 (m, 2H), 2.58-2.42 (m, 2H), 2.16-2.02 (m, 2H), 1.85-1.75 (m, 4H), 1.25 (d, 6H, J = 7.2 Hz); ESMS m / e: 520.2 (M + H) ⁺
[2970] Example 851
[2971] 2-methyl-N- [3- (1-{[1- (2-nitrophenyl) -1H-indol-5-yl] methyl} -4-piperidinyl) phenyl] propanamide: with CuBr instead of Cu, Procedure C and Scheme Using 1-iodo-2-nitrobenzene and N- {3- [1- (1H-indol-5-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide Manufactured by Q1: ESMS m / e: 497.2 (M + H) ⁺
[2972] Example 852
[2973] N- [3- (1-{[1- (2-fluorophenyl) -1H-indol-5-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: with CuBr instead of Cu Procedure C, using 1-fluoro-2-iodobenzene and N- {3- [1- (1H-indol-5-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide And prepared by scheme Q1: ESMS m / e: 470.2 (M + H) ⁺
[2974] Example 853
[2975] 2-methyl-N- [3- (1-{[1- (1-naphthyl) -1H-indol-5-yl] methyl} -4-piperidinyl) phenyl] propanamide: with CuBr instead of Cu, Prepared by Procedure C and Scheme Q1 using 1-iodonaphthalene and N- {3- [1- (1H-indol-5-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide ESMS m / e: 502.2 (M + H) ⁺
[2976] Example 854
[2977] N- [3- (1-{[1- (2,3-dichlorophenyl) -1H-indol-5-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: CuBr instead of Cu Using 1,2-dichloro-3-iodobenzene and N- {3- [1- (1H-indol-5-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide Prepared by Procedure C and Scheme Q1: ¹ H NMR (400 MHz, CDCl ₃ ) δ7.68-6.94 (m, 12H), 6.68 (d, 1H, J = 2.8 Hz), 3.69 (s, 2H), 3.15 -3.02 (m, 2H), 2.54-2.42 (m, 2H), 2.18-2.02 (m, 2H), 1.88-1.76 (m, 4H), 1.25 (d, 6H, J = 6.8 Hz); ESMS m / e: 520.1 (M + H) ⁺
[2978] Example 855
[2979] N- [3- (1-{[1- (2,3-dichlorophenyl) -1H-indol-7-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: CuBr instead of Cu Using 1,2-dichloro-3-iodobenzene and N- {3- [1- (1H-indol-7-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide Prepared by Procedure C and Scheme Q1: ESMS m / e: 520.2 (M + H) ⁺
[2980] Example 856
[2981] N- [3- (1-{[1- (3-methoxyphenyl) -1H-indol-4-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: with CuBr instead of Cu Procedure C, using 1-iodo-3-methoxybenzene and N- {3- [1- (1H-indol-4-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide And prepared by scheme Q1: ESMS m / e: 482.3 (M + H) ⁺
[2982] Example 857
[2983] N- [3- (1-{[1- (2,3-dichlorophenyl) -1H-indol-4-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: CuBr instead of Cu Using 1,2-dichloro-3-iodobenzene and N- {3- [1- (1H-indol-4-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide Prepared by Procedure C and Scheme Q1: ESMS m / e: 520.2 (M + H) ⁺
[2984] Example 858
[2985] N- [3- (1-{[1- (3-chlorophenyl) -1H-indol-4-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: with CuBr instead of Cu, Procedure C and Scheme Using 1-Chloro-3-iodobenzene and N- {3- [1- (1H-indol-4-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide Manufactured by Q1: ESMS m / e: 486.2 (M + H) ⁺
[2986] Example 859
[2987] 2-methyl-N- [3- (1-{[1- (3-methylphenyl) -1H-indol-4-yl] methyl} -4-piperidinyl) phenyl] propanamide: with CuBr instead of Cu, 1 Procedure C and Scheme Q1 using iodo-3-methylbenzene and N- {3- [1- (1H-indol-4-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide Manufactured by: ESMS m / e: 466.3 (M + H) ⁺
[2988] Example 860
[2989] N- [3- (1-{[1- (3-methoxyphenyl) -1H-indol-7-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: with CuBr instead of Cu Procedure C, using 1-iodo-3-methoxybenzene and N- {3- [1- (1H-indol-7-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide And prepared by scheme Q1: ESMS m / e: 482.3 (M + H) ⁺
[2990] Example 861
[2991] 2-methyl-N- {3- [1-({1- [3- (trifluoromethyl) phenyl] -1H-indol-4-yl} methyl) -4-piperidinyl] phenyl} propanamide: 1-iodo-3- (trifluoromethyl) benzene and N- {3- [1- (1H-indol-4-ylmethyl) -4-piperidinyl] phenyl} -2- with CuBr instead of Cu Prepared by Procedure C and Scheme Q1 using methylpropanamide: ESMS m / e: 520.2 (M + H) ⁺
[2992] Example 862
[2993] N- [3- (1-{[1- (3,4-dimethylphenyl) -1H-indol-4-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: CuBr instead of Cu Using N- {3- [1- (1H-indol-4-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide and 4-iodo-1,2-dimethylbenzene Prepared by Procedure C and Scheme Q1: ESMS m / e: 480.0 (M + H) ⁺
[2994] Example 863
[2995] N- [3- (1-{[1- (3,4-difluorophenyl) -1H-indol-4-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: Cu As CuBr instead of 1,3-dichloro-5-iodobenzene and N- {3- [1- (1H-indol4-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide Prepared by Procedure C and Scheme Q1 by: ESMS m / e: 520.0 (M + H) ⁺
[2996] Example 864
[2997] N- [3- (1-{[1- (3,4-dichlorophenyl) -1H-indol-4-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: CuBr instead of Cu Using 1,2-dichloro-4-iodobenzene and N- {3- [1- (1H-indol-4-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide Prepared by Procedure C and Scheme Q1: ESMS m / e: 520.0 (M + H) ⁺
[2998] Example 865
[2999] N- [3- (1-{[1- (2-chloro-4-fluorophenyl) -1H-indol-4-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: 2-chloro-4-fluoro-1-iodobenzene and N- {3- [1- (1H-indol-4-ylmethyl) -4-piperidinyl] phenyl} -2- with CuBr instead of Cu Prepared by Procedure C and Scheme Q1 using methylpropanamide: ESMS m / e: 504.0 (M + H) ⁺
[3000] Example 866
[3001] N- [3- (1-{[1- (2,4-difluorophenyl) -1H-indol-4-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: Cu Instead of CuBr, 2,4-difluoro-1-iodobenzene and N- {3- [1- (1H-indol-4-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropane Prepared by Procedure C and Scheme Q1 using amide: ESMS m / e: 488.0 (M + H) ⁺
[3002] Example 867
[3003] 2-methyl-N- [3- (1-{[1- (3-pyridinyl) -1H-indol-7-yl] methyl} 4-piperidinyl) phenyl] propanamide: CuBr instead of Cu, 3 Prepared by Procedure C and Scheme Q1 using iodopyridine and N- {3- [1- (1H-indol-7-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide: ESMS m / e: 453.1 (M + H) ⁺
[3004] Example 868
[3005] N- {3- [1- (1H-Indol-6-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide: 1H-indol-6-carbaaldehyde and 2-methyl-N- Prepared by Procedure F and Scheme R using [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 376.2 (M + H) ⁺
[3006] Example 869
[3007] 2-methyl-N- [3- (1-{[1- (4-pyridinyl) -1H-indol-4-yl] methyl} -4-piperidinyl) phenyl] propanamide: with CuBr instead of Cu, Prepared by Procedure C and Scheme Q1 using 4-iodopyridine and N- {3- [1- (1H-indol-4-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide ESMS m / e: 453.2 (M + H) ⁺
[3008] Example 870
[3009] 2-methyl-N- [3- (1-{[1- (2-pyridinyl) -1H-indol-4-yl] methyl} -4-piperidinyl) phenyl] propanamide: with CuBr instead of Cu, Prepared by Procedure C and Scheme Q1 using 2-iodopyridine and N- {3- [1- (1H-indol-4-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide ESMS m / e: 453.2 (M + H) ⁺
[3010] Example 871
[3011] N- [3- (1-{[1- (2-fluorophenyl) -1H-indol-4-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: with CuBr instead of Cu Procedure C, using 1-fluoro-2-iodobenzene and N- {3- [1- (1H-indol-4-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide And prepared by scheme Q1: ESMS m / e: 470.1 (M + H) ⁺
[3012] Example 872
[3013] N- [3- (1-{[1- (4-chlorophenyl) -1H-indol-4-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: with CuBr instead of Cu, Procedure C and Schemes Using 1-chloro-4-iodobenzene and N- {3- [1- (1H-indol-4-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide Manufactured by Q1: ESMS m / e: 486.1 (M + H) ⁺
[3014] Example 873
[3015] 2-methyl-N- [3- (1-{[1- (3-pyridinyl) -1H-indol-4-yl] methyl} -4-piperidinyl) phenyl] propanamide: with CuBr instead of Cu, Prepared by Procedure C and Scheme Q1 using 3-iodopyridine and N- {3- [1- (1H-indol-4-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide ESMS m / e: 453.2 (M + H) ⁺
[3016] Example 874
[3017] N- [3- (1-{[1- (2,3-dimethylphenyl) -1H-indol-4-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: CuBr instead of Cu Using 1-iodo-2,3-dimethylbenzene and N- {3- [1- (1H-indol-4-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide Prepared by Procedure C and Scheme Q1: ESMS m / e: 480.1 (M + H) ⁺
[3018] Example 875
[3019] N- [3- (1-{[1- (3-fluorophenyl) -1H-indol-4-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: with CuBr instead of Cu Procedure C, using 1-fluoro-3-iodobenzene and N- {3- [1- (1H-indol-4-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide And prepared by scheme Q1: ESMS m / e: 470.1 (M + H) ⁺
[3020] Example 876
[3021] 2-methyl-N- {3- [1-({1- [2- (trifluoromethyl) phenyl] -1H-indol-4-yl} methyl) -4-piperidinyl] phenyl} propanamide: 1-iodo-2- (trifluoromethyl) benzene and N- {3- [1- (1H-indol-4-ylmethyl) -4-piperidinyl] phenyl} -2- with CuBr instead of Cu Prepared by Procedure C and Scheme Q1 using methylpropanamide: ESMS m / e: 520.1 (M + H) ⁺
[3022] Example 877
[3023] N- [3- (1-{[1- (2-chlorophenyl) -1H-indol-4-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: with CuBr instead of Cu, Procedure C and Schemes Using 1-chloro-2-iodobenzene and N- {3- [1- (1H-indol-4-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide Manufactured by Q1: ESMS m / e: 486.1 (M + H) ⁺
[3024] Example 878
[3025] N- [3- (1-{[1- (2,3-dimethylphenyl) -1H-indol-7-yl] methyl} -4-piperidinyl) phenyl] -2-methylpropanamide: CuBr instead of Cu With 1-iodo-2,3-dimethylbenzene and N- {3- [1- (1H-indol-7-ylmethyl) -4-piperidinyl] phenyl} -2-methylpropanamide Prepared by Procedure C and Scheme Q1: ESMS m / e: 480.0 (M + H) ⁺
[3026] 2-methyl-N- [3- (1- {5-oxo-5- (trifluoromethyl) phenyl] pentyl} -4-piperidinyl) phenyl] propanamide: 5-chloro-1- [4- Prepared by Procedure K and Scheme E using (trifluoromethyl) phenyl] -1-pentanone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e : 475.1 (M + H) ⁺
[3027] N- (3- {1- [5- (4-fluorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 5-chloro-1- (4-fluoro Prepared by Procedure K and Scheme E using rophenyl) -1-pentanone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 425.2 (M + H) ⁺
[3028] N- (3- {1- [5- (3-fluorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 5-chloro-1- (3-fluoro Prepared by Procedure K and Scheme E using rophenyl) -1-pentanone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 425.2 (M + H) ⁺
[3029] N- (3- {1- [5- (3-chlorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 5-chloro-1- (3-chlorophenyl Prepared by Procedure K and Scheme E using) -1-pentanone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 441.1 (M + H) ⁺
[3030] N- (3- {1- [5- (4-chlorophenyl) -5-oxopentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 5-chloro-1- (4-chlorophenyl Prepared by Procedure K and Scheme E using) -1-pentanone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 441.1 (M + H) ⁺
[3031] Example 879
[3032] 2-methyl-N- {3- [1- (3-oxo-3-phenylpropyl) -4-piperidinyl] phenyl} propanamide: NaI instead of K ₂ CO ₃ and KI instead of Na ₂ CO ₃ , and 3 Prepared by Procedure K and Scheme E using -chloro-1-phenyl-1-propaneone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m / e: 379.3 (M + H) ⁺
[3033] Example 880
[3034] N- (3- {1- [7- (2-fluorophenyl) -7-oxo-heptyl] -4-piperidinyl} phenyl) -2-methylpropanamide: Na ₂ CO ₃ instead of K ₂ CO ₃ and Procedure K using NaI, and 7-chloro-1- (2-fluorophenyl) -1-heptanone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide instead of KI and Prepared by Scheme E: ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.17 (s, br, 1H), 8.06-6.88 (m, 8H), 3.08-2.94 (m, 4H), 2.62-2.48 (m , 1H), 2.48-2.38 (m, 1H), 2.38-2.15 (m, 2H), 2.02-1.92 (m, 2H), 1.84-1.77 (m, 4H), 1.77-1.66 (m, 2H), 1.62 -1.46 (m, 2H), 1.46-1.29 (m, 4H), 1.21 (d, 6H, J = 6.8 Hz); ESMS m / e: 453.2 (M + H) ⁺
[3035] Example 881
[3036] N- (3- {1- [5- (2-fluorophenyl) -5-oxo-pentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: Na ₂ CO ₃ instead of K ₂ CO ₃ and Procedure K and NaI, and 5-chloro-1- (2-fluorophenyl) -1-pentanone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide instead of KI and Prepared by scheme E: ESMS m / e: 425.2 (M + H) ⁺
[3037] Example 882
[3038] N- (3- {1- [6- (3-fluorophenyl) -6-oxo-hexyl] -4-piperidinyl} phenyl) -2-methylpropanamide: Na ₂ CO ₃ instead of K ₂ CO ₃ and Procedure K using NaI and 6-chloro-1- (3-fluorophenyl) -1-hexanone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide instead of KI and Prepared by scheme E: ESMS m / e: 439.2 (M + H) ⁺
[3039] Example 883
[3040] N- (3- {1- [6- (2-fluorophenyl) -6-oxo-hexyl] -4-piperidinyl} phenyl) -2-methylpropanamide: Na ₂ CO ₃ instead of K ₂ CO ₃ and Procedure K using NaI and 6-chloro-1- (2-fluorophenyl) -1-hexanone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide instead of KI and Prepared by scheme E: ESMS m / e: 439.2 (M + H) ⁺
