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AU2002316531B2 - Substituted anilinic piperidines as MCH selective antagonists - Google Patents

Substituted anilinic piperidines as MCH selective antagonists Download PDF

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AU2002316531B2
AU2002316531B2 AU2002316531A AU2002316531A AU2002316531B2 AU 2002316531 B2 AU2002316531 B2 AU 2002316531B2 AU 2002316531 A AU2002316531 A AU 2002316531A AU 2002316531 A AU2002316531 A AU 2002316531A AU 2002316531 B2 AU2002316531 B2 AU 2002316531B2
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compound
branched
phenyl
alkyl
mmol
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AU2002316531A1 (en
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Chien-An Chen
John E. Deleon
Yu Jiang
Bharat Lagu
Kai Lu
Mohammad R. Marzabadi
John Wetzel
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H Lundbeck AS
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Description

WO 03/004027 PCT/US02/21063 SUBSTITUTED ANILINIC PIPERIDINES AS MCH SELECTIVE
ANTAGONISTS
BACKGROUND OF THE INVENTION This application is a continuation-in-part of U.S.
Serial No. 10/042,582, filed January 9, 2002, and of U.S. Serial No. 09/899,794, filed July 5, 2001, the contents of both of which are hereby incorporated by reference into the subject application.
Throughout this application, various publications are referenced in parentheses by author and year. Full citations for these references may be found at the end of the specification immediately preceding the sequence listings and the claims. The disclosure of these publications in their entireties are hereby incorporated by reference into this application to describe more fully the state of the art to which this invention pertains. Melanin-concentrating hormone (MCH) is a cyclic peptide originally isolated from salmonid (teleost fish) pituitaries (Kawauchi et al., 1983). In fish the 17 amino acid peptide causes aggregation of melanin within the melanophores and inhibits the release of ACTH, acting as a functional antagonist of a-MSH.
Mammalian MCH (19 amino acids) is highly conserved between rat, mouse, and human, exhibiting 100% amino acid identity, but its physiological roles are less clear. MCH has been reported to participate in a variety of processes including feeding, water balance, energy metabolism, general arousal/attention state, WO 03/004027 PCT/US02/21063 2 memory and cognitive functions, and psychiatric disorders (for reviews, see Baker, 1991; Baker, 1994; Nahon, 1994; Knigge et al., 1996). Its role in feeding or body weight regulation is supported by a recent Nature publication (Qu et al., 1996) demonstrating that MCH is overexpressed in the hypothalamus of ob/ob mice compared with ob/+ mice, and that fasting further increased MCH mRNA in both obese and normal mice during fasting. MCH also stimulated feeding in normal rats when injected into the lateral ventricles (Rossi et al., 1997). MCH also has been reported to functionally antagonize the behavioral effects of a-MSH (Miller et al., 1993; Gonzalez et al, 1996; Sanchez et al., 1997); in addition, stress has been shown to increase POMC mRNA levels while decreasing the MCH precursor preproMCH (ppMCH) mRNA levels (Presse et al., 1992). Thus MCH may serve as an integrative neuropeptide involved in the reaction to stress, as well as in the regulation of feeding and sexual activity (Baker, 1991; Knigge et al., 1996).
Although the biological effects of MCH are believed to be mediated by specific receptors, binding sites for MCH have not been well described. A tritiated ligand MCH) was reported to exhibit specific binding to brain membranes but was unusable for saturation analyses, so neither affinity nor Bma were determined (Drozdz and Eberle, 1995). Radioiodination of the* tyrosine at position thirteen resulted in a ligand with dramatically reduced biological activity (see Drozdz and Eberle, 1995). In contrast, the radioiodination of the MCH analogue [Phe 13 ,Tyr19]-MCH was successful (Drozdz et al., 1995); the ligand retained biological activity and WO 03/004027 PCT/US02/21063 3 exhibited specific binding to a variety of cell lines including mouse melanoma (B16-F1, G4F, and G4F-7), PC12, and COS cells. In G4F-7 cells, the KD 0.118nM and the Bma -1100 sites/cell. Importantly, the binding was not inhibited by a-MSH but was weakly inhibited by rat ANF (Ki 116 nM vs. 12 nM for native MCH) (Drozdz et al., 1995). More recently specific MCH binding was reported in transformed keratinocytes (Burgaud et al., 1997) and melanoma cells (Drozdz et al., 1998), where photocrosslinking studies suggest that the receptor is a membrane protein with an apparent molecular weight of 45-50 kDaltons, compatible with the molecular weight range of the GPCR superfamily of receptors. No radioautoradiographic studies of MCH receptor localization using this ligand have been reported as yet.
The localization and biological activities of MCH peptide suggest that the modulation of MCH receptor activity may be useful in a number of therapeutic applications. The role of MCH in feeding is the best characterized of its potential clinical uses. MCH is expressed in the lateral hypothalamus, a brain area implicated in the regulation of thirst and hunger (Grillon et al., 1997); recently orexins A and B, which are potent orexigenic agents, have been shown to have very similar localization to MCH in the lateral hypothalamus (Sakurai et al., 1998). MCH mRNA levels in this brain region are increased in rats after 24 hours of food-deprivation (Herv6 and Fellman, 1997); after insulin injection, a significant increase in the abundance and staining intensity of MCH immunoreactive perikarya and fibres was observed concurrent with a WO 03/004027 PCT/US02/21063 4 significant increase in the level of MCH mRNA (Bahjaoui-Bouhaddi et al., 1994). Consistent with the ability of MCH to stimulate feeding in rats (Rossi et al., 1997) is the observation that MCH mRNA levels are upregulated in the hypothalami of obese ob/ob mice (Qu et al., 1996), and decreased in the hypothalami of rats treated with leptin, whose food intake and body weight gains are also decreased (Sahu, 1998). MCH appears to act as a functional antagonist of the melanocortin system in its effects on food intake and on hormone secretion within the HPA (hypothalamopituitary/adrenal axis) (Ludwig et al., 1998). Together these data suggest a role for endogenous MCH in the regulation of energy balance and response to stress, and provide a rationale for the development of specific compounds acting at MCH receptors for use in the treatment of obesity and stress-related disorders.
In all species studied to date, a major portion of the neurons of the MCH cell group occupies a rather constant location in those areas of the lateral hypothalamus and subthalamus where they lie and may be a part of some of the so-called "extrapyramidal" motor circuits. These involve substantial striato- and pallidofugal pathways involving the thalamus and cerebral cortex, hypothalamic areas, and reciprocal connections to subthalamic nucleus, substantia nigra, and mid-brain centers (Bittencourt et al., 1992). In their location, the MCH cell group may offer a bridge or mechanism for expressing hypothalamic visceral activity with appropriate and coordinated motor activity. Clinically it may be of some value to consider the involvement of this MCH system in movement disorders, such as WO 03/004027 PCT/US02/21063 Parkinson's disease and Huntingdon's Chorea in which extrapyramidal circuits are known to be involved.
Human genetic linkage studies have located authentic hMCH loci on chromosome 12 (12q23-24) and the variant hMCH loci on chromosome 5 (5q12-13) (Pedeutour et al., 1994). Locus 12q23-24 coincides with a locus to which autosomal dominant cerebellar ataxia type II (SCA2) has been mapped (Auburger et al., 1992; Twells et al., 1992). This disease comprises neurodegenerative disorders, including an olivopontocerebellar atrophy.
Furthermore, the gene for Darier's disease, has been mapped to locus 12q23-24 (Craddock et al., 1993).
Dariers' disease is characterized by abnormalities I keratinocyte adhesion and mental illnesses in some families. In view of the functional and neuroanatomical patterns of the MCH neural system in the rat and human brains, the MCH gene may represent a good candidate for SCA2 or Darier's disease. Interestingly, diseases with high social impact have been mapped to this locus.
Indeed, the gene responsible for chronic or acute forms of spinal muscular atrophies has been assigned to chromosome 5q12-13 using genetic linkage analysis (Melki et al., 1990; Westbrook et al., 1992). Furthermore, independent lines of evidence support the assignment of a major schizophrenia locus to chromosome 5q11.2-13.3 (Sherrington et al., 1988; Bassett et al., 1988; Gilliam et al., 1989). The above studies suggest.that MCH may play a role in neurodegenerative diseases and disorders of emotion.
Additional therapeutic applications for MCH-related compounds are suggested by the observed effects of MCH WO 03/004027 PCT/US02/21063 6 in other biological systems. For example, MCH may regulate reproductive functions in male and female rats. MCH transcripts and MCH peptide were found within germ cells in .testes of adult rats, suggesting that MCH may participate in stem cell renewal and/or differentiation of early spermatocytes (Hervieu et al., 1996). MCH injected directly into the medial preoptic area (MPOA) or ventromedial nucleus (VMN) stimulated sexual activity in female rats (Gonzalez et al., 1996).
In ovariectomized rats primed with estradiol, MCH stimulated luteinizing hormone (LH) release while anti- MCH antiserum inhibited LH release (Gonzalez et al., 1997). The zona incerta, which contains a large population of MCH cell bodies, has previously been identified as a regulatory site for the pre-ovulatory LH surge (MacKenzie et al., 1984). MCH has been reported to influence release of pituitary hormones including ACTH and oxytocin. MCH analogues may also be useful, in treating epilepsy. In the PTZ seizure model, injection of MCH prior to seizure induction prevented seizure activity in both rats and guinea pigs, suggesting that MCH-containing neurons may participate in the neural circuitry underlying PTZ-induced seizure (Knigge and Wagner, 1997). MCH has also been observed to affect behavioral correlates of cognitive functions. MCH treatment hastened extinction of the passive avoidance response in rats (McBride et al., 1994), raising the possibility that MCH receptor antagonists may be beneficial for memory storage. and/or retention. A possible role for MCH in the modulation or perception of pain is supported by the dense innervation of the periaqueductal grey (PAG) by MCH-positive fibers.
Finally, MCH may participate in the regulation of fluid WO 03/004027 PCT/US02/21063 7 intake. ICV infusion of MCH in conscious sheep produced diuretic, natriuretic, and kaliuretic changes in response to increased plasma volume (Parkes, 1996).
Together with anatomical data reporting the presence of MCH in fluid regulatory areas of the brain, the results indicate that MCH may be an important peptide involved in the central control of fluid homeostasis in mammals.
The identification of a G-protein coupled receptor for MCH has recently been published (Chambers et al., 1999; Saito et al., 1999). These groups identified MCH as the endogenous ligand for the human orphan G-protein coupled receptor SLC-1 (Lakaye et al., 1998). The rat homologue of this receptor (now called MCH-1) was reported to be localized in regions of the rat brain associated with feeding behavior dorsomedial and ventromedial hypothalamus). The link between MCH-1 and the effects of MCH on feeding has been strengthened by recent reports on the phenotype of MCH-1 knockout mice. Two groups have shown independently (Marsh et al, 2002; Chen et al, 2002) that the targeted disruption of the MCH-1 receptor gene (MCH-1 knockout) in mice results in animals that are hyperphagic but are lean and have decreased body mass relative to wild-type littermates.
The decrease in body mass is attributed to an increase in metabolism. Each group demonstrated that the MCH-1 knockout mice are resistant to diet-induced obesity, and generally exhibit weights similar to. littermates maintained on regular chow.
Finally, synthetic antagonist molecules for the MCH-1 receptor have now been described in the literature.
Bednarek et al. (2002) have reported on the synthesis of WO 03/004027 PCT/US02/21063 8 high affinity peptide antagonists of MCH-1. In addition, a small molecule antagonist of MCH-1 has been described by Takekawa et al. (Takekawa et al., 2002).
This compound, T-226296, exhibits high affinity for the MCH-1 receptor 5-9 nM for rat and human MCH-1), and was shown to inhibit food intake induced by the intracerebroventricular application of MCH. These data validate the strategy of using an MCH-1 receptor antagonist to treat obesity.
Furthermore, in our own studies, we have tested MCH1 antagonists in several animal models that are well known as predictive for the efficacy of compounds in humans (Borowsky, et al., in press; unpublished data). These experiments indicate that MCH1 antagonists are useful to treat obesity, depression, anxiety, as well as urinary disorders.
As used in this invention, the term "antagonist" refers to a compound which binds to, and decreases the activity of, a receptor in the presence of an agonist. In the case of a G-protein coupled receptor, activation may be measured using any appropriate second messenger system which is coupled to the receptor in a cell or tissue in which the receptor is expressed. Some specific, but by no means limiting, examples of well-known second messenger systems are adenylate cyclase, intracellular calcium mobilization, ion channel activation, guanylate cyclase and inositol phospholipid hydrolysis.
Conversely, the term "agonist" refers to a compound which binds to, and increases activity of, a receptor as compared with the activity of the receptor in the absence of any agonist.
WO 03/004027 PCT/US02/21063 9 In one embodiment of this invention, the synthesis of novel compounds which bind selectively to the cloned human melanin-concentrating hormone-1 (MCH1) receptor, compared to other cloned G-protein coupled receptors, and inhibit the activation of the cloned receptors as measured in in vitro assays is disclosed. The in vitro receptor binding assays described hereinafter were performed using various cultured cell lines, each transfected with and expressing only a single cloned receptor.
Furthermore, the compounds of the present invention may also be used to treat abnormal conditions such as feeding disorders (obesity, bulimia and bulimia nervosa), sexual/reproductive disorders, depression, anxiety, depression and anxiety, epileptic seizure, hypertension, cerebral hemorrhage, congestive heart failure, sleep disturbances, or any condition in which antagonism of an MCH1 receptor may be beneficial. In addition, the compounds of the present invention may be used to reduce the body mass of a subject. Furthermore, the compounds of the present invention may be used to treat urinary disorders.
WO 03/004027 PCT/US02/21063 Summary of the Invention This invention provides a compound having the structure: RI-X
N
R3 N-H R2 wherein Ri is hydrogen, straight chained or branched
C
1
-C
7 alkyl, monofluoroalkyl or polyfluoroalkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more -Cl, -Br, -CN,
-NO
2
-CH
3
-CF
3
-COR
2 -C0 2
R
2 phenyl, phenoxy or straight chained or branched C 1
-C
7 alkyl; wherein R 2 is straight-chained or branched C 3
-C
4 alkyl or cyclopropyl; wherein R 3 is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more -C1, -Br, -CN, -NO 2 straight chained or branched CI-C 7 alkyl; wherein A is -C1, -Br, -CN, -NO 2
-COR
3 -C0 2
R
3 straight chained or branched CI-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; wherein X is 0 or NH; and wherein n is an integer from 0 to 5 inclusive.
WO 03/004027 PCT/US02/21063 11 In one embodiment, RI is aryl optionally substituted with one or more -Cl, -Br, -CN, -NO 2
-COR
2
-CO
2
R
2 straight chained or branched CI-C 7 alkyl; wherein R3 is phenyl; wherein A is H; and wherein X is O.
In one embodiment, R 2 is isopropyl.
In one embodiment, the compound has the structure: 0
N
In one embodiment, compound has the structure: 0 0-
S°N
In one embodiment, R 1 is hydrogen, straight chained or branched Ci-C 7 alkyl; and wherein R 3 is aryl.
In one embodiment, R 2 is isopropyl; and A is hydrogen.
lla In a preferred embodiment of the invention there is provided a compound having the structure:
O=<
wherein RL is hydrogen or alkyl; straight chained or branched C1-C7 wherein R 2 is straight-chained or branched C3-C4 alkyl or cyclopropyl; wherein R 3 is aryl; wherein A is -Cl, -Br, -CN, -NO 2
-COR
3 -C0 2
R
3 straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; wherein X is 0 or NH; and wherein n is an integer from 0 to 5 inclusive.
WO 03/004027 PCT/US02/21063 12 In one embodiment, the compound has the structure: 0 N
N
In one embodiment, the compound has the structure:
N
0= 0
H/
The present invention also provides a compound having the structure:
R
1
N
0 N-H
O=<
R2 wherein RL is aryl or heteroaryl optionally substituted with one or more -Cl, -Br, -CN, -NO 2
-OCH
3 phenoxy, fused cyclopentanyl, straight chained or branched C 1
-C
7 alkyl, monofluoroalkyl or polyfluoroalkyl; wherein R 2 is straight-chained or branched Ci-C 4 alkyl or cyclopropyl; WO 03/004027 PCT/US02/21063 13 wherein A is -Cl, Br, -CN, -NO 2 straight chained or branched C 1
-C
7 alkyl, monofluoroalkyl or polyfluoroalkyl; and wherein n is an integer from 1 to 5 inclusive.
In one embodiment, R, is aryl optionally substituted with one or more -Cl, -Br, -I or straight chained or branched CI-C 4 alkyl; and wherein A is H.
In one embodiment, R 2 is isopropyl; and wherein n is 2.
In one embodiment, the compound has the structure: In one embodiment, the compound has the structure: In one embodiment, the compound has the structure: WO 03/004027 PCT/US02/21063 14 In one embodiment, the compound has the structure: F N In one embodiment, R 1 is-thienyl; and wherein A is H.
In one embodiment, R 2 is isopropyl.
In one embodiment, the compound has the structure: 0 o No The invention provides a compound having the structure:
A
/-NI
W
N-H
R2.
wherein W is H A or N R 1 R,
H
wherein each R, is independently hydrogen, methyl or ethyl; WO 03/004027 PCT/US02/21063 wherein R 2 is straight- chained or branched' C 3
-C
4 alkyl or cyclopropyl; wherein R 3 is hydrogen, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more -C1, -Br, -CN, -NO 2 straight chained or branched C 1
-C
7 alkyl.
wherein each A is independently -Cl, -Br, -CN,
-NO
2
-COR
3
-CO
2
R
3 straight chained or branched C 1
-C
7 alkyl, monofluoroalkyl or polyfluoroalkyl; wherein X is O, NR 3 CO or may be absent; and wherein Y is hydrogen, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more -C1, -Br, -CN, -NO 2 straight chained or branched C 1
-C
7 alkyl.
In one embodiment, W is H A H X-Y
H
and wherein X is 0 or may be absent.
In one embodiment, R 2 is isopropyl.
WO 03/004027 PCT/US02/21063 16 In one embodiment, the compound has the structure: N N 0 F F In one embodiment, the compound has the structure:
N
In one embodiment, W is
RI
In one embodiment, A is -Cl, -Br.
In one embodiment, R 2 is isopropyl; and A is hydrogen.
In one embodiment, the compound has the structure: WO 03/004027 WO 0/00027PCT/UJS02/21063 17 N NN 0 This invention provides a compound having the structure:
A
w +I
N-H
R2K wherein W is B B B \>or I wherein R, is hydrogen, straight chained or branched
CI-C
7 alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more -Cl, -Br, -CM, -NO 2 -OC-1 3
-CO
2
CH-
3
-CF
3 phenyl, straight chained or branched C 1
-C
7 alkyl; wherein R.
2 is straight -chained or branched C 3
-C
4 alkyl or cyclopropyl; wherein A is -Cl, -Br, -CN, -NO 2
-CO.
1 -CO2R3., straight chained or branched C 2
-C
7 alkyl, monotluoroalkyl or polyflucroalkyl or phenyl.
wherein each B is independently -Cl, -Br, -I, WO 03/004027 WO 0/00027PCT/UJS02/21063 i8 -CN, -N0 2
-COR
1 -C0 2 OCH3, -OCF 3
-CF
2 3, straight chained or branched CI-C- 7 alkyl, monofluoroalkyl or polyfluoroalkyl or aryl, phenoxy or benzyloxy, wherein the aryl, phenoxy or benzyloxy is optionally substituted with one or more -Cl, -Br, -CN, -NO 2
-COR
1 -C0 2
R,,
-OCH
3
-OCF
3
-CF
3 or straight chained or branched Cl -C3 alkyl.
In one embodiment, W is
N>
R
In one embodiment, R, is hydrogen or phenyl. optionally substituted with one or more -Cl, -Br, -CN, -NO 2 straight chained or branched CI-C 7 alkyl.
In one embodiment, R 2 is isopropyl.
In one embodiment, the compound has the structure:
N
r
N
WO 03/004027 PCT/US02/21063 19 In one embodiment, the compound has the structure:
N
TO- °O
N
This invention provides a compound having the structure: R3 jr R N-H N 0< R 4 R2 wherein R 1 is hydrogen, straight chained or branched
C
1
-C
7 alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more -Cl, -Br, -CN, -NO 2
-CF
3
-OCH
3 straight chained or branched Ci-C 3 alkyl; wherein R 2 is straight-chained or branched C 3
-C
4 alkyl or cyclopropyl; wherein R3 is -Cl, -Br, -CN, -NO 2
-CF
3
-OCH
3 or straight chained 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; wherein R 4 is hydrogen or aryl optionally substituted with one or more -Cl, -Br, -CN, -NO 2
-CF
3 straight chained or branched Ci-C 3 alkyl; WO 03/004027 PCT/US02/21063 wherein A is -Cl, -Br, -CN, -NO 2 straight chained or branched Ci-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; and wherein n is an integer from 2 to 4 inclusive.
In one embodiment, R 3 is -Cl, -Br, -CN, -NO 2
-OCF
3 or -OCH 3 and wherein R4 is hydrogen or phenyl optionally substituted with one or more -Cl or -CF 3 In one embodiment, Ri is hydrogen or phenyl optionally substituted with one or more -Cl, -Br, -CN, -NO 2 -CF3, -OCH 3 or straight chained or branched C 1
-C
3 alkyl; In one embodiment, R 2 is isopropyl.
In one embodiment, the compound has the structure: WO 03/004027 PCT/US02/21063 21 In one embodiment, the compound has the structure: In one embodiment, the compound has the structure: This invention provides a compound having the structure: S R 3
I
R
1 R N N-X
N-H
0o 0=< o R2 wherein each Ra is independently hydrogen or CH 3 wherein R 2 is straight-chained or branched CI-C 4 alkyl or cyclopropyl; wherein R 3 is benzyl or phenyl, wherein the benzyl or phenyl is optionally substituted with a methylenenedioxy group or one or more -F or -Cl; WO 03/004027 PCT/US02/21063 22 wherein A is -Cl, Br, -CN, -NO 2 straight chained or branched CI-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; wherein X is (CH 2 2
COCH
2 or CONH; In one embodiment, R 3 is phenyl optionally' substituted with one or more and wherein A is hydrogen.
In one embodiment, X is CONH.
In one embodiment, R 2 is methyl.
In one embodiment, the compound has the structure: 0 F O
V
2O N In one embodiment, the compound has the structure:
F
N-X N-H 020 wherein each Y is independently hydrogen or -F.
In one embodiment, the compound has the structure: WO 03/004027 PCT/US02/21063
F
F F
C
II
In one embodiment, the compound has the structure:
F
0 04N JL In one embodiment, R 3 is benzyl optionally substituted with a methylenedioxy group or one or more -F or -Cl.
In one embodiment, the compound has the structure: F y
Y
N-X N-H o o= wherein each Y is independently hydrogen or -F.
WO 03/004027 PCT/US02/21063 24 In one embodiment, the compound has the structure: 0 NN N In one embodiment, the compound is enantiomerically pure.
In one embodiment, the compound is diastereomerically pure.
In one embodiment, the compound is enantiomerically and diastereomerically pure.
This invention also provides a pharmaceutical composition comprising a therapeutically amount of a compound of the invention and a pharmaceutically acceptable carrier.
In one embodiment, the amount of the compound is from about 0.01mg to about 500mg.
In one embodiment, the amount of the compound is from about 0.1mg to about In one embodiment, the amount of the compound is from about Img to about WO 03/004027 PCT/US02/21063 In one embodiment, the pharmaceutical composition consists of a carrier which is a liquid and the composition is a solution.
In one embodiment, the pharmaceutical composition consists of a carrier which is a solid and the composition is a tablet.
In one embodiment, the pharmaceutical composition consists of a carrier which is a gel and the composition is a suppository.
The invention also provides a process for making a pharmaceutical composition comprising admixing a therapeutically effective amount of the compound of any of the invention and a pharmaceutically acceptable carrier.
This invention also provides the method of treating a subject suffering from a disorder selected from the group consisting of depression, anxiety, urge incontinence, or obesity comprising administering to the subject a therapeutically effective amount of the compound of the invention.
In one embodiment, the therapeutically effective amount is between about 0.03 and about 1000 mg per day.
In one embodiment, the therapeutically effective amount is between about 0.30 and about 300 mg per day.
In one embodiment, the therapeutically effective amount is between about 1.0 and about 100 mg per day.
WO 03/004027 PCT/US02/21063 26 In one embodiment, the disorder is depression.
In one embodiment, the disorder is anxiety.
In one embodiment, the disorder is obesity.
In one embodiment, the disorder is urge incontinence.
The invention provides the method of reducing the body mass of a subject, which comprises administering to the subject an amount of a compound of the invention effective to reduce the body mass of the subject.
The invention provides the method of treating a subject suffering from depression, which comprises administering to the subject an amount of a compound of any of claims of the invention effective to treat the subject's depression.
The invention'provides the method of treating a subject suffering from anxiety, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's anxiety.
The invention provides the method of alleviating urge urinary incontinence in a subject suffering from an overactive bladder, which comprises administering to the subject an amount of the compound of the invention effective to alleviate the subject's urge urinary incontinence.
WO 03/004027 PCT/US02/21063 27 The invention provides the method of managing obesity in a subject in need of weight loss, which comprises administering to the subject an amount of a compound of the invention effective to induce weight loss in the subject.
The invention provides the method of managing obesity in a subject who has experienced weight loss, which comprises administering to the subject an amount of a compound of the invention effective to maintain such weight loss in the subject.
The invention provides the method of treating overactive bladder in a subject, which comprises administering to the subject an amount of a compound of any of the invention effective to treat the subject's overactive bladder.
The invention provides the method of treating a disorder in a subject, wherein the symptoms of the subject can be alleviated by treatment with an MCH1 antagonist, wherein the MCH1 antagonist is the compound of the invention.
The invention provides the method of alleviating the symptoms of a disor4der in a subject, which comprises administering to the subject an amount of an MCH1 antagonist effective to alleviate the symptoms, wherein the MCH1 antagonist is the compound of the invention.
WO 03/004027 PCT/UJSO2/21063 28 Detailed Description of the Invention This invention provides a compound having the structure:
RR
xI R "eN R 6 V n N R Rr
Y
R
6 n N WO 03/004027 WO 0/00027PCT/UJS02/21063 29 R N R 6 Y+ M z x
N
Y
wherein each V is independently phthalimide, aryl, phenoxy or heteroaryl, wherein the aryl, phenoxy or heteroaryl is optionally substituted with one or more F'; Cl; Br; I; CORS; C0 2
R
5
-OCOR
5
-CON(RS)
2 -N(Rs)COR5; CN;
-NO
2
-N(R
5 2
-OR
5
-SR
5
(CH
2 )qOR5; (CH2),R5; (CH 2 )qSR 5 straight chained or branched C 1
-C
7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2
-C
7 alkenyl, C 2
-C
7 alkynyl; aryl; phenoxy; C 3
-C
7 cycloalkyl, monofJluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; is wherein each W is independently aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; COR 3
-OCOR
3 C0 2
R
3 -CON (R 3 2 -N (R 3 COR,; CN; -NO 2 -N (R3) 2
-OR
3
-SR
3
(CH
2 qOR3 i (CH 2 )qSR 3 straight chained or branched Cl-C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2
-C
7 alkenyl, C 2
-C
7 alkynyl; aryl; phenoxy; C3-C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; WO 03/004027 WO 0/00027PCT/UJS02/21063 wherein X is hydrogen or OR 3 provided that when X is -OR 3 the V geminal to X cannot be phthalimide; wherein Y -Is hydrogen, =0 (carbonyl oxygen) OR 3
OV,
COy, =NNHV, =NNR 5
NZR
5 NZV, NCONSV (ureas) NCONRs, NR 3 carbazole, indole or phthalimide; wherein each R is independently straight chained or branched CJ.-C 7 alkyl, monofluoroa-kyl or polyfluoroalkyl; straight chained or branched C 2
-C
7 alkenyl or alkynyl; -N(R 3 2
-NO
2 -CN; -C0 2
R
3
-OCOR
3
-OR
3 or -N(R 3 )COR3; -CON(R 3 2 wherein each R 3 is independently straight chained or is branched Cj-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2
-C
7 alkenyl or aJlkynyl;
C
3
-C
7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein each R 5 is -N 2 3; -CN; straight chained or branched C 1
-C
7 alkyl, monotluoroalkyl or polyfluoroalkyl; straight chained 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 pOR; -COR, -C0 2
R
3
-OCOR
3
-CON(R
3 2 -N(R3)COR 3 aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; CORE; C0 2
R
3
-OCOR
3
-CON(R
3 2 -N (R 3
COR
3 CN; -NO 2 -N (RD) 2 -ORe; -SR6; (CH2) qOR6;
(CH
2 )qSRG; straight chained or branched C 2
-C
7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2
-C
7 alkenyl, C 2
-C
7 alkynyl; C 3
-C
7 cycloalkyl, WO 03/004027 WO 0/00027PCT/UJS02/21063 31 monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein R 6 is. straight chained or branched C 1
-C
7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2
-C
7 alkenyl or alkynyl; C 3
-C
7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -NCR 3 2
-OR
3
(CH
2 )pOR 3
-COR
3 -C0 2
R
3
-OCOR
3
-CON(R
3 2
-N(R
3
)COR
3 aryl, benzyl or heteroaryl, optionally substituted with 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 i -N(R3) 2
-OR
3
-SR
3
(CH
2 )qOR 3
(CH
2 )qSR3; straight chained or branched C3 1
-C
7 alkyl, monofluoroalkyl, polyf luoroalkyl, aminoalkyl, or carboxamidoalkyl; aryl; benzyl; straight chained or branched C 2
-C
7 alkenyl, C 2
-C
7 alkynyl; C 3 -C7 cycloalkyl, ronofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein Z is CO, SO 2 or SO 2
NR
6 wherein each m is independently an integer from 0 to 3 inclusive; wherein each' n is independently an integer from 0 to inclusive; wherein each p is independently an integer from 1 to 7 inclusive; and wherein q is an integer from 1 to 3 inclusive; or a pharmaceutically acceptable salt thereof.
WO 03/004027 WO 0/00027PCT/UJS02/21063 32 As used in the present invention, the term "cycloalkyl" includes C 3
-C
7 cycloalky moities which may be substituted with one or more of the following: F; CN;
-NO
2 straight chained or branched C 1
-C
7 alkyl, straight chained or branched C 1 -C7 monofluoroalkyl,straight chained or branched CI-C 7 polyfluoroalky., straight chained or branched C 2
-C
7 alkenyl, straight chained or branched C 2
-C
7 alkynyl; C 3
-C
7 cycloalkyl, C 3
-C
7 monofluorocycloalkyl, C 3
-C
7 polyfluorocycloalkyl, C 5
-C
7 cycloalkenyl, -N (R 3 2
-OR
3 -NCOR3; -COR 3 -C0 2 R3;
-CON(R
2 3) 2 or (CH 2 )p-O-CCH 3 )m-CH 3 In the present invention, the term "cycloalkenyl" includes C 5
-C
7 cycloalkenyl moities which may be substituted with one or more of the following: -F; -Cl; -Br, CN; -NO 2 straight chained or branched C C, alkyl, straight chained or branched C C, monof'uoroalkyl, straight chained or branched CI-C 7 polyfluoroalkyl, straight chained or branched C 2 -C-1 alkenyl, straight chained or branched C 2
-C
7 alkynyl; C 3 -C7 cycloalkyl, C 3
-C
7 monofluorocycloalkyl, 3C polyfluorocycloalkyl, CS-C 7 cycloalkenyl, -N CR 3 2; -OR 3
-NCOR
3
-COR
3 -C0 2
R
3 CON (R 3 2 or (CH 2 P -O0- (CHO) m -CH 3 As used in the present invention, the term "heteroaryl" is used to include five and six membered unsaturated rings that may contain one or more oxygen, sulfur, or nitrogen atoms. Examples of heteroaryl groups include, but are not limited to, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazzolyl, thiadiazolyl, WO 03/004027 WO 0/00027PCT/UJS02/21063 33 pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.
In addition, the term "heteroaryl" is used to include fused bicyclic ring systems that may contain one or more heteroatoms such as oxygen, sulfur and nitrogen.
Examples of such heteroaryl groups include, but are not limited to, indolizinyl, indolyl, iscindolyl, benzo 1b] furanyl, benzo Eb)thiophenyl, indazolyl, benzimidazclyl, purinyl, benzoxazolyl, benzisoxazolyl, benzo Eb)thiazolyl, imidazo 1-b) thiazolyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1, 8-naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, phthalimidyl and 2, 1, 3-benzothiazolyl.
The term "heteroaryl" also includes those chemical moieties recited above which may be substituted with one or more of the following: -Cl; -Br, CN;
-NO
2 straight chained or branched Cl-C-7 alkyl, straight chained or branched C 1
-C
7 monofluoroalkyl, straight chained or branched CI-C 7 polyfluoroalkyl, straight chained or branched C 2
-C-
7 alkenyl, straight chained or branched C 2
-C
7 alkynyl; C 3
-C
7 cycloalkyl, C2-C, monofluorocycloalkyl, C 3
-C
7 polyfluorocycloalkyl, C 5
-C
7 cycloalkenyl, -N (R 3 2
-OR
3
-NCOR
3
-COR
3
-CC
2
TZ
3
CON(R
3 2 or (CH 2 )p-O-(CH 3 ),-CI-1 3 WO 03/004027 WO 0/00027PCT/UJS02/21063 34 In still another embodiment Of the above invention, the compound has the structure: H 0 R Nj, .R 6 V- R V H described ,or r"c,'R6 b In a further embodiment of the instant invention, R 6 is straight chained or branched C 2
-C
7 alkyl; C 3
-C
7 cycloalkyl; -N(R 3 2
-OR
3
-(CH
2 )pOR 3 aryl, benzyl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; -OR 3 -<CH2)qOR3; or straight chained or branched C 1
-C
7 alkyl.
WO 03/004027 PCT/US02/21063 In an embodiment of the present compound has the structure: invention, the or In a further embodiment of the present invention, at least one V is phenyl optionally substituted with one or more F; Cl; Br; -OR 3 (CH2)qOR3; straight chained or branched C 1
-C
7 alkyl; CI-C 7 polyfluoroalkyl; or phenoxy.
In one embodiment of the present invention, the compound is: In one embodiment, the compound is: WO 03/004027 PCT/US02/21063 In one embodiment, the compound is: In another embodiment of the present invention, the compound has the structure: H 0 I X II or In a further embodiment of the present invention, at least one V is phenyl optionally substituted with one or more F; Cl; Br; -OR 3 (CH2)qOR3; straight chained or branched CI-C 7 alkyl; Ci-C 7 polyfluoroalkyl; or phenoxy.
In another embodiment of the present invention, the compound is WO 03/004027 PCT/US02/21063 37 In one embodiment, the compound is HQ
N
NH
0O= In a further embodiment of the present invention, the compound has the structure: 0 vor 0 F; C; Br; -OR; -COR; (CHOR; traight or V n
R
OV
H
R N C ,R6 V n
R
OV
In another embodiment of the present invention, at least one V is phenyl optionally substituted with one or more F; Cl; Br; -OR 3
-COR
3
(CH
2 qOR 3 straight chained or branched Ci-C 7 alkyl; CI-C7 polyfluoroalkyl; aryl or phenoxy.
WO 03/004027 PCT/US02/21063 38 In yet another embodiment of the present invention, the compound is In one embodiment, the compound is In one embodiment, the compound is In one embodiment, the compound is WO 03/004027 PCT/US02/21063 39 the compound is In one embodiment,
NH
O-
In one embodiment, the compound is In an embodiment of the present invention, the compound has the structure: 0 Vor
R
In a further embodiment of the present invention, at least one V is phenyl optionally substituted with one or more F; Cl; Br; -OR 3
(CH
2 )qOR 3 straight chained or branched Ci-C 7 alkyl; Ci-C 7 polyfluoroalkyl; or phenoxy.
WO 03/004027 PCT/US02/21063 In yet another embodiment of the present invention, the compound is In one embodiment, the compound has the structure: F N-H F F In one embodiment, the compound has the structure:
N-H
In one embodiment, the compound has the structure:
N-H
CI
WO 03/004027 PCT/US02/21063 41 In one embodiment, the compound has the structure:
N-H
CI CI In one embodiment, the compound has the structure: Br N ,N
N-H
N 0
CI
In one embodiment, the compound has the structure:
N-H
N O In one embodiment, the compound has the structure: NN -H N^l" WO 03/004027 PCT/US02/21063 42 In one embodiment, the compound has the structure: 0 N-H
F
F
In an additional embodiment of the present invention, Y is hydrogen and V is phthalimide.
In an additional embodiment of the present invention, R 6 is straight chained or branched Ci-C 7 alkyl; C 3
-C
7 cycloalkyl; -N(R 3 2
-OR
3
-(CH
2 )pOR 3 aryl, benzyl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; -OR 3
-(CH
2 )qOR 3 or straight chained or branched Ci-C 7 alkyl.
In a further embodiment of the present invention, the compound is H HY 0
H
0
R
N\
NH
V
WO 03/004027 WO 0/00027PCT/UJS02/21063 43 In one embodiment of the compound, at least one V is phenyl or heteroaryl optionally substituted with one or more F; Cl; Br; I; Rs; -OR5; (CH 2 qOR5; (CH 2 qRE;; straight chained or branched C 2
-C
7 alkyl; C 1
-C
7 monoflouroalky. or polyflouroalkyl; or phenoxy.
In one embodiment, the compound has the structure: I -N N' NH N H
NO)
In one embodiment, the compound has the structure: R H
RI
H V In one embodiment of the compound, V is phenyl which is optionally substituted with one or more F; Cl; Br; -OR 5
(CH
2 qO R5; (CH 2 qR5; straight chained cr branched CJ-C 7 alkyl; C 1
-C
7 mono flouroalkyl or polyflouroalkyl; or phenoxy.
in one embodiment, the compound has the structure:
F
0- H-N No
N-H
0 WO 03/004027 WO 0/00027PCT/UJS02/21063 44 In one embodiment, the compound has the structure:
H
NN R In one embodiment, the compound has the structure: R H
~NR
6 VZN
N
VN R In one embodiment, the compound has the structure: -P0
S-
R HH0 R
N_/
'N
RR
In one embodiment of the compound, R 5 is straight chained or branched Cl-C 7 alkyl; C 3
-C
7 cycloalkyl;
-N(R
6 2 i -OR 6
-(CH
2 -)qOR 6 CU-(PR6) 2
-(CH
2 )qR 6 or aryl, benzyl or heteroaryl, wherein the aryl, be nzyl or heteroaryl is optionally substituted with one or- more F; Cl; I; R 6 -NCRs) 2
-OR
6
-(CH
2 )qOR 6
-(CH
2 )qR 6 or straight chained or branched Cl-C 7 alkyl.
WO 03/004027 PCT/US02/21063 In one embodiment, the compound has the structure: H
-N
0 H/ In one embodiment, the compound has the structure: c1 N o C1 0 NH
H
In one embodiment of the compound, X is hydrogen and Y is carbazole optionally substituted with one or more F; Cl; Br; Rs; -ORs; -(CH 2 )qORs; -(CH 2 )qRs straight chained or branched C 1
C
7 alkyl; or CI-C 7 monoflouroalkyl or polyflouroalkyl; or phenoxy.
In one embodiment, the compound has the structure: /N I 0 In one embodiment, the compound has the structure: WO 03/004027 PCT/US02/21063 46 In one embodiment of the compound, Y is hydrogen and V is an indole, which can be optionally substituted with one or more F; Cl; Br; Rs; -C0 2 Rs; -ORs; -(CH 2 )qORs; (CH2)qR 5 straight chained or branched C C, alkyl; Ci-C 7 monoflouroalkyl or polyflouroalkyl; or phenoxy on the 1, 2, 3, 4 5, 6 or 7 positions.
In one embodiment, the compound has the structure:
R
\NN
S R N-H N 0 In one embodiment, the compound has the structure:
N-H
In one embodiment, the compound has the structure:
SNH
0 is- In one embodiment, the compound has the structure: C 0= N-H N N-H
N-H
WO 03/004027 PCT/US02/21063 47 In one embodiment, the compound has the structure: N SN-H N 0 In one embodiment, the compound has the structure:
NN
H
N 0=1 In one embodiment, the compound has the structure:
N-H
In one embodiment, the compound has the structure:
N
H
CN-H
O WO 03/004027 In one embodiment, PCT/US02/21063 48 the compound has the structure: In one embodiment, the compound has the structure: In one embodiment, the compound has the structure:
N
N n H In one embodiment, the compound has the structure: WO 03/004027 PCT/US02/21063 49 In one embodiment, the compound has the structure:
N-H
0- In one embodiment, the compound has the structure: WO 03/004027 PCT/US02/21063 The present invention provides a compond having the srucuture: o R N AR, x N N N wherein each X is independently O or S;
-N(R)
2 -CON(R) or R 3 straight chained or branched C 2
-C
7 alkenyl, or alkynyl; or C 3
-C
7 cycloalkyl or orNR'N
C-C
7 cycloalkenylR; wherein each t is independently an integer rom to 4 wherein q is or 2; wherein each R is independently H; (CHstraight chained or (CH2)cC(X)N(R3)2; (CH2)tC02R3; -C02R3; straight chained or branched C 1
-C
7 alkyl optionally substituted with C -N(R3)2; -CON(R3)2 or -N (R3)C(O)R3; straight chained or branched 2-alkenyl, or alkynyl; or 3-C-C cycloalkyl or C-C S-C7 cycloalkenyl; wherein each t is independently an integer from 1 to 4 inclusive; wherein each R3 is independently H; straight chained or branched Cl-C7 alkyl, straight chained or branched C2-C7 alkenyl, or alkynyl; or C3-C7 cycloalkyl or Cs-C7 cycloalkenyl; WO 03/004027 WO 0/00027PCT/UJS02/21063 51 wherein R 4 is aryl, heteroaryl, C 1
C
7 alkyl substituted with one or two aryl, or CI-C 7 alkyl substituted with one or two heteroaryl; wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -CN, -NO 2 -N (R 3 2
-COR
3
(CT
2
)XR
3
(CH
2 C YR 3
(CH
2 nN (R 3 CC(X) R 3
(CH
2 1
-ICO
2
R
3
(CH-
2 COCOR,, straight chained or branched Cl-C 7 alkyl, monofluoroalkyl OR polyfluoroalkyl or straight chained or branched C 2
-C
7 aminoalkyl, alkenyl or alkynyl, or C 3
-C
7 cycloalkyl or
CI-C
7 cycloalkenyl; wherein each n independently is an integer from 0 to 7 inclusive; wherein R 5 is H; aryl, Cl-C 7 alkyl substituted with aryl, heteroaryl, or CI-C 7 alkyl substituted with heteroaryl; wherein the aryl1 or heteroaryl may be substituted with one or more of F, Cl, Br, 1, -CN, -NO 2
-N(R
3 2
-COR
3
(CH
2 )nXR 3
-(CH
2 )nC(X)NR 3
-(CH
2 )nCO 2
R
3 straight chained or branched CI-C 7 alkyl, monofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched C 2
-C,
aminoalkyl, alkenyl or alkynyl, or C 3
-C
7 cycloalkyl or
C
5
-C
7 cycloalkenyl; where R 5 and one R 2 on adjacent carbon atoms together may form aryl, heteroaryl, indane or tetrahydronaphthyl, C 3 C, cycloalkyl, or heterocycloalkyl wherein one or two heteroatoms may be 0, N or S; wherein R, is WO 03/004027 WO 0/00027PCT/UJS02/21063 52 R6 8 ZN. ,or R6
Z-N
wherein- each V is independently aryl, phenoxy or heteroaryl, wherein the aryl, phenoxy or heteroaryl is optionally substituted with one or more F, Cl; Br; I;
COR
5 C0 2
R
5
'-OCOR
5 -CON (R 5 2 -N (Rq) COR 5 CN; -NO 2
N(RS)
2 -OPIS; -SR 5 S; (CH 2 )qOR5; (C112)qSRS5; straight chained or branched C 1
-C
7 alkyl optionally substituted with CON (R 5 2 -N(Rs)C(O)R 3 or N(R 3 2 straight chained or branched monofiluoroalkyl or polyfluoroalkyl, straight is chained or branched C 2
-C
7 alkenyl, C 2 alkynyl; phenoxy; or C 3
-C
7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein each R 6 is independently H; (CH 2 )tXR 3
(CIH
2 )tC NR 3
(CM
2 tN (R 3 C(X) R 3 (C4 2 tCO 2
R
3
(CM
2 tOCOR3; straight chained or branched C 1
-C
7 alkyl optionally substituted with -CON(R 3 2 or -NC(O)R 3 straight chained or branched C 2
-C
7 alkyl subst.ituted with -N(R 3 2 straight WO 03/004027 PCT/US02/21063 53 chained or branched C 2
-C
7 alkenyl or alkynyl; or C 3
-C
7 cycloalky or C 5
-C
7 cycloalkenyl; where each R 7 is independently H; F; Cl; Br; I; -COR 3 C0 2
R
3
(CH
2
XR
3
-(CH
2
N(R
3
)C(O)R
3
.(CH
2 nC (X)N(R 3 2
(CH
2 )'nCO 2
R
3 -CN; -NO 2 -N (R 3 2 straight chained or branched C 1
-C
7 alkyl, hydroxyalky, aninoalkyl, carboxamidoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroakyl; straight chained or branched C 2
-C
7 alkenyl or alkynyl; C 3
-C
7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C 5
-C
7 cycloalkenyl, wherein the alkyl, aminoalkyl, carboxamidoalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl may be substituted with one or more aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, (CH 2
XR
3
-COR
3
(CH
2 nC (X)N(R 3 2
(CH
2 nC0 2
R
3 CN, -NO 2
-(CH
2
N(R
3 )C(O)R -N(R 3 2 -S0 2
R
3 straight chained or branched C 1
-C
7 alkyl, monofluoroalkyl or polyfluoroaJkyl, straight chained or branched C 2
-C
7 alkenyl or alkynyl, or C 3
-C
7 cycJoalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C 5 -C7 cycloalkenyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -(CI 2
),XR
3
-COR
3
(CH
2 3 2 WO 03/004027 WO 0/00027PCT/UJS02/21063 54
(CI-
2
ICO
2
R
3
(CH
2 )nN(R3)C(O)R 3 -CN, -NO 2
-N(R
3 2 -S0 2 R3, straight chained or branched C 1
-C
7 alkyl, straight chained or branched C3.-C 7 monofluoroalkyl or polyfluoroalkyl, straight chained or branched C 2
-C
7 alkenyl or alkynyl, or C C, cycloalkyl, monofluorocycloa-kyl, polyfluorocycloalkyl or C 5
-C
7 cycloalkenyl; wherein B is CO, S02 or SO 2
NR
6 wherein R 8 is straight chained or branched C 1
-C
7 alkyl, ronofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2
-C
7 alkenyl or alkynyl; C 3
-C
7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 2 2
-NR
3
C(O)R
2
-OR
3
-(CH
2 )pOR 3
COR
3 -C0 2
R
3
-OCOR
3 -CON (R 3 2 aryl or heteroaryl, optionally substituted with one or more F, Cl; Br; I;
COR
3 C0 2
R
3
-OCOR
3
-NR
3
C(O)R
3
-CON(R
3 2 i CN; -NO 2
N(R
3 2
-OR
3
-SR
3
(CH
2 )qOR3; (CH 2 )qSR3; straight chained or branched CI-C 7 alkyl optionally substituted with CON (R 3 2
-NR
3
C(O)R
3 or -N(R 3 2 straight chained or branched rnmonofluoroalkyl, polyfluoroalkyl; straight chained or branched C 2
-C
7 alkenyl, C 2
-C
7 alkynyl; C3-C 7 cycloalkyl, ronofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein each m independently is an integer from 0 to 3 inclusive; wherein Z is WO 03/004027 PCT/UJS02/21063 0 0 .,lKy, WO 03/004027 WO 0/00027PCT/UJS02/21063 56 R6R6 0 j N
R
9 R6 6R6 R 9 R6 m Y t ,or R2 R 9 0 R 2
R
P
2
R
9 t
P
2
R
9 or C 2
-C
7 alkenyl, wherein the C 2
-C
7 alkeny. may be unsubstituted or substituted with one or more R 9 groups; wherein each R9 is independently F; F; Cl; Br; I;
-(CH
2 mXR 3
(CH
2 C NR 3
(CH
2 mCO 2
R
3 straight chained or branched Cl-C 7 alkyl, mono fluoroalkyl, polyfluoroalkyl, arninoalkyl, or carboxamidoalkyl; straight chained or branched C 2
-C
7 alkenyl, or alkynyl; or C 3
-C
7 cycloalkyl or
C
5
-C
7 cycloalkenyl; WO 03/004027 WO 0/00027PCT/UJS02/21063 57 wherein Rio is H; (CH 2 tXR 3
(CH
2 tC(X) NR 3
(CH
2 tC0 2 R3; straight chained or branched C 1
-C
7 alkyl, carboxamidoalkyl; straight chained or branched C 2
-C
7 aminoalkyl, alkenyl, or alkynyl; or C3-C 7 cycloalkyl or
C
5
-C
7 cycloalkenyl; wherein Y is S, 0, or NR 10 wherein each p is independently an integer from 1 to 7 inclusive; or a pharmaceutically acceptable salt thereof.
In a further embodiment of the present invention, the compound has the following structure:
R
2 ~~4~R Rs
R
4
AN
Rs
R
4 In an additional embodiment of the present invention, the compound has the structure: WO 03/004027 WO 0/00027PCT/UJS02/21063 58 0 R 6
N-Z-N
R2 R 4 R6 0 0 R R0 In an additional embodiment of the present invention, the compound has the structure: 0 Z N
R
2 D_ NN
R
8 In one embodiment of the present invention, Z is: 0 R tt y r
R
2 R 1R9 WO 03/004027 PCT/US02/21063 In one embodiment of the present invention, Z is: In an additional embodiment of the present .invention, the compound has the structure: In one embodiment of the present invention, the compound has the strucuture: WO 03/004027 PCT/US02/21063 This invention provides a compound having the structure:
R
1 -X N R3
N-H
R2 wherein Ri is hydrogen, straight chained or branched Ci-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more -Cl, -Br, -CN,
-NO
2
-CH
3
-CF
3
-COCH
3 -C0 2
R
2 phenyl, phenoxy or straight chained or branched Ci-C 7 alkyl; wherein R 2 is straight-chained or branched C 3
-C
4 alkyl or cyclopropyl; wherein R 3 is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more -C1, -Br, -CN, ,-NO 2 straight chained or branched Cl-C7 alkyl; wherein A is -Cl, -Br, -CN, -NO 2
-COR
3 -COzR 3 straight chained or branched CI-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; wherein X is O or NH; wherein n is an integer from 0 to 5 inclusive; In one embodiment, RI is aryl optionally substituted with one or more -Cl, -Br, -CN, -NO 2 -COCH3, WO 03/004027 PCT/US02/21063 -C0 2 Ra, straight chained or branched Cl-C 7 alkyl; wherein R 3 is phenyl; wherein A is H; and wherein X is O.
In one embodiment, R 2 is isopropyl.
In a preferred embodiment, X is NH, Ri is alkyl and n is 1 or 2.
In the most preferred embodiment, X is O, R, is 3-acetyl phenyl, R 2 is isopropyl, R 3 is phenyl and n is 1.
In one embodiment, the compound has the structure: 0o
N
In one embodiment, compound has the structure: WO 03/004027 PCT/US02/21063 62 In one embodiment, RI is hydrogen, straight chained or branched CI-C 7 alkyl; and wherein R 3 is aryl.
In one embodiment, R 2 is isopropyl; and A is hydrogen.
In one embodiment,.the compound has the structure: 0N
N
In one embodiment, the compound has the structure:
HQ
SN
The present invention also provides a compound having the structure:
A
0 N-H R 2 wherein Ri is aryl or heteroaryl optionally substituted with one or more -Cl, -Br, -CN, -NO 2
-OCH
3 phenoxy, fused cyclopentanyl, straight chained or branched Ci-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; WO 03/004027 PCT/US02/21063 63 wherein R2 is straight-chained or branched CI-C 4 alkyl or cyclopropyl; wherein A is -Cl, -Br, -CN, -NO 2 straight chained or branched CI-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; and wherein n is an integer from 1 to 5 inclusive.
In one embodiment, R 1 is aryl optionally substituted with one or more -Cl, -Br, -I or straight chained or branched C 1
-C
4 alkyl; and wherein A is H.
In one embodiment, R 2 is isopropyl; and wherein n is 2.
In a preferred embodiment, n is 2 and R2 is isopropyl.
In one embodiment, the compound has the structure:
N
In one embodiment, the compound has the structure: 0 0 WO 03/004027 PCT/US02/21063 64 In one embodiment, the compound has the structure: 0 o N N In one embodiment, R 1 is thienyl; and wherein A is H.
In one embodiment, R 2 is isopropyl.
In one embodiment, the compound has the structure: S N N The invention provides a compound having the structure:
A
I-
W
N-H
R2 wherein W is H A or ^N R 1 R,
H
wherein each Ri is independently hydrogen, methyl or ethyl; wherein R 2 is straight-chained or branched C 3
-C
4 alkyl or WO 03/004027 PCT/US02/21063 wherein R 2 is straight- chained or branched C 3
-C
4 alkyl or cyclopropyl; wherein R 3 is hydrogen, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more -Cl, -Br, -CN, -NO 2 straight chained or branched CI-C 7 alkyl.
wherein each A is independently -Cl, -Br, -CN,
-NO
2 -COR3, -CO 2
R
3 straight chained or branched CI-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; wherein X is O, NR 3 CO or may be absent; and wherein Y is hydrogen, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more -Cl, -Br, -CN, -NO 2 straight chained or branched Cl-C 7 alkyl.
In one embodiment, W is H A
-X-Y
H
and wherein X is 0 or may be absent.
In one embodiment, R 2 is isopropyl.
WO 03/004027 PCT/US02/21063 66 In one embodiment, the compound has the structure: N N 0 F F In one embodiment, the compound has the structure: In one embodiment, W is N RI
R,
In one embodiment, A is -Cl, -Br.
In one embodiment, R 2 is isopropyl; and A is hydrogen.
In one embodiment, the compound has the structure: K- vKX WO 03/004027 WO 03/04027PCTIUS02/2 1063 67 This invention provides a compound having the structure:
A
N-H
o=K wherein W is B B0 I or wherein R, is hydrogen, straight chained or branched Cj-C 7 alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more -Cl, -Br, -CN, -NO 2 -OCH3, -CO 2
CH
2 3, -CF 3 phenyl, straight chained or branched CI 1
-C
7 alkyl; wherein R 2 is straight -chained or branched C 3
-C
4 alkyl or cyclopropyl; wherein A is -Cl, -Br, -CN, -NO 2
-COR
1 L, -CO 2 Rj, straight chained or branched CI-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl or phenyl.
wherein each B is independently -Cl, -Br, -I, -CN, -NO 2 -CORI, -C0 2 RI, -OCH 3 -OCF,, straight chained or branched Cj-C7 alkyl, monofluoroalkyl or polyfluoroalkyl or aryl, phenoxy or benzyloxy, wherein the aryl, phenoxy or benzyloxy is optionally substituted with one or more -Cl, -B3r, -CN, -NO 2 -CORI, -C0 2 Rj, WO 03/004027 PCT/US02/21063 68
-OCH
3
-OCF
3
-CF
3 or straight chained or branched C1 -C3 alkyl.
In one embodiment, W is B
B
N>8 R1 In one embodiment, Ri is hydrogen or phenyl optionally substituted with one or more -Cl, -Br, -CN, -NO 2 straight chained or branched Ci-C 7 alkyl.
In one embodiment, R 2 is isopropyl.
In one embodiment, the compound has the structure: Cl N N
°O
In one embodiment, the compound has the structure:
N
0°' WO 03/004027 PCT/US02/21063 69 This invention provides a compound having the structure: 3- D R
N-H
N 0= R1 R2 wherein RI is hydrogen, straight chained or branched Ci-C 7 alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more -Cl, -Br, -CN, -NO 2 -CF3, -OCH 3 straight chained or branched Ci-C 3 alkyl; wherein R 2 is straight-chained or branched C 3
-C
4 alkyl or cyclopropyl; wherein R 3 is -Cl, -Br, -CN, -NO 2
-CF
3
-OCH
3 or straight chained or branched C 1
-C
3 alkyl, monofluoroalkyl or polyfluoroalkyl, or a phenyl ring fused to CG and C 7 of the indole moiety; wherein Ra is hydrogen or aryl optionally substituted with one or more -Cl, -Br, -CN, -NO 2
-CF
3 straight chained or branched CI-C 3 alkyl; wherein A is -Cl, -Br, -CN, -NO 2 straight chained or branched Ci-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; and wherein n is an integer from 2 to 4 inclusive.
WO 03/004027 PCT/US02/21063 In one embodiment, R 3 is H, -Cl, -Br, -CN,
NO
2
-OCF
3 or -OCH3; and wherein R 4 is hydrogen or phenyl optionally substituted with one or more -Cl or -CF 3 In one embodiment, Ri is hydrogen or phenyl optionally substituted with one or more -Cl, -Br, -CN, -NO 2
-CF
3
-OCH
3 or straight chained or branched CI-C 3 alkyl; In one embodiment, R 2 is isopropyl.
In one embodiment, the compound has the structure: N N
NN
In one embodiment, the compound has the structure:
FF
F O Cl In one embodiment, the compound has the structure: WO 03/004027 PCT/US02/21063 71 This invention provides a compound having the structure:
A
R1 R 3 N N N-X N-H o= 0 R2 wherein each R, is independently hydrogen or CH 3 wherein R 2 is straight-chained or branched C 1
-C
4 alkyl or cyclopropyl; wherein R 3 is benzyl or phenyl, wherein the benzyl or phenyl is optionally substituted with a methylenenedioxy group or one or more -F or -Cl; wherein A is -Cl, -Br, -CN, -NO 2 straight chained or branched C 1
-C
7 alkyl, monofluoroalkyl or polyfluoroalkyl; wherein X is (CH2) 2
COCH
2 or CONH; -In one embodiment, R 3 is phenyl optionally substituted with one or more and wherein A is hydrogen.
In one embodiment, X is CONH.
In one embodiment, R 2 is methyl.
In one embodiment, the compound has the structure: WO 03/004027 PCT/US02/21063 72 F F
O
0-OO
N
In one embodiment, the compound has the structure:
F
R N N-X N-H wherein each Y is independently hydrogen or -F.
In one embodiment, the compound has the structure: In one embodiment, the compound has the structure: WO 03/004027 PCT/US02/21063 73 In one embodiment, R 3 is benzyl optionally substituted with a methylenedioxy group or one or more -F or -Cl.
In one embodiment, the compound has the structure: R R, No N-X
N-H
0 wherein each Y is independently hydrogen or -F.
In one embodiment, the compound has the structure: F0 0 S NN In one embodiment, the compound is enantiomerically pure.
In one embodiment, the compound is diastereomerically pure.
In one embodiment, the compound is enantiomerically and diastereomerically pure.
This invention also provides a pharmaceutical composition comprising a therapeutically amount of a WO 03/004027 PCT/US02/21063 74 compound of the invention and acceptable carrier.
In one embodiment, the amount of about 0.01mg to about 500mg.
In one embodiment, the amount of about 0.1mg to about In one embodiment, the amount of about Img to about a pharmaceutically the compound is from the compound is from the compound is from In one embodiment, the pharmaceutical composition consists of a carrier which is a liquid and the composition is a solution.
In one embodiment, the pharmaceutical composition consists of a carrier which is a solid and the composition is a tablet.
In one embodiment, the pharmaceutical composition consists of a carrier which is a gel and the composition is a suppository.
The invention also- provides a process for making a pharmaceutical composition comprising admixing a therapeutically effective amount of the compound of any of the invention and a pharmaceutically acceptable carrier.
This invention also provides the method of treating a subject suffering from a disorder selected from the group consisting of depression, anxiety, urge WO 03/004027 PCT/US02/21063 incontinence, or obesity comprising administering to the subject a therapeutically effective amount of the compound of the invention.
In one embodiment, the therapeutically effective amount is between about 0.03 and about 1000 mg per day.
In one embodiment, the therapeutically effective amount is between about 0.30 and about 300 mg per day.
In one embodiment, the therapeutically effective amount is between about 1.0 and about 100 mg per day.
In one embodiment, the disorder is depression.
In one embodiment, the disorder is anxiety.
In one embodiment, the disorder is obesity.
In one embodiment, the disorder is urge incontinence.
The invention provides the method of reducing the body mass of a subject, which comprises administering to the subject an amount of a compound of the invention effective to reduce the body mass of the subject.
The invention provides the method of treating a subject suffering from depression, which comprises administering to the subject an amount of a compound of any of claims of the invention effective to treat the subject's depression.
WO 03/004027 PCT/US02/21063 76 The invention provides the method of treating a subject suffering from anxiety, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's anxiety.
The 'invention provides the method of alleviating urge urinary incontinence in a subject suffering from an overactive bladder, which comprises administering to the subject an amount of the compound of the invention effective to alleviate the subject's urge urinary incontinence.
The invention-provides the method of managing obesity in a subject in need of weight loss, which comprises administering to the subject an amount of a compound of the invention effective to induce weight loss in the subject.
The invention provides the method of managing obesity in a subject who has experienced weight loss, which comprises administering to the subject an amount of a compound of the invention effective to maintain such weight loss in the subject.
The invention provides the method of treating overactive bladder in a subject, which comprises administering to the subject an amount of a compound of any of the invention effective to treat the subject'.s overactive bladder.
The invention provides the method of treating a disorder in a subject, wherein the symptoms of the subject can be WO 03/004027 PCT/US02/21063 77 alleviated by treatment with an MCH1 antagonist, wherein the MCH1 antagonist is the compound of the invention.
The invention provides the method of alleviating the symptoms of a disor4der in a subject, which comprises administering to the subject an amount ,of an MCH1 antagonist effective to alleviate the symptoms,'wherein the MCH1 antagonist is the compound of the invention As used in the present invention, the term "heteroaryl" is used to include five and six membered unsaturated rings that may contain one or more oxygen, sulfur, or nitrogen atoms. Examples of heteroaryl groups include, but are not limited to, carbazole, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.
In addition, the term "heteroaryl" is used to include fused bicyclic ring systems that may contain one or more heteroatoms such as oxygen, sulfur and nitrogen.
Examples of such heteroaryl groups include, but are not limited to, indolizinyl, indolyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzimidazolyl, purinyl, benzoxazolyl, benzisoxazolyl, benzo[b]thiazolyl, imidazo[2,1-b]thiazolyl,, cinnolinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, phthalimidyl and 2,1,3-benzothiazolyl.
WO 03/004027 PCT/US02/21063 78 The term "heteroaryl" also includes those chemical moieties recited above which may be substituted with one or more of the following: -Cl, -Br, CN, -NO 2 straight chained or branched C 1
-C
7 alkyl, straight chained or branched C 1
-C
7 monofluoroalkyl, straight chained or branched CI-C 7 polyfluoroalkyl, straight chained or branched C 2
-C
7 alkenyl, straight chained or branched C 2
-C
7 alkynyl; C 3
-C
7 cycloalkyl, C3-C7 monofluorocycloalkyl, C 3
-C
7 polyfluorocycloalkyl, Cs-C 7 cycloalkenyl, The term "heteroaryl" further includes the N-oxides of those chemical moieties recited above which include at least one nitrogen atom.
In the present invention, the term "aryl" is phenyl or naphthyl.
The invention provides for each pure stereoisomer of any of the compounds described herein. Such stereoisomers may include enantiomers, diastereomers, or E or Z alkene or imine isomers. The invention also provides for stereoisomeric 'mixtures, including racemic mixtures, diastereomeric mixtures, or E/Z isomeric mixtures.
Stereoisomers can be synthesized in pure form (N6grddi,- Stereoselective Synthesis, (1987) VCH Editor Ebel, H. and Asymmetric Synthesis, Volumes 3 *B 5, (1983) Academic Press, Editor Morrison, or they' can be resolved by a variety of methods such as crystallization and chromatographic techniques (Jaques, Collet, A.; Wilen, Enantiomer, Racemates, and Resolutions, 1981, WO 03/004027 PCT/US02/21063 79 John Wiley and Sons and Asymmetric Synthesis, Vol.
2, 1983, Academic Press, Editor Morrison, J).
In addition the compounds of the present invention may be present as enantiomers, diasteriomers, isomers or two or- more of the compounds may be present to form a racemic or diastereomeric mixture.
The compounds of the present invention are preferably 80% pure, more preferably 90% pure, and most preferably pure. Included in this invention are pharmaceutically acceptable salts and complexes of all of the compounds described herein. The acids and bases from which these salts are prepared include but are not limited to the acids and bases listed herein. The acids include, but are not limited to, the following inorganic acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and boric acid. The acids include, but are not limited to, the following organic acids: acetic acid, malonic acid, succinic acid; fumaric acid, tartaric acid, maleic acid, citric acid, methanesulfonic acid, benzoic acid, glycolic acid, lactic acid and mandelic acid. The bases include, but are not limited to ammonia, methylamine, ethylamine, propylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, ethylenediamine, hydroxyethylamine, morpholine, piperazine .and guanidine. This invention further provides for the hydrates and polymorphs of all of the compounds described herein.
The present invention includes within its scope prodrugs of the compounds of the invention. In general, such prodrugs will be functional derivatives of the compounds WO 03/004027 PCT/US02/21063 of the invention which are readily convertible in vivo into the required compound. Thus, in the present invention, the term "administering" shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection.
and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H..
Bundgaard, Elsevier, 1985.
The present invention further includes metabolites of the compounds of the present invention. Metabolites include active species produced upon introduction of compounds of this invention into the biological milieu.
This invention 'further provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the invention and a pharmaceutically acceptable carrier. In one embodiment, the amount Of the compound is from about 0.01 mg to about 800 mg. In another embodiment, the amount of the compound is from about 0.01 mg to about 500 mg. In yet another embodiment, the amount of the compound is from about 0.1 mg to about 250 mg. In another embodiment, the amount of the compound is from about 0.1 mg to about mg. In yet another embodiment, the amount of the compound is -from about 1 mg to about 20 mg. In a further embodiment, the carrier is a liquid and the composition is a solution. In another embodiment,- the carrier is a solid and the composition is a tablet. In another embodiment, the carrier is a gel and the WO 03/004027 PCT/US02/21063 81 composition is a capsule, suppository or a cream. In a further embodiment the compound may be formulated as a part of a pharmaceutically acceptable transdermal patch.
In yet a further embodiment, the compound may be delivered to. 'the subject by means of a spray or inhalant.
This invention also provides a pharmaceutical composition made by combining a therapeutically effective amount of the compound of this invention and a pharmaceutically acceptable carrier.
This invention provides a process for making a pharmaceutical composition comprising combining a therapeutically 'effective amount of the compound of this invention and a pharmaceutically acceptable carrier.
A-solid carrier can include one or more substances which may also act as endogenous carriers nutrient or micronutrient carriers), flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material. In powders', the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
In tablets, -the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, WO 03/004027 PCT/US02/21063 82 gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized.
compositions. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, coloring agents, viscosity regulators, stabilizers or osmoregulators. Suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils fractionated coconut oil and arachis cil) For parenteral administration, the carrier can also be an oily ester such as ethyl oleate or isopropyl myristate.
Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be a halogenated hydrocarbon or other pharmaceutically acceptable propellent.
Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by for example, intramuscular, intrathecal, epidural, intraperitoneal or.
subcutaneous injection. Sterile solutions can also be WO 03/004027 PCT/US02/21063 83 administered intravenously. The compounds may be prepared as a sterile solid composition which may be dissolved or suspended at the time of administration using sterile water, saline, or other appropriate sterile injectable medium. Carriers are intended to include, necessary and inert binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings. The compound can be administered orally in- the form of a sbr-ile- solution or suspension, containing other solutes or suspending agents (for example, enough-saline or glucose to make the solution isotonic), bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide) and the like.
The compound can also be administered orally either in liquid or solid composition form. Compositions suitable for oral administration include solid forms, such as pills, capsules, granuLs, tablets, and powders, and liquid forms, such as solutions, syrups, elixirs, and suspensions. Forms useful for parenteral administration include-sterile solutions, emulsions, and suspenions.
Optimal dosages to be administered may be .determined by those skilled in the art, and will vary with the particular compound in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular subject being treated will result i a need to adjust dosages, including subject age, weight, gender, diet, and time of administration.
WO 03/004027 PCT/US02/21063 84 In the subject application a "therapeutically effective amount" is any amount of a compound which, when administered to a subject suffering from a disease against which the compounds are effective, causes reduction, remission, or regression of the disease. In a subject application, a "subject" is a vertebrate, a mammal or a human.
This invention provides a method of treating a subject suffering from an abnormality wherein the abnormality is alleviated by decreasing the activity of an MCH1 receptor which comprises administering to the subject an amount of a compound of the invention which is an MCH1 receptor antagonist effective to treat the subject=s abnormality.
In separate embodiments, the abnormality is a regulation of a steroid or pituitary hormone disorder, an epinephrine release disorder, a gastrointestinal disorder,- a cardiovascular disorder, an electrolyte balance disorder, hypertension, diabetes, a respiratory disorder, asthma, a reproductive function disorder, an immune disorder, an endocrine disorder, a musculoskeletal disorder, a neuroendocrine disorder, a cognitive disorder, a memory disorder such as Alzheimer=s disease, a sensory modulation and transmission disorder, a motor coordination disorder, a sensory integration disorder,. a motor integration disorder, a dopaminergic function disorder such as Parkinson=s disease, a sensory transmission disorder, an olfaction disorder, a sympathetic innervation disorder, an affective disorder such as depression and anxiety, a WO 03/004027 PCT/US02/21063 stress-related disorder, a fluid-balance disorder, a seizure disorder, pain, psychotic behavior such as schizophrenia, morphine tolerance, opiate addiction, migraine or a urinary disorder such as urinary incontinence.
The following description of depressive .and anxiety disorders is for the purpose of illustrating the utility of the compounds of this invention. The definitions of depressive and anxiety disorders given below are those listed in Diagnostic and Statistical Manual of Mental Disorders. 4th ed. (DSM-IV; American Psychiatric Association, 1994a) or Diagnostic and Statistical Manual of Mental Disorders. 3rd ed. Revised (DSM-III-R; American Psychiatric Association, 1987). Additional information regarding these disorders can be found in this reference, as well as the others cited below, all of which are incorporated herein by reference.
Depressive disorders include major depressive disorder and dysthymic disorder (American Psychiatric Association, 1994a; American Psychiatric Association, 1994b). Major depressive disorder is characterized by the occurrence of one or more major depressive episodes without manic or hypomanic episodes. A major depressive episode is defined as a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks) it should include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or WO 03/004027 PCT/US02/21063 86 worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation (Medical Economics Company, 2002). Dysthymic disorder involves a type of depression that is not severe enough to be called a major depressive episode, but that lasts much longer than major depressive disorder, without high phases.
It is contemplated that the compounds of this invention will be effective in treating depression in patients who have been diagnosed with depression by administration of any of the following tests: Hamilton Depression Rating Scale (HDRS), Hamilton depressed mood item, Clinical Global Impressions (CGI)-Severity of Illness. It is further contemplated that the compounds of the invention will be effective in inducing improvements in certain of the factors measured in these tests, such as the HDRS subfactor scores, including the depressed mood item, sleep disturbance factor and anxiety factor, and the CGI-Severity of Illness rating. It is also contemplated that the compounds of this invention will be effective in preventing relapse of major depressive episodes.
Anxiety disorders include panic disorder, agoraphobia with or without history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder and generalized anxiety disorder. It is contemplated that the compounds of this invention will be effective in treating any of all of these disorders in patients who have been diagnosed with these disorders.
WO 03/004027 PCT/US02/21063 87 Obsessive compulsive disorder is characterized by recurrent and persistent ideas, thoughts, impulses or images (obsessions) that are ego-dystonic and/or repetitive, purposeful and intentional behaviors (compulsions) that are recognized by the person as excessive or unreasonable (American Psychiatric Association, 1994a). The obsessions or compulsions cause marked distress, are time-consuming, or significantly interfere with social or occupational functioning.
It is contemplated that the compounds of this invention will be effective in treating obsessions and compulsions in patients who have been diagnosed with obsessive compulsive disorder by administration of appropriate tests, which may include, but are not limited to any of the following: Yale Brown Obsessive Compulsive Scale (YBOCS) (Goodman, 1989) (for adults), National Institute of Mental Health Global OCD Scale (NIMH GOCS), CGI- Severity of Illness scale. It is further contemplated that the compounds of the invention will be effective in inducing improvements in certain of the factors measured in these tests, such as a reduction of several points in the YBOCS total score. It is also contemplated that the compounds of this- invention will be effective in preventing relapse of obsessive compulsive disorder.
Panic disorder is characterized by recurrent unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks (American Psychiatric Association, 1994a). A panic attack is defined as a WO 03/004027 PCT/US02/21063 88 discrete period of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated heart rate; sweating; trembling or shaking; sensations of shortness of breath or smothering; feeling of choking; chest pain or discomfort; nausea or abdominal distress; feeling dizzy, unsteady, lightheaded, or faint; derealization (feelings of unreality) or depersonalization (being detached from oneself); fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes. Panic disorder may or may not be associated with agoraphobia, or an irrational and often disabling fear of being out in public.
It is contemplated that the compounds of this invention will be effective in treating panic disorder in patients who have been diagnosed with panic disorder on the basis of frequency of occurrence of panic attacks, or by means of the CGI-Severity of Illness scale. It is further contemplated that the compounds of the invention will be effective in inducing improvements in certain of the factors measured in these evaluations, such- as a reduction in frequency or elimination of panic attacks, an improvement in the CGI-Severity of Illness scale or a CGI-Global Improvement score of 1 (very much improved), 2 (much improved) or 3 (minimally improved).. It is also contemplated that the compounds of this invention will be effective in preventing relapse of panic disorder.
Social anxiety disorder, also known as social phobia, is characterized by a marked and persistent fear of one or WO 03/004027 PCT/US02/21063 89 more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others (American Psychiatric Association, 1994a). Exposure to the feared situation almost invariably provokes anxiety, which may approach the intensity of a panic attack. The feared situations are avoided or endured with intense anxiety or distress.
The avoidance, anxious anticipation, or distress in the feared situation(s) interferes significantly with the person's normal routine, occupational or academic functioning, or social activities or relationships, or there is marked distress about having the phobias.
Lesser degrees of performance anxiety or shyness generally do not require psychopharmacological treatment.
It is contemplated that the compounds of this invention will be effective in treating social anxiety disorder in patients who have been diagnosed with social anxiety disorder by administration of any of the following tests: the Liebowitz Social Anxiety Scale (LSAS), the CGI-Severity of Illness scale, the Hamilton Rating Scale for Anxiety (HAM-A), the Hamilton Rating Scale for Depression (HAM-D), the axis V Social and Occupational Functioning Assessment Scale of DSM-IV, the axis II World Health Organization Disability Assessment, Schedule 2 (DAS-2), the Sheehan Disability Scales, the Schneier Disability Profile., the World Health Organization Quality of Life-100 (WHOQOL-100), or other tests as described in Bobes, 1998, which is incorporated herein by reference. It is further contemplated that the compounds of the invention will be effective in inducing improvements as measured by these WO 03/004027 PCT/US02/21063 tests, such as the a change from baseline in the Liebowitz Social Anxiety Scale (LSAS), or a CGI- Global Improvement score of 1 (very much improved), 2 (much improved) or 3 (minimally improved). It is also contemplated that the compounds of this invention will be effective in preventing relapse of social anxiety disorder.
Generalized anxiety disorder is characterized by excessive anxiety and worry (apprehensive expectation) that is persistent for at least 6 months and which the person finds difficult to control (American Psychiatric Association, 1994a) It must be associated with at least 3 of the following 6 symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, sleep disturbance. The diagnostic criteria for this disorder are described in further detail in DSM-IV, which is incorporated herein by reference (American Psychiatric Association, 1994a).
It is contemplated that the compounds of this invention will be effective in treating generalized anxiety disorder in patients who have been diagnosed with this disorder according to the diagnostic criteria described in DSM-IV. It is further contemplated that the compounds of the invention will be effective in reducing symptoms of this disorder, such as the following: excessive worry and anxiety, difficulty controlling worry, restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, or sleep disturbance. It is also contemplated that the compounds WO 03/004027 PCT/US02/21063 91 of this invention will be effective in preventing relapse of general anxiety disorder.
Post-traumatic stress disorder (PTSD), as defined by DSM-III-R/IV (American Psychiatric Association, 1987, American Psychiatric Association, 1994a), requires exposure to a traumatic event that involved actual or threatened death or serious injury, or threat to the physical integrity of self or others, and a response which involves intense fear, helplessness, or horror.
Symptoms that occur as a result of exposure to the traumatic event include re-experiencing of the event in the form of intrusive thoughts, flashbacks or dreams, and intense psychological distress and physiological reactivity on exposure to cues to the event; avoidance of situations reminiscent of the traumatic event, inability to recall details of the event, and/or numbing of general responsiveness manifested as diminished interest in significant activities, estrangement from others, restricted range of affect, or sense of foreshortened future; and symptoms of autonomic arousal including hypervigilance, exaggerated startle response, sleep disturbance, impaired concentration, and irritability or outbursts of anger. A PTSD diagnosis requires that the symptoms are present for at least a month and that they cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
It is contemplated that the compounds of this invention will be effective in treating PTSD in patients who have been diagnosed with PTSD by administration of any of the following tests: Clinician-Administered PTSD Scale Part WO 03/004027 PCT/US02/21063 92 2 (CAPS), the patient-rated Impact of Event Scale (IES) (Medical Economics Company, 2002, p. 2752). It is further contemplated that the compounds of the invention will be effective in inducing improvements in the scores of the CAPS, IES, CGI-Severity of Illness or CGI-Global Improvement tests. It is also contemplated that the compounds of this invention will be effective in preventing relapse of PTSD.
In a preferred embodiment, the subject invention provides a method of treatment or management of the following indications: depressive disorders, anxiety disorders, eating/body weight disorders, and urinary disorders. Examples of depressive disorders are major depressive disorder or dysthymic disorder. Examples of anxiety disorders are panic disorder, agoraphobia without history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, posttraumatic stress disorder, acute stress disorder or generalized anxiety disorder. Examples of eating/body weight disorders are obesity, weight gain, bulimia, bulimia nervosa or anorexia nervosa. Examples of urinary disorders include, but are not limited to urinary incontinence overactive bladder, urge incontinence, urinary frequency, urinary urgency, nocturia or enuresis. Overactive bladder and urinary urgency may or may not be associated with benign prostatic hyperplasia.
This invention provides a method of modifying the feeding behavior of a subject, which comprises administering to the subject an amount of a compound of the invention effective to decrease the consumption of WO 03/004027 PCT/US02/21063 93 food by the subject. This invention also provides a method of treating an eating disorder in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the eating disorder. In an embodiment of the present invention, the eating disorder is obesity, bulimia, bulimia nervosa or anorexia nervosa.
The present invention further provides a method of reducing the body mass of a subject, which comprises administering to the subject an amount of a compound of the invention effective to reduce the body mass of the subject. This invention also provides a method of managing obesity in a subject in need of weight loss, which comprises administering to the subject an amount of a compound of the invention effective to induce weight loss in the subject. This invention also provides a method of managing obesity in a subject who has experienced weight loss, which comprises administering to the subject an amount of a compound of the invention effective to maintain such weight loss in the subject.
The present invention also provides a method of treating depression in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's depression. This invention also provides a method of treating anxiety in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's anxiety. This invention also provides a method of treating depression and anxiety in a subject, which comprises administering to the subject WO 03/004027 PCT/US02/21063 94 an amount of a compound of the invention effective to treat the subject's depression and anxiety. This invention also provides a method of treating major depressive disorder in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's major depressive disorder. This invention also provides a method of treating dysthymic disorder in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's dysthymic disorder. This invention also provides a method of treating obsessions and compulsions in a subject with obsessive compulsive disorder, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's obsessions and compulsions. This invention also provides a method of treating panic disorder, with or without agoraphobia, in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's panic disorder. This invention also provides a method of treating social anxiety disorder in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's social anxiety disorder. This invention also provides a method of treating generalized anxiety disorder in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's generalized anxiety disorder. This invention also provides a method of treating post-traumatic stress disorder in a subject, which comprises administering to the subject an amount WO 03/004027 PCT/US02/21063 of a compound of the invention effective to treat the subject's post-traumatic stress disorder.
It is contemplated that the compounds of this invention will be effective in treating obesity, including weight loss and maintenance of weight loss in patients, who have been diagnosed with obesity by the one or more of the following measurements: an increased body mass index, increased waist circumference (an indicator of intra-adominal fat), Dual Energy X-Ray Absorptiometry (DEXA) and trucal (android) fat mass. It is further contemplated that the compounds of the invention will be effective in inducing improvements in certain factors measured in-these tests.
It is contemplated that the compounds of this invention will be effective in treating urinary disorders in patients who have urge or mixed (with a predominance of urge) incontinence as evidenced by the number of unnecessary episodes per week, the number of unnecessary micturitions per day and a low volume voided per micturition. It is further contemplated that the compounds of the invention will be effective in inducing improvements in certain factors measured in these tests.
The present invention also provides a method of treating a subject suffering from bipolar I or II disorder, schizoaffective disorder, a cognitive disorder with depressed mood, a personality disorder, insomnia, hypersomnia, narcolepsy, circadian rhythm sleep disorder, nightmare disorder, sleep terror disorder or sleepwalking disorder.
WO 03/004027 PCT/US02/21063 96 The present invention provides a method of treating overactive bladder with symptoms of urge urinary incontinence, urgency and/or frequency in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's overactive bladder. This invention also provides a method of alleviating urge urinary incontinence in a subject suffering from overactive bladder, which comprises administering to the subject an amount of a compound of the invention effective to alleviate the subject's urge urinary incontinence. This invention further provides a method of alleviating urinary urgency in a subject suffering from overactive bladder, which comprises administering to the subject an amount of a compound of the invention effective to alleviate the subject's urinary urgency. Additionally, this invention provides a method of alleviating urinary frequency in a subject suffering from overactive bladder, which comprises administering to the subject an amount of a compound of the invention effective to alleviate the subject's urinary frequency.
The present invention also provides a method of treating a subject suffering from a urinary disorder, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's urinary disorder. In some embodiments the urinary disorder is urinary incontinence, overactive bladder, urge incontinence, urinary frequency, urinary urgency, nocturia or enuresis.
WO 03/004027 PCT/US02/21063 97 The present invention provides a method of alleviating the symptoms of a disorder in a subject, which comprises administering to the subject an amount of an MCH1 antagonist effective to alleviate the symptoms, wherein the MCH1 antagonist is any of the compounds of the invention.
In an embodiment of the invention, the subject is a vertebrate, a mammal, a human or a canine. In another embodiment, the compound is administered orally. In yet another embodiment, the compound is administered in combination with food.
This invention will be better understood from the Experimental Details In a preferred embodiment, the subject invention provides a method of treatment for the following indications: depression, anxiety, eating/body weight disorders, and urinary disorders. Examples of eating/body weight disorders are obesity, bulimia, or bulimia nervosa. Examples of urinary disorders include, but are not limited to, urinary incontinence, overactive bladder, urge incontinence, urinary frequency, urinary urgency, nocturia, or enuresis. Overactive bladder and urinary urgency may or may not be associated with benign prostatic hyperplasia.
This invention provides a method of modifying the feeding behavior of a subject which comprises administering to the subject an amount of a compound of the invention effective to decrease the consumption of food by the subject.
WO 03/004027 PCT/US02/21063 98 This invention also provides a method of treating an eating disorder in a subject which comprises administering to the subject an amount of a compound of this invention effective to decrease the consumption of food by the subject. In an embodiment of the present invention, the eating disorder is bulimia, obesity or bulimia nervosa. In an embodiment of the present invention, the subject is a vertebrate, a mammal, a human or a canine. In a further embodiment, the compound is administered in combination with food.
The present invention further provides a method of reducing the body mass of a subject which comprises administering to the subject an amount of a compound of the invention effective to reduce the body mass of the subject.
The present invention also provides a method of treating a subject suffering from depression which comprises administering to the subject an amount of a compound of this invention effective to treat the subject's depression. The present invention further provides a method of treating a subject suffering from anxiety which comprises administering to the subject an amount of a compound of this invention effective to treat the subject's anxiety. The present invention also provides a method of treating a subject suffering from depression and anxiety which comprises administering to the subject an amount of a compound of this invention effective to treat the subject's depression and anxiety.
The present invention also provides a method of treating a subject suffering from major depressive disorder, WO 03/004027 PCT/US02/21063 99 dysthymic disorder, bipolar I and II disorders, schizoaffective disorder, cognitive disorders with depressed mood, personality disorders, insomnia, hypersomnia, .narcolepsy, circadian rhythm sleep disorder, nightmare disorder, sleep terror disorder, sleepwalking disorder, obsessive-compulsive disorder, panic disorder, with or without agoraphobia, posttraumatic stress disorder, social anxiety disorder, social phobia and generalized anxiety disorder.
The present invention also provides a method of treating a subject suffering from a urinary disorder which comprises administering to the subject an amount of a compound -of this invention effective to treat the subject's a urinary disorder. In some embodiments, the urinary disorder is urinary incontinence, overactive bladder, urge incontinence, urinary frequency, urinary urgency, nocturia, or enuresis.
This invention will be better understood from the Experimental Details which follow. However, one skilled in the. art will readily appreciate that the specific methods and results discussed are merely illustrative of the invention as described more fully in the claims which follow thereafter.
WO 03/004027 PCT/US02/21063 100 Experimental Section I. Synthetic Methods for Examples General Methods: All reactions (except for those done by parallel synthesis reaction arrays) were performed under an Argon atmosphere and the reagents, neat or in appropriate solvents, were transferred to the reaction vessel via syringe and cannula techniques. The parallel synthesis reaction arrays were performed in vials (without an inert atmosphere) using J-KEM heating shakers (Saint Louis, MO). Anhydrous solvents were purchased from Aldrich Chemical Company and used as received. The examples described in the patent were named using ACD/Name program (version 2.51, Advanced Chemistry Development Inc., Toronto, Ontario, M5H2L3, Canada). Unless otherwise noted, the 1H spectra were recorded at 300 and 400 MHz (QE Plus and Bruker respectively) with tetramethylsilane as internal standard. s singlet; d doublet; t triplet; q quartet; p pentet; sext; sept; br broad; m multiplet. Elemental analyses were performed by Robertson Microlit Laboratories, Inc. Unless otherwise noted, mass spectra were obtained using low-resolution electrospray (ESMS) and MH is reported. Thin-layer chromatography (TLC) was carried out on glass plates precoated with silica gel 60 F 254 (0.25 mm, EM Separations Tech.). Preparative thin-layer chromatography was carried out on glass sheets precoated with silica gel GF (2 mm, Analtech). Flash column chromatography was performed on Merck silica gel 60 (230 400 mesh). Melting points (mp) were determined in WO 03/004027 WO 0/00027PCT/UJS02/21063 101 open capillary tubes on a Mel-Temp apparatus and are uncorrected.
Piperidine Side Chain intermediates T ERT-BUTYL 4 ((TRIFLUOROMETHYL) SULFONYLJ OXY) -1,213-,6 -TETRAHYDRO- 1- PYRIDINECARBOXYLATE: n-Butyl lithium (17.6 mLh, 44.2 mmol, 2.S M in hexanes) was added to a solution of diisopropyl amine (96.2 mL, 44.2 mmcl) in 40 mL of dry THF at 0 0 C and stirred for 20 minutes. The reaction mixture was co oled to -78 0 C and tert-butyl 4-oxo- 1-piperidinecarboxylate (Aldrich Chemical Company, 0 mmol) in THF (40 mL) was added dropwise to the reaction mixture and stirred for 30 minutes. Tf 2 NPh (42.0 mmol, 15.0 g) in THF (40 mL) was added dropwise to the reaction mixture and stirred at 0 C overnight. The reaction mixture was concentrated in vacuo, re-dissolved in hexanes:EtOAc passed through a plug of alumina and the alumina plug was washed. with hexanes:EtOAc (91. The combined extracts were concentrated to yield 16.5 g of the desired product that was contaminated with some starting Tf 2 NPh.
'K NMR (40 0 MHz, 400 MHz, CDCl 3 6 5. 77 1 H) 4. (din, 2 H, J=3.0 Hz), 3.63 2 H, J=5.7 Hz), 2.45 (in, 2 1.47 9 H).
TERT-BUTYL 4- (AMINO) PHENYL) -l,2,3,6-TETRAXYDRO-1- PYRIDIN'ECARBOXYLATE: A mixture of 2 M aqueous Na 2
CO
3 solution (4.2 mL) tert-butyl [(trifluoromethyl)sulfonyljoxy}-1,2,3,6-tetrahydro- 1-pyridine-carboxylate (0.500 g, 1.51 mmcl), 3-aminoph enylboronic acid hemisulfate (0.393 g, 2.11 inmol), lithium chloride (0.191 g, 4.50 mmcl) and WO 03/004027 PCT/US02/21063 102 tetrakis- triphenylphosphine palladium (0.080 g, 0.075 mmol) in dimethoxyethane mL) was heated at reflux temperature for 3 hours, under an inert atmosphere (an initial degassing of the mixture is recommended 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 The combined organic extracts were dried and concentrated in vacuo.
The crude product was chromatographed (silica, hexanes:EtOAc:dichloromethane with 1% added isopropylamine to protect the BOC group from hydrolysis) to give 0.330 g of the desired product in 81% yield. 1H NMR (400 MHz, CDC13) 8 7.12 1H, J= 7.60 Hz), 6.78 (d, 1H, J= 8.4 Hz), 6.69 1H, J= 2.0 Hz), 6.59 (dd, 1H, J= 2.2, 8.0 Hz), 6.01 1H), 4.10 4.01 2H, J= 2.4 Hz), 3.61 2H, J= 5.6 Hz), 2.52 2.46 2H), 1.49 9H); ESMS m/e 275.2 (M Anal. Calc. for C1,H 24
N
2 0 2 C, 70.04; H, 8.08; N, 10.21. Found: C, 69.78; H, 7.80; N, 9.92.
TERT-BUTYL 4-[3-(AMINO)PHENYL]-1-PIPERIDINECARBOXYLATE: A mixture of 3.10 g of tert-butyl 4-(3-aminophenyl)- 1,2,3,6-tetrahydropyridine-l-carboxylate (11.3 mmol) and 1.0 g of 10% Pd/C in 200 mL of ethanol was hydrogenated at room temperature using the balloon method for 2 days.
The reaction mixture was filtered 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% isopropylamine added to protect the BOC group from hydrolysis) to give 2.63 g of the desired product 1H NMR (400 MHz, CDC13) 6 7.10 1H, J= WO 03/004027 PCT/US02/21063 103 7.60 Hz), 6.62 1H, J= 8.4 Hz), 6.60 6.59 (m, 2H), 4.27 4.18 2H), 3.62 3.58 2H), 2.80 2.72 2H), 2.62 2.59 1H), 1.89 1.52 4H), 1.49 9H); ESMS m/e 277.2 (M TERT-BUTYL 4- [3-(ACETYLAMINO)PHENYL]-1,2,3,6-TETRAHYDRO- 1-PYRIDINECARBOXYLATE: A mixture of saturated aqueous Na 2 CO3 solution (25 mL), tert-butyl 4-{[(trifluoromethyl)sulfonyl]oxy)-1,2,3,6-tetrahydro- 1-pyridine-carboxylate (20 mmol), 3-acetamidophenylboronic acid (30 mmol) and tetrakistriphenylphosphine palladium (1.15 g) and dimethoxyethane (40 mL) was heated at reflux temperature overnight. The organic layer of the cooled reaction mixture was separated and the aqueous layer was washed with ethyl acetate The combined organic extracts were dried and concentrated in vacuo. The crude product was chromatograghed, giving the desired product: 'H NMR (CDC,) 6 8.11 (br s, 1 7.57 (br s, 1 7.41 (br d 1 H, J=7.8 Hz), 7.25 (apparent t, 1 H, J=7.8 Hz), 7.08 (br d, 1 H, J=7.8 Hz), 5.99 (br s, 1 4.03 (br m, 2 H, J=2.7 Hz), 3.59 2 H, J=5.7 Hz), 2.46 2 2.16 3 1.49 9 H).
N1-[3-(1,2,3,6-TETRAHYDRO-4-PYRIDINYL)PHENYL]ACETAMIDE: A solution of 4 M HC1 in dioxane (10 mL) was added to tert-butyl 4-[3-(acetylamino)phenyl]-1,2,3,6-tetrahydro- 1-pyridinecarboxylate (8.25 mmol) in dichloromethane mL). The reaction mixture was stirred at room temperature overnight, concentrated in vacuo, giving the desired product as the hydrochloride salt (2.1 'H NMR (CDC1,) 6 7.41-7.00 4 6.10 (br, 1 3.55 2 WO 03/004027 PCT/US02/21063 104 3.16 2 H, J 5.7 Hz), 2.44 2 2.19 3 H).
TERT-BUTYL N-(3-BROMOPROPYL)CARBAMATE: Prepared from 3-bromopropylamine hydrobromide and BOC20 in the presence of base in dichloromethane, 9.89 mmol: IH NMR (CDC1 3 8 5.07 (br, 1 3.31 2 H, J=6.6 Hz), 3.12 (apparent br q, 2 H, J=6.0 Hz), 1.92 2 H, J=6.6 Hz), 1.30 (s, 9H).
TERT-BUTYL (3-{4-[3-(ACETYLAMINO)PHENYL]-1,2,3, 6-TETRAHYDRO-1-PYRIDINYL}PROPYL)CARBAMATE: A solution of N1- [3-(1,2,3,6-tetrahydro-4pyridinyl)phenyl]acetamide.HCl (8.24 mmol), tert-butyl N-(3-bromopropyl)carbamate and potassium carbonate (33 mmol) in dry dioxane (30 mL) was heated at reflux temperature overnight. The solids were removed by filtration, the solution was concentrated in vacuo and the product was chromatograghed, giving the desired product (110 mg). 'H NMR (CDC13) 5 7.65 1 6.98 1 7.45 1 H, J=7.8 Hz), 7.16 (apparent t, 1 H, J=7.8 Hz), 7.10 1 H, J=7.8 Hz), 6.02 1 H), 5.23 1 3.40 2 3.30-1.80 10 2.18 3 1.45 9 H).
N1-{3-[1-(3-AMINOPROPYL)-1,2,3,6-TETRAHYDRO-4- PYRIDINYL]PHENYL}ACETAMIDE: A 1:1 solution of TFA:CH 2 Cl 2 mL) was added to tert-butyl N-(3-(4-[3-(acetylamino)phenyl]-1,2,3,6-tetrahydro-lpyridinyl}propyl)carbamate in dichloromethane (5 mL).
The resulting solution was stirred at room temperature for 1-3 days, saturated NaHC0 3 was added until pH 6, the organic layer was separated, and dried in vacuo, WO 03/004027 WO 0/00027PCT/UJS02/21063 105 giving the desired product (4 5 mug) 'H NMR (CDC1 3 8~ 7.68 (br, 1 7.35 (din, 1 H, J=7.8 Hz), 7.25 (apparent t, 1 H, J=7.8 Hz), 7.15 (dmn, I H, J=7.8 Hz), 6.12 (in, I H) 3.22 (in, 2 H) 3. 03 2 H, J=7.3 Hz), 2.78 2 H, J=S.5S Hz) 2.70-2. 50 (in, 4 H) 2. 10 3 H) 1. 87 2 H, J=7.3 Hz).
TERT-BUTYL 4- (ACETYIJAMINO) PHENYLJ -1- PIPERIDINECARBOXYLATE: A mixture tert-butyl 4-[3- (acetylaminc)phenylJ -1,2,3,6-tetrahydro-1pyri dine carboxylate (710 mg) and 5% Pd/C (100 mug) in EtCH (10 inL) was hydrogenated (balloon technique) at room temperature overnight. The reaction mixture was .passed through a pad of Celite 545 and the pad of Celite was washed with ethanol. The combined ethanol extracts were concentrated and chromatograghed, giving the desired product (660 mg) 'H NMR (CCDC1,9 6 7.80 Cs, 1 7.41-7.20 Cm, 3 6.94 Cd, 1.K, J=7.5 Hz) 4.21 2 H) 2. 75 (in, 2 2.62 1 2.16 3 1.78 2 H) 1.56 2 H) 1.48 9 H) Nl-[3-(4-PIPERIDYL)PHENYL]ACETAMIDE: A solution of HC1 in dioxane (4N, 5 ruL) was added to tert-buty! 4-[3- (acetylamino)phenyl2 -1-piperidinecarboxylate (660 rug) in dry dichioromethane (15 ruL) The reaction mixture was stirred at room temperature overnight and concentrated in vacuo, giving the desired product. C550 mug) mp 102-104 0 C; 1H NMR (CDCl 3 8 2.02 J=13.2 Hz, 211), 2.11-2.45 (in, 5H), 2.67-2.77 Cm, 1H), 3.00-3.10 (in, 2H) 3.51 J=10.5 Hz, 2H1), 6.94 Cd, 7=7.5 Hz, 1H) 7.20-7.46 (mn, 3H), 7.60 1H); Anal. Calcd. For C1 3 Hl 9
N
2 OCJ.+0.86 CH 2 C1 2 C, 50.78; H, 6.37; N, 8.55. Found: C, 50.80; H, 7.55; N, 7.01.
WO 03/004027 PCT/US02/21063 106
TERT-BUTYL
N- 3- (ACETYLAMINO)PHENYL]PIPERIDINO}PROPYL)CARBAMATE:
A
solution of N1-[3-(4-piperidyl)phenyl]acetamide (550 mg, 0.210 mmol), tert-butyl N-(3-bromopropyl)carbamate (550 mg, 0.230 mmol), K 2 CO3 (1.10 g, 0.890 mmol), diisopropylethyl amine (1.50 mL) and a few crystals of KI in dioxane (20 mL) was heated at reflux temperature for 2 days. The precipitated salts were removed by filtration, concentrated in vacuo and the crude product was chromatographed, giving the desired product (340 mg) -H NMR (CDC1 3 6 8.15 1 7.47-7.44 2 H), 7.22 1 H, J=7.8 Hz), 6.94 1 H, J=7.8 Hz), 5.53 1 3.23 6 2.80-1.60 9 2.20 3 1.45 9 H).
Nl- {3-[1-(3-AMINOPROPYL)-4-PIPERIDYL]PHENYL}ACETAMIDE: TFA (1.0 mL) was added to a solution of tert-butyl N- [3- (acetylamino)phenyl]piperidino}propyl)carbamate (340 mg) in dry dichloromethane (10 mL) and stirred at room temperature for 5 h. A 10% aqueous solution of KOH was added co the reaction mixture until pH 6 and then the dichloromethane was removed in vacuo. The aqueous layer was frozen and lyophilized to give a solid, which was extracted with methanol. Removal of the solvent gave the desired product (120 mg) as an oil: 1H NMR (CDC1 3 6 7.23-7.16 (apparent t, 1H, J=7.5 Hz), 6.95-6.92 1H), 3.03-2.99 2H), 2.77-2.73 2H, J 6.6 Hz), 2.50- 1.60 10 2.13 3 H).
WO 03/004027 WO 0/00027PCT/UJS02/21063 107 TERT-BUTYL 4- (3-NITROPHENYL) -3,6-DIHYDRO-1(2H) PYRIDINECARBOXYLATE: According to the procedure used for the synthesis of tert-butyl 4- (amino) phenyll 2,3, 6s tetrahydro-l-pyridinecarboxylate,a mixture of 2 M aqueous Na 2 CO3 solution (2.2 mL), tert-butyl E(trifluoromethyl)sulfonylloxy}-l,2,3,6-tetrahydro-lpyridine-carboxylate (0.5,00 g, 1.51 mmcl), 3-nitrophenylboronic acid (0.353 g, 2.11 mmol), lithium chloride (0.191 g, 4.50 mmcl) and tetrakistriphenyiphcsphine palladium (0.080 g, 0.075 mmcl) in dimethoxyethane (5 mL) afforded 0.380g of the desired product.
1H NMR (400 MHz, CDCl 3 8 8.23 1H) 8. 11 Cd, 1H, J=8.0 Hz), 7.69 1H, J=8.0 Hz), 7.51 1H, Hz), 6.20 1Hi), 4.17-4.08 (in, 3.67 2H, Hz) 2. 61- 2. 52 Cm, 2H) 1. 50 Cs, 9H); ESMS m/e :249. 1 (M H C 4
H
8
Y.
1,2,3,6-TETRAHYDRO-4- (3-NITROPHENYL)PYRIDINE: Into a stirred solution of 5.00 g (16.0 mmcl) of tert-butyl l,2,3,6-tetrahydro-4-(3-nitrophenyl)pyridine-lcarboxylate in 100 ml of 1,4-dioxane at 0OC was bubbled HC1 gas for 10 minutes. The reaction mixture was allowed to warm to 2boom temperature and the bubbling of the HCl gas was continued for an additional 1 hour. The solvent was removed in vacuo, the residue was dissolved in 50, mL of water and was 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 vaCuIO. The residue was purified by column chromatography (silica, 9 1 ,dichloromethane WO 03/004027 WO 0/00027PCT/UJS02/21063 108 methanol 1% isopropyl amine) to afford 2.85 g (87.5% yield) of the desired product: NMR (400 MHz, CDCl 2 3) 8 8. 24 1H) 8. 09 1H-, J=8. 4 Hz) 7. 71 Cd, III, J=8.0 Hz) 7.49 1H, J=8.0 Hz) 6.35-6.25 (in, 1H), 3.58 (apparent q, 2H, J=3.0 Hz), 3.14 2H-, Hz), 2.54-2.46 (in, 2H).
TERT-BtJTYL 3-(4-(3-NITROPHENYL)-3,6-DIHYDRO-1(2H) PYRIDINYL)PROPYLCARBAMATE: A mixture of 2.80 g (14.0 rrmol) of l,2,3,6-tetrahydro-4- C3-nitrophenyl)pyridine, 3.60 g (15.0 mmol) of tert-butyl N-(3-bromopropyl)carbamate, 21.6 g (84.0 inmol) of K 2 C0 3 14.6 mL (84.0 inmol) of di is opropyl ethyl amine and 0.78 g (2.00 inmol) of tetrabutylamnmonium iodide in 250 mL of 1,4-dioxane was heated at ref lux temperature for 14 hours. The reaction mixture was filtered and the f iltrate was dried (MgSO 4 concentrated in vacuo and the residue was purified by column chromatography (silica, 9:1, dichioromethane: methanol 1% isopropyl amine) to afford 4.35 g (85.7% yield) of the desired product: 1H NMR (400 MHz, aDC1 3 6 8.24 t, 1H, J=l. 9 Hz) 8. 09 (dd, IH, J=1.9, 8.0 Hz), 7.70 (apparent d, 1H, J=8.0 Hz), 7.49 1H, J=8.0 Hz), 6.23 (in, 1H), 3.29-3.18 (mn, 4H), 2.75 t, 2H, J=5.6 Hz), 2.64-2.54 Cm, 4H), 1.82-1.70 (m, 2H), 1.44 9H); ESMS m/e 362.2 (M 3- (3-NITROPHENYL) -31 6-DIHYDRO-l -PYRIDINYL) -1- PROPANAkMINE: Into a stirred solution of 4.35 (12.0 minol) of tert-butyl 3- (3-nitrophenyl) -3,6-dihydro-1 (2H) pyridinyl)propylcarbamate in 100 ml of 1,4-dioxane at 0 0 C was bubbled HCl gas for 10 minutes. The reaction mixture was allowed to warm to room temperature and. the WO 03/004027 PCT/US02/21063 109 bubbling was continued for an additional 1 hour. The solvent was removed in vacuo, the residue was dissolved in 50 mL of water and was neutralized by the addition of KOH pellets. .The aqueous solution was extracted with 3 X 80 mL of dichloromethane, the combined organic extracts were dried (MgS0 4 filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 9 :1 ,dichloromethane methanol 1% isopropyl amine) to afford 3.05 g (97.0% yield) of the desired product: 'H NMR (400 MHz, CDC13) 6 8.24 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 1H, J=8.2 Hz), 6.24 1H), 3.21 2H, J=3.6 Hz), 2.84 2H, J=6.6 Hz), 2.75 2H, J=5.8 Hz), 2.64-2.54 4H), 1.76 (m, 2H); ESMS m/e 262.2 (M H) Anal. Calc. for
C
14
H
1 9
N
3 0 2 (0.06 CHC1 3 C, 62.90; H, 7.16; N, 15.65.
Found: C, 63.20; H, 7.16; N, 15.65.
METHYL (4S)-3-[({3-[4-(3-AMINOPHENYL)-1- PIPERIDINYL]PROPYL}AMINO)CARBONYL]-4-(3,4- DIFLUOROPHENYL)-6-(METHOXYMETHYL)-2-OXO-1,2,3,4- A mixture of 3.02 g (6.33 mmol) 5-methyl 1-(4-nitrophenyl) difluorophenyl)-4-(methoxymethyl)-2-oxo-3,6-dihydro- 1,5(2H)-pyrimidinedicarboxylate, 1.50 g (5.80 mmol) of 3-(4-(3-nitrophenyl)-3,6-dihydro-1(2H)-pyridinyl)-1propanamine, 7.94 g (75.5 mmol) of K 2 C0 3 and 1.00 mL of methanol in 200 mL dichloromethane (under argon) was stirred at room temperature for 1 hour. The reaction mixture was filtered and concentrated in vacuo. The residue was dissolved in 100 mL of ethyl acetate and washed 3 X 50 mL of 5% aqueous NaOH solution, the organic layer was dried (MgS04) and concentrated in WO 03/004027 PCT/US02/21063 110 vacuo. The residue was dissolved in 100 mL of anhydrous ethanol containing 0.50 g 10% Pd/C and the reaction mixture was stirred under a hydrogen balloon for 24 hours. The reaction mixture was passed through a column of Celite 545 filtering agent, washed with ethanol, the filtrate was dried (MgSO 4 and concentrated in vacuo. The residue was purified, by column chromatography (silica, 9.5 0.5 ,dichloromethane methanol 1% isopropyl amine) to afford 1.65 g (52.0% yield) of the desired product: 'H NMR (400 MHz, CDC13) 7.80 1H), 7.22-7.02 2H), 6.95 J 8.70 Hz, 1H), 6.63-6.44 4H), 4.56 (Abq, 2H), 3.62 3H) 3.33 3H) 3.32-3.20 4H), 2.96 (br s, 2H), 2.33 J 7.50 Hz, 2H), 2.11-1.94 3H), 1.81-1.64 (m, 4H); ESMS m/e 572.3 (M TERT-BUTYL 4-[3-(ISOBUTYRYLAMINO)PHENYL]-3,6-DIHYDRO- 1(2H)-PYRIDINECARBOXYLATE: Into a solution of 4.00 g (16.0 mmol) of tert-butyl 4-(3-aminophenyl)-3,6-dihydro- 1(2H)-pyridinecarboxylate and 5.60 mL (32.0 mmol) of diisopropylethylamine in 100 mL dichloromethane was slowly added 1.90 mL (19.0 mmol) of isobutyryl chloride.
The reaction mixture was stirred at room temperature for 2 hours, washed with water, dried (MgSO 4 and concentrated in vacuo. The residue was purified by column chromatography (silica, 50 46 3 1, hexanes :dichloromethane methanol isopropyl amine) to afford 2.90 g (52.0% yield) of the desired product: 1H NMR (400 MHz, CDC1 3 8 7.69 1 7.34 1 H, J=7.8 Hz), 7.27 1H, J=7.8 Hz), 7.11 1H, J=7.8 Hz), 6.04 1H), 4.05 2H), 3.62 (apparent t, 2 H, J=4.9 Hz), 2.51 3H), 1.49 9H), 1.25 6H, J=7.4 Hz); ESMS m/e: 345.5 (M H) Anal. Calc. for WO 03/004027 PCT/US02/21063 111
C
20
H
28
N
2 0 3 +0.1 75 CHC13: C, 66.33; H, 7.77; N, 7.67.
Found: C, 66.20; H, 7.41; N, 7.88 TERT-BUTYL 4-[3-(ISOBUTYRYLAMINO)PHENYL]-1 -PIPERIDINECARBOXYLATE: A mixture of 2.90 g (8.40 mmol) of tert-butyl 4-[3-(isobutyrylamino)phenyl]-3,6-dihydro- 1(2H)-pyridinecarboxylate and 0.80 g of 10% yield Pd/C in 100 mL of ethanol was stirred under a hydrogen balloon for 24 hours. The reaction mixture was passed through a column of Celite 545 filtering agent, the filtrate was dried (MgSO 4 and concentrated in vacuo.
The residue was purified by column chromatography (silica, 9.5 0.5 ,dichloromethane methanol 1% isopropyl amine) to afford 2.40 g (84.0% yield) of the desired product: 1H NMR (400 MHz, CDC13) 8 7.49-7.44 (m, 2H), 7.24 1H, J=7.6 Hz), 6.93 1H, J=7.6 Hz), 4.20-4.10 2H), 2.86-2.45 4H), 1.86-1.75 4H), 1.48 9H), 1.24 6H, J=6.8 Hz); ESMS m/e 345.2 (M Anal. Calc. for C 20
H
3 0
N
2 03+0.3H 2 0: C, 68.27; H, 8.77; N, 7.96. Found: C, 68.25; H, 8.54; N, 7.84.
