TW201105327A - Modulators of metabolism and the treatment of disorders related thereto - Google Patents

Abstract

The present invention relates to the GPR119 agonist, N-(2-fluoro-4-(methylsulfonyl) phenyl)-5-methyl-6-(1-(5-methylpyrazin-2-yl)piperidin-4-yloxy)pyrimidin-4-amine (Compound 1, Formula (I)), and pharmaceutically acceptable salts, solvates, and hydrates thereof, that are useful in the treatment of GPR119-related disorders, such as, metabolic-related disorders and complications thereof, such as, diabetes and obesity.

Description

201105327 VI. Description of the invention: [Technical field to which the invention pertains] The present invention relates to a GPR119 agonist N-(2-fluoro-4-(methylsulfonyl)phenyl)-5-methyl·6-(1_( 5-methyl-2-pyridyl)hexahydropyridin-4-yloxy)pyrimidine-4-amine (Chemical Formula (1)), and pharmaceutically acceptable salts, solvates and hydrates thereof, which are used for Treatment of GPR119 related disorders, such as metabolic related disorders and their complications, such as diabetes and obesity. [Prior Art] A · Diabetes Diabetes affects more than 100 million people worldwide. There are more than 12 million diabetic patients in the United States and 600,000 new diagnoses each year. Diabetes is a diagnostic term for a class of conditions in which abnormal glucose homeostasis leads to elevated blood glucose. There are many types of diabetes, but the two most common types are type 1 diabetes (also known as insulin-dependent diabetes or iddm) and type 2 diabetes (also known as non-insulin-dependent diabetes or NIDDM). The causes of different types of diabetes are different; however, each patient with diabetes has the same symptoms: the liver (4) is overproduced with sugar and has less or no ability to transfer glucose from the blood to the cells and become the body's main fuel in the cells. _ People without diabetes rely on a hormone produced by the parotid gland. The stomach II is from jk to the body cells. However, diabetic patients do not produce membrane 2 or cannot effectively use the insulin produced by them; therefore, they cannot move grapevines into their cells. Glucose accumulates in the blood, causing a condition called hyperglycemia, which can cause serious health problems over time. Diabetes is a syndrome with associated metabolic, vascular, and neurological symptoms. The general hallmark of metabolic syndrome is hyperglycemia, which involves changes in carbohydrate, fat, and protein metabolism caused by a deficiency or significant reduction in insulin secretion and/or ineffective insulin action. Vascular syndrome consists of vascular abnormalities that lead to cardiovascular, retinal, and renal complications. Peripheral and autonomous neurological abnormalities are also part of the diabetes syndrome. About 5% to 10% of diabetic patients have IDDM. These individuals do not produce insulin and therefore must maintain their blood glucose levels by injecting insulin. IDDM is characterized by a low or no detectable amount of endogenous insulin production caused by destruction of pancreatic beta cells that produce temsin, a feature that is most likely to distinguish IDDM from NIDDM. IDDM, once known as juvenile diabetes, also invades teenagers and adults. About 90% to 95% of people with diabetes have type 2 diabetes (or NIDDM). NIDDM individuals produce insulin, but the cells in their bodies have insulin resistance: these cells do not respond correctly to hormones, so glucose accumulates in their blood. NIDDM is characterized by a relative imbalance between endogenous insulin production and insulin demand, resulting in higher blood glucose concentrations. In contrast to IDDM, there are always some endogenous oxytocin production in NIDDM; many NIDDM patients have normal or even souther blood oxygen levels, while other Niddm patients produce insulin deficiency (Rotwein, R. et al. n. Engl J. Med. 308, 65-71 (1983)) » Most people diagnosed with NIDDM are 30 years of age or older' and half of the new cases are 55 years of age and older. Compared with whites and Asians, NIDDM is more common in Native Americans, African Americans, Latin 149380.doc 201105327 Americans and Hispanics. In addition, the onset may be insidious or even clinically insignificant, resulting in diagnostic difficulties. The main pathogenic lesions of NIDDM remain unclear. Many people have suggested that the main temperament resistance of peripheral tissues is the main event. The transmission of epidemiological studies supports this view. Similarly, it has been advocated that the abnormal secretion of 姨 素 is a major defect of NIDDM. It is possible that both phenomena are an important part of the disease process (Rimom, D. L_ et al. Emery and Rim〇in, s Principles and

Practice of Medical Genetics^3^ . 1:1401-1402 (1996)) 〇 Many niddm patients have a sedentary lifestyle and are obese; their body weight is about 20% more than the recommended weight for their height and physique. In addition, obesity is characterized by hyperinsulinemia and insulin resistance (which is also characteristic of niddm), hypertension, and atherosclerosis. Diabetes patients face a reduction in life expectancy of 3〇β/” After 45 years of age, diabetic patients are more than three times more likely to have significant heart disease than those without diabetes and five times more likely to have heartbeat. These findings emphasize The interrelationship between NIDDM and risk factors for coronary heart disease and the potential value of a comprehensive approach to prevent such conditions (perry, l., et al, BMJ 310 560 564 (1995)). Diabetes also suffers from kidney disease, eye disease It is related to nervous system problems. Kidney disease, also known as kidney disease, occurs when the "filtration mechanism" of the kidney is impaired, and at this time, the protein is excessively leaked into the urine and eventually the kidney cannot perform its function. Diabetes is also the leading cause of retinal damage in the back of the eye and increases the risk of cataracts and menstrual eyes. H diabetes is particularly associated with the damage of the legs and the limbs. It interferes with the ability to feel pain and promotes serious infections. In general, 'diabetes complications are one of the leading causes of death in the country. 149380.doc 201105327 B. Obesity The most common human health problem in the industrialized society of obesity and diabetes. One third of the population in industrialized countries is at least 2% overweight. In the United States, the percentage of obese people has increased from 25% in the late 1970s to 33% in the early 1990s. Obesity is one of the most important risk factors for NIDDM. Obesity is defined differently, but in general, the body is considered to be obese by weighing more than 2% of the weight recommended for its height and physique. The risk of developing an NIDDM in an overweight 301⁄4 person is tripled, and three-quarters of NIDDM patients are overweight. In experimental animals and humans, obesity is highly correlated with insulin resistance and diabetes as a result of an imbalance between caloric intake and energy expenditure. However, the molecular mechanisms involved in the obesity-hypercrine disorder are still unclear. During the early development of obesity, increased glandular secretion can balance membrane resistance and protect patients from hyperglycemia (Le Stunff et al. Diabetes 43, 696-702 (1989)). However, decades later, beta cell function degraded and approximately 2% of obese populations developed non-Tenger-dependent diabetes mellitus (Pederson, P. Diab. Metab.

Rev. 5, 505-509 (1989)) and (Brancati, F. L. #A, Arch·

Intern. Med. 159, 957-963 (1999)). Given the high prevalence of obesity in contemporary society, it has therefore become a primary risk factor for NIDDM (Hill, J. 〇. et al. Science 280, 1371-1374 (1998)). However, it is still unknown that some patients are prone to changes in insulin secretion due to fat accumulation. The classification of a person as overweight or obesity can be determined by a number of different methods (eg, based on their body mass index (BMI)), which is calculated by dividing body weight (kg) by the square of the south (m2) of 149380.doc 201105327. Therefore, the unit of the face is kg/m2 and the painting related to the minimum mortality rate of each age group can be calculated (4). Overweight is defined as 8 milk in the range of 25-3 〇 kg/m2, and obesity is defined as _ greater than 3 〇 kg/m2 (see table below). The problem with this definition is that it does not account for the body weight ratio of muscle to fat (fatty tissue). In order to consider this problem, obesity can also be defined as based on body fat content, which is greater than 25% and 30% in men and women, respectively. . Body weight by weight; ^B (BMI) BMI _ Classification <18.5 Weight is 18.5-24.9 Normal 25.0 - 29.9 - Overweight _:~30.0-34.9 Obesity α) 35.0-39.9 Obesity αι) ~~ ~ >40 Extremely obese (Level III) - As BMI increases, the risk of death is increased by a variety of factors independent of other risk factors. The most common diseases associated with obesity are cardiovascular disease (especially hypertension), diabetes (obesity worsens diabetes development), gallbladder disease (especially cancer), and reproductive diseases. Studies have shown that even moderate weight loss can correspond to a significant reduction in the risk of coronary heart disease. Obesity also significantly increases the risk of cardiovascular disease. Coronary arterial insufficiency, atherosclerotic disease, and cardiac insufficiency are preceded by cardiovascular complications caused by obesity. It is estimated that if all people have an ideal body weight, the risk of coronary insufficiency will be reduced by 25% and the risk of cardiac insufficiency and cerebrovascular accidents will be reduced by 35%. The incidence of coronary heart disease is doubled in individuals over 50% of those under 50 years of age. 149380.doc 201105327 c. Atherosclerosis Atherosclerosis is characterized by complex diseases of inflammation, lipid accumulation, cell death and fibrosis. "Atherosclerosis is characterized by cholesterol deposition and monocyte infiltration into the subendothelial space. This results in the formation of foam cells. A thrombosis after atherosclerosis can lead to myocardial infarction and stroke. Atherosclerosis is the leading cause of death in many countries, including the United States. (See, for example, Ruggeri, Nat Med (2002) 8: 1227-1234; Arehart et al, Circ Res, Circ. Res. (2008) 102: 986-993.) D. Osteoporosis Osteoporosis Resilience Disease, characterized by loss of bone mass and microstructural deterioration of the skeletal structure leading to impaired bone strength, which makes patients susceptible to increased risk of fragility fractures. Osteoporosis affects more than 75 million people in Europe, Japan and the United States. More than 2.3 million fractures were caused in Europe and the United States alone. In the United States, osteoporosis affects at least 25% of all postmenopausal white women, and this proportion rises to 70% among women over 8 years of age. One third of women over 5 years of age will have f f loose fractures, which will cause enormous social and financial burden on Du Hui. The disease is not limited to women; it can also affect older men. By 2050, the incidence of hip fractures in men worldwide is expected to increase by 310% and women by 24%. Clinically, the lifetime risk of hip, forearm, and spinal fractures is approximately 4%, which is equivalent to the risk of cardiovascular disease. Therefore, osteoporotic fractures cause major mortality, morbidity and economic costs. Unless an effective prevention strategy is developed, the number and cost of osteoporotic fractures will increase at least twice in the next five years as the elderly population increases. (For example, see Stealing 149380.doc 201105327, Clin Orthop Relat Res (2006) 443:19-24; Raisz, J Clin Invest (2005) 1 15:3318-3325; and World Health Organization

Technical Report Series 921 (2003), Prevention and

Management of Osteopoosis ° ) E. Inflammatory Bowel Disease (IBD) Inflammatory bowel disease (IBD) is a generic name for diseases causing intestinal inflammation and includes, for example, Crohn's disease, ulcerative colitis, ulcers Sexual proctitis. It is estimated that the medical expenses of inflammatory bowel disease in the United States in 1990 were between $1.4 billion and $1.8 billion. It is estimated that the lost productivity increased by an additional $400 million to $800 million, making the estimated cost of inflammatory bowel disease between $1.8 billion and $2.6 billion. (See, for example, Pearson, Nursing Times (2004) 100:86-90 ' Hay et al, j Clin Gastroenterol (1992) 14:309-317; Keighley et al., Ailment Pharmacol Ther (2003) 18:66-70 〇) Enteritis refers to the inflammation of the intestines, especially the small intestines, which can be caused by a general condition caused by any of a number of different causes. Enterocolitis refers to inflammation of the small intestine and colon. Crohn's disease (CD) is an inflammatory process that can invade any part of the digestive tract, but is most commonly found in the last part of the small intestine, which is otherwise referred to as the (end) ileum and cecum. This area is also collectively referred to as the ileocecal area. Other conditions may affect one or more of the following: colon only, small intestine (duodenum, jejunum and/or ileum), anus, stomach or esophagus. In contrast to ulcerative colitis, CD does not invade the rectum and often attacks the anus. The sputum extends deep into the lining of the affected organ. Inflammation can cause pain and can cause frequent emptying of the intestines, leading to diarrhea. Crohn's disease can also be called enteritis. 149380.doc 201105327 Granulomatous colitis is another name for Crohn's disease that invades the colon. The ileum is the CD of the ileum and the third part of the small intestine of the ileum. The Crohn's disease affects the CD of some or all of the colon. Ulcerative colitis (UC) is commonly referred to as the inflammatory disease of the large intestine of the colon. Uc causes inflammation and ulceration of the colon and rectum. Uc inflammation - is most severe in the rectal area, and the severity decreases toward the cecum of the junction of the large intestine and the small intestine (the rate varies from patient to patient). Rectal inflammation is called proctitis. The inflammation of the sigmoid colon (just above the rectum) is called sigmoid colitis. Inflammation involving the entire colon is called total colitis. This inflammation causes frequent colon emptying, which leads to diarrhea. Muscle, pus and blood are released as a result of the destruction of the colonic lining. Ulcerative proctitis is a form of UC that only invades the rectum. F. GPR119 GPR119 is a G protein-coupled receptor (GPR119; for example, human GPR119 ' GenBank® accession number AAP72125 and its allele; for example, mouse GPR119, GenBank® accession number AY288423 and its allele) and in the pancreas beta The selective expression of GPR11 9 on cells produces an increase in intracellular cAMp concentration associated with GPR119 coupled to G. An agonist of GPR119 activates glucose-dependent insulin secretion in vitro and reduces elevated blood glucose concentrations in vivo; for example, see International Application Nos. WO 04/065380 and WO 04/076413, and EP 1338651, all of which are incorporated herein by reference. The disclosure is incorporated herein by reference. In the literature, GPR119 is also known as RUP3 (see 'International Application No. 00/31258') and is referred to as the glucose dependent pro-apoptotic receptor GDIR (see, J〇nes et al. Expert 149380.doc-10). - 201105327

Opin. Ther. Patents (2009), 19(10): 1339-1359). GPR119 agonists also stimulate the release of glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and at least one other L-cell peptide (peptide YY (PYY)) (Jones et al. Expert Opin. Ther. Patents (2009), 19(10): 1339-1359); specific references related to the release of GPR119 agonists and the following peptides are as follows: GIP, see Shah, Current Opinion in Drug Discovery & Development, (2009) 12:519-532; Jones et al, Ann·Rep. Med. Chem., (2009) 44: 149-170; WO 2007/120689; and WO 2007/120702; GLP-1, see Shah, Current Opinion in Drug Discovery & Development, (2009) 12:519-532; Jones et al, Ann. Rep. Med. Chem., (2009) 44:149-170; Schwartz et al, Cell Metabolism, 2010, 11:445-447 And WO 2006/076231; and PYY, see Schwartz et al, Cell Metabolism, 2010, 11: 445-447; and WO 2009/126245. As described above, GPR119 agonists can promote glucagon release and are therefore useful in the treatment of conditions associated with incretins such as GIP, GLP-1 and PYY. However, the receptors of various incretin enzymes such as GIP and GLP-1 are DPP-IV. Jones and co-workers (Jones et al., Ann. Rep. Med_Chem., (2009) 44: 149-170) have demonstrated that a combination of GPR119 agonist (2-fluoro-4-nonanesulfonyl-phenyl) has been demonstrated. )-{6-[4-(3-isopropyl-[1,2,4] ° dioxin. sit-5-yl)-hexahydro-β-biti-1-yl]-5-nitro-. Mickey-4-yl}-amine (see, Compound Bill in WO 2004/065380) and DPP-IV inhibitor dramatically increase blood GLP-1 concentration by 149380.doc 201105327 significantly greater than either agent alone Improve glucose tolerance. G·glucose-dependent insulinotropic polypeptide (GIP) The glucose-dependent insulinotropic polypeptide (GIP, also known as gastric inhibitory peptide) is a 42 amino acid peptide incretin hormone, which is derived from the duodenum after dietary intake. Endocrine K cells are released. The amount of GIP released depends primarily on the amount of glucose consumed. GIP has been shown to stimulate the secretion of glucose-dependent insulin in pancreatic beta cells. GIP mediates its effects by means of a specific G protein-coupled receptor, GIPR. Since GIP contains alanine at the 2-position, it is an excellent substrate for regulating the GIP-degrading enzyme dipeptidyl peptidase-4 (DPP-IV). Full-length GIP (1_42) is rapidly converted to bioinactive GIP (3-42) within minutes of secretion from intestinal K cells. Inhibition of DPP-IV has been shown to enhance the biological activity of GIP. (See, for example, Drucker, Cell Metab (2006) 3: 153-165; McIntosh et al, Regul Pept (2005) 128: 159-165; Deacon, Regul Pept (2005) 128: 117-124; and Ahren et al. Endocrinology (2005) 146:2055-2059). An N-terminal specific assay can be used to perform an analysis of, for example, full-length bioactive GIP in blood (see, for example, see

Deacon et al, J Clin Endocrinol Metab (2000) 85: 3575-3581). Recently, GIP has been shown to promote bone formation. GIP has been shown to activate osteoblast receptors, thereby increasing type I collagen synthesis and alkaline phosphatase activity, both of which are involved in bone formation. GIP has been shown to inhibit the activity and differentiation of osteoclasts in vitro. Administration of GIP has been shown to prevent ovarian resection due to ovarian resection 149380.doc 12 201105327 Bone loss. GIP receptor (GIPR) knockout mice show altered bone size, decreased bone mass, altered bone microstructure and biochemical properties, and altered bone turnover (especially in bone formation). (For example, see Zhong et al., Am J Physiol

Endocrinol Metab (2007) 292: E543-E548; Bollag et al, Endocrinology (2000) 141:1228-1235; Bollag et al, Mol Cell Endocrinol (2001) 177: 35-41; Xie et al, Bone (2005) 37 :759-769; and Tsukiyama et al., Mol Endocrinol (2006) 20:1644-1651. The usefulness of GIP for maintaining or increasing bone density or formation has been recognized by the United States Trademark and Patent Office by issuing US Patent No. 6,410,508, which is used to administer GIP peptides. To treat bone mineralization is reduced. However, current GIP peptide agonists lack oral bioavailability, which adversely affects patient compliance. An attractive alternative is the development of oral active compositions for increasing the endogenous level of GIp activity. H. High Glucagon-Like Peptide The glucagon-like peptide, UGLP-1, is an incretin hormone obtained by post-translational modification of proglucagon and secreted by enteroendocrine cells. GLP4 mediates its effects by means of a specific G-protein coupled receptor (ie, GLp_1R). The best feature of GLp_ 1 is the hormone that regulates glucose homeostasis. GLP-1 has been shown to stimulate glucose-dependent insulin secretion and increase pancreatic p-cell mass. GLP-1 has also been shown to reduce gastric emptying rates and improve satiety. The efficacy of GLp_丨 peptide agonists in controlling blood glucose in type 2 diabetes has been demonstrated in several clinical studies [see, for example, Nauck et al., Drug News Perspect 149380.doc • 13· 201105327 (2003) 16:413- 422], its efficacy in reducing body weight has also been demonstrated [Zander et al, Lancet (2002) 359: 824-830]. GLP-1 receptor agonists are additionally useful for protecting against myocardial infarction and cognitive and neurodegenerative disorders. GLP-1 has been shown to be cardioprotective in a rat model of myocardial infarction [Bose et al, Diabetes (2005) 54: 146 151], and GLP-1R has been shown in rodent models with learning and neuroprotection Related to [During et al, Nat. Med. (2003) 9: 1173-1179; and Greig et al, Ann NY Acad Sci (2004) 1035: 290-315]. Certain conditions, such as type 2 diabetes, are characterized by a lack of GLP-1 [see, for example, Nauck et al., Diabetes (2004) 53 Supplement 3: S190-196]. Current GLP-1 peptide agonists lack oral bioavailability, which adversely affects patient compliance. To date, efforts to develop non-peptide small molecule agonists of GLP-1R that are orally bioavailable have not been successful [Mentlein, Expert Opin Investig Drugs (2005) 14: 57-64]. An attractive alternative is the development of oral active compositions for increasing the endogenous concentration of GLP-1 in the blood. I. Peptide YY (PYY) Peptone ΡΥΥ (ΡΥΥ) is the 36 amino acid peptide originally isolated from pig intestine in 1980 (Tatemoto et al, Nature (1980) 285: 417-418). The sputum is secreted from the enteroendocrine L-cells in both the large intestine and the small intestine. It has been shown that in the intestine of rats and humans, the concentration of immunoreactive PYY is lower in the duodenum and jejunum, higher in the ileum and colon, and highest in the rectum (Lundberg et al., PNAS USA (1982) 79:4471 -4475; Adrian et al., Gastroenterol. (1985) 89:1070-1077; Ekblad et al., 149380.doc 14 201105327

Peptides (2002) 23:251-261; Ueno et al., Regul Pept (2008) 145:12-16). It has been reported that the expression of PYY in rats also extends to the alpha cells of the islets of Langerhans and the cells in the medulla oblongata (Ekblad et al., Peptides (2002) 23:251-261); PYY is in the form of PYYN36 and ργγ3_36 Release into the circulation (Eberlein et al, Peptides (1989) 10: 797-803). ΡΥΥ3_3 ό is produced by dipeptidyl peptidase IV cleavage of ΡΥΥ, N-terminal Tyr and Pro residues of hydrazine. The main form of ργγ3_36 ργγ in human postprandial plasma (Grandt et al, Regul. Pept. (1994) 51:151-159). It has been reported that ΡΥΥ··36 and PYY3-36 have comparable agonist activities to the G protein-coupled receptor NPY Y2 receptor (Y2R) (Parker et al., Br. J. Pharmacol. (2008) 153:420-431); However, it has been reported that 卩丫丫3 36 is a high affinity Y2R selective agonist (Keire et al., Am. J. Physiol.

Gastrointest. Liver Physiol (2000) 279: G126-G131). It has been reported that PYY can reduce the high-fat food intake of rats after peripheral administration (Okada et al., Endocrinology Supplement (1993) 180) and causes weight loss in mice after peripheral administration (Morley et al., Life Sciences (1987). 41:2157-2165) ° Peripheral administration of PYYS_36 has been reported to significantly reduce food intake and weight gain in rats, reduce appetite and food intake in humans, and reduce food intake in mice, but does not exist in non-Y2R mice. These conditions, according to this, indicate that the food intake effect requires Y2R. In human studies, infusion of ργγ3_36 significantly reduced appetite and reduced food intake by 33% within 24 hours. Infusion of ργγ3·36 until the normal postprandial circulating concentration of the peptide is reached such that 1>¥¥3 36 peaks in serum concentration within 5 minutes' which then rapidly drops to the base I49380.doc 15 201105327 level within 3 minutes. It has been reported that PYY3·36 significantly inhibited food intake during the 12-hour period after infusion, but had no effect on food intake during the 12-hour to 24-hour period. In the rat study, cumulative food intake was reduced by intraperitoneal administration of ΡΥΥ3 % (2 injections per sputum for 7 曰) (Batterham et al., Nature (2002) 418:650-654; Renshaw et al. , Current Drug Targets (2005) 6: 171-179). Peripheral administration of PYY3-36 has been reported to reduce food intake, weight gain, and glycemic index in a variety of rodent models of metabolic diseases of both genders (glycemic indicesKPittner et al., int. j· 〇b?s Relat Metab)

Disord· (2004) 28: 963-971). Blocking Y2R with the specific antagonist BIIE-246 has been reported to attenuate the effects of peripherally administered endogenous and exogenous ργγ3 on reducing food intake (Abbott et al., Brain Res (2005) 1 043 :1 39- 144). Peripheral administration of a new long-acting selective Y2R polyethylene glycol-conjugated peptide agonist in rodents has been reported to reduce food intake and improve glucose metabolism (glucose clearance, mortar insulin, and blood glucose) (0rtiz et al., JPET) (2007) 323: 692-700; Lamb et al., J. Med. Chem. (2007) 50: 2264-2268). Removal of PYY in mice has been reported to produce hyperinsulinemia and obesity (Boey et al, Diabetologia (2006) 49: 1360-1370). Peripheral administration of long-acting, highly selective Y2R agonists has been shown to inhibit food intake and promote fat metabolism in mice (Balasubramaniam et al. Peptides (2007) 28: 235-240). There is evidence that stimulation of P YY is in vivo. Internally synthesized agents can confer protection against diet-induced and hereditary obesity and can increase glucose yield (Boey et al, Neuropeptides (2008) 42: 19-30). 149380.doc -16- 201105327 It has been reported that Y2R agonists such as PYYi-36 and ΡΥΥ3_36 confer protection against seizures (eg against seizure-induced seizures) (Ε1 Bahh et al., Eur. J. Neurosci) (2005) 22: 1417-1430; Woldbye et al., Neurobiology of Disease (2005) 20: 760-772). It has been reported that Y2R agonists such as PYYu36 and PYY3-36 have been used as pro-absorbent (or anti-secretory) hormones, which increase the absorption of both water and sodium in various parts of the intestine after intravenous administration (Bilchik) Et al, Gastroenterol. (1993) 105: 1441-1448; Liu et al, J. Surg_ Res. (1995) 58:6-11; Nightingale et al, Gut (1996) 39:267-272; Liu et al. Am Surg (1996) 62: 232-236; Balasubramaniam et al, J. Med. Chem. (2000) 43: 3420-3427). Y2R agonists such as PYY analogs have been reported to inhibit intestinal epithelial secretion and promote absorption and growth (Balasubramaniam et al, J. Med. Chem. (2000) 43:3420-3427). PYY has been reported to promote intestinal growth in normal rats (Gomez et al, Am. J. Physiol. (1995) 268: G71-G81). Y2R agonists such as ΡΥΥ!_36 and PYY3-36 have been reported to inhibit bowel movement and prevent diarrhea (ΕΡ 1902730; see also Cox, Peptides (2007) 28:345-35 1). It has been reported that Y2R agonists such as PYY丨36 and ΡΥΥ3·36 can confer protection against inflammatory bowel diseases such as ulcerative colitis and Crohn's disease (WO 03/105763). It has been reported that deficient mice exhibit an osteoporotic phenotype, ie, sputum can increase bone mass and/or can confer protection against loss of bone mass (eg, reduce bone mass loss) (Wortley et al, Gastroenterol (2007) 133: 1534-1543). PYY3_36 has been reported to confer protection to the pancreatitis 149380.doc -17· 201105327 Tooth model (Vona-Davis et al, Peptides (2007) 28: 334-338) 血管 has been reported to be angiogenic in Y2R-deficient mice Lesions (Lee et al, Peptides (2003) 24: 99-106), ie agonists of Y2R such as PYY!.36 and PYY3-36 promote angiogenesis. Y2R-deficient mice have been reported to have impaired wound healing (Ekstrand et al, PNAS USA (2003) 100: 6033-6038), ie, agonists of Y2R such as ΡΥΥ!.% and PYY3_36 promote wound healing. Ischemic angiogenesis in Y2R-deficient mice has been reported to be impaired (Lee et al., J. Clin. Invest. (2003) 11 1:1853-1862), ie, the stimulation of Y2R such as PYY丨36 and PYY3-36 The agent promotes revascularization and functional recovery of ischemic tissue. An increase in collateral-dependent blood flow in a rat model of peripheral arterial disease such as ΡΥΥ^δ and ΡΥΥ3-36 has been reported (Cruze et al., Peptides (2007) 28:269-280) It is reported that PYY and Y2R agonists such as PYY3-36 can inhibit tumor growth in, for example, pancreatic cancer (eg, pancreatic ductal adenocarcinoma), breast cancer (eg, breast invasive ductal adenocarcinoma), colon cancer (eg, colon gland) Cancer) and Barrett's adenocarcinoma (Liu et al., Surgery (1995) 118: 229-236; Liu et al, J. Surg. Res. (1995) 58: 707-712; Grise et al. J. Surg·Res. (1999) 82:151-155; Tseng et al., Peptides (2002) 23:389-395; McFadden et al., Am. J. Surg. (2004) 188:516-519). Stimulation of Y2R by, for example, PYY3_36 has been reported to result in an increase in plasma adiponectin (Ortiz et al, JPET (2007) 323:692-700). Adiponectin is an adipokine with potent anti-inflammatory properties. 149380.doc • 18-201105327 (Ouchi et al., Clin Chim Acta (2007) 380:24-30; Tilg et al., Nat· Rev. Immunol· (2006) 6:772-783). Adiponectin exerts anti-atherosclerotic effects and insulin sensitization effects mainly in muscle and liver by targeting vascular endothelial cells and macrophages (Kubota et al., J. Biol. Chem. (2002) 277:25863 -25866; Maeda et al., Nat. Med. (2002) 8: 731-737). Low adiponectin concentrations have been reported to be associated with atherosclerotic lipoproteins in dyslipidemia (triglyceride elevation, small dense LDL cholesterol, low HDL cholesterol) (Marso et al., Diabetes Care (2008) February 5曰, electronic publication before printing). Adiponectin is involved in the assembly of high density lipoprotein (HDL) (Oku et al., FEBS Letters (2007) 581: 5029-5033). Adiponectin has been shown to improve metabolic syndrome abnormalities in a mouse model of obesity-associated metabolic syndrome associated with decreased adiponectin concentrations, including insulin resistance, hyperglycemia, and dyslipidemia (Hara et al' Diabetes Care ( 2006) 29:13 57-1362). Adiponectin has been reported to stimulate angiogenesis in response to tissue ischemia (Shibata et al, J. Biol. Chem. (2004) 279:28670-28674). Adiponectin has been reported to prevent cerebral ischemic injury by means of an endothelial nitric oxide synthase-dependent mechanism (Nishimura et al., Circulation (2008) 117:216-223). Adiponectin has been reported to confer protection against myocardial ischemia-reperfusion injury (Shibata et al., Nat

Med (2005) 11:1096-1103; Tao et al., Circulation (2007) 115:1408-1416). Adiponectin has been reported to confer protection against myocardial ischemia-reperfusion injury via amp-activated protein kinase, Akt and nitric oxide (Gonon et al, Cardiovasc Res. (2008) 78:1 16-122). It has been reported that adiponectin can protect against cardiac hypertrophy and interstitial fibrosis and protect against muscle cell and capillary loss from 149380.doc 19 201105327 to protect against myocardial contraction after myocardial infarction (Shibata et al., J_) Mol. Cell Cardiol. (2007) 42:1065-1074). Adiponectin has been reported to confer protection against inflammatory lung disease; adiponectin-deficient mice exhibit an emphysema-like phenotype (Sumnier et al.