[3041] Example 884
[3042] N- (3- {1- [7- (4-fluorophenyl) -7-oxo-heptyl] -4-piperidinyl} phenyl) -2-methylpropanamide: Na ₂ CO ₃ instead of K ₂ CO ₃ and Procedure K using NaI and 7-chloro-1- (4-fluorophenyl) -1-heptanone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide instead of KI and Prepared by Scheme E: ESMS m / e: 453.2 (M + H) ⁺
[3043] Example 885
[3044] N- (3- {1- [6- (4-chlorophenyl) -6-oxohexyl] -4-piperidinyl} phenyl) -2-methylpropanamide: K ₂ CO ₃ and KI instead of Na ₂ CO ₃ Procedure K and Scheme E using NaI and 6-chloro-1- (4-chlorophenyl) -1-hexanone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide instead Manufactured by: ESMS m / e: 455.1 (M + H) ⁺
[3045] Example 886
[3046] N- (3- {1- [7- (4-chlorophenyl) -7-oxoheptyl] -4-piperidinyl} phenyl) -2-methylpropanamide: K ₂ CO ₃ and KI instead of Na ₂ CO ₃ Procedure K and Scheme E instead using NaI and 7-chloro-1- (4-chlorophenyl) -1-heptanone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide Manufactured by: ESMS m / e: 469.1 (M + H) ⁺
[3047] Example 887
[3048] N- (3- {1- [6- (4-fluorophenyl) -6-oxo-hexyl] -4-piperidinyl} phenyl) -2-methylpropanamide: Na ₂ CO ₃ instead of K ₂ CO ₃ and Procedure K using NaI, and 6-chloro-1- (4-fluorophenyl) -1-hexanone and 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide instead of KI and Prepared by scheme E: ESMS m / e: 439.1 (M + H) ⁺
[3049] Example 888
[3050] N- (3- {1- [6- (3-acetylphenoxy) -6- (2-fluorophenyl) hexyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1- (3 -Hydroxyphenyl) ethanone and N- (3- {1- [6- (2-fluorophenyl) -6-hydroxyhexyl] -4-piperidinyl} phenyl) -2-methylpropanamide Prepared by Procedure A and Scheme AN by: ESMS m / e: 559.5 (M + H) ⁺
[3051] Example 889
[3052] N- (3- {1- [6- (2-fluorophenoxy) -6- (2-fluorophenyl) hexyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 2-fluoro Procedure A and Scheme Using Rophenol and N- (3- {1- [6- (2-fluorophenyl) -6-hydroxyhexyl] -4-piperidinyl} phenyl) -2-methylpropanamide Manufactured by AN: ESMS m / e: 535.1 (M + H) ⁺
[3053] Example 890
[3054] N- (3- {1- [6- (4-fluorophenoxy) -6- (2-fluorophenyl) hexyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4-fluoro Procedure A and Scheme Using Rophenol and N- (3- {1- [6- (2-fluorophenyl) -6-hydroxyhexyl] -4-piperidinyl} phenyl) -2-methylpropanamide Prepared by AN: ¹ H NMR (400 MHz, CDCl ₃ ), HCl salt δ7.72-6.72 (m, 12H), 5.42-5.34 (m, 1H), 3.68-3.58 (m, br, 2H), 3.02 -2.92 (m, 2H), 2.80-2.46 (m, 6H), 2.05-1.78 (m, 6H), 1.68-1.56 (m, 1H), 1.56-1.38 (m, 3H), 1.25 (d, 6H, J = 6.8 Hz); ESMS m / e: 535.1 (M + H) ⁺
[3055] Example 891
[3056] N- (3- {1- [6- (2-fluorophenyl) -6- (2-methoxyphenoxy) hexyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 2-meth Procedure A and Scheme Using Oxyphenol and N- (3- {1- [6- (2-fluorophenyl) -6-hydroxyhexyl] -4-piperidinyl} phenyl) -2-methylpropanamide Manufactured by AN: ESMS m / e: 547.0 (M + H) ⁺
[3057] Example 892
[3058] N- (3- {1- [6- (2-fluorophenyl) -6- (4-methoxyphenoxy) hexyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4-meth Procedure A and Scheme Using Oxyphenol and N- (3- {1- [6- (2-fluorophenyl) -6-hydroxyhexyl] -4-piperidinyl} phenyl) -2-methylpropanamide Manufactured by AN: ESMS m / e: 547.1 (M + H) ⁺
[3059] Example 893
[3060] N- (3- {1- [6- (4-acetylphenoxy) -6- (2-fluorophenyl) hexyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1- (4 -Hydroxyphenyl) ethanone and N- (3- {1- [6- (2-fluorophenyl) -6-hydroxyhexyl] -4-piperidinyl} phenyl) -2-methylpropanamide Prepared by Procedure A and Scheme AN by: ESMS m / e: 559.2 (M + H) ⁺
[3061] Example 894
[3062] N- (3- {1- [6- (3,4-dimethoxyphenoxy) -6- (2-fluorophenyl) hexyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 3 , 4-dimethoxyphenol and N- (3- {1- [6- (2-fluorophenyl) -6-hydroxyhexyl] -4-piperidinyl} phenyl) -2-methylpropanamide Manufactured by Procedure A and Scheme AN: ESMS m / e: 577.6 (M + H) ⁺
[3063] Example 895
[3064] N- (3- {1- [6- (2-ethoxyphenoxy) -6- (2-fluorophenyl) hexyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 2-in Procedure A and Scheme Using Oxyphenol and N- (3- {1- [6- (2-fluorophenyl) -6-hydroxyhexyl] -4-piperidinyl} phenyl) -2-methylpropanamide Manufactured by AN: ESMS m / e: 561.1 (M + H) ⁺
[3065] Example 896
[3066] N- (3- {1- [6- (4-bromophenoxy) -6-phenylhexyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4-bromophenol and N- { Prepared by Procedure A and Scheme AN using 3- [1- (6-hydroxy-6-phenylhexyl) -4-piperidinyl] phenyl} -2-methylpropanamide: ESMS m / e: 577.0 ( M + H) ⁺
[3067] Example 897
[3068] N- (3- {1- [6- (4-fluorophenoxy) -6- (4-fluorophenyl) hexyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4-fluoro Procedure A and Scheme Using Rophenol and N- (3- {1- [6- (4-fluorophenyl) -6-hydroxyhexyl] -4-piperidinyl} phenyl) -2-methylpropanamide Prepared by AN: ¹ H NMR (400 MHz, CDCl ₃ ), HC1 salt δ8.22 (s, br, 1H), 7.74-6.70 (m, 12H), 5.05-4.94 (m, 1H), 3.66-3.52 (m, br, 2H), 3.02-2.83 (m, br, 2H), 2.81-2.58 (m, br, 4H), 2.58-2.36 (m, br, 2H), 2.02-1.66 (m, br, 6H ), 1.66-1.46 (m, br, 1H), 1.46-1.35 (m, br, 3H), 1.26 (d, 6H, J = 6.0 Hz); ESMS m / e: 535.1 (M + H) ⁺
[3069] Example 898
[3070] N- (3- {1- [6- (4-methoxyphenoxy) -6-phenylhexyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4-methoxyphenol and N- { Prepared by Procedure A and Scheme AN using 3- [1- (6-hydroxy-6-phenylhexyl) -4-piperidinyl] phenyl} -2-methylpropanamide: ESMS m / e: 529.6 ( M + H) ⁺
[3071] Example 899
[3072] N- (3- (1- [6- (4-chlorophenoxy) -6- (4-chlorophenyl) hexyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4-chlorophenol and Prepared by Procedure A and Scheme AN using N- {3- (1- [6- (4-chlorophenyl) -6-hydroxyhexyl] -4-piperidinyl} phenyl) -2-methylpropanamide ESMS m / e: 566.9 (M + H) ⁺
[3073] Example 900
[3074] N- (3- {1- [6- (4-bromophenoxy) -6- (4-fluorophenyl) hexyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4-bro Procedure A and Scheme Using Morphenol and N- (3- {1- [6- (4-fluorophenyl) -6-hydroxyhexyl] -4-piperidinyl} phenyl) -2-methylpropanamide Manufactured by AN: ESMS m / e: 595.0 (M + H) ⁺
[3075] Example 901
[3076] N- (3- {1- [6- (4-chlorophenoxy) -6- (4-fluorophenyl) hexyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4-chlorophenol And N- (3- {1- [6- (4-fluorophenyl) -6-hydroxyhexyl] -4-piperidinyl} phenyl) -2-methylpropanamide in Procedure A and Scheme AN Prepared by: ¹ H NMR (400 MHz, CDCl ₃ ), HCl salt δ7.93 (s, 1H), 7.72-6.68 (m, 12H), 5.06-4.98 (m, 1H), 3.66-3.50 (m, br , 2H), 3.02-2.82 (m, br, 2H), 2.80-2.57 (m, br, 4H), 2.57-2.38 (m, br, 2H), 2.02-1.76 (m, br, 6H), 1.64- 1.48 (m, br, 1 H), 1.48-1.36 (m, br, 3 H), 1.25 (d, 6H, J = 6.8 Hz); Analytical calcd. For C ₃₃ H ₄₁ Cl ₂ FN ₂ 0 ₂ .0.5EtOAc: C, 66.55; H, 7. 18; N, 4.43; Found C, 66.35; H, 6. 86; N, 4.46. ESMS m / e: 550.8 (M + H) ⁺
[3077] Example 902
[3078] N- (3- {1- [6- (4-chlorophenyl) -6- (4-fluorophenoxy) hexyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4-fluoro Procedure A and Scheme AN using phenol and N- (3- {1- [6- (4-chlorophenyl) -6-hydroxyhexyl] -4-piperidinyl} phenyl) -2-methylpropanamide Prepared by: ¹ H NMR (400 MHz, CDCl ₃ ), HCl salt δ8.22 (s, br, 1H), 7.74-6.68 (m, 12H), 5.04-4.92 (m, 1H), 3.66-3.50 (m , br, 2H), 3.00-2.82 (br, 2H), 2.80-2.58 (m, br, 4H), 2.58-2.40 (m, br, 2H), 2.00-1.68 (m, br, 6H), 1.66- 1.46 (m, br, 1 H), 1.46-1.36 (br, 3H), 1.25 (d, 6H, J = 7.2 Hz); ESMS m / e: 551.1 (M + H) ⁺
[3079] Example 903
[3080] N- (3- {1- [6- (3-acetylphenoxy) -6-phenylhexyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1- (3-hydroxyphenyl) eta Prepared by Procedure A and Scheme AN using non and N- {3- [1- (6-hydroxy-6-phenylhexyl) -4-piperidinyl] phenyl} -2-methylpropanamide: ESMS m / e: 541.2 (M + H) ⁺
[3081] Example 904
[3082] N- (3- {1- [6- (4-chlorophenoxy) -6-phenylhexyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4-chlorophenol and N- {3- Prepared by Procedure A and Scheme AN using [1- (6-hydroxy-6-phenylhexyl) -4-piperidinyl] phenyl} -2-methylpropanamide: ¹ H NMR (400 MHz, CDCl ₃ ), HCl salt δ8.28 (s, 1H), 7.78-6.70 (m, 13H), 5.08-4.98 (m, 1H), 3.64-3.46 (m, br, 2H), 3.02-2.82 (br, 2H) , 2.82-2.56 (m, br, 4H), 2.56-2.34 (m, br, 2H), 2.05-1.75 (m, br, 6H), 1.64-1.48 (m, br, 1H), 1.48-1.34 (br , 3H), 1.25 (d, 6H, J = 6.8 Hz); ESMS m / e: 533.1 (M + H) ⁺
[3083] Example 905
[3084] N- (3- {1- [6- (4-bromophenoxy) -6- (4-chlorophenyl) hexyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4-bromo Procedure A and Scheme AN using phenol and N- (3- {1- [6- (4-chlorophenyl) -6-hydroxyhexyl] -4-piperidinyl} phenyl) -2-methylpropanamide Manufactured by: ESMS m / e: 611.0 (M + H) ⁺
[3085] Example 906
[3086] N- (3- {1- [6- (4-chlorophenyl) -6- (4-methoxyphenoxy) hexyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4-methoxy Procedure A and Scheme AN using phenol and N- (3- {1- [6- (4-chlorophenyl) -6-hydroxyhexyl] -4-piperidinyl} phenyl) -2-methylpropanamide Manufactured by: ESMS m / e: 563.1 (M + H) ⁺
[3087] Example 907
[3088] N- (3- {1- [6- (4-fluorophenyl) -6- (4-methoxyphenoxy) hexyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4-meth Procedure A and Scheme AN using oxyphenol and N- (3- {1- [6- (4-fluorophenyl) -6-hydroxy] -4-piperidinyl} phenyl) -2-methylpropanamide Prepared by: ¹ H NMR (400 MHz, CDCl ₃ ), HCl salt δ8.11 (s, 1H), 7.65-6.84 (m, 12H), 5.21-5.10 (m, 1H), 3.66-3.56 (m, br, 2H), 3.02-2.82 (br, 2H), 2.82-2.56 (m, br, 4H), 2.54 (s, 3H), 2.53-2.32 (m, br, 2H), 2.02-1.70 (m, br , 6H), 1.64-1.48 (m, br, 1H), 1.48-1.34 (br, 3H), 1.25 (d, 6H, J = 6.8 Hz); ESMS m / e: 547.1 (M + H) ⁺
[3089] Example 908
[3090] N- (3- {1- [6- (3-acetylphenoxy) -6- (4-fluorophenyl) hexyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1- (3 -Hydroxyphenyl) ethanone and N- (3- {1- [6- (4-fluorophenyl) -6-hydroxyhexyl] -4-piperidinyl} phenyl) -2-methylpropanamide Prepared by Procedure A and Scheme AN by: ESMS m / e: 559.1 (M + H) ⁺
[3091] Example 909
[3092] N- (3- {1- [6- (4-fluorophenoxy) -6-phenylhexyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4-fluorophenol and N- { Prepared by Procedure A and Scheme AN using 3- [1- (6-hydroxy-6-phenylhexyl) -4-piperidinyl] phenyl} -2-methylpropanamide: ¹ H NMR (400 MHz, CDCl ₃ ), HCl salt δ 8.05 (s, br, 1H), 7.72-6.70 (m, 13H), 5.06-4.96 (m, 1H), 3.66-3.51 (m, 2H), 3.01-2.82 (m, br, 2H), 2.82-2.57 (m, br, 4H), 2.57-2.34 (m, br, 2H), 2.05-1.78 (m, br, 6H), 1.64-1.52 (m, br, 1H), 1.52 -1.16 (m, br, 3H), 1.25 (d, 6H, J = 7.2 Hz); ESMS m / e: 517.0 (M + H) ⁺
[3093] Example 910
[3094] N- (3- {1- [6- (2-acetylphenoxy) -6- (2-fluorophenyl) hexyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1- (2 -Hydroxyphenyl) ethanone and N- (3- {1- [6- (2-fluorophenyl) -6-hydroxyhexyl] -4-piperidinyl} phenyl) -2-methylpropanamide Prepared by Procedure A and Scheme AN by: ESMS m / e: 559.0 (M + H) ⁺
[3095] Example 911
[3096] N- [3- (1- {6- (4-fluorophenyl) -6- [2-fluoro-5- (trifluoromethyl) phenoxy] hexyl} -4-piperidinyl) phenyl]- 2-methylpropanamide: 2-fluoro-5- (trifluoromethyl) phenol and N- (3- {1- [6- (4-fluorophenyl) -6-hydroxyhexyl] -4-pipe Prepared by Procedure A and Scheme AN using ridinyl} phenyl) -2-methylpropanamide: ¹ H NMR (400 MHz, CDCl ₃ ), HCl salt δ8.23 (s, br, 1H), 7.74-6.88 (m, 11H), 5.20-5.12 (m, 1H), 3.68-3.52 (m, br, 2H), 3.02-2.82 (m, br, 2H), 2.82-2.60 (m, 4H), 2.58-2.38 ( m, br, 2H), 2.12-2.02 (m, br, 1H), 2.02-1.80 (m, br, 5H), 1.68-1.52 (m, br, 1H), 1.52-1.36 (br, 3H), 1.25 (d, 6H, J = 7.2 Hz); ESMS m / e: 603.3 (M + H) ⁺
[3097] Example 912
[3098] N- (3- {1- [6- (3-acetylphenoxy) -6- (4-chlorophenyl) hexyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1- (3- Procedure using hydroxyphenyl) ethanone and N- (3- {1- [6- (4-chlorophenyl) -6-hydroxyhexyl] -4-piperidinyl} phenyl) -2-methylpropanamide Prepared by A and Scheme AN: ¹ H NMR (400 MHz, CDCl ₃ ), HCl salt δ8.41 (s, 1H), 7.72-6.84 (m, 12H), 5.18-5.10 (m, 1H), 3.62- 3.50 (m, br, 2H), 3.00-2.92 (m, 2H), 2.90-2.58 (m, 4H), 2.54 (s, 3H), 2.50-2.12 (m, 2H), 2.02-1.70 (m, br , 6H), 1.64-1.50 (m, br, 1H), 1.50-1.14 (m, br, 3H), 1.25 (d, 6H, J = 6.8 Hz); ESMS m / e: 575.3 (M + H) ⁺
[3099] Example 913
