AU7319201A - Selective melanin concentrating hormone-1 (MCH1) receptor antagonists and uses thereof - Google Patents

Selective melanin concentrating hormone-1 (MCH1) receptor antagonists and uses thereof Download PDF

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AU7319201A
AU7319201A AU73192/01A AU7319201A AU7319201A AU 7319201 A AU7319201 A AU 7319201A AU 73192/01 A AU73192/01 A AU 73192/01A AU 7319201 A AU7319201 A AU 7319201A AU 7319201 A AU7319201 A AU 7319201A
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branched
straight chained
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pct
cycloalkyl
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George Chiu
John E. Deleon
Charles Gluchowski
Bharat Lagu
Mohammad R Marzabadi
Dhanapalan Nagarathnam
Stewart Noble
John Wetzel
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H Lundbeck AS
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Synaptic Pharmaceutical Corp
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Description

WO 02/06245 PCT/USO1/21286 SELECTIVE MELANIN CONCENTRATING HORMONE-1 (MCH1) RECEPTOR ANTAGONISTS AND USES THEREOF BACKGROUND OF THE INVENTION 5 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 10 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. 15 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 20 functional antagonist of oa-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, 25 energy metabolism, general arousal/attention state, memory and cognitive functions, and psychiatric disorders (for reviews, see Baker, 1991; Baker, 1994; Nahon, 1994; Knigge et al., 1996). Its role in feeding or body weight regulation is supported by a recent Nature publication (Qu 30 et al., 1996) demonstrating that MCH is overexpressed in the hypothalamus of ob/ob mice compared with ob/+ mice, and WO 02/06245 PCT/USO1/21286 -2 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 5 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 MC precursor preproMCH (ppMCH) mRNA levels (Presse et al., 1992). Thus MCH may 10 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 beli6vedto be 15 mediated by specific receptors, binding sites for MC-H have not been well described. A tritiated ligand ([ 3 H] -[CH) was reported to exhibit specific binding to brain membranes but was unusable for saturation analyses, so neither affinity nor B. were determined (Drozdz and Eberle, 1995). 20 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, 1 3 Tyr" 9 ]-MCH was successful (Drozdz et al., 1995); the ligand retained 25 biological activity and exhibited specific binding to a variety of cell lines including mouse melanoma (B16-Fl, G4F, and G4F-7), PC12, and COS cells. In G4F-7 cells, the K, = 0.118nM and the Bm ~1100 sites/cell. Importantly, the binding was not inhibited by a-MSH but was weakly 30 inhibited by rat ANF (Ki = 116 nM vs. 12 nM for native MCH) (Drozdz et al., 1995). More recently specific MCH binding was reported in transformed keratinocytes (Burgaud et al., 1997) and melanoma cells (Drozdz et al., 1998), where photo-crosslinking studies suggest that the receptor is a 35 membrane protein with an apparent molecular weight of 45-50 WO 02/06245 PCT/USO1/21286 -3 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. 5 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 10 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 15 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 20 fibres was observed concurrent with a significant increase in the level of MCH mRNA (.Bahjaoui-Bouhaddi et al., 1994). Consistent with the ability of MCH to stimulate feeding in rats (Rossi et al., 1997) is the observation that MCH mRNA levels are upregulated in the hypothalami of obese ob/ob 25 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 30 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 35 treatment of obesity and stress-related disorders.
WO 02/06245 PCT/USO1/21286 -4 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 5 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 10 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 15 involvement of this MCH system in movement disorders, such as Parkinson's disease and Huntingdon's Chorea in which extrapyramidal circuits are known to be involved. Human genetic linkage studies have located authentic hMCH 20 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 25 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 30 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 35 locus. Indeed, the gene responsible for chronic or acute WO 02/06245 PCT/USO1/21286 -5 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 5 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. 10 Additional therapeutic applications for MCH-related compounds are suggested by the observed effects of MCH in other biological systems. For example, MCH may regulate reproductive functions in male and female rats. MCH 15 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 20 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 25 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 30 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 35 Wagner, 1997). MCH has also been observed to affect WO 02/06245 PCT/USO1/21286 -6 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 5 for memory storage and/or retention. A possible role for MCH in the modulation or perception of pain is supported by the dense innervation of the periaqueductal grey (PAG) by MCH-positive fibers. Finally, MCH may participate in the regulation of fluid intake. ICV infusion of MCH in 10 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 15 involved in the central control of fluid homeostasis in mammals. As used in this invention, the term "antagonist" refers to a compound which binds to, and decreases the activity of, 20 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 25 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 30 of, a receptor as compared with the activity of the receptor in the absence of any agonist. In one embodiment of this invention, the synthesis of novel compounds which bind selectively to the cloned human 35 melanin-concentrating hormone-1 (MCHl) receptor, compared WO 02/06245 PCT/USO1/21286 -7 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 and activation assays described hereinafter were performed 5 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 10 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 15 MCH1 receptor may be beneficial. In addition, the compounds of the present invention may be used to reduce the body mass of a subject.
WO 02/06245 PCT/USO1/21286 -8 Summary Of The Invention This invention provides a compound having the structure: 5 A 0 A 0 10 R2 R4 R3 NR4 AIO
R
2 N X X N R 2 or R3RR A 0 A 0 R, N N R 3- NR ~ H ,or li
R
2 N SN
R
2
V
WO 02/06245 PCT/USO1/21286 -9 wherein A is 5 Y2 y3 Y2 y3 5 y 1 Y1
-Y
4 N 10 Y 5 Y2 15 20 Y Y O ' 20 N 3 /0 X N 25 2 y or 30 Y1 35 wherein each of Y1, Y,, Y 3 , Y 4 and Y 5 is independently -H; straight chained or branched CI-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or 40 cycloalkenyl; -F, -Cl, -Br, or -I; -NO 2 ; -N 3 ; -CN; -OR 3 ,
-OCOR
3 , -COR 3 , -CON(R 3
)
2 , or -COOR 3 ; or any two of Y 1 , Y 2 ,
Y
3 , Y 4 and Y 5 present on adjacent carbon atoms can constitute a methylenedioxy group; 45 wherein each X is independently S; 0; or NR 3
;
WO 02/06245 PCT/USO1/21286 -10 wherein R 1 is -H; -NO 2 ; -CN; straight chained or branched CI-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C 3
-C
7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or 5 cycloalkenyl;
-N(R
3
)
2 ; -OR 3 ; -(CH 2 ) pOR 3 ; -COR 3 ; -C0 2
R
3 ; -CON (R 3
)
2 ; or -CO 2
(CH
2 )nV; wherein R 2 is -H; straight chained or branched C-C7 alkyl, hydroxyalkyl, alkoxyalkyl, monofluoroalkyl or 10 polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C 3 -CIe cycloalkyl-C-Cio-alkyl, C3-010 cycloalkyl-C-Cio-monofluoroalkyl or C 3
-C
1 i cycloalkyl-C 15 Ci-polyfluoroalkyl; -CN; -CH 2
XR
3 , -CH 2
X(CH
2 )pNHR 3 ,
-(CH
2 )nNHR 3 , -CH 2
X(CH
2 )pN(R 3
)
2 , -CH 2
X(CH
2 )pN 3 , -CHX (CH 2 )pNHCXR7 ; or -OR 3 ; or wherein R, and R 2 together may form a lactone ring; 20 wherein each R 3 is independently -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3 C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; 25 wherein
R
4 is (i) 30 x R 6 R [ Rt- \/R5 WO 02/06245 PCT/USO1/21286 R XyR 6 RR 10 R NNR 5 15 0 Mv R5 20 R [mVXflR6 0 R R 25 (v) m R Im R 5 R 30 (v)R V R 3 5r \ N - + + R i R 5 R 40 (vi) RrA-R 5 0 tt-N R \- [c -,- / R 8
R
7 WO 02/06245 PCT/USO1/21286 -12 (viii) R A-DR5 0 5 >,mx 5 '\ N t-N N N 10 (i x) Z R7 R IM- ; or 15 m R 5 z (x) 20 R tN [m R 5 25 wherein the dashed line represents a single bond or a double bond; wherein each R is independently -H; -F; straight chained 30 or branched C 1
-C
7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2
-C
7 alkenyl or alkynyl; -N(R 3
)
2 ; -NO3; -CN; -C0 2
R
3 ; -OR 3 ; or -CON
(R
3 ) 2; 35 wherein each V is independently aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I;
COR
3 ; C0 2
R
3 ; -CON(R 3
)
2 ; CN; -NO 2 ; -N(R 3
)
2 ; -OR 3 ; -SR 3 ;
(CH
2 )qOR 3 ; (CH 2 )qSR 3 ; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or 40 carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; WO 02/06245 PCT/USO1/21286 -13 wherein each R 5 is -H; -NO 2 ; -N 3 ; -CN; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3 C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl 5 or cycloalkenyl;
-N(R
3
)
2 ; -OR 3 ; -(CH 2 )pOR 3 ; -COR 3 ; -C0 2
R
3 ;
-CON(R
3
)
2 ; aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2
R
3 ; -CON(R 3
)
2 ; CN; -NO 2 ; -N(R 3
)
2 ; -OR 3 ;
-SR
3 ; (CH 2 )qOR 3 ; (CH2)qSR 3 ; straight chained or branched 10 Ci-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 aikenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; 15 wherein R 6 is -H; straight chained or branched CI-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or 20 cycloalkenyl; -N(R 3
)
2 ; -OR 3 ; -(CH 2 )pOR 3 ; -COR 3 ; -C0 2
R
3 ; -CON(R3) 2 ; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2
R
3 ; -CON(R 3
)
2 ; CN; -NO?;
-N(R
3
)
2 ; -OR 3 ; -SR 3 ; (CH 2 )qOR 3 ; (CH 2 )qSR 3 ; straight chained or branched C-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, 25 aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; 30 wherein R 7 is H; F; Cl; Br; I; -NO 2 ; -N 3 ; -CN; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or 35 cycloalkenyl; -N(R 3
)
2 ; -OR 3 ; -(CH 2 )pOR 3 ; -COR 3 ; -C0 2
R
3 ; or WO 02/06245 PCT/USO1/21286 -14 -CON (R3) 2; wherein R 8 is independently straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight 5 chained or branched C2-C7 alkenyl or alkynyl; C 3 -C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein Z is naphthyl, quinolinyl, isoquinolinyl, 10 quinazolinyl, phthalazinyl, quinoxalinyl, indolyl, benzo[b]furanyl, or benzo[b]thiophenyl; wherein the naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, phthalazinyl, quinoxalinyl, indolyl, benzo[b]furanyl, or benzo[b]thiophenyl may be substituted with one or more F; 15 Cl; Br; I; COR 3 ; COR 3 ; -CON(R 3 )2; CN; -NO 2 ; -N(R 3
)
2 ; -OR 3 ;
-SR
3 ; (CH2)qOR 3 ; (CH 2 )qSR 3 ; straight chained or branched Ci-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C 3
-C
7 cycloalkyl, 20 monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein each m is independently an integer from 0 to 3 inclusive; 25 wherein each n is independently an integer from 0 to 5 inclusive; wherein each p is independently an integer from 1 to 7 30 inclusive; wherein q is an integer from 1 to 3 inclusive; wherein r is an integer from 0 to 3 inclusive; 35 WO 02/06245 PCT/US01/21286 -15 wherein t is an integer from 2 to 6 inclusive; or a pharmaceutically acceptable salt thereof. 5 This invention further provides a compound having the structure: 10 0 R R M N R, R, 2 R R 15 wherein each R is independently -H; -F; straight chained or branched C 1
-C
7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C7 alkenyl or alkynyl; -N(R 3
)
2 ; -NO,; -CN; -SR 3 ; ~C0 2
R
3 ; or 20
-OR
3 ; wherein each R, is independently -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3 25 C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -(CH 2
),OR
3 ; -COR 3 ; -C0 2
R
3 ; or -CON(R3)2; wherein each R 2 is -H; -NO 2 ; -N 3 ; -CN; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; 30 straight chained or branched C2-C7 alkenyl or alkynyl; C3 C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3
)
2 ; -OR 3 ; -(CH 2 )pOR 3 ; -COR 3 ; -C0 2
R
3 ; or -CON(R 3
)
2 ; or aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2
R
3 ; 35 -CON (R 3 ) 2; CN; -NO 2 ; -N (R 3 ) 2; -OR 3 ; -SR 3 ; (CH 2 ) qOR3; (CH,)qSR 3 ; straight chained or branched C 1 -C7 alkyl, WO 02/06245 PCT/USO1/21286 -1G monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight. chained or branched C 2 ~C7 alkenyl, C 2
-C
7 alkynyl; C 3
-C
7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or 5 cycloalkenyl; wherein each R 3 is independently -H; straight chained or branched CI-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C.-C 7 alkenyl or alkynyl; C 3 10 C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein M is aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2
R
3 ; -CON(R 3
)
2 ; CN; 15 -No 2 ; -N(R 3
)
2 ; -OR 3 ; -SR 3 ; (CH 2 )qOR 3 ; (CH 2 )qSR 3 ; 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;
C
3
-C
7 cycloalkyl, monofluorocycloalkyl, 20 polyfluorocycloalkyl or cycloalkenyl; wherein X is (CH 2 )n, 0, S or NR 3 ; wherein W is 25 (a) C 3
-C
7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl optionally substituted with one or more COR 3 ; C0 2
R
3 ; -CON(R 3
)
2 ; CN; -NO 2 ; -N(R 3
)
2 ; -OR 3 ; -SR 3 ; (CH 2 )qOR 3 ; (CH 2 )qSR 3 ; 30 straight chained or branched C 1 -C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C7 alkenyl, C 2
-C
7 alkynyl; C 3
-C
7 cycloalkyl; or 35 (b) aryl or heteroaryl optionally substituted with one WO 02/06245 PCT/USO1/21286 -17 or more F; Cl; Br; I; COR 3 ; C0 2
R
3 ; -CON(R 3
)
2 ; CN;
-NO
2 ; -N(R 3
)
2 ; -OR3; -SR 3 ; (CH2)qOR 3 ; (CH 2 )qSR 3 ; straight chained or branched Ci-C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or 5 carboxamidoalkyl; straight chained or branched C 2
-C
7 alkenyl, C 2
-C
7 alkynyl; C 3 -C7 cycloalkyl; wherein m is an integer from 0 to 4 inclusive; 10 wherein n is an integer from 0 to 6 inclusive; wherein p is an integer from 1 to 4 inclusive; wherein q is an integer from 1 to 3 inclusive; 15 or a pharmaceutically acceptable salt thereof. This invention also provides a compound having the structure: 20 0
R
5 5 NW 0 R3 25 R n R wherein each R is independently -H; -F; straight chained or branched Ci-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2
-C
7 30 alkenyl or alkynyl; -N(R 3
)
2 ; -NO 2 ; -CN; -C0 2
R
3 ; -OR 3 ; or -CON
(R
3 ) 2; wherein each R, is independently -H; F; Cl; Br; I; -NO 2 ;
-N
3 ; -CN; straight chained or branched CI-C 7 alkyl, 35 monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2
-C
7 alkenyl or alkynyl; C 3
-C
7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or WO 02/06245 PCT/USO1/21286 -18 cycloalkenyl;
-N(R
3
)
2 ; -OR 3 ; -(CH 2 )pOR 3 ; -COR 3 ; -C0 2
R
3 ;
-CON(R
3
)
2 ; aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2
R
3 ; -CON(R 3
)
2 ; CN; -NO 2 ; -N(R 3
)
2 ; -OR 3 ; 5 -SR 3 ; (CH 2 )qOR 3 ; (CH 2 )qSR 3 ; straight chained or branched Ci-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C 2
-C
7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or 10 cycloalkenyl; wherein each R 3 is independently -H; straight chained or branched Cl-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C 3 15 C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein R 5 is -H; -NO 2 ; -N 3 ; -CN; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; 20 straight chained or branched C2-C7 alkenyl or alkynyl; C3 C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
-N(R
3
)
2 ; -OR 3 ; -(CH 2 )pOR 3 ; -COR 3 ; -C0 2
R
3 ;
-CON(R
3
)
2 ; aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; 25 Cl; Br; I; COR 3 ; C0 2
R
3 ; -CON(R 3
)
2 ; CN; -NO 2 ; -N(R 3
)
2 ; -OR 3 ;
-SR
3 ; (CH 2 )qOR 3 ; (CH 2 )qSR 3 ; straight chained or branched Cl-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, 30 monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein V is H; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2
R
3 ; 35 -CON(R 3 )2; CN; -NO 2 ; -N(R 3 )2; -OR 3 ; -SR 3 ; (CH 2 )qOR3; WO 02/06245 PCT/USO1/21286 -19
(CH
2 )qSR 3 ; straight chained or branched C 1 -C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2
-C
7 alkenyl, C 2 -C7 alkynyl; C 3
-C
7 cycloalkyl, 5 monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein W is 10 (a) C 3 -C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl optionally substituted with one or more COR 3 ; C02R 3 ; ~
CON(R
3
)
2 ; CN; -NO 2 ; -N(R 3
)
2 ; -OR 3 ; -SR 3 ;
(CH
2 )qOR 3 ; (CH 2 ) qSR 3 ; straight chained or 15 branched CI-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; or 20 (b) aryl or heteroaryl optionally substituted with one or more F; Cl; Br; I; COR 3 ; CO 2
R
3 ; -CON(R 3
)
2 ; CN; -NO 2 ; -N(R 3
)
2 ; -OR 3 ; -SR 3 ; (CH 2 )qOR 3 ;
(CH
2 )qSR 3 ; straight chained or branched C 1
-C
7 25 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; 30 wherein each m is independently an integer from 0 to 3 inclusive; wherein n is an integer from 0 to 2 inclusive; 35 wherein p is an integer from 1 to 7 inclusive; WO 02/06245 PCT/USO1/21286 -20 wherein q is an integer from 1 to 3 inclusive; wherein t is an integer from 2 to 6 inclusive; 5 or a pharmaceutically acceptable salt thereof.
WO 02/06245 PCT/USO1/21286 -21 This invention further provides a method of modifying feeding behavior of a subject which comprises administering to the subject an amount of a compound effective to decrease the consumption of food by the 5 subject wherein the compound has the structure: 10 AA 0 N N R3N N R4 H I
R
2 X X N R 2 15R3 A 0 A 0 20 R N NR4 RN H or II
R
2 N S H N 2 S N R2 25 n 0n V 30 WO 02/06245 PCT/USO1/21286 -22 wherein A is 1 -- Y 'fi y Y1~Tj-Y 4 ' _ 4~ Y4
Y
5 10 2 Y _ Y 20 Y > X N 25 Y2y or 30 X wherein each of Y 1 , Y 2 , Y 3 , Y 4 and Y 5 is independently -H; straight chained or branched CI-C 7 alkyl, monofluoroalkyl 35 or polyfluoroalkyl; straight chained or branched C 2
-C
7 alkenyl or alkynyl; C 3 -C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -F, -Cl, -Br, or -I; -NO2; -N 3 ; -CN; -OR 3 , -OCOR 3 , -COR 3 , -CON (R 3 ) 2 , or -COOR 3 ; 40 or any two of YI, Y 2 , Y 3 , Y 4 and Y 5 present on adjacent carbon atoms can constitute a methylenedioxy group; wherein each X is independently S; 0; or NR 3 ; 45 wherein R, is -H; -NO 2 ; -CN; straight chained or branched WO 02/06245 PCT/USO1/21286 -23
CI-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;
-N(R
3 )2; -OR3; -(CH2),OR 3 ; -COR 3 ; -C0 2
R
3 ; 5 -CON(R 3 ) 2 ; or CO 2
(CH
2 )nV; wherein R 2 is -H; straight chained or branched Ci-C 7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or poiyfluoroalkyl; straight chained or 10 branched C 2
-C
7 alkenyl or alkynyl; C 3
-C
7 cycloalkyl, monofluorocycloalkyl, polyfiuorocycloalkyl or cycloalkenyl; C 3
-CI
0 cycloalkyl-C-C 1 0 -alkyl, C 3 -Ci cycloalkyl-Ci-Clo-monofluoroalkyl or C 3
-C
1 cycloalkyl-Cl Cio-polyfluoroalkyl; -CN; -CH 9
XR
3 , -CH 2 X (CH 2 )pNHR 3 , 15 - (CH 2 ) nNHR 3 , -CH 2 X (CH 2 ) pN (R 3 ) 2 , -CHX (CH 2 ) pN 3 ,
-CH
2
X(CH
2
),NHCXR
5 ; -OR 3 ; or wherein R, and R 2 together form a lactone ring; wherein each R 3 is independently -H; straight chained or 20 branched Cl-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; 25 WO 02/06245 PCT/USO1/21286 -24 wherein
R
4 is (i) R 5 5 V R Lm R 6 ()R7 R N mR5 R t \m R 6 is (iii)R7 R 'm 1 m Nb 20 Rm Z
R
6 ys (iv)
Y
1 2 25
R
6 R m [
Y
3 R N 30 R m D- Id (v) Y2 35 Y 1 40 N Id R [.im Z (vi) R m W
R
6 50 R WO 02/06245 PCT/US01/21286 -25 (vii) R m R 5 N Re R Y2 B 10 Y 3 (viii) R R R 15 N m R R R m 6 RR 20 (ix) R UR m I \N---U ;or m or 25 R R 30 R R (x) SR m U R m 5 R 35 wherein each R is independently -H; -F; straight chained or branched C 1
-C
7 alkyl, monofluoroalkyl or 40 polyfluoroalkyl; straight chained or branched C 2
-C
7 alkenyl or alkynyl; -N(R3) 2 ; -NO 2 ; -CN; -C0 2
R
3 ; -OR 3 ; or -CN
(R
3 ) 2; wherein B is N or CY 4 ; 45 wherein each D is independently C (R 3 ) 2 ; 0; S; NR 3 ; CO; or
CS;
WO 02/06245 PCT/USO1/21286 -26 wherein each U is independently aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I;
COR
3 ; C0 2
R
3 ; -CON(R 3
)
2 ; CN; -NO 2 ; -N(R 3 )2; -OR 3 ; -SR 3 ;
(CH
2 )qOR 3 ; (CH 2 )qSR 3 ; straight chained or branched C1-C7 5 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C 2
~C
7 alkynyl; C 3 -C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; 10 wherein V is C(R 5
)
2 ; CR 5
R
6 ; -NR 5 or NR 6 ; wherein W is CR 5 ; CR 6 or N; 15 wherein Z is S; 0; C(R 3
)
2 ; or NR 3 ; wherein each R 5 is -H; -NO 2 ; -N 3 ; -CN; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3 20 C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3
)
2 ; -OR 3 ; -(CH 2 )pOR 3 ; -COR 3 ; ~CO 2
R
3 ; or -CON(R 3
)
2 ; -XCOR; or aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2
R
3 ; -CON(R 3
)
2 ; CN; -NO 2 ; 25 -N(R 3
)
2 ; -OR 3 ; -SR 3 ; (CH 2 )qOR3; (CH 2 )qSR 3 ; -XCOR 8 ; straight chained or branched C1-C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7.alkynyl; C 3 -C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or 30 cycloalkenyl; wherein each R 6 is independently -H; straight chained or branched CI-C7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight 35 chained or branched C 2 -C7 alkenyl or alkynyl; C3-C7 WO 02/06245 PCT/USO1/21286 -27 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3
)
2 ; -OR 3 ; -(CH 2 )pOR 3 ; -COR 3 ; -C0 2
R
3 ; or -CON
(R
3 ) 2; 5 wherein R 7 is -H; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2
R
3 ; -CON (R 3 ) 2; CN; -NO 2 ; -N (R 3 ) 2; OR3; -SR 3 ; (CH 2 ) qOR3;
(CH
2 )qSR 3 ; -XCORB; straight chained or branched C 1 -C7 alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; 10 straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl;
C
3
-C
7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein R 8 is -H; straight chained or branched C 1 -C7 15 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-07 alkenyl or alkynyl; C 3 -C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3
)
2 ; -OR 3 ; - (CH 2 )pOR 3 ; -COR 3 ; ~C0 2
R
3 ; or -CON(R3) 2 ; aryl or heteroaryl, optionally substituted with 20 one or more F; Cl; Br; I; COR 3 ; C0 2
R
3 ; -CON(R 3
)
2 ; CN; -NO 2 ;
-N(R
3
)
2 ; -OR 3 ; -SR 3 ; (CH2)qOR 3 ; (CH 2 )qSR 3 ; straight chained or branched CI-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2
-C
7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, 25 monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein b is 1 or 2; 30 wherein d is an integer from 0 to 2 inclusive; wherein each m is independently an integer from 0 to 3 inclusive; 35 wherein each n is independently an integer from 0 to 5 WO 02/06245 PCT/USO1/21286 -28 inclusive; wherein each p is independently an integer from 1 to 7 inclusive; 5 wherein q is an integer from 1 to 3 inclusive; wherein t is an integer from 2 to 6 inclusive; 10 or a pharmaceutically acceptable salt thereof.
WO 02/06245 PCT/USO1/21286 -29 This invention further provides a method of reducing the body mass of a subject which comprises administering to the subject an amount of a compound effective to reduce the body mass of the subject wherein the compound has the 5 structure: A 0 A 0 1, N J N' R4 - R3-, -R4 10 1 R N X H- H 2 X N R 2
R
3
I
3 A 0 A 0 15 R N 'NR4
R
3
-
R4 H or N N
R
2 N S s N R 2
V
WO 02/06245 PCT/USO1/21286 -30 wherein A is 5 2 3 2 3
Y
2 r~ 1 ,j ,Y 4 ' Y Yg N
Y
5 Y2 10 Y3 -S 2 Y3
Y
2
Y
3 151 YO ' X N 20 Y2 y or x wherein each of Yi, Y 2 r Y 3 r Y4 and Y 5 is independently -H; 25 straight chained or branched C 1
-C
7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -F, -Cl, -Br, or -I; 30 -NO 2 ; -N 3 ; -CN; -OR 3 , -OCOR 3 , -COR 3 , -CON(R 3
)
2 , or -COOR 3 ; or any two of Yl, Y 2 r Y 3 , Y 4 and Y 5 present on adjacent carbon atoms can constitute a methylenedioxy group; wherein each X is independently S; 0; or NR 3 ; 35 WO 02/06245 PCT/US01/21286 -31 wherein R, is -H; -NO 2 ; -CN; straight chained or branched CI-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or 5 cycloalkenyl; -N(R 3
)
2 ; -OR 3 ; -(CH 2 )pOR 3 ; -COR 3 ; -CO 2
R
3 ;
-CON(R
3
)
2 ; or CO 2
(CH
2 )nV; wherein R 2 is -H; straight chained or branched C-C7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, 10 monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C3-Cie cycloalkyl-Ci-Clo-alkyl, C3-Cia cycloalkyl-Ci-C 1 o-monofluoroalkyl or C3-Cia cycloalkyl-Cl 15 Cio-polyfluoroalkyl; -CN; -CH 2
XR
3 , -CH 2 X (CH 2 ) pNHR 3 , - (CH 2 ) nNHR 3 , -CH 2 X (CH 2 ) pN (R 3 ) 2 , -CHX (CH 2 ) pN 3 r
-CH
2
X(CH
2 )pNHCXR 5 ; -OR 3 ; or wherein R 1 and R 2 together form a lactone ring; 20 wherein each R 3 is independently -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3 C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; 25 wherein R 4 is (i) R5 30 N V R .m[ R .. R7 (ii) R R5 35 1 kMX N R t [m R 6 R7 WO 02/06245 PCT/USO1/21286 -32 (iii)R m b R Y1 LI N Y2 R [m z 10 (iv) 10' 1, Y2
R
6 15 R [m m Y 3 t N R 1 m D-D d (v) 20 '2
Y
1 3 25 R [ m N [I d 30 R m Z 0 (vi) 35 Rm R 5 tN R [m
R
WO 02/06245 PCT/US01/21286 -33 (vii) 5 R R6 R Y2 10 B
Y
3 15 (viii) R R6 R 15N m R5 Al N R m 6 20 R7 (ix) R UR m ;or 25 R N mU R R ()R [m R 30 m N mU R [m R 5 R 35 wherein each R is independently -H; -F; straight chained or branched C 1
-C
7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2
-C
7 alkenyl or alkynyl; -N (R 3 ) 2 ; -NO 2 ; -CN; -C0 2
R
3 ; -OR 3 ; or 40 -CN (R3) 2; wherein B is N or CY 4 ; wherein each D is independently C (R 3 ) 2 ; 0; S; NR 3 ; CO; or 45 CS; WO 02/06245 PCT/USO1/21286 -34 wherein each U is independently aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I;
COR
3 ; COR 3 ; -CON (R 3 ) 2; CN; -NO 2 ; -N (R 3 ) 2; -OR 3 ; -SR 3 ; (CH2) qOR 3 ; (CH 2 ) qSR 3 ; straight chained or branched C1-C7 5 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C 2
-C
7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; 10 wherein V is C(R 5
)
2 ; CRSR 6 ; NR 5 or NR 6 ; wherein W is CR 5 ; CR 6 or N; 15 wherein Z is S; 0; C (R 3 ) 2 ; or NR 3 ; wherein each R 5 is -H; -NO,; -N 3 ; -CN; straight chained or branched C 1
-C
7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2~C7 alkenyl or alkynyl; C 3 20 C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3
)
2 ; -OR 3 ; -(CH 2 )pOR 3 ; -COR 3 ; -CO 2
R
3 ; or -CON(R 3
)
2 ; -XCOR8; or aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; COR 3 ; CO 2
R
3 ; -CON(R 3
)
2 ; CN; -NO,; 25 -N(R 3
)
2 ; -OR 3 ; -SR 3 ; (CH 2 )qOR 3 ; (CH 2 )qSR 3 ; -XCORB; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or 30 cycloalkenyl; wherein each R 6 is independently -H; straight chained or branched Cj-C7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight 35 chained or branched C2-C7 alkenyl or alkynyl; C3-C7 WO 02/06245 PCT/USO1/21286 -35 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3
)
2 ; -OR 3 .; -(CH 2 )pOR 3 ; -COR 3 ; -CO 2
R
3 ; or -CON
(R
3 ) 2; 5 wherein R 7 is -H; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; CO 2
R
3 ; -CON(R3) 2 ; CN; -NO 2 ; -N(R3) 2 ; -OR 3 ; -SR 3 ; (CH 2 )qOR 3 ; (CH2)qSR 3 ; -XCOR 8 ; straight chained or branched CI-C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; 10 straight chained or branched CI-C 7 alkenyl, C 2 -C7 alkynyl;
C
3
-C
7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein R 8 is -H; straight chained or branched C 1 -C7 15 alkyl, monofluoroalkyl 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 ; -(CH2)pOR 3 ; -COR 3 ; -C0 2
R
3 ; or
-CON(R
3
)
2 ; aryl or heteroaryl, optionally substituted with 20 one or more F; Cl; Br; I; COR 3 ; C0 2
R
3 ; -CON(R 3
)
2 ; CN; -NO,;
-N(R
3 )2; -OR 3 ; -SR 3 ; (CH 2 )qOR 3 ; (CH 2 )qSR 3 ; 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; C 3
~C
7 cycloalkyl, 25 monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein b is 1 or 2; 30 wherein d is an integer from 0 to 2 inclusive; wherein each m is independently an integer from 0 to 3 inclusive; 35 wherein each n is independently an integer from 0 to 5 WO 02/06245 PCT/USO1/21286 -36 inclusive; wherein each p is independently an integer from 1 to 7 inclusive; 5 wherein q is an integer from 1 to 3 inclusive; wherein t is an integer from 2 to 6 inclusive; 10 or a pharmaceutically acceptable salt thereof. In addition, the present invention provides a method of treating a subject suffering from depression and/or anxiety which comprises administering to the subject a 15 compound of the aforementioned formula in an amount effective to treat the subject's depression and/or anxiety. This invention also provides a method of modifying 20 feeding behavior of a subject which comprises administering to the subject an amount of a compound effective to decrease the consumption of food by the subject wherein the compound is selected from the group consisting of: WO 02/06245 PCT/USO1/21286 -37 a) O 5 N-O (b) O 20 N)N S-S F NN NN 25 O 'NN 0O e) N~\ \O ; 30 35 400 50 400 g) NK 0I NN 500 WO 02/06245 PCT/USO1/21286 -38 F h) 5 N N F 10 This invention further provides a method of treating a feeding disorder in a subject which comprises 15 administering to the subject an amount of a compound of the invention effective to decrease the consumption of food by the subject. This invention also provides a pharmaceutical composition 20 comprising a therapeutically effective amount of the compound of the invention and a pharmaceutically acceptable carrier. This invention further provides a pharmaceutical 25 composition made by combining a therapeutically effective amount of the compound of this invention and a pharmaceutically acceptable carrier. This invention further provides a process for making a pharmaceutical composition comprising combining a therapeutically 30 effective amount of the compound of the invention and a pharmaceutically acceptable carrier.
WO 02/06245 PCT/USO1/21286 -39 Detailed Description Of The Invention This invention provides a compound having the structure: 5 A 0 A 0 10 N)NR4 R3 R4
R
2 N X X 2 H X N R2 A 0 A 0 I ,or N R N S H 2 N n , N R2
V
WO 02/06245 PCT/USO1/21286 -40 wherein A is Y2 y3 Y2 Y t1 15; ~~4 Y - --- Y4 , N
Y
5 10 Y2
Y
3 YJ i -S 15 20 Yi \ Y O/ ' 25 y2 y3 30 wherein each of Y 1 , Y 2 r Y 3 r Y 4 and Y 5 is independently -H; 35 straight chained or branched Ci-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; -F, -Cl, -Br, or -I; -NO 2 ; -N 3 ; -CN; -OR 3 , 40 -OCOR 3 r -COR 3 r -CON(R 3
)
2 , or -COOR 3 ; or any two of Y 1 , Y 2 ,
Y
3 , Y 4 and Y 5 present on adjacent carbon atoms can constitute a methylenedioxy group; wherein each X is independently S; 0; or NR 3 ; 45 wherein R 1 is -H; -NO 2 ; -CN; straight chained or branched WO 02/06245 PCT/USO1/21286 -41
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; -N (R 3 ) 2; -OR3; - (CH 2 ) pOR 3 ; -COR 3 ; -C0 2
R
3 ; 5 -CON(R 3
)
2 ; or -CO 2
(CH
2 )nV; wherein R 2 is -H; straight chained or branched Ci-C 7 alkyl, hydroxyalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2
-C
7 10 alkenyl or alkynyl; C 3
-C
7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
C
3
-C
10 cycloalkyl-CI-Cio-alkyl,
C
3
-C
1 cycloalkyl-Cl-Clo-monofluoroalkyl or C 3 -C1 0 cycloalkyl-C
C
1 0 -polyfluoroalkyl; -CN; -CH 2
XR
3 , -CH 2
X(CH
2 )pNHR 3 , 15 -(CH 2 )nNHR 3 , -CH 2
X(CH
2 )pN(R 3
)
2 , -CH 2
X(CH
2 )pN 3 ,
-CH
2
X(CH
2 )pNHCXR 7 ; -OR 3 ; or wherein R 1 and R 2 together form a lactone ring; wherein each R 3 is independently -H; straight chained or 20 branched Cl-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2
-C
7 alkenyl or alkynyl; C3
C
7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; 25 WO 02/06245 PCT/USO1/21286 -42 wherein
R
4 is (i) X
R
6 5R-N R (ii) 10 X R R tN 15 R RS (iii) R Rs 20 R X 6 R NR 0 25 (iv) R tN (v) R R 35 R mh rr 40 (vi) 45 R V[ R N(V) R [m R5 R WO 02/06245 PCT/USO1/21286 -43 (vii) 5 N-RN R [ 10 (viii) R R R7 NN R-]p-NNR8 R 15 R7 ( ix ) Z R ; or 2 0 -i-tN R [m R5 z (x) 25 R R [m
R
5 30 V wherein the dashed line represents a single bond or a double bond; 35 wherein each R is independently -H; -F; straight chained or branched CI-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2
-C
7 alkenyl or alkynyl; -N(R 3 )2; -NO 2 ; -CN; -C0 2
R
3 ; -OR 3 ; or -CON
(R
3 ) 2; 40 wherein each V is independently aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I;
COR
3 ; C0 2
R
3 ; -CON (R 3 ) 2 ; CN; -NO 2 ; -N (R 3 ) 2 ; -OR 3 ; -SR 3 ;
(CH
2 ) qOR3; (CH 2 ) qSR 3 ; straight chained or branched Ci-C 7 45 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or WO 02/06245 PCT/USO1/21286 -44 carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; 5 wherein each R 5 is -H; -NO 2 ; -N 3 ; -CN; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or' alkynyl; C 3 C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl 10 or cycloalkenyl;
-N(R
3
)
2 ; -OR 3 ; -(CH 2 )pOR 3 ; -COR 3 ; ~C0 2
R
3 ;
-CON(R
3
)
2 ; aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2
R
3 ; -CON(R 3
)
2 ; CN; -NO 2 ; -N(R 3
)
2 ; -OR 3 ;
-SR
3 ; (CH 2 )qOR 3 ; (CH 2 )qSR 3 ; straight chained or branched 15 CI-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C 3
-C
7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; 20 wherein R 6 is -H; straight chained or branched C-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or 25 cycloalkenyl;
-N(R
3
)
2 ; -OR 3 ; -(CH 2 )pOR 3 ; -COR 3 ; -C0 2
R
3 ;
-CON(R
3
)
2 ; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2
R
3 ; -CON(R 3
)
2 ; CN; -NO 2 ;
-N(R
3
)
2 ; -OR 3 ; -SR 3 ; (CH 2 )qOR 3 ; (CH 2 )qSR 3 ; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, 30 aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; 35 wherein R 7 is H; F; Cl; Br; I; -NO 2 ; -N 3 ; -CN; straight WO 02/06245 PCT/USO1/21286 -45 chained or branched CI-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or 5 cycloalkenyl;
-N(R
3 )2; -OR 3 ; -(CH 2 )p OR 3 ; -COR 3 ; -C0 2
R
3 ; or -CON
(R
3 ) 2; wherein R 8 is independently straight chained or branched Cj-C, alkyl, monofluoroalkyl or polyfluoroalkyl; straight 10 chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein Z is naphthyl, quinolinyl, isoquinolinyl, 15 quinazolinyl, phthalazinyl, quinoxalinyl, indolyl, benzo[bjfuranyl, or benzo[b]thiophenyl; wherein the naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, phthalazinyl, quinoxalinyl, indolyl, benzo[b]furanyl, or benzo[b]thiophenyl may be substituted with one or more F; 20 Cl; Br; I; COR 3 ; C0 2
R
3 ; -CON(R 3
)
2 ; CN; -NO 2 ; -N(R 3
)
2 ; -OR 3 ;
-SR
3 ; (CH 2 )qOR 3 ; (CH 2 )qSR 3 ; straight chained or branched CI-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, 25 monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein each m is independently an integer from 0 to 3 inclusive; 30 wherein each n is independently an integer from 0 to 5 inclusive; wherein each p is independently an integer from 1 to 7 35 inclusive; WO 02/06245 PCT/USO1/21286 -46 wherein q is an integer -from 1 to 3 inclusive; wherein r is an integer from 0 to 3 inclusive; 5 wherein t is an integer from 2 to 6 inclusive; or a pharmaceutically acceptable salt thereof. In one embodiment the compounds of this invention 10 comprise the (+) enantiomer. In another embodiment, the compounds comprise the (-) enantiomer.
WO 02/06245 PCT/USO1/21286 -47 In one embodiment, the compound has the structure: A 0
R
1 N NmN -R5
R
2 N X m V X R 6 , or 1 0 10 R 3 15 A 0 R; N 20
R
2 [ m V X R6
R
3 0 25 WO 02/06245 PCT/USO1/21286 -48 In another embodiment, the compound has the structure: A 0 5N N NR5 O N O X yR6 ,or 0 10 H 15 A 0 O N N- Rj v X R6 * 20 Nk 1 1 0~~~ H In a further embodiment, the compound has the structure: 25 0 A 0 O--0 1 N N N H H 0 N N N R 6 / 0 H 30 WO 02/06245 PCT/USO1/21286 -49 In yet another embodiment of the present invention variable A is Y2 Y 3 y 2 Y 5 Yi _ Y ' or N\ N
Y
5 10 In an embodiment of the present invention, the compound is 15 F F o- O 20 0 N N N N O N 0 25 F F 0 0 30 -0 NNN O' N '- O 0 35 F F 40 0 -O C - 0 O N N -N N O N 45 0 O 50 WO 02/06245 PCT/USO1/21286 -50 F F 0 0 5 0O N ' N N N O ; or 0 10 F F 15 0 0 0 N N N O N O N O 20 O 25 In another embodiment, the compound has the structure: A 0 X R6 Ri N N0 30
R
2 N X rm R 5
R
3 35 In further embodiments, the compound has the structure: A 0 X R 6 40 RR N /ON O Rs H 45 In an embodiment, the compound has the structure: WO 02/06245 PCT/USO1/21286 -51 0 A 0 R6 O N N NO O N O R 5 I a H 10 In other embodiments, A is 15 Y 3 Y2 y. Y r4 or\ 20 5N In an embodiment of the invention, the compound has the structure: 25 F F 30 0 N NN 30 0 N Ol '--" ' O NOO 35 In other embodiments, the compound has the structure: 40 A 0 R R, N '" N N-- r-V 45 R N x [m R R 3 WO 02/06245 PCT/US01/21286 -52 In additional embodiments, the compound has the structure: 5 A 0 R 10 R N N Rl-V NO
R
5 R H 15 In one embodiment of the present invention, the compound has the structure:
R
3 20 0 A 0 R 25 N 0 R 5 R H In another embodiment of the instant invention, A is 30 2 3 Y2 y3 35 In other embodiments of the invention, the compound has the 40 structure: N-O~ / N 0 0 45 'R NN N 0 N N -_ WO 02/06245 PCT/USO1/21286 -53 In an embodiment, the compound has the structure: A 0 NN NNR__N R2 X Nx N Rs
K
3 10 R7 In another embodiment, the compound has the structure: 15 A 0 0
R
5 N N N N 2 0 0NNR* H 25 In yet another embodiment, the compound has the structure: 30 0 A 0 0 N N N N 35 O R7 40 In an embodiment, A is 2 y 3 Y2 y3 45 Y ' or , j--Y4/O KN
Y
5 WO 02/06245 PCT/USO1/21286 -54 In a further embodiment, the compound has the structure F 5 F O O NN 10" 0NaO N -\ 15 In another embodiment, the compound has the structure: 20 A 0 z R, N ) N N I: Im R ) N X-L x- R5 25 2 1 R3 In yet another embodiment, the compound has the structure: 30 A 0 Z 35 R, N ' N"- "-N/ N O R 5 H 40 In an additional embodiment, the compound has the structure: 45 0 A 0 O-- N ' N N 50 N O H R 5 WO 02/06245 PCT/USO1/21286 -55 In other embodiments, A is 5 Y Y 2 Yi y r or N 10 In an embodiment, the compound has the structure: F 15 F 0 0 20 N O 25 In yet another embodiment, the compound is (+)-1,2,3,6-tetra-hydro-1-{n-[4-(3,-acetamido)-phenyl piperidin-1-yl] propyl}carboxamido-4-methoxymethyl-6- (3,4 difluoro-phenyl)-2-oxopyrimidine-5-carboxylic acid methyl ester. In a further embodiment, the compound is 30 (-)-1,2,3,6-tetra-hydro-1-{n-[4-(3,-acet-amido)-phenyl piperidin-1-yllpropyl}carboxamido-4-methoxymethyl-6-(3,4 difluoro-phenyl) -2-oxopyriinidine-5-carboxylic acid methyl ester. 35 In a further embodiment, the compound is: F F 0 0 O N -N N N 0 NH 2 ,o~ WO 02/06245 PCT/USO1/21286 -56 In a further embodiment, the compound has the structure: 0 R p W 2 R R 10 wherein each R is independently -H; -F; straight chained or branched Ci-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; -N(R 3
)
2 ; -NO 2 ; -CN; -SR 3 ; -C0 2
R
3 ; or 15
-OR
3 ; wherein each Ri is independently -H; straight chained or branched C-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3 20 C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -(CH 2 )pOR 3 ; -COR 3 ; -C0 2
R
3 ; or -CON(R 3
)
2 ; wherein each R 2 is -H; -NO 2 ; -N 3 ; -CN; straight chained or branched CI-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; 25 straight chained or branched C2-C7 alkenyl or alkynyl; C3 C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycl6alkyl or cycloalkenyl; -N (R 3 ) 2; -OR 3 ; - (CH 2 ) pOR 3 ; -COR 3 ; -COR 3 ; or -CON(R 3
)
2 ; or aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2
R
3 ; 30 -CON(R 3
)
2 ; CN; -NO 2 ; -N(R 3
)
2 ; -OR 3 ; -SR 3 ; (CH 2 ) qOR 3 ; (CH,) gSR 3 ; straight chained or branched Cj-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, 35 monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein each R 3 is independently -H; straight chained or WO 02/06245 PCT/USO1/21286 -57 branched CI-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2~07 alkenyl or alkynyl; C3~ C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; 5 wherein M is aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; CO 2
R
3 ; -CON(R 3 )2; CN;
-NO
2 ; -N(R 3
)
2 ; -OR 3 ; -SR 3 ; (CH 2 )qOR 3 ; (CH 2 )qSR 3 ; straight chained or branched CI-C7 alkyl, monofluoroalkyl, 10 polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C 2
-C
7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; 15 wherein X is (CH2)n, 0, S or NR 3 ; wherein W is (a) C3-C7 cycloalkyl, monofluorocycloalkyl, 20 polyfluorocycloalkyl or cycloalkenyl optionally substituted with one or more COR 3 ; CO 2
R
3 ; -CON(R 3
)
2 ; CN; -NO 2 ; -N(R3) 2 ; -OR 3 ; -SR 3 ; (CH 2 )qOR 3 ; (CH 2 )qSR 3 ; straight chained or branched CI-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or 25 carboxamidoalkyl; straight chained or branched C2-C alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl; or (b) aryl or heteroaryl optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2
R
3 ; -CON(R 3
)
2 ; CN; 30 -NO 2 ; -N(R 3
)
2 ; -OR 3 ; -SR 3 ; (CH 2 )qOR 3 ; (CH 2 )qSR 3 ; straight chained or branched Ci-C alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl; 35 wherein m is an integer from 0 to 4 inclusive; WO 02/06245 PCT/USO1/21286 -58 wherein n is an integer from 0 to 6 inclusive; wherein p is an integer from 1 to 4 inclusive; 5 wherein q is an integer from 1 to 3 inclusive; or a pharmaceutically acceptable salt thereof. In one embodiment the compounds of this invention comprise 10 the (+) enantiomer. In another embodiment, the compounds comprise the (-) enantiomer. In an embodiment, the compound has the structure: 15 0 M N W 20 H /N-7 or R2 R R 25 0 M4K N W H N 30 RR In a further embodiment, W is phenyl optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2
R
3 ; 35 -CON(R 3
)
2 ; CN; -NO 2 ; -N(R 3
)
2 ; -OR 3 ; -SR 3 ; (CH 2 )qOR 3 ; or
(CH
2 ) qSR 3 In another embodiment, the compound has the structure 40 0 0N N 45 WO 02/06245 PCT/US01/21286 -59 In one embodiment, the compound has the structure: 0
R
5 5 N W 5\ tRR3 R, n R 10 wherein each R is independently -H; -F; straight chained or branched C 1
-C
7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2
-C
7 alkenyl or alkynyl; -N(R 3
)
2 ; -NO 2 ; -CN; -C0 2
R
3 ; -OR 3 ; or -CON
(R
3 ) 2; 15 wherein each R 1 is independently -H; F; Cl; Br; I; -NO 2 ;
-N
3 ; -CN; straight chained or branched C 1 -C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C7 alkenyl or alkynyl; C 3
-C
7 cycloalkyl, 20 monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N (R 3 ) 2; -OR 3 ; - (CH2) pOR 3 ; -COR 3 ; -C0 2
R
3 ;
-CON(R
3
)
2 ; aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2
R
3 ; -CON(R 3
)
2 ; CN; -NO 2 ; -N(R 3
)
2 ; -OR 3 ; 25 -SR 3 ; (CH 2 )qOR 3 ; (CH 2 )qSR 3 ; 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; C 3
-C
7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or 30 cycloalkenyl; wherein each R 3 is independently -H; 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 35 C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl WO 02/06245 PCT/USO1/21286 -60 or cycloalkenyl; wherein R 5 is -H; -NO 2 ; -N 3 ; -CN; straight chained or branched C 1
-C
7 alkyl, monofluoroalkyl or polyfluoroalkyl; 5 straight chained or branched C2-C7 alkenyl or alkynyl; C3 C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3
)
2 ; -OR 3 ; -(CH 2 )pOR 3 ; -COR 3 ; -C0 2
R
3 ; -CON(R3) 2 ; aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; 10 Cl; Br; I; COR 3 ; C0 2
R
3 ; -CON(R 3
)
2 ; CN; -NO 2 ; -N(R 3
)
2 ; -OR 3 ;
-SR
3 ; (CH2)qOR 3 ; (CH 2 )qSR 3 ; straight chained or branched Cl-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, 15 monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein V is H; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; CO 2
R
3 ; 20 -CON(R 3 )2; CN; -NO 2 ; -N(R 3 )2; -OR 3 ; -SR 3 ; (CH 2 )qOR3;
(CH
2 )qSR 3 ; straight chained or branched CI-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2~C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, 25 monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein W is 30 (a) C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl optionally substituted with one or more COR 3 ; C0 2
R
3 ;
-CON(R
3
)
2 ; CN; -NO 2 ; -N(R 3
)
2 ; -OR 3 ; -SR 3 ;
(CH
2 )qOR3; (CH 2 )qSR3; straight chained or 35 branched C1-C7 alkyl, monofluoroalkyl, WO 02/06245 PCT/USO1/21286 -61 polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl~; straight chained or branched
C
2
-C
7 alkenyl, C 2 -C7 alkynyl; C 3 -C7 cycloalkyl; or 5 (b) aryl or heteroaryl optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2
R
3 ; -CON(R 3
)
2 ; CN; -NO 2 ; -N(R 3
)
2 ; -OR 3 ; -SR 3 ; (CH 2 ) gOR 3 ;
(CH
2 )qSR 3 ; straight chained or branched C 1
-C
7 10 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C7 alkenyl, C 2
-C
7 alkynyl; C 3
-C
7 cycloalkyl; 15 wherein each m is independently an integer from 0 to 3 inclusive; wherein n is an integer from 0 to 2 inclusive; 20 wherein p is an integer from 1 to 7 inclusive; wherein q is an integer from 1 to 3 inclusive; wherein t is an integer from 2 to 6 inclusive; 25 or a pharmaceutically acceptable salt thereof. In one embodiment the compounds of this invention comprise the (+) enantiomer. In another embodiment, the compounds 30 comprise the (-) enantiomer. In an additional embodiment, the compound has the structure: WO 02/06245 PCT/USO1/21286 -62 NR 10 In a further embodiment, the compound has the structure 15 0 R O3 R N R3 20 R In yet another embodiment, W is phenyl optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2
R
3 ;
-CON(R
3
)
2 ; CN; -NO 2 ; -N(R 3
)
2 ; -OR 3 ; -SR 3 ; (CH 2 )qOR 3 ; 25 (CH 2 )qSR 3 ; or straight chained or branched C 1
-C
7 alkyl groups. In yet another embodiment, the compound has the structure 30 N 00 35 WO 02/06245 PCT/USO1/21286 -63 In the present invention, the term "aryl" includes phenyl and naphthyl and the term "heteroaryl" is used to include five and six membered unsaturated rings that may contain one or more heteroatoms such as oxygen, sulfur, and 5 nitrogen. Examples of heteroaryl groups include, but are not limited to, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl. 10 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, 15 indolizinyl, indolyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, purinyl, imidazo[2,1-b]thiazolyl, quinolinyl, isoquinolinyl, quinolizinyl, and 2,1,3 benzothiazolyl. 20 Included in this invention are pharmaceutically acceptable salts and complexes of all of the compounds described herein. The salts include but are not limited to the acids and bases listed herein. The salts include, but are not 25 limited to the following inorganic acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and boric acid. The salts include, but are not limited to the following organic acids: acetic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, maleic acid, 30 citric acid, methanesulfonic acid, benzoic acid, glycolic acid, lactic acid and mandelic acid. The salts -include, but are not limited to the inorganic base, ammonia. The salts include, but are not limited to the following organic bases: methylamine, ethylamine, propylamine, 35 dimethylamine, diethylamine, trimethylamine, triethylamine, WO 02/06245 PCT/USO1/21286 -64 ethylenediamine, hydroxyethylamine, morpholine, piperazine and guanidine. This invention further provides for the hydrates and polymorphs of all of the compounds described herein. 5 The present invention includes within its scope prodrugs of the compounds of the invention. In general, such prodrugs will be functional derivatives of the compounds of the invention which are readily convertible in vivo into the 10 required compound. Thus, in the present invention, the term "administering" shall emcompass 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 15 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. 20 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. 25 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 an amount from about 0.01 mg to about 800 mg. 30 In another embodiment, the amount of the compound is an amount from about 0.01 mg to about 500 mg. In another embodiment, the amount of the compound is an amount from about 0.01 mg to about 250 mg. In another embodiment, the amount of the compound is an amount from about 0.1 mg to 35 about 60 mg. In another embodiment, the amount of the WO 02/06245 PCT/USO1/21286 -65 compound is an amount 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 a 5 further embodiment, the carrier is a gel and the composition is a suppository. This invention provides a pharmaceutical composition made by combining a therapeutically effective amount of the 10 compound of this invention and a pharmaceutically acceptable carrier. This invention provides a process for making a pharmaceutical composition comprising combining a 15 therapeutically effective amount of the compound of this invention and a pharmaceutically acceptable carrier. In the practice of this invention the "pharmaceutically acceptable carrier" is any physiological carrier known to 20 those of ordinary skill in the art useful in formulating pharmaceutical compositions. In one preferred embodiment the pharmaceutical carrier may be a liquid and the pharmaceutical composition would be in 25 the form of a solution. In another equally preferred embodiment, the pharmaceutically acceptable carrier is a solid and the composition is in the form of a powder or tablet. In a further embodiment, the pharmaceutical carrier is a gel and the composition is in the form of a 30 suppository or cream. In a further embodiment the compound may be formulated as a part of a pharmaceutically acceptable transdermal patch. A solid carrier can include one or more substances which 35 may also act as flavoring agents, lubricants, solubilizers, WO 02/06245 PCT/USO1/21286 -66 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 5 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 10 ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins. 15 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 20 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 25 agents, colors, viscosity regulators, stabilizers or osmo-regulators. 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), 30 alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. 35 Sterile liquid carriers are useful in sterile liquid form WO 02/06245 PCT/USO1/21286 -67 compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellent. 5 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 10 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 15 inert binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings. The compound can be administered orally in the form of a sterile solution or suspension containing other solutes or 20 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. 25 The compound can also be administered orally either in liquid or solid composition form. Compositions suitable for oral administration include solid forms, such as pills, capsules, granules, tablets, and powders, and liquid forms, 30 such as solutions, syrups, elixirs, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions, and suspensions.
WO 02/06245 PCT/USO1/21286 -68 The present invention also provides a method of modifying feeding behavior of a subject which comprises administering to the subject an amount of a compound effective to decrease the consumption of food by the subject wherein the 5 compound has the structure: A 0 fi A 0 N ' ,R4 R3-N N 10 H 1 | r R2 N X H 2 Nx N
R
2 K3 R3 A 0 Rii R -A 0 R, N N -R R3- - NR4 NN x , H ,or I I
R
2 N s H n N R 2
V
WO 02/06245 PCT/USO1/21286 -69 wherein A is Y2 Y, Y2 y 3 5 N
Y
5 Y3 Y 10 S
Y
2 y Y2 y 3 N 15 Y2 y3 Y 20 or wherein each of Y 1 , Y 2 , Y 3 , Y 4 and Y 5 is independently -H; straight chained or branched Cl-C 7 alkyl, monofluoroalkyl 25 or polyfluoroalkyl; straight chained or branched C 2
-C
7 alkenyl or alkynyl; C 3
-C
7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -F, -Cl, -Br, or -I; -NO 2 ; -N 3 ; -CN; -OR 3 ,
-OCOR
3 r -COR 3 , -CON(R 3
)
2 , or -COOR 3 ; or any two of Y 1 , Y 2 r 30 Y 3 , Y4 and Y 5 present on adjacent carbon atoms can constitute a methylenedioxy group; wherein each X is independently S; 0; or NR 3 ; 35 wherein R 1 is -H; -NO 2 ; -CN; straight chained or branched WO 02/06245 PCT/USO1/21286 -70 Ci-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2
-C
7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
-N(R
3
)
2 ; -OR 3 ; -(CH 2 )pOR 3 ; -COR 3 ; -C0 2
R
3 ; 5 -CON(R 3
)
2 ; or CO 2
(CH
2 )nV; wherein R 2 is -H; straight chained or branched Ci-C 7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or 10 branched C 2 -C7 alkenyl or alkynyl; C 3
-C
7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
C
3 -Ci 0 cycloalkyl-C 1 -Cio-alkyl, C 3 -CiO cycloalkyl-Ci-Cio-monofluoroalkyl or C 3
-C
1 cycloalkyl-Ci
C
1 0 -polyfluoroalkyl; -CN; -CH 2
XR
3 , -CH 2 X (CH 2 ) pNHR 3 , 15 -(CH 2 ) nNHR 3 , -CH 2
X(CH
2 )pN(R 3
)
2 r -CH 2
X(CH
2 )pN 3 , -CH3X(CH 2 )pNHCXR 5 ; -OR 3 ; or R, and R 2 together form a lactone ring; wherein each R 3 is independently -H; straight chained or 20 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; 25 wherein
R
4 is (i) R 5 (ii) R m R\ 30 R mR5 N t R R [\m R 35 Ry WO 02/06245 PCT/USO1/21286 -71 (iii) R 'm [ tN Xb Y 5 R t m Z 10 ,2(iv)
R
6 R [.I m3 N R [m D-D 15 Y2 20 (v) 3 R [ R N [ld R m Z 0 25 WO 02/06245 PCT/USO1/21286 -72 (vi) 5 6 ' R R7 (vii) 10 R R6 R i1 B1Y 15 Y 3 (viii) R R6R t m
R
5 20 AN Ry 25 (ix) R U R N U or m N m U R [m R 30 R m R (x) m N m-U 35 WO 02/06245 PCT/USO1/21286 -73 wherein each R is independently -H; -F; straight chained or branched CI-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; -N (R 3 ) 2; -N2; -CN; -C0 2
R
3 ; -OR 3 ; or 5
-CN(R
3
)
2 ; wherein B is N or CY 4 ; wherein each D is independently
C(R
3
)
2 ; 0; S; NR 3 ; CO; or 10 CS; wherein each U is independently aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I;
COR
3 ; CO 2
R
3 ; -CON(R 3
)
2 ; CN; -NO 2 ; -N(R 3
)
2 ; -OR 3 ; -SR 3 ; 15 (CH 2 )qOR 3 ; (CH 2 )qSR 3 ; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or 20 cycloalkenyl; wherein V is C(R 5
)
2 ; CR 5
R
6 ; NRs or NR 6 ; wherein W is CR 5 ; CR 6 or N; 25 wherein Z is S; 0; C(R 3
)
2 ; or NR 3 ; wherein each R 5 is -H; -NO 2 ; -N 3 ; -CN; straight chained or branched CI-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; 30 straight chained or branched C2-C7 alkenyl or alkynyl; C3 C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
-N(R
3
)
2 ; -OR 3 ; -(CH 2 )pOR 3 ; -COR 3 ; -C0 2
R
3 ; or -CON(R 3
)
2 ; -XCORB; or aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or 35 more F; Cl; Br; I; COR 3 ; C0 2
R
3 ; -CON(R 3
)
2 ; CN; -NO 2
;
WO 02/06245 PCT/USO1/21286 -74
-N(R
3
)
2 ; -OR 3 ; -SR 3 ; (CH 2 )qOR 3 ; (CH 2 )qSR 3 ; -XCOR 8 ; straight chained or branched C 1 -C7 alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; straight chained or branched C 2
-C
7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, 5 monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein each R 6 is independently -H; straight chained or branched CI-C7 alkyl, hydro.xyalkyl, aminoalkyl, 10 alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7.-alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
-N(R
3
)
2 ; -OR 3 ; -(CH2)pOR 3 ; -COR 3 ; -C0 2
R
3 ; or -CON(R 3
)
2 ; 15 wherein R7 is -H; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2
R
3 ;
-CON(R
3
)
2 ; CN; -NO 2 ; -N(R 3
)
2 ; -OR 3 ; -SR 3 ; (CH 2 )qOR 3 ;
(CH
2 )qSR 3 ; -XCOR 8 ; straight chained or branched CI-C7 20 alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; 25 wherein R 8 is -H; straight chained or branched C 1 -C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C 3 -C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3
)
2 ; -OR 3 ; -(CH2)pOR 3 ; -COR 3 ; -C0 2
R
3 ; or 30 -CON(R 3
)
2 ; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2
R
3 ; -CON(R 3
)
2 ; CN; -NO 2 ;
-N(R
3
)
2 ; -OR 3 ; -SR 3 ; (CH 2 )qOR 3 ; (CH 2 )qSR 3 ; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or 35 branched C2-C alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, WO 02/06245 PCT/USO1/21286 -75 monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein b is 1 or 2; 5 wherein d is an integer from 0 to 2 inclusive; wherein each m is independently an integer from 0 to 3 inclusive; 10 wherein each n is independently an integer from 0 to 5 inclusive; wherein each p is independently an integer from 1 to 7 15 inclusive; wherein q is an integer from 1 to 3 inclusive; wherein t is an integer from 2 to 6 inclusive; 20 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound has the structure 25 A 0 5 Ri R N N -N N--R5 R2 N R H - R 6 R3 30 Rs A O N N- N C(Rs)2 H Rt R 35 R7 35 R3 WO 02/06245 PCT/USO1/21286 -76 In a further embodiment, the compound has the structure 5 A 0 R R R5 N N N V H t R, R,: N '1 X R 17M 2 RR7 10 R 3 In an additional embodiment, the compound has the structure 15 A 0 R It HN N---R
R
2 N O H ; or 1 R 5 20 A 0 R, N N R H N C(R 5
)
2
R
2 N--- ' 25 R5 In a further embodiment, at least one R 5 group is an aryl or heteroaryl group optionally substituted with one or 30 more F; Cl; Br; I; -NO 2 ; -N(R 3
)
2 ; -OR 3 ; -XCORB; or straight chained or branched C 1
-C
7 alkyl. 35 WO 02/06245 PCT/USO1/21286 -77 In another embodiment, A is: Y2 y 2 3 Y2 y3 5 4 or Ys N
Y
5 In further embodiments, the compound is selected from the 10 group consisting of: F (a) F 00 00 15ON NN N O ~~ (b) 20 F F 0 0 ON N N O 0 N Ok N- 25 N 3 (c) F F 30 0 O O N 5NN N - -O 35 WO 02/06245 PCT/USO1/21286 -78 (d) F F 0 0 0 N N cii 5N -O 70 F (e) 10 F F O O 0 N N N ;and 15 N OF F F 20 (f) F F NI 0 0 25 0 N N O N. O 0 In other embodiments, the compound has the structure 30 A 0 RR, N NN Rm I HR t R NN RRm7
X
3 WO 02/06245 PCT/US01/21286 -79 In a further embodiment, the compound has the structure A 0 5 . N 0 HR H R7 In additional embodiments, A is 10 1/ 3 N
Y
5 15 and R 7 is phenyl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2
R
3 ; -CON (R 3 ) 2 ; CN; -NO 2 ; -N (R 3 ) 2 ;
-OR
3 ; -SR 3 ; (CH 2 )qOR 3 ; (CH 2 )q SR 3 ; -XCOP ; or straight chained or branched C 1
-C
7 alkyl. 20 In one embodiment, the compound has the structure F 25 F 0 0 O N ) N" N O N O N - 0 30 WO 02/06245 PCT/USO1/21286 -80 In an embodiment of the present invention, the compound has the structure A 0 Y1 N N4RN Y2j, I H Rt [m
R
2 N X3 R3 10 In yet another embodiment, the compound has the structure A 0 y 15R N Y2 H 20 In further embodiments, A is 25 4YO
Y
5 and Z is 0 or CH 2 30 WO 02/06245 PCT/USO1/21286 -81 In an additional embodiment, the compound is selected from the group consisting of 5 N-O N 0 0 O N N N 10 N1 0 15 N-O N 0 N N O \/ ;and 20 F F 251 0 0 N N N N N -1O 0 30 WO 02/06245 PCT/USO1/21286 -82 In one embodiment, the compound has the structure Y2
Y
1 Y A 0 R R6 N NH t N[ Rd N XR m Z 0
R
3 10 In a further embodiment, the compound has the structure Y2 1 Y 15 A 0 R, N ) N- H N N 0 IO H 0 20 In another embodiment, A is Y2 y3 y2 3 25' 25 y4 ' or Y / y N
,
WO 02/06245 PCT/USO1/21286 -83 In yet another embodiment, the compound is N O ; or 10 F F O O 0 N N"- N 15 N O 0 In a further embodiment, the compound has the structure A 0 20 R, N Nm N R R2 N' X H Y2t
R
3 Y3 25 In another embodiment, the compound has the structure A 0 RiNN N YJ 30 N O H Y
HY
3 WO 02/06245 PCT/USO1/21286 -84 In yet another embodiment, the compound has the structure F F 5 0 O O N N N N 0 N e 10 In one embodiment, the compound has the structure A 0 R m R R2 N X RU
R
3 In another embodiment, the compound has the structure 20 A 0
R
1 NHN U XN 0 1 0 H 25 In another embodiment, the compound has the structure N--O 30 N 0 0 O N N N N 35 0 WO 02/06245 PCT/USO1/21286 -85 This invention further provides a method of reducing the body mass of a subject which comprises administering to the subject an amount of a compound effective to reduce the body mass of the subject wherein the compound has the 5 structure: A 0 A 0 10 R, N N R4 R3,N NR4
R
2 N X X N R 2
R
3 3 A 0 A 0 15~ R R4N N-R4 1N N *kN R3, H ,or NI
R
2 N s H S N R2
V
WO 02/06245 PCT/USO1/21286 -86 wherein A is 5 3 Y5 4N Y2 10 3 YI L yS Y2 Y3 Y2 y3 15 X N / 20 Y2 y or wherein each of YI, Y 2
Y
3 ,. Y 4 and Y 5 is independently -H; 25 straight chained or branched CI-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C, alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -F, -C1, -Br, or -I; 30 -No 2 ; -N 3 ; -CN; -OR 3 , -OCOR 3 , -COR 3 , -CON (R 3 ) 2r or -COOR 3 ; or any two of Y 1 , Y 2 , Y 3 r Y 4 and Y 5 present on adjacent carbon atoms can constitute a methylenedioxy group; wherein each X is independently S; 0; or NR 3 ; 35 WO 02/06245 PCT/USO1/21286 -87 wherein R 1 is -H; -NO 2 ; -CN; straight chained or branched C1-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C 3
-C
7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or 5 cycloalkenyl; -N(R 3
)
2 ; -OR 3 ; -(CH 2 )pOR 3 ; -COR 3 ; ~C0 2
R
3 ;
-CON(R
3
)
2 ; or CO 2
(CH
2 )nV; wherein R 2 is -H; straight chained or branched CI-C7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, 10 monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2
-C
7 alkenyl or alkynyl; C 3 -C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C3-C10 cycloalkyl-Ci-Cio-alkyl, C3~CIO cycloalkyl-Cl-Cio-monofluoroalkyl or C3-C10 cycloalkyl-Ci 15 C 1 0 -polyfluoroalkyl; -CN; -CH 2
XR
3 , -CH 2
X(CH
2 )pNHR 3 ,
-(CH
2 ) nNHR 3 , -CH 2
X(CH
2 )pN(R 3
)
2 , -CH 2
X(CH
2 )pN 3 ,
-CH
2
X(CH
2 )pNHCXR 5 ; -OR 3 ; or wherein R, and R 2 together form a lactone ring; 20 wherein each R 3 is independently -H; straight chained or branched Ci-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3 C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; 25 wherein R 4 is (i ) N R 30 R7 R mR5 (ii) NRR R [m\ 6 35 Ry WO 02/06245 PCT/USO1/21286 -88 (iii) R 1 b R m Y, N Y2 R m 5
R
6 y3 (iv) 10 1 2 R6 R [m i Y3 R D DD (v) Y2 20 Y1 y3 R Re6 m R N I ld t Z R m Z 25
O
WO 02/06245 PCT/USO1/21286 -89 (vi) RR 10 N R 6 R m R tm W
R
6 (vii) 6 10 R m R I R7 B 15 Y 3 20 (viii) R R R5 Al N R "tnR n m R
R
7 25 (ix) m Uor m \N LmJ 30 R [m R5 R R R m m /\N-j mU 35 (X) m R 5
R
WO 02/06245 PCT/USO1/21286 -90 wherein each R is independently -H; -F; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; -N(R 3
)
2 ; -NO 2 ; -CN; -C0 2
R
3 ; -OR 3 ; or 5
-CN(R
3
)
2 ; wherein B is N or CY 4 ; wherein each D is independently C(R 3
)
2 ; 0; S; NR 3 ; CO; or 10 CS; wherein each U is independently aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I;
COR
3 ; C0 2
R
3 ; -CON(R 3
)
2 ; CN; -NO 2 ; -N(R 3
)
2 ; -OR 3 ; -SR 3 ; 15 (CH2)qOR 3 ; (CH 2 )qSR 3 ; straight chained or branched CI-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C 3
-C
7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or 20 cycloalkenyl; wherein V is C(R 5
)
2 ; CR 5
R
6 ; NR 5 or NR 6 ; wherein W is CRS; CR 6 or N; 25 wherein Z is S; 0; C(R 3
)
2 ; or NR 3 ; wherein each R 5 is -H; -NO 2 ; -N 3 ; -CN; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; 30 straight chained or branched C2-C7 alkenyl or alkynyl; C3 C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3
)
2 ; -OR 3 ; -(CH 2 )pOR 3 ; -COR 3 ; -C0 2
R
3 ; or -CON(R 3
)
2 ; -XCOR8; or aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or 35 more F; Cl; Br; I; COR 3 ; C0 2
R
3 ; -CON(R 3
)
2 ; CN; -NO 2
;
WO 02/06245 PCT/USO1/21286 -91 -N (R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 ) qOR 3 ; (CH 2 ) qSR 3 ; -XCOR 8 ; straight chained or branched C 1
-C
7 alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; straight chained or branched C 2
-C
7 alkenyl, C 2 -C7 alkynyl; C 3
-C
7 cycloalkyl, 5 monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein each R 6 is independently -H; straight chained or branched C3-C 7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, 10 monofluoroalkyl 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 3 ; -COR 3 ; -C0 2
R
3 ; or -CON
(R
3 ) 2; 15 wherein R 7 is -H; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2
R
3 ; -CON (R 3 ) 2; CN; -NO 2 ; -N (R 3 ) 2; -OR 3 ; -SR 3 ; (CH 2 ) qOR3;
(CH
2 )qSR 3 ; -XCOR 8 ; straight chained or branched C 1
-C
7 20 alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; straight chained or branched C 2
-C
7 alkenyl, C 2
-C
7 alkynyl;
C
3
-C
7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; 25 wherein R 8 is -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl 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 3 ; -COR 3 ; -C0 2
R
3 ; or 30 -CON(R 3
)
2 ; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2
R
3 ; -CON(R 3
)
2 ; CN; -NO 2 ; -N (R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 ) qOR 3 ; (CH 2 ) qSR 3 ; straight chained or branched C 1
-C
7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or 35 branched C 2
-C
7 alkenyl, C 2
-C
7 alkynyl; C 3
-C
7 cycloalkyl, WO 02/06245 PCT/USO1/21286 -92 monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein b is 1 or 2; 5 wherein d is an integer from 0 to 2 inclusive; wherein each m is independently an integer from 0 to 3 inclusive; 10 wherein each n is independently an integer from 0 to 5 inclusive; wherein each p is independently an integer from 1 to 7 15 inclusive; wherein q is an integer from 1 to 3 inclusive; wherein t is an integer from 2 to 6 inclusive; 20 or a pharmaceutically acceptable salt thereof. In addition, the present invention provides a method of treating a subject suffering from depression and/or anxiety 25 which comprises administering to the subject a compound of the aforementioned formula in an amount effective to treat the subject's depression and/or anxiety.
WO 02/06245 PCT/USO1/21286 -93 This invention also provides a method of modifying feeding behavior of a subject which comprises administering to the subject an amount of a compound effective to decrease the consumption of food by the subject wherein the compound is 5 selected from the group consisting of: ,a) O N-O (b) 0 - 1 0 N - S-N .N 10 S N o N S - 0 F 0 c) NN No N d) N O N N 0 0 e) - \ - /\/ zz 'N a F WO 02/06245 PCT/USO1/21286 -94 0 f 0 f) CIN C1I 5 CI g)N 0 10 C N N and F 15 h) 9N N F 20 This invention further provides a method of modifying feeding behavior of a subject which comprises administering to the subject an amount of a compound of the present invention effective to decrease the consumption of food by 25 the subject. This invention also provides a method of treating a feeding disorder in a subject which comprises administering to the subject an amount of a compound of the present invention 30 effective to decrease the consumption of food by the subject. In an embodiment of the present invention, the feeding disorder is bulimia, obesity or bulimia nervosa. In a further embodiment, the subject is a vertebrate, a mammal, a human or a canine. In yet another embodiment, 35 the compound is administered in combination with food.
WO 02/06245 PCT/USO1/21286 -95 In the subject invention a "therapeutically effective amount" is any amount of a compound which, when administered to a subject suffering from a disease against 5 which the compounds are effective, causes reduction, remission, or regression of the disease. One skilled in the art will readily appreciate that appropriate biological assays will be used to determine the 10 therapeutic potential of the claimed compounds for treating the above noted disorders.. Optimal dosages to be administered may be determined by those skilled in the art, and will vary with the particular 15 compound in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular subject being treated will result in a need to adjust dosages, including subject age, weight, gender, diet, and 20 time of administration. This invention further provides compositions which need not be pharmaceutical as that term is understood in the art. Such compositions comprise a compound in accordance with 25 the subject invention in an amount effective to antagonize an MCH1 receptor and a suitable carrier. Still further, the invention provides a method of agonizing and/or antagonizing an MCH1 receptor which comprises 30 contacting the receptor, e.g. in vitro or in in vivo, with an amount of a compound of this invention effective to agonize and/or antagonize the receptor. This invention will be better understood from the 35 Experimental Details which follow. However, one skilled in WO 02/06245 PCT/USO1/21286 -96 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. 5 WO 02/06245 PCT/USO1/21286 -97 Experimental Section I. Synthetic Methods for Examples General Methods: All reactions (except for those done by 5 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 10 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 (1-37) were named using ACD/Name program (version 2.51, Advanced Chemistry Development Inc., Toronto, 15 Ontario, M5H2L3, Canada) . Unless otherwise noted, the 1 H and 13 C NMR spectra were recorded at 300 and 75 MHz (QE Plus) with CDCl 3 as solvent and tetramethylsilane as internal standard. s = singlet; d = doublet; t = triplet; q = quartet; p = pentet; sextet; septet; br = broad; m = 20 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 25 60 F254 (0.25 mm, EM Separations Tech.). Preparative thin-layer chromatography was carried out on glass sheets precoated with silica gel GF (2 mm, Analtech) . Flash column chromatography was performed on Merck silica gel 60 (230 - 400 mesh). Melting points (mp) were determined in 30 open capillary tubes on a Mel-Temp apparatus and are uncorrected. Procedures for the Synthesis of the Dihydropyrimidine Intermediates 35 WO 02/06245 PCT/USO1/21286 -98 5-METHOXYCARBONYL-4-METHOXYMETHYL-1,2,3,6-TETRAHYDRO-2 OXO-6- (3,4-DIFLUOROPHENYL)-PYRIMIDINE: To a stirring mixture of methyl 4-methoxyacetoacetate (50.0 g, 0.342 mol), 3,4-difluorobenz-aldehyde (51.4 g, 0.362 mol), and 5 urea (31.6 g, 0.527 mole) in THF (300 mL) at room temperature were added copper(I) oxide (5.06 g, 0.035 mole) and acetic acid (2.05 mL), sequentially, followed by dropwise addition of boron trifluoride diethyl etherate (56.0 mL, 0.442 mole). The mixture was stirred and 10 refluxed for 8 h, whereupon TLC (1/1 EtOAc/hexanes) analysis indicated completion of the reaction. The reaction mixture was cooled and poured into a mixture of ice and sodium bicarbonate (100 g) and the resulting mixture was filtered through Celite. The Celite pad was washed with 15 dichloromethane (400 mL). The organic layer was separated from the filtrate and the aqueous layer was extracted with more dichloromethane (3 X.300 mL). The combined organic extracts were dried (sodium sulfate) and the solvent evaporated. The crude product was purified by flash column 20 (ethyl acetate/hexanes, 1/1; then ethyl acetate), giving the product as pale yellow foam, which on trituration with hexane became white powder (103 g, 97%) .
1 H NMR d 3.48 (s, 3H), 3.65 (s, 3H), 4.65 (s, 2H), 5.39 (s, 1H), 6.60 (br s, 1H, NH), 7.00 - 7.20 (m, 3H), 7.72 (br s, 1H, NH). 25 (+) -5-METHOXYCARBONYL-4-METHOXYMETHYL-1, 2,3, 6-TETRAHYDRO-2 OXO-6-(3,4-DIFLUOROPHENYL)-PYRIMIDINE: The racemic intermediate 5-methoxycarbonyl-4-methoxymethyl-1,2,3,6 30 tetrahydro-2-oxo-6- (3,4-difluorophenyl)pyrimidine was resolved by chiral HPLC. [Chiralcel OD 20 X 250 mm #369-703-30604; lambda 254 nm; hexanes/ethanol 90/10; 85 mg per injection; retention time of the desired enantiomer: 16.94 min., the first enantiomer peak to elute], giving 35 (+)-5-methoxycarbonyl-4-methoxymethyl- WO 02/06245 PCT/USO1/21286 -99 1,2,3,6-tetrahydro-2oxo-6-(3,4-difluorophenyl)-pyrimidine (40-42 wt% isolation of the desired enantiomer from the racemate); [a]D = + 83.8 (c = 0.5, chloroform). The (-)-isomer was also isolated as the later eluting fraction 5 from the chiral chromatography column. (+)-5-METHOXYCARBONYL-4-METHOXYMETHYL-1,2,3,6-TETRAHYDRO 2-OXO- 6-(3,4-DIFLUOROPHENYL)-1-[(4-NITROPHENYLOXY) CARBONYL]PYRIMIDINE: To a solution of 10 (+)-5-methoxycarbonyl-4-methoxymethyl-1,2,3,6 tetrahydro-2-oxo-6-(3,4- 'difluorophenyl)-pyrimidine (1.98 g, 6.34 mmol) in anhydrous THF (20 mL) at -78 'C under argon atmosphere, a solution of lithium hexamethyldisilazide in THF (1M, 18.0 mL, 18.0 mmol) was added over 2-3 min. and 15 the mixture was stirred for 10 min. This solution was added over 6 min., via a cannula, to a stirred solution of 4-nitrophenyl chloroformate (4.47 g, 22.2 mmol) in THF (20 mL) at -78 'C. Stirring was continued for 10 min. and the mixture was poured onto ice (50 g) and extracted with 20 chloroform (2 X 50 mL). The combined extracts were dried (sodium sulfate) and the solvent was evaporated. The residue was purified by flash column chromatography (hexanes/ethyl acetate, 4/1 to 3.5/1) as the eluent. The product was obtained as yellow syrup which upon trituration 25 with hexanes became a white powder (2.40 g, 79%) : 'H NMR d 3.52 (s, 3H), 3.74 (s, 3H), 4.65-4.80 (q, J=16.5 Hz, 2H), 6.32 (s, 1H), 7.10-7.30 (m, 4H), 7.36 (d, J=9 Hz, 2H), 8.27 (d, J=9 Hz, 2H). 30 BENZYL 3- [(3, 4-DIFLUOROPHENYL) METHYLENE] -4-OXOPENTANOATE: A solution of benzyl propionylacetate (36.3 g, 176 mmol), 3,4- difluorobenzaldehyde (25.0 g, 176 mmol), piperidine (0.86 mL, 9.0 mmol) and acetic acid (0.49 mL, 9.0 mmol) was 35 refluxed with removal of water using a Dean-Stark apparatus WO 02/06245 PCT/USO1/21286 -100 for 5 h. The solvent was removed in vacuo and the residue was dissolved in EtOAc. The reaction mixture was washed with water (100 mL), followed by brine (100 mL) and dried over anhydrous Na 2
SO
4 . The solvent was evaporated, giving a 5 pale yellow syrup (60.2 g) . The product was used in the next step without further purification. 5- (BENZYLOXYCARBONYL) -1, 6-DIHYDRO-2-METHOXY-4-ETHYL-6- (3, 4-DI-FLUOROPHENYL)PYRIMIDINE: A suspension of benzyl 10 3-[(3,4-di-fluorophenyl)methylene]-4-oxopentanoate (16.0 g, 48.0 mmol), 0-methylisourea hydrogen sulfate (16.7 g, 97.0 mmol) and NaHCO3 (16.3 g, 130 mmol) in DMF (190 mL) was stirred at 70 'C for 20 h. After cooling to room temperature, the mixture was filtered and the filtrate was 15 diluted with EtOAc (300 mL) and then washed with water (4X100 mL), brine (200 mL) and dried over Na 2
SO
4 . After removal of solvent, the residue was purified by column chromatography (EtOAc/Hexane, 1/9 to 3/7), giving the title compound as a colorless oil (10.6 g, 58%). The NMR 20 analysis showed it to be a mixture of amine/imine tautomers and was used as is in the next step. 5-(BENZYLOXYCARBONYL)-4-ETHYL-1,6-DTHYDRO-2-METHOXY-6-(3, 25 4-DI-FLUOROPHENYL)-1-[(4-NITROPHENYLOXY)CARBONYLI PYRIMIDINE: To a stirring solution of 5-(benzyloxycarbonyl)-1,6-dihydro-2- methoxy-4-ethyl-6 (3,4-difluorophenyl)pyrimidine (17.0 g, 44.0 mmol) and 4-dimethylaminopyridine (7.00 g, 57.3 mmol) in CH 2 C1 2 (200 30 mL) was added 4-nitrophenyl chloroformate as a powder (11.5 g, 57.1 mmol) at room temperature. The reaction mixture was stirred for 12 h and then the solvent was removed in vacuo. The residue was purified by chromatography (EtOAc/Hexane, 1 / 9 t o 3 / 7), g i v i n g 35 5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2- methoxy- WO 02/06245 PCT/USO1/21286 -101 6-(3,4-difluorophenyl)-1-[(4-nitrophenyloxy)carbonylipyr imidine as a colorless viscous oil (12.6 g, 50%). 1H NMR d 1.24 (t, J=7.2 Hz, 3H), 2.81-2.98 (m, 3H), 3.97 (s, 3H), 5.14 (ABq, A=5.08, B= 5.20, J= 12.3 Hz, 2H), 6.28 (s, 5 3H), 7.03-7.29 (m, 8H), 7.35 (d, J=9.2 Hz, 2H), 8.26 (d, J=9.2 Hz, 2H). 5-(BENZYLOXYCARBONYL)-4-ETHYL-1,6-DIHYDRO-1-{N-[1-PHENYL) ETHYL]}-CARBOXAMIDO-2-METHOXY-6-(3,4-DIFLUOROPHENYL) 10 PYRIMIDINE: To a stirred mixture of 5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2 methoxy-6-(3,4-difluorophenyl)-1-[(4-nitrophenyloxy)carbo nyl]pyr-imidine. (12.6 g, 22.9 mmol) in THF (150 mL) was added a solution of R-(+)-ax-methyl benzylamine (3.53 mL, 15 27.1 mmol) at room temperature. The stirring was continued for 12 h and the solvent was removed in vacuo. The yellow residue was dissolved in chloroform (200 mL) and was washed with 10% K 2
CO
3 solution (2x30 mL) . The organic layer was dried over Na 2
SO
4 , filtered and solvent was removed in 20 vacuo. The resulting mixture of diastereomers was separated by column chromatography (petroleum ether/ether, 9/1 to 4/1). The first major product to elute was (+)-5-(benzyloxycarbonyl)-4-ethyl 1,6-dihydro-l-{N-[1- phenyl)-ethyl]}carboxamido-2 25 methoxy-6-(3,4-difluorophenyl)pyrimidine. Colorless oil; Rf= 0.31 (petroleum ether/ether, 4/1); yield: 3.8 g (31%); [a] = +267.05 (c = 0.76, CHCl 3 ); 'H NMR d 1.22 (t, J=7.5 Hz, 3H), 1.52 (d, J=6.9 Hz, 3H), 2.88 (q, J=6.0 Hz, 2H), 3.99 (s, 3H), 4.99 (m, 1H), 5.09 (ABq, A=5.00, B= 5.19, J= 30 12.6 Hz, 2H), 6.66 (s, 1H), 6.99-7.36 (m, 13H). The second m a j o r p r o d u c t . t o e l u t e w a s (-)-5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-l-{N [2-phenyl)ethyl]}carboxamido-2-methoxy-6-(3,4-difluorophe nyl)pyr-imidine. Colorless oil; Rf= 0.22 (petroleum WO 02/06245 PCT/USO1/21286 -102 ether/ether, 4/1); yield: 3.20 g (26%); [a]D 8(c 0.38, CHCl 3 ); 'H NMR 6 1.22 (t, J=7.2 Hz, 3H), 1.49 (d, J=6.6 Hz, 3H),2.88 (q, J=6.0 Hz, 2H), 3.94 (s, 3H), 5.03 (m, 1H) , 5.11 (ABq, A=5.02, B= 5.19, J= 12.6 Hz, 2H), 5 6.68 (s, 1H), 6.91-7.34 (m, 13H) . (+)-5-(BENZYLOXYCARBONYL)-1,6-DIHYDRO-2-METHOXY-4-ETHYL-6 -(3,4-DI-FLUOROPHENYL)PYRIMIDINE: To a stirred solution of (.+)-5-(benz-yloxycarbonyl)-4-ethyl-1,6-dihydro-1 10 {N-[2-phenyl)ethyl]}carbox-amido-2-methoxy-6 (3,4-difluorophenyl)pyrimidine (1.00 g, 1.83 mmol) in toluene (10 mL) was added 1,8-diazabicyclo[5,4,0]-undec 7-ene (0.120 mL, 0.810 mmol) at room temperature and the resulting solution was heated at reflux temperature for 5 15 h and then stirred for 12 h at room temperature. The solvent was evaporated and the residue was purified by flash column (EtOAc/Hexanes, 1/3), giving (+)-5-(benzyloxycarbonyl)-1,6- dihydro-2-methoxy-4-ethyl -6- (3,4-difluorophenyl)pyrimidine (0.560 g, 77%). 20 (+)-5-(BENZYLOXYCARBONYL),4-ETHYL-1,6-DIHYDRO-2-METHOXY-6 -(3,4-DI-FLUOROPHENYL)-1-[(4-NITROPHENYLOXY) CARBONYL]PYRIMIDINE: To a stirring solution of (+)-5-(benzyloxycarbonyl)-1,6-dihydro-2 25 methoxy-4-ethyl-6-(3, 4-difluorophen-yl)pyrimidine (17.0 g, 44.0 mmol) and 4-dimethylaminopyridine (6.99 g, 57.3 mmol) in CH 2 C1 2 (200 mL) was added 4-nitrophenyl chloroformate (11.6 g, 57.3 mmol) at room temperature. The reaction mixture was stirred for 12 h and then the solvent was 30 removed in vacuo. The residue was purified by chromatography (EtOAc/Hexane, 1/9 to 3/7), giving (+)-5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6 -(3,4- difluorophenyl)-1-[(4-nitrophenyloxy) carbonylipyrimidine as a viscous colorless oil (19.3 g, WO 02/06245 PCT/USO1/21286 -103 76%) 5-METHYLBENZFUROXAN: 4-Methyl-2-nitroaniline (100 g, 0.650 mol) was suspended in saturated methanolic sodium hydroxide 5 solution (1.50 L). This suspension was cooled (5 0 C) and aqueous sodium hypochlorite until the red color disappeared. The resulting fluffy yellow precipitate was filtered, washed with cold water and recrystallized from ethanol, giving 5-methylbenzfuroxan (88.2 g, 89 % yield) as 10 a pale yellow solid: 'H NMR d 2.39 (s, 3 H), 6.90-7.40 (br m. 3 H). 5-METHYLBENZOFURAZAN: To 5-Methylbenzfuroxan (88.2 g, 0.590 mol) in refluxing EtOH (75 mL) was added dropwise P(OEt) 3 15 (150 mL) . Heating was continued at reflux temperature for 1 h. The solvent was removed in vacuo and the residue was shaken with water (200 mL) and allowed to stand overnight at (0-5 'C) . The resulting brown solid was filtered, washed with water. The crude product was purified by flash 20 chromatography, giving 5-methylbenzofurazan (70.0 g, 87 %) as white needles; 'H NMR 5 2.41 (s, 1 H), 7.19 (dd, J=9.3, 1.1 Hz, 1 H), 7.48 (d, J=1.1 Hz, 1 H), 7.66 (d, J=9.3 Hz, 1 H). 25 5-DIBROMOMETHYLBENZOFURAZAN: An anhydrous solution of 5-methylbenzofurazan (70.0 g, 0.520 mol), N-bromosuccinamide (325 g), and benzoyl peroxide (0.50 g) in carbon tetrachloride (1.5 L) was heated at reflux temperature with stirring for 30 h. The reaction mixture 30 was washed with water (2 X 500 mL), dried (NaSO 4 ), and the solvent was removed in vacuo. The residue was chromatograghed (EtOAc/hexane, 1/150), giving 122 g (80%) of the title compound as a white solid: 'H NMR d 6.69 (s, 1 H), 7.69 (d, J=9.6 Hz, 1 H), 7.77 (s, 1 H), 7.89 (d, J=9.6 35 Hz, 1 H).
