EA040124B1 - GPR119 RECEPTOR MODULATORS AND THE TREATMENT OF RELATED DISORDERS - Google Patents

Description

The field of technology to which the invention belongs

The present invention relates to GPR119 receptor agonists:

-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4ylamino) -N,N-dimethylbenzamide;

-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4ylamino) -N-methylbenzamide and

-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4ylamino) benzamide and their pharmaceutically acceptable salts, solvates and hydrates, which may be useful as a single pharmaceutical agent or in combination with one or more additional pharmaceutical agents such as a DPP-IV inhibitor, a biguanide, an alpha-glucosidase inhibitor, an insulin analog, a sulfonylurea, an SGLT2 inhibitor, meglitinide, a thiazolidinedione, or an antidiabetic peptide analog, in the treatment of, for example, a disorder selected from a GPR119 receptor-associated disorder; a condition ameliorated by increased incretin secretion; a condition improved by increasing the level of incretin in the blood; a condition characterized by low bone mass; neurological disorder; metabolic-related disorder; type 2 diabetes; obesity and related complications.

State of the art

A. Diabetes mellitus.

Diabetes is a serious disease that affects more than 100 million people worldwide. There are more than 12 million people with diabetes in the United States, with 600,000 new cases diagnosed each year.

Diabetes mellitus is a diagnostic term for a group of disorders characterized by abnormal glucose homeostasis, resulting in elevated blood sugar levels. There are many types of diabetes, but the two most common are type 1 (also known as non-insulin dependent diabetes mellitus or IDDM) and type 2 (also known as non-insulin dependent diabetes mellitus or NIDDM).

The etiology of the different types of diabetes is not the same, but everyone with diabetes has two things in common: overproduction of glucose in the liver and little or no ability for glucose to move from the blood to the cells, where it becomes the body's main fuel.

People who do not have diabetes rely on insulin, a hormone produced in the pancreas, to move glucose from the blood into the body's cells. On the other hand, people who are diabetic or who do not produce insulin or cannot effectively use the one they produce; so they can't move glucose into their cells. Glucose builds up in the blood, creating a condition called hyperglycemia, and over time can lead to serious health problems.

Diabetes mellitus is a syndrome with interrelated metabolic, vascular and neuropathic components. The metabolic syndrome, usually characterized by hyperglycemia, includes changes in carbohydrate, fat, and protein metabolism caused by absent or markedly reduced insulin secretion and/or ineffective insulin action. Vascular syndrome consists of disorders in the blood vessels, which leads to cardiovascular, retinal and renal complications. Disorders in the work of the peripheral and autonomic nervous system are also part of the syndrome of diabetes mellitus.

Approximately 5 to 10% of people who have diabetes have IDDM. These people do not produce insulin, and therefore insulin must be administered to maintain normal blood glucose levels. IDDM is characterized by low or undetectable levels of endogenous insulin production caused by the destruction of insulin-producing pancreatic beta cells, a characteristic that most easily distinguishes IDDM from NIDDM. IDDM, once called juvenile diabetes, affects young and old alike.

Approximately 90 to 95% of people with diabetes have NIDDM (type 2). Subjects with NIDDM produce insulin, but the cells in their bodies are insulin resistant: the cells do not respond properly to the hormone, so glucose builds up in their blood. NIDDM is characterized by a relative mismatch between endogenous insulin production and insulin demand, resulting in elevated blood glucose levels. Unlike IDDM, NIDDM always produces some endogenous insulin, many NIDDM patients have normal or even elevated blood insulin levels, while other NIDDM patients have insufficient insulin production (Rotwein, R. et al., N (Engl. J. Med. 308, 65-71 (1983)). Most people diagnosed with NIDDM are aged 30 or older, and half of all new cases are aged 55 or older. Comparing whites and Asians, NIDDM is more common among Native Americans, African Americans, Hispanics, and Hispanics. In addition, onset may be insidious or even clinically asymptomatic, making diagnosis difficult.

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The initial pathogenic change in NIDDM remains unclear. Many believed that initial insulin resistance in peripheral tissues was the initial factor. Genetic epidemiological studies have supported this view. Similarly, disturbances in insulin secretion were indicative of the original disturbance in NIDDM. It is likely that both of these phenomena play an important role in the disease process (Rimoin, DL, et al., Emery and Rimoin's Principles and Practice of Medical Genetics ^3rd Ed. 1:1401-1402 (1996)).

Many people with NIDDM are sedentary and obese: they weigh about 20% more than the recommended weight for their height and build. In addition, obesity is characterized by hyperinsulinemia and insulin resistance, a common feature in association with NIDDM, hypertension, and atherosclerosis.

In patients with diabetes, life expectancy is reduced by 30%. After age 45, people with diabetes are about three times more likely than people without diabetes to develop significant heart disease and up to five times their risk of stroke. These results highlight the relationship between risk factors for NIDDM and coronary heart disease and the potential value of an integrated approach for the prevention of these conditions (Perry, I.J., et al., BMJ, 310, 560-564 (1995)).

Diabetes has also been directly linked to the development of kidney disease, eye disease, and nervous system problems. Kidney disease, also called nephropathy, occurs when the filtering mechanism of the kidney is damaged and excess protein enters the urine and eventually the kidneys fail. Diabetes is also a major cause of damage to the retina at the back of the eye and increases the risk of developing cataracts and glaucoma. Finally, diabetes is associated with nerve damage, especially in the legs and feet, which affects the ability to feel pain and leads to serious infections. Taken together, the complications of diabetes are one of the leading causes of death in a nation.

B. Obesity.

Obesity and diabetes are among the most common human health problems in industrialized societies. In industrialized countries, a third of the population is at least 20% overweight. In the United States, the percentage of obese people increased from 25% in the late 1970s to 33% in the early 1990s. Obesity is one of the most important risk factors for NIDDM. Definitions of obesity vary, but in general, an object weighing at least 20% more than the recommended weight for his/her height and build is considered obese. The risk of developing NIDDM is tripled in subjects 30% overweight, and three-quarters of those with NIDDM are overweight.

Obesity, which is the result of an imbalance between calorie intake and energy expenditure, is closely correlated with insulin resistance and diabetes mellitus in experimental animals and humans. However, the molecular mechanisms that are associated with obesity and diabetes mellitus syndromes remain unclear. During the early development of obesity, increased insulin secretion counterbalances insulin resistance and protects patients from hyperglycemia (Le Stunff, et al., Diabetes, 43, 696-702 (1989)). However, after several decades, β-cell function deteriorates and insulin-dependent diabetes mellitus develops in approximately 20% of the obese population (Pederson, P. Diab. Metab. Rev. 5, 505-509 (1989) and Brancati, F. L., et al., Arch Intern Med 159, 957-963 (1999)). Given the high prevalence in today's society, obesity thus becomes a major risk factor for NIDDM (Hill, J.O., et al., Science, 280, 1371-1374 (1998)). However, the factors that predispose some patients to alter insulin secretion in response to fat accumulation remain unknown.

Whether someone is classified as overweight or obese can be determined in a number of different ways, such as by their body mass index (BMI), which is calculated by dividing body weight (kg) by height squared ( ^m2 ). Thus, the units of BMI are kg/m ² and it is possible to calculate the range of BMI associated with the minimum mortality in each decade of life. Overweight is defined as a BMI in the range of 25-30 kg/m ² and obesity as a BMI over 30 kg/m ² (see table below). There are problems with this definition, for example it does not take into account the proportion of body mass that is muscle in relation to fat (adipose tissue). To explain this, alternatively, obesity can be defined on the basis of body fat content: more than 25 and 30% in men and women, respectively.

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Weight classification using body mass index

As BMI increases, there is an increased risk of death from various causes that are independent of other risk factors. The most common diseases associated with obesity are cardiovascular disease (particularly hypertension), diabetes mellitus (obesity exacerbates the development of diabetes mellitus), gallbladder disease (particularly cancer), and diseases of the reproductive system. The study showed that even modest weight loss can correspond to a significant reduction in the risk of coronary heart disease.

Obesity also significantly increases the risk of developing cardiovascular disease. Coronary insufficiency, atheromatous disease and heart failure are the main cardiovascular complications caused by obesity. It is believed that if the entire population had an ideal weight, the risk of coronary insufficiency would decrease by 25%, and the risk of heart failure and acute cerebrovascular accident by 35%. The incidence of coronary heart disease doubles in subjects less than 50 years of age who are 30% overweight.

C. Atherosclerosis.

Atherosclerosis is a complex disease characterized by inflammation, lipid accumulation, cell death, and fibrosis. Atherosclerosis is characterized by the deposition of cholesterol and infiltration of monocytes into the subendothelial space, resulting in the formation of xanthoma (foam) cells. Thrombosis after atherosclerosis leads 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 is a disabling disease characterized by bone loss and microarchitectural destruction of the skeletal structure, resulting in impaired bone strength that predisposes the patient to an increased risk of osteoporotic fractures. Osteoporosis affects more than 75 million people in Europe, Japan and the United States and causes more than 2.3 million fractures in Europe and the United States separately. In the United States, osteoporosis affects at least 25% of all white postmenopausal women, and the proportion rises to 70% in women over 80 years of age. One in three women over the age of 50 will have an osteoporotic fracture, which causes a significant social and financial burden on society. The disease is not limited to women; older men may also be affected. By 2050, worldwide, the incidence of hip fracture is projected to increase by 310% in men and 240% in women. The combined lifetime risk of hip, forearm, and spinal fracture present clinically is approximately 40%, which is equivalent to the risk of cardiovascular disease. Osteoporotic fractures therefore cause significant mortality, morbidity and economic costs. As the population ages, the number and cost of osteoporotic fractures will at least double in the next 50 years until effective preventive strategies are developed (See, for example, Atik et al., Clin. Orthop. Relat. Res. (2006), 443:19-24; Raisz, J. Clin. Invest. (2005), 115:3318-3325; and World Health Organization Technical Report Series, 921 (2003), Prevention and Management of Osteoporosis).

E. Inflammatory bowel disease (IBD).

Inflammatory bowel disease is a general name for diseases that cause inflammation in the intestines and includes, for example, Crohn's disease, ulcerative colitis, and ulcerative proctitis. In the United States, the cost of treating inflammatory bowel disease in 1990 was estimated to be between $1.4 billion and $1.8 billion. The decline in productivity was estimated to add an additional $0.4 to $0.8 billion, bringing the expected cost of treating inflammatory bowel disease to $1.8 to $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).

Enteritis refers to inflammation of the intestines, in particular the small intestine, the general condition of which can have any of a variety of different causes. Enterocolitis refers to inflammation

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Crohn's disease (CD) is an inflammatory process that can affect any part of the gastrointestinal tract, but is most commonly seen in the last part of the small intestine, otherwise known as the (terminal) ileum and caecum. In general, this area is also known as the ileocecal region. In other cases, it may affect one or more of: the colon only, the small intestine only (duodenum, jejunum, and/or ileum), anus, stomach, or esophagus. Unlike ulcerative colitis, CD usually does not affect the rectum, but often affects the anus instead. Inflammation spreads deep into the mucous membrane of the affected organ. Inflammation can cause pain and can often clear the intestines, leading to diarrhea. CD can also be called enteritis. Granulomatous colitis is another name for CD that affects the colon. Ileitis is CD of the ileum, which is the third part of the small intestine. Crohn's colitis is CD that affects all or part of the colon.

Ulcerative colitis (UC) is an inflammatory disease of the large intestine, commonly referred to as the colon. UC causes inflammation and ulceration of the inner lining of the colon and rectum. Inflammation of UC tends to be most severe in the rectal region, with a decrease in severity (at a rate that varies from patient to patient) towards the caecum, where the large and small intestines come together. Inflammation of the rectum is called proctitis. Inflammation of the sigmoid colon (located just above the rectum) is called sigmoiditis. Inflammation that involves the entire large intestine is called pancolitis. The inflammation causes the colon to empty, often resulting in diarrhea. As the lining of the colon breaks down, ulcers produce mucus, pus, and blood. Ulcerative proctitis is a form of UC that only affects the rectum.

F. GPR119.

GPR119 is a G protein coupled receptor (GPR119, eg human GPR119, GenBank® Accession No. AAP72125 and alleles thereof; eg murine GPR119, GenBank® Accession No. AY288423 and alleles thereof) and is selectively expressed on pancreatic beta cells. Activation of GPR119 leads to an increase in intracellular cAMP, consistent with GPR119 coupled to Gs. GPR119 agonists stimulate glucose-dependent insulin secretion in vitro and reduce elevated blood glucose levels in vivo, see for example International Patent Applications WO 04/065380 and WO 04/076413 and EP 1338651. international patent application WO 00/31258) and as a glucose-dependent insulinotropic receptor GDIR (see Jones, et al., Expert 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):13391359); for specific references related to GPR119 agonists and release: 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 mentioned above, GPR119 agonists increase incretin release and therefore can be used in the treatment of incretin related disorders such as GIP, GLP-1 and PYY. However, a number of incretins, such as GIP and GLP-1, are substrates for the dipeptidyl peptidase-4 (DPP-IV) enzyme. Jones and colleagues (Jones, et al., Ann. Rep. Med. Chem., (2009), 44:149-170) demonstrated that the combined administration of a GPR119 agonist, (2-fluoro-4-methanesulfonylphenyl)-{6 -[4-(3-isopropyl[1,2,4]oxadiazol-5-yl)piperidin-1-yl]-5-nitropyrimidin-4-yl}amine (see Compound B111 in WO 2004/065380) and an inhibitor DPP-IV dramatically increased plasma GLP-1 levels and improved glucose tolerance to a much greater extent than either agent alone.

G. Glucose-dependent insulinotropic polypeptide (GIP).

Glucose-dependent insulinotropic polypeptide, also known as gastroinhibitory polypeptide), is a 42 amino acid peptide incretin hormone that is released from duodenal endocrine K cells after ingestion. The amount of GIP released is largely dependent on the amount of glucose consumed. GIP has been shown to stimulate glucose-dependent insulin secretion in pancreatic beta cells. GIP mediates its actions through a specific G-protein coupled receptor, namely GIPR.

Since GIP contains an alanine in the 2-position, it is an excellent substrate for the DPP-IV enzyme that regulates the degradation of GIP. The full-length GIP (1-42) is rapidly converted to the bioinactive GIP (3-42) within minutes of secretion from the endocrine K cell. Inhibition of DPP-IV has been shown to increase the biological activity of GIP. (See, for example,

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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). Analysis of full-length biologically active GIP, for example in blood, can be performed using N-terminal specific assays (see, for example, Deacon et al., J. Clin. Endocrinol. Metab. (2000), 85:3575-3581).

GIP has recently been shown to promote bone formation. GIP has been shown to activate osteoblastic receptors, resulting in increased collagen type I synthesis and alkaline phosphatase activity, both associated with bone formation. GIP has been shown to inhibit osteoclast activity and differentiation in vitro. HIP administration has been shown to prevent bone loss due to oophorectomy. GIP receptor (GIPR) knockout mice confirmed reduced bone size, reduced bone mass, altered bone microarchitecture and biochemical properties, and altered bone remodeling parameters, especially in bone formation. (See, for example, 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 suitability of HIP for maintaining or increasing bone density or formation has been recognized by the US Patent and Trademark Office with US Patent No. 6,410,508 for the treatment of low bone mineralization by administering a GIP peptide. However, at present, GIP peptide agonists have insufficient oral bioavailability and negatively affect patient compliance with the regimen and treatment regimen. An effective alternative approach is to develop an orally active composition to increase the endogenous level of GIP activity.

GPR119 agonists have been shown to stimulate GIP release, see Shah, Current Opinion in Drug Discovery & Development, (2009), 12:519-532; Jones, et al., Ann. Rep. Med. Chem., (2009), 44:149170; WO 2007/120689 and WO 2007/120702.

H. Glucagon-like peptide-1 (GLP-1).

Glucagon-like peptide-1 is an incretin hormone derived from the post-translational modification of proglucagon and secreted by intestinal endocrine cells. GLP-1 mediates its actions through a specific G-protein coupled receptor (GPCR), namely GLP-IR. GLP-1 is best described as a hormone that regulates glucose homeostasis. GLP-1 has been shown to stimulate glucose-dependent insulin secretion and increase pancreatic beta cell mass. GLP-1 has also been shown to decrease the rate of gastric emptying and promote satiety. The efficacy of GLP-1 peptide agonists in controlling blood glucose levels in type 2 diabetic patients has been demonstrated in a number of clinical studies [see, e.g., Nauck et al., Drug News Perspect (2003), 16:413-422] , as well as its effectiveness in reducing body weight [Zander et al., Lancet (2002), 359:824-830].

GLP-1 receptor agonists are additionally useful in protecting against myocardial infarction and against cognitive and neurodegenerative disorders. GLP-1 has been shown to have a cardioprotective effect in rat models of myocardial infarction [Bose et al., Diabetes (2005), 54:146-151], and GLP-IR has been shown in rodent models to be involved in learning and neuroprotection. [During et al., Nat. Med. (2003), 9:1173-1179 and Greig et al., Ann. NY Acad. sci. (2004), 1035:290-315].

Some disorders, such as type 2 diabetes mellitus, are characterized by GLP-1 deficiency [see, for example, Nauck et al., Diabetes (2004), 53 Suppl. 3:S190-196].

Currently, GLP-1 peptide agonists have insufficient oral bioavailability, negatively affecting efficacy. Efforts to develop orally bioavailable, non-peptidergic, small molecule GLP-IR agonists have so far been unsuccessful (Mentlein, Expert Opin Investig Drugs (2005), 14:57-64). An effective alternative approach is to develop an orally active composition to increase endogenous blood levels of GLP-1.

GPR119 agonists have been shown to stimulate GLP-1 release, 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.

I. Peptide YY (PYY).

Peptide YY is a 36 amino acid peptide originally isolated in 1980 from porcine intestine (Tatemoto et al., Nature (1980), 285:417-418). PYY is secreted from enteroendocrine L-cells in both the large and small intestines. In the intestines of rats and humans, immunoreactive PYY concentrations have been shown to be low in the duodenum and jejunum, high 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., Peptides (2002), 23:251-261; Ueno et al., Regul. Pept. (2008), 145 :12-16). PYY expression in rats has also been reported to extend to alpha cells of the islets of Langerhans and cells in the medulla oblongata (Ekblad et al., Peptides (2002), 23:251-261); PYY is released into the circulation as PYY1-36 and PYY3-36 (Eberlein et al., Peptides (1989) 10:797-803). PYY ₃ - ₃₆ is formed from PYY1-36 by cleavage of the N-terminal residues of TYr and Pro DPP-IV. PYY ₃ - ₃₆ is the predominant form of PYY in human postprandial plasma (Grandt et al., Regul. Pept. (1994), 51:151-159). It was reported that

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PYY _1-36 and PYY3-36 have comparable agonist activities at the NPY Y2 receptor (Y2R), the G-protein coupled receptor (Parker et al., Br. J. Pharmacol. (2008), 153:420-431); however, PYY _3-36 has been reported to have a high affinity for a Y2R selective agonist (Keire et al., Am. J. Physiol. Gastrointest. Liver Physiol. (2000)? 279:G126-G131). Subsequently, PYY was reported to reduce high-fat food intake in rats after peripheral administration (Okada et al., Endocrinology Supplement (1993), 180) and cause weight loss in mice after peripheral administration (Morley et al., Life Sciences (1987 ), 41:2157-2165).

Peripheral administration of PYY _3-36 has been reported to markedly reduce food intake and weight gain in rats, decrease appetite and food intake in humans, and reduce food intake in mice, but not in Y2R-null mice, which were said to be suggestive of the effect of eating requires Y2R. In human studies, _PYY3-36 infusion was found to significantly reduce appetite and reduce food intake by 33% over 24 h. 15 minutes followed by a rapid decline to basal levels over 30 minutes. Significant inhibition of food intake was reported to occur over a 12-hour period following PYY _3-36 infusion, but virtually no effect on food intake was observed between 12 and 24 hours. In a rat study, repeated administration of PYY _3-36 ip twice daily for 7 days) reduced cumulative food intake (Batterham et al., Nature (2002), 418:650-654; Renshaw et al., Current Drug Targets (2005), 6:171-179).

Peripheral administration of PYY _3-36 has been reported to reduce food intake, weight gain, and glycemic indices in various models of metabolic disease in rodents of both sexes (Pittner et al., Int. J. Obes. Relat. Metab. Disord. (2004), 28:963-971). Blockade of Y2R by a certain BIIE-246 antagonist has been reported to attenuate the effect of peripheral administration of endogenous and exogenous PYY _3-36 on reducing food intake (Abbott et al., Brain. Res. (2005), 1043:139-144). Peripheral administration of a new long-acting selective Y2R agonist polyethylene glycol-conjugated peptide has been reported to reduce food intake and improve glucose metabolism (glucose utilization, plasma insulin and plasma glucose) in rodents (Ortiz et al., JPET (2007), 323 :692-700; Lamb et al., J. Med. Chem. (2007) 50:2264-2268). It has been reported that PYY ablation in mice leads to the development of hyperinsulinemia and obesity (Boey et al., Diabetologia (2006), 49:1360-1370). Peripheral administration of a long acting, potent and highly selective Y2R agonist has been reported to inhibit food intake and promote fat metabolism in mice (Balasubramaniam et al., Peptides (2007), 28:235-240).

There is evidence that agents that stimulate PYY synthesis in vivo may confer protection against dietary and genetic obesity and may improve glucose tolerance (Boey et al., Neuropeptides (2008), 42:19-30).

It has been reported that Y2R agonists such as PYY _1-36 and PYY _3-36 can provide protection against epileptic seizures such as kainate seizures (El Bahh et al., Eur. J. Neurosci. (2005), 22:1417 -1430; Woldbye et al., Neurobiology of Disease (2005), 20:760-772).

Y2R agonists such as PYY _1-36 and PYY _3-36 have been reported to act as pro-absorptive (or anti-secretory) hormones, increasing intravenous uptake of both water and sodium in various parts of the intestine (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. 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 secretion and promote absorption and growth in the intestinal epithelium (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 PYY _1-36 and PYY _3-36 have been reported to inhibit intestinal motility and function to prevent diarrhea (EP 1902730; see also Cox, Peptides (2007), 28:345-351).

It has been reported that Y2R agonists such as PYY _1-36 and PYY _3-36 can provide protection against inflammatory bowel diseases such as ulcerative colitis and Crohn's disease (WO 03/105763). PYY-deficient mice have been reported to exhibit an osteopenic phenotype, i. PYY may increase bone mass and/or may provide protection against bone loss (eg, reduce bone loss) (Wortley et al., Gastroenterol. (2007), 133:1534-1543). It has been reported that PYY _3-36 can confer protection in rodent models of pancreatitis (Vona-Davis et al., Peptides (2007), 28:334-338).

Angiogenesis has been reported to be impaired in Y2R-deficient mice (Lee et al., Peptides (2003), 24:99-106), i. Y2R agonists such as PYY _1-36 and PYY _3-36 promote angiogenesis. Wound healing has been reported to be impaired in Y2R-deficient mice (Ekstrand et al., PNAS USA (2003) 100:60336038), ie. Y2R agonists such as PYY _1-36 and PYY _3-36 promote wound healing. Ischemic angiogenesis has been reported to be impaired in Y2R-deficient mice (Lee et al., J. Clin. Invest. (2003), 111:1853-1862), i. Y2R agonists such as PYY _1-36 and PYY ₃ - ₃₆ promote revascularization and restoration of ischemic tissue function. It has been reported that Y2R agonists such as PYY _1-36 and

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PYY ₃ - ₃₆ mediate increases in collateral dependent blood flow in a rat model of peripheral arterial disease (Cruze et al., Peptides (2007), 28:269-280).

It has been reported that PYY and Y2R agonists such as PYY _3-36 can suppress tumor growth in cases of, for example, pancreatic cancer such as pancreatic ductal adenocarcinoma, breast cancer such as infiltrative ductal adenocarcinoma of the breast, colon cancer such as colon adenocarcinoma 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 Y2Rs such as PYY3-36 has been reported to result in increased plasma levels of adiponectin (Ortiz et al., JPET (2007), 323:692-700). Adiponectin is an adipokine with potent anti-inflammatory properties (Ouchi et al., Clin Chim Acta (2007), 380:24-30; Tilg et al., Nat. Rev. Immunol. (2006), 6:772-783). Adiponectin exhibits anti-atherogenic effects by targeting vascular endothelial cells and macrophages, and insulin-sensitizing effects, predominantly in muscle and liver (Kubota et al., J. Biol. Chem. (2002), 277:25863-25866; Maeda et al., Nat Med (2002) 8:731-737). Low levels of adiponectin have been reported to be associated with atherogenic lipoproteins in dyslipidaemia (elevated triglycerides, low LDL cholesterol density, and low HDL cholesterol) (Marso et al., Diabetes Care (2008), 31:989-994). Adiponectin is directly associated with high density lipoprotein (HDL) accumulation (Oku et al., FEBS Letters (2007), 581:5029-5033). Adiponectin has been found to improve metabolic syndrome disorders, including insulin resistance, hyperglycemia, and dyslipidemia, in a mouse model of obesity-associated metabolic syndrome associated with reduced levels of adiponectin (Hara et al., Diabetes Care (2006), 29:1357- 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 via endothelial nitric oxide synthase-dependent mechanisms (Nishimura et al., Circulation (2008), 117:216-223). Adiponectin has been reported to provide protection against ischemic-reperfusion injury of the myocardium (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 ischemia-reperfusion injury of the myocardium via AMP-activated protein kinase, Akt, and nitric oxide (Gonon et al., Cardiovasc Res. (2008), 78:116-122). Adiponectin has been reported to provide protection against the development of systolic dysfunction after myocardial infarction through its ability to suppress cardiac hypertrophy and interstitial fibrosis and protect against myocyte and capillary loss (Shibata et al., J. Mol. Cell Cardiol. (2007), 42:10651074 ). Adiponectin has been reported to provide protection against inflammatory lung disease; adiponectin-deficient mice show an emphysema-like phenotype (Summer et al., Am. J. Physiol. Lung Cell Mol. Physiol (March 7, 2008)). Adiponectin has been reported to provide protection against allergic airway inflammation and airway hypersensitivity, such as may be associated with asthma (Shore et al., J. Allergy Clin. Immunol (2006), 118:389-395). Adiponectin has been suggested to provide protection against pulmonary arterial hypertension due to its insulin sensitizing effects (Hansmann et al., Circulation (2007), 115:1275-1284). Adiponectin has been reported to improve obesity-related hypertension, this improvement in hypertension being due in part to increased prostacyclin expression (Ohashi et al., Hypertension (2006), 47:1108-1116). Adiponectin has been reported to reduce tumor necrosis factor (TNF)-α-induced expression of adhesion molecules VCAM-1, E-selectin and ICAM-1 in human arterial endothelial cells (HAEC) (Ouchi et al., Circulation (1999), 100: 2473-2476) and inhibit the production of TNF-α in macrophages (Yokota et al., Blood (2000) 96:1723-1732). Adiponectin has been reported to provide protection against restenosis after vascular intervention (Matsuda et al., J. Biol. Chem. (2002), 277:37487-37491). The major role of TNF-α in inflammation has been demonstrated by the ability of agents that block the action of TNF-α to treat a range of inflammatory conditions. TNF-a mediated inflammatory conditions include rheumatoid arthritis, inflammatory bowel disease such as Crohn's disease, ankylosing spondylitis, psoriasis, ischemic brain injury, cardiac allograft rejection, asthma, and the like (Bradley, J. Pathol. (2008), 214: 149160). See, for example, 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.

GPR119 agonists have been shown to stimulate the release of PYY; see Schwartz et al., Cell Metabolism, 2010, 11:445-447; and WO 2009/126245.

The essence of the invention

The present invention relates to 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4oxadiazol-5-yl)piperidin-1-yl)pyrimidine -4-ylamino)-N,N-dimethylbenzamide (formula (Ia), compound 1) and its pharmaceutically acceptable salts, solvates and hydrates:

- 7 040124

3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4ylamino )-\-methidebenzamide (formula (Ib), compound 2) and its pharmaceutically acceptable salts, solvates and hydrates:

(la)

(ib); And

3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4ylamino ) benzamide (formula (Ic), compound 3) and its pharmaceutically acceptable salts, solvates and hydrates:

ABOUT

(1c) which bind to and modulate the activity of the GPCR, referred to herein as GPR119, and their applications.

One aspect of the present invention relates to compounds selected from 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5- yl)piperidin-1-yl)pyrimidin-4ylamino)-N,N-dimethylbenzamide (formula (Ia), Compound 1) and pharmaceutically acceptable salts, solvates and hydrates thereof.

One aspect of the present invention relates to compositions containing a compound of the present invention.

One aspect of the present invention relates to compositions containing a compound of the present invention and a pharmaceutically acceptable carrier.

One aspect of the present invention relates to methods for preparing a composition comprising the step of mixing a compound of the present invention and a pharmaceutically acceptable carrier.

One aspect of the present invention relates to pharmaceutical products selected from: pharmaceutical composition, formulation, dosage form, combined preparation, dual pack and kit; containing the compound of the present invention.

One aspect of the present invention relates to compositions containing a compound of the present invention and a second pharmaceutical agent.

One aspect of the present invention relates to methods for preparing a composition comprising the step of mixing a compound of the present invention and a second pharmaceutical agent.

One aspect of the present invention relates to compositions containing a compound of the present invention, a second pharmaceutical agent and a pharmaceutically acceptable carrier.

One aspect of the present invention relates to methods for preparing a composition comprising the step of mixing a compound of the present invention, a second pharmaceutical agent and a pharmaceutically acceptable carrier.

One aspect of the present invention relates to compositions obtained using the method of the present invention.

One aspect of the present invention relates to pharmaceutical products selected from: pharmaceutical composition, formulation, dosage form, combined preparation, dual pack and kit; containing a compound of the present invention and a second pharmaceutical agent.

One aspect of the present invention relates to methods for modulating GPR119 receptor activity comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of the present invention; compositions of the present invention or

- 8 040124 pharmaceutical product according to the present invention.

One aspect of the present invention relates to methods for modulating receptor activity.

GPR119 comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of the present invention; compositions of the present invention or a pharmaceutical product of the present invention.

One aspect of the present invention relates to the use of a compound of the present invention or a composition of the present invention in the manufacture of a medicament for modulating GPR119 receptor activity in a patient.

One aspect of the present invention relates to the compound of the present invention; a composition of the present invention or a pharmaceutical product of the present invention for use in a method of treating a human or animal with therapy.

One aspect of the present invention relates to the compound of the present invention; compositions of the present invention or a pharmaceutical product of the present invention for use in a method for modulating GPR119 receptor activity in a patient.

One aspect of the present invention relates to a pharmaceutical product selected from a pharmaceutical composition, formulation, dosage form, combined preparation, dual pack and kit; containing the compound of the present invention; for use in a method of treating a human or animal with therapy.

One aspect of the present invention relates to a pharmaceutical product selected from a pharmaceutical composition, formulation, dosage form, combined preparation, dual pack and kit; containing the compound of the present invention; for use in a method for modulating GPR119 receptor activity in a patient.

One aspect of the present invention relates to compounds, methods, compositions, uses of the compounds, and pharmaceutical products, each as described herein, in combination with a second pharmaceutical agent. For example, one aspect of the present invention relates to methods for modulating GPR119 receptor activity comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of the present invention in combination with a therapeutically effective amount of a second pharmaceutical agent.

One aspect of the present invention relates to compositions, methods, pharmaceutical products, uses, and compounds, each as described herein, in combination with a second pharmaceutical agent, wherein the second pharmaceutical agent is selected from a DPP-IV inhibitor, a biguanide, an alpha- glucosidase, an insulin analog, a sulfonylurea, an SGLT2 inhibitor, meglitinide, a thiazolidinedione, and an antidiabetic peptide analog.

One aspect of the present invention relates to compounds, methods, compositions, uses of the compounds, and pharmaceutical products, each as described herein, wherein the modulation of GPR119 receptor activity in a patient is GPR119 receptor agonization.

One aspect of the present invention relates to compounds, methods, compositions, uses of the compounds, and pharmaceutical products, each as described herein, wherein the modulation of GPR119 receptor activity in a patient is an increase in incretin secretion.

One aspect of the present invention relates to compounds, methods, compositions, uses of the compounds, and pharmaceutical products, each as described herein, wherein the modulation of GPR119 receptor activity in a patient is an increase in blood incretin levels.

One aspect of the present invention relates to compounds, methods, compositions, uses of the compounds, and pharmaceutical products, each as described herein, wherein modulating GPR119 receptor activity in a patient is a treatment for a disorder, wherein the disorder is selected from GPR119 receptor-associated violations; a condition ameliorated by increased incretin secretion; a condition improved by increasing the level of incretin in the blood; a condition characterized by low bone mass; neurological disorder; metabolic-related disorder; and obesity.

One aspect of the present invention relates to compounds, methods, compositions, uses of the compounds, and pharmaceutical products, each as described herein, wherein the metabolic disorder is type 2 diabetes mellitus.

These and other aspects of the invention disclosed in the present description will be set forth in more detail as the description of the invention continues.

Brief description of the drawings

In FIG. 1 shows the effect of 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5yl)piperidin-1-yl)pyrimidin- 4-ylamino)-K,K-dimethylbenzamide on glucose homeostasis in diabetic male ZDF rats (oral glucose tolerance test (oGTT)).

In FIG. 2 shows the effect of 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-9 040124 yl)piperidine-1- yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide on percent glycemic inhibition in male diabetic ZDF rats.

In FIG. 3 shows the effect of 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5yl)piperidin-1-yl)pyrimidin- 4-ylamino)-N,N-dimethylbenzamide on glucose homeostasis in male mice 129 SVE (oGTT).

In FIG. 4 shows the effect of 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5yl)piperidin-1-yl)pyrimidin- 4-ylamino)-N,N-dimethylbenzamide on percent glycemic inhibition in male 129 SVE mice.

In FIG. 5 shows the in vivo effect of 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol5-yl)piperidin-1-yl) pyrimidin-4-ylamino)-N,N-dimethylbenzamide on the release of the incretin hormone GIP.

In FIG. 6 shows PXRD for the anhydrous form of 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)1,2,4-oxadiazol-5-yl)piperidin-1 - yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide.

In FIG. 7 shows DSC and TGA for the anhydrous form of 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2yl)-1,2,4-oxadiazol-5-yl)piperidin-1 -yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide.

In FIG. 8 shows the DSV for the anhydrous form of 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4oxadiazol-5-yl)piperidin-1-yl )pyrimidin-4-ylamino)-M/M-dimethylbenzamide.

In FIG. 9 shows the formation of the M1 metabolite upon incubation with liver microsomes (mouse, monkey, dog, rat and human).

In FIG. 10 shows the formation of the M2 metabolite upon incubation with liver microsomes (mouse, monkey, dog, rat and human).

In FIG. 11 shows the formation of the M3 metabolite upon incubation with liver microsomes (mouse, monkey, dog, rat and human).

Detailed description of the invention

It should be understood that certain features of the invention, which are described in the context of separate embodiments for clarity, may also be provided in combination in one embodiment. On the other hand, various features of the invention, which for brevity are described in the context of one embodiment, may also be provided separately or in any suitable subcombination. Accordingly, all combinations of uses and medical indications described herein are expressly covered by the present invention, just as if each subcombination of uses and medical indications were separately and explicitly set forth herein.

Definitions

For clarity and consistency, the following definitions will be used throughout this patent document.

As used herein, the term agonist refers to a moiety that interacts with and activates a G protein-coupled receptor, such as the GPR119 receptor, and thus can initiate a physiological or pharmacological response of that receptor. For example, an agonist may activate an intracellular response upon binding to a receptor, or enhance GTP binding to a membrane. The agonist may be a full agonist or a partial agonist.

As used herein, the term antagonist refers to a moiety that competitively binds to a receptor at the same site as an agonist (e.g., an endogenous ligand), but which does not activate the intracellular response initiated by the active form of the receptor, and thus can inhibit intracellular responses. agonist or partial agonist. The antagonist does not attenuate the original intracellular response in the absence of an agonist or partial agonist.

As used herein, the term GPR119 includes the human amino acid sequences found in GenBank accession number AY288416 and their naturally occurring allelic variants, and their mammalian orthologues. A preferred human GPR119 for use in screening and testing compounds of the invention is provided in the nucleotide sequence of SEQ ID NO: 1 and the corresponding amino acid sequence in SEQ ID NO: 2 found in PCT application WO 2005/007647.

The term in need of such treatment and the term in need of it when referring to treatment are used interchangeably and refer to a judgment made by a caregiver (e.g., physician in charge, nurse, paramedic, and the like in the case of a human; veterinarian in the case of animals, including non-human mammals) that the human or animal requires or will benefit from treatment. This conclusion is made based on a number of factors that are within the expertise of the caregiver, but which include information about the patient, or prospective patient, as a result of the disease, condition, or disorder that can be treated with the compounds of the invention. Accordingly, the compounds of the invention may be used for protective or prophylactic purposes; or the compounds of the invention may be used to alleviate, inhibit or mitigate a disease, condition or

- 10 040124 violations.

The term patient refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or primates, and most preferably humans.

The term inverse agonist refers to a moiety that binds to an endogenous form of a receptor or a constitutively activated form of a receptor and which inhibits the initial intracellular response initiated by the active form of the receptor below the normal basal level of activity that occurs in the absence of an agonist or partial agonist, or reduces GTP binding to membrane. Preferably, the initial intracellular response is inhibited in the presence of an inverse agonist by at least 30%, more preferably at least 50% and most preferably at least 75% compared to the initial response in the absence of an inverse agonist.

The term modulate or modulation refers to an increase or decrease in the quantity, quality, response, or effect of a particular activity, function, or molecule.

The term composition refers to a compound, including, but not limited to, a compound of the present invention and its salts, solvates, and hydrates, in combination with at least one additional component.

The term pharmaceutical composition refers to a composition containing at least one active ingredient such as a compound of the present invention; including, but not limited to, a compound of the present invention and its salts, solvates, and hydrates, whereby the composition is useful for treating and/or investigating a specific, effective outcome in mammals (e.g., without limitation, in humans). The person skilled in the art will be able to understand and evaluate the appropriate techniques for determining whether the active ingredient has the desired effective result based on the mandatory requirements of the person skilled in the art.

The term "therapeutically effective amount" refers to the amount of an active compound or pharmaceutical agent that elicits a biological or medical response in tissues, systems, an animal, patient, or human, as sought by a researcher, veterinarian, physician, or other clinician or caregiver, or by a patient that includes one or more of the following:

(1) disease prevention, such as prevention of a disease, condition, or disorder in a patient that may be predisposed to the disease, condition, or disorder, but is not yet experiencing or showing pathology or symptoms of the disease;

(2) inhibition of the disease, eg, inhibition of the disease, condition, or disorder in a patient who is experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder (ie, stopping further development of the pathology and/or symptom); and (3) improving the disease, eg, improving the disease, condition, or disorder in a patient who is experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder (ie, regression of the pathology and/or symptoms).

The term weight management as used herein means controlling body weight and in the context of the present invention is directed to weight loss and maintenance of weight loss (also referred to herein as weight maintenance). In addition to body weight control, weight management includes the control of body weight-related parameters such as BMI, body fat percentage, and waist circumference. For example, weight management for a patient who is overweight or obese may refer to weight loss in order to maintain weight in a healthy range. In addition, for example, weight management for a patient who is overweight or obese may include a reduction in adipose tissue or waist circumference with or without reduction in body weight.

As used herein, maintaining weight loss or maintaining weight includes preventing, reducing, or controlling weight gain after weight loss. It is well known that weight gain often occurs after weight loss. Weight loss can come from, for example, diet, exercise, disease, medication, surgery, or any combination of these, but often a patient who loses weight will regain some or all of the weight lost. Therefore, maintaining weight in a patient who is losing weight may include preventing weight gain after weight loss, reducing the amount of weight gained after weight loss, controlling weight gain after weight loss, or slowing the rate of weight gain after weight loss.

Compounds according to the invention.

One aspect of the present invention provides, in particular, compounds selected from the following compounds and their pharmaceutically acceptable salts, solvates and hydrates:

-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4ylamino) -K,K-dimethylbenzamide;

-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4- 11 040124 ylamino)-K-methylbenzamide and

-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4ylamino) benzamide

One aspect of the present invention provides compounds selected from 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl )piperidin-1-yl)pyrimidin-4ylamino)-N,N-dimethylbenzamide (formula (Ia), Compound 1) and pharmaceutically acceptable salts, solvates and hydrates thereof.

The compounds of the invention may also include tautomeric forms such as ketoenol tautomers and the like. It should be understood that various tautomeric forms are within the scope of the compounds of the present invention.

Compounds of the present invention can be obtained according to the appropriate published literature methods that are used by a person skilled in the art. Typical reagents and procedures for these reactions will be presented later in the working examples. Protection and deprotection can be carried out using techniques well known in the art (see, for example, Greene, T.W. and Wuts, PGM, Protecting Groups in Organic Synthesis, ^3rd Edition, 1999 [Wiley]).

Crystal forms of compound 1.

One aspect of the present invention relates to crystalline forms of 3-fluoro-4-(5-fluoro6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidine- 1-yl)pyrimidin-4-ylamino)-K,Kdimethylbenzamide (formula (Ia), compound 1).

The crystalline forms of compound 1 can be identified by their unique solid state identity relative to, for example, differential scanning calorimetry (DSC), powder x-ray diffraction (PXRD) and other solid state methods.

An additional characteristic regarding the content of water or solvent of crystalline forms can be measured using any of the following methods, for example, thermogravimetric analysis (TGA), DSC and the like.

It is known that for DSC, the observed temperatures will depend on the purity of the sample, the rate of temperature change, as well as the sample preparation technique and the specific instrument used. Thus, the values presented herein relating to DSC thermograms may vary by approximately ±4°C. The values presented herein relating to DSC thermograms may also vary by approximately ±20 J/g.

For PXRD, the relative peak intensities may vary depending on the sample acquisition technique, sample setup technique, and the specific instrument used. In addition, tool changes and other factors can often affect 2θ° values. Therefore, the positions of the peaks of the diffraction patterns can vary by ±0.2° 2θ°.

For TGA, the features described herein may vary by plus or minus approximately 10°C. For TGA, the features described herein may also vary by plus or minus approximately 2% weight change due to, for example, sample change.

Additional characterization regarding the hygroscopicity of crystalline forms can be measured using, for example, dynamic moisture sorption (DSW). Described in the present description, the characteristic features of the DWR can vary by approximately ±5% relative humidity. The DWR features described herein may also vary by approximately ±5% weight change.

Compound 1 (anhydrous form).

One aspect of the present invention relates to the anhydrous form of 3-fluoro-4-(5-fluoro-6-(4-(3(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidine -1 -yl)pyrimidin-4-ylamino)-K,K-dimethylbenzamide (compound 1). The physical properties of the crystalline form of the anhydrous form of compound 1 are summarized in the following table.

- 12 040124

Compound 1 (anhydrous form) PXRD Figure 6: Peaks approximately >9.5% relative intensity at 8.6, 12.2, 13.6, 14.9, 17.5, 18.3, 20, 1, 21.1, 21.9, 24 .2, 24.5, 25, 0, 27.2, 30.5 and 31.0 °2θ TGA Figure 7: Slight weight loss DSC Figure 7: Extrapolated initial temperature: approx. 148.9° C. and enthalpy of fusion 99.5 joules per gram. DSV Figure 8: Less than about 0.35% weight gain at about 90% RH and 25°C.

One aspect of the present invention relates to the anhydrous crystalline form of 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl )piperidin-1-yl)pyrimidin-4ylamino)-N,N-dimethylbenzamide (compound 1), in which the anhydrous crystalline form has an X-ray powder diffraction pattern containing each combination of one or more peaks in units of °2θ selected from the peaks found in following table.

Floor. [°2Θ] cl- parameter [A] Rel. INT. [%] Floor. [°2Θ] d-parameter [A] Rel. INT. [%] 8, 6 10.3 64.4 21.9 4, 1 34.1 8.8 100 4.8 23.7 3, 8 4, 6 12.1 7.3 5, 5 24.2 3.7 17, 1 12.2 7.2 10.1 24.5 3, 6 12.2 13, 6 6, 5 85.8 25.0 3, 6 76.9 14.9 5, 9 13, 8 25, 9 3.4 6, 3 17.2 5, 2 5, 1 27.2 3.3 57.2 17.5 5, 1 20.7 29, 4 thirty 7.3 18.3 4.9 44.5 29, 8 thirty 5, 2 19, 3 4, 6 5, 3 30.5 2.9 9.5 20, 1 4.4 100.0 31.0 2.9 10.5 21.1 4.2 51.0 32.9 2.7 4.4 21.3 4.2 5, 8 38.3 2.3 50

One aspect of the present invention relates to an anhydrous crystalline form of 3-fluoro-4(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl) piperidin-1-yl)pyrimidin-4-ylamino)-N,Ndimethylbenzamide, in which the anhydrous crystalline form has an X-ray powder diffraction pattern containing a peak in 2Θ units at 20.1±0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern containing peaks in 2θ units at 13.6±0.2° and 20.1±0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern containing peaks in 2θ units at 13.6±0.2°, 20.1±0.2°, and 25.0±0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern containing peaks in 2θ units at 8.6±0.2°, 13.6±0.2°, 20.1±0.2°, 25.0±0 .2° and 27.2±0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern containing peaks in 2Θ units at 8.6±0.2°, 13.6±0.2°, 18.3±0.2°, 20.1±0 .2°, 21.1+0.2°, 25.0+0.2° and 27.2+0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern containing peaks in 2Θ units at 8.6±0.2°, 13.6±0.2°, 17.5±0.2°, 18.3+0 .2°, 20.1±0.2°, 21.1±0.2°, 21.9±0.2°, 25.0±0.2° and 27.2±0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern containing peaks in 2Θ units at 8.6±0.2°, 13.6±0.2°, 14.9±0.2°, 17.5±0 .2°, 18.3±0.2°, 20.1±0.2°, 21.1±0.2°, 21.9±0.2°, 24.2±0.2°, 24 .5±0.2°, 25.0±0.2° and

27.2±0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern substantially as shown in FIG. 6, which essentially means that the represented peaks can vary by approximately ±0.2°2Θ. In some variants

The anhydrous crystalline form has a differential scanning calorimetry thermogram containing an endotherm with an extrapolated initial temperature between about 143.9 and about 153.9°C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram containing an endotherm with an extrapolated onset temperature between 145.9 and approximately 151.9°C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram containing an endotherm with an extrapolated onset temperature between about 146.9 and about 150.9°C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram containing an endotherm with an extrapolated onset temperature between about 147.9 and about 149.9°C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram containing an endotherm with an extrapolated initial temperature of approximately 148.9°C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram substantially as shown in FIG. 7, which essentially means that the reported DSC signatures may vary by approximately ±4° C. and the reported DSC signatures may vary by approximately ±20 J/g.

In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing <1.0% weight loss up to about 120°C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing <0.5% weight loss up to about 120°C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing <0.25% weight loss up to about 120°C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing <0.05% weight loss up to about 120°C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile substantially as shown in FIG. 7, which essentially means that the reported TGA characteristics may vary by approximately ±10° C. and the reported TGA characteristics may vary by approximately ±2% change in weight.

In some embodiments, the anhydrous crystalline form has a dynamic moisture sorption assay profile of less than about 0.35 wt% increasing to about 90% RH at about 25°C. In some embodiments, the anhydrous crystalline form has a dynamic moisture sorption assay profile substantially as shown in FIG. 8, which essentially means that the presented characteristics of the DWT can change by plus or minus approximately 5% change in weight.

One aspect of the present invention relates to an anhydrous crystalline form having:

1) X-ray powder diffraction pattern containing peaks in 2θ units at 13.6+0.2° and 20.1+0.2°;

2) a differential scanning calorimetry thermogram containing an endotherm with an extrapolated starting temperature between about 143.9 and about 153.9°C; and/or

3) thermogravimetric analysis profile showing <0.5% weight loss up to approximately 120°C.

One aspect of the present invention relates to an anhydrous crystalline form having:

1) X-ray powder diffraction pattern containing peaks in 2θ units at 13.6+0.2°, 20.1+0.2° and 25.0+0.2°;

2) a differential scanning calorimetry thermogram containing an endotherm with an extrapolated starting temperature between about 145.9 and about 151.9°C; and/or

3) thermogravimetric analysis profile showing <0.25% weight loss up to approximately 120°C.

One aspect of the present invention relates to an anhydrous crystalline form having:

1) X-ray powder diffraction pattern containing peaks in 2θ units at 8.6±0.2°, 13.6+0.2°, 20.1+0.2°, 25.0+0.2° and 27, 2+0.2°;

2) a differential scanning calorimetry thermogram containing an endotherm with an extrapolated starting temperature between about 146.9 and about 150.9°C; and/or

3) thermogravimetric analysis profile showing <0.05% weight loss up to approximately 120°C.

One aspect of the present invention relates to an anhydrous crystalline form having:

- 14 040124

1) X-ray powder diffraction pattern containing peaks in 2θ units at 8.6+0.2°,

13.6+0.2°, 18.3+0.2°, 20.1+0.2°, 21.1+0.2°, 25.0+0.2° and 27.2+0 .2°;

2) a differential scanning calorimetry thermogram containing an endotherm with an extrapolated starting temperature between about 147.9 and about 149.9°C; and/or

3) thermogravimetric analysis profile showing <0.05% weight loss up to approximately 120°C.

One aspect of the present invention relates to an anhydrous crystalline form having:

1) X-ray powder diffraction pattern containing peaks in 2θ units at 8.6+0.2°, 13.6+0.2°, 17.5+0.2°, 18.3+0.2°, 20, 1+0.2°, 21.1+0.2°, 21.9+0.2°, 25.0+0.2° and 27.2+0.2°;

2) a differential scanning calorimetry thermogram containing an extrapolated start temperature endotherm at about 147.9 and about 149.9°C; and/or

3) thermogravimetric analysis profile showing <0.05% weight loss up to approximately 120°C.

One aspect of the present invention relates to an anhydrous crystalline form having:

1) X-ray powder diffraction pattern containing peaks in 2θ units at 8.6+0.2°, 13.6+0.2°, 14.9+0.2°, 17.5+0.2°, 18, 3+0.2°, 20.1+0.2°, 21.1+0.2°, 21.9+0.2°, 24.2+0.2°, 24.5+0.2 °, 25.0+0.2° and 27.2+0.2°;

2) a differential scanning calorimetry thermogram containing an endotherm with an extrapolated starting temperature at approximately 148.9°C; and/or

3) thermogravimetric analysis profile showing <0.05% weight loss up to approximately 120°C.

One aspect of the present invention relates to an anhydrous crystalline form having:

1) an X-ray powder diffraction pattern essentially as shown in FIG. 6;

2) a differential scanning calorimetry thermogram essentially as shown in FIG. 7;

3) a thermogravimetric analysis profile essentially as shown in FIG. 7; and/or

4) a dynamic moisture sorption analysis profile essentially as shown in FIG. 8.

Some embodiments: compositions, methods, indications, pharmaceutical products, combinations and uses of the compounds of the present invention.

In addition to the foregoing, without limitation, some other embodiments are described and presented below.

Some Compositions of the Present Invention.

One aspect of the present invention relates to compositions containing a compound of the present invention.

The term composition refers to at least one compound of the invention in combination with at least one other component. It should be understood that the amount of the compound of the present invention in the composition may be any amount in the range from less than 100.00 to more than 0.00%. Examples of compositions include, but are not limited to, a reference material containing a compound of the present invention (eg, for use in a development method, in process control, and the like); bulk API (ie, active pharmaceutical ingredient) of a compound of the present invention (eg, for use in a pharmaceutical composition); combination preparation (ie, a compound of the present invention in combination with a pharmaceutical/therapeutic agent or agents); a biological sample containing a compound of the present invention (eg, for use or obtained from a patient, animal, pharmacokinetic study, ADME study, LADME study, and the like); a reaction mixture containing a compound of the present invention, such as a reaction mixture as described in any of the examples in this application; industrial reaction mixture containing the compound of the present invention in combination with one or more components such as solvents, reagents, by-products, etc.; and the like. It should be understood that pharmaceutical compositions are a specific set of compositions.

One aspect of the present invention relates to compositions containing a compound of the present invention and a pharmaceutically acceptable carrier.

One aspect of the present invention relates to methods for preparing a composition comprising the step of mixing a compound of the present invention and a pharmaceutically acceptable carrier.

One aspect of the present invention relates to pharmaceutical products selected from: pharmaceutical composition, formulation, dosage form, combined preparation, dual pack and kit; containing the compound of the present invention.

- 15 040124

One aspect of the present invention relates to compositions containing a compound of the present invention and a second pharmaceutical agent.

In any embodiment in which the terms pharmaceutical agent and/or second pharmaceutical agent are used, it should be understood that these terms are further limited in some aspects to a pharmaceutical agent or second pharmaceutical agent that is not a compound of formula (Ia). It should be understood that the terms pharmaceutical agent and second pharmaceutical agent may refer to a pharmaceutical agent or second pharmaceutical agent that is not detectable or has an EC ₅₀ greater than a value selected from 50, 10, 1, and 0.1 μM in a GPR119 receptor activity assay. as described in example 5.

One aspect of the present invention relates to methods for preparing a composition comprising the step of mixing a compound of the present invention and a second pharmaceutical agent.

One aspect of the present invention relates to compositions containing a compound of the present invention, a second pharmaceutical agent and a pharmaceutically acceptable carrier.

One aspect of the present invention relates to methods for preparing a composition comprising the step of mixing a compound of the present invention, a second pharmaceutical agent and a pharmaceutically acceptable carrier.

The present invention further provides pharmaceutical compositions. Accordingly, one aspect of the present invention relates to pharmaceutical compositions containing a compound of the present invention and a pharmaceutically acceptable carrier. One aspect of the present invention relates to methods for preparing a composition comprising the step of mixing a compound of the present invention and a pharmaceutically acceptable carrier. One aspect of the present invention relates to pharmaceutical compositions containing a compound of the present invention, a second pharmaceutical agent and a pharmaceutically acceptable carrier. One aspect of the present invention relates to methods for preparing a composition comprising the step of mixing a compound of the present invention, a second pharmaceutical agent and a pharmaceutically acceptable carrier.

One aspect of the present invention relates to a pharmaceutical product selected from a pharmaceutical composition, formulation, dosage form, combined preparation, dual pack and kit; containing a compound of the present invention and a second pharmaceutical agent.

One aspect of the present invention relates to compositions obtained using the methods of the present invention, as described in this document.

Certain Methods, Pharmaceutical Products, Combinations and Uses of the Present Invention.

One aspect of the present invention relates to methods for modulating GPR119 receptor activity comprising administering to a patient in need of such treatment: a therapeutically effective amount of a compound of the present invention; compositions of the present invention or a pharmaceutical product of the present invention.

One aspect of the present invention relates to methods for treating a disorder selected from a GPR119 receptor-associated disorder; a condition ameliorated by increased incretin secretion; a condition improved by increasing the level of incretin in the blood; a condition characterized by low bone mass; neurological disorder; metabolic-related disorder; and obesity; in a patient; comprising administering to a patient in need of such treatment: a therapeutically effective amount of a compound of the present invention; compositions of the present invention or a pharmaceutical product of the present invention.

One aspect of the present invention relates to methods for increasing the secretion of incretin in a patient or increasing the level of incretin in the blood of a patient, comprising administering to a patient in need of such treatment, a therapeutically effective amount of a compound of the present invention; compositions of the present invention or a pharmaceutical product of the present invention.

One aspect of the present invention relates to methods for treating a disorder selected from a GPR 119 receptor-associated disorder; a condition ameliorated by increased incretin secretion; a condition improved by increasing the level of incretin in the blood; a condition characterized by low bone mass; neurological disorder; metabolic-related disorder; and obesity; in a patient; comprising administering to a patient in need of such treatment: a therapeutically effective amount of a compound of the present invention; compositions of the present invention or a pharmaceutical product of the present invention.

Example 6 shows that Compound 1 is converted to Compound 2 and Compound 3. Accordingly, one aspect of the present invention relates to methods for increasing incretin secretion in a patient or increasing blood incretin levels in a patient, comprising administering to a patient in need of such treatment, therapeutically an effective amount of a compound of the present invention, in which the compound is formed as a result of a metabolic chemical reaction

3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4ylamino )-K,K-dimethylbenzamide (compound 1) or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention relates to methods for treating a disorder selected from a GPR119 receptor-associated disorder; a condition ameliorated by increased incretin secretion; a condition improved by increasing the level of incretin in the blood; a condition characterized by low bone mass; neurological disorder; metabolic-related disorder; and obesity; in a patient; comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of the present invention wherein the compound is formed by the metabolic chemical reaction 3-fluoro-4-(5-fluoro-6-(4-(3-(2fluoropropane-2- yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-M,K-dimethylbenzamide (compound 1) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5yl)piperidine-1- yl)pyrimidin-4-ylamino)-N-methylbenzamide (compound 2) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-fluoro-4-(5fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1- yl)pyrimidin-4-ylamino)benzamide (compound 3) or a pharmaceutically acceptable salt thereof.

One aspect of the present invention relates to the use of a compound of the present invention or a composition of the present invention in the manufacture of a medicament for modulating GPR119 receptor activity in a patient.

One aspect of the present invention relates to the use of a compound of the present invention or a composition of the present invention in the manufacture of a medicament for increasing the secretion of incretin in a patient or increasing the level of incretin in the blood of a patient.

One aspect of the present invention relates to the use of a compound of the present invention or a composition of the present invention in the manufacture of a medicament for the treatment of a disorder in a patient, wherein the disorder is selected from a GPR119 receptor-associated disorder; a condition ameliorated by increased incretin secretion; a condition improved by increasing the level of incretin in the blood; a condition characterized by low bone mass; neurological disorder; metabolic-related disorder; and obesity.

One aspect of the present invention relates to the compound of the present invention; a composition of the present invention or a pharmaceutical product of the present invention for use in a method of treating a human or animal with therapy.

One aspect of the present invention relates to the compound of the present invention; compositions of the present invention or a pharmaceutical product of the present invention for use in a method for modulating GPR119 receptor activity in a patient.

One aspect of the present invention relates to the compound of the present invention; a composition of the present invention or a pharmaceutical product of the present invention for use in a method for increasing incretin secretion in a patient or increasing blood incretin levels in a patient.

One aspect of the present invention relates to the compound of the present invention; compositions of the present invention or a pharmaceutical product of the present invention for use in a method of treating a disorder in a patient, wherein the disorder is selected from a GPR119 receptor-associated disorder; a condition ameliorated by increased incretin secretion; a condition improved by increasing the level of incretin in the blood; a condition characterized by low bone mass; neurological disorder; metabolic-related disorder; and obesity.

One aspect of the present invention relates to a compound of the present invention for use in a method of treating a human or animal with therapy, in which the compound is formed as a result of the metabolic chemical reaction 3-fluoro-4-(5-fluoro-6-(4-(3 -(2-fluoropropan-2yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,K-dimethylbenzamide or a pharmaceutically acceptable salt thereof.

One aspect of the present invention relates to a compound of the present invention for use in a method for increasing the secretion of incretin in a patient or increasing the level of incretin in the blood of a patient, in which the compound is formed by the metabolic chemical reaction 3-fluoro-4-(5-fluoro-6 -(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4ylamino)-N,K-dimethylbenzamide or a pharmaceutically acceptable salt thereof .

One aspect of the present invention relates to a compound of the present invention for use in a method of treating a disorder in a patient, wherein the compound is formed from the metabolic chemical reaction 3-fluoro-4-(5-fluoro-6-(4-(3-(2 -fluoropropan-2-yl)-1,2,4-oxadiazol-5yl)piperidin-1-yl)pyrimidin-4-ylamino)-K,K-dimethylbenzamide or a pharmaceutically acceptable salt thereof, and the disorder is selected from associated with GPR119- receptor disturbance; a condition ameliorated by increased incretin secretion; state improved by leveling up

- 17 040124 incretin in the blood; a condition characterized by low bone mass; neurological disorder; metabolic-related disorder; and obesity.

One aspect of the present invention relates to a pharmaceutical product selected from a pharmaceutical composition, formulation, dosage form, combined preparation, dual pack and kit; containing the compound of the present invention; for use in a method of treating a human or animal with therapy.

One aspect of the present invention relates to a pharmaceutical product selected from a pharmaceutical composition, formulation, dosage form, combined preparation, dual pack and kit; containing the compound of the present invention; for use in a method for modulating GPR119 receptor activity in a patient.

One aspect of the present invention relates to a pharmaceutical product selected from a pharmaceutical composition, formulation, dosage form, combined preparation, dual pack and kit; containing the compound according to claim 1; for use in a method of increasing the secretion of incretin in a patient or increasing the level of incretin in the blood of a patient.

One aspect of the present invention relates to a pharmaceutical product selected from a pharmaceutical composition, formulation, dosage form, combined preparation, dual pack and kit; containing a compound of the present invention for use in a method of treating a disorder selected from a GPR119 receptor-associated disorder; a condition ameliorated by increased incretin secretion; a condition improved by increasing the level of incretin in the blood; a condition characterized by low bone mass; neurological disorder; metabolic-related disorder; and obesity in the patient.

One aspect of the present invention relates to methods for modulating GPR119 receptor activity comprising administering to a patient in need of such treatment a compound of the present invention in combination with a second pharmaceutical agent.

One aspect of the present invention relates to methods of GPR119 receptor agonization comprising administering to a patient in need of such treatment a compound of the present invention in combination with a second pharmaceutical agent.

One aspect of the present invention relates to methods for increasing the secretion of incretin in a patient or increasing the level of incretin in the blood of a patient, comprising administering to a patient in need of such treatment, the compounds of the present invention in combination with a second pharmaceutical agent.

One aspect of the present invention relates to methods for increasing the secretion of incretin in a patient or increasing the level of incretin in the blood of a patient, comprising administering to a patient in need of such treatment, the compounds of the present invention in combination with a second pharmaceutical agent.

One aspect of the present invention relates to methods for treating a disorder selected from a GPR119 receptor-associated disorder; a condition ameliorated by increased incretin secretion; a condition improved by increasing the level of incretin in the blood; a condition characterized by low bone mass; neurological disorder; metabolic-related disorder; and obesity; in a patient; comprising administering to a patient in need of such treatment a compound of the present invention in combination with a second pharmaceutical agent.

One aspect of the present invention relates to methods for treating a disorder selected from a GPR119 receptor-associated disorder; a condition ameliorated by increased incretin secretion; a condition improved by increasing the level of incretin in the blood; a condition characterized by low bone mass; neurological disorder; metabolic-related disorder; and obesity; in a patient; comprising administering to a patient in need of such treatment a compound of the present invention in combination with a second pharmaceutical agent.

One aspect of the present invention relates to the use of a compound of the present invention in combination with a second pharmaceutical agent in the manufacture of a medicament for modulating GPR119 receptor activity in a patient.

One aspect of the present invention relates to the use of a compound of the present invention in combination with a second pharmaceutical agent in the manufacture of a medicament for GPR119 receptor agonization in a patient.

One aspect of the present invention relates to the use of a compound of the present invention in combination with a second pharmaceutical agent in the manufacture of a medicament to increase incretin secretion in a patient or to increase blood incretin levels in a patient.

One aspect of the present invention relates to the use of a compound of the present invention in combination with a second pharmaceutical agent in the manufacture of a medicament for the treatment of a disorder selected from a GPR119 receptor-associated disorder; condition improved by increased secretion of incretin; a condition improved by increasing the level of incretin in the blood; a condition characterized by low bone mass;

neurological disorder; metabolic-related disorder; and obesity.

One aspect of the present invention relates to the use of a pharmaceutical agent in combination with a compound of the present invention in the manufacture of a medicament for modulating GPR119 receptor activity in a patient.

One aspect of the present invention relates to the use of a pharmaceutical agent in combination with a compound of the present invention in the manufacture of a medicament for GPR119 receptor agonization in a patient.

One aspect of the present invention relates to the use of a pharmaceutical agent in combination with a compound of the present invention in the manufacture of a medicament for increasing the secretion of incretin in a patient or increasing the level of incretin in the blood of a patient.

One aspect of the present invention relates to the use of a pharmaceutical agent in combination with a compound of the present invention in the manufacture of a medicament for the treatment of a disorder selected from a GPR119 receptor-associated disorder; a condition ameliorated by increased incretin secretion; a condition improved by increasing the level of incretin in the blood; a condition characterized by low bone mass; neurological disorder; metabolic-related disorder; and obesity.

One aspect of the present invention relates to a compound of the present invention for use in combination with a second pharmaceutical agent in a method of treating a human or animal with therapy.

One aspect of the present invention relates to a compound of the present invention for use in combination with a second pharmaceutical agent in a method for modulating GPR119 receptor activity in a patient.

One aspect of the present invention relates to a compound of the present invention for use in combination with a second pharmaceutical agent in a method of GPR119 receptor agonization in a patient.

One aspect of the present invention relates to a compound of the present invention for use in combination with a second pharmaceutical agent to increase the secretion of incretin in a patient or to increase the level of incretin in the blood of a patient.

One aspect of the present invention relates to a compound of the present invention for use in combination with a second pharmaceutical agent in a method of treating a disorder selected from a GPR119 receptor-associated disorder; a condition ameliorated by increased incretin secretion; a condition improved by increasing the level of incretin in the blood; a condition characterized by low bone mass; neurological disorder; metabolic-related disorder; and obesity; at the patient.

One aspect of the present invention relates to a pharmaceutical agent for use in combination with a compound of the present invention in a method of treating a human or animal with therapy.

One aspect of the present invention relates to a pharmaceutical agent for use in combination with a compound of the present invention in modulating GPR119 receptor activity in a patient.

One aspect of the present invention relates to a pharmaceutical agent for use in combination with a compound of the present invention in a method of GPR119 receptor agonization in a patient.

One aspect of the present invention relates to a pharmaceutical agent in combination with a compound of the present invention for increasing the secretion of incretin in a patient or increasing the level of incretin in the blood of a patient.

One aspect of the present invention relates to a pharmaceutical agent for use in combination with a compound of the present invention in a method of treating a disorder selected from a GPR119 receptor-associated disorder; a condition ameliorated by increased incretin secretion; a condition improved by increasing the level of incretin in the blood; a condition characterized by low bone mass; neurological disorder; metabolic-related disorder; and obesity in the patient.

One aspect of the present invention relates to a pharmaceutical product selected from a pharmaceutical composition, formulation, dosage form, combined preparation, dual pack and kit; containing the compound of the present invention and the second pharmaceutical agent; for use in a method of treating a human or animal with therapy.

One aspect of the present invention relates to a pharmaceutical product selected from a pharmaceutical composition, formulation, dosage form, combined preparation, dual pack and kit; containing the compound of the present invention and the second pharmaceutical agent; for use in a method for modulating GPR119 receptor activity in a patient.

- 19 040124

One aspect of the present invention relates to a pharmaceutical product selected from a pharmaceutical composition, formulation, dosage form, combined preparation, dual pack and kit; containing the compound of the present invention and the second pharmaceutical agent; for use in a method of GPR119 receptor agonization in a patient.

One aspect of the present invention relates to a pharmaceutical product selected from a pharmaceutical composition, formulation, dosage form, combined preparation, dual pack and kit; containing the compound of the present invention and the second pharmaceutical agent; for use in a method of increasing the secretion of incretin in a patient or increasing the level of incretin in the blood of a patient.

One aspect of the present invention relates to a pharmaceutical product selected from a pharmaceutical composition, formulation, dosage form, combined preparation, dual pack and kit; containing a compound of the present invention and a second pharmaceutical agent for use in a method of treating a disorder selected from a GPR119 receptor-associated disorder; a condition ameliorated by increased incretin secretion; a condition improved by increasing the level of incretin in the blood; a condition characterized by low bone mass; neurological disorder; metabolic-related disorder; and obesity in the patient.

One aspect of the present invention relates to compounds, methods, compositions, uses of the compounds, pharmaceutical agents, and pharmaceutical products, each as described herein, wherein the modulation of GPR119 receptor activity is GPR119 receptor agonization in a patient.

One aspect of the present invention relates to compounds, methods, compositions, uses of the compounds, pharmaceutical agents and pharmaceutical products, each as described herein, wherein the modulation of GPR119 receptor activity is an increase in incretin secretion in a patient.

One aspect of the present invention relates to compounds, methods, compositions, uses of the compounds, pharmaceutical agents, and pharmaceutical products, each as described herein, wherein the modulation of GPR119 receptor activity is an increase in blood incretin levels in a patient.

One aspect of the present invention relates to compounds, methods, compositions, uses of the compounds, pharmaceutical agents, and pharmaceutical products, each as described herein, wherein modulation of GPR119 receptor activity is a treatment for a disorder, wherein the disorder is selected from: GPR119 related -receptor disorders; a condition ameliorated by increased incretin secretion; a condition improved by increasing the level of incretin in the blood; a condition characterized by low bone mass; neurological disorder; metabolic-related disorder; and obesity.

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is selected from: a DPP-IV inhibitor, a biguanide, an alpha-glucosidase inhibitor, a sulfonylurea, an SGLT2 inhibitor, and meglitinide. In some embodiments, the pharmaceutical agent or second pharmaceutical agent is selected from: sitagliptin, vildagliptin, saxagliptin, alogliptin, linagliptin, phenformin, metformin, buformin, acarbose, miglitol, voglibose, tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide, glibenclamide, glimepiride, gliclazide , dapagliflozin, remogliflozin and sergliflozin.

In some embodiments, the disorder is type 2 diabetes mellitus. In some embodiments, the implementation of the violation is hyperglycemia. In some embodiments, the implementation of the violation is hyperlipidemia. In some embodiments, the disorder is hypertriglyceridemia. In some embodiments, the disorder is type 1 diabetes mellitus. In some embodiments, the implementation of the violation is a dyslipidemia. In some embodiments, the disorder is Syndrome X. In some embodiments, the disorder is obesity.

In some embodiments, the implementation of the pharmaceutical product contains a pharmaceutical composition. In some embodiments, the implementation of the pharmaceutical product contains the composition. In some embodiments, the implementation of the pharmaceutical product contains a dosage form. In some embodiments, the implementation of the pharmaceutical product contains a combination drug. In some embodiments, the implementation of the pharmaceutical product contains a double package. In some embodiments, the pharmaceutical product contains a kit.

In some embodiments, the compound and the second pharmaceutical agent are administered simultaneously, separately, or sequentially. In some embodiments, the compound and the pharmaceutical agent or second pharmaceutical agent are administered simultaneously. In some embodiments, the compound and the pharmaceutical agent or second pharmaceutical agent are administered separately. In some embodiments, the compound and the pharmaceutical agent or second pharmaceutical agent are administered sequentially.

- 20 040124

In some embodiments, the incretin is GLP-1. In some embodiments, the incretin is a GIP. In some embodiments, the incretin is PYY.

One aspect of the present invention relates to compounds, methods, compositions, uses of the compounds, pharmaceutical agents and pharmaceutical products, in which the amount of the compound of the present invention and the amount of the second pharmaceutical agent, when administered alone, are essentially therapeutically ineffective (i.e., a subtherapeutic amount ); however, the amount of the compound of the present invention and the amount of the second pharmaceutical agent, when administered simultaneously, separately or sequentially, are sufficiently therapeutically effective in treating the disorder.

In some embodiments, the compound and the pharmaceutical agent or second pharmaceutical agent are provided in amounts that are synergistic in treating the disorder. In some embodiments, the amount of the compound alone is substantially therapeutically ineffective in treating the disorder. In some embodiments, the amount of the pharmaceutical agent alone, or the second pharmaceutical agent alone, is substantially therapeutically ineffective in treating the disorder.

One aspect of the present invention relates to methods for preparing a pharmaceutical product as described herein, including: mixing a compound of the present invention with a first pharmaceutically acceptable carrier to obtain a dosage form of the compound, mixing a second pharmaceutical agent with a second pharmaceutically acceptable carrier to obtain a dosage form of the second pharmaceutical agent and combining the dosage form of the compound and the dosage form of the second pharmaceutical agent into a combined dosage form for simultaneous, separate or sequential use.

In some embodiments, the first pharmaceutically acceptable carrier and the second pharmaceutically acceptable carrier are different. In some embodiments, different pharmaceutically acceptable carriers are suitable for administration via the same route or different routes. In some embodiments, the first pharmaceutically acceptable carrier and the second pharmaceutically acceptable carrier are substantially the same. In some embodiments, substantially the same pharmaceutically acceptable carriers are suitable for administration by the same route. In some embodiments, substantially the same pharmaceutically acceptable carriers are suitable for oral administration.

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is selected from: a DPP-IV inhibitor, a biguanide, an alpha-glucosidase inhibitor, an insulin analog, a sulfonylurea, an SGLT2 inhibitor, meglitinide, a thiazolidinedione, and an antidiabetic peptide analog. In some embodiments, the pharmaceutical agent or second pharmaceutical agent is selected from: a DPP-IV inhibitor, a biguanide, an alpha-glucosidase inhibitor, a sulfonylurea, an SGLT2 inhibitor, and meglitinide. In some embodiments, the pharmaceutical agent or second pharmaceutical agent is selected from: a DPP-IV inhibitor, a biguanide, and an alpha-glucosidase inhibitor. In some embodiments, the pharmaceutical agent or second pharmaceutical agent is a DPP-IV inhibitor. In some embodiments, the pharmaceutical agent or second pharmaceutical agent is a biguanide. In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is an alpha-glucosidase inhibitor. In some embodiments, the pharmaceutical agent or second pharmaceutical agent is a sulfonylurea. In some embodiments, the pharmaceutical agent or second pharmaceutical agent is an SGLT2 inhibitor. In some embodiments, the pharmaceutical agent or second pharmaceutical agent is meglitinide. In some embodiments, the pharmaceutical agent or second pharmaceutical agent is a biguanide selected from the following compounds and their pharmaceutically acceptable salts, solvates, and hydrates: metformin, phenformin, buformin, and proguanil. In some embodiments, the pharmaceutical agent or second pharmaceutical agent is an alpha-glucosidase inhibitor selected from the following compounds and their pharmaceutically acceptable salts, solvates, and hydrates: acarbose, miglitol, and voglibose.

One aspect of the present invention relates to weight management methods comprising administering to a patient in need of such treatment a compound of the present invention in combination with a second pharmaceutical agent, such as any agent described herein.

In some embodiments, weight management includes weight loss. In some embodiments, weight management includes maintaining weight loss. In some embodiments, weight management further includes a low calorie diet. In some embodiments, weight management further includes a regular exercise program.

- 21 040124 exercises. In some embodiments, weight management further includes both a low calorie diet and a regular exercise program.

In some embodiments, the patient in need of weight management is a patient with an initial body mass index >40;>39;>38;>37;>36;>35;>34;>33;>32;>31;>30;>29;>28;>27;>26;>25;>24;>23;>22;>21 or >20 kg/m ² ; and the patient optionally has at least one or at least two weight-related comorbid conditions.

In some embodiments, the comorbid condition(s), if present, is selected from hypertension, dyslipidaemia, cardiovascular disease, glucose intolerance, and sleep apnea.

Some indications for the use of the present invention.

In the context of the present invention, a compound as described herein or a pharmaceutical composition thereof can be used to modulate the activity of GPR119 receptor related diseases, conditions and/or disorders as described herein.

In some embodiments, modulating GPR119 receptor activity comprises treating a GPR119 receptor-associated disorder. In some embodiments, the GPR119 receptor-associated disorder is a condition ameliorated by increased incretin secretion. In some embodiments, the GPR119 receptor-associated disorder is a condition ameliorated by an increase in blood incretin levels. In some embodiments, the incretin is GLP-1. In some embodiments, the incretin is a GIP. In some embodiments, the incretin is PYY.

In some embodiments, the GPR119 receptor-associated disorder is a condition characterized by low bone mass. In some embodiments, the GPR119 receptor-associated disorder is a neurological disorder. In some embodiments, the GPR119 receptor-associated disorder is a metabolic disorder. In some embodiments, the GPR119 receptor-associated disorder is type 2 diabetes mellitus. In some embodiments, the GPR119 receptor-associated disorder is obesity.

Some embodiments of the present invention include each combination of one or more conditions characterized by low bone mass selected from osteopenia, osteoporosis, rheumatoid arthritis, osteoarthritis, periodontitis, alveolar bone atrophy, bone mass osteotomy, childhood idiopathic bone loss, Paget's disease , bone loss due to metastatic cancer, osteolytic lesions, curvature of the spine and loss of growth.

In some embodiments, the neurological disorder is selected from stroke and Parkinson's disease.

Some embodiments of the present invention include each combination of one or more metabolic-related disorders selected from type 1 diabetes mellitus, type 2 diabetes mellitus and related conditions such as, but not limited to, ischemic heart disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease, intermittent claudication, myocardial infarction (eg, necrosis and apoptosis), dyslipidemia, postprandial lipemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, osteoporosis, hypertension, chronic heart failure, left ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy, macular degeneration, cataracts, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, premenstrual syndrome, coronary heart disease, angina pectoris, thrombosis, atherosclerosis, myocardial infarction, transient ischemic attacks, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, insulin resistance, impaired glucose metabolism, erectile dysfunction, skin and connective tissue diseases, ulceration foot and ulcerative colitis, endothelial dysfunction and impaired vascular compliance.

Some embodiments of the present invention include each combination of one or more metabolic-related disorders selected from diabetes mellitus, type 1 diabetes mellitus, type 2 diabetes mellitus, glucose intolerance, impaired glucose tolerance, insulin resistance, hyperglycemia , hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, atherosclerosis, stroke, syndrome X, hypertension, pancreatic beta cell deficiency, argentaffin cell deficiency, glycosuria, metabolic acidosis, cataract, diabetic nephropathy, diabetic neuropathy, peripheral neuropathy, diabetic atherosclerotic heart disease, diabetic cerebrovascular disease, diabetic peripheral vascular disease, diabetic retinopathy, metabolic syndrome, diabetes-related condition, myocardial infarction, learning disabilities, memory impairment, neuro degenerative disorder, condition ameliorated by increased blood levels of GLP-1 in a patient with a neurodegenerative disorder, excitotoxic brain injury caused by severe epileptic seizures, Alzheimer's disease, Parkinson's disease, Huntington's disease, prion-associated disease, stroke, motor neuron disease , traumatic brain injury, spinal cord injury and obesity.

In some embodiments, the disorder is type 2 diabetes mellitus. In some embodiments, the implementation of the violation is hyperglycemia. In some embodiments, the implementation of the violation is hyperlipidemia. In some embodiments, the disorder is hypertriglyceridemia. In some embodiments, the disorder is type 1 diabetes mellitus. In some embodiments, the implementation of the violation is a dyslipidemia. In some embodiments, the disorder is Syndrome X. In some embodiments, the disorder is obesity. In some embodiments, the disorder is a metabolic syndrome.

As used herein, the term metabolic syndrome refers to a set of risk factors that make a patient more susceptible to cardiovascular disease and/or type 2 diabetes mellitus. A patient is diagnosed with metabolic syndrome if the patient simultaneously has three or more of the following five risk factors, as outlined by the American Heart Association and the National Heart, Lung, and Blood Institute: (1) increased waist circumference: in men >40 inches (102 cm) , women >35 inches (88 cm); (2) elevated triglyceride levels: >150 mg/dL; (3) decreased HDL (good) cholesterol: <40 mg/dl in men, <50 mg/dl in women; (4) high blood pressure: >130/85 mmHg. and (5) elevated fasting glucose: >100 mg/dL.

Compositions and compositions.

Formulations may be prepared by any suitable method, generally by uniformly mixing the active compound(s) with liquids or finely divided solid carriers or both in the required proportions and then, if necessary, shaping the resulting mixture into the desired shape.

Standard excipients such as binders, fillers, suitable wetting agents, tableting glidants and disintegrants can be used in tablets and capsules for oral administration. Liquid preparations for oral administration may be in the form of solutions, emulsions, aqueous or oily suspensions and syrups. Alternatively, oral preparations may be in the form of a dry powder which may be dissolved in water or other suitable liquid vehicle prior to use.

Additional additives such as suspending or emulsifying agents, non-aqueous excipients (including edible oils), preservatives, and flavoring and coloring agents may be added to liquid preparations. Parenteral dosage forms can be prepared by dissolving a compound of the invention in a suitable liquid vehicle and sterilized by filtering the solution prior to filling and sealing in an appropriate vial or ampoule. These are just a few examples of the many relevant methods well known in the art for preparing dosage forms.

The compound of the present invention may be formulated into pharmaceutical compositions using techniques well known to those skilled in the art. Suitable pharmaceutically acceptable carriers, other than those mentioned herein, are known in the art; for example, see Remington, The Science and Practice of Pharmacy, ^20th Edition, 2000, Lippincott Williams & Wilkins (Editors: Gennaro et al.).

While it is possible that for prophylactic or therapeutic use a compound of the invention may be administered in alternative uses as a raw material or pure chemical, it is preferred to present the compound or active ingredient as a pharmaceutical formulation or composition further comprising a pharmaceutically acceptable carrier.

Pharmaceutical formulations include formulations suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including intramuscular, subcutaneous and intravenous) administration, or in a form suitable for administration by inhalation, insufflation or via a transdermal patch. Transdermal patches distribute the drug at a controlled rate, presenting the drug for absorption in an efficient manner with minimal drug disruption. Typically, transdermal patches comprise an impervious backsheet, a disposable self-adhesive material, and a liner-removable backsheet. One of ordinary skill in the art will be able to understand and evaluate techniques suitable for the production of the desired effective transdermal patch based on the mandatory requirements of one of skill in the art.

Compounds of the invention together with a standard adjuvant, carrier or diluent

- 23 040124 can be put into the form of pharmaceutical compositions and their dosage units and in this form can be used in the form of solids such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, gels or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration, or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and their unit dosage forms may contain standard ingredients in standard proportions with or without additional active compounds or components, and such unit dosage forms may contain any suitable effective amount of the active ingredient in accordance with the intended daily dosage range that is used.

For oral administration, the pharmaceutical composition may be in the form of, for example, tablets, capsules, suspensions or liquids. The pharmaceutical composition is preferably prepared in the form of a dosage unit containing a certain amount of the active ingredient. Examples of such dosage units are capsules, tablets, powders, granules or suspension with standard additives such as lactose, mannitol, corn starch or potato starch; with binders such as crystalline cellulose, cellulose derivatives, acacia, cornstarch or gelatins; with disintegrants such as corn starch, potato starch or sodium carboxymethyl cellulose; and with lubricants such as talc or magnesium stearate. The active ingredient can also be administered by injection as a composition in which, for example, saline, dextrose or water can be used as a suitable pharmaceutically acceptable carrier.

The compounds of the present invention, or a solvate, hydrate or physiologically functional derivative thereof, can be used as active ingredients in pharmaceutical compositions, in particular as GPR119 receptor modulators. The term active ingredient, defined in the context of a pharmaceutical composition, refers to a component of a pharmaceutical composition that provides a primary pharmacological effect, as opposed to an inactive ingredient that does not normally provide a pharmaceutical effect.

The dose when using the compounds of the present invention may vary within wide limits and, as usual, known to the attending physician, it must be calculated taking into account individual conditions in each individual case. It depends, for example, on the nature and severity of the disease to be treated, on the condition of the patient, on the compound used, or on the acute or chronic course of the disease being treated or prevented, or on additional active compounds that are administered in addition to the compounds of the present invention. . Typical dosages of the present invention include, but are not limited to, from about 0.001 to about 5000 mg, from about 0.001 to about 2500 mg, from about 0.001 to about 1000 mg, from 0.001 to about 500 mg, from 0.001 to about 250 mg, from about 0.001 to 100 mg, from about 0.001 to about 50 mg, and from about 0.001 to about 25 mg. Multiple doses may be administered throughout the day, especially when relatively large amounts are deemed necessary, such as 2, 3 or 4 doses. Depending on the patient and at the discretion of the treating physician or caregiver, it may be necessary to deviate up or down from the doses described herein.

The amount of active ingredient or active salt or derivative thereof required for use in treatment will vary not only with the particular salt chosen, but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the patient. physician or clinician. Typically, one skilled in the art will understand how to extrapolate in vivo data from a model system, typically an animal model, otherwise such as a human model. In some cases, these extrapolations may be based simply on the weight of the animal model compared to another weight, such as a mammal, preferably a human, however, most often, these extrapolations are not simply based on weight, but rather include various factors. Typical factors include the type, age, weight, sex, diet and medical condition of the patient, disease severity, route of administration, pharmacological considerations such as potency, efficacy, pharmacokinetic and toxicological profiles of the particular compound used or the drug delivery system being used, or acute or chronic disease being treated or prophylactic, or additional active compounds administered in addition to the compounds of the present invention and as part of a drug combination. The dosage regimen for treating a disease state with the compounds and/or compositions of this invention is selected in accordance with various factors, as discussed above. Thus, the actual dosage regimen used may vary widely and therefore may differ from the preferred dosage regimen, and it will be apparent to one skilled in the art that dosage and dosage regimens outside of these typical ranges may be tested and appropriate cases can be used in the methods of this invention.

The desired dose may conveniently be presented as a single dose or as divided doses administered at appropriate time intervals, for example as two, three, four or more sub-doses per day. The subdose itself may be further divided, for example, into a number of discrete, freely spaced administrations. The daily dose may be divided, especially with relatively large administration amounts, optionally into several, for example 2, 3 or 4, administration portions. In the appropriate case, depending on individual behavior, it may deviate up or down from the indicated daily dose.

The compounds of the present invention may be administered in a wide variety of oral and parenteral dosage forms. It will be apparent to a person skilled in the art that the following dosage forms may contain as active ingredient either a compound of the invention, or a pharmaceutically acceptable salt, solvate or hydrate of a compound of the invention.

For the preparation of pharmaceutical compositions from the compounds of the present invention, the appropriate pharmaceutically acceptable carrier selected may be either a solid, a liquid, or a mixture thereof. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. The solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, disintegrants, tablets, or an encapsulating material.

In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.

In tablets, the active ingredient is mixed in appropriate proportions with a carrier having the necessary binding capacity and compressed into the desired shape and size. Powders and tablets may contain varying percentages of the active compound. A typical amount in a powder or tablet may contain from 0.5% to about 90% active compound; however, one skilled in the art will know when amounts outside this range are needed. Suitable carriers for powders and tablets are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter, and the like. The term preparation refers to the formulation of the active compound with an encapsulating material as a carrier, providing a capsule in which the active ingredient, with or without carriers, is surrounded by a carrier, which is thus in combination with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets and lozenges can be used as solid forms suitable for oral administration.

To prepare suppositories, a low-melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active ingredient is uniformly dispersed in it, as with stirring. The molten homogeneous mixture is then poured into suitable sized molds, cooled and thus solidified.

Formulations suitable for vaginal administration may be presented as vaginal suppositories, tampons, creams, gels, pastes, foams or sprays containing, in addition to the active ingredient, such carriers as are known in the art to be useful.

Liquid form preparations include solutions, suspensions and emulsions, for example aqueous or aqueous propylene glycol solutions. For example, liquid form preparations for parenteral injection may be formulated as solutions in an aqueous polyethylene glycol solution. Injectable preparations, for example sterile injectable aqueous or oily suspensions, can be prepared according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fatty oils are commonly used as a solvent or suspending medium. Any bland fixed oil can be used for this purpose, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectable drugs.

The compounds of the present invention may thus be formulated for parenteral administration (eg by injection, eg bolus injection or continuous infusion) and may be presented as a dosage unit in ampoules, pre-filled syringes, small volume infusion or multi-dose containers with added preservative. The pharmaceutical compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain adjuvants such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in the form of a powder obtained by aseptic isolation of a sterile

- 25 040124 solid or by lyophilization from a solution for dilution with a suitable vehicle, such as sterile, pyrogen-free water before use.

Aqueous formulations suitable for oral administration may be prepared by dissolving or suspending the active ingredient in water and adding suitable coloring, flavoring, stabilizing and thickening agents as desired.

Aqueous suspensions suitable for oral administration can be prepared by dispersing the finely divided active ingredient in water with a viscous material such as natural or synthetic gums, gums, methylcellulose, sodium carboxymethylcellulose or other well known suspending agents.

Also included are solid form preparations which are intended to be converted shortly before use to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions and emulsions. These formulations may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, synthetic and natural sweeteners, dispersing agents, thickening agents, solubilizing agents, and the like.

For topical administration to the epidermis, the compounds of the invention may be prepared as ointments, creams or lotions, or as a transdermal patch.

Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening agents and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will also typically contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, and coloring agents.

Formulations suitable for topical oral administration include lozenges containing the active agent in a flavored base, usually sucrose and acacia or tragacanth; lozenges containing the active ingredient with an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes containing the active ingredient in a suitable liquid carrier.

Solutions or suspensions are injected directly into the nasal cavity using standard means, such as a dropper bottle, pipette or sprayer. The formulations may be presented in unit or multiple dose form. In the latter case of a dropper bottle or pipette, this can be achieved by administering to the patient an appropriate predetermined volume of the solution or suspension. In the case of atomization, this can be achieved, for example, by measuring the atomization of an injection pump.

Administration to the respiratory tract can also be achieved with an aerosol formulation in which the active ingredient is provided in pressurized packaging with a suitable propellant. When the compounds of the present invention, or pharmaceutical compositions containing them, are administered as aerosols, for example as nasal sprays or by inhalation, this can be done, for example, using a spray, nebulizer, pump nebulizer, inhaler, metered dose inhaler or dry powder inhaler. Aerosol pharmaceutical forms for administering the compounds of the present invention can be prepared using methods well known to those skilled in the art. For their preparation, for example, solutions or dispersions of the compounds of the present invention in water, water/alcohol mixtures, or suitable saline solutions can be used, using standard additives, for example, benzyl alcohol or other suitable preservatives, absorption enhancers to increase bioavailability, solubilizers, dispersing agents, and other and optionally standard propellants including, for example, carbon dioxide, CFCs such as dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane; and the like. The aerosol may also conveniently contain a surfactant such as lecithin. The dose of the drug can be controlled by providing a metering valve.

In formulations intended for administration to the respiratory tract, including intranasal formulations, the compound will typically have a small particle size, eg on the order of 10 microns or less. This particle size can be obtained using methods known in the art, for example using fine grinding. If desired, formulations adapted to provide sustained release of the active ingredient can be used.

Alternatively, the active ingredients may be provided in the form of a dry powder, for example a powdered mixture of the compound with a suitable powdered base such as lactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidone (PVP). Conveniently, the powdered carrier forms a gel in the nasal cavity. The powder composition may be presented in unit dosage form, for example in capsules or cartridges, for example gelatin or blister packs, from which the powder can be administered by inhaler.

The pharmaceutical preparations are preferably in unit dosage forms. In this form, the preparation is subdivided into dosage units containing appropriate quantities of the active ingredient. The unit dosage form may be a packaged preparation, a package containing discrete amounts of the drug, such as packaged tablets, capsules and powders.

- 26 040124 in vials or ampoules. In addition, the unit dosage form may be a capsule, tablet, cachet, or lozenge on its own, or it may be the appropriate number of any of these in packaged form.

Tablets or capsules for oral administration and liquids for intravenous administration are the preferred compositions.

The compounds of the invention may optionally exist as pharmaceutically acceptable salts, including pharmaceutically acceptable acid addition salts derived from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Representative acids include, but are not limited to, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethensulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethic, lactic, maleic, malic, mandelic, methanesulfonic, mucic , nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, oxalic, p-toluenesulfonic and the like. Some compounds of the present invention that contain a carboxylic acid functional group may optionally exist as pharmaceutically acceptable salts containing non-toxic pharmaceutically acceptable metal cations and cations derived from organic bases. Representative metals include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and the like. In some embodiments, the pharmaceutically acceptable metal is sodium. Typical organic bases include, but are not limited to, benzathine (N ¹ ,N ² -dibenzylethαn-1,2-diαmin), chlorprocaine (2-(diethylamino)ethyl-4-(chloramino)benzoate), choline, diethanolamine, ethylenediamine, meglumine ((2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentaol), procaine (2-(diethylamino)ethyl-4-aminobenzoate) and the like. Some pharmaceutically acceptable salts are listed in Berge, et al., Journal of Pharmaceutical Sciences, 66:1-19 (1977).

Acid addition salts can be obtained as direct products of the synthesis of the compound. Alternatively, the free base can be dissolved in a suitable solvent containing the appropriate acid and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent. The compounds of this invention can form solvates with standard low molecular weight solvents using methods known to the person skilled in the art.

The compounds of the present invention can also be administered by a fast dissolving or slow release composition wherein the composition comprises a biodegradable fast dissolving or slow release carrier (such as a polymeric carrier and the like) and the compounds of the invention. Rapid dissolution or slow release of carriers are well known in the art and are used to form complexes that entrap the active compound(s) and/or are rapidly or slowly decomposed/dissolved in a suitable medium (e.g., aqueous, acidic, basic, etc.). d.). Such particles are useful because they break down/dissolve in body fluids and release the active compound(s) therein. The particle size of the compound of the present invention, carrier or any excipient used in such a composition can be optimally set using techniques known to the person skilled in the art.

Particle size can play an important role in composition. Particle size reduction can be used to change the physical characteristics. Reducing the particle size increases both the number of particles and the amount of surface area per unit volume. The increased surface area can improve the dissolution rate and hence solubility. In addition, particle size reduction can improve gastrointestinal absorption of less soluble compounds. Particle size reduction can be achieved by any of the methods known in the art, such as precipitation/crystallization, milling (mechanical size reduction), and the like, see, for example, Remington, The Science and Practice of Pharmacy, 20 ^th Edition, 2000, Lippincott Williams & Wilkins, (Editors: Gennaro et al.).

The compounds of the present invention can be converted into prodrugs. The term prodrug refers to compounds that have been modified with certain chemical groups known in the art, and when administered to a patient, these groups undergo biotransformation to produce the parent compound. Prodrugs can thus be considered as compounds of the invention containing one or more specialized non-toxic protecting groups used temporarily to alter or remove a property of the compound. In one general aspect, the prodrug approach is used to facilitate oral absorption. For a comprehensive discussion, see T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems Vol. 14 of the A.C.S. Symposium Series; and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

Some embodiments of the present invention include a method of obtaining a pharmaceutical composition for combination therapy, including mixing at least

- 27 040124 one compound according to any one of the embodiments described herein, together with at least one known pharmaceutical agent as described herein, and a pharmaceutically acceptable carrier.

It should be noted that when GPR119 receptor modulators are used as active ingredients in pharmaceutical compositions, they are not intended for use only in humans, but also in non-human mammals. Recent advances in animal health dictate that consideration be given to the use of active agents, such as GPR119 receptor modulators, for the treatment of a GPR119 receptor-associated disease or disorder in companion animals [e.g., cats, dogs, etc.) and livestock. (eg horses, cows, etc.). The person skilled in the art clearly understands the suitability of such compounds under such conditions.

Hydrates and solvates.

Whenever the phrase pharmaceutically acceptable salts, solvates and hydrates or the phrase pharmaceutically acceptable salt, solvate or hydrate is used, when referring to the compounds described herein, it should be understood to include pharmaceutically acceptable solvates and/or hydrates of compounds, pharmaceutically acceptable salts of compounds, such as well as pharmaceutically acceptable solvates and/or hydrates of pharmaceutically acceptable salts of the compounds. It should also be understood that when the phrase pharmaceutically acceptable solvates and hydrates or the phrase pharmaceutically acceptable solvate or hydrate is used, when referring to the salts described herein, it is meant to encompass pharmaceutically acceptable solvates and/or hydrates of such salts.

One of skill in the art will appreciate that the dosage forms described herein may contain, as the active ingredient, either the compound described herein or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate or hydrate thereof. In addition, various hydrates and solvates of the compounds described herein and their salts will find use as intermediates in the preparation of pharmaceutical compositions. Exemplary procedures for the preparation and identification of suitable hydrates and solvates other than those mentioned herein are well known to those skilled in the art; see, for example, pages 202-209 of K.J. Guillory, Generation of Polymorphs, Hydrates, Solvates, and Amorphous Solids in: Polymorphism in Pharmaceutical Solids, ed. Harry G. Britain, Vol. 95, Marcel Dekker, Inc., New York, 1999. Accordingly, one aspect of the present invention relates to methods for administering hydrates and solvates of the compounds described herein and/or their pharmaceutically acceptable salts, which can be isolated and characterized using methods known in the art, such as thermogravimetric analysis (TGA), TGA mass spectroscopy, TGA-IR spectroscopy, X-ray powder diffraction (XRPD), Karl Fischer titration, high resolution X-ray diffraction, and the like. There are several commercial entities that provide fast and efficient services for the identification of solvates and hydrates on the job. Examples of companies offering these services include Wilmington PharmaTech (Wilmington, DE), Avantium Technologies (Amsterdam), and Aptuit (Greenwich, CT).

Polymorphic and pseudopolymorphic modifications.

Polymorphism is the ability of a substance to exist in the form of two or more crystalline phases that have different structures and/or conformations of molecules in the crystal lattice. Polymorphs exhibit the same properties in the liquid or gaseous state, but they behave differently in the solid state.

Besides single component polymorphs, drugs can also exist as salts and other multicomponent crystalline phases. For example, solvates and hydrates may contain an API as host and solvent or water molecules, respectively, as guests. 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 may also exhibit polymorphism. Crystalline phases that share the same API as a host, but differ in relation to their guests, can be referred to as pseudopolymorphs of each other.

Solvates contain crystallization solvent molecules in a specific crystal lattice. Solvates in which the crystallization solvent is water are called hydrates. Because water is a constituent of the atmosphere, drug hydrates can form quite easily. For example, Stahly recently published a polymorph analysis of 245 compounds consisting of a wide variety of structural types, which revealed approximately 90% of the compounds having multiple solid forms. Overall, approximately half of the compounds were polymorphs, often with one to three forms. Approximately one third of the compounds formed hydrates and approximately one third formed solvates. Co-crystal analysis data of 64 compounds showed that 60% formed co-crystals other than hydrates or solvates. (G.P. Stahly, Crystal Growth & Design (2007), 7(6), 1007-1026.)

- 28 040124

Combined therapy.

The compound of the invention may be administered as the sole active pharmaceutical agent (i.e. monotherapy), or it may be used in combination with one or more pharmaceutical agents (i.e. combination therapy), such as known antidiabetic agents, or administered together, or separately, for the treatment of diseases, conditions and disorders described herein. Therefore, another aspect of the present invention encompasses methods of treating a metabolic-related disorder, including a weight-related disorder such as obesity, comprising administering to a patient in need of such treatment a compound of formula (Ia), or a pharmaceutically acceptable salt, solvate or hydrate thereof, in combination with one or more pharmaceutical agents, such as anti-diabetic agents, as described herein.

In accordance with the present invention, the combination can be used by mixing the respective active ingredients, the compound of formula (Ia) and the pharmaceutical agent, either together or separately, optionally with a physiologically acceptable carrier, excipient, coupling agent, diluent, etc., as described herein, and administering the mixture or mixtures either orally or non-orally as pharmaceutical composition(s). When the compound of formula (Ia) is administered as a combination therapy with another active compound, the compound of formula (Ia) and the pharmaceutical agent may be formulated as separate pharmaceutical compositions prepared at the same time or at different times; or the compound of formula (Ia) and the pharmaceutical agent may be formulated together as a unit dosage form.

Suitable pharmaceutical agents that can be used in combination with the compounds of the present invention include anti-obesity agents such as inhibitors of apolipoprotein-B/microsomal triglyceride transfer protein (apo-B/MTP) secretion; MCR-4 agonists, cholecystokinin-A (CCK-A) agonists; serotonin and norepinephrine reuptake inhibitors (eg sibutramine); sympathomimetic agents; β3-adrenergic receptor agonists; dopamine agonists (eg, bromocriptine); melanocyte-stimulating hormone receptor analogs; cannabinoid receptor 1 antagonists [eg SR141716: N(piperidin-1-yl)-5-(4-chlorophenyl)1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide]; melanin-concentrating hormone antagonists; leptin (OB protein); leptin analogues; leptin receptor agonists; galanin antagonists; lipase inhibitors (such as tetrahydrolipstatin, i.e. orlistat); anorectic agents (such as bombesin agonist); neuropeptide-Y antagonists; thyromimetic agents; dehydroepiandrosterone or its equivalent; glucocorticoid receptor agonists or antagonists; orexin receptor antagonists; antagonists of urocortin binding protein; glucagon-like peptide-1 (GLP-1) receptor agonists; ciliary neurotrophic factors (such as Axokine™ available from Regeneron Pharmaceuticals, Inc., Tarrytown, NY and Procter & Gamble Company, Cincinnati, OH); human agoutis-associated proteins (AGRP); ghrelin receptor antagonists; histamine 3 receptor (H3R) antagonists or inverse agonists; neuromedin U receptor agonists; noradrenergic anorectic substances (eg phentermine, mazindol and the like); appetite suppressants (eg bupropion); and 5- _HT2c agonists (eg lorcaserin).

Other anti-obesity agents, including those set forth below, are well known or will be readily apparent in view of the present disclosure to one of skill in the art. In some embodiments, the anti-obesity agents are selected from the group consisting of orlistat, sibutramine, bromocriptine, ephedrine, leptin, pseudoephedrine, and lorcaserin. In a further embodiment, the compounds of the present invention and combination therapies are administered in conjunction with exercise and/or a low calorie diet.

It should be understood that the scope of combination therapy using the compounds of the present invention with anti-obesity agents, anorectic agents, appetite suppressants and related agents is not limited to the above, but includes essentially any combination with any pharmaceutical agent or pharmaceutical composition suitable for the treatment of overweight and obese patients.

It should be understood that the scope of combination therapy using the compounds of the present invention with other pharmaceutical agents is not limited to those listed herein above or below, but includes essentially any combination with any pharmaceutical agent or pharmaceutical composition useful for the treatment of diseases, conditions or disorders. associated with metabolic disorders.

Some embodiments of the present invention include methods of treating a disease, disorder, condition, or complication thereof, as described herein, comprising administering to a patient in need of such treatment a therapeutically effective amount or dose of a compound of formula (Ia) in combination with at least one pharmaceutical an agent selected from the group consisting of sulfonylureas (e.g., tolbutamide (Orinase); acetohexamide (Dimelor); tolazamide (Tolinase); chlorpropamide (Diabinez); glipizide (Glucotrol); glyburide (Diabeta, Micronase, Glinase); glimepiride (Amaryl) ; gliclazide (Diamicron) and sulfonylurea, known in

- 29 040124 of this field of technology); meglitinides (eg repaglinide (Prandin), nateglinide (Starlix), mitiglinide and other meglitinides known in the art); biguanides (eg phenformin, metformin, buformin and biguanides known in the art); α-glucosidase inhibitors (eg, acarbose, miglitol, and alpha-glucosidase inhibitors known in the art); peroxisome proliferator-activated (ie, PPAR-γ) thiazolidinedione receptor-γ agonists (eg, rosiglitazone (Avandia), pioglitazone (Actos), troglitazone (Rezulin), rivoglitazone, ciglitazone, and the thiazolidinediones known in the art); insulin and insulin analogues; antidiabetic peptide analogs (eg, exenatide, liraglutide, taspoglutide, and antidiabetic peptide analogs known in the art); HMG-CoA reductase inhibitors (eg, rosuvastatin, pravastatin and its sodium salt, simvastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin, rosuvastatin, pitavastatin, pravastatin, and other HMG-CoA reductase inhibitors known in the art); cholesterol-lowering drugs (e.g., fibrates, which include bezafibrate, beclobrate, binifibrate, ciprofibrate, clinofibrate, clofibrate, clofibric acid, etofibrate, fenofibrate, gemfibrozil, nicofibrate, pyrifibrate, ronifibrate, simfibrate, theofibrate, and other fibrates known in the art technical fields; bile acid sequestrants, which include cholestyramine, colestipol and the like; and niacin); antiplatelet agents (eg, aspirin and adenosine diphosphate receptor antagonists, which include clopidogrel, ticlopidine, and the like); angiotensin-converting enzyme inhibitors (eg, captopril, enalapril, alacepril, delapril, ramipril, lisinopril, imidapril, benazepril, ceronapril, cilazapril, enalaprilat, fosinopril, moveltopril, perindopril, quinapril, spirapril, temocapril, trandolapril, and other known angiotensin-converting enzyme inhibitors technical fields); angiotensin II receptor antagonists [eg, losartan (and the potassium salt form) and other angiotensin II receptor antagonists known in the art]; adiponectin; squalene synthesis inhibitors (e.g. (S)-α-[bis[2,2-dimethyl-1oxopropoxy)methoxy]phosphinyl]-3-phenoxybenzenebutanesulfonic acid, mono-potassium salt (BMS-188494) and other squalene synthesis inhibitors known in this field of technology; and the like. In some embodiments, the compounds of the present invention and the pharmaceutical agents are administered separately. In additional embodiments, the compounds of the present invention and pharmaceutical agents are administered simultaneously.

Suitable pharmaceutical agents that can be used in combination with the compounds of the present invention include, but are not limited to, amylin agonists (eg pramlintide); insulin secretagogues (eg, GLP-1 agonists, exendin-4, and insulinotropin (NN2211)); acyl CoA cholesterol acetyltransferase inhibitors (eg, ezetimibe, eflucimib, and other acyl CoA cholesterol acetyl transferase inhibitors known in the art); cholesterol absorption inhibitors (eg, ezetimibe, pamaqueside, and other cholesterol absorption inhibitors known in the art); cholesteryl ester transfer protein inhibitors (eg, CP-529414, JTT-705, CETi-1 and other cholesteryl ester transfer protein inhibitors known in the art); microsomal triglyceride transport protein inhibitors (eg, implitapid and other microsomal triglyceride transport protein inhibitors known in the art); cholesterol modulators (eg NO-1886 and other cholesterol modulators known in the art); bile acid modulators (eg, GT103-279 and other bile acid modulators known in the art); insulin signaling pathway modulators; protein tyrosine phosphatase (PTPase) inhibitors; non-small molecular weight mimetics and inhibitors of glutamine-fructose-6-phosphate amidotransferase (GFAT); compounds that affect the deregulated production of glucose in the liver; inhibitors of glucose-6-phosphatase (G6Pase); fructose-1,6-bisphosphatase (F-1,6-BPase) inhibitors; glycogen phosphorylase (GP) inhibitors; glucagon receptor antagonists; phosphoenolpyruvate carboxykinase (PEPCK) inhibitors; pyruvate dehydrogenase kinase (PDHK) inhibitors; insulin sensitivity enhancers; insulin secretion enhancers; gastric emptying inhibitors; a ₂ -adrenergic antagonists; retinoid X receptor (RXR) agonists; dipeptidyl peptidase-4 (DPP-IV) inhibitors; and the like.

Trinity combinations.

Some aspects of the present invention include compounds of formula (Ia), which can be used in any of the methods, pharmaceutical products, applications, compounds and pharmaceutical agents as described herein, in combination with two different pharmaceutical agents.

In some embodiments, the two different pharmaceutical agents are selected from any of the pharmaceutical agents or classes of pharmaceutical agents described herein. In some embodiments, the two different pharmaceutical agents are selected from: a DPP-IV inhibitor, a biguanide, an alpha-glucosidase inhibitor, an insulin analog, a sulfonylurea, an SGLT2 inhibitor, meglitinide, a thiazolidinedione, and an antidiabetic peptide analog. In some embodiments, the two different pharmaceutical agents comprise each combination selected from the following groups of pharmaceutical agents: a DPP-IV inhibitor, a biguanide, an alpha-glucosidase inhibitor, a sulfonylurea, and an SGLT2 inhibitor.

Some embodiments of the present invention include each combination of one or more compounds selected from the compounds of the following group and their pharmaceutically acceptable salts, solvates and hydrates: a DPP-IV inhibitor selected from:

3(R)-amino-1-[3-(trifluoromethyl)-5,6,7,8tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2, 4,5trifluorophenyl)butan-1-one; 1-[2-(3-hydroxyadamant-1ylamino)acetyl]pyrrolidine-2(S)-carbonitrile; (15,33,53)-2[2(3)-amino-2-(3-hydroxyadamantan-1-yl)acetyl]-2azabicyclo[3.1.0]hexane-3-carbonitrile; 2-[6-[3(R)aminopiperidin-1-yl]-3-methyl-2,4-dioxo-1,2,3,4tetrahydropyrimidin-1-ylmethyl]benzonitrile; 8-[3(R)aminopiperidin-1-yl]-7-(2-butynyl)-3-methyl-1-(4-methylquinazolin2-ylmethyl)xanthine; 1-[Y-[3(R)-pyrrolidinyl]glycyl]pyrrolidin2(R)-yl boronic acid; 4(3)-fluoro-1-[2-[(1R,33)-3-(1H-1,2,4triazol-1-ylmethyl)cyclopentylamino]acetyl]pyrrolidine-2(3)carbonitrile; 1-[(23,33,11b3)-2-amino-9,10-dimethoxy2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-3-yl]— 4(3)-(fluoromethyl)pyrrolidin-2-one; (23.43)-2-cyano-4-fluoro-1-[(2hydroxy-1,1-dimethyl)ethylamino]acetylpyrrolidine; 8-(cishexahydro-pyrrolo[3,2-b]pyrrol-1-yl)-3-methyl-7-(3-methyl-but-2enyl)-1-(2-oxo-2-phenylethyl)-3, 7-dihydro-purine-2,6-dione; 1((33.43)-4-amino-1-(4-(3,3-difluoropyrrolidin-1-yl)-1,3,5triazin-2-yl)pyrrolidin-3-yl)-5,5- difluoropiperidin-2-one; (R)-2((6-(3-aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3,4dihydropyrimidin-1(2H)-yl)methyl)-4-fluorobenzonitrile; 5-{(3)-2[2-((3)-2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-propyl}-5(1H-tetrazol-5-yl)-10, 11-dihydro-5H-dibenzo[a,d]cycloheptene2,8-dicarboxylic acid bis-dimethylamide; ((23.43)-4-(4-(3methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2yl)(thiazolidin-3-yl)methanone; (23.43)-1-[2-[(4-ethoxycarbonyl-bicyclo[2.2.2]οκτ-1-yl)amino]acetyl]-4fluoropyrrolidine-2-carbonitrile; 6-[(3Λ)-3-amino-piperidin-1-yl]5-(2-chloro-5-fluoro-benzyl)-1,3-dimethyl-1,5-dihydro-pyrrolo[3,2d]pyrimidine -2,4-diones; 2— ({6—[ (3Λ)-3-amino-3-methylpiperidin-1yl]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3, 2-d]pyrimidin-5-yl}methyl)-4-fluorobenzonitrile; (23)-1-{[2-(5methyl-2-phenyl-oxazol-4-yl)-ethylamino]-acetyl}-pyrrolidine-2-carbonitrile; (23)-1-{[1,1-dimethyl-3-(4-pyridin-3-yl-imidazol1-yl)-propylamino]-acetyl}-pyrrolidine-2-carbonitrile; (3,3difluoropyrrolidin-1-yl)-((23.43)-4-(4-(pyrimidin-2-yl)piperazin1-yl)pyrrolidin-2-yl)methanone; (23.43)-1-[(23)-2-amino-3,3bis(4-fluorophenyl)propanoyl]-4-fluoropyrrolidine-2-carbonitrile; (23.5Λ)-5-ETHYNyl-1-{Y-(4-methyl-1-(4-carboxy-pyridin-2yl)piperidin-4-yl)glycyl}pyrrolidin-2-carbonitrile; and (IS,6R)3-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine7(8H)-yl]carbonyl}-6-(2 ,4,5-trifluorophenyl)cyclohex-3-en-1amine; biguanide selected from phenformin ((phenylethyl)biguanide); metformin (dimethylbiguanide);

- 31 040124 buformin (butyl biguanide); and proguanil (1-(p-chlorophenyl)-5-isopropyl biguanide); an alpha-glucosidase inhibitor selected from acarbose ((2R,3R,4R,5R)-4-((2R,3R,4R,5s,6R)-5-((2R,3R,4s,5S,6R)-3 ,4-dihydroxy-6-methyl-5((1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)cyclohex-2-enylamino)tetrahydro-2H-pyran-2yloxy)-3 ,4-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yloxy)-2,3,5,6tetrahydroxyhexanal);

miglitol ((2R,3R,4R,5S)-1-(2-hydroxyethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol); and vogliboses ((1S,2S,3R,4S,5S)-5-(1,3-dihydroxupropαn-2-ylamino)-1-(hydroxumethyl)cyclohexan1,2,3,4-tetraol);

an insulin analogue selected from NPH insulin (also known as Humulin H, Novolin H, NPH Iletin II and insulin isophane);

insulin lispro (28BT-lysine-29BT-proline-insulin, wherein the insulin is human insulin);

insulin aspart (28B-L-aspartic acid-insulin, wherein the insulin is human insulin); and insulin glulisine (3B-L-lysine-29B-L-glutamic acid-insulin, wherein the insulin is human insulin);

a sulfonylurea selected from tolbutamide (Orinase, N-(butylcarbamoyl)-4-methylbenzenesulfonamide);

acetohexamide (Dimelor, 4-αcetyl-N-(cyclohexylcarbαmoyl)benzenesulfonαamide);

tolazamide (Tolinase, N-(azepan-1-ylcarbamoyl)-4-methylbenzenesulfonamide);

chlorpropamide (Diabenez, 4-chloro-N-(propylcarbamoyl)benzenesulfonamide);

glipizide (Glucotrol, N-(4-{N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-5-methylpyrazine-2carboxamide);

glibenclamide, also known as glyburide (Diabeta, Micronase, Glinase, 5-χλορ-N-(4-(N(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-2-methoxybenzamide);

glimepiride (Amaryl, 3-ethyl-4-methyl-N-(4-(N-((1r,4r)-4-methylcyclohexylcarbamoyl)sulfamoyl)phenethyl)-2-oxo-2,5-dihydro-1H-pyrrole- 1-carboxamide); and gliclazide (Diamicron, N-(hexahydrocyclopenta[c]pyrrol-2(1 H)-ylcarbamoyl)-4-methylbenzenesulfonamide);

an SGLT2 inhibitor selected from dapagliflozin ((2S,3R,4R,5S,6R)-2-(4-chloro-3-(4ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5 -triol);

remogliflozin (ethyl((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(4-(4-isopropoxybenzyl)-1isopropyl-5-methyl-1H-pyrazol-3-yloxy)tetrahydro -2H-pyran-2-yl)methyl carbonate);

ASP1941, canagliflozin ((2S,3R,4R,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4methylphenyl)-6-(hydroxymethyl)tetrahydro-2H -pyran-3,4,5-triol);

ISIS 388626; sergliflozin (ethyl ((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(2-(4-methoxybenzyl)phenoxy)tetrahydro-2H-pyran-2-yl)methyl carbonate);

AVE2268 ((2R,3S,4S,5R,6S)-2-(hydroxymethyl)-6-(2-(4-methoxybenzyl)thiophen-3-yloxy)tetrahydro2H-pyran-3,4,5-triol), BI10773 .CSG453; and LX4211;

meglitinide selected from repaglinide (Prandin, (S)-2-ethoxy-4-(2-(3-methyl-1-(2-(piperidin-1yl)phenyl)butylamino)-2-oxoethyl)benzoic acid);

nateglinide (Starlix, (R)-2-((1r,4R)-4-isopropylcyclohexanecarboxamido)-3-phenylpropionic acid); and mitiglinide ((S)-2-benzyl-4-((3aR,7aS)-1H-isoindole-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)-4oxobutanoic acid);

a thiazolidinedione selected from rosiglitazone (Avandia, 5-(4-(2-(methyl(pyridin-2yl)amino)ethoxy)benzyl)thiazolidine-2,4-dione);

pioglitazone (Actos, 5-(4-(2-(5-ethylpyridin-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione); troglitazone (Rezulin, 5-(4-((6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)methoxy)benzyl)thiazolidine-2,4-dione);

rivoglitazone (5-(4-((6-methoxy-1-methyl-1H-benzo[d]imidazol-2-yl)methoxy)benzyl)thiazolidine-2,4dione); and ciglitazone (5-(4-((1-methylcyclohexyl)methoxy)benzyl)thiazolidine-2,4-dione); and an antidiabetic peptide analog selected from exenatide, liraglutide and taspoglutide.

In some embodiments, two different pharmaceutical agents include each combination selected from the following group of pharmaceutical agents: sitagliptin, vildagliptin, saxagliptin, alogliptin, linagliptin, phenformin, metformin, buformin, acarbose, miglitol, voglibose, tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide , glibenclamide, glimepiride, gliclazide, dapagliflozin, remogliflozin and sergliflozin.

Dipeptidyl peptidase IV inhibitors.

Dipeptidyl peptidase IV (DPP-IV, EC 3.4.14.5) has catalytic activity against a wide range of peptide substrates, which include peptide hormones, neuropeptides, and

- 32 040124 chemokines. The incretins glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which stimulate glucose-dependent insulin secretion and otherwise maintain blood glucose homeostasis, are rapidly cleaved by DPP-IV at position-2 of alanine, resulting in inactivation of their biological activity. Peptide YY (PYY) is a gut peptide that has been directly linked to the modulation of satiety (Chaudhri et al., Annu Rev Physiol (2008), 70:239-255). PYY is released into the circulation as PYY1-36 and PYY ₃ . ₃₆ (Eberlein et al., Peptides (1989), 10:797-803). PYY ₃ . ₃₆ is formed from PYY1-36 by DPP-IV cleavage of the N-terminal Tyr and Pro residues. Both pharmacological and genetic attenuation of DPP-IV activity is associated with increased incretin action, elevated insulin levels, and reduced blood glucose levels in vivo. Genetic attenuation of DPP-IV activity has been shown to confer resistance to obesity and increased insulin sensitivity. DPP-IV inhibitors have been shown to be useful as therapeutic agents, for example oral administration of vildagliptin (1-[2-(3-hydroxyadαmant-1-ylamino)acetyl]pyrrolidine-2(S)-carbonitrile) or sitagliptin (3( J)-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) in patients suffering from type 2 diabetes mellitus has been found to reduce fasting blood glucose and postprandial blood glucose elevation due to significantly reduced HbA _1c levels. For a review on the use of DPP-IV inhibitors for the treatment of type 2 diabetes, reference is made to the following publications:

(1) H.-U. Demuth, et al., Type 2 diabetes-therapy with DPP-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).

Accordingly, suitable pharmaceutical agents include DPP-IV inhibitors, which can be used in combination with the compounds of the present invention, either dosed separately or together. DPP-IV inhibitors are well known in the art or can be readily identified and their in vitro biological activity determined using any number of available methods, e.g. O'Brien, M., Daily, B., Schurria, M., Assay for DPPIV activity using a homogeneous, luminescent method, Cell Notes, Issue 11, 2005; see also the DPPIV-Glo™ Protease Assay Technical Bulletin #TB339.

Examples of DPP-IV inhibitors are described in Villhauer et al., J. Med. Chem. (2003), 46:2774-2789, for LAF237; Ahren et al., J. Clin. Endocrinol. Metab. (2004), 89:2078-2084; Villhauer et al., J. Med. Chem. (2002), 45:2362-2365 for NVP-DPP728; Ahren et al., Diabetes Care (2002), 25:869-875 for NVP-DPP728; Peters et al., Bioorg. Med. Chem. Lett. (2004), 14:1491-1493; Caldwell et al., Bioorg. Med Chem. Lett. (2004), 14:12651268; Edmondson et al., Bioorg. Med. Chem. Lett. (2004), 14:5151-5155; and Abe et al., J. Na.t Prod. (2004), 67:999-1004.

Certain examples of DPP-IV inhibitors include, but are not limited to, dipeptide derivatives or dipeptide mimetics such as alanine pyrrolidide, isoleucine thiazolidide, and pseudosubstrate IV-valyl-prolyl, O-benzoyl-hydroxylamine, as described, for example, in US Pat. No. 6303661.

Some embodiments of the present invention include each combination of one or more DPP-IV inhibitors selected from the DPP-IV inhibitors found in US Pat. Nos. 6,869,947; 6,867,205; 6645995, 6617340, 6699871, 6573287, 6432969, 6395767, 6380398, 6303661, 6242422, 6166063, 61100234 and 6040145.

Some embodiments of the present invention include each combination of one or more DPP-IV inhibitors selected from the DPP-IV inhibitors found in the US patents:

2005059724, 2005059716, 2005043292, 2005038020, 2005032804, 2005004205, 2004259903, 2004259902, 2004259883, 2004254226, 2004242898, 2004229926, 2004180925, 2004176406, 2004138214, 2004116328, 2004110817, 2004106656, 2004097510, 2004087587, 2004082570, 2004077645, 2004072892, 2004063935, 2004034014, 2003232788, 2003225102, 2003216450, 2003216382, 2003199528, 2003195188, 2003162820, 2003149071, 2003134802, 2003130281, 2003130199, 2003125304, 2003119750, 2003119738, 2003105077, 2003100563, 2003087950, 2003078247, 2002198205, 2002183367,

2002103384, 2002049164 and 2002006899.

Some embodiments of the present invention include each combination of one or more DPP-IV inhibitors selected from DPP-IV inhibitors found in international patent applications:

- 33 040124

Wo 2005/087235, Wo 2005/082348, Wo 2005/082849, Wo 2005/079795, Wo 2005/075426, Wo 2005/072530, Wo 2005/063750, Wo 2005/058849, Wo 2005/049022, Wo 2005/047297,, Wo 2005/047297, Wo 2005/044195, Wo 2005/042488, Wo 2005/040095, Wo 2005/037828, Wo 2005/037779, Wo 2005/034940, Wo 2005/033099, WO 2005/032590, Wo 2005/030751, Wo 2005/030127, Wo 2005/030127, WO 2005/026148, WO 2005/025554, WO 2005/023762, WO 2005/020920, WO 05/19168, WO 05/12312, WO

05/12308, WO 05/12249, WO 05/11581, WO 05/09956, WO 05/03135, 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 03/22 871, WO 03/15775, WO 03/04498, WO 03/04496, WO 03/02530, WO

03/02596, 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

02/83128, 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 present invention include each combination of one or more DPP-IV inhibitors selected from the DPP-IV inhibitors found in patent publications:

- 34 040124

1489088,

EP

1465891,

EP

1442049,

EP

1406872,

EP

1399470,

EP

1377288,

EP

1304327,

EP

1261586,

EP

1215207,

EP

1082314,

EP

0975359,

EP

2466870,

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2123128,

DD

19616486,

EP 1517907, EP 1513808, EP 1492777,

1480961,

1463727,

1441719,

1406622,

1399469,

1355886,

1301187,

1258476,

1228061,

1050540,

0731789,

2433090,

EP

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EP

EP

EP

EP

EP

EP

EP

EP

EP

EP

EP

SA

1476435

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1476429,

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1461337, EP

1426366, EP

1404675,

1399433,

1354882,

1296974,

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1137635,

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0641347,

2339537,

296075, DE 19834591,

DE

EP

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EP

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EP

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SA

1450794,

1412357,

1399420,

1399154,

1338592,

1280797,

1248604,

1123272,

0995440,

0610317,

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DE 19828113,

EP

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EP1406873,

EP 1399471

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1385508,

1333025,

1282600,

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1104293,

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EP

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EP

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SA

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DE 10251927,

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2004244412,

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2003535034

2003524591,

2003238566,

2002516318,

2002265439,

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DE 10238477,

FR2822826,

10333935, DE 10327439, DE 10256264,

DE 10238470, DE 10238243, DE 10143840, FR 2824825, JP 2005507261, JP 2005505531, JP 2005502624, JP JP 2005500308, JP 2005023038, JP 2004536115, JP JP 2004535433, JP 2004534836, JP 2004534815, JP JP 2004530729, JP 2004525929, JP 2004525179, JP JP 2004521149, JP 2004503531, JP 2004315496, JP JP 2004043429, JP 2004035574, JP 2004026820, JP JP 2004002368, JP 2004002367, JP 2003535898, JP JP 2003531204, JP 2003531191, JP 2003531118, JP JP 2003520849, JP 2003327532, JP 2003300977, JP JP 2002531547, JP 2002527504, JP 2002517401, JP JP 2002363157, JP 2002356472, JP 2002356471, JP JP 2001510442, JP 2000511559, JP 2000327689, JP JP 1998182613, JP 1998081666, JP 1997509921, JP JP 1993508624. implementation of the DPP-IV inhibitor has IC50 less than approximately

than than

1995501078 and

In some embodiments, µM, less than about 1 µM, less than about 100 nM, less than about 75 nM, less than about 50 nM, less than about 25 nM, less than about 20 nM, less than about 15 nM, less than about 10 nM , less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, or less than about 1 nM in any one of the DPP-IV inhibitor assays known in the art, including those in references disclosed in the present description. In some embodiments, the DPP-IV inhibitor has an IC50 of less than about 50 nM, less than about 25 nM, less than about 20 nM, less than about 15 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than less than about 3 nM, less than about 2 nM, or less than about 1 nM in any one of the DPP-IV inhibitor studies known in the art, including those in the references disclosed herein.

In some embodiments, the DPP-IV inhibitor is a selective DPP-IV inhibitor, wherein the selective DPP-IV inhibitor has selectivity for human plasma DPP-IV over one or more of PPCE, DPP-II, DPP-8, and DPP- 9 at least about 10 times. In some embodiments, the DPP-IV inhibitor is a selective DPP-IV inhibitor, wherein the selective DPP-IV inhibitor has selectivity for human plasma DPP-IV over one or more of PPCE, DPP-II, DPP-8, and DPP -9 at least about 100 times. In some embodiments, the DPP-IV inhibitor is a selective DPP-IV inhibitor, wherein the selective DPP-IV inhibitor has selectivity for human plasma DPP-IV over one or more of PPCE, DPP-II, DPP-8, and DPP -9 at least about 10 times. In some embodiments

- 35 040124 DPP-IV inhibitor is a selective DPP-IV inhibitor, wherein the selective DPP-IV inhibitor has selectivity for human plasma DPP-IV over one or more of PPCE, DPP-II, DPP-8 and DPP- 9 at least about 1000 times.

In some embodiments, the DPP-IV inhibitor is orally active.

In some embodiments, the DPP-IV inhibitor is a human DPP-IV inhibitor.

Some embodiments of the present invention include each combination of one or more DPP-IV inhibitors selected from the following group of DPP-IV inhibitors and their pharmaceutically acceptable salts, solvates and hydrates:

h (R)amino-1-[3-(trifluoromethyl)-5,6,7,8tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4 ,5trifluorophenyl)butan-1-one; 1-[2-(3-hydroxyadamant-1ylamino)acetyl]pyrrolidine-2(S)-carbonitrile; (IS,3S,5S)-2[2(S)-amino-2-(3-hydroxyadamantan-1-yl)acetyl]-2azabicyclo[3.1.0]hexane-3-carbonitrile; 2-[6-[3(5)aminopiperidin-1-yl]-3-methyl-2,4-dioxo-1,2,3,4tetrahydropyrimidin-1-ylmethyl]benzonitrile; 8-[3(R)aminopiperidin-1-yl]-7-(2-butynyl)-3-methyl-1-(4-methylquinazolin-36 040124

2-ylmethyl)xanthine; 1-[R-[3(R)-pyrrolidinyl]glycyl]pyrrolidin2(R)-yl boronic acid; 4(5)-fluoro-1-[2-[(1R,35)-3-(1H-1,2,4triazol-1-ylmethyl)cyclopentylamino]acetyl]pyrrolidine-2(5)carbonitrile; 1-[(25, 35, 11b5)-2-amino-9,10-dimethoxy2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-3-yl]- 4(5)(fluoromethyl)pyrrolidin-2-one; (25.45)-2-cyano-4-fluoro-1-[(2hydroxy-1,1-dimethyl)ethylamino]acetylpyrrolidine; 8-(cishexahydro-pyrrolo[3,2-b]pyrrol-1-yl)-3-methyl-7-(3-methyl-but-2enyl)-1-(2-oxo-2-phenylethyl)-3, 7-dihydro-purine-2,6-dione; 1((35.45)-4-amino-1-(4-(3,3-difluoropyrrolidin-1-yl)-1,3,5triazin-2-yl)pyrrolidin-3-yl)-5,5- difluoropiperidin-2-one; (R)-2((6-(3-aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3,4dihydropyrimidin-1(2H)-yl)methyl)-4-fluorobenzonitrile; 5-{(67)-2[2-((5)-2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-propyl}-5(1H-tetrazol-5-yl)-10, 11-dihydro-5R-dibenzo[a,d]cycloheptene2,8-dicarboxylic acid bis-dimethylamide; ((25, 45)-4-(4-(3methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2yl)(thiazolidin-3-yl)methanone; (25, 45)-1-[2-[(4ethoxycarbonylbicyclo[2.2.2]οκτ-1-yl)amino]acetyl]-4fluoropyrrolidine-2-carbonitrile; 6-[(3A)-3-Amino-piperidin-1-yl]5-(2-chloro-5-fluoro-benzyl)-1,3-dimethyl-1,5-dihydro-pyrrolo[3,2d]pyrimidine -2,4-diones; 2-({6-[(3A)-3-amino-3-methylpiperidin-1yl]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5R-pyrrolo[3, 2-d]pyrimidin-5-yl[methyl)-4-fluorobenzonitrile; (25)-1-{[2-(5methyl-2-phenyl-oxazol-4-yl)-ethylamino]-acetyl}-pyrrolidine-2-carbonitrile; (25)-1-{[1,1-dimethyl-3-(4-pyridin-3-yl-imidazol1-yl)-propylamino]-acetyl}-pyrrolidine-2-carbonitrile; (3,3difluoropyrrolidin-1-yl)-((25.45)-4-(4-(pyrimidin-2-yl)piperazin1-yl)pyrrolidin-2-yl)methanone; (25, 45) -1-[(25)-2-amino-3,3bis(4-fluorophenyl)propanoyl]-4-fluoropyrrolidine-2-carbonitrile; (25.5A)-5-ETHYNyl-1-{N-(4-methyl-1-(4-carboxy-pyridin-2yl)piperidin-4-yl)glycyl}pyrrolidin-2-carbonitrile; and (15.6A)3-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine7(8R)-yl]carbonyl}-6-(2 ,4,5-trifluorophenyl)cyclohex-3-en-1amine.

Sitagliptin phosphate (Januvia®, MK-0431, dihydrogen phosphate 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 is marketed by Merck & Co. for the once-daily oral treatment of type 2 diabetes Januvia was first released in Mexico with followed by commercial release in the U.S. In 2007, the product was approved by the European Medicines Evaluation Agency (EMEA) and is currently available in the UK, Germany, and Spain.In 2009, Januvia was approved and released in Japan.In addition, Merck also filed for approval by Januvia in the US as an adjunct to diet and exercise and in combination with other therapies to improve glycemic control in the treatment of diabetes mellitus Compound 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 and pharmaceutically acceptable salts thereof are disclosed in international patent published in WO 2003/004498. Some embodiments of the present invention include each combination of one or more compounds selected from those described in WO 2003/004498 and their pharmaceutically acceptable salts, solvates and hydrates. In some embodiments, the DPP-IV inhibitor is selected from 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 and its pharmaceutically acceptable salts, solvates and hydrates:

- 37 040124

In some embodiments, the DPP-IV inhibitor is 3^)-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-1one phosphate:

Crystalline form of 3(R)-amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3а]pyrazin-7-yl]-4-( 2,4,5-trifluorophenyl)butan-1-one phosphate monohydrate is disclosed in International Patent Publication WO 2005/003135. In some embodiments, the DPP-IV inhibitor is crystalline 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 phosphate monohydrate.

Vildagliptin (Galvus®, LAF-237, 1-[2-(3-hydroxyadamant-1-ylamino)acetyl]pyrrolidine-2(S)carbonitrile) is another DPP-IV inhibitor and was first marketed in Brazil and Mexico by Novartis for oral treatment of type 2 diabetes mellitus once a day. In 2008, an application for registration (MAA) was approved in the EU for this indication, and release took place in the UK in March 2008. An approval letter has been received for a regulatory application filed in the US. Vildagliptin was approved in Japan in 2010. The compound 1-[2-(3-hydroxyadamant1-ylamino)acetyl]pyrrolidine-2(S)-carbonitrile is disclosed in International Patent Publication WO 2000/034241. Some embodiments of the present invention include each combination of one or more compounds selected from those disclosed in WO 2000/034241 and their pharmaceutically acceptable salts, solvates and hydrates. In some embodiments, the DPP-IV inhibitor is selected from 1-[2-(3-hydroxyadamant-1-ylamino)acetyl]pyrrolidine-2(S)-carbonitrile and pharmaceutically acceptable salts, solvates and hydrates thereof:

Certain salts of the 1-[2-(3-hydroxyadamant-1-ylamino)acetyl]pyrrolidine-2(S)carbonitrile compound are disclosed in International Patent Publication WO 2007/019255. In some embodiments, the DPP-IV inhibitor is 1-[2-(3-hydroxyadamant-1ylamino)acetyl]pyrrolidine-2(S)-carbonitrile HCl:

Saxagliptin (Ongliza™, BMS-477118, (1S,3S,5S)-2-[2(S)-amino-2-(3-hydroxyadamantan-1yl)acetyl]-2-azabicyclo[3.1.0]hexane-3 -carbonitrile) is another DPP-IV inhibitor that was launched by AstraZeneca and Bristol-Myers Squibb in the USA for the treatment of type 2 diabetes in 2009. In 2009, the product was approved in the EU for the treatment of type 2 diabetes, either alone or in combination with metformin. Phase III clinical trials are ongoing in Japan for the treatment of type 2 diabetes. The compound (1S,3S,5S)-2-[2(S)-amino-2-(3hydroxyadamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile is disclosed in International Patent Publication WO 2001/068603. Some embodiments of the present invention include each combination of one or more compounds selected from those disclosed in WO 2001/068603 and their pharmaceutically acceptable salts, solvates and hydrates. In some embodiments, the DPP-IV inhibitor is selected from (1S,3S,5S)-2-[2(S)-amino-2-(3-hydroxyadamantan-1yl)acetyl]-2-azabicyclo[3.1.0]hexane- 3-carbonitrile and its pharmaceutically acceptable salts, solvates and hydrates:

- 38 040124

Takeda has filed for regulatory approval of a DPP-IV inhibitor, alogliptin (SYR-322, Nezina®,

2-[6-[3^)-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-ylmethyl]benzonitrile) in Japan and USA for oral treatment type 2 diabetes mellitus, once a day.

Compound

2-[6-[3^)-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1 ylmethyl]benzonitrile and pharmaceutically acceptable salts thereof are disclosed in International Patent publications WO 2005/095381. Some embodiments of the present invention include each combination of one or more compounds selected from those disclosed in WO 2005/095381 and their pharmaceutically acceptable salts, solvates and hydrates. In some embodiments, the DPP-IV inhibitor is selected from 2-[6-[3^)-aminopiperidin-1-yl]-3-methyl-2,4-dioxo1,2,3,4-tetrahydropyrimidin-1-ylmethyl]benzonitrile and its pharmaceutically acceptable salts, solvates and hydrates:

The crystalline form of 2-[6-[3(R)-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-ylmethyl]benzonitrile is disclosed in International Patent Publication WO 2007/035372. In some embodiments, the DPP-IV inhibitor is 2-[6-[3(R)-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1- ylmethyl]benzonitrile benzoate:

Linagliptin (BI-1356, Ondero®, Tragenta™, 8-[3(R)-aminopiperidin-1-yl]-7-(2-butynyl)-3methyl-1-(4-methylquinazolin-2-ylmethyl)xanthine) is a DPP-IV inhibitor in a Phase 3 clinical trial by Boehringer Ingelheim to evaluate its potential as an add-on therapy to metformin for the treatment of type 2 diabetes mellitus. The compound 8-[3(R)-aminopiperidin-1-yl]7-(2-butynyl)-3-methyl-1-(4-methylquinazolin-2-ylmethyl)xanthine is disclosed in International Patent Publication WO 2004/018468. Some embodiments of the present invention include each combination of one or more compounds selected from those disclosed in WO 2004/018468 and their pharmaceutically acceptable salts, solvates and hydrates. In some embodiments, the DPP-IV inhibitor is selected from 8-[3(R)-aminopiperidin-1-yl]-7-(2-butynyl)-3-methyl1-(4-methylquinazolin-2-ylmethyl)xanthine and its pharmaceutically acceptable salts, solvates and hydrates:

Some polymorphic modifications of the compound 8-[3(R)-aminopiperidin-1-yl]-7-(2-butynyl)3-methyl-1-(4-methylquinazolin-2-ylmethyl)xanthine are disclosed in international patent publication WO 2007/ 128721. In some embodiments, the DPP-IV inhibitor is a crystalline form of 8-[3(R)-aminopiperidin-1-yl]-7-(2-butynyl)-3-methyl-1-(4-methylquinazolin-2ylmethyl)xanthine.

Dutogliptin (PHX-1149, 1-[N-[3(R)-pyrrolidinyl]glycyl]pyrrolidin-2(R)-yl boronic acid) is a DPP-IV inhibitor in the Phenomix and Forest Phase III clinical trials for the oral treatment of diabetes. type 2 diabetes once a day. The compound 1-[N-[3(R)pyrrolidinyl]glycyl]pyrrolidin-2(R)-yl boronic acid and pharmaceutically acceptable salts thereof are disclosed in International Patent Publication WO 2005/047297. Some embodiments of the present invention include each combination of one or more compounds selected from those disclosed in WO 2005/047297 and their pharmaceutically acceptable salts, solvates and hydrates. In some embodiments, the DPP-IV inhibitor is selected from 1-[N-[3(R)pyrrolidinyl]glycyl]pyrrolidin-2(R)-yl boronic acid and pharmaceutically acceptable salts, solvates and hydrates thereof:

- 39 040124

The crystalline form of 1-[N-[3(R)-pyrrolidinyl]glycyl]pyrrolidin-2(R)-yl boronic acid tartrate is disclosed in International Patent Publication WO 2008/027273. In some embodiments, the DPP-IV inhibitor is 1-[N-[3(R)-pyrrolidinyl]glycyl]pyrrolidin2(R)-yl boronic acid tartrate:

Melogliptin (GRC-8200, 4(S)-fluoro-1-[2-[(1 R,3 S)-3-( 1H-1,2,4-triazol-1 -ylmethyl)cyclopentylamino]acetyl]pyrrolidine- 2(S)-carbonitrile) is a DPP-IV inhibitor currently in phase II clinical trials by Glenmark Pharmaceuticals and Merck KGaA for the treatment of type 2 diabetes mellitus. The compound 4(S)-fluoro-1-[2-[(1R,3S)-3-(1H-1,2,4-triazol-1ylmethyl)cyclopentylamino]acetyl]pyrrolidine-2(S)-carbonitrile is disclosed in an international patent publication WO 2006/040625. Some embodiments of the present invention include each combination of one or more compounds selected from those disclosed in WO 2006/040625 and their pharmaceutically acceptable salts, solvates and hydrates. In some embodiments, the DPP-IV inhibitor is selected from 4(S)-fluoro-1-[2-[(1R,3S)-3-(1H-1,2,4-triazol-1ylmethyl)cyclopentylamino]acetyl]pyrrolidin- 2(S)-carbonitrile and its pharmaceutically acceptable salts, solvates and hydrates:

Carmegliptin (R-1579, 1-[(2S,3S,11bs)-2-amino-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1Hpyrido[2,1-a]isoquinoline -3-yl]-4(S)-(fluoromethyl)pyrrolidin-2-one) is a DPP-IV inhibitor. Compound 1-[(2S,3S,11bs)-2-amino-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1a]isoquinolin-3-yl] -4(S)-(fluoromethyl)pyrrolidin-2-one is disclosed in International Patent Publication WO 2005/000848. Some embodiments of the present invention include each combination of one or more compounds selected from those disclosed in WO 2005/000848 and their pharmaceutically acceptable salts, solvates and hydrates. In some embodiments, the DPP-IV inhibitor is selected from -a]isoquinolin-3-yl]-4(S)-(fluoromethyl)pyrrolidin-2-one and its pharmaceutically acceptable salts, solvates and hydrates:

Taisho has disclosed a (2S,4S)-2-cyano-4-fluoro-1-[(2-hydroxy-1,1-dimethyl)ethylamino]acetylpyrrolidine DPP-IV inhibitor in US Patent Publication 2007/0112059. Some embodiments of the present invention include each combination of one or more compounds selected from those disclosed in US Publication 2007/0112059 and their pharmaceutically acceptable salts, solvates and hydrates. In some embodiments, the DPP-IV inhibitor is selected from (2S,4S)-2-cyano-4-fluoro-1-[(2-hydroxy-1,1-dimethyl)ethylamino]acetylpyrrolidine and pharmaceutically acceptable salts, solvates and hydrates thereof :

Sanofi-Aventis has disclosed a range of substituted bicyclic 8-pyrrolidinoxanthine derivatives as DPP-IV inhibitors in US Publication 2007/0167468. Some embodiments of the present invention include each combination of one or more compounds selected from those disclosed in US 2007/0167468 and their pharmaceutically acceptable salts, solvates and hydrates. In some embodiments, the DPP-IV inhibitor is selected from 8-(cis-hexahydro-pyrrolo[3,2-b]pyrrol-1-yl)-3-methyl-7-(3-methyl-but-2-enyl)- 1-(2-oxo-2-phenylethyl)3,7-dihydro-purine-2,6-dione and its pharmaceutically acceptable salts, solvates and hydrates:

- 40 040124

Pfizer has disclosed a range of 3-aminopyrrolidine-4-lactam derivatives as DPP-IV inhibitors in International Patent Publication WO 2007/148185. Some embodiments of the present invention include each combination of one or more compounds selected from those disclosed in WO 2007/148185 and their pharmaceutically acceptable salts, solvates and hydrates. One such compound is 1-((3S,4S)-4-amino-1-(4-(3,3-difluoropyrrolidin-1-yl)-1,3,5triazin-2-yl)pyrrolidin-3-yl )-5,5-difluoropiperidin-2-one. In some embodiments, the DPP-IV inhibitor is selected from 1-((3S,4S)-4-amino-1-(4-(3,3-difluoropyrrolidin-1-yl)-1,3,5-triazin-2yl) pyrrolidin-3-yl)-5,5-difluoropiperidin-2-one and its pharmaceutically acceptable salts, solvates and hydrates:

Syrrx has disclosed a range of substituted pyrimidine-2,4(1H,3H)-dione derivatives as DPP-IV inhibitors in International Patent Publication WO 2005/095381. Some embodiments of the present invention include each combination of one or more compounds selected from those disclosed in WO 2005/095381 and their pharmaceutically acceptable salts, solvates and hydrates. One such compound is (R)-2-((6-(3-aminopiperidin-1-yl)-3-methyl-2,4-dioxo3,4-dihydropyrimidin-1(2H)-yl)methyl)-4 -fluorobenzonitrile. In some embodiments, the DPP-IV inhibitor is selected from (R)-2-((6-(3-aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3,4dihydropyrimidin-1(2H)-yl )methyl)-4-fluorobenzonitrile and its pharmaceutically acceptable salts, solvates and hydrates:

Various crystalline forms of (R)-2-((6-(3-aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3,4dihydropyrimidin-1(2H)-yl)methyl)-4-fluorobenzonitrile succinic acid salts are disclosed in international patent publication WO 2008/067465. One embodiment of the present invention relates to any one or more crystalline forms of (R)-2-((6-(3-aminopiperidin-1-yl)-3methyl-2,4-dioxo-3,4-dihydropyrimidine-1(2H )-yl)methyl)-4-fluorobenzonitrile salt of succinic acid as described in International Patent Publication WO 2008/067465. In some embodiments, the DPP-IV inhibitor is crystalline (R)-2-((6-(3-aminopiperidin-1-yl)-3methyl-2,4-dioxo-3,4-dihydropyrimidine-1(2H)- yl)methyl)-4-fluorobenzonitrile acid:

amber salt

Alantos has disclosed a range of substituted 2-cyanopyrrolidine derivatives as DPP-IV inhibitors in International Patent Publication WO 2006/116157. Some embodiments of the present invention include each combination of one or more compounds selected from those disclosed in WO 2006/116157 and their pharmaceutically acceptable salts, solvates and hydrates. One such compound is 5-{(S)-2-[2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethylamino]propyl}-5-( 1 H-tetrazol-5-yl) -10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2,8-dicarboxylic acid bis-dimethylamide. In some embodiments, the DPP-IV inhibitor is selected from 5-{(S)-2-[2-((S)2-cyanopyrrolidin-1-yl)-2-oxoethylamino]propyl} -5-( 1 H-tetrazol- 5-yl)-10,11-dihydro-5Hdibenzo[a,d]cycloheptene-2,8-dicarboxylic acid bis-dimethylamide and its pharmaceutically acceptable salts, solvates and hydrates:

- 41 040124

Mitsubishi has disclosed a series of 2,4-disubstituted pyrrolidine derivatives as DPP-IV inhibitors in International Patent Publication WO 2002/0014271. Some embodiments of the present invention include each combination of one or more compounds selected from those disclosed in WO 2002/0014271 and their pharmaceutically acceptable salts, solvates and hydrates. One such compound is ((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5yl)piperazin-1-yl)pyrrolidin-2-yl)(thiazolidin-3-yl ) methanone. In some embodiments, the DPP-IV inhibitor is selected from ((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1yl)pyrrolidin-2-yl)( thiazolidin-3-yl)methanone and its pharmaceutically acceptable salts, solvates and hydrates:

Various crystalline forms of ((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1yl)pyrrolidin-2-yl)(thiazolidin-3-yl)methanone salts are disclosed in International Patent Publication WO 2006/088129 and US Publication 2009/0216016. One embodiment of the present invention relates to any one or more crystalline forms of ((2S,4S)-4-(4-(3-methyl-1-phenyl1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2- yl)(thiazolidin-3-yl)methanone salt as described in International Patent Publication WO 2006/088129 and US Publication 2009/0216016. In some embodiments, the DPP-IV inhibitor is crystalline ((2S,4S)-4-(4-(3methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl )(thiazolidin-3-yl) methanone 2,5-hydrobromide:

or its mono- or dihydrate.

In some embodiments, the DPP-IV inhibitor is crystalline 2-yl)(thiazolidin-3 yl)methanone dihydrobromide.

Kyorin has disclosed a range of pyrrolidinecarbonitrile derivatives as DPP-IV inhibitors in International Patent Publication WO 2008/114857 and US Publication 2008/0146818. Some embodiments of the present invention include each combination of one or more compounds selected from those disclosed in WO 2008/114857 and US 2008/0146818 and their pharmaceutically acceptable salts, solvates and hydrates. One such compound is (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile. In some embodiments, the DPP-IV inhibitor is selected from (2S,4S)-1-[2-[(4ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile and its pharmaceutically acceptable salts, solvates and hydrates:

Dainippon Sumitomo has disclosed a series of bicyclic pyrrole derivatives as DPP-IV inhibitors in International Patent Publication WO 2006/068163 and US Publication 2009/0192129. Some embodiments of the present invention include each combination of one or more compounds selected from those disclosed in WO 2006/068163 and US 2009/0192129 and their pharmaceutically acceptable salts, solvates and hydrates. One such compound is 6-[(3R)-3-aminopiperidin-1-yl]-5-(2-chloro-5-fluorobenzyl)-1,3-dimethyl-1,5-dihydropyrrolo[3,2-d ]pyrimidine-2,4-dione. In some embodiments, the DPP-IV inhibitor is selected

- 42 040124 from 6-[(3R)-3-amino-piperidin-1-yl]-5-(2-chloro-5-fluorobenzyl)-1,3-dimethyl-1,5-dihydropyrrolo[3,2d] pyrimidine-2,4-dione and its pharmaceutically acceptable salts, solvates and hydrates:

Dainippon Sumitomo disclosed 2-({6-[(3R)-3-amino-3-methylpiperidin-1-yl]-1,3-dimethyl-2,4dioxo-1,2,3,4-tetrahydro-5H-pyrrolo [3,2^]pyrimidin-5-yl}methyl)-4-fluorobenzonitrile as a DPP-IV inhibitor in International Patent Publication WO 2009/084497. In some embodiments, the DPP-IV inhibitor is selected from 2-({6-[(3R)-3-amino-3-methylpiperidin-1-yl]-1,3-dimethyl2,4-dioxo-1,2,3, 4-tetrahydro-5H-nurrolo[3,2-d]pyrimidin-5-yl}methyl)-4-fluorobenzonitrile and its pharmaceutically acceptable salts, solvates and hydrates:

Hoffmann-La Roche has disclosed a series of N-substituted pyrrolidine derivatives as DPP-IV inhibitors in International Patent Publication WO 03/037327. Some embodiments of the present invention include each combination of one or more compounds selected from those disclosed in WO 03/037327 and their pharmaceutically acceptable salts, solvates and hydrates. One such compound is (2S)-1-{[2-(5-methyl-2-phenyloxazol-4-yl)ethylamino]acetyl}pyrrolidine-2-carbonitrile. In some embodiments, the DPP-IV inhibitor is selected from ((2S)-1-{[2-(5-methyl-2-phenyloxazol-4-yl)ethylamino]acetyl}pyrrolidine-2-carbonitrile and pharmaceutically acceptable salts, solvates thereof and hydrates:

Various crystalline forms of ((2S)-1-{[2-(5-methyl-2-phenyloxazol-4-yl)ethylamino]acetyl}pyrrolidine-2-carbonitrile salt of methanesulfonic acid are disclosed in International Patent Publication WO 2006/100181. In some embodiments, the DPP-IV inhibitor is ((28)-1-{[2-(5-methyl-2-phenyloxazol-4-yl)ethylamino]acetyl}pyrrolidine-2-carbonitrile salt of methanesulfonic acid (i.e. mesylate):

Other compounds disclosed by Hoffmann-La Roche in International Patent Publication WO 03/037327 include (2S)-1-{[1,1-dimethyl-3-(4-pyridin-3-yl-imidazol-1-yl)propylamino ]acetyl} pyrrolidine-2-carbonitrile; and pharmaceutically acceptable salts thereof such as the methanesulfonic acid salt. In some embodiments, the DPP-IV inhibitor is selected from (2S)-1-{[1,1-dimethyl-3(4-pyridin-3-yl-imidazol-1-yl)propylamino]acetyl}pyrrolidine-2-carbonitrile and its pharmaceutically acceptable salts, solvates and hydrates:

In some embodiments, the DPP-IV inhibitor is (2S)-1-{[1,1dimethyl-3-(4-pyridin-3-yl-imidazol-1-yl)propylamino]acetyl}pyrrolidine-2-carbonitrile methanesulfonic salt acids:

- 43 040124

Various crystalline forms of (2S)-1-{[1,1-dimethyl-3-(4-pyridin-3-yl-imidazol-1yl)propylamino]acetyl}pyrrolidine-2-carbonitrile salt of fumaric acid are disclosed in International Patent Publication WO 2007/071576. In some embodiments, the DPP-IV inhibitor is (2S)-1-{[1,1-dimethyl-3-(4-pyridin-3-yl-imidazol-1-yl)propylamino]acetyl}pyrrolidine-2-carbonitrile fumaric acid salt (i.e. fumarate):

Pfizer has disclosed a range of proline derivatives as DPP-IV inhibitors in International Patent Publication WO 2005/116014. Some embodiments of the present invention include each combination of one or more compounds selected from those disclosed in WO 2005/116014 and their pharmaceutically acceptable salts, solvates and hydrates. One such compound is (3,3-difluoropyrrolidin-1-yl)-((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1 yl)pyrrolidin-2-yl)methanone. In some embodiments, the DPP-IV inhibitor is selected from -yl) methanone and its pharmaceutically acceptable salts, solvates and hydrates:

GlaxoSmithKline has disclosed a range of fluoropyrrolidine derivatives as DPP-IV inhibitors in International Patent Publication WO 03/002531. Some embodiments of the present invention include each combination of one or more compounds selected from the DPP-IV inhibitors disclosed in WO 03/037327 and their pharmaceutically acceptable salts, solvates and hydrates. One such compound is (2S,4S)-1-[(2S)-2-amino-3,3-bis-(4-fluorophenyl)propanoyl]-4fluoropyrrolidine-2-carbonitrile (Denagliptin). In some embodiments, the DPPIV inhibitor is selected from (2S,4S)-1-[(2S)-2-amino-3,3-bis-(4-fluorophenyl)propanoyl]-4-fluoropyrrolidine-2carbonitrile and pharmaceutically acceptable salts thereof, solvates and hydrates:

Various crystalline forms of (2S,4S)-1-[(2S)-2-amino-3,3-bis-(4-fluorophenyl)propanoyl]-4fluoropyrrolidine-2-carbonitrile and salts have been disclosed in International Patent Publication WO 2005/ 009956. One of the disclosed salts is the (2S,4S)-1-[(2S)-2-amino-3,3-bis-(4fluorophenyl)propanoyl]-4-fluoropyrrolidine-2-carbonitrile salt of p-toluenesulfonic acid (also called as (2S,4S)-4-fluoro-1-[4-fluoro-β-(4-fluorophenyl)-L-phenylalanyl]-2-pyrrolidinecarbonitrile salt of p-toluenesulfonic acid or denagliptin tosylate). In some embodiments, the DPP-IV inhibitor is (2S,4S)-1-[(2S)-2-amino-3,3-bis-(4-fluorophenyl)propanoyl]-4fluoropyrrolidine-2-carbonitrile p-toluenesulfonic salt acids:

Abbott has disclosed a range of substituted pyrrolidinyl derivatives as DPP-IV inhibitors in International Patent Publication WO 2004/026822. Some embodiments of the present invention include each combination of one or more compounds selected from the DPP-IV inhibitors disclosed in WO 2004/026822 and their pharmaceutically acceptable salts, solvates and hydrates. One such compound is (2S,5R)-5-ethynyl-1-{N-(4-methyl-1-(4-carboxypyridin-2yl)piperidin-4-yl)glycyl}pyrrolidine-2-carbonitrile. In some embodiments, the DPP-IV inhibitor is selected from (2S,5R)-5-ethynyl-1-{N-(4-methyl-1-(4-carboxypyridin-2-yl)piperidin-4yl)glycyl}pyrrolidin-2 -carbonitrile and its pharmaceutically acceptable salts, solvates and hydrates:

- 44 040124

Abbott further discloses a range of substituted cyclohexanyl/cyclohexenyl derivatives as DPP-IV inhibitors in International Patent Publication WO 2007/027651. Some embodiments of the present invention include each combination of one or more compounds selected from the DPP-IV inhibitors disclosed in WO 2007/027651 and their pharmaceutically acceptable salts, solvates and hydrates. One of these compounds is (1S,6R)-3-{[3(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl }-6-(2,4,5-trifluorophenyl)cyclohex-3-en-1-amine. In some embodiments, the DPP-IV inhibitor is selected from (1S,6R)-3-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine-7( 8H)-yl]carbonyl}-6-(2,4,5trifluorophenyl)cyclohex-3-en-1-amine and its pharmaceutically acceptable salts, solvates and hydrates:

biguanides

Biguanides are a class of drugs that stimulate anaerobic glycolysis, increase insulin sensitivity in peripheral tissues, inhibit glucose absorption from the intestine, suppress hepatic gluconeogenesis, and inhibit fatty acid oxidation. Examples of biguanides include phenformin ((phenylethyl)biguanide), metformin (dimethylbiguanide), buformin (butylbiguanide), proguanyl (1-(p-chlorophenyl)-5-isopropylbiguanide), and biguanides known in the art.

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is a biguanide selected from the following biguanides and their pharmaceutically acceptable salts, solvates and hydrates: (phenylethyl) biguanide, dimethyl biguanide, butyl biguanide, 1-(p-chlorophenyl)-5-isopropyl biguanide.

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is a biguanide selected from (phenylethyl)biguanide (chemical structure shown below) and its pharmaceutically acceptable salts, solvates, and hydrates:

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is a biguanide selected from dimethylbiguanide (chemical structure shown below) and pharmaceutically acceptable salts, solvates and hydrates thereof; the chemical structure is as follows:

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is a biguanide selected from butyl biguanide (chemical structure shown below) and pharmaceutically acceptable salts, solvates, and hydrates thereof; the chemical structure is as follows:

NH NH

A A N NH ₂ HH _

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is a biguanide selected from 1-(p-chlorophenyl)-5-isopropylbiguanide (chemical structure shown below) and pharmaceutically acceptable salts, solvates, and hydrates thereof; the chemical structure is as follows:

NH NH I

ΙΑαλΑ N N N H H H

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is a biguanide selected from the following biguanides: metformin, phenformin,

- 45 040124 buformin and proguanil. In some embodiments, the implementation of the pharmaceutical agent or the second pharmaceutical agent is metformin. In some embodiments, the pharmaceutical agent or second pharmaceutical agent is phenformin. In some embodiments, the implementation of the pharmaceutical agent or the second pharmaceutical agent is buformin. In some embodiments, the pharmaceutical agent or second pharmaceutical agent is proguanil.

Alpha-glucosidase inhibitors.

Alpha-glucosidase inhibitors are a class of drugs that competitively inhibit digestive enzymes such as alpha-amylase, maltase, alpha-dextrinase, sucrase, etc. in the pancreas and/or small intestine. Reversible inhibition by alpha-glucosidase inhibitors slows, reduces, or otherwise lowers blood glucose levels by delaying the digestion of starches and sugars.

Some representative examples of alpha-glucosidase inhibitors include acarbose ((2R,3R,4R,5R)-4-((2R,3R,4R,5S,6R)-5-((2R,3R,4S,5S,6R)- 3,4-dihydroxy-6-methyl-5((1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)cyclohex-2-enylamino)tetrahydro-2H-pyran-2yloxy)- 3,4-dihydroxy-6-(hydroxymethyl)tetrahydro-2I-pyran-2-yloxy)-2,3,5,6-tetrahydroxyhexanal), miglitol ((2R,3R,4R,5S)-1-(2- hydroxyethyl)-2-(hydroxymethyl)piperidin-3,4,5-triol), voglibose ((1 S,2S,3R,4S,5S)-5-(1,3-dihydroxypropan-2-ylamino)-1 - (hydroxymethyl)cyclohexane 1,2,3,4-tetraol) and alpha-glucosidase inhibitors known in the art.

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is an alpha-glucosidase inhibitor selected from the following alpha-glucosidase inhibitors and their pharmaceutically acceptable salts, solvates, and hydrates:

(2R,3R,4R,5R)-4-((2R,3R,4R,5S,6R)-5-((2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl- 5-((1S,4R,5S,6S)4,5,6-trihydroxy-3-(hydroxymethyl)cyclohex-2-enylamino)tetrahydro-2H-pyran-2-yloxy)-3,4dihydroxy-6-(hydroxymethyl )tetrahydro-2H-pyran-2-yloxy)-2,3,5,6-tetrahydroxyhexanal;

(2R,3R,4R,5S)-1-(2-hydroxyethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol;

(1 S,2S,3R,4S,5S)-5-(1,3-dihydroxypropan-2-ylamino)-1-(hydroxymethyl)cyclohexane-1,2,3,4tetraol.

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is an alpha-glucosidase inhibitor selected from (2R,3R,4R,5R)-4((2R,3R,4R,5R,6R)-5-((2R,3R ,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-((1S,4R,5S,6S)-4,5,6-trihydroxy-3(hydroxymethyl)cyclohex-2-enylamino)tetrahydro -2N-pyran-2-yloxy)-3,4-dihydroxy-6-(hydroxymethyl)tetrahydro-2I-pyran-2-yloxy)-2,3,5,6-tetrahydroxyhexanal (chemical structure shown below) and its pharmaceutical acceptable salts, solvates and hydrates:

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is an alpha-glucosidase inhibitor selected from (2R,3R,4R,5S)-1-(2hydroxyethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol ( chemical structure shown below) and its pharmaceutically acceptable salts, solvates and hydrates:

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is an alpha-glucosidase inhibitor selected from (1S,2S,3R,4S,5S)-5-(1,3dihydroxypropan-2-ylamino)-1-(hydroxymethyl)cyclohexane- 1,2,3,4-tetraol (chemical structure shown below) and its pharmaceutically acceptable salts, solvates and hydrates:

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is an alpha-glucosidase inhibitor selected from acarbose, miglitol, and voglibose. In some embodiments, the pharmaceutical agent or second pharmaceutical agent

- 46 040124 is acarbose. In some embodiments, the pharmaceutical agent or second pharmaceutical agent is miglitol. In some embodiments, the pharmaceutical agent or second pharmaceutical agent is voglibose.

Insulin and insulin analogues.

The term insulin analog refers to naturally occurring human hormone and insulin receptor ligands (ie, synthetic insulin analogs). Insulin receptor ligands are structurally different from naturally occurring human hormone, but have essentially the same activity as human insulin in terms of glycemic control. Examples of an insulin analog include NPH insulin (also known as Humulin H, Novolin H, NPH Iletin II and insulin isophane), insulin lispro (28B-L-lysine-29B-L-proline insulin, in which the insulin is human insulin) , insulin aspart (28B-L-aspartic acid-insulin, in which insulin is human insulin), insulin glulisine (3B-L-lysine-29B-L-glutamic acid-insulin, in which insulin is human insulin) and insulin analogs, known in the art.

NPH insulin is marketed by Eli Lilly and Company under the name Humulin N and is regarded as an intermediate-acting analogue of insulin, providing assistance in controlling blood sugar levels in diabetic patients. Insulin lispro is marketed by Eli Lilly and Company under the name Humalog and is considered a fast-acting insulin analogue. Insulin aspart is marketed by Novo Nordisk and sold as NovoRapid. Insulin aspart is considered a fast-acting insulin analogue. Insulin glulisine was developed by Sanofi-Aventis and sold under the brand name Apidra. Insulin glulisine is considered to be a fast-acting insulin analogue, but with a shorter duration of action than human insulin.

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is an insulin analogue selected from the NPH of insulin and pharmaceutically acceptable salts, solvates and hydrates thereof. In some embodiments, the pharmaceutical agent or second pharmaceutical agent is an insulin analogue selected from insulin lispro and pharmaceutically acceptable salts, solvates and hydrates thereof. In some embodiments, the pharmaceutical agent or second pharmaceutical agent is an insulin analogue selected from insulin aspart and pharmaceutically acceptable salts, solvates and hydrates thereof. In some embodiments, the pharmaceutical agent or second pharmaceutical agent is an insulin analogue selected from insulin glulisine and pharmaceutically acceptable salts, solvates and hydrates thereof.

Sulfonylureas.

Sulfonylureas are drugs that promote insulin secretion from pancreatic beta cells by signaling insulin secretion through cell membrane receptors. Examples of sulfonylurea include tolbutamide (Orinase, N-(butylcarbamoyl)-4-methylbenzenesulfonamide); acetohexamide (Dimelor, 4-acetyl-N-(cyclohexylcarbamoyl)benzenesulfonamide); tolazamide (Tolinase, N-(azepan-1-ylcarbamoyl)-4-methylbenzenesulfonamide); chlorpropamide (Diabenez, 4-chloro-N-(propylcarbamoyl)benzenesulfonamide); glipizide (Glucotrol, N-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-5-methylpyrazine-2-carboxamide); glibenclamide, also known as glyburide (Diabeta, Micronase, Glinase, 5-χλορ-N-(4-(N(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-2-methoxybenzamide); glimepiride (Amaryl, 3-ethyl-4methyl-N-(4-(N-((1r,4r)-4-methylcyclohexylcarbamoyl)sulfamoyl)phenethyl)-2-oxo-2,5-dihydro-1Hpyrrole-1-carboxamide) ; gliclazide (Diamikron, N-(hexahydrocyclopenta[c]pyrrol-2(1H)-ylcarbamoyl)4-methylbenzenesulfonamide); and sulfonylureas known in the art.

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is a sulfonylurea selected from sulfonylurea and their pharmaceutically acceptable salts, solvates and hydrates:

N-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-5-methylpyrazine-2-carboxamide);

5-chloro-N-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-2-methoxybenzamide;

3-ethyl-4-methyl-N-(4-(N-((1r,4r)-4-methylcyclohexylcarbamoyl)sulfamoyl)phenethyl)-2-oxo-2,5dihydro-1H-pyrrole-1-carboxamide.

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is a sulfonylurea selected from N-(butylcarbamoyl)-4methylbenzenesulfonamide (chemical structure shown below) and its pharmaceutically acceptable salts, solvates, and hydrates:

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is a sulfonylurea selected from 4-acetyl-N-(cyclohexylcarbamoyl)benzenesulfonamide (chemical structure shown below) and its pharmaceutically acceptable salts,

- 47 040124

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is a sulfonylurea selected from N-(azepan-1-ylcarbamoyl)-4methylbenzenesulfonamide (chemical structure shown below) and pharmaceutically acceptable salts, solvates, and hydrates thereof:

solvates and hydrates:

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is a sulfonylurea selected from 4-chloro-N-(propylcarbamoyl)benzenesulfonamide (chemical structure shown below) and its pharmaceutically acceptable salts, solvates, and hydrates:

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is a sulfonylurea selected from N-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-5-methylpyrazine-2-carboxamide (chemical structure shown below) and its pharmaceutically acceptable salts , solvates and hydrates:

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is a sulfonylurea selected from 5-chloro-N-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-2-methoxybenzamide (chemical structure shown below) and its pharmaceutically acceptable salts , solvates and hydrates:

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is a sulfonylurea selected from 3-ethyl-4-methyl-N-(4-(N-((1r,4r)-4methylcyclohexylcarbamoyl)sulfamoyl)phenethyl)-2-oxo- 2,5-dihydro-1H-pyrrole-1-carboxamide (chemical structure shown below) and its pharmaceutically acceptable salts, solvates and hydrates:

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is a sulfonylurea selected from N-(hexahydrocyclopenta[c]pyrrol-2(1H)ylcarbamoyl)-4-methylbenzenesulfonamide (chemical structure shown below) and its pharmaceutically acceptable salts, solvates, and hydrates :

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is a sulfonylurea selected from the following sulfonylureas and their pharmaceutically acceptable salts, solvates, and hydrates: glipizide, glimepiride, and glibenclamide. IN

- 48 040124 in some embodiments, the pharmaceutical agent or the second pharmaceutical agent is tolbutamide. In some embodiments, the pharmaceutical agent or second pharmaceutical agent is acetohexamide. In some embodiments, the pharmaceutical agent or second pharmaceutical agent is tolazamide. In some embodiments, the pharmaceutical agent or second pharmaceutical agent is chlorpropamide. In some embodiments, the pharmaceutical agent or second pharmaceutical agent is glipizide. In some embodiments, the pharmaceutical agent or second pharmaceutical agent is a glyburide. In some embodiments, the pharmaceutical agent or second pharmaceutical agent is glimepiride. In some embodiments, the pharmaceutical agent or second pharmaceutical agent is gliclazide.

SGLT2 inhibitors.

Sodium-dependent glucose-2 transporter (SGLT2) inhibitors are a class of drugs that inhibit the SGLT2 protein and glucose reabsorption in the kidney. Inhibition by SGLT2 inhibitors slows, decreases, or otherwise reduces levels of glucose that is reabsorbed and therefore excreted in the urine.

Some representative examples of SGLT2 inhibitors include dapagliflozin ((2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3, 4,5-triol, Bristol-Myers Squibb and AstraZeneca), remogliflozin (ethyl((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(4-(4-isopropoxybenzyl)-1 -isopropyl5-methyl-1H-pyrazol-3-yloxy)tetrahydro-2H-pyran-2-yl)methyl carbonate, GlaxoSmithKline), ASP 1941 (Kotobuki/Astellas), canagliflozin ((2S,3R,4R,5S,6R)- 2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, Johnson & Johnson/ Mitsubishi/Tanabe), ISIS 388626 (antisense oligonucleotide, Isis Pharmaceuticals), sergliflozin (ethyl ((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(2-(4-methoxybenzyl)phenoxy ) _tetrag and _dro 2H-pyran-2-yl)methyl carbonate, GlaxoSmithKline),

AVE2268 ((2R,3S,4S,5R,6S)-2-(hydroxymethyl)-6-(2-(4-methoxybenzyl)thiophen-3-yloxy)tetrahydro2H-pyran-3,4,5-triol, Sanofi- Aventis)

BI10773 (Boehringer Ingelheim), CSG453 (Chugai/Roche), LX4211 (Lexicon) and SGLT2 inhibitors known in the art.

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is an SGLT2 inhibitor selected from the following SGLT2 inhibitors and their pharmaceutically acceptable salts, solvates, and hydrates:

(2S, 3R, AR, 5S, 6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

ethyl ( (2R, 3S, AS,5R,6S)-3,4,5-trihydroxy-6-(4-(4isopropoxybenzyl)-1-isopropyl-5-methyl-1H-pyrazol-3yloxy)tetrahydro-2H-pyran -2-yl)methyl carbonate;

ethyl ((2R, 3S, AS, 5R,6S)-3,A, 5-trihydroxy-6-(2-(4methoxybenzyl)phenoxy)tetrahydro-2H-pyran-2-yl)methyl carbonate;

(2R, 3S, AS, 5R, 6S)-2-(hydroxymethyl)-6-(2-(4methoxybenzyl)thiophen-3-yloxy)tetrahydro-2H-pyran-3,A, 5-triol;

(2S, 3R,AR,5S, 6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4methylphenyl)-6-(hydroxymethyl)tetrahydro-2R-pyran-3 , A, 5-triol.

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is a sulfonylurea selected from (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro- 2H-pyran-3,4,5-triol (chemical structure shown below) and its pharmaceutically acceptable salts, solvates and hydrates:

/HE

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is a sulfonylurea selected from ethyl((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6(4-(4-isopropoxybenzyl)-1- isopropyl-5-methyl-1H-pyrazol-3-yloxy)tetrahydro-2H-pyran-2-yl)methyl carbonate (chemical structure shown below) and its pharmaceutically acceptable salts, solvates and

- 49 040124

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is a sulfonylurea selected from ethyl((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6(2-(4-methoxybenzyl)phenoxy)tetrahydro -2H-pyran-2-yl)methyl carbonate (chemical structure shown below) and its pharmaceutically acceptable salts, solvates and hydrates:

hydrates:

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is an SGLT2 inhibitor selected from dapagliflozin, remogliflozin, and sergliflozin. In some embodiments, the pharmaceutical agent or second pharmaceutical agent is dapagliflozin. In some embodiments, the pharmaceutical agent or second pharmaceutical agent is remogliflozin. In some embodiments, the pharmaceutical agent or second pharmaceutical agent is sergliflozin.

Astellas and Kotobuki have disclosed a range of SGLT2 inhibitors in International Patent Publication WO 2004/080990. Some embodiments of the present invention include each combination of one or more compounds selected from those disclosed in WO 2004/080990 and their pharmaceutically acceptable salts, solvates and hydrates.

Aventis has disclosed a range of SGLT2 inhibitors in International Patent Publication WO 2004/007517. Some embodiments of the present invention include each combination of one or more compounds selected from those disclosed in WO 2004/007517 and their pharmaceutically acceptable salts, solvates and hydrates. One such compound is (2R,3S,4S,5R,6S)-2-(hydroxymethyl)-6-(2-(4-methoxybenzyl)thiophen-3-yloxy)tetrahydro-2H-pyran-3,4,5triol . In some embodiments, the SGLT2 inhibitor is selected from (2R,3S,4S,5R,6S)-2(hydroxymethyl)-6-(2-(4-methoxybenzyl)thiophen-3-yloxy)tetrahydro-2H-pyran-3,4 ,5-triol and its pharmaceutically acceptable salts, solvates and hydrates:

Tanabe has disclosed a range of SGLT2 inhibitors in International Patent Publication WO 2005/012326. Some embodiments of the present invention include each combination of one or more compounds selected from those disclosed in WO 2005/012326 and their pharmaceutically acceptable salts, solvates and hydrates. One such compound is (2S,3R,4R,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol. In some embodiments, the SGLT2 inhibitor is selected from (2S,3R,4R,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol and its pharmaceutically acceptable salts, solvates and hydrates:

Boehringer Ingelheim has disclosed a number of SGLT2 inhibitors in International Patent Publication WO 2005/092877. Some embodiments of the present invention include each combination of one or more compounds selected from those disclosed in WO 2005/092877 and their

- 50 040124 pharmaceutically acceptable salts, solvates and hydrates.

Chugai Disclosed a Range of SGLT2 Inhibitors in an International Patent Publication

WO 2006/080421. Some embodiments of the present invention include each combination of one or more compounds selected from those disclosed in WO 2006/080421 and their pharmaceutically acceptable salts, solvates and hydrates.

Lexicon has disclosed a range of SGLT2 inhibitors in International Patent Publication WO 2008/109591. Some embodiments of the present invention include each combination of one or more compounds selected from those disclosed in WO 2008/109591 and their pharmaceutically acceptable salts, solvates and hydrates.

Meglitinides.

Meglitinides promote insulin secretion by binding to pancreatic beta cells in the same manner as sulfonylureas, but at an alternative binding site.

Examples of meglitinides include Novo Nordisk repaglinide (Prandin, (S)-2-ethoxy-4-(2-(3-methyl-1-(2-(piperidin-1-yl)phenyl)butylamino)-2-oxoethyl)benzoic acid ), nateglinide (Starlix, (R)-2-((1R,4R)-4-isopropylcyclohexanecarboxamido)-3-phenylpropionic acid), mitiglinide S)-2-benzyl-4-((3aR,7aS)-1H-isoindole -2(3H,3aH,4H,5H,6H,7H,7aH)-yl)-4-oxobutanoic acid) and the like.

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is a meglitinide selected from the following meglitinides and their pharmaceutically acceptable salts, solvates and hydrates:

(S)-2-ethoxy-4-(2-(3-methyl-1-(2-(piperidin-1-yl)phenyl)butylamino)-2-oxoethyl)benzoic acid;

(R)-2-(( 1 r,4R)-4-isopropylcyclohexanecarboxamido)-3-phenylpropionic acid;

(S)-2-benzyl-4-((3aR,7aS)-1H-isoindole-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)-4-oxobutanoic acid.

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is (S)-2-ethoxy-4-(2-(3-methyl-1-(2-(piperidin-1-yl)phenyl)butylamino)-2oxoethyl)benzoic acid (chemical structure shown below) and its pharmaceutically acceptable salts, solvates and hydrates:

/k P ^X^CO ₂ H

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is a sulfonylurea selected from (R)-2-((1r,4R)-4-isopropylcyclohexanecarboxamido)-3-phenylpropionic acid (chemical structure shown below) and its pharmaceutically acceptable salts, solvates and hydrates:

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is a sulfonylurea selected from (S)-2-benzyl-4-((3aR,7aS)-1H-isoindole2(3H,3aH,4H,5H,6H,7H,7aH )-yl)-4-oxobutanoic acid (chemical structure shown below) and its pharmaceutically acceptable salts, solvates and hydrates:

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is a meglitinide selected from the following meglitinides: repaglinide, nateglinide, mitiglinide, and pharmaceutically acceptable salts, solvates, and hydrates thereof. In some embodiments, the pharmaceutical agent or second pharmaceutical agent is meglitinide selected from repaglinide and pharmaceutically acceptable salts, solvates and hydrates thereof. In some embodiments, the pharmaceutical agent or second pharmaceutical agent is meglitinide selected from nateglinide and pharmaceutically acceptable salts, solvates and hydrates thereof. In some embodiments, the pharmaceutical agent or second pharmaceutical agent is meglitinide selected from mitiglinide and pharmaceutically acceptable salts, solvates and hydrates thereof.

T iazolidinediones.

Thiazolidinediones belong to a class of drugs better known as TZDs. These drugs act by binding to the nuclear receptor, peroxisome proliferator-activated receptor gamma (PPARy), and activate the transcription of a number of specific genes, leading to a decrease in insulin resistance.

Examples of thiazolidinediones include rosiglitazone (Avandia, 5-(4-(2-(methyl(pyridin-2-yl)amino)ethoxy)benzyl)thiazolidine-2,4-dione), pioglitazone (Actos, 5-(4-(2 -(5-ethylpyridin-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione), troglitazone (Rezulin, 5-(4-((6-hydroxy-2,5,7,8-tetramethylchroman-2- yl)methoxy)benzyl)thiazolidin-2,4-dione), rivoglitazone (5-(4-((6-methoxy-1-methyl-1H-benzo[d]imidαzol-2-yl)methoxy)benzyl)thiazolidine- 2,4dione), ciglitazone (5-(4-((1-methylcyclohexyl)methoxy)benzyl)thiazolidine-2,4-dione), and thiazolidinediones known in the art.

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is a thiazolidinedione selected from the following thiazolidinediones and their pharmaceutically acceptable salts, solvates and hydrates:

5-(4-(2-(methyl(pyridin-2-yl)amino)ethoxy)benzyl)thiazolidine-2,4-dione;

5-(4-(2-(5-ethylpyridin-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione;

5-(4-((6-methoxy-1H-benzo[d]imidazol-2-yl)methoxy)benzyl)thiazolidine-2,4-dione;

5-(4-((1-methylcyclohexyl)methoxy)benzyl)thiazolidine-2,4-dione.

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is 5-(4-(2-(methyl(pyridin-2-yl)amino)ethoxy)benzyl)thiazolidine-2,4-dione (chemical structure shown below) and its pharmaceutically acceptable salts, solvates and hydrates:

O .

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is 5-(4-(2-(5-ethylpyridin-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione (chemical structure shown below) and its pharmaceutically acceptable salts, solvates and hydrates:

O

ABOUT .

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is 5-(4-((6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)methoxy)benzyl)thiazolidine2,4-dione (chemical structure shown below) and its pharmaceutically acceptable salts, solvates and hydrates:

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is 5-(4-((6-methoxy-1-methyl-1H-benzo[d]imidazol-2-yl)methoxy)benzyl)thiazolidine-2,4-dione (chemical structure shown below) and its pharmaceutically acceptable salts, solvates and hydrates:

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is 5-(4-((1-methylcyclohexyl)methoxy)benzyl)thiazolidine-2,4-dione (chemical structure shown below) and its pharmaceutically acceptable salts, solvates, and hydrates:

- 52 040124

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is a thiazolidinedione selected from rosiglitazone and pharmaceutically acceptable salts, solvates and hydrates thereof. In some embodiments, the pharmaceutical agent or second pharmaceutical agent is a thiazolidinedione selected from pioglitazone and pharmaceutically acceptable salts, solvates and hydrates thereof. In some embodiments, the pharmaceutical agent or second pharmaceutical agent is a thiazolidinedione selected from troglitazone and pharmaceutically acceptable salts, solvates and hydrates thereof. In some embodiments, the pharmaceutical agent or second pharmaceutical agent is a thiazolidinedione selected from rivoglitazone and pharmaceutically acceptable salts, solvates and hydrates thereof. In some embodiments, the pharmaceutical agent or second pharmaceutical agent is a thiazolidinedione selected from ciglitazone and pharmaceutically acceptable salts, solvates and hydrates thereof.

Antidiabetic peptide analogues.

Antidiabetic peptide analogs are peptides that promote insulin secretion by acting as an incretin mimetic such as GLP-1 and GIP. Examples of an antidiabetic peptide analog include exenatide, liraglutide, taspoglutide, and antidiabetic peptide analogs known in the art.

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is an anti-diabetic peptide analog selected from: exenatide; liraglutide; and taspoglutide. In some embodiments, the pharmaceutical agent or second pharmaceutical agent is exenatide. In some embodiments, the pharmaceutical agent or second pharmaceutical agent is liraglutide. In some embodiments, the pharmaceutical agent or second pharmaceutical agent is taspoglutide.

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is L-histidylglycyl-L-α-glutamylglycyl-L-threonyl-L-phenylalanyl-L-threonylL-seryl-L-α-asnarthyl-L-leucyl-L-seryl- L-lysyl-L-glutaminyl-L-methionyl-L-α-glutamyl-L-α-glutamyl-L-α-glutamyl-L-alanyl-L-valyl-L-arginyl-L-leucyl-L-phenylalanyl-L- isoleucyl-L-α-glutamyl-L-tryptophyl-L-leucyl-L-lysyl-L-asparaginylglycylglycyl-L-prolyl-L-seryl-Lserylglycyl-L-alanyl-L-prolyl-L-prolyl-L-prolyl-L- serinamide (ie exenatide) and its pharmaceutically acceptable salts, solvates and hydrates.

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is L-histidyl-L-alanyl-L-α-glutamylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-α-aspartyl-L-valyl- L-seryl-L-seryl-L-tyrosyl-L-leucyl-L-α-glutamylglycyl-L-glutaminyl-L-alanyl-L-alanyl-N6-[N-(1-oxohexadecyl)-L-α-glutamyl]- L-lysyl-L-α-glutamyl-L-phenylalanyl-L-isoleucyl-L-alanyl-L-tryptophyl-L-leucyl-L-valyl-L-arginylglycyl-L-arginylglycine (liraglutide) and its pharmaceutically acceptable salts, solvates and hydrates.

In some embodiments, the pharmaceutical agent or second pharmaceutical agent is H ₂ N-His-2-methyl-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-GluGly- Gln-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-2-methyl-Ala-Arg-CONH ₂ (taspoglutide) and pharmaceutically acceptable salts, solvates and hydrates thereof.

Other excipients.

Another object of the present invention relates to the radiolabelled compounds of the present invention, which would be useful not only in radio imaging, but also in both in vitro and in vivo studies for the localization and quantification of GPR119 receptors in tissue samples, including human, and to identify GPR119 receptor ligands by inhibiting the binding of radiolabeled compounds. It is a further object of this invention to develop novel GPR119 receptor assays that contain such radiolabeled compounds.

This disclosure includes all isotopes of atoms found in the present compounds, their intermediates, salts and crystalline forms. Isotopes include those atoms having the same atomic number but different mass numbers. One aspect of the present invention includes each combination of one or more atoms in the present compounds, their intermediates, salts and crystalline forms, which is replaced by an atom having the same atomic number but a different mass number. One such example is the substitution of an atom, which is the most common isotope in nature, such as 1H and ^12C , found in one of the present compounds.

- 53 040124 ions, its intermediates, salts and crystalline forms, by another atom that is not the most common isotope in nature, such as ² H or ³ H (substitution 'H) or ^PS , ¹³ C or ¹⁴ C (substitution ¹² WITH). A compound in which such a substitution has occurred is commonly referred to as an isotopically labeled compound. Isotopic labeling of the present compounds, their intermediates, salts and crystalline forms can be achieved using any one of the various synthetic methods known to the person skilled in the art, and he is easily credited with understanding the synthetic methods and available reagents needed to perform such isotopic labeling. As a general example and without limitation, isotopes of hydrogen include ² H (deuterium) and ³ H (tritium). The isotopes of carbon include ^PS , ¹³ C and ¹⁴ C. The isotopes of nitrogen include ¹³ N and ¹⁵ N. The isotopes of oxygen include ¹⁵ O, ¹⁷ O and ¹⁸ O. The isotope of fluorine includes F. The isotope of sulfur includes ³⁵ S. The isotope of chlorine includes ³⁶ Cl. Isotopes of bromine include ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br and ⁸² Br. The isotopes of iodine include ¹²³ I, ¹²⁴ I, ¹²⁵ I and ¹³¹ I. Another aspect of the present invention includes compositions such as compositions obtained from synthesis, preformulation and the like, and pharmaceutical compositions such as compositions prepared for use in mammals. in the treatment of one or more of the disorders described herein, comprising one or more of the present compounds, their intermediates, salts, and crystalline forms in which the naturally occurring distribution of isotopes in the composition is disrupted. Another aspect of the present invention includes compositions and pharmaceutical compositions containing compounds as described herein, wherein the compound is enriched at one or more positions in an isotope other than the naturally occurring isotope. Techniques are readily available to measure such isotopic impairments or enrichments, such as mass spectrometry, and for isotopes that are radioisotopes, additional methods are available, such as radio detectors used in combination with HPLC or GC.