Am J. Physiol. Lung Cell Mol. Physiol (March 7, 2008)). Adiponectin has been reported to confer protection against allergic airway inflammation and airway hyperresponsiveness that may be associated with asthma (Sh〇re et al., j. Allergy Clin.

Immunol (2006) 118: 389-395). Adiponectin has been shown to confer protection against high pulmonary arteries by virtue of its insulin sensitization effect (Hansmann et al., Circulation (2007) 1 15..1275-1284). Adiponectin has been reported to improve obesity-related hypertension, where the improvement in this hypertension is partly related to the upregulation of prostacyclin (Ohashi et al., Hypertension (2006) 47: 1108-1 116). Adiponectin has been reported to reduce the expression of adhesion molecules VCAM-1, E-selectin and ICAM-1 induced by tumor necrosis factor (TNF)-a in human main endothelial cells (HAEC) (〇uchi et al., Circulation ( 1999) 100: 2473-2476) and inhibits the production of TNF_α in macrophages (Yokota et al., Blood (2000) 96: 1723-1732). Adiponectin has been reported to confer protection against restenosis after vascular intervention (Elbow, et al., J Biol Chem (2002) 277: 37487-37491). The important role of tnf-cx in inflammation has been demonstrated by agents capable of preventing the action of TNF-a in the treatment of various inflammatory conditions. TNF-a-mediated inflammatory conditions include rheumatoid arthritis, inflammatory bowel disease (eg, Crohn's disease), ankylosing spondylitis, psoriasis, ischemic brain damage, cardiac allograft rejection, asthma, and the like (Bradley, J Pathol (2008) 214: 149-160). For example, 149380.doc •20-201105327 See Yamamoto et al., Clinical Science (2002) 103:137-142; Behre, Scand J Clin Lab Invest (2007) 67:449-458; Guerre-Millo, Diabetes & Metabolism ( 2008) 34:12-18; Parker et al., Br. J. Pharmacol. (2008) 153:420-431. SUMMARY OF THE INVENTION The present invention relates to N-(2-fluoro-4-(methylsulfonyl)phenyl)-5-methyl-6-(1-(5-methyl-pyrazine-2-yl) Hexahydron-pyridin-4-yloxy)pyrimidine-4-amine (Compound 1, Formula (I)), and pharmaceutically acceptable salts, solvates and hydrates thereof, and uses thereof, and the like It binds to GPCR (herein referred to as GPR119) and modulates its activity. The term GPR119 as used herein includes human sequences, naturally occurring allelic variants, mammalian orthologs, and recombinant mutants thereof, found in GeneBank Accession No. AY28 84 16. A preferred human GPR119 for screening and testing a compound of the invention is provided in the nucleotide sequence of Seq. ID. No: 1 found in pcT application No. WO 2005/007647 and Seq. ID. No: 2 The entire disclosure of this application is incorporated herein by reference. One aspect of the present invention encompasses a compound selected from the group consisting of the following compounds of the formula (1) and pharmaceutically acceptable salts, solvates and hydrates thereof:

One aspect of the present invention relates to a pharmaceutical composition comprising a compound selected from the group consisting of a compound of the formula (I) and a pharmaceutically acceptable salt thereof, a solvate and a hydrate thereof, 149380.doc -21 - 201105327, and a pharmaceutically acceptable Accepted carrier. One aspect of the present invention relates to a composition comprising a compound selected from the group consisting of a compound of the formula (1) and a pharmaceutically acceptable salt, solvate thereof and hydrate thereof, and an inhibitor of dipeptidyl peptidase IV (DPP-IV) . One aspect of the invention pertains to compositions wherein the inhibitor of Dpp-iv is selected from the group consisting of the following compounds and pharmaceutically acceptable salts, solvates and hydrates thereof: 3(R)-amino-1-[3 -(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-8]°pyrazine-7-yl]-4-(2,4 , 5-trifluorophenyl)butan-1-one; 1-[2-(3-hydroxyadamantan-1-ylamino)ethenyl]D-pyridyl-2(s)-carbonitrile; 18,38,58)-2-[2(8)-Amino-2-(3-hydroxydext-1-yl)ethenyl]- 2-azabicyclo[3.1.0]hexane -3-carbonitrile; 2-[6-[3(R)-aminohexahydropyridin-1-yl]-3-indolyl-2,4-di-oxy-1,2,3,4- Tetrahydropyrimidin-1-ylindenyl]benzonitrile; 8-[3(R)-aminohexahydropyridin-1-yl]-7-(2-butynyl)-3-indolyl-1 -(4-mercaptoquinazolin-2-ylindenyl)xanthine; 1-[N-[3(R)-pyrrolidinyl]glycidyl]pyrrolidine-2(R)-ylboronic acid; 4(S)-fluoro-l-[2-[(lR,3S)-3-(lH-l,2,4-triazol-1-ylindenyl)cyclopentylamino]ethinyl]0 Bilobidine-2(S)-indene nitrile; l-[(2S,3S,llbS)-2-amino-9,10-dimethoxy-2,3,4,6,7,1113-hexa Hydrogen-1H-. Bis-[2,l-a]isoquinolin-3-yl]-4(S)-(fluoromethyl). Biloxidin-2-one; (2S,4S)-2-cyano-4-fluoro-l-[(2-hydroxy-i,i-dimethyl)ethylamino]ethyl 149380.doc •22 · 201105327 The base is more than each bite; 8_(cis-hexahydro-pyrrolo[3,2-b]pyrrol-1-yl)-3-indolyl-7-(3-methyl-but-2 -alkenyl)-bu(2-o-oxy-2-phenylethyl)-3,7-dihydroindol-2,6-dione; 1-((38,43)-4-amino group 1-(4-(3,3-difluoropyrrolidin-1-yl)-1,3,5-triazin-2-ylpyridinium _3_yl)-5,5 difluorohexahydro ° ratio ketone-2-ketone; (R)-2-((6-(3-aminohexahydro.bipyridin-1-yl)-3-methyl-2,4-di-oxyl- 3.4- Dihydropyrimidin-1(2H)-yl)methyl)-4-fluorobenzonitrile; 5-{(S)-2-[2-((S)-2-cyano-indolyl-1-yl) -2-Sideoxy-ethylamino]-propyl}-5-(1Η-tetra. sit-5-yl) 10,11-dihydro-5H-dibenzo[a,d]cycloheptane Ethylene-2,8-dicarboxylic acid bis-dimethyl decylamine; ((2S,4S)-4-(4-(3-indolyl-1-phenyl-indole-n-biazole-5-yl)hexa Hydropyridinium _1 _1 · · -2 -2 -2 四 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( Carbonylbicyclo[2.2 2]octyl-1amino)amino]ethinyl]-4-fluoropyrrolidin-2-carbonitrile; 6-[(3R)-3-amine -hexahydropyridin-1-yl]-5-(2-chloro,5-fluoro-benzyl)-indole, 3-dimercapto-1,5-dihydro-pyrrolo[3,2-d]pyrimidine·2 , 4-di steel; 2-({6-[(311)-3-amino-3-indenylhexahydro 1> ratio 0--1]-]13-dimethyl-2.4-di-oxy- 1,2,3,4-tetrahydro-5-pyrido[3,2-d]pyrimidin-5-yl)indolyl-4-fluorobenzonitrile; (2S)-l-{[2-(5-曱-22-·phenyl-嗔 _4_yl)-ethylamino]-ethenyl}-pyrrolidine-2-carbonitrile; (Talk 1-{[1,1-dimercapto-3- (4-carduyl-3-yl-imidazolyl)-propylamino]-ethenyl}-pyrrolidine-2-carbonitrile; -23- 149380.doc 201105327 (3,3-difluoropyrrolidine) · 1_yl)-((23,48)-4-(4-(pyrimidin-2-yl)hexahydropyridin-1-yl)0-Butyl-2-yl)anthone; (23,48) -1-[(28)-2-amino-3,3-bis(4-fluorophenyl)propanyl]_4_fluoro 0-pyridin-2-indene nitrile; (2S,5R)-5- Ethynyl_ι_{Ν_(4-mercapto-1-(4-indolylpyridin-2-yl)hexahydro 0-indol-4-yl)glycidyl}. Billion. _2_carbonitrile; and (lS,6R)-3-{[3-(trifluoromethyl)_5,6-dihydro[124]triazolo[43a]pyrazine-7(8H)-yl] Carbonyl}_6-(2,4,5-trifluorophenyl)cyclohexene-ene"-amine. One aspect of the present invention relates to a composition wherein the inhibitor of Dpp_iv is selected from the group consisting of the following compounds and pharmaceutically acceptable salts, solvates and hydrates thereof: 3(R)-aminol_1-[3-( Trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]4b °Q-7-yl]-4-(2,4,5 -trifluorophenyl)butanthone; 1-[2-(3-hydroxyadamantan-1-ylamino)ethenyl]pyrrolidine-2(s)-indenenitrile; (18,38, 58)-2-[2(3)-Amino-2-(3- via fund-frost-1_yl)ethenyl]- 2-azabicyclo[3.1.0]hexane-3-anthracene Nitrile; 2-[6-[3(R)-aminohexahydropyridine-i-yl]_3_indolyl-2,4-dioxy-1,2,3,4-tetrahydropyrimidine-1 -ylmethyl]benzonitrile; 8-[3(11)-aminohexahydro. Bipyridin-1_yl]_7_(2-butynyl)_3_methyl_1_(4_decyl-thaspazole-2-ylindenyl)xanthine; 1-[N-[3(R)-pyrrole Pyridyl]glycidyl]pyridinium-2(R)-ylboronic acid; 4(8)-fluoro-1-[2-[(111,38)-3-(11^-1,2,4 -triazol-1-ylindenyl)cyclopentylamino]ethanoyl]anthrolidine-2(S)-carbonitrile; 149380.doc •24- 201105327 l-[(2S,3S,llbS)- 2-Amino-9,l-dimethoxy-2,3,4,6,7,1115-hexahydro-1H-pyrido[2,la]isoquinoline-3-yl]_4(S )-(fluoroindolyl)pyrrolidin-2-one; and (2S,4S)-l-[(2S)-2-amino-3,3-bis(4-fluorophenyl)propanyl]- 4·Fluorine 咐°bit 2 - 曱 guess. One aspect of the invention pertains to compositions wherein the inhibitor of DPP-IV is selected from the group consisting of the following compounds and pharmaceutically acceptable salts, solvates and hydrates thereof: 3(R)-amino-1-[3 -(trifluoromethyl)_5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine-7-yl]-4-(2,4,5 -trifluorophenyl)butan-1-one; 1-[2-(3-hydroxyadamantan-1-ylamino)ethenyl]anthrolidine-2(s)-carbonitrile; (lS,3S ,5S)-2-[2(S)-Amino-2-(3-hydroxyadamantan-1-yl)ethenyl]-2-azabicyclo[3.1.0]hexane-3-anthracene Nitrile; 2-[6-[3(R)-Amino hexahydroacridine-!•yl]_3_methyl-2,4-di-oxy-1,2,3,4-tetrahydropyrimidine- 1-ylmethyl]benzonitrile; 8-[3(R)-aminohexahydroacridine-i-yl]_7_(2-butynyl)_3_methyl-1-(4-methylquinazoline -2-ylmethyl)xanthine; 1-[N-[3(R)-la-rrolidyl]glycidyl]D-pyridyl-2(R)-ylboronic acid; 4(S)-fluoro - l-[2-[(lR,3S)-3-(lH-l,2,4-triazol-1-ylmethyl)cyclopentylamino]ethinyl]pyrrolidine-2(S) -f nitrile; and l-[(2S,3S,llbS)-2-amino-9,l-dimethoxy-2,3,4,6,7,llb-hexahydro-1H-. Bipyrido[2,14]isoquinolin-3-yl]-4(8)-(fluoromethyl)lahydropyridin-2-one 0 149380.doc -25·201105327 The present invention for a DPIMV inhibitor Some examples include __ or each of the various DPIMV inhibitors and pharmaceutically acceptable salts, solvates and hydrates thereof. The inhibitors are selected from the group consisting of: 3(R)-amino-1 -[3-(trifluoromethyl b to tetrahydrofuranium [4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butane丨 ketone; 1-[2-(3-hydroxyadamantan-1-ylamino)ethenyl]pyrrolidine_2(s)·phthalonitrile; (lS,3S,5S)-2-[2( S)_Amino-2-(3-hydroxyd-alkyl)-ethenyl]- 2-azabicyclo[3.1.0]hexane-3-indene nitrile; 2- [6-[3(R )-amino hexahydro.pyridinyl small group]_3_methyl-2,4_di-oxyl-1,2,3,4-tetrahydropyrimidin-1-ylindenyl]benzonitrile; 8-[ 3(R)-Aminohexahydro'pyridin-1-yl;]_7_(2-butynyl)_3methyl-1(4-decylquinazolin-2-ylmethyl)xanthine; 1-[ N-[3(R)-pyrrolidinyl]glycidyl]pyrrole _2(R)-ylboronic acid; 4(S)-fluoro-l-[2-[(lR,3S)-3-( lH-l,2,4-triazolylmethyl)cyclopentylamino]ethinyl]0 is more than each bite-2(8)-carbonitrile; -WSJS'HbS)-?-Amino-9,10_dimethoxy_23,4,6,711^hexahydro-1H-pyrido[2,la]isoquinoline-3-yl]_4 (!§) _(fluoromethyl)pyrrolidine_2_Steel 0 In some embodiments, the dipeptidyl peptidase is selected from the group consisting of the following compounds and pharmaceutically acceptable salts, solvates and hydrates thereof: 3 (R )-amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]npyrazine-7- Base]-4-(2,4,5-trifluorophenyl)butanthone. In some embodiments, the inhibitor of dipeptidyl peptidase IV is 3 (R) amine group _ 149380.doc • 26· 201105327 1-[3-(trifluoromethyl)-5,6,7,8 .tetrahydro (1) to triazolo[4 3♦pyrazine-7.yl]-4-(2,4,5·trifluorophenyl)butanthone ketone phosphate (1:1) monohydrate . One aspect of the invention pertains to compositions which comprise a pharmaceutically acceptable carrier. μ A aspect of the invention relates to a composition wherein: the compound is selected from the group consisting of the following compounds of formula (1), and pharmaceutically acceptable salts, solvates and hydrates thereof:

The inhibitor of dipeptidyl peptidase IV is selected from the group consisting of the following compounds and pharmaceutically acceptable salts, solvates and hydrates thereof: 3(R)-amino-l-[3-(trifluoromethyl)-5, 6,7,8_tetrahydroπ,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butane_丨_ ketone. Some embodiments of the invention relate to compositions further comprising a pharmaceutically acceptable carrier. One aspect of the invention relates to a method of modulating the activity of a receptor by contacting a GPR1-9 receptor with a compound or a composition thereof, the compound being selected from the group consisting of a compound of formula (I) and a pharmaceutically acceptable salt thereof, Solvates and hydrates. One aspect of the present invention relates to a method for stimulating a receptor by contacting a GPRi-9 receptor with a compound or a composition thereof, the compound being selected from the group consisting of a compound of the formula (1) and a pharmaceutically acceptable salt or solvate thereof And hydrates. One aspect of the invention relates to the treatment of a Gprh 9 receptor associated with an individual 149380. Doc 27. The method of a condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound or a composition selected from the group consisting of a compound of formula (I), and pharmaceutically acceptable salts, solvates thereof, and Hydrate. In some embodiments the 'GPRl 19 receptor associated disorder is a metabolically related disorder. One aspect of the invention relates to a method of treating a metabolic-related disorder in an individual comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of a compound of formula (I) and a pharmaceutically acceptable compound thereof Accepted salts, solvates and hydrates. One aspect of the invention relates to a method of treating a metabolic-related disorder selected from the group consisting of: diabetes, type 1 diabetes, type 2 diabetes, inadequate glucose tolerance, impaired glucose tolerance, insulin resistance, hyperglycemia Symptoms, hyperlipidemia, triglycerideemia, hypercholesterolemia, dyslipidemia, atherosclerosis, stroke, X syndrome, hypertension, pancreatic insufficient, intestinal endocrine cells, diabetes, Metabolic acidosis, cataract, diabetic nephropathy, diabetic neuropathy, peripheral neuropathy, diabetic coronary artery disease, diabetic cerebrovascular disease, diabetic peripheral vascular disease, diabetic retinopathy, metabolic syndrome, diabetes related money, Myocardial infarction, learning disabilities, memory disorders, neurodegenerative disorders, conditions in which blood GLP-1 levels are improved by increasing the number of individuals with neurodegenerative disorders, by severe epilepsy. Excited toxic brain damage caused by seizures in the village, Alzheimer's disease (Alzh丨imer s dlsease), Parkinson's disease (ParkinS〇n, S heart mail 6), Huntington's disease ( Huntington, s 149380. Doc -28- 201105327 disease), diseases related to pri〇n, stroke, motor neuron disease, traumatic brain injury, spinal cord injury and obesity. One aspect of the invention is a method of treating type 2 diabetes in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound or a composition selected from the group consisting of a compound of formula (1) and a pharmaceutically acceptable compound thereof Salts, solvates and hydrates. One aspect of the invention relates to a method of treating hyperglycemia in an individual comprising administering to a subject in need thereof a therapeutically effective amount of a compound or a composition selected from the group consisting of a compound of formula (I) and a pharmaceutically acceptable compound thereof Accepted salts, solvates and hydrates. One aspect of the invention relates to a method of treating hyperlipidemia in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound or a composition selected from the group consisting of a compound of formula (I) and a medicament thereof Acceptable salts, solvates and hydrates. One aspect of the invention relates to a method of treating hypertriglyceridemia in an individual comprising administering to a subject in need thereof a therapeutically effective amount of a compound or a composition selected from the group consisting of a compound of formula (1) and a medicament thereof. Acceptable salts, solvates and hydrates. One aspect of the invention relates to a method of treating i-type diabetes in an individual comprising administering to a subject in need thereof a therapeutically effective amount of a compound or a composition selected from the group consisting of a compound of formula () and a pharmaceutically acceptable compound thereof Accepted salts, solvates and hydrates. One aspect of the invention relates to a method of treating dyslipidemia in an individual comprising administering to a subject in need thereof a therapeutically effective amount of a compound or a combination thereof 149380. Doc • 29. 201105327, the compound is selected from the group consisting of a compound of formula (i), and pharmaceutically acceptable salts, solvates and hydrates thereof. One aspect of the invention relates to a method of treating a syndrome in an individual comprising administering to a subject in need thereof a therapeutically effective amount of a compound or a composition thereof, wherein the beta 玄 compound is selected from the group consisting of a compound of formula (I) and pharmaceutically acceptable thereof Salts, solvates and hydrates. In some embodiments, the system is a mammal. In some embodiments, the suckling animal is a human. One aspect of the invention relates to a method of treating obesity in an individual comprising administering to a subject in need of treatment a therapeutically effective amount of a compound or a composition selected from the group consisting of a compound of formula (1) and a pharmaceutically acceptable salt thereof. , solvates and hydrates. One aspect of the invention relates to a method of reducing food intake in an individual comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of a compound of formula (I) and a pharmaceutically acceptable compound thereof Salts, solvates and hydrates. One aspect of the invention is a method of inducing satiety in an individual comprising administering to a subject in need thereof a therapeutically effective amount of a compound or a composition selected from the group consisting of a compound of formula (1) and a pharmaceutically acceptable compound thereof Salts, solvates and hydrates. One aspect of the invention relates to a method of controlling or reducing the weight gain of an individual comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of a compound of formula (1) and a pharmaceutically acceptable compound thereof. Salt, gluten, and hydrate. 149380. Doc • 30· 201105327 A version of the invention relates to a method of treating a GPR19 receptor-associated disorder in an individual comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 and a DPP-IV inhibitor A combination wherein the compound is administered simultaneously, separately or sequentially with the DPP-ΐν inhibitor system. In some embodiments, the compound is administered concurrently with a DPP-IV inhibitor system. In some embodiments, the compound is administered separately from the DPP-IV inhibitor. In some embodiments, the compound is administered sequentially with a DPP-IV inhibitor. In some embodiments, the GPR119 receptor associated disorder is a metabolic related disorder. In some embodiments, the metabolic related disorder is selected from the group consisting of: diabetes, type 1 diabetes, type 2 diabetes, inadequate glucose tolerance, impaired glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia , high glycerol, hypercholesterolemia, dyslipidemia, atherosclerosis, stroke X syndrome, hypertension, parotid P cell deficiency, intestinal endocrine deficiency, diabetes, metabolic acidosis, cataract, diabetic nephropathy, Diabetic neuropathy, external (four) meridian lesions, diabetic coronary artery disease, diabetic brain A & A >& disease, diabetic peripheral vascular disease, diabetic retinopathy, metabolic syndrome, diabetes-related conditions, heart Z Sputum, learning disabilities, memory disorders, neurodegenerative disorders, disease-induced GML in patients with increased degenerative conditions, excitotoxic brain damage caused by seizures, Alzheimer's stroke, exercise; Disease "Tington's disease, disease related to Prian, = sports phase _, her injury, injury and obesity 149380. Doc • 31· 201105327 In some embodiments, the metabolic related disorder is type 2 diabetes. In some embodiments, the metabolic related disorder is a glycemic disorder. In some embodiments the 'metabolic related disorder is hyperlipidemia. In some embodiments the 'metabolic related disorder is hypertriglyceridemia. In some embodiments the 'metabolic related disorder is type 1 diabetes. In some embodiments, the metabolic related disorder is dyslipidemia. In some embodiments, the metabolic related disorder is X syndrome. One aspect of the invention relates to a method of treating obesity in an individual comprising administering to a subject in need of treatment a therapeutically effective amount of a combination of a compound of claim 1 and a DPP-IV inhibitor, wherein the compound is Dpp-iv Inhibitors are administered simultaneously, separately or sequentially. One aspect of the invention relates to a method of reducing food intake in an individual comprising administering to a subject in need thereof a therapeutically effective amount of a combination of a compound of the formula i and a DPP-IV inhibitor, wherein the compound and the oxime 1>1>_1¥ inhibitors are administered simultaneously, separately or sequentially. One aspect of the present invention relates to a method for inducing satiety in an individual, which comprises administering to a subject in need thereof a therapeutically effective amount of a combination of a chemical substance, a DPP-IV inhibitor, wherein The compound is administered simultaneously, separately or sequentially with the Dpp_iV inhibitor. One aspect of the invention relates to a method of controlling or reducing the weight gain of an individual comprising administering to a subject in need thereof a therapeutically effective amount of a combination of a compound of claim 1 and a DPIMV inhibitor, wherein the compound and the attached IV Inhibitors are administered simultaneously, separately or sequentially. In some embodiments, the compound is administered concurrently with the Dpp_IV inhibitor system. L49380. D〇c • 32· 201105327 In some embodiments, the compound is administered separately from the DPP-IV inhibitor. In some embodiments, the compound is administered sequentially with a DPP-IV inhibitor. One aspect of the invention relates to the use of a compound or composition thereof for the manufacture of a medicament for modulating the activity of a GPR119 receptor. The compound is selected from the group consisting of a compound of formula (I), and pharmaceutically acceptable salts, solvates thereof, and Hydrate. One aspect of the present invention relates to the use of a compound or a composition thereof for the manufacture of a medicament for agonizing the GPR119 receptor, which compound is selected from the group consisting of the compound of the formula (1) and pharmaceutically acceptable salts, solvates and hydrates thereof. One aspect of the invention relates to the use of a compound or composition thereof for the manufacture of a medicament for the treatment of a GPR1 19 receptor-related disorder selected from the group consisting of a compound of formula (I), and a pharmaceutically acceptable salt thereof, a solvent combination thereof And hydrates. One aspect of the invention relates to the use of a compound or composition thereof for the manufacture of a medicament for the treatment of a metabolic-related disorder selected from the group consisting of a compound of formula (1), and pharmaceutically acceptable salts, solvates and hydrates thereof. One aspect of the invention relates to the use of a compound or composition thereof for the manufacture of a medicament for the treatment of a metabolic-related disorder selected from the group consisting of a compound of formula (1), and pharmaceutically acceptable salts, solvates and hydrates thereof, The metabolic-related disorder is selected from the group consisting of: diabetes, type 1 diabetes, type 2 diabetes, inadequate glucose tolerance, impaired glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, sputum triglycerides Hypertension, hypercholesterolemia, dyslipidemia, atherosclerosis, stroke, X syndrome, hypertension, pancreatic P cell deficiency, intestinal endocrine cell deficiency, diabetes, metabolic acidosis, cataract, diabetic kidney 149380. Doc •33· 201105327 urinary light lesions, external (four) menstrual disease, diabetes 2 diseases, diabetic cerebrovascular disease 'diabetic peripheral vascular disease, urinary retinopathy, metabolic syndrome, diabetes-related conditions, heart attack infarction Disorders, memory disorders, neurodegenerative disorders, conditions in which blood GLM levels are improved by individuals with increased neurodegenerative disorders, excitotoxic brain damage caused by severe epileptic seizures, Alzheimer's disease Parkinson Disease, Huntington's disease, diseases associated with Prian, A motor neurosis, traumatic brain injury, spinal cord injury and obesity. A mode of the present invention relates to the use of a compound or a composition thereof for the manufacture of a medicament for the treatment of type 2 diabetes, the compound being selected from the group consisting of a compound of the formula (1) and a pharmaceutically acceptable salt, solvate thereof and hydrate thereof Things. The present invention relates to the use of a compound or a composition thereof for the manufacture of a medicament for the treatment of hyperglycemia. The compound is selected from the group consisting of the compound of the formula (1) and its pharmaceutically acceptable salts, solvates and hydrates. . One aspect of the invention relates to the use of a compound or composition thereof for the manufacture of a medicament for the treatment of lipoemia for /alpha therapy, the compound being selected from the group consisting of a compound of formula (I) and a pharmaceutically acceptable salt thereof, a solvent Compounds and hydrates. One aspect of the present invention relates to the use of a compound or a composition thereof for the manufacture of a medicament for the treatment of glycerol bisemia, which is selected from the group consisting of a compound of the formula (1), and pharmaceutically acceptable salts, solvates thereof and Hydrate. One aspect of the present invention relates to the use of a compound or a composition thereof for the manufacture of a medicament for the treatment of type 1 diabetes, which is selected from the group consisting of a compound of the formula (1) and pharmaceutically acceptable salts, solvates and hydrates thereof . 149380. Doc-34-201105327 A version of the invention relates to the use of a compound or a ruthenium complex thereof for the manufacture of a medicament for the treatment of dyslipidemia, which compound is selected from the group consisting of a compound of formula (I) and a pharmaceutically acceptable salt thereof , solvates and hydrates. One aspect of the invention relates to the use of a compound or composition thereof for the manufacture of a medicament for the treatment of x syndrome, which compound is selected from the group consisting of a compound of formula (I) and pharmaceutically acceptable salts, solvates and hydrates thereof . One aspect of the present invention relates to the use of a compound selected from the compounds of formula (I), and pharmaceutically acceptable salts, solvates and hydrates thereof, or compositions thereof, for the manufacture of a medicament for the treatment of obesity. One aspect of the present invention relates to the use of a compound selected from the compounds of formula (I), and pharmaceutically acceptable salts, solvates and hydrates thereof, or compositions thereof, for the manufacture of a medicament for reducing food intake in an individual. One aspect of the present invention relates to the use of a compound selected from the compounds of formula (I) and pharmaceutically acceptable salts, solvates and hydrates thereof, or compositions thereof, for the manufacture of a medicament for inducing satiety in an individual. One aspect of the present invention relates to the use of a compound selected from the compound of formula (1) and a pharmaceutically acceptable salt, solvate or hydrate thereof, or a composition thereof, for the manufacture of a medicament for controlling or reducing the weight gain of an individual. One aspect of the invention pertains to a method of treating a human or animal body by therapy with a compound of the invention or a composition thereof. One aspect of the invention pertains to a method of modulating GPR119 receptor activity with respect to a compound of the invention or a composition thereof. One aspect of the invention pertains to methods of using the compounds of the invention or compositions thereof for agonizing the GPR119 receptor. ; ' 149380. Doc-35-201105327 One aspect of the invention pertains to a method of treating a GPR119 receptor-associated disorder with a compound of the invention or a composition thereof. One aspect of the invention pertains to a method of treating a metabolic related disorder with a compound of the invention or a composition thereof. One aspect of the invention pertains to a method of treating a metabolic-related disorder with a compound of the invention or a composition thereof, the metabolic-related disorder being selected from the group consisting of: diabetes, type 1 diabetes, type 2 diabetes, inadequate glucose tolerance , impaired glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, and diglycerideemia, hypercholesterolemia, dyslipidemia, atherosclerosis, stroke, X syndrome, hypertension, gonads Insufficient beta cells, intestinal endocrine cells, diabetes, metabolic acidosis, cataracts, diabetic nephropathy, diabetic neuropathy, peripheral neuropathy, diabetic coronary artery disease, diabetic cerebrovascular disease, diabetic peripheral vascular disease, diabetes Retinopathy, metabolic syndrome, diabetes-related conditions, myocardial infarction, learning disabilities, memory disorders, neurodegenerative disorders, conditions in which the blood GLpq concentration is improved by an individual with a neurodegenerative disorder, caused by severe seizures Excitatory toxic brain damage, Alzheimer's disease, Parkin Disease, Huntington's disease, disease associated with Prian, stroke, motor neuron disease, traumatic brain injury, spinal cord injury, and obesity 0 One aspect of the present invention relates to a method for treating type 2 diabetes A compound of the invention or a composition thereof. One aspect of the invention relates to a method for treating hyperglycemia 149380. Doc • 36- 201105327 A compound of the invention or a composition thereof. One aspect of the invention pertains to a compound of the invention or a composition thereof for use in a method of treating hyperlipidemia. One aspect of the invention pertains to a compound of the invention or a composition thereof for use in a method of treating hypertriglyceridemia. One aspect of the invention pertains to a compound of the invention or a composition thereof for use in a method of treating type 1 diabetes. One aspect of the invention pertains to a compound of the invention or a composition thereof for use in a method of treating dyslipidemia. One aspect of the invention pertains to a compound of the invention or a composition thereof for use in a method of treating X syndrome. One aspect of the invention pertains to a compound of the invention or a composition thereof for use in a method of treating obesity. One aspect of the invention pertains to a compound of the invention or a composition thereof for use in reducing food intake in an individual. One aspect of the invention pertains to the compounds of the invention for use in inducing satiety in an individual. One aspect of the invention pertains to a compound of the invention or a composition thereof for use in controlling or reducing the weight gain of an individual. In some embodiments, the system is a mammal. In some embodiments, the 3 Hai mammal is a human. In some embodiments, the human body weight index is about 18. 5 to about 45 or more. In some embodiments, the human body: index is between about 18 5 and about 45. In some embodiments, the human body is between about 25 and about 45. In some embodiments, the human body weight is 149,380. Doc -37- 201105327 The number is about 3〇 to about 45. Name: One such caution &&&&&&&&&&> In these examples, the human body mass index is about 35 to about 45. The present invention encompasses each combination of one or more metabolically related disorders selected from the group consisting of diabetes, type 2 diabetes, type 2 diabetes, impaired glucose tolerance, impaired glucose tolerance, Tengdaosu resistance, blood sugar, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, atherosclerosis, stroke, X syndrome, hypertension, TB deficiency, enteroendocrine Cell deficiency, diabetes, metabolic acidosis, cataract, diabetic nephropathy, diabetic neuropathy, peripheral neuropathy, diabetic coronary artery disease, diabetic cerebrovascular disease, diabetic peripheral disease, diabetic retinopathy, generation "shot syndrome, diabetes-related conditions, myocardial infarction, learning disabilities, memory disorders, neurodegenerative disorders, conditions in which blood GLP-1 is improved by increased neurodegenerative disorders, by severe tumor onset Excitatory toxic brain damage, Alzheimer's disease, Parkinson's disease, Huntington's disease, and Aung about the disease, stroke, motor neuron disease, traumatic brain injury, spinal cord injury and obesity. Some examples of the present month include each combination of one or more metabolically related disorders selected from the group consisting of type 2 diabetes, hyperglycemia, hyperinsulinemia, hyperlipidemia, Hypertriglyceridemia, insulin resistance, type 1 diabetes, idiopathic (four) diabetes type), adult occult autoimmune diabetes (LADA), early onset type 2 diabetes (EOD), atypical pneumonia Type 2 diabetes (y〇ad), adolescent mature onset diabetes (MODY), malnutrition-related diabetes, sputum sugar 149380. Doc -38· 201105327 Urinary coronary heart disease, vascular restenosis, restenosis, angioplasty, narrow-neck peripheral vascular disease, lameness, intermittent breaks, cell death associated with myocardial infarction (eg necrosis and apoptosis) , dyslipidemia, postprandial lipemia, impaired glucose tolerance (IGT), impaired glucose metabolism, glucose metabolism and disease, fasting plasma glucose abnormalities, metabolic acid ketosis, arthritis, obesity, Osteoporosis, hypertension, and congestion ratio. Dirty failure, left ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy. ! , macular degeneration, intradermal $, diabetic nephropathy, glomerular sclerosis, k I1 renal failure, diabetic neuropathy, metabolic syndrome, X syndrome, sputum syndrome, angina pectoris, thrombosis, atherosclerosis, ischemic Stroke, transient ischemic attack, stroke, erectile dysfunction, skin and connective tissue disorders, foot ulcers, ulcerative colitis, endothelial dysfunction, and vascular compliance disorders. A mode of the present invention relates to a method of preparing a composition comprising mixing a compound selected from the group consisting of a compound of the formula (1) and a pharmaceutically acceptable salt, solvate thereof and hydrate thereof with a pharmaceutically acceptable carrier. One aspect of the present invention relates to a method of preparing a pharmaceutical composition comprising mixing a compound selected from the group consisting of a compound of the formula (1) and a pharmaceutically acceptable salt, solvate thereof and hydrate thereof with a pharmaceutically acceptable carrier step. One aspect of the present invention relates to a method of preparing a composition comprising the step of mixing a compound selected from the group consisting of a compound of the formula (I) and a pharmaceutically acceptable salt, solvate thereof and hydrate thereof with a DPP-IV inhibitor . One aspect of the present invention relates to a method of preparing a composition comprising a compound selected from the group consisting of a compound of formula (I), and a pharmaceutically acceptable salt thereof, a solvating compound, and hydrated 149,380. Doc • 39· 201105327 Step of mixing a compound of a compound with a DPP-IV inhibitor and a pharmaceutically acceptable carrier. A method of the present invention relates to a method of preparing a composition, which further comprises preparing a unit dosage form from the composition The steps. One aspect of the invention relates to a method of preparing a pharmaceutical composition for treating a Gpri 19 receptor-associated disorder in a subject, the pharmaceutical composition comprising a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate And a hydrate, and a DPP-IV inhibitor; the method comprises: (a) mixing the compound with a first pharmaceutically acceptable carrier to prepare a dosage form of the compound; (b) the DPP-IV inhibitor A dosage form prepared by mixing with a second pharmaceutically acceptable carrier to prepare the DPP-IV inhibitor; and (4) providing a dosage form in the form of a combined preparation for use in a time, separate or sequential application. A mode of the invention is a method of preparing a pharmaceutical composition for treating a GpRn9 receptor-associated disorder, the disorder being selected from the group consisting of: diabetes, type 1 diabetes, type 2 撼 _ diabetes, Insufficient glucose tolerance, impaired glucose tolerance, islet specific> ancient, horse resistance, blood sugar, hyperlipidemia, inter-diglyceridemia, high cholesterol, upper blood stasis Abnormalities, atherosclerosis, stroke, X syndrome, ancient group blood pressure, pancreatic β-cell deficiency, enteroendocrine,, field cell deficiency, diabetes, metabolism into k ρ 0 poisoning, cataract, diabetic nephropathy, diabetes Neuropathy, ^ # -r- Ρ 周 周神! Lesions, diabetic coronary artery disease, diabetic cerebral blood s disease, diabetic peripheral vascular disease, 149,380. Doc 201105327 Diabetic retinopathy, metabolic syndrome, diabetes-related conditions, myocardial infarction, _ learning disabilities, memory disorders, neurodegenerative disorders, increased blood concentration by individuals with increased _ extensive degenerative disease Excitotoxic brain damage caused by severe onset of oncosis, Alzheimer's disease, Parkinson's disease, Huntington's disease associated with Prian, wind, motor neuron disease, traumatic brain injury, Spinal Cord Injury and Obesity 0 In some embodiments, the combination formulation is in the form of a dual kit. In some embodiments, the first pharmaceutically acceptable carrier in steps (4) and (8) is different than the second pharmaceutically acceptable carrier. In some embodiments, the first pharmaceutically acceptable carrier in steps (4) and (8) is substantially the same as the first pharmaceutically acceptable carrier. In some embodiments, the combination formulation is for simultaneous application. In some embodiments, the combination formulation is for separate application. In some embodiments, the combination formulation is for sequential application. The present invention relates to a method for preparing a pharmaceutical composition for increasing the blood GLP-1 concentration of an individual. The pharmaceutical composition comprises a compound of the formula (1), a pharmaceutically acceptable salt thereof, a solvate thereof, and a hydrate, and a DPP-IV inhibitor; the method comprising: (4) mixing the compound with a first pharmaceutically acceptable carrier to prepare a dosage form of the compound; (b) treating the 6 〇ΡΡ Ι Ι 抑制剂 inhibitor with the second The pharmaceutically acceptable carrier is prepared by mixing the WMV inhibitor; and (c) providing the combined preparation form 149380 for simultaneous, separate or sequential application. Doc -41 201105327 dosage form. Double kit form. The first medicine in the acceptance is different. In some embodiments, the 'combination formulation is in some embodiments' the step (a) and the carrier and the second pharmaceutically acceptable carrier. In some embodiments, the first of steps (4) and (b) The pharmaceutically acceptable carrier is substantially the same as the second pharmaceutically acceptable carrier. In some embodiments, the combination formulation is for simultaneous application. In some embodiments, the combination formulation is for separate applications. In some embodiments, the combination formulation is for sequential application. In some embodiments, only the amount of the compound of formula (1) and its pharmaceutically acceptable salts, solvates, and hydrates, and the amount of DPIMV inhibited sputum, are not therapeutically effective in increasing blood GLP-1 concentration in an individual. The present invention relates to a compound of the formula (1) and a pharmaceutically acceptable salt, solvate and hydrate thereof for use in combination with a Dpp_IV inhibitor: for treating blood of a mammal by boosting the mouth The concentration is to improve the disease. In some embodiments, only the amount of the compound of formula (1) and its pharmaceutically acceptable salts, solvates, and hydrates is improved for treatment by increasing the blood GLP-1 concentration in a mammal. The condition has no therapeutic effectiveness. A mode of the present invention relates to a DPP-IV inhibitor for use in combination with a compound of the formula (1) and a pharmaceutically acceptable salt, solvate thereof and hydrate thereof for the treatment of blood glucose by increasing the mammalian blood GLP -1 concentration to improve the disease In some embodiments, only the amount of DPP-IV inhibitor is increased by 149,380 for treatment. Doc -42- 201105327 Adding mammalian blood GLP-! concentration to improve the condition without treatment effectiveness. In some embodiments, the condition improved by increasing blood GLp_uf is selected from the group consisting of: diabetes, type 1 diabetes, type 2 diabetes, inadequate glucose tolerance, impaired glucose tolerance, and resistance to tamsin , hyperglycemia, hyperlipidemia, hyperglycerin trisodium semia, hypercholesterolemia, dyslipidemia, atherosclerosis, wind, X syndrome, hypertension, pancreatic p cells, and intestinal endocrine cells ,diabetes, metabolic acidosis, cataract, diabetic nephropathy, diabetic neuropathy, peripheral neuropathy, diabetic coronary artery disease, diabetic cerebrovascular disease, diabetic peripheral vascular disease, diabetic retinopathy, metabolic syndrome, diabetes Related conditions, myocardial infarction, learning disabilities, memory disorders, neurodegenerative disorders, excitotoxic brain damage caused by severe seizures caused by increased blood GL p _ i concentration in individuals with degenerative conditions of the Year of the Sen, Alzheimer's disease, Parkinson's disease, Huntington's disease, diseases associated with Prian, medium Wind, motor neuron disease, ·! 丨丨德 4 film illusory fine injury, spinal cord injury and obesity. One aspect of the month relates to a pharmaceutical composition comprising a compound of the formula (1) A: a salt, a solvate and a hydrate which are accepted, the formula (1), and a therapeutically acceptable salt or solvent thereof The substance and the DP1MV inhibitor group are used for the condition of the oral phase Μ/α 猎 由 由 由 。 。 。 。 。 。 。 。 。 动物 动物 动物 动物 动物 Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ . Doc -43- 201105327 The concentration of GLP·1 in mammalian blood to improve the condition is ineffective. One aspect of the present invention relates to a pharmaceutical composition comprising a Dpp-iv inhibitor for use in combination with a compound of formula (1) and a pharmaceutically acceptable salt, solvate thereof and hydrate thereof for treatment The condition is improved by increasing the blood GLP-1 concentration in the mammal. In some embodiments, the condition improved by increasing blood GLPdi is selected from the group consisting of: diabetes, type 1 diabetes, type 2 diabetes, inadequate glucose tolerance, impaired glucose tolerance, membrane island capture p — 丨 又 又 ^ 岛 岛 京 京 京 京 京 京 京 京 京 京 京 京 京 京 京 京 京 京 京 京 京 京 京 京 京 京 京 京 京 ^ 京 ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ Pancreatic _ cell deficiency, intestinal endocrine cell deficiency, diabetes, metabolic acidosis, cataract, diabetic nephropathy, diabetic neuropathy, peripheral neuropathy, diabetic coronary artery disease, diabetic brain 4 disease, diabetic peripheral vascular disease, Diabetic dysplasia, metabolic syndrome, diabetes-related conditions, myocardial infarction, paralysis disorder, memory disorder, neurodegenerative disorder, neurodegenerative disorder, excitotoxic brain damage caused by severe seizures, Alzheimer's disease Disease, Parkinson's disease, Huntington's disease, Spirion-related disease stroke, motor neuron disease, traumatic Injury, spinal injury and Zhao obesity. The present invention relates to a pharmaceutical composition as described herein. One aspect of the month relates to a combined preparation comprising a compound of the formula (1) and a pharmaceutically acceptable salt or solvate thereof. And hydrate, and DPP tone 149380. Doc 201105327 A simultaneous preparation for the treatment of diabetes or its separate or sequential application. In some embodiments, the amount of the compound selected from the group consisting of the compound of the formula (1) and its pharmaceutically acceptable salts, solvates and hydrates, and the Dpp_iv inhibitor are not therapeutically effective in lowering the blood glucose concentration of the individual. In some implementations, the compound is mixed with a DPP_IV inhibitor, a pharmaceutically acceptable carrier. In some embodiments, the compound and the DPP-IV inhibitor are mixed with different pharmaceutically acceptable carriers. In some embodiments, the diabetes-related condition is selected from the group consisting of hyperglycemia, impaired glucose tolerance, temperament resistance, pancreatic beta cell deficiency, intestinal endocrine deficiencies, diabetes, metabolic acidosis, cataract , diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic coronary artery disease, diabetic cerebrovascular disease, diabetic peripheral vascular disease, metabolic syndrome, hyperlipidemia, atherosclerosis, stroke, hypertension And obesity. The invention relates to a dual kit comprising a compound of the formula (1) and an octagonal pharmaceutically acceptable salt, a solvate and a hydrate thereof, and an inhibitor as a combined preparation for treating diabetes or Its related conditions. In a two-dimensional example, the compound and the DPP-IV inhibitor are mixed with different pharmaceutically acceptable carriers. In some embodiments, the different pharmaceutically acceptable carriers are suitable for administration by different routes. H9380. Doc •45· 201105327 In some embodiments, the diabetes-related condition is selected from the group consisting of hyperglycemia, impaired glucose tolerance, insulin resistance, pancreatic p-cell deficiency, intestinal endocytosis, diabetes, metabolic acid Poisoning, cataract: diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic coronary artery disease, diabetic brain tube disease, diabetic peripheral 4 tube disease, metabolic syndrome, hyperlipidemia, atherosclerosis, Stroke, high blood pressure and obesity. One aspect of the invention pertains to a kit comprising (a) a first package comprising a compound of claim 1 or a pharmaceutical composition thereof; and (b) a second package comprising a DPP-IV inhibitor. These and other aspects disclosed in this document are set forth in more detail in the context of the disclosure of this disclosure. [Embodiment] It is to be understood that certain features of the present invention, which are set forth in the context of a single embodiment, may also be provided in combination in a single embodiment. In contrast, the various features set forth above for a single embodiment are also provided solely or in any suitable sub-combination. Accordingly, the present invention encompasses all combinations of uses and medical indications described herein, as the present illusion and expressly recites each sub-combination of use and medical indications. The present disclosure includes all isotopes of atoms occurring in the compounds of the present invention, their salts, and crystalline forms i. Isotopes include atoms that have the same: number of sub-sequences but different mass numbers. By way of general example and not, the isotope of dichlorobenzene includes the isotopes of 2 Qing 3 Lu carbon including I49380. Doc • 46- 201105327 Unless otherwise stated, the present invention is explained in detail using terms defined below. The term "agonist" means a moiety that interacts with a receptor and activates a receptor (e.g., the GPR119 receptor) and elicits a physiological or pharmacological response characterized by the receptor. For example, when multiple moieties bind to a receptor, they activate intracellular responses or enhance binding of GTP to the membrane. The term "composition" means a material comprising at least two components; for example and without limitation, a composition comprising a compound of the invention and a pharmaceutically acceptable carrier. Contact or contact means the placement of designated parts together in an in vitro system or in an in vivo system. Thus, contacting a GpR19 receptor with a compound of the invention comprises administering to a subject having a GpR1丨9 receptor (preferably a human) a compound of the invention, for example, by introducing the compound of the (4) into a sample. Cells containing the GpRii9 receptor or a purified preparation are included. As used herein, the term "hydrated sputum j. & 物" is a compound of the present invention or a salt thereof, which includes stoichiometry or non-彳h lifting. Non-covalent intermolecular forces combined with water. - - into the mouth; ^ machi spoon parent, which means by the caregiver (for example, material 1 j for doctors, gentlemen, nurses, etc. for humans; for animals including non-human mammals The individual or animal needs made by the veterinarian) or "' „ , ^ will also benefit from the judgment of treatment. The judgement is based on various factors in the care professional's field of expertise, and includes the disease or condition that the individual or animal can treat due to the eight-month compound of the present invention or 149,380. Doc -47· 201105327 Knowledge of illness or illness. The compounds of the invention may be used in a (four) protective or prophylactic manner; or the compounds of the invention may be used to alleviate 'inhibiting or ameliorating a disease, condition or disorder. The term "individual" or "patient" means any animal, including a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, snail, cow, sheep, horse or primate. Animals, and the best is human. In another embodiment, the human system, and in some embodiments, the human infant, child, youth or adult. In one embodiment, the individual is at risk of developing a GPR119 related disorder. In one embodiment, the individual is at risk of developing a metabolic related disease or condition. Individuals at risk include, but are not limited to, those who have a genetic history of a metabolically related disease or condition or who are in a state of health in which they are at risk of developing a metabolic related disease or condition. In another embodiment, the patient has been determined to have a metabolic related disease or condition by a caregiver or a person operating according to the caregiver's instructions. The term "modulate or modulating" means to increase or decrease the amount, quality, response or effect of a particular activity, function or molecule. The term "pharmaceutical composition" means a composition comprising at least one active ingredient; including but not limited to salts, solvates and hydrates of the compounds of the invention; whereby the composition is suitable for studying mammals (eg, but Specific effective results in not limited to humans. Those skilled in the art will understand and understand the techniques appropriate to determining, based on the needs of the skilled person, whether the active ingredient has the desired effective results. The term "solvate" as used herein means a compound of the present invention or a salt thereof, 149,380. Doc -48- 201105327 =Steps include stoichiometric or non-stoichiometric amounts of non-covalent intermolecular forces, "the solvent is preferred, volatile, non-toxic and/or acceptable for use in trace amounts Solvent for humans. The term "therapeutically effective amount" means an active compound or pharmaceutical agent that is caused by a researcher, veterinarian, doctor or other l-bowl so as to cause a biological or medical response to a tissue, system, animal, individual or human. The biological or medical response comprises one or more of the following: (1) preventing a disease', for example, preventing a disease, condition or disorder in an individual who may be susceptible to the disease, condition or condition but has not experienced or presented the pathology or symptoms of the disease. (2) inhibiting a disease; for example, inhibiting a disease, condition or condition of an individual who is undergoing or exhibiting a pathology or symptom of the disease, condition or condition (ie, preventing further progression of the pathology and/or symptom); and (3) Ameliorating a disease; for example, ameliorating a disease, condition or condition of an individual who is undergoing or exhibiting the pathology or symptoms of the disease, conditional bite disorder (ie, reversing the pathology and/or symptom) . A compound of the invention is a novel compound N-(2-fluoro-4-(fluorenyl fluorenyl)phenyl)-5-indenyl-. (丄(5 - 曱 ° ° ° ° Qin-2-yl) hexahydropyrene ratio. _4_ yloxy) cancer bite _4_amine (compound) is an effective selective agonist of GPR119. In HTRF cAMP In the analysis, N-(2-fluoro-4-(methyl-decyl)phenyl)-5-methyl-6-(1-(5-methyl-n-r-methyl-2-yl)hexahydropyridine- 4-yloxy)pyrimidine-4-amine is a "complete agonist". Compound N-(2-|t-4-(indenyl)phenyl)-5-methyl-6-(1) -(5-methyl η ratio. Qin 2-yl) hexahydropyridyl. 1,4--4-yloxy) ° butyl-4-amine can increase the performance of human 149380. Doc • 49-201105327 The cAMP concentration of CHO cells of GPR119 (GDIR), and the observed EC50 is 6 nM (see Example 1A). N-(2-Fluoro-4-(indolylsulfonyl)phenyl)-5-mercapto-6-(1-(5-methylpyrazin-2-yl)hexahydropyridin-4-yloxy The pyrimidine-4-amine can stimulate the release of GLP-1 from mouse GLUTag cells, and the observed EC5 lanthanide 54. 1 nM (see Example 1B) and is a potent G P R119 agonist in the in vivo of SpragUe-Dawley rats. In each of these models, N-(2-gas-4-(methyl aryl)) benzyl)-5-methyl-6-(1-(5-methyl- 0-° Qin-2_yl) Hexahydropyridinium-4-yloxy)pyrimidine. D-amines are effective in increasing glucose clearance during the oral glucose tolerance test (oGTT) (see Example 2). In addition, N-(2-^-4-(曱基石石基基基基)-5-methyl-6-(1-(5-methylindole ratio. Qin_2_yl)hexahydropyridinium -4-yloxy)pyrimidine-4-amine is 1. A dose of 5 mg/kg significantly reduced blood glucose concentrations during the oral glucose tolerance test (see Example 3). In the recombinant CYP enzyme preparation, N-(2-fluoro-4·(methylsulfonyl)phenyl)-5(indolyl-6-(1-(5-methylpyrazin-2-yl)hexahydro) Pyridine_4_yloxy)pyrimidine-4 amine can inhibit 3A4, 2C9 and 2C19 and the IC5〇 inhibition value is about 9 〇 5 μΜ, respectively. 82 μΜ and >10 μΜ and showed no inhibition for 1A2 and 2D0. In human liver microsome preparations, the ICw inhibition value for 2C9 was approximately 6 μΜ and for the other 1 > 450 tested (i.e., '2C19 and 3Α4), the ic50 value > 30 μΜ (see Examples 4 and 5). One aspect of the present invention pertains to the following compound selected from the group consisting of hydrazine-(2-fluoro-4-(fluorenylsulfonyl)phenyl)-5-methyl-6-(1(5-fluorenyl) as shown in formula (1) Pyridazin-2-yl)hexahydropyridin-4-yloxy)pyrimidine-4-amine (Compound 丨): 149380. Doc -50- 201105327

(I) A compound of a pharmaceutically acceptable salt, solvate or hydrate thereof. Indications and Methods of Treatment In addition to the foregoing beneficial uses of the compounds of the invention disclosed herein, the compounds of the invention may also be used in the treatment of other conditions. Such diseases include, but are not limited to, those described below. The most prominent pathology of type 2 diabetes is that the insulin signaling weakening ("insulin resistance") at the target tissue and the insulin-producing cells of the pancreas cannot secrete an appropriate level of insulin in response to the southern glucose signal. Current therapeutic therapies include beta cell ATP-sensitive potassium channel inhibitors to stimulate the release of endogenous insulin stores or to administer exogenous insulin. Neither of these can achieve accurate normalization of blood glucose levels and both of them present a risk of inducing hypoglycemia. For these reasons, the development of drugs that can play a role in glucose-dependent effects, i.e., glucose signaling synergists, has attracted strong interest. Physiological signaling systems that function in this manner are well characterized and include the intestinal peptides GLpi, GIP and pACAP. These hormones act via their homologous G-protein coupled receptors to stimulate the production of cAMP in pancreatic p cells. The increased cAMP does not appear to produce stimulation of insulin release during fasting or pre-prandial conditions. However, a series of cAMP signal biochemical targets including ATp-sensitive potassium channels, voltage-sensitive potassium channels, and extracellular secretion mechanisms have been modified to significantly increase the response to postprandial glucose-stimulated insulin secretion. Therefore, 'new novels with similar functions 149380.doc -51 - 201105327 ACTIVATOR β-cell GPCRs (including GPR119) can also stimulate the release of endogenous insulin and thus promote normal blood glucose levels in type 2 diabetes. It has also been determined that an increase in cAMP caused by, for example, stimulation of GLP-1 promotes beta cell proliferation, inhibits beta cell death, and thus increases islet mass. This positive effect on beta cell mass is expected to be effective for type 2 diabetes, in which sputum is insufficient, and type 1 diabetes, in which beta cells are damaged by inappropriate autoimmune responses. Some beta cell GPCRs, including GPR119, are also present in the hypothalamus, where they regulate hunger, satiety, and reduce food intake, thereby controlling or reducing weight and energy expenditure. Thus, in view of the function of these receptors in the hypothalamic a loop, their agonists or inverse agonists can alleviate hunger, increase satiety and thereby regulate weight. It has also been well established that metabolic diseases can have a negative impact on other physiological systems. Therefore, a variety of disease states usually occur together (eg, type 2 diabetes, type 2 diabetes, glucose tolerance, sputum resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hyperbilirubin) Hypertension, blood abnormalities, obesity (cardiovascular disease in "X syndrome") or disease secondary to diabetes (eg, kidney disease, peripheral neuropathy). Therefore, it is expected that the treatment of diabetes will be beneficial to this (iv) disease state, in some embodiments of the invention, the metabolic-related disorder is selected from the group consisting of: type 2 diabetes, hyperglycemia, hyperinsulinemia Symptoms, high-fat, glycerol, serotonin, insulin resistance, type 1 diabetes, idiopathic, Μ ^tanguria Ub type, adult occult autoimmune diabetes a ·) type 2 diabetes (excitation), Atypical diabetes in the following year 149380.doc -52· 201105327 (YOAD), adolescent mature onset diabetes (m〇dy), malnutrition-related diabetes, gestational diabetes, cardiovascular disease, coronary heart disease, vascular restenosis, re Stenosis, restenosis after angioplasty, peripheral vascular disease, lameness, intermittent claudication, cell death associated with myocardial infarction (eg necrosis and apoptosis), dyslipidemia, postprandial lipemia, impaired glucose tolerance (IGT) condition, impaired glucose metabolism, impaired glucose metabolism, fasting plasma glucose abnormalities, metabolic acidosis, ketosis, glenoid obesity, osteoporosis , 咼 blood pressure, congestive heart failure, left ~ to hypertrophy, peripheral arterial disease, diabetic retinopathy 'macular degeneration, cataract, diabetic nephropathy, glomerular sclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, X Syndrome, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, ischemic stroke, transient ischemic attack, stroke, erectile dysfunction, skin and connective tissue disorders, foot ulcers, ulcerative colitis, endothelium Dysfunction and vascular compliance disorders. Compositions and Salts Another aspect of the invention pertains to compositions comprising a compound selected from the group consisting of N-(2-fluoro-4-(methylsulfonyl)phenyl)-5-methyl-6-(1_ (5-fluorenyl.pyrazine-2-yl)hexahydro-D-pyridyl-4-yloxy)pyrimidine-4-amine (compound) and pharmaceutically acceptable salts, solvates and hydrates thereof. A further aspect of the invention relates to a composition comprising a compound and one or more pharmaceutically accessible carriers selected from the group consisting of N_(2_fluoro_4_(methylsulfanyl)phenyl)_5·A Kei (4) - 曱 base. Biazin-2-yl)hexahydroindole-4-yloxy)pyrimidine-4-amine (Compound 1) and pharmaceutically acceptable salts thereof, solvent combination 149380.doc

S -53· 201105327 Physicochemicals and hydrates. A further aspect of the invention relates to a pharmaceutical composition comprising a compound and one or more pharmaceutically accessible carriers selected from the group consisting of ice (2-fluoro-4-(indolyl)phenyl)- 5-methyl-6-(1_(5_mercaptopurinyl)-2-hexyl hexazapine -4-yloxy)pyrimidine-4-amine (compound) and pharmaceutically acceptable salts thereof , solvates and hydrates. Some embodiments of the invention relate to the inclusion of N_(2_fluoro_4_(methyl hydrazino) phenyl)-5-mercapto-6-(1-(5-A) A composition of a pharmaceutically acceptable carrier and a pharmaceutically acceptable carrier. Some embodiments of the invention include methods of preparing a pharmaceutical composition, Containing N-(2-fluoro-4-(indolyl)phenyl)-5 methyl winter (κ(5·methyl. 唤 基)) hexamyl-yloxy)(tetra)·4-amine Or a pharmaceutically acceptable salt thereof is admixed with a pharmaceutically acceptable carrier. The composition may be prepared by any suitable method, usually by bringing the active compound to liquid or fine solid carrier or both in a desired ratio Hook and mix, and then if necessary, the resulting mixture is formed into a desired Prepared in the form of a mixture, such as a mixture, a filler, an acceptable wetting agent, a pressure-bonding lubricant, and a disintegrating agent, in a tablet or capsule for oral administration. The liquid preparation to be administered may be in the form of a solution, emulsion, aqueous or oily suspension and sugar incineration. Alternatively, the oral preparation may be in the form of a dry powder which may be reconstituted with water or another suitable liquid vehicle before use. Additional additives such as suspending or emulsifying agents, non-aqueous vehicles (including edible 'supplements), preservatives, and flavoring agents and coloring agents may be added to the preparations. The parental dosage form is prepared by dissolving the compound of the invention 149380.doc • 54-201105327 in a suitable liquid vehicle and sterile filtering the solution. These examples are merely among the many suitable methods known in the art of preparing dosage forms. A number of examples. The compounds of the present invention can be formulated into pharmaceutical compositions using techniques well known to those skilled in the art, and are suitable for use in addition to the carriers mentioned herein. Carrier has been The well known; for example, see

