WO2013055910A1 - Modulators of the gpr119 receptor and the treatment of disorders related thereto - Google Patents

Modulators of the gpr119 receptor and the treatment of disorders related thereto Download PDF

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Publication number
WO2013055910A1
WO2013055910A1 PCT/US2012/059736 US2012059736W WO2013055910A1 WO 2013055910 A1 WO2013055910 A1 WO 2013055910A1 US 2012059736 W US2012059736 W US 2012059736W WO 2013055910 A1 WO2013055910 A1 WO 2013055910A1
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Prior art keywords
azabicyclo
pyridin
cyclohexyloxy
octane
carboxylate
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PCT/US2012/059736
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French (fr)
Inventor
Robert M. Jones
Daniel J. Buzard
Sangdon Han
Sun Hee Kim
Juerg Lehmann
Xiuwen Zhu
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Arena Pharmaceuticals, Inc.
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Publication of WO2013055910A1 publication Critical patent/WO2013055910A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism

Definitions

  • the present invention relates to compounds of Formula (I) and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof, that are useful as single
  • an inhibitor of DPP-IV a biguanide, an alpha-glucosidase inhibitor, an insulin analogue, a sulfonylurea, an SGLT2 inhibitor, a meglitinide, a thiazolidinedione, or an antidiabetic peptide analogue, in the treatment of, for example, a disorder selected from: a GPR119- receptor-related disorder; a condition ameliorated by increasing secretion of an incretin; a condition ameliorated by increasing a blood incretin level; a condition characterized by low bone mass; a neurological disorder; a metabolic -related disorder; type 2 diabetes; obesity; and complications related thereto.
  • additional pharmaceutical agents such as, an inhibitor of DPP-IV, a biguanide, an alpha-glucosidase inhibitor, an insulin analogue, a sulfonylurea, an SGLT2 inhibitor, a meglitinide, a thiazolidinedione,
  • Diabetes mellitus is a serious disease afflicting over 100 million people worldwide. In the United States, there are more than 12 million diabetics, 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.
  • IDDM insulin-dependent diabetes mellitus
  • NIDDM non-insulin-dependent diabetes mellitus
  • the etiology of the different types of diabetes is not the same; however, everyone with diabetes has two things in common: overproduction of glucose by the liver and little or no ability to move glucose out of the blood into the cells where it becomes the body's primary fuel.
  • Diabetes is a syndrome with interrelated metabolic, vascular, and neuropathic components.
  • the metabolic syndrome generally characterized by hyperglycemia, comprises alterations in carbohydrate, fat and protein metabolism caused by absent or markedly reduced insulin secretion and/or ineffective insulin action.
  • the vascular syndrome consists of abnormalities in the blood vessels leading to cardiovascular, retinal and renal complications. Abnormalities in the peripheral and autonomic nervous systems are also part of the diabetic syndrome.
  • IDDM is characterized by low or undetectable levels of endogenous insulin production caused by destruction of the insulin-producing ⁇ cells of the pancreas, the characteristic that most readily distinguishes IDDM from NIDDM. IDDM, once termed juvenile-onset diabetes, strikes young and older adults alike.
  • NIDDM type 2
  • NIDDM NIDDM-associated neoplasm originating from whites and Asians.
  • NIDDM is more common among Native Americans, African- Americans, Latinos, and Hispanics.
  • the onset can be insidious or even clinically unapparent, making diagnosis difficult.
  • NIDDM neurodegenerative disease
  • Kidney disease also called nephropathy
  • Diabetes occurs when the kidney's "filter mechanism” is damaged and protein leaks into urine in excessive amounts and eventually the kidney fails. Diabetes is also a leading cause of damage to the retina at the back of the eye and increases risk of cataracts and glaucoma.
  • diabetes is associated with nerve damage, especially in the legs and feet, which interferes with the ability to sense pain and contributes to serious infections. Taken together, diabetes complications are one of the nation's leading causes of death.
  • 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 has increased from 25% at the end of the 1970's, to 33% at the beginning the 1990's. Obesity is one of the most important risk factors for NIDDM. Definitions of obesity differ, but in general, a subject 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 with NIDDM are overweight.
  • Obesity which is the result of an imbalance between caloric intake and energy expenditure, is highly correlated with insulin resistance and diabetes in experimental animals and human.
  • Whether someone is classified as overweight or obese can be determined by a number of different methods, such as, on the basis of their body mass index (BMI) which is calculated by dividing body weight (kg) by height squared (m 2 ).
  • BMI body mass index
  • m 2 height squared
  • Overweight is defined as a BMI in the range 25-30 kg/m 2
  • obesity as a BMI greater than 30 kg/m 2 (see table below).
  • body fat content greater than 25% and 30% in males and females, respectively.
  • Coronary insufficiency, atheromatous disease, and cardiac insufficiency are at the forefront of the cardiovascular complication induced by obesity. It is estimated that if the entire population had an ideal weight, the risk of coronary insufficiency would decrease by 25% and the risk of cardiac insufficiency and of cerebral vascular accidents by 35%. The incidence of coronary diseases is doubled in subjects less than 50 years of age who are 30% overweight.
  • Atherosclerosis is a complex disease characterized by inflammation, lipid accumulation, cell death and fibrosis. Atherosclerosis is characterized by cholesterol deposition and monocyte infiltration into the subendothelial space, resulting in foam cell formation. Thrombosis subsequent to atherosclerosis leads to myocardial infarction and stroke. Atherosclerosis is the leading cause of mortality in many countries, including the United States. (See, e.g., Ruggeri, Nat Med (2002) 8: 1227-1234; Arehart et al, Circ Res, Circ. Res. (2008) 102:986-993.)
  • Osteoporosis is a disabling disease characterized by the loss of bone mass and microarchitectural deterioration of skeletal structure leading to compromised bone strength, which predisposes a patient to increased risk of fragility 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 alone. In the United States, osteoporosis affects at least 25% of all post-menopausal white women, and the proportion rises to 70% in women older than 80 years. One in three women older than 50 years will have an osteoporotic fracture that causes a considerable social and financial burden on society. The disease is not limited to women; older men also can be affected.
  • IBD Inflammatory bowel disease
  • Crohn's disease ulcerative colitis
  • ulcerative proctitis U.S. medical costs of inflammatory bowel disease for 1990 have been estimated to be $1.4 to $1.8 billion. Lost productivity has been estimated to have added an additional $0.4 to $0.8 billion, making the estimated cost of inflammatory bowel disease $1.8 to $2.6 billion.
  • Enteritis refers to inflammation of the intestine, especially the small intestine, a general condition that can have any of numerous different causes. Enterocolitis refers to inflammation of the small intestine and colon.
  • CD Crohn's disease
  • Ileitis is CD of the ileum which is the third part of the small intestine.
  • Crohn's colitis is CD affecting part or all of the colon.
  • Ulcerative colitis is an inflammatory disease of the large intestine, commonly called the colon. UC causes inflammation and ulceration of the inner lining of the colon and rectum. The inflammation of UC is usually most severe in the rectal area with severity diminishing (at a rate that varies from patient to patient) toward the cecum, where the large and small intestine join. Inflammation of the rectum is called proctitis. Inflammation of the sigmoid colon (located just above the rectum) is called sigmoiditis. Inflammation involving the entire colon is termed pancolitis. The inflammation causes the colon to empty frequently resulting in diarrhea. As the lining of the colon is destroyed ulcers form releasing mucus, pus and blood. Ulcerative proctitis is a form of UC that affects only the rectum.
  • GPR119 is a G protein-coupled receptor (GPR119; e.g. , human GPR119, GenBank ® Accession No. AAP72125 and alleles thereof; e.g. , mouse GPR119, GenBank ® Accession No. AY288423 and alleles thereof) and is selectively expressed on pancreatic beta cells. GPR119 activation leads to elevation of a level of intracellular cAMP, consistent with GPR119 being coupled to Gs. Agonists to GPR119 stimulate glucose-dependent insulin secretion in vitro and lower an elevated blood glucose level in vivo; see, e.g. , International Applications WO
  • GPR119 has also been referred to as RUP3 (see, International Application WO 00/31258) and as 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): 1339-1359); for specific references related to GPR119 agonists and the release of:
  • GIP Glucose-dependent Insulinotropic Polypeptide
  • GLP-1 Glucagon-Like Peptide- 1
  • PYY Peptide YY
  • GLP-1 see Shah, Current Opinion in Drug Discovery & Development, (2009) 12:519-532;
  • GPR119 agonists enhance incretin release and therefore can be used in treatment of disorders related to the incretins, such as, GIP, GLP-1, and PYY.
  • GIP and GLP-1 are substrates for the enzyme DPP-IV. Jones and co-workers (Jones, et ⁇ ., ⁇ . Rep. Med.
  • GIP Glucose-dependent insulinotropic polypeptide
  • gastric inhibitory polypeptide is a peptide incretin hormone of 42 amino acids that is released from duodenal endocrine K cells after meal 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.
  • GIP contains an alanine at position 2, it is an excellent substrate for dipeptidyl peptidase-4 (DPP-IV), an enzyme regulating the degradation of GIP.
  • DPP-IV dipeptidyl peptidase-4
  • Full-length GIP(l-42) is rapidly converted to bioinactive GIP(3-42) within minutes of secretion from the gut K cell. Inhibition of DPP-IV has been shown to augment GIP bioactivity.
  • GIP has been shown to promote bone formation.
  • GIP has been shown to activate osteoblastic receptors, resulting in increases in 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.
  • GIP administration has been shown to prevent the bone loss due to ovariectomy.
  • GIP receptor (GIPR) knockout mice evidence a decreased bone size, lower bone mass, altered bone microarchitecture and biochemical properties, and altered parameters for bone turnover, especially in bone formation.
  • GIP usefulness of GIP for maintaining or increasing bone density or formation has been acknowledged by the United State Trademark and Patent Office by issuance of United States Patent No. 6,410,508 for the treatment of reduced bone mineralization by administration of GIP peptide.
  • current GIP peptide agonists suffer from a lack of oral bioavailability, negatively impacting patient compliance.
  • An attractive alternative approach is to develop an orally active composition for increasing an endogenous level of GIP activity.
  • GLP-1 Glucagon-Like Peptide-1
  • Glucagon-like peptide-1 (GLP-1) is an incretin hormone derived from the
  • GLP-1 mediates its actions through a specific G protein-coupled receptor (GPCR), namely GLP-1R.
  • GLP-1 is best characterized as a hormone that regulates glucose homeostasis.
  • GLP-1 has been shown to stimulate glucose-dependent insulin secretion and to increase pancreatic beta cell mass.
  • GLP-1 has also been shown to reduce the rate of gastric emptying and to promote satiety.
  • the efficacy of GLP-1 peptide agonists in controlling blood glucose in Type 2 diabetics has been demonstrated in several clinical studies [see, e.g. , Nauck et al, Drug News Perspect (2003) 16:413-422], as has its efficacy in reducing body mass [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 be cardioprotective in a rat model of myocardial infarction [Bose et al, Diabetes (2005) 54: 146- 151], and GLP-1 R has been shown in rodent models to be involved in learning and
  • GLP-1 peptide agonists suffer from a lack of oral bioavailability, negatively impacting patient compliance. Efforts to develop orally bioavailable non-peptidergic, small- molecule agonists of GLP-1 R have so far been unsuccessful [Mentlein, Expert Opin Investig Drugs (2005) 14:57-64]. An attractive alternative approach is to develop an orally active composition for increasing an endogenous level of GLP-1 in the blood.
  • 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 within both the large and small intestine. It has been shown that in rat and human gut concentrations of immunoreactive PYY are low in duodenum and jejunum, high in ileum and colon, and highest in rectum (Lundberg et al, PNAS USA (1982) 79:4471-4475; Adrian et al, Gastroenterol.
  • PYY 3 - 36 is generated from PYYi_ 36 by cleavage of the N-terminal Tyr and Pro residues by dipeptidyl peptidase IV.
  • PYY 3 . 36 is the predominant form of PYY in human postprandial plasma (Grandt et al, Regul. Pept. (1994) 51 : 151-159).
  • PYYi- 36 and PYY 3 . 36 have been reported to have comparable agonist activity at NPY Y2 receptor (Y2R), a G protein- coupled receptor (Parker et al, Br. J. Pharmacol. (2008) 153:420-431); however, PYY 3 . 36 has been reported to be a high-affinity Y2R selective agonist (Keire et al, Am. J. Physiol.
  • Peripheral administration of PYY 3 . 36 has been reported to markedly reduce food intake and weight gain in rats, to decrease appetite and food intake in humans, and to decrease food intake in mice, but not in Y2R-null mice, which was said to suggest that the food intake effect requires the Y2R.
  • infusion of PYY 3 . 36 was found to significantly decrease appetite and reduce food intake by 33% over 24 hours.
  • Peripheral administration of PYY 3 . 36 has been reported to reduce food intake, body weight gain and glycemic indices in diverse rodent models of metabolic diseases of both sexes (Pittner et al, Int. J. Obes. Relat. Metab. Disord. (2004) 28:963-971). It has been reported that blockade of Y2R with the specific antagonist BIIE-246 attenuates the effect of peripherally administered endogenous and exogenous PYY 3 _ 36 for reducing food intake (Abbott et al, Brain Res (2005) 1043: 139-144).
  • peripheral administration of a novel long- acting selective Y2R polyethylene gly col-conjugated peptide agonist reduces food intake and improves glucose metabolism (glucose disposal, 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). It has been reported that peripheral administration of a long-acting, potent and highly selective Y2R agonist inhibits food intake and promotes fat metabolism in mice (Balasubramaniam et al, Peptides (2007) 28:235-240).
  • Y2R agonists such as PYY 1 36 and PYY 3 . 36 can confer protection against epileptic seizures, such as against kainate seizures (El Bahh et al, Eur. J.
  • Y2R agonists such as PYY 1 36 and PYY 3 . 36 act as proabsorbtive (or anti-secretory) hormones, increasing upon intravenous administration the absorption of both water and sodium in various parts of the bowel (Bilchik et al, Gastroenterol. (1993) 105: 1441- 1448; Liu et al, J. Surg. Res. (1995) 58:6-11 ; Nightingale et al, Gut (1996) 39:267-272; Liu et al, Am Surg (1996) 62:232-236; Balasubramaniam et al, J. Med. Chem. (2000) 43:3420-3427). It has been reported that Y2R agonists such as PYY analogues inhibit secretion and promote absorption and growth in the intestinal epithelium (Balasubramaniam et al, J. Med. Chem.
  • Y2R agonists such as PYY 1 36 and PYY 3 . 36 can confer protection against inflammatory bowel disease such as ulcerative colitis and Crohn's disease (WO 03/105763). It has been reported that PYY-deficient mice exhibit an osteopenic phenotype, i.e. that PYY can increase bone mass and/or can confer protection against loss of bone mass (e.g. , decreases loss of bone mass) (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).
  • PYY and Y2R agonists such as PYY 3 . 36 can suppress tumor growth in the cases of, e.g. , pancreatic cancer such as pancreatic ductal adenocarcinoma, breast cancer such as breast infiltrative ductal adenocarcinoma, colon cancer such as colon
  • 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 exerts 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.
  • adiponectin has been implicated in high density lipoprotein (HDL) assembly (Oku et al, FEBS Letters (2007) 581 :5029-5033).
  • HDL high density lipoprotein
  • Adiponectin has been found to ameliorate the abnormalities of metabolic syndrome, including insulin resistance, hyperglycemia, and dyslipidemia, in a mouse model of obesity-linked metabolic syndrome associated with decreased adiponectin levels (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 through endothelial nitric oxide synthase-dependent mechanisms (Nishimura et al, Circulation (2008) 117:216-223). Adiponectin has been reported to confer protection against myocardial ischemia-reperfusion injury (Shibata et al, Nat Med (2005) 11 : 1096-1103; Tao et al, Circulation (2007) 115: 1408- 1416). Adiponectin has been reported to confer protection against myocardial ischemia- reperfusion injury via AMP-activated protein kinase, Akt, and nitric oxide (Gonon et al, Cardiovasc Res. (2008) 78: 116-122).
  • Adiponectin has been reported to confer protection against the development of systolic dysfunction following myocardial infarction, through its abilities to suppress cardiac hypertrophy and interstitial fibrosis, and protect against myocyte and capillary loss (Shibata et al, J. Mol. Cell Cardiol. (2007) 42: 1065-1074). Adiponectin has been reported to confer protection against inflammatory lung disease; adiponectin-deficient mice exhibit an emphysema-like phenotype (Summer et al, Am J. Physiol. Lung Cell Mol. Physiol (March 7, 2008)).
  • Adiponectin has been reported to confer protection against allergic airway inflammation and airway hyperresponsiveness such as may be associated with asthma (Shore et al, J. Allergy Clin. Immunol (2006) 118:389-395). Adiponectin has been suggested to confer protection against pulmonary arterial hypertension by virtue of its insulin-sensitizing effects (Hansmann et al, Circulation (2007) 115:1275-1284). Adiponectin has been reported to ameliorate obesity- related hypertension, with said amelioration of hypertension being associated in part with upregulated prostacyclin expression (Ohashi et al, Hypertension (2006) 47: 1108-1116).
  • Adiponectin has been reported to decrease tumor necrosis factor (TNF)-a-induced expression of the adhesion molecules VCAM-1, E-selectin and ICAM-1 in human aortic endothelial cells (HAECs) (Ouchi et al, Circulation (1999) 100:2473-2476) and to inhibit production of TNF-a in macrophages (Yokota et al, Blood (2000) 96:1723-1732). Adiponectin has been reported to confer protection against restenosis after vascular intervention (Matsuda et al, J Biol Chem
  • TNF-a-mediated inflammatory conditions encompass 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: 149-160). See, e.g.,
  • One aspect of the present invention is directed to compounds, as described herein, and pharmaceutically acceptable salts, solvates, and hydrates thereof, which bind to and modulate the activity of a GPCR, referred to herein as GPR119, and uses thereof.
  • One aspect of the present invention encompasses, inter alia, certain cyclohexane derivatives selected from compounds of Formula (I) and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof:
  • Ar is selected from: aryl and heteroaryl; each optionally substituted with one or more substituents selected from: Ci-C 6 alkyl, C 1 -C4 alkylcarboxamide, Ci-C 6 alkylsulfinyl, Ci-C 6 alkylsulfonyl, heterocyclylsulfonyl, Ci-C 6 alkylthio, carboxamide, cyano, C 3 -C 7
  • Ci-C 6 alkyl is optionally substituted with one or more substituents selected from: Ci-C 6 alkoxy, hydroxyl, cyano, C 2 -C 6 dialkylamino, and heterocyclyl; and
  • R 1 is selected from: C 1 -C6 alkoxycarbonyl, C3-C7 cycloalkoxycarbonyl, and heteroaryl; each optionally substituted with one or more substituents selected from: C 1 -C6 alkyl, C 1 -C6 haloalkyl, and halogen.
  • One aspect of the present invention encompasses, inter alia, certain cyclohexane derivatives selected from compounds of Formula (lb) and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides
  • One aspect of the present invention encompasses, inter alia, certain cyclohexane derivatives selected from compounds of Formula (If) and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides
  • compositions comprising a compound of the present invention.
  • One aspect of the present invention pertains to a pharmaceutical product selected from: a pharmaceutical composition, a formulation, a unit dosage form, and a kit; each comprising a compound of the present invention.
  • One aspect of the present invention pertains to pharmaceutical compositions comprising a compound of the present invention, and a pharmaceutically acceptable carrier.
  • One aspect of the present invention pertains to methods for preparing a pharmaceutical composition comprising the step of admixing a compound of the present invention, and a pharmaceutically acceptable carrier.
  • One aspect of the present invention pertains to compositions comprising a compound of the present invention, and a second pharmaceutical agent.
  • One aspect of the present invention pertains to methods for preparing a composition comprising the step of admixing a compound of the present invention, and a second pharmaceutical agent.
  • One aspect of the present invention pertains to a pharmaceutical product selected from: a pharmaceutical composition, a formulation, a unit dosage form, a combined preparation, a twin pack, and a kit; each comprising a compound of the present invention, and a second pharmaceutical agent.
  • One aspect of the present invention pertains to pharmaceutical compositions comprising a compound of the present invention, a second pharmaceutical agent, and a pharmaceutically acceptable carrier.
  • One aspect of the present invention pertains to methods for preparing a pharmaceutical composition
  • methods for preparing a pharmaceutical composition comprising the step of admixing a compound of the present invention, a second pharmaceutical agent, and a pharmaceutically acceptable carrier.
  • One aspect of the present invention pertains to methods for modulating the activity of a GPRl 19 receptor, comprising administering to an individual in need thereof, a therapeutically effective amount of: a compound of the present invention; a composition of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention
  • One aspect of the present invention pertains to methods for modulating the activity of a GPRl 19 receptor, comprising prescribing to an individual in need thereof, a therapeutically effective amount of: a compound of the present invention; a composition of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention.
  • One aspect of the present invention pertains to the use of a compound of the present invention in the manufacture of a medicament for modulating the activity of a GPRl 19 receptor in an individual.
  • One aspect of the present invention pertains to a compound of the present invention; a composition of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention; for use in a method of treatment of the human or animal body by therapy.
  • One aspect of the present invention pertains to a compound of the present invention; a composition of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention; for use in a method of modulating the activity of a GPRl 19 receptor in an individual.
  • One aspect of the present invention pertains to methods for modulating the activity of a GPRl 19 receptor, comprising administering to an individual in need thereof, a therapeutically effective amount of a compound of the present invention; a composition of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention; each in combination with a therapeutically effective amount of a second pharmaceutical agent.
  • One aspect of the present invention pertains to methods for modulating the activity of a GPRl 19 receptor, comprising prescribing to an individual in need thereof, a therapeutically effective amount of a compound of the present invention; a composition of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention; each in combination with a therapeutically effective amount of a second pharmaceutical agent.
  • One aspect of the present invention pertains 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 the activity of a GPRl 19 receptor in an individual.
  • One aspect of the present invention pertains to the use of a pharmaceutical agent in combination with a compound of the present invention, in the manufacture of a medicament for modulating the activity of a GPRl 19 receptor in an individual.
  • One aspect of the present invention pertains to a compound of the present invention; a composition of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention; each in combination with a second pharmaceutical agent for use in a method of treatment of the human or animal body by therapy.
  • One aspect of the present invention pertains to a compound of the present invention; a composition of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention; each in combination with a second pharmaceutical agent for use in a method of modulating the activity of a GPRl 19 receptor in an individual.
  • One aspect of the present invention pertains to a pharmaceutical agent in combination with a compound of the present invention; a composition of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention; for use in a method of treatment of the human or animal body by therapy.
  • One aspect of the present invention pertains to a pharmaceutical agent in combination with a compound of the present invention; a composition of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention; for use in modulating the activity of a GPRl 19 receptor in an individual.
  • the pharmaceutical agent or the second pharmaceutical agent is selected from: a DPP-IV inhibitor, a biguanide, an alpha-glucosidase inhibitor, an insulin analogue, a sulfonylurea, an SGLT2 inhibitor, a meglitinide, a thiazolidinedione, and an antidiabetic peptide analogue.
  • modulating the activity of a GPR119 receptor is agonizing a GPR119 receptor.
  • agonizing a GPR119 receptor is selected from:
  • Figure 1 shows the in vivo effects of Compound 5 on incretin hormone GIP release.
  • Figure 2 shows the in vivo effects of Compound 5 on glucose homeostasis in male
  • Figure 3 shows the in vivo effects of Compound 5 on glucose excursion in terms of percent glycemic inhibition (i.e., percent AUC reduction) in male 129SVE mice.
  • Figure 4 shows a general synthetic scheme for the preparation of intermediates useful in preparing compounds of Formula (I).
  • Figure 5 shows a general synthetic scheme for the preparation of intermediates useful in preparing compounds of Formula (I), and when PG 2 is R 1 then using either Method A or Method B provides Compounds of Formula (I).
  • Figure 6 shows a general synthetic scheme for the preparation of compounds of Formula (I) wherein R 1 is C 1 -C6 alkoxycarbonyl or C 3 -C 7 cycloalkoxycarbonyl, each optionally substituted as described herein, and wherein R 1 is heteroaryl optionally substituted as described herein.
  • Figure 7 shows a general synthetic scheme for the preparation of compounds of Formula (I) wherein R 1 is oxadiazole and R a selected from H, C 1 -C6 alkyl and C 1 -C6 haloalkyl.
  • Figure 8 shows a general synthetic scheme for the preparation of cis-exo and trans-exo intermediates useful in the preparation of Compounds of Formula (If).
  • Figure 9 shows a general synthetic scheme for the preparation of the trans-exo intermediates useful in the preparation of Compounds of Formula (If) wherein PG 2 is a protection group, and when PG 2 is R 1 then using either Method A or Method B provides Compounds of Formula (If).
  • Figure 10 shows a general synthetic scheme for the preparation of Compounds of Formula (If) wherein R 1 is Ci-C 6 alkoxycarbonyl or C 3 -C 7 cycloalkoxycarbonyl, each optionally substituted as described herein, and wherein R 1 is heteroaryl optionally substituted as described herein.
  • Figure 11 shows a general synthetic scheme for the preparation of Compounds of Formula (If) wherein R 1 is oxadiazole and R a selected from H, Ci-C 6 alkyl and Ci-C 6 haloalkyl.
  • agonist refers to a moiety that interacts with and activates a
  • G-protein-coupled receptor for instance a GPR119-receptor
  • GPR119-receptor a GPR119-receptor
  • an agonist may activate an intracellular response upon binding to a receptor, or enhance GTP binding to a membrane.
  • antagonist refers to a moiety that competitively binds to the receptor at the same site as an agonist (for example, the endogenous ligand), but which does not activate the intracellular response initiated by the active form of the receptor and can thereby inhibit the intracellular responses by an agonist or partial agonist.
  • An antagonist does not diminish the baseline intracellular response in the absence of an agonist or partial agonist.
  • hydrate refers to a compound of the invention or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
  • solvate refers to a compound of the invention or a salt, thereof, that further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces.
  • Preferred solvents are volatile, non-toxic, and/or acceptable for administration to humans in trace amounts.
  • the term "in need of treatment” and the term “in need thereof” when referring to treatment are used interchangeably and refer to a judgment made by a caregiver (e.g. physician, nurse, nurse practitioner, etc. in the case of humans; veterinarian in the case of animals, including non-human mammals) that an individual or animal requires or will benefit from treatment. This judgment is made based on a variety of factors that are in the realm of a caregiver's expertise, but that includes the knowledge that the individual or animal is ill, or will become ill, as the result of a disease, condition or disorder that is treatable by the compounds of the invention. Accordingly, the compounds of the invention can be used in a protective or preventive manner; or compounds of the invention can be used to alleviate, inhibit or ameliorate the disease, condition or disorder.
  • the term "individual” refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • inverse agonist refers to a moiety that binds to the endogenous form of the receptor or to the constitutively activated form of the receptor and which inhibits the baseline intracellular response initiated by the active form of the receptor below the normal base level of activity which is observed in the absence of an agonist or partial agonist, or decreases GTP binding to a membrane.
  • the baseline intracellular response is inhibited in the presence of the inverse agonist by at least 30%, more preferably by at least 50% and most preferably by at least 75%, as compared with the baseline response in the absence of the inverse agonist.
  • modulate or modulating refers to an increase or decrease in the amount, quality, response or effect of a particular activity, function or molecule.
  • composition refers to a composition comprising at least one active ingredient; including but not limited to, salts, solvates, and hydrates of compounds of the present invention, whereby the composition is amenable to investigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human).
  • a mammal for example, without limitation, a human
  • Those of ordinary skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based upon the needs of the artisan.
  • terapéuticaally effective amount refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician or caregiver or by an individual, which includes one or more of the following:
  • Preventing the disease for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease;
  • Inhibiting the disease for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or
  • Ameliorating the disease for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology).
  • unit dosage form refers to a single dose form which is capable of being administered to a subject, and which can be readily handled and packaged, remaining as a physically and chemically stable unit comprising a compound of the present invention (i.e., compound used neat, such as in a dry powder inhaler (DPI) consisting of neat drug substance or for use in sublingual or buccal administration) or a pharmaceutically acceptable composition comprising a compound of the present invention such as in a pill, capsule, tablet, and the like.
  • DPI dry powder inhaler
  • C 1 -C6 acyl denotes a C 1 -C6 alkyl radical attached to a carbonyl wherein alkyl has the same definition as described herein, some embodiments are when acyl is C 1 -C5 acyl; some embodiments are when acyl is C 1 -C4 acyl; some examples include, but are not limited to, acetyl, propionyl, «-butanoyl, wo-butanoyl, seobutanoyl, i-butanoyl (i.e., pivaloyl), pentanoyl and the like.
  • amino refers to the group -NH 2 .
  • C 1 -C6 alkoxy refers to a radical comprising a C 1 -C6 alkyl group attached directly to an oxygen atom, wherein C 1 -C6 alkyl has the same definition as found herein. Some embodiments contain 1 to 5 carbons. Some embodiments contain 1 to 4 carbons. Some embodiments contain 1 to 3 carbons. Some embodiments contain one or two carbons. Examples of an alkoxy group include, but are not limited to methoxy, ethoxy, «-propoxy, isopropoxy, n- butoxy, i-butoxy, isobutoxy, s-butoxy, and the like.
  • Ci-C 6 alkoxycarbonyl refers to a radical consisting of a Ci-C 6 alkoxy group attached to a carbonyl group, wherein Ci-C 6 alkoxy has the same definition as found herein. Examples include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, and tert- butoxycarbonyl.
  • Ci-C 6 alkyl refers to a straight or branched carbon radical containing 1 to 6 carbons. Some embodiments contain 1 to 5 carbons. Some embodiments contain 1 to 4 carbons. Some embodiments contain 1 to 3 carbons. Some embodiments contain one or two carbons.
  • alkyl group examples include, but are not limited to, methyl, ethyl, w-propyl, isopropyl, n- butyl, s-butyl, isobutyl, i-butyl, pentyl, isopentyl, i-pentyl, neopentyl, 1-methylbutyl [i.e. , -CH(CH 3 )CH 2 CH 2 CH 3 ], 2-methylbutyl [i.e. , -CH 2 CH(CH 3 )CH 2 CH 3 ], ra-hexyl, and the like.
  • C 1 -C4 alkylcarboxamide refers to a radical consisting of one C 1 -C4 alkyl group attached to either the carbon or the nitrogen of an amide group, wherein C 1 -C4 alkyl has the same definition as found herein.
  • the C 1 -C4 alkylcarboxamide group can be represented by the following formulae:
  • Ci-C 6 alkylsulfinyl refers to a radical consisting of a Ci-C 6 alkyl group attached to the sulfur of an sulfinyl group (i.e., -S(O)-), wherein Ci-C 6 alkyl has the same definition as described herein.
  • Examples include, but are not limited to, methylsulfinyl, ethylsulfinyl, «-propylsulfinyl, isopropylsulfinyl, «-butylsulfinyl, seobutylsulfinyl,
  • C 1 -C6 alkylsulfonyl refers to a radical comprising a C 1 -C6 alkyl group attached to the sulfur of a sulfonyl group, wherein the C 1 -C6 alkyl radical has the same definition as described herein. Examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, «-propylsulfonyl, isopropylsulfonyl, «-butylsulfonyl, s-butylsulfonyl, isobutylsulfonyl, i-butylsulfonyl, and the like.
  • C 1 -C6 alkylthio denotes a C 1 -C6 alkyl radical attached to a sulfur atom to form the group: C 1 -C6 alkyl-S-, wherein the alkyl radical has the same definition as described herein. Examples include, but are not limited to, methylthio (i.e., CH 3 S-), ethylthio, n- propylthio, iso-propylthio, n-butylthio, sec-butylthio, iso-butylthio, t-butylthio, and the like.
  • aryl denotes a 6- to 12-membered mono- or bicyclic ring system containing only ring carbons wherein at least one ring is aromatic. Examples include phenyl, 1,2,3,4- tetrahydro-naphthalen-l-yl, l,2,3,4-tetrahydro-naphthalen-2-yl, 5,6,7, 8-tetrahydro-naphthalen-l- yl, 5,6,7,8-tetrahydro-naphthalen-2-yl, indan-4-yl, naphtha-l-yl, naphtha-2-yl, and the like. In some embodiments, aryl is phenyl.
  • carboxylate refers to the group -CONH 2 .
  • cyano refers to the group -CN.
  • C 3 -C 7 cycloalkoxycarbonyl refers to a radical consisting of a C 3 -C 7 cycloalkoxy group attached to a carbonyl group, wherein C3-C7 cycloalkoxy has the same definition as found herein. Examples include, but are not limited to, cyclopropoxycarbonyl, cyclobutoxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, and
  • C3-C7 cycloalkylsulfinyl refers to a radical consisting of a C3-C7 cycloalkyl group attached to the sulfur of an sulfinyl group (i.e., -S(O)-), wherein C3-C7 cycloalkyl has the same definition as described herein. Examples include cyclopropylsulfinyl, cyclobutylsulfinyl, cyclopentylsulfinyl, cyclohexylsulfinyl, and cycloheptylsulfinyl.
  • C3-C7 cycloalkylsulfonyl refers to a radical comprising a C3-C7 cycloalkyl group attached to the sulfur of a sulfonyl group, wherein the C 3 -C 7 cycloalkyl radical has the same definition as described herein. Examples include cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl, and cycloheptylsulfonyl.
  • C 3 -C 7 cycloalkylthio denotes a C 3 -C 7 cycloalkyl radical attached to a sulfur atom to form the group: C 3 -C 7 cycloalkyl-S-, wherein the C 3 -C 7 cycloalkyl radical has the same definition as described herein. Examples include cyclopropylthio, cyclobutylthio,
  • C 3 -C 7 cycloalkoxy refers to a radical comprising a C 3 -C 7 cycloalkyl group attached directly to an oxygen atom, wherein C 3 -C 7 cycloalkyl has the same definition as found herein. Some embodiments contain 3 to 6 carbons. Some embodiments contain 3 to 5 carbons. Some embodiments contain 3 to 4 carbons. Examples of a cycloalkoxy group include, but are not limited to cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and cycloheptyloxy.
  • C 3 -C 7 cycloalkyl refers to a saturated ring radical containing 3 to 7 carbons. Some embodiments contain 3 to 4 carbons. Some embodiments contain 3 to 5 carbons. Some embodiments contain 4 to 6 carbons. Some embodiments contain 5 to 6 carbons. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • C 2 -C6 dialkylamino denotes an amino group substituted with two of the same or different Ci-C 3 alkyl radicals wherein alkyl has the same definition as described herein. Some embodiments are "C 2 -C 4 dialkylamino". Some examples include, but are not limited to, dimethylamino, methylethylamino, diethylamino, methylpropylamino, methylisopropylamino, ethylpropylamino, ethylisopropylamino, dipropylamino, propylisopropylamino and the like.
  • C 2 -C 8 dialkylcarboxamide refers to two alkyl radicals, that are the same or different, attached to a carboxamide group, wherein alkyl has the same definition as described herein.
  • a C 2 -C 8 dialkylcarboxamide may be represented by the following groups:
  • Ci-C 4 has the same definition as described herein.
  • dialkylcarboxamide examples include, but are not limited to, N,N-dimethylcarboxamide, N-methyl-N-ethylcarboxamide, N,N- diethylcarboxamide, N-methyl-N-isopropylcarboxamide, and the like.
  • C 1 -C6 haloalkyl refers to a radical comprising a C 1 -C6 alkyl group substituted with one or more halogens, wherein C 1 -C6 alkyl has the same definition as found herein.
  • the C 1 -C6 haloalkyl may be fully substituted in which case it can be represented by the formula C q L 2q+ i, wherein L is a halogen and "q" is 1, 2, 3, 4, 5 or 6. When more than one halogen is present then they may be the same or different and selected from: fluorine, chlorine, bromine, and iodine. In some embodiments, haloalkyl contains 1 to 5 carbons.
  • haloalkyl contains 1 to 4 carbons. In some embodiments, haloalkyl contains 1 to 3 carbons. In some embodiments, haloalkyl contains one or two carbons. Examples of a haloalkyl group include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2- trifluoroethyl, pentafluoroethyl, 2-fluoropropan-2-yl, 1,1-difluoropropyl, l,3-difluoropropan-2- yl, (5)-l-fluoropropan-2-yl, (R)-l-fluoropropan-2-yl, l,l,l-trifluoropropan-2-yl, 1,1,1,3,3,3- hexafluoropropan-2-yl, and the like.
  • halogen refers to a fluoro, chloro, bromo or iodo
  • heteroaryl refers to a ring system containing 5 to 10 ring atoms, that may contain a single ring or two fused rings, and wherein at least one ring is aromatic and at least one ring atom of the aromatic ring is a heteroatom selected from, for example: O, S and N, wherein N is optionally substituted with H, C 1 -C4 acyl, Ci-C alkyl, or O (i.e., forming an N- oxide) and S is optionally substituted with one or two oxygens.
  • the aromatic ring contains one heteroatom.
  • the aromatic ring contains two heteroatoms.
  • the aromatic ring contains three heteroatoms.
  • Examples include furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolyl, isoindolyl, indazolyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl.
  • Some embodiments are directed to 5-membered heteroaryl rings.
  • Examples of a 5-membered heteroaryl ring include furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, and the like.
  • Some embodiments are directed to 6-membered heteroaryl rings. Examples of a 6-membered heteroaryl ring include pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and the like.
  • Some embodiments are directed to 8 to 10-membered heteroaryl rings.
  • Examples of a 8 to 10-membered heteroaryl ring include quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolyl, isoindolyl, indazolyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl. phenazinyl,
  • heterocyclyl refers to a non-aromatic ring radical containing 3 to 7 ring atoms, wherein one, two or three ring atoms are heteroatoms is selected independently from, for example: O, S, and N, wherein N is optionally substituted with ⁇ , Ci-C acyl or Ci-C alkyl; and S is optionally substituted with one or two oxygens.
  • heterocyclyl group examples include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, [l ,3]-dioxolanyl, thiomo holinyl, [l ,4]oxazepanyl, l , l-dioxothiomo holinyl, azepanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, l-oxo-hexahydro- ⁇ 4 - thiopyranyl, l,l-dioxo-hexahydro- ⁇ 6 -thiopyranyl, and the like.
  • heterocyclylsulfonyl refers to a radical comprising a heterocyclyl group attached to the sulfur of a sulfonyl group, wherein the heterocyclyl radical has the same definition as described herein. Examples include aziridinylsulfonyl, azetidinylsulfonyl, oxetan- 3-ylsulfonyl, piperidinylsulfonyl, morpholinylsulfonyl, piperazinylsulfonyl,
  • hydroxyl refers to the group -OH.
  • phenyl refers to the group -CeH 5 .
  • One aspect of the present invention provides, inter alia, compounds selected from compounds of Formula (I) and pharmaceutically acceptable salts, solvates, hydrates, and N- oxides thereof:
  • One aspect of the present invention provides, inter alia, compounds selected from compounds of Formula (lb) and pharmaceutically acceptable salts, solvates, hydrates, and N- oxides thereof:
  • One aspect of the present invention provides, inter alia, compounds selected from compounds of Formula (If) and pharmaceutically acceptable salts, solvates, hydrates, and N- oxides thereof:
  • One aspect of the present invention provides, inter alia, compounds selected from compounds of Formulae (I), (la), (la'), (lb), (Ic), (Id), (Ie), and (If), and pharmaceutically acceptable salts, solvates, and hydrates thereof; wherein Ar and R 1 have the same definitions described herein, supra and infra. It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of the embodiments pertaining to the chemical groups represented by the variables (e.g.
  • some embodiments of the present invention include every combination of one or more embodiments pertaining to the chemical groups represented by the variables and generic chemical formulae as described herein or every combination of one or more compounds of Formula (I), and related Formulae, together/in combination with every combination of one or more pharmaceutical agents, such as an inhibitor of DPP-IV, a biguanide, an alpha-glucosidase inhibitor, and the like, either specifically disclosed herein or specifically disclosed in any reference recited herein just as if each and every combination was individually and explicitly recited.
  • pharmaceutical agents such as an inhibitor of DPP-IV, a biguanide, an alpha-glucosidase inhibitor, and the like, either specifically disclosed herein or specifically disclosed in any reference recited herein just as if each and every combination was individually and explicitly recited.
  • substituted indicates that at least one hydrogen atom of the chemical group is replaced by a non-hydrogen substituent or group, the non-hydrogen substituent or group can be monovalent or divalent. When the substituent or group is divalent, then it is understood that this group is further substituted with another substituent or group.
  • a chemical group herein when a chemical group herein is "substituted" it may have up to the full valance of substitution; for example, a methyl group can be substituted by 1 , 2, or 3 substituents, a methylene group can be substituted by one or two substituents, a phenyl group can be substituted by 1 , 2, 3, 4, or 5 substituents, a naphthyl group can be substituted by 1 , 2, 3, 4, 5, 6, or 7 substituents, and the like.
  • substituted with one or more substituents refers to the substitution of a group with one substituent up to the total number of substituents physically allowed by the group. Further, when a group is substituted with more than one group they can be identical or they can be different.
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. It is understood that the various tautomeric forms are within the scope of the compounds of the present invention.
  • meso isomers Such meso isomers may be referred to as cis and trans.
  • the cis meso isomers of compounds of the present invention are named herein using the designation (Is, 4s) and the trans meso isomers of compounds of the present invention are named herein using the designation (lr,4r) as shown below using Formula (la) and Formula (la')
  • Ar is selected from: aryl and heteroaryl; each optionally substituted with one or more substituents selected from: C 1 -C6 alkyl, C 1 -C4 alkylcarboxamide, C 1 -C6 alkylsulfinyl, C 1 -C6 alkylsulfonyl, heterocyclylsulfonyl, C 1 -C6 alkylthio, carboxamide, cyano, C3-C7 cycloalkylsulfinyl, C3-C7 cycloalkylsulfonyl, C3-C7 cycloalkylthio, C 2 -C 8 dialkylcarboxamide, C 1 -C6 haloalkyl, halogen, and heteroaryl; wherein said C 1 -C6 alkyl is optionally substituted with one or more substituents selected from: C 1 -C6 alkoxy, hydroxyl, cyano, C 2 -C6
  • Ar is selected from: phenyl and heteroaryl; each optionally substituted with one or more substituents selected from: C 1 -C6 alkyl, C 1 -C6 alkylsulfonyl, heterocyclylsulfonyl, cyano, C 3 -C 7 cycloalkylsulfonyl, C 2 -C 8 dialkylcarboxamide, Ci-C 6 haloalkyl, halogen, and heteroaryl; wherein said Ci-C 6 alkyl is optionally substituted with one or more substituents selected from: Ci-C 6 alkoxy, hydroxyl, cyano, C 2 -C 6 dialkylamino, and heterocyclyl.
  • Ar is selected from: pyridin-4-yl, pyridin-2-yl, phenyl, thieno[3,2-c]pyridin-4-yl, furo[3,2-c]pyridin-4-yl, pyrimidin-2-yl, pyridin-3-yl, 1,6- naphthyridin-4-yl, pyrazin-2-yl, isoquinolin-8-yl, quinoxalin-2-yl, benzo[d]thiazol-2-yl, 1H- pyrazol-5-yl, thieno[3,2-d]pyrimidin-4-yl, and pyrimidin-4-yl; each optionally substituted with one or more substituents selected from: Ci-C 6 alkyl, Ci-C 6 alkylsulfonyl, heterocyclylsulfonyl, cyano, C3-C7 cycloalkylsulfonyl, C 2 -C 8 dialky
  • Ar is selected from: phenyl and heteroaryl; each optionally substituted with one or more substituents selected from: cyano, fluoro, methyl, bromo, methylsulionyl, chloro, 2-methoxyethyl, lH-l,2,4-triazol-l-yl, trifluoromethyl, 2-hydroxyethyl, 2-cyanoethyl, 2-(dimethylamino)ethyl, 2-morpholinoethyl, lH-tetrazol-l-yl, oxetan-3- ylsulfonyl, cyclopropylsulfonyl, pyridazin-4-yl, and dimethylcarbamoyl.
  • substituents selected from: cyano, fluoro, methyl, bromo, methylsulionyl, chloro, 2-methoxyethyl, lH-l,2,4-triazol-l-yl, tri
  • Ar is selected from: pyridin-4-yl, pyridin-2-yl, phenyl, thieno[3,2-c]pyridin-4-yl, furo[3,2-c]pyridin-4-yl, pyrimidin-2-yl, pyridin-3-yl, 1,6- naphthyridin-4-yl, pyrazin-2-yl, isoquinolin-8-yl, quinoxalin-2-yl, benzo[d]thiazol-2-yl, 1H- pyrazol-5-yl, thieno[3,2-d]pyrimidin-4-yl, and pyrimidin-4-yl; each optionally substituted with one or more substituents selected from: cyano, fluoro, methyl, bromo, methylsulionyl, chloro, 2- methoxyethyl, lH-l,2,4-triazol-l-yl, trifluoromethyl, 2-hydroxyeth
  • Ar is selected from: 3-cyanopyridin-4-yl, 3,5-difluoropyridin-4- yl, 3-cyano-5-methylpyridin-4-yl, 3-cyano-5-fluoropyridin-4-yl, 3-cyano-5-fluoropyridin-2-yl, 4-bromo-2-cyanophenyl, 2,4-dicyanophenyl, 2-cyano-4-(methylsulfonyl)phenyl, thieno[3,2- c]pyridin-4-yl, furo[3,2-c]pyridin-4-yl, 5-bromopyrimidin-2-yl, 4-chloro-2-cyanophenyl, 2- fluoro-4-(methylsulfonyl)phenyl, 5-(methylsulfonyl)pyridin-3-yl, 2-cyano-4-fluorophenyl, 4-(2- methoxyethyl)phenyl, 1 ,6-naphth
  • Ar is 3-cyanopyridin-4-yl. In some embodiments, Ar is 3,5- difluoropyridin-4-yl. In some embodiments, Ar is 3-cyano-5-methylpyridin-4-yl. In some embodiments, Ar is 3-cyano-5-fluoropyridin-4-yl. In some embodiments, Ar is 3-cyano-5- fluoropyridin-2-yl. In some embodiments, Ar is 4-bromo-2-cyanophenyl. In some embodiments, Ar is 2,4-dicyanophenyl. In some embodiments, Ar is 2-cyano-4-(methylsulfonyl)phenyl. In some embodiments, Ar is thieno[3,2-c]pyridin-4-yl.
  • Ar is furo[3,2- c]pyridin-4-yl. In some embodiments, Ar is 5-bromopyrimidin-2-yl. In some embodiments, Ar is 4-chloro-2-cyanophenyl. In some embodiments, Ar is 2-fluoro-4-(methylsulfonyl)phenyl. In some embodiments, Ar is 5-(methylsulfonyl)pyridin-3-yl. In some embodiments, Ar is 2-cyano- 4-fluorophenyl. In some embodiments, Ar is 4-(2-methoxyethyl)phenyl. In some embodiments, Ar is 1 ,6-naphthyridin-4-yl.
  • Ar is pyridin-4-yl. In some embodiments, Ar is 5-(lH-l ,2,4-triazol-l -yl)pyrazin-2-yl. In some embodiments, Ar is 2-methyl-6-(lH- 1 ,2,4- triazol-l-yl)pyridin-3-yl. In some embodiments, Ar is isoquinolin-8 -yl. In some embodiments, Ar is 5-(trifluoromethyl)pyridin-2-yl. In some embodiments, Ar is quinoxalin-2-yl. In some embodiments, Ar is 4-cyanopyridin-2-yl. In some embodiments, Ar is 4-(2- hydroxyethyl)phenyl.
  • Ar is 4-bromo-3-fluorophenyl. In some embodiments, Ar is 5-cyanopyridin-2-yl. In some embodiments, Ar is 4-(2-cyanoethyl)phenyl. In some embodiments, Ar is benzo[d]thiazol-2-yl. In some embodiments, Ar is 5- (methylsulfonyl)pyrimidin-2-yl. In some embodiments, Ar is 4-(2-(dimethylamino)ethyl)phenyl. In some embodiments, Ar is 4-(2-morpholinoethyl)phenyl. In some embodiments, Ar is 1- methyl-3-(trifluoromethyl)-lH-pyrazol-5-yl.
  • Ar is 3-cyanopyridin-2-yl. In some embodiments, Ar is thieno[3,2-d]pyrimidin-4-yl. In some embodiments, Ar is 4-(lH- tetrazol-l -yl)phenyl. In some embodiments, Ar is 4-(2-methyl-6-(oxetan-3-ylsulfonyl)pyridin-3- yl. In some embodiments, Ar is 4-(6-(cyclopropylsulfonyl)-2-methylpyridin-3-yl. In some embodiments, Ar is 2-cyanopyridin-3-yl. In some embodiments, Ar is 5-bromo-3- methylpyrazin-2-yl.
  • Ar is 3-methyl-5-(methylsulfonyl)pyrazin-2-yl. In some embodiments, Ar is 6-(trifluoromethyl)pyridin-3-yl. In some embodiments, Ar is 4- cyanopyridin-3-yl. In some embodiments, Ar is 5-cyanopyrimidin-4-yl. In some embodiments, Ar is 4-cyano-2,6-difluorophenyl. In some embodiments, Ar is 2-methyl-6-(pyridazin-4- yl)pyridin-3-yl. In some embodiments, Ar is 4-(dimethylcarbamoyl)-2 -fluorophenyl.
  • Ar is 5-(methylsulfonyl)pyridin-2-yl. In some embodiments, Ar is 2-methyl-6- (methylsulfonyl)pyridin-3-yl. In some embodiments, Ar is 3-fluoro-4-(lH-l ,2,4-triazol-l - yl)phenyl. In some embodiments, Ar is 5-(methylsulfonyl)pyrazin-2-yl. In some embodiments, Ar is 5-(dimethylcarbamoyl)pyridin-2-yl. In some embodiments, Ar is 4- (methylsulfonyl)phenyl. In some embodiments, Ar is pyrimidin-4-yl.
  • R 1 is selected from: Ci-C 6 alkoxycarbonyl, C 3 -C 7
  • cycloalkoxycarbonyl and heteroaryl; each optionally substituted with one or more substituents selected from: C 1 -C6 alkyl, C 1 -C6 haloalkyl, and halogen.
  • R 1 is selected from: C 1 -C6 alkoxycarbonyl, C 3 -C 7
  • cycloalkoxycarbonyl, and heteroaryl each optionally substituted with one or more substituents selected from: chloro, ethyl, fluoro, 2-fluoropropan-2-yl, isopropyl, methyl, and trifluoromethyl.
  • R 1 is selected from: teri-butoxycarbonyl, isopropoxycarbonyl, cyclopropoxycarbonyl, 1 ,2,4-oxadiazolyl, and pyrimidin-2-yl; each optionally substituted with one or more substituents selected from: chloro, ethyl, fluoro, 2-fluoropropan-2-yl, isopropyl, methyl, and trifluoromethyl.
  • R 1 is heteroaryl optionally substituted with one or more substituents selected from: Ci-C 6 alkyl, Ci-C 6 haloalkyl, and halogen.
  • R 1 is selected from: 1 ,2,4-oxadiazolyl and pyrimidin-2-yl; each optionally substituted with one or more substituents selected from: Ci-C 6 alkyl, Ci-C 6 haloalkyl, and halogen. In some embodiments, R 1 is selected from: 1 ,2,4-oxadiazolyl and pyrimidin-2-yl; each optionally substituted with one or more substituents selected from: chloro, ethyl, isopropyl, trifluoromethyl, and 2-fluoropropan-2-yl.
  • R 1 is selected from: Ci-C 6 alkoxycarbonyl, and C 3 -C 7 cycloalkoxycarbonyl; each optionally substituted with one or more substituents selected from: halogen and C 1 -C6 alkyl.
  • R 1 is selected from: C 1 -C6 alkoxycarbonyl, and C3-C7 cycloalkoxycarbonyl; each optionally substituted with one or more substituents selected from: fluoro and methyl.
  • R 1 is selected from: teri-butoxycarbonyl, isopropoxycarbonyl, and cyclopropoxycarbonyl; each optionally substituted with one or more substituents selected from: fluoro and methyl.
  • R 1 is selected from: teri-butoxycarbonyl, ( 1 ,1 ,1 -trifluoropropan- 2-yloxy)carbonyl, 5-chloropyrimidin-2-yl, (1 -methylcyclopropoxy)carbonyl,
  • R 1 is teri-butoxycarbonyl. In some embodiments, R 1 is (1 , 1, 1- trifluoropropan-2-yloxy)carbonyl. In some embodiments, R 1 is 5-chloropyrimidin-2-yl. In some embodiments, R 1 is (l-methylcyclopropoxy)carbonyl. In some embodiments, R 1 is
  • R 1 isopropoxycarbonyl.
  • R 1 is 5-ethylpyrimidin-2-yl.
  • R 1 is 3-isopropyl-l ,2,4-oxadiazol-5-yl.
  • R 1 is 3-(trifluoromethyl)-l ,2,4- oxadiazol-5-yl.
  • R 1 is 3-(2-fluoropropan-2-yl)-l ,2,4-oxadiazol-5-yl.
  • One aspect of the present invention encompasses certain cyclohexyl derivatives selected from compounds of Formula (lb) and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof:
  • Ar is selected from: phenyl and heteroaryl; each optionally substituted with one or more substituents selected from: Ci-C 6 alkyl, Ci-C 6 alkylsulfonyl, heterocyclylsulionyl, cyano, C 3 -C 7 cycloalkylsulfonyl, C 2 -C 8 dialkylcarboxamide, Ci-C 6 haloalkyl, halogen, and heteroaryl;
  • Ci-C 6 alkyl is optionally substituted with one or more substituents selected from: Ci-C 6 alkoxy, hydroxyl, C 2 -C 6 dialkylamino, and heterocyclyl; and R 1 is selected from: Ci-C 6 alkoxycarbonyl, C 3 -C 7 cycloalkoxycarbonyl, and heteroaryl; each optionally substituted with one or more substituents selected from: chloro, ethyl, fluoro, 2- fluoropropan-2-yl, isopropyl, methyl, and trifluoromethyl.
  • One aspect of the present invention encompasses certain cyclohexyl derivatives selected from compounds of Formula (lb) and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof:
  • Ar is selected from: phenyl and heteroaryl; each optionally substituted with one or more substituents selected from: cyano, fluoro, methyl, bromo, methylsulfonyl, chloro, 2- methoxyethyl, lH-l,2,4-triazol-l-yl, trifluoromethyl, 2-hydroxyethyl, 2-(dimethylamino)ethyl, 2-morpholinoethyl, lH-tetrazol-l-yl, oxetan-3-ylsulfonyl, cyclopropylsulfonyl, pyridazin-4-yl, and dimethylcarbamoyl; and
  • R 1 is selected from: C 1 -C6 alkoxycarbonyl, C 3 -C 7 cycloalkoxycarbonyl, and heteroaryl; each optionally substituted with one or more substituents selected from: chloro, ethyl, fluoro, 2- fluoropropan-2-yl, isopropyl, methyl, and trifluoromethyl.
  • One aspect of the present invention encompasses certain cyclohexyl derivatives selected from compounds of Formula (lb) and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof:
  • Ar is selected from: pyridin-4-yl, pyridin-2-yl, phenyl, thieno[3,2-c]pyridin-4-yl, furo[3,2-c]pyridin-4-yl, pyrimidin-2-yl, pyridin-3-yl, l,6-naphthyridin-4-yl, pyrazin-2-yl, isoquinolin-8-yl, quinoxalin-2-yl, benzo[d]thiazol-2-yl, lH-pyrazol-5-yl, thieno[3,2- d]pyrimidin-4-yl, and pyrimidin-4-yl; each optionally substituted with one or more substituents selected from: C 1 -C6 alkyl, C 1 -C6 alkylsulfonyl, heterocyclylsulfonyl, cyano, C 3 -C 7 cycloalkylsulfonyl, C 2
  • C 1 -C6 alkyl is optionally substituted with one or more substituents selected from: C 1 -C6 alkoxy, hydroxyl, C 2 -C6 dialkylamino, and heterocyclyl; and
  • R 1 is selected from: C 1 -C6 alkoxycarbonyl, C 3 -C 7 cycloalkoxycarbonyl, and heteroaryl; each optionally substituted with one or more substituents selected from: chloro, ethyl, fluoro, 2- fluoropropan-2-yl, isopropyl, methyl, and trifluoromethyl.
  • One aspect of the present invention encompasses certain cyclohexyl derivatives selected from compounds of Formula (If) and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof:
  • Ar is selected from: phenyl and heteroaryl; each optionally substituted with one or more substituents selected from: Ci-C 6 alkyl, Ci-C 6 alkylsulfonyl, heterocyclylsulfonyl, cyano, C 3 -C 7 cycloalkylsulfonyl, C 2 -C 8 dialkylcarboxamide, Ci-C 6 haloalkyl, halogen, and heteroaryl;
  • Ci-C 6 alkyl is optionally substituted with one or more substituents selected from: Ci-C 6 alkoxy, hydroxyl, C 2 -C 6 dialkylamino, and heterocyclyl; and
  • R 1 is selected from: C 1 -C6 alkoxycarbonyl, C3-C7 cycloalkoxycarbonyl, and heteroaryl; each optionally substituted with one or more substituents selected from: chloro, ethyl, fluoro, 2- fluoropropan-2-yl, isopropyl, methyl, and trifluoromethyl.
  • One aspect of the present invention encompasses certain cyclohexyl derivatives selected from compounds of Formula (If) and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof:
  • Ar is selected from: phenyl and heteroaryl; each optionally substituted with one or more substituents selected from: cyano, fluoro, methyl, bromo, methylsulