JP2009508805A - Macrocyclic ghrelin receptor antagonists and inverse agonists and methods of use thereof - Google Patents

Abstract

  The present invention is a novel, constitutive modulator that has been demonstrated to be a selective modulator of the ghrelin receptor (growth hormone secretagogue receptor, GHS-R1a and subtypes, isoforms and / or variants thereof). Provided are macrocycles having a defined locus. Methods for synthesizing new compounds are also described herein. These compounds, as ghrelin receptor antagonists or inverse agonists, further include, but are not limited to, metabolic and / or endocrine disorders, cardiovascular diseases, obesity and obesity related diseases, gastrointestinal disorders, genetic diseases It is useful as an agent for the treatment and prevention of a range of medical conditions, including hyperproliferative disorders and inflammatory diseases.

Description

RELATED APPLICATION INFORMATION This application claims priority from International Application No. PCT / US2005 / 02087, filed June 13, 2005, the disclosure of which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION The present invention relates to novel conformationally defined macrocycles that have been demonstrated to act as modulators, particularly antagonists or inverse agonists, ghrelin (growth hormone secretagogue) receptor (GHS-R1a). About. The present invention also relates to intermediates of these compounds, pharmaceutical compositions containing these compounds, and methods of using the compounds. These novel macrocyclic compounds are in a range of indications including metabolic and / or endocrine disorders, cardiovascular diseases, obesity and obesity-related diseases, gastrointestinal disorders, genetic diseases, hyperproliferative disorders and inflammatory diseases Useful for treatment.

Improved understanding of the various physiological regulatory pathways enabled by research efforts in genomics and proteomics has influenced the discovery of new drugs. In particular, the identification of major receptors and their endogenous ligands has created new opportunities to exploit these receptor / ligand pairs as therapeutic targets. For example, ghrelin is a recently characterized 28-amino acid peptide hormone that has been shown to mediate a variety of important physiological functions (Kojima, M .; Hosoda, H. et al. Nature 1999, 402). , 656-660.). A novel feature of this structure is the presence of the n-octanoyl group of Ser ³ that appears to be related to the activity of ghrelin. This peptide has so far been demonstrated to be an endogenous ligand for the orphan G protein-coupled receptor (GPCR) of type 1 growth hormone secretagogue receptor (hGHS-R1a). (Howard, AD; Feighner, SD; Curly, DF; Arena, JP; Libertor, PA; Rosenblum, CI; Hamelin, M; Hreniuk, Plyha, OC; Anderson, J .; Paress, PS; Diaz, C .; Chou, M .; Liu, KK; McKee, KK; S.-S .; Chaung, LY; Elbrecht, A.; Dashkevicz, M.; Heavens, R.; Rigby, M.; Sirinathsingji, D.J.S. Patchett, A. A .; Nargund, R .; Griffin, PR; Gupta, SK; Schaeffer, JM; Smith, RG; Van der Ploeg, L. H. A. Receptor in pits and recirculations in the heat of the water Science 1996, 273, 974-977.) GHS-R1a has recently been classified as a ghrelin receptor with its endogenous ligand recognized (Davenport, AP; et al. International Union of Pharmacology. LVI. .Ghrelin Receptor Nomenclature, Distribution, and Function.Pharmacol.Re .2005,57,541-546).

  Even prior to the isolation of this receptor and its endogenous peptide ligand, a considerable amount of research was devoted to the discovery of substances that could stimulate growth hormone (GH) secretion. Proper control of human GH is important not only for proper body growth, but also for a series of other important physiological effects. GH and other GH stimulating peptides, such as growth hormone releasing hormone (GHRH) and growth hormone releasing factor (GRF), and derivatives and analogs thereof are administered by injection. Therefore, in order to make better use of these positive effects, the focus has been on the development of orally effective therapeutic agents that can increase GH secretion, called GH secretion enhancers (GHS). Furthermore, the use of these materials was expected to mimic the GH physiological pulse release more closely.

  Beginning with the identification of growth hormone-releasing peptide (GHRP) in the late 1970s (Bowers, CY Growth home-releasing peptides: physology and clinical applications. Curr. Opin. 16-1). Ghigo, E .; Arvat, E. Growth hormone-releasing peptides and theair analogs. Front. Neurosci. 1998, 19, 47-72: Locelli, V .; Torsello, o. g owth hormone-releasing peptides.Pharmacol.Res.1997,36,415-423.), a number of substances have been studied for potential to act as their GHS. In addition to the concurrent positive effects associated with stimulating GH release and related effects, GHS is a debilitating disease (cachexia) found in HIV patients and cancer-induced anorexia, musculoskeletal vulnerability in the elderly, As well as useful in a variety of other diseases, including growth hormone deficiency. Much effort over the last 25 years has resulted in a number of potent, orally available GHSs (Isidro, ML; Cordido, F. Groth hormone secretagogues. Comb. Chem. High Throughput Screen. 2006, 9, 9). 178-180; Smith, R.G .; Sun, Y.X .; Beatancourt, L.; Asnicar, M. Growth hormone secretagogues: prospects and pitfalls.Best Pract.Res.Clin.End. 333-347; Fehrentz, J.-A.; Martinez, J.; Boeglin, D .; Deghenghi, R. Growth hormone secretagogues: Past, present and future. IDrugs 2002, 5, 804-814; Svensson, J. Exp. Opin. Ther. Patents 2000, 10, 1071.un. Patch, A.A.; Bach, MA; Murphy, MG; Smith, RG Peptidomimetic growth hormonet secretagogues.Design condensates and therapies. -3127; Ghigo, E; Arbat, E .; (Cannani, F. Originally active growth harmonic secretagogues: state of the art and clinical perspective. Ann. Med. 1998, 30, 159-168.). These include small peptides such as hexarelin (Zentaris) and ipamorelin (Novo Nordisk), and adenosine analogues, as well as capromorelin (Pfizer), L-252,564 (Merck), MK-0677 (Merck), Small molecules such as NN703 (Tabmorelin, Novo Nordisk), G-7203 (Genentech), S-37435 (Kaken) and SM-130868 (Sumitomo) are mentioned. However, clinical trials with such substances have been disappointing due to undesirable side effects, including lack of efficacy in long-term treatment or irreversible inhibition of cytochrome P450 enzymes, among others (Zdravkovic Olse, AK; Christiansen, T .; et al. Eur. J. Clin. Pharmacol. 2003, 58, 683-688.

  The cloning of the human receptor that was actually enabled by the use of synthetic GHS, and the subsequent identification of ghrelin, opened up a variety of new chemistry fields for both agonist and antagonist studies (Carpino, P. et al. A. Exp. Opin. The Patents 2002, 12, 1599-1618). In particular, ghrelin peptides, apart from stimulation of GH release, are available in several other ways, including regulating food intake and appetite, promoting weight gain, controlling energy balance, and regulating gastrointestinal (GI) motility and gastric acid secretion. It was found to have the following physiological functions. This hormone is also involved in the control of glucose homeostasis, circadian cycle and memory. (Van der Lely, A.J .; Tschop, M .; Heiman, ML; Ghigo, E. Biological, physological, pathologicological, and pharmacologic infect. Asakawa, A .; Bowers, C.Y; Mantovani, G.; Laviano, A.; Meguid, M.M.; Fujimiya, M. Ghrelin, appetite, and gastricity: e.g. stomach as an endocrine organ.FASEB J 2004, 18, 439-456; Diano, S. Farr, SA; Benoit, SC; et al. Ghrelin controls hippocampal spine synthesizing density and memory perform. ) These myriad physiological effects have increased studies of ghrelin receptor modulation for therapeutic indices other than those associated with GH secretory function (Dodge, JA; Heiman, M.). L. Ghrelin receptor modulators. Ann. Rep. Med. Chem. 2003, 38, 81-88.). For example, International Patent Applications WO 2006/009645 and WO 2006/009674 describe the use of macrocyclic compounds as ghrelin modulators for the treatment of gastrointestinal (GI) disorders. Similarly, WO 2006/020930 and WO 2006/023608 describe structurally different ghrelin agonists (growth hormone secretagogues) used for such GI disorders. Moreover, International Patent Applications WO 2004/09124 and WO 2005/68639 describe modified viruses derived from a short peptide sequence from the N-terminus of ghrelin that can be used as a vaccine for the treatment of obesity. Particles are described. Another vaccine approach for obesity is described in WO 2004/024183.

  Indeed, like the regulation of numerous peptide hormones and their receptors, the role of ghrelin in the control of appetite and feeding also led to the development of ghrelin antagonists and inverse agonists as novel anti-obesity agents. Special interest was triggered. (Spanwick, D .; Lee, K. Emerging Antiology Drugs. Exp. Opin. Emerging Drugs 2003, 8, 217-237; Horvath, T. L .; Castaneda, T .; Tang-Christen; Tschop, MH Ghrelin as a potential anti-obesity target.Curr.Pharm.Design 2003,9,1383-1395; Crowley, V.E.F.; Yeo, GSH; Rahilly, S. Obesity therapy: altering the energy intact-and-expenditure balance she et. Nat. Rev. Drug Disc. 2002, 1, 276-286.) In contrast to the dominant ghrelin agonists in GHS research, the field of exploratory research on ghrelin antagonists and inverse agonists is significantly less mature. Absent. US Published Patent Application 2003/02111967 and WO 01/87335 address the use of ghrelin antagonists as a treatment for various disease states including obesity and related diseases. Similarly, WO 01/56592 and US 2001/020012 describe the use of antagonists for the control of food intake. Similarly, WO 2004/004772 describes the use of GHS-R antagonists as a treatment for diabetes, obesity and appetite control. Their use for the treatment of enteritis has also been described (WO 2004/084943). However, these applications do not provide examples of specific compounds other than ghrelin peptides and analogs for this purpose. More recently, oxadiazole ghrelin antagonists have been reported (WO 2005/112903), which are also claimed to be effective in improving cognitive, memory and other CNS disorders.

  Ghrelin antagonists and inverse agonists are also associated with obesity related symptoms, including diabetes, complications due to diabetes such as retinopathy, cardiovascular disease, hypertension, dyslipidemia, osteoarthritis and certain types of cancer It is thought to play a role in reducing morbidity. In fact, in addition to the anti-obesity effect seen in animal studies, engineered transgenic rats without the GHS-R1a receptor showed reduced food intake, reduced fat deposition, and reduced body weight. However, hormonal involvement in numerous physiological processes, including control of cardiovascular function and stress response and growth hormone release, may indicate a potential drawback of this strategy. Thus, complete deficiency of ghrelin is undesirable, but suppression may be sufficient to control obesity. Of note, recent studies with ghrelin knockout mice have revealed that these mice do not present alterations in size and food intake among other physiological characteristics. (Sun, Y .; Ahmed, S .; Smith, RG Deletion of ghrelin impairs neigher grow nor appetite. Mol. Cell Biol. 2003, 23, 7793-7981; Wortley, K. er; Garcia, K .; et al. Genetic deletion of ghrelin does not decrease food intake but influens metabolic fuel preferences, 27. Aci.

  Recently, it was reported that BIM- 28163 acts as an antagonist at the GHS-R1a receptor and inhibits receptor activation by natural ghrelin. However, this same molecule is a full agonist in that it stimulates weight gain and food intake. This and related peptidic ghrelin analogs effectively separate GH-regulating activity of ghrelin from the effects of the peptide on weight gain and appetite. (Halem, HA; Taylor, JE; Dong, JZ; Shen, Y .; Datta, R .; Abizaid, A .; Diano, S .; Horvath, T .; Zizzari, P Blue-Pajot, MT-Epelbaum, J .; Culler, MD Novel analogs of ghrelin: physical and clinical implications. Eur. J. Endocrinol. In addition, the macrocyclic ghrelin agonists described in WO 2006/009645 and WO 2006/009674 report a separation of the GI effect from the GH releasing action in animal models. Such separation indicates that the involvement of ghrelin and its receptor in metabolism may be more complex than originally thought.

  Prader-Willi syndrome, the most common form of human symptomatic obesity, has been paradoxically characterized by GH deficiency and high ghrelin levels that do not decrease after feeding. (Cummings, DE; Clement, K .; Purnell, JQ; Vaisse, C .; Foster, KE; Frayo, RS; Schwartz, MW; Basdevant, A .; Weigle, DS Elevated ghrelin plasma levels in Prader-Willi syndrom. Nat. Med. 2002, 8, 643-644.) Antagonists could play a role in the treatment of this syndrome as well. Similarly, such substances can be potentially diabetic bulimia. Bulimia and altered fuel metabolism result from uncontrolled diabetes mellitus in humans. This has been suggested to occur by a combination of elevated ghrelin levels and reduced leptin through the NPY / AGRP pathway. Although ghrelin levels are essentially the same in healthy subjects and diabetic subjects, different levels of ghrelin in diabetic bulimia make dietary survival difficult, and antagonists are useful in helping control. obtain. (Shishi, S .; Kamegai, J .; Tamura, H .; Shimizu, T .; Sugihara, H .; Oikawa, S. Role of ghrelin in streptozotocin-induced diabetic 3, 49. , D.K., Mystkowski, P., Marsh, D.J., Palmiter, R.D .; Schwartz, M. W Attenuation of diabetic hyperpeptide Y-defective3, 78. )

  Ghrelin levels rise in cirrhosis and rise with complications from chronic liver disease, but unlike levels of insulin-like growth factor-1 (IGF-1), they are not associated with liver function. (Brack, E .; Horn, R .; Schoffski, P .; Hecker, H .; Manns, MP; Trautwein, C. Ghrrelin in chronic liver disease. J. (Tacke, F .; Brabant, G .; (Hepatology 2003, 38, 447-454.) Ghrelin antagonists may be useful in the control of these liver diseases. Furthermore, ghrelin and its receptor are overexpressed in many cancers. Antagonists will have potential use in the treatment of cancer. International Patent Application Publication No. WO 02/90387 describes the use of interference strategies targeting GHS-R1a as an approach to the treatment of cancer of the reproductive organs.

  Despite interest in ghrelin antagonists, only a limited number of small molecule ghrelin antagonists have been reported in the patent or scientific literature, including diaminopyrimidine, tetralin carboxamide, isoxazole carboxamide, β-carboline and Oxadiazole is mentioned. (US Patent Application Publication No. 2005/0171131; US Patent Publication No. 2005/0171132; International Patent Application Publication WO 2005/030734; WO 2005/112903; WO 2005/48916; Zhao, H .; Xin, Z .; Schaefer, VG; Falls, HD; Kaszubska, W .; Collins, CA; Sham, HL J. Med. Chem. 2004, 47, 6655- Xhain, Z .; Zhao, H .; Serby, MD; Liu, B.; Schaefer, VG; Falls, HD, Kaszubska, W.; Colins, CA; Sham, HL; Liu, G. Bioorg.Med.Chem.Lett.2005, 1 Zhao, H .; Xin, Z .; Patel, JR, Nelson, T.J .; Liu, B .; Szczepankiewicz, B.G .; Schaefer, VG; Kaszubska, W .; Collins, CA; Sham, HL; Liu, G. Bioorg. Med. Chem. Lett., 2005, 15, 1825-1828; Xin, Z .; Serby, MD; Zhao, H .; Schaefer, V. G., Falls, HD, Kaszubska, W .; Collins, CA; L. Bioorg. Med. Chem. Lett. 2004, 14, 5223-5226.) WO 2005/11. No. 4180 includes a number of individual compounds containing heteroaryl core structures such as isoazoles, 1,2,4-oxadiazoles and 1,2,4-triazoles as “functional ghrelin antagonists”, and their obesity As a therapeutic for the treatment of diabetes and diabetes. Other heterocyclic structures, some of which have shown antagonist activity, are reported in WO 2005/035498; WO 2005/097788 and US 2005/0187237. The remaining known ghrelin antagonists are primarily peptidic in nature (WO 2004/09616, WO 02/08250, WO 03/04518, US 2002/0187938, Pinilla, L .; Barreiro, ML; Tena-Sempere, M .; Aguilar E. Neuroendocrinology 2003, 77, 83-90), nucleic acid-based antagonists are also disclosed (WO 2004/013274; WO 2005/49828; Helling) Maash, C .; Euberg, D., et al. Inhibition of ghrelin action in vitro and in vivo by RNA-Spigee. Mer.Proc.Natl.Acad.Sci USA 2004,101,13174-13179; Shearman, L.P.; Wang, SP; Helmling, S .; et al.Ghrelin neutralization by a ribonucleic acid by SPM. in diet-induced obesity. Endocrinology 2006, 147, 1517-1526). The compounds of the present invention differ structurally from all these previously reported ghrelin antagonist structures.

A small somatostatin mimetic, the 14 amino acid compound vapreotide, has been demonstrated to be a ghrelin antagonist. (Deghenghi R, Papotti M, Ghigo E, Muccioli G, Locatelli V.Somatostatin octapeptides (lanreotide, octreotide, vapreotide, and their analogs) share the growth hormone-releasing peptide receptor in the human pituitary gland.Endocrine 2001,14,29- 33.) The binding activity of cyclic neuropeptide cortisatin analogues to growth hormone secretagogue receptor has been disclosed (WO 03/004518). These compounds exhibit an IC ₅₀ of 24-33 nM. In particular, one of these analogs, EP-01492 (cortisatin 8), is proceeding to preclinical trials for the treatment of obesity as a ghrelin antagonist. (Dehenghi R, Broglio F, Papotti M, et al. Targeting the ghrelin receptor- Originally active GHS and cortistatin analogs. Endocrine, 1.3.18. DeLuca, V .; Rapetti, D.; Locatelli, V.; Netti, C. Evidence for a role of the GHS-R1a receptor in ghretin in thre. 18,1 2-128.)

A limited series of peptides has been reported as ghrelin antagonists containing very specific octanoylated short sequences known to be crucial for binding to GHS-R1a (US patent application). 2002/0187938; international patent application WO 02/08250). [D-Lys ^3] action of -GHRP-6 is described as a ghrelin antagonist. (Pinilla, L .; Barreiro, ML; Tena-Sempere, M .; Aguilar E. Neuroendocrinology 2003, 77, 83-90) More recently, a substance P peptide derivative, L-756, which is a weak ghrelin antagonist 867 (EP-80317, [DArg ¹ , DPhe ⁵ , DTrp ^7,9 , Leu ¹¹ ] -substance P) opens another potential approach to the treatment of obesity targeting the ghrelin receptor It was demonstrated to be a potent inverse agonist (K _{d / i} = 45 nM). (Scholtz, T.W. Constitutive ghrelin receptor activity as a signaling set-point in appetite reregulation. Trends, Col. I., 2004; 25; Ankersen, M.; Schwartz, TW High constitutive signaling of the ghrelin receptor, identification of a potential insol., 210.E.n. Chaung, L.-Y., et al.Inhibition of L-692,429-stimulated rat growth harmony release by a weak substantagonist, L-756, n. 155-158.) However, since this substance also interacts with neurokinin-1 and the bombesin receptor, the use of this particular substance may be limited due to its weak selectivity.

  It has been suggested that the use of inverse agonists may be a more relevant use for the control of appetite due to the high constitutive activity of the ghrelin receptor. (Holday, B .; Holday, N.D .; Bach, A .; Elling, CE; Cox, HM; Schwartz, T. W. Common structural for constitutive for the strength of the energy. J. Biol. Chem. 2004, 279, 53806-53817.) However, other than L-756,867 peptide and a single pyrrole compound, TM27810, (WO 2004/056869), no inverse agonist has been reported yet. . Thus, the compounds of the present invention constitute the first series of identified ghrelin inverse agonist molecules.

  Indeed, it has been argued that it is indeed beneficial to have compounds that act both as ghrelin receptor antagonists and inverse agonists in order to best control feeding (Holst, B. Schwartz, T. Ghrelin). (receptor mutations-too title height and too much hunger. J. Clin. Invest. 2006, 116, 637-641). The recent finding that humans carrying a ghrelin receptor mutation that impairs constitutive activity is short explains the importance of constitutive activity on the normal in vivo function of this receptor. (Pantel, J .; Legendre, M. Cabrol, S .; et al. Loss of constitutive activity of the growth hormone secretegoreceptor in family. 116. Int. As shown in Figure 2, some compounds of the invention act as both ghrelin receptor antagonists and inverse agonists.

  Thus, since there are very few examples of ghrelin antagonists or inverse agonists suitable for pharmacological intervention, there is a need for additional compounds that modulate ghrelin receptors and inhibit ghrelin release.

  The present invention provides novel conformationally defined macrocycles that can function as modulators, particularly antagonists or inverse agonists of the ghrelin (growth hormone secretagogue) receptor (GHS-R1a).

（式中：
ＸはＮＲ₁₃であり、Ｒ₁₃は水素またはＣ_1-4アルキルであるか、またはＲ₁₃およびＲ₂は一緒に３員、４員、５員、６員もしくは７員の複素環を形成し、前記環は、所望によりＯ、ＳもしくはさらなるＮ原子を環中に含み、所望により下に定義されたＲ₈で置換され；
Ｚ₁はＮＲ₁₁であり、Ｒ₁₁は水素またはＣ_1-4アルキルであるか、Ｒ₁₁およびＲ₃は一緒に４員、５員、６員、７員もしくは８員の複素環を形成し、前記環は、所望によりＯ、ＳもしくはさらなるＮ原子を環中に含み、所望により下に定義されたＲ₈で置換され；
Ｚ₂はＮＨであり；
ｍ、ｎおよびｐは、各々０であり；
Ｒ₁およびＲ₆は、各々独立に水素であり；
Ｒ₂は、−（ＣＨ₂）_SＣＨ₃、−ＣＨ（ＣＨ₃）（ＣＨ₂）_tＣＨ₃、−（ＣＨ₂）_uＣＨ（ＣＨ₃）₂、−Ｃ（ＣＨ₃）₃、−（ＣＨ₂）_v−Ｒ₁₄、−ＣＨ（ＯＲ₁₅）ＣＨ₃、シクロアルキル、もしくは置換シクロアルキルであり、ｓは１、２、３、４もしくは５であり；ｔは１、２もしくは３であり；ｕは０、１、２もしくは３であり；かつ、ｖは０、１、２、３もしくは４であり；Ｒ₁₄はアリール、置換アリール、ヘテロアリール、置換ヘテロアリール、シクロアルキルもしくは置換シクロアルキルであり；Ｒ₁₅は水素、アルキル、置換アルキル、シクロアルキル、置換シクロアルキル、複素環、置換複素環、アシル、アミノアシル、スルホニル、カルボキシアルキル、カルボキシアリール、アミド、アリール、置換アリール、ヘテロアリールもしくは置換ヘテロアリールであり；また、あるいは、Ｒ₂およびＲ₁₃は一緒に３員、４員、５員、６員もしくは７員の複素環を形成し、前記環は、所望によりＯ、ＳもしくはさらなるＮ原子を環中に含み、所望により下に定義されたＲ₈で置換され；
Ｒ₃およびＲ₄は、各々独立に−ＣＨ₃、−ＣＨ₂ＣＨ₃、−ＣＨ（ＣＨ₃）₂、−ＣＲ_17aＲ_17b（ＯＲ₁₆）−を含むアミノ酸側鎖または水素であるか；あるいは、Ｒ₃およびＲ₄は一緒に、またはＲ₃およびＲ₇は一緒に、それぞれ、所望によりＯもしくはＳ原子を環中に含み、所望により下に定義されたＲ₈で置換されている３員、４員、５員、６員もしくは７員環を形成し；あるいは、Ｒ₃およびＲ₁₁は一緒に、４員、５員、６員、７員もしくは８員の複素環を形成し、前記環は、所望によりＯ、ＳもしくはさらなるＮ原子を環中に含み、所望により下に定義されたＲ₈で置換され；
Ｒ₁₆は、水素、アルキル、置換アルキル、シクロアルキル、置換シクロアルキル、複素環、置換複素環、アシル、アミノアシル、スルホニル、カルボキシアルキル、カルボキシアリール、アミド、アリール、置換アリール、ヘテロアリールおよび置換ヘテロアリールであり；かつ
Ｒ_17aおよびＲ_17bは、各々独立に、水素、−ＣＨ₃、−ＣＨ₂ＣＨ₃−ＣＨ（ＣＨ₃）₂もしくは−Ｃ（ＣＨ₃）₃であり；
Ｒ₅は、−（ＣＨ₂）_WＣＨ₃、−ＣＨ（ＣＨ₃）（ＣＨ₂）_XＣＨ₃、−（ＣＨ₂）_yＣＨ（ＣＨ₃）₂、−Ｃ（ＣＨ₃）₃、−（ＣＨ₂）_Z1−Ｒ_18a、−（ＣＲ₁₁₀Ｒ₁₁₁）_z2−Ｒ_18bを含むアミノ酸側鎖であり、ｗは、２、３、４もしくは５であり；ｘは、１、２もしくは３であり；ｙは０、１、２もしくは３であり；ｚ１は０、１、２、３もしくは４であり；ｚ２は、０、１もしくは２であり；Ｒ_18aおよびＲ_18bは、各々独立に、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、シクロアルキルおよび置換シクロアルキルであり；Ｒ₁₁₀およびＲ₁₁₁は、各々独立に、水素、Ｃ₁−Ｃ₄アルキル、ヒドロキシル、アミノもしくはフルオロであり（但し、Ｒ₁₁₀およびＲ₁₁₁のうちの少なくとも１つは水素でない）；
Ｒ₇は、水素またはＣ₁−Ｃ₄アルキルであり、またはＲ₇およびＲ₃は一緒に、それぞれ、所望によりＯもしくはＳ原子を環中に含みおよび所望により、下に定義されたＲ₈で置換されている３員、４員、５員、６員もしくは７員環を形成し；
Ｒ₈は、３員、４員、５員、６員もしくは７員の環構造の１個以上の水素原子を置換し、独立に、アルキル、置換アルキル、シクロアルキル、置換シクロアルキル、複素環、置換複素環、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、ヒドロキシ、アルコキシ、アリールオキシ、オキソ、アミノ、ハロゲン、ホルミル、アシル、カルボキシ、カルボキシアルキル、カルボキシアリール、アミド、カルバモイル、グアニジノ、ウレイド、アミジノ、メルカプト、スルフィニル、スルホニルおよびスルホンアミドからなる群から選択されるか、あるいは、Ｒ₈は、隣接する２個の原子に結合する水素原子を置換された、縮合シクロアルキル、置換縮合シクロアルキル、縮合複素環、置換縮合複素環基、縮合アリール、置換縮合アリール、縮合へテロアリールもしくは置換縮合へテロアリール環であり；かつ
Ｔは、式ＩＶの２価の基であり：
−Ｕ−（ＣＨ₂）_d−Ｗ−Ｙ−Ｚ−（ＣＨ₂）_e− （ＩＶ）
（式中、ｄおよびｅは、各々独立に、０、１、２、３、４もしくは５であり；ＹおよびＺは、各々所望により存在し；Ｕは、−ＣＲ₂₁Ｒ₂₂−、または−Ｃ（＝Ｏ）−であり、式ＩのＸと結合しており；Ｗ、ＹおよびＺは、各々、−Ｏ−、−ＮＲ₂₃−、−Ｓ−、−ＳＯ−、−ＳＯ₂−、−Ｃ（＝Ｏ）−Ｏ−、−Ｏ−Ｃ（＝Ｏ）−、−Ｃ（＝Ｏ）−ＮＨ−、−ＮＨ−Ｃ（＝Ｏ）−、−ＳＯ₂−ＮＨ−、−ＮＨ−ＳＯ₂−、−ＣＲ₂₄Ｒ₂₅−、ＺもしくはＥ配置の−ＣＨ＝ＣＨ−、−Ｃ≡Ｃ−、または下記の環構造：

（式中、Ｇ₁およびＧ₂は、各々独立に、共有結合、または−Ｏ−、−ＮＲ₃₉−、−Ｓ−、−ＳＯ−、−ＳＯ₂−、−Ｃ（＝Ｏ）−、−Ｃ（＝Ｏ）−Ｏ−、−Ｏ−Ｃ（＝Ｏ）−、−Ｃ（＝Ｏ）ＮＨ−、−ＮＨ−Ｃ（＝Ｏ）−、−ＳＯ₂−ＮＨ−、−ＮＨ−ＳＯ₂−、−ＣＲ₄₀Ｒ₄₁−、ＺもしくはＥ配置の−ＣＨ＝ＣＨ−、および−Ｃ≡Ｃ−からなる群から選択される２価の基であり；Ｇ₁は基Ｕに最も近くで結合している；環中の任意の炭素原子は、別に定義されていなければ、所望によりＮに置き換えられる（但し、この環はＮ原子を４個より多く含むことはできない）；Ｋ₁、Ｋ₂、Ｋ₃、Ｋ₄およびＫ₅は、各々独立に、Ｏ、ＮＲ₄₂もしくはＳであり、Ｒ₄₂は下に定義される）；
Ｒ₂₁およびＲ₂₂は、各々独立に、水素、低級アルキル、もしくは置換低級アルキルであるか、または、Ｒ₂₁およびＲ₂₂は一緒に、所望によりＯ、ＳおよびＮからなる群から選択される１個以上のヘテロ原子を含む３員〜１２員の環状環を形成し、前記環は、所望により既に定義されたＲ₈で置換され；
Ｒ₂₃、Ｒ₃₉およびＲ₄₂は、各々独立に、水素、アルキル、置換アルキル、シクロアルキル、置換シクロアルキル、複素環、置換複素環、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、ホルミル、アシル、カルボキシアルキル、カルボキシアリール、アミド、アミジノ、スルホニルもしくはスルホンアミドであり；
Ｒ₂₄およびＲ₂₅は、各々独立に、水素、低級アルキル、置換低級アルキル、Ｒ_AAであり、Ｒ_AAは一般的もしくは珍しいアミノ酸の側鎖であるか、または、Ｒ₂₄およびＲ₂₅は一緒に、所望によりＯ、ＳおよびＮからなる群から選択される１個以上のヘテロ原子を含む３員〜１２員の環状環を形成し；または、Ｒ₂₄およびＲ₂₅のうちの一方はヒドロキシ、アルコキシ、アリールオキシ、アミノ、メルカプト、カルバモイル、アミジノ、ウレイドもしくはグアニジノであり、もう一方は水素、低級アルキルもしくは置換低級アルキルであり（Ｒ₂₄およびＲ₂₅が結合している炭素も別のヘテロ原子と結合している場合は除く）；
Ｒ₂₆は所望により存在し、存在する場合、示された環の１個以上の水素原子を置換し、各々独立に、ハロゲン、トリフルオロメチル、アルキル、置換アルキル、シクロアルキル、置換シクロアルキル、複素環、置換複素環、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、ヒドロキシ、アルコキシ、アリールオキシ、アミノ、ホルミル、アシル、カルボキシ、カルボキシアルキル、カルボキシアリール、アミド、カルバモイル、グアニジノ、ウレイド、アミジノ、シアノ、ニトロ、メルカプト、スルフィニル、スルホニルおよびスルホンアミドからなる群から選択され；
Ｒ₂₇は所望により存在し、存在する場合、示された環の１個以上の水素原子を置換し、各々独立に、アルキル、置換アルキル、シクロアルキル、置換シクロアルキル、複素環、置換複素環、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、ヒドロキシ、アルコキシ、アリールオキシ、オキソ、アミノ、ホルミル、アシル、カルボキシ、カルボキシアルキル、カルボキシアリール、アミド、カルバモイル、グアニジノ、ウレイド、アミジノ、メルカプト、スルフィニル、スルホニルおよびスルホンアミドからなる群から選択され；
Ｒ₂₈、Ｒ₂₉、Ｒ₃₀、Ｒ₃₂、Ｒ₃₃、Ｒ₃₄、Ｒ₃₆およびＲ₃₇は、各々所望により存在し、環中で結合している炭素原子に二重結合が存在しない場合、所望により２個の基が存在し、存在する場合、環に存在する１個の水素を置換し、または、環中で結合している炭素原子に二重結合が存在しない場合、環に存在する２個の水素原子のうちの１個または両方を置換し、各々は独立にアルキル、置換アルキル、シクロアルキル、置換シクロアルキル、複素環、置換複素環、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、ヒドロキシ、アルコキシ、アリールオキシ、オキソ、アミノ、ホルミル、アシル、カルボキシ、カルボキシアルキル、カルボキシアリール、アミド、カルバモイル、グアニジノ、ウレイド、アミジノ、メルカプト、スルフィニル、スルホニル、スルホンアミドおよび、結合している炭素原子に二重結合が存在する場合のみハロゲン、からなる群から選択され；
Ｒ₃₁、Ｒ₃₅およびＲ₃₈は、各々所望により存在し、存在する場合、示された環の１個以上の水素原子を置換し、各々独立に、ハロゲン、トリフルオロメチル、アルキル、置換アルキル、シクロアルキル、置換シクロアルキル、複素環、置換複素環、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、ヒドロキシ、アルコキシ、アリールオキシ、アミノ、ホルミル、アシル、カルボキシ、カルボキシアルキル、カルボキシアリール、アミド、カルバモイル、グアニジノ、ウレイド、アミジノ、シアノ、ニトロ、メルカプト、スルフィニル、スルホニルおよびスルホンアミドからなる群から選択され；かつ
Ｒ₄₀およびＲ₄₁は各々独立に、水素、低級アルキル、置換低級アルキル、上記定義のＲ_AAであるか、またはＲ₄₀およびＲ₄₁は一緒に、所望によりＯ、ＳおよびＮからなる群から選択される１個以上のヘテロ原子を含む３員〜１２員の環状環を形成し、前記環は、所望により既に定義されたＲ₈で置換された、あるいは、Ｒ₄₀およびＲ₄₁のうちの一方はヒドロキシ、アルコキシ、アリールオキシ、アミノ、メルカプト、カルバモイル、アミジノ、ウレイドもしくはグアニジノ、もう一方は水素、低級アルキルもしくは置換低級アルキルである（Ｒ₄₀およびＲ₄₁が結合している炭素も別のヘテロ原子と結合している場合は除く）；
但し、Ｔは、アミノ酸残基、ジペプチド断片、トリペプチド断片または標準アミノ酸を含む高次ペプチド断片ではない。）
による化合物またはその光学異性体、エナンチオマー、ジアステレオマー、ラセミ化合物あるいは立体化学混合物に関する。 According to an aspect of the present invention, the present invention provides compounds of formula (I):

(Where:
X is NR ₁₃ and R ₁₃ is hydrogen or C _1-4 alkyl, or R ₁₃ and R ₂ together form a 3-, 4-, 5-, 6- or 7-membered heterocycle. The ring optionally contains O, S or an additional N atom in the ring, optionally substituted with R ₈ as defined below;
Z ₁ is NR ₁₁ and R ₁₁ is hydrogen or C _1-4 alkyl, or R ₁₁ and R ₃ together form a 4-membered, 5-membered, 6-membered, 7-membered or 8-membered heterocyclic ring. The ring optionally contains O, S or an additional N atom in the ring, optionally substituted with R ₈ as defined below;
Z ₂ is NH;
m, n and p are each 0;
R ₁ and R ₆ are each independently hydrogen;
R ₂ represents — (CH ₂ ) _S CH ₃ , —CH (CH ₃ ) (CH ₂ ) _t CH ₃ , — (CH ₂ ) _u CH (CH ₃ ) ₂ , —C (CH ₃ ) ₃ , — ( _{CH 2) v -R 14, -CH} (oR 15) CH 3, cycloalkyl or substituted cycloalkyl,, s is 3, 4 or 5; t is 1, 2 or 3 U is 0, 1, 2 or 3; and v is 0, 1, 2, 3 or 4; R ₁₄ is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl or substituted cycloalkyl; R ₁₅ is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, acyl, aminoacyl, sulfonyl, carboxyalkyl, carboxyaryl, amide, aryl, substituted aryl, hete Alternatively, R ₂ and R ₁₃ together form a 3-membered, 4-membered, 5-membered, 6-membered or 7-membered heterocyclic ring, said ring optionally comprising O, S Or an additional N atom in the ring, optionally substituted with R ₈ as defined below;
R ₃ and R ₄ are each independently an amino acid side chain or hydrogen comprising —CH ₃ , —CH ₂ CH ₃ , —CH (CH ₃ ) ₂ , —CR _17a R _17b (OR ₁₆ ) —; or , R ₃ and R ₄ together, or R ₃ and R ₇ together, each optionally containing an O or S atom in the ring, optionally substituted with R ₈ as defined below A 4-membered, 5-membered, 6-membered or 7-membered ring; or R ₃ and R ₁₁ together form a 4-membered, 5-membered, 6-membered, 7-membered or 8-membered heterocyclic ring, The ring optionally contains O, S or an additional N atom in the ring, optionally substituted with R ₈ as defined below;
R ₁₆ is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, acyl, aminoacyl, sulfonyl, carboxyalkyl, carboxyaryl, amide, aryl, substituted aryl, heteroaryl and substituted heteroaryl And R _17a and R _17b are each independently hydrogen, —CH ₃ , —CH ₂ CH ₃ —CH (CH ₃ ) ₂ or —C (CH ₃ ) ₃ ;
R _{5 is, - (CH 2) W CH} 3, -CH (CH 3) (CH 2) X CH 3, - (CH 2) y CH (CH 3) 2, -C (CH 3) 3, - ( _{CH 2) Z1 -R 18a, -} (CR 110 R 111) is an amino acid side chain comprising _z2 -R _18b, w is an 2, 3, 4 or 5; x is 1, 2 or 3 Y is 0, 1, 2 or 3; z1 is 0, 1, 2, 3 or 4; z2 is 0, 1 or 2; and R _18a and R _18b are each independently aryl , Substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl and substituted cycloalkyl; R ₁₁₀ and R ₁₁₁ are each independently hydrogen, C ₁ -C ₄ alkyl, hydroxyl, amino or fluoro, provided that At least one of R ₁₁₀ and R ₁₁₁ is not hydrogen);
R ₇ is hydrogen or C ₁ -C ₄ alkyl, or R ₇ and R ₃ together each optionally contain an O or S atom in the ring and optionally at R ₈ as defined below Forming a substituted 3-, 4-, 5-, 6- or 7-membered ring;
R ₈ replaces one or more hydrogen atoms of a 3-membered, 4-membered, 5-membered, 6-membered or 7-membered ring structure, and is independently alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, Substituted heterocycle, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hydroxy, alkoxy, aryloxy, oxo, amino, halogen, formyl, acyl, carboxy, carboxyalkyl, carboxyaryl, amide, carbamoyl, guanidino, ureido, amidino R ₈ is selected from the group consisting of, mercapto, sulfinyl, sulfonyl and sulfonamide, or R ₈ is a condensed cycloalkyl, substituted condensed cycloalkyl, condensed, substituted with hydrogen atoms bonded to two adjacent atoms Heterocycle, substituted fused heterocyclic group, fused aryl, substituted fused aryl A reel, a fused heteroaryl or substituted fused heteroaryl ring; and T is a divalent group of formula IV:
_{-U- (CH 2) d -W-} Y-Z- (CH 2) e - (IV)
Wherein d and e are each independently 0, 1, 2, 3, 4 or 5; Y and Z are each optionally present; U is —CR ₂₁ R ₂₂ —, or — C (═O) — and bonded to X of formula I; W, Y and Z are each —O—, —NR ₂₃ —, —S—, —SO—, —SO ₂ —, —C (═O) —O—, —O—C (═O) —, —C (═O) —NH—, —NH—C (═O) —, —SO ₂ —NH—, —NH—. SO ₂ —, —CR ₂₄ R ₂₅ —, —CH═CH—, —C≡C— in the Z or E configuration, or the following ring structure:

Wherein G ₁ and G ₂ are each independently a covalent bond, or —O—, —NR ₃₉ —, —S—, —SO—, —SO ₂ —, —C (═O) —, — C (═O) —O—, —O—C (═O) —, —C (═O) NH—, —NH—C (═O) —, —SO ₂ —NH—, —NH—SO ₂ A divalent group selected from the group consisting of —, —CR ₄₀ R ₄₁ —, —CH═CH— in the Z or E configuration, and —C≡C—; G ₁ is the closest bond to the group U Any carbon atom in the ring, unless otherwise defined, is optionally replaced by N (provided that the ring cannot contain more than 4 N atoms); K ₁ , K ₂ , K ₃ , K ₄ and K ₅ are each independently O, NR ₄₂ or S, and R ₄₂ is defined below);
R ₂₁ and R ₂₂ are each independently hydrogen, lower alkyl, or substituted lower alkyl, or R ₂₁ and R ₂₂ together are optionally selected from the group consisting of O, S and N Forming a 3- to 12-membered cyclic ring containing one or more heteroatoms, said ring optionally being substituted with R ₈ as defined above;
R ₂₃ , R ₃₉ and R ₄₂ are each independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, aryl, substituted aryl, heteroaryl, substituted heteroaryl, formyl, acyl , Carboxyalkyl, carboxyaryl, amide, amidino, sulfonyl or sulfonamide;
R ₂₄ and R ₂₅ are each independently hydrogen, lower alkyl, substituted lower alkyl, R _AA , R _AA is a common or unusual amino acid side chain, or R ₂₄ and R ₂₅ together Optionally forms a 3- to 12-membered cyclic ring containing one or more heteroatoms selected from the group consisting of O, S and N; or one of R ₂₄ and R ₂₅ is hydroxy, alkoxy , Aryloxy, amino, mercapto, carbamoyl, amidino, ureido or guanidino, the other being hydrogen, lower alkyl or substituted lower alkyl (the carbon to which R ₂₄ and R ₂₅ are bound is also bound to another heteroatom Except when)
R ₂₆ is optionally present and, when present, replaces one or more hydrogen atoms of the indicated ring, each independently of halogen, trifluoromethyl, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic Ring, substituted heterocycle, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hydroxy, alkoxy, aryloxy, amino, formyl, acyl, carboxy, carboxyalkyl, carboxyaryl, amide, carbamoyl, guanidino, ureido, amidino, cyano Selected from the group consisting of nitro, mercapto, sulfinyl, sulfonyl and sulfonamide;
R ₂₇ is optionally present and, when present, replaces one or more hydrogen atoms of the indicated ring, each independently alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, Aryl, substituted aryl, heteroaryl, substituted heteroaryl, hydroxy, alkoxy, aryloxy, oxo, amino, formyl, acyl, carboxy, carboxyalkyl, carboxyaryl, amide, carbamoyl, guanidino, ureido, amidino, mercapto, sulfinyl, sulfonyl And selected from the group consisting of sulfonamides;
R ₂₈ , R ₂₉ , R ₃₀ , R ₃₂ , R ₃₃ , R ₃₄ , R ₃₆ and R ₃₇ are each optionally present, and are desired if there is no double bond at the carbon atom bonded in the ring. 2 groups are present, if present, replace one hydrogen present in the ring, or if there is no double bond at the carbon atom bonded in the ring, 2 present in the ring One or both of the hydrogen atoms are substituted, each independently alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, aryl, substituted aryl, heteroaryl, substituted heteroaryl, Hydroxy, alkoxy, aryloxy, oxo, amino, formyl, acyl, carboxy, carboxyalkyl, carboxyaryl, amide, carbamoyl, guanidino, ureido, amidino, merca DOO, sulfinyl, sulfonyl, sulfonamido and halogen only when the double bond to a carbon atom bound to exist, is selected from the group consisting of;
R ₃₁ , R ₃₅ and R ₃₈ are each optionally present, and when present, replace one or more hydrogen atoms of the indicated ring, each independently halogen, trifluoromethyl, alkyl, substituted alkyl, Cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hydroxy, alkoxy, aryloxy, amino, formyl, acyl, carboxy, carboxyalkyl, carboxyaryl, amide, carbamoyl , Guanidino, ureido, amidino, cyano, nitro, mercapto, sulfinyl, sulfonyl and sulfonamide; and R ₄₀ and R ₄₁ are each independently hydrogen, lower alkyl, substituted lower alkyl, R as defined above whether it is _AA or R ₄₀ and R _41, Together, optionally O, to form a cyclic ring of 3-membered to 12-membered containing one or more heteroatoms selected from the group consisting of S and N, said ring in R ₈ previously defined optionally Substituted or one of R ₄₀ and R ₄₁ is hydroxy, alkoxy, aryloxy, amino, mercapto, carbamoyl, amidino, ureido or guanidino, the other is hydrogen, lower alkyl or substituted lower alkyl (R _The carbon to which ₄₀ and R ₄₁ are bonded is also bonded to another heteroatom);
However, T is not an amino acid residue, a dipeptide fragment, a tripeptide fragment or a higher order peptide fragment containing standard amino acids. )
Or an optical isomer, enantiomer, diastereomer, racemate or stereochemical mixture thereof.

  A further aspect of the invention provides a pharmaceutical composition comprising (a) a compound of the invention; and (b) a pharmaceutically acceptable carrier, excipient or diluent.

  A further aspect of the invention provides a kit comprising one or more containers containing a pharmaceutical dosage unit containing an effective amount of one or more compounds of the invention and packaged with optional instructions for its use.

  In a further aspect, the present invention provides a method of modulating GHS-R1a receptor activity in a mammal comprising administering an effective GHS-R1a receptor activity modulating amount of a compound of the present invention. According to some aspects of the invention, an effective GHS-R1a receptor activity modulating amount of a compound does not result in a significant amount of growth hormone release. According to another aspect, the compound is a ghrelin receptor antagonist or a GHS-R1a receptor antagonist. In yet another aspect, the compound is a ghrelin receptor inverse agonist or a GHS-R1a receptor inverse agonist. According to another aspect of the invention, the compound is also a ghrelin receptor antagonist, a ghrelin receptor inverse agonist, or a GHS-R1a receptor antagonist, and a GHS-R1a receptor inverse agonist.

  Aspects of the invention further relate to methods for preventing and / or treating diseases such as metabolic and / or endocrine disorders, cardiovascular diseases, genetic diseases, hyperproliferative disorders and inflammatory diseases.

  A further aspect of the invention relates to a method of making a compound of formula I.

  The present invention also relates to compounds of formula I useful for the preparation of a medicament for the prevention and / or treatment of the diseases described herein.

  The foregoing and other aspects of the invention are described in more detail in the specification set forth below.

  The foregoing and other aspects of the present invention will now be described in more detail with respect to other embodiments described herein. Of course, the present invention may be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.

  The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used in the description of the present invention and the appended claims, the singular forms “a”, “an”, and “the” are intended to include the plural forms as well, unless expressly stated otherwise in the text. . Further, as used herein, the term “and / or” includes any and all combinations of one or more of the associated listed items and is abbreviated as “/”.

  Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

  All publications, US patent applications, US patents and other references mentioned herein are hereby incorporated by reference in their entirety.

  The term “alkyl” refers to a straight or branched chain saturated or partially unsaturated hydrocarbon group having 1 to 20 carbon atoms, and optionally 1 to 8 carbon atoms. The term “lower alkyl” refers to an alkyl group containing 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, isopropyl, tert-butyl, 3-hexenyl, and 2-butynyl. “Unsaturated” means that there are 1, 2 or 3 double bonds or triple bonds, or a combination of the two. Such alkyl groups may also be optionally substituted as described below.

When a subscript is used in reference to an alkyl or other hydrocarbon group as defined herein, the subscript refers to the number of carbon atoms that the group can contain. For example, C ₂ -C ₄ alkyl represents a 2, 3 or 4 alkyl groups containing carbon atoms.

  The term “cycloalkyl” refers to a saturated or partially unsaturated cyclic hydrocarbon group having 3 to 15 and optionally 3 to 7 carbon atoms in the ring, as well as said cyclic hydrocarbon Refers to an alkyl group containing a group. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopropylmethyl, cyclopentyl, 2- (cyclohexyl) ethyl, cycloheptyl, and cyclohexenyl. Cycloalkyl as defined herein also includes groups having multiple carbocycles, each of which is saturated or partially unsaturated, such as decalinyl, [2.2.1]. -May be bicycloheptanyl or adamantanyl. Any such cycloalkyl group may be optionally substituted as described below.

  The term “aromatic” refers to an unsaturated cyclic hydrocarbon group having a conjugated π electron system containing 4n + 2 (n is an integer greater than or equal to 1) electrons. Aromatic molecules are generally stable and are represented as planar atomic rings having a resonant structure consisting of alternating double and single bonds, such as benzene or naphthalene.

  The term “aryl” refers to an aromatic group of a single carbocyclic or fused carbocyclic ring system having 6 to 15, and optionally 6 to 10 ring atoms, as well as the aromatic Refers to an alkyl group containing a group. Examples of aryl groups include, but are not limited to, phenyl, 1-naphthyl, 2-naphthyl and benzyl. In addition, aryl as defined herein includes groups having multiple aryl rings, each of which may be condensed such as naphthyl and anthracenyl, or condensed such as biphenyl and terphenyl. It does not have to be. Aryl is also a bicyclic or tricyclic carbocycle in which one of the rings is aromatic and the other is saturated, partially unsaturated or aromatic, such as indanyl or tetrahydronaphthyl ( Tetralinyl). Any such aryl group may be optionally substituted as described below.

  The term “heterocycle” or “heterocyclic” refers to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring having 3 to 15 and optionally 3 to 7 atoms. A group of formula wherein at least one of the rings comprises at least one heteroatom, wherein the heteroatom is selected from O, S or N. Each ring of the heterocyclic group has one or two O atoms, one or two if the total number of heteroatoms in each ring is 4 or less and each ring contains at least one carbon atom Of S atoms and 1-4 N atoms. The fused ring that completes the bicyclic or tricyclic heterocyclic group may contain only carbon atoms and may be saturated or partially unsaturated. N and S atoms may be optionally oxidized, and N atoms may be quaternized if desired. Heterocyclic also refers to an alkyl group containing the monocyclic, bicyclic or tricyclic heterocyclic group. Examples of heterocycles include, but are not limited to, 2- or 3-piperidinyl, 2- or 3-piperazinyl, 2- or 3-morpholinyl. Any such heterocyclic group may be optionally substituted as described below.

  The term “heteroaryl” is an aromatic group of a single or fused ring system having 5 to 15 and optionally 5 to 10 ring atoms, wherein at least one ring of said rings Having at least one heteroatom, wherein the heteroatom is selected from O, S or N. Each ring of the heteroaryl group has 1 or 2 O atoms, 1 or 2 if the total number of heteroatoms in each ring is 4 or less and each ring contains at least 1 carbon atom Of S atoms and 1-4 N atoms. The fused ring that completes a bicyclic or tricyclic group may contain only one carbon atom and may be saturated or partially unsaturated or aromatic. In structures where the lone pair of nitrogen atoms is not involved in completing the aromatic pi-electron system, the N atom may be quaternized or oxidized to N-oxide as desired. Heteroaryl also refers to an alkyl group containing the cyclic group. Examples of monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl And triazinyl. Examples of bicyclic heteroaryl groups include, but are not limited to, indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, isobenzofuranyl Nyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, purinyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, dihydroisoindolyl, and tetrahydroquinolinyl. Examples of tricyclic heteroaryl groups include, but are not limited to, carbazolyl, benzoindolyl, phenanthrolinyl, acridinyl, phenanthridinyl, and xanthenyl. Any such heteroaryl group may be optionally substituted as described below.

  The term “hydroxy” refers to an —OH group.

The term “alkoxy” refers to the group —OR _a , where R _a is alkyl, cycloalkyl or heterocycle. Examples include, but are not limited to, methoxy, ethoxy, tert-butoxy, cyclohexyloxy, and tetrahydropyranyloxy.

The term “aryloxy” refers to the group —OR _b , where R _b is aryl or heteroaryl. Examples include, but are not limited to, phenoxy, benzyloxy and 2-naphthyloxy.

The term “acyl” refers to the group —C (═O) —R _c , where R _c is alkyl, cycloalkyl, heterocycle, aryl or heteroaryl. Examples include but are not limited to acetyl, benzoyl and furoyl.

  The term “aminoacyl” refers to an acyl group derived from an amino acid.

The term “amino” refers to the group —NR _d R _e , wherein R _d and R _e are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycle, aryl and heteroaryl. Alternatively, R _d and R _e together are optionally substituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocycle, unsubstituted aryl, unsubstituted heteroaryl, hydroxy, alkoxy, aryloxy, acyl, amino, amide, carboxy Substituted with, carboxyalkyl, carboxyaryl, mercapto, sulfinyl, sulfonyl, sulfonamido, amidino, carbamoyl, guanidino or ureido, optionally containing 1 to 3 additional heteroatoms selected from O, S or N To form a 3- to 8-membered heterocyclic ring.

The term “amide” refers to the group —C (═O) —NR _f R _g , wherein R _f and R _g are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycle, aryl and heteroaryl. Point to. Alternatively, R _f and R _g are optionally taken together as unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocycle, unsubstituted aryl, unsubstituted heteroaryl, hydroxy, alkoxy, aryloxy, acyl, amino, amide, 1-3 additional heteroatoms substituted with carboxy, carboxyalkyl, carboxyaryl, mercapto, sulfinyl, sulfonyl, sulfonamido, amidino, carbamoyl, guanidino or ureido, optionally selected from O, S, or N Contains a 3- to 8-membered heterocyclic ring.

The term “amidino” is selected from the group wherein R _h is hydrogen, alkyl, cycloalkyl, heterocycle, aryl and heteroaryl; and R _i and R _j are independently hydrogen, alkyl, cycloalkyl, heterocycle, Refers to a —C (═NR _h ) NR _i R _j group selected from the group consisting of aryl and heteroaryl. Alternatively, R _i and R _j are optionally taken together as unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocycle, unsubstituted aryl, unsubstituted heteroaryl, hydroxy, alkoxy, aryloxy, acyl, amino, amide, 1-3 additional heteroatoms substituted with carboxy, carboxyalkyl, carboxyaryl, mercapto, sulfinyl, sulfonyl, sulfonamido, amidino, carbamoyl, guanidino or ureido, optionally selected from O, S, or N Contains a 3- to 8-membered heterocyclic ring.

The term “carboxy” refers to the group —CO ₂ H.

The term “carboxyalkyl” refers to the group —CO ₂ R _k , where R _k is alkyl, cycloalkyl, or heterocyclic.

The term “carboxyaryl” refers to the group —CO ₂ R _m , where R _m is aryl or heteroaryl.

  The term “cyano” refers to a —CN group.

  The term “formyl” refers to the group —C (═O) H, also denoted —CHO.

  The term “halo”, “halogen” or “halide” refers to fluoro, fluorine or fluoride, chloro, chlorine or chloride, bromo, bromine or bromide, and iodo, iodine or iodide, respectively.

  The term “oxo” refers to a divalent ═O group that is substituted in place of two hydrogen atoms on the same carbon to form a carbonyl group.

The term “mercapto” refers to the group —SR _n , where R _n is hydrogen, alkyl, cycloalkyl, heterocycle, aryl or heteroaryl.

The term “nitro” refers to the —NO ₂ group.

The term “trifluoromethyl” refers to the group —CF ₃ .

The term “sulfinyl” refers to the group —S (═O) R _p , where R _p is alkyl, cycloalkyl, heterocycle, aryl or heteroaryl.

The term “sulfonyl” refers to the group —S (═O) ₂ —R _q1 , wherein R _q1 is alkyl, cycloalkyl, heterocycle, aryl or heteroaryl.

The term “aminosulfonyl” refers to —NR _q2 where R _q2 is hydrogen, alkyl, cycloalkyl, heterocycle, aryl or heteroaryl; and R _q3 is alkyl, cycloalkyl, heterocycle, aryl or heteroaryl. —S (═O) ₂ —R _q3 group.

The term “sulfonamido” refers to the group —S (═O) ₂ —NR _r R _s , where R _r and R _s are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycle, aryl or heteroaryl. Point to. Alternatively, R _r and R _s are optionally taken together as unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocycle, unsubstituted aryl, unsubstituted heteroaryl, hydroxy, alkoxy, aryloxy, acyl, amino, amide, 1-3 additional heteroatoms substituted with carboxy, carboxyalkyl, carboxyaryl, mercapto, sulfinyl, sulfonyl, sulfonamido, amidino, carbamoyl, guanidino or ureido, optionally selected from O, S, or N Contains a 3- to 8-membered heterocyclic ring.

The term “carbamoyl” has the formula — wherein R _t is selected from hydrogen, alkyl, cycloalkyl, heterocycle, aryl or heteroaryl; and R _u is selected from alkyl, cycloalkyl, heterocycle, aryl or heteroaryl. N (R _t ) —C (═O) —OR _u group.

The term “guanidino” has the formula —N (R _v ) —C (═, wherein R _v , R _w , R _x and R _y are independently selected from hydrogen, alkyl, cycloalkyl, heterocycle, aryl or heteroaryl. NR _w ) —NR _x R _y . Alternatively, R _x and R _y are optionally taken together as unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocycle, unsubstituted aryl, unsubstituted heteroaryl, hydroxy, alkoxy, aryloxy, acyl, amino, amide, 1-3 additional heteroatoms substituted with carboxy, carboxyalkyl, carboxyaryl, mercapto, sulfinyl, sulfonyl, sulfonamido, amidino, carbamoyl, guanidino or ureido, optionally selected from O, S, or N Contains a 3- to 8-membered heterocyclic ring.

The term “ureido” has the formula —N (R _z ) —C (═O) —, wherein R _z , R _aa and R _bb are independently selected from hydrogen, alkyl, cycloalkyl, heterocycle, aryl or heteroaryl. Refers to the group NR _aa R _bb . Alternatively, R _aa and R _bb , together with the nitrogen atom to which they are each attached, optionally, unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocycle, unsubstituted aryl, unsubstituted heteroaryl, hydroxy, Substituted with alkoxy, aryloxy, acyl, amino, amide, carboxy, carboxyalkyl, carboxyaryl, mercapto, sulfinyl, sulfonyl, sulfonamide, amidino, carbamoyl, guanidino or ureido, optionally selected from O, S, or N To form a 3 to 8 membered heterocycle containing 1 to 3 additional heteroatoms.

  The term “optionally substituted” is intended to explicitly indicate that a particular group is unsubstituted or substituted with one or more suitable substituents, provided that Optional substituents are excluded where specified, in which case the term indicates that the group is unsubstituted or substituted with the specified substituent. As defined above, various groups are unsubstituted or substituted unless otherwise indicated herein (eg, by indicating that the particular group is unsubstituted). (Ie they are optionally substituted).

The term “substituted” when used with the terms alkyl, cycloalkyl, heterocycle, aryl and heteroaryl independently refers to unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocycle, unsubstituted aryl , Unsubstituted heteroaryl, hydroxy, alkoxy, aryloxy, acyl, amino, amide, carboxy, carboxyalkyl, carboxyaryl, halo, oxo, mercapto, sulfinyl, sulfonyl, sulfonamide, amidino, carbamoyl, guanidino, ureido and formula- _{NR cc C (= O) R} dd, -NR ee C (= NR ff) R gg, -OC (= O) NR hh R ii, -OC (= O) R jj, -OC (= O) OR kk , —NR _mm SO ₂ R _nn , or —NR _pp SO ₂ NR _qq R _rr , wherein R _cc , R _dd , R _ee , R _ff , R _gg , R _hh , R _ii , R _jj , R _mm , R _pp , R _qq and R _rr are independently hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocycle, unsubstituted aryl or Selected from unsubstituted heteroaryl; and R _kk and R _nn are independently selected from unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocycle, unsubstituted aryl, or unsubstituted heteroaryl An alkyl, cycloalkyl, heterocycle, aryl or heteroaryl group substituted with one or more hydrogen atoms by a group. Alternatively, R _gg and R _hh , R _jj and R _kk or R _pp and NR _qq are optionally substituted with unsubstituted nitrogen, unsubstituted cycloalkyl, unsubstituted heterocycle, together with the nitrogen atom to which they are attached, respectively. Substituted with unsubstituted aryl, unsubstituted heteroaryl, hydroxy, alkoxy, aryloxy, acyl, amino, amide, carboxy, carboxyalkyl, carboxyaryl, mercapto, sulfinyl, sulfonyl, sulfonamide, amidino, carbamoyl, guanidino or ureido Optionally forming a 3 to 8 membered heterocycle containing 1 to 3 further heteroatoms selected from O, S or N. Furthermore, the term “substituted” for aryl and heteroaryl groups includes the option of replacing one of the hydrogen atoms with cyano, nitro or trifluoromethyl.

  Substitutions are made when the standard valence of any atom is not exceeded and the substitution results in a stable compound. In general, when a substituted form of a group is present, such substituted group may not be further substituted, and if so substituted, the substituent may contain a limited number of substituted groups. (E.g. 1, 2, 3 or 4 such substituents).

  If any variable occurs more than one time in any component or any expression herein, its definition at each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and / or variables are allowed only if such a combination results in a stable compound.

  By “stable compound” or “stable structure” is meant a compound that is sufficiently stable to be isolated to a useful degree of purity and formulated into an effective therapeutic agent.

  The term “amino acid” refers to normal natural (gene-encoded) amino acids or synthetic amino acids and their normal derivatives known to those skilled in the art. As used for amino acids, “standard” or “protein organization” refers to the 20 amino acids in their natural configuration, encoded by a gene. Similarly, when used with amino acids, “non-natural” or “abnormal” refers to non-natural, rare or synthetic amino acids, such as Hunt, S. et al. in Chemistry and Biochemistry of the Amino Acids, Barrett, G .; C. Ed. , Chapman and Hall: New York, 1985.

（式中、Ｒ_AAは、アミノ酸側鎖であり、この場合ｎ＝０、１または２である）
の基を指す。 The term “residue” with respect to amino acids or amino acid derivatives has the formula:

(Wherein R _AA is an amino acid side chain, where n = 0, 1, or 2)
Refers to the group of

  The term “fragment” with respect to a dipeptide, tripeptide or higher order peptide derivative refers to a group comprising two, three or more amino acid residues, respectively.

The term “amino acid side chain” refers to any side chain of a standard or unnatural amino acid and is denoted by R _AA −. For example, the side chain of alanine is methyl, the side chain of valine is isopropyl, and the side chain of tryptophan is 3-indolylmethyl.

  The term “agonist” refers to a compound that reproduces at least some of the effects of an endogenous ligand such as a protein, receptor, enzyme, and the like.

  The term “antagonist” refers to a compound that inhibits at least some of the effects of endogenous ligands such as proteins, receptors, enzymes and the like.

  The term “inverse agonist” refers to a compound that reduces the functional activity of a baseline of a protein, receptor, enzyme, etc., such as the constitutive signaling activity of a G protein coupled receptor or variant thereof, at least to some extent. Inverse agonists can also be antagonists.

  The term “baseline functional activity” refers to the activity of proteins, receptors, enzymes, etc. and includes constitutive signaling activity in the absence of endogenous ligands.

  The term “growth hormone secretagogue (GHS)” is a compound administered from outside the body that directly or indirectly stimulates or increases the endogenous release of growth hormone, growth hormone releasing hormone, or somatostatin in animals, particularly humans. Or refers to a drug. The GHS may be peptidic or non-peptidic in nature and is preferably with an agent that can be administered orally. Furthermore, agents that induce a pulsatile response are preferred.

  The term “modulator” refers to a compound that affects a biological or chemical process or mechanism. For example, a modulator increases, promotes, upregulates, activates, inhibits, decreases, blocks, suppresses, delays, desensitizes, inactivates, downregulates biological or chemical processes or mechanisms, etc. Can do. Thus, the modulator may be an “agonist”, “antagonist” or “inverse agonist”. Exemplary biological processes or mechanisms affected by the modulator include, but are not limited to, receptor binding and hormone release or secretion. Exemplary chemical processes or mechanisms that are affected by the modifier include, but are not limited to, catalysis and hydrolysis.

  The term “variant” when used in a receptor is intended to include dimers, trimers, tetramers, pentamers, and other biological complexes containing multiple components. These components may be the same or different.

  The term “peptide” refers to a compound composed of two or more amino acids covalently linked together.

  The term `` peptidomimetic '' refers to a compound designed to mimic a peptide, but to modulate activity or other properties such as solubility, metabolic stability, oral bioavailability, lipophilicity, permeability, etc. Includes structural differences due to addition or substitution of one or more functional groups of the peptide. This includes peptide bond substitution, side chain modification, truncation, functional group addition, and the like. If the chemical structure is not derived from a peptide and mimics its activity, it is often referred to as a “non-peptidic peptidomimetic”.

  The term “peptide bond” generally refers to an amide [—C (═O) —NH—] functional group covalently bonded to each other in a peptide.

The term “protecting group” is any that can be used to prevent a potentially reactive functional group, such as an amine, hydroxyl or carboxyl, from undergoing a chemical reaction during a chemical change elsewhere in the molecule. Of the compound. A number of such protecting groups are known to those skilled in the art and are described in “Protective Groups in Organic Synthesis,” Theodora W. et al. Greene and Peter G. Wuts, can be found editors, John Wiley & Sons, an example ^{New York, 3 rd edition, 1999} [ISBN 0471160199]. Examples of amino protecting groups include, but are not limited to, phthalimide, trichloroacetyl, benzyloxycarbonyl, tert-butoxycarbonyl, and adamantyloxycarbonyl. Preferred amino protecting groups are carbamate amino protecting groups, which are defined as amino protecting groups that when combined with an amino group form a carbamate. Preferred aminocarbamate protecting groups are allyloxycarbonyl (Alloc), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), tert-butoxycarbonyl (Boc) and α, α-dimethyl-3,5- Dimethoxybenzyloxycarbonyl (Ddz). A recent discussion of the latest nitrogen protecting groups is: Theodoridis, G .; Tetrahedron 2000, 56, 2339-2358. Examples of hydroxyl protecting groups include, but are not limited to, acetyl, tert-butyldimethylsilyl (TBDMS), trityl (Trt), tert-butyl, and tetrahydropyranyl (THP). Examples of carboxyl protecting groups include, but are not limited to, methyl ester, tert-butyl ester, benzyl ester, trimethylsilylethyl ester, and 2,2,2-trichloroethyl ester.

  The term “solid phase chemistry” refers to the action of a chemical reaction in which one component of the chemical reaction is covalently bound to a polymeric material (as a solid support as defined below). Reaction methods for performing chemistry in the solid phase are widely known and established outside the traditional field of peptide and oligonucleotide chemistry.

によって表示される。 The terms “solid support”, “solid phase” or “resin” refer to a mechanically and chemically stable polymeric matrix utilized in the practice of solid phase chemistry. This may be “resin” “p-” or the following symbols:

Is displayed.

Examples of suitable polymeric materials include, but are not limited to, polystyrene, polyethylene, polyethylene glycol, polyethylene glycol grafted or covalently bonded to polystyrene (PEG-polystyrene, also called TentaGel ™, Rapp, W Zhang, L .; Bayer, E. In Innovations and Perseptives in Solid Phase Synthesis. Peptides, Polypeptides and Oligonucleotides; (Trademark)), polyacrylamide, polyurethane, PEGA [polyethylene glycol (N, N-dimethyl acrylamide) copolymer, Meldal, M. Tetrahedron Lett. 1992, 33, 3077-3080], cellulose and the like. These materials can optionally include additional compounds to form crosslinks to mechanically stabilize the structure, for example polystyrene cross-linked with divinylbenzene (DVB, usually 0.1 ~ 5%, or 0.5-2%). This solid support includes, but is not limited to, aminomethyl polystyrene, hydroxymethyl polystyrene, benzhydrylamine polystyrene (BHA), methylbenzhydrylamine (MBHA) polystyrene, and other free chemical functional groups, most commonly Includes a polymeric backbone containing —NH ₂ or —OH for further derivatization or reaction. This term is intended to include “super-resins” (Barth, M .; Rademann, JJ) that contain a high percentage of these functional groups (“loaded”), such as those prepared from polyethyleneimine and cross-linked molecules. Comb.Chem.2004,6,340-349). At the end of the synthesis, the resin is generally discarded, but Frechet, J. et al. M.M. J. et al. Haque, K .; E. Tetrahedron Lett. Some have been shown to be reusable, such as those found in 1975, 16, 3055.

  In general, the materials used as resins are insoluble polymers, but certain polymers have different solubilities depending on the solvent and can also be used for solid phase chemistry. For example, polyethylene glycol is soluble in many organic solvents capable of performing chemical reactions, but is insoluble in other solvents such as diethyl ether and can be utilized in this method. Thus, the reaction can be carried out uniformly in solution, after which the product on the polymer precipitates upon addition of diethyl ether and can be treated as a solid. This is called “liquid phase” chemistry.

  The term “linker” as used in connection with solid phase chemistry generally refers to the chemistry that is covalently bonded to and attached between the solid support and the substrate to allow release (cleavage) of the substrate from the solid support. Refers to the group. However, the linker can also be used to provide stability of binding to the solid support or, rarely, as a spacer molecule. Many solid supports are commercially available with the linker already attached.

  Abbreviations used for amino acids and peptide nomenclature are described in J. Am. Biol. Chem. Follow the rules of the IUPAC-IUB Biochemical Nomenclature Committee of 1972, 247, 977-983. This document has been amended: Biochem. J. et al. , 1984, 219, 345-373; Eur. J. et al. Biochem. 1984, 138, 9-37; 1985, 152, 1; Int. J. et al. Pept. Prot. Res. 1984, 24, p 84; Biol. Chem. , 1985, 260, 14-42; Pure Appl. Chem. , 1984, 56, 595-624; Amino Acids and Peptides, 1985, 16, 387-410; and in Biochemical Nomenclature and Related Documents, 2nd edition, Portland Press, 1992, pp 39-67. An extension of this rule was published in the JCBN / NC-IUB newsletter 1985, 1986, 1989; see Biochemical Nomenclature and Related Documents, 2nd edition, Portland Press, 1992, pp 68-69.

  The term “effective amount” or “effective” is detected by those skilled in the art with respect to doses that result in a reduction in the symptoms of the disease or disorder noticed from clinical trials and evaluations, patient observation, etc., and / or related mechanisms or processes. It is intended to specify a dose that results in a biological change or chemical activity. As is generally understood in the art, dosage will vary depending on the route of administration, symptoms and patient weight, but will also vary depending on the compound being administered.

  “Combination” administration of two or more compounds means that the two compounds are administered in a time sufficiently close that the presence of one changes the biological effect of the other. The two compounds may be administered simultaneously (simultaneously) or sequentially. Co-administration can be done by mixing the compounds prior to administration, or by administering the compounds at the same time, but at different anatomical sites, or using different routes of administration. As used herein, the phrase “co-administration”, “combination administration”, “simultaneous administration” or “administered simultaneously” means that the compounds are administered at the same time or immediately after each other. In the latter case, the two compounds are administered at a time point sufficiently close to be indistinguishable from the results achieved when the compounds are administered at the same time point.

  The term “pharmaceutically active metabolite” is intended to mean a pharmacologically active product of a particular compound produced through body metabolism.

  The term “solvate” is intended to mean a pharmaceutically acceptable solvate form of a particular compound that retains the biological effectiveness of such compound. Non-limiting examples of solvates include compounds of the invention in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.

（式中の置換基は上に記載されている）の化合物、またはその光学異性体、エナンチオマー、ジアステレオマー、ラセミ化合物あるいは立体化学混合物が挙げられる。 1. Compounds The novel macrocyclic compounds of the present invention include compounds of formula I:

Or the optical isomers, enantiomers, diastereomers, racemates or stereochemical mixtures thereof (wherein the substituents are as described above).

In some embodiments, R ₃ is H; R ₄ is —CR _43a R _43b (OR ₄₄ ), wherein R _43a and R _43b are each independently hydrogen, lower alkyl, or substituted lower alkyl. And R ₄₄ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, or acyl); R ₇ is hydrogen or lower alkyl.

のいずれか、またはそれらの光学異性体、エナンチオマー、ジアステレオマー、ラセミ化合物あるいは立体化学混合物であり得る。 In other embodiments, the compound has the following structure:

Or their optical isomers, enantiomers, diastereomers, racemates or stereochemical mixtures.

  The present invention includes isolated compounds. Isolated compound refers, in some embodiments, to a compound comprising at least 10%, at least 25%, at least 50%, or at least 70% of the compound of the mixture. In some embodiments, the compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the compound has a statistically significant binding activity when tested with a human ghrelin receptor in a biological assay. Shows antagonist activity.

  In the case of compounds, salts, or solid solvates, it will be understood by those skilled in the art that the compounds, salts, and solvates of the present invention may exist in different crystals or polymorphs, all of which are described in the present invention and specified. Are within the scope of the formula given.

  The compounds of formula I disclosed herein have asymmetric centers. The compounds of the invention may exist as single stereoisomers, racemates, and / or mixtures of enantiomers and / or diastereomers. All such single stereoisomers, racemates, and mixtures thereof are intended to be within the scope of the present invention. However, the compounds of the invention are used in optically pure form. The terms “S” and “R” configurations used herein are defined by IUPAC 1974, Section E, Recommendations for Stereochemistry Fundamentals (Pure Appl. Chem. 1976, 45, 13-30. ).

  Unless otherwise expressed as being in a particular orientation, the present invention describes all stereoisomeric forms. The compounds may be prepared as a single stereoisomer or a mixture of stereoisomers. Non-racemic forms may be obtained by synthesis or by resolution. Compounds can be resolved into the component enantiomers, for example, by standard methods, for example, the formation of diastereomeric pairs by salt formation. Alternatively, the compound may be resolved by covalently bonding to the chiral moiety. The diastereomers can then be resolved by chromatographic separation and / or crystallographic separation. In the case of a chiral auxiliary, it can then be removed. Alternatively, compounds may be resolved using chiral chromatography. In certain cases, enzymatic method resolution may be used.

  As generally understood by those skilled in the art, an “optically pure” compound is a compound that contains only a single enantiomer. As used herein, the term “optical activity” is intended to mean a compound containing one enantiomer in excess of the other enantiomer, at least enough for the mixture to rotate plane polarized light. Enantiomeric excess (ee) indicates the excess of one enantiomer over the other. The optically active compound has the ability to rotate the polarization plane. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration with respect to the chiral center of the molecule. The prefixes “d” and “l” or (+) and (−) are used to indicate the optical rotation of the compound (ie, the direction in which the plane of polarization is rotated by the optically active compound). The “l” or (−) prefix indicates that the compound is levorotatory (ie, rotates the plane of polarization left or counterclockwise), and the “d” or (+) prefix indicates that the compound is dextrorotatory. Indicates that there is (ie, the polarization plane is rotated to the right or clockwise). The signs of optical rotation, (-) and (+) are not related to the absolute configuration of the molecules, R and S.

  Compounds of the invention having the desired pharmacological properties are optically active and are at least 90% (ee 80%), at least 95% (ee 90%), at least 97.5% (Ee 95%) or at least 99% (ee 98%) of a single isomer.

  Similarly, many geometric isomers, such as double bonds, can exist in the compounds disclosed herein, and all such stable isomers are within the scope of the present invention unless otherwise indicated. Included in the range. Also included in the invention are tautomers and rotamers of formula I.

を使用する場合は、示された環の１以上の水素原子が、定義された置換基Ｒで置換されていることを示す。 Next symbol on the right

Is used, it indicates that one or more hydrogen atoms of the indicated ring are substituted with the defined substituent R.

を使用する場合は、一重結合または任意選択の二重結合を示す。 Next symbol

When is used, it represents a single bond or an optional double bond.

  Embodiments of the present invention further provide intermediate compounds produced by the synthetic methods described herein to provide compounds of formula I. Intermediates may have utility as therapeutic agents and / or reagents for further synthetic methods and reactions.

2. Synthetic Methods The compounds of Formula I can be synthesized using conventional solution synthesis techniques or solid phase chemistry methods. In any case, the construction involves four aspects. The first is the synthesis of building blocks that contain one tether moiety primarily for the control and definition of conformation in addition to the biological target receptor recognition elements. These building blocks are generally built together in sequence, in a second aspect using standard chemical transformations. Next, in the third step, the building precursor is cyclized to obtain the macrocyclic structure. Finally, the fourth stage of post-cyclization treatment including removal of the protecting group and optional purification yields the desired final compound. Methods for synthesizing this general class of macrocyclic structures are described in international patent applications WO 01/25257, WO 2004/110107, WO 2005/012331, WO 2005/012332, WO 2006/009645 and WO 2006 /. Also included are purification procedures described in WO 009674 and described in WO 2004/110107 and WO 2005/012331.

  In some embodiments of the present invention, macrocycles of formula I may be synthesized using solid phase chemistry with a soluble or insoluble polymeric matrix as previously defined. For solid phase chemistry, a preparatory step must be performed that involves attaching the first building block to the resin (also referred to as “loading”). The resin preferentially used in the present invention is attached to the linker portion, L. These linkers are suitable free chemical functional groups on the base resin by standard reaction methods known in the art, such as any of a number of reaction conditions developed for the formation of ester or amide bonds, Usually attached to an alcohol or amine, but other functional groups are possible. Some linker moieties for the present invention are designed to allow simultaneous cleavage from the resin as well as formation of a macrocyclic polymer in a process commonly referred to as “cyclization-release”. (Van Maarseveen, J.H.Solid phase synthesis of heterocycles by cyclization / cleavage methodologies.Comb.Chem.High Throughput Screen.1998,1,185-214; Ian W.James, Linkers for solid phase organic synthesis.Tetrahedron 1999, Eggenweiler, H.-M. Linkers for solid-phase synthesis of small molecules: coupling and cleavage techniques. Drug Discovery ry Today 1998, 3, 552-560; Backes, BJ; Ellman, JA Solid support linker strategies. Curr. Opin. Chem. Biol. 1997, 1, 86-93. For compounds of the invention is the 3thipropionic acid linker.Hojo, H.; Aimoto, S. Bull.Chem.Soc.Jpn.1991, 64, 111-117, Zhang, L. Soc. 1999, 121, 3311-3320.)

  Such a method results in a high purity material in which only the cyclic product is released from the solid support to the same extent as occurs in the solution phase, with minimal contamination of the linear precursor. Appropriate nucleophilicity that is part of the tether building block after sequential construction of all building blocks and tethers into linear precursors using known or standard reaction chemistry for the formation of ester or amide bonds As a result of base-mediated intramolecular attack at the carbonyl attached to this linker by a functional group, an amide or ester bond is formed that completes the cyclic structure, as shown (Scheme 1). Similar methodologies adapted to the solution phase, which may be preferable for larger scale applications, can also be applied.

この説明は、本発明の方法の１つ、チオエステル戦略のための経路を的確に表しているが、本発明の別の方法である、閉環メタセシス（ＲＣＭ）は、テザー成分が環化ステップ中に実際に構築される、改変された経路を進む。しかし、ＲＣＭの方法論も同様にビルディングブロックの構築が順次進行し、その後に環化（固相の場合はさらに樹脂からの放出）が続く。ＲＣＭ反応の特定の副生成物を除去するためにはさらなる環化後の処理ステップが必要であるが、残ったその後の処理はチオエステルまたは類似の塩基に媒介される環化戦略の方法と同じ方法でなされる。 Scheme 1. Cyclization release strategy

While this description accurately represents one of the methods of the present invention, the pathway for the thioester strategy, another method of the present invention, ring-closing metathesis (RCM), is used when the tether component is in the cyclization step. Follow the modified path that is actually constructed. However, in the RCM methodology, construction of building blocks proceeds sequentially, followed by cyclization (in the case of solid phase, further release from the resin). Additional post-cyclization processing steps are required to remove certain by-products of the RCM reaction, but the remaining subsequent processing is the same method as that of thioester or similar base mediated cyclization strategies Made in

  Further, it will be appreciated that the steps including the methods provided herein can be performed independently or at least two steps can be combined. Further, if the steps comprising the methods provided herein are performed independently or in combination, they may be performed at the same temperature or at different temperatures without departing from the teachings of the present invention. Good.

  Accordingly, the present invention includes (a) building a building block structure, (b) chemically converting the building block structure, (c) cyclizing the building block structure including a tether component, (d) There is provided a method for preparing a compound of the invention comprising removing a protecting group from a building block structure, and (e) optionally purifying the product obtained in step (d). In some embodiments, building block structure construction may be continuous. In further embodiments, the synthesis method is performed using conventional solution synthesis techniques or solid phase chemistry techniques.

A. Amino acid Side chain protected derivatives, including amino acid, Boc- and Fmoc-protected amino acids, and side chain protected derivatives of N-methyl amino acids and unnatural amino acids are available from commercial suppliers [eg, Advanced ChemTech (Louisville, KY, USA). ), Astatech (Princeton, NJ, USA), Bachem (Bubendorf, Switzerland), ChemImpex (Wood Dale, IL, USA), Novabiochem (Merck KGaA, Darmstadt, Germany) (Albany, OR, USA)] or synthesized by standard methods known to those skilled in the art. Ddz- amino acids, Orpegen (Heidelberg, Germany) or Advanced ChemTech (Louisville, KY, USA ) or obtained from commercially or synthesized using standard methods utilizing Ddz-OPh or Ddz-N _3. (Birr, C .; Lochinger, W .; Stahnke, G .; Lang, P. The α, α-dimethyl-3,5-dimoxybenzyloxycarboniyl (Ddz) residue, an N-protecting group. Liebigs Ann. Chem. 1972, 763, 162-172.) Bts-amino acids were synthesized by known methods. .... (Vedejs, E ; Lin, S; Klapara, A; Wang, J "Heteroarene-2-sulfonyl Chlorides (BtsCl , ThsCl): Reagents for Nitrogen Protection and> 99% Racemization-Free Phenylglycine Activation with SOCl 2. "J. Am. Chem. Soc. 1996, 118, 9796-9797; also WO 01/25257, WO 2004/110107). N-alkyl amino acids, particularly N-methyl amino acids, are commercially available from multiple vendors (Bachem, Novabiochem, Advanced ChemTech, Chemnpex). Furthermore, N-alkylamino acid derivatives were used by methods described in the literature. (Hansen, D.W., Jr .; Piripauskas, D.J. Org. Chem. 1985, 50, 945-950.) Allothreonine and β-hydroxyvaline can be synthesized by known procedures (Shao, Goodman, M. An Enantiomeric Synthesis of allo-Threoneses and β-Hydroxyvalines.J.Org.Chem.1996,61,582, Blaskovich, M.A .; Wilkinson, S .; Luo, Y.; Lajoie, GA, Stereoselective Synthesis of Threo and Erythro β-Hydroxy and β-Dis Uttituted-β-Hydroxy α-Amino Acids.J.Org.Chem.1998,63,3631; Dettwiller; J.E.Lubell, WD.Serine as Chiral Manufacturing for the Practical. J. Org. Chem. 2003, 68, 177-179.). Chiral isomers of β-methylphenylalanine and β-methyltyrosine can be used using methods described in the literature. (Dharanipragada, R .; Van Hulle, K .; Bannister, A .; Bearn, S .; Kennedy, L .; Hruby, V. J. Asymmetrical Sciences in the United Amino Acids Pid. Methylphenylalanine.Tetrahedron 1992, 48, 4733-4748; Nicolas, E.; Russell, K.C.; Knollenberg, J.; Hruby, V.J. Efficient Method for the Tot. osine J. Org. Chem. 1993, 59, 7565-7571.) Incorporation of alloisomers of L-threonine (2S, 3S) is also based on a similar transformation used for the synthesis of the natural product ustyroxin D. It can be achieved from the syn-L-isomer (2S, 3R) using the synthetic procedure shown in FIG. (Wandless, TJ; et al. J. Am. Chem. Soc. 2003, 115, 6864-6865.)

（式中、（Ｚ₂）は、ＴのＺ₂に対する共有結合の部位であり、Ｚ２は上に定義され、（Ｘ）はＴのＸに対する共有結合の部位であり、Ｘは上に定義され、；Ｌ₇は、−ＣＨ₂−または−Ｏ−であり；Ｕ₁およびＵ₃は、各々独立に、−ＣＲ₁₀₁Ｒ₁₀₂−または−Ｃ（＝Ｏ）−であり；Ｕ₂は、−ＣＲ₁₀₁Ｒ₁₀₂−であり；Ｒ₁₀₀は、低級アルキルであり；Ｒ₁₀₁およびＲ₁₀₂は各々独立に、水素、低級アルキルまたは置換低級アルキルであり；ｘｘは２または３であり；ｙｙは１または２であり；ｚｚは１または２であり；さらにａａａは０または１である）およびその製造の際の中間体が挙げられる。 B. Tethers Tethers were obtained from the methods already described in international patent applications WO 01/25257, WO 2004/110107, WO 2005/012331, WO 2006/009645, and WO 2006/009674. Exemplary tethers (T) include, but are not limited to:

(Wherein (Z ₂ ) is the site of covalent bonding of T to Z ₂ , Z ₂ is defined above, (X) is the site of covalent bonding of T to X, and X is defined above. L ₇ is —CH ₂ — or —O—; U ₁ and U ₃ are each independently —CR ₁₀₁ R ₁₀₂ — or —C (═O) —; U ₂ is — CR ₁₀₁ R ₁₀₂ - a and; R ₁₀₀ is lower alkyl; R ₁₀₁ and R ₁₀₂ are each independently hydrogen, lower alkyl or substituted lower alkyl; xx is 2 or 3; yy is 1 or 2; zz is 1 or 2, and aaa is 0 or 1) and intermediates in the production thereof.

C. Solid Phase and Solution Phase Techniques Specific solid phase techniques for the synthesis of the macrocycles of the present invention are described in WO 01/25257, WO 2004/111107, WO 2005/012331 and WO 2005/012332. Has been. Solution phase synthetic routes, including methods that follow larger scale production, were described in International Patent Application Publication Nos. WO 2006/009645 and WO 2006/009674.

  In particular, the macrocyclic compounds of the present invention can be made using the solution phase procedure illustrated for the representative compound 502 of FIG. Synthetic yields of representative compounds of the present invention are shown in Table 1.

D. Analytical Techniques Specific analytical techniques for characterization of the macrocyclic compounds of the present invention are described in WO 01/25257, WO 2004/110107, WO 2005/012331 and WO 2005/012332.

  Analytical data for some of the representative compounds of the present invention are summarized in Table 2.

3. Biological Methods The compounds of the present invention were evaluated for their ability to interact with the human ghrelin receptor using a competitive radioligand binding assay, fluorescence assay or aequorin functional assay as described in the Examples below. Such a method can be carried out in a high throughput method that allows simultaneous evaluation of many compounds, if desired.

  Human (GHS-R1a), porcine and rat GHS receptors (US Pat. No. 6,242,199, international patent applications WO 97/21730 and 97/2004), and canine GHS receptors (US Pat. No. 6,645,726) are known and their use in identifying agonists and antagonists in general.

  Functional ghrelin antagonists can be identified using the methods described in WO 2005/114180, whereas inverse agonists of the receptors can be assayed using the methods of WO 2004/056869.

  Suitable methods for determining the functional activity of compounds of the present invention that interact at the human ghrelin receptor are also described in the examples below.

  The in vivo efficacy of the compounds of the present invention is, for example, animal models of obesity, such as those described in the literature (WO 2004/056869; Nakazato, M .; Murakami, N .; Date, Y .; et al. A roll for ghrelin in the central regulation of feeding. Nature 2001, 409, 194-198; Murakami, N .; Hayashida, T .; Kuroiwa, T .; et al. Role in hrent. stromach ghrelin in rats.J.Endocrinol.2002,174,283-288; Sakawa, A .; Inui, A.; Kaga, T .; et al.Antagonismo of ghrelin receptor reduce food intake and body weight gain, 95.S. Smith, RG Deletion of ghrelin impairs neigher growth nor appite.Mol.Cell Biol.2003,23,7973-7981; Wortley, KE; Anderson, KD; alc; Genetic deletion of ghrelin does not decreased food int Shen, J. E .; Dong, J. Z., Shen, Y .; Abitaid, A .; Diano, S .; Horvath, T .; Zizzari, P .; Blue-Pajot, M.-T., Epelbaum, J., Culler, MD, Novel analogs of ghrelin. : Physiological and clinical implications. Eur. J. et al. Endocrinol. 2004, 151, S71-S75; Helling, S .; Maach, C .; Euberg, D .; Et al. Inhibition of ghrelin action in vitro and in vivo by RNA-Spiegelmer. Proc. Natl. Acad. Sci USA 2004, 101, 13174-13179; Shearman, L .; P. Wang, S .; P. Helmling, S .; Et al. Ghrelin neutralization by a ribonucleic acid-SPM ameliorates obesity in diet-induced obesity. Endocrinology 2006, 147, 1517-1526).

4). Pharmaceutical Compositions The macrocyclic compounds of the present invention or pharmacologically acceptable salts thereof according to the present invention can be formulated into various dosage forms of pharmaceutical compositions. In order to prepare the pharmaceutical composition of the present invention, as an active ingredient, one or more kinds of compounds including optical isomers, enantiomers, diastereomers, racemates or stereochemical mixtures thereof, or pharmaceutically acceptable salts thereof are used. Intimately mixed with appropriate carriers and additives according to pharmaceutical formulation techniques known to those skilled in the art.

  A pharmaceutically acceptable salt refers to a salt form of a compound of the present invention that allows the compound of the present invention to be used or formulated as a pharmaceutical, which biologically or otherwise. Retains the biological effectiveness of the free acids and bases of certain compounds, which are undesirable. Examples of such salts are described in Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Wermuth, C.I. G. and Stahl, P.A. H. (Eds.), Wiley-Verlag Helvetica Acta, Zuerich, 2002 [ISBN 3-906390-26-8]. Examples of such salts include alkali metal salts and free acid and base addition salts. Examples of pharmaceutically acceptable salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metalin Acid salt, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiol Acid salt, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioates, hexyne-1,6-dioates, benzoate Acid salt, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, Rubutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate, methanesulfonate, ethanesulfonate, propanesulfonate, toluenesulfonate, naphthalene-1-sulfonic acid Salts, naphthalene-2-sulfonate, and mandelate.

  When the compound of the present invention is a base, the desired salt is a treatment of the free base with an inorganic acid such as, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, carbonic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Or but not limited to formic acid, acetic acid, propionic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, stearic acid, ascorbic acid, glycolic acid, salicylic acid, glucuronic acid or galacturon Pyranosidyl acid such as acid, α-hydroxy acid such as citric acid or tartaric acid, amino acid such as aspartic acid or glutamic acid, aromatic acid such as benzoic acid or cinnamic acid, p-toluenesulfonic acid, methanesulfonic acid, Ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfone It may be prepared by any suitable method known to those skilled in the art, including treatment with acids, sulfonic acids such as cyclohexylaminosulfonic acid, or organic acids including the same.

  When the compound of the present invention is an acid, desirable salts are inorganic or organic bases such as amines (primary, secondary, or tertiary); free acids such as alkali metal or alkaline earth metal hydroxides. May be prepared by any suitable method known in the art. Illustrative examples of suitable salts include: organic salts derived from amino acids such as glycine, lysine and arginine; ammonia; primary, primary such as ethylenediamine, N, N′-dibenzylethylenediamine, diethanolamine, choline, and procaine Secondary and tertiary amines and cyclic amines such as piperidine, morpholine, and piperazine; and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

  The carriers and additives used in such pharmaceutical compositions can take a variety of forms depending on the expected mode of administration. Thus, compositions for oral administration include solid formulations such as tablets, including suitable carriers and additives such as starches, sugars, binders, diluents, granulating agents, lubricants, disintegrants, and the like. , Sugar-coated tablets, hard capsules, soft capsules, granules, powders, and the like. Tablets and capsules represent the most advantageous oral dosage forms for many medical conditions because of their ease of use and high patient compliance.

  Similarly, compositions for liquid formulations include solutions, emulsions, including suitable carriers and additives such as water, alcohols, oils, glycols, preservatives, flavoring agents, coloring agents, suspending agents, and the like. Examples thereof include dispersions, suspensions, syrups, and elixirs. Typical parenteral formulations contain the active ingredient together with a carrier such as parenterally acceptable oil, including sterile water or polyethylene glycol, polyvinyl pyrrolidone, lecithin, peanut oil or sesame oil, and solubility or storage Other additives to help can be included. In the case of a solution, it can be lyophilized to a powder and then reconstituted immediately before use. For dispersions and suspensions, suitable carriers and additives include aqueous gums, celluloses, silicates or oils.

  Pharmaceutical compositions according to embodiments of the invention include oral, rectal, topical, inhalation (eg, by aerosol), oral (eg, sublingual), vaginal, topical (ie, skin and mucosal surfaces, including airway surfaces) Both), transdermal, and parenteral (eg, subcutaneous, intramuscular, intradermal, intraarticular, intrapleural, intraperitoneal, intrathecal, intracerebral, intracranial, intraarterial, or intravenous) Although the most suitable route in any given case depends on the nature and severity of the condition being treated and the nature of the particular active substance used.

  For injectable compositions, the active ingredient is propylene glycol-alcohol-water, isotonic water, sterile water for injection (USP), emulPhor ™ -alcohol-water, cremophor-EL ™ or known to those skilled in the art. Included with a suitable carrier, including other suitable carriers. These carriers may be used alone or in combination with other conventional solubilizers such as ethanol, propylene glycol, or other materials known to those skilled in the art.

  When the macrocyclic compound of the invention is applied in the form of a solution or injection, the compound can be used dissolved or suspended in any conventional diluent. Examples of the diluent include physiological saline, Ringer's solution, glucose aqueous solution, dextrose aqueous solution, alcohol, fatty acid ester, glycerol, glycol, oil derived from plants or animals, paraffin, and the like. These formulations may be prepared according to any method known to those of ordinary skill in the art.

  Compositions for nasal administration can be formulated as aerosols, droplets, powders and gels. Aerosol dosage forms generally comprise a solution or fine suspension of the active ingredient in a physiologically acceptable aqueous or non-aqueous solvent. Such dosage forms are generally presented in single or multiple doses in sterile form in a sealed container. The sealed container can be a cartridge or refill for use with a spray device. Alternatively, the sealed container may be a single use nasal inhaler, a pump nebulizer or an aerosol dispenser with a throttling valve set to deliver a therapeutically effective amount that is discarded after full use. Unit dispenser. Where the dosage form includes an aerosol dispenser, it includes a propellant such as a compressed gas, for example air, or an organic propellant comprising a fluorochlorohydrocarbon or fluorohydrocarbon.

  Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles where the active ingredient is formulated with a carrier such as sugar and gum arabic, gum tragacanth or gelatin and glycerin.

  Compositions for rectal administration include suppositories containing a conventional suppository base such as cocoa butter.

  Compositions suitable for transdermal administration include ointments, gels and patches.

  Other compositions known to those skilled in the art, such as plasters, can also be applied transdermally or subcutaneously.

  In addition, other conventional pharmacologically acceptable additives such as excipients, stabilizers, preservatives may be used in the preparation of pharmaceutical compositions containing the active ingredients mixed with the ingredients required for formulation of the composition. , Wetting agents, emulsifying agents, lubricants, sweetening agents, coloring agents, flavoring agents, isotonic agents, buffering agents, antioxidants and the like. Examples of additives include starch, sucrose, fructose, lactose, glucose, dextrose, mannitol, sorbitol, precipitated calcium carbonate, crystalline cellulose, carboxymethylcellulose, dextrin, gelatin, gum arabic, EDTA, magnesium stearate, talc, hydroxypropyl Mention may be made of methylcellulose, sodium metabisulfite and the like.

  In some embodiments, the composition is provided in a unit dosage form such as a tablet or capsule.

  In a further embodiment, the present invention provides a kit comprising one or more containers comprising a pharmaceutical dosage unit comprising an effective amount of one or more compounds of the present invention.

  The present invention further provides prodrugs comprising the compounds described herein. The term “prodrug” is intended to mean a compound that is converted under physiological conditions, or by solvolysis, or to a metabolically pharmaceutically active compound. A “prodrug” is a chemical derivative that (i) retains some, all or none of the biological activity of the parent drug compound, and (ii) is metabolized in the subject to yield the parent drug compound. It can be a compound of the present invention. Also, the prodrugs of the present invention (i) retain some, all or none of the biological activity of the parent drug compound, and (ii) are metabolized in a subject to yield a biologically active derivative of the compound. It can also be a “partial prodrug” in that the compound is chemically derivatized. Known techniques for derivatizing compounds to provide prodrugs may be used. Such methods may be utilized to form hydrolyzable bonds with the compound.

  The present invention further provides compounds of the present invention for metabolic and / or endocrine disorders, cardiovascular diseases, obesity and obesity related diseases, gastrointestinal disorders, genetic diseases, hyperproliferative diseases and inflammatory diseases. It can be administered in combination with a therapeutic agent used to prevent and / or treat. Examples of therapeutic agents include analgesics including opioid analgesics, anesthetics, antifungals, antibiotics, anti-inflammatory drugs including nonsteroidal anti-inflammatory drugs, anthelmintics, antiemetics, antihistamines, antihypertensives , Antipsychotics, anti-arthritics, antitussives, antivirals, cardioactives, laxatives, chemotherapeutics such as DNA interactors, antimetabolites, tubulin interactors, hormones, and asparaginase or hydroxyurea Substances such as corticoids (steroids), antidepressants, inhibitors, diuretics, hypnotics, minerals, nutritional supplements, parasympathomimetics, corticotropin releasing hormone, adrenocorticotropin, growth hormone releasing hormone, growth hormone, thyroid stimulation Hormones such as released hormone and thyroid stimulating hormone, sedatives, sulfonamides, stimulants, sympathetic effects , Tranquilizers, vasoconstrictors, vasodilators, include vitamins and xanthine derivatives.

  Subjects suitable for treatment according to the present invention include, but are not limited to, avian and mammalian subjects, preferably mammals. Mammals of the present invention include, but are not limited to, dogs, cats, cows, goats, horses, sheep, pigs, rodents (eg, rats and mice), rabbit eyes, primates, humans, and the uterus. Including mammals within. Any mammalian subject in need of treatment according to the present invention is suitable. A human subject is preferred. Men and women and human subjects of any growth stage (ie, neonates, infants, adolescents, adolescents, adults) can be treated according to the present invention.

  Illustrative birds according to the present invention include chickens, ducks, turkeys, geese, quails, pheasants, migratory birds (eg, ostriches) and reared birds (eg, parrots and canaries), and birds in eggs. Can be mentioned.

  Although the present invention relates primarily to the treatment of human subjects, the present invention also relates to animal subjects, particularly mammalian subjects such as mice, rats, dogs, cats, for veterinary purposes and drug screening and drug development purposes. It can also be carried out on livestock and horses.

  In therapeutic uses for the treatment of conditions in mammals (ie, humans or animals) where ghrelin receptor antagonists or inverse agonists are effective, an effective amount of a compound of the invention or an appropriate pharmaceutical composition thereof is administered. be able to. Because the compound's activity and degree of therapeutic effect vary, the actual dosage administered is determined based on commonly recognized factors such as the subject's age, condition, route of delivery, and subject's weight. . The dosage is about 0.1 to about 100 mg / kg, administered orally 1 to 4 times a day. In addition, the compounds may be administered by injection at about 0.01-20 mg / kg per dose, administered 1 to 4 times per day. Treatment can continue for weeks, months, or longer. Determination of the optimal dosage for a particular situation is within the skill of the artisan.

5. Methods of Use The compounds of the present invention include, but are not limited to, metabolic and / or endocrine disorders, cardiovascular diseases, obesity and obesity related diseases, gastrointestinal disorders, genetic diseases, hyperproliferative disorders, inflammatory diseases And the disease can be used for the prevention and treatment of a range of medical conditions, including combinations thereof, which are the result of multiple underlying diseases.

  Metabolic and / or endocrine disorders include, but are not limited to obesity and diabetes, particularly type II diabetes. Cardiovascular diseases include but are not limited to hypertension and dyslipidemia. Hyperproliferative disorders include, but are not limited to, tumors, cancers, and neoplastic tissues, including diseases such as breast cancer, osteosarcoma, angiosarcoma, fibrosarcoma and other sarcomas, leukemia , Lymphoma, sinus tumor, ovarian cancer, ureteral cancer, bladder cancer, prostate cancer and other genitourinary cancers, colon cancer, esophageal cancer and gastric cancer and other gastrointestinal cancers, lung cancer, myeloma, pancreatic cancer, liver cancer Malignant or benign, brain or central and peripheral nerve (CNS) tumors, including renal cancer, endocrine cancer, skin cancer, and glioma and neuroblastoma. Obesity and obesity-related diseases include but are not limited to obesity characterized as metabolic and / or endocrine disorders, as well as retinopathy, bulimia and regulation of food intake and appetite control. Related diseases are mentioned. Gastrointestinal disorders include, but are not limited to, irritable bowel syndrome, dyspepsia, opioid-induced intestinal dysfunction and gastric failure paralysis. Inflammatory diseases include, but are not limited to, general inflammation, arthritis, such as rheumatoid arthritis and osteoarthritis, and inflammatory bowel disease. The compounds of the present invention can further be used for the prevention and / or treatment of cirrhosis and chronic liver disease. As used herein, “treatment” does not necessarily imply that the disease or condition associated with the treatment is cured or completely eliminated.

  The compounds of the present invention may further include, but are not limited to, metabolic and / or endocrine disorders, cardiovascular diseases, obesity and obesity related diseases, gastrointestinal disorders, genetic diseases, hyperproliferative disorders and inflammatory diseases Can be used for the preparation of a medicament for the treatment of a range of medical conditions.

  Further embodiments of the invention will now be described in connection with the following examples. It will be appreciated that these examples are for the purpose of illustrating embodiments of the invention and are not intended to limit the scope of the invention.

Competitive radioligand binding assay (ghrelin receptor)
Competition binding assays with the human growth hormone secretagogue receptor (hGHS-R1a) were performed in the same manner as described in the literature. (Bednarek MA et al.Structure-function studies on the new growth hormone-releasing peptide ghrelin: minimal sequence of ghrelin necessary for activation of growth hormone secretagogue receptor 1a; J.Med.Chem.2000,43,4370-4376; Palucki, B. L. et al. Spiro (indoleline-3,4'-piperidine) growth horne secretagoges as ghrelin mimetics; Bioorg.Med.Chem.Lett. 2002, 11, 195. -1957)

Materials Membranes (GHS-R / HEK 293) were prepared from HEK-293 cells stably transfected with human ghrelin receptor (hGHS-R1a). These membranes were provided by PerkinElmer BioSignal (#RBHGHSM, lot number 1887) and were used in an amount of 0.71 μg / assay point.
1. [ ¹²⁵ I] -ghrelin (PerkinElmer, # NEX-388); final concentration: 0.0070-0.0085 nM
2. Ghrelin (Bachem, # H-4864); final concentration: 1 μM
3. Multi-screen harvest plate-GF / C (Millipore, # MAHFC1H60)
4). Deep well polypropylene titer plate (Beckman Coulter, # 267006)
5. Top seal-A (PerkinElmer, # 6005185)
6). Bottom seal (Millipore, # MATAH0P00)
7). MicroScint-0 (PerkinElmer, # 6013611)
8). Binding buffer: 25 mM Hepes (pH 7.4), 1 mM CaCl ₂ , 5 mM MgCl ₂ , 2.5 mM EDTA, 0.4% BSA

Competition experiments were performed in a filtration analysis format with an assay volume of 300 μl.
1. 220 μL of membrane diluted in binding buffer
2. 40 μL of compound diluted in binding buffer
3. 40 μL of radioligand ([ ¹²⁵ I] -ghrelin) diluted in binding buffer
Final test concentrations for compounds of the invention (N = 1): 10, 1, 0.5, 0.2, 0.1, 0.05, 0.02, 0.01, 0.005, 0.002. 0.001 μM.

Handling of Compound A compound having a storage concentration of 10 mM, diluted in 100% DMSO and stored at −80 ° C. until the test day, was prepared in a frozen state on dry ice. On the day of testing, compounds were thawed overnight at room temperature and then diluted in assay buffer according to the desired test concentration. Under these conditions, the maximum final DMSO concentration in the assay was 0.1%.

Assay Procedure In a deep well plate, add 220 μL of diluted cell membrane (final concentration: 0.71 μg / well) to 40 μL of binding buffer (total binding, N = 5), 1 μM ghrelin (non-specific binding, N = 3). Or an appropriate concentration of test compound (N = 2 for each test concentration). The reaction was initiated by the addition of 40 μl [ ¹²⁵ I] -ghrelin (final concentration 0.0070-0.0085 nM) to each well. Plates were sealed with TopSeal-A, gently vortexed and incubated for 30 minutes at room temperature. The reaction was stopped by filtering the sample through a multiscreen harvest plate (pre-soaked in 0.5% polyethyleneimine) using a Tomtec Harvester, and 500 μL of cold 50 mM Tris-HCl (pH 7.4, 4). The plate was then air-dried for 30 minutes in a draft chamber. After the bottom seal was applied to the plate, 25 μL of MicroScint-0 was added to each well. The plates were then sealed with TopSeal-A and counted in a top count microplate scintillation and luminescence counter (PerkinElmer) for 30 seconds per well with a 60 second count delay. Results were expressed as counts per minute (cpm).

Data were analyzed by GraphPad Prism (GraphPad Software, San Diego, Calif.) Using variable gradient nonlinear regression analysis. K _i values were calculated using [ ¹²⁵ I] -ghrelin with a K _d value of 0.01 nM (already determined during membrane characterization).
The D _max value was calculated using the following formula.
D _max = 1−test concentration including maximum displacement−nonspecific binding / total binding−nonspecific binding × 100
In the formula, total binding and non-specific binding represent cpm obtained in the presence or absence of 1 μM ghrelin, respectively.

The results of testing representative compounds of the present invention are shown in Table 3 below.

Fluorescence functional assay (ghrelin receptor)
Device 1. ImageTrak Epi-Fluorescence system (Perkin-Elmer)
2. MultiDrop TiterTek
3. CO ₂ incubator: 5% CO ₂ , humidified, 37 ° C

Material 1. Hanks' BSS (Life Technologies) without phenol red
2. Hepes buffer3. Probenecid (Sigma)
4). FLIPR Calcium-3 Assay Kit (Molecular Devices # R-8091)
5. Falcon cell culture 96 well black / clear bottom plate 6. 0.05% trypsin-EDTA
7). Cells: HEK293 cells expressing the GHS-R1a receptor (Perkin-Elmer BioSignal) in DMEM (Dulbecco's Modified Eagle Medium) containing 10% FBS, 1% sodium pyruvate, 1% NEAA and 400 μg / mL geneticin. Allowed to grow.
8). Ghrelin (control agonist; Bachem, # H-4864)
9. ^{[D-Lys 3] -GHRP-} 6 ( control antagonists, Phoenix # 031-22)
10. Assay buffer: HBSS-20 mM Hepes containing 2.5 mM probenecid and 0.1% BSA (bovine serum albumin); pH 7.4

Compound Handling A stock solution of compound (10 mM in 100% DMSO) was prepared frozen on dry ice and stored at −80 ° C. until use. From the stock solution, a mother solution having a concentration of 100 μM diluted 100-fold in 26% DMSO was prepared. The assay plate was then prepared by appropriate dilution in assay buffer.
Final test concentration of test compound (agonist) (N = 10): 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001, 0.0003, 0.0001, 0 0.0003 μM.
Final test concentration of test compound (antagonist) (N = 10): 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001, 0.0003 μM.

Cell preparation Cells were maintained in culture as indicated above. The day before the experiment, cells were collected at a culture density of 70-90%. The growth medium was removed and the cells were rinsed briefly with PBS without Ca ⁺² and Mg ⁺² . 0.05% trypsin was added and the plates were incubated at 37 ° C. for 5 minutes to detach the cells. DMEM medium supplemented with 10% FBS was added to inactivate trypsin and the cell concentration was measured. The inoculum was adjusted to a final concentration of 200 cells / μL, and 200 μL per well was dispensed into a 96-well black plate. Plates were incubated overnight at 37 ° C. Cell density on the day of the experiment should be 70-95%.

Assay Procedure Plates were removed from the incubator and the plates were inverted to remove the media. After adding 50 μL of calcium-3 dye, it was incubated at 37 ° C. for 1 hour. The plate was inverted again and then 25 μL of assay buffer was added. The plates were then transferred to the ImageTrak system for analysis. For agonist testing, after reading for 10 seconds, 25 μL of twice the test compound or control was injected into the assay plate. Fluorescence was monitored for an additional 50 seconds. Readings were taken every 2 seconds and a total of 30 readings per assay point.

For the antagonist test, after reading for 10 seconds, 12.5 μL of 3 × test compound or control was injected into the assay plate and allowed to react for 3 minutes. At that time, 4 nM ghrelin (equivalent to EC ₈₀ ) was injected and fluorescence was monitored for an additional 60 seconds. Readings were taken every 2 seconds, totaling 125 readings per data point.

For analysis of results and displayed agonists, the value obtained at each assay point is that Max represents the maximum of 30 readings and Min represents the minimum observed from the first 5 readings to compound injection. Reflects the fluorescence reading of Max-Min. Concentration response curves were analyzed by non-linear regression analysis (sigmoidal dose response) using GraphPad Prism (GraphPad Software, San Diego, Calif.). EC ₅₀ values are calculated using GraphPad.
The E _max value was calculated using the following formula: :
E _max = count at the maximum reaction compound concentration−Basal / Ago (E _max ) −Basal × 100
In the formula, Basal and Ago (E _max ) represent the average counts obtained in the absence or presence of 1 μM ghrelin, respectively.

For antagonists, the value obtained at each assay point represents the maximum value obtained after injection of ghrelin with EC ₈₀ EC, and Min represents the minimum value observed between the first 5 readings and the compound injection. Reflects the fluorescence reading of Max-Min. Concentration response curves were analyzed by nonlinear regression analysis (sigmoidal dose response) using GraphPad Prism (GraphPad Software, San Diego, Calif.). IC ₅₀ values are calculated using GraphPad.
The I _max value was calculated using the following formula: :
I _max = maximum reaction compound concentration in the count _{-Ago (EC 80) / Basal-} Ago (EC 80) × 100
Where Basal and Ago (EC ₈₀ ) represent the average counts obtained in the absence or presence of 5 nM ghrelin, respectively, in the second addition step.

Aequorin functional assay (ghrelin receptor)
The functional activity of the compounds of the invention found to bind to the GHS-R1a receptor can be determined using the methods described below. (LePoul, E .; et al. Adaptation of aequorin functional assignment to high throughput screening. J. Biomol. Screen. 2002, 7, 57-65; Bednarek, M.A. 43, J. 43. 43. growth hormone-releasing peptide ghrelin: minimal sequence of ghrelin necessary of activation of growth harmony secretagogue receptor. al.Spiro (indoline-3,4'-piperidine) growth hormone secretagogues as ghrelin mimetics.Bioorg.Med.Chem.Lett.2001,11,1955-1957).

Materials Membranes were prepared using the cell line AequoScreen ™ (EUROSCREEN, Belgium) expressing the human ghrelin receptor (ES-410-A cell line; receptor accession number # 60179). This cell line was constructed by transfection of human ghrelin receptor into CHO-K1 cells co-expressing Gα ₁₆ and mitochondria targeted aequorin (reference number ES-WT-A5).
1. Ghrelin (control agonist; Bachem, # H-4864)
2. Assay buffer: DMEM (Dulbecco's modified Eagle medium) containing 0.1% BSA (bovine serum albumin; pH 7.0)
3. Coelenterazine (Molecular Probes, Leiden, The Netherlands)
Final test concentration of compound (N = 8): 10, 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001 μM.

Compound Handling A stock solution of compound (10 mM in 100% DMSO) was prepared frozen on dry ice and stored at −20 ° C. until use. A 500 μM concentration mother solution diluted 20-fold in 26% DMSO was made from the stock solution. Next, assay plates were prepared by appropriate dilution in DMEM medium containing 0.1% BSA. Under these conditions, the maximum final DMSO concentration in this assay was <0.6%.

Cell Preparation AequoScreen ™ cells were harvested from culture plates containing phosphate buffered saline (PBS) without Ca ²⁺ and Mg ²⁺ supplemented with 5 mM EDTA, pelleted at 1000 × g for 2 minutes, Resuspended in DMEM-Ham's F12 containing 0.1% BSA at a density of 5 × 10 ⁶ cells / ml and incubated overnight at room temperature in the presence of 5 μM coelenterazine. After the addition, the cells were diluted with assay buffer to a concentration of 5 × 10 ⁵ cells / ml.

Assay Procedure For agonist testing, 50 μl of cell suspension was mixed with 50 μl of the appropriate concentration of test compound or ghrelin (control agonist) in 96 well plates (duplicate samples). To confirm the experiment, ghrelin (control agonist) was tested at several concentrations simultaneously with the test compound. Luminescence produced by receptor activation in response to ghrelin or test compound was recorded using a Hamamatsu FDSS 6000 reader (Hamamatsu Photonics KK, Japan).

For antagonist testing, ghrelin at an EC ₈₀ concentration (ie 3.7 nM; 100 μL) is injected into a cell suspension (duplicate sample) containing the test compound 15-30 minutes after the end of the agonist test, The resulting luminescence caused by receptor activation was measured as described in the above paragraph.

Results analysis and display results are expressed as relative light units (RLU). Concentration response curves were analyzed by nonlinear regression analysis (sigmoidal dose response) using GraphPad Prism (GraphPad Software, San Diego, Calif.), Where E = Emax / (1 + EC ₅₀ / C) n, where E is RLU values (C) measured at a given agonist concentration, E _max is the maximum response, EC ₅₀ is the concentration producing 50% stimulation, and n is the slope index). For agonist testing, the results for each concentration of test compound were expressed as percent activation compared to the signal induced by a concentration of ghrelin equal to EC ₈₀ (ie 3.7 nM). EC ₅₀ , Hill slope and% E _max values are reported.