The Science and Practice of Pharmacy, Remington, 20th Edition '2000, LipPincott Wuiiams & Wilkins (Editor: Gennaro, A. R et al.). It is contemplated that the compounds of the present invention may be administered in the form of a crude chemical or a pure chemical, but it is preferred to have the compound or active ingredient in a pharmaceutical formulation which may additionally comprise a pharmaceutically acceptable carrier or Provided in the form of a composition. The invention therefore further provides a pharmaceutical formulation comprising a compound of the invention or a pharmaceutically acceptable salt or derivative thereof together with one or more pharmaceutically acceptable carriers and/or prophylactic ingredients thereof. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not excessively toxic to the recipient. The pharmaceutical formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including intramuscular, subcutaneous and intravenous) administration or are suitable for inhaling Formulations that are administered by blowing, or by means of a transdermal patch, etc. "Transdermal patches dispense drugs at a controlled rate by providing drug absorption in a minimally degradable and effective manner. Typically, a transdermal patch comprises an impermeable backing layer, a single pressure sensitive adhesive layer, and a release liner. 149380.doc -55-201105327 Removal of the protective layer. Those skilled in the art will understand and appreciate techniques suitable for making the desired effective transdermal patch to the needs of the skilled artisan. Thus, the compounds of the present invention can be formulated into a pharmaceutical combination and a unit dosage thereof together with conventional adjuvants, carriers or diluents, and such forms can be used in solid form such as a tablet or a filling capsule; or in liquid form, For example, solutions, suspensions, emulsions, granules, gels or capsules filled with such materials (all forms are used orally); used as a suppository for straight history; or as a sterile injectable solution for non-menstrual use Use in the intestines (including subcutaneous). These pharmaceutical compositions and unit dosage forms may contain conventional ingredients in the conventional proportions with or without additional active compounds or elements, and such unit dosage forms may contain any suitable effective amount of active ingredient commensurate with the desired dosage range employed. . For oral administration, the pharmaceutical compositions may be in the form of, for example, a troche, a capsule, a suspension or a liquid. The pharmaceutical compositions are preferably in the form of dosage units containing a particular amount of active ingredient. Examples of such dosage units are capsules, ingots, granules or suspensions, which contain conventional additives, such as lactose mannitol, corn house powder or horse bell powder; containing binders, example 2 , cellulose derivatives, gum arabic, corn house powder or Ming; 3 have a friend's agent such as corn house powder, potato house powder or slow methyl fiber material; and contain lubricants, such as talcum powder or stearic acid town. The active ingredient can be administered as a composition by injection, wherein, for example, salt water ♦ right brown sugar or water can be used as a suitable pharmaceutically acceptable carrier. The dosage of the compound of the present invention may vary within wide limits and, as is customary and understood by the physician, should be adjusted according to individual conditions in each individual case. 149380.doc • 56· 201105327. This depends, for example, on the nature and severity of the condition to be treated, the condition of the patient, whether the compound or treatment being treated is acute or chronic, or whether prevention or administration of other active compounds other than the compounds of the invention is administered. For example, dosages of the invention include, but are not limited to, from about 〇〇〇i mg to about 5000 mg, from about 〇·〇〇ι to about 25 〇〇mg, from about 〇〇〇1 to about 1 〇〇〇, 0.001 To about 500 mg, 0_001 mg to about 25 〇, about 〇 _ to 100 mg, about o.ooi mg to about 5 〇 mg, and about 〇〇〇 1 mg to about 25. Each sputum may conveniently be administered in a dose at a desired dose or may be administered as a plurality of doses at appropriate intervals, e.g., each sputum is administered as 2 '3 or 4 or more divided doses. The divided dose itself can be further divided into, for example, a number of discrete loose intervals. Depending on the individual and the physician or caregiver of the patient considers it appropriate, it may be necessary to float the dose described herein up or down. The compound of the present invention or a pharmaceutically acceptable salt thereof for use in the treatment varies not only by the particular salt selected, but also by the route of administration, the nature of the condition being treated, and the age and condition of the patient. And finally judged by the master doctor or the fe bed doctor. Often, those skilled in the art understand how to extrapolate in vivo data obtained from a model system that is typically used in animal models to another model (e. g., humans). In general, animal models include, but are not limited to, the rodent diabetes model described in Example 1 below (as well as other animal models well known in the art, such as reported by Reed and Scribner in Diabetes, Obesity and Metabolism, U 1999, 75-86). Their models). In some cases, such extrapolation may be based solely on the weight of the animal model compared to another animal model (eg, a mammal, preferably a human), although it is more common that such extrapolation is not simply based on weight, but rather Combined with 149380.doc •57- 201105327 a variety of factors. Representative factors include, but are not limited to, the age, weight, sex, diet and medical condition of the patient, the severity of the disease, the route of administration, the consideration of the drug, factors such as the activity of the particular compound employed, efficacy, drug motility Learning and toxicological characteristics), whether a drug delivery system is utilized, whether the disease to be treated is acute or chronic, or whether prevention or administration of other active compounds other than the compounds of the invention is administered and as part of a pharmaceutical combination. The dosage regimen of the compounds and/or compositions of the invention for treating diseases is selected in accordance with a variety of factors as described above. Therefore, the solution used in the sputum agent can be very large and must be deviated from the preferred dosage regimen, and those skilled in the art should recognize that doses and agents outside the typical range of Xiao et al. It can be tested and, if appropriate, used in the process of the invention. The compounds of the invention may be administered in a variety of oral and parenteral dosage forms. It will be apparent to those skilled in the art that the following dosage forms may comprise a compound of the invention or a pharmaceutically acceptable salt of a compound of the invention as the active ingredient. For the preparation of a pharmaceutical composition from a compound of the invention, a suitable pharmaceutically acceptable carrier can be selected as a solid, a liquid or a mixture of the two. Solid form preparations include powders, troches, pills, capsules, cachets, suppositories, and dispersible granules. The solid carrier can be - or a plurality of materials f, which can also act as a diluent, a drier, a solubilizer, a slip agent, a suspending agent, a binder, a preservative, a key disintegrating agent or an encapsulating material. A fine solid in which the carrier is mixed with the finely active component. In the tablet, the active ingredient is mixed with a carrier having the necessary adhesive ability in an appropriate ratio and compressed into a desired shape and size. Powders and lozenges may contain varying percentages of active compound. A representative amount of the powder or 149380.doc-58-201105327 lozenge may contain from 05% to about 90% of the compound of the invention; however, the skilled artisan will appreciate that amounts outside of this range are sometimes required. Suitable carriers for powders and lozenges are magnesium carbonate, magnesium stearate, talc, sucrose, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, Low melting waxes, cocoa butter, and the like. The term "preparation" is intended to include a formulation of the active compound with an encapsulating material which provides a capsule as a carrier, wherein the active ingredient with or without the carrier is surrounded by the carrier and thereby combined therewith. Similarly, cachets and rhomboid tablets are also included. Tablets, powders, capsules, pills, cachets, and ampoules can be used in solid form for oral administration. To prepare a suppository, a low melting wax such as a fatty acid glyceride mixture or cocoa butter is first melted and the active component is uniformly dispersed therein by, for example, stirring. After Ik, the molten homogeneous mixture is poured into a mold of suitable size to cool and thereby solidify. Compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays, in addition to the active ingredient: there are, for example, suitable carriers known in the art Agent. Liquid form preparations include solutions, suspensions and emulsions such as water or water-propylene glycol solutions. For example, a parenteral injection liquid preparation can be formulated into a solution in an aqueous solution of polyethylene glycol. Injectable (iv), for example, water- or oil-based suspensions may be formulated according to the known techniques using the remedies or agents and agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic non-missible diluent or solvent, such as a solution in u-butylene glycol. The acceptable vehicles and solvents that can be used are sigma sigma 149380.doc -59- 201105327 water, Ringeris soluti〇n and isotonic gasification nanosolution. In addition, sterile fixed oils are usually employed as a solvent or suspending medium. Any mild fixed oil, including human glycerol early ester or diglyceride, can be used for this purpose. In addition, fatty acids such as oleic acid find use in the injectable formulations. Thus, the compounds of the invention may be formulated for non-borrowing: injection, such as bolus injection or continuous infusion), and may be in units of: for virgin, prefilled syringes, small volume infusion tubes or with more preservatives added. In the dose container. The pharmaceutical composition may be in the form of a suspension, solution or emulsion, for example, in an oily or aqueous vehicle, and may contain a formulation such as a suspending agent, a stabilizer, and/or a dispersing agent. Alternatively, the active ingredient may be in the form of a powder which is isolated by sterilization of sterile solids or by lyophilization from solution for constitution with a suitable vehicle (for example, sterile pyrogen-free water) before use. An aqueous composition suitable for oral use can be prepared by dissolving or suspending the active ingredient in water and, if necessary, adding suitable coloring agents, humectants, stabilizers and thickening agents. Aqueous suspensions suitable for oral use can be dispersed in water and viscous materials (for example, natural or synthetic gums, resins, sulfhydryl cellulose, sodium carboxymethylcellulose or other conventional suspending agents) ) to prepare. The present invention also encompasses solid form preparations which are intended to be converted into liquid form preparations for oral administration just prior to use. Such liquid forms include solutions, suspensions and emulsions. These preparations may contain, in addition to the active ingredient, coloring agents, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersing agents, thickening agents, solubilizing agents, and the like. 149380.doc -60· 201105327 For topical administration to the epidermis, the compounds of the invention may be formulated as a cream, cream or lotion, or as a transdermal patch. For example, ointments and creams can be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with aqueous or oily bases and will usually contain one or more emulsifying, stabilizing, dispersing, suspending, thickening or coloring agents. Compositions suitable for topical administration in the mouth include: rhomboid tablets which comprise active wounds in a flavoring base which is typically sucrose and gum arabic or tragacanth, and which are in the form of gelatin and glycerin or sucrose, and An inert matrix such as gum arabic contains an active ingredient; and a 漱σ syrup which contains the active ingredient in a suitable liquid carrier. The solution or suspension is applied directly to the nasal cavity by conventional means (e.g., using a dropper, pipette or ejector). The compositions may be provided in single or multiple doses. In the case of (4) or after the inhalation of f, this can be achieved by the patient administering a suitable volume or solution or suspension. In the case of an ejector, this can be achieved, for example, by metering an atomizing spray pump. Respiratory administration can also be achieved by means of an aerosol composition wherein the active ingredient is provided in a pressurized package with a suitable propellant. If the drug is administered in the form of an aerosol (for example in the form of a nasal aerosol or by inhalation) or a pharmaceutical composition comprising the same, it is possible to use, for example, an ejector, a mister: a pump sprayer, a suction device, The metering of the inhaler or the dry powder for the administration of the pharmaceutical form of the compound of the present invention as an aerosol can be carried out by the skilled artisan, for example, by using the present invention: for example, a solution or dispersion in water, a water/alcohol mixture or a suitable saline solution of 149380.doc 61 201105327, and using conventional additives such as sterols or other suitable preservatives, absorption enhancers for increasing bioavailability, Solubilizers, dispersants, and other agents, and where appropriate, conventional propellants' include, for example, carbon dioxide, CFCs such as dichlorodifluorodecane, tri-fluorofluoromethane or di-tetrafluoroethane; and the like. Aerosols may also conveniently contain a surfactant such as lecithin. A metering valve can be used to control the dose of the drug. This is done in compositions and compositions to the respiratory tract, including intranasal compositions. The material should generally have a small particle size of, for example, about 1 micron or less. This granulated straw can be obtained by means known in the art (for example by micronization). When necessary, a composition suitable for sustained release of the active ingredient can be employed. Or the 'active ingredient' may be provided in the form of a dry powder, for example, a compound in a powder: a powder mixture of the powder: the powder base may be, for example, milk π, such as hydroxypropyl fluorenyl cellulose and polyvinylpyrrole Pyridine

Vp) and other starch derivatives. The powder carrier will be in the nasal cavity. For example, a gentleman may enter a gel or a blister pack to form a blister pack: the unit dosage form is present in, for example, gelatin or a pharmaceutical bay where the powder can be administered by means of an inhaler. Contains two suitable unit dosage forms. In this form, the formulation can be subdivided into an agent, which has an early dose of the injury. The unit dosage form may be a sealed agricultural bottle or an Ancai: a two-component preparation such as a small package, a capsule and a small form, a cachet or an L. The early dosage form itself may also be a capsule or an ingot. The agent, or any suitable package thereof, may be preferably a combination of a tablet or capsule administered thereto and an intravenously administered liquid system 149380.doc -62-201105327. The compounds of the present invention may optionally be present as pharmaceutically acceptable salts, including pharmaceutically acceptable acid addition salts prepared from pharmaceutically acceptable non-toxic acids including inorganic acids and organic acids. These acid addition salts can be obtained as a direct product of the synthesis of the compound. In an alternative embodiment, the free assay can be dissolved in a suitable solvent containing the appropriate acid and the salt isolated by evaporation of the solvent or separation of the salt from the solvent. The compounds of the present invention can be formed into solvates with low molecular weight solvents using methods known to those skilled in the art. It should be noted that when the GPR119 agonist and its pharmaceutically acceptable salts, solvates and hydrates are used as active ingredients in compositions such as pharmaceutical compositions, they are not necessarily intended for use in humans, but are also used in other Non-human feeding animals. In fact, recent advances in animal health care have shown that active agents such as GPR119 receptor modulators should be considered for the treatment of obesity in livestock (eg cats and dogs) and GPR119 receptor modulators for disease or Other animals such as livestock, such as animals, such as cattle, chickens, fish, etc., whose condition is unknown. It is believed that those skilled in the art will readily appreciate the use of such compounds in such occasions. Pharmaceutically acceptable salts, solvates and hydrates should be understood as 'when using the phrase "pharmaceutically acceptable salts, solvates and hydrates" when referring to Ν·(2-fluoro·4_(曱基) Continuation of fluorenyl)phenyl)_5_methyl winter (1-(5-methyloxain-2-yl)hexahydro. When biting _4_yloxy) π-Bite-4. : 1) N-(2-Fluoro-4-(methylsulfonyl)phenyl)_5•methylmethyl I49380.doc •63- 201105327. a pharmaceutically acceptable salt of a pyridinium-2(yl)hexahydrom_4_yloxy)(tetra)-4-amine; 2) N-(2-fluoro-4-((methylsulfonyl)phenyl)-5-methyl _6·(ι_(5•methylpyrazine-2·yl)hexahydropyridin-4-yloxy)pyrimidin-4-amine and a pharmaceutically acceptable salt thereof; and 3) Ν -(2"Fluoro-4-(methylsulfonyl)phenyl)-5-methylmethylpyrazin-2-yl)hexahydropyridyl-4-yloxy)pyrimidine-4-amine and its medicinal The hydrate of the salt of the invention may be administered in a variety of oral and parenteral dosage forms. It will be readily apparent to those skilled in the art that the following dosage forms may comprise a compound selected from the compound ν_(2_fluoro-4-(methyl) Sulfhydryl)phenyl)_5.methyl_6·(1_(5-methylpyridazine-2-yl)hexafluoropyridin-4-yloxy)pyrimidine-4 amine (compound i) and A pharmaceutically acceptable salt, solvate, and hydrate compound is used as an active ingredient. Further, various hydrates and solvates of the compound of the present invention and salts thereof can be used as an intermediate for the manufacture of a pharmaceutical composition. And determining suitable hydrates and solvates other than those mentioned herein Typical procedures are well known to those skilled in the art; for example, see K.j GuiUory, "Generati()n of

Polymorphs, Hydrates, Solvates, and Amorphous Solidsj: Polymorphism in Pharmaceutical Solids > Harry G. Brittan, eds., vol. 95, Marcel Dekker, New York, 1999, pp. 202-209, all of which is incorporated herein by reference. in. Thus, one aspect of the invention pertains to N-(2-fluoro-4-(methylsulfonyl)phenyl)-5-mercapto-6-(1-(5-methylpyrazine-2- And pharmaceutically acceptable salt hydrates and solvates thereof, which are known in the art by one or 149380.doc-64 - 201105327 Methods for separation and characterization, such as thermogravimetric analysis (TGA), TGA-mass spectrometry, TGA-infrared spectroscopy, powder X-ray diffraction (XRPD), Karl Fisher titration, high resolution X-ray diffraction and the like. Several commercial entities provide fast and efficient services for identifying solvates and hydrates on a regular basis. Exemplary companies that provide such services include Wilmington PharmaTech (Wilmington, DE) 'Avantium Technologies (Amsterdam) and Aptuit (Greenwich, CT). Polymorphs and Pseudopolymorphs Polymorphic materials have the ability to exist in two or more crystalline phases that have different molecular arrangements and/or conformations in the crystal lattice. Polymorphs exhibit the same properties in liquid or gaseous form, but they behave differently in solid state. In addition to the one-component polymorph, the drug may also be present in the form of a salt and other multi-component crystalline phases. For example, solvates and hydrates may each contain an API host and a solvent or water molecule as a guest. Similarly, when the guest compound is a solid at room temperature, the resulting form is often referred to as a co-crystal. Salts, solvates, hydrates, and co-crystals can also exhibit polymorphism. Crystal phases having the same API host but having different guest bodies may be referred to each other as pseudopolymorphs. The solvate contains a crystalline solvent molecule in a defined lattice. The solvating solvent in which the crystallization solvent is water is referred to as a hydrate. Due to the composition of the aqueous system of the atmosphere, drug hydrates can be formed quite easily. For example, Stahly recently published 245 polymorphic screenings of compounds consisting of "many species of structural class 149380.doc -65- 201105327", which showed that about 90% of these compounds exhibited multiple solid forms. . In summary, about half of these compounds are polymorphic and usually have one to three forms. About 1/3 of these compounds form a hydrate' and about 1/3 form a solvate. Co-crystal screen data for 64 compounds showed 60% formation of eutectics rather than hydrates or solvates. (GP Stahly, Crystal Growth & Design (2007), 7(6), 1007-1026.) Combination Therapy In the context of the present invention, a compound described herein or a compound thereof for use in modulating a GPR119 receptor-associated disease as described herein , conditions and/or sorrowful activities. Examples of activities that modulate GPR119 receptor-associated diseases include treatment of metabolic related disorders. Metabolic related disorders include, but are not limited to, g-lipidemia; type 1 diabetes; type 2 diabetes, and related conditions, including but not limited to coronary heart disease, ischemic stroke, restenosis after angioplasty Peripheral vascular disease, lameness, intermittent claudication, island cell death associated with myocardial infarction (eg, necrosis and apoptosis), dyslipidemia, postprandial lipids, impaired glucose tolerance (IGT) condition, fasting plasma Glucose _ condition, metabolic acidosis, ketosis, arthritis, obesity, osteoporosis, hypertension, congestive heart failure 'left ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy, macular degeneration, cataract ,diabetes _ nephropathy, renal arteries ▲ tube sclerosis, chronic renal failure, diabetic sensation, metabolic syndrome, X syndrome, premenstrual syndrome, coronary heart disease, striated pain, thrombosis, atherosclerosis, myocardial infarction Transient analgesia, stroke, vascular stenosis, high-grade disease, sorghum, high 149380.doc • 66 - 201105327 Hypertension, hypertriglyceridemia, Insulin resistance, impaired glucose metabolism, impaired glucose tolerance, abnormal conditions of fasting blood polydextrose, obesity, erectile dysfunction, skin and connective tissue disorders, foot ulcers, ulcerative colitis, endothelial dysfunction and blood vessels Compliance disorder. In some embodiments, 'metabolic related conditions include type I diabetes, type 2 diabetes, inadequate glucose tolerance, sputum resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia 'Hyperlipidemia and snoring syndrome. Other examples of activities that modulate GPR119 receptor-associated diseases include loss of weight and/or maintenance by reducing food intake, inducing satiety (ie, feeling full), controlling weight gain, reducing body weight, and/or affecting metabolism Weight to treat obesity and / or overweight. While the compounds of the invention may be used as a single active pharmaceutical agent (ie, monotherapy), the compounds may also be administered in combination with one or more of the pharmaceutical agents (ie, combination therapies) for the treatment of the diseases described herein. Condition / illness. Thus, another aspect of the invention includes a method of treating a metabolic-related disorder, including a weight-related disorder, eg, obesity, comprising administering to a subject in need of prophylaxis and/or treatment a therapeutically effective amount of a compound of the invention and a Or a plurality of additional pharmaceutical agents described herein. Suitable pharmaceutical agents that can be used in combination with the compounds of the invention include anti-obesity agents such as apolipoprotein-B secreting/microsomal triglyceride transfer protein (apo_B/MTP) inhibitors, MCR-4 agonists, cholecystokinin A (cholescystoldnin-AKCCK-A) agonists, serotonin and norepinephrine reuptake inhibitors (eg, sibutramine), sympathomimetic agents, beta 3 adrenergic receptor agonists, dopamine agonists ( Example I49380.doc • 67-201105327 For example, bromocriptine, melanocyte stimulating hormone receptor analog, cannabinoid 1 receptor antagonist [eg, SR14i716: > 1-(mother. Dec-1-yl)-5-(4-phenylphenyl)-1-(2,4-dichlorophenyl)_4_methyl-1幵- °biazole-3-formamide], melanin Concentrated hormone antagonists, leptin (〇B protein), leptin analogs, alizarin receptor agonists, galanin antagonists, lipase inhibitors (eg tetrahydrolipidin) (tetrahydr〇lipstatin), ie Orlistat), anorectic agent (such as 〇 es es es 、 、 、), neuropeptide-Y antagonist Anti-agent, pseudo-like gonadotropin, dehydroepiandrosterone or its analogue, glucocorticoid receptor agonist or antagonist, orexin receptor antagonist, uroc〇rtin binding Protein antagonists, glucagon-like peptide-1 receptor agonists, ciliary neurotrophic factors (eg self-

Regeneron Pharmaceuticals (Tarrytown, NY) and Procter & Gamble (Cincinnati, 〇H) purchased AxokineTM), human squirrel-associated protein (AGRP), ghrelin receptor antagonist, histamine 3 a receptor antagonist or inverse agonist, a neuromodulin U receptor agonist, an anorectic agent that produces norepinephrine (eg, phentermine, mazindol, and the like), And appetite suppressants (e.g., bupropion), other anti-obesity agents, including the agents listed below, are well known and are readily understood by those skilled in the art in light of the present disclosure. In some embodiments, the anti-obesity agent is selected from the group consisting of orlistat, sibutramine, bromocriptine, ephedrine, leptin, phentermine, and pseudoephedrine. In yet another embodiment, the compounds of the invention and combination therapies are administered in combination with exercise and/or a reasonable diet. 149380.doc -68- 201105327 It should be understood that the scope of combination therapy of the compounds of the present invention with other anti-obesity agents, anorectic agents, appetite suppressants and related agents is not limited to the above-listed conditions, and the principle of 疋Included in any combination with any of the pharmaceutical or pharmaceutical compositions for treating overweight and obese individuals. It will be appreciated that the scope of combination therapies of the compounds of the invention with other pharmaceutical agents is not limited to those listed above or below, but includes, in principle, any disease or condition associated with a treatment-related metabolic-related disorder. Or any pharmaceutical agent or combination of pharmaceutical compositions of the condition. Some embodiments of the invention include methods of treating a disease, disorder, condition, or complication thereof, as described herein, comprising administering to a subject in need of such treatment a therapeutically effective amount or dose of a compound of the invention and at least one selected from the group consisting of a combination of pharmaceutical agents comprising: sulfonylureas (eg, glybunde, glipizide, glimepiride, and other sulfonamides known in the art), Meglitinides (eg, repaglinide, nateglinide, and other melamines known in the art), biguanides (eg biguanides) Including phenformin, metfor-min, buformin, and known biguanides in the industry, alpha-glucosidase inhibitors [eg acarbose, N-(l, 3-dihydroxy-2-propyl)vali〇lamine (common name: v〇glibose), miglitol, and alpha known in the industry _glucosidase inhibitor], peroxisome proliferative factor Chemo-receptor-gamma (ie, PPAR-gamma) agonists (eg, rosiglitazone, pioglitazone, tesaglitazar, negoglitazone, GW) - 149380.doc -69- 201105327 40954|, GW-501516 and PPAR-gamma agonists known in the art), insulin, insulin analogues, HMG-CoA reductase inhibitors (eg rosuvastatin, butyl ( Rosuvastatin), pravastatin and its sodium salts, simvastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin (cerivastatin), rosuvastatin, pitavastatin, BMS "super-he; j: superstatin j, and HMG-CoA reductase inhibitors known in the industry", Cholesterol drugs (eg, fibrates, including bezafibrate, beclobrate, binifibrate, ciprofibrate, clino-fibrate ), gas beetin S (clofibrate), gas benign acid (cl Ofibric acid), etofibrate, fenofibrate, gemfibrozil, nicofibrate, pirifibrate, ronifibrate , simfibrate, theofibrate, and fiber acids known in the art; bile acid sequestrants, including: cholestyramine, colestipol And the like; and acid detection), antiplatelet agents (such as aspirin and adenosine diphosphate receptor antagonists, including: clopidogrel, ticlopidine, and the like), Angiotensin-converting enzyme inhibitors (eg, captopril, enalapril, alapril, delapril, ramipril, lamapi Lisinopril, imidapril, benazepril, ceronaprU 'cilazapril, enalaprilat, fossip Lee (fosinopril), 149380.doc -70- 2 01105327 moveltopdl, perind〇prii, quinapril, spirapril, temocapril, trandolapdl, and Angiotensin-converting enzyme inhibitors known in the art), angiotensin-receptor inhibitors [eg, sarsartan (and potassium salt forms), and angiotensin- Η known in the art) Inhibitors, adiponectin, squalene synthesis inhibitors (eg (S)_a-[bis[2,2-dimethyl-1-oxooxypropoxy)decyloxy]phosphinyl) Phosphylyl]]-3-phenoxybenzidine monosodium salt (BMS-188494) and known squalene synthesis inhibitors in the art), and the like. In some embodiments, the compounds of the invention and pharmaceutical agents are administered separately. In other embodiments, the compounds of the invention and pharmaceutical agents are administered together. Suitable pharmaceutical agents that can be used in combination with the compounds of the invention include, but are not limited to, dinol agonists (e.g., pramlintide), insulin secretagogues (e.g., 'GLP-1 agonists; exenatide (exendin-4); insulinotropin (NN2211)), sulfhydryl-based CoA cholesterol-based transferase inhibitor (eg, ezetimibe, eflucimibe, And similar compounds), cholesterol absorption inhibitors (eg 'Ezetimibe, pamaqueside and similar compounds), cholesterol ester transfer protein inhibitors (eg, CP-529414, iTT_7G5, CETi-1) And similar compounds), microsomal triglyceride transfer protein inhibitors (such as 'impitapide and similar compounds), cholesterol regulators (eg, NO-1886 and similar compounds), cholic acid modulators (eg ' GT103-279 and similar compounds), insulin signaling pathway regulators (such as protein tyrosine phosphatase inhibitor (PTPase)), glutamine 149380.doc 71 201105327 fructose-6-phosphorus Non-small molecule mimetic compounds and inhibitors of aminotransferases (GFAT), compounds that affect the production of dysfunctional hepatic glucose (such as glucose-6-phosphatase (G6P enzyme) inhibitors, fructose-i,6-bisphosphatase ( F-1,6-BP enzyme) inhibitor, glycogenate phosphatase (GP) inhibitor, glucagon receptor antagonist and phosphoenolpyruvate carboxykinase (PEPCK) inhibitor, pyruvate dehydrogenase Kinase (PDHK) inhibitor, insulin sensitivity enhancer, insulin secretion enhancer, gastric emptying inhibitor, α2_adrenergic antagonist, retinoid X receptor (RXR) agonist and dipeptidyl peptidase -4 (DPP-IV) inhibitor. Dipeptidyl peptidase IV (DPP-IV) inhibitor dipeptidyl peptidase 1 ¥ (0??-1乂£€3.4.14.5) for a wide range of peptide receptors Showing catalytic activity, peptide receptors including peptide hormones, neuropeptides and chemokines. Incretin-glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) stimulate glucose-dependent insulin Secretion and additionally promote blood glucose homeostasis, the two peptides are rapidly cleaved by DPP-IV at position 2 alanine Its biological activity is inactivated. Both pharmacological and genetic attenuation of DPP-IV activity are associated with increased incretin action, increased insulin and lower blood glucose in vivo. The genetic attenuation of DPP-IV activity has been shown to provide Resistance to disease and increased insulin sensitivity. DPP-IV inhibitors have been shown to be useful as therapeutic agents, for example, it has been found that oral administration of vildagliptin to human patients with type 2 diabetes (l- [2-(3-Hydroxyadamantan-1-ylamino)ethylidene]pyrrolidine-2(S)-carbonitrile) or sitagliptin (3(R)-amino-l- [3-(Trifluoromethyl)-5,6,7,8·tetrahydro[1,2,4]disindol [4,3-&]°°°Q-7-yl]-4- (2,4,5-three|^ stupid) D-1- 1 149380.doc • 72-201105327 Ketone) can reduce the drift of fasting glucose and postprandial glucose associated with significantly reduced HbAlc concentration. For a review of the use of DPP-IV inhibitors for the treatment of type 2 diabetes, refer to the following publications: (1) H.-U. Demuth et al., "Type 2 diabetes-Therapy with dipeptidyl peptidase IV inhibitors" Biochim. Biophys. Acta, 1751: 33-44 (2005); and (2) K. Augustyns et al., "Inhibitors of proline-specific dipeptidyl peptidases: DPP-IV inhibitors as a novel approach for the treatment of Type 2 diabetes", Expert

Opin. Ther. Patents, 15: 1387-1407 (2005). Thus, suitable pharmaceutical agents include DPP-IV inhibitors which can be used in combination with the compounds of the invention administered separately or together. DPP-IV inhibitors are well known in the art or can be readily determined and their in vitro biological activity can be determined using any number of available methods, for example, O'Brien, M., Daily, B., Schurria, Μ., "Assay for DPPIV activity using a homogeneous, luminescent method", Cell Notes, No. 11, 2005; see also DPPIV-GloTM Protease Analysis Technical Bulletin No. TB339. Examples of DPP-IV inhibitors are set forth in the literature: for LAF237, Villhauer et al, J Med Chem (2003) 46: 2774-2789; Ahren et al, J Clin Endocrinol Metab (2004) 89: 2078-2084 For NVP-DPP728, Villhauer et al., J Med Chem (2002) 45: 2362-2365; for NVP-DPP728, Ahren et al., Diabetes Care (2002) 25: 869-875; Peters et al. Bioorg Med Chem Lett (2004) 14: 1491-1493; Caldwell 149380. doc-73-201105327 et al, Bioorg Med Chem Lett (2004) 14: 1265-1268;

Edmondson et al, Bioorg Med Chem Lett (2004) 14:5151-515 5 ; and Abe et al, J Nat Prod (2004) 67:999-1004 o Specific examples of DPP-IV inhibitors include (but are not limited to) two Peptide derivatives or dipeptide mimetics, such as alanine-° ratios of each pyridine, isoleucine-thiazole bite and pseudo-nuclear N-chloroamine decyl amidoxime, hydrazine-benzoquinone , for example, as described in U.S. Patent No. 6,303,661. Some embodiments of the invention include each combination of one or more DPP-IV inhibitors selected from the group consisting of DPP-IV inhibitors as disclosed in U.S. Patent Nos. 6,869,947, 6,867,205, 6,861,440 No. 6,849,622, 6,812,350, 6,803,357, 6,800,650, 6,727,261, 6,716,843, 6,710,040, 6,706,742, 6,645,995, 6,617,340, 6,699,871, 6,573,287, Nos. 6,432,969, 6,395,767, 6,380,398, 6,303,661, 6,242,422, 6,166,063, 6,100,234, and 6,040,145. Some embodiments of the invention include each combination of one or more DPP-IV inhibitors selected from the group consisting of DPP-IV inhibitors found in the following U.S. patent applications: No. 2005059724, No. 2005059716, No. 2005043292 No. 2005038020, 2005032804, 2005004205, 2004259903, 2004259902, 2004259883, 2004254226, 2004242898, 2004229926, 2004180925, 2004176406, 149380. • 74-201105327 No. 2004116328, No. 2004097510, No. 2004077645, No. 2004034014, No. 2003216450, No. 2003195188, No. 2003134802, No. 2003125304, No. 2003105077, No. 2003078247, No. 2002103384, 2004138214 2004106656 No. 2004082570 No. 2004063935 No. 2003225102 No. 2003199528 No. 2003 149071 No. 2003130199 No. 2003 1 19738 No. 2003087950 No. 2002183367 No. 2004110817, No. 2004087587, No. 2004072892, No. 2003232788, No. 2003216382, No. 20031628 No. 20, No. 2003130281, No. 2003119750, No. 2003100563, No. 2002198205, No. 2002049164 and No. 2002006899. Some embodiments of the invention include each combination of one or more DPP-IV inhibitors selected from the following International Patent Application Publications.