2-METHYL-N-[3-(4-PIPERIDINYL)PHENYL]PROPANAMIDE: Into a stirred solution of 2.20 (6.50 mmol) of tert-butyl 4-[3- (isobutyrylamino)phenyl]-1-piperidinecarboxylate in 100 ml of 1,4-dioxane at 0 °C was bubbled HC1 gas for minutes. The reaction mixture was allowed to warm to room temperature and the bubbling of the HC1 gas was continued for 1 hour. The solvent was removed in vacuo, the residue was dissolved in 50 mL of water and was neutralized by the addition of KOH pellets. The aqueous solution was extracted with 3 X 80 mL of dichloromethane, the combined organic extracts were dried (MgSO 4 filtered and concentrated in vacuo. The WO 03/004027 WO 0/00027PCT/UJS02/21063 112 residue was purified by column chromatography (silica, 9 1 ,dichloromethanle :methanol 1% isopropyl amine) to afford 0.700 g (46.0% yield) of the desired product: NNR (400 MHz, CDC1 3 8 7.47 lI) 7.40 lH, J=7.8 Hz), 7.24 1H-, J=7.8 Hz), 7.00 (d, lH, J=7.8 Hz), 3.23-3.14 5H), 2.82-2.57 4H), 1. 20 6H, JT=6. 8 Hz) ESMS m/e 247. 2 (M The hydrochloride salt was used for the combustion analysis: Anal. Caic. for CI.
5
H
2 2
N
2 0+HCl+0.1S CHC1 3 C, 60.51; H, 7.76; N, 9.32. Found: C, 60.57; H, 7.83; N, 8.88.
3-(4-PIPERIDINYL)ANILINE: A solution of 4 M HCl 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). The reaction mixture was stirred at room temperature overnight, concentrated in -vacuo, and the residue was dissolved in water mL) The mixture was nuetralized 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) NMR (400 MHz, CDCl 3 6 7.01 1H-, J=7.6 Hz) 6.62-6.54 (in, 3H) 3.16 (br d, 2H, J=10.3 Hz) 2.75 Cdt, 2H, J=2.7, 12.3 Hz) 2.56 (tt, lH, J=3.6, 12.3 Hz), 1.81 (br d, 2H, J=12.3 Hz), 1.65 (dq, 2H, 12.3 Hz); ESMS m/e 177.2 (M HT)+.
TERT-BUTYL 4- (4-NITROPHENYL) -3,6-DflIHYDRQ-1(2H) PYRIDINECARBOXYUL.TE: To a 2S-mL RB flask, equipped with a condensor, was added tert-butyl 4f(trifluoromethyl) sulfonyl) oxy}-3, 6-dihydro-l (2H) pyridinecarboxylate (1.0 4-nitrophenylboronic acid (0.71 sodium carbonate (0.430 mL of 2M solution), WO 03/004027 PCT/US02/21063 113 lithium chloride (0.382 9), tetrakis(triphenylphosphine)- palladium (0.173 g) and ethylene glycol dimethyl ether (10 mL). The reaction mixture was flushed with Argon three times, then the reaction mixture was heated to 100 °C for 3 hrs.
After cooling to room temperature, the reaction mixture was diluted with methylene chloride (30 mL) and water mL) and the organic layer was separated. The aqueous layer was extracted with methylene chloride (3x20 mL) and the combined organic extracts were washed with sat NH 4 C1 (20 mL) and brine (20 mL), dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by chromatography (6:l=hexane:ethyl acetate with 1% NH 3 to afford the product (0.55 g, 59.9%) as a yellow oil. The compound is not stable at room temperature and should be used as promptly as practical: 1 H NMR (400 MHz, CDC13) 6 8.20 2H, J=8.6 Hz), 7.51 2H, J=8.6 Hz), 6.24 1H), 4.13 2H), 3.67 (apparent t, 2H, J=5.5 Hz), 2.55 2H), 1.49 (s, 9H).
4-(4-NITROPHENYL)-1,2,3,6-TETRAHYDROPYRIDINE: 4-(4- Nitrophenyl)-1,2,3,6-tetrahydropyridine was prepared by a similar procedure to that used for the preparation of 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide using HC1 gas and tert-Butyl 4-(4-Nitrophenyl)-3,6-dihydro- 1(2H)-pyridinecarboxylate (130 mg) in dioxane (5.0 mL) at room temperature. The reaction -mixture was concentrated in vacuo to give the crude product (69.8 mg) which used in the next reaction without further purification.
Oxazolidinone Intermediates: WO 03/004027 PCT/US02/21063 114 AMINO-(3,4-DIFLUOROPHENYL)-ACETONITRILE: Through a solution of 3,4-difluorobenzaldehyde (25.0 g, 0.176 mol) in MeOH (500 mL) in a round bottom flask, was bubbled ammonia gas for two hours at room temperature. The flask was then cooled to 0 OC and trimethylsilyl cyanide was then added slowly. The reaction mixture was stirred for 2 h, at which time TLC analysis indicated that the reaction was complete (Rf 0.35, 3:2 hexane/EtOAc) The solvent was removed in vacuo and the residue was subjected to flash column chromatography on silica gel to obtain the desired product, which was used in the next step without purification.
AMINO-(3,4-DIFLUOROPHENYL)-ACETIC ACID METHYL ESTER: Into a well-stirred solution of amino-(3,4difluorophenyl)-acetonitrile (22.0 g, 0.130 mol), a solution of HC1 in MeOH (200 mL) was added at room temperature. The resulting yellow solution was stirred at room temperature for 10 h and was heated at reflux temperature for 1.5 h. After cooling, the solvent was removed in vacuo and the resulting yellow solid was dissolved in water (200 mL). The aqueous solution was then carefully basified with 20% NaOH solution to pH 9.
The aqueous layer was extracted with CH 2 C1 2 (3 x 100 mL).
The organic layer was separated and dried over Na 2
SO
4 filtered and the solvent was removed in vacuo to obtain the desired product which was used in the next step without purification.
2-AMINO-2-(3,4-DIFLUOROPHENYL)-ETHANOL; Into a wellstirred suspension of LiAlH 4 (4.7 g, 0.125 mol) in THF (120 mL) in a 3-necked round bottom flask fitted with a WO 03/004027 PCT/US02/21063 115 condenser and a dropping funnel, was added a solution of amino-(3,4-difluorophenyl)-acetic acid methyl ester (10.0 g, 0.05 mol) in THF (100 mL) dropwise at 0 OC. The resulting greenish brown suspension was heated at reflux temperature for 2 h. The reaction mixture was cooled to 0 OC and then carefully quenched sequentially with 5 mL of water, 5 mL .of 3N NaOH followed by 15 mL of water. The resulting suspension was filtered through a fritted glass funnel. To the filter cake was added 100 mL Et 2 O and the suspension was heated at reflux temperature for 20 min. The suspension was filtered and the combined filtrates were dried over MgS0 4 filtered and the solvent was removed in vacuo. 2- Amino-2-(3,4-difluorophenyl)-ethanol was obtained as a yellow glassy syrup which was used in the next step without further purification.
[1-(3,4-DIFLUOROPHENYL)-2-HYDROXY-ETHYL]-CARBAMIC
ACID-
TERT-BUTYL ESTER: Into a solution of 2-amino-2-(3,4difluorophenyl)-ethanol (8.6 g, 49.7 mmol) in CHC13 (150 mL) at 0 OC was added a solution of di-tert-butyl dicarbonate (11.4 g, 52.0 mmol) in CHC13 (50 mL) in one portion and the resulting solution was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was subjected to column chromatography on silica gel (2:1 hexane-EtOAc followed by EtOAc) to obtain [1-(3,4-difluorophenyl)-2-hydroxy-ethyl]-carbamic acid-tert-butyl ester as a white solid (10.0 g, 74% yield).
(+)-4-(3,4-DIFLUOROPHENYL)-OXAZOLIDIN-2-ONE: Into a well-stirred suspension of NaH (1.1 g, 45.8 mmol) in THF mL) at R.T. was added a solution of WO 03/004027 PCT/US02/21063 116 difluorophenyl)-2-hydroxy- ethyl]-carbamic acid-tertbutyl ester (5.0 g, 18.3 mmol) in THF (20 mL) via a dropping funnel at room temperature. The resulting suspension was stirred for 3 h and then quenched carefully with 10 mL of water. The biphasic mixture was extracted with 100 mL of Et20, washed with brine, filtered and the solvent was removed in vacuo. The gummy residue thus obtained was purified by column chromatography over silica gel (Rf 0.15, 3:2 hexane- EtOAc) to obtain 4-(3,5-difluorophenyl)-oxazolidin-2-one as a white flaky solid (2.8 g, 77% yield). M.P. 81-83 OC; 1H NMR (300 MHz, CDC13) 6 7.23-7.03 (br s, 1H), 4.94 (dd, J=6.6 Hz, J=8.7 Hz, 1 4.73 (t, J=8.7 Hz, 1 4.13 (dd, J=6.6 Hz, J=8.7 Hz, 1 The enantiomers were separated by HPLC on a Chiralcel OD x 250 mm) column using 80% hexane/20% isopropyl alcohol as the eluting system at 12.0 mL/min 254 nm). The retention times for the two isomers were 16.19 min and 20.08 min respectively.
4-NITROPHENYL (4S)-4-(3,4-DIFLUOROPHENYL)-2-OXO-1,3- OXAZOLIDINE-3-CARBOXYLATE: Into a suspension of NaH (0.14 g, 5.30 mmol) in 20 mL of anhydrous THF under argon, a solution of (+)-4-(3,4-difluorophenyl)oxazolidin-2-one (0.80 g, 4.42 mmol) in THF was added dropwise (dropping funnel). The resulting suspension was stirred at room temperature for 30 min. This suspension was then added dropwise via -cannula into another round bottom flask containing a solution of 4nitrophenylchloroformate (1.11 g, 5.30 mmol) in 25 mL of THF and cooled at -78 OC over a period of 15 min. The stirring was continued for 2 h after which the solvent was removed and the residue was purified by column WO 03/004027 WO 0/00027PCT/UJS02/21063 117 chromatography on silica gel with 1: 1 hexane/CH 2 C1 2 followed by CH 2 C1 2 (Rf= 0.4, CH 2 C1 2 to obtain the desired product as a white solid (1.55 g, 86% yield).
Similarly, following the above procedure, 4-(3,5difluorophenyl) -2-xo-xazolidine-3-carboxylic acid-4nitro-phenyl ester and 4- 5-trifluorophenyl) -2-oxooxazolidine-3-carboxylic acid- 4-nitro-phenyl ester were obtained by substituting 3,4-diflourobenzaldehyde in the first step with 3,5-diflourobenzaldehyde or 3,4,5triflourobenzaldehyde, respectively. The oxazolidinone enantiomers were resolved by HPILC on a Chiralcel OD column (as in the previous example) and the 4-nitrophenyl carbamates were prepared using 4-nitrophenyl 1s chloroformate.
4-NITROPHENYlL (3,5-D)IFLUOROPHENYL)-2-OXO-1,3- OXAZOLIDINE-3-CARBOXYLATE: Following the procedure for the synthesis of 4- (3,4-difluorophenyl) -2-oxooxazolidine-3-carboxylic acid- 4-nitro-phenyl ester, ditlourobenzaldehyde yielded the desired product.
-H NMR (400 MHz, CDCl 3 5 8.26 Cd, 2H, J= 9.3 Hz) 7.33 6.81 Cm, SH), 5.41 (dd, IH, J=4.1, 8.7 Hz), 4.81 Ct, 1H, J=9.3 Hz), 4.33 (dd, 1H, J=.1 9.3 Hz); Anal. Calc.
for C2 6
H
1 0
F
2
N
2
O
6 +0.2EtOAc: C, 52.84; H, 3 .06; N, 7.34.
Found: C, 53.26; H, 2.83; N, 7.73 4-NITROPHENYL (4S)-2-OXO-4-(3,4,5-TRIFLUOROPHENYL) -1,3- OXAZOLIDINE-3-CARBOXYLATE: Following the procedure for the synthesis of 4-(3,4-difluorophenyl)-2-oxocxazolidine-3-carboxylic acid-4-nitro-phenyl ester, 3,4, s-triflourobenzaldehyde yielded the desired product.
WO 03/004027 PCT/US02/21063 118 'H NMR (400 MHz, CDC1 3 6 8.27 2H, J=9.0 Hz), 7.31 2H, J=9.0 Hz), 7.11-7.02 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); Anal. Calc. for Ci 6
H
9
F
3 N206: C, 50.27; H, 2.37; N, 7.33. Found: C, 50.56; H, 2.50; N, 7.49.
1-(3,4-DIFLUOROPHENYL)-2-METHYL-2-HYDROXYPROPYLAMINE: Into a well-stirred solution of methyl 2-amino-2-(3,4difluorophenyl)acetate (10.5 g, 52.19 mmol) in anhydrous ether (200 mL) at 0 OC a solution of methylmagnesium bromide (3 M, 87 mL, 261 mmol) in ether was added over minutes. The reaction mixture was stirred at 0 oC for h and allowed to warm to room temperature. After 12 h, the reaction mixture was carefully poured onto a mixture of ice (300 g) and saturated aqueous ammonium chloride (50 The ether layer was separated and the aqueous layer was extracted with more ether (4 X 200 mL). The combined extracts were dried with magnesium sulfate and the solvent evaporated. The crude product was purified by column chromatography on silica gel using chloroform/methanol/2M ammonia in methanol (1000:20:10, 1000:40:20, 1000:80:40) as the eluent to give the product as an oil (6.5 g, 62% yield) which was used in the next step without further purification.
4-(3,4-DIFLUOROPHENYL)-5,5-DIMETHYL-2-OXO-OXAZOLIDINE:
A
mixture of 1-(3,4-difluorophenyl)-2-methyl-2hydroxypropylamine (3.00 g, 14.9 mmol) and carbonyldiimidazole (2.418 g, 14.9 mmol) in dichloromethane (150 mL) was heated at reflux temperature for 36 h and the solvent evaporated. The residue was purified by column chromatography on silica WO 03/004027 PCT/US02/21063 119 gel using chloroform/ethyl acetate to give the product as a viscous oil which solidified on standing (1.80 g, 50% yield). The product was used in the next step without further characterization.
4-NITROPHENYL 4-(3,4-DIFLUOROPHENYL)-5,5-DIMETHYL-2-OXO- 1,3-OXAZOLIDINE-3-CARBOXYLATE: Into a stirred suspension of sodium hydride (60% suspension in paraffin 203 mg, 1.4 eq.) in THF (20 mL) at 0 OC, a solution of 4-(3,4difluorophenyl)-5,5-dimethyl-2-oxo-oxazolidine (870 mg, 3.622 mmol) in THF (5 mL) was added followed by stirring for 30 minutes. This suspension was added to a solution of 4-nitrophenyl chloroformate (950 mg, 4.71 mmol) in THF (20 mL) at -78 OC under argon and the stirring was continued for 2 h. It was slowly warmed to room temperature and after 4 h 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 as the eluent to give the product as a white powder (860 mg, 59% yield).
1H NMR (400 MHz, CDC13) 6 8.24 2H, J=9 Hz), 7.29 6.97 5H) 5.04 1H) 1.09 6H) Anal. Calc.
for Ci 8
H
14
F
2
N
2 0 6 H20: C, 54.61; H, 3.67; N, 7.08.
Found: C, 54.89; H, 3.59; N, 7.41.
(3,4-DIFLOUROHENYL)PHENYL)-N(DIPHELMETHYLENE)METHANAMINE: Into 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 temperature for WO 03/004027 PCT/US02/21063 120 12 h. The reaction mixture was concentrated in vacuo, yielding an oil (21 g, which was characterized by NMR analysis and subjected to the following reaction without any further purification. -H NMR (CDC13) 5 4.57 2H), 7.80-6.80 13H).
1-(3,4-DIFLOUROPHENYL)-1- [(DIPHENYLMETHYLENE)AMINO]PROPAN-2-OL: Into a solution of the benzhydrylindene-(3,4-difluoro-benzyl)-amine (21 g, 69 mmol) in 250 ml of dry THF was added tertbutyllithium (1.7 M, 60 ml) dropwise and the resulting solution was stirred at -78 oC for 0.5 h. To the .solution was added acetaldehyde (10 ml, 180 mmol) in 100 ml of THF and the solution was stirred at -78 OC for 2 h and 25 OC for 1 h. The reaction mixture was quenched by addition of brine. The reaction mixture was diluted with 500 ml of Et 2 O and washed with brine. The organic layer was dried over Na 2 S0 4 and concentrated in vacuo to give an oil, which was taken to the next step without any further purification. 1 H NMR (CDC1 3 5 1.04 3H), 2.77 (broad s. 1H), 4.08(m, 1H), 4.15 1H), 7.80-6.80 13H).
1-AMINO-1-(3,4-DIFLUORO-PHENYL)-PROPAN-2-OL: A solution of crude product from the previous procedure and MeONH 2 .HC1 (10 g, 120 mmol) was diluted in 200 ml of MeOH and stirred 'for 12 h. The reaction mixture was concentrated in vacuo, yielding an oily residue, which was re-dissolved in 200 ml of EtOAc and washed with brine. The organic layer was concentrated in vacuo to produce an oily mixture, which was subjected to column chromatography NH3 (2.0 M in MeOH) in CHC1 3 to yield the desired product (8.8 g, 68% yield from 3,4- WO 03/004027 WO 03/04027PCTIUS02/2 1063 121 difluorobelzylamile) as a mixture of diastereomers.
1H NMR (CDCl 3 4: 1 mixture of the diastereomers) 1. 02 J=6.-0 Hz, 3 H) 1. 04 J=6. 3 Hz, 3 H) 2. (br, 6 H) 3.56-3.69 (in, 2 H) 3.88-3.92 (in, 2 H) 7.02- 7.17 (in, 6 f).
El- (3,4 -DIFLUOROPE1EYL) -2-HYDROXY-PROPYLJ -CARBAMIC ACID- TERT-BUTYL ESTER: Into a solution of l-amino-l-(3,4difluorophenyl)-propan-2-oJ. (13.1 g, 70.1 minol) in CRCl 3 1 (150 mL) at 0 0 C was added a solution of di-tert-butyl dicarbonate (19.3 g, 87.6 minol) in CHC1 3 (50 mL) in one portion and the resulting solution was stirred overnight at room temperature. The solvent was removed in vacuo, and the residue was subjected to column chromatography.
on silica gel (2:1 hexane-EtOAc followed by EtOAc) to obtain (3,4-difluorophenyl) -2-hydroxy-propyll carbamic acid-tert-butyl ester as a viscous oil (18.4 g, 91%* yield) 'H NMR (CDCl 3 mixture of the diastereomers) 5 1.C5 J=6.6 Hz, 3 1.25 J Hz, 3 1.41 (br, 20 3.92-4.19 (hr, 2 4.45- 4.60 (mn, 2 5.41-5.49 (br, 2 7.02-7.17 (in, 6 H).
4- (3,4 -DIFLOROPHENTYL) 5-METHYL-OXAZOLIDIN- 2-ONE: Into a well-stirred solution of (3,4-difluorophenyl) -2hydroxy-propylJ-carbanic acid-tert-butyl ester (0.43 g, iniol) in THF (20 mL) was added 95% NaH (0.09 g, 3.8 inmol) at room temperature. when the reaction was carried out on a larger 5 g) scale, 1.0 equivalent of KH and 1. 5 eq. of NaH was used as the base. The resulting suspension was stirred for 3 h at about 35 0
C
(warm water bath) and then quenched carefully with ice.
The biphasic mixture was extracted with 100 mL of EtOAc, washed with brine, dried over Na 2
SO
4 filtered and the WO 03/004027 PCT/US02/21063 122 solvent was removed in vacuo. The two diastereomers were separated by column chromatography over silica gel (First isomer: 0.16 g, Rf 0.6, 3:1 hexane-EtOAc; second isomer: 0.18 g, Rf 0.5, 3:1 hexane-EtOAc). NOE experiments suggested that the first diastereomer had the methyl and the aryl group in trans configuration while the second diastereomer had cis relationship between the two groups. The 'H NMR spectrum for the trans diastereomer is as follows. 1H NMR (CDC13) 5 1.49 J 6.0 Hz, 3H), 4.37 (dq, J 6.0 Hz, J 7.2 Hz, 1H), 4.45 J 7.2 Hz, 1H), 6.63 (br s, 1H), 7.08-7.28 3H).
The 'H NMR spectrum for the cis diastereomer is as follows. 'H NMR (CDC13) 5 0.96 J 6.6 Hz, 3H), 4.91 J 8.1 Hz, 1H), 4.99 (dq, J 6.6 Hz, J 8.1 Hz, 1H), 6.63 (br s, 1H), 7.08-7.28 3H).
4-(3,4-DIFLUOROPHENYL)-5-METHYL-2-OXO-OXAZOLIDINE-3- CARBOXYLIC ACID-4-NITRO-PHENYL ESTER Into a solution of one of the two diastereomers of 4-(3,4difluorophenyl)-5-methyl-oxazolidin-2-one (0.97 g, 4.55 mmol) in 60 mL THF was added a solution of nbutyllithium in hexane (3.06 mmol, 4.9 mmol) dropwise via a syringe under argon atmosphere at -78 OC. The resulting yellow solution was stirred at -78 OC for min. This solution was then added dropwise via a cannula into another round bottom flask containing a solution of 4-nitrophenylchloroformate (1.03 g, 5.1 mmol) in 60 mL of THF, cooled at -78 OC, over a period of min. After five minutes, the flask was removed from the cooling bath and stirring was continued for 1 h. The reaction mixture was quenched by adding ice and it was WO 03/004027 PCT/US02/21063 123 extracted with EtOAc. The organic extracts were washed with brine and the organic layer was dried over Na 2
SO
4 The solvent was removed after filtration and the residue was purified by column chromatography on silica gel with 1:1 hexane/CH 2 Cl 2 followed by CH 2 C12 to give the desired product.
The relative configurations of the cis and trans isomers were assigned on the basis of 1H NMR analysis of the respective p-nitrophenyloxycarbonyl derivatives. For the trans isomer, an NOE was observed between the protons of the C-5 methyl group and the proton at C-4.
No NOE was observed between the protons at the C-4 and positions of this isomer, which was thus assigned trans stereochemistry. For the cis isomer, no NOE was observed between the protons of the C-5 methyl group and the proton at C-4. However, a NOE was observed between the protons at the C-4 and C-5 positions, leading us to assign this isomer cis stereochemistry. The vicinal coupling constants of the 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 were thus helpful in making the stereochemical assignments (Dondoni, Perrone, Semola, T. Synthesis 1995, 181).
Enantiomers of the diastereomers were separated by HPLC by using a Chiralcel OD column (20 x 250 mm) with isopropyl alcohol/ 0.1 diethylamine as the eluting system (12 mL/min) under isocratic conditions 254 nm).
In order to assign the absolute configurations at the WO 03/004027 PCT/US02/21063 124 stereogenic centers of the oxazolidinone rings, a new synthetic route was designed which employed an enantiomerically pure substrate derived from the chiral pool. Commercially available (S)-(+)-methyl lactate was converted into its pyrrolidine amide according to the method of Martin et al (Martin, Pascual, Romea, Rovira, Urpi, Vilarrasa, J. Tetrahedron Lett. 1997, 38, 1633). Following the protection of the hydroxy group of (2S)-1-oxo-l-(1-pyrrolidinyl)-2propanol to a TBDMS group, treatment of tertbutyl(dimethyl)silyl (IS)-l-methyl-2-oxo-2-(1pyrrolidinyl)ethyl ether with 3,4-difluorophenyllithium yielded (2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-l-(3,4difluorophenyl)-l-propanone as the sole product, which was then converted to (2S)-2-{[tertbutyl(dimethyl)silyl]oxy}-1-(3,4-difluorophenyl)-1propanone oxime. Reduction of the (2S)-2-{[tertbutyl(dimethyl)silyl]oxy}-l-(3,4-difluorophenyl)-1propanone oxime with LiAlH 4 N-acylation, and base induced cyclization provided oxazolidinone diastereomers, which were separated by flash column chromatography. The enantiomeric purity of these isomers was confirmed by chiral HPLC analysis and their relative configurations were assigned by comparison of their 1H NMR spectra with those of the racemic isomers.
As the absolute configuration at C-5 of the lactic acid derived oxazolidinone described above is the C-4 center in trans compounds also has the (S) configuration. Accordingly, the.absolute configurations for the stereogenic centers in the cis compounds are assigned accordingly WO 03/004027 PCT/US02/21063 125 4-NITROPHENYL (4S,5R)-4- (3,4-DIFLUOROPHENYL)-5- METHYL-2-OXO-1,3-OXAZOLIDINE-3-CARBOXYLATE: 1H NMR (400 MHz, CDC1 3 8 8.25 2H, J=8.8 Hz), 7.30 6.99 (m, 5.35 1H, J=7.7 Hz), 5.07 (apparent quintet, 1H), 1.17 3H, J=6.5 Hz); Anal. Calc. for
C
1 7 nH 2
F
2
N
2 0 6 +0.5H 2 0: C, 52.72; H, 3.38; N, 7.23. Found: C, 53.09; H, 3.19; N, 7.50.
(+)-2-AMINO-3-(3,4-DIFLUORO)-PHENYL-PROPAN-1-OL: 3,4-difluorophenyl alanine (1.0 g, 5.0 mmol) was added in small portions to a stirring suspension of LiA1H4 (0.480 g, 12.5 mmol) in THF (30 mL) at 0 OC. The resulting gray suspension was then heated at reflux for 2 h. The reaction mixture was cooled to 0 OC and then carefully quenched sequentially with 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 temperature for 20 min.
The suspension was filtered and was combined with the previous filtrate. The combined organics were dried over MgSO 4 filtered and the solvent was removed in vacuo. 2-Amino-3-(3,4-difluoro)-phenyl-propan-l-ol was obtained as a white solid (0.500 g, 100%) which was used in the next step without further purification.
(+)-[1-(3,4-DIFLUOROBENZYL)-2-HYDROXY-ETHYL]-CARBAMIC ACID-TERT-BUTYL ESTER: A solution of di-tert-butyl dicarbonate (0.640 g, 2.90 mmol) in CHC13 (10 mL) was added in one portion to a solution of (+)-2-amino-3- (3,4-difluoro)-phenyl-propan-l-ol (0.500 g, 2.62 mmol) in CHC13 (20 mL) at 0 0 C and the resulting solution was stirred overnight at room temperature. The solvent was WO 03/004027 PCT/US02/21063 126 removed in vacuo and the residue was chromatographed (2:1 hexane-EtOAc, followed by EtOAc), giving (+)-[l-(3,4-difluorobenzyl)-2-hydroxy-ethyl]carbamic acid-tert-butyl ester as a white solid (0.640 g, 99%).
(3,4-DIFLUORO-BENZYL) -OXAZOLIDIN-2-ONE: A solution of (+)-[l-(3,4-difluorobenzyl)-2-hydroxy-ethyl]-carbamic acid-tert-butyl ester (1.00 g, 4.00 mmol) in THF (10 mL) was added via a dropping funnel to a stirring suspension of 95% NaH (0.12 g, 5.0 mmol) in THF (20 mL) at room temperature. The resulting suspension was stirred for 3 h and then quenched carefully with water (10 mL). The biphasic mixture was extracted with Et20 (50 mL), washed with brine, filtered and the solvent was removed in vacuo. The resulting gummy residue was purified by column chromatography (Rf 0.25, 3:2 hexane-EtOAc), to give the desired product as a white solid (0.320 g, 76%).
(+)-4-(3,4-DIFLUORO-BENZYL)-OXAZOLIDIN-2-ONE-3- CARBOXYLIC ACID-4-NITRO-PHENYL ESTER: A solution of 4-(3,4-difluoro-benzyl)-oxazolidin-2-one (0.210 g, mmol) in THF (10 mL) was added dropwise via a dropping funnel to a stirring suspension of NaH (30.0 mg, 1.30 mmol) in anhydrous THF (10 mL) under argon. The resulting suspension was stirred at room temperature for min. 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 OC over min. Stirring was continued for 2 h after which the solvent was removed and the residue was purified by column chromatography (1:1 hexane/CH 2 Cl 2 followed by WO 03/004027 WO 0/00027PCT/UJS02/21063 127
CH
2 C1 2 Rf= 0 CH 2 Cl 2 to give the desired product as a yellow solid (0.350 g, 82%).
similarly, following the above procedure, 4-nitrophenyl 4- (4-f luorobenzyl) -2-oxo-l,3-oxazolidine-3-carboxylate was obtained by substituting 4-diflourophenyl alanine with p-f luorophenyl alanine: 4-NITROPEENYL 4- (4 -FLUOROBENZYL) -2-OXO-l, 3-OXAZOLID)INE- 3-CARBOXYLATE: 'H NIAR (400 MHz, CDCl 3 5 8.32 2H, J=9.3 Hz), 7.42 2H, J=8.9 Hz), 7.24-6.99 (in, 4H1), 4.69 4.59 (in, 1H), 4.35 1HI, J=8.6 Hz) 4.23 (dd, IH, J=2.7, .9.3 Hz), 3-37 (dd, IH, J=3.8, 13.6 Hz), 2.94 (dd, lH, J=9.3, 13.6 Hz); Anal.-- Cab,. for C1 7
H,
3
FN
2 0 6
C,
56.67; H, 3.64; N, 7.77. Found: C, 56.94; H, 3.76; N, 7.71.
2- (4-PHiENYL-l-PIPERIDINYL)HEXYL) -lH-ISOINDOLE- 1,3(2H)-DIONE: To the 500 ml RB-flask was added 4phenylp ip eri dine hydrochloride (5 g, 25 mmol), N- (6bromohexyl) phthalimide (15.5 g, 50 mmol), N,Ndiisopropylethylamine (21.8 ml, 12S mmrol) tetrabutylammonium iodide (0.2 g) and dioxane (250 ml) at room temperature. The reaction mixture was stirred at 100 "C for 72 h. The solvent was removed in vacuo and the crude product was purified by flash chromatography (98:2 Chloroform 2N *ammonia in methanol) to afford 7.67 g of the desired product (77% yield) IH NMR (400 MHz, CDC1 3 857.78-7.79 Cm, 2H1), 7.74-7.65 Cm, 2H) 7.32- 7.14 5H) 3.69 211, J=7.35 Hz) 3.06 2H, J=11.0 Hz), 2.49 (quintet, 1H1, J=7.6 Hz), 2.36 Ct, 2H1, J=7.6 Hz), 2.02 211, J=12.5 Hz), 1.82 Cbr s, 4H), 1. 69 2H, J'=6.3 Hz) 1. 54 (br s, 2H) 1.37 (br s, WO 03/004027 PCT/US02/21063 128 41); ESMS m/e: 391.3 (M Anal. Calc. for C2 5
H
30
N
2 0 2 +0.2H 2 0: C, 76.19; H, 7.77; N, 7.11. Found: C, 76.14; H, 7.38; N, 7.13.
METHOD I. General procedure for the Preparation of the substituted 4-[4-(3-aminophenyl)-1-piperidinyll-l- (phenyl)-l-butanones: A mixture of 4-(3aminophenyl)piperidine (2.0 rmol), 2.4 mmol of the appropriate substituted phenyl butyryl chloride 4chloro-4'-phenoxybutyrophenone, 4-chloro-3',4'dimethylbutyrophenone, 4-chloro-4'-chiorobutyrophenone, y-chlorobutyrophenone, 4-chloro-3',4'dimethoxybutyrophenone), 3.0 mmol of K 2 C0 3 and 10 mg of 18-cr=n-6 in 5 mL of toluene were heated at 110 0 C for 2.5 days. The reaction mixture was concentrated and chromatographed on silica methanol in dichloromethane) to give the desired compound: 4-[4-(3-AMINOPHENYL)-1-PIPERIDINYL-1-(4-PENOXYPHENYL) 1-BTANONE: Using Method T, the desired product was obtained. 305 mg; ESMS m/e 415.4 (M 4-[4-(3-AMINOPHENYL)-1-PIPERIDINYL-1-(3,4- DIMETHYLPHENYL)-1-BUTANONE: Using Method I, the desired product was obtained. 320 mg; ESMS m/e 351.3 (M 4-[4-(3-AMINOPHENYL)-1-PIPERIDINYL-1-(4-CHLOROPHENYL)- 1-BUTANONE: Using Method I, the desired product was obtained. 500 mg; Anal. Calc for C 2 jH 25 C1N 2 0+0.3H 2 0: C, 69.62; H, 7.12; N, 7.73. Found: C, 69.63; H, 7.34; N, 7.60; ESMS m/e 357.3 (M WO 03/004027 WO 0/00027PCT/UJS02/21063 129 4 4- (3 _AMINOPHENYL) 1- PIPERIDINYL] -l-PHENYL-1- BUJTANONE: using Method I, the desired product was obtained. 250 mig; Anal. Caic for C 21
H
2 6N 2 0+0.2H 2 0: C, 77.36; H, 8.16; N, 8.59. Found: C, 77.55; H, 8.12; N, 8.75; ESMS m/e 323.3 (M (3-AMINOPHEEYL) -l-PIPERIDINYL] DIMETHOXYPHENYL)-l-BUTANONE: Using Method I, the desired product was obtained. 330 mg; Anal. Calc for
C
23
H
30
N
2 0 3 +0.5H 2 0: C, 70.56; H, 7.98; N, 7.16. Found: C, 70.69; H, 7.87; N, 6.99; ESMS nile 383.3 CM METHOD II. General Procedure for the Acylation or Sulfonylation of the Substituted 4-[4-(3-Aminophenyl)-lpiperidinyl]-1-(4-phenyl)-1-butanones: A mixture of 1 equivalent of a substituted 4-[4-(3-aminophenyl)-1piperidinyll -1-(4-phenyl) -1-butanone, 1.5 equivalent of an acid chloride or a sulfonyl chloride, and equivalents of di is opropyl ethyl amine, in dichloromethane was stirred at room temperature for two days. The reaction mixture was applied to a preparative TLC plate and eluted with dichioromethane: methanol (15:1, containing isopropyl amine) to give the desired product.
METHOD 111. General procedure for the Preparation of the substituted 4-N- (phenyl) -4-oxobutyl] -4piperidinyl)'phenyl) acetamides: A mixture -of N- (4piperidinyl)phenyllacetamide (1.0 eq) and an aryl substituted chlorobutyrophenone (2.0 eq), K 2 C0 3 (5.0 eq), diisopropylethylamine (3.0 eg) and tetrabutylammonium iodide (cat. 5-10%) in dioxane (0.5 to 1.0 M) were heated at ref lux temperature for 16 h. The reaction WO 03/004027 WO 0/00027PCT/UJS02/21063 130 mixture was filtered and concentrated in vacuo.
The crude product was chrornatographed using silica preparative TLC (chloroform methanol containing isopropyl amine) to give the desired product.
Example 1 N- (3,4-DI4ETHYLPHENYL) -4-OXOBUTYL']-4- PIPERIDINYL}PHENYL)ACETAMIDE: Using Method III, the desired product was obtained. 'H NMR (CDCl 3 5 7.75 (s, 1H) 7.71 1H, JT=7.6 Hz) 7.45 2H, J=7.2 Hz) 7.35 1H) 7.26-7.22 (in, 2H) 6.93 1H, J=7i.6 Hz), 3.24-3.21 (in, 2H), 3.04 2H, J=7.0 Hz), 2.67-2.63 (in, 2H), 2.59-2.48 (in, 1H), 2.32 6H), 2.30-2.27 (in, 2H), 2.18 3H), 2.14-2.06 (in, 2H), 2.00-1.80 (in, 4H); ESMS m/e 393.3 (M Example 2 N- (3,4-DIMETHYLPHENYL.)-4-OXOBUTYL) -4- PIPERIDINYL)PHENYL) -2 -METHYLPRQPANAMIDE: A mixture of 0.0500 g (0.200 mmol) of 2-methyl-N-[3-(4piperidinyl)phenyllpropanamide, 0.100 g (0.480 inmol) of 4-chloro-3' ,4'-dimethylbutyrophenone, 0.080 g (0.600 inmol) of K 2 C0 3 and 0.090 g (0.600 mmol) of NaT in 5 mL of DMF was heated at reflux temperature for 18 hours. The reaction mixture was filtered, the filtrate was poured into 5 mL of water and washed with 3 X 5 mL cf ethyl acetate. The combined organic extracts were dried (MgSO 4 concentrated in vacuo and purified by preparative TLC (silica; 9.5 dichioromethane: methanol 1% isopropyl amine) to afford 0.067 g (80.0% yield) of the desired product: 1 H NMR (400 MHz, CDC1 3 6 7.72 1H, J=8.0 Hz), 7.44 1H1), 7.38 1H1, WO 03/004027 PCT/US02/21063 131 Hz) 3.13-3.11 2H), 3.02 2H, J=7.0 Hz), 2.56-2.40 4H), 2.32 6H), 2.17-2.15 2H), 2.04-1.78 6H), 1.25 6H, J=6.8 Hz); ESMS m/e 421.3 (M H).
Example 3 [4-(3,4-DIMETHYLPHENYL)-4-OXOBUTYL]-4- PIPERIDINYL}PHENYL)CYCLOHEXANECARBOXAMIDE: Using Method II, the desired compound was obtained. 1H NMR (400 MHz, CDC1 3 6 7.80-6.81 7H), 3.41-3.00 4H), 2.95-2.41 4H), 2.32 6H), 2.22-1.05 18H) ESMS m/e 461.4 (M H) Example 4 [4,4(3,4-DIMETHYLPHENYL)-4-OXOBUTYL]-4- PIPERIDINYL}PHENYL)-2 -PHENYLACETAMIDE: Using Method II, the desired product was obtained. 1 H NMR (400 MHz, CDC1 3 6 7.85-7.65 2H), 7.45-6.92 10H), 3.76 2H), 3.10-2.90 4H) 2.50-2.35 3H) 2.32 6H), 2.10-1.85 4H), 1.80-1.60 41H); ESMS m/e 469.4 (M Example [4-(3,4-DIMETHYLPHENYL)-4-OXOBUTYL]-4- PIPERIDINYL)PHENYL)-2-(3-METHOXYPHENYL)ACETAMIDE: Using Method II, the desired product was obtained. 1H NMR (400 MHz, CDC13) 6 7.76-7.65 2H), 7.38-7.12 6H), 6.95- 6.80 3H), 3.82 3H), 3.70 2H), 3.10-2.90 (m, 4H), 2.50-2.38 3H), 2.32 6H), 2.10-1.85 4H), 1.80 -1.60 4H); ESMS m/e 499.4 (M H) Example 6 WO 03/004027 PCT/US02/21063 132 N- DIMETHYLPHENYL)-4- OXOBUTYL]-4-PIPERIDINYL}PHENYL)-2-METHOXYACETAMIDE: Using Method II, the desired product was obtained. 1H NMR (400 MHz, CDC1 3 8 7.80-7.75 2H), 7.50-7.38 2H), 7.34-6.90 3H), 4.00 2H), 3.51 3H), 3.30-2.95 4H), 2.70-2.50 3H), 2.32 6H), 2.15 -1.80 (m, 8H) ESMS m/e 423.3 (M H) Example 7 N-(3-{1-[4-(3,4-DIMETHYLPHENYL)-4-OXOBUTYL]-4- PIPERIDINYL}PHENYL)METHANESULFONAMIDE: Using Method II, the desired product was obtained. 'H NMR (400 MHz, CDC1 3 8 7.82-7.10 7H), 3.41 3H), 3.40-2.85 4H), 2.82-2.35 5H), 2.32 6H), 2.22-1.80 ESMS m/e 429.3 (M Example 8 [4-(3,4-DIMETHYLPHENYL)-4-OXOBUTYL]-4- PIPERIDINYL}PHENYL)ETHANESULFONAMIDE: Using Method II, the desired product was obtained. 1H NMR (400 MHz, CDC1 3 8 7.75 1H), 7.71 1H, J=7.6 Hz), 7.30-7.09 (m, 4H), 7.02 1H, J=7.2 Hz), 3.36-3.05 6H), 2.77- 2.52 3H), 2.32 6H), 2.15-1.82 8H), 1.37 (t, 3H, J=7.4 Hz); ESMS m/e 443.3 (M H) Example 9 N-(3-(1-[4-(4-CHLOROPHENYL)-4-OXOBUTYL -4- PIPERIDINYL}PHENYL)ACETAMIDE: Using Method III, the desired product was obtained. 1H NMR (400 MHz, CDC13) 6 7.92 2H, J=B.8 Hz), 7.55-7.40 3H), 7.35 1H), 7.22 1H, J=8.0 Hz), 6.92 1H, J=8.0 Hz), 3.30- 3.27 2H), 3.09 2H, J=7.0 Hz), 2.76-2.39 WO 03/004027 PCT/US02/21063 133 2.20 Cs, 3H), 2.17-1.85 Cm, 6H); ESMS m/e 399.3 (M Example N-(3-{1-[4-(4-CHLOROPHENYL)-4-OXOBUTYL-4- PIPERIDINYL)PHENYL) -2-METHYLPROPANAMIDE: Using Method II, the desired product was obtained. "H NMR (400 MHz, CDC1 3 5 7.93 2H, J=8.6 Hz), 7.45 2H, J=8.6 Hz), 7.39 1H, J=7.2 Hz), 7.32 Cs, 1H), 7.24 1H, J=7.8 Hz), 6.94 1H, J=8.4 Hz), 3.21-3.18 2H), 3.05 t, 2H, J=7.0 Hz), 2.64-2.51 4H), 2.28-1.86 Cm, 8H), 1.26 Cd, 6H, J=6.8 Hz); ESMS m/e 427.3 CM Example 1.
Is N-C3-(l- (4-CHLOROPHENYL)-4-OXOBUTYL -4- PIPERIDINYL)PHENYL) CYCLOHEXANECARBOXAMIDE: Using Method II, the desired product was obtained. aK NMR (400 MHz, CDC1 2 6 7.93 Cd, 2H, J=8.4 Hz), 7.55-7.19 5H), 6.93 1H, J=7.6 Hz), 3.25-3.00 Cm, 4H), 2.65-2.45 4H), 2.30-1.50 18H); ESMS m/e 467.3 CM Example 12 N-(3-{1-[4-(4-CHLOROPHENYL)-4-OXOBUTYLI-4- PIPERIDINYL)PHENYL) -2-PHENYLACETAMIDE: Using Method II, the desired product was obtained. 'H NMR (400 MHz, CDCT 3 6 7.92 Cd, 2H, J=8.4 Hz), 7.46-7.26 Cm, 9H), 7.20 t, 1K, J=7.6 Hz), 6.92 1H, J=7.6 Hz), 3.75 Cs, 2H), 3.15-3.13 Cm, 2H), 3.03 Ct, 2H, J=7.0 Hz), 2.64-2.46 Cm, 3H), 2.22-1.60 Cm, 8H); ESMS m/e 475.3 CM Example 13 N-(3-{1-[4-(4-CHLOROPIIENYL)-4-OXOBUTYLJ-4- PIPERIDINYL PHENYL)-2-(3-METHOXYPHENYL)ACETAMIDE: Using WO 03/004027 PCT/US02/21063 134 Method II, the desired product was obtained. IH NMR (400 MHz, CDC1 3 6 7.92 2H, J=8.4 Hz), 7.44 (d, 2H, J=8.4 Hz) 7.38 1H), 7.35-7.25 3H), 7.19 (t, 1H, J=7.8 Hz), 6.94-6.86 3H), 3.81 3H), 3.72 (s, 2H), 3.12-3.09 2H), 3.02 2H, J=6.8 Hz), 2.57- 2.44 3H), 2.20-1.60 8H); ESMS m/e 505.3 (M
H).
Example 14 N-(3-{1-[4-(4-CHLOROPHENYL)-4-OXOBUTYL]-4- PIPERIDINYL}PHENYL)-2-METHOXYACETAMIDE: Using Method II, the desired product was obtained. 1H NMR (400 MHz, CDC1 3 6 7.93 2H, J=8.4 Hz), 7.50-7.25 5H), 6.98 1H, J=7.B Hz), 4.01 2H), 3.57 3H), 3.30-3.15 2H), 3.06 2H, J=6.8 Hz), 2.70-2.50 3H), 2.35-1.80 8H); ESMS m/e 429.3 (M Example N-(3-{1-[4-(4-CHLOROPHENYL)-4-OXOBUTYL] -4- PIPERIDINYL)PHENYL)METHANESULFONAMIDE: Using Method II, the desired product was obtained. H NMR (400 MHz, CDC1 3 6 7.95-6.96 8H), 3.48 3H), 3.28-2.90 (m, 6H), 2.80-2.57 3H), 2.38-1.86 6H); ESMS m/e 435.2 (M Example 16 N-(3-{1-[4-(4-CHLOROPHENYL)-4-OXOBUTYL]-4- PIPERIDINYL}PHENYL)ETHANESULFONAMIDE: Using Method II, the desired product was obtained. 1 H NMR (400 MHz,- CDC1 3 6 7.93 2H, J=8.2 Hz), 7.45 2H, J=8.2 Hz), 7.30-7.08 3H), 6.99 1H, J=7.6 Hz), 3.26-3.02 (m, 6H), 2.69-2.45 3H), 2.32-1.75 8H), 1.36 3H, J=7.4 Hz); ESMS m/e 449.3 (M H) WO 03/004027 WO 0/00027PCT/UJS02/21063 135 Example 17 El- (4-OXO-4-PHENYLB.TYL) -4- PIPERIDINYL]PHEY,}kCETAMIDE: Using Method III, the desired product was obtained. NMR (400 MHz, CDC1 3 8.10-6.80 (in, 9H), 3.40-2.95 (in, 4H), 2.85-2.20 (mn, 3H4), 2. 19 3H), 2. 15-1. 70 Cm, 8H4); ESMS m/e :365.3 (M Example 18 2-METHYL-N-{3- El- (4-OXO-4-PHENIYLBUTYL) -4- PIPERIDINYLJPHENYL)PROPANAMIDE: Using Method II, the desired product was obtained. 1H NMP. (400 MHz, CDC1,) 8 7.99 2H, J=7.4 Hz), 7.57 1H4, J=7.4 Hz), 7.48 (t, 214, J=7.4 Hz), 7.45-7.20 214), 7.24 114, Hz), 6.94 Cd, 1H, 8.0 Hz), 3.24-3.21 Cm, 214), 32.09 t, 214, J=7.0 Hz), 2.57-2.25 Cm, 414), 2.31-1.84 Cm, 814), 1.26 614, J=7.2 Hz); ESMS m/e :393.3 CM Example 19 N-{3-E1- (4-OXO-4-PHENYLBUTYL)-4-PIPERIDflTYLJPHENYL}-2- PHENYLACETAMIDE: Using Method II, the desired product was obtained. :LH NMR (400 MHz, CDC1 3 5 7.98 2H4, J=7.6 Hz), 7.65-7.15 Cm, 1114), 6.92 Cd, 214, J=7.2 Hz), 3.74 Cs, 214), 3.20-2.95 4H), 2.65-2.40 Cm, 314), 2.25-1.70 Cm, BH); ESMS m/e :441.3 CM H4)4.
Example 2- (3-METIIOXYPHENYL) (4-OXO-4-PHENYLBUJTYL) -4- PIPERIDINYLJPEENYLIACETAMIDE: Using Method II, the desired product was obtained. 1H NMR (400 MHz, CDC1 3 8 7.98 214, J=7.6 Hz) 7.56 114, J=7.62 Hz) 7.46 2H4, J=7.6 Hz), 7.40 Cs, 114), 7.37-7.26 2H), 7.19 WO 03/004027 PCT/US02/21063 136 1H, J=7.8 Hz), 6.94- 6.86 3H), 3.81 (s, 3H), 3.71 3H), 3.12-3.03 4H), 2.57-2.44 3H), 2.16-1.77 8H); ESMS m/e 471.3 (M H) Example 21 [4-(2,4-DIMETHOXYPHENYL)-4-OXOBUTYL]-4- PIPERIDINYL}PHENYL)ACETAMIDE: Using Method III, the desired product was obtained. IH NMR (400 MHz, CDC1 3 6 7.82 1H, J=8.8 Hz), 7.54 1H, J=7.6 Hz), 7.33 (s, 1H), 7.22 1H, J=7.6 Hz), 6.93 1H, J=7.6 Hz), 6.53 1H, J=8.8 Hz), 6.46 1H), 3.90 3H), 3.86 3H), 3.48-3.27 2H), 3.05 2H, J=6.8 Hz), 2.90-2.68 2H), 2.65-2.38 3H) 2.25 3H), 2.18-1.80 6H); ESMS m/e 425.3 (M H) Example 22 N-(3-{1-[4-(2,4-DIMETHOXYPHENYL)-4-OXOBUTYL]-4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Using Method II, the desired product was obtained. H NMR (400 MHz, CDC1 3 6 7.98 1H, J=8.6 Hz), 7.41-7.37 2H), 7.24 1H, J=7.8 Hz), 6.96 1H, J=7.8 Hz), 6.54 1H, J=8.6 Hz), 6.46 1H), 3.89 3H), 3.86 3H), 3.11-3.08 2H), 2.98 2H, J=7.2 Hz), 2.53-2.46 (m, 4H), 2.13-1.79 8H), 1.25 6H, J=6.8 Hz); ESMS m/e 453.3 (M Example 23 N-(3-{1-[4-(2,4-DIMETHOXYPHENYL)-4-OXOBUTYL] -4- PIPERIDINYL}PHENYL)-2-PHENYLACETAMIDE: Using Method II, the desired product was obtained. 'H NMR (400 MHz, CDC13) 6 7.85 12H), 3.89 3H), 3.86 3H), 3.74 2H), 3.22-2.90 4H), 2.64-2.40 3H), 2.25-1.70 8H); ESMS m/e 501.3 (M WO 03/004027 PCT/US02/21063 137 Example 24 N-(3-{1-[4-(2,4-DIMETHOXYPHENYL)-4-OXOBUTYL]-4- PIPERIDINYL}PHENYL)-2-(3-METHOXYPHENYL)ACETAMIDE:Using Method II, the desired product was obtained. 1H NMR (400 MHz, CDC1 3 6 7.82 1H, J=8.8 Hz), 7.48-7.15 6.95-6.80 3H), 6.58-6.45 2H), 3.89 3H), 3.86 3H), 3.81 3H), 3.72 2H), 3.25-2.95 4H), 2.65-2.40 3H), 2.30-1.95 4H), 1.93-1.72 4H); ESMS m/e 531.3 (M H).
Example [4-OXO-4-(4-PHENOXYPHENYL)BUTYL]-4- PIPERIDINYL}PHENYL)ACETAMIDE: Using Method 3II, the desired product was obtained.
1H NMR (400 MHz, CDC1 3 6 8.15-6.75 13H), 3.30-2.80 4H), 2.75-2.10 5H), 2.03 3H), 2.00-1.60 (m, 6H); ESMS m/e 457.3 (M Example 26 2-METHYL-N-(3-{1-[4-OXO-4-(4-PHENOXYPHENYL) BUTYL]-4- PIPERIDINYL}PHENYL)PROPANAMIDE: Using Method II, the desired product was obtained. 'H NMR (400 MHz, CDC1 3 6 7.96 2H, J=8.8 Hz), 7.43-7.15 6H), 7.10-6.93 (m, 3.42-2.95 4H), 2.80-2.45 4H), 2.20-1.80 8H), 1.14 6H, J=6.8 Hz); ESMS m/e 485.4 (M H) Example 27 2-(3-METHOXYPHENYL)-N-(3-{l-[4-OXO-4-(4- PHENOXYPHENYL)BUTYL]-4-PIPERIDINYL}PHENYL)ACETAMIDE: Using Method II, the desired product was obtained. 'H NMR (400 MHz, CDC1 3 6 7.97 2H, J=8.8 Hz), 7.41-7.18 7H), 7.08-6.99 5H), 6.94-6.87 3H), 3.82 (s, 3H), 3.70 2H), 3.10-2.95 4H), 2.55-2.40 3H), WO 03/004027 PCT/US02/21063 138 2.15-1.95 Cm, 4H), 1.81- 1.70 (in, 4H); ESMS m/e 563.4 (M Example 28 N'-(3-{1-[4-(4-CHLOROPHENYL)-4-OXOBUTYL-4- PIPERTDINYL}PHENYL) -N,N-DIMETHYLSULFAMIDE: Using Method II, the desired product was obtained. 'H NMR (400 MHz, CDC13) 5'7.93 2H, J=8.8 Hz), 7.44 2H, J=8.8 Hz), 7.27 1H), 7.25-7.10 2H), 6.94 1H, J=7.6 Hz), 3.30-3.10 2H), 3.04 2H, J=6.8 Hz), 2.83 6H), 2.68-2.45 Cm, 3H), 2.30-1.75 8H); ESMS m/e 464.3 (M Example 29 N-(3-(1-[4-OXO-4-(2-THIENYL)BUTYL]-4- PIPERIDINYL}PHENYL)ACETAMIDE: Using Method III, the desired product was obtained. 1H NMR (400 MHz, CDC13) 7.90-6.78 Cm, 7H), 3.22-2.88 Cm, 4H), 2.69-2.25 2.02 3H), 2.00-1.64 6H); ESMS m/e 371.2 (M Example N-(3-1-[4-(4-ISOPROPYLPHENYL)-4-OXOBUTYL)-4- PIPERIDINYL}PHENYL)ACETAMIDE: Using Method III, the desired product was obtained. 1H NMR C400 MHz, CDC1,) 8.00-6.78 Cm, 8H), 3.15-2.98 Cm, 4H), 2.77-2.15 4H), 2.03 3H), 2.00-1.62 811), 0.927 6H, Hz); ESMS m/e 407.3 CM Example 31 N-(3-{1-[4-(4-METHYLPHEINYL)-4-OXOBUTYL -4- PIPERIDINYL)PHEYL)ACETAMIDE: Using Method III, the desired product was obtained. 'F NMR (400 MHz, CDC1 3 WO 03/004027 PCT/US02/21063 139 7.90-6.80 8H), 3.10- 2.45 7H), 2.32 (S, 3H), 2.02 3H), 2.01-1.68 8H); ESMS m/e 379.3 (M Example 32 N-(3-{1-[4-(4-BROMOPHENYL)-4-OXOBTTYL -4- PIPERIDINYL}PHENYL)ACETAMIDE: Using Method III, the desired product was obtained. 1H NMR (400 MHz, CDC1 3 6 7.90-6.80 8K), 3.30-S.05 Cm, 4H), 2.70-2.45 3H), 2.05 3H), 1.98-1.65 Cm, 8H); ESMS m/e 444.0 (M EXAMPLE 33 N-(3-{1-[4-(3,4-DIMETHYLPHENYL)-4-OXOBUTYLJ-4- PIPERIDINYL}PHENYL)-2-PROPANESLFONAMIDE: Using Method II, the desired product was obtained. 1H NNR (400 MHz, CDC1 3 6 7.75 Cs, 1H), 7.71 Cd, 1H, J=7.6 Hz), 7.27-7.00 5K), 3.32-3.24 3H), 3.10-3.02 2H), 2.78-2.50 3H), 2.32 6H), 2.19-1.84 8H), 1.39 6H, J=6.8 Hz); ESMS m/e 4-.4 (M Example 34 N-(3-1--4-OXO-4-(4-PHENOXYPHENYL)BUTYL-4- PIPERIDINYL}PHENYL)-2-PROPANESULFONAMIDE: Using Method II, the desired product was obtained. 'H NMR (400 MHz, CDC1 3 6 7.97 2H, J=7.6 Hz), 7.44 2H, J=7.6 Hz), 7.27-7.00 Cm, 9H), 3.35-2.96 Cm, 5K), 2.69-2.45 Cm, 3K), 2.14-1.79 Cm, 8H), 1.39 Cd, 6H, J=6.8 Hz); ESMS m/e 521.4 (M Example [3-(4-CHLOROPHENYL)-3-METHOXYPROPYL)-4- PIPERIDINYL)PHENYL) -2-METHYLPROPANAMIDE: A mixture of 3- WO 03/004027 WO 0/00027PCT/UJS02/21063 140 methoxy-3- Cp- chlorophenyl) -1chioropropane (27.4 mg, 0.125 mmcl) 2 -methyl 3-(4 piperidinyl)phenyllpropanamide (28.3 mg, 0.125 mmcl), di isopropyl ethyl amine (0.50 mL) and catalytic amount of tetrabutylammonium iodide in dioxane (2.0 mL) was stirred at 90 0 C for 72 hrs. The reaction mixture was concentrated to a small volume and chromatographed using preparative TLC plates of NH 3 (2.0 M in methanol) in CHC1 3 1 gave N-(3-{l--E3-(4-chlorophenyl)-3methoxypropyll -4-piperidinyl }phenyl) -2 -methyipropanamide (39.5 mg, 73.8% yield) as a thick oil: 'H NMR 6 7.48 (S, 1 7.34-7.3 Cm, 2H), 7.25 (in, 4H), 6.96 Cd, 1H1, 7=7.4 Hz), 4.20 (apparent dd, 1H1, 3=5.9, 7.G Hz), 3.2 Cs, 3H), 3.04 1H, J=10.1 Hz) 2.99 1H, J=10.1I Hz) 2.49 4H1, J=6.6 Hz), 2.20-2.10 4H), 1.82 (mn, 4H), 1.25 Cd, 6H1, J=7.1 Hz); ESMS m/e: 429.4 (M Example 36 N.-(3-{1-[6-(.,3-DIOXO-1,3-DIHYDRO-2H-ISOINDOL-2- YL) HEXYL) -4 -PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE:. The synthetic method is the same as described for 2- (4phenyl-l-piperidinyl)hexyl] -lH-isoindole-l,3 (211)-dione.
N- (3-{l-[6-Cl,3-dioxo-l,3-dihydro-211-isoindol-2yl) hexyl) -4-piperidinyllphenyl) -2-rnethylpropanamide: 506 mg yield); -H NMR (400 MHz, CDCl 3 67.86-7.80 Cm, 2H), 7.73-7.68 Cm, 2H1), 7.44 Cs, 111), 7.37 111, J=8.3 Hz), 7.22 111T, 3=7.7'Hz), 6.96 1H, J=7.7 Hz), 3.69 2H1, 3=7.2 Hz), 3.01 (apparent d, 2H, 3=11.3 Hz), 2.58-2.40 (in, 211), 2.33 (in, 211) 1.98 (dt, 2H, 3=3.2, 11.3 Hz), 1.84-1.64 (in, 4H), 1.51 2H, 3=7.1 Hz), 1.43-1.30 Cm, 6H), 1.24 Cd, 6H1, JT=6.8 Hz); ESMS in/e: 476.4 (M H+ WO 03/004027 WO 0/00027PCT/UJS02/21063 141 Example 37 [1-(3-METHOXy-3-PHENY.LPROPYL) -4- PIPERIDINYL1PHENYL}-2-METHYLPROPANAMIDE: A mixture of 3methoxy-3-phenyl-l-chloropropale (23.1 mg, 0.126 mmol), 2-methyl-N- (4-piperidinyl)phelyllpropaflamide (28.3 mg, 0.126 mmol), dilsopropylethylamine (0.50 mL) and catalytic amount of tetrabutylammonium iodide in dioxane mL) was stirred at 90 0 C for 72 hrs. Chromatography using silica preparative TLC plates of NH 3 (2.0 M in methanol) in CHC1 3 gave N-{3-[1-C3-methoxy-3phenyipropyl) -4-piperidinyl] phenyl)}-2-methylpropanamide (45.4 mg, 91.2-. yield) as a thick oil: 1H N\MR (400 MHz, CDC13) 8 7.45 1 7.34-7.25 (in, 51) 7.25 (in, 2H) 6.96 1H, J=7.4 Hz), 4.20 (apparent dd, 1H1, J=5.9, 7.6 Hz), 3.2 3H), 3.04 lH, J=10.1 Hz), 2.99 (d, 111, J=l0.iHz), 2.49 (apparent sept, partially hidden, 4H, J=6.6 Hz), 2.3-2.1(m, 4H), 1.82 (in, 4H), 1.25 (d, 6H1, J=7.1 Hz); ESMS in/e: 395.4 (M Example 38 N- (1,3-DI:OXO-l,3-DI:HYDRO-211-lSOlNDOL-2- YL) BUTYL] -4 -PIPERIDI:NYL}PH-ENYL) -2 -METHYLPROPANAMIDE: The synthetic method is the same as described for phenyl-l-piperidinyl)hexyll -1H-isoindole-l,3 (211)-dione.
N-(3-{l-[4-(1,3-dioxo-l-,3-dihydro-2H-isoindol-2yl) butyl I 4-pip eridinyl) phenyl) 2-methyipropanaiide: 664 mg (74% yield); 1H NMP. (400 MHz, CDC13) 8 7.87-7.78 (m, 211), 7.76-7.64 211), 7.47 1H1), 7.3.9 111, J=7.6 Hz) 7.21 111, J=8.1 Hz) 6.94 1H, J=7.6 Hz) 3.72 211, J=6.8 Hz), 3.37-3.22 (in, 211), 3.0 (apparent d, 2H, J=10.7 Hz), 2.75 211, J=7.0 Hz), 2.64-2.33 (mn, 4H), 1.99 Cdt, 2H, J=2.6, 11.7 Hz), 1.86-1.65 (in, 211), 1.63-1.50 (mn, 211), 1.23 and 1,21 (two d, 611, J=5.5 Hz); WO 03/004027 PCT/US02/21063 142 ESMS m/e: 448.4 (M Anal. Calc. for
C
27
H
3 4
N
3 C0 3 +0.4H 2 0: C, 66.02; H, 7.14; N, 8.55. Found: C, 65.07; H, 6.78; N, 8.65.
Example 39 N- (3-Cl- (,3-DIOXO-1,3-DIHYDRO-2H-ISOINDOL-2- YL) BUTYL] -4 -PIPEPIDINYL}PHENYL) -2 -HETHYLPROPANAMIDE: The synthetic method is the same as described for phenyl-1-piperidinyl)hexyl]-1H-isoindole-1,3(2H)-diane.
N-C3-{l-[5-(l,3-dioxo-l,3-dihydro-2H-isoindol-2yl)pentyl)-4-piperidinyl~phenyl)-2-methyipropanamide: 614 mg (64% yield); 'H NMR (400 MHz, CDC1 3 8 7.87-7.8 2H) 7.76-7.68 2H), 7.48 Cs, 1H), 7.41 1H, J=7.6 Hz), 7.21 Ct, 1H, J=7.6 Hz), 6.95 1H, J=7.6 Hz), 3.69 2H, J= 7.2 Hz), 3.39-3.28 Cm, 2H), 3.02 (apparent d, 2H, J=11.6 Hz), 2.78 Cq, 2K, J=7.2 Hz), 2.64-2.52 1H), 2.52-2.40 Cm, 1H), 2.40-2.31 Cm, 2H), 2.01 (dt, 2K, J=3.7, 11.1 Hz), 1.85-1.64 Cm, 2H), 1.58 2K, J=7.6 Hz), 1.45-1.32 Cm, 2H), 1.23 Cd, 6H, J=6.9 Hz); ESMS m/e: 462.4 CM H) Anal. Calc. for
C
2
BH
3 6
N
3 C10 3 C, 67.52; H, 7.29; N, 8.44. Found: C, 67.04; H, 7.06; N, 8.38.
Example 2-METHYL-N-{3-El-(4-PHENYLBUTYL)-4- PIPERIDINYLIPHENYL}PROPANAMIDE: A mixture of 2-methyl- N-[3-(4-piperidinyl)phenyllpropanamide (28.3 mg, 0.100 mmol), 4-phenyl-1-chlorobutane (21.1 mg, 0.125 mmoli), diisopropylethylamine (0.50 mL), catalytic amount of tetrabutylammonium iodide and dioxane (2.0 mL) was heated at reflux temperature for 3 days. The reaction mixture was concentrated and chromatographed using preparative TLC plates of NH 3 (2.0 M in methanol) WO 03/004027 PCT/US02/21063 143 in CHC1 3 afforded the product, 2-methyl-N-{3-E1- (4-phenylbutyl)-4-piperidinyl.phenyproPafaride (9.50 mg, 25.1% yield) as a thick oil: 1H IMR 8 7.37 Cs, 1H), 7.29 (apparent d, 1H,. J=7.9 Hz), 7.18 31), 7.11 (m, 3H), 6.90 (apparent d, 1H, J=7.9 Hz), 3.02 2H, J=6.8 Hz), 2.41 4H, partially hidden), 2.01 2H), 1.78 Cm, 4H), 1.57(m, 4H), 1.18 6H, J=7.7 ESMS n/e: 379.4 CM Example 41 [3-(i,3-DIOXO-1,3-DIHYDRO-2H-ISOINDOL-2- YL)PROPYLI-4-PIPERIDINYLPHENYL) -2 -METHYLPRPANAMIDE: The synthetic method is the same as described for 2-[6- (4-phenyl-l-piperidinyl)hexyl)-1H-isoindole-1,3(21)dione. N-(3-{1-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2yl)propyl]-4-piperidinyljphenyl)-2-methyipropanamide: 810 mg (93% yield); 'H NMR (400 MHz, CDC1 3 5 7.87-7.82 Cm, 2H), 7.73-7.68 Cm, 2H), 7.57 Cs, 1H), 7.366 1H, Hz), 7.18 1I, J=7.7 Hz), 6.79 1H, J=7.1 Hz), 3.78 Ct, 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 Cm, 4H) 1.96-1.83 2H), 1.70 (apparent d, 2H, J=12.1 Hz), 1.52 Cdt, 21, J=3.5, 12.5 Hz), 1.03 Cd, 6H, J=6.5 Hz); ESMS m/e: 434.4 (M Example 42 (3S) -3-HYDROXY-3-PHENYLPROPYL]-4- PIPERIDINYLPHENYL)-2-METHYLPROPANAMIDE: A' mixture of (S)-(-)-3-chlorc-l-phenyl-1-propanol (0.426 g, 2.50 imol, 99ee), 2-methyl-N-[3-C4piperidiryl)phenyllpropanamide (0.565 g, 2.00 mmol), diisopropylethylamine (1.29 g, 10.0 mmol), dioxane mL) and catalytic amount of tetrabutylammonium iodide WO 03/004027 WO 0/00027PCT/UJS02/21063 144 was stirred at 90 0 C for 72 hrs. Chromatography using silica preparative TLC plates of NH 3 (2.0 M in methanol) in CHCl 3 gave the desired product (306 mg, 39.3 yield) as a thick oil: 'H NMR (400 MHz, CDCl 3 8 7.46 CS, 1 7.42 (di, 4H, J=8.1 Hz), 7.35 (in, 1 H), 7.30 1 H, J=8.0 Hz), 7.23 111, J=8.1 Hz), 7.12 Cs, lH), 6.96 (apparent dd, 1H, J=8.0 Hz), 5.0 (apparent dd, lH, J=4.4, 8.3 Hz), 3.18 (apparent dd, 2H, 12. 5 Hz) 2. 74 (in, 2 2. 50 Cm, 2H) 2. 3 1 Cm, 6H) 1. 8 (in, 2H) 1. 25 61H, J=7.l1 Hz) ESMS mle: 389.2 (M IH) Example 43 N- E3-METHOXY-3-( 4-METHYLPH-ENYL)PROPYL] -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE; A mixture of 3-methoxy-3- (p-tolyl) -1-chioropropane (24.9 mng, 0.126 minol), 2-methyl-N- (4-piperidinyl)phenylllpropanamide (28.3 mg, 0.126 mmol) di is opropyl ethyl amine (0.50 mL) and catalytic amount of t et rabutyl ammonium iodide in dioxane (2.0 mL) was stirred at 90 0 C for 72 hrs.
Chromatography using silica preparative TLC plates of NH 3 (2.06 M' in methanol) in CHC1 3 1 gave the desired product (10.9 mg, 21.2 yield) as a thick oil: 1H NMR (4 00 MHz, CDC1 3 8 7.44 1 H) 7. 38 Cm, lH) 7. 3 1 S 6.96 Cd, 1H, J=7.4 Hz), 4.18 (apparent dd, 1H1, J=5.6, 7.9 Hz) 3.24- 1H1, J=8.2 Hz) 3.-2 3H) 3.11 (mn, 2H, J=10.lHz), 2.49 Cm, 4H1), 2.35 311), 2.3- 2.1Cm, 3H1), 1.92 Cd, 4H), 1.25 6H1, J=7.1 Hz); ESMS m/e: 409.4 (M Example 44 N-{3-El- (3-ISOPROPOXY-3-PHENYLPROPYL) -4- PIPERIDINYL]PHENYL}-2-METHYLPROPANAMIDE: A mixture of 3- WO 03/004027 PCT/US02/21063 145 isopropyl-3'-phenyl-1- chloropropane (26.6 mg, 0.126 mmol), 2-methyl-N-[3-(4piperidinyl)phenyl]propanamide (28.3 mg, 0.126 mmol), diisopropylethylamine (0.50 mL) and catalytic amount of tetrabutylammonium iodide in dioxane (2.0 mL) was stirred at 90 'C for 72 hrs. Chromatography using silica preparative TLC plates of NH 3 (2.0 M in methanol) in CHCl3] gave the desired product (14.1 mg, 26.5% yield) as a thick oil: IH NMR (400 MHz, CDC13) 6 7.46 1H) 7.43-7.37 2H), 7.33 3H), 7.23 2H), 6.95 (d, 1H, J=8.4 Hz), 4.46 (apparent dd, 1H, J=5.0, 8.3 Hz), 3.49 (apparent sept, 1H, J=7.1 Hz), 3.10 2H), 2.70 2H), 2.52 (apparent sept, partially hidden, 4H, J=6.6 Hz), 2.30-2.10 2H), 1.90-1.80 4H), 1.25 6H, J=7.1 Hz), 1.15 3H, J=6.4 Hz), 1.08 3H, J=6.4 Hz); ESMS m/e: 423.4 (M Example N-(3-{1-[4,4-BIS(4-FLUOROPHENYL)BUTYL]-4- PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE: A mixture of 4,4-bis(4-fluoro-phenyl)-l-chloro-butane (39.0 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 in dioxane (2.0 mL) was stirred at 90 OC for 72 hrs.
Chromatography using silica preparative TLC plates of NH 3 (2.0 M in methanol) in CHC1 3 gave the desired product (15.9 mg, 25.2 yield) as a thick oil: 1H NMR (400 MHz, CDC13) 5 8.02 1H), 7.41 1H), 7.3-7.15 4H) 7.10 3H), 6.89 (apparent t, 5H), 3.81 (t, 1H, J=7.8 Hz), 3.30 1H), 2.91 1H, J=12,5 Hz), 2.80 1H), 2.40 2H), 2.31 1H, J=8.0 Hz), 1.93 (apparent q, 3H, J=8.0 Hz), 1.72 3H), 1.40 2H), WO 03/004027 WO 0/00027PCT/UJS02/21063 146 1 20 Cmn, 2H) 1 .15 6H, J=8.1 Hz); ESMS m/e: 491.4 (M EXAMPLE 46 (3-METHOXYBENZYL) -4-PIPERIDI:NYL]PHENYL}-2- METHYLPROPANAMIDE: A mixture of 2-methyl-N- piperidinyl)phenyllpropanamide (28.3 mg, 0.100 mmol), 3methoxybenzyl chloride (19.6 Mgt 0.125 mmcl), diisopropylethylamine (0.50 mL) catalytic amount of tetrabutylammonium iodide and dioxane (2.0 mL).
Chromatography using silica preparative TLC plates of NH 3 (2.0 M in methanol) in CHC1 3 1 afforded the desired product (10.2 mg, 27.9-% yield) as a yellow solid: 'H NNR (400 MHz, CDCl 3 8 7.46 1H1), 7.35 (apparent d, 1H1, J=8.3 Hz), 7.27-7.21 211) 6. 95 (apparent t, 3H, J=6.9 Hz), 6.82 (apparent dd, 111, J=2.4, 8.3 Hz), 3.84 Cm, 3H1), 3.56 2H1), 3.05 Cd, 2H, J=10.5 Hz), 2.51 (apparent sept, partially hidden, 4H1, J=7.2 Hz), 2.13 (apparent t, 2H1, J= 9. 7 Hz) 1. 88 Cm, 2H) 1. 25 Cd, 6H, J=6.7 Hz); ESMS m/e: 367.3 CM Example 47 N- [3,5-BIS (TRIFLUOROME.THYL)BENZYLI -4- PIPERZIDIN'YL)PHENYL) -2-METIIYLPROPANAMIDE: A mixture of 2methyl--N- (4-piperidinyl)phenyllpropanamide (20.3 mg, 0.100 mmcl), 3,5-bis(trifluoromethyl)benzyl bromide (38.4 mg, 0.125 mmol), diisopropylethylamine (0.50 mnL), catalytic amount of t et rabutyl ammonium -iodide and dioxane (2.0 mL) Chromatography using silica preparative TLC plates of NH 2 (2.0 M in methanol) in CHCl 3 J gave the desired product (12.2 mg, 25.8% yield) as a thick oil: 'H NMR (400 Mlz, CDCl 3 8 7.83 Cs, 211), 7.77 Cs, 111), 7.53 111), 7.30-7.21 Cm, 211), 7.16 (s, WO 03/004027 PCT/US02/21063 147 1H), 6.98 (apparent d, 1H, J=7.6 Hz), 3.62 2H), 2.94 2H, J=9.4 Hz), 2.51 (apparent sept, partially hidden, 2H, J=6.6 Hz), 2.14 2H), 1.82 4H), 1.25 6H, J=6.6 Hz); ESMS m/e: 473.2 (M H) Example 48 N-(3-{1-[(3R)-3-(3,4-DIMETHOXYPHENOXY)-3-PHENYLPROPYL]- 4-PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE Method A 4-{[(1R)-3-chloro-l-phenylpropyl]oxy)-l,2dimethoxybenzene: A mixture of 3,4-dimethoxyphenol (4.07 g, 26.4 mmol), (S)-(-)-3-chloro-phenyl-l-propanol (4.50 g, 26.4 mmol, 99%ee, Aldrich Chemical Co.), triphenylphosphine (6.92 g, 26.4 mmol) and diethyl azodicarboxylate (4.59 g, 26.4 mmol) in THF (110 mL) was stirred at room temperature for 24 h. The reaction mixture was concentrated in vacuo. At this point, the residue can either be washed with pentane (x3) and the combined pentane extracts were concentrated and chromatographed (silica with hexanes-EtOAc 8:1 as the eluent) to give the desired product (as described as a general procedure by: Srebnik, Ramachandran, P.V.; Brown, H.C. J. Org. Chem. 1988, 53, 2916-2920) This procedure was performed on a smaller scale reaction and only a 40% yield of the product was realized.
Alternatively, 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. The filtrate was concentrated and the crude product was chromatographed to give the desired product as a thick yellow oil (7.30 g, 88.9% WO 03/004027 WO 0/00027PCT/UJS02/21063 148 yield): 1 H NMR (400 MHz, CDC1,) 5 -7.39-7.32 (in, 4H), 7. 20 (i,1H) 6. 64 1H, J= 8.7 Hz) 6. 51 1H, J=2. 7 Hz) 6.30 (dd, 1H, J=2.7, 8.7 Hz) S.27 (apparent dd, 1H-, J=4.5, 8.7 Hz) 3, 79 3H) 3.77 3H), 3.61 (in, 1H) 2. 45 (in, 1 H) 2. 20 (mn, 1H) 1 .8 0 1H) ESMS m/e: 307.11 (M-iH) 4 N- E (3R) (3,4-DIMETHOKYPHENOXY) -3-PHENYLPROPYL) 4 -PIPERIDINYL}PENYL) -2-METEYLPROPANAMIDE: A mixture of potassium carbonate (321 mg, 2.32 minol), sodium iodide (522 mg, 3.48 mmol), 2-inethyl--N-[3-(4piperidinyl)phenyllpropanamide (570 mg, 2.32 minol) and (IR)-3-chloro-1-phenylpropylloxy}-1,2dimethoxybenzene (712 mg, 2.32 inmol) in DMF (5.0 mL) was stirred at 100 0 C for 3 hrs, at which time TLC indicated that the reaction was complete. The reaction mixture was poured into water (50 mL) and the aqueous layer was extracted with methylene chloride (3x30 mL). The combined ocrganic extracts were washed with brine mL) dried over M9S0 4 and concentrated under reduced pressure. The crude product was purified by Prep-TLC plates [2.5o% of NHl 3 (2.0 M in methanol) in CHC1 3 to afford the product (970 mg, 90.1%) as a thick oil.
Method B Into a 25-mL RB-flask was added triphenylphosphine (9.80 mg, 0.0375 mmcl), diethyl azodicarboxylate (5.22 mg, 0.0300 inmol), N-(3-{l-[(3S)-3-hydroxy-3-phehylpropyl]-4piperidinyl~phenyl) -2-iethyipropanamide (9.53 mg, 0.0250 inmol), 3,4-dimethoxyphenol (7.70 my, 0.050 inmol) and THF mL) at room temperature. The reaction mixture was stirred at room temperature overnight (16 hrs) The solvent was removed under reduced pressure and the WO 03/004027 WO 0/00027PCT/UJS02/21063 149 residue was purified by preparative TLC plates [2.5%0 of NH-j (2.0 M in methanol) in CHC1 3 1 to afford the desired product (4.4 mg, 34.1 yield) as a thick oil: IH NM4R (400 MHz, CDC1 3 5 7.46 Cs, I H) 7.40-7.30 Cm, 4H), 7.25 (in, 3H), 6.97 Cd, 1H, J=7.8 Hz), 6.64 IH, J=9.1 Hz), 6.51 Cd, 1H1, J=2.6 Hz), 6.29 1H, J=2.6, 9.1 Hz), 5.20 Capparent dd, 1H1, J=4.4, 8.5 Hz), 3.80 Cs, 311), 3.77 Cs, 3H), 3.23 Cm, 2H), 2.77 2 2.5 Cm, 2H), 2.3-2.1Cm, 6H1), 1.80 (mn, 211), 1.25 Cd, 6H, J=7.9 Hz); ESMS m/e: 517.4 CM Example 49 2-METHYL-N- -3-PHENOXY-3-PHENYLPROPYL] -4- PIPERIDINYL}PIIENYL)PROPANMIDE: A mixture of N-(37{l-- 15[C3R) -3-hydroxy-3-phenylpropylj -4-piperidinyl~phenyl) -2iethylpropanamide (9.53 mg, 0.0250 mmol), phenol (4.70 mg, 0.050 mmol), triphenylphosphine C9.80 mg, 0.0375 minol) and diethyl. azodicarboxylate (5.22 mg, 0.0300 mmol) in THF (1.0 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates of N- 3 (2.0 M in methanol) in CHC1 3 gave the desired product (2.7 mg, 23.6 yield) as a thick oil: 1H NMR 8 7.46 2H), 7.40-7.30 (in, 4H), 7.25 Cmn, 3 H) 7.20 (mn, 2H) 6. 97 (apparent d, iH, J=7.4 Hz), 6.89 (apparent tt, 1H1, J=0.8, 7.6 Hz), 6.84 (apparent dt, 1H1, J=0.8, 8.0 Hz), 5.20 (apparent dd, 1H, J=4.4, Hz), 3.35 2H), 2.91 Cm, 211), 2.60 Cm, 2H1), 2.30- 2.10 Cm, 6H), 1.90 (in, 2H), 1.2S Cd, 6H, J=7.9 Hz); ESMS m/e: 457.4' (M Example N- (4-METHOXYPHiENOXY) -3-PHENYLPROPYL2 -4- PIPERIDIYL)PHENYL) -2-METHYLPROPANAMIDE: A mixture of N- WO 03/004027 WO 0/00027PCT/UJS02/21063 150 E(3R)-3-hydroxy-3- phenyipropyll-4piperidinyllphelyl) -2-methylpropanamide (9.53 mg, 0.0250 mmol), 4-methoxypheno. (6.20 mg, 0.050 mmol), triphenyiphosphine (9.80 mg, 0.0375 mmol) and diethyl.
azodicarboxylate (5.2 mg, 0.0300 mmol) in THF (1.0 mL) was stirred at roam temperature for 3 days.
Chromatography using silica preparative TLC plates of~ NH3 0 M in methanol) in dCC13 gave the desired product (4.6 mg, 37.9 yield) as a thick oil. 1H NMR (400 MHz, CDC13) 5 7.38-7.14 (in, 8H), 6.90 (apparent d, IH, J=7.7 Hz), 6.72-6.46 (in, 4H), 5.09 (apparent dd, 1H, J=4.8, 8.1 IHz) 3.64 3H) 3.18 (in, 2H) 2.73 (in, 2H), 2.50 2H), 2.37-1.72 (in, 8H), 1.25 61q, J=7.4 Hz) ESMS m/e; 487.4 (M Example 51 N- (3-fl- (3-CELOROPHENOXY) -3-PHENYLPROPYL] -4- PIPERIDINYL)PHENYL) -2-METHYLPROPANAMIDE: A mixture of N- -3-hydroxy-3-phenylpropyll -4pip eri dinyl) phenyl) 2-methyipropanami de (9.53 mg, 0.0250 minol), 3-chiorophenol (6.40 mg, 0.050 inmol), triphenylphosphine (9.80 mng, 0.0375 iniol) and diethyl azodicarboxylate (5.22 mg, 0.0300 mmol) in TEF (1.0 inL) was stirred at room temperature for 3 days.
Chromnatography using silica preparative TL.C plates of NH 3 (2.0 M in methanol) in CHC131 gave the desired product (4.9 mg, 40.0 -yield) as a thick oil: aH NMR (400 MIHz, CDC13) 5 7.39 Cs, 1H), 7.35-7.10 7H), 7.02 1H, J=8.0 Hz), 6.90 1H, J=7.6 Hz), 6.84-6.75 (in, 2H), 6.65 (in, 1H), 5.09 (apparent dd, 1H1, J=4.99, 8.1 Hz), 3.10 (in, 2H), 2.60 (in, 2H), 2.50 Cm, 2H), 2.30-1.70 Cm, 8H) 1.18 6H, J=6.8 Hz) ESMS m/e: 491.4 CM WO 03/004027 WO 0/00027PCT/UJS02/21063 Example 52 N- (4-CHLOROPHENOXY) -3-PHENYLPROPYLJ -4- PIPERIDINYL)PHENYL) -2-METHYLPROPANAMIDE: A mixture of N- :C3R)-:3-hydroxy-3-phenylpropyl]-4piperidinyl~phenyl) -2-methyipropanamide (9.53 mg, 0.0250 mmol), 4-chiorophenol (6.40 Mgt 0.050 ml), triphenyiphosphine (9.80 mg, 0.0375 mmcl) and diethyl azodicarboxylate (5.22 mg, 0.0300 mmol) in THF (1.0 mL) was stirred at room temperature for 3 days.
Chromatography using silica preparative TLC plates of NH13 (2.0 M in methanol) in CHC1 3 1 gave the desired product (3.3 mg, 26.9 yield) as a thick oil: 1H NMR 7.36 Cs, 1H), 7.35-7.22 (in, 7H), 7.12 Cm, 2H1), 6.97 (apparent d, 111, J=7.2 Hz), 6.77 (in, 2H), 5.23 (in, 111), 3.18 2H1), 2.70 (mn, 2H1), 2.50 (in, 2H1), 2.40-1.80 Cm, 8H), 1.25 6H, J='6.8 Hz); ESMS m/e: 491.4 (M +f Example 53 2-METHYL-N- (3S) -3-PHEN1YL-3- [4- (TRIFLUOROMETHYL) PHENOXY) PROPYL} -4- PIPERIDINYL)PHENYL)PROPANAMIDE: A mixture of -3-hydroxy-3--phenylpropyl) -4-piperidinyllphenyl) -2iethylpropanainide (9.53 Mg, 0.0250 mmcl), 4trifluoroinethylphenol (0.100 mg, 0.050 mmcl), triphenylphosphine (9.8 my, 0.0375 minol) and diethyl azodicarboxylate (5.22 my, 0.0300 mmol) in THE (1.0 mL) was stirred at room temperature for 3 days.
Chromatography using silica preparative TLC plates of 1113 (2.0 M in methanol) in CHC1 3 1 gave the desired product (5.10 mg, 38.9 yield) as a thick oil: 'H NM'R 8 8.06 111), 7.49 1H1), 7.44 (apparent d, 2H, 6 Hz), 7.38-7.30 4H), 7.30-7.20 Cm, 6.96 WO 03/004027 PCT/US02/21063 152 (apparent d, 1H, J=7.6 Hz), 6.91 (apparent d, 2H, J=8.6 Hz), 5.34 Cm, li), 3.19 2H), 2.72 2H), 2.53 Cm, 2H), 2.40-1.80 Cm, 8H), 1.25 6H, J=6.8 Hz); ESMS m/e: 525.4 (M W.
Example 54 N-(3-(1-[(3R)-3-(2,5-DIFLUOROPENOXY) -3-PHENYLPROPYL]-4- PIPERIDINYLPHENYL)-2-METHYLPROPA1AMIDE: A mixture of N- C3-{l-[(3R)-3-hydroxy-3-phenylpropyl -4piperidinyl~phenyl)-2-iethyipropanaiide (9.53 mg, 0.0250 mnol), 2,5-difluorophenol (6.50 mg, 0.050 mmcl), triphenyiphosphine '(9.80 mg, 0.0375 mmol) and diethyl azodicarboxylate (5.22 mg, 0.0300 mmcl) in THF (1.0 mL) was stirred at room temperature for 3 days.
Chromatography using silica preparative TLC plates of NH 3 (2.0 M in methanol) in CHC1 3 J gave the desired product (3.60 mg, 29.3 56 yield) as a thick oil: 'H NNR 7.46 1H), 7.40-7.32 4H), 7.31-7.20 m, 2H), 7.17 Cs, 1H), 7.01-6.92 2H), 6.65-6.42 Cm, 2H), 5.27 (m, 1H), 3.13 2H), 2.64 2H), 2.51 Cm, 2H), 2.28-1.80 8 1.25 Cd, 6H, J=7.1 Hz); ESS m/e: 493.4 (M Example N-(3-{1-[(3R)-3-(3,4-DICHLOROPHENOXY)-3-PENYLPROPYL)-4- PIPERIDINYL)PHENYL)-2-HETHYLPROPANAIDE: A mixture of N- (3-{.l-[(3S)-3-hydroxy-3-phenylpropyl-4piperidinyljphenyl)-2-iethylpropanamide C9.53 mg, 0.0250 mmol), 3,4-dichlorophenol (8.20 mg, 0.050 mmcl), triphenylphosphine (9.80 mg, 0.0375 mnol) and diethyl azodicarboxylate C5.22 mg, 0.0300 mmcl) in THF (1.0 mL) was stirred at room temperature for 3 days.
Chromatography using silica preparative TLC plates WO 03/004027 PCT/US02/21063 153 of NH 3 (2.0 M in methanol) in CHC1 3 gave the desired product (5.20 mg, 39.7 yield) as a thick oil: 1H NMR (CDC1 3 5 7.70-7.63 2H), 7.55 1H), 7.47-7.43 (m, 3H), 7.40-7.19 3H), 7.00-6.50 2H), 6.69 (dd, 1H, J=2.2, 8.8 Hz), 5.25 1H), 3.20 2H) 2.70 (m, 2H), 2.53 2H), 2.40-2.20 4H), 2.10-1.80 4H), 1.25 6H, J=7.1 Hz); ESMS m/e: 525.4 (M Example 56 2-METHYL-N-(3-{l-[(3R)-3-PHENOXY-3-PHENYLPROPYL]-4- PIPERIDINYL}PHENYL)PROPANAMIDE: A mixture of [(3S)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2methylpropanamide (9.53 mg, 0.0250 mmol), phenol (4.70 mg, 0.050 mmol), triphenylphosphine (9.80 mg, 0.0375 mmol) and diethyl azodicarboxylate (5.22 mg, 0.0300 mmol) in THF (1.0 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates of NH 3 (2.0 M in methanol) in CHC1 3 gave the desired product (4.1 mg, 36.0 yield) as a thick oil: 'H NMR (400 MHz, CDC1 3 5 7.45 1H), 7.40-7.15 10H), 6.97 1H, J=7.6 Hz), 6.88-6.82 2H), 5.26 1H), 3.18 2H), 2.75 2H), 2.53 2H), 2.40-2.10 4H), 2.10-1.80 4H), 1.25 6H, J=6.9 Hz); ESMS m/e: 457.4 (M H) Example 57 [(3R)-3-HYDROXY-3-PHENYLPROPYL] -4- PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE Method A Into a 25-mL RB-flask was added (R)-(+)-3-chloro-lphenyl-1-propanol (0.545 g, 3.19 mmol, 99%ee, Aldrich Chemical 2-methyl-N- WO 03/004027 PCT/US02/21063 154 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) at room temperature. After stirring at 100 oC for 3 hrs, the TLC showed the reaction was complete. The reaction mixture was poured into water (50 mL) and the aqueous layer was extracted with methylene chloride (3x20 mL). The combined organic extracts were washed with brine mL), dried over Na 2
SO
4 and concentrated under reduced pressure. The residue was purified by flash chromatography hexane: ethyl acetate with 1% isopropylamine) to afford the desired product (1.09 g, 94.3 yield) as light-yellow solid: H NMR (400 MHz, CDC1 3 6 8.10 1H), 7.46-7.35 6H), 7.27 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 2 2.50 2H), 2.30-2.10 6H), 1.80 (m, 2H), 1.25 6H, J=7.1 Hz); ESMS m/e: 381.2 (M H) The hydrochloric salt was prepared by addition of a slight excess of 1 N HC1 in ether (1.2 eq.) to a solution of the free base in dichloromethane. The solvent was removed under reduced pressure, the residue was washed with ether and dried under reduced pressure: Anal. Calc. for C 24
H
32
N
2 0 2 +HC1+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.
Method B Into a 25-mL RB-flask was added (R)-(+)-3-chloro-lphenyl-l-propanol (0.426 g, 2.50 mmol), 2-methyl-N-[3- (4-piperidinyl)phenyl]propanamide (0.565 g, 2.00 mmol), WO 03/004027 PCT/US02/21063 155 diisopropylethylamine (1.29 g, 10.0 mmol), dioxane (5.0 mL) and catalytic amount of tetrabutylammonium iodide at room temperature. After stirring at 90 OC for 72 hrs, the reaction mixture was poured into water (50 mL) and the aqueous layer was extracted with methylene chloride (3x20 mL). The combined organic extracts were washed with brine mL), dried over Na 2
SO
4 and concentrated under reduced pressure. The residue was purified by preparative TLC plates (1:5:100=isopropylamine:methanol:ethyl acetate) to afford the desired product (0.260 g, 34.2 yield) as light-yellow solid.
Example 58 [(3S)-3-(4-CYANO-PHEONXY)-3-PHENYLPROPYL]-4- PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE: 3-(4-cyanophenoxy)-3-phenylpropyl]-4piperidinyl}phenyl)-2-methylpropanamide A mixture of N-(3-{l-[(3R)-3-hydroxy-3-phenylpropyl]-4piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 4-cyanophenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates of NH 3 (2.0 M in methanol) in CHC13] gave the desired product (4.70 mg, 71.3 yield) as a thick oil: -H NMR (400 MHz, CDC1 3 5 7.54 2H), 7.48 2H, J=8.4 Hz), 7.30-7.20 3H), 7.20 3H), 6.97 (apparent 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 2H), 2.61 2H) 2.53 (apparent sept, partially hidden, 2H, J=7.6 Hz), 2.30-2.10 6H), 1.82 WO 03/004027 PCT/US02/21063 156 2H), 1.25 6H, J=6.8 Hz); ESMS m/e: 482.2 (M H) Example 59 N-(3-{1-[(3S)-3-(4-FLUOROPHENOXY)-3-PHENYLPROPYL]-4- PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE: A mixture of N- [(3R)-3-hydroxy-3-phenylpropyl]-4piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 4-fluorophenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates of NH 3 (2.0 M in methanol) in CHCi 3 gave the desired product (4.20 mg, 64.7% yield) as a thick oil: 1H NMR (400 MHz, CDC1 3 8 7.40 2H), 7.30-7.20 5H), 7.20 3H), 6.97 (apparent d, 1H, J=7.7 Hz), 6.87 1H), 6.76 1H), 5.26 (apparent dd, 1H, J=4.0, 8.1 Hz), 3.09 2H), 2.66 2H), 2.51 2H) 2.3-2.1 6H) 1.82 2H) 1.25 6H, overlapped); ESMS m/e: 475.2 (M Example N-(3-{1-[(3S)-3-(4-BROMOPHENOXY)-3-PHENYLPROPYL]-4- PIPERIDINYL)PHENYL)-2-METHYLPROPANAMIDE: A mixture of N- (3-{l-[(3R)-3-hydroxy-3-phenylpropyl]-4piperidinyl)phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 4-bromophenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates of NH 3 (2.0 M in methanol) in CHC13] the desired product (0.70 mg, 9.6% yield) as a thick oil: 1H NMR (400 MHz, CDC13) 6 8.06 1H), 7.48 WO 03/004027 WO 0/00027PCT/UJS02/21063 157 m, 2H), 7.30-7.20 CM, 5H), 7.20 3H), 6.97 (apparent d, 1H, J=8.5 Hz), 6.73 (apparent d, 2H, Hz) S. 22 (apparent dd, 1H1, J=4-9, 7. 8 Hz) 3. 15 (m, 2H)f, 2-65 (m.
7 2H), 2.51 (apparent sept, partially hidden, 2H, J=7. 6 Hz) 2.3 0 10 (in, 6H) 1. 82 2H), 1.25 6H, J=6.8 Hz); ESMS m/e: 535.1 (M Example 61.
N- (3-fl- (3-METHOXYPHENOXY) -3-PHENYLPROPYLJ -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: A mixture of N- -3-hydroxy--3-phenylpropyl) -4piperidinyllphenyl) -2-methylpropanainide (5.20 mg, 0.0137 mmol), 3-methoxyphenol (100 mg), triphenyiphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mig, 0.0426 mmcl) in THF (0.50 niL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.S-6 of NH 3 (2.0 M in methanol) in CHC1 3 1 gave the desired product (3.1 mig, 46.6 yield) as a thick oil: 1 LH NMR (400 MHz, CDCl 3 6 7.47 1K, J=6.7 Hz), 7.42 Cs, 1K), 7.3-7.20 31K), 7.20 (in, 3H), 7.07 1H, J=8.4 Hz), 6.97 (apparent d, 1H, J=6.7 Hz), 6.40 (mn, 3H), 5.27 (apparent ad, 1K, J=S. 3, 8. 0 Hz), 3. 74 Cs, 3H), 3. 38 Cm, 2. 93 Cm, 2H) 2. 61 Cs, 1H), 2.53 (apparent sept, partially hidden, 11-, J=6.5 Hz), 2.30-2.10 Cm, 6H), 1.82 (mn, 2H), 1.25 Cd, 6K, J=6.9 Hz); ESMS m/e: 487.3 CM Example 62 [(3S)-3-(4-CYANO-2-METHOXYPHENOXY)-3- PHEN-YLPROPYL] -4-PIPERIDINYL)PHENYL) -2-ZMETHYLPROPANAMIDE: A mixture of N- C3-{l- EC3R) -3-hydroxy-3-phenylpropyll -4piperidinyl~phenyl) -2-methylpropanamide (5.20 mng, 0.0137 mml), 2-methoxy-4-cyanophenol (100 zig), WO 03/004027 WO 0/00027PCT/UJS02/21063 158 triphenyiphosPhine (30.0 mg/ 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0. 0426 mmcl) in THF (0.50 mL) was stirred at roam temperature for 3 days.
Chromatography using silica preparative TLJC plates of NH 3 0 M in methanol) in CHC1 3 1 gave the desired product (5.50 mg, 76.5 yield) as a thick oil: 'H NMR (400 MHz, CDCl,) 8 7.51 Cs, 1H) 7.38 Cs, lH) 7.37 (d, 2H, J=2.4 Hz), 7.20 4H1), 7.10 1H, J=2.4 Hz), 7.08 Cs, 1H), 6.99 (apparent d, 1H, J=8.3 Hz) 6.76 (apparent d, lH, J=8.3 Hz) 5.43 (apparent dd, lH, J=S. 1, 8. 0 Hz) 3. 91 Cs, 3H) 3.34 Cm, 2H) 2.63 (in, 2H), 2.63 Cs, 111), 2.53 (apparent sept, partially hidden, lH; J=7.7 Hz) 2.30-2. 10 Cm, 6H1) 1. 82 Cm, 21-1) 1.28 Cd, 6H, J=6.8 Hz); ESMS m/e: 512.2 (M Example 63 N- C3-{1-[E(3S) (5-ACETYL-2-METOXYPHENOXY) -3- PHENYLPROPYL] -4 -PIPERID)INYL}PH.ENYL) -2 -METHYLPROPANAMIDE: A mixture of N- [C3R) -3-hydro~xy-3-phenylpropyl] -4piperidinyllphenyl) -2-methylpropanamide (5.20 mng, 0.0137 inmol), 2-methoxy-5-acetylphenol (100 mg), triphenylphosphine (30.0 mg, 0.115 inmol) and diethyl azodicarboxylate (7.42 mng, 0.0426 mmcl) in TH8' (0.50 mL) was stirred at room temperature f or 3 days.
Chromatography using silica preparative TLJC plates of NH 3 0 M in methanol) in CHC1 3 1 gave the desired product (1.60 mg. 22.2 yield) as a thick oil: 1H NMR (400 MHz, CDCl 3 8 7.52 211, J=2.4 7.3-7'.2 Cm, 5H1), 7.20 Cm, 311), 6.97 (apparent d, 1H, J=6.7 Hz), 6.69 (apparent d, 111, J=8.0 Hz), 5.47 (apparent dd, 1lH, J=4.3, 7.8 Hz), 3.95 3H1), 3.38 (mn, 211), 2.93 (in, 211), 2.61 111), 2.53 (apparent sept, partially hidden, 1H1, J=7.6 Hz), 2.50 Cs, 3H), 2.30-2.10 6H)-, WO 03/004027 PCT/US02/21063 159 1.82 2H), 1.25 6H, J=6.8 Hz); ESMS m/e: 529.6 (M H) Example 64 N-(3-{1-[(3R)-3-(2-ACETYLPHENOXY)-3-PHENYLPROPYL]-4- PIPERIDINYL)PHENYL)-2-METHYLPROPANAMIDE: A mixture of N- (3-{1-[(3S)-3-hydroxy-3-phenylpropyl]-4piperidinyl}phenyl)-2-methylpropanamide (5.2 mg, 0.0137 mmol), 2-acetylphenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates of NH 3 (2.0 M in methanol) in CHC1 3 gave the desired product (1.70 mg, 24.9 yield) as a thick oil: 1 H NMR (400 MHz, CDC13) 5 7.65 (m, 1H), 7.55 1H), 7.30-7.20 5H), 7.20 3H), 6.97 2H), 6.76 (apparent d, 1H), 5.49 (apparent dd, 1H, J=4.3, 8.0 Hz), 3.38 2H), 2.93 2H), 2.71 (s, 3H), 2.60 1H), 2.53 (apparent sept, partially hidden, 1H, J=7.6 Hz), 2.30-2.10 6H), 1.82 2H), 1.25 6H, J=6.9 Hz); ESMS m/e: 498.8 (M Example (3R)-3-[2-FLUORO-5-(TRIFLUOROMETHYL)PHENOXY]-3- PHENYLPROPYL}-4-PIPERIDINYL)PHENYL]--2-METHYLPROPANAMIDE; A mixture of N-(3-{l-[(3S)-3-hydroxy-3-phenylpropyl]-4piperidinyl}phenyl) -2-methylpropanamide (5.20 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) in THF (0.50 mL) was stirred at room temperature for 3 days.
Chromatography using silica preparative TLC plates of NH3 (2.0 M in methanol) in CHC13] gave the desired WO 03/004027 WO 0/00027PCT/UJS02/21063 160 product (2.50 mg, 33.7 yield) as a thick oil: IH NMR (40 0 MHz, CDCl 3 5 8. 07 1H) 7. 67 Cm, 1H1), 7. 54 Cm, 1H1), 7.45 Cm, 211), 7.30-7.10 Cm, 6H) 7.14 1H1, J=7.4 Hz), 6.97 (apparent d, 1H1, J=7.7 Hz), 5.37 (apparent dd, 1H, J=S. 0, 8. 5 Hz) 3.4 Cm, 211), 2. 8 (in, 2H), 2.6 Cs, lH), 2.53 (apparent sept, partially hidden, 1H1, JT=7.4 Hz), 2.30-2.10 Cm, 6H), 1.80 2H), 1.25 (d, 6H1, J=7.1 Hz, overlapped); ESMS mle: 542.6 543.54 CM Examnple 66 N- (3S) [2-FLUORO-5- (TRIFLUOROMETHYL) PHENOXYJ -3- PHENYLPROPYLI PIPERIDINYL) PHENYL] -2 -METHYLPROPANAMIDE: A mixture of N- C3-{l-[E 3R) -3-hydroxy-3-phenylpropylj -4piperidinyllphenyl) -2-methylpropanamide (5.20 mng, 0.0137 mmol) 2-fluoro-5-trifluoromethylphenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 minol) in THF (0.50 mL) was stirred at room temperature for 3 days.
Chromatography using silica preparative TLC plates of NH 3 0 M in methanol) in CHC1 3 (gave the desired product 00 mg, 40.4% yield) as a thick oil: IH NMR (4 00 MHz, CDC1 3 8 8.0 6 Cs, 11) 7. 67 211) 7. 55 Cm, 2H), 7.50-7.40 C,3H), 7.30-7.10 Cm, 3H1), 7.17 Cd, 1H1, J=8.9 Hz), 7.07 (apparent d 1H1, J=6.7 6.97 (apparent d, 1H, J=7.8 Hz), 5.37 (apparent dd, 1H, L7=4.2, 8.1 Hz) 3.37 Cm,, 2H) 2.93 (in, 211), 2.63 Cs, 1H) 2.50 (apparent sept, partially hidden, 1H, J=7.9 Hz) 2. 30 10 (in, 6H1), 1. 85 Cm, 211), 1.25 6H, J=6.9 Hz); ESMS m/e: 542.7 CM Excample 67 WO 03/004027 WO 0/00027PCT/UJS02/21063 161 DIFLUOROPHENOXY)-3- PHENYLPROPYL] -4-PIPERIDIN1YL)PHENYL) -2 -METHYLPROPANAMIDE: A mixture of N- -3-hydroxy-3-phelylpropyl] -4piperidinyllphenyl) -2-methyipropanamide (5.20 mug, 0.0137 mmol), 2,5-difluorophelol (100 mg), triphenyiphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in TH-F (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates of NH 3 (2.0 M in methanol) in CHC1 3 1 gave the desired product (2.70 mg, 40.1 yield) as a thick oil: 1H NMR (400 MHz, CDC1,) 6 7.46. Cs, 111), 7.40-7.30 (in, 4H1), 7.20 (mn, 2H), 7.17 1H1), 6.97 2H) 6.58 (in, lH) 6.51 Cm, 1H1), 5.27 (apparent dd, 1H, J=5.1, 8.2 Hz) 3.13 (apparent d, J=9.7 Hz, -2H) 2.64 2H), 2.51 (in, 2H1), 2.34 (apparent sept, partially hidden, J=7.1 Hz, 1H), 2.17 (in, 3H), 1.90-1.80 Cm, 4H), 1.25 6H1, J=7.1 Hz); ESMS m/le: 493.1 (M Example 68.
N- [C3R) (3-CHLOROPHENOXY) -3-PHENYLPROPYLJ -4- PIPERIDINYL)PHENYL)-2-METHYLPROPANAMIDE: A mixture of N- -3-hydroxy-3-phenylpropyl) -4pip eri dinyl Iphenyl) 2-me thylpropanamide (5.20 mng, 0.0137 mmcl), 3-chioropheno. (100 mg), triphenyiphosphine (30.0 mg, 0.115 inmol) and diethyl azodicarboxylate (7.42 mng, 0.0426 tumol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using. silica preparative TLC plates [2.5'1 of N- 3 (2.0 M in methanol) in CHC1 3 gave the desired product (2.4 mng, 35.8% yield) as a thick oil: '11 NMR (400 MHz, CDC1 3 5 7.30 (in, 2H) 7.30-7.20 (in, 311), 7.20 Cm, 3H), 6.90 (apparent d, 1H, J=7.7 Hz), 6.71 (apparent d, 1H, J=2.9 Hz), 6.69 WO 03/004027 WO 0/00027PCT/UJS02/21063 162 (apparent t, 1H, j=2.9 Hz), 6.67 (apparent t, 1H, J=2.9 Hz), 6.65 (apparent d, 1H, J=2.9 Hz), 5.09 (apparent dd, 1H, J=4.8, 8.1 Hz), 3.18 2H), 2.73 (in, 2H) 2.50 (apparent sept, partially hidden, 2H, J=7.1 Hz) 2.3 10 Cm, 6H) 1. 89 (in, 2H) 1. 25 6H, overlapped); ESMS m/e: 491.1 (M Example 69 (16) (ISOBUTYRYLAMINO)PEYL]-1-PIPERIDI:NYL}-1- PHENYLPROPYL 1-NAPHTHOATE: Into a 25-mL RB-flask was added N- -3-hydroxy-3-phenylpropyl) -4p iperi dinyl )phenyl) 2-met hyipropanami de (5.20 mg, 0.0137 minol), 1-naphthalenecarbonyl chloride (100 mg), diisopropylethylamine (0.30 mL) in THF (0.50 mL) at room temperature. After stirring for 16 hrs at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified using preparative TLC plates of NH 3 (2.0 M in methanol) in CHC1 3 1 gave the desired product (4.70 mng, 71.3 yield) as a thick oil: 'R NMR (400 MHz, CDC1 3 6 8.90 Cd, 1H, J=B.'9 Hz) 8.28 (apparent dd, 1H, 7.2 -Hz) 8.03 Cd, 1H, J=8.7 Hz), 7.88 (din, 2H, J=8.7 Hz), 7.60- 7.48 Cm, 7H1), 7.40-7.32 Cm, 3H), 7.25 Cm, 1H1), 6.90 (apparent d, 1H, J=s7.4 Hz), 6.18 (apparent dd, 1H1, J=5.7, 7.8 Hz) 3.42 Cm, 2H1), 2.84 2H) 2.53 Cm, 2H) ,2.44 (apparent sept, partially hidden, 4H1, Hz), 2.30-2.10 2H) 1.82 Cm, 2H) 1.25 6H, J=6.8 Hz); ESMS mle: 535.6 (M Example N- (3-ACETYLPIENOXY) -3-PHENYLPROPYL] -4- PIPERIDINYLPHENYL)-2-METYLPROPANAMIDE: A mixture of N- -3-hydroxy-3-phenylpropyll -4- WO 03/004027 WO 0/00027PCT/UJS02/21063 163 piperidinyl~phenyl) methylpropanamide (5.20 mg, 0.0137 mmol), 2-acetyiphenol (100 mg), triphenyiphosphine (30.0 mg, 0.115 mmol) and diethyl.
azodicarboxylate (7.42 mg, 0.0426 mmcl) in THF (0.50 mL) was stirred at room temperature for 3 days.
Chromatography using silica preparative TLC plates of NH 3 (2.0 M in methanol) in CHC1 3 1 gave ,the desired product (1.50 mg, 22.0% yield) as a thick oil: 1H NMR (400 MHz, CDCl 3 8 7.65 IH), 7.55 lH), 7.30-7.20 (in, 5H) 7. 20 (mn, 3 H) 6. 97 (in, 2H) 6. 76 (apparent d, lH), 5.49 (apparent dd, lH, J=4.3, 8.0 Hz), 3.3B (in, 2H), 2.93 (mn, 2H), 2.75 3H), 2.53 (apparent sept, partially hidden, 214, J=7.6 Hz 2.30-2.10 (mn, 6H), 1.92 (in, 2H) 1.25 6H4, J='6.9 Hz); ESMS m/e: 498.81 499.6 (M Exam~ple 71 N- (2-FLUOROPHENOXY) -3-PHENYLPROPYLJ -4- PIPERIDINYL)PHENYL)-2-METHYLPROPANAMIDE: A mixture of N- -3-hydroxy-3-phenylpropyl) -4pip eri dinyl )phenyl) 2 ethylpropanami de (5.20 my, 0.0137 mmol), 2-f luorophenol (100 mg), triphenyiphosphine (30.0 mng, 0.115 mmcl) and diethyl azodicarboxylate (7.42 my, 0.0426 minol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates of NH 3 (2.0 M in methanol) in CHC1 3 1 gave the desired product (3.5 mg, 53.9% yield) as a thick oil: 1H NMR (400 MHz, CDCl 3 68 8.07 1H) 7.65 (in, 1H), 7.41 1H), 7.40-7.10 (mn, 514), 7.05 (in, 2H4), 6.97 (apparent d, 1H4, J=8.7 Hz), 6.86 (in, 2H4), 6.79 (apparent dt, 114, J=2.4, 7.9 Hz), 5.31 (apparent dd, lH, 8.0 Hz), 3.39 (mn, 2H), 2.97 Cm, 2H4), 2.53 (apparent sept, partially hidden, 2H4, J=7.5 Hz), 2.3-2.1 WO 03/004027 WO 0/00027PCT/UJS02/21063 164 6H), 1.92 2H), 1.25 6H, J=6. 7 Hz); ESMS rn/c: 475.7 (M H+ Example 72 (4S) (ACETYIJMINO) PHENYL) -1- PI:PERIDINYL}PROPYL) (3,5-DIFLUOROPHENYL) -2-OXO-1,3- OXAZOLIDINE CARBOXAMIDE Method: Into a 20 ml vial was added aminopropyl) -4-piperidyllphenyl~acetamide (15 mg, 0.054 mmol), (4S)-4-(3,5-difluorophenyl)-2-oxo-oxazolidile-3carboxylic acid-4-nitro-phenyl ester (39.3 mg, 1.08 mmol, 2 eq) and dichiloromethane with 0.6% of methanol (3 ml) at room -temperature. After stirring at room temperature for 3 hrs, the reaction mixture was filtered, and purified by preparative silica TLC (19:1 chloroform methanol) to afford the desired product (18.3 mg, 68%6 yield); 'H NMR (400 MHz, CDCl 3 5 8.09 (br s, 1H), 7.40 1H, J=8.0 Hz), 7.36-7.28 (in, 2H), 7.24 1H, J=8.0 Hz), 6.99 1H, J=8.0 Hz), 6.86-6.82 (m, 2H), 5.41 (dd, 1H, J=4.1, 9. 0 Hz) 4.72 1H4, J=9. 0 Hz), 4.22 (dd, 1H, J=3.9, 9.1 Hz), 3.42-3.29 (in, 21H); 3.02 2H4 J=11.1 Hz), 2.52-2.38 (in, 3H), 2.16 3H4), 2.08-1.98 Cm, 2H4), 1.86-1.70 (mn, 6H4); ESMS in/c: 501.2 (M +i Anal. Calc. for C 2 gH 30
F
2
N
4 0 4 -i0.5H 2 0: C, 60.64; H, 6.18; N, 10.88. Found: C, 60.67; H, 5.79; N, 10.86.
Example 73 The synthetic method is the same as described for the synthesis of (4S)-.N-(3-{4-[3-(acetylamino)phenyl) -1piperidinyllpropyl) (3,5-difluorophenyl)-2-oxo-l,3oxazolidine-3-carboxamide.
WO 03/004027 PCTIUS02/21063 165 (4S) (ACETYLAMINO)PHENYL]-1- PIPERIDINYLIPROPYL)-2-OXO-4-(3,4,5-TRIFLUOROPHENYL)-1,3- OXAZOLIDINE-3-CARBOXAMIDE: 18.8 mg (67% yield); 'H NMR (400 MHz, CDCl 3 8 8.09 (br s, 1H), 7.41-7.20 311), 7.02-6.91 31), 5.37 (dd, 1H, J 3.8, 8.9 Hz), 4.71 1H, J=9 Hz), 4.21 (dd, 1H, J=4, 9.3 Hz), 3.43-3.27 21), 3.02 2H, J=11.0 Hz), 2.53-2.37 31), 2.16 31), 2.08-1.97 Cm, 2H), 1.85-1.69 6H); ESMS m/e: 519.2 CM Anal. Calc. for C 2 6
H
2 9
F
3
N
4 0 4 +0.5H 2 0: C, 59.20; H, 5.73; N, 10.62. Found: C, 59.40; H, 5.35; N, 10.65.
Example 74 The synthetic method is the same as described for the synthesis of C4S)-N-C3-{4- 3-Cacetylamino)phenyl)-1piperidinyllpropyl)-4-(3,5-difluorophenyl)-2-oxo-1,3oxazolidine-3-carboxamide.
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 C68% yield); 1H NMR C400 MHz, CDC1 3 8 8.18 Ct, 1H, J5.9 Hz), 7.41 11, J=8.8 Hz), 7.33 Cs, 1H), 7.27-7.14 21), 7.02-6.88 Cm, 3H), 5.04 Cs, 1H), 3.34 (qm, 2H, J=6.3 Hz), 3.02 (di, 21, J=10.9 Hz), 2.53-2.38 Cm, 31), 2.16 Cs, 3H), 2.07-1.96 Cm, 2H), 1.87-1.69 6H), 1.62 Cs, 31), 1.02 Cs, 3H); ESMS m/e: 529.3 (M Anal. CaIc. for C 28 H3 4
F
2
N
4 0 4 C, 63.62; H, 6.48; N, 10.60. Found: C, 63.15; H, 6.27; N; 10.48.
Example The synthetic method is the same as described for the synthesis of Cacetylamino)phenyl]-l- WO 03/004027 PCTUS02/21063 166 piperidinyllpropyl)-4- (3,5-difluorophenyl)-2oxo-1,3-oxazolidine-3-carboxamide.
(4S,5R)-N-(3-{4-[3-(ACETYLAMNO)P{ENYL-1- PIPERIDINYL}PROPYL)-4-(3,4-DIFLUOROPHENYL)-5-METHYL-2- OXO-1,3-OXAZOLIDINE-3-CARBOXAMIDE: 20.5 mg (74% yield); 'H NvR (400 MHz, CDC13) 8 8.14 1H, J=5.5 Hz), 7.40 1H, J=7.8 Hz), 7,37-6.89 Cm, 6H), 5.35 1H, Hz), 5.02-4.93 lH), 3.41-3.25 Cm, 2H), 3.02 2H, J=10.8 Hz), 2.53-2.37 Cm, 3H), 2.16 3H), 2.07 (m, 2H), 1.89-1.68 Cm, 61), 1.04 Cd, 31, J=6.4 Hz); ESMS m/e: 515.3 CM Anal. Calc. for C 27
H
32
F
2 NjO 4 +0.5H 2
O:
C, 61.94; H, 6.35; N, 10.70. Found: C, 61.90; H, 6.13; N, 10.64.
Example 76 The synthetic method is the same as described for the synthesis of (4S)-N-C3-{4-£3-Cacetylamino)phenyl]-lpiperidinyl~propyl)-4-(3,5-difluorophenyl)-2-oxo-1,3oxazolidine-3-carboxamide.
N-C3-{4-£3-(ACETYLAMINO)PHENYL-1-PIPERIDINYL}PROPYL)-4- (4-FLUOROBENZYL) -2 -OXO-1,3-OXAZOLIDINE-3-CARBOXAMIDE: 17.4 mg (65% yield); 11H NMR (400 MHz, CDC1 3 5 8.08 (t, 1H, J=5.6 Hz), 7.4 11, J=7.2 Hz), 7.34 Cs, 1H), 7.28-7.14 Cm, 31), 7.05-6.95 Cm, 3H), 4.69-4.60 Cm, 11), 4.26 Ct, 1H, J=8.8 Hz), 4.15 (dd, 1H, J=3.2, 9 Hz), 3.43 21, J=6.2 Hz), 3.3 (dm 1H, J=13.6 Hz), '3.04 Cdm, 2H, J=11 Hz), 2.87 Cdd, 11, J-9.3, 14.4 Hz), 2.53-2.42 (m, 31), 2.16 Cs, 31), 2.09-1.99 21), 1.87-1.65 Cm, 61); ESMS m/e: 497.3 CM Anal. Calc. for
C
2 7
H
33
FN
4 0 4 +0.5H 2 0: C, 64.14; H, 6.78; N, 11.08. Found: C, 64.26; H, 6.39; N, 11.12.
WO 03/004027 PCT/US02/21063 167 Example 77 2-METHYL-N-(3-{1-[(3R)-3-(2-NITROPHENOXY)-3- PHENYLPROPYL]-4-PIPERIDINYL}PHENYL)PROPANAMIDE:
A
mixture of N-(3-{1-[(3S)-3-hydroxy-3-phenylpropyl]-4piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 2-nitrophenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates of NH3 (2.0 M in methanol) in CHC13] gave the desired product (2.37 mg, 34.5% yield) as a thick oil: IH NMR (400 MHz, CDC13) 8 7.84 1H), 7.90 1H) 7.45 (m 1H) 7.30-7.20 5H), 7.20 (m, 2H), 6.98 2H), 6.89 (apparent d, 1H, J=7.7 Hz), 5.62 (apparent dd, 1H, J=4.1, 8.9 Hz), 3.10 2H), 2.60 (m, 2H), 2.53 2H), 2.30-2.10 6H), 1.90 2H), 1.25 6H, overlapped); ESMS m/e: 502.3 (M H) Example 78 N-(3-{1-[(3S)-3-([1,1'-BIPHENYL]-4-YLOXY)-3- PHENYLPROPYL] -4-PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE: A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 4-phenylphenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography -using silica preparative TLC plates of.NH 3 (2.0 M in methanol) in CHC1 3 gave the desired product (3.00 mg, 41.2% yield) as a thick oil: 'H NMR (400 MHz, CDC13) 8 8.06 1H), 7.48 2H), 7.40-7.30 8H), 7.30-7.25 4H), 6.97 (apparent d, 1H, J=7.6 Hz), 6.91 (apparent d, 2H, J=8.7 WO 03/004027 PCT/US02/21063 168 Hz), 5.34 (apparent dd, 1H, J=4.4, 8.0 Hz), 3.40 2H), 2.98 2H), 2.53 (apparent sept, partially hidden, 1H, J=8.1 Hz), 2.44 1H), 2.30-2.10 6H), 1.93 2H), 1.26 6H, J=6.9 Hz); ESMS m/e: 533.4 (M
H)
Example 79 2-METHYL-N-(3-{1-[(3R)-3 -(3-NITROPHENOXY)-3-
PHENYLPROPYL]-
4-PIPERIDINYL}PHENYL)PROPANAMIDE: A mixture of [(3S)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2methylpropanamide (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) in THF (0.50 mL) was stirred at room temperature for 3 days.
Chromatography using silica preparative TLC plates of NH 3 (2.0 M in methanol) in CHC1 3 gave the desired product (2.80 mg, 40.8 yield) as a thick oil: 1 H NMR (400 MHz, CDC1 3 6 7.76 (dm, 1H), 7.71 1H, J=1.8 Hz), 7.50-7.40 2H), 7.40-7.25 7H), 7.17 (apparent dd, 1H, J=2.4, 6.97 (apparent d, 1H, J=7.7 Hz), 5.45 (apparent dd, 1H, J=5.0, 8.1 Hz), 3.45 2H), 2.89 (m, 2H), 2.53 (apparent sept, partially hidden, 2H, J=8.3 Hz), 2.30-2.10 6H), 1.92 2H), 1.25 6H, J=6.8 Hz); ESMS m/e: 502.3 (M H) Example N-(3-{1-[(3S)-3-(2-ETHOXYPHENOXY)-3-PHENYLPROPYL]-4- PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE: A mixture of N- (3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 2-ethoxyphenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, WO 03/004027 WO 03/04027PCTIUS02/2 1063 169 0.0426 mmol) in THF (0.50 ruL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates of NH 3 (2.0 M in methanol) in CHC.
3 J gave the desired product (1.16 mug, 15.5% yield) as a thick oil: 'H NMR (400 MHz, CDCl 3 6 8.06 Cs, 1H), 7.52 1H), 7.40-7.33 Cm, 4H), 7.30-7.20 3H), 6.97 (apparent d, 1H, J= 7. 7 Hz) 6. 88 (in, 2H) 6. 68 (in, 2H), 5.21 Cm, 111), 4.11 2H, J=7.3 Hz), 3.37 (in, 2H), 2.71 2H), 2.53 (apparent sept, partially hidden, 2H, J=7.6 Hz), 2.30-2.10 Cm, 6H), 1.89 (in, 2H), 1.49 Ct, 3H, J=7.3 Hz), 1.25 6H, J=6.8_ Hz); ESMS rn/e: 501.4 CM Example 81.
2-METHYL-N- (3-tl-[(3S)-3-(1-NAPHTHYLOXY)-3- PHENYLPROPYL] -4-PIPERIDIINYL}PHENYL)PROPANAMIDE: A mixture of N- 3R) -3-hydroxy-3-phenylpropyl] -4piperidinyllphenyl) -2-methylpropanamide (5.20 mug, 0.0137 mmcl), 1-naphthol (100 mug), triphenyiphosphine (30.0 mg, 0.115 mmcl) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmci) in THF (0.50 inL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.50- of Nit 3 (2.0 M in methanol) in CHC1 3 gave the desired product (4.30 rug, 66.2% yield) as a thick oil: 1H NMR (400 MHz, CDC1 3 5 8.06 Cs, 11) 7. 72 Cd, 1H1, J= 8 .5 H z) 7. 59 1H1, J= 8. 5 H z) 7. 5 Cm, 2H), 7.45-7.30 GH), 7.25 3H1), 7.17 (apparent dd, 111, J=2.6, 9.0 Hz), 7.01 (apparent d, 1K, J=2.6 Hz), 6.97 (apparent d, lH, J=7.9 Hz), 5.46 (apparent dd, 1H1, J=4.5, 8.1 Hz), 3.12 Cm, 2H), 2.61 Cm, 211), 2.53 (apparent sept, partially hidden, 2H, J=7.9 Hz), 2.30- 2.10 6H1), 1.90 211), 1.25 6H1, J=7.3 Hz, overlapped); ESMS m/e: 507.2 CM +j WO 03/004027 PCT/US02/21063 170 Example 82 (1,3-DIOXO-l,3-DIHYDRO-2H-ISINDOL-2- YL)-3-PHENYLPRPYLI-4-PIPERIDINYLPHEYL)-2-
METHYLPROPANAMIDE
Step 1: 2-[(1S)-3-CHLORO-1-PHENYLPROPYLJ-1H-ISOINDOLE-1,3C2H)- DIONE: According to the general procedure descibed in Srebnik, Ramachandra, Brown, I.C. J. Org.
Chem. 1988, 53, 2916-2920, a mixture of phthalimide (0.147 g, 1.0 mmol), (R)-(+)-3-chloro-phenyl-1-propanol (0.171 g, 1.0 mmol), triphenyiphosphine (0.262 g, mmol) and diethyl azodicarboxylate (0.174 g, 1.0 mmol) in 5.0 mL of THF was stirred at room temperature for 24 h. The reaction mixture was concentrated in vacuo. The residue was washed with pentane (x3) and the combined pentane extracts were concentrated and chromatographed (silica with hexanes-EtOAc 8:1 as the eluent) to give the desired product (0.121 g, 50.2 as a yellow solid: 1 H NMR (400 MHz, CDCl 3 6 7.82 (apparent dd, 2H, J=2.9 Hz), 7.70 (apparent dd, 2H, J=2.9 Hz), 7.56 2H), 7.39-7.27 3H), *5.64 (apparent dd, 1H, J 7.0, 9.2 Hz), 3.57 2H), 3.05 1H), 2.82 (apparent sept, 1H, J=7.0 Hz); ESMS m/e: 300.13 Step 2: N-(3-{1-[(3S)-3-(1,3-DIOXO-1,3-DIEYDRO-2H-ISOINDOL-2- YL)-3-PHENYLPROPYL]-4-PIPERIDIYL}PHENYL)-2- METHYLPROPANAMIDE: A mixture of potassium carbonate WO 03/004027 PCT/US02/21063 171 (29.2 mg, 0.211 mmol), sodium iodide (47.5 mg, 0.317 mmol), 2-methyl-N-[3-(4piperidinyl)phenyl]propanamide (51.8 mg, 0.211 mmol) 2- [(1S)-3-chloro-l-phenylpropyl]-1H-isoindole-1,3(2H)dione (63.1 mg, 0.211 mmol) in DMF (5.0 mL) was stirred at 100 OC for 3 hrs, at which time TLC indicated that the reaction was complete. The reaction mixture was poured into water (50 mL) and the aqueous layer was extracted with methylene chloride (3x30 mL). The combined organic extracts were washed with brine (30 mL), dried over MgS04 and concentrated under reduced pressure. The crude product was purified by Prep-TLC plates of NH 3 M in methanol) in CHC13] to give the desired product (74.1 mg, 77.1 as a thick oil: 1 H NMR (400 MHz, CDC13) 5 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 4H), 7.21 1H, J=7.8 Hz), 7.09 1H), 6.81 (apparent d, 1H, J=7.8 Hz), 5.49 (apparent dd, 1H, 9.5 Hz), 2.98 1H, J=9.5 Hz), 2.87 2H), 2.50 (apparent sept, 1H, J=6.7 Hz), 2.40-2.35 4H), 1.94 2H), 1.70-1.50 4H), 1.25 6H, J=7.9 Hz); ESMS m/e: 510.37 (M+H) 4 Example 83 2-METHYL-N-(3-{1-[(3S)-3-(4-PHENOXYPHENOXY)-3- PHENYLPROPYL]-4-PIPERIDINYL}PHENYL)PROPANAMIDE STEP 1: (S)-3-CHLORO-1-PHENYLPROPYL]OXY}-(4- PHENOXY)BENZENE: A mixture of 4-phenoxyphenol (1.86 g, 10.0 mmol), (R)-(-)-3-chloro-phenyl-l-propanol (1.70 g, 10.0 mmol), triphenylphosphine (2.62 g, 10.0 mmol), WO 03/004027 PCT/US02/21063 172 diethyl azodicarboxylate (1.57 mL, 10.0 mmol) in mL of THF was stirred at room temperature for 24 h.
The reaction mixture was concentrated in vacuo. The residue was washed with pentane (x3) and the combined pentane extracts were concentrated and chromatographed (silica with hexanes-EtOAc 97:3 as the eluent) to give the desired product as a thick oil which solidified on standing (2.51 g, 75.7 'H NMR (400 MHz, CDC13) 6 7.4- 7.23 7H), 7.03 (apparent t, 1H, J=7.3 Hz), 6.91 (apparent dm, 2H, J=7.8 Hz), 6.93 (apparent q, 4H, J=7.8 Hz), 5.31 (apparent dd, 1H, J=4.5, 8.6 Hz), 3.82 (m, 1H), 3.62 (apparent quintet, 1H, J=5.6 Hz), 2.47 (m, 1H), 2.20 1H).
Step 2: 2-METHYL-N-(3-{l- [(3S)-3-(4-PHENOXYPHENOXY)-3- PHENYLPROPYL]-4-PIPERIDINYL}PHENYL)PROPANAMIDE: A mixture of 2-methyl-N-[3-(4piperidinyl)phenyllpropanamide (65.5 mg, 0.266 mmol), 4- {[(iS)-3-chloro-l-phenylpropyl]oxy}-(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) in DMF (1.0 mL) at 100 OC for 3 hours. The reaction mixture was poured into water (50 mL) and the aqueous layer was extracted with methylene chloride (3x30 mL). The combined organic extracts were washed with brine mL), dried over MgSO 4 and concentrated under reduced pressure. The crude product was purified by Prep-TLC plates of NH 3 (2.0 M in methanol) in CHC13] to give the desired product (0.109 g, 74.6 as a thick oil: IH NMR (400 MHz, CDC13) 6 7.48 1H), 7.40-7.30 4H), 7.20-7.10 6 7.09 1H), 6.99 (apparent d, 1H, WO 03/004027 PCT/US02/21063 173 J=7.8 Hz), 6.98 (apparent t, 1H, J=7.8 Hz), 6.93 (apparent d, 2H, J=8.4 Hz), 6.84 2H), 5.20 (apparent dd, 1H, J=4.4, 8.5 Hz), 3.03 2H), 2.51 4H), 2.24 (apparent sept, 1H, J=7.8 Hz), 2.20-2.10 3H), 1.90 4H), 1.25 6H, J=7.9 Hz); ESMS m/e: 549.41 Anal. Calc. for C 3 6
H
40
N
2 0 3 C, 78.80; H, 7.35; N, 5.11.
Found: C, 78.58; H, 7.48; N, 5.09.
Example 84 N-(4-{1-[(3R)-3-(3,4-DIMETHOXYPHENOXY)-3-PHENYLPROPYL]- 4-PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE Step 1: 1-[(3R)-3-(3,4-DIMETHOXYPHENOXY)-3-PHENYLPROPYL]-4-(4- NITROPHENYL)-1,2,3,6-TETRARYDROPYRIDINE: A mixture of potassium carbonate (24.0 mg, 0.174 mmol), sodium iodide (39.0 mg, 0.260 mmol), 4-(4-nitrophenyl)-l,2,3,6tetrahydropyridine (35.4 mg, 0.174 mmol) and chloro-l-phenylpropyl]oxy}-1,2-dimethoxybenzene (53.4 mg, 0.174 mmol) in DMF (0.5 mL) was stirred at 100 °C for 3 hrs, at which time TLC indicated that the reaction was complete. The reaction mixture was poured into water mL) and the aqueous layer was extracted with methylene chloride (3x30 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 Prep-TLC plates [l:l=hexane:ethyl acetate with 1% NH3] afforded the product (63.1 mg, 76.6 as a yellow oil. The product was used in next reaction without further purification.
Step 2: WO 03/004027 PCT/US02/21063 174 4-{1-[(3R)-3-(3,4-DIMETHOXYPHENOXY)-3-PHENYLPROPYL]-4- PIPERIDINYL}ANILINE: A 25-mL RB flask, equipped with a hydrogen-filled balloon, was charged with (3,4-dimethoxyphenoxy)-3-phenylpropyl]-4-(4nitrophenyl)-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) at room temperature.
After 1 hr the reaction mixture was filtered through a plug of Celite 545 and concentrated under reduced pressure. The crude product (54.1 mg, 89.4%) was used in next reaction without further purification.
STEP 3: N-(4-{1-[(3R)-3-(3,4-DIMETHOXYPHENOXY)-3-PHENYLPROPYL]- 4-PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE: A mixture of 4-{l-[(3R)-3-(3,4-dimethoxyphenoxy)-3-phenylpropyl]-4piperidinyl}aniline (5.31 mg, 0.0119 mmol), isobutyryl chloride (2.08 mg, 0.019 mmol), N,Ndiisopropylethylamine (8.40 mg, 0.0650 mmol) in methylene chloride (1.0 mL) was stirred at room temperature for 24 hours. The reaction mixture was concentrated and chromatographed using a preparative TLC plate of NH 3 (2.0 M in methanol) in CHC1 3 to give the product (3.5 mg, 56.5 as a thick oil: 1H NMR (400 MHz, CDC1 3 6 7.38 1H, J=8.6 Hz), 7.30-7.20 4H), 7.20(m, 1H), 7.11 2H, J=8.6 Hz), 7.04 1H), 6.57 1H, J=8.3 Hz), 6.44 1H, J=2.6 Hz), 6.22 (dd, 1H, J=2.6, 8.3 Hz), 5.09 (apparent dd, 1H, J=4.4, 8.1 Hz), 3.72 3H), 3.70 3H), 3.08 2H), 2.57 2 H), 2.43 (apparent sept, partially hidden, 2H, J=6.8 Hz), WO 03/004027 PCT/US02/21063 175 2.30-2.10 6H), 1.80 2H), 1.25 6H, J=7.9 Hz); ESMS m/e: 517.3 (M+H) Example N-(3-{1-[(3S)-3-(3-ACETYLPHENOXY)-3-PHENYLPROPYL]-4- PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE: Into a RB-flask was added triphenylphosphine (9.80 mg, 0.0375 mmol), diethyl azodicarboxylate (5.22 mg, 0.0300 mmol), N-(3-{l-[(3R)-3-hydroxy-3-phenylpropyl]-4piperidinyl}phenyl)-2-methylpropanamide (9.53 mg, 0.0250 mmol), 3-hydroxyacetophenone (100 mg) and THF (1.0 mL) at room temperature. The reaction mixture was stirred at room temperature overnight (16 hrs). The solvent was removed under reduced pressure and the residue was purified by preparative TLC plates of NH 3 (2.0 M in methanol) in CHC13] to afford the desired product (2.73 mg, 39.9%) as a thick oil: 1H NMR (CDC13) 8 7.70-7.64 (m, 2H), 7.54 2H), 7.49-7.44 6H), 7.25 1H), 7.05 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 2H), 2.67 (m, 2H), 2.52 3H), 2.53 (apparent sept, partially hidden, 2H, J=7.6 Hz), 2.30-2.10 6H), 1.89 2H), 1.25 6H, J=6.9 Hz); ESMS m/e: 499.4 (M H) WO 03/004027 WO 03/04027PCT/US02/21063 176 Scheme A. Synthesis of tert-Butyl 4-(3-aminophenyl)-1-piperidinecarboxylate 0 C N
SNH
2 0 'S
F
a
N
NH
b a. n-BuUi, diisopropylamine, THF, PhN(Tf) 2 -78 00 to room temperature, 81 b. 3-aminophenylboronic acid hemisuifate, LiCI, tetrakis-triphenyiphosphine -palladium Na 2
CO
3
DME-H
2 0, reflux, 81% c. 10% PdIC, ethanol, H 2 room temperature, balloon method, 84% WO 03/004027 WO 03/04027PCT/US02/21063 177 Scheme B31. A General Synthesis of the MCH Antagonists OTf (Ph 3
P)
4 Pd(0), Na 2 00 3 LiCI, o-NI-I or p-NO 2
H
2 0, dimethoxyethane, reflux N- ,_NH 2 or N I or p-N0 2 BO0CO or N N
B(OH)
2
B(OH)
2 BOG BOG 2 3
SNH-
2 1. RX(=O)CI H R 2. H 2 Pd/C, EtOH
X
3. MCI in dioxane
R
2 -halide, cat. BU 4 Ni, dioxane, reflux 4 N or R 2 -halide, cat. 18-crown-B, toluene, reflux N BOG or R 2 -halide, cat. Nal, Na 2 00a, DMF, 10000 R SNH 2 1. H 2 Pd/C, EtOH
H~R
2. MCI in dioxane X 1 0 3. RZ-halidle, cat. BU 4 NI, dioxane, reflux 2 or R 2 -halide, cat. 18-crown-B, toluene, reflux4 N or R 2 -halide, cat. Nal, Na 2
CO
3 DMF, 100 "CN BOO 4. RIX(=0)C1
R
2 Scheme B2. A General Synthesis of the MOM Antagonists 1. MCI !In dioxane H orpN 2 2. R 2 -halide, cat. BuAN, dioxane, reflux or R 2 -halide, cat. N1l Na 2 00 3 n, tolen, 100u 00 3 or R 2 -halide, cat. 1l 8-2rown-, toluen, N 3. H 2 Pd/C, EtOH- N BOC 4. RX(=O)CI R, 1. H 2 Pd/C, EtCH 0 H rn,- or p-NO 2
R,
3. Rz-halide, cat. BU 4 NI, dioxane, reflu 0 3 or R 2 -halide, cat. 18-crown-B, toluene, reflux4 N or R 2 -halide, cat. Nal, Na 2 00 3 OM F, 10000C N BOG 4. RX(=O)CI R 2 X C, halide CI, Br WO 03/004027 WO 03/04027PCT/US02/21063
NNH
2 N2
N
BOO;
178 Scheme CI. Specific Examples of thie Syntheses of the MCH Antagonists 1. isobutyryl chloride, dichloromethane 2. H 2 10% Pd/C, EtOH 3. HOI in dioxane 4. R 2 -CI (or Br), cat. BU 4 NI, dioxane, reflux or R 2 -01 (or Br), cat. Nal, Na 2
CO
3 DMVF, >90 'CN
OH
N O" diethylazodicarboxylate THF. PPh 3 -0 0 -0H -0
NH
6 0 Scheme C2. Specific Examples of the Syntheses of the MCH Antagonists dilsopropylethylamine
THF,
0
NH
retention of the absolute stereochemistry HO I Cl commercially available HO 1 cl 1. diethylazodicarboxylate THF, 4-phenyiphenol, PPh 3 2. DMVF, heat, 1(3003, KI
HND-Q
HN0 1. diethylazodicarboxylate THF, phthalimide, PPh 3 2. DMF, heat, K(2C03, 1(1
HND-Q
0 inversion of sterochemistry WO 03/004027 WO 03/04027PCT/US02/21063 Scheme D1 Specific Examples of the Syntheses of the MCH Antagonists 0
NH
2 2
N
BOC
SNH
2 2
N
BOO
1. H 2 10% Pd/C, EtCH 2. HOI in dioxane 3. cat. 1 B-crown-6, toluene, reflux, 0 C 4. isobutyryl chloride, dichioromethane 1. isobutyryl chloride, dichioromethane 2. H 2 Pd/C, EtCH 3. HCI in dioxane 4. Cat- BUAN, dioxane, reflux, 0 _/-Br 0 Scheme D2. Specific Examples of the Syntheses of the MCH Antagonists N0 2
N
BCc 1. HOI in dioxane 2. cat. Nal, Na 2 C00 3
DMF,
3. H 2 10% PdIC, EtCH 4. isobutyryl chloride, dichloromethane 0 000 100 OC' 00
H'-
WO 03/004027 WO 03/04027PCT/US02/21063 180 Scheme E: General Synthesis of the MCH Antagonists 0+ Rj I C 0+ 2
N-X
R,
4
NH,
3 N-X
R,
0 NF1 0 N
NH
2
R
2 00CI b
SR
2 S0 2 C[ 00 6
HN-X-R
2 a. dioxane, diisopropylethylamine, BU 4 NI1, reflux or DMF, Ki, Na 2 C0 3 90-100 0
C
or toluene, 11000C, 18-crown-6 b. diisopyropylethylamine. dichioromethane X C R, Aromatic, substituted aromatic or heterocyclic
R
2 aliphatic oraromatic WO 03/004027 WO 03/04027PCT/US02/21063 181 Scheme F. General Synthesis of the MCH Antagonists H-ND- 0
,N-
If R (CH 2 ),CHOH-Ar, then, R-halide; dilsopropylethylamine or Na 2 00 3
BU
4 NI, or KI; dioxane, toluene, or DMVF; heat R-ND- 0 50-90% or the other enantiomer DEAD, Ph 3
P,
THF, R-PhOH inversion of the absolute stereochemistry acid chloride, Hunig's base retention of the absolute stereochemistry
NN
S/ 50-70% 0~N
R
0=
NO-
NH
0" or the other enantiomer WO 03/004027 WO 03/04027PCT/US02/21063 182 Scheme G. General Synthesis of the MCH Antagonists HO I c 0 0 CI or- DEAD, Ph 3
P,
THF, R-phOH or phthalimide H-Na
N-X
R
diiso propylethyla mine or Na 2
CO
3
BU
4 NI, or KI; dioxane, toluene, or DMF; heat ?N0 N 0
R-
WO 03/004027 WO 0/00027PCT/UJS02/21063 Scheme H: Synthesis of Oxazolidinones a ArCHO Ar NC 1 NH- 2 b Ar MeO 2 C NH 2 0 Ar HO0,,
NH
2 d Ar 0 0 O' "NH Ar f 0
OINH
Ar O INH Ar 0 0 NH 0 0 N0 2 0 I N 0 '-Ar a. NH 3 then TMS-CN; b. HCI in MeOH (room temperature to reflux); c. LAH, THF, reflux; d. (200)20, chloroform; e. NaH, THE; f. Chiralcel 00 column g. NaH, p-nitrophenyl ohloroforrnate, THE; h. an amine such as N-{3-1-(3-aminopropyl)-4-piperidinyllphenyl~acetamide Ar 3,4-ditluorophenyl, 3,5-difluorophenyl or 3,4,5-tdfluorophenyl WO 03/004027 WO 03/04027PCT/US02/21063 184 Scheme 1: Synthesis of gem-Dialkyl Substituted Oxazolidinones a IMe -i-0ic 0-'N-'OPhNO 2 d
IF
F
a. methyl magnesium bromide, THF; b. N,N-carbonyldiimidazole, DCM; c. NaH, THE, p-nitrophenyl chloroform ate; d. an amine such as -(3-aminopropy)-4-piperidinyI~phenyllacetamide Schemne J- Synthesis and Chiral Resolution of Oxazolidinones N.j NN Ph a,b F Ph
IF
c,d A NH e
QF
F
0 ANH
F
IF
f~ 0 N AOPh-NO, g~
IF
IF
a(a) t-BuLl, THF, RCH-O CH30NH 2 .HCI, MeOH, 50-68% over 2 steps Boc 2 O, CHCI 3 >90% (d) NaH,THF, 76-92% separate diastereomers by column chromatography and separate enantlomers by chiral phase HPLC, 10-16% (f)n-BuLi, THF, 4-nitrophenylchlorcformate. THF, an amrine such as -(3-aminopropyl)-4-piperidinylphenyllacetamide WO 03/004027 WO 03/04027PCT/US02/21063 Scheme K: Synthesis Oxazolidinones from Amino Acids Ar-
H
2
N-)COOH
a Ar
H
2 N) 0H b, c 0) NH Ar d Ar h
F
a. LAH, THF; b. (BOC) 2 0, CHCI 3 c. NaH, THF; d. p-nitrophenylchloroformate, NaH, THF; h. an amnine such as N-{3-[l-(3-am-inopropyl)-4-piperidinyi]phenyilacetamide Ar aromatic such as 4-fluorophenyl or 3,4-difluorophenyl WO 03/004027 WO 03/04027PCT/US02/21063 186 Scheme IL: Determination of the Absolute Stereochemistry of the Di-Substituted Oxazolidinones Using Lactic Acid Derivatives 0 110
OH
0
Y-N
OHJ
0 d e 3.F
OHF
F
9
NH
0
F
NH
0
F
&F
K0NH 0 a. pyrrolidine, methanol, heat; b. t-butyldimethylsilyl chloride; c. LAH, ether, reflux d. (BOC) 2 0, chloroform; e. NaH, THF; h. silica gel chromatography For more details, See: Lagu, Wetzel, J. Forray, Patane, M. Bock, M. G.
"Determination of the Relative and Absolute Stereochemistry of a Potent aIA Selective Adrenoceptor Antagonist" Bioorg. Med. Chem. Lett. 2000, 10, 2705.
WO 03/004027 WO 03/04027PCT/US02/21063 K H4 R,
R
Scheme M +3 &i-2 Example (Z H&
R
3 R2 N~i ZRCI 2 HOAc, NVH 75 C 0 hrs NO0 -n-I n12, RI=H, R2=Ph, R3=H RI=H, R2-H, n=1, Rl=H, R2rrPh, R3=H n=4, R1=H. R2=H. R3=5-0Me WO 03/004027 WO 03/04027PCT/US02/21063 188 Scheme N
H
dioxonetHOAO H)I+ rt,
H
Example
H
dioxane/HOAc
N
H
R1=6-CI, R2=H R1zH. R2=4-tolyl WO 03/004027 WO 03/04027PCT/US02/21063 189 Scheme P
-~N
H
1. Nail, DMF Ri ~KC0 3 Nal, 3 I BrC2(C"2.CH!C NDMF, 90 0 C, 12 h
CH
2
(CH
2
CH
2
CI
3:
NH
Example
N
H
1. Nail, DMF 2. BrCH 2
(CH
2 )3CH 2
CI
K 2 C0 3 NaL 3 N /DMF, 90 0 C, 12 h 2a: n-3 CH 2
(CH
2 )nCH 2 CI f)-N 2b: n=4 N:H- 0,
NH
H) 4a0 4a: n 4 WO 03/004027 WO 03/04027PCT/US02/21063 190 Scheme 0
H
IN
16> Cu, K 2
CC
3
NMP
150 0 C, 12 hrs R1 R1=H, R2=4-Me Scheme Q H K 2 C0 3 CuBr, 6, ~Ne 150'C,12 h NH K- R 2 Example N N 0 N H7
K
2 C0 3 CuBr, 6, 150'C, 12 h 6a: I, o 6b:1-&
I--&C
2 Me 6d: RI 7a: RI p-OMe 7b- Ri=p-F~ 7c: R I =p-CO 2 Me 7d: RI- p-Me WO 03/004027 WO 0/00027PCT/UJS02/21063 191 Scheme R NaBH(OAc) 3 R1CHO HN 1,2-dichioroethane N HOAc, At overnight R, N Example NaBH(OAc) 3 R1CHO +1 2-dichloroethane HOAc, rt overnight R, NH NH 0 0 WO 03/004027 WO 0/00027PCT/UJS02/21063 192 EXPERIMENTAL SECTION The following additional abbreviations are used: HOAc, acetic acid; DMF, N,.N-dimethylformamide; EtOAc, ethyl acetate; MeOH, methanol; NMP, l-methyl-2-pyrrolidinone; TEA, triethylamine; THF, tetrahydrofuran; All solvent ratios are volume/volume unless stated otherwise.
1- (4-METHYLPHENYL) lH-INDOLE: A mixture of 1-H- indole (58.5 mg, 0.500 mmol), l-(iodo)-4-methylbenzene (0.218 g, 1.00 mmol), copper powder (32.0 mg, 0.500 mmol), and
K
2 C0 3 (0.138 g, 1.00 mmol) in l-methyl-2-pyrrolidinone (I mL) was heated at 150 0 C for 12 h under argon. The resulting mixture was diluted with H 2 0 (6 mL). The aqueous layer was extracted with CH 2 Cl 2 (3 X 10 mL). The combined organic extracts were washed with brine ML) dried over MgSO 4 and concentrated in vacuo. The residue was purified by preparative TLC using EtOAc/hexane to give the desired product (82 mg, 7996). 'H NMR (400 MHz, CDCl 3 5 7.67 1H, T 7.7 Hz) 7.52 1H, J 7.4 Hz) 7.38 2K, LT 8.4 Hz) 7.34-7.29 (in, 3H) 7.21 1K, LJ 7. 0 Hz) 7.15 1H, J =7.0 Hz), 6.66 1H, 3.3 Hz), 2.43 3H); ESMS m/e: 208.0 (M Example 86 N- [(6-CHLORO-lH- INDOL-3-YL) METHYL] -4- PIPERIDINYL PHENYL) -2-METHYLPROPANAMIDE: A solution of 2-methyl-N- 3- (4-piperidinyl) phenyl] propanamide (0.369 g, 1.S0 mmcl) and 37 wt -3 aqueous formaldehyde (30.0 mg, 1.50 mmol) in 1 mL of HOAc~dioxane was added to 6-chloro-l-H-indole (0.152 g, 1.00 mmol) and the reaction mixture was stirred for 12 h at room WO 03/004027 PCT/US02/21063 193 temperature. The resulting mixture was diluted with
H
2 0 (10 mL). The aqueous layer was extracted with CH 2 C1 2 (3 X 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 using 5% of NH 3 (2.0 M in methanol) in CH 2 C12 to give the desired product (79 mg, 1 H NMR (400 MHz, CDC13) 8 9.14 1H), 8.04 1H), 7.52 2H, J 8.1 Hz), 7.35 2H, J 13.3 Hz), 7.18 1H, J 7.9 Hz), 7.09 (dd, 1H, J 1.9, 8.5 Hz), 6.85 1H, J 7.4 Hz), 5.18 1H), 4.01 2H), 2.55 (septet, 1H, J 6.8 Hz), 2.48-2.34 3H), 2.08-1.95 4H), 1.78 2H, J 12.8 Hz), 1.22 6H, J 6.8 Hz); ESMS m/e: 410.1 (M Example 87 2-METHYL-N- [3-(1-{[-(4-METHYLPHENYL)-1H-INDOL-3- YL]METHYL} -4-PIPERIDINYL)PHENYL]PROPANAMIDE: According to the procedure used for the synthesis of chloro-lH-indol-3-yl)methyl]-4-piperidinyl}phenyl)-2methylpropanamide, 1-(4-methylphenyl) -1H-indole (0.207 g, 1.00 mmol) provided 2-methyl-N-[3-(1-{[1-(4methylphenyl)-1H-indol-3-yl]methyl}-4piperidinyl)phenyl]propanamide (0.441 g, 'H NMR (400 MHz, CDC1 3 6 7.90 1H), 7.73 1H, J 7.2 Hz), 7.58-7.51 2H), 7.43-7.36 3H), 7.35-7.29 (m, 3H), 7.26-7.15 3H), 6.89 1H, J 7.7 Hz), 4.07 2H), 3.36 2H, J 11.6 Hz), 2.59-2.39 6H), 2.55 (sept, 1H, J 6.7 Hz), 2.10-1.98 2H), 1.83 (d, 2H, J 12.9 Hz), 1.23 6H, J 6.9 Hz); ESMS m/e: 466.2 (M WO 03/004027 PCT/US02/21063 194 2-[(IS)-3-CHLORO-1- PHENYLPROPYL]-IH- ISOINDOLE-1,3(2H)-DIONE: Triphenylphosphine (5.25 g, 20.0 mmol) and diethyl azodicarboxylate (3.58 g, 20.0 mmol) were added to a solution of (1R)-3-chloro-lphenyl-1-propanol (3.42 g, 20.0 mmol) and phthalimide (2.94 g, 20.0 mmol) in THF (100 mL) The reaction mixture was stirred for 4 h at room temperature. The solvent was removed under reduced pressure and the residue was 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/hexane (3:97) to give the desired product (4.40 g, 74%) 1 H NMR (400 MHz, CDC1 3 6 7.82 1H, J 5.7 Hz), 7.81 1H, J 5.5 Hz), 7.70 (d, 1H, J 5.4 Hz), 7.69 1H, J 5.8 Hz), 7.55 2H, J 7.2 Hz), 7.38-7.28 3H), 5.64 (dd, 1H, J 6.8, 9.2 Hz), 3.56 2H, J 6.4 Hz), 3.11-3.02 1H), 2.85-2.75 1H); ESMS m/e: 300.1 (M H) N-(3-(1-[(3S)-3-(1,3-DIOXO-1,3-DIHYDRO-2H-ISOINDOL-2- YL)-3-PHENYLPROPYL]-4-PIPERIDINYL}PHENYL)-2- METHYLPROPANAMIDE: A mixture of 2-[(IS)-3-chloro-lphenylpropyl]-IH-isoindole-1,3(2H)-dione (4.50 g, 15.0 mmol), 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide (4.26 g, 15.0 mmol), K2CO 3 (4.16 g, 30.0 mmol), and Nal (3.40 g, 20.0 mmol) in DMF (40 mL) was stirred at 90 °C for 12 hrs. The reaction mixture was diluted with water mL), extracted with CH 2 C12 (3 X 50 mL), and the combined organic extracts were washed with brine mL), dried over MgS04, and concentrated under reduced pressure. The residue was purified by chromatography on silica using 5% of NH3 (2.0 M in methanol) in CH 2 C1 2 to give the desired product (5.10 g, 1 H NMR (400 MHz, WO 03/004027 WO 0/00027PCT/UJS02/21063 195
CD)CT
3 8 7. 83 1H, J 5 5.5 Hz) 7. 82 1H, J= 5 Hz) 7. 71 Cd, 1IH, J 5. 5 Hz) 7. 70 1H, LT 5.4 H-z) 7. 56 2H, J 7. 1 Hz) 7.3 5 27 (in, 5H) 7.2 2 IH, J '7.5 Hz) 7 .09 1H) 6.281 1H, J 7 .8 Hz) 5. 49 (dd, 1K, J 5 5.5, 9. 6 Hz) 2 .97 IH, J 1 H-z) 2. 92-2. 82 2 .44 (sept, 1H, J 6. 7 Hz), 2 .40-2 .29 (in, 3H), 2. 00-1. 83 Cm, 2H) 1.79-1. 39 (mn, 1.26 6H, J 6.9 Hz) ESMS m/e: 510.4 (M N- (3-fl- -3-AMINO-3-PHEN'YLPROPYL] -4- PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE: A mixture of N- C3-{1- C1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) 3-phenylpropyll -4--piperidinyl~phenyl) -2methyipropanamide (4.60 g, 9.06 minol) and hydrazine (3.62 g, 72.4 inmol) in ethanol (150 mL) was refluxed for 12 h. The resulting white precipitate was filtered out and the filtrate was concentrated under vacuum. The residue was washed with CH 2 C1 2 /EtCAc 3 X 50 rnL) and the combined organic fractions were concentrated in vacuo to give the desired product 90 g, 95%) 'H NMR (400 MHz, aDC1 3 8 7.45 Cs, 1H) 7.39-7.30 6H) 7.29- 7.19 2H) 6.95 1K, J 4.01 t, 1H, J 6.8 Hz) 3.04 2H, J 10.6 Hz), 2.62-2.30 6H-), 2.05-1.70 8H) 1. 24 Cd, 6H, J 8 Hz) ESMS m/e: 380.4 (M Example 88 WO 03/004027 PCT/US02/21063 196 2-METHYL-N-(3-{1-[(3s)-3- PHENYL-3- (PROPIONYLAMINO) PROPYL -4- PIPERIDINYLIPHENYL)PROPANAMIDE: According to the procedure used for the synthesis of S (acetylamino)-3-phenyipropyl]-4-piperidinyl}phenyl)-2methyipropanamide, N- -3-anino-3phenyipropyl-4-piperidinyl}phenyl)-2-methylpropanamide (11.0 mg, 0.0280 rmol) and propionyl chloride (3.80 mg, 0.0420 mmcl) provided 2-methyl-N-(3-{1-[(3S)-3-phenyl-3- (propionylamino)propyl]-4-piperidinylphenyl)propanamide (12 mg, 97-. yield) 'H NMR (400 MHz, CDCl 3 6 8.05 (s, lI), 7.59 1H), 7.40-7.20 7H), 6.96 1H), 5.19-5.12 1H), 3.18 1 H, J 12.0 Hz), 2.99 (d, 1H, J 10.4 Hz), 2.93-2.86 Cm, 1H), 2.61-2.40 3H), 2.38-2.23 3H), 2.19-1.75 8H), 1.25 6H, J 6.9 Hz), 1.22-1.08 3H); ESMS m/e: 436.4 (M Example 89 N-(3-[1-((38)-3-{[(4-FLUOROPHENYL)ACETYLJMINOI-3- PHENYLPROPYL)-4-PIPERIDINYLPHENYL-2-METHYLPROPANAMIDE: A mixture of [(3S)-3-amino-3-phenylpropyl]-4piperidinyl~phenyl) -2-methylpropanamide (11.0 mg, 0.0280 nmol) and C4-fluorophenyl)acetyl chloride (7.20 mg, 0.0420 mmol) in THF (5 iL) was stirred at room temperature for 4 h. The solvent was removed under reduced pressure and the residue was purified by preparative TLC using Hexane:EtOAc to give the desired product (13 mg, 90% yield). NMR (400 MHz, CDC1 3 8 7.89 Cd, 1H, J 8.4 Hz), 7.59 Cs, 1H), 7.31- 6.93 13H), 5.13 1H, J 6.0 Hz), 3.56 Cs, 2H), 3.07 Cd, 1H, J 11.7 Hz), 2.91 Cd, 1H, J 11.0 Hz), 2.62-2.42 Cm, 2H), 2.40-2.30 Cm, lH), 2.12-1.54 9H), 1.24 6H, J 6.7 Hz); ESMS n/e: 515.3 CM WO 03/004027 WO 0/00027PCT/UJS02/21063 197 Example (1,2-DIPHENrtL-lH-INDOL-3-YL) PROPYL] -4- PIPERIDINYL)PHENYL) -2 -METHYLPROPANANIDE: A mixture of 1,1-diphenyihydrazine hydrochloride (10.3 mrg, 0.0470 mmol), 2-methyl-N-(3-[1-(5-oxo-5-phenylpentyl)-4piperidinyllphenyl~propanamide (14.7 mg, 0.0362 mmol), ZnC1 2 (14.85 mg, 0.109 mmol), and H-OAc (0.5 mL) was heated for 4 h at 80 The resulting crude mixture was diluted with water (10 mL), the aqueous layer was neutralized with saturated K 2 C0 3 and extracted with CH 2 Cl 2 (3 X 20 mL). The combined organic layers were concentrated in vacuo and the residue was purified by preparative TLC using 5%6 of NH 3 (2.0 M in methanol) in
CH
2 C1 2 to give the desired product diphenyl-1H-indol-3-yl)propyll -4-piperidinyl~phenyl) -2methyipropanamide (4.1 mg, 1H NMR (400 MHz, CDC1 3 6 7.7.1-7.65 Cm, 111), 7.42 Cd, 1H1, J 7.4 Hz) 7.39 Cs, iH) 7.36-7.1 ISCm, 15H-) 6.94 Cd, TH, LT 7. 8 Hz) 3.12 2H, LTJ 11. 2 Hz) 2. 90 2H1, JLT 7.8 Hz) 2.59-2.45 3H), 2.19-1.91 (in, 7 H) 1 82 2H1, J 13. 5 Hz) 24 6H, LT 6.9 Hz) ESMS m/e: 555.3 CM Example 91 [3-(5-METHOXY-2-PHENYL-:lH-INDOL-3-YL)PROPYLJ-4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: According to the procedure used for the synthesis of N- (1,2-diphenyl-1H-indol-3-yl)propyl] -4piperidinyllphenyl) -2-methyipropanamide, 2-methyl-N- {3- (5-oxo-5-phenylpentyl) -4piperidinyllphenyl) prop anami de (15.6 mg, 38.2 minol), and 1- (4-methoxyphenyl) hydrazine hydrochloride (8.00 mg, WO 03/004027 WO 0/00027PCT/UJS02/21063 0.0458 mm0l) provided N- 19 3-f1-[3-(5-methoxy-2phenyl-1H-ildol-3-yl)propYJ.]-4-piperidinyl~phelyl) -2methyipropanamide (3.9 mg, 1H NMR (400 MHz, CDC1 3 8 B. 06 Cs, IH) 7.55 d, 21H, J 7.4 Hz), 7.43-7.3 9 (m, 311), 7.38-7.35 211), 7.27-7.19 311), 7.02 Cd, 111, J =7.4 Hz), 6.94 Cd, 1H1, J 7.6 Hz), 6.87 (dd, 1H, 7 6. 6 Hz) 3. 88 3H1), 3.8 0 69 (in, 1H) 2. 99 (d, 211, J 11. 7 Hz) 2.89 t, 2H, J 2.55-2.39 (in, 4H-) 02-1. 88 (mn, 311), 1. 82-1.68 (mn, 4H1), 1. 24 611, J =6.9 Hz) ESMS mle: 510.3 (M Example 92 E4- (5-METHOXY-2-PHENYL-1H-INDOL-3-YL)BUTYLJ -4- PIPERIDINYLPHENYlL) -2-METHYLPROPANAMIDE: According to the procedure used for the synthesis of NC-lC-12 diphenyl-1H-indol-3-yl)propyl) -4-piperidinyl~phenyl) -2methyipropanamide, 2-methyl--N-{3-El- C6-oxophenylhiexyl) -4-piperidinyl] phenyllpropananide (14.3 Mng, 0.0339 inmol) and 1- (4-methoxyphenyl) hydrazine hydrochloride (7.10 mng, 0.0407 mrnol) provided NV-C3-{l- C5-methoxy-2-phenyl-lH-indol-3-yl)butyl] -4piperidinyl'phenyl) -2-methyipropanamide C5 .8 mng, 33%).
1H NMR (400 MHz, CDCl 3 8 7.95 211, JLT 7.8 Hz), 7.61- 7.15 Cm, 11H) 6.97 Cd, 11-, J 7. 0 Hz), 3.88B 3H) 3. 09 2H1, LJ 11. 3 Hz) 2. 99 t, 211, J 7. 0 Hz) 2.55-2.35 Cm, 411), 2.12-1.70 611), 1.68-1.52 211), 1. 4 8-1. 34 Cm, 2H1), 1. 25 Cd, 6H1, J 6. 7 Hz) ESMS mie: 524.3 CM Example 93 2-METHYL-N- C3-{1-[E(l-PHENYL-1H-INDOL-3-YL)METHYLJ -4- PIPERIDINYL}PHIENYL)PROPANAMIDE; According to the procedure used for the synthesis of N-C3-{1-[3-Cl,2- WO 03/004027 PCTUS02/21063 199 dipheny-1H-indol-3- yl)propy 1 -4piperidinyl~phenyl)-2-methylpropanamide, 1-(3,3dimethoxypropyl)-4-piperidinyllphenyl}-2methylpropanamide (15.2 mg, 0.0436 mmol) and 1,1diphenyihydrazine hydrochloride (11.6 mg, 0.0524 mmol) provided 2-methyl-N-(3-{1-[(1-phenyl-1H-indol-3yl)methyl)-4-piperidinylphenyl)propananide (11 mg, 1H NNR (400 MHz, CDC 3 5 7.79 1H, J 7.8 Hz), 7.57 1H, J 7.7 Hz), 7.54-7.47 4H), 7.43- 7.32 4H), 7.25-7.16 Cm, 4H), 6.95 Cd, 1H, J 7.8 Hz), 3.87 2H), 2.53-2.47 (in, 2H), 2.21 (dt, 2H, J 10.5 Hz), 2.12-1.77 Cm, 6T), 1.24 6H, J= 6.9 Hz) ESMS mle: 451.3 (M Example 94 2-METHYL-N- (3-fl-[(4E)-4-PHENYL-4-(2- PYRIDINYLHYDRAZONO)BUTYL -4- PIPERIDINYL}PHENYL)PROPANAMIDE: According to the procedure used for the synthesis of diphenyl-lH-indol-3-yl)propyl)-4-piperidirylphenyl)-2methyipropanamide, 2-methyl-N-{3-[1-C4-oxo-4phenylbutyl)-4-piperidinyllphenyl~propanamide (8.70 mg, 0.0223 miol) and 2-hydrazinopyridine (2.92 mg, 0.0268 mmCl) provided 2-methyl-N-(3-{1-[(4E)-4-phenyl-4- pyridinylhydrazono)butyl]-4piperidinyl~phenyl)propanamide (2.5 mg, 'H NMR (400 MHz, CDCl 3 6 7.97 lH, J 8.6 Hz), 7.85 1H, J 7.3 Hz), 7.64 -7.2 7 9H), 7.09 lH, J Hz), 6.97 lH, J 8.4 Hz), 6.73 1H, J 6.6 Hz), 3.52-3.48 Cm, 2H), 3.20-3.10 2H), 2.85-1.75 (m, 13H), 1.26 6H, J 6.8 Hz); ESMS m/e: 484.4 (M H) WO 03/004027 PCT/US02/21063 200 Example N-(3-{1-[3-(5-METHOXY-1H-INDOL-3-YL)PROPYL]-4- PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE: According to the procedure used for the synthesis of diphenyl-1H-indol-3-yl)propyl]-4-piperidinyl}phenyl)-2methylpropanamide, [4-(1,3-dioxolan-2-yl)butyl]- 4-piperidinyl}phenyl)-2-methylpropanamide (23.5 mg, 0.0628 mmol) and 1- (4-methoxyphenyl) hydrazine hydrochloride (13.2 mg, 0.0774 mmol) provided [3-(5-methoxy-lH-indol-3-yl)propyl] -4piperidinyl}phenyl)-2-methylpropanamide (11 mg, 1H NMR (400 MHz, CDC1 3 8 7.86 1H), 7.45 1H), 7.32 1H, J 8.4 Hz), 7.28-7.21 2H), 7.10 1H), 7.05 1H, J 2.3 Hz), 7.00-6.91 2H), 6.85 (dd, 1H, J 2.7, 9.0 Hz), 3.87 3H), 3.06 2H, J 11.6 Hz), 2.75 2H, J 7.2 Hz), 2.55-2.42 4H), 2.08-1.90 4H), 1.88-1.74 4H), 1.25 6H, J 6.9 Hz); ESMS m/e: 434.2 (M H) TERT-BUTYL 4- (PROPIONYLAMINO) PHENYL] -1- PIPERIDINECARBOXYLATE: Propionyl chloride (5.53 g, 0.0597 mol) was added dropwise to a solution of tertbutyl 4-(3-aminophenyl)-1-piperidinecarboxylate (15.0 g, 0.0543 mol) and TEA' (16.5 g, 0.163 mol) in THF (200 mL) and the mixture was stirred at room temperature for 3 h.
Water (50 mL) was added to the reaction mixture, the aqueous layer was extracted with CH 2 C1 2 (3 X 100 mL), and the combined organic extracts were washed with brine mL) dried over Na 2
SO
4 and concentrated under reduced pressure. The residue s- purified by chromatography on silica using hexane/EtOAc (10:1) to afford the product (18.8 g, 99%) 1H NMR (400 MHz, CDC13) 6 7.48 1H) WO 03/004027 WO 03/04027PCTIUS02/2 1063 201 7.34-7.21 Cm, 311), 6.93 111, JT 7.4 Hz) 2.77 Ct, 2H, JLT 11.5 Hz) 2. 68 58 Cm, 1H), 2. 38 2H, LT 7.6 Hz), 1.87-1.67 Cm, 4H1), 1.67-1.54 Cm, 2H) 1.48 Cs, 91), 1.2S Ct, 3H, JT 7.5 Hz) ESMS m/e: 333.4 CM H) J- (4-PIPERIDINYL)PHNNYL) PROPANAMIDE: Into a stirred solution of tert-butyl 4- E3- (propionylamino)phenyl] -1piperidinecarboxylate (18.8 g, 0.0543 mmol) in dioxane C100 mL) at 5 0 C was bubbled HC1 gas for 2 h. The solvent was removed in vacuo, the residue was dissolved in water C100 mL) and neutralized by adding 10% KOH aqueous solution. The aqueous layer was extracted (3 X 200 mL) with a mixture of CHCl 3 /isopropyl alcohol and the combined organic layers were washed with brine (100 mL), dried over Na 2 SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica using 5% of NH 3 (2.0 M in methanol) in CH 2 Cl 2 to afford the desired product (12.6 9, 'H NNR (40C MHz, CDC1 3 6 7.44 Cs, 111), 7.32 (d, 111, CT 7.2 Hz), 7.28-7.21 (in, 111), 7.09 1H1), 6.97 Cd, 1H1, JT 7. 6 Hz) 3. 18 211, CT 12. 6 Hz) 2.7 3 Cdt, 2H1, CTJ 2.2, 11. 2 H-z) 2.65-2.57 Cm, 111), 2.38 (q, 211, CT= 7.4 Hz) 1.33 2H1, JT 12.1 Hz) 1.70-1.61 3H1), 1.25 3H, JT 7.5 Hz); ESMS m/e: 233.1 (M TERT-BtJTYL 4- {3 -[(CYCLOPROPYLCARBONYL) AMINO] PHENYL} -1- PIPERIDINECARBOXYLATE: According to the procedure used for the synthesis of tert-butyl 4- [3- Cpropionylamino)phenyl] -1-piperidinecarboxylate, tertbutyl 4- (3-aminophenyl) -1-piperidinecarboxylate (16.47 g 0.0596 mol) and cyclopropanecarbonyl chloride (6.27 g, WO 03/004027 PCT/US02/21063 202 0.0597 mol) provided the tert-butyl 4-(3- [(cyclopropylcarbonyl)amino]phenyl}-1piperidinecarboxylate (18.1 g, 100%). 1 H NMR (400 MHz, CDC13) 8 7.55-7.46 2H), 7.29-7.21 2H), 6.96-6.89 1H) 2.79 2H, J 12.1 Hz), 2.68-2.58(m, 1H) 1.84 2H, J 12.6 Hz), 1.83-1.76 4H), 1.48 (s, 9H), 1.19-1.12 1H), 1.09-1.05 2H), 0.89-0.75 (m, 2H); ESMS m/e: 345.5 (M H) N-[3-(4-PIPERIDINYL)PHENYL]CYCLOPROPANECARBOXAMIDE: According to the procedure used for the synthesis of N- [3-(4-piperidinyl)phenyl]propanamide, tert-butyl 4-{3- [(cyclopropylcarbonyl)amino]phenyl}-lpiperidinecarboxylate (18.9 g, 0.0543 mol) provided N- [3-(4-piperidinyl)phenyl]cyclopropanecarboxamide (13.2 g, 100 1 H NMR (400 MHz, CDC13) 6 7.46 1H), 7.36- 7.22 3H), 7.23 1H, J 6.9 Hz), 3.17 2H, J 11.9 Hz), 2.72 (dt, 2H, J 2.6, 12.2 Hz), 2.65-2.55 (m, 1H), 1.82 2H, J 13.9 Hz), 1.63 (dt, 3H, J 4.1, 12.5 Hz), 1.53-1.45 1H), 1.11-1.06 2H), 0.87- 0.81 2H); ESMS m/e: 245.03 (M 1-(6-CHLOROHEXYL)-1H-INDOLE: To a mixture of NaH (0.249 g, 10.0 mmol) in DMF (5 mL) at 0 °C was added a solution of 1-H-indole (0.585 g, 5.00 mmol) in DMF (2 mL). The reaction mixture was stirred for 30 minutes and warmed up to room temperature. Then l-bromo-6-chlorohexane (0.998 g, 5.00 mmol) was added dropwise by syringe and the reaction mixture was stirred overnight. The reaction mixture was diluted with EtOAc (30 mL), washed with water (3 X 10 mL), dried over MgSO 4 concentrated in vacuo and purified by chromatography using hexane/EtOAc (97.5:2.5) to give the desired product (0.900 g, 76 WO 03/004027 WO 03/04027PCTIUS02/2 1063 203 NM.R (CDC1 3 5 7.76-7.54 1H1), 7.47-6.96 Cm, 4H1), 6.60-6.34 11T) 4.13 (ft, 2H, J- 6.8 Hz) 3.50 2H-, J 5.6 Hz), 1.98-1.79 (mn, 211), 1.79-1.64 (mn, 211), 1. 54-1. 17 (in, 4H).
According to the procedure used for the synthesis of 1-(6-chlorohexyl)-1H- indole, 1-H-indole (0.585 g, 5.00 mmcl) and chioropentane (0.928 g, 5.00 inmol) gave the desired product (0.890 g, 80%) 'H1 NMR (CIDCl- 3 63 7.76-7.51 (mn, 111), 7.44-6.96 Cm, 4H), 6.60-6.38 111), 4.11 211, LT 6. 8 Hz) 3. 47 t, 2H, J 6. 4 Hz), 1. 97-1. 79 Cm, 2H1)1 1.79-1.61 (in, 211), 1.58-1.32 Cm, 211).
Example 96 N- (1H-INDOL-1-YL)HEXYL) -4-PIPERIDINYLPHENYL) 2-METHYLPROPANAMIDE: 1- (6-Chiorohexyl) -1H-indole (23.6 mg, 0.100 mmol), 2-methyl--N-t3-(4piperidinyl)phenyllpropanamide (24.6 mng, 0.100 mmol),
K
2 C0 3 (27.6 mg, 0.200 mmol) NaT (22.5 mg, 0.150 mmcl) and DMF (1.00 inL) were combined and stirred overnight at 100 0 C. The reaction mixture was cooled to room temperature and the crude material was purified by preparative TLC using 5 of NH3 (2.0 M in methanol) in C11 2 C1 2 to give the desired product as a yellow solid mng, 'H NMR (400 MHz, CDCl 3 6 B.08-6.52 11H), 4. 17 211, LT 7. 2 Hz) 3. 26 211, LTJ 11 .6 Hz), 2 .74-2. 52 Cm, 411), 2 .44-2.28 Cm, 211), 2 .20-2 .02 Cm, 211), 1.98-1.82 1.78-1.62 (mn, 211), 1.43-1.28 411), 1. 28 Cd, 611, LT 6. 8 Hz) ESMS rn/e: 446. 5 (M H) WO 03/004027 PCT/US02/21063 .204 Example 97 (2-INDOL-1-YL)PENTYL-4-PIPERIDINYL}PHENYL)- 2-METHYLPROPANAMIDE: Prepared as above, using 1 chloropentyl)-lH-indole (22.2 mg, 0.100 mmol), 2-methyl- N-[3-(4-piperidinyl)phenyl]propanaide (24.6 mg, 0.100 mmol), K 2 C0 3 (27.6 rg, 0.200 rmol), NaT (23.0 mg, 0.150 mmol) and DMF (1.00 mL), giving the desired product as a yellow oil (36 mg, 1H NMR (400 MHz, CDC 3 6 8.08-6.52 11H) 4.19 2H, J 7.2 Hz), 3.26-3.10 2H), 2.71-2.55 2H), 2.55-2.42 2H), 2.35-2.12 2H), 2.12-1.80 6H), 1.80-1.57 Cm, 2H), 1.51-1.34 2H), 1.31 6H, J 6.8 Hz); ESMS m/e: 432.2 (M
H).
Example 98 N-(4-{l-[(9-ETHYL-91-CARBAZOL-3-YL)METHYL)-4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: According to the procedure used for the synthesis of CHLOROPHENXY)BENZYL]-4-PIPERIDINYL}PHENYL)-2- METHYLPROPANAMIDE (Example 108) diphenyl-lH-indol-3-yl)propyl]-4-piperidiryllphenyl)-2methylpropanamide, 9-ethyl-9H-carbazole-3-carbaldehyde (22.3 Mg, 0.100 mmol) and 2-methyl-N- (4piperidinyli phenyl]propanamide (24.6 rg, 0.100 mmol) provided N-(4-{l-[(C9-ethyl-9H-carbazol-3-yl)methyl]-4piperidinyl}phenyl) -2-methyipropanamide. The product was obtained as a white crystalline solid (20 mg, 44%) IH NMR (400 MHz, CDCl 3 6 8.21-7.09 Cm, 12H), 4.38 2H, LJ 7.2 Hz), 3.81 Cs, 2H), 3.25-3.03 2H), 2.60-2.38 2F), 2.31-2.09 2H), 1.98-1.69 4H), 1.44 Ct, 3H, J 7.2 Hz), 1.23 6H, J 6.8 Hz); ESMS m/e: 454.3 CM WO 03/004027 WO 0/00027PCT/UJS02/21063 205 Excample 99 N- [(9-ETHYL-9H-CARBAZOL-3-YL)NdETHEYL-4- PIPERIDfIYL)PHiENYL) -2-METHiYLPROPANAMIDE: According to the procedure used for the synthesis of CHLOROPHENOXY) BENZYL) -4-PTPERIDINYL}PHENYL) -2- METHYLPROPANAM'IDE (Example 108) N- [(9-ethyl-91carbazol-3-y1)methyl) -4-piperidinyl~phenyl) -2rethyipropanamide, 9-ethyl- 9H-carbazole-3 -carbaldehyde and 2-methyl-NV- 3- (4-piperidinyl)phenyl) propanamide afforded [(9-ethyl-9H-carbazol-3-yl)methyl2 -4piperidinyl~phenyl) -2-methylpropanamide (37 mg, 'H NNR (400 MHz, CDCT 3 5 8.24-6.29 (in, 12H) 4.37 (q, 211, JLT 7.2 Hz) 3.82 211), 3.23-3.06 211), 2.65- 2.38 (i,211), 2.31-2.11 (mn, 2H) 2.01-1.73 (in, 411), 1.43 31-1, J 7.2 Hz), 1.25 6H1, J 4.0 Hz) ESMS m/e: 454.3 (M H" Example 100 N- (4-METHO)XYPHENYL) -lH-INDOL-5-YLJMETHYL}-4- PIPERIDINYL) PHENYL] -2-METHYLPRQPANAMIDE: According to the procedure used for the synthesis of 1- (4methyiphenyl) 1H -indole, [1-(lH-indol-5-ylmethyl) 4-piperidinyljphenyl}-2-methylpropanamide (37.5 Mgt 0.100 inmol) and l-iodo-4-methoxybenzene (46.8 mg, 0.200 mmol) gave the desired product (27 mg, 56%) 'H N14R (400 MHz, CDCl 3 5 7.70-6.58 Cm, 1411), 3 .88 311), 3 .67 (s, 211), 3.14-3.01 211), 2.57-2.41 (mn, 211), 2.25-2.01 (in, 2H1), 1.93-1.69 (mn, 411), 1.24 611, J 7.2 Hz) ESMS m/e: 482.2 (M Example 101 Nf-[3- [1-(4-FLUOROPHENYL) -lH-INDOL-5-YL]HETHYL}-4- PIPERIDINYL)PHENYL) -2-METHYLPROPANAMIDE: According to WO 03/004027 WO 0/00027PCT/UJS02/21063 206 the procedure used for the synthesis of -4 methyiphenyl) 1H-indole, N- (H-indol-5-ylmethy-) -4piperidinyll phenyl} -2-methyipropanamide (37.5 mg, 0.100 mmol) and 1-fluoro-4-iodobenzele (44.4 mg, 0.200 mmcl) gave the desired product (21 mg, 45%) 1H NMR (400 MHz, CDCl 3 8 7.71-6.60 1411), 3.69 Cs, 2H1), 3.19-2.99 Cm, 2H), 2.62-2.41 Cm, 2H), 2.22-2.07 Cm, 211), 1.94-1.70 (m, 4H) 1. 24 6H, LT 6.8B Hz) ESMS m/e: 470.2 CM Example 102 METH-YIL-4- E5- C4- (ISOBUTYRYLAMINO) PHENYLJ -1- IPERIDINYL)METHYL) -1H-INDOL-1-YL]BENZOATE: According to the procedure used for the synthesis of l-C4methyiphenyl) lH-indole, N-{3-El- (lH-indol-5-ylmethyl) 4-piperidinyl] phenyl} -2-methylpropanamide (37.5 mg, 0.100 mmcl) and methyl 4-iodobenzoate (52.4 mg, 0.200 mmcl) gave the desired product (11 mug, 22%) 1H NMR (400 MHz, CDCl 3 5 8. 31-6. 64 14H) 3 .96 3H) 3. 67 (s, 2H), 3.16-2.96 211), 2.57-2.41 Cm, 211), 2.18-2.02 (m, 2H) 1. 91-1.73 4H) 1. 24 6H, LT 6. 8 Hz) ESMS m/e: 510.2 CM Example 103 2-METHYL-N- l- (3-METHYLPH-ENYL) YLJ METHYL} -4-PIPERIDINYL) PHENYL] 2ROPANAMIDE:. According to the procedure used for the synthesis of l-(4methylphenyl) lH-indole, Nv-{3- l- ClH-indol-5-ylmethyl) -4piperidinyllphenyl)-2-methylpropanamide (37.5 rug, 0.100 mmcl) and 1-iodo-3-methylbenzene (43.6 mug, 0.200 mmcl) gave the desired product (28 mug, 60%) 'H NMR (400 MHz, CDCl 3 37.68-6.60 Cm, 1411), 3.66 Cs, 2H1), :3.16-2.96 Cm, 2H1), 2.59-2.44 211), 2.44 Cs, 311), 2.18-2.01 Cm, 2H1), WO 03/004027 PCT/US02/21063 207 1.91-1.68 4H), 1.24 6H, J 6.8 Hz); ESMS m/e: 466.2 (M Example 104 N-{3-[1-(3-{[(4-CHLORO-3- NITROPHENYL)SULFONYLAMINO)PROPYL) -4- PIPERIDINYLPHENYL}-2-METHYLPROPANAMIDE: A mixture of N- (3[1-(2-aminopropyl)-4-piperidinyl]phenyl}-2methyipropanamide (10.0 mg, 0.0350 mtol), 4-chloro-3nitrobenzenesulfonyl chloride (9.90 mg, 0.0380 mmol), and TEA (7.00>ng, 0.0700 mmol) in THF (2 mL) was stirred for 12 h at room temperature. The crude product was purified by preparative TLC (CH 2 C1 2 /MeOH/isopropyl amine 19:1:0.2) to give the desired product (16 mg, IH NMR (400 MHz, CDC13) 5 8.45-8.38 1H), 8.02 1H, J 8.4 Hz), 7.72 1H, J 8.8 Hz), 7.48-7.40 3H)), 7.29-7.24 2H), 6.96 11, J 7.5 Hz), 3.17-3.09 4H), 2.63-2.48 4H), 2.15 2H, J 11.8 Hz), 1.96-1.72 1.25 6H, LT 6.9 Hz); ESMS m/e: 523.2 (M Example 105 N-[3-(1-{59-[4-(3,4-DIFLUOROPHENYL)-2-OXO-1,3-OXAZOLIDIN- 3-YL]PENTYL}-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: A mixture of 3-(5-bromopentyl)-4-(3,4-difluorophenyl)- 1,3-oxazolidin-2-one (38.0 mg, 0.110 mmol), 2-methyl-N- [3-(4-piperidinyl)phenyllpropanaride (26.0 mg, 0.100 mmcl), NaI (23.0 mg, 0.150 miol), and K 2 00 3 (14.0 mg, 0.100 mmol) in DMF (2 iL) was heated fo2 1 h at 50 0
C.
The crude product was purified by preparative TLC using
CH
2 Cl 2 /MeOH/isopropyl amine (19:1:0.2) to give the desired product (21 mg, 'H NMR (400 MHz, CDC1,) 8 7.49 1H), 7.39-7.32 2H), 7.26-7.20 2H), WO 03/004027 PCT/US02/21063 208 7.18-7.11 1H), 7.10- 7.03 1H), 6.96 1H, J 7.6 Hz), 4.80-4.73 1H), 4.62 1H, J 7.9 Hz), 4.09-4.04 1H), 3.51-3.42 1H), 3.03 2H, J 11.7 Hz), 2.82-2.72 1H), 2.51-2.42 2H), 2.32 2H, J 7.9 Hz), 2.11 1H), 2.03-1.97 2H) 1.85-1.70 4H), 1.49 4H), 1.31-1.27 1H), 1.24 6H, J 6.9 Hz); ESMS m/e: 514.4 (M H) Example 106 3-(2,6-DICHLOROPHENYL)-N-(5-{4-[3- (ISOBUTYRYLAMINO)PHENYL] 4-ISOXAZOLECARBOXAMIDE: A mixture of 3-(2,6chloride (69.0 mg, 0.250 mmol), N-{3-[1-(5-aminopentyl)-4piperidinyl]phenyl}-2-ethylpropanamide (44.0 mg, 0.150 mmol), TEA (30.0 mg, 0.300 mmol) in THF (2 mL) was stirred for 12 h at room temperature. The crude product was purified by preparative TLC using CH 2 C1 2 /MeOH/ isopropyl amine (19:1:0.2) to give the desired product (52 mg, 1H NMR (400 MHz, CDC1 3 8 7.52-7.49 (m, 2H), 7.49-7.41 2H), 7.39-7.31 2H), 7.29-7.21 (m, 2H), 6.92 1H, J 7.6 Hz), 3.25-3.11 5H), 2.81- 2.74 4H), 2.58-2.44 4H), 2.30-2.19 2H), 1.93- 1.78 4H) 1.56-1.44 2H), 1.31-1.28 (m, 2H), 1.24 6H, J 6.6 Hz); ESMS m/e: 585.2 (M H) Example 107 N-[3-(1-{2-[(DIPHENYLACETYL)AMINO]ETHYL}-4- PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: A mixture of N- {3[1-(2-aminoethyl)-4-piperidinyl]phenyl}-2methylpropanamide (20.0 mg, 0.0700 mmol), diphenylacetyl chloride (23.0 mg, 0.110 mmol), and TEA (20.0 mg, 0.140 mmol) in THF (2 mL) was stirred overnight at 23 The WO 03/004027 WO 0/00027PCT/UJS02/21063 209 crude product was purified by preparative TLC using C1 2 C1 2 /MeOH/isopropyl amine (19:1.0.2) to give the desired product (8.0 mg, 'H NMR (400 MHz, CDC1 3 6 7.53 1H) 7.37-7 .20 Cm, 13H) 6. 97-6.92 Cm, lH) 6.67 Cs, 1H) 4.98 Cs, 1H) 3.43 2H4, J =5.9 Hz) 2.90 2H4, J 11. 6 Hz) 2.57-2.42 Cm, 4H), 2. 11 (t, 2H4, J 10.4 Hz) 1.7S 2H4, J =12.4I Hz) 1.70-1.58 Cm, 2H), 1.25 6H1, J =6.7 Hz); ESMS m/e: 484.2 (M Example 108 NV- C4-CHLOROPHENOXY)BENZYL] -4- PIPEIRIDINYLPHEY) -2 -METHYLPROPANAMIDE: 4- (4chlorophenoxy)benzaldehyde (0.119' g, 0.510 mmol) and 2methyl-N- E3- (4-piperidinyl)phenyllpropanamide (0.126 g, 0.510 mmol) were mixed in 1,2-diohioroethane (5 mL) and then treated with sodium triacetoxyborohydride (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 NaHCO 3 aqueous solution and the aqueous layer was extracted with CH 2 C1 2 (3 X 10 mL) .The combined organic layers were washed with brine, dried over MgSO 4 concentrated in vacuo, and purif ied by preparative TLC using S% of NH 3 0 M in methanol) in CH 2 Cl 2 to give the desired product (53 mg, '1H NMR (400 MHz, CDCl 3 5 7.50 Cs, 11) 7.34-7.19 711), 6.98-6.87 Cm, 511), 3.50 2H1), 2.98 211, J 11. 8 2.58-2.44 2H), 2.10-1.98 (in, 211), 1. 83- 1. 76 Cm, 414), 1. 24 611, JT 6.8 Hz) ESMS ml/e: 463.2 (IM Example 109 WO 03/004027 PCT/US02/21063 210 N-{-[l2,5-1)3METHYL-1- [3- (TRIFLUOROMETHYL)PHENYL-1H-PYRROL-3-YL)METHYL)-4- PIPERIDINYL)PHENYL}-2-METHYLPROPANAIDE: Prepared by the procedure described in example 108, substituting direthyl-l- 3-(trifluoromethyl)phenyl]-lH-pyrrole-3carbaldehyde (0.136 g, 0.510 mmol) for 4-(4chlorophenoxy)benzaldehyde. 1H NMR (400 MHz, CDC 3 8 7.69-7.56 7.53-7.32 4H), 7.28-7.18 2H), 6.99 Cs, 11), 5.98 11), 3.43 Cs, 2H), 3.16-3.06 (m, 2H), 2.57-2.42 Cm, 2H), 2.07-1.95 8H), 1.89-1.76 (m, 4H), 1.24 6H, J 6.8 Hz); ESMS m/e: 498.2 (M Example 110 N-C3-{1-[4-(3,4-,-DIFLUOROPHEOXY)BENZYL -4- PIPERIDIYL}PHENYL)-2-METHYLPROPANAMIDE: Prepared by the procedure described in example 108, substituting 4-(3,4difluorophenoxy)benzaldehyde (0.119 g, 0.510 mmol) for 4-(4-chlorophenoxy)benzaldehyde. 1H NMR (400 MHz, CDC 3 6 7.52 Cs, 11), 7.32 Cd, 2H, J 8.4 Hz), 7.28-7.21 Cm, 21), 7.14-7.06 Cm, 21), 6.98-6.94 31), 6.86-6.79 (m, 11), 6.76-6.69 1H), 3.51 2H), 2.99 2H, J 11.7 Hz), 2.55-2.44 2H), 2.12-2.02 2H), 1.86- 1.74 41), 1.25 61, J 7.0 Hz); ESMS m/e: 465.2 (M Example 111 (5-CHLORO-3-METHYL-1-PHENYL-1H-PYRAZOL-4- YL)METHYL)-4-PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE: Prepared by the procedure described in example 108, substituting 5-chloro-3-iethyl--phenyl-1H-pyrazole-4carbaldehyde (0.113 g, 0.510 mmol) for 4-(4chlorophenoxy)benzaldehyde. 1H NMR (400 MHz, CDC1 3 6 7.62-7.19 9H), 6.97 11), 3.43 21), 3.08-2.98 WO 03/004027 PCTUS02/21063 211 2H), 2.58-2.43 2H), 2.39-2.32 3H), 2.18-1.71 6H), 1.24 6H, J 6.9 Hz); ESMS m/e: 451.2 (M Example 112 4- (3,4-DICHLOROPHENOXY)BENZYL -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by the procedure described in example 108, substituting 4-(3,4dichlorophenoxy)benzaldehyde (0.136 g, 0.510 mmol) for 4-(4-chlorophenoxy)benzaldehyde. 'H NMR (400 Mlz, CDC1 3 6 7.53 1H), 7.36-7.18 Cm, 6H), 7.08 1K, J 1.8 Hz), 6.96 3K, J 6.8 Hz), 6.84 (dd, 1K, J 2.8, 8.9 Hz), 3.51 Cs, 2H), 2.99 2H, J 11.5 Hz), 2.55- 2.42 2H), 2.12-2.02 Cm, 2H), 1.84-1.73 Cm, 4H), 1.24 6H, J 7.0 Hz); ESMS m/e: 497.1 (M Example 113 2-METHYL-N- (3-{1-(2-PHENYL-lH-IMIDAZOL-4-YL)METHYLJ-4- PIPERIDINYL}PHENYL)PROPANAMIDE: Prepared by the procedure described in example 108, substituting 2phenyl-H-imidazole-4-carbaldehyde (88.0 mg, 0.510 miol) for 4-C4-chlorophenoxy)benzaldehyde. 'H NMR (400 MHz, CDC1 3 6 7.92 2H, J 7.4 Hz), 7.65-7.31 6H), 7.28-7.18 2H), 7.12-7.05 Cm, 1H), 6.95-6.88 Cm, 1K), 3.69 Cs, 2H), 3.17-3.05 2H), 2.62-2.45 Cm, 2H), 2.28-2.18 Cm, 2H), .1.88-1.70 Cm, 4H), 1.25 Cd, 6H, J 6.8 Hz); ESMS m/e; 403.2 CM Example 114 N-(3-{1-(4-(DIPHENYLAMINQ)BENZYL) -4-PPERIDINYLPHENYL) 2-METHYLPROPANAMIDE: Prepared by the procedure described in example 108, substituting 4- (diphenylamino)benza1dehyde (0.139 g, 0.510 mmol) for 4- WO 03/004027 WO 03/04027PCTIUS02/2 1063 212 (4chlorophenoxy)benzaldehyde. 111 NMR (400 MHz, CDC1 3 7.49 1H1), 7.39-6.92 (mn, 18H1), 3.49 2H1), 3.02- 2.99 211), 2.59-2.43 (in, 211), 2.15-2.03 (in, 2H), 1. 92 76 Cm, 4H1), 1. 23 Cd, 6H, J 8 HZ) ESMS M/e: 504.2 (M H1).
Example 115 N- [4-BROXO-1- (4-CNLOROEZYL) YL] METHYL}-4 -PIPERIDINYL) PHENYL] -2 -METHYLPROPANAMIDE: Prepared by the procedure described in example 108, substituting 4-bromo-l- (4-chlorobenzyl) carbaldehyde (0.153 g, 0.510 inmol) for 4-(4chlorophenoxy)benzaldehyde. NMR (4 00 MHz, CDC1,) 6 7.41 Cs, 111), 7.36 111, LT 8.8 Hz) 7.34-7.30 (m, 311), 7.29-7.26 Cm, 111), 7.22 Ct, 1H, J 7.8 Hz), 7.16' Cd, 2H, J 8.6 Hz) 6.95 111, LT 7.5 Hz), 5.24 Cs, 211), 3.61 211), 3. 09 Cd, 2H1, J =11. 9 Hz) 2.55-2.42 Cm, 2H), 2.19 Cdt, 2H1, J 4.4, 11.4 Hz), 1.89-1.76 Cm, 411), 1.24 6H1, JT 6.7 Hz); ESMS m/e: 529.1 CM 1- (lR)-3 -CHLORO-PHENYLPROPYL) OXY}PHEIYL) ETHANONE- Azodicarboxylate (5.37 g, 0.0310 mol) was added to a solution of triphenyiphosphine (8.09 9, 0.0308 mol), 1S- 3-chloro-l-phenyl-1-propanol (4.20 g, 0.031 mci) and, I- C3-hydroxyphenyl)ethanone in THE (150 mL). The reaction mixture was stirred for 4* days at 23 CC. The solvent was removed under reduced pressure and the residue was triturated with ether/hexane (3 X 100 mL) .The combined organic fractions were concentrated in vacuo and the crude product was purified by chromatography using EtOAc/hexane (1:14) to give the desired product (6.55 g, 1H1 NMR C400 MHz, CDC1 3 6 7.48-7.31 (mn, WO 03/004027 PCT/US02/21063 213 6H), 7.26 Ct, 2H, J 8.2 Hz), 7.04 1IL J 8.1 Hz), 5.44 (dd, 1H, LT= 4.4, 8.1 Hz), 3.83-3.74 1H), 3.63-3.56 Cm, 1H), 2.51 3H), 2.51-2.45 1H), 2.29-2.17 1H); ESMS z/e: 289.0 CM H).
Example 116 (3-ACETYLPIENOXY) -3-PHEYLPROPYLJ-4- PIPERIDENYL}PHENYL)-2-METHYLPROPANAMIDE: A mixture of 1- (3-{[(iR)-3-chloro-1-phenylpropyloxylphenyl)ethanone (58.5 mg, 0.200 mmol), 2-methyl-N-[3-C4piperidinylphenylpropanamide (56.8 mg, 0.200 mmol), Nal (34.0 mg, 0.200 mmol) and K 2 C0 3 C55.5 mg, 0.400 mmol)in DMF (1 mL) was stirred at 100 0 C for 3 h. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica using of NH 3 (2.0 M in methanol) in CH 2 Cl 2 to give the desired product (98 mg, 'H NMR C400 MHz, CDCl 3 6 8.01 Cs, 1H), 7.49-7.21 11H), 7.09-7.03 Cm, 1H), 6.96 Cd, 1H, LT 7.9 Hz), 5.32 Cdd, 1H, J 5.0, 7.9 Hz) 3.08-2.98 2H), 2.57-2.43 Cm, 6H), 2.11-1.72 Cm, 9H), 1.25 (d, 6H, LT 6.8 Hz); ESMS m/e: 499.4 CM Procedures: Procedure A (see also exampe 48) N-(3-{l-[(3R)-3-(3,4-DIMETHOXYPHENOXY) -3-PHEYLPROPYL]- 4-PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE: 0 0- 0 -N
IN
C3 O 0 WO 03/004027 PCT/US02/21063 214 Method A 4-{[(1R)-3-CHLORO-1-PHENYLPROPYL]OXY}-1,2- DIMETHOXYBENZENE: A mixture of 3,4-dimethoxyphenol (4.07 g, 26.4 mmol), (S)-(-)-3-chloro-phenyl-l-propanol (4.50 g, 26.4 mmol, 99% ee, Aldrich Chemical Co.), triphenylphosphine (6.92 g, 26.4 mmol) and diethyl azodicarboxylate (4.59 g, 26.4 mmol) in THF (110 mL) was stirred at room temperature for 24 h. The reaction mixture was concentrated in vacuo. At this point, the residue can either be washed with pentane and the combined pentane extracts were concentrated and chromatographed with hexane:EtOAc as the eluent to give the desired product (as described as a general procedure by: Srebnik, Ramachandran, Brown, H.C. J. Org. Chem. 1988, 53, 2916-2920). This procedure was performed on a smaller scale reaction and only a yield of the product was realized.
Alternatively, 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. The filtrate was concentrated and the crude product was chromatographed to give the desired product as a thick yellow oil (7.30 g, 88.9% yield): IH NMR (400 MHz, CDC1 3 6 7.39-7.32 4H), 7.20 1H), 6.64 1H, J 8.7 Hz), 6.51 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 3.77 3H) 3.61 1H), 2.45 1 2.20 1H), 1.80 1H); ESMS m/e: 307.1 (M H) WO 03/004027 PCT/US02/21063 215 DIMETHOXYPHENOXY)-3- PHENYLPROPYL]-4-PIPERIDINYL)PHENYL)-2-METHYLPROPANAMIDE: A mixture of potassium carbonate (321 mg, 2.32 mmol), sodium iodide (522 mg, 3.48 mmol), 2-methyl-N-[3-(4piperidinyl)phenyl]propanamide (570 mg, 2.32 mmol) and 4-{[(1.R)-3-chloro-l-phenylpropyl]oxy)-1,2dimethoxybenzene (712 mg, 2.32 mmol) in DMF (5.00 mL) was stirred at 100 oC for 3 h, at which time TLC indicated that 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 mL), dried over MgS04 and concentrated under reduced pressure. The crude product was purified by Preparatory TLC of NH 3 (2.0 M in methanol) in CHC1 3 to afford the product (970 mg, 90.1%) as a thick oil.
Method B Into a 25-mL RB-flask was added triphenylphosphine (9.80 mg, 0.0375 mmol), diethyl azodicarboxylate (5.22 mg, 0.0300 mmol), N-(3-{l-[(3S)-3-hydroxy-3-phenylpropyl]-4piperidinyl}phenyl)-2-methylpropanamide (9.53 mg, 0.0250 mmol), 3,4-dimethoxyphenol (7.70 mg, 0.0500 mmol) and THF (1.00 mL) at room temperature. The reaction mixture was stirred at room temperature overnight (16 The solvent was removed under reduced pressure and the residue was purified by preparative TLC plates of
NH
3 (2.0 M in methanol) in CHC1 3 to afford the desired product (4.40 mg, 34.1 yield) as a thick oil: 'H NMR (400 MHZ, CDC13) 6 7.46 1 7.40-7.30 4H), 7.25 3H), 6.97 1H, J 7.8 Hz), 6.64 1H, J 9.1 Hz), 6.51 1H, J 2.6 Hz), 6.29 1H, J 2.6, 9.1 Hz), 5.20 (apparent dd, 1H, J 4.4, 8.5 Hz), 3.80 WO 03/004027 WO 0/00027PCT/UJS02/21063 216 3H), 3.77 3H), 3.23 Cm, 2H), 2.77 (in, 2H) 2.5 (in, 2H) 2 .3-2.1 Cm, 6H) 1. 80 (mn, 2H) 1.25 6H, J =7.9 Hz) ESMS mnle: 517.4 (M Procedure B (see also example 49) 2-METHYL-N- -3-PHENOXY-3-PHENYLPROPYL] -4- PIPERIDINYL}PHENYL)PROPANAMIDE: A mixture of N-C3-{l- -3-hydroxy--3-phenylpropyl) -4-piperidinyl}pheny1) -2methyipropanamide (9.53 mng, 0.0250 mmol) phenol (4.70 mg, 0.050 inmol), triphenyiphosphine C9.80 mg, 0.0375 minol) and diethyl azodicarboxylate (5.22 mng, 0.0300 inmol) in THF (1.00 mfL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC 1s plates [2.50- of NH 3 C2.0 M in methanol) in CHCl 2 gave the desired product (2.70 mg, 23.6 yield) as a thick oil: 1H NMR 5 7.46 2H), 7.40-7.30 Cm, 4H), 7.25 Cm, 7.20 Cm, 2H1), 6.97 (apparent d, 111, J 7. 4 Hz) 6.89 (apparent tt, 1H, J 0.8, 7.6 Hz) 6.84 (apparent dt, lH, J 0. 8, 8. 0 Hz), 5. 20 (apparent dd, IH, J 4. 4, 8. 5 Hz) 3. 35 2H)( 2. 91 Cm, 2H1), 2. 60 Cm, 2H) 2.30-2.10 (in, 6H) 1.90 (in, 2H), 1.25 6H, J =7.9 Hz); ESMS m/e: 457.4 (M H+ Procedure C WO 03/004027 WO 0/00027PCT/UJS02/21063 217 Scheme 0 SCu, K 2 C03, NMP RI-+ 2 N Q 150 0 C, 12 h R1-R
HR
Rl=H, R 2 =4'-Me 1-(4-METHYLPHENYL)lH-INDOLE: A mixture of 1-H-indole (58.5 mg, 0.500 mmoi), 1-iodo-4-methylbenzene (0.218 g, 1.00 mmol), copper powder (32.0 mg, 0.500 mmol), and
K
2 C0 3 (0.138 g, 1.00 mmcl) in 1-methyl-2-pyrrolidinone 00 mL) was heated at 150 0 C for 12 h under argon. The resulting mixture was diluted with H 2 0 (6 mL) The aqueous layer was extracted with CH 2 Cl 2 (3 X 10 mL) .The combined organic extracts were washed with brine mL) dried over MgSO 4 and concentrated in vacuo. The residue was purified by preparative TLC using EtOAc:hexane to give the desired product (82.0 my, 79.0 NIVR (400 MHz, CDCl 3 (5 7.67 1H, J 7.7 Hz), 7.52 1H, J 7.4 Hz), 7.38 2H, J 8.4 Hz), 7.34-7.29 Cm, 3H), 7.21 (t, 1 lH, J =7.0 Hz), 7.15 t, lIH, J 7.0 Hz), 6.66 1H-, J =3.3 Hz), 2.43 3H); ESMS mn/e: 208.0 CM Procedure D (see also example 86) WO 03/004027 WO 0/00027PCT/UJS02/21063 218 Scheme N
H
N R 3
I
S dioxane/HOAc
R
3 H H rt, 5h
R
1
R
2 R N
R
H
Example N
NH
dioxanetHOAc0 G-N H H
R
1
R
2 N-R N
R
H
R
1 =6-CI. R 2
=H
R
1
R
2 =4'-toiyl N- (3-{1-[(6-CHLORO-lH-I'IOL-3-YL) METHYL) -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE; A solution of 2-methyl-N-[3- (4-piperidinyl)phenyllpropanamide (0.369 g1.50 mmol) and 37 wt Fs aqueous formaldehyde (30.0 mg, 1.50 mmol) in 1.00 mIL of HOAc:dioxane was added to 6-chloro-l-H-indole (0.152 g, 1.00 mmol) and the reaction mixture was stirred for 12 h at room temperature. The resulting mixture was diluted with 1120.
niL) The aqueous layer was extracted with C11 2 C1 2 (3 X 100 niL) -The combined organic extracts were washed with brine (10 mL) dried over M9S0 4 and concentrated in Vacuo. The residue was purified by preparative TLC plates using 5% of NH 3 0 M in methanol) in CH 2 Cl 2 to give the desired product (79.0 mg, 42.0 1H1 NMR (400 MHz, CDCl 3 5 9. 14 (s 111), 8 .04 IH) f 7. 52 t, 211, J 8. 1 Hz) 7.35 2H, J 13.3 Hz) 7. 18 111, J= 7.9 Hz) 7.09 (dd, IH, J 8.5 Hz) 6.85 1H, J WO 03/004027 WO 0/00027PCT/UJS02/21063 7. 4 Hz) 5.18 11), 219(s H) (septet, 1H1, J 6.8 Hz), 2.48-2 .34 3H1), 2. 08-1 (in, 4H) 1. 78 2H, J 12. 8 Hz) 1. 22 6H, J 6. 8 Hz) ESMS 410.1 (M Procedure E (see also example Scheme M 0 /R 3 n NRH R2N ZnC1 2 HOAc /O 0 N 0 1
NH
2 75 0 C,10h R3i N Example 0 H
R
3 R 3 Nr n R ZnC1 2 HOAc
NO
R1 0 NH 2 75 R2 2R n=2, Rl=H, R 2 =Ph, R 3
=H-
R
1
R
2
R
3 n=1, Rl=H, R 2 =Ph, R 3
=H
n=4, R 1
R
2
R
3 N-(3-{l-f3-(l,2-DIPHENYL-lH-INDOL-3-YL)PROPYL]-4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: A mixture of 1,1-diphenyihydrazine hydrochloride (10.3 mg, 0.0470 mmcl), 2-methyl-N-{3-[T-(5-oxo-S-phenylpentyl)-4piperidinyllphenyllpropanamide (14.7 mg, 0 .0362 mmol) ZnC1 2 (14.8 mng, 0.109 mmcl), and HOAc (0.500 mL) was heated for 4 h at 80 0 C. The resulting crude mixture was diluted with water (10 rnL), the aqueous layer was neutralized with saturated K 2 C0 3 (10 mL) and extracted with CH 2 Cl 2 (3 X 20 mL) The combined organic layers were concentrated in vacuo and the residue was purified WO 03/004027 WO 0/00027PCT/UJS02/21063 220 by preparative TLC plates using of NH 3 0 M in methanol) in CH 2 C1 2 to give the desired product N- {l- (1,2-diphenyJ.-lH-indol-3-yl)propyli)-4piperidinyl~phenyl) -2-methylpropanamide (4.10 mg, 37.0 %)1H NMR (400 MHz, CDC1 3 5 7.71-7. 65 (in, 1H1), 7.42 (d, 1H, J 7.4 Hz) 7.39 Cs, IH) 7.36-7.15 (in, 15H-) 6.94 111, J 7.8 Hz), 3.12 211, J =11.2 Hz), 2.90 (t, 2H, J 7.8 Hz), 2.S9-2.45 Cm, 2.19-1.91 (mn, 7H), 1. 82 211, J =13. 5 Hz) 1. 24 Cd, 611, J 9 Hz); ESMS nile: 555.3 (M H) 4 Procedure F (see also example 108) Scheme R NaBH(OAc) 3 H N I,2-dichloroethane "N HOAc, rt, overnight R 1 N R2
R
2 Example NaBH(OAc) 3 RjCH Ha -Q 1 ,2-dichloroethane HOAc, rt, overnight R, NH NH 0 0 NT- (4-CHLOROPHENTOXY)BENZYL] -4- PIPERIDINYL)PHENYL) -2 -METHYLPROPANAMIDE; A solution of 4-C4-chlorophenoxy)benzaldehyde (0.119 g, 0.510 rnmol) and 2-methyl-N- C4-piperidinyl)phenyllpropariamide (0-126 g, 0.510 minol) in 1,2-dichlorcethane (5.00 ML) WO 03/004027 WO 0/00027PCT/UJS02/21063 221 was treated with sodium triacetoxybcrohydride (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 NaHCO 3 aqueous solution (10 mL) and the aqueous layer was extracted with CH 2 Cl 2 (3 x 10 mL). The combined organic layers were washed with brine, dried over MgSO 4 concentrated in vacuo and purified by preparative TLC plates using 5% of NH 3 (2.0 M in methanol) in CH 2 C1 2 to give the desired product (53.0 mg, 23.0 '1 2 NMR (400 MHz, CDC1 3 5 7.50 1H) 7.34- 7.19 6.98-6.87 (in, 5H), 3.50 2H), 2.98 (d, 2H, J =11.8 Hz), 2.58-2.44 (in, 2H), 2.10-1.98 (mn, 2H), 1. 83-1.76 4H) 1. 24 6H, J 6. 8 Hz) ESMS m/e: 463.2 (M Procedure G (see also example 116) Scheme F R-halide; diisopropylethylamine HN/ or Na 2 00 3 R-Nc:- ql/ 0 BU 4 NIor KI; 0 N dioxane, touene, N or DMF; heat 50-90% N- (3-ACETYLPHENOXY) -3-PHENYLPROPYL] -4- A mixture of 1- -3-chloro-l-phenylpropyl) oxy~phenyl) ethanone (58.5 mg, 0.200 mmol), 2-methyl-N-[3-(4piperidinyl)phenyllpropanamide (56.8 mg, 0.200 minol), Nal (34.0 mg, 0.200 mmol) and K 2 C0 2 (55.5 mg, 0.400 inmol) in DMP (1.00 mL,) was stirred at 100 0 C for 3 h. The WO 03/004027 WO 0/00027PCT/UJS02/21063 222 solvent was removed under reduced pressure and the residue was purified by chromatography on silica using of NH 3 (2.0 M in methanol) in CH 2 Cl 2 to give the desired product (98.0 mg, 98.0 'H NMR (400 MHz, CDCl 3 8.01 1H) 7.49-7.21 11H) 7.09-71.03 (in, 1H), 6.96 1H, J 7.9 Hz) 5.32 Cdd, 1H, J 5.0, 7.9 Hz), 3.08-2.98 2H), 2.57-2.43 (in, 6H), 2.11-1.72 (in, 9H) 1. 25 6H, J 6.8 Hz) ESMS m/le: 499.4 (M H).
Scheme S
-R
2 ZnCI 2 HOAc RN3L 80 NH2 n= 0 -3 Procedure H 0
N
NH
2 ZnCt 2 HOAc 80 0 C, 12 h 2-METHYL-NV-(3-{1- (1-METHYL-1H-INDQL-3-YL) PROPYL] -4- PIPERIDINYLPHENYL)PROPANAMIDE: A mixture of N- WO 03/004027 WO 0/00027PCT/UJS02/21063 223 3-dioxolan-2-yl)butyl] 4-piperidinyllphenyl) -2methyipropanamide (100 mg, 0.270 mmol), 1-methyl-iphenylhyd'razine (106 mg, 0.870 mmol) ZnC1 2 (119 mg, C.870 minol), and HOAc (1.00 mL) was heated for 12 h at s0 0 C. The resulting crude mixture was diluted with water (20 mL) the aqueous layer was neutralized with saturated T{ 2 C0 3 solotion (10 mL) and extracted with CH 2 Cl 2 (3 X 20 mL) The combined organic layers were concentrated in vacua and the residue was purified by preparative TLJC using 3 of NH 3 (2.0 M in methanol) in
CH
2 C1 2 to give the desired product 2-methyl-N-C3-1-[3- (1-methyl-lH-indol-3--yl)propyl] -4piperidinyl~phenyl)propanamide (20.7 mg, 18.7%) NMR (400 MHz, CDC1 3 5 7.60 1H, J 8.1 Hz), 7.45 1H) 7.35 1H, J 7.4 Hz) 7.26-7.24 (in, 4H), 7.09 1H, J =7.3 Hz), 6.97 Cd, 1H, J 7.3 Hz), 6.86 1H) 3.75 3H) 3. 11 2H, J 11. 6 Hz) 2.79 2H, J -7.3 Hz) 2.51-2.50 4H) 2.12-1.8 BI m, 8H), 1.25 6H, J =7.1 Hz); Anal. Calcd for
C
2 7
H
3 5
N
3 0+O.225CHC1 3 C, 73.57; H, 7.99; N, 9.45. Found: C, 73.93; H, 7.90; N, 9.23; ESMS rn/c: 418.2 (M Procedure I Scheme T
B(OH)
2 Pd(PPh 3 4 Na 2
CO
3 LiCI, I I Br- IR N N DM/ 2 0, 90 0 C H H R WO 03/004027 WO 0/00027PCT/UJS02/21063 224 HO" BIC F Pd(PPh), LICI, Na 2 00 3
N
3)4,
N'
N ~DME, 75 OC,1 2hF Br 7-(2-FLUOROPHENYL)-1H-INDOLE: A mixture of 2fluorophenylboronic acid (83.4 mg, 0.600 mmol), 7-bromo- 1H-indole (98.0 mg, 0.500 mind), LiC. (42.0 ing, 1.00 iniol), Na 2
CO
3 (2.0 M, 0.100 inL), Pd(PPh 3 4 (115 Mng, 0.100 iniol) and DME (2.00 mL) was heated at 75 0 C for 12 h under Argon. The resulting crude mixture was diluted with water (40 inL), the aqueous layer was extracted with
CH
2 Cl 2 (3 X 20 rnL) .The combined organic layers were washed with brine (30 inL) dried over Na 2 SO4, filtered, and concentrated in2 vacuc. The residue was purified by preparative TLC using hexane:EtOAc to give the desired product 7- (2-f luorophenyl) -lH-indole (108 mng, 100 NNR (400 MHz, CDCl 3 8.21 (hr s, 1H) 7.71 (din, IH, J 7-55 (dt, lH, J 7.3, 1.6 Hz), 7.39 (mn, 1 H) 7.30-7.19 (in, SH) 6.62 (dd, l1H, J 2.1-3.3 Hz) ESMS m/e: 211.9 (M Procedure J Scheme U
OH
Br X Cu, K 2 C0 3 0_ II I C N NMP, 160 0 C H H RRH WO 03/004027 WO 0/00027PCT/UJS02/21063 225 Br Cu, K 2 00 3 N DMF, 160 OC0 (4-ZMETHYLPHENOXY) lE-INDOLE: A mixture of 5-bromo- IHindole (98.0 mg, 0.500 mmcl), p-cresol (10B mg, 1.00 mmol), Cu (32.0 mg, 0.500 mmol), K 2 C0 2 1 (138 mg, 1.00 mL) and DMF (1.00 mL) was heated at 160 0 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 X 20 mL).
The combined organic layers were washed with brine mL), dried over Na 2
SO
4 filtered, and concentrated in vacuo. The residue was purified by preparative TLC using hexane:EtOAc to give the desired product (4-methylphenoxy)-IH--indole (57.5 mg, 51.5 ESMS m/e: 224.0 (Mv Procedure K 0N Y--Nal, K.2C03, DMF 0 RL NI 1 I ci 0 90 12h >R-(N
N
WO 03/004027 WO 0/00027PCT/UJS02/21063 226 Scheme AN 0 N 0 0 NaI, K 2 C0 3 DMF NE N -CY NH
N
Ar NaBH 4 MeOH Cr
OH
N N DEAD, PPh 3 ArOH R+ NH 1 NH n 1-4 N- (2-FLIJOROPHENYL) -7-OXOHEPTYL] -4- PIPERIDINYL)PHENYL) -2 -METHYLPROPAIAMIDE: A 50 -mL roundbottom flask was charged with a solution of 7-chloro-1-oxo-l(2-fluorophenyl)heptane (2.42 g, 10.0 mmol), 2-methyl-N- E3- (4-piperidyl)phenyl) propanamide (2.46 g, 10.0 mmol), K 2 C0 3 (2.76 g, 20.0 mmol) and NaI (2.25 g, 15.0 mmol) in DMF (25.0 mL). The mixture was stirred for 10 min at 25 'C and then heated at 100 0 C for 12 h, 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 layers were 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 give the desired product (3.70 g, 82.0 Procedure L WO 03/004027 WO 0/00027PCT/UJS02/21063 227
OH
N N NaBH 4 MeOH R N
NHNH
0H0 Scheme AN o NN 0 +L I NaI, K 2 C0 3 DMF N
NH
0 NaBH 4 MeOH c_ N N DEAD, PPh 3 ArOH OH N n N H
H
n =1-4 N- (2-FLUOROPHENYL) -7-IYDROXYHEPTYLJ -4- PIPERIDINYL}PHENYL) -2 -METHYLPROPANAMIDE: To a round-bottomed flask charged with fluorophenyl) -7-oxoheptyl] -4-piperidinyl~phenyl) -2methyipropanamide 0 mmcl) and methanol (20 mL) was added NaBH 4 (7.5 mmol) at 0 'C in an ice-bath. The reaction mixture was warmed to 25 'C and stirred for 2 h.
The reaction was monitored by TLEC (EtOAc:MeOH 95:5) if necessary, another 5.C mmol of NaBH 4 Was added 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 WO 03/004027 WO 0/00027PCT/UJS02/21063 228 product was purified by chromatography (EtOAc:MeOH 97:3) to give the desired product Procedure K Scheme A 0 R C1 TEA, THF HC1 or TEA
~-R
N
H
Step 1: If reacted individually, a solution of the amine or aniline (1.00 eq), diisopropylethylamine or TEA (2.00 eg) and an electrophile (1.50 eq) in CH 2 Cl 2 was stirred fcr 24 h at 23 The solvent was removed in vacuo and the crude product was chromatographed (silica) to give the final product.
N H 2 C1 &XNO
CI
TEA, THF TERT-BUTYL [(4-CHLOROBtJTANOYL) AMINO] PHENYL}-1- PIPERIDINECARBOXYLATE (3.32 g, 87.4 was synthesized according to Scheme A and Procedure M: 1 H NMR (400 MHz, CDCl 3 5 7.55 1H) 7.47 1H) 7.37 (in, 1H), 7.28 (in, 1H) 6.97 1H, J 7.6 Hz) 3.89 1H, J =6.4 WO 03/004027 WO 0/00027PCT/UJS02/21063 229 lz) 3. 74 Cm, 2H) 2.79- 2.75 (in, 2.64 (m, 2H1), 1.88-1.77 Cm, 4H), 1.60-1.59 (in, 4H), 1.48 9H).
0 0
N
HCI or TEA N
N
BOC H Step B: TERT-BUTYL 4- (2-OXO-1-PYRROLIDINYL) PHENYL) -1- PIPERIDINECARBOXYLATE: To a solution of tert-butyl 4- 13- (2-oxo-1-pyrrolidinyl)phenyl] -1-piperidinecarboxylate (0.429 g, 16.9 mmol) in dioxane (100 mL) was bubbled HCi gas for 1 h at 25 The resulting crude mixture was basified with 10% KOH solution C100 mL), the aqueous layer was extracted with 3:1 CHCl 3 :iso-propyl alcohol C3 X 150 mL) The combined organic layers were washed with brine C100 mL), dried over Na 2
SO
4 filtered, and concentrated in vacuo. The residue was purified by preparative TLC using 20% NH 3 A 0 M in MeOH) in CH 2 Cl 2 solution to give the desired product tert-butyl 4-[3-C2oxo-1-pyrrolidinyl) phenyl) -1-piperidinecarboxylate (245 mg, 78.7 H NMR C400 MHz, CDCl 3 8 7.52 Ct, 111, J 1.8 Hz), 7.41 Cddd, 1H1, J 8.1, 2.3, 0.9 7.30 Ct, 1H, J 7. 9 Hz) 7. 02 lH, J 7. 9 Hz) *3.86 2H, J 7.3 Hz) 3 .21 Cdt, 2H, J 11. 9, 2. 9 Hz) 2. 76 (dt, 2H, J =12. 1, 2. 4 Hz) 2. 65 Ct t, 1H1, J 11. 9, 3.5S Hz), 2.61 Ct, 2H1, J 8.3 Hz), 2.22 Cbr s, 1H), 2.16 Cqt, 2H, J 7.5 Hz), 1.85 2H, J 12.4 Hz), 1.67 Cdq, 2H, J 12.5, 4.0 Hz).
WO 03/004027 WO 0/00027PCT/UJS02/21063 230 0 0 NH N R N N~R 1-H 2 ROOCI, E^ 3 N THF, 2 h TFA, CH 2
CI
2 rlt, 6 h R Et, i-Pr, n-Ru, cyc-Pr, atc.
N
N
I
H
boc buc TERT-BTJTYL 4- (4 -AMINOPHENYL) -1-PIPERIDINECARBOXYLATE: Available from Arch Chemical Company, NJ.
2-METHYL-N- (4 -PIPERIDINYL) PHE'YL) PROPANAMIDE: To a solution of tert-butyl 4- (4-aminophenyl) -1piperidinecarboxylate (8.20 9, 29.7 mmol) and trietihylamine (8.4 mL, 60 mmol) in dry THE (100 mL) at 0 'Cwas slowly added a solution of 2-methyipropanoyl chloride (3.84 9, 36.0 mmol) in THF (50 mL) The reaction mixture was then warmed up to room temperature and stirred for 2 hi. After removing the solvent in vacuo, the crude product, was purified by recrystallization (hexane/THF), affording the desired amnide, tert-butyl 4- A- (isobutyrylamino)phenyl -1piperidinecarboxylate, as a white solid (8.60 9, 84%).
The tert-butyl 4- (isobutyrylamino) phenyl] -1piperidinecarboxylate was dissolved in CH 2 C1 2 (50 mL) at room temperature, TFA (13.68 g, 120 mmol, 5 equiv.) was added by syringe. The reaction mixture was stirred for 3 or 4 h and another 5 equivalents of TFA was added and the mixture was stirred for 2 or 3 more hours. The reaction solution was then basified to pH 14 by KOH WO 03/004027 WO 0/00027PCT/UJS02/21063 231 (aq, 2 The solution was extracted with CH 2 Cl 2 (8 x 200 mL) The combined organic layer was dried over
K
2 C0 3 Removal of solvent under reduced pressure gave the free amine, 2-methyl-N--E4-(4piperidinyl)phenyllpropanamide, as a brownish solid (5.9.9 g, .98%0) NMR (400 MI-z, CDCl 3 3 7.55-7.35 (m, 211), 7.35-6.9 (in, 31) 3.26-2.98 (in, 211), 2.84-2.64 (mn, 211), 2.64-2.53 (mn, 1H1), 2.53-2.32 Cm, 111), 1.90-1.68 (in, 211), 1.68-1.36 Cm, 311), 1.22 6H, J =6.0 Hz); ESMS rn/c: 2 47. 1 (M H) 4.
N- (4-PIPERIDINYL) PIENYL] PROPANAMIDE: the procedure for piperidinyl)phenylJ propanamide using aminophenyl) -1-piperidinecarboxylate chloride: ESMS rn/e: 233.1 (M N- 14- PIPERIDINYL) PHEINYL] BUTANAMIDE: proceduare for piperidinyl) phenyl) propanamide using aminophenyl) -1-piperidinecarboxylate chloride: ESMS rn/e: 247.2 (M Prepared by 2-methyl-NV- 4- (4tert-butyl 4-(4and propanoyl Prepared by the 2-methyl-N- f4- (4tert-butyl 4- (4and butanoyl N- (4-PIPERIDINYL) PHENYL) CYCLOPROPANECARBOXAMIDE: Prepared by the procedure for 2-methyl-N-[4-(4piperidinyl)phenyl] propanainide using tert-butyl 4- (3aininophenyl) -1-piperidinecarboxylate and cyclopropanecarbonyl chloride: Anal. Calod for Cj 5
H
2 0
N
2 0+0.15CH 2 Cl 2 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)4.
WO 03/004027 PCT/US02/21063 232 N-[3-(4-PIPERIDINYL)PHENYL]PROPANAMIDE; Prepared by the procedure for 2-methyl-N-[4-(4piperidinyl)phenyl]propanamide using tert-butyl 4-(3aminophenyl)-1-piperidinecarboxylate and propanoyl chloride: Anal. Calcd for C 1 4
H
20
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.
Procedure N Scheme AV PS-TBD resin N C N R benzyl bromide or benzyl iodide CH 3
CN
R
1 RT,16 h Ar 0
RI
The library was constructed in polypropylene Robbins 46 well plates Reactor Blocks. In the initial incubation period, each well was charged with PS-TBD resin (from Argonaut Technologies, 0.280 mmol, 2.50 eq, 200 mg) and piperidine (0.120 mmol, 1.10 eq) in acetonitrile (0.500 mL) and agitated for 1 h. A solution of benzyl iodide or bromide (0.110 mmol, 1.00 eq) in acetonitrile (0.500 mL) was added to each well followed by additional acetonitrile (1.00 mL) to make a total volume of 2.00 mL and the mixture was rotated in a Robbins rotating oven at room temperature for 16 h. Then AP-Isocyanate resin (Argonaut Technologies, 250 mg, 0.430 mmol, 4.00 eq) was added to each well and reacted further at room temperature for another 12 h. The mixture was filtered WO 03/004027 PCT/US02/21063 233 and the filtrate was concentrated in vacuo to obtain the desired product that was characterized via
LC-MS.
Procedure 0 Alkylation of Piperidines Using Alcohols and PS-TSC1 Resin in Robbins 48 well "Reactor Blocks" Scheme W R1
R
The library was constructed in polypropylene Robbins "Reactor Blocks", 46 well plates. PS-TSC1 resin (100 mg, 1.00 eq, purchased from Argonaut Technologies) was placed in each well of the "Reactor Blocks" 46 well plates. To each well was added an alcohol (1.50 mmol) in 3.00 mL of CH 2 C12 and pyridine The mixture was stirred for 5 h.and the resin was washed with CH 2 C1 2 (3 x 4mL), DMF (5 x 4.0 mL), DMF/H 2 0 5 x 4.0 mL), THF (3 x 4.0 mL), CH 2 C1 2 (3 x 4.0 mL), acetonitrile (2 x 4.0 mL) and dried under reduced pressure. A solution of an amine (0.0750 mmol, 0.500 eq) and N,N-diisopropylethyl amine (19.0 mg, 0.150 mmol, 1.00 eq) in acetonitrile (3.00 mL) was added to the well containing the derivatized resin and the mixture was reacted at 70 °C for 16 h. Finally, AP-Isocyanate resin (120 mg, 0.150 mmol, 1.00 eq) and THF (2.00 mL) was added to the reaction vessel and reacted at room temperature for another 3 h. The solution was filtered into the Robbins receiving plates and concentrated in vacuo to give the desired tertiary amine, which was analyzed via LC-MS.
WO 03/004027 PCT/US02/21063 234 Procedure P Scheme AB THF, RT, 12h
RI
R
3 R N=GCX 2 N R X=OorRS N 0 3-{[(4-FLUOROANILINO)CARBO XYL)AMINO)PROPYL)-4- PIPERIDINYL)PHENYL}-2-METHYLPROPANAMIDE: A solution of N-{3-El-(3-aminopropyl)-4-piperidinyl]phenyl}-2ttethylpropanamide (26.4 mg, 0.0870 mol), l-fluoro-4isocyanatobenzene (11.9 mg, 0.0870 mmol), in TEF (1.00 mL) was stirred for 12 h at 25 0 C. The resulting crude mixture was diluted with water (10 mL), the aqueous layer was extracted with CH 2 C12 (3 X 20 mL). The combined organic layers were concentrated in vacuo and the residue was purified by preparative TLC using 2.5 of NH 3 (2.0 M in methanol) in CI-1 2 C1 2 to give the desired produot N-{3-[I-(3-{[(4-fluoroanilino)carbonylamino) propyl)-4-piperidinyllphenyl-2-methylpropanamide (4.18 mg, 10.9 -H NMR (400 MHz, CDCl 3 7.45 2H, J 4.7 Hz), 7.23-7.21 Cm, 4H), 7.05 4H, J 7.8 Hz), 6.75 Cm, 1H), 4.05 Cm, 1H), 3.19 lH), 2.71 1H), WO 03/004027 WO 0/00027PCT/UJS02/21063 235 2.53 (in, 1H), 2.26-2.21 (in, 3H), 1.80-1.60 (mn, 9H), 1.25 6H, J 6 .4 Hz); ESMS nile; 439.4 (M Procedure Q, Scheme AT 0 electrophile, base- C
H
2 P I R 3 -NH NL If reacted individually, a solution of the amine eq), an electrophile (1.5 eq), di is opropyl ethyl amine eq) in CH 2 C1 2 was stirred for 1 day. The solvent was removed in vacuo and the crude product was chromatographed to give the final product.
0 N- :N -N "0 N N is 0 2-METHYL--{3- E(4- METHYLPHENYL) SULFONYL] AMINO}PROPYL) -4 -PIPERIDINYL] PHENYL}PROPANAMIDE: A solution of 4iethylbenzenesulf ony. chloride (16. 6 mng, 0. 0870 inmol) (3-aminopropyl)-4-piperidinyllphenyl}-2methylpropanamide (26.4 mug, 0.0870 inmol), TEA (10.0 mug, 0.174 inmol) in THF (1.00 ruL) was stirred for 12 h at 0 C. The resulting crude mixture was diluted with water (20 inL) the aqueous layer was extracted with CH 2 Cl 2 (2 X inL) The combined organic layers were concentrated WO 03/004027 PCT/US02/21063 236 in vacuo and the residue was purified by preparative TLC using 2.5 of NH 3 (2.0 M in methanol) in
CH
2 C1 2 to give the desired product 2-methyl-N-(3-[1- (3- {[(4-methylphenyl)sulfonyl]amino} propyl)-4piperidinyl]phenyl}propanamide (17.3 mg, 43.6 'H NMR (400 MHz, CDC13) 5 8.19 1H), 7.53 1H), 7.41 (s, 1H) 7.32-7.21 4H), 7.16 1H) 6.97 1H, J 7.9 Hz), 3.44 2H, J 6.3 Hz), 3.15 2H, J 9.8 Hz), 2.62-2.45 4H), 2.15 3H), 2.05 3H), 1.95-1.71 5H), 1.26 6H, J 6.6 Hz); ESMS m/e: 458.2 (M Procedure Q 2 The Capture and Release Method for the Synthesis and Purification of the Piperidine Library The commercially obtained Amberlyst 15 exchange resin (Aldrich) was activated using the following procedure: 1. The resin was shaken in methanol for 24 hr.
2. The resin was filtered and washed with methanol on a fritted funnel.
3. The resin was neutralized with 2N NH 3 in MeOH (pH checked) shaken for 1 hr.
4. The neutralized resin was acidified with 3M HC1 in MeOH (pH checked) shaken for 1 hr.
The resin was captured on a fritted funnel and washed with MeOH.
6. The resin was dried in vacuo and stored.
Synthesis (Acylation of the Amines): The library was constructed in polypropylene Robbins "Reactor Blocks", 46 well plates. In each plate an array of 5 amines (0.10 mmol) and 8 electrophiles (acid WO 03/004027 PCT/US02/21063 237 chlorides, sulfonyl chlorides, 1.5 eq.) in the presence of triethylamine (2.0 eq) in THF/DCM 3;1 mL) were reacted overnight to give 40 compounds/plate.
The reactions were rigorously monitored via TLC to the depletion of the starting amine due to the ensuing purification methodology via the acidic Amberlyst resin. Following the disappearance of the starting amine, the desired products were captured and then released using the process outlined below.
Purification of the Piperidine Products: Activated Amberlyst 15 ion-exchange resin (0.90 g, Aldrich) was added to each well, and the plates were rotated for 2 hours in a Robbins rotating oven to capture the desired final product from the reaction mixture. The solvent was filtered and the resin was washed with CH30H and CH 2 Cl 2 (x 3) alternately with each of the solvents (for minutes each time). After the last filtration, 2 N ammonia in methanol was added to the resin (2 mL to each well) and the reaction blocks were rotated for 2 hours to release the desired compounds from the resin. The final compounds were filtered into Robbins' "Receiving Blocks", the solvent was removed and the compounds were analyzed via LC-MS.
Procedure R WO 03/004027 WO 0/00027PCT/UJS02/21063 238 Scheme Z x TEA, TI-F Bir CI SH n 12 h, RT S n =1-4 n =1-4 X F, CI, Br, I [(3-CHLOROPROPYL)SULFANYLJBENZENE: A mixture of benzenethiol (0.550 9, 5.00 mmol), 1-bromo-3chioropropane (106 mg, 5.50 mmol), TEA (1.01 g, 10.0 mmol) and THP (10.0 mL) was stirred for 12 h at 25 0
C.
The resulting crude mixture was diluted with water mL), the aqueous layer was extracted with CH 2 Cl 2 (3 X mL) The combined organic layers were concentrated in vacuo and the residue was purified by preparative TLC using hexane:EtOAc (10:1) to give the desired product [(3-chloropropyl)sulfanyllbenzene (1.05 g, 100%) Scheme AA x x m-CPBA, CH 2
CI
2 'N S CI 4 h, RT S -I CI n 0 n 1-4 n=1-4 X F, CI, Br, I Procedure S 3-CHLOROPROPYL 4-FLUOROPHENYL SUILFOXIDE: A solution of 3-chioropropyl 4-fluorophenyl sulfide (77.5 mg, 0.380 mrnol) in CH 2 Cl 2 (2.00 mL) was cooled to 0 cC. To this solution m-CPBA (78.7 mrg, 0.460 mrmol) was added. The reaction mixture was stirred at 0 OC for 30 min, then at WO 03/004027 WO 0/00027PCT/UJS02/21063 239 23 0 C for 4 h. The resulting crude mixture was diluted with 10% aqueous Na 2
SO
3 (10 mL), the aqueous layer was extracted with CH 2 C1 2 (2 X 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.S of
NH
3 0 M in methanol) in C11 2 C1 2 to give the desired product 3-chioropropyl 4-f luorophenyl suif oxide (47.8 mg, 57.0%.
Procedure T Scheme ADl R-N -q room R-N Base, THF, CH 3
I
N-H N- Nb N- Me, Base, THF 0 N- (3,4-DIMETHYLPHENYL) -4-OXOBtITYL] -4- PIPERIDINYL}PHENYL) -N,2-DIMETHYLPR0PANMIDE: A mixture of (3,4-dimethyiphenyl) -4-oxobutyl] -4piperidinyllphenyl) -2-methyipropanamide (15.0 mg, 0.0357 mmol), Mel (5.07 mg, 0.0357 mmol), NaOtBu (6.86 mg, 0.0714 mmol) and TI-F (1.00 mL) was stirred for 5 h at 0 C. The resulting crude mixture was diluted with water mL), the aqueous layer was e xtracted with CH 2 Cl 2 (3 X 2 0 mL) The combined organic layers were concentrated in vacuo and the residue was purified by preparative TLC using 4. 0 of NH 3 0 M in methanol) in C-1 2 C1 2 to afford the desired product WO 03/004027 WO 0/00027PCT/UJS02/21063 240 dimethyiphenyl) oxobutyl] -4piperidinyl~phenyl) 2-dimethyipropanamide (13.8 mg, 89.1. :H NMR (400 MHz, CDC1 3 7. 76 1H) 7. 72 (dd, 1K, J 8, 7.7. Hz) 7.33 1H, J 8. 8 Hz), 7.22 1H, J 8 Hz) 1. 18(d, 1H, J B. 88 Hz), 7.01 (m, 2H) 3.24 Cs, 3H) 3.10 1K, J =10.6 Hz), 3.00 Ct, 1H, J 7.6 Hz), 2.49-2.44 (mn, 4H), 2.33 6H), 2.112.1.0 2H), 1.99 (in, 1H), 1.79-1.77 (in, 4H1), 1.26 2H, J 7.6 Hz), 1.02 6K, J 7.6 Hz); ESMS rn/e: 435.2 (M H) Procedure U Scheme AK X NaH, DMF Bir CI OH n1n4 95 -C,12 h 0 C1 X CI, Br, In 1- 0 0
N
0 Br NaH, DMF, 95 OC 1- (3 -CHLOROPROPOXY) PHENYL] ETHANONE: To a suspension of NaH (50.5 mng, 2.00 tumol) in DMF (1.00 inL) was added 1- (3-hydroxyphenyl)ethanone (2.36 mug, 1.00 inmol) at 0 CC.
The reaction mixture was stirred at room temperature for 1 h. To this mixture was added a solution of 1-bromo-3chioropropane (188 tug, 1.20 inmol) in DM8' (0.500 inL). The reaction mixture was stirred at room temperature for h. The resulting crude mixture was diluted with water (20 mL), the aqueous layer was extracted with CH 2 C1 2 (3 x WO 03/004027 WO 0/00027PCT/UJS02/21063 241 ML) The combined organic layers were washed with brine (20 mL) dried over Na 2 E0O 4 filtered, and concentrated in vacua. The residue was purified by preparative TLC using hexane:EtOAc to afford the desired product 1- (3-chloropropoxy)phenyl] ethanone (235 mg, 55.2 1 H NMR (400 MHz, CDCl 3 5 '7.7 1H, J 6.6 Hz), 7.52(s, 1H), 7.25 t, 1H, J 6.6 Hz), 7.01 (in, 1H-) 4. 11 t, 2H1, J 7. 9 Hz) 3. 69 2H1, LJ 7. 9 Hz), 2.61 3N1), 1.95-1.92 211).
Procedure V Scheme AE
N
1-E(2,2-DIMETHYLPROPANOYL)OXY] (4,4,5,5-TETRAMETHYL- 1,3,2-DIOXABOROLAN-2-YL) -1,2,3,6-TETRAHYDROPYRIDINE: To a 50-mL RB-flask, charged with bis(pinacolato)diboron (422 Mg; l.66 inmol) ,KOAc (444 mng, 4.53 minol) and PdCl 2 dppf (37.0 mng, 3.00 mol%), dppf (25.0 mg, 3.00 was added a solution af dimethylpropanoyl)oxy] 6-tetrahydro-4-pyridinyl trifluoroinethanesulfonate (SOO mg, 1.51 mmol) in 1,4dioxane (10.0 mL) at room temperature under. argon. The mixture was heated at 80 0 C overnight. After cooled to room temperature, the mixture was filtered through celite and the celite was washed with EtOAc (3 x 20 md).
The filtrates were concentrated in vacua. The resulting residue was dissolved in EtOAc and washed with H120 and WO 03/004027 WO 03/04027PCTIUS02/2 1063 242 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- dimethylpropanoyl)oxy] (4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl) -1,2,3,6-tetrahydropyridine (3 55 mg, 76.0 Procedure W Scheme AF ~N 0 B r N
HH
N
0
N
BI
N
BOO
TERT-BUTYL 4- (ISOBUTYRYLAIMINO) -2 -METHYLPHENYL] -3,6- DIHYDRO-1(2H)-PYRIDINECARBOXYLATE: To a 50-mL RB flask containing 1-1 (2-,2-dimethylpropanoyl)oxy] (4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl) -1,2,3,6t etrahydropyri dine (500 mg, 1.62 mmol), K( 2 C0 3 (670 mg, 4.86 mmol) and PdCl 2 dppf (155 mg) was added a. solution of N- (3-bromo-4-methylphenyl) -2-methylpropanamide (415mg, 1.62 mmcl) in DMF (10.0 mL) at room temperature under argon. The mixture was heated tc 80 'C under argon overnight. After cooled to room temperature, the mixture was filtered through celite and the celite was WO 03/004027 WO 0/00027PCT/UJS02/21063 243 washed with EtOAC (3 x 20 mL). The filtrates were washed with H~20 (20 mL) brine (20 mL) dried over MgSO 4 filtered and concentrated in vacuo. The crude material was purified flash chromatography (20% EtOAc/ hexane) to give tert-butyl 4- [5-(isobutyrylamino) -2-methyiphenyl) 3,6-dihydro-l -pyridinecarboxylate (360 mg, 62.0 Scheme AG H H N N r 0 x 0 N N BO0O BOG Procedure X TERT-BTJTYL 4- [5-(ISOBUTYRYLAMINO) -2 -METHYLPHENYL] -1- PIPERIDINECAREOXYLATE: A solution of tert-butyl 4-E[S- (isobutyrylamino) -2-methylphenyl] -3,6-dihydro-l (2H) pyridinecarboxylate (335 mg, 0..93 mmol) and 10% Pd/c (35.0 mg) in EtOI{ (20.0 mL) was hydrogenated at room temperature overnight using the hydrogen balloon method.
The reaction mixture was filtered through celite and washed with ethanol (3 x 10 mL) .The combined extracts were concentrated in vacuo to afford tert-butyl 4- (isobutyrylamino) -2 -rethylphenyll -1piperidinecarboxylate (335 mg, 100 Procedure Y WO 03/004027 WO 0/00027PCT/UJS02/21063 244 Scheme All
H
0 2-METHYL-N- [4-METHYL-3- (4-PIPERIDINYL) PHENYLI PROPANA!MIDE:- Into a solution of tert-butyl 4- (isobutyrylamino) -2-methyiphenyl] -1piperidinecarboxylate (335 mg, 0.930 mmol) in CH 2 Cl 2 (10.0 mL) was added TFA (10.0 mL) at room temperature.
The reaction mixture was stirred for 2 h and concentrated in vacuo. The residue was dissolved in mL of CHC13/i-PrOH and was basified with 5% KOH solution (10 mL) The aqueous layer was extracted with CHCl 3 /i-PrOH 3 x 10 mL) The combined organic extracts were washed with brine, dried over Mg90 4 filtered and concentrated in vacuo to give 2-methyl-N- [4-methyl-3- (4-piperidinyl)phenyllpropanamide (190 rug, 78.0 Procedure Z Scheme Al
H
N YR 2 R1 0 N X=C,N
H
Nal, K 2
CO
3
DMF,
95 overnight R3,CI
R
R,-ND"
NH
R2 WO 03/004027 PCT/US02/21063 245 N o F 0 C0
N
F F 4,4-BIS(4-FLUOROPHENYL)BtTYL -4-PIPERIDINYL}-4- METHYLPHENYL)-2-METHYLPROPANAMIDE A solution of 2methyl-N-[4-methyl-3-(4-piperidinyl)phenyl]propanamide (49.0 tg/ 0.190 tmol), 1-[4-chloro-l-(4fluorophenyl)butyl]-4-fluorobenzene (58.0 tg, 0.210 mmol), NaI (42'.0 mg, 0.280 muol) and K 2 C0 3 (52.0 mg, 0.380 mmol) in DM' (10.0 ut) was heated at 95 OC overnight. The mixture was diluted with water (20 rt) and the aqueous layer was extracted with EtOAc (3 x 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
NH
3 (2.0 M in MeOH) in CH 2 C1 2 I to afford bis(4-fluorophenyl)butyl]-4-piperidinyl}-4methyiphenyl)-2-methylpropanamide (37.0 mg, 38.0 Procedure AA WO 03/004027 WO 03/04027PCTIUS02/2 1063 246 Scheme AJ H
H
1,2-Dichioroethane, NaBH(OAc) 3
N.R
'1 0X AcOH, RT, overnight R-j x
R
3
CHO
N X=C, N N
HR
H
N 0N 0 FN 0
N
N F
(F
F
(3,4-DIFLUOROPHENOXY)BENZYL) -4-PIPERIDI.YL}- 4-METHYLPHENYL)-2-METHYLjPROPANAMIDE: To a solution of 4-(3,4-Diffluorophenoxy)benzaldehyde (41.0 mg, 0.170 mmol) and 2-methyl-.N- [4-methyl-3- (4piperidinyl)phenyllpropanamide (45.0 mg, 0.170 mmol) in 1,2-dichioroethane (5.00 mL) was added sodium triacetoxyborohydride (110 mg, 0.520 mmol) and AcOH (10.0 PlL, 0.170 mmol) at room temperature. The mixture was stirred overnight. The reaction mixture was quenched by saturated NaHC0 3 solution (10 mL) and extracted with CH 2 C1 2 (3 x 10 rnL) .The combined organic layers were washed with brine, dried over MgSO 4 concentrated in vacuo. The crude product was purified by preparative TLC using 5% NH 3 (2.0 M in MeOH) in CH 2 C1 2 to give the desired product difluorophenoxy) benzyl] -4-piperidinyl} -4-methylphenyl) 2-methyipropanamide (44.0 mg, 54.0 Procedure AC WO 03/004027 WO 03/04027PCTIUS02/2 1063 247 Scheme AT: Synthesis of Amides using PS- Carbodiimide Resin o NKR PS-Carbodiimide HN R? +R
H
R
1 CI H 2 NH DCMIDMF 1011 0 C, 12 h
F
F
FN
F N 0 PS-Carbodfmide 0 0 H N -U DG I M 01N
H
2 ,N H 0 N O N 2.5 C, 12h H H
H-
A mixture of a carboxylic acid (0.0800 mmcl) and PS- Carbodilmide Resin (2.00 eq, 80.0 mg, 1.34 mmol/g) in DCM:DMF (10:1, 3.00 mL) was shaken for 30 min. To the reaction mixture was added amine (0.0540 mmcl) and the resulting mixture was shaken for 12 h at room temperature. The reaction mixture was filtered and the resin was 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 0 M in MeOH) in CH 2 Cl 2 to give the desired product.
Procedure AD WO 03/004027 WO 0/00027PCT/UJS02/21063 248 Scheme X bromopropylamine.HBr
(BOC)
2 0 base 0 0 I H H TERT-BUTYL N-(3-BROMOPROPYL)CARBAM4ATE: Prepared from 3bromopropylamine hydrobromide and BOC 2 0 in the presence of base in CH 2 Cl 2 NMR (300 MHz) ~5 5. 07 (br, 1 H) S 3.31 2 H, J 6.6 Hz), 3.12 (apparent br q, 2 H, J Hz), 1.92 2 H, J 6.6 Hz), 1.30 Cs, 9H).
0 Step 1. To a solution of piperidine (19.3 mmol) in dioxane (20.0 mL) was N-(tert-butoxycarbonyl)-3brornopropylamine (21.2 mmol) and potassium carbonate (38.7 mmoi) at room temperature and the mixture was heated at ref lux temperature for 24 h. The reaction mixture was cooled to room temperature, concentrated in vacuo and partitioned between CHC1 3 (40 mL) and water (S 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 yield the req~uired product tert-butyl 3- 3- (acetylamino)phenyl] -1- WO 03/004027 WO 0/00027PCT/UJS02/21063 249 piperidinyllpropyicarbamate as a colorless oil: ESMS W/e: 376.2 IM+H]'.
Step 2. HCl gas was bubbled into a solution of the bocprotected amine (12.1 mmol) in dioxane (5.00 mL) for minutes at 0-5 C. The resulting solution was stirred at 0-5 'C for 1 h, concentrated, neutralized with KOH solution (10 mL) and extracted into CH 2
C.
2 (25 mL).
The organic extract was washed with brine, dried over sodium sulfate and concentrated in vacua. The crude product was chromatographed to give the desired product N- {3-El- (3-aminopropyl) -4-piperidinylJ phenyllacetamide: ESMS M/e: 276.1 1s Procedure AE Scheme Y 0 0 0 HN 0 Br N N H THE, DIPEA R
R
1 hydrazine, EtOH, reflux, HNT N
H
0 N -0 R 2
RI
Step 1: A mixture of piperidine 00 eq, 0. 022 6 mmcl) N-(bromoalkyl)phthalimide (1.50 eq, 0.0338 mmol), BU 4
NI
(200 mg) and diisopropylethylamine (5.00 eq, 0.113 mmol) WO 03/004027 PCT/US02/21063 250 in dioxane (200 mL) was heated at 99 OC for 24 h.
The reaction was followed by TLC analysis (95:5
CH
2 Cl 2 :methanol). If necessary additional 0.0113 mmol of the appropriate bromoalkylphthalimides was added to each reaction mixture and the heating was continued for additional 48 h. The reaction mixture was cooled to room temperature, the ammonium salts were,filtered out and the solvent was removed under reduced pressure. The crude product was chromatographed to give the desired product.
ESMS m/e: 420.2 ESMS m/e: 434.4 [M+H] [M+H] o N ESMS m/e: 448.4
[M+H]
O
0 ESMS m/e: 462.4
N
O-
ESMS m/e: 476.4 WO 03/004027 PCT/US02/21063 251 Step 2: Deprotection of the resulting phthalimides was conducted by heating a solution of phthaliamideprotected amines with excess hydrazine hydrate (10 eq) in ethanol (0.5-1.0 M) at 90 OC for 4 h. The reaction mixture was monitored by TLC to completion. Upon- the reaction was completed, the mixture was cooled to room temperature, the insoluble by-products were filtered out through celite and the solvent was removed in vacuo.
The crude product was chromatographed (dichloromethanemethanol-isoprpylamine) to give the desired products.
H N N 0 ESMS m/e: 290.2 [M+H]
H
2 N-
N
ESMS m/e: 318.2 [M+H] H2N N 0 ESMS m/e: 304.1 [M+H] HNS m 3 [N ESMS m/e: 332.2
N
E /e 346.3 [MHN ESMS m/e: 346.3 [M+H]J WO 03/004027 WO 0/00027PCT/UJS02/21063 252 Procedure AF
F
0 0 N, 0 LDA, THF, 78 N CI A 0a N
K
2 C0 3 DCM/MeOH 0 00 Scheme H
NH
04\ 0 0NO
CI
LDA, THF, -78 0
C
H
2
NN
NN
K
2 00 3 DCM/MeOH n 0-4 (4R) (3,4-DIFLUOROPHENYL) (3- (ISOBUTYRYLAMINO) PHENYL] -1-PIPERIDINYL}PROPYL) -2 -OXO- 1,3-OXAZOLIDINE-3-CARBOXAMIDE was synthesized according to Scheme H and Prdcedure AF: To a solution of (4R)-4- 4-dif luorophenyl) 3-oxazolidin- 2-one (this compound and analogs were prepared according to J. Med. Chem 2000, 43, 2775) (0.300 mol, 60.0 mg) in TI-F (5.00 mL) was added LDA (2.0 M in THF, 0.390 mnrol, 0.200 mL) at 78 0 C under argon. After 30 min at -78 oCt to the mixture was added a solution of 4-nitrophenyl chioroformate (0.330 mmol, 51.2 mg) in TI-IF (0.500 rnL) at -78 00. After stirring for 30 min at -78 'C the reaction WO 03/004027 WO 0/00027PCT/UJS02/21063 253 mixture was diluted with a saturated Na 2
CO
3 solution mL) and the aqueous layer was extracted with CH 2 Cl 2 (3 x 10 mL) .The combined organic layers were washed with brine (10 mL) dried over Na 2
SO
4 and concentrated in vacuo. The residue was purified by preparative TLC plates (10:1 hexane:ethyl acetate) to afford 4nitrophenyl (3,4-difluorophenyl) -2-oxo-1,3cxazolidine-3-carboxylate (51.5 mg, 54.0 1).
4-Nitrophenyl (4R) (3,4-difluorophenyl) -2-oxol,3-oxazolidine-3-carboxylate (169 mg, 0.465 mmcl), N- El- (3-am,'Inopropyl) -4-piperidinyllphenyl}-2methylpropanamide (141 mg, 0.465 mmol), K 2 C0 3 193 g 1. 39 mmol) CH 2 Cl 2 (10 mL) and methanol 1 mL) were combined in a f lask. The mixture was stirred overnight at room temperature, the solvent was removed in vacuo, and the residue was purified by chromatography of
NH
3 (2.0 M in methanol) in CH 2 Cl 2 1 to afford the desired product (26.1 mg, 10.6 1 H NMR (400 MHz, CDCl 3 8.08 1H, J S.5 Hz), 7.45 2H), 7.38 1Hi, J 8.6 Hz), 7.24-7.12 (in, 3H), 7.06 (in, 1H), 6.97 1H, J 8.6 Hz), 5.40 (dd, 1H, J 3.9-8.8 Hz), 4.71 1H, J 8.8 Hz), 4.23 (dd, 1H, J 9.1 Hz), 3.32 (qt, 2H, J 1 Hz) 2. 99 2H, J 11. 0 Hz) 1 2. 49 (qt, 2H, J 7.0 Hz), 2.41(t, 2H, J 7.0 Hz), 1.99-1.97 (mn, 2H), 1.82-1.68 (mn, 6H) 1.23 6H, J 7.3 Hz) Anal.
Calcd. for C 2
BH
3 4
F
2
N
4 0 4 +Cl+0. 18SCHC1 3 C, 57.6; H, 6.04; N, 9.54. Found: C, 58.5; H, 6.08; N, 9.47; ESMS m/e: 529.1 (M Procedure AG WO 03/004027 WO 0/00027PCT/UJS02/21063 254 Scheme AR:
CHO
I 0 1 0 R 4 0 N R 2
R
3 01r 0 0 R 3
NH
3 OAc, HOAc if R 4 =benzyl, then 0 10% Pd/C, H 2
O
methanol,I room temperture 0 N R 2
R
3 51
N
0 0' 0 N R 2
R
3 Step 1: A solution of ketoester (10 mmol) Meidrum' s acid (10 amol) aldehyde (10 mmol) and an ammonium acetate (12. mmcl) in HOAc (10 mL) was heated at reflJux temperature for 18 h.1 The cooled reaction mixture was poured over ice (100 g) The precipitated oils were collected and dried under reduced pressure. The benzyl ester protected analogs solidified upon trituration with a mixture of ether/hexane.
1.05 g, 29.0 523 mg, 15.0% IMORALES, OCHOA, SUAREZ, VERDECIA, Y.i GONZALEZ, MARTIN, QUINTEIRO, SEOANE, C.; SOTO, J. L. LT. Heterocycl. Chem. [JHTCADJ 1996, 33 103-107.
WO 03/004027 WO 0/00027PCT/UJS02/21063 255 Step 2: A mixture of a benzyl ester and 10% Pd/C in methanol was hydrogenated using the balloon method at room temperature. The reaction mixture was monitored (TLC) to completion, filtered through Celite 545 and the Celite filter cake was washed with methanol (3 x 10 mL).
The combined methanol. extracts were concentrated in vacuo to give the desired carboxylic acid that was used in the next step without any further purification.
F
F 0
OH
0
N'
4-(2,4-DIFLOROPHENYL) -2-METHYL-6-OXO-1,4,5,6- TETRAIIYDRO-32-PYRIDINECARBOXYLIC ACID was synthesized according to Procedure AG and Scheme AR: 'H NMR (CDC1 3 400 MHz) 6 7.82 1H), 7.00-6.72 (in, 3H), 4.51 1H, is J 8.4 Hz) 2.90 (dd, 1H, J 8.4, 16.3 Hz) 2.68 (d, 1H1, J =16.3 Hz), 2.46 3H1).
F
F
I
~~0
OH
O N 4-(3,4-DIFLUOROPENYL) -2-METIYL-6-OXO-1,4,5,6- TETRAHYDRO-3-PYRIDINECARBOXYLIC ACID was synthesized according to Procedure AG and Scheme AR: 1H1 NMR (CDC13, 300 MHz) 8 7.40-6.80 4 4.23 1 H, J avg. Hz), 2.93 (dd, 1 H, J 16.8, 7.5 avg. Hz), 2.68 I1H, J 16.5 avg. Hz), 2.45 3 H).
WO 03/004027 WO 0/00027PCT/UJS02/21063 256 Procedure AH-
K
2 C0 3 NaI 1. NaH, DMF DMF, 900C,12 h N 2. BrCH 2
(CH
2
)CCHNH
HH
NN y~
(CH
2 CN
C
1-(6-CHLOROHfEXYL)-1H-IINDOA: To aL mixture'-of Nail (0.249 g, 10.0 mmol) in DMP (5.00 mL) was added a solution of l-H-indole (0.585 g, 5.00 mmnol) in DMF (2.00 mL) at 0 0
C.
The reaction mixture was stirred for 30 minutes at 0 0
C
and warmed up to room temperature. To the reaction mixture 1-bromo-6-chlorohexane (0.998 g, 5.00 mmol) was added dropwise via syringe and the reaction mixture was stirred overnight. The reaction mixture was diluted with EtOAc (30 mL), washed with water (3 X 10 tnL), brine mL) dried over MgSO 4 concentrated in vacuo and purified by chromatography using hexane :EtOAc (97.5:2.5) to give the desired prcd~v-t 900 g, 76. 0 'H NNR (400 MHz, CDCl 3 8 7. 76-7 .54 (in, lH) 7.47-6. 96 4H) 6.60-6.34 (in, 1H4), 4.13 2H4, J =6.8 Hz), 3.50 (t, 2H-, J 5.5 Hz), 1.98-1.79 (mn, 214), 1.79-1.64 Cm, 214), 1.54-1.17 4H).
N- E6- (1I-INfOL--YL)HEXYL] -4-PIPERIDINYL}PHENYL) 2-METHYLPROPANAMIDE: A mixture of 1- (6-Chiorohexyl) Hindole (23.6 Mng, 0.100 mol), 2-inethyl-N-[3-(4- )iperidiny1)phenyljpropanamide (24.6 mg, 0.100 inmol),
K
2 C0 3 (27.6 mg, 0. 200 minol) Nal (22.5 my, 0. 150 mind) and DMF (1.00 mL) was h~ted at 100 'C for 12 h. The reaction mixture was cooled to room temperature and the crude material was purified by preparative TLC using 5 WO 03/004027 PCT/US02/21063 257 of NH 3 (2.0 M in methanol) in CH 2 C12 to give the desired product as a yellow solid (40 mg, 90 1H NMR (400 MHz, CDC13) 5 8.08-6.52 11H), 4.17 2H, J 7.2 Hz), 3.26 2H, J 11.6 Hz), 2.74-2.52 4H), 2.44-2.28 2H), 2.20-2.02 2H), 1.98-1.82 4H), 1.78-1.62 2H) 1.43-1.28 4H) 1.28 6H, J 6.8 Hz); ESMS m/e: 446.5 (M H) Procedure AI: Scheme AU: Preparation of tert-Piperdines Usingd PS-SO2C1 Resin P--SO,Ci R-OH -SO 3 R N R2 R1 R-R2 R1 The library was constructed in polypropylene Robbins "Reactor Blocks", 48 well plates. PS-TSC1 resin (100 mg, 1.00 eq, purchased from Argonaut Technologies) was placed in each well of the "Reactor Blocks" 48 well plates. To each well was added 2-10 eq of an alcohol in dichloromethane:pyridine 3.00 mL). The mixture was stirred at room temperature for 5 h and the resin was washed with dichloromethane (3 x 4.00 mL), DMF (5 x 4.00 mL), DMF/H 2 0 5 x 4.00 mL), THF (3 x 4.00 mL), dichloromethane (3 x 4.00 mL), acetonitrile (2 x 4.00 mL) and dried under reduced pressure. A solution of an amine (0.0750 mmol, 0.500 eq) and N,N-diisopropylethyl amine (19.0 mg, 0.150 mmol, 1.00 eq) in acetonitrile WO 03/004027 PCT/US02/21063 258 (3.00 mL) was added to the well containing the derivatized resin and the mixture was reacted at 70 °C for 16 h in the Robbins rotating oven. After cooling, AP-isocyanate- resin (120 mg, 0.150 mmol, 1.00 eq) and THF (2.00 mL) was added to the each reaction vessel and reacted at room temperature for additional 3 h. The solution was filtered into the Robbins receiving plates and concentrated in vacuo to give the desired tertiary amines which were analyzed via LC-MS.
Procedure AJ: Scheme AV: Preparation of tert-Piperidines Using Piperdines, S PS-TBD resin N N 2 benzyl bromide N R2 or benzyl iodide CH 3
CN
R1 RT, 16h Ar R R2 R1 The library was constructed in polypropylene Robbins® 48 well plates Reactor Blocks. In the initial incubation period, each well was charged with PS-TBD resin (from Argonaut Technologies, 200 mg, 0.280 mmol, 2.50 eq) and piperidine (0.120 mmol, 1.10 eq) in acetonitrile (0.500 mL) and agitated for 1 h. A solution of .benzyl iodide or bromide (0.110 mmol, 1.00 eq) in acetonitrile (0.500 mL) was added to each well followed by additional acetonitrile (1.00 mL) to make a total volume of 2 mL and the mixture was rotated in a Robbins rotating oven at room temperature for 16 h. Then AP-Isocyanate resin (Argonaut Technologies, 250 mg (0.430 mmol, 4.00 eq) was WO 03/004027 WO 0/00027PCT/UJS02/21063 259 added to each well and reacted further at room temperature for another 12 h. The mixture was filtered and the filtrate was concentrated in vacuo to obtain the desired product that was characterized via LC-MS.
Scheme AX 0ZnC! 2 HOAc N-3 RN R375 0 C, 10h N R,0 NH 2
N,
Examiple 117 (4-BROMOPHENYL) -3-OXOPROPYL] -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMID)E: Procedure K (KI) and Scheme E (K 2 C0 3 using 1- (4-hromophenyl) -3chlorc-1-propanone arid 2-methyl-N- (4piperidinyl)phenyllpropanami'de:. ESMS m/e. 457. 1 (M Example 118 (4-CHLOROPHENYL) -3-OXOPROPYLI -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Procedure K (KI) and Scheme E (K 2 C0 3 using 3-chloro-1-(4chlorcphenyl) -1-propanone and 2-methyl-N- (4piperidinyl)phenyllpropanamide: ESMS m/e: 413. 1 (M Example 119 (4-METHOXYPHENYL) -3-QXOPROPYLJ -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Procedure K (KI) and Scheme E (K 2 C0 3 using 3-chloro-1-(4- WO 03/004027 WO 0/00027PCT/UJS02/21063 260 methoxyphenyl) -1-propanone and 2-methyl-N- (4piperidinyl)phenyllpropanamide: ESMS m/e: 409.2 (M Example 120 (2,3-DIHYDRO-lH-INDEN-!5-Th) -3-OXOPROPYL] -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Procedure K (KT) and Scheme E (K 2 C0 3 using 3-chloro-1-(2,3-dihydro- -l-propanone and 2-methyl-NV- (4piperidinyl)phenyllpropanamide: ESMS m/e: 419.2 (M H) Example 121 2-METHYL-N-{3- [1-(3-OXO-3-PHENYLPROPYL) -4- PIPERIDI1NYL]PHEN'YLPROPANAMIDE: Procedure K (KT) and Scheme F (K 2 C0 3 using 3-chloro-1-phenyl-l-propanone and 2-methyl-N- (4-piperidinyl)phenyl) propanamide: ESMS m/e: 379.2 (M H+ Example 122 2-METHYL-N- (4-METHYLPHENYL) -3-OXOPROPYL] -4- PIPERIDINYL}PHENYL)PROPANMIDE: Procedure K (KI) and Scheme E (K 2 C0 3 using 3-chloro-l- (4-rethylphenyl) -1propanone and 2-methyl-N-[3-(4piperidinyl)phenyllpropananide:. ESMS m/e: 393.2 (M
H).
Example 123 N-(3-(l-[3-(4-FLUOROPHENYL)-3-OXOPROPYL) -4- PIPERIDINYL}PHENYL) -2 -METHYLPROPANhMIDE: Procedure K (KI) and Scheme E (K 2 C0 3 using 3-cliloro-1-(4fluorophenyl) -1-propanone and 2-methyl-N- (4- WO 03/004027 WO 0/00027PCT/UJS02/21063 261 piperidinyl)phenyllpropanamide: ESMS mle: 397.2 (M Exaniple'124 3- (4-CHLOROPHENYL) -3-HYDROXYPROPYL] -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure L and Scheme AN using N- (3-11-E[3- (4chiorophenyl) -3 -oxopropylJ -4 -piperidiny. phenyl) -2methyipropanamide: ESMS m/e: 415.1 (M Example 125 (4-CHLOROPHENqYL) (3 14- DIFILUOROPIIENOXY) PROPYL] -4-PIPERIDINYL}PHENYL) -2- METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using 3- (4-chlorophenyl) -3-hydroxypropyl] -4piperidinyllphenyl)-2-methylpropanamide and 34 difluorophenol: ESMS m/e: 526.B (M Example 126 (4-CHLOROPHENYL) (2-METHYLPHENOXY) PROPYL] 4 -PIPERIDINYL}PHENYL) -2 -METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using NV-(3- chiorcphenyl) -3-hydroxypropyl- -4-piperidinyllphenyl) -2methyipropanamide and o-cresol: ESMS nle: 505.4 (M +i
H).
Example 127 E3- (4-FLUOROPHENYL) -3-HYDROXYPROPYL] -4- PIPERIDINYL}PHENYL) -2-METHYLPROPA.NAMIDE: Prepared by Procedure L and Scheme AN using (4fluorcphenyl) -3-oxopropyl] -4-piperidinyl~phenyl) -2methyipropanamide: ESMS m/e: 399.2 CM Example 128 WO 03/004027 WO 0/00027PCT/UJS02/21063 262 [3-HYDROXY-3- METEOXYPEENYL) PROPYL) -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE; Prepared by Procedure L and Scheme AN using N- (4methoxypheiy) -3 -oxoprapyl] -4-piperidinyl }phenyl) -2methyipropanamide: ESMS nile: 411.2 (M Example 129 (4-BROMOPHENYL) -3-HYDROXYPROPYL 4- PIPERIDINYL)PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure L and Scheme AN using M- [3 bromophenyl) -3-oxopropyl] -4-piperidinyl~phenyl) -2methyipropanamide: ESMS m/e: 459.1 (M Example 130 (4-CHLOROPHENYL) (4-METHOXYPHENOXY) PROPYLI 4 -PIPERIDINYL}PHENYL) -2 -METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using M- chiorophenyl) -3 -hydroxypropyl] -4 -piperidinyl }phenyl) -2methyipropanamide and 4-methoxyphenol: ESMS m/e: 520.8 (M I1 Example 131 3- (4-CHLORO)PHENOXY) (4-FLUOROPHENYL) PRO)PYL] 4-PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure A and 'Scheme AN using fluorophenyl) -3-hydroxypropyl] -4-piperidinyllphenyl) -2methyipropanamide and 4-chiorophenol: ESMS m/e: 509.1 (M Example 132 N-(3-{l-[3-(4-FLUOROPHENYL)-3-(2,3,4,5,6- PENTAFLjUOROPHENOXY) PROPYLJ -4-PIPERIDINYL)PHENYL) -2- METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN WO 03/004027 WO 0/00027PCT/UJS02/21063 263 using N(3{-3-4-fluorophenyl) -3hydroxypropylj -4 -piperidinyl }phenyl) -2-methyJlpropanamide and 2,3,4,5,6-pentafluorophenol: ESMS m/e: 564.7 (M Example 133 (4-BROMOPRENYL) (2-METHYLPIHENOXY)PROPYL) -4- PIPERIDIN'YL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using bromophenyl) -3 -hydroxypropyl] -4-piperidinyl }phenyl) -2methyipropanamide and 2-methylphenol: ESMS m/e: 548.8 (M H).
Example 134 N-(3-{l-[3-(3,4-DIFLUQROPHENOXY)-3-(4- FLUOROPHENYL) PROPYL] -4 -PIPERIDINYLPHENYL) -2lETHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using N- (4-fluorophenyl)-3-hydroxypropyl) -4piperidinyllphenyl) -2-rethylpropanamide and 3,4difluorophenol: ESMS m/e: 511.1 (M Example 135 E3- (4-BROMOPHENOXY) (4-FLUOROPHENYL)PROPYL] -4- PIPERIDINYL)PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using N- (4fluoraphenyl) -3-hydroxypropyl] -4-piperidinyl~phenyl) -2methyipropanamide and 4-bromophenol: ESMS m/e: 553.0 (M Example 136 N-(.3-{1-[3-(3,4-DICHLOROPHENOXY)-3-(4- FLUOROPHENYL) PROPYL] -4-PIPERIDINYL}PHENYL) -2- METHYLPROPAlAMIDE: Prepared by Procedure A and Scheme AN WO 03/004027 WO 0/00027PCT/UJS02/21063 264 using N 3{-3-(-fluorophenyl) -3hydroxypropyl] -4-piperidinyl~phenyl) -2-methylpropanamide and 3,4-dichiorophenol: ESMS ni/e: 542.7 (M H) Example 137 N- (4-FLT3OROPHENYL) (4- (TRIFLUOROMETHYL) PHENO)XY) PROPYL}-4-PI:PERIDINYL) PHENYL] 2-METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using NV-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropy.J-4piperidinyl~phenyl) -2 -methyipropanamide and 4- (trifluoromethyl)phenol: ESMS le: 543.1 (M Example 138 (3-BROMOPHENOXY) (4-FLUOROPHENYL)PRO)PYL] -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using fluorophenyl) -3-hydroxypropyl) -4-piperidinyl~phenyl) iethylpropanamide and 3-bromophenol: ESMS mle: 552.7 (M +i Example 139 (4-FLUOROPHEN'OXY) (4-FLUOROPHENYL)PROPYL] 4-PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using fluorophenyl) -3-hydroxypropyl] -4-piperidinyl~phenyl) -2methyipropanamide and 4-fluorophenol: ESMS m/e: 493.2 CM Example 140 N-(3-{1-[3-(3-FLUOROPHENOXY) -3-(4-FLUOROPHENYL)PROPYL]- 4-PIPERIDINYL}PHENYL) -2-METHYLPROPANAM4IDE: Prepared by Procedure A and Scheme AN using [3-C(4fluorophenyl) -3-hydroxypropyl] -4-piperidinyl~phenyl) -2- WO 03/004027 WO 0/00027PCT/UJS02/21063 265 methyipropanamide and 3- fluorophenol: ESMS m/le: 492.9 (M Example 141 N-(3-{1-[3-(2,6-DICHLOROPHENOXY)-3-(4- FLUOROPHENYL) PROPYL] -4-PIPERIDINYL}PHENYL) -2- METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using N- (4-fluorophenyl) -3-hydroxypropyl] -4piperidinyllphenyl) -2-methyipropanamide and 2,6dichiorophenol: ESMS rn/e: 543.0 (M Example 142 (2,5-DI:FLUOROPHENOXY) (4- FLUOROPHENYL)'PROPYLJ -4 -PIPERIDIINYL}PHENYL) -2- METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using N- (4-f luorophenyl) -3-hydroxypropyl] -4piperidinyllphenyl) -2-methyipropanamide and difluorophenol: ESMS m/e: 511.5 CM H+ Example 143 (3-CHLOROPHENOXY) (4-FLUJOROPHEINYL) PROPYL] 4-PIPERIDINYL)PHiENYL) -2 -METHYLPROPAflAMIDE: Prepared by Procedure A and Scheme AN using (4fluorophenyl) -3-hydroxypropyl] -4-piperidinyllhenyl) -2methyipropanamide and 3-chiorophenol: ESMS rn/c: 509.1 (M Example 144 (4-BROMOPHENYL) (3-METHYLPHENOXY)PROPYL] -4- PIPERIDINYLPEENYL) -2-METHYLPROPANAI4IDE: Prepared by Procedure A and Scheme AN using N- bromophenyl) -3-hydroxypropyl] -4-piperidinyl~phenyl) -2- WO 03/004027 WO 0/00027PCT/UJS02/21063 266 me-Lhylpropananide and 3- methyiphenol: ESMS m/e: 549.1 (M H) Example 145 N-(3-.(1-E3-([l,1'-BIPHENYL]-4-YLOXY)-3-(4- BROMOPHENYL) PROPYL] -4-PIPERIDINYLPHENYL) -2- METHYLPROPANAMIDE2 Prepared by Procedure A and Scheme AN using NT- (3 (3 (4 -bromophenyl) 3- hydroxypropyl I -4 piperidinyl }phenyl) -2 -methyipropanamide and 4phenyiphenol: ESMS ra/e: 611.2 (M Example 146 (2,4-DIFLUOROPHENOXY) (4- FLUOROPHENYL) PROPYL] -4-PIPERIDINYLPHENYL) -2- METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using [3-(4-fluoropheny1) -3-hydroxypropyl] -4piperidinyllphenyl) -2-methyipropanamide and 2,4difluorophenol: ESMS m/e: 511.1 (M H+ Example 147 (4-BROMOPHENYL) (3-METHOXYPHENOXY)PROPYL] 4-PIPERIDINYL}PHENYL) -2-METHYLPROPATAMIDE: Prepared by Procedure A and Scheme AN using bromophenyl) -3 -hydroxypropyl] -4 -piperidinyl }phenyl) -2methyipropanamide and 3-methoxyphenol: ESMS mle: 564.6 (M H).
Example 148 METHYL 4- (1-(4-BROMOPHENYL) [3- (ISOBUTYRYLAMINO) PFENYLJ -1-PIPERIDINYL}PROPOXY) BENZOATE: Prepared by Procedure A and Scheme AN using N-(3-1-D- (4-bromophenyl) -3-hydroxypropyl) -4-piperidinyllphenyl) WO 03/004027 WO 0/00027PCT/UJS02/21063 267 2-methyipropanamide and methyl 4-hydroxybenzoate: ESMS m/e: 593.0 (M Example 149 S N- E3- (4-BROMOPHENYL) (4-PHENOXYPHENOXY) PROPYL] 4-PIPERIDINYL)PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using bromophenyl) -3 -hydroxypropyl) -4-piperidiny. phenyl) -2methyipropanamide and 4-phenoxyphenol: ESMS m/e: 626.6 (M H).
Example 150 (4-BROMOPHENYL)-3-(2,-CHLORO-4- METHYLPHENOXY) PROPYL] -4-PIPERIDINYL}PHENYL) -2- METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using E3-(4-bromophenyl) -3-hydroxypropyl] -4piperidinyl}phenyl) -2-methyipropanamide and 2-chloro-4methyiphenol: ESMS m/e: 583.0 (M IW Example 151 N-(3-t1- 13- (4-BROMOPHENYL) -3-PHENOXYPROPYL] -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using N-r 1-E[3 bromophenyl) -3-hydroxypropyl] -4-piperidinyl~phenyl) -2methyipropanamide and phenol: ESMS m/e: 535.0 (M Example 152 N- 13- (4-BROMOPHENYL) -3-14- (TRIFLUOROMETHYL) PHENOXY] PROPYL}-4 -PIPERIDINY-L) PHENYL] 2-METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using (4-bromophenyl) -3-hydroxypropyl] -4piperidinyl }phenyl) -2 -methyipropanamide and 4- (trifluoromethyl)phenol: ESMS m/e: 603.1 (M H) 4 WO 03/004027 WO 0/00027PCT/UJS02/21063 268 Example 153 (2-ACETYLPHENOXY) (4-BROMOPHEENYL) PROPYII-4- PIPERIDINYL}PHENYL) -2-I ETHYLPROP.ANMIDE: Prepared by Procedure A -and Scheme AN using NV-(3- [3 bromophenyl) -3 -hydroxypropyll]-4-piperidinyl}phenyi) -2rethylpropanamide and 2-acetylphenol: ESMS mle: 576.6 (M Example 154 E3-(3-ACETYLPHENOXY) -3-(4-BROMOPHENYL)PROPYL]-4- PIPERIDINYL}PEENYL) -2-METHYLPROPANAIDE: Prepared by Procedure A and Scheme AN using 1-[3 (4bromophenyl) -3-hydroxypropyl] -4-piperidinyl~phenyl) -2rethylpropanamide and 3-acetyiphenol: ESMS m/e: 576.9 (M Example 155 E3-(3-ACETYLPI{ENOXY) (2,3-DIHYDRO-JJ-I3NDEN-5- YL) PROPYLI -4 -PIPERIDINYL}PHENYL) -2-METHYLPRZOPANAMIDE: Prepared by Procedure A and Scheme AN using 3-dihaydro-1H-indeni-5-yl) -3-hydroxypropylJ -4piperidinyl~phenyl) -2-methylpropanamide and 3acetyiphenol: ESMS zn/e: 539.2 (M Example 156 (2,3-DIHYDRO)-1H-INDEN-5-YL) -3-PHiENOXYPROPYL] 4 -PIPERIDINYL}PHENYL) -2 -METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using N-(3-{2.-L3-(2,3-dihydro- -3-hydroxypropyl) -4.-piperidinyllphenyl) -2methyipropanamide and phenol; ESMS m/e: 497.2 (M Example 157 WO 03/004027 WO 0/00027PCT/UJS02/21063 269 13 (2-ACETYLPHENOXY)-3-(2,3- PROPYLI -4-PIPERIDINqYL}PHENYL) -2-
METHYLPROPANAMIDE:
Prepared by Procedure A and Scheme AN using (2,3-dihydro--1H-inden-5-yl)-3-hydroxypropylJ-4piperidinyl }phenyl) -2-methylpropanamide 2-acetyiphenol: ESMS m/e: 539.1 (M H)+ Example 158 [3-(4-BROMOPHENOXY)-3-(4-BROMOPHENYL)PROPYLJ-4- PIPERIDINYL}PHENYL) -2-METHYLPROPANMIIDE: Prepared by Procedure A and Scheme AN using N- [3 bromophenyl) -3 -hydroxypropylj -4 -piperidinyl }phenylj -2methyipropanamide and 4-bromophenol: ESMS m/e: 612.7 CM Example 159 [3-(4-BROMOPHENTYL)-3-(4-CIHLOROP1HENOXY)PROPYL]-4- PIPERIDINYL}PHENYL) -2 -METHYLPROP.ANAMIDE; Prepared by Procedure A and Scheme AN using bromophenyl) -3-hydroxypropyl] -4-piperidinyl~phenyl) -2methyipropanamide and 4-chlorophenol: ESMS m/e: 568.7 (M Example 160 (4-BROMOPHENYL) (4-FLUOROPHENOXY) PROPYLI -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using (4bromophenyl) -3-hydrox-ypropyl] -4-piperidinyl~phenyl) -2methayipropanamide and 4-f luorophenol:. ESMS m/e: 552.8 (M H' Example 161 WO 03/004027 WO 0/00027PCT/UJS02/21063 270 N-(3-{1-[3-(2,3-DIHYDRO- 1H-INDEN-5-YL)-3-(4- METHOXYPHENOXY) PROPYL] -4 -PIPERIDINYL}PHENYL) -2- METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using NV- 3- 3-dihydro- IH- inden- 5-yl) -3 hydroxypropyl] -4-piperidinyl~phenyl) -2 -methyipropanamide and 4-methoxyphenol: ESMS inle: S27.3 (M +H) Example 162 E3- (2,3-DIHYDRO-1H-INDEN-5-YL) FLUOROPHENOXY)PROPYLJ-4-PIPERIDINYL)PHIENYL) -2- METHYLPROPA.NAMIDE: Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(2,3--dihydro-lH-inden-5-yl)-3hydroxypropyl] -4 -piperidinyl }phenyl) -2 -methyipropanamide and 4-fluorophenol: ESMS m/e: 515.2 (M Example 163 E3-(2,3-flIHYD1RO-1H-INDEN-5-YL) -3-HYDROXYPROPYL]- 4- PIPERIDINYL}PHENYL) -2 -METHYLPROPANAMIDE Prepared by Procedure L and Scheme AN using 3- 3-dihydro-1H-inden-5-yl) -3-oxopropyl] -4piperidinyl~phenyl) -2-methylpropanamide: ESMS m/e: 421.2 (M Example 164 N-3(-3(,-IYROl-NE--L--4 (TRIFLtJOROMETHYL) PHENOXY] PROPYL} -4-PIPERIDINYL) PHENYL] 2-METHYLPROP.ANAMIDE: Prepared by Procedure A and Scheme AN using N-(2-{1-[3-(2,3-dihydro-1H-inden-5-yl)-3hydroxypropylJ -4 -piperidinyl }phenyl) -2 -rethylpropanamide and 4-trifluoromethylphenol: ESMS m/e: 565.0 (M Example 165 WO 03/004027 WO 0/00027PCT/UJS02/21063 271 BROMOPHENOXY) (2,3- DIHYDRO- 1H-IINDEN-5-YL) PROPYL] -4-PIPERIDINYL)PHENYL) -2-
METHYLPROPANANIDE:
Prepared by Procedure A and Scheme AN using (2,3-dihydro-1H-inden-5-y1) -3-hydroxypropyl] -4piperidinyl~phenyl) -2-methyipropanamide and 4bromophenol: ESMS m/e: 577.4 (M Example 166 (3-ACETYLPEENOXY) (4-CHLOROPHENYL)PROPYL] 4-PIPERIDINYL}PHENYL) -2-METHYLPROPANA4IDE: Prepared by Procedure A and Scheme AN using (4chiorophenyl) -3 -hydroxypropyl]-4-piperidinyl phenyl) -2methyipropanamide and 3-acetylpheno2.: SMS mle: 533.1 (M Example 167 (4-METHiOXYPHENOXY) (4- METHOXYPHENYL) PROPYL] -4 -PIPERIDINYL}PHENYL) -2- METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using N- [3-hydroxy-3- (4-methoxyphenyl)propyll -4piperidinyl~phenyl) -2-methyipropanamide and 4methoxyphenol: ESMS nile: 517.4 CM Example 168 [3-(4-CHLOROPHENOXY)-3- (2,3-DIHYDRO-1H-I:NDEN-5- YL) PROPYL] -4 -PIPERIDINYL}PHENYL) -2 -METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using M- 1- [3 (2,3-dihydro-lH-inden-5-yl) -3-hydroxyprcpyl] -4piperidinyllphenyl) -2--methyipropanamide and 4chiorophenol: ESMS ni/e: 531.1 (M WO 03/004027 WO 0/00027PCT/UJS02/21063 272 Example 169 (2-ACETYLPHENOXY) (4-CHLOROPHENYL) PROPYL] 4-PIPERIDfIYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using chiorophenyl) -3 -hydroxypropyl] -4-p iperidinyl }phenyl) -2methylpropanamide and 2-acetylphenol: ESMS m/e: 533.4 (M H) 4 Example 170 (4-BROMOPHENYL) (4-METH-OXYPH-ENOXY) PROPYL] 4-PIPERIDINYLPHENYL) -2-METHYLPROPATAMIDE: Prepared by Procedure A and Scheme AN using N- [3 bromophenyl) -3 -hydroxypropyl) -4 -piperidinyl }phenyl) -2rethylpropanamide and 4-methoxyphenol: ESMS mle: 565.0 is (M H).
Example 171 (4-BROM4OPHENOXY) (4-CIELOROPHENYL) PROPYL] -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using N- [3 chloropheiyl) -3 -hydroxypropylj -4 -piperidinyl }phenyl) -2methyipropanamide and 4-bromophenol: ESMS m/e: 568.8 (M Example 172 (4-CHLOROPHENOXY) (4-CELOROPHENYL) PROPYL] 4-PIPERIDINYL)PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using (4chiorophenyl) -3 -hydroxypropyl) -4 -piperidinyl }phenyl) -2methyipropananide and 4-chiorophenol: ESMS ni/e: 525.0 (M H) Example 173 WO 03/004027 WO 0/00027PCT/UJS02/21063 273 Al- (3fl- (4-METHOXYPENYJ) -3- PHENOXYPROPYL] -4 -PIPERIDIN.YL}PHENYL) -2- METHYLPROPANANIDE: Prepared by Procedure A and Scheme AN using N- 13-hydroxy-3- (4-methoxyphenyl)propyl) -4piperidinyllphenyl) -2-methyipropanamide and phenol: ESM'S rn/: 487.4 (M Example 174 J- (3-fl- (4-FLUOROPHENYL) -3-PHENOXYPROPYL) -4- PIPERIDINYL)PHENYL) -2-METHYLPROPANqAMIDE: Prepared by Procedure A and Scheme AN using NV-(3- f{1- (4fluorophenyl) -3-hydroxypro:y.]-4-piperidinyl }plenyl) -2methyipropanamide and phenol: ESMS m/e: 475.6 (M Example 175 (2-ACETYLPEENOXY) (4-FLUOROPHENYL) PROPYLI 4-PIPERIDINYL)PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using X- (4- E2uorophenyl) -3-hydroxypropyl] -4-piperidinyl~phenyl) -2methyipropanamide and 2-acetylphenol: ESMS 517.1 (M H).
Example 176 (3-ACETYLPHENOXY) (4-FLUJOROPEENYL) PROPYL] 4- PIPERIDINYL}PHENYL) -2 -METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using fJluorophenyl) -3-hydroxypropyl) -4-piperidinyl~phenyl) -2methyipropanamide and 3-acetyiphenol: ESMS rn/c: 516.9 (M Example 177 N- (3-fl- (4 -FLUOROPHENYL) (4-METHOXYPHENOXY) PROPYL] 4-PIPERIDINYJ)PHENYL) -2-METHYLPROPANAM4IDE: Prepared by WO 03/004027 WO 0/00027PCT/UJS02/21063 274 Procedure A and Scheme AN using N 3-( fluorophenyl) -3 -hydroxypropyl] -4-piperidinyl }phenyl) -2methyipropanamide and 4-methoxyphenol: ESMS mle: 505.2 (M H).
Example 178 (4-CHLOROPEENOXY) (4-METHOXYPHENYL) PROPYL] 4-PIPERIDINYL}PHENYL) -2 -METHYLPROPANAMIDE: Prepared by Procedure A arnd Scheme AN using N-(3-{1-[3-hydroxy-3-(4methoxyphenyl~propylJ -4-piperidiny1lphenyl) -2methyipropanamide and 4-cholorophenol: ESMS m/e: 521.5 (M H).
Example 179 N- (3 -ACETYLPHENOXY) (4-METHOXYPEENYL) PROPYL) 4 -PIPERIDINYL}PHENYL) -2-METHYLPROPMIAMIDE: Prepared by Procedure A and Scheme AN using N- (3-{(1-E[3-hydroxy-3- (4methoxyphenyl)propyl] -4-p~iperidinyl~phenyl) -2methyipropanamide and 3-acetylphenol:. ESMS mle: 529.0 (M Example 180 (4-CHLOROPHENYL) -3-PHENOXYPROPYL] -4- PIPERIDINYL}PHENYL) -2 -METHYIPROPANAMIDE: Prepared by Procedure A and Scheme AN using N- (3-11- (4chiorophenyl) -3 -hydroxypropylj -4 -piperidinyl Iphenyl) -2methyipropanamide and phenol. ESMS m/e: 490.9 (M Example 181 (4-BROMOPIIENOXY) (4-METHOXYPHIENYL) PROPYL) 4 -PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using N-(3-{1-[3-hydroxy-3-(4methoxypheny.)propyl3 -4-piperidinyl~phenyl) -2- WO 03/004027 WO 0/00027PCT/UJS02/21063 275 methyipropanamide and 4- bromophenol: ESMS m/e: 564.9 (M Example 182 N- (4-METHOXYPHENYL) [4- (TRIFLUOROMETHYL) PHENOXY] PROPYL) -4 -PIPERIDINYL) PHENYL] 2-METHYLPROP.ANAMIDE: Prepared by Procedure A and Scheme AN using N- t3-hydroxy-3- (4-methoxyphenyl)propyl] 4-piperidinyl. phenyl) -2-methylpropanamide and 4trifluoromethyphenol: ESMS m/e: 555.1 (M Example 183 (4-CHLOROPHENYL) (4-FLTJOROPHENOXY) PROPYL] 4 -PIPERIDI1NYL)PHENYL) -2 -METHYLPROPAIAMIDE: Prepared by 1s Procedure A and Scheme AN using V- (4chiorophenyl) -3-hydroxypropylI-4-piperidinyl~phenyl) -2methyipropanamide and 4-f luorophenol: ESMS m/e: 509.1 (M Example 184 (4-FLUOROPHENOXY) (4-METIHOXYPIHENYL)PROPYL] 4-PIPERIDINYLPHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using N-(3-{1-[3-hydroxy-3- (4methoxyphenyl) propyl] -4 -piperidinyl }phenyl) -2methyipropanamide and 4-f luorophenol: ESMS mle: 505.5 (M H) Example 185 N- (2 -ACETYLPHENOXY) (4-METHOXYPHENYL) PROPYL] 4 -PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE; Prepared .by Procedure A and Scheme AN using N-(3-{1-[3-hydroxy-3-(4methoxyphenyl)propyl) -4-piperidinyllphenyl) -2- WO 03/004027 PCT/US02/21063 276 methylpropanamide and 2- acetyiphenol: ESMS m/e: 529.2 (M Example 186 N-[3-(1-{3-(4-CHLOROPHENYL)-3-[4- (TRIFLUOROMETHYL)PHENOXY]PROPYL)-4-PIPERIDINYL)PHENYL]- 2-METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using N-(3-{l-[3-(4-chlorophenyl)-3-hydroxypropyl-4piperidinyl}phenyl)-2-methyipropanamide and 4trifluoromethylphenol: SMS r/e: 559.1 (M Example 187 N-(3-1-[(3S)-3-(3-ACETYLPHENOXY)-3-PHENYLPROPYL]-4- PIPERIDINYL}-4-METHYLPHENYL)-2-METHYLPROPANAMIDE: Prepared by Procedure G and Scheme AI using 3-chloro-1-phenylpropyl)oxy~phenyl)ethanone and 2methyl-N-[4-methyl-3-(4-piperidinyl)phenyllpropanamide: ESMS m/e: 513.0 (M 2-(ISOPENTYLOXY)-l-NAPHTHALDEHYDE; 2-Hydroxy-1napbthaldehyde (1.72 g, 10.0 mmcl) and THF (50 ml) were combined in a flask. NaH (312 mg, 13 mmol) was added, followed by l-bromo-3-methylbutane (1.20 tL, 10.0 mmol).
The solution was stirred at room temperature overnight, the solvent was removed in vacuo, and the residue was purified by chromatography (5-10 ethyl acetate hexane): IH NMR (400 MHz, CDCl 3 5 10.9 1E), 9.28 (dd, 1H, J 0.7 Hz, 8.6 Hz), 8.02 1H, J 9.1 Hz), 7.75 1H, J 8.1 Hz), 7.63-7.59 1K), 7.43-7.39 1K), 7.27 1I, J 9.2 Hz), 4.25 2H, LT Hz), 1.98-1.84 1H), 1.80-1.75 2H), 0.99 6H, J 6.6 Hz); ESMS m/e: 242.8 CM H) WO 03/004027 WO 0/00027PCT/UJS02/21063 277 Example 188 N- (ISOPENTYLOXY) -l-NAPHTHYL]METHYL}-4- PIPERIDflNYL) PHENYL) -2-METHYLPROPANA4IDE: Prepared by Procedure F and Scheme R using 2-(isopentyloxy)-lnaphthaldehyde and 2-methyil--3-(4piperidinyl)phenyllpropalamide: ESMS mle: 473.3 (M 2-PROPOXY-1-NAPHTHiALDEHYDE: Prepared according to the Procedure for 2-(isopentyloxy)-1-naphthaldehyde using 2hydroxy-l-naphthaldehyde and 1-bromopropane.
Example 189 2-METHYL-N- [(2-PROPOXY-l-NAPHTHYL)METHYL) -4- PIPERIDINLIPHENYL)PROPANAMIDE: Prepared by Procedure F is and Scheme R using 2-propcxy-1-naphthaldehyde and 2methyl-N- (4-piperidinyl)phenyl] propanamide: ESMS m/e: 445.2 (M H* 4- ((-FORMYL-2-NAPHTHYL) OXY] METHYL LBENZONITRILE: Prepared according to the Procedure for 2- (isopentyloxy) -1-naphthaldehyde using 2-hydroxy-lnaphthaldehyde and 4- (bromomethyl) benzonitrile.
Example 190 [(4-CYANOBENZYL)OXYJ -1-NAPHTHYL)METHYL) -4- PIPERIDINYL] PHENYL) -2 -METHYLPROPANAMIDE: Prepared by Procedure F and Scheme R using 4-{[(l--formyl-2naphthyl)oxylmethyl~benzonitrile and 2-methyl-NV- (4piperidinyl)phenyljpropanamide: ESMS m/e: 518.2 (M [(2-FORMYL-2 -NAPHTHYL) OXY] ACETONITRILE; Prepared according to the Procedure for 2-(isopentyloxy)-1- WO 03/004027 WO 0/00027PCT/UJS02/21063 278 naplithaldehyde using 2- hydroxy-l1-naphthaldehyde and bromoacetonitrile.
Example 191 (CYANOMETHOXY) -l-NAPHTHYL]METHYL}-4- PIPERIDINYL) PHENYLJ -2 -METHYLPROPANAMIDE: Prepared by Procedure F and Scheme R using ormyl-2naphthyl) oxy] acetonitrile and 2-methyl-N- (4piperidinyl)phenyllpropanamide: ESMS m/e: 442.2 (M 2- -CHLOROBENZYL) OXY] -1-NAPETHALDEHYDE:. Prepared according to the Procedure for 2-(isopentyloxy)-1naphthaldehyde using 2-hydroxy-1-naphthaldehyde and 1- (bromomethyl) -3-chlorobenzene.
is Example 192 {2-[E(3-CHLOROBENZYL)OXY] -1-NAPHTHYL}METHYL) -4- PIPERIDINYlLJ PHENYL}-2-METHYLPROPANAMIDE! Prepared by Procedure F and Scheme R using 2-[(3-chlorobenzyl)oxy]- 1-naphthaldehyde and 2-methyl-N- (4piperidinyl)phenyllpropanamide: ESMS m/e: 527.2 CM Example 193 (4-CHLOROPHENOXY)BENZYL] -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure F and Scheme R using 4- (4chlorophenoxy)benzaldehyde and 2-methyl-N- (4piperidinyl)phenyljpropanamide: 1H NMR (400 MHz, CD)Cl 3 7.50 1H), 7.34-7.19 (in, 7H1), .6.98-6.87 (mn, 511), 3.50 2H1), 2.98 Cd, 2H, J 11. 8 Hz) 2.58-2.44 Cm, 2H), 2.10-1.98 Cm, 211), 1.83-1.76 (in, 4H1), 1.24 6H, J 6.8 Hz); ESMS m/e: 463.2 CM H).
Example 194 WO 03/004027 WO 0/00027PCT/UJS02/21063 279 V- (3 [4 4- DIFLUOROPHENOXY)BENZYLJ -4- PIPERIDINYL)PHENYL) -2 -METHYLPROPANAMIDE: Prepared by Procedure F arnd Scheme PR using 4-(3,4difluorophenoxy) berizaldehyde and 2-methyl-N- (4- S piperidinyl)phenyllpropanamide: ESMS mle: 465.2 (M 4- (ISOPENTYLOXY) -1-NAPHTHALDEHYDE: Prepared according to the Procedure for 2-(isopentyloxy)-1-naphthaldehyde using 4-hydroxy- 1-naphthaldehyde and l-bromo-3 methylbutane Example 195 NL- (ISOPENTYLOXY) -1-NAPHTHYL]METHYL}-4- PIPERIDINYL) PHENYLJ -2-METHYLPROPANA4IDE: Prepared by Procedure F and Scheme R. using 4-(isopentyloxy)-lnaphthaldehyde and 2-methyl-N- piperidinyl)phenyllpropanamide: ESMS m/e: 473.3 (M Example 196 (4-METHOXYPHENOXY)BENZYLJ -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure F and Scheme R using 4- (4methoxyphenoxy) benzaldehyde and 2-methyl-N- (4piperidinyl)phenyllpropanamide: ESMS m/e: 459.2 (M 4-PR0POXY-1-NAPHTHALDEHYDE: Prepared according to the Procedure for 2-(isopentyloxy)-1-naphthaldehyde using 4hydroxy- 1-naphthaldehyde and 1-bromopropane.
Example 1.97 2-METHYL-N- [(4-PROPOXY-1-NAPHTHYL)METHYLJ -4- PIPERIDITYL}PHENYL)PROPAINAMIDE: Prepared by Procedure F WO 03/004027 WO 0/00027PCT/UJS02/21063 280 and Scheme pR using 4- propoxy-l-naphthaldehyde and 2-methyl-N- (4-piperidinyl)phenyl) propananide:.
ESMS m/e: 445.2 (M Example 198 C4-(3,4-DICHLOROPHENOXY)BENZYLJ-4- PIPERIDINYL}PHiENYL) -2 -METHYLPROPANAMIDE: Prepared by Procedure F and Scheme R using 4-(3,4dichiorophenoxy) benzaldehyde and 2 -methyl-N- (4piperidinyl)phenyllpropanafide: ESMS m/e:497.l (M Example 199 (DIPHENYT.AINO)BENZYL] -4-PIPERIDINYL}PHENYL) 2-METHYLPROPA.NAMIDE: Prepared by Procedure F and Scheme R. using 4-(diphenylamino)benzaldehyde and 2-methyl-N- [3- (4-piperidinyl)pheny1)propanamide: ESMS m/e: 504.2 (M Example 200 [1-({2,5-DIMETHYL-1-[E3- (TRIFLUOROMETHYL)PHENYL] -lH- PYRROL-3-YL)METHYL) -4-PIPERIDINYLJ PHENYL)-2- METHYLPROPANAMIDE: Prepared by Procedure F and Scheme R using 2,5-dima-thyl-l- (tritluoromethyl)phenyll -1Hpyrrole-3-carbaldehyde and 2-methyl-N- (4piperidinyl)phenylipropanamide: ESMS mlie: 498.2 (M Example 201 2-METHYL-N-(3-{1- I1-(2-PHENYL-1,3-THIAZOL-4-YL)ETHYLJ-4- PIPERIDINYLIPHENYL)PROPANAMIDE: Prepared by Procedure F and Scheme R using 1-(2-phenyl-1,3-thiazol-4-yl)ethanone and 2-methyl-N- (4-piperidinyl)phenyllpropanamide: ESMS m/e:-434.2 (M WO 03/004027 WO 0/00027PCT/UJS02/21063 281 Example 202 [(5-CHLORO-3-METHiYL-l-PHENYL-lH-PYRAZOL-4- YL) METHYL] -4-PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure F and Scheme R using 5-chloro-3methyl-1-phenyl-lH-pyrazole-4-carbaldehYde and 2-methyl- N- (4-piperidinyl)phenyl] propanamide: ESMS rn/e: 451.2 H) Example 203 2-METHYLa-N-(3-{1- E(2-PHEINYL-1H-IMIDAZOL-4-YL)METHiYLJ -4- PIPERIDINYL}PHENYL)PROPANAMIDE: Prepared by Procedure F' and Scheme R using 2-phenyl-lH-imidazcle-4-carbaldehyde and 2-methyl-N- (4-pipe-ridinyl)phenyl] propanarnide: ESMS rn/e: 403.2 (M Example 204 N-E3- [4-BROMO-l- (4-CHLOROBENZYL) YL) METHYL)-4 -PIPERIDINYL) PHENYL] -2 -METHYLPROPANAMIDE: Prepared by Procedure F and Scheme R using 4-brcmo--(4chlorobenzyl) -lH-pyrazole--5-carbaldehyde and 2-methyl-N- (4-piperidinyl)phenyllpropanamide:. ESMS rn/c; 529.1 (MI H) 4 Example 205 2-METHYL-N-{3- [1-(3-PHENOXYBENZYL) -4- PIPERIflINYLJPHENYL)PROPANAMIDE: Prepared by Procedure F and Scheme R using 3-phenoxybenzaldehyde and 2-methyl-N- 13- (4-piperidinyl)phenyljpropanamide: ESMS rn/e: 429.2 (M Example 206 [3-(3,4-DICHLOROPHENOXY)BEN~ZYL] -4- PIPERIDINYL}PHENYL) -2-METHYLPRQPANAMIDE: Prepared by WO 03/004027 WO 0/00027PCT/UJS02/21063 282 Procedure F and Scheme R. using 3(3,4dichlorophenoxy)benzaldehyde and 2-methyl-N- (4piperidinyl)phenyllpropanamide: ESMS m/e: 497.15 (M Example 207 E3-(3,5-di-hlorophenoxy)benzyl]-4piperidinyl~phenyl) -2-methylpropanamide: Prepared by Procedure F and Scheme R using 3-(3,5dichiorophenoxy) benzaldehyde arnd 2-methyl-N- (4piperidinyl)phenyllpropanamide: ESMS 497.2 CM Example 208 2-METHYL-N-(3-{l- 13- (4-METHYLPHENOXY)BENZYLJ -4- PIPERIDINYL}PEENYL)PROPANAMIDE: Prepared by Procedure F and Scheme R. using 3-C4-methylphencxy)benzaldehyde and 2-methyl-N- (4-piperidinyl)phenyl] propanamide: ESMS m/e: 443.2 (M Example 209 2-METH-YL-N- (TRIFLUJOROMETHYL) PHENOXYJ BENZYL} 4-PIPERIDINYj) PHE1NYL] PROPANANIDE: Prepared by Procedure F and Scheme R using, -3 (t ri fluorome thyl) phenoxy] ben z aldehyde and 2-methyl-N- [3- (4=-piperidinyl)phenyllpropanamide: ESMS rn/c: 497.2 (M Example 210 (4-CHLOROPHEN'OXY)BENZYLJ -4- PIPERIDIN'YL)PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure F and Scheme R using -4 chlorophenoxy)benzaldehyde and 2-methyl-N- (4piperidinyl)phenyllprcpanamide: ESMS nile: 463.2 (M WO 03/004027 WO 0/00027PCT/UJS02/21063 283 Example 211 E3- (DIMETHYLAM(INO) BENZYL) -4-PIPERIDINYL)PHENYL) 2-METHYLPROPANAMIDE: Prepared by Procedure F and Scheme R using 3 -(dimethyl amno) benz al debyde and 2-methyl-N- [3- (4-piperidinyl)phenyllpropanamide: ESMS m/e: 380.2 (M Example 212 [3-(4-METHOXYPHENOXY)BENZYL)-4- PIPERIDINYL }PHENYL) -2 -METHYLPROPANAMIDE; Prepared by Procedure F and Scheme R using -4 methoxyphenoxy) benzaldehyde and 2-methyl-N- (4piperidinyl)phenylipropanamide: ESMS m/e: 459.2 (M Example 213 C4-TERT-BUTYLPHENOXY)BENZYL] -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure F and Scheme R using 3-(4-tertbutylphenoxy)benzaldehyde and 2-methyl-N- (4piperidinyl) phenyll propanamide: ESMS mle: 485.3 CM Example 214 2-METHYL-N-(.3-{1-[3-NIETRO-4- (l-PIPERIDINYL)BENZYLJ -4- PIPERIDINYL}PHENYL) PROPANAMIDE- Prepared by Procedure F and Scheme R using 3-nitro-4- (1-piperidinyl)-benzaldehyde and 2-methyl-N- (4-piperidinyl)phenyllpropanamide: ESMS in/e: 465.2 (M Example 215 WO 03/004027 WO 0/00027PCT/UJS02/21063 284 DINETRYLTHIENO [2,3- B] THIEIN-2-YL) METHYL] -4-PIPERIDINYLPHEN.YL) -2- METHYLPROPANAMIDE: Prepared by Procedure F and Scheme R using 3, 4-dimethylthielo 3-b] thiophene-2-carbaldehyde and 2-methyl-N- (4-piperidinyl)phenyl] propanamide: ESMS m/e: 427.1 (M Example 216 2-METHYL-N-(3-[1- (TRIFLUOROMETHiYL)PHENYL] -1H- PYRAZOL-4-YL)METHYL) -4-PIPERIDINYL] PHENYL}PROPANAMIDE: Prepared by Procedure F and Scheme R using 3- [4- (trifluoromethyl)pheny1l -lH-pyrazole-4-carbaldehyde and 2-methyl-N- (4-piperidinyl)phenyl] propanamide: ESMS m/e: 471.1 (M Example 217 2-METHYL-N-(3-(1-E4- (1H--1,2,4-TRIAZOL-1-YL)BENZYL] -4- PIPERIDI1NYL}PHENYL) PROPANAMIDE: Prepared by Procedure F and Scheme R using 4-(JH-1,2,4-triazol-1-yl)benzaldehyde and 2-methyl-N- (4-piperidinyl) phenyl] propanamide: ESMS m/e: 404.1 (M Example 218 2-METHYL-N- [(5-METHYL-1-PHENYL-lH-PYRAZOL-4- YL) METHYLJ -4 -PIPERIDINYL}PHENYL) PROPANAMIDE: Prepared by 2S Procedure F and Scheme R using 5-methyl-1-phenyl-.Hpyrazole-4-carbaldehyde and 2-methyl-N- (4piperidinyl)phenyllpropanamide: ESMS m/e: 417.1 (M Example 219 2-METHiYL-.N- (4-MORPHOLINYL) -3-NITROBENZYLJ -4- PIPERIDINYL}PHENYL) PROPANAMIDE: Prepared by Procedure F and Scheme R using 4- (4-morpholinvl) -3-nitrobenzaldehyde WO 03/004027 WO 0/00027PCT/UJS02/21063 285 and 2-methyl-N- (4piperidinyl)phenyllpropanamide: ESMS m/e: 467.1 (M Example 220 E2-CHLORO-4- (TRIFLUOROMETHYL)PHENYLI-2- FURYL}METHYL) PIPERIDlNYLJ PHENYL} -2 -METHYLPROPANA4IDE: Prepared by Procedure F and Scheme R using 5- [2-chioro- 4- (trifluoromethyl)phenyl) -2-furaldehyde and 2-methyl-N- (4-piperidinyl)phenyllpropanamnide: ESMS m/e: 505.0 (M Example 221 ETHYL 4- (ISOBUTYRYLAMINO) PHENYLI -1- PIPERIDINYL}METHYL) -2,5-DIMETHYL-l-PHENYL-lH-PYRROLE-3- CARBOXYLATE: Prepared by Procedure F and Scheme R using ethyl 4-formyl-2,5-dimethyl-l-phenyl-lH-pyrrole-3carboxylate and 2-methyl-N- (4piperidinyl)phenyllpropanamide: ESMS m/e: 502.2 (M Example 222 ETHYL 5- (4-CHLOROPHENYL) [3- (ISOBUTYRYLAMINO) PHENYL] -l-PIPERIDINYL}METHYL) -3- FUROATE: Prepared by Procedure F and scheme R using ethyl 5- (4-chiorophenyl) -2-f ormyl-3-furoate and 2methyl-N- (4-piperidinyl) phenyl] propanamide: ESMS m/e: 509.0 (M +i Example 223 El-(2,3-DIHYDRO-l,4-BENZODIOXIN-6-YLMETHYL)-4- PIPERIDINYL] PHENYL} -2 -METHYLPROPANAMIDE: Prepared by Procedure F and Scheme R. using 2,3-dihydro-l,4benzodioxine-6-carbaldehyde and 2-methyl-N- (4piperidinyl)phenyllpropanamide: ESMS m/e: 395.1 (M H) 4 WO 03/004027 WO 03/04027PCTIUS02/2 1063 26 Example 224 2-METHYL-N- E(6-PHENOXY-3-PYRIDINYL)METHYL] -4- PIPERIDINYL}PHENYL) PROPANAMIDE: Prepared by Procedure F and Scheme R using 6-phenoxynicotinaldehyde and 2methyl-N- (4 -piperidinyl) phenyl] propanamide: ESMS m/e: 430.1 (M Example 225 2-METH-YL-N- (2-PYRIDIN-YL) -2-THIETYL]METHYL}-4- PIPERIDINYL)PHENYLPROPANA4IDE: Prepared by Procedure F and Scheme R using S-(2-pyridinyl)-2thiophenecarbaldehyde and 2-methyl-N- (4piperidinyl)phenyllpropanamide: ESMS m/e: 420.1 (M Example 226 2-METHIYL-N-{3-El- E1-METHYL-3- (TRIFLUOROMETHYL) -11- -2-THIENYL}METHYL) -4- PIPERIDINYLJPHENYL)PROPANAMIDE: Prepared by Procedure F and Scheme R using S-[l-methyl-3-(tritluoromethyl)-lH- -2-thiophenecarbaldehyde and 2-methyl-N- [3- (4-piperidinyl)phenyllpropanamide: ESMS m/e: 491.0 (M Example 227 2-METHYL-N- [1-(PH-ENYLSULFONYL) -lH-INDOL-3- YL] METHYL) -4-PIPERIDINYL) PHENYL) PROPANAMIDE: Prepared by Procedure F and Scheme R using l-(phenylsulfonyl)-1Hindcle-3-carbaldehyde and 2-methyl-N- (4piperidinyl)phenyllpropanamide: ESMS m/e: 516.1 (N Example 228 WO 03/004027 WO 0/00027PCT/UJS02/21063 287 M- 5-DIMETHYL-3 OXO- 2 -PHEkTYL- 2, 3-DIHYDROlH-PYRAZOL-4-YL) METHYL] -4-PIPERIDINYLPIENYL) -2- METHYLPROPANAMIDE: Prepared by Procedure F and Scheme R using l,5-dimethyl-3-oxo-2-phenyl-2,3-dihydr--Hpyrazole-4-carbaldehyde and 2-methyl-N- (4piperidinyl~phenyllpropanamide: ESMS m/e: 447.2 (M Example 229 [4-(4-TIRT-BUTYL-1,3-THIAZOL-2-YL)BENZYL]-4- PIPERIDINYLPHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure F and Scheme R using 4-(4-tert-butyl-l,3thiazol-2-yl)benzaldehyde and 2-methyl-N- (4piperidinyl) phenyll propanamide.
Example 230 (2,3-DIHYDRO-l-BEINZOFURAN-5-YLMETHYL) -4- PIPERIDINYL] PHENYL}-2-METHYLPROPANAMIDE: Prepared by Procedure F and Scheme R using 2,3-dihydro-1-benzofuranand 2-methyl-NV-[3- (4piperidinyl)phenyllpropanamide: ESMS m/e: 379.1 (M Example 231 2-METHYL-N- -1ETHYL-2-PHENYL-5- PYRIMIDINYL) METHYL] -4 -PIPERIDINYL}PHENYL) PROPANIAMIDE: Prepared by Procedure F and Scheme R using 4-methyl-2and 2-methyl-N- (4piperidinyl)phenyllpropanamide: ESMS m/e: 429.2 (M Example 232 N,-{3-[l-(2,1,3-BENZOTHIADIAZOL-5-YLMETHYL)-4- PIPERIDINYL] PHENYL) -2 -METHYLPROPANAMIDE: Prepared by Procedure F and Scheme R using 2,l,3-benzothiadiazole-5- WO 03/004027 WO 0/00027PCT/UJS02/21063 288 carbaldehyde and 2-methyl- N 3 4 piperidinyl)phenyllpropanamide: ESMS m/e; 395.1 (M Example 233 2-METHYL-N- E(5-PHENYL-2-THIENYL)METHYLJ -4- PIPERIDINYL}PHENYL)PROPANAMIDE: Prepared by Procedure F and Scheme R using 5-phenyl-2-thiophenecarbaldehyde and 2-methyl-N- 13- (4-piperidinyl)phenyl] propanamide: ESMS m/e: 419.1 (M Example 234 N-{3-El- (3,4-DIHYDRO-2H-1,5-BENZODIOXEPIN-7-YLMETHYL) -4- PIPERIDINYL] PHENYL}-2-METHiYLPROPANAMIDE: Prepared by Procedure F and Scheme R using 3,4-dihydro-2H-l,5benzodioxepine-7-carbaldehyde and 2-methyl-NV-[13- (4piperidinyl)phenyllpropanamide: ESMS m/e: 409.2 (M Example 235 2-METHYL-N-E3-(l-{ E3-(2-THIENYL)-lH-PYRAZOL-4- YL) METHYL.-4 -PIPERIDINYL) PHENYL) PROPANAMIDE: Prepared by Procedure F and Scheme R using 3-(2-thienyl)-lHpyrazole-4-carbaldehyde and 2-methyl-N- (4piperidinyl)phenyllpropanamide: ESMS mle: 409.1 (M Example 236 El- ((l,1'-BITHIENYL] -4-YLMETHYL) -4- PIPERIDINYLJPHENYL}-2-METHIYLPROPANAMIDE: Prepared by Procedure F and Scheme R using 2,21-Bithiophene-5carboxaldehyde and 2-methyl-N- piperidinyl)phenyllpropanamide: ESMS m/e: 425.0 (M Example 237 WO 03/004027 WO 0/00027PCT/UJS02/21063 289 IV-(3 2- DIMETHYL 3,4-DIHYDRO-2H-CHROMEN-6- YL) METHYL] -4 -PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prep ared by Procedure F and Scheme R using 2,2-dimethyl- 6-chromanecarbaldehyde and 2 -methyl [3 (4 piperidinyl)phenyllpropanamide: ESMS rn/e: 421.2 (M Example 238 2-METHYL-N-{3- El- j-METHYL-5- (TRIFLUOROMETHYL) -1H- PYRAZOL-3-YL] -2-THIENYL}METHYL) -4- PIPERIDINYLJ PHENYL}PROPANAMIDE: Prepared by Procedure F and Scheme R using 5- [1-methyl-5- (trifluoromethyl) -lHpyrazol-3-yl) -2-thiopheniecarbaldehyde and 2-methyl-N- [3- (4-piperidinyl)phenyllpropanamide: ESMS m/e: 491.1 (M
H).
is Example 239 2-METHYL-N-(3-{1- E(2-PHENYL-1,3-THIAZOL-4-YL) METHYL] -4.
PIPERIDINYLPHENYL) PROPANAMIDE.: Prepared by Procedure F and Scheme R using 2-phenyl-l, 3-thiazole-4-carhaldehyde and 2-methyl-N- E3- (4-piperidinyl) phenyljpropanamide: ESMS mle: 420.0 (M H) 4 Example 240 2-METHYL-N- (3-{l-[E(3-PHENOXY-2-THIENYL)METHYL] -4- PIPERIDINYL}PHENYL)PROPANAMIDE: Prepared by Procedure F and Scheme R using 3-phenoxy-2-thiophenecarbaldehyde and 2-methyl-NL- (4-piperidinyl)phenyl) propanamide: ESMS zn/e: 4 35. 0 (M H).
Example 241 El- ({2-[(4-CHLOROPHEBYL) SULFANYL] -3- THIENYL)METHYL) -4 -PIPERIDINYL] PHENYL} -2- METHYLPROPANAMIDE: Prepared by Procedure F and Scheme R WO 03/004027 WO 03/04027PCTIUS02/2 1063 290 using chiorophenyl) sulfanyl] -3thiophenecarbaldehyde and 2-methyl-NV-[3- (4piperidinyl)phenyllpropanahide: ESMS nile: 485.0 (M Example 242 N- (4-CHLOROPHE9NYL) -1H-PYRROL-2-YLJMETHYL}-4- PIPERIDINYL)PHiENYL] -2-METHYLPROPAAMIDE: Prepared by Procedure F and Scheme R using 1-(4-chlorophenyl)-1Hpyrrole-2-carbaldehyde and 2-methyl-N- (4piperidinyl)phenyllpropalamide: ESMS m/e: 436.0 (M Example 243 2-METHYL-NV-{3- (TRIFLTJOROMETHOXY)PHENYL] -2- FUJRYL)METHYL) -4 -PIPERIDINYL] PHENYL)PROPANAMdIDE: Prepared by Procedure F and Scheme R using 5-[2- (trifluoromethoxy) phenyl) furaldehyde and 2-methyl-N- (4-piperidinyl)phenyljpropalamide: ESMS m/e: 487.1 (M Example 244 2-METHYL-N- (4-MO)RPHOLINYL)BENZYL) -4- PIPERIDINYL)PHENYL)PROPANAMIDE: Prepared by Procedure F and Scheme R using 2-(4-morpholinyl)benzaldehyde and 2methyl-N- (4-piperidinyl)phenyl] propanamide: ESMSq m/e: 4 22.2 (M H).
Example 245 NV-[3- (4-METHOXYPHENYL) -lH-PYR.AZOL-4.-YL]METHYL}-4- PIPERIDINYL)PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure F and Scheme R using 3-(4-methoxyphenyl)-lHpyrazole-4-carbaldehyde and 2-methyl-N- (4piperidinyl)phenyllpropanamide: ESMS m/le: 433.1 (M WO 03/004027 WO 0/00027PCT/UJS02/21063 291 Example 246 2-METHYL-N- (lH-PYRAZOL-1-YL)BENIZYL] -4- PIPERIDINYL}PEENYL) PROPANAMIDE: Prepared by Procedure F and Scheme R using 4-(1H-pyrazol-l-y.)beflzaldehiyde and 2-methyl-N- (4-piperidinyl)phen-yll propanamide: ESMS rn/c: 402.8 (M H) 4 Example 247 2-METHYL-N-{3- El- (4-QUINOLINYLMETHYL) -4- PIPERIDINYL]PHENYL}PROPANAMIDE: Prepared by Procedure F and Scheme R using 4-quinolinecarbaldehyde and 2-methyl- N-13- (4-piperidinyl)phelyllpropalamide: ESMS rn/e: 388.1 (Mi Example 248 2-METHYL-N- (4-MORPHOLINYL)BENZYL) -4- PIPERIDIN'YL)PHENYL) PROPANAMIDE: Prepared by Procedure F and Scheme PR using 4-(4-morpholinyl)benzaldehyde and 2methyl-N-[13- (4-piperidinyl)phenylllpropanamide: ESMS rn/e: 422.5 (Mi Example 249 2-METHYL-N-(3-{1- 14- (2-THIENYL)BENZYL] -4- PIPERIDINYL)PHENYL)PROPANAMIDE: Prepared by Procedure F and Scheme R using 4-(2-thienyl)benzaldehyde and 2methyl-N- (4-piperidinyl phenyl) propanamide: ESMS rn/c: 419. 1 (Mi H Example 250 2-METHYL-N- (3-{1-[E(2-METHYL-5-PHENYL-3-FUJRYL)METHYLJ -4- PIPERIDINYL)PHENYL)PROPANA4IDE: Prepared by Procedure F and Scheme R using 2-methyl-5-phenyl-3-furaldehyde and 2-methyl-N- (4-piperidinyl)phenylJ propanamide: ESMS rn/e: 417.2 (M +i WO 03/004027 WO 03/04027PCTIUS02/2 1063 292 Example 251 N- 1- (CYCLOPENTYLOXY) -4 -METHOXYBENZYL] -4- PIPERID)INYL)PHENYL) -2 -METIIYLPROPANAMIDE: Prepared by Procedure F and Scheme R using 3- (cyclopentyloxy) -4methoxybenzaldehyde and 2-methyl-N- E3- (4piperidinyl~phenyllpropanamide; ESMS m/e: 451.1 (M
H).
Example 252 2-METHYL-N-{3- (TRIFLUOROMETHOXY)PHENYL) -2- FURYL}METHYL) -4 -PIPERIDINYL] PHENYL}PROPANAMIDE: Prepared by Procedure F and Scheme R. using 5-[4- (trifluoromethoxy)phenyl) -2-furaldehyde and 2-methyl-N- (4-piperidinyl)phenyllpropanamide: ESMS m/e: 487.1 (M H+ Example 253 (l-BENZOTHIEN-2-YLMETHYL) -4-PIPERIDINYL] PHENYL)- 2-METHYLPROPANAMIDE; Prepared by Procedure F and Scheme R using 1-benzothiophene-2-carbaldehyde and 2-methyl-Nq- (4-piperidinyl)phenyllpropanamide: ESMS m/e: 393.2 (M Example 254 2-METHYL-N-{3- (TRIFLUORON4ETHOXY)P{ENYL) -2- FURYL}METHYL) -4 -PIPERIDINYL] PHEINYL}PROPANAMIDE: Prepared by Procedure F and Scheme R. using 5-[3- (trifluoromethoxy)phenyl] -2-furaldehyde and 2-methyl-N- [3-(4-piperidinyl)phenyllpropanamide: ESMS m/e: 487.2 CM Example 255 WO 03/004027 WO 0/00027PCT/UJS02/21063 293 2-METHYL-Nq-{3- QUI:NOLINYLMETHYL) -4- PIPERIDINYLJ PHENYL}PROPANAMIDE: Prepared by Procedure F and Scheme R using 2-quinolinecarbaldehyde and 2-methyl- N- (4-piperidinyl)phenyl2 propanamide: ESMS m/e: 388.1 Example 256 N-(3-{l-[4-(lH-lIDAZOL-1-YL)BENZYL) -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure F and Scheme R using 4-(l-H-imidazol-1yl)benzaldehyde and 2-methyl-N- (4piperidinyl)phenyllpropanamide: ESMS m/e: 403.2 (M Example 257 is (9H-FLUOREN-2-YLMETHYL) -4-PIPERIDINYLJ PHENYL}-2- METHYLPROP.ANAMIDE: Prepared by Procedure F and Scheme R using 9H-fluorene-2-carbaldehyde and 2-methyl-N- (4piperidinyl)phenyllpropanamide: ESMS m/e: 42S.1 (M Example 258 METHYL 3- [5-((4-[3-(ISOSUTYRYLAMINO)PHENYL) -1- PIPERIDINYL METHYL) -2-FtJRYLJ -2-THIOPHENECARBOXYLATE: Prepared by Procedure F and Scheme R using methyl tormyl-2-turyl) -2-thiophenecarboxylate and 2-methyl-NV- [3-(4-piperidinyl)phenyllpropanamide: ESMS m/e: 467.1 CM
H)
4 Example 259 2-METHIYL-N-{3- l- (4-PHENOXYBENZYL) -4- PIPERIDINYL)PHENYL}PROPANAMIDE: Prepared by Procedure F and Scheme R using 4-phenoxybenzaldehyde and 2-methyl-N- (4-piperidinyl)phenyllpropanamide: ESMS m/e: 429.2 (M H) WO 03/004027 WO 0/00027PCT/UJS02/21063 294 Example 260 N-{3-El- -BIPHEEqYL) -4-YLMETHYL) -4- PIPERIDINYL1 PHENYL}-2-METHYLPROPANAMIDE: Prepared by Procedure F and Scheme R using [1,11-biphenyl)-4carbaldehyde and 2-methyJ.-N-[3-C4piperidinyl)phenyllpropanamide: ESMS m/e: 413.2 Example 261 (DIBUTYLAMINO) BENZYL] -4-PI:PERI:DINYL}PHENYL) 2-METHYLPROPANAMIDE: Prepared by Procedure F and Scheme R using 4- (dibutylamino)benzaldehyde and 2-methyl-N- [3- (4-piperidinyl)phenyllpropanamide: ESMS 464.6 (M 1s Example 262 2-METHYL-N- i:(4-METHYLPHENqYL) SULFANYL) -3- NITROEENZYL}-4 -PIPERIDINYL) PHENYL] PROPANAMIDE: Prepared by Procedure F and Scheme R using methyiphenyl) sul fanyl) -3-nit robenz aldehyde and 2-methyl- N- (4-piperidinyJ.)phenyllpropanamide: ESMS m/:e 504.2 (M H) Example 263 2-METHYL-N- (l,2,3-THIADI:AZOL-4-YL)BENZYLJ -4- PIPERIDINYL}PRENYL) PROPANAMIDE: Prepared by Procedure F and Scheme R using 4- 3-thiadiazol-4-yl)benzaldehyde and 2-methyl-N- (4-piperidinyl)pheny1l propanamide: ESMS m/e: 421.1 (M H)Y.
-3-CHLORO-1-PHENYLPROPYL]OXY}PHENYL)ETHANONE: (lR)-3-Chloro-l-pheny1-1-propano. (1.000 g, 5.86 mmol), 1-(3-hydroxyphenyl)ethanone (0.797 g, 5.86 mmol)., triphenyiphosphine (1.54 g, 5.86 rnmol) and WO 03/004027 PCT/US02/21063 295 diethylazodicarboxylate (1.53 g, 8.79 mmol) were combined in a flask, which was immediately flushed with argon. THF (20 mL) was added and the mixture was stirred overnight under argon. THF was removed in vacuo, the crude product was dissolved in 50 mL of
CH
2 C12/H 2 0 and the organic layer was separated and dried over MgSO 4 After removing the solvent in vacuo, the residue was purified by flash chromatography using ethyl acetate/hexane to yield the desired product (900 mg, 76.0 1H NMR (400 MHz, CDC13) 5 7.49-7.46 (m, 2H), 7.40-7.26 6H), 7.07-7.04 1H), 5.46-5.43 (dd, 1H, J 4.4 Hz, 8.8 Hz), 3.84-3.78 1H), 3.64- 3.59 1H), 2.52 3H), 2.51-2.46 1H), 2.29-2.22 1H).
4-(3,4-DIFLUOROPHENOXY)BENZALDEHYDE: 4- Fluorobenzaldehyde (5.32 mL, 49.6 mmol), 3,4difluorophenol (7.10 g, 54.6 mmol) and K 2 C0 3 (8.31 g, 60.1 mmol) were combined in a flask, which was immediately flushed with argon. DMF (50.0 mL) was added and the mixture was heated at reflux under argon for 6 h. Upon cooling to room temperature, EtOAc (100 mL) and
H
2 O (100 mL) were added; the ethyl acetate layer was separated and washed with H 2 0 (2 X 100 mL). The combined organic layers were washed with brine, dried over MgS0 4 and the solvent was removed in vacuo. The desired product was obtained (11.4 g, 98.0 H NMR (400 MHz, CDC13) 5 9.95 1H), 7.88 (dd, 2H, J 0.8 Hz, 8.8 Hz), 7.24-7.17 1H), 7.07 2H, J 8.8 Hz), 6.97-6.92 1H) 6.86-6.82 1H) ESMS m/e: 235.0 (M H) TERT-BUTYL 4-(4,4,5,5-TETRAMETHYL-1,3,2-DIOXABOROLAN-2- YL)-3,6-DIHYDRO-1(2H)-PYRIDINECARBOXYLATE: To a flask WO 03/004027 PCTIUS02/21063 296 were added bis(pinacolato)diboron (422 mg, 1.66 mmol), KOAc (444 mg, 4.53 mmol), PdCl 2 dppf (37.0 mg, 3.00 mol), dppf (25.0 mg, 3.00 mol%) and the flask was flushed with argon. A solution of tert-butyl 4-{[(trifluoromethyl)sulfonylloxy}-1,2,3,6-tetrahydro-lpyridinecarboxylate (500 mg, 1.51 mmol) in 1,4-dioxane (10.0 ml) was added and the mixture was stirred at 80 OC overnight. The mixture was filtered through Celite and the filtrate was evaporated in vacua. The resulting residue was dissolved in EtOAc and washed with H 2 0, followed by brine. The organic layer was dried over MgSO 4 filtered and concentrated in vacua. The crude material was purified by flash chromatography EtOAC/hexane) to give tert-butyl 4-(4,4,5,5-tetramethyll,3,2-dioxaborolan--2-yl)-3,6-dihydro-1(2H)pyridinecarboxylate (355 mg, 'H NMR (400 MHz, CDCl 3 5 6.44 (br s, 111), 3.93 (br s, 2E), 3.42 (br s, 2H), 2.21 (br s, 2H), 1.45 9H), 1.25 12H); ESMS m/e: 310.4 (M N-(6-BROMO-2-PYRIDINYL)-2-METHYLPROPANAMIDE: Prepared by Procedure Q1 using 2-methylpropanoyl chloride and 6bromo-2-pyridinanine: ESMS m/e: 242.8 (M H) 4 TERT-BUTYL 4-Eg-(ISOBUTYPYLAMINO)-2-PYRIDINYL]-3,6- DIHYDRO-1(2H)-PYRIDINECARBOXYLATE: Prepared by Procedure W and Scheme AF using N-(6-bromo-2-pyridinyl)- 2-methylpropanamide and tert-butyl 4- (4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-l(2H)pyridinecarboxylate: ESMS mle: 245.8 (M 100)+.
2-METHYL-N-[6-(4-PIPERIDINYL)-2-PYRIDINYL)PROPANANIDE: Prepared by Procedures X and Y, Schemes AG and AH, WO 03/004027 WO 03/04027PCTIUS02/2 1063 297 respectively using tert- butyl -6 (isobutyrylamino) -2--pyridinyl] 6-dihydrc-l (2H) pyridinecarboxylate: ESMS m/e: 248.1 (M Example 264 N-(6-{1-4-(3,4-DIMETHYLPHENL)-4-OXOBUTYL]-4- PIPERIDINYL}-2-PYRIDINYL) -2-METHYLPROPANAMIDE: Prepared by Procedure G and Scheme AI using 4-chloro-l- (3,4dirnethyiphenyl) -1-butanone and 2-methyl-N- (4pi-peridinyl)-2-pyridinyllpropalamide: ESMS m/e: 422.1 (M Excample 265 N-(6-{1-E4,4-BISC4-FLUJOROPHENYL)BUTYL)-4-PIPERIDINYL}-2- PYRIDINYL)-2-METHYLPROPANAMIDE: Prepared by Procedure G and Scheme AI using 1-[4-chloro-l-(4fluorophenyl)butyl] -4-f luorcbenzene and 2-methyl-NV-[6- (4-piperidinyl) -2-pyridinyllpropanamide: ESMS xn/e: 492.2 (M H).
Example 266 (3,4-DIFLUOROPHENOXY)BENZYL] -4-PIPERID)INYL)- 2-PYRIDINYL) -2-METHYLPROPANAMIDE: Prepared by Procedure AAX and Scheme ACT using 4-(3,4difluorophenoxy)benzaldehyde and. 2-methyl-NV- 6- (4piperidinyl)-2-pyridinyllprcpanamide: ESMS zn/e: 466.0 (M
H).
N- (3-BROMO-4 -ZETHYLPHENYL) -2 -NETBYLPROPANAMIDE: Prepared by Procedure Q1 using 2-methyipropanoyl chloride and 3-bromo-4-methylaniline: ESMS mle: 255.9 (M
H).
WO 03/004027 WO 03/04027PCTIUS02/2 1063 298 TERT-BUTYL 4- (ISOBUTYRYLAMINO) -2- METHYLPHEN~YL) -3,6 -DIHYDRO-1 (2H) -PYRIDINECARBOXYLATE: Prepared by Procedure W and Scheme AF using N- (3-bromo- 4 -met hyiphenyl) 2 -methyipropanami de and tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolal-2-yl)-3, 6 dihydro-1(21-)--pyridinecarboxylate: ESMS m/e: 259.1 (M 100)+ 2-METHYL-N- [4-METHYL-3- (4- PIPERIDINYL) PHENYL] PROPANAMIDE: Prepared by Procedures X and Y, Schemes AG and All, respectively using tertbutyl Cisobutyrylamino) -2-methyiphenyl] -3,6dihydro-l(2H)-pyridinecarboxylate: ESMS m/e: 261.0 CM Example 267 N- (3,4-DIFLUOROPHENOXY)BENZYLI -4-PIPERIDIN'YL}- 4 -METHYLPHENYL) -2 -METEYLPROPANAMIDE: Prepared by Procedure AA and Scheme AJ using 4-(3,4difluorophenoxy)benzaldehyde and using 2-methyl-.N-E4methyl-3- (4-piperidinyl)phenyl] propanamide: ESMS m/e: 4 79. 1 (M N- (5-BROMO-2 -METHYLPHEINYL) -2 -METHYLPROPANAMIDE: Prepared by Procedure Qi using 2-methylpropanoyl chloride and 5-bromo-2-methylaniline: ESMS m/e: 255.9 (M
H~
TERT-BUTYL 4- (ISOBUTYRYLA4INO) -4-METHYLPHENYLJ -3,6 DIHYDRO-1C2H)-PYRIDINECARBOXYLATE: Prepared by Procedure W and Scheme AF using N-(S-bromno-2methyiphenyl) -2-methyipropanamide and tert-butyl 4- (4,4,5,S-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6- WO 03/004027 WO 03/04027PCTIUS02/2 1063 299 dihydro-1 (2H) pyridinecarboxylate: ESMS rn/e: 259.1 (M 100)*.
2-METHYL-V- [2-METHYL-.5- (4- PIPERIDINYL) PHENYL] PROPANAMIDE: Prepoared by Procedures X and Y, Schemes AG and AH, respectively using tertbutyl 4- (isobutyrylamino) -4-methyiphenyl] -3,6dihydro -I(2H) -pyri dine carboxyl ate: ESMS m/e: 261.0 (M Example 268 [(9-ETHYL-9H-CARBAZOL-3-YL) METHIYL] -4- PIPERIDINYL 2-METHYLPHENYL) -2 -METHYLPROPANAMIDE: Prepared by Procedure AA and Scheme AJ using 9-ethyl-9Hcarbazole-3-carbaldehyde and 2-methyl-N- [2-methyl-5- (4piperidinyl)phenyllpropanamide: ESMS m/e: 468.1 (M Example 269 (3,4-DIFLUOROPHENOXY)BENZYL] -4-PIPERI:DINYLI- 2-METHYLPHENYL)-2-METHYLPROPANAMIDE: Prepared by Procedure AA and Scheme Al using 4-(3,4difluorophenoxy) benzaldehyde and 2-methyl-N- (4-piperidinyl)phenyllpropanamide: ESMS m/e: 479.2 (M Example 270 N-(3-{1-[E(9-ETHYL-9H-CARBAZOL-3-YL)METHYL] -4- PIPERIDINYL} -4 -METHYLPHENYL) -2 -METHYLPROPANANIDE: Prepared by Procedure AA and Scheme AJ using 9-ethyl-9Hcarbazole-3-carbaldehyde and 2-methyl-N- [4-methyl-3- (4piperidinyl)phenyllpropanamide: ESMS m/e: 468.1 (M WO 03/004027 WO 03/04027PCTIUS02/2 1063 300 Example 271 2-METHYL-N- t2-METHYL-5- (4- PI:PERIDINYL)PHENYLPROPANAMI:DE: Prepared by Procedure G and Scheme AI using 1-[4-chloro-i-(4fluorophenyl)butyl] -4-fluorobenzene and 2-methyl-N- [2- (4-piperidinyl)phenyllpropanamide: ESMS m/s: 505.1 (M H+ Example 272 E(3S)-3- (3-ACETYLPHENOXY)-3-PHENYLPROPYL] -4- PIPERIDINYL} -4 -METHYLPHENYL) -2 -METHYLPROPANANIDE: Prepared by Procedure G and Scheme AI using 3 -chloro-l -phenyipropyl) oxylphenyl) ethanone and 2methyl-N- t4-methyl-3- (4-piperidinyl) phenyl] propanamide: ESMS rn/c: 513.0 (M Example 273 (3-ACETYLPHENOXY) -3-PHENYLPROPYL] -4- PIPERIDINYL} -2 -METHYLPHiEN'YL) -2-METHYLPRQPANAMIDE: Prepared by Procedure G and Scheme AI using 3- chioro- 1-phenylpropyl] oxy~phenyl) ethanone and 2methyl-N- [2-methyl-5- (4-piperidinyl) phenyl) propanamide: ESMS rn/e: 512.9 (M +i N- IODOPHENYL) -2 -METHYLPROPANAI4IDE: Prepared by Procedure Q1 using 2-methylpropanoyl chloride and 2lodoaniline: ESMS m/e: 289.9 (M TERT-BUTYL 4-[12- (ISOBUTYRYLAMINO) PHENYLJ 6-DIHYDRO- 1(2H)-PYRIDINECARBOXYLATE: Prepared by Procedure W and Scheme AF using N-(2-iodophenyl)-2-methylpropanamide and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxahorolan-2- WO 03/004027 WO 03/04027PCTIUS02/2 1063 301 yl) 6-dihydro-l (2H) pyridinecarboxylate: ESMS m/e: 245.1 (M 100)+.
2 -METHYL-N- (4 -PIPERIDINYL) PHEN~YL] PROPANAMIDE: Prepared by Procedures X and Y, Schemes AG and AR, respectively using tert-butyl 4- [2- (isobutyrylamino)phenyl-]-3, 6-dihydro-l (211)pyridinecarboxylate: ESMS m/e: 247.1 (M Example 274 E(9-ETHYL-9H-CARBAZOL-3-YL)METHYL] -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure AA. and Scheme AJ using 9-ethyl-9H-carbazole-3carbaldehyde and 2-methyl-N- (4piperidinyl)phenyllpropanamide: ESMS mle: 454.1 (M Hl)'.
Example 275 [4,4-BIS(4-FLUOROPHENYL)BUTYL-4-PIPERIDIENYL}-4- METHYLPHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure G and Scheme AI using 1- [4-chloro-1- (4fluorophenyl)butylJ -4-fluorobenzene and 2-methyl-.N- [4methyl-3 -(4-piperidinyl) phenylipropanamide: ESMS m/e: 505.0 (M Example 276 Z!V-(2-{1.-[4,4-BIS(4-FLUOROPHENYL)BUTYLJ-4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure G and Scheme AI using 1- [4-chloro-1- (4fluorophenyl) butyll -4-f luorobenzene and 2-methyl-N- [2- (4-piperidinyl)phenyllpropanamnide: ESMS m/e: 490.9 (M WO 03/004027 WO 03/04027PCTIUS02/2 1063 302 N- [2-BROMO-4- (TRIFLUOROMETHOXY)PHENYL] 2-METRYLPROPANAMIDE: Prepared by Procedure Q1 using 2methyipropanoyl chloride and 2-bromo-4- (trifluoromethoxy)alhline: ESMS m/e: 325.9 (M THRT-BUTYL 4- (ISOBUTYRYLAMINO) (TRIFLUOROMETHOXY) PHE1NYLJ 6-DIHYDRO-1 (2H) PYRIDINECARBOXYLATE: Prepared by Procedure W and Scheme AF using N- t2-bromo-4- (trifluoromethoxy)phenyl] -2methyipropanamide and tert-butyl 4- 1,3,2-dioxaborc-an-2-yl) -3,6-dihydro-lC2H)pyridinecarboxylate: ESMS m~e: 329.0 (M 100)+.
2-METHYL-N- (4-PIPERIDINYL) -4- (TRIFLUOROMETHOXY)PHENYL)PROPANAMIDE: Prepared by Procedures X and Y, Schemes AG and AH, respectively using tert-butyl 4- Cisobutyrylamino) (trifluoromethoxy)phenyl-J-31 6-dihydro-1 (2H) pyridinecarboxylate: ESMS m/e: 330.9 (M Example 277 NV- [4,4-BIS(4-FLUOROPENYL)BUTYL] -4-PIPERIDINYL)-4- (TRIFLUOROMETHOXY) PHENYL] -2 -HETHYLPROPANAMIDE: Prepared by Procedure G and Scheme AI using 1- [4-chloro-1- (4fluorophenyl)butyll -4-f luorobenzene and 2-methyl-N- [2- (4-piperidinyl) (trifluoromethoxy)phenyl] propanamide: ESMS M/e: 574.8 (M WO 03/004027 WO 03/04027PCTIUS02/2 1063 303 [1-(4-HYDROXYBUTYL) 4-PIPERIDflNYLJPHENYL)-2- METHYLPROPANMIDE: Prepared by Procedure G and Scheme Bi1 using 4-chloro-1-butanol and 2-methyl-N-[13- (4piperidinyl)phenyllpropalamide: ESME m/e: 319.3 (M (5-HYDROXYPENTYL) -4-PIPERIDINqYL) PHENYLI-2- METHYLiPROPANAMIDE: Prepared by Procedure G and Scheme Bi using 5-chloro-l-peltaol and 2-methyl-N-1[3- (4piperidinyl)phenyllpropalamide: ESMS m/e: 333.3 (M N-{3-El- (6-HYDROXYHEXYL) -4-PIPERIDINYL]PHENYL}-2- NETHYLPROPANAMIDE: Prepared by Procedure G and Scheme Bl using 6-chlorc-l-hexanol and 2-methyl-N-[3-(4piperidinyl)phenylpropalamide: ESMS m/e: 347.3 (M NV-{3-El- (3-HYDROXYPROPYL) -4-PIEPERI:DIN-YL) PHENYL}-2- METHYLPROPANA.MTDE: Prepared by Procedure G and Scheme BI using 3-chJloro-1-propanol and 2-tnethyl-N\- (4piperidinyl)phenyllpropalamide: ESMS m/e: 305.3 (M N- -2-HYDROXY-2-PHENYLETIIYL] -4- PIPERIDINYL}PHENYL) -2 -METHYLPROPANAMIDE: Prepared by Procedure G and Scheme Bl using (1S)-2-chloro-lphenylethanol and 2-methyl-N-[13- C4piperidinyl)phenyllpropanamide: ESMS m/e: 367.2 (M N- -2-HYDROXY-2-PHENYLET-YLJ -4- PIPERIDINYL)PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure G and .Scheme B1. using (1R) -2chloro-1-phenylethanol and 2-methyl-N- 3- (4piperidinyl)phenyllpropanamide: ESMS m/e: 367.2 (M -3-HYDRQXY-2-METHYLPROPYL] -4- PIPERIDIN'YL)PHENYL) -2-METHYLPROPANAMIDE: Prepared by WO 03/004027 WO 03/04027PCTIUS02/2 1063 304 Procedure G and Scheme B1 using (2R)-3-chloro--2methyl-1-propanol and 2-methyl-N- (4piperidinyl)pheflyllpropanamide: ESMS m/e: 319.2 (M -3-HYDROXY-2-METHYLPROPYLJ -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure G and Scheme BI using (2S)-3-chl.oro-2--methyl- 1-propanol and 2-methyl-N-[-4 piperidinyl)phenyllpropanamide: ESMS m/e: 319.2.(M Example 278 [(3R)--3-YDROXY-3-PHENYLPROPYLJ-4- PIPERIDINYL}PHENYL) CYCLOPROPANECARBOXAMIDE: Prepared by Procedure G and Scheme B1 using (1R)-3chloro-l-phenyl-l-propanol and N 3 4 piperidinyl)phenyl) cyclopropanecarboxamide: ESMS m/e: 379.2 (M Example 279 [1-(4-HYDROXY-4-PHENYLBUTYL) -4-PIPERIDINYLIPHENYL)- 2-METHYLPROPANAMIDE: Prepared by Procedure L and Scheme AN, Step 1 using 2-methyl-N-{3- [1-(4-cxo-4-phenylbutyl) 4-piperidinyllphenyllpropanamide: Anal. Calcd for C23H34N202+D.O8CHC1 3 C, 74.5; H, 8.50; N, 6.93. Found: C, 74.5; H, 8.63; N, 6.81; ESMS m/e. 395.2 (M Example 280 zN-(3- [1-(5-HYDROXY-59-PHENYLPENTYL) -4- PIPERIDINYLJ PEYL}-2-METHYLPROPANAMIDE: Prepared by Procedure L and Scheme AN, Step 1 using 2-methyl-N-{3- (5-oxo-S-phenylpentyl) -4piperidinyllphenyl~propanamide: Anal. Calcd for WO 03/004027 WO 03/04027PCTIUS02/2 1063 305 C26H36N2O2+0.25CHC1 3 C,1 71.9; H, 8.33; N, 6.39.
Found: C, 71.3; H, 8.96; N, 6.86; ESMS m/e: 409.2 CM Example 281 1- (6-HYDROXY-6-PHEI4YLHEXYL) -4-PIPERIDINYL) P}ENYL}- 2-METHYLPROP.ANAZ41DE: Prepared by Procedure L and Scheme AN, Step 1 using 2-methyl-N-{3-E1--(6-oxo-6-phelylhexyl)- 4-piperidnyllphelyl~propalamide: Anal. Calcd for C27H38N202+0.1CHC1 3 C, 75.5; H, 8.93; N, 6.50. Found: C, 75.3; H, 8.52; N, 6.00; ESMS m/e: 423.2 (Mv Example 282 [1-(7-HYDROXY-7-P{ENYLHEPTYL) -4- PIPERIDINYL] PHENYL} -2-HETHYLPROPANAMIDE: Prepared by Procedure L and Scheme AN, Step 1 using 2-methyl-N-{3- (7-oxo-7-phenylheptyl) -4piperidinyllphenyllpropanamide: Anal. Calcd for C28H40N202+0.lCHC1 3 C, 75.8; H, 9.10; N, 6.29. Found: C, 75.1; H, 9.24; N, 6.51; ESMS m/e: 437.1 (M Example 283 (4-FLUOROPHENYL) -4-HYD)ROXYBUTYL) -4- PIPERIDINYL)PBENYL) -2-METHYLPOPANAMID)E: Prepared by Procedure L and Scheme AN, Step I using fluorophenyl) -4-oxobutyl) -4-piperidinyl~phenyl) -2methyipropanamide: ESMS m/e: 413.1 (M Example 284 E3- (ISOBUTYRYLAMINO)PHENYL] -1-PIPERI:DINYL)-1- PHENYLBUTYL 3- 6-DICHLORQPHENYL) -5-METHYL-4- ISOXAZOLECARBOXYLATE: Prepared by Procedure Q1 and Scheme C2 (TEA) using (4-hydroxy-4-phenylbutyl) WO 03/004027 PCTIUS02/21063 306 4-piperidinyl]phenyl}-2- methyipropanamide and 3- (2,6-dichiorophenyl)-5-methyl-4-isoxazolecarbofly chloride: 1H NMR (400 MHz, CDC1 3 5 7.56 Cm, lH), 7.47 21), 7.44-7.39 3H), 7.25 Cm, 21), 7.09 Cs, 11), 7.03 Cm, 2H), 6.95 Cm, 1H), 6.83 1H), 5.75 1H, J 7.1 Hz), 3.03 2H, J 7.2 Hz), 2.93 Cm, 2H), 2.78 31), 2.48 31), 2.25 Cm, 21), 1.48 31), 1.77 Cm, 2H), 1.54 Cm, 2H), 1.25 6H, J 7.3 Hz); ESMS m/e: 647.7 (M Example 285 (ISOBUTYRYLAMINO)PHENYLI-1-PIPERIDINYL}-l- PHENYLBUTYL (4-FLUOROPHENYL)ACETATE: Prepared by Procedure Q1 and Scheme C2 (TEA) using N-{3-E1-(4hydroxy-4-phenylbutyl)-4-piperidinyllphenyl}-2methyipropanamide and (4-fluorophenyl) acetyl chloride: 1H NMR (400 MHz, CDC1 3 5 7.45 1H), 7.34-7.19 8H), 7.11 Cm, 11), 6.98 Cm, 31), 5.75 1H, J 6.8 Hz), 3.61 Cs, 2H), 2.92 Cd, 2H, J 8.1 Hz), 2.48 2H), 2.31 Cm, 2H), 1.99-1.84 Cm, 41), 1.84-1.67 51), 1.55-1.35 Cm, 21), 1.25 Cd, 6H, J 6.9 Hz); ESMS m/e: 531.1 CM Example 286 (ISOBUTYRYLAMINO)PENYL-1-PIPERIDINYL}PROPYL (4-FLUOROPHENYL)ACETATE; Prepared by Procedure Q1 and Scheme C2 (TEA) using [1-(3-hydroxypropyl) -4piperidinyl)phenyl}-2-methyipropanamide and (4fluorophenyl)acetyl chloride: ESMS m/e: 441.3 (M Example 287 3-{4-[3-(ISOBUTYRYLAMINO)PHENYL-1-PIPERIDINYL}PROPYL 3- (2-CHLORO-6-FLUOROPHENYL)-5-METHYL-4- WO 03/004027 WO 03/04027PCTIUS02/2 1063 307 ISOXAZOLECARBOXYLATE: Prepared by Procedure Q1 and Scheme C2 (TEA) using 3-hydroxypropyl)-4pi-oeridinyllphenyl} -2-methyipropanamide and 3- (2-chioro- 6-f luorophenyl) -5-methyl-4-isoxazolecarbony- chloride: ESMS m/e: 542.2 (M Example 288 (ISOBUTYRYLAMINO) PHENYLJ -1-PIPERIDINYL}PROPYL 3- 6-DICHLORQPHENYi) -5-XETHYL-4-ISOXAZOLECARBOXYLATE; Prepared by Procedure Q1 and Scheme C2 (TEA) using N-{3- (3-hydroxypropyl) -4-piperidinyllphenyl} -2methyipropanamide and 3- (2 ,6-dichlorophenyl) -5-methylL-4isoxazolecarbonyl chloride: ESMS mle: 558.2 (M Example 289 (ISOBUTYRYLAMINO)PHENYL] -i-PIPERIDINYL)PROPYL 3- (2 -CHLOROPHENYL) -5-METHYL- 4- ISOXAZOLECARBOXYLATE: Prepared by Procedure Q1 and Scheme C2 (TEA) using N-{3- El- (3-hydroxypropyl) -4-piperidinyllphenyl}-2methyipropanamide and 3- (2-chiorophenyl) -5-methyl-4isoxazolecarbonyl chloride: ESMS m/e: 524.2 (M Example 290 (iS) (ISOBUTYRYLAMINO) PHENYL] -i-PI:PERID1INYL}-i- PHENYLPROPYL 3- 6-DICHLOROPHENYL) -5-METHYL-4- ISOXtAZOLECARBOXYLATE: Prepared by Procedure Q1 and Scheme C2 (TEA) using N-(3-{1-[(3S)-3-hydroxy-3phenyipropyl] -4-piperidinyl }phenyl) -2-methylpropanamide and 3- 6-dichiorophenyl) -5-methyl-4-isoxazolecarbonyl chloride: ESMS m/e: 633.6 (M +i WO 03/004027 WO 03/04027PCTIUS02/2 1063 308 Example 291 4 3- (ISOBUTYRYLAMINO) PHENYL) -l1- PIPERIDINYL)BUTYL 3- (2-CHLORO- 6-FLUOROPHENYL) -5-METHYL-4- ISOXAZOLECARBOXYLATE: Prepared by Procedure Q1 and Scheme C2 (TEA) using N-(3-[l-(4-hydroxybutyl)-4piperidinyllphenyl} -2-methyipropanamide and 3- (2-chioro- 6-f luorophenyl) -5-methyl-4-isoxazolecarbolyl chloride: Anal. Calcd for C30H35ClFN304+CH 2 Cl 2 C, 63.3; H, 6.23; N, 7.33. Found: C, 63.0; H, 6.39; N, 7.03; ESMS m/e: 556.2 (M Example 292 13- (ISOBUTYRYLAMINO) PHENYL] -1-PI:PERIDINYL}BUTYL 3- (2 -CHLOROPHENYL) -5-METHYL-4 -ISOXAZOLECARBOXYLATE! Prepared by Procedure Q1 and Scheme C2 (TEA) using N-{3- (4-hydroxybutyl) -4-piperidinyllphenyl} -2methyipropanamide and 3- (2-chiorophenyl) -5-methyl-4isoxazolecarbony. chloride: ESMS m/e: 538.2 (M H) Example 293 (ISOBUTYRYLAMINO) PHENYL] -1-PIPERIDI:NYL}PROPYL METHYL- 3-PHENYL-4-ISOX7AZOLECARBOXYLATE: Prepared by Procedure Q1 and Scheme C2 (TEA) using hydroxypropyl) -4 -piperidinyl) phenyl)}-2 -methyipropanamide and 5-methyl-3-pheayl--4-isoxazolecarbonyI chloride: ESMS ni/e: 490.3 (M H) Example 294 (ISOBUTYRYLAMINO) PHENYLJ PIPERIDINYL)BUTYL 3- 6-DICELOROPHENYL) -5-METHYL-4 -ISOXAZOLECARBOXYLATE: Prepared by Procedure Qi and Scheme C2 (TEA) using N-{3- (4-hydroxybutyl) -4-piperidinyllphenyl}-2- WO 03/004027 WO 03/04027PCTIUS02/2 1063 309 methyipropanamide and 3- 6-dichloropheny-) methyl-4-isoxazolecarbolyl chloride: ESMS m/e: 572.2 (M H Example 295 (ISOBUTYRYLAMIENO) PHENYL] -1-PI:PERI:DINYL}-1- PHENYLBUTYL 3- (2 -CHLORO- 6-FLUOROPHENYL) -5-METHYL-4 ISOXAZOLECARBOXYLATE: Prepared by Procedure Q1 and Scheme C2 (TEA) using (4-hydroxy-4-phenylbutyl) 4-piperidinyl] phenyl}-2-methylpropanamide and 3- (2chloro-6-fluorophenyl) -5-methyl-4-isoxazolecarbonyl chloride: Anal. Calcd for C36H39C1FN304 0.54CHC1 3
C,
63.0; 5.72; N, 6.03. Found: C, 63.0; H, 5.54; N, 6.05; ESMS m/e: 632.2 CM Example 296 (ISOBUTYRYLAMINO)PHENYLJ -l-PIPERIDINYL)BUTYL METHYL-3 -PHENYL-4 -ISOXAZOLECARBOXYLATE: Prepared by Procedure Q1 and Scheme C2 (TEA) using hydroxybutyl) -4 -piperidinyl] phenyl }-2-methylpropanamide and 5-methyl-3-phenyl-4-isoxazolecarbonyl chloride: ESMS ni/e: 504.3 (M Example 297 (ISOBUTYRYLAMI:NO) PHENYL) -1-PIPERDINYL)HEXYL 3- 6-DICHLOROPHENYL) -5-METHYL-4- ISOXAZOLECARBOXYLATE: Prepared by Procedure Q1 and Scheme C2 (TEA) using N-{3- (6-hydroxyhexyl) -4-piperidinyl) phenyl) -2methylpropanamide and 3- 6-dichiorophenyl) -5-methyl-4isoxazolecarbonyl chloride: ESMS m/e: 600.0 CM WO 03/004027 WO 03/04027PCTIUS02/2 1063 310 Example 298 (ISOBUTYRYLAMINO) PHENYI]-l-PIPERIDINYL)HEXYL METHYL-3 -PHENYL-4 -ISOXAZOLECARBOXYLATE: Prepared by Procedure Q1 and Scheme C2 (TEA) using N-{3-[1-CGhydroxyhexy.) -4 -piperidinyl] phenyl -methyipropanamide and 5-methyl-3-phenyl-4-isoxazlecarbolyl chloride: ESMS m/e: 5 32. 1 (M H).
Example 299 (ISOBUTYRYLAMINO)PHENYLJ -1-PIPERIDINYL}BUTYL (4- FLUOROPHENYL)ACETATE: Prepared by Procedure Q1 and Scheme C2 (TEA) using (4-hydroxybutyl) -4piperidinyl] phenyl)}-2 -methyipropanamide and (4fluorophenyl)acetyl chloride: ESMS m/e: 455.3 (M H) t Example 300 (ISOBUTYRYLAMINO) PHENYLJ -1-PIPERIDINYL}-l- PHENYLBUTYL 3- (2 -CHLOROPHENYL) -5 -METHYL-4 ISOXAZOLECARBOXYLATE: Prepared by Procedure Qi and Scheme C2 (TEA) using [1-(4-hydroxy-4-phenylbutyl) 4-piperidinyl] phenyl} -2-methyipropariamide and 3- (2chlorophenyl) -5-methyl-4-isoxazolecarhonyl chloride: ESMS m/e: 614.2 (M Example 301 (ISOBUJTYRYLAMINO)PHENYLJ -1-PIPERIDINYL}-1- PHENYLBUJTYL 5-METHYL- 3-PHENYL-4 -ISOXAZOLECARBOXYLATE: Prepared by Procedure Q1 and Scheme C2 (TEA) using N-{3- (4-hydroxy-4-phenylbutyl) -4-piperidinyllphenyl} -2methylpropanamide and 5-methyl-3-phenyl-4isoxazolecarbonyl chloride: ESMS m/e: 580.0 (M WO 03/004027 WO 03/04027PCTIUS02/2 1063 311 Example 302 (13) (ISOBUTYRYLrAMINO) PHENYI-l.-PIPERID)INYL}-1- PHENYLPROPYL (4 -FILtOROPHENYL) ACETATE: Prepared by Procedure Qi and Scheme (22 (TEA) using s haydroxy-3--phenylpropyl) -4-piperidinyl~phelyl) -2methyipropanamide and (4 -flucrophenyl) acetyl chloride: Anal. Calod for C32137FN203+0.O7CHCl 3 C, 73.4; H, 7.12; N, 5.34. Found: C, 73.4; H, 6.96; N, 5.14; ESMS m/e: 517.1 (M Example 303 (ISOBUTYRYLAMINO)PHENYLJ -1-PIPERIDINYL)- I-PHENYLPROPYL)BENIZAMIDE: Prepared by Procedure Q1 and Scheme AC using N- (3.-{1-[E(3S)-3-amino-3-phenylpropyl] -4is piperidinyl }phenyl) -2-rethylpropanamide and benzoyl chloride: Anal. Calcd for C31H37N32+~0.S5CHC1 3 C, 69.0; H, 6.89; N, 7.65. Found: C, 69.7; H, 6.73; N, 6.03; ESMS m/e: 484.4 (M Example 304 N- 13- [(DIPHENYLACETYL)AMINOI -3-PHENYLPROPYL)- 4-PIPERIDrINYL)PHENYL] -2-METHYLPROPANAMIDE: Prepared by Procedure Qi and Scheme AC using NV-(3-{1-E(3S)-3-amino- 3 henylpropyl] -4 -piperidinyl }phenyl) -2methylpropanamide and diphenylacetyl chloride: ESMS m/e: 574.3 (M H+ Example 305 3-CHLORO-N-( (iS) 13- (ISOBUTYRYLAMINO)PHENYLJ -1- PIPERIDINYL)-1-PHENYLPROPYL)BENZAMIDE: Prepared by Procedure Q1 and Scheme AC using N- (3-11-[F(3S) -3-amino- 3-phenylpropyl) -4-piperidinyllphenyl) -2- WO 03/004027 WO 03/04027PCTIUS02/2 1063 312 methyipropanamide, and 3- chlorobenzoyl chloride: ESMS mle: 518.3 (M Example 306 S 3,5-DICH4LORO-N-((2.S)-3-{4- 13-(ISOBUTYRYLAMINO)PHENYL]-1- PIPERIDINYL}-I-PHENYLPROPYL) BENZAMIDE: Prepared by Procedure Q1 and Scheme AC using N-(.3-{1-[(3S)-3-amino- 3 -phenylpropylJ -4-piperidinyl }phenyl) -2methyipropanamide and 3,5-dichlorobenzoy. chloride: ESMS nile: 552.3 (M Example 307 2- (ETRYLSULFANYL) N-C [3- (ISOBUTYRYLAMINO) PHENYL] -1-PIPERIDINYL}-1 PHENYLPROPYL)NICOTINAMIDE: Prepared by Procedure Q1 and Scheme AC using -3--amino-3-phenylpropyll -4piperidinyl~phenyl) -2-methylpropanamide and 2- (ethylsulfanyl)nicotinoyl chloride: ESMS m/e: 545.3 (M
H).
Example 308 N- (is) E3- (ISOBUTYRYLAMINO)PHENYL] -1-PIPERIDINYL)- 1-PHENYLPROPYL) -BIPlENYL] -4-CARBOX.AMIDE: Prepared by Procedure Q1 and Scheme AC using N(-1E3)3 amino-3-phenylpropyll -4-piperidinyl~phenyl) -2methylpropanamide and (i,12.-biphen-yl] -4-carbonyl chloride: ESMS m/e: 560.3 (M +i Example 309 IJ-((lS) (ISOBUTYRYLAMNO)PHENYL-1-PI:PERIDINYL)- 1-PHENYLPROPYL) -2-PYRIDINECARBOXAMIDE: Prepared by Procedure Q1 and Scheme AC using N-(3-1-[(33)-3-amino- 3--ohenylpropy1) -4-piperidinyl~phenyl) -2- WO 03/004027 WO 03/04027PCTIUS02/2 1063 313 methyipropanamide and 2- pyridinecarbonyl chloride: ESMS mle: 484.6 (M Example 310- N-C C1S)-3-{4-[3-(ISOBUTYRYLAMINO)PHENYL-1-PIPERIDINYL)- 1- PHENYLPROPYJ) -2 -METHOXYBENZMIDE: Prepared by Procedure Q1 and Scheme AC using N-(3-{l-[(3S)-3-amino- 3-phenylpropyl] -4-piperidinyl~phenyl) -2methyipropanamide and 2-methoxybenzoyl chloride: ESMS zn/e: 514.1 (M Example 311 (iS) (ISOBUTYRYLAMINO)PHENYLI -1-PIPERIDI:NY.L}i-PHENYLPROPYL)-1-NAPHTRAMIDE: Prepared by Procedure Q1 is and Scheme AC using N-(3-{1-[(3S)-3-amino-3phenyipropyl] -4 -piperidinyl }phenyl) -2-methyipropanamide and 1-naphthoyl chloride: ESMS m/e: 533.7 (N Example 312 2,4-DIFLUORO-N-( [3-(ISOEUTYRYLAMINO)PHiENYL]-1- PIPERIDINYL}-l-PHENYLPROPYL) BENZAMIDE: Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino- 3-phenylpropyl] -4-piperidinyl~pheny.) -2methylpropanamide and 2,4-difluorobelzoyl chloride: ESMS m/e: 520.2 (M HY'.
Example 313 3- (2-CHLORO-6-FLUOROPHENYL) (3S) E3-- (ISOBUTYRYLAMINO) PHENTYL] -l-PIPERIDIN-YL} -1-PHENYLPROPYL) 5-METHYL-4-ISOXAZOLECARBOX.AMIDE: Prepared by Procedure Qi and Scheme AC using N-(3-{l-[C3S)-3-anino-3phenyipropyl] -4-piperidinyl }phenyl) -2 -methyipropanamide WO 03/004027 WO 03/04027PCTIUS02/2 1063 314 anid 3- (2-chloro-6- fluorophenyl) -5-methyl-4isoxazolecarbonyl chloride: ESMS m/e: 617.2 CM Example 314 S 3-CHLORO-N-( (1S)-3-{4-E3-(ISOBUTYRYLAMINO)PHE1YLJ-1- PIPERIDINYL) -1-PHENYLPROPYL) -2 -THIOPHENECARBOXAMIDE: Prepared by Procedure Q1 and Scheme AC using -3-amino-3-pheflylpropyll -4-piperidinyllphenyl) -2met-hylpropanamide and 3 -chioro- 2-thiophenecarbonyl chloride: ESMS m/e: 524.2 (M +i Example 315 E3- (ISOBUTYRYLAMINO) PHENYL] -1-PIPERI:DINYL]l-PHENYLPROPYL) -2-PHENOXYN~ICOTI1TAMIDE: Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amilo- 3-phenylpropyl] -4-piperidinylphelyl) -2meLthyipropanamide and 2-phenoxynicotinoyl chloride; ESMS zn/e: 577.3 (M H+ Example 316 1- (4-CHLOROPHENYL) -N-C E3- (ISOBUTYRYLAMINO) PHENYL] -1-PIPERIDINYL} -1 -PHENYLPROPYL) 3 -PROPYL- 1H-PYRAZOLE-4-CARBOXAMIDE: Prepared by Procedure Q1 and Scheme AC using N\-(3-{1-[(3S)-3-amino- 3-phenyipropyl] -4-piperidinyllphenyl) -2methyipropanamide and 1- (4-chicrophenyl) -3 -propyl- 1Hpyrazole-4-carbonyl chloride: ESMS m/e: 626.3 (M Example 317 4-CI{LORO-N-( (iS) -3-{4-[3-(I:SOBUTYRYLAMINO)PHENYL]-1- PIPERIDINYL}-1-PHENYLPROPYL) 3-DIMETHYL-UIf- PYRAZ0LQE3 PYRIDINE- 5-CARBOXAMIDE: Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-aminc- WO 03/004027 WO 03/04027PCTIUS02/2 1063 315 3-phenyipropyll piperidinyllpheiyl) -2methyipropanamide and 4-chloro-1, 3-dimetbhyl- lHpyrazolo pyridine-5-carbonyl chloride: ESMS m,/e: 587.3 (M Example 318 5-DICHLOROPHENOXY) -NV-C(13) [3- (ISOBUTYRYLAMINO) PHENYL] -1-PIPERIDflqYL} -1-PHENqYLPROPYL) iH-PYRROLE-2-CARBOXAMIDE: Prepared by Procedure Q1 and Scheme AC using [(3S)-3-ami-no-3-pheflylpropyl)-4piperidinyl~phenyl) -2-methylpropanamide and 5- dichiorophenoxy) H-pyrrole-2 -carbonyl chloride: ESMS m/e: 6 34. 2 (M H) Example 319 (ISOBUTYRYLAMINO) PHENYL] -1-PIPERIDINYL)- 1-PHENYLPROPYL)NICOTINAMIDE: Prepared by Procedure Q1 and Scheme AC using NV-(3-(l-[(3S)-3-amino-3phenyipropyl) -4-piperidinyl }phenyl) -2 -methlylpropanamide and nicotinoyl chloride: ESMS ni/e: 485.3 (M Example 3243 3,4-DIFLUORO-N-( (ISOBUTYRYLAMINO)PIENYL) -1- PIPERIDINYL}-1-PHENYLPROPYL) BENZAMIDE: Prepared by Procedure Q1 and Scheme AC using N-(.3-{1-[(3S)-3-amino- 3-phenyilropyl] -4-piperidinyl~phenyl) -2methyipropanamide and 3,4-difluorobenzoyl chloride: ESMS m/e: 520.3 (M Example 321 (ISQBTJTYRYLAMINO) PHENYL] -2-PIPERIDINYL)- 1-PHENYLPROPYL) -1-PHENYL-3-PROPYL-1H-PYRAZOLE-4- CARBO2XAMIDE: Prepared by Procedure Q1 and Scheme AC WO 03/004027 WO 03/04027PCTIUS02/2 1063 316 using amino-3-phenylpropylj -4piperidinyllpheny-) -2-methyipropanamide and 1-phenyl-3propyl-lI-pyrazole-4-carbonyl chloride: ESMS nm/e: 592.2 (M Example 322 (ISOBUTYRYLAMINO) PHENYL] -PIPERI:DINYLI -1- PHENYLPROPYL)BENZAMIDE: Prepared by Procedure Q1 and Scheme AC using -3-aminc-3--phenylpropyl] -4piperidinyl~phenyl) -2-methylprcpanamide and 4- (dimethyl amino) benzoyl chloride: ESMS mle: 527.3 (M Example 323 (iS) (ISOBUTYRYLAMINO) PHENYL] -1-PIPERIDINYL}- I-PHENYLPROPYL) -2-THIOPHENECARBOXAMIDE: Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino- 3-phenyipropyl) -4-piperidinyllphenyl) -2methyipropanamide and 2-thiophenecarbony. chloride: ESMS rn/e: 4 90.2 (M H).
Example 324 (ISOBUTYRYLAMINO)PHENYL] -1-PIPERIDINYL}- 1-PHENYLPROPYL) -5-NITRO-2-TR.AMIDE: Prepared by Procedure Q1 and Scheme AC using N-fl3-{l-[(3S)-3-amino- 3-phenyipropyl) -4-piperidinyl~phenyl) -2methyipropanamide and 5-nitrc-2-furoyl chloride: ESMS m/e: 519.2 (M H).
Example 325 (ISOBUTYRYLAMINO)PHENYL] -1- PIPERIDINYL}PROPYL) -5-METHYL-3 -PHENTYL-4- WO 03/004027 WO 03/04027PCTIUS02/2 1063 317 ISOXAZOLECARBOXAMIDE: Prepared by Procedure Q1 and Scheme AC using N-{3-fl-(3-aminopropyl)- 4 piperidinyl) phenyl -methyipropaflamide and 5-methyl-3 phenyl-4-isoxazolecarboflyl chloride: ESMS m/e: 489.1 (M
+H+
Example 326 (ISOBITYRYLAMINO)PEENYL) -1-PIPERIDINYL)- 1-PHENYLPROPYIJ)-2-FURAMIDE: Prepared by Procedure Q1 and Scheme AC using N-{3-[l-(3-amiflopropyl)- 4 piperidinyllphenyl} -2-methyipropanamide and 2-furoyl chloride: ESMS zile: 474.2 (M Example 327 N- (ISOBUTYRYLAMINO) PHENYLI -1-PIPERIDINYL)- I-PHENYLPROPYL) -NITROPIIENYL) -5-(TRIFLUORQMETHYL) 1IffPYRAZOLE-4-CARBOXAMIDE: Prepared by Procedure Ql and Scheme AC using N- -3-amino-3-phenylpropylJ-4piperidinyl }phenyl) -2-methylpropaniamide and 1- (4nitrophenyl) -5-(trifluoromethy-) -lH-pyrazole-4-carbonyl chloride: ESMS m/e: 663.2 (M Example 328 3-(2-CHLORO-6-FLUOROPHENYL) [3- (ISOBUTYRYLAMINO) PHENYL PIPERIDINYL}PROPYL) 4-ISOXAZOLECARBOXAMIDE: Prepared by Procedure Q1 and Scheme AC using N-{3-[l-(3-aminopropyl)-4piperidinylphenyl} -2-methyipropaflamide and 3- (2-chloro- 6-f luorophenyl) -5-methyl-4-isoxazolecarbolyI chloride: ESMS m/e: 541.2 CM Example 329 N- L DIPHENYLACETYL)AMINQJPROPYLI-4- PIPERIDINYL) PHENYLJ -2-METHYLPROPANAMIDE: Prepared by WO 03/004027 WO 03/04027PCTIUS02/2 1063 318 Procedure Q1 and Scheme AC using Vf-:(3 aminopropyl) -4 -piperidinylJ phenyl -methyipropanamide and diphenylacetyl chloride: 1 H NMR (400 MHz, CDCl 3 6 7.51 Cs, IH), 7..33-7.21 (in, 13H), 6.94 (in, 2H), 4.88 (s, 111), 3.39 2H, J 5.6 Hz), 2.93 2H-, J 11.3 Hz), 2.52-2.36 4H), 1.97 Ct, 2H, J =11.3 Hz), 1.83- 1. 58 (mn, 6H) 1. 24 61-1, J 7.6G Hz); Anal. Calcd f or
C
3 2
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) Example 330 (ISOBUTYRYLAMINO)PHENYL] -1- PIPERIDINYL}PROPYL) -l-BENZOTHIOPHENE- 3-CARBOXAMIDE: Prepared by Procedure Q1 and Scheme AC using aininopropy-) -4 -piperidinyl]phenyl 1-2 -iethyipropanamide and i-benzothiophene-3-carbonyl chloride: ESMS m/e: 464.2 CM H+ Example 331 3- (2-CHLOROPHENYL) 4- (ISOBUTYRYLAMINO)PHENYL] 1-PIPERIDINYL)PROPYL) -5-METHYL-4 -ISOXAZOLECARBOXAMIDE: Prepared by Procedure Q1 and Scheme AC usingN-3[Caminopropyl) -4 -piperidinyl) pl-enyl -methyipropananide and 3- C2-chlorophenyl) -S-methyl-4-isoxazolecarbonyl chloride: ESMS mle: 523.1 CM Example 332 3- (2,6-DICHLOROP{ENYL) [3- (ISOBUTYRYLAMINO) PHENYL] -1-PIPERIDINYL}PROPYL) 4-ISOXAZOLECARBOXAMIDE: Prepared by Procedure Qi and Scheme AC using tl-C3-aminopropyl)-4piperidinyl] phenyl}-2-inethylpropananide and 3- (2,6- WO 03/004027 PCTIUS02/21063 319 4-isoxazolecarbonyl chloride: 1 H NMR (400 MHz, CDC1 3 6 7.50 1H, J 2.3 Hz), 7.48 1H), 7.4 1H), 7.39 1H), 7.37 2H), 7.24 1H, J .7.2 Hz), 6.92 1H, J 7.9 Hz), 51 6.06 lH), 3.31 2H, J 6.4 Hz), 2.94 2H, J 10.8 Hz), 2.79 3H), 2.53 1H, J 2.47 (tt, IH, J 4.2, 11.4 Hz), 2.29 2H, J 7.2 Hz), 1.99 2H, J 11.4 Hz), 1.81 2H), 1.69 (dt, 2H, J 2.4, 11.6), 1.59 2H, J 6.6 Hz), 1.24 6H, J 6.5 Hz); ESMS inie: 557.0 (M H) 4 [3-(3-CHLOROPROPOXY) PHENYL) ETH.ANONE: Prepared by Procedure U and Scheme AK using 1-(3hydroxyphenyl)ethanone and l-bromo-3-chioropropane.
1-(3-CHLOROPROPOXY)-2-FLUOROBENZENE: Prepared by Procedure U and Scheme AK using 2-fluorophenol and 1bromo-3-chloropropane.
1-CHLORO-3-(3-CHLOROPROPOXY)BENZENE: Prepared by Procedure U and Scheme AK using 3-chlorophenol and 1broo-3-chloropropane.
1-CHLORO-4-(3-CHLOROPROPOXY) BENZENE: Prepared by Procedure U and Scheme AK using 4-chlorophenol and 1bromo-3-chloropropane.
1-(3-CHLOROPROPOXY)-3-FLUORBENZENE Prepared by Procedure U and Scheme AK using 3-fluorophenol and 1broo-3-chioropropane.
WO 03/004027 WO 03/04027PCTIUS02/2 1063 320 1- (3-CHLOROPROPOXY) FLUOROBENZENE: Prepared by Procedure U and Scheme AK using 4-fluorophenol and 1bromo chl.oropropane.
1-CHLORO-2 -CHLOROPRQPOXY) BENZENE: Prepared by Procedure U and Scheme AK using 2-chlorophenol and Ibromo chioropropane.
4- (3 -CHLOROPROPOXY) 2-DIMETEYLBENZENE: Prepared by Procedure U and Scheme AK using 3,j-dimethylphenol and 1-brorno-3-chloropropane.
1-BROMO- 2- (3-CHLOROPROPOXY) BENZENE z Prepared by Procedure U and Scheme AK using 2-bromophenol and 1bromo chioropropane.
1-BROMO- 3- (3-CHLOROPROPOXY) BENZENE: Prepared by Procedure U and Scheme AK using 3-bromophenol and 1bromo chioropropane.
1-BROMO-4 -CHLQROPROPOXY) BENZENE: Prepared by Procedure U and Scheme AK using 4-bromophenol and 1brorno-3-chlcropropane.
1- (3 -CHLOROPROPOXY) -4-METHYLBENZENE: Prepared by Procedure U and -Scheme AK using p-cresol and 1-bromo-3chioropropane.
4-BROMOPHEIIYL (2R) -3 -CHLORO-2 -METHYLPROPYL ETHER: Prepared by Procedure U and Scheme AK using 4bromopheno. and (2S) -l-bromo-3-chloro-2-methylpropane.
1-{[(2R)-3--CHLORO-2-METHYLPROPYL]OXY}-2,4,5- TRIFLUOROBENZENE: Prepared by Procedure U and Scheme AK WO 03/004027 WO 03/04027PCTIUS02/2 1063 321 using 2,4,5- trifluorophenol and (29)- 1 -bromo-3-chloro-2 -methyipropane.
1-CELORO-3-{ -3-CHLORO-2-METHYLPROPYL] OXY}BENZENE: Prepared by Procedure U and Scheme AK using 3chioropheno. and (29) -1-hromo-3-chloro-2-methylpropane.
1- {E (2R) -3 -CHLORO-2 -METHYLPROPYLJ OXY) -4 -FLUOROBENZENE: Prepared by Procedure U and Scheme AK using 4fluorophenol and (29) -1-bromo-3-chloro-2-methylpropane.
1- -3 -CHLORO-2 -METHYLPROPYLJ OXY) -3 -FLTOROBENZENE: Prepared by Procedure U and Scheme AK using 3fluorophenol and (29) -1-bromo-3-chloro-2-methylpropane.
1-CHLORO-2 -3 -CHLORO-2 -METHYLPROPYLJ OXY}BENZENE: Prepared by Procedure U and Scheme AK using 2chiorophenol and (29) -l-bromo-3-chloro-2-methylpropane.
-3-CHLORO-2-METHYLPROPYL] OXYJ-2-FLUOROBENZENE: Prepared by Procedure U and Scheme AK using 2fluorophenol and (2S) -1-bromo-3-chloro-2-methylpropane.
I-CHLORO-4 -3 -CHLDRO-2 -METHYLPROPYLJ OXY}BENZENE: Prepared by Procedure U and Scheme AK using 4- 2S chiorophenol and (2SP'-l-bromo-3-chlorc-2-methylpropane.
3 -BROMOPHENYL (2R) -3 -CHLORO-2 -METHYLPROPYLj ETHER: Prepared by Procedure U and Scheme AK using 3bromophenol and (29) -brcmo-3-chloro-2-methylpropane.
2 -BROMOPHENYL (2R) -3 -CHLjORO- 2-METHYLPROPYL ETHER: Prepared by Procedure U and Scheme AK using 2brornophenol and (29) -1-bromo-3 -chloro-2-meth-ylpropane.
WO 03/004027 WO 03/04027PCTIUS02/2 1063 322 1- -3 -CHLORO- 2-METHYLPRQPYL] OXY} -3 -FLUOROBENZENE: Prepared by Procedure U and Scheme AK using 3fluorophenol and (2R) -l-bromo-3-chloro-2-methylpropane.-- 1- E(2S) -3 -CHLORO-2 -METHYLPROPYL] OXY) -4 -FLUOROBENZENE:- Prepared by Procedure U and Scheme AK using 4fluorophenol and (2R) -1-bromo-3-chloro-2-methylpropale.
1- -3-CHLORO-2-METHYLPROPYLJ OXY}-2-FLUOROBENZENE: Prepared by Procedure U and Scheme AK using 2fluorophenol and (2R) -l-bromo-3-chloro-2-methylpropane.
1-CHLORO-2-{ -3-CHTLORO-2-METHYLPROPYLJ OXY}BENZENE: is Prepared by Procedure U and Scheme AK using 2chiorophenol and (2R) -1-bromo-3-chloro-2-methylpropane.
1-CHLORO-4-{ E(2S) -3-CHLORO-2-METHYLPROPYLJ OXY}BENZENE: Prepared by Procedure U and Scheme AK using 4chiorophenol and (2R) -l-bromo-3-chloro-2-methylpropane.
4-BROMOPHENYL (2S) CHLORO-2 -METHYLPROPYL ETHER: Prepared by Procedure U and Scheme AK using 4bromo-phenol and (2R) -1-bromo-3 -chloro-2-methylpropane.
3-BROMOPHENYL (2S) -3-CHLORO-2 -METHYLPROPYL ETHER: Prepared by Procedure U and Scheme AK using 3bromophenol and (2R) -l-bromo-3-chloro-2-methylpropane.
2-BROMOPHENYL C2S) -3-CHLORO-2-METHYLPROPYL ETHER: Prepared by Procedure ~U-and Scheme -AK using- 2bromophenol and (2R) -1-bromo-3-chloro-2-methylpropane.
WO 03/004027 WO 03/04027PCTIUS02/2 1063 323 1-CHLORO-3-{ CHLORO-2 HETHYLPROPYL)OXY}BENZENE: Prepared by Procedure U and Scheme AK using 3-chiorophenol and (2R) -1-bromo-3chloro-2 -methyipropane..
S
1- (4 -CHLOROBUTOXY) PHENYLJ ETHANONE: Prepared by Procedure U and Scheme AK using hydroxyphenyl) etlaanone and 1-bromo-4 -chiorobutane.
1- (4-CHLOROBUTOXY) PHENYLJ ETHANONE: Prepared by Procedure U and Scheme AK using -3 hydroxyphenyl) ethanone and 1-bromo-4 -chiorobutane.
1- (4 -CHLOROBUTOXY) -3 -METHOXYBENZENE: Prepared by Procedure U and Scheme AK using 3-methoxyphencl and 1 brcmo-4-chlorobutane.
1- CHLOROBUTOXY) -4 -METHOXYBENZENE: Prepared by Procedure U and Scheme AK using 4-methoxyphenol and 1bromo-4-chlorobutane.
1- (4-CHLOROBUTOXY) -2 -METHOXYBENZENE: Prepared by Procedure U and Scheme AK using 2-methoxyphenol and 1bromo-4-chlorobutane.
2S 4- (4-CHLOROBUTOXY) 2-DIMETHYLBENZENE: Prepared by Procedure U and Scheme AK using 3,4-dimethyiphenol and 1-bromo-4 -chiorobutane.
[(5-CHLOROPENTYL) OXYJ PHENqYL)ETHANONE:. Prepared by Procedure U and Scheme AK using -3 hydroxyphenyl) ethanone and 1-bromo-5 -chioropentane.
WO 03/004027 WO 03/04027PCTIUS02/2 1063 324 (3 CHLOROPENTYL) OXY] PHEN'YLETHIANONE: Prepared by Procedure U and Scheme AK using 1-C3-hydroxyphenyl)ethanone and Ibromo- 5- chioropentane.
1- [(6-CHLOROHEXYL) OXY] PHENYL}ETHANONE: Prepared by Procedure U and Scheme AK using -3 hydroxyphenyl) ethanone and 1 -bromo- 6-chiorohexane.
1- [(6-CHLOROHEXYL) OXYJ PHENYL}ETHANONE: Prepared by Procedure U and Scheme AK using 1-C3hydroxyphenyl) ethanone and 1-bromo-6 -chiorohexane.
Example 333 NV-(3-{1-E(2$)-2-(3-ACETYLPHENOXY)-2-PHENYLETIHYLJ-4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure B and Scheme BI using -3 hydroxyphenyl) ethanone and N- -2--hydroxy-2phenylethyl) -4-piperidinyl~phelyl) -2-rethylpropanamide: ESMS mle: 485.0 (M Example 334 (2-ACETYLPHENOXY) -2-PHENYLETHYLI -4- PIPERIDINYLPHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure B and Scheme B1 using -2 hydroxyphenyl) ethanone and NV-(3- -2-hydroxy-2phenylethyl] -4-piperidinyl~phenyl) -2-methyipropananide: ESMS m/e: 485.2 (M Example 335 (22) (3-CHLOROPHENOXY) -2-PHENYLETHYL) -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure B and Scheme BI using 3-chJlorophenol and N-(3- WO 03/004027 WO 03/04027PCTIUS02/2 1063 325 [(2R)-2-hydroxy-2- phenylethyl] -4piperidinyllphenyl) -2-methyipropalamide: ESMS m/e: 477.1 (M H) Example 336 E(2S) (3,4-DI:METHOXYPHENOXY) -2-PIIENYLETHYLI -4- PIPERIDINYL)PHENYL) -2 -METHYLPROPANAMIDE: Prepared by Procedure B and Scheme BI using 3, 4-dimnethoxyp~henol and N- i:(2R) -2-hydroxy-2-phenylethyl] -4piperidinyl~phenyl) -2-methyipropaflamide: ESMS m/e: 503.2 (M H) Example 337 E(2R) (4-FLUOROPHENOXY) -2-PHENYLETHYL] -4- PIPERIDINYL}PHENYL) -2 -METHYLPROPANAMIDE: Prepared by Procedure B and Scheme B1 using 4-f luorophenol and NV-(3- -2-hydroxy-2-phenylethylj -4-piperidinyl~phenyl)- 2-methylpropanamide: ESMS m/e: 461.2 (M Example 338 (3-METHOXYPHENOXY) -2-PEEN'YLETHIYL] -4- PIPERIDINYL }PHENYL) METHYLPROPANAMIDE: Prepared by Procedure B and Scheme BI using 3-methoxyphenol and N- -2-hydroxy-2-pheriylethylj -4piperidinyllphenyl) -2-methyipropanamide: ESMS m/e; 472.9 (M H Example 339 [(2R)-2-(3-CHLOROPHENOXY)-2-PHENYLETHYL]-4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure B and Scheme B1 using 3-ch].orophenol and -2-hydroxy-2-phenylethyl) -4-piperidinyllphenyl) 2-methyipropanamide: ESMS mn/e: 478.5 (M WO 03/004027 WO 0/00027PCT/UJS02/21063 32G 3-DIMETHOXYPROPYL) -4-PIPERIDINYL] PHENYL}-2- METHYLPROPANAMIDE: Prepared by Procedure G and Scheme Bl using 3-bromo-l, 1-dimethoxypropane and 2-methyl-N- [3- (4-piperidinyl)phenyllpropanamide: ESMS rn/e- 349.2 (M
H)+
Example 340 -3 -(3-ACETYLPHENOXY) -3-PHENqYLPROPYL] -4- PI:PERIDINYL)PHENYL) CYCLOPROPANECARBOXAM(IDE: Prepared by Procedure 3 and Scheme BI using -3 hydroxyphenyl) ethanone and N- -3-hydroxy-3phenyipropyl] -4piperidinyl~phenyl) cyclopropanecarboxamide: ESMS mn/e: 497.1 (M Example 341 [3-(3-ACETYLPHENOXY)PROPYL) -4- PIPERIDINYL}PHIENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure G and Scheme using 1- (3chioropropoxy) phenyl] ethanone and 2-methyl-1- (4piperidinyl)phenyllpropanamide: ESMS m/e: 423.2 (M Example 342 [3-(3-ACETYLPHENOXY)PROPYL) -4- PIPERIDINYLIPHENYL) PROPANAMIDE: Prepared b and Scheme BI using chioropiropoxy) phenyl] ethanone and piperidinyl) phenyl] cyclopropanecarboxamide: 421.2 (M Example 343 E3-(2-FLUOROPHENOXY)PROPYL] -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: y Procedure G I1- (3- ESMS m/e: Prepared by WO 03/004027 PCT/US02/21063 327 procedure G and scheme B1 using 1-(3-chloropropoxy)- 2-fluorobenzene and 2-methyl-N-[3-(4piperidinyl)phenyllpropanamide: ESMS m/e: 399.2 (M Example 344 .N-(3-{1-[3-(3-CHLOROPHENOXY)PROPYL]-4- PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE: Prepared by Procedure G and Scheme B. using 1-chloro-3-(3chioropropoxy)benzene and 2-methyl-N- (4piperidinyl)phenyl]propanamide: ESMS m/e: 415.2 (M Example 345 N-(3-{1-[3-(4-CHLOROPHENOXY)PROPYL-4- PIPERIDINYLIPHENYL)-2-METYLPROPANAMIDE: Prepared by Procedure G and Scheme BI using 1-chloro-4-(3chloropropoxy)benzene and 2-methyl-N,- (4piperidinyl)phenyllpropanamide: NMR (400 MHz, CDC1 3 7.71 (dd, 1H, J 3.2, 5.7 Hz), 7.53 (dd, 1H, J 3.2, 5.7 Hz), 7.50 1H), 7.31 1H), 7.24-7.20 2H), 6.94 1H, J 7.9 Hz), 6.85-6.82 2H), 4.00 (t, 2H, J 6.1 Hz), 3.07 Cd, 2H, J 10.9 Hz), 2.55 (m, 3H), 2.50 (sept, 1H, J 6.2 Hz), 2.08 Cdt, 2H, J 3.1, 10.9 Hz), 2.00 2H), 1.83 Cm, 3H), 1.69 (qt, 1H, J 6.2 Hz), 1.24 6H, J 6.8 Hz); Anal. Calcd for C2 4
H
31 C1N 2 0 2 +HC1: C, 63.8; H, 7.09; N, 6.21. Found: C, 63.3; H, 7.04; N, 6.27; ESMS r/e: 415.2 (M Example 346 N-(3-{1-[3-(3-FLUOROPHENOXY)PROPYL]-4- PIPERIDINYL}PHEYL)-2-METHYLPROPANAMIDE: Prepared by Procedure G and Scheme B1 using 1-(3-chloropropoxy)-3fluorobenzene and .2-methyl-N- (4piperidinyl)phenyl]propanamide: ESMS m/e: 399.2 CM WO 03/004027 WO 03/04027PCTIUS02/2 1063 328 Example 347 (4-FLUOROPHENOXY)PROPYL] -4- PIPERIDINYL}PHENYL) -27METHYLPROPANAMIDE: Prepared by Procedure G and Scheme BI using l-(3-chloropropoxy)-4fluorcbenzene and 2-methyl-NV-[3- (4piperidinyl)phenyllpropananide: ESMS m/e: 399.2 (M +4 Example 348 [3-(2-CHLOROPHENOXY)PROPYL]-4- PIPERIDINYL}PEENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure G and Scheme B1 using 1-chloro-2--(3chioropropoxy) benzene and 2-methyl-.N- piperidinyl)phenyllpropanamide: ESMS m/e: 415.2 (M Example 349 (3,4-DMETHYLPHENOXY)PROPYLJ -4- PIPERIDINYL}P{ENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure G and Scheme BI using 4-(3-chloropropoxy)-1,2dimethylbenzene and 2-methyl-N- (4piperidinyl)phenyllprcpanamide: ESMS m/e: 409.2 (M Example 350 3- (2-BROMOPHiENOXY)PROPYL) -4- PIPERIDIIIYL}PHENYL) -2 -METHYLPROPANAMIDE: Prepared by Procedure G and Scheme BI using 1-bromo-2-(3chloropropoxy)benzene and 2-methyl-N- (4piperidinyl)phenyllpropanamide: 1H NMR (400 MHz, CDC1 3 7.53 (dd, 1H, J 1. 6, 7.9 Hz) 7.48 1H) 7.32 (in, 1H) 7.28-7.22 Cm, 3H) 7.17 1H) 6.98 Cd, 1H1, J 7.7 Hz) 6.93 (dd, 1H-, J 8.4 Hz) 6.82 (dt, 1H, J 7.6, 1.4 Hz) 4.11 211, J 6.3 Hz) 3.07 2H1, J 11.3 Hz), 2.61 2H1, J 6.9 2.50 Cm, 3H), 2.07 WO 03/004027 PCT/US02/21063 329 1H), 1.8-1.75 5H), 1.25 6H, J 6.7 Hz); Anal. Calcd for C 2 4H 31 BrN 2 2 .HCl+O.2 CHC1 3 C, 55.9; H, 6.24; N, 5.39. Found: C, 55.8; H, 6.23; N, 5.47; ESMS m/e: 459.1 (M Example 351 3-(3-BROMOPHENOXY)PROPYL -4- PIPERIDINYL}PHENYL)-2-METHYLPROPA2AMIDE: Prepared by Procedure G and Scheme BI using 1-bromo-3-C3chloropropoxy)benzene and 2-methyl-N-[3-(4piperidinyl)phenyl]propanamide: ESMS m/e: 459.1 (M Example 352 N-(3-{1-[3-(4-BROMOPENOXY)PROPYL -4- PIPERIDINYL)PHENYL)-2-METHYLPROPANAMIDE: Prepared by Procedure G and Scheme B1 using 1-bromo-4-(3chloropropoxy)benzene and 2-methyl-N- piperidinyl)phenyllpropanamide: 1H NMR (400 MHz, CDC 3 7.51 7.37 2H, J 7.6 Hz), 7.26 3H)), 6.97 1H, J 7.7 Hz), 6.79 2H, J 7.7 Hz), 4.01 2H, J 5.6 Hz), 3.08 Cd, 2H, J 9.4 Hz), 2.53 (m, 4H), 2.05 Cm, 4H), 1.84 Cm, 4H), 1.24 6H, J 5.9 Hz); Anal. Calcd for C 24
H
3 BrN02-IC+0.34CHC1 3 C, 54.5; H, 6.08; N, 5.22. Found: C, 54.5; H, 6.22; N, 5.22; ESMS r/c: 459.1 (M Example 353 N-(3-(1-[(3R)-3-(3,4-DIMETHOXYPHENOXY)-3-PHENYLPROPYL]- 4-PIPERIDINYL) PHENYL)-N, 2-DIMETHYLPROPANAMIDE: Prepared by Procedure T and Scheme AD using diinethoxyphenoxy) -3-phenylpropyl] -4-piperidinylphenyl) 2-iethyipropanaiide and methyl iodide: ESMS n/e: 531.2 (M WO 03/004027 WO 0/00027PCT/UJS02/21063 330 Example 354 (3-ACETYLPHENOXY) -3-PHENYLPROPYLJ -4- PIPERIDINYL}PHENYL) -N,2-DIMETHYLPROPANAMIDE: Prepared by Procedure T and Scheme AD using acetyi~phenoxy) -3 -phenyipropyl] -4-piperidinyl }phenyl) -2methyipropanamide and methyl iodide; ESMS m/e: 513.2 (M Example 355 (3-ACETYLPHENOXY) -3-PHENYLPROPYL] -4- PIPERIDINYL}PHENYL) -N,2-DIMETHYLPROPANAMIDE: Prepared by Procedure T and Scheme AD using acetyiphenoxy) -3-phenyipropyl) -4-piperidinyl~phenyl) -2- 1s methyipropanamide and methyl iodide: ESMS m/e: 513.2 CM Example 356 (4-BROMOPHENOXY) -2-METHYLPROPYL] -4- PIPERIDINYLPHENYL) -2 -METHYLPROPANAMIDE: Prepared by Procedure G and Scheme B1 using 4-bromophenyl (2R)-3chloro-2-methylpropyl ether and 2 -methyl-.N- 3- (4 piperidinyl)phenyllpropanamide: ESMS ni/e: 473.0 (M H+ Example 357 2-METHYL-V- -2-METHYL-3- (2,4,5- TRIFLUOROPHENOXY) PROPYL) -4- PIPERIDINYLIPHENYL) PROPANAMIDE: Prepared by Procedure G and Scheme BI using 1-{[(2R)-3-chloro-2methyipropyl] oxy}-2,4, 5-trifluorobenzene and 2-methyl-N- [3-(4-piperidinyl)phenyllpropanamide: ESMS m/e: 449.2 CM I-0+ WO 03/004027 WO 0/00027PCT/UJS02/21063 331 Example 358 N- (3-CHLOROPHENOXY) -2-HETHYLPROPYLJ -4- PIPERIDINYL)PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure G and Scheme BI using I-chloro-3-{[(2R)-3chloro-2-methylpropy-)oxy~benzene and 2-methyl-N- (4piperidinyl)phenyllpropanamide: ESMS rn/e: 429.2 (M Example 359 1- (4-FLUOROPHENOXY) -2-METHYLPROPYLJ -4- PrPERIDINYLPHENYz) -2-METHYLPROPANAMIDE: Prepared by Procedure G and Scheme Bl using 1-{[(2R)-3-chloro-2methyipropyl] oxy}-4-fluorobenzene and 2-methyl-N- (4piperidinyl)phenyllpropanamide: ESMS m/e: 413.2 (M Example 360 N-(3-(1-U2S) -3-(3-FLtTOROPHENOXY)-2-METHYLPROPYLJ -4- PIPERIDINYL}PIENYL) -2-METHYLPROPAIIAMIDE: Prepared by Procedure G and Scheme B1 using -3-chloro-2rethylpropyl] oxy)-3-fluorobenzene and 2-methyl-N\- (4piperidinyl)phenyllpropanamide: ESMS m/e: 413.2 (M H) 4 Example 361 (2-CHLOROPHENOXY) -2-METHYLPROPYLJ -4- PIPERIDINYL)PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure G and Scheme B1 using 1-chloro-2-{ (2R) -3chloro- 2-methylpropylj oxy) benzene and 2-methyl-N- (4piperidinyl)phenyljpropanamide: ESMS m/e: 429.1 (M Example 362 NV- (2-FLUOROPHENOXY) -2-METHYLPRQPYL] -4- PIPERIDINYL)PENYL) -2-HETHYLPROPANAMIDE: Prepared by Procedure G and Scheme BI using l-{[(2R)-3-chloro-2methyipropyl] oxy}-2-fluorohenzene and 2-met"hyl-N- (4piperidinyl)phenyllpropanamide: ESMS rn/c: 413.2 (M WO 03/004027 WO 0/00027PCT/UJS02/21063 332 Example 363 E(2S) (4-CHLOROPHENOXY) -2-METHYLPROPYL] -4- PIPERIDINYL)PFENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure G and Scheme Di using 1-chloro-4-{E(2R)-3chloro-2-methylpropyll oxylbenzene and 2-methyl--N- (4piperidinyl)phenyllpropanamide; ESMS m/e: 429.2 (M Hl)+.
Example 364 (2S) (3-BROMdOPHENOXY) -2-METHYLPROPYLJ -4- PIPERIDINYL)PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure G and Scheme B1 using 3-bromophenyl (2R)-3chloro-2-methylpropyl ether and 2-methyl-NV- (4piperidinyl)phenyllpropanamide: ESMS mlne: 474.0 (M Example 365 (2-BROMOPHENO)XY) -2-METHYLPROPYL] -4- PIPERIDINYL)PHENYJ) -2-METHYLPROPANAMIDE: Prepared by Procedure G and Scheme B1 using 2-bromophenyl (2R)-3cbioro-2-methylpropyl ether and 2-methyl-.N- piperidinyl)phenyllpropanamide: ESMS m/e: 473.0 (M Example 366 (3-FLUOROPHENqOXY) -2-METHYLPROPYL] -4- PIPERIDINYL)PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure G and Scheme B1 using l-{[(2S)-3-chloro-2methyipropyl] oxy) -3-f luorobenzene and 2-methyl-N- (4piperidinyl)phenyllpropanamide: ESMS m/e: 413.2 (M Example 367 [(2R)-3-(4-FLUTOROPHENOXY)-2-METHYLPROPYL -4- PIPERIDINYL)PHENYL) -2 -METHYLPROPANAMIDE: Prepared by Procedure G and Scheme B1 using 1-{E(2S9)-3-chloro-2- WO 03/004027 WO 0/00027PCT/UJS02/21063 333 methyipropyl] oxy} fluorobenzene and 2methyl-N- (4-piperidinyl)phenyl] propanamide: ESMS m/e: 413. 8 (M H).
Example 368 E(2R) (2-CIHLOROPHENOXY) -2-METHYLPROPYL] -4- PIPERIDINYL}FHENYL) -2-METHYLP1ROPANAMIDE: Prepared by Procedure G and Scheme B1 using 1-chlorc-2-{[(2S)-3chloro-2-meth- ylpropyl) oxylbenzene and 2-methyl-N- (4piperidinyl)phenyllpropanamide: ESMS mn/e: 429.1 (M Example 369 (4-CILOROPHENOXY) -2-METHYLPROPYL] -4- PIPERIDINYL)PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure G and Scheme B1 using I-chloro-4-{[(2S)-3chloro-2-methylpropylloxy~benzene and 2-methyl-N- (4piperidinyl)phenyllpropanamide: ESMS m/e: 429.1 (M Example 370 (4-BROMOPHENOXY) -2-M(ETHYLPROPYL] -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure G and Scheme BI using 4-bromophenyl (2S) -3chJloro-2-methylpropyl ether and 2-methyl-N- (4piperidinyl)phenyllpropanamide: ESMS m/le: 473.0 (M H) t Example 371 (3-BROMOPHENOXY) -2-METHYLPROPYL) -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared. by Procedure G and Scheme B1 using 3-bromophenyl (2S)-3chloro-2-methylpropyl ether and 2-methyl-.N- (4piperidinyl)phenyllpropanamide: ESMS m/e: 473.0 (M WO 03/004027 WO 0/00027PCT/UJS02/21063 334 Example 372 I(2R) (2-BROMOPHENOXY) -2-METHYLPROPYLJ -4- PIPERIDINYL)PHENYL) -2 -METHYL PROPANAMIDE: Prepared by Procedure G and Scheme BI using 2-bromopbhenyl (2S)-3chloro-2-methylpropyl ether and 2-methyl-NV-[3-C4pilperidinyl)phenyllpropanamide: ESMS ni/e: 473.0 (M Example 373 l((2R) (3-CHLOROPHENOXY) -2-METHYLPROPYL) -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure G and Scheme B1 using 1-chloro-3-{(E[(2S)-3 chloro-2-methylpropy.]oxylbenzene and 2-methyl-NV-[3- (4piperidinyl)phenyllpropanamide: ESMS m/e: 429.1 (M Example 374 [3-(5,5-DI:METHYL-1,3-DIOXAkN-2-YL)PROPYL]-4- PIPERIDINYL}PHENYL) -2-METHYLPROPATAMIDE: Prepared by Procedure G and Scheme BI using 2-(3-bromoprapyl)-5,5dimethyl-1,3-dioxane and 2-methyl-NV- (4piperidinyl)phenyllpropanamide: ESMS m/e: 403.2 (M +H) Example 375 14- (3-ACETYLPHENOXY)BUTYL) -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE! Prepared by Procedure G and Scheme Bi using chicrobutoxy) phenyl] ethanone and 2-methyl-N\- (4piperidinyl)phenyllpropanamide: ESMS m/e. 437.2 (M Example 376 (3-METHiOXYPHENOXY) BUTYi] -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure G and Scheme B1 using l-(4-chlorobutoxy)-3methoxybenzene and 2-methyl-N- (4piperidinyl)phenyllpropanamide: ESMS m/e: 425.2 (M WO 03/004027 WO 0/00027PCT/UJS02/21063 Example 377 (4-METHOXYPHENOXY)BUTYL] -4- PIPERIDINYIJ}PHENYL) -2 -METHYLPROPANAMIDE: Prepared by Procedure G and Scheme BI using l- (4-chlcrobutoxy) -4methoxybenzene and 2-methyl-N- (4piperidinyl)phenyllpropanamide: EGMS mle: 425.2 CM H+ Example 378 N-(3-{l-14-(2-METHOXYPHENOXY)BUTYL)-4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure G and Scheme 13l using l-(4-chlorobutcxy)-2methoxybenzene and 2 -methyl-NV- [3 (4 p--peridinyl)phenyllpropanamide: ESMS m/e: 425.2 (M Example 379 (3,4-DIMETYLPHENOXY)BUTYL] -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure G and Scheme 51 using 4-(4-chlorobutoxy)-1,2dimethylbenzene and 2-methyl--N- piperidinyl)phenyilpropanamide: ESMS m/e: 423.2 (M Example 380 N-(3-{1L-[4-C1,3-DI:OXOLAN-2-YL)BUTYL]-4- PIPERIDINYL}PMENYL) -2-METHYLPROPAIAMIDE: Prepared by Procedure G and Scheme B1 using 2-(4-chlorobutyl)-1,3dioxolane and. 2-methyl-.N- piperidinyl)phenyllpropanamide: ESMS m/e: 375.2 (M +H) Example 381 (3-ACETYLPHENOXY)PENqTYLJ -4- PIPERIDINYL}PEENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure G and Scheme Bl using WO 03/004027 WO 0/00027PCT/UJS02/21063 336 chioropentyl) oxy) phenyl} ethanone and 2-methyl-N- (4piperidinyl)phenylipropalamide; ESMS m/e: 451.3 (M Example 382 N-(3-{1-[5-(3-ACETYLPHENOXY)PENTYL)-4- PIPERID)INYLPHENYJ) CYCLO)PROPANECARBOXAMIDE: Procedure G and Scheme Bi using chioropentyl) oxy] phenyl }ethanone and piperidinyl) phenyl) cyclopropanecarboxamide: 449.2 (M Prepared by N- (4- ESMS rn/a: Example 383 [6-(3-ACETYLPHENOXY)HEXYL] -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure G and Scheme BI using chiorohexyl) oxy] phenyl }ethanone and 2 -methyl-N- (4piperidinyl~phenyllpropananide: ESMS ni/e: 465.73 (M Example 384 j6- (3-ACETYLPHENOXY)HEXYLJ -4- PIPERIDINYL }PHENYL) CYCLOPROPANECARBO2CAMIDE: Procedure G and Scheme B1 using chiorohexyl) oxy] phenyl }ethanone and piperidinyl) phenyl] cyc-lopropanecarboxamide: 463.3 (M Prepared by (4- ESMS rn/a: Example 385 (4-C!HLOROPHENOXY) (4-CHLOROPHENYL)BUTYL] -4- PIPERIDINYL}PHENYL) -2-METHYLPROPAlAMIDE: Prepared by Procedure B arnd Scheme AN using 4-chiorophenol and (3- (4-chiorophenyl) -4-hydroxybutyl] -4p iperi dinyl Iphenyl) 2-met hyipropanami de: ESMS rn/a: 562.9 (M 23) WO 03/004027 WO 0/00027PCT/UJS02/21063 337 Example 386 2-METHYL-N- C3-{1- E2- (1-METHYL-2-PHENYL-1H-INDOL-3- YL) ETHYL) -4-PI.PERIDINYL}PHENYL) PROPAN.AMIDE: Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(4-oxo- 4 -phenylbutyl) -4-piperidinyl] phenyl }propanamide and 1methyl-l-phenylhydrazine; ESMS rn/c: 420.3 CM Example 387 2-METHYL-N-(3-{1-[2-(2-PHENYL-LH-BENZO[G]INDOL-3- YL) ETHYL) -4 -PIPERIDINYL}PHENYL) PROPANAMIDE: Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(4-oxo- 4 -phenylbutyl) 4-piper idinylI phenyl Iprcpanamfide and I- (1-naphthyl)hydrazine hydrochloride: ESMS rn/e: 516.4 (M
H+
Example 388 2-METHYL-N-(3-{1-E3-(2-PIHENYL-1H-EENZO[G]INDOL-3- YL) PROPYL] -4-PIPERIDINYLIPHENYL) PROPANAMIDE: Prepared by Procedure E and Scheme M using 2-methyl-NV-{3-El-(5- -4-p iperidinyl phenyl~propanamide and 1-C1-naphthyl)hydrazine hydrochloride: ESMS rn/e: 530.2 (M H)+ Example 389 2-METHYL-N- [2-PHENYL-5- (TRIFLUOROMETHOXY) -1K- I1'DOL-3 -YL] PROPYL) -4-PZPERIDINYL) PHENYLI PROPANAMIDE: Prepared by Procedure E and Scheme M using 2-methyl-Nl- (5-oxo-5-phenylpentyl) piperidinyl] phenyl }propanamide and 1 4 (trifluoromethoxy) phenyl] hydrazine hydrochloride: ESMS Wne 564.2 CM WO 03/004027 WO 0/00027PCT/UJS02/21063 338 Example 390 2-METHYL-N- [2-PHENYL-5- (TRIFLUOROMETHOXY) -lH- INPOL-3-YLJ BUTYL}-4-PIPERIDlJYL) PHENYLI PROPANAMIDE: Prepared by Procedure E and Scheme M using 2-methyl-N- (6-oxo-6--phenylhexyl) -4piperidinyllphenyl~propalamfide and 1- [4- (trifluoromethoxy) phenyl) hydrazine hydrochloride; ESMS m/e: 578.2 (M Example 391 2-METHYL-N- (l-METHYL-2-PHiENYL-lH-INDOL-3- YL) PROPYLI -4-PIPERIDINYL}PHENYL) PROPAN~AMIDE: Prepared by Procedure E and Scheme M using 2-methyj.-N-{3--[1-(5-oxo- -4 -piperidinyl] phenyl }propanamide and 1methyl-1-phenylhydrazile: ESMS m/e: 495.3 (M Example 392 N- (3-{1.-[4-C1,2-DIPHENYL-1H-INDOL-3-YL)BUTYL1 -4- PIPERIDINYLPHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using 2-methyl-N-{3-E1-(6-oxo- 6-phenyihexyl) -4-piperidinyllphenyllpropanamide and 1,1-diphenylhydrazine hydrochloride: ESMS m/e: (M 570.3 Example 393 2-METHYL-N-[3- (l-(5-[2-PHENYL-5-(TRIFLOPOMETHOXY)-JH- INDOL-3-YL) PENTYL}-4-PIPERIDTNYL) PHENYL] PROPANAMIDE: Prepared by Procedure E and Scheme M using 2-methyl-N- El- (7-oxo-7-phenylheptyl) -4piperidinyllphenyl~propanamide and 1- [4- (c-rlf luoromethoxy) phenyl] hydrazine hydrochloride: ESMS m/e: 592.3 (M Example 394 WO 03/004027 WO 0/00027PCT/UJS02/21063 329 N-C3-{1- (1,2-DIPHENYL- 1H-INDOL-3-YL)PENTYL]-4- PIPERIDINYLI PI-ENYL) -2-METHYLPROPANAM~IDE: Prepared by Procedure E and Scheme M using 2-methyl-N-{3-El-(7-oxo- 7 -phenyiheptyl) -4 -piperidiny.]phenyl }propanamide and 1,1-diphenyihydrazine hydrochloride: ESMS mle: 584.3 (M Example 395 2-METHYL-N- (1-METHYL-2-PHENYL-1H-INDOL-3- YL) PENTYL] -4-PIPEPIDINYL)PHENYL) PROPANAMIDE: Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(7-oxo- 7 -phenyiheptyl) -4-piperidiny.]phenyl~propanamide and 1methyl-l-phenylhydrazine: ESMS m/e: 522.3 (M Example 396 2-METHYL-N- E4- (2-PHENYL-lH-BENZO[G] INDOL-3- YL) BUTYL) -4-PIPERIDTNYL}PHENYL) PROPANAMVIDE: Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[l-(6-oxo- 6 -phenyihexyl) -4 -piperidinyl] phenyllpropanamide and 1- (1-naphthyl)hydrazine hydrochloride: ESMS rn/c: 544.3 (M Example 397 2 -METHYL-N- (3 (l-METHYL-2-PHENYL-lH-INDQL-3 YL)BUTYL) -4-PIPERIDINYL}PHENYL)PROPANAMIDE: Prepared by Procedure E and Scheme M using 2-methy1-N-{3-[1-(6-oXo- 6 -phenyihexyl) -4 -piperidinyl) phenyl }propanamide and Imethyl-1-phenylhydrazine: ESMS m/e: 508.3 Example 398 2-METHYL-N- (2-PHENYL-1H-BENZO [GI INDOL-3- YL) PENTYL] -4-PIPERIDINYL} PHENYL) PROPANANTDE: Prepared by Procedure E and Scheme M using 2-methyl-Nq-{3-[l-(7- WO 03/004027 WO 0/00027PCT/UJS02/21063 340 oxo-7-phenylheptyl) -4piperidinyllphenylpropanamide and 1- (1naphthyl)hydrazine hydrochloride: ESMS mle: 558.2 (M4
H).
Example 399 2-MET-YL-N--(3-{1- [2-(5-METHYL-2-PHENYL-lH-INDOL-3- YL) ETHYL] PIPERTDINYL} 2HENYL) PROPANAMIDE: Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[l-(4-oxo- 4 -phenylbutyl) -4 -piperidinyl] phenyllpropanamide and 1- (4-methylphenyl)hydrazine hydrochloride: ESMS m/e: 480.2 (M4 H) Example 400 N- (7-METHOXY-2-PHENYL-lH-INDOL-3-YL) ETHYL] -4- P'IPERIDINYL} PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure E and Scheme H using 2-methyl-N-{3-[l-(4-oxo- 4 -phenylbutyl) -4 -piperidinyl] phenyllpropanamide and 1- (2 -methoxyphenyl) hydrazine hydrochloride: ESMS m/e: 496.2 (M4 Example 401 2-METHYL-N-(3-{1-[2-(7-METHYL-2-PHENYL-lH-INDOL-3- YL) ETHYL] -4-PTPERITNYL}PHENYL) PROPANANIDE: Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[l-(4-oxo- 4-phenylbutyl) -4-piporidinyllphenyl~propanamide and 1- (2 -methyiphenyl) hydrazine hydrochloride: ESMS m/e: 480 .2
H)~
Example 402 N-(3-{1-[3-(7-METI-OXY-2-PHENYL-1H-INDOL-3-YL)PROPYL]-4- PIPERTDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using 2-methyl-NV-{3-[1-(5-oxco- -4 -piperidinylJ phenyllpropanamide and 1- WO 03/004027 WO 0/00027PCT/UJS02/21063 341 -4piperidinyllphenyl~propanamide and 1- (2methoxyphenyl)hydrazile hydrochloride: ESMS m/e: 510.2 (M H)~ Example 403 2-METHYL-l- 4- (7-METHIYL-2-PHENYL-1Ii-INDOL-3 YL) BUTYL] -4 -PIPERIDINYLPHENYL) PROPANAMIDE: Prepared by Procedure E and Scheme M using 2-methyl--N-{3-[l-(6oxo-6-phenylhexyl) -4-piperidinylJ phenyl }propanamide and 1- (2-methyiphenyl) hydrazine hydrochloride: ESMS m/e: 508.3 (M +I Example 404 E2-(5-METHOXY-2-PH.ENYL-1H-INDOL-3-YL)ETHYL.I-4- PIPERIDINYLPIENYL) -2-METHIYLPROPANAMIDE: Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[l-(4-oxo- 4-'phenylbutyl) -4-piperidinyl] phenyllpropanamide and 1- (4 -methoxyphenyl) hydrazine hydrochloride: ESMS mlie: 496.2 (M H) Example 405 2-METHYL-N- (5-METHYL-2-PHENYL-lH-INDOL-3- YL)PROPYL] -4-PIPERIDINYL}PHENYL)PROPANAMIDE: Prepared by Procedure E and Scheme M using 2-methyl-.N-{3-[l-(5oxo- 5-phenylpentyl) -4-piperidinyl] phenyl }propanamide and 1- (4-methylphenyl) hydrazine hydrochloride: ESMS M/e: 494.3 (M Example 406 [4-(7-METHOXY-2-PDHENYL-lH-INDO)L-3-YL)BUTYL]-4- PTPERIDTNYL} PHENYL) -2-METHYLPROPANAMIDE WO 03/004027 WO 0/00027PCT/UJS02/21063 342 Prepared by Procedure E and Scheme M using 2methyl-N-{3- [1-(6-oxo-6-phenlylhexyl) -4piperidinyl] phenyl }propanamide and 1- (2methoxyphenyl)hydrazine hydrochloride: ESMS m/e: 524.3 (M Example 407 2-METHYL-N- (l-PHENYL-1H-I:NDOL-3-YL)PROPYL) -4- PIPERIDINYL PHENYL)PROPAHAXIDE; Prepared by Procedure Hand Scheme S using N-(3-{l-[4-(1,3-dioxo-an-2-yl)butyl]- 4-piperidinyllphenyl) -2-methyipropanamide and 1,1diphenyihydrazine hydrochloride: ESMS ml/e: 480.2 (M Example 408 2-METH-YL-N- (l-PHENYL-lH-:NDOL-3-YL)ETHYLJ -4- PIPERIDINLPHENYL)PROPANAMIDE: Prepared by Procedure H and Scheme S using NV-(3-{l-[3-(1,3-dioxolan-2yl) propyl) -4 -piperidinyl }phenyl) -2 -methyipropanamide and 1,1-diphenyihydrazine hydrochloride: ESMS m/e: 466.2 (M Example 409 2-METHYL-N- (7-METHYL-lH-INDOL-3-YL) ETHYL] -4- PIPERIDINYL}PHENYL)PROPANAMIDE: Prepared by Procedure H arnd Scheme S using NV-(3-{l-[3-(l,3-dioxolan-2yl) prcpyl] -4-piperidinyllphenyl) -2-methylpropanamide and 1- (2-methylo)henyl) hydrazine hydrochloride:. ESMS m/e: 404.2 (M Example 410 2-METHYL-N- (l-METHYL-lH-INDfOL-3-YL) ETHYL) -4- PIPERIDINYL)PHENYL)PROPANAMIDE: Prepared by Procedure WO 03/004027 WO 0/00027PCT/UJS02/21063 343 H and Scheme S using {1-[3-(1,3-dioxolan-2yl) propyl] -4-piperidinyl~phenyl) -2-methyJlpropanamide and 1-methyl-l--phenylhydrazine: ESMS m/e: 404.2 (M Example 411 2-METHYL-N- E2- (S-METHYL-lH-INDOL-3-YL) ETH-YL] -4- PIPERTDINYL}PHENYL)PROPANAMIDE: Prepared by Procedure H and Scheme S using N-(3-{1-E3-(1,3-dioxolan-2yl) propyl) -4 -piperidinyl)phenyl) -2 -methyipropanwmide and l-(4-methylphenyl)hydrazine hydrochloride: ESMS m/e: 404.2 (M Example 412 2-METHYL-N- E5- (TRI:FLUOROMETHOXY) -lH-INDOL-3is YLJ ETHYL) -4-PIPERIDINYL) PHENYL] PROPANAMIDE: Prepared by Procedure H and Scheme S using NV-(3-{1-[3-(1,3-dioxolan- 2-yl) propyl] -4-piperidinyllphenyl) -2-methyipropanamide and 1- (trifluoromethoxy)phenyl] hydrazine hydrochloride: ESMS m/e: 474.2 (M Example 413 N-(3-{l-(3-(lH-BENZO[G]INDOL-3-YL)PROPYL]-4- PIPERIDINYL)PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure H and Scheme S using N-(.3-{1-[4-(1,.3-dioxolan- 2-yl) butyl] -4-piperidinyl~phenyl) -2-methyipropanamide and 2.-(1-naphthyl) hydrazine hydrochloride: ESMS 454.2 Example 414 2-METHYL-NV-(3-{l- [3-(l-METHYL-1H-INDOL-3-YL)PROPYLJ -4- PIPERIDINYL}PHENYL)PROPANAMIDE: Prepared by Procedure H and Scheme S. A mixture of N-(3-{l-[4-(1,3-dioxolan-2yl)butyl] -4-piperidinyllphenyl) -2-methyipropanamide (100 WO 03/004027 PCT/US02/21063 344 mg, 0.270 mmol), i-methyl- 1-phenylhydrazine (106 mg, 0.870 mmol), ZnCl 2 (119 mg, 0.870 mmol) and HOAc (1.00 mL) was heated for 12 h at 80 0 C. The resulting crude mixture was diluted with water (20 mnL), the aqueous layer was neutralized with a saturated K 2 C0 3 solution nL) and extracted with CH 2 C1 2 (3 X 20 mL). The combined organic layers were concentrated in vacuo and the residue was purified by preparative TLC using 3 of NH 3 M in methanol) in CH 2 C1 2 to give the desired product 2-methyl-N-(3-{l-[3-Cl-methyl-1H-indol-3-yl)propyl>4piperidinyl~phenyl)propanamide (20.7 mg, 18.7 1H NMR (400 MHz, CDC1 3 5 7.60 IH, J 8.1 Hz), 7.45 (s, 1H), 7.35 IB, J 7.4 Hz), 7.25 4H), 7.09 (t, lH, J 7.3 Hz), 6.97 iH, J 7.3 Hz), 6.86 1H),- 3.75 3H), 3.11 2H, J 11.6 Hz), 2.79 Ct, 2H, J 7.3 Hz), 2.51 4H), 2.12-1.81 Cm, 8H), 1.25 6H, J 7.1 Hz) Anal. Calcd for C 2 7
H
3 5
N
3 0+0.225 CHC1 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 Example 415 2-METHYL-N-(3-{l- (5-ETHYL-1H-INDOL-3-YL)PROPYLI-4- PIPERIDINYL}PEENYL)PROPZNAMIDE: Prepared by Procedure H and Scheme S using N-(3-{1-[4-(1,3-dioxolan-2yl)butyl]-4-piperidinyljphenyl)-2-methyipropanamide and 1- (4-methyiphenyl) hydrazine hydrochloride: ESMS m/e: 418.2 (M Example 416 2-METHYL-N-[3-Cl-{3-[5-(TRIFLUOROMETHOXY)-lH-INDOL-3- YL] PROPYL}-4-PIPERIDINYL) PHENYL) PROPANAMIDE: Prepared by Procedure H and Scheme S using N-(3-{1-[4-(l,3-dioxolan- 2-yl)butyl)-4-piperidinyl)phenyl)-2-methyipropanamide WO 03/004027 WO 0/00027PCT/UJS02/21063 345 and 1 4 (trifluoromethoxy) phenyl] hydrazine hydrochloride: ESMS ml/e: 488.2 (M +I H) 4 Example 417 2-METHYL-N- (7-METHYL-1H-I:NDOL-3-YL)PROPYLJ -4- PIPERIDINYL)PHIENYL)PROPANAMIDE: Prepared by Procedure H and Scheme S using N- (1,3-dioxolan-2-yl)butyl] 4-piperidinyl~phenyl) -2-methyipropanamide and 1- (2methylphenyl)hydrazine hydrochloride: ESMS m/e: 418.2 (M Example 418 N- (7-METHOXY-1H-INDOL-3-YL)PROPYL) -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure H and Scheme S using N-(3-{1-[4-(1,3-dioxolan- 2-yl) butylj -4-piperidinyl~phenyl) -2-methyipropanamide and 1- (2-methoxyphenyl) hydrazine hydrochloride: ESMS m/e: 4 34. 0 (M H).
Example 419 (7-METHOXY-1H-INDOL-3-YL)ETHYLJ -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure H and Scheme S using N-(3-{1-[3-(1.3-dioxolan- 2-yl)propyl] -4-piperidinyl~phenyl) -2-methyipropanamide and 1- (2-methoxyphenyl) hydrazine hydrochloride: ESMS m/e. 420.2 (M Example 420 (5-METHOXY-lH-INqDOL-3-YL)ETHYL) -4- PIPERIDINYL}PHiENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure H and Scheme S using N-(3-{1-[3-(1,3-dioxolan- 2-yl)propyll -4-piperidinyl~phenyl) -2-methylpropanamide WO 03/004027 WO 0/00027PCT/UJS02/21063 346 and methoxyphenyl)hydrazine hydrochloride: ESMS rn/c: 420.2 (M Example 421 2-METHYL-N-(3-{l-[4-(5-METHL-2-PHENYL-l-INlOL-3- YL) BUTYL] -4 -PIPERIDINYL}PHENYL) PROPANAMIIDE: Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[l-(6-oxo- 6-phenyihexyl) -4-piperidinyl) pheny. propanamide and I- (4-methaylphenyl) hydrazine hydrochloride: ESMS m/e: 508.3 (M H) Example 422 2-METHYL-N- El- (4-IETHYLPHENYL) -lH-INDOL-3- YLJ METHYL} -4 -PIPERIDI:NYL) PHENYL] PROPANA2MIDE: Prepared by 1s Procedure D and Scheme N using 2-methyl-N-[4-(4piperidinyl) phenylJ propanamide and 1- (4 -methyiphenyl) IH-indole: ESMS rn/c: 466.2 (M Example 423 N- l- (4-METHYLPHENYL)-lH-INDOL-3-YLJMETHYL}-4- PIPERIDINYL)PHENYLJBUTANAMIDE: Prepared by Procedure D and Scheme N using N-[4-(4-piperidinyl)phenyllbutanamide and l-(4-methylphenyl)-lH-indole: ESMS rn/c: 466.2 (M Example 424 N- (2-AMI:NOPHiEN'YL) -lH-INDOL-3-YL]METHYL}-4- PIPERIDINYL)PHENYL] -2-METHYLPROPANAMIDE: Prepared by Procedure D and Scheme N using 2 -methyl (4 piperidinyl)phenyl]propanamide and 2- (IH-indol-2yl)aniline: ESMS rn/c: 467.2 CM Example 425 WO 03/004027 WO 0/00027PCT/UJS02/21063 347 ETHYL (ISOBUTYRYLAMINO)PHENYLJ 1-PIPERIDINYL}METHYL) -1H-INDOLE-2-CARBOXYLATE: Prepared by Procedure D and Scheme N using 2-methyl-.N-[3-(4piperidinyl )phenylJ propanamide and ethyl 1H- indole-2 carboxylate: ESMS mle: 448.2 (M Example 426 2-METHiYL-N- [(1-METHYL-lH-INDOL-3-YL)METHYL) -4- PIPERIDINYL}PHENYL)PROPANAMIDE: Prepared by Procedure D and Scheme N using 2-methyl-.N--[3-(4piperidinyl)phenyl] propanamide and 1-methyl-lH-indole: ESMS m/e: 390.2 (M Example 427 N- [C5-METHOXY-2-METHYL-lH-INDOL-3-YL)METHYL] -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure D and Scheme N using 2 -methyl 3-(4 piperidiriyl )phenyl) propanamide and 5-methoxy-2 -methyl- 1FI-indole: ESMS m/e: 420.2 (M Example 428 2-METHYL-N- E(1-METHYL-2-PHENYL-1H-I1NDOL-3- YL) METHYL] -4-PIPERIDIENYL}PHiENYL) PRQPANAMIDE: Prepared by Procedure D and Scheme N using 2-methyl-X-[3-(4piperidinyl)phenyl] propanamide and 1-methyl-2--phenyl-lHindole: ESMS W/e: 466.2 (M Example 429 2-METHYL-N- (3-{l-[((5-NITRO-1H-INDOL-3-YL) METHYL] -4- PIPERIDINYL)PHENYL)PROPANAMIDE: Prepared by Procedure D and Scheme N using 2-methyl-IN-[3-(4piperidinyl)phenyl] propanamide and 5-nitro-1H-indole: ESMS m/e: 421.1 (M 14)+.
WO 03/004027 WO 0/00027PCT/UJS02/21063 348 Example 430 2-METHYL-N- [(2-METHYL-1H-INDOL-3-YL) METHYL) -4- PIEPERIEDINYL)PHENYL) PROPANAMIDE: Prepared by Procedure D and Scheme N using 2-methyl-N-[3-(4piperidinyl)phenyl) propanamide and 2-methyl-1H- indale: ESMS 390.2 (M Example 431 N- [(4-BROMO-lH-INDOL-3-YL)METHYL] -4- PIPERIDINYL)PHEIYL) -2-METHYLPROPANAMIDE: Prepared by Procedure D and Scheme N using 2-methyl-N-[3-(4piperidinyl) phenyl] propanamide and 4-bromo-lH- indole: ESMS m/e: 455.0 (M is.
Example 432 N- (4-FLUOROP-ENYL) -1H-INDOL-3-YL]METHYL}-4- PTPERIDINYL)PHENYL] -2-METHYLPROPANAMIDE: Prepared by Procedure D and Scheme N using 2-methyl-N-[3-C4piperidinyl) phenyl] propanamide and 2- (4 -fluorophenyl) 1H-indole: ESMS m/e: 470.0 (M Example 433 N- [(1,2'-DTPHENYL-1H-TNDOL-3-YL)MET-YL) -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMTDE: Prepared by Procedure D and Scheme N using 2-methyl-N,-[3-(4piperidinyl) phenyl] propanamide and 1 ,2-diphenyl-1Hindole: ESMS m/e: 528.2 (M Example 434 N- C1-{ (4-CHLOROPHENYL) -l-ETHYL-1H-I:NDOL-3- YL] METHYL) -4 -PIPERIDINYL) PHENYL] -2 -METHYLPROPANAMIDE: Prepared by Procedure D and Scheme N using 2-methyl-N- WO 03/004027 WO 0/00027PCT/UJS02/21063 349 [3 (4piperidiiyl) phenYl] propanamide and 2- (4-chlorophelyl)-1ethyl-1H4-indole: ESMS in/e: 514.1 (M Example 435 N- E(5-CHLORO-2-METYL-lH-INDOL-3-YL)METHYL1-4- PIPERIDINYL)PHENYL) -2-METHYLPlZOPANAMIDE: Prepared by Procedure D and Scheme N using 2-methyl-N- (4piperidinyl)phenyllpropanamide and 5-chloro-2-methyl-Iindole: ESMS mie: 424.1(M Example 436 N- [(5-CYANO-1H-INDOL-3-YL) METHYL] -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANMIDE: Prepared by is Procedure D and Scheme N using 2-methyl-N- (4piperidinyl)phenylJ propanam-'Ide and 1H4-indole-5carbonitrile: ESMS m/e: 401.1 CM H) Example 437 2-METHYL-N- [(5-METHYL-2-PHENYL-lH-INDOL-3- YL) METHYL] -4-PIPRRIDTNYL}PHENYL) PROPANANIDE: Prepared by Procedure D and Scheme N using 2-methyl-N- E3- (4-piperidinyl)phenyllpropanamide and methyl-2-phenyl-IH-indole: ESMS m/e: 466.2 (M Example 438 2-METHYL-N- (4-NITROPIENYL) -1H--INDOL-3- YL] METHYL}-4 -PIPERIDINYL) PHENIf)PROPANAMIDE:- Prepared by Procedure D and Scheme N using 2-methyl-N- (4piperidinyl)phenyl] propanamide and 1- (4-nitrophenyl) -lHindole: ESMS m/e: 497.2 (M Example 439 WO 03/004027 WO 0/00027PCT/UJS02/21063 350 N- (1 (2-FLUORQPHENYL) -IH-INDOL-3- YL] METHYL}-4 -PIPERIDINYL) PHENYL) -2 -METHYLPROPANAMIDE: Prepared by Procedure D and Scheme N using 2-methyl-N- (4-piperidinyl)phenylpropalamfide and 1- (2fluorophenyl)-lH-indo-e: ESMS m/e: 470.1 CM Example 440 N- 6-DIMETHOXY-1Hi-INDOL-3-YL) METHYL) -4- PIPERIDINYL}PHiENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure D and Scheme N using 2-methyl-N--[3-(4piperidinyl) phenyl] propanarnide and 5, 6-dimethoxy- 1Hindole: ESMS m/e: 436.2 (M Example 441 2-METHYL-N-[3-(1-{[1-(3-METIHYLPHENL)-lH-INDOL-3- YL) METHYL) -4 -PIPERIDINYL) PHENYL] PROPANAMIDE: Prepared by Procedure D and Scheme N using 2-methyl-N- (4piperidinyl) phenyl] propanamide and 1- (3-methyiphenyl) TH-indole: ESMS m/e: 466.2 (M Example 442 2-METHYL-N-(3- (TRI.FLUOROMETHiYL)PHENYL] -1H- INDQL-3 -YL}METHYL) -4 -PIPERIDINYL] PHENYL)PROPANAMIDE: Prepared by Procedure D and Scheme N using 2-methyl-NV- (4-piperidinyl)phenyllpropanaTtide and 1- [3- (trifluoromethyl)phenylj-J-H-indole: ESMS ni/e: 520.2 (M Example 443 Cl-{ (4-METHOXYPHENYL)-lH-INlOL-3-YLJMETHYLI}-4- PIPERIDINYL)PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure D and Scheme N using 2-methyl-N- (4- WO 03/004027 WO 0/00027PCT/UJS02/21063 351 piper idinyl) phenYlI p ropanamide and 5-methoxy-2-phelyllH-indole: ESMS m/e: 482.2 (M Example 445 2-METHYL-N- [(5-METHYL-!H-INDOL-3-YL)METHYL]-4- PIPERIDINYL}PHENYL)PROPANAMTDE: Prepared by Procedure D and Scheme N using 2-methyl-N-E3-(4piperidinyl) phenyl] propanamide and 5-methyl- 1H- indole: ESMS m/e: 390.2 (M Example 446 N-E3- [1-(2-NITROPH-ENYL) -lH-fllfOL-3-YLJMETHYL)-4- PIPERIDINYL) PHENYL] -2-METHYLPROPANAMIDE:. Prepared by Procedure D and Scheme N using 1-(2-nitropherlyl)-lHindole and 2-methyl-N-[3-(4piperidinyl)phenyllpropalaide: ESMS m/e: 497.2 (M H) 4 Example 447 N- [1-(2-METHOXYPHENYL) -lH-INDOL-3-YL]METHYL}-4- PIPERIDINYL) PHENYLJ -2-METHYLPROPANAMIDE: Prepared by Procedure D and Scheme N using 1-(2-methoxyphenyl)-1Hindole and 2-methyl-NL- (4piperidinyl)phenyllpropanamide: ESMS m/e: 482.2 (M Example 448 2-HETHYL-N-{3- El- CTRIFLUOROMETHYL)PHENYL] -lH- IINDOL-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)phenyllpropanamide: ESMS m/e: 520.2 (M H) Example 449 WO 03/004027 WO 0/00027PCT/UJS02/21063 352 NV-(3-{1-[E(5-METHOXY-1H- INDOL-3-YL) METHYL] -4- PIPERIDINYLIPHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure D and Scheme N using 1H-indol-5-yl methyl ether and 2-methyl-NV-[3- (4piperidinyl)phenylpropalamfide: ESMS rn/e: 406.2 (M Example 450 NV-[3- [1-(4-FLUOROPE'YL) -1H-INDOL-3-YL]METHYL)-4- PIPERIDINYL) PHENYL] -2 -METHYLPROPANAMIDE: Prepared by Procedure D and Scheme N using 1-(4-fluorophenyl)-lHindole and 2-methyl-.N-t3-(4piperidinyl)phenyllpropalamide: ESMS m/e: 470.2 (M H' Example 451 N- [3-(l-{E1-C3-METHOXYPHENYL)-1H-INDOL-3-YLJMETHIYL1-4- PIPERflYINYL) PHENYL] -2 -METHYLPROPAINhMIDE: Prepared by Procedure D and Scheme N using l-(3-methoxyphenyl)-lHindole and 2-methyl-N-[3-(4piperidinyl)phenyllpropanamide: ESMS m/e: 482.2 (M Example 452 2-METHYL-N- [1-(2-METHiYLPHENYL) -1H-INDOL-3- YLJ METHYL} -4 -PIPERIDI:NYL) PHENYIJPROPANAD4IDE: Prepared by Procedure D and Scheme N using l-(2-methylpheny)-lHindole and 2-methyl-N-[3-(4piperidinyl)phenyllpropanamide: ESMS m/e: 466.2 (M4 H) 4 Example 453 ETHYL 3- (ISOBUTYRYLAMdINO)PHENYL] -1- PIPERIDINYL}METHYL) -5-METHOXY- lH-INDOLE-2-CARBOXYLATE: Prepared by Procedure D and Scheme N using ethyl methoxy-lH-indole-2-carboxylate and 2-methyl-N- (4piperidinyl)phenyllpropanamide: ESMS m/e: 478.2 (M WO 03/004027 WO 0/00027PCT/UJS02/21063 353 Examiple 454 [(5-FLUORO-1H-INDOL-3-YL) METHYL] -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure D an~d Scheme N using 5-fluoro-lH-indole and 2methyl -N-E3 (4-piperidinyl) phenyl) propanamide: ESMS m/e: 394.2 (M I-PHENYL-lH-INDOLE: Prepared by Procedure C and Scheme 0 using IH-indole and lodobenzene: ESMS m/e: 193.9 (M 1-(4-CHLOROPHEINYL)-lH-INDOLE: Prepared by Procedure C and Scheme 0 using IH-indole and 1-chloro-4-iodobenzene: ESMS mle: 227.9 (M 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) 4 1-(2-CHLOROPHEINYL)-1H-INDOLE: Prepared by Procedure C and Scheme 0 using IH-indole and l-chloro-2-iodobenzene: ESMS m/e: 227.9 (M H) 4 1-E2- (TRIFLUOROMETHYL) PHENYLI -1H-INDOLE: Prepared by Procedure C and Scheme 0 using 1H-indole and I-iodo-2- (trifluoromethyl)benzene: ESMS m/e: 2G2.0 (M H) 4 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).
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 WO 03/004027 WO 0/00027PCT/UJS02/21063 354 1-(2-NITROPHENYL)-lH-INDOLE: Prepared by Procedure C and Scheme 0 using lH-indole and 1-iodo-2-nitrobenzele: ESMS m/e: 238.2 (M Example 455 NL- (4-CHLOROPHENYL) -lH-INDOL-3-YL)METHYI-4- PIPERIDINYL)PHENqYLJPROPANAMIDE: Prepared by Procedure D and Scheme N using 1-(4-chlorophenyl)-1H-indole and N- (4-piperidinyl)phenylpropalamide: ESMS m/e: 472.1 (M Example 456 V- [1-(3-CHLOROPHENYL) -1H-INflOL-3-YL]METHYL}-4- PIPERIDINYL)PHENYLJPROPANAMIIlE: Prepared by Procedure D and Scheme N using l-C3-chlorophenyl)-1N-ildcle and N- (4-piperidinyl)phenyJlpropanamide: ESMS m/e: 472.1 (M +I H) 4 Example 457 N-E3- (2-CHiLOROPHENYL) -lH-I1NDfOL-3-YLMETHYL}-4- PIPERIDINYL) PHENYL] CYCLOPROPANECARBOXAMIDE: Prepared by Procedure ID and Scheme N using 1-(2-chlorophenyl)-1Hindole and U[-4 piperidinyl) phenyl cyclopropanecarboxamide: ESMS m/e: 484.1 (M Example 458 N- El- (3-CELOROPHENYL) -lH-INDOL-3-YL]METHYL}-4- PIPERIDINYL) PHENYL] -2 -METHYLPROPANAMIDE: Prepared by Procedure D and Scheme N using 1-(3-chlorophenyl)-1Hindole and 2-methyl-N-[3-(4piperidinyl)phenyllpropanamide: ESMS m/e: 486.1 (M WO 03/004027 WO 0/00027PCT/UJS02/21063 355 Example 459 N- (4-CHLOROPHENYL) -lH-I:NDOL-3-YL)METHYL)-4- PIPERIDINYL)PHENYIJ-2-METHYLPROPANAMIDE: Prepared by Procedure D and Scheme N using l- (4-chlorophenyl) -1H4indole and 2-methyl-N\- (4piperidinyl)phenylpropalamide: ESMS m/e: 486.2 (M Example 460 N- [3-(l-{[1-(2-CHLOROPHENYL)-1H-INDOLl-3-YLJMETEYLY-4- PIPERIDINYL) PEENYL) -2 -METHYLPROPANAMIDE: Prepared by Procedure D and Scheme N using l- (2-chlorophenyl) -Hindole and 2-methyl-N-[3-(4piperidinyl)phenyllpropalamide: ESMS m/e: 486.2 (M H) 4 Example 461 N- [1-(2-CHLOROPHENYL) -1H-I:NfOL-3-YL]METHYL}-4- PIPERIDINYL)PHENYLJPROPANAMIDE: Prepared by Procedure D and Scheme N using 1-(2-chlorophenyl)-H-idole and N- E3-(4-piperidinyl)phenyalpropaniamide: ESMS rr/e: 472.1 (M H) Example 462 NV-[3- [1-(4-CHLOROPHENYL) -1H-INDOL-3-YL)METHYL}-4- PIPERIDINYL) PHEbIYL] CYCLOPROPANECARBOXAMIDE! Prepared by Procedure D and Scheme N using 1-(4-chlorophenyl)-1Hindole, and piperidiny1l phenyl) cyclopropanecarboxamide: -ESMS mie: 484.1 (M Example 463 N- (3-CEiLOROPHENYL) -lH-INDOL-3-YL]METHYL}-4- PIPERIDINYL) PHENYL] CYCLOPROPANECARBOXAMIDE: Prepared by WO 03/004027 WO 0/00027PCT/UJS02/21063 356 Procedure D and Scheme N using 1-(3-chlaropheny-)- IH-indole and N[-4 piperidinyl) phenyl] cyclopropanecarboxamide: ESMS in/e: 4B4.1 (M Example 464 PIPERIDINYLIPHENYL) PROPANAMIDE: Prepared by Procedure D and Scheme N using I-pherayl-1H-indole and piperidinyl)phenyllpropalamide: ESMS rn/c: 438.2 (M Example 465 N- i:(1-PHENYL-2LH-IN~DOL-3-YL)METHYL] -4- PIPERIDINYL)PHENYJ) CYCLOPROPANECARBOXAMIDE: Prepared by Procedure D and Scheme N using 1-phenyl-1H-indole and N- (4-piperidinyl) phenyl] cyclopropanecarboxamide:
ESMS
rn/c: 450.2 (M 6-CHLORO-1- (4-NITROPEYL) H- INDOLE: Prepared by Procedure C and Sch~eme 0 using 6-chloro-1H--indole and 1iodo-4-nitrobenzene: ESMS mie: 272.6 (M 6-CHLORO-1- 3-DICHLOROPHENYL) -lH-INDOLE: Prepared by Procedure C and Scheme 0 using 6-chloro-IH-indole and 1,2-dichloro-3-iodobenzene: ESMS rn/c: 296.5 (M 1.
6-CHLORO-l- (3 -METHYLPHENYL) 11- INDOLE: Prepared by Procedure C and Scheme 0 using 6-chloro-1H--indole and 1iodo-3-methylbenzene: ESMS rn/e: 241.9 (M 6 -CHLORO-1- (2-METHYLPHENYL) H-INDOLE:- Prepared by Procedure C and Scheme 0 using 6-chloro-lHU-indole and 1iodo-2-methylbenzene: ESMS m/e: 241.9 (M WO 03/004027 WO 0/00027PCT/UJS02/21063 357 2- (6-CHLORO-1H-INDOL-1-YL) PHENYL KETHYL ETHER: Prepared by Procedure C and Scheme 0 using 6-chloro-1H-indole and 1-iodo-2-methoxybenzele: ESMS m/e: 257.9 (M 6 -CHLORO-. (TRIFLUOROMETHYL) PHENYL) -2H-INDOLE: Prepared by Procedure C and Scheme 0 using 6-chloro-1H4indole and I-iodo-3- (trif luoromethyl) benzene: ESMS m/e: 295.6 (M +i 6-CHLORO-1- (2-FLUOROPHENYL) -1H-INIJOLE: Prepared by Procedure C and Scheme 0 using 6-chloro-lH-indole and 1fluoro-2--iodobenzene: ESMS mle: 245.9 (M 6-CHLORO-1- (3-CHLOROPHENYL) -lH-INDOLE: Prepared by Procedure C and Scheme 0 using 6-chloro-1N-indole and 1chloro-3-iodobenzene: ESMS m/e: 261.9 (M 6-CHLORO--1- (4-CHLOROPHENYL) -1H-INDOLE: Prepared by Procedure C and Scheme 0 using 6-chloro-1H-indole and 1chloro-4-iodobenzene: ESMS m/e: 262.9 (M 6-CHLORO-1- (2-CHLORPHENYL) H-INDOLE: Prepared by Procedure C and Scheme 0 using 6-chloro-lH-indole and 1chloro-2-iodobenzene: ESMS ni/e: 262.9 (M 3- (6-CHLORO-1H-INDOL-1-YL) PHENYL METHYL ETHER: Prepared by Procedure C and Scheme 0 using 6-chloro-l1H-indole and 1-iodo-3-methoxybenzene: ESMS mle: 257.9 (M 6 -CHLORO- (TRIFLUOROMETHYj) PHENYL] -1R-INDOLE- Prepared by Procedure C and Scheme 0 using 6-cbhloro-1H- WO 03/004027 WO 0/00027PCT/UJS02/21063 358 indole and 1-iodo-4- (trifluoromethyl) benzene ESMS mle: 295.6 (M H" 6 -CHLORO-1- (4 -METHYLPRENYL) lH-INDOLE: Prepared by Procedure C and Scheme 0 using 6-chloro-1H-indole and Iiodo-4--methylbenzene: ESMS m/e: 241.9 (M 6 -CHLORO-1- (4 -FLUOROPHENYL) H-INDOLE: Prepared by Procedure C and Scheme 0 using 6-chloro-1H-iridole and 1fluoro-4-iodobenzene: ESMS m/e: 245.9 CM Example 466 N- t3- (i-([6-CHLORO-1- (4-FLUOROPHENYL) -1H-INDOL-3- YLJ METRYL} -4 -PIPERIDINYL) PHENYL] CYCLOPROPANECARBOXAMIDE: is Prepared by Procedure D and Scheme N using 6-chloro-1- (4-fluorophenyl) -1H-indole and N- (4piperidinyl )phenyl] cycJlopropanecarboxamide: ESMS ni/e: 502.1 CM E)l+.
Example 467 N- E3- (l-([6-CHLORO-1- (4-FLUOROPHENYL) -lH-INDO)L-3- YLI METHYL} -4 -PIPERIDINYL) PHENYL] PROPANAHIDE: Prepared by Procedure D and Scheme N using 6-chloro-1-(4fluorophenyl) -1H-indole and N- (4piperidinyl)phenyllpropanamide: ESMS m/e: 490.1 (M Example 468 [(6-FLUORO)-1H-INDOL-3-YL)METHYL] -4- PIPERIDINYL}PHENYL)PROPANAMIDE: Prepared by Procedure D and Scheme N using 6-fluoro-1H-indole and piperidinyl)phenyllpropanamide: ESMS m/e: 380.1 (M H).
WO 03/004027 WO 0/00027PCT/UJS02/21063 359 Example 469 N-(3-{1-[E(6-FLUORO-1H-INDOL-3-YL) METHYL] -4- PIPERIDINYL}PHENYL) CYCLOPROPANECARBOXAMIDE: Prepared by Procedure D and Scheme N using 6-f luoro-1H-indole and NV- (4-piperidinyl)pheny-)cyclopropanecarboxanide:
ESMS
rn/e: 3 92. 1 (M H Example 470 [(6-FLUORO-lH-INDOL-3-YL)METHYLJ -4- PIPERIDIN'YL}PHENYL) -2 -METHYLPROPANAMIDE: Prepared by Procedure D and Scheme N using 6-tluoro-lH-indole and 2methyl-.N- (4-piperidinyl)phenyllpropanamide: ESMS m/e: 394.1 (M Example 471 N- [6-CIILORO-l- (4-FLUOROPHEENYL) -lH-INDO)L-3- YL] METHYL) -4-PIPERIEDINYL) PHENYL] -2 -METHYLPROPA.NAMIDE: Prepared by Procedure D and Scheme N using 6-chloro-1- (4-f luorophenyl) -1H-indole and 2 -methyl 3- (4 piperidinyl~phenyllpropanamide: ESMS m/e: 504.1 (M Example 472 N- [6-CHLORO-1- (2-FLUOROPHENYL) -1H-INDOL-3- YL) METHYL) -4-PIPERI:DINYL) PHENYL] PROPANAMIDE: Prepared by Procedure D and scheme N using 6-chloro-1-(2fluorophenyl) -1.-indole and (4piperidinyl)phenyllpropanamide: ESMS m/e: 490.1 (M Example 473 N- E3-(l-{[6-CHLORO-l-(2-FLUOROPHENYL)-1H-INDOL-3- YL] METHYL) -4 -PIPERIDINYL) PHENYLJ CYCLOPROPANECARBOXAMIDE: Prepared by Procedure D and Scheme N using 6-chloro-l- (2-fluorophenyl)-lH-indole and NV-[3- (4- WO 03/004027 WO 0/00027PCT/UJS02/21063 360 piperidinyl) phenyl] cyclopropanecarboxamide: ESMS ral/e: 502.1 (M Example 474 N..3-(1-{E6-CHiLORO-1-(2-FLUOROPHENYL) -lH-INDOL-3- YL] METHYL} -4-PIPERIDI4YL) PHENYL] -2 -METHYLPROPANAMI:DE: Prepared by Procedure D and Scheme N using 6-chloro-l- (2-f luorophenyl) -lH--indole and 2-methyl-N-[3- (4piperidinyl)phenyllpropanamide ESMS m/e: 504.1 (M Example 475 N- E3- (1-{[6-CI{LORO-1- (4-CHLOROPHENYL) -lH-INDOL-3- YI]METHYL} -4 -PIPERID.INYL) PHENYL) PROPANAMIDE: Prepared by Procedure D and Scheme N using 6-chloro-1- (4chiorophenyl) -lH-indole and N- E3- (4piperidinyl)phenylpropalamide ESMS rn/e: 506.1 (M Example 476 N-E3- (6-CHLORQ-1- (4-CHLOROPHENYL) -1H-INJJOL-3- YL] METHYL} -4 -PIPERIDINYL) PHENYL CYCLOPROPANECARBOXAMIDE: Prepared by Procedure D and Scheme N using 6-chloro-1- (4-chlorophenyl) -1H-indole and N7- [3 (4piperidinyl)phenyl) cyclopropanecarboxanide ESMS m/e: 518.1 CM Example 477 N- E3- (l-{[6-CHLORO-1- (4-CHLOROPHENYL) -1H-INDOL-3- YL] METHYL} -4 -PIPERIDINYL) PHENYL] -2 -METHYLPROPANAMIDE: Prepared by Procedure D and Scheme N using 6-chloro-1- (4-chiorophenyl) -1H-indole and 2-methyl-N- (4piperidinyl)phenyl]propanamide ESMS m/e: 520.1 CM H) 4 WO 03/004027 WO 0/00027PCT/UJS02/21063 3G1 Example 478 M- [6-CHLORO-1- (3-CHLOROPHENYL) -lH-INDOL-3- YL] METH-YL} -4 -PIPERIDI:NYL) PHENYL) PROPANMIDE: Prepared by Procedure -D and Scheme N using 6-chloro-l-(3chiorophenyl) -lH-indole and N- (4piperidinyl)phenyllpropalamide: ESMS iile: 506.1 (M Examzpl~e 479 N- [6-CHLORO-1- (3-CHLOROPHENYL) -2H-INDOL-3- YL] METHYL}-4-PIPERIDINYL) PHENYL] CYCLOPROPANECARBOXAMIDE: Prepared by Procedure D and Scheme N using 6-chloro-1- (3-chiorophenyl) -lH-indole and N- (4piperidinyl) phenyl] cyclopropanecarboxamide: 1H NMR (400 MI-z, CDC1 3 5 7.72 1H, J =8.4 Hz) 7.68 1H-), 7.49 (mn, 2H) 7.44 2H1, J 7.9 Hz) 7.49-7.25 (m, 4H) 7.21 1H1, J 7.9 Hz) 7.17 1H, J 7.9 Hz), 6.93 111, J 7.9 Hz) 3.79 2K1), 3.13 2H, J= 9.4 Hz), 2.48 (sept, 111, J 7.5 Hz) 2.16 (mn, 211), 1.80 (in, 4H), 1..51 lH) 1.06 (in, 2H1), 0.806 (in, 2H); Anal. Calcd for C 3 0
H
2 9 Cl 2 NO+HC1+1.4H 2 O: C, 62. 11; H, 5.70; N, 7.24. F'ound: C, 62.19; H, 6.21; N, 7.06; ESMS ni/e: 519.2 (M H).
Example 480 NV-[3- [6-CIHLORO-1-(3-CHLOROPHENYL)-I-I:NDOL-3- YL] METHYL}-4 -PI:PERIDINYL) PHENYL] -2 -METHYLPROPANAMIDE:.
Prepared by Procedure D and Scheme N using 6-chloro-l- (3-chloropbhenyl) -lH-indole and 2-methyl-N- (4pip~eridinyl)phenyllpropanamide: ESMS m/e: 520.1 CM Example 481 [(5-FLUORO-1H-INDOL-3-YL)METHIYLJ -4- PIPERIDINYL)PHiENYL) CYCLOPROPANECARBOXAMIDE: Prepared by WO 03/004027 WO 0/00027PCT/UJS02/21063 362 Procedure D and Scheme N using 5-f luoro-1H-indole and N- (4-piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m/e: 392.1 (M H+ Example 482 N- E6-CHLORO-1- (2-CFILOROPH-ENYL) -1H-INDOL-3- YLJ METHYL}-4-PIPERIDINYL) PEENYLJ -2-METHYLPROPANAMIDE: Prepared by Procedure D and Scheme N using 6-chloro-l- (2-chiorophenyl) -1H-indole and 2-methyl-N- (4piperidinyl)phenyllpropanamide: ESMS m/e: 520.2 (M Example 483 N- [6-CHLORO-1- (3-METHOXYPHENYL) -lH-INDOL-3- YLI METHYL}-4 -PIPERIDINYL) PHENYL] -2 -METHYLPROPANAMIDE: Prepared by Procedure D and Scheme N using 3-(6-chlorolH-indo1-l1-y1)phenyI methyl ether and 2-methyl-N- (4piperidinyl)phenyllpropanamide: ESMS m/e: 516.2 (M Example 484 N-[3-(l-{[6-CHLORO-l.-(2-METHOXYPHENYL) -lH-INDOL-3- YLJ METHYI}-4 -PIPERIINYL) PHENYL] -2 -METHYLPROPANAMIDE: Prepared by Procedure D and Scheme N using 2-(6-chlorol.H-indol-1-yl)phenyl methyl ether and 2-methyl-N- (4piperidinyl)phenyllpropanamide: ESMS m/e: 516.2 (M H+ Example 485 N- (1-{[6-CHLORO-l- (2,3-DICHLOROPHENYL) -lH-INDOL-3- YL]METHYL}-4-PIPERIDINYL) PHENYL] -2-METHYLPRO.PANAMIDE: Prepared by Procedure D and Scheme N using 6-chloro-l- (2,3-dichlorophenyl) -lH-indole and 2-methyl-Nv- L3- (4piperidinyl)phenyllpropanamide: ESMS m/e: 555.1 (M H) WO 03/004027 WO 0/00027PCT/UJS02/21063 363 Example 486 N- (i-{[6-CHLORO-1- (4-METHYLPHENYL) -JH-INDOL-3- YLJ METHYL} -4 -PIPERIDINYL) PHEN'YL] -2-METHYLPROPANAMIDE: Prepared by Procedure D and Scheme N using E-chloro-l- (4-methyiphenyl) -lH-indole and 2-methyl-N- (4piperidinyl)pheny.]propalamide: ESMS m/e: 500.2 (M Example 487 ({6-CHLOR)-l- (TRIFLUJOROMETHYL) PHE'NYLJ -lT- INDOL-3-YL}METHYL) -4-PIPER,3IDTNYLJ PHENYL}-2- METHYLPROPANAMIDE: Prepared by Procedure D arnd Scheme N using 6-chloro---[3- (trifluoromethyl)phelylj -lH-indole and 2-methyl-N- (4-piperidinyl)phenylpropaamide:.
ESMS M/e: 554.2 (M Example 488 (TRI:FLUOROMETHYL)PHENYL] -lH- INDOL-3-YL}METHYL) -4-PlPERIDINYL) PHENYL}-2- METHYLPROPANAMIDE: Prepared by Procedure D and Scheme N using 6-chloro-l- (trifluoromethy~phelyl]-lH-indole and 2-methyl-N- (4-piperidinyl)phenyllpropalamide: ESMS m/e: 554.2 CM Example 489 N- [6-CHLORO-l- (2-METHYLPEENYL) -lH-INDOL-3- YL)METHYL-4-PIPERIDINYL) PHENYL) -2-METHYLPROPANAMI:DE: Prepared by Procedure D and Scheme N using 6-chloro-l- (2-methyiphenyl) -lH-indole and 2-methyl-N- (4piperidinyl)phenyllpropalamide: ESMS m/e: 500.2 CM H) 4 Example 490 E6-CHLORO-l-(3-METHiYLPHENYL)-1H-INDOL-3- YLJ METHYL) -4 -PIPERIDINYL) PEENYL 2-HETHYLPROPANqAMIDE: Prepared by Procedure D and Scheme N using 6-chloro-1- WO 03/004027 WO 0/00027PCT/UJS02/21063 364 (3-methylphenyl) -lH-indole and 2-methyl-N- E3- (4piperidinyl)phenyllpropanamide: ESMS m/e: 500.2 (M Excample 491 N-(3-{l-[(C7-CHLORO-1H-INflOL-3-YL)HETRIYL)-4- PIPERIDINYL}PHENYL) CYCLOPROPANECARBOXAMIDE: Prepared by Procedure D and Scheme N using 7-chloro-lH-indole and N- (4-piperidinyl) phenyl] cyclopropanecarboxamide:
ESMS
m/e: 408.1 (M Example 492 N- (3-tI-[E(7-CHLORO-lH-I:NDOL-3-YL)METHYLJ -4- PIPERIDINYLPHENYL)-2-METHYLPROPANAMIDE: Prepared by Procedure D and Scheme N using 7-chloro-1H-indole and 2methyl-NV-[3- (4-piperidinyl)phenyllpropanamide: ESMS m/e: 410.1 (M Example 493 [(4-FLUORO-lH-INDOL-3-YL)METHYL] -4- PIPERIDINYL)PHEN~YL)PROPANAMIDE: Prepared by Procedure D and Scheme N using 4-fluoro-1H-indole and piperidinyl)phenyllpropanamide: ESMS mle: 380.2 CM Example 494 t(7-CHLORO-lH-INOL-3-YL)METHYLJ -4- PIPERIDIN~YLPHENYL)PROPANAMIDE: Prepared by Procedure D and Scheme N using 7-.chloro-1-indole and piperidinyl)phenyllpropanamide: ESMS rn/e: 3.9-.1 (M Example 495 2-METHYL-N- t(6-METHYL-1H-INDOL-3-YL) METHYL) -4- PIPERIDINYL}PHENYL)PROPANAMIDE: Prepared by Procedure D and Scheme N using 6-methyl-1H-indole and 2-methyl-N- 13- WO 03/004027 WO 0/00027PCT/UJS02/21063 365 (4piperidinyl)phenylpropalamide: ESMS m/e: 390.2 (M H).
Example 496 ZJ-[3-(l.{[6-(BENZYLOXY)-lH-INDOL-3-YL)METHYL}-4- PIPERIDINYL) PHENYL) -2 -METHYLPROPANAMIDE: Prepared by Procedure D and Scheme N using 6- (benzyloxy) -1H-indole and 2-methyl-NV- (4-pipoeridinyl)phenyl] propanamide: ESMS ni/e: 482.2 (M Example 497 N-(3-{l-[E(6-METHOXY- lH-INDOL-3-YL) METHYL) -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure D and Scheme N using 1H-indol-6-yl methyl ether and 2-methyl-NV-[3-(4piperidinyl)phenyllpropanamide: ESMS m/e: 406.2 (M Example 498 METHYL 3- (ISOBUTYRYLAMINO) PHENYL) -1- PIPERIDINYL}METHYL) -lH-INDOLE- 6-CARBOXYLATE: Prepared by Procedure D and Scheme N using methyl 1H-indole-6carboxylate and 2-rnethyl-N-[3-(4piperidinyl)phenyllpropanamide: ESMS m/e: 434.2 (M Example 499 2-METHYL-N- (TRIFLUOROMETHYL) -lH-INDOL-3- YL) METHYL}-4 -PIPERIDINYL) PHENYL) PROPANAMIDE: Prepared by Procedure D and Scheme N using 6-(trif-luoromethyl)- IH-indole and 2-methyl-N-[3-(4piperidinyl)phenyllpropanamide: 3H NMR (400 MHz, CDC1 3 6 8.11 1H) 7.66 1H) 7.63 2H), 7.44 1H., J 8.4 Hz), 7.39 2H), 7.32 1H, J -8.4 Hz), 7.16 1K, J 8.4 Hz), 6.84 1H, J 8.4 Hz), 4.06 (s, WO 03/004027 WO 0/00027PCT/UJS02/21063 366 2H) 3.27 2H, J 11.6 Hz) 2.56 (sept, 1H, J= 6.-8 Hz) 2. 37 3H1), 1. 93 CM, 2H) 1. 75 (in, 2H1), 1. 22 6H1, J 6.8 Hz); Anal Calcd f or
C
2 5HF 3
N
3 +2HC1+0. SEtOAc: C, 57. 8; H, 6.11; N, 7.50.
Found: C, 56.5; H1, 6.46; N, 7.77; ESMS m/e: 444.2 (M H) 1- (2 -PYRIDINYL) H- INDOLE: Prepared by Procedure C and Scheme 0 using 2-iodopyridile and IN-indole: ESMS m/e: 195.0 CM 1-(3-PYRIDINYL)-lH-INDOLE:. Prepared by Procedure C and Scheme 0 using 3-iodopyridile and 1H-indole: ESMS m/e: 19 5. 0 (M H) Example 500 2-METHYL-N- [1-(3-PYRIDIrNYL) -lH-INDOL-3- YLJ METHYL}-4PIPERIDINYL) PHENYL) PROPANAMIDE: Prepared by Procedure D and Scheme N using 1-(3--pyridifl)-1Hindole and 2-methyl-N- [3-C(4piperidinyl)phellPrcpalamide: ESMS m/e: 453.2 CM Example 501 2-METHYL-N-E3- (2-PYRIDINYL) -lH-INDOL-3- YLI METHYL} -4 -PIPERIDINYL) PHE:NYL] PROPANAMIDE: Prepared by Procedure D and Scheme N using 1-(2-pyridinyl)-1Iindole and 2-methyl-N- [3-C(4piperidinyl)pheiylPropalaide: ESMS m/e: 453.2 (M Example 502 [(6-FLUOROl-PHENYLlH-INDOL-3YL)METHYL] -4- PIPERIDINYL}PHENYL) -2-METHIYLPROPANAMIDE: Prepared by Procedure D and Scheme N using 6-f luoro-1-phenyl-1H- WO 03/004027 WO 0/00027PCT/UJS02/21063 367 indole and 2-methyl-NV-[3- (4piperidinylphelyllpropalaide: ESMS m/e: 470.2 (M H+ Example 503 [(6-CHLORO-1-PHENYL-lH-INDOL-3-YL)METHYL] -4- PIPERIDINYL}PHENYL) -2-METHYLPRQPANAMIDE: Prepared by Procedure D, and Scheme N using 6-chloro-l1-phenyl-lHindole and 2-methyl-N-[3-(4piperidinyl~pheny]propalamide:- ESMS m/e: 486.2 (M 7-METHYL-l-PHENYL-1H-INDOLE: Prepared by Procedure C and Scheme 0 using 7-methyl-lH-indoJle and iodobenzene: ESMS zn/e: 208.1 (M METHYL 1-PHENYL-lH-INDOLE-6-CARBOXYLATE: Prepared by Procedure C and Scheme 0 using methyl 1H-indole-6carboxylate and iodobenzene: ESMS m/e: 252.0 (M 6-METHYL-1-PHENYL-lH-INDOLE: Prepared by Procedure C and Scheme 0 using 6-methyl-1H-indole and iodobenzene: ESMS ni/e: 208.0 (M 7-CHLORO-1-PHENYL-lH-INDOLE: Prepared by Procedure C and Scheme 0 using 7-chloro-lH-indole and iodobenzene: ESMS m/e: 2 28. 0 (M H).
6-NITRO-1-PEEN'YL-1H-INDOLE: Prepared by Procedure C and Scheme 0 using 6 -nitro- IH-indole and iodobenzene: ESMS W/e: 2 38. 2 (M H) 4 6-METHOXY-1-PEENYLj-1H-INDOLE: Prepared by Procedure C and scheme 0 using 1H-indol-G--yl methyl ether and iodobenzene: ESMS m/e: 224.0 (M H) 4 WO 03/004027 WO 0/00027PCT/UJS02/21063 368 BENZYL 1-PHENYL-lH-INDfOL- 6-YL ETHER: Prepared by Procedure C and Scheme 0 using 6- (benzyloxy) -lH-ildole and iodobenzene: ESMS mle: 300.0 (M l-PHENYL-1H-INDOL-6-YL TRIFLUOROMETHYL ETHER: Prepared by Procedure C and Scheme 0 using 6-(trifluoromethoxy)lH-indole and iodobenzene: ESMS m/e: 278.0 (M 7-METHOXY-l-PHENYL-H-INDfOLE: Prepared by Procedure C and Scheme 0 using lH-indol-7-y. methyl ether and iodobenzene: ESMS m/e: 224.0 (M H+ l-PHENYL-6- (TRIFLUOROMETHYL) -lH-flNDOLE: Prepared by Procedure C and Scheme 0 using 6-(trifluoromethy1)-lHis indole and iodobenzene: ESMS m/e: 262.0 (M 1-(4-PYRIDINYL)-lI-INDOLE. Prepared by Procedure C and Scheme 0 using IH-indole and 4-iodopyridine: ESMS m/e: 195 (M H).
Example 504 N- 6- (BENZYLOXY) -l-PHENYL-lfI-INDOL-3-YLJ
METHYL)-
4 -PIPERIDINYL) PHENYL] -2-METHYLPROPANAMIDE: Prepared by Procedure D and Scheme N using benzyl 1-phenyl-IH-indol- 6-yl ether and 2-methyl-N- (4piperidinyl)phenylprcpalamide: ESMS ni/e: 558.0 (M Examp le 505 2-METHYL-NV-(3- [(6-METHYL-1-PHENYL-lH-INDOL-3- YL) METHYL] -4-PIrPERI:DINYL)PHENYL) PROPMA.AMIDE; Prepared by Procedure D and Scheme N using- 6-methyl-l-phenyl-iHindole and 2-methyl-N- E3-C4piperidinyl)phenyllpropanamide: NMR (400 MHz, CDC1 3 6 WO 03/004027 PCT/US02/21063 369 7.66 1H), 7.64 1H, J 7.8 Hz), 7.51 1H, J 3.9 Hz), 7.50 3H), 7.4 Cm, 2H), 7.36-7.32 (m, 2H), 7.31 Cs, 1H), 7.19 Ct, 1H, J= 7.8 Hz), 7.04 1H, J 7.8 Hz), 6.91 1H, J 7.8 Hz), 3.94 2H), 3.25 2H, J 9.2 Hz), 2.52 (sept, 1H, J 6.4 Hz), 2.46 Cs, 3H), 2.28 Cdt, 2H, J 11.8, 2.6 Hz), 1.89 (dq, 2H, J 2.9 Hz), 1.80 3H), 1.22 6H, J 6.9 Hz); Anal. Calcd for C 31 35
N
3 0+HC1+0.6EtOAc: C, 72.2; H, 7.41; N, 7.57. Found. C, 71.0; H, 7.40; N, 7.66; ESMS m/e: 466 CM H)4.
Example 506 METHYL 3-((4-3-(ISOBUTYRYLAMINO)PHEN'YL)-1- PIPERIDINYLIMETHYL)-lP NENY L NOL--CRBXLAE Prepared by Procedure D and Scheme N using methyl 1phenyl- H-indole-6-carboxylate and 2-methyl-N- (4piperidinyl)phenyllpropanamide: ESMS m/e: 510.0 CM Example 507 2-METHYL-N-(3-I-[(6-NITRO-H-INDOL-3-YL)M PIPERIDINYL)PHENYL)PROPANAMIDE: Prepared by Procedure D and Scheme N using 6-nitro-1H-indole and 2-methyl-N- [3- (4-piperidinyl)Phenyl] propanamide: ESMS m/e: 421.0 (M Example 508 2-METHYL-N- [1-PHEITYL-6- (TRIFLUOROMETHYL) -1H- INDOL-3-YL]METHYL -4-PIPERIDINYL)PHENYLJPROPANAMIDE: Prepared by Procedure D and Scheme N using l-phenyl-6- (trifluoromethyl)-lH-indole and 2-methyl-N-[3-C4piperidinyl)phenylropanarnide: ESMS m/e: 520.0 CM WO 03/004027 WO 03/04027PCT/US02/21063 370 Example 509 2-METHYL-N- (3-fl- [(7-METHYL-1-PHENYL-lH-INDOL-3- YL) METHYL] -4-PIPERIDINYL}PHENYL)PROPANAMIDE:. Prepared by Procedure D and Scheme N using 7-methyl-l-pheflyl-1Hindole and 2-methyl-N-[3-(4piperidiny1~phenyl1propalamide: ESMS rn/c: 466.0 (M Example 510 EC7-METHOXY-1.H-IliDOL-3-YL)METHYLI-4- PIPERIDINYL}PHENYL) -2-METHYLPROP.ANAMIDE: Prepared by Procedure D and Scheme N using 1H-indol-7-yl methyl ether and 2-methyl-N-D3-(4piperidinyl)phenyllpropanamide: ESMS rn/c: 406.3 (MA Example 511 [(7-METHOXY-1-PHENYL-lH-INDOL-3-YL)METHiYL] -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure -D and Scheme N using 7-methoxy-l-phenyl-lHindole and 2-methyl-N- (4piperidinyl)pheny1]propapaude.-ESMS rn/e: 482.0 (M Example 512 N-(3-{l-E(7-CELORO-1-PHiElYL-lH-INDO)L-3-YL)METIIYL)-4- PIPERIDINYL)PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure D and Scheme N using 7-chloro-1-phenyl-1H- ~ino~-and 2-methyl-N-[3-(4piperidinyl)phenyllpropanamide: ESMS rn/e: 488.6 (M Example 513 2-METHYL-N-(3-{l- [(7-NITRO-lH-INDOL-3-YL)METHYL] -4- PIPERIDINYLIPHENYL)PROPA#&M'E: Prepared by Procedure D and Scheme N using 7 -nitro- 1H- indole and 2-methyl-N-[3- WO 03/004027 PCT/US02/21063 371 (4piperidinyl)phenyllpropanamide: ESMS mle: 421.1 (M Example 514 N-(3-{1-[(7-NITRO-H-INDOL-3-YL)METHYL-4- PIPERIDINYL}PHENYL) CYCLOPROPANECARBOXAMIDE: Prepared by Procedure D and Scheme N using 7-nitro-1H-indole and N- [3-(4-piperidinyl)phenyl]cyclopropanecarboxamide:
ESMS
m/e: 419.5 (M Example 515 -(7-NITRO-1H-INflOL-3-YL)METHYL]-4- PIPERIDINYL}PIIENYL)PROPANAMIDE: Prepared by Procedure D and Scheme N using 7-nitro-1H-indole and piperidinyl)phenylpropanamide: ESMS m/e: 407.3 (M 7-(2-FLUOROPHENYL)-1H-INDOLE: Prepared by Procedure .1 and Scheme T using 7-bromo-1H-indole and 2fluorphenylboronic acid: ESMS m/e: 211.9 (M Example 516 N- (2-FLUOROPHENYL) -lH-INDOL-3-YLJHETHYL}-4- PIPERIDINYL)PHENYL-2-METHYLPROPANAMIDE: Prepared by Procedure D and Scheme N. A solution of 2-methyl-N-[3- (4-piperidinyl) phenyl Ipropanamide (23.3 mg, 0.0948 mmol) and 37 wt aqueous formaldehyde (11.4 mg, 0.142 mmol) in 1.00 mL of HOAc:dioxane was added to 7-(2fluorophenyl)-1H-indole (20.0 mg, 0.0948 mmol) and the reaction mixture was stirred for 12 h at room temperature. The resulting mixture was diluted with mL). The aqueous layer was extracted with CH 2 Cl 2 (3 X 10 mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO 4 and concentrated in WO 03/004027 WO 0/00027PCT/UJS02/21063 372 Vacuo. The residue was purified by preparative TLC on silica using 4 of NH 3 0 M in methanol) in
CH
2 C1 2 to give the desired product (56.1 Mg, 100%-) 'H NMR (400 MHz, CDC1 3 6 8.58 1H), 7.73 (dd, 1H, J 2.8, 6. 3 Hz) 7.69 IH), 7.53 (dt, IH, J 7.6 Hz), 7.44 1H, LT 8. 1 Hz) 7. 38 (in, 2H), 7. 32 (s, 1H1), 7.27-7.21 (in, 4H), 7.17 1H, J 7.6 Hz), 6.88 1H, J 7.6 Hz) 3.92 2H) 3.20 1H, J 11.6 Hz), 2.51 (qt, IH, J G. 67 Hz) 2.42 1H) 2.25 (dt, 2H, J 2.2, 11.6 Hz), 1. 89-1.72 (in, 5H) 1. 22 6H, J =7.3 Hz); ESMS nile: 470.1 (M 7-(4-ETHYLPHENYL)-1H-INDOLE: Prepared by Procedure I and Scheme T using 7-brorno-1H-indole and 4ethyiphenylboronic acid: ESMS nile: 222.0 (M 7-(2-NAPHTHYL)-H-INDOLE: Prepared by Procedure I and Scheme T using 7-bromo-1H-indole and 2-naphthylboronic acid: ESMS nile: 244.0 (M H+ 7-(3-CHLjOROPHENYL)-1H-INDOLE: Prepared by Procedure I and Scheme T using 7-bromo-1I1-indole and 3chiorophenylboronic acid: ESMS m/e: 227.9 (M H 6-(2-FLUOROPHENYL)-1H-INDOLE: Prepared by Procedure I and Scheme T using 6-bromo-lH-indcle and 2fluorophenylboronic acid: ESMS nile: 211.9 (M 7-(3-NITROPHENYL)-1H-INDOLE: Prepared by Procedure I and Scheme T using 7-bromo-1R-indole and 3nitrophenylboronic acid: ESMS nile: 238.9 (M WO 03/004027 WO 0/00027PCT/UJS02/21063 373 1- (1H-INDOL-7- YL) PHENYLJETRANONE: Prepared by Procedure I and Scheme T using 7-bromo-11Hindole and 4-acetyiphenyilboronic acid: ESMS rn/a: 235.2 (M
S
6-(2-METHYLPHENYLV1IH-INDOLE: Prepared by Procedure I and Scheme T using 6-bromo-1N-indole and 2methylphenylborolic acid: ESMS m/e: 207.9 (M H) 4 6-(3-CHLOROPHENYL)-1H-INDOLE: Prepared by Procedure I and Scheme T using 6-bromo-1H-indole and 3chiorophenylboronic acid: ESMS rn/a: 227.9 (M H) 4 1- (2H-INDOL-6-YL) PHENYL] ETHIANONE: Prepared by 1s Procedure I and Scheme T using 6-bromo-lH-indole and 4acetyiphenylboronic acid: ESMS rn/e: 235.8 (M H+ 7-(2-METHYLPHENYL)-1H-INDOLE: Prepared by Procedure T and Scheme T using 7-bromo-1H-indole and 2methyiphenylboronic acid: ESMS rn/a: 208 CM 6-(4-ETHYLPHENYL)-lH-flNDOLE: Prepared by Procedure I and Scheme T using 6-bromo-1H-indole and 4ethyiphenylboronic acid: ESMS rn/a: 221.9 (M Example 517 2-METHYL-N!- (2-NAPHTHYL) -1H-T:NDOL-3-YL)METHYL)- 4-PIPERIDINYL) PHENYL] PROPA2NAMIDE: Prepared. by Procedure D and Scheme N using 7-(2--naphthyl)-lH-indole and 2methyl-N- t3- (4-piperidinyl)phenyllpropanamide. ESMS rn/a: 502.2 CM Example 518 WO 03/004027 WO 0/00027PCT/UJS02/21063 374 N- ETHYLPHENYL) -21-INDOL-3- YLJ METHYL}-4-PIPERIDINYL)PHENYLJ -2-METHYLPROPANAMIDE; Prepared by Procedure D arid Scheme N Using 7-(4ethylphenyl 1H- indole and 2-methyl-N- (4piperidinyl)phenyljpropanamide: ESMS m/e: 480.2 (M Example 519 2-METHYL-N- 6- (2-METHYLPHENYL) -IH-INDOL-3- YL] METHYL) -4 -PIPERIDINYL) PHENYL] PROPANAMIDE: Prepared by Procedure D and Scheme N using 6-(2-methylphenyl)-iRindole and 2-methyl-N-[3-(4piperidinyl)phenyljpropanamiLde: 1H- NMR (400 MHz, CDCl 3 8.2 1H) 7.53 4H) 7.41 Cd, IH, J 8.4 Hz) 7.34 2H), 7.27-7.12 (mn, 5H), 6.81 1H-, J 8.4 Hz), 4.09 211), 3.32 Cd, 2H1, J 11.4 Hz) 2.57 (q, 211, J =7.6 Hz), 2.43 Cm, 311), 2.08 3H), 1.98 (mn, 111), 1.75 Cm, 2H1), 1.22 611, J 6.3 Anal. Calcd for C 31
.H
3 5
N
3 0+CHC1 3 iDMF: C, 57.0; H1, 6.09; N, 8.06.
Found: C, 56.5; H1, 5.94; N, 7.76; ESMS m/e: 466.2 (M Example 520 NV-[3- (3-CHLOROPEN'YL) -1H-INDOL-3-YL]METHYL}-4- PIPERIDINYL)PHENYLJ -2-METHYLPROPANAMdIDE: Prepared by Procedure D and Scheme N using 7-(3-chlorophenyl)-1Hindole and 2-methyl-N-[3-C(4piperidinyl)phenyllpropanamide: ESMS m/e: 486.1 CM Example 521 2-METHYL-N-[3-(1-{ (3-NITROPHEN~YL)-1H-IrNDOL-3- YIIMETHYL) -4 -PIPERIDINYL) PHiENYL] PROPANAMIDE: Prepared by Procedure D and Scheme N using 7-(3-nitrophenyl)-1H- WO 03/004027 WO 0/00027PCT/UJS02/21063 375 indole and 2-methyl-N-[3- (4piperidinyl)phenylpropanaide: ESMS m/e: 497.0 CM Example 522 (4-ACETYLPHENYL)-1H-II:fOL-3-YLJMETHYL)-4- PIPERIDINYL) PHEINYL]-2 -METHYLPROPANAMIDE: Prepared by Procedure D and Scheme N using l- [4-(1I-I-indol-7yl) phenyl Iethanone and 2-methyl-Ni- (4piperidinyl)phenyllpropanamide; ESMS m/e; 493.6 (M H) 4 Example 523 N- (4-ETHYLPHENYL) -1H-IND)OL-3-YL]METHYL}-4- PIPERIDINYL) PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure D and Scheme N using 6- (4-ethylphenyl) -lHindole and 2-methyl--E3- (4piperidinyl)phenyllpropanamide: ESMS m/e: 480.1 (M H) 4 Example 524 2-METHYL-V- C2-METHYLPHENYL) -lH-INDOL-3- YL] METHYL)-4 -PIPERIDINYL) PHENYL] PROPANAI4IDE: Prepared by Procedure D and Scheme N using 7-(2-rnethylphenyl)-1Hindole and 2-methyl-N- (4piperidinyl)phenyllpropanamide: ESMS mle: 466.1 CM Example 525 V- 6- (2-FLUOROPHENYL) -lH-INDOL-3-YL]METHYL}-4- PIPERIDINYL) PHENYL] -2-METHYLPROPANAMIDE: Prepared by Procedure D and Scheme N using 6-(2-fluorophenyl)-1Hindole and 2-methyl-N- (4piperidinyl)phenyljpropanamide: ESMS m/e: 470.2 (M 5-(4-METHYLPHENOXY)-1H-INlOLE: Prepared by Procedure J and Scheme U using 5-bromo-lH-indole and p-cresol: ESMS mle: 224.0 (M WO 03/004027 WO 0/00027PCT/UJS02/21063 376 Example 526 E(5-BROMO-l1I-INTJOL-3-YL)I4ETHYL] -4- PIPERIDIYLPEEYL) -2 -METHYLPROPANAMIDE: Prepared by Procedure D and Scheme N using 5-bromo-1H-indole and 2methyl-N- (4-piperidinyl) phenyll propanamide: ESMS mie: 454.0 (M 1- (4-PYRIDINYL) (TRIFLUOROMETHYL) -1H-INDOLE: Prepared by Procedure C and Scheme 0 using 6-(trifluoromethyl)- IH-indole and 4-iodopyridine: ESMS m/e; 262.9 (M Example 527 2-METHYL-N- E3- [5-(4-METHYLPHENOXY) -1H-INDOL-3- 1s YL]METHYL-4-PIPERIDINYL)PENqYLJ PROPANAMIDE: Prepared by Procedure D and Scheme N using 5-(4-methylphenoxy)- IH-indole and 2-methyl-N-[3-(4 7 piperidinyl)pheny.Jpropanamide: ESMS m/e: 481.9 (M 1-(4-METHYLPHENYL)-lH-INDOLE% Prepared by Procedure C and Scheme 0 using 1H-indole and 1-iodo-4-methylbenzene: ESMS m/e: 208.0 CM l-(3-METHYLPHENYL)-lH-INDOLE: Prepared by Procedure C and Scheme 0 using 1H-indole and 1-iodo-3-methylbenzene: ESMS ni/e: 208.0 (M 1- (TRIFLUOROMETHYL) PHENYIJ-11- INDOLE: Prepared by Procedure C and Scheme 0 using 1H-indole and 1-iodo-3- (trifluoromethyl)benzene: ESMS m/e: 262.0 (M WO 03/004027 WO 0/00027PCT/UJS02/21063 377 1-(4-METHOXYPHEN'YL)-1H- fIDOLE: Prepared by Procedure C and Scheme 0 using 1H-indole and 1-iodo-4methoxybenzele: ESMS m/e: 224.0 (M +i 1-(2-METHOXYPHENYL)-12-INDOLE: Prepared by Procedure C and Scheme 0 using 1H--indole and I-iodo-2methoxybenzene: ESMS m/e: 224.0 CM H+ 1-(3-METHOXYPHEtrLL)-1H-INDOLE: Prepared by Procedure C and Scheme 0 using 1H-indole and I-iodo-3methoxybenzene: ESMS m/e: 224.0 (M +i 1-(2-METHYLPHENYL)-1H-INDOLE: Prepared by Procedure C and Scheme 0 using 1H-indole and 1-iodo-2-methylbenzene: ESMS m/e: 208.0 (M H) 4 6-FLU01R0-1-PHENYL-1H-IND0LE: Prepared by Procedure C and Scheme 0 using 6-f luoro-lH-indole and iodobenzene: ESMS m/e: 212.0 (M 6-CHLORO-1-PHENYL-lH-INDOLE: 'Prepared by Procedure C and Scheme 0 using 6-chloro-lH-indole and iodobenzene: ESMS ni/e: 228.0 (Mv 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 6-(2-FLUORQPHENYL)-H-INDfOLE: Prepared by Procedure I and Scheme T using 6-bromo-1H-indole and 2fluorophenylboronic acid: ESMS m/e: 211.9 (M H) 4 WO 03/004027 WO 03/04027PCT/US02/21063 378 Example 528 2-METHYL-Nf-{3-[l-(7-OXO-7-PHENYLHEPTYL)-4- PIPERIDINYL] PH-ENYL) PR0P1ANAMIDE: Prepared by Procedure K and Scheme BI using 7-chloro-l-phenyl-l-heptaloe and 2methyl-N-[3- (4-piperidinyl)phenyll propanamide: ESMS m/e: 435.1 (M H+ Example 529 2-METHYL-N-{3- [1-(6-OXO-6-PHENYLIEXYL) -4- PIPERIDINYL]PHENYL}PROPANAMIDE: Prepared by Procedure K and Scheme B1 using 6-chloro-1-phenyl-l-hexanone and 2methyl-NV-[3- (4-piperidinyl)phelyl] propanamide: Anal.
Calcd for C27H36N202+0.TCHC1 2 C, 75.3; H, 8.39; N, 6.46.
Found: C, 75.4; H, 7.89; N, 6.18; ESMS m/e: 421.1 CM 1H)'.
Example 530 2-METHYL-N-{3-El- (5-OXO-5-PHENYLPENTYL) -4- PIPERIDINYL]PHENYL}PROPANMIDE; Prepared by Procedure K and Scheme Bl using 5-chloro-l-phenyl-1-pentanone and 2methyl-.N- (4-piperidinyl) phenyl] propanamnide: ESMS m/e: 407.1 (M H+ Example 531 E4-(4-METHOXYPHENYL)-4-OXCOBUTYL] -4- PIPERIDINYL)PHENYL)PROPANAMIDE: Prepared by Procedure K and Scheme 3l using .4-chloro-1- (4-methoxyphenyl) -1butanone and N- (4-piperidinyl)phenyl] propanamide: ESMS rn/e: 409.2 (M H) Example 532 (4-CHLOROPHENYL) -4-OXOBUTYL] -4- PIPERIDINYL}PHENYL)PROPANAMIDE: Prepared by Procedure K and Scheme El using 4-chloro-l- (4-chlorophenyl) -1- WO 03/004027 WO 0/00027PCT/UJS02/21063 379 butanone and piperidinyl)pheflyllpropanamide: ESMS 413.1 (M Example 533 [4-(4-BROMOPHENYL)-4-OXOBUTYLJ-4- PIPERIDINYL)PHENYL)PROPANAMIDE: Prepared by Procedure K and Scheme Bi using 1-(4--bromopheflyl)-4-chloro-lbutanone and N- (4-piperidinyl) phenyl] propanamide: ESMS m/le: 457.1 (M Example 534 E4- (4-TERT-BUTYLPHENYL) -4-OXOBUTYL] -4- PIPERIDINYL)PHENYL)PROPANAMIDE: Prepared by Procedure K and Scheme B1 using 1- (4-tert-butyiphenyl) -4-chloro-1butanone and N- (4-piperidinyl)phenyllpropanamide: ESMS rn/e: 435.2 (M Example 535 (4-FLUJOROPHENYL) -4-OXOBUTYL!-4- PIPERIDINYL}PHENYL)PROPANAMIDE: Prepared by Procedure K and Scheme B1 using 4-chloro-l-(4-fluorophenyl)-1butanone and N- (4-piperidinyl)phenyllpropanamide: ESMS m/e: 397.2 (M W Example 536 l- [4-OXO-4- (4-PHENOXYPHENYL)BUTYL] -4- PIPERIDINYLPENYL)PROPANAMIDE: Prepared by Procedure K and Scheme B1 using 4-chloro-l- (4-phenoxyphenyl) -1butanone and N- (4-piperidinyl)phenyllpropanamide: ESMS m/e: 471.2 (M WO 03/004027 WO 0/00027PCT/UJS02/21063 380 Example 537 1J-(3-{1I-(4-ISOPROPYLPHENYL) -4-OXOBUTYL] -4- PIPERIDINYL}PHENYL) CYCLOPROPANECARBOXAMIDE: Prepared by Procedure K. and Scheme BI using 4-chloro-l-(4isopropylphenyl) -butanone and N- (4piperidinyl) phenylJ cyclopropanecarboxamide: ESMS rn/e: 433.2 (M H) 4 Example 538 N-(3-{1-[4-(4-METHOXYPHENYL)-4-OXOBUTYL] -4- PIPERIDIN~YL)PHENYL) CYCLOPROPANECARBOXAHIDE: Prepared by Procedure K and Scheme B1 using 4-chloro-l-(4methoxyphenyl) -1-butanone and N- (4piperidinyl) phenyll cyclopropanecarboxamide: ESMS rn/a: 421.2 (M Example 539 [4-OXO-4- (4-PHENOXYPHENYL)BUTYL] -4- PIPERIDINYLPHEN~YL) CYCLOPROPANECARBOXAMIDE: Prepared by Procedure K and Scheme Bi using 4-cliloro-l-(4phenoxyphenyl) -1-butanone and N- (4piperidinyl) phenyl] cyclopropanecarboxamide: ESMS rn/e: 48:3.2 (M Example 540 (4-ISOPROPYLPHENYL) -4-OXOBUJTYL) -4- PIPERIDINYL}PHENYL)PROPANAMIDE: Prepared by Procedure K and Scheme B1 using 4-chloro-1- (4-isopropylphenyl) -1butanone and N- (4-piperidinyl)phenyllpropanamide: ESMS rn/e: 421.3 (M WO 03/004027 WO 0/00027PCT/UJS02/21063 381 Example 541 E4- (4-T-ERT-BUTYLPHENYL) -4-OXOBUTYL] -4- PIPERIDINYL}PHENYL) CYCLOPROPANECARBOXAMIDE: Prepared by Procedure K and Scheme B1 using 1-(4-tert-butylphenyl)- 4-chloro-1-hutanole and N- (4piperidinyl)phenylj cyclopropanecarboxamide: ESMS m/e: 447.2 (M Example 542 f4-(4-METHYLPHENYL) -4-OXOBUTYL] -4- PIPERIDINYL}PEENYL)PROPANAMIDE; Prepared by Procedure K and Scheme B1 using 4-chloro-1-(4-methylphenyl)-1butanone and N- (4-piperidinyl)phenyll propanamide: ESMS m/le: 393.2 (M 11)+.
Example 543 E4-(3,4-DIMETHYLPHENYL) -4-OXOBUTYL] -4- PIPERIDI.NYL)PHENYL)PROPANAMIDE: Prepared by Procedure K and Scheme Bi using 4-chl-oro-l-(3,4-dimethylphelyl)butanone and N- (4-piperidinyl)phenyllpropanamide: RSMS M/e: 407.2 (M Example 544 (4-BROMOPHiENYL) -4-OXOBTJTYL] -4- PIPERIDINYL}PHENYL) CYCLOPIROPANECAflBOXAMIDE: Prepared by Procedure K and Scheme BI using l-C(4-bromophenyl) -4chloro-l-butanone and V[3(4 piperidinyl) phenyil cyclopropanecarboxamide:- ESMS m/e: 469.1 (M Example 545 [5-(4-FLUOROPHENYL)-5-OXOPENTYL]-4- PIPERIDINYL}PENYL)PROPANAMIDE: Prepared by Procedure K and Scheme B1 using 5-chloro-l- (4-f luorophenyl) -1- WO 03/004027 WO 0/00027PCT/UJS02/21063 382 peritanone and piperidiny.)pheny].]propanamide: ESMS rn/e: 411.2 (M Example 546 (3,4-DIMETHYLPHENYL) -4-OXOBUTYLI -4- P IPERIDINYL )PHENYL) CYCLOPROPANECARBOXAMIDE- Prepared by Procedure K and Scheme BI using 4-chloro-J.-(3,4dimethyiphenyl) -1-butanone and N- t3- (4piperidinyl) phenyl) cyclopropanecarboxamide: ESMS m/e: 419.2 (M Example 547 (4-METHYLPHENYL) -4-OXOBUTYL] -4- PIPERIDINYL}PHENYL) CYCLOPROPANECARBOXAMIDE: Prepared by Procedure K and Scheme D1 using 4-chloro-1- (4methyiphenyl) -1-butanone and N 3 4 piperidinyl) phenyl) cyclopropanecarboxamide: ESMS m/e: 405.2 (M Example 548 (4-FLUOROPHENYL) -4-OXOBUTYL] -4- PIPERIDINYL}PHENYL) CYCLOPROPANECARBOXAMIDE: Prepared by Procedure K and S cheme Bi using 4-chloro-l-(4fluorophenyl) -l-butanone and N- (4piperidinyl)phenyl) cyclopropanecarboxamide: ESMS m/e: 409.2 (M Example 549 (3-FLUOROP-HENYL) -5-OXOPENTYL] -4- PIPERIDINYL}PHENYL) CYCLOPROPANECARBOXAMIDE: Prepared by Procedure K and Scheme 131 using 5-chloro-l-(3- 'luorophenyl) -l-pentanone and N- (4- WO 03/004027 WO 0/00027PCT/UJS02/21063 383 piperidinyl) phenylJ cyclopropanecarboxamide: ESMS M/e: 423.2 (M Example 550 NV- 3- (1-{5-OXO-5- (TRIFLUOROMETHYL)PHENYL]PENTYL}-4- PIPERIDINYL) PHENYL] PROPANAI(IDE: Prepared by Procedure K and Scheme BI using 5-chloro-l- [4- (trifluoromethyl)phenyl] -1-pentanone and N- (4piperidinyl)phenylpropaamfide: ESMS m/e: 461.2 (M Example 551 (4-FLJOROPHENYL) -5-OXOPENTYL] -4- PIPERIDINYL}PHENYL) CYCLOPROPANECARDOXAMIDE: Prepared by Procedure K and Scheme Bl using 5-chloro-l-(4fluorcphenyl)-1-pentanone and N[-4 piperidinyl)phenyllcyclopropanecarboxamide: ESMS m/e: 423.2 (M Example 552 (3-NITROPHENYL) -5-OXOPENTYL] -4- PIPERIDINYL}PHENYL)PROPANAMIDE: Prepared by Procedure K and Scheme Bl using 5-chloro-l- (3-nitrophenyl) -1pentanone and N- (4-piperidinyl) phenyl] propanamide: ESMS m/e: 438.2 (M H) Example 553 (3-NITROPHENYL) -5-OXOPENTYL] -4- PIPERIDINYL}PHENYL) CYCLOPROPANECARBOXAMIDE: Prepared by Procedure K and Scheme El using 5-chloro-1-(3nitrophenyl) -1-pentanone and N- (4piperidinyl) phenyli1cyclopropanecarboxamide: ESMS In/e: 4 50. 2 (M H WO 03/004027 WO 0/00027PCT/UJS02/21063 384 Example 554 C2-FLUOROPHENYL) -5-OXOPENTYL] -4- P:EpERIDINLPHENYlL)PROPANAMIDE: Prepared by Procedure K and Scheme BI using 5-chloro-1- (2-f luorophenyl) -1pentanone and N- (4-piperidinyl)phenyl) propanamide: ESMS rn/c: 411.2 (M H).
Example 555 (3-FLUOROPHEN~YL) -5-OXOPENTYI-4- PIPERIDINYL}PIIENYL)PROPANAMIDE: Prepared by Procedure K and Scheme Bi1 using S-cbioro-l- (3-f luorophenyl) -1pentanone and N-[13- (4-piperidinyl)phenyll propanamide: ESMS ni/e: 411.2 (M Example 556 ES- (4-NITROPHENYL) -5-OXOPEN~TYL] -4- PIPERIDINYL}PHENYL)PROPMNAMIDE: Prepared by Procedure K and Scheme B1 using 5-chloro-l-(4-nitrophenyl)-1pentanone and N- (4-piperidinyl)pheny-]propanamide: ESYS rn/c: 438.1 (M Example 557 (5-(4-NITROPH-ENYL)-5-OXOPENTYL]-4- PIPERIDINYL)PHENYL) CYCLOPROPANECARBOXAMIDE: Prepared by Procedure K and Scheme 131 using 5-chloro-1- (4nitrophenyl) -1-pentanone and N- [4piperidinyl) phenyl) cyclopropanecarboxanide: ESMS m/e: 450.1 (M Example 558 ES- (4-CELOROPHENYL) -5-OXOPENTYL] -4- PIPERIDINYL} PHENYL) CYCLOPROPANECARBOXAMIDE: Prepared by Procedure K and Scheme B1 using 5-chloro-1-C4- WO 03/004027 WO 0/00027PCT/UJS02/21063 38BS chiorophenyl) -1-pentanone and NV-[13-14piperidinyl)phelyl) cyclopropanecarboxamide: ESMS m/e: 439.1 (M Example 559 NL- [3 5 -OXO- 5- [2 (TRIFLUOROMETHYL) PKENYL] PENTYL 4 PIPERIDI1NYL)PHENYLJPROPANAMIDE: Prepared by Procedure K and Scheme B1 using 5-chloro-1- [2- (trifluoromethyl) phenyl) -1-pentanone and N-[13- (4piperidinyl)phenyllpropanamide: ESMS zn/e: 461.2 CM H)4.
Example 560 q- (1-{5-OXO-5- (TRIFLUOROMETHYL)PHENYLIPENTYL}-4- PIPERIDIN'YL) PHENYL] CYCLOPROPANECARBOXAMIDE- Prepared by Procedure K and Scheme B1 using 5-chloro-.1-[2- (trifluoromethyl) phenyl] -1-p,-entanone and N- (4piperidinyl)phenyl] cyclopropanecarboxamide: ESMS m/e: 473.2 (M Example 561 [5-(4-CI-LOROPENYL)--OXOPENTYL]-4- PIPERIDINYL}PHENYL)PROPANAMIDE: Prepared by Procedure K and Scheme BI using 5-chlcro-1- (4-chicrophenyl) -1pentanone and N- (4-piperidinyl)phenyllpropanamide: ESMS mn/e: 427.1 CM Example 562 (3-CHLOROPHENYL) -5-OXOPENTYLJ PIPERIDINYL}PHENYL) PROPANAMIDE: .Prepared by Procedure K and Scheme B1 using 5-chloro-1-(3-chlorophenyl)-1pentanone and N- (4-piperidinyl) phenyllpropanamide: ESMS m/e: 427.1 CM H) 4 WO 03/004027 WO 0/00027PCT/UJS02/21063 386 Example 563 N- [5-(2-FTJUDROPHENYL) -5-OXOPENTYL] -4- PIPERIDINYL}PHENYL) CYCLOPROPANECARBOXAMIDE: Prepared by Procedure K and Scheme Bi using 5-chloro-l-C2fluorophenyl) -1-pentanone and N- (4piperidiny-) phenyl) cyclopropanecarboxatide: ESMS m/e: 423.1 (M +i Example 564 iV(-lE5(-EOOHML--XPNYI4 PIPERIDINYL}PHENYL) CYCLOPROPANECARBOXAMIDE: Prepared by Procedure K and Scheme Bi1 using 5-chloro-1-(3chiorophenyl) -1-pentanone and N- (4piperidinyl) phenyll cyclopropanecarboxamide: ESMS mile: 439.1 (M Example 565 N- (1-{5-OXO-5- (TRIFLUOROMETHYL)PHENYLI PENTYL}-4- PIPER IDINYL) PHENYL] CYCLOPROPANECARBOXAMIDE: Prepared by Procedure K and Scheme B1 using 5-chloro-1-[4- (trifluoromethy1)pheyl- pentanone and N- (4piperidinyl) phenyll cyclopropanecarboxamide: ESMS nile: 473.2 (M H+ Example 566 (2-CELOROPHENYL) -5-OXOPENTYLJ -4- PIPERIDINYL}PHENYL)PRDPANAMIDE: Prepared by Procedure K and Scheme B1 using 5-chloro-1- (2-chlorophenyl) -1pentanone and N- (4-piperidinyl) phenylipropanamide: ESMS M/e: 427.1 (M H) 4 WO 03/004027 WO 0/00027PCT/UJS02/21063 387 Example 567 ES- (2-CHiLOROPHENYL) -5-OXOPENTYLJ -4- PIPERIDINYL}PHENYL) CYCLOPROPANECARBOXAMIDE: Prepared by Procedure K and Scheme B1 using 5-chloro-1- (2chiorophenyl) -1-pentanone and NV- (4piperidinyl)phenyl] cyclopropanecarboxamide: ESMS m/e: 439.1 (M Example 568 N- (1-(5-OXO-5- (TRIFLUOROMETHYL)PHENYLJPENTYL}-4- PIPERIDINYL) PHENYL) CYCLOPROPANECARBOX.AMIDE: Prepared by Procedure K and Scheme Bi using 5-chlor-o-1- [3- (trifluoromethy1)pheny1] -1-pentanone and N- (4piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m/e: is 473.2 (M H+ Example 569 NV-(3-(-[4-(3,4-DIMETHYLPHENYL)4-XOBJTYLJ -4- PIPERIDINYL}PHENYL) -N,2-DIMETHYLPROPANAMIDE: Prepared by Procedure T and Scheme AD using dimethyiphenyl) -4-oxobutyl] -4-piperidinyllphenyl) -2methyipropanamide and methyl iodide: 'H NMR (400 MHz, CDC1 3 5 7.76 1H), 7.72 Cdd, 1H, J 7.7 Hz) 7.33 114, J 8.8 Hz), 7.22 114, J =7.8 Hz), 7.18 1H-, J =8.8 Hz), 7.01 Cm, 214), 3.24 3H4), 3.10 IH, J =10.6 Hz), 3.00 1H-, J 7.6 Hz), 2.49 (mn, 414), 2.33 614), 2.11 (in, 3H), 1.99 (in, 114), 1.79 (in, 414), 1.26 t, 2H, J 7.6 Hz), 1.02 6H,. J 7.6 Hz); ESMS m/e: 435.2 (M H+ Example 570 2-METHYL-N-{3- El- (l-METHYL-4-OXO-4-PEI'YLBJTYL) -4- PIPERID)INYLPHENYLPROPANAMIDE: Prepared by Procedure K WO 03/004027 WO 0/00027PCT/UJS02/21063 388 and scheme B1 using 4- chloro-1-phenl].1 pentalofe and 2-methyl-NC[ 3 piperidinyl)pheflylipropanamide- ESMS m/e: 407.2 (M Example 571 N- (TRIFLUOROMETHYL)PHENYL]PENTYL}-4- PIPERIDINYL) PHENYL] PROPMNAMIDE;. Prepared by Procedure K and Scheme BI using 5-chloro-l-E3- (tritluoromethyl)phell-1-pentanone and N- (4piperidinyl)phenyl]Propanamide: ESMS 461.2 (M 3- (5-CHLOROPENTANOYL) (3,4-IFLOROPHENYL) -1,3- OXAZOLIDIN-2-ONE: Prepared by Procedure AF and Scheme H using 4- (3,4-difluorophenyl) -1,3-cxazolidin-2-ofle and -chloropentanoyl chloride.
3- (5-CHLOROPENTYL) (3,4-DIFLUJOROPHiENYL) -1,3- OXAZOLIDIN-2-ONE: Prepared by Procedure G and Scheme C1 using 4 -dif luorophel) 1, 3 -oxazo1Jdin-2-one and 1bromo-S-chloropeltane.
Example 572 N- (3,4-DIFLUIOOPHENYL) -2-OXO-1,3- OXAZOLIDIN-3-YL] -5-OXOPENTYL}-4-PIPERIDINYL) PHENYL] -2- METHYLPROPANAMIDE; 'Prepared by Procedure G and Scheme BI using (4R)-3-(5-chloropentancyl)-4-(3,4dif luorophenyl) 1, 3-oxazolidin-2 -one and 2-methyl-N- [3- (4-piperidinyl)phenyllpropanamide: ESMS m/e: 528.2 (M Example 573 (4R) (3,4-DIFLTOROPHENYL) [3- (ISOBtTTYRYLAMINO) PHENYL] -1-PIPERIDINYL}PROPYL) -2 -OXO- WO 03/004027 WO 0/00027PCT/UJS02/21063 389 1,3-OXAZOLIDINE-3- CARBOXAMIDE: Prepared by Procedure AF and Scheme H using 4-nitrophenyl (4R)-4- (3,4-difluorophenyl) -2-oxo-1,3-oxazolidirle-3-carboxylate and [1-(3-aminopropyl) -4-piperidinyllphenyll-2methyipropanamide: 'H NMR (400 MHz, CDC1 3 6 8.08 1H, J- 5.5 Hz), 7.45 2H), 7.38 1H1, J 8.6 Hz), 7.24-7.12 (in, 3H), 7.06 Cm, 1H1), 6.97 1H, J =8.6 Hz), 5.40 (dd, 1H, J =3.9,8.8 Hz), 4.71 1H1, J =8.8 Hz), 4.23 (dd, 1H, J 9.1 Hz) 3.32 (qt, 2H, J 6.1 Hz), 2.99 2H, JT 11. 0 Hz) 2. 49 (qt, 2H, J Hz), 2.41 Ct, 2H, J 0 Hz) 1. 99 (in, 2H) 1. 82- 1.68 6H), 1.23 6H, J 7.3 Hz); ESMS m/e: 529.1 (M (4S) -3-(5-CI.LOROPENTYL)-4-(3,4-DIFLUOROPIENYL)-1,3- OXAZOLIDIN-2-ONE: Prepared by Procedure G and Scheme CI using (3,4-difluorophenyl) -1,3-oxazolidin-2-one and Example 574 NU- 3- (115- C48) (3,4-DIFLUOROPHENYL) -2-OXO-1,3- OXAZOLIDIN-3-YL] PENTYL}-4-PIPERIDIIYL) PHENYLJ -2- METHYLPROPANAMIDE: .Prepared by Procedure G and Scheme B;1 using (4S) (5-chioropentyl) (3,4-difluorophenyl) 1,3-oxazolidin-2-one and 2 -methyl [3 (4 piperidinyl)phenyllpropanamide: 'H NMR (400 MHz, CDC1 3 7.48 Cs, 1H1), 7.32 Cd, IH, J =8.6 Hz), 7.26-7.21 Cm, 2H), 7.20-7.12 Cm, 2H), 7.06 C,1H1), 6.97 Cd, 1H, J 6.96 Hz), 4.76 (dd, 1H, J 8.3 Hz), 4.62 1H, LT 9.0 Hz), 4.06 Cdd, 1H, J 8.7 Hz), 3.46 Cm, 1H), 3 .0 Cd, 2H, J 9. 0 Hz) 2. 77 Cq, IH, J 6. 8 Hz) 2.5 0 Cq, 2H1, J 6. 8 Hz) 2. 31 2H1, J 6. 8 Hz) 2. 01 Cm, 4H1), 1.81 Cm, 411), 1.48 Cm, 4H1), 1.26 Cd, 6H1, J 7.3 WO 03/004027 WO 0/00027PCT/UJS02/21063 Hz); Anal. Calcd for 30C 2 8
H
3 7
F
2 N0+HCl+0 .25CHCl 3 C, 60.6; 6.65; N, 7.25. Found: C, 60.7; H, 6.91; N, 7.05; ESMS M/e: 514.2 (M HI)+.
Example 575 N- (3,4-DIFLUOROPHENYL) -2-oxo-1,3- OXAZOLIDIN-3-YL] -5-OXOPENTYL-4-PIPERIDINYL) PHENYL] -2- METHYLPROPMXANIDE: Prepared by Procedure G and Scheme Bl using (5-chioropentanoyl) (3,4di fluorophenyl) 3 -oxazolidin-2 -onle and 2-methyl-N- £3- (4-piperidinyl)phelyllpropalamide: ESMS ni/e: 528.1 (M Example 576 (4S) 4- 4- DIFLOROPHENYL) [3 (ISOBUTYRYLAMINO) PHENYI-1-PIPERIDINYL PROPYL) -2-OXO- 1,3-OXAZOLIDINE-3-CARBOXAMIDE: Prepared by Procedure AF and Scheme H using 4-nitrophenyl (4S) (3,4difluorophenyl) -2-oxo-1,3-oxazolidine-3-oarboxylate and El- (3-aminopropyl)-4-piperidinyllphenyl}-2methyipropanamide: ESMS rn/e: 529.1 (M Example 577 (4S) (ISOBUTYRYLAMITNO) PHENYL] -1- PIPERIDINYL}PROPYL)-2-OXO-4- (3,4,5-TRIFLUOROPHENYL) -1,3- OXAZOLI DINTE -3 -CARBOXAMIDE: tPrepared by Procedure AF and Scheme H using 4-nitrophenyl (4S)-(34 difluorophenyl) -2-oxo-l, 3-oxazolidine-3-carboxylate and [1-(3-aminopropyl) -4-piperidinyl] phenyl.}-2methylpropanamide: ESMS ni/e: 547.1 (M Example 578 (4S) (3,5-DIFLUOROPHENYL) [3- (ISOBTJTYRYLAMINO) PIENYL] -I-PIPERIDINYL}PROPYL) -2-O)XO- WO 03/004027 WO 0/00027PCT/UJS02/21063 391 1,3-OXAZOLIDINE-3- CARBOXAM4IDE: Prepared by Procedure AF and Scheme H using 4-nitrophenyl (4S)-4- (3,4-difluorophenyl) -2-oxo-1,3-oxazolidine-3-carboxylate and [1-(3-arninopropyl) -4-piperidinyllpheny-}-2methyipropanamide: ESMS m/e: 529.2 (M Example 579 V- (PHENYLSULFANYL)PROPYL] -4- PIPERIDINYL)PHENYL)PROPANAMIDE: Prepared by Procedure G and Scheme B1 using [(3-chloropropyl) sultanyl] benzene and T- (4-piperidinyl)phenyllpropananide: ESMS rn/e: 382.9 (M +4 Example 580 (PHENYLSULF.AIYL)PROPYL] -4- PIPERIDINYLPHENYtL) CYCLOPROP.ANECARBOXAMIDE: Prepared by Procedure G and Scheme BI using chioropropyl) sulfanyljbenzene and N- (4piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m/e;.
3 95. 1 (M H Example 581 2-METHYL-N- (PHENYLSULFANYL)PROPYL] -4- PIPERIDINYL}PHENYL)PROPANAMdIDE: Prepared by Procedure G and Scheme B1 using (3-chloropropyl) sulfanyl] benzene and 2-methyl-N- (4-piperidinyl)phenyllpropanamide: 1
H
NMR (400 MHz, CDC1 3 5 7.63 1H), 7.48 1H), 7.33 (mn, 3H), 7.27 2H, J 7.5 Hz), 7.20 Ct, 1K, J =7.9 Hz), 7.15 (tt, IH, J 7.2, 1.4 Hz) 6.95. 1K, J 7.6 Hz), 2.97 4H1, J =7.3 Hz), 2.46 (in, 4H), 1.99 Cdt, 2H, J 11.4, 3.0 Hz), 1.84 (qt, 2H, J =7.3 Hz), 1.77 (mn, 4H), 1.21 6H, J 6.8 Hz); ESMS mle: 396.8 (M WO 03/004027 WO 0/00027PCT/UJS02/21063 392 Example 582 N- (PHENYL 1 SULFAMqYL)HEXYLJ -4- PI:PERIDINYL] PHENYL) CYCLOPROPANECARBOXAMIDE: Prepared by Procedure G and Scheme B1 using chiorohexyl) sulfanyl] benzene and N- (4piperidinyl)phenyl) cyclopropanecarboxamide: ESMS m/e: 437.4 (M Example 583 (PHENYLSULFANYL)BUTYL] -4- PIPERIDINYL)PHENYL)PROPANAMIDE: Prepared by Procedure G and Sche me B1 using [(4-chlorobutyl)sulfanyl]benzene and N- (4-piperidinyl)phenyllpropanamide: ESMS mle: 396.8 (M H4)4 Example 584 (PHENYLjSULFANYL)BUTYLJ -4- PIPERIDINYL)PHENqYL) CYCLOPROPANECARBOXAMIDE: Prepared by Procedure G and Scheme B1 using chlorobutyl)sultanyl]benzene and NV- (4piperidinyl) phenyl] cyclopropanecarboxamide: ESMS m/e: 409.5 (M H+ Example 585 2-METHIYL-N- (PHENYLSULFANYL)BUTYL] -4- PIPERIDINYL)PHENYL)PROPANMIDE: Prepared by Procedure G and Scheme B1 using (4-chlorobutyl) sulf anyll benzene and 2-methyl-N- (4-piperidinyl)phenyl] propanamide: ESMS m/e: 410.6 (M Example 586 2-METHYL-N-(3-(1- S- (PHENYLSULFANYL)PENTYL) -4- PIPERIDINTYL}PHEN1YL)PROPANAMIDE: Prepared by Procedure G WO 03/004027 WO 0/00027PCT/UJS02/21063 393 and scheme B1 using (5 chloropenty.) sulfanyllbenzene and 2-methyl-N- (4piperidinyl)phenyljpropanamide: ESMS mle: 425.1 (M Example 587 [5-(PHENYLSULFANYL)PENTYL] -4- PIPERIDINYL)PHENYL) CYCLOPROPANECARBOXAMIDE:. Prepared by Procedure G and Scheme BI using chloropentyl) suit anyl) benzene and NV- (4piperidinyl) phenyl] cyclopropanecarboxamide: ESMS rn/ez 423.1 CM HI).
CHEJOROHEXYL) STLFANYLJ BENZENE: Prepared by Procedure R and Scheme Z using benzenetbioi and 1-bromo-6chiorohexane.
(4-CHLOROBUTYL) SULFANYLJ BENZENE: Prepared by Procedure R and Scheme Z using benzenethiol and 1-bromo-4chiorobutane.
Example 588 (PH-ENYL8ULFANYL)HEXYLI -4- PIPERIDINYLIPHENYL)PROPMTAMIDE: Prepared by Procedure G and Scheme B1 using [(6-chlorohexyl)sulfanyllbenzene and N- (4-piperidinyl)jphenyllpropanamide: ESMS rn/c: 425.4 (M SULFANYLJ BENZENE: Prepared by Procedure P. and Scheme Z using benzenethiol and 1-bromo- [(3-CHLOROPROPYL) SULFANYLI BENZENE: Prepared by Procedure R and Scheme Z using benzenethiol and 1-bromo- WO 03/004027 WO 0/00027PCT/UJS02/21063 394 3-chloropropane: 'H NMR (400 MHz, CDC13) 65 7.37- 7. 34 Cm, 211) 7. 3 2-7. 26 (in, 211), 7 .19 (tt, 1H, J 1. 4, 7. 3 Hz), 3. 67 211, J 6. 6 Hz) 3. 08 t, 2H1, J 6 Hz), 2.06 (qt, 21-1, J =6.6 Hiz).
Example 589 (PHENYISTJLFMYL)PE1NTYL1 -4- PIPERIDINYL)PHENYL) PROPANAKIDE; Prepared by Procedure G and Scheme B1 using and N-[13- (4-piperidinyl)phenylpropaamide: ESMS m/e:.
411.1 (M 3-CHLOROPRQPYL 4-FLUOROPHENYL SULFIDE: Prepared by Procedure R and Scheme Z using 4-f luorobenzenethiol and 1 -brano- 3- chioropropane.
1-BROND-2 (3-CHLOROPROPYL) SULFANYLJ BENZENE. Prepared by Procedure R and Scheme Z using 2-bromobenzenethiol and 1-bromo-3 -chicropropane.
3-CHLOROPROPYL 4-FLUOROPHENqYL SULFOXIDE: Prepared by Procedure S and Scheme AA using 3-chloropropyl 4fluorophenyl sulfide and 1 eq m-CPBA: 1H NMR (400 MHz, CDC1,) '5 7.65-7.62 Cm, 2H1), 7.28-7.21 Cm, 211), 3.65 (mn, 211), 2.94 (in, 211), 2.28 Cm, 1H1), 2.06 111); ESMS-m/e: 220.9 (M H1)+.
3-CHLOROPROPYL 3-FLUOROPHENYL SULFIDE; Prepared by Procedure R and Scheme Z using 3-fluorobenzenethiol and 1-bromo-3-chloropropane.
3-CHLORQPROPYL 2-FLUOROPHENYL SULFIDE: Prepared by Procedure R and Scheme Z using 2-f luorobenzenethiol and 1 -brorno- 3-chioropropane.
WO 03/004027 WO 0/00027PCT/UJS02/21063 395 1-BROMO-2- E(3-CHLOROPROPYL) SUL~FINYL] BENZENE: Prepared by Procedure S and Scheme A.A using 1-bromo-2-t (3chloropropyl)sulfanylbelzee and 1 eq m-CPBA: ESMS nm/e: 282.8 (M 1-CHLORO-2 -CHLOROPROPYL) SULFANYL] BENZENE: Prepared by Procedure R and Scheme Z using 2-chlorcbenzenethiol and 1-bromo-3-chlorapropane.
1-CHLORO-3 -CHLOROPROPYL) SULFANYL] BENZENE: Prepared by Procedure R and Scheme Z using 3-chlorobenzenethiol and 1-bromo-3-chloropropane.
1-CHLORO-4-[(3-CHLOROPROPYL) SULFANYLJ BENZENE: Prepared by Procedure R and Scheme Z using 4-chlorobenzenethiol and 1-bromo--3-chloropropane.
1-BROMO-3- -CHLOROPROPYL) SULFANYL) BENZENE: Prepared by Procedure R and Scheme Z using 3-bromobenzenethiol and 1-bromo-3-chloropropane.
1-BROMO-4- [(3-CHLOROPROPYL) SULFANYL1BENZEN!E: Prepared by Procedure R and Scheme Z using 4-bromobenzenethiol 2S and 1-bromo-3-chJ-oropropane.
3-CHLOROPROPYL 3,4-DIMETHYLPHENYL SULFIDE: Prepared by Procedure R and Scheme Z using 3, 4-dime thylbenzenethio 1 and 1-bromo-3-chloropropane.
Example 590 N- [(4-FLOROPHEN~YL) SULFINYtL]PROPYL)-4- PIPERIDINYL)PEENYL] -2-METHYLPROPANAMIDE: Prepared by Procedure G and Scheme B1 using 3-chioropropyl 4- WO 03/004027 WO 0/00027PCT/UJS02/21063 396 fiuoropheny. suif oxide and 2 -methyl 3- (4 piperidinyl)phenyllpropanamide: 'H NMR (400 MHz, CDC1 3 7. 64 Cm, 2H) 7.53 1H) 7.24 SH) 6. 94 Cd, 1H, J 7.7 Hz), 2.89 (in, 2.45 4H ),1.99 3H), 1. 77 5H) 1. 24 6H, J 8 Hz); Anal. Calcd f or
C
2 4
H
3
,FN
2 0 2 S+0. 6EtOAC: C, 65.5; H, 7.45; N, 5.79.
Found- C, 65.4; H, 7.30; N, 5.73; ESMS mle: 431.1 (M H) Example 591 N- C1-{3- [(2-BROMOPHENYL) SULFINYL) PROPYL) -4- PIPERIDflNYL) PHENYL] -2-METHYLPROPANAMIDE: Prepared by Procedure G and Scheme BI using 1-bromo-2-[C3chioropropyl) sulfinyllbenzene and 2-methyl-N- (4piperidinyl~pheriy11propanamide: Anal. Calcd for
C
2 4
H
3 1 BrN 2
O
2 S+ 3CIHC1 3 ESMS ni/: 491.0 (M H) 4 Example 592 [(3,4-DIFLUOROPHENYL) SULFONTYL]AMINO}-3- PHENYLPROPYL) -4-PIPERIDINYL) PHENYL) -2-METHYLPROPANA4IDE: Prepared by Procedure Q1 and Scheme AC using 3,4difluorobenzenesulfonyl chloride and N- -3amino-3 -phenyipropyl) -4 -piperidinyl }phenyl) -2methyipropanamide: ESMS m/le: 556.2 CM Example 593 3-CHLORO-N-( (ISOBUTYRYLAMINO)PHENYL] -1- PIPERIDINYL}-i-PHENYLPROPYL) -2-THIOPHENECARBOXAMIDE: Prepared by Procedure Q1 and Scheme AC using 3-chlcro-2thiophenecarbonyl chloride and N- [C3S) -3-amino-3phenylpropyl3 -4 -piperidinyl }phenyl) -2-methylpropanamide: ESMS xn/e: 524.2 CM WO 03/004027 WO 0/00027PCT/UJS02/21063 397 Example 594 E(3S) NAPHTHYL] SULFONYL}AMINO) PHENYLPROPYLJ -4- PIPERIDINYLPHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure Q1 and Scheme AC us-ing 5-(dimethylamino)-1naphthalenesulfonyl chloride and -3-amino- 3-phenyipropyl) -4-piperidinylphelyl) -2methylporopanamide: ESMS m/e: 613.3 (M Example 595 2-METHYL-N-{3-[Ea-((3S)-3-{[(4- METHYLPEENYL) SULFONYLI AMINO] -3 -PHENYLPROPYL) -4- PIPERIDINYLPHENYLPROPANAMIDE: Prepared by Procedure Q1 and Scheme AC using 4-methylbenzenesulfonyl chloride and -3-amino-3-phenylpropyl] -4is piperidinyllphenyl) -2-methyipropanamide: ESMS m/e: 534.2 (M Example 596 -3-f [(3,5-DICHLORO-2- HYDROXYPHENTYL) SULFONYL] AMINO}-3 -PHENYLPROPYL) -4- PIPERIDINYL) PHENYL}-2-METHYLPROPANAMIDE: Prepared Procedure Q1 and Scheme AC using 3,5-dichloro-2hydroxybenzenesulfonyl chloride and (3 1- (3S9) -3 amino-3-phenylpropyl2 -4-piperidinyl~phenyl) -2methyipropanamide: ESMS m/e: 605.4 (M Example 597 2-METHYL-N- E(METHYLSULFONYL) AMINO] -3- PHENYLPROPYL} -4 -PIPERIDINYL) PHENYL] PROPAINAMIDE: Prepared by Procedure Q1 and Scheme AC using methanesulfonyl chloride andN-({l[3)-3aiophenyipropyl) -4-piperidinyl~phenyl) -2-methylpropanamile: ESMS m/e; 458.6 (M H" WO 03/004027 WO 0/00027PCT/UJS02/21063 398 Example 598 AV- 1- (3S) (4 -FLUJOROPHENYL) SULFONYL] AMINO 3 PHE1NYLPROPYL) -4 -PIPERIDINYL] PHENYL) -2 -METHYLPROPANAMIDE: Prepared by Procedure Q1 and Scheme AC using 4fluorobenzenesulfonly chloride and amino-3-phenylpropyl-)-4-piperidinyl~phenyl) -2methyipropanamide: ESMS m/e: 538.1 (M Example 599 [1-((3S)-3-{[(4-TERT-BUTYLPHENYL)SULFONYL]AMINO}-3- PHENYLPROPYL) -4 -PIPERIDINYL] PHENYLI -2-METHYLPROPANAMIDE: Prepared by Procedure Q1 and Scheme AC using 4-tertbutylbenzenesulfonyl chloride and N- -3-amino- 3-phenyipropyl) -4-piperidinyl~phenyl) -2mbthyipropanamide: ESMS m/e: 576.2 (M Example 600 N-{3-[l-((3S)-3-{U(2,5-DI:CHLOROPHENYL,)SUJLFONYL]AMINO}-3- PHENYLPROPYL) -4-PIPERIDINYL] PHENYL}-2-METHYLPROPANAMIDE: Prepared by Procedure Q1 and Scheme AC using dichlorobenzenesulfonyl chloride and N- [C3S) -3amino-3-phenylpropyl] -4-piperidinyllphenyl) -2methyipropanamide: ESMS ni/e: 588.0 CM -4 Example 601 2-METHYL-N- (3S) -3-PHiENYL-3- [(PROPYLSULFONY,) AMINO] PROPYL}-4- PIPERIDINYL)PHENYL]PROPANAMIDE: Prepared *by Procedure Q1 and Scheme AC using 1-propanesulfonyl chloride and N- 3S) -3-amino-3-phenylpropyl] -4piperidinyl }phenyl) -2-methylpropanamide: ESMS m/e: 486.2 (M WO 03/004027 WO 0/00027PCT/UJS02/21063 399 Example 602 [(3,5-DIMETHYL-4- I SOXAZOLYL) STJLFONYL) AMINO) PHENYLPROPYL) -4- PIPERIDINYL) PHENYL}-2-METHYLPROPANAMIDE: Prepared by Procedure Qi and Scheme AC using 3,5-dimethyl-4isoxazolesulfonyl chloride and N-(3-{l-PE3S) -3-amino-3phenyipropyl) -4-piperidinyl }phenyl) -2 -methyipropanamide: Hf NMR (400 MHz, CDCl 3 6 7.53 2H), 7.3-7.1 (in, 511), 7.05 2H, J 6.5 Hz), 6.81 Cd, I:H, J =7.1 Hz), 4.65 (dd, lH, J 6.3, 2.2 Hz), 3.11 2H, J =7.2 Hz), 2.4 (in, 4H), 2.2 3H), 2.05 2H), 2.01 3H), 1.8 (in, 7H) 1. 21 6H, J 7. 1 Hz) ESMS m/e: 53.9.5 (M Example 603 METHYL (ISOBUTYRYLAMINO)PHENYL) -1- PIPERIDINYL}PROPYL) AMINOJ SULFONYL.-2- THIOPHENECARBOXYLATE: Prepared Procedure Q1 and Scheme AC using methyl 3-(chlorosulfonyl)-2thiophenecarboxylate and (3-aminopropyl) -4piperidinyllphenyl)-2-methylpropanamide: Anal. Calcd for
C
2 4
H
3 3
N
3 0 5 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 Excample 604 2 -METHYL-N- E1- (3S) PHENOXYANILINO) CARBONYL) AMINO) -3 -PHENYLPROPYL) -4- PIPERIDINYL]PHENYLIPROPANAMIDE: Prepared by Procedure P and Scheme AB using 1-isocyanato-4-phenoxybenzele and Nv- (3-{1-[(3S)-3-amino-3-phenylpropyl] -4piperidinyllphenyl) -2-methylpropanamide: ESMS m/e: 591.3 CM H+ WO 03/004027 WO 0/00027PCT/UJS02/21063 400 PIPERIDINYLI PHENYL}-2-
METHYILPROPANAMIDE:
Prepared by Procedure Q1 and Scheme AC using dimethyl-4-isoxazolesulflnyl chloride and N- 3-amina-3-phenylpropyl] -4-piperidinyl~phenyl) -2methylpropanamide: 'H NMR (400 MHz, CDCl 3 6 7.53 (s, 2H1), 7.3-7.1 Cm, 5H1), 7.05 2H, J 6.5 Hz), 6.821 (d, 1H1, J 7.2. Hz), 4.65 (ddI 1H, J 6.3, 2.2 Hz), 3.11 2H-, J 7.2 Hz), 2.4.(in, 4H), 2.2 311), 2.05 (m, 2H1), 2. 01 3H1), 2.0-1.8 (in, 7H) 1. 21 6H1, J 7. 1 Hz); ESMS m/e: 539.5 CM H) Example 603 METHYL (ISOEUTYRYLAMINO)PHENYL] -1- PIPERIDINYL .PROPYL) AMINO] SULFONYL) -2- THIOPHENECARBOXYLATE: Prepared Procedure Q1 and Scheme AC using methyl 3-(chlorosulfonyl)-2thiophenecarboxylate and N- [1-(3-aininopropyl) -4piperidinylj phenyl} -2-methyipropanamide: Anal. Calcd for
C
2 4
H
3 3
N
2 0 5 S.HCl: C, 6.00; H, 5.30; N, 7.72. Found: C, 52.97 H, 6.04; N, 7.59; ESMS m/e: 508.2 CM H) 4 Example 604 2-METRYL-NV-{3- C(3S) PHEN~OXYANILINO) CARBONYL]AMINO)-3-PHENYLPROPYL) -4- PIPERIDINYL)PHENYL}PROPANAMID)E: Prepared by Procedure P and Scheme AD using l-isocyanato-4-phenoxybenzene and N- EC3S) -3-amino-3-phenylpropylj -4piperidinyllphenyl) -2-inethylpropananide: ESMS ni/e: 591.3 (M H).
Example 605 N- [(ANILINOCARBONYL)AMIN'O] -3- PHEN'YLPROPYL-4-PIPERIDINYL) PHENYL] -2-METHYLPROPANAMIDE: WO 03/004027 WO 0/00027PCT/UJS02/21063 401 Prepared by Procedure P and Scheme AB using isocyanatobenzene and N- (3S) -3-amino-3phenyipropyl) -4 -piperidinyl }phenyl) -2 -methyipropanafide: ESMS ni/e: 499.2 (M Example 606 NL-{3- El-((3S) E(TERT-BUTYLAMINO)CARBOTHIOYL]AMINO}-3- PHENYLPROPYL) -4 -PIPERIDINYL] PHENYL} -2 -METHYLPROPANAMIDE: Prepared by Procedure P Aid Scheme AB using 2isothiocyanato-2-methylpropale and V- -3amino-3-phenylpropyl] -4-piperidinyllphenyl) -2methyipcropanamide: ESMS mlie: 495.1 (M +r Example 607 N-{3-El-((3S)-3-{E(2-FLUOROANILINO)CARBONYL]AMIENO}-3- PHENYLPROPYL) -4-PIPERIDINYL] PHENYL}-2-METIIYLPROPANAMIDE: Prepared by Procedure P and Scheme AB using 1-f1uoroisocyanatobenzene and NV-(3-{1-E(3S)-3-amino-3phenyipropyll -4-piperidinyl }phenyl) -2 -methyipropananide: ESMS m/e: 517 .0 (M H Example 608 2-METHYL-N- Cl-{ (3S) -3-PHENYL-3- TOLTJIDINOCARBOTHIOYL) AMINO] PROPYL} -4- PIPERIDINYL)PHENYLJPROPANAMIDE: Prepared by Procedure P and Scheme AB using 1-isothiocyanato-2--methylbenzene and N- -3-amino-3-phenylpropyl] -4piperidinyl}phenyl) -2-methyilpropanamide: ESMS m/e: 529.1 (M H).
Example 609 N-{3-El- (C3S) [(BENZYLAMI:NO) CARBONYLJAMINO}-3- PHENYLPROPYL) -4-PIPERIDINYL] PHEYL) -2-METHYLPROPANAMIDE: WO 03/004027 WO 0/00027PCT/UJS02/21063 402 phenyipropyl] 4- piperidinyl~phenyl) -2methyipropanamide: 'H NMP. (400 MHz, CDC1 3 Z5 8.44 (s, IH), 7.67 1H, J 7.9 Hz), 7.31-7.13 13H), 6.38 1H) 6. 80 1H, J 7. 9 Hz) 5. 54 1H) 4.-81 (in, 1TV), 4.41 (dd, 1H, J 14.8, 6.2 Hz), 4.29 (dd, 1H, J =14.9, 5.4 Hz), 2.99 1H-, J 11.2 Hz) 2.87 (d, IH, J 11.2 Hz) 2.67 1H, J 6.2 Hz) 2.3 3H) 2.0-1.5 7H), 1.23 6H, J 6.7 Hz); ESMS m/e: 513.2 (M Example 610 2-METHYL-N-(3- l- i:(2- NITROANILINO) CARBONYL]AMINO)-3-PHENYLPROPYL) -4- PIPERIDINYLIPENYLIPROPANAMIDE: Prepared by Procedure P and Scheme AB using 1-isocyanato-2-nitrobenzene and N- C -3-ainino-3-phenylpropyll-4piperidinyllphenyl) -2-methyipropanamide: ESMS m/e: 543.6 'M H+ Example 611 [(3,4-DICHLOROANTLIN)CARBONYLJAMINO}- 3-PHENYLPROPYL) -4-PIPERIDINYL]PHE1NYL}-2- METHYLPROPANAMIDE: Prepared by Procedure P and Scheme AB using 1, 2-dichloro-4-isocyanatobenzene andN-({i L (3S) -3-amin-o-3-phenylpropylj -4-piperidinyllphenyl) -2methylpropanamide: ESMS m/e: 567.1 (M H)4.
Example 612 (METHYLSULFANYL) ANILINO] CARBONYL}AMINO) -3 -PHENYLPROPYLJ 4-PIPERIDINYL}PHENYL) PROPANAMIDE: Prepared by Procedure P and Scheme AR using 1-isocyanato-2- (methylsulfanyl)benzene and -3-amino-3- WO 03/004027 WO 0/00027PCT/UJS02/21063 403 phenyipropyl] piperidinyl }phenyl) -2methyipropanamide: ESMS m/e: 545.0 (M Example 613 NV-{3- [(4-FLUOROANILINO)CARBONYLJAMINO}PROPYL) -4- PIPERIDINYL] PHENYL} -2 -METHiYLPROPANAMIDE: Prepared by Procedure P and Scheme A2 using. 1-f luoro-4isocyanatobenzene and N-(3 [1 (3 -aminopropyl) -4 piperidinyl] phenyl}-2-methylpropanamide: 'H NMR (400 MHz, CDC1 3 5 7. 45 2H, J 4 .7 Hz) 7 .23 (mn, 4H) 7.05 4H, J= 7.8 Hz), 6.75 1H), 4.05 CM, iii), 3.19 1H) 2.71 Cm, 1H) 2.53 1H) 2 .25 Cm, 3H) 1.B (in, 9H) 1. 25 Cd, 6H, J 6.4 Hz); ESMS m/e: 441. 1 CM H).
Example 614 DICELOROANILINO) CARBONYL] AMI:NO) PROPYL) -4- PIPERIDINYL] PHENYL)-2-METHYLPROFANAMIDE: Prepared by Procedure P and Scheme AB using 1,2-dichlcro-4isocyanatobenzene and N- (3-aminopropyl) -4piperidinyl] phenyl} -2-methylpropanamide: ESMS In/e: 493.2 (M +I H) Example 615 2-METHYL-N- TOLUIDINOCARBOTHIOYL) AMINO) PROPYL) -4- PIPERIDINYL)PHENYLPROPANA4IDE: Prepared b~y Procedure P and Scheme AB using 1-isothiocyanato-2-methylbenzene and NV-{3-[1-(3-aminopropyl)-4-piperidiyllphenlyl}-2methylpropanamide: ESMS mle: 453.2 CM WO 03/004027 WO 0/00027PCT/UJS02/21063 404 Example 616 [(BENZYLAMINO) CARBONYL]AM4INO}PROPYL) -4- PIPERIDINYL] PHENYL}-2-METHYLPROPANAMIDE: Prepared by Procedure P and Scheme AB using (isocyanatomethyl) benzenle and NV-{3- [1-(3-aminopropyl) -4piperidinyl.Jpheny. -methyipropanamide: ESMS rn/a: 437.2 (M H) 4 Example 617 El- E(4-ETHOXYANILINO)CARBONYLAMI'O}PROPYL) -4- PIPERIDINYL] PHENYL}-2-METHYLPROPANAMIDE: Prepared by Procedure P and Scheme AB using 1-ethoxy-4isocyanatobenzene and N- (3-aminopropyl) -4piperidinyl] phenyl}-2-methylpropanamide: ESMS rn/a: 467 .2 is (M H) Example 618 N- (1-{3-[(ANILI:NOCARBONYL)AMI:NO] PROPYL}-4- PIPERIDINYL) PHENYL] -2-METHYLPROPANAMID)E: Prepared by Procedure P and Scheme AB using isocyanatobenzene and N- [1-(3-aminopropyl) -4-piperidinyllphenyl}-2rmethyipropanamide: ESMS rn/a: 422.9 (M Example 619 2-METHYL-N- [2- (METHYLSULFANYL) ANILINO] CARBONYL}AMINO) PROPYL] -4- PIPERIDINYL)PHEN'YL)PROPANAMIDE: Prepared by Procedure P and Scheme AR using 1-isocyanato-2- (methylsulfanyl)benzene and [1-(3-aminopropyl)-4piperidinyl] phenyl}-2-methylpropanamide: ESMS rn/a: 469.1 (M WO 03/004027 WO 0/00027PCT/UJS02/21063 405 Example 620 N-{3 r(TERT-BUTYLAMINO) CARBOTHIOYL) AMINO}PROPYL) 4 -PIPERIDINYL] PHENYL}- 2-METHYLPROPANAMIDE: Prepared by Procedure P arnd Scheme AR using 2-isothiocyanato-2methylpropane and N- (3 (3 -aminopropyl) -4 piperidinyl2 phenyl }-2-methyipropanamide: ESMS m/e: 419.0 (M H) Example 621 2-METHYL-N-{3-[l-(3-{[(4- PHENOXYANILINO) CARBONYLJ AMINO}PROPYL) -4- PIPERIDINYL)PHENYL).PROPANAMIDE: Prepared by Procedure P and Scheme AB using l-isocyanato-4-phenoxybenzene -and N- [1-(3-aminopropyl) -4-piperidinyllphenyl}-2fnethylpropanamide: ESMS m/e: 515.5 (M Example 622 N- (ACETYLAMINO) PHENYL] -l-PI:PERIEDINYL}PROPYL) -4- (2,4-DIFLUOROPHENYL) -2-METHYL-6-OXO-1,4,5,6-TET.AHYDRO- 3-PYRIDINECARBOXAMIDE: Prepared by Procedure AC and Scheme AM using N-{3-[1-(3-aminopropyl)-4piperidinyllphenyl~acetamide and 4- 4-difluorophenyl) 2-methyl-6-oxo-1,4,5,6-tetrahydrc-3-pyridinecarboxylic acid: ESMS m/e: 525.2 CM H+ Example 623 (ACETYLAMINO)PHENYL] -l-PIPERIDNYLPROPYL) -4- (3,4-DIFLUOROPHEIYL) -2-METHYL-6-OXO-l,4,5,6-TETRAHYDRO- 3-PYRIDINECARBOXAMIDE: Prepared by Procedure AC and Scheme AM using 3 (3 aminopropyl) -4 piperidinyliphenyllacetamide and 4-(3,4diflucrophenyl) -2-methyl-6-oxo-1,4,5,6-tetrahydro-3pyridinecarboxylic acid: ESMS nile: 525.2 CM WO 03/004027 WO 0/00027PCT/UJS02/21063 406 Examiple 624 (ISOBUTYRYLAMINO)PHENYL] -1- PIPERIDINYL}HEXYL) -1-(4-NITROPHENYL) (TRIFLUOROMETHYL) -3--PYRAZOLE-4-CARBOXAMIDE: Prepared by Procedure Q1 (THF) and Scheme AT using aminohexyl) -4-piperidinylj phenyl) -2 -methyipropanamide and 1- (4-nitrophenyl) (trifluoromethyl) -lH-pyrazole-4carbonyl chloride: ESMS rn/e: 629.2 (Mv +i Example 625 N- (1-{6-[t(D)IPHENYLACETYL)AMINOIHEXYL}-4- PIPERIDINYL)PHENYL] -2-METHYLPROPANAMIDE: Prepared by Procedure Q1 (THF) and Scheme AT using aminohexyl) -4-piperidinyl:Iphenyl} -2-methyipropanamide, and diphenylacety. chloride: ESMvS rn/c: 540.3 (M Example 626 (3,5-DICHLOROPHENOXY) [3- (ISOBUTYRYLAMINO) PHENYL]J-l-PIPERIDINYL)HEXYL) -2-
FURAMIDE:
Prepared by Procedure Q1 (TEP) and Scheme AT using N-{3- El- (6-aminohexyl) -4-piperidinyllphenyl}-2methylzropanamide, and 5- 5-dichiorophenoxy) -2-furoy1 chloride: ESMS rn/c: 600.2 (M Example 627 (ISOBUTYRYLAMINO) PHENYLI -1- PIPERIDINYL HEXYL) -2-PHENOXYNICOTINAMIDE: Prepared by Procedure Qi (THE) and Scheme Ar using aminohexyl) -4--piperidinyl] phenyl} -2 -methyipropanamide and 2-phenoxynicotinoyl chloride: ESMS rn/c: 543.3 (M 14)1.
WO 03/004027 WO 0/00027PCT/UJS02/21063 407 Examiple 628 (ISOBUTYRYLAMINO) PHENYL] -1- PIPERIDINYL}HEXYL) -2-NAPHTHAMIDE: Prepared by Procedure Qi CTHF) and Scheme AT using N-{3-[l-(6-aminoheyl)-4piperidinylJ phenyl -methyipropanamide and 2 -naphthoyl chloride: ESMS m/e: 500.3 (M Example 629 1-BENZYL-3-TERT-BUTYL-N-(6-(4- [3- (ISOBUTYRYLAMINO) PHE'YL] -1-PIPERIDINYL}HEXYL) -1H- PYRAZOLE-5-CARBOA4IDE: Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-El--(6-aminohexyl)-4piperidinyl) phenyl -methyipropanamide and l-benzyl -3 is tert-butyl-lH-pyrazole-5-carbonyl chloride: ESMS mie: 506.3 (M Example 630 3-CHLORO-N-(6--{4- (ISOBUTYRYLAMINO)PHENYZL)-1- PIPERIDINYL}HEXYL) (ISOPROPYLSULFOIYL) -2- THIOPHENECARBOXAMIDE: Prepared by Procedure Qi (THF) and Scheme AT using N-{3--[l-(6-aminohexyl)-4piperidinyljphenyl} -2-methyipropanamide and 3-chloro-4- (isopropylsulfonyl) -2-thiophenecarbony. chloride: ESMS m/e: 59G.2 (M Hl)+.
Example 631 N- E ANILINOCARBONYI.4AMINOJHEXYL-4- PIPERIDINYL) PHENYL] -2 -METHYLPROPANAMIDE: Prepared by Procedure Q1 (THF) and Scheme AT using aminohexyl) -4-piperidinyllphenyl)-2-methylpropanamide and phenyl isocyanate ESMS m/s: 465.2 (M T4)+.
WO 03/004027 WO 0/00027PCT/UJS02/21063 408 Example 632 N-{3-El- 4-DICHLOROAlILINO) CARBON'YLLAMINO)HEXYL) 4-PIPERIDINYLJ PHENYL}-2-METHYLPROPANAMIDE: Prepared by Procedure Qi (THE). and Scheme AT using mnhxl 4pprdnl pey 2-ehirpnmd and 2,4-dichiorophenyl isocyanate: ESMS mle: 533.2 (M Example 633 (ISOBUTYRYLAMINO) PHEN'YL] -1- PIPERIDINYL}HEXYL) -l-PHENYL-5-PROPYL-1H-PYRAZOLE-4- CARBOXAMIDE: Prepared by Procedure Q1 (THF) and Scheme AT using [l-(6-aminohexyl)-4-piperidinyllphenyl}-2methyipropanamide and l-phenyl-5-propyl-1H-pyrazole-4carbonyl chloride: ESMS m/e: 558.3 (M Example 634 2-METHYL-N-(3- NAPHTHYLAMINO) CARBONYLJ MINO)HiEXYL) -4- PIPERIDINYL]PHENYL}PROPANAMIDE: Prepared by Procedure Q1 (THF) and Scheme AT using N-f3-[l-(G-aminchexyl)-4piperidinyl] phenyl} -2-methyipropanamide and l-naphthyl isocyanate: ESMS zn/e: 515.3 (M Example 635 1'-BIPI-ENYLJ -4- YLAMINO) CARBONYLJAMINO}HEXYL) -4-PIPERIDINYLJ PHENYL}-2- METHYLPROPANAMIDE: Prepared by Procedure Qi (THE) and Scheme AT using N-{3-[1-(6-aminohexyl)-4pip eri dinyl Iphenyl -2 -methylpropanamide and 4-biphenyl isocyanate: ESMS m/e: 541.3 (M Example 636 WO 03/004027 WO 0/00027PCT/UJS02/21063 409 2-METHYL-N-{3- NAPHiTHYLAMINO) CAREONYL) AMINO}HEXYL) -4- PIPERIDIN-YL] PHEMYLIPROPANIAMIDE: Prepared by Procedure Q1 (THF) and Scheme AT using N-(3-E1-(6-arninohexyl)-4piperidinyl] pheny. -methyipropanamide and 2-naphthyl isocyanate: ESMS rn/e: 515.3 (M Example 637 3- (3,4- DIMETHOXYPHENYL) SULFONYL]AMINO}PROPYL) -4- PIPERIDITYL] PHENYL}-2-METHYLPROPAN.AMIDE: Prepared by Procedure Q1 (THF) and Scheme AT usingN-31aminopropyl) -4 -piperidinyl] phenyl 1-2 -methyipropanamide and 3,4-dimethoxybenzenesulfonyl chloride: RSMS m/e: 504.2 (M H+ Example 638 (ISOBUTYRYLAMINO)PHENYL] -1- PIPERIDINYL4'ROPYL) -5-METHYL-3-PHENYL-4- ISOXAZOLECARBOXAMIDE: Prepared by Procedure Q1 (THF) and Scheme AT using (3-aminopropyl) -4piperidinyl) phenyl}-2-methylpropanamide and 5-methyl-3phenyl-4-isoxazolecarbonyl chloride: ESMS m/e: 489.3 (M Example 639 l- E(4-FLUOROPHENYL)ACETYLJAMINO}PROPYL) -4- PIPERIDINYL) PHENYL)-2-METHYLPROPANAMIDE: Prepared by Procedure Q1 (THF) and Scheme AT using aminopropyl) -4-piperidinyl] phenyl -methyizropanamide and (4-fluorophenyl~acetyl chloride: ESMS m/e: 440.3 (M WO 03/004027 WO 0/00027PCT/UJS02/21063 410 Example 640 El- E(4-CHLORO-3- NITROPHEN~YL) SULFONYL) AMINO}PROPYL) -4- PIPERIDINYL) PHENYL}-2-METHYLPROPANAMIDE: Prepared by Procedure Q1 (THF) and Scheme AT using aminopropyl) -4-piperidinyl) phenyl} -2 -methyipropanamide and 4-chloro-3-nitrobenzenesulfolyl chloride: ESMS m/e: 523.1 (M Example 641 2- (4-CHLOROPEENOXY) -IJ- (ISOBUTYRYLAMINO) PHENYL) I-PIPERIDINYL)PROPYL) NICOTINAI4IDE: Prepared by Procedure Q1 (THE) and Scheme AT using N-{3-[1-(3-aminopropyl)-4piperidinyl) phenyl} -2 -methyipropanamide and 2- (4chlorophenoxy) ni cot inoyl chloride: ESMS m/e: 535.2 (M Example 642 (3,5-DIC-LOROPENOXY) [3- (ISOBUTYRYLAMINO) PHENqYL) -1-PIPERIDINYL}PROPYL) -2-
FURAMIDE:
Prepared by Procedure Q1. (THF) and Scheme AT using N-{3- (3-aminopropyl) -4-piperidinyllphenyl} -2methyipropanamide and 5- 5-dichiorophenoxy) -2--furoyl chloride: ESMS m/e:,558.2 (M Example 643 IN-{3-El- (31 E(2-FLUOROPHENYL) SULFONYLJAMdINO}PROPYL) -4- PIPERIDINTYL] PHENYL}-2-METHYLPROPANAMIDE: Prepared by Procedure Q1 (THE) and Scheme AT using aminopropyl) -4-piperidinyl] pheny. -methylpropanamide and 2-f luorobenzenesulfony. chloride: ESMS m/e: 462.2 (M WO 03/004027 WO 0/00027PCT/UJS02/21063 411 Example 644 (3-.{U[3,5-DIHTHYL-4- ISOXAZOLYL) StLFOXYL] AMINO}PROPYL) -4-PI:PERIDINYL] PHENYL} 2-METHYLPROPANAMIDE: Prepared by Procedure Q1 (THF) and Scheme AT using [l-(3-aminopropyl)-4piperidinyllphenyl} -2-methyipropanamide and dimethyl-4-isoxazolesulfonyl chloride: ESMS rn/e: 463.2 (M H 4 Example 644 [(4-TERT-BUTYLPHENYL) SULFONYL]AMINO}PROPYL) 4-PIPERIDINYL] PHENYL}-2 -METHYLPROPANAMIDE: Prepared by Procedure Q1 (THF) and Scheme AT usingN-3[(is aminopropyl) -4-piperidinyllphenyl} -2-methylpropanamide and 4-te-rt-butylbenzenesulfonyl chloride: ESMS m/e:- 500.3 (M Example 646 N-{3-El- C6-AMdINOHEXYL) -4-PIPERIDINYLJPHENYL}-2- METHYLPROPANAMIDE: Prepared by Procedure AE and Scheme Y using N-(3-{1-[6-(1,3-dioxo-1,3-dihydro-2H-isoindol-2yl) hexyl) -4-piperidinyl~phenyl) -2-methyipropanamide and hydrazine hydrate: ESMS ni/e: 346.2 (M H) 4 Example 647 NV-{3- -BIPHENYL] -4- YLAMINO) CARBONYL] A1MINO}ETHYL) -4 -PIPERIDINYL].PHENYL} -2- METHYLPROPANAMIDE: Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[l-(2-aminoethyl)-4piperidinyl] phenyl }-2-methyjlpropanamide and 4-biphenyl isocyanate: ESMS mn/e: 485.2 (M H) 4 WO 03/004027 WO 0/00027PCT/UJS02/21063 412 Example 648 (3,5-DICRI 1 OROPHENOXY) [3- (ISOBT3TYRYLAMINO) PHENYL] -1-PIPERIDINYL}ETHYL) -3-
FURAMIDE:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3- El- (2-amirioethyl) -4-piperidinyllphenyl}-2methyipropanamide and 5- 5-dichiorophenoxy) furoyl chloride: ESMS m/e: 544.1 (M Example 649 N- i:(DIPHENYLACETYL) AMINO) ETHYL}-4- PIPERIDINYL) PHENYL] -2 -METHYLPROPANAMIDE: Prepared by Procedure Q1 (THF) and Scheme AT using aminoethyl) -4-piperidinyl] phenyl)}-2 -methlpropanamide and diphenylacetyl chloride: ESMS m/e: 484.2 (M Example 650 (ISOBUTYRYLAMINO)PHENYL] -1- P IPERIDINYL} ETHYL) 2 -NAPHTHAMIDE: Prepared by Procedure Q1 (THF) and Scheme AT using N-(3-[1-(2-aminoethyl)-4piperidinyil pheny. -methyipropanamide and 2-naphthoyl chloride: ESMS m/e: 444. 2 (M Example 651 3-(2,6-DICHLOROPH-ENYL) [3- (ISOBUTYRYLAMINO) PHENYL] -1-PIPERIDINYL)BUTYL)- 4 -ISOXAZOLECARBOXAMIDE: Prepared by Procedure Ql (THF) and Scheme AT using N-{3- (4-aminobutyl) -4-piperidinyllphenyl} -2methyipropananide and 3- 5-dichiorophenyl) -5-methyl-4isoxazolecarbonyl chloride: ESMS mle: 571.2 (M H) 4 Example 652 WO 03/004027 WO 0/00027PCT/UJS02/21063 3- 6-DICELOROPHENYL) 413 4-( (ISOBTJTYRYLAMINO) PHENYI-l-PIPERIDINYL}PENTYL) 4- ISOXAZOLECARBOXAMIDE: Prepared by Procedure Qi (74F) and Scheme AT using N-{3- (5-aminopentyl) -4-piperidinyllphenyl} -2methyipropanamide and 3- 6-dichiorophenyl) -5-methyl -4isoxazolecarbonyl chloride. ESMS rn/e: 585.2.~(M Example 653 N- [(DIPHENYLACETYL) AMINO] BUTYL}-4- PIPERIDINYL)PHENYL) -2-METHYLPROPANA14IDE: Prepared by Procedure Q2(THF/DCM, and Scheme AT using N-{3- (4-aminobutyl) -4-piperidinyllphenyl}-2methyipropanamide and diphenylacetyl chloride: ESMS rn/c: 512.0 CM H+ Example 654 N- [(DIPIENYLACETYL)AMINO] PENTYL}-4- PIPERIDINYL) PHENYL) -2 -METHYLPROPANAMIDE:- Prepared by Procedure Q2(THF/DCM, and Scheme AT using N-{3- (5-aminopentyl) -4-piperidinyllphenyl} -2methylpropanamide and diphenylacety. chloride: ESMS rn/c: S26.0 (M H+ Example 655 3,5-DICHLORO-N-(4-{4- (ISOBUTYRYLAMINO) PHENYL] -1- PIPERIDINYL}BUTYL)BENZAMIDE: Prepared by Procedure Q2 (THF/DCM, 1:3) and Scheme AT using I-3[-4 aminobutyl) -4-piperidinyl) phenyl 1-2 -methylpropanamide and 3,5-dichlorobenzoyi chloride: ESMS rn/c: 490.0 CM Example 656 WO 03/004027 WO 0/00027PCT/UJS02/21063 414 (3,5-DICHLOROPHENOXY) [3- (ISOBUTYRYLAMINO) PHENYL) -1-PIPERIDINYLIBUTYL) -2-
FURAMIDE-
Prepared by Procedure Q2 (THF/DCM, 1: 3) and Scheme AT using [1-(4-aminobutyl)-4-piperidilyllphelyl}-2methyipropanamide and 5- 5-dichiorophenoxy) -2 -furoyl chloride: ESMS mle: 572.0 (M Example 657 3-CHLORO-N-(4-(4- (ISOBUTYRYLAMIbIO)PHiEHYL] -1- PIPERIDINYL}BUTYL)BENZAMIDE: Prepared by Procedure Q2 (THF/DCM, 1:3) and Scheme AT using Vf3-[1(4 aminobutyl) -4 -piperidinyll phenyl)}-2 -methyipropanamide and 3-chlorobenzoyl chloride: ESMS m/le: 456.0 (M is Example 658 3,4-DIFLUORO-N-(4-{4- (ISOBUTYRYLAMI:NO)PHENYL] -1- PIPERIDINYL}BUTYL)BENZAMIDE; Prepared by Procedure Q2 (THF/DCM, 1:3) and Scheme AT using -3[(4 aminobutyl) -4-piperidinyl) phenyl}-2-rnethylpropanamide and 3,4-difluorobenzoyl chloride: ESMS m/e: 458.0 (M Example 659 (4-{CE(3,5-DICHLOROANILINO)CARBONYLIAMNO)BUTYL) 4-PIPERIDINYL) PHENYL} -2 -METHYLPROPANAMIDE: Prepared by Procedure Q2 (THF/DCM, 1:3) and Scheme AT using N-(3- (formylamino)butyl) -4-piperidinyl~phenyl) -2methylpropanamide and 3, 5-dichiorophenyl isocyanate: ESMS m/e: 505.0 (M Example 660 WO 03/004027 WO 0/00027PCT/UJS02/21063 415 N-{3 [1-(4-([([11'-BIPHENYL] -4- YLAMINO) CARBONYLIA.MINO)BTJTYL) -4-PIPERIDINYLJ PHENYL} -2- METHYLPROPANAMIDE: Prepared by Procedure Q2 (THF/DCM, 1:3) and Scheme AT using -N-f3-[1-(4-aminobuty)-4- S pip eri dinyl]I phenyl} -2-methyipropanami de and 4-biphenyl 4socyanate: ESMS m/e: 513.0 (M Example 661 2-METHYL-N(3-{1 E5 (4-NI:TROPHENYL) -5-OXOPENTYL) 4- PIPERIDINYL}PHENYL)PROPANAMIDE:. Prepared by Procedure K and Scheme R1 (I 2 C0 3 using 5-cbhloro-1-(4-nitropheflyl)- 1-pentanone and 2-methy1-N- (4piperidinyl)phenyllpropanamide: ESMS nile: 452.2 (M Example 662 N- (4-FLUOROPHENYL) -5-OXOPENTYL] -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure K and Scheme Bi (K 2 C0 3 using 5-chloro-l- (4tiucrophenyl) -1-pentanone and 2-methyl-N- (4piperidinyl)phenyljpropanamide: ESMS ml/e: 425.2 (M H) Example 663 2-METHYL-N- (1-{5-OXO-5- [2- (TRIFLUOROI4ETHYL) PHENYL) PENTYL) -4- PIPERIDINYL)PHENYL]PROPANAMIDE.- Prepared by Procedure K and Scheme B1 (K 2 C0 3 using 5-chlcro-1- [2- (trifluoromethyl) phenyll-1-pentanone and 2-methyl-.N- [3- (4-piperidinyl)pheriyllpropanamide: ESMS m/e: 475.2 (M Example 664 (3-BROMOPH-ENYL) -5-OXOPENTYL] -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by WO 03/004027 WO 0/00027PCT/UJS02/21063 416 Procedure K and Scheme Bl (K 2 C0 3 using 1- (3bromophenyl) -5-chloro-1-pentaloe and 2-methyl-N- (4piperidinyl)phenyllpropanamide: ESMS rile: 485.1 (M Example 665 2-METHYL-N-(3-(l- (3-NI:TROPHETYL) -5-OXOPENTYL) -4- PIPERIDINYL}PHENYL)PROPANAMIDE: Prepared by Procedure K and Scheme B1 (K 2 C0 3 using 5-chloro-l-(3-nitrophenyl)- 1-pentanone and 2-methyl-N-[3-(4piperidinyl)phenyllpropanamide: ESMS m/e: 452.2 (M H) 4 Example 666 (3-CIHLOROPHENYL) -5-OXOPENTYL) -4- PIPERIDINYLPHENYL) -2-METHYLPROPANAMIDE: Prepared by 1s Procedure K and Scheme BI (K 2 C0 3 using 1-(3chlorophenyl) -5-chloro-l-pentanone and 2-methyl-N- (4piperidinyl)phenyllpropanamide: ESMS m/e: 441.1 (M Example 667 N-(3-1-[5-(4-BROMOPHENYL)-5-OXOPENTYL] -4- PIPERIDIN'YL)PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure K and Scheme El (K 2 C0 3 using 1- (4bromophenyl) -5-chloro-1-pentanone and 2-methyl-N- 3- (4piperidinyl)phenyllpropanamide: ESMS mle: 485.1 (M Example 668 q- (2-IODOPHENYL) -5-OXOPENTYL) -4- PIPERIDINYLPHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure K and Scheme Bl (K 2 C0 3 using 1- (2iodophenyl) 5 -chloro-l1-pent anone and 2-methyl-N- (4piperidinyl)phenyljprcpanamide: ESMS m/e: 533.0 (M Example 669 WO 03/004027 WO 0/00027PCT/UJS02/21063 417 [5 (3-FLUOROPHENYj) OXOPENTYLI -4-PIPER.IDINYL}PHENYL) -2 -METHYLPROPAIAMIDE: Prepared by Procedure K and Scheme Bi (K 2 C0 3 using 1L- (3-f luorophenyl) -5-chloro-l-pentanone and 2-methyl-N- 13- (4-piperidinyl)phenylpropalamide: ESMS m/e: 425.2 (M Example 670 2-METHYL-N- (1-{5-OXO-5- [3- (TRIFLETOROMETHYL) PHENYL) PENTYL}-4- PIPERIDINYL) PHENYL] PROPANAMIDE: Prepared by Procedure K and Scheme BI (K 2 C0 3 using 1- [3- (trifluoromethyl)phenyl] -5-chloro-l-pentanone and 2methyl-N- (4-piperidinyl) phenyl] propanamide: ESMS m/e:.
475.2 (M Example 671 (2-FLUOROPHENYL) -5-OXOPENTYL] -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure K and scheme B1 (K 2 C0 3 using 1- (2fluorophenyl) -5-chloro-l-pentanone and 2-methyl-N- (4piperidinyl)phenyllpropanamide: ESMS m/e: 425.2 (M Example 672 [5-(3-IODOPHENYL) -5-OXOPENTYL] -4- PIPERIDINYL}PHENYL) -2 -METHYLPROPANAMIDE: Prepared by Procedure K and Scheme BI (K 2 C0 3 using l-(3lodophenyl) -5-chloro-l-pentanone and 2-methyl-N- (4piperidinyl)phenyllpropanamide: ESMS m/e: 533.0 (M Example 673 (2-CHLOROPEMYL) -5-OXOPENTYL) -4- PIPERID)INYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by WO 03/004027 WO 0/00027PCT/UJS02/21063 418 Procedure K and Scheme B1 (K 2 C0 3 us ing 1 2 chiorophenyl) -5-chloro-1-pentanone and 2-methyl-N- (4piperidinyl)pheflyllpropanamide: ESMS nile: 441.1 (M Example 674 2-METHYL-N- E3- (1-{5-OXO-5- [4- (TRIFLUOROMETHYL) PHE'YL] PENTYL} -4- PIPERIDINYL) PHENYL PROPANAMIDE: Prepared by Procedure K and Scheme BI (K 2 C0 3 using 1[4 (trifluoromethyl)phenyl] -5-chloro-l-pentanone and 2methyl-N- (4-piperidinyl)phenyl] propanamide: ESMS m/e: 475.2 CM H+ Example 675 ES- (4-CHLOROPHENYL) -5-OXOPENTYL) -4- PIPERIDfIYL}PEE1L) -2-METHYLPROPANAMIDE: Prepared by Procedure K and Scheme BI (K 2 C0 3 using 1- (4chiorophenyl) 5 -chl oro- 1-pent anone and 2-methyl-N- (4piperidinyl)phenyllpropanamide: ESMS m/e: 441.1 (M Example 676 (4-IODOPHENYL) -5-OXOPENTYLJ -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure K and Scheme B1 (K 2 C0 3 using 1- (4- 2S iodophenyl)-5-chloro-1-pentanone and 2-methyl-NV-[3- (4piperidinyl)phenyllpropanamide: ESMS m/e: 533 (M Example 677 (2-BROMOPHENYL) -5-OXOPENTYL] -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMI1DE: Prepared by Procedure K and Scheme B1 (K 2 C0 3 using l-C2bromophenyl) -5-chloro-l-pentanone and 2-methyl-N- (4piperidinyl)phenyljpropanamide: ESMS nile: 485.1 (M WO 03/004027 WO 0/00027PCT/UJS02/21063 419 Example 678 2- (4-CHLOROPHENOXY) (TSOBUTYRYLMINO) PHENYL] 1-PIPERIDINYL}BUTYL) NICOTINAMIDE: Prepared by Procedure Q2 (THF/DCM, 1:3) and Scheme AT using aminobutyl) -4-piperidinyl) phenyl)}-2-methyipropanamide and 2-(4-chlorophenoxy)nicotinoyl chloride: ESMS m/e: 549.0 (M H" Example 679 (ISOBUTYRYLAMINO)PHENYL] -1- PIPERIDINYL}BUTYL) -3,4 -DIMETHOXYBENZAMIDE: Prepared by Procedure Q2 (THF/DCM, 1:3) and Scheme AT using N-{3- (4-aminobutyl) -4-piperidinyllphenyl} -2- 1s methyipropanamide and 3,4-dimethoxybenzoyl chloride: ESMS m/e: 482.0 (M Example 680 3- (2-CHLOROPHENYL) (ISOBUTYRYLAMINO)PHENYLJ 1-PIPERIDINYL}BUTYL) -5 -METHYL-4 -ISOXAZOLECARBOXAMIDE: Prepared by Procedure Q2 (THF/DCM, 1:3) and Scheme AT using NV-(3- (4-aminobutyl) -4-piperidinyllphenyl}-2methyipropanamide and 3- (2-chiorophenyl) -5-methyl-4isoxazolecarbonyl chloride: ESMS m/e: 537.0 (M Example 681 3- (2-CIILOROPHENYL) (ISOBUTYRYLAMINO)PHENYL] 1-PIPERIDINYL)PENTYL) -5-METHYL-4-ISOXAZOLECARBOXAMIDE: Prepared by Procedure Q2 (THF/DCM, 1:3) and Scheme AT using El-(5-aminopentyl)-4-piperidinyllphenyl}-2methyipropanamide and 3- (2-chiorophenyl) -S-methyl-4isoxazolecarbonyl chloride: ESMS m/e: 551.0 (M WO 03/004027 WO 0/00027PCT/UJS02/21063 420 Example 682 2-METHYL-NV-{3-(1- (3-{l-METHYL-2- 14- (TRIFLUOROMETHYL) PHE1NYLJ U- flDOL-3 -YL}PROPYL) -4- PIPERIDI1NYL3PHENYL}PROPANAMIDE: Prepared by Procedure E and Scheme M usin~g 2-methyl-N-[3-(-{5-oxo--5-[4- (trifluoromethyl) phenyl] pentyl} -4piperidinyl phenyl] propanamide and 1-methyl-lphenylhydrazine: ESMS m/e: 562.2 CM H+ Example 683 2-METHYL-N-{3- [1-(3-{1-XETHYL-2- [4- (TRIFLUOROMETHYL) PHENYL) -lH-INDOL-3 -YL)PROPYL) -4- PIPERIDINYLJPHENYLIPROPANMIDE: Prepared by Procedure E and Scheme M using 2-methyl---3-(1-{5--oXo-5-[4- (triluoromethyl)phenyllpentyl} -4piperidinyl~ phenyll propanamide and 4- (trifluoromethoxy) phenyihydrazine hydrochloride: ESMS Wie: 632.2 (M Example 684 2-METHYL-N-{3- (TRIFLUOROMETHYL)PH-ENYL] -1H- INDOL-3 -YL}PROPYL) -4 -PIPERIDINYL] PHENYL}PROP.ANAMI:DE: Prepared by Procedure E and Scheme M using 2-methyl-N- (trifluoromethyl)phenyllpenty}--4-.
piperidinyl~ phenyl] propanamide and phenyihydrazine: ESMS m/e: 548.2 (M Example 685 2-METHYL-N-{3- (3-{l-PHENYL-2- [4- (TRIFLUOROMETHYL) PHENYL] -1H-INDOL-3 -YL}PROPYL) -4- PIPERIDINYL)PEENYL)PROPANAMIDE: Prepared by Procedure E and Scheme M using 2-methyl-N-[3-(l-{5-oxo-5-[4- (trifluoromethyl) phenyl] pentyl) -4- WO 03/004027 WO 0/00027PCT/UJS02/21063 421 piperidinyl) phenyl] propanamide and 1, 1-diphenyihydrazine hydrochloride: ESMS m/e: 624.2 (M Example 686 2-METHYL-N-{3-[:- [4-(TRIFLUO)ROMETHYL) PHENYL] -lH- BENZO G] INDOL-3-YL}PROPYL) -4- PIPERIDINYLJPHE:NYLIPROPANAMIDE: Prepared by Procedure E and Scheme M using 2-methyl-N-.[3-(1-{5-oxo-S-[4- (trifluoromethyl) phenyl) pentyl} -4piperidiny1l phenyl] propanamide and 1 -naphthylhydrazine hydrochloride: ESMS m/e: 592.2 (M H) 4 Example 687 2-METHYL-N-{3- [1-(3-{7-METHYL-2- [4- (TRIFLUOROMETHYL) PHENYL] -1H- INDOL- 3-YL}PROPYL) -4- PIPERIDINYL)PHENYL)PROPANAMIDE: Prepared by Procedure E and Scheme M using 2-methyl-N-[13- (l-t5-oxo-5- [4- (trifluoromethyl) phenyl] pentyl 1-4piperidinyl) phenyl] propanamide and1-2 methylphenyl)hydrazine hydrochloride: ESMS rn/e: 562.2(M Example 688 2-METHYL-NV-(3- [1-(3-{5-METHYL-2- [4- (TRIFLUOROMETHYL) PHENYL] -1H-INDOL-3-YL}PROPYL) -4- PIPERIDINYL]PHENYLIPROPANAMIDE: Prepared by Procedure E and Scheme M using 2-methyl--N-[3-(1-{5-oxo-5-[4trifluoromethyl) pherlyl] pentyl piperidinyl) phenyl] propanamide and 4methyiphenyihydrazine hydrochloride: ESMS m/e: 562.2(M Example 689 WO 03/004027 WO 0/00027PCT/UJS02/21063 422 N(3..[J..(3-(5-METHOXY-2- 4 (TRIFLUOROMETHYL) PHENYL) -1H-INDOL-3 -YL}PROPYL) -4- PIPERIDINYLI PHENYL}-2-METHYLPROPANAMIDE: Prepared by Procedure R and Scheme M using 2-methyl-N-[3-(1-{5-oxo- (trifjuoromethyl)phenyllpentyl}-4piperidinyl) phenyl) propanamide and 4methoxyphenyihydrazine hydrochloride: ESMS m/e: 578.2 (M Example 690 N- (3-FLUOROPHENYL) -7-METHYL-lH-IENDOL-3- YL] PROPYL}-4 -PIPERIDI:NYL) PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using (3-f 1uorophenyl) -5-oxopentylJ -4-piperidinyl~phenyl) -2methyipropanamide and 1- (2 -methyiphenyl) hydrazine hydrochloride: ESMS m/e: 512.2 (M Example 691.
V- (4-CH-LOROPHE'YL) -1-METHiYL-1H-fl4DOL-3- YL] PROPYL}-4 -PIPERIDINYL) PHENYL] -2 -METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using (4-chlorophenyl) -5-oxopentyl] -4-piperidinyllphenyl) -2methyipropanamide and 1-methyl-1-phenylhydrazine: ESMS in/e: 528.2 (M H" Example 692 N- (4-FLUOROPHENYL) -5-METHOXY-2.H-INDOL-3- YL] PROPYL}-4 -PIPERI:DINYL) PHENYL] -2 -METHYLPROPANANIDE: Prepared by Procedure E and Scheme M using N-(3-11-[5- (4-tluorophenyl) -5-oxopentyl] -4-piperidinyllphenyl) -2methyipropanamide and 4 -methoxyphenyihydrazine hydrochloride; ESMS ni/e: 528.2(M WO 03/004027 WO 0/00027PCT/UJS02/21063 423 Example 693 NL- (2-FLUOROPHENYL) -lH-INDOL-3-YLIPROPYL}-4- PIPERIDINYL) PHENYL] -2-METHYLPROPANAMIDE: Prepared by Procedure E and .Scheme M using fluorophenyl) -5-oxopentyl) -4 -piperidinyl }phenyl) -2methyipropanamide and phenyihydrazine: ESMS m/e: 498.2 (M H) t Example 694 N- Cl-{3- (3-FLUOROPHEENYL) (TRI:FLUOROMETHOXY) -1H- INflOL-3-YL] PROPYL)-4-PIPERIDINYL) PHENYL] -2- METHYLPROPANAMIDEi Prepared by Procedure E and Scheme M using (3-fluorophenyl)-5-oxopentyl] -4piperidinyl~phenyl) -2-methyipropanamide and 4- (trifluromrethoxy) phenyihydrazine hydrochloride: ESMS m/e: 582.2 (M Example 695 N- (2-FLUOROPHENYL) (TRIFLUOROMETHOXY) -11- INDOL-3-YL]PROPYL}-4-PIPERIDINYL)PHiENYLJ -2- METHYILPROPANAMIDE: Prepared by Procedure E and Scheme M using [5-(2-fluorophenyl) -5-oxopentyl] -4piperidinyllphenyl) -2-methyipropanamide and 4- (trifluoromethoxy) phenylhydrazine hydrochloride: ESMS m/e: 582.2 (M Example 696 N- (4-FLUOROPHENYL) -1-PHENYL-lH-INDOL-3- YL] PROPYL PIPERIDINYL) PHENYL] -2 -METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using (4-f luorophenyl) -5-oxopentyl] -4-niperidiny}phenyl) -2methylpropanamide and 1, 1-diphenyihydrazine hydrochloride: ESMS m/e: 548.2 (M WO 03/004027 WO 0/00027PCT/UJS02/21063 424 Example 697 q- (2-FLUOROPHENYL) -1H-BENZO [G]INDOL-3- YL] PROPYL}-4 -PI:PERIDINYL) PIHENYL) -2-METRYLPROPANAMIDE: Prepared by Procedure E and Scheme M using (2-f lucrophenyl) -5-oxopentyl]-4-piperidinyl~phelyl) -2methyipropanamide and 1 -naphthylhydrazine hydrochloride: ESMS rn/e: 547.7 (M Example 698 N- (2-FLUOROPHENYL) -5-METHiYL-1H-IND)OL-3- YL] PROPYL} -4 -PIPERIDINYL) PHENYLI -2-METHYLPROPANAMIDE:.
Prepared by Procedure E and Scheme M using (2-f luorophenyl) -5-oxopentyl] -4-piperidinyl~phenyl) -2methylpropanamide and 4 -methylphenylhydrazine hydrochloride: ESMS m/e: 512.2( M H+ Example 699 N- (3-FLUOROPHENYL) -lH-BENZOEGJ INDOL-3- YLJ PROPYJ}-4 -PIPERI:DINYL) PHENYL] -2 -METHiYLPROPANANIDE: Prepared by Procedure E and Scheme M using (3-f luorophenyl) -S-oxopentyl] -4-piperidinyl~phenyl) -2methyipropanamide and 1-naphthylhydrazine hydrochloride: ESMS m/e: 548.2 (M Example 700 N- ('-FLUOROPHENYL) -l-METHYL-lH-INDOL-3- YL) PROPYL}-4-PIPERIDINYL) PHEIWYL] -2-METHYLPROPANAMIDE: Prepared by Procedure E and Scheme N using (4-f luorophenyl) -5-oxopentyl] -4-piperidinyl~phenyl) -2methyipropanamide and l-methyl-1-phenylhydrazine: ESMS m/e: 512.2 (M Example 701 WO 03/004027 WO 0/00027PCT/UJS02/21063 425 N- E2-(3- FLtIOROPHENqYL) 1H-INDOL-3-YL] PROPYL}-4-PIPERIDINYL) PHENYLI -2-
METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using (3-f luorophenyl) -5-oxopentyl] -4-piperidinyllphenyl) -2met hyipropanamide and 4 -methoxyphenyihydrazime hydrochloride: ESMS zn/e: 528.2 (M H4 Example 702 N-E3-C1-{3-[2-(3-FLUOROPHENYL) -1-PHENYL-lH-INDOL-3- YLJ PROPYL}-4-PIPERIDINYL) PHENYL] -2-METHYLPROPANANIDE: Prepared by Procedure E and scheme M using (3-f luorophenyl) -5-oxopentylj -4-piperidinyl~phenyl) -2methyipropanamide and 1, 1-diphenyihydrazine hydrochloride: ESMS m/e: 574.2 (M H+ Example 703 N- (4-CHLORQPHENYL) (TRIFLUORONETHOXY) -1H- INDOL-3 -YL] PROPYL)-4- PIPERIDINYL) PHENYL] -2 -METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using chlorophenyl) -5-oxopentylJ -4-piperidinyl~phenyl) -2methyipropanamide and 4- (trifluoromethoxy) phenyihydrazine hydrochloride: ESMS m/e: 598.2 (M Example 704 T- (3-FLLTOROPHENYL) -lH-INDOL-3-YL]PROPYL}-4- PIPERIDINYL)PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using fluorophenyl) -5-oxopentyl] -4-piperidinyl }phenyl) -2rethylpropanamide anid phenyihydrazine: ESMS m/e: 498.2 (M 14) WO 03/004027 WO 0/00027PCT/UJS02/21063 426 Example 705 [3-(l-{3-[2-(3-FLUJOROPHENYL)-1-METHYL-1H-INDOL-3- YLJ PROPYL}-4 -PIPERIDINYL) PHENYL] -2 -METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using N(-l (3-f luorophenyl) -5-oxopentyl) -4-piperidinyl~phenyl) -2methyipropananide and l-methyl-l-phenylhydrazine: ESMS rale: 512.2 (M Example 706 N- (3-FLUOROPHENYL) -5-METHYL-1H-INDOL-3- YL] PROPYL}-4 -PIPERIDINYL) PHENYL] -2-METHYLPROPANAMIDE: Prepared by Procedure R and Scheme M using (3-f luorophenyl) -5-oxopentyl) -4-piperidinyl'phenyl) -2methyipropanamide and 4 -methyiphenyihydrazine hydrochloride: ESMS m/e: 512.2 (M Example 707 N- (4-CHLOROPHENYL) -2H-BENZO[G] INDOL-3- YLI PROPYL}-4 -PIPERIDINYL) PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using *(4-chiorophenyl) -5-oxopentyl] -4-piperidinyllphenyl) -2rethylpropanamide and l-naphthylhydrazine hydrochloride: ESMS M/e: 564.2 (M Example 708 N-E3- (4-CHiLOROPHENYL) -lH-I1%1DOL-3-YLPROPYL}-4- PIPERIDINYL) PHENYL] -2-METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using chiorophenyl) -5-oxopentyl] -4-piperidinyllphenyl) -2methyipropanamide and 1-phenylhydrazine hydrochloride: ESMS ni/e: 514.2 (M H)+i.
WO 03/004027 WO 0/00027PCT/UJS02/21063 427 Example 709 7- (2-FLITOROPHENYL) -1-METHYL-1H-INDOL-3- YL] PROPYL}-4 -PIPERI:DINYL) PHENYL) -2 -METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using S (2-f luorophenyl) -5-oxopentyl] -4-piperidinyl~phenyl) -2rethylpropanamide and 1-methyl-i -phenylhydrazine: ESMS m/e: 512.2 (M Example 710 N-[3-(l-{3-[2-(2-FLUOROPHENYL)-7-METHYL-lH-INDOL-3- YL] PROPYL}-4 -PIPERIDINYL) PHEN~YL] -2-METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using (2-f luorophenyl) -5-oxopentyl] -4-piperidinyllphenyl) -2rethylpropanamide and 1- (2 -methyiphenyl) hydrazine hydrochloride: ESMS m/e: 512.2 (M Example 711 V- (2-FLUOROPHENYL) -1-PHENYL-1H-INDOL-3- YL] PROPYL}-4 -PIPERIDINYL) PHENYL] -2-METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using (2-f luorophenyl) -5-oxopentyl] -4-piperidinyl'phenyl) -2methyipropanamide and 1, 1-diphenylhydrazine hydrochloride: ESMS m/e: 574.2 (M H1)+.
Example 712 V- (2-FLUOROPHENYL) -5-METHOXY-1H-INDOL-3- YL] PROPYL)-4 -PIPERIDIENYL) PHEbYL] -2-METHYLPROPANAMNIDE: Prepared by Procedure E and Schem e M using (2-f luorophenyl) -5-oxopentyl) -4-piperidinyl~phenyl) -2methylpropanamide and 4-methoxyphenyihydrazine hydrochloride: ESMS m/e: 528.2 (M Example 713 WO 03/004027 WO 0/00027PCT/UJS02/21063 428, N- CHLOROPHENYL) lIH-INDOL-3-YL] PROPYL}-4-PIPERTDINYL)PHENYLJ-2-
METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using (4-chiorophenyl) -5--oxopentyl) -4-piperidinyl~phenyl) -2methylpropanamide and 4 -methoxyphenyihydrazine hydrochloride: ESMS m/e: 544.2 (M H) Example 714 N-[3-C2.-{3-[2-(4-FLUOROPHENYL)-1H-BENZOEGINDOLz-3- YL] PROPYL}-4 -PIPERIDINYL) PHENYLI -2 -METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using (4-f luorophenyl) -5-oxopentyl) -4-p~iperidinyl)phenyl) -2methyipropanamide and 1-naphthylhydrazine hydrochloride: ESD'S ni/e: 548.2 H)4-.
Example 715 NU-[3- (4-BLUOROPHENYL) -5-(TRIFLUOROMETHOXY) -1H- INDOL-3-YLJ PROPYL}-4-PI:PERIDINYL) PHENYLJ -2-
METHYLPROPAZANIDE:
Prepared by Procedure E and Scheme M using N(-1 (4-f luorophenyl) -5-oxopentylJ -4-piperidinyl~phenyl) -2methylpropananide and 4- (trifluoromethoxy) phenyihydrazine hydrochloride: ESMS m/e: 582.9 (M H) 4 Example 716 N- (4-FLUOROPHENYL) -7-METHYL-1LH-INDOL-3- YLJ PROPYL) -4 -PIPERIDINYL) PHENYLJ -2 -METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using (4-f luorophenyl) -5-oxopentyl] -4-piperidinyl~phenyl) -2methyipropanamide and 1- (2 -methyiphenyl) hydrazine hydrochloride: ESMS m/e: 512.2 (M H1)4.
WO 03/004027 WO 0/00027PCT/UJS02/21063 429 Example 717 U- (4-FLUOROPHENYL) -lH-INflOL-3-YLJPROPYL}-4- PIPERIDINYL) PHENYL) -2 -METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using fluoropheny.) -5-oxopentyl] -4-piperidinyllphenyl) -2methyipropanamide and pheriylhydrazine: ESMS m/e: 498.2 (M Example 718 N- (4-FLUOROPHENYL) -5-METHYL-1H-INDOL-3- YLJ PROPYL} -4 -PIPERIDINYL) PHENYLJ -2-METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M~ using (4-f luorophenyl) -5-oxopenty1l -4-piperidinyl~phenyl) -2is methyipropanamide and 4-methylphenylhydrazine hydrochloride: ESMS m/e: 512.2 (M Example 719 N- (4-CHLOROPHENYL) -7-METHYL-lH-INDOL-3- YLI PROPYL} -4 -PIPERIDINYL) PHENYL] -2 -METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using (4-chloropheiyl) -5-oxopentyl] -4-piperidinyl~phenyl) -2methyipropanamide and 1- (2-methyiphenyl) hydrazine hydrochloride: ESMS m/e: 528.2 CM H+ Example 720 N- (4-CHLOROPHIENYL) -5-METHYL-lH-IND)OL-3- YL] PROPYL) -4-PIPERIDINYL) PHENYL] -2 -METHYLPRQPANAMIDE: Prepared by Procedure E and Scheme M using (4-chiorophenyl) -5-oxopentyl] -4-piperidinyl~phenyl) -2methyipropanamide and 4 -methyiphenyihydrazine hydrochloride: ESMS rn/e: 528.2 (M WO 03/004027 WO 0/00027PCT/UJS02/21063 430 Example 721 (4-CHLOROPHENYL) -1-PHENYL-1H-INDOL-3- YLJ PROPYL) -4 -PIPERIDINYL) PHEIYLJ -2-METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using N-(3-(1-IiS- (4-chiorophenyl) -5-oxopentyl) -4-piperidinyllphenyl) -2methyJlpropanamide and 1, l-diphenyJlhydrazine hydrochloride: ESMS 590.2 (M Example 722 N-[3-(1-{3-[2-(3-CHLOROPHEINYL)-7-METHYL-1H-INDOL-3- YLJ PROPYL) -4-PIEPERIDINYL) PHENYL] -2 -METHYLPROPANAMIDE:.
Prepared by Procedure E and Scheme M using (3-chiorophenyl) -5-oxopentyll -4-piperidinyl~phenyl) -2methyipropanamide and 1- (2-methylphenyl)hydrazine is hydrochloride: ESMS m/e: 528.1 (M Example 723 N- (3-CHLOROPHENYL) (TRIFLUOROMETHOXY) -11- INDOL-3-YL] PROPYL}-4-PIPERIDINYL) PHENYL] -2-
METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using (3-chlorophenyl) -S-oxopentyl] -4-piperidinyl~phenyl) -2methyipropanamide and 4- (trifluoromethoxy) phenyihydrazine hydrochloride: ESMS m/e: 598.2 (M Example 724 N- (3-CHiLOROPHENYL) -l-METHYL-lR-INDQL-3- YL] PROPYL}-4-PIPERIDINYL) PHENYLJ -2-METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using N-(3-t1-[5- (3-chiorophenyl) -5-oxopentyll -4-piperidinyl~phenyl) -2methyipropanamide and l-methyl-l-phenylhydrazine: ESMS m/e: 5 28. 2 (M WO 03/004027 WO 0/00027PCT/UJS02/21063 431 Example 725 N- (3-CH-LoRoPHJENYL) -l-PHENYL-1H-IN'DOL-3- YL] PROPYL} -4 -PIPERIDINYL) PHENYL 2-METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using N(-l (3-chiorophenyl) -5-oxopentyl] -4-piperidinyllphenyl) -2methylipropanarnide and 1, 1-diphenyihydrazine hydrochloride: ESMS m/e: 590.3 (M Example 726 N- (3-CHLOROPHENYL) -S-METHOXY-H-INDOL-3- YLJ PROPYL}-4-PI:PERIDITNYL) PHENYL] -2-METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M (3-chiorophenyl) -5--oxopentyll -4-piperidinyllphenyl) -2methylpropanamide and 4-methoxy-phenylhydrazile hydrochloride: ESMS 544.3 (M H) 4 Example 727 (3-CHLOROPHENYL) -5-METHYL-1H-IND)OL-3- YL] PROPYL} -4-PIPERIDINYL) PHENYL] -2 -HETHYLPROPANAMIDE:.
Prepared by Procedure E and Scheme M usingN-31E5 (3-chlorophenyl) -5-oxopentyll -4-piperidinyllphenyl) -2methylpropanamide and 4-methylphenylhydrazine hydrochloride: ESMS m/e: 528.2 (M Example 728 N- (3-CHLOROPHiENYL) -1H-BENZO[G]INDOL-3- YL] PROPYL} -4-PIPERIDINYL) PHENYL] -2 -METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using (3-chlorophenyl) -5-oxopentylj -4-piperidinyllphenyl) -2methylpropanamide and l-naphthylhydrazine hydrochloride: ESMS mle: 564.2 (M WO 03/004027 WO 0/00027PCT/UJS02/21063 432 Example 729 N- (3-CFHTOROPHENYL) -lH-INDOL-3-YL] PROPYL}-4- PIPERIDINYL) PHENYL] -2-METHYLPRQPANAMIDE: Prepared by Procedure E and Scheme M using N(-1 (3-chiorophenyl) -5-oxopentyl] -4-piperidinyl~phenyl) -2methyipropanamide and phenylhydrazine: ESMS rn/e: 514.2 M H Example 730 NV-[3-(l-{3-[2-(2-CHLOROPHENYL)-lH-INDOL-3-YL]PROPYL}-4- PIPERIDINIL) PHENYL] -2 -METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using chiorophenyl) -5-oxopentyl) -4-piperidinyllphenyl) -2methyipropanamide and phenyihydrazine: ESMS mle: 514.2 (M Example 731.
N- (2-CHiLOROPHENYL) -5-(TRIFLUOROMETHOXY) -1K- INDOL-3-YL] PROPYL}-4-PIPERIDINYL)PHENYL) -2- ZETHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using N-(3--{1-[5-(2-chlorophenyl)-5-oxopentyl] -4piperidinyl~phenyl) methyiprcpanamide and 4- (trifluorornethoxy) phenyihydrazine hydrochloride: ESMS m/e: 5.98.2 (M Example 732 N- (2-CHLQROPHENYL) -1H-BENZO[GJ INDOL-3- YLJ PRQPYL} -4 -PIPERIDINYL) PIENYL 2-METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using (2-chiorophenyl) -5-oxopentyl] -4-piperidinyl~phenyl) -2methylpropanamide and l-naphthylhydrazine hydrochloride: ESMS m/e: 564.2 (M H+ WO 03/004027 WO 0/00027PCT/UJS02/21063 433 Example 733 N- (2-CHiLORoPHEN4YL) -7-METHYL-lH-INDfOL-3- YL] PROPYL) -4 -PIPERIDINYL) PHEbIYLI -2 -IETHYLPROPANAMIDE: Prepared by Procedure E and Scheme M (2-chiorophenyl) -5-oxopentylj -4-piperidinyllphenyl) -2methyipropanamide and 1- (2-methylphenyl)hydrazine hydrochloride: ESMS m/e: 528.2 (M Example 734 N- [3-(1-{3-E2-(2-CHLOROPHENYL)-l-PHENYL-lH-INDQL-3- YL] PROPYL} -4 -PIPERIDINYL) PHENYLJ -2 -METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M (2-chiorophenyl) -5-oxopentyl] -4-piperidinyllphenyl) -2methylpropananide and 1, 1-diphenyihydrazine hydrochloride: ESMS m/e: 590.2 (M H-)4.
Example 735 N- (2-CELOROPHENYL) -l-METHYL-lH-INDOL-3- YLJ PROPYL) -4 -PIPERIDINYL) PHiEYL] -2 -METHYLPROPANAMIDE: 2C Prepared by Procedure E and Scheme M using N-(3-{l-15- (2-chiorophenyl) -5-oxopentyll -4-piperidinyl~phenyl) -2methylpropanamide and 1-methyl- 1-phenyihydrazine: ESMS m/e: 5 28. 2 (M H).
Example 736 N- (2-CHLOROPHENYL) -5-METHYL-lH-INDOL-3- YLJ PROPYL}-4-PI:PERI:DINYL) PHENYL] -2-METHYLPROPANAMIDE:.
Prepared by Procedure E and Scheme M using (2-chlorophenyl) -5-oxopenty.J-4-piperidinyl~phenyl) -2methylpropanamide and 4 -methylphenylhydrazine hydrochloride: ESMS m/e: 528.2 (M Example 737 WO 03/004027 WO 0/00027PCT/UJS02/21063 434 YL] PROPYL}-4 -PIPERIDINYL) PHENYL2 -2-ZETHYLPROPANAMIDE; Prepared by Procedure E and Scheme M using N- (3-iodophenyl) -5-oxopentyl) -4-piperidinyl~phenyl) -2methyipropanamide, and phenyihydrazine: ESMS nile: 606.2 (M Example 738 N- E3- (3-IODOPH-ENYL) -l-METHYL-lII-INDOL-3- YLI PROPYL) -4 -PIPERIDIqYL) PHEINYLJ -2-METHYLPROPANAMdIDE: Prepared by Procedure E and Scheme M using (3-iodophenyl) -5-oxopentyl] -4-piperidinyl~phenyl) -2methyipropanamide and 1-methyl-1-phenylhydrazine: ESMS m/e: 620.2 (M Example 739 N- (3-IODOPHENYL) -1-PHENYL-lH-INDOL-3- YLJ PROPYL) -4 -PIPERIDINYL) PHEINYLJ-2 -HETHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using (3-lodophenyl) -5-oxopentyll -4-piperidinyllphenyl) -2methyipropanamide and 1, 1-diphenyihydrazine hydrochloride: ESMS m/e: 682.2 (M Example 740 N- [3-(l-{3-[2-(3-IODOPHENYL)-lH-BENZO[G]INDOL-3- YL) PROPYL) -4 -PIPERIDINYL) PHENYL] -2 -METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using (3-lodophenyl) -5-oxopentyl] -4-piperidinyl~phenyl) -2methyipropanamide and l-naphthylhydrazine hydrochloride: ESMS m/e: 656.2 (M Example 741 WO 03/004027 WO 0/00027PCT/UJS02/21063 435 H- IODOPHENYL) (TRIFLUOROMETHOXY) -1H-INDOL-3 -YL] PROPYL} -4- PIPERIDINYL) PHENYL) -2 -METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using ES- (3-iodophenyl) -5-oxopentyll -4-piperidinyllphenyl) -2methyipropanamide and 4- (trifluoromethoxy) phenyihydrazine hydrochloride: ESMS mle: 690.2 (M Example 742 NM- 3- (3-IODOPHENYL) -5-METHYL-lH-INDOL-3- YL] PROPYL) -4 -PIPERIDINYL) PHENYL] -2-METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using (3-iodophenyl) -5-oxopentyl] -4-piperidinyl~phenyl) -2methylpropanamide and 4 -methyiphenyihydrazine hydrochloride; ESMS m/e: 620.2 CM Example 743 N- (3-IODOPHENYL) -7-METHiYL-lH-INDOL-3- YLJ PROPYL} -4 -PIPERIDINYL) PHENYL] -2 -METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using (3-iodophenyl) -5-oxopentyl] -4-piperidinyl~phenyl) -2methylpropanamide and 1- (2 -methyiphenyl) hydrazine hydrochloride: ESMS m/e: 620.2 CM Example 744 N- (4-IODOPHENYL) (TRIFLUOROMETHOXY) -1ff- INDOL-3-YL] PROPYL}-4-PIPERIDINYL) PHENYL]
METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using (4-iodophenyl) -5-oxopentyl] -4-piperidinyllphenyl) -2methyipropanamide and 4- WO 03/004027 WO 0/00027PCT/UJS02/21063 436 (trifluoromethoxY) phenyihydrazine hydrochloride: ESMS in/e: 690.1 (M Examrple. 745 N- (4-IODOPHENYL)-5-METHYL-1H-INDQL-3- YL] PROPYL) -4 -PIPERIDINYL) PHE1NYLJ -2-METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M usingN-3{-- (4-iodophenyl) -5-oxopentyl] -4-piperidinyllphenyl) -2methylpropanamide and 4 -methyiphenyihydrazine hydrochloride: ESMS m/e: 620.1 (M Example 746 N- (4-I:ODOPHENYL) -7-METHYL-lH-I:NDOL-3- YL] PROPYL} -4 -PIPERIDINYL) PHENYL] -2 -METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using (4-iodophenyl) -5-oxopentyll -4-piperidinyl~phenyl) -2methyipropanamide and 1- (2-methylphenyl)hydrazine Hydrochloride: ESMS ni/e: 620.1 (M H+ Example 747 N- (4-IODOPHENYL) -1-PHENYL-lH-INDOL-3- YLJ PROPYL} -4-PIPERIDINYL) PHENYL] -2-METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using (4-iodophenyl) -5-oxopentyl] -4-piperidinyl~phienyl) -2methyipropanamide and 1,1-diphenylhydrazine hydrochloride: ESMS m/e: 682.1 (M Example 748 N- (4-IODOPHENYL) -1-METHYL-lH-INDOL-3- YL) PROPYLI -4-PI:PERIINYL) PHENYL] -2 -METHYLPROPANMIDE: Prepared by Procedure E and Scheme M using (4-iodophenyl) -5-oxopentyl] -4-piperidinyl }phenyl) -2- WO 03/004027 WO 0/00027PCT/UJS02/21063 437 methyipropanamide and 1- methyl-l-phenylhydrazine: ESMS rn/e: 620.1 (M H" Example 749 N- [3-(l-{3-[2-(4-IODOPHENYL)-1H-BENZOEC]INDOL-3- YLI PROPYLI -4 -PIPERIDINYL) PHENYLJ -2 -METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using (4-iodaphenyl) -5-oxopentyl) -4-piperidinyllphenyl) -2methylpropananide and 1-naphthyllaydraz ine hydrochloride: ESMS m/e: 656.1 (M Example 750 N- (4-I:ODOPHENYL) -1H-INDOL-3-YLJPROPYL}-4- PIPERIDINYL) PHENYLJ -2 -METHYL 1
PROPANAMIDE:
Prepared by Procedure E and Scheme M using (4-lodophenyl) -5-oxopentyl] -4-piperidinyllphenyl) -2methyipropanamide and phenyihydrazine: ESMS m/e: 606.1 (M H' Example 751 N- (3-BROMOPHENYL) (TRIFLUOROMETHOKY) -lH- INDOL-3-YL] PROPYL}-4-PIPERIDINYL) PHENYLJ -2- METRYLPROPANAMIDE: Prepared by Procedure E and Scheme M using (3-bromophenyl) -5-oxopentyl] -4piperidinyl~phenyl)-2-methylpropanamide and 4- (trifluoromethoxy) phenyihydrazine hydrochloride: ESMS m/e: 642.0 (M Example 752 N- (4-BROMOPHENYL)-1H-BENZO[G]INDOL-3- YLJ PROPYL} -4-PIPERIDINYL) PHENYL] -2 -METHYLPRDPANAMIDE: Prepared by Procedure E and Scheme M using (4-bromophenyl) -5-oxopentyl] -4-piperidinyllphenyl) -2- WO 03/004027 WO 0/00027PCT/UJS02/21063 438 methyipropananide and 1- naphthylhydrazine hydrochloride: ESMS m/e: 608.0 (M Example 753 (1-{3-[2-(4-BROMOPHENYL)-7-M.ETHYL-lH-INDOL-3- YL] PRCPYL}-4 -PIPERIDI:NYL) PHENYL] -2 -METIHYLPROPANAMNIDE- Prepared by Procedure E and Scheme M using, N- C4-brcmophenyl) -5-oxopentyl] -4-piperidinyllphenyl) -2methyipropanamide and 1- (2-methylphenyl)hydrazine hydrochloride: ESMS zn/e: 572 (M H) 4 Example 754 N- (4-BROMOPHENYL) -5-(TRI:FLUOROMETHiOXY) -lH- INDOL-3-YL] PROPYL}-4-PIPERIDINYL) PHIIYL] -2- METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using N- (4-bromopheny.) -5-oxopentyl] -4piperidinyl~phenyl) -2-methylpropanamide and 4- (trifluoromethoxy) phenylhydrazine hydrochloride: ESMS mle: 642 (M Example 755 Nq-[3- (3-BROMOPHENYL) -lH-BEN~ZO [GJINDOL-3- YLJ PROPYL) -4 -PIPERIDINYL) PHENYL] -2-METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using (3-brornophenyl) -5-oxopentyl] -4-piperidinyllphenyl) -2methylpropanamide and 1-naphthylhydrazine hydrochloride: ESMS nile: 608.0 (M Example 756 N- [3-(l-{3-[2-(4-BROMOPHENYL)-lH-INDOL-3-YL]PROPYL}-4- PIPERIDINYL) PHENYL] -2-METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using bromophenyl) -5-oxopentyli -4-piperidinyllphenyl) -2- WO 03/004027 WO 0/00027PCT/UJS02/21063 439 methyipropanamide and phenyihydrazine: ESMS mie: 558.1 (M H)4*.
Example 757 N- E2- (3-BROMOPHENYL) -l-PHENYL-lH-INDfOL-3- YLI PROPYL} -4 -PIPERIDINYL) PHIEYL] -2-METHYLPROPANAMI:DE.
Prepared by Procedure E and Scheme M usir n (3-bromophenyl) -5-oxopentylj -4-piperidinyl~phenyl) -2rethylpropanamide and 1, 1-diphenyihydrazine hydrochloride: ESMS m/e: 634.0 (M Example 758 U- (3-BROMOPHENYL) -1-METHYL-1H-INDOL-3- YL] PROPYkL}-4-PIPEP.IDINYL)PHENYL] -2-METIIYLPROPANAM4IDE: Prepared by Procedure 2 and Scheme M using (3-broihophenyl) -5-oxopentylJ -4-piperidinyllphenyl) -2methyipropanamide and 1-methyl -1-phenyihydrazine: ESMS m/e: 5 72. 0 (MV H Example 759 NL- (4-BROMOPHENYL) -1-METHYL-lH-INDOL-3- YL] PROPYL) -4 -PIPERI:DINYL) PHENYL] -2-METHYLPROPANAMIDE: Prepared by Procedure 2 and Scheme M using (4-bromophenyl) -5-oxopentyl] -4-piperidinyl~phenyl) -2methyipropanamide and 1-methyl -1-phenylhydrazine; ESMS m/e: 572.0 (MV Example 760 N- (4-BROHOPHENYL) -l-PHENYL-lH-INDOL-3- YLJ PROPYi) -4 -PI:PERI:DINYL) PHENYLJ -2-METHYLPROPANAMIDE: Prepared by Procedure E, and Scheme M using (4-bromophenyl) -5-oxopentyl] -4-piperidinyllphenyl) -2- WO 03/004027 WO 03/04027PCTIUS02/2 1063 440 methyipropanamide and 1,1- diphenyihydrazine hydrochloride: ESMS m/e: 634.0 (M Example 761 N- [3-(l-3-2-(4-ROMOPHENL)--METHOXY-lH-INflOL-3- YL] PROPYL}-4-PIPERIDIN~YL)PHENYL) -2-METH-YLPROPANA4IDE: Prepared by Procedure E and Scheme M using (4-brornophenyl) -5-oxopentyll]-4-piperidinyl~phenyl) -2mechylpropanamide and 4 -methoxyphenyihydrazine hydrochloride: ESMS m/e: 588.1 (M Example 762 N- (3-BROMOPHENYL) -7-METH.YL-lH-INDOL-3- YL] PROPYL) -4 -PIPERIDINYL) PHENYL] -2-METHYLPROPAN kMIDE- Prepared by Procedure E and Scheme M using (3-bromopheayl) -5-oxopentyl] -4-piperidinyl~phenyl) -2methylpropananide and 1- (2-miethyiphenyl) hydrazine hydrochloride: ESMS m/e: 572 (M H) 4 Example 763 C1-{3- (3-BROMOPHENYL) -5-METHYL-lH-INDOL-3- YL] PROPYL} -4 -PIPERI:DINYL) PHENYL] -2-METHYLPROPANAMIDE- Prepared by Procedure E and Scheme MI using (3-bromophenyl) -5-oxopentyl] -4-piperidinyl~phenyl) -2methylpropanamide and 4-methyl-ohenylhydrazine hydrochloride: ESMS m/e: 572 (M Example 764 N- (4-BROMOPHENYL) -5-METHYL-lH-INDOL-3- YLI PROPYL} -4 -PIPERIDINYL) PHENYL] -2-METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using (4-bromophenyl) -5-oxopentyl] -4-piperidinyllphenyl) -2- WO 03/004027 WO 0/00027PCT/UJS02/21063 441 methyipropanamide and 4- methylphenylhydrazine hydrochloride: ESMS mle: 572.0 (M Example 765 N-E3- (3-BROMOPHENYL)-5-METHOXY-l-INDfOL-3- YL] PROPYL) -4 -PIPERIDINYL) PHENYL] -2 -METHYLPROPANAMI:DE: Prepared by Procedure E and Scheme M using (3-bromophenyl) -5-oxopentyl] -4-pi-peridinyllphenyl) -2methylpropananide and 4 -methoxyphenylhydrazime hydrochloride: ESMS rn/a: 588.0 (M Example 766 2-METHYL-N- C3-NITROPHENYL) -lH-INDOL-3- YLJ PROPYL}-4-PIPERIDINYL) PHENYL] PROPANAMIDE: Prepared by Procedure E and Scheme M using 2-methyl-Ni- [5-(3-nitrophenyl) -5-oxopentyll -4piperidinyllphenyl) propanamide and phenyihydrazine: ESMS rn/a: 52-5.2 (M H) 4 2b Example 767 2-METHYL-N- (3-NITROPHENYL) -1H-BENZO[G] INDOL- 3-YL] PROPYL}-4-PIPERIDINYL)PHENYLIPROPANAMIDE: Prepared by Procedure E and Scheme M using 2-iTethyl-.N- [5-(3-nitrophenyl) -5-oxopentyl] -4piperidinyllphenyl)propanamide and 1-naphthylhydrazine hydrochloride: ESMS rn/e: 575.1 (M Example 768 2-METHYL-N- (3-NITROPHiENYL) (TRIFLUOROMETHOXY) -1H-INDOL-3-YL] PROPYL}-4- PIPERIDINYL)PHENYLJPROPANAMIDE: Prepared by Procedure E and Scheme M using 2-methyl-N- (3-nitrophenyl) -oxopentyl] -4 -piperidinyl. phenyl) propanamide and 4- WO 03/004027 WO 0/00027PCT/UJS02/21063 442 (trifluoromethoxy)phenylhydrazile hydrochloride: ESMS mle: 609.1 (M Example 769 2-METHYL-N- E5-METHYL-2- (3-NITROPHENYL)-1H- INDOL- 3-YL) PROPYL) -4 -PIPERIDINYL) PHENYL] PROPMIAMIDE: Prepared by Procedure E and Scheme M using 2-methyl-N7- [5-(3-nitrophenyl) -5-oxopentyl] -4piper--dinyllphenyl) propanarnide 'and 4 methyiphenyihydrazine hydrochloride: ESMS m/e: 539.2 (M H) Example 770 N- [5-METHOXY-2- (3-NITROPHENYL) -1H-INDOL-3- 1s YL] PROPYL} -4-PIPERIDINYL) PHENYL] -2 -METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using 2-methyl-NV- (3-nitrophenyl) -5-oxopentyl] piperidinyl }phenyl) propanarnide and 4methoxyphenyihydrazine hydrochloride: ESMS ni/e: 555.2 (M Example 771 2-METHYL-N- (3-NITROPHENYL) -l-PHENYL-lH- INDOL-3 -YL] PROPYL} -4 -PIPERIDINYL) PHENYLJ PROPANAMIDE: Prepared by Procedure E and Scheme M using 2-methyl-N- (3-nitrophenyl) -5--oxopentyl] -4piperidinyl }phenyl) propanamide and 1.1 -diphenyihydrazine hydrochloride: ESMS m/e: 601.1 (M Example 772 2-METHYL-N- [l-METHYL-2- (3-NITROPHENYL) -lH- INDOL-3 -YLI PROPYL} -4 -PIPERIDINYL) PHENYL) PROPANAMIDE: Prepared by Procedure E and Scheme M using 2-methyl-N- WO 03/004027 WO 0/00027PCT/UJS02/21063 443 (3-nitrophenyl) 5-oxopentyl] -4piperidinyll}phenyl) propanamide and 1-methyl-i phenylhydrazine: ESMS m/e: 539.2 (M Example 773 2-METHYL-N- [7-METHYL-2- (3-NITROPHENYL) -3MflJDOL-3-YLJ PROPYL}-4-PIPERIDINYL) PHENqYLJ PROPANAMIDE: Prepared by Procedure E and Scheme M using 2-methyl-N- (3-nitrophenyl) -5-oxopentyll -4piperidinyllphenyl) propanamide and -2 methylphenyl)hydrazine hydrochloride: ESMS m/e: 539.2 (M Example 774 N- [3-(l-(3-[5-METHOXY-2- (4-NITROPHiENYL)-1H-INDOL-3- YLJ PROPYL) -4 -PIPERIDI:NYL) PHENYL] -2-METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using 2-methyl-N- (4-nitrophenyl) -5-oxopentyl] -4piperidinyl~phenvl) propanamide and 4methoxyphenyihydrazine hydrochloride: ESMS mle: 555.6 (M Example 775 N- (2-BROMOPHENYL) -lH-I:NDOL-3-YL]PROPYL>-4- PIPERID)INYL) PHENYL] -2-METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using bromophenyl) -5-oxopentyl] -4-piperidinyl }phenyl) -2methyipropanamide and phenyihydrazine: ESMS m/e: 557.9 (M H+ Example 776 2-METHYL-N- [5-METHYL-2- (4-NITROPHENYL) -iN- INDOL- 3-YLJ PROPYL)-4 -PIPERIDIQYL) PHENYL] PROPA.NAMIDE: WO 03/004027 WO 0/00027PCT/UJS02/21063 444 Prepared by Procedure E and Scheme M using 2methyl-N- 5- (4-nitrophenyl) -5-oxopentyl] -4piperidinyl }phenyl) propanamide and 4met hyiphenyihydra zine hydrochloride: ESMS m/e: 539.1 (M +H Example 777 2-METHYL-N- (4-NITROPHENYL) -lH-BENZO INDOL- 3 -YL] PROPYL} -4 -PIPERIDINYL) PHENYL] PROPANAMIDE: Prepared by Procedure E and Scheme M using 2-methyl--N-(3-{l- (4-nitrophenyl) -5-oxopentyl] -4piperidinyl }phenyl) propanamide and 1-naphthylhydrazine hydrochloride: ESMS in/e: 574.7 (M Example 778 2-METHiYL-N- (4-NITROPIIENYL) (PHENYLEYDRAZONO) PENTYLJ -4- PIPERIDINYL}PHENYL) PROPANAMIDE: Prepared by Procedure E and Scheme AX using 2-methyl-N- [5-(4-nitrophenyl)-5-oxopentyl]-4piperidinyl }phenyl) propanamide and phenyihydrazine: ESMS m/e: S42.4 (M H' Example 779 2-METHYL-N-[3-(l-{3- E7-METHIYL-2-(4-NITROPHENYL)-lH- INDOL-3-YL] PROPYL) -4 -PIPERIDINYL) PHENYLJ PROPANAMIDE: Prepared by Procedure E and Scheme M using 2-methyl-N- (4-nitrophenyl) -5-oxopentyl] -4piperidinyllphenyl)propanamide and 1- (2methylphenyl)hydrazine hydrochloride: ESMS m/e: 538.8 CM n)+ Example 780 WO 03/004027 WO 0/00027PCT/UJS02/21063 4145 2 -METHYL-N-(3 (SE) -5 (4-NITROPHENYL)-5-{ [4- (TRIFLUOROMETHOXY) PEENYL) HYDRAZONO}PENTYL) -4- PIPERIDINYL]PHENYL}PROPANAMIDE: Prepared by Procedure E and Scheme M using 2-methyl--N-(3-{l-ES-(4-litrophelyl)- 5-oxopentyll -4-piperidinyllphenyl) propanamide and 4- (trifluoromethoxy) phenyihydrazine hydrochloride: ESMS m/e: 626.2 (M Example 781 (1-{3-E2-(2-BROMOPHENYL)-1H-BENZO[G]INDOL-3- YL] PROPYL) -4 -PIPERI:DINYL) PHEN~YL] -2-METHYLPROPANMIDE: Prepared by Procedure E and Scheme M using (2-bromophenyl) -5-oxopentyl) -4-piperidinyllphenyl) -2methyipropanamide and l-naphthylhydrazine hydrochloride: ESMS m/e: 608.0 (M Example 782 N- (2-BROHOPHENYL) (TRIFLUOROMETHOXY) -lH- INDOL-3-YL) PROPYL}-4-PlPERIDINYL) PHENYL) -2- METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using NV-(3--{l-[5-(2-bromophenyl)-5-oxopentyl) -4piperidinyl }phenyl) -2 -methyipropanamide and 4- (trifluoromethoxy) phenylhydrazine hydrochloride: ESMS m/e: 641.9 (M H+ Example 783 N- (2-BROMOPHENYL) -7-METHYL-lH-INDOL-3- YL] PROPYL} -4 -PIPERIDINYL) PHENYL] -2 -METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M usingN-3{[- (2-bromophenyl) -5-oxopentyl] -4-piperidinyl~phenyl) -2methylpropanamide and 1- (2-methyiphenyl) hydrazine hydrochloride: ESMS m/e: 572.0 (M WO 03/004027 WO 0/00027PCT/UJS02/21063 446 Example 784 2- (2-B3ROMOPHENYL) -1-PHENTYL-1H-IND)OL-3- YL] PROPYL}-4 -PIPERIDINYL) PHENYLJ -2 -METHYLPROPANAMIDE: Prepared by Procedure E and Scheme -M using N- (2-bromophenyl) -5-oxopentyl2 -4-piperidinyllphenyl) -2methylpropanamide and 1, 1-diphenyihydrazine hydrochloride: ESMS rn/e: 634 (M H) 4 Examiple 785 N- [2-(2-BROMOPHENYL)-5-METHYL-1H-INDOL-3- YL] PROPYL}-4 -PIPERIEDINqYL) PHENYL] -2-METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using (2-bromophenyl) -5-oxopentyl] -4-piperidinyllphenyl) -2methyipropanamide and 4 -methyiphenyihydrazine hydrochloride: ESMS m/e: 572.0 (M +i Example 786 N- (2-IODOPHENYL) -5-(TRIFLUOROMETHOXY) -1H- INDOL-3-YL] PROPYL}-4-PIPERIDINYL) PHENYLJ -2-
METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using (2-lodophenyl) -5-oxopentyl) -4-piperidinyllphenyl) -2methyipropanamide and 4- (trifluoromethoxy) phenyihydrazine hydrochloride: ESMS m/e: 6 90. 0 (M H).
Example 787 N- (2-IODOPHENYL) -5-METHYL-lH-INDOL-3- YL] PROPYL) -4 -PIPERIDINYL) PHENYLJ -2 -METHYLPROP.ANAMIDE: Prepared by Procedure E and Scheme M usingN-3{[- (2-iodophenyl) -5-oxopentyl] -4-piperidinyllphenyl) -2methyipropanamide and 4 -methylphenylhydrazine hydrochloride: ESMS m/e: 620.2 (M WO 03/004027 WO 03/04027PCTIUS02/2 1063 447 Example 788 2-METHYL-N- [1-METHYL-2- (4-NITROPHENYL) -lH- INDOL-3 -YL] PROPYL} -4 -PIPERIDINYL) PHENYL] PROPANAMIDE: Prepared by Procedure E and Scheme M using 2-methyl--N- ES- (4-nitrophenyl) -5-oxopentyl] -4pi-oeridinyl~phenyl) propanamide and 1-methyl-1phenyihydrazine: ESMS m/e: 539.6 (M Example 789 2-METHYL-N- (4-NITROPHENYL) -1-PHENYL-1H- INDOL-3-YL] PROPYL}-4-PIPERIDINYL) PHENYL] PROPANAMIDE: Prepared by Procedure E and Scheme M using 2-methyl-.N- (4-nitrophenyl) -5-oxopentyl] -4is piperidinyllphenyl) propanamide and 1, 1-diphenyihydrazine hydrochloride: ESMS m/e: 601.6 (M Example 790~ (1-{3-f2 (2-I:ODOPHENYL) -lH-INDOL-3-YL]PROPYL}-4- PIPERIDINYL)PHE-YLJ -2-METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using (2-lodophenyl) -5-oxopentyl] -4-piperidinyllphenyl) -2methyipropanamide and phenyihydrazine: ESMS m/e: 606.1 (M 2S Example 791.
N- (2-IODOPHENYL) -lH-BENZO[G]INDOL-3- YL] PROPYL}-4 -PIPERIDINYL) PHENYL] -2-METHYLPROPANANIDE; Prepared by Procedure E and Scheme M using NV-(3-{1-C5- (2-iodophenyl) -5-oxopentyll -4-piperidinyllphenyl) -2methyipropanamide and 1 -naphthylhydrazine hydrochloride: ESMS m/e: 656.1 (M WO 03/004027 WO 0/00027PCT/UJS02/21063 448 Example 792 N- (2-IODOPHENYL) -1-PHiENYL-lH-INDOL-3- YLJ PROPYL}-4 -PIPERIDINYL) PHENYL] -2 -METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using N-(3-{1-E5- (2-iodophenyl) -5-oxopentyl] -4-piperidinyllphelyl) -2methyipropanamide and 1, 1-diphenyihydrazine hydrochloride: ESMS nile: 682.1 (M H+ Example 793 N- E2-(2-IODOPH-ENYL)-7-METHYL-lE-I:NDOL-3- YL) PROPYL) -4 -PIPERIDINYL) PHENYL] -2 -METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using (2-iodophenyl) -5-oxopentyl) -4-piperidinyl~phenyl) -2methyipropanamide and 1- (2-methylphenyl)hydrazine hydrochloride: ESMS m/e: 619.6 (M Example 794 N- Cl-{3- (2-BROMOPHENYL) -l-METHYL-lH-INDOL-3- YL] PROPYL>.4 -PIPERIDINYL) PHENYL] -2 -METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M using N(-l (2-bromophenyl) -5-oxopentyl) -4-piperidinyl~phenyl) -2methyipropanamide and 1-methyli--phenylhydrazine: ESMS m/e: 572 (M Example 795 4-(3,4-DIFLUOROPIIENYL)-N-(3-{4- [3- (ISOBUTYRYLAMINO) PHENYL] -l-PIPERIDINYL}PROPYL) -2 -METHYL- 6 -OXQ-1, 415,6 -TETRAHYDRO-3 -PYRIDINECARBOXAMIDE: Prepared by Procedure AC and Scheme AM using 4- (3,4difluorophenyl)-2-methyl-6-oxo-1,4,5,6-tetrahydro-3pyridinecarboxylic acid and [1-(3-aminopropyl) -4piperidinyl] phenyl} -2-methyipropanamide: ESMS nile: 553.0 (M WO 03/004027 WO 0/00027PCT/UJS02/21063 449 Example 796 4- (2,4-DIFL UOROPHENYL) (ISOBTJTYRYLAMINO) PHENYL) -1- PIPERIDINYL}PROPYL) -2-METHYL-6-OXO-l,4,5,6-TETRAHYDRO-3- PYRIDINECARBOXAMIDE: Prepared by Procedure AC and Scheme AM using 4- (2,4-difluorophenyl) -2-methy1-6-oxo- 1,4, 5,6-tetrahydro-3-pyridinecarboxylic acid and N-{3- (3-aminopropyl) -4-piperidinyljphenyl} -2methyipropanamide: ESMS m/e: 553.0 CM Example 797 (4-METHOXYPHENYL)BUTYL] -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure 0 and Scheme W using 4-(4-methoxyphenyl)-1butanci and 2-methyl-N-[3-(4piperidinyl)phenyllpropanamide: ESMS m/e: 409 (M Example 798 [3-(1,2-DIPHENYL-2LH-INDO)L-3-YL)PROPYL]-4- PIPERIDINYL}PHENYL)PROPANAMIDE: Prepared by Procedure 0 and Scheme W using 3-(J.,2-diphenyl-1H-indol-3-yl)-1propanol and N- (4-piperidinyl)phenyl] propanamide: ESMS m/e: 542.0 (M H+ Example 799 [1-(3,3-DIPHENYLPROPYL) -4- PIPERIDINYL] PHENYL}PROPANAMIDE. Prepared by Procedure 0 and Scheme W using 3,3-diphenyl-1-propanol and N- (4-piperidinyl)phenyljpropanamide: ESMS m/e: 427.0 (M H Example 800 WO 03/004027 WO 0/00027PCT/UJS02/21063 450 2-METHYL-N-(.3-{1- NITROPHENYL)BUTYLJ -4- PIPERIDINYL}PHENYL) Prepared by Procedure 0 and Scheme W using 4-(4-nitrophenyl)-L-butalol and 2-methyl-N-[3- (4-piperidinyl).phenyllpropalamide: ESMS m/e: 424.2 CM
H).
Example 803.
2-METHiYL-N-(3-{l- (1-NAPHTHYL) ETHYL] -4- PIPERIDIYL)PHENL) PROPANA(IDE Prepared by Procedure 0 and Scheme W using 2-(1-naphthyl)ethanol and 2-methyl-N- (4-piperidinyl)phenyllpropanamide: ESMS rn/e: 401.2 (M
H~
Example 802 is [1-(3,3-DIPHENYLPROPYL) -4-PIPERIDINYL]PHENYL}-2- METHYLPROPARAMIDE: Prepared by Procedure 0 and Scheme W using 3, 3-diphenyl-l-propanol and 2-methyl-NV- piperidinyl)phenyllpropanamide: ESMS m/e: 441.2 (M H+ Example 803 [3-(3,4-DIMETHOXYPHENYL)PROPYL] -4- PIPERIDIN~YL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure 0 and Scheme W using 3-(3,4-dimethoxyphenyl)- 1-propanol and 2-methyl-N-[3-(4piperidinyl)phenyllpropanamide: ESMS m/e: 425.2 (M Example 804 2-METHiYL-N-(3- [1-(3-PHENYLPROPYL) -4- PIPERIDIINYL]PHENYL)PROPMNAMIDE: Prepared by Procedure 0 and Scheme W using 3-phenyl-l-prcpanol and 2-methyl-N- (4-piperidinyl)phenyllpropanamide: ESMS m/e: 365.2 (M H).
WO 03/004027 WO 0/00027PCT/UJS02/21063 451 Example 805 2-METHYL-N- E3- (4-PYRID)INYL)PROPYL] -4- PIPERIDIN.YLPHENYL) PROPANAMIDE: Prepared by Procedure 0 and Scheme W using 3-(4-pyridinyl)-l-propanlol and 2methyl-N- (4-piperidinyl)phenylj propanamide: ESMS m/e: 366.2 (M HI)+.
Example 806 [1-(4-TERT-BUTYLBENZYL) -4-PIPERIDINYL]PHENYL}-2- ZETHYLPROPANAMIDE: Prepared by Procedure AJ and Scheme AV using 1-bromomethyl)-4-tert-butylbenzene and 2mnethyl (4-piperidinyl)phenyl] propanamide: ESMS m/e: 393.0 (M is Example 807 (4-BENZOYLBENZYL) -4-PIPERIDINYL]PHENYL}-2- METHYLPROPANAMIDE: Prepared by Procedure AJ and Scheme AV using [4-(bromomethyl)phenyll (phenyl)methanone and 2mrethyl-NL- (4-piperidinyl)phenylj propanamide: ESMS m/e: 441.0 (M l,2-DICHLOIRO-4-{ -3-CHLORO-l- PHENYLPROPYL]OXY}BENZENE: Prepared by Procedure A using 3,4-dichiorophenol and (IR) -3-chloro-l-phenyl-lpropanol.
Example 808 N-(3-.{1-[(3S)-3-(3,4-ITCHLOROPHENOXY)-3-PHENTYLPROPYL]-4- PIPERIDZINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure A using 1,2-dichloro-4-( -3-chloro-lphenylpropylloxy~benzene and 2 -methyl [3 (4 piperidinyl)phenyllpropanamide: ESMS mle: 525.3 (M WO 03/004027 WO 0/00027PCT/UJS02/21063 452 Example 809 (2-FLUOROPHENYL) -6-HYDROXYHEXYL] -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure L and Scheme AN using fluorophenyl) -6-oxohexylj -4-piperidinyl~phenyl) -2methyipropanamide: ESMS rn/c: 441.3 (M Example 810 N- (1-{5-HYDROXY-5- (TRIFLUOROMETHYL) PHENYL]PENTYL}- 4-PIPERIDINYL) PHENYL] -2 -METHYLPROPANAMIDE: Prepared by Procedure L and Scheme AN using 2-methyl-N- [3-(1-{5-oxo- (trifluoromethyl)phenyll pentyl} -4piperidinyl)phenyllpropanamide:- ESMS m/e: 477.2 (M Example 811 NV-(.3-f1- [-(4-FLUOROPHENYL) -5-HYDROXYPENTYLJ -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE; Prepared by Procedure L and Scheme AN using fluorophenyl) -5-oxopentyl) -4-piperidinyl~phenyl) -2methyipropanamide: ESMS m/le: 427.2 (M Example 812 (2-FLUOROPHENYL) -7-HYDROXYHEPTYL] -4- PIPERIDINYL}PHENYL) -2-METHiYLPROPANAMIDE: Prepared by Procedure L and Scheme AN using N- 1- (2fluorophenyl) -7-oxoheptyJ2 -4-piperidinyllphenyl) -2methyJlpropanamide: ESMS m/e: 455.2 (M Example 813 (3-FLUORO)PHENYL) -6-HYDROXYHEXYL] -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure L and Scheme AN using V- (3 6 WO 03/004027 WO 0/00027PCT/UJS02/21063 453 fluorophenyl) -6-oxohexyl] 4-piperidinyllphenyl) -2methyipropanamide: ESMS rn/e: 441.2 (M H' Example 814 NV-(3-{1-E5-(2-FLUT.OROPIENYL)--HYDROXYPENTYL) -4- PIPERIDINYL} PHENYL) -2 -METHYLPROPANAMIDE: Prepared by Procedure L and Scheme AN using V- (3 5-(2 f2uorophenyl) -5-oxopentylj -4-piperidinyl~phenyl) -2methyipropanamide: ESMS m/e: 427.2 (M Example 815 (3-FLUOROPHENYL) -5-HiYDROXYPENTYL] -4- PIPERIDINYLIPHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure L and Scheme AN using V- (3 1 fluorophenyl) -5-oxopentyl] -4-piperidinyl~phenyl) -2methyipropanamide: ESMS m/e: 427.2 (M Example 816 (3-CHLOROPlEENYL) -5-HiYDROXYPENTYL] -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure L and Scheme AN using [5 chiorophenyl) -5-oxopentyl] -4-piperidinyllphenyl) -2methyipropanamide: ESMS m/e: 443.1 (M Example 817 E6- (4-FLUOROPHENYL) -6-HYDROXYHiEXYLJ -4- PIPERIDINYL}PHENYL) -2-MET-HYLPROPANAMIDE: Prepared by Procedure L and Scheme AN using N- (4fluorophenyl) -6-oxohexylj -4-piperidinyl~phenyl) -2methy7.propanamide: ESMS mle: 441.2 CM WO 03/004027 WO 0/00027PCT/UJS02/21063 454 Example 818 S- (4-CHILOROPHIENYL) -6-H-YDROXYHEXYL] -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure L and Scheme AN using chiorophenyl) -6-oxohexyl] -4-piperidinyl~phenyl) -2methyipropanamide: ESMS rn/e: 456.9 (M Example 819 (4-CHLOROPHENYL) -5-HYDROXYPENTYL] -4- PIPERIDINYL}PHENYL) -2-METHYLPRQPANAMlIDE: Prepared by Procedure L and Scheme AN using chiorephenyl) -5-oxopentyl] -4-piperidinyl~phenyl) -2methyipropanamide; ESMS rn/c: 443.0 (M Example 820 L(.9-ETHYL-9H-CARBAZOL-3-YL) METHYL] -4- PIPERIDINYL}PHENYL)BUTANAMIDE: Prepared by Procedure F and Scheme R, without HOAc, using 9- ethyl -9H-carbazole- 3-carbaldehyde and piperidinyl)phenyl]butanamide: ESMS rn/e: 454.2 (M Example 821 [(9-ETHYL-9H-CARBAZOL-3-YL)METHYL] -4- PIPERIDI1NYL}PHENYL)PROPANAMIDE: Prepared by Procedure F and Scheme R, without HOAc, using 9 -ethyl 9-carbazole- 3-carbaldehyde andIV[3 4 piperidinyl)phenyllpropanamide: ESMS rn/e: 440.5 (M Example 822 [(1,9-DIMETHYL-9H-CARBAZOL-3-YL) METHYL] -4- PIPERIDINYL}PHiENYL) -2 -NETHYLPROPANAMIDE: Prepared by Procedure F and Scheme R, without HOAc, using 1,9dimethyl-9H-carbazole-3-carbaldehyde and 2-methyl-N- [3- WO 03/004027 WO 0/00027PCT/UJS02/21063 455 (4piperidinyl)phenyl-lpropanamide: 1H NMR (400 MHz, CDC1,) 6 8.05-G. 77 101-) 5. 20-5.12 (in, 1IH) 4. 04 3H) 3.93 2H) 3 .34-3.24 2H) 2.79 2.56-2.38 2H), 2.38-2.26 Cm, 2H) 2.08-1.88 2H), 1.82-1.70 Cm, 2H), 1. 16 Cd, 6H, J 6. 8 Hz) ESMSm/ae: 454. 2 (M
H).
Example 823 [(9-ETHYL-9H-CARBAZOL-3-YL)METHYLJ -4- PIPERIDINYLPHENYL) CYCLOPROPANECARBOXAM4IDE: Prepared by Procedure F and Scheme R, without KOAc, using 9-ethyl- 9H-carbazole-3-carbaldehyde and N- (4piperidinyl)phenyl] cyclopropanecarboxamide: ESMS nile: 452.6 CM Example 824 1- C3-{1- [(9-ETHYL-9H-CARBAZ.OL-3-YL)METHYLJ -4- PIPERIDINYL}PHENYL) -2-PYRROLIDINONE: Prepared by Scheme R and Procedure F. A solution of l-C9-ethyl-9Hcarbazol-3-yl)ethanone (22.3 mg, 0.100 mmol) and 1-[3- (4-piperidinyl)phenyl] -2-pyrrolidinone (27.2 mng, 0.100 minol) in 1,2-dichioroethane (1.00 mL) was treated with sodium triacetoxyborohydride (63.6 mg, 0.300 mmol) and HOAc (5.70 uL, 0.100 inmol) The mixture was stirred overnight at room temperature. The reaction mixture was treated with a saturated aqueous NaHCO 3 solution (10 inL).
The aqueous layer was extracted with CH 2 Clf (3 X 10 mL) and the combined organic layers. were washed with brine (10 mL) dried over MgSO 4 and concentrated in vacuo. The residue was purified by preparative TLC using 5% of NH, 0 M in methanol) in CH 2 C1 2 to give the desired product 1-C3-{i- [C9-ethyl-9H-carbazol-3-yl)methyl] -4- WO 03/004027 PCT/US02/21063 456 piperidinyl~phenyl)-2- pyrrolidinone (4.60 mg, 9.43 'H NMR (400 MHz, CDC1 3 6 8.04 1H, J 7.4 Hz), 7.99 1H), 7.43-7.28 5H), 6.96 Cd, 1H, J 7.4 Hz), 4.31 2H,, J= 6.8 Hz), 3.77 t, 2H, J 7.3 Hz), 3.70 2H), 3.06 2H, J 10.6 Hz), 2.56-2.42 3H) 2.07 4H) 1.77 4H) 1.36 (in, 3H); ESMS r/c: 452.5 CM N-{3-El-(1H-INDOL-5-YLMETHYL)-4-PIPERIDZINYL]PHENYL}-2- METHYLPROPANAMIDE: Prepared by Procedure F and Scheme R, without HOAc, using 1H-indole-5-carbaldehyde and 2methyl-N- [3-(4-piperidinyl)phenyl] propanaide: ESMS zn/e: 376.2 (M 1-(4-CHLOROBUTYL)-1U-INDOLE: Prepared by Procedure AH, and Scheme P using 1H-indole and 1-bromo-4-chlorobutane: 'NMR (400 MHz, CDCT 3 5 7.72-7.02 Cm, 5H), 6.49 1H, .J 2.8 Hz), 4.13 Ct, 2H, J 6.8 Hz), 3.48 Ct, 2H, J 6.8 Hz), 2.06-1.92 2H), 1.80-1.70 Cm, 2H).
1-(3-CHLOROPROPYL)-1H-INDOLE: Prepared by Procedure AH, and Scheme P using 1H-indole and 1-broio-3chioropropane: 'H NMR (400 MHz, CDC1 3 5 7.70-7.04 (m, 6.50 1H, LT 2.8 Hz), 4.31 2H, J 6.8 Hz), 3.42 Ct, 21, J 6.4 Hz), 2.28-2.20 2H).
Example 825 N- (1H-INDOL-1-YL)PENTYLJ-4-PPPERDINYL)PHENYL)- 2-METHYLPROPANAMIDE: Prepared by Procedure AH and Scheme P using 1-(5-chlcropentyl)-1H-indole and 2methyl-N- C4-piperidinyl)phenyllpropanamide: ESMS m/e: 432.3 (M WO 03/004027 WO 0/00027PCT/UJS02/21063 457 Example 826 (1H-INDOL-1-YL)PENTYL] -4- PIPERIDINYLPHENYL)BUTANAM(IDE: Prepared by Procedure All and Scheme P using 1-(5-chloropentyl)-1H-indole and N- [4-(4-piperidinyl)pheny1Jbutalamide.- ESMS m/e: 432.3 (M 4 Example 827 V- (1H-INDOL-1-YL) PENTYL] -4- PIPERIDINYLPHEN~Yta)PROPANAMIDE: Prepared by Procedure All and Scheme P using I- (5-chloropentyl) -1R-indole and N- (4-piperidinyl)phenyllpropanamide: ESMS in/e: 418.2 (M is Example 828 (1H-INDOL-1-YL)HiEXYL] -4- PIPERIDINYL}PHENYL)PROPANAMIDE: Prepared by Procedure All and Scheme P using 1-(6-chlorohexyl)-1H-indole and N- (4-piperidinyl)phenyll prcpanamide: ESMS m/e: 432.3 (M
H)
4 Example 829 2-METHYL-N-(3-{1-E(1-METHYL-1H-INDOL-2-YL)METHYLI-4- PIPERIDINYL}PHENYL)PROPANAMIDE: Prepared by Procedure F and Scheme R, without HOAc, using 1-methyl-IH-indole-2carbaldehyde and 2-methyl-N-[3- (4piperidinyl)phenyljpropanamide: ESMS m/e: 390.3 CM H) 4 Example 830 (lH-INDfOL-4-YLMETHYL)-4-PIPERIDINYL)PHENYL]-2- METHYLPROPANAMIDE: Prepared by Procedure F and Scheme R, without HOAc, using 1H-indole-4-carbaldehyde and 2- WO 03/004027 WO 0/00027PCT/UJS02/21063 458 methyl-N- (4piperidinyl)phenyllpropanamide: ESMS ni/e: 376.2 (M H) t Example 831 (1H-INDOL-1-YL)HEXYL] -4-PIPERIDINYLPHENYL) 2-METHYLPROPANAMIDE: Prepared by Procedure All and Scheme P using 1-(6-chlorohexyl)-lH-indole and 2-methyl- N- [4I-(4-piperidinyl)phenyllpropanamide: ESMS zn/e: 446.3 (M H).
Example 832 N-{3-El-(H-ETDOL-7-YLMETHYL) -4-P:PERIDINYLIPHENYL}-2- METHYLPROPAflAMIDE: Prepared by Procedure F and Scheme R, without I4OAc, using lH-indole-7-carbaldehyde and 2methyl-N- (4-piperidinyl)phenyllpropanamide: ESMS m/e: 376.2 (M E+ Example 833 N-E3- (4-METHOXYPHENYL) -lH-INDOL-5-YLJMETHiYL}-4- PIPERIDINYL) PHENYLJ -2-METHYLPROPANAMIDE: Prepared by Procedure C and Scheme Q1, with Cu~r in place of Cu, using l-iodo-4-methoxybenzene and ylmethyl) -4-piperidinyl] phenyl}-2-methylpropanamide: ESMS m/e: 4 82. 0(M H).
Example 834 METHYL 4- A- (ISOBUTYRYL1AMINO)PHENYL] -1- PIPERIDINYLMETHYL) -1H-INDOL-l-YLJ BENZOATE: Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using methyl. 4-iodobenzoate and N-{3-[l-(lH-indol-4ylmethyl) -4-piperidinyllphenyl}-2-methylpropanamide: ESMS 510.3 (M WO 03/004027 WO 0/00027PCT/UJS02/21063 459 Example 835 2-METHYL-N- [1-(3-METHYLPHENYL) YL] METHYL) -4 -PIPERIDINYL) PHENYL) PROPANAMIDE: Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using l-iodo-3-methylbenzene and ylmethyl) -4-piperidinyllphenyl} -2-methyipropanamide: ESMS m/e: 466.3 (M Example 836 N-[3-(l-{[-(4-FLUOROPHENYL)-lH-INDOL-4-YL)METHiYL}-4- PIPERIDINYL) PHENYL] -2 -lETHYLPROPANADMIDE: Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using l-fluoro-4-iodobenzene and Nv-{3- El- (1H-indol-4ylmethyl) -4-piperidinyllphenyl} -2-Tethylpropanamide: 'H NMR (400 MHz, ODC1 3 6 7.66-6.92 12H-) 6.65 1H, J 3.2 Hz), 3.69 2H), 3.15-3.02 (in, 2H), 2.58-2.40 2H), 2.20-2.04 2H), 1.94-1.76 4H), 1.25 (d, 6H1, J 6.8 Hz); ESMS m/e: 470.6 (M Example 837 E4- (1H-INDOL-l-YL)BUTYL] -4-PIPERIDINYL)PHENYL) 2-METRYLPROPANAMIDE: Prepared by Procedure All and Scheme P using l-(4-chlorobutyl)-lH-indole and 2-methyl- N- (4-piperidinyl)phenyll propanamide: ESMS m/e: 418.3 CM Example 838 NV-[3- (I1E- (4-CHLOROPHENYL) -1H-INDOL-5-YL)METHYL}-4- PIPERIDINYL) PHENYL] -2-METHYLPROPANAMIDE: Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-chloro-4-iodobenzene and yJlmethyl) -4 -piperidinyl) phenyl }-2-methylpropanamide: ESMS M/e: 486.2 (M WO 03/004027 WO 0/00027PCT/UJS02/21063 460 Example 839 N- l- (3-METHOXYPHENYL) -1H-IDfOL-5-YLJMETHYL}-4- PIPERIDINYL)PHENYL]-2-METHiYLPROPANAMIDE: Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using l-iodo-3-methoxybenzene and NV-{3- ylmethyl) -4-piperidinyl] phenyl 1-2 -methyipropanamide: ESMS rn/e: 482.2 (M Example 840 N- (4-(l1 4- (1H-IbJDOL-1-YL) BUTYL] -4- PIPERIDINYL}PHENYL)BUTANAMIlE: Prepared by Procedure AB and Scheme P using 1-(4-chlorobutyl)-1H-indole and N-[4- (4-piperidinyl)phenyllbutanamide: ESMS 418.2 (M Example 841 N- l- (2-METHOXYPHENYL) -lH-I:NDOL-!5-YL]METHYL)-4- PIPERIDINYL)PHENYL] -2-METHYLPROPANAMIDE: Prepared by Procedure C and Scheme Q1., with CuBr in place of Cu, using 1-iodo-2-methoxybenzene and NV-{3- ylmethyl) -4-piperidinyllphenyl} -2-methyipropanamide: ESMS 4 82. 2 (M 1H).
Example 842 N- El- (3-CHLOROPHENYL) -1H-INDOL-5-YL]METHYL}-4- PIPERIDINYL) PHENYL] -2 -HETHYLPROPANAMIDE: Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-chloro--3-iodobenzene and N-{3-El- ylmethyl) -4-piperidinyllphen-yl}-2-methylpropanamide: ESMS m/e: 486.2 (M WO 03/004027 WO 0/00027PCT/UJS02/21063 461 Example 843 METHYL 2- (ISOBUTYRYLAMINO) PHENYL] -1- PIPERIDINYL}METHYJ) -1H-INDOL-1-YL] EENZOATE: Prepared by Procedure C and Sceme Q1, with Cu~r in place of Cu, using methyl 2-iodobenzoate and N-{3-[1-(lH-ifldol-5ylmethyl) -4-piperidinyll phenyl }-2-methyipropanamide: ESMS m/e: 510.2 (M Example 844 (1H-INDOL-1-YL)PROPYL] -4-PIPERIIDINYL}PHENYL) 2-METHYLPROPANAMIDE: Prepared by Procedure AH and Scheme P using 1-(3-chloropropyl)-1H-indole and 2methyl-N- (4-piperidinyl)phenyl propanamide: ESMS xn/e: 404.2 (M H+ 1s Example 845 2-METHYL-N-{3- (TRIFLUOROMETHYL) PHENYL] -1H- -4-PIPERIDINYL] PHENYL}PROPANAMIDE: Prepared by Procedure C and Scheme Q1., with CuBr in place of Cu, using 1-iodo-4-(trif luoromethy) benzenie and N-{3-tl- (lH-indol-5-ylmethyl) -4-piperidinyllphenyl}-2methyipropanamide: ESMS mle: 520.2 (M Example 846 [(l-[1,1'-BIPHENYL)-2-YL-lH-INDOL-5-YL)METHYL]- 4-PIPERIDINYL)PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 2-iodo-1,11-biphenyl and N-{3-[1-(lH-indol-5ylmethyl) -4-piperidinyl:Iphenyl} -2-methylpropanamide: ESMS m/e: 528.3 (M WO 03/004027 WO 0/00027PCT/UJS02/21063 462 Example 847 2-METHYL-N- (l-fEl- (2-METHYLPHEN'YL) YLJ METHYL) -4-PIPERIDlTYL) PHENYL] PROPA.NAMIDE: Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-iodo-2-methylbenzene and l- (1H-indol-Sylmethyl) -4-piperidinyli phenyl)}-2-methyipropanamide: ESMS isle: 466.2 (M Example 848 2-METHYL-N- YL] METHYL) -4-PIPERIDINYL) PHENYL] PROPANAMIDE: Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-iodo-4-methylbenzene and [i-1I- ylmethyl) -4-piperidinyllphenyl}-2-methylpropanamide: ESMS m/e: 466.3 (M Example 849 N- E3- (2-CHLOROPHENYL) -lH-INDOL-5-YL]METHiYL}-4- PIPERIDINYL)PHENYLJ -2-METHYLPROPANAMIDE: Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using l-chJloro-2-iodobenzene and El- ylmethyl) -4-piperidinyllphenyl} -2-methyipropanamide: ESMS m/e: 486.2 (M H)4.
Example 850 2-METHYL-N-{3-(1- (TRIFLtTOROMETHYL) PHENYL] -1H- -4 -PIPERIDINYL] PHENYL}PROPANAMIDE; Prepared by Procedure C and Scheme Q1, with Cu~r in place of Cu, using l-iodo-3-Ctrif luoromethyl) benzene and (H-indolL-5-ylmethyi) -4-piLperidinyllphenyl}-2methyipropanamide: 1'H NMR (400 MHz, CDCl 3 5 7.80-6.94 (in, 1211); 6.69 Cd, l1H, J 3.6 Hz), 3.36 Cs, 3.10- 3.00 Cm, 211), 2.58-2.42 2H), 2.16-2.02 (mn, 2H1), WO 03/004027 WO 0/00027PCT/UJS02/21063 463 1.85-1.75 4H), 1.25 6H, J =7.2 Hz) ESMS mle: 520.2 (M H t Example 851 2-METHYL-N7-[3- (1-{[l-(2-NITOPHENYL) YLJMETHYL}-4-PIrPERIDINYL)PHENYL) PROPANAMIDE: Prepared by Procedure C and Scheme Qi, with CuBr in place of Cu, using 1-iodo-2-nitrobenzene and N-13- ylmethyl) -4-piperidinyl) phenyl}-2-methylpropanamide: ESMS 497.2 (M Example 852 N- (i-fEl- (2-FLUOROPHENYL) -lH-INDOL-5-YL]METHYL}-4- PIPERIDINYL)PHENYLJ -2-METHYLPROPANAMIDE: Prepared by 1s Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-fluoro-2-iodobenzene and ylmethyl) -4-piperidinyl] phenyl) -2-methyipropanamide: ESMS m/e: 470.2 CM Example 853 2-METHYL-N- (l-NAPHTHYL) 4-PIPERIDINYL) PHENYLI PROPANAMIDE: Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1iodonaphthalene and (H-indol-5-ylmethyl) -4piperidinyllphenyl} -2-rethylpropanamide: ESMS rn/e: 502.2 (M Example 854 N- (i-fLi- (2,3-DICHLOROPHENYL) 4 -PIPERIDINYL) PHENYL] -2 -METHYLPROPANAMIDE: Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1,2-dichloro-3-iodobenzene and (1H-indol- S-ylmethyl) -4-piperidinyl) phenyl} -2-methylpropanamide: 3"H WO 03/004027 WO 0/00027PCT/UJS02/21063 464 N34R (400 MHz, CDC1 3 5 7.66-6.94 (in, 12H), 6.68 111, J 8 Hz) 3. 69 s,2H1), 3. 15 02 (mn, 2H) 2. 54-2. 42 (i,2H1), 2.18-2. 02 C,211), 1. 88-1.76 Cm, 4H) 1.25 6H-, J 6.8 Hz); ESMS M/e: 520.1 (M Example 855 N- (2,3-DICHLOROPHENYL) -1H-INDOL-7-YLMETHiYL}- 4-PIPERIDINL)PHENYL] -2-METHYLPROPANAMIDE: Prepared by Procedure C and Scheme Qi, with CuBr in place of Cu, using 1,2-dichloro-3-iodobenzene and N-{3-[1-(lH-indol- 7-ylmethyl) -4-piperidinyl] phenyl}-2-methylpropanamide: ESMS m/e: 520.2 CM Example 856 N- l- (3-METHOXYPHENYL) -1H-INDfOL-4-YLJI4ETEYL}-4- PIPERIDINYL)PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure C and Scheme Q1, with Cu~r in place of Cu, using 1-iodo-3-methoxybenzene and (H-indolL-4ylmethyl) -4 -piperidinyl] phenyl)}-2 -methyipropanamide: ES3MS m/e: 422.3 (M Example 857 N- l- (2,3-DCIILOOPHENYL) -lH-INDOL-4-YL) METHiYL)- 4-PIPERIDINYL) PHENYLJ -2-METHYLPROPANAMIDE: Prepared by Procedure C and Scheme Q1, with CuBr in clace of Cu, using 1,2-dichloro-3-iodobenzene and N-{3-[1-(1H-indol- 4-ylmethyl) -4-piperidinyl] phenyl} -2-methyipropanamide: ESMS rn/e: 520.2 CM Example 858 V- [1-(3-CHLOROPHENYL) -1H-INDOL-4-YL)METHiYL}-4- PIPERIDINYL)PHENYLJ -2-METHYLPROPANAMIDE: Prepared by Procedure C and Scheme Q1, with Cu~r in place of Cu, WO 03/004027 WO 0/00027PCT/UJS02/21063 using l-chloro-3- 45iodobenzene and N{-l (lH-indol-4-ylmethyl) -4-piperidinyllphenyl}-2methyipropanamide: ESMS m/e: 486.2 (M Example 859 2-METHYL-N- (3-METHYLPHENYL) -1H-INDOL-4- YL] METHYL} -4 -PIPERIDINYL) PHENYLJ PROPANAMIDE: Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using l-iodo-3-methylbenzene and N-{3-lIi- (1Z-indol-4ylmethyl) -4-piperidinyllphenyl} -2-methyipropanamide: ESMSm/e: 466.3 (M Example 860 N- [1-(3-METHOXYPHENYL) -1H-I:NDOL-7-YL]METHYL}-4- PIEPERIDINYL)PHENYLJ-2-METHYLPROPANANIDE: Prepared by Procedure C and Scheme Q1, with Cu~r in place of Cu, using 1-iodo-3-methoxybenzene and NV-{3-El- (lH-indol-7ylmethyl) -4-piperidinylilphenyl} -2-methyipropanamide: ESMS 482.3 (M Example 861 2-METHYL-N-3-[l-(l-[3- (TRIFLtTOROMETHYL)PHENYL-lH- INDOL-4 -YL)METHYL) -4 -PIPERIDINYLJ PEENYL}PROPANAMIDE: Prepared by Procedure C and Scheme Ql, with CuBr in place of Cu, using 1-iodo-3- (trif luoromethyl) benzene and [1-(lH-indol-4-ylmethyl) -4-piperidinyllphenyl}-2methylpropanamide: ESMS m/e: 520.2 (M Example 862 NT-[3-Cl-{ (3,4-DIMETHiYLPHENYL)-1H-INDOL-4-YLJMETHYL}- 4-PIPERIDINYL)PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure C and Scheme Ql, with CuBr in place of Cu, using El- (lH-indol-4-ylmethyl) -4- WO 03/004027 WO 0/00027PCT/UJS02/21063 466 piperidinyllphenyll-2- methyipropanamide and 4iodo-1,2-dimethylbenzene: ESMS m/e: 480.0 (M +i Example 863 NT-[3-(1.-{[-(3,4-DIFLUOROPHEYL)-H-NDOL-4-YLMETHYL}- 4-PIPERIDIIYL) PHENYL] -2-METHYLPROPANAMIDE: Prepared by Procedure C and Scheme Q1, with Cu~r in place of Cu, using 1,3-dichloro-5-iodobenzene and [1-(1H--indol- 4-ylmethyl) -4-piperidinyl) phenyl }-2-methyipropanamide: ESMS m/e: 520.0 (M Example 864 l- (3,4-DICHLOROPHENYL) -1H-INDOL-4-YLMETHYL}- 4-PIPERIDINYL) PHENYL] -2-METHYLPROPANAMIDE- Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1,2-dichloro-4-iodobenzene and bT-{3-[J.-(1H-indol- 4-ylmethyl) -4-piperidinyllphenyl}-2-methylpropanamide: ESMS m/le: 520.0 (M H+ Example 865 NV- 3- (J.-t[1-(2-CHLORO-4-FLUOROPHENYL) -1H-INDOL-4- YLI METHYL} -4 -PIPERIDINYL) PHENYL] -2 -METHYLPROPANAMIDE: Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 2-chloro-4-fluoro-1-iodobenzene and Ng-{3- (H-indol-4-ylmethyl)-4-piperidinyllphenyl}-2methyipropanamide: ESMS mle: 504.0 (M Example 866 N- 1- (2,4-DIFLUOROPHENYL) -1H-INDOL-4-YL)METHYL}- 4-PIPERIDINYL) PHENYL] -2 -METHYLPROPANAMIDE: Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 2,4-difluoro-1-iodobenzene and NV-f3-E-C1H-indol1- WO 03/004027 WO 0/00027PCT/UJS02/21063 467 4-ylmethyl) piperidinyllphenyll-2methyipropanamide: ESMS mle: 488.0 (M Example 867 2-METHYL-N-E3-(l-{[l-(3-PYRIDINYL)-lH-INDOL-7- YL]METHYL}-4-PIPERIDIENYL)PHENYL] PROPAN.AMIDE: Prepared by Procedure C and Scheme Q1, with Cu~r in place of Cu, using 3-iodopyridine and NV-{3- [1-.(l-indol-7-ylmethyl) 4-piperidinyllphenyl}-2-methylpropanamide: ESMS m/e: 453.1 (M Example 868 (H-IENDOL-6-YLMETHYL) -4-PIPERIDINYL]PHiENYL}-2- METHYLPROPANAMIDE: Prepared by Procedure F and Scheme R using 1H-indole-6-carbaldehyde and 2-methyl-N- (4piperidinyl)phenyllpropanamide: ESMS m/e: 376.2 (M Example 869 2-METHYL-N- El- (4-PYRIDINYL) -lH-INDOL-4- YLJ METHYL}-4 -PIPERIDINYL) PHE1NYL) FROPANAMIDE: Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 4-iodopyridine and NV-{3- (lH-indol-4-ylmethyl) 4 -piperidinyl) phenyl -methyipropanamide: ESMS mie: 453.2 (M H)+ Example 870' 2-METHYL-N- Ei-(2-PYRID)INYL) -lH-INDOL-4- YL]METHYL}-4-PIPERIDINYL) PHENYLJ PROPANAMIDE: Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 2-iodopyridine and EL- lH-indol-4-ylmethyl) 4-piperidinyllphenyl} -2-methylpropanamide: ESMS mie: 453.2 (M WO 03/004027 WO 0/00027PCT/UJS02/21063 468 Example 871 N- (2-FLTOROPHENYL) -lH-INDOL-4-YL]METHYL}-4- PIPERIDINYL) PHENYL1-2-METHYLPROPANMIDE: Prepared by Procedure C and Scheme Qi, with CuBr in place of Cu, using l-fluoro-2-iodcbenzene and i:-(iH-indol-4ylmethyl) -4 -piperidinyll phenyl 2-methyipropanamide: ESMS m/e: 470.1 (M Example 872 NV-E3- (4-CHLOROPHENYL) -lH-INDOL-4-YL)METHYL)-4- PIPERIDINYL) PHE'YL] -2 -METHYLPROPANAMIDE: Prepared by Procedure C and Scheme Qi, with Cu~r in place of Cu, using 1-chloro-4-iodobenzene and (lH-indol-4ylmethyl) -4 -piperidinyl] phenyl -methyipropanamide: is RSMS ni/e: 4B6.1 (M I-I).
Example 873 2-METHYL-N- E3- El- (3-PYRIDINYL) -1H-INDOL-4- YL] METHYL}-4 -PIPERILDINYL) PHENYL] PROPANAMIDE: Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 3-iodopyridine and (H-indol-4-ylmethyl) 4-piperidinyllphenyl} -2-rethylpropanamide: ESMS m/e: 453.2 (M 14)+.
Example 874 NT-[3- (2,3-DIMETHYLPHENYL) -1H-INDOL-4-YLJ METHYL)- 4-PIPERIDINYL)PHENYLI -2-METHYLPROPANAMI1DE: Prepared by Procedure C and Scheme Q1, with CuBr in -place of Cu, using l-iodo-2,3-dimethylbenzene and N-{3-El- (lH-indol- 4-ylmethyl) -4-piperidinyllphenyl} -2-methylpropanamide: ESMS m/e: 480.1 (M WO 03/004027 WO 0/00027PCT/UJS02/21063 469 Example 875 NL- l- (3-FLUOROPHENYL) -lH-INDOL-4-YL]METHYL}-4- PIPERIDINYL)PHENYL] -2-IETHYLPROPANAMIDE: Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, S using 1-fluoro-3-iodobenzene and (1H-indol-4ylmethyl) -4-piperidinyl] phen-y. -2-methyipropananide: ESMSmrn/: 470.1 (M Example 876 2-Z4ETH-YL-N-{3- El- (TRIFLUOROMETHYL)PHENYLJ -lH- INDOL- 4-YL}METHYL) -4-PIPERIDINYL] PHENYL)PROPANAMIDE: Prepared by Procedure C and Scheme Q1, with Cu~r in place of Cu, using 1-iodo-2- (trif luoromethyl) benzene and (H-indol-4-ylmethyl) -4-piperidinyllpheny1 -2tethylpropanamide: ESMS rn/e: 520.1 (M Example 877 NV- 3- [1-(2-CHLOROPIIENYL) -lH--INDOL-4-YL]METHYL}-4- PIPERIDINYL) PHENYL] -2-METHYLPROPANA4IDE: Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using l-chloro-2-iodobenzene and N-f3- fl-(2H-indol-4ylmethyl) -4-piperidinyl] phenyl} -2-methyipropanamide: ESMS rn/e: 486.1 CM H+ Example 878 N- (2,3-DIMETHYLPHENYL) -1H-INDOL-7-YLJMETHYL}- 4-PIPERIDINYL)PHENYLJ -2-METHYLPROPANAMIDE: Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-iodo-2,3-dimethylbenzene and (1H-indol- 7-ylmethyl) -4-piperidinyljphenyl}-2-methylpropanamide: ESMS rn/e: 480.0 (M WO 03/004027 WO 0/00027PCT/UJS02/21063 470 2-METHYL-N- (1-(5-OXo-5- [4 (TRIFLUOROMETHYL) PHENYL] PENTYL) -4- PIPERIDINYL) PHEINYL] PROPANAMIDE: Prepared by Procedure K and Scheme E using 5-chloro-l- [4- (trifluoromethy)phenyl]-1-pentanone and 2-methyl-N- [3- (4-piperidinyl)phenyllpropanamide: ESMS rn/a: 475.1 (M N- (4-FLUOROPHENYL) -5-OXOPENTYL] -4- PIPERIDINYL)PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure K and Scheme E using 5-chloro-l-(4fluorophenyl) -1-pentanone and 2-methyl-N- (4piperidinyl)phenyllpropanamide: ESMS m/e: 425.2 (M N-(3-{l-[5-(3-FLUOROPHENYL)-5-OXOPENTYL]-4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure K and Scheme E using 5-chloro-1--(3fluorophenyl) -l-pentanone and 2-methyl-N-D[- (4piperidinyl)phenyljpropanamide: ESMS m/e: 425.2 (M (3-CHLOROPHENYL) -5-OXOPENTYL] -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure K and Scheme E using 5-chloro-l- (3chiorophenyl) -1-pentanone and 2-methyl-NT-[3- (4piperidinyl)phenyllpropanamide: ESMS rn/e: 441.1 (M H+ (4-CHLOROPHENYL) -5-OXOPENTYL) -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure K and Scheme E .using 5-chloro-l-(4chicrophenyl) -1-pentanone and 2-methyl-N- (4piperidinyl)phenyllpropanamide: ESMS m/e: 441.1 (M H+ WO 03/004027 WO 0/00027PCT/UJS02/21063 471.
Example 879 2-METHYL-N-{3- El- (3-OXO-3-PHEbNYLPROPYL) -4- PIPERIDINYL]PHEbJYL}PRQPANAMIDE: Prepared by Procedure K and Scheme E using K 2 qO 3 instead of Na 2
CO
3 and NaI instead of KI and 3-chloro-1-phenyl-l-propanone and 2-methyl-Nv- (4-piperidinyl)phenylj propanamide: ESMS mn/e: 379.3 (M
H)+
Example 880 E7- (2-FLUOROPHENYL) -7-OXOHEPTYL] -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure K and Scheme E using K 2 CO3 instead of Na 2
CO
3 and NaT instead of KI and 7-chloro-l-(2-fluorophenyl)-1heptanone and 2-methyl-N-[3-C4is piperidinyl)phenyllpropanamide: 1H NMR (400 MHz, CDC1 2 3), S8.17 Cs, br, 1H), 8.06-6.88 8H), 3.08-2.94 (in, 4H), 2.62-2.48 Cm, 1H), 2.48-2.38 Cm, iI), 2.38-2.15 (in, 2H1), 2.02-1.92 2H), 1.84-1.77 (in, 4H), 1.77-1.66 (in, 2H), 1.62-1.46 (mn, 2H), 1.46-1.29 1.21 6H, J 6.8 Hz); ESMS m/e: 453.2 CM Example 881 (2-PLUOROPHENYL) -5-OXOPENTYL] -4- PIPERIDIN'YL}PHENYL) -2-METHYLPROPANIAMIDE: Prepared by Procedure K and Scheme E using K 2 C0 3 instead of Na 2
CO
3 and NaT instead of KI and 5-chloro-1-(2-fluorophenyl)-1pentanone and 2-methyl-N-E3-(4piperidinyl)phenyllpropanami-de: ESMS m/e: 425.2 CM Example 882 (3-FLt7OROPHENYL) -6-OXOHEXYL] -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAM(IDE: Prepared by Procedure K and Scheme E using K 2 C0 3 instead of Na 2
CO
3 and WO 03/004027 WO 0/00027PCT/UJS02/21063 472 NaI instead of KI and 6- chloro-1-(3-fluorophenyl)- 1-hexanone and 2-methyi-ND- piperidinyl)phenyllpropanamide: ESMS nile: 439.2 (M Example 883 (2-FLUOROPHEN'YL) -6-OXOHEXYL) -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure K and Scheme E using I( 2 C0 3 instead of Na 2
CO
3 and NaI instead of KI and 6-chloro-1-(2-fluorophenyl)-1hexanone and 2-methyl-U- piperidinylL)phenyllpropanamide: ESMS m/e: 439.2 (M Example 884 (4-FLUOROPHENYL) -7-OXOHEPTYLJ -4- PIPERIDINYL)PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure K and Scheme E using K 2 C0 3 instead of Na 2
CO
3 and NaI instead of KI and 7-chloro-i-(4-fluorophenyl)-1heptanone and 2-methyl-NU-[3-(4piperidinyl~phenyljpropananide: ESMS m/e: 453.2 (M Example 885 t6- (4-CHLOROPHENYL) -6-OXOHEXYL] -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure K and Scheme E using K 2 C0 3 instead of Na 2
CO
3 and NaI instead of KI and 6-chloro-l-(4-chlorophenyl)hexanone and 2-methyl-N-[3-(4piperidinyl)phenyllpropanamide: ESMS m/e: 455.1 (M Example 886 [7-(4-CHLOROPHElNYL)-7-OXOHEPTYL1-4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by P-ocedure K and Scheme E using K 2 C0 3 instead of Na 2
CO
3 and NaI instead of KI and 7-chloro-l-(4-chlorophenyl)-1- WO 03/004027 WO 0/00027PCT/UJS02/21063 473 heptanone and 2-methyl-N- (4piperidinyl)phenyljpropalamide: ESMS m/e: 469.1 (M Example 887 C4-FLUOROPHENYL) -6-OXOHEXYL] -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure K and Scheme E using K 2 C0 3 instead of Na 2
CO
3 and NaI instead of KI and 6-chloro-1-(4-fluorophenyl)-ihexanone and 2-methyl-N-[3-(4piperidinyl)phenyllpropanamide: ESMS m/e: 439.1 (M Example 888 (3-ACETYLPHENOXY) (2-FLUO)ROPHENYL)HEXYLJ -4- PIPERID)INYL}PHENYL) -2 -METHYLPROPANAMID)E: Prepared by Procedure A and Scheme AN using 1- (3hydroxyphenyl) ethanone and N- (2 -fluoropheny.) 6 -hydroxyhexyll -4 -piperidinyl }phenyl) -2methyipropanamide: ESMS m/e; 559.5 (M Example 889 (2-FLUOROPHENOXY) -6-(2-FLUOROPHENYL)HEXYL] -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using 2-f luorophenci and N- (3- (2-fluorophenyl) -6-hydroxyhexyl] -4piperidinyl~phenyl) -2-methyipropanamide: ESMS m/e: 535.1
H).
Example 890 (4-FLUOROPHENOXY) (2-FLUOROPHENYL)HEXYL) -4- PIPERIDINYL}PHENYL) -2-NETHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using 4-fluorophenol and N-(3luorophenyl) -6-hydroxyhexyl] -4piperidinyl~phenyl) -2-methylpropanamide: 1 H NMR (400 MHz, WO 03/004027 WO 0/00027PCT/UJS02/21063 474 CDC1 3 HC1 salt 5 7.72- 6.72 (in, 12H), 5.42-5.34 (mi, 11) 3. 68-3 .58 br, 2H) 3. 02-2.-92 2H) 2. 2.46 6H) 2.05-1.78 65), 1.68-1.56 111), 1.56-1.38 Cm, 3H-) 1.25 6H-, J 6.8 Hz) ESMS m/e: 535.1 (M H)4".
Example 891 (2-FLUOROPHENYL) (2-METHOXYP-ENOXY)HEXYLJ 4-PIPERIDI1NYL}PHENYL) -2-METHYLPROPANAlIDE: Prepared by Procedure A and Scheme AN using 2-methoxyphenol and N- C2-fluorophenyl) -6-hydroxyhexyl] -4piperidinyl~phenyl) -2-methylpropanamide: ESMS rn/e: 547.0 (M Example 892 2- E6- (2-FLUOROPHENYL) (4-METHOXYPHENOXY)HEXYL) 4-PIPERIDINYL)PHENYL) -2-METHYLPROPANA4IDE: _Prepared by Procedure A and Scheme AN using 4-methaoxypheno. and N- C2-fluorophelyl) -6-hydroxyhexyll -4piperidinyl~phenyl) -2-methylpropanamide: ESMS mle: 547.1 CM Example 893 (4-ACETYLPHENOXY) (2-FLUOROPH-ENYL)HEXYL] -4- PIPERZIDINYLI PHENYL) -2 -METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using 1-C4hydroxyphenyl) ethanone and N- (2-f luorophenyl) 6-hydroxyhexyl] -4-piperidinyl }phenyl) -2methyipropanamide: ESMS m/e: 559.2 (M Example 894 (3,4-DIMETHOXYPHENOXY) (2- FLUOROPHENYL)HEXYLJ -4-PIPERIDINYL)PHENYL) -2- WO 03/004027 WO 0/00027PCT/UJS02/21063 475 METRYLPROP.ANAMIDE: Prepared by Procedure A and Scheme AN using 3,4-dimethoxyphel and N- (3-11- [6fluorophenyl) -6-hydroxyhexyll -4 -piperidinyl }phenyl) 2-methyipropanamide: ESMS m/e: 577.6 (M H) Example 895 (2-ETHOXYPHENOXY) (2-FLUOROPHEENYL)HEXYL] -4- PIPERIDI1NYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using 2-ethoxyphenol and N-(3- ID (2-f luorophenyl) -6-hydroxyhexyl) -4piperidinyl~phenyl) -2-methylpropanamide: ESMS rn/c: 561.1 (M Example 896 (4-BROMOPHENOXY) -6-PHENYLHEXCYL 4- PIPERIDI1NYL)PHENYL) -2-METHYLPROPANAMIDEt Prepared by Procedure A and Scheme AN using 4-bromophenol and N-{3- (6-hydroxy-6-phenylhexyl) -4-piperidinyl] pheny1} -2methyipropanamide: ESMS mne: 577.0 (M Example 897 (4-FLUOROPH-ENOXY) (4-FLUOROPHENYL)HEXYL] -4- PIPERTDINYL}PHENYL) -2-METHYLPROPANA4IDE: Prepared by Procedure A and Scheme AN using 4-f luorophenol and N- (3- (4-fluorophenyl) -6-hydroxyhexyl) -4piperidinyllphenyl) -2-methylpropanamide: 'H NMR (400 MHz, CuDC 3 HCU salt 8 8.22 br, IH) 7.74-6.70 (mn, 12H) 5.05-4.94 (in, 1H), 3.66-3.52 (mn, br, 2H), 3.02-2.83 (in, br, 2H1), 2.81-2.58 br, 2.58-2.36 Cm, br, 2H), 2.02-1.66 Cm, br, 6H), 1-66-1.46 br, 111), 1-46-1.35 (in, br, 3H) 1.26 Cd, 611, J 6. 0 Hz) ESMS rn/c: 535.1 (M H) WO 03/004027 WO 0/00027PCT/UJS02/21063 476 Example 898 E6- (4-METHOXYPHENOXY) -6-PEILHEXYL] -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using 4-methoxyphenal and Nv- [1-(6-h-ydroxy-6-phenylhexyl) -4-piperidinyllphenyl}-2methyipropanamide: ESMS rn/e: 529.6 (M Example 899 (4-CHLOROPH-ENOXY) (4-CHLOROPHE1NYL)HEXYL] -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN' using 4-chlorophenol and N- (3- 1- (4-chiorophenyl) -6-hydroxyhexyl] -4piperidinyllphenyl) -2-methyipropanamide: ESMS m/e: 566.9 (M Example 900 (4-BROMOPEEcOXY) (4-FLUOROPHENYJ)HEXYJJ .4- PIPERIDINYLPHENYL) -2-METHYLPROPANMIDE: Prepared by Procedure A and Scheme AN using 4-bromophenol and N- (3- (4-fluorophenyl)-6-hydroxyhexylj -4piperidinyl~phenyl) -2-methyipropanamide: ESMS nile: 595.0 (M Example 901 E6-(4-CHLOROPHENOXY)-6-(4-FLUOROPHENYL)HEXYL]-4- PIPERIDINYL}PHENYL) -2-METHiYLPROPANMIDE: Prepared by Procedure A and Scheme AN using 4-chiorophenol and N- (3- (4-fluorophenyl) -6-hydroxyhexyl] -4piperidinyllphenyl) -2-methyipropanamnide: 1 H NMR (400 MHz, CDC1 3 FIC1 salt 5 7.93 IH), 7.72-6.68 12H), 5.06-4.98 11-1), 3.66-3.50 br, 2H)f, 3.02-2.82 Cm, br, 2H), 2.80-2.S7 br, 4H), 2.57-2.38 (in, br, 2H)f, 2.02-1.76 br, 6H), 1.64-1.48 Cm, br, IH), 1.48-1.36 WO 03/004027 PCT/US02/21063 477 br, 3H), 1.25 6H, J 6.8 Hz); Anal. Calc.
for C 33
H
4 Cl1 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 mle: 550.8 (M
H).
Example 902 N-(3-{l-[6-(4-CHLOROPHElYL)-6-(4-FLUOROPHENOXY)HEXYL]-4- PIPERIDINYIJPHENYL)-2-METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using 4-fluorophenol and N-(3- {l-[6-C4-chlorophenyl)-6-hydroxyhexyl)-4piperidinyijphenyl) -2-ethylproparamide: 1H NMR (400 MHz, CDC1 3 HC1 salt 8 8.22 Cs, br, 1H), 7.74-6.68 Cm, 12H), 5.04-4.92 1H), 3.66-3.50 br, 2H), 3.00-2.82 (hr, 2H), 2.80-2.58 Cm, br, 4H), 2.58-2.40 Cm, br, 2H), 2.00- 1.68 Cm, br, 6H), 1.66-1.46 br, 1H), 1.46-1.36 br, 3H), 1.25 6H, J 7.2 Hz); ESMS m/e: 551.1 CM Example 903 3-ACETYLPHENOXY)-6-PHENYLIEXYL -4- PIPERIDINYL)PHENYL)-2-METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using 1-(3hydroxyphenyl)ethanone and N-{3-[1-(6-hydroxy-6phenyihexyl)-4-piperidinyl]phenyl)-2-methyipropanamide: ESMS m/e: 541.2 CM Example 904 N-(3-{1-[6-(4-CHLOROPHENOXY)-6-PHENYLHEXYLJ-4- PIPERIDINYLPHENYL)-2-METHYLPROPANAMIDE: -Prepared by Procedure A and Scheme AN using 4-chlorophenol -and N-{3- [1-(6-hydroxy-6-phenylexyl)-4-piperidinyllphenyl}-2methyipropanamide: 'H NMR (400 MHz, CDC1 3 HCl salt 8 8.28 1H), 7.78-6.70 Cm, 13H), 5.08-4.98 1H), 3.64-3.46 br, 2H), 3.02-2.82 (br, 2H), 2.82-2.56 (m, WO 03/004027 WO 0/00027PCT/UJS02/21063 478 hr, 4H) 2.56-2.34 (in, br, 2H), 2.05-1.75 (in, br, 6H) 1.64-1.48 (mn, br, 1H) 1.48-1.34 br, 3H) 1.25 6H, J 6.8 Hz); ESMS mle: 533.1 (M Example 905 (4-BROMOPHENqOXY) (4-CHLOROPHENYL)HEXYLI -4- PIPERIDINYL} PEENYL) -2 -METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using 4-bronophenoJ. and N- (3- (4-chiorophenyl) -6-hiydroxyh-exyl) -4piperidinyl~phenyl) -2-methylpropananide: ESMS ni/e: 611 .0 (M Example 906 (4-CHLOROPH-E:NYL) (4-METHOXYPHENOXY) HEXYI- 4-PIPERIDfIYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using 4-inethoxyphenol and N- (4-chiorophenyl) -6-hydroxyhexyl] -4piperidinyl~pheny1) -2-methyipropanamide: ESMS nile: 563.1 (M H)> Example 907 N- 1- (4 -FLUOROPH-ENYL) (4-METHOXYPHENOXY) HEXYL] 4-PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE:- Prepared by Procedure A and Scheme AN using 4-inethoxyphenol and N- (4-fluorophenyl)-6-hydroxyhexy1J-4piperidinyllphenyl)-2-inethylpropanamide: 1H NMR (400 MHz, CDC1 3 HC1 salt 8 8.11 111), 7.65-6.84 1211), 5.21-5.10 (in, 1H), 3.66-3.56 (mn, br, 2H), 3.02-2.82 (br, 2H), 2.82-2.56 (in, br, 411), 2.54 311), 2.53-2.32 (m, br, 211), 2.02-1.70 br, 1.64-1.48 (mn, br, 1H1), 1.48-1.34 (br, 311), 1.25 611, J 6.8 Hz); ESMS m/e: 547.1 (M WO 03/004027 WO 0/00027PCT/UJS02/21063 479 Example 908 (3-ACETYLPENOXY) (4-FLUOROPHENYL)HEXYL] -4- PIPERIDINYL}PHENYL) -2 -METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using 1- (3hydroxypheny-) ethanone and N- (4-f luorophenyl) 6-hydroxyhexyl) -4-piperidinyllphenyl) -2methyipropanamide: ESMS m/s: 559.1 (M Example 909 E6-(4-FLUOROPHENOXY)-6-PHENYLHEXYLJ -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure A and-Scheme AN using 4-f luorophenol and N-{3- El- (6-hydroxy-6--phenylhexyl) -4-piperidinyl] phenyl} -2methyipropanamide: H NMR (400 MHz, CDC1 3 HC1 salt 8 8.05 br, IH), 7.72-6.70 Cm, 13H), 5.06-4.96 (mn, 1H), 3.66-3.51 211), '3.01-2.82 (in, br, 211), 2.82-2.57 (in, br, 4H) 2.57-2.134 Cm, br, 2H) 2.05-1.78 br, 6H) 1.64-1.52 br, 1H), 1.52-1.16 br, 3H), 2.25 (d, 6H1, J 7.2 Hz); ESMS m/e: 517.0 (M Example 910 (2-ACETYLPHENOXY) (2-FLUORO)PHENYL) HEXYLI -4- PIPERIDINYL}PUENYL) -2 -METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using (2hydroxyphenyl) ethanone and N- (2-f luorophenyl) 6-hydroxyhexyl] -4 -piperidinyl }phenyl) -2methyipropanamide: ESMS in/e: 559.0 (M H) Example 911 N-[3-(1-{6-(4-FLUORQPHENYL)-6-[2-FLUORO-5- (TRIFLTJOROMETHYL) PHENOXY] HEXYL} -4 -PIPERIDINYL) PHENYL) -2- METRYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using 2-f luoro-5- (trif luorornethyl)phenol and N- WO 03/004027 PCT/US02/21063 480 [6-(4-fluorophenyl)-6- hydroxyhexyl)-4piperidinyljphenyl)-2-methyipropanamide: 1H NMR (400 MHz, CDC1 3 HC1 salt 5 8.23 br, 1H), 7.74-6.88 11H), 5.20-5.12 1H), 3.68-3.52 Cm, br, 2H), 3.02-2.82 (m, br, 21), 2.82-2.60 Cm, 4H), 2.58-2.38 br, 21), 2.12- 2.02 Cm, br, 11), 2.02-1.80 br, 5H), 1.68-1.52 Cm, br, 1H), 1.52-1.36 Cbr, 3H), 1.25 6H, J 7.2 Hz) ESMS m/e: 603.3 (M Example 912 N-(3-{1-[6-(3-ACETYLPHENOXY)-6-(4-CHLOROPHENYL)HEXYL]-4- PIPERIDINYL}PHEYL) -2-METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using 1-(3hydroxyphenyl) ethanone and (4-chiorophenyl)- 6-hydroxyhexyl)-4-piperidinyl~phenyl)-2methypropanaide: -H NMR (400 MHz, CDC13), IC1 salt 6 8.41 Cs, 1H), 7.72-6.84 12H), 5.18-5.10 Cm, 1H), 3.62-3.50 br, 2H), 3.00-2.92 Cm, 21), 2.90-2.58 Cm, 4H), 2.54 Cs, 3H), 2.50-2.12 Cm, 21), 2.02-1.70 Cm, br, 61), 1.64-1.50 Cm, br, 1H), 1.50-1.14 br, 3H), 1.25 61, J 6.8 Hz); ESMS m/e: 575.3 CM H).
Example 913 N-[3-(1-{6-(2-FLUOROPHENYL)-6-[2-FLUORO-5- (TRIFLUOROMETHYL)PHENOXY] HEYL}-4-PIPERIDINYL)PHENYLI-2- METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using 2-fluoro-5-(trifluoromethyl)phenol and (6-2-fluorophenyl)-6-hydroxyhexyl]-4piperidinyllphenyl)-2-methylprooanamide: 1H NNR (400 MHz, CDC1 3 HC1 salt 6 8.35 Cs, 1H), 7.68-6.82 Cm, 111), 5.58-5.48 11), 3.64-3.50 2H), 3.01-2.94 br, 2H), 2.92-2.54 Cm, 4H), 2.48-2.32 br, 21), 2.20-2.04 1H), 2.01-1.80 Cm, 5H), 1.70-1.54 Cm, 11), 1.54-1.36 WO 03/004027 WO 0/00027PCT/UJS02/21063 481 (in, 3H) 1 .2 5 6H, J 7.2 Hz) Anal Caic. for C3 4
H
40 C1FN 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 Example 914 N- (4-CHLOROPIEENYL) [2-FLUORO0-5- (TRIFLUOROMETHYL) PHENOXY] HIEXYL) -4-PIPERIDINY.L) PHENYL] -2- METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using 2-f luoro-5- (trif luoromethyl) phenol and (4-chiorophenyl) -6-hydroxyhexyl] -4piperidinyl'phenyl) -2-inethylpropananide: ESMS mle: 619.2 (M +I H) Example 915 1s N- (3-FLUOROPIHENYL)-6- (TRIFLUOROMETHYL) PHENOXYJ HEXYLI -4-PIPERI3DINYL) PHENYL] -2- METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using 2-f luoro-5- (trif lucromethyl) phenol and (3-fluorophenyl) -6-hydroxyhexyl] -4piperidinyllphenyl) -2-methyipropananide: ESMS m/e: 503.3 Example 916 N- [2-FLUORO-5- (TRIFLUQROMETHYL)PHENOXY] -6- PHENYLHEXYL} -4 -PIPERIDIYL) PHENYL] -2 -METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using 2-f (trifluoromethyl)phenol and (-hydroxy-6phenyihexyl) -4 -piperidinyl) phenyl) -2 -methyipropanamide: ESMS xn/e: 585.3 (M Example 917 N- (2-FLUOROPHENYL) (TRIFLUOROMETHYL) PHENOXY) HEPTYL}-4-.PIPERIDINYL) PHENYL] 2-METHYLPROPANAMIDE: Prepared by Procedure A and Scheme WO 03/004027 WO 0/00027PCT/UJS02/21063 482 AN using 2-f luoro-5- (trifluorcmethyl)phenol and N- (2-flucrophenyl) -7-hydroxyheptyll -4piperidinyl~phenyl) -2-methylpropanamiLde: ESMS mle: 617.3 (M Example 918 N- (4-FLUOROPHENYL) (4 -METHOXYPHENOXY)-PENTYLJ 4-PIPERIDINYL)PHENYL) -2-METHYLPROPANAMIDE; Prepared by Procedure A and Scheme AN using 4-methoxyphenol and Nv- C4-fluorophenyl)-5-hydrcxypentyl] -4piperidinyllphenyl) -2-methylpropanamide: ESMS m/e: 533.1 (M H+ Example 919 (4-BROMOPHENflXY) C4-FLUOROPHENYL)PENTYLJ -4- PIPERIDI1NYL}PHENYL) -2-METRYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using 4-bromophenol and N- (4-fluorophenyl) -5-hydroxypentyll -4piperidinyl~phenyl)-2-methylpropanamide: 'H NMR (400 MHz, CDC1 3 HC1 salt 5 7.94 br, IH) 7.68-6.64 (in, 12H) 5.12-5.04 IH) 3.68-3.52 br, 2H) 3.01-2.82 (hr, 2H), 2.78-2.S8 (in, br, 2.57-2.38 Cm, br, 2H), 2.05- 1.80 (in, br, 6H), 1.64-1.38 Cm, br, 2H), 1.25 6H-, J 7.2 Hz); ESMS m/e; 581.0 CM H)- Example 920 (4-CHLOROPHENOXY) -5-(4-CHLOROPHEINYL)PENTYL] 4-PIPERIflINYL)PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure A and-Scheme AN using 4-chiorophenol and N-(3- C4-chlorophenyl) -5-hydroxypentyl) -4piperidinyllphenyl) -2-methylpropanamide: 'H NMR (400 MHz, CDC1 3 HC1 salt 6 7.86 br, IH) 7.62-6.72 Cm, 12H) 5.12-5.02 (in, IH) 3.68-3.52 Cm, br, 2H) 3.02-2.82 (br, 2H), 2.82-2.56 (mn, br, 4H), 2.56-2.40 (in, br, 2H), 2.06- WO 03/004027 PCT/US02/21063 483 1.80 br, 6H), 1.64- 1.40 br, 2H), 1.25 (d, 6H, J 6.8 Hz). Anal. Calc. for C 3 2
H
3 9 C1 3
N
2 02'1.3MeOH: 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 Example 921 N-(3-{1-[5-(4-CHLOROPHENOXY)-5-PHENYLPENTYLJ-4- PIPERIDINYL)PHENYL)-2-METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using 4-chiorophenol and N-{3- [1-(5-hydroxy-5-phenylpenty)-4-piperidinyljphenyl}-2methylpropanamide: 1H. NMR (400 MHz, CDC1 3 HC1 salt 7.72-6.72 13H), 5.12-5.04 1H), 3.66-3.52 br, 2H), 3.01-2.83 (br, 2H), 2.68-2.62 br, 2H), 2.62- 2.48 br, 4H), 2.04-1.82 br, 1.62-1.40 (m, br, 2H), 1.25 6H, J 7.2 Hz); ESMS m/e: 519.1 CM Example 922 N-(3-{1-[5-(3-ACETYLPHEOXY)-5-(4-FLUOROPHENYL)PENTYLJ- 4-PIPERIDINYL}PHENYL)-2-IETHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using 1-(3hydroxyphenyl)ethanone and N-(3-{1-[5-(4-fluorophenyl)- 5-hydroxypentyl-4-piperidinyl~phenyl)-2methypropanaide: ESMS m/e: 545.1 (M Example 923 N-(3-{1-[5-(4-CHLOROPHENYL)-5-(4-FLtOROPHENOXY)PENTYL]- 4-PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using 4-fluorophenol and N-(3- (1-f5-(4-chiorophenyl)-5-hydroxypentyl]-4piperidinylphenyl)-2-methylpropanamide: 'H NMR (400 MHz, CDC1 3 HC1 salt 6 8.05 br, 1H), 7.74-6.68 12H), 5.08-4.99 1H), 3.67-3.56 br, 2H), 3.02-2.82 (br, 2H), 2.80-2.57 br, 4H), 2.57-2.38 br, 2H), 2.05- WO 03/004027 WO 0/00027PCT/UJS02/21063 484 1.80 Cm, hr, 6H) 1.64- 1.40 (in, br, 2H), 1.25 (d, 6H, J 7.2 Hz) Anal. Caic. for C 3 2 H3 9 C1 2
FN
2
O
2 *l.3EtOAZ: 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 Example 924 [5-(4-BROMOPHENOXY) -5-PHENYLPENTYL] -4- PIPERIDINYL)PHENYL) -2-METBIYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using 4-bromophenol and N-{3- CS-hydroxy-5-phenylpeltyl) -4-piperidinyl) phenyl} -2methyipropanamide: 1H NMR (400 MHz, CDC1 3 HCl salt 8 7.74-6.66 (mn, 13H), 5.13-S.02 Cm, 1H), 3.73-3.51 Cm, br, 2H), 3.05-2.83 Cbr, 2H), 2.83-2.62 (br, 4H), 2.62-2.42 Cm, br, 2H), 2.10-1.80 (mn, br, 6H), 1.65-1.37 (mn, br, 2H), 1.25 -Cd, 6H, J 6.8 Hz); ESMS m/e: 562.9 (M Example 925 C4-CHLOROPHENYL) (4-METHOXYPHENOXY) PENTYL] 4 -PIPERIDINYLPHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN usi -ng 4-methoxyphenol and N- ES-(4-chiorophenyl) -5-hydroxypentyll -4piperidinyllphenyl) -2-inethyipropanainide: H NNR (400 MHz, CDCl 3 HC1 salt 5 8. 13 br, 1H) 7.72-6.70 Cm, 12H) 5.08-4.97 (in, 1H) 3.72 3H) 3.66-3.50 (in, br, 2H) 3.03-2.82 (hr. 2H), 2.80-2.54 Cm, br, 4H), 2.53-2.17 Cm, br, 2F), 2.08-1.78 (mn, br, 6H), 1.65-1.38 Cm, br, 2H), 1.25 6H, J 6.8 Hz). Anal. Caic. for
C
3 3
H
4 1 2 C1 2
N
2 0 3 0. 54CH 2 C1 2 C, 63.80; H, 6. 88; N, 4.44.
Found: C, 63.84; H, 7.18; N, 4.00. ESMS in/e: 549.1 CM WO 03/004027 WO 0/00027PCT/UJS02/21063 485 Example 926 (4-FLUOROPHENOXY) (4-FLUOROPHENYL)PENTYLI 4-PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using 4-f luorcphenol and N-(3- [5-(4-fluorophenyl) -5-hydroxypentyl] -4piperidinyllphenyl)-2-methylpropalamide: 1 H NMR (400 MHz, CDC1 3 HC1 salt 5 7.62-6.70 12H1), 5.10-5.00 (in, 1H) 3.71-3.56 (in, br, 2H), 3.04-2.82 (br, 2H), 2.78-2.64 (m, br, 3H) 2.64-2.48 (in, br, 3H-) 2.05-1.82 br, 611), 1. 62-1.42 Cm, br, 2H) 1.25 6H, J 6. 0 Hz) ESMS m/e: 5 21. 2 (M H Example 927 (3-ACETYLPH-ENOXY) -5-PHEINYLPENTYLI -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANMIDE: Prepared by Procedure A and Scheme AN using -3 hydroxyphenyl) ethanone and N- (5 -hydroxy-5 phenylpentyl) -4 -piperidinyl] phenyl }-2-methylpropanamide: ESMS M/e: 526.9 CM Example 928 (4-METH-OXYPHENOXY) -5-PHE1NYLPENTYL] -4- PIPERIDINYL'PHENYL) -2-METHYLPIROPANAMIDE: Prepared by Procedure A and Scheme AN using 4-methoxyphenol and N- (-hydroxy-5-phenylpentyl) -4-piperidinyllphenyl} 2-rnethylpropanamide: ESMS m/e: 515.6 CM Example 929 [2-FLUIOO-5- CTRIFLTJOROMETIIYL)PHENOXY) [4- (TRIFLUOROMETHYL) PIENYL) PENTYL) PIPERIDINYL) PHENYL] -2- METHYLPRQPANAMIDE: Prepared by Procedure A and Scheme AN using 2-fluorc-5-Ctrifluoromethyl)phenol and N-[3-C1- Ctrifluoromethyl)phenyllpentyl}-4- WO 03/004027 PCT/US02/21063 486 piperidinyl)phenyl-2- methylpropanamide: ESMS r/e: 639.2 (M Example 930 S LOROPHETYL) (TRIFLUOROMETHYL)PHENOXY]PENTYL)-4-PIPERIDINYL)PHENYI- 2-METHYLPROPANAMIDE: Prepared by Procedure-A and Scheme AN using 2-fluoro-5-(trifluoromethyl)phenol and [5-(3-chiorophenyl) -5-hydroxypentyl]-4piperidinyl~phenyl)-2-methylpropanamide: 'H NMR (400 MHz, CDC1 3 HCi salt 6 8.17 br, 1H), 7.75-6.88 Cm, 11H), 5.26-5.14 1H), 3.68-3.56 br, 2H), 3.05-2.90 (br, 2H), 2.90-2.60 Cm, br, 41), 2.56-2.36 br, 2H), 2.18- 1.84 br, 6H), 1.70-1.44 Cm, br, 2H), 1.25 Cd, 6H, J 7.2 Hz) Anal. Calc. for C 33
H
38 Cl 2 F4N 2 02 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 Example 931 N-E3-(1-{5-(2-FLUOROPHENYL)-5- (TRIFLUOROMETHYL)PHENOXY]PENTYj}-4-PIPERIDINYL)PHENYL]- 2-METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using 2-fluoro-5-Ctrif luoromethyl) phenol and N-(34 1- S-(2-fluorophenyl) 5-hydroxypentyl)-4piperidinyljphenyl)-2-methylpropanamide: NMR (400 MHz, CDCl 3 HC1 salt 6 7.89 Cs, br, 1H), 7.72-6.88 Cm, 11H), 5.59-5.48 1H), 3.70-3.48 Cbr, 2H), 3.05-2.84 Cbr, 2H), 2.82-2.58 Cm, br, 4H), 2.58-2.40 Cm, br, 2H), 2.22- 1.82 br, 6H), 1.71-1.42 br, 2H), 1.25 Cd, 6H, J 6.4 Hz); ESMS m/e: 589.3 (M WO 03/004027 PCT/US02/21063 487 Example 932 N- [3-(1-{5-3-FLUOROPHEN YL)-5-[2-FLUORO-S- (TRIFLUOROMETHYL)PHENOXYJ PENTYL)-4-PIPERIDINYL) PENYL]- 2-METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using 2-f luoro-5- (trifluoromethyl)phenol and [5-(3-fluorophenyl)-5-hydroxypentyl-4piperidinyl~phenyl)-2-methylpropanamide: 1 NMR (400 MHz, CDCl 3 HCl salt 6 7.79 Cs, hr, 11), 7.63-6.82 Cm, 11H), 5.24-5.15 1H), 3.70-3.56 (br, 2H), 3.04-2.84 (br, 2H), 2.82-2.60 br, 4H), 2.60-2.42 Cm, br, 2H), 2.20- 1.83 br, 6H), 1.70-1.44 Cm, br, 2H), 1.25 6H, J 6.4 Hz); ESMS mn/e: 589.3 (M Example 933 N-(3-{1-5-(3-ACETYLPHENOXY)-5-(4-CHLOROPHENYL)PENTYL]- 4 -PIPERIDINYL}PHENYL) -2 -METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using 1-(3hydroxyphenyl)ethanone and N-(3-{1-[5-(4-chiorophenyl)- 5-hydroxypentyl]-4-piperidinyljphenyl)-2methyipropanamide: 1H NMR (400 MHz, CDC1 3 HCl salt 8 8.05 Cs, br, 1H), 7.74-6.88 12H), 5.27-5.16 Cm, 1H), 3.69-3.52 br, 2H), 3.10-2.81 (br, 2H), 2.81-2.57 (m, br, 4H), 2.54 Cs, 3H), 2.52-2.40 Cm, br, 2H), 2.05-1.80 br, 6H), 1.66-1.42 br, 2H), 1.25 Cd, 6H, J 6.8 Hz); Anal. Calc. for C 34
H
4 2 C1 2
N
2 0 3 5CH 2 Cl'1 OH 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 Example 934 N-[3-(1-{5-(4-CHLOROPHENYL)-5-[2-FLUORO-5- (TRIFLUOROMETHYL)PHENOXY]PENTYL)-4-PIPERIDINYL)PHENYL]- 2-METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using 2-f luor-5- trifluoroiethyl)phenol and WO 03/004027 WO 0/00027PCT/UJS02/21063 488 (4-chiorophenyl) hydroxypentyl] -4piperidinyllphenyl) -2-methyipropanamide: 2'H NMR (400 MHz, CDC1 3 HIi salt 8 7.61-6.92 11H) 5.24-5.16 1H) 3.70-3.58 (in, 2H), 3.02-2.91- (br, 211), '2.80-2.64 br, 3H1), 2.64-2.50 311), 2.18-1.94 (mn, br, 6H), 1.62-1.44 br, 2H1), 1.25 6H-, J 7.2 Hz) ESMS m/e: 605.3 (M Example 935 (1-{5-(4-FLUOROPHENYL)-5-[2-FLUORO-5- (TRIFLUOROMET-YL) PHENOXY] PENTYL}-4-PIPERIDINYL) PHENYL] 2-METHYLPRQPANAMIDE: Prepared by Procedure A and Scheme AN us ing 2 fluoro- 5- (trif luoroinethyl) phenol N- 1 5 (4-f luorophenyl) -5-hydroxypentyli -4-piperidinyl~phenyl) 2-methyipropanamide: ESMS m/e: 589.3 (M Example 936 (4-BROMOPHENOXY) (4-CIHLOROPHENYL)PENTYLJ -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using 4-bromophenol and N- (3- (4-chiorophenyl) -5-hydroxypentyl] -4piperidinyl~phenyl) -2-methyipropanamide: ESMS m/e: 597.2 (M Example 937 (4-CHLOROPHENOXY) (4-FLTOROPHENYL)PENTYLJ 4-PIPERIDINYL}PHENYL) -2 -IETHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using 4-chiorophenol and N- (3luorophenyl) -5-hydroxypentyll]-4piperidinyllphenyl) -2-methyipropanamide: ESMS m/e: 537.3 (M 14) WO 03/004027 WO 0/00027PCT/UJS02/21063 489 Example 938 NV-(3-1- (2-ACETYLPHENOXY) -5-PHENYLPENTYLJ -4- PIPERIDINYL}PHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using 1-2 hydroxyphenyl) ethanone and N- (5-hydroxy- phenylpentyl) -4-piperidinyl] phenyl }-2-methylpropanamide: ESMS nile: 527.0 (M Example 939 [5-(2-ETHOXYPHENOXY)-5-PHiENYLPENTYL]-4- PIPERIDINYLPENYL) -2-METHiYLPROPANAMIDE: Prepared by Procedure A and Scheme AN using 2-ethoxyphenol and N-{3- (5-hydroxy-5-phenylpentyl) -4-piperidinyljpheriyl}-2methyipropanamide: ESMS m/e: S29-2 (M is Example 940 IV- [5 (4 -FLUOROPHENTOXY) 5- PHENYLPENTYL] -4 PIPERIDINYL}PHENYL) -2-METHYLPROPANAMID)E; Prepared by Procedure A and Scheme AN using 4-fluorophenol and N-{3- (5-hydroxy-5-phenylpentyl) -4-piperidinyllphenyl}-2methyipropanamide: ESMS m/e: 503.2 (M Example 941 (4-FLUOROPHENYL) -4-OXOBtITYL] -4- PIPERIDINYL)PIENYL) -2 -METHYLPROPANAMIDE: Prepared by Procedure K (KI) and Scheme E (K 2 C0 3 using 2-methyl-N- (4-piperidinyl)phenyl] propanamide and 4-chloro-l- (4fluoropbhenyl)-l-butanone: ESMS m/e: 411.2 CM Example 942 2-METHiYL-N-(3-{1- (lH-PYRROL-3-YL)PROPYL] -4- PIPERIDINYL}PHENYL)PROPANAMIDE: Prepared by Procedure K (KI) and Scheme E (K 2 C0 3 using 2-methyl-N- (4- WO 03/004027 WO 0/00027PCT/UJS02/21063 490 piperidinyl) phenyl] propanamide and 3- (3-bromopropyl) -1Hpyrrole: ESMS m/e: 354.2 (M Example 943 [4-(4-ISOPROPYLPHENYL).-4-OXOBUTYL] -4- PIPERIDINYL}PHENYL) -2-lvETHYLPROPANAMIDE: Prepared by Procedure K (KI) and Scheme E (K 2 C0 3 using 2-methyl-NV- (4-piperiLdinyl)phenyllpropanamide and 4-chloro-1- (4isopropylphenyl)-1-butanone: ESMS m/e: 435.2 (M Example 944 (4-METHOXYPHENYL) -4-OXOBUTYLJ -4- PIPERIDINYLPHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure K and Scheme E (K 2 C0 3 using 2-methyl-N- (4-piperidinyl)phenylilpropanamide and 4-chloro-l- (4methoxyphenyl)-1-butanone: ESMS rn/e:423.2 (M H 4 Example 945 2-METHYL-NV-(3-{1- (4-METHYLPHENYL) -4-OXOBUTYL2 -4- PIPERIDINYL}PHENYL)PROPA.NAMIDE: Prepared by Procedure K (KI) and Scheme E (K 2 C0 3 using 2-methyl-N- (4piperidinyl) phenyl] propanamide and 4-chloro-l- (4methylphenyl)-1-butanone: ESMS ni/e: 407.2 (M II)*.
Example 946 (4-TERT-BUTYLPHENYL) -4-OXOBUTYL] -4- PIPERIDflJYL}PHENYL) -2 -METHYLPROPANAMIDE: Prepared by Procedure K (KI) and Scheme E (K 2 C0 3 using 2-methyl-N- (4-piperidinyl)phenylipropanamide and 1- (4-tertbutylphenyl) -4-chloro-l-butanone: ESMS m/e: 449.2 (M Example 947 WO 03/004027 WO 03/04027PCTIUS02/2 1063 491 BROMOPHENYL) -4-OXOBUTYL] 4-PIPERIDINYLPHENYL) -2-METHYLPROPANAMIDE: Prepared by Procedure K (KI) and Scheme E (K 2 C0 3 using 2-methyl-N- (4-piperidin-yl)phenyljpropananide and 1- (4- S hromophenyl) -4-chloro-1--butanone: ESMS m/e: 471.3 (M Example 948 2-METHYL-N-(3-{1-[4-OXO-4-(2-THEYL)BUTYL] -4- PIPERIDINYLPHENYL)PROPANAMIDE. Prepared by Procedure K (KI) and Scheme E (K 2 C0 3 using 2-methyl piperidinyl)phenyl] propanamide and 4-chloro-l- (2thienyl)-1-butanone: ESMS m/e: 399.1 (M WO 03/004027 PCT/US02/21063 492 II. Synthetic Methods for General Structures The examples described in Section I are merely illustrative of the methods used to synthesize MCH1 antagonists. Further derivatives may be obtained utilizing generalized methods based on the synthetic methods used to synthesize the examples.
It may be necessary to incorporate protection and deprotection strategies for substituents such as amino, amido, carboxylic acid, and hydroxyl groups in the generalized synthetic methods to form further derivatives. Methods for protection and deprotection of such groups are well-known in the art, and may be found, for example in Green, T.W. and Wuts, P.G.M. (1991) Protection Groups in Organic Synthesis, 2 nd Edition John Wiley Sons, New York.
III. Oral Compositions As a specific embodiment of an oral composition of a compound of this invention, 100 mg of one of the compounds described herein is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule.
IV. Pharmacological Evaluation of Compounds at Cloned rat MCH1 Receptor The pharmacological properties of the compounds of the present invention were evaluated at the cloned rat MCH1 receptor using protocols described below.
Host Cells WO 03/004027 PCT/US02/21063 493 A broad variety of host cells can be used to study heterologously expressed proteins. These cells include but are not restricted to assorted mammalian lines such as: Cos-7, CHO, LM(tk-), HEK293, Peak rapid 293, etc.; insect cell lines such as: Sf9, Sf21, etc.; amphibian cells such as xenopus oocytes; and others.
COS 7 cells are grown on 150 mm plates in DMEM with supplements (Dulbecco's Modified Eagle Medium with bovine calf serum, 4 mM glutamine, 100 units/ml penicillin/100 Fg/ml streptomycin) at 37 0 C, 5% CO 2 Stock plates of COS-7 cells are trypsinized and split 1:6 every 3-4 days.
Human embryonic kidney 293 cells are grown on 150 mm plates in DMEM with supplements (10% bovine calf serum, 4 mM glutamine, 100 units/ml penicillin/100 Fg/ml streptomycin) at 37 0 C, 5% CO 2 Stock plates of 293 cells are trypsinized and split 1:6 every 3-4 days.
Human embryonic kidney Peak rapid 293 (Peakr293) cells are grown on 150 mm plates in DMEM with supplements fetal bovine serum, 10% L-glutamine, 50 Fg/ml gentamycin) at 37 0 C, 5% CO 2 Stock plates of Peak rapid 293 cells are trypsinized and split 1:12 every 3-4 days.
Mouse fibroblast LM(tk-) cells are grown on 150 mm plates in DMEM with supplements (Dulbecco's Modified Eagle Medium with 10% bovine calf serum, 4 mM glutamine, 100 units/ml penicillin/100 Fg/ml streptomycin) at 37 0
C,
CO
2 Stock plates of LM(tk-) cells are trypsinized and split 1:10 every 3-4 days.
WO 03/004027 PCT/US02/21063 494 Chinese hamster ovary (CHO) cells were grown on 150 mm plates in HAM=s F-12 medium with supplements bovine calf serum, 4 mM L-glutamine and 100 units/ml penicillin/ 100 Fg/ml streptomycin) at 37 0 C, 5% CO 2 Stock plates of CHO cells are trypsinized and split 1:8 every 3-4 days.
Mouse embryonic fibroblast NIH-3T3 cells are grown on 150 mm plates in Dulbecco=s Modified Eagle Medium (DMEM) with supplements (10% bovine calf serum, 4 mM glutamine, 100 units/ml penicillin/100 Fg/ml streptomycin) at 37 0
C,
CO
2 Stock plates of NIH-3T3 cells are trypsinized and split 1:15 every 3-4 days.
Sf9 and Sf21 cells are grown in monolayers on 150 mm tissue culture dishes in TMN-FH media supplemented with fetal calf serum, at 27 0 C, no CO 2 High Five insect cells are grown on 150 mm tissue culture dishes in Ex- Cell 4 00 TM medium supplemented with L-Glutamine, also at 27 0 C, no CO 2 In some cases, cell lines that grow as adherent monolayers can be converted to suspension culture to increase cell yield and provide large batches of uniform assay material for routine receptor screening projects.
Transient expression DNA encoding proteins to be studied can be transiently expressed in a variety of mammalian, insect, amphibian and other cell lines by several methods including but not restricted to; calcium phosphate-mediated, DEAEdextran mediated, Liposomal-mediated, viral-mediated, electroporation-mediated and microinjection delivery.
WO 03/004027 PCT/US02/21063 495 Each of these methods may require optimization of assorted experimental parameters depending on the DNA, cell line, and the type of assay to be subsequently employed.
A-typical protocol for the calcium phosphate method as applied to Peak rapid 293 cells is described as follows: Adherent cells are harvested approximately twenty-four hours before transfection and replated at a density of x 106 cells/dish in a 150 mm tissue culture dish and allowed to incubate over night at 37 0 C at 5% C02. 250 Fl of a mixture of CaC12 and DNA (15 Fg DNA in 250 mM CaC1 2 is added to a 5 ml plastic tube and 500 Fl of 2X HBS (280 mM NaC1, 10 mM KC1, 1.5 mM Na 2 HP0 4 12 mM dextrose, mM HEPES) is slowly added with gentle mixing. The mixture is allowed to incubate for 20 minutes at room temperature to allow a DNA precipitate to form. The DNA precipitate mixture is then added to the culture medium in each plate and incubated for 5 hours at 37 0 C, 5% C0 2 After the incubation, 5ml of culture medium (DMEM, FBS, 10% L-glut and 50 pg/ml gentamycin) is added to each plate. The cells are then incubated for 24 to 48 hours at 37 0 C, 5% CO 2 A typical protocol for the DEAE-dextran method as applied to Cos-7 cells is described as follows; Cells to be used for transfection are split 24 hours prior to the transfection to provide flasks which are 70-80% confluent at the time of transfection. Briefly, 8 Fg of receptor DNA plus 8 Fg of any additional DNA needed G protein expression vector, reporter construct, antibiotic resistance marker, mock vector, etc.) are WO 03/004027 PCT/US02/21063 496 added to 9 ml of complete DMEM plus DEAE-dextran mixture (10 mg/ml in PBS). Cos-7 cells plated into a T225 flask (sub-confluent) are washed once with PBS and the DNA mixture is added to each flask. The cells are allowed to incubate for 30 minutes at 37 0 C, 5% CO z Following the incubation, 36 ml of complete DMEM with FM chloroquine is added to each flask and allowed to incubate an additional 3 hours. The medium is then aspirated and 24 ml of complete medium containing DMSO for exactly 2 minutes and then aspirated. The cells are then washed 2 times with PBS and 30 ml of complete DMEM added to each flask. The cells are then allowed to incubate over night. The next day the cells are harvested by trypsinization and reseeded as needed depending upon the type of assay to be performed.
A typical protocol for liposomal-mediated transfection as applied to CHO cells is described as follows; Cells to be used for transfection are split 24 hours prior to the transfection to provide flasks which are 70-80% confluent at the time of transfection. A total of of DNA which may include varying ratios of receptor DNA plus any additional DNA needed Go protein expression vector, reporter construct, antibiotic resistance marker, mock vector, etc.) is used to transfect each 75 cm 2 flask of cells. Liposomal mediated transfection is carried out according to the manufacturer=s recommendations (LipofectAMINE, GibcoBRL, Bethesda, MD). Transfected cells are harvested 24 hours post transfection and used or reseeded according the requirements of the assay to be employed.
WO 03/004027 PCT/US02/21063 497 A typical protocol for the electroporation method as applied to Cos-7 cells is described as follows; Cells to be used for transfection are split 24 hours prior to the transfection to provide flasks which are subconfluent at the time of transfection. The cells are harvested by trypsinization resuspended in their growth media and counted. 4 x 106 cells are suspended in 30,0 Fl of DMEM and placed into an electroporation cuvette. 8 Fg of receptor DNA plus 8 Fg of any additional DNA needed G protein expression vector, reporter construct, antibiotic resistance marker, mock vector, etc.) is added to the cell suspension, the cuvette is placed into a BioRad Gene Pulser and subjected to an electrical pulse (Gene Pulser settings: 0.25 kV voltage, 950 FF capacitance). Following the pulse, 800 Fl of complete DMEM is added to each cuvette and the suspension transferred to a sterile tube. Complete medium is added to each tube to bring the final cell concentration to 1 x 10 s cells/100 Fl. The cells are then plated as needed depending upon the type of assay to be performed.
A typical protocol for viral mediated expression of heterologous 'proteins is described as follows for baculovirus infection of insect Sf9 cells. The coding region of DNA encoding the receptor disclosed herein may be subcloned into pBlueBacIII into existing restriction sites or sites engineered into sequences 5' and 3' to the coding region of the polypeptides.. To generate baculovirus, 0.5 Fg of viral DNA (BaculoGold) and 3 Fg of DNA construct encoding a polypeptide may be cotransfected into 2 x 106 Spodoptera frugiperda insect Sf9 cells by the calcium phosphate co-precipitation method, as outlined in by Pharmingen (in "Baculovirus Expression WO 03/004027 PCT/US02/21063 498 Vector System: Procedures and Methods Manual"). The cells then are incubated for 5 days at 27 0 C. The supernatant of the co-transfection plate may be collected by centrifugation and the recombinant virus plaque purified. The procedure to infect cells with virus, to prepare stocks of virus and to titer the virus stocks are as described in Pharmingen=s manual. Similar principals would in general apply to mammalian cell expression via retro-viruses, Simliki forest virus and double stranded DNA viruses such as adeno-, herpes-, and vacinia-viruses, and the like.
Stable expression Heterologous DNA can be stably incorporated into host cells, causing the cell to perpetually express a foreign protein. Methods for the delivery of the DNA into the cell are similar to those described above for transient expression but require the co-transfection of an ancillary gene to confer drug resistance on the targeted host cell. The ensuing drug resistance can be exploited to select and maintain cells that have taken up the heterologous DNA. An assortment of resistance genes are available including but not restricted to Neomycin, Kanamycin, and Hygromycin. For the purposes of receptor studies, stable expression of a heterologous receptor protein is carried out in, but not necessarily restricted to, mammalian cells including, CHO, HEK293, LM(tk-), etc.
Cell membrane preparation For binding assays, pellets of transfected cells are suspended in ice-cold buffer (20 mM Tris.HCl, 5 mM EDTA, pH 7.4) and homogenized by sonication for 7 sec. The WO 03/004027 PCT/US02/21063 499 cell lysates are centrifuged at 200 x g for min at 4 0 C. The supernatants are then centrifuged at 40,000 x g for 20 min at 4 0 C. The resulting pellets are washed once in the homogenization buffer and suspended in binding buffer (see methods for radioligand binding).
Protein concentrations are determined by the method of Bradford (1976) using bovine serum albumin as the standard. Binding assays are usually performed immediately, however it is possible to prepare membranes in batch and store frozen in liquid nitrogen for future use.
Radioligand binding assays Radioligand binding assays for the rat MCH1 receptor were carried out using plasmid pcDNA3.1-rMCH1-f (ATCC Patent Deposit Designation No. PTA-3505). Plasmid pcDNA3.1-rMCHl-f comprises the regulatory elements necessary for expression of DNA in a mammalian cell operatively linked to DNA encoding the rat MCH1 receptor so as to permit expression thereof. Plasmid pcDNA3.1rMCHl-f was deposited on July 05, 2001, with the American Type Culture Collection (ATCC), 12301 Parklawn Drive, Rockville, Maryland 20852, U.S.A. under the provisions of the Budapest Treaty for the International Recognition of the' Deposit of Microorganisms for the Purposes of Patent Procedure and was accorded ATCC Patent Deposit Designation No. PTA-3505.
Binding assays can also be performed as described hereinafter using plasmid pEXJ.HR-TL231 (ATCC Accession No. 203197) Plasmid pEXJ.HR-TL231 encodes the human MCH1 receptor and was deposited on September 17, 1998, with the American Type Culture Collection (ATCC), 12301 WO 03/004027 PCT/US02/21063 500 Parklawn Drive, Rockville, Maryland 20852, U.S.A.
under the provisions of the Budapest Treaty for the International Recognition of the Deposit of Microorganisms for the Purposes of Patent Procedure and was accorded ATCC Accession No. 203197.
Human embryonic kidney Peak rapid 293 cells (Peakr293 cells) were transiently transfected with DNA encoding the MCH1 receptor utilizing the calcium phosphate method and cell membranes were prepared as described above. Binding experiments with membranes from Peakr293 cells transfected with the rat MCH1 receptor were performed with 0.08 nM 3 H]Compound A (the synthesis of Compound A is described in detail below) using an incubation buffer consisting of 50 mM Tris pH 7.4, 10 mM MgC12, 0.16 mM PMSF, 1 mM 1,10 phenantroline and 0.2% BSA. Binding was performed at 25 0 C for 90 minutes. Incubations were terminated by rapid vacuum filtration over GF/C glass fiber filters, presoaked in 5% PEI using 50 nM Tris pH 7.4 as wash buffer. In all experiments, nonspecific binding is defined using 10 pM Compound A.
Functional assays Cells may be screened for the presence of endogenous mammalian receptor using functional assays. Cells with no or a low level of endogenous receptor present may be transfected with the exogenous receptor for use in functional assays.
A wide spectrum of assays can be employed to screen for receptor activation. These range from traditional measurements of phosphatidyl inositol, cAMP, Ca and WO 03/004027 PCT/US02/21063 501 K, for example; to systems measuring these same second messengers but which have been modified or adapted to be higher throughput, more generic, and more sensitive; to cell based platforms reporting more general cellular events resulting from receptor activation such as metabolic changes, differentiation, and cell division/proliferation, for example; to high level organism assays which monitor complex physiological or behavioral changes thought to be involved with receptor activation including cardiovascular, analgesic, orexigenic, anxiolytic, and sedation effects, for example.
Radioligand Binding Assay Results The compounds described above were assayed using cloned rat MCH1. The binding affinities of the compounds are shown in Table I.
WO 03/004027 WO 0/00027PCT/UJS02/21063 502 EXAMPLE No. STRUCTURE ri(MH 09 0- N4 2
N
0 0 7 0 000 N o 0 N- WO 03/004027 WO 0/00027PCT/UJS02/21063 503 9 0 4 69 0 0 2.8 0 0 N /197 0 Np 0 0 12 8 a N 00 13 -j.
14 NN 0 167 00 I 0 15 1 720 0-C/ N-S- 0 I) 0 0 16 N 7 00 WO 03/004027 WO 0/00027PCT/UJS02/21063 19 0 01-- N 29.5 506 21 630 -52 1036 67 463 192 q C-NOP 26N WO 03/004027 WO 0/00027PCT/UJS02/21063 505 27 NO- 0- 91 0 N 0 281 511
N-S-N
0
/N-
29 654 0 N0 N o 382 31 0 362 N4 o2 160 0 0 33 -bND 615 N-Sd 34 651 N ~'H 0 N N 11.5 WO 03/004027 WO 0/00027PCT/UJS02/21063 506 36 62 37 N 29.1 040 00 39 N I o 11.8 01 41 9 'NCo 946 0
N
42 N118 o
N
43 N 12 01- 44 \N11.5
N
WO 03/004027 PCT/US02/21063 507 N 1.6
F
/0 N 187 47 FN 52 F F0 48 6.7 49 r" Y -7.1 49, 0N C3_/--D-Q3.
N
cl 00 51 03.1 00-- 3.8
N
0 WO 03/004027 PCT/UJS02/21063 508 54 \/4.9
N
0N N N 0-'
N
0-I 57 N 16.6
NN
59 0 ND 12.9
N
01- Br 0 N Q 0.923
N
61 N13.6 WO 03/004027 PCT/UJS02/21063 509 ya0 63 0 22.4 64 (14.8 0 -K 17
N
0>/
F
O)OF
F
00 l
N
N
69 0 32.5 WO 03/004027 PCT/UJS02/21063 Fy
NCN
F
F F 73 0.N~ 22.3
F
F
74 0 48.6 o ~4.
0 N 76 No o~ 44.6 77 N25.7 78 22.2 79 0- 19.4 WO 03/004027 WO 0/00027PCT/UJS02/21063 0 0 14.3
N
81 Nj- 4 377
N
82 N N 11.2 o2 0
N
83 -N48.1 0-0 0-2 84 2 0"-0 0 0 0" No Q 3.2
N
EIXAMPLEI STRUCTUIRE Ki (nM) rMCI-1 WO 03/004027 PCT/UJS02/21063 512 WO 03/004027 PCT/UJS02/21063 513 WO 03/004027 WO 0/00027PCT/UJS02/21063 514 97 -27.3
NN
98 N N 37.9
NN
N-
CN 'No~
N
N N 1.7 127.5 i 38.4 I WO 03/004027 WO 0/00027PCT/UJS02/21063 103 N 21.3 1 K N C b,
JN
0 104 11.2 cI\ -N 0 0 105 F F 4.6 o 0 106 CI/\ 7.1 N= Cl 107 00.
N a
NN
108 5.2 0 0 ~HN--r 0
CI
WO 03/004027 PCT/UJS02/21063 WO 03/004027 PCT/UJS02/21063 517 WO 03/004027 WO 0/00027PCT/UJS02/21063 518 118 0 43.6
IN
OH
3
CH
3 119 0 75.7
NN
O -H 3 CH 3 120 0 31.1 IN;I N 0
N
OH1 3
OH
3 121 183.7
NN
N
WO 03/004027 WO 0/00027PCT/UJS02/21063 519 122 0 85.1 N 0
H
3 Cj N-
C
CH
3 123 0 449.8 7 0 F N
CH
CH 3 Example Structure rMCHI Ki (nM) 124 OH 33.0 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 520 126 13.8
H
3
C--
0 0 N
CH
3
CH,
127 OH 168.5 F N CH 3 128 OH 328.8 N. N
CH,
CH,
WO 03/004027 WO 03/04027PCTIUS02/2 1063 521 130 0 O-CH, 00 CI N
CH,
CH,
131 ci 11.9 0 FD
N
CH 3 132 F F 41.7
F
F
0 0 F D N-
H
H
3 133 14.1
H
3 0 0 K 0 Er N-
H
H
3 WO 03/004027 WO 03/04027PCTIUS02/2 1063 522 134 F 36.6
F
0 Na- F N- CH
CH
3
CH
3 1356B 10.9 0
CH
136 ci 15.9 0
NO-H
3
CH,
WO 03/004027 WO 03/04027PCTIUS02/2 1063 138 Br 239.3 00 F' N 0
CH,
139 38.7 0 0 FD
N-_H
CH 3 140 F 27.4 00 FD N-1C3 CH 3 WO 03/004027 WO 03/04027PCTIUS02/2 1063 524 142 18.3 0 0 0
FN
CH 3 H3H 143 8 1.7 0 C 00 0- F N
CH,
CH,
WO 03/004027 WO 03/04027PCTIUS02/2 1063 525 146 F 19.2 0 'N N F'
CH
3
CH,
147 HCO8.7 00 N
CH,
CH,
148 0 24.7 0/
H
0 0
CH,
149 0 N148.9 0 0
CH,
WO 03/004027 WO 03/04027PCTIUS02/2 1063 526 150 OH, ci 0 Br N-
H
O-r H 3
CH
3 151 14.2 0 0
CH,
152 0 81.
HCjYF 0
CH
3
CH,
WO 03/004027 WO 03/04027PCTIUS02/2 1063 527 154 09.3
HC
0 B N
CH
3
CH,
155 07.4 -0 7 0 N-
CH
156 8.8 0 C I N-
H
CH
157 0 15.4
H
3 c 0 0
N
CYH,
CH,
WO 03/004027 WO 03/04027PCTIUS02/2 1063 528 158 Br 7.8 0 0 Or
CH
CH
159 cI 0 0 Br N
CH,
OH
3 160 F 6.2 0 0 BrN
CH
161 D~-CH 3 7.9 0 0
N
CH,
WO 03/004027 WO 03/04027PCTIUS02/2 1063 529 162 F 7.2 0 111:1 No 0
N
O -H, CH 3 163 OH 58.3 0
CH
3 164 F16.3 00 N N 0
CH
3 165 Sr6.2 0 0 N-
H
3 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 166 0307.7 00 CI N CH 3
CH
167 OC,80.4 0 0 N
CH,
CH 3 168 aI 0 0
CH,
CH,
169 0 7.7 WO 03/004027 WO 03/04027PCTIUS02/2 1063 531 170 0 O-CH3 00 Br N
CH,
CH
3 171 Br 3.7 0 0
CH
3 172 0 0 N-
-CH
3 CH 3 173 /112.3 0
H
3 C, 0 0
N
O -H 3
CH,
WO 03/004027 WO 03/04027PCTIUSO2/2 1063 532 174 17.0 0 F' N- CH,
CH,
175 0 16.2
H
3 0 /-n 0 0 F N
CH
3 176 011.8
HNC
0 0
CH
177 0
'-CH
3 6.8 0 0
CH,
CH,
WO 03/004027 WO 03/04027PCTIUS02/2 1063 533 178 ci 119.2 0
CH
3 179 082.3 0
H
2 O'o 0
CH
180 9.7 0
N(
N 0
H
3 181 B, 91.9 0 0 N
CH
3 WO 03/004027 WO 03/04027PCTIUS02/2 1063 534 182 F101.3 0 00 Na
CH,
183 F 00 N-4
H
CH
184 F105.2 0 0 N O -H 3
CH,
185 0 20.6 HC- 0 0
CH
WO 03/004027 WO 03/04027PCTIUS02/2 1063 535 186 d 4.9 0 0 CI N
CH
187 HCH Chiral 15.6 0N
N
0
OH
3 Example Structure rMCH1 Ki (nM) 438.3 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 435.6 648.7 80.5 0 'N
CH
3 CH 3 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 537 194 1.8 0
N
CH
F F 195 N 0 t 106.0 N QN
CH,
196 35.2 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 538 195 N 6.1
N
0 0 H CI6
CH,
-3 NNH
H
3
N
20020.
FF
996.1 WO 03/004027 PCTIUS02/2 1063 539 154.7 79.6 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 540 206 207 208 209 cI aCl 17.7 136.8 30.8 64.8 WO 03/004027 WO 03/04027PCTIUS02/2 1063 541 23.3 111.3 519.1 WO 03/004027 WO 03/04027PCT11JS02/21063 542 214 056.3
N
N N CH 3 215 HC OH 3 CH 283.1
N
0:I CH 3
OH
3 216 F817.9 300.1 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 543 125.6 68.8 158.6 545.7
H
3 C 0' WO 03/004027 WO 03/04027PCTIUSO2/2 1063 544 222 223 224 152.4 318.2 213.6 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 238.8 26 1.6 841,1
H
3
C,
H3C 884.5 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 546 230
N
CH
3
CH
3 231 596.4 eN H30
NCH
3
CH
3 232 431.2 124.7 WO 03/004027 WO 03/04027PCTIUS02/2 1063 547 234 "16.1 0 N 0-:I
OH
3
CH
3 235 411.7 sN O-:I H 3
OH
3 236 NIO 097.7
OH
3
CH
3 237
H
3 C- A N
H
3 0 0:-I OH 3
CH
3 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 548 238 65.9 F 0~ CH 3 F I
OH
3
OH
3 239
N
0
CH
3
CH
3 240 y 0
S-
N
O~l
CH,
CH,
WO 03/004027 WO 03/04027PCTIUSO2/2 1063 549 242
N
NN
243
F
F 0 No 244 N J
N
0 YCH 3
CH
3 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 550 246
CH
3 N
CH
3 247 -0
H
3
N
CH
3 248 N N 0 O~yCHI
CH
3 249
S
N
0:-I
OH
3
CH
3 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 250
N
K OH 3
CH
3
OH
3 251 0
N
UH
3 0
H
3
OH
3 252 N 0 F
N
F
OH
3 253 361.6
NZN
N
O7l H 3
CH
3 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 254 52400.7 0 N9 07::I
OH
3 CH 3 255 589.8 No
NN
0--l CH 3
CH
3 256 320.5 37.2 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 258 110.3 0 N 0 CH 0 CH 3 o
CH
3 259 15.4 0 N o -I
CH
3
OH
3 260 77.7
NN
0: O H 3
CH
3 261
H
3
O;
WO 03/004027 WO 03/04027PCTIUS02/2 1063 262 263 Example 264 64.1 156.0 Structure rMCH-1 Ki (nM) 54.7 0 'N ly
CH
3
CH
3 WO 03/004027 WO 03/04027PCTIUS02/2 1063 266 556.4 No C CH .JD' N N-l a OH 3 c F
F
267 HC 2.2
NN
0 0=
CH
HC
F
268 C3 20.3 N CHN N0 H3C
H
3 C -H 269 27.4
N
CH,
HC
F
F
WO 03/004027 WO 03/04027PCTIUSO2/2 1063 556 270 H 3 C; 3.4
NN
0 N,
-CH
3 271 F 40.1 N
CH
3 0-
CH
3 F
H
3
C
272 H3 Chiral 15.6 0N
N.N
CH,
H
3
C
273 Chiral 196.4 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 557 843.5 734.4 117.8 EX2mple ExmpleStructure rMCH-1 Ki (nM) WO 03/004027 WO 03/04027PCTIUSO2/2 1063 558 278 OH Chiral 85.8 0 N 279 OH NC74.5
NN
0 O H 3 1- 3
C
280 HO 27.6 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 559 282 HO 23.5 61\- QH 3 C H
NT
0 283 F OH
*N
0: OCH 3
H
3
C
284 ,ci 16.3 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 560 67.8 34.3 0 CH 3 CH 3 WO 03/004027 290 291 292 561 PCTIUSO2/2 1063 51.9 24.3 18.4 WO 03/004027 WO 03/04027PCTIUS02/2 1063 562 294 c' 15.8 A N-0 ci 0 0
NN
HCH
295 a8.7 N-0
ACH,
N
0=
CH,
HC
296 _j-0 20.0 7CH 3 o 0
NN
00 cl 0 CH3
H
3 C3 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 298 N/ 0 H 3 5340.1 0 N
CH
3
OH
3 299 F37.5
CH,
HC
300 '7.6 WO 03/004027 PCTIUS02/2 1063 564 302 Chrl 20.5 Ch0a 0
CH,
H,c Example Structure rMCH-1 Ki (nM) 303 F 0 r
CH,
CH,
304 /\Chiral 0
N
'NN
H
3
C
305 Chiral 177.2 0 I
N
NN
CH
3
HC
WO 03/004027 WO 03/04027PCTIUS02/2 1063 565 306 CI Chiral 167.9 N CI 0
CH,
H
3
C
307 H 3 C Chiral 97.4
N
0
CH,
H~c 308 0 Chiral 401.6
N
CH,
H
3
C
309 -Chiral 310.1 O N
N
NN
HGC
WO 03/004027 PCTIUS02/2 1063 566 310 TH. Ciral 152.2
N
N
0= CH, H
C/
311 /\Chiral 43.0
NI
CH,
HC
312 F Chiral 61.5 O' F
NN
0
CH,
HC
313 Chiral 249.3 ci
F
0 -N\ fN 0 N CH
N
0
HC
WO 03/004027 WO 03/04027PCTIUSO2/2 1063 567 314 Chra 7.6
NN
NN
0
HC
315 Chiral 18.4
N
N
NN N \N 00 N cl CH3
NN
HC
WO 03/004027 WO 03/04027PCTIUS02/2 1063 568 318 cI Chiral 251.2
NN
0 CH,
H
3
C
319 0 N Chiral 89.8
N
NN
0
CH,
HC
320 F Chiral 10.6
F
N
N
N
H
3
C
321 HC Chiral 50.9
N
CH
3
H
3
C
WO 03/004027 WO 03/04027PCTIUSO2/2 1063 569 322 0 1CH 3 Chiral 99.9
N\
NOCH
3 N N
IN
0
OH
3 1- 3
C
323 s Chiral 37.0
N
NN
NCH
0 324 0 Chiral 75.8 0 00 H~c WO 03/004027 WO 03/04027PCTIUSO2/2 1063 570 326 0Chiral 19.2 NY 0
N
N
CH,
HC
370 Chiral 7.7 F F
IN
H C 328 H C 0 47.6 0
N
cKo N
H
3 C C H, 329 2.9 o N
'H
3
CXCH,
WO 03/004027 WO 03/04027PCTIUS02/2 1063 330 0 331 H 3 C 0 0
N
0 N
H
215.0 51.3 29.0 rMCH-1 Ki (nM) 567.8 332 H C 0 0
N
Example 333 H 3 C 0 0 0 N
HGCH.
Structure Chiral WO 03/004027 WO 03/04027PCTIUSO2/2 1063 Chiral 612.81 Chiral 887.7 Chiral 693.0 337 F 33 Chiral 907.4 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 573 338 0 CH, Chiral 843.9
N
N CH3
CH
3 339 cI Chiral 889.9 'N N N 0 CH 3
CHS
340 HC~OChiral 15.6 255.6 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 574 342 183.0
CH,
343 F 194.7 IO H 3
C
N
344 44.6 H3
N
WO 03/004027 WO 03/04027PCTIUS02/2 1063 575 106.9 54.8 84.0 WO 03/004027 WO 03/04027PCTIUS02/2 1063 576 350 Br 12.1
CH
3
N
351 Bra N HC 061.8
N
352 Br H 3 13.3
KN
Chiral 41.8
H
3 C CH WO 03/004027 WO 03/04027PCTIUSO2/2 1063 577 354 CH, Chiral 81.6 0 N N-CH H 3
C
355 CH, Chiral 116.6 0: 0
CH,
H
3
C
356
H
3 C Chiral N-
CH
Br/\ 0
OH
0
O
3 .157 r 115.4 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 135.7 Chiral Chiral 83.2 o 163.0 Chiral
N
0=
CH
3
H
3
C
AR
Chiral 311.2 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 Chiral 281.2 Chiral 31.6 144.4 Chiral Chiral 42.9 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 Chiral 64.
-CH 3 Chiral 235.7
-H
3 Chiral 313.0
-OH
3 Chiral 145.0 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 370 Chiral
N
Br -Q/0 CH 3 N 0 CH 3
H
3
C
371 Chiral 162.7 Br N D /01 OH N 0 CH 3
H
3
C
372 Chiral Chiral 428.5 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 582 374 H 3 C CH 3 96.8 N 0
ZN
H
3 0 CH, 375 185.6
N
0 c O H 3
H
3
C
37 887.6 0 N
H
3 C ICH 3 377071.
H
3 0j 00 H 3 c H 3 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 583 378 0. 307.8 IH I 0 N H C xICHS z3 3 C H3H
CH
3 H CH 380 -~309.1 235.0 WO 03/004027 WO 03/04027PCT11JS02/21063 S84 382 318.8 o 'N
CH
3
N
0 383 H 3 C 0 289.6 H HC CH 3 0 N 38 N 69.0
N
O OH 3
N
0 385 C1 324.6 0
N
7l:: 0 H 3
H
3
C
Example Structure rMCHI Ki (nM) WO 03/004027 WO 03/04027PCTIUS02/2 1063 585 26.3 19.7 20.7 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 586 390 H CH 3 o
NN
F
11N 391 21.9
N
N
HC
3 c N
):CH,
392 H 3 C ;CH 18.1
*-N
N
N
393I WO 03/004027 WO 03/04027PCTIUS02/2 1063 587 394
N
0
N
395 2.4
N
N
H
3 C 0 N HC
CH
3 396
NN
N
N
NN
H
3
C
WO 03/004027 WO 03/04027PCTIUSO2/2 1063 588 398 13.6
NN
NN
H
3 C
CH
400 4H,3.9
NN
401 44.6 WO 03/004027 PCTIUSO2/2 1063 589
N
0-
CH,
H
3
C
WO 03/004027 WO 03/04027PCTIUSO2/2 1063 590 406 12.3
N
NN
N C H 3 407 -16.6 0
CH,
H
3
C
N0 409 N 0H 9.
00
N
N
CH,
WO 03/004027 WO 03/04027PCTIUS02/2 1063 591 410 H 262.7
N
CHH,
411 N CH, 27.3 0 F~ N 41 /*OH 2.
00 413 76.8
H
3
C
WO 03/004027 WO 03/04027PCTIUSO2/2 1063 592 414 _Q 2.9
NN
0 IrCH 3
NH
3
C
CH
3 415 -8.1
NN
H
3 C H 3 C OH 3 416 -12.6 0 O H 3 0 3 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 593 418 9 1.6
N
0-
CH,
H
3
C
419 83.9
NN
420 H C
N
0 WO 03/004027 WO 03/04027PCTIUS02/2 1063 422 N /F 173.0 N \C0H, 0
N
423 N405.2
('N
q3 3 Nor-
N
0CH 3
H
424 114.2
N
NON
0-
CH
3 N 1111
HNC
CH
3 WO 03/004027 WO 03/04027PCTIUS02/2 1063 595 426 -Q556.1 0
H
3
CHH
3
C
427 CH3N248.3 0H N H N 3 428 132.4 N
CH
NN
CHOH
3
NN
0
NH
1+ N
H
3
C
WO 03/004027 WO 03/04027PCTIUS02/2 1063 430 96647.4
NN
CH
3 OH 3
CN
H
3 c 431 967.7 Br
NN
-CH
3
N
H 3 432 198.2 N 0 3
H
3 0
F
433 N -Q 30.4
HCH
WO 03/004027 WO 03/04027PCTIUSO2/2 1063 597 434 214.2 N. O- CH 3 Nl )H3-H
H
3
CC
435 214.4 552.1 WO 031004027 WO 03104027PCT/US02/21063 59B 438 -1.3 0 CH, rN 0 439
N
N F H 3
C
440 106.9 H I> Cl-i 3 H 3
C
441 -10.1
HC
O-H
3 WO 03/004027 WO 03/04027PCTIUS02/2 1063 599 442 -7.81
O'N
HC
F
F
443 -23.4
HC
0 H C 444 C3N544.7
CH
3
N
0 N CH
N
H
3 0 445 -Q486.3 H 3 G i N
H
I~rN
H
3
C
WO 03/004027 WO 03/04027PCTIUS02/2 1063 600 446 -17.9
NN
447 -Q 9.8
NN
'NN
N
NN
cc F F 0 )CH, F H 3
C
449 CN Q623.4 1 3
N
0 0
OH
3
H
3
C
WO 03/004027 WO 03/04027PCTIUS02/2 1063 601.
450 NO 7.1 0
CH,
H,0
F
451 -18.7
NN
CN
HC
b0
OH
3 452 12,7
N
C H, HC 453 -194.8 CH, N I jo N N 0 0 -H 3 r0
H
3 c
CH,
WO 03/004027 WO 03/04027PCTIUS02/2 1063 602 454 772.0
NN
F
OH
3
N
H
3
C
455 -10.6 456 28.0 CI3 457 27.4
NO-
C N c WO 03/004027 WO 03/04027PCTIUSO2/2 1063 603 458 -15.3 0N
C
SNN
459 -10.4 0NH
SNN
0CH 3 0H 3
G
N l H 3 c 461 35.6
N
0
H
3
C
WO 03/004027 WO 03/04027PCTIUSO2/2 1063 604 462 -12.4 0N CC N jN\ b H3 463 17.2
N
(DS
N
b 0~ WO 03/004027 WO 03/04027PCTIUS02/2 1063 605 466 N
-Z
N0 C1,
N
F
467
NN
No 0 F N H3I3 469-- 49.5 WO 03/004027 PCTIUS02/2 1063 654.1 606 WO 03/004027 WO 03/04027PCTUS02/2 1063 607 47 13.3 N0 .l CH 3 475 -12.4 0I0 476 12.
NN
477 14.9 N 0: CH 3
C'CH
WO 03/004027 WO 03/04027PCTIUSO2/2 1063 608 478 -11.7 I 0 Cj N
H
CCH
479 -8.1
N
I 0
SN
480
H
664.0 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 609
N
0 :)CH 3
HC
N
0 CH 3
H
3
C
WO 03/004027 WO 03/04027PCTIUS02/2 1063 48q WO 03/004027 WO 03/04027PCTIUSO2/2 1063 611
.NOQ
H
3
C
N
0 CH 3
H
3 c
N
0
H
3
C
WO 03/004027 WO 03/04027PCTIUSO2/2 1063 612 494
N
N
SN
H
3
C
495 95.1
NN
0N~ CH 3
H
3 CJ N
H
3 c 496 -288.0 0 0
CH
3 4q7 97.7 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 52.2
N
CH
3 H 3 c
N
Ct-I 3
H
H
3
C
N~rQ
C'N
N WO 03/004027 WO 03/04027PCTIUSO2/2 1063 614 225
N
0
CH
3
H
3
C
WO 03/004027 WO 03/04027PCTIUSO2/2 1063 615 506 0 -Q
N
CH CH ol
N
507 57.9 N0 0- ICH 3 N+
NH
0 508
NN
0
CH
3 F
N
F H 3 c WO 03/004027 WO 03/04027PCTIUSO2/2 1063 510 16304.9 Na
N
I0
CH
3
N
HGC
H
3 0" 511
N
0 CH,
PN
H~C
3C 512 42.7
N
N
0 CH 3
N
Hc 513 178.7 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 151.4 296.2 90.9 r17 ~17 286.9 WO 03/004027 WO 03/04027PCTIUS02/2 1063 618 518 -226.2
NN
HC
HC
519 80.9 I 0N
CH
3
H
3
C
CH
3 520 -135.1 CH 3
H
3
C
CcI WO 03/004027 WO 03/04027PCTIUSO2/2 1063 619
N
HC
0 CH, 247.0 54.8 198.7 91.4
N
0
CH
3
H
3 c WO 03/004027 WO 03/04027PCTIUS02/2 1063 620 526 B 1Q N410.6
N
I0
CH
3
N
Ho 528 0H 226.5
'NN
H 3
H
3
C
528 0411.1
H
3
H
3
C
WO 03/004027 WO 03/04027PCTIUS02/2 1063 105.3
H
3 C1 0 WO 03/004027 534 535 536 PCTIUSO2/2 1063 154.9 28.1 150.4 WO 03/004027 WO 03/04027PCTIUS02/2 1063 268.4 172.3 318.6 WO 03/004027 WO 03/04027PCTIUS02/2 1063 624 542 31.3 0 N
N
N 0 7
CH
3
H
3 0 543 27.6 0 N o3 N 0)
H
3 C
H
544 16.2
NN
NN
N 0 7 WO 03/004027 WO 03/04027PCTIUS02/2 1063 546 6587.9 0 7
N
HCH
547 75,5 o O'0 N
H
3
C"
548 125.6 0N
F
54q 39.7 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 1526 550 06D.9
F
F
0 N H CX 551 021.6
N
N
0
F
552 0 24.7 N 1
H
3
C
N 0 IN' 0 0 553 27.5 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 554 0 2770.9 N 0 555 0 50.3 H3C
N
N
556 0 35.6 H3O
NN
557 025.6 0 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 628 558 020.2 0 N F59 0 HC 62.3 N 560 Q55.7 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 629 562 0 48.1
N
cl 0 N 563 050.2
&FN
0 564 028.9
NN
0 965 0 49.2 0 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 630 566 0 77.8
NT
HC
567 o 92.2
OIN
568 0 68.8
NN
FF
549.3 WO 03/004027 WO 0/00027PCT/UJS02/21063 136.3 571
F'
Example 572 F.
88.3 rMCH1 Ki (nM-) 181.5 Structure Chiral Chiral 114.3 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 574 F F
N
575 F bF0
N
576 F Chiral Chiral 192.6
CH
3 1 CH 3 0 Chiral 74.3 Chiral 64.7 WO 03/004027 WO 0/00027PCT/UJS02/21063 578 Example 579 580 633 F Chiral 98.8 N CH, N 3 Structure rMCH1 Ki (nM) 131.1 as 0
N
54.Q 86.4
N-I
S
N
0= C3
CH
3 WO 03/004027 WO 03/04027PCTUSO2/2 1063 634 582 58.3
I
7
~,N
583 C3 N N 584 51.8 s NO 585 H 3 C CH 3 37.2 Naa N0 WO 03/004027 WO 03/04027PCTIUS02/2 1063 635 586 No q42.9
NN
S
N=
cHCH 3
C-
3 587 46.9 S
N
S 0= 588 H C 283.9 as3 589 66.6
NN
N
S 0 WO 03/004027 WO 0/00027PCT/UJS02/21063 636 590 157.1 0 N 11 N NO H 3 C, 0 7
OH
3 591 137.5 0 N N N H 3 C, 0 a-Br
OH
3 Example Structure rMCHI Ki (nM) 592 FChiral 1
F
N
0
HG
593 S Chiral 7.6 Ni C(
NN
0
H
3
C
WO 03/004027 PCTIUS02/2 1063 637 594 CH 3 Chiral 67.0
N
0
H
3
C
59-0 Chiral 36.3 N
N
1- 3 C OH 3 596 cI Chiral 596.7 HO 0 cI 0N 597 0~ Chiral 222.7 sI~-OH 3
N
N HC O H, WO 031004027 WO 03104027PCT/US02/21063 638 598 0 0 -Chiral 25.3 S F
H
3 C CH, 599 0 H, Chiral 50.0 S CH, N CH,
N
C N 600 01 Chiral 41.3
N
cl 0 N HC 'CH, 601 OlChiral 144.2 N
OXN
HC CH, WO 03/004027 PCTIUS02/2 1063 639 602 0 Chiral 44.6
N
N 8.
CH,
C
IIIC
Example MOLSTRUCTURE rMCH1 Ki (nM) 604 O<>Chiral 36.8
N
H C CH 3 605 Chiral 94.5
HOX:-N
H
3 C CH, WO 03/004027 WO 03/04027PCTIUSO2/2 1063 640 J~H Chiral
NCH
N C 0 N H ,C:i iCH, Chiral 142.1 Chi ral Chiral
N
0 :-N WO 03/004027 PCTIUSO2/2 1063 641 610 Chiral 529.8
N
N
0 N H C CH 611 Chiral 65.1 0
:,N
H-4c CH 612 HChiral 121.0 0XN H C CH 613 F 34.9 0 N H C CIICH3 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 642 614 CI 84.8 o N
H
3
CXCH,
615 s210.5
CH,
O N H, 3
CIICH,
616 0 405.6
NX
H
3 :C H O 3 617 Hc 608.9 0 0 WO 03/004027 WO 03/04027PCTIUS02/2 1063 643 61839.
0 619 177.5
H
3
C.-
0XN
H
3 G OH 3 620 OH 3 S 223.3 HO N N-'-N H0 NH 621 0 204.6
NX
H
3 0 CH 3 XaMDie Structure rMCH E 1
E
Ki (nM) WO 03/004027 WO 03/04027PCTIUSO2/2 1063 644 622 F 162.4 F 0 N NN
CH
3 0 N CH 3 E 623 F 23.1
F
0 0 N 0H 624 z 47.8 WO 03/004027 WO 03/04027PCTIUS02/2 1063 626 0I 64 H 3 20.9 0 N CH N 0
N
628 ii9 160.6 0 N CH 3 N.
H
3 629 42.9 N i N CH, 0N WO 03/004027 WO 03/04027PCTIUSO2/2 1063 646 630 7 0 201.8 0 )yNHN 631 N y0 258.8 ~N CH 7 0 632 cl76.6 NaCN CH H 0 633 107.8 0 CH Nl H Cr CH 3 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 647 116.1 634 635 636 73.6 40.8 105.6 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 648 538 029.8 CH3 N
C
0 CH 3 0 639 36.3 0 N CH 3 -7 0
F
640 11.2 0
N
S-N 0 0
H
3 C CH WO 03/004027 WO 03/04027PCTIUS02/2 1063 649 642 Cl 8.3 -0
H
3 ol0 r
CH
3 6x N~/ 0 643 129.9 N
CHN
F
0 644 196.1 N H 3
H
3 C 0
OH
3 y 0 0
CH
3 645 85.3 s
CH
3
HH
H
3 ca
CH
3 WO 03/004027 PCTIUS02/2 1063 235.7 650 WO 03/004027 WO 03/04027PCTIUS02/2 1063 651 660 21.1 N
CH,
0 N -I N N CH, N7N 651 OH 3 16.7 HC N HC 0\N ci 652 CH, 7.1 0
N-\
N
Ci WO 03/004027 WO 03/04027PCTIUS02/2 1063 652 654 43.6 N o
H
0
N
655 H,0 31.1 0
-CH,
N
CI
0 Cl 656 /49.7
N
aN
CF
a0 N _C 0
N
657 I77.9
H
WO 03/004027 WO 03/04027PCTIUS02/2 1063 653 658 F12.0 I -N 0 0 N
H
3 C CH, 659 40.2 cI 0N N)ICH3 CI N
OH
3
H
660 128.9 0 N' N N~
H
661 33.3 0 0 r)I
CH
3 0
OH
3 662 50.3 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 654 663 73.4 F F1 F
NN
o
CHO
664 21.9 Br N N o CH 3 665 038.4 N N N CHO 0
CHO
WO 03/004027 WO 03/04027PCTIUS02/2 1063 25.8 42.2 WO 03/004027 PCTIUS02/2 1063 F~ ,.F B8.6 WO 03/004027 WO 03/04027PCTIUS02/2 1063 657 39.6 32.6 21.9 WO 03/004027 WO 03/04027PCTIUS02/2 1063 658 678 014.7 0 679 97.9 I 0 0 N' -4C''N -N
N
o H 680 CH 3 28.1i N /N N CH 3 CI l-ICH N~ 0 681 HCG CH~ 23.9 ojN P
CH,
N
Cl WO 031004027 WO 03104027PCT/US02/21063 659
CH,
CH,
0 WO 03/004027 PCTIUS02/2 1063 33.9 20.6 41.0 WO 03/004027 PCTIUS02/2 1063 661 WO 03/004027 PCTIUS02/2 1063 WO 03/004027 PCTIUS02/2 1063
CH
3 A
H
3 0 WO 03/004027 PCTIUSO2/2 1063 27.0 16.6 1.2 CH 3
KCH-
3 0 WO 03/004027 PCTIUS02/2 1063 WO 03/004027 PCTIUS02/2 1063 WO 03/004027 PCTIUS02/2 1063
CH,
Y CH 3 0 WO 03/004027 PCTIUS02/2 1063 WO 03/004027 PCTUSO2/21063 151.6
CH
3
CH
3 0 WO 03/004027 PCTIUS02/2 1063 WO 03/004027 PCTIUS02/2 1063 WO 03/004027 WO 03/04027PCTIUS02/2 1063 CH3
.N-KCH
3 0 WO 03/004027 WO 03/04027PCTIUS02/2 1063 213.6 12.2 WO 03/004027 WO 03/04027PCTIUS02/2 1063 674 7 4.r WO 03/004027 WO 03/04027PCTIUS02/2 1063 675 160.6 3.1 23.2 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 676 750 2.6
CH
3
N
N OH3 751 F F 12.4 N C
NN
Sr WO 03/004027 WO 03/04027PCTIUSO2/2 1063 49.2 23.8 CH 3 OH 3 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 678 110.0 92.3 ,I
H
3 0 WO 03/004027 PCTIUS02/2 1063 679 WO 03/004027 WO 03/04027PCTIUS02/2 1063 680 766 7.6
CH,
N' N Y CH, 00 767 34.8
OH
3 N N OH 3 0 0- 768 FF17.5
H
3 N N -I-CH 3 0 WO 03/004027 WO 03/04027PCTIUS02/2 1063 12.7 189.0 14.9 WO 03/004027 PCTIUS02/2 1063 WO 03/004027 PCTIUS02/2 1063 WO 03/004027 WO 03/04027PCTIUS02/2 1063 684 18.0 121.2 WO 03/004027 WO 03/04027PCTIUS02/2 1063 19.7 21.6 11.1 36.4 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 12.7 122.0
CH
3 0 WO 03/004027 WO 03/04027PCTIUS02/2 1063 6874.
CH
3
NN
H
3 C 0 Br 51.1
F
0 IN -~N O N
NN
0 796 43.0
F
F 0 N NN 0 Example Structure rMCHI Ki (nM) 797 42.4 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 798 68 474.7 N CH3 799 370.6 800 H CH 3 9.9
NN
801 311.1 N )K CH 3 o- Nr CH3 WO 03/004027 WO 03/04027PCTIUS02/2 1063 689 802 36.7
H
3
C
B03 298.6
HC
CH,
804 89.2 805 903.9
OH
3 N H 3
C
WO 03/004027 WO 03/04027PCTIUS02/2 1063 690 806 H3C C,14.1 N C)
NN
CH,
H
3
C
807 2.7 0 0
CH
3 808 10.8 C1 Chiral N N, Example Structure rMCH1 Ki (nM) 809 56.8 WO 03/004027 WO 03/04027PCTIUS02/2 1063 691 810 191.2 F F
N
F CH 3
CH
3
OH
a11 190.8 F
CH
OH
3
OH
3
OH
812 244.8
N
ii:0
H
3 OH OH 3 813 F 57.3 CI
N_
OH
0 N
H
3 C: OH 3 WO 03/004027 WO 03/04027PCTIUS02/2 1063 159.5 126.9 89.6 WO 03/004027 WO 0/00027PCT/UJS02/21063 693 818 38.2 HO IN 0--aH 3 C C 3
GI
819 OH 80.2 N
NN
CIm C CH Example Structure rMCH1 Ki (nM) 820 N N108.6
H
3 C
I
H
3 C 0l WO 03/004027 WO 0/00027PCT/UJS02/21063 694 8221.
HN
N CH, HC 0
CH,
823 N2.7
N
H3C9 0 824 N 3.
HC
Example Structure rMCH1 Ki (nM) 825 60D.7
N
H H 3 C 0
OH,
826 785.6 N N 0
HGC
WO 03/004027 WO 0/00027PCT/UJS02/21063 215.4 515.9 228.0 WO 03/004027 PCT/UJSO2/21063 468.6 696 569.8 614.3 27.5 WO 03/004027 WO 0/00027PCT/UJS02/21063 834 835 836 35.9 WO 03/004027 WO 0/00027PCT/UJS02/21063 698 838 11 .2 N
N
839 62.2 N' N
NN
H
3
C'CH,
840 663.5 H 3 WO 03/004027 PCT/UJSO2/21063 15.8 WO 03/004027 PCTIUS02/2 1063 700 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 0 11 0
N,
27.4 14.5 WO 03/004027 WO 03/04027PCTIUS02/2 1063 256.0 122.6 WO 03/004027 WO 03/04027PCTIUS02/2 1063 703 858 0 HCIO 44.9 r CH 3
N
859 H 3 C 320.7
NN
860 0 CH 3 40.5 N CH N 0
HC
WO 03/004027 WO 03/04027PCTIUSO2/2 1063 704 862 437.6
#NAME
863 4NM?269.0
/H
3 C N N H 3 C 0
CI__
864 292-0
N
H
3 C 865 94.6
HN
N HC 0
F
WO 03/004027 WO 03/04027PCTIUSO2/2 1063 705
N,
N HI 3 C 0
FF
169.2 891.9 403.4 430.9
H
3 0 N H 3 0
N:
WO 03/004027 WO 03/04027PCTIUS02/2 1063 706 87016.
N
87 1 251.7
/H
3 C N N H 300
F
872 306.3 345.0 WO 03/004027 WO 03/04027PCT/US02/21063 707 874 -247.1
NN
N
3
CH
875 1301
H
3 C><j N C 0
F
876 758.*2 H 3C N N H H 3
G
F
F F 245.1 WO 03/004027 WO 0/00027PCT/UJS02/21063 878 Example 888 889 Structure 168.8 rMCHI Ki (nM) 19.8 8.6 WO 03/004027 709 PCT/USO2/21063 17.3 23.0 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 6.4 30.3 )7 0 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 899 c 71 18.0 N0
K
0 3 900 F 1.
F11.2
N
901 F
K
0 3 3~ 902 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 712 903 12.2 N N 0
H
3 C CH, 0 CH, 904 14.2 N N C3 /HC H 3 905 Cl"
N
K
0 Br~a H HC OH 3 WO 03/004027 PCTIUS02/2 1063 WO 03/004027 PCTIUS02/2 1063 WO 03/004027 WO 03/04027PCTIUS02/2 1063 715 915 F22.6 N
NN
F
F
916 F F 20.2 Fj" 0 1N ly
CH
3 0 C H 3
FN
917 F 7.
F-
F
7 N0 0 F
-H
WO 03/004027 WO 03/04027PCTIUSO2/2 1063 716 919 0 14.0
CH,
0 920 0 6.9 N-l CH 3
CH
3 01 C: 921 0 6.8 N-l
CH,
OH,
N'r N.0 25.0 WO 03/004027 PCTIUS02/2 1063 WO 03/004027 PCTIUSO2/2 1063 718 927 0 60.7 N -Y CHt Ci N H3,C 0 928 0 14.9 N -y
CH,
CH,
0 929 F 29.9
F
,9-F FN
CH,
F 0 WO 03/004027 WO 0/00027PCT/UJS02/21063 931 799.6 F
F
CH,
F
N-
0
F
932 F 0 9.4 N
CH
3
HC
F 0N FrF
F
933 0 10.9 N
CH
3
CIH
0 Ul C41 3 934 12.3
F
K-
F
F
O H 3 N0 CH 3 WO 03/004027 PCTIUSO2/2 1063 720 935 19.7
CH
F
F
936 0 11.6 N -Y CH, 937 9 28.4 608.6 WO 03/004027 WO 03/04027PCTIUSO2/2 1063 939 940 Example 941 1
CH
3 62.0 1.8 rMGH1 Ki (nM) 15.2- Structure 187.9 WO 03/004027 WO 0/00027PCT/UJS02/21063 722 101.7 0 N CH 3 38.8 31.2 .945 336.6 WO 03/004027 PCTIUS02/2 1063 21.2 Table 2: Binding affinities (Ni) at the rat MOHi1, human Dopamine D2, human Histamine HI and human Alpha-l a Adrenergic receptors.
Compound JrMCH1 Ki (nM) 1 90 2 3.9 3 768-- 4 357 14.2 6 274 7 1000 8 627 9 69 1 0 2.8 11 197 12 84 13 11.9 14 167 72U 16 272 17 342 18 29.5 19 506 21 21. 630 hD2 1(1 (nM) 6092 2839V
ND
'1139
ND
ND
ND
1430 862
ND
771 551
ND
ND
N D N D 782
ND
hHI K! (nM) 823 700
ND
ND
1618
ND
ND
ND
1733 461
ND
571
ND
ND
ND
ND
ND
ND
ND
hAipha-la KI (nM) 49 32.1
ND
ND
9.1
ND
ND
ND
26.4 19.4
ND
57 61 ND0 N D N D N D N D j4704 ND 41.3 INO ND ND Table 2: Binding affinities (Ki) at the rat MCH1, human Dopamine D2, human Histamine Hi and human Alpha-l a Adrenergic receptors.
22 52 5181 2277 ~~284 23 1036 ND IND ND 267 1252 N D 127 463 ND ND ND 26 192 -1977 ND 516 27 91 503 ND 130 28 511 1ND ND ND 29 654 ND ND ND 382 ND ND ND 31 362 ND ND ND 32 160 IND ND ND tn33 615 ND ND IND CA 34 651 ND ND ND 11.5 09654 r-2000 533 36 62 112,026 2464 1489 37 29.1 4,9 16,734 1087 38 18.2 1>50000 6595 1592 39 11.8 >50000 6401 2937 50 7451 273 12.3 41 946 IND ND ND 42 118 1 ND ND ND 43 12 10,428 2560 434 44 11.5 8673' 11,092 704 Table 2: Binding affinities (Ki) at the rat MOHi, human Dopamine D2. human Histamine Hi and human Alpha-l a Adrenergic receptors.
1.6 42.2 3.4 18 46 1 87 ND: ND ND 47 52 >50000 36,907 >50000 48 6.7 735 6390 '152 49 7.1 471 39.1 140 3.9 1077 304 161 51 3.1 152 130 33.5 52 3.8 244 264 13.2 53~. 7. 9 1320 221 54 4.9 83 283 187 5 162 1100 125 -56 22.3 4532.5 57 16.6 _4_,99 48,658 3206 58 20.1 1390 590 233 12.9 262 46.9 49.1 0.923 52 546 22.3 61 13.6 3 28-6 62 12.8 319 25,320 719 63 22.4 766_. 25,307 1058 64 14.8 313 6994 1142 }1 3311 9390 1720 66 j 3.3 132 3473 944.
6 7 5.9 133 2146 511 Table 2: Binding affinities at the r-at MCH1, human Dopamine D2, human Histamine Hi and human Alpha-i a Adrenergic receptors.
68 9,3 66 329 204 69 32.5 46.6 >50000 232 50 1050 7998 1521 71 6.6 119 1710 226 72 31.4 !41,454 33,096 645 73 22.3 41,454 6522 381 74 48.6 39,511 1862 333 11,8 19,041 2844 2469 76 44.6 '41,454 39,710 10,965 77 25.7 447 4178 .167 78 22.2 37.6 >50000 1313 79 19.4 244 507 722 14.3 833 9789 620 81 377 ND ND ND 82 11.2 ND ND ND 83 48.1 ND ND ND 84 121 ND ND ND 3.2 2440) 3816 3021 WO 03/004027 WO 0/00027PCT/UJS02/21063 728 V. Synthesis of Compound A Described below is the synthesis of Compound A.
Compound A is the radiolabeled compound that was used in the radioligand binding assays described above.
N- 6-TETRAHYDRO-4-PYRIDlNYL)PHENYL]ACETAMIDE: The reaction of saturated of aqueous Na 2
CQ
3 solution mL) tert-butyl 4-{[F(trifluoromethyl) sulfonyljoxy}- 1,2, 3,6-tetrahydro-l-pyridine-carboxylate (20 mmol) 3acetamidophenylboronic acid (30 mmcl) and tetrakistriphenyiphosphine palladium (1.15 g) in dimethoxyethane (40 mL) at ref lux temperature overnight gave tert-butyl 4-1:3- (acetylarnino)phenyll -3,6-dihydro- 1l(2H) -pyridinecarboxylate. Deprotection of the BOC group using HCl in dioxane followed by basification (pH 11-12) gave the desired product.
TERT-BUTYL N-(3-BROMOPROPYL)CARBAMATE: was prepared from 3-bromopropylamine hydrobromide and BOC 2 0 in the presence of base in dichioromethane.
N-{3-[l-(3-AMIENOPROPYL)-1,2,3,6-TETRAH-YDRO-4- PYRIDINYLPHENYLACETAM~IDE: The reaction of tert-butyl N- (3-bromopropyl)carbarnate and NV-[3-(1,2,3,6-tetrahydro- 4-pyridinyl)phenyllacetamide in refluxing dioxane with catalytic Bu 4 NI and base as described in Scheme A gave tert-butyl 3- (acetylaniino)phenyl] -3,6-dihydro- 1(2H1)-pyridinyl)propylcarbamate. Deprotection of the BOC group using HCl in dioxane followed by basification (pH 11-12) gave the desired product.
WO 03/004027 WO 0/00027PCT/UJS02/21063 729 METHYL (ACETYLAMINO)PHENYL] -3,6- DIHYDRO-1 (2H) -PYRIDINYL) PROPYL] AMINO)CARBONYL) (3,4 DIFLUOROPHENYL) (METHOXYMETHYL) -2-OXO-l,2,3,4- Prepared from the reaction of 5-methyl 1-(4-nitrophenyl) difluorophenyl) (methoxymethyl) -2-oxo-3, 6-dihydro- 1,5(2H)-pyrimidinedicarboxylate (describe in PCT Publication No. Wo 00/37026, published June 29, 2000) and N-{3-[I-(3-aminopropyl)-1,2,3,6-tetrahydro-4pyridinyllphenyl~acetamide: 1 H NMR 6 8.90 1 H, J=3.6 Hz) 7.75 1 H) 7.50-7. 00 8 H) 6.68 1 H) 6.03 (br s, 1 4.67 2 3.71 Cs, 3 3.47(s 3 H) 3.38 CABin, 2 H) 3.16 (in, 2 H) 2.71 2 H, J =5.4 2.56 Cm, 4 2.35-1.90 Cbr, 2 2.17 3 1.82 2 H, J=7.2 Hz); ESMS, 612.25 (M+H) t TRITIATED METHYL (4S) (ACETYLAMINO) PHENYL] 1-PIPERIDIN~YL)PROPYL)AMINO] CARBONYL}-4- (3,4- DIFLUOROPHENYL) (METHOXYMETHYL) -2-OXO-1,2,3,4- TETRAHYDRO-5-PYRIMIDINECARBOXYLATE 3 H] COMPOUND A): This radiochemical synthesis was carried cut by Amersham Pharmacia Biotech, Cardiff, Wales. A methanolic solution of methyl (4S) [3- (acetylamino)phenyl) 6-dihydro-l (2H) pyridinyl)propyl) amino~carbonyl) 4-difluorophenyl) 6T.(lethoxymethyl)-2-oxo-1,2,3,4-tetrahydro5S pyrimidinecarboxylate was exposed to tritium gas at 1 atmosphere pressure in the presence of palladium on carbon with stirring overnight to give the tritiated methyl tC3-{4- [3-(acetylamino)phenyl]-1piperidinyllpropyl) amino] carbonyl} (3,4difluorophenyl) -6-(methoxyinethyl)-2-oxo-l,2,3,4- -isomer) After WO 03/004027 PCT/US02/21063 730 purification by reverse phase HPLC (Hypersil ODS, 4.6 x 100 mm, methanol:H 2 0:Et 3 N 10:90:1 to 100:0:1 in min at 1.0 mL/min, with radiochemical and UV detection), this product was used as a radioligand in the MCH1 binding assays. The same procedure was carried out with
H
2 gas in place of 3
H
2 to afford the non-radioactive version of Compound A.
VI. In-Vivo Methods The following in vivo methods were performed to predict the efficacy of MCH1 antagonists for the treatment of obesity (3-day body weight and sweetened condensed milk), depression (forced swim test), anxiety' (social interaction test), and urinary disorders (DIRC and
CSTI).
Effects of MCH1 Antagonists on Body Weight (3 Day) Male Long Evans rats (Charles River) weighing 180-200 grams were housed in groups of four on a 12-hour light/dark cycle with free access to food and water.
Test compounds were administered twice daily via i.p.
injection, 1 hour before the dark cycle and 2 hours after lights on, for three days. All rats were weighed daily after each morning injection. Overall results were expressed as body weight (grams) gained per day (mean SEM) and were analyzed by two-way ANOVA. Data for each time point were analyzed by one-way ANOVA followed by post hoc Newman-Keuls test. The data were analyzed using the GraphPad Prism (v2.01) (GraphPad Software, Inc., San Diego, CA). All data were presented as means S.E.M.
WO 03/004027 PCT/US02/21063 731 Effects of MCH1 Antagonists on Consumption of Sweetened Condensed Milk Male C57BL/6 mice (Charles River) weighing 17-19 grams at the start of experiments were housed in groups of four or five on a 12 hour light/dark cycle with free access to food and water. For 7 days, mice were weighed, placed in individual cages and allowed to drink sweetened condensed milk (Nestle, diluted 1:3 with water) for 1 hour, 2-4 hours into the light cycle. The amount of milk consumed was determined by weighing the milk bottle before and after each drinking bout. On the test day, mice received i.p. injections of Test Compound 10 or 30 mg/kg in 0.01 lactic acid), vehicle (0.01 lactic acid) of d-fenfluramine (10 mg/kg in 0.01 lactic acid) 30 min. prior to exposure to milk. The amount of milk consumed on the test day (in mls milk/ kg body weight) was compared to the baseline consumption for each mouse determined on the previous 2 days. Data for each time point were analyzed by one-way ANOVA.
Forced Swim Test (FST) in the Rat Animals Male Sprague-Dawley rats (Taconic Farms, NY) were used in all experiments. Rats were housed 5 per cage and maintained on a 12:12-h light-dark cycle. Rats were handled for 1 minutes each day for 4 days prior to behavioral testing.
WO 03/004027 PCT/US02/21063 732 Drug Administration Animals were randomly assigned to receive a single i.p.
administration of vehicle EtOH 2.5% imipramine (positive control; 60 mg/kg), or Test Compound 60 minutes before the start of the 5 minute test period. All injections were given using 1 cc tuberculin syringe with 26 3/8 gauge needles (Becton- Dickinson, VWR Scientific, Bridgeport, NJ). The volume of injection was 1 ml/kg.
Experimental Design The procedure used in this study was similar to that previously described (Porsolt, et al., 1978), except the water depth was 31 cm in this procedure. The greater depth in this test prevents the rats from supporting themselves by touching the bottom of the cylinder with their feet. Swim sessions were conducted by placing rats in individual plexiglass cylinders (46 cm tall x 20 cm in diameter) containing 23-25 0 C water 31 cm deep. Swim tests were conducted always between 900 and 1700 hours and consisted of an initial 15-min conditioning test followed 24h later by a 5-minute test. Drug treatments were administered 60 minutes before the 5-minute test period. Following all swim sessions, rats were removed from the cylinders, dried with paper towels and placed in a heated cage for 15 minutes and returned to their home cages. All test sessions were videotaped using a color video camera and recorded for scoring later.
WO 03/004027 PCT/US02/21063 733 Behavioral Scoring The rat's behavior was rated at 5-second intervals during the 5-minute test by a single individual, who was blind to the treatment condition. Scored behaviors were: 1. Immobility- rat remains floating in the water without struggling and was only making those movements necessary to keep its head above water; 2. Climbing rat was making active movements with its forepaws in and out of the water, usually directed against the walls; 3. Swimming rat was making active .swimming motions, more than necessary to merely maintain its head above water, e.g. moving around in the cylinder; and 4. Diving entire body of the rat was submerged.
Data Analysis The forced swim test data (immobility, swimming, climbing, diving) were subjected to a randomized, oneway ANOVA and post hoc tests conducted using the Newman- Keuls test. The data were analyzed using the GraphPad Prism (v2.01) (GraphPad Software, Inc., San Diego, CA).
All data were presented as means S.E.M. All data were presented as means S.E.M.
Forced Swim Test (FST) in the Mouse Animals DBA/2 mice (Taconic Farms, NY) were used in all experiments. Animals were housed 5 per cage in a controlled environment under a 12:12 hour light:dark cycle. Animals were handled 1 min each day for 4 days WO 03/004027 PCT/US02/21063 734 prior to the experiment. This procedure included a mock gavage with a 1.5 inch feeding tube.
Drug Administration Animals were randomly assigned to receive a single administration of vehicle EtOH/5% Tween-80), Test Compound, or imipramine (60 mg/kg) by oral gavage 1 hour before the swim test.
Experimental Design The procedure for the forced swim test in the mouse was similar to that described above for the rat, with some modifications. The cylinder used for the test was a 1liter beaker (10.5cm diameter X 15 cm height) fill to 800ml (10cm depth) of 23-25 0 C water. Only one swim test was conducted for each mouse, between 1300 and 1700 hours. Drug treatments were administered 30-60 minutes before the 5-minute test period. Following all swim sessions, mice were removed from the cylinders, dried with paper towels and placed in a heated cage for minutes. All test sessions were videotaped using a Sony color video camera and recorder for scoring later.
Behavioral Scoring The behavior during minutes 2-5 of the test was played back on a TV monitor and scored by the investigator.
The total time spent immobile (animal floating with only minimal movements to remain afloat) and mobile (swimming and movements beyond those required to remain afloat) were recorded.
WO 03/004027 PCT/US02/21063 735 Data Analysis The forced swim test data (time exhibiting immobility, mobility; seconds) were subjected to a randomized, oneway ANOVA and post hoc tests conducted using the Newman- Keuls test. The data were analyzed using the GraphPad Prism (v2.01) (GraphPad Software, Inc., San Diego, CA).
All data were presented as means S.E.M.
Social Interaction Test (SIT) Rats are allowed to acclimate to the animal care facility for 5 days and are housed singly for 5 days prior to testing. Animals are handled for 5 minutes per day. The design and procedure for the Social Interaction Test is carried out as previously described by Kennett, et al. (1997). On the test day, weight matched pairs of rats unfamiliar to each other, are given identical treatments and returned to their-home cages.
Animals are randomly divided into 5 treatment groups, with 5 pairs per group, and are given one of the following i.p. treatments: Test Compound (10, 30 or 100 mg/kg), vehicle (1 ml/kg) or chlordiazepoxide (5 mg/kg).
Dosing is 1 hour prior to testing. Rats are subsequently placed in a white perspex test box or arena (54 x 37 x 26 cm), whose floor is divided up into 24 equal squares, for 15 minutes. An air conditioner is used to generate background noise and to keep the room at approximately 74 0 F. All sessions are videotaped using a JVC camcorder (model GR-SZ1, Elmwood Park, NJ) with either TDK (HG ultimate brand) or Sony 30 minute videocassettes. All sessions are conducted between 1300 1630 hours.
Active social interaction, defined as grooming, sniffing, biting, boxing, wrestling, following and crawling over or under, is scored using a stopwatch WO 03/004027 PCT/US02/21063 736 (Sportsline model no. 226, 1/100 sec.
discriminability). The number of episodes of rearing (animal completely raises up its body on its hind limbs), grooming (licking, biting, scratching of body), and face washing hands are moved repeatedly over face), and number of squares crossed are scored. Passive social interaction (animals are lying beside or on top of each other) is not scored. All behaviors are assessed later by an observer who is blind as to the treatment of each pair. At the end of each test, the box is thoroughly wiped with moistened paper towels.
Animals Male albino Sprague-Dawley rats (Taconic Farms, NY) are housed in pairs under a 12 hr light dark cycle (lights on at 0700 hrs.) with free access to food and water.
Drug Administration Test Compound is dissolved in either 100% DMSO or lactic acid, v/v (Sigma Chemical Co., St. Louis, MO).
Chlordiazepoxide (Sigma Chemical Co., St. Louis, MO) is dissolved in double distilled water. The vehicle consists of 50% DMSO or 100% dimethylacetamide (DMA) All drug solutions are made up 10 minutes prior to injection and the solutions are discarded at the end of the test day. The volume of drug solution administered is 1 ml/kg.
Data Analysis The social interaction data (time interacting, rearing and squares crossed) are subjected to a randomized, oneway ANOVA and post hoc tests conducted using the WO 03/004027 PCT/US02/21063 737 Student-Newman-Keuls test. The data are subjected to a test of normality (Shapiro-Wilk test). The data are analyzed using the GBSTAT program, version 6.5 (Dynamics Microsystems, Inc., Silver Spring, MD, 1997).
In Vivo Models of the Micturition Reflex The effects of compounds on the micturition reflex were assessed in the "distension-induced rhythmic contraction" (DIRC), as described in previous publications Maggi et al, 1987; Morikawa et al, 1992), and Continuous Slow Transvesicular Infusion (CSTI) models in rats.
DIRC Model Female Sprague Dawley rats weighing approximately 300 g were anesthetized with subcutaneous urethane (1.2 g/kg).
The trachea was cannulated with PE240 tubing to provide a clear airway throughout the experiment. A midline abdominal incision was made and the left and right ureters were isolated. The ureters were ligated distally (to prevent escape of fluids from the bladder) and cannulated proximally with PE10 tubing. The incision was closed using 4-0 silk sutures, leaving the lines routed to the exterior for the elimination of urine. The bladder was' canulated via the transurethral route using PE50 tubing inserted 2.5 cm beyond the urethral opening. This cannula was secured to the tail using tape and connected to a pressure transducer. To prevent leakage from the bladder, the cannula was tied tightly to the exterior urethral opening using 4-0 silk.
WO 03/004027 PCT/US02/21063 738 To initiate the micturition reflex, the bladder was first emptied by applying pressure to the lower abdomen, and then filled with normal saline in 100 increments (maximum 2 ml) until spontaneous bladder contractions occurred (typically 20-40 mmHg at a rate of one contraction every 2 to 3 minutes. Once a regular rhythm was established, vehicle (saline) or Test Compounds were administered i.v. or i.p. to explore their effects on bladder activity. The 5-HT1A antagonist WAY-100635 was given as a positive control. Data were expressed as contraction interval (in seconds) before drug application (basal), or after the application of vehicle or test article.
Continuous Slow Transvesicular Infusion (CSTI) rat Model Male Sprague Dawley rats weighing approximately 300 g were used for the study. Rats were anaesthetized with pentobarbitone sodium (50 mg/kg, Through a median abdominal incision, bladder was exposed and a polyethylene cannula (PE 50) was introduced into the bladder through a small cut on the dome of the bladder and the cannula was secured with a purse string suture.
The other end of the cannula was exteriorized subcutaneously at the dorsal neck area. Similarly, another cannula (PE 50) was introduced into the stomach through a paramedian abdominal incision with the free end exteriorized subcutaneously to the neck region. The surgical wounds were closed with silk 4-0 suture and the animal was allowed to recover with appropriate post surgical care. On the following day, the animal was placed in a rat restrainer. The open end of the bladdercannula was connected to a pressure transducer as well WO 03/004027 PCT/US02/21063 739 as infusion pump through a three-way stopcock. The bladder voiding cycles were initiated by continuous infusion of normal saline at the rate of 100 pl/min. The repetitive voiding contractions were recorded on a Power Lab on-line data acquisition software. After recording the basal voiding pattern for an hour, the test drug or vehicle was administered directly into stomach through the intragastric catheter and the voiding cycles were monitored for 5 hours. Micturition pressure and frequency were calculated before and after the treatment (at every 30 min interval) for each animal. Bladder capacity was calculated from the micturition frequency, based on the constant infusion of 100ul/min. The effect of the test drug was expressed as a percentage of basal, pre-drug bladder capacity. WAY 100635 was used as positive control for comparison.
WO 03/004027 PCT/US02/21063 740 In Vivo Results Table 2 Effect of MCH1 antagonist (Example No.) in the following in vivo models: 3-day Body Weight (3D BW), mouse Sweetened Condensed Milk (mSwCM), mouse Forced Swim Test (mFST), rat Forced Swim Test (rFST), DIRC model, or CSTI model.
.0 Example 3D BW mSwCM mFST rFST DIRC CSTI No.
2 A B C D E F Not Not Not C E F Done Done Done Not D Not Not 39 A B Done Done Done Not C No t Not Not Done Done Done Done Not Not No Not Not Not 44 Done Done effect Done Done Done Not No Not Not- Not 89 B Done effect Done Done Done Not No No Not Not Not Done effect effect Done Done Done Not Not Not 91 C E F Done Done Done Not Not No Not Not Not 93 Done Done effect Done Done Done Not No Not Not Not
B
Done effect Done Done Done 99 A Not C Not E F Done Done Not C Not Not Not 105 B Done Done Done Done Not Not 106 Not B C E F Done Done Not Not No Not Not Not 112 Done Done effect Done Done Done 116 A Not C Not F Done Done A Produced a significant reduction in weight gain relative to vehicle-treated controls WO 03/004027 PCT/US02/21063 741 B Produced a significant decrease in consumption of milk relative to vehicletreated controls C Produced a significant decrease in immobility relative to vehicle-treated animals when administered orally.
D Produced a significant decrease in immobility or a significant increase in swimming activity relative to vehicle-treated animals E Produced a significant increase in contraction interval relative to pre-drug interval F Produced an increase in bladder capacity in rats relative to baseline capacity.
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Claims (31)

1. A compound having the structure: A R 1 -X N R 3 N-H R2 wherein Ri is hydrogen or straight chained or branched C 1 -C7 alkyl; wherein R 2 is straight-chained or branched C 3 -C 4 alkyl or cyclopropyl; wherein R 3 is aryl; wherein A is -Cl, -Br, -CN, -NO 2 -COR 3 -C0 2 R 3 straight chained or branched C 1 -C7 alkyl, monofluoroalkyl or polyfluoroalkyl; wherein X is 0 or NH; and wherein n is an integer from 0 to 5 inclusive.
2. The compound of claim 1, wherein R 2 is isopropyl; and A is hydrogen.
3. The compound of claim 2, wherein the compound has the structure: 0 N N 0/ 751 H NO N
4. A compound having the structure: A R N 0 N-H 0= R2 wherein Ri is a thienyl; wherein R 2 is straight chained or branched Ci-C 4 alkyl or cyclopropyl; wherein A is and wherein n is an integer from 1 to 5 inclusive. The compound of claim 4, wherein R 2 is isopropyl.
6. The compound of claim 5, wherein the compound has the structure: S N
7. A compound having the structure: A N I- W N-H 0-( R2 wherein W is 1 752 H A X-Y or N R, 'R H wherein each RI is independently hydrogen, methyl or ethyl; wherein R 2 is straight-chained or branched C 3 -C 4 alkyl or cyclopropyl; wherein R 3 is hydrogen, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more of -F, -Cl, -Br, -CN, -NO 2 straight chained or branched C 1 -C 7 alkyl; wherein each A is independently -Cl, -Br, -CN, -NO 2 COR 3 -C0 2 R 3 straight chained or branched Ci-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; wherein X is O, NR 3 CO or may be absent; and wherein Y is hydrogen, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more of Cl, -Br, -CN, -NO 2 straight chained or branched C 1 -C 7 alkyl.
8. The compound of claim 7, wherein W is H X H and wherein X is 0 or may be absent.
9. The compound of claim 8, wherein R 2 is isopropyl. The compound of claim 7, wherein the compound has the structure: o O N 0 F F or
11. The compound of claim 7, wherein W is SN R 1 R,
12. The compound of claim 11, wherein A is -Cl, -Br.
13. The compound of claim 12, wherein R 2 is isopropyl; and A is hydrogen.
14. The compound of claim 13, wherein the compound has the structure: N N0 A compound having the structure: A N-H wherein W is 754 B B I or \N N Ri Ri wherein RI is hydrogen, straight chained or branched C1-C7 alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more of -Cl, -Br, -CN, -NO 2 -OCH 3 C02CH 3 -CF 3 phenyl, straight chained or branched C1-C7 alkyl; wherein R 2 is straight-chained or branched C3-C4 alkyl or cyclopropyl; wherein A is -Cl, -Br, -CN, -NO 2 -CORI, -C0 2 RI, straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl or phenyl; and wherein each B is independently -Cl, -Br, -CN, -NO 2 -CORI, -C0 2 RI, -OCH 3 -OCF 3 -CF 3 straight chained or branched C1- C7 alkyl, monofluoroalkyl or polyfluoroalkyl or aryl, phenoxy or benzyloxy, wherein the aryl, phenoxy or benzyloxy is optionally substituted with one or more of -Cl, -Br, -CN, -NO 2 -CORI, C0 2 R 1 -OCH3, -OCF 3 -CF 3 or straight chained or branched Ci-C7 alkyl
16. The compound of claim 15, wherein W is B0 B N R,
17. The compound of claim 16, wherein Ri is hydrogen or phenyl optionally substituted with one or more of -Cl, -Br, -CN, NO 2 straight chained or branched C-C7 alkyl.
18. The compound of claim 17, wherein R 2 is isopropyl. 755 C1 19. The compound of claim 18, wherein the compound has the structure: N N ci N en or 0 o A compound having the structure: A N O R N\R4 O N-H RI R2 wherein R 1 is hydrogen, straight chained or branched Ci-C 7 alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more of -Cl, -Br, -CN, -NO 2 -CF 3 OCH3, straight chained or branched Ci-C 3 alkyl; wherein R 2 is straight-chained or branched C 3 -C 4 alkyl or cyclopropyl; wherein R 3 is -Cl, -Br, -CN, -NO 2 -CF 3 -OCH 3 or straight chained or branched C1-C3 alkyl, monofluoroalkyl or polyfluoroalkyl, or a phenyl ring fused to C6 and C7 of the indole moiety; wherein R 4 is hydrogen or aryl optionally substituted with one or more of -Cl, -Br, -CN, -NO 2 -CF 3 straight chained or branched Ci-C 3 alkyl; 756 wherein A is -Cl, -Br, -CN, -NO 2 straight chained or branched C 1 -C7 alkyl, monofluoroalkyl or polyfluoroalkyl; and wherein n is an integer from 2 to 4 inclusive.
21. The compound of claim 20, wherein R 3 is -Cl, -Br, I, -CN, -NO 2 -OCF 3 or -OCH3; and wherein R 4 is hydrogen or phenyl optionally substituted with one or more of -Cl or -CF 3
22. The compound of claim 21, wherein RI is hydrogen or phenyl optionally substituted with one or more of -Cl, -Br, -CN, NO 2 -CF 3 -OCH 3 or straight chained or branched C 1 -C 3 alkyl.
23. The compound of claim 22, wherein R 2 is isopropyl.
24. The compound of claim 23, wherein the compound has the structure: N N O I ^-N FF F^O 0 757 A compound of any one of claims 1 to 24, wherein the compound is enantiomerically pure.
26. A compound of any one of claims 1 to 24, wherein the compound is diastereomerically pure.
27. The compound of claim 25 or 26, wherein the compound is enantiomerically and diastereomerically pure.
28. A pharmaceutical composition comprising a therapeutically amount of a compound of any one of claims 1 to 24 and a pharmaceutically acceptable carrier, preferably the amount of the compound is from about 0.01mg to about 500mg, more preferably from about 0.1mg to about 60mg, and most preferably from about Img to about
29. The pharmaceutical composition of claim 28, wherein the carrier is a liquid and the composition is a solution. The pharmaceutical composition of claim 28, wherein the carrier is a solid and the composition is a tablet.
31. The pharmaceutical composition of claim 28, wherein the carrier is a gel and the composition is a suppository.
32. A process for making a pharmaceutical composition comprising admixing a therapeutically effective amount of the compound of any one of claims 1 to 24 and a pharmaceutically acceptable carrier.
33. Use of a compound according to any one of claims 1 to 24 for the preparation of a medicament useful for treating a 758 disorder selected from the group consisting of depression, anxiety, urge incontinence and obesity in a subject.
34. Use of a compound according to any one of claims 1 to 24 for the preparation of a medicament useful for reducing the body mass or managing obesity in a subject. Use of a compound according to any one of claims 1 to 24 for the preparation of a medicament useful for inducing or maintaining weight loss in a subject.
36. Use of a compound according to any one of claims 1 to 24 for the preparation of a medicament useful for treating a disorder in a subject that is mediated by the MCH1 receptor.
37. A compound according to any one of claims i, 4, 7, 15 and substantially as hereinbefore described with reference to the examples.
38. A pharmaceutical composition according to any one of claims 28 to 31, substantially as hereinbefore described with reference to the examples.
39. Use of a compound according to any one of claims 33-36, substantially as hereinbefore described with reference to the examples.
AU2002316531A 2001-07-05 2002-07-03 Substituted anilinic piperidines as MCH selective antagonists Ceased AU2002316531B8 (en)

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US89979401A 2001-07-05 2001-07-05
US09/899,794 2001-07-05
US4258202A 2002-01-09 2002-01-09
US10/042,582 2002-01-09
PCT/US2002/021063 WO2003004027A1 (en) 2001-07-05 2002-07-03 Substituted anilinic piperidines as mch selective antagonists

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AU2002316531B2 true AU2002316531B2 (en) 2007-09-13
AU2002316531B8 AU2002316531B8 (en) 2007-09-27

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002002744A2 (en) * 2000-07-05 2002-01-10 Synaptic Pharmaceutical Corporation Dna encoding a human melanin concentrating hormone receptor (mch1) and uses thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002002744A2 (en) * 2000-07-05 2002-01-10 Synaptic Pharmaceutical Corporation Dna encoding a human melanin concentrating hormone receptor (mch1) and uses thereof

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MXPA03011886A (en) 2005-03-07
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EA005934B1 (en) 2005-08-25
KR20040027870A (en) 2004-04-01
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IS7085A (en) 2003-12-18
EP1411942A1 (en) 2004-04-28
JP2004536104A (en) 2004-12-02
CA2454613A1 (en) 2003-01-16
EP1411942A4 (en) 2005-01-26
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WO2003004027A1 (en) 2003-01-16
PL366624A1 (en) 2005-02-07

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Free format text: IN VOL 21, NO 36, PAGE(S) 4189 UNDER THE HEADING APPLICATIONS ACCEPTED - NAME INDEX UNDER THE NAME H. LUNDBECK A/S, APPLICATION NO. 2002316531, UNDER INID (72) CORRECT THE CO-INVENTOR NAMES TO READ CHEN, CHIEN-AN; JIANG, YU; WETZEL, JOHN; LAGU, BHARAT; MARZABADI, MOHAMMAD R.; DELEON, JOHN E. AND LU, KAI

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