TWI414523B - Heterocyclic receptor agonists for the treatment of diabetes and metabolic disorders - Google Patents

Abstract

Compounds and methods are provided for the treatment of, inter alia, Type II diabetes and other diseases associated with poor glycemic control. The compounds of the invention are orally active.

Description

Heterocyclic receptor agonist for the treatment of diabetes and metabolic disorders

Diabetes can be divided into two clinical syndromes, type I and type II diabetes. Type I diabetes, or insulin-dependent diabetes, is a chronic autoimmune disease characterized by beta cells in the Langerhans' islet island that produces insulin (hereinafter referred to as "islet cells" or "pancreatic islet cells"). The vast loss. Because these cell lines are progressively destroyed, the amount of insulin secreted is reduced, so when the amount secreted falls below the level required for normal blood glucose (normal blood sugar content), it eventually leads to hyperglycemia (abnormally high content). Glucose in the blood). Although it is not known that the immune response is indeed the beginning, patients with type I diabetes have high levels of antibodies against pancreatic beta cells (hereinafter "β cells"). However, not all patients with high levels of these antibodies develop Type I diabetes.

Type II diabetes, or non-insulin-dependent diabetes, develops when muscle, fat, and liver cells fail to respond normally to insulin. Such failure to respond (referred to as insulin resistance) may be due to a decrease in the number of insulin receptors on such cells, or a dysfunction of signaling pathways within the cell, or both. Beta cells initially compensate for this insulin resistance by increasing their insulin output. Over time, these cells became unable to produce sufficient insulin to maintain normal glucose levels, indicating progression to type 2 diabetes (Kahn SE, Am. J. Med . (2000) 108 Supplement 6a, 2S-8S).

Fasting hyperglycemia characterized by type II diabetes occurs due to combined damage of insulin resistance and beta cell dysfunction. Beta cell defects have two components: the first component, the elevation of basal insulin release (lower non-stab It occurs in the presence of stimulating glucose concentrations and is found in obese insulin-resistant pre-diabetes and type II diabetes. The second component is the failure to increase insulin release above the elevated substrate output in response to hyperglycemia challenge. This lesion is not present in the pre-diabetes and is shown to shift from a normal glycemic insulin resistant state to significant diabetes. There is currently no cure for diabetes. Therapeutic treatments for diabetes are extremely limited and focus on attempts to control blood glucose levels to minimize or delay complications. Current treatments are based on either insulin resistance (metformin, thiazolidinedione ("TZD")) or insulin release from beta cells (sulfonylureas, exanatide). Sulfonamides and other compounds that act by depolarizing beta cells have side effects of hypoglycemia, which cause insulin secretion that is unrelated to circulating glucose levels. One licensed drug, Byetta (exanatide), stimulates insulin secretion only in the presence of high glucose, but is not effective for oral administration and must be injected. Januvia (sitagliptin) is another recently licensed drug that increases the blood levels of incretin hormone, which increases insulin secretion, reduces glucagon secretion, and has Others are less well characterized. However, allovir and other dipeptidyl peptidase IV inhibitors may also affect the tissue content of other hormones and peptides, and the long-term results of this broader effect have not been fully investigated. There are unmet needs for oral drugs that stimulate insulin secretion in a glucose-dependent manner.

Progressive insulin resistance and loss of insulin-secreting pancreatic β-cells are major features of type II diabetes. Under normal conditions, the decrease in insulin sensitivity in muscle and fat is compensated by increasing insulin secretion from β-cells. However, loss of beta-cell function and quality can lead to insulin insufficiency and diabetes (Kahn BB, Cell 92: 593-596, 1998; Cavaghan MK et al, J. Clin. Invest . 106: 329-333. 2000; Saltiel AR, Cell 104: 517-529, 2001; Prentki M and Nolan CJ. J Clin Invest . 116: 1802-1812. (2006); and Kahn SE. J. Clin. Endocrinol. Metab . 86: 4047-4058, 2001 ). Hyperglycemia further accelerates the decline in beta-cell function (UKPDS Group, JAMA . 281: 2005-2012, 1999; Levy J et al, Diabetes Med . 15: 290-296, 1998; and Zhou YP et al, J Biol Chem 278: 51316-23, 2003). Several genes in which the duality variant is associated with an increased risk of type 2 diabetes are selectively expressed in beta cells (Bell GI and Polonsky KS, Nature 414: 788-791 (2001); Saxena R et al. People, Science . (2007) April 26; [pre-press Epub]; and Valgerdur Steinthorsdottir et al., Nature Genetics (2007) April 26; [pre-press Epub]).

Insulin secretion from pancreatic islet β cells is induced by increased blood glucose levels. Glucose is mainly dissolved in beta cells by beta cells and the liver selective transporter GLUT2 (Thorens B. Mol Membr Biol . 2001-December 2001; 18(4): 265-73). Once inside the cell, glucose is phosphorylated by glucokinase, which is the major glucose sensor in beta cells, as it catalyzes the irreversible rate-limiting step in glucose metabolism (Matschinsky FM. Curr Diab Rep . 2005 June; 5(3): 171-6). The rate of glucose-6-phosphate production by glucokinase is determined by the concentration of glucose around the beta cells. Therefore, this enzyme allows a direct relationship between the glucose content in the blood and the overall rate of glucose oxidation by the cells. Mutations in glucokinase produce abnormalities in glucose-dependent insulin secretion in humans, which leads to further evidence that members of this hexokinase group play a key role in the response to glucose islets (Gloyn AL et al., J Biol) Chem . April 8, 2005; 280(14): 14105-13. Epub January 25, 2005). Small molecule activators of glucokinase enhance insulin secretion and provide therapeutics for the use of this enzyme (Guertin KR and Grimsby J. Curr Med Chem . 2006; 13(15): 1839-43; with Matschinsky FM et al, Diabetes 2006 January; 55(1): 1-12) A way of characterizing diabetes. Glucose metabolism via glycogenolysis and mitochondrial oxidative phosphorylation ultimately results in ATP production, and the amount of ATP produced in beta cells is directly related to the glucose concentration exposed by the beta cells.

Increasing the ATP to ADP ratio in the presence of higher glucose results in closure of the Kir6.2 channel via interaction with the SUR1 subunit of the channel complex. The closure of these channels on the beta cell plasma membrane results in depolarization of the cell membrane and subsequent activation of voltage-dependent calcium channels (VDCC) (Ashcroft FM and Gribble FM, Diabetologia 42: 903-919, 1999; And Seino S, Annu Rev Physiol . 61: 337-362, 1999). The entry of calcium ions and the release of calcium from intracellular stores triggers the cleavage of insulin particles, causing the secretion of insulin into the bloodstream. Agents for the Kir6.2 channel, such as sulfonyl ureas and metaglitinide, are closed (Rendell M. Drugs 2004; 64(12): 1339-58; and Blickle JF, Diabetes Metab . 2006 4 Month; 32(2): 113-20) also causes cell membrane depolarization, so these agents stimulate insulin secretion in a glucose-independent manner. Potassium channel opener, such as chlorotoluene By preventing the increased ratio of ATP/ADP, the Kir6.2 channel is prevented from being shut down to inhibit insulin secretion (Hansen JB. Curr Med Chem . 2006; 13(4): 361-76). Calcium channel blockers, such as verapamil and nifedipine, also inhibit insulin secretion (Henquin, JC (2004) Diabetes 53, S48-S58). Although sulfonyl ureas and metaglitinides are clinically effective glucose lowering agents, they may work without regard to blood glucose levels. These drugs may cause hypoglycemia because their function does not correlate with glucose levels.

Glucose-dependent insulin secretion from beta cells is dependent on a variety of neurotransmitters and hormones with blood, as well as local islet factors. CNS activation of the vagus nerve distribution of islets can lead to the release of small molecules such as acetylcholine and peptides, such as vascular intestinal polypeptide (VIP), gastrin releasing peptide (GRP), and pituitary adenylate cyclase Activated peptide (PACAP). Phospholipase C undergoes G _{αq -coupled} GPCR M3 muscarinic receptor acetylcholine activation, resulting in the release of Ca++ from intracellular stores (Gilon P and Henquin JC. Endocr Rev. 2001 October; 22 (5): 565-604). Cholinergic agonists also lead to ingenious Na+-dependent serosal depolarization, which works synergistically with glucose-induced depolarization to enhance insulin release (Gilon P and Henquin JC. Endocr Rev. 2001) October; 22(5): 565-604). The overlapping combination of VIP and PACAP binding to G[ _alpha] -coupled GPCRs (PAC1, VIPR1 and VIPR2) on beta cells leads to stimulation of adenylate cyclase and increased intracellular cAMP (Filipsson K et al, Diabetes , September 2001; 50(9): 1959-69; Yamada H et al., Regul Pept . December 15, 2004; 123(1-3): 147-53; and Qader SS et al., Am J Physiol Endocrinol Metab . May 2007; 292(5): E1447-55).

An increase in beta cell cAMP, in the presence of stimulating glucose, has a substantial potentiation of insulin secretion (see below). Unfortunately, many enhancers of glucose-stimulated insulin secretion also have an effect on the outside of the islet, which limits its ability to be used as a therapeutic agent for diabetes. For example, the most potent selective muscarine agonist that stimulates insulin secretion can also stimulate a variety of undesired responses in a variety of tissues (Rhoades RA and Tanner GA (2003) Medical Physiology , 2nd Edition, Lippincott, Williams and Wilkins. ISBN 0-7817-1936-4). Similarly, VIP and PACAP receptor systems exist in a variety of organ systems and mediate effects on reproduction, immunity, and a variety of other systems, making them less attractive as specific enhancers of glucose-dependent insulin secretion.

Incretin hormones, such as glucagon peptide 1 (GLP-1) and glucose-dependent insulin polypeptides (GIP, also known as gastric inhibitory polypeptides), also bind to islet cells, including specific Galpha _s on the surface of beta cells. Coupling GPCR receptors and increasing intracellular cAMP (Drucker DJ, J Clin Invest . January 2007; 117(1): 24-32). Although the system of hormone receptors is present in other cells and tissues, the overall sum of the effects of these peptides has been shown to be beneficial in controlling glucose metabolism in organisms (Hansotia T et al., J Clin Invest . 2007). January; 117(1): 143-52. Epub December 21, 2006). GIP and GLP-1 are produced and secreted separately from intestinal K and L cells, and these peptide hormones are released in response to three meals, by the direct action of nutrients in the intestinal lumen, and due to food feeding. The nerve stimulation of the formation. GIP and GLP-1 have a short half-life in the human circulation, which is caused by the action of the protease dipeptidyl-peptidase IV (DPP IV), and the inhibitor of this protease can lower blood sugar, which is due to its elevation of the intestine. Due to the ability of the insulinotropic peptide to be in the form of an active form. However, the glucose reduction system that can be obtained with DPPIV inhibitors is somewhat limited because these drugs rely on endogenous release of incretin hormones. Peptides that bind to the GIP or GLP-1 receptor but are resistant to serum protease cleavage (such as exanatide (Byetta)) and peptide conjugates can also substantially lower blood glucose (Gonzalez C et al, Expert Opin Investig Drugs August 2006; 15(8): 887-95), but these incretins must be injected and tend to cause high nausea, so it is not used for general purposes. The ideal treatment in a group of individuals with type 2 diabetes. The clinical success of DPPIV inhibitors and incretin mimetic, although not ideal, does indicate potential use of compounds that increase incretin activity in the blood or directly stimulate cAMP in beta cells. Some studies have shown a reduction in the beta cell response line of GIP in type II diabetes (Nauck MA et al, J. Clin. Invest . 91: 301-307 (1993); and Elahi D et al, Regul . Pept . 51: 63-74 (1994)). This responsive repair (Meneilly GS et al., Diabetes Care . January 1993; 16(1): 110-4) is a promising way to improve beta cell function in vivo.

Since increased incretin activity has a positive effect on glucose-dependent insulin secretion and other mechanisms that may lead to lowering blood glucose, it is also of interest to excavate treatments that increase intestinal insulin release from intestinal K and L cells. way. The GLP-1 secretory line has been shown to be attenuated in type 2 diabetes (Vilsboll T et al, Diabetes 50: 609-613), so improving incretin release can correct this metabolic dysfunction component. Nutrients, such as glucose and fat in the lumen of the intestine, promote incretin secretion by interaction with apical receptors (Vilsboll T et al, Diabetes 50: 609-613). GLP-1 and GIP release can also be caused by nerve stimulation; for insulin secretion, acetylcholine and GRP may be similar to the way these neurotransmitters act on beta cells, enhancing incretin release (Brubaker P, Ann NY Acad Sci . July 2006; 1070: 10-26; and Reimann F et al, Diabetes December 2006; 55 (Supplement 2): S78-S85). Growth hormone releasing inhibitors, leptin and free fatty acids have also been shown to modulate incretin secretion (Brubaker P, Ann NY Acad Sci . July 2006; 1070: 10-26; and Reimann F et al., Diabetes 2006) December; 55 (Supplement 2): S78-S85). However, there has not yet been a way to selectively impact these pathways to promote incretin secretion that provides therapeutic benefits. There is a need for oral medications that stimulate incretin secretion to treat diabetes.

Incretin is also available in animal models (Farilla L et al., Endocrinology , November 2002; 143(11): 4397-408) and in vitro human islets (Farilla L et al., Endocrinology , December 2003; 144 ( 12): 5149-58) increases the rate of beta cell proliferation and decreases the cell wilting rate of beta cells. The net result of these changes is an increase in the number of beta cells and the quality of the islets, and this should provide increased insulin secretion capacity, which is another desirable goal of anti-diabetic therapy. GLP-1 has also been shown to protect the islets from the destructive effects of agents (such as streptavidin) by blocking cell dying (Li Y et al, J Biol Chem . January 3, 2003; 278(1): 471-8). Cyclin D1, a key regulator of cell cycle progression, is regulated by GLP-1 and has a similar effect on other agents that increase cAMP and PKA activity (Friedrichsen BN et al., J Endocrinol . March 2006; 188(3): 481-92; with Kim MJ et al., J Endocrinol . March 2006; 188(3): 623-33). Increased cyclin D1 gene transcription occurs in response to PKA phosphorylation of CREB (cAMP-responsive element binding) transcription factor (Hussain MA et al, Mol Cell Biol. 2006 October; 26(20): 7747-59 ). There is a need for oral medications that increase the number of beta cells and islet mass to treat diabetes.

The beta cell cAMP content can also be increased by inhibiting the degradation of this second messenger by phosphodiesterase to AMP (Furman B and Pyne N, Curr Opin Investig Drugs October 2006; 7(10): 898-905) . There are several different cAMP phosphodiesterases in beta cells, and many of them have been shown to act as brakes on glucose-dependent insulin secretion. cAMP phosphodiesterase inhibitors of PDE have been demonstrated in vitro and in vivo to increase insulin secretion, comprising PDE1C, PDE3B, PDE10 (Han P, et al., J Biol Chem, 1999 August 6; 274 (32): 22337-44; Harndahl L et al., J Biol Chem . October 4, 2002; 277(40): 37446-55; Walz HA et al., J Endocrinol . June 2006; 189(3): 629-41 Choi YH et al., J Clin Invest . December 2006; 116(12): 3240-51; and Cantin LD et al., Bioorg Med Chem Lett . May 15, 2007; 17(10): 2869-73 ), but until now, PDE has not been found to have the cell type selectivity necessary to avoid unwanted effects. However, this is still an area of active research due to the expansion of incretins and other possibilities that stimulate the action of adenylate cyclase agents.

Presenting multiple mechanisms, elevated cAMP in beta cells can enhance glucose-dependent insulin secretion. Classically, many of the intracellular effects of cAMP are mediated by cAMP-dependent protein kinases (protein kinase A, PKA) (Hatakeyama H et al., J Physiol . January 15, 2006; 570(Pt 2): 271- 82). PKA contains two complexes that modulate the two catalytic functional sites; the binding of cAMP to the catalytic functional site releases the catalytic functional site and results in increased protein phosphorylation activity. One of the downstream effects of this kinase activity is enhanced insulin cytosolic efflux efficiency (Gromada J et al, Diabetes January 1998; 47(1): 57-65). Another cAMP-binding protein is Epac, a guanine nucleotide exchange factor (GEF) (Kashima Y et al, J Biol Chem . December 7, 2001; 276(49): 46046-53. Epub October 2001 11; and Shibasaki T et al, J Biol Chem . February 27, 2004; 279(9): 7956-61), which is cAMP-dependent on the cytosolic efflux of the vector, but not related to PKA. Epac activated by cAMP also enhances the release of intracellular Ca++ (Holz GG Diabetes , January 2004; 53(1): 5-13). The effect of cAMP on insulin secretion is dependent on increased glucose levels, so increasing cAMP in pancreatic beta cells is an important target for type II diabetes therapy.

The agent that increases the intracellular cAMP content in beta cells increases insulin secretion in a glucose-dependent manner (Miura Y and Matsui H, Am. J. Physiol Endocrinol. Metab (2003) 285, E1001-E1009). One mechanism for augmenting cAMP is by G-protein coupling to cell surface receptors, which stimulate the enzyme adenylate cyclase to produce more cAMP. The GLP-1 receptor system, which is the subject of exanatide, is an example of such a receptor (Thorens B et al, Diabetes (1993) 42, 1678-1682). There is a need for oral medications that increase the intracellular content of cAMP to treat diabetes.

Quite surprisingly, we have now discovered that another novel agonist IC-GPCR2, a G-protein coupled receptor ("GPCR"), can be used to treat diabetes. IC-GPCR2 also increased intracellular cAMP content (see Table 1 for in vitro activity in Biological Example 1). IC-GPCR2 is also known as RUP3 and GPR119. Such The elevated cAMP content increases insulin secretion in a glucose-dependent manner (see Biological Examples 2, 3, and 5), and thus provides a useful treatment for, inter alia, Type II diabetes. The novel agonists described in the present invention are orally active (see Biological Examples 3 and 5), providing significant differential characteristics of exanatide. In addition, Biological Example 5 provides data on the effects of GPRl 19 agonist on glucose content, insulin secretion, and body weight in diabetic ZDF rats (see Figures 3, 4, and 5). Biological Example 6 shows the triglyceride of the GPR119 agonist of the present invention with a glucose lowering effect. Biological Example 4 shows the tissue specific performance of GPR119. We have also found that nucleic acid probes corresponding to IC-GPCR2 are highly enriched in pancreatic islets (mostly beta cells) and are not detected in any other examined tissues (see figure). 1 and 2). This surprising event means that the novel agonists described in the present invention will be useful for diagnosing diseases affecting pancreatic islets, including beta cells, such as diabetes. IC-GPCR2 agonists capable of increasing intracellular cAMP levels have now been confirmed using cell-based screening (see Biological Example 1).

The present invention provides a compound represented by Formula I:

And pharmaceutical compositions containing such compounds.

The present invention further provides a compound represented by Formula II:

And a pharmaceutical composition comprising a compound of formula II.

Also provided are methods of treating diseases such as Type II diabetes and other diseases and conditions using one or more of such compounds or compositions, as further detailed below. The invention also provides methods of increasing the intracellular content of cyclic AMP (cAMP) using one or more of the compounds described herein. Furthermore, the compounds are useful in mammals, particularly humans, to stimulate insulin production and to stimulate the secretion of insulin, glucagon-like peptide 1 (GLP1) and glucose-dependent insulin polypeptide (GIP). In addition, the compounds described herein can be used to lower blood glucose when administered to a patient in need of treatment to lower blood glucose. The compounds of the invention may also be used to lower blood triglyceride levels in those in need of such treatment.

In a related aspect, the invention provides methods of diagnosing a variety of diseases and conditions using the identified compounds of Formula I or Formula II.

Detailed description of the invention Abbreviations and definitions

The abbreviations used herein are conventional unless otherwise defined: AcOH: acetic acid; nBuLi: n-butyllithium; Cs ₂ CO ₃ : cesium carbonate; CH ₂ Cl ₂ : dichloromethane; CH ₃ MgI: A Magnesium iodide; CuCl ₂ : copper chloride; DAST: (diethylamino) sulfur trifluoride; DEAD: diethyl azodicarboxylate; DIBAL: diisobutylaluminum hydride; DIPEA: diisopropyl Ethylethylamine; DMSO: dimethyl hydrazine; Et ₃ N: triethylamine; EtOAc: ethyl acetate; H ₂ : hydrogen; HBr: hydrogen bromide; HCl: hydrogen chloride; H ₂ O: water; H ₂ O ₂ : hydrogen peroxide; HPLC: high performance liquid chromatography; KCN: potassium cyanide; LHMDS: lithium hexamethyldifluoride; LiAlH ₄ : lithium aluminum hydride; LiOH: lithium hydroxide; MeCN: acetonitrile; MeI Methane iodide; MeOH: methanol; MgSO ₄ : magnesium sulfate; MgCO ₃ : magnesium carbonate; MsCl: methanesulfonyl chloride; NaHSO ₃ : sodium hydrogen sulfite; mCPBA: m-chloroperoxybenzoic acid; N ₂ : Ni; Na ₂ CO ₃ : sodium carbonate; NaHCO ₃ : sodium hydrogencarbonate; NaNO ₂ : sodium nitrite; NaOH: sodium hydroxide; Na ₂ S ₂ O ₃ : acid sodium sulfate; Na ₂ SO ₄ : sodium sulfate; NBS : N-bromine Amber (PEI); NH ₄ Cl: ammonium chloride; NH ₄ OAc: ammonium acetate; NMR: nuclear magnetic resonance; Pd / C: palladium / carbon; PPh _3: triphenylphosphine; iPrOH: isopropanol; SOCl _2: two Thionyl chloride; THF: tetrahydrofuran; TLC: thin layer chromatography.

Unless otherwise stated, the following terms used in this specification and claims have the following meanings: "alkyl" means a monovalent saturated aliphatic hydrocarbon group having from 1 to 10 carbon atoms. In some embodiments, it is from 1 to 6 carbon atoms. "C _uv alkyl" means an alkyl group having from u to v carbon atoms. By way of example, the term includes both linear and branched hydrocarbon radicals such as methyl (CH ₃ -), ethyl (CH ₃ CH ₂ -), n-propyl (CH ₃ CH ₂ CH ₂ -), isopropyl ((CH ₃ ) ₂ CH-), n-butyl (CH ₃ CH ₂ CH ₂ CH ₂ -), isobutyl ((CH ₃ ) ₂ CHCH ₂ -), second-butyl ((CH ₃ ) (CH ₃ CH ₂ )CH-), tert-butyl ((CH ₃ ) ₃ C-), n-pentyl (CH ₃ CH ₂ CH ₂ CH ₂ CH ₂ -) and neopentyl (CH ₃ ) 3CCH ₂ -).

"Substituted alkyl" means an alkyl group having from 1 to 5, and in some embodiments, from 1 to 3 or from 1 to 2 substituents selected from alkenyl, substituted alkenyl groups. , alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, decyl, decylamino, decyloxy, amine, substituted amine, amine carbonyl, amine thio Carbonyl group, aminocarbonylamino group, aminothiocarbonylamino group, aminocarbonyloxy group, aminosulfonyl group, aminosulfonyloxy group, aminosulfonylamino group, formazanyl group, aryl group Substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, azide, carboxyl, carboxy ester, (carboxy ester) amine, (carboxy ester) An oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, fluorenyl Substituted fluorenyl, halo, hydroxy, hydroxyamino, alkoxyamino, fluorenyl, substituted fluorenyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted Heteroaryloxy, heteroaryl Substituted, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylsulfide a nitro group, a spirocycloalkyl group, a SO ₃ H group, a substituted sulfonyl group, a sulfonyloxy group, a thiol group, a thiocyanate, a thiol, an alkylthio group, and a substituted alkylthio group, wherein This substituent is as defined herein.

"Alkylene" or "alkylidene" refers to a divalent saturated aliphatic hydrocarbon radical having from 1 to 10 carbon atoms, and in some embodiments, from 1 to 6 carbon atoms. "(C _uv )alkylene" means a secondary alkyl group having from u to v carbon atoms. Alkylene groups and alkylene groups include branched and straight chain hydrocarbon groups. For example, "(C _1-6 ) alkylene" is meant to include methylene, methine, propylene, 2-methyl propyl, pentylene, and the like.

"Substituted alkylene" or "substituted alkylidene" refers to an alkylene group having from 1 to 5, and in some embodiments, from 1 to 3 or from 1 to 2 substituents, Selected from alkoxy groups, substituted alkoxy groups, mercapto groups, mercaptoamine groups, nonyloxy groups, amine groups, substituted amino groups, aminocarbonyl groups, aminothiocarbonyl groups, aminocarbonylamino groups Aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, decyl, aryl, substituted aryl, Aryloxy, substituted aryloxy, arylthio, substituted arylthio, azide, carboxyl, carboxy ester, (carboxy ester) amine, (carboxy ester)oxy, cyano, Cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, fluorenyl, substituted thiol, Halo, hydroxy, hydroxyamino, alkoxyamino, fluorenyl, substituted fluorenyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, hetero Arylthio, substituted heteroaryl Thio group, heterocyclic group, substituted heterocyclic group, heterocyclic oxy group, substituted heterocyclic oxy group, heterocyclic thio group, substituted heterocyclic thio group, nitro group, ketone group, Thiol, spirocycloalkyl, SO ₃ H, substituted sulfonyl, sulfonyloxy, thiol, thiocyanate, thiol, alkylthio, and substituted alkylthio, wherein the substitution Bases are as defined herein.

"Alkenyl" means a linear or branched hydrocarbon radical having from 2 to 10 carbon atoms, and in some embodiments, from 2 to 6 carbon atoms or from 2 to 4 carbon atoms, and having at least one ethylene The base is not saturated (>C=C<). For example, (C _uv )alkenyl means an alkenyl group having from u to v carbon atoms, and is meant to include, for example, ethenyl, propenyl, 1,3-butadienyl and the like.

"Substituted alkenyl" means an alkenyl group having from 1 to 3 substituents, and in some embodiments, from 1 to 2 substituents selected from alkoxy groups, substituted alkoxy groups, Mercapto, mercaptoamine, decyloxy, alkyl, substituted alkyl, alkynyl, substituted alkynyl, amine, substituted amine, amine carbonyl, amine thiocarbonyl, amine Alkylcarbonylamino group, aminothiocarbonylamino group, aminocarbonyloxy group, aminosulfonyl group, aminosulfonyloxy group, aminosulfonylamino group, formazanyl group, aryl group, substituted Aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxy, carboxy ester, (carboxy ester) amine, (carboxy ester)oxy, cyano, Cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, fluorenyl, substituted thiol, Halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, Substituted heterocyclic group, Heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO ₃ H, substituted sulfonyl, sulfonyloxy, sulphur Mercapto, thiol, alkylthio and substituted alkylthio, wherein the substituents are as defined herein, with the proviso that any hydroxyl or thiol substitution is not attached to the acetylene carbon atom.

"Alkynyl" means a linear monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical containing at least one reference bond. The term "alkynyl" is also meant to include a hydrocarbon radical having one key bond and one double bond. For example, a (C ₂ -C ₆ )alkynyl group is meant to include ethynyl, propynyl and the like.

"Substituted alkynyl" refers to an alkynyl group having from 1 to 3 substituents, and in some embodiments, from 1 to 2 substituents selected from alkoxy groups, substituted alkoxy groups, Indenyl, mercaptoamine, nonyloxy, amine, substituted amine, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy , Aminosulfonyl, Aminosulfonyloxy, Aminosulfonylamino, Mercapto, Aryl, Substituted Aryl, Aryloxy, Substituted Aroyloxy, Aryl Sulfide Base, substituted arylthio, carboxyl, carboxy ester, (carboxy ester) amine, (carboxy ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, Substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, ring Alkenylthio, substituted cycloalkenylthio, fluorenyl, substituted fluorenyl, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryl Baseoxy, heteroaryl Substituted, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylsulfide a base, a nitro group, a SO ₃ H, a substituted sulfonyl group, a sulfonyloxy group, a thiol group, a thiol group, an alkylthio group, and a substituted alkylthio group, wherein the substituent is defined herein, and The proviso is that any hydroxyl or thiol substitution is not attached to the acetylene carbon atom.

"Alkoxy" refers to the group -O-alkyl, wherein alkyl is defined herein. For example, alkoxy includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, second-butoxy and n-pentane. Oxygen.

"Substituted alkoxy" refers to the group -O-(substituted alkyl) wherein the substituted alkyl is as defined herein.

"Mercapto" refers to the group HC(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl- C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, substituted fluorenyl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl- C(O)-, heterocyclic-C(O)- and substituted heterocyclic-C(O)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl Substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, substituted fluorenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted The heterocyclic groups are as defined herein. The fluorenyl group includes "ethenyl" CH ₃ C(O)-.

"N-mercaptoalkyl" refers to the group -NR ²⁰ C(O)H, -NR ²⁰ C(O)alkyl, -NR ²⁰ C(O) substituted alkyl, -NR ²⁰ C(O)cycloalkane , -NR ²⁰ C(O) substituted cycloalkyl, -NR ²⁰ C(O)alkenyl, -NR ²⁰ C(O) substituted alkenyl, -NR ²⁰ C(O) alkynyl, -NR ²⁰ C(O) substituted alkynyl, -NR ²⁰ C(O)aryl, -NR ²⁰ C(O) substituted aryl, -NR ²⁰ C(O)heteroaryl, -NR ²⁰ C(O) substitution a heterocyclic group, a -NR ²⁰ C(O) heterocyclic group and a -NR ²⁰ C(O) substituted heterocyclic ring wherein R ²⁰ is hydrogen or an alkyl group, and wherein the alkyl group, the substituted alkyl group, the alkene Alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic Both families and substituted heterocyclic groups are as defined herein.

"Alkoxy" means a group of HC(O)O-, alkyl-C(O)O-, substituted alkyl-C(O)O-, alkenyl-C(O)O-, Substituted alkenyl-C(O)O-, alkynyl-C(O)O-, substituted alkynyl-C(O)O-, aryl-C(O)O-, substituted aryl -C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, heteroaryl-C(O)O-, substituted heteroaryl -C(O)O-, heterocyclic-C(O)O- and substituted heterocyclic-C(O)O-, wherein alkyl, substituted alkyl, alkenyl, substituted alkene Alkyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted The ring family is as defined herein.

"Amino" means the group -NH _2.

"Substituted amine group" refers to the group -NR ²¹ R ²² wherein R ²¹ and R ²² are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl Substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, SO ₂ -alkyl, -SO ₂ -substituted alkyl, -SO ₂ -alkenyl, -SO ₂ -substituted alkenyl, -SO ₂ -cycloalkyl, -SO ₂ -substituted cycloalkyl, - SO ₂ -aryl, -SO ₂ -substituted aryl, -SO ₂ -heteroaryl, -SO ₂ -substituted heteroaryl, -SO ₂ -heterocyclyl and -SO ₂ -substituted heterocyclic And wherein R ²¹ and R ²² are bonded together with the nitrogen bonded thereto as appropriate to form a heterocyclic group or a substituted heterocyclic group, provided that neither R ²¹ nor R ²² is hydrogen. And wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, hetero An aryl group, a substituted heteroaryl group, a heterocyclic group, and a substituted heterocyclic group are as defined herein. When R ²¹ is hydrogen and R ²² is alkyl, the substituted amine is sometimes referred to herein as an alkylamine group. When R ²¹ and R ²² are alkyl groups, the substituted amines are sometimes referred to herein as dialkylamino groups. When referring to a monosubstituted amine group, it means that either R ²¹ or R ²² is hydrogen, but not both. When referring to a disubstituted amine group, it means neither R ²¹ nor R ²² is hydrogen.

"Hydroxyamino" refers to the group -NHOH.

"Alkoxyamino" refers to the group -NHO-alkyl, wherein alkyl is defined herein.

"Aminocarbonyl" refers to the group -C(O)NR ²³ R ²⁴ wherein R ²³ and R ²⁴ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, Alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic a hydroxyl group, an alkoxy group, a substituted alkoxy group, an amine group, a substituted amine group, and a mercaptoamine group, and wherein R ²³ and R ²⁴ are bonded together with the nitrogen bonded thereto as appropriate Forming a heterocyclic or substituted heterocyclic group wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted Cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

"Aminothiocarbonyl" refers to the group -C(S)NR ²³ R ²⁴ wherein R ²³ and R ²⁴ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkene. Alkyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted a cyclic group, and wherein R ²³ and R ²⁴ are bonded together with the nitrogen bonded thereto as appropriate to form a heterocyclic or substituted heterocyclic group, wherein an alkyl group, a substituted alkyl group, Alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hetero Both cyclo and substituted heterocyclic are as defined herein.

"Aminocarbonylamino" refers to the group -NR ²⁰ C(O)NR ²³ R ²⁴ wherein R ²⁰ is hydrogen or alkyl, and R ²³ and R ²⁴ are independently selected from the group consisting of hydrogen, alkyl, and substituted. Alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted An aryl group, a heterocyclic group and a substituted heterocyclic group, wherein R ²³ and R ²⁴ are bonded together with the nitrogen bonded thereto, as appropriate, to form a heterocyclic group or a substituted heterocyclic group, And wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, hetero The aryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are all as defined herein.

"Aminothiocarbonylamino" refers to the group -NR ²⁰ C(S)NR ²³ R ²⁴ wherein R ²⁰ is hydrogen or alkyl, and R ²³ and R ²⁴ are independently selected from the group consisting of hydrogen, alkyl, Substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted a heteroaryl group, a heterocyclic group and a substituted heterocyclic group, wherein R ²³ and R ²⁴ are bonded together with the nitrogen bonded thereto as appropriate to form a heterocyclic group or a substituted heterocyclic group. a group, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl , heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

"Aminocarbonyloxy" refers to the group -OC(O)NR ²³ R ²⁴ wherein R ²³ and R ²⁴ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkene. Alkyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted a cyclic group, and wherein R ²³ and R ²⁴ are bonded together with the nitrogen bonded thereto as appropriate to form a heterocyclic or substituted heterocyclic group, wherein an alkyl group, a substituted alkyl group, Alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hetero Both cyclo and substituted heterocyclic are as defined herein.

"Aminosulfonyl" refers to the group -SO ₂ NR ²³ R ²⁴ wherein R ²³ and R ²⁴ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, Alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic And wherein R ²³ and R ²⁴ are bonded together with the nitrogen bonded thereto as appropriate to form a heterocyclic or substituted heterocyclic group, wherein alkyl, substituted alkyl, alkenyl Substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic And substituted heterocyclic groups are as defined herein.

"Aminosulfonyloxy" refers to the group -O-SO ₂ NR ²³ R ²⁴ wherein R ²³ and R ²⁴ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted Alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted a heterocyclic group, wherein R ²³ and R ²⁴ are bonded together with the nitrogen bonded thereto as appropriate to form a heterocyclic or substituted heterocyclic group, wherein the alkyl group, the substituted alkane Alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl And a heterocyclic group and a substituted heterocyclic group are as defined herein.

"Aminosulfonylamino" refers to the group -NR ²⁰ -SO ₂ NR ²³ R ²⁴ wherein R ²⁰ is hydrogen or alkyl, and R ²³ and R ²⁴ are independently selected from the group consisting of hydrogen, alkyl, and Substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted a heteroaryl group, a heterocyclic group, and a substituted heterocyclic group, and wherein R ²³ and R ²⁴ are bonded together with the nitrogen bonded thereto as appropriate to form a heterocyclic group or a substituted heterocyclic group And wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, Heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are all as defined herein.

"Methyl" refers to the group -C(=NR ²⁵ )NR ²³ R ²⁴ , wherein R ²⁵ , R ²³ and R ²⁴ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and a substituted heterocyclic group, wherein R ²³ and R ²⁴ are bonded together with the nitrogen bonded thereto, as appropriate, to form a heterocyclic or substituted heterocyclic group, wherein the alkyl group, substituted Alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl The base, heterocyclic, and substituted heterocyclic are all as defined herein.

"Aryl" means an aromatic group of 6 to 14 carbon atoms and has no ring heteroatom, but a monocyclic (eg phenyl) or multiple condensed (fused) ring (eg naphthyl or anthracenyl). For multiple ring systems, including fused, bridged, and spiro ring systems with aromatic and non-aromatic rings without ring heteroatoms, the term "aryl" or "Ar" applies to when the point of attachment is in an aromatic carbon. On the atom (for example, 5,6,7,8 tetrahydronaphthalen-2-yl is an aryl group because its point of attachment is at the 2-position of the aromatic benzene ring).

"Substituted aryl" means an aryl group which is 1 to 8 and, in some embodiments, 1 to 5, 1 to 3, or 1 to 2 substituents, substituents Selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, decyl, decylamino, hydrazine Oxy group, amine group, substituted amine group, aminocarbonyl group, aminothiocarbonyl group, aminocarbonylamino group, aminothiocarbonylamino group, aminocarbonyloxy group, aminosulfonyl group, amine group Sulfhydryloxy, aminosulfonylamino, carbenyl, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio , azido, carboxyl, carboxy ester, (carboxy ester) amine, (carboxy ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyl Oxyl, cycloalkylthio, substituted cycloalkylthio, fluorenyl, substituted fluorenyl, halo, hydroxy, hydroxyamino, alkoxyamino, fluorenyl, substituted fluorenyl, Heteroaryl, substituted heteroaryl , heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted Heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO ₃ H, substituted sulfonyl, sulfonyloxy, thiol, thiocyanate, Mercaptan, alkylthio and substituted alkylthio, wherein the substituents are each defined herein.

"Aralkyl" or "aryl(C ₁ -C _z )alkyl" refers to the group -R ^u R ^v , wherein R ^u is an alkylene group (having eight or fewer backbone carbon atoms), And R ^v is an aryl group as defined herein. Thus, "aralkyl" refers to groups such as benzyl and phenylethyl. Similarly, "alkenyl" refers to the group -R ^u R ^v , wherein R ^u is an alkenyl group (a secondary alkyl group having one or two double bonds), and R ^v is as defined herein. A group such as a styryl group, a 3-phenyl-2-propenyl group or the like.

"Aryloxy" refers to the group -O-aryl, wherein aryl is as defined herein, including, by way of example, phenoxy and naphthyloxy.

"Substituted aryloxy" refers to the group -O-(substituted aryl) wherein the substituted aryl is as defined herein.

"Arylthio" refers to the group -S-aryl, wherein aryl is as defined herein.

"Substituted arylthio" refers to the group -S-(substituted aryl) wherein the substituted aryl is as defined herein.

"Azide" refers to the group -N ₃ .

"Mercapto" refers to the group -NHNH ₂ .

"Substituted thiol" refers to the group -NR ²⁶ NR ²⁷ R ²⁸ wherein R ²⁶ , R ²⁷ and R ²⁸ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted Alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, carboxy ester, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, Substituted heterocyclic, -SO ₂ -alkyl, -SO ₂ -substituted alkyl, -SO ₂ -alkenyl, -SO ₂ -substituted alkenyl, -SO ₂ -cycloalkyl, -SO ₂ - substituted cycloalkyl, -SO ₂ -aryl, -SO ₂ -substituted aryl, -SO ₂ -heteroaryl, -SO ₂ -substituted heteroaryl, -SO ₂ -heterocyclic and - a SO ₂ -substituted heterocyclic group, and wherein R ²⁷ and R ²⁸ are bonded together with the nitrogen bonded thereto, as appropriate, to form a heterocyclic or substituted heterocyclic group, provided that R ²⁷ And R ²⁸ are not hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, Cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted The heteroaryl, heterocyclic, and substituted heterocyclic are all as defined herein.

"Cyano" or "carbonitrile" refers to the group -CN.

"Carbonyl" means a divalent group -C(O)- which is equivalent to -C(=O)-.

"Carboxy" or "carboxy" means -COOH or a salt thereof.

"Carboxy ester" or "carboxylate" refers to the group -C(O)O-alkyl, -C(O)O-substituted alkyl, -C(O)O-alkenyl, -C(O) O-substituted alkenyl, -C(O)O-alkynyl, -C(O)O- Substituted alkynyl, -C(O)O-aryl, -C(O)O-substituted aryl, -C(O)O-cycloalkyl, -C(O)O-substituted cycloalkyl , -C(O)O-heteroaryl, -C(O)O-substituted heteroaryl, -C(O)O-heterocyclic, and -C(O)O-substituted heterocyclic, wherein Alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl The substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

"(Carboxy ester) Amine" refers to the group -NR ²⁰ -C(O)O-alkyl, -NR ²⁰ -C(O)O-substituted alkyl, -NR ²⁰ -C(O)O- Alkenyl, -NR ²⁰ -C(O)O-substituted alkenyl, -NR ²⁰ -C(O)O-alkynyl, -NR ²⁰ -C(O)O-substituted alkynyl, -NR ²⁰ - C(O)O-aryl, -NR ²⁰ -C(O)O-substituted aryl, -NR ²⁰ -C(O)O-cycloalkyl, -NR ²⁰ -C(O)O-substituted Cycloalkyl, -NR ²⁰ -C(O)O-heteroaryl, -NR ²⁰ -C(O)O-substituted heteroaryl, -NR ²⁰ -C(O)O-heterocyclic and -NR ^{a 20-} C(O)O-substituted heterocyclic ring wherein R ²⁰ is alkyl or hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkyne The base, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are all as defined herein.

"(Carboxy ester)oxy" refers to the group -OC(O)O-alkyl, -OC(O)O-substituted alkyl, -OC(O)O-alkenyl, -OC(O)O - substituted alkenyl, -OC(O)O-alkynyl, -OC(O)O-substituted alkynyl, -OC(O)O-aryl, -OC(O)O-substituted aryl, -OC(O)O-cycloalkyl, -OC(O)O-substituted cycloalkyl, -OC(O)O-heteroaryl, -OC(O)O-substituted heteroaryl, -OC (O) O-heterocyclic and -OC(O)O-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, Cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted The heteroaryl, heterocyclic, and substituted heterocyclic are all as defined herein.

"Cycloalkyl" means a saturated or partially saturated cyclic group of 3 to 14 carbon atoms and has no ring heteroatoms, but has a single or multiple ring, including fused, bridged, and spiro ring systems. For polycyclic systems having aromatic and non-aromatic rings without ring heteroatoms, the term "cycloalkyl" is used when the point of attachment is attached to a non-aromatic carbon atom (eg, 5, 6, 7 8-tetrahydronaphthalen-5-yl). The term "cycloalkyl" includes cycloalkenyl. Examples of the cycloalkyl group include, for example, adamantyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclooctyl group, and cyclohexenyl group. "C _uv cycloalkyl" means a cycloalkyl group having from 0 to v carbon atoms as a ring member. "C _uv cycloalkenyl" means a cycloalkenyl group having from 0 to v carbon atoms as a ring member.

"Cycloalkenyl" refers to a partially saturated cycloalkyl ring having at least one >C=C<ring-unsaturated position.

"Substituted cycloalkyl" refers to a cycloalkyl group, as defined herein, having from 1 to 8, or from 1 to 5, or in some embodiments, from 1 to 3 substituents, selected from the group consisting of Keto group, thioketone, alkyl group, substituted alkyl group, alkenyl group, substituted alkenyl group, alkynyl group, substituted alkynyl group, alkoxy group, substituted alkoxy group, mercapto group, mercaptoamine Base, decyloxy, amine, substituted amine, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl , aminosulfonyloxy, aminosulfonylamino, decyl, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted aryl Thiothio, azide, carboxyl, carboxy ester, (carboxy ester) amine, (carboxy ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted Cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, fluorenyl, substituted fluorenyl, halo, hydroxy, hydroxyamino, alkoxyamino, fluorenyl, substituted Sulfhydryl, heteroaryl, warp Substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclic Oxyl, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO ₃ H, substituted sulfonyl, sulfonyloxy, thiol, Thiocyanate, thiol, alkylthio and substituted alkylthio, wherein the substituents are as defined herein. The term "substituted cycloalkyl" includes substituted cycloalkenyl.

"Cycloalkyloxy" refers to -O-cycloalkyl, wherein cycloalkyl is as defined herein.

"Substituted cycloalkyloxy" refers to -O-(substituted cycloalkyl) wherein substituted cycloalkyl is as defined herein.

"Cycloalkylthio" refers to -S-cycloalkyl, wherein substituted cycloalkyl is as defined herein.

"Substituted cycloalkylthio" refers to -S-(substituted cycloalkyl) wherein substituted cycloalkyl is as defined herein.

"Guanidino" refers to the group -NHC (= NH) NH _2.

"Substituted thiol" means -NR ²⁹ C(=NR ²⁹ )N(R ²⁹ ) ₂ wherein each R ²⁹ is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted An aryl group, a heteroaryl group, a substituted heteroaryl group, a heterocyclic group, and a substituted heterocyclic group, and two R ²⁹ groups bonded to a common sulfhydryl nitrogen atom are optionally bonded thereto The nitrogens are joined together to form a heterocyclic or substituted heterocyclic group, provided that at least one R ^{29 is} not hydrogen, and wherein the substituents are as defined herein.

"Halo" or "halogen" means fluoro, chloro, bromo and iodo.

"Haloalkyl" means that the alkyl group is substituted with 1 to 5 or, in some embodiments, 1 to 3 halo groups, for example -CH ₂ Cl, -CH ₂ F, -CH ₂ Br, -CFClBr , -CH ₂ CH ₂ Cl, -CH ₂ CH ₂ F, -CF ₃ , -CH ₂ CF ₃ , -CH ₂ CCl _{3 ,} etc., and further includes an alkyl group such as a perfluoroalkyl group in which all hydrogen atoms are Replacement of fluorine atoms.

"Haloalkoxy" means that the alkoxy group is substituted by 1 to 5 or, in some embodiments, 1 to 3 halo groups, for example -OCH ₂ Cl, -OCH ₂ F, -OCH ₂ CH ₂ Br, -OCH ₂ CH ₂ Cl, -OCF ₃ and the like.

"Hydroxy" or "hydroxy" refers to the group -OH.

"Heteroalkyl" means an alkyl group, as defined herein, having one, two or three substituents independently selected from cyano, -OR ^w , -NR ^x R ^y and -S(O) _n R ^z (where n is an integer from 0 to 2) and it is understood that the point of attachment of the heteroalkyl group is through the carbon atom of the heteroalkyl group. R ^w is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, alkoxycarbonyl, aryloxycarbonyl, carboguanamine or mono- or di-alkylamine formazan base. R ^x is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl or aralkyl. R ^y is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, alkoxycarbonyl, aryloxycarbonyl, carboguanamine, mono- or di-alkylamine formazan Or alkylsulfonyl. R ^z is hydrogen (provided that n is 0), alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, amine, mono-alkylamino, di-alkylamino or hydroxy alkyl. Representative examples include, for example, 2-hydroxyethyl, 2,3-dihydroxypropyl, 2-methoxyethyl, benzyloxymethyl, 2-cyanoethyl, and 2-methylsulfonyl-ethyl . For each of the above, R ^w , R ^x , R ^y and R ^z may be further substituted with an amine group, a fluorine, an alkylamino group, a di-alkylamino group, an OH group or an alkoxy group. Further, the prefix indicating the number of carbon atoms (for example, C ₁ - C ₁₀ ) refers to the total number of carbon atoms in the heteroalkyl moiety, cyano, -OR ^w , -NR ^x R ^y or -S(O) _n R Except for the ^z part.

"Heteroaryl" means an aromatic radical of 1 to 14 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and includes 5 to 18 membered ring or ring systems, including Monocyclic (eg imidazolyl) or polycyclic (eg benzimidazol-2-yl and benzimidazol-6-yl). For polycyclic systems, including fused, bridged, and spiro ring systems with aromatic and non-aromatic rings, if there are at least one ring heteroatom and the point of attachment is at the atom of the aromatic ring, then "heteroaryl" The term is applicable (for example, 1,2,3,4-tetrahydroquinolin-6-yl and 5,6,7,8-tetrahydroquinolin-3-yl). In a particular embodiment, the nitrogen and/or sulfur ring atoms of the heteroaryl are optionally oxidized to provide an N-oxide (N→O), sulfinyl or sulfonyl moiety. More specifically, the term heteroaryl includes, but is not limited to, pyridinyl, furyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isomeric Azyl, pyrrolyl, pyrazolyl, anthracene Base, pyrimidinyl, benzofuranyl, tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, fluorenyl, isodecyl, benzene and Azyl, quinolyl, tetrahydroquinolyl, isoquinolinyl, quinazolinone, benzimidazolyl, benziso Azolyl or benzothienyl.

"Substituted heteroaryl" means a heteroaryl substituted by 1 to 8, or in some embodiments 1 to 5, or 1 to 3, or 1 to 2 substituents. The group is selected from the group consisting of substituents as defined for the substituted aryl group.

"Heteroaryloxy" refers to -O-heteroaryl, wherein heteroaryl is as defined herein.

"Substituted heteroaryloxy" refers to the group -O-(substituted heteroaryl), Wherein heteroaryl is as defined herein.

"Heteroarylthio" refers to the group -S-heteroaryl, wherein heteroaryl is as defined herein.

"Substituted heteroarylthio" refers to the group -S-(substituted heteroaryl) wherein heteroaryl is as defined herein.

"Heterocyclic" or "heterocyclic" or "heterocyclic" or "heterocycloalkyl" or "heterocyclyl" means a saturated or partially saturated cyclic group having from 1 to 14 carbon atoms and Up to 6 heteroatoms selected from nitrogen, sulfur or oxygen, and including monocyclic and polycyclic systems, including fused, bridged and spiro ring systems. For polycyclic systems having aromatic and/or non-aromatic rings, the terms "heterocyclic", "heterocyclic", "heterocyclic", "heterocycloalkyl" or "heterocyclyl" are used when When there is at least one ring hetero atom and the point of attachment is on the atom of the non-aromatic ring (for example, 1,2,3,4-tetrahydroquinolin-3-yl, 5,6,7,8-tetrahydroquine Polin-6-yl and decahydroquinolin-6-yl). In a particular embodiment, the nitrogen and/or sulfur atom of the heterocyclic group is optionally oxidized to provide an N-oxide, sulfinyl, sulfonyl moiety. More specifically, heterocyclic groups include, but are not limited to, tetrahydropyranyl, hexahydropyridyl, N-methylhexahydropyridin-3-yl, hexahydropyridyl Base, N-methyltetrahydropyrrol-3-yl, 3-tetrahydropyrrolyl, 2-tetrahydropyrrolidone-1, oxabulinyl and tetrahydropyrrolyl. The prefix indicating the number of carbon atoms (e.g., C ₃ - C ₁₀ ) refers to the total number of carbon atoms in the heterocyclic moiety, with the exception of the number of heteroatoms.

"Substituted heterocyclic ring" or "substituted heterocyclic group" or "substituted heterocyclic ring" or "substituted heterocycloalkyl group" or "substituted heterocyclic group" means as defined herein a heterocyclic group of from 1 to 5, or in some embodiments, from 1 to 3, as defined for the substituted cycloalkyl group generation.

"Heterocyclyloxy" refers to the group -O-heterocyclyl, wherein heterocyclyl is as defined herein.

"Substituted heterocyclyloxy" refers to the group -O-(substituted heterocyclic) wherein heterocyclyl is as defined herein.

"Heterocyclylthio" refers to the group -S-heterocyclyl, wherein heterocyclyl is as defined herein.

"Substituted heterocyclylthio" refers to the group -S-(substituted heterocyclic) wherein heterocyclyl is as defined herein.

Examples of heterocyclic and heteroaryl groups include, but are not limited to, nitratetrazine, pyrrole, imidazole, pyrazole, pyridine, pyridyl Pyrimidine 吲 , isoindole, hydrazine, dihydroanthracene, carbazole, anthracene, quinine , isoquinoline, quinoline, anthracene Naphthylpyridine, quin Porphyrin, quinazoline, porphyrin, acridine, oxazole, porphyrin, phenanthridine, acridine, morpholine, isothiazole, brown ,different Oxazole, brown Phenolthiophene , tetrahydroimidazole, dihydroimidazole, hexahydropyridine, hexahydropyridyl , indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazole, Thiophene, benzo[b]thiophene, morpholinyl, thionorfosyl (also known as thiophyllinyl), 1,1-dionethiomorpholine, hexahydropyridine Base, tetrahydropyrrole and tetrahydrofuranyl.

"Nitro" refers to the group -NO ₂ .

"Ketyl" refers to an atom (=O).

"Oxide" means a product formed by the oxidation of one or more heteroatoms. Examples include N-oxides, anthraquinones, and anthraquinones.

"Spirocycloalkyl" means a 3 to 10 membered cyclic substituent formed by displacement of two hydrogen atoms on a common carbon atom by a secondary alkyl group having 2 to 9 carbon atoms, as in the following structure For example, wherein the methylene group attached to the bond indicated by the wavy line is replaced by a spirocycloalkyl group as shown below:

"Sulfo" refers to the divalent group -S(O) ₂ -.

"Substituted sulfonyl" refers to the group -SO ₂ -alkyl, -SO ₂ -substituted alkyl, -SO ₂ -alkenyl, -SO ₂ -substituted alkenyl, -SO ₂ -alkynyl , -SO ₂ -substituted alkynyl, -SO ₂ -cycloalkyl, -SO ₂ -substituted cycloalkyl, -SO ₂ -aryl, -SO ₂ -substituted aryl, -SO ₂ -heteroaryl a -SO ₂ -substituted heteroaryl, -SO ₂ -heterocyclic, -SO ₂ -substituted heterocyclic ring wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkyne a substituted alkynyl group, a cycloalkyl group, a substituted cycloalkyl group, an aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl group, a heterocyclic group, and a substituted heterocyclic group. As defined herein. Substituted sulfonyl groups include groups such as methyl-SO ₂ -, phenyl-SO ₂ -, and 4-methylphenyl-SO ₂ -.

"Sulfomethoxy" refers to the group -OSO ₂ -alkyl, -OSO ₂ -substituted alkyl, -OSO ₂ -alkenyl, -OSO ₂ -substituted alkenyl, -OSO ₂ -cycloalkyl, -OSO ₂ -substituted cycloalkyl, -OSO ₂ -aryl, -OSO ₂ -substituted aryl, -OSO ₂ -heteroaryl, -OSO ₂ -substituted heteroaryl, -OSO ₂ -heterocyclic a family, -OSO ₂ -substituted heterocyclic ring wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl An aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl group, a heterocyclic group, and a substituted heterocyclic group are as defined herein.

"Thioinyl" refers to the group H-C(S)-, alkyl-C(S)-, substituted alkyl -C(S)-, alkenyl-C(S)-, substituted alkenyl-C(S)-, alkynyl-C(S)-, substituted alkynyl-C(S)-, ring Alkyl-C(S)-, substituted cycloalkyl-C(S)-, aryl-C(S)-, substituted aryl-C(S)-, heteroaryl-C(S -, substituted heteroaryl-C(S)-, heterocyclic-C(S)- and substituted heterocyclic-C(S)-, wherein alkyl, substituted alkyl, alkene Alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic Both families and substituted heterocyclic groups are as defined herein.

"Mercaptan" refers to the group -SH.

"Alkylthio" refers to the group -S-alkyl, wherein alkyl is as defined herein.

"Substituted alkylthio" refers to the group -S-(substituted alkyl) wherein substituted alkyl is as defined herein.

"Thiocarbonyl" means a divalent group -C(S)- which is equivalent to -C(=S)-.

"thione" refers to an atom (=S).

"Thiocyanate" refers to the group -SCN.

As used herein, "compound" and "the compound" are intended to mean a compound encompassed by the general formula disclosed herein, any subgenus of such general formula, and any form of the compound in the general and subgeneric formulas, For example, oxides, esters, prodrugs, pharmaceutically acceptable salts or solvates. Unless otherwise specified, the term further includes racemates, stereoisomers, and tautomers of one or more compounds.

"Racemate" refers to a mixture of palmomers.

A "solvate" or "solvate" of a compound means a compound that is bound to a stoichiometric or non-stoichiometric amount of a solvent, wherein the compound Defined above. Solvates of the compounds include solvates of all compound forms, such as the oxides, esters, prodrugs or pharmaceutically acceptable salts of the general formula and sub-generics as disclosed. Preferred solvents are volatile, non-toxic and/or acceptable for administration to humans.

"Stereoisomers" or "stereoisomers" refers to compounds that differ in palmarity at one or more stereocenters. Stereoisomers include palmomere and diastereomers. If the compound of the invention has one or more asymmetric centers or double bonds with asymmetric substitutions, it may exist in stereoisomeric forms and thus may be prepared as individual stereoisomers or as a mixture. Unless otherwise indicated, this description is intended to include individual stereoisomers as well as mixtures. Methods for determining stereochemistry and isolating stereoisomers are well known in the art (see discussion in Advanced Organic Chemistry, Chapter 4, 4th Ed., J. March, John Wiley & Sons, New York 1992).

"Tautomer" means an alternating form of a compound that differs at the position of a proton, such as an enol-keto group and an imine-enamine tautomer, or a tautomeric form of a heteroaryl group, which contains A ring atom attached to both a ring-NH- moiety and a ring-N-part group, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole.

"Prodrug" means any derivative of a particular embodiment compound which, when administered to a patient, is capable of providing, directly or indirectly, a compound of a particular embodiment or an active metabolic product or residue thereof. The prodrug of the compound of the present invention is prepared by modifying a functional group present in the compound in such a manner that the modified substance can be cleaved in vivo to release the parent compound or the active metabolic product. For example, prodrugs include some compounds, The hydroxy, amine or thiol group in the compound I is individually bonded to any group which can be cleaved in vivo to regenerate the free hydroxy group, amine group or thiol group. Particularly advantageous derivatives and prodrugs are those which, when administered to a patient, increase the bioavailability of a particular embodiment of the compound (e.g., by allowing the compound to be administered orally to be more readily absorbed) In the blood, or relative to the parent species, it enhances the delivery of the parent compound to the biological compartment (eg, the brain or lymphatic system). Prodrugs include the esters of hydroxy functional groups of the compounds of the invention, guanamines, urethanes (e.g., N,N-dimethylaminocarbonyl). Examples of ester prodrugs include formates, acetates, propionates, butyrates, acrylates, and diethyl succinate derivatives. A general introduction to prodrugs is provided at T Higuchi and V Stella, Prodrugs as Novel Delivery Systems, ACS Collection Series, Volume 14, and edited by Edward B Roche, Bioreversible Carriers in Drug Design, American Medical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

"Pharmaceutically acceptable salt" means a pharmaceutically acceptable salt derived from a variety of organic and inorganic counterions conventionally known in the art, and by way of example only, includes sodium, potassium, calcium, magnesium, ammonium, and Tetraalkylammonium. When the molecule contains a basic functional group, it is an acid addition salt of an organic or inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or formed with an organic acid such as acetic acid or C. Acid, caproic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3 -(4-hydroxybenzhydryl)benzoic acid, cinnamic acid, phenylglycolic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonate Acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, oxalic acid, 4-toluenesulfonic acid, camphorsulfonic acid, methanesulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, t-butyl acetate, lauryl sulfate, gluconic acid, glutamic acid, naphtholcarboxylic acid, salicylic acid, stearic acid, muconic acid, and the like. When the acidic proton present in the parent compound is replaced by a metal ion such as an alkali metal ion, an alkaline earth ion or an aluminum ion; or when it is coordinated with an organic base, such as ethanolamine, diethanolamine, triethanolamine, trimethylamine, N- Methyl glucosamine or the like can also form a salt. Pharmaceutically acceptable salts are suitable for administration in patients and have the desired pharmacological properties. Suitable salts are further included in the handbook of P. Heinrich Stahl, Camille G. Wermuth (ed.), The Nature of Pharmaceutical Salts, Selection and Use;

Unless otherwise indicated, nomenclature of substituents, which is not explicitly defined herein, is achieved by referring to the terminal portion of the functional group followed by the adjacent functional group toward the point of attachment. For example, the substituent "aralkyloxycarbonyl" refers to the group (aryl)-(alkyl)-O-C(O)-.

It should be understood that in all of the substituted groups defined above, by substituting a substituent with a further substituent for itself (for example, a substituted aryl group having a substituted aryl group as a substituent, the basic substitution The body is replaced by a substituted aryl group which is further substituted by a substituted aryl group, etc., and is not intended to be included herein. In this case, the maximum number of such substituents is three. For example, a substituted aryl group is substituted with a sequence of two other substituted aryl groups to the -substituted aryl-(substituted aryl)-substituted aryl group.

Similarly, it should be understood that the above definition is not intended to include Substitutional form (eg methyl substituted by 5 fluoro groups). Such an unacceptable type is well known to the skilled artisan.

"Patient" means a mammal and includes both human and non-human mammals. Examples of patients include, but are not limited to, mice, rats, big hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cows, and humans.

The term "mammal" includes, but is not limited to, humans, domestic animals (such as dogs or cats), farm animals (dairy cows, horses or pigs), and laboratory animals (rats, rats, big rats, guinea pigs, pigs, rabbits). , dog or monkey).

The use of the term "optional" or "as appropriate" when used throughout this specification means that the event or condition described hereinafter may, but does not necessarily, occur, and the description includes the occurrence of the event or condition, and There is no such situation. For example, "heterocyclic group is optionally mono- or disubstituted by an alkyl group" means that an alkyl group may, but does not necessarily exist, and the description includes a condition in which a heterocyclic group is mono- or disubstituted by an alkyl group, and The case where the heterocyclic group is not substituted by an alkyl group.

"Protecting group" refers to a group of atoms that, when attached to a reactive group in a molecule, obscures, reduces or prevents the reactivity. Examples of protecting groups can be found in TW Greene and PG Wuts, Protective Groups in Organic Chemistry (Wiley, 2nd ed., 1991) and Harrison and Harrison et al., Synthetic Organic Methods, Vol. 1-8 (John Wiley & Sons. 1971-1996). Representative amine protecting groups include indolyl, ethyl fluorenyl, trifluoroethenyl, benzyl, benzyloxycarbonyl (CBZ), tris-butoxycarbonyl (Boc), trimethyldecyl (TMS), 2-trimethyldecyl-ethanesulfonyl (SES), trityl and substituted trityl, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC), nitrate Glutamic acid oxycarbonyl Base (NVOC) and so on. Representative hydroxy protecting groups include those in which the hydroxy group is either thiolated or alkylated, such as benzyl and trityl ether, and alkyl ethers, tetrahydropyranyl ethers, trialkyl decanes. Alkyl ethers and allyl ethers.

Turning next to the compositions of the present invention, the term "pharmaceutically acceptable carrier or excipient" means a carrier or excipient which can be used in the preparation of a pharmaceutical composition which is normally safe and has acceptable toxicity. Acceptable carriers or excipients include those that are acceptable for veterinary use as well as for human medical use. "Pharmaceutically acceptable carrier or excipient" when used in the specification and claims, includes one or more than one such carrier or excipient.

With reference to the method of the present invention, the following terms are used in conjunction with the indicated meanings: The term "treatment" or "treatment" of a disease includes: (1) preventing or reducing the risk of developing a disease, meaning that the clinical signs of the disease are not likely to be exposed or susceptible to the disease, but have not been experienced or shown Development in a mammal with the disease sign, (2) inhibition of the disease, that is, suppression or reduction of the development of the disease or its clinical signs, or (3) resolution of the disease, meaning the disease or its clinical signs are degraded.

A preferred embodiment of the invention is the treatment of a disease which includes alleviating the disease.

The term "diagnosis" refers to the determination of the presence or absence of a particular disease or condition. Moreover, the term refers to determining the extent or severity of a particular disease or condition, and monitoring the disease or condition to determine its response to a particular therapeutic regimen.

The term "therapeutically effective amount" means the amount of a subject compound that elicits a biological or medical response from a tissue, system, animal, individual or human being sought by a researcher, veterinarian, doctor or other clinician. "Therapeutically effective amount" includes an amount of a compound sufficient to achieve such treatment of the disease when administered to a mammal to treat the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc. of the mammal to be treated.

"Patient" means a mammal and includes both human and non-human mammals. Examples of patients include, but are not limited to, mice, rats, big hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cows, and humans.

The term "mammal" includes, but is not limited to, humans, domestic animals (such as dogs or cats), farm animals (dairy cows, horses or pigs), and laboratory animals (rats, rats, big rats, guinea pigs, pigs, rabbits). , dog or monkey).

The term "insulin resistance" is generally defined as a condition of glucose metabolism. More specifically, insulin resistance can be defined as the ability of reduced insulin to exert its biological effects over a broad range of concentrations, resulting in lower than expected biological effects (see, for example, Reaven GM, J. Basic & Clin. Phys). & 1998. [1998] 9: 387-406 and Flie J, Ann Rev. Med . (1983) 34: 145-60). Insulin resistance has a reduced ability to properly metabolize glucose and is a poor response to insulin therapy, both limited and limited. The manifestations of insulin resistance include inadequate glucose activation in glucose absorption, oxidation, and storage, as well as inappropriate insulin repression in fat tissue in fat tissue and glucose production and secretion in the liver. Insulin resistance can cause or contribute to polycystic ovarian syndrome, impaired glucose tolerance, gestational diabetes, metabolic syndrome, hypertension, obesity, atherosclerosis, and a variety of other conditions. Finally, an insulin resistant individual can progress to the point in time when the diabetic state is reached.

The term "diabetes mellitus" or "diabetes" means a disease or condition that is generally characterized by a metabolic defect in the production and utilization of glucose that causes failure to maintain adequate blood glucose levels in the body. . The result of these defects is elevated blood sugar, called "hyperglycemia." The two main forms of diabetes are Type I diabetes and Type II diabetes. As mentioned above, Type I diabetes is usually the result of an absolute deficiency of insulin, which is a hormone that regulates glucose utilization. Type II diabetes often occurs despite normal or even increased insulin levels and can result from the tissue not being able to respond appropriately to insulin. Most type 2 diabetic patients are insulin resistant and have relatively poor insulin because insulin secretion does not compensate for the resistance of the peripheral tissue to insulin response. In addition, many type 2 diabetic patients are obese. Other types of stable disorders such as glucose include attenuated glucose tolerance, which is intermediate between the normal glucose and other metabolic stages, and gestational diabetes, which does not have type I or type II diabetes. Glucose inadmissibility in pregnant women with previous medical history.

The term "metabolic syndrome" refers to a cluster of metabolic abnormalities, including abdominal obesity, insulin resistance, glucose intolerance, diabetes, hypertension, and lipid disorders. These abnormalities are known to be associated with increased risk of vascular events.

The term "abdominal obesity" is defined by the cut-off point of 102 cm in the waist circumference and 80 cm in the female, as detected by the adult, The third report of the National Cholesterol Education Program Panel for the Assessment and Treatment of High Blood Cholesterol (NCEP/ATP Group III).

Guidelines for the diagnosis of type 2 diabetes, impaired glucose tolerance, and gestational diabetes have been presented by the American Diabetes Association (see, for example, the Expert Committee on Diagnosis and Classification of Diabetes, Diabetes Care, (1999) Vol. 2 (Supplement 1): S5-19).

The term "secret secretin" means a substance or compound that stimulates secretion. For example, insulin secretagogues are substances or compounds that stimulate insulin secretion.

The term "symptoms" of diabetes includes, but is not limited to, polyuria, thirst, and bulimia, as used herein, incorporating its usual methods. For example, "polyuria" means a large amount of urine excretion during a specific period; "thirst" means chronic excessive thirst; and "pasta" means excessive eating. Other signs of diabetes include, for example, increased susceptibility to certain infections (especially fungal and staphylococcal infections), nausea, and ketoacidosis (enhanced ketone body production in the blood).

The term "complications" of diabetes includes but is not limited to microvascular complications and macrovascular complications. Microvascular complications are complications that generally cause small blood vessel damage. Such complications include, for example, retinopathy (visual attenuation or loss due to vascular injury in the eye); neuropathy (neural damage and foot problems due to vascular injury to the nervous system); and kidney disease (due to the kidneys) Kidney disease caused by vascular injury). Giant vascular complications are generally complications caused by large blood vessel injuries. Such complications include, for example, cardiovascular disease and peripheral vascular disease. Cardiovascular disease refers to a disease of the heart's blood vessels. See, for example, Kaplan RM et al., "Cardiovascular Diseases" in Health and Human Behavior, pp. 206-242 (McGraw-Hill, New York 1993). Cardiovascular disease Often in one of several forms, including, for example, high blood pressure (also known as high blood pressure), coronary heart disease, stroke, and rheumatic heart disease. Peripheral vascular disease refers to a disease of any blood vessel outside the heart. It is often narrowed to transport blood to the blood vessels of the feet and arm muscles.

The term "atherosclerosis" encompasses vascular diseases and symptoms, which are recognized and understood by physicians in the medical field. Atherosclerotic cardiovascular disease, coronary heart disease (also known as coronary artery disease or cardiogenic heart disease), cerebrovascular disease and peripheral vascular disease are clinical manifestations of atherosclerosis, and therefore are "atherosclerosis" "With "terminology of atherosclerotic disease" is covered.

The term "anti-hyperlipidemic" refers to lowering the excess lipid concentration in the blood to the desired level.

The term "modulation" refers to the treatment, prevention, inhibition, enhancement or induction of a function or symptom. For example, a compound can modulate type 2 diabetes by increasing insulin in humans, thereby inhibiting hyperglycemia.

The term "triglyceride" ("TG") as used herein is incorporated into its usual use. TG contains three fatty acid molecules that are esterified to glycerol molecules. TG is used to store fatty acids, which are used by muscle cells for energy production, or are dissolved and stored in adipose tissue.

Since cholesterol and TG are water insoluble, they must be packaged in a special molecular complex called "lipoprotein" to be delivered in plasma. Lipoproteins can accumulate in plasma due to overproduction and/or lack of removal. There are at least five unique lipoproteins that vary in size, composition, density, and function. In the cells of the small intestine, the food lipids are packaged into "chylomicrons" "The large lipoprotein complex has high TG and low cholesterol content. In the liver, TG and cholesterol esters are packaged and released into the plasma, which is called very low density lipoprotein ("VLDL"). TG is rich in lipoprotein, its main function is endogenously transported in the liver or TG released by adipose tissue. By enzyme action, VLDL can be reduced and absorbed by the liver, or converted into intermediate density lipid. Protein ("IDL"). IDL is sequentially absorbed by the liver or further modified to form low-density lipoprotein ("LDL"). LDL is absorbed or decomposed by the liver or absorbed by extrahepatic tissues. High-density lipoprotein ("HDL") helps remove cholesterol from peripheral tissues during a process called reverse cholesterol delivery.

The term "lipidemia disorder" refers to an abnormal amount of lipoprotein in plasma, including reduced and/or increased levels of lipoproteins (eg, increased levels of LDL and/or VLDL, and reduced levels of HDL).

The term "excessive blood fat" includes, but is not limited to, the following: (1) Excessive amounts of chylomicrons in familial blood , a rare genetic disorder that results in the lack of an enzyme LP lipase that breaks down fat molecules. LP lipase deficiency can cause a large amount of fat or lipoprotein to accumulate in the blood; (2) familial hypercholesterolemia , a relatively common genetic disorder caused by subordinate defects in a series of mutations in the LDL receptor gene It can cause dysfunction of LDL receptors and/or the absence of LDL receptors. This causes LDL to increase LDL and total cholesterol in plasma by ineffective clearance of LDL receptors; (3) too much blood fat in familial combination , also known as multiple lipoproteins, hyperlipidemia, a genetic The condition, in which the patient and one of his influences, can be distinguished by high cholesterol and high triglyceride at different times.

The HDL cholesterol content is often moderately reduced; (4) Familial defective apolipoprotein B-100 is a relatively common chromosomal dominant gene abnormality. This defect is caused by a single nucleotide mutation that replaces arginine with branamide, which can cause a decrease in the affinity of the LDL particles for the LDL receptor. Therefore, this can cause high plasma LDL and total cholesterol levels; (5) familial beta lipoprotein disorder , also known as type III hyperlipoprotein, is a rare genetic disorder that causes moderate levels of serum TG and cholesterol. To a severe increase, accompanied by abnormal apolipoprotein E function. HDL levels are generally normal; and (6) familial triglycerides are a common genetic disorder in which the concentration of plasma VLDL is increased. This can result in a mild to moderately elevated TG content (and usually not a cholesterol content) and can often be accompanied by a low plasma HDL content.

Risk factors for hyperlipidemia include, but are not limited to, the following: (1) disease risk factors such as Type I diabetes, Type II diabetes, Cushing's syndrome, hypothyroidism, and a history of certain types of renal failure; 2) drug risk factors, including birth control pills; hormones, such as estrogen, and corticosteroids; certain diuretics; and various beta blockers; (3) food risk factors, including food fat intake per total calories greater than 40%; saturated calorie intake per total calorie greater than 10%; daily cholesterol intake greater than 300 mg; habits and excessive alcohol use; and obesity.

The terms "obesity" and "obesity", according to the World Health Organization, refer to the body mass index ("BMI") for males greater than 27.8 kg/m2 and for women 27.3 kg/m2 (BMI equals weight ( Kg) / height (m2)). Obesity is linked to a variety of medical conditions, including diabetes and hyperlipidemia. Obesity is also a known risk factor for the development of type 2 diabetes (see, for example, Barre-Conner E, Epidemol. Rev. (1989) 11: 172-181; and Knowler et al., Am. J. Clin. Nutr . 1991) 53: 1543-1551).

The term "pancreas" refers to glandular organs in the digestive and endocrine systems of vertebrates, including mammals. The pancreas secretes both digestive enzymes and hormones such as insulin, GLP-1 and GIP, and other hormones.

The term "islet" or "Langhans' islet" refers to the endocrine cells of the pancreas that are clustered together in the islets and secrete insulin and other hormones.

The term "β cell" refers to a cell found in the islets of Langerhans, which secrete insulin, dextrin and other hormones.

The term "endocrine cells" refers to cells that secrete hormones into the bloodstream. Endocrine cell lines are found in various glandular and organ systems of the body, including the pancreas, intestines, and other organs.

The term "L cell" refers to the enteroendocrine cells that produce GLP-1.

The term "K cell" refers to the enteroendocrine cells that produce GIP.

The term "incretin" refers to a group of hormones that increase insulin secretion in response to food intake. Incretins include GLP-1 and GIP.

The term "insulin" refers to a polypeptide hormone that regulates the metabolism of glucose. Insulin binds to insulin receptors in insulin-sensitive cells and mediates glucose absorption. Insulin is used to treat type 1 diabetes, and Used to treat type 2 diabetes.

The term "GLP-1" or "glucagon-like peptide" is a peptide hormone mainly produced by L cells. GLP-1 increases insulin secretion, reduces glucagon secretion, increases beta cell mass and insulin gene expression, inhibits acid secretion and gastric emptying in the stomach, and reduces food intake by increasing satiety.

The term "GIP" or "stomach-inhibiting peptide" or "glucose-dependent insulin polypeptide" refers to a peptide hormone produced primarily by K cells. GIP stimulates insulin secretion. GIP also has a significant effect on lipid metabolism.

The term "cAMP" or "cyclic adenosine monophosphate" refers to intracellular signaling island molecules involved in many biological processes, including glucose and lipid metabolism.

The term "agonist" refers to a compound that binds to a receptor and triggers a response in the cell. An agonist mimics the action of an endogenous ligand, such as a hormone, and produces a physiological response similar to that produced by the endogenous ligand.

The term "partial agonist" refers to a compound that binds to a receptor and triggers a partial response in the cell. Part of the agonist only produces a partial physiological response to the endogenous ligand.

The present invention is derived from the discovery of compounds that use cell-based screening as an agonist for IC-GPCR2 (Sequence Identification Code 1). The stable CHO cell line expressing IC-GPCR2 under the control of the CMV promoter was used, and the cAMP content was in the cells, and the fluorescence detection metric was analyzed using the homogeneous time. Using the parent CHO cell line as a control group, the increased cAMP content can be measured, and the confirmed compound, such as exanatide, can increase cAMP in the cell (see the in vitro activity table in Biological Example 1). . Due to the mention in beta cells The high intracellular cAMP content increases insulin secretion in a glucose-dependent manner (see Biological Examples 2 and 3), so the present invention can be used to treat, in particular, Type II diabetes and other diseases associated with adverse glycemic control. The novel agonist described in the present invention is orally active (see Biological Example 3), providing significant differential characteristics of exanatide. Furthermore, the islet specific performance of the receptors of the novel agonists of the invention (see Biological Example 4) also makes the invention useful for the diagnosis of diseases, particularly diabetes and other diseases associated with beta cell health.

Specific embodiment of the present invention

Compounds The compounds of the invention are represented by Formula I: Wherein the letters X, Y and Z are each independently selected from the group consisting of O, N, N(R ³ ), S and C(R ³ ), and at least one of X, Y and Z is selected from the group consisting of O, N, N(R ³ ) And S. The subscript q is an integer from 0 to 4; the subscript r is an integer from 0 to 3; the subscript s is an integer from 0 to 3, and the sum of r + s is ≦4. The letter A is C(R ⁴ ) or N; L is -(CH ₂ ) _n -, where n is an integer from 2 to 4, and at least one CH ₂ is O, N(R ⁵ ), S, S(O Or S(O) _{2 is} substituted, and any remaining CH ₂ is optionally substituted with one or two members selected from the group consisting of halogen, C _1-4 alkyl and C _1-4 haloalkyl. Ar is a 5- to 10-membered aryl or heteroaryl group, optionally substituted with one to five R ⁶ substituents.

Next, turning to the R group, R ¹ is selected from C _1-10 alkyl, C _1-10 haloalkyl, C _3-7 cycloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, -X ¹ -COR ^a , -X ¹ -CO ₂ R ^a , -X ¹ -CONR ^a R ^b , -SO ₂ R ^a , 4- to 7-membered heterocyclic group, aryl group and 5- to 10-membered heteroaryl a member of the group wherein each heterocyclic group and the aryl group and the heteroaryl group are optionally substituted by one to four substituents independently selected from the group consisting of halo, C _1-10 alkyl, C _1-10 haloalkyl, C _3-7 cycloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, heteroaryl, CN, NO ₂ , -OR ^a , -NR ^a R ^b , -CO ₂ R ^a , -CONR ^a R ^b , -NR ^a COR ^b , -NR ^a CO ₂ R ^b , -S(O) _m R ^a , -NR ^a S(O) ₂ R ^b and -SO ₂ NR ^a R ^b ; and X ¹ is selected from the group consisting of a bond, -C(O)-, and -C(O)-(CH ₂ ) _1-4 -, wherein the aliphatic moiety of X ¹ is optionally selected from the group consisting of halogen and C. Substituted by members of _1-4 alkyl and C _1-4 haloalkyl.

Each R ² is independently selected from halo, C _1-8 alkyl, C _1-8 haloalkyl, C _3-7 cycloalkyl, -COR ^a , -CO ₂ R ^a , -CONR ^a R ^b , - Members of OR ^a , -NR ^a R ^b , -NR ^a COR ^b , -SO ₂ R ^a and -SO ₂ NR ^a R ^b .

R ³ is a member selected from the group consisting of hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _3-7 cycloalkyl, aryl, and OR ^a .

R ⁴ is a member selected from the group consisting of H, halo, C _1-6 alkyl, OR ^a and CN.

R ⁵ is a member selected from the group consisting of -R ^a , -COR ^a and -SO ₂ R ^a .

Each R ⁶ is independently selected from the group consisting of halo, C _1-10 alkyl, C _1-10 haloalkyl, C _3-7 cycloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, CN, NO ₂ , -OR ^a , -NR ^a R ^b , -COR ^a , -CO ₂ R ^a , -CONR ^a R ^b , -NR ^a COR ^b , -NR ^a CO ₂ R ^b , -S(O) _m R ^a , -NR ^a S(O) _m R ^b , -SO ₂ NR ^a R ^b , 4- to 7-membered heterocyclic group, aryl group and 5- to 10-membered heteroaryl group, wherein the subscript m is 0 to An integer of 2, and each heterocyclic group, aryl group and heteroaryl group are optionally substituted by one to four substituents independently selected from halo, keto, C _1-4 alkyl, C _1-4 halo Alkyl, C _3-7 cycloalkyl, CN, NO ₂ , -OR ^a , -NR ^a R ^b , -CO ₂ R ^a , -CONR ^a R ^b , -NR ^a COR ^b , -NR ^a CO ₂ R ^b , -S(O) _m R ^a , -N ^a SO ₂ R ^b and -SO ₂ NR ^a R ^b .

For each of the above groups, each of R ^a and R ^b is independently selected from the group consisting of hydrogen, C _1-10 alkyl, C _1-10 haloalkyl, C _3-10 cycloalkyl, heterocyclyl, C _2-10 olefin. a C _2-10 alkynyl group, an aryl group, a 5- to 6-membered heteroaryl group, and an aryl C _1-4 alkyl group; and wherein the aliphatic portions of each of R ^a and R ^b are optionally one to three Substituted by members, the member is selected from -OR ⁿ , -OC(O)N(R ⁿ ) ₂ , -SR ⁿ , -S(O)R ⁿ , -S(O) ₂ R ⁿ , -S(O) ₂ N(R ⁿ ) ₂ , -NR ⁿ S(O) ₂ R ⁿ , -C(O)N(R ⁿ ) ₂ , -C(O)R ⁿ , -NR ⁿ C(O)R ⁿ ,- NR ⁿ C(O)N(R ⁿ ) ₂ , -CO ₂ R ⁿ , -NR ⁿ CO ₂ R ⁿ , -CN, -NO ₂ , -N(R ⁿ ) ₂ and -NR ⁿ S(O) ₂ N(R ⁿ ) ₂ , wherein each R ⁿ is independently hydrogen or an unsubstituted C _1-6 alkyl group; and wherein the aryl and heteroaryl portions are optionally substituted by one to three members, the member is selected From halogen, -OR ^m , -OC(O)N(R ^m ) ₂ , -SR ^m , -S(O)R ^m , -S(O) ₂ R ^m , -S(O) ₂ N(R ^m ₂ , -NR ^m S(O) ₂ R ^m , -C(O)N(R ^m ) ₂ , -C(O)R ^m , -NR ^m C(O)R ^m , -NR ^m C(O N(R ^m ) ₂ , -CO ₂ R ^m , -NR ^m CO ₂ R ^m , -CN, -NO ₂ , -N(R ^m ) ₂ and -NR ^m S(O) ₂ N(R ^m ) _2, wherein each R ^m is independently hydrogen or lines The substituted C _1-6 alkyl.

The compounds provided herein also include any pharmaceutically acceptable salt of the compound, as well as any isomericly identified isomers thereof. In general, the compounds useful in the methods described herein are those of the above formula wherein the molecular weight of the compound is less than 1200, more preferably less than about 1,000, still more preferably less than about 800, and still more Good is about 200 to about 600.

Rings having X, Y and Z as ring members, in a specific embodiment, are those in which X, Y and Z are independently selected from the group consisting of O, N, N(R ³ ) and S. In another specific embodiment, the ring is one in which all three X, Y, and Z are independently selected from the group consisting of O, N, N(R ³ ), and S. A set of preferred ring systems is represented by the following formula The wavy line indicates the connection position for either L or A.

In another specific embodiment, A is CR ⁴ .

For each of the above specific embodiment groups, another set of specific embodiments is wherein r is 1, s is 0 or 1, q is 0 to 2, and Ar is phenyl, optionally 1 to 3 Substituting R ⁶ substituents. Still another specific embodiment is one wherein r is 1, s is 0 or 1, q is 0, and Ar is selected from the group consisting of pyridyl, pyrimidinyl and pyridyl Each of which is optionally substituted with 1 to 3 R ⁶ substituents. Yet another set of specific embodiments are those wherein r is 1, s is 0 or 1, q is 0 to 2, and n is 2. In still another specific embodiment, r is 1, s is 0 or 1, q is 0 to 2, n is 2, and one CH ₂ is replaced by O.

In another specific embodiment of Formula I, r is 1; s is 0 or 1; q is 0 to 2; n is 2, and one CH ₂ of L is replaced by O, S or N(R ⁵ ) ; A is selected from the group consisting of CH, C(CH ₃ ), CF, and C(OH); and the ring having X, Y, and Z as ring members is selected from the group consisting of thiazoles, Oxazole, thiadiazole and Diazole. Ar is preferably a phenyl group, optionally substituted with from 1 to 3 R ⁶ substituents. More preferably, Ar is substituted with 1 to 2 R ⁶ substituents independently selected from the group consisting of halo, C _1-10 alkyl, C _1-10 haloalkyl, CN, NO ₂ , -OR ^a , -NR ^a R ^b , -COR ^a , -CO ₂ R ^a , -CONR ^a R ^b , -NR ^a COR ^b , -NR ^a CO ₂ R ^b , -S(O) _m R ^a , -NR ^a S(O) _m R ^b , -SO ₂ NR ^a R ^b , 4- to 5-membered heterocyclic group, aryl group and 5- to 6-membered heteroaryl group. In some embodiments, each R ⁶ is independently selected from the group consisting of halo, -OR ^a , -NR ^a R ^b , -NR ^a COR ^b , -NR ^a CO ₂ R ^b , -S(O) _m R ^a -NR ^a S(O) _m R ^b , -SO ₂ NR ^a R ^b , 4- to 5-membered heterocyclic group, aryl group and 5- to 6-membered heteroaryl group. Within each of the specific embodiments and preferred embodiments, a further preferred embodiment is one wherein R ¹ is a 5- to 10-membered heteroaryl group and is optionally Substituted by two substituents, the substituents are independently selected from halo, C _1-10 alkyl, C _1-10 haloalkyl, C _3-7 cycloalkyl, C _2-10 alkenyl, C _2-10 alkynyl , aryl, heteroaryl, CN, NO ₂ , -OR ^a , -NR ^a R ^b , -CO ₂ R ^a , -CONR ^a R ^b , -NR ^a COR ^b , -NR ^a CO ₂ R ^b ,- S(O) _m R ^a , -N ^a S(O) ₂ R ^b and -SO ₂ NR ^a R ^b . Still further preferred are the following specific examples wherein R ¹ is pyridine or pyrimidine and is optionally substituted with one to two substituents independently selected from halo, C _1-10 alkyl, C _1-10 Haloalkyl, C _3-7 cycloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, heteroaryl, CN, NO ₂ , -OR ^a , -NR ^a R ^b , -CO ₂ R ^a , -CONR ^a R ^b , -NR ^a COR ^b , -NR ^a CO ₂ R ^b , -S(O) _m R ^a , -N ^a S(O) ₂ R ^b and -SO ₂ NR ^a R ^b . In yet another specific embodiment, R ¹ is selected from the group consisting of -X ¹ -COR ^a , -X ¹ -CO ₂ R ^a , -X ¹ -CONR ^a R ^{b ,} and -SO ₂ R ^a .

In another aspect, the invention provides a compound represented by Formula II.

Wherein the letters X, Y and Z are each independently selected from the group consisting of O, N, S and C(R ³ ), and at least one of X, Y and Z is O, N, NR ⁸ or S; J, K, T and U Each of the independent selections includes C and N; the subscript p is an integer from 0 to 4; and the subscript q is an integer from 0 to 4.

In Formula II, R ¹ is selected from the group consisting of H, C _1-10 alkyl, C _1-10 substituted alkyl, C _3-7 cycloalkyl, C _2-10 alkenyl, C _2-10 alkynyl , -X ¹ -COR ^a , -X ¹ -CO ₂ R ^a , -X ¹ -CONR ^a R ^b , SO ₂ R ^a , 4- to 7-membered heterocyclic group, aryl group and 5- to 10-member a member of a heteroaryl group, wherein each of the cycloalkyl, heterocyclic, aryl and heteroaryl groups is optionally substituted with from 1 to 4 substituents independently selected from halo, C _1-10 alkyl, C _1-10 substituted alkyl, C _3-7 cycloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, heteroaryl, CN, -NR ^a COR ^b , -NR ^a CONR ^a R ^b , -NO ₂ , -OR ^a , -NR ^a R ^b , -COR ^a , -CO ₂ R ^a , -CONR ^a R ^b , -S(O) _m R ^a , -NR ^a S(O) ₂ R ^b and -SO ₂ NR ^a R ^b , or R ^a and R ^b are combined as appropriate to form a tetra-, penta- or six-membered ring, and X ¹ is selected from the group consisting of a bond, a C _2-6 olefin , C _2-6 alkyne, -C(O)-, and -C(O)-(CH ₂ ) _1-4 -, wherein the aliphatic moiety of X ¹ is optionally substituted by one to three members, the member It is selected from the group consisting of halogen, C _1-4 alkyl, C _1-4 substituted alkyl and C _1-4 haloalkyl.

Next, it is turned to R ² , and each R ² is independently selected from the group consisting of halogen, C _1-5 alkyl, C _1-5 -substituted alkyl, C _3-7 cycloalkyl, -COR ^a , -CO ₂ R ^a , a member of CONR ^a R ^b , -OR ^a , -NR ^a R ^b , -NR ^a COR ^b , -SOR ^a R ^b , -SO ₂ R ^a and -SO ₂ NR ^a R ^b , and wherein the subscript q is 2 When R ² is an alkyl group or a substituted alkyl group, the two R ² members may optionally be cyclized to form a ring.

R ³ is a member selected from the group consisting of hydrogen, halogen, C _1-4 alkyl and C _1-4 haloalkyl.

Each R ⁷ of formula II is independently selected from the group consisting of halo, C _1-10 alkyl, C _1-10 substituted alkyl, C _3-7 cycloalkyl, C _2-10 alkenyl, C _2-10 alkyne Base, CN, NO ₂ , -OR ^a , -NR ^a R ^b , -COR ^a , -CO ₂ R ^a , -CONR ^a R ^b , -NR ^a COR ^b , -NR ^a CO ₂ R ^b , -NR ^a CONR ^a R ^b , -S(O) _m R ^a , -NR ^a S(O) _m R ^b , -SO ₂ NR ^a R ^b , 4- to 7-membered heterocyclic group, aryl group and 5- to 10 a heteroaryl group, wherein each of the heterocyclic group, the aryl group and the heteroaryl group is optionally substituted with one to four substituents independently selected from the group consisting of halo, keto, C _1-4 alkyl, C _1-4 haloalkyl, C _3-7 cycloalkyl, CN, NO ₂ , -OR ^a , -NR ^a R ^b , -COR ^a , -CO ₂ R ^a , -CONR ^a R ^b , -NR ^a COR ^b , -NR ^a CO ₂ R ^b , -NR ^a CONR ^a R ^b , -S(O) _m R ^a , -NR ^a SO ₂ R ^b and -SO ₂ NR ^a R ^b , and wherein the subscript m is 0 An integer of up to 2, or R ^a and R ^b are combined as appropriate to form a four, five- or six-membered ring.

R ⁸ is independently selected from the group consisting of hydrogen, C _1-4 alkyl, and C _1-4 haloalkyl.

For each of the above groups, each of R ^a and R ^b is independently selected from the group consisting of hydrogen, C _1-10 alkyl, C _1-10 haloalkyl, C _3-10 cycloalkyl, heterocyclyl, C _2-10. An alkenyl group, a C _2-10 alkynyl group, an aryl group, a 5- to 6-membered heteroaryl group, and an aryl C _1-4 alkyl group; and wherein the aliphatic moiety of each of R ^a and R ^b is optionally Substituted by one to three members selected from the group consisting of halo, -OR ⁿ , -OCOR ⁿ , -OC(O)N(R ⁿ ) ₂ , -SR ⁿ , -S(O)R ⁿ , -S(O ₂ R ⁿ , -S(O) ₂ N(R ⁿ ) ₂ , -NR ⁿ S(O) ₂ R ⁿ , -C(O)N(R ⁿ ) ₂ , -C(O)R ⁿ ,- NR ⁿ C(O)R ⁿ , -NR ⁿ C(O)N(R ⁿ ) ₂ , -CO ₂ R ⁿ , -NR ⁿ CO ₂ R ⁿ , -CN, -NO ₂ , -N(R ⁿ ) ₂ and -NR ⁿ S(O) ₂ N(R ⁿ ) ₂ , wherein each R ⁿ is independently hydrogen or an unsubstituted C _1-6 alkyl group; and wherein the aryl group and the heteroaryl moiety are as appropriate Substituted by one to three members selected from the group consisting of halogen, -OR ^m , -OC(O)N(R ^m ) ₂ , -SR ^m , -S(O)R ^m , -S(O) ₂ R ^m , -S(O) ₂ N(R ^m ) ₂ , -NR ^m S(O) ₂ R ^m , -C(O)N(R ^m ) ₂ , -C(O)R ^m , -NR ^m C(O R ^m , -NR ^m C(O)N(R ^m ) ₂ , -CO ₂ R ^m , -NR ^m CO ₂ R ^m , -CN, -NO ₂ , -N(R ^m ) ₂ and -NR ^m S(O) ₂ N(R ^m ) ₂ Wherein each R ^m is independently hydrogen or an unsubstituted C _1-6 alkyl group.

The compounds provided herein also include any pharmaceutically acceptable compound of the compound Accepted salt, and any isomers identified by isotopes. In general, the compounds useful in the methods described herein are those of the above formula wherein the molecular weight of the compound is less than 1200, more preferably less than about 1,000, still more preferably less than about 800, and still more Good is about 200 to about 600.

In a particular embodiment, preferred R ¹ groups are selected from the group consisting of -X ¹ -COR ^a , -X ¹ -CO ₂ R ^a , -X ¹ -CONR ^a R ^b , SO ₂ R ^a , aryl a heteroaryl group, a substituted aryl group, and a substituted heteroaryl group. When R ¹ is an aromatic substituent, R ^{1 is} preferably selected from the group consisting of pyridyl, substituted pyridyl, pyrimidinyl, substituted pyrimidinyl, pyridyl Substituted pyridyl Base Base, replaced Base, phenyl, substituted phenyl, imidazolyl, triazolyl, substituted triazolyl, substituted imidazolyl, Azolyl, substituted Azolyl, thiazolyl, substituted thiazolyl, Diazolyl, substituted Diazolyl, tetrazolyl and substituted tetrazolyl.

When R ¹ is an aromatic substituent such as an aryl or heteroaryl group, R ¹ may be substituted with one to three substituents selected from the group consisting of C _1-10 alkyl, C _1-10 haloalkyl, C _{3 -7} cycloalkyl, aryl, heteroaryl, NO ₂ , -OR ^a , -NR ^a R ^b , -CO ₂ R ^a , -CONR ^a R ^b , -S(O) _m R ^a , -NR ^a S(O) ₂ R ^b and -SO ₂ NR ^a R ^b .

In a particular embodiment, preferably R ² is independently selected from the group consisting of halo, C _1-5 alkyl, C _1-5 haloalkyl, and the subscript q is an integer from 0 to 2.

In another preferred embodiment, D is O. In the compound of formula II, when D is O, preferably the R ¹ group is selected from the group consisting of -X ¹ -COR ^a , -X ¹ -CO ₂ R ^a , -X ¹ -CONR ^a R ^b , SO ₂ R ^a , aryl, heteroaryl, substituted aryl and substituted heteroaryl. When R ¹ is an aromatic substituent, R ^{1 is} preferably selected from the group consisting of pyridyl, substituted pyridyl, pyrimidinyl, substituted pyrimidinyl, pyridyl Substituted pyridyl Base Base, replaced Base, phenyl, substituted phenyl, imidazolyl, triazolyl, substituted triazolyl, substituted imidazolyl, Azolyl, substituted Azolyl, thiazolyl, substituted thiazolyl, Diazolyl, substituted Diazolyl, tetrazolyl and substituted tetrazolyl.

Further, when D is O and R ¹ is an aromatic substituent such as an aryl group or a heteroaryl group, R ¹ may be substituted with one to three substituents selected from C _1-10 alkyl groups, C _{1- 10} haloalkyl, C _3-7 cycloalkyl, aryl, heteroaryl, NO ₂ , -OR ^a , -NR ^a R ^b , -CO ₂ R ^a , -CONR ^a R ^b , -S(O) _m R ^a , -NR ^a S(O) ₂ R ^b and -SO ₂ NR ^a R ^b .

Yet another embodiment of the invention is a compound of formula II wherein J, K, T and U are both C. In this particular embodiment, preferred R ¹ groups are selected from the group consisting of -X ¹ -COR ^a , -X ¹ -CO ₂ R ^a , -X ¹ -CONR ^a R ^b , SO ₂ R ^a , aryl a heteroaryl group, a substituted aryl group, and a substituted heteroaryl group. When R ¹ is an aromatic substituent, R ^{1 is} preferably selected from the group consisting of pyridyl, substituted pyridyl, pyrimidinyl, substituted pyrimidinyl, pyridyl Substituted pyridyl Base Base, replaced Base, phenyl, substituted phenyl, imidazolyl, triazolyl, substituted triazolyl, substituted imidazolyl, Azolyl, substituted Azolyl, thiazolyl, substituted thiazolyl, Diazolyl, substituted Diazolyl, tetrazolyl and substituted tetrazolyl. Further, when J, K, T and U are both C, and R ¹ is an aromatic substituent such as an aryl or heteroaryl group, R ¹ may be substituted by one to three substituents selected from the group consisting of C _{1 -10} alkyl, C _1-10 haloalkyl, C _3-7 cycloalkyl, aryl, heteroaryl, NO ₂ , -OR ^a , -NR ^a R ^b , -CO ₂ R ^a , -CONR ^a R ^b , -S(O) _m R ^a , -NR ^a S(O) ₂ R ^b and -SO ₂ NR ^a R ^b .

A specific embodiment of the invention comprises a compound of formula II wherein subscript p is an integer from 1 to 3, and each R ⁷ is independently selected from the group consisting of halo, C _1-10 alkyl, C _1-10 halo Base, CN, NO ₂ , -OR ^a , -NR ^a R ^b , -COR ^a , -CO ₂ R ^a , -CONR ^a R ^b , -NR ^a COR ^b , -NR ^a CO ₂ R ^b , -S( O) _m R ^a , -NR ^a S(O) _m R ^b , -SO ₂ NR ^a R ^b , 4- to 7-membered heterocyclic group, aryl group and 5- to 10-membered heteroaryl group, each of which The heterocyclic group, the aryl group and the heteroaryl group are optionally substituted by one to four substituents independently selected from the group consisting of halo, keto, C _1-4 alkyl, C _1-4 haloalkyl, C _3-7 cycloalkyl, CN, NO ₂ , -OR ^a , -NR ^a R ^b , -CO ₂ R ^a , -CONR ^a R ^b , -NR ^a COR ^b , -NR ^a CO ₂ R ^b , -S (O) _m R ^a , -NR ^a SO ₂ R ^b and -SO ₂ NR ^a R ^b , wherein the subscript m is an integer from 0 to 2.

Yet another aspect of the invention provides a compound of formula II wherein J, K, T and U are both C; preferably the R ¹ group is selected from the group consisting of -X ¹ -COR ^a , -X ¹ -CO ₂ R ^a —X ¹ —CONR ^a R ^b , SO ₂ R ^a , aryl, heteroaryl, substituted aryl, and substituted heteroaryl. When R ¹ is an aromatic substituent, R ^{1 is} preferably selected from the group consisting of pyridyl, substituted pyridyl, pyrimidinyl, substituted pyrimidinyl, pyridyl Substituted pyridyl Base Base, replaced Base, phenyl, substituted phenyl, imidazolyl, triazolyl, substituted triazolyl, substituted imidazolyl, Azolyl, substituted Azolyl, thiazolyl, substituted thiazolyl, Diazolyl, substituted a oxadiazolyl, a tetrazolyl group and a substituted tetrazolyl group; and the subscript p is an integer from 1 to 3, and each R ⁷ is independently selected from the group consisting of halo, C _1-10 alkyl, C _1-10 halo Alkyl, CN, NO ₂ , -OR ^a , -NR ^a R ^b , -COR ^a , -CO ₂ R ^a , -CONR ^a R ^b , -NR ^a COR ^b , -NR ^a CO ₂ R ^b , -S (O) _m R ^a , -NR ^a S(O) _m R ^b , -SO ₂ NR ^a R ^b , 4- to 7-membered heterocyclic group, aryl group and 5- to 10-membered heteroaryl group, wherein Each of the heterocyclic group, the aryl group and the heteroaryl group is optionally substituted by one to four substituents independently selected from the group consisting of a halogen group, a ketone group, a C _1-4 alkyl group, a C _1-4 haloalkyl group, C _3-7 cycloalkyl, CN, NO ₂ , -OR ^a , -NR ^a R ^b , -CO ₂ R ^a , -CONR ^a R ^b , -NR ^a COR ^b , -NR ^a CO ₂ R ^b ,- S(O) _m R ^a , -NR ^a SO ₂ R ^b and -SO ₂ NR ^a R ^b , and wherein the subscript m is an integer from 0 to 2. R ¹ is optionally substituted with one to three substituents selected from the group consisting of C _1-10 alkyl, C _1-10 haloalkyl, C _3-7 cycloalkyl, aryl, heteroaryl, NO ₂ , -OR ^a , -NR ^a R ^b , -CO ₂ R ^a , -CONR ^a R ^b , -S(O) _m R ^a , -NR ^a S(O) ₂ R ^b and -SO ₂ NR ^a R ^b .

A further embodiment of the compound of the invention is a compound of formula II wherein at least one of J, K, T and U is N. In this particular embodiment, D is O, S or NR ⁸ .

Preferred embodiments of Formula II provide compounds wherein at least one of J, K, T and U is N and D is O.

In the compound of formula II, when at least one of J, K, T and U is N and D is O, preferably the R ¹ group is selected from the group consisting of -X ¹ -COR ^a , -X ¹ -CO ₂ R ^a , -X ¹ -CONR ^a R ^b , SO ₂ R ^a , aryl, heteroaryl, substituted aryl and substituted heteroaryl. When R ¹ is an aromatic substituent, R ^{1 is} preferably selected from the group consisting of pyridyl, substituted pyridyl, pyrimidinyl, substituted pyrimidinyl, pyridyl Substituted pyridyl Base Base, replaced Base, phenyl, substituted phenyl, imidazolyl, substituted imidazolyl, triazolyl, substituted triazolyl, Azolyl, substituted Azolyl, thiazolyl, substituted thiazolyl, Diazolyl, substituted a oxadiazolyl, a tetrazolyl group and a substituted tetrazolyl group; and the subscript p is an integer from 1 to 3, and each R ⁷ is independently selected from the group consisting of halo, C _1-10 alkyl, C _1-10 halo Alkyl, CN, NO ₂ , -OR ^a , -NR ^a R ^b , -COR ^a , -CO ₂ R ^a , -CONR ^a R ^b , -NR ^a COR ^b , -NR ^a CO ₂ R ^b , -S (O) _m R ^a , -NR ^a S(O) _m R ^b , -SO ₂ NR ^a R ^b , 4- to 7-membered heterocyclic group, aryl group and 5- to 10-membered heteroaryl group, wherein Each of the heterocyclic group, the aryl group and the heteroaryl group is optionally substituted by one to four substituents independently selected from the group consisting of a halogen group, a ketone group, a C _1-4 alkyl group, a C _1-4 haloalkyl group, C _3-7 cycloalkyl, CN, NO ₂ , -OR ^a , -NR ^a R ^b , -CO ₂ R ^a , -CONR ^a R ^b , -NR ^a COR ^b , -NR ^a CO ₂ R ^b ,- S(O) _m R ^a , -NR ^a SO ₂ R ^b and -SO ₂ NR ^a R ^b , and wherein the subscript m is an integer from 0 to 2. R ¹ is optionally substituted with one to three substituents selected from the group consisting of C _1-10 alkyl, C _1-10 haloalkyl, C _3-7 cycloalkyl, aryl, heteroaryl, NO ₂ , -OR ^a , -NR ^a R ^b , -CO ₂ R ^a , -CONR ^a R ^b , -S(O) _m R ^a , -NR ^a S(O) ₂ R ^b and -SO ₂ NR ^a R ^b .

A preferred embodiment provides a compound of formula II wherein at least one of J, K, T and U is N and D is O, and R ¹ is as described in the preceding paragraph, subscript p is 1. An integer of up to 3, and each R ⁷ is independently selected from the group consisting of halo, C _1-10 alkyl, C _1-10 haloalkyl, CN, NO ₂ , —OR ^a , —NR ^a R ^b , —COR ^a , -CO ₂ R ^a , -CONR ^a R ^b , -NR ^a COR ^b , -NR ^a CO ₂ R ^b , -S(O) _m R ^a , -NR ^a S(O) _m R ^b , -SO ₂ NR ^a R ^b , 4- to 7-membered heterocyclic group, aryl group and 5- to 10-membered heteroaryl group, wherein each of the heterocyclic group, the aryl group and the heteroaryl group is optionally substituted by one to four Substituent, the substituent is independently selected from halo, keto, C _1-4 alkyl, C _1-4 haloalkyl, C _3-7 cycloalkyl, CN, NO ₂ , -OR ^a , -NR ^a R _{^{b, -CO 2 R a, -CONR}} a R b, -NR a COR b, -NR a CO 2 R b, -S (O) m R a, -NR a SO 2 R b and -SO ₂ NR ^a R ^b , and wherein the subscript m is an integer from 0 to 2.

Yet another preferred compound of formula II provides a compound wherein J, T and U are both C and D is O, S or NR ⁸ .

Still more preferred is a compound of formula II which provides a compound wherein J, T and U are both C and D is O.

For the compound of formula II, when J, T and U are both C and D is O, the R ⁷ group is independently selected from the group consisting of halo, C _1-10 alkyl, C _1-10 haloalkyl, CN, NO ₂ , -OR ^a , -NR ^a R ^b , -COR ^a , -CO ₂ R ^a , -CONR ^a R ^b , -NR ^a COR ^b , -NR ^a CO ₂ R ^b , -S(O) _m R ^{a member of a} , -NR ^a S(O) _m R ^b , -SO ₂ NR ^a R ^b , a 4- to 5-membered heterocyclic group and a 5- to 6-membered heteroaryl group, wherein the subscript m is 0 An integer of up to 2. Preferred R ⁷ groups are independently selected from the group consisting of halo, C _1-5 alkyl, C _1-5 haloalkyl, -SOR ^a , -SO ₂ R ^a and 5-membered heteroaryl. Still more preferably, the R ⁷ groups are independently selected from the group consisting of fluoro, chloro, methyl, ethyl, -CF ₃ , -SO ₂ CH ₃ , imidazolyl, triazolyl and tetrazolyl, and wherein the subscript p It is an integer from 1 to 2.

In Formula II, when J, T and U are both C and D is O, preferred compounds are the following compounds wherein the R ⁷ group is independently selected from the group consisting of halo, C _1-10 alkyl, C. _1-10 haloalkyl, CN, NO ₂ , -OR ^a , -NR ^a R ^b , -COR ^a , -CO ₂ R ^a , -CONR ^a R ^b , -NR ^a COR ^b , -NR ^a CO ₂ R ^a , -S(O) _m R ^a , -NR ^a S(O) _m R ^b , -SO ₂ NR ^a R ^b , 4- to 5-membered heterocyclic group and 5- to 6-membered heteroaryl group a member, wherein the subscript m is an integer from 0 to 2, and each R ² is independently selected from the group consisting of a halo group, a C _1-5 alkyl group, a C _1-5 haloalkyl group, and the subscript q is 0 to An integer of 2. Preferred R ⁷ groups are independently selected from the group consisting of halo, C _1-5 alkyl, C _1-5 haloalkyl, -SOR ^a , -SO ₂ R ^a and 5-membered heteroaryl. Still more preferably, the R ⁷ groups are independently selected from the group consisting of fluoro, chloro, methyl, ethyl, —CF ₃ , —SO ₂ C _1-3 alkyl, imidazolyl, triazolyl and tetrazolyl, and Wherein the subscript p is an integer from 1 to 2.

Another embodiment of the present invention provides a compound of formula II, wherein when J, T and U are both C and D is O, R ⁷ is a member as described above, and R ¹ is selected from the group consisting of - X ¹ -COR ^a , -X ¹ CO ₂ R ^a , -X ¹ -CONR ^a R ^b , SO ₂ R ^a , aryl, heteroaryl, substituted aryl and substituted heteroaryl. Preferred R ¹ groups are selected from the group consisting of aryl, heteroaryl, substituted aryl and substituted heteroaryl. Still more preferably, the compound wherein R ¹ is selected from the group consisting of pyridyl, substituted pyridyl, pyrimidinyl, substituted pyrimidinyl, pyridyl Substituted pyridyl Base Base, replaced Base, phenyl, substituted phenyl, imidazolyl, triazolyl, substituted triazolyl, substituted imidazolyl, Azolyl, substituted Azolyl, thiazolyl, substituted thiazolyl, Diazolyl, substituted Diazolyl, tetrazolyl and substituted tetrazolyl. Still more preferably, the compound wherein R ¹ is selected from the group consisting of pyrimidinyl, substituted pyrimidinyl, Diazolyl, substituted A oxazolyl group and -X ¹ -CO ₂ R ^a , and wherein X ¹ is a bond.

Other preferred compounds of the invention are those wherein J, T and U are all C; and D is O, X is S, Y is C, Z is N; R ¹ is selected from pyrimidyl groups, substituted Pyrimidinyl, pyridyl and substituted pyridyl, each R ⁷ is independently selected from the group consisting of fluoro and tetrazolyl.

In one aspect, the invention provides a method of treating a disease or condition selected from the group consisting of Type I diabetes, Type II diabetes, and metabolic syndrome. This method comprises administering to a patient in need of such treatment an effective amount of a compound of formula I or formula II.

Another aspect of the invention provides a method of stimulating insulin production in a mammal comprising administering to the mammal an effective amount of a compound of Formula I or Formula II. In one aspect, the beta cell line of the pancreas is stimulated to produce insulin.

Yet another aspect of the invention provides a method of stimulating glucose-dependent insulin secretion or production in a mammal comprising administering to the mammal an effective amount of a compound of Formula I or Formula II. On one hand, the beta cell line of the pancreas Stimulate to secrete insulin.

A further aspect of the invention is a method of lowering blood glucose in a mammal. This method comprises administering to the mammal an effective amount of a compound of Formula I or Formula II. The method further comprises the step of measuring the blood glucose level before and after administration of the compound of the invention. The blood glucose level is readily measurable by a number of commercially available glucose monitoring devices that measure blood glucose from blood or urine samples. Blood glucose can also be measured by commercially available glucose meters, which do not require blood or urine samples. Biological Example 5 provides a method of measuring glucose content.

In another specific embodiment, the invention provides a method of lowering blood triglyceride in a mammal. This method comprises administering to the mammal an effective amount of a compound of Formula I or Formula II. The method further comprises the step of measuring the blood triglyceride content before and after administration of the compound of the invention. The blood triglyceride content is readily measurable by a number of commercially available devices which measure the blood triglyceride content from a sample of blood. Biological Example 6 provides a method for measuring the triglyceride content.

Preparation of the Compounds of the Invention The compounds of the invention can be prepared in a variety of ways familiar to those skilled in the art of organic synthesis. The synthetic route of the compounds of the invention is not limited to the methods outlined below or as provided in the examples. Individual compounds may require manipulation of the conditions to conform to various functional groups and may require the appropriate use of protecting groups. Purification, if necessary, can be accomplished on a ruthenium tube column and dissolved in a suitable organic solvent system. Reverse phase HPLC or recrystallization can also be employed.

One aspect of the invention provides a method of increasing the intracellular content of cyclic AMP (cAMP) in cells expressing GPR119. This method includes performance Cells of GPR119 are exposed to a compound as described herein. The cyclic AMP content is determined by the methods disclosed herein. Preferred cells which exhibit GPR119 are pancreatic cells, islet cells, beta cells, enteroendocrine cells, and L cells or K cells.

The selected thiazole compound of formula I can be prepared using the methods generally outlined in Scheme 1.

According to Scheme 1, thioguanamine can be condensed with a chloromethyl ketone to form an appropriate thiazole intermediate. Manipulation of the R ₁ and R ₂ groups can be accomplished as provided in the examples below.

Similarly, Formula I The oxadiazole compound can be prepared as generally shown in Scheme 2.

Here, a suitable nitrile is treated with NH ₂ OH HCl in the presence of K ₂ CO ₃ (step 1) to provide N-hydroxyindole, which may be used, for example, R ₂ COOH, isobutyl chloroformate and triethylamine. Be converted into Diazole compound. As described above, further manipulation of R ₁ and R ₂ can be performed as provided in the examples below.

Compositions and Methods of Treatment In accordance with the present invention, a therapeutically effective amount of a compound of formula I can be used to prepare a pharmaceutical composition useful for treating Type II diabetes and/or reducing plasma plasma levels of glucose. In addition, a therapeutically effective amount of a compound of formula I can be used to prepare a pharmaceutical composition useful for treating other indications comprising diabetes as a component, such as metabolic syndrome, and indications that can be improved as a result of increased insulin production. (such as the early stages of type I diabetes).

The compositions of the present invention may comprise a compound of formula I and formula II, a pharmaceutically acceptable salt thereof or a hydrolyzable precursor thereof. In general, the compounds are mixed in a therapeutically effective amount with a suitable carrier or excipient. By "therapeutically effective dose", "therapeutically effective amount", or interchangeably, "pharmacologically acceptable dose" or "pharmacologically acceptable amount", means a sufficient amount of a compound of the invention It is present with a pharmaceutically acceptable carrier to achieve the desired result, such as amelioration of signs or complications of Type II diabetes.

The compounds of formula I and formula II for use in the methods of the invention can be incorporated into a variety of formulations for therapeutic administration. More specifically, the compounds of formula I and formula II can be formulated into pharmaceutical compositions by combining with a suitable pharmaceutically acceptable carrier or diluent, and can be formulated into a solid, semi-solid, liquid or gaseous Forms such as tablets, capsules, pills, powders, granules, dragees, gels, slurries, ointments, solutions, suppositories, injections, inhalation and aerosols. Thus, administration of the compound can be accomplished in a variety of ways, including buccal, buccal, rectal, parenteral, intraperitoneal, intradermal, transdermal, and/or intratracheal administration. Furthermore, the compounds can be administered in a localized rather than systemic manner in a stored or sustained release formulation. In addition, the compound can be administered as a liposome.

The compounds of formula I and formula II can be formulated with excipients, diluents or carriers, and compressed into tablets, or formulated into elixirs or solutions for oral administration or by intramuscular or intravenous routes. . The compounds can be administered transdermally and can be formulated into sustained release dosage forms and the like. The compounds of formula I or formula II can be administered alone or in combination with one another, or they can be combined with other known compounds (see combination therapies below).

Suitable formulations for use in the present invention can be found in Remington's Medical Sciences (Mack Publishing Company (1985) Philadelphia, PA, 17th Edition), which is incorporated herein by reference. Further, for a brief review of drug delivery methods, see Langer, Science (1990) 249: 1527-1533, which is incorporated herein by reference. The pharmaceutical compositions described herein can be made by methods known to those skilled in the art, that is, by conventional mixing, dissolving, granulating, dragee manufacturing, grinding, emulsifying, encapsulating, capturing or lyophilizing methods. The following methods and excipients are by way of example only and are in no way limiting.

For injection, the compounds can be formulated into preparations by dissolving, suspending or emulsifying them in aqueous or nonaqueous solvents such as, for example, plants or other similar oils, synthetic fatty acid glycerides, high carbon aliphatic acid esters. Or propylene glycol; and if necessary, conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives. Preferably, the compounds of the invention are formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution or physiological saline buffer. For transmucosal administration, a suitable permeation agent for the barrier to be infiltrated is used in the formulation. Such penetrants are generally known in the art.

For oral administration, the compound of Formula I or Formula II can be readily formulated by combining with a pharmaceutically acceptable carrier as is known in the art. The carrier enables the compound to be formulated into tablets, pills, dragees, capsules, emulsions, lipophilic and hydrophilic suspensions, liquids, gels, syrups, slurries, suspensions, etc. for the patient to be treated Oral feeding. For oral use The pharmaceutical preparation can be obtained by mixing the compound with a solid excipient, optionally grinding the resulting mixture, and treating the mixture of granules, and if necessary, obtaining a tablet or dragee core after adding an appropriate adjuvant. . Suitable excipients are, in particular, fillers, such as sugars, including lactose, sucrose, mannitol or sterol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, scutellaria, a Cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose and/or polyvinyltetrahydropyrrolidone. If necessary, a disintegrating agent such as crosslinked polyvinylpyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate may be added.

The dragee core has a suitable coating. For this project, a concentrated sugar solution may be used, which may optionally contain gum arabic, talc, polyvinyl tetrahydropyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, a lacquer solution and a suitable organic solvent. Or solvent mixture. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or characterisation to exhibit different combinations of active compound doses.

Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or phytosterol. The push-fit capsules may contain the active ingredient in admixture with a filler such as lactose, a binder, such as a starch, and/or a lubricant, such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid, such as a fatty oil, liquid paraffin or liquid polyethylene glycol. In addition, a stabilizer can be added. All formulations for oral administration should be in dosages suitable for such administration.

For chewing, the composition can be prepared by conventionally used tablets or sugar. Ingot form.

For administration by inhalation, the compounds for use according to the invention are conveniently delivered in the form of an aerosol spray, delivered from a pressurized pack or atomization tank, and using a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, Dichlorotetrafluoroethane, carbon dioxide or other suitable gas, or from a propellant-free, dry powder inhaler. In the case of a pressurized aerosol, the dosage unit can be determined via the provision of a valve to deliver a metered amount. Capsules and cartridges for use in an inhaler or insufflator, such as gelatin, may be formulated to contain a powder mixture of the compound and a suitable powder base such as lactose or starch.

The compounds can be formulated for parenteral administration by injection, for example by bolus injection or continuous infusion. The formulation for injection can be presented in unit dosage form, for example in ampoules or in multi-dose containers, with added preservatives. The compositions may take some form, such as a suspension, solution or emulsion, in an oily or aqueous vehicle, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents.

Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Furthermore, suspensions of the active compounds can be formulated into suitable oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or vesicles. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sterol or dextran. The suspension may also contain suitable stabilizers, as appropriate, or may increase the solubility of the compound to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in the form of a powder which is shaped in a suitable vehicle before use, for example, sterile, ex The water of the pyrogen.

The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, for example, containing conventional suppository bases such as cocoa butter, carbowax, polyethylene glycol or other glycerides, all of which are melted at body temperature, It is cured at room temperature.

In addition to the foregoing formulations, the compounds may also be formulated as a stocking formulation. Such long-acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compound may be formulated, using a suitable polymerizable or hydrophobic material (for example, as an emulsion in an acceptable oil) or an ion exchange resin, or as a controlled soluble derivative, for example, as a moderately soluble solution. salt.

Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. The vesicles and emulsions are conventional examples of delivery vehicles or carriers for hydrophobic drugs. In a presently preferred embodiment, a long cycle, meaning a secret vesicle, can be employed. Such vesicles are generally described in Woodle et al., U.S. Patent 5,013,556. The compounds of the present invention can also be administered by controlled release means and/or delivery devices, such as those described in U.S. Patent Nos. 3,845,770, 3,916,899, 3,536,809, 3,598,123, and 4,008,719.

Certain organic solvents, such as dimethyl hydrazine ("DMSO"), may also be employed, but often at the expense of greater toxicity. In addition, the compounds can be delivered using a sustained release system, such as a semipermeable matrix of a solid hydrophobic polymer containing a therapeutic agent. Various types of sustained release materials have been established and are known to those skilled in the art. Sustained release of the capsule, depending on its chemical nature, releases the compound over a period of up to more than 100 days.

The pharmaceutical compositions may also contain suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycol.

Pharmaceutical compositions suitable for use in the present invention include those in which the active ingredient is included in a therapeutically effective amount. The amount of the composition to be administered will of course be determined by the patient being treated, the weight of the patient, the severity of the condition, the mode of administration, and the judgment of the designated physician. The effective amount of the determination is well within the skill of the artisan, especially after the detailed disclosure provided herein.

For any compound used in the methods of the invention, the therapeutically effective dose can be initially estimated from cell culture assays, animal models or micromedication of a human patient.

Furthermore, toxic and therapeutic effects of the compounds described herein, may be in cell cultures or experimental animals by standard pharmaceutical procedures determined by measurement, e.g. LD ₅₀ (50% of the population of individuals lethal dose) with ED ₅₀ (Dose that is therapeutically effective in 50% of the individual population). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio between LD ₅₀ and ED ₅₀ . Compounds which exhibit a high therapeutic index are preferred. Data from such cell culture assays and animal studies can be used to formulate dose ranges that are not toxic in humans. The dosage of such compounds preferably located within the system a circulating concentration range that includes an ED ₅₀ with little or no toxicity it. The dosage can vary within this range, depending on the dosage form employed and the route of administration employed. The correct formulation, route of administration and dosage can be selected by the individual physician in view of the patient's symptoms (see, for example, Fingl et al., 1975: Pharmacological Basis of Therapeutics , Chapter 1).

The amount of active compound that can be combined with the carrier materials to produce a single dosage form will vary depending on the condition being treated, the mammalian species, and the particular mode of administration. However, as a general guideline, a suitable unit dose of the compound of the present invention may, for example, preferably contain from 0.1 mg to about 1000 mg of the active compound. Preferred unit dosages are between 1 mg and about 100 mg. More preferred unit dosages are between 1 mg and about 20 mg. Such unit dose may be administered more than once a day, for example 2, 3, 4, 5 or 6 times a day, but preferably 1 or 2 times a day, so that the total dose for 70 kg of adult is per kg of disease per dose. The body weight is in the range of 0.001 to about 15 mg. The preferred dosage is from 0.01 to about 1.5 mg per kilogram of patient weight per administration, and such therapy may be extended for weeks or months, and in some cases for several years. However, it should be understood that the specific dosage level for any particular patient will depend on a number of factors, including the activity of the particular compound employed; the age, weight, general health, sex, and diet of the individual being treated; Route; rate of excretion; other drugs that have been previously administered; and the severity of the particular disease being treated, as is well known to those skilled in the art.

A typical dose may be from 1 mg to about 20 mg of the tablet, taken once a day or multiple times a day, or one capsule or tablet that is released on a daily basis and containing a proportionately higher amount of active ingredient. The release on time can be obtained by capsules which are dissolved at different pH values, by capsules which are slowly released by osmotic pressure, or by any other known controlled release means.

In some cases, it may be necessary to use dosages outside of these ranges, as will be apparent to those skilled in the art. Furthermore, it should be noted that the clinician or therapist The division will work with individual patients to know how and when to interrupt, adjust or terminate treatment.

Combination Therapy As noted above, the compounds of the invention will, in some instances, be combined with other therapeutic agents to produce the desired effect. Most of the choice of other agents depends on the desired therapy (see, for example, Turner N et al, Prog . Drug Res . (1998) 51: 33-94; Haffner S, Diabetes Care (1998) 21: 160- 178; and DeFronzo R et al. (eds.), Diabetes Review (1997), Vol. 5, No. 4). Many studies have investigated the benefits of combination therapies with oral agents (see, for example, Mahler R, J. Clin . Endocrinol . Metab . (1999) 84: 1165-71; UK Prospective Diabetes Research Group: UKPDS 28, Diabetes Care (1998) 21: 87-92; Bardin CW (Bianzhu), the current therapy of endocrinology and metabolism, Version 6 (Mosby- Yearbook company, St Louis, Mo 1997.) ; Chiasson J , et al., Ann Intern Med... (1994) 121: 928-935; Coniff R et al., Clin . Ther . (1997) 19: 16-26; Coniff R et al., Am . J. Med . (1995) 98: 443-451; and Iwamoto Y Et al ., Diabet . Med . (1996) 13 365-370; Kwiterovich P, Am . J. Cardiol (1998) 82(12A): 3U-17U). These studies show that diabetes modulation can be further improved by adding a second agent to the therapeutic regimen. Combination therapy comprises administering a single pharmaceutical dosage formulation comprising a compound of the general structure of Formula I or Formula II, and one or more additional active agents, and formulating a compound of Formula I or Formula II in its own individual pharmaceutical dosage formulation. Active agent. For example, a compound of Formula I or Formula II and a DPP-IV inhibitor can be administered to a human patient, such as a tablet or capsule, together with a single oral dosage composition, or each agent can be administered in an individual oral dosage formulation. Where individual dosage formulations are employed, the compound of Formula I or Formula II and one or more additional active agents can be administered at substantially the same time (i.e., collectively), or at individual staggered times (i.e., sequentially). It should be understood that the combination therapy system includes all such usages.

Examples of combination therapies can be seen in the modulation (prevention of the development of symptoms or complications associated with diabetes) diabetes (or the treatment, prevention or reduction of the risk of developing diabetes and its associated signs, complications, and conditions), where Formula I or The compound of formula II can be effectively used in combination with, for example, a bismuth (e.g., metformin); a thiazolidinedione (e.g., ciglitazone, pioglitazone, zoeg Troglitazone and rosiglitazone; dipeptidyl-peptidase-4 ("DPP-IV") inhibitors (such as vildagliptin and sitagliptin) )); glucagon-like peptide-1 ("GLP-1") receptor agonist (such as exanatide) (or GLP-1 mimetic); PPARγ agonist or partial agonist Agent; double PPARα, PPARγ agonist or partial agonist; double PPARδ, PPARγ agonist or partial agonist; total PPAR agonist or partial agonist; dehydroepiandrosterone Known as DHEA, or its conjugated sulfate DHEA-SO ₄ ); anti-corticosteroids; TNFα inhibitors; α-glucosidase inhibitors (such as acarbose (acarb) Os), miglitol and voglibose; sulfonyl ureas (such as chlorpropamide, tolbutamide, acesulfame), methylsulfonate Urea, glyburide, gliclazide, glynase, glimepiride, and glipizide; pralin Pramlintide (a synthetic analog of human hormone dextrin); other insulin secretagogues (such as repaglinide, gliquidone, and nateglinide); insulin (or insulin mimicry) Glucagon receptor antagonist; gastric inhibitory peptide ("GIP"); or GIP mimetic; and as discussed below for the treatment of obesity, hyperlipidemia, atherosclerosis and/or metabolic syndrome Active agent.

Another example of a combination therapy can be seen in the treatment of obesity or obesity-related conditions, wherein a compound of Formula I or Formula II can be effectively used in combination with, for example, phenylpropanolamine, phenteramine; diethylamine Benzophenone; mazindol; fenfluramine; dexfenfluramine; phentiramine, beta-3 adrenergic receptor agonist; Sibutramine; a gastrointestinal lipase inhibitor (such as orlistat); and lepasoline. Other agents for the treatment of obesity or obesity-related disorders wherein the compound of Formula I or Formula II is effective for use in combination with, for example, a cannabinoid-1 ("CB-1") receptor antagonist (such as Limoneban) (rimonabant)); PPARδ agonist or partial agonist; double PPARα, PPARδ agonist or partial agonist; double PPARδ, PPARγ agonist or partial agonist; total PPAR agonist or Partial agonist; neuropeptide Y; enter bacteriocin; chosome kinin; bombesin; dextrin; histamine H ₃ receptor; dopamine D ₂ receptor; melanocytic hormone; adrenal gland Corticosteroid releasing factor; galangin; and gamma aminobutyric acid (GABA).

Yet another example of combination therapy can be seen in the modulation of hyperlipidemia (treatment of hyperlipidemia and its associated complications), wherein the compound of Formula I or Formula II can be effectively used in combination with, for example, bacteriocin (e.g. Atorvastatin, fluvastatin, lovastatin, pravastatin and simvastatin, CETP inhibition Agent (such as torcetrapib); cholesterol absorption inhibitor (such as also Ezetimibe); PPARα agonist or partial agonist; PPARδ agonist or partial agonist; double PPARα, PPARδ agonist or partial agonist; double PPARα, PPARγ Agent or partial agonist; double PPARδ, PPARγ agonist or partial agonist; total PPAR agonist or partial agonist; non-noic acid derivative (such as gemfbrozil ), clofibrate, fenofibrate and bezafibrate; bile acid-binding resins (such as colestipol or cholestyramine) )); nicotinic acid; probucol; beta carotene; vitamin E; or vitamin C.

Further examples of combination therapies can be seen in the modulation of atherosclerosis, wherein the compound of Formula I or Formula II is administered in combination with one or more of the following active agents: an antihyperlipidemic agent; a plasma HDL booster; an antihypercholesterolemia Agents, such as cholesterol biosynthesis inhibitors, such as hydroxymethylpentamethylene (HMG) CoA reductase inhibitors (also known as bacteriocins, such as lovastatin, simvastatin) Simvastatin), pravastatin, fluvastatin and atorvastatin; HMG-CoA synthetase inhibitor; squalene epoxidase inhibitor; Or a squalene synthase inhibitor (also known as a squalene synthase inhibitor); a thiol-coenzyme A cholesterol thiol transferase (ACAT) inhibitor, such as melinamide ); probucol; nicotinic acid and its salts and nicotinamide; cholesterol absorption inhibitors, such as β-sitosterol; bile acid sequestrant anion exchange resins, such as cholestyramine, Derivatization of colesipol or crosslinked dextran dialkylaminoalkyl LDL receptor inducer; fiber ester, such as clofibrate, benzoate. Bezafibrate), fenofibrate and gemfibrizol; vitamin B ₆ (also known as pyridoxine), and pharmaceutically acceptable salts thereof, such as HCl salts; vitamin B ₁₂ (also known as Is cyanocobalaminate; vitamin B ₃ (also known as niacin and nicotinamide); antioxidant vitamins such as vitamin C and E and beta carrot Β-blocker; angiotensin II antagonist; angiotensin-converting enzyme inhibitor; PPARα agonist or partial agonist; PPARδ agonist or partial agonist; PPARγ agonist or Partial agonist; double PPARα, PPARδ agonist or partial agonist; double PPARα, PPARγ agonist or partial agonist; double PPARδ, PPARγ agonist or partial agonist; total PPAR An agonist or partial agonist; and an inhibitor of platelet aggregation, such as a fibrinogen receptor antagonist (ie, glycoprotein IIb/IIIa fibrinogen receptor antagonist) and aspirin. As described above, the compound of Formula I or Formula II can be administered in combination with more than one other active agent, such as a compound of Formula I or Formula II and an HMG-CoA reductase inhibitor (eg, atorvastatin, F. faecalis) Fluvastatin, lovastatin, pravastatin and simvastatin, and aspirin, or a compound of formula I or formula II with HMG-CoA A combination of a reductase inhibitor and a beta blocker.

Furthermore, an effective amount of a compound of formula I or formula II and a therapeutically effective amount of one or more active agents can be used together in the preparation of a pharmaceutical composition for use in the treatment described above, the active agent being selected from the group consisting of: an antihyperlipidemic agent; plasma HDL-boosting agent; anti-hypercholesterolemia agent, such as cholesterol biosynthesis inhibitors, such as HMG-CoA reductase inhibitors; HMG-CoA synthetase inhibitors; squalene epoxidase inhibitors or squalene synthetase (synthetase) inhibitor (also known as squalene synthase inhibitor); thiol-coenzyme A cholesterol thiol transferase inhibitor; probucol; nicotinic acid and its salt; CETP Inhibitors, such as torcetrapib; cholesterol absorption inhibitors, such as ezetimibe; PPARα agonists or partial agonists; PPARδ agonists or partial agonists; PPARα, PPARδ agonist or partial agonist; double PPARα, PPARγ agonist or partial agonist; double PPARδ, PPARγ agonist or partial agonist; total PPAR agonist or partial promotion Agent; nicotinamide; cholesterol absorption inhibitor; bile acid sequestrant Ion exchange resin; LDL receptor inducer; clofibrate, fenofibrate and gemfibrozil; vitamin B ₆ and pharmaceutically acceptable salts thereof; vitamin B ₁₂ ; antioxidant vitamins; beta-blockers; angiotensin II antagonists; angiotensin-converting enzyme inhibitors; platelet aggregation inhibitors; fibrinogen receptor antagonists; aspirin; (phentiramine), β-3 adrenergic receptor agonist; sulfonyl urea, double vasoconstrictor, α-glucosidase inhibitor, other insulin secretagogue and insulin.

Another example of combination therapy can be seen in modulating metabolic syndrome (or treating metabolic syndromes and their associated signs, complications, and conditions), wherein a compound of Formula I or Formula II can be effectively used in combination with, for example, Active agents discussed in the modulation or treatment of diabetes, obesity, hyperlipidemia, atherosclerosis, and/or its associated associated signs, complications, and conditions.

In a further embodiment, the compound of the present invention may be administered in combination with a halofenic acid, an ester of a halomorphic acid or another prodrug of a halo-based acid, preferably in combination with (-)-(4). -Chlorophenyl)-(3-trifluoromethylphenoxy)-acetic acid 2-acetamidoethyl ester (metaglidasen).

Methods of Diagnosis and/or Imaging The compounds of the invention may also be used in methods of diagnosis and/or imaging. Many direct methods can be used to assess the biodistribution of agents in the body, such as magnetic resonance imaging ("MRI"), positive electron emission local X-ray ("PET"), and single photon emission local X-ray ("SPECT") . If the compound contains atoms of suitable nuclear nature, each of these methods can detect the distribution of the compound within the body. The MRI system detects the paramagnetic nucleus; the PET and SPECT systems detect the emission of particles from the radioactive nuclear attenuation.

Most therapeutic agents cannot be detected by such techniques without modification. Therefore, for PET, it is necessary to incorporate a radionuclide that appropriately emits positrons. There are relatively few electron-emitting isotope systems suitable for labeling therapeutic agents. The carbon isotope ¹¹ C has been used in PET but has a short half-life of 20.5 minutes. Thus, the equipment for synthesis and use is typically near a cyclotron in which a precursor ¹¹ C starting material is produced. Other isotopes have a shorter half-life. ¹³ N has a half-life of 10 minutes, while ¹⁵ O has a shorter half-life of 2 minutes. However, both emissions are more active than ¹¹ C, and PET studies have used these isotopes (see Clinical X-ray Local X-ray Examination, Mosby Yearbook, 1992, KF Hubner et al., Chapter 2). Another isotopic ¹⁸ F system that can be used has a half-life of 110 minutes. This allows sufficient time for incorporation of the radiolabeled tracer for purification and for administration to human or animal patients. ^{The 18} F-labeled compound has been used in the study of glucose metabolism and localization of glucose absorption associated with brain activity. For example, ¹⁸ FL-fluorodopa and other dopamine receptor analogs have also been used to map dopamine receptor profiles.

SPECT imaging uses an isotope tracer that emits high energy photons (gamma-emitters). The range of available isotopes is greater than for PET, but the SPECT provides a lower three-dimensional resolution. Nonetheless, SPECT is widely used to obtain clinically important information about analog binding, localization, and clearance. One of the SPECT imaging uses a γ-emitter with an isotopes of ¹²³ I and a 13.3 hour half-life. The compound identified by ¹²³ I can be transported to a height of about 1000 Å from the manufacturing site, or the isotope itself can be delivered for in situ synthesis. Eighty-five percent of the isotope emissions are 159 KeV photons, which are easily measurable by the SPECT instrument configuration currently in use. Other halogen isotopes can be used for PET or SPECT imaging, or for conventional tracer identification. It includes ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br and ⁸² Br due to the useful half-life and emission characteristics. In general, chemical means exist to replace any of the isotopes with any halogen moiety. Thus, the biochemical or physiological activity of any halogenated homologue of the compound is currently available to those skilled in the art, including the stable isotope halogen homologue.

For the purposes of the present invention, there is provided a method of diagnosing a disease or condition selected from Type I diabetes and Type II diabetes, the method comprising (a) being at risk or at risk of having the disease or condition The patient is administered an imaging amount of a compound of the invention wherein the compound is labeled as isotope; and (b) imaging the patient to determine the number, mass or volume of pancreatic beta cells or islet endocrine cells; or assessing pancreatic beta The function of cells or islet endocrine cells.

Preferably, the compound is identified by ¹¹ C or ¹⁴ C. In other preferred embodiments, the imaging is performed via PET or SPECT.

Kits Further, the invention provides kits having a unit dose of a compound of Formula I or Formula II, whether administered orally or injectable. In addition to containers containing unit doses, the use of descriptive drugs in the treatment of type 2 diabetes, obesity, hyperlipidemia, atherosclerosis and metabolic syndrome, and/or their associated related signs, complications, and conditions A package of instructions for the message of interest. Preferred compounds and unit dosages are those described above.

With regard to the compositions, methods and kits provided above, it will be apparent to those skilled in the art that the preferred compounds for use in each of the above are preferred compounds as indicated above. Still further preferred compounds for the compositions, methods and kits are the compounds provided in the non-limiting examples below.

Instance Experimental paragraph

General Method : All operations involving moisture and/or oxygen sensitive materials are carried out in a pre-dried glassware under a dry nitrogen atmosphere. Unless otherwise indicated, the materials were obtained from commercially available sources and used without further purification.

Flash chromatography was performed on E. Merck Silicone 60 (240-400 mesh) according to the work of Still, Kahn and Mitra ( J. Org . Chem . (1978) 43, 2923). Thin layer chromatography was performed using a pre-coated plate (silicone 60 PF ₂₅₄ , 0.25 mm) purchased from E. Merck, and the spots were presented in ultraviolet light, followed by appropriate coloring reagents.

Nuclear magnetic resonance ("NMR") spectroscopy was recorded on a Varian Inova-400 Resonance Spectrometer. ^{The 1} H NMR chemical shift is expressed in parts per million (δ) of the low magnetic field from tetramethyl decane ("TMS") using TMS or residual solvent signal (CHCl ₃ = δ 7.24, DMSO = δ 2.50) As an internal standard. ¹ H NMR messages are listed in the following format: number of protons, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), coupling constant ( J), expressed in Hertz, and in the selected case, the position is specified. The prefix app is sometimes applied to situations where the true signal multiplicity is unresolved, while the br system indicates that the signal in the discussion is widened.

Preparation of intermediate 1 : 4-(4-chloromethyl-thiazol-2-yl)-hexahydropyridine-1-carboxylic acid tert-butyl ester

Add 1,3-dichloroacetone to a solution of 4-aminothiomethyl-pyridinium-1-carboxylic acid tert-butyl ester (4.9 g, 20 mmol) in acetone (80 mL) (3.3 g, 26 mmol), MgSO ₄ (3.6 g, 30 mmol) and MgCO ₃ (1.68 g, 20 mmol). The mixture was heated at reflux overnight, cooled and filtered over EtOAc. The solvent was removed in vacuo and EtOAc (EtOAc) The solution of the formed continuous to 5% NaHSO _3, saturated NaHCO ₃ and washed with brine. After dehydration drying (Na ₂ SO ₄ ), the solvent was removed to give the desired product. ¹ H NMR (CDCl ₃ ): δ 7.20 (1H, s), 4.67 (2H, s), 4.20 (2H, br), 3.16 (1H, m), 2.87 (2H, m), 2.09 (2H, m) , 1.72 (2H, m), 1.47 (9H, s).

Preparation of Intermediate 2 : 2-[4-(4-Chloromethyl-thiazol-2-yl)-hexahydropyridin-1-yl]-5-ethyl-pyrimidine

The intermediate 2 is made in a manner similar to the above intermediate 1 . ¹ H NMR (DMSO-d ₆ ): δ 8.45 (2H, d), 7.62 (1H, s), 4.79 (2H, s), 4.61 (2H, m), 3.41 (1H, m), 3.24 (2H, m), 2.52 (2H, q), 2.15 (2H, m), 1.66 (2H, m), 1.17 (3H, m).

Preparation of intermediate 3 : 4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine

3-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (615 mg, 1.36 mmol) The solution in methanol (10 mL) was treated with 10 mL of 4N HCl in dioxane. The resulting solution was stirred at room temperature for 30 minutes. The entire solvent is then removed in vacuo to give the desired product as the HCl salt.

Preparation of intermediate 4 : 4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine

The intermediate 4 is made in a manner similar to the above intermediate 3 . ¹ H NMR (DMSO-d ₆ ): δ 9.98 (1H, s), 7.82 (2H, m), 7.63 (1H, s), 7.28 (2H, m), 5.19 (2H, s), 3.01 (3H, m), 2.54 (3H, m), 1.92 (2H, m), 1.54 (2H, m).

Preparation of Intermediate 5 : 4-[4-(2-Fluoro-4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine

Intermediate 5 are made of a manner analogous to Intermediate 3 above the.

Preparation of intermediate 6 : 4-[4-(2-Fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine

The intermediate 6 is made in a manner similar to the above intermediate 3 .

Preparation of intermediate 7 : 4-[4-(3-Fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine

The intermediate 7 is made in a manner similar to the above intermediate 3 .

Preparation of intermediate 8 : 4-[4-(2,6-difluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine

The intermediate 8 is made in a manner similar to the above intermediate 3 .

Preparation of intermediate 9 : 4-[4-(4-pyrrol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine

The intermediate 9 is made in a manner similar to the above intermediate 3 .

Preparation of intermediate 10 : (2-hexahydropyridin-4-yl-thiazol-4-ylmethyl)-(4-tetrazol-1-yl-phenyl)-amine

The intermediate 10 is made in a manner similar to the above intermediate 3 .

Preparation of intermediate 11 : 4-[4-(2-methyl-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine

The intermediate 11 is made in a manner similar to the above intermediate 3 .

Preparation of intermediate 12 : 4-[4-(2-isopropyl-5-methyl-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine

The intermediate 12 is made in a manner similar to the intermediate 3 described above.

Preparation of intermediate 13 : 4-[4-(2-chloro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine

The intermediate 13 is made in a manner similar to the above intermediate 3 .

Preparation of intermediate 14 : 4-(4-chloromethyl- Zin-2-yl)-hexahydropyridine-1-carboxylic acid tert-butyl ester

4-(4-hydroxymethyl- Zyrom-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (800 mg, 2.84 mmol) (via 4-(4-ethoxycarbonyl- Reduction of the tris-butyl ester of oxazol-2-yl)-hexahydropyridine-1-carboxylic acid, which is synthesized according to US Patent Publication No. 2006/0135501 Al, TsCl (812 mg, 4.26 mmol) A mixture of triethylamine (1 ml, 752 mg, 7.44 mmol) in dichloromethane (20 ml) was stirred at room temperature for 5 hr. The solution of the formed continuous to 5% NaHSO _3, saturated NaHCO ₃ and washed with brine. After dehydration drying (Na ₂ SO ₄ ), the solvent was removed to give the desired product. ¹ H NMR (CDCl ₃ ): δ 7.53 (s, 1H), 4.40 (s, 2H), 4.06 (m, 2H), 2.89 (m, 3H), 1.98 (m, 2H), 1.74 (m, 2H) , 1.41 (s, 9H).

Preparation of intermediate 15 : 4-[4-(4-tetrazol-1-yl-phenoxymethyl)- Zin-2-yl]-hexahydropyridine

The intermediate 15 is made in a manner similar to the above intermediate 3 .

Preparation of intermediate 16 : 4-[4-(2-Fluoro-4-tetrazol-1-yl-phenoxymethyl)- Zin-2-yl]-hexahydropyridine

The intermediate 16 is made in a manner similar to the intermediate 3 described above.

Preparation of intermediate 17 : 5-(2-hexahydropyridin-4-yl-thiazol-4-ylmethoxy)-2-tetrazol-1-yl-pyridine

The intermediate 17 is made in a manner similar to the above intermediate 3 .

Preparation of intermediate 18 : (6-fluoro-pyridin-3-yl)-(2-hexahydropyridin-4-yl-thiazol-4-ylmethyl)-amine

The intermediate 18 is made in a manner similar to the intermediate 3 described above.

Preparation of intermediate 19 : 4-[4-(2,6-difluoro-4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine

The intermediate 19 is made in a manner similar to the above intermediate 3 .

Preparation of intermediate 20 : 4-[4-(2-hexahydropyridin-4-yl-thiazol-4-ylmethoxy)-phenyl]-morpholine

The intermediate 20 is made in a manner similar to the intermediate 3 described above.

Preparation of intermediate 21 : 4-[4-(2-hexahydropyridin-4-yl-thiazol-4-ylmethoxy)-phenyl]-morpholine

The intermediate 21 is made in a manner similar to the above intermediate 3 .

Preparation of intermediate 22 : 4-(4-chloromethyl-thiazol-2-yl)-3-methyl-hexahydropyridine-1-carboxylic acid tert-butyl ester

The intermediate 22 is made in a manner similar to the above intermediate 1 .

Preparation of intermediate 23 : 3-methyl-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine

The intermediate 23 is made in a manner similar to the above intermediate 3 .

Preparation of intermediate 24 : 4-[4-(2-Fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-3-methyl-hexahydropyridine

The intermediate 24 is made in a manner similar to the intermediate 3 described above.

Preparation of intermediate 25 : 4-[4-(4-methanesulfonyl-benzyloxymethyl)-thiazol-2-yl]-hexahydropyridine

The intermediate 25 is made in a manner similar to the above intermediate 3 .

Example 1

4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

3-(4-Chloromethyl-thiazol-2-yl)-hexahydropyridine-1-carboxylic acid tert-butyl ester ( intermediate 1 , 463 mg, 1.46 mmol), 4-methanesulfonate A mixture of phenol (252 mg, 1.46 mmol) and K ₂ CO ₃ (404 mg, 2.92 mmol) in acetone (25 mL) After cooling, the solid was filtered through a pad of celite. The filtrate was concentrated in vacuo. The residue was purified on EtOAc (EtOAcEtOAcEtOAcEtOAc ¹ H NMR (CDCl ₃ ): δ 7.88 (2H, d, J = 8.8 Hz), 7.23 (1H, s), 7.12 (2H, d, J = 8.8 Hz), 5.24 (2H, s), 4.21 (2H , br), 3.17 (1H, m), 3.04 (3H, s), 2.88 (2H, m), 2.11 (2H, m), 1.73 (2H, m), 1.47 (9H, s).

The compounds of Examples 2-19 were obtained from 4-(4-chloromethyl-thiazol-2-yl)-hexahydropyridine-1-carboxylic acid tert-butyl ester in a manner similar to that described in Example 1 . Intermediate 1 ), 2-[4-(4-Chloromethyl-thiazol-2-yl)-hexahydropyridin-1-yl]-5-ethyl-pyrimidine ( Intermediate 2 ), 4-(4 -Chloromethyl- Zyridin-2-yl)-hexahydropyridine-1-carboxylic acid tert-butyl ester ( intermediate 14 ), synthesized with the corresponding phenol, thiophenol, amine or aniline. Those skilled in the art of organic synthesis will be aware of conditions such as solvents (eg DMF, CH ₃ CN); temperatures, bases (eg NEt ₃ , K ₂ CO ₃ , NaHCO ₃ , Na ₂ CO ₃ , Cs ₂ CO ₃ ) And the concentration can be selected through routine experimentation to optimize the yield. In addition, alternative coupling methods as are known in the art of organic synthesis can be used.

Example 2

3-[4-(4-imidazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

¹ H NMR (DMSO-d ₆ ): δ 8.12 (1H, s), 7.63 (2H, m), 7.54 (2H, d, J = 9.2 Hz), 7.15 (2H, d, J = 9.2 Hz), 7.05 (1H, s), 5.15 (2H, s), 3.98 (2H, m), 3.21 (1H, m), 2.87 (2H, m), 2.01 (2H, m), 1.52 (2H, m), 1.39 ( 9H, s).

Example 3

4-[4-(4-acetamido-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

¹ H NMR (DMSO-d ₆ ): δ 9.77 (1H, s), 7.57 (1H, s), 7.45 (2H, d, J = 9.0 Hz), 6.94 (2H, d, J = 9.0 Hz), 5.04 (2H, s), 3.98 (2H, m), 3.18 (1H, m), 2.82 (2H, m), 2.02 (2H, m), 1.99 (3H, s), 1.51 (2H, m), 1.39 ( 9H, s).

Example 4

3-[4-(4-methoxy-benzenesulfonyloxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

¹ H NMR (CDCl ₃ ): δ 7.60 (2H, d, J = 9.0 Hz), 7.24 (1H, s), 6.91 (2H, d, J = 9.0 Hz), 4.50 (2H, s), 4.10 (2H , m), 3.85 (3H, s), 2.99 (1H, m), 2.82 (2H, m), 1.89~1.92 (2H, m), 1.53~1.57 (2H, m), 1.46 (9H, s).

Example 5

4-[4-(4-[1,2,4]triazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

¹ H NMR (CDCl ₃ ): δ 8.47 (1H, s), 8.08 (1H, s), 7.58 (2H, d, J = 9.2 Hz), 7.24 (1H, s), 7.11 (2H, d, J= 9.2 Hz), 5.21 (2H, s), 4.2 (2H, m), 3.18 (1H, m), 2.88 (2H, m), 2.11 (2H, m), 1.74 (2H, m), 1.47 (9H, s).

Example 6

4-{4-[4-(2-keto-tetrahydropyrrol-1-yl)-phenoxymethyl]-thiazol-2-yl}-piperidine-1-carboxylic acid tert-butyl ester

¹ H NMR (CDCl ₃ ): δ 7.50 (2H, d), 7.20 (1H, s), 6.98 (2H, d), 5.17 (2H, s), 4.20 (2H, br), 3.81 (2H, m) , 3.18 (1H, m), 2.88 (2H, m), 2.59 (2H, m), 2.16 (4H, m), 1.73 (2H, m), 1.46 (9H, s).

Example 7

4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

¹ H NMR (CDCl ₃ ): δ 8.94 (1H, s), 7.61 (2H, d), 7.25 (1H, s), 7.19 (2H, d), 5.21 (2H, s), 4.20 (2H, br) , 3.20 (1H, m), 2.90 (2H, m), 2.16 (2H, m), 1.77 (2H, m), 1.49 (9H, s).

Example 8

4-[4-(4-methanesulfonyl-phenylthiomethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

¹ H NMR (CDCl ₃ ): δ 7.7 (2H, d, J = 9.0 Hz), 7.36 (2H, d, J = 9.0 Hz), 7.00 (1H, s), 4.24 (2H, s), 4.3 (2H , m), 3.05 (1H, m), 2.95 (3H, s), 2.78 (2H, m), 1.99 (2H, m), 1.62 (2H, m), 1.38 (9H, s).

Example 9

4-{2-[1-(5-ethyl-pyrimidin-2-yl)-hexahydropyridin-4-yl]-thiazol-4-ylmethoxy}-benzenesulfonamide

¹ H NMR (DMSO-d ₆ ): δ 8.24 (2H, s), 7.73 (2H, d), 7.64 (1H, s), 7.20 (4H, m), 5.18 (2H, s), 4.67 (2H, m), 3.38 (1H, m), 3.01 (2H, m), 2.47 (2H, m), 2.08 (2H, m), 1.62 (2H, m), 1.53 (3H, m).

Example 10

2-{4-[4-(2,6-Dichloro-4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-5-ethyl -pyrimidine

¹ H NMR (DMSO-d ₆ ): δ 8.23 (2H, s), 7.99 (2H, s), 7.68 (1H, s), 5.20 (2H, s), 4.64 (2H, m), 3.31 (3H, s), 3.30 (1H, m), 3.0 (2H, m), 2.40 (2H, m), 1.98 (2H, m), 1.54 (2H, m), 1.15 (3H, m).

Example 11

5-ethyl-2-{4-[4-(3-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine

¹ H NMR (CDCl ₃ ): δ 9.05 (1H, s), 8.19 (2H, s), 7.55-7.10 (5H, m), 5.24 (2H, s), 4.83 (2H, m), 3.30 (1H, m), 3.04 (2H, m), 2.47 (2H, q, J=7.6 Hz), 2.21 (2H, m), 1.80 (2H, m), 1.19 (3H, t, J=7.6 Hz).

Example 12

5-ethyl-2-(4-{4-[4-(5-methyl-tetrazol-1-yl)-phenoxymethyl]-thiazol-2-yl}-hexahydropyridine-1- Pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.19 (2H, s), 7.38 (2H, d, J = 9.0 Hz), 7.26 (1H, s), 7.17 (2H, d, J = 9.0 Hz), 5.24 (2H , s), 4.84 (2H, m), 3.31 (1H, m), 3.05 (2H, m), 2.58 (3H, s), 2.47 (2H, q, J=7.8 Hz), 2.22 (2H, m) , 1.82 (2H, m), 1.20 (3H, t, J=7.8 Hz).

Example 13

5-ethyl-2-{4-[4-(3-methyl-4-methylthio-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine

¹ H NMR (DMSO-d ₆ ): δ 8.23 (2H, s), 7.56 (1H, s), 7.16 (1H, m), 6.90 (1H, m), 6.86 (1H, m), 5.06 (2H, s), 4.67 (2H, m), 3.55 (4H, m), 3.01 (2H, m), 2.48 (3H, s), 2.40 (2H, m), 2.09 (2H, m), 1.57 (2H, m ), 1.09 (3H, m).

Example 14

5-ethyl-2-{4-[4-(4-methanesulfonyl-3-methyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine

¹ H NMR (DMSO-d ₆ ): δ 8.13 (2H, s), 7.91 (1H, m), 7.20 (1H, s), 6.85 (2H, m), 5.14 (2H, s), 4.76 (2H, m), 3.23 (1H, m), 2.98 (3H, s), 2.60 (3H, s), 2.42 (2H, m), 2.15 (2H, m), 1.97 (2H, m), 1.76 (2H, m ), 1.13 (3H, m).

Example 15

6-{2-[1-(5-ethyl-pyrimidin-2-yl)-hexahydropyridin-4-yl]-thiazol-4-ylmethoxy}-benzo[1,3]oxysulfur Indole-2-one

¹ H NMR (DMSO-d ₆ ): δ 8.23 (2H, s), 7.64 (1H, m), 7.62 (1H, s), 7.30 (1H, m), 7.03 (1H, m), 5.14 (2H, s), 4.64 (2H, m), 3.31 (1H, m), 3.02 (2H, m), 2.40 (2H, q), 2.09 (2H, m), 1.58 (2H, m), 1.12 (3H, t ).

Example 16

5-ethyl-2-{4-[4-(4-trifluoromethylthio-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine

¹ H NMR (DMSO-d ₆ ): δ 8.23 (2H, s), 7.63 (3H, m), 7.18 (2H, m), 5.17 (2H, s), 4.67 (2H, m), 3.32 (1H, m), 3.01 (2H, m), 2.40 (2H, q), 2.08 (2H, m), 1.59 (2H, m), 1.13 (3H, t).

Example 17

4-[4-(3-Fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

¹ H NMR (CDCl ₃ ): δ 9.04 (1H, s), 7.79 (1H, m), 7.29 (1H, s), 7.01 (2H, m), 5.24 (2H, s), 4.22 (2H, m) , 3.19 (1H, m), 2.89 (2H, m), 2.11 (2H, m), 1.74 (2H, m), 1.48 (9H, s).

Example 18

3-[4-(2-Fluoro-4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

¹ H NMR (DMSO-d ₆ ): δ 7.79 (1H, m), 7.72 (1H, m), 7.70 (1H, s), 7.57 (1H, m), 5.31 (2H, s), 3.99 (2H, m), 3.21 (3H, s), 3.20 (1H, m), 2.85 (2H, m), 2.02 (2H, m), 1.52 (2H, m), 1.39 (9H, s).

Example 19

4-[4-(2-Fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

¹ H NMR (CDCl ₃ ): δ 8.98 (s, 1H), 7.53 (m, 1H), 7.44 (m, 1H), 7.31 (s, 1H), 7.27 (m, 1H), 5.31 (s, 2H) , 4.21 (m, 2H), 3.16 (m, 1H), 2.89 (m, 2H), 2.11 (m, 2H), 1.74 (m, 2H), 1.47 (s, 9H).

Example 20

5-ethyl-2-{4-[4-(4-trifluoromethanesulfinyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine

5-Ethyl-2-{4-[4-(4-trifluoromethylsulfanyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine ( example) 16 ) 3-Chloro-phenylcarbon peroxyacid (2 equivalents) was added to the solution in DCM at room temperature. The reaction was stirred for 1.5 hours and another portion of 3-chloro-phenylcarbon peroxyacid (1 eq.) was added to the mixture. The reaction was stirred at room temperature for a further 4 hours. The organic solution was washed with sodium bicarbonate; the organic layer was separated, dried over sodium sulfate and filtered. The filtrate was concentrated and the crude product was purified by column chromatography to afford desired product. ¹ H NMR (DMSO-d ₆ ): δ 8.40 (2H, s), 7.58 (2H, d), 7.22 (1H, s), 7.02 (2H, d), 5.17 (2H, s), 3.74 (2H, m), 3.16 (1H, m), 2.96 (2H, m), 2.57 (2H, m), 2.22 (4H, m), 1.24 (3H, m).

Example 21

4-[4-(4-methanesulfonyl-benzenesulfonylmethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

4-[4-(4-Methanesulfonyl-phenylthiomethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester ( Example 8 , 0.1 g, 0.21 mmol) in a) in a solution of CH ₂ Cl ₂ (5 mL, at room temperature, mCPBA (0.11 g, 0.42 mmol). The resulting mixture was stirred at room temperature for 2 hours and at 5% NaHSO _3, saturated NaHCO ₃ and washed with brine. The organic layer was dried over Na ₂ SO ₄ and the solvent was removed in vacuo. The residue is purified by flash chromatography on silica gel to give the desired product. ¹ H NMR (CDCl ₃ ): δ 8.03 (2H, d, J = 9.0 Hz), 7.88 (2H, d, J = 9.0 Hz), 7.29 (1H, s), 4.57 (2H, s), 4.10 (2H , m), 3.07 (3H, s), 2.92 (1H, m), 2.75 (2H, m), 1.85 (2H, m), 1.46 (2H, m), 1.44 (9H, s).

Example 22

4-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid isopropyl ester

In the HCl salt of 4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine ( intermediate 3 , 43 mg, ~0.12 mmol), 3 ml of THF was added, followed by isopropyl chloroformate (1.0M in toluene solution of 0.15 mL, 0.15 mmol) and Et ₃ N (0.05 mL). The resulting mixture was stirred at room temperature for 2 hours and then treated as partitioned between EtOAc and H ₂ O. After concentrating the organic layer <RTI ID=0.0></RTI> ¹ H NMR (CDCl ₃ ): δ 7.86 (2H, d, J = 9.0 Hz), 7.23 (1H, s), 7.11 (2H, d, J = 9.0 Hz), 5.22 (2H, s), 4.92 (1H , m), 4.24 (2H, m), 3.17 (1H, m), 3.03 (3H, s), 2.90 (2H, m), 2.10 (2H, m), 1.72 (2H, m), 1.23 (6H, d, J = 6.4 Hz).

The compounds of Examples 23-46 were one of the intermediates 3-13 or the intermediates 15-25 in the manner described in Example 22 , and the corresponding sulfonium chloride, alkyl chloride, alkyl bromide. Synthesis of chloroformate, cesium chloride, amine amide or isocyanate. Those skilled in the art of organic synthesis will be aware of conditions such as solvents (eg DMF, CH ₃ CN); temperatures, bases (eg NEt ₃ , K ₂ CO ₃ , NaHCO ₃ , Na ₂ CO ₃ , Cs ₂ CO ₃ ) And the concentration can be selected through routine experimentation to optimize the yield. In addition, alternative coupling methods as are known in the art of organic synthesis can be used.

Example 23

Benzyl 4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylate

¹ H NMR (CDCl ₃ ): δ 7.87 (2H, d, J = 9.2 Hz), 7.31~7.37 (5H, m), 7.23 (1H, s), 7.11 (2H, d, J = 9.2 Hz), 5.22 (2H, s), 5.14 (2H, s), 4.29 (2H, m), 3.16~3.22 (1H, m), 3.03 (3H, s), 2.96 (2H, m), 2.12 (2H, m), 1.70~1.80 (2H, m).

Example 24

4-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid isobutyl ester

¹ H NMR (CDCl ₃ ): δ 7.87 (2H, d, J = 9.0 Hz), 7.23 (1H, s), 7.11 (2H, d, J = 9.0 Hz), 5.22 (2H, s), 4.25 (2H , m), 3.87 (2H, d, J=6.6 Hz), 3.17 (1H, m), 3.03 (3H, s), 2.94 (2H, m), 2.12 (2H, m), 1.94 (1H, m) , 1.75 (2H, m), 0.93 (6H, d, J=6.6 Hz).

Example 25

4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine-1-carboxylic acid adamantyl-1-yl ester

¹ H NMR (CDCl ₃ ): δ 7.89 (2H, d, J = 8.8 Hz), 7.24 (1H, s), 7.12 (2H, d, J = 8.8 Hz), 5.23 (2H, s), 4.21 (2H , m), 3.12~3.20 (1H, m), 3.03 (3H, s), 2.87 (2H, m), 2.05~2.17 (11H, m), 1.62~1.79 (8H, m).

Example 26

Methyl 4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine-1-carboxylate

¹ H NMR (CDCl ₃ ): δ 7.87 (2H, d, J = 9.0 Hz), 7.23 (1H, s), 7.11 (2H, d, J = 9.0 Hz), 5.22 (2H, s), 4.24 (2H , m), 3.71 (3H, s), 3.14~3.17 (1H, m), 3.03 (3H, s), 2.94 (2H, m), 2.12 (2H, m), 1.70~1.80 (2H, m).

Example 27

4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine-1-carboxylic acid 4-fluorophenyl ester

¹ H NMR (CDCl ₃ ): δ 7.88 (2H, d, J = 8.8 Hz), 7.12 (2H, d, J = 8.8 Hz), 7.01~7.09 (5H, m), 5.24 (2H, s), 4.37 (2H, m), 3.23~3.27 (1H, m), 3.19 (2H, m), 3.04 (3H, s), 2.20 (2H, m), 1.88 (2H, m).

Example 28

4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine-1-carboxylic acid 4-methoxy-phenyl ester

¹ H NMR (CDCl ₃ ): δ 7.88 (2H, d, J = 8.2 Hz), 7.26 (1H, s), 7.12 (2H, d, J = 8.6 Hz), 7.02 (2H, d, J = 8.6 Hz ), 6.87 (2H, d, J=8.2 Hz), 5.24 (2H, s), 4.38 (2H, m), 3.79 (3H, s), 3.15~3.28 (3H, m), 3.03 (3H, s) , 2.19 (2H, m), 1.87 (2H, m).

Example 29

4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid naphthalen-1-yl ester

¹ H NMR (CDCl ₃ ): δ 7.88 (4H, m), 7.72 (1H, m), 7.49 (3H, m), 7.29 (2H, m), 7.14 (2H, m), 5.26 (2H, s) , 4.64 (1H, m), 4.41 (1H, m), 3.34 (2H, m), 3.12 (1H, m), 3.04 (3H, s), 2.27 (2H, m), 2.00 (2H, m).

Example 30

4-[4-(4-Tetrazolyl-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid isobutyl ester

¹ H NMR (CDCl ₃ ): δ 8.94 (1H, s), 7.60 (2H, d), 7.24 (1H, s), 7.14 (2H, d), 5.20 (2H, s), 4.24 (2H, br) , 3.85 (2H, d), 3.18 (1H, m), 2.92 (2H, m), 2.11 (2H, m), 1.91 (1H, m), 1.75 (2H, m), 0.91 (6H, d).

Example 31

4-[4-(4-Tetrazolyl-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine-1-carboxylic acid amyl ester

¹ H NMR (CDCl ₃ ): δ 8.94 (1H, s), 7.62 (2H, d, J = 9.2 Hz), 7.28 (1H, s), 7.18 (2H, d, J = 9.2 Hz), 5.24 (2H , s), 4.27 (2H, br), 4.09 (2H, m), 3.21 (1H, m), 2.94 (2H, m), 2.14 (2H, m), 1.78 (2H, m), 1.65 (2H, m), 1.35 (4H, m), 0.91 (3H, m).

Example 32

4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine-1-carboxylic acid 2-fluoro-ethyl ester

¹ H NMR (CDCl ₃ ): δ 8.97 (1H, s), 7.62 (2H, d, J = 9.0 Hz), 7.28 (1H, s), 7.17 (2H, d, J = 9.0 Hz), 5.24 (2H , s), 4.70-4.30 (6H, m), 3.22 (1H, m), 2.99 (2H, m), 2.15 (2H, m), 1.78 (2H, m).

Example 33

4-[4-(4-Tetrazolyl-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid butyl ester

¹ H NMR (CDCl ₃ ): δ 9.01 (1H, s), 7.64 (2H, d, J = 8.8 Hz), 7.29 (1H, s), 7.17 (2H, d, J = 8.8 Hz), 5.24 (2H , s), 4.26 (2H, m), 4.10 (2H, t), 3.21 (1H, m), 2.95 (2H, m), 2.14 (2H, m), 1.78 (2H, m), 1.63 (2H, m), 1.40 (2H, m), 0.95 (3H, t, J=7.4 Hz).

Example 34

4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid 2,2-dimethyl-propyl ester

¹ H NMR (CDCl ₃ ): δ 9.00 (1H, s), 7.56 (2H, d, J = 8.8 Hz), 7.21 (1H, s), 7.08 (2H, d, J = 8.8 Hz), 5.14 (2H , s), 4.17 (2H, br), 3.69 (2H, s), 3.13 (1H, m), 2.88 (2H, m), 2.06 (2H, m), 1.73 (2H, m), 0.86 (9H, s).

Example 35

4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl 1-hexahydropyridine-1-carboxylate

¹ H NMR (CDCl ₃ ): δ 9.06 (1H, s), 7.65 (2H, d, J = 8.8 Hz), 7.29 (1H, s), 7.18 (2H, d, J = 8.8 Hz), 5.24 (2H , s), 4.27 (2H, br), 4.09 (2H, t), 3.21 (1H, m), 2.95 (2H, m), 2.14 (2H, m), 1.78 (2H, m), 1.64 (2H, m), 1.33 (6H, m), 0.89 (3H, m).

Example 36

2-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid 2-ethyl-hexyl ester

¹ H NMR (CDCl ₃ ): δ 8.98 (1H, s), 7.58 (2H, d, J = 8.8 Hz), 7.23 (1H, s), 7.10 (2H, d, J = 8.8 Hz), 5.17 (2H , s), 4.19 (2H, br), 3.95 (2H, m), 3.15 (1H, m), 2.89 (2H, m), 2.07 (2H, m), 1.69 (2H, m), 1.52 (1H, m), 1.35-1.20 (8H, m), 0.90-0.80 (6H, m).

Example 37

4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid 2-benzyloxy-ethyl ester

¹ H NMR (CDCl ₃ ): δ 8.98 (1H, s), 7.57 (2H, d, J = 8.0 Hz), 7.30-7.20 (6H, m), 7.11 (2H, d, J = 8.0 Hz), 5.17 (2H, s), 4.52 (2H, s), 4.25-4.20 (4H, m), 3.65 (2H, m), 3.15 (1H, m), 2.91 (2H, m), 2.08 (2H, m), 1.73 (2H, m).

Example 38

4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid 2-isopropyl-5-methyl-cyclohexane ester

¹ H NMR (CDCl ₃ ): δ 8.97 (1H, s), 7.58 (2H, m), 7.23 (1H, s), 7.11 (2H, m), 5.18 (2H, s), 4.21 (2H, br) , 3.13 (1H, m), 2.88 (2H, m), 2.05-0.70 (23H, m).

Example 39

Adamantan-1-yl-{4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-methanone

¹ H NMR (CDCl ₃ ): δ 7.88 (2H, d, J = 8.8 Hz), 7.24 (1H, s), 7.12 (2H, d, J = 8.8 Hz), 5.23 (2H, s), 4.61 (2H , m), 3.24~3.30 (1H, m), 3.03 (3H, s), 2.93~3.00 (2H, m), 2.16 (2H, m), 2.02~2.04 (9H, m), 1.70~1.80 (8H , m).

Example 40

{4-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyridin-3-yl-methanone

¹ H NMR (CDCl ₃ ): δ 8.69 (2H, m), 7.88 (2H, d, J = 8.4 Hz), 7.79 (1H, m), 7.38 (1H, m), 7.27 (1H, s), 7.12 (2H, d, J=8.4 Hz), 5.24 (2H, s), 4.79 (2H, br), 3.86 (2H, br), 3.31 (1H, m), 3.04 (3H, s), 2.20 (2H, m), 1.84 (2H, m).

Example 41

3,3-Dimethyl-1-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-butyl 1-ketone

¹ H NMR (DMSO-d ₆ ): δ 9.98 (1H, s), 7.81 (2H, d, J = 8.8 Hz), 7.66 (1H, s), 7.29 (2H, d, J = 8.8 Hz), 5.20 (2H, s), 4.52 (1H, m), 4.10 (1H, m), 3.26 (1H, m), 3.19 (1H, m), 2.70 (1H, m), 2.25 (2H, m), 2.15 ( 2H, m), 1.50 (2H, m), 0.96 (9H, s).

Example 42

Keto-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-methyl acetate

¹ H NMR (DMSO-d ₆ ): δ 9.98 (1H, s), 7.81 (2H, d, J = 8.8 Hz), 7.68 (1H, s), 7.29 (2H, d, J = 8.8 Hz), 5.21 (2H, s), 4.32 (1H, m), 3.80 (3H, s), 3.60 (1H, m), 3.32 (1H, m), 2.94 (2H, m), 2.13 (2H, m), 1.57 ( 2H, m).

Example 43

3-keto-3-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-propionic acid ethyl ester

¹ H NMR (DMSO-d ₆ ): δ 8.94 (1H, s), 7.61 (2H, m), 7.26 (1H, s), 7.15 (2H, m), 5.20 (2H, s), 4.65 (1H, m), 4.17 (2H, q), 3.87 (1H, m), 3.48 (2H, s), 3.26 (2H, m), 2.81 (1H, m), 2.18 (2H, m), 1.78 (2H, m ), 1.27 (3H, t).

Example 44

(4-methyl-hexahydropyridyl) -1-yl)-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-methanone

¹ H NMR (DMSO-d ₆ ): δ 9.98 (1H, s), 7.81 (2H, d, J = 8.9 Hz), 7.64 (1H, s), 7.29 (2H, d), 5.20 (2H, s) , 3.29 (2H, m), 3.18 (5H, m), 2.95 (2H, d), 2.61 (3H, s), 2.38 (2H, m), 2.03 (4H, m), 1.65 (2H, m).

Example 45

4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid diethyl decylamine

¹ H NMR (DMSO-d ₆ ): δ 9.98 (1H, s), 7.81 (2H, d, J = 8.9 Hz), 7.66 (1H, s), 7.29 (2H, d, J = 8.9 Hz), 5.20 (2H, s), 3.55 (2H, m), 3.20 (1H, m), 3.14 (4H, q), 2.81 (2H, m), 2.02 (2H, m), 1.64 (2H, m), 1.02 ( 6H, t, J = 6.8 Hz).

Example 46

4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid ethyl decylamine

¹ H NMR (DMSO-d ₆ ): δ 9.98 (1H, s), 7.81 (2H, d, J = 8.9 Hz), 7.65 (1H, s), 7.29 (2H, d, J = 8.9 Hz), 6.47 (1H, m), 5.20 (2H, s), 4.01 (2H, d), 3.17 (1H, m), 3.04 (2H, m), 2.78 (2H, m), 1.97 (2H, m), 1.52 ( 2H, m), 0.99 (3H, t, J=6.8 Hz).

Example 47

2-{4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine

4-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine hydrochloride (100 mg, 0.24 mmol), 2-chloropyrimidine ( A mixture of 30 mg, 1.1 eq.) and diisopropylethylamine (122 mg, 4 eq.) in i-PrOH (5 mL). The solvent was removed in vacuo. The residue was purified on EtOAc (EtOAc:EtOAc) ¹ H NMR (CDCl ₃ ): δ 8.32 (2H, d, J = 4.8 Hz), 7.88 (2H, d, J = 8.8 Hz), 7.23 (1H, s), 7.12 (2H, d, J = 8.8 Hz ), 6.49 (1H, t, J=4.8 Hz), 5.24 (2H, s), 4.89 (2H, m), 3.32 (1H, m), 3.06 (2H, m), 3.04 (3H, s), 2.22 (2H, m), 1.81 (2H, m).

The compounds of Examples 48-77 were isolated from one of Intermediates 3-13 or Intermediates 15-25 in the manner described in Example 47 , and the corresponding substituted 2-chloropyrimidine, 2-iodopyrimidine , 2-chloropyridine, 2-fluoropyridine, 2-methanesulfonyl-pyrimidine, 2-chloropyridyl 2-chloroguanidine Or other suitable heterocyclic synthesis. Those skilled in the art of organic synthesis will understand that certain conditions, such as solvents (such as DMF, CH ₃ CN); temperature, alkali (such as NEt ₃ , K ₂ CO ₃ , NaHCO ₃ , Na ₂ CO ₃ , Cs ₂ CO ₃ ) And the concentration can be selected through routine experimentation to optimize the yield. In addition, alternative coupling methods as are known in the art of organic synthesis can be used.

Example 48

2-{4-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-4-methoxy-pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.06 (1H, d, J = 6.0 Hz), 7.87 (2H, d, J = 8.8 Hz), 7.23 (1H, s) 7.12 (2H, d, J = 8.8 Hz) , 5.98 (1H, d, J=6.0 Hz), 5.24 (2H, s), 4.88 (2H, m), 3.90 (3H, s), 3.31 (1H, m), 3.04 (5H, m), 2.20 ( 2H, m), 1.81 (2H, m).

Example 49

2-{4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-4-trifluoromethylpyrimidine

¹ H NMR (CDCl ₃ ): δ 8.50 (1H, d, J = 4.8 Hz), 7.88 (2H, d, J = 8.8 Hz), 7.24 (1H, s), 7.12 (2H, d, J = 8.8 Hz ), 6.76 (1H, d, J=4.8 Hz), 5.24 (2H, s), 4.92 (2H, m), 3.34 (1H, m), 3.11 (2H, m), 3.04 (3H, s), 2.24 (2H, m), 1.84 (2H, m).

Example 50

2-{4-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-4,6-dimethyl-pyrimidine

¹ H NMR (CDCl ₃ ): δ 7.88 (2H, d, J = 8.4 Hz), 7.22 (1H, s), 7.12 (2H, d, J = 8.4 Hz), 6.27 (1H, s), 5.24 (2H , s), 4.96 (2H, m), 3.28 (1H, m), 3.04 (3H, s), 2.99 (2H, m), 2.29 (6H, s), 2.19 (2H, m), 1.80 (2H, m).

Example 51

5-ethyl-2-{4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.19 (2H, s), 7.87 (2H, d, J = 8.8 Hz), 7.22 (1H, s), 7.12 (2H, d, J = 8.8 Hz), 5.24 (2H , s), 4.84 (2H, m), 3.30 (1H, m), 3.04 (2H, m), 3.03 (3H, s), 2.47 (2H, q, J=7.2 Hz), 2.22 (2H, m) , 1.81 (2H, m), 1.20 (3H, t, J=7.2 Hz).

Example 52

5-ethyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine

1 H NMR (DMSO-d ₆ ): δ 9.98 (1H, s), 8.24 (2H, s), 7.80 (2H, d, J = 8.8 Hz), 7.66 (1H, s), 7.28 (2H, d, J=8.8 Hz), 5.20 (2H, s), 4.67 (2H, m), 3.32 (1H, m), 3.01 (2H, m), 2.43 (2H, q, J=7.2 Hz), 2.07 (2H, m), 1.59 (2H, m), 1.11 (3H, t, J=7.2 Hz).