Antagonists test, represents the result of each concentration of test compound, as percent inhibition compared to induced signals in ghrelin concentration equal to EC _80.

In the assay of Example 3, representative compounds of the present invention demonstrated the activities shown in Table 4. The results for compound 152 are shown in FIG. Furthermore, compound 152 did not demonstrate any receptor activation compared to known ghrelin agonists. In the assay of Example 2, Compound 502 was produced functional K _i of level B.

Inverse Agonist Assay Inverse agonist activity at the ghrelin receptor of the compounds of the present invention is described in International Patent Application Publication No. WO 2004/056869 and Holst, B. et al. Cygankiewicz, A .; Halkjaer, T .; Ankersen, A .; Schwartz, T .; W. High constitutive signaling of the ghrelin receptor-identification of a potential investigator. Mol. Endocrinol. It can be determined using the method described in 2003, 17, 2201-2210. Results of representative compounds of the present invention are shown in Table 5.

  The foregoing is illustrative of the present invention and should not be construed as limiting the invention. The invention is defined in the claims, and equivalent language in the claims is also included therein.

2 is a graph showing the results of a study evaluating the functional activity of exemplary compounds of the invention. FIG. 1 (A) is a graph depicting the lack of agonist activity of exemplary compounds at the hGHS-R1a receptor. FIG. 1 (B) is a graph showing the lack of antagonist activity at the hGHS-R1a receptor. The materials and methods of this study are described in more detail in Example 3. 1 shows a chemical synthesis scheme of exemplary compounds of the present invention. 2 shows a chemical synthesis scheme of another exemplary compound of the invention.

Claims (27)

Formula (I):

(Where:
X is NR ₁₃ and R ₁₃ is hydrogen or C _1-4 alkyl or R ₁₂ and R ₂ together form a 3-, 4-, 5-, 6- or 7-membered heterocycle and, wherein the ring is optionally include O, and S or additional N atoms in the ring, optionally substituted with R _8, R ₈ is a hydrogen atom bonded to two atoms adjacent are substituted, substituted cycloalkyl Alkyl, substituted fused cycloalkyl, heterocycle, substituted heterocycle, aryl, substituted aryl, heteroaryl or substituted heteroaryl ring;
Z ₁ is NR ₁₁ , R ₁₁ is hydrogen, or C _1-4 alkyl, or R ₁₁ together with R ₃ is a 4-membered, 5-membered, 7-membered or 8-membered heterocyclic ring. Formed, said ring optionally containing O, S or an additional N atom in the ring, optionally substituted with R ₈ as defined above;
Z ₂ is NH;
m, n and p are each 0;
R ₁ and R ₆ are each independently hydrogen;
R ₂ represents — (CH ₂ ) _S CH ₃ , —CH (CH ₃ ) (CH ₂ ) _t CH ₃ , — (CH ₂ ) _u CH (CH ₃ ) ₂ , —C (CH ₃ ) ₃ , — ( _{CH 2) v -R 14, -CH} (oR 15) CH 3, cycloalkyl or substituted cycloalkyl,, s is 3, 4 or 5; t is 1, 2 or 3 U is 0, 1, 2 or 3; and v is 0, 1, 2, 3 or 4; R ₁₄ is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl or substituted cycloalkyl; R ₁₅ is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, acyl, aminoacyl, sulfonyl, carboxyalkyl, carboxyaryl, amide, aryl, substituted aryl, hete Alternatively, R ₂ and R ₁₃ together form a 3-membered, 4-membered, 5-membered, 6-membered or 7-membered heterocyclic ring, said ring optionally comprising O, S Or an additional N atom in the ring, optionally substituted with R ₈ as defined above;
R ₃ and R ₄ are each independently an amino acid side chain comprising —CH ₃ , —CH ₂ CH ₃ , —CH (CH ₃ ) ₂ , —CR _17a R _17b (OR ₁₆ ) —, or hydrogen. Yes; or R ₃ and R ₄ together, or R ₃ and R ₇ together, each optionally contains an O or S atom in the ring, optionally substituted with an already defined R ₈ Forms a 3-membered, 4-membered, 5-membered, 6-membered or 7-membered ring; alternatively, R ₃ and R ₁₁ together form a 4-membered, 5-membered, 6-membered, 7-membered or 8-membered heterocyclic ring. Formed, said ring optionally containing O, S or an additional N atom in the ring, optionally substituted with R ₈ as defined above;
In the above formula,
R ₁₆ is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, acyl, aminoacyl, sulfonyl, carboxyalkyl, carboxyaryl, amide, aryl, substituted aryl, heteroaryl and substituted heteroaryl And R _17a and R _17b are each independently hydrogen, —CH ₃ , —CH ₂ CH ₃ , —CH (CH ₃ ) ₂ or —C (CH ₃ ) ₃ ;
R _{5 is, - (CH 2) W CH} 3, -CH (CH 3) (CH 2) X CH 3, - (CH 2) y CH (CH 3) 2, -C (CH 3) 3, - ( _{CH 2) Z1 -R 18a, -} (CR 110 R 111) is an amino acid side chain comprising _z2 -R _18b, w is an 2, 3, 4 or 5; x is 1, 2 or 3 Y is 0, 1, 2 or 3; z1 is 0, 1, 2, 3 or 4; z2 is 0, 1 or 2; and R _18a and R _18b are each independently aryl , Substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl and substituted cycloalkyl; R ₁₁₀ and R ₁₁₁ are each independently hydrogen, C ₁ -C ₄ alkyl, hydroxyl, amino or fluoro, provided that At least one of R ₁₁₀ and R ₁₁₁ is not hydrogen);
R ₇ is hydrogen, or C ₁ -C ₄ alkyl, or R ₇ and R ₃ together each optionally contain an O or S atom in the ring, optionally with R ₈ as defined below Forming a substituted 3-, 4-, 5-, 6- or 7-membered ring;
R ₈ is substituted with one or more hydrogen atoms of a 3-membered, 4-membered, 5-membered, 6-membered or 7-membered ring structure, and is independently alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, Ring, substituted heterocycle, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hydroxy, alkoxy, aryloxy, oxo, amino, halogen, formyl, acyl, carboxy, carboxyalkyl, carboxyaryl, amide, carbamoyl, guanidino, ureido R ₈ is selected from the group consisting of amidino, mercapto, sulfinyl, sulfonyl and sulfonamide, or R ₈ is a substituted cycloalkyl, substituted fused cycloalkyl, fused, which replaces a hydrogen atom bonded to two adjacent atoms Heterocycle, substituted fused heterocyclic group, fused aryl, substituted fused An aryl, fused heteroaryl or substituted fused heteroaryl ring; and T is of the formula IV:
_{-U- (CH 2) d -W-} Y-Z- (CH 2) e - (IV)
Wherein d and e are each independently 0, 1, 2, 3, 4 or 5; Y and Z are each optionally present; U is —CR ₂₁ R ₂₂ —, or —C (═O) —, which is bonded to X in Formula I; W, Y, and Z are —O—, —NR ₂₃ —, —S—, —SO, respectively. —, —SO ₂ —, —C (═O) —O—, —O—C (═O) —, —C (═O) —NH—, —NH—C (═O) —, —SO _2. —NH—, —NH—SO ₂ —, —CR ₂₄ R ₂₅ —, —CH═CH—, —C≡C— in the Z or E configuration, or the following ring structure:

Wherein G ₁ and G ₂ are each independently a covalent bond, or —O—, —NR ₃₉ —, —S—, —SO—, —SO ₂ —, —C (═O) —, — C (═O) —O—, —O—C (═O) —, —C (═O) NH—, —NH—C (═O) —, —SO ₂ —NH—, —NH—SO ₂ A divalent group selected from the group consisting of —, —CR ₄₀ R ₄₁ —, —CH═CH— in the Z or E configuration, and —C≡C—; G ₁ is the closest bond to the group U Any carbon atom in the ring, unless otherwise defined, is optionally replaced by N (provided that the ring cannot contain more than 4 N atoms); K ₁ , K ₂ , K ₃ , K ₄ and K ₅ are each independently O, NR ₄₂ or S, and R ₄₂ is defined below);
R ₂₁ and R ₂₂ are each independently hydrogen, lower alkyl, or substituted lower alkyl, or R ₂₁ and R ₂₂ together are optionally selected from the group consisting of O, S and N Forming a 3- to 12-membered cyclic ring containing one or more heteroatoms, said ring optionally being substituted with R ₈ as defined above;
R ₂₃ , R ₃₉ and R ₄₂ are each independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, aryl, substituted aryl, heteroaryl, substituted heteroaryl, formyl, acyl , Carboxyalkyl, carboxyaryl, amide, amidino, sulfonyl or sulfonamide;
R ₂₄ and R ₂₅ are each independently hydrogen, lower alkyl, substituted lower alkyl, R _AA (R _AA is a side chain of a common or unusual amino acid), or R ₂₄ and R ₂₅ together Optionally forms a 3- to 12-membered cyclic ring containing one or more heteroatoms selected from the group consisting of O, S and N; or one of R ₂₄ and R ₂₅ is hydroxy, alkoxy , Aryloxy, amino, mercapto, carbamoyl, amidino, ureido or guanidino, the other being hydrogen, lower alkyl or substituted lower alkyl (the carbon bound to R ₂₄ and R ₂₅ is also bound to another heteroatom Except when)
R ₂₆ is optionally present and, when present, replaces one or more hydrogen atoms of the indicated ring, each independently of halogen, trifluoromethyl, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic Ring, substituted heterocycle, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hydroxy, alkoxy, aryloxy, amino, formyl, acyl, carboxy, carboxyalkyl, carboxyaryl, amide, carbamoyl, guanidino, ureido, amidino, cyano Selected from the group consisting of nitro, mercapto, sulfinyl, sulfonyl and sulfonamide;
R ₂₇ is optionally present and, when present, replaces one or more hydrogen atoms of the indicated ring, each independently alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, Aryl, substituted aryl, heteroaryl, substituted heteroaryl, hydroxy, alkoxy, aryloxy, oxo, amino, formyl, acyl, carboxy, carboxyalkyl, carboxyaryl, amide, carbamoyl, guanidino, ureido, amidino, mercapto, sulfinyl, sulfonyl And selected from the group consisting of sulfonamides;
R ₂₈ , R ₂₉ , R ₃₀ , R ₃₂ , R ₃₃ , R ₃₄ , R ₃₆ and R ₃₇ are each optionally present, and are desired if there is no double bond at the carbon atom bonded in the ring. 2 groups are present, if present, replace one hydrogen present in the ring, or if there is no double bond at the carbon atom bonded in the ring, 2 present in the ring One or both of the hydrogen atoms are substituted, each independently alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, aryl, substituted aryl, heteroaryl, substituted heteroaryl, Hydroxy, alkoxy, aryloxy, oxo, amino, formyl, acyl, carboxy, carboxyalkyl, carboxyaryl, amide, carbamoyl, guanidino, ureido, amidino, merca DOO, sulfinyl, sulfonyl, sulfonamido and halogen only when the double bond to a carbon atom bound to exist, is selected from the group consisting of;
R ₃₁ , R ₃₅ and R ₃₈ are each optionally present, and when present, replace one or more hydrogen atoms of the indicated ring, each independently halogen, trifluoromethyl, alkyl, substituted alkyl, Cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hydroxy, alkoxy, aryloxy, amino, formyl, acyl, carboxy, carboxyalkyl, carboxyaryl, amide, carbamoyl , Guanidino, ureido, amidino, cyano, nitro, mercapto, sulfinyl, sulfonyl and sulfonamide; and R ₄₀ and R ₄₁ are each independently hydrogen, lower alkyl, substituted lower alkyl, or as defined above whether it is R _AA, or R ₄₀ Hoyo R ₄₁ together optionally O, to form a cyclic ring of 3-membered to 12-membered containing one or more heteroatoms selected from the group consisting of S and N, wherein said ring previously defined optionally Substituted with R ₈ or one of R ₄₀ and R ₄₁ is hydroxy, alkoxy, aryloxy, amino, mercapto, carbamoyl, amidino, ureido or guanidino, the other is hydrogen, lower alkyl or substituted lower alkyl Yes (except when the carbon to which R ₄₀ and R ₄₁ are attached is also attached to another heteroatom);
However, T is not an amino acid residue, a dipeptide fragment, a tripeptide fragment or a higher order peptide fragment containing standard amino acids. )
Or an optical isomer, enantiomer, diastereomer, racemate or stereochemical mixture thereof. T has the following structure:

(Wherein (Z ₂ ) is the site of covalent bonding of T to Z ₂ , Z ₂ is defined above, (X) is the site of covalent bonding of T to X, and X is As defined above;
U ₁ and U ₃ are each independently —CR ₁₀₁ R ₁₀₂ — or —C (═O) —;
U ₂ is —CR ₁₀₁ R ₁₀₂ — and R ₁₀₀ is lower alkyl;
R ₁₀₁ and R ₁₀₂ are each independently hydrogen, lower alkyl or substituted lower alkyl;
L ₇ is —CH ₂ — or —O—;
xx is 2 or 3;
yy is 1 or 2;
zz is 1 or 2; and aaa is 0 or 1. )
2. A compound according to claim 1 selected from one of: R ₃ is H;
R ₄ is —CR _43a R _43b (OR ₄₄ ) (R _43a and R _43b are each independently hydrogen or lower alkyl, and R ₄₄ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, or acyl. Is));
The compound according to claim 1, wherein R ₇ is hydrogen or lower alkyl. The following structure:

Or an optical isomer, enantiomer, diastereomer, racemate or stereochemical mixture thereof. A pharmaceutical composition comprising (a) the compound of claim 1; and (b) a pharmaceutically acceptable carrier, excipient or diluent. A pharmaceutical composition comprising (a) a compound according to claim 4; and (b) a pharmaceutically acceptable carrier, excipient or diluent. The following structure:

Comprising one or more containers having a drug dosage unit further comprising an effective amount of one or more compounds having the formula: or optical isomers, enantiomers, diastereomers, racemates or stereochemical mixtures thereof, wherein said containers are optional A kit packaged with the instructions for use.   8. A method of modulating GHS-R1a receptor activity in a mammal comprising administering to the mammal an effective amount of a GHS-R1a receptor activity modulating compound of claim 1.   9. The method of claim 8, wherein administering a GHS-R1 receptor activity effective amount of Compound 1 does not result in a significant amount of growth hormone release.   9. The method of claim 8, wherein the compound is a ghrelin receptor antagonist.   9. The method of claim 8, wherein the compound is a GHS-R1a receptor antagonist.   9. The method of claim 8, wherein the compound is a ghrelin receptor inverse agonist.   9. The method of claim 8, wherein the compound is a ghrelin receptor antagonist and a ghrelin receptor inverse agonist.   A method of treating a metabolic and / or endocrine disorder comprising administering an effective amount of the compound of claim 1 to a subject in need of treatment.   The method according to claim 14, wherein the metabolic disorder and / or endocrine disorder is obesity or an obesity-related disease.   15. The method according to claim 14, wherein the metabolic disorder and / or endocrine disorder is type II diabetes.   A method of treating a metabolic and / or endocrine disorder comprising administering an effective amount of the compound of claim 4 to a subject in need of treatment.   A method of treating an inflammatory disease comprising administering to a subject in need of treatment an effective amount of a compound of claim 1.   A method of treating cardiovascular disease comprising administering to a subject in need of treatment an effective amount of a compound of claim 1.   A method of treating a hyperproliferative disorder comprising administering an effective amount of a compound of claim 1 to a subject in need of treatment.   A method of treating an appetite disorder or eating disorder comprising administering an effective amount of the compound of claim 1 to a subject in need of treatment.   A method of treating Prader-Willi syndrome comprising administering an effective amount of a compound of claim 1 to a subject in need of treatment.   A method of treating a gastrointestinal disorder comprising administering an effective amount of the compound of claim 1 to a subject in need of treatment.   A method of treating liver disease comprising administering to a subject in need of treatment an effective amount of a compound of claim 1.   The method according to claim 24, wherein the liver disease is cirrhosis or chronic liver disease.   A method of treating bulimia comprising administering an effective amount of a compound of claim 1 to a subject in need of treatment.   27. The method of claim 26, wherein the bulimia is diabetic bulimia.

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