Certain isotopically labeled compounds of the present invention are useful in tissue distribution studies of the compound and/or substrate. In some embodiments, ³ H and/or ¹⁴ C radionuclide isotopes are useful in these studies. In addition, substitution with heavier isotopes such as deuterium (i.e., ² H) may provide certain therapeutic benefits resulting from greater metabolic stability (eg, increased in vivo half-life or reduced dosage requirement), and, therefore, may be preferred under certain circumstances. The isotopically labeled compounds of the present invention can generally be prepared using the following procedures, similar to those described in the Brief Description of the Drawings and Examples sections below, substituting an isotopically labeled reagent for a non-isotopically labeled reagent. Other synthetic methods that are suitable are discussed below. In addition, it should be understood that all atoms present in the compounds of the invention may be either the most frequently occurring isotope of such atoms, or a rare radioactive isotope, or a non-radioactive isotope.

Synthetic methods for incorporating radioactive isotopes into organic compounds are applicable to the compounds of the invention and are well known in the art. These synthetic methods, for example incorporating activity levels of tritium into target molecules, are as follows:

A) catalytic reduction with gaseous tritium: This technique usually produces products with high specific activity and requires halogenated or unsaturated precursors;

B) reduction with sodium borohydride [ ³ H]: This technique is quite inexpensive and requires precursors containing reducible functional groups such as aldehydes, ketones, lactones, esters and the like;

C) reduction with lithium aluminum hydride [ ³ H]: This procedure provides products with near theoretical specific activities. It also requires precursors containing reducible functional groups such as aldehydes, ketones, lactones, esters and the like;

D) tritium gas irradiation marking: This technique involves exposing precursors containing interchangeable protons to tritium gas in the presence of a suitable catalyst;

E) N-methylation using methyl iodide [ ³ H]: This procedure is commonly used to obtain O-methyl or N-methyl-( ³ H) products by treating the appropriate precursors with methyl iodide ( ³ H) with high specific activity. This method generally provides a higher specific activity, such as, for example, about 70-90 Ci/mmol.

Synthetic methods for incorporating ¹²⁵ I activity levels into target molecules include:

A) Sandmeyer reaction and the like: This procedure converts an arylamine or heteroarylamine to a diazonium salt such as diazonium tetrafluoroborate and further ¹²⁵ I labeling of the compound using Na ¹²⁵ I. A typical procedure has been described by Zhu, G.-D. and co-workers in J. Dept. Chem., 2002, 67, 943-948;

B) Ortoiodination of Phenols: This procedure provides for the incorporation of ¹²⁵ I into the ortho position of the phenol as described by Collier, TL and co-workers in J. Labeled Compel. Radiopharm., 1999, 42, S264-S266;

C) replacement of aryl and heteroaryl bromide by ¹²⁵ I: This method usually takes place in two stages.

- 54 040124

The first step is the conversion of the aryl or heteroaryl bromide to the corresponding trialkyltin intermediate using, for example, a Pd-catalyzed reaction [i.e. Pd(Ph ₃ P) ₄ ] or via aryl or heteroaryl lithium, in the presence of tri-alkyltin halide or hexaalkyldiol [eg (CH ₃ ) ₃ SnSn(CH ₃ ) ₃ ]. A typical technique has been described by Le Bas, M.-D. and co-workers in J. Labelled Compd.

Radiopharm. 2001, 44, S280-S282.

The radiolabeled GPR119 receptor of the compound of formula (Ia) can be used in a screening assay to identify/evaluate compounds. In general, a newly synthesized or identified compound (ie, test compound) can be evaluated for its ability to reduce the binding of a radiolabeled compound of formula (Ia) to the GPR119 receptor. Accordingly, the ability of a test compound to compete with a radiolabeled compound of formula (Ia) for binding to the GPR119 receptor is directly correlated with its binding ability.

Certain labeled compounds of the present invention bind to certain GPR119 receptors. In one embodiment, the labeled compound has an IC ₅₀ of less than about 500 μM. In one embodiment, the labeled compound has an IC ₅₀ of less than about 100 μM. In one embodiment, the labeled compound has an IC ₅₀ of less than about 10 μM. In one embodiment, the labeled compound has an IC ₅₀ of less than about 1 μM. In one embodiment, the labeled compound has an IC ₅₀ of less than about 0.1 μM. In one embodiment, the labeled compound has an IC ₅₀ of less than about 0.01 μM. In one embodiment, the labeled compound has an IC ₅₀ of less than about 0.005 μM.

Other uses of the described receptors and methods will become apparent to those skilled in the art based, inter alia, on consideration of this disclosure.

Examples

The compounds of the invention and their synthesis are further illustrated by the following examples. The following examples are intended to further define the invention, however, without limiting the invention to specific examples. The compounds presented herein above and below are named according to AutoNom version 2.2, AutoNom 2000, CS ChemDraw Ultra Version 7.0.1 or CS ChemDraw Ultra Version 9.0.7. In some cases, literary names and/or trivial names are used, and it should be understood that these names will be recognized by a person skilled in the art.

Proton nuclear magnetic resonance (1H NMR) spectra were recorded on a Bruker Avance-400 equipped with QNP (quadrature nuclear sensor) or BBI (broadband inversion) and z-gradient. Chemical shifts are given in parts per million (ppm) with residual solvent signal used as a reference. The following NMR abbreviations are used: s = singlet, d = doublet, dd = doublet of doublets, ddd = doublet of doublets of doublets, dt = doublet of triplets, t = triplet, td = triplet of doublets, tt = triplet of triplets, q = quartet, m = multiplet , br.s = broadened singlet, br.d = broadened doublet, br.t = broadened triplet, br.q = broadened quartet.

Microwaves were performed using Smith Synthesizer™ or Emrys Optimizer™ (Biotage). Thin layer chromatography (TLC) was performed on silica gel 60 F ₂₅₄ (Merck), preparative thin layer chromatography (prep. TLC) was performed on PK6F 60 A 1 mm silica gel plates (Whatman) and column chromatography was performed on a silica gel column using Kieselgel 60, 0.063 -0.200 mm (Merck). Evaporation was carried out under reduced pressure on a Buchi rotary evaporator.

LCMS types: HPLC pumps: LC-10AD VP, Shimadzu Inc.; HPLC system controller: SCL-10A VP, Shimadzu Inc; UV detector: SPD-10A VP, Shimadzu Inc; autosampler: СТС HTS, PAL, Leap Scientific; mass spectrometer: API 150EX with Turbo Ion Spray source, AB/MDS Sciex; software: Analyst 1.2.

Example 1.1. Preparation of 5-fluoropyrimidine-4,6-diol.

Method A.

To a three neck round bottom flask equipped with an overhead stirrer, nitrogen inlet and reflux condenser was added 25 wt% sodium methoxide in methanol (950 mL, 4.15 mol) and formamide (357 mL, 8.98 mol). The mixture was heated to approximately 64°C. Diethyl 2-fluoromalonate (177 mL, 1.12 mol) was added to the reaction mixture over 1 h using an addition funnel. The reaction temperature was maintained at 64° C. for 72 h. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The precipitate was cooled to 0°C and slowly acidified with concentrated hydrochloric acid to pH 1-2, leading to precipitation of the product. The product was filtered off and washed with an ice-cold aqueous solution of 1N. HCl. A white to yellowish or greyish solid was suspended in acetonitrile, filtered and dried in a vacuum oven to give 5-fluoropyrimidine-4,6-diol (170 g, 1.31 mol) as a light brownish-brown solid which was used without additional cleaning.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.57 (s, 2H), 8.25 (s, 1H).

- 55 040124

Method B.

A 5 L 3-neck round bottom flask equipped with a magnetic stirrer, nitrogen inlet and reflux condenser was charged with the following components: sodium methoxide (25% NaOMe in methanol) (1.425 L, 6.230 mol) and formamide (0.535 L, 13.5 mol) under nitrogen atmosphere and heated to 64°C. Diethyl 2-fluoromalonate (CAS # 685-88-1, 0.266 L, 1.684 mol) was slowly added to the reaction mixture using an addition funnel (exothermic reaction). The reaction mixture was heated at 64° C. for 72 hours. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The precipitate was cooled to 0°C in an ice bath. The mixture was stirred and slowly acidified with 10N HCl to pH ~1-2. The product precipitated and was filtered off. The product was washed with ice-cold 1N. HCl. A white to yellowish or greyish solid was suspended in ACN, filtered and dried (in a vacuum oven) at 30°C for 16 hours to give 5-fluoropyrimidine-4,6-diol (349.4 g, 2.686 mol, 160 % yield) as a light brown-pinkish solid. 5-Fluoropyrimidine-4,6-diol (CAS # 106615-61-6, 600 g, 4.613 mol, 62% pure) was powdered (sieved) and placed in a sintered glass funnel (4 L coarse). The material was suspended in ice-cold 0.5 M HCl (aq) and the material was suspended (for 5 minutes) and then filtered. The filter cake was then washed with 1.2 L of ACN, EtOAc and finally with hexane. The solid was dried (in a vacuum oven) overnight to give 5-fluoropyrimidine-4,6-diol (276.459 g, 2.125 mol, 74% yield) as a violet-pinkish solid.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 7.9 (s, 1H), 12.3 (br. s, 2H).

Example 1.2. Preparation of 4,6-dichloro-5-fluoropyrimidine.

Method A.

To a 500 ml three-necked round bottom flask containing phosphorus oxychloride (45.3 ml, 487 mmol) was slowly added 5-fluoropyrimidine-4,6-diol (20.0 g, 154 mmol) and the resulting reaction mixture was heated to 60°C. . N,N-dimethylaniline (42.2 ml, 331 mmol) was slowly added to the resulting suspension over 4 h using a syringe pump and the reaction mixture was stirred at 60°C for 16 h. The reaction mixture was cooled to room temperature and slowly added to the mixture saline and ice (400 ml) with stirring. The aqueous layer was extracted with dichloromethane (2x250 ml). The combined organic layers (light amber) were washed with cold aqueous 6N. HCl (200 ml), dried over sodium sulfate and filtered through glass fiber paper using vacuum filtration, and the solvent was removed under reduced pressure (without heating) to give 4,6-dichloro-5-fluoropyrimidine (13 g, 78 mmol, yield 50 .6%) as an amber oily substance.

1 H NMR (400 MHz, CDCl ₃ ) δ ppm 8.62 (s, 1H).

Method B.

Phosphoryl chloride (0.593 L, 6.376 mol) was slowly added to a 2 L 3-necked round bottom flask containing 5-fluoropyrimidine-4,6-diol (276.459 g, 2.125 mol) at room temperature until a suspension formed. To this suspension was added very slowly using an addition funnel (exothermic reaction) N,N-dimethylaniline (81 ml, 0.638 mol) and the reaction was continued for 6 h at 110°C. After 6 hours, the reaction mixture was cooled to room temperature and added slowly to brine and ice (2 L) with stirring. The aqueous layer (red) was extracted with DCM (2x2 L). The combined organic layers were washed with cold bn HCl (honey brown) (2x1 L) and washed with saturated NaHCO ₃ (1 L). The organic layer was dried (Na ₂ SO ₄ ), filtered using vacuum filtration through glass fiber paper, and the solvent was removed under reduced pressure (without heating) to obtain 4,6-dichloro-5-fluoropyrimidine (CAS # 21326583-9, 347.9 g, 2.084 mol, 98% yield as an amber oil. NMR showed traces of DXM in the oil. 4,6-Dichloro-5-fluoropyrimidine (420 g, 2.515 mol) was distilled by vacuum distillation to give 4,6-dichloro-5-fluoropyrimidine (332.574 g, 1.992 mol, 79% yield) as a colorless oil. The product solidified in the flask at -78°C and melted when brought to room temperature.

Distillation conditions: Oil bath: 100°C; Product boiling point: 35°C; Pressure: 1 Torr.

1 H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.8 (s, 1H).

Example 1.3. Obtaining 2-fluoro-2-methylpropanenitrile.

Method A.

To a 1 L 3-necked round bottom flask containing 2-hydroxy-2-methylpropanenitrile (120 mL, 1.31 mol) was slowly added (diethylamino)sulfur trifluoride (DAST) (172 mL, 1.31 mol) at 4°C over 1 h through addition funnel. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was directly purified by vacuum distillation (40-45°C/45 mmHg) to give 2-fluoro-2-methylpropanenitrile (83.36 g, 0.957 mol, 73.0% yield) as a colorless oil containing methacrylonitrile (~10%).

- 56 040124 ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.77 (d, J=20 Hz, 6H).

Method B.

2-Hydroxy-2-methylpropanenitrile (CAS # 75-86-5, 221 mL, 2.420 mol) was cooled to -10°C (ice/acetone/dry ice) in a 1 L 3-necked round bottom flask and added slowly using an addition funnel , DAST (246 ml, 1.861 mol) over 2 h. After the addition was complete, the reaction mixture was warmed to room temperature and stirred overnight. The product was distilled by vacuum distillation (30° C., 4 Torr) to give 2-fluoro-2-methylpropanenitrile (CAS # 138999-34-5, 148.65 g, 1.707 mol, 92% yield) as a colorless oil. The title compound turned amber when not protected from light. The final product contained methacrylonitrile (according to NMR ~10%).

1H NMR (400 MHz, CDCl ₃ ) δ ppm 1.8 (d, 6H).

Example 1.4. (Z)-2-Fluoro-N'-hydroxy-2-methylpropanimidamide.

Method A.

To a 1 L round bottom flask was added 2-fluoro-2-methylpropanenitrile (80.7 g, 0.927 mol) in ethanol (400 ml). A 50% aqueous solution of hydroxylamine (81.0 ml, 1.32 mol) was slowly added to the resulting solution through an addition funnel. The mixture was heated at 60° C. for 3 hours. The mixture was cooled to room temperature and the ethanol was removed under reduced pressure. The precipitate was dissolved in dichloromethane (200 ml) and the organic layer was washed with water (2x200 ml) and brine (200 ml). The aqueous layer was back extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give (Z)-2-fluoro-N'-hydroxy-2-methylpropanimidamide (60.0 g, 0.499 mol, 53.9% yield) as a off-white to off-white to greyish solid.

Exact mass calculated for C ₄ H ₉ FN ₂ O: 120.07 found: LCMS m/z=121.0 (M+H+) (M+H) ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ ppm 1.58 (d, J=24 Hz, 6H), 4.64 (br.s, 1H), 4.81 (br.s, 2H).

Method B.

2-Fluoro-2-methylpropanenitrile (148.65 g, 1.707 mol) was dissolved in EtOH (700 ml) and hydroxylamine 50% water by weight (135 g, 2.048 mol) was added very slowly, maintaining the temperature at approximately 35°C, then the reaction the mixture was heated to 80° C. for 16 h in a 1 L round bottom flask. After 16 h the reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The precipitate was dissolved in DCM (500 ml) with slight heating and the solids that did not dissolve were decanted. DCM was removed under reduced pressure to give (Ζ)-2-Φτορ-Ν'hydroxy-2-methylpropanimidamide 127 g as a light yellow solid. The solid was sublimated at 100° C. and 3 Torr to give (Z)-2-fluoro-N'-hydroxy-2-methylpropanimidamide (74 g, 0.616 mol, 36.1% yield) as a white solid. The final product contained approximately 7% (according to NMR) of the removed by-product (CAS # 339075-08-0).

(Z)-2-Fluoro-N'-hydroxy-2-methylpropanimidamide (120 g, 999 mmol) was purified by recrystallization from MTBE. The material was dissolved in MTBE, 5X-10X by volume. The solution was then cooled to 78°C using dry ice and acetone. The resulting precipitate was collected by vacuum filtration and washed with cold MTBE to give (Z)-2-fluoro-N'-hydroxy-2-methylpropanimidamide (114.019 g, 949 mmol, 95% yield) as a white solid. The title compound contained approximately 1% by NMR of (Z)-N'hydroxymethacrylimidamide.

Pace. melting point: 101.9°C.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 1.6 (d, 6H), 4.75 (br. s, 2H), 7.55 (br. s, 1H).

Example 1.5. Preparation of tert-butyl 4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidine-1carboxylate.

To a solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (85 g, 372 mmol) in acetonitrile (450 ml) was added di-(1H-imidazol-1-yl)methanone (72.4 g, 447 mmol) at room temperature and the reaction mixture was heated at 45°C for 1 h, the Reaction was monitored using the negative mode LC/MS. The reaction mixture was cooled to room temperature and (Z)-2-fluoro-N'-hydroxy-2-methylpropanimidamide (44.7 g, 372 mmol) was added. The reaction mixture was stirred at room temperature for 1.5 h and the volatile organic compounds were removed under vacuum. The precipitate was poured into a cold aqueous solution of 1 M HCl (500 ml). The aqueous phase was extracted with ethyl acetate (3x250 ml). The organic layers were combined and washed with an aqueous solution of 1 M HCl (3x150 ml). The organic layers were combined and washed with saturated NaHCO ₃ solution (2x100 ml) and brine. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to give (Z)-tert-butyl 4-(2-fluoro-1-(hydroxyimino)-2-methylpropylcarbamoyl)piperidine-1-carboxylate (114 g, 344 mmol , 92% yield as a white solid.

A flask containing (Z)-tert-butyl 4-(2-fluoro-1-(hydroxyimino)-2-methylpropylcarbamoyl)piperidine-1-carboxylate was heated in a mantle heater at 115° C. for 16 hours under reduced pressure. The reaction mixture was further dried at 50° C. under reduced pressure to give tert-butyl 4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate (94 g, 300 mmol, 81% yield) as a thick amber oil.

Exact mass calculated for C ₁₅ H ₂₄ FN ₃ O ₃ : 313.37 found: LCMS m/z=314.2 [M+H]+.

¹ H NMR (400 MHz, CDCI3) δ ppm 1.46 (s, 9H), 1.75 (s, 3H), 1.77-1.90 (m, 5H), 2.02-2, 11 (m, 2H), 2.893.01 (m, 2H), 3.06-3.16 (m, 1H), 4.04-4.14 (m, 2H).

Example 1.6. Preparation of tert-butyl 4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidine-1carboxylate hydrochloride.

To a mixture of a solution of 4 M HCl in dioxane (244 ml, 975 mmol), cooled to 0°C (external ice bath), was added tert-butyl 4-(3-(2-fluoropropan-2-yl)-1,2, 4-oxadiazol-5-yl)piperidine-1-carboxylate (94 g, 300 mmol). The ice bath was removed and the reaction mixture was stirred at room temperature for 1 hour. The reaction was monitored by LC/MS. The volatile organics were removed under reduced pressure to give a yellowish solid. The solid was triturated with tert-butyl methyl ether (MTBE) and collected by filtration to give 3-(2-fluoropropan-2-yl)-5-(piperidin-4-yl)-1,2,4-oxadiazole hydrochloride ( 70.1 g, 281 mmol, 94% yield as a white solid.

Exact mass calculated for C ₁₀ H ₁₇ ClFN ₃ O: 213.2 found: LCMS m/z=214.0 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.71-1.77 (d, J=20 Hz, 6H), 1.90-2.01 (m, 2H), 2.18- 2.25 (m, 2H), 3.00-3.09 (m, 2H), 3.30-3.37 (m, 2H), 3.42-3.50 (m, 1H), 8, 85 (br.s, 1H), 9.02 (br.s, 1H).

Example 1.7. Preparation of 5-(1-(6-chloro-5-fluoropyrimidin-4-yl)piperidin-4-yl)-3-(2-fluoropropan-2yl)-1,2,4-oxadiazoles.

Diisopropylethylamine (94 ml, 541 mmol) followed by the addition of 4,6-dichloro-5-fluoropyrimidine (18.81 ml, 180 mmol). The reaction mixture was stirred at 40° C. for 1 hour. The volatile organics were removed under vacuum to give a thick amber oil. The oily substance was poured into water and the product was extracted with ethyl acetate (2x250 ml). The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo to give a yellowish solid. This solid was purified by Biotage™ column chromatography (hexane:ethyl acetate gradient) to give 5-(1-(6-chloro-5-fluoropyrimidin-4-yl)piperidin-4-yl)-3-(2-fluoropropan- 2-yl)-1,2,4-oxadiazole (40.4 g, 118 mmol, 65.2% yield) as a white solid.

Exact mass calculated for C ₁₄ H ₁₆ ClF ₂ N ₅ O: 343.76 found: LCMS m/z=344.2 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ,) δ ppm 1.77-1.81 (d, J=20 Hz, 6H), 1.98-2.07 (m, 2H), 2.20- 2.27 (m, 2H), 3.28-3.35 (m, 3H), 4.48-4.54 (m, 2H), 8.17 (s, 1H).

Example 1.8. Preparation of 4-amino-3-fluoro-N,N-dimethylbenzamide.

Method A.

To a three neck round bottom flask equipped with a mechanical stirrer, thermometer and addition funnel was added 4-amino-3-fluorobenzoic acid (40 g, 258 mmol), dimethylamine (520 ml, 1.04 mol) and dichloromethane (1 L). The reaction mixture was cooled in an ice bath and 1-propanephosphonic acid cyclic anhydride (250 g, 393 mmol) was slowly added with an addition funnel. After 1 h, the addition was completed and the mixture was warmed to room temperature. After stirring overnight, the solution was concentrated under reduced pressure and the residue was extracted with dichloromethane and washed with an aqueous solution of 2 M NaOH. The organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified using Biotage™ column chromatography (hexane:ethyl acetate gradient) to give 4-amino-3-fluoro-N,N-dimethylbenzamide (31.9 g, 175 mmol, 67.9% yield) as a brown solid.

Exact mass calculated for C ₉ H ₁₁ FN ₂ O: 182.2 found: LCMS m/z=183.3 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCI3) δ ppm 3.05 (s, 6H), 3.91 (br. s, 2H), 6.76 (t, J=10 Hz, 1H), 7.07 (dt, J=8.15, 0.85 Hz, 1H), 7.13 (dd, J=11.43, 1.83 Hz, 1H).

Method B.

4-Amino-3-fluorobenzoic acid (CAS # 455-87-8, 221.85 g, 1.402 mol) was suspended in acetonitrile (1.80 L). To this suspension was added di(1H-imidazol-1-yl)methanone (250 g, 1.542 mol) at room temperature and the reaction boiled and the solution became clear. The reaction mixture was cooled to 0° C., then N-ethyl-N'-isopropylpropan-2-amine (0.416 L, 2.383 mol) was added followed by dimethylamine hydrochloride (137 g, 1.682 mol). The reaction mixture was stirred at room temperature for 30 minutes. LCMS indicated that the reaction was complete. The solvent was removed under reduced pressure. The precipitate was dissolved in DCM (2 L) and washed with 1 M HCl (2x2 L). Layer separation was difficult to observe due to the presence of some solids. The resulting mixture was filtered and the layers were separated. The aqueous layer was back extracted with DCM (2x2 L). The organic layers were combined and dried (Na ₂ SO ₄ ), filtered off using vacuum filtration through a sintered glass funnel, and the solvent was removed under reduced pressure to obtain 270 g of a dark brown solid. To this solid was added a mixture of 2:1 toluene:hexane

- 58 040124 (2000 ml) and the mixture was heated to 45°C to form a suspension. The resulting precipitate was collected by vacuum filtration and washed with 1:1 toluene:hexane (2 L) and hexane (2 L). The resulting solid was dried (in a vacuum oven). The filtrate contained some product and the solvent was removed under reduced pressure and the suspension repeated. The first batch was 196 g and the 2nd batch contained 32.528 g. Both batches were identical according to NMR and LC/MS and were combined to give 4-αmino-3-fluoro-N,N-dimethylbenzαmideα (CAS # 536748-06-8 , 228.93 g, 1.257 mol, 90% yield as a light brown solid.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 2.9 (s, 6H), 5.5 (s, 2H), 6.8 (t, 1H), 7.0 (dd, J= 8.21, 1.9 Hz, 1H), 7.1 (dd, J=12.13, 1.8 Hz, 1H).

Exact mass calculated for C ₉ H11FN ₂ O: 182.2 found: LCMS m/z=183.2 [M+H]+.

Example 1.9. Preparation of ethyl 1-(6-chloro-5-fluoropyrimidin-4-yl)piperidine-4-carboxylate.

A 5 L 3-neck round bottom flask equipped with a magnetic stirrer and nitrogen inlet was charged with the following components: 4,6-dichloro-5-fluoropyrimidine (332.574 g, 1.992 mol) with acetonitrile (2.6 L). The following components were combined in an addition funnel: ethyl piperidine-4-carboxylate (CSA # 1126-09-6, 0.316 L, 1.992 mol) and DIEA (0.522 L, 2.988 mol). The content of the addition funnel was slowly added to the flask (exothermic reaction). The addition funnel was washed with ACN. LC/MS took 30 min after completion of the addition and the reaction was determined to be complete. The solvent was removed under reduced pressure to give an oily residue. The precipitate was dissolved in EtOAc (3.0 L) and washed with 1 M HCl (2x2.0 L), washed with saturated NaHCO ₃ (1x2.0 L) and washed with saturated NaCl (1 L). The organic layer was dried (Na ₂ SO ₄ ), filtered by vacuum filtration through glass fiber paper and the solvent was removed under reduced pressure to give ethyl 1-(6-chloro-5-fluoropyrimidin-4-yl)piperidine-4-carboxylate (586, 2 g, 2.037 mol, 102% yield as a light yellow oil which was used without further purification. The title compound contained some EtOAc as determined by NMR.

Exact weight calculated for C ₁₂ H ₁₅ ClFN ₃ O ₂ : 287.08 found: LCMS m/z=288.4/290.2 [M+H]+).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.2 (t, J=7.1 Hz, 3H), 1.6 (sq., J=13.6, 3.8 Hz, 2H), 1.9 (dd, J=13.5, 3.7 Hz, 2H), 2.7-2.8 (m, 1H), 3.2-3.3 (m, 2H), 4 .1 (sq., J=7.2 Hz, 2H), 4.3 (d, 2H), 8.2 (d, J=1.5 Hz, 1H).

Example 1.10. Preparation of ethyl 1-(6-(4-(dimethylcarbamoyl)-2-fluorophenylamino)-5-fluoropyrimidin-4yl)piperidine-4-carboxylate.

A 5-L 3-neck round-bottom flask equipped with an overhead stirrer, nitrogen inlet, and reflux condenser was charged with the following components under N ₂ atmosphere: ethyl 1-(6chloro-5-fluoropyrimidin-4-yl)piperidine-4-carboxylate (362 g, 1.257 mol), 4-amino-3-fluoro-N,N-dimethylbenzamide (229 g, 1.257 mol), 1,1'-bis-(di-tert-butylphosphino)ferrocene (59.6 g, 126 mmol), cesium carbonate (491 g, 1.508 mol) and diacetoxypalladium (14.11 g, 62.8 mmol) with dioxane (2 L). The mixture was heated to 102° C. for 2 hours. After 2 hours, the reaction was completed by LC/MS. The reaction mixture was cooled to room temperature. The mixture was diluted with EtOAc (2 L) and treated with a small amount of charcoal. This crude mixture was filtered through a plug of silica gel (12 cm high in a 6 L filter funnel) and washed with additional EtOAc (6x2 L). The filtrate was concentrated under reduced pressure to dryness and dried under high vacuum to give ethyl 1-(6-(4-(dimethylcarbamoyl)-2-fluorophenylamino)-5-fluoropyrimidin-4-yl)piperidine-4-carboxylate (520.02 g, 1. 2 mol, 95% yield as a brown solid.

Exact mass calculated for C ₂₁ H ₂₅ F ₂ N ₅ O ₃ : 433.19 found: LCMS m/z=434.4 [M+H]+).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.2 (t, J=7.2 Hz, 3H), 1.5-1.7 (m, 2H), 1.9 (dd, J=13.3, 3.4 Hz, 2H), 2 .61-2.71 (m, 1H), 3.0 (s, 6H), 3.1 (t, J=11.2 Hz, 2H), 4.08 (sq., J=7.07 Hz , 2H), 4.2 (d, J=13.4 Hz, 2H), 7.2 (dd, J=8.1, 1.5 Hz, 1H), 7.30 (dd, J=11, 1, 1.8 Hz, 1H), 7.6 (t, J=8.1 Hz, 1H), 7.9 (d, J=1.8 Hz, 1H), 8.8 (s, 1H) .

Example 1.11. Preparation of 1-(6-(4-(dimethylcarbamoyl)-2-fluorophenylamino)-5-fluoropyrimidin-4yl)piperidine-4-carboxylic acid.

A 5 L 3-necked round-bottom flask equipped with an overhead stirrer and a reflux condenser was charged with the following components: g, 0.6 mol) and triethylamine (251 ml, 1.8 mol) with MeCN (2 L) and water (40.8 ml). To this was added lithium bromide (521 g, 5.998 mol) in portions (exothermic reaction) while maintaining the internal temperature below 50°C. The mixture was heated at 75° C. for 16 hours. The mixture was filtered and the solid was washed with MeCN (2x1 L). The solid was dissolved in hot water (2 L) and the solution was cooled in an ice bath. To the cold mixture was slowly added 10N. HCl (aqueous) using an addition funnel to pH 1. The resulting precipitate was collected by vacuum filtration, washed with 1N. HCl (aqueous) (1 L) and dried in an oven at 45°C and under high vacuum to give 1-(6-(4-(dimethylcarbamoyl)-2-fluorophenylamino)-5fluoropyrimidin-4-yl)piperidin-4- carboxylic acid (231 g, 0.570 mol, 95% yield) as light brown solid,

The exact mass calculated for C ₁₉ H ₂₁ F ₂ N ₅ O ₃ : 405.16 found: LCMS m/z=406.4 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ ppm 1.5-1.7 (m, 2H), 1.9 (dd, J=13.4, 3.0 Hz, 2H), 2.5-2.6 (m, J=10.8,

- 59 040124

10.8, 4.0, 3.9 Hz, 1H), 3.0 (s, 6H), 3.1 (t, J=11.2 Hz, 2H), 4.2 (d, J=13 .39 Hz, 2H), 7.2 (dd, J=8.2, 1.6 Hz, 1H),

7.3 (dd, J=10.9, 1.8 Hz, 1H), 7.6 (t, J=8.1 Hz, 1H), 8.0 (d, J=1.3 Hz, 1H ), 9.1 (br.s, 1H), 11.3 (br.s, 1H).

Example 1.12. Preparation of 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5yl)piperidin-1-yl)pyrimidin-4- ylamino)-N,N-damethylbenzamide (compound 1).

Method A.

To a suspension of 5-(1-(6-chloro-5-fluoropyrimidin-4-yl)piperidin-4-yl)-3-(2-fluoropropan-2-yl)-1,2,4oxadiazole (1.0 g, 2.91 mmol) and 4-amino-3-fluoro-N,N-dimethylbenzamide (0.530 g, 2.91 mmol) in dioxane (9 ml) were added palladium(II) acetate (0.131 g, 0.582 mmol), 1, 1'-bis-(di-tert-butylphosphino)ferrocene (0.552 g, 1.164 mmol) and cesium carbonate (3.32 g, 10.18 mmol) under nitrogen atmosphere. The suspension was gradually heated to 95° C. in an oil bath and stirred at this temperature for 1 hour. The reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was washed with water (2x50 ml), dried over magnesium sulfate, filtered, concentrated under reduced pressure and purified using Biotage™ column chromatography (hexane:ethyl acetate gradient) to give 3-fluoro4-(5-fluoro-6-(4- (3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)N,N-dimethylbenzamide (0.715 g, 1.461 mmol, yield 50.2%) as a light yellow solid.

Exact mass calculated for C ₂₃ H2 ₆ F ₃ N ₇ O ₂ : 489.5 found: LCMS m/z=490.4 [M+H]+ ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.79 (d, J=20 Hz, 6H), 2.02 (dd, J=13.83, 3.85 Hz, 2H), 2.21 (dd, J=13.52, 3.66 Hz , 2H), 3.07 (br.s, 6H), 3.19-3.40 (m, 3H), 4.36-4.56 (m, 2H), 6.86-7.02 (m , 1H), 7.18-7.32 (m, 2H), 8.14 (d, J=1.26 Hz, 1H), 8.55 (t, J=8.46 Hz, 1H).

Method B.

The following components were charged into a 5-L three-necked round-bottom flask equipped with an overhead stirrer and a nitrogen inlet: 340 g, 0.839 mol) and di-(1H-imidazol-1yl) methanone (143 g, 0.881 mol) with MeCN (2 L). After 5 min the reaction mixture became homogeneous. The reaction was continued for 30 minutes. LCMS at t=30 min (455.46 [M+H]+) indicated that the acid-activated reaction was complete. (Z)-2-Φτορ-Ν'hydroxy-2-methylpropanimidamide (106 g, 0.881 mol) was added to the resulting mixture, and the reaction was continued for 16 hours. After 16 hours, the resulting precipitate was collected by vacuum filtration. The solid was washed with MeCN (2 L) followed by MTBE (2 L) and hexane (2 L) and dried (in a vacuum oven) under high vacuum and without heat to give (E)-1-(6-(4-(dimethylcarbamoyl )-2-fluorophenylamino)-5fluoropyrimidin-4-yl)-N-(2-fluoro-1-(hydroxyimino)-2-methylpropyl)piperidine-4-carboxamide (330 g, 650 mmol, 78% yield) as white with a yellowish or grayish tint of solid.

Exact mass calculated for C ₂₃ H ₂₈ F ₃ N ₇ O ₃ : 507.22 found: LCMS m/z=508.2 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ ppm 1.7 (s, 3H), 1.8 (s, 3H), 1.8-1.9 (m, 2H), 2.1 (dd , J=13.1, 2.8 Hz, 2H), 3.0 (s, 6H), 3.2-3.3 (m, 2H), 3.4-3.5 (m, J=11 .0, 11.0, 4.0, 3.9 Hz, 1H), 4.3 (d, J=13.4 Hz, 2H), 7.2 (dd, J=8.2, 1.6 Hz, 1H), 7.3 (dd, J=11.0, 1.6 Hz, 1H), 7.6 (t, J=8.1 Hz, 1H), 7.9 (d, J=1 .5 Hz, 1H), 8.8 (s, 1H).

The filtrate still contained some product as assessed by LC/MS. The solvent was removed under reduced pressure to give a black oil (250 g). The black oil was not combined with the solid but was instead heated to 90° C. under vacuum for 16 hours. After 16 hours the reaction was complete and the solvent was removed under reduced pressure. The precipitate was diluted with EtOAc and passed through a plug of silica gel using a 2 L coarse funnel with a diameter of 14 cm and filled with 7 cm of silica gel. The product was eluted with 2 L of EtOAc to give 36 g of a pinkish solid. The solid was triturated with MTBE to give 3-fluoro-4-(5-fluoro-6-(4(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1 -yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide (19.2 g, 39.2 mmol, 4.68% yield) as a off-white to greyish-yellow solid, yield 2.

(E)-1-(6-(4-(Dimethylcarbamoyl)-2-fluorophenylamino)-5-fluoropyrimidin-4-yl)-N-(2-fluoro-1(hydroxyimino)-2-methylpropyl)piperidine-4- carboxamide (330 g, 650 mmol) was transferred to a 2 L round bottom flask and DMA (500 ml) was added. The reaction mixture was heated to 110° C. for 4 hours. The reaction was complete as judged by LC/MS. The reaction mixture was cooled to room temperature and diluted with MeCN. The resulting precipitate was collected by vacuum filtration to give 3-fluoro-4-(5fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidine- 1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide (250 g, 511 mmol, 60.9% yield) as a white solid (yield 1). The filtrate still contained some product. DMA and MeCN were removed under reduced pressure, and the resulting precipitate was triturated with MTBE to give 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4oxadiazole -5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide (96 g, 196 mmol, 23.38% yield) as a light brown solid (yield 3). All yields 4-ylamino)-N,N-dimethylbenzamide contained less than 6% starting material 1-(6-(4-(dimethylcarbamoyl)-2-fluorophenylamino)-5fluoropyrimidin-4-yl)piperidine-4-carboxylic acid. To remove starting material, each yield was dissolved (yield 2 and yield 3 combined) in DMA (500 ml for yield 1 and 230 ml for yield 2.3 combined) at 100°C. Once the solid had dissolved, saturated aqueous NaHCO ₃ (500 ml for yield 1 and 230 ml for a combined yield of 2.3) was carefully added to isolate the product. The mixture was diluted with DI water (1.250 L for yield 1 and 0.576 L for a combined yield of 2.3). The mixture was cooled to room temperature and the resulting precipitate was collected by vacuum filtration and washed with water to give 200 g as a white to yellowish or greyish solid (from Yield 1) and 92.8 g as a light brown solid (from Yield 1). 2.3), in total 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidine -1yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide (292.8 g, 598 mmol, 71.3% yield).

3-Fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4ylamino )-N,N-dimethylbenzamide (281.8 g, 576 mmol) was dissolved in DMA (600 ml) and heated to 100° C. in a 5 L three-necked round bottom flask attached to a mechanical stirrer. After all solids went into solution, DI water (600 ml) was carefully added. The reaction mixture was then diluted with more DI water (1800 ml) to bring the total volume to 10X by weight. The resulting precipitate was collected by vacuum filtration and washed with water. The precipitate was dried under vacuum on a sintered glass funnel. When the precipitate was predominantly dried, it was dried further (in a vacuum oven) at 45° C. under high vacuum overnight to give 3-fluoro-4-(5-fluoro-6-(4-(3(2-fluoropropane-2- yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)-N,Ndimethylbenzamide (279.4 g, 571 mmol, 99% yield) as a brown solid.

Example 1.13. Preparation of 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5yl)piperidin-1-yl)pyrimidin-4- ylamino)-N-methylbenzamide (compound 2).

Step A. Preparation of ethyl 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5yl)piperidin-1-yl )pyrimidin-4-ylamino)benzoate.

Suspension of 5-(1-(6-chloro-5-fluoropyrimidin-4-yl)piperidin-4-yl)-3-(2-fluoropropan-2-yl)-1,2,4oxadiazole (1.0 g, 2 .91 mmol), ethyl 4-amino-3-fluorobenzoate (0.533 g, 2.91 mmol), diacetoxypalladium (0.098 g, 0.436 mmol), 1,1'-bis-(di-tert-butylphosphino)ferrocene (0.414 g, 0.873 mmol) and Cs ₂ CO ₃ (2.464 g, 7.56 mmol) in dioxane (10 ml) were standardly heated at 85°C for 1 h. The reaction was quenched with water and extracted with AcOEt. The organic layer was concentrated to give a precipitate and the precipitate was purified by prep-HPLC. Fractions containing the desired product were combined, made basic with saturated NaHCO ₃ (aq.), partially concentrated in vacuo and extracted with AcOEt. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give the title compound (1.0 g, 2.039 mmol, 70% yield).

The exact mass calculated for C ₂₃ H ₂₅ F ₃ N ₆ O ₃ : 490.2 found: LCMS m/z=491.3 [M+H]+.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.39 (t, J=7.07 Hz, 3H), 1.77 (s, 3H), 1.82 (s, 3H), 1, 97-2.08 (m, 2H), 2.17-2.25 (m, 2H), 3.22-3.33 (m, 3H), 4.37 (sq., J=7.07 Hz , 2H), 4.42-4.50 (m, 2H), 7.04-7.10 (m, 1H), 7.78 (dd, J=11.87, 1.89 Hz, 1H), 7.84-7.89 (m, 1H), 8.15-8.18 (m, 1H), 8.66 (t, J=8.46 Hz, 1H).

Step C. Preparation of 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5yl)piperidin-1-yl)pyrimidine -4-ylamino)benzoic acid.

To a solution of ethyl 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1yl)pyrimidine -4-ylamino)benzoate (440 mg, 0.897 mmol) in a mixed solvent of methanol (15 ml) and THF (5.0 ml) was added lithium hydroxide hydrate (188 mg, 4.49 mmol) and water (5.0 ml ). The mixture was stirred at room temperature overnight. The mixture was acidified with 1N. HCl (aq.) to pH 2-3 and concentrated under vacuum to remove organic solvents. The solid was collected by vacuum filtration to give the title compound (394.3 mg, 0.853 mmol, 95% yield).

The exact mass calculated for C ₂₁ H ₂₁ F ₃ N ₆ O ₃ : 462.2 found: LCMS m/z=463.4 [M+H] ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ ppm 1.77 (s, 3H), 1.82 (s, 3H), 1.98-2.07 (m, 2H), 2.19-2, 23 (m, 2H), 3.233.34 (m, 3H), 4.43-4.51 (m, 2H), 7.16-7.20 (m, 1H), 7.83 (dd, J= 11.87, 1.89 Hz, 1H), 7.90-7.94 (m, 1H), 8.178.19 (m, 1H), 8.71 (t, J=8, 34 Hz, 1H).

Step C. Preparation of 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5yl)piperidin-1-yl)pyrimidine -4-ylamino)-N-methylbenzamide (compound 2).

To a solution of 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1yl)pyrimidin-4 -ylamino)benzoic acid (73 mg, 0.158 mmol) and HATU (70 mg, 0.184 mmol) in DMF (2 ml) was added methanamine (315 μl, 0.630 mmol). After stirring at room temperature for 1 hour, the mixture was purified by HPLC (5-95% CH ₃ CN). Fractions containing the target product were partially concentrated and the residue was extracted with 1 M NaOH and CH ₂ Cl ₂ . The organic phases were dried over MgSO ₄ , filtered and concentrated to give the title compound (51.9 mg, 0.109 mmol, 69% yield).

The exact mass calculated for C ₂₂ H ₂₄ F ₃ N ₇ O ₂ : 475.2 found: LCMS m/z=476.4 [M+H] ⁺ .

1H NMR (400 MHz, CDC13) δ ppm 1.77 (s, 3H), 1.82 (s, 3H), 1.98-2.07 (m, 2H), 2.19-2.23 (m, 2H), 3.02 (d, J=4.80 Hz, 3H), 3.23-3.31 (m, 3H), 4.43-4.48 (m, 2H), 6, 04-6.05 (m, 1H), 7.00-7.02 (m, 1H), 7.47-7.50 (m, 1H), 7.62 (dd, J=11.87, 1 .89 Hz, 1H), 8.15 (d, J=1.39 Hz, 1H), 8.61 (t, J=8.34 Hz, 1H).

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Example 1.14. Preparation of 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5yl)piperidin-1-yl)pyrimidin-4- ylamino)benzamide (compound 3).

To the suspension of 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1yl)pyrimidin-4 -ylamino)benzoic acid (see example 1.13, step B, 50 mg, 0.108 mmol), ammonium chloride (17.35 mg, 0.324 mmol) and HATU (61.7 mg, 0.162 mmol) in DMF (2 ml) in N-ethyl-N'-isopropylpropan-2-amine (0.094 mL, 0.541 mmol) was added to a sealed tube. The mixture was stirred at RT for 1 h. The mixture was directly purified with prep. HPLC. Purified fractions were combined, neutralized with saturated NaHCO ₃ (aq.) and evaporated MeCN with the formation of solids. The solid was collected by vacuum filtration to give the title compound (22.5 mg, 0.049 mmol, 45.1% yield) as a white solid.

Exact mass calculated for C ₂₁ H ₂₂ F ₃ N ₇ O ₂ : 461.2 found: LCMS m/z=462.4 (M+H+).

1H NMR (400 MHz, CDCl ₃ ) δ ppm 1.80 (d, J=21.5 Hz, 6H), 2.00-2.07 (m, 2H), 2.19-2.23 (m, 2H), 3.233.32 (m, 3H) , 4.44-4.49 (m, 2H), 5.74 (br.s, 2H), 7.06 (t, J=3.7 Hz, 1H), 7.55 (dd, J=8 .6, 1.6 Hz, 1H), 7.66 (dd, J=11.9, 2.0 Hz, 1H), 8.16 (d, J=1.4 Hz, 1H), 8.66 (t, J=8.3 Hz, 1H).

Example 2 In vivo effect of 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5yl)piperidin-1-yl )pyrimidin-4-ylamino)-N,N-damethylbenzamide (compound 1) on glucose homeostasis in diabetic male ZDF rats (oral glucose tolerance test (OTTG)).

Male ZDF rats were fasted for 18 hours and randomly grouped (n=6) to obtain a GPR119 agonist (compound 1) at 0.3, 3, 10 or 30 mg/kg (mg compound per kg body weight). Compound was delivered orally via gavage (po volume 4 ml/kg) 60 min prior to a bolus of glucose (3 g/kg) (time=-60 min in Figure 1), with a separate group receiving vehicle (20% hydroxypropyl -beta-cyclodextrin) as a control. At time 0 min, a bolus of glucose was administered. Blood glucose levels were assessed with a glucometer (One-Touch Ultra™, LifeScan) at -60 min (prior to compound administration), at 0 min (when the glucose bolus was administered), and at 30, 60, 90, and 120 min. after a glucose bolus. Plasma glucose concentration (mg/dL) at various time points is shown in FIG. 1 and in table. 1. The increase in glucose level (AUC (area under the curve) decrease) in animals treated with the compound relative to the vehicle control is shown in FIG. 2 and in table. 2. These results indicated that the GPR119 agonist, 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2yl)-1,2,4-oxadiazol-5-yl)piperidine -1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide (compound 1) lowered blood glucose levels after glucose administration in diabetic ZDF rats.

Table 1

Plasma glucose (mg/dl) Compound 1 dose (mg/kg) Time (min) 20% HPCD 0.3 3.0 10.0 30.0 Average value SEM Average value SEM Average value SEM Average value SEM Average value SEM -60 106.7 3.2* 106.3 5.7* 110.0 5.2* 108.7 3.1* 104.8 4.8* 0 93.2 4.8* 89.7 3.0* 82.7 3.0* 76.0 3.0* 93.0 4.1* thirty 217.7 14.7* 201.7 17.7* 184.5 15.0* 174.0 19.3* 197.0 23.6* 60 197.3 16.2* 192.2 21.7* 144.2 12.5* 135.8 11.5* 124.8 10.8* 90 182.3 17.7* 185.3 15.0* 151.2 8.9* 141.3 10.2* 135.8 6.7* 120 163.0 10.3* 154.8 13.2* 146.2 4.6* 132.5 7.9* 130.2 6.7*

*N=6.

SEM = Standard error of the mean.

table 2

Compound 1 dose (mg/kg) % Inhibition of glucose gain 0.3 6.5 3 47.0 10 60.1 thirty 52.1

Example 3 In vivo effect of 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5yl)piperidin-1-yl )pyrimidin-4-ylamino)-N,N-damethylbenzamide (compound 1) on glucose homeostasis (oral glucose tolerance test (OTTG)) in male 129SVE mice.

Male 129SVE mice (approximately 8 weeks of age) were fasted for 18 hours and randomly grouped (n=6) to obtain a GPR119 agonist (compound 1) at 0.3, 3, or 30 mg/kg (mg/kg bw bodies). Compound was delivered orally via gavage (po volume 4 ml/kg) 30 min before a bolus of glucose (3 g/kg) (time=-30 min in Figure 3), with a separate group receiving vehicle (20% hydroxypropyl -beta-cyclodextrin) as a control. At time 0 min, a bolus of glucose was administered. Blood glucose levels were measured using a glucometer (One-Touch

- 62 040124

Ultra™, LifeScan) at -30 minutes (prior to compound administration), at 0 minutes (when the glucose bolus was administered), and 20, 40, 60, 120 minutes after the glucose bolus. Plasma glucose concentration (mg/dL) at various time points is shown in FIG. 3 and in table. 3. The increase in glucose level (AUC (area under the curve) decrease) in animals treated with the compound relative to the vehicle control is shown in FIG. 4 and in table. 4. These results indicated that the GPR119 agonist, 3-fluoro-4(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl) piperidin-1-yl)pyrimidin-4-ylamino)-N,N-dimethylbenzamide (Compound 1) lowered blood glucose levels after glucose administration in 129SVE mice.

Table 3

Plasma glucose (mg/dl) Compound 1 dose (mg/kg) Time 20% HPCD 0.3 3.0 30.0 (min) Average value SEM Average value SEM Average value SEM Average value SEM -thirty 52.2 3.0* 58.5 4.0* 63.5 3.3* 64.5 7.6* 0 64.7 2.7* 74.2 5.1* 75.2 2.1* 78.7 7.6* 20 249.5 9.4* 221.3 13.4* 206.7 11.0* 185.8 8.1* 40 294.3 18.5* 274.8 6.4* 233.0 9.8* 216.0 7.7* 60 291.3 13.8* 258.2 9.6* 213.5 12.1* 191.7 10.8* 120 185.8 13.3* 154.5 8.5* 138.2 4.6* 138.7 13.4*

*N=6.

SEM = Standard error of the mean.

Table 4

Compound 1 dose (mg/kg) % Inhibition of Glucose Growth 0.3 16.9 3 34.8 thirty 42.1

Example 4 In vivo effect of 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5yl)piperidin-1-yl )pyrimidin-4-ylamino)-N,N-dαmethylbenzamide (compound 1) on the release of the incretin hormone GIP.

Male 129SVE mice (approximately 8 weeks of age) were fasted for 18 h and randomly grouped (n=6) to obtain a GPR119 agonist (compound 1) at an oral dose of 0.1, 0.3, 1, 3, 10 or 30 mg/kg (mg/kg body weight). Compounds were delivered orally by gavage (po volume 4 ml/kg) and blood samples were collected after 45 minutes to determine total plasma GIP levels. A separate group received vehicle (PET: 80% PEG400, 10% ethanol, 10% Tween80) as a control. Plasma GIP levels were determined using the Total GIP ELISA kit from Millipore. The results are shown in FIG. 6 and in table. 5.

Table 5

Compound 1 dose (mg/kg) Total plasma GIP level in mice Total GIP level, pg/ml Compound 1 dose (mg/kg) Total plasma GIP level in mice Total GIP level, pg/ml filler 36.01 3 318.5 0.1 60.92 10 444.8 0.3 68.21 thirty 695.0 1 183.8

Example 5 Homogeneous Time-Resolved Fluorescence (HTRF®) Assay for Direct Measurement of cAMP.

The GPR119 agonist Compound 1 was evaluated by the manufacturer's HTRF® cAMP detection assay (Cisbio, cAMP Dynamic 2 Assay Kit; #62AM4PEJ) using Cho-Κι cells stably expressing the GPR119 receptor. Briefly, Cho-Κι cells were transfected with a lentiviral vector encoding the GPR119 nucleotide sequence (NCBI mRNA and protein control sequences: NM_178471.2 & NP_848566, (GPR119 was also referred to as the glucose-dependent insulinotropic receptor (GDIR)). The N-terminus of the GPR119 nucleotide sequence was modified to substitution of the first methionine-coding codon with a nucleotide sequence encoding the standard nine amino acids, hemagglutinin tags.After transduction, cells expressing the GPR119 receptor were isolated and a single clone was isolated following standard serial dilution cloning methods.On the day of the study, cultured CHO-GPR119 cells were harvested, suspended in assay buffer and plated in 384-well plates (PerkinElmer Proxiplate #6008280) at a density of 2000 cells/well cAMP calibration curve was included on each plate Test compounds were dissolved in DMSO, serially diluted

- 63 040124 in DMSO and then diluted in assay buffer before adding to cells. Test compounds were evaluated in triplicate using a 10-point, 5-fold serial dilution starting at 10 μM. The final concentration of DMSO in the study was 0.5%. Compounds and cells were incubated for 1 hour at room temperature and then developing reagents (cAMP-D2 in cell lysis buffer followed by europium cryptate labeled anti-cAMP antibody) were added to each well. The plates were then incubated at room temperature for 1 hour until data was read. Time-resolved fluorescence measurements were performed on PerkinElmer Envision™ or BMG Pherastar™ plate readers. Compound N(2-fluoro-4(methylsulfonyl)phenyl)-6-(4-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-5-nitropyrimidine4-amine was used in as a positive control in each measurement, while assay buffer containing 0.5% DMSO was used as a negative control. Using the HTRF® assay, EC ₅₀ values were observed for the following GPR119 agonists:

3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4ylamino )-N,N-dimethylbenzamide (compound 1), 23.4 nM (n=32);

3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4ylamino )-N-methylbenzamide (compound 2), 27.0 nM (n=9) and

3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4ylamino )benzamide (compound 3), 28.2 nM (n=3).

Example 6 In vivo and in vitro metabolism of 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4oxadiazol-5-yl)piperidine- 1-yl) pyrimidin-4-ylamino)-N,N-dimethylbenzamide (compound 1).

Example 6.1: In vivo metabolism of compound 1:

Compound 1 metabolites were identified/ in plasma samples collected from various pharmacokinetic studies in various species.

Four species, mouse, rat, dog and monkey, were administered Compound 1 and plasma samples were taken at predetermined time points from each of the species in accordance with defined study protocols. The samples were then processed and subjected to LC/MS/MS analysis to identify and quantify metabolites. Three metabolites, designated M1 (compound 2), M2 (compound 3) and M3, were identified in plasma samples from various species. The M1 metabolite was identified as the mono-N-demethylation product of Compound 1, and the M2 metabolite was the di-N-demethylation product of Compound 1. The third M3 metabolite (i.e., 3-fluoro-4-(5-fluoro-6-(4 -(3-(2fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-ylamino)benzoic acid, see below) was identified as the carboxylic acid of compound 1 .

O

Ν^Ν

I n I I I

The M1 and M2 metabolites were found to be pharmacologically active (see Example 5), while the M3 metabolite was shown to have essentially little activity (EC ₅₀ =100 μM, HTRF® assay). Quantification of these three metabolites showed that the order of formation in the plasma samples was M3>M1>M2. M3 has been found to be the major circulating metabolite in all species. M2 was not observed in dog plasma samples under the analytical conditions used.

Example 6.2: In vitro metabolism of compound 1 in liver microsomes in various species.

Compound 1 was incubated with mouse, rat, dog, monkey and human liver microsomal protein (0.25 mg/ml final concentration) in 100 mM potassium phosphate buffer containing 3 mM MgCl ₂ and 1 mM EDTA (pH 7.4), over a period of time in the presence or absence of β-NADPH. The samples were then processed and the supernatant analyzed by LC-MS/MS to identify and quantify metabolites.

Three metabolites, M1 (mono-N-demethylation), M2 (di-N-demethylation), and M3 (carboxylic acid), have been found in microsomal incubation of all species, including humans. Metabolites M1, M2 and M3 were also quantified by incubation of liver microsomes in all species. The rates of formation of these metabolites varied between species, however, three metabolites observed in liver microsomes of preclinical species were found in human liver microsomes (FIGS. 9-11). The rate of formation of M1 was the highest followed by M2 and M3 under the in vitro experimental conditions used. M2 turned out to be a secondary metabolite of M1. M2 formation in dog liver microsomes was negligible.

Example 7 X-ray powder diffraction.

Powder X-ray diffraction (PXRD) data were collected on an X'Pert PRO MPD powder diffractometer (PANalytical, Inc.) with a Cu source set at 45 kV and 40 mA, Cu(Ka) radiation

- 64 040124 niem and X'Celerator detector. The samples were added to the sample holder and the surface was leveled with a spatula and weighing paper. With the rotation of the samples, an X-ray diffraction pattern was obtained using a 12-min scan in the range of 5-40°2θ. Diffraction data were viewed and analyzed with X'Pert Data Viewer Software, version 1.0a and X'Pert HighScore Software, version 1.0b. The X-ray powder diffraction pattern for the anhydrous crystalline form of Compound 1 is shown in FIG. 6.

Example 8 Differential Scanning Calorimetry

Differential scanning calorimetry (DSC) studies were performed using TA Instruments, Q2000 at a heating rate of 10° C./min. The measuring instruments were calibrated for temperature and energy using the melting point and enthalpy of melting of the indium standard. Thermal phenomena (desolvation, melting, etc.) were evaluated using Universal Analysis 2000 software, version 4.1D, Build 4.1.0.16. The DSC thermogram for the anhydrous crystalline form of Compound 1 is shown in FIG. 7.

Example 9 Thermogravimetric analysis.

Thermogravimetric analyzes (TGA) were performed using TA Instruments TGA Q500 or Q5000 at a heating rate of 10°C/min. The measuring instrument was calibrated using the standard weight for the balance and the alumel and nickel standards for the heat chamber (Curie point measurements). Thermal phenomena such as weight loss are calculated using Universal Analysis 2000 software, version 4.1D, Build 4.1.0.16. The TGA thermogram for the anhydrous crystalline form of compound 1 is shown in FIG. 7.

Example 10 Dynamic Moisture Sorption Analysis.

The study of dynamic moisture sorption (DSW) was carried out using a dynamic moisture sorption analyzer VTI Corporation, SGA-100. Samples were prepared for DWV analysis by placing 5 to 20 mg of sample in a tared sample holder. The sample was placed on the suspended wire of a VTI balance. The drying step was typically carried out at 40°C and 0.5-1% RH for 1 hour. The temperature of the isotherm is 25°C. Certain %RH readings typically ranged from 10 to 90% RH, with intervals of 10 to 20% RH. A wt% change of less than 0.010% over 10 minutes or up to 2 hours, whichever happened first, was required before continuing to the next %RH reading. The water content of the balanced sample, as described above, was determined at each %RH reading. The dynamic moisture sorption profile for the anhydrous crystalline form of Compound 1 is shown in FIG. 8.

One skilled in the art will appreciate that various modifications, additions, and substitutions to the illustrative examples set forth herein may be made without departing from the spirit of the invention and are thus considered within the scope of the invention.

The citation of any reference throughout this document should not be construed as an admission that such reference is a prior art application for this invention.

Claims (23)

CLAIM 1. A compound selected from the following compounds and their pharmaceutically acceptable salts, solvates and hydrates: 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4ylamino )-K,K-dimethylbenzamide; 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4ylamino )-K-methylbenzamide and 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4ylamino )benzamide. 2. A compound selected from 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5yl)piperidin-1-yl )pyrimidin-4-ylamino)-K,K-dimethylbenzamide and its pharmaceutically acceptable salts, solvates and hydrates. 3. A compound selected from the following compounds and their pharmaceutically acceptable salts, solvates and hydrates: 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4ylamino )-K-methylbenzamide and 3-fluoro-4-(5-fluoro-6-(4-(3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4ylamino )benzamide. 4. A pharmaceutical composition containing a compound according to any one of claims 1 to 3 and a pharmaceutically acceptable carrier. 5. A method for preparing a composition according to claim 4, comprising the step of mixing a compound according to any one of claims 1 to 3 and a pharmaceutically acceptable carrier. 6. A method for increasing the secretion of incretin in a patient or increasing the level of incretin in the blood of a patient, comprising administering to said patient in need of such treatment, therapeutically - 65 040124 an effective amount of a compound according to any one of claims 1 to 3 or a composition according to claim 4. 7. The use of a compound according to any one of claims 1 to 3 in the preparation of a medicament for increasing the secretion of incretin in a patient or increasing the level of incretin in the blood of a patient. 8. A drug for modulating GPR119 receptor activity in a human or animal, comprising a compound according to any one of claims 1-3. 9. A drug for increasing the secretion of incretin in a patient or increasing the level of incretin in the blood of a patient, containing a compound according to any one of claims 1 to 3. 10. Use of a pharmaceutical composition containing a compound according to any one of claims 1 to 3 in a method of treatment by modulating the activity of the GPR119 receptor in a human or animal. 11. The use of a pharmaceutical composition containing a compound according to any one of claims 1 to 3 in a method for increasing the secretion of incretin in a patient or increasing the level of incretin in the blood of a patient. 12. The method of claim 6 wherein said incretin is GLP-1. 13. The method of claim 6 wherein said incretin is a GIP. 14. The method of claim 6 wherein said incretin is PYY. 15. Use according to claim 7, wherein said incretin is GLP-1. 16. Use according to claim 7, wherein said incretin is a GIP. 17. Use according to claim 7, wherein said incretin is PYY. 18. The drug according to claim 9, wherein said incretin is GLP-1. 19. The drug according to claim 9, wherein said incretin is a GIP. 20. The drug according to claim 9, wherein said incretin is PYY. 21. Use according to claim 11, wherein said incretin is GLP-1. 22. Use according to claim 11, wherein said incretin is a GIP. 23. Use according to claim 11, wherein said incretin is PYY. EFFECT OF COMPOUND 1 ON GLUCOSE HOMEOSTASIS IN ZDF MALE RATS WITH DIABETES (ORAL GLUCOSE TOLERANCE TEST (ΟΤΤΓ)