HK1080471B - Secondary amino anilinic piperidines as mch1 antagonists and uses thereof - Google Patents

Description

Secondary aminoanilinopiperidines as MCH1 antagonists and uses thereof

This application claims priority from U.S. application serial No. 10/189,145 filed on 3/7/2002, the contents of which are incorporated herein by reference.

Throughout this application, the authors and years of the various publications referred to are placed in parentheses. The complete disclosures of these references are found at the end of this specification, i.e., at the front of the claims.

The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to describe in detail the state of the art to which this invention pertains.

Background

Melanin-concentrating hormone (MCH) is a cyclic peptide originally isolated from the pituitary of salmon (teleost fish) (Kawauchi et al, 1983). In fish, this 17 amino acid peptide causes melanin aggregation in melanocytes and inhibits ACTH release, acting as a functional antagonist of α -MSH. Mammalian MCH (19 amino acids) is stored in large quantities between rat, mouse and human and exhibits 100% amino acid homology, but its physiological function is not well understood. MCH has been reported to be involved in a variety of processes including diet, water balance, energy metabolism, general arousal/attention states, memory and cognitive functions, and mental illness (for review, see Baker, 1991; Baker, 1994; Nahon, 1994; Knigge et al, 1996). The latest Nature publication (Qu et al, 1996) supports its role in diet or weight regulation, confirming that MCH is overexpressed in the hypothalamus of ob/ob mice compared to ob/+ mice, and that fasting further increases MCH mRNA levels in both obese and normal mice during fasting. MCH also stimulates the diet of normal rats when injected into the lateral ventricles (Rossi et al, 1997).

MCH has also been reported to functionally antagonize the behavioral effects of alpha-MSH (Miller et al, 1993; Gonzalez et al, 1996; Sanchez et al, 1997); in addition, stress has also been shown to increase POMCmRNA levels while reducing MCH precursor pretreatment MCH (ppMCH) mRNA levels (Presse et al, 1992). Thus, MCH may be used as an integral neuropeptide involved in stress responses and in regulating dietary and sexual activity (Baker, 1991; Knigge et al, 1996).

It is believed that the biological effects of MCH are mediated through specific receptors. A tritiated ligand (,) is reported³H]MCH) exhibits specific binding to meninges, but cannot be used in saturation assays and therefore neither affinity nor B can be determined_max(Drozdz and Eberle, 1995). Radioiodination of tyrosine at position 13 resulted in an unexpected reduction in ligand bioactivity (see Drozdz and Eberle, 1995). In contrast, the MCH analog [ Phe¹³，Tyr¹⁹]Radioiodination of MCH was successful (Drozdz et al, 1995); the ligand retains biological activity and exhibits specific binding to various cell lines including mouse melanoma (B16-F1, G4F, and G4F-7), PC12, and COS cells. In G4F-7 cells, K_D＝0.118nM，B_max1100 sites/cell. Importantly, this binding was not inhibited by α -MSH, but was weakly inhibited by rat ANF (Ki 116nM versus native MCH 12nM) (Drozdz et al, 1995). Specific MCH binding in transformed keratinocytes (Burglad et al, 1997) and melanoma cells (Drozdz et al, 1998) has been recently reported, with photocrosslinking studies suggesting the instituteThe receptors are membrane proteins with apparent molecular weights of 45-50K daltons, which fit the molecular weight range of receptors of the GPCR superfamily. There have been no reports of autoradiography studies of MCH receptor localization using this ligand.

The localization and biological activity of MCH peptides suggest that modulation of MCH receptor activity may be useful for a variety of therapeutic uses. The role of MCH in the diet is the best feature for its potential clinical use. MCH is expressed in the lateral hypothalamus of brain regions involved in regulating thirst and hunger (grilon et al, 1997); orexin (orexins) a and B, both of which are potent appetizing drugs, have recently been shown to have a very similar localization to MCH in the lateral hypothalamus (Sakurai et al, 1998). MCH mRNA levels in this brain region increased in rats after 24 hours fasting (Herv é and ferlman, 1997); a significant increase in MCH immunoreactive periplasmic and fibrous mass and staining intensity was observed following insulin injection, along with a significant increase in MCH mRNA levels (Bahjaoui-Bouhadd et al, 1994).

Consistent with the ability of MCH to stimulate rat diet (Rossi et al, 1997) was the observation that MCH mRNA levels were positively regulated in the hypothalamus of obese ob/ob mice (Qu et al, 1996) and were reduced in the hypothalamus of rats treated with leptin (leptin), with reduced food intake and weight gain (Sahu et al, 1998). MCH appears to act as a functional antagonist of the melanocortin system in its role in food intake and hormone secretion in HPA (hypothalamus pituitary/renal axis) (Ludwig et al, 1998). Together, these data suggest a role for endogenous MCH in regulating energy balance and stress response and provide the rationale for developing specific compounds acting on MCH receptors for the treatment of obesity and stress-related diseases.

In all the various studies to date, the neurons of most MCH cell groups occupy a relatively stable position in those regions outside the hypothalamus and at the base of the thalamus where they reside, and may be part of some so-called "extrapyramidal" motor circuits. These include a number of striated and globus-free pathways involving the thalamus and cerebral cortex, the hypothalamic region, the cross-linked region with the subthalamic nucleus, the substantia nigra and the center of the midbrain (Bittencourt et al, 1992). In their localization, MCH cell groups may provide a pons or mechanism that expresses hypothalamic visceral activity with appropriate and synergistic motor activity. Clinically it may have some value for this MCH system that is thought to be involved in dyskinetic diseases such as parkinson's disease and huntington's chorea, where the extra-pyramidal tract is known to be involved.

Human genetic linkage studies have mapped the locus for hMCH at chromosome 12 (12q23-24) and the variant hMCH at chromosome 5 (5q12-13) (Pedeutouter et al, 1994). Site 12q23-24 coincides with a site where autosomal dominant cerebellar ataxia type II (SCA2) has been mapped (Auburger et al, 1992; Twells et al, 1992). Such diseases include neurodegenerative diseases, including atrophy of olivopontocerebellum.

In addition, the gene for Darley's disease has been mapped to position 12q23-24(Craddock et al, 1993). Darrieus disease is characterized by adhesion of abnormal type I keratinocytes in certain families and psychogenic disorders. Based on the functional and neuroanatomical patterns of the MCH nervous system in rat and human brains, the MCH gene may represent a good candidate for SCA2 or darriella disease. Interestingly, a variety of diseases with high social impact have been mapped to this genetic map. Indeed, using genetic linkage analysis, the gene for spinal muscular atrophy in either chronic or acute form has been designated as chromosome 5q12-13(Melki et al, 1990; Westbrook et al, 1992). In addition, several lines of independent evidence support the proposal that the major schizophrenia site is at 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 mood disorders.

Other therapeutic uses of MCH-related compounds are suggested by the observed effects of MCH in other biological systems. For example, MCH can modulate reproductive function in male and female rats. In adult rat germ cell assays, MCH transcripts and MCH peptides were found, suggesting that MCH may be involved in stem cell renewal and/or early spermatocyte differentiation (Hervieu et al, 1996). Injection of MCH directly into the anteromedial nucleus region (MPOA) or the ventral-medial nucleus (VMN) stimulates sexual activity in female rats (Gonzalez et al, 1996). In ovariectomized rats treated with estradiol, MCH stimulates Luteinizing Hormone (LH) release, while anti-MCH antisera inhibits LH release (Gonzalez et al, 1997). The undefined region containing large amounts of MCH cell bodies has previously been identified as the pre-ovulatory LH passive regulatory region (Mackenzie et al, 1984).

MCH has been reported to affect the release of pituitary hormones, including ACTH and oxytocin. MCH analogs are also useful in the treatment of epilepsy. In the PTZ tic model, injection of MCH prior to tic induction prevented tic activity in rats and guinea pigs, suggesting that neurons containing MCH may participate in the neural cycle undergoing PTZ-induced tics (Knigge and Wagner, 1997). Behavioral correlations for MCH to affect cognitive function have also been observed. MCH treatment promotes the abrogation of the passive avoidance response in rats (McBride et al, 1994), raising the possibility that MCH receptor antagonists may contribute to memory storage and/or retention. The possible role of MCH in the regulation or involvement of pain is supported by dense neo-shoots around the aqueduct (PAG) of MCH-positive fibers. Ultimately, MCH may be involved in the regulation of fluid uptake. ICV perfusion of MCH in conscious sheep produces changes in diuresis, natriuresis and potassium excretion in response to increased blood volume (Parkes, 1996). These results, together with anatomical data reporting the presence of MCH in fluid regulatory regions of the brain, indicate that MCH may be an important peptide involved in central control of fluid homeostasis in mammals.

The identification of the G-protein coupled receptor for MCH has recently been disclosed (Chambers et al, 1999; Saito et al, 1999). These groups identified MCH as an endogenous ligand for the human orphan G-protein coupled receptor SLC-1 (Lakaye et al, 1998). The rat homologue of this receptor (now referred to as MCH-1) was reported to localize to brain regions of rats associated with eating behavior (e.g., dorsolateral and ventral hypothalamus). Recent reports of the phenotype of MCH-1 deprived mice enhanced the association between MCH-1 and MCH effects on diet. Two groups have independently shown (Mash et al, 2002; Chen et al, 2002) that targeted disruption of the mouse MCH-1 receptor gene (MCH-1 ablation) results in animals that eat too much but are lean and lose weight compared to wild-type littermates. The weight loss is due to increased metabolism. Each group demonstrated that MCH-1-deprived mice were resistant to diet-induced obesity and generally exhibited a body weight similar to that of regular diet-sustained, avian-identical mice.

Finally, synthetic antagonist molecules for the MCH-1 receptor have now been described in the literature. Bednaek et al (2002) have reported the synthesis of high affinity peptide antagonists of MCH-1. In addition, Takekawa et al have described small molecule antagonists of MCH-1 (Takekawa et al, 2002). This compound, T-226296, exhibited high affinity for the MCH-1 receptor (-5-9 nM for rat and human MCH-1) and was shown to inhibit food intake induced by intracerebroventricular application of MCH. These data demonstrate a strategy for treating obesity using MCH-1 receptor antagonists.

In addition, in our own studies, we have tested MCH1 antagonists in several animal models that are well known as predictors of the efficacy of compounds in humans (Borowsky et al, Nature Medicine 2003). These experiments indicate that MCH1 antagonists may be useful in the treatment of obesity, depression, anxiety and urinary disorders.

Here, we report the synthesis of secondary amino-anilinopiperidines (anilic piperidines) that bind to the cloned human melanin-concentrating hormone 1(MCH1) receptor. In addition, these compounds bind selectively to the MCH-1 receptor compared to other cloned G-protein coupled receptors. The ability to inhibit the activation of cloned receptors as measured by in vitro assay is disclosed.

In addition, the compounds of the invention may also be useful in the treatment of abnormal conditions mediated by the inactivation of the MCH-1 receptor, such as eating disorders (obesity, bulimia nervosa), sexual/reproductive disorders, depression, anxiety, depression and anxiety, absence convulsions, hypertension, cerebral ischemia, congestive heart failure, sleep disorders or any disease in which MCH1 receptor antagonism may be beneficial.

In addition, the compounds of the invention may be used to reduce body weight in a patient. Furthermore, the compounds of the invention can be used for the treatment of urinary disorders.

Summary of The Invention

The present invention provides a compound having the structure:

wherein each A is independently-H, -F, -Cl, -Br, -I, -CN, -NO₂、-OR₃Or straight or branched C₁-C₇An alkyl group;

wherein each B is independently N or CH;

wherein Z is CO or SO₂；

Wherein each R is independently-H, -F or straight or branched C₁-C₇Alkyl, monofluoroalkyl or polyfluoroalkyl;

wherein R is₄Independently is-OR₃、-NHR₃、-SR₃、-COR₃Straight or branched chain C₁-C₇An alkyl, monofluoroalkyl or polyfluoroalkyl, aryl or heteroaryl group, wherein the aryl or heteroaryl group is optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -OR₂Or straight or branched C₁-C₇An alkyl group;

wherein each R₃Independently is-H, straight or branched chain C₁-C₇An alkyl, monofluoroalkyl or polyfluoroalkyl, aryl or heteroaryl group, wherein the aryl or heteroaryl group is optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -NO₂、-CN、-OR₂or-NHR₂；

Wherein each R₂Independently is-H, straight or branched chain C₁-C₇Alkyl, aryl or heteroaryl, wherein aryl or heteroaryl is optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -NO₂-CN; or

Wherein n is an integer from 1 to 6.

In another embodiment of the above invention, the compound is enantiomerically and diastereomerically pure. In another embodiment, the compounds are enantiomerically and diastereomerically pure compounds. In one embodiment, the compound is the (+) enantiomer. In one embodiment, the compound is the (-) enantiomer.

The present invention is exemplified by pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of any one of the compounds of the present invention.

An example of the present invention is a pharmaceutical composition made by mixing any of the above compounds with a pharmaceutically acceptable carrier.

An illustrative example of the invention is a process for preparing a pharmaceutical composition comprising mixing any of the compounds of the invention with a pharmaceutically acceptable carrier.

The present invention is exemplified by a synthetic method for preparing any of the compounds of the present invention.

The present invention is exemplified by a method of treating a disease mediated by the MCH1 receptor in a patient in need thereof comprising administering to the patient a therapeutically effective amount of any one of the compounds or pharmaceutical compositions of the invention and a pharmaceutically acceptable carrier.

In one embodiment, the therapeutically effective amount is between about 0.03 and about 300 mg.

In one embodiment, the disorder is depression. In one embodiment, the disorder is anxiety. In one embodiment, the disease is obesity. In one embodiment, the disorder is urinary incontinence.

One embodiment is a method of treating a patient in need thereof with a disorder selected from depression, anxiety, obesity or urinary incontinence comprising administering to said patient a therapeutically effective amount of a compound of the present invention.

In one embodiment, the therapeutically effective amount is between about 0.03 and about 300 mg.

In another embodiment, the disorder is depression. In another embodiment, the disorder is anxiety. In another embodiment, the disease is obesity. In another embodiment, the disorder is urinary incontinence.

Detailed Description

The present invention provides a compound having the structure:

wherein each A is independently-H, -F, -Cl, -Br, -I, -CN, -NO₂、-OR₃Or straight or branched C₁-C₇An alkyl group;

wherein each B is independently N or CH;

wherein Z is CO or SO₂；

Wherein each R is independently-H, -F or straight or branched C₁-C₇Alkyl, monofluoroalkyl or polyfluoroalkyl;

wherein R is₄Independently is-OR₃、-NHR₃、-SR₃、-COR₃Straight or branched chain C₁-C₇An alkyl, monofluoroalkyl or polyfluoroalkyl, aryl or heteroaryl group, wherein the aryl or heteroaryl group is optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -OR₂Or straight or branched chainC₁-C₇An alkyl group;

wherein each R₃Independently is-H, straight or branched chain C₁-C₇An alkyl, monofluoroalkyl or polyfluoroalkyl, aryl or heteroaryl group, wherein the aryl or heteroaryl group is optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -NO₂、-CN、-OR₂or-NHR₂；

Wherein each R₂Independently is-H, straight or branched chain C₁-C₇Alkyl, aryl or heteroaryl, wherein aryl or heteroaryl is optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -NO₂-CN; and

wherein n is an integer from 1 to 6.

In one embodiment, the compound has the following structure:

in one embodiment, the compound has the following structure:

wherein R is₄Is aryl or heteroaryl, wherein aryl or heteroaryl is optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -OR₃Or straight or branched C₁-C₇An alkyl group; wherein each R₃Is straight chain or branched C₁-C₇Alkyl, aryl or heteroaryl, wherein aryl or heteroaryl is optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -NO₂-CN OR-OR₂(ii) a And

wherein each R₂Independently is-H, straight or branched chain C₁-C₇Alkyl, aryl or heteroaryl, wherein aryl or heteroaryl isOptionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -NO₂、-CN。

One embodiment of the present invention is a compound having the structure:

wherein R is₂Independently is-H, straight or branched chain C₁-C₇Alkyl, or aryl, wherein aryl is optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -NO₂or-CN.

In one embodiment, the compound has the following structure:

wherein R is₂Is straight chain or branched C₁-C₇An alkyl group; and

wherein n is an integer from 3 to 6.

Compounds of the present invention wherein the compound has the structure:

wherein each A is independently-H, -F, -Cl, -Br or-I.

In one embodiment, the compound has the following structure:

wherein each A is independently-H, -F, or-Cl; and

wherein R is₂Is straight chain or branched C₁-C₃An alkyl group.

Compounds of the invention having the structure:

compounds of the invention having the structure:

in one embodiment, the compound has the following structure:

wherein R is₂Is aryl, wherein aryl is optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -NO₂or-CN; and

wherein n is an integer from 1 to 6.

In one embodiment, the compound has the following structure:

wherein each A is independently-H, -F, -Cl, -Br or-I.

In one embodiment, the compound has the following structure:

wherein each A is independently-H, -F, or-Cl; and

wherein R is₂To be one or moreAryl optionally substituted with-F, -Cl or-Br.

In one embodiment, the compound has the following structure:

wherein each A is independently-H, -F, or-Cl; and

wherein R is₂Is aryl optionally substituted by one or more-F.

In one embodiment, the compound has the following structure:

in one embodiment, the compound has the following structure:

in one embodiment, the compound has the following structure:

wherein R is₄Aryl optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -OR₃Or straight or branched C₁-C₇An alkyl group;

wherein each R₃Independently is a straight or branched chain C₁-C₇Alkyl, aryl or heteroaryl, wherein aryl or heteroaryl is optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -NO₂-CN OR-OR₂；

Wherein each R₂Independently is a straight or branched chain C₁-C₇An alkyl group.

The present invention also provides compounds having the structure:

wherein R is₄Independently is-OR₃、-NHR₃、-COR₃or-SR₃；

Wherein R is₃Each independently of the others being straight-chain or branched C₁-C₇Alkyl, aryl or heteroaryl, wherein aryl or heteroaryl is optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -NO₂、-CN、-OR₂or-NHR₂；

Wherein each R₂Independently is-H, straight or branched chain C₁-C₇Alkyl, or aryl optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -NO₂-CN; and

wherein n is an integer from 1 to 6.

In one embodiment, the compound has the following structure:

wherein each A is independently-H, -F, -Cl, -Br, or-I;

wherein R is₄Independently is-OR₃、-NHR₃or-COR₃；

Wherein R is₃Is aryl optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -NO₂、-CN、-OR₂or-NHR₂；

Wherein each R₂Independently is-H, straight or branched chain C₁-C₇Alkyl, or aryl optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -NO₂-CN; and

wherein n is an integer from 1 to 6.