, WO WO 2005/037828, WO WO 2005/037828 ' WO WO 2005/033099 ' WO WO 2005/030127 , WO WO 2005/023762 , WO WO 05/12312, WO DPP-IV inhibitor: WO 2005/087235 2005/082849 2005/072530 2005/049022 2005/042488 2005/037779 2005/032590 2005/026148 2005/020920, WO 2005/079795, WO 2005/063750 WO 2005/047297, 'WO 2005/040095 ' 'WO 2005/034940 ', WO 2005/030751, 'WO 2005/025554 >, WO 05/19168, 05/12308, WO 05/12249, WO 05/ 11581, WO 05/09956, 149380.doc -75-201105327 WO 05/03 135 'WO 05/00848, WO 05/00846 'WO 04/112701, WO 04/111051 WO 04/111041, wo 04/110436, wo 04/110375 wo 04/108730 , wo 04/104216 , wo 04/104215 wo 04/103993 ' wo 04/103276 , wo 04/99134 wo 04/96806 , wo 04/92128 , WO 04/87650 , WO 04/87053 , WO 04/85661, WO 04/85378, WO 04/76434, WO 04/76433, WO 04/71454, WO 04/69162, WO 04/67509, WO 04/64778, WO 04/58266, WO 04/52362 , WO 04/ 52850, WO 04/50022, WO 04/50658, WO 04/48379 'WO 04/46106, WO 04/43940, WO 04/41820, WO 04/41795, WO 04/37169, WO 04/37181, WO 04/ 33455, WO 04/32836, WO 04/20407, WO 04/18469, WO 04/18468, WO 04/18467 'WO 04/14860, WO 04/09544, WO 04/07468, WO 04/07446, WO 04/ 04661, WO 04/00327, WO 03/106456, WO 03/104229, WO 03/101958, WO 03/101448, WO 03/99279, WO 03/95425, WO 03/84940, WO 03/82817, WO 03/ 80633, WO 03/74500, WO 03/72556, WO 03/72528, WO 03/68757, WO 03/68748 > WO 03/57666, WO 03/57144, WO 03/55881, WO 03/45228 'WO 03 /40174 'WO 03/38123 ' WO 03/37327 'WO 03/35067, WO 03/35057, WO 03/24965, WO 03/24942, WO 03/22871, WO 03/15775, WO 03/04498, WO 03 /04496, WO 03/02530, WO 03/02596, -76- 149380.doc 201105327 WO 03/02595, WO 03/02593, WO 03/02553, WO 03/02531, WO 03/00181, WO 03/00180, WO 03/00250, WO 02/83109, WO 02/83 128, WO 02/76450, WO 02/68420, WO 02/62764, WO 02/55088, WO 02/51836, WO 02/38541 > WO 02/34900 'WO 02/30891 'WO 02/30890, WO 02/14271, WO 02/02560, WO 01/97808, WO 01/96295, WO 01/81337, WO 01/81304 WO 01/68603, WO 01/55105, WO 01/52825, WO 01/34594, WO 00/71135, WO 00/69868, WO 00/56297, WO 00/56296, WO 00/34241 'WO 00/23421 WO 00/10549, WO 99/67278, WO 99/62914, WO 99/61431, WO 99/56753, WO 99/25719, WO 99/16864, WO 98/50066, WO 98/50046, WO 98/19998 WO 98/18763, WO 97/40832, WO 95/29691, WO 95/15309 'WO 93/10127 ' WO 93/08259 and WO 91/16339. Some embodiments of the invention include each combination of one or more DPP-IV inhibitors selected from the group consisting of DPP-IV as disclosed in the following patent publications.

Preparation: EP 1517907, EP 1513808, EP 1492777, EP

1490335, EP 1 476 429, EP 1 461 337, EP 1441719, EP 1406872, EP 1399471, EP 1489088, EP 1469873, EP 1450794, EP 1426366, EP 1406622, EP 1399470, EP 1480961, EP 1465891, EP 1446116, EP 1412357, EP 1404675, EP 1399469, EP 1476435, EP 1463727, EP 1442049, EP 1406873, EP 1399420, EP 1399433 'EP 149380.doc 77- 201105327

1399154 > EP 1354882 , EP 1301187 , EP 1261586 , EP 1245568 , EP 1123272 ' EP 1043328 , EP 0731789 , EP 2466870 , CA 2289124 , CA 1385508 ' EP 1338592 ' EP 1296974 ' EP 1258476 ' EP 1215207 , EP 1104293 , EP 0995440 , EP 0 641 347, EP 2433090 'CA 2123128, DD 1377288, EP 1333025, EP 1280797, EP 1254113 > EP 1228061, EP 1082314, EP 0980249, EP 0610317, EP 2339537, CA 296075, DE

1355886, EP 1304327, EP 1282600, EP 1248604, EP 1137635, EP 1050540, EP 0975359, EP 0528858, CA 2289125, CA 19834591, DE 19828113, DE 19823831, DE 19616486, DE 10333935,

DE 10 327 439 </ RTI> </ RTI> </ RTI> <RTIgt; JP 2004534836 \ JP 2004534815 , JP 2004532220 JP 2004530729 % JP 2004525929 , JP 2004525179 JP 2004522786 JP 2004521149 , JP 2004503531 JP 2004315496 JP 2004244412 , JP 2004043429 JP 2004035574 JP 2004026820 , JP 2004026678 &gt; JP 2004002368 JP 2004002367 ' JP 2003535898 , JP 2003535034 JP 2003531204 &gt; JP 2003531191 JP 2003531118 JP 149380.doc -78- 201105327

2003524591 , JP 2003520849 , JP 2003327532 , JP 2003300977 , JP 2003238566 , JP 2002531547 JP 2002527504 , JP 2002517401 , JP 2002516318 , JP 2002363157 , JP 2002356472 &gt; JP 2002356471 · &gt; JP 2002265439 , JP 2001510442 , JP 2000511559 JP 2000327689 ' JP 2000191616 JP 1998182613 X JP 1998081666 , JP 1997509921 , JP 1995501078 and JP 1993508624. In some embodiments, the DPP-IV inhibitor has an IC50 of less than about 10 μΜ, less than about 1 μΜ, less than about 100 μΜ, less than about 75 ηΜ, less than about 50 ηΜ, less than about 25 ηΜ, less than about 20 ηΜ, less than About 15 η Μ, less than about 10 η Μ, less than about 5 η Μ, less than about 4 η Μ, less than about 3 η Μ, less than about 2 η Μ or less than about 1 η Μ. In some embodiments, the DPP-IV inhibitor has an IC5 〇 of less than about 50 η Μ, less than about 25 η Μ, less than about 20 Μ Μ, less than about 1 5 η Μ, less than about 10 η Μ, less than about 5 η Μ, less than about 4 η Μ, Less than about 3 η Μ, less than about 2 η Μ or less than about 1 η Μ. In some embodiments, the DPP-IV inhibitor is a selective DPP-IV inhibitor, wherein the selectivity of the selective DPP-IV inhibitor for human plasma DPP-IV is selective for one or more of the following enzymes; At least about 10 times, more preferably at least about 100 times and optimally at least about 1000 times: prolyl lyase (PPCE), dipeptidyl peptidase II (DPPII), dipeptidyl peptidase-8 ( DPP-8) and dipeptidyl peptidase-9 (DPP-9). In some embodiments, the DPP-IV inhibitor has oral activity. In some embodiments, the DPP-IV inhibitor is a human DPP-IV inhibitor 149380.doc-79-201105327 agent. Some embodiments of the invention include one or more selected from the group consisting of ruthenium b compounds and pharmaceutically acceptable salts, solvates and hydrates thereof: 3(R)-Amine_1-[3 -(Trifluoromethyl)_5,6,7,8-tetrahydro[1,2,4]oxazolo[4,3-a]. Bipyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butanone; hydroxy hydroxymethyl-1-ylamino) ethyl ketone] „ „ each. _2(s)-carbonitrile; (18,38,58)-2-[2(8)-amino-2-(3- via fund gang _1_yl) ethoxylate]_2-nitrogen Heterobicyclo[3.1.0]hexyl-3-indene nitrile; 2-[6-[3(11)-aminohexahydropyridin-1-yl]-3-indolyl-2,4-dioxy -1,2,3,4_tetrahydropyranyl-1-ylmethyl]phthalonitrile; 8-[3(R)-aminohexahydro. Specific bite-1·yl]-7-(2-butynyl)-3-methyl_1_(4-mercaptoquinazolin-2-ylmethyl)xanthine; l-[N-[3( R)-n 比哈°定基]Glycidyl]pyrrolidine-2(R)-ylboronic acid; 4(S)-fluoro-l-[2-[(lR,3S)-3-(1H-1) , 2,4-triazol-1-ylindenyl)cyclopentylamino]ethionyl]pyrrolidine-2(S)-phthalonitrile; 1-[(2S,3S,llbS)-2-amine -9,10-Dimethoxy· 2,3,4,6,7,111?-hexahydro-111-° ratio. And [2,1-&amp;]isoindol-3-yl]-4(8)-(fluoromethyl)pyrrolidin-2-one; (2S,4S)-2-cyano-4-fluoro -l-[(2-hydroxy-1,1-dimethyl)ethylamino]ethinylpyrrolidine; 8-(cis-hexahydro-pyrrolo[3,2-b]. -1-yl)-3-methyl-7-(3-indolyl-but-2-yl)-1-(2-oxo-2-phenylethyl)-3,7-dihydro -嘌呤-2,6-dione; 1-((33,48)-4-amino-1-(4-(3,3-dipyridyrridin-1-yl)-1,3,5-three Pyridin-2-yl)pyrrolidin-3-yl)-5,5,2,6,6,6,6,6,6,6,6,(R)-2-((6-(3-Amino hexahydroindole) -1-yl)_3-methyl-2,4-di-oxy-3,4-dihydropyrimidine-l(2H)-yl)methyl)-4-fluorobenzonitrile; 5-{(S -2-[2-((S)-2-cyano-0-bilo.-1-yl)-2-yloxy-ethylamino]propyl}-5-(1Η-tetrazole -5-yl)10,11-dihydro-5H-dibenzo[a,d] 149380.doc -80 - 201105327 Cycloheptene-2,8-dicarboxylic acid bis-dimethyl decylamine; ((2S , 4S) -4-(4-(3-methyl-1-phenyl-1 Η-β-biazole-5-yl)hexahydropyrazin-1-yl) ° ratio 11 pyridin-2-yl) ( Tetrahydrocarbazol-3-yl)anthone; (2S,4S)-l-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetamidine 4-fluoropyrrolidin-2-carbonitrile; 6-[(3R)-3-amino-hexahydropyridin-1-yl]-5-(2-chloro-5-fluoro-benzyl)- 1,3-Dimercapto-1,5-dihydro-pyrrolo[3,2-d]pyrimidine-2,4·dione; 2-({6-[(3R)-3-amino-3- Mercaptohexahydropyridin-1-yl]-1,3-dimethyl-2,4-di-oxy-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-d] Pyrimidin-5-yl}fluorenyl-4-fluorobenzonitrile; (2S)-l-{[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethylamino] -ethylidene}-pyrrolidine-2-carbonitrile; (2S)-1-{[1,1-dimethyl-3·(4-π ratio 0-but-3-yl- miso sitting-1- ))-propylamino]-ethyl aryl}-»Bilo bite-2-indene nitrile; (3,3-difluoropyrazole l-l-yl)-((2S,4S)-4 -(4-(pyrimidin-2-yl)hexahydropyrazine-1-yl).Byrrolidin-2-yl)methanone; (2S,4S)-l-[(2S)-2-amino]3 ,3-bis(4-fluorophenyl)propanyl]-4-fluoropyrrolidin-2-carbonitrile; (2S,5R)-5-ethynyl·1-{Ν-(4-methyl-1 -(4-carboxy-pyridin-2-yl)hexahydropyridin-4-yl)glycidyl}pyrrolidin-2-carbonitrile; and (1 S,6R)-3-{[3-(trifluoro Indenyl)-5,6-dihydro[1,2,4]triazino[4,3-a]pyrazine-7(8H)-yl]carbonyl}-6-(2,4,5-tri Fluorophenyl)cyclohex-3-ene-1 -amine. Some embodiments of the invention include one or more compounds selected from the group consisting of: pharmaceutically acceptable salts, solvates, and hydrates: 3(11)-amino-1-[3-(three Fluorinyl)-5,6,7,8-tetrahydro[1,2,4]tri. Sit and [4,3-a]°bazine-7-yl]-4-(2,4,5-trifluorophenyl)butan-i-one; ^[2-(3-hydroxyadamantane-1- Ethylamino)pyridinylpyrrolidine_2(S)-carbonitrile; (18,3 8,5 8)-2-[2(3)-amino-2-(3- via fund just entertainment 1 -1-yl)ethinyl]-2-azabicyclo[3.1.0]hexane-3-indene nitrile; 2-[6-[3(R)-amino hexahydropyridine-1- 149380. Doc •81- 201105327 】]]-mercapto-2,4-di-oxy-1,2,3,4-tetrahydron-n-butylmethyl]benzonitrile; 8-[3(R)- Amino hexahydro"pyridin-1-yl]_7_(2.butynyl)3.methyl-^ (4-methyl 1 坐 琳·2 曱 曱) 嗓吟 嗓吟; 1-[N- [3(R)-pyrrolidinyl]glycidyl]anthrolidine-2(R)-ylboronic acid; 4(8)-fluoro_1[2[(111,33) winter (1H-1,2 ,4-dioxazol-1-ylmethyl)cyclopentylamino]ethidyl]pyrrolidinium-2(s)_carbonitrile; 1-[(2S,3S,llbS)-2-amino]-91 〇_Dimethoxy_ 2,3,4,6,7,111^hexahydro-111-acridino[2,1-&amp;]isoquinoline_3_yl]_4(8)_(fluorine Methyl)pyrrolidin-2-one; (2S,4S)-2-cyano-4·fluorohydroxy "behenyldiyl)ethylamino]ethinyl. Ratio ν» each; 8_(cis - hexahydro _ π piroxi[3,2_ b]. pyrrol-1-yl)-3-mercapto-7-(3-indolyl- But-2-enyl)-1-(2-oxo-2-phenylethyl)-3,7-dihydro-indole-2,6-dione; i_((3S,4S)-4 -amino-1-(4-(3,3-difluoro.Bilobitone_1_yl)_i,3,5-triazine·2·yl)η ratio bite_3_base)· 5, 5 difluorohexahydropyridin-2-one; (R)-2-((6-(3-aminohexahydro)pyridin-1-yl)-3-indolyl-2,4-dioxy -3,4-dihydropyrimidine-purine (2ίί)-yl)methyl)-4-fluorobenzonitrile; 5-{(S)-2-[2-((S)-2-cyano" Acridine-1-yl)-2-oxo-ethylamino]-propyl b 5-(1Η-tetrazol-5-yl)10,11-dihydro-5H-dibenzo[a,d Cycloheptene-2,8-didecanoic acid bis-didecyl decylamine; ((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-.biazole-5) -yl)hexahydro.pyrazine-1-ylpyrrolidin-2-yl)(tetrahydrothiazol-3-yl)anthone; (2S,4S)-l-[2-[(4-ethoxy) Carbonylbicyclo[2.2.2]oct-1-yl)amino]ethinyl]-4-fluoropyrrolidin-2-indene nitrile; 6-[(3R)-3-amino-hexahydropyridine-1 -yl]-5-(2-a-5-fluoro-benzyl)-1,3-dimercapto-1,5-dihydro-pyrrolo[3,2-d]pyrimidine-2,4-dione ;2-({6-[(3R)-3-amino-3-mercaptohexahydropyridin-1-yl]-1,3-dimethyl-2,4-di-oxy-1,2 ,3,4-tetrahydro-5.H-pyrrole And [3,2-d]pyrimidin-5-yl}methyl)·4_fluorobenzonitrile; (2S)-l-{[2-(5-methyl-2- 149380.doc -82- 201105327 phenyl · Oxazol-4-yl)-ethylamino]•Ethyl}-pyrrolidine-2_indoleonitrile; (2S)-1-{[1,1-dimethyl-3-(4-pyridine) -3-yl-imidazol-1-yl)-propylamino]-ethenyl}•pyrrolidine-2-carbonitrile; and (3,3-difluoropyrrole-1-yl)-((2S) , 4S) - 4 - (4 - (pyrimidin-2-yl) hexahydropyrazine-1 -yl) ° pyridin-2-yl) formazan. Some embodiments of the invention include one or more compounds selected from the group consisting of: pharmaceutically acceptable salts, solvates, and hydrates: (2S, 4S)-l-[(2S)-2- Amino-3,3-bis(4-fluorophenyl)propanyl]-nuclear fluoride. Bibromopyridine-2-carbonitrile; (2S,5R)-5-ethynyl-1-{Ν-(4-mercapto-1-(4-carboxy-pyridin-2-yl)hexahydropyridine-4- Glycosyl}pyrrolidine-2-carbonitrile; and (lS,6R)-3-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazole And [4,3-a]°bazine-7(8H)-yl]carbonyl}-6-(2,4,5-trifluorophenyl)cyclohex-3-en-1-amine. Sitagliptin phosphate (Januvia, MK-043 1,3(R)-amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4] Triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one dihydrogen phosphate) sold by Merck &amp; Co. For oral treatment of type 2 diabetes once a day ^ januvia was first placed on the market in Mexico' and subsequently commercialized in the United States. In 2007, the product was approved by the European Medicines Evaluation Agency (ΕΜΕA) and is currently available in the UK 'Germany and Spain. In 2〇〇9 years, Januvia was approved and put on the market in Japan. In addition, 厘 “仏 has also applied for approval of Januvia as an adjunct to diet and exercise in the United States and combined with other therapies to improve glycemic control in the treatment of diabetes (8)” (10) 沁 (10) (10) ^ Compound cleavage - amine nickname Wang fluoromethyl )-5,6,7,8·^^ [1'2,4]disindol [4,3-a]pyrene-7-yl]·4-(2,4,5-trifluorobenzene Base butyl ketone 149380.doc •83- 201105327 and its pharmaceutically acceptable salts are disclosed in the international patent publication w〇

Each of the compounds of the DPP-IV inhibitors of WO 2003/004498 and pharmaceutically acceptable salts, solvates and hydrates thereof are disclosed. In some embodiments, the DPP_IV inhibitor of the present invention is selected from the group consisting of 3(R)-amino (difluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4 , 3-a]pyridazin-7-yl]-4-(2,4,5-difluorophenyl)butan- ketone and pharmaceutically acceptable salts, solvates and hydrates thereof:

In some embodiments, the 'dipeptidyl peptidase 1 ¥ (Dpp4) inhibitor is amine 1_1-[3_(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]3 Zoxa[4,3-a]. Bisazine-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one:

3(R)-Aminotrifluoromethyl)_5,6,7,8-tetrahydro[152,4]triazolo[4,3-a]pyridazine-7-yl]-4-(2, The crystalline form of the 4,5-trifluorophenyl)butan-1-one phosphate monohydrate is disclosed in International Patent Publication No. WO 2005/003 1335, the entire disclosure of which is incorporated herein by reference. In some embodiments, the 'dipeptidyl peptidase IV (DPP4) inhibitor is crystalline 3(R)-aminotrifluoromethyl)-149380.doc-84 - 201105327 5,6,7,8-tetrahydro[ 1,2,4] three-degree sitting and [4,3-3]° 嗓-7-yl]-4-(;2,4,5-trifluoro-4-phenyl)butan-1-one phosphate Hydrate. Vidastatin (Galvus, LAF-237, 1-[2-(3-hydroxyadamantane-i-ylamino)ethyl)]. Biluo-1 (S)-carbonitrile) is another The dipeptidyl-peptidase iv (dpp_IV) inhibitor was first commercialized by Novartis in Brazil and Mexico for oral treatment of type 2 diabetes once per week. In 2008, the drug marketing authorization application (MAA) was approved for use in the EU in the EU and was launched in the UK in March 2008. A regulatory letter has been received in the regulatory application for filing in the United States. 2〇 1 The following year, it was approved in 曰. The compound 1-[2-(3-hydroxyadamantane-1-ylamino)ethylidene]pyrrolidine-2(S)-indene is disclosed in International Patent Publication No. 2000/034241. Some embodiments of the invention include one or more compounds selected from the group consisting of DPP-IV inhibitors disclosed in WO 2000/034241, and each combination of pharmaceutically acceptable salts, solvates and hydrates thereof. In some embodiments, the DPP-IV inhibitor of the present invention is selected from the group consisting of 1-[2-(3·hydroxyadamantan-1-ylamino)ethylidene]pyrrolidine-2(S)-phthalonitrile and Pharmaceutically acceptable salts, solvates and hydrates:

Certain salts of the compound 1-[2-(3-hydroxyadamantane-ylamino)ethenyl]pyrrolidine-2(S)-phthalonitrile are disclosed in International Patent Publication No. 2007/019255. In some embodiments, the DPP-IV inhibitor is [2-(3-hydroxyadamantan-1-ylamino)ethyl). Bilo bite-2(S)-indole nitrile HC1 : I49380.doc -85- 201105327

Saxagliptin (Onglyza, BMS-477118, (1S, 3S, 5S)-2-[2(S)-amino-2·(3-hydroxyadamantane-i-yl)ethenyl] 2-Azabicyclo[3.1·0]hexan-3-carbonitrile is another DPP-IV inhibitor and was marketed in the United States in 2009 by AstraZeneca and Bristol-Myers Squibb for the treatment of type 2 diabetes. In 2009, the product was also approved in the European Union for the treatment of type 2 diabetes independently and in combination with diterpene. Its use in the treatment of type 2 diabetes is undergoing a phase III clinical study in Japan. Compound (1S,3S,5S)_2_[2(S)-Amino-2-(3-hydroxyadamantane-indenyl)ethenyl]_2_azabicyclo[3 ·1.0]hexane-3 -Methonitrile is disclosed in International Patent Publication No. 2001/068603. Some embodiments of the invention include one or more compounds selected from the group consisting of DPP-IV inhibitors disclosed in WO 2001/068603, and pharmaceutically acceptable salts, solvates and hydrates thereof. In some embodiments, the DPP-IV inhibitor of the present invention is selected from the group consisting of (iS, 3S, 5S)_2_[2(s)-amino-2-(3-hydroxyadamantyl-1-yl)ethenyl] _2_Azabicyclo[31〇]hexane_3_carbonitrile and pharmaceutically acceptable salts, solvates and hydrates thereof:

SYR-322 (Aglitapine (A1〇gliptin), amino hexahydropyridin 1 yl]3-methyl-2,4-di-oxy-1,2,3,4-tetrahydro" 〇 _1 _ 基 ] 苄 苄 苄 苄 苄 , , , , , _1 _1 _1 _1 _1 _1 _1 _1 _1 _1 _1 _1 _1 _1 _1 _1 _1 _1 _1 _1 _1 _1 _1 _1 _1 _1 _1 _1 _1 _1 Compound 149380.doc *86· 201105327 2-[6-[3(R)-Amino hexahydro&lt;«biidine-i-yl]_3_methyl·2,4-di-oxy-1,2 , 3,4-tetrahydropyrimidin-1-ylmethyl]benzonitrile and pharmaceutically acceptable salts thereof are disclosed in International Patent Publication WO 2005/095381. Some embodiments of the invention include one or more compounds selected from the group consisting of DPP-IV inhibitors disclosed in WO 2005/095381, and pharmaceutically acceptable salts, solvates and hydrates thereof. In some embodiments, the Dpp-iv inhibitor of the present invention is selected from the group consisting of 2-[6-[3(11)-amino hexahydropyridin-1-yl]-3-methyl-2,4-di Sideoxy-1,2,3,4-tetrahydrol nozzle. Formulation: 1-ylmethyl]benzonitrile and pharmaceutically acceptable salts, solvates and hydrates thereof:

2-[6-[3(R)-Aminohexahydro'pyridin-1-yl]_3·methyl-2,4-dioxyl-1,2,3,4-tetrahydropyrimidine-1 The crystalline form of -bensyl]benzonitrile is disclosed in International Patent Publication WO 2007/035372, the entire disclosure of which is incorporated herein by reference. In some embodiments 'DPP-IV inhibitor system 2_[6_[3(11)-amino hexahydro 0-0--1-yl]-3-methyl-2,4-one-oxyl- , 2,3,4-tetrahydrogen. Bite_Bulk methyl]benzonitrile benzoate:

BI-1356(Ondero, 8-[3(R)-Aminohexahydropyridinyl]_7_(2 butyl)-3-methyl-1-(4-methylindole-2-yl-methyl Base) Astragalus) Dpp_IV 149380.doc -87- 201105327 Inhibitor and in Phase III clinical development of Boehringer Ingelheim to evaluate its monthly b-type as adjunctive therapy for metformin for the treatment of type 2 diabetes. Compound 8_[3(r)-Amino hexahydro. The specific enthalpy _ 丨 基 ] _ 7_(2_butynyl)-3-methyl·ι_(4-methylquinazoline-2-ylmethyl) ruthenium is disclosed in International Patent Publication No. WO 2004/018468. Some embodiments of the invention include one or more compounds selected from the group consisting of DPP-IV inhibitors disclosed in WO 2004/018468, and pharmaceutically acceptable salts, solvates and hydrates thereof. In some embodiments, the DPP-IV inhibitor of the present invention is selected from the group consisting of 8-[3(R)-amino hexahydroacridine-buquib? · 丁 alkynyl fluorenyl-1 (4 fluorenyl. sulphone-2-yl fluorenyl) xanthine and its pharmaceutically acceptable salts, solvates and hydrates:

Compound 8-[3(R)-Amino hexahydro. ratio. Certain polymorphs of -1 -yl]-7-(2-butynyl)·3-methyl-1-(4-methylquinazolin-2-ylmethyl)xanthine are disclosed in International Patent Publication No. WO2007/128721. In some embodiments, the DPP-IV inhibitor is 8-[3(r)-amino hexahydro. The crystalline form of pyridinium-butynyl)-3-methyl-1-(4-methylquinazolin-2-ylindenyl)xanthine. PHX_1149 (Dutogliptin), 1-[N,[3(R)_pyrrolidyl]glycidyl]pyrrolidine-2(R)-ylboronic acid) is a DPP-IV inhibitor, It is in a phase III clinical trial conducted by Phenomix and Forest for a daily oral treatment of type 2 diabetes. Compound i_[N-[3(R)-.比 咬 】 】 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 149 . Some embodiments of the invention include one or more compounds selected from the group consisting of DPP-lv inhibitors disclosed in WO 2005/047297, and each combination of pharmaceutically acceptable salts, solvates and hydrates thereof, in some embodiments In one embodiment, the DPP-IV inhibitor k of the present invention is derived from 1-[N-[3(R)-.嘻 基 ] ] ] ] ] ] ] ] ] ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( (

L-[N-[3(R)-°Bididyl]glycine]. The crystal form of the pyridinium 2(R)-based boric acid tartar is disclosed in International Patent Publication No. 2008/027273. In some embodiments, the DPP-IV inhibitor is i_[N_[3(r)·. Pyrrolidinyl]glycidyl]pyrrolidine_2(R)-ylboronic acid tartrate:

GRC_8200 (Melogliptin, 4(S)-fluoro-1-[2-[(1R,3S)-3_(1H-1,2,4-triazol-1-ylindenyl)cyclopentyl) Amino]ethinyl]. Bilota-2(S)-carbonitrile is a DPP_IV inhibitor and is currently in the process of

In π phase clinical trials for the treatment of type 2 diabetes by Glenmark Pharmaceuticals and Merck KGaA. Compound 4(s)_Fluoro[(111,33)-3-(111-1,2,4-triazol-1-ylindenyl)cyclopentylamino]ethinyl] D is more than 嚏-2 (S)-nitrile is disclosed in International Patent Publication No. 2006/040625. Some embodiments of the present invention include one or more compounds selected from the group consisting of DPP-IV inhibitors disclosed in WO 149380.doc-89-201105327 2006/040625, and pharmaceutically acceptable salts, solvates and hydrates thereof Each combination. In some embodiments, the DPP-IV inhibitor of the invention is selected from the group consisting of 4(S)-fluoro-l-[2-[(lR,3S)-3-(1H-1,2,4-triazole-1 -ylmethyl)cyclopentylamino]ethinyl]pyrrolidinium-2(s)-phthalonitrile and pharmaceutically acceptable salts, solvates and hydrates thereof:

R-1579 (Carmegliptin, l-[(2S,3S,llbS)-2-amino-9,10-dimethoxy 2,3,4,6,7, lib-six Hydrogen-1 Η-» ratio bite [2,1-a]isoindol-3-yl]-4(S)-(fluoromethyl)pyrrolidin-2-one) is a DPP-IV inhibitor. Compound l-[(2S,3S,llbS)-2-amino-9,10-dimethoxy-2,3,4,6,7,llb-hexahydro-1Η-η is pyridine [2, 1-a]Isoquinolin-3-yl]-4(S)-(fluoromethyl V-pyridin-2-one is disclosed in International Patent Publication No. 2005/000848. Some embodiments of the invention include a Or a combination of each of the compounds selected from the group consisting of DPP-IV inhibitors disclosed in WO 2005/000848, and pharmaceutically acceptable salts, solvates and hydrates thereof. In some embodiments, the DPP- of the invention The IV inhibitor is selected from the group consisting of l-[(2S,3S,llbS)-2-amino-9,10-dimethoxy-2,3,4,6,7,1113-hexahydro-111-acridine. [2,1-&amp;]isoquinolin-3-yl]-4(8)-(fluorodecylpyrrolidin-2-one and pharmaceutically acceptable salts, solvates and hydrates thereof:

149380.doc •90· 201105327

Taisho Reveals (2S,4S)-2-Cyano-4-fluoro-1·[(2-hydroxy-1,1-dimethyl)ethylamino]ethinylpyrrolidine as Dpp-iv Inhibitor^ The compound (2S,4S)-2-cyano-4-fluoro-i-[(2-hydroxydimethyl)ethylamino]ethyl oxime is disclosed in US Publication No. US 2007/0112059 in. Some embodiments of the invention include one or more compounds selected from the group consisting of DPP-IV inhibitors disclosed in US 2007/0112059, and pharmaceutically acceptable salts, solvates and hydrates thereof. In some embodiments, the DPP-IV inhibitor of the present invention is selected from the group consisting of (2S,4S)_2-cyano-4tetrahydro[(2-trans-diyl)ethylamino]ethenylpyrrolidine And pharmaceutically acceptable salts, solvates and hydrates thereof:

A series of substituted bicyclic 8-pyrrolidine xanthine 7 derivatives are disclosed as DPP_iV inhibitors in U.S. Patent No. 2,7/〇 167,468, the entire disclosure of which is incorporated herein by reference. Some embodiments of the invention include - or a compound selected from the group consisting of DPP-IV inhibitors disclosed in U.S. Publication No. 2007/0167468, and each of their pharmaceutically acceptable salts, solvates and hydrazines -combination. In some embodiments, the inhibitory oxime of the present invention is selected from the group consisting of 8-(cis-hexahydropyrolo[3,2-b].pyrrol-1-yl)-3-methyl-7-(3. -2-alkenyl)_丨_(2_ fluorenyl-2-phenylethyl)_3,7-dihydro-indole _ 'Sun and its pharmaceutically acceptable salts, solvates and hydrates: 149380.doc -91- 201105327

The 3-amino group Μ$·4·lactam derivative is used as a Dpp_iv inhibitor. Some embodiments of the invention include one or more selected from the group consisting of disclosed in w〇 2〇〇7/

Pfizer discloses in each of the series of DPP-IV inhibitor compounds and their pharmaceutically acceptable salts, solvates and nozzles in the International Patent Publication No. 4/7/i48 t. One such compound is 牝 牝 牝 · · · · _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ -5,5-Difluorohexahydropyridin-2-one and pharmaceutically acceptable salts thereof. In some embodiments, the DPP_IV inhibitor of the present invention is selected from the group consisting of small amines (4_(3,3_) Two gas ° 〇 each bite -1 · base) -1,3,5-tripa-2-yl) 吼 _ 3_ base)-5,5 difluorohexahydropyridine 2 - ketone and its medicine Acceptable salts, solvates and hydrates:

Syrrx discloses a series of substituted pyrimidine(^)-dione derivatives as a ^^^^^^^^^ in the International Patent Publication No. 5〇〇5/〇95381. Some embodiments of the invention include one or more compounds selected from the group consisting of DPP-IV inhibitors disclosed in WO 2005/095381, and pharmaceutically acceptable salts, solvates and hydrates thereof. One such compound is (R)-2-((6-(3-aminohexahydroacridinyl)_3_indolyl-2,4-dioxy 3'4-dihydropyrimidin-1 (2H) )-yl)methyl)_4_fluorobenzonitrile and its pharmaceutically acceptable salt of 149380.doc •92·201105327. In some embodiments, the Dpp_IV inhibitor of the present invention is selected from the group consisting of 2-((6-(3-aminohexahydropyridine_ι_yl)_3_methyl-2,4 di-oxy3,4_ Dihydropyrimidin-1(2Η)-yl)indolyl-4-fluorobenzonitrile and pharmaceutically acceptable salts, solvates and hydrates thereof:

(R)-2-((6-(3-Aminohexahydro.biidine-丨-yl)_3_indolyl-2,4 di-oxyl-3,4-monohydropyrimidine_ι(2Η) Various crystalline forms of -yl)methyl)_4_fluorobenzonitrile succinate have been disclosed in International Patent Publication No. 2005/003 1335. A consistent embodiment of the present invention relates to (R)-2-((6-(3-aminohexahydropyridinyl)-yl)_3 as described in International Patent Publication No. 2〇5/〇〇31335 _Methyl-2,4_di-oxy-3,4-dihydropyrimidine t_1(2H)-yl)methyl)_4_fluorobenzonitrile succinate

One or more crystalline forms. In some embodiments, the dipeptidyl peptidase IV (DPP4) inhibits the indole crystal (r)_2_((6_(3_aminohexahydrobeta) than the bite_ι_yl)·3_methyl_2,4 _Di-sideoxy_3,4-dihydropyrimidin-1(211)-yl)methyl)-4-fluorobenzonitrile succinate:

A series of substituted 2-cyano-pyrrolidine derivatives as Dppjv inhibitors are disclosed in International Patent Publication No. WO 2006/116157. Some embodiments of the invention include one or more per-combinations of a compound selected from the group consisting of DPP_IV inhibitors disclosed in WO 2006/116157 I49380.doc-93 201105327, and pharmaceutically acceptable compositions thereof. - This compound is di-((S)-2-lacylpyrrolidine+yl)_2 oxoethylethylamino]-propyl b^ (1H-tetra. Sodium-based (10)^dihydrogen Di-dibenzoxanthene bis-monomethylammonium dicarboxylate and a pharmaceutically acceptable salt thereof. In some embodiments, 'the present invention; 〇ΡΡ·Ιν inhibitor is selected from the group consisting of Η(8)_2K(8)2 基 _疋1 yl)_2-sideoxy-ethylamino]propyl}_5_(ιηtetrazole_5.yl)10'11-_hydrogen_SH_dibenzo[ad]cycloheptene 2,8 Diglycidyl diamine and its pharmaceutically acceptable salts; compatibilizers and hydrates:

Mitsubishi discloses a series of 2,4-monosubstituted pyrrolidine derivatives as DPP-IV inhibitors in International Patent Publication No. 2〇〇2/〇〇14271. Some embodiments of the invention include one or more compounds selected from the group consisting of DPP-IV inhibitors disclosed in W〇2〇〇2/〇〇14271, and pharmaceutically acceptable salts, solvates and hydrates thereof A combination of one such compound ((2S,4S)_4_(4_(3_indolyl-buphenyl-1 Η- °-biazole-5-yl)hexahydropyridazin-1 -yl)pyrrolidine-2 -yl)(tetrahydrocarbazole-3-yl)fluorenone and pharmaceutically acceptable salts thereof. In some embodiments, the DPP-iv inhibitor of the present invention is selected from the group consisting of ((2S, 4S)-4-(4-(3-mercapto-1-indolyl-1H-. than sal-5-yl) hexa Hydroquinone-1-yl) guanluo. -2- 149380.doc • 94· 201105327 yl) (tetrahydrothiazol-3-yl)methanone and its pharmaceutically acceptable salts, solvates and hydrates :

((2S,4S)-4-(4-(3-methyl-1-bensin-1Η-Π is 0--5-yl) hexahydro'•bi-i-yl)pyrrolidin-2-yl The various crystalline forms of the ketone salt are disclosed in International Patent Publication No. 2006/088129 and U.S. Publication No. 2009/0216016. One embodiment of the present invention is described in the International Patent Publication No. WO 2006/088129 and the US Publication No. 2009/0216016 ((2S, 4S)-4_(4-(3-methyl-1-phenyl-1H). -pyrazol-5-yl)hexahydropyrazine-diyl). Any one or more crystalline forms of the indole ketone salt. In some embodiments, the DPP-IV inhibitor is crystalline ((2S,4SM-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)hexahydropyrazine)) ) „比n各唆_2_ base)(tetrahydrothiazole_3_yl)methanone 2·5 hydrobromide:

Or its mono- or dihydrate

In some embodiments, the 'dipeptidyl peptidase IV (DPP4) inhibitor is crystallized ((2S,4S)-4-(4-(3-methyl-1-phenyl)-out-0-by-azole_5_ )) hexahydropyrazine·1 dihydrobromide. -base)° ratio 0 each bit-2-yl)(tetrahydroindole-3-yl)methanone 149380.doc -95- 201105327

A series of pyrrolidinium nitrile derivatives are disclosed as DPP-IV inhibitors in Kyorin, International Patent Publication No. WO 2008/114857, and U.S. Publication No. 2008/0146818. Some embodiments of the present invention include one or more compounds selected from the group consisting of DPP-IV inhibitors disclosed in WO 2008/114857 and US Publication No. 2008/0146818, and pharmaceutically acceptable salts, solvates and hydrates thereof. Every combination of things. One such compound is (2S,4S)-l-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]ethinyl]-4-fluoro. Birozidine_2·phthalonitrile and its pharmaceutically acceptable salts. In some embodiments, the DPP-IV inhibitor of the present invention is selected from the group consisting of (2S,4S)-l-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino ] Ethyl]-4-fluoro. Biloxidin-2-indene nitrile and its pharmaceutically acceptable salts 'solvates and hydrates:

A series of bicyclopyrryl derivatives are disclosed as DPP-IV inhibitors in International Patent Publication No. 2006/068163 and U.S. Patent Publication No. 2009/0192129. Some embodiments of the present invention include one or more compounds selected from the group consisting of DPP-IV inhibitors disclosed in WO 2006/068163 and U.S. Publication No. 2009/0192129, and pharmaceutically acceptable salts, solvates and hydrates thereof. Every combination of things. One such compound is 6 [(3R)_3_amino-hexahydropyridin-1-yl]-5.(2-a-5-fluoro-benzyldiindenyl), methane dihydro-pyrrolo[3,2 -d]pyrimidine-2,4-dione and pharmaceutically acceptable salts thereof. In some embodiments, the DPP-IV inhibitor of the present invention is selected from (6_[(3r)_3_ 149380.doc-96- 201105327 Amino-hexahydroacridin-1-yl]-5-(2-chloro-5-fluoro-benzyl)qj.dimercapto-indole-5-dihydro-pyrrolo[3,2-d]pyrimidine- 2,4-dione and its pharmaceutically acceptable salts, solvates and hydrates:

Dainippon Sumitomo, in International Patent Publication No. 2009/084497, discloses 2-({6-[(3R)-3-amino-3-methylhexahydro) than bite-buji]-I]. -2,4-di-oxy-,1,3,4-tetrahydro-5-pyrrolo[3,2-d]pyrimidin-5-yl} fluorenyl-4-fluorobenzonitrile as DPP- IV inhibitor. Some embodiments of the invention include each combination of one or more compounds selected from the group consisting of DPP-IV inhibitors disclosed in International Patent Publication No. WO 9/9/844, filed in some embodiments, the present invention The DPP-IV inhibitor is selected from the group consisting of 2-({6-[(3R)-3-amino-3-methyl/, hydrogen 0 to 0疋-1-yl], 3_dimercapto-2, 4_ Bi-oxyl_i,2,3,4-tetrahydro-5H-.pyrolo[3,2-d]pyrimidin-5-yl}indolyl-4-fluorobenzonitrile and its pharmaceutically acceptable Salts, solvates and hydrates:

Hoffmann-La Roche discloses a series of N-substituted D-pyrrolidine derivatives as Dpp_IV inhibitors in International Patent Publication No. 3/〇37327. 149380.doc •97-201105327 Some examples of the invention include one or more compounds selected from the group consisting of DPP-IV inhibitors disclosed in WO 03/037327, and pharmaceutically acceptable salts and solvates thereof And each combination of hydrates ^ _ this compound is (2s) _i{[2_(5_methyl_2·phenyl-&quot; oxa. sit-4-yl)-ethylamino]-ethyl fluorenyl Bobbi 唆 1 carbonitrile and its pharmaceutically acceptable salts. In some embodiments, the DPP-IV inhibitor of the present invention is selected from the group consisting of (28) small {[2_(5-methyl 2phenyloxazolyl-4-yl)-ethylamino]-ethenyl}- Pyrrolidine-2-carbonitrile and pharmaceutically acceptable salts, solvates and hydrates thereof: broad. (2S)-l-{[2-(5-Methyl-2-phenyl-oxazole·4-yl)-ethylamino]-ethenyl}-pyrrolidine-2-indole sulfonic acid Various crystalline forms of the salt are disclosed in International Patent Publication WO 2006/100181. In some embodiments, the DPP-IV inhibitor of the present invention is a thiol-2 phenyl-oxazole _4_yl)-ethylamino]-ethyl aryl} - n 洛洛 bite _ 2 _ A Nitrile oxime acid salt (ie, mesylate):

CH3SO3H Another compound (2S)-1-{[1,1-dimethyl-3-(4-pyridin-3-yl) disclosed by Hoffmann-La Roche in International Patent Publication No. 03/037327 Saliv-1-yl)-propylamino]-ethenyl}-pyrrolidin-2-indene nitrile and pharmaceutically acceptable salts thereof such as a carbaryl salt. In some embodiments, the DPP-IV inhibitor of the invention 149380.doc-98-201105327 is selected from the group consisting of (2S)-1-{[1,1-dimethyl-3-(4-pyridine-3, benzyl imidazole) -1-yl)-propylamino]-ethenylpyrrolidin-2-indene nitrile and pharmaceutically acceptable salts, solvates and hydrates thereof:

In some embodiments, the DPP-IV inhibitor of the invention is (2Sy_{[1,1-dimethyl-3-(4-pyridin-3-yl-imidazol-1-yl)-propylamino) Ethyl}-pyrrolidine-2-carbonitrile sulfonate:

(2S)-1-{[1,1-dimercapto-3-(4-0 butyl-3-yl-indolyl-1-yl)-propyl-hydanto]-ethenyl}- The various crystalline forms of pyrrolidine-2-indolesulfonic acid fumarate are disclosed in International Patent Publication No. WO 2007/071576, the entire disclosure of which is incorporated herein by reference. In some embodiments, the DPP-IV inhibitor of the present invention is (28)-1-{[1,1-dimercapto-3-(4-° ratio -3-yl-methan-1-yl) ) _ propylamino]-ethyl aryl}-» 比 a 定 曱 曱 曱 曱 ( ( ( ( fumarate):

A series of proline derivatives are disclosed as formulations in Pfizer, International Patent Publication No. WO 2005/116014, the entire disclosure of which is incorporated herein by reference. Some embodiments of the invention include one or more compounds selected from the group consisting of DPP-IV inhibitors disclosed in WO 2005/116014, and pharmaceutically acceptable salts, solvates and hydrates thereof. One such compound is (3'3·difluoropyrrolidin-1·yl H(2S,4S)-4-(4-(pyrimidin-2-yl)hexahydropyrazine-1-yl)pyrrolidin-2-yl Anthrone and its pharmaceutically acceptable salts. In some embodiments, the DPP_IV inhibitor of the invention is selected from the group consisting of (3,3-difluoropyrrolidinyl-bu)-((2S,4S)-4-(4-(pyrimidin-2-yl)hexahydropyrazine _丨_yl)pyrrolidine_2-yl) fluorenone and pharmaceutically acceptable salts, solvates and hydrates thereof:

GlaxoSmithKline, in International Patent Publication No. 03/002531, discloses a series of fluoropyrrolidine derivatives as Ε)ΡΡι inhibitors. One of the embodiments of the present invention comprises one or more compounds selected from the group consisting of DPP-IV inhibitors disclosed in WO 03/037327, and pharmaceutically acceptable salts, solvates and hydrates thereof. One such compound is amino-3,3-bis(4-fluorophenyl)propanyl]_4-fluoropyrrolidine-2-indene nitrile (Denaghptin). In some embodiments, the Dpp_IV inhibitor of the present invention is selected from the group consisting of (2S,4S)-l-[(2S)-2-amino-3,3-bis(4-fluorophenyl)propanyl]-4 - fluoropyrrolidine_2-carbonitrile and its pharmaceutically acceptable salts, solvates and hydrates: 149380.doc •100- 201105327

F

(2S,4S)-l-[(2S)-2-Amino-3,3-bis(4-fluorophenyl)propanyl]_4·Fluorine °bit 2 -carbonitrile and its salts Various crystalline forms are disclosed in International Patent Publication WO 2005/009956. A disclosed salt system (2S,4S)-l-[(2S)-2-amino-3,3-bis(4-fluorophenyl)propanyl]-4-fluoro&quot;Bihabite-2 - carbonitrile p-toluenesulfonate (also known as (2S,4S)-4-fluoro-l-[4-fluoro-β-(4-fluorophenyl)-L-phenylpropylamine fluorenyl]-2- Bilobidinonitrile p-toluenesulfonate or dynastatine terpene salt). In some embodiments, the DPP-IV inhibitor of the invention is (28,48)-1-[(28)-2-amino-3,3-bis(4-phenylphenyl)propyl]_4 -Fluorine»Bilozine-2-indonitrile nitrile sulfonate:

A series of substituted pyrrolidinyl derivatives as DPP-IV inhibitors are disclosed by Abbott in International Patent Publication No. 2004/026822. Some embodiments of the invention include one or more compounds selected from the group consisting of DPP-IV inhibitors disclosed in WO 2004/026822, and pharmaceutically acceptable salts, solvates and hydrates thereof. One such compound is (2S,5R)_5-ethynyl-l_{N-(4-methyl-1-(4-carboxy-acridin-2-yl)hexahydropyridine-4-yl)glycine 醯149380 .doc -101- 201105327 base}. Birolidine-2-indene nitrile. In some embodiments, the 〇卩1)_1乂 inhibitor of the present invention is selected from the group consisting of (2S,5R)_5-ethynylfluorenyl-1-(4-carboxy-pyridyl-2-yl)hexahydropyridinium -4-yl)glycidyl}. Specific bite _2-carbonitrile and its pharmaceutically acceptable salts, solvates and hydrates:

A series of substituted cyclohexane/cyclohexenyl derivatives have been further disclosed by Abbott as a Dpp_iv inhibitor in International Patent Publication No. 2〇〇7/〇2765丨. Some embodiments of the invention include one or more compounds selected from the group consisting of DPP_IV inhibitors disclosed in WO 2007/02765 i and pharmaceutically acceptable salts, solvates and hydrates thereof. One such compound is (lS,6R)-3-{[3-(difluoromethyl)_5,6-dihydro[12,4]triazolo[4,3_small 嗓-7(8H)- Base] number base}_6_(2,4,5-trifluorophenyl)cyclohexane% dilute amine. In some embodiments, the DPP_IV inhibitor of the present invention is selected from the group consisting of (is, 3_{[3-(trimethyl))-5,6-dihydro[12,4]triazolo[4,3_small ratio ___)_基基基基}冬(2,4,5-三乳基基)cyclohexa-3-ene+amine and pharmaceutically acceptable salts, solvates and hydrates thereof: According to the invention

'The combination can be used to make the injury, that is, the compound of the present invention and the pharmaceutical agent together or separately: to make the physiological group 149380.doc •102-201105327 The agent, the binder, the diluent, and the like are mixed and the or more, 'man' a sigma substance is administered as a pharmaceutical composition orally or parenterally. When a deuterated alpha or a mixture of compounds of the invention is administered as a combination therapy with an additional active compound, the therapeutic agent can be formulated as a separate pharmaceutical composition for administration at the same time or at different times; or The inventive compound or a mixture of the compounds of the invention is formulated as a single unit dose. Other uses The present invention relates to radiolabeled compounds that are used not only for radiography but also for in vitro and in vivo analysis for localization in tissue samples including humans. And quantifying the GPR119 receptor; and secondly, by inhibiting the binding of the radiolabeled compound to recognize the OPR-19 receptor ligand. A further object of the invention is to develop a novel (1) receptor assay comprising a radiolabeled compound. The inventive compound may also include all isotopes of atoms occurring in the intermediates and/or final compounds and their pharmaceutically acceptable salts, solvates and hydrates. Isotopes include those atoms that have the same atomic number but different mass numbers. An isotope-labeled or radiolabeled compound is the same compound as the compounds disclosed herein, but in practice one or more atoms are different from the atomic mass or mass found in nature (ie, naturally occurring). The atomic Berry or mass atom is substituted or replaced. Suitable radionuclides that can be included in the sigma sigma include "not limited to" 咕 (for 氘 also written d), 3 Η (for 氚 also writing), 丨沧, &quot;η 15Ν, 150, 丨7 〇, U0, 18f, 35 77

Br 123, 124ι 12 5i and 131 S, 36C Bu 82Br, 75gr

Br is included in the radiolabeled compound of the invention 149380.doc 201105327 = Radionuclides will depend on the particular application of the radiolabeled compound used. For example, for in vitro GpRU9 receptor labeling and competition, JTL + .. -&gt; ... analysis, inclusion of 4, 14 匚 will often be most useful. For radiology applications

Br 4 or 35s compounds pass 2411, 131.

'C 18

F 125, 75

Br 76Br or 77Br will generally be most useful to be understood that a radiolabeled or labeled compound is a compound of the invention that has been incorporated into at least one radionuclide; in some embodiments, the radionuclide is selected from the group consisting of H, and 82. To form a group. Certain isotopically labeled compounds of the invention are useful in the analysis of compound and/or tissue distribution. In certain embodiments, radionuclides and/or C isotopes can be used in such studies. In addition, substitution with heavier isotopes such as the atmosphere (ie 2(1)) may provide certain therapeutic advantages derived from higher metabolic stability (eg, 'in vivo half-life increase or dose demand reduction) and thus may be, in some cases, Preferably, the isotopically labeled compound of the present invention is typically prepared by substituting an isotopically labeled reagent for an isotopically labeled reagent by procedures similar to those disclosed in the above schemes and the following examples. In addition, it will be understood that all of the atoms represented in the compounds of the present invention may be the most common isotopes of this (four) or the rarer radioisotope or non-radioactive isotope. The synthetic method in the organic compound of the human can be applied to the compound of the present invention and is known in the art as a helium gas exposure marker. The procedure involves making the 艚Λ 4 + _ body suitable for the exchange of protons. Exposure to helium in the presence of radiation. The GPP GPRU9 receptor compound of the invention, which is radiolabeled, can be used for screening analysis for identification/evaluation. In summary, the newly synthesized or identified 149380.doc • 104· 201105327 compound (ie, test compound) reduces the ability of the radiolabeled compound of the invention to bind to the -19 motif. Thus, the test compound &amp; (d) (iv) The ability of a compound of the invention to compete for binding to the GpRU9 receptor and its binding affinity is directly related. "The compound of the invention is bound to the GpRi 19 receptor. In one embodiment, the labeled compound is 1(:5〇 is less than about 5〇〇• In another embodiment, the labeled compound is less than about 100 μΜ; in yet another embodiment, the labeled compound has an IC5G of less than about 10 μΜ; For example, the labeled compound has an ICM of less than about i ρ Μ; in yet another embodiment, the labeled inhibitor has a KM of less than about 〇"μΜ; in yet another embodiment, the labeled inhibitor has a ZCm of less than about 〇〇1 μΜ; and in yet another embodiment, the labeled inhibitor IC5() is less than about 〇〇〇5. It will be appreciated that the steps of the method of the invention need not be performed any particular number of times or in any particular order. Other objects, advantages and novel features of the invention will become apparent to those skilled in the <RTIgt; 1 : Ν-(2-fluoro-4-(methylsulfonic acid)phenyl)-5-methyl-6-(1-(5-methylβ-pyridin-2-yl)hexahydropyridine-4 Preliminary pharmacology-in vitro analysis of -yloxy)pyrimidine-4-amine (Compound 1) Α. cAMP in CHO or RIN-5F cells expressing human or rat glucose-dependent insulinotropic receptor (GDIR) generate"

CHO 149380.doc-105-201105327 cells expressing human GDIR (hGDIR) and rat GDIR (rGDIR) were used. CHO cells were cultured in DMEM/F12K medium containing penicillin/bondin, 10% FBS and selected antibiotics (500 pg/mL G418 for rats and 3 pg/mL for human pure cells) Mycin). To establish the analysis conditions, 100 pL of cells were seeded in an lysine coated 96-well culture plate at 5 x 1 〇 5 cells/mL (2 x 1 〇 5 cells/mL) and allowed to recover for 24 hours. After 24 hours of adhesion and growth, the medium was replaced with DMEM/F12 containing penicillin/streptomycin and 250 μM isobutylmethylxanthine (ibmX, bowl acid diesterase inhibitor). Compounds or DMSO (vehicle) were added to the cells and incubated for 45 minutes at 37 ° C in the presence of 〇%, 4% or 20% serum. After incubation, the cells were lysed and processed according to the manufacturer's instructions (the Tropix cAMP-ScreenTM System Chemiluminescence Immunoassay System for quantification of cAMP from cultured mammalian cells). Cell culture medium was removed and 100 pL of analysis/lysis buffer was added and mixed to perform cAMP analysis using an ELISA kit (Tropix cAMP-ScreenTM System Chemiluminescence Immunoassay System, Applied Biosystems, Foster City, CA). Calculate the EC5〇 calculation value using the GraphPadPrism data analysis software. Potency of Compound 1 in cAMP production in CHO-h GDIR and CHO-r GDIR cells CHO- h GDIR CHO- r GDIR EC5〇(nM) EC5〇(nM) Compound 1 with 0% serum 6 65 with 4% serum 18±8 26±6 with 20% serum 116+38 389±118 149380.doc •106- 201105327 B. GLP-1 release from GLUTag cells Growth medium (DMEM GIBCO catalog number 11995-065, 10% FBS GIBCO catalog G.luTag cells in No. 16000-044) were seeded in 96-well plates at 90,000 cells/well and incubated at 37 ° C for 24 hours in a CO 2 incubator. The growth medium was removed by aspiration and 2 〇〇 a assay medium (DMEM with 5 mM glucose and 0.1% BSA) was added to each well. After incubation for 30 min at 37 °C, 'removing the assay medium and replenishing each well with 175 μL of fresh assay medium with DPP-IV inhibitor. Next, add 25 μιη of challenge solution to each well at 37 °C. The reaction was incubated for 2 hours. After the reaction was completed, 180 pL of the supernatant was transferred to a new 96-well plate, which was then placed in a -80 ° C storage cryostat until analysis. Use from

The Lincoln Research ELISA kit (catalog number EGLP-35K) measures GLP-1 according to the manufacturer's instructions. Potency of Compound 1 in the release of GLP-1 from GLUTag cells EC5〇(nM) Compound 1 54.1 Example 2: Single dose of 0.3 mg/kg and 3 mg/kg (2F- 4 (methylsulfonyl) Phenyl)-5-methyl-6-(1-(5-methylpyridazin-2-yl)hexahydropyridyl-4-yloxy)pyrimidine-4-amine in male SD rats (PK/PD In vivo effects of the oral glucose tolerance test (〇GTT). The oral glucose tolerance test (〇 G T T) measures the ability of an animal to metabolize an exogenous glucose bolus. A decrease in glucose AUC from baseline drift indicates better glucose control. Have it! Male SD rats (6 to 7 weeks old) were housed in 1 149380.doc 201105327 rats per cage in a 2 hour light/dark cycle temperature control chamber. It is free to get water and food. Rats were fasted overnight before the study. The rats were first administered orally by vehicle (0.5% HPMC) or Compound 1 at a dose of 0.3 mg/kg or 3 mg/kg at 8:30 am. One hour after the administration of the compound, glucose was administered to the rats by oral gavage (2 g/kg, using 50% G) and at 0 mi η, 3 0 mi η, 60 mi η and 120 mi η Collect tail blood samples to measure blood glucose and plasma insulin. A separate group of rats was administered in a similar manner and blood samples were collected for 1 11 , 211, 411, 611, 8 11 and 24 11 after administration. 1!: Analysis. Administration of Compound 1 at both 0.3 mg/kg and 3 mg/kg doses during OGTT significantly reduced blood glucose AUC. The concentration of the compound in the plasma showed an increase in dose correlation. N-(2-Fluoro-4-(methylsulfanyl)phenyl)-5-methyl-6-(1-(5-methylpyrazin-2-yl)hexahydropyridine-4 during oGTT -Baseoxy)pyrimidine-4-amine (Compound 1) Efficacy of glucose drift in SD rats (PD group) Treatment vehicle compound 1 0.3 mg/kg 3 mg/kg Weight (g) 273.1 ±2.4 269.2 ± 0.2 270.4 ±3_4 Blood glucose before administration of compound (mg/dL) 72.1 ±3.5 69.5 ± 2.4 68.3 ±3.1 Blood glucose during OGTT (mg/dL) 0 min 76.1 ±4.2 81.4±3.3 70.6 ±2.0 30 min 187.8 ± 12.1 160.0 ± 8.1 159.1 ±7.3 60 min 192.0 ±6.8 164.3 ±7.9 158.9 ±4.5 120 min 123.4 ±8.8 107.1 ±8.3 98.6 ±7.0 AUCglu mg12h / mL during OGTT 19116 ±609 16626 ±6811 15939 ±3441 Vehicle % 100 ±3 87 ±41 83 ±21 A baseline mg12h / mL 9981 ±542 6861 ±9521 7470 ±4191 Vehicle △%% 100 ±5 69± 101 75 ±41 149380.doc *108- 1 Statistically compared with the vehicle treated group Differences (implementation of single factor repeated measures analysis of variance (ANOVA) and Dunnett's post test). 201105327 N-(2-Fluoro-4-(methylsulfonyl)phenyl)-5-methyl-6-(1-(5-mercaptopyridazin-2-yl)hexahydropyridine - during OGTT Plasma concentration of 4-aminooxypyrimidine-4-amine (Compound 1) during glucose drift in SD rats (PK group) Treatment Compound 1 0.3 mg/kg 3 mg/kg Compound 1 Concentration (ng/mL) 1 h, (0 min of OGTT) 56.6 ± 35.5 933.0 ± 417.6 2 h, (60 min for OGTT) 54.9 ± 28.6 894.3 ± 98.2 4 h, (180 min for OGTT) 35.5 ± 21.5 397.0 ± 207.7 Example 3: Single dose N -(2-fluoro-4-(methylsulfonyl)phenyl)-5-methyl-6-(1-(5-methylpyrazin-2-yl)hexahydropyridin-4-yloxy) Effect of pyrimidine-4-amine (Compound 1) on oGTT administered in normal male cynomolgus monkeys (Cynomo丨gus Monkey). The effect of Compound 1 on glycemic control was tested in healthy male cynomolgus monkeys. Pure cockroach male cynomolgus monkeys were used in this study. The monkeys were divided into 3 groups based on the basic fasting blood glucose concentration. Blood samples were collected at 30 min, 60 min and 120 min after administration of the compound, administration of glucose and after nasal gavage of glucose (6 g/kg, using 50% glucose solution). The results of this study indicate that Compound 1 at a dose of 1.5 mg/kg significantly reduced blood glucose concentrations during the oral glucose test. N-(2-Fluoro-4-(methylsulfonyl)phenyl)-5.methyl-6-(1-(5-methylpyrazin-2-yl)hexahydropyridine-4 during oGTT -Glyoxypyrimidine-4-amine (Compound 1) Effect on blood glucose concentration of cynomolgus monkeys Blood glucose concentration (mg/dL) AUCglu -60 0 30 60 120 mg *2 h/dL Vehicle% Vehicle 78 ±14 70±15 133士28 165±24 66士11 14413±1378 100%±10% Compound 1 · 1.5 mg/kg 82±19.6 73±11.9 115±32.3 119±19.8 65 ±40.8 13320±2431 82% 17% 149380.doc •109- 201105327 Example 4: Inhibition of recombinant P450 enzymes The human cytochrome P450 protein family is involved in endogenous metabolic metabolism and a family of enzymes that detoxify drugs and other exogenous chemicals. The p45 chymase converts various compounds into molecules with higher polarity, and the transforming molecules are easier to remove from the body. Drug-drug interactions occur when a co-injection of two drugs and competing for the same P450 enzyme' may result in incomplete detoxification. The analysis conditions are summarized in the table below. Specific enzyme mother liquor and substrate enzyme positive control (inhibitor mother liquor) for P450 analysis Enzyme substrate mixture incubation time (bandwidth) Emission (bandwidth) 1Α2 5 mM Furaylline 1A2-E/S mixture 20 Min 409 nm (20 nm) 460 run (40 nm) 2C9 0.5 mM sulfaphenazole 2C9-MFC-E/S mixture 45 min 409 nm (20 nm) 530 nm (25 nm) 2C19 25 mM anti-cyclopropylamine 2C19 -CEC-E/S mixture 45 min 409 nm (20 nm) 460 nm (40 nm) 2D6 0.025 mM Quinidine 2D6-AMMC-E/S mixture 30 min 390 nm (20 nm) 460 nm (40 Nm) 2Ε1 5 mM DDTC 2E1-DDTC-E/S mixture 45 min 409 nm (20 nm) 530 nm (25 nm) 3Α4 10 mM oleoleomycin 3A4-BFC-E/S mixture 30 min 409 Nm (20 nm) 530 nm (25 nm) We observed 10 μΜ N-(2-fluoro-4-(methylsulfonyl)phenyl)-5-mercapto-6-(1-(5-A) The inhibition of the isozymes 3A4, 2C9 and 2C19 is about 50% with an IC50 value of 9.05 μΜ, respectively. The ratio of pyridyl-2-yl)hexahydro&quot;pyridin-4-yloxy)pyrimidine-4-amine is about 50%. , 8.82 μΜ and >10 μΜ. No inhibition of 1A2 or 2D6 was observed. 149380.doc -110- 201105327 N-(2-Fluoro-4-(methylsulfanyl)phenyl)-5-methyl-6-(1-(5-methyl.pyrazine-2-yl) Inhibition of recombinant CYP-450 enzyme by hexahydropyridin-4-yloxy)pyrimidine-4-amine (Compound 1) Inhibition of subtype 10 μΜ ic50 (μΜ) 3Α4 40.2 9.05 1Α2 0 &gt;10 2C19 46.7 &gt;10 2C9 54.1 8.82 2D6 0 &gt;10 Example 5: N-(2-Fluoro-4-(methylsulfonyl)phenyl)-5-methyl-6-(1-(5-methylpyridyl) Inhibition of P450 2C9 and 2C19 in HLM by pyrazin-2-yl)hexahydropyridin-4-yloxy)pyrimidine-4-amine (Compound 1). Metabolic incubation using standard probe matrices (tolbutamide for CYP2C9 and (S)-mephenytoin for CYP2C19) was performed using a 96-well plate format. The general incubation mixture contains 0.5 mg/mL microsomal protein, 〇μΜ to 50 μΜ N-(2-fluoro-4-(methylsulfonyl)phenyl)-5-mercapto-6-(1-(5- Methyl. Ratio ° Qin-2-yl) Hexaphos π vs. 0--4-yloxy). Azetone-4 _ amine (as inhibitor), 1 mM NADPH and 100 mM potassium phosphate buffer containing 3 mM MgCl2 and lmMEDTA (pH 7.5), and a final volume of 100 pL. For CYP2C9, 150 μM of fenfluramine was added to the reaction mixture and incubated at 37 ° C for 10 min. For CYP2C19, 50 μM (S)-mefentoin was added to the reaction mixture and incubated at 37 ° C for 40 min. Parallel control incubations were performed with meflutamine and (S)-mefentoin without the addition of Compound 1, and these were used as positive controls for the reactants. All analyses were performed in triplicate. Termination of incubation by adding 100 μί of acetonitrile containing one of 149380.doc • 111 · 201105327 as the internal standard: 4'-hydroxymefentoin-d9 for CYP2C9 and 4' for CYP2C19 - Hydroxymethafen-d3 (final concentration 1 ng/mL). After the addition of the internal standard, the 96-well plate was centrifuged at 3000 rpm for 10 min and 100 μL of the supernatant was transferred to a clean 96-well plate for analysis by LC/MS/MS. Ν-(2-Fluoro-4-(methylsulfonyl)phenyl)-5-methyl-6-(1-(5-methyl&quot; 嗓-2-yl) hexazaβ ratio bite- Inhibition of recombinant CYP _450 enzyme by 4 - oxy) tert-4-amines 1A2 2C9 2C19 2D6 3A4 (anthrone) 3Α4 (Midazolam) &gt;30 6 &gt;30 &gt;30 &gt;30 &gt;30 &gt;30 4 &gt;30 &gt;30 &gt;30 &gt;30 Example 6 : Ν-(2-fluoro-4-(methylsulfonyl)phenyl)-5-methyl- The synthesis of 6-(1-(5-methyl.pyrazine-2-yl)hexahydropyridin-4-yloxy)pyrimidine-4-amine is shown in the following examples. The following examples are provided to further define the invention, however, the invention is not limited to the details of the examples. The compounds described herein are named according to CS ChemDraw Ultra version 9.0.7. In some cases, generic names are used and it should be understood that such generic names will be recognized by those skilled in the art. Chemical properties: proton NMR &quot;Η NMR) lineage in a Varian Mercury Vx-400 equipped with a 4-core automatic shift probe and z-gradient or equipped with QNP (Quad nuclear probe) or BBI (broadband reverse probe) and Recorded on the z-gradient Bruker Avance-400. Chemical shifts are given in parts per million (ppm) and the residual solvent signal is used as a reference in 149380.doc • 112-201105327. The following NMR abbreviations are used: s = unimodal, d = doublet, t = triplet, q = quartet, m = multiplet, sept = sigma, br = broad cold. Microwave irradiation was carried out using an Emyrs synthesizer (Personal Chemistry). Thin layer chromatography (TLC) was performed on silica gel 60 F254 (Merck), and preparative thin layer chromatography (prep TLC) was performed on PK6F Shijiao 60 A 1 mm plate (Whatman), and 0.063-0.200 mm was used. Kieselgel 60 (Merck) was subjected to column chromatography on a silica gel column. Vacuum evaporation was carried out on a Biichi rotary evaporator. Use diatomaceous earth 545® during palladium filtration. LCMS spectrum: 1) PC·· HPLC-Gang: LC-10AD VP, Shimadzu; HPLC system controller: SCL-10A VP, Shimadzu; UV-detector: SPD-10A VP, Shimadzu; autosampler : CTC HTS, PAL, Leap Scientific ; Mass spectrometer: API 150EX with Turbo Ion Spray source, AB/MDS Sciex; Software: Analyst 1·2. 2) Mac: HPLC-Pump: LC-8A VP, Shimadzu HPLC system controller: SCL-10A VP, Shimadzu; UV-detector: SPD-10A VP, Shimadzu; autosampler: 215 Liquid Handler, Gilson; mass spectrometer: API 150EX with Turbo Ion Spray source , AB/MDS Sciex, software: Masschrom 1.5.2. Example 6.1: Preparation of 1-(5-methylpyrazin-2-yl)hexahydropyridin-4-ol h〇-Cn-〇-ch3 2-bromo-5-mercaptopyrazine (73 g, 422 mmol) to hexahydrogen. The mixture of 1,4-ol (107 g, 1055 mmol) in 470 mL of isopropanol was charged into 149380.doc -113-201105327 into two high pressure vessels. in! The reaction was stirred for 17 h. The solvent was removed to half volume under reduced pressure and the residue was diluted with DCM and water. The organic layer was separated and the aqueous layer was extracted with DCM. The organic layer was dried over anhydrous MgSO.sub.d., and concentrated in vacuo. The residue was filtered with a pad of EtOAc (EtOAc) eluting eluting eluting with with with with with with with with with with with with with with with ).

The exact mass calculated for GoHbNsO is 19312 and the experimental value is 194 3 [M+H]+. Example 6.2: Preparation of 4-gas-5-methyl-6-(1-(5-methylpyrazin-2-yl)hexahydropyridin-4-yloxy)pyrimidine.

In a dry ice-acetone bath at 0. (: Downward isopropyl 1_(5·decylpyrazine-2-yl) /, hydrogen. Ratio. 4--4-ol (69.75 g, 361 mmol) and 4,6-di-5-fluorenyl , bite (61.8 g, 379 mm 〇l) in a solution of 125 mL of THF was added dropwise to 1 Μ of the third butyl alcohol in THF (3 75 mL, 3 75 mmol). The reaction mixture was allowed to warm. The mixture was stirred at room temperature for 17 h. A further 5 mL of 1 Μ second butanol clock in THF was added. After two additional hours of stirring no change was observed. The reaction mixture was filtered with EtOAc (500 mL) Washing. Concentrate the solvent to about 1/3 volume under reduced pressure. The resulting suspension was filtered, and the solid was washed with cold CH.sub.3CN and concentrated under reduced pressure. , Shixi gum, AcOElHex, 1:1 '34〇g size column) to purify the residue, 149380.doc -114· 201105327 for solid 4-chloro-5-mercapto-6-(1-(5 -Methyl 0 is more than 嗓-2-yl) hexahydro η than β-1,4-yloxy)pyrimidine (80.35 g, 70%). The exact mass of Ci5H18C1N50 is 319.12, the experimental value is 320.3 [河+印+. Example 6.3: N-(2-Fluoro-4-(methyl) Sulfomethyl)phenyl)-5-methyl-6-(1-(5-methylpyrazin-2-yl)hexahydropyridin-4-yloxy)pyrimidine-4-amine (Compound 1) preparation.

To a 2 L 3-neck round bottom flask was charged 4-cyclo-5-mercapto-6-(1-(5-methylpyrazin-2-yl)hexahydropyridin-4-yloxy)pyrimidine (63.8 g) , 200 mmol), 2-fluoro-4-(decyl-decyl) aniline (37.7 g, 199 mmol), diethoxycarbonyl (2_24 g, 9.98 mmol), 1,1'-bis (di- Tert-butylphosphino)ferrocene (9.47 g, 19.71 mmol) and dioxane (1 L). N2 was bubbled through the solution for 5 min. Sodium 2-methylpropan-2-olate (46.02 g, 479 mmol) was added at room temperature and then the mixture was heated to 1 °C. A yellow solid formed and the color changed from dark brown to yellow. The mixture was maintained at 1 °C for 1 h. The resulting reaction mixture was poured into 2 L of ice water. The solid (80 3 g) was filtered and suspended in acetonitrile (1 L) at EtOAc. The mixture was allowed to cool and the solid was filtered to give a pale-yellow solid N-(2-fluoro-4-(decylsulfonyl)phenyl)-5-indolyl_6_(1_(5-decylpyrazin-2-yl) Hexahydropyridine-4-yloxy)pyrimidine-4-amine (74.26 g, 157 mmol, 79% yield). 4 NMR (CDC13, 400 MHz) δ 1.90- I49380.doc -115- 201105327 1.95 (m, 2H), 2.12-2.17 (m, 2H), 2.12 (s, 3H), 2.44 (s, 3H), 3.08 ( s, 3H), 3.50-3.56 (m, 2H), 3.89-3.95 (m, 2H), 5.44-5.46 (sept, J= 3.79 Hz, 1H), 6.84-6.85 (d, J= 4.17 Hz, 1H) , 7.71-7.77 (m, 2H), 7.99 (s, 1H), 8.13 (s, 1H), 8.44 (s, 1H), 8.84-8.88 (t, J = 8.34 Hz, 1H). The accurate mass calculation for C22H25FN603S is 472.17' experimental value is 473 5 []^+11]+. The material was further characterized by powder X-ray diffraction (XRpD), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC). The powder X-ray diffraction (XRPD) pattern shows that the material is a crystalline material (see Figure 丨) ^ Thermogravimetric analysis (TGA) thermogram shows the melting temperature range (about n (rc to about ι8 〇 β (:, see figure) 2) The material has an initial weight loss of about 1.%. The differential scanning calorimetry (DSC) thermogram shows that the material has a narrow endotherm at the melting temperature, wherein the onset temperature and peak temperature are about 18, respectively. 〇· 7 〇C and approximately 1 82·8 C, and the enthalpy due to sample melting and subsequent exothermic decomposition is 3 J/g (see Figure 3). Those skilled in the art will recognize that The illustrative examples described herein are subject to various modifications, additions, substitutions and alterations without departing from the spirit of the invention and are therefore considered to be within the scope of the invention. All of the documents cited above (including but not limited to) The entire contents of the publications, and the provisional and official patent applications are hereby incorporated herein by reference. PXRD) Figure; Figure 2 shows according to Example 6 The procedure for preparing the compound 丨热重八 149380.doc • 116-201105327 analysis (TGA) thermogram; and Figure 3 shows the differential scanning calorimetry (DSC) of Compound 1 prepared according to the procedure described in Example 6. Thermogram. 149380.doc -117·

Claims (1)