Example 53

5-fluoro-2-{4-[4-(6-tetrazol-1-yl-pyridin-3-yloxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}- Pyrimidine

¹ H NMR (DMSO-d ₆ ): δ 10.07 (1H, s), 8.43 (2H, s), 8.41 (1H, d, J = 3.2 Hz), 7.98 (1H, d, J = 9.2 Hz), 7.86 (1H, dd, J=9.2, 3.2 Hz), 7.71 (1H, s), 5.30 (2H, s), 4.58 (2H, m), 3.31 (1H, m), 3.01 (2H, m), 2.10 ( 2H, m), 1.59 (2H, m).

Example 54

5-bromo-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.90 (1H, s), 8.29 (2H, s), 7.60 (2H, d, J = 9.0 Hz), 7.25 (1H, s), 7.16 (2H, d, J= 9.0 Hz), 5.23 (2H, s), 4.81 (2H, m), 3.31 (1H, m), 3.06 (2H, m), 2.21 (2H, m), 1.79 (2H, m).

Example 55

5-fluoro-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.91 (1H, s), 8.20 (2H, s), 7.60 (2H, d, J = 8.6 Hz), 7.25 (1H, s), 7.16 (2H, d, J= 8.6 Hz), 5.23 (2H, s), 4.78 (2H, m), 3.31 (1H, m), 3.06 (2H, m), 2.21 (2H, m), 1.83 (2H, m).

Example 56

4,5-Dichloro-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.91 (1H, s), 8.10 (1H, s), 7.61 (2H, d, J = 8.8 Hz), 7.27 (1H, s), 7.16 (2H, d, J= 8.8 Hz), 5.23 (2H, s), 4.62 (2H, m), 3.34 (1H, m), 3.18 (2H, m), 2.25 (2H, m), 1.98 (2H, m).

Example 57

4-Chloro-5-methyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl} -pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.90 (1H, s), 8.08 (1H, s), 7.60 (2H, d, J = 8.8 Hz), 7.24 (1H, s), 7.17 (2H, d, J= 8.8 Hz), 5.23 (2H, s), 4.80 (2H, m), 3.30 (1H, m), 3.04 (2H, m), 2.19 (2H, m), 2.16 (3H, s), 1.81 (2H, m).

Example 58

2-Chloro-5-methyl-4-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl} -pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.92 (1H, s), 7.96 (1H, s), 7.60 (2H, d, J = 8.8 Hz), 7.27 (1H, s), 7.16 (2H, d, J= 8.8 Hz), 5.23 (2H, s), 4.17 (2H, m), 3.31 (1H, m), 3.10 (2H, m), 2.26 (2H, m), 2.21 (3H, s), 1.95 (2H, m).

Example 59

5-(4-Chlorophenyl)-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl} -pyrimidine

¹ H NMR (DMSO-d ₆ ): δ 9.97 (1H, s), 8.71 (2H, s), 7.80 (2H, d, J = 8.8 Hz), 7.67 (2H, d, J = 8.4 Hz), 7.66 (1H, s), 7.48 (2H, d, J=8.4 Hz), 7.28 (2H, d, J=8.8 Hz), 5.21 (2H, s), 4.76 (2H, m), 3.37 (1H, m) , 3.13 (2H, m), 2.12 (2H, m), 1.66 (2H, m).

Example 60

5-Chloro-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.91 (1H, s), 8.23 (2H, s), 7.61 (2H, d, J = 8.8 Hz), 7.26 (1H, s), 7.17 (2H, d, J= 8.8 Hz), 5.24 (2H, s), 4.82 (2H, m), 3.32 (1H, m), 3.07 (2H, m), 2.22 (2H, m), 1.81 (2H, m).

Example 61

5-heptyl-2-{4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.16 (2H, s), 7.87 (2H, d, J = 9.0 Hz), 7.22 (1H, s), 7.12 (2H, d, J = 9.0 Hz), 5.24 (2H , s), 4.83 (2H, m), 3.29 (1H, m), 3.04 (2H, m), 3.03 (3H, s), 2.42 (2H, t, J=7.4 Hz), 2.21 (2H, m) , 1.80 (2H, m), 1.52 (2H, m), 1.28 (8H, m), 0.89 (3H, t).

Example 62

2-{4-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-5-pentyl-pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.16 (2H, s), 7.87 (2H, d, J = 8.8 Hz), 7.22 (1H, s), 7.12 (2H, d, J = 8.8 Hz), 5.23 (2H , s), 4.83 (2H, m), 3.29 (1H, m), 3.04 (2H, m), 3.03 (3H, s), 2.42 (2H, t, J=7.6 Hz), 2.21 (2H, m) , 1.81 (2H, m), 1.56 (2H, m), 1.32 (4H, m), 0.90 (3H, t).

Example 63

5-heptyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.90 (1H, s), 8.16 (2H, s), 7.60 (2H, d, J = 8.8 Hz), 7.24 (1H, s), 7.17 (2H, d, J= 8.8 Hz), 5.23 (2H, s), 4.82 (2H, m), 3.29 (1H, m), 3.04 (2H, m), 2.42 (2H, t), 2.20 (2H, m), 1.80 (2H, m), 1.53 (2H, m), 1.28 (8H, m), 0.87 (3H, t).

Example 64

5-pentyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.90 (1H, s), 8.16 (2H, s), 7.60 (2H, d, J = 8.8 Hz), 7.24 (1H, s), 7.17 (2H, d, J= 8.8 Hz), 5.23 (2H, s), 4.83 (2H, m), 3.30 (1H, m), 3.04 (2H, m), 2.42 (2H, t), 2.20 (2H, m), 1.80 (2H, m), 1.54 (2H, m), 1.30 (4H, m), 0.89 (3H, t).

Example 65

5-methyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.94 (1H, s), 8.17 (2H, s), 7.62 (2H, d, J = 8.8 Hz), 7.25 (1H, s), 7.17 (2H, d, J= 8.8 Hz), 5.24 (2H, s), 4.82 (2H, d), 3.30 (1H, m), 3.04 (2H, m), 2.22 (2H, m), 2.13 (3H, s), 1.81 (2H, m).

Example 66

5-(4-methoxy-phenyl)-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1 -yl}-pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.90 (1H, s), 8.52 (s, 2H), 7.61 (2H, d, J = 9.0 Hz), 7.41 (2H, d, J = 8.6 Hz), 7.25 (1H , s), 7.17 (2H, d, J=9.0 Hz), 6.99 (2H, d, J=8.6 Hz), 5.24 (2H, s), 4.92 (2H, m), 3.85 (3H, s), 3.34 (1H, m), 3.12 (2H, m), 2.25 (2H, m), 1.85 (2H, m).

Example 67

5-propyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.9 (1H, s), 8.17 (2H, s), 7.61 (2H, d, J = 8.8 Hz), 7.24 (1H, s), 7.17 (2H, d, J= 8.8 Hz), 5.24 (2H, s), 4.83 (2H, m), 3.31 (1H, m), 3.04 (2H, m), 2.4 (2H, t, J=7.6 Hz), 2.22 (2H, m) , 1.81 (2H, m), 1.58 (2H, m), 0.94 (3H, t, J=7.6 Hz).

Example 68

5-methoxy-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.93 (1H, s), 8.11 (2H, s), 7.61 (2H, d, J = 8.8 Hz), 7.25 (1H, s), 7.17 (2H, d, J= 8.8 Hz), 5.24 (2H, s), 4.74 (2H, m), 3.81 (3H, s), 3.31 (1H, m), 3.03 (2H, m), 2.22 (2H, m), 1.82 (2H, m).

Example 69

5'-Methyl-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-3,4,5,6-tetrahydro-2H-[1 , 2']bipyridine

¹ H NMR (CDCl ₃ ): δ 8.91 (1H, s), 8.03 (1H, m), 7.61 (2H, m), 7.33 (1H, m), 7.26 (1H, s), 7.18 (2H, m) , 6.65 (1H, d, J=8.8 Hz), 5.24 (2H, s), 4.33 (2H, m), 3.25 (1H, m), 2.97 (2H, m), 2.22 (2H, m), 2.21 ( 3H, s), 1.89 (2H, m).

Example 70

4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-5',6"-bis-trifluoromethyl-3,4,5,6- Tetrahydro-2H-[1,2';6',2"]tripyridine

¹ H NMR (DMSO-d ₆ ): δ 8.81 (1H, m), 8.39 (1H, m), 8.13 (1H, dd, J = 8.8, 2.4 Hz), 7.76 (1H, dd, J=8.8, 2.8 Hz), 7.66 (1H, s), 7.59 (2H, m), 7.25 (2H, m), 6.99 (1H, d, J=9 Hz), 6.8 (1H, d, J=9 Hz), 5.19 ( 2H, s), 4.48 (2H, d), 3.37 (1H, m), 3.10 (2H, m), 2.11 (2H, m), 1.65 (2H, m).

Example 71

4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-5'-trifluoromethyl-3,4,5,6-tetrahydro-2H- [1,2']bipyridine

¹ H NMR (DMSO-d ₆ ): δ 9.98 (1H, s), 8.40 (1H, m), 7.81-7.75 (3H, m), 7.66 (1H, s), 7.28 (2H, d), 6.99 ( 1H, d, J=8.8 Hz), 5.21 (2H, s), 4.48 (2H, d), 3.37 (1H, m), 3.1 (2H, m), 2.12 (2H, m), 1.65 (2H, m ).

Example 72

4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-3,4,5,6-tetrahydro-2H-[1,2]bipyridyl -5'-carboxycarboxaldehyde

¹ H NMR (DMSO-d ₆ ): δ 9.98 (1H, s), 9.72 (1H, s), 8.58 (1H, d, J = 2.4 Hz), 7.86 (1H, dd, J=9.2, 2 Hz) , 7.8 (2H, d, J=8.4 Hz), 7.67 (1H, s), 7.28 (2H, d, J=8.4 Hz), 6.99 (1H, d, J=8.8 Hz), 5.2 (2H, s) , 4.58 (2H, d), 3.41 (1H, m), 3.17 (2H, m), 2.13 (2H, m), 1.65 (2H, m).

Example 73

1-(3-isopropyl-[1,2,4] Diazol-5-yl)-4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine

¹ H NMR (CDCl ₃ ): δ 7.87 (2H, m), 7.26 (1H, s), 7.11 (2H, m), 5.23 (2H, s), 4.76-4.68 (1H, m), 4.26-4.18 ( 1H, m), 3.4~3.3 (2H, m), 3.2~3.04 (2H, m), 3.03 (3H, s), 2.32-2.2 (2H, m), 2.00-1.86 (2H, m), 1.36 ( 6H, d, J = 7.2 Hz).

Example 74

2-{4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-benzo Azole

¹ H NMR (CDCl ₃ ): δ 7.87 (2H, d, J = 8.4 Hz), 7.36 (1H, d, J = 7.6 Hz), 7.01~7.19 (6H, m), 5.24 (2H, s), 4.42 (2H, m), 3.30 (3H, m), 3.03 (3H, s), 2.27 (2H, m), 1.95 (2H, m).

Example 75

4-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-5'-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1 , 2']bipyridine

¹ H NMR (CDCl ₃ ): δ 8.4 (1H, s), 7.87 (2H, d), 7.63 (1H, m), 7.26 (1H, s), 7.12 (2H, d), 6.69 (1H, d) , 5.23 (2H, s), 4.55-4.50 (2H, m), 3.38-3.28 (1H, m), 3.20-3.10 (2H, m), 3.04 (3H, s), 2.30-2.20 (2H, m) , 1.90-1.80 (2H, m).

Example 76

5-ethyl-2-{4-[4-(2-fluoro-4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.18 (2H, s), 7.65~7.70 (2H, m), 7.21~7.26 (2H, m), 5.30 (2H, s), 4.81~4.84 (2H, m), 3.25~3.28 (1H, m), 3.03 (3H, s), 3.00~3.07 (2H, m), 2.44 (2H, q), 2.21 (2H, m), 1.77~1.81 (2H, m), 1.19 ( 3H, t).

Example 77

5-ethyl-2-{4-[4-(2-fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl} -pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.96 (1H, s), 8.19 (2H, s), 7.55-7.25 (4H, m), 5.31 (2H, s), 4.82 (2H, m), 3.30 (1H, m), 3.04 (2H, m), 2.47 (2H, q), 2.23 (2H, m), 1.81 (2H, m), 1.20 (3H, t).

Example 78

4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-4-methyl-hexahydropyridine-1-carboxylic acid tert-butyl ester

Step 1: 4-Cyano-4-methyl-hexahydropyridine-1-carboxylic acid tert-butyl ester

Addition of LHMDS in THF at 0 ° C in a solution of 4-cyano-hexahydropyridine-1-carboxylic acid tert-butyl ester (4.52 g, 20 mmol) in THF (50 mL) 24 ml, 24 mM). After stirring at 0 ° C for 1 hour, MeI (5.7 g) was added. The reaction mixture was kept at 0 ℃ 2 hours and then treated as partitioned between EtOAc and H ₂ O. After concentrating in vacuo, EtOAc EtOAc m.

Step 2: 4-Aminoformyl-4-methyl-hexahydropyridine-1-carboxylic acid tert-butyl ester

Addition of 4-cyano-4-methyl-hexahydropyridine-1-carboxylic acid tert-butyl ester (2.24 g, 10 mmol) in methanol (25 ml) at room temperature DMSO (1 mL), 1N aqueous solution of NaOH (12 mL, 12 mmol) and H ₂ O ₂ (4 mL). The mixture was heated at 50 ° C for 3 hours. After cooling to room temperature, the mixture was partitioned between EtOAc and H ₂ O as a liquid separation treatment. The organic layer was washed successively with H ₂ O and brine. After dehydration drying (Na ₂ SO ₄ ), the solvent was removed to give the desired product.

Step 3: 4-Methyl-4-aminethiomethane-piperidine-1-carboxylic acid tert-butyl ester

In a solution of 4-aminomercapto-4-methyl-hexahydropyridine-1-carboxylic acid tert-butyl ester (2.1 g, 8.7 mmol) in THF (30 mL) at room temperature Add Lawesson's reagent (3.5 g, 8.7 mmol). The mixture was heated at 50 ° C for 3 hours. After cooling to room temperature, the solvent was removed in vacuo, and the residue was partitioned between EtOAc and H ₂ O as a liquid separation treatment. The organic layer was washed with saturated NaHCO ₃ and brine. In dried (Na ₂ SO _4), the solvent was removed in vacuo, and the residue was separated by silica gel column chromatography, purified EtOAc / hexanes, to give the desired product.

Step 4: 4-(4-Ethoxycarbonyl-thiazol-2-yl)-4-methyl-hexahydropyridine-1-carboxylic acid tert-butyl ester

In a solution of 4-methyl-4-amine thiomethionyl-hexahydropyridine-1-carboxylic acid tert-butyl ester (1 g, 4 mmol) in EtOH (10 mL) at room temperature Next, ethyl bromopyruvate (0.78 g, 4 mmol) was added. The mixture was heated to reflux for 3 hours. After cooling to room temperature, the solvent was removed in vacuo. The residue was dissolved in dichloromethane (15 ml), and the di Et ₃ N (1 mL) - was added to the solution ester (1.3 g) - the third. The mixture was stirred at room temperature overnight. The mixture was washed with H ₂ O and brine. After dried on (Na ₂ SO _4), solvent was removed in vacuo, and the residue was separated by silica gel column chromatography, purified EtOAc / hexanes, to give the desired product.

Step 5: 4-(4-Hydroxymethyl-thiazol-2-yl)-4-methyl-hexahydropyridine-1-carboxylic acid tert-butyl ester

4-(4-Ethoxycarbonyl-thiazol-2-yl)-4-methyl-hexahydropyridine-1-carboxylic acid tert-butyl ester (0.6 g, 1.7 mmol) in anhydrous THF (10 mL Within the solution, LiAlH ₄ (0.1 g, 2.6 mmol) was added at 0 °C. The mixture was kept at 0 °C for 2 hours and quenched with EtOH. The solvent was evaporated, and the~~~~~ After dried (Na ₂ SO _4), remove the solvent in vacuo, and the residue was separated by silica gel column chromatography, purified EtOAc / hexanes, to give the desired product.

Step 6: 4-(4-methanesulfonyloxymethyl-thiazol-2-yl)-4-methyl-hexahydropyridine-1-carboxylic acid tert-butyl ester

4-(4-Hydroxymethyl-thiazol-2-yl)-4-methyl-hexahydropyridine-1-carboxylic acid tert-butyl ester (0.42 g, 1.3 mmol) in dichloromethane (10) Methane sulfonate (0.19 g, 1.7 mmol) and triethylamine (0.2 g, 2 mmol) were added to the solution in cc) at 0 °C. After stirring at 0 ℃ 1 h, the mixture was diluted with EtOAc, and washed with H ₂ O and brine. After dried (Na ₂ SO _4), solvent was removed in vacuo, and the residue was separated by silica gel column chromatography, purified EtOAc / hexanes, to give the desired product.

Step 7: 4-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-4-methyl-hexahydropyridine-1-carboxylic acid tert-butyl ester

4-(4-Methanesulfonyloxymethyl-thiazol-2-yl)-4-methyl-hexahydropyridine-1-carboxylic acid tert-butyl ester (0.2 g, 0.5 mmol), 4 - methanesulfonamide acyl - phenol (86 mg, 0.5 mmol) and Cs ₂ CO ₃ (170 mg, 0.52 mmol) in acetonitrile (4 ml) of the heated overnight at 40 ℃. After cooling, the solid was filtered through a pad of celite. The filtrate was concentrated in vacuo. The residue was purified on EtOAc (EtOAc-hexanes EtOAc) ¹ H NMR (CDCl ₃ ): δ 7.83 (2H, m), 7.23 (1H, s), 7.09 (2H, m), 5.2 (2H, s), 3.64-3.54 (2H, m), 3.3~3.24 ( 2H, m), 2.99 (3H, s), 2.2~2.1 (2H, m), 1.72-1.64 (2H, m), 1.41 (9H, s), 1.36 (3H, s).

Example 79

4-[4-(4-methanesulfonyl-phenoxymethyl)-5-methyl-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

4-(4-Hydroxymethyl-5-methyl-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.18 g, 0.6 mmol), 4-methanesulfonate Add azodicarboxylate (at a solution of base-phenol (0.1 g, 0.6 mmol) and PPh ₃ (0.19 g, 0.72 mmol) in THF (5 mL) DEAD) (0.22 g, 0.72 mmol). The resulting mixture was stirred at room temperature for 30 minutes. The solvent is removed and the residue is purified by flash chromatography on silica gel to give the desired product. ¹ H NMR (CDCl ₃ ): δ 7.9 (2H, d, J = 9 Hz), 7.09 (2H, d, J = 9 Hz), 5.2 (2H, s), 4.28-4.10 (2H, m), 3.14 -3.04 (1H, m), 3.04 (3H, s), 2.9-2.8 (2H, m), 2.44 (3H, s), 2.1~2 (2H, m), 1.76-1.64 (2H, m), 1.47 (9H, s).

Example 80

4-{4-[1-(4-methanesulfonyl-phenoxy)-ethyl]-5-methyl-thiazol-2-yl}-piperidine-1-carboxylic acid tert-butyl ester

Step 1 : 4-[4-(1-Hydroxy-ethyl)-5-methyl-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

Tetra-butyl 4-(4-carbamimido-5-methyl-thiazol-2-yl)-piperidine-1-carboxylate (0.31 g, 1 mmol) in THF (10 mL) in the inner solution, at room temperature, in the Et ₂ O was added MeMgI (1 mL, 3 mmol). The resulting mixture was stirred at room temperature for 1 hour. Saturated aqueous NH ₄ Cl The reaction was quenched and extracted with EtOAc. The organic layer was washed with H ₂ O and brine. After dehydration drying with Na ₂ SO ₄ , the solvent was removed. The residue is purified by flash chromatography on silica gel to give the desired product.

Step 2 : 4-{4-[1-(4-Methanesulfonyl-phenoxy)-ethyl]-5-methyl-thiazol-2-yl}-piperidine-1-carboxylic acid III -butyl ester

4-[4-(1-Hydroxy-ethyl)-5-methyl-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.15 g, 0.46 mmol), 4-Methanesulfonyl-phenol (0.08 g, 0.46 mmol) and PPh ₃ (0.14 g, 0.55 mmol) in THF (5 mL). , 0.55 millimoles). The resulting mixture was stirred at room temperature for 30 minutes. Remove the solvent. The residue is purified by flash chromatography on silica gel to give the desired product. ¹ H NMR (CDCl ₃ ): δ 7.79 (2H, m), 6.94 (2H, m), 5.59 (1H, q, J=6 Hz), 4.2-4.04 (2H, m), 3.04-2.94 (1H, m), 2.98 (3H, s), 2.86-2.72 (2H, m), 2.39 (3H, s), 2.04-1.96 (2H, m), 1.67 (3H, d, J=6 Hz), 1.66-1.58 (2H, m), 1.42 (9H, s).

Example 81

4-[3-(4-methanesulfonyl-phenoxymethyl)-[1,2,4] Diazol-5-yl]-hexahydropyridine-1-carboxylic acid tert-butyl ester

Step 1 : N-Hydroxy-2-(4-methanesulfonyl-phenoxy)-acetamidine

(4-Methanesulfonyl-phenoxy)-acetonitrile (2 g, 9.5 mmol), K ₂ CO ₃ (1.3 g, 9.5 mmol) in H ₂ O (30 mL) and EtOH (15) Hydroxylamine hydrogen chloride (1.32 g, 19 mmol) was added to the mixture in ML). The mixture was heated with EtOAc (150 mL)EtOAc. The organic layer was washed successively with H ₂ O and brine. After dehydration drying (Na ₂ SO ₄ ), the solvent was removed to give the desired product.

Step 2 : 4-[3-(4-Methanesulfonyl-phenoxymethyl)-[1,2,4] Diazol-5-yl]-hexahydropyridine-1-carboxylic acid tert-butyl ester

In a solution of hexahydropyridine-1,4-dicarboxylic acid mono-tert-butyl ester (2.06 g, 9 mmol), NEt ₃ (1.2 g, 12 mmol) in toluene (150 mL) Isobutyl chloroformate (1.23 g, 9 mmol) was added at 0 °C. The mixture was stirred at room temperature for 1.5 hours. N-Hydroxy-2-(4-methanesulfonyl-phenoxy)-acetamidine (1.5 g, 6 mmol) was added to the mixture. The mixture was heated at reflux overnight, cooled, and successively washed with H ₂ O and brine mixture. After dehydration drying (Na ₂ SO ₄ ), the solvent was removed. The residue is purified by flash chromatography on silica gel to give the desired product. ¹ H NMR (CDCl ₃ ): δ 7.98 (2H, m), 7.14 (2H, m), 5.24 (2H, s), 4.2-4.05 (2H, m), 3.14 (1H, m), 3.03 (3H, s), 2.95 (2H, m), 2.12~2.04 (2H, m), 1.80 (2H, m), 1.46 (9H, s).

Example 82

4-[5-(4-methanesulfonyl-phenoxymethyl)-[1,2,4] Diazol-3-yl]-hexahydropyridine-1-carboxylic acid tert-butyl ester

Step 1 : 4-(N-Hydroxycarbamicimido)-hexahydropyridine-1-carboxylic acid tert-butyl ester

4-Cyano-hexahydropyridine-1-carboxylic acid tert-butyl ester (6.3 g, 30 mmol), K ₂ CO ₃ (4.2 g, 30 mmol) in H ₂ O (50 mL) Hydroxylamine hydrochloride (4.17 g, 60 mmol) was added to a mixture with EtOH (30 mL). The mixture was heated at reflux overnight, cooled to room temperature and the ethanol was removed in vacuo. The residue was extracted with EtOAc (EtOAc) The organic layer was washed successively with H ₂ O and brine. After dehydration drying (Na ₂ SO ₄ ), the solvent was removed to give the desired product.

Step 2 : 4-(5-Hydroxymethyl-[1,2,4] Diazol-3-yl)-hexahydropyridine-1-carboxylic acid tert-butyl ester

Add isobutyl chloroformate (6 g) at 0 ° C in a solution of hydroxy-acetic acid (1.67 g, 22 mmol), NEt ₃ (4.4 g, 44 mmol) in toluene (150 mL) , 44 millimoles). The mixture was stirred at room temperature for 1.5 hours. 4-(N-Hydroxycarbamicimido)-hexahydropyridine-1-carboxylic acid tert-butyl ester (5.35 g, 22 mmol) was added to the mixture. The mixture was heated at reflux overnight, then cooled to rt; washed successively with H ₂ O and brine mixture. After dehydration drying (Na ₂ SO ₄ ), the solvent was removed. The residue was dissolved in THF (20 mL) EtOAc. The mixture was stirred at room temperature for 2 h and diluted with EtOAc EtOAc. The organic layer was washed with brine, dehydrated and dried (Na ₂ SO _4), the solvent was removed in vacuo, and the residue was separated by silica gel column chromatography, purified EtOAc / hexanes, to give the desired product.

Step 3 : 4-(5-Methanesulfonyloxymethyl-[1,2,4] Diazol-3-yl)-hexahydropyridine-1-carboxylic acid tert-butyl ester

4-(5-hydroxymethyl-[1,2,4] Addition of oxazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.2 g, 0.7 mmol) in dichloromethane (5 mL) at 0 ° C Methanesulfonate (0.1 g, 0.9 mmol) and triethylamine (0.14 g, 1.4 mmol). After stirring at 0 ℃ 1 h, the mixture was diluted with EtOAc, and to H ₂ O, washed with brine. After dried (Na ₂ SO _4), solvent was removed in vacuo, and the residue was separated by silica gel column chromatography, purified EtOAc / hexanes, to give the desired product.

Step 4 : 4-[5-(4-Methanesulfonyl-phenoxymethyl)-[1,2,4] Diazol-3-yl]-hexahydropyridine-1-carboxylic acid tert-butyl ester

4-(5-methanesulfonyloxymethyl-[1,2,4] Diazol-3-yl)-hexahydropyridine-1-carboxylic acid tert-butyl ester (0.12 g, 0.33 mmol), 4-methanesulfonyl-phenol (86 mg, 0.5 mmol) and Cs ₂ CO ₃ (0.33 g, 1 mmol) in acetonitrile (5 ml) and the mixture was heated at 50 ℃ 2 hours. After cooling, the solid was filtered through a pad of celite. The filtrate was concentrated in vacuo. The residue was purified on EtOAc (EtOAcEtOAcEtOAcEtOAc ¹ H NMR (CDCl ₃ ): δ 7.9 (2H, d, J = 8.8 Hz), 7.12 (2H, d, J = 8.8 Hz), 5.34 (2H, s), 4.2~4.05 (2H, m), 3.03 (3H, s), 3.04~2.85 (3H, m), 2.05~1.96 (2H, m), 1.8~1.7 (2H, m), 1.45 (9H, s).

Example 83

4-(5-benzyloxymethyl-[1,2,4] Diazol-5-yl)-hexahydropyridine-1-carboxylic acid tert-butyl ester

Add isobutyl chloroformate at 0 ° C in a solution of benzyloxy-acetic acid (5 g, 30 mmol), NEt ₃ (3.6 g, 36 mmol) in toluene (150 mL) 4.1 grams, 30 millimoles). The mixture was stirred at room temperature for 1.5 hours. 4-(N-Hydroxycarbamicimido)-hexahydropyridine-1-carboxylic acid tert-butyl ester (7.3 g, 30 mmol) was added to the mixture. The mixture was heated at reflux overnight, cooled, and successively washed with H ₂ O and brine mixture. After dehydration drying (Na ₂ SO ₄ ), the solvent was removed. The residue is purified by flash chromatography on silica gel to give the desired product. ¹ H NMR (CDCl ₃ ): δ 7.4~7.3 (5H, m), 4.7 (2H, s), 4.69 (2H, s), 4.2~4.04 (2H, m), 3.02~2.84 (3H, m), 2.04~1.94 (2H, m), 1.84~1.7 (2H, m), 1.46 (9H, s).

Example 84

5-ethyl-2-{4-[3-(4-methanesulfonyl-phenoxymethyl)-[1,2,4] Diazol-5-yl]-hexahydropyridin-1-yl}-pyrimidine

4-[3-(4-methanesulfonyl-phenoxymethyl)-[1,2,4] Crude HCl salt of oxazol-5-yl]-hexahydropyridine (0.18 g, ～0.5 mmol) by 4-[3-(4-methanesulfonyl-phenoxymethyl)-[1 , 2, 4] Triazol-5-yl]-piperidine-1-carboxylic acid tert-butyl ester ( Example 81 ) was prepared by treatment with 4N HCl in dioxane, to which 2-propanol (3 mL) was added. Next, DIPEA (0.13 g, 1 mmol) with 2-chloro-5-ethyl-pyrimidine (0.14 g, 1 mmol). The resulting mixture was stirred at 70 ° C overnight. After concentrating in vacuo, EtOAc m. ¹ H NMR (CDCl ₃ ): δ 8.18 (2H, s), 7.89 (2H, d, J = 8.8 Hz), 7.15 (2H, d, J = 8.8 Hz), 5.24 (2H, s), 4.75~4.65 (2H, m), 3.3~3.2 (1H, m), 3.2~3.1 (2H, m), 3.03 (3H, s), 2.47 (2H, q, J=7.6 Hz), 2.22~2.16 (2H, m ), 1.96~1.84 (2H, m), 1.19 (3H, t, J=7.6 Hz).

Example 85

4-hydroxy-4-[4-(4-methylthio-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

Step 1 : 4-(4-Methylthio-phenoxymethyl)-thiazole

4-Chloromethylthiazole hydrochloride (3.0 g, 17.6 mmol), 4-methylthio-phenol (2.5 g, 1 equivalent) and K ₂ CO ₃ (6.1 g, 2.5 eq.) in acetone ( The mixture in 60 ml) was heated to reflux for 48 hours. After cooling, the solid was filtered off. The filtrate was evaporated to dryness in vacuo. The crude product was redissolved in diethyl ether. The solution 2N NaOH solution, and then washed with H ₂ O twice. In the dried Na ₂ SO _4, solvent was removed to give the desired product as an off-white solid.

Step 2 : 4-Hydroxy-4-[4-(4-methylthio-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

Add n-BuLi at -78 ° C in a stirred solution of 4-(4-methanethio-phenoxymethyl)-thiazole (3.92 g, 16.5 mmol) in THF (40 mL) (1.73 mL, 1.05 eq, 10.0 M in hexanes). The resulting solution was stirred at this temperature for 30 minutes. A solution of 1-Boc-4-hexahydropyridone (3.30 g, 1 eq.) in THF (20 mL). The resulting mixture was stirred for 30 minutes. By addition of H ₂ O (5 mL), the reaction was quenched. Most of the THF was removed in vacuo. The mixture was extracted with EtOAc. The organic layer was separated, washed with brine, and is dried Na ₂ SO _4. After the solvent was removed, the crude product was purified (EtOAc: hexane = 2:3) to give the desired product as a foam. ¹ H NMR (CDCl ₃ ): δ 7.27 (2H, d, J = 8.8 Hz), 7.26 (1H, s), 6.93 (2H, d, J = 8.8 Hz), 5.14 (2H, s), 4.02 (2H , br), 3.27 (2H, br), 2.97 (1H, br), 2.45 (3H, s), 2.11 (2H, m), 1.86 (2H, m), 1.48 (9H, s).

Example 86

4-hydroxy-4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

3-Hydroxy-4-[4-(4-methylthio-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester ( Example 85 , 6.8 g , 15.6 mmol) in a) in a solution of CH ₂ Cl ₂ (150 mL, at room temperature, was added portionwise m-CPBA (8.4 g, 2.2 eq). The resulting solution was stirred for 30 minutes, then it was washed twice with a 2N NaOH solution and dried over Na ₂ SO ₄ . After the solvent was removed, the crude material was purified eluted eluted elut elut elut elut ¹ H NMR (CDCl ₃ ): δ 7.88 (2H, d, J = 8.8 Hz), 7.31 (1H, s), 7.12 (2H, d, J = 8.8 Hz), 5.24 (2H, s), 4.03 (2H , br), 3.27 (2H, br), 3.04 (3H, s), 2.13 (2H, m), 1.86 (2H, m), 1.48 (9H, s).

Example 87

4-fluoro-4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

3-Hydroxy-4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester ( Example 86 , 5.29 g, 11.3 mmol) in a) in a solution of CH ₂ Cl ₂ (100 ml at 0 deg.] C, was added DAST (1.8 mL, 1.2 equiv). The reaction mixture was stirred for 30 min, then, with saturated NaHCO ₃ solution (20 mL) it was quenched. The organic phase was separated and dried over Na ₂ SO ₄ . After the solvent was removed, the crude material was purified eluted elut elut elut elut elut ¹ H NMR (CDCl ₃ ): δ 7.86 (2H, d, J = 9.2 Hz), 7.35 (1H, s), 7.10 (2H, d, J = 9.2 Hz), 5.22 (2H, s), 4.08 (2H , br), 3.19 (2H, br), 3.02 (3H, s), 2.05~2.32 (4H, m), 1.46 (9H, s).

Example 88

5-ethyl-2-{4-fluoro-4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine

Step 1 : 4-Fluoro-4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine hydrochloride

4-Fluoro-4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester ( Example 87 , 4.24 g, 9.01 mmol. In a solution of methanol (50 mL), 4N HCl (15 mL). The resulting solution was stirred overnight. The mixture was then evaporated to dryness in vacuo to give the desired product as white solid.

Step 2 : 5-Ethyl-2-{4-fluoro-4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl }-pyrimidine

4-Fluoro-4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine hydrochloride (4.0 g, 9.01) in a sealed pressure vessel a solution of 2-chloro-5-ethyl-pyrimidine (1.55 g, 1.2 eq.) and DIPEA (4.7 g, 4 eq.) in 2-propanol (30 mL) at 160 ° C Stir overnight at bath temperature. After cooling, the solvent was removed in vacuo. The residue was partitioned between water and EtOAc. The organic phases are washed with brine and dried Na ₂ SO _4. After the solvent was removed, the crude material was purified eluted elut elut elut elut elut ¹ H NMR (CDCl ₃ ): δ 8.19 (2H, s), 7.87 (2H, d, J = 9.2 Hz), 7.36 (1H, s), 7.10 (2H, d, J = 9.2 Hz), 5.23 (2H , s), 4.69 (2H, m), 3.44 (2H, m), 3.03 (3H, s), 2.48 (2H, q, J=7.6 Hz), 2.15~2.39 (4H, m), 1.21 (3H, t, J = 7.6 Hz).

Example 89

4-fluoro-4-[5-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

Step 1 : 4-Hydroxy-4-thiazol-2-yl-hexahydropyridine-1-carboxylic acid tert-butyl ester

To n-BuLi (2.6 mL, 1.05 equiv, 10.0M, in hexane) was cooled in dry Et ₂ O (20 mL) of (-78 deg.] C) and the stirred solution was added dropwise 2-bromo-thiazole (4.0 g, 24.4 mmol) in THF (10 mL) over 10 min. After the yellow mixture had been stirred at -78 °C for 30 minutes, a solution of 1-Boc-4-hexahydropyridone (4.9 g, 1 eq.) in THF (20 mL). Then, the mixture was further stirred for further 30 minutes, and then the reaction was quenched by the addition of water (5 ml). The mixture was allowed to warm to rt and extracted with EtOAc. The organic phase was separated, washed with brine, Na ₂ SO ₄ and to dried. After removal of the solvent, the crude material was purified eluting elut elut elut elut

Step 2 : 4-Fluoro-4-thiazol-2-yl-hexahydropyridine-1-carboxylic acid tert-butyl ester

In a solution of 4-hydroxy-4-thiazol-2-yl-piperidine-1-carboxylic acid tert-butyl ester (4.36 g, 15.3 mmol) in CH ₂ Cl ₂ (50 mL) DAST (2.4 mL, 1.2 eq.) was added at 0 °C. The reaction mixture was stirred for 30 min, then, with saturated NaHCO ₃ solution (20 mL) it was quenched. The organic phase was separated and dried over Na ₂ SO ₄ . After the solvent was removed, the crude material was purified eluting elut elut elut elut elut

Step 3 : 4-Fluoro-4-(5-hydroxymethyl-thiazol-2-yl)-hexahydropyridine-1-carboxylic acid tert-butyl ester

Tetra-butyl 4-fluoro-4-thiazol-2-yl-hexahydropyridine-1-carboxylate (3.65 g, 12.7 mmol) in THF (20 mL) cooled (-78 ° C And while stirring the solution, n-BuLi (1.33 mL, 1.05 eq., 10.0 M in hexane) was added. The mixture was stirred at this temperature for 30 minutes. Then, a suspension of polyformaldehyde (383 mg, 1 equivalent) in THF (10 mL) was added. The resulting mixture was stirred at -78 ° C for an additional 30 minutes and gradually warmed to room temperature overnight. The reaction was quenched by the addition of water (10 mL). The mixture was extracted with EtOAc. The organic phase was washed with brine, Na ₂ SO ₄ and to dried. After the solvent was removed, the crude material was purified eluted elut elut elut elut elut elut

Step 4 : 4-(5-Chloromethyl-thiazol-2-yl)-4-fluoro-hexahydropyridine-1-carboxylic acid tert-butyl ester

4-Fluoro-4-(5-hydroxymethyl-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.34 g, 4.24 mmol) and pyridine (426 mg, MsCl (631 mg, 1.3 eq.) was added at 0 ° C in a mixture of CH ₂ Cl ₂ (30 mL). The mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was _washed with saturated solution MaHCO, Na ₂ SO ₄ and is dried. The solvent was removed to give the desired product which was used directly in the next reaction without further purification.

Step 5 : 4-Fluoro-4-[5-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

3-(5-Chloromethyl-thiazol-2-yl)-4-fluoro-hexahydropyridine-1-carboxylic acid tert-butyl ester (1.42 g, 4.24 mmol), 4-methanesulfonate group - phenol (731 mg, 1.0 eq) and K ₂ CO ₃ (878 mg, 1.5 equiv) was heated to reflux overnight in acetone (30 ml) of the mixture. After cooling, the solid was filtered through a pad of celite. The filtrate was concentrated in vacuo. The crude product was purified on EtOAc (EtOAc:EtOAc) ¹ H NMR (CDCl ₃ ): δ 7.86 (2H, d, J = 9.2 Hz), 7.35 (1H, s), 7.10 (2H, d, J = 9.2 Hz), 5.22 (2H, s), 4.08 (2H , br), 3.19 (2H, br), 3.02 (3H, s), 2.05~2.32 (4H, m), 1.46 (9H, s).

Example 90

5-ethyl-2-{4-fluoro-4-[5-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine

Step 1 : 4-Fluoro-4-[5-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine hydrochloride

4-Fluoro-4-[5-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester ( Example 89 , To a solution of 1.30 g, 2.76 mmol, in MeOH (5 mL), 4N HCl (10 mL). The resulting solution was stirred overnight. The mixture was then evaporated to dryness in vacuo to give the desired product as a white solid.

Step 2 : 5-Ethyl-2-{4-fluoro-4-[5-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl }-pyrimidine

4-Fluoro-4-[5-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine hydrochloride (1.2 g, 2.76) in a sealed pressure vessel a solution of 2-chloro-5-ethyl-pyrimidine (425 mg, 1.1 eq.) and DIPEA (1.4 g, 4 eq.) in 2-propanol (20 mL) at 160 ° C (oil bath) Stir overnight at temperature). After cooling, the solvent was removed in vacuo. The residue was partitioned between water and EtOAc. The organic phase was washed with brine, Na ₂ SO ₄ and to dried. After the solvent was removed, the crude material was purified eluting elut elut elut ¹ H NMR (CDCl ₃ ): δ 8.19 (2H, s), 7.90 (2H, d, J = 8.8 Hz), 7.73 (1H, d), 7.10 (2H, d, J = 8.8 Hz), 5.31 (2H , s), 4.67 (2H, m), 3.44 (2H, m), 3.04 (3H, s), 2.48 (2H, q, J=7.6 Hz), 2.13~2.38 (4H, m), 1.20 (3H, t, J = 7.6 Hz).

Example 91

4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridyl 1-carboxylic acid tert-butyl ester

Step 1 : 4-(4-Ethoxycarbonyl-thiazol-2-yl)-hexahydropyridyl 1-carboxylic acid tert-butyl ester

Ethyl 2-bromo-thiazole-4-carboxylate (1.4 g, 5.93 mmol), hexahydropyridyl A mixture of 1-carboxylic acid tert-butyl ester (1.16 g, 1.05 eq.) and DIPEA (1.15 g, 1.5 eq.) in 1,4-dioxane (20 mL) was heated to reflux overnight. After cooling, the solvent was removed in vacuo. The crude product was purified on EtOAc (EtOAc:EtOAc:EtOAc)

Step 2 : 4-(4-Hydroxymethyl-thiazol-2-yl)-hexahydropyridyl 1-carboxylic acid tert-butyl ester

4-(4-Ethoxycarbonyl-thiazol-2-yl)-hexahydropyridyl A third 1-carboxylic acid - butyl ester (1.15 g, 3.37 mmol) in THF (15 ml) and the solution, at 0 deg.] C, treated to LiAlH ₄ (128 mg, 1 eq). The mixture was stirred for 1 hour and then quenched with 2N NaOH solution. The solid was filtered through EtOAc (EtOAc)EtOAc. The filtrate was washed with water and dried over Na ₂ SO ₄ . The solvent was removed to give the desired product as an oil.

Step 3 : 4-(4-Chloromethyl-thiazol-2-yl)-hexahydropyridyl 1-carboxylic acid tert-butyl ester

4-(4-Hydroxymethyl-thiazol-2-yl)-hexahydropyridyl M-Cl (285 μl) was added dropwise to a solution of 1-carboxylic acid tert-butyl ester (848 mg, 2.83 mmol) and DIPEA (550 mg, 1.5 eq.) in CH ₂ Cl ₂ (10 mL) , 1.3 equivalents). The resulting mixture was stirred overnight. Then, the reaction solution was concentrated in a vacuum. The crude product was purified on EtOAc (EtOAc:EtOAc:EtOAc)

Step 4 : 4-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridyl 1-carboxylic acid tert-butyl ester

4-(4-Chloromethyl-thiazol-2-yl)-hexahydropyridyl 1-carboxylic acid tert-butyl ester (700 mg, 2.20 mmol), 4-methanesulfonyl-phenol (417 mg, 1.1 equivalents) and K ₂ CO ₃ (609 mg, 2 equivalents) in acetone ( The mixture in 30 ml) was heated to reflux overnight. After cooling, the solid was filtered through a pad of celite. The filtrate was concentrated in vacuo. The crude product was purified on EtOAc (EtOAc:EtOAc) ¹ H NMR (CDCl ₃ ): δ 7.87 (2H, d, J = 8.8 Hz), 7.12 (2H, d, J = 8.8 Hz), 6.59 (1H, s), 5.05 (2H, s), 3.56 (4H , m), 3.48 (4H, m), 3.04 (3H, s), 1.49 (9H, s).

Example 92

1-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-4-(2-methyl-propan-1-sulfonyl)-hexahydropyridyl

Step 1 : 1-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridyl Hydrochloride

4-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridyl To a solution of 1-carboxylic acid tert-butyl ester ( Example 91 , 430 mg, 0.95 mmol) in methanol (5 mL), 4N HCl (5 mL). The resulting solution was stirred at room temperature for 30 minutes. The mixture was then evaporated to dryness in vacuo to give the desired product as a pale yellow solid.

Step 2 : 1-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-4-(2-methyl-propan-1-sulfonyl)-hexahydropyridyl

In 1-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridyl Hydrochloride (100 mg, 0.26 mmol) and DIPEA (134 mL, 3 eq) in a solution of the CH ₂ Cl ₂ (5 mL) was added isobutane sulfonylurea chloride (41 mL, 1.2 equiv) . The mixture was stirred for 1 hour, then the title compound was crystallised eluted elute ¹ H NMR (CDCl ₃ ): δ 7.87 (2H, d, J = 8.8 Hz), 7.12 (2H, d, J = 8.8 Hz), 6.62 (1H, s), 5.05 (2H, s), 3.61 (4H , m), 3.39 (4H, m), 3.04 (3H, s), 2.78 (2H, d, J=6.8 Hz), 2.32 (1H, m), 1.12 (6H, d, J=6.8 Hz).