[3100] N- [3- (1- {6- (2-fluorophenyl) -6- [2-fluoro-5- (trifluoromethyl) phenoxy] hexyl} -4-piperidinyl) phenyl]- 2-methylpropanamide: 2-fluoro-5- (trifluoromethyl) phenol and N- (3- {1- [6- (2-fluorophenyl) -6-hydroxyhexyl] -4-pipe Prepared by Procedure A and Scheme AN using ridinyl} phenyl) -2-methylpropanamide: ¹ H NMR (400 MHz, CDCl ₃ ), HCl salt δ8.35 (s, 1H), 7.68-6.82 (m , 11H), 5.58-5.48 (m, 1H), 3.64-3.50 (m, 2H), 3.01-2.94 (m, br, 2H), 2.92-2.54 (m, 4H), 2.48-2.32 (m, br, 2H), 2.20-2.04 (m, 1H), 2.01-1.80 (m, 5H), 1.70-1.54 (m, 1H), 1.54-1.36 (m, 3H), 1.25 (d, 6H, J = 7.2 Hz) . Analytical calcd. For C ₃₄ H ₄₀ ClF ₅ N ₂ 0 ₂ .0.6MeOH: C, 63.12; H, 6. 49; N, 4.25; Found: C, 63.38; H, 6. 61; N, 3.95. ESMS m / e: 603.3 (M + H) ⁺
[3101] Example 914
[3102] N- [3- (1- {6- (4-chlorophenyl) -6- [2-fluoro-5- (trifluoromethyl) phenoxy] hexyl} -4-piperidinyl) phenyl] -2 -Methylpropanamide: 2-fluoro-5- (trifluoromethyl) phenol and N- (3- {1- [6- (4-chlorophenyl) -6-hydroxyhexyl] -4-piperidinyl Prepared by Procedure A and Scheme AN using phenyl) -2-methylpropanamide: ESMS m / e: 619.2 (M + H) ⁺
[3103] Example 915
[3104] N- [3- (1- {6- (3-fluorophenyl) -6- [2-fluoro-5- (trifluoromethyl) phenoxy] hexyl} -4-piperidinyl) phenyl]- 2-methylpropanamide: 2-fluoro-5- (trifluoromethyl) phenol and N- (3- {1- [6- (3-fluorophenyl) -6-hydroxyhexyl] -4-pipe Prepared by Procedure A and Scheme AN using ridinyl} phenyl) -2-methylpropanamide: ESMS m / e: 603.3 (M + H) ⁺
[3105] Example 916
[3106] N- [3- (1- {6- [2-fluoro-5- (trifluoromethyl) phenoxy] -6-phenylhexyl} -4-piperidinyl) phenyl] -2-methylpropanamide: 2-fluoro-5- (trifluoromethyl) phenol and N- {3- [1- (6-hydroxy-6-phenylhexyl) -4-piperidinyl] phenyl} -2-methylpropanamide Prepared by Procedure A and Scheme AN using: ESMS m / e: 585.3 (M + H) ⁺
[3107] Example 917
[3108] N- [3- (1- {7- (2-fluorophenyl) -7- [2-fluoro-5- (trifluoromethyl) phenoxy] heptyl} -4-piperidinyl) phenyl]- 2-methylpropanamide: 2-fluoro-5- (trifluoromethyl) phenol and N- (3- {1- [7- (2-fluorophenyl) -7-hydroxyheptyl] -4-pipe Prepared by Procedure A and Scheme AN using ridinyl} phenyl) -2-methylpropanamide: ESMS m / e: 617.3 (M + H) ⁺
[3109] Example 918
[3110] N- (3- {1- [5- (4-fluorophenyl) -5- (4-methoxyphenoxy) pentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4-meth Procedure A and Scheme Using Oxyphenol and N- (3- {1- [5- (4-fluorophenyl) -5-hydroxypentyl] -4-piperidinyl} phenyl) -2-methylpropanamide Manufactured by AN: ESMS m / e: 533.1 (M + H) ⁺
[3111] Example 919
[3112] N- (3- {1- [5- (4-bromophenoxy) -5- (4-fluorophenyl) pentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4-bro Procedure A and Scheme Using Morphenol and N- (3- {1- [5- (4-fluorophenyl) -5-hydroxypentyl] -4-piperidinyl} phenyl) -2-methylpropanamide Prepared by AN: ¹ H NMR (400 MHz, CDCl ₃ ), HCl salt δ7.94 (s, br, 1H), 7.68-6.64 (m, 12H), 5.12-5.04 (m, 1H), 3.68-3.52 (m, br, 2H), 3.01-2.82 (br, 2H), 2.78-2.58 (m, br, 4H), 2.57-2.38 (m, br, 2H), 2.05-1.80 (m, br, 6H), 1.64-1.38 (m, br, 2H), 1.25 (d, 6H, J = 7. 2 Hz); ESMS m / e: 581.0 (M + H) ⁺
[3113] Example 920
[3114] N- (3- {1- [5- (4-chlorophenoxy) -5- (4-chlorophenyl) pentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4-chlorophenol and Prepared by Procedure A and Scheme AN using N- (3- {1- [5- (4-chlorophenyl) -5-hydroxypentyl] -4-piperidinyl} phenyl) -2-methylpropanamide : ¹ H NMR (400 MHz, CDCl ₃ ), HCl salt δ 7.86 (s, br, 1H), 7.62-6.72 (m, 12H), 5.12-5.02 (m, 1H), 3.68-3.52 (m, br , 2H), 3.02-2.82 (br, 2H), 2.82-2.56 (m, br, 4H), 2.56-2.40 (m, br, 2H), 2.06-1.80 (m, br, 6H), 1.64-1.40 ( m, br, 2H), 1.25 (d, 6H, J = 6.8 Hz). Analytical calcd. For C ₃₂ H ₃₉ Cl ₃ N ₂ 0 ₂ .1.3MeOH: C, 63.25; H, 7.07; N, 4. 42; Found: C, 63.41; H, 6. 99; N, 4.17. ESMS m / e: 553.0 (M + H) ⁺
[3115] Example 921
[3116] N- (3- {1- [5- (4-chlorophenoxy) -5-phenylpentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4-chlorophenol and N- {3- Prepared by Procedure A and Scheme AN using [1- (5-hydroxy-5-phenylpentyl) -4-piperidinyl] phenyl} -2-methylpropanamide: ¹ H NMR (400 MHz, CDCl ₃ ), HCl salt δ7.72-6.72 (m, 13H), 5.12-5.04 (m, 1H), 3.66-3.52 (m, br, 2H), 3.01-2.83 (br, 2H), 2.68-2.62 (m, br, 2H), 2.62-2.48 (m, br, 4H), 2.04-1.82 (m, br, 6H), 1.62-1.40 (m, br, 2H), 1.25 (d, 6H, J = 7.2 Hz); ESMS m / e: 519.1 (M + H) ⁺
[3117] Example 922
[3118] N- (3- {1- [5- (3-acetylphenoxy) -5- (4-fluorophenyl) pentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1- (3 -Hydroxyphenyl) ethanone and N- (3- {1- [5- (4-fluorophenyl) -5-hydroxypentyl] -4-piperidinyl} phenyl) -2-methylpropanamide Prepared by Procedure A and Scheme AN by: ESMS m / e: 545.1 (M + H) ⁺
[3119] Example 923
[3120] N- (3- {1- [5- (4-chlorophenyl) -5- (4-fluorophenoxy) pentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4-fluoro Procedure A and Scheme AN using phenol and N- (3- {1- [5- (4-chlorophenyl) -5-hydroxypentyl] -4-piperidinyl} phenyl) -2-methylpropanamide Prepared by: ¹ H NMR (400 MHz, CDCl ₃ ), HCl salt δ8.05 (s, br, 1H), 7.74-6.68 (m, 12H), 5.08-4.99 (m, 1H), 3.67-3.56 (m , br, 2H), 3.02-2.82 (br, 2H), 2.80-2.57 (m, br, 4H), 2.57-2.38 (m, br, 2H), 2.05-1.80 (m, br, 6H), 1.64- 1.40 (m, br, 2H), 1.25 (d, 6H, J = 7.2 Hz). Analytical calcd. For C ₃₂ H ₃₉ Cl ₂ FN ₂ 0 ₂ .1.3EtOAc: C, 64.93; H, 7.24; N, 4.07. Found: C, 65.01; H, 6.97; N, 3.85. ESMS m / e: 537.1 (M + H) ⁺
[3121] Example 924
[3122] N- (3- {1- [5- (4-bromophenoxy) -5-phenylpentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4-bromophenol and N- { Prepared by Procedure A and Scheme AN using 3- [1- (5-hydroxy-5-phenylpentyl) -4-piperidinyl] phenyl} -2-methylpropanamide: ¹ H NMR (400 MHz, CDCl ₃ ), HCl salt δ7.74-6.66 (m, 13H), 5.13-5.02 (m, 1H), 3.73-3.51 (m, br, 2H), 3.05-2.83 (br, 2H), 2.83-2.62 ( br, 4H), 2.62-2.42 (m, br, 2H), 2.10-1.80 (m, br, 6H), 1.65-1.37 (m, br, 2H), 1.25 (d, 6H, J = 6.8 Hz); ESMS m / e: 562.9 (M + H) ⁺
[3123] Example 925
[3124] N- (3- {1- [5- (4-chlorophenyl) -5- (4-methoxyphenoxy) pentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4-methoxy Procedure A and Scheme AN using phenol and N- (3- {1- [5- (4-chlorophenyl) -5-hydroxypentyl] -4-piperidinyl} phenyl) -2-methylpropanamide Prepared by: ¹ H NMR (400 MHz, CDCl ₃ ), HCl salt δ8.13 (s, br, 1H), 7.72-6.70 (m, 12H), 5.08-4.97 (m, 1H), 3.72 (s, 3H ), 3.66-3.50 (m, br, 2H), 3.03-2.82 (br, 2H), 2.80-2.54 (m, br, 4H), 2.53-2.17 (m, br, 2H), 2.08-1.78 (m, br, 6H), 1.65-1.38 (m, br, 2H), 1.25 (d, 6H, J = 6.8 Hz). Analytical calcd. For C ₃₃ H ₄₂ Cl ₂ N ₂ 0 ₃ .0.54CH ₂ Cl ₂ : C, 63.80; H, 6.88; N, 4.44. Found: C, 63.84; H, 7. 18; N, 4.00. ESMS m / e: 549.1 (M + H) ⁺
[3125] Example 926
[3126] N- (3- {1- [5- (4-fluorophenoxy) -5- (4-fluorophenyl) pentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4-fluoro Procedure A and Scheme Using Rophenol and N- (3- {1- [5- (4-fluorophenyl) -5-hydroxypentyl] -4-piperidinyl} phenyl) -2-methylpropanamide Prepared by AN: ¹ H NMR (400 MHz, CDCl ₃ ), HCl salt δ7.62-6.70 (m, 12H), 5.10-5.00 (m, 1H), 3.71-3.56 (m, br, 2H), 3.04 -2.82 (br, 2H), 2.78-2.64 (m, br, 3H), 2.64-2.48 (m, br, 3H), 2.05-1.82 (m, br, 6H), 1.62-1.42 (m, br, 2H ), 1.25 (d, 6H, J = 6.0 Hz); ESMS m / e: 521.2 (M + H) ⁺
[3127] Example 927
[3128] N- (3- {1- [5- (3-acetylphenoxy) -5-phenylpentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1- (3-hydroxyphenyl) eta Prepared by Procedure A and Scheme AN using non and N- {3- [1- (5-hydroxy-5-phenylpentyl) -4-piperidinyl] phenyl} -2-methylpropanamide: ESMS m / e: 526.9 (M + H) ⁺
[3129] Example 928
[3130] N- (3- {1- [5- (4-methoxyphenoxy) -5-phenylpentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4-methoxyphenol and N- { Prepared by Procedure A and Scheme AN using 3- [1- (5-hydroxy-5-phenylpentyl) -4-piperidinyl] phenyl} -2-methylpropanamide: ESMS m / e: 515.6 ( M + H) ⁺
[3131] Example 929
[3132] N- [3- (1- {5- [2-fluoro-5- (trifluoromethyl) phenoxy] -5- [4- (trifluoromethyl) phenyl] pentyl} -4-piperidinyl ) Phenyl] -2-methylpropanamide: 2-fluoro-5- (trifluoromethyl) phenol and N- [3- (1- {5-hydroxy-5- [4- (trifluoromethyl) Prepared by Procedure A and Scheme AN using phenyl] pentyl} -4-piperidinyl) phenyl] -2-methylpropanamide: ESMS m / e: 639.2 (M + H) ⁺
[3133] Example 930
[3134] N- [3- (1- {5- (3-chlorophenyl) -5- [2-fluoro-5- (trifluoromethyl) phenoxy] pentyl} -4-piperidinyl) phenyl] -2 -Methylpropanamide: 2-fluoro-5- (trifluoromethyl) phenol and N- (3- {1- [5- (3-chlorophenyl) -5-hydroxypentyl] -4-piperidinyl Prepared by Procedure A and Scheme AN using phenyl) -2-methylpropanamide: ¹ H NMR (400 MHz, CDCl ₃ ), HCl salt δ8.17 (s, br, 1H), 7.75-6.88 (m , 11H), 5.26-5.14 (m, 1H), 3.68-3.56 (m, br, 2H), 3.05-2.90 (br, 2H), 2.90-2.60 (m, br, 4H), 2.56-2.36 (m, br, 2H), 2.18-1.84 (m, br, 6H), 1.70-1.44 (m, br, 2H), 1.25 (d, 6H, J = 7.2 Hz). C ₃₃ H ₃₈ Cl ₂ F ₄ N ₂ 0 Analytical Calcd for ₂ · 0.9EtOAc: C, 60.98; H, 6. 32; N, 3.89; Found: C, 60.99; H, 6. 17; N, 3.81. ESMS m / e: 605.2 (M + H) ⁺
[3135] Example 931
[3136] N- [3- (1- {5- (2-fluorophenyl) -5- [2-fluoro-5- (trifluoromethyl) phenoxy] pentyl} -4-piperidinyl) phenyl]- 2-methylpropanamide: 2-fluoro-5- (trifluoromethyl) phenol and N- (3- {1- [5- (2-fluorophenyl) -5-hydroxypentyl] -4-pipe Prepared by Procedure A and Scheme AN using ridinyl} phenyl) -2-methylpropanamide: ¹ H NMR (400 MHz, CDCl ₃ ), HCl salt 7.89 (s, br, 1H), 7.72-6.88 (m 11H), 5.59-5.48 (m, 1H), 3.70-3.48 (br, 2H), 3.05-2.84 (br, 2H), 2.82-2.58 (m, br, 4H), 2.58-2.40 (m, br, 2H), 2.22-1.82 (m, br, 6H), 1.71-1.42 (m, br, 2H), 1.25 (d, 6H, J = 6.4 Hz); ESMS m / e: 589.3 (M + H) ⁺
[3137] Example 932
[3138] N- [3- (1- {5- (3-fluorophenyl) -5- [2-fluoro-5- (trifluoromethyl) phenoxy] pentyl} -4-piperidinyl) phenyl]- 2-methylpropanamide: 2-fluoro-5- (trifluoromethyl) phenol and N- (3- {1- [5- (3-fluorophenyl) -5-hydroxypentyl] -4-pipe Prepared by Procedure A and Scheme AN using ridinyl} phenyl) -2-methylpropanamide: ¹ H NMR (400 MHz, CDCl ₃ ), HCl salt δ 7.79 (s, br, 1H), 7.63-6.82 (m, 11H), 5.24-5.15 (m, 1H), 3.70-3.56 (br, 2H), 3.04-2.84 (br, 2H), 2.82-2.60 (m, br, 4H), 2.60-2.42 (m, br, 2H), 2.20-1.83 (m, br, 6H), 1.70-1.44 (m, br, 2H), 1.25 (d, 6H, J = 6.4 Hz); ESMS m / e: 589.3 (M + H) ⁺
[3139] Example 933
[3140] N- (3- {1- [5- (3-acetylphenoxy) -5- (4-chlorophenyl) pentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1- (3- Procedure using hydroxyphenyl) ethanone and N- (3- {1- [5- (4-chlorophenyl) -5-hydroxypentyl] -4-piperidinyl} phenyl) -2-methylpropanamide Prepared by A and Scheme AN: ¹ H NMR (400 MHz, CDCl ₃ ), HCl salt δ8.05 (s, br, 1H), 7.74-6.88 (m, 12H), 5.27-5.16 (m, 1H), 3.69-3.52 (m, br, 2H), 3.10-2.81 (br, 2H), 2.81-2.57 (m, br, 4H), 2.54 (s, 3H), 2.52-2.40 (m, br, 2H), 2.05 -1.80 (m, br, 6H), 1.66-1.42 (m, br, 2H), 1.25 (d, 6H, J = 6.8 Hz); Analytical calcd. For C ₃₄ H ₄₂ Cl ₂ N ₂ 0 ₃ .0.5CH ₂ Cl ₂ .1.0H ₂ 0: C, 63.46; H, 6.91; N, 4.30. Found: C, 63.46; H, 7.09; N, 4.00. ESMS m / e: 561.1 (M + H) ⁺
[3141] Example 934
[3142] N- [3- (1- {5- (4-chlorophenyl) -5- [2-fluoro-5- (trifluoromethyl) phenoxy] pentyl} -4-piperidinyl) phenyl] -2 -Methylpropanamide: 2-fluoro-5- (trifluoromethyl) phenol and N- (3- {1- [5- (4-chlorophenyl) -5-hydroxypentyl] -4-piperidinyl Prepared by Procedure A and Scheme AN using phenyl) -2-methylpropanamide: ¹ H NMR (400 MHz, CDCl ₃ ), HCl salt δ7.61-6.92 (m, 11H), 5.24-5.16 (m , 1H), 3.70-3.58 (m, 2H), 3.02-2.91 (br, 2H), 2.80-2.64 (m, br, 3H), 2.64-2.50 (m, 3H), 2.18-1.94 (m, br, 6H), 1.62-1.44 (m, br, 2H), 1.25 (d, 6H, J = 7.2 Hz); ESMS m / e: 605.3 (M + H) ⁺
[3143] Example 935
[3144] N- [3- (1- {5- (4-fluorophenyl) -5- [2-fluoro-5- (trifluoromethyl) phenoxy] pentyl} -4-piperidinyl) phenyl]- 2-methylpropanamide: 2-fluoro-5- (trifluoromethyl) phenol and N- (3- {1- [5- (4-fluorophenyl) -5-hydroxypentyl] -4-pipe Prepared by Procedure A and Scheme AN using ridinyl} phenyl) -2-methylpropanamide: ESMS m / e: 589.3 (M + H) ⁺
[3145] Example 936
[3146] N- (3- {1- [5- (4-bromophenoxy) -5- (4-chlorophenyl) pentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4-bromo Procedure A and Scheme AN using phenol and N- (3- {1- [5- (4-chlorophenyl) -5-hydroxypentyl] -4-piperidinyl} phenyl) -2-methylpropanamide Manufactured by: ESMS m / e: 597.2 (M + H) ⁺
[3147] Example 937
[3148] N- (3- {1- [5- (4-chlorophenoxy) -5- (4-fluorophenyl) pentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4-chlorophenol And N- (3- {1- [5- (4-fluorophenyl) -5-hydroxypentyl] -4-piperidinyl} phenyl) -2-methylpropanamide in Procedure A and Scheme AN Manufactured by: ESMS m / e: 537.3 (M + H) ⁺
[3149] Example 938
[3150] N- (3- {1- [5- (2-acetylphenoxy) -5-phenylpentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 1- (2-hydroxyphenyl) eta Prepared by Procedure A and Scheme AN using non and N- {3- [1- (5-hydroxy-5-phenylpentyl) -4-piperidinyl] phenyl} -2-methylpropanamide: ESMS m / e: 527.0 (M + H) ⁺
[3151] Example 939
[3152] N- (3- {1- [5- (2-ethoxyphenoxy) -5-phenylpentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 2-ethoxyphenol and N- { Prepared by Procedure A and Scheme AN using 3- [1- (5-hydroxy-5-phenylpentyl) -4-piperidinyl] phenyl} -2-methylpropanamide: ESMS m / e: 529.2 ( M + H) ⁺
[3153] Example 940
[3154] N- (3- {1- [5- (4-fluorophenoxy) -5-phenylpentyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 4-fluorophenol and N- { Prepared by Procedure A and Scheme AN using 3- [1- (5-hydroxy-5-phenylpentyl) -4-piperidinyl] phenyl} -2-methylpropanamide: ESMS m / e: 503.2 ( M + H) ⁺
[3155] Example 941
[3156] N- (3- {1- [4- (4-fluorophenyl) -4-oxobutyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 2-methyl-N- [3- ( Prepared by Procedure K (KI) and Scheme E (K ₂ CO ₃ ) using 4-piperidinyl) phenyl] propanamide and 4-chloro-1- (4-fluorophenyl) -1-butanone: ESMS m / e: 411.2 (M + H) ⁺
[3157] Example 942
[3158] 2-methyl-N- (3- {1- [3- (1H-pyrrole-3-yl) propyl] -4-piperidinyl} phenyl) propanamide: 2-methyl-N- [3- (4- Prepared by procedure K (KI) and scheme E (K ₂ CO 3) using piperidinyl) phenyl] propanamide and 3- (3-bromopropyl) -1H-pyrrole: ESMS m / e: 354.2 (M + H) ⁺
[3159] Example 943
[3160] N- (3- {1- [4- (4-isopropylphenyl) -4-oxobutyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 2-methyl-N- [3- ( Prepared by Procedure K (KI) and Scheme E (K ₂ CO 3) using 4-piperidinyl) phenyl] propanamide and 4-chloro-1- (4-isopropylphenyl) -1-butanone: ESMS m / e: 435.2 (M + H) ⁺
[3161] Example 944
[3162] N- (3- {1- [4- (4-methoxyphenyl) -4-oxobutyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 2-methyl-N- [3- ( Prepared by Procedure K (KI) and Scheme E (K ₂ CO 3) using 4-piperidinyl) phenyl] propanamide and 4-chloro-1- (4-methoxyphenyl) -1-butanone: ESMSm / e: 423.2 (M + H) ⁺
[3163] Example 945
[3164] 2-methyl-N- (3- {1- [4- (4-methylphenyl) -4-oxobutyl] -4-piperidinyl} phenyl) propanamide: 2-methyl-N- [3- (4- Prepared by Procedure K (KI) and Scheme E (K ₂ CO 3) using piperidinyl) phenyl] propanamide and 4-chloro-1- (4-methylphenyl) -1-butanone: ESMS m / e: 407.2 (M + H) ⁺
[3165] Example 946
[3166] N- (3- {1- [4- (4-TERT-butylphenyl) -4-oxobutyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 2-methyl-N- [3- Prepared by Procedure K (KI) and Scheme E (K ₂ CO 3) using (4-piperidinyl) phenyl] propanamide and 1- (4-tert-butylphenyl) -4-chloro-1-butanone ESMS m / e: 449.2 (M + H) ⁺
[3167] Example 947
[3168] N- (3- {1- [4- (4-bromophenyl) -4-oxobutyl] -4-piperidinyl} phenyl) -2-methylpropanamide: 2-methyl-N- [3- ( Prepared by Procedure K (KI) and Scheme E (K ₂ CO 3) using 4-piperidinyl) phenyl] propanamide and 1- (4-bromophenyl) -4-chloro-1-butanone: ESMS m / e: 471.3 (M + H) ⁺
[3169] Example 948
[3170] 2-methyl-N- (3- {1- [4-oxo-4- (2-thienyl) butyl] -4-piperidinyl} phenyl) propanamide: 2-methyl-N- [3- (4 Prepared by Procedure K (KI) and Scheme E (K ₂ CO 3) using -piperidinyl) phenyl] propanamide and 4-chloro-1- (2-thienyl) -1-butanone: ESMS m / e: 399.1 (M + H) ⁺
[3171] II. Synthesis method of general structure
[3172] The example described in paragraph I merely illustrates the method used to synthesize MCH1 antagonists. Other derivatives can be obtained using generalized methods based on the synthetic methods used to synthesize the examples.
[3173] It may be necessary to incorporate protection and deprotection methods for substituents such as amino, amido, carboxylic acid and hydroxyl groups into generalized synthetic methods to form other derivatives. Found in the protection and deprotection methods of such groups are are well known in the art, for example, literature [in Green, TW and Wuts, PGM (1991) Protection Groups in Organic Synthesis, 2 nd Edition John Wiley & Sons, New York] can do.
[3174] III. Oral Composition
[3175] In a particular embodiment of the oral composition of a compound of the present invention, one 100 mg of one of the compounds described herein is formulated with fully micronized lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule.
[3176] IV. Pharmacological evaluation of compounds at cloned rat MCH1 receptor
[3177] The pharmacological properties of the compounds of the present invention were evaluated at the cloned rat MCH1 receptor using the protocol described below.
[3178] Host cell
[3179] A wide range of host cells can be used to study heterologously expressed proteins. These cells include selected mammalian lines such as Cos-7, CHO, LM (tk-), HEK293, Peak rapid 293, and the like; Insect cell lines such as Sf9, Sf2l and the like; Amphibian cell lines such as xenopus oocytes; And others, including but not limited to.
[3180] COS 7 cells were 150 mm in DMEM with supplement (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% CO ₂ . Grow on plate. The storage plate of the COS-7 cells is trypsinized and cleaved 1: 6 every 3-4 days.
[3181] Human fetal kidney 293 cells are grown on 150 mm plates in DMEM with supplement (10% calf serum, 4 mM glutamine, 100 units / ml penicillin / 100 Fg / ml streptomycin) at 37 ° C., 5% CO ₂ . . The storage plate of 293 cells is trypsinized and split 1: 6 every 3-4 days.
[3182] Human fetal kidney Peak rapid 293 (Peakr293) cells were loaded on a 150 mm plate in DMEM with supplements (10% fetal bovine serum, 10% L-glutamine, 50 Fg / ml gentamycin) at 37 ° C., 5% CO ₂ . To grow. Storage plates of Peak rapid 293 cells are trypsinized and cleaved 1:12 every 3-4 days.
[3183] Mouse fibroblast LM (tk-) cells were supplemented at 37 ° C., 5% CO ₂ (Dulbecco's modified eagle medium with 10% bovine calf serum, 4 mM glutamine, 100 units / ml penicillin / 100 Fg / ml streptomycin). Grow on a 150 mm plate in DMEM with. The storage plate of LM (tk-) cells is trypsinized and cleaved 1:10 every 3-4 days.
[3184] Chinese hamster ovary (CHO) cells were HAM's F- with supplements (10% calf serum, 4 mM L-glutamine and 100 units / ml penicillin / 100 Fg / ml streptomycin) at 37 ° C., 5% CO ₂ . Incubated on 150 mm plate in 12 medium. Stock plates of CHO cells were trypsinized and divided 1: 8 every 3-4 days.
[3185] Mouse embryo fibroblast NIH-3T3, at 37 ° C., 5% CO _2, was treated with Dulbecco's Modified Eagle Medium (10% calf serum, 4 mM glutamine, 100 units / ml penicillin / 100 Fg / ml streptomycin). DMEM) in a 150 mm plate plate. Storage plates of NIH-3T3 cells were trypsinized and divided 1: 3 every 3-4 days.
[3186] Sf9 and Sf21 cells are cultured in monolayers on 150 mm tissue culture dishes in TMN-FH medium supplemented with 10% fetal calf serum at 27 ° C. without CO ₂ . In addition, high-five insect cells are cultured on 150 mm tissue culture dishes in Ex Cell 400 ™ medium supplemented with L-glutamine at 27 ° C. without CO ₂ .
[3187] In some cases, cell lines that develop as adherent monolayers can be converted to suspension culture, thereby increasing cell yield and providing large batches of homogeneous analytes for conventional receptor selection schemes.
[3188] Transient manifestation
[3189] The DNA encoding the protein to be studied can be transiently expressed in various mammals, insects, amphibians and other cell lines by a number of methods, including but not limited to: Calcium phosphate mediated, DEAE-dextran mediated, liposome mediated, viral mediated, electroporation mediated and microinjection delivered. Each of these methods may require optimization of sorted experimental variables, depending on the DNA, cell line, and assay form used in succession.
[3190] Conventional procedures for the calcium phosphate method applied to Peak rapid 293 cells are described below:
[3191] Adherent cells were harvested about 24 hours prior to transfection, replated to a density of 3.5 × 10 ⁶ cells / dish in a 150 mm tissue culture dish and incubated overnight at 37 ° C., 5% CO ₂ . do. 250 Fl of a mixture of CaCl ₂ and DNA (15 Fg of DNA in 250 mM CaCl ₂ ) is added to a 5 ml plastic tube and 500 Fl of 2X HBS (280 mM NaC1, 10 mM KCl, 1.5 mM Na ₂ HPO ₄ , 12 mM). Dextrose, 50 mM HEPES) is slowly added while gently mixing. The mixture is incubated at room temperature for 20 minutes to allow DNA precipitate to form. The DNA precipitation mixture is then added to the culture medium in each plate and incubated at 37 ° C., 5% CO ₂ for 5 hours. After incubation, 5 ml of culture medium (DMEM, 10% FBS, 10% L-glut and 50 μg / ml gentamicin) is added to each plate. The cells are then incubated at 37 ° C., 5% CO ₂ for 24 to 48 hours.
[3192] Conventional procedures for the DEAE-dextran method applied to Cos-7 cells are described as follows; Cells used for transfection are split 24 hours prior to transfection to provide a flask that joins at 70-80% upon transfection. Briefly, 9 ml of complete DMEM is added to 8 Fg of receptor DNA plus 8 Fg of any necessary additional DNA (eg, G _α protein expression vector, reporter construct, antibiotic resistance marker, mock vector, etc.). Is added to the DEAE-dextran mixture (10 mg / ml in PBS). Flat plate cultured Cos-7 cells in T225 flasks (coming down) are washed once with PBS and DNA mixture is added to each flask. The cells are incubated at 37 ° C., 5% CO ₂ for 30 minutes. After incubation, 36 ml of complete DMEM with 80 FM chloroquine is added to each flask and allowed to incubate for an additional 3 hours. The medium is then aspirated, followed by 24 ml of complete medium containing 10% DMSO for exactly 2 minutes. The cells are then washed twice with PBS and 30 ml of complete DMEM is added to each flask. The cells are then allowed to incubate overnight. The next day the cells are harvested by trypsinization and reseed as needed depending on the type of assay being performed.
[3193] General procedures for liposome-mediated transfection applied to CHO cells are described as follows; Cells used for transfection are split 24 hours prior to transfection to provide a flask that joins 70-80% upon transfection. A total of 10 Fg of DNA, each of which can contain various proportions of the receptor DNA plus any additional DNA required (e.g., G _α protein expression vector, reporter construct, antibiotic resistance marker, mock vector, etc.), will be used for each 75 cm ² flask. Used to transfect cells. Liposomal mediated transfection is performed according to manufacturer's recommendations (LipofectAMINE, GibcoBRL, Bethesda, MD). Transfected cells are harvested 24 hours after transfection and used or reseed as required by the assay used.
[3194] The general procedure for electroporation applied to Cos-7 cells is described as follows; Cells used for transfection are split 24 hours prior to transfection to provide a flask that joins downward upon transfection. The cells were harvested and counted by trypsinization resuspended in its culture medium. 4 × 10 ⁶ cells are suspended in 30.0 Fl of DMEM and placed in an electroporation cuvette. 8 Fg of receptor DNA plus 8 Fg of any necessary additional DNA (eg, G _α protein expression vector, reporter construct, antibiotic resistance marker, neck vector, etc.) is added to the cell suspension, and the cuvettes are added to the BioRad Gene Pulser. And place an electric pulse (Gene Pulser device: 0.25 kV volts, 950 FF capacity). After the pulse, 800 Fl of complete DMEM is added to each cuvette and the suspension is delivered to a sterile tube. Complete media is added to each tube to bring the final cell concentration to 1 × 10 ⁵ cells / 100 Fl. Subsequently, the cells are flat plated as needed depending on the type of assay performed.
[3195] General procedures for viral mediated expression of heterologous proteins are described as follows for baculovirus infection of insect Sf9 cells. The coding region of the DNA encoding the receptors disclosed herein can be subcloned into pBlueBacIII at sites that are engineered in sequence 5 'and 3' to the restriction region or to the coding region of the polypeptide. To generate baculovirus, DNA constructs encoding 0.5 Fg of viral DNA (BaculoGold) and 3 Fg of polypeptide, as outlined by Pharmingen (in the "Baculovirus Expression Vector System: Procedures and Methods Manual"), Simultaneous transfection of 2 × 10 ⁶ Spodoptera frugiperda insect Sf9 cells can be performed by the calcium phosphate co-precipitation method. The cells are then incubated at 27 ° C. for 5 days. The supernatant of the simultaneous transfection plate can be harvested by centrifugation and the recombinant virus plaques can be purified. The procedure for infecting cells with the virus, the procedure for preparing the virus stock, and the procedure for measuring the titer of the virus stock are as described in the manual of Pharmingen. In general, similar theories will apply to mammalian cell expression via double-stranded DNA viruses such as retroviruses, psychokey forest viruses and adeno-, herpes- and vaccinia viruses.
[3196] Stable expression
[3197] Heterologous DNA can be stably incorporated into host cells, allowing cells to permanently express foreign proteins. The method of delivery of DNA to cells is similar to that described above for transient expression, but requires simultaneous transfection of the dependent genes to confer drug resistance to the host cell of interest. The resulting drug resistance can be used to select and maintain cells that take heterologous DNA. The classification of resistance genes may include, but is not limited to, neomycin, kanamycin and hygromycin. For the purpose of receptor research, stable expression of heterologous receptor proteins can be performed in mammalian cells including, but not necessarily limited to, CHO, HEK293, LM (tk-), and the like.
[3198] Cell membrane manufacturing
[3199] For binding assays, transfected cell pellets are suspended in ice-cold buffer (20 mM tirs. HCl, 5 mM EDTA, pH 7.4) and homogenized by sonication for 7 seconds. Cell lysates are centrifuged at 200 × g for 5 minutes at 4 ° C. The supernatant is then centrifuged at 40,000 x g for 20 minutes at 4 ° C. The resulting pellet is washed once in homogenization buffer and suspended in binding buffer (see method for radioligand binding). Protein concentration is determined by the Bradford (1976) method using bovine serum albumin as standard. Binding assays are typically performed immediately, but the membrane can be prepared in a batch and frozen in liquid nitrogen for future use.
[3200] Radioligand Binding Assay
[3201] Radioligand binding assays for the rat MCH1 receptor were performed using plasmid pcDNA3.l-rMCH1-f (ATCC Patent Accession No. PTA-350S). Plasmid pcDNA3.1-rMCH1-f contains the regulatory elements necessary for DNA expression in mammalian cells operably linked to DNA encoding the rat MCH1 receptor to enable expression of the rat MCH1 receptor. Plasmid pcDNA3.1-rMCH1-f was established in 2001 as the American Type Culture Collection (ATCC) (12301 Parklawn Drive, Rockville, Maryland 20852, USA), under the Butafest Treaty for the International Recognition of Deposits of Microorganisms for Patent Procedures. It was deposited on July 5 and was assigned ATCC Patent Accession No. PTA-3505.
[3202] Binding assays can also be performed using plasmid pEXJ.HR-TL231 (ATCC Accession No. 203197), as described below. Plasmid pEXJ.HR-TL231 encodes the human MCH1 receptor and under the Butafest Treaty for the international recognition of the deposit of microorganisms for the purposes of patent procedures, the American Type Culture Collection (ATCC) (12301 Parklawn Drive, Rockville, Maryland 20852, USA, deposited on September 17, 1998, and was assigned ATCC registration number 203197.
[3203] Using the calcium phosphate method, human embryonic liver peak rapid 293 cells (Peakr293 cells) were transiently transfected with DNA encoding the MCH1 receptor and cell membranes were prepared as above. Binding experiments with membranes from Peakr293 cells transfected with rat MCH1 receptor were carried out using a culture buffer consisting of 50 mM Tris pH 7.4, 10 mM MgC1 ₂ , 0.16 mM PMSF, 1 mM 1,10 phenanthroline and 0.2% BSA. Using, 0.08 nM [ ³ H] Compound A (synthesis of Compound A is described in detail below). Bonding was performed at 25 ° C. for 90 minutes. Incubation was terminated by rapid vacuum filtration on GF / C glass fiber filters pre-soaked 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.
[3204] Functional analysis
[3205] Cells can be screened for the presence of endogenous mammalian receptors using functional assays. Cells that do not have intrinsic receptors or are present at low levels can be transfected with exogenous receptors for use in functional analysis.
[3206] Extensive assays can be used to screen for the activity of the receptor. These include, for example, traditional measurements of phosphatidyl inositol, cAMP, Ca ⁺⁺ and K ⁺ ; A secondary carrier, as described above, but having a higher material throughput and measuring or modified to be more general and more sensitive; Cell based platforms that report more common cellular events resulting from receptor activity such as, for example, metabolic changes, differentiation and cell division / proliferation; For example, it is an advanced organic assay that monitors complex physiological or behavioral changes that are thought to be involved with receptor activation, including cardiovascular, analgesic, appetite stimulating, anxiolytic and sedative effects.
[3207] Radioligand Binding Assay
[3208] The aforementioned compounds were analyzed using cloned rat MCH1. The binding affinity of these compounds is shown in Table 1.
[3209] Table 1
[3210]
[3211]
[3212]
[3213]
[3214]
[3215]
[3216]
[3217]
[3218]
[3219]
[3220]
[3221]
[3222]
[3223]
[3224]
[3225]
[3226]
[3227]
[3228]
[3229]
[3230]
[3231]
[3232]
[3233]
[3234]
[3235]
[3236]
[3237]
[3238]
[3239]
[3240]
[3241]
[3242]
[3243]
[3244]
[3245]
[3246]
[3247]
[3248]
[3249]
[3250]
[3251]
[3252]
[3253]
[3254]
[3255]
[3256]
[3257]
[3258]
[3259]
[3260]
[3261]
[3262]
[3263]
[3264]
[3265]
[3266]
[3267]
[3268]
[3269]
[3270]
[3271]
[3272]
[3273]
[3274]
[3275]
[3276]
[3277]
[3278]
[3279]
[3280]
[3281]
[3282]
[3283]
[3284]
[3285]
[3286]
[3287]
[3288]
[3289]
[3290]
[3291]
[3292]
[3293]
[3294]
[3295]
[3296]
[3297]
[3298]
[3299]
[3300]
[3301]
[3302]
[3303]
[3304]
[3305]
[3306]
[3307]
[3308]
[3309]
[3310]
[3311]
[3312]
[3313]
[3314]
[3315]
[3316]
[3317]
[3318]
[3319]
[3320]
[3321]
[3322]
[3323]
[3324]
[3325]
[3326]
[3327]
[3328]
[3329]
[3330]
[3331]
[3332]
[3333]
[3334]
[3335]
[3336]
[3337]
[3338]
[3339]
[3340]
[3341]
[3342]
[3343]
[3344]
[3345]
[3346]
[3347]
[3348]
[3349]
[3350]
[3351]
[3352]
[3353]
[3354]
[3355]
[3356]
[3357]
[3358]
[3359]
[3360]
[3361]
[3362]
[3363]
[3364]
[3365]
[3366]
[3367]
[3368]
[3369]
[3370]
[3371]
[3372]
[3373]
[3374]
[3375]
[3376]
[3377]
[3378]
[3379]
[3380]
[3381]
[3382]
[3383]
[3384]
[3385]
[3386]
[3387]
[3388]
[3389]
[3390]
[3391]
[3392]
[3393]
[3394]
[3395]
[3396]
[3397]
[3398]
[3399]
[3400]
[3401]
[3402]
[3403]
[3404]
[3405]
[3406]
[3407]
[3408]
[3409]
[3410]
[3411]
[3412]
[3413]
[3414]
[3415]
[3416]
[3417]
[3418]
[3419]
[3420]
[3421]
[3422]
[3423]
[3424]
[3425]
[3426]
[3427]
[3428]
[3429]
[3430]
[3431]
[3432]
[3433]
[3434]
[3435]
[3436]
[3437]
[3438]
[3439]
[3440]
[3441]
[3442]
[3443]
[3444] Binding Affinity (Ki) at Rat MCH1, Human Dopamine D2, Human Histamine H1, and Human Alpha-1a Adrenergic Receptors
[3445]
[3446]
[3447]
[3448]
[3449] V. Synthesis of Compound A
[3450] The synthesis of compound A is described below. Compound A is an identifying radioisotope compound that has been used in the above described radioligand binding assays.
[3451] N- [3- (1,2,3,6-tetrahydro-4-pyridinyl) phenyl] acetamide :
[3452] Over night at reflux temperature, saturated aqueous Na ₂ CO ₃ solution in dimethoxyethane (40 mL) (25 mL), t-butyl 4-{[(trifluoromethyl) sulfonyl] oxy} -1,2,3 Reaction of, 6-tetrahydro-1-pyridine-carboxylate (20 mmol), 3-acetamidophenylboronic acid (30 mmol) and tetrakis-triphenylphosphine palladium (0) (1.15 g) -Butyl 4- [3- (acetylamino) phenyl] -3,6-dihydro-1 (2H) -pyridinecarboxylate was provided. After deprotection of the BOC group with HC1 in dioxane, basicization (pH 11-12) provided the desired product.
[3453] t-butyl N- (3-bromopropyl) carbamate: Prepared from 3-bromopropylamine bromic acid and BOC ₂ O in the presence of a base in dichloromethane.
[3454] N- {3- [1- (3-aminopropyl) -1,2,3,6-tetrahydro-4-pyridinyl] phenyl} acetamide : refluxed with catalyst Bu ₄ NI and base described in Scheme A dioxane in, t- butyl N - (3- bromopropyl) carbamate and N- [3- (1,2,3,6- tetrahydro-4-pyridinyl) phenyl] acetamide the reaction was t-butyl 3- (4- [3- (acetylamino) phenyl] -3,6-dihydro-l (2H) -pyridinyl) propylcarbamate was provided. After deprotection of the BOC group with HC1 in dioxane, basicization (pH 11-12) provided the desired product.
[3455] Methyl (4S) -3-({[3- (4- [3- (acetylamino) phenyl] -3,6-dihydro-1 (2H) -pyridinyl) propyl] amino} carbonyl) -4- (3,4-Difluorophenyl) -6- (methoxymethyl) -2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate: 5-methyl l- (4- Nitrophenyl) (6S) -6- (3,4-difluorophenyl) -4- (methoxymethyl) -2-oxo-3,6-dihydro-1,5 (2H) -pyrimidinedicar Voxylates (described in PCT Publication No. WO 00/37026 published June 29, 2000) and N- {3- [l- (3-aminopropyl) -1,2,3,6-tetrahydro Prepared from the reaction of -4-pyridinyl] phenyl} acetamide: ¹ H NMR σ8.90 (t, 1 H, J = 3.6 Hz), 7.75 (s, 1H), 7.50-7.00 (m, 8H ), 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, 2H), 2.71 (t, 2H, J = 5.4 Hz), 2.56 (m, 4H), 2.35-1.90 (br, 2H), 2.17 (s, 3H), 1.82 ( p, 2 H, J = 7.2 Hz); ESMS, 612.25 (M + H) ⁺
[3456] Deuterium methyl (4S) -3-{[(3- {4- [3- (acetylamino) phenyl] -l-piperidinyl} propyl) amino] carbonyl} -4- (3,4-difluoro Phenyl) -6- (methoxymethyl) -2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate ([ ³ H] Compound A): The radiochemical synthesis is Amersham Pharmacia Biotech , By Cardiff, Wales. While stirring overnight, methyl (4S) -3-({[3- (4- [3- (acetylamino) phenyl] -3,6-dihydro-l (2H) -pyri) in the presence of 5% palladium on carbon Diyl) propyl] amino} carbonyl) -4- (3,4-difluorophenyl) -6- (methoxymethyl) -2-oxo-1,2,3,4-tetrahydro-5-pyrimidine Methanol solution of carboxylate was exposed to tritium gas at 1 atmospheric pressure, and deuterium methyl (4S) -3-{[(3- {4- [3- (acetylamino) phenyl] -l-piperidinyl} Propyl) amino] carbonyl} -4- (3,4-difluorophenyl) -6- (methoxymethyl) -2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxyl The rate ((+)-isomer) was provided. Reversed phase HPLC (Hypersil ODS, 4.6 × 100 mm, 15 min at 1.0 mL / min, with methanol: H ₂ O: Et ₃ N 10: 90: 1 to 100: 0: 1, with radiochemical and UV detectors After purification by), the product was used as radioligand in MCH1 binding assays. The same method was performed with H ₂ gas instead of ³ H ₂ to provide a non-radioactive form of compound A.
[3457] VI. Internal labeling
[3458] To predict the effects of MCH1 antagonists for the treatment of obesity (3 days weight and sweetened condensed milk), depression (forced swimming test), anxiety (social interaction test) and urinary disorders (DIRC and CSTI) Labeling was performed.
[3459] Effect of MCH1 antagonists on body weight (3 days)
[3460] Male Long Evans rats (Charles River) weighing 180-200 g were housed in four groups on a 12 hour light / dark cycle with free access to food and water. For three days, the test compound was administered via intraperitoneal injection twice a day, 2 hours before the dark cycle and 2 hours after light entered. Every day, all rats were weighed after each morning injection. The overall results are expressed as body weight (grams) obtained per day (mean ± standard deviation) and analyzed by ANOVA in both modes. Data at each time point was analyzed in one way, ANOVA, and then Newman-Keuls post-validation was performed. The data were analyzed using GraphPad Prism (v2.0l) (GraphPad Software, Inc., San Diego, Calif.). All data are presented as mean ± standard deviation.
[3461] Effect of MCH1 antagonists on sweetened condensed milk
[3462] At the start of the experiment, male C57BL / 6 mice (Charles River) weighing 17-19 grams were housed in four groups on a 12 hour light / dark cycle with free access to food and water. For 7 days, mice were weighed and placed in individual cages and allowed to drink sweetened condensed milk (Nestle diluted 1: 3 with water) for 1 hour 2-4 hours after entering the photocirculation. The milk bottle consumed was determined by weighing the bottles before and after each drinking. On the day of the test, the mice were vehicle (0.01% lactic acid) of test compound (3, 10 or 30 mg / kg in 0.01% lactic acid) and d-phenfluramine (10 mg / kg in 0.01% lactic acid) 30 minutes before exposure to milk. Was injected intraperitoneally. The milk content consumed on the day of the test (in milk ml / kg body weight) was compared with the petrolatum consumption of each mouse determined two days ago. Data at each time point was analyzed in one way, Anova.
[3463] Rat's Forced Swimming Test (FST)
[3464] animal
[3465] Sprague-Dawley rats (Taconic Farms, NY) were used for all experiments. Five rats were housed per cage and preserved in the 12: 12-hour light-dark cycle. Rats were treated for 1 minute daily for four days before the behavioral test.
[3466] drug injection
[3467] 60 minutes before the start of 5 minutes of testing, the vehicle (2.5% EtOH / 2.5% Tween-80), imipramine (positive control; 60 mg / kg) or a single i.p. of the test compound. To receive dosing, animals were randomly assigned. All injections were provided using a 1 ㏄ tubular curin syringe with 26 3/8 gauge needles (Becton-- Dickinson, VWR Scientific, Bridgeport, NJ). The volume of injection was 1 ml / kg.
[3468] Experimental Design
[3469] The method used in this study is similar to that described above except that the water depth in this method is 31 cm (Porsolt et al., 1978). Deeper depths in this experiment prevent the rat's feet from touching the bottom of the cylinder and supporting the rat itself. Swimming activity was performed by placing rats in individual plexiglass cylinders (46 cm high x 20 cm in diameter) containing water at a depth of 31 cm and a temperature of 23-25 ° C. The swimming test was always performed for 900 to 1700 hours, consisting of an initial 15 minute adaptation test and a 24 minute test after 24 hours. Drug treatment was administered 60 minutes before the 5 minute test. After all swimming activities, the rats were removed from the cylinder, dried with a paper towel, placed in a heated cage for 15 minutes and then returned to their cage. All test activities were video recorded using a color video camera and recorder.
[3470] Behavioral evaluation
[3471] Rat behavior was assessed at 5 second intervals during the 5 minute trial by one person who did not know the status of the treatment. The behavior evaluated was as follows:
[3472] 1. immobility- The rat floated in the water without resistance and did only the movement necessary to raise its head above the water;
[3473] 2. Climbing-The rat was actively moving with its paws, in and out of the water, usually against the wall;
[3474] 3. The swim-rat was moving around an active swimming motion, ie around the cylinder, just beyond keeping its head above the water;
[3475] 4. Diving-The whole body of the rat is submerged.
[3476] Data analysis
[3477] Random one-way analysis of variance was performed with forced swimming test data (floatability, swimming, climbing, diving), and post hoc tests were performed using the Newman-Keuis test. The data were analyzed using Graphpad Prism (v2.01) (Graphpad Software, Inc., San Diego, Calif.). All data are presented as mean ± standard deviation.
[3478] Forced Swimming Test (FST) in Mice
[3479] animal
[3480] DBA / 2 mice (Taconic Farms, NY) were used for all experiments. In a controlled situation under the 12: 12-hour light-dark cycle, five animals were housed per cage. Animals were treated 1 minute daily for 4 days prior to behavioral experiments. The method involved mock gavage with a 1.5 inch feed tube.
[3481] drug injection
[3482] One hour before the swimming test, animals were randomly assigned to receive a single dose of vehicle (5% EtOH / 5% Tween-80), test compound, imipramine (positive control; 60 mg / kg).
[3483] Experimental Design
[3484] The forced swimming test method in mice is similar to that described above for rats, with a few modifications. The cylinder used for the test was a 1 liter beaker (10.5 cm diameter x 15 cm height) filled with 800 ml of water at 23-25 ° C. Only one 5-minute swim test was performed for each mouse for 1300-1700 hours. Drug treatment was administered 30-60 minutes before the 5-minute test. After all swimming activities, the mice were removed from the cylinders, dried with paper towels and placed in the cages warmed for 15 minutes. Later, he returned to his cage. All test activities were video recorded using a Sony color video camera and recorder for later evaluation.
[3485] Behavioral evaluation
[3486] Behavior for 2-5 minutes of the test was reproduced on a TV monitor and evaluated by a coroner. The total time spent on floating (floating animals with minimal movement to keep them afloat) and activities (swimming and activities that are more than necessary to keep them afloat) were recorded.
[3487] analysis
[3488] Forced swim test data (time to indicate kinetic, motility; seconds) is processed by random one-way analysis of variance (ANOVA) and subsequent tests are performed using the Newman-Keuls test. Data is analyzed using GraphPad Prism (version 2.01) (GraphPad Software, Inc., San Diego, Calif.). All data were averaged ± S.E.M. It is shown as.
[3489] Social Interaction Test (SIT)
[3490] Rats are acclimated for 5 days in an animal care facility prior to testing and then housed alone for 5 days. Animals are treated for 5 minutes daily. The design and procedure of the social interaction test is performed as previously described by Kennett et al. (1997). On the day of the test, the same treatment is applied to pairs of rats (± 5%) that are unfamiliar and similar to each other, and returned to their original cages. Animals are randomly divided into 5 treatment groups, 5 pairs per treatment group, and one of the following intraperitoneal treatments is performed: test compound (10, 30 or 100 mg / kg), carrier (1 ml / kg) or chlor Diazepoxide (5 mg / kg). Dosing is 1 hour before the start of the test. The rats are then placed in a white pulsepex test box or arena (54 × 37 × 26 cm) divided into 24 identical squares at the bottom for 15 minutes. An air conditioner is used to generate background noise and keep the room at approximately 74 ° F. All sessions are videoed using a JVC camcorder (model GR-SZ1, Elmwood Park, NJ) and TDK (HG top brand) or Sony's 30-minute video cassette. All sessions are conducted for 1300-1630 hours. Use the stopwatch (Sportsline Model 226, 1/100 second distinguishable) to define active social interactions such as grooming, sniffing, sniffing, biting, hitting, wrestling, chasing and crawling up and down Scored. Scores the number of straight standing (animal standing with hind feet to fully raise the body), grooming (licking, biting, scraping of the body) and washing the face (ie, hand repeatedly moving on the face), and the number of squares that have passed . Passive social interactions (animals lying next to or on top of each other) do not score. All behavior is later analyzed by observers who do not know about each pair of treatments. At the end of each test, the box is thoroughly cleaned with a damp paper towel.
[3491] animal
[3492] Under a 12-hour light cycle (lights up at 0700 hours) in pairs of male albino Sprague-Dawley rats (Taconic Farms, NY), food and water are allowed to access freely.
[3493] drug injection
[3494] Test compounds are dissolved in 100% DMSO or 5% lactic acid (v / v) (Sigma Chemical Co., St. Louis, MO). Chlordiazepoxide (Sigma Chemical Co., St. Louis, Mo.) is dissolved in secondary distilled water. The carrier consists of 50% DMSO (v / v) or 100% dimethylacetamide (DMA). All drug solutions are made 10 minutes before injection and the solution is discarded at the end of the test day. The volume of drug solution administered is 1 ml / kg.
[3495] Data analysis
[3496] Social interaction data (interaction time, standing upright and passing squares) are processed by random one-way analysis of variance (ANOVA) and subsequent tests are performed using the Student-Newman-Keuls test. Data is processed for normality test (Shapiro-Wilk test). Data is analyzed using the GBSTAT program, version 6.5 (Dynamics Microsystems, Inc., Silver Spring, MD, 1997).
[3497] In vivo model of urination reflex
[3498] The effect of compounds on urination reflexes in rats is described in "distension-induced rhythmic contraction (DIRC) as described in previous publications (eg, Maggi et al., 1987; Morikawa et al., 1992). And, as a Continuous Slow Transvesicular Infusion (CSTI) model.
[3499] DIRC model
[3500] Female Sprague Dawley rats weighing approximately 300 g were anesthetized with subcutaneous urethane (1.2 g / kg). Cannulates with PE240 tubes in the bronchus provided clean airways throughout the experiment. A midline abdominal incision was performed and the left and right ureters were separated. The ureter was ligated at the distal end (to prevent leakage of body fluids from the bladder) and a cannula was inserted at the front with a PE10 tube. The incision was closed using a 4-0 pongee suture with the PE10 tube facing out for removal of urine. The cannula was inserted into the bladder via the urethral passage through a PE50 tube inserted 2.5 cm from the urinary tract. The cannula was fixed to the tail with tape and connected to a pressure transducer. To prevent leakage from the bladder, the cannula was firmly fixed to the external ureter using 4-0 pongee.
[3501] To initiate urination reflexes, the saline is first emptied by applying pressure to the lower abdomen, and then usually saline until spontaneous bladder contractions occur (usually 20-40 mmHg at a rate of one contraction every two to three minutes). With 100 increments (max = 2 ml). Once a regular rhythm was established, carriers (saline) or test compounds were administered intravenously or intraperitoneally to investigate their effect on bladder activity. 5-HT _1A antagonist WAY-100635 served as a positive control. Data are expressed as contraction interval (in seconds) prior to drug application (base) or after application of carrier or test article.
[3502] Continuous Vascular Pain and Slow Transfusion (CSTI) Rat Model
[3503] Male Sprague Dawley rats weighing approximately 300 g were used for the study. Rats were anesthetized with pentobarbitone sodium (50 mg / kg, intraperitoneally). The bladder was exposed through an intermediate abdominal incision, polyethylene cannula (PE50) was introduced into the bladder through a small incision on the dome of the bladder and the cannula was fixed with a purse-string suture. The other end of the cannula was placed subcutaneously out of the back of the neck. Similarly, another cannula (PE50) was introduced into the stomach via a paramedian abdominal incision and the free end was subcutaneously pulled out of the neck. Surgical wounds were sutured with silk 4-0 sutures and allowed animals to recover under appropriate postoperative care. The next day, the animals were placed in a rat restrainer. The open end of the bladder-cannula was connected to a pressure transducer and a transfusion pump via a three-necked stopcock. The bladder excretion cycle was initiated by continuous saline of conventional saline at a rate of 100 μl / min. Repeated excretion contractions were recorded on Power Lab online data acquisition software. After the basic excretion pattern was recorded for one hour, the test drug or carrier was administered directly through the gastrointestinal catheter and the excretion cycle was observed for 5 hours. Urination pressure and frequency for each animal were calculated before and after treatment (every 30 minutes). Bladder capacity was calculated from the frequency of urination based on a constant sap of 100 μl / min. The effect of the test drug is expressed as a percentage of the basic, predose bladder dose. WAY 100635 was used as a comparative positive control.
[3504] Internal results
[3505] TABLE 2
[3506] Effect of MCH1 antagonist (Example No.) in the following body models: 3-day body weight (3D BW), mouse sweetened milk (mSwCM), mouse forced swimming test (mFST), rat forced swimming test (rFST), DIRC model Or CSTI model
[3507] Example number 3D BW mSwCM mFST rFST DIRC CSTI 2 A B C D E F 10 Not performed Not performed C Not performed E F 39 A B Not performed D Not performed Not performed 43 Not performed B C Not performed Not performed Not performed 44 Not performed Not performed no effect Not performed Not performed Not performed 89 Not performed B no effect Not performed Not performed Not performed 90 Not performed no effect no effect Not performed Not performed Not performed 91 Not performed Not performed C Not performed E F 93 Not performed Not performed no effect Not performed Not performed Not performed 95 Not performed B no effect Not performed Not performed Not performed 99 A Not performed C Not performed E F 105 Not performed B C Not performed Not performed Not performed 106 Not performed B C Not performed E FF 112 Not performed Not performed no effect Not performed Not performed Not performed 116 A Not performed C Not performed E F A = caused a significant decrease in weight gain compared to the carrier treated control B = caused a significant decrease in milk consumption compared to the carrier treated control C = caused a significant decrease in immobility upon oral administration D = Elevated immobility and significant increase in swimming activity compared to carrier treated animals E = caused a significant increase in contraction interval compared to predose interval F = induced increased bladder capacity in rats relative to base dose
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权利要求:
Claims (79)
[1" claim-type="Currently amended] Compounds having the structure

[Wherein R ₁ is hydrogen, straight or branched C ₁ -C ₇ alkyl, monofluoroalkyl or polyfluoroalkyl, aryl or heteroaryl, said aryl or heteroaryl is one or more -F, -Cl, -Br, -I, -CN, -NO ₂ , -CH ₃ , -CF ₃ , -COCH ₃ , -CO ₂ R ₂ , phenyl, phenoxy, or linear or branched C ₁ -C ₇ alkyl Can;
R ₂ is straight or branched C ₃ -C ₄ alkyl or cyclopropyl;
R ₃ is aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more -F, -Cl, -Br, -I, -CN, -NO ₂ , straight or branched C ₁ -C ₇ alkyl There is;
A is —H, —F, —Cl, —Br, —CN, —NO ₂ , —COR ₃ , —CO ₂ R ₃ , straight or branched C ₁ -C ₇ alkyl, monofluoroalkyl or polyfluoro Alkyl;
X is O or NH; And
n is an integer from 0 to 5, inclusive.
[2" claim-type="Currently amended] The compound of claim 1, wherein R ₁ is at least one —F, —Cl, —Br, —I, —CN, —NO ₂ , —COCH ₃ , —CO ₂ R ₂ , straight or branched C ₁ -C ₇ alkyl Aryl which may be substituted by;
R ₃ is phenyl;
A is H;
X is O.
[3" claim-type="Currently amended] The compound of claim 2, wherein R ₂ is isopropyl.
[4" claim-type="Currently amended] The compound of claim 3 having the structure

[5" claim-type="Currently amended] The compound of claim 3 having the structure

[6" claim-type="Currently amended] The compound of claim 1, wherein R ₁ is hydrogen, straight or branched C ₁ -C ₇ alkyl; R ₃ is aryl.
[7" claim-type="Currently amended] The compound of claim 6, wherein R ₂ is isopropyl; A is hydrogen.
[8" claim-type="Currently amended] A compound according to claim 7 having the structure

[9" claim-type="Currently amended] A compound according to claim 7 having the structure

[10" claim-type="Currently amended] Compounds having the structure

[Wherein R ₁ is one or more —F, —Cl, —Br, —I, —CN, —NO ₂ , —OCH ₃ , phenoxy, fused cyclopentanyl, straight or branched C ₁ -C ₇ alkyl, Aryl or heteroaryl, which may be substituted with monofluoroalkyl or polyfluoroalkyl;
R ₂ is straight or branched C ₁ -C ₄ alkyl, or cyclopropyl;
A is —H, —F, —Cl, —Br, —CN, —NO ₂ , straight or branched C ₁ -C ₇ alkyl, monofluoroalkyl or polyfluoroalkyl;
n is an integer from 1 to 5, inclusive.
[11" claim-type="Currently amended] The compound of claim 10, wherein R ₁ is one or more —F, —Cl, —Br, —I, or straight or branched C ₁ -C ₄ alkyl; A is H.
[12" claim-type="Currently amended] 12. The compound of claim 11, wherein R ₂ is isopropyl; n is 2;
[13" claim-type="Currently amended] 13. A compound according to claim 12 having the structure

[14" claim-type="Currently amended] 13. A compound according to claim 12 having the structure

[15" claim-type="Currently amended] 13. A compound according to claim 12 having the structure

[16" claim-type="Currently amended] The compound of claim 10, wherein R ₁ is thienyl; A is H.
[17" claim-type="Currently amended] The compound of claim 16, wherein R ₂ is isopropyl.
[18" claim-type="Currently amended] 18. A compound according to claim 17 having the structure

[19" claim-type="Currently amended] Compounds having the structure

[Wherein W is the following;

Each R ₁ is independently hydrogen, methyl or ethyl;
R ₂ is straight or branched C ₃ -C ₄ alkyl or cyclopropyl;
R ₃ is hydrogen, aryl or heteroaryl, wherein the aryl or heteroaryl is one or more -H, -F, -Cl, -Br, -I, -CN, -NO ₂ , straight or branched chain C ₁ -C ₇ Optionally substituted with alkyl;
Each A is independently —H, —F, —Cl, —Br, —CN, —NO ₂ , —COR ₃ , —CO ₂ R ₃ , straight or branched C ₁ -C ₇ alkyl, monofluoroalkyl or Polyfluoroalkyl;
X may be O, NR ₃ , CO or absent;
Y is hydrogen, aryl or heteroaryl, said aryl or heteroaryl being substituted with one or more -F, -Cl, -Br, -I, -CN, -NO ₂ , straight or branched C ₁ -C ₇ alkyl Can be].
[20" claim-type="Currently amended] The compound of claim 19, wherein W is

Compound in which X may be O or absent.
[21" claim-type="Currently amended] The compound of claim 20, wherein R ₂ is isopropyl.
[22" claim-type="Currently amended] The compound of claim 21 having the structure

[23" claim-type="Currently amended] The compound of claim 21 having the structure

[24" claim-type="Currently amended] The compound of claim 19, wherein W is

[25" claim-type="Currently amended] The compound of claim 24, wherein A is -H, -F, -Cl, or -Br.
[26" claim-type="Currently amended] The compound of claim 25, wherein R ₂ is isopropyl; A is hydrogen.
[27" claim-type="Currently amended] The compound of claim 26 having the structure

[28" claim-type="Currently amended] Compounds having the structure

[Wherein W is

R ₁ is hydrogen, straight or branched C ₁ -C ₇ alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is one or more —F, —Cl, —Br, —CN, —NO ₂ , —OCH ₃ , May be substituted with -CO ₂ CH ₃ , -CF ₃ , phenyl, straight or branched C ₁ -C ₇ alkyl;
R ₂ is straight or branched C ₃ -C ₄ alkyl or cyclopropyl;
A is —H, —F, —Cl, —Br, —CN, —NO ₂ , —COR ₁ , —CO ₂ R ₁ , straight or branched C ₁ -C ₇ alkyl, monofluoroalkyl or polyfluoro Alkyl or phenyl;
B are each independently -H, -F, -Cl, -Br, -I, -CN, -NO 2, -COR 1, -CO 2 R 1, -OCH 3, -OCF 3, -CF 3, straight-chain Or branched C ₁ -C ₇ alkyl, monofluoroalkyl or polyfluoroalkyl or aryl, phenoxy or benzyloxy, wherein the aryl, phenoxy or benzyloxy is one or more -F, -Cl, -Br,- _{CN, -NO 2, -COR 1,} -CO 2 R 1, -OCH 3, -OCF 3, -CF 3, or straight or branched chain optionally substituted with C ₁ -C ₇ alkyl;
[29" claim-type="Currently amended] The compound of claim 28, wherein W is

[30" claim-type="Currently amended] The compound of claim 29, wherein R ₁ is hydrogen or phenyl which may be substituted with one or more —F, —Cl, —Br, —CN, —NO ₂ , straight or branched chain C ₁ -C ₇ alkyl.
[31" claim-type="Currently amended] 31. The compound of claim 30, wherein R ₂ is isopropyl.
[32" claim-type="Currently amended] 32. A compound according to claim 31 having the structure:

[33" claim-type="Currently amended] 32. A compound according to claim 31 having the structure:

[34" claim-type="Currently amended] Compounds having the structure

[Wherein R ₁ is hydrogen, straight or branched C ₁ -C ₇ alkyl, aryl or heteroaryl, the aryl or heteroaryl being one or more -F, -Cl, -Br, -CN, -NO ₂ , May be substituted with -CF ₃ , -OCH ₃ , straight or branched C ₁ -C ₃ alkyl;
R ₂ is straight or branched C ₃ -C ₄ alkyl or cyclopropyl;
R ₃ is —H, —F, —Cl, —Br, —I, —CN, —NO ₂ , —CF ₃ , —OCH ₃ , or straight or branched C ₁ -C ₃ alkyl, monofluoroalkyl or Polyfluoroalkyl, or a phenyl ring fused to C ₆ and C ₇ of the indole moiety;
R ₄ is hydrogen or aryl which may be substituted with one or more —F, —Cl, —Br, —I, —CN, —NO ₂ , —CF ₃ , straight or branched C ₁ -C ₃ alkyl;
A is —H, —F, —Cl, —Br, —CN, —NO ₂ , straight or branched C ₁ -C ₇ alkyl, monofluoroalkyl or polyfluoroalkyl; And,
n is an integer from 2 to 4, inclusive.
[35" claim-type="Currently amended] 35. The method of claim 34, R ₃ is -H, -F, -Cl, -Br, -I, -CN, -NO 2, -OCF 3, or -OCH _3, and;
R ₄ is hydrogen or phenyl which may be substituted with one or more -F, -Cl, or -CF ₃ .
[36" claim-type="Currently amended] 36. The compound of claim 35, wherein R ₁ is hydrogen or one or more -F, -Cl, -Br, -CN, -NO ₂ , -CF ₃ , -OCH ₃ , or straight or branched C ₁ -C ₃ alkyl A compound that is phenyl which may be substituted.
[37" claim-type="Currently amended] 37. The compound of claim 36, wherein R ₂ is isopropyl.
[38" claim-type="Currently amended] The compound of claim 37 having the structure

[39" claim-type="Currently amended] The compound of claim 37 having the structure

[40" claim-type="Currently amended] The compound of claim 37 having the structure

[41" claim-type="Currently amended] Compounds having the structure

[Wherein, R ₁ is each independently hydrogen or CH ₃ ;
R ₂ is straight or branched C ₁ -C ₄ alkyl or cyclopropyl;
R ₃ is benzyl or phenyl, which benzyl or phenyl may be substituted with a methylenedioxy group or one or more -F or -Cl;
A is —H, —F, —Cl, —Br, —CN, —NO ₂ , straight or branched C ₁ -C ₇ alkyl, monofluoroalkyl or polyfluoroalkyl;
X is (CH ₂ ) ₂ , COCH ₂ or CONH].
[42" claim-type="Currently amended] 42. The compound of claim 41, wherein R ₃ is phenyl which may be substituted with one or more -F;
A is hydrogen.
[43" claim-type="Currently amended] 43. The compound of claim 42, wherein x is CONH.
[44" claim-type="Currently amended] The compound of claim 43, wherein R ₂ is methyl.
[45" claim-type="Currently amended] The compound of claim 44 having the structure

[46" claim-type="Currently amended] The compound of claim 44 having the structure

[Wherein, each Y is independently hydrogen or -F].
[47" claim-type="Currently amended] The compound of claim 46 having the structure

[48" claim-type="Currently amended] The compound of claim 46 having the structure

[49" claim-type="Currently amended] 42. The compound of claim 41, wherein R ₃ is benzyl, which may be substituted with a methylenedioxy group or one or more -F or -Cl.
[50" claim-type="Currently amended] The compound of claim 49 having the structure

[Wherein, each Y is independently hydrogen or -F].
[51" claim-type="Currently amended] The compound of claim 50 having the structure

[52" claim-type="Currently amended] The compound of any one of claims 1-51, wherein the compound is pure in terms of enantiomers.
[53" claim-type="Currently amended] The compound of any one of claims 1-51, wherein the compound is pure in terms of diastereomers.
[54" claim-type="Currently amended] 55. The compound of claim 52 or 53, wherein the compound is pure in terms of enantiomers and diastereomers.
[55" claim-type="Currently amended] A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 51 and a pharmaceutically acceptable carrier.
[56" claim-type="Currently amended] The pharmaceutical composition of claim 55 wherein the amount of the compound is from about 0.01 mg to about 500 mg.
[57" claim-type="Currently amended] The pharmaceutical composition of claim 56 wherein the amount of the compound is from about 0.1 mg to about 60 mg.
[58" claim-type="Currently amended] The pharmaceutical composition of claim 57 wherein the amount of the compound is from about 1 mg to about 20 mg.
[59" claim-type="Currently amended] The pharmaceutical composition of claim 55, wherein the carrier is a liquid and the composition is a solution.
[60" claim-type="Currently amended] The pharmaceutical composition of claim 55, wherein the carrier is a solid and the composition is a tablet.
[61" claim-type="Currently amended] The pharmaceutical composition of claim 55, wherein the carrier is a gel and the composition is a suppository.
[62" claim-type="Currently amended] 52. A method of preparing a pharmaceutical composition comprising mixing a therapeutically effective amount of a compound of any one of claims 1 to 51 with a pharmaceutically acceptable carrier.
[63" claim-type="Currently amended] A method of treating a subject suffering from a disease selected from the group consisting of depression, nervous anxiety, hyper-urgency, or obesity, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-51. Method of treatment.
[64" claim-type="Currently amended] 64. The method of claim 63, wherein the therapeutically effective amount is from about 0.03 mg to about 1000 mg per day.
[65" claim-type="Currently amended] The method of claim 64, wherein the therapeutically effective amount is from about 0.30 mg to about 300 mg per day.
[66" claim-type="Currently amended] 66. The method of claim 65, wherein the therapeutically effective amount is from about 1.0 mg to about 100 mg per day.
[67" claim-type="Currently amended] 64. The method of claim 63, wherein said disease is depression.
[68" claim-type="Currently amended] 64. The method of claim 63, wherein said disease is neuroanxiety.
[69" claim-type="Currently amended] 64. The method of claim 63, wherein said disease is obesity.
[70" claim-type="Currently amended] 64. The method of claim 63, wherein said disease is hyper impulse.
[71" claim-type="Currently amended] A method of slimming a subject, the method comprising administering to the subject a compound of any one of claims 1 to 51 in an amount effective to reduce the weight of the subject.
[72" claim-type="Currently amended] A method of treating a subject suffering from depression, the method comprising administering to the subject a compound of any one of claims 1 to 51 in an amount effective to treat the subject's depression.
[73" claim-type="Currently amended] A method of treating a subject suffering from neuroanxiety, the method comprising administering to a subject an amount of the compound of any one of claims 1 to 51 in an amount effective to treat the neuroanxiety of the subject.
[74" claim-type="Currently amended] 52. A method of alleviating excessive urination urge in a subject suffering from an overactive bladder, the method comprising administering to a subject an amount of the compound of any one of claims 1 to 51 in an amount effective to alleviate the excess urination urge in the subject. .
[75" claim-type="Currently amended] A method of controlling obesity in a subject in need of weight loss, the method comprising administering to the subject an amount of the compound of any one of claims 1 to 51 in an amount effective to induce weight loss in the subject.
[76" claim-type="Currently amended] A method of controlling obesity in a subject that has undergone weight loss, the method comprising administering to the subject an amount of the compound of any one of claims 1-51 in an amount effective to maintain weight loss in the subject.
[77" claim-type="Currently amended] A method of treating a subject's overactive bladder, the method comprising administering to the subject a compound of any one of claims 1 to 51 in an amount effective to treat the subject's overactive bladder.
[78" claim-type="Currently amended] 52. A method of treating disorders in a subject, wherein the subject's symptoms can be alleviated by treatment with an MCH1 antagonist, and the MCH1 antagonist is a compound of any one of claims 1-51.
[79" claim-type="Currently amended] 52. A method for alleviating disorder symptoms in a subject, comprising administering to the subject an amount of MCH1 antagonist effective for alleviating the symptom, wherein the MCH1 antagonist is a compound of any one of claims 1-51.