In one embodiment, the compound has the following structure:

wherein each A is independently-H or-F;

wherein R is₃Is aryl optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -NO₂、-CN、-OR₂or-NHR₂；

Wherein R is₂Independently is a straight or branched chain C₁-C₇Alkyl, or aryl optionally substituted with one or more of the following groups: -F, -Cl, -Br or-I; and

wherein n is an integer from 1 to 6.

In one embodiment, the compound has the following structure:

wherein each A is-H, -F, -Cl, -Br or-I;

wherein aryl is optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I.

In one embodiment, the compound has the following structure:

in one embodiment, the compound has the following structure:

in one embodiment, the compound has the following structure:

wherein A is independently-H, -F, -Cl, -Br or-I;

wherein R is₃Is aryl optionally substituted with one or more of the following groups: -F, -Cl, -Br or-I.

The compound has the following structure:

the compound has the following structure:

the present invention also provides a compound having the structure:

wherein each Q is independently hydrogen;

wherein X is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or moreAnd (3) group substitution: -F, -Cl, -Br, -I, -ZR₃、-ZOR₃、-OZR₃、-ZN(R₃)₂、-N(R₃)ZR₃、-N(R₃)ZN(R₃)₂、-CN、-NO₂、-SR₃、-(CH₂)_qOR₃、-(CH₂)_qSR₃Aryl, phenoxy or heteroaryl, straight-chain or branched C₁-C₇Alkyl, monofluoroalkyl or polyfluoroalkyl, straight-chain or branched C₂-C₇Alkenyl or alkynyl, or C₃-C₇Cycloalkyl, monofluorocycloalkyl, polyfluoroalkyl or cycloalkenyl;

wherein each Z is independently CO, CS, SO₂(ii) a Or absent (null);

wherein each R is independently-H, -F, straight or branched C₁-C₇Alkyl, monofluoroalkyl or polyfluoroalkyl, straight-chain or branched C₂-C₇Alkenyl or alkynyl, -N (R)₃)₂、-NO₂、-CN、-CO₂R₃、-OCOR₃、-OR₃、-N(R₃)COR₃or-CON (R)₃)₂；

Wherein each R₂Independently is-H, straight or branched chain C₁-C₇Alkyl, aryl or heteroaryl, wherein aryl or heteroaryl is optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -NO₂-CN, straight or branched C₁-C₇Alkyl, monofluoroalkyl or polyfluoroalkyl or straight-chain or branched C₂-C₇Alkenyl or alkynyl;

wherein each R₃Independently is-H, straight or branched chain C₁-C₇Alkyl, monofluoroalkyl or polyfluoroalkyl, straight-chain or branched C₂-C₇Alkenyl or alkynyl, C₃-C₇Cycloalkyl, monofluorocycloalkyl, polyfluoroalkyl or cycloalkenyl, aryl or heteroaryl, wherein aryl or heteroaryl is optionally substituted with one or more of the following groups: -F,-Cl、-Br、-I、-N(R₂)₂、-NO₂、-CN、-COR₂、-CO₂R₂、-OCOR₂、-OR₂、-N(R₂)COR₂、-N(R₂)CON(R₂)₂、-CON(R₂)₂Aryl, heteroaryl, phenoxy, straight or branched C₁-C₇Alkyl, monofluoroalkyl or polyfluoroalkyl, straight-chain or branched C₂-C₇Alkenyl or alkynyl, C₃-C₇Cycloalkyl, monofluorocycloalkyl, polyfluoroalkyl or cycloalkenyl;

wherein each R₄Independently is-H, -ZR₃、-ZOR₃、-OZR₃、-ZN(R₃)₂、-N(R₃)ZR₃、-N(R₃)ZN(R₃)₂Straight or branched chain C₁-C₇Alkyl, monofluoroalkyl or polyfluoroalkyl, aryl, benzyl or heteroaryl, wherein aryl, benzyl or heteroaryl is optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -ZR₃、-ZOR₃、-OZR₃、-ZN(R₃)₂、-N(R₃)ZR₃、-N(R₃)ZN(R₃)₂、-CN、-NO₂、-SR₃、-(CH₂)_qOR₃、-(CH₂)_qSR₃Aryl, benzyl, heteroaryl, straight or branched C₁-C₇Alkyl, monofluoroalkyl or polyfluoroalkyl, straight-chain or branched C₂-C₇Alkenyl or alkynyl, or C₃-C₇Cycloalkyl, monofluorocycloalkyl, polyfluoroalkyl or cycloalkenyl;

wherein each k is independently an integer from 1 to 3;

wherein each m is independently an integer from 0 to 1;

wherein n is an integer of 0 to 6;

wherein q is an integer of 1 to 3.

The present invention also provides a compound having the structure:

wherein each Q is independently hydrogen;

wherein X is aryl or heteroaryl, wherein aryl or heteroaryl is optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -ZR₃、-ZOR₃、-OZR₃、-ZN(R₃)₂、-N(R₃)ZR₃、-N(R₃)ZN(R₃)₂、-CN、-NO₂、-SR₃、-(CH₂)_qOR₃、-(CH₂)_qSR₃Aryl, phenoxy or heteroaryl, straight-chain or branched C₁-C₇Alkyl, monofluoroalkyl or polyfluoroalkyl, straight-chain or branched C₂-C₇Alkenyl or alkynyl, or C₃-C₇Cycloalkyl, monofluorocycloalkyl, polyfluoroalkyl or cycloalkenyl;

wherein each Z is independently CO, CS, SO₂(ii) a Or is absent;

wherein each R is independently-H, -F, straight or branched C₁-C₇Alkyl, monofluoroalkyl or polyfluoroalkyl, straight-chain or branched C₂-C₇Alkenyl or alkynyl, -N (R)₃)₂、-NO₂、-CN、-CO₂R₃、-OCOR₃、-OR₃、-N(R₃)COR₃or-CON (R)₃)₂；

Wherein each R₂Independently is-H, straight or branched chain C₁-C₇Alkyl, aryl or heteroaryl, wherein aryl or heteroaryl is optionally substituted by one or more ofThe group (b) is substituted: -F, -Cl, -Br, -I, -NO₂-CN, straight or branched C₁-C₇Alkyl, monofluoroalkyl or polyfluoroalkyl, straight-chain or branched C₂-C₇Alkenyl or alkynyl;

wherein each R₃Independently is-H, straight or branched chain C₁-C₇Alkyl, monofluoroalkyl or polyfluoroalkyl, straight-chain or branched C₂-C₇Alkenyl or alkynyl, C₃-C₇Cycloalkyl, monofluorocycloalkyl, polyfluoroalkyl or cycloalkenyl, aryl or heteroaryl, wherein aryl or heteroaryl is optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -N (R)₂)₂、-NO₂、-CN、-COR₂、-CO₂R₂、-OCOR₂、-OR₂、-N(R₂)COR₂、-N(R₂)CON(R₂)₂、-CON(R₂)₂Aryl, heteroaryl, phenoxy, straight or branched C₁-C₇Alkyl, monofluoroalkyl or polyfluoroalkyl, straight-chain or branched C₂-C₇Alkenyl or alkynyl, C₃-C₇Cycloalkyl, monofluorocycloalkyl, polyfluoroalkyl or cycloalkenyl;

wherein each R₄Independently is-H, -ZR₃、-ZOR₃、-OZR₃、-ZN(R₃)₂、-N(R₃)ZR₃、-N(R₃)ZN(R₃)₂Straight or branched chain C₁-C₇Alkyl, monofluoroalkyl or polyfluoroalkyl, aryl, benzyl or heteroaryl, wherein aryl, benzyl or heteroaryl is optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -ZR₃、-ZOR₃、-OZR₃、-ZN(R₃)₂、-N(R₃)ZR₃、-N(R₃)ZN(R₃)₂、-CN、-NO₂、-SR₃、-(CH₂)_qOR₃、-(CH₂)_qSR₃Aryl, benzyl, heteroaryl, straight or branched C₁-C₇Alkyl, monofluoroalkyl or polyfluoroalkyl, straight-chain or branched C₂-C₇Alkenyl or alkynyl, or C₃-C₇Cycloalkyl, monofluorocycloalkyl, polyfluoroalkyl or cycloalkenyl;

wherein each k is independently an integer from 1 to 3;

wherein n is an integer of 0 to 6;

wherein q is an integer of 1 to 3.

The present invention is exemplified by a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically therapeutically effective amount of any of the compounds described above.

The present invention is exemplified by a pharmaceutical composition prepared by mixing any one of the above compounds with a pharmaceutically acceptable carrier.

An illustrative example of the invention is a process for preparing a pharmaceutical composition comprising mixing any of the above compounds with a pharmaceutically acceptable carrier.

An example of the present invention is a synthetic method for preparing any of the above compounds.

The present invention is exemplified by a method of treating a MCH-1 receptor mediated disease in a patient in need thereof comprising administering to said patient a therapeutically effective amount of any one of the compounds or pharmaceutical compositions described above and a pharmaceutically acceptable carrier.

The present invention also provides a compound having the structure:

wherein each Q is independently hydrogen;

wherein X is phenyl or a nitrogen-containing heterocycle, wherein the phenyl or nitrogen-containing heterocycle is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -ZR₃、-ZOR₃、-OZR₃、-ZN(R₃)₂、-N(R₃)ZR₃、-N(R₃)ZN(R₃)₂、-CN、-NO₂、-SR₃、-(CH₂)_qOR₃、-(CH₂)_qSR₃Aryl, phenoxy or heteroaryl, straight or branched C₁-C₇Alkyl, monofluoroalkyl or polyfluoroalkyl, straight-chain or branched C₂-C₇Alkenyl or alkynyl, or C₃-C₇Cycloalkyl, monofluorocycloalkyl, polyfluoroalkyl or cycloalkenyl;

wherein each Z is independently CO, CS, SO₂(ii) a Or is absent;

wherein each R is independently-H, -F, straight or branched C₁-C₇Alkyl, monofluoroalkyl or polyfluoroalkyl, straight-chain or branched C₂-C₇Alkenyl or alkynyl, -N (R)₃)₂、-NO₂、-CN、-CO₂R₃、-OCOR₃、-OR₃、-N(R₃)COR₃or-CON (R)₃)₂；

Wherein each R₂Independently is-H, straight or branched chain C₁-C₇Alkyl, aryl or heteroaryl, wherein aryl or heteroaryl is optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -NO₂-CN, straight or branched C₁-C₇Alkyl, monofluoroalkyl or polyfluoroalkyl, straight-chain or branched C₂-C₇Alkenyl or alkynyl;

wherein each R₃Independently is-H, straight or branched chain C₁-C₇Alkyl, monofluoroalkyl or polyfluoroalkyl, straight-chain or branched C₂-C₇Alkenyl or alkynyl, C₃-C₇Cycloalkyl, monofluoroCycloalkylene, polyfluoroalkylene or cycloalkenyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -N (R)₂)₂、-NO₂、-CN、-COR₂、-CO₂R₂、-OCOR₂、-OR₂、-N(R₂)COR₂、-N(R₂)CON(R₂)₂、-CON(R₂)₂Aryl, heteroaryl, phenoxy, straight or branched C₁-C₇Alkyl, monofluoroalkyl or polyfluoroalkyl, straight-chain or branched C₂-C₇Alkenyl or alkynyl, C₃-C₇Cycloalkyl, monofluorocycloalkyl, polyfluoroalkyl or cycloalkenyl;

wherein each R₄Independently is-H, -ZR₃、-ZOR₃、-OZR₃、-ZN(R₃)₂、-N(R₃)ZR₃、-N(R₃)ZN(R₃)₂Straight or branched chain C₁-C₇Alkyl, monofluoroalkyl or polyfluoroalkyl, aryl, benzyl or heteroaryl, wherein aryl, benzyl or heteroaryl is optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -ZR₃、-ZOR₃、-OZR₃、-ZN(R₃)₂、-N(R₃)ZR₃、-N(R₃)ZN(R₃)₂、-CN、-NO₂、-SR₃、-(CH₂)_qOR₃、-(CH₂)_qSR₃Aryl, benzyl, heteroaryl, straight or branched C₁-C₇Alkyl, monofluoroalkyl or polyfluoroalkyl, straight-chain or branched C₂-C₇Alkenyl or alkynyl, or C₃-C₇Cycloalkyl, monofluorocycloalkyl, polyfluoroalkyl or cycloalkenyl;

wherein each k is independently an integer from 1 to 3;

wherein n is an integer of 0 to 6;

wherein q is an integer of 1 to 3.

The present invention also provides a compound having the structure:

wherein each Q is independently hydrogen;

wherein each A is independently-H, -F, -Cl, -Br, -I, -ZR₃、-ZOR₃、-OZR₃、-ZN(R₃)₂、-N(R₃)ZR₃、-N(R₃)ZN(R₃)₂、-CN、-NO₂、-N(R₃)₂、-OR₃、-SR₃、-(CH₂)_qOR₃、-(CH₂)_qSR₃Straight or branched chain C₁-C₇Alkyl, monofluoroalkyl or polyfluoroalkyl, straight-chain or branched C₂-C₇Alkenyl or alkynyl, C₃-C₇Cycloalkyl, monofluorocycloalkyl, polyfluoroalkyl or cycloalkenyl;

wherein each B is independently N or CH;

wherein each Z is independently CO, CS, SO₂(ii) a Or is absent;

wherein each R is independently-H, -F, straight or branched C₁-C₇Alkyl, monofluoroalkyl or polyfluoroalkyl, straight-chain or branched C₂-C₇Alkenyl or alkynyl, -N (R)₃)₂、-NO₂、-CN、-CO₂R₃、-OCOR₃、-OR₃、-N(R₃)COR₃or-CON (R)₃)₂；

Wherein each R₂Independently is-H, straight or branched chain C₁-C₇Alkyl radicalAryl or heteroaryl, wherein aryl or heteroaryl is optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -NO₂-CN, straight or branched C₁-C₇Alkyl, monofluoroalkyl or polyfluoroalkyl, straight-chain or branched C₂-C₇Alkenyl or alkynyl;

wherein each R₃Independently is-H, straight or branched chain C₁-C₇Alkyl, monofluoroalkyl or polyfluoroalkyl, straight-chain or branched C₂-C₇Alkenyl or alkynyl, C₃-C₇Cycloalkyl, monofluorocycloalkyl, polyfluoroalkyl or cycloalkenyl, aryl or heteroaryl, wherein aryl or heteroaryl is optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -N (R)₂)₂、-NO₂、-CN、-COR₂、-CO₂R₂、-OCOR₂、-OR₂、-N(R₂)COR₂、-N(R₂)CON(R₂)₂、-CON(R₂)₂Aryl, heteroaryl, phenoxy, straight or branched C₁-C₇Alkyl, monofluoroalkyl or polyfluoroalkyl, straight-chain or branched C₂-C₇Alkenyl or alkynyl, C₃-C₇Cycloalkyl, monofluorocycloalkyl, polyfluoroalkyl or cycloalkenyl;

wherein each R₄Independently is-H, -ZR₃、-ZOR₃、-OZR₃、-ZN(R₃)₂、-N(R₃)ZR₃、-N(R₃)ZN(R₃)₂Straight or branched chain C₁-C₇Alkyl, monofluoroalkyl or polyfluoroalkyl, aryl, benzyl or heteroaryl, wherein aryl, benzyl or heteroaryl is optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -ZR₃、-ZOR₃、-OZR₃、-ZN(R₃)₂、-N(R₃)ZR₃、-N(R₃)ZN(R₃)₂、-CN、-NO₂、-SR₃、-(CH₂)_qOR₃、-(CH₂)_qSR₃Aryl, benzyl, heteroaryl, straight or branched C₁-C₇Alkyl, monofluoroalkyl or polyfluoroalkyl, straight-chain or branched C₂-C₇Alkenyl or alkynyl, or C₃-C₇Cycloalkyl, monofluorocycloalkyl, polyfluoroalkyl or cycloalkenyl;

wherein each k is independently an integer from 1 to 3;

wherein n is an integer of 0 to 6;

wherein q is an integer of 1 to 3.

In one embodiment, each A is independently-H, -F, -Cl, -Br, -I, -ZR₃、-ZOR₃、-OZR₃、-ZN(R₃)₂、-N(R₃)ZR₃、-N(R₃)ZN(R₃)₂、-N(R₃)₂、-OR₃、-SR₃、-(CH₂)_qOR₃、-(CH₂)_qSR₃Straight or branched chain C₁-C₇Alkyl, monofluoroalkyl or polyfluoroalkyl;

wherein each Z is independently CO, CS, or absent;

wherein each R is independently-H, -F, straight or branched C₁-C₇An alkyl group;

wherein each R₂Independently is-H, straight or branched chain C₁-C₇Alkyl, aryl or heteroaryl, wherein aryl or heteroaryl is optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -NO₂-CN, straight or branched C₁-C₇Alkyl, monofluoroalkyl or polyfluoroalkyl, straight-chain or branched C₂-C₇Alkenyl or alkynyl;

wherein each R₃Independently is-H, straight or branched chain C₁-C₇Alkyl, aryl or heteroaryl, wherein aryl or heteroaryl is optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -N (R)₂)₂、-NO₂、-CN、-COR₂、-CO₂R₂、-OCOR₂、-OR₂、-N(R₂)COR₂、-N(R₂)CON(R₂)₂、-CON(R₂)₂Aryl, heteroaryl, phenoxy, straight or branched C₁-C₇Alkyl, monofluoroalkyl or polyfluoroalkyl, straight-chain or branched C₂-C₇Alkenyl or alkynyl, C₃-C₇Cycloalkyl, monofluorocycloalkyl, polyfluoroalkyl or cycloalkenyl.

In one embodiment, the compound has the following structure:

in one embodiment, the compound has the following structure:

in one embodiment, the compound has the following structure:

in one embodiment, the compound has the following structure:

wherein R is₄Is aryl, wherein the aryl is optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, straight or branched C₁-C₇Alkyl, monofluoroalkyl or polyfluoroalkyl, straight-chain or branched C₂-C₇Alkenyl orAlkynyl, or C₃-C₇Cycloalkyl, monofluorocycloalkyl, polyfluoroalkyl or cycloalkenyl.

In one embodiment, the compound has the following structure:

in one embodiment, the compound has the following structure:

in one embodiment, the compound has the following structure:

wherein R is₃Is aryl or heteroaryl, wherein aryl or heteroaryl is optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -N (R)₂)₂、-NO₂、-CN、-COR₂、-CO₂R₂、-OCOR₂、-OR₂、-N(R₂)COR₂、-N(R₂)CON(R₂)₂、-CON(R₂)₂Aryl, heteroaryl, phenoxy, straight or branched C₁-C₇An alkyl group.

In one embodiment, the compound has the following structure:

in one embodiment, the compound has the following structure:

the term "heteroaryl" as used herein includes 5 and 6 membered unsaturated rings, which rings may contain one or more oxygen, sulfur or nitrogen atoms. Examples of heteroaryl groups include, but are not limited to, carbazole, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.

In addition, the term "heteroaryl" as used herein includes fused bicyclic ring systems which may contain one or more heteroatoms such as oxygen, sulfur and nitrogen. Examples of such heteroaryl groups include, but are not limited to, indolizinyl, indolyl, isoindolyl, benzo [ b ] furanyl, benzo [ b ] thienyl, indazolyl, benzimidazolyl, purinyl, benzoxazolyl, benzisoxazolyl, benzo [ b ] thiazolyl, imidazo [2, 1-b ] thiazolyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1, 8-naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, phthalimidyl, and2, 1, 3-benzothiazolyl groups.

The term "heteroaryl" also includes the above chemical groups that may be substituted with one or more of the following: -F, -Cl, -Br, -I, CN, -NO₂Straight or branched chain C₁-C₇Alkyl, straight or branched C₁-C₇Monofluoroalkyl, straight-chain or branched C₁-C₇Polyfluoroalkyl, straight or branched C₂-C₇Alkenyl, straight-chain or branched C₂-C₇Alkynyl, C₃-C₇Cycloalkyl radical, C₃-C₇Fluorocycloalkyl group, C₃-C₇Polyfluoroalkyl radical, C₅-C₇A cycloalkenyl group.

The term "heteroaryl" also includes N-oxides of the above chemical groups containing at least one nitrogen atom. In the present invention, the term "aryl" is phenyl or naphthyl.

In another embodiment of the above invention, the compound is enantiomerically and diastereomerically pure. In another embodiment, the compounds are enantiomerically and diastereomerically pure compounds.

In one embodiment, the compound is the (+) enantiomer. In one embodiment, the compound is the (-) enantiomer.

The present invention provides various pure stereoisomers of any of the compounds described herein. These stereoisomers may include enantiomers, diastereomers or E or Z alkene or imine isomers. The invention also provides mixtures of stereoisomers, including racemic, diastereomeric, or E/Z isomer mixtures. The pure stereoisomer (N Lorgr di, M.;Stereoselective Synthesis，(1987) VCH Edit or Ebel, H, andAsymmetric Synthesisvolumes 3B 5, (1983) Academic Press, EditorMorrison, J.), or they can be resolved by various methods such as crystallization and chromatographic techniques (Jaques, J.; collet, A.; wilen, s.;Enantiomer，Racemates，and Resolutions，1981，John Wiley and Sons and Asymmetric Synthesis，vol.2，1983，Academic Press，Editor Morrison，J)。

in addition, the compounds of the present invention may exist in the form of enantiomers, diastereomers, isomers, or two or more of these compounds may exist to form a racemic mixture or a diastereomeric mixture.

Preferably, the compounds of the invention are 80% pure, more preferably 90% pure and most preferably 95% pure. Pharmaceutically acceptable salts and complexes of all compounds described herein are included in the present invention. The acids and bases used to prepare these salts include, but are not limited to, the various acids and bases listed in this specification. Acids include, but are not limited to, the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, and boric acids. Acids also include, but are not limited to, the following organic acids: acetic, malic, succinic, fumaric, tartaric, maleic, citric, methanesulfonic, benzoic, glycolic, lactic and mandelic acids. Bases include, but are not limited to, ammonia, methylamine, ethylamine, propylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, ethylenediamine, hydroxyethylamine, morpholine, piperazine, and guanidine. The present invention also provides hydrates and polymorphs of all of the compounds described herein.

The invention also includes prodrugs of the compounds of the invention within their scope. In general, these prodrugs are functionalized derivatives of the compounds of the present invention that are readily converted in vivo to the desired compound. Thus, in the present invention, the term "administering" shall include the treatment of various diseases with the specifically disclosed compounds or with compounds not specifically disclosed, but which are convertible in vivo to the specified compounds after administration to a patient. Conventional methods for selecting and preparing suitable prodrug derivatives are described, for example, in Design of produgs, h.

The invention also includes metabolites of the compounds of the invention. Metabolites include active substances produced upon introduction of the compounds of the present invention into a biological environment.

The present invention is exemplified by a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of any one of the compounds of the present invention.

The present invention is exemplified by a pharmaceutical composition prepared by mixing any one of the above compounds with a pharmaceutically acceptable carrier.

An illustrative example of the invention is a process for preparing a pharmaceutical composition comprising mixing any of the compounds of the invention with a pharmaceutically acceptable carrier.

The solid support may include one or more substances that may also act as reagents: endogenous carriers (e.g., nutrient carriers or micronutrient carriers), flavoring agents, lubricants, co-solvents, suspending agents, fillers, glidants, compression aids, binders, or tablet disintegrating agents, and the solid carrier can also be an encapsulating material. In the case of powders, the carrier is a finely divided solid which is mixed with the finely divided active ingredient. For 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. Powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinyl pyrrolidine, low melting waxes and ion exchange resins.

Liquid carriers are used in the preparation of solutions, suspensions, emulsions, syrups, elixirs and compressed compositions. The active ingredient may be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent or a mixture of both, or a pharmaceutically acceptable oil or fat. The liquid carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickeners, colorants, viscosity regulators, stabilizers or osmo-regulators. Examples of liquid carriers suitable for oral and parenteral administration include water (partially containing additives as described above, such as cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, such as glycols) and their derivatives, and oils (such as fractionated coconut oil and arachis oil). For parenteral administration, the carrier may also be an oily ester, such as ethyl oleate or isopropyl myristate. Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration. The liquid carrier used in the compressed composition may be a halogenated hydrocarbon or other pharmaceutically acceptable propellant.

Liquid pharmaceutical compositions in the form of sterile solutions or suspensions may be administered by injection, for example, intramuscularly, intrathecally, epidurally, intraperitoneally, or subcutaneously. Sterile solutions can also be administered intravenously. The compounds may be prepared as sterile solid compositions which, when administered, may be dissolved or suspended in sterile water, saline, or other suitable sterile injectable medium. Carriers may include binding agents, suspending agents, lubricants, flavoring agents, sweetening agents, preserving agents, dyes and coatings, as necessary and inert. The compounds may be administered orally in the form of sterile solutions or suspensions containing other solutes or suspending agents, such as saline or glucose sufficient to prepare an isotonic solution, bile acid salts, acacia, gelatin, sorbitan monooleate, polysorbate-80 (oleate esters of copolymers of sorbitol and its anhydrides with ethylene oxide), and the like.

The compounds may also be administered orally in the form of liquid or solid compositions. Compositions suitable for oral administration include solid forms such as pills, capsules, granules, tablets and powders, and liquid forms such as solutions, syrups, elixirs and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions and suspensions.

The optimal dosage to be administered may be determined by one skilled in the art and will vary with the particular compound employed, the strength of action of the formulation, the mode of administration and the advancement of the disease. In addition, the dosage is adjusted according to factors such as the age, body weight, sex, diet and time of administration of the particular patient to be treated.

The present invention is exemplified by a synthetic method for preparing any of the compounds of the present invention.

The present invention is exemplified by a method of treating a MCH-1 receptor mediated disease in a patient in need thereof comprising administering to said patient a therapeutically effective amount of any one of the compounds or pharmaceutical compositions of the present invention and a pharmaceutically acceptable carrier.

In one embodiment, the therapeutically effective amount is between about 0.03 and about 300 mg.

In one embodiment, the disorder is depression. In one embodiment, the disorder is anxiety. In one embodiment, the disease is obesity. In one embodiment, the disorder is urinary incontinence.

One embodiment is a method of treating a patient in need thereof with a disorder selected from depression, anxiety, obesity or urinary incontinence comprising administering to said patient a therapeutically effective amount of a compound of the present invention.

In one embodiment, the therapeutically effective amount is between about 0.03 and about 300 mg.

In another embodiment, the disorder is depression. In another embodiment, the disorder is anxiety. In another embodiment, the disease is obesity. In another embodiment, the disorder is urinary incontinence.

In this application, a "therapeutically effective amount" refers to any amount of a compound that, when administered to a patient having a disease treatable with the compound, alleviates, or resolves the disease. In the present application, a "patient" is a vertebrate, a mammal, or a human.

The present invention provides a method of treating a patient suffering from an abnormal condition that is alleviated by reducing MCH1 receptor activity, comprising administering to the patient an amount of a compound of the invention that is an MCH1 receptor antagonist effective in treating the abnormal condition in the patient.

In separate embodiments, the abnormal condition is a steroid or pituitary hormone regulation disorder, an adrenoceptor release disorder, a gastrointestinal disorder, a cardiovascular disorder, an electrolyte balance disorder, hypertension, diabetes, a respiratory disorder, asthma, a reproductive dysfunction, an immunological disorder, an endocrine disorder, a musculoskeletal disorder, a neuroendocrine disorder, a cognitive disorder, a memory disorder (e.g., Alzheimer's disease), a sensory modulation and transmission disorder, a motor coordination disorder, a sensory integration disorder, a motor integration disorder, a dopaminergic disorder (e.g., Parkinson's disease), a sensory transmission disorder, an olfactory disorder, a sympathetic innervation disorder, an affective disorder (e.g., depression and anxiety), a stress-related disorder, a fluid balance disorder, epilepsy, pain, a psychotic behavior (e.g., schizophrenia), morphine tolerance, or morphine, Opiate addiction, migraine or micturition disorders (e.g. urinary incontinence).

A preferred embodiment of the present invention provides a method of treating the following diseases: depression, anxiety, eating disorders/body weight disorders and micturition disorders. Examples of eating disorders/body weight disorders are obesity, bulimia or bulimia nervosa. Examples of micturition disorders include, but are not limited to, urinary incontinence, overactive bladder, urge incontinence, urinary frequency, urgency, nocturia, or enuresis. Overactive bladder or urgency may or may not be accompanied by benign prostatic hyperplasia.

The present invention provides a method of improving the eating behavior of a patient comprising administering to the patient an amount of a compound of the present invention effective to reduce the food consumption of the patient.

The present invention also provides a method of treating a dietary disorder in a subject, comprising administering to the subject an amount of a compound of the present invention effective to reduce the food consumption of the subject. In one embodiment of the invention, the eating disorder is bulimia, obesity, or bulimia nervosa. In one embodiment of the invention, the patient is a vertebrate, mammal, human or canine. In another embodiment, the compound is administered with food.

The invention also provides a method of reducing body weight in a subject, comprising administering to the subject an amount of a compound of the invention effective to reduce the body weight of the subject.

The invention also provides a method of treating a subject suffering from depression comprising administering to the subject a compound of the invention in an amount effective to treat the subject's depression. The invention also provides a method of treating a subject suffering from anxiety comprising administering to the subject an amount of a compound of the invention effective to treat the subject's anxiety. The invention also provides a method of treating a subject suffering from depression and anxiety, comprising administering to the subject an amount of a compound of the invention effective to treat the subject's depression and anxiety.

The present invention also provides a method of treating a patient suffering from: major depression, bipolar I or II disorder, schizoaffective disorder, cognitive disorders with depressed mood, personality disorder, insomnia, hypersomnia, narcolepsy, 24 hour rhythm sleep disorder, nightmares, sleep walking, obsessive compulsive disorder, panic with or without agoraphobia, post-traumatic stress disorder, social anxiety disorder, social phobia, and generalized anxiety disorder.

The invention also provides a method of treating a patient suffering from a micturition disorder, comprising administering to the patient a compound of the invention in an amount effective to treat the patient's micturition disorder. In some embodiments, the micturition disorder is urinary incontinence, overactive bladder, urge incontinence, urinary frequency, urgency, nocturia, or enuresis.

The present invention will be better understood from the following detailed description of experiments. However, those skilled in the art will readily understand that: the specific methods and results discussed are merely illustrative of the invention, which is more fully described in the claims appended hereto.

Experimental part

I. Method for synthesizing chemical compound

The general method comprises the following steps:

all reactions were carried out under argon atmosphere and the reagents (neat or in a suitable solvent) were transferred to the reaction vessel via syringe and cannula. Parallel synthesis reactions were performed in vials (without an inert atmosphere) using a J-KEM heated shaker (Saint Louis, MO). The anhydrous solvent was purchased from Aldrich Chemical Company (Milwaukee, Wis.) and used without further purification.

Unless otherwise stated, all references to "a", "an", and "the" are intended to mean that the elements are not in any way limiting¹The H spectra were recorded at 400MHz (Bru ker, Model; Avance) using tetramethylsilane as internal standard. s is singlet; d is bimodal; t is a triplet; q is quartet; p is quintet, hepta; br is broad peak; m is multiplet.

Elemental analysis was tested by Robertson Microlit Laboratories, inc. Unless otherwise stated, mass spectra were obtained using electrospray (ESI-MS) on a VG Patform II instrument and MH was reported⁺The data of (1). Thin Layer Chromatography (TLC) precoated with silica gel 60F₂₅₄(0.25mm, EMSeparations Tech.) on glass plates. Preparative thin layer chromatography was carried out on glass plates precoated with silica gel GF (2mm, Analtech). Flash column chromatography was performed on Merck silica gel 60(230- & 400 mesh). Melting points (mp) were measured on a Mel-Temp apparatus using open capillaries, and the data was uncorrected.

The following scheme illustrates the method of synthesizing the compounds of the present invention.

Scheme I

(a)LDA/PhNTf₂THF/-78 ℃ and then 0 ℃ overnight. (b) Aminophenylboronic acid/Pd (PPh)₄/LiCl/Na₂CO₃/DME-H₂O/reflux for 3 hours. (c) 10% Pd/C/H₂EtOH/room temperature 24-48 hours. (d) Acid chloride/triethylamine/THF/0 deg.C and then 2-3 hours at room temperature or carboxylic acid/EDC/DMAP/CH₂Cl₂DMF/room temperature 12 h. (e)4M HCl in 1, 4-dioxane/room temperature for 1 hour or TFA/CH₂C1₂Room temperature for 10 min.

Scheme 2

(a) Bis (pinacol ester) diboronate/KOAc/PdCl₂dppf/dppf/80 ℃ overnight. (b) K₂CO₃/PdCl₂dppf/DMF/80 ℃ overnight. (c) 10% Pd/C/H₂EtOH/room temperature 24-72 hours. (d)4M HCl in 1, 4-dioxahexaRing/room temperature 1 hr or TFA/CH₂Cl₂Room temperature for 10 min. (e) Carboxylic acid/EDC/DMAP/CH₂Cl₂DMF/room temperature 12 h. (f) H₂SO₄/HNO₃0 ℃ for 10 minutes. (g) Fe/NH₄Cl/THF/H₂O/EtOH/95 ℃ for 1.5 hours. (h) Cbz-Cl/NaHCO₃/CH₃CN/RT 12 h.

Scheme 3

(b)K₂CO₃/PdCl₂dppf/DMF/85 ℃ for 24 hours. (c) 10% Pd/C/H₂(200 psi)/EtOAc/MeOH/RT 24-72 hours. (d)4M HCl in 1, 4-dioxane/room temperature for 1 hour or TFA/CH₂Cl₂Room temperature 0.2 h. (e) Carboxylic acid/EDC/DMAP/CH₂Cl₂DMF/room temperature 12 h.

General procedure for piperidine Synthesis (scheme 1)

Synthesis of tert-butyl 4- { [ (trifluoromethyl) sulfonyl ] oxy } -3, 6-dihydro-1 (2H) -picolinate:

n-butyllithium (17.6ml, 44.2mmol, 2.5M in hexane) was added to a solution of diisopropylamine (96.2ml, 44.2mmol) in dry THF (40.0ml) at 0 deg.C, and the resulting mixture was stirred for 20 minutes. The reaction mixture was cooled to-78 deg.C, and a solution of tert-butyl 4-oxo-1-piperidinecarboxylate (Aldrich Chemical Company, 7.97g, 40.0mmol) in THF (40.0ml) was added dropwise to the reaction mixture, which was then stirred for 30 minutes. To the reaction mixture was added dropwise (Tf)₂NPh (42.0mmol, 15.0g) in THF (40.0ml) and the reaction mixture was stirred at 0 deg.C overnight. The reaction mixture was concentrated in vacuo and redissolved in hexane: ethyl acetateIn ester (9: 1), pass through an alumina packing tube and wash the alumina packing tube with hexane: ethyl acetate (9: 1). The combined extracts were concentrated in vacuo to give the desired product (16.5g) with some starting material Tf occluded₂NPh。

¹H NMR(400MHz，CDCl₃)δ5.77(s，1H)，4.05(dm，2H，J＝3.0Hz)，3.63(t，2H，J＝5.7Hz)，2.45(m，2H)，1.47(s，9H).

4- (3- (aminophenyl) -3, 6-dihydro-1 (2H) -pyridinecarboxylic acid tert-butyl ester

A degassed mixture of 2.0M aqueous sodium carbonate (4.20mL), tert-butyl 4- { [ (trifluoromethyl) sulfonyl ] oxy } -3, 6-dihydro-1 (2H) -pyridinecarboxylate (0.500g, 1.51mmol), 3-aminophenylboronic acid hemisulfate (0.393g, 2.11mmol), lithium chloride (0.191g, 4.50mmol) and tetrakis (triphenylphosphine) palladium (0.080g, 0.075mmol) in dimethoxyethane (5.00mL) was heated at reflux temperature under an argon atmosphere for 3 hours. The organic layer of the cooled reaction mixture was separated and the aqueous layer was washed with ethyl acetate (3X 50 ml). The combined organic extracts were dried and concentrated in vacuo. The crude product was purified by chromatography (silica gel, hexane: ethyl acetate: dichloromethane with 1% isopropylamine (6: 1)) to give the desired product (0.330g, 81%).

¹H NMR(400MHz，CDCl₃)δ7.12(t，1H，J＝7.60Hz)，6.78(d，1H，J＝8.4Hz)，6.69(t，1H，J＝2.0Hz)，6.59(dd，1H，J＝2.2，8.0Hz)，6.01(br，1H)，4.10-4.01(d，2H，J＝2.4Hz)，3.61(t，2H，J＝5.6Hz)，2.52-2.46(m，2H)，1.49(s，9H)；ESMS m/e：275.2(M+H)⁺.

To C₁₆H₂₄N₂O₂The calculated value of (a): c, 70.04; h, 8.08; n, 10.21;

measured value: c, 69.78; h, 7.80; n, 9.92.

4- [3- (amino) phenyl ] -1-piperidinecarboxylic acid tert-butyl ester

A mixture of tert-butyl 4- (3-aminophenyl) -3, 6-dihydro-1 (2H) -picolinate (3.10g, 11.3mmol) and 10% Pd/C (1.00g) in ethanol (100ml) was hydrogenated using the hydrogen balloon (balloon) method at room temperature for 2 days. The reaction mixture was filtered through celite, then washed with ethanol. The combined ethanol extracts were concentrated in vacuo and the residue chromatographed on silica gel (dichloromethane: methanol: isopropylamine ═ 95: 5: 1) to give the desired product (2.63g, 84%).

¹H NMR(400MHz，CDCl₃)δ7.10(t，1H，J＝7.6Hz)，6.62(d，1H，J＝8.4Hz)，6.60-6.59(m，2H)，4.27-4.18(m，2H)，3.62-3.58(m，2H)，2.80-2.72(m，2H)，2.62-2.59(m，1H)，1.89-1.52(m，4H)，1.49(s，9H)；ESMS m/e：277.2(M+H)⁺.

4- {3- [ (6-Bromohexanoyl) amino ] phenyl } -1-piperidinecarboxylic acid tert-butyl ester

A25-ml RB-flask was charged with tert-butyl 4- [3- (amino) phenyl ] -1-piperidinecarboxylate (2.00mmol, 0.553g), 6-bromohexanoyl chloride (0.427g, 2.00mmol, 1.0eq.), triethylamine (0.404g, 4.00mmol) and THF (8.00ml) and stirred at room temperature for 4 hours. The reaction mixture was diluted with chloroform (50ml), washed with water (100ml), brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography (silica gel, hexane/ethyl acetate 10: 1) to give the desired product (0.921g, 95.8%).

¹H NMR(400MHz，CDCl₃)δ7.47(s，1H)，7.28-7.22(m，2H)，7.11(s，1H)，6.5(d，1H，J＝7.0Hz)，3.45-3.39(m，2H)，2.85-2.70(m，2H)，2.68-2.58(m，1H)，2.37(t，2H，J＝7.4Hz)，1.96-1.71(m，7H)，1.68-1.50(m，5H)，1.48(s，9H)；ESMS m/e：355.4，476.6.

4- (3- { [6- (3, 4-difluoroanilino) hexanoyl ] amino } phenyl) -1-piperidinecarboxylic acid tert-butyl ester

A5-ml RB-flask was charged with 4- {3- [ (6-bromohexanoyl) amino ] phenyl } -1-piperidinecarboxylic acid tert-butyl ester (40.9mg, 0.100mmol), 3, 4-difluoroaniline (0.100mmol, 12.9mg), potassium carbonate (0.100mmol, 13.8mg), NaI (22.5mg, 0.150mmol) and DMF (1.00ml), and heated at 120 ℃ for 12 hours. The mixture was diluted with water (10ml), the aqueous layer was extracted with chloroform (3X 10ml), the combined extracts were washed with brine, dried over magnesium sulphate and concentrated in vacuo. The residue was purified by chromatography (hexane/ethyl acetate 10: 1) to give the desired product as a pale yellow oil (7.14mg, 14.3%).

¹H NMR(400MHz，CDCl₃)δ7.47(s，1H)，7.31-7.18(m，1H)，6.98-6.90(m，3H)，6.50-6.43(m，1H)，6.40-6.30(m，2H)，6.26-6,20(m，1H)，4.28-4.18(m，2H)，3.06(t，2H，J＝7.2Hz)，2.97-2.87(m，1H)，2.84-2.72(m，2H)，2.68-2.58(m，2H)，2.38(t，2H，J＝7.4Hz)，1.85-1.73(m，4H)，1.7-1.54(m，4H)，1.48(s，9H)；ESMS m/e：502.2(M+H)⁺.

Example 6: 6- (3, 4-difluoroanilino) -N- [3- (4-piperidinyl) phenyl ] hexanamide

To 4- (3- { [6- (3, 4-difluoroanilino) hexanoyl group at 0 ℃ C]Amino } phenyl) -1-piperidinecarboxylic acid tert-butyl ester (11.2mg, 0.0224mmol) in dichloromethane (0.500ml) trifluoroacetic acid (25.5mg, 2.24mmol) was added slowly. The reaction mixture was stirred at room temperature for 10 min and concentrated in vacuo. The residue was dissolved in isopropanol/CHCl₃(1: 3, 10ml), basified to pH11 with 10% KOH, washed with water and then brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo to afford the desired product (8.98mg, 99%):

¹H NMR(400.MHz，CDCl₃)δ7.39-7.08(m，5H)，7.06-6.94(m，2H)，6.91-6.81(m，1H)，6.77-6.67(m，1H)，3.54-3.42(m，2H)，3.25-3.04(m，3H)，2.91-2.80(m，1H)，2.45-2.32(m，2H)，2.11-1.99(m，2H)，1.98-1.83(m，2H)，1.80-1.62(m，4H)，1.55-1.40(m，2H)，1.34-1.23(m，1H)；ESMS m/e：402.2(M+H)⁺.

the following compounds were prepared according to scheme 1.

Example 1

5- (2-methoxyphenyl) -N- [3- (4-piperidinyl) phenyl ] pentanamide:

scheme 1 is performed using tert-butyl 4- (3- { [5- (2-methoxyphenyl) pentanoyl ] amino } phenyl) -1-piperidinecarboxylate to provide the product.

¹H NMR(400MHz，CDCl₃)δ7.52-6.68(m，8H)，3.74(s，3H)，3.61-3.35(m，2H)，3.14-2.90(m，2H)，2.88-2.56(m，3H)，2.52-2.27(m，2H)，2.10-1.51(m，8H)；ESIMSm/e：367.2[M+H]⁺.

Example 2

5-phenyl-N- [3- (4-piperidinyl) phenyl ] pentanamide:

scheme 1 is performed using tert-butyl 4- {3- [ (5-phenylpentanoyl) amino ] phenyl } -1-piperidinecarboxylate to provide the product.

¹H NMR(400MHz，CDCl₃)δ7.51-6.83(m，9H)，3.66-3.40(m，2H)，3.08-2.80(m，2H)，2.78-2.45(m，3H)，2.43-2.28(m，2H)，2.08-1.60(m，8H)；ESIMS m/e：337.2[M+H]⁺.

Example 3

6-oxo-6-phenyl-N- [3- (4-piperidinyl) phenyl ] hexanamide:

scheme 1 is performed using tert-butyl 4- {3- [ (6-oxo-6-phenylhexanoyl) amino ] phenyl } -1-piperidinecarboxylate to provide the product.

¹H NMR(400MHz，CD₃OD)δ7.98-7.83(m，2H)，7.60-7.31(m，4H)，7.28-7.12(m，2H)，6.97-6.87(m，1H)，3.48-3.31(m，2H)，3.10-2.68(m，5H)，2.40-2.26(m，2H)，2.05-1.63(m，8H)；ESIMS m/e：365.2[M+H]⁺.

Example 4

2-phenoxy-N- [3- (4-piperidinyl) phenyl ] nicotinamide:

a mixture of tert-butyl 4- [3- (amino) phenyl ] -1-piperidinecarboxylate (0.15mmol), 2-phenoxynicotinoyl chloride (0.23mmol) and triethylamine (0.30mmol) in 3ml of solvent (dichloromethane: THF, 1: 3) was stirred at room temperature for 12 hours. The reaction mixture was purified by preparative TLC (silica gel, EtOAc: hexane 1: 1) to give the desired product tert-butyl 4- (3- { [ (2-phenoxy-3-pyridyl) carbonyl ] amino } phenyl) -1-piperidinecarboxylate. Trifluoroacetic acid (1.0ml) was added to the purified product dissolved in 1.0ml of dichloromethane. The solution was stirred at room temperature for 1 minute and the reaction mixture was concentrated in vacuo to afford the TFA salt of the desired product.

¹H NMR(400MHz，CDCl₃)δ9.85(s，1H)，8.76-8.64(br，1H)，8.30-8.14(br，1H)，7.67(s，1H)，7.49(t，2H，J＝7.8Hz)，7.42-7.29(m，3H)，7.24(t，3H，J＝5.2Hz)，7.03(d，1H，J＝7.2Hz)，3.59(bd，2H，J＝11.5)，3.16-3.02(m，2H)，2.9-2.79(m，1H)，2.14-2.01(m，4H)；ESIMS m/e：374.1[M+H]⁺.

Example 5

5- (4-methoxyphenyl) -N- [3- (4-piperidinyl) phenyl ] pentanamide:

prepared according to the procedure described in scheme 1.

(2Z) -2-acetyl-3- (4-fluorophenyl) -2-propionic acid methyl ester

A mixture of 4-fluorobenzaldehyde (25.5g, 0.220mol), methyl 3-oxobutanoate (21.80g, 0.220mol) and piperidine (1.0ml) in dry benzene (250ml) was stirred at room temperature for 10 minutes, followed by reflux in a Dean-Stark apparatus overnight. The reaction mixture was then cooled to room temperature and the solvent was evaporated in vacuo to give (2Z) -2-acetyl-3- (4-fluorophenyl) -2-propionic acid methyl ester as a black solid (48.6g, 99%) which was used in the following step without purification.

6- (4-fluorophenyl) -2-methoxy-4-methyl-1, 6-dihydro-5-pyrimidinecarboxylic acid methyl ester

A mixture of methyl (2Z) -2-acetyl-3- (4-fluorophenyl) -2-acrylate (0.220mol, 48.8g), O-methylisourea hydrogen sulfate (53.40g, 0.310mol, 1.5eq.), sodium bicarbonate (61.74g, 0.74mol, 3.5eq.) and ethanol (1.2L) was refluxed for 24 hours, cooled to room temperature and then filtered. The solid was washed with ethanol (200ml) and the combined filtrates were concentrated in vacuo. The residue was purified by chromatography (silica gel, hexane/ethyl acetate/triethylamine 50: 0.1) to give a mixture of tautomers (4: 1, 33.0g, 53.9%).

¹HNMR(CDCl₃)δ7.32-7.24(m，2H)，7.04-6.95(m，2H)，5.81(s，1H)，5.38(d，1H，J＝2.9Hz)，4.00(s，3H)，3.63(s，3H)，2.34(s，3H).

6- (4-fluorophenyl) -2-methoxy-4-methyl-1, 5(6H) -pyrimidinedicarboxylic acid 5-methyl ester 1- (4-nitrophenyl ester)

To a solution of methyl 6- (4-fluorophenyl) -2-methoxy-4-methyl-1, 6-dihydro-5-pyrimidinecarboxylate (1.76g, 6.34mmol) and 4-dimethylaminopyridine (12.7mmol, 1.55g) in anhydrous dichloromethane (20.0ml) was added a solution of 4-nitrophenyl chloroformate (4.47g, 22.2mmol) in dichloromethane (20.0ml) at 23 ℃. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane (50ml), washed with water, brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (hexane: ethyl acetate 4: 1). The product was obtained as a yellow syrup which was triturated with hexane as a white powder (2.40g, 84.3%). The crude product was used in the following step without purification.

1- { [ (4-tert-butoxy-4-oxobutyl) amino ] carbonyl } -6- (4-fluorophenyl) -2-methoxy-4-methyl-1, 6-dihydro-5-pyrimidinecarboxylic acid methyl ester

To a solution of 5-methyl 1- (4-nitrophenyl) 6- (4-fluorophenyl) -2-methoxy-4-methyl-1, 5(6H) -pyrimidinedicarboxylic acid (88.7mg, 0.200mmol) and potassium carbonate (41.5mg, 0.300mmol) in methanol/dichloromethane (0.1/2.0ml) was added tert-butyl 4-aminobutyrate (31.8mg, 0.200 mmol). After stirring at room temperature for 1 hour, the mixture was washed with saturated sodium carbonate and brine. Sulfur-containing compoundsThe organic layer was dried over magnesium and concentrated in vacuo. The crude material was purified by flash chromatography (5% -10% 2M ammonia/methanol in 50% ethyl acetate/hexane) to afford the product (92.2g, 99%). mp 135-138 ℃;¹H NMR(CD₃OD)δ7.29-7.23(m，2H)，6.97-6.88(m，2H)，6.65(s，1H)，3.98(s，3H)，3.66(s，3H)，3.38-3.30(m，2H)，2.43(s，3H)，2.28(t，2H，J＝7.2Hz)，1.89-1.78(m，2H)，1.43(s，9H)；ESMS m/e：464.1(M+H)⁺.

4- { [ (6- (4-fluorophenyl) -5- (methoxycarbonyl) -4-methyl-2-oxo-3, 6-dihydro-1 (2H) -pyrimidinyl) carbonyl ] amino } butanoic acid

To 1- { [ (4-tert-butoxy-4-oxobutyl) amino at 0 deg.C]To a solution of methyl carbonyl } -6- (4-fluorophenyl) -2-methoxy-4-methyl-1, 6-dihydro-5-pyrimidinecarboxylate (77.3mg, 0.166mmol) in dichloromethane (2.00ml) was slowly added trifluoroacetic acid (189mg, 1.66 mmol). The reaction mixture was stirred at room temperature for 10 min and concentrated in vacuo. The residue was dissolved in isopropanol/chloroform (1: 3, 10ml), basified to pH11 with 10% KOH solution, washed with water and then brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo to afford the desired product (58.1mg, 88.9%). ESMS m/e: 394.1(M + H)⁺.

3- { [ (4- {3- [1- (tert-Butoxycarbonyl) -4-piperidinyl ] anilino } -4-oxobutyl) amino ] carbonyl } -4- (4-fluorophenyl) -6-methyl-2-oxo-1, 2, 3, 4-tetrahydro-5-pyrimidinylcarboxylic acid methyl ester

A10-ml RB-flask was charged with 4- { [ (6- (4-fluorophenyl) -5- (methoxycarbonyl) -4-methyl-2-oxo-3, 6-dihydro-1 (2H) -pyrimidinyl) carbonyl at room temperature]Amino } butyric acid (77.0mg, 0.189mmol), 4- [3- (amino) phenyl]-1-Piperidinecarboxylic acid tert-butyl esterEster (52.2mg, 0.189mmol), 1- [3- (dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride (0.567mmol, 87.8mg), 4-dimethylaminopyridine (11.5mg, 0.0945mmol) in DMF: DCM (0.2: 2.0 ml). The reaction mixture was stirred for 12 hours, and water (10.0ml) was added to the reaction mixture. The organic layer was separated and the combined organics extracted with chloroform (3X 10 ml). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Chromatography of the residue (silica gel, hexane/ethyl acetate 9: 1) gave the desired product (40.9mg, 33.2%):¹H NMR(400MHz，CDCl₃)δ8.03(m，3H)，7.57(s，1H)，7.36-7.28(m，3H)，7.27-7.22(m，1H)，6.97-6.89(m，3H)，6.72(s，1H)，3.72(s，3H)，3.47-3.37(m，2H)，2.42(s，3H)，2.37-2.29(m，2H)，1.98-1.91(m，2H)，1.86-1.75(m，2H)，1.72-1.54(m，7H)，1.48(s，9H)；ESMSm/e：652.2(M+H)⁺.

example 7: 4- (4-fluorophenyl) -6-methyl-2-oxo-3- [ ({ 4-oxo-4- [3- (4-piperidinyl) anilino ] butyl } amino) carbonyl ] -1, 2, 3, 4-tetrahydro-5-pyrimidinylcarboxylic acid methyl ester

Trifluoroacetic acid (71.6mg, 0.628mmol) was slowly added to a solution of methyl 3- { [ (4- {3- [1- (tert-butoxycarbonyl) -4-piperidinyl ] anilino } -4-oxobutyl) amino ] carbonyl } -4- (4-fluorophenyl) -6-methyl-2-oxo-1, 2, 3, 4-tetrahydro-5-pyrimidinylcarboxylate (40.9mg, 0.0628mmol) in dichloromethane (2.00ml) at 0 ℃. The reaction mixture was stirred at room temperature for 10 min and concentrated in vacuo. The residue was dissolved in isopropanol/chloroform (1: 3, 10ml), basified to pH11 with 10% KOH solution, washed with water and then brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo to afford the desired product (34.6mg, 99%):

¹H NMR(400MHz，CDCl₃)δ8.00(m，3H)，7.67(s，1H)，7.35-7.27(m，4H)，7.04-6.98(m，3H)，6.65(s，1H)，3.72(s，3H)，3.5-3.48(m，2H)，3.20-3.11(m，3H)，2.42(t，2H，J＝7.5Hz)，2.36(s，3H)，2.13-2.06(m，2H)，1.97-1.88(m，4H)；ESMS m/e：552.3(M+H)⁺.

4- {3- [ (4- { [ (5-methoxycarbonyl) -6- (3, 4-difluorophenyl) -4-methyl-2-oxo-3, 6-dihydro-1 (2H) -pyrimidinyl) carbonyl ] amino } butyryl) amino ] phenyl } -1-piperidinecarboxylic acid tert-butyl ester

A50-ml RB-flask was charged with 4- { [ (5-acetyl) -6- (3, 4-difluorophenyl) -4-methyl-2-oxo-3, 6-dihydro-1 (2H) -pyrimidinyl) carbonyl at room temperature]Amino } butyric acid (313mg, 0.854mmol), 4- [3- (amino) phenyl [ ]]-1-Piperidinecarboxylic acid tert-butyl ester (235mg, 0.857mmol), 1- [3- (dimethylamino) propyl group]-3-ethylcarbodiimide hydrochloride (7.71mmol, 265mg), 4-dimethylaminopyridine (10.4mg, 0.0854mmol) in DMF: DCM (0.8: 8.0 ml). The reaction mixture was stirred for 12 hours, and water (20.0ml) was added to the reaction mixture. The organic layer was separated and the combined organic layers were extracted with chloroform (3X 10 ml). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography of the residue (silica gel, hexane/ethyl acetate 9: 1) gave the desired product (378mg, 67.8%):¹H NMR(400MHz，CDCl₃)δ8.03(m，2H)，7.57(s，1H)，7.36-7.28(m，3H)，7.27-7.22(m，1H)，6.97-6.89(m，3H)，6.72(s，1H)，3.72(s，3H)，3.47-3.37(m，2H)，2.42(s，3H)，2.37-2.29(m，2H)，1.98-1.91(m，2H)，1.86-1.75(m，2H)，1.72-1.54(m，7H)，1.48(s，9H)；ESMSm/e：554.3(M-100).

example 8: 5-methoxycarbonyl-6- (3, 4-difluorophenyl) -4-methyl-2-oxo-N- { 4-oxo-4- [3- (4-piperidinyl) anilino ] butyl } -3, 6-dihydro-1 (2H) -pyrimidinecarboxamide

To a solution of tert-butyl 4- {3- [ (4- { [ (5-methoxycarbonyl) -6- (3, 4-difluorophenyl) -4-methyl-2-oxo-3, 6-dihydro-1 (2H) -pyrimidinyl) carbonyl ] amino } butanoyl) amino ] phenyl } -1-piperidinecarboxylate (378mg, 0.579mmol) in dichloromethane (5.00ml) was slowly added trifluoroacetic acid (659mg, 5.79mmol) at 0 ℃. The reaction mixture was stirred at room temperature for 10 min and concentrated in vacuo. The residue was dissolved in isopropanol/chloroform (1: 3, 10ml), basified to pH11 with 10% KOH solution, washed with water and then brine. The organic layer was dried over magnesium sulfate, concentrated in vacuo, and the residue was purified by flash chromatography (dichloromethane: methanol 5: 1) to give the desired product (93.8mg, 29.3%)

¹H NMR(400MHz，CDCl₃)δ7.46-7.43(m，3H)，7.35-7.29(m，2H)，7.12-7.06(m，3H)，6.63-6.60(m，1H)，6.56-6.52(m，2H)，3.26(s，3H)，3.22(s，3H)，2.72(dt，6H，J＝2.3，12.3Hz)，2.66(tt，2H，J＝3.6，11.9Hz)，2.55(tt，1H，J＝3.8，11.9Hz)，1.88-1.82(m，1H)，1.75-1.63(m，6H)；ESMS m/e：554.3(M+H)⁺.

General procedure for piperidine Synthesis (scheme 2)

4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydro-1 (2H) -pyridinecarboxylic acid tert-butyl ester

Bis (pinacol ester) diboronate (422mg, 1.66mmol), potassium acetate (444mg, 4.53mmol), PdCl were charged under argon at room temperature₂To a 50-ml RB-flask of dppf (37.0mg, 3.00 mol%) and dppf (25.0mg, 3.00 mol%) was added 4- { [ (trifluoromethyl) sulfonyl]A solution of tert-butyl oxy } -3, 6-dihydro-1 (2H) -picolinate (500mg, 1.51mmol) in 1, 4-dioxane (10.0 mL). The mixture was heated at 80 ℃ overnight. After the mixture is cooled to the room temperature,the mixture was filtered through Celite and the Celite was washed with ethyl acetate (3X 20 ml). The combined filtrates were washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (ethyl acetate/hexane 1: 9) to give tert-butyl 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydro-1 (2H) -picolinate (355mg, 76%):

¹H NMR(400MHz，CDCl₃)δ6.60-6.34(br，1H)，4.06-3.86(br，2H)，3.55-3.34(br，2H)，2.35-2.09(br，2H)，1.46(s，9H)，1.26(s，12H)；ESMSm/e：310.4(M+H)⁺.

5-bromo-2, 4-difluoronitrobenzene

To a suspension of 1-bromo-2, 4-difluorobenzene (53.0mmol, 6.00ml) in concentrated sulfuric acid (38.5ml) at 0 ℃ was added dropwise concentrated nitric acid (34.0ml) while maintaining the internal temperature below 20 ℃. The resulting mixture was stirred at 0 ℃ for 10 minutes and then poured into ice/water with vigorous stirring. The mixture was extracted with diethyl ether (3X 100 ml). The combined organic extracts were washed with aqueous sodium bicarbonate (3 × 100ml) and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (ethyl acetate/hexanes 1: 9) to give 5-bromo-2, 4-difluoronitrobenzene as a yellow oil (12.2g, 97%).¹H NMR(400MHz，CDCl₃)δ8.45(t，1H，J＝7.5Hz)，7.16(dd，1H，J＝11.0，8.6Hz)；ESMS m/e：240，238，223，221，112

5-bromo-2, 4-difluoroaniline

A250-ml RB-flask was charged with 5-bromo-2, 4-difluoronitrobenzene (5.04g, 21.3mmol), saturated ammonium chloride (25.0ml), iron powder (5.00g, 89.5mmol), ethanol (100)ml), THF (50.0ml) and water (25.0ml) were added and the mixture was refluxed at 95 ℃ for 1.5 hours. After cooling to room temperature, saturated sodium bicarbonate (100ml) was added, the mixture was filtered through Celite, and the Celite was washed with ethyl acetate (3X 50 ml). The combined filtrates were washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (EtOAc/hexane 1: 9) to give 5-bromo-2, 4-difluoroaniline (2.61g, 59.1%).¹H NMR(400MHz，CDCl₃)δ6.97(dd，1H，J＝7.2，6.7Hz)，6.85(t，1H，J＝8.2Hz)，3.63(br，2H).

Benzyl 5-bromo-2, 4-difluorophenyl carbamate

A250-ml RB-flask was charged with 5-bromo-2, 4-difluoroaniline (5.00g, 24.2mmol), chlorobenzyl formate (4.10ml, 29.0mmol), sodium bicarbonate (6.10g, 72.6mmol), and acetonitrile (100 ml). The mixture was stirred at 25 ℃ for 12 h, then filtered through a fritted glass funnel (glass funnel), washed with ethyl acetate (3X 20ml) and concentrated in vacuo. The filtrate was washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (ethyl acetate/hexane 1: 9) to give benzyl 5-bromo-2, 4-difluorophenyl carbamate (5.05g, 61.0%).¹H NMR(400MHz，CDCl₃)δ8.38(s，1H)，7.49-7.31(m，5H)，6.94-6.89(m，1H)，6.81-6.77(m，1H)，5.22(s，2H)；ESMS m/e：340.1(M-H⁺).

4- (5- { [ (benzyloxy) carbonyl ] amino } -2, 4-difluorophenyl) -3, 6-dihydro-1 (2H) -pyridinecarboxylic acid tert-butyl ester

4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydro-one-substituted benzene at room temperature under argon1(2H) -Pyridinecarboxylic acid tert-butyl ester (4.58g, 14.8mmol), potassium carbonate (6.14g, 44.4mmol) and PdCl₂A250-ml RB-flask of dppf (1.48mmol, 1.21g) was charged with a solution of benzyl 5-bromo-2, 4-difluorophenyl carbamate (5.05g, 14.8mmol) in DMF (150 ml). The mixture was heated at 80 ℃ under argon overnight. After cooling to room temperature, the mixture was filtered through Celite, and the Celite was washed with ethyl acetate (3X 100 ml). The filtrate was washed with water (3X 200ml), brine (100ml), dried over magnesium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (ethyl acetate/hexane 1: 9) to give 4- (5- { [ (benzyloxy) carbonyl]Amino } -2, 4-difluorophenyl) -3, 6-dihydro-1 (2H) -pyridinecarboxylic acid tert-butyl ester (1.60g, 24.5%):¹H NMR(400MHz，CDCl₃)δ8.08(s，1H)，7.45-7.35(m，5H)，6.85-6.70(m，1H)，5.95-5.85(m，1H)，5.20(s，2H)，4.05(m，2H)，3.6-3.5(m，2H)，2.5-2.4(m，2H)，1.50(s，9H)；ESMS m/e：443.3(M-H⁺).

4- (5-amino-2, 4-difluorophenyl) -1-pyridinecarboxylic acid tert-butyl ester

4- (5- { [ (benzyloxy) carbonyl was pumped with hydrogen pump (200psi) at room temperature]A mixture of amino } -2, 4-difluorophenyl) -3, 6-dihydro-1 (2H) -pyridinecarboxylic acid tert-butyl ester (1.60g, 3.60mmol) and 5% Pd/C (320mg, 0.100mmol) in ethyl acetate (25.0ml) and methanol (25.0ml) was hydrogenated for 72H. The reaction mixture was filtered through Celite and washed with ethyl acetate/methanol (1: 1, 3X 50 ml). The filtrate was concentrated in vacuo to give tert-butyl 4- (5-amino-2, 4-difluorophenyl) -1-pyridinecarboxylate (1.39g, 100%).¹HNMR(400MHz，CDCl₃)δ6.73(t，1H，J＝10.6Hz)，6.60-6.54(da，1H，J＝7.6，6.57Hz)，4.20(br，2H)，3.55(s，2H)，2.96-2.72(m，3H)，1.79-1.71(m，2H)，1.58-1.52(m，2H)，1.47(s，9H)；ESMS m/e：257.3(M-56).

(4E) -5- (2-methoxyphenyl) -4-pentenoic acid ethyl ester

To a 200-ml RB-flask was added 2-iodoanisole (5.00g, 21.4mmol), ethyl 4-pentenoate (3.30g, 25.6mmol), tetrakis (triphenylphosphine) palladium (0) (0.740g, 0.600mmol), triethylamine (6.00ml, 42.7mmol), and a mixture of acetonitrile (45.0ml) and THF (15.0 ml). The reaction mixture was refluxed overnight and then cooled to room temperature. After removal of the solvent in vacuo, the resulting dark brown residue was dissolved in 5% aqueous HCl and extracted 3 times with dichloromethane. The combined extracts were washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo. The dark brown oil was purified by chromatography (silica gel, EtOAc/hexane 1: 10) to give the product as a light yellow oil (3.40g, 68%).

5- (2-methoxyphenyl) pentanoic acid ethyl ester

To a solution of ethyl (4E) -5- (2-methoxyphenyl) -4-pentenoate (3.40g, 14.5mmol) in a mixture of ethyl acetate and methanol (40.0/10.0ml) was added Pd/C (10% palladium on carbon, 0.700g) in small portions to avoid a vigorous exothermic reaction. The reaction mixture was then stirred at room temperature under 300psi hydrogen overnight. After releasing the pressure, the mixture was filtered through Celite, and the Celite was washed with ethyl acetate (3X 50 ml). The filtrate was concentrated in vacuo to give the crude product as a pale yellow oil (3.40g, 100%), which was used without further purification.

5- (2-methoxyphenyl) pentanoic acid

To a 250-ml RB-flask was added ethyl 5- (2-methoxyphenyl) pentanoate (3.40g, 14.5 g)mmol), NaOH (1.74g, 42.8mmol), THF (25.0ml) and water (25.0 ml). The reaction mixture was refluxed for 2 hours and cooled to room temperature. The reaction mixture was concentrated in vacuo and the resulting aqueous solution was acidified with 6MHCl to a pH < 5. The acidic mixture was extracted with chloroform/isopropanol (3: 1, 3X 50ml), and the combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo to give the product as a white solid (2.68g, 90%), which was used without further purification.¹H NMR(400MHz，MeOD)δ7.23-7.03(m，2H)，6.95-6.76(m，2H)，3.81(s，3H)，2.63(t，2H，J＝7.2Hz)，2.38(t，2H，J＝7.2Hz)，1.77-1.53(m，4H).

4- (2, 4-difluoro-5- { [5- (2-methoxyphenyl) pentanoyl ] amino } phenyl) -1-piperidinecarboxylic acid tert-butyl ester

A15-ml RB-flask was charged with 5- (2-methoxyphenyl) pentanoic acid (69.0mg, 0.810mmol), tert-butyl 4- (5-amino-2, 4-difluorophenyl) -1-pyridinecarboxylate (229mg, 0.740mmol), 1- [3- (dimethylamino) propyl ] at room temperature]-3-ethylcarbodiimide hydrochloride (2.22mmol, 426mg), 4-dimethylaminopyridine (9mg, 0.07mmol) in DMF: DCM (0.2: 5.0 ml). The reaction mixture was stirred for 12 hours, and water (10.0ml) was added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with chloroform (3X 10 ml). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 4- (2, 4-difluoro-5- { [5- (2-methoxyphenyl) pentanoyl]Amino } phenyl) -1-piperidinecarboxylic acid tert-butyl ester (310mg, 83.2%):¹H NMR(400MHzCDCl₃)δ8.36-8.13(m，1H)，7.39(s，1H)，7.26-7.06(m，1H)，7.06-6.92(m，1H)，6.92-6.75(m，3H)，4.41-4.02(m，2H)，3.80(s，3H)，2.90-2.70(m，2H)，2.70-2.63(m，2H)，2.63-2.51(m，1H)，2.49-2.32(m，2H)，1.87-1.72(m，4H)，1.72-1.63(m，2H)，1.63-1.52(m，2H)，1.48(s，9H).

example 11: n- [2, 4-difluoro-5- (4-piperidinyl) phenyl ] -5- (2-methoxyphenyl) pentanamide

To 4- (2, 4-difluoro-5- { [5- (2-methoxyphenyl) pentanoyl at 0 DEG C]Amino } phenyl) -1-piperidinecarboxylic acid tert-butyl ester (310mg, 0.620mmol) in dichloromethane (5.00ml) trifluoroacetic acid (707mg, 6.20mmol) was added slowly. The reaction mixture was stirred at room temperature for 10 min and concentrated in vacuo. The residue was dissolved in isopropanol/chloroform (1: 3, 10ml), basified to pH11 with 10% KOH solution, washed with water and then brine. The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo to give the desired product (108mg, 43.3%).¹HNMR(400MHz，CDCl₃)δ7.59(t，1H，J＝8.2Hz)，7.10-6.96(m，2H)，6.90-6.68(m，3H)，3.67(s，3H)，3.09(d，2H，J＝12.4Hz)，2.89(tt，1H，J＝11.8Hz)，2.69(dt，2H，J ＝2.6，12.4Hz)，2.54(t，2H，J＝7.2Hz)，2.33(t，2H，J＝7.2Hz)，1.76-1.48(m，8H)；ESMS m/e：403.3(M+H)⁺.

General procedure for piperidine Synthesis (scheme 3)

4- (4-fluoro-3-nitrophenyl) -3, 6-dihydro-1 (2H) -pyridinecarboxylic acid tert-butyl ester

To a solution of tert-butyl 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydro-1 (2H) -picolinate (5.58g, 16.5mmol), potassium carbonate (5.60g, 40.5mmol) and PdCl under argon at room temperature₂A150-ml RB-flask of dppf (1.48mmol, 1.21g) was charged with a solution of 4-bromo-1-fluoro-2-nitrobenzene (3.30g, 15.0mmol) in DMF (50.0 ml). The mixture was heated at 80 ℃ under argon for 12 hours. After cooling to room temperature, the mixture was filtered through Celite, and the Celite was washed with ethyl acetate (3X 100 ml). The filtrate was washed with water (3X 200ml), brine (100ml) and treated with sulphuric acidMagnesium was dried, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (ethyl acetate/hexane 1: 9) to give tert-butyl 4- (4-fluoro-3-nitrophenyl) -3, 6-dihydro-1 (2H) -picolinate (3.13g, 65.1%):

¹HNMR(400MHz，CDCl₃)δ8.06-7.89(m，1H)，7.66-7.49(m，1H)，7.30-7.10(m，1H)，6.19-5.95(br，1H)，4.10-3.95(m，2H)，3.58(t，2H，J＝5.6Hz)，2.49-2.34(m，2H)，1.42(s，9H).

4- (3-amino-4-fluorophenyl) -1-piperidinecarboxylic acid tert-butyl ester

A mixture of 4- (4-fluoro-3-nitrophenyl) -3, 6-dihydro-1 (2H) -pyridinecarboxylic acid tert-butyl ester (2.35g, 8.85mmol) and 10% Pd/C (400mg) in ethyl acetate (40.0ml) and methanol (10.0ml) was hydrogenated with a hydrogen pump (200psi) at room temperature for 72H. The reaction mixture was filtered through Celite and the Celite was washed with ethyl acetate/methanol (1: 1, 3X 50 ml). The filtrate was concentrated in vacuo to give tert-butyl 4- (3-amino-4-fluorophenyl) -1-piperidinecarboxylate (2.10g, 98.0%).

¹HNMR(400MHz，CDCl₃)δ6.96-6.76(m，1H)，6.67-6.54(m，1H)，6.54-6.40(m，1H)，4.38-4.09(br，2H)，4.09-3.58(br，2H)，2.87-2.62(m，2H)，2.60-2.39(m，1H)，1.85-1.65(m，2H)，1.64-1.40(m，2H)，1.48(s，9H).

4- (4-fluoro-3- { [5- (2-methoxyphenyl) pentanoyl ] amino } phenyl) -1-piperidinecarboxylic acid tert-butyl ester

A25-ml RB-flask was charged with 5- (2-methoxyphenyl) pentanoic acid (53) at room temperature.0mg, 0.250mmol), tert-butyl 4- (3-amino-4-fluorophenyl) -1-piperidinecarboxylate (59.0mg, 0.200mmol), 1- [3- (dimethylamino) propyl group]-3-ethylcarbodiimide hydrochloride (0.400mmol, 62.0mg), 4-dimethylaminopyridine (10mg) in DMF: DCM (0.2: 2.0 ml). The reaction mixture was stirred for 12 hours, and water (10.0ml) was added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with chloroform (3X 10 ml). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by chromatography (silica gel, hexane: ethyl acetate 6: 1) to give 4- (4-fluoro-3- { [5- (2-methoxyphenyl) pentanoyl]Amino } phenyl) -1-piperidinecarboxylic acid tert-butyl ester (48.4mg, 50.0%):¹H NMR(400MHzCDCl₃)δ8.36-8.13(m，1H)，7.39(s，1H)，7.26-7.06(m，2H)，7.06-6.92(m，1H)，6.92-6.75(m，3H)，4.41-4.02(m，2H)，3.80(s，3H)，2.90-2.70(m，2H)，2.70-2.63(m，2H)，2.63-2.51(m，1H)，2.49-2.32(m，2H)，1.87-1.72(m，4H)，1.72-1.63(m，2H)，1.63-1.52(m，2H)，1.48(s，9H).

example 10: n- [ 2-fluoro-5- (4-piperidinyl) phenyl ] -5- (2-methoxyphenyl) pentanamide

To a solution of tert-butyl 4- (4-fluoro-3- { [5- (2-methoxyphenyl) pentanoyl ] amino } phenyl) -1-piperidinecarboxylate (48.4mg, 0.100mmol) in dichloromethane (2.0ml) at room temperature was added trifluoroacetic acid (114mg, 1.0 mmol). The reaction mixture was stirred for 30 minutes and concentrated in vacuo. The residue was dissolved in chloroform/isopropanol (3: 1, 10ml) and basified with 5% KOH solution to pH 11. The organic layer was separated and the aqueous layer was extracted with chloroform/isopropanol (3: 1, 3X 10 ml). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to afford N- [ 2-fluoro-5- (4-piperidinyl) phenyl ] -5- (2-methoxyphenyl) pentanamide (38.0mg, 95%):

¹H NMR(400MHz，CD₃OD)δ8.30-8.12(m，1H)，7.64-7.41(m，1H)，7.24-7.07(m，2H)，7.06-6.92(m，1H)，6.92-6.74(m，3H)，3.80(s，3H)，3.25-3.06(m，2H)，2.80-2.49(m，5H)，2.48-2.24(m，3H)，1.89-1.71(m，4H)，1.71-1.46(m，4H)；ESMS m/e：385.2(M+H)⁺.

3- [4- (3, 4-Difluorophenoxy) phenyl ] propanoic acid

A50-ml RB-flask was charged with 3- (4-hydroxyphenyl) propionic acid (1.66g, 10.0mmol), 3, 4-difluoroiodobenzene (2.40g, 10.0mmol), copper (I) bromide (0.100g), potassium carbonate (2.76g, 20.0mmol) and n-methyl-2-pyrrolidone (20ml) as a solvent. The mixture was stirred at room temperature for 5 minutes and then heated to 140 ℃ (oil bath). After stirring at 140 ℃ for 12 hours, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (100 ml). The diluted mixture was washed with citric acid (30ml aqueous solution), water (3X 50ml), brine and dried over magnesium sulfate. The solvent was removed in vacuo to give the crude product, which was purified by chromatography (0.901g, 32%):

¹H NMR(400MHz，CDCl₃)δ11.44-11.06(br，1H)，7.24-7.14(m，2H)，7.14-7.00(m，1H)，7.00-6.86(m，2H)，6.86-6.75(m，1H)，6.75-6.61(m，1H)，2.94(t，2H，J＝7.6Hz)，2.68(t，2H，J＝7.6Hz)；ESMS m/e：277.2(M-H⁺).

4- [3- ({3- [4- (3, 4-Difluorophenoxy) phenyl ] propanoyl } amino) -4-fluorophenyl ] -1-piperidinecarboxylic acid tert-butyl ester

A25-ml RB-flask was charged with a solution of 3- [4- (3, 4-difluorophenoxy) phenyl ] propionic acid (180mg, 0.650mmol), tert-butyl 4- (3-amino-4-fluorophenyl) -1-piperidinecarboxylate (180mg, 0.610mmol), 1- [3- (dimethylamino) propyl ] -3-ethylcarbodiimide hydrochloride (1.22mmol, 190mg), 4-dimethylaminopyridine (20mg) in DMF: DCM (0.4: 4.0ml) at room temperature. The reaction mixture was stirred for 12 hours, and water (10.0ml) was added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with chloroform (3X 10 ml). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by chromatography (silica gel, hexane: ethyl acetate 6: 1) to give tert-butyl 4- [3- ({3- [4- (3, 4-difluorophenoxy) phenyl ] propanoyl } amino) -4-fluorophenyl ] -1-piperidinecarboxylate (85.0mg, 25.0%):

¹H NMR(400MHz，CDCl₃)δ8.32-8.15(m，1H)，7.47-6.45(m，10H)，4.41-4.07(br，2H)，3.17-2.96(m，2H)，2.90-2.67(m，4H)，2.67-2.56(m，1H)，1.91-1.69(m，2H)，1.68-1.48(m，2H)，1.47(s，9H)；ESMS m/e 553.3(M-H⁺).

example 12: 3- [4- (3, 4-Difluorophenoxy) phenyl ] -N- [ 2-fluoro-5- (4-piperidinyl) phenyl ] propanamide

To 4- [3- ({3- [4- (3, 4-difluorophenoxy) phenyl at room temperature]Propionyl } amino) -4-fluorophenyl]To a solution of tert-butyl-1-piperidinecarboxylate (85.0mg, 0.150mmol) in dichloromethane (2.0ml) was added trifluoroacetic acid (170mg, 1.50 mmol). The reaction mixture was stirred for 10 minutes and concentrated in vacuo. The residue was dissolved in chloroform/isopropanol (3: 1, 10ml), basified to pH11 with 5% KOH solution, the organic layer was extracted, and the aqueous layer was extracted with chloroform/isopropanol (3: 1, 3X 10 ml). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give 3- [4- (3, 4-difluorophenoxy) phenyl]-N- [ 2-fluoro-5- (4-piperidinyl) phenyl]Propionamide (65.0mg, 92%):¹H NMR(400MHz，CD₃OD)δ8.27-8.12(m，1H)，7.39(s，1H)，7.33-7.17(m，2H)，7.17-7.06(m，1H)，7.06-6.97(m，1H)，6.97-6.87(m，3H)，6.86-6.74(m，1H)，6.74-6.62(m，1H)，6.15-5.63(br，1H)，3.55-3.31(m，2H)，3.15-2.97(m，2H)，2.97-2.79(m，2H)，2.79-2.59(m，3H)，2.05-1.79(m，4H)；ESMSm/e：455.2(M+H)⁺.

4- { 4-fluoro-3- [ (6-oxo-6-phenylhexanoyl) amino ] phenyl } -1-piperidinecarboxylic acid tert-butyl ester

A25-ml RB-flask was charged with 6-oxo-6-phenylhexanoic acid (51.0mg, 0.250mmol), tert-butyl 4- (3-amino-4-fluorophenyl) -1-piperidinecarboxylate (59.0mg, 0.200mmol), 1- [3- (dimethylamino) propyl ] -3-ethylcarbodiimide hydrochloride (0.400mmol, 62.0mg), 4-dimethylaminopyridine (10mg) in DMF: DCM (0.2: 2.0ml) at room temperature. The reaction mixture was stirred for 12 hours, and water (10.0ml) was added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with chloroform (3X 10 ml). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by chromatography (silica gel, hexane: ethyl acetate 6: 1) to give tert-butyl 4- { 4-fluoro-3- [ (6-oxo-6-phenylhexanoyl) amino ] phenyl } -1-piperidinecarboxylate

(49.0mg，51.0％)：¹H NMR(400MHz，CDCl₃)δ8.30-8.14(m，1H)，8.04-7.89(m，2H)，7.62-7.50(m，1H)，7.50-7.37(m，3H)，7.09-6.93(m，1H)，6.93-6.76(m，1H)，4.38-4.01(br，2H)，3.13-2.95(m，2H)，2.89-2.69(m，2H)，2.65-2.54(m，1H)，2.54-2.35(m，2H)，1.95-1.74(m，6H)，1.69-1.48(m，2H)，1.47(s，9H).

Example 9: n- [ 2-fluoro-5- (4-piperidinyl) phenyl ] -6-oxo-6-phenylhexanamide

To a solution of tert-butyl 4- { 4-fluoro-3- [ (6-oxo-6-phenylhexanoyl) amino ] phenyl } -1-piperidinecarboxylate (49.0mg, 0.101mmol) in dichloromethane (3.0ml) at room temperature was added trifluoroacetic acid (114mg, 1.01 mmol). The reaction mixture was stirred for 30 minutes and concentrated in vacuo. The residue was dissolved in chloroform/isopropanol (3: 1, 10ml), basified to pH11 with 5% KOH solution, the organic layer was separated and the aqueous layer was extracted with chloroform/isopropanol (3: 1, 3X 10 ml). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give N- [ 2-fluoro-5- (4-piperidinyl) phenyl ] -6-oxo-6-phenylhexanamide (35.5mg, 86.0%). Hydrochloride salt:

¹H NMR(400MHz，CDCl₃)δ8.14-8.01(br，1H)，8.01-7.89(m，2H)，7.65-7.52(m，1H)，7.52-7.43(m，2H)，7.43-7.26(br，1H)，7.13-7.00(m，1H)，7.00-6.88(br，1H)，3.68-3.43(m，2H)，3.19-2.92(br，4H)，2.89-2.67(m，1H)，2.61-2.36(br，2H)，2.26-2.06(m，2H)，2.06-1.93(m，2H)，1.93-1.71(br，4H)；ESMS m/e：383.2(M+H)⁺.

synthesis of the general Structure

The embodiments described in section I are merely illustrative of methods for synthesizing MCH1 antagonists. Further derivatives can be obtained using the general methods according to the synthetic methods used for the synthesis of the examples.

In the outlined method of synthesis of further derivatives, protection and deprotection of various substituents such as amino, amido, carboxylic acid and hydroxyl groups may be required. Methods for protecting and deprotecting such groups are well known in the art and can be found, for example, in Green, T.W. and Wuts, P.G.M. (1991),Protection Groups in Organic Synthesissecond edition, John Wiley&Sons，New Y0rk。

Oral compositions

As a specific embodiment of the oral composition of the compounds of the present invention, 100mg of one of the compounds described herein is formulated with lactose well dispersed to give a total amount of 580mg to 590mg of micelle agent filled in O-type hard capsules.

Pharmacological evaluation of each compound on cloned rat MCH1 receptor

The pharmacological performance of the compounds of the invention was evaluated on a cloned rat MCH1 receptor using the methods described below.

Host cell

A wide variety of host cells can be used to study a variety of heterologously expressed proteins. These cells include, but are not limited to: various mammalian cell lines, such as Cos-7, CHO, LM (tk-), HEK293, Peak rapid293, etc.; insect cell lines such as Sf9, Sf21, etc.; amphibian cell lines, such as Xenopus oocytes and the like.

At 37 ℃ and 5% CO₂COS-7 cells were grown in DMEM supplemented medium (Dulbecco's modified Eagle's medium supplemented with 10% calf serum, 4mM glutamine, 100 units/ml penicillin/100 Fg/ml streptomycin) on 150mM plates in an atmosphere. The mother plate of COS-7 cells (stock plate) was trypsinized every 3-4 days and grown in plates at a ratio of 1: 6.

At 37 ℃ and 5% CO₂Human embryonic kidney cells 293 were grown in DMEM supplemented medium (supplemented with 10% calf serum, 4mM glutamine, 100 units/ml penicillin/100 Fg/ml streptomycin) on 150mM culture plates in an atmosphere. The master plate of 293 cells was trypsinized every 3-4 days and plated at a ratio of 1: 6.

At 37 ℃ and 5% CO₂Human embryonic kidney cells, Peak rapid293(Peakr293), were grown in DMEM supplemented medium (supplemented with 10% fetal bovine serum, 10% L-glutamine, 50Fg/ml gentamicin) in an atmosphere on 150mm plates. The mother plates of Peak rapid293 cells were trypsinized every 3-4 days and plated at a ratio of 1: 12.

At 37 ℃ and 5% CO₂Mouse fibroblasts, LM (tk-) were grown in 150mM culture plates under an atmosphere in DMEM supplemented medium (Dulbecco's modified Eagle medium supplemented with 10% calf serum, 4mM glutamine, 100 units/ml penicillin/100 Fg/ml streptomycin). The mother plate of LM (tk-) cells was trypsinized every 3-4 days and grown in plates at a ratio of 1: 10.

At 37 ℃ and 5% CO₂Chinese Hamster Ovary (CHO) cells were grown in HAM's F-12 medium (supplemented with 10% calf serum, 4 mML-glutamine, 100 units/ml penicillin/100 Fg/ml streptomycin) on 150mm plates in an atmosphere. The mother plates of CHO cells were trypsinized every 3-4 days and plated at a ratio of 1: 8.

At 37 ℃ and 5% CO₂Mouse embryonic fibroblasts, NIH-3T3 cells, were grown in Dulbecco's modified Eagle's medium (DMEM supplemented with 10% calf serum, 4mM glutamine, 100 units/ml penicillin/100 Fg/ml streptomycin) in an atmosphere on 150mM plates. The NIH-3T3 cell mother plate was trypsinized every 3-4 days and grown in plates at a ratio of 1: 15.

At 27 ℃ without CO₂Sf9 and Sf21 cells were grown as monolayers in TMN-FH medium (supplemented with 10% fetal bovine serum) on 150mm tissue culture dishes in an atmosphere. Also at 27 ℃ without CO₂Under the atmosphere, High Five insect cells were placed on a 150mm tissue culture dish and placed in Ex-Cell 400^TMGrowth in medium (supplemented with L-glutamine).

In some cases, cell lines grown as adherent monolayers can be converted to suspension cultures to increase cell productivity, providing a large batch of homogeneous test material for routine receptor screening.

Transient expression

Proteins encoding DNA to be studied can be transiently expressed in various mammalian, insect, amphibian, and other cell lines by several methods including, but not limited to: calcium phosphate-mediated transfection, DEAE-dextran-mediated transfection, liposome-mediated transfection, virus-mediated transfection, electroporation-mediated transfection, and microinjection-mediated transfection. These methods all require optimization of the appropriate experimental parameters depending on the DNA, cell line, and type of test method to be used subsequently.

The following illustrates the general protocol for the calcium phosphate method applied to Peak rapid293 cells:

adherent cells were harvested approximately 24 hours prior to transfection and then cultured at 3.5X 10⁶Cell/dish Density, cells were reseeded in 150mm tissue culture dishes at 37 ℃ with 5% CO₂Cultured overnight in the medium. Adding 250Fl of CaCl₂And DNA (15Fg DNA at 250mM CaCl₂Solution of (4) was added to a 5ml plastic tube followed by slow addition of 500Fl of 2 XHBS (280mM NaCl, 10mM KCl, 1.5mM Na) with gentle mixing₂HPO₄12mM dextran and 50mM HEPES). The mixture was incubated at room temperature for 20 minutes to form a DNA precipitate. The DNA precipitation mixture was then added to the medium on each plate at 37 ℃ with 5% CO₂And culturing for 5 hours. After culturing, 5ml of medium (DMEM, 10% FBS, 10% L-glut and 50. mu.g/ml gentamicin) was added to each plate. The cells were then incubated at 37 ℃ with 5% CO₂And culturing for 24 to 48 hours.

The general protocol for the DEAE-dextran method applied to Cos-7 cells is described below: cells for transfection were grown in flasks 24 hours prior to transfection such that cells in each flask reached 70-80% confluence at the time of transfection. Briefly, 8Fg acceptor DNA and any other desired DNA (e.g., G) of 8Fg_αProtein expression vectors, reporter gene constructs (construct), antibiotic resistance markers, mock vectors, etc.) were added to 9ml of a complete DMEM and DEAE dextran mixture (10mg/ml PBS solution). COS-7 cells seeded in T225 flasks (sub-confluent) were washed once with PBS and the DNA mixture was added to each flask. Cells were incubated at 37 ℃ with 5% CO₂And (3) culturing for 30 minutes. After the cultivation, go to eachThe flask was charged with 36ml of complete DMEM and 80FM chloroquine and incubation was continued for 3 hours. The medium was then aspirated, washed with 24ml of complete medium containing 10% DMSO for 2 minutes, followed by aspiration. The cells were then washed twice with PBS and 30ml of complete DMEM was added to each flask. The cells were subsequently cultured overnight. The next day, cells were harvested by trypsinization and re-inoculated as required by the type of test being performed.

The following illustrates the general protocol applied to the liposome-mediated transfection of CHO cells: cells for transfection were grown in flasks 24 hours prior to transfection such that cells in each flask reached 70-80% confluence at the time of transfection. Transfection per 75cm²Flask cells always share 10FgDNA (which may include various ratios of recipient DNA and other desired DNA (e.g., G)_αProtein expression vectors, reporter gene components (construct), antibiotic resistance markers, mimic vectors, etc.)). Liposome-mediated transfection was performed according to the manufacturer's requirements (LipofectAMINE, GibcoBRL, Bethesda, Md.). Transfected cells were harvested 24 hours after transfection and used or re-seeded as required for the assay being performed.

The following illustrates the general protocol applied to electroporation transfection of Cos-7 cells: cells for transfection were grown in flasks 24 hours prior to transfection, so that cells in each flask were confluent at the time of transfection. Cells were harvested by trypsinization, resuspended in their growth medium and counted. Will be 4X 10⁶Individual cells were suspended in 300Fl DMEM and placed in electroporation cuvettes. To the cell suspension, 8Fg receptor DNA and 8Fg of other desired DNA (e.g., G) are added_αProtein expression vector, reporter Gene component (construct), antibiotic resistance marker, mimic vector, etc.), cuvettes were placed in BioRad Gene Pulser, and electric pulses were applied (Gene Pulser set: voltage 0.25kV, capacitance 950 FF). After pulsing, 800Fl complete DMEM was added to each cuvette and the suspension was transferred to a sterile tube. Complete medium was added to each tube to give a final cell concentration of 1X 10⁵Cells/100 Fl. The cells are then seeded as needed for the test being performed.

The general protocol for virus-mediated expression of heterologous proteins is described below as baculovirus infection of insect Sf9 cells. The coding region of the DNA-encoding receptor described herein may be subcloned into pBlueBacIII into the existing restriction sites or into sites engineered into the sequences 5 'and 3' of the coding region of the polypeptide. For Baculovirus production, 0.5Fg viral DNA (Baculogold) and a polypeptide of 3Fg encoding DNA construct were co-transfected to 2X 10 by calcium phosphate co-precipitation method as described by Pharmingen (described in "Baculoviral Expression Vector System: products and Methods Manual⁶Fall armyworm (Spodoptera frugiperda) insect Sf9 cells. The cells were then cultured at 27 ℃ for 5 days. Supernatants from the co-transfection plates were collected by centrifugation and recombinant viral plaques were purified. Methods for infecting cells with virus, preparing virus stocks, and titrating virus stocks are described in the handbook of Pharmingen. Similar principles apply to mammalian cell expression via retroviruses, Simliki forest viruses, and double-stranded DNA viruses (e.g., adenovirus, herpes virus, vaccinia virus, etc.).

Stable expression

The heterologous DNA can be stably incorporated into the host cell, allowing the cell to continue to express the heterologous protein. Methods for delivering DNA into cells are similar to those described above for transient expression, but require co-transfection of helper genes to render the target host cells resistant. The desired resistance can be used to select and maintain cells that have taken up the foreign DNA. One class of drug resistance genes available includes, but is not limited to, neomycin, kanamycin, and hygromycin. For receptor studies, stable expression of heterologous receptor proteins is performed in mammalian cells (but not limited to mammalian cells, including CHO, HEK293, LM (tk-), etc.).

Preparation of cell membranes

For binding assays, transfected cell particles were suspended in ice-cold buffer (20mM Tris & HCl, 5mM EDTA, pH7.4) and homogenized for 7 seconds with ultrasound. At 4 ℃, the cell lysate in 200 x g centrifugal 5 minutes. The supernatant was then centrifuged at 40,000 Xg for 20 minutes at 4 ℃. The resulting particles are washed once with homogenization buffer and then suspended in binding buffer (see methods for radioligand binding). Protein concentrations were determined according to the method of Bradford (1976) using bovine serum albumin as a standard. The binding test is usually performed immediately, but it is also possible to prepare the membrane in batches and then store it in liquid nitrogen for use.

Radioligand binding assay

The radioligand binding assay at the rat MCH1 receptor was performed using plasmid pcDNA3.1-rMCH1-f (ATCC patent deposit number PTA-3505). The plasmid pcDNA3.1-rMCH1-f contains regulatory elements necessary for expression of the DNA in mammalian cells, which are operatively linked to the rat MCH1 receptor encoding the DNA for expression. Plasmid pcDNA3.1-rMCH1-f was deposited at American Type Culture Collection (ATCC) at 7.5.2001, 12301ParklawnDrive, Rockville, Maryland20852, USA, ATCC patent deposit number PTA-3505, in accordance with the provisions of the International recognized Budapest treaty on the deposit of microorganisms for patent procedures.

The binding test was also performed using the plasmid pEXJ. HR-TL231(ATCC patent accession number 203197) as described below. Plasmid pEXJ. HR-TL231 encodes the human MCH1 receptor, deposited under the provisions of the International recognized Budapest treaty on the deposit of microorganisms for patent procedures, No. 17, 1998, in the American Type Culture Collection (ATCC), 12301Parklawn Drive, Rockville, Maryland20852, USA, ATCC number 203197.

Human embryonic kidney cells, Peak rapid293 cells (Peakr293 cells), were transiently transfected with the MCH1 receptor encoding DNA using the calcium phosphate method and the cell membrane method as described above. Binding assay with membranes from Peakr293 cells transfected with the rat MCH1 receptor Using 0.08nM 2³H]Compound A (Amersham identified as specified) (Synthesis of Compound A is described in detail below), using culture bufferLiquid (50 mM Tris pH7.4, 10mM MgCl)₂0.16mM PMSF, 1mM 1, 10-phenanthroline and 0.2% BSA). Binding was carried out at 25 ℃ for 90 minutes. The incubation was stopped by rapid vacuum filtration on a GF/C glass fiber filter (pre-soaked in 5% PEI, using 50nM pH7.4 Tris as wash buffer). In all experiments, non-specific binding was determined using 10FM compound a.

Functional testing

Cells presenting an endogenous mammalian receptor can be screened using a functional assay. Cells that are present without or with minimal endogenous receptors can be transfected with endogenous receptors used in functional assays.

The receptor activity can be screened using a broad-spectrum assay. These tests include, for example: conventional P-phosphatidylinositol, cAMP, Ca⁺⁺And K⁺Testing of (2); these same systems of second messengers are tested, but these systems can be modified or adapted to make the test method faster, more universal and more sensitive; cell-based platforms (cell based platforms) reporting more general cellular events resulting from receptor activation such as metabolic changes, differentiation and cell division/proliferation; high level of organic testing that monitors complex physiological and behavioral changes believed to be involved in receptor activation including cardiovascular, analgesic, appetizing, anxiolytic and sedative effects.

Radioligand binding assay results

Each of the above compounds was tested using cloned rat MCH 1. The binding affinities of the compounds are shown in table I.

Synthesis of Compound A

The synthesis of compound a is described below. Compound a is a radiolabeled compound used in the radioligand binding assay described above.

N- [3- (1, 2, 3, 6-tetrahydro-4-pyridinyl) phenyl ] acetamide

A mixture of saturated aqueous sodium carbonate (25mL), tert-butyl 4- { [ (trifluoromethyl) sulfonyl ] oxy } -1, 2, 3, 6-tetrahydro-1-pyridine-carboxylate (20mmol), 3-acetamidophenylboronic acid (30mmol), and tetrakis (triphenylphosphine) palladium (0) (1.15g) in dimethoxyethane (40mL) was heated at reflux overnight to give tert-butyl 4- [3- (acetylamino) phenyl ] -3, 6-dihydro-1 (2H) -picolinate. Deprotection of the BOC gene using HCl in dioxane followed by basification (pH11-12) affords the desired product.

N- (3-Bromopropyl) carbamic acid tert-butyl ester

From 3-bromopropylamine hydrobromide and BOC in dichloromethane in the presence of a base₂O preparation of the title compound.

N- {3- [1- (3-aminopropyl) -1, 2, 3, 6-tetrahydro-4-pyridinyl ] phenyl } acetamide

As depicted in scheme A from tert-butyl N- (3-bromopropyl) carbamate and N- [3- (1, 2, 3, 6-tetrahydro-4-pyridinyl) phenyl]Acetamide and catalytic amount of Bu₄NI and a base in refluxing dioxane to give 3- (4- [3- (acetylamino) phenyl)]-3, 6-dihydro-1 (2H) -pyridinyl) propylcarbamic acid tert-butyl ester. Deprotection of the BOC group using HCl in dioxane followed by basification (pH11-12) affords the desired product.

(4S) -3- ({ [3- (4- [3- (acetylamino) phenyl ] -3, 6-dihydro-1 (2H) -pyridinyl ] propyl) amino ] carbonyl } -4- (3, 4-difluorophenyl) -6- (methoxymethyl) -2-oxo-1, 2, 3, 4-tetrahydro-5-pyrimidinecarboxylic acid methyl ester

The title compound was prepared from the reaction of 5-methyl1- (4-nitrophenyl) 6- (3, 4-difluorophenyl) -4- (methoxymethyl) -2-oxo-3, 6-dihydro-1, 5(2H) -pyrimidinedicarboxylic acid (prepared according to PCT publication No. WO 00/37026, published on 6.29.2000) and N- {3- [1- (3-aminopropyl) -1, 2, 3, 6-tetrahydro-4-pyridinyl ] phenyl } acetamide.

¹H NMR δ8.90(t，1H，J＝3.6Hz)，7.75(s，1H)，7.50-7.00(m，8H)，6.68(s，1H)，6.03(br s，1H)，4.67(s，2H)，3.71(s，3H)，3.47(s，3H)，3.38(ABm，2H)，3.16(m，2H)，2.71(t，2H，J＝5.4Hz)，2.56(m，4H)，2.35-1.90(br，2H)，2.17(s，3H)，1.82(p，2H，J＝7.2Hz)；ESMS，612.25(M+H)⁺.

Deuterated methyl (4S) -3- { [ (3- {4- [3- (acetylamino) phenyl ] -1-piperidinyl } propyl) amino ] carbonyl } -4- (3, 4-difluorophenyl) -6- (methoxymethyl) -2-oxo-1, 2, 3, 4-tetrahydro-5-pyrimidinecarboxylate

By the cooling method described (H)₂Balloon method, methanol, Pd/C, overnight) and (4S) -3- ({ [3- (4- [3- (acetylamino) phenyl)]-3, 6-dihydro-1 (2H) -pyridinyl) propyl]Tritiation of methyl amino } carbonyl) -4- (3, 4-difluorophenyl) -6- (methoxymethyl) -2-oxo-1, 2, 3, 4-tetrahydro-5-pyrimidinecarboxylate (Amersham) to give tritiated (4S) -3- { [ (3- {4- [3- (acetylamino) phenyl ] methyl]-1-piperidinyl } propyl) amino]Carbonyl } -4- (3, 4-difluorophenyl) -6- (methoxymethyl) -2-oxo-1, 2, 3, 4-tetrahydro-5-pyrimidinecarboxylic acid methyl ester ((+) -isomer), which was then used as radioligand in MCH pharmacological tests.

TABLE 1

TABLE 1 (continuation)

In vivo methods

The following in vivo methods were performed to predict the effect of MCH1 antagonists for the treatment of obesity (3-day body weight and sweetened condensed milk), depression (forced swimming test), anxiety (social interaction test) and urinary disorder (DIRC and CSTI).

Effect of MCH1 antagonists on body weight (3 days)

Male Long Evans rats (Charles River) weighing 180-. Test compounds were administered twice daily (1 hour before dark cycle and2 hours after light) via i.p. injection for 3 days. Each rat was weighed daily after each morning injection. All results are expressed as daily amounts (g) (mean ± SEM) and analyzed by two-way anova. Data at each time point was analyzed using one-way analysis of variance followed by a post hoc Newman/Keuls analysis. Data analysis was performed using GraphPad Prism (version 2.01 (GraphPad software, inc., San Diego, CA.) all data are expressed as mean ± s.e.m.

Effect of MCH1 antagonists on consumption of sweetened concentrated milk

At the start of the experiment, male C57BL/6 mice (Charles River) weighing 17-19g were housed in groups of 4 or 5 in cages with 12 hours light/dark cycle, and allowed free access to food and water. Within 7 days, each mouse was weighed, placed in a separate cage, and allowed to drink sweetened condensed milk (Nestle, diluted with water at a ratio of 1: 3) for 1 hour 2-4 hours before entering the light cycle. The amount of milk consumed was determined by weighing the milk bottle before and after drinking. On the test day, mice were injected i.p. with test compounds (3, 10 or 30mg/kg in 0.01% lactic acid), d-fenfluramine (10mg/kg in 0.01% lactic acid) in vehicle (0.01% lactic acid) 30 minutes before drinking milk. The amount of milk consumed on the test day (in mls milk/kg body weight) was compared to the baseline drinking amount measured on each mouse on the first two days. The data at each time point was analyzed using one-way analysis of variance.

Forced Swim Test (FST) in rats

Animal(s) production

Male Sprague-Dawley rats (Taconic farm, NY) were used for all experiments. Rats were treated with 5 per cage, 12:12 hours light: raising in dark cycle. Rats were trained daily for 1 minute for 4 consecutive days before behavioral testing.

Administration of drugs

Animals were randomly selected to receive a single dose of i.p. vehicle (2.5% EtOH/2.5% Tween-80), imipramine (positive control; 60mg/kg) or test compound 60 minutes prior to the start of the 5 minute test period. All injections were performed using a 1cc tuberculin syringe with 263/8 syringes (Becton-Dickinson, VWR Scientific, Bridgeport, NJ). The injection volume was 1 ml/kg.

Design of experiments

The process used in this study was similar to the previous process (Porsolt et al, 1978) except that the water depth was 31 cm. The deeper water depth used in this experiment was to prevent the rat's paw from touching the bottom of the sink and supporting their body. Each rat was placed in a separate plexiglass water tank (height 46 cm. times.20 cm diameter) at 31cm water depth and 23-25 ℃ water temperature for swimming tests. The swimming test is typically run for 900 to 1700 hours, consisting of an initial 15 minute commissioning phase and a 5 minute testing phase that is run 24 hours later. Rats were given drug treatment 60 minutes prior to the 5 minute test period. After all swimming tests, each rat was taken out of the water tank, wiped dry with a paper towel, then placed in a heated cage for 15 minutes, and then returned to their cage. The entire test procedure was videotaped using a color camera and then recorded for subsequent scoring.

Behavior scoring

The behaviour of the rats was evaluated every 5 seconds by a single evaluator (who was not aware of the treatment conditions) during the 5 minute test period. The behavior recorded is as follows:

1. immobilizing: rats float on water, have no water-hitting action, and only make some necessary actions to extend their heads out of the water;

2. climbing: rats make positive behaviors, with their forepaws stroking water, usually climbing towards the wall;

3. swimming: rats swim aggressively, rather than just keeping their heads above the water surface, as they move along a sink; and

4. and (3) sinking: the whole body of the rat was immersed in water.

Data analysis

Forced swim test data (immobility, swimming, climbing, and sinking) were subjected to a random, one-way analysis of variance, and post hoc tests were performed using the Newman-Keuls test. Data analysis was performed using GraphPad Prism (version 2.01) (GraphPad Software, inc., San Diego, CA). All data are expressed as mean ± s.e.m.

Forced Swim Test (FST) on mice

Animal(s) production

DBA/2 mice (Taconic farm, NY) were used for all experiments. Mice were treated at 5 per cage, 12:12 hours light: raising is carried out in a controlled environment with dark cycles. Mice were trained daily for 1 minute for 4 consecutive days prior to the test. The method includes simulated gavage (mock gavage) using a 1.5 inch feeding tube.

Administration of drugs

Animals were randomly selected to receive a single vehicle (5% EtOH/5% Tween-80) dose, test compound dose, or mipramine (60mg/kg) dose by oral gavage 1 hour prior to the start of the swimming test.

Design of experiments

The method for forced swim testing of mice is similar to that described above for rats, with minor modifications. The water tank used for this test was a 1 liter beaker (diameter 10.5 cm. times. height 15cm) filled with 800ml (depth 10cm) of water at 23-25 ℃. Only one swimming test of 5 minutes was performed per mouse over the test period of 1300 to 1700 hours. Drug treatment was given 30-60 minutes prior to the 5 minute test period. After all swimming tests, each mouse was taken out of the water tank, wiped dry with a paper towel, and then placed in a heated cage for 15 minutes. The entire test procedure was videotaped using a color camera and recorded for subsequent scoring.

Behavior scoring

The 2-5 minute test activity was played back on a television monitor and scored by an auditor. The total time of immobility (animals floating on water, making only some actions that enable them to float) and movement (swimming and making movements that are not just made to keep floating) was recorded.

Data analysis

Forced swim test data (immobility, time to exercise, seconds) were subjected to a random, one-way analysis of variance and post hoc test using the Newman-Keuls test. Data analysis was performed using GraphPad Prism (version 2.01, GraphPad Software, inc., San Diego, CA). All data are expressed as mean ± s.e.m.

Social activity test (SIT)

Rats were subjected to 5-day acclimation to animal care facilities and then housed for 5 days in individual cages prior to testing. Animals were trained for 5 minutes daily. The design and procedure of the social activity test was performed according to the method previously described by Kennett et al (1997). On the test day, pairs of rats that matched in weight (+ -5%, not familiar to each other) were treated identically and then returned to their own cages. Animals were randomized into 5 treatment groups of 5 pairs each, given one of the following i.p. treatments: test compound (10, 30 or 100mg/kg), vehicle (1ml/kg) or chlorine nitrogen * (5 mg/kg). Dosing was 1 hour prior to testing. Each rat was then placed in a white transparent plastic test box or field (54X 37X 26cm, with the floor divided into 24 squares) for 15 minutes. The air conditioner was used to generate background noise and the room temperature was maintained at about 74 ° f. All procedures were recorded using a JVC camera (model GR-SZ1, Elmwood Park, NJ) with either TDK (HG ultimate brand) or Sony 30 minute cassettes. All procedures were performed for 1300-1630 hours. Positive social activities such as self-cleaning, smelling, biting, fighting, wrestling, chasing, and crawling up and down were recorded using a timetable (model 226 sportline, 1/100 seconds, discrimination). The number of erections (animals fully supported their entire body with their hind limbs), self-cleaning (licking, biting and raking the body), face washes (i.e. repeated movements of the animal's paw on its face) and the number of squares traversed were recorded. Passive social activity (animals lying alongside or overlapping each other) was not recorded. All behaviors were then evaluated by an observer blinded to the treatment. After each test was completed, the box was thoroughly wiped with a wet wipe.

Animal(s) production

Male albino Sprague-Dawley rats (Tastic Farms, NY) were paired in cages with 12 hours light/dark cycle (light time 0700 hours) and allowed free access to food and water.

Administration of drugs

Test compounds were dissolved in 100% v/v DMSO or 5% v/v lactic acid (sigma chemical co., st. Chlorine nitrogen * (Sigma Chemical co., st. louis, MO) was dissolved in double distilled water. The vehicle consisted of 50% DMSO (v/v) or 100% Dimethylacetamide (DMA). All drug solutions were prepared 10 minutes before injection and the solutions were decanted off after testing. The volume of the drug solution administered was 1 ml/kg.

Data analysis

Social data (time of day, number of blocks upright and traversed) were subjected to a stochastic, one-way analysis of variance and post hoc test using Student-Newman-Keuls test. The data were subjected to a normality test (Shapiro-Wilk test). Data analysis was performed using the GBSTAT program, version 6.5 (Dynamics Microsystems, inc., Silver Spring, MD, 1997). All data are expressed as an average + -S.E.M.

Internal model of micturition reflex

The effect of compounds on micturition reflexes was evaluated in accordance with the "expansion-induced rhythmic contraction" (DIRC) and Continuous Slow bladder Infusion (CSTI) models in rats described in the aforementioned publications (e.g., Maggi et al, 1987; Morikawa et al, 1992).

DIRC model

Urethane (1.2g/kg) was administered subcutaneously and female Sprague Dawley rats weighing approximately 300g were anesthetized. The trachea was cannulated with PE240 tubing to provide a clean airway for the entire experiment. In the middle abdominal incision, the left and right ureters were separated. Each ureter was ligated distally (to prevent fluid leakage from the bladder) and cannulated proximally with PE10 tubing. The notch was sutured using 4-0 silk suture, leaving the PE10 tube open to the outside to drain urine. The bladder was inserted transurethrally using a PE50 tube inserted 2.5cm from the urethral opening. The cannula is secured to the tail using tape, in connection with the pressure sensor. To prevent leakage from the bladder, the cannula was tied using a 4-0 wire, extending outside the urethral opening.

To begin the micturition reflex, the bladder is first emptied by applying pressure to the abdominal base, then filled with 100 increments of saline (up to 2ml) until spontaneous bladder contractions occur (typically 20-40mmHg, contractions every 2 to 3 minutes). Once a rhythmic contraction occurs, the vehicle (saline) or test compound is administered i.v. or i.p. to have an effect on bladder activity. Using 5-HT_1AThe antagonist WAY-100635 was used as a positive control. Data are presented as the interval of contraction (seconds) before drug administration (baseline) or after vehicle or test compound administration.

Rat model for continuous slow bladder infusion (CSTI)

The study was performed using male Sprague Dawley rats weighing approximately 300 g. Rats were anesthetized with sodium pentobarbital (50mg/kg, i.p.). At the medial abdominal incision, the bladder is exposed, a polyethylene tube (PE50) is introduced through a small incision in the dome of the bladder, and the cannula is secured with a purse string suture (pursesring suture). The other end of the cannula is led out from the back and neck part from the inside of the abdomen through the skin. Similarly, another cannula (PE50) was inserted into the stomach via the median lateral incision in the abdomen, with the free end extending subcutaneously to the neck. The external wound was closed with 4-0 silk suture and the animal was given appropriate post-operative care to recover it. The following day, animals were placed in the rat brakes. The open end of the bladder intubation is connected with a pressure sensor and an infusion pump through a three-way switch. The bladder void cycle was started by continuous infusion of saline at a rate of 100. mu.l/min. Repetitive blank contractions were recorded using Power Lab online data collection software. After recording the baseline blank curve for 1 hour, the test drug or vehicle was administered directly into the stomach via the intragastric catheter and the blank cycle was monitored for 5 hours. The voiding pressure and frequency before and after treatment (30 minute intervals) were calculated for each animal. Bladder capacity was calculated from the frequency of urination according to a constant infusion rate of 100 μ l/min. The effect of the test drug is expressed as a baseline, percentage of bladder capacity prior to administration. Comparison was performed using WAY 100635 as a positive control.

Reference documents:

(iii) autonomous, G. et al (1992) assessment of the second located (cuban) of the autosomal dominant cerebellar ataxia to chromosome 12q23-24.1, between flash markers D12S58 and PLA2 (location of the second (smallpox-like) locus of autosomal dominant cerebellar ataxia on chromosome 12q23-24.1 between flanking markers D12S58 and PLA 2). Cytogene.61：252-256。

Bahjaoui-Bouhadd, M. et al (1994), Insulin treatment stimulants thermal-concentrating hormone-producing neurons stimulations in rats Neuroppeptides24：251-258。

Baker, b.i. (1991), Melanin-concentrating hormone: a generallverterbrate neuropeptide (melanin-concentrating hormone: a common vertebrate neuropeptide) int.rev.cytol.126: 1-47.

Baker, b.i. (1994), Melanin-concentrating hormone update: functional conseration (melanin-concentrated hormone study near-term: functional study)5：120-126。

Bassett, A.S. et al, (1988), Partial trisomy chromosome 5 gathering with schizophagia (partially trisomy 5 co-segregating with schizophrenia)1：799-801。

Bednarek, M.A., et al, "Synthesis and biological evaluation in video of active, high-tension peptide agonist of human melanin-concentrating hormone action at human melanin-concentrating hormone receptor 1 (selectivity of human melanin-concentrating hormone action at human melanin-concentrating hormone receptor 1, Synthesis and in vivo physiological evaluation of high-potency peptide agonists)", J Biol Chem277(16)：13821-13826(2002)。

Bittencourt, J.C. et al (1992), The mean-centering hosronesystem of The rat brain: an immunization-and hybridization histochemical characterization (melanin-concentrating hormone system in rat brain: immunological and hybrid tissue chemical characterization).319：218-245。

Borowsky, B. et al, Nature Medicine, 2003.

Bradford, M.M (1976) A Rapid and reactive method for the quantification of microorganisms such as protein digestion, analytical. biochem.72：248-254。

Burglad, J.L. et al (1997) Meinin-concentrating hormone binding sites in human SVK14 keratinocytes (binding sites for Melanin-concentrating hormone in human SVK14 keratinocytes).241(3)：622-629。

Chambers, J.et al, "melanon-concentrating hormone is the cognatellign and for the orphan G-protein-coupled receptor SLC-1 (Melanin-concentrating hormone is a cognate ligand for the orphan G-protein-coupled receptor SLe-1)," Nature400(6741)：261-6(1999)。

Chen, Y, et al, "Targeted division of the melanin-concentrating hormone receptor-1 residues in hyperphagia and resistance to diet-induced obesity" Endocrinology143(7)：2469-2477(2002)。

Craddock, N. et al (1993), The gene for Darie's disease maps hyperchromosome 12q23-q24.1 (chromosome map drawn from Darley's disease gene 12q23-q 24.1.) hum.2：1941-1943.

Dondondoni, a. et al (1995), t.synthesis, 181.

Drozdz, r. and Eberle, a.n. (1995), Binding sites for a melanin-Binding hormone (MCH) in blue synthesis receptors and membrane from peripheral tissue identified MCH (identification of Binding site of melanin-concentrating hormone (MCH) in brain synaptosomes and peripheral tissue membranes from highly deuterated MCH), j.receptor.signal.transfer.res.15 (1-4): 487-502.

Drozdz, R. et al (1995), melano-concentrating hormone binding to melanoma cells in vitro (binding of Melanin-concentrating hormone to melanoma cells in mice)359：199-202。

Drozdz, R. et al (1998), charateristic of the receptor for melanon-concentrating hormone on melanomas cells by photocrosslinking,. Ann.NY. Acad.Sci.839 (1): 210-213.

Gilliam, T.C. et al (1989), Deletion mapping of DNA markers to areas of chromosome 5 which are cosegregylates with schizoopening5：940-944。

Gonzalez, m.i. et al (1997), stimulation effect of Melanin-concentrating hormone on luteinizing hormone release neuroendiology 66 (4): 254-262.

Gonzalez, m.i. et al (1996), behavial effects of α -melanophore-stimulating hormone (α -MSH) and melanophore-concentrating hormone (MCH) after central nervous administration of α -melanin stimulating hormone (α -MSH) and melanin-concentrating hormone (MCH) to female rats. 171-177.

Grilon, S. et al (1997), expanding the expression of the melanoin-concentrating hormone messenger RNA in the rat molecular hypothalamus injection (study of the expression of Melanin-concentrating hormone messenger RNA in the rat lateral hypothalamus after aurothioglucose injection.) neuropeps 31 (2): 131-136.

Herve, C.and Fellmann, D. (1997), change in rat melanophore-concentrating hormone and dynorphin messenger ribosomal nucleic acid bound by food depletion (fasting induced Changes in rat melanophore hormone and dynorphin messenger RNA)31(3)：237-242。

Hervieu, G.et al (1996), Development and stage-dependent expression of melanoin-concentrating hormone in mammalian germ cells (Development and stage-dependent expression of Melanin-concentrating hormone in mammalian germ cells.) Biology of reproduction54：1161-1172。

Kauwachi, H. et al (1983), characterisation of Melanin-concentrating hormone in chum salmon pituitaries (characterisation of Melanin-concentrating hormone in the pituitary gland of chum salmon.) Nature 305: 321-333.

Knigge, K.M. et al (1996), Melanotropic peptides in the mammalianbrain: the Melanin-concentrating hornone (melanotropic peptide in mammalian brain: melanin concentrating hormone)17：1063-1073。

Knigge, K.M. and Wagner, J.E. (1997) Melanin Conjugating Hormone (MCH) involvent in Pendenetetrazole (PTZ) -induced seizurin rat and guineag pig (Melanin-aggregating hormone involved in Pentamethylenetetrazole (PTZ) -induced seizures in rats and guinea pigs)18(7)：1095-1097。

Lakaye, B, et al, "Cloning of the rat cDNA encoding the SLC-1G protein-coupled receptor the expression of an intron in the gene (Cloning of the rat brain cDNA encoding the SLC-1G protein-coupled receptor indicates the presence of an intron in the gene)," Biochem Biophys Acta1401(2)：216-220(1998)。

Ludwig, d.s. et al (1998), Melanin-concentrating hormon: afungical melanocortin antagnostist in the hypothalamus, am.j.pysiol.endocrinol.meta.274(4)：E627-E633。

Mackenzie, F.J. et al (1984), Evidence of the stimulatory of the dopaminergic endothelial polypeptide a proliferative effect on inflammation and gonadotropinerelease (Evidence that the hypothalamic tract where dopaminergic is not located has a stimulatory effect on ovulation and gonadotropin secretion)39：289-295。

Maggi, C.A., et al, "Spinal and subasplanal compositions of GABAergic inhibition of the micturition reflexes in rats," J Pharmacol Exp Ther240：998-1005(1987)。

Marsh, D.J., et al, "melanon-concentrating hormone receptor-specific microorganism area, hyperactive, and hyperthermic and have altered metabolism in mice deficient in Melanin-concentrating hormone 1 receptor," Proc Natl Acad Sci USA99 (5): 3240-3245(2002).

Martin, r. et al (1997), j.tetrahedron Letters, 38, 1633.

McBride, R.B. et al (1994), The actions of a Mean Centralized Hormone (MCH) on passive avidity in rates: a preliminary study (effect of melanin-concentrating hormone (MCH) on passive evasion in rats: preliminary study.) Peptides 15: 757-759.

Melki, J.et al (1990), Gene for viral protein mucoratopes maps to chromosome 5q (genetic map of the fifth pair of chromosomes associated with chronic adjacent spinal muscular atrophy)344：767-768。

Miller, c.l. et al (1993), alpha-MSH and MCH are functional antagonists a CNS audio partner (alpha-MSH and MCH are functional antagonists of CNS hearing). 1-10.

Morikawa, K. et al, "inhibition of urinary reflex by inhibition of endothelial effect of endothelial hydrogen chloride, a new central acting muscle relaxant," Eur J Pharmacol213：409-415(1992)。

NaHon, J-L. (1994) The Melanin-concentrating hormon: from the peptide to the gene, clinical Rev221：221-262。

Parkes, D.G, (1996) Diuretic and natrietic actions of melanogenic concentrating hormone in a coherent sheep, J.neuroendocrinol.8: 57-63.

Pedeutouter, F. et al (1994), Assignment ofthe human pro-Melanin-localizing hormone gene (PMCH) to chromosome 12q23-24 and twogenetic genes (PMCHL1 and PMCHL2) to chromosome 5p14 and 5q12-q13 (location of human pre-Melanin concentrating hormone gene (PMCH) on chromosome 12q23-24 and location of two variant genes (PMCHL1 and PMCHL2) on chromosomes 5p14 and 5q12-q 13)19：31-37。

Porsolt, R.D., et al, "Behavioural despain in rates; a new model sensory negative anti-depressive approaches (rat desperate behavior: a novel model susceptible to treatment against depression)' Eur J Pharmacol47(4)：379-391(1978)。

Pressure, F.et al (1992) Rat methylene-confining hormone monomer acid expression: market changes during development and after stress and glucocorticoids stimuli (expression of messenger RNA of the rat melanin-aggregating hormone: significant changes during development and after stress and glucocorticoid stimulation)131：1241-1250。

Qu, D.et al (1996) A role for a Melanin-concentrating hormone in the central regulation of feeding behavior380：243-247。

Rossi, m. et al (1997), Melanin-concentrating hormone administration of enzymes, but slow administration of Melanin-concentrating hormone does not affect body weight138：351-355。

Sahu, A. (1998) evaluation of stimulating hormone (GAL), Melanin-concentrating hormone (MCH), Neurogenin (NT), Proanthocyanin (POMC) and neuropeptide Y (NPY) are hypothalamic targets of Galanin (GAL), Melanin-aggregating hormone (MCH), Neurotensin (NT), Proopiomelanocortin (POMC) and neuropeptide Y (NPY)Evidence of leptin signaling target)139(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 behavior92：573-585。

Sanchez, M. et al (1997), Melanin-concentrating hormon (MCH) antagonists of alpha-MSH and neuropeptide E-I on growing and cyanocomotor activities in the rat18：393-396。

Saito, Y, et al, "Molecular characterization of the melanin-concentrating-hormone receptor," Nature400(6741)：265-269(1999)。

Sherrington, R. et al (1988), Localization of a Susc radioactivity loci for schizophrenic on chromosome 5 (fifth pair of chromosome-associated sensitive sites for schizophrenia)336：164-167。

Srebnik, M. et al (1988), J.Org.Chem., 53, 2916-S2920.

Takekawa, S. et al, "T-226296: a novel, oral active and selective melanomin-concentrating hormone receptor antagonist (T-226296: a novel, orally active, selective melanin-concentrating hormone receptor antagonist), "Eur JPharmacol 438 (3): 129-35(2002)

Twells, R. et al (1992), chromosome assembly of the heart of the human being, a chromosome-positing of the heart of the human being, a chromosome 2 in a cornea fountain of the human being, a chromosome location of the part of the human being, which causes the atrophy of the heart of the human being, a chromosome 2. Cytogenet.Cell.Genet. 61：262-265。

Westbrook, c.a. et al (1992), Report of the second international work on human chromosome 5 mapping (second international Report on the fifth human work on chromosome maps).61：225-231。

Claims (32)

1. A compound having the structure:

wherein each A is independently-H, -F, -Cl, -Br, -I, -CN, -NO₂、-OR₃Or straight or branched C₁-C₇An alkyl group;

wherein each B is independently N or CH;

wherein Z is CO or SO₂；

Wherein R is₄Independently is-OR₃、-NHR₃、-SR₃、-COR₃Aryl or heteroaryl, wherein aryl or heteroaryl is optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -OR₂Or straight or branched C₁-C₇An alkyl group;

wherein each R₃Independently is-H, straight or branched chain C₁-C₇An alkyl, monofluoroalkyl or polyfluoroalkyl, aryl or heteroaryl group, wherein the aryl or heteroaryl group is optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -NO₂、-CN、-OR₂or-NHR₂；

Wherein each R₂Independently is-H, straight or branched chain C₁-C₇Alkyl, aryl or heteroaryl, wherein aryl or heteroaryl is optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -NO₂-CN; and

wherein n is an integer from 1 to 6.

2. The compound of claim 1, wherein the compound has the structure:

wherein A and Z are as defined in claim 1;

wherein R is₄Is aryl or heteroaryl, wherein aryl or heteroaryl is optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -OR₃Or straight or branched C₁-C₇An alkyl group;

wherein each R₃Is straight chain or branched C₁-C₇Alkyl, aryl or heteroaryl, wherein aryl or heteroaryl is optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -NO₂-CN OR-OR₂；

Wherein each R₂is-H, straight or branched chain C₁-C₇Alkyl, aryl or heteroaryl, wherein aryl or heteroaryl is optionally substituted by oneOr a plurality of the following groups: -F, -Cl, -Br, -I, -NO₂-CN; and

wherein n is as defined in claim 1.

3. The compound of claim 2, wherein the compound has the structure:

wherein a is as defined in claim 1;

wherein R is₂is-H, straight or branched chain C₁-C₇Alkyl, or aryl, wherein aryl is optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -NO₂or-CN; and

wherein n is as defined in claim 1.

4. The compound of claim 3, wherein the compound has the structure:

wherein a is as defined in claim 1;

wherein R is₂Is straight chain or branched C₁-C₇An alkyl group; and

wherein n is an integer from 3 to 6.

5. The compound of claim 4, wherein the compound has the structure:

wherein each A is independently-H, -F, -Cl, -Br, or-I; and

R₂as defined in claim 4.

6. The compound of claim 5, wherein the compound has the structure:

wherein each A is independently-H, -F, or-Cl; and

wherein R is₂Is straight chain or branched C₁-C₃An alkyl group.

7. The compound of claim 6, wherein the compound has the structure:

8. the compound of claim 6, wherein the compound has the structure:

9. the compound of claim 1, wherein the compound has the structure:

wherein a is as defined in claim 1; and

wherein R is₂Is aryl, wherein aryl is optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -NO₂or-CN; and

wherein n is an integer from 1 to 6.

10. The compound of claim 9, wherein the compound has the structure:

wherein each A is independently-H, -F, -Cl, -Br, or-I; and

wherein R is₂As defined in claim 9.

11. The compound of claim 10, wherein the compound has the structure:

wherein each A is independently-H, -F, or-Cl; and

wherein R is₂Is aryl optionally substituted with one or more-F, -Cl or-Br.

12. The compound of claim 11, wherein the compound has the structure:

wherein each A is independently-H, -F, or-Cl; and

wherein R is₂Is aryl optionally substituted by one or more-F.

13. The compound of claim 12, wherein the compound has the structure:

14. the compound of claim 1, wherein the compound has the structure:

wherein A, Z, n and R₄As defined in claim 1.

15. The compound of claim 14, wherein the compound has the structure:

wherein a is as defined in claim 1; and

wherein R is₄Aryl optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -OR₃Or straight or branched C₁-C₇An alkyl group;

wherein each R₃Independently is a straight or branched chain C₁-C₇Alkyl, aryl or heteroaryl, wherein aryl or heteroaryl is optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -NO₂-CN OR-OR₂；

Wherein each R₂Independently is a straight or branched chain C₁-C₇An alkyl group; and

wherein n is as defined in claim 1.

16. The compound of claim 1, wherein the compound has the structure:

wherein Z is as defined in claim 1;

wherein each A is independently-H, -F, -Cl, -Br, or-I;

wherein R is₄Independently is-OR₃、-NHR₃or-COR₃；

Wherein R is₃Is aryl optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -NO₂、-CN、-OR₂or-NHR₂；

Wherein each R₂Independently is-H, straight or branched chain C₁-C₇Alkyl, or aryl optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -NO₂-CN; and

wherein n is an integer from 1 to 6.

17. The compound of claim 16, wherein the compound has the structure:

wherein each A is independently-H or-F;

wherein R is₃Is aryl optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I, -NO₂、-CN、-OR₂or-NHR₂；

Wherein R is₂Independently is a straight or branched chain C₁-C₇Alkyl, or aryl optionally substituted with one or more of the following groups: -F, -Cl, -Br or-I; and

wherein n is an integer from 1 to 6.

18. The compound of claim 16, wherein the compound has the structure:

wherein A is-H, -F, -Cl, -Br or-I;

wherein R is₃Is optionally-NHR₂A substituted aryl group; and

wherein R is₂Is aryl optionally substituted with one or more of the following groups: -F, -Cl, -Br, -I.

19. The compound of claim 18, wherein the compound has the structure:

20. the compound of claim 16, wherein the compound has the structure:

21. the compound of claim 20, wherein the compound has the structure:

wherein A is-H, -F, -Cl, -Br or-I;

wherein R is₃Is aryl optionally substituted with one or more of the following groups: -F, -Cl, -Br or-I.

22. The compound of claim 21, wherein the compound has the structure:

23. the compound of claim 21, wherein the compound has the structure:

24. a pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

25. A pharmaceutical composition prepared by combining a compound of claim 1 and a pharmaceutically acceptable carrier.

26. A process for preparing a pharmaceutical composition comprising admixing a compound of claim 1 and a pharmaceutically acceptable carrier.

27. The use of a compound according to claim 1 for the manufacture of medicaments for the treatment of diseases mediated by the MCH1 receptor.

28. The use of claim 27, wherein the effective dose of said medicament is between about 0.03 and about 300 mg.

29. The use of claim 28, wherein the disorder is depression.

30. The use according to claim 28, wherein the disorder is anxiety.

31. The use of claim 28, wherein the disease is obesity.

32. The use of claim 28, wherein the disorder is urinary incontinence.