201105327 VII. Scope of Application: 1. The σ substance is selected from the following formula (1) and its pharmaceutically acceptable salts, solvates and hydrates: A sauce composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier. 3. A composition comprising a compound of claim i and a Dpp iv inhibition. 4. The composition of claim 3, wherein the Dpp_IV inhibitor is selected from the group consisting of the following compounds and pharmaceutically acceptable salts, solvates thereof And hydrate: 3(R)-amino-1-[3-(trifluoromethyl)_5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a] Pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butanone; 1-[2-(3-hydroxyadamantane-ι-ylamino)ethenyl]pyrrolidine _2(s)-carbonitrile; (18,38,58)-2-[2(8)-amino-2-(3-hydroxyd-l-yl)-ethenyl]-2-nitrogen Heterobicyclo[3.1.0]hexane-3-carbonitrile; 2-[6-[3(R)-aminohexahydroacridin-1-yl]-3-methyl-2,4-di Oxy (oxo) -1,2,3,4-tetrahydropyrimidin-1-ylindenyl]benzonitrile; 8-[3(R)-aminohexahydro. Bipyridin-1-yl]-7-(2-butynyl)-3-mercapto-1-(4-methylquinazolin-2-ylindenyl)xanthine; 1-[N-[3 (R)-pyrrolidinyl]glycidyl]pyrrolidine-2(R)-ylboronic acid; 149380.doc 201105327 4(S)-fluoro-1-[2-[(111,38)-3- (except _1,2,4-triazol-1-ylmethyl)cyclopentylamino]ethinyl]°pyrrolidine-2(S)-carbonitrile; l-[(2S,3S,llbS )-2-amino-9,10-dimethoxy-2,3,4,6,7,lib_hexahydro-1Η-»pyrido[2,la]isoquinolin-3-yl]- 4(S)-(fluoromethyl)pyrrolidin-2-one; (2S,4S)-2-cyano-4-fluoro-l-[(2-hydroxy-1,1-didecyl)ethyl The amine group has a ratio of π to π. 8-(cis-hexahydro-pyrolo[3,2-indene]pyrrol-1-yl)-3-indolyl-7-(3-methyl-but-2-enyl) 1-(2-oxo-2-phenylethyl)-3,7-dihydro-indole·2,6-dione; 1-((38,48)-4-amino-1- (4-(3,3-two gas ratio 11 each *1 -1-yl)-1,3,5-triazin-2-yl)pyrrolidin-3-yl)-5,5 difluorohexa Hydropyridin-2-one; (foot)_2-((6-(3-amino-6 gas-to-one-1-yl)-3-mercapto-2,4-di-oxy-3,4- Dihydropyrimidine-i(2H)-yl)methyl)-4-fluorobenzonitrile; 5_{(S)-2-[2-((S)-2-cyano-. 2-yloxy-ethylamino]-propyl}-5-(1Η-tetrazol-5-yl)10,11-dihydro-5H-dibenzo[a,d]cycloheptane Alkene-2,8-dicarboxylic acid bis-didecylguanamine; ((2S,4S)-4-(4-(3-mercapto-1-phenyl-1H-0 ratio. sit-5-yl) Hexahydroindole 嗓 1- 1-yl) pyrrolidin-2-yl)(tetrahydrothiazol-3-yl)methanone; (2S,4S)-l-[2-[(4-ethoxylated) bicyclic [2.2.2] oct-1-yl)amino] ethinyl]-4-fluoropyrrolidin-2-indene nitrile; 6-[(3R)-3-amino-hexahydropyridin-1- 5-(2-chloro-5-fluoro-nodal)-1,3-dimercapto-1,5-dihydro-tondro[3,2-pyrimidine-2,4-dione;2-({6-[(3R)-3-Amino-3-indolylhexahydro 0-biten-1-yl]_ι,3_dimercapto_ 149380.doc -2- 201105327 2,4-II Sideoxy-1,2,3,4-tetrahydro-511-'1 ratio|1 each [3,2- &lt;1]°Bite-5-yl}methyl)-4_fluorobenzonitrile; (2S)-l-{[2-(5-methyl-2-phenyl-oxazole-4-yl) -ethylamino]-ethenyl}-pyrrolidin-2-indene nitrile; (2S)-1-{[1,1-dimercapto-3-(4-0 ratio -3-amino) -1--1-yl)-propylamino]-ethenyl}-pyrrolidine-2-carbonitrile; (3,3-difluoropyrrolidin-1-yl)-((2S,4S)-4- (4-(pyrimidin-2-yl)hexahydrogen ratio ° Qin-1-yl) 0-pyridin-2-yl)methyl steel; (2S,4S)-l_[(2S)-2-amino-3 ,3-bis(4-fluorophenyl)propanyl]-4-fluoropyrrolidin-2-indene nitrile; (2S,5R)-5-ethynyl-1-{Ν·(4-methyl-1 · (4- 叛 比 比 bit -2- base) hexagram bit -4- base) glycidinium } η than β each bite _2 carbonitrile; and (18,6 feet) -3-{[3 -(Trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]. Bis-7(8Η)-yl]carbonyl}-6-(2,4,5-trifluorophenyl)cyclohexa-3-ene-amine. 5. The pharmaceutical composition of claim 3 or 4 further comprising a pharmaceutically acceptable carrier. 6. A method for treating a GpRU9 receptor-associated disorder in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound of claim 1 or a combination of any one of claims 2 to 5 Things. 7. The method of claim 6, wherein the GpRU9 receptor-associated disorder is a metabolic related disorder. 8. The method of claim 7, wherein the metabolic-related disorder is selected from the group consisting of: '149380.doc 201105327 diabetes, type 1 diabetes, type 2 diabetes, inadequate glucose tolerance, impaired glucose tolerance, sputum Island resistance, "glycosis, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia,: atherosclerosis, stroke, x syndrome, hypertension, insufficiency" Intestinal endocrine cell deficiency, diabetes, 'metabolic acidosis, cataract, diabetic nephropathy, diabetic neuropathy, peripheral neuropathy, diabetic coronary artery disease' diabetic cerebrovascular disease, diabetic peripheral vascular disease, diabetic retinopathy , metabolic syndrome, diabetes-related conditions, myocardial infarction, learning disabilities, memory disorders, neurodegenerative disorders, conditions in which blood GUM concentrations are increased by individuals with neurodegenerative disorders, excitotoxicity caused by severe seizures Brain damage, Alzheimer's disease, Parkinson's disease (parkins〇n) , s(1) ""About, Himtington's disease, disease related to prion, stroke, motor neuron disease, traumatic brain injury, spinal cord injury, and obesity. The method of claim 7, wherein the metabolic-related disorder is type 2 diabetes. ίο. A method for treating a GPR119 receptor-associated disorder in a subject, comprising administering to the individual in need thereof a therapeutically effective amount as claimed in claim 1 A combination of a compound and a DPP-IV inhibitor, wherein the compound is administered simultaneously, separately or sequentially with the Dpp_IV inhibitor system. 11 - The method of claim </RTI> wherein the compound is administered concurrently with the DPp_IV inhibitor system 1 2. The method of claim 1, wherein the compound is administered separately from the 〇1&gt;1}_1¥ inhibitor system 149380.doc 201105327 η. The method of claim 10, wherein the compound and the DPP The method of claim 14, wherein the receptor-related disorder is a metabolic-related disorder. 15. The method of claim 14, wherein the metabolic correlation is The condition is selected from Group of components: 'diabetes, type 1 diabetes, type 2 diabetes, inadequate glucose tolerance, impaired glucose tolerance, resistance to tetanyl, hyperglycemia, hyperlipidemia, diglyceride, high cholesterol Hypertension, dyslipidemia, atherosclerosis, stroke, x syndrome, hypertension, pancreatic dysfunction, intestinal endocrine cell deficiency, diabetes, metabolic acidosis, cataract diabetic nephropathy, diabetic neuropathy, peripheral neuropathy , diabetic coronary artery disease, diabetic brain disease 4, diabetic peripheral vascular disease, diabetic retinopathy, metabolic syndrome, diabetes-related conditions, myocardial infarction, learning disabilities, memory disorders, neurodegenerative disorders, increased by nerves Individuals with degenerative conditions, blood GUM-rich New Zealand H caused by severe _ seizures caused by excitotoxic brain damage, Alzheimer's disease, Parkinson's disease, Huntington's disease and prion-related diseases, stroke , motor neuron disease, traumatic brain injury, spinal cord injury and obesity. 16. The method of claim 14, wherein the metabolic-related disorder is type 2 diabetes 0 wherein the DPP-IV inhibitor is 17. The method of any one of claims 10 to 16 149380.doc 201105327 is selected from the group consisting of And pharmaceutically acceptable salts, solvates and hydrates thereof: 3(R)-amino-1-[3-(trifluoromethyl), ^^ hydrogen^like saliva[4,3-a] Pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-g; 1 -[2-(3-hydroxyadamantan-1-ylamino)ethenyl Pyrrrolidine_2(s)-carbonitrile; (lS,3S,5S)-2-[2(S)-amino-2-(3- via fund just burned_ι_ its, soil JG brewing base]- 2-Azabicyclo[3.1.0]hexane-3-carbonitrile; 2-[6-[3(R)-Aminohexahydropyridinyl]_3_methyl-2,4_dioxaxy 1,2,3,4-tetrahydropyrimidin-1-ylmethyl]benzonitrile; 8-[3(11)-aminohexahydropyridine-1-yl; |_7_(2-butynyl)_3_ Methyl-1(4-mercaptoquinazolin-2-ylmethyl)xanthine; 1-[N-[3(R)-pyrrolidinyl]glycine]pyrrolidinylboronic acid. 4( S)-fluoro-1-[2-[(111,38)-3-(11^1,2,4-triazol-1-ylmethyl)cyclopentylamino]ethenyl; 1° ratio L-pyridine-2(S)-carbonitrile; l-[(2S,3S,llbS)-2-amino-9,10- Methoxy-2,3,4,6,7,llb-hexahydro-1H-acridino[2,la]isoquinolin-3-yl]-4(S)-(fluoroindolyl)pyrene (2S,4S)-2-cyano-4-fluoro-l-[(2-hydroxy-i,i-dimethyl)ethylamino]ethylidene 8-(cis-hexahydro-pyrrolo[3,2-b].pyrrol-1-yl)-3-methyl-7-(3-indolyl-but-2-enyl)- 1-(2-Sideoxy-2-phenylethyl)-3,7-dihydro-indole-2,6-dione; l_((3S,4S)-4-Amino-1-(4) -(3,3 - 二气.Biluo~-1-yl)-1,3,5- 149380.doc •6- 201105327 Triazin-2-yl).Byrrolidine_3_yl)_5, 5 difluorohexahydropyridine 2 ketone; (R)-2-((6-(3-aminohexahydro)••bit-1-yl)_3_methyl-2,4 di-oxy- 3,4-dihydropyrimidine- to 2!^.yl)methyl)_4•fluorobenzonitrile; 5-{(S)-2-[2-((S)-2-cyanopyrrolidine-i _ base)·2_sideoxy-ethylamino]-propyl}-5-(1Η-tetrazol-5-yl)10,li-dihydro-5Η-dibenzo[a,d] ring Heptene-2,8-didecanoic acid bis-dimethylamine; ((2S,4S)-4-(4-(3-indolyl-1-phenyl-1H-. ratio. (5,48)-1-[2-[(4-) Ethoxycyclobicyclo[2.2.2]oct-1-yl)amino]ethynyl]-4-fluoropyrrolidin-2-indene nitrile; 6-[(3R)-3-amino--6 Hydropyridin-1-yl]-5-(2-gas-5-1-pyringyl)·1,3-dimercapto-1,5-dihydropyrolo[3,2-d]pyrimidine_2 , 4-dione; 2-({6-[(3R)-3.amino-3-mercaptohexahydropyridyl]-ι,3-dimethyl-2,4-di-oxyl-l, 2,3,4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl}methyl)-4-fluorobenzonitrile; (2S)-l-{[2-(5-曱(2-S)-Ethyloxy-4-yl)-ethylamino]-ethyl-7-pyrrolidin-2-indene; (2S)-1-{[1,1-dimercapto-3 -(4-pyridin-3-yl-imidazol-1-yl)-propylamino]-ethenyl}-pyrrolidine-2-carbonitrile; (3,3-difluoropyrrolidin-1-yl) -((2S,4S)-4-(4-(pyrimidin-2-yl)hexahydropyrazin-1-yl)pyrrolidin-2-yl)anthone; (25,43)-1-[(28) 2-amino-3,3-bis(4-fluorophenyl)propanyl]-4-fluoropyrrolidin-2-indene nitrile; (2S,5R)-5-ethynyl-1-{Ν· (4-mercapto-1-(4-carboxypyridin-2-yl) 149380.doc 201105327 Hexahydropyridyl-4-yl) } Pyrazol acyl amine. Each (1S,6R)-3-{[3-(trifluoromethyl) a]. Bis-7-(8H)-yl]carbonyl}_6-(2,4 amine. 定-2-indene nitrile; and, 6' digas [I, 2, 4] triazole and μ, 3_, 5- Difluorophenyl)cyclohexyl-3-ene-i. 18. A use of the compound or compound of claim 1 for the manufacture of a medicament. The group of any one of claims 2 to 5 for treating a GPR119 receptor-related disorder. 19. A use of the compound or compound of claim 1 for the manufacture of a medicament 0 &quot; a group of any one of 5 for treating a metabolic-related disorder. 20. A species such as the request item ^, "A group of soils: a substance: used for the manufacture of a medicament for treating a metabolic-related disorder" The sputum condition is selected from the group consisting of: ', foot sugar type 1 diabetes, type 2 diabetes, glucose tolerance, (four) impaired glucose tolerance, sputum resistance, hyperglycemia, high fat two: Γ Oil, hypercholesterolemia, dyslipidemia, motility: =, stroke, x syndrome, hypertension, parotid gland (4), insufficient intestinal cells for intestinal deficiency, diabetes, dysfunction, diabetic nephropathy, diabetic neuropathy, Outside; = variable, diabetic coronary artery disease 'diabetic cerebral blood disease, diabetic retinopathy, metabolic syndrome-related disease K-muscle infarction, learning f disorder, remembering! = inflammatory disease, increased by MGUM concentration improvement in individuals with neurodegenerative disorders Excitatory toxic brain damage caused by severe seizures 149380.doc 201105327, A (10) Morse disease, Parkinson's disease, Huntington's disease and prion-related diseases, stroke, motor neuron disease, trauma Sexual brain injury, spinal cord injury, and obesity. 21. The use of a compound of claim 1 or a group according to any one of claims 2 to 5 for the manufacture of a medicament for the treatment of type 2 diabetes 22. A compound according to any one of claims 2 to 3, which is for use in a method of treating a human or animal body by therapy. The composition of any one of 2 to 5 for use in the treatment of a GPR119 receptor-related disorder. 24. The compound of claim 1 or the composition according to any one of claims 2 to 5 for use in therapy A method of metabolizing a related disorder. 25. A method of claiming a compound or a composition according to any one of claims 2 to 5, wherein the condition is selected from the group consisting of: diabetes, Type 1 diabetes, type 2 diabetes, grapes Insufficient tolerance, impaired glucose tolerance, knee resistance, hyperglycemia, hyperlipidemia, triglycerideemia, hypercholesterolemia, dyslipidemia, atherosclerosis, stroke, X syndrome High blood dust, parotid β cells are not j 'Intestinal secretory cells are insufficient, diabetes, metabolic acidosis, leucorrhea, gynecological disease, diabetic neuropathy, peripheral neuropathy 'diabetic coronary artery disease, diabetes Cerebrovascular disease, diabetes, peripheral vascular disease, diabetic retinopathy, metabolic syndrome, nephropathy-related conditions, myocardial infarction, learning disabilities, memory disorders, neurodegenerative disorders, increased by neurodegenerative disorders 149380.doc 201105327 Body blood GLP-丨 concentration changed to 忐 ®® i * 〇 兄 brother, excitotoxic brain damage caused by severe seizures, Azil ^ β Haimo's disease, Parkinson's disease, Henry Wendun's disease, related to Pryon 4 disease 'stroke, motor neuron disease 26. 27. 28. 29. 30. Disease, traumatic brain injury, spinal injury and obesity. The method of claim 1, wherein the compound of claim 1 or any one of claims 2 to 5 is used for the treatment of type 2 diabetes. , '. A method of preparing a composition, which comprises the step of mixing a compound of claim 1 with 4 a reagent which is acceptable. A method of preparing a composition, t h ^ @ t ± 1 which comprises the step of mixing a compound of claim 1 with a DPP-IV inhibitor. A method of preparing a composition, which comprises mixing a compound of the formula 1 with a DPP-W inhibitor and a pharmaceutically acceptable carrier. A method of preparing a composition according to claim 28 or 29, wherein the DPP_IV inhibitor is selected from the group consisting of the following compounds and pharmaceutically acceptable salts, solvates and hydrates thereof: 3(R)-amino group-^ 3-(trifluoromethyl)5,67,8•tetrahydrotriazino[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl) _丨__ ; 1 -[2-(3-hydroxyadamantan-1-ylamino)ethyl)]pyrrolidine-2(s)carbonitrile; (lS,3S,5S)-2-[ 2(S)·Amino-2-(3- via fundo-fired]-yl)ethinyl]-2-azabicyclo[3.1.0]hexan-3-ylcarbonitrile; 2-[6- [3(R)-Amino hexahydropyridine 丨 基 基 ] ] ] , , , , , , ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; 8-[3(R)-Aminohexahydroacridin-1-yl]_7_(2-butynyl)_3_曱小小149380.doc -10· 201105327 (4-methylquinazoline_2_yl Alkyl) xanthine; 1-[N-[3(R)-pyrrolidinyl]glycine]pyrrolidine_2(R)-ylboronic acid; 4(S)_fluoro-l- [2-[ (lR,3S)-3-(lH-l,2,4-trisylmethyl)cyclopentylamino]ethionyl]pyrrolidine-2(S)-phthalonitrile; 1-[(28, 38,1153)-2-Amino-9,10-dimethoxy-2,3,4,6,71115_hexahydropyridinyl pj-a]isoquinoline·3_ ]_1 2 3 4 5(s)_(fluoromethyl)pyrrole °-2 · Stuffed; ; (2MS)-2-cyano-4-fluoro-l-[(2-hydroxy-1,1-di曱基)ethylamino] ethyl ketone ° ratio σ each set; 8 (cis-hexaoxy-. ratio σ each [3, 2-1)] 11 〇 each _1-base)_3- Methyl-7-(3-methylbutylidene)-indole-(2-o-oxy-2-phenylethyl)_3,7-dihydropene · 2,6-- Ming; « 149380.doc -11 · 1 ((3S,4S)-4-amino-1-(4-(3,3-difluoro)(比哈σ定小基)_1,3,5_ 2 triazin-2-yl)pyrrolidine ·3_yl)_5,5 difluorohexahydropyridine·2•one; 3 (R)-2-((6-(3-aminohexahydropyridin-1-yl)-3-methyl_ 2,4_2 Side Oxygen 4 Base_3, Heart Dihydropyrimidine_ι(2Η)_yl)fluorenyl)-4-fluorosulfononitrile; 5 {(S)-2-[2-((S)_2 -Cyano-1 each. +K)·2 side oxy-ethylamino]-propyl}-5-(1Η-tetrazol-5-yl)10,U-dihydro-5H_diphenyl And [a, d] cycloheptene 2,8-dicarboxylic acid bis-dimethyl decylamine; ((2S,4S)-4-(4-(3-mercapto-1-phenyl." _5_ base) hexahydroquinone. (1-7,4S)-l-[2_[(4-ethoxycarbonylbicyclo[2 2] 2] 丨 丨 基 基 ) 胺 胺 ] ] 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 (2_Gas_5_Fluoro-nodal)_201105327 1,3-Dimercapto-1,5-dihydro-pyrrolo[3,2-d]pyrimidine-2,4-dione; 2-({ 6-[(3R)-3-Amino-3-mercaptohexahydroacridin-1-yl]-1,3-dimercapto-2,4-di-oxy-1,2,3,4 -tetrahydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl}indenyl)-4-fluorobenzonitrile; , (2S)-l-{[2-(5-methyl-2- Phenyl-oxazol-4-yl)-ethylamino]-ethenyl}-pyrrolidin-2-indene nitrile; (2S)-1-{[1,1-dimercapto-3-(4) -° ratio. 1,4--3-yl-σm0-n-yl)-propylamino]-ethenyl}-pyrrolidin-2-indene nitrile; (3,3-difluoropyrrolidine- 1-yl)-((2S,4S)-4-(4-(pyrimidin-2-yl)hexahydropyrazin-1-yl)indolyl-2-yl)anthone; (2S,4S)-l -[(2S)-2-amino-3,3-bis(4-fluorophenyl)propanyl]-4-fluoropyrrolidin-2-yl·complement·; (28,511)-5-ethynyl- 1-{]^-(4-mercapto-1-(4-reyl-anthracene-2-yl) hexahydrogen ratio bite-4-yl) } ° acyl ratio. Each bite 2-carbonitrile; and (lS,6R)-3-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a Pyridazin-7(8H)-yl]yl}-6-(2,4,5-trifluorophenyl)cyclohexa-3-ene-p-amine. 3 1 . The compound of claim 1 which is for use in combination with a DPP-IV inhibitor for the treatment of a condition which is improved by increasing the blood GLP-1 concentration in a mammal. 32. The compound of claim 3, wherein the compound alone is ineffective for treating a condition which is ameliorated by increasing the blood glucose level of the mammal. 33. The compound of claim 31 or 32, wherein the condition ameliorated by an increase in blood GLp-丨 concentration is selected from the group consisting of: 149380.doc • 12-201105327 diabetes, type 1 diabetes, type 2 diabetes, glucose tolerance Insufficiency, impaired glucose tolerance, insulin resistance, hyperglycemia, hyperplasia, equine glycerol triglyceride, hypercholesterolemia, dyslipidemia, atherosclerosis, stroke, x syndrome, high Blood pressure, pancreatic p-cell deficiency, intestinal endocrine cell deficiency, diabetes, metabolic acidosis, cataract diabetic nephropathy, diabetic neuropathy, peripheral neuropathy, diabetic coronary artery disease, diabetic cerebrovascular disease, diabetic peripheral vascular disease , diabetic retinopathy, metabolic syndrome, diabetes-related conditions, myocardial infarction, learning disabilities, memory disorders, neurodegenerative disorders, increased neurodegenerative disorders: the condition of the individual's fluid GLP-l m is improved by Severe _ epileptic seizure caused by excitotoxic brain damage, Alzheimer's disease, Parkinson's disease, Huntington Disease, and the prion-related disease, stroke, motor neuron disease, traumatic brain injury, spinal cord injury and obesity. 34. The compound of claim 31 or 32, wherein the condition is type II diabetes. 35. The compound of any one of claims 31 to 34 wherein the Dpp_iv inhibitor is selected from the group consisting of the following compounds and pharmaceutically acceptable salts, solvates and hydrates thereof: 3(R)-amino-H3- (三敦methyl)_5,6,7,8_four gas π,2,4]three saliva[4,3♦ than 嗓-7-yl]-4-(2,4,5-three I stupid Butyl ketone; Η2-0--------------------------------------- (2) Benzyl-2-(3-hydroxyadamantanyl)-ethenyl]-2-azabicyclo[3.1.0]hexane_3_carbonitrile; 149380.doc •13· 201105327 2-[6-[ 3(11)-Aminohexahydro"Bist-1-yl]_3_methyl-2,4-dioxy-1,2,3,4-tetrahydropyrimidin-1-ylindenyl]benzyl Nitrile; 8-[3(R)-amino hexahydropyridinium-i-yl]_7·(2-butynyl)_3-methyl-1-(4-mercaptoquinazolin-2-yl Alkyl) Astragalus; 1 - [N-[3 (R) - °pyrrolidyl]glycine oxime^ than B pyridine 2(R)-ylboronic acid; 4(3)-fluoro-1- [2-[(111,3$)-3-(111-1,2,4~Triazol-buylindolyl)cyclopentylamino]ethinyl]. Birolidine-2(S)-carbonitrile; 1-[(23,3 8,1155)-2-amino-9,10-dimethoxy-2,3,4,6,7,111) - hexahydro-1 Η-° than pyridine and [2,la]isoquinolin-3-yl]_4(S)-(fluoromethyl) 13 to singly -2- ( ;28,48)-2- Cyano-4-pyrene-1-([(2-yl-1,1-didecyl)ethylamino]ethyl)-pyrrolidine; 8-(cis-hexahydro-pyrrolo[ 3,2-b]pyrrole-l-yl)-3-indolyl-7·(3-indolyl-but-2-yl)-1-(2-oxo-2-phenyl)ethyl _3,7-Dihydro-indole-2,6-di-copper; 1-((38,48)-4-amino-1-(4-(3,3-difluoro]1 嘻. 1_基)_1,3,5_三嗓-2-yl). Ratio: each 11 -3-yl)-5,5 di-hexahydropyrene than bite _2·鲷; (R)_2-(( 6-(3-Amino6-gas D ratio 0-dec-1-yl)-3-mercapto-2,4-di-oxy-3,4-dihydropyrimidin-1(2H)-yl) fluorenyl )-4-fluorobenzonitrile; 5-{(S)-2-[2-((S)-2-cyanopyrobitone-l-yl)_2·sideoxy-ethylamino]-propyl }--5-(1Η-tetrazol-5-yl)10,11-dihydro-5Η-dibenzo[a,d]cycloheptene-2,8-dioxalate bis-didecyl decylamine ((2S,4S)-4-(4-(3-indolyl-1-phenyl-1H-.bazin-5-yl)hexahydropyridazine-bu)pyrrolidin-2-yl)( Tetrahydrogen Thiazol-3-yl)methanone; 149380.doc -14- 201105327 (28'48)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino Ethyl]-4-fluoropyrrolidine-2·phthalonitrile; 6-[(3R)-3·amino-hexahydron-pyridinyl-p-yl]_5_(2_chloro-5·fluoro-benzyl _ 1,3-dimercapto-1,5-dihydro-pyrrolo[3,2-(1]pyrimidine-2,4-dione; 2-({6-[(3R)-3-amino) -3 -Methylhexahydrogen ratio bite_ι·基]4,3. Dimethyl_ 2,4-one oxy-1,2,3,4-tetrahydro-5Η-°Λ D [3,2-d] mouth bite-5-yl} methyl)-4-fluorobenzonitrile; (2S)-l-{[2-(5-mercapto-2-phenyl-oxazole-4- ()ethylamino)-ethylidene}-pyrrolidine-2-carbonitrile; (2S)-1-{[1,1-didecyl-3-(4-° ratio.基-咪. Sodium _ propyl) propylamino]-acetic acid}-D ratio slightly biting-2-carbonitrile; (3,3-difluoropyrrolidin-1-yl)_((2S,4S -4-(4-(pyrimidin-2-yl)hexahydropyrazin-1-yl)pyrrolidin-2-yl)anthone; (2S,4S)-l-[(2S)-2.Amino- 3,3-bis(4-fluorophenyl)propanyl]_4_ gas pyrrolidine-2-carbonitrile; (2S,5R)-5-ethynyl-1-{Ν-(4-mercapto-helium Anal carboxy-pyridine-2-yl) hexahydro-ratio -4-amino)glycine fluorenyl}. Than a little bite _2_A guess; and (lS,6R)-3-{[3-(diI decyl)-5,6-dihydro[1,2,4]triazolo[4,3_ a Pyridazine-7(8H)-yl]carbonyl}-6-(2,4,5-trifluorophenyl)cyclohexa-3-enamine. 36. A DPP-IV inhibitor for use in combination with a compound of claim i for the treatment of a condition which is ameliorated by increasing the concentration of blood GLP-i in a mammal. 37_ The DPP-IV inhibitor of claim 36, wherein the amount of the Dpp_IV inhibitor alone 149380.doc •15·201105327 is improved for the treatment of the blood of the animal by increasing the number of squirting The condition is ineffective. 38. The DPP_IV of claim 36 or 37 inhibits the fasting of P ^ ^ μ 8. The condition improved by increasing the concentration of blood GLP-ί is selected from the group consisting of: diabetes, type 2 diabetes, type 2 broadcast, 5 • diabetes Insufficient glucose tolerance, impaired glucose tolerance, 姨岛^ and Shimao resistance, 咼 咼 咼 、, hyperlipidemia, hypertriglyceridemia, cholelithiasis, dyslipidemia, atherosclerosis Sclerotherapy, stroke, X syndrome ▲ ▲ group, sputum blood pressure, pancreatic β cell deficiency, enteroendocrine cells are not dragon, her Ρ I + 疋, urinary tract, metabolic acidosis, cataract, diabetic nephropathy, diabetic neuropathy Peripheral neuropathy, diabetic coronary artery disease, diabetic cerebrovascular disease, diabetes, peripheral Jk tube disease, diabetic retinopathy, metabolic syndrome, diabetes-related conditions, myocardial infarction, learning disabilities, memory disorders, neurodegenerative disorders , neurodegenerative disorders, excitatory brain damage caused by severe seizures, Alzheimer's disease, Parkinson's disease Disease, diseases associated with Prian, stroke, motor sputum, traumatic brain injury, spinal cord injury and obesity. 39. The DPP-ΐν inhibitor of claim 36 or 37, wherein the condition is type 2 urinary disease. The DpiMV inhibitor according to any one of the items 36 to 39, wherein the DPP-IV inhibitor is selected from the group consisting of the following compounds and pharmaceutically acceptable salts, solvates and hydrates thereof: 3(R)- Amino-1_[3_(tri-indolyl)_5,6,7,8 tetraarzolo[4,3-a].嘻7_基__4_(2,4,5-trifluorophenyl)butanone; 149380.doc •16, 201105327 lJ2-(3-hydroxyadamantan-1-ylamino)ethylidene] Pyrrolidine-2(S)-carbonitrile; (lS,3S,5S)-2-[2(S)-amino-2-(3-hydroxydong-1-yl)ethenyl]-2 - azabicyclo[3·1·0]hexane-3-indene nitrile; 2-[6-[3(R)-amino hexahydro. Bis-1-yl]_3_fluorenyl 2,4-di-oxy-1,2,3,4-tetrahydropyrimidin-1-ylindenyl]benzonitrile; 8-[3(R)- Amino hexahydrooxazin-1-yl]-7-(2-butynyl)-3-methyl-1-(4-methylquinazolin-2-ylindenyl)xanthine; 1 -[ N-[3(R)-»pyrrolidyl]glycidyl]anthrolidine-2(R)-ylboronic acid; 4(S)-fluoro-l-[2-[(lR,3S)- 3-(lH-l,2,4-tris.-1-ylindolyl)cyclopentylamino]ethinyl]npyrrolidine-2(S)-carbonitrile; l-[(2S, 3S,llbS)-2-amino-9,10-dimethoxy-2,3,4,6,7,llb_hexahydro-1H-pyrido[2,la]isoquinolin-3-yl] -4(S)-(fluoromethyl)pyrrolidin-2-one; (2S,4S)-2-cyano-4-ran-1-[(2-yl-l-i-diyl) Ethylamino]ethyl hydrazide ° bit each; 8-(cis-hexahydro-pyrrolo[3,2-b]pyrrole·ι·yl)-3 -mercapto-7-(3-A -but-2-enyl)-1-(2-o-oxy-2-phenylethyl)-3,7-dihydro-indole-2,6-dione; 1-((38,48 )-4-amino-1-(4-(3,3-difluoro 1&gt; piroxicam-1_yl)-1,3,5-triazin-2-yl)pyrrolidin-3-yl) -5,5 difluorohexahydropyridin-2-one; (foot)-2-((6-(3-aminohexahydro-1)-pyridin-1-yl)_3-methyl-2,4-di Sideoxy-3,4- Dihydropyrimidine-i(2H)-yl)methyl)-4-fluorobenzonitrile; 5-{(S)_2-[2-((S)-2-cyano-.pyrrolidine small base 2 - sideoxy-ethyl 149380.doc -17- 201105327 Amino]-propyl}-5·(1Η-tetrazol-5-yl)10,11-dihydro·5Η_dibenzo[a,d Cycloheptene-2,8-didecanoic acid bis-didecyl decylamine; ((2S'4S)_4-(4-(3-mercapto-1-phenyl-IH-nb azole-5) ) hexahydro 0 to 嗓 _ 1-yl) 0 〇 each bite-2-yl) (tetrahydro) plug. sit _3_ base) brewing I; (23.48) -1-[2-[(4- Ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]ethynyl]-4-fluoronpyrrolidine-2-carbonitrile; 6-[(3R)-3-amino- Hexahydro"pyridinyl-indole-yl]-5-(2-gas-5-fluoro-]benzyl 1,3-dimethyl-1,5-dihydro-pyrrolo[3,2-d]pyrimidine-2 , 4-dione; 2-({6-[(3R)-3-amino-3-indolylhexahydro 0-biten-1-yl]_ι,3-didecyl _ 2,4_ two side Oxy-1,2,3,4-tetrahydro-:5H-pyrido[3,2-d]bitat-5-yl} fluorenyl-4-fluorobenzonitrile; (2S)-l- {[2_(5-Mercapto-2-phenyloxazolyl-4-yl)-ethylamino]-ethenyl}-pyrrolidine-2-carbonitrile; (2S)-1-{[1 , 1-dimethyl-3-(4-0 is more than -3-yl-m-O-O-l-l-yl)-propylamino]-ethenyl}-. Than a little bit of chitocarbonitrile; (3,3-difluoropyrane ratio quot&quot;dine-1-yl)-((2S,4S)-4-(4-(. 密-2) hexahydro嗓-1-yl) ° ratio of each pyridin-2-yl) fluorenone; (23.48) -1-[(28)-2-amino-3,3-bis(4-fluorophenyl)propene醯基]_4-fluoropyrrolidine-2-indene nitrile; (2S,5R)-5-ethylidene-1-{Ν-(4-methyl_ι_(4-slow-base_0 than bite_2- Hexyl. Hexahydrogenate is more than a bit of chiral-2-ylcarbamate; and (1 S,6R)-3-{[3-(trimethylsulfonyl)-5 ,6-Dihydro[ι,2,4]triterpenoid[4,3-a]0-pyridin-7(8Η)-yl]carbonyl}-6-(2,4,5-trifluorophenyl Cyclohexyl-3-ene-amine. 149380.doc -18- 201105327 41. A kit of parts comprising a compound of claim i and a Dpp iv inhibitor as a combined preparation for treating diabetes or a condition associated therewith. 42. The kit of claim 41, wherein the compound and the inhibitor are mixed with the same or different pharmaceutically acceptable carrier. 43. The dual kit of claim 41, wherein the compound and the Dpp_iv inhibitor are combined with a different pharmaceutically acceptable carrier. 44. The dual kit of claim 43, wherein the different pharmaceutically acceptable carriers are suitable for administration by different routes. 45. The dual kit of any one of claims 41 to 44, wherein the condition associated with diabetes is selected from the group consisting of hyperglycemia, impaired glucose tolerance, resistance to sputum, and deficiency of parotid beta cells Intestinal endocrine cell deficiency, diabetes, metabolic acidosis, cataract, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic coronary artery disease, diabetic cerebrovascular disease, diabetic peripheral vascular disease, metabolic syndrome, Hyperlipidemia, atherosclerosis, stroke, hypertension, and obesity. 46. The dual kit of any one of claims 41 to 45, wherein the 〇1&gt;1)_1¥ inhibitor is selected from the group consisting of the following compounds and pharmaceutically acceptable salts, solvates and hydrates thereof: 3 ( R)-Amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine_7· ]]_4_(2,4,5-trifluorophenyl)butan-1-one; hydroxyadamantylamino)ethinyl]pyrrolidine_2(s)-indeneonitrile; (lS,3S,5S) -2-[2(S)-amino 2-(3-hydroxyadamantane-yl)acetamidine 149380.doc •19·201105327 base]-2-azabicyclo[3.1.0] -3-phthalonitrile; 2-[6-[3(R)-aminohexahydropyridyl]_3_methyl-2,4-dioxy-1,2,3,4-tetrahydropyrimidine- 1-ylindenyl]benzonitrile; 8-[3(R)-aminohexahydropyridin-1yl]_7_(2-butynyl)_3_methyl, ^(4-methylquinazoline-2 -ylmethyl)xanthine; l-[N-[3(R)-°pyridinyl]glycine]pyrazole 2(r)-ylboronic acid; 4(S)-fluoro-1 -[2-[(111,38)-3-(111-1,2,4-triazol-1-ylindenyl)cyclopentylamino]ethenyl]. Bilobidine-2(S)-carbonitrile; l-[(2S,3S,llbS)-2-amino-9,10-dimethoxy 2,3,4,6,7,llb- Hydrogen-1H-. Bis-[2,la]isoquinolin-3-yl]-4(S)-(fluoromethyl)pyrrolidin-2-one; (2S,4S)-2-cyano-4 - gas-l -[(2-transyl-l,i-dimethyl)ethylamino] ethyl ketone ° bit each bit; 8-(cis-hexahydro-. than B each [3,2-b嘻-1-yl)-3 -mercapto-7-(3-indolyl-but-2-yl)-1-(2-oxo-2-phenylethyl)-3, 7-Dihydrogen ticket. _ 2,6-dione; 1-((38,48)-4-amino-1-(4-(3,3-di-f.) 〇略〇-1_yl)_1,3,5 -tripa-2-yl)β-pyridyl-3-yl)-5,5 difluorohexahydropyridin-2-one; (R)-2-((6-(3-aminohexahydropyridine)- 1·yl)-3-mercapto-2,4-di-oxy-3,4-dihydro-β-densyl.-1 (2Η)-yl)indenyl)-4-1 benzyl nitrile; 5-{ (S)-2-[2-((S)-2-cyanopyridin-1-yl)-2-oxo-ethylamino]-propyl}-5-(1Η-® ° Sodium-5-yl)10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2,8-dicarboxylic acid bis-didecyl decylamine; ((2S,4S)-4- (4-(3-Methyl-buphenyl-1H-.bazol-5-yl)hexahydropyridazine- I49380.doc -20- 201105327 1-yl)pyrrolidin-2-yl)(tetrahydrothiazole (3S,4S)-H2-[(4-ethoxycyclobicyclo[2 2 2]octyl)amino]ethinyl]-4-fluoropyrrolidine-2- Nitrile; 6_[(3R)_3_Amino. Hexahydroquinone]•Base]·5_(2ϋFluoro)=1.3-Dimethyl-1,5-dihydro-pyrrolo[3,2-d] Pyrimidine·2,4-dione. 2-({6-[(3R)-3.Amino-3-methylhexahydro 0-bite small base]13-dimethyl-2.4-di-oxy- 1,2,3'4-tetrahydro·5Η-. The ratio of η is [3,2_d b. _5_ base} -4-fluorobenzonitrile; phenyl _^|yl)-ethylamino]-ethylidene}-pyrrolidine-2-carbonitrile; (2S)-l-{[l, lc methyl- 3-(4_〇 ratio. 定_3_基_imidazole small group) propylamino]-ethenyl}-pyrrolidine-2-indene nitrile; (3,3-difluoropyrrolidin-1-yl H(2S,4S)-4-(4-(pyrimidin-2-yl)hexahydropyrazin-1-yl)pyrrolidin-2-yl)methanone; (28,48)-1-[(25)- 2-Amino-3,3-bis(4-fluorophenyl)propanyl]_4_fluoropyrrolidine-2-indene nitrile; (2S,5R)-5-ethynyl-1-{Ν-(4 - mercapto-1-(4-fluorenyl-0 to bit_2_yl) hexahydropyridin-4-yl)glycidyl}pyrrolidine-2-carbonitrile; and (1 S,6R)-3 -{[3-(trimethylsulfonyl)-5,6-dihydro[ι,2,4]triazino[4 3· a]°pyrazine-7(8H)-yl]carbonyl}-6- (2,4,5-Trifluorophenyl)cyclohexyl-3-ene oxide. 47. A kit comprising (a) a first package containing the request item! A compound or a pharmaceutical composition thereof&apos; and (b) a second pack comprising an inhibitor or a pharmaceutical composition thereof. 129380.doc • 21 201105327 48. The kit of claim 47, wherein the 〇ρρ·Ιν inhibitor is selected from the group consisting of the following compounds and pharmaceutically acceptable salts, solvates and hydrates thereof: 3(R)-amine Trifluoroindolyl)_5,6,7,8-tetrahydro[U4]triazolo[4,3-a]pyrazine·7-yl]-4_(2,4,5-trifluorophenyl) Butanone; 1 [2-(3 - via fund just calcined _ 1 _ylamino)ethyl). Ratio η each bite _2(s)_carbonitrile; (lS,3S,5S)-2-[2(S)-amino-2-(3-hydroxydone-1-yl)ethenyl] 2-Azabicyclo[3.1.oxime]hexane_3_carbonitrile; 2-[6-[3(R)-aminohexahydro. Bis-i-yl]_3_mercapto-2,4_di-oxyl-1,2,3,4-tetrahydropyrimidine-indole-yl fluorenyl; j-benzonitrile; 8-[3(R) -amino hexaazin-1-yl]-7-(2-butynyl)-3-methyl-1-(4-mercaptoquinazolin-2-ylindenyl) xanthine; 1-[ N-[3(R)-. Bilo bite] glycine aryl] η than bite _2 (r) _ base acid; 4 (S)-fluoro-1-[2-[(111,3 8)-3-(111-1 , 2,4-triazol-1-ylindenyl)cyclopentylamino]ethinyl]-r-pyridine-2-(S)-phthalonitrile; 1-[(28,3 3,1153)-2- Amino-9,10-dimethoxy-2,3,4,6,7,1113-hexahydro-1H-. Bis-[2,l-a]isoquinolin-3-yl]-4(S)-(fluoroindolyl). Bilobidine-2·one; (2S,4S)-2-cyano-4-fluoro-l-[(2-hydroxy-1,1-diindenyl)ethylamino]acetic acid. each. 8-(cis-hexahydro-pyrrolo[3,2-b]pyrrol-1-yl)-3-methyl-7-(3-indolyl-but-2-enyl)-1- (2-Sideoxy-2-phenylethyl)-3,7-dihydro-indole-2,6-dione; l-((3S,4S)-4-amino-1-(4- (3,3-difluoropyrrolidine-1,yl)-1,3,5- 149380.doc -22- 201105327 triazin-2-yl)pyrrolidin-3-yl)_5,5 difluorohexahydropyridine _2 ketone; (R)-2-((6-(3-aminohexahydropyridyl)-yl)- 2,2-di-oxy-3,4-dihydropyrimidin-1 ( 2H)-yl)methyl)_4_fluorobenzonitrile; 5-{(S)-2-[2-((S)-2-cyano-.pyrrolidine-丨-yl)·2_side oxygen —ethylamino]-propyl}-5-(1Η-tetrazole-5-yl) 1011_dihydro·5Ηdibenzo[a,d]cycloheptene-2,8-dicarboxylic acid double _ Dimethyl decylamine; ((2S,4S)-4-(4-(3-methylphenyl_ιη-. 〇 -5-5-yl) hexahydro 1·0 0 _ 1-yl)0 (0S,4S)-l-[2-[(4·ethoxycarbonylbicyclo[2 2 2] octyl) Q-amino)amino]ethinyl]-4-fluoropyrrolidine-2-carbonitrile; 6-[(3R)-3-amino-hexahydropyridine-purinyl]-5·(2-chloro-5) _Fluorobenzyl)_1,3-dimethyl-1,5-dihydro-pyrrolo[3,2-d] Pyridine-2,4-dione; 2-({6-[(3R)-3-amino-3-methylhexahydro-β ratio. s-yl]-13-dimethyl-2,4-. Side oxy-1,2,3,4 -four winds - 弁[3,2-d]^ff定-5-yl} methyl)-4 - gas knot guess, (2S)-l-{[ 2-(5-Methyl-2-phenyloxa)-ethyl-4-yl)-ethylamino]-ethenyl}-pyrrolidine-2-carbonitrile; (2S)-1-{[1 , 1-dimethyl-3-(4-indolepyrimidin-3-yl-mouth-sodium-1-yl)-propylamino]-ethenyl}-pyrrolidine-2-indoleonitrile; 3,3-:^Dtb^°^-lS)-((2S,4S)-4-(4-(^^-2S)AiL 0 is 0-0-1 -base) 0 to 0 each bite-2- (2S,4S)-l-[(2S)-2-amino-3,3-bis(4-fluorophenyl)propanyl]-4-fluoropyrrolidine-2-carbonitrile (2S,5R)-5-ethynyl-1-{Ν-(4-methyl-1-(4-carboxy-pyridin-2-yl) 149380.doc •23· 201105327 Hexahydropyridin-4-yl Glycosyl thiol"pyrrolidin-2-indene nitrile; and (13,611)-3-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[ 4,3-a]. Bis-7-(8H)-yl]carbonyl}-6-(2,4,5-trifluorophenyl)cyclohex-3-en-1-amine 0 149380.doc .24-