Example 93

4-[4-methyl-5-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

4-(5-Hydroxymethyl-4-methyl-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.00 g, 3.2 mmol) in THF (6.4 mL) In the solution, 4-tetrazol-1-yl-phenol (0.52 g, 3.2 mmol), polymer-bound triphenylphosphine (3 mmol/g, 1.6 g) was added. Di-tert-butyl azodicarboxylate (1.1 g, 4.8 mmol) was added to the solution, stirred for 4 hours, and filtered through a pad of Celite. The filtrate is concentrated and purified by chromatography on silica gel to afford the desired product. ¹ H NMR (CDCl ₃ ): δ 9.01 (1H, s), 7.66 (2H, d), 7.15 (2H, d), 5.21 (2H, s), 4.19 (2H, m), 3.10 (1H, m) , 2.86 (2H, m), 2.45 (3H, s), 2.08 (2H, m), 1.72 (2H, m), 1.47 (9H, s).

Example 94

4-{4-[(6-fluoro-pyridin-3-ylamino)-methyl]-thiazol-2-yl}-piperidine-1-carboxylic acid tert-butyl ester

Add 5-Amino-2-fluoropyridine (0.476 g, 4.2 mmol) to 4-(4-carbamidothiazol-2-yl)-hexahydropyridine-1 in anhydrous DCM (10 mL) - Carboxylic acid - tributyl ester (0.84 g, 2.8 mmol). Sodium triethoxy borohydride (0.9 g, 4.2 mmol) was then added. The reaction was stirred for 3 hours at room temperature and N _2. The organic layer was 2M NaOH solution, water, brine, dried (MgSO _4), and the solvent removed in vacuo. The material was purified by silica gel chromatography (DCM / methanol: 10:1 v/v) to give the desired product. ¹ H NMR (CDCl ₃ ): δ 7.59-7.60 (1H, m), 7.06-7.10 (1H, m), 7.02 (1H, s), 6.76 (1H, dd, J=8.8, 3.6 Hz), 4.4 ( 2H, d), 4.20-4.31 (3H, m), 3.09-3.17 (1H, m), 2.8-2.95 (2H, m), 2.07-2.10 (2H, m), 1.77-1.47 (2H, m), 1.47 (9H, s).

Example 95

1-(3-isopropyl-[1,2,4] Diazol-5-yl)-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine

Step 1 : 4-[4-(4-Tetrazolyl-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carbonitrile

4-[4-(4-Tetrazolyl-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine (1.00 g, 2.92 mmol) and potassium carbonate (1.5 g, 10.9 To a mixture of chloroform (25 ml) was added cyanogen bromide (0.371 g, 3.5 mmol). The slurry was refluxed for 48 hours and then stirred at room temperature for a further 48 hours. The reaction was filtered through a pad of EtOAc (EtOAc)EtOAc.

Step 2 : 1-(3-isopropyl-[1,2,4] Diazol-5-yl)-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine

4-[4-(4-Tetrazolyl-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carbonitrile (0.450, 1.22 mmol) with N-hydroxyl To a solution of isobutyl hydrazine (0.150 g, 1.47 mmol) in dry THF (10 mL), EtOAc (EtOAc) The suspension was left to stand for 15 minutes and a white precipitate was collected by filtration and dissolved in 4N HCl in ethanol and water (1:1). The solution was refluxed for 1 hour, cooled, and the solid precipitate was filtered. The filtrate was neutralized by the addition of excess sodium carbonate. Excess sodium carbonate was filtered off and the filtrate was diluted with EtOAc. The solution was washed with water, separated, dried (Na ₂ SO _4), filtered, and concentrated. The residual oil was chromatographed on silica gel (1:1 hexanes /EtOAc) to give the desired compound. ¹ H NMR (CDCl ₃ ): δ 8.92 (1H, s), 7.62 (2H, d), 7.28 (1H, s), 7.19 (2H, d), 5.24 (2H, s), 4.26 (2H, m) , 3.20 (3H, m), 2.89 (1H, m), 2.26 (2H, m), 1.92 (2H, m), 1.30 (6H, d).

The following three examples were carried out in a similar manner as in Example 95 using the desired hydroxyindole and 4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]- Synthesis of hexahydropyridine-1-carbonitrile.

Example 96

1-(3-ethyl-[1,2,4] Diazol-5-yl)-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine

¹ H NMR (CDCl ₃ ): δ 8.85 (1H, s), 7.57 (2H, d), 7.28 (1H, s), 7.19 (2H, d), 5.17 (2H, s), 4.22 (2H, m) , 3.22 (3H, m), 2.55 (2H, q), 2.17 (2H, m), 1.89 (2H, m), 1.35 (3H, t).

Example 97

1-(3-cyclopropyl-[1,2,4] Diazol-5-yl)-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine

¹ H NMR (CDCl ₃ ): δ 8.90 (1H, s), 7.61 (2H, d), 7.27 (1H, s), 7.17 (2H, d), 5.23 (2H, s), 4.22 (2H, m) , 3.22 (3H, m), 2.25 (2H, m), 1.88 (3H, m), 0.96 (4H, m).

Example 98

4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-1-(3-trifluoromethyl-[1,2,4] Diazol-5-yl)-hexahydropyridine

¹ H NMR (CDCl ₃ ): δ 8.92 (1H, s), 7.60 (2H, d), 7.23 (1H, s), 7.16 (2H, d), 5.21 (2H, s), 4.25 (2H, m) , 4.15 (2H, m), 3.22 (1H, m), 2.90 (2H, m), 2.18 (2H, m).

Example 99

4-[4-(4-Tetrazolyl-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid decylamine Step 1 : 4-[4-(4- Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine-1-carbonitrile

4-[4-(4-Tetrazolyl-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine (1.00 g, 2.92 mmol) and potassium carbonate (1.5 g, 10.9 To a mixture of chloroform (25 ml) was added cyanogen bromide (0.371 g, 3.5 mmol). The slurry was refluxed for 48 hours and then stirred at room temperature for a further 48 hours. The reaction was filtered through a pad of EtOAc (EtOAc)EtOAc.

Step 2 : 4-[4-(4-Tetrend-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid decylamine

4-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carbonitrile (1.07 g, 2.92 mmol) was dissolved in ethanol /4N HCl in water (1:1). The solution was refluxed for 1 hour, cooled, and a solid precipitate was filtered. The filtrate was neutralized by the addition of excess sodium carbonate. Excess sodium carbonate was filtered off and the filtrate was diluted with EtOAc. The solution was washed with water, separated, dried (Na ₂ SO _4), filtered, and concentrated. The residual oil was chromatographed on silica gel (1:1 hexanes /EtOAc) to give the desired compound. ¹ H NMR (CDCl ₃ ): δ 8.92 (1H, s), 7.60 (2H, d), 7.23 (1H, s), 7.167 (2H, d), 5.21 (2H, s), 4.25 (2H, m) , 4.15 (2H, m), 3.22 (1H, m), 2.90 (2H, m), 2.18 (2H, m).

Example 100

4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxyformamidine

4-[4-(4-Tetrazolyl-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine (300 mg, 0.876 mmol), pyrazole-1-carboxyl A mixture of hydrazine hydrochloride (0.128 g, 0.876 mmol) and triethylamine (0.122 mL, 0.876 m.). The precipitate was collected by filtration and washed with ether to give the desired product. ¹ H NMR (DMSO-d ₆ ): δ 10.02 (1H, s), 7.93 (1H, s), 7.82 (2H, m), 7.70 (1H, s), 7.60 (2H, br), 7.28 (2H, m), 5.20 (2H, s), 3.95 (2H, m), 3.38 (1H, m), 3.15 (2H, m), 2.09 (2H, m), 1.66 (2H, m).

Example 101

3-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-nazatetraindole-1-carboxylic acid tert-butyl ester

Step 1 : 3-(4-Chloromethyl-thiazol-2-yl)-azatetraindole-1-carboxylic acid tert-butyl ester

Addition of 1,3-dichloromethane to a solution of 3-aminothiomethanyl-nitroazin-1-carboxylic acid tert-butyl ester (0.800 g, 3.7 mmol) in acetone (15 ml) acetone (0.611 g, 4.81 mmol), MgSO ₄ (0.67 g, 5.6 mmol) and MgCO ₃ (3.12 g, 3.7 mmol). The mixture was heated at reflux overnight, cooled and filtered over EtOAc. The solvent was removed in vacuo and the residue was crystallised from EtOAc (EtOAc) The solution of the formed continuous to 5% NaHSO _3, saturated NaHCO ₃ and washed with brine. After dehydration (Na ₂ SO ₄ ), the solvent was removed to give the desired product, which was used without further purification.

Step 2 : 3-[4-(4-Tetrazolyl-1-yl-phenoxymethyl)-thiazol-2-yl]-azatetraindole-1-carboxylic acid tert-butyl ester

3-(4-Chloromethyl-thiazol-2-yl)-azatetraindole-1-carboxylic acid tert-butyl ester ( from step 1 ) (386 mg, 1.34 mmol), 4- Tetrazol-1-yl-phenol (217 mg, 1.34 mmol), Cs ₂ CO ₃ (655 mg, 2.01 mmol) and KI (22 mg, 0.13 mmol) in acetonitrile (5 mL) The mixture was heated under reflux for 4 hours. After cooling, the solid was filtered through a pad of celite. The filtrate was concentrated in vacuo. The residue was purified on EtOAc (EtOAc-hexanes EtOAc) ¹ H NMR (CDCl ₃ ): δ 8.92 (1H, s), 7.61 (2H, d), 7.32 (1H, s), 7.19 (2H, d), 5.25 (2H, s), 4.39 (2H, m) , 4.18 (2H, m), 4.14 (1H, m), 1.46 (9H, s).

Example 102

3-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-tetrahydropyrrole-1-carboxylic acid tert-butyl ester

Step 1 : 3-(4-Chloromethyl-thiazol-2-yl)-tetrahydropyrrole-1-carboxylic acid tert-butyl ester

Add 1,3-dichloroacetone to a solution of 3-aminothiomethyl-tetrahydropyrrole-1-carboxylic acid tert-butyl ester (1.06 g, 4.60 mmol) in acetone (25 mL) (0.76 g, 5.98 mmol), MgSO ₄ (0.83 g, 6.1 mmol) and MgCO ₃ (3.87 g, 4.6 mmol). The mixture was heated at reflux overnight, cooled and filtered over EtOAc. The solvent was removed in vacuo and the residue was crystallised from EtOAc (EtOAc) The solution of the formed continuous to 5% NaHSO _3, saturated NaHCO ₃ and washed with brine. After dehydration (Na ₂ SO ₄ ), the solvent was removed to give the desired product, which was used without further purification.

Step 2 : 3-[4-(4-Tetrend-1-yl-phenoxymethyl)-thiazol-2-yl]-tetrahydropyrrole-1-carboxylic acid tert-butyl ester

3-(4-Chloromethyl-thiazol-2-yl)-tetrahydropyrrole-1-carboxylic acid tert-butyl ester ( from step 1 ) (775 mg, 2.56 mmol), 4-four yl-l - phenol (415 mg, 2.56 mmol), CsCO ₃ (1.25 mg, 3.84 mmol) and KI (44 mg, 0.26 mmol) in acetonitrile (20 ml) at the reflux Heat overnight. After cooling, the solid was filtered through a pad of celite. The filtrate was concentrated in vacuo. The residue was purified on EtOAc (EtOAc-hexanes EtOAc) ¹ H NMR (CDCl ₃ ): δ 8.92 (1H, s), 7.63 (2H, d), 7.27 (1H, s), 7.17 (2H, d), 5.24 (2H, s), 3.87 (1H, m) , 3.79 (1H, m), 3.65 (2H, m), 3.45 (1H, m), 2.40 (1H, m), 2.23 (1H, m), 1.47 (9H, s).

Example 103

5-ethyl-2-{3-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-tetrahydropyrrol-1-yl}-pyrimidine

Step 1 : 1-[4-(2-Tetrahydropyrrol-3-yl-thiazol-4-ylmethoxy)-phenyl]-1H-tetrazole

3-[4-(4-Tetrend-1-yl-phenoxymethyl)-thiazol-2-yl]-tetrahydropyrrole-1-carboxylic acid tert-butyl ester ( from Example 102 ) A solution of 411 mg (0.959 mmol) in dichloromethane (10 mL) and methanol (2 mL). The resulting solution was stirred at room temperature for 30 minutes. The solvent was removed in vacuo to give the desired product as HCl salt.

Step 2 : 5-Ethyl-2-{3-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-tetrahydropyrrol-1-yl}-pyrimidine

1-[4-(2-Tetrahydropyrrol-3-yl-thiazol-4-ylmethoxy)-phenyl]-1H-tetrazole hydrochloride ( from step 1 ) (350 mg, 0.959 m mole), 2-chloro-pyrimidine (0.23 mL, 2.0 equiv.) and K ₂ CO ₃ (398 mg, 2.88 mmol) was heated in a mixture (5 ml) of DMF at 90 ℃ 4 hours. Water was added and the solution was extracted with ethyl acetate, separated, dried over sodium sulfate, filtered and concentrated. The residue was purified on EtOAc (EtOAc:EtOAc) ¹ H NMR (CDCl ₃ ): δ 8.91 (1H, s), 8.21 (2H, s), 7.62 (2H, d), 7.27 (1H, s), 7.17 (2H, d), 5.24 (2H, s) , 4.12 (1H, m), 3.98 (1H, m), 3.87 (2H, m), 3.69 (1H, m), 2.56 (1H, m), 2.47 (2H, m), 2.37 (1H, m), 1.21 (3H, t).

Example 104

3-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

Step 1 : 3-(4-Chloromethyl-thiazol-2-yl)-hexahydropyridine-1-carboxylic acid tert-butyl ester

Add 1,3-dichloroacetone to a solution of 3-aminothiomethanyl-hexahydropyridine-1-carboxylic acid tert-butyl ester (2.2 g, 9.02 mmol) in acetone (45 ml) (1.49 g, 11.7 mmol), MgSO ₄ (1.63 g, 13.5 mmol) and MgCO ₃ (0.76 g, 9.02 mmol). The mixture was heated at reflux overnight, cooled and filtered over EtOAc. The solvent was removed in vacuo and the residue was crystallised from EtOAc (EtOAc) The solution of the formed continuous to 5% NaHSO _3, saturated NaHCO ₃ and washed with brine. After dehydration (Na ₂ SO ₄ ), the solvent was removed to give the desired product, which was used without further purification.

Step 2 : 3-[4-(4-Tetrend-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

3-(4-Chloromethyl-thiazol-2-yl)-hexahydropyridine-1-carboxylic acid tert-butyl ester ( from step 1 ) (300 mg, 0.946 mmol), 4-four a mixture of oxazol-1-yl-phenol (155 mg, 0.946 mmol), CsCO ₃ (467 mg, 1.42 mmol) and KI (16 mg, 0.095 mmol) in acetonitrile (10 mL) Heat for 4 hours. After cooling, the solid was filtered through a pad of celite. The filtrate was concentrated in vacuo. The residue was purified on EtOAc (EtOAc-hexanes EtOAc) ¹ H NMR (CDCl ₃ ): δ 8.91 (1H, s), 7.63 (2H, d), 7.26 (1H, s), 7.17 (2H, d), 5.24 (2H, s), 4.30 (1H, br) , 4.02 (1H, m), 3.20 (1H, m), 3.10 (1H, br), 2.88 (1H, t), 2.21 (1H, m), 1.77 (2H, m), 1.61 (1H, m), 1.47 (9H, s).

Example 105

5-ethyl-2-{3-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine

Step 1 : 3-[4-(4-Teazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine

3-[4-(4-Tetrend-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.13 mmol) A solution of dichloromethane (10 mL) in methanol (2 mL) was taken in 4 mL EtOAc EtOAc. The resulting solution was stirred at room temperature for 30 minutes. Remove the solution in a vacuum The desired product is the HCl salt.

Step 2 : 5-Ethyl-2-{3-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine

3-[4-(4-Teazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine hydrochloride (150 mg, 0.407 mmol), 2-chloro pyrimidine (0.074 ml, 2.0 equiv.) and NaHCO ₃ (171 mg, 2.03 mmol) was heated in a mixture (5 ml) of DMF at 90 ℃ 4 hours. Water was added and the solution was extracted with ethyl acetate, separated, dried over sodium sulfate, filtered and concentrated. The residue was purified on EtOAc (EtOAc:EtOAc) ¹ H NMR (CDCl ₃ ): δ 8.91 (1H, s), 8.19 (2H, s), 7.63 (2H, m), 7.26 (1H, s), 7.17 (2H, m), 5.25 (2H, s) , 4.97 (1H, m), 4.62 (1H, m), 3.25 (2H, m), 3.07 (1H, m), 2.46 (2H, q), 2.28 (1H, m), 1.88 (2H, m), 1.68 (1H, m), 1.20 (3H, t).

Example 106

4-[4-(4-methanesulfonyl-benzyloxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

The hydroxybenzyl-4-methylindole (1.7 eq.) was dissolved in dry DMF (10 mL). The reaction was stirred at 0 °C for 30 minutes and at room temperature for a further 30 minutes. 4-(4-Chloromethyl-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester ( Intermediate 1 ) (0.632 mmol) was added and the mixture was stirred overnight. The reaction was quenched with EtOAc (EtOAc)EtOAc. The residue was purified by EtOAc (EtOAc/EtOAc) ¹ H NMR (CDCl ₃ ): δ 7.92 (2H, d, J = 8.8 Hz), 7.57 (2H, d, J = 8.8 Hz), 7.14 (1H, s), 4.71 (2H, s), 4.66 (2H , s), 4.19 (2H, m), 3.13 (1H, m), 3.05 (3H, s), 2.86 (2H, m), 2.09 (2H, m), 1.72 (2H, m), 1.45 (9H, s).

Example 107

2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidin-5-ylamine

Making 5-nitro-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine ( example 192 ) (1.07 mmol), ammonium chloride (3 equivalents) and iron powder (3 equivalents) were suspended in EtOH: THF: H ₂ O (40: 20: 10) and heated at 100 ° C for 5 hours. The hot reaction mixture was filtered through a pad of celite and concentrated. The oil formed was dissolved in DMF and water and extracted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The resulting filtrate was concentrated under reduced pressure. Purification using silica gel chromatography (DCM / MeOH 98:2) afforded the desired product. ¹ H NMR (DMSO-d ₆ ): δ 9.96 (1H, s), 7.97 (2H, m), 7.90 (2H, m), 7.63 (1H, s), 5.19 (2H, s), 4.44 (2H, m), 3.73 (1H, m), 2.97 (2H, m), 2.20 (2H, m), 1.95 (2H, m).

Example 108

N-(2-{4-[4-(4-Tetrazolyl-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidin-5-yl) -Acetamine

2-{4-[4-(4-Tetrazolyl-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl)-pyrimidin-5-ylamine ( example 107 ) (0.321 mmol) was dissolved in DCM and triethylamine (2 eq.) was added. The reaction was cooled to 0&lt;0&gt;C, EtOAc (1 EtOAc) Water was added, and the mixture was extracted with ethyl acetate, dried over sodium sulfate, filtered, and evaporated. The oil formed by gel chromatography (DCM/MeOH) provided the desired product. ¹ H NMR (CDCl ₃ ): δ 8.84 (1H, s), 8.36 (2H, s), 7.55 (2H, m), 7.19 (1H, s), 7.11 (2H, m), 6.94 (1H, s) , 5.16 (2H, s), 4.77 (2H, m), 3.25 (1H, m), 3.01 (2H, m), 2.16 (2H, m), 2.15 (3H, s), 1.75 (2H, m).

Example 109

4-[4-(4-tetrazol-1-yl-anilinomethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

4-(4-Carboxy-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.28 mmol) was dissolved in anhydrous DMF (20 mL). Add triethylamine (4 equivalents) to O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyltetrafluoroborate to this solution. (TBTU) (1.5 equivalents). The reaction was stirred at room temperature for 5 minutes and then 4-tetrazol-1-yl-phenylamine (1.2 eq.) was added. The reaction was stirred with EtOAc (EtOAc)EtOAc. The organic filtrate was concentrated in vacuo and EtOAcqqqqqqq ¹ H NMR (CDCl ₃ ): δ 9.37 (1H, s), 9.02 (1H, s), 8.14 (1H, s), 7.96 (2H, d), 7.72 (2H, d), 4.23 (2H, m) , 3.20 (1H, m), 2.91 (2H, m), 2.14 (2H, m), 1.79 (2H, m), 1.45 (9H, s).

Example 110

3-[4-(4-Trifluoromethanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

[4-(4-Trifluoromethanethio-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester ( Example 134 ) (1.12 mmol) 3-Chloro-phenylcarbon peroxyacid (2 equivalents) was added to a solution in DCM (20 mL) at room temperature. The reaction was stirred for 1.5 hours and another portion of 3-chloro-phenylcarbon peroxyacid (1 eq.) was added to the mixture. The reaction was stirred at room temperature for a further 4 hours. The organic solution was washed with sodium bicarbonate, the organic layer was separated, dried over sodium sulfate and filtered. The filtrate was concentrated and the crude product was purified by column chromatography to yield two desired hydr.碸: ¹ H NMR (DMSO-d ₆ ): δ 8.05 (2H, d, J = 8.6 Hz), 7.70 (1H, s), 7.44 (2H, d, J = 8.6 Hz), 5.32 (2H, s) , 3.98 (2H, m), 3.19 (1H, m), 2.86 (2H, m), 2.02 (2H, m), 1.56 (2H, m), 1.38 (9H, s).

Example 111

3-[4-(4-Trifluoromethanesulfinyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

This compound was isolated from the reaction mixture of the foregoing examples. ¹ H NMR (DMSO-d ₆ ): δ 8.02 (2H, d, J = 8.6 Hz), 7.75 (1H, s), 7.32 (2H, d, J = 8.6 Hz), 5.31 (2H, s), 3.96 (2H, m), 3.20 (1H, m), 2.85 (2H, m), 2.02 (2H, m), 1.50 (2H, m), 1.38 (9H, s).

Examples 112-145 are in a similar manner to that described in Example 1 , from 4-(4-chloromethyl-thiazol-2-yl)-hexahydropyridine-1-carboxylic acid tert-butyl ester ( Intermediate 1 , 2-[4-(4-Chloromethyl-thiazol-2-yl)-hexahydropyridin-1-yl]-5-ethyl-pyrimidine ( Intermediate 2 ) or 4-(4-Chloryl) methyl- Zyridin-2-yl)-hexahydropyridine-1-carboxylic acid tert-butyl ester ( intermediate 14 ), synthesized with the corresponding phenol, thiophenol, amine or aniline. Those skilled in the art of organic synthesis will understand that certain conditions, such as solvents (such as DMF, CH ₃ CN); temperature, alkali (such as NEt ₃ , K ₂ CO ₃ , NaHCO ₃ , Na ₂ CO ₃ , Cs ₂ CO ₃ ) And the concentration can be selected through routine experimentation to optimize the yield. In addition, alternative coupling methods as are known in the art of organic synthesis can be used.

Example 112

4-[4-(2,6-difluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

¹ H NMR (CDCl ₃ ): δ 8.98 (1H, s), 7.34 (2H, m), 7.30 (1H, s), 5.36 (2H, s), 4.19 (2H, m), 3.15 (1H, m) , 2.87 (2H, m), 2.07 (2H, m), 1.70 (2H, m), 1.47 (9H, s).

Example 113

3-[4-(4-pyrrol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

¹ H NMR (CDCl ₃ ): δ 7.24 (3H, m), 7.01 (4H, m), 6.31 (2H, m), 5.17 (2H, s), 4.21 (2H, m), 3.14 (1H, m) , 2.87 (2H, m), 2.01 (2H, m), 1.74 (2H, m), 1.47 (9H, s).

Example 114

4-{4-[(4-tetrazol-1-yl-phenylamino)-methyl]-thiazol-2-yl}-piperidine-1-carboxylic acid tert-butyl ester

¹ H NMR (CDCl ₃ ): δ 8.85 (1H, s), 7.40 (2H, m), 7.01 (1H, s), 6.72 (2H, m), 4.76 (1H, s), 4.44 (2H, s) , 4.15 (2H, m), 3.08 (1H, m), 2.83 (2H, m), 2.04 (2H, m), 1.66 (2H, m), 1.43 (9H, s).

Example 115

2-{4-[4-(3-Chloro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-5-ethyl -pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.93 (1H, s), 8.18 (2H, s), 7.48 (1H, m), 7.25 (1H, s), 7.08 (2H, m), 5.22 (2H, s) , 4.82 (2H, m), 3.29 (1H, m), 3.04 (2H, m), 2.46 (2H, q), 2.21 (2H, m), 1.80 (2H, m), 1.18 (3H, t).

Example 116

N-(4-{2-[1-(5-ethyl-pyrimidin-2-yl)-hexahydropyridin-4-yl]-thiazol-4-ylmethoxy}-phenyl)-carboxamide

¹ H NMR (CDCl ₃ ): δ 8.55-8.30 (1H, m), 8.18 (2H, s), 7.50-6.90 (6H, m), 5.14 (2H, s), 4.83 (2H, m), 3.29 ( 1H, m), 3.03 (2H, m), 2.46 (2H, q), 2.20 (2H, m), 1.80 (2H, m), 1.19 (3H, t).

Example 117

N-(4-{2-[1-(5-ethyl-pyrimidin-2-yl)-hexahydropyridin-4-yl]-thiazol-4-ylmethoxy}-phenyl)-methanesulfonate amine

¹ H NMR (CDCl ₃ ): δ 8.20 (s, 2H), 7.21 (m, 3H), 6.95 (m, 2H), 5.13 (s, 2H), 4.81 (m, 2H), 3.29 (m, 1H) , 3.06 (m, 2H), 2.94 (s, 3H), 2.47 (q, 2H), 2.20 (m, 2H), 1.81 (m, 2H), 1.19 (t, 3H).

Example 118

4-[4-(2-methyl-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

¹ H NMR (CDCl ₃ ): δ 8.89 (1H, s), 7.48 (1H, s), 7.43 (1H, m), 7.25 (1H, m), 7.05 (1H, m), 5.27 (2H, s) , 4.27 (2H, m), 3.18 (1H, m), 2.89 (2H, m), 2.37 (3H, s), 2.21 (2H, m), 1.74 (2H, m), 1.47 (9H, s).

Example 119

5-ethyl-2-{4-[4-(4-tetrazol-1-yl-2-trifluoromethyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine-1- Pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.97 (1H, s), 8.18 (2H, s), 7.92 (1H, m), 7.84 (1H, m), 7.33 (1H, m), 7.26 (1H, s) , 5.38 (2H, s), 4.81 (2H, m), 3.27 (1H, m), 3.05 (2H, m), 2.46 (2H, q), 2.19 (2H, m), 1.79 (2H, m), 1.19 (3H, t).

Example 120

2-{4-[4-(2-Chloro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-5-ethyl -pyrimidine

¹ H NMR (acetone-d ₆ ) δ 9.68 (1H, s), 8.24 (2H, s), 8.01 (1H, s), 7.86 (1H, m), 7.60 (1H, m), 7.59 (1H, s ), 5.40 (2H, s), 4.82 (2H, m), 3.36 (1H, m), 3.08 (2H, m), 2.48 (2H, q), 2.17 (2H, m), 1.75 (2H, m) , 1.18 (3H, t).

Example 121

4-[4-(4-tetrazol-1-yl-phenoxymethyl)- Zin-2-yl]-hexahydropyridine-1-carboxylic acid tert-butyl ester

¹ H NMR (CDCl ₃ ): δ 8.94 (1H, s), 7.65 (1H, s), 7.60 (2H, m), 7.13 (2H, m), 5.01 (2H, s), 4.08 (2H, m) , 2.94 (3H, m), 2.03 (2H, m), 1.75 (2H, m), 1.43 (9H, s).

Example 122

4-[4-(2-Fluoro-4-tetrazol-1-yl-phenoxymethyl)- Zin-2-yl]-hexahydropyridine-1-carboxylic acid tert-butyl ester

¹ H NMR (CDCl ₃ ): δ 8.88 (1H, s), 7.62 (1H, s), 7.45 (1H, m), 7.36 (1H, m), 7.23 (1H, m), 5.05 (2H, s) , 4.04 (2H, m), 2.85 (3H, m), 1.97 (2H, m), 1.71 (2H, m), 1.40 (9H, s).

Example 123

5-ethyl-2-{4-[4-(4-methanesulfonyl-phenoxymethyl)- Zin-2-yl]-hexahydropyridin-1-yl}-pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.16 (2H, s), 7.84 (2H, m), 7.63 (1H, s), 7.08 (2H, m), 5.02 (2H, s), 4.67 (2H, m) , 3.08 (3H, m), 3.01 (3H, s), 2.44 (2H, q), 2.12 (2H, m), 1.84 (2H, m), 1.17 (3H, t).

Example 124

4-[4-(2,6-difluoro-4-propenyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

¹ H NMR (CDCl ₃ ): δ 7.51 (2H, d), 7.27 (1H, s), 5.37 (2H, s), 4.18 (2H, m), 3.14 (1H, m), 2.92 (2H, q, J=7.4 Hz), 2.88 (2H, m), 2.07 (2H, m), 1.71 (2H, m), 1.47 (9H, s), 1.21 (3H, t, J=7.4 Hz).

Example 125

4-[4-(4-Ethyl-2-fluoro-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

¹ H NMR (CDCl ₃ ): δ 7.70~7.72 (2H, m), 7.28 (1H, s), 7.09~7.13 (1H, m), 5.30 (2H, s), 4.20 (2H, m), 3.17 ( 1H, m), 2.88 (2H, m), 2.55 (3H, s), 2.10 (2H, m), 1.72 (2H, m), 1.47 (9H, s).

Example 126

4-[4-(4-cyano-2-fluoro-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

¹ H NMR (CDCl ₃ ): δ 7.37~7.42 (2H, m), 7.27 (1H, s), 7.13~7.17 (1H, m), 5.28 (2H, s), 4.20 (2H, m), 3.15 ( 1H, m), 2.89 (2H, m), 2.09 (2H, m), 1.72 (2H, m), 1.47 (9H, s).

Example 127

4-[4-(6-tetrazol-1-yl-pyridin-3-yloxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

¹ H NMR (CDCl ₃ ): δ 9.41 (1H, s), 8.27 (1H, d), 8.01 (1H, d), 7.58 (1H, dd), 7.28 (1H, s), 5.27 (2H, s) , 4.20 (2H, m), 3.14-3.20 (1H, m), 2.87 (2H, m), 2.09-2.12 (2H, m), 1.68-1.78 (2H, m), 1.46 (9H, s)

Example 128

4-[4-(4-[1,2,3]triazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

¹ H NMR (CDCl ₃ ): δ 7.92 (1H, s), 7.84 (1H, s), 7.65 (2H, d), 7.25 (1H, s), 7.11 (2H, d), 5.22 (2H, s) , 4.21 (2H, br), 3.18 (1H, m), 2.88 (2H, br), 2.12 (2H, m), 1.75 (2H, m), 1.47 (9H, s).

Example 129

4-[4-(4-ethoxycarbonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

¹ H NMR (CDCl ₃ ): δ 8.01 (2H, d), 7.23 (1H, s), 7.01 (2H, d), 5.22 (2H, s), 4.36 (2H, q), 4.22 (2H, br) , 3.17 (1H, m), 2.87 (2H, br), 2.12 (2H, m), 1.75 (2H, m), 1.47 (9H, s), 1.39 (2H, t).

Example 130

4-[4-(4-Terti-butoxycarbonylamino-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

¹ H NMR (CDCl ₃ ): δ 7.28 (2H, d), 7.19 (1H, s), 6.92 (2H, d), 6.40 (1H, s), 5.12 (2H, s), 4.22 (2H, br) , 3.17 (1H, m), 2.87 (2H, br), 2.12 (2H, m), 1.75 (2H, m), 1.50 (9H, s), 1.47 (9H, s).

Example 131

4-[4-(4-carboxy-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

¹ H NMR (DMSO-d ₆ ): δ 7.86 (2H, d), 7.64 (1H, s), 7.10 (2H, d), 5.17 (2H, s), 3.96 (2H, m), 3.18 (1H, m), 2.87 (2H, br), 1.96 (2H, m), 1.49 (2H, m), 1.38 (9H, s).

Example 132

4-[4-(2,6-difluoro-4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

¹ H NMR (CDCl ₃ ): δ 7.42 (2H, d), 7.21 (1H, s), 5.25 (2H, s), 4.12 (2H, br), 3.17 (1H, m), 3.00 (3H, s) , 2.87 (2H, br), 1.98 (2H, m), 1.71 (2H, m).

Example 133

4-[4-(4-Mofolin-4-yl-phenoxymethyl)-thiazole 2-yl]-hexahydropyridine-1-carboxylic acid tert-butyl ester

¹ H NMR (CDCl ₃ ): δ 7.19 (1H, s), 6.92 (4H, m), 5.12 (2H, s), 4.20 (2H, br), 3.85 (4H, br), 3.16 (1H, m) , 3.07 (4H, m), 2.86 (2H, m), 2.10 (2H, m), 1.72 (2H, m), 1.47 (9H, s).

Example 134

3-[4-(4-Trifluoromethylthio-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

¹ H NMR (DMSO-d ₆ ): δ 7.64 (1H, s), 7.63 (2H, d, J = 8.6 Hz), 7.17 (2H, d, J = 8.6 Hz), 5.17 (2H, s), 3.99 (2H, m), 3.18 (1H, m), 2.83 (2H, m), 2.01 (2H, m), 1.52 (2H, m), 1.38 (9H, s).

Example 135

4-[4-(4-benzyloxy-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

¹ H NMR (DMSO-d ₆ ): δ 7.55 (1H, s), 7.41 (5H, m), 6.92 (4H, m), 5.12 (4H, s), 3.98 (2H, m), 3.20 (1H, m), 2.84 (2H, m), 2.01 (2H, m), 1.52 (2H, m), 1.38 (9H, s).

Example 136

4-[4-(2-Ethylamino-4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

¹ H NMR (CDCl ₃ ): δ 8.81 (1H, s), 7.97 (1H, s), 7.53 (1H, d), 7.25 (1H, s), 7.09 (1H, d), 5.24 (2H, s) , 4.16 (2H, m), 3.10 (3H, m), 2.83 (2H, m), 2.16 (3H, s), 2.04 (2H, d), 1.66 (2H, m), 1.40 (9H, s), 1.19 (3H, t).

Example 137

4-(4-phenoxymethyl-thiazol-2-yl)-hexahydropyridine-1-carboxylic acid tert-butyl ester

¹ H NMR (CDCl ₃ ): δ 7.28 (2H, m), 7.19 (1H, s), 6.93 (3H, m), 5.14 (2H, s), 4.19 (2H, s), 3.15 (1H, m) , 2.85 (2H, m), 2.07 (2H, d), 1.67 (2H, m), 1.45 (9H, s).

Example 138

4-{4-[(4-methanesulfonyl-phenylamino)-methyl]-thiazol-2-yl}-piperidine-1-carboxylic acid tert-butyl ester

¹ H NMR (CDCl ₃ ): δ 7.67 (2H, d, J = 8.8 Hz), 6.99 (1H, s), 6.67 (2H, d, J = 8.8 Hz), 5.07 (1H, m), 4.45 (2H , d), 4.18 (2H, s), 3.13 (1H, m), 2.97 (3H, s), 2.85 (2H, m), 2.04 (2H, d), 1.68 (2H, m), 1.44 (9H, s).

Example 139

4-{4-[(2-Fluoro-4-methanesulfonyl-phenylamino)-methyl]-thiazol-2-yl}-piperidine-1-carboxylic acid isopropyl ester

¹ H NMR (CDCl ₃ ): δ 7.55 (2H, m), 7.05 (1H, s), 6.76 (1H, m), 5.12 (1H, m), 4.52 (2H, d), 4.19 (2H, m) , 3.13 (1H, m), 3.05 (3H, s), 2.86 (2H, m), 2.10 (2H, m), 1.76 (2H, m), 1.46 (9H, s).

Example 140

4-[4-(4-bromo-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

¹ H NMR (CDCl ₃ ): δ 7.36 (2H, m), 7.17 (1H, s), 6.82 (2H, m), 5.10 (2H, s), 4.18 (2H, s), 3.13 (1H, m) , 2.85 (2H, m), 2.09 (2H, d), 1.75 (2H, m), 1.43 (9H, s).

Example 141

{2-[1-(5-Ethyl-pyrimidin-2-yl)-hexahydropyridin-4-yl]-thiazol-4-ylmethyl}-(2-fluoro-4-methanesulfonyl- Phenyl)-amine

¹ H NMR (CDCl ₃ ): δ 8.16 (2H, s), 7.52 (2H, m), 7.01 (1H, s), 6.74 (1H, m), 5.15 (1H, m), 4.83 (2H, m) , 4.51 (2H, d), 3.26 (1H, m), 3.02 (5H, m), 2.46 (2H, m), 2.19 (2H, m), 1.78 (2H, m), 1.19 (3H, t).

Example 142

4-{4-[(4-methanesulfonyl-benzylamino)-methyl]-thiazol-2-yl}-piperidine-1-carboxylic acid tert-butyl ester

¹ H NMR (CDCl ₃ ): δ 7.85 (2H, d, J = 8.8 Hz), 7.53 (2H, d, J = 8.8 Hz), 6.95 (1H, s), 4.14 (2H, s), 3.87 (2H , s), 3.83 (2H, s), 3.11 (1H, m), 3.04 (3H, s), 2.86 (2H, m), 2.07 (3H, m), 1.67 (2H, m), 1.42 (9H, s).

Example 143

4-(4-{[1-(4-methanesulfonyl-phenyl)-ethylamino]-methyl}-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester

¹ H NMR (CDCl ₃ ): δ 7.87 (2H, d, J = 8.8 Hz), 7.56 (2H, d, J = 8.8 Hz), 6.87 (1H, s), 4.22 (2H, m), 3.90 (1H , s), 3.66 (2H, m), 3.09 (1H, m), 3.04 (3H, s), 2.82 (3H, m), 2.02 (2H, m), 1.71 (2H, m), 1.40 (9H, s), 1.29 (3H, d).

Example 144

3-methyl-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

¹ H NMR (CDCl ₃ ): δ 8.93 (1H, s), 7.61 (2H, m), 7.25 (1H, m), 7.12 (2H, m), 5.22 (2H, m), 4.2 (1H, m) , 3.95 (1H, m), 3.33 (1H, m), 3.13 (1H, m), 2.8 (1H, m), 2.34 (1H, m), 2.04 (1H, m), 1.89 (1H, m), 1.45 (9H, s), 0.85 (3H, m).

Example 145

4-[4-(2-Fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-3-methyl-hexahydropyridine-1-carboxylic acid third- Butyl ester

¹ H NMR (CDCl ₃ ): δ 9.07 (1H, s), 7.51 (1H, m), 7.41 (1H, m), 7.23 (2H, m), 5.25 (2H, s), 4.16 (1H, m) , 3.88 (1H, m), 3.34 (1H, m), 3.09 (1H, m), 2.8 (1H, m), 2.26 (1H, m), 1.96 (1H, m), 1.83 (1H, m), 1.39 (9H, s), 0.76 (3H, m).

Examples 146-157 are in the same manner as described in Example 22 , from one of intermediates 3-13 or intermediates 15-25 , with the corresponding sulfonium chloride, alkyl chloride, alkyl bromide, chloroformic acid. Synthesis of esters, ruthenium chloride, amine guanidine or isocyanate. Those skilled in the art of organic synthesis will be aware of conditions such as solvents (eg DMF, CH ₃ CN); temperatures, bases (eg NEt ₃ , K ₂ CO ₃ , NaHCO ₃ , Na ₂ CO ₃ , Cs ₂ CO ₃ ) And the concentration can be selected through routine experimentation to optimize the yield. In addition, alternative coupling methods as are known in the art of organic synthesis can be used.

Example 146

4-[4-(2-Fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid allyl ester

¹ H NMR (CDCl ₃ ), δ 9.00 (1H, s), 7.54 (1H, m), 7.45 (1H, m), 7.29 (2H, m), 5.95 (1H, m), 5.30 (3H, m) , 5.22 (1H, m), 4.61 (2H, m), 4.28 (2H, m), 3.20 (1H, m), 2.98 (2H, m), 2.14 (2H, m), 1.78 (2H, m).

Example 147

4-[4-(4-Tetrazolyl-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid cyclohexyl ester

¹ H NMR (CDCl ₃ ): δ 8.91 (1H, s), 7.60 (2H, m), 7.25 (1H, s), 7.16 (2H, m), 5.22 (2H, s), 4.68 (1H, m) , 4.36 (2H, m), 3.19 (1H, m), 2.91 (2H, m), 2.12 (2H, m), 1.88 (6H, m), 1.40 (6H, m).

Example 148

4-[4-(2-Fluoro-4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid isopropyl ester

¹ H NMR (CDCl ₃ ): δ 7.64~7.70 (2H, m), 7.20~7.26 (2H, m), 5.29 (2H, s), 4.89~4.95 (1H, m), 4.24 (2H, m), 3.13~3.19 (1H, m), 3.03 (3H, s), 2.86~2.93 (2H, m), 2.11 (2H, m), 1.69~1.78 (2H, m), 1.23 (6H, d, J=6.4 Hz).

Example 149

1-isopropyl-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine

¹ H NMR (DMSO-d ₆ ): δ 9.98 (1H, s), 7.79 (2H, d, J = 8.8 Hz), 7.63 (1H, s), 7.28 (2H, d, J = 8.8 Hz), 5.19 (2H, s), 2.91 (1H, m), 2.82 (2H, m), 2.68 (1H, m), 2.20 (2H, m), 2.01 (2H, m), 1.63 (2H, m), 0.94 ( 6H, d, J = 6.4 Hz).

Example 150

1-propyl-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine

¹ H NMR (DMSO-d ₆ ): δ 9.97 (1H, s), 7.80 (2H, d, J = 8.8 Hz), 7.64 (1H, s), 7.28 (2H, d, J = 8.8 Hz), 5.20 (2H, s), 2.94 (1H, m). 2.88 (2H, m), 2.22 (2H, t, J=7.2 Hz), 1.99 (4H, m), 1.64 (2H, m), 1.41 (2H, m), 0.83 (3H, t, J = 7.2 Hz).

Example 151

3,3-Dimethyl-1-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-butyl 2-ketone

¹ H NMR (DMSO-d ₆ ): δ 9.98 (1H, s), 7.80 (2H, d, J = 8.8 Hz), 7.64 (1H, s), 7.28 (2H, d, J = 8.8 Hz), 5.20 (2H, s), 3.41 (2H, s), 2.95 (1H, m), 2.82 (2H, m), 2.18 (2H, m), 1.98 (2H, m), 1.69 (2H, m), 1.07 ( 9H, s).

Example 152

1-butyl-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine

¹ H NMR (DMSO-d ₆ ): δ 9.97 (1H, s), 7.80 (2H, d, J = 8.8 Hz), 7.64 (1H, s), 7.28 (2H, d, J = 8.8 Hz), 5.20 (2H, s), 2.94 (1H, m), 2.88 (2H, m), 2.26 (2H, t, J=6.8 Hz), 1.98 (4H, m), 1.66 (2H, m), 1.39 (2H, m), 1.26 (2H, m), 0.86 (3H, t, J=7.2 Hz).

Example 153

2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-1-(4-trifluoromethoxy Base-phenyl)-ethanone

¹ H NMR (DMSO-d ₆ ): δ 9.97 (1H, s), 8.14 (2H, d, J = 6.4 Hz), 8.02 (2H, d, J = 6.4 Hz), 7.80 (2H, d, J= 8.8 Hz), 7.64 (1H, s), 7.28 (2H, d, J=8.8 Hz), 5.20 (2H, s), 3.84 (2H, s), 2.98 (1H, m), 2.93 (2H, m) , 2.38 (2H, m), 2.00 (2H, m), 1.68 (2H, m).

Example 154

1-methanesulfonyl-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine

¹ H NMR (DMSO-d ₆ ): δ 9.98 (1H, s), 7.81 (2H, d, J = 8.8 Hz), 7.69 (1H, s), 7.29 (2H, d, J = 8.8 Hz), 5.21 (2H, s), 3.60-3.63 (2H, m), 3.32 (3H, s), 3.12-3.18 (1H, m), 2.83-2.90 (2H, m), 2.14-2.17 (2H, m), 1.71 (2H, m).

Example 155

4-[4-(4-Tetrend-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine-1-carboxylic acid heptyl ester

¹ H NMR (CDCl ₃ ): δ 8.91 (1H, s), 7.60 (2H, d), 7.25 (1H, s), 7.19 (2H, d), 5.24 (2H, s), 4.26 (2H, br) , 4.09 (2H, t), 3.20 (1H, m), 2.94 (2H, m), 2.16 (2H, m), 1.77 (2H, m), 1.60 (2H, m), 1.32 (8H, m), 0.90 (3H, t).

Example 156

4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-1-(toluene-4-sulfonyl)-hexahydropyridine

¹ H NMR (CDCl ₃ ): δ 8.91 (1H, s), 7.67 (2H, d, J = 8.8 Hz), 7.59 (2H, d, J = 8.8 Hz), 7.35 (2H, d, J = 8.8 Hz ), 7.25 (1H, s), 7.15 (2H, m), 5.19 (2H, s), 3.91 (2H, d), 2.95 (1H, m), 2.44 (3H, s), 2.37 (2H, m) , 2.17 (2H, d), 1.94 (2H, m).

Example 157

2-Terti-butoxy-1-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}- Ethyl ketone

¹ H NMR (DMSO-d ₆ ): δ 9.99 (1H, s), 7.81 (2H, m), 7.26 (2H, m), 5.20 (2H, s), 4.36 (1H, m), 3.97 (3H, m), 3.28 (1H, m), 3.12 (1H, m), 2.71 (1H, m), 2.04 (2H, m), 1.67 (1H, m), 1.46 (1H, m), 1.13 (9H, s ).

Examples 158-205 are in a similar manner to that described in Example 47 , from intermediates 3-13 or one of the intermediates 15-25 , and the corresponding 2-chloropyrimidine, 2-iodopyrimidine, 2-chloropyridine. , 2-fluoropyridine, 2-methanesulfonyl-pyrimidine, 2-chloropyridyl 2-chloroguanidine Or other suitable heterocyclic synthesis. Those skilled in the art of organic synthesis will understand that certain conditions, such as solvents (such as DMF, CH ₃ CN); temperature, alkali (such as NEt ₃ , K ₂ CO ₃ , NaHCO ₃ , Na ₂ CO ₃ , Cs ₂ CO ₃ ) And the concentration can be selected through routine experimentation to optimize the yield. In addition, alternative coupling methods as are known in the art of organic synthesis can be used.

Example 158

5-ethyl-2-{4-[4-(3-fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl} -pyrimidine

¹ H NMR (CDCl ₃ ): δ 9.04 (1H, s), 8.19 (2H, s), 7.78 (1H, m), 7.28 (1H, s), 6.70 (2H, m), 5.23 (2H, s) , 4.83 (2H, m), 3.31 (1H, m), 3.05 (2H, m), 2.47 (2H, q), 2.21 (2H, m), 1.81 (2H, m), 1.20 (3H, t).

Example 159

2-{4-[4-(2,6-Difluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-5- Ethyl-pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.95 (1H, s), 8.17 (2H, s), 7.34 (2H, m), 7.28 (1H, s), 5.35 (2H, s), 4.76 (2H, m) , 3.27 (1H, m), 3.04 (2H, m), 2.46 (2H, q), 2.16 (2H, m), 1.76 (2H, m), 1.19 (3H, t).

Example 160

5-ethyl-2-{4-[4-(4-pyrrol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.18 (2H, s), 7.29 (2H, m), 7.20 (1H, s), 6.99 (4H, m), 6.31 (2H, m), 5.17 (2H, s) , 4.84 (2H, m), 3.28 (1H, m), 3.03 (2H, m), 2.46 (2H, q), 2.21 (2H, m), 1.81 (2H, m), 1.19 (3H, t).

Example 161

{2-[1-(5-Ethyl-pyrimidin-2-yl)-hexahydropyridin-4-yl]-thiazol-4-ylmethyl}-(4-tetrazol-1-yl-phenyl) -amine

¹ H NMR (CDCl ₃ ): δ 8.83 (1H, s), 8.16 (2H, s), 7.41 (2H, m), 7.02 (1H, s), 6.74 (2H, m), 4.82 (1H, s) , 4.79 (2H, s), 4.45 (2H, m), 3.25 (1H, m), 3.01 (2H, m), 2.44 (2H, q), 2.17 (2H, m), 1.77 (2H, m), 1.11 (3H, t).

Example 162

2-{4-[4-(2-Fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-5-isopropyl Base-pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.92 (1H, s), 8.21 (2H, s), 7.51 (1H, m), 7.40 (1H, m), 7.29 (1H, s), 7.26 (1H, m) , 5.30 (2H, m), 3.28 (1H, m), 3.04 (2H, m), 2.77 (1H, m), 2.20 (2H, m), 1.80 (2H, m), 1.23 (6H, d).

Example 163

¹ H NMR (CDCl ₃ ): δ 8.97 (1H, s), 7.80 (1H, s), 7.50 (1H, m), 7.40 (1H, m), 7.27 (1H, s), 7.24 (1H, m) , 5.27 (2H, s), 4.42 (4H, m), 3.24 (1H, m), 3.04 (9H, m), 2.16 (2H, m), 1.88 (2H, m).

Example 164

5-ethyl-2-{4-[4-(2-methyl-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl} -pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.88 (1H, s), 8.19 (2H, s), 7.48 (1H, s), 7.44 (1H, m), 7.24 (1H, m), 7.05 (1H, m) , 5.26 (2H, s), 4.83 (2H, m), 3.27 (1H, m), 3.05 (2H, m), 2.47 (2H, q), 2.37 (3H, s), 2.22 (2H, m), 1.81 (2H, m), 1.19 (3H, t).

Example 165

5-Chloro-2-{4-[4-(2-chloro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl} -pyrimidine

¹ H NMR (acetone-d ₆ ), δ 9.68 (1H, s), 8.33 (2H, s), 8.01 (1H, s), 7.86 (1H, m), 7.60 (1H, m), 7.59 (1H, s), 5.40 (2H, s), 4.78 (2H, m), 3.40 (1H, m), 3.16 (2H, m), 2.20 (2H, m), 1.77 (2H, m).

Example 166

2-{4-[4-(2-Chloro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-5-trifluoro Methyl-pyrimidine

¹ H NMR (acetone-d ₆ ), δ 9.68 (1H, s), 8.62 (2H, s), 8.01 (1H, s), 7.86 (1H, m), 7.61 (1H, s), 7.60 (1H, m), 5.41 (2H, s), 4.92 (2H, m), 3.46 (1H, m), 3.27 (2H, m), 2.25 (2H, m), 1.80 (2H, m).

Example 167

2-{4-[4-(2-isopropyl-5-methyl-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl }-5-trifluoromethyl-pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.73 (1H, s), 8.46 (2H, s), 7.22 (1H, s), 7.10 (1H, s), 6.90 (1H, s), 5.24 (2H, s) , 4.93 (2H, m), 3.35 (2H, m), 3.17 (2H, m), 2.23 (2H, m), 2.09 (3H, s), 1.82 (2H, m), 1.20 (6H, d).

Example 168

5-Chloro-2-{4-[4-(2-isopropyl-5-methyl-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydro Pyridin-1-yl}-pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.73 (1H, s), 8.20 (2H, s), 7.21 (1H, s), 7.09 (1H, s), 6.90 (1H, s), 5.24 (2H, s) , 4.78 (2H, m), 3.35 (1H, m), 3.28 (1H, m), 3.07 (2H, m), 2.19 (2H, m), 2.09 (3H, s), 1.79 (2H, m), 1.20 (6H, d).

Example 169

5-ethyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)- Zin-2-yl]-hexahydropyridin-1-yl}-pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.91 (1H, s), 8.18 (2H, s), 7.65 (1H, s), 7.60 (2H, m), 7.15 (2H, m), 5.03 (2H, s) , 4.69 (2H, m), 3.10 (3H, m), 2.44 (2H, q), 2.14 (2H, m), 1.86 (2H, m), 1.19 (3H, t).

Example 170

5-ethyl-2-{4-[4-(2-fluoro-4-tetrazol-1-yl-phenoxymethyl)- Zin-2-yl]-hexahydropyridin-1-yl}-pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.93 (1H, s), 8.17 (2H, s), 7.67 (1H, s), 7.50 (1H, m), 7.41 (1H, m), 7.29 (1H, m) , 5.11 (2H, s), 4.67 (2H, m), 3.08 (3H, m), 2.45 (2H, q), 2.12 (2H, m), 1.84 (2H, m), 1.18 (3H, t).

Example 171

2-{4-[4-(2-Fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-5-trifluoro Methyl-pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.91 (1H, s), 8.49 (2H, s), 7.52 (1H, d, J = 7.6 Hz), 7.41 (1H, d, J = 7.6 Hz), 7.32 (1H , s), 7.29 (1H, m), 5.32 (2H, s), 4.95 (2H, m), 3.37 (1H, m), 3.15 (2H, m), 2.24 (2H, m), 1.81 (2H, m).

Example 172

5-mercapto-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine

¹ H NMR (DMSO-d ₆ ): δ 9.97 (1H, s), 8.21 (2H, s), 7.80 (2H, d, J = 8.8 Hz), 7.65 (1H, s), 7.28 (2H, d, J=8.8 Hz), 5.20 (2H, s), 4.66 (2H, m), 3.32 (1H, m), 3.01 (2H, m), 2.37 (2H, m), 2.09 (2H, m), 1.60 ( 2H, m), 1.45 (2H, m), 1.21 (14H, m), 0.82 (3H, m).

Example 173

6-Methyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine-4- Methyl carboxylate

¹ H NMR (DMSO-d ₆ ): δ 9.97 (1H, s), 7.80 (2H, d, J = 8.8 Hz), 7.66 (1H, s), 7.28 (2H, d, J = 8.8 Hz), 7.01 (1H, s), 5.21 (2H, s), 4.76 (2H, m), 3.84 (3H, s), 3.33 (1H, m), 3.06 (2H, m), 2.36 (3H, s), 2.14 ( 2H, m), 1.61 (2H, m).

Example 174

4-Chloro-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.91 (1H, s), 8.15 (1H, d, J = 5.2 Hz), 7.60 (2H, d, J = 8.8 Hz), 7.25 (1H, s), 7.16 (2H , d, J=8.8 Hz), 6.49 (1H, d, J=5.2 Hz), 5.22 (2H, s), 4.85 (2H, m), 3.30 (1H, m), 3.07 (2H, m), 2.21 (2H, m), 1.80 (2H, m).

Example 175

2-Chloro-4-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.90 (1H, s), 8.05 (1H, d, J = 6.4 Hz), 7.61 (2H, d, J = 8.8 Hz), 7.28 (1H, s), 7.17 (2H , d, J=8.8 Hz), 6.46 (1H, d, J=6.4 Hz), 5.23 (2H, s), 4.45 (2H, m), 3.35 (1H, m), 3.15 (2H, m), 2.27 (2H, m), 1.85 (2H, m).

Example 176

6-Methyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine-4- carboxylic acid

¹ H NMR (DMSO-d ₆ ): δ 13.3 (1H, br), 9.97 (1H, s), 7.80 (2H, d, J = 8.8 Hz), 7.66 (1H, s), 7.28 (2H, d, J=8.8 Hz), 6.98 (1H, s), 5.21 (2H, s), 4.79 (2H, m), 3.34 (1H, m), 3.05 (2H, m), 2.35 (3H, s), 2.13 ( 2H, m), 1.62 (2H, m).

Example 177

5-Chloro-4,6-difluoro-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine-1- Pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.91 (1H, s), 7.61 (2H, d, J = 8.8 Hz), 7.27 (1H, s), 7.16 (2H, d, J = 8.8 Hz), 5.23 (2H , s), 4.69 (2H, m), 3.32 (1H, m), 3.10 (2H, m), 2.23 (2H, m), 1.80 (2H, m).

Example 178

4-fluoro-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine

¹ H NMR (DMSO-d ₆ ): δ 9.97 (1H, s), 8.41 (1H, m), 7.80 (2H, d, J = 8.0 Hz), 7.66 (1H, s), 7.28 (2H, d, J=8.0 Hz), 6.34 (1H, m), 5.20 (2H, s), 4.60 (2H, m), 3.32 (1H, m), 3.10 (2H, m), 2.11 (2H, m), 1.61 ( 2H, m).

Example 179

2-fluoro-4-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine

¹ H NMR (DMSO-d ₆ ): δ 9.98 (1H, s), 8.08 (1H, m), 7.80 (2H, d, J = 9.2 Hz), 7.67 (1H, s), 7.28 (2H, d, J=9.2 Hz), 6.84 (1H, m), 5.20 (2H, s), 4.40 (2H, m), 3.40 (1H, m), 3.14 (2H, m), 2.13 (2H, m), 1.63 ( 2H, m).

Example 180

Ethyl 2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-thiazole-5-carboxylate

¹ H NMR (DMSO-d ₆ ): δ 9.97 (1H, s), 7.84 (1H, m), 7.80 (2H, d, J = 9.0 Hz), 7.68 (1H, s), 7.28 (2H, d, J=9.0 Hz), 5.21 (2H, s), 4.19 (2H, t, J=7.20 Hz), 4.03 (2H, m), 3.35 (3H, m), 2.15 (2H, m), 1.75 (2H, m), 1.23 (3H, t, J=7.20 Hz).

Example 181

4-imidazol-1-yl-6-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine

¹ H NMR (DMSO-d ₆ ): δ 9.98 (1H, s), 8.59 (1H, s), 8.43 (1H, s), 8.01 (1H, d, J = 1.2 Hz), 7.81 (2H, d, J=8.8 Hz), 7.67 (1H, s), 7.27 (2H, d, J=8.8 Hz), 7.14 (1H, s), 7.10 (1H, d, J=1.2 Hz), 5.20 (2H, s) , 4.61 (2H, m), 3.40 (1H, m), 3.15 (2H, m), 2.15 (2H, m), 1.66 (2H, m).

Example 182

5-ethyl-2-{4-[4-(6-tetrazol-1-yl-pyridin-3-yloxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}- Pyrimidine

¹ H NMR (CDCl ₃ ): δ 9.44 (1H, s), 8.28 (1H, d, J = 3.0 Hz), 8.2 (2H, s), 8.02 (1H, d, J = 8.8 Hz), 7.58 (1H , dd, J=8.8 Hz, 3.0 Hz), 7.27 (1H, s), 5.27 (2H, s), 4.82-4.85 (2H, m), 3.22-3.35 (1H, m), 3.0-3.1, (2H , m), 2.47 (2H, q, J=7.2 Hz), 2.2-2.23 (2H, m), 1.76-1.86 (2H, m), 1.19 (3H, t, J=7.2 Hz).

Example 183

5-methyl-2-{4-[4-(6-tetrazol-1-yl-pyridin-3-yloxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}- Pyrimidine

¹ H NMR (DMSO-d ₆ ): δ 10.07 (1H, s), 8.42 (1H, d, J = 3.0 Hz), 8.21 (2H, s), 7.99 (1H, d, J = 9.2 Hz), 7.86 (1H, dd, J=9.2 Hz, 3.0 Hz), 7.70 (1H, s), 5.30 (2H, s), 4.62 (2H, m), 3.56-3.6 (1H, m), 2.98-3.04 (2H, m), 2.06 (3H, s), 1.72-1.76 (2H, m), 1.59 (2H, m).

Example 184

5-Chloro-2-{4-[4-(6-tetrazol-1-yl-pyridin-3-yloxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}- Pyrimidine

¹ H NMR (CDCl ₃ ) δ 9.44 (1H, s), 8.28 (1H, d, J = 3.0 Hz), 8.23 (2H, s), 8.02 (1H, d, J = 9.0 Hz), 7.58 (1H, Dd, J=9.0 Hz, 3.0 Hz), 7.28 (1H, s), 5.27 (2H, s), 4.8-4.83 (2H, m), 3.22-3.38 (1H, m), 3.04-3.11 (2H, m ), 2.20-2.23 (2H, m), 1.80 (2H, m)

Example 185

2-{4-[4-(6-tetrazol-1-yl-pyridin-3-yloxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-5-trifluoromethyl Base-pyrimidine

¹ H NMR (DMSO-d ₆ ): δ 10.07 (1H, s), 8.68 (2H, s), 8.42 (1H, d, J = 3.0 Hz), 7.99 (1H, d, J = 9.2 Hz), 7.86 (1H, dd, J=9.2 Hz, 3.0 Hz), 7.72 (1H, s), 5.73 (2H, s), 4.74-4.77 (2H, m), 3.37-3.43 (1H, m), 3.15-3.21 ( 2H, m), 2.12-2.16 (2H, m), 1.59-1.68 (2H, m).

Example 186

3-Chloro-6-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-oxime

¹ H NMR (CDCl ₃ ): δ 8.91 (1H, s), 7.61 (2H, d, J = 9.0 Hz), 7.26 (1H, s), 7.22 (1H, d, J = 9.6 Hz), 7.17 (2H , d, J=9.0 Hz), 6.95 (1H, d, J=9.6 Hz), 5.23 (2H, s), 4.43-4.47 (2H, m), 3.31-3.37 (1H, m), 3.12-3.19 ( 2H, m), 2.25-2.28 (2H, m), 1.90 (2H, m).

Example 187

2-tetrazol-1-yl-5-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}- Pyridine

¹ H NMR (DMSO-d ₆ ): δ 9.97 (2H, s), 8.67 (1H, s), 8.37 (1H, s), 7.80 (2H, d, J = 8.8 Hz), 7.67 (1H, s) , 7.28 (2H, d, J=8.8 Hz), 5.21 (2H, s), 4.50-4.53 (2H, m), 3.38-3.44 (1H, m), 3.17-3.23 (2H, m), 2.15-2.18 (2H, m), 1.69-1.77 (2H, m).

Example 188

{2-[1-(5-Ethyl-pyrimidin-2-yl)-hexahydropyridin-4-yl]-thiazol-4-ylmethyl}-(6-fluoro-pyridin-3-yl)-amine

¹ H NMR (CDCl ₃ ): δ 8.19 (2H, s), 7.58-7.62 (1H, m), 7.05-7.10 (1H, m), 7.01 (1H, s), 6.75 (1H, dd, J=8.4 Hz, 2.8 Hz), 4.81-4.85 (2H, m), 4.40 (2H, d, J=5.2 Hz), 4.29 (1H, brs), 3.23-3.29 (1H, m), 3.00-3.06 (2H, m ), 2.47 (2H, q, J=7.6 Hz), 2.18-2.20 (2H, m), 1.79 (2H, m), 1.20 (3H, t, J=7.6 Hz).

Example 189

2-{4-[4-(2,6-difluoro-4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-5-ethyl -pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.19 (2H, s), 7.51 (2H, d), 7.25 (1H, s), 5.40 (2H, s), 4.82 (2H, m), 3.30 (1H, m) , 3.06 (3H, s), 3.03 (2H, m), 2.48 (2H, q), 2.15 (2H, m), 1.74 (2H, m), 1.20 (3H, t).

Example 190

5-butyl 2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.92 (1H, s), 8.17 (2H, s), 7.62 (2H, m), 7.25 (1H, s), 7.17 (2H, m), 5.24 (2H, s) , 4.83 (2H, m), 3.30 (1H, m), 3.04 (2H, m), 2.42 (2H, t), 2.23 (2H, m), 1.84 (2H, m), 1.52 (2H, m), 1.34 (2H, m), 0.92 (3H, m).

Example 191

4-(4-{2-[1-(5-ethyl-pyrimidin-2-yl)-hexahydropyridin-4-yl]-thiazol-4-ylmethoxy}-phenyl)-morpholine

¹ H NMR (CDCl ₃ ): δ 8.18 (2H, s), 7.19 (1H, s), 6.92 (4H, m), 5.12 (2H, s), 4.84 (2H, m), 3.86 (4H, br) , 3.30 (1H, m), 3.05 (6H, m), 2.46 (2H, q), 2.21 (2H, m), 1.78 (2H, m), 1.19 (3H, t).

Example 192

5-nitro-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine

¹ H NMR (DMSO-d ₆ ): δ 9.91 (1H, s), 9.11 (2H, s), 7.83 (2H, d, J = 8.8 Hz), 7.68 (1H, s), 7.25 (2H, d, J=8.8 Hz), 5.22 (2H, s), 4.81 (2H, m), 3.39 (1H, m), 3.31 (2H, m), 2.23 (2H, s), 1.68 (2H, m).

Example 193

3'-Chloro-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-5'-trifluoromethyl-3,4,5,6 -tetrahydro-2H-[1,2']bipyridine

¹ H NMR (CDCl ₃ ): δ 8.91 (1H, s), 8.39 (1H, s), 7.76 (1H, s), 7.61 (2H, m), 7.25 (1H, s), 7.18 (2H, m) , 5.24 (2H, s), 4.16 (2H, m), 3.26 (1H, m), 3.06 (2H, m), 2.25 (2H, m), 2.01 (2H, m).

Example 194

3'-Chloro-4-[4-(2-fluoro-4-pyrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-5'-trifluoromethyl-3, 4,5,6-tetrahydro-2H-[1,2]bipyridine

¹ H NMR (CDCl ₃ ): δ 8.94 (1H, s), 8.38 (1H, s), 7.75 (1H, s), 7.53 (1H, m), 7.40 (1H, m), 7.31 (1H, s) , 7.25 (1H, m), 5.31 (2H, s), 4.15 (2H, d), 3.25 (1H, m), 3.09 (2H, m), 2.23 (2H, d), 1.99 (2H, m).

Example 195

5-Chloro-2-{4-[4-(2-fluoro-4-pyrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl} -pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.96 (1H, s), 8.20 (2H, s), 7.52 (1H, m), 7.40 (1H, m), 7.28 (1H, s), 7.25 (1H, m) , 5.28 (2H, s), 4.78 (2H, m), 3.30 (1H, m), 3.07 (2H, m), 2.20 (2H, m), 1.79 (2H, m).

Example 196

3',5'-Dichloro-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-3,4,5,6-tetrahydro-2H -[1,2']bipyridine

¹ H NMR (DMSO-d ₆ ): δ 9.98 (1H, s), 8.26 (1H, s), 8.03 (1H, s), 7.81 (2H, d), 7.67 (1H, s), 7.29 (2H, d), 5.21 (2H, s), 3.79 (2H, m), 3.24 (1H, m), 2.97 (2H, m), 2.14 (2H, m), 1.84 (2H, m).

Example 197

3'-Chloro-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-3,4,5,6-tetrahydro-2H-[1 , 2'] bipyridyl-5'-carboxylic acid ethyl ester

¹ H NMR (CDCl ₃ ): δ 8.92 (1H, s), 8.74 (1H, s), 8.11 (1H, s), 7.61 (2H, d), 7.25 (1H, s), 7.17 (2H, d) , 5.23 (2H, s), 4.37 (2H, m), 4.22 (2H, m), 3.31 (1H, m), 3.08 (2H, m), 2.26 (2H, m), 1.98 (2H, m), 1.38 (3H, m).

Example 198

5'-Chloro-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-3,4,5,6-tetrahydro-2H-[1 , 2'] bipyridyl-3'-carboxylic acid methyl ester

¹ H NMR (CDCl ₃ ): δ 8.91 (1H, s), 8.20 (1H, s), 7.99 (1H, s), 7.61 (2H, d), 7.25 (1H, s), 7.16 (2H, d) , 5.21 (2H, s), 3.91 (2H, m), 3.88 (3H, s), 3.28 (1H, m), 3.08 (2H, m), 2.20 (2H, m), 1.93 (2H, m).

Example 199

5-ethyl-2-{3-methyl-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl} -pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.90 (1H, s), 8.18 (2H), 7.60 (2H, m), 7.25 (1H, s), 7.17 (2H, m), 5.26 (2H), 4.89-4.51 (2H, m), 3.49-3.20 (2H, m), 2.92 (1H, m), 2.65-2.45 (1H, m), 2.45 (2H, m), 2.17-1.81 (2H, m), 1.20 (3H , m), 0.82-0.92 (3H).

Example 200

5-ethyl-2-{4-[4-(2-fluoro-4-pyrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-3-methyl-hexahydropyridine -1-yl}-pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.93 (1H, s), 8.17 (2H), 7.52-7.25 (4H, m), 5.32 (2H), 4.84-4.46 (2H, m), 3.47-3.22 (2H, m), 2.91 (1H, m), 2.62-2.43 (1H, m), 2.42 (2H, m), 2.07 (2H, m), 1.18 (3H, m), 0.90-0.79 (3H, m).

Example 201

5-Chloro-2-{4-[4-(2-fluoro-4-pyrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-3-methyl-hexahydropyridine -1-yl}-pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.93 (1H, s), 8.19 (2H), 7.52-7.25 (4H, m), 5.29 (2H), 4.82-4.51 (2H, m), 3.46-3.21 (2H, m), 2.95 (1H, m), 2.64-2.42 (1H, m), 2.02 (2H, m), 0.90-0.78 (3H, m).

Example 202

2-{4-[4-(2-Fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-3-methyl-hexahydropyridin-1-yl} -5-trifluoromethyl-pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.94 (1H, s), 8.47 (2H), 7.53-7.27 (4H, m), 5.34 (2H), 5.02-4.62 (2H, m), 3.52-2.97 (3H, m), 2.73-2.47 (1H, m), 2.17-2.01 (2H, m), 0.94-0.78 (3H, m).

Example 203

5-ethyl-2-{4-[4-(4-methanesulfonyl-benzyloxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.17 (2H, s), 7.92 (2H, d, J = 8.8 Hz), 7.58 (2H, d, J = 8.8 Hz), 7.13 (1H, s), 4.83 (2H , m), 4.71 (2H, s), 4.66 (2H, s), 3.27 (1H, m), 3.03 (3H, s), 2.98 (2H, m), 2.46 (2H, m), 2.19 (2H, m), 1.76 (2H, m), 1.19 (3H, m).

Example 204

5-fluoro-2-{4-[4-(2-fluoro-4-pyrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl} -pyrimidine

¹ H NMR (CDCl ₃ ): δ 8.91 (1H, s), 8.21 (2H, s), 7.52 (1H, m), 7.41 (1H, m), 7.27 (1H, m), 7.25 (1H, s) , 5.31 (2H, s), 4.76 (2H, m), 3.28 (1H, m), 3.06 (2H, m), 2.20 (2H, m), 1.81 (2H, m).

Example 205

¹ H NMR (CDCl ₃ ): δ 8.91 (1H, s), 8.49 (2H, s), 7.61 (2H, d), 7.27 (1H, s), 7.17 (2H, d), 5.24 (2H, s) , 4.96 (2H, m), 3.38 (1H, m), 3.14 (2H, m), 2.26 (2H, m), 1.82 (2H, m).

Example 206

3-(4-{[(4-methanesulfonyl-phenyl)-methyl-amino]-methyl}-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester

4-{4-[(4-Methanesulfonyl-phenylamino)-methyl]-thiazol-2-yl}-piperidine-1-carboxylic acid tert-butyl ester ( Example 138 ) 0.10 mmol was dissolved in DMF (2 mL) and NaH (2 eq.) was added in one portion at room temperature. The reaction was stirred for 30 minutes and methane iodide (10 eq.) was added. After stirring for 3 h, the reaction was quenched with water andEtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by EtOAc (hexane /EtOAc EtOAc) ¹ H NMR (CDCl ₃ ): δ 7.73 (2H, m), 6.78 (2H, m), 6.76 (1H, s), 4.70 (2H, s), 4.20 (2H, br), 3.19 (3H, s) , 3.12 (1H, m), 3.01 (3H, s), 2.87 (2H, m), 2.07 (2H, m), 1.80 (2H, m), 1.47 (9H, s).

Example 207

(2-[1-(5-Ethyl-pyrimidin-2-yl)-hexahydropyridin-4-yl]-thiazol-4-ylmethyl}-(2-fluoro-4-methanesulfonyl- Phenyl)-methyl-amine

Example 207 utilizes {2-[1-(5-ethyl-pyrimidin-2-yl)-hexahydropyridin-4-yl]-thiazol-4-ylmethyl}-(2) in a similar manner to Example 206 -Fluoro-4-methanesulfonyl-phenyl)-amine ( Example 141 ) was synthesized as a starting material. ¹ H NMR (CDCl ₃ ): δ 8.19 (2H, s), 7.47-7.57 (2H, m), 6.94 (1H, s), 6.91 (1H, m), 4.80 (2H, m), 4.62 (2H, s), 3.24 (1H, m), 3.09 (3H, s), 3.03 (3H, s), 3.00 (2H, m), 2.47 (2H, m), 2.17 (2H, m), 1.74 (2H, m ), 1.19 (3H, t).

Example 208

4-[4-(2-Methylthio-pyrimidin-5-yloxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

Example 208 was prepared in a similar manner as described in Example 1 from 4-(4-chloromethyl-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester ( Intermediate 1 ) With 2-methylthio-pyrimidine-5-ol. ¹ H NMR (CDCl ₃ ): δ 8.35 (2H, s), 7.23 (1H, s), 5.19 (2H, s), 4.22 (2H, m), 3.16 (1H, m), 2.87 (2H, m) , 2.55 (3H, s), 2.10 (2H, m), 1.71 (2H, m), 1.46 (9H, s).

Example 209

4-[4-(4-Tetrazolyl-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid allyl ester

Example 209 was prepared in a similar manner as described in Example 22 from 4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine ( intermediate) 4 ) with allyl chloroformate. ¹ H NMR (CDCl ₃ ): δ 8.96 (1H, s), 7.63 (2H, m), 7.20 (1H, s), 7.18 (2H, m), 5.96 (1H, m), 5.31 (1H, m) , 5.22 (3H, m), 4.61 (2H, m), 4.29 (2H, m), 3.21 (1H, m), 2.97 (2H, m), 2.15 (2H, m), 1.78 (2H, m).

Example 210

2-{4-[4-Methyl-5-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-5-trifluoro Methyl-pyrimidine

Step 1 : 4-[4-Methyl-5-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine

4-[4-Methyl-5-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester ( example) 93 ) (500 mg, 1.10 mmol) in dichloromethane (5 mL). The resulting solution was stirred at room temperature for 5 hours and all solvent was removed in vacuo to give the desired product as HCl salt.

Step 2 : 2-{4-[4-Methyl-5-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-5 -trifluoromethyl-pyrimidine

This compound was prepared in a similar manner as described in Example 47 from 4-[4-methyl-5-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]- Hexahydropyridine hydrochloride.

¹ H NMR (CDCl ₃ ): δ 8.94 (1H, s), 8.49 (2H, s), 7.64 (2H, m), 7.14 (2H, m), 5.20 (2H, s), 4.95 (2H, m) , 3.27 (1H, m), 3.13 (2H, m), 2.46 (3H, s), 2.21 (2H, m), 1.77 (2H, m).

Biological example 1

Stimulation of cAMP The compounds of the invention were evaluated in assays demonstrating the potency of IC-GPCR2. This assay uses the development of a stable cell line that exhibits IC-GPCR-2 as described below. IC-GPCR2 (sequence identification code 1) was clonalized into the Gateway pDEST 40 vector (Invitrogen) using the Gateway clonal propagation system (invitrogen) according to the manufacturer's instructions. The diazepam cell line was generated using a Transit-CHO transfer infection kit (Mirus) via a 10 cm plate that was infected with 8 micrograms of this construct to infect CHO cells (source). CHO cell lines were overlaid at a density of 3,000,000 cells/plate one day prior to metastatic infection. The vegetative propagation line was selected using the antibiotic G418 at 500 μg/ml. Twenty-three asexual reproduction lines were selected and the expression of the receptor was detected by measuring changes in the intracellular cAMP content of the IC-GPCR2 agonist.

To measure the cAMP activity of the IC-GPCR2 agonist, the clonal propagation line was overlaid in 96 well plates at 17,500 cells per well. One day after the cover, The cells were cultured in Ham's F12 medium (Gibco) with 0.04% DMSO and incubated with IC-CPCR2 agonist at 10 μM for 30 minutes. cAMP was measured using the cAMP dynamic kit from Cis Bio (Bedford, MA) according to the manufacturer's instructions. Briefly, cells were lysed and cAMP levels were determined by competitive immunoassays using D2-labeled cAMP and sputum-labeled anti-cAMP antibodies. When in close proximity, D2 performs a fluorescence resonance energy transfer (FRET) with the cryptic system, which is measured in a fluorescent ratio (665 nm / 620 nm). The unidentified cAMP line in the cell lysate competes with the D2-labeled cAMP for the antibody of the recessive identity. The resulting FRET signal reduction corresponds to intracellular cAMP content. Fluorescence was read on BMG Labtech PHERAstar software version 1.50.

The asexual reproduction line with the greatest response to the IC-GPCR2 agonist was selected for screening assays.

Determination of Compound Activity The compound was dissolved in 100% DMSO to a concentration of 10 μM to provide a stock solution. To determine the activity against IC-GPCR2, the compound is expressed in a stable cell of IC-GPCR2 (described above) at a concentration ranging from 0.00003 to 10 micromolar at 6-8 concentrations in a 96 well plate. The cells were cultured in 50 μl of Hams F12 medium for 30 minutes. One day prior to the operation of this assay, cells were covered at 17,500 cells per well. All compounds were also screened for maternal CHO cells. cAMP was measured using the cAMP dynamic kit from Cis Bio (Bedford, MA) according to the manufacturer's instructions. Briefly, cells were lysed and cAMP levels were determined by competitive immunoassays using D2-labeled cAMP and sputum-labeled anti-cAMP antibodies. When in close proximity, D2 performs a fluorescence resonance energy transfer (FRET) with the cryptic system, which is measured in a fluorescent ratio (665 nm / 620 nm). The unidentified cAMP line in the cell lysate competes with the D2-labeled cAMP for the antibody of the recessive identity. The resulting FRET signal reduction corresponds to intracellular cAMP content.

The activities of the compounds disclosed in Tables 1 and 2 below are expressed as % change in the FRET signal from the DMSO control group. "*" When tested at 10 micromolar concentrations, no activity was found, but higher concentrations were not tested. NT indicates that the compound was not tested at the indicated concentrations.

Biological example 2

Insulin secretion (peri-islet fusion) is a measure of the effect of the IC-GPCR2 agonist on insulin secretion from islets, which is obtained from the islets of Sprague Dawley rats. 200-250 grams of Spoeldogley (Charles River Laboratory) were kept under regular food (Purina 5001). Prior to this procedure, rats were anesthetized with intraperitoneal injection of pentobarbital at 200 mg/kg. The bile duct is clamped where it enters the duodenum and the catheter is placed in the bile duct between the liver and the pancreas. The pancreas was perfused through a catheter with a solution of 0.75 mg/ml collagenase P (Roche) supplemented with 0.1% glucose and 0.02% BSA in HBSS buffer (Biowhitaker). Next, the pancreas was excised from the rats and placed in 5 ml of collagenase P solution in a 37 ° C water bath for 8 minutes. After 8 minutes, the digested pancreas was vigorously shaken by hand for 30 seconds. The resulting digest was washed four times in HBSS buffer and then applied to a discontinuous polysucrose gradient. To make the gradient, the digest was resuspended in 7.5 ml of Ficoll DL400 solution (Sigma) at a density of 1.108 in a 15 ml tube. Next, three 2 ml layers of reduced density (1.096, 1.069, 1.037) of polysucrose solution were added to the tube to create a density gradient. The gradient was centrifuged at 1500 rpm for 15 minutes and then islets were removed from the upper two layers. Islet was washed four times in HBSS buffer followed by RPMI 1640 medium (Gibco) supplemented with 1% fetal bovine serum. On the next day, 25 size-matched islets were placed in the surrounding fusion chamber and exposed to Krebs Ringer buffer (KRB; 119 mM NaCl) using a Cellex Acu-sys S surrounding fusion culture system at a rate of 1 ml/min. , 4.7 mM KCl, 25 mM NaHCO ₃ , 2.5 mM CaCl ₂ , 1.2 mM MgSO ₄ , 1.2 mM KH2PO ₄ ). The islets were exposed to KRB containing 2 mM glucose in the presence of 1 μM of IC-GPCR2 agonist or vehicle (DMSO) for 30 minutes, followed by a buffer containing 16 mM glucose for 30 minutes. Then return to 2 mM glucose for another 30 minutes. Peripheral fusions were collected at 1 minute intervals using a detached collector and insulin was detected using an ELISA kit (Mercodia Supersensitive Mouse Insulin ELISA Kit, ALPCO). The insulin secretion rate in response to glucose was plotted against time and the AUC of the curve was determined to quantify the insulin secretion response to 16 mM glucose during the 30 minute surrounding fusion. The statistical significance of the difference in AUC between treated and untreated islets was determined by paired Student's t-test.

The table below shows the fold stimulation of insulin secretion induced by each of the tested IC-GPCR2 agonists at 16 mM glucose. The compounds tested are selected from the exemplified compounds as examples. These results confirm that the IC-GPCR2 agonist stimulates insulin secretion in response to glucose.

Biological example 3

Oral Glucose Tolerance Male male C57/6J mice (Harlan), 8-10 weeks old, were maintained under a regular food diet (Purina 5001). On the day of the experiment, the rats were fasted for 6 hours and then randomly divided into arrays (n=8) to receive the tested IC-GPCR2 agonist or vehicle (1% CMC) at a dose ranging from 3-30 mg/kg. , 2% TWEEN 80). The compound was delivered orally at 10 ml/kg via a feeding method. The blood glucose level is measured by a glucose meter (Ascensia Elite XL, Bayer) at time 0 prior to administration of the compound. The blood glucose was measured again after 30 minutes, and then the mice were orally administered with 2 g/kg of glucose at 10 ml/kg. The blood glucose metric was obtained by means of a glucose meter (Ascensia Elite XL, Bayer) at 15, 30, 60, 90 and 120 minutes after glucose administration.

The glucose content was plotted against time and the incremental area (AUC) below the glucose drift curve was from T0 to T120 as determined using GraphPad Prism 5.0. Outliers were measured at various points in the OGTT, and for the AUC values, Tukey's block plots were used. Animals with any distance from the point were excluded from this analysis, and the statistical significance of the AUC difference between the compound treatment and the vehicle was determined by the non-parametric Kruskal-Wallis test and the Dunn's post test. Differences with a p-value of ≦0.05 are considered to be meaningful.

Tables 3 and 4 below show the average percent inhibition of glucose drift at 30 mg/kg and 3 mg/kg. The values indicated by the asterisk (*) in Tables 3 and 4 are meaningful. These results confirm that the IC-GPCR2 agonist lowers blood glucose in response to oral glucose challenge.

Biological example 4

Tissue-specific RNA is extracted from isolated rat and mouse islets and used to prepare double-stranded cDNA using standard techniques (see Sambrook et al., Molecular Asexual Reproduction, Laboratory Manual (3rd ed. 2001); Molecules Current developments in biology (Ausubel et al., 1994)). The cDNA was vegetatively propagated into the pZL1 vector (Invitrogen), and the 3' end of the individual clonal propagation lines was sequenced in multiple rounds of sequencing reactions. Sequence data representing approximately 12,000 independent clonal lines were used to construct oligonucleotide probes synthesized on GENECHIP ^® (Affymetrix, Santa ClaRa, CA) to produce mouse and rat islet fragments. The islet preparations from the five groups of rats (the preparations obtained from different mice) and the RNA obtained from the test group of the rat tissue test group were hybridized to the fragments of the rats. Performance data was analyzed by the Affymetrix MAS 4.0 algorithm to obtain relative gene performance values as mean difference scores, and to indicate presence/absence. Two sets of preparations from the mouse beta cell line BHC-9, four groups of mouse islet preparations (reagents obtained from different mice), and RNA from the mouse tissue test group preparation were hybridized to mouse fragments. The performance data was analyzed by the Affymetrix MAS 5.0 algorithm to obtain relative gene performance values, as signals, and to indicate presence/absence.

Figures 1 (large rats) and 2 (rats) show tissue specificity for receptors of novel agonists of the invention, showing tissue specificity for islet cells, including beta cells therein.

Sequence identifier 1 atggaatcatctttctcatttggagtgatccttgctgtcctggcctccctcatcattgct actaacacactagtggctgtggctgtgctgctgttgatccacaagaatgatggtgtcagt ctctgcttcaccttgaatctggctgtggctgacaccttgattggtgtggccatctctggc ctactcacagaccagctctccagcccttctcggcccacacagaagaccctgtgcagcctg cggatggcatttgtcacttcctccgcagctgcctctgtcctcacggtcatgctgatcacc tttgacaggtaccttgccatcaagcagcccttccgctacttgaagatcatgagtgggttc gtggccggggcctgcattgccgggctgtggttagtgtcttacctcattggcttcctccca ctcggaatccccatgttccagcagactgcctacaaagggcagtgcagcttctttgctgta tttcaccctcacttcgtgctgaccctctcctgcgttggcttcttcccagccatgctcctc tttgtcttcttctactgcgacatgctcaagattgcctccatgcacagccagcagattcga aagatggaacatgcaggagccatggctggaggttatcgatccccacggactcccagcgac ttcaaagctctccgtactgtgtctgttctcattgggagctttgctctatcctggaccccc ttccttatcactggcattgtgcaggtggcctgccaggagtgtcacctctacctagtgctg gaacggtacctgtggctgctcggcgtgggcaactccctgctcaacccactcatctatgcc tattggcagaaggaggtgcgactgcagctctaccacatggccctaggagtgaagaaggtg ctcacctcattcctcctctttctcttggccaggaattgtggcccagagaggcccagggaa agttcctgtcacatcgtcactatc Tccagctcagagtttgatggctaa

Sequence identifier 2 MESSFSFGVILAVLASLIIATNTLVAVAVLLLIHKNDGVSLCFTLNLAVADTLIGVAISG LLTDQLSSPSRPTQKTLCSLRMAFVTSSAAASVLTVMLITFDRYLAIKQPFRYLKIMSGF VAGACIAGLWLVSYLIGFLPLGIPMFQQTAYKGQCSFFAVFHPHFVLTLSCVGFFPAMLL FVFFYCDMLKIASMHSQQIRKMEHAGAMAGGYRSPRTPSDFKALRTVSVLIGSFALSWTP FLITGIVQVACQECHLYLVLERYLWLLGVGNSLLNPLIYAYWQKEVRLQLYHMALGVKKV LTSFLLFLLARNCGPERPRESSCHIVTISSSEFDG

Biological example 5

Improvement in Glucose Content, Insulin Content, and Body Weight in High-fat Female ZDF Rats ZDF rats are a mode of lack of leptin receptors in obesity, overfeeding, and insulin resistance. Animals develop diabetes because pancreatic islets fail to fight insulin resistance. Male animal lines spontaneously develop diabetes between 9 and 11 weeks of age, whereas females remain non-diabetic unless placed under a high-fat diet. This diet makes the animal more insulin resistant, and the increased demand for insulin promotes islet failure. Female ZDF rats usually become diabetic within 2 weeks of being placed on a high-fat diet (Corsetti et al.; 2000).

Five-week-old female ZDF rats were obtained and adapted to the environment for 9 days. The rats were then classified into 8 study groups based on body weight, insulin content and glucose content. One group was kept under regular food, while the other 7 groups were placed under a high fat diet. The drug or vehicle treatment is initiated simultaneously with the meal. The statistical significance of the differences found was assessed by two-way ANOVA and post-Bonferroni trials. The analysis was performed with GraphPad Prism 5.0.

The agonist 2 was administered orally in 1% carboxymethylcellulose and 2% Tween 80 (vehicle) by a feeding method. The agonist 2 was administered at 10, 30 and 100 mg/kg. Blood samples were collected from the tail vein on days 0, 7, 14, 21 and 35 under non-fasting conditions. On day 28, blood samples were collected after 16 hours of overnight fasting. Glucose was measured using a glucose meter (Ascensia Elite XL, Bayer); insulin was measured using the Mercodia Supersensitive Mouse Insulin ELISA Kit (ALPCO). Insulin, glucose, and levels were compared to vehicle-treated animals to determine efficacy and the statistical significance of the differences was determined by one-way ANOVA.

Feeding Plasma Glucose Content Figure 3 shows the plasma glucose levels of the animals during the course of the study. High fat fed female ZDF rats showed a gradual increase in dietary glucose levels during the 35 day study period. Animals under the food diet showed only a slight increase in the plasma glucose content during the study period. Animals treated with agonist 2 showed an increase in plasma glucose during the study, but when treated with 30 and 100 mg/kg of agonist 2, at all time points tested, the treated animals were compared The control group had a statistically significantly lower plasma glucose. Animals treated with 10 mg/kg agonist 2 showed lower plasma glucose levels than vehicle-treated high fat fed control animals, but did not reach statistical significance of p≦0.05.

Ingestion of Plasma Insulin Content Figure 4 shows the plasma insulin levels of the fed food during the course of the study. After 7 days of high fat intake, the vehicle treated group showed an increased fasting insulin content compared to the food feeding group. Animals treated with 30 and 100 mg/kg agonist 2 had significantly lower insulin levels than the vehicle group after 7 days. After 14 days under the high-fat diet, the vehicle-treated animals still had an increased insulin content compared to the food-fed control group, but this content was lower than 7 days. Animals treated with agonist 2 at 10, 30 and 100 mg/kg were not significantly different from the vehicle treated group at 14 days. On the 21st day of high-fat diet, the insulin content in the vehicle-treated animals had dropped back to a level similar to that seen in the food-feeding control group, but at 30 mg/kg and 100 mg/kg. The insulin content in the treated animals is significantly greater. On the 35th day of high-fat diet, the insulin content in the vehicle group has dropped below the level found in the food-feeding group, but at 30 mg/kg and 100 mg/kg agonist 2 The insulin content in the group was significantly greater than that of the untreated animals. Animals treated with 10 mg/kg agonist 2 did not have significantly different insulin levels than those treated with vehicle at any time point measured in the study.

Effect of agonist 2 treatment for 28 days on fasting plasma glucose and insulin levels in high-fat female ZDF rats. After 28 days of high fat diet, fasting plasma glucose and insulin levels were assessed. The data is provided in Figure 5. The vehicle-treated animals under a high-fat diet had significantly increased fasting plasma glucose compared to the food-fed control group. Animals treated with 30 and 100 mg/kg agonist 2 had significantly lower than the vehicle, and the food-feeding control group had an fasting plasma glucose content. The vehicle-treated animals under a high-fat diet had a fasting insulin content similar to the food-fed control group. The insulin content in animals treated with agonist 2 at 30 and 100 mg/kg was significantly improved compared to the vehicle group. This reflects the role of high fat diets in increasing insulin resistance in these animals. In the absence of drug treatment, islets are not able to continuously compensate for insulin resistance and insulin levels are reduced. Treatment with 30 and 100 mg/kg agonist 2 allows the islets to continue to be manufactured as insulin required to maintain glucose control against insulin resistance.

The changes in insulin levels seen in the vehicle group under a high-fat diet reflect the etiology of diabetes development in this model. Due to the high-fat diet, the animals become more insulin-resistant, and the islets initially compensate for the increased insulin resistance, which is due to increased insulin output. This was reflected on higher plasma insulin levels on days 7 and 14 of the study. After the 14th day, the insulin content began to decrease due to the islet failure inherent in female ZDF rats. This decrease in insulin content is associated with plasma The increase in sugar is consistent, as shown in Figure 3. Treatment with 30 and 100 mg/kg agonist 2 attenuates the initial increase in insulin secretion and prevents subsequent decline.

Biological example 6

Improvement in Triglyceride Content in Female ZDF Rats Female ZDF rats (Charles River Laboratory) were obtained at 6 weeks of age and were placed on a high fat diet (RD 13004, Before the study diet, adapt it to the environment for 1 week. Rats were divided into a control group (n=10) and a treatment group (n=10). Compounds (Activator 2 and Agonist 10) were administered to rats in 1% CMC, 2% TWEEN 80 by daily feeding. The agonist 2 was administered at 30 and 100 mg/kg, and the agonist 10 was at 30 mg/kg. The consumption of triglyceride content was measured on day 28, while the dietary glucose content was measured on day 32. Glucose was also measured on day 35 after overnight fasting. Glucose was measured using a glucose meter (Ascensia Elite XL, Bayer); insulin was measured using the Mercodia Supersensitive Mouse Insulin ELISA Kit (ALPCO). Triglycerides were measured using the serum triglyceride assay kit (Sigma TR0100). Insulin, glucose, and triglyceride levels were compared to vehicle treated animals to determine efficacy, and the statistical significance of the differences was determined by one-way ANOVA.

Table 5 below shows the percentage change in the amount of triglyceride consumed on day 28, the glucose content on day 32, and the glucose content on day 35 in the vehicle treated animals. .

A significant reduction in the level of triglyceride consumed was found after treatment with 100 mg/kg agonist 2 and 30 mg/kg agonist 10 for 28 days. Comparison with vehicle treated animals. A significant reduction in the consumption of plasma glucose was found after treatment with 100 mg/kg agonist 2 and 30 mg/kg agonist 10 for 32 days, as compared to vehicle treated animals. A significant reduction in fasting plasma glucose was found after 35 days of treatment with 100 mg/kg agonist 2 and 30 mg/kg agonist 10 compared to vehicle treated animals.

*p≦0.01, with one-way ANOVA.

Biological example 7

Measure incretin in C57 / 6J mice, the measurement IC-GPCR2 agonists of glucagon-like peptide -1 (GLP-1) and the secreted GIP-based action in the following.

Male 8-10 week old C57/6J mice (Harlan) were kept under regular food diet (Purina 5001). On the day of the experiment, the rats were fasted for 6 hours and then randomly divided into arrays (n=8). All groups were treated with the DPPIV inhibitor sitagliptin at 100 mg/kg to prevent degradation of active GLP-1. The IC-GPCR-2 agonist compound is administered at a concentration ranging from 0.3 to 300 mg/kg in 1% CMC, 2% TWEEN 80 at -30 minutes. Sibutin is administered in the same dosage regimen. 2 grams at 0 minutes Oral glucose under /kg. Ten minutes after the glucose administration, the animals were anesthetized with pentobarbital (40 mg/ml in 10% ethanol), and the blood was collected by cardiac puncture and collected in a microfilter tube (BD) having potassium EDTA. For the GLP-1 assay, the collection tube also contains the DPP-IV inhibitor that is provided in the GLP-1 assay kit.

Insulin was measured using the Mercodia Mouse Insulin ELISA Kit (ALPCO) according to the manufacturer's instructions. Bioactive GLP-1 was measured using the glucagon peptide-1 (active) ELISA assay kit (Linco) according to the manufacturer's instructions. GIP was measured using the Rat/Mouse GIP Total ELISA Assay Kit (Linco) according to the manufacturer's instructions.

All patents, patent applications, publications and publications cited herein are hereby incorporated by reference in their entirety. Any conflict between any of the references cited herein and the statements of this patent specification is intended to be resolved in a manner that facilitates the latter. Similarly, any conflict between the definition of a word or wording and the definition of a word or wording as provided in this patent specification is intended to be resolved in a manner that facilitates the latter.

Figure 1 is a graph showing the results of islet fragment hybridization in rats, confirming that the islets of IC-GPCR2 mRNA are abundant relative to other tissues. Fragments are hybridized with equal amounts of cRNA from five groups of isolated rat islets, and rat tissues: brain, duodenum, fat (fat), kidney, liver, skeletal muscle, pancreas and spleen. The "mean difference" score reflects the relative abundance of IC-GPCR2 mRNA in each tissue. The Affymetrix GeneChip Analysis Kit software indicated that the IC-GPCR2 mRNA was "present" in four of the five islet samples and was "not present" in each of the other tissues.

Figure 2 is a graph showing the results of mouse islet fragment hybridization, confirming that the islets of IC-GPCR2 mRNA are abundant relative to other tissues. Fragments are hybridized with equal amounts of cRNA from the pancreatic beta cell line (βHC9), four groups of isolated mouse islets, and mouse tissues: fat (fat), brain, heart, kidney, liver, Lung, pituitary, skeletal muscle, small intestine, thymus, hypothalamus, adrenal gland, thyroid gland and pancreas. The "signal" score reflects the relative abundance of IC-GPCR2 mRNA in each tissue. The Affymetrix GeneChip assay kit software indicated that the IC-GPCR2 mRNA was "present" in three of the beta HC9 and four islet samples. The Affymetrix GeneChip Analysis Suite software indicates that the IC-GPCR2 mRNA is "absent" in various tissues.

Figure 3 is a graph showing changes in dietary glucose levels in female ZDF rats under a high fat diet. *p≦0.05 at 30 mg/kg and 100 mg/kg agonist 2 pairs of high fat diet (HFD) vehicle. #p≦0.05 HFD vs. food control group, tested by 2-way ANOVA and Bonferroni. This experiment was carried out as described in Biological Example 5.

Figure 4 is a graph showing changes in dietary glucose levels in female ZDF rats under a high fat diet. *p≦0.05 at 30 mg/kg agonist 2 for high fat diet (HFD) vehicle, #p≦0.05 at 100 mg/kg agonist 2 for HFD vehicle, $p≦0.05 HFD Vehicle versus food vehicle, tested by 2-way ANOVA with Bonferroni. This experiment was carried out as described in Biological Example 5.

Figure 5 is a graph showing the effect of treatment with agonist 2 for 28 days on the interruption of plasma glucose and insulin levels in female ZDF rats under a high fat diet. *p≦0.05 treatment for high-fat diet (HFD) vehicle, #p≦0.05 HFD vehicle versus food vehicle, with one-way ANOVA and Dunnet's post-test. This experiment was carried out as described in Biological Example 5.

<110> American Maitre Polex Co., Ltd.

<120> Heterocyclic Receptor Agonist for the Treatment of Diabetes and Metabolic Disorders

<140> 096150669

<141> 2007-12-27

<150> US 60/877,903

<151> 2006-12-28

<160> 2

<170> PatentIn Ver.2.1

<210> 1

<211> 1008

<212> DNA

<213> Homo sapiens

<220>

<223> G protein coupled receptor (GPCR) IC-GPCR2, GPR119, RUP3

<400> 1

<210> 2

<211> 335

<212> PRT

<213> Homo sapiens

<220>

<223> G protein coupled receptor (GPCR) IC-GPCR2, GPR119, RUP3

<400> 2

Claims (15)

a compound of formula II, Wherein D is selected from the group consisting of O, S and NR ⁸ ; the ring system having X, Y and Z or ; J, K, T and U are each independently selected from the group consisting of CH and N; the subscript p is an integer from 0 to 4; the subscript q is an integer from 0 to 4; and R ¹ is selected from H, C _1-10 alkyl group, C _1-10 substituted alkyl group of, C _3-7 cycloalkyl, C ₂ - ₁₀ alkenyl, C ₂ - ₁₀ alkynyl ^{group, -X 1 -COR a, -X 1} -CO 2 R a ^a member of the group consisting of -X ¹ -CONR ^a R ^b , SO ₂ R ^a , 4- to 7-membered heterocyclic group, aryl group and 5- to 10-membered heteroaryl group, wherein each of the cycloalkyl groups, The heterocyclic group, the aryl group and the heteroaryl group are optionally substituted by 1 to 4 substituents independently selected from a halogen group, a C _1-10 alkyl group, a C _1-10 substituted alkyl group, C _{3 - 7} cycloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, heteroaryl, CN, -NR ^a COR ^b , -NR ^a CONR ^a R ^b , -NO ₂ , -OR ^a , -NR ^a R ^b , -COR ^a , -CO ₂ R ^a , -CONR ^a R ^b , -S(O) _m R ^a , -NR ^a S(O) ₂ R ^b and -SO ₂ NR ^a R ^b , Or R ^a and R ^b are combined as appropriate to form a 4-, 5- or 6-membered ring, and X ¹ is selected from the group consisting of a bond, a C _2-6 olefin, a C _2-6 alkyne, a -C(O a group of - and -C(O)-(CH ₂ ) _1-4 - wherein the aliphatic moiety of X ¹ is optionally substituted by one to three members selected from the group consisting of halogen a C _1-4 alkyl group, a C _1-4 substituted alkyl group, and a C _1-4 haloalkyl group, wherein the substituted alkyl group is an alkane having 1 to 5 substituents selected from the group consisting of Base group: C _2-10 alkenyl, C _2-10 alkynyl, -OR ^m , -C(O)R ^m , -NR ^m C(O)R ^m , -OC(O)R ^m , -N (R ^m ) ₂ , -C(O)N(R ^m ) ₂ , -C(S)N(R ^m ) ₂ , -NR ^m C(O)N(R ^m ) ₂ , -NR ^m C(S N(R ^m ) ₂ , -OC(O)N(R ^m ) ₂ , -S(O) ₂ N(R ^m ) ₂ , -OS(O) ₂ N(R ^m ) ₂ , -NR ^m S (O) ₂ N(R ^m ) ₂ , -C(=R ^m )N(R ^m ) ₂ , C _6-14 aryl, C _6-14 aryloxy, C _6-14 arylthio, stack Nitrogen, carboxyl, -C(O)OR ^m , -NR ^m C(O)OR ^m , -OC(O)OR ^m , cyano, C _3-10 cycloalkyl, C _3-10 cycloalkyl oxygen Base, C _3-10 cycloalkylthio group, -NR ^m C(=R ^m )N(R ^m ) ₂ , halogen, hydroxyl group, -NHOR ^m , -NR ^m N(R ^m ) ₂ , 5 to 18 members Heteroaryl, 5 to 18 membered heteroaryloxy, 5 to 18 membered heteroarylthio, heterocyclyl, heterocyclyloxy, heterocyclylthio, nitro, spirocycloalkyl, SO ₃ H , -S(O) ₂ R ^m , -OS(O) ₂ R ^m , -C(S)R ^m , thiocyanate, thiol and C _1-10 alkylthio; each R ² is independently selected from halo, C _1-5 alkyl The C _1-5 alkyl group substituted, C _{3-7 ^{cycloalkyl, -COR a, -CO 2 R a}} , -CONR a R b, -OR a, -NR a R b, -NR a COR b, ^a member of the group consisting of -SOR ^a R ^b , -SO ₂ R ^a and -SO ₂ NR ^a R ^b , and wherein when the subscript q is 2 and R ² is an alkyl group or a substituted alkyl group, the two R ² members may optionally be cyclized to form a ring; each R ⁷ is independently selected from the group consisting of halo, C _1-10 alkyl, C _1-10 substituted alkyl, C _3-7 cycloalkyl, C _{2- 10} alkenyl, C _2-10 alkynyl, CN, NO ₂ , -OR ^a , -NR ^a R ^b , -COR ^a , -CO ₂ R ^a , -CONR ^a R ^b , -NR ^a COR ^b , -NR ^a CO ₂ R ^b , -NR ^a CONR ^a R ^b , -S(O) _m R ^a , -NR ^a S(O) _m R ^b , -SO ₂ NR ^a R ^b , 4- to 7-membered heterocyclic ring a group consisting of a aryl group, an aryl group and a 5- to 10-membered heteroaryl group, wherein each of the heterocyclic group, the aryl group and the heteroaryl group is optionally substituted with one to four substituents independently selected from a halogen group , keto, C _1-4 alkyl, C _1-4 haloalkyl, C _3-7 cycloalkyl, CN, NO ₂ , -OR ^a , -NR ^a R ^b , -COR ^a , -CO ₂ R ^a , -CONR ^a R ^b , -NR ^a COR ^b , -NR ^a CO ₂ R ^b , -NR ^a CONR ^a R ^b , -S(O) _m R ^a , -NR ^a SO ₂ R ^b and -SO ₂ NR ^a R ^b , and wherein the subscript m is an integer from 0 to 2, or R ^a and R ^b are combined as appropriate to form a 4-, 5- or 6-membered ring, wherein the The substituted alkyl group is an alkyl group having 1 to 5 substituents selected from the group consisting of C _2-10 alkenyl, C _2-10 alkynyl, -OR ^m , -C(O)R ^m , -NR ^m C(O)R ^m , -OC(O)R ^m , -N(R ^m ) ₂ , -C(O)N(R ^m ) ₂ , -C(S)N(R ^m ) ₂ , -NR ^m C(O)N(R ^m ) ₂ , -NR ^m C(S)N(R ^m ) ₂ , -OC(O)N(R ^m ) ₂ , -S(O) ₂ N(R ^m ) ₂ , -OS(O) ₂ N(R ^m ) ₂ , -NR ^m S(O) ₂ N(R ^m ) ₂ , -C(=R ^m )N(R ^m ) ₂ , C _6-14 Aryl, C _6-14 aryloxy, C _6-14 arylthio, azide, carboxyl, -C(O)OR ^m , -NR ^m C(O)OR ^m , -OC(O)OR ^m , cyano, C _3-10 cycloalkyl, C _3-10 cycloalkyloxy, C _3-10 cycloalkylthio, -NR ^m C(=R ^m )N(R ^m ) ₂ , halogen Base, hydroxy, -NHOR ^m , -NR ^m N(R ^m ) ₂ , 5 to 18 membered heteroaryl, 5 to 18 membered heteroaryloxy, 5 to 18 membered heteroarylthio, heterocyclic, hetero Cyclooxy, heterocyclylthio, nitro, spirocycloalkyl, SO ₃ H, -S(O) ₂ R ^m , -OS(O) ₂ R ^m , -C(S)R ^m , sulfur Cyanate, mercaptan and C _{1 a -10} alkylthio group; R ⁸ is a member independently selected from the group consisting of hydrogen, C _1-4 alkyl, and C _1-4 haloalkyl; and each of R ^a and R ^b is independently selected from hydrogen, C _{1- 10} alkyl, C _1-10 haloalkyl, C _3-10 cycloalkyl, heterocyclyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, 5- to 6-membered heteroaryl And a group of aryl C _1-4 alkyl groups; wherein each of the aliphatic portions of R ^a and R ^b is optionally substituted by one to three members selected from the group consisting of halo, -OR ⁿ , -OCOR ⁿ , -OC(O)N(R ⁿ ) ₂ , -SR ⁿ , -S(O)R ⁿ , -S(O) ₂ R ⁿ , -S(O) ₂ N(R ⁿ ) ₂ , -NR ⁿ S(O) ₂ R ⁿ , -C(O)N(R ⁿ ) ₂ , -C(O)R ⁿ , -NR ⁿ C(O)R ⁿ , -NR ⁿ C(O)N(R ⁿ ) _a group consisting of -CO ₂ R ⁿ , -NR ⁿ CO ₂ R ⁿ , -CN, -NO ₂ , -N(R ⁿ ) ₂ and -NR ⁿ S(O) ₂ N(R ⁿ ) ₂ , wherein Each R ⁿ is independently hydrogen or an unsubstituted C _1-6 alkyl group; and wherein the aryl and heteroaryl moieties are optionally substituted by one to three members selected from the group consisting of halogen, -OR ^m , OC(O)N(R ^m ) ₂ , -SR ^m , -S(O)R ^m , -S(O) ₂ R ^m , -S(O) ₂ N(R ^m ) ₂ , -NR ^m S( O) ₂ R ^m , -C(O)N(R ^m ) ₂ , -C(O)R ^m , -NR ^m C(O)R ^m , -NR ^m C(O)N(R ^m ) ₂ , —CO ₂ R ^m , —NR ^m CO ₂ R ^m , —CN, —NO ₂ , —N(R ^m ) ₂ and —NR ^m S(O) ₂ N(R ^m ) ₂ , each of which The R ^m is independently hydrogen or an unsubstituted C _1-6 alkyl group; and a pharmaceutically acceptable salt thereof; wherein the compound has a molecular weight of less than 1200. The compound of claim 1 , wherein D is O. The compound of claim 2 , wherein J, T, K and U are both CH. The compound of claim 3 , wherein each R ⁷ is independently selected from the group consisting of fluoro, chloro, methyl, ethyl, -CF ₃ , -SO ₂ C _1-3 alkyl, imidazolyl, triazolyl, and tetrazole A group consisting of bases, and wherein the subscript p is an integer from 1 to 2. The compound of claim 4 , wherein each R7 is tetrazolyl or methylsulfonyl. The compound of any one of claims 1 to 5 , wherein R ¹ is selected from the group consisting of -X ¹ -COR ^a , -X ¹ CO ₂ R ^a , -X ¹ -CONR ^a R ^b , SO ₂ R ^a , aryl a group consisting of a heteroaryl group, a substituted aryl group, and a substituted heteroaryl group. The compound of claim 6 , wherein R ¹ is selected from the group consisting of pyridyl, substituted pyridyl, pyrimidinyl, substituted pyrimidinyl, pyridyl Substituted pyridyl Base Base, replaced Base, phenyl, substituted phenyl, imidazolyl, triazolyl, substituted triazolyl, substituted imidazolyl, Azolyl, substituted Azolyl, thiazolyl, substituted thiazolyl, Diazolyl, substituted A group consisting of a oxazolyl group, a tetrazolyl group, and a substituted tetrazolyl group. The compound of claim 6 , wherein R ¹ is selected from the group consisting of pyrimidinyl, substituted pyrimidinyl, -CO ₂ R ^a , Diazolyl and substituted A group consisting of oxadiazole groups. The compound of claim 6 , wherein R ¹ is pyridine or pyrimidine, and is optionally substituted with one to two substituents independently selected from halo, C _1-10 alkyl, C _1-10 haloalkyl, C _3-7 cycloalkyl, C _2-10 alkenyl, C _{2 -10} alkynyl, aryl, heteroaryl, CN, NO ₂ , -OR ^a , -NR ^a R ^b , -CO ₂ R ^a , -CONR ^a R ^b , -NR ^a COR ^b , -NR ^a CO ₂ R ^b , -S(O) _m R ^a , -NR ^a S(O) ₂ R ^b and -SO ₂ NR ^a R ^b . The compound of claim 1 , wherein J, T and U are both CH; D is O; one of X or Y is S, and Z is N; and R ¹ is selected from pyrimidinyl, substituted pyrimidinyl, pyridyl and The group of substituted pyridyl groups, each R ⁷ is independently selected from the group consisting of a fluoro group and a tetrazolyl group. The compound of claim 1 , which is selected from the group consisting of 4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine-1-carboxylate Acidic third-butyl ester; 4-[4-(4-imidazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester; 4 -[4-(4-Ethylamino-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester; 4-[4-(4-methoxy 3-phenylsulfonyloxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester; 4-[4-(4-[1,2,4]triazole -1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine-1-carboxylic acid tert-butyl ester; 4-{4-[4-(2-keto-tetrahydropyrrole) -1-yl)-phenoxymethyl]-thiazol-2-yl}-piperidine-1-carboxylic acid tert-butyl ester; 4-[4-(4-tetrazol-1-yl-benzene Oxymethyl)-thiazol-2-yl]-hexahydropyridine-1-carboxylic acid tert-butyl ester; 4-[4-(4-methanesulfonyl-phenylthiomethyl)-thiazole- 2-based]-hexahydropyridine-1-carboxylic acid tert-butyl ester; 4-{2-[1-(5-ethyl-pyrimidin-2-yl)-hexahydropyridin-4-yl]-thiazole 4-ylmethoxy}-benzenesulfonamide; 2-{4-[4-(2,6-dichloro-4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl] -hexahydropyridin-1-yl}-5-B -pyrimidine; 5-ethyl-2-{4-[4-(3-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine ; 5-ethyl-2-(4-{4-[4-(5-methyl-tetrazol-1-yl)-phenoxymethyl]-thiazol-2-yl}-hexahydropyridine-1 -yl)-pyrimidine; 5-ethyl-2-{4-[4-(3-methyl-4-methylthio-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine-1 -yl}-pyrimidine; 5-ethyl-2-{4-[4-(4-methanesulfonyl-3-methyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine- 1-yl}-pyrimidine; 6-{2-[1-(5-ethyl-pyrimidin-2-yl)-hexahydropyridin-4-yl]-thiazol-4-ylmethoxy}-benzo[ 1,3] oxysulfuron-2-one; 5-ethyl-2-{4-[4-(4-trifluoromethylthio-phenoxymethyl)-thiazol-2-yl]- Hexahydropyridin-1-yl}-pyrimidine; 4-[4-(3-fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1 -carboxylic acid tert-butyl ester; 4-[4-(2-fluoro-4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid Tri-butyl ester; 4-[4-(2-fluoro-4-pyrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid third- Butyl ester; 5-ethyl-2-{4-[4-(4-trifluoromethanesulfinyl-phenoxymethyl)-thiazol-2-yl]-hexahydro Pyridin-1-yl}-pyrimidine; 4-[4-(4-methanesulfonyl-benzenesulfonylmethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester 4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid isopropyl ester; 4-[4-(4-methanesulfonate) Benzyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid benzyl ester; 4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazole- 2-yl]-hexahydropyridine-1-carboxylic acid isobutyl ester; 4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine-1- Amantacyclo-1-yl carboxylate; methyl 4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine-1-carboxylate; 4- [4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine-1-carboxylic acid 4-fluorophenyl ester; 4-[4-(4-methanesulfonate) 4-methoxy-phenyl ester of 4-phenyloxymethyl)-thiazol-2-yl]-hexahydropyridine-1-carboxylate; 4-[4-(4-methanesulfonyl-phenoxymethyl) Na)-thiazol-2-yl]-hexahydropyridine-1-carboxylic acid naphthalen-1-yl ester; 4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazole-2 -yl]-hexahydropyridine-1-carboxylic acid isobutyl ester; 4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine-1 -carboxylic acid pentane 4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine-1-carboxylic acid 2-fluoro-ethyl ester; 4-[4- (4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid butyl ester; 4-[4-(4-tetrazol-1-yl- Phenoxymethyl)-thiazol-2-yl]-hexahydropyridine-1-carboxylic acid 2,2-dimethyl-propyl ester; 4-[4-(4-tetrazol-1-yl-phenoxy) Methyl)-thiazol-2-yl]-hexahydropyridine-1-carboxylate; 4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl ]-hexahydropyridine-1-carboxylic acid 2-ethyl-hexyl ester; 4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine 2-benzyloxy-ethyl ester of 1-carboxylic acid; 4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine-1-carboxylate 2-isopropyl-5-methyl-cyclohexyl acid; adamantyl-1-yl-{4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl] -hexahydropyridin-1-yl}-methanone; {4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}- Pyridin-3-yl-methanone; 3,3-dimethyl-1-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexa Hydropyridin-1-yl}-butan-1-one; keto-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazole-2- Methyl]-hexahydropyridin-1-yl}-methyl acetate; 3-keto-3-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazole-2- Ethyl]-hexahydropyridin-1-yl}-propionic acid ethyl ester; (4-methyl-hexahydropyridyl) 1-yl)-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-methanone; 4- [4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid diethyl decylamine; 4-[4-(4-tetra Zin-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid ethyl decylamine; 2-{4-[4-(4-methanesulfonyl-benzene Oxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine; 2-{4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazole-2 -yl]-hexahydropyridin-1-yl}-4-methoxy-pyrimidine; 2-{4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl] -hexahydropyridin-1-yl}-4-trifluoromethylpyrimidine; 2-{4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydro Pyridin-1-yl}-4,6-dimethyl-pyrimidine; 5-ethyl-2-{4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl ]-hexahydropyridin-1-yl}-pyrimidine; 5-ethyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]- Hexahydropyridin-1-yl}-pyrimidine; 5-fluoro-2-{4-[4-(6-tetrazol-1-yl-pyridin-3-yloxymethyl)-thiazol-2-yl ]-hexahydropyridin-1-yl}-pyrimidine; 5-bromo-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)- Zin-2-yl]-hexahydropyridin-1-yl}-pyrimidine; 5-fluoro-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazole- 2-yl]-hexahydropyridin-1-yl}-pyrimidine; 4,5-dichloro-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazole- 2-yl]-hexahydropyridin-1-yl}-pyrimidine; 4-chloro-5-methyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl) -thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine; 2-chloro-5-methyl-4-{4-[4-(4-tetrazol-1-yl-phenoxy) Methyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine; 5-(4-chlorophenyl)-2-{4-[4-(4-tetrazol-1-yl- Phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine; 5-chloro-2-{4-[4-(4-tetrazol-1-yl-phenoxy) Methyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine; 5-heptyl-2-{4-[4-(4-methanesulfonyl-phenoxymethyl) -thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine; 2-{4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexa Hydropyridin-1-yl}-5-pentyl-pyrimidine; 5-heptyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl ]-hexahydropyridin-1-yl}-pyrimidine; 5-pentyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]- Hexahydropyridin-1-yl}-pyrimidine ; 5-methyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine; -(4-methoxy-phenyl)-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine-1- 5-pyrimidine; 5-propyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl} -pyrimidine; 5-methoxy-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}- Pyrimidine; 5'-methyl-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-3,4,5,6-tetrahydro-2H- [1,2']bipyridine;4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-5',6"-bis-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2';6',2"]tripyridine; 4-[4-(4-tetrazol-1-yl-phenoxymethyl) -thiazol-2-yl]-5'-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridine; 4-[4-(4-tetrazole-1 -yl-phenoxymethyl)-thiazol-2-yl]-3,4,5,6-tetrahydro-2H-[1,2']bipyridyl-5'-carboxaldehyde; 1-(3 -isopropyl-[1,2,4] Diazol-5-yl)-4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine; 2-{4-[4-(4- Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-benzo Azole; 4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-5'-trifluoromethyl-3,4,5,6-tetrahydro-2H- [1,2']bipyridine; 5-ethyl-2-{4-[4-(2-fluoro-4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexa Hydropyridin-1-yl}-pyrimidine; 5-ethyl-2-{4-[4-(2-fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl ]-hexahydropyridin-1-yl}-pyrimidine; 4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-4-methyl-hexahydropyridine-1 -carboxylic acid tert-butyl ester; 4-[4-(4-methanesulfonyl-phenoxymethyl)-5-methyl-thiazol-2-yl]-piperidine-1-carboxylic acid Tri-butyl ester; 4-{4-[1-(4-methanesulfonyl-phenoxy)-ethyl]-5-methyl-thiazol-2-yl}-hexahydropyridine-1-carboxylic acid Third-butyl ester; 4-hydroxy-4-[4-(4-methylthio-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester; 4-hydroxy-4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester; 4-fluoro group- 3-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester; 5-ethyl-2-{4 -fluoro-4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl] -hexahydropyridin-1-yl}-pyrimidine; 4-fluoro-4-[5-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine-1- Tri-butyl carboxylic acid; 5-ethyl-2-{4-fluoro-4-[5-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydro Pyridin-1-yl}-pyrimidine; 4-{4-[(6-fluoro-pyridin-3-ylamino)-methyl]-thiazol-2-yl}-piperidine-1-carboxylic acid third -butyl ester; 1-(3-isopropyl-[1,2,4] Diazol-5-yl)-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine; 1-(3-ethyl-[ 1,2,4] Diazol-5-yl)-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine; 1-(3-cyclopropyl- [1,2,4] Oxazol-5-yl)-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine; 4-[4-(4-tetra Zin-1-yl-phenoxymethyl)-thiazol-2-yl]-1-(3-trifluoromethyl-[1,2,4] Oxazol-5-yl)-hexahydropyridine; 4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine-1-carboxylic acid hydrazine Amine; 4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine-1-carboxyformamidine; 3-[4-(4-tetra 3-oxazol-1-yl-phenoxymethyl)-thiazol-2-yl]-azatetraindole-1-carboxylic acid tert-butyl ester; 3-[4-(4-tetrazol-1-yl- Phenoxymethyl)-thiazol-2-yl]-tetrahydropyrrole-1-carboxylic acid tert-butyl ester; 5-ethyl-2-{3-[4-(4-tetrazol-1-yl) -phenoxymethyl)-thiazol-2-yl]-tetrahydropyrrol-1-yl}-pyrimidine; 3-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazole- 3-butyryl-trihydropyridine-1-carboxylic acid tert-butyl ester; 5-ethyl-2-{3-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazole -2-yl]-hexahydropyridin-1-yl}-pyrimidine; 4-[4-(4-methanesulfonyl-benzyloxymethyl)-thiazol-2-yl]-hexahydropyridine-1- Tri-butyl carboxylic acid; 2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine -5-ylamine; N-(2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}- Pyrimidin-5-yl)-acetamide; 4-[4-(4-tetrazol-1-yl-anilinyryl)-thiazol-2-yl]-hexahydropyridine-1- Acidic third-butyl ester; 4-[4-(4-trifluoromethanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester; 4-[4-(4-Trifluoromethanesulfinyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester; 4-[4-( 2,6-difluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester; 4-[4-( 4-pyrrol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine-1-carboxylic acid tert-butyl ester; 4-{4-[(4-tetrazole-1- 3-phenylamino)-methyl]-thiazol-2-yl}-hexahydropyridine-1-carboxylic acid tert-butyl ester; 2-{4-[4-(3-chloro-4-pyrene-4) Zin-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-5-ethyl-pyrimidine; N-(4-{2-[1-(5- Ethyl-pyrimidin-2-yl)-hexahydropyridin-4-yl]-thiazol-4-ylmethoxy}-phenyl)-carboxamide; N-(4-{2-[1-(5 -ethyl-pyrimidin-2-yl)-hexahydropyridin-4-yl]-thiazol-4-ylmethoxy}-phenyl)-methanesulfonamide; 4-[4-(2-methyl- 3-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester; 5-ethyl-2-{4-[4- (4-tetrazol-1-yl-2-trifluoromethyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine-1- 2-{4-[4-(2-chloro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl} -5-ethyl-pyrimidine; 4-[4-(2,6-difluoro-4-propenyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid Tri-butyl ester; 4-[4-(4-acetamido-2-fluoro-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester; 4 -[4-(4-Cyano-2-fluoro-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester; 4-[4-(6- Tetrazolyl-1-yl-pyridin-3-yloxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester; 4-[4-(4-[1, 2,3]triazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester; 4-[4-(4-ethoxycarbonyl) -phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester; 4-[4-(4-tris-butoxycarbonylamino-phenoxymethyl) Tris-butyl ester of 4-thiazol-2-yl]-hexahydropyridine-1-carboxylate; 4-[4-(4-carboxy-phenoxymethyl)-thiazol-2-yl]-hexahydro Pyridine-1-carboxylic acid tert-butyl ester; 4-[4-(2,6-difluoro-4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine- 1-carboxylic acid tert-butyl ester; 4-[4-(4-morpholin-4-yl-phenoxy) 3-)-thiazol-2-yl]-hexahydropyridine-1-carboxylic acid tert-butyl ester; 4-[4-(4-trifluoromethylsulfanyl-phenoxymethyl)-thiazole-2- Tert-butyl hexahydropyridine-1-carboxylic acid; 4-[4-(4-benzyloxy-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine-1-carboxylate Acidic third-butyl ester; 4-[4-(2-acetamido-4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine-1-carboxylic acid Tri-butyl ester; 4-(4-phenoxymethyl-thiazol-2-yl)-hexahydropyridine-1-carboxylic acid tert-butyl ester; 4-{4-[(4-methanesulfonyl) -Phenylamino)-methyl]-thiazol-2-yl}-piperidine-1-carboxylic acid tert-butyl ester; 4-{4-[(2-fluoro-4-methanesulfonyl) -Phenylamino)-methyl]-thiazol-2-yl}-piperidine-1-carboxylic acid isopropyl; 4-[4-(4-bromo-phenoxymethyl)-thiazole-2 -yl]-hexahydropyridine-1-carboxylic acid tert-butyl ester; {2-[1-(5-ethyl-pyrimidin-2-yl)-hexahydropyridin-4-yl]-thiazole-4- Methyl}-(2-fluoro-4-methanesulfonyl-phenyl)-amine; 4-{4-[(4-methanesulfonyl-benzylamino)-methyl]-thiazole-2 -yl}-hexahydropyridine-1-carboxylic acid tert-butyl ester; 4-(4-{[1-(4-methanesulfonyl-phenyl)-ethylamino]-methyl}-thiazole- 2-yl)-hexahydropyridine-1-carboxylic acid -butyl ester; 3-methyl-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl Ester; 4-[4-(2-fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-3-methyl-hexahydropyridine-1-carboxylic acid Tri-butyl ester; 4-[4-(2-fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid allyl ester 4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid cyclohexyl ester; 4-[4-(2- Fluoro-4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid isopropyl ester; 1-isopropyl-4-[4-(4- Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine; 1-propyl-4-[4-(4-tetrazol-1-yl-phenoxymethyl) )-thiazol-2-yl]-hexahydropyridine; 3,3-dimethyl-1-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazole-2- And hexahydropyridin-1-yl}-butan-2-one; 1-butyl-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl ]-hexahydropyridine; 2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-1-( 4-trifluoromethoxy-phenyl)-ethanone; 1-methanesulfonyl-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazole -2-yl]-hexahydropyridine; 4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridine-1-carboxylic acid heptyl ester; 4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-1-(toluene-4-sulfonyl)-hexahydropyridine; 2-third- Butoxy-1-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-ethanone; 5- Ethyl-2-{4-[4-(3-fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine ;2-{4-[4-(2,6-difluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-5 -ethyl-pyrimidine; 5-ethyl-2-{4-[4-(4-pyrrol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl} -pyrimidine; {2-[1-(5-ethyl-pyrimidin-2-yl)-hexahydropyridin-4-yl]-thiazol-4-ylmethyl}-(4-tetrazol-1-yl- Phenyl)-amine; 2-{4-[4-(2-fluoro-4-pyrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl }-5-isopropyl-pyrimidine; 5-ethyl-2-{4-[4-(2-methyl-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl} -pyrimidine; 5-chloro-2-{4-[4-(2-chloro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1 -yl}-pyrimidine; 2-{4-[4-(2-chloro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl }-5-trifluoromethyl-pyrimidine; 2-{4-[4-(2-isopropyl-5-methyl-4-tetrazol-1-yl-phenoxymethyl)-thiazole-2 -yl]-hexahydropyridin-1-yl}-5-trifluoromethyl-pyrimidine; 5-chloro-2-{4-[4-(2-isopropyl-5-methyl-4-tetra Zin-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine; 2-{4-[4-(2-fluoro-4-tetrazole- 1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-5-trifluoromethyl-pyrimidine; 5-nonyl-2-{4-[4-( 4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine; 6-methyl-2-{4-[4-(4- Methyl tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine-4-carboxylate; 4-chloro-2-{4-[ 4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine; 2-chloro-4-{4-[4- (4-tetrazol-1-yl-phenoxymethyl)- Zyridin-2-yl]-hexahydropyridin-1-yl}-pyrimidine; 6-methyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazole- 2-yl]-hexahydropyridin-1-yl}-pyrimidine-4-carboxylic acid; 5-chloro-4,6-difluoro-2-{4-[4-(4-tetrazol-1-yl) -phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine; 4-fluoro-2-{4-[4-(4-tetrazol-1-yl-benzene Oxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine; 2-fluoro-4-{4-[4-(4-tetrazol-1-yl-phenoxy) Methyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine; 2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazole-2 -yl]-hexahydropyridin-1-yl}-thiazole-5-carboxylic acid ethyl ester; 4-imidazol-1-yl-6-{4-[4-(4-tetrazol-1-yl-phenoxy) Methyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine; 5-ethyl-2-{4-[4-(6-tetrazol-1-yl-pyridine-3- Benzyloxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine; 5-methyl-2-{4-[4-(6-tetrazol-1-yl-pyridine- 3-yloxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine; 5-chloro-2-{4-[4-(6-tetrazol-1-yl- Pyridin-3-yloxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine; 2-{4-[4-(6-tetrazol-1-yl-pyridine-3 -yloxymethyl)-thiazol-2-yl ]-hexahydropyridin-1-yl}-5-trifluoromethyl-pyrimidine; 3-chloro-6-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)- Thiazol-2-yl]-hexahydropyridin-1-yl}-oxime ;2-tetrazol-1-yl-5-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl} -pyridyl {2-[1-(5-ethyl-pyrimidin-2-yl)-hexahydropyridin-4-yl]-thiazol-4-ylmethyl}-(6-fluoro-pyridin-3-yl)- Amine; 2-{4-[4-(2,6-difluoro-4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-5- Ethyl-pyrimidine; 5-butyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl} -pyrimidine; 4-(4-{2-[1-(5-ethyl-pyrimidin-2-yl)-hexahydropyridin-4-yl]-thiazol-4-ylmethoxy}-phenyl)- Morpholine; 5-nitro-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}- Pyrimidine; 3'-chloro-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-5'-trifluoromethyl-3,4,5 ,6-tetrahydro-2H-[1,2']bipyridine;3'-chloro-4-[4-(2-fluoro-4-tetrazol-1-yl-phenoxymethyl)-Thiazol-2-yl]-5'-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridine; 5-chloro-2-{4-[4- (2-fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine; 3',5'-dichloro-4 -[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-3,4,5,6-tetrahydro-2H-[1,2']bipyridine;3'-Chloro-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-3,4,5,6-tetrahydro-2H-[1,2']bipyridyl-5'-carboxylic acid ethyl ester; 5'-chloro-4-[4-(4-tetrazol-1-yl-phenoxymethyl) Methyl)-thiazol-2-yl]-3,4,5,6-tetrahydro-2H-[1,2']bipyridyl-3'-carboxylic acid methyl ester; 5-ethyl-2-{3 -methyl-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine; 5-ethyl-2 -{4-[4-(2-Fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-3-methyl-hexahydropyridin-1-yl}- Pyrimidine; 5-chloro-2-{4-[4-(2-fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-3-methyl-hexa Hydropyridin-1-yl}-pyrimidine; 2-{4-[4-(2-fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-3-methyl -hexahydropyridin-1-yl}-5-trifluoromethyl-pyrimidine; 5-ethyl-2-{4-[4-(4-methanesulfonyl-benzyloxymethyl)-thiazole- 2-yl]-hexahydropyridin-1-yl}-pyrimidine; 5-fluoro-2-{4-[4-(2-fluoro-4-tetrazol-1-yl-phenoxymethyl) -thiazol-2-yl]-hexahydropyridin-1-yl}-pyrimidine; 3-(4-{[(4-methanesulfonyl-phenyl)-methyl-amino]-methyl}-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (2-[1-(5-ethyl-pyrimidin-2-yl)-hexahydropyridin-4-yl]-thiazol-4-ylmethyl}-(2-fluoro-4-methanesulfonyl) -phenyl)-methyl-amine; 4-[4-(2-methylthio-pyrimidin-5-yloxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid -butyl ester; 4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid allyl ester; and pharmaceutically acceptable Accepted salts. The compound of claim 1 Or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of claim 1, 11 or 12. Use of a compound according to claim 1, 11 or 12 for the preparation of a medicament for the treatment of a disease or condition selected from the group consisting of Type I diabetes, Type II diabetes and metabolic syndrome group. A compound of 11 or 12 for use in the treatment of a disease or condition selected from the group consisting of Type I diabetes, Type II diabetes, and metabolic syndrome.