WO 02/06245 PCT/USO1/21286 -104 5-FORMYLBENZOFURAZAN: AgNO 3 (163 g) in 2 L of water was added to a refluxing mixture of dibromomethylbenzofurazan (122 g, 418 mmol) in EtOH (1 L) . Heating at reflux temperature was continued for 2 h. The mixture was cooled, 5 the precipitated AgBr was removed by filtration through Celite, and the solvent was concentrated. The resulting solution was extracted with toluene (10 X 100 mL) , dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was chromatograghed (EtOAc/hexane, 10 1/125), giving the title aldehyde (48.2 g, 78%) as a white solid: 'H NMR 5 7.92 (m, 2H), 8.39 (s, 1 H), 10.10 (s, 1 H) . METHYL 2-{(BENZOFURAN-5-YL)METHYLENE}-3-OXOBUTYRATE: A 15 mixture of 5-formylbenzofurazan (0.60 g, 4.1 mmol), methyl acetoacetate (0.52 g, 4.5 mmol), piperidine (0.019 g, 0.23 mmol), and acetic acid (0.014 g, 0.23 mmol) in benzene (30 mL) was heated at reflux temperature (equipped with a Dean-Stark trap) for 8 h. Benzene was evaporated in vacuo, 20 the residue was dissolved in ethyl acetate (80 mL) and washed with brine (50 mL), saturated potassium bisulfate solution (50 mL), and saturated sodium bicarbonate solution. The ethyl acetate solution was dried over magnesium sulfate, the solvent removed under reduced 25 pressure and the residue was purified by column chromatography (EtOAc/hexane, 1/9 to 3/20). The desired product was obtained as oil (0.98 g, 98%) and was used in the next step without any further characterization. 30 6-(BENZOFURAZAN-5-YL)-1,6-DIHYDRO-2-METHOXY-5-METHOXYCARB ONYL-4- METHYLPYRIMIDINE: A mixture of methyl 2-{(benzofuran-5-yl)-methylene}-3-oxobutyrate (1.02 g, 4.10 mmol), 0-methylisourea hydrogen sulfate (1.06 g, 6.20 WO 02/06245 PCT/USO1/21286 -105 mmol), and NaHCO 3 (1.30 g, 16.4 mmol) in DMF (15 mL) was stirred and heated at 70 'C for 16 h. The mixture was cooled, diluted with EtOAc (50 mL) and washed with water (5X 50 mL), brine (50 mL) and dried over magnesium sulfate. 5 The solvent was evaporated and the crude product was purified by flash chromatography (EtOAc/hexane, 1/9 to 1/5), giving the desired product as an oil (0.520 g, 43%): 'HNMR 5 2.38 and 2.42 (2 s, 3 H), 3.60 and 3.66 (2 s, 3 H), 3.74 and 3.82 (2 s, 3 H), 5.53 and 5.68 (2 s, 1 H), 6.31 10 and 6.32 (br s, 1 H), 7.0-7.8 (m, 3 H). 6-(BENZOFURAZAN-5-YL)-1,6-DIHYDRO-2-METHOXY-5-METHOXYCARB ONYL-4- METHYL-1-[(4-NITROPHENYLOXY)CARBONYL]PYRIMIDINE: 15 To a solution of 6-(benzofuran-5-yl)-1,6-dihydro 2-methoxy-5-methoxycarbonyl-4- methylpyrimidine (0.485 g, 1.6 mmol) and 4-dimethylaminopyridine (0.200 g, 1.64 mmol) in CH 2 Cl 2 (20 mL) at 0-5 'C was added 4-nitrophenyl chloroformate (0.307 g, 1.52 mmol) . The mixture was then 20 allowed to warm to room temperature. After 12 h, the solvent was evaporated and the residue was purified by flash chromatography (EtOAc/hexane, 1/9 to 3/20), giving the desired product as white crystals (0.665 g, 89%); mp 180-183 0 C; 'H NMR 6 2.54 (s, 3 H), 3.75 (s, 3 H), 3.98 (s, 25 3 H), 6.37 (s, 1 H), 7.40 (d, J=9.3 Hz, 2 H), 7.52 (d, J=9.0 Hz, 1 H), 7.68 (s, 1 H), 7.84 (d, J=9.0 Hz, 1 H), 8.32 (d, J=9.3 Hz, 2 H). 30 (+) and (-)-6-(BENZOFURAZAN-5-YL)-1,6-DIHYDRO-2-METHOXY-5 METHOXYCARBONYL-1-[N-(S)-1-(1-PHENYLETHYL)]-4-METHYLPYRIM IDINE: A solution of 6-(benzofurazan-5 yl)-1,6-dihydro-2-methoxy-5- methoxycarbonyl-4-methyl 1- (4-nitrophenoxy)carbonylpyrimidine (800 mg, 1.71 mmol) WO 02/06245 PCT/USO1/21286 -106 and (S)-(-)-a-methylbenzylamine (269 mg, 2.22 mmol) in THF (50 mL) was stirred at room temperature for 12 h. The THF was removed in vacuo and the residue was dissolved in EtOAc (100 mL), washed by 10% aqueous K 2 CO3 5 solution (3x50 mL), brine (50 mL) and dried (Na 2
SO
4 ). After removal of the solvent, the residue was purified by chromatography (EtOAc/hexane, 1/20 to 3/20), separating the two diastereomers. The isomers of 6-(benzofurazan-5-yl)-1,6-dihydro-2-methoxy-5-methoxycarb 10 onyl-1-[N-(S)-1-(1-phenylethyl)]- 4-methylpyrimidine were obtained as colorless oils. 1st Isomer (367 mg, 47.7%): [c], = +278 (c=0.50, CHC1 3 ); 'H NMR 8 1.54 (d, J=6.9 Hz, 3H), 2.45 (s, 3H), 3.68 (s, 3H), 3.99 (s, 3H), 5.02 (quintet, J=6.9 Hz, 1H), 6.71 (s, 1H), 6.89 (d, J=6.6 Hz, 15 1H), 7.2-7.9 (m, 8H). 2nd Isomer (205 mg, 26.6%):[a]D =-81 (c=0.43, CHCl 3 ); 1 H NMR81.52 (d, J=6.6 Hz, 3H), 2.48 (s, 3H), 3.71 (s, 3H), 3.96 (s, 3H), 5.00 (quintet, J=6.6 Hz, 1H), 6.74 (s, 1H), 6.90 (d, J=6.5 Hz, 1H), 7.2-7.9 (m, 8H). 20 6-(BENZOFURAZAN-5-YL)-1,6-DIHYDRO-2-METHOXY-5-METHOXYCARB ONYL-4- METHYLPYRIMIDNE: A solution of the 1st isomer of 6-(benzofura-zan-5-yl)-1,6-dihydro-2-methoxy 5-methoxycarbon-yl-l-[N-(S)-1-(1-phenylethyl)]-4-methylpy 25 rimidine (960 mg, 2.14 mmol) and 1,8-diazabicyclo [5,4,O]undec-7-ene (107 mg, 0.705 mmol) in toluene (50 mL) was stirred at 100 0C for 5 h. After cooling to room temperature, toluene was r-emoved in vacuo and the residue was purified by chromatography (EtOAc/hexane, 1/9 to 3/7) 30 6-(Benzofurazan-5- yl)-1,6-dihydro-2-methoxy 5-methoxycarbonyl- 4-methylpyrimidine was obtained as a colorless oil (635 mg, 98.3%). 'H NMRS2.38 (s, 3H), 3.66 (s, 3H), 3.74 (s, 3H), 5.68 (s, 1H), 6.32 (br s, 1H), 7.0-7.8 (m, 3H).
WO 02/06245 PCT/USO1/21286 -107 6-(BENZOFURAZAN-5-YL)-1,6-DIHYDRO-2-METHOXY-5-METHOXYCARB ONYL-4-METHYL-1-(4-NITROPHENOXY)CARBONYLPYRIMIDINE: T o a solution of 6-(benzofuran-5-yl)-1,6-dihydro-2-methoxy 5-methoxycarbonyl- 4-methylpyrimidine (0.485 g, 1.60 mmol) 5 and 4-dimethylamino-pyridine (0.200 g, 1.60 mmol) in CH2Cl, (20 mL), at 0-5 0C, was added 4-nitrophenyl chloroformate (0.307 g, 1.52 mmol) . After addition, the mixture was allowed to warm to room temperature. After 12 hours, the solvent was evaporated and the residue was purified by 10 flash column chromatography (EtOAc/hexane, 1/9 to 3/20), giving the desired product as white crystals (0.665 g, 89%): mp 180-183 0C; 'H NMRS2.54 (s, 3 H), 3.75 (s, 3 H), 3.98 (s, 3 H), 6.37 (s, 1 H), 7.40 (d, J = 9.3 Hz, 2 H), 7.52 (d, J = 9.0 Hz, 1 H), 7.68 (s, 1 H), 7.84 (d, J = 9.0 15 Hz, 1 H), 8.32 (d, J = 9.3 Hz, 2 H); [a]D = +266 (c=2.70,
CH
2 C1 2 ) METHYL 2-{(3,4-DIFLUOROPHENYL)METHYLENE}-3-OXOBUTYRATE: A mixture of 3,4-difluorobenzaldehyde (14.2 g, 0.100 mol), 20 methyl acetoacetate (12.2 g, 0.105 mol), piperidine (0.430 g, 5 mmol), and acetic acid (0.30 g, 5 mmol) in benzene (150 mL) was stirred and heated at reflux temperature (equipped with a Dean-Stark trap) for 8 h. The benzene was evaporated and the residue was dissolved in ethyl acetate 25 (200 mL). The resulting solution was washed with brine (50 mL), saturated potassium bisulfate solution (50 mL), and saturated sodium bicarbonate solution. The ethyl acetate solution was dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was 30 purified by column chromatography (EtOAc/hexane, 1/9 to 3/20), giving the desired product as a yellow oil (9.80 g, 41%) which was used in the subsequent step without any further characterization.
WO 02/06245 PCT/USO1/21286 -108 6-(3,4-DIFLUOROPHENYL)-1,6-DIHYDRO-2-METHOXY-5-METHOXYCAR BONYL-4-METHYLPYRIMIDINE: -A mixture of methyl 2-{(3,4 difluorophenyl)-methylene}-3-oxobutyrate (8.80 g, 36.3 mmol), 0-methylisourea hydrogen sulfate (9.40 g, 546 mmol), 5 and NaHCO3 (12.3 g, 146 mol) in DMF (30 mL) was heated at 70 'C with stirring for 16 h. The mixture was cooled, diluted with EtOAc (300 mL) and washed with water (5 X 300 mL), brine (300 mL), and dried over magnesium sulfate. The solvent was evaporated and the crude product was purified 10 by flash chromatography (EtOAc/hexane, 1/9 to 3/7) as the gradient eluent, giving the desired product as an oil (3.82 g, 35%). 6-(3,4-DIFLUOROPHENYL)-1,6-DIHYDRO-2-METHOXY-5-METHOXYCAR 15 BONYL-4-METHYL-1-[(4-NITROPHENYLOXY)CARBONYL]PYRIMIDINE: 4-Nitrophenyl chloroformate (1.82 g, 9.04 mmol) was added to a solution of 6-(3,4-difluorophenyl)-1,6-dihydro 2-methoxy-5-methoxycarbonyl-4-methylpyrimidine (2.82 g, 9.46 mmol) and 4-dimethylaminopyridine (1.16 g, 9.52 mmol) 20 in CH 2 C12 (50 mL), at 0-5 'C and the mixture was then allowed to warm to room temperature. After 12 h, the solvent was. evaporated and the residue was purified by flash chromatography (EtOAc/hexane, 1/9 to 3/20), giving the desired product as white crystals (3.72, 85%): mp 172-174 25 C. 6-(3,4-DIFLUOROPHENYL)-1,2,3,6-TETRAHYDRO-2-OXO-5-METHOXY CARBON-YL-4-METHYL-1-(4-NITROPHENOXY)CARBONYLPYRIMIDINE: Aqueous 6 N hydrochloric acid (10 mL) was added to a 30 stirring solution of 6-(3,4-difluorophenyl)-1,6- dihydro 2-methoxy-5-methoxycarbonyl- 4-methyl-1 (4-nitrophenoxy)carbonylpyrimidine (10.0 g) in THF (200 mL) at room temperature. The stirring was continued for 3 h. The solvent was evaporated and the residue was dried under 35 vacuum, giving the desired product as a white powder (9.70 WO 02/06245 PCT/USO1/21286 -109 g, 100%) : mp 185-186 OC. (+)-1-(3-BROMO-PROPYLCARBAMOYL)-6-(3,4-DIFLUOROPHENYL)-4 METHYL- 2-OXO-1,6-DIHYDRO-PYRIMIDINE-5-CARBOXYLIC ACID 5 METHYL ESTER: A solution of 10% aqueous HCl (5 mL) was added to a stirring solution of (+)-6-(3,4 difluorophenyl)-1,6-dihydro- 2-methoxy-5-methoxycarbonyl 4-methyl-1- [ (4-nitrophenyloxy) -carbonylIpyrim-idine (4.10 g, 9.10 mmol) in THF (20 mL) at room temperature and the 10 resulting solution was stirred overnight. The THF was removed in vacuo and the. resulting residue was extracted with EtOAc (3 X 20 mL), washed with brine (10 mL) and then dried over Na 2
SO
4 . The solvent was removed in vacuo, giving (+)-6-(3,4-di-fluorophenyl)-1,6-dihydro-2- oxo-5 15 methoxycarbonyl-4-methyl-1- [(4-nitrophenyloxy)carbonyl] pyrimidine as a viscous oil (3.8 g, 8.5 mmol). The oil was dissolved in THF (20 mL) and 3-bromo-propylamine hydrobromide (2.33 g, 10.8 mmol) and NaHCO 3 (1.81 g, 21.5 mmol) were added. The resulting suspension was stirred at 20 room temperature overnight. The THF was removed in vacuo and the resulting residue was dissolved in water (10 mL) and then extracted with EtOAc (3 X 20 mL). The EtOAc extracts were combined, dried over Na 2
SO
4 , filtered and the solvent was removed , giving (+)-l-(3-bromo 25 propylcarbamoyl)-6- (3,4-difluorophenyl) 4-methyl-2-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester (3.28 g, 83%): 'H NMR6 2.05-2.15 (m, 2 H), 2.43 (s, 3 H), 3.40-3.56 (m, 4 H), 3.72 (s, 3 H), 6.69 (s, 1 H), 7.08-7.27 (m, 3 H), 7.57 (br s, 1 H), 8.84 (br t, 1 H) . 30 Anal. Calcd for C 1 7
H,
8
N
3 0 4 F2Br: C, 45.76; H, 4.07; N, 9.42. Found: C, 45.70; H, 3.99; N, 9.16. 3-{(3,4,5-TRIFLUOROPHENYL)METHYLENE}-2,4-PENTANEDIONE: A stirring mixture of 3,4,5-trifluorobenzaldehyde (4.20 g, WO 02/06245 PCT/USO1/21286 -110 26.2 mmol), 2,4-pentanedione (2.62 g, 26.2 mmol), piperidine (0.430 g, 5.00 mmol) in benzene (150 mL) was heated at reflux temperature (equipped with a Dean-Stark trap) for 8 h. The benzene was evaporated and the yellow 5 oily residue, 2-{ (3,4,5-trifluorophenyl)methylene} 2,4-pentanedione, was used in the next step without further purification. 6-(3,4,5-TRIFLUOROPHENYL)-1,6-DI-HYDRO-2-METHOXY-5-ACETYL 10 4-METHYLPYRIMIDINE: A mixture of 2-{(3,4,5 trifluorophenyl)methylene}- 2,4-pentanedione (26.2 mmol), 0-methylisourea hydrogen sulfate (3.22 g, 39.3 mmol), and NaHCO 3 (6.6 g, 78.6 mmol) in EtOH (400 mL) was stirred and heated at 95-100 'C for 6 h. The mixture was filtered and 15 the solid residue was washed with ethanol (100 mL) . The solvent was evaporated from the combined filtrates and the crude product was purified by flash column chromatography (EtOAc/hexane, 1/9 to 1/4), giving the desired product as an oil (2.80 g, 36%). 20 6-(3,4,5-TRIFLUOROPHENYL)-1,6-DIHYDRO-2-METHOXY-5-ACETYL 4-METH-YL-1-[(4-NITROPHENYLOXY)CARBONYL]PYRIMIDINE: 4-Nitrophenyl chloroformate (1.89 g, 9.38 mmol) was -added to a solution of 6-(3,4,5-trifluorophenyl)-1,6 25 dihydro-2-methoxy-5-acetyl-4-meth-ylpyrimidine (2.80 g, 9.38 mmol) and pyridine (10 mL) in CH 2 C1 2 (200 mL) at 0-5 IC, and the resulting mixture was allowed to warm to room temperature. After 12 h, the solvent was evaporated and the residue was purified by flash chromatography 30 (dichloro-methane/EtOAc, 1/9 to 3/20), giving the desired product as a white powder (4.00 g, 92%). 6-(3,4,5-TRIFLUOROPHENYL)-1,2,3,6-TETRAHYDRO-2-OXO-5-ACET YL-4- METHYL-1-[(4-NITROPHENYLOXY)CARBONYL]PYRIMIDINE: A 35 solution of 6 N aqueous HCl (4 mL) was added to a stirring WO 02/06245 PCT/USO1/21286 -111 solution of 6- (3,4,5-trifluorophenyl)-1,6 dihydro-2-methoxy-5-acetyl-4-methyl- 1-[(4 nitrophenyloxy)carbonyl]pyrimidine (4.00 g, 8.63 mmol) in THF (100 mL) at 0-5 'C, and the mixture was allowed to warm 5 to room temperature. After 2 h, solvent was evaporated and the product dried under vacuum. The product was obtained as a pure single component and used in the next step without any further purification (3.88 g, 100%). 10 Procedures for the Synthesis of the Piperidine Intermediates (reference for the general procedure for Pd coupling of vinyl triflate and boronic acids or tributyl tin reagents: See, Wuston, Wise Synthesis (1991), 993) 15 TERT-BUTYL 4-{[(TRIFLUOROMETHYL)SULFONYL]OXY} 1,2,3,6-TETRA-HYDRO-1-PYRIDINECARBOXYLATE: n-Butyllithium (17.6 mL, 44.2 mmol, 2.5 M in hexanes) was added to a solution of diisopropyl amine (96.2 mL, 44.2 mmol) in 40 mL 20 of dry THF at 0 'C and stirred for 20 minutes. The reaction mixture was cooled to -78 GC and tert- butyl 4-oxo-1-piperidinecarboxylate (40.0 mmol) in THF (40 mL) was added dropwise to the reaction mixture and stirred for 30 minutes. Tf 2 NPh (15.0 g, 42.0 mmol) in THF (40 mL) was 25 added dropwise to the reaction mixture and the mixture was stirred at 0 'C overnight. The reaction mixture was concentrated in vacuo, re-dissolved in hexanes/EtOAc (9/1), passed through a plug of alumina and washed with hexanes/EtOAc (9/1) . The combined extracts were 30 concentrated to yield 16.5 g of the desired product that was contaminated with a small amount of Tf 2 Nph. 'H NMR 8 5.77 (s, 1 H), 4.05 (dm, 2 H, J=3.0 Hz), 3.63 (t, 2 H, J=5.7 Hz), 2.45 (m, 2 H), 1.47 (s, 9 H).
WO 02/06245 PCT/USO1/21286 -112 TERT-BUTYL 4-[3-(ACETYLAMINO)PHENYL]-1,2,3, 6 TETRAHYDRO-1- PYRIDINECARBOXYLATE: A mixture of saturated of aqueous Na2CO3 solution (25 mL), tert-butyl 4-{[(trifluoromethyl)sulfonylloxy}- 1,2,3,6 5 tetrahydro-1-pyridine-carboxylate (20 mmol), 3-acet amidophenylboronic acid (30 mmol) and tetrakis triphenylphosphine palladium (0) (1.15 g) and dimethoxyethane (40 mL) was heated at reflux temperature overnight. The organic layer of the cooled reaction 10 mixture was separated and the aqueous layer was washed with ethyl acetate (3X) . The combined organic extracts were dried and concentrated in vacuo. The crude product was chromatograghed, giving the desired product 'H NMR 6 8.11 (br s, 1 H), 7.57 (br s, 1 H), 7.41 (br8, 1 H, J=7.8 Hz), 15 7.25 (apparent t, 1 H, J=7.8 Hz), 7.08 (br d, 1 H, J=7.8 Hz), 5.99 (b s, 1 H), 4.03 (br m, 2 H, J=2.7 Hz), 3.59 (t, 2 H, J=5.7 Hz), 2.46 (m, 2. H,), 2.16 (s, 3 H), 1.49 (s, 9 H). 20 N1-[3-(1,2,3,6-TETRAHYDRO-4-PYRIDINYL)PHENYL]ACETAMIDE: A solution of 4 M HCl in dioxane (10 mL) was added to tert-butyl 4-[3-(acetylamino)phenyl]-1,2,3,6 tetrahydro-1-pyridinecarboxyl-ate (8.25 mmol) in dichloromethane (30 mL). The reaction mixture was stirred 25 at room temperature overnight, concentrated in vacuo, giving the desired product as the hydrochloride salt (2.1 g) . 'H NMR 8 7.41-7.00 (m, 4 H), 6.10 (br, 1 H), 3.55 (m, 2 H), 3.16 (t, 2 H, J = 5.7 Hz), 2.44 (m, 2 H), 2.19 (s, 3 H). 30 TERT-BUTYL N-(3-BROMOPROPYL)CARBAMATE: Prepared from 3-bromopropylamine hydrobromide and BOC 2 0 in the presence of base in dichloromethane: 'H NMR 5 5.07 (br, 1 H), 3.31 (t, 2 'H, J=6.6 Hz), 3.12 (apparent br q, 2 H, J=6.0 Hz), 1.92 WO 02/06245 PCT/US01/21286 -113 (p, 2 H, J=6.6 Hz), 1.30 (s, 9H). REACTION OF Ni-[3-(1,2,3,6-TETRAHYDRO-4-PYRIDINYL)PHENYL] ACETAMIDE WITH TERT-BUTYL N-(3-BROMOPROPYL)CARBAMATE 5 TERT-BUTYL N-(3-{4-[3-(ACETYLAMINO)PHENYL] 1,2,3,6-TETRAHYDRO- 1-PYRIDINYLIPROPYL)CARBAMATE: A solution of N1-[3-(1,2,3,6- tetrahydro-4-pyridinyl) phenyl]acetamide hydrochloride (8.24 mmol), tert-butyl 10 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 chromatographed, giving the desired product 15 (110 mg). 1 H NMR57.65 (s, 1 H), 6.98 (s, 1 H), 7.45 (d, 1 H, J=7.8 Hz), 7.16 (apparent t, 1 H, J=7.8 Hz), 7.10 (d, 1 H, J=7.8 Hz), 6.02 (s, 1 H), 5.23 (b, 1 H), 3.40 (b, 2 H), 3.30-1.80 (m, 10 H), 2.18 (s, 3 H), 1.45 (s, 9 H). 20 Deprotection of BOC: N1-{3-[1-(3-AMINOPROPYL) -1,2,3,6-TETRAHYDRO-4-PYRIDINYL]P HENYL}ACETAMIDE: A 1:1 solution of TFA:CH 2 Cl 2 (5 mL) was added to tert-butyl N-(3-{4-[3-(acetylamino)phenyll 1,2,3,6-tetrahydro-1- pyridinyl}propel)carbamate in 25 dichloromethane (5 mL). The resulting solution was stirred at room temperature for 1-3 days, saturated NaHCO3 was added until pH > 6, the organic layer was separated, and dried in vacuo, giving the desired product (45 mg): 1 H NMR 5 7.68 (br, 1 H), 7.35 (dm, 1 H, J=7.8 Hz), 7.25 (apparent 30 t, 1 H, J=7.8 Hz), 7.15 (dm, 1 H, J=7.8 Hz), 6.12 (m, 1 H), 3.22 (m, 2 H), 3.03 (t, 2 H, J=7.3 Hz), 2.78 (t, 2 H, J=5.5 Hz), 2.70-2.50 (m, 4 H), 2.10 (s, 3 H), 1.87 (p, 2 H, J=7.3 Hz).
WO 02/06245 PCT/USO1/21286 -114 TERT-BUTYL 4-[3-(ACETYLAMINO)PHENYL)-1 PIPERIDINECARBOXYLATE: A mixture tert-butyl 4-[3-(acetylamino)phenyl]-1,2,3,6-tetra-hydro-1 pyridinecarboxylate (710 mg) and 5% Pd/C (100 mg) in EtOH 5 (10 mL) 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 10 product (660 mg) . 'H NMR 5 7.80 (s, 1 H), 7.41-7.20 (m, 3 H), 6.94 (d, 1 H, J=7.5 Hz)., 4.21 (m, 2 H), 2.75 (m, 2 H), 2.62 (m, 1 H), 2.16 (s, 3 H), 1.78 (m, 2 H), 1.56 (m, 2 H), 1.48 (s, 9 H). 15 N1-[3-(4-PIPERIDYL)PHENYLJACETAMIDE: A solution of HCl in dioxane (4N, 5 mL) was added to tert-butyl 4-[3 (acetylamino)-phenyl]-1-piperidinecarboxylate (660 mg) in dry dichloromethane (15 mL) . The reaction mixture was stirred at room temperature overnight and concentrated in 20 vacuo, giving the desired product (550 mg): mp 102-104 'C; 'H NMR 5 2.02 (d, J=13.2 Hz, 2H), 2.11-2.45 (m, 5H), 2.67-2.77 (m, 1H), 3.00-3.10 (m, 2H), 3.51 (d, J=10.5 Hz, 2H), 6.94 (d, J=7.5 Hz, 1H), 7.20-7.46 (m, 3H), 7.60 (s, 1H). 25 TERT-BUTYL N-(3-{4-[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 30 mmol), K2CO3 (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 WO 02/06245 PCT/US01/21286 -115 product (340 mg). 'H NMR 5 8.15 (s, 1 H) , 7. 47-7. 44 (m, 2 H), 7.22 (t, 1 H, J=7.8 Hz), 6.94 (d, 1 H, J=7.8 Hz), 5.53 (b, 1 H), 3.23 (b, 6 H), 2.80-1.60 (m, 9 H), 2.20 ('s, 3 H), 1.45 (s, 9 H). 5 N1-{3-[1-(3-AMINOPROPYL)-4-PIPERIDYL]PHENYL}ACETAMIDE: TFA (1.0 mL) was added to a solution of tert-butyl N-(3-{4-[3-(acetyl-amino)phenyllpiperidino} 10 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 to the reaction mixture until pH > 6 and then the dichloromethane was removed in vacuo. The aqueous layer was frozen and lyophilized, giving a solid 15 which was then extracted with methanol. Removal of methanol gave the desired product (120 mg) as an oil. 'H NMR 5 8.56 - 8.46 (s, 1H), 7.43 - 7.30 (m, 2H), 7.23 - 7.16 (apparent t, 1H, J=7.5 Hz), 6.95 - 6.92 (m, 1H), 3.03 2.99 (m, 2H), 2.77 - 2.73 (t, 2H, J = 6.6 Hz), 2.50-1.60 20 (m, 10 H), 2.13 (s, 3 H). 1-BENZYL-4-HYDROXY-4-(4-FLUORO-2-METHYLPHENYL)PIPERIDINE: 'H NMR 5 7.40-7.26 (M, 5 H), 6.91-6.76 (m, 3 H), 3.57 (s, 2 H), 2.83- 2.72 (m, 2 H), 2.61 (s, 3 H), 2.58-2.43 (m, 2 25 H), 2.23-2.12 (m, 2 H). 1-BENZYL-4-(4-FLUORO-2-METHYLPHENYL)-1,2,3,6-TETRAHYDROPY RIDINE: 'H NMR 8 7.41-7.26 (m, 5 H), 7.05 (dd, 1 H, J=6.0, 8.1 Hz), 6.87-6.80 (m, 2 H), 5.52-5.50 (m, 2 H), 3.65 (s, 30 2 H), 3.13 (q, 2 H, J=3.3 Hz), 2.69-2.66 (t, 2 H, J=5.1 Hz), 2.35-2.31 (m, 2 H), 2.27 (s, 3 H). 4-(4-FLUORO-2-METHYLPHENYL)PIPERIDINE: 1H NMR 6 7.17 (t, 1 WO 02/06245 PCT/USO1/21286 -116 H, J=7.2 Hz), 6.83-6.80 (m, 2 H), 3.22 (m, 2 H), 2.81-2.73 (m, 2 H), 2.66 (br s, 1 H), 2.33 (s, 3 H), 1.80-1.60 (m, 4 H). 5 1-BENZYL-4-(3,4,5-TRIFLUOROPHENYL)-1,2,3,6-TETRAHYDROPYRI DINE: 'H NMR 5 7.50-7.20 (m, 7 H), 5.67 (m, 1 H), 3.69 (s, 2 H), 3.19 (apparent q, 2 H, J=2.7 Hz), 2.75 (t, 2 H, J=5.7 Hz), 2.34 (m, 2 H). 10 4-(3,4,5-TRIFLUOROPHENYL)PIPERIDINE: mp 197-199 0C; 'H NMR 5 2.05 (d, J=13.2 Hz, 2H), ), 2.33 (dd, J=25.5 Hz, J=12.9 Hz, 2H), 3.06-3.23 (m, 3H), 3.73 (d, J=12.0 Hz, 2H), 6.94-7.04 (m, 2H). 15 4-(3, 4,5-TRIFLUOROPHENYL) PIPERIDINE: IH NMR 5 7.20-6.80 (m, 2 H), 3.73 (m, 2 H), 3.14 (m, 3 H), 2.33 (m, 2 H), 2.05 (m, 2 H). TERT-BUTYL N-3-[4-(3,4,5-TRIFLUOROPHENYL)PIPERIDINO] 20 PROPYL-CARBAMATE: 'H NMR 6 6.91 (m, 2 H), 5.62 (b, 1 H), 4.31 (t, 2 H, J=5.4 Hz), 3.63 (m, 2 H), 3.39 (dt, 2 H, J= 2.1, 6.0 Hz), 3.40-2.70 (m, 7 H), 2.46 (t, 2 H, J=6.9 Hz), 2.10-1.60 (m, 4 H), 1.45 (s, 9 H). 25 3-[4-(3,4,5-TRIFLUOROPHENYL) PIPERIDINO]-1-PROPANAMINE: 'H NMR 66.93 (m, 2 H), 4.30 (b, 1 H), 3.36 (b, 1 H), 3.06 (m, 2 H), 2.77 (m, 2 H), 2.43 (m, 2 H), 2.20-1.40 (m, 9 H). 1-BENZYL-4-(5-FLUORO-2-METHOXYPHENYL)-4-PIPERIDINOL: 'H NMR 30 57.40-6.80 (m, 8 H), 3.94 and 3.85 (s, 3 H), 3.61 and 3.58 (s, 2 H), 2.80-1.90 (m, 8 H). 1-BENZYL-4-(5-FLUORO-2-METHOXYPHENYL)-1,2,3,6-TETRAHYDROP WO 02/06245 PCT/USO1/21286 -117 YRIDINE: 'H NMR 6 7. 40-6.70 (m, 8 H) , 5.84 (m, 1 H) , 3.77 (s, 3 H), 3.64 (s, 2 H), 3.17 (m, 2 H), 2.68 (t, 2 H, J=5.7 Hz), 2.54 (m, 2 H). 5 4-(5-FLUORO-2-METHOXY)PHENYL PIPERIDINE: mp 254-258 IC; 1H NMR 61.53-1.68 (m, 2H), 1.79 (d, J=11.7 Hz, 2H), 2.12 (dt, J=2.1 Hz, J=11.7 Hz, 1H), 2.77 (dt, J=1.8 Hz, J=12.3 Hz, 1H), 2.90-3.05 (m, 1H), 3.10-3.22 (m, 2H), 3.68 (s, 1H), 3.79 (s, 3H), 6.72-6.93 (m, 3H). Anal. Calcd. For 10 C1 2 H,,NOFC1 + 0.14 CH 2 C12: C, 56.60; H, 6.76; N, 5.44. Found: C, 56.60; H, 6.92; N, 5.28. TERT-BUTYL N-3-[4-(5-FLUORO-2-METHOXYPHENYL)PIPERIDINO] PROPYL-CARBAMATE: 'H NMR 8 6.90-6.70 (m, 3 H), 5.76 (b, 1 15 H), 3.80 (s, 3 H), 3.68 (m, 1 H), 3.40-2.90 (m, 4 H), 2.45 (t, 2 H, J=6.6 Hz), 2.20-1.60 (m, 9 H), 1.45 (s, 9 H) . 3-[4-(5-FLUORO-2-METHOXYPHENYL)PIPERIDINO]-1-PROPANAMINE: 'H NMR 6 7.00-6.80 (m, 3 H), 3.80 (s, 3 H), 3.05 (d, 2 H, 20 J=11.4 Hz), 2.76 (t, 2 H, J=6.9 Hz), 2.43 (dd, 2 H, J=7.8 Hz), 2.05 (dt, 2 H, J=2.4, 11.7 Hz), 1.90-1.20 (m, 10 H). TERT-BUTYL 4-(1-NAPHTHYL)-1,2,3,6-TETRAHYDRO-1 PYRIDINECARBOXYL-ATE: 'H NMR68.00-7.80 (m, 2 H), 7.76 (d, 25 1 H, J=8.1 Hz), 7.50-7.44 (m, 2 H), 7.42 (d, 1 H, J=8.1 Hz), 7.27 (d, 1 H, J=8.1 Hz), 5.76 (br, 1 H), 4.14 (m, 2 H), 4 or 3.29 (t, 2 H, J=5.7 Hz), 2.52 (br m, 2 H), 1.53 (s, 9H). 30 4-(1-NAPHTHYL)PIPERIDINE: HC1 salt; mp 330-332 0 C; 'H NMR8 1.66-1.70 (m, 2H), 2.20-2.26 (m, 2H), 2.30-2.43 (m, 2H), 2.72-2.84 (m, 1H), 3.15-3.26 (m, 2H), 7.42-7.56 (m, 4H), 7.78 (d, J=8.1 Hz, 1H), 7.90 ( d, J=8.1 Hz, 1H), 8.04 (d, WO 02/06245 PCT/US01/21286 -118 J=8.1 Hz, 1H) . Anal. Calcd. For C, 5 H,NOCl + 0.20 CH 2 Cl 2 : C, 68.96; H, 7.00; N, 5.29. Found: C, 68.64; H, 7.04; N, 5.24. 5 TERT-BUTYL N-3- [4- (1-NAPHTHYL) PIPERIDINO] PROPYLCARBAMATE: 'H NMR58.09 (d, 1 H, J=8.4 Hz), 7.86 (dd, 1 H, J=1.8, 7.5 Hz), 7.71 (dd, 1 H, J=2.4, 6.9 Hz), 7.60-7.30 (m, 4 H), 6.31 (br, 1 H), 5.75 (br, 1 H), 4.26 (t, 1 H, J=5.4 Hz), 3.40-3.00 (m, 6 H), 2.54 (t, 2 H, J=6.9 Hz), 2.24 (dt, 2 H, 10 J= 3.0, 11.4 Hz), 2.00-1.60 (m, 6 H), 1.45 (s, 9 H). 4-(3-METHYL-2-PYRIDYL)-4-PIPERIDINOL: 'H NMRS8.21 (dd, 1 H, J=1.2, 4.5 Hz), 7.36 (dd, 1 H, J=6.6, 7.8 Hz), 7.02 (dd, 1 H, J=4.8, 7.5 Hz), 3.07 (dt, 2 H, J=2.7, 12.3 Hz), 2.89 (m, 15 2 H), 2.46 (s, 3 H), 2.22 (dt, 2 H, J=4.8, 12.3 Hz), 1.39 (dm, 2 H, J=12.3 Hz). TERT-BUTYL 4-(3-METHYL-2-PYRIDYL)-1,2,3,6-TETRAHYDRO 1-PYRIDINE-CARBOXYLATE: 'H NMR 8.16 (dd, 1 H, J=1.2, 3.3 20 Hz), 7.51 (dm, 1 H, J=7.5 Hz), 7.15 (dd, 1 H, J=4.8, 7.5 Hz), 5.73 (br, 1 H), 4.01 (m, 2 H), 3.59 (t, 2 H, J=5.7 Hz), 2.40 (m, 2 H), 1.44 (s, 9 H). T E R T - B U T Y L 25 N-3-[4-(3-METHYL-2-PYRIDYL)PIPERIDINO]PROPYLCARBAMATE: 'H NMR 88.37 (dd, 1 H, J=4.2, 4.8 Hz), 7.51 (dd, 1 H, J=7.2, 7.5 Hz), 7.20 (dd, 1 H, J=4.5, 7.5 Hz), 6.73 (br, 1 H), 3.26 (m, 4 H), 3.05 (d, 2 H, J=12.0 Hz), 2.80-2.40 (m, 4 H), 2.61 (s, 3 H), 1.82 (p, 2 H, J=6.3 Hz), 1.54 (d, 2 H, 30 J= 12.0 Hz). T E R T - B U T Y L 4- (3-METHOXYPHENYL) -1,2,3, 6-TETRAHYDRO-1-PYRIDINECARB OXYLATE: 'H NMRS 7.23 (t, 1 H, J= 8.1 Hz), 6.96 (d, 1 H, WO 02/06245 PCT/USO1/21286 -119 J=7.5 Hz), 6.89 (d, 1 H, J=l.8 Hz), 6.80 (dd, 1 H, J=2.4, 8.1 Hz), 6.02 (br, 1 H), 4.'20-4.00 (m, 3 H), 3.80 (s, 3 H), 3.62 (t, 2 H, J=5.7 Hz), 2.51 (br, 2 H), 1.49 (s, 9 H). 5 1-BENZYL-4-METHYL-PIPERIDIN-4-OL: Methyllithium (1.4 M in Et2O, 54.0 mL) was added to a solution of 1-benzyl 4-piperidone (5.00 mL, 27.0 mmol) in anhydrous ether at -78 0C under argon. Stirring was continued at -78 DC for 1.5 hours. Ether (200 mL) and water (40 mL) were added, 10 and the two phases were separated. The aqueous solution was extracted with Et 2 O (3 x 50 mL). The combined organic solutions were dried over magnesium sulfate and concentrated. The residue was chromatographed (EtOAc to EtOAc-MeOH 9/1), giving 4.81 g (87%) of the desired product 15 as a colorless oil: 'H NMR6 1.21 (s, 3 H), 1.56 (dt, J = 13, 3 Hz, 2 H), 1.65 (td, J = 10, 4 Hz, 2 H), 2.35 (td, J = 10, 3 Hz, 2 H), 2.53 (m, 2 H), 7.24 (m, 1 H), 7.29 (m, 4 H); " 3 C NMR 5 30.44, 39.37, 50.39, 63.80, 68.50, 127.56, 128.80, 129.80, 139.17. 20 1-BENZYL-4-METHYL-4-PHENYLPIPERIDINE: 1-Benzyl-4-methyl piperidin-4-ol (4.81 g, 23.4 mmol) was added to a suspension of AlC1 3 (15.62 g, 117 mmol) in benzene (100 mL) 25 at room temperature under argon. The mixture was stirred at reflux for 24 hours, then cooled and poured cautiously into ice water (100 g of ice, 50 mL of water). The aqueous phase was adjusted to pH 11-12 by addition of 6 N aqueous NaOH at 0 0C, and extracted with EtOAc (3 x 100 mL). The 30 combined organic solutions were dried over magnesium sulfate and concentrated. The residue was chromatographed (hexane- Et 2 O 19/1 to 9/1, followed by hexane-EtOAc 3/1), giving the desired product (3.23 g, 52%) as a brown oil: 'H NMR 6 1.25 (s, 3 H), 1.80 (m, 2 H), 2.17 (m, 2 H), 2.44 WO 02/06245 PCT/USO1/21286 -120 (m, 2 H), 2.55 (m, 2 H), 3.50 (s, 2 H), 7.25 (m, 1 H), 7.35 (m, 4 H); 13 C NMRS36.82, 37.65, 50.95, 54.93, 64.08, 126.19, 126.51, 127.59, 128.83, 128.95, 129.05, 129.89, 139.24. 5 4-METHYL-4-PHENYLPIPERIDINE: Freshly prepared methanolic formic acid solution (4.4% by weight, 70 mL) was added to 1-benzyl-4-methyl-4-phenylpiperidine (3.23 g, 12.2 mmol) . To the resulting solution was added 10% palladium on carbon 10 (2.00 g) . The mixture was stirred at room temperature for 24 hours. The solid was filtered out and washed with MeOH (30 mL), H 2 0 (15 mL), CH 2 C1 2 (30 mL) and MeOH (15 mL) . The combined filtrate and washings were concentrated, and the residue was dissolved in CH 2 Cl 2 (50 mL) and H 2 0 (10 mL) . The 15 aqueous phase was adjusted to pH 11 by addition of 1 N aqueous NaOH. The organic phase was separated, dried over magnesium sulfate and concentrated. The residual oil was purified by flash chromatography (CHCl3/MeOH/2 N NH 3 in MeOH 100/4/0 to 100/20/10), giving 1-benzyl-4- methyl-4 20 phenylpiperidine (1.20 g) and 1.10 g (51%, 82% based on consumed starting material) of 4i-methyl-4-phenylpiperidine: 'H NMR51.24 (s, 3 H), 1.71 (m, 2 H), 2.06 (m, 2 H), 2.82 (m, 3 H), 2.94 (m, 2 H), 7.19 (m, 1 H), 7.32 (m, 4 H); "C NMR 6 37.22, 38.54, 43.44, 47.74, 126.31, 127.43, 129.01, 25 149.73. 3-AMINOPROPYL-4-METHYL-4-PHENYLPIPERIDINE: A solution of 4-methyl-4-phenylpiperidine (1.00 g, 5.70 mmol), 3-bromo 30 propylamine hydrobromide (1.87 g, 8.55 mmol) and potassium carbonate (1.97 g, 14.2 mmol) in refluxing dioxane (20 mL) was stirred for 36 hours. After removal of the solvent, water (50 mL) was added and the pH adjusted to 11-12 by the addition of 1 N aqueous NaOH. The mixture was extracted WO 02/06245 PCT/USO1/21286 -121 with CH 2 Cl 2 (150 mL + 3 x 100 mL) . The combined organic solutions were dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography (CHCl 3 /MeOH/2 N NH 3 in MeOH 100/20/10), 5 giving the desired product as a colorless oil (241 mg, 18%): 'H NMR81.18 (s, 3 H), 1.61 (p, J = 7 Hz, 2 H), 1.75 (m, 2 H), 2.10 (m, 2 H), 2.33 (t, J = 7 Hz, 2 H), 2.40 (m, 2 H), 2.45 (m, 2 H), 2.72 (t, J = 6 Hz, 2 H), 3.02 (br s, 2 H), 7.14 (m, 1 H), 7.3.0 -(m, 4 H); "C NMRS30.28, 36.78, 10 37.64, 41.51, 50.96, 57.51, 126.16, 126.40, 128.91, 149.20. Preparation of 3-[4-(4-Fluorophenyl)piperidin-1-yl]propylamine 15 4-(4-FLUOROPHENYL)PIPERIDINE HYDROCHLORIDE: To a solution of 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (10 g) in methanol (200 mL) was added 10% palladium on charcoal (0.5 g) and the mixture was hydrogenated at 50 psi for 3 h. The catalyst was removed 20 by filtration and solvent was evaporated, leaving the product (10.0 g) as a white powder, which was used in the next step without purification. The product appeared to be pure based on 'H NMR and TLC analysis. 'H NMRS 1.95-2.03 (br d, 2H), 2.14-2.29 (m, 2H), 2.70-2.80 (m, 25 1H), 2.91-3.07 (br q, 2H), 3.60-3.64 (br d, 2H), 6.96-7.03 (m, 2H), 7.19-7.22 (m, 2H), 9.60 (br s, 1H), 9.71 (br s, 1H). 4-(4-FLUOROPHENYL)PIPERIDINE: mp 0 C; 1H NMRS1.51-1.66 (m, 30 2H), 1.80 (d, J=7.2 Hz, 2H), 2.53-2.64 (m, 1H), 2.67-2.77 (m, 2H), 3.17 (d, J=12.0 Hz, 2H), 6.94-7.03 (m, 2H), 7.13-7.21 (m, 2H) . Anal. Calcd. For ClHl 4 NF + C 4
H
4 0 4 : C, 58.70; H, 5.83; N, 4.18.
WO 02/06245 PCT/USO1/21286 -122 Found: C, 58.72; H, 5.84; N, 3.98. 3- [4- (4-FLUOROPHENYL) PIPERIDIN-1-YL] PROPYLPHTHALIMIDE: A mixture of 4-(4-fluorophenyl)piperidine hydrochloride 5 (5.08 g, 23.2 mmol), 3-bromopropylphthalimide (6.22 g, 23.2 mmol), and potassium carbonate (15 g) in DMF (100 mL) was stirred at 95-100 0C for 12 h. About 80% of the solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate (200 mL) and 10 washed with brine (3 X 100 mL) and dried (Na 2 SO4) . The solvent was evaporated from the ethyl acetate solution and the residue was purified by column chromatography (1/1 hexane-ethyl acetate to 100% ethyl acetate), giving crude product (7.50 g, 88%). This crude product was 15 crystallized from isopropanol, giving a white crystalline solid (4.50 g, 1st crop). This material was used in the next step. Concentration of the mother liquor and cooling gave the second crop of desired product (1.0 g). 1 H NMRS 1.43-1.52 (m, 2H), 1.67-1.75 (m, 2H), 1.80-1.96 (i, 4H), 20 2.33-2.46 (n, 3H), 2.94-2.99 (br d, 2H), 3.78 (t, J=7 Hz, 2H), 6.90-7.04 (n, 4H), 7.70-7.74 (n, 2H), 7.84-7.87 (m, 2H). 3-[4-(4-FLUOROPHENYL)PIPERIDIN-1-YL]PROPYLAMINE: 25 Hydrazine (4 mL) was added to a solution of 3-[4 (4-fluorophenyl)piperidin- 1-yl]propylphthalimide (4.50 g, 12.3 mmol) in methanol '(200 mL), and the mixture was stirred at reflux for 8 h. The solution was cooled to room temperature, and the resulting white solid which 30 formed was filtered and washed with methanol (20 mL). The solvent was evaporated from the filtrate and residue was dried under vacuum for 4 h. The crude product was dissolved in 50 mL of chloroform, stirred for 1 h, and filtered. The white solid was washed with additional 35 chloroform (20 mL), the solvent was evaporated from the WO 02/06245 PCT/USO1/21286 -123 combined filtrates to leave the crude product as an oil. The oil was purified by column chromatography (dichloromethane / methanol / 2 M ammonia in methanol, 10/3/1), giving the desired product (2.70 g, 93%). 1H NMR 5 5 1.60-1.83 (m, 6H), 1.96-2.07 (m, 4H), 2.40-2.55 (m, 3H), 2.70-2.85 (br t, 2H), 3.03-3.07 (br d, 2H), 6.93-7.00 (m, 2H), 7.14-7.20 (m, 2H). 4-(4-METHYL-4-(3,5-DIMETHYLPHENYL)PIPERIDINE: 10 hygroscopic; 'H NMR 5 1.20 (s, 3H) , 1.74-1.80 (m, 2H), 2.08-2.16 (m, 2H), 2.30 (s, 6H), 2.50-2.56 (m, 2H), 2.64-2.68 (m, 2H), 2.97-3.04 (m, 1H), 6.87 (s, 1H), 6.94 (s, 2H).
WO 02/06245 PCT/USO1/21286 124 Piperidine Side Chain Intermediates TERT-BUTYL 4-{ [(TRIFLUOROME THYL) SULFONYL] OXY}-1 ,2,3,6 TETRAHYDRO-1-PYRIDINECARBOXYLATE: 5 n-Butyl lithium (17.6 mL, 44.2 mmol, 2.5 M in hexanes) was added to a solution of diisopropyl amine (96.2 mL, 44.2 mmol) in 40 mL of dry THF at 0 'C and stirred for 20 'minutes. The reaction mixture was cooled to -78 0C and tert-butyl 4 -oxo-1-piperidinecarboxylate (Aldrich 10 Chemical Company, 40.0 mmol) in THF (40 mL) was added dropwise to the reaction mixture and stirred for 30 minutes. Tf 2 NPh (42.0 mmcl, 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 15 vacuo, re-dissolved in hexanes:EtOAc (9:1), passed through a plug of alumina and the alumina plug was washed with hexanes:EtOAc (9:1) . The combined extracts were concentrated to yield 16.5 g of the desired product that was contaminated with some starting Tf 2 NPh. 20 1H NMR (400 MHz, CDCl 3 ) 8 5.77 (s, 1 H), 4.05 (dm, 2 H, J=3.0 Hz), 3.63 (t, 2 H, -J=5.7 Hz), 2.45 (m, 2 H), 1.47 (s, 9 H). TERT-BUTYL 4- [3- (AMINO) PHENYL] -1,2,3, 6-TETRAHYDRO-1 25 PYRIDINECARBOXYLATE: A mixture of 2 M aqueous Na 2
CO
3 solution (4.2 mL), tert butyl 4-{[(trifluoromethyl)sulfonyl]oxy}-1,2,3,6 tetrahydro-1-pyridine-carboxylate (0.500 g, 1.51 mmol), 3-aminophenylboronic acid hemisulfate (0.393 g, 2.11 30 mmol), lithium chloride (0.191 g, 4.50 mmol) and tetrakis-triphenylphosphine palladium (0) (0.080 g, 0.075 mmol) in dimethoxyethane (5 mL) was heated at reflux temperature for 3 hours, under an inert WO 02/06245 PCT/USO1/21286 125 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 5 layer was washed with ethyl acetate (3X). The combined organic extracts were dried and concentrated in vacuo. The crude product was chromatograghed (silica, hexanes:EtOAc:dichloromethane (6:1:1) with 1% added isopropylamine to protect the BOC group from hydrolysis) 10 to give 0.330 g of the desired product in 81% yield: H NMR (400 MHz, CDCl 3 ) 6 7.12 (t, 1H, J= 7.60 Hz), 6.78 (d, 1H, J= 8.4 Hz), 6.69 (t, 1H, J= 2.0 Hz), 6.59 (dd, 1H, J= 2.2, 8.0 Hz), 6.01 (m, 1H), 4.10-4.01 (d, 2H, J= 15 2.40 Hz), 3.61 (t, 2H, J= 5.6 Hz), 2.52-2.46 (m, 2H), 1.49 (s, 9H); ESMS m/e : 275.2 (M + H)+. Anal. Calc. for C 16
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 20 TERT-BUTYL 4- [3- (AMINO) PHENYL] -l-PIPERIDINECARBOXYLATE A mixture of 3.10 g of tert-butyl 4 -(3-aminophenyl) 1,2,3, 6 -tetrahydropyridine-1-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. 25 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 30 group from hydrolysis) to give 2.63 g of the desired product (84%) .
WO 02/06245 PCT/US01/21286 126 TERT-BUTYL 4-(3-NITROPHENYL)-3,6-DIHYDRO-1(2H) PYRIDINECARBOXYLATE iH NMR (400 MHz, CHCl 3 ) 8 8.23 (s, 1H), 8.11 (d, 1H, 5 J=8.0 Hz), 7.69 (d, 1H, J=8.0 Hz), 7.51 (t, 1H, J=8.0 Hz), 6.20 (m, 1H), 4.17-4.08 (m, 2H), 3.67 (t, 2H, J=5.6 Hz), 2.61-2.52 (m, 2H), 1.50 (s, 9H); ESMS m/e : 249.1 (M + H - C 4
H
8 )+. 10 1,2,3,6-TETRAHYDRO-4-(3-NITROPHENYL)PYRIDINE: Into a stirred solution of 5 .00.g (16.0 mmol) of tert-butyl 1,2,3,6-tetrahydro-4-(3-nitrophenyl)pyridine-1 carboxylate in 100 ml of 1,4-dioxane at 0*C was bubbled HCl gas for 10 minutes. The reaction mixture was 15 allowed to warm to room 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 20 X 80 mL of dichloromethane and the combined organic extracts were dried (MgSO 4 ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 9 : 1 ,dichloromethane methanol + 1% isopropyl amine) to afford 2.85 g (87.5% 25 yield) of the desired product: 1 H NMR (400 MHz, CDCl 3 ) S 8.24 (s, 1H), 8.09 (d, 1H, J=8.4 Hz), 7.71 (d, 1H, J=8.0 Hz), 7.49 (t, 1H, J=8.0 Hz), 6.35-6.25 (m, 1H), 3.58 (apparent q, 2H, J=3.'0 Hz), 3.14 (t, 2H, J=5.6 Hz), 2.54-2.46 (m, 2H). 30 TERT-BUTYL 3-(4-(3-NITROPHENYL)-3,6-DIHYDRO-1(2H) PYRIDINYL)PROPYLCARBAMATE: A mixture of 2.80 g (14.0 mmol) of 1,2,3,6-tetrahydro-4-(3-nitrophenyl)pyridine, WO 02/06245 PCT/US01/21286 127 3.60 g (15.0 mmol) of tert-butyl N-(3 bromopropyl)carbamate, 11.6 g (84.0 mmol) of 1203, 14.6 mL (84.0 mmol) of diisopropylethylamine and 0.78 g (2.00 mmol) of tetrabutylammonium iodide in 250 mL of 1,4 5 dioxane was heated at reflux temperature for 14 hours. The reaction mixture was filtered and the filtrate was dried (MgSO 4 ), concentrated in vacuo and the residue was purified by column chromatography (silica, 9:1, dichloromethane: methanol + 1% isopropyl amine) to 10 afford 4.35 g (85.7% yield) of the desired product: 'H NMR (400 MHz, CDC13) 5 8.24 (t, 1H, J=1.9 Hz), 8.09 (dd, 1H, J=1.9, 8.0 Hz), 7.70 (apparent d, 1H, J=8.0 Hz), 7.49 (t, 1H, J=8.0 Hz), 6.23 (m, 1H), 3.29-3.18 (m, 4H), 2.75 (t, 2H, J=5.6 Hz), 2.64-2.54 (m, 4H), 1.82-1.70 (m, 15 2H), 1.44 (s, 9H); ESMS m/e : 362.2 (M + H)+. 3-(4-(3-NITROPHENYL)-3,6-DIHYDRO-1(2H)-PYRIDINYL)-1 PROPANAMINE: Into a stirred solution of 4.35 (12.0 mmol) of tert-butyl 3-(4-(3-nitrophenyl)-3,6-dihydro-1(2H) 20 pyridinyl)propylcarbamate in 100 ml of 1,4-dioxane at 00C was bubbled HCl gas for 10 minutes. The reaction mixture was allowed to warm to room temperature and the bubbling was continued for an additional 1 hour. The solvent was removed in vacuo, the residue was dissolved 25 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 residue was purified by column 30 chromatography (silica, 9 : 1 ,dichloromethane methanol + 1% isopropyl amine) to afford 3.05 g (97.0% yield) of the desired product: IH NMR (400 MHz, CDCl 3 ) 6 8.24 (t, 1H, J=1.8 Hz), 8.09 (dd, 1H, J=1.8, 8.2 Hz), WO 02/06245 PCT/USO1/21286 128 7.69 (dd, 1H, J=1.8, 8.2 Hz), 7.48 (t, 1H, J=8.2 Hz), 6.24 Cm, 1H), 3.21 (d, 2H, J=3.6 Hz), 2.84 (t, 2H, J=6.6 Hz), 2.75 (t, 2H, J=5.8 Hz), 2.64-2.54 Cm, 4H), 1.76 (m, 2H); ESMS m/e : 262.2 (M + H)+; Anal. Calc. for 5 C 1 4
H
19
N
3 0 2 (0.06 CHCl 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 10 DIFLUOROPHENYL)-6-(METHOXYMETHYL)-2-OXO-1,2,3,4 TETRAHYDRO-5-PYRIMIDINECARBOXYLATE: A mixture of 3.02 g (6.33 mmol) 5-methyl 1-(4-nitrophenyl) (6S)-6-(3,4 difluorophenyl)-4-(methoxymethyl)-2-oxo-3,6-dihydro 1,5(2H)-pyrimidinedicarboxylate, 1.50 g (5.80 mmol) of 15 3-(4-(3-nitrophenyl)-3,6-dihydro-1(2H)-pyridinyl)-1 propanamine, 7.94 g (75.5 mmol) of K2CO3 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 20 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 (MgSO 4 ) and concentrated in vacuo. The residue was dissolved in 100 mL of anhydrous ethanol containing 0.50 g 10% Pd/C and the reaction 25 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 30 (silica, 9.5 : 0.5 ,dichloromethane : methanol + 1% isopropyl amine) to afford 1.65 g (52.0% yield) of the desired product.
WO 02/06245 PCT/USO1/21286 129 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 5 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 10 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, CDCl 3 ) 8 7.69 (s, 1 H), 7.34 (d, 1 H, J=7.8 Hz), 7.27 (t, 1H, J=7.8 Hz), 7.11 (d, 1H, J=7.8 Hz), 15 6.04 (s, 1H), 4.05 (s,, 2H), 3.62 (apparent t, 2. H, J=4.9 Hz), 2.51.(m, 3H), 1.49 (s, 9H), 1.25 (d, 6H, J=7.4 Hz); ESMS m/e: 345.5 (M + H)+. Anal. Calc. for C2OH 2
N
2
O
3 +0.175 CHC1 3 : C, 66.33; H, 7.77; N, 7.67. Found: C, 66.20; H, 7.41; N, 7.88 20 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 25 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 30 (silica, 9.5 : 0.5 ,dichloromethane : methanol + 1% isopropyl amine) to afford 2.40 g (84.0% yield) of the desired product: 1 H NMR (400 MHz, CDCl 3 ) 5 7.49-7.44 (m, 2H), 7.24 (t, 1H, J=7.6 Hz), 6.93 (d, 1H, J=7.6 Hz), WO 02/06245 PCT/US01/21286 130 4.20-4.10 (m, 2H), 2.86-2.45 (m, 4H), 1.86-1.75 (m, 4H), 1.48 (s, 9H), 1.24 (d, 6H, J=6.8 Hz); ESMS m/e : 345.2 (M + H)+; Anal. Calc. for C20H 3 0N 2
O
3 +0.3H 2 0: C, 68.27; H, 8.77; N, 7.96. Found: C, 68.25; H, 8.54; N, 7.84. 5 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]-l-piperidinecarboxylate in 100 ml of 1,4-dioxane at 0 0 C was bubbled HCl gas for 10 10 minutes. The reaction mixture was allowed to warm to room temperature and the bubbling of the HCl 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 15 solution was extracted with 3 X 80 mL of dichloromethane, the combined organic extracts were dried (MgSO 4 ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 9 : 1 ,dichloromethane : methanol + 1% isopropyl amine) to 20 afford 0.700 g (46.0% yield) of the desired product: 1 H NMR (400 MHz, CDCl 3 ) 6 7.47 (s, 1H), 7.40 (d, 1H, J=7.8 Hz), 7.24 (t, 1H, J=7.8 Hz), 7.00 (d, 1H, J=7.8 Hz), 3.23-3.14 (m, 5H), 2.82-2.57 (m, 4H), 1.20 (d, 6H, J=6.8 Hz); ESMS m/e : 247.2 (M + H)+; 25 The hydrochloride salt was used for the combustion analysis: Anal. Calc. for C 1 3H 22
N
2 0+HCl+0.15 CHCl 3 : C, 60.51; H, 7.76; N, 9.32. Found: C, 60.57; H, 7.83; N, 8.88. 30 3-(4-PIPERDINYL)ANILINE: 1H NMR (400 MHz, CDCl 3 ) 5 7.01 (t, 1H, J=7.6 Hz), 6.62-6.54 (m, 3H), 3.16 (br d, 2H, J=10.3 Hz), 2.75 (dt, 2H, J=2.7, 12.3 Hz), 2.56 (tt, 1H, WO 02/06245 PCT/USO1/21286 131 J=3.6, 12.3 Hz), 1.81 (br d, 2H, J=12.3 Hz), 1.65 (dq, 2H, J=4.0, 12.3 Hz); ESMS m/e : 177.2 (M + H)+. TERT-BUTYL 4-(4-NITROPHENYL)-3,6-DIHYDRO-1(2H) 5 PYRIDINECARBOXYLATE: To a 25-mL RB flask, equipped with a condensor, was added tert-butyl 4 {[(trifluoromethyl)sulfonylloxy}-3,6-dihydro-1(2H) pyridinecarboxylate (1.0 g), 4-nitrophenylboronic acid (0.71 g), sodium carbonate (0.430 mL of 2M solution), 10 lithium chloride (0.382 g), tetrakis(triphenylphosphine)- palladium (0) (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 0C for 3 hrs. 15 After cooling to room'temperature, the reaction mixture was diluted with methylene chloride (30 mL) and water (30 mL) and the organic layer was separated. The aqueous layer was extracted with methylene chloride (3x20 mL) and the combined organic extracts were washed 20 with sat NH 4 Cl (20 mL) and brine (20 mL), dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by chromatography (6:1=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 25 room temperature and should be used as prompt as practical: 1H NMR (400 MHz, CDCl 3 ) 8 8.20 (d, 2H, J=8.6 Hz), 7.51 (d, 2H, J=8.6 Hz), 6.24 (m, 1H), 4.13 (m, 2H), 3.67 (apparent t, 2H, J=5.5 Hz), 2.55 (m, 2H), 1.49 (s, 9H). 30 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 WO 02/06245 PCT/USO1/21286 132 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 5 temperature. The reaction mixture was concentrated in vacuo to give the crude product (69.8 mg) that used in the next reaction without further purification. 10 Dihydropyrimidine Intermediates 3- (3,4, 5-TRIFLUOROBENZYLIDENE) -2, 4-PENTANEDIONE: A stirring mixture of 3,4,5-trifluorobenzaldehyde (4.20 g, 26.2 mmol), 2,4-pentanedione (2.62 g, 26.2 mmol), 15 piperidine (0.430 g, 5.00 mmol) in benzene (150 mL) was heated at reflux temperature in a Dean-Stark apparatus for 8 h. The benzene was evaporated and the yellow oily residue was used in the next step without further purification. 20 ,1- [2-METHOXY-4-METHYL-6- (3,4 , 5-TRIFLUOROPHENYL) -1,6 DIHYDRO-5-PYRIMIDINYL]ETHANONE: A mixture 3- (3,4,5 trifluorobenzylidene) -2,4-pentanedione (26.2 mmol), 0 methylisourea hydrogen sulfate (3.22 g, 39.3 mmol), and 25 NaHCO 3 (6.6 g, 78.6 mmol) in EtOH (400 mL) was stirred and heated at 95-100 'C for 6 h. The mixture was filtered and the solid filter cake was washed with ethanol (100 mL). The solvent was evaporated from the combined filtrates and the crude product was purified by 30 flash column chromatography (EtOAc/hexane, 1/9 to 1/4), to afford the desired product as an oil (2.80 g, 36%).
WO 02/06245 PCT/USO1/21286 133 4-NITROPHENYL 5-ACETYL-2-METHOXY-4-METHYL-6-(3,4,5 TRIFLUOROPHENYL) -1 (6H) -PYRIMIDINECARBOXYLATE: 4-Nitrophenyl chloroformate (1.89 g, 9.38 mmol) was added to a solution of 1-[2-methoxy-4-methyl-6-(3,4,5 5 trifluorophenyl)-1,6-dihydro-5-pyrimidinyl]ethanone (2.80 g, 9.38 mmol) and pyridine (10 mL) in CH 2 C12 (200 mL) at 0-5 0 C, and the resulting mixture was allowed to warm to room temperature. After 12 h, the solvent was evaporated and the residue was purified by flash 10 chromatography (dichloromethane/EtOAc, 1/9 to 3/20), to give the desired product as a white powder (4.00 g, 92%). 4-NITROPHENYL 5-ACETYL-4-METHYL-2-OXO-6- (3,4,5 15 TRIFLUOROPHENYL) -3, 6-DIHYDRO-1 (2H) PYRIMIDINECARBOXYLATE: A solution of 6 N aqueous HCl (4 mL) was added to a well-stirred solution of 4-nitrophenyl 5-acetyl-2 methoxy-4-methyl-6-(3,4,5-trifluorophenyl)-1(6H) 20 pyrimidinecarboxylate (4.00 g, 8.63 mmol) in THF (100 mL) at 0-5 oC, and the mixture was allowed to warm to room temperature. After 2 h, solvent was evaporated and the product dried under vacuum. The product was obtained as a pure single component and used in the next 25 step without further purification (3.88 g, 100%). :H NMR (DMSO) 6 10.29 (s, 1H), 8.23 (d, 2H, J=9. 1 Hz), 7.51 (d, 2H, J=9.1 Hz), 7.15-7.07 (m, 2H), 6.18 (s, 1H), 2.30 (s, 3H), 2.28 (s, 3H); ESMS m/e: 450.2 (M + H)*; 30 Anal. Calc. for C 20
H
1 4
F
3
N
3 0 6 : C, 53.46; H, 3.14; N, 9.35. Found: C, 53.26; H, 3.21; N, 9.35.
WO 02/06245 PCT/USO1/21286 134 BENZYL 2-PROPIONYL-3-(3,4,5-TRIFLUOROPHENYL)-2 PROPENOATE. A solution of benzyl propionylacetate (36.3 g, 176 mmol), 3
,
4 -difluorobenzaldehyde (25.0 g, 176 mmol), piperidine (0.86 mL, 9.0 mmol) and acetic acid 5 (0.49 mL, 9.0 mmol) were heated at reflux temperature with removal of water using a Dean-Stark apparatus for 5h. The solvent was removed in vacuo and the residue was ,dissolved in EtOAc. The organic layer was washed with water (100 mL) followed by brine (100 mL) and dried over 10 anhydrous Na 2
SO
4 . The solvent was evaporated to afford a pale yellow syrup (60.2 g), which was used in the next step without further purification. BENZYL 6-(3,4-DIFLUOROPHENYL)-4-ETHYL-2-METHOXY-1,6 15 DIHYDRO-5-PYRIMIDINECARBOXYLATE. A suspension of benzyl 2-propionyl-3-( 3
,
4 ,5-trifluorophenyl)- 2 -propenoate (16.0 g, 48.0 mmol), 0-methylisourea hydrogen sulfate (16.65 g, 97.02 mmol), NaHCO 3 (16.3 g, 130.2 mmol) in DMF (190 mL) was stirred at 70 0 C for 20h. After cooling to room 20 temperature, the reaction mixture was filtered and the filtrate was diluted with EtOAc (300 mL) and then washed with water (4X100 mL), brine (200 mL) and dried over Na2S0 4 . After removal of solvent, the residue was purified by column chromatography (SiO 2 , EtOAc/Hexane, 25 10%-30%) to afford benzyl 6
-(
3
,
4 -difluorophenyl)-4 ethyl-2-methoxy-1,6-dihydro-5-pyrimidinecarboxylate as a colorless oil (10.6 g, 58% yield). The product was directly used in the next step after 1 H NMR spectroscopy which showed it to be a mixture of amine/imine 30 tautomers. 5-BENZYL 1-(4-NITROPHENYL) 6-(3,4-DIFLUOROPHENYL)-4 ETHYL-2-METHOXY-1,5(6H)-PYRIMIDINEDICARBOXYLATE.
WO 02/06245 PCT/US01/21286 135 Into a well-stirred solution of benzyl 6-(3,4 difluorophenyl)-4-ethyl-2-methoxy1,6-dihydro-5 pyrimidinecarboxylate (27.5 g, 68.75 mmol) and pyridine (9.2 mL) in CH 2 C1 2 (300 mL) was added 4-nitrophenyl 5 chloroformate (14.49 g, 82.5 mmol) at room temperature. The reaction mixture was stirred for 4 h and then washed with 10% aqueous KOH solution (2 X 150 mL). The organic layer was separated and dried over Na 2
SO
4 . The solvent was removed in vacuo and the residue was used in the 10 next step without further purification: 'H NMR (CDCl 3 ) 1.24 (t, J=7.2 Hz, 3H), 2.81-2.98 (m, 3H), 3.97 (s, 3H), 5.14 (ABq, 2H), 6.28 (s, 3H), 7.03-7.29 (m, 8H), 7.35 (d, J=9.2 Hz, 2H), 8.26 (d, J=9.2 Hz, 2H). 15 BENZYL 6-(3,4-DIFLUOROPHENYL)-4-ETHYL-2-METHOXY-1 ({[(lR)-l-PHENYLETHYL]AMINO}CARBONYL)-1,6-DIHYDRO-5 PYRIMIDINECARBOXYLATE. Into a stirred mixture of 5-benzyl 1-(4-nitrophenyl) 6 (3,4-difluorophenyl)-4-ethyl-2-methoxy-1,5(6H) 20 pyrimidinedicarboxylate (12.6 g, 22.86 mmol) in THF (150 mL) was added a solution of R-(+)-a.-methyl benzylamine (3.53 mL, 27.44 mmol) at room temperature. The stirring was continued for 12 h and the solvent was removed in vacuo. The yellow residue was dissolved in chloroform 25 (200 mL) and was washed with 10% K 2
CO
3 solution (2 x 30 mL) . The organic layer was dried over Na 2
SO
4 , filtered and the solvent was removed in vacuo. The resulting mixture of diastereomers was separated by column chromatography over silica gel with 9:1 pet. ether:ether 30 to 4:1 pet. ether:ether. First major product to elute was (+)-benzyl 6-(3,4-difluorophenyl)-4-ethyl-2-methoxy 1-({I[(1R)-l-phenylethyllamino}carbonyl)-1,6-dihydro-5 pyrimidinecarboxylate: Colorless oil, Rf= 0.31(4:1 pet WO 02/06245 PCT/USO1/21286 136 ether:ether); wt.= 3.8 g (60% yield); [a]D = +267.05 (c = 0.76, CHCl 3 ); 1 H NMR (CDCl 3 ) 8 1.22 (t, J=7.5 Hz, 3H), 1.52 (d, J=6.9 Hz, 3H), 2.88 (q, J=6.0 Hz, 2H)), 3.99 (s, 3H), 4.99 (m, 1H), 5.09 (ABq, 2H), 6.66 (s, 1H), 6.99 5 7.36 (m, 13H); The second major product to elute was ( )-benzyl 6-(3,4-difluorophenyl)- 4 -ethyl-2-methoxy-1 ({[(1R)-l-phenylethyl]aminolcarbonyl)-1,6-dihydro-5 pyrimidinecarboxylate: Colorless oil; Rf= 0.22 (4:1 pet ether:ether); wt.= 3.2 g (51.2% yield); [aID = -146.89 10 (c = 0.38, CHC1 3 ); 'H NMR (CDC1 3 ) 6 1.22 (t, J=7.2 Hz, 3H), 1.49 (d, J=6.6 Hz, 3H), 2.88 (q, J=6.0 Hz, 2H), 3.94 (s, 3H), 5.03 (m, 1H), 5.11 (ABq, 2H), 6.68 (s, 1H), 6.91-7.34 (m, 13H). 15 (+)-BENZYL 6-(3,4-DIFLUOROPHENYL)-4-ETHYL-2-METHOXY-1,6 DIHYDRO-5-PYRIMIDINECARBOXYLATE. Into a stirred solution of (+)-benzyl 6-(3, 4 -difluorophenyl)-4-ethyl-2-methoxy 1-({[(lR)-1-phenylethyl]amino}carbonyl)-1,6-dihydro-5 pyrimidinecarboxylate (17.1 mmol, 9.35 g) in CH 2 C1 2 was 20 added 1,8-diazabicyclo[5,4,0J-undec-7-ene (17.1 mmol, 2.56 mL) and stirring was continued for 16 h at room temperature. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel with 3:1 EtOAc/Hexanes as the eluting system. 5.27 g 25 of the (+)-benzyl 6-( 3
,
4 -difluorophenyl)-4-ethyl-2 methoxy-1,6-dihydro-5-pyrimidinecarboxylate was obtained (77% yield). (+)-5-BENZYL 1-(4-NITROPHENYL) 6-(3,4-DIFLUOROPHENYL)-4 30 ETHYL-2-METHOXY-1,5 (6H) -PYRIMIDINEDICARBOXYLATE Into a well-stirred solution of (+)-benzyl 6-(3,4 difluorophenyl)- 4 -ethyl-2-methoxy-1,6-dihydro-5- WO 02/06245 PCT/US01/21286 137 pyrimidinecarboxylate (6.4 g, 16.0 mmol) and pyridine (1.5 mL) in CH2C12 (150 mL) was added 4-nitrophenyl chloroformate (3.41 g, 19.2 mmol) at room temperature. The reaction mixture was stirred for 4 h and then it was 5 washed with 10% aqueous KOH solution (2 X 100 mL). The organic layer was separated and dried over Na 2
SO
4 . The solvent was removed in vacuo. The residue of (+)-5 benzyl 1-( 4 -nitrophenyl) 6-( 3
,
4 -difluorophenyl)-4-ethvl 2-methoxy-1,5(6H)-pyrimidinedicarboxylate was used in 10 the next step without further purification. a. 2-(4-METHOXYBENZYL)-2-THIOPSEUDOUREA HYDROCHLORIDE. Into a well-stirred suspension of thiourea (7.6 g, 0.1 mol) in THF (50 mL) at 0 0C, 4-methoxybenzyl chloride (16 -15 g, 0.1 mol) was added in 10 min and the reaction mixture was allowed to warm to room temperature. After 2 hours the reaction mixture was heated to 65 0C and kept at that temperature for 5 hours. The reaction mixture was cooled to room temperature and diluted with diethyl 20 ether (200 mL). The white precipitate that formed was filtered and dried (22.5 g, 96% yield); m. p. 161-163 C. b. METHYL 2-{(4-NITROPHENYL)METHYLENE}-3-OXOBUTYRATE. A mixture of 4 -nitrobenzaldehyde (15.1 g, 0.1 mol), 25 methyl acetoacetate (12.773 g, 0.11 mol), piperidine (0.41 g, 4.80 mmol), and acetic acid (0.288 g, 4.8 mmol) in 2-propanol (400 mL) was stirred at room temperature for 48 hours. The resulting white solid, methyl 2-{(4 nitrophenyl)methylene}-3-oxobutyrate was filtered, 30 washed with 2 -propanol (2 X 50 mL) and dried (21.8 g, - 93% yield).
WO 02/06245 PCT/USO1/21286 138 C. 1, 6-DIHYDRO-5-METHOXYCARBONYL-2- [{(4-METHOXYPHENYL) METHY L}THIO] -4-METHYL-6- (4-NITROPHENYL) PYRIMIDINE. A mixture of methyl 2-{( 4 -nitrophenyl)methylene}-3 5 oxobutyrate (8.96 g, 0.04 mol), 2-(4-methoxybenzyl)-2 thiopseudourea hydrochloride (9.28 g, 0.04 mol), and NaOAc (3.28 g, 0.04 mol) in DMF (100 mL) was stirred and heated at 70-75 0 C for 4.5 hours. The reaction mixture was cooled to room temperature, poured into ice-water 10 (300 mL) and extracted with EtOAc (2 X 400 mL). The combined EtOAc extracts were washed with 10% NaHCO 3 solution (2 X 60 mL), brine (100 mL), and then dried (MgSO 4 ). The solvent was evaporated and the crude product was purified by flash column chromatography on 15 silica gel using 10% through 30% EtOAc in hexane as the gradient eluent. The desired product was obtained as an oil, which on trituration-with EtOAc/hexane became a yellow solid (11.4 g, 66.7% yield) which was shown by 1 H NMR to be a mixture of tautomers: m.p. 138-139 0 C; 1 H NMR 20 (CDCl 3 ) 8 2.15 (s, 3 H), 3.62 (s, 3 H), 3.72 (s, 3 H), 4.05 and 5.78 (s and d, J=3 Hz, 1 H), 4.08, 4.20 (AB q, J=12.5 Hz, 2 H), 4.21 and 6.40 (s and d, J=3 Hz, 1 H), 6.66 (2 d, J=8.5 Hz, 2 H), 7.08 (2 d, J=8.5 Hz, 2 H), 7.37 (2 d, J=8.8 Hz, 2 H), 8.7 (2 d, J=8.8 Hz, 2 H); 25 Anal. Calcd. for C 2 1
H
21
N
3 0 5 S: C, 59.00; H, 4.95; N, 9.83. Found: C, 59.02; H, 4.93; N, 9.77. d. 1,6-DIHYDRO-5-METHOXYCARBONYL-2-[{(4-METHOXYPHENYL) METHYL}THIO]-4-METHYL-6-(4-NITROPHENYL)-1-[(4-NITROPHENY 30 LOXY)CARBONYL]PYRIMIDINE.. Into a well-stirred mixture of 1,6-dihydro-5-methoxy carbonyl-2-[{( 4 -methoxyphenyl)methyl}thioJ-4-methyl-6-(4 -nitrophenyl)pyrimidine (4.50 g, 10.5 mmol), NaHCO 3 (3.69 WO 02/06245 PCT/USO1/21286 139 g, 0.044 mol), CH 2 C1 2 (200 mL), and water (50 mL) at 0-5 'C, 4-nitrophenyl chloroformate (2.40 g, 12.0 mmol) was added over a 5 min period and the reaction mixture was allowed to warm to room temperature. After 10 hours, 5 the TLC analysis of the reaction mixture showed the presence of a small amount of starting pyrimidine, therefore, more 4-nitrophenyl chloroformate (0.65 g, ,0.0032 mol) was added and the stirring was continued for an additional 4 hours. The two layers were separated, 10 the CH 2 C1 2 layer was washed with saturated aqueous NaHCO 3 solution (3 X 50 mL), dried (MgSO 4 ), and the solvent evaporated. The residue was recrystallized from CH 2 Cl> and hexane to give the product as white crystals (5.50 g, 88.4% yield): m.p. 156-157 0 C; 1H-NMR (CDCl 3 ) 8 2.53 15 (s, 3 H), 3.70 (s, 3 H), 3.81 (s, 3 H), 4.06, 4.36 (ABq, J=13.5 Hz, 2 H), 6.30 (s, 1 H), 6.78 (d, J=8.6 Hz, 2 H), 7.17 (d, J=8.6 Hz, 2 H), 7.20 (d, J=8.8 Hz, 2 H), 7.32 (d, J=8.8 Hz, 2 H), 7.97 (d, J=8.8 Hz, 2 H), 8.25 (d, J=8.8 Hz, 2 H); Anal. Calcd. for C 28
H
24
N
4 0 9 S: C, 56.75; H, 20 4.08; N, 9.45. Found: C, 56.49; H, 4.28; N, 9.25. a. 6- (BENZOFURAZAN-5-YL) -1, 6-DIHYDRO-2-OXO-5 METHOXYCARBONYL-4-BROMOMETHYL-1- [(4-NITROPHENYL OXY)CARBONYL]PYRIMIDINE. 25 Into a well-stirred solution of 6-(benzofurazan-5-yl) 1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1-[(4 nitrophenyl-oxy)carbonylJpyrimidine (0.310 mmol, 0.140 g) in 1.5 mL of chloroform was added a solution of bromine (0.310 mmol, 0.020 mL) in 1.5 mL of chloroform 30 at 0 OC and the solution was allowed to attain room temperature over 1.5 h. The solvent was removed in vacuo and the residue was again dissolved in CHCl 3 (10 mL) and washed with brine. The organic layer was WO 02/06245 PCT/USO1/21286 140 separated, dried over Na 2
SO
4 , filtered and the solvent was removed in vacuo to obtain 0.15 g (88% yield) of 6 (benzofurazan-5-yl)-1,6-dihydro-2-oxo-5-methoxycarbonyl 4-bromomethyl-1-[(4-nitrophenyl-oxy)carbonylipyrimidine 5 as a yellow foam. The crude product was used in the next step without purification. 1H NMR (CDCl 3 ) 8 3.79 (s, 3 H), 4.72 (ABq, 2 H), 6.47 (s, 1 H), 7.37 (d, J=9.1 Hz, 2 H), 7.51 (d, J=7.8 Hz, 1 H), 7.80 (s, 1 H), 7.92 (d, J=9.1 Hz, 1 H), 8.30 (d, J=9.1 Hz, 2 H). 10 c. 4-NITROPHENYL 4-(2,1,3-BENZOXADIAZOL-5-YL)-2,5-DIOXO 1,2,5,7-TETRAHYDROFURO[3,4-D]PYRIMIDINE-3(4H) CARBOXYLATE. 6-(3,4-Benzofurazan-5-yl)-1,6-dihydro-2-oxo-5-methoxy 15 carbonyl-4-bromomethyl'-l-[(4 nitrophenyloxy)carbonyllpyrimidine (0.27 mmol, 0.15 g) was heated in oil bath for 3 h (bath temperature 130 OC. The brownish-yellow residue thus obtained was washed with CHCl 3 and 4-nitrophenyl 4-(2,1,3-benzoxadiazol-5 20 yl)- 2 ,5-dioxo-1, 2 ,5, 7 -tetrahydrofuro[3,4-d]pyrimidine 3(4H)-carboxylate was obtained as an off-white solid which was used in the next step without further purification (crude wt. 0.11 g, 93% yield): 1 H NMR (DMSO d 6 ) 8 8.38-7.56 (m, 7H), 6~.33 (s, 1H), 5.02 (s, 2H); 25 Anal. Calc. for C19HiiN 5
O
8 +2.3H20: C, 47.85; H, 3.28; N, 14.63. Found: C, 47.73; H, 2.51; N, 14.77. 5-METHYL 1-(4-NITROPHENYL) 4-(BROMOMETHYL)-6-(3,4 30 DIFLUOROPHENYL)-2-OXO-3,6-DIHYDRO-1,5(2H) PYRIMIDINEDICARBOXYLATE: Into a well-stirred solution of 6-(3,4-Difluorophenyl)-1,6-dihydro-2-methoxy-5 methoxycarbonyl-4-methyl-1-[(4- WO 02/06245 PCT/USO1/21286 141 nitrophenyloxy)carbonyllpyrimidine (1.5 mmol, 0.66 g) in 5 mL of chloroform was added a solution of bromine (1.5 mmol, 0.09 mL) in 3 mL of chloroform at 0 0C and the solution was allowed to attain room temperature over 1.5 5 h. The solvent was removed in vacuo and the residue was again dissolved in CHCl 3 (20 mL) and washed with brine. The organic layer was separated, dried over Na 2
SO
4 , 'filtered and the solvent was removed in vacuo to afford the desired product as a yellow foam, which was used in 10 the next step without purification. 1H NMR 5 3.75 (s, 3 H), 4.67 (ABq, 2 H), 6.35 (s, 1 H), 7.09-7.19 (m, 4 H), 7.37 (d, J=9.0 Hz, 2 H), 8.27 (d, J=9.0 Hz, 2 H). 4-NITROPHENYL 4-(3,4-DIFLUOROPHENYL)-2,5-DIOXO-1,2,5,7 15 TETRAHYDROFURO [3, 4-D] PYRIMIDINE-3 (4H) -CARBOXYLATE. 5-methyl 1-(4-nitrophenyl) 4-(bromomethyl)-6-(3,4 difluorophenyl)-2-oxo-3,6-dihydro-1,5(2H) pyrimidinedicarboxylate (1.5 mmol, 0.81 g) was heated in an oil bath for 3 h (bath temperature 130 0C). The brown 20 residue thus obtained was washed with CHCl 3 and the desired product was obtained as a pale brown solid which was used in the next step without further purification (crude wt. 0.51 g): 1H NMR (DMSO-d,) 8 4.94 (br s, 2 H), 6.08 (s, 1 H), 7.20-7.43 (m, 4 H), 8.35 (d, J=10.2 Hz, 2 25 H). 4-NITROPHENYL 4-(1,3-BENZODIOXOL-5-YL)-2,5 DIOXOHEXAHYDROFURO[3, 4-D] PYRIMIDINE-3 (4H) -CARBOXYLATE: H NMR (DMSO) 5 11.35 (s, 1H), 8.16 (d, 2H, J=9.5 Hz), 7.32 30 -(d,_2H, J=8.9_ Hz), 6.81-6.65 (m, 3H), 5.88 (s,. 1H)-,-4-8-5 (ABq, 2H); ESMS m/e : 440.1 (M + H)+; Anal. Calc. for
C
2 oHi 5
N
3 0 9 +1.5H 2 0: C, 51.29; H, 3.87; N, 8.97. Found: C, 51.38; H, 2.85; N, 8.73.
WO 02/06245 PCT/USO1/21286 142 5-METHYL 1- (4-NITROPHENYL) (6S) -6- (3,4-DIFLUOROPHENYL) 4-METHYL-2-OXO-3, 6-DIHYDRO-1, 5 (2H) PYRIMIDINEDICARBOXYLATE: 1H NMR (400 MHz, CDCl 3 ) 6 8.29 5 (d, 2H, J=9.1 Hz), 7.36 (d, 2H, J=8.9 Hz), 7.25-7.11 (m, 3H), 6.37 (s, 1H), 3.75 (s, 3H), 2.46 (s, 3H); ESMS m/e: 448.1 (M + H)+; Anal. Calc. for C 20 Hi 5
F
2
N
3 0 7 : C, 53.70; H, 3.38; N, 9.39. Found: C, 53.35; H, 3.36; N, 9.27.
WO 02/06245 PCT/USO1/21286 -143 BENZYL 4-{[(TERT-BUTOXYCARBONYL)AMINO]METHYLICYCLOHEXYLCARBAMATE : Oxalyl chloride (1.1 equivalents) was added dropwise to 5 a mixture of 4-[[(tert-butoxycarbonyl)-amino]methyl] cyclohexanecarboxylic acid (1 equivalent, Maybridge) in toluene. The reaction mixture was stirred at room temperature for 2-6 h. The solvent was removed in vacuo, the residue was dissolved in acetone and the resulting 10 mixture was added dropwise to an aqueous solution of sodium azide (1.2 equivalents) at a rate such as to maintain a temperature of 10-15 'C. After the completion of the reaction, the reaction mixture was extracted with ethyl acetate, the combined extracts were dried and 15 concentrated in vacuo. The residue was dissolved in acetone and added slowly to warm (60 'C) benzene. After the completion of the reaction, benzyl alcohol was added to the reaction mixture, stirred for 2 days and the desired product was isolated (For Typical References, 20 See: G. Schroeter Ber. 1909, 42, 3356; and Allen, C.F.H.; Bell, A. Org. Syn. Coll. Vol. 3 (1955) 846.). A solution of benzyl 4-{[(tert-butoxycarbonyl)amino] methyl}-cyclohexyl carbamate in MeOH containing 10% Pd/C 25 was hydrogenated at 50 psi overnight. The reaction mixture was filtered through Celite 545 and the Celite 545 was washed with methanol. The combined methanol extracts were concentrated.in vacuo, giving trans tert-butyl 4-aminocyclohexylmethylcarbamate (95 %). 30 9H-9-FLUORENYLMETHYL N-[4-(AMINOMETHYL)CYCLOHEXYL] CARBAMATE: : 'H NMR58.02 (br, 1 H), 7.33 (m, 5 H), 5.07 (s, 2 H), 3.71 (s, 1 H), 3.40 (br m, 1 H), 2.80 (br m, 2 H), 1.94 (ABq, 4 H), 1.68 (br, 1 H), 1.30-1.00 (m, 5 H). 35 WO 02/06245 PCT/USO1/21286 -144 Ni-[4-(AMINOMETHYL)CYCLOHEXYL]-1-NAPHTHAMIDE: HC1 in dioxane (10 mL, 4 N) was added to a solution of tert butyl[4-(1-naphthoyl-amino)cyclohexyl]methylcarbamate (0.350 g) in dichloromethane (20 mL), stirred overnight, 5 concentrated in vacuo, giving the desired product: 'H NMR 5 8.24 (dd, 1 H, J=1.2, 8.7 Hz), 7.85 (dt, 2 H, J=2.7, 9.7 Hz), 7.60-7.30 (m, 4 H), 5.98 (m, 1 H), 4.02 (m, 1 H), 3.80-3.40 (m, 4 H), 2.53 (d, 2 H, J=6.0 Hz), 2.02 (ABq, 4 H), 1.41-1.90 (m, 4 H). 10 TERT-BUTYL N-(4-[(1-NAPHTHYLCARBONYL)AMINO] CYCLOHEXYLMETHYL)-CARBAMATE: A mixture of 1-naphthoic acid (1.00 mmol, 0.172 g), DMAP (2.00 mmol, 0.250 g) and ECD (0.383 g, 2.00 mmol) in dry dichloromethane (20 mL) 15 was stirred at room temperature for 0.5 h followed by the addition of tert-butyl(4-amino)cyclohexyl)methyl carbamate amine (1.09 mmol, 0.250 g). The reaction mixture was stirred at room temperature overnight and purified by flash chromatography, giving the desired 20 product as a white solid (0.160 g): 'H NMRS8.29 (dd, 1 H, J=1.8, 9.1 Hz), 7.89 (m, 2 H), 7.60-7.40 (m, 4 H), 5.85 (br d, 1 H, J=6.3 Hz), 4.65 (m, 1 H), 4.04 (m, 1 H), 3.02 (t, 1 H, J=6.3 Hz), 2.05 (ABq, 4 H), 1.62 (m, 2 H), 1.46 (s, 9 H), 1.40-1.10 (m, 4 H). 25 4-ACETYL-1-(3-AMINOPROPYL)-4-PHENYLPIPERIDINE: A solution of 4-Acetyl-4-phenylpiperidine (7, 1.53 g, 7.50 mmol), 3-bromo-propylamine hydrobromide (1.64 g, 7.50 mmol) and potassium carbonate (1.24 g, 9.00 mmol) was stirred in 30 refluxing 1,4-dioxane (50 mL) for 12 h. After removal of dioxane, water (50 mL) was added and the pH was adjusted to 11-12 by addition of 1 N aqueous NaOH. The mixture was extracted with CH 2 Cl 2 (100 mL + 3 x 50 mL) . The combined organic solutions were dried over magnesium WO 02/06245 PCT/USO1/21286 -145 sulfate and concentrated. The residue was purified by flash chromatography (EtOAc-MeOH-Et3N 100/40/20), giving the desired product as a colorless oil (780 mg, 40%): IH NMR61.56 (p, J = 7 Hz, 2 H), 1.84 (s, 3 H), 1.98 (m, 2 5 H), 2.15 (br t, J = 12 Hz, 2 H), 2.29 (t, J = 7 Hz, 2 H), 2.41 (br d, J = 12 Hz, 2 H), 2.66 (t, J = 7 Hz, 4 H), 7.18 - 7.30 (m, 5 H); "C NMRS 26.28, 31.11, 33.43, 41.47, 51.62, 55.31, 57.19, 77.32, 77.74, 78.17, 126.95, 127.69, 129.44, 142.25, 210.15. 10 For the preparation of benzo-4',5'[H]furanpiperidine refer to W.E.Parham et al, J. Org. Chem. (1976) 41, 2268. TERT-BUTOXY{[3-(BENZO-4',5'[H]FURANPIPERIDIN-1-YL)PROPYL] 15 AMINO}METHANOL: To a stirred solution of the N-[4-(benzo 4',5'[H]furanpiperidine (0.566 g, 3.27 mmol) in dioxane (20 mL), N-(tert-butoxycarbonyl)-3-bromopropylamine (0.772 g, 3.27 mmol) and potassium carbonate (0.904 g, 6.54 mmol) were added and the solution was refluxed for 20 24 h. The reaction mixture was cooled to room temperature, concentrated and partitioned between chloroform (40 mL) and water (5 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography 25 (ethyl acetate/ methanol, 4.5/0.5), giving the desired product as a colorless oil (0.856 g, 79 %); 1H NMR (1.45 (s, 9 H), 1.63-2.04 (m, 6 H), 2.33-2.52 (m, 4 H), 2.87 (d, J=11.0 Hz, 2 H), 3.2 (br s, 2 H), 5.07 (s, 2 H), 5.6 (br s, 1 H), 7.13-7.28 (m, 4 H). 30 3-(4-METHYL-4-PHENYL-1-PIPERDINYL)PROPYLAMINE: Trifluoroacetic acid (1 mL) was added to tert-butoxy{[3 (4-methyl-4-phenyl-1-piperdinyl)propyl]-amino}methanol (0.500 g, 1.51 mmol) in dichloromethane (5 mL) and the WO 02/06245 PCT/USO1/21286 -146 solution was stirred at room temperature for 1 h. The solution was concentrated, neutralized with 10 % KOH solution and extracted with dichloromethane (25 mL). The organic layer was dried over sodium sulfate, filtered and 5 concentrated, giving 0.340 g (98%) of 3-(4-methyl-4 phenyl-l-piperdinyl)propylamine which was used without further purification in the subsequent step. Procedures for the Reaction of the Amine Side Chains with 10 the p-Nitrophenylcarbamate Intermediates: General Procedure: An equimolar solution of an amine side chain such as 3 (4-methyl-4-phenyl-l-piperdinyl)propylamine and a 15 p-nitrophenylcarbamate intermediate such as 5-methoxycarbonyl-4-methoxymethyl- 1,2,3,6 tetrahydro-2-oxo-6-(3,4-difluorophenyl)-1-[(4-nitrophen yloxy)carbonyl]pyrimidine and 1-2 equivalents of a base such as diisopropylethylamine in dichioromethane were 20 stirred at room temperature overnight. The reaction mixture was concentrated and purified by flash chromatography, giving the desired product. In case of 2-methoxy intermediates, conversion to the oxo derivatives was accomplished by treatment of the 25 2-methoxy product with HCl.in dioxane. 2-OXO-3-{SPIRO[lH-INDANE-1,4'-PIPERIDINE]PROPYLAMINE(0.03 19 g, 0.123 mmol) was added to (±)-6-(3,4 -difluorophenyl)-1,6-dihydro- 2-methoxy-5 30 methoxycarbonyl-4-ethyl-l-(4-nitrophenoxy)carbonyl pyrimidine (0.052 g, 0.112 mmol) in dry dichloromethane (10 mL) and the solution was stirred at room temperature for 24 h. The reaction mixture was stirred for another 1 h after addition of 6 N HCl (2 mL). After neutralization 35 with aqueous 10% KOH solution, the reaction mixture was WO 02/06245 PCT/USO1/21286 -147 extracted into dichloromethane (3 x 10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography (EtOAc/ MeOH, 4.5/0.5), giving of the 5 desired product (0.040 g) as a syrup. 1 N HCl in ether (5 mL) was added to the free base (0.040 g, 0.072 mmol) in dichloromethane (4 mL) and the solution was concentrated under reduced pressure. The crude 10 product was recrystallized from ether, giving the desired compound (0.042 g, 99 %) as a pale yellow solid; mp 178-182 0C; Anal. Calcd. for C 2 9
H
34
F
2
N
4 0 5 Cl + 0.6 H 2 0: C, 57.87; H,5.73, N 9.31. Found: C, 58.11; H 5.90; N 8.95. 15 General Procedure for the reaction of the piperidines and piperazines with 1-(3-bromo-propylcarbamoyl)-6-(3,4 difluoro-phenyl)-4-methyl-2-oxo-1,6-dihydro-pyrimidine 5-carboxylic acid methyl ester: 20 The amine (0.15 mmol) was added to a solution of 1-(3-bromo- propylcarbamoyl)-6-(3,4-difluorophenyl)-4 methyl-2-oxo-1,6-di-hydropyrimidine-5-carboxylic acid methyl ester (43.0 mg, 0.100 mmol) in anhydrous acetone (10 mL), followed by NaHCO 3 (41 mg, 0.3 mmol) and KI (16 25 mg, 0.1 mmol). The resulting suspension was heated to reflux for 10 h and then cooled to room temperature. The solvent was removed in vacuo and the residue was purified by flash column chromatography (EtOAc, followed by EtOAc/MeOH, 9/1). The product was then dissolved in 2 mL 30 of chloroform, acetone or EtOAc and HCl in Et 2 0 (1 M, 0.5 mL) was added at room temperature. The solvent was removed in vacuo, giving the desired compound as an HCl salt. 35 WO 02/06245 PCT/USO1/21286 -148 Example 1 (-)-1,2,3,6-TETRAHYDRO-1-{N-[4-(3,-ACETAMIDO)-PHENYL PIPERIDIN-1- YL]PROPYL}CARBOXAMIDO-4-METHOXYMETHYL-6 (3,4- DIFLUORO-PHENYL)-2- OXOPYRIMIDINE-5-CARBOXYLIC ACID 5 METHYL ESTER: ESMS, 612.25 (M+1); 1H NMR81.76-1.87 (m, 6H), 2.03-2.13 (m, 2H), 2.18 (s, 3H), 2.49 (t, J=6.9 Hz, 3H), 3.10 (d, J=11.1 Hz, 2H), 3.30-3.42 (m, 2H), 3.45 (s, 3H), 3.71 (s, 3H), 4.68 (s, 2H), 6.68 (s, 1H), 6.96 (d, J=7.5 Hz, 1H), 7.04-7.11 (m, 2H), 7.16-7.26 (m, 2H), 7.34 10 (d, J=6.3 Hz, 1H), 7.45 (s, 1H), 7.94 (s, 1H), 8.98 (t, J=5.4 Hz, 1H). Example 2 15 METHYL 3-[(3-4-[3-(ACETYLAMINO)PHENYL]-1,2,3,6 TETRAHYDRO-1-PYR-IDINYLPROPYL)AMINO]CARBONYL-4-(3,4 DIFLUOROPHENYL)-6-(METHOXY-METHYL)-2-OXO-1,2,3,4 TETRAHYDRO-5-PYRIMIDINECARBOXYLATE: 1H NMRS8.90 (t, 1 H, J=3.6 Hz), 7.75 (s, 1 H), 7.50-7.00 (m, 8 H), 6.68 (s, 1 20 H), 6.03 (br s, 1 H), 4.67 (s, 2 H), 3.71 (s, 3 H), 3.47 (s, 3 H), 3.38 (ABm, 2 H), 3.16 (m, 2 H), 2.71 (t, 2 H, J =5.4 Hz), 2.56 (m, 4 H), 2.35-1.90 (br, 2 H), 2.17 (s, 3 H), 1.82 (p, 2 H, J=7.2 Hz); ESMS, 612.25 (M+1). 25 Example 3 (1)-1,2,3,6-TETRAHYDRO-1-{N-[3-(4-0-ACETYL)-4-PHENYLPIPER IDIN-1- YL]PROPYL}CARBOXAMIDO-5-METHOXYCARBONYL 4-METHOXYMETHYL-6-(3,4- DIFLUOROPHENYL)-2-OXOPYRIMIDINE: 4-Acetyl-1-(3-aminopropyl)- 4-phenylpiperidine (190 mg, 30 0.687 mmol) was added to a stirring solution of 5-methoxy carbonyl-4-methoxymethyl- 1,2,3,6-tetra-hydro-2-oxo 6-(3,4-difluorophenyl)-1-[-(4-nitrophenyloxy)carbon yl]pyrimidine (281 mg, 0.573 mmol) in dry dichloromethane (3 mL) and THF (4 mL). The reaction WO 02/06245 PCT/USO1/21286 -149 mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with aqueous 6 N HCl. The reaction mixture was concentrated to a small volume, partitioned between dichloromethane and water (100 mL 5 each), the mixture was adjusted to pH 8 by addition of NaCO 3 , the layers were separated, and the aqueous layer was extracted with dichloromethane (3 x 30 mL). The combined organic extracts were dried (Na 2
SO
4 ) and the product was chromatographed, giving the desired product. 10 The HCl salt was prepared by the addition of 1 N HCl in ether to a solution of the product in CH2C12- The precipitated salt was filtered, washed with ether and dried in vacuo, giving (1)-1,2,3,6-tetrahydro-1-{N [3-(4-0-acetyl)-4- phenylpiperidin-1-ylpropyl} 15 carboxamido-5-methoxycarbonyl-4- methoxymethyl-6 (3,4-difluorophenyl)-2-oxopyrimidine (170 mg, 47%) as the hydrochloride salt: (C 3 1
H
36
N
4 F.O + HCl + 0. 6 CH C1 2 ) ; mp 82-84 0 C. 20 Example 4 Benzyl ester precursor to the product of Example 4: (+)-1,2,3,6-TETRAHYDRO-1-{N-[4-(BENZO-4',5'(H)FURAN)PIPER IDIN-1- YL]PROPYL}-CARBOXAMIDO-4-ETHYL-6- (3,4 DIFLUOROPHENYL)-2-OXO- PYRIMIDINE-5- CARBOXYLIC ACID 25 PHENYLMETHYL ESTER: 'H NMRS7.60-7.00 (m, 12 H), 6.85 (br, 1 H), 6.62 (s, 1 H), 5.10 (ABq, 2 H), 5.67 (s, 2 H), 4.03 (br, 1 H), 4.01 (s, 3 H), 3.40 (apparent q, 2 H, J=6.8 Hz), 3.20-1.60 (m, 12 H), 2.86 (q, 2 H, J=2.5 Hz), 1.19 (t, 3 H, J=7.5 Hz). 30 (+)-1,2,3,6-TETRAHYDRO-1-{N-[4-(BENZO-4',5' (H)FURAN)PIPER IDIN-1-YLIPROPYL}-CARBOXAMIDO-4-ETHYL-6-(3,4 DIFLUOROPHENYL)-2-OXO- PYRIMIDINE-5 CARBOXYLIC ACID HYDROCHLORIDE: 'H NMR 8 8. 95 (br s, 1 H) , 8.22 (br s, 1 H), WO 02/06245 PCT/USO1/21286 -150 7.40-6.95 (m, 7 H), 6.95 (s, 1 H), 6.63 (s, 1 H), 5.10-4.95 (m, 2 H), 3.40-3.20 (m, 4 H), 3.10-2.80 (m, 4 H), 2.55-2.20 (m, 1 H), 2.15 (m, 1 H), 1.85 (m, 2 H), 1.55-1.30 (m, 4 H), 1.20 (t, 3 H, J=7.6 Hz); Anal. Calc. 5 For C 9 9
H
32
N
4 0 5
F
2 + HCl + 1.5 H, 0 : C, 56.36; H, 5.87; N, 8.06. Found: C, 56.72; H, 6.11; N, 7.61. Example 5 1,2,3,4-TETRAHYDRO-1-OXO-2-NAPHTHACETIC ACID METHYL 10 ESTER: Under argon, c-tetralone (5.00 g, 34.2 mmol) in dry THF (300 mL) was treated with LDA in THF (2 M, 18.8 mL) at -78 0 C. The solution was stirred at -78 'C for 1 h. Methyl bromoacetate (15.7 g, 0.103 mole) was then added to the solution, the mixture was stirred overnight 15 and allowed to warm to room temperature. The solvent was evaporated and the residue was dissolved into CHCl 3 (300 mL), washed with water and saturated brine, and then dried over Na 2
SO
4 . After filtration and removal of solvent, the residue was vacuum distilled. The product, 20 a colorless oil (7.21 g, 96.5%) was collected at 180 'C/1 mm Hg; 'H NMR (400 Mhz) 61.98 (m, 1H), 2.25 (m, 1H), 2.44 (m, 1H), 2.90-3.20 (m, 4H), 3.73 (s, 3H), 7.10-8.10 (m, 4H); EI mass spectrum M+ at m/z 218. 25 1-HYDROXY-2-(2-HYDROXYETHYL)-1,2,3,4-TETRAHYDRONAPHTHALEN E: A solution of 1,2,3,4-tetrahydro-l-oxo-naphthacetic acid methyl ester (6.15 g, 28.2 mmol) in THF (150 mL) was treated with LiAlH 4 (2.82 g, 70.5 mmol) and then the reaction mixture was heated at reflux temperature for 5 30 h. The suspension was cooled to 0 IC and quenched by addition of solid Na 9 SO10 H2O.. The mixture was stirred at room temperature for 4 hrs. The solid was removed by filtration and concentration of the filtrate in vacuo gave a yellow oil (5.33 g, 98.3%); 'H NMR indicated the WO 02/06245 PCT/USO1/21286 -151 formation of an isomeric mixture. EI mass spectrum M+ at m/z 192. The mixture was directly used in next reaction without further purification. 5 2-(2-HYDROXYETHYL)-1,2,3,4-TETRAHYDRO-1-OXO-NAPHTHALENE: A solution of isomeric mixture of 1-hydroxyl-2 (2-hydroxyethyl)- 1,2,3,4-tetrahydronaphthalene (3.00 g, 15.6 mmol) in CH 2 Cl 2 (100 mL) was treated with MnO 2 (20.4 g, 0.234 mole). The suspension was stirred at room 10 temperature for 16 h and the solids were removed by filtration. Concentration of the filtrate in vacuo gave a brown oil, which was further purified by flash chromatography (MeOH/ CHC1 3 , 5/95), giving a yellow oil (2.00 g, 67.4%): 'H NMRb1.76 (m, 1H), 1.98 (m, 1H), 2.21 15 (m, 2H), 2.57 (br, 1H), 2.70 (m, 2H), 3.20 (m, 2H), 3.81 (m, 2H), 7.00-8.20 (m, 4H); CI mass spectrum (M+1)+ at m/z 191. 2-(2-BROMOETHYL)-1,2,3,4-TETRAHYDRO-1-OXONAPHTHALENE: A 20 solution of 2-(2-hydroxethyl)-1,2,3,4-tetrahydro 1-oxo-naphthalene (2.00 g, 10.5 mmol) in CH 2 C1 2 (100 mL) was treated with PBr 3 (948 mg, 3.50 mmol) at 0 'C. The mixture was stirred at room temperature for 72 h and then poured onto 100 g of ice. The organic layer was 25 separated, washed with aqueous 10% KCO 3 solution, H 0 0, saturated NaCl and dried over Na 2
SO
4 . After filtration and removal of the solvent, the residue was purified by chromatography (EtOAc/hexane, 1/10), giving a yellow oil (1.18 g, 44.4%); 'H NMR51..49 (m, 2 H), 2.24 (m, 1H), 30 2.60 (m, 1H), 2.75 (n, 1H), 3.03 (n, 2H), 3.64 (m, 2H), 7.10-8.10 (m, 4H); EIMS M+ m/z 223, M/M+2=1:1. 2-[2-(4-BENZAMINO-1-PIPERIDYL)ETHYL]-1,2,3,4-TETRAHYDRO-1 -OXO- NAPHTHALENE: A mixture of 2-(2-bromoethyl)- WO 02/06245 PCT/US01/21286 -152 1,2,3,4-tetrahydro-l-oxonaphthalene (1.18 g, 4.66 mmol), 4-benzamidopiperidine (952 mg, 4.66 mmol) and K 2
CO
3 (1.29 g, 9.32 mmol) in acetone (200 mL) was stirred at room temperature for 48 h. The solids were removed by 5 filtration. Concentration.of filtrate in vacuo gave a yellow solid which was purified by chromatography (MeOH: CHC1 3 , 5/95). The product was recrystallized from an EtOAc/hexane mixture, giving a white powder (268 mg, 15.3%); mp 158-159 "C; 'H NMRS1.53 (m, 2H), 1.67 (m, 1H), 10 1.91 (m, 1H), 2.02 (m, 2H), 2.21 (m, 4H), 2.50 (m, 3H), 2.95 (m, 4H), 4.01 (m, 1H), 5.95 (d, J=8.0 Hz, 1H), 7.20-8.10 (m, 9H); CI MS (M+1) +m/z 377; Anal. Calcd for C2 4 H 8
NO
0 : C, 76.55; H. 7.51; N, 7.44. Found: C, 76.28; H, 7.46; N, 7.37. 15 Example 6 METHYL 4-(2,1,3-BENZOXADIAZOL-5-YL)-3-[(1-[4-(DIBUTYLAMINO) BENZYL]-4-PIPERIDYLMETHYL)AMINO]CARBONYL-6-METHYL-2-OXO-1 20 ,2,3,4- TETRAHYDRO-5-PYRIMIDINECARBOXYLATE: 'H NMR 6 7.72 (dd, 1 H, J=0.6, 9.6 Hz), 7.70-7.50 (m, 2 H), 7.11 (d, 2 H, J=8.7 Hz), 6.59 (d, 2 H, J=8.7 Hz), 5.90 (s, 1 H), 3.94 (s, 3 H), 3.63 (s, 2h), 3.24 (t, 4 H, J=7.8 Hz), 2.80 (m, 2 H), 2.49 (d, 2 H, J=6.3 Hz), 2.38 (s, 3 H), 25 2.90-1.00 (m, 5 H), 1.54 (p, 4 H, J= 7.8 Hz), 1.35 (sextet, 4 H, J=7.8 Hz), 0.94 (t, 6 H, J=7.8 Hz). Example 7 (+)-1,2,3,6-TETRAHYDRO-1-{N-[4-(N'-ETHYL)-N-BENZIMIDAZOLY 30 L- PIPERIDIN-1YL]PROPYL}CARBOXAMIDO-4-METHYL-6-(3,4 DIFLUOROPHENYL)- 2-OXOPYRIMIDINE HYDROCHLORIDE: 'H NMR6 8.95 (t, 1 H, J=3.6 Hz), 7.61 (b, 1 H), 7.60-6.95 (m, 7 H), 6.69 (s, 1 H), 4.36 (m, 1 H), 3.94 (q, 2 H, J=7.2 Hz), 3.72 (s, 3 H), 3.42 (ABm, 4 H), 3.30 (m , 2 H, 4.76 WO 02/06245 PCT/USO1/21286 -153 (m, 4 H), 2.43 (s, 3 H), 2.13 (m, 2 H), 1.77 (m, 4 H), 1.33 (t, 3 H, J=7.2 Hz). Example 8 5 6-(BENZOFURAZAN-5-YL)-1,2,3,6-TETRAHYDRO-5-METHOXYCARBONY L-4- METHYL-2-OXO-1-{N-[3-(4-PHENYLPIPERIDIN-1-YL)PROPYLI }CARBOXAMIDO-PYRIMIDINE: A solution of 6-(benzofurazan 5-yl)-1,6-dihydro-2- methoxy-5-methoxycarbonyl 4-methyl-1-{N-[3-(4-phenylpiperidin-1- yl)propyl]} 10 carboxamidopyrimidine in MeOH was treated with 6 N HCl at 0 1C. The solution was stirred at room temperature for 2 h and the MeOH was removed in vacuo. 6-(Benzofurazan-5-yl)- 1,2,3,6-tetrahydro 5-methoxycarbonyl-4-methyl-2-oxo-1-{N-[3-(4 15 phenylpiperidin-1-yl)propyll}carboxamidopyrimidine hydrochloride was obtained as a white powder: mp 134-137 Oc . Example 9 20 4-(3-METHOXY)-PHENYL PIPERIDINE: HCl salt; mp 150-154 0C; 'H NMR82.04 (s, br, 2H), 2.25 (s, br, 2H), 2.80 (s, br, 1H), 3.09 (s, br, 2H), 3.66 (s, 2H), 3.78 (s, 3H), 6.79 (s, br, 3H), 7.23 (s, 1H), 9.41 (s, br, 1H). Anal. Calcd. For C 12 H,NOC1 + 0.30 CHQCl : C, 58.34; H, 7.40; N, 25 5.53. Found: C, 58.30; H, 7.71; N, 5.35. (+)-1,2,3,6-TETRAHYDRO-1-N-[4-(3-METHOXY)-PHENYL}-PIPERID IN-1- YL]-PROPYL-CARBOXAMIDO-4- METHOXYMETHYL-6- (3,4 DIFLUOROPHENYL)- 2-OXOPYRIMIDINE-5-CARBOXYLIC ACID METHYL 30 ESTER: mp 80-84 0C; [a], = +94.7, (c = 0.25, MeOH); 1H NMR 51.74-1.84 (m, 6H), 1.99-2.09 (m, 2H), 2.38-2.51 (m, 3H), 3.03 (d, J=11.1 Hz, 2H), 3.24-3.43 (m, 2H), 3.48 (s, 3H), 3.71 (s, 3H), 3.80 (s, 3H), 4.72 (s, 2H), 6.68 (s, 1H), 6.72-6.84 (m, 3H), 7.05-7.11 (m, 2H), 7.15-7.27 (m, WO 02/06245 PCT/USO1/21286 -154 2H) , 7.72 (s, 1H), 8.84 (t, J=5.4 Hz, 1H). Anal. Calcd. For C 30
H
37
N
4 0 6 FCl: C, 57.8; H, 6.0; N, 9.0. Found: C, 57.61; H, 6.57; N, 6.97. 5 Example 10 (+)-1,2,3,6-TETRAHYDRO-1-{N-[4-(3,-ACETAMIDO)-PHENYL-PIPE RIDIN-1-YL]PROPYL}CARBOXAMIDO-4-METHOXYMETHYL-6-(3,4-DIFL UORO-PHENYL)-2- OXOPYRIMIDINE-5-CARBOXYLIC ACID METHYL ESTER: mp 135-138 0 C; [a] I, = +105.5, (c = 0.11, MeOH); 10 ESMS, 614.25 (M+1); 1 H NMR61.76-1.87 (m, 6H), 2.03-2.13 (m, 2H), 2.18 (s, 3H), 2.49 (t, J=6.9 Hz, 3H), 3.10 (d, J=11.1 Hz, 2H), 3.30-3.42 .(m, 2H), 3.46 (s, 3H), 3.71 (s, 3H), 4.68 (s, 2H), 6.68 (s, 1H), 6.96 (d, J=7.5 Hz, 1H), 7.04-7.11 (m, 2H), 7.16-7.26 (m, 2H), 7.34 (d, J=6.3 Hz, 15 1H), 7.45 (s, 1H), 7.94 (s, 1H), 8.97 (t, J=5.4 Hz, 1H); ESMS, M+1 614.25 The compound of Example 10 may also be prepared via hydrogenation of the compoun of example 2 (H 2 balloon 20 method, methanol, Pd/C, overnight). A synthetic path analogous to the latter route (Scheme 11) was used in the preparation of the tritiated analog, which in turn, was used as a radioligand in the MCH pharmacological assays. 25 Example 11 3-(4-PHENYLPIPERIDIN-1-YL)PROPIONITRILE: Acrylonitrile (3.1 mL, 44 mmol, 2.5 eq) was added to a solution of 4-phenylpiperidine (3.00 g, 18.0 mmol) in EtOH (40 mL) and the mixture was stirred at room temperature for 1.5 30 h. The volatiles were removed, giving 3.80 g of the desired product (brown oil, 99%). 3-(4-PHENYLPIPERIDIN-1-YL)PROPYLAMINE: A solution of BH 3 in THF (1.0 M, 83.0 mL, 83.0 mmol, 3.5 eq) was added to a WO 02/06245 PCT/USO1/21286 -155 stirring solution of 3-(4-phenylpiperidin-1-yl) propionitrile (5.10 g, 24.0 mmol) in anhydrous THF (20 mL) under argon at room temperature. The mixture was heated at reflux temperature for 4.5 hours and then 5 cooled to room temperature. Aqueous 6 N HC1 (130 mL) was added and stirring was continued for 2 hours at 50-70 'C. The mixture was basified to pH 9 by addition of aqueous 6 N NaOH and extracted with EtOAc (100 mL) and CH 2 Cl- (3 x 100 mL). The combined organic extracts were dried over 10 magnesium sulfate and concentrated. The residue was dissolved in CH 2 C1 2 (20 mL) and treated with HCl in ether (1.0 M, 50 mL). The solvents were removed, ether (250 mL) was added, the mixture was filtered, and the filter cake was washed with ether. Water (60 mL) was added to 15 the resulting white solid, 1 N NaOH was added until pH 10-11 was reached, and then the aqueous phase was extracted with CH 2 Cl 2 (3 X 50 mL). The combined extracts were dried over magnesium sulfate and the solvents were evaporated, giving the desired product (4.50 g, 87%). 20 6-(3,4-DIFLOUROPHENYL)-1,2,3,6-TETRAHYDRO-5-METHOXYCARBON YL-4- METHYL-2-OXO-1-{N-[3-(4-PHENYLPIPERIDIN-1-YL) PROPYL]}CARBOXAMIDO-PYRIMIDINE: A solution of 6-(3,4 difluorophenyl)-1,6-dihydro- 2-methoxy-5-methoxy 25 carbonyl-4-methyl-1-{N-[3-(4-phenyl-piperidin- 1 -yl) propyl]}carboxamidopyrimidine (100 mg, 0.185 mmol, mp = 43-45 'C) in MeOH (5 mL) was treated with aqueous 6 N HCl (1.5 mL) at 0 0 C. The solution was stirred at room temperature for 2 hrs and MeOH was removed in vacuo. 30 6-(3,4-Diflourophenyl)- 1,2,3,6-tetrahydro 5-methoxycarbonyl-4-methyl-2-oxo-1-{N-[3-(4 phenylpiperidin-1-yl)propyll}carboxamidopyrimidine hydrochloride was obtained as a white powder (89 mg, 86%) . mp 133-136 'C. 35 WO 02/06245 PCT/USO1/21286 -156 Example 12 3-{(3,4,5-TRIFLUOROPHENYL)METHYLENE}-2,4-PENTANEDIONE: A stirring mixture of 3,4,5-trifluorobenzaldehyde (4.2 g, 26.2 mmol), 2,4-pentanedione (2.62 g, 26.2 mmol), 5 piperidine (0.430 g, 5 mmol) in benzene (150 mL) was heated at reflux temperature (equipped with a Dean-Stark trap) for 8 h. The benzene was evaporated, the yellow oily residue, 2-{(3,4,5-trifluorophenyl)-methylene}-2,4 pentanedione, was used in the next step without further 10 purification. 6-(3,4,5-TRIFLUOROPHENYL)-1,6-DIHYDRO-2-METHOXY-5-ACETYL 4- METHYLPYRIMIDINE: A stirring mixture of 2-{(3,4,5 trifluoro-phenyl)methylene}-2,4-pentanedione (26.2 mmol), 15 0-methylisourea hydrogen sulfate (3.22 g, 39.3 mmol), and NaHCO 3 (6.60 g, 78.6 mmol) in EtOH (400 mL) was heated at 95-100 0 C for 6 h. The mixture was filtered, the solid residue was washed with ethanol (100 mL). The solvent was evaporated from the combined filtrates and the crude 20 product was purified by flash column chromatography (EtOAc/hexane, 9/1 to 4/1), giving the desired product as an oil (2.80 g, 36%). 6-(3,4,5-TRIFLUOROPHENYL)-1,6-DIHYDRO-2-METHOXY-5-ACETYL 25 4- METHYL-1-[(4-NITROPHENYLOXY)CARBONYL]PYRIMIDINE: 4-Nitrophenyl chloroformate (1.886 g, 9.38 mmol) was added to a solution of 6-(3,4,5-trifluorophenyl) 1,6-dihydro-2-methoxy-5-acetyl-4- methylpyrimidine (2.80 g, 9.38 mmol) and pyridine (10 mL) in CH 2 C1 2 (200 mL) at 30 0-5 0C and then the mixture was allowed to warm to room temperature. After 12 h, the solvent was evaporated and the residue was purified by flash chromatography (CHCl 2 /EtOAc, 9/1 to 20/3), giving the desired product as a white powder (4.0 g, 92%). 35 WO 02/06245 PCT/US01/21286 -157 6-(3,4,5-TRIFLUOROPHENYL)-1,2,3,6-TETRAHYDRO-2-OXO-5-ACET YL-4- METHYL-1-[(4-NITROPHENYLOXY)CARBONYL]PYRIMIDINE: Aqueous 6 N aqueous HCl (4 mL) was added to a stirring solution of 6-(3,4,5-trifluorophenyl)-1,6-dihydro 5 2-methoxy-5-acetyl-4- methyl-1-[(4-nitrophenyloxy) carbonyllpyrimidine (4.0 g, 8.63 mmol) in THF (100 mL) at 0-5 'C, and the mixture was allowed to warm to room temperature. After 2 h, the solvent was evaporated and the product was dried under vacuum, giving the desired 10 product as a pure single component which was used in the next step without further purification (3.88 g, 100%). (+)- 1,2,3,6- TETRA HYDRO-1-{N-[4- (4-FLUOROPHENYL) PIPERIDINE- 1-YL)- PROPYL} CARBOXAMIDO- 5- ACETYL- 2 15 OXO-6-( 3,4 ,5-TRI FLUORO PHENYL)- 4- METHYL PYRIMIDINE HYDROCHLORIDE: 1H NMRS 7.20-6.86 (m, 6 H), 6.64 (s, 1 H), 5.56 (s, 1 H), 3.70-3.80 (m, 2 H), 3.43-3.35 (m, 2 H), 3.19-2.98 (m, 2 H), 2.40 (s, 3 H), 2.28 (s, 3 H), 2.50-1.60 (m, 8 H). 20 Example 13 N1-[4-([4-(DIBUTYLAMINO)BENZYL]AMINOMETHYL)CYCLOHEXYL]-1 NAPHTH-AMIDE: 'H NMRS8.26 (dd, 1 H, J=2.1, 7.2 Hz), 7.87 (m, 2 H), 7.51 (m, 2 H), 7.40 (apparent t, 1 H, J=7.8 25 Hz), 7.17 (d, 1 H, J=8.7 Hz), 6.61 (d, 2 H, J=8.7 Hz), 5.94 (d, 1 H, J=8,1 Hz), 4.04 (m, 1 H), 3.76 (m, 1 H), 3.63 (m, 2 H), 3.21 (t, 4 H, J=7.6 Hz average), 2.53 (d, 2 H, J=6.7 Hz), 2.10, ABm, 4 H), 1.55 (p, 4 H, J=7.7 Hz average), 1.34 (sept, 4 H, J=7.6 Hz average), 1.17 (m, 4 30 H), 0.95 (t, 6 H, J=7.6 Hz average). Example 14 (+)-1,2,3,6-TETRAHYDRO-1-{N-[4-(1-NAPHTHYL)-PIPERIDIN-1-Y L]PROP-YL}CARBOXAMIDO-4- METHOXYMETHYL-6-(3,4- WO 02/06245 PCT/USO1/21286 -158 DIFLUOROPHENYL)-2-OXO-PYRIMIDINE-5-CARBOXYLIC ACID METHYL ESTER: mp 168-172 "C; [a]D = +94.7, (c = 0.25, MeOH); 'H NMRS1.75-1.84 (m, 2H), 1.87-2.01 (m, 4H), 2.14-2.28 (m, 2H), 2.47 (t, J=7.2 Hz, 2H), 3.10 (d, J=11.1 Hz, 2H), 5 3.28-3.45 (m, 3H), 3.48 (s, 3H), 3.71 (s, 3H), 4.68 (s, 2H), 6.70 (s, 1H), 7.05-7.12 (m, 2H), 7.16-7.24 (m, 1H), 7.42-7.54 (m, 4H), 7.69-7.75 (m, 2H), 7.85 (d, J=11.4 Hz, 1H), 8.09 (d, J=11.1 Hz, 1H), 8.91 (t, J=5.4 Hz, 1H). 10 Example 15 4-(5-FLUORO-2-METHOXY)PHENYL PIPERIDINE: mp 254-258 0 C; 'H NMR81.53-1.68 (m, 2H), 1.79 (d, J=11.7 Hz, 2H), 2.12 (dt, J=2.1 Hz, J=11.7 Hz, 1H), 2.77 (dt, J=1.8 Hz, J=12.3 Hz, 1H), 2.90-3.05 (m, 1H), 3.10-3.22 (m, 2H), 3.68 (s, 1H), 15 3.79 (s, 3H), 6.72-6.93 (m, 3H). Anal. Calcd. For C12H, 7 NOFC1 + 0.14 CHC1 2 : C, 56.60; H, 6.76; N, 5.44. Found: C, 56.60; H, 6.92; N, 5.28. (+)-1,2,3,6-TETRAHYDRO-1-{N-[4-(5-FLUORO-2-METHOXY)PHENYL 20 PIPERI-DIN-1-YL]PROPYL}CARBOXAMIDO-4- METHOXYMETHYL-6 (3,4-DIFLUORO-PHENYL)-2-OXOPYRIMIDINE-5-CARBOXYLIC ACID METHYL ESTER: 'H NMR68.93 (t, 1 H, J=5.4 Hz), 7.76 (br, 1 H), 7.30-6.69 (m, 7 H), 4.69 (s, 2 H), 3.79 (s, 3 H), 3.71 (s, 3 H), 3.48 (s, 3 H), 3.38 (m, 2 H), 3.10-2.80 25 (m, 3 H), 2.42 (t, 2 H, J=7.2 Hz), 2.07 (dt, 2 H, J=3.0, 8.4 Hz), 2.00-1.60 (m, 6 H). Example 16 (+)-1,2,3,6-TETRAHYDRO-1-{N-[4-HYDROXY-4-(2-PYRIDYL)-PIPE 30 RIDIN-1-YL]PROPYL}CARBOXAMIDO-4- METHOXYMETHYL-6 (3,4-DIFLUOROPHENYL)-2- OXOPYRIMIDINE-5-CARBOXYLIC ACID METHYL ESTER: mp 132-135 'C; [aEc = +94.7, (c = 0.25, MeOH); 'H NMRS1.47 (d, J=11.7 Hz, 2H), 1.74-1.85 (m, 2H), 2.43-2.63 (m, 9H), 2.87 (d, J=10.2 Hz, 2H), 3.30-3.47 (m, WO 02/06245 PCT/US01/21286 -159 2H), 3.49 (s, 3H), 3.71 (s, 3H), 4.69 (s, 2H), 6.69 (s, 1H), 7.04-7.21 (m, 4H), 7.49 (dd, J=0.6 Hz, J=6.9 Hz, 1H), 7.72 (s, br, 1H), 8.36 (dd, J=1.2, 4.8 Hz, 1H), 8.89 (t, J=5.4 Hz, 1H) 5 Example 17 1-(3-AMINOPROPYL)-4-[2-PYRIDYL]PYRIDINIUM BROMIDE HYDROBROMIDE: A solution~of 2,4'-dipyridyl (25.0 g, 160 10 mmol) and 3-bromopropyl-amine hydrobromide (35.0 g, 160 mmol) in DMF (60 mL) was heated at 90-95 0 C for 10 h. After cooling to room temperature, anhydrous ether (500 mL) was added to the mixture, the resulting white solid was filtered, washed with Et 2 0 and dried, giving 15 1-(3-aminopropyl)-4-[2-pyridyl]pyridinium bromide hydrobromide (60 g, 100%)). 'H NMR (DMSO-d 6 ) 62.35-2.44 (m, 2 H), 3.08-3.13 (m, 2 H), 4.76-4.81 (m, 2 H), 7.58 (dd, J=4.8 Hz, J=7.5 Hz, 1 H), 8.03 (dt, J=1.8 Hz, J=7.8 Hz, 1 H), 8.32 (d, J=7.8 Hz, 1 H), 8.77-8.81 (m, 3 H), 20 9.12 (d, J=6.3 Hz, 2 H). Anal. Calcd. for C1 3
H
6
N
3 Br + HBr + 0.5 H 0: C, 40.65; H, 4.72; N, 10.94. Found: C, 40.83; H, 4.37; N, 11.05. 3-(3',6'-DIHYDRO-2 1 -H-[2,4']BIPYRIDINYL-1'-YL)-PROPYLAMIN 25 E: NaBH 4 (2 g, 53 mmol) in small portions was added to a solution of 1-(3-aminopropyl)-4-[2-pyridyllpyridinium bromide hydrobromide (6 g, 16 mmol) in MeOH (150 mL) at 0-5 'C over a period of 2 h. The reaction mixture was stirred overnight at room temperature and then the 30 solvent was evaporated. The residue was suspended in ether (200 mL) and treated'with aqueous 50% NaOH solution (100 mL). The ether layer was separated and the aqueous layer was extracted with additional ether (2 X 50 mL). The combined ether extracts were dried over potassium 35 carbonate and the solvent was removed, giving WO 02/06245 PCT/USO1/21286 -160 3-(3',6'-dihydro-2'-H-[2,4']bipyridinyl-l'-yl) propylamine (3.48 g) as an oil. The crude product was used in the next step immediately without further purification. 5 3-AMINOPROPYL-4-(2-PYRIDYL)PIPERIDINE: A suspension of 3-(3',6'-dihydro-2'-H-[2,4']bipyridinyl-1'-yl)-propylamin e (3.48 g crude, 15.9 mmol) and Pearlman's catalyst (1.0 g) in MeOH (40 mL) was hydrogenated under 120 psi for 10 10 h, after which the reaction mixture was filtered through a pad of Celite and the solvent was removed. The residue was purified by column chromatography over silica gel (30 g) [Note: If a large excess of silica gel is used the recovery of the product will be very low] 15 (CH 2 Cl 2 /methanol/2M NH3 in MeOH, 90/8/4 to 90/40/40). The product was obtained as a pale yellow oil (3.21 g, 91%). 'H NMR6 (CD 3 0D) 1.50-1.99 (m, 10 H), 2.02-2.06 (m, 2 H), 2.37-2.75 (m, 3 H), 3.02-3.06 (br m, 2 H), 7.05-7.09 (m, 4 H), 7.16 (dt, J=0.9 Hz, J=8.7 Hz, 1 H), 8.48 (dd, J=0.9 20 Hz, J=4.2 Hz, 1 H). Part II (+)-6-(3,4-DIFLUOROPHENYL)-1-{N-[4-(2-PYRIDYL)PIPERIDIN-1
-YL]
25 PROPYL]}CARBOXAMIDO-5-METHOXYCARBONYL-4-METHOXYMETHYL-2-0 XO- 1,2,3,6-TETRAHYDROPYRIMIDINE DIHYDROCHLORIDE 5-METHOXYCARBONYL-4-METHOXYMETHYL-1,2,3,6-TETRAHYDRO-2-OX 0-6- (3,4-DIFLUOROPHENYL)-PYRIMIDINE: Copper(I) oxide 30 (5.06 g, 0.035 mole) and acetic acid (2.05 mL) were added sequentially to a stirring solution of methyl 4-methoxyacetoacetate (50.0 g, 0.351 mol), 3,4-difluorobenzaldehyde (51.4 g, 0.351 mmol), and urea (31.6 g, 0.527 mole) in THF (300 mL) at room temperature, 35 followed by dropwise addition of boron trifluoride WO 02/06245 PCT/USO1/21286 -161 diethyl etherate (56.0 mL, 0.456 mole). The mixture was stirred at reflux temperature for 8 h, whereupon TLC (1/1 EtOAc/hexanes) indicated completion of the reaction. The reaction mixture was cooled and poured into a mixture of 5 ice and sodium bicarbonate (100 g) and the resulting mixture was filtered through Celite. The Celite pad was washed with dichloromethane (400 mL). The organic layer was separated from the filtrate and the aqueous layer was extracted with more dichloromethane (3 X 300 mL). The 10 combined organic extracts were dried (sodium sulfate) and the solvent was evaporated. The crude product was purified by flash chromatography (ethyl acetate/hexanes, 1/1;then ethyl acetate), giving the desired product as'a pale yellow foam. The foam was triturated with hexanes, 15 giving a white powder (103.3 g, 94%). 'H NMR83.476 (s, 3H), 3.651 (s, 3H), 4.653 (s, 2H), 5.39 (s, 1H), 6.60 (br s, 1H, NH), 7.00-7.20 (m, 3H), 7.72 (br s, 1H, NH). (+)-5-METHOXYCARBONYL-4-METHOXYMETHYL-1,2,3,6-TETRAHYDRO 20 2-OXO-6-(3,4-DIFLUOROPHENYL)-PYRIMIDINE: The racemic intermediate 5-methoxycarbonyl-4-methoxymethyl 1,2,3,6-tetrahydro-2-oxo-6- (3,4-difluorophenyl) pyrimidine was resolved by chiral HPLC [Chiralcel OD 20 X 250 mm #369-703-30604; lambda 254 nm; hexanes/ethanol 25 90/10 ; 85 mg per injection; retention time of the desired enantiomer: 16.94 min., the first enantiomer peak to elute], giving (+)-5-methoxycarbonyl-4 methoxymethyl-1,2,3,6- tetrahydro-2-oxo-6-(3,4 difluorophenyl)-pyrimidine (40-42 wt% isolation of the 30 desired enantiomer from the racemate); [a]D +83.8 (c 0.5, chloroform). (+)-5-METHOXYCARBONYL-4-METHOXYMETHYL-1,2,3,6-TETRAHYDRO 2-OXO-6-(3,4-DIFLUOROPHENYL)-1-[(4-NITROPHENYLOXY)CARBONY WO 02/06245 PCT/USO1/21286 -162 L]PYRIMIDINE: A solution of lithium hexamethyldisilazide in THF (1M, 18.0 mL, 18.0 mmol) was added over 2-3 min. to a solution of (+)-5-methoxycarbonyl-4-methoxymethyl 1,2,3,6-tetrahydro-2-oxo-6-(3,4-difluorophenyl)-pyrimidin 5 e (1.98 g, 6.34 mmol) in anhydrous THF (20 mL) at -78 0C under argon atmosphere and the mixture was stirred for 10 min. The resulting solution was added over 6 min., via a cannula, to a stirred solution of 4-nitrophenyl chloroformate (4.47 g, 22.2 mmol) in THF (20 mL) at -78 10 0C. The mixture was stirred for an additional 10 min. and the mixture was poured onto ice (50 g) and extracted with chloroform (2 X 50 mL). The combined extracts were dried (sodium sulfate) and the solvent evaporated. The residue was purified by flash chromatography (hexanes/ethyl 15 acetate, 4/1 to 3.5/1), giving the product as a yellow syrup, which on trituration with hexanes became a white powder (2.40 g, 79%). 'H NMR63.52 (s, 3H), 3.74 (s, 3H), 4.65-4.80 (q, J=16.5 Hz, 2H), 6.32 (s, 1H), 7.10-7.30 (m, 4H), 7.36 (d, J=9 Hz, 2H), 8.27 (d, J=9 Hz, 2H). 20 (+)-6-(3,4-DIFLUOROPHENYL)-1-{N-[4-(2-PYRIDYL)PIPERIDIN-1 -YL]-PROPYL]}CARBOXAMIDO-5-METHOXYCARBONYL-4 METHOXYMETHYL-2-OXO- 1,2,3,6-TETRAHYDROPYRIMIDINE DIHYDROCHLORIDE: A solution of (+)-5-methoxycarbonyl 25 4-methoxymethyl-1,2,3,6-tetrahydro-2-oxo-6-(3,4-difluorop henyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine (2.38 g, 5 mmol), 3-aminopropyl-4-(2-pyridyl)piperidine (1.21 g, 5.5 mmol) in THF (20 mL) was stirred at room temperature for 12 h. The solvent was evaporated and the residue was 30. re-dissolved in ethyl acetate (100 mL). The resulting solution was washed with ice-cold 1 N NaOH (4 X 50 mL), brine (2 X 50 mL) and dried over potassium carbonate. The solvent was evaporated in vacuo and the residue was purified by flash chromatography (dichloromethane/MeOH/2 35 M ammonia in MeOH, 980/10/10 to 940/30/30 ), giving a WO 02/06245 PCT/USO1/21286 -163 clean fraction of the desired product (2.45 g, 88%) as a foam and a slightly impure fraction (0.30 g, 10%). 'H NMR 61.60-2.00 (m, 6H), 2.05-2.15 (m, 2H), 2.38-2.43 (br t, 2H), 2.65-2.80 (m, 1H), 3.05-3.06 (br d, 2H), 3.30-3.45 5 (m, 2H), 3.48 (s, 3H), 3.704 (s, 3H), 4.68 (s, 2H), 6.68 (s, 1H), 7.05-7.20 (m, 5H), 7.58-7.63 (dt, 1H), 7.70 (s, 1H, NH), 8.50-8.52 (dd, 1H), 8.88 (br t, 1H). The HCl salt was prepared by treatment of a solution of 10 the free base in ether with 1 N HCl in ether. The white powder was dried under reduced pressure: 'H NMR6 2.05-2.20 (m, 4H), 2.77-2.88 (m, 2H), 3.00-3.20 (m, 4H), 3.35-3.47 (m, 2H), 3.47 (s, 3H), 3.64-3.70 (m, 2H), 3.71 (s, 3H), 4.05 (br t, 1H), 4.67 (s, 2H), 6.59 (s, 1H), 15 7.05-7.20 (m, 3H), 7.79 (t, 1H), 8.00 (d, 1H), 8.43 (dt, 1H), 8.96 (br t, 1H, NH), 12.4 (br s, 1H). m.p. 188-191 'C; [a]D = +141.13 (c = 0.265, MeOH); Anal. Calcd. for
C
28
H
34
N
5 0 5
F
2 Cl + 0.6 H 2 0:C, 52.36; H, 5.84; N, 10.90. Found: C, 52.24; H, 5.96; N, 10.80. (Note: NMR analysis of this 20 product did not show the presence of any water. However, it was noted by the lab that performed the elemental analysis that this sample gains weight during handling by absorbing water from the atmosphere). 25 Example 18 (1)-1,2,3,6-TETRAHYDRO-1-{N-[4-(ISOBENZOFURAN)PIPERIDINE 1-YL]-PROPYLICARBOXAMIDO-5-METHOXYCARBONYL-2-OXO 6-(3,4-BENZOFURAZAN)- 4-METHYLPYRIMIDINE HYDROCHLORIDE 30 4-(3,4-BENZOFURAZAN)-6-METHYL-2-OXO-3-{[3-(4-SPIRO[ISOBEN ZO-FURAN-1(3H),4'-PIPERIDINE]PROPYL}-1,2,3,4 TETRAHYDROPYRIMIDINE-5-CARBOXYLIC ACID METHYL ESTER 1-(3-Aminopropyl)-4- spiro[iso-benzofuran-1 (3H),4'- WO 02/06245 PCT/US01/21286 -164 piperidine] (0.028 g, 0.110 mmol) was added to (±)-6-(benzofurazan)-1,6-dihydro-2-methoxy 5-methoxycarbonyl-4-methyl-1-(4-nitrophenoxy)carbonylpyri midine (0.047 g, 0.100 mmol) in dry dichloromethane (10 5 mL) and the solution was stirred at room temperature for 24 h. Aquesous 6 N HCl (2 mL) was added to the reaction mixture which was stirred for another 1 h. The reaction mixture was basified with aqueous 10% KOH solution (pH 9) and extracted into dichloromethane (3 x 10 mL). The 10 organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography (EtOAc/ MeOH, 4.5/0.5), giving the desired product (41.0 mg, 73 %) as a syrup: 'H NMR51.76-1.81 (m, 7 H), 1.94-2.04 (m, 6 H), 2.32-2.48 (m, 1 H), 2.83 15 (d, J=10.6 Hz, 2 H), 3.36-3.43 (m, 2 H), 3.75 (s, 3 H), 5.05 (s, 2 H), 6.83 (s, 1 H), 7.07-7.27 (m, 4 H), 7.54 (d, J=9.5 Hz, 1 H), 7.69 (s, 1 H), 7.78 (d, J=9.5 Hz, 1 H), 8.85 (d, J=5.2 Hz, 1 H). 20 HCl in ether (1 N, 5 mL) was added to the free base (0.041 g, 0.073 mmol) in dichloromethane (4 mL), and the solution was concentrated under reduced pressure. The product was recrystallized from ether, giving the hydrochloride salt as a pale yellow solid (42.0 mg, 96 25 %); mp 180-182 0C; Anal. Calcd. for C 2 9
H
3 4
N
6 0 6 Cl + 0.5 moles H20: C, 57.47; H, 5.65; N, 13.87. Found: C, 57.42; H, 5.71; N, 13.70. Example 19 30 2-(3,4-DIFLUOROPHENYL)4,5-DIHYDROIMIDAZOLE-1-CARBOXYLIC ACID {3-[4-PHENYL-4-(4-BROMO-5-METHYLTHIOPNEN-2-YL)] -PROPYL}-AMIDE: Anal. Calcd. for C 30
H
30
N
4
(
5 ClF 3 + HCl + 1.5 H,10: C, 55.26; H, 6.03; N, 8.59. Found: C, 55.29; H, 5.95; N, 8.39. 35 WO 02/06245 PCT/USO1/21286 -165 Example 20 4-(3,4-DIFLUORPHENYL)-6-METHYL-2-OXO-3-{[3-(4-SPIRO[ISOBE NZO-FURAN-1(3H),4'-PIPERIDINE]PROPYL}-1,2,3,4 TETRAHYDROPYRIMIDINE-5-CARBOXYLIC ACID METHYL ESTER 5 For the preparation of the ether piperidine precursor of the compound of Example 20,refer to W.E.Parham et al, J. Org. Chem. (1976) 41, 2268. 1-TERT-BUTOXYCARBONYL-3-(4-SPIRO[ISOBENZOFURAN-1(3H),4' 10 PIPERIDINE])PROPYLAMINE: N-(tert-utoxycarbonyl)-3-bromo propylamine (0.772 g, 3.27.mmol) and potassium carbonate (0.904 g, 6.54 mmol) were added to a stirring solution of the amine (0.566 g, 3.27 mmol) in dioxane ( 20 mL) and the reaction mixture was heated at reflux temperature for 15 24 h. The reaction mixture was cooled to room temperature, concentrated and partitioned between chloroform (40 mL) and water (5 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography 20 (ethyl acetate/ methanol, 4.5/0.5), giving the desired product (0.856 g, 79 %) as a colorless oil; 1 H NMR61.45 (s, 9 H), 1.63-2.04 (m, 6 H), 2.33-2.52 (m, 4 H), 2.87 (d, J=11.0 Hz, 2 H), 3.2 (br s, 2 H), 5.07 (s, 2 H), 5.6 (br s, 1 H), 7.13-7.28 (m, 4 H). 25 3-(4-SPIRO[ISOBENZO-FURAN-1(3H),4'-PIPERIDINE]) PROPYLAMINE: Trifluoroacetic acid (1 mL) was added to 1-tert-butoxycarbonyl 3-(4-spiro[isobenzo-furan 1(3H),4'-piperidine])propylamine (0.500 g, 1.51 mmol) in 30 dichloromethane (5 mL) and the solution was stirred at room temperature for 1 h. The reaction mixture was concentrated, neutralized with 10 % KOH solution and extracted into dichloromethane (25 mL). The organic layer was dried over sodium sulfate, filtered and WO 02/06245 PCT/USO1/21286 -166 concentrated, giving the desired amine (0.340 g, 98%) which was used in the subsequent step without further purification. 5 4-(3,4-DIFLUORPHENYL)-6-METHYL-2-OXO-3-{[3-(4-SPIRO[ISOBE NZO-FURAN-1(3H),4'-PIPERIDINE]PROPYL}-1,2,3,4 TETRAHYDROPYRIMIDINE-5-CARBOXYLIC ACID METHYL ESTER: 3-(4-spiro[isobenzo-furan-1(3H),4'-piperidine]) propylamine (0.0319 g, 0.123 mmol) was added to 10 (±)-6-(3,4-Difluorophenyl)-1,6-dihydro- 2-methoxy-5 methoxycarbonyl-4-methyl-1-(4-nitrophenoxy)carbonylpyrimi dine (0.052 g, 0.112 mmol) in dry dichloromethane (10 mL) and the solution was stirred at room temperature for 24 h. Aqueous 6 N HCl (2 mL) was added and the reaction 15 mixture was stirred for an'additional 1 h. After neutralization with 10% aqueous KOH solution, the reaction mixture was extracted with dichloromethane (3 x 10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was 20 purified by flash chromatography (EtOAc/ MeOH, 4.5/0.5), giving the desired product (0.040 g, 64 %) as a syrup; 1H-NMR61.73-1.78 (m, 7 H), 1.93-2.04 (m, 2 H), 2.33-2.48 (m,, 6 H), 2.83 (d, J=11.8 Hz, 2 H), 3.35-3.41 (m, 2 H), 3.71 (s, 3 H), 5.06 (s, 2 H), 6.75 (s, 1 H), 7.04-7.26 25 (m, 7 H), 8.82 (t, J=5.1 Hz, 1 H). A solution of 1 N HCl in ether (5 mL) was added to the free base (0.040 g, 0.072 mmol) in dichloromethane (4 mL) and the solution was concentrated in vacuo. The product 30 was recrystallized from ether, giving the dihydrochloride as a pale yellow solid (0.042 g, 99 %); mp 178-182 0C; Anal. Calcd. for C 2 9
H
3 4
F
2
N
4 0 5 C1 2 + 0.6 H 2 0: C, 57.87; H, 5.73, N 9.31. Found: C, 58.11; H 5.90; N 8.95. 35 WO 02/06245 PCT/USO1/21286 -167 Example 21 1,2,3,6-TETRAHYDRO-1-{N-[4-(DIHYDROINDENE)-1-YL}PROPYL}CA RBOXAMIDO-5-METHOXYCARBONYL- 2-OXO-6-(3,4-BENZOFURAZAN) 4-METHYLPYRIMID-INE 5 For the preparation of the indane piperidine precursor of the compound of Example 21, refer to M.S.Chambers J. Med. Chem. (1992) 35,2033. 10 N-(tert-butoxycarbonyl)3-(4-spiro[isobenzo-furan 1(3H),4'- piperidine])propylamine(1.10 g, 4.64 mmol) and potassium carbonate (1.17 g, 8.44 mmol) were added to a stirring solution of the amine (0.790 g, 4.22 mmol) in dioxane (20 ml), and the resulting solution was heated at 15 reflux temperature for 24 h. The reaction mixture was cooled to room temperature, concentrated and partitioned between chloroform (40 mL) and water (5 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column 20 chromatography (ethyl acetate/ methanol, 4.5/0.5), giving the desired product (0.886 g, 61 %) as a colorless oil; 'H NMR6 1.46 (s, 9 H), 1.55 (d, J = 11.3 Hz, 2 H), 1.69 (t, J = 6.3 Hz, 2 H), 1.88-2.47 (m, 6 H), 2.47 (t, J 6.3 Hz, 2 H), 2.88 (t, J = 3.3 Hz, 4 H), 3.23 (d, J = 5.6 Hz, 25 2 H), 5.85 (br s, 1 H), 7.18 (s, 4 H). Trifluoroacetic acid (1 ml) was added to 1-tert butoxycarbonyl-3-(4-spiro[isobenzo-furan-1(3H),4' piperidine])propylamine(0.180 g, 0.52 mmol) in 30 dichloromethane (5 ml) and the resulting solution was stirred at room temperature for 1 hour. The solution was concentrated, neutralized with 10% KOH solution and extracted into dichloromethane (25 ml). The organic layer was dried over sodium sulfate, filtered and WO 02/06245 PCT/USO1/21286 -168 concentrated, giving propylamine (0.156 g, 100%) which was used in the subsequent step without further purification. 5 (±)-4-(3,4-BENZOFURAZAN)-6-METHYL-2-OXO-3-{SPIRO[1H-INDAN E-1,4'-PIPERIDINEIPROPYL}-1,2,3,4-TETRAIYDROPYRIMIDINE-5 CARBOXYLIC ACID METHYL ESTER HYDROCHLORIDE: To (±)-4-(3,4-benzofurazan)-1,6- dihydro-2-methoxy-5 methoxycarbonyl-4-methyl-1-(4-nitrophenoxy) 10 carbonylpyrimidine (0.059 g, 0.126 mmol) in dry dichloromethane (10 mL), 1-(3-aminopropyl)spiro [H-indane-1,4'- piperidine] (0.062 g, 0.252 mmol) was added and the solution was stirred at room temperature for 24 h. The reaction mixture was stirred for another 1 15 h after addition of 2 mL of 6N HCl. The reaction mixture was basified with 10% aqueous KOH solution (pH = 9) and extracted with dichloromethane (3 x 10 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The crude product was purified by 20 flash chromatography (EtOAc/ MeOH, 4.5/0.5), giving 0.070 g (100%) of the desired product as a syrup: 'H NMRS1.51 (d, J=12.5 Hz, 2 H), 1.76-2.08 (m, 4 H), 2.12 (t, J=10.3 Hz, 2 H), 2.45 (s, 5 H), 2.86-2.91 (m, 4 H), 3.30-3.45 (m, 2 H), 3.75 (s, 3 H), 6.83 (s, 1 H), 7.02 (br s, 1 H), 25 7.0 (m, 4 H), 7.54 (d, J=9.6 Hz, 1 H), 7.69 (s, 1 H), 7.78 (d, J=9.2 Hz, 1 H), 8.84, (t, J=5.2 Hz, 1 H). To the free base (0.070 g, 0.125 mmol) in 4 mL of dichloromethane, 5 mL of 1 N HC1 in ether was added, and 30 the solution was concentrated under reduced pressure. Recrystallization from ether gave 0.088 g (100 %) of (±)-4-(3,4-benzofurazan)-6-methyl-2-oxo-3-{spiro[1H-indan e- 1,4'-piperidine]propyl}-1,2,3,4-tetrahydro pyrimidine-5-carboxylic acid methyl ester hydrochloride 35 as a white solid: m.p. 155-157 'C; Anal. Calcd. for WO 02/06245 PCT/US01/21286 -169
C
30
H
36
N
6
O
5 Cl: C, 57.12; H, 5.76; N, 13.33. Found: C, 57.40; H, 5.96; N, 13.02. Example 22 5 (+)-1,2,3,6-TETRAHYDRO-1-{N-[4-(BENZO-4',5' (H)FURAN)PIPER IDIN-1- YL]PROPYL}CARBOXAMIDO-4-ETHYL- 6-(3,4 DIFLUOROPHENYL)-2-OXO- PYRIMIDINE-5-CARBOXAMIDE HYDROCHLORIDE: DMAP- ECD (0.250 mmol, 0.050 g) was added to a stirred mixture of (+)-1,2,3,6-tetra-hydro-1 10 {N-[4-(benzo-4',5'(h)furan)piperidin-1-yl]propyl}carbox amido-4-ethyl-6-(3,4-difluorophenyl)-2-oxo-pyrimidine-5-c arboxyl-ic acid hydrochloride (0.100 mmol, 0.055 g) and N-methylmorpholine (0.330 mL) in dry dichloromethane (10 mL). The resulting mixture was stirred at room 15 temperature for 1 h and quenched with NH 3 . The reaction mixture was stirred at room temperature overnight, concentrated and chromatographed, giving the desired product. The HC1 salt was prepared by the addition of HCl in ether to a solution of the product in 20 dichloromethane, followed by evaporation of the solvents. Anal. Calc. For C 29
H
33
N
5 0 4 F2 + HCl + 0.7 CHCl 3 : C, 52.96; H, 5.29; N, 9.40. Found: C, 52.81; H, 5.69; N, 8.97. Example 23 25 (1)-1,2,3,6-TETRAHYDRO-1-{N-[4-(3,4-DIHYDRO-2-OXOSPIRO NAPHTHALENE-1(2H))-PIPERIDINE-1-YL]PROPYL}CARBOXAMIDO-5 METHOXYCARBONYL-2- OXO-6-(3,4-BENZOFURAZAN)-4 METHYLPYRIMIDINE HYDROCHLORIDE 30 1-(3-TERT-BUTOXYCARBONYLAMINOPROPYL)SPIRO[ISOCHROMAN-3,4' PIPERIDIN]-l-ONE: To a stirred solution of spiro [piperidine-4,1'-tetralin] To a stirred solution of spiro[isochroman-3,4'-piperidin]-l-one (K.Hashigaki et al. Chem.Pharm.Bull. (1984) 32, 3568.) (0.587 g, 2.58 35 mmol) in dioxane ( 20 mL), N-(tert- butoxycarbonyl)- WO 02/06245 PCT/USO1/21286 -170 3-bromopropylamine (0.615 g, 2.84 mmol) and potassium carbonate (0.714 g, 5.17 mmol) were added and the solution was refluxed for 24 h. The reaction mixture was cooled to room temperature, concentrated and partitioned 5 between 40 mL chloroform and 5 mL water. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (ethyl acetate/ methanol, 4.5/0.5) to yield 0.465 g (47 %) of the desired product as a 10 colorless oil; 1H NMR1.45 (s, 9 H), 1.64-2.18 (m, 7 H), 2.45-2.84 (m, 6 H), 3.19-3.95 (m, 4 H), 6.01 (br s, 1 H), 7.13-7.26 (m, 3 H), 7.42 (d, J=7.7 H). Step B. 15 1-(3-AMINOPROPYL)SPIRO[ISOCHROMAN-3,4'PIPERIDIN]-1-ONE: To 1-(3-tert-Butoxycarbonylaminopropyl)spiro [isochroman-3,4'-piperidin]-l-one (0.144 g, 0.375 mmol) in 5 mL of dichloromethane, 1 mL of trifluoroacetic acid was added and the solution stirred at room temperature 20 for 1 h. The solution was concentrated, neutralized with 10 % KOH solution and extracted into 25 mL of dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated, giving 0.110 g (100%) of the product which was used as such for the subsequent 25 step. (±)-4-(3,4-BENZOFURAZAN)-6-METHYL-2-OXO-3-{(SPIRO[ISOCHRO MAN- 3,4'-PIPERIDINI-1-ONE)PROPYL}-1,2,3,4 TETRAHYDROPYRIMIDINE-5- CARBOXYL-IC ACID METHYL ESTER: 30 To (±)-4-(3,4-Benzofurazan)-1,6- dihydro-2-methoxy 5-methoxycarbonyl-4-methyl-l-(4-nitrophenoxy) carbonylpyrimidine (40.0 mg, 0.0865 mmol) in 10 mL of dry dichloromethane, spiro[isochroman-3,4'piperidin]-1-one (44.0 mg, 0.173 mmol) was added and the solution was 35 stirred at room temperature for 24 h. The reaction WO 02/06245 PCT/USO1/21286 -171 mixture was stirred for another 1 h after addition of 2 mL of 6N HCl. The reaction mixture was basified with 10% aqueous KOH solution (pH = 9) and extracted into dichloromethane (3 x 10 mL). The organic layer was dried 5 over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography (EtOAc/ MeOH, 4.5/0.5), giving 50.0 mg (100%) of the desired product as a syrup: 1H NMRS1.67-2.13 (m, 8 H), 2.45 (m, 5 H), 2.70 (t, J=7.4 Hz, 2 H), 2.72-2.75 (m, 2 10 H), 3.19 (t, J=7.4 Hz, 2 H), 3.34-3.45 (m, 2 H), 3.75 (s, 3 H), 6.82 (s, 1 H), 6.87 (s, 1 H), 7.13-7.44 (m, 3 H), 7.54 (d, J=9.6 Hz, 1 H), 7.43 (d, J=7.4 Hz, 1 H), 7.69 (s, 1 H), 7.79 (d, J=9.6 Hz, 1 H), 8.87 (t, J=5.2 Hz, 1 H). 15 To the free base (50.0 mg, 0.084 mmol) in 4 mL of dichloromethane, 5 mL of 1 N HCl in ether was added, and the solution concentrated under reduced pressure. Recrystallization from ether gave 30.0 mg (86 %) of the 20 product as a white solid: m.p. 165-167 'C; Anal. Calcd. for C 3
,H
36 N.0 6 Cl + 1.5 H 2 0: C, 57.81; H, 5.95. Found: C, 57.75; H, 5.91. 25 Example 24 (1)-1,2,3,6-TETRAHYDRO-1-{N-[4-(3,4-DIHYDRO-2-OXOSPIRO NAPHTHALENE-1(2H))-PIPERIDINE-1-YL]PROPYL}CARBOXAMIDO-5-M ETHOXY-CARBONYL-2- OXO-6-(3,4-DIFLUOROPHENYL)-4-METHYL PYRIMIDINE 30 (±)-4-(3,4-DIFLUOROPHENYL)-6-METHYL-2-OXO-3-{(SPIRO[ISOCH ROMAN- 3,4'PIPERIDIN]-1-ONE)PROPYL}-1,2,3,4-TETRAHYDRO PYRIMIDINE-5- CARBOXYLIC ACID METHYL ESTER: To (±)-4-(3,4-Difluorophenyl)- 1,6-dihydro-2-methoxy-5 35 methoxycarbonyl-4-methyl-1-(4-nitrophen-oxy)carbonyl- WO 02/06245 PCT/US01/21286 -172 pyrimidine (40.0 mg, 0.0865 mmol) in 10 mL of dry dichloromethane, spiro[isochroman-3,4'piperidin]-1-one (44.0 mg, 0.173 mmol) was added and the solution was stirred at room temperature for 24 h. The reaction 5 mixture was stirred for another 1 h after addition of 2 mL of 6N HCl. The reaction mixture was basified with 10% aqueous KOH solution (pH = 9) and extracted into dichloromethane (3 x 10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The 10 crude product was purified by flash chromatography (EtOAc/ MeOH, 4.5/0.5), giving 45.0 mg (90%) of (±)-4-(3,4-difluorophenyl)- 6-methyl-2-oxo-3-{(spiro [isochroman-3,4'piperidin]-l-one)propyl}-1,2,3,4-tetrahyd ropyrimi-dine-5-carboxylic acid methyl ester as a syrup; 15 IH NMRS1.75-1.94 (m, 9B), 2.05-2.13 (n, 4 H), 2.36-2.41 (m, 5 H), 2.70 (t, J=7.35 Hz, 2 H), 2.77 (m, 2 H), 3.19 (t, J=7.4 Hz, 2 H), 3.39-3.43 (m, 2 H), 6.69 (s, 1 H), 7.04-7.45 (m, 8 H), 8.82 (t, J=5.2 Hz, 1 H). 20 To the free base (45.0 g, 0.077 mmol) in 4 mL of dichloromethane, 5 mL of 1 N HCl in ether was added, and the solution was concentrated in vacuo. Recrystallization from ether gave 0.050 g (100%) of (±)-4-(3,4-difluorophenyl)-6-methyl-2-oxo-3-{(spiro 25 [isochroman-3,4'piperidinl- 1-one)propyl}-1,2,3,4 tetrahydro-pyrimidine-5-carboxylic acid methyl ester hydrochloride as a white solid: m.p. 150-152 'C; Anal. Calcd. for C 3 lH 3
BF
2
N
4 0Cl + 2 HO: C, 56.49; H,5.96. Found: C, 56.40; H, 5.95. 30 Example 25 5-[(Z)-1-(l-ETHYL-2,2,4-TRIMETHYL-1,2-DIHYDRO-6-QUINOLINY L)-METHYLIDENE]-2-THIOXO-1,3-THIAZOLAN-4-ONE WO 02/06245 PCT/USO1/21286 -173 Example 26 1-[BIS(4-FLUOROPHENYL)METHYL]-4-(3-PHENYL-2-PROPENYL)PIPE RAZINE 5 Example 27 4-[(4-TMIDAZO[1,2-A]PYRIDTN-2-YLPHENYL)IMINO]METHYL-5-MET HYL-1,3-BENZENEDIOL Example 28 10 1-[3-(4-CHLOROBENZOYL)]PROPYL-4-BENZAMIDOPIPERIDINE Preparation of 1-[3-(4-chlorobenzoyl)propyl]-4-benzamidopiperidine 15 1-[3-(4-CHLOROBENZOYL)PROPYL]-4-BENZAMIDOPIPERIDINE: A mixture of 3-(4-chlorobenzol)propyl bromide (640 mg, 2.45 mmol), 4-benzamidopiperidine (500 mg, 2.45 mmol) and KQCO 3 (1.01 g, 7.34 mmol) in 50 ml of acetone was heated at reflux temperature for 48 h. The cooled reaction mixture 20 was filtered to remove the solids, concentrated in vacuo, giving a yellow solid, which was purified by chromatography (MeOH/CHCl 3 , 5/95) . The product (320 mg 33.9%) was isolated as a white powder: 1H NMR61.46 (dq, J1=1.0 Hz, J2=8.4 Hz, 2H), 1.90-2.10 (m, 4H), 2.16 (m, 25 2H), 2.43 (t, J=6.9 Hz, 2H), 2.80-2.90 (m, 2H), 2.97 (t, J=6.9 Hz, 2H), 3.97 (m, 1H), 5.92 (d, J=7.8 Hz, 1H, N-H), 7.40-8.00 (m, 9H). The product was converted to the HCl salt and recrystallized from MeOH/Et 2 O, m.p. 243-244 'C; Anal. Calcd for C_2 2 HO2ClNO 2 + HCl + H 9 0: C, 60.15; H, 6.37; 30 N, 6.37; Found: C, 60.18; H, 6.34; N, 6.29. Example 29 4-[4-(4-CHLOROPHENYL)-4-HYDROXY-1-PIPERIDINYL]-1-(4-CHLOR OPHEN-YL)-1-BUTANONE WO 02/06245 PCT/USO1/21286 -174 Example 30 N-METHYL-8-[4-(4-FLUOROPHENYL)-4-OXOBUTYL]-1-PHENYL-1,3,8 -TRI-AZASPIRO-[4.5]DECAN-4-ONE 5 Example 31 1H-1,2,3-BENZOTRIAZOL-1-YL (2-NITROPHENYL) SULFONE Example 32 (1)-1,2,3,6-TETRAHYDRO-1-{N-[4-(DIHYDROINDENE)-1-YL}PROPY 10 L} CARBOXAMIDO-5-METHOXYCARBONYL-2-OXO-6-(3,4-DIFLUORO)-4-ME THYL-PYRIMIDINE 1-(3-TERT-BUTOXYCARBONYLAMINOPROPYL)SPIRO[1H-INDANE-1,4' 15 PIPERIDINE]: To a stirred solution of spiro[1H-indane 1,4'-piperidine] (M.S.Chambers et al. J. Med. Chem. (1992) 35, 2033.) (0.790 g, 4.22 mmol) in dioxane (20 mL), N-(tert-butoxy-carbonyl)-3-bromopropylamine (1.1 g, 4.64 mmol) and potassium carbonate (1.17 g, 8.44 mmol) 20 were added and the resulting solution was heated at reflux temperature for 24 h. The reaction mixture was cooled to room temperature, concentrated and partitioned between 40 mL of chloroform and 5 mL of water. The organic layer was dried over sodium sulfate, filtered and 25 concentrated. The crude product was purified by column chromatography (ethyl acetate/ methanol, 4.5/0.5) to yield 0.886 g (61 %) of the required product as a colorless oil: 'H NMRS 1.46 (s, 9 H), 1.55 (d, J=11.3 Hz, 2 H), 1.69 (t, J=6.3 Hz, 2 H), 1.88-2.47 (m, 6 H), 2.47 30 (t, J=6.3 Hz, 2 H), 2.88 (t, J=3.3 Hz, 4 H), 3.23 (d, J=5.6 Hz, 2 H), 5.85 (br s, 1 H), 7.18 (s, 4 H). 1-(3-AMINOPROPYL)SPIRO[1H-INDANE-1,4'-PIPERIDINE]: To 1-(3-tert- Butoxycarbonylaminopropyl)spiro[lH-indane- WO 02/06245 PCT/US01/21286 -175 1,4'-piperidine] (0.180 g, 0.52 mmol) in 5 mL of dichloromethane, 1 mL of trifluoroacetic acid was added and the solution stirred at room temperature for 1 h. The solution was concentrated, neutralized with 10 % KOH 5 solution and extracted into 25 mL of dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated, giving 0.156 g (100%) of the product which was used as such for the subsequent step. 10 (±)-4-(3,4-DIFLUORO)-6-METHYL-2-OXO-3-{SPIRO[1H-INDANE-1, 4'-PIPERIDINE]PROPYL}-1,2,3,4-TETRAHYDROPYRIMIDINE-5-CARB OXYLIC ACID METHYL ESTER: To (±)-4-(3,4-difluoro)1,6 dihydro-2-methoxy- 5-methoxycarbonyl- 4-methyl-1 (4-nitrophenoxy)carbonylpyrimidine (50.0 g, 0.108 mmol) 15 in 10 mL of dry dichloromethane, 1-(3- aminopropyl) spiro[1H-indane-1,4'-piperidine] (53.0 mg, 0.216 mmol) was added and the solution was stirred at room temperature for 24 h. The reaction mixture was stirred for another 1 h after addition of 2 mL of 6N HCl. The 20 reaction mixture was basified with 10% aqueous KOH solution (pH = 9) and extracted into dichloromethane (3 x 10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography (EtOAc/ MeOH, 4.5/0.5), 25 giving 60.0 mg (100%) of the product as a syrup: 1H NMRS 1.52 (d, J=13.2 Hz, 2 H), 1.70-2.07 (m, 8 H), 2.12 (t, J=10.3 Hz, 2 H), 2.42 (s, 4 H), 2.86-2.91 (m, 3 H), 3.32-3.43 (m, 2 H), 3.72 (s, 3 H), 6.71 (s, 1 H), 6.81 (br s, 1 H), 7.04-7.19 (m, 7 H), 8.82 (t, J=5.2 Hz, 1 H). 30 To the free base (0.060 g, 0.108 mmol) in 4 mL of dichloromethane, 5 mL of 1 N HCl in ether was added, and the solution was concentrated under reduced pressure. Recrystallization from ether gave 0.070 g (100%) of the 35 product as a white solid; m.p. 150-153 'C; Anal. Calcd.
WO 02/06245 PCT/USO1/21286 -176 for C 30
H
36
F
0
N
4 0C1: C, 54.86; H,5.53; N, 8.54. Found: C, 54.96; H, 5.57; N, 8.27. 5 Example 33 (+)-1,2,3,6-TETRAHYDRO-1-{N-[4-(3,4,5-TRIFLUORO)-PHENYL-P IPER-IDIN-1-YL]PROPYL}CARBOXAMIDO-4- METHOXYMETHYL-6 (3,4- DIFLUOROPHENYL)-2-OXOPYRIMIDINE-5-CARBOXYLIC ACID METHYL ESTER: mp 0 C; [a]D +123.0, (c = 0.15, MeOH); 1H 10 NMR61.70-1.82 (m, 6H), 1.97-2.08 (m, 2H), 2.40 (t, J=6.9 Hz, 2H), 2.74-2.87 (m, 1H), 3.01 (d, J=11.1 Hz, 2H), 3.29-3.40 (m, 2H), 3.49 (s, 3H), 3.71 (s, 3H), 4.69 (s, 2H), 6.68 (s, 1H), 6.88-6.95 (m, 2H), 7.05-7.11 (m, 2H), 7.15-7.22 (m, 1H), 7.71 (s, 1H), 8.90 (t, J=5.4 Hz, 1H). 15 Example 34 (+) -1,2,3,6-TETRAHYDRO-1-{N-[2-(S)-METHYL)-4-(2-NITROPHEN YL)-PIPERAZIN-1YL]PROPYL}-CARBOXAMIDO-4-METHYL-6-(3,4 DIFLUOROPHEN-YL)-2-OXO-PYRIMIDINE 20 (S)-(+)-3-METHYL-1-(2-NITROPHENYL)-PIPERAZINE: To a solution of 2-bromonitrobenzene (0.600 g, 3.00 mmol) in 1,4-dioxane (15 mL) was added (S)-(+)-2-methylpiperazine (0.500 g, 0.500 mmol) and powdered K.C0 3 (15.0 mol, 1.50 25 g) and the resulting suspension was heated at reflux for 10 h. After the suspension was cooled, it was filtered through a sintered glass funnel and the solvent was removed in vacuo. The resulting residue was purified by column chromatography (1/1 hexane/EtOAc followed by 4/1 30 EtOAc/MeOH), giving (S)-(+)-3-methyl-1-(2-nitrophenyl)-piperazine as an orange oil (0.53 g, 80%). (+)-1,2,3,6-TETRAHYDRO-1-{N-[2-(S)-METHYL)-4-(2-NITROPHEN WO 02/06245 PCT/USO1/21286 -177 YL)PIPERAZIN-lYL]PROPYL}-CARBOXAMIDO-4-METHYL-6-(3,4-DIFL UOROPHENYL)-2-OXO-PYRIMIDINE: To a solution of (+)-1-(3 bromo-propylcarbamoyl)- 6-(3,4-difluorophenyl)-4-methyl 2-oxo-1,6-dihydro-pyrimidine-5- carboxylic acid methyl 5 ester (0.200 g, 0.500 mmol) and (S)-(+)-3-methyl-1-(2 nitrophenyl)-piperazine (0.170 g, 0.750 mmol) in 20 mL of anhydrous acetone was added powdered K 2
CO
3 (0.34 g, 3.5 mmol) and KI (0.07 g, 0.5 mmol) and the resulting suspension was heated at reflux temperature for 10 h. 10 TLC indicated a new spot for the product (Rf = 0.3, 3/0.5 EtOAc/MeOH) and mostly the starting material. The suspension was cooled, filtered and the solvent was evaporated and the residue was purified by column chromatography (EtOAc/MeOH, 5/1). (+)-1,2,3,6 15 Tetrahydro-1-{N-[2-(S)-methyl)-4-(2-nitrophenyl)piperazin -1-yl)-propyl}-carboxamido-4-methyl-6-(3,4 difluorophenyl)-2-oxo-pyr-imidine was obtained as yellow oil (0.030 g, 10% yield). The HCl salt was prepared by the addition of HC1 in ether to a solution of the product 20 in dichloromethane, followed by evaporation of the solvents; mp 150-153 'C; [a]D = 58.3 (c = 0.3, MeOH); 1 H NMR (CD 3 OD)d 1.04 (d, J=6.0 Hz, 3 H), 1.71-1.78 (m, 2 H), 2.33-2.49 (m, 3 H), 2.42 (s, 3 H), 2.55-2.92 (m, 5 H), 3.00-3.10 (m, 3 H), 3.34 -3.42 (m, 2 H), 3.72 (s, 3 H), 25 6.71 (s, 1 H), 7.01-7.32 (m, 6 H), 7.46 (dt, J=0.7 Hz, J=8.4 Hz, 1 H), 7.74 (dd, J=1.5, 8.4 Hz, 1 H), 8.82 (t, J=3.9 Hz, 1 H) . Anal calcd.. for C 2 8
H
3 3
N
6
F
9 0 6 + 0.20 CH2Cl 2 C, 52.92; H, 5.26; N, 13.13. Found: C, 52.84; H, 5.68; N, 12.94. 30 Example 35 1,2,3,6-TETRAHYDRO-1{N-[4-(2'-METHYL-PHENYL)PIPERAZIN-1-Y L]-PROPYL}-CARBOXAMIDO-4-METHYL-6-(3,4 DIFLUOROPHENYL)-2-OXO- PYRIMIDINE: The amine used was WO 02/06245 PCT/USO1/21286 -178 4-(2'-methyl-phenyl)piperazine. 1H NMR61.75-1.80 (m, 2 H), 2.29 (s, 3 H), 2.42 (s, 3 H), 2.41-2.48 (m, 2 H), 2.58-2.62 (m, 4 H), 2.91-2.97 (m, 4 H), 3.35 -3.42 (m, 2 H), 3.72 (s, 3 H), 6.71 (s, 1 H), 6.97-7.26 (m, 8 H), 5 8.81 (t, J=3.9 Hz, 1 H). The product was dissolved in ether and 1 N HCl in ether was added. The ether was evaporated, giving the dihydrochloride salt; mp 66-71 0 C. Anal calcd. for C,,H 3
N
5 F2O 4 Cl, + 1.75 acetone: C, 55.73; H, 6.40; N, 9.78. Found; C, 56.16; H, 6.29; N, 10.06. 10 Example 36 (+)-1,2,3,6-TETRAHYDRO-5-METHOXYCARBONYL-4-METHOXYMETHYL 2-OXO-1-{N-[3-(4-METHYL-4-PHENYL PIPERIDINE-1-YL]PROPYL} 6-(3,4-DIFLUOROPHENYL) PYRIMIDINE: Hygroscopic; [clD = + 15 82.1(c = 0.31, MeOH); 'H NMR 61.14 (s, 3 H), 1.61-1.72 (m, 4 H), 2.03-2.08 (m, 2 H), 2.25 (t, J=7.2 Hz, 2 H), 2.30-2.42 (m, 4 H), 3.19-3.31 (m, 2 H), 3.40 (s, 3 H), 3.63 (s, 3 H), 4.60 (s, 2 H), 6.60 (s, 1 H), 6.97-7.29 (m, 8 H), 7.63 (br s, 1 H), 8.78 (t, J=5.7 Hz, 1 H) . 20 Anal calcd. for C 30
H
37
N
4 0 5 F2Cl + CHCl 0 : C, 53.80; H, 5.68; N, 8.10. Found: C, 53.79; H, 6.03; N, 7.83. EXAMPLE 37 5-(5-BUTYL-2-THIENYL)PYRIDO[2,3-d]PYRIMIDINE 25 2, 4, 7 (1H, 3H, 8H) -TRIONE WO 02/06245 PCT/USO1/21286 179 General Procedure for the reaction ,opyrimidine-3 carboxylic acid-4-nitrophenyl esters with amines: A solution of substituted pyrimidine-3-carboxylic acid 4-nitrophenyl ester ((0.29 mmol) and a substituted 4 5 phenyl-l-(3-propylaminopiperidine (0.30 mmol) in 10 mL of anhydrous THF was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography. 10 Example 38 METHYL (4S)-3-[({3-[4-(3-AMINOPHENYL)-1 PIPERIDINYL]PROPYL}AMINO)CARBONYL]-4-(3,4 DIFLUOROPHENYL)-6-(METHOXYMETHYL)-2-OXO-1,2,3,4 TETRAHYDRO-5-PYRIMIDINECARBOXYLATE: H NMR (400 MHz, 15 CDC) 8 7.80 (s, 1H), 7.22-7.02 (m, 2H), 6.95 (t, 2H, J=8.7 Hz), 6.63-6.44 (m, 4H), 4.56 (ABq, 2H), 3.62 (s, 3H), 3.33 (s, 3H), 3.32 (m, 4H), 2.96 (br s, 2H), 2.34 (t, 2H, J=7.5 Hz), 2.11-1.94 (m, 3H), 1.81-1.64 (m, 4H); ESMS m/e: 572.3 (M + H)+. 20 Example 39 The product was obtained according to the method described for Example 40. 25 METHYL (4S)-4-(3,4-DIFLUOROPHENYL)-3-({[3-(4-{3 [(METHOXYACETYL)AMINO]PHENYL}-1 PIPERIDINYL)PROPYL]AMINO}CARBONYL)-6-(METHOXYMETHYL)-2 OXO-1,2,3,4-TETRAHYDRO-5-PYRIMIDINECARBOXYLATE: 15.6 mg (69% yield); 'H NMR (400 MHz, CDC 3 ) 6 9.01 (s, 1H), 8.25 30 (s, 1H), 7.60 (s, 1H), 7.37 (d, 1H, J=7.2 Hz), 7.30-7.05 (m, 5H), 7.02 (d, 1H, J=8.0 Hz), 6.71 (s, 1H), 4.70 (s, 2H), 4.03 (s, 2H), 3.73 (s, 3H), 3.53 (s, 3H), 3.47 (s, 3H), 3.42-3.33 (m, 2H), 3.08 (br s, 2H), 2.49 (br s, WO 02/06245 PCT/USO1/21286 180 2H) , 2.20 (s, 2H), 2.07 (br s, 1H), 1.97-1.75 (m, 4H); ESMS m/e: 644.3 (M + H)+ Example 40 5 METHYL (4S)-4-(3,4-DIFLUOROPHENYL)-3-({[3-(4-{3-[(3,3 DIMETHYLBUTANOYL)AMINO]PHENYL}-1 PIPERIDINYL)PROPYL]AMINO}CARBONYL)-6-(METHOXYMETHYL)-2 OXO-1,2,3, 4 -TETRAHYDRO-5-PYRIMIDINECARBOXYLATE 10 To the 20 ml vial was added methyl (4S)-3-[({3-[4-(3 aminophenyl)-l-piperidinyl]propyl}amino)carbonyl]-4 (3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4 tetrahydro-5-pyrimidinecarboxylate (0.035 mmol), an acid chloride or sulfonyl chloride (1.5 eq), N,N 15 diisopropylethylamine (5 eq) and dichloromethane (2 ml) at room temperature. The reaction mixture was stirred at room temperature for 24 h, at which time the TLC analysis indicated the reaction was completed. The reaction mixture was concentrated to a small volume and 20 purified by preparative TLC (silica, 2000 microns, 95:5 = dichloromethane : methanol with 1% of isopropylamine) to give 5.6 mg of methyl (4S)-4-(3,4-difluorophenyl)-3
({[
3
-(
4
-{
3 -[(3,3-dimethylbutanoyl)amino]phenyl}-1 piperidinyl)propyllaminolcarbonyl)-6-(methoxymethyl)-2 25 oxo-1, 2
,
3
,
4 -tetrahydro-5-pyrimidinecarboxylate: 24.6% yield; 1 H NMR (400 MHz, CDC3) 6 7.50 (s, 1H), 7.26 (d, 1H, J=8.3 Hz), 7.15-7.02 (m, 5H), 6.88 (d, 1H, J=8.3 Hz), 6.55 (s, 1H), 4.56 (ABq, 2H), 3.62 (s, 3H), 3.32 (s, 3H), 3.25 (t, 4H, J=9.0 Hz), 2.99 (d, 2H, J=10.8 30 Hz), 2.49-2.37 (m, 3H), 2.08 (t, 2H, J=11.7 Hz), 1.78 1.65 (m, 14H); ESMS m/e: 670.4 (M + H)+.
WO 02/06245 PCT/USO1/21286 181 Example 41 The product was obtained according to the method described for methyl ( 4
S)-
4 -(3,4-difluorophenyl)-3-({[3 (4-{3-[( 3
,
3 -dimethylbutanoyl)amino]phenyl}-1 5 piperidinyl)propyl]amino}carbonyl)-6-(methoxymethyl)-2 oxo-1,2,3, 4 -tetrahydro-5-pyrimidinecarboxylate. METHYL ( 4
S)-
4
-(
3
,
4 -DIFLUOROPHENYL)-6-(METHOXYMETHYL)-2 OXO-3-{[(3-{4-[3-(PROPIONYLAMINO)PHENYL]-1 10 PIPERIDINYL}PROPYL)AMINO]CARBONYL}-1,2,3,4-TETRAHYDRO-5 PYRIMIDINECARBOXYLATE: 9.9 mg (45% yield) 5 'H NMR (400 MHz, CDC1 3 ) 8 7.36 (s, 1H), 7.28 (d, 1H, J=8.0 Hz), 7.16 7.02 (m, 5H), 6.86 (d, 1H, J=7.6 Hz), 6.54 (s, 1H), 4.56 (ABq, 2H), 3.62 (s, 3H), 3.32 (s, 3H), 3.27-3.19 (m, 15 4H), 2.95 (d, 2H, J=10.3 Hz), 2.41 (m, 1H), 2.34 (t, 2H, J=7.7 Hz), 2.28 (q, 2H, J=7.6 Hz), 2.01 (t, 2H, J=11.1 Hz), 1.73-1.64 (m, 8H); ESMS m/e: 628.4 (M + H)+ Example 42 20 The product was obtained according to the method described for methyl ( 4 S)-4-(3,4-difluorophenyl)-3-({[3 (4-{3-[( 3 ,3-dimethylbutanoyl)amino]phenyl}-1 piperidinyl)propyllamino}carbonyl)-6-(methoxymethyl)-2 oxo-1,2,3, 4 -tetrahydro-5-pyrimidinecarboxylate. 25 METHYL (4S)-4-(3,4-DIFLUOROPHENYL)-6-(METHOXYMETHYL)-3
({[
3
-(
4
-{
3 -[(3-METHYLBUTANOYL)AMINO]PHENYL}-1 PIPERIDINYL)PROPYL]AMINOICARBONYL)-2-OXO-1,2,3,4 TETRAHYDRO-5-PYRIMIDINECARBOXYLATE: 10.4 mg (45% yield) 30 6 'H NMR (400 MHz, CDCI 3 ) 8 7.36 (s, 1H), 7.28 (d, 1H, J=7.9 Hz), 7.16-7.03 (m, 5H), 6.88 (d, 1H, J=7.4 Hz), 6.56 (s, 1H), 4.56 (ABq, 2H), 3.62 (s, 3H), 3.32 (s, 3H), 3.25 (t, 4H, J=6.7 Hz), 2.98 (d, 2H, J=11.1 Hz), WO 02/06245 PCT/USO1/21286 182 2.43 (m, 1H), 2.38 (t, 2H, J=7.5 Hz), 1.13 (d, 2H, J=7.5 Hz), 2.10-2.01 (m, 2H), 1.75-1.64 (m, 6H), 0.91 (d, 6H, J=5.8 Hz); ESMS m/e: 656.4 (M + H)+ 5 Example 43 The product was obtained according to the method described for methyl (4S)-4-(3,4-difluorophenyl)-3-({[3 (4-{3-[ (3,3-dimethylbutanoyl) amino]phenyl}-1 piperidinyl)propylamino}carbonyl)-6-(methoxymethyl)-2 10 oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate. METHYL (4S)-4-(3,4-DIFLUOROPHENYL)-3-{[(3-{4-[3 (ISOBUTYRYLAMINO)PHENYLI-1 PIPERIDINYL}PROPYL)AMINO]CARBONYL}-6-(METHOXYMETHYL)-2 15 OXO-1,2,3,4-TETRAHYDRO-5-PYRIMIDINECARBOXYLATE: 16.4 mg (73% yield) 8 "H NMR (400 MHz, CDCl 3 ) 6 7.37 (s, 1H), 7.28 (d, 1H, J=7.3 Hz), 7.16-7.01 (m, 5H), 6.88 (d, 2H, J=7.3 Hz), 6.54 (s, 1H), 4.56 (ABq, 2H), 3.62 (s, 3H), 3.32 (s, 3H), 3.25 (t, 2H, J=6.8 Hz), 3.23-3.18 (m, 2H), 3.03 20 (d, 2H, J=11.7 Hz), 2.57-2.48 (m, 1H), 2.43 (t, 2H, J=8.0 Hz), 2.14 (t, 2H, J=9.4 Hz), 1.8-1.65 (m, 5H), 1.09 (d, 6H, J=6.3 Hz); ESMS m/e: 642.4 (M + H)+ Example 44 25 The product was obtained according to the method described for methyl (4S)-4-(3,4-difluorophenyl)-3-({[3 (4-{3-[(3,3-dimethylbutanoyl)amino]phenyl}-1 piperidinyl)propyl]amino)carbonyl)-6-(methoxymethyl)-2 oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate. 30 METHYL (4S)-3-{[(3-{4-[3-(BUTYRYLAMINO)PHENYL]-1 PIPERIDINYL}PROPYL)AMINO]CARBONYL}-4-(3,4 DIFLUOROPHENYL)-6-(METHOXYMETHYL)-2-OXO-1,2,3,4- WO 02/06245 PCT/USO1/21286 183 TETRAHYDRO-5-PYRIMIDINECARBOXYLATE: 14.7 mg (65.5% yield) 5 1 H NMR (400 MHz-, CDC 3 ) 6 7.38 (s, 1H), 7.26 (s, 1H), 7.17-6.99 (m, 5H), 6.87 (s, iH), 6.55 (s, 1H), 4.56 (ABq, 2H), 3.63 (s, 3H), 3.33 (s, 3H), 3.28-3.17 (m, 5 6H), 3.0 (br s, 2H), 2.51-2.36 (m, 3H), 2.25 (t, 2H, J=5.0 Hz), 2.10 (br s, 2H), 1.8-1.56 (m, 6H), 0.90 (t, 3H, J=5.0 Hz); ESMS m/e: 642.4 (M + H)+. Example 45 10 (4R)-N-(3-{4-[3-(BUTYRYLAMINO)PHENYL]-1 PIPERIDINYLIPROPYL)-4-(3,4-DIFLUOROPHENYL)-6 (METHOXYMETHYL)-2-OXO-1,2,3,4-TETRAHYDRO-5 PYRIMIDINECARBOXAMIDE 15 Method: (4R)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo 1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid: A stirred mixture of one mole equivalent of methyl (4R)-4 20 (3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4 tetrahydro-5-pyrimidinecarboxylate (10.0 g, 32.0 mmol) and lithium hydroxide (2 equivalents, 1.53 g, 64.0 mol) in H 2 0-THF (2:1, 300 mL) was heated at reflux temperature for 1 h. The reaction mixture was concentrated, 25 dissolved in water, washed with ethyl acetate and acidified (1 N HCl) to pH 3-4 -(pH paper). The precipitated product was collected, washed with water and dried under reduced pressure to give the desired product in 90% yield. 30 (4R)-4-(3,4-DIFLUOROPHENYL)-6-(METHOXYMETHYL)-N-[3-(4 (3-NITROPHENYL)-3,6-DIHYDRO-1(2H)-PYRIDINYL)PROPYL]-2 OXO-1,2,3,4-TETRAHYDRO-5-PYRIMIDINECARBOXAMIDE:
A
WO 02/06245 PCT/USO1/21286 184 solution of (4R)-4-(3,4-difluorophenyl)-6 (methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5 pyrimidinecarboxylic acid (1.2 eq), EDC (1.5 Eq.), N methylmorpholine (2.0 Eq.) in dichloromethane was 5 stirred at room temperature for 15 minutes, followed by addition of 3-(4-(3-nitrophenyl)-3,6-dihydro-1(2H) pyridinyl)-1-propanamine (1.0 eq.) to the reaction mixture. The resulting solution was stirred for 18 hours, concentrated and chromatographed on silica to 10 give (4R)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-N-[3 (4-(3-nitrophenyl)-3,6-dihydro-1(2H)-pyridinyl)propyl] 2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxamide. (4R)-N-{3-[4-(3-AMINOPHENYL)-1-PIPERIDINYL]PROPYL}-4 15 (3,4-DIFLUOROPHENYL)-6-(METHOXYMETHYL)-2-OXO-1,2,3,4 TETRAHYDRO-5-PYRIMIDINECARBOXAMIDE: A mixture of (4R)-4 (3,4-difluorophenyl)-6-(methoxymethyl)-N-[3-(4-(3 nitrophenyl)-3,6-dihydro-1(2H)-pyridinyl)propyl]-2-oxo 1,2,3,4-tetrahydro-5-pyrimidinecarboxamide, 10% Pd/C in 20 ethanol was hydrogenated .(balloon method) for 2 days. The reaction mixture was filtered through Celite 545, washed with ethanol and concentrated to give the desired product. 25 (4R)-N-(3-{4-[3-(BUTYRYLAMINO)PHENYL]-1 PIPERIDINYL}PROPYL) -4- (3, 4-DIFLUOROPHENYL) -6 (METHOXYMETHYL) -2-OXO-1,2,3, 4-TETRAHYDRO-5 PYRIMIDINECARBOXAMIDE: Into a 20 mL vial was added(4R) N-{3-[4-(3-aminophenyl)-1-piperidinyllpropyll-4-(3,4 30 difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4 tetrahydro-5-pyrimidinecarboxamide (0.040 mmol), acid chloride (1.5 eq) and N,N-diisopropylethylamine (5.0 eq) in 2.0 mL of dichloromethane at room temperature. After WO 02/06245 PCT/USO1/21286 185 24 hrs, the reaction mixture was concentrated in vacuo and purified by preparative TLC (silica, 2000 microns, 95:5 = dichloromethane :.methanol with 1% of isopropylamine) to give 9.2 mg (45% yield) of the 5 desired product: 1H NMR (400'MHz, CD 3 0D) 3 7.49 (s, 1H), 7.25 (d, 1H, J=7.6 Hz), 7.20-7.02 (m, 5H), 6.91 (d, 1H, J=8 Hz), 5.29 (s, 1H), 4.24 (ABq, 2H), 3.30 and 3.24 (two s, 3H), 3.46-3.12 (m, partially hidden by three s, 4H), 2.74 (br s, 4H), 2.25 (t, 2H, J=8.2 Hz), 2.04-1.69 10 (m, 7H), 1.63 (sextet, 2H, J=7.4 Hz), 0.91 (t, 3H, 7.4 Hz); ESMS m/e: 584.4 (M + H)+. Example 46 The product was obtained according to the method 15 described for (-4R)-N-(3-{4-[3-(butyrylamino)phenyl]-l piperidinyllpropyl)-4-(3,4-difluorophenyl)-6 (methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5 pyrimidinecarboxamide. 20 (4R)-4-(3,4-DIFLUOROPHENYL)-6-(METHOXYMETHYL)-2-OXO-N (3-{4-[3-(PROPIONYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL) 1,2,3,4-TETRAHYDRO-5-PYRIMIDINECARBOXAMIDE: 5.6 mg (24.6% yield); 1 H NMR (400 MHz, CD30D) 5 7.56 (s, 1H), 7.35 (d, 1H, J=6.9 Hz), 7.3-7.03 .(m, 4H), 7.17 (br s, 25 1H), 6.99 (d, 1H, J=7.0 Hz), 5.45 (s, 1H), 4..33 (ABq, 2H), 3.41 (s, 3H), 3.37-3.23 (m, partially hidden, 4H), 2.8 (br s, 4H), 2.39 (d, 2H, J=9.3 Hz), 2.14-1.78 (m, 7H), 1.21 (t, 3H, J=7.6 Hz); ESMS m/e: 570.4 (M + H)*. 30 Example 47 The product was obtained according to the method described for (4R)-N-(3-{4-[3-(butyrylamino)phenyl]-l piperidinyl}propyl)-4-(3,4-difluorophenyl)-6- WO 02/06245 PCT/USO1/21286 186 (methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5 pyrimidinecarboxamide. (4R)-4-(3,4-DIFLUOROPHENYL)-6-(METHOXYMETHYL)-N-[3-(4 5 {3-[(3-METHYLBUTANOYLIAMINO]PHENYL}-1 PIPERIDINYL)PROPYL]-2-OXO-1,2,3,4-TETRAHYDRO-5 PYRIMIDINECARBOXAMIDE: 11.1 mg (46% yield); H NMR (400 MHz, CD 3 0D) 8 7.81 (d, 1H, J=8.5 Hz), 7.6 (s, 1H), 7.55 (s, 1H), 7.36 (br s, 1 H), 7.31-7.17 (m, 3H), 7.01 (t, 1H, 10 J=6.7 Hz) 6.64-6.61 (m, 1H), 5.45 (br s, 1H), 4.32 (ABq, 2H), 3.94 and 3.87 (two s, 3H), 3.42-3.12 (m, partially hidden, 2H), 3.1 (br s, 2H), 3.0 (t, 2H, J=11.1 Hz), 2.79-2.57 (m, 4H), 2.27-1.73 (m, 8H), 1.19 and 1.01 (two d, 6H, J=6.6 Hz); ESMS m/e: 598.4 (M + H)+. 15 Example 48 The product was obtained according to the method described for (4R)-N-(3-{4-[3-(butyrylamino)phenyl]-1 piperidinyl}propyl)-4-(3,4-difluorophenyl)-6 20 (methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5 pyrimidinecarboxamide. (4R)-4-(3,4-DIFLUOROPHENYL)-6-(METHOXYMETHYL)-N-[3-(4 {3-[(2-METHYLBUTANOYL)AMINO]PHENYL}-1 25 PIPERIDINYL)PROPYL]-2-OXO-1,2,3,4-TETRAHYDRO-5 PYRIMIDINECARBOXAMIDE: 6.7 mg (28% yield); 1 H NMR (400 MHz, CD 3 0D) 8 7.59 (s, 1H), 7.35 (br s, 1H), 7.3-7.2 (m, 3H), 7.17 (br s, 1H), 7.01 (d, 1H, J=6.8 Hz), 5.45 (s, 1H), 4.33 (ABq, 2H), 3.39 (s, 3H), 3.29 (m, 2H), 2.84 30 (br s, 4H), 2.42 (m, 1H), 2.14-1.78 (m, 9H), 1.7 (m, 1H), 1.49 (m, 1H), 1.20 (d, 3H, J=6.7 Hz), 0.95 (t, 3H, J=6.6 Hz); ESMS m/e: 598.4 (M + H)+.
WO 02/06245 PCT/USO1/21286 187 Example 49 The product was obtained according to the method described for (4R)-N-(3-{4-[3-(butyrylamino)-phenyl]-1 piperidinyl}propyl)-4-(3,4-difluorophenyl) -6 5 (methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5 pyrimidinecarboxamide. (4R)-4-(3,4-DIFLUOROPHENYL)-N-[3-(4-{3-[(3,3 DIMETHYLBUTANOYL)AMINO]PHENYL}-1-PIPERIDINYL)PROPYL]-6 10 (METHOXYMETHYL)-2-OXO-1,2,3,4-TETRAHYDRO-5 PYRIMIDINECARBOXAMIDE: 1.1 mg (4.4% yield); 1H NMR (400 MHz, CD 3 0D) 8 7.6-6.91 (m, 7H), 5.43 (s, 1H), 4.31 (ABq, 2H), 3.40 (s, 3H), 3.27-1.26 (m, 17 H), 1.09 (s, 9H); ESMS m/e: 612.4 (M + H)*. 15 Example 50 The product was obtained according to the method described for (4R)-N-(3-{4-[3-(butyrylamino)phenyll-1 piperidinyllpropyl)-4-(3,4-difluorophenyl)-6 20 -(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5 pyrimidinecarboxamide. (4R)-4-(3,4-DIFLUOROPHENYL)-N-(3-{4-[3 (ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-6 25 (METHOXYMETHYL)-2-OXO-1,2,3,4-TETRAHYDRO-5 PYRIMIDINECARBOXAMIDE: 12.7 mg (54% yield); IH NMR (400.. MHz, CD 3 0D) 8 7.59(s, 1H), .7.36 (d, 1H, J=8.6 Hz), 7.31 7.07 (m, 4H), 7.01 (d, 1H, J=6.5 Hz), 5.39 (s, 1H), 4.34 (ABq, 2H), 3.35 (s, 3H), 3.33-3.19 (m, partially hidden, 30 2H), 3.08-2.72 (m, 4H), 2.63 (t, 2H, J=7.2 Hz), 2.14 1.82 (m, 8H), 1.19 (d, 6H, J=6.9 Hz); ESMS m/e: 5.84.4 (M + H)+.
WO 02/06245 PCT/USO1/21286 188 Example 51 The synthetic method is the same as described for the synthesis of (4S)-N-(3-{4-[3-(acetylamino)phenyl)-l piperidinyl}propyl)-4-(3,5-difluorophenyl)-2-oxo-1,3 5 oxazolidine-3-carboxamide. 5-ACETYL-N-(3-{4-[3-'(ACETYLAMINO)PHENYL]-1 PIPERIDINYLIPROPYL)-4-METHYL-2-OXO-6-(3,4,5 TRIFLUOROPHENYL)-3,6-DIHYDRO-1(2H) 10 PYRIMIDINECARBOXAMIDE: 14.5 mg (46% yield); 1 H NMR (400 MHz, CDC 3 ) 8 9.56 (s, 1H), 9.20 (s, 1 H), 8.21 (s, 1H), 7.52 (s, 1H), 7.18 (t, 1H, J=7.8 Hz), 7.07-6.75 (m, 5H), 3.59-3.37 (m, 1H), 3.48-3.38 (m, 1H), 3.08 (br s, 2H), 2.57-2.39 (m, 5H), 2.25 (s, 3H), 2.21 (s, 3H), 2.19-1.59 15 (m, 9H); ESMS m/e: 586.3 (M + H)+; Anal. Calc. for
C
30
H
34
F
3
N
5 0 4 +0.1CHC13: C, 60.50; H, 5'.75; N, 11.72. Found: C, 60.59; H, 5.40; N, 11.73. Example 52 20 The synthetic method is the same as described for the synthesis of (4S)-N-(3-{4-[3-(acetylamino)phenyll-1 piperidinyl}propyl)-4-(3,5-difluorophenyl)-2-oxo-1,3 oxazolidine-3-carboxamide. 25 BENZYL 3-{[(3-{4-[3-(ACETYLAMINO)PHENYL]-1 PIPERIDINYL}PROPYL)AMINO]CARBONYL}-4-( 2
,
4 DIFLUOROPHENYL)-6-ETHYL-2-OXO-1,2,3,4-TETRAHYDRO-5 PYRIMIDINECARBOXYLATE: 14.8 mg (41% yield); 1H NMR (400 MHz, CDC1 3 ) 8 9.05 -(br s, 1H), 8.14 (s, 1H), 7.47 (s, 1H), 30 7.37-7.21 (m, 8H), 7.18 (t, 1H, J=7.7 Hz), 6.94 (d, 1H, J=6.9 Hz), 6.87 (d, 1H, J=7.4 Hz), 6.7-6.62 (m, 3H), 5.09 (q, 2H, J=17.8 Hz), 3.48-3.24 (m, 2H), 3.04 (ABq, 2H), 2.88-2.71 (m, 2H), 2.52-2.39 (m, 2H), 2.19 (s, 3H), WO 02/06245 PCT/USO1/21286 189 2.17-1.88 (m, 3H), 1.77-1.58 (m, 3H), 1.19 (t, 3H, J=7.5 Hz); ESMS m/e: 674.4 (M + H)+. Example 53 5 The synthetic method is the same as described for the synthesis of (4S)-N-(3-{4-[3-(acetylamino)phenyl]-1 piperidinyllpropyl) -4- (3, 5-difluorophenyl) -2-oxo-1, 3 oxazolidine-3-carboxamide. 10 N-(3-{4-[3-(ACETYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-4 (1,3-BENZODIOXOL-5-YL)-2,5-DIOXO-1,2,5,7 TETRAHYDROFURO[3,4-D] PYRIMIDINE-3 (4H) -CARBOXAMIDE: 8.75 mg (28% yield); 1 H NMR (400 MHz, CDCl 3 ) 8 9.81 (s, 1H), 8.14 (s, 1H), 7.53 (s, 1H). 7.21 (t, 1H, J=7.7 Hz), 6.99 15 (d, 1H, J=7.7 Hz), 6.91-6.7 (m, 4H), 6.42 (s, 1H), 5.9 (s, 2H), 4.75 (s, 2H), 3.61-3.5 (m, 1H), 3.37-3.27 (m, 1H), 3.08 (br s, 2H), 2.56-2.40 (m, 3H), 2.18 (s, 3H), 2.16-1.85 (m, 4H), 1.78-1.6 (m, 5H); ESMS m/e: 576.3 (M + H)*. 20 Example 54 The synthetic method is the same as described for the synthesis of (4S)-N-(3-{4-[3-(acetylamino)phenyl]-1 piperidinyl}propyl)-4-(3,5-difluorophenyl) -2-oxo-1,3 25 oxazolidine-3-carboxamide. METHYL 1-{[(3-{4-[3-(ACETYLAMINO)PHENYLI-1 PIPERIDINYL}PROPYL)AMINOICARBONYL}-2-[(4 METHOXYBENZYL)SULFANYL]-4-METHYL-6-(4-NITROPHENYL)-1,6 30 DIHYDRO-5-PYRIMIDINECARBOXYLATE: 10.1 mg (26% yield); 1H NMR (400 MHz, CDC 3 ) 6 8.02 (d, 2H, J=7.5 Hz), 7.53 (br s, 1H), 7.44-7.27 (m, 6H), 7.14 (d, 2H, J=8.5 Hz), 6.99 (d, 1H, J=7.6 Hz), 6.75 (d, 2H, J=8.5 Hz), 6.2 (s, 1H), 4.23 WO 02/06245 PCT/USO1/21286 190 (ABq, 2H), 3.78 (s, 3H), 3.7 (s, 3H), 3.58-3.48 (m, 1H) 3.37-3.26 (m, 2H), 3.04 (m, 2H), 2.61-2.43 (m, 3H), 2.41 (s, 3H), 2.16 (s, 3H), 2.15-1.64 (m, 8H); ESMS m/e: 729.3 (M + H)+. 5 Example 55 The synthetic method is the same as described for the synthesis of (4S)-N-(3-{4-[3-(acetylamino)phenyl]-1 piperidinyl}propyl)-4-(3,5-difluorophenyl)-2-oxo-1,3 10 oxazolidine-3-carboxamide. N-(3-{4-[3-(ACETYLAMINO)PHENYL]-1-PIPERIDINYL)PROPYL)-4 (2,1,3-BENZOXADIAZOL-5-YL)-2,5-DIOXO-1,2,5,7 TETRAHYDROFURO[3,4-D]PYRIMIDINE-3(4H)-CARBOXAMIDE: 7.7 15 mg (12% yield); 'H NMR (400 MHz, CDC 3 ) 8 7.97-6.83 (m, 7H), 6.49 (s, 1H), 5.51(s, 1H), 3.43-2.02 (m, 17 H), 1.82 (s, 3H); ESMS m/e: 574.3 (M + H)'. Example 56 20 The synthetic method is the same as described for the synthesis of (4S)-N-(3-{4-[3-(acetylamino)phenyl]-1 piperidinyl}propyl)-4-(3,5-difluorophenyl)-2-oxo-1,3 oxazolidine-3-carboxamide. 25 METHYL (4S)-3-{[(3-{4-[3-(ACETYLAMINO)PHENYL]-1 PIPERIDINYLIPROPYL)AMINO]CARBONYL}-4-(3,4 DIFLUOROPHENYL)-6-METHYL-2-OXO-1,2,3,4-TETRAHYDRO-5 PYRIMIDINECARBOXYLATE: 16.6 mg (52% yield); 'H NMR (400 MHz, CDCl 3 ) 5 9.55 '(br s, 1H), 9.07 (s, 1H), 8.19 (s, 30 1H), 7.54 (s, 1H), 7.25-6.98 (m, 4H), 6.95 (d, 1H, J=8.0 Hz), 6.81 (d, 1H, J=7.5 Hz), 6.69 (s, 1H), 3.70 (s, 3H), 3.57-3.34 (m, 2H), 3.06 (t, 2H, J=11.6 Hz), 2.47 (t, 2H, J=8.1 Hz), 2.42 (s, 3H), 2.20 (s, 3H), 2.18-1.61 (m, WO 02/06245 PCT/USO1/21286 191 9H) ; ESMS m/e: 584.3 (M + H)*; Anal. Calc. for
C
30
H
3 5
F
2
N
5 0+0.25CHCl 3 : C, 59.23; H, 5.79; N, 11.42. Found: C, 59.61; H, 5.31; N, 11.48.
WO 02/06245 PCT/USO1/21286 -192 Peptide Synthesis: Abbreviations: Fmoc: 9-Fluorenyloxycarbonyl-; Trityl: 5 triphenylmethyl-; tBu-: tertiary butyl ester; OtBu-: tertiary butyl ether; Ng: N-guanidinyl; Nin: N-Indole; MBHA : methylbenzhydlamine; DMF: N,N-dimethylformamide; NMP: N-Methylpyrrolidinone; DIEA: diisopripylethyl amine; TFA: trifluoroacetic acid. 10 Small scale peptide syntheses were performed either manually, by using a sintered glass column with argon pressure to remove solvents and reagents, or by using an Advanced ChemTech 396-9000 automated peptide synthesizer 15 (Advanced ChemTech, Louisville, KY). Large scale peptide syntheses were performed on a CS Bio 536 (CS Bio Inc., San Carlos, CA). Fmoc-Alanine-OH, Fmoc-Cysteine (Trityl)-OH, Fmoc-Aspartic acid(tBu)-OH, Fmoc-Glutamic acid(tBu)-OH, Fmoc-Phenylalanine-OH, 20 Fmoc-Glycine-OH, Fmoc-Histidine(Trityl)-OH, Fmoc-Isoleucine-OH, Fmoc-Lysine (Boc)-OH, Fmoc-Leucine-OH, Fmoc-Methionine-OH, Fmoc-Asparagine(Trityl)-OH, Fmoc-Proline-OH, Fmoc-Glutamine (Trityl)-OH, Fmoc-Arginine(Ng-2,2,4,6,7-Pentamethyldihydrobenzofuran-5 25 -sulfonyl)-OH, Fmoc-Serine(OtBu-OH, Fmoc-Threonine(OtBu)-OH, Fmoc-Valine-OH, Fmoc-Tryptophan(NinBoc)-OH, Fmoc-Tyrosine(OtBu)-OH, Fmoc-Cyclohexylalanine-OH, and Fmoc-Norleucine , Fmoc -O-benzyl-phosphotyrosine were used as protected amino 30 acids. Any corresponding D-amino acids had the same side-chain protecting groups, with the exception of Fmoc-D-Arginine, which had a Ng-2,2,5,7,8-pentamethyl chroman-6-sulfonyl protecting group. 35 Peptides with C-terminal amides were synthesized on solid WO 02/06245 PCT/USO1/21286 -193 phase using Rink amide-MBHA resin. The Fmoc group of the Rink Amide MBHA resin was removed by treatment with 30% piperidine in DMF for 5 and 30 minutes respectively. After washing with DMF (3 times), methanol (2 times) and 5 DMF/NMP (3 times), the appropriate Fmoc-protected amino acid (4 eq.) was coupled for 2 hours with HBTU or HATU (4eq.) as the activating agent and DIEA (8eq.) as the base. In manual syntheses, the ninhydrin test was used to test for complete coupling of the amino acids. The 10 Fmoc groups were removed by treatment with 30% piperidine in DMF for 5 and 30 minutes respectively. After washing with DMF (3 times), methanol (2 times) and DMF/NMP (3 times), the next Fmoc-protected amino acid (4 eq.) was coupled for 2 hours with HBTU or HATU (4eq.) as the 15 activating agent and DIEA (8eq.) as the base. This process of coupling and deprotection of the Fmoc group was continued until the desired peptide was assembled on the resin. The N-terminal Fmoc group was removed by treatment with 30% piperidine in DMF for 5 and 30 minutes 20 respectively. After washing with DMF (3 times), methanol (2 times), the resin(s) was vacuum dried for 2 hours. Cleavage of the peptide-on-resin and removal of the side chain protecting groups was achieved by treating with TFA : ethanedithiol : thioanisole: m-cresol : water : 25 triisopropylsilane : phenol, 78/5/3/3/3/5/3 (5 mL per 100 mg resin) for 2.5-3 hours. The cleavage cocktail containing the peptide was filtered into a round bottom flask and the volatile liquids were removed by rotary evaporation at 30-40 'C. The peptides were precipitated 30 with anhydrous ether, collected on a medium-pore sintered glass funnel by vacuum filtration, washed with ether and vacuum dried. Peptides with C-terminal acids were synthesized using 35 2-chlorotrityl chloride resin. The first amino acid was WO 02/06245 PCT/USO1/21286 -194 attached to the resin by dissolving 0.6-1.2eq. of the appropriate Fmoc-protected amino acid described above in dichloromethane (a minimal amount of DMF was added to facilitate the dissolution, if necessary). To this was 5 added DIEA (4 eq. Relative to the Fmoc-amino acid) and the solution was added to the resin and shaken for 30-120 minutes. The solvents and the excess reagents were drained and the resin was washed with dichloromethane / methanol / DIEA (17/2/1) (3 times), dichloromethane (3 10 times), DMF (2 times), dichloromethane (2 times), and vacuum dried. The process of deprotection of the Fmoc group and coupling the appropriate Fmoc-protected amino acid was continued as described above, until the desired, fully protected peptide was assembled on the resin. The 15 process for removal of the final Fmoc group and the cleavage and deprotection of the peptides was the same as described above for the peptides with C-terminal amides. Purification of the peptides was achieved by preparative 20 high performance column chromatography (HPLC), using a reverse-phase C-18 column (25 x 250mm) (Primesphere or Vydac) with a gradient of acetonitrile (0.1% TFA) in water (0.1% TFA). The general gradient was from 10%-90% acetonitrile in water over 40 minutes. The fractions 25 corresponding to each peak on the HPLC trace was collected, freeze dried and analyzed by electrospray mass spectrometery. The fraction having the correct mass spectral data corresponding to the desired peptide was then further analyzed by amino acid analysis, if 30 necessary. All purified peptides were tested for homogeneity by analytical HPLC using conditions similar to that described above, but by using a 2.5x250 mm analytical column, and generally were found to have >95% purity. 35 WO 02/06245 PCT/USO1/21286 -195 References: See our published dihydropyrimidinone and oxazolidinone patents as references for the synthesis of the templates 5 and the piperidines. Also, for the synthesis of'the aminopropyl piperidines and the templates, see: Lagu, Bharat, et al., Design and synthesis of novel al 10 adrenoceptor-selective antagonists. 3. Approaches to eliminate opioid agonist metabolites by using substituted phenylpiperazine side chains. J. Med. Chem. (1999), 42(23), 4794-4803. CODEN: JMCMAR ISSN:0022-2623. CAN 132:78527 AN 1999:680975 CAPLUS 15 Dhar, T. G. Murali, et al., Design and Synthesis of Novel a,a Adrenoceptor-Selective Antagonists. 2. Approaches To Eliminate Opioid Agonist Metabolites via Modification of Linker and 4-Methoxycarbonyl-4-phenyl 20 piperidine Moiety. J. Med. Chem. (1999), 42(23), 4778-4793. CODEN: JMCMAR ISSN:0022-2623. CAN 132:18483 AN 1999:680971 CAPLUS Nagarathnam, Dhanapalan, et al., Design and Synthesis of 25 Novel a, Adrenoceptor-Selective Antagonists. 1. Structure-Activity Relationship in Dihydropyrimidinones. J. Med. Chem. (1999), 42(23), 4764-4777. CODEN: JMCMAR ISSN:0022-2623. CAN 132:18482 AN 1999:680967 CAPLUS 30 Wong, Wai C., et al., Design and Synthesis of Novelcha Adrenoceptor-Selective Antagonists. 4. Structure-Activity Relationship in the Dihydropyrimidine Series. J. Med. Chem. (1999), 42(23), 4804-4813. CODEN: JMCMAR WO 02/06245 PCT/USO1/21286 -196 ISSN:0022-2623. CAN 132:30317 AN 1999:680947 CAPLUS Marzabadi, Mohammad R., et al., Design and synthesis of novel dihydropyridine alpha-lA antagonists. Bioorg. 5 Med. Chem. Lett. (1999), 9(19), 2843-2848. CODEN: BMCLE8 ISSN:0960-894X. CAN 132:44482 AN 1999:662323 CAPLUS Wong, Wai C., et al., Alpha-la adrenoceptor selective 10 antagonists as novel agents for treating benign prostatic hyperplasia. Book of Abstracts, 217th ACS National Meeting, Anaheim, Calif., March 21-25 (1999), MEDI-156. CODEN: 67GHA6 AN 1999:92669 CAPLUS 15 Nagarathnam, D., et al., Design, synthesis and evaluation of dihydropyrimidinones as alpha-la selective antagonists: 7. Modification of the piperidine moiety into 4-aminocyclohexane; identification and structure-activity relationship of SNAP 6991 analogs. 20 Book of Abstracts, 217th ACS National Meeting, Anaheim, Calif., March 21-25 (1999), MEDI-110. CODEN: 67GHA6 AN 1999:92624 CAPLUS Lagu, Bharat, et al., Heterocyclic substituted 25 oxazolidinones for use as selective antagonists for human a 1A receptors. PCT Int. Apple. (1998), 258 pp. CODEN: PIXXD2 WO 9857940 Al 19981223 CAN 130:81508 AN 1999:9823 CAPLUS 30 Wong, Wai C., et al., Preparation of piperidinylpropyl aminocarbonyldihydropyrimidones and related compounds as selective adrenergic a 1A receptor antagonists. . PCT Int. Appl. (1998), 314 pp. CODEN: PIXXD2 WO 9851311 A2 19981119 CAN 130:25077 AN 1998:764290 35 CAPLUS WO 02/06245 PCT/USO1/21286 -197 Nagarathnam, Dhanapalan, et al., Design and synthesis of novel a adrenoceptor-selective dihydropyridine antagonists for the treatment of benign prostatic hyperplasia. J. Med. Chem. (1998), 41(26), 5 5320-5333. CODEN: JMCMAR ISSN:0022-2623. CAN 130:110137 AN 1998:742998 CAPLUS For the general procedure for Pd coupling of vinyl triflate and bononic acids or tributyl tin reagents: See, 10 Wuston, Wise Synthesis 1991, 993) (For Typical References, See:Schroeter, G. Ber. (1909) 42, 3356; and Allen, C.F.H..; Bell, A. Org. Syn. Coll. Vol. 3, (1955) 846) 15 For the preparation of the ether N-[4-(benzo-4',5'[H] furanpiperidine refer to W.E.Parham et al, J. Org. Chem. (1976) 41, 2268. 20 For the preparation of the ether piperidine precursor of Example 20, refer to W.E.Parham et al, J. Org. Chem. (1976) 41, 2268. For the preparation of the indane piperidine precursor of 25 Example 21, refer to M.S.Chambers J. Med. Chem. (1992) 35, 2033. For the preparation of the piperidine precursor of Example 23, (K.Hashigaki et al. Chem.Pharm.Bull. (1984) 30 32, 3568.) For the preparation of the piperidine precursor of Example 32, spiro[1H-indane-1,4'-piperidine], refer to M.S.Chambers et al. J. Med. Chem. (1992) 35, 2033.) WO 02/06245 PCT/USO1/21286 -198 00 00 0 0 Zo/ o ;vw cQ 7 oc z ~C) 00 00 0= ~CD ( 00 0 =3 z CD :113 =~ CD 00 OD% 0 WO 02/06245 PCT/US O1/21286 -199 0z zp z z CCD II 0 z 22 o z m' ez 0 0~ 0 C3~ p 0 0 0 ez CD
I
WO 02/06245 PCT/USO1/21286 -200 apA 0*0 ty~ zz 00 0 yz 0 WO 02/06245 PCT/USO1/21286 -201 o -Z=o za + (D2 0 0o 0 0 Z zD 0r -0 0 Q((D 0~j 0 $0 It. Mz c z CD 0c 0~~= z 0 m I WO 02/06245 PCT/USO1/21286 -202 -HI C) 0 (D j-J 0 z+ 0- 0) 0 0 o:; 0 0C (D 0Ir hC) 0.J 0 0 00 0P (D -Ln - to N :10 C) 0J z 0 zz I0 WO 02/06245 PCT/USO1/21286 -203 (D 0 _n CD 0 U (D -- ~ W~dCI 0 .01 0 V . (D (D rt( 0 (D N 11 0D 0o 00 (D 0 CD 0 0 z 1j. CD 0 0 z 1 00 D 0 DZ 0 zS -a WO 02/06245 PCT/USO1/21286 -204 -4-- 0 0 04 w 0 co ICt 0 0 zI hi ZI-a 'B 0 to
I
WO 02/06245 PCT/USO1/21286 -205 0 0 a) 00 00 00 00 00 00 0 z~ 3:N WO 02/06245 PCT/USO1/21286 -206 00 fC D t3' P (~V D (- D (ZD 0L~ 0 (D rtcr CD0 w ~ I(D z- -nz ( to CD Ixa z -n 0
(D
WO 02/06245 PCT/USO1/21286 -207 Im Q0 O~H- 0 (DO ?1 H (DtOP-( (D (DD 0 0 0 (D (<~ D~ -ni - 0 1- DN N :7 W 0 (D 3 I rt 0 (D~ C M :Z H~ 0 0D1 0-t 0 7 0. 0 0: Dl 00 D .0 >=O 0 - (D 3Z (~ D I N o co 00 Z 0 00 0 H Iz Z 0 00 z 1 I Ve WO 02/06245 PCT/USO1/21286 -208 0 0 0 0 0 0 0 0 0
-
-n w~>= 1 0 03 z z 00 + z 0 z / l z 0 0 0 rt z -) rt 0 -/t WO 02/06245 PCT/USO1/21286 -209 * 0 C / z
-
0 =r CD .- K. Cl) '0 D:5< 0 z C0 to 00 -p -- -L = w 3- - (D 3 _ - CD z -. 0 In =- CD= q !V 0 00 00 'r- z z 3V CD ED y
~
1 D =5 0 0 CD 5* 0 j5 =3 0 Is 0.- 6n uiw 0 WD CD ZC -- o0 2 r 0 0 C aw0. 0/ CD -. 0 0 0 0 \- 2 a -' Iz m n 0-i CD 0 2 CD0 0) CD
CD
WO 02/06245 PCT/USO1/21286 -210 I CCD -2 0 z~o CD o0- 0 0~ I to K -u CtC, 00 03 0 00 0 Iz 0 C) 0 12 z 00 <i -t WO 02/06245 PCT/USO1/21286 -211 Scheme 14: Synthesis of Substituted Dihyropyrimidinones and Reverse Dihydropyrimidinones
NO
2 NO 2 reagent 1 N N BOC
NH
2 F 1. base, p-nitrophenyl- F F chloroformate F 2. reagent 1 3. H 2 , Pd/C O 4. acylate or O O 0 NH sulfonylate O N N NH N O N O H N, 0 H H From chiral chromatography F F F 1. LiOH, heat F 2. EDO, reagent 1 3. H 2 , Pd/C 0 0 NH 4. acylate or HN N N H N O sulfonylate O H N N" O O,,N N N x O H H 0 0 From chiral chromatography EDO = ethyl dimethylaminopropyl carbodiimide hydrochloride X = C, S(=O) WO 02/06245 PCT/US01/21286 -212 II. Synthetic Methods for General Structures The examples described in Section I are merely illustrative of the methods used to synthesize MCHl antagonists. 5 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 10 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 15 Green, T.W. and Wuts, P.G.M. (1991) Protection Groups in Organic Synthesis, 24n Edition John Wiley & Sons, New York. III. Oral Compositions As a specific embodiment of an oral composition of a 20 compound of this invention, 100 mg of one of the compounds described herein is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gel capsule. 25 IV. Pharmacological Evaluation of Compounds at Cloned MCH1, NPY, Galanin, and 5-HT2C Receptors The pharmacological properties of the compounds of the present invention were evaluated at one or more of the cloned human MCH1, NPYl, NPY5, GALR1, GALR2, and GALR3 and 30 rat 5-HT2C receptors using protocols described below. Host cells A broad variety of host cells can be used to study heterologously expressed proteins. These cells include but WO 02/06245 PCT/USO1/21286 -213 are not restricted to assorted mammalian lines such as; Cos-7, CHO, LM(tk-), HEK293, etc.; insect cell lines such as; Sf9, Sf21, etc.; amphibian cells such as xenopus oocytes; and others. 5 COS-7 cells are grown on 150 mm plates in DMEM with supplements (Dulbecco's Modified Eagle Medium with 10% bovine calf serum, 4 mM glutamine, 100 units/ml penicillin/100 pg/ml streptomycin) at 37'C, 5% C02. Stock 10 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 15 glutamine, 100 units/ml penicillin/100 pg/ml streptomycin) at 370C, 5% C02- Stock plates of 293 cells are trypsinized and split 1:6 every 3-4 days. Mouse fibroblast LM(tk-) cells are grown on 150 mm plates 20 in D-MEM with supplements (Dulbecco's Modified Eagle Medium with 10% bovine calf serum, 4 mM glutamine, 100 units/ml penicillin/100 pg/ml streptomycin) at 37'C, 5% CO,. Stock plates of LM(tk-) cells are trypsinized and split 1:10 every 3-4 days. 25 Chinese hamster ovary (CHO) cells were grown on 150 mm plates in HAM's F-12 medium with supplements -(10% bovine calf serum, 4 mM L-glutamine and 100 units/ml penicillin/ 100 pg/ml streptomycin) at 370C, 5% C02. Stock plates of 30 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 35 units/ml penicillin/100 pg/ml streptomycin) at 370C, 5% C02- WO 02/06245 PCT/USO1/21286 -214 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 5 culture dishes in TMN-FH media supplemented with 10% fetal calf serum, at 27'C, no CO,. High Five insect cells are grown on 150 mm tissue culture dishes in Ex-Cell 400TM medium supplemented with L-Glutamine, also at 270C, no C02. 10 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. 15 Transient expression DNA encoding proteins to be studied can be transiently expressed in a variety of mammalian, insect, amphibian and other cell lines by several methods including but not restricted to; calcium phosphate-mediated, DEAE-dextran 20 mediated, Liposomal-mediated, viral-mediated, electroporation-mediated and microinjection delivery. Each of these methods may require optimization of assorted experimental parameters depending on the DNA, cell line, and the type of assay to be subsequently employed. 25 A typical protocol for the calcium phosphate method as applied to LM(tk-) cells is described as follows; Adherent cells are harvested approximately twenty-four hours before transfection and replated at a density of 1-2 x 105 30 cells/cm2 in a 100 mm tissue culture dish and allowed to incubate over night at 37'C at 5% C02. 250 pl of a mixture of CaCl 2 and DNA (20 pg DNA in 250 mM CaCl 2 ) is added to a 5 ml plastic tube and 250 ul of 2X HBS (250 mM NaCl, 10 mM KCl, 1.5 mM Na 2
HPO
4 , 12 mM dextrose, 50 mM HEPES) is slowly 35 added with gentle mixing. The mixture is allowed to WO 02/06245 PCT/USO1/21286 -215 incubate for 20 minutes at room temperature to allow a DNA precipitate to form. The cells are then washed with complete medium, 10 ml of culture medium is added to each plate, followed by addition of the DNA precipitate. The 5 cells are then incubated for 24 to 48 hours at 37'C at 5% Co,. A typical protocol for the DEAE-dextran method as applied to Cos-7 cells is described as follows; Cells to be used 10 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 pg of receptor DNA plus 8 pg of any additional DNA needed (e.g. Ga protein expression vector, reporter construct, antibiotic 15 resistance marker, mock vector, etc.) are added to 9 ml of complete DMEM plus DEAE-dextran mixture (10 mg/ml in PBS). Cos-7 cells plated into a T225 flask (sub-confluent) are washed once with PBS and the DNA mixture is added to each flask. The cells are allowed to incubate for 30 minutes at 20 37 0 C, 5% CO2. Following the incubation, 36 ml of complete DMEM with 80 pM chloroquine is added to each flask and allowed to incubate an additional 3 hours. The medium is then aspirated and 24 ml of complete medium containing 10% DMSO for exactly 2 minutes and then aspirated. The cells 25 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. 30 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 35 at the time of transfection. A total of l0pg of DNA which WO 02/06245 PCT/USO1/21286 -216 may include varying ratios of receptor DNA plus any additional DNA needed (e.g. Ga protein expression vector, reporter construct, antibiotic resistance marker, mock vector, etc.) is used to transfect each 75 cm 2 flask of 5 cells. Liposomal mediated transfection is carried out according to the manufacturer's recommendations (LipofectAMINE, GibcoBRL, Bethesda, MD). Transfected cells are harvested 24 h post transfection and used or reseeded according the requirements of the assay to be employed. 10 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 15 the time of transfection. The cells are harvested by trypsinization resuspended in their growth media and counted. 4 x 106 cells are suspended in 300 pl of DMEM and placed into an electroporation cuvette. 8 pg of receptor DNA plus 8 pg of any additional DNA needed (e.g. Ga protein 20 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 pF capacitance). Following the pulse, 25 800 pl of complete DMEM is added to each cuvette and the suspension transferred to a sterile tube. Complete medium is added to each tube to bring the final cell concentration to 1 x 105 cells/100 pl. The cells are then plated as needed depending upon the type of assay to be performed. 30 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 35 subcloned into pBlueBacIII into existing restriction sites WO 02/06245 PCT/USO1/21286 -217 or sites engineered into sequences 5' and 3' to the coding region of the polypeptides. To generate baculovirus, 0.5 pg of viral DNA (BaculoGold) and 3 pg of DNA construct encoding a polypeptide may be co-transfected into 2 x 106 5 Spodoptera frugiperda insect Sf9 cells by the calcium phosphate co-precipitation method, as outlined in by Pharmingen (in "Baculovirus Expression Vector System: Procedures and Methods Manual") . The cells then are incubated for 5 days at 27 0 C. The supernatant of the co 10 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 15 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 20 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 25 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 30 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. 35 WO 02/06245 PCT/USO1/21286 -218 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 cell 5 lysates are centrifuged at 200 x g for 5 min at 4'C. The supernatants are then centrifuged at 40,000 x g for 20 min at 4'C. The resulting pellets are washed once in the homogenization buffer and suspended in binding buffer (see methods for radioligand binding). Protein concentrations 10 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. 15 Radioligand binding assays Radioligand binding assays for the MCH1 receptor were carried out using plasmid pEXJ.HR-TL231 (ATCC Accession No. 203197). Plasmid pEXJ.HR-TL231 comprises the regulatory 20 elements necessary for expression of DNA in a mammalian cell operatively linked to DNA encoding the human MCH1 receptor so as to permit expression thereof. Plasmid pEXJ.HR-TL231 was deposited on September 17, 1998, with the American Type Culture Collection (ATCC), 12301 Parklawn 25 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. 30 Human embryonic kidney 293 cells (A293 cells) were stably transfected with DNA encoding the MCH1 receptor utilizing the calcium phosphate method and cell membranes were prepared as described above. Binding experiments with 35 membranes from A293 cells transfected with the human MCH1 WO 02/06245 PCT/USO1/21286 -219 receptor were performed with 0.08 nM [ 3 H]Compound 10 (custom labeled by Amersham) using an incubation buffer consisting of 50 mM Tris pH 7.4, 10 mM MgCl 2 , 0.16 mM PMSF, 1 mM 1,10 phenantroline and 0.2% BSA. Binding was performed at 25'C 5 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 tM Compound 10. 10 The methods to obtain the cDNA of the human NPY1, NPY5, GALR1, GALR2, and GALR3 and rat 5-HT2C receptors, express said receptors in heterologous systems, and carry out assays to determine binding affinity are described in the 15 following publications and above: human NPY1 (Larhammar et al., 1992), human NPY5 (U.S. Patent No. 5,602,024, the disclosure of which is hereby incorporated by reference in its entirety into this application), human Gall (Habert Ortoli et al., 1994), human Gal2 (Smith et al., 1997), 20 human Gal3 (Smith et al., 1998), and rat 5-HT2C (Julius et al., 1988). Functional assays Cells may be screened for the presence of endogenous 25 mammalian receptor using functional assays (described in detail below). Cells with no or a low level of endogenous receptor present may be transfected with the exogenous receptor for use in the following functional assays. 30 A wide spectrum of assays can be employed to screen for receptor activation. These range from traditional measurements of phosphatidyl inositol, cAMP, Ca*, and K*, for example; to systems. measuring these same second messengers but which have been modified or adapted to be 35 higher throughput, more generic, and more sensitive; to WO 02/06245 PCT/USO1/21286 -220 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 5 complex physiological or behavioral changes thought to be involved with receptor activation including cardiovascular, analgesic, orexigenic, anxiolytic, and sedation effects, for example. 10 Functional assay: Intracellular calcium mobilization assay Intracellular calcium mobilization assays for the MCH1 receptor were carried out using plasmid pEXJ.HR-TL231 (ATCC Accession No. 203197). COS-7 cells were transiently 15 transfected with DNA encoding the MCH1 receptor utilizing the DEAE-dextran method as described above. The intracellular free calcium concentration was measured by fluorescent imaging using the calcium sensitive fluorscent dye Fluo-3. COS-7 cells expressing the human MCH1 receptor 20 were seeded onto sterile 96 well plates, washed with Hank's balanced salt solution (HBSS), containing 20 mM HEPES, 2.5 mM probenecid, and 0.1% BSA, and loaded with the same buffer containing 3.8 pLtM Fluo-3 for 1 hour at 370C. After washing with HBSS to remove the fluo-3 solution, cells were 25 equilibrated for 10 minutes. Cells were then incubated with, or without MCH, and the fluorescence is measured using a Fluorescence Imaging Plate Reader (FLIPR, Molecular Devices). 30 Materials Cell culture media and supplements were from Specialty Media (Lavallette, NJ) . Cell culture plates (150 mm and 96-well microtiter) were from Corning (Corning, NY). Sf9, Sf21, and High Five insect cells, as well as the 35 baculovirus transfer plasmid, pBlueBacIII T M , were purchased WO 02/06245 PCT/USO1/21286 -221 from Invitrogen (San Diego, CA). TMN-FH insect medium complemented with 10% fetal calf serum, and the baculovirus DNA, BaculoGold
TM
, was obtained from Pharmingen (San Diego, CA.) . Ex-Cell 4 0 0 TM medium with L-Glutamine was purchased 5 from JRH Scientific. Polypropylene 96-well microtiter plates were from Co-star (Cambridge, MA) . Commercially available MCH and related peptide analogs were either from Bachem California (Torrance, CA) or Peninsula (Belmont, CA). Bio-Rad Reagent was from Bio-Rad (Hercules, CA). 10 Bovine serum albumin (ultra-fat free, A-7511) was from Sigma (St. Louis. MO) . All other materials were reagent grade. Functional Assay Results 15 The compounds of Examples 1-37 were assayed using the cloned human MCH1 receptor. The preferred compounds were found to be selective MCH1 antagonists. The results are summarized in Table 1. 20 WO 02/06245 PCT/USO1/21286 -222 7able I EXAMPLE No. STRUCTURE K (nM) hMCH1 F F N42 00 1(-) O4NN2 F F 2 18 0h N N0O N F F 0 0 3 lOO. k 201 'N - O 0 F F 4 0 0 187 0 N N N 0 N3 N Y 258 N-0 I N 6 0 0 42 N N N N N N0 N1 N.
WO 02/06245 PCT/USO1/21286 -223 EXAMPLE No. STRUCTURE () F F 0 0 7 N N 41 K-1 N N-0, NO F F N 90 0 35
N
0 N N-"N F F 10N0 0 0.3 0 N N-" NN 1N1 0 F NF 010 331 0 N lkN N N- -O WO 02/06245 PCT/USO1/21286 -224 Ab (12M) EXAMPLE No. STRUCTURE hmcH1 F F F 12 29 NI 13 NeN N~~' N 284 F I F 14 0 F o 0 15"0 ~ N 'N N 289 N - 'NO F F 16 0329 NO0 WO 02/06245 PCT/USO1/21286 -225 EXAMPLE No. STRUCTURE Xb hMCH1 F F 0 0 17 O 373 N O NON N-ON
N
18 0 0 0 N N N Ok 0 F F 0 0 19 ) 7 1 0 N N N N 0 F F F 20 0 0 5 N N - N ~ N O N-0N 21 0 0 28 O N ) N NQ N 0 F F 22 0 O 40 N N N W N N_ _
N
WO 02/06245 PCT/USO1/21286 -226 EXAMPLE No. STRUCTURE (nM) hmc~l N-O ,N 23 0 N 68 '0 N O-* F F 24 O N 102 NNO 00 25 N 126 SN F 26 N N 260 F 0. 27 N 0 279 0N 28 C 60 290 CN QC 29 N If )c Nq cl WO 02/06245 PCT/USO1/21286 -227 EXAMPLE No. STRUCTURE Kb (Dn) - 0 30 No N479 NN b 32 0 67
N
F F 32o 0 6 0 N 'k 12" FF F NI 0 0 33 0. ~N N N 1 N~0 F FF FF 0 0 35 0 A0 276 N 0~ WO 02/06245 PCT/USO1/21286 -228 EXAMPLE No.- STRUCTURE Kb (nM F F 36 0 0406 37 162 0 0O'N NO0 WO 02/06245 PCT/USO1/21286 -229 Radioligand Binding Assay Results The compounds of Examples 1 to 37 were assayed using cloned human MCH1, NPY1, NPY5, GALR1, GALR2, and GALR3 and rat 5 HT2C receptors. The binding affinities of several 5 compounds are shown in Tables 2 and 3. The compounds of Examples 38 to 56 were assayed using the cloned rat MCH1 receptor. The binding affinities (Ki) of these compounds are shown in Table 4.
WO 02/06245 PCT/USO1/21286 4J -230 E-1 ~ ~ ~ -n "o 0 s- C) m=n0 0C -m0 0 cc .A A1 AY A A A A C"J A A A A A N~ 4 a)C)C)C)C C : )L)0 C C DC)C D C C: )C )c )M 0 DC DC DC 0C WA A A A A A A N A A A A A A AA CD 0 Lfl 0 0C )C N 0 C )CD C ,C a4 C ) 0 0 , C) C) 00 00DC0 00C 4-) ~ AA AA A AHA AA AA AA A 040 A AA A A AA A r4AA AA A AA A %n CD - -) 0 - ( a) w DC ) D( )C 4tf CsJ C) C0 C) 040 o C )Q (a C C) r-~-C J- C C C C .CD 0 C C C)(DCD CI- >- C C 4-) 0 4 -4wNQ-C (a )C- 0 to r 0 1 WO 02/06245 PCT/USO1/21286 - 231 Li CD) 0 -00 0 CD0-00 CdD C14 o00 N~ r- LC) CD Mc o -) M C)1 E4 LOt 0' D D C C') 0D U Lo) m ri (N LC) OGn C Lfl LU) Cd Nd Ni MN- C H AC~ Cq M .N A N C0 >1 ~~00 DD a ~0 0D C O G) GOOD D GODC3 -) Ln u-) Lnu-) Ln ) n n L~ --- >1 AH AA A A A A A A AN CdJ _ -44A U) C14 C) GO D 0D GO D M 0 0D - *(4 w GOOD(DCCDGOOD 0> O)( DN *H U) C00 O 00 CD CDC D 0C C 4~0 0 C0 > CD CD CdC ) I D C 0 * LO LO If) U-) If) i) N LO u-) 3, 41A A A A A A A -4H 4 CD CD 000000CDCD0 NO> Q Cd0 C)dD CDC CD CD CD Coo D o c N CD( 1 C C) CD 0 0 0 0 0 ND CD *D CDC CDd 1 4 N~ Un o LO LOU- HLOHL - -)- H o E- 'Hc ~AA A A A A A A -AH Cd CDCCDd C - D L H C)D 0 0 0 0 0D CD) CDCd( o 0 D0000Z 0000C I:: Z n Ln Lr) in LC) Ln in W-H C ~AA A A A A A (D CD -DI r D ) -- D): S~~( w00 D CD 0 0 00 CD CDCCd wa Q) z U- U ->U- L 0 L~ nCd CN ~ A A A N A A A 4J4 H ~~~~~00 0a 0 i I ;:I Ln-H >1 u r n - - - - -- ->1 (-q CD >, 4-J Ln N~ 000 C~N N- 00 m N 4-4 4 H 2a4 00 0 HD 4N m J 0() Q0 H C Cd Hr-4H HN H H N - rj i 41 a 414 Cd 0 0-1 4o Cd U -4 WO 02/06245 PCT/USO1/21286 -232 Table 4 EXAMPLE No. STRUCTURE rMC F F 38 1.34 O ~ N F F 0 0 49 A N. N27 F O N F 0 0 40 2.72 N NO 'N - 0 F F 41 O0 N N F N NN F 0 N0 WO 02/06245 PCT/USO1/21286 -233 6F F 46 -08.16 34.28 0 KN 48 N N 22.15 491~ 225.47 50 N F 51 01.74 I r XN "N N
NO
WO 02/06245 PCT/USO1/21286 -234 F F 520 0 N NC 0--\ 0 53 0 N0 No 0 50.76 N 0 N 54 N N 29.87 N--O NS 55N N O 203.74 N 0 F F 56 NN O 0.26 N 0 N WO 02/06245 PCT/USO1/21286 -235 REFERENCES Auburger, G., et al., (1992) Assignment of the second (cuban) locus of autosomal dominant cerebellar ataxia to 5 chromosome 12q23-24.1, between flanking markers D12S58 and PLA2. Cytogenet. Cell. Genet. 61:252-256. Bahjaoui-Bouhaddi, M., et al., (1994) Insulin treatment stimulates the rat melanin-concentrating hormone-producing 10 neurons. Neuropeptides 24:251-258. Baker, B.I. (1991) Melanin-concentrating hormone: a general vertebrate neuropeptide. Int. Rev. Cytol. 126:1-47. 15 Baker, B.I. (1994) Melanin-concentrating hormone update: functional consideration. TEM 5:120-126. Bassett, A.S., et al., (1988) Partial trisomy chromosome 5 cosegregating with schizophrenia. Lancet 1:799-801. 20 Bittencourt, J.C., et al., (1992) The melanin-concentrating hormone system of the rat brain: An immuno- and hybridization histochemical characterization . J. Comp. Neurol. 319:218-245. 25 Burgaud, J.L., et al., (1997) Melanin-concentrating hormone binding sites in human SVK14 keratinocytes. Biochem.Biophys.Res.Commun. 241(3) :622-629. 30 Craddock, N., et al., (1993) The gene for Darier's disease maps to chromosome 12q23-q24.1. Hum. Mol. Genet. 2:1941 1943. Drozdz, R. and Eberle, A.N. (1995) Binding sites for WO 02/06245 PCT/USO1/21286 -236 melanin-concentrating hormone (MCH) in brain synaptosomes and membranes from peripheral tissues identified with highly tritiated MCH. J. Recept. Signal. Transduct. Res. 15(1-4) :487-502. 5 Drozdz, R., et al., (1995) Melanin-concentrating hormone binding to mouse melanoma cells in vitro. FEBS 359:199-202. Drozdz, R., et al., (1998) Characterization of the receptor 10 for melanin-concentrating hormone on melanoma cells by photocrosslinking. Ann. NY Acad. Sci. 839(1) :210-213. Gilliam, T.C., et al., (1989) Deletion mapping of DNA markers to a region of chromosome 5 that cosegregates with 15 schizophrenia. Genomics 5:940-944. Gonzalez, M.I., et al., (1997) Stimulatory effect of melanin-concentrating hormone on luteinizing hormone release. Neuroendocrinology 66(4) :254-262. 20 Gonzalez, M.I., et al., .(1997) a-melanocyte-stimulating hormone (a-MSH) and melanin-concentrating hormone (MCH) modify monoaminergic levels in the preoptic area of the rat. Peptides 18:387-392. 25 Gonzalez, M.I., et al., (1996) Behavioral effects of a melanocyte-stimulating hormone (a-MSH) and melanin concentrating hormone (MCH) after central administration in female rats. Peptides 17:171-177. 30 Grillon, S., et al., (1997) Exploring the expression of the melanin-concentrating hormone messenger RNA in the rat lateral hypothalamus after goldthioglucose injection. Neuropeptides 31(2) :131-136. 35 WO 02/06245 PCT/USO1/21286 -237 Habert-Ortoli, E., et al., (1994) Molecular cloning of a functional human galanin receptor. Proc Natl Acad Sci USA 91:9780-9783. 5 Herve, C. and Fellmann, D. (1997) Changes in rat melanin concentrating hormone and dynorphin messenger ribonucleic acids induced by food deprivation. Neuropeptides 31(3) :237 242. 10 Hervieu, G., et al., (1996) Development and stage-dependent expression of melanin-concentrating hormone in mammalian germ cells. Biology of Reproduction 54:1161-1172. Julius, D., et al., (1988) Molecular characterization of a 15 functional cDNA encoding the serotonin 1c receptor. Science 241:558-564. Kauwachi, H., et al., (1983) Characterization of melanin concentrating hormone in chum salmon pituitaries. Nature 20 305:321-333. Knigge, K.M., et al., (1996) Melanotropic peptides in the mammalian brain: The melanin-concentrating hormone. Peptides 17:1063-1073. 25 Knigge, K.M. and Wagner, J.E. (1997) Melanin-concentrating hormone (MCH) involvement in pentylenetetrazole (PTZ) induced seizure in rat and guinea pig. Peptides 18(7):1095 1097. 30 Larhammar, D.', et al., (1992) Cloning and functional expression of a human neuropeptide Y/peptide YY receptor of the Y1 type. J Biol Chem. 267:10935-10938. 35 Ludwig, D.S., et al., (1998) Melanin-concentrating hormone: WO 02/06245 PCT/USO1/21286 -238 a functional melanocortin -antagonist in the hypothalamus. Am. J. Physiol. Endocrinol. Metab. 274(4) :E627-E633. MacKenzie, F.J., et al., (1984) Evidence that the 5 dopaminergic incerto-hypothalamic tract has a stimulatory effect on ovulation and gonadotropin release. Neuroendocrinology 39:289-295. McBride, R.B., et al., - (1994) The actions of melanin 10 concentrating hormone (MCH) on passive avoidance in rats: A preliminary study. Peptides 15:757-759. Melki, J., et al., (1990) Gene for chronic proximal spinal muscular atrophies maps to chromosome 5q. Nature (London) 15 344:767-768. Miller, C.L., et al., (1993) a-MSH and MCH are functional antagonists in a CNS auditory paradigm. Peptides 14:1-10. 20 Nahon, J.L., et al., (1989) The rat melanin-concentrating hormone mRNA encodes multiple putative neuropeptides coexpressed in the dorsolateral hypothalamus. Endocrinology 125:2056-2065. 25 Nahon, J-L. (1994) The melanin-concentrating hormone: from the peptide to the gene. Critical Rev. in Neurobiol 221:221-262. Parkes, D.G. (1996) Diuretic and natriuretic actions of 30 melanin concentrating hormone in conscious sheep. J. Neuroendocrinol. 8:57-63. Pedeutour, F., et al., (1994) Assignment of the human pro melanin-concentrating hormone gene (PMCH) to chromosome 35 12q23-24 and two variant genes (PMCHL1 and PMCHL2) to WO 02/06245 PCT/USO1/21286 -239 chromosome 5p14 and 5ql2-q13. Genomics 19:31-37. Presse, F., et al. (1992) Rat melanin-concentrating hormone messenger ribonucleic acid expression: marked changes 5 during development and after stress and glucocorticoid stimuli. Endocrinology 131:1241-1250. Qu, D., et al. (1996) A role for melanin-concentrating hormone in the central regulation of feeding behaviour. 10 Nature 380:243-247. Rossi, M., et al., (1997) Melanin-concentrating hormone acutely stimulates feeding, but chronic administration has no effect on body weight. Endocrinology 13_:351-355. 15 Sahu, A. (1998) Evidence suggesting that galanin (GAL), melanin-concentrating hormone (MCH), neurotensin (NT), proopiomelanocortin (POMC) and neuropeptide Y (NPY) are targets of leptin signaling in the hypothalamus. 20 Endocrinology 1_9(2) :795-798. Sakurai, T., et al., (1998) Orexins and orexin receptors: A family of hypothalamic neuropeptides and G protein coupled receptors that regulate feeding behavior. Cell 25 92:573-585. Sanchez, M., et al., (1997) Melanin-concentrating hormone (MCH) antagonizes the effects of a-MSH and neuropeptide E-I on grooming and locomotor activities in the rat. Peptides 30 18:393-396. Sherrington, R., et al., (1988) Localization of a susceptibility locus for -schizophrenia on chromosome 5. Nature (London) 336:164-167. 35 WO 02/06245 PCT/USO1/21286 -240 Smith. K.E., et al., (1998) Cloned human and rat galanin GALR3 receptors. Pharmacology and activation of G-protein inwardly rectifying K+ channels. J Biol Chem 273:23321-23326. 5 Smith, K.E., et al. (1997) Expression cloning of a rat hypothalamic galanin receptor coupled to phosphoinositide turnover. J Biol Chem 272:24612-24616. 10 Twells, R., et al., (1992) Chromosomal assignment of the locus causing olivo-ponto-cerebellar atrophy (SCA2) in a cuban founder population. Cytogent. Cell. Cenet. 61:262 265. 15 Westbrook, C.A., et al., (1992) Report of the second international workshop on human chromosome 5 mapping. Cytogenet. Cell. Genet. 61:225-231.

Claims (90)

1. A compound having the structure: 5 A 0 A 0 R 2 k R 4 R 3 - -N R 4 N N H H I NX N R 2 10 R 3 A 0 A 0 R, N ) N R4 R3N R ,orN N 15 R, or' S N R 2 4 V 20 25 30 WO 02/06245 PCT/USO1/21286 -242 wherein A is Y2 Y3 Y2 y3 1 -- Y4 - Y5 Y2 10 S 2 Y 3 N2 y 1 5 Y 2 y or 20 X wherein each of YI, Y 2 , Y 3 r Y 4 and Y 5 is independently -H; straight chained or branched Cl-C 7 alkyl, 25 monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -F, -Cl, -Br, or -I; -NO 2 ; -N 3 ; -CN; OR 3 , -OCOR 3 , -COR 3 , -CON(R 3 ) 2 , or -COOR 3 ; or any two of 30 Y 1 , Y 2 r Y 3 r Y 4 and Y 5 present on adjacent carbon atoms can constitute a methylenedioxy group; wherein each X is independently S; 0; or NR 3 ; 35 wherein R, is -H; -NO 2 ; -CN; straight chained or WO 02/06245 PCT/USO1/21286 -243 branched CI-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or 5 cycloalkenyl; -N(R 3 ) 2 ; -OR 3 ; -(CH 2 )pOR 3 ; -COR 3 ; -CO 2 R 3 ; -CON(R 3 ) 2 or -CO 2 (CH 2 )nV; wherein R 2 is -H; straight chained or branched C 1 -C 7 alkyl, hydroxyalkyl, alkoxyalkyl, monofluoroalkyl or 10 polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C 3 -C 1 cycloalkyl-Ci-Cio-alkyl, C 3 -C 1 0 cycloalkyl-C-Cio-monofluoroalkyl or C 3 -C 10 cycloalkyl 15 C-Cio-polyfluoroalkyl; -CN; -CH 2 XR 3 , -CH 2 X (CH 2 ) pNHR 3 , - (CH 9 ) nNHR 3 , -CH 2 X (CH2)pN (R 3 ) 2' -CH 2 X (CH 2 ) pN 3 , or -CH2X (CH 2 ) pNHCXR 7 ; -OR 3 ; or wherein R, and R 2 together form a lactone ring; 20 wherein each R 3 is independently -H; straight chained or branched C 1 -C 7 . alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or 25 cycloalkenyl; wherein R 4 is (i) X R 6 30 R tN R [m R 5 35 WO 02/06245 PCT/USO1/21286 -244 (ii) R 5R [ my~N~lR 0 R R 5 10 (iii) X R6 0 X R 15 R R} 3 55 I 20 R R m 25 [ 5 R 30 RV mN rV R [ 5 R 35 WO 02/06245 PCT/USO1/21286 -245 (vii) R R 5 0 NN R Nm 5R7 (viii) R N 10 R [mN-R 8 z (ix) R5 NN (x)R [N Rs z 20 R -Ni R R 5 V 25 wherein the dashed line represents a single bond or a double bond; wherein each R is independently -H; -F; straight chained or branched C-C 7 alkyl, monofluoroalkyl or 30 polyfluoroalkyl; straight chained or branched C 2 -C7 alkenyl or alkynyl; -N(R 3 ) 2 ; -NO 2 ; -CN; -CO 2 R 3 ; -OR 3 ; or -CON (R 3 ) 2; wherein each V is independently aryl or hetercaryl, 35 optionally substituted with one or more F; Cl; Br; I; WO 02/06245 PCT/USO1/21286 -246 COR 3 ; C0 2 R 3 ; -CON (R 3 ) 2 ; CN; -NO 2 ; -N (R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 )qOR 3 ; (CH 2 )qSP3 ; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or 5 branched C 2 -C7 alkenyl, C 2 ~C 7 alkynyl; C 3 -C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein each R 5 is -H; -NO 2 ; -N 3 ; -CN; straight chained 10 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; -N (R 3 ) 2; -OR 3 ; - (CH 2 ) pOR 3 ; -COR 3 ; -C0 2 R 3 ; 15 -CON(R 3 ) 2 ; aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -NO 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ;. (C H 2 )qOR3; (CH 2 )qSR 3 ; straight chained or branched CI-C7 alkyl, monofluoroalkyl, 20 polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C 2 -C 7 alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; 25 wherein R 6 is -H; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -.OR 3 ; -(CH 2 )pOR 3 ; -COR 3 ; 30 C0 2 R 3 ; -CON(R 3 ) 2 ; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -NO 2 ; -N (R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 )qOR 3 ; (CH 2 )qSR 3 ; straight chained or branched C1-C7 alkyl, monofluoroalkyl, 35 polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; WO 02/06245 PCT/USO1/21286 -247 straight chained or branched C 2 -C7 alkenyl, C 2 -C7 alkynyl; C 3 -C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; 5 wherein R 7 is H; F; Cl; Br; I; -NO 2 ; -N3; -CN; straight chained or branched C 1 -C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C3~C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or 10 cycloalkenyl; -N(R 3 ) 2 ; -OR 3 ; -(CH 2 )pOR 3 ; -COR 3 ; -COR 3 ; or -CON (R 3 ) 2; wherein R 8 is independently straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or 15 polyfluoroalkyl; straight chained or branched C 2 ~C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; 20 wherein Z is naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, phthalazinyl, quinoxalinyl, indolyl, benzo[b]furanyl, or -benzo[b]thiophenyl; wherein the naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, phthalazinyl, quinoxalinyl, indolyl, benzo[b]furanyl, 25 or benzo[b]thiophenyl may be substituted with one or more F; Cl; Br; I; COR 3 ; COR 3 ; -CON(R 3 ) 2 ; CN; -NO,; N (R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH2)qOR 3 ; (CH 2 )qSR 3 ; straight chained or branched CI-C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, 30 aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 ~C7 alkenyl, C 2 -C 7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; 35 wherein each m is independently an integer from 0 to WO 02/06245 PCT/USO1/21286 -248 3 inclusive; wherein each n is independently an integer from 0 to 5 inclusive; 5 wherein each p is independently an integer from 1 to 7 inclusive; wherein q is an integer from 1 to 3 inclusive; 10 wherein r is an integer from 0 to 3 inclusive; wherein t is an integer from 2 to 6 inclusive; 15 or a pharmaceutically acceptable salt thereof.
2. A (+) enantiomer of the compound of claim 1.
3. A (-) enantiomer of the compound of claim 1. 20
4. The compound of claim 1 having the structure: A 0 fti>R5 R, N N N 25 [ m ,VX R6 or R2I N X 1 0 R 3 30 A 0 R, R5 R 1 N N X R6' R 2 N Xm V R 3 35 WO 02/06245 PCT/USO1/21286 -249
5. The compound of claim 4 having the structure: A 0 R 5 R, 5 0 N O X R 6 ,or N 0 H 10 A 0 R, 5 Ri N N NR O N O / X R 6 H 0 15
6. The compound of claim 5, having the structure: 0 A 0 O N 0 N Hr H 0 H O A N N R6 HN N1 N / H WO 02/06245 PCT/USO1/21286 -250
7. The compound of claim 6, wherein A is Y2 y y r or 5 Y 5 ~ Y 5 /
8. The compound of claim 7, wherein the compound is F 10 F 0 0 O N N N N O N 0 15 F F o - 0 0 N IkN N 20 NN a-a 0 F F 25 O N N N N O0 0 30 WO 02/06245 PCT/USO1/21286 -251 F F O N N O N ; or O O0 10 F F 0 0 O N If"N N 15 O N O "N N 0
9. The compound of claim 1, wherein the compound has the structure: 20 A 0 X R 6 R2 N X [ R R 3 25
10. The compound of claim 9, wherein the compound has the structure: 30 A 0 X R 6 Ri N N N-, O \ NN O N -O R 5 H 35 WO 02/06245 PCT/USO1/21286 -252
11. The compound of claim 10, wherein the compound has the structure: 5 o A 0 0 R 6 O N NO O N H 10 15
12. The compound of claim 11, wherein A is Y2 y3 y2 3 Y y r o r 20 4 Y1~~~ /0 Y 5 25
13. The compound of claim 12 having the structure: F F 30 0 0 O N N N N O 0 35 WO 02/06245 PCT/USO1/21286 -253
14. The compound of claim 1, having the structure: A 0 R N~X m R, 5R2 N N R-} R3 10
15. The compound of claim 14, having the structure: 15 A 0 R R N N N }r-V H 20
16. The compound of claim 15 having the structure: 25 R3 0 A 0 R N Ii 30 0N N 5 RR3 H WO 02/06245 PCT/USO1/21286 -254
17. The compound of claim 16 wherein A is Y2 y _1 -NY or 4 Yi/ - N Y 5 10
18. The compound of claim 17 having the structure: N-O 15 / N O O N N N N N 20 25
19. The compound of claim 1 having the structure: 30 A 0 0 35 RR7 WO 02/06245 PCT/USO1/21286 -255
20. The compound of claim 19 having the structure: A 0 5 A I0 0 5R N NNN N N N-R R7 10
21. The compound of claim 20 having the structure: 15 0 A 0 O N N N N R7 20~ H~ I 25
22. The compound of claim 21 wherein A is Y 2 y Y Y y or Y 5 WO 02/06245 PCT/USO1/21286 -256
23. The compound of claim 22 having the structure F 5 F F 0 0 0 N N N 0 N ''O NA 10 N 15
24. The compound of claim 1 having the structure: z A 0 RN N N 20 R, N X R5 R 3
25. The compound of claim 24 having the structure: 25 z A 0 R, N NN 300 N N O R 5 H WO 02/06245 PCT/USO1/21286 -257
26. The compound of claim 25 having the structure: 5 0 A 0 O N N N o N -- z O 10 H R 5
27. The compound of claim 26 wherein A is 15 3 Y 2 y3 __ or Yi 4 'Yo N Y 5 20
28. The compound of claim 27 having the structure: 25 F F 0 0 O N 1 N N 30 N O
29. The compound of claim 1, wherein the compound is (+)-1,2,3,6-tetrahydro-1-{n-[4-(3,-acetamido)-phenyl 35 -piperidin-1-yll propyl}carboxamido-4-methoxymethyl 6-(3,4-difluoro-phenyl)-2-oxopyrimidine-5 carboxylic acid methyl ester. WO 02/06245 PCT/USO1/21286 -258
30. The compound of claim 4 having the structure: A 0 5 N NNX R6 R 2 N' X 10
31. The compound of claim 30 having the structure: 15 A 0 15 NNN N R 6 R2 X 20
32. The compound of claim 31 having the structure: F F 0 0 H 0 N N NN 0 N 0N H 25 WO 02/06245 PCT/USO1/21286 -259
33. A compound having the structure: F F 5 0 0 'O N N N N1 o / NH 2 ~~0 10
34. A compound having the structure: 15 0 R 2 R W M- X N 20 2 R R wherein each R is independently -H; -F; straight chained or branched Ci-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C7 25 alkenyl or alkynyl; -N(R 3 ) 2 ; -NO 2 ; -CN; -SR 3 ; -CO 2 R 3 ; or -OR 3 ; wherein each R 1 is independently -H; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or 30 polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -(CH 2 )pOR 3 ; -COR 3 ; -C0 2 R 3 ; or -CON(R 3 ) 2 ; 35 wherein each R 2 is -H; -NO 2 ; -N 3 ; -CN; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 WO 02/06245 PCT/USO1/21286 -260 alkenyl or alkynyl; C 3 -C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 )2; -OR 3 ; -(CH 2 )pOR 3 ; -COR 3 ; -C0 2 R 3 ; or -CON(R 3 ) 2 ; or aryl or heteroaryl, optionally 5 substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON (R 3 ) 2 ; CN; -NO 2 ; -N (R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 )qOR 3 ; (CH 2 )qSR 3 ; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or 10 branched C 2 -C7 alkenyl, C 2 -C 7 alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein each R 3 is independently -H; straight chained 15 or branched C 1 -C 7 . alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; 20 wherein M is aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON (R 3 ) 2 ; CN; -NO 2 ; -N (R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 )qOR 3 ; (CH 2 ) qSR 3 ; straight chained or branched 25 C1-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, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; 30 wherein X is (CH 2 )n, 0, S or NR 3 ; wherein W is 35 (a) C 3 -C 7 cycloalkyl, monofluorocycloalkyl, WO 02/06245 PCT/USO1/21286 -261 polyfluorocycloalkyl or cycloalkenyl optionally substituted with one or more COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -NO 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; 5 (CH 2 )qOR 3 ; -(CH 2 )qSR 3 ; 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; C 3 -C 7 10 cycloalkyl; or (b) aryl or heteroaryl optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -NO 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; 15 (CH 2 )qOR 3 ; (CH2)qSR 3 ; 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; C 3 -C 7 20 cycloalkyl;. wherein m is an integer from 0 to 4 inclusive; wherein n is an integer from 0 to 6 inclusive; 25 wherein p is an integer from 1 to 4 inclusive; wherein q is an integer from 1 to 3 inclusive; 30 or a pharmaceutically acceptable salt thereof.
35. A (+) enantiomer of the compound of claim 34.
36. A (-) enantiomer of the compound of claim 34. 35 WO 02/06245 PCT/USO1/21286 -262
37. The compound of claim 34 having the structure: 0 5 x4 M N W H N ; or Ri R R 10 M M4 N W H 'N R RR 15
38. The compound of claim 37, wherein W is phenyl optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON(R3) 2 ; CN; -NO 2 ; -N(R 3 ) 2 ; -OR 3 ; 20 -SR 3 ; (CH2)qOR 3 ; or (CH2)qSR 3 .
39. The compound of claim 38 having the structure 25 0 O N N 30 35 WO 02/06245 PCT/USO1/21286 -263
40. A compound having the structure: 0 5 R~~ R 5 R 5 / R tR3 R n R 10 wherein each R is independently -H; -F; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; -N(R 3 ) 2 ; -NO 2 ; -CN; -C0 2 R 3 ; -OR 3 ; or -CON (R 3 ) 2; 15 wherein each R, is independently -H; F; Cl; Br; I; -NO 2 ; -N 3 ; -CN; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C7 alkenyl or alkynyl; C 3 -C, 20 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -OR 3 ; - (CH 2 ) pOR 3 ; -COR 3 ; '-C0 2 R 3 ; -CON (R 3 ) 2; aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; 25 I; COR 3 ; CO 2 R 3 ; -CON(R 3 ) 2 ; CN; -NO 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 )qOR 3 ; (CH 2 )qSR 3 ; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C 2 -C7 30 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl br cycloalkenyl; wherein each R 3 is independently -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or 35 polyfluoroalkyl; straight chained or branched C2-C WO 02/06245 PCT/US01/21286 -264 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; 5 wherein R 5 is -H; -NO ; -N 3 ; -CN; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or 10 cycloalkenyl; -N(R 3 ) 2 ; -OR 3 ; -(CH 2 )pOR 3 ; -COR 3 ; -C0 2 R 3 ; -CON(R 3 ) 2 ; aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -NO 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 )qOR 3 ; (CH 2 )qSR 3 ; straight 15 chained or branched C 1 -C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3~C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; 20 wherein V is H; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -NO,; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 )qOR 3 ; (CH2)qSR 3 ; straight chained or branched C 25 C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; 30 wherein W is (a) C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl 35 optionally substituted with one or more WO 02/06245 PCT/USO1/21286 -265 COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -NO 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 )qOR 3 ; (CH 2 )qSR 3 ; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, 5 aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, C 2 -C 7 alkynyl; C 3 -C 7 cycloalkyl; or (b) aryl or heteroaryl optionally substituted 10 with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -NO 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 )qOR 3 ; (CH 2 )qSR 3 ; straight chained or branched CI-C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or 15 carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, C 2 -C 7 alkynyl; C 3 -C 7 cycloalkyl; wherein each m is independently an integer from 0 to 20 3 inclusive; wherein n is an integer from 0 to 2 inclusive; wherein p is an integer from 1 to 7 inclusive; 25 wherein q is an integer from 1 to 3 inclusive; wherein t is an integer from 2 to 6 inclusive; 30 or a pharmaceutically acceptable salt thereof.
41. A (+) enantiomer of the compound of claim 40.
42. A (-) enantiomer of the compound of claim 40. 35 WO 02/06245 PCT/USO1/21286 -266
43. The compound of claim 40 having the structure: 0 5 1N R3 R1 R 5 10
44. The compound of claim 43 having the structure R15 15 R, N R3 RR3 RR WO 02/06245 PCT/USO1/21286 -267
45. A compound of claim 43 wherein W is phenyl optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -NO 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 )qOR 3 ; (CH2)qSR 3 ; or straight chained or 5 branched C 1 -C 7 alkyl groups.
46. A compound of claim 45 having the structure 10 N N O N 0 155 WO 02/06245 PCT/USO1/21286 -268
47. A method of modifying feeding behavior of a subject which comprises administering to the subject an amount of a compound effective to decrease the consumption of food by the subject wherein the 5 compound has the structure:having the structure: A 0 A 0 10 R NR4RN 10 R, N 'J N 4 R3, N N ,R4 l H R2 N X Hly , I NX N R 2 R 3 I R3 15 A 0 A 0 N N R3 N N R4 H ,oroN R 2 N S H '2 N R 2 20 V 25 30 WO 02/06245 PCT/USO1/21286 -269 wherein A is Y2 y3 Y2 y3 5 Y1 4 _J 4 N Y 5 Y3 N YY 15 Yi Y O/ ' Y2 y3 or 20 wherein each of Y 1 , Y 2 , Y 3 , Y 4 and Y 5 is independently -H; straight chained or branched C1-C7 alkyl, 25 monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -F, -C1, -Br, or -I; -NO 2 ; -N 3 ; -CN; -OR 3 , -OCOR 3 , -COR 3 , -CON (R 3 ) 2r 30 or -COOR 3 ; or any two of Y 1 , Y 2 r Y 3 , Y 4 and Y 5 present on adjacent carbon atoms can constitute a methylenedioxy group; wherein each X is independently S; 0; or NR 3 ; 35 WO 02/06245 PCT/USO1/21286 -270 wherein R 1 is -H; -NO 2 ; -CN; straight chained or branched C-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C 7 cycloalkyl, 5 monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N (R 3 ) 2; -OR 3 ; - (CH 2 ) pOR 3 ; -COR 3 ; -C0 2 R 3 ; -CON(R 3 ) 2 ; or -CO 2 (CH 2 )nV; wherein R 2 is -H; straight chained or branched C-C7 10 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C3-C1 15 cycloalkyl-C-Cio-alkyl, C3-C1 cycloalkyl-Ci-C-o monofluoroalkyl or C 3 -Cie cycloalkyl-Cl-Clo polyfluoroalkyl; -CN; -CH2XR 3 , -CH 2 X (CH 2 ) pNHR 3 , -(CH 2 )nNHR 3 , -CH 2 X(CH 2 )pN(R 3 ) 2 , -CH 2 X(CH 2 )pN 3 , or -CH 2 X (CH 2 ) pNHCXR 5 ; -OR 3 ; or wherein R, and. R 2 together 20 form a lactone ring; wherein each R 3 is independently -H; straight chained or branched C-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 25 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein R 4 is 30 (i) R R Im\R R3 35 WO 02/06245 PCT/USO1/21286 -271 (ii) R R5 R [ R 6 (iii) y 1 R [\\, 10 i N Y2 10 R [m Z R 6 y3 1 Y2 15 (iv) R6 R [m m Y3 t N R m D'D d 20 "2 Y 1 I 1 Y3 25 (v) R N ( Lpt N lI d R m Z 0 30 R6 R5 (vi) R m WR6 R3 35 WO 02/06245 PCT/USO1/21286 -272 (vii) 5 R N R6 R H Y 10 B Y 3 15 (viii) R R6 R 6 20 R7 (ix) 25 R U R ;or m / N m U R m R 5 R 30 (x) R r R m m NR m R [m R 5 R 35 WO 02/06245 PCT/USO1/21286 -273 wherein each R is independently -H; -F; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; -N(R 3 ) 2 ; -NO 2 ; -CN; -C0 2 R 3 ; -OR 3 ; 5 or -CN(R3)2; wherein B is N or CY 4 ; wherein each D is independently C(R 3 ) 2 ; 0; S; NR 3 ; 10 CO; or CS; wherein each U is independently aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; CO 2 R 3 ; -CON(R 3 ) 2 ; CN; -NO 2 ; -N(R 3 ) 2 ; -OR 3 ; 15 -SR 3 ; (CH 2 )qOR 3 ; (CH9)qSR 3 ; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C7 alkenyl, C 2 -C 7 alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, 20 polyfluorocycloalkyl or cycloalkenyl; wherein V is C(R 5 ) 2 ; CR 5 R 6 ; NR 5 or NR 6 ; wherein W is CR 5 ; CR 6 or N; 25 wherein Z is S; 0; C(R 3 ) 2 ; or NR 3 ; wherein each R 5 is -H; -NO 2 ; -N 3 ; -CN; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or 30 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 ; -(CH2)pOR 3 ; -COR 3 ; -C0 2 R 3 ; or -CON(R 3 ) 2 ; -XCOR 8 ; or aryl or heteroaryl, wherein 35 the aryl or heteroaryl is optionally substituted WO 02/06245 PCT/USO1/21286 -274 with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -NO 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 )qOR 3 ; (CH 2 )qSR 3 ; -XCOR 8 ; straight chained or branched Cl-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; 5 straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein each R 6 is independently -H; straight chained 10 or branched Ci-C7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -OR 3 ; 15 -(CH,) OR 3 ; -COR 3 ; -COR 3 ; or -CON(R 3 ) 2 ; wherein R 7 is -H; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -NO 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; 20 (CH 2 )qOR 3 ; (CH 2 )qSR 3 ; -XCOR; straight chained or branched Cj-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; straight chained or branched C2-C7 alkenyl, C2~C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, 25 polyfluorocycloalkyl or cycloalkenyl; wherein R 8 is -H; straight chained or branched CI-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 30 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -OR 3 ; -(CH 2 )pOR 3 ; -COR3; -C0 2 R 3 ; or -CON(R 3 ) 2 ; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -NO 2 ; 35 -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 )qOR 3 ; (CH 2 )qSR 3 ; straight WO 02/06245 PCT/USO1/21286 -275 chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, 5 polyfluorocycloalkyl or cycloalkenyl; wherein b is 1 or 2; wherein d is an integer from 0 to 2 inclusive; 10 wherein each m is independently an integer from 0 to 3 inclusive; wherein each n is independently an integer from 0 to 15 5 inclusive; wherein each p is independently an integer from 1 to 7 inclusive; 20 wherein q is an integer from 1 to 3 inclusive; wherein t is an integer from 2 to 6 inclusive; or a pharmaceutically acceptable salt thereof. 25
48. The method of claim 47, wherein the compound has the structure A 0 RA R JA-i >R 5 30 N N -- N V H Rt [ R6 R 2 N X IR7 R3 WO 02/06245 PCT/USO1/21286 -276
49. The method of claim 48, wherein the compound has the structure A 0 R 5 RN R N";o 5 N I -5 ;or H R j'/ R 6 R 3 R 5 10 A 0 N --- N N C(R H 5) R R 6 1 R7 R 3 15 20 WO 02/06245 PCT/USO1/21286 -277
50. The method of claim 49, wherein the compound has the structure 5 A 0 R, N N H N N-R 5 ; or R 2 N 0 1 R5 H 10 A 0 R N 15 R 2 N 0 H R 5
51. The method of claim 50, wherein at least one R 5 group 20 is an aryl or heteroaryl group optionally substituted with one or more F; Cl; Br; I; -NO 2 ; -N(R 3 ) 2 ; -OR 3 ; -XCOR 8 ; or straight chained or branched CI-C 7 alkyl. 25
52. The method of claim 51, wherein A is: 2 3 y 2 y3 30 0 or i 3074 ij /0 - N WO 02/06245 PCT/USO1/21286 -278
53. The method of claim 52, wherein the compound is selected from the group consisting of: F 5 (a) F O O O N N N N - O ~ O 10 /O0 (b) F F O O 15 O N N 'N. N 0 N O NA\ (c) 20 F F O O NO N N N 25 N O O (d) F F 30 0 0 O N N N -'N N N 70 F 35 WO 02/06245 PCT/USO1/21286 -279 (e) 5 F F O O O N N N ;and N O F 10 F F (f) F 15 F o 0 O N N N,, N O NN 20 0
54. The method of claim 47, wherein the compound has the structure 25 A 0 R 5 R N N m I [ H t R6 30 WO 02/06245 PCT/USO1/21286 -280
55. The method of claim 54, wherein the compound has the structure A 0 R N N N 5O N O Ho R6 H R7 10
56. The method of claim 55, wherein A is /Y 3 Y2 y Y y ' or - N 15 and R 7 is phenyl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -NO 2 ; -N (R 3 ) 2; -OR 3 ; -SR 3 ; (CH 2 ) qOR3; (CH 2 ) qSR 3 ; -XCOR 8 ; or 20 straight chained or branched CI-C 7 alkyl.
57. The method of claim 56, wherein the compound has the structure 25 F F 0 0 O N N---N 30 o I NO -N - 0 WO 02/06245 PCT/USO1/21286 -281
58. The method of claim 47, wherein the compound has the structure A 0 Y1 R R m b N 2 NX R 3 10
59. The method of claim 58, wherein the compound has the structure 15 A 0 Y R N NH N 3 2 N 1 0 R 2 1~ H 3 H 20
60. The method of claim 59, wherein A is 25 2 3 Y2 y Y ' or Y 5 30 and Z is 0 or OH 2 . WO 02/06245 PCT/USO1/21286 -282
61. The method of claim 60, wherein the compound is selected from the group consisting of N-O N 5 0 / O N N N N O P 00 10 N--O N 0 0 15 NN N N O ; and 20 F F 0 0 N N Nfl N N 25 N O WO 02/06245 PCT/USO1/21286 -283
62. The method of claim 47, wherein the compound has the structure Y2 5 Y3 1 Y A 0 R N NH N [ Id I Z R N 2 1 R mZ 10 0 R 3
63. The method of claim 62, wherein the compound has the 15 structure Y2 Y 1 y A 0 20 H N HO 25
64. The method of claim 63, wherein A is 0 Y 2 O - -N WO 02/06245 PCT/USO1/21286 .- 284
65. The method of claim 64, wherein the compound is N-O N 5 O O N N N o NN''NNO ;or NO 10 F F 0 O O N N N 15 NiO 0
66. The method of claim 47, wherein the compound has the structure 20 A 0 R~ m R R 2 R R2 N X H R2 R 3 Y3 25
67. The method of claim 66, wherein the compound has the structure A 0 30 N N N YN N O H H 35 WO 02/06245 PCT/USO1/21286 -285
68. The method of claim 67, wherein the compound has the structure F 5 F 0 O O N N N N O 0N. 10
69. The method of claim 47, wherein the compound has the 15 structure A 0 R m R R 1 N N m N- m--U 20 1 H .M m IR9 R 2 N X R R RK3
70. The method of claim 69, wherein the compound has the structure 25 A 0 N 0 U H 30 WO 02/06245 PCT/USO1/21286 -286
71. The method of claim 70, wherein the compound has the structure 5 N-0 N O O N N N 10
72. A method of reducing the body mass of a subject which comprises administering to the subject an 15 amount of a compound effective to reduce the body mass of the subject wherein the compound has the structure: A 0 A 0 20 R2 R4 R 3 , R4 NX 1X N R 2 X 3 1 3 25 A 0 A 0 R1NN R4 R 3 -R4 H ,or N 2 N sH V n 1VI N R 2 WO 02/06245 PCT/USO1/21286 -287 wherein A is Y2 y3 Y2 Y 3/Y3 5 Y4 I -Y N Y 5 Y2 \~3 10 U > Y2 y3 2 y3 N 15 x N Y2 Y3 or 20 Y__ wherein each of Y 1 , Y 2 r Y 3 , Y 4 and Y 5 is independently -H; straight chained or branched CI-C 7 alkyl, 25 monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -F, -C1, -Br, or -I; -NO 2 ; -N 3 ; -CN; -OR 3 , -OCOR 3 , -COR 3 , -CON(R 3 ) 2 , 30 or -COOR 3 ; or any two of Y 1 , Y 2 r Y 3 r Y 4 and Y 5 present on adjacent carbon atoms can constitute a methylenedioxy group; wherein each X is independently S; 0; or NR 3 ; 35 WO 02/06245 PCT/USO1/21286 -288 wherein R, is -H; -NO 2 ; -CN; 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, 5 monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -OR 3 ; -(CH 2 )pOR 3 ; -COR 3 ; ~C0 2 R 3 ; -CON (R 3 ) 2 ; or -CO 2 (CH 2 ) nV; wherein R 2 is -H; straight chained or branched C 1 -C 7 10 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C 3 -CI 0 15 cycloalkyl-C-Cio-alkyl, C 3 -C1 0 cycloalkyl-Ci-Clo monofluoroalkyl or C 3 -Ci 0 cycloalkyl-Ci-Cio polyfluoroalkyl; -CN; -CH 2 XR 3 , -CH 2 X(CH 2 )pNHR 3 , - (CH 2 ) NHR 3 , -CH 2 X (CH 2 ) pN (R 3 ) 2, -CH2X (CH 2 ) pN 3 , or -CH 2 X (CH 2 ) pNHCXR 5 ; -OR 3 ; or wherein R 1 and R 2 together 20 form a lactone ring; wherein each R 3 is independently -H; straight chained or branched C 1 -C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 25 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein R 4 is 30 (i) R R R N[ R 6 R7 35 WO 02/06245 PCT/USO1/21286 -289 (ii) R mR5 N R R [R m N 10 R m Z 1, Y2 15 (iv) R 6 R [ [iY3 R m D ,Dd 20 Y2 1 Y R R 6 25 (v) N [Id R m Z 0 30 R R6 R (vi) R m WR R7 35 WO 02/06245 PCT/USO1/21286 -290 (vii) 5 R m R R R2 10B Y 3 15 (viii) R R6R R R Im R 6 20 R7 (ix) R U R 25 N or m R R 5 R 30 R i:mR / m R [m R 5 R 35 WO 02/06245 PCT/USO1/21286 -291 wherein each R is independently -H; -F; straight chained or branched Ci-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; -N(R 3 ) 2 ; -NO 2 ; -CN; -C0 2 R 3 ; -OR 3 ; 5 or -CN(R 3 ) 2 ; wherein B is N or CY 4 ; wherein each D is independently C(R 3 ) 2 ; 0; S; NR 3 ; 10 CO; or CS; wherein each U is independently aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -NO 2 ; -N(R 3 ) 2 ; -OR 3 ; 15 -SR 3 ; (CH 2 )qOR 3 ; (CH 2 )qSR 3 ; straight chained or branched Ci-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, 20 polyfluorocycloalkyl or cycloalkenyl; wherein V is C(R 5 ) 2 ; CR 5 R 6 ; NRs or NR 6 ; wherein W is CR 5 ; CR 6 or N; 25 wherein Z is S; 0; C(R 3 ) 2 ; or NR 3 ; wherein each R 5 is -H; -NO 2 ; -N 3 ; -CN; straight chained or branched Cl-C7 alkyl, monofluoroalkyl or 30 polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 )2; -OR 3 ; -(CH 2 )pOR 3 ; -COR 3 ; ~C0 2 R 3 ; or -CON(R 3 ) 2 ; -XCOR 8 ; or aryl or heteroaryl, wherein 35 the aryl or heteroaryl is optionally substituted WO 02/06245 PCT/USO1/21286 -292 with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -NO?; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 )qOR 3 ; (CH 2 )qSR 3 ; -XCOR 8 ; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; 5 straight chained or branched C 2 -C 7 alkenyl, C 2 -C 7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein each R 6 is independently -H; straight chained 10 or branched C 1 -C 7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3) 2 ; -OR 3 ; 15 -(CH2)pOR 3 ; -COR 3 ; -C0 2 R 3 ; or -CON(R 3 ) 2 ; wherein R 7 is -H; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -NO 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; 20 (CH,)qOR 3 ; (CH 2 )qSR 3 ; -XCOR8; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; straight chained or branched C 2 -C 7 alkenyl, C 2 -C 7 alkynyl; C 3 -C7 cycloalkyl, monofluorocycloalkyl, 25 polyfluorocycloalkyl or cycloalkenyl; wherein R 8 is -H; straight chained or branched CI-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C7 30 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 )2; -OR 3 ; -(CH2)pOR 3 ; -COR 3 ; -CO 2 R 3 ; or -CON(R 3 ) 2 ; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; COR 3 ; -CON(R 3 ) 2 ; CN; -NO 2 ; 35 -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH2)qOR 3 ; (CH 2 )qSR 3 ; straight WO 02/06245 PCT/USO1/21286 -293 chained or branched C 1 -C, alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, C 2 -C7 alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, 5 polyfluorocycloalkyl or cycloalkenyl; wherein b is 1 or 2; wherein d is an integer from 0 to 2 inclusive; 10 wherein each m is independently an integer from 0 to 3 inclusive; wherein each n is independently an integer from 0 to 15 5 inclusive; wherein each p is independently an integer from 1 to 7 inclusive; 20 wherein q is an integer from 1 to 3 inclusive; wherein t is an integer from 2 to 6 inclusive; or a pharmaceutically acceptable salt thereof. 25 WO 02/06245 PCT/USO1/21286 -294
73. A method of treating a subject suffering from depression and/or anxiety which comprises administering to the subject an amount of a compound effective to treat the subject's depression and/or 5 anxiety wherein the compound has the structure: A 0 A 0 10 RSKN4R 10 R, N J N 3RY N N -R4 I H r 2 N X H XN R 2 15 A O A O R, J N R4 R3- N YN R4 R2 N S HH R 20 V 25 30 WO 02/06245 PCT/USO1/21286 -295 wherein A is Y3 5 Y4 1 '-y N YS Y 2 10 T Y2 y3 Y2 y3 N 15 Y1Y--0 15x N / Y2 y3 or 20__ x wherein each of Y 1 , Y2r Y 3 , Y 4 and Y 5 is independently -H; straight chained or branched Cl-C 7 alkyl, 25 monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -F, -Cl, -Br, or -I; -NO 2 ; -N 3 ; -CN; -OR 3 , -OCOR 3 , -COR 3 , -CON(R 3 ) 2 , 30 or -COOR 3 ; or any two of Y 1 , Y 2 r Y 3 , Y 4 and Y 5 present on adjacent carbon atoms can constitute a methylenedioxy group; wherein each X is independently S; 0; or NR 3 ; 35 WO 02/06245 PCT/USO1/21286 -296 wherein R 1 is -H; -NO 2 ; -CN; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2~C7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, 5 monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N (R 3 ) 2; -OR 3 ; - (CH 2 ) pOR 3 ; -COR 3 ; -C0 2 R 3 ; -CON (R 3 ) 2 ; or -CO 2 (CH 2 ) nV; wherein R 2 is -H; straight chained or branched CI-C7 10 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C3-C10 15 cycloalkyl-C 1 -Cio-alkyl, C 3 -C 1 0 cycloalkyl-C-Clo monofluoroalkyl or C 3 -Cie cycloalkyl-C-C 1 polyfluoroalkyl; -CN; -CH3XR 3 , -CH 2 X (CH 2 ) pNHR 3 , -(CH 2 )nNHR 3 , -CH 2 X(CH 2 )pN(R 3 ) 2 , -CH 2 X(CH 2 )pN 3 , or -CH 2 X(CH2)pNHCXR 5 ; -OR 3 ; or wherein R 1 and R 2 together 20 form a lactone ring; wherein each R 3 is independently -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C 25 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein R 4 is 30 (i) R 5 N R R Im R 6 R7 35 WO 02/06245 PCT/USO1/21286 -297 (ii) R mR5 t [ R 6 5 R7 (iii) y 1 R Ym N b 10 R m 1, Y2 15 (iv) R 6 R [M[m Y3 N R t m D--D 20 Y2 y1 Y(3 R [+ R6 25 (v) N ( d R Z R m Z 0 30 R R5 (vi) R I m W R7 35 WO 02/06245 PCT/USO1/21286 -298 (vii) 5 R m R 6 LItN Re R [m 10 B Y 3 15 (viii) R R6 nNm R6 R R m 20 R7 (ix) R U R m ;or 25 N mU R m R5Rm\" (X) 30 R R 3m R 5 R 35 WO 02/06245 PCT/USO1/21286 -299 wherein each R is independently -H; -F; straight chained or branched CI-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; -N(R 3 )2; -NO 2 ; -CN; -C0 2 R 3 ; -OR 3 ; 5 or -CN (R 3 ) 2 ; wherein B is N or CY 4 ; wherein each D is independently C(R 3 ) 2 ; 0; S; NR 3 ; 10 CO; or CS; wherein each U is independently aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -NO 2 ; -N(R 3 ) 2 ; -OR 3 ; 15 -SR 3 ; (CH 2 )qOR 3 ; (CH 2 )qSR 3 ; 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; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, 20 polyfluorocycloalkyl or cycloalkenyl; wherein V is C(R 5 ) 2 ; CR 5 R 6 ; NR 5 or NR 6 ; wherein W is CR 5 ; CR 6 or N; 25 wherein Z is S; 0; C(R 3 ) 2 ; or NR 3 ; wherein each R 5 is -H; -NO 2 ; -N 3 ; -CN; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or 30 polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2; -OR 3 ; -(CH 2 )pOR 3 ; -COR 3 ; -C0 2 R 3 ; or -CON(R 3 ) 2 ; -XCOR 8 ; or aryl or heteroaryl, wherein 35 the aryl or heteroaryl is optionally substituted WO 02/06245 PCT/USO1/21286 300 with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -NO,; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 )qOR3; (CH 2 )qSR3; -XCOR 8 ; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; 5 straight chained or branched C2-C7 alkenyl, C 2 ~C7 alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein each R 6 is independently -H; straight chained 10 or branched CI-C 7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C 3 -C 7 cycloal.kyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -OR 3 ; 15 -(CH2)pOR 3 ; -COR 3 ; -COR 3 ; or -CON(R 3 ) 2 ; wherein R 7 is -H; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C02R 3 ; -CON(R 3 ) 2 ; CN; -NO 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; 20 (CH 2 )qOR 3 ; (CH 2 )qSR 3 ; -XCOR 8 ; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; straight chained or branched C 2 -C 7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, 25 polyfluorocycloalkyl or cycloalkenyl; wherein R 8 is -H; 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 30 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3) 2 ; -OR 3 ; -(CH 2 )pOR 3 ; -COR 3 ; -C0 2 R 3 ; or -CON(R 3 ) 2 ; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -NO 2 ; 35 -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 )qOR 3 ; (CH 2 )qSR 3 ; straight WO 02/06245 PCT/USO1/21286 -301 chained or branched Cl-C. 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, monofluorocycloalkyl, 5 polyfluorocycloalkyl or cycloalkenyl; wherein b is 1 or 2; wherein d is an integer from 0 to 2 inclusive; 10 wherein each m is independently an integer from 0 to 3 inclusive; wherein each n is independently an integer from 0 to 15 5 inclusive; wherein each p is independently an integer from 1 to 7 inclusive; 20 wherein q is an integer from 1 to 3 inclusive; wherein t is an integer from 2 to 6 inclusive; or a pharmaceutically acceptable salt thereof. 25 WO 02/06245 PCT/USO1/21286 -302
74. A method of modifying feeding behavior of a subject which comprises administering to the subject an amount of a compound effective to decrease the consumption of food by the subject wherein the 5 compound is selected from the group consisting of: a) O N-- (b) 0 -0 N /S-N . N 10 0 N S F 0 c) N 7 N WO 02/06245 PCT/USO1/21286 -303 5 d ) O N O'N N 0 10 0 0 15 N 0 0 20 f) N ci C' 25 g) 0 N OrN CN; and 30 35 WO 02/06245 PCT/USO1/21286 -304 F - FF h) h) -N N 5 F
75. A method of modifying feeding behavior of a subject 10 which comprises administering to the subject an amount of a compound of claim 34 or 38 effective to decrease the consumption of food by the subject.
76. A method of treating a feeding disorder in a subject 15 which comprises administering to the subject an amount of a compound of claim 1, 34 or 38 effective to decrease the consumption of food by the subject.
77. The method of claim 76, wherein the feeding disorder 20 is bulimia, obesity or bulimia nervosa.
78. A method of reducing the body mass of a subject which comprises administering to the subject an amount of a compound of claim 34 or 38 effective to 25 reduce the body mass of the subject.
79. A method of treating a subject suffering from depression and/or anxiety which comprises administering to the subject an amount of a compound 30 of claim 34 or 38 effective to treat the subject's depression and/or anxiety.
80. The method of claim 47, 74, 75 or 76, wherein the subject is a vertebrate, a mammal, a human or a 35 canine. WO 02/06245 PCT/USO1/21286 -305
81. The method of claim 47, 74, 75 or 7G, wherein the compound is administered in combination with food.
82. A pharmaceutical composition comprising a 5 therapeutically effective amount of the compound of claim 1, 34 or 38 and a pharmaceutically acceptable carrier.
83. The pharmaceutical composition of claim 82 wherein 10 the amount of the compound is from about 0.01 mg to about 500 mg.
84. The pharmaceutical composition of claim 83 wherein the amount of the compound is from about 0.1 mg to 15 about 60 mg.
85. The pharmaceutical composition of claim 84 wherein the amount of the compound is from about 1 mg to about 20 mg. 20
86. The pharmaceutical composition of claim 82, wherein the carrier is a liquid and the composition is a solution. 25
87. The pharmaceutical composition of claim 82, wherein the carrier is a solid and the composition is a tablet.
88. The pharmaceutical composition of claim 82, wherein 30 the carrier is a gel and the composition is a suppository.
89. A pharmaceutical composition made by combining a therapeutically effective amount of the compound of 35 claim 1, 34 or 38 and a pharmaceutically acceptable carrier. WO 02/06245 PCT/USO1/21286 -306
90. A process for making a pharmaceutical composition comprising combining a therapeutically effective amount of the compound of claim 1, 34 or 38 and a pharmaceutically acceptable carrier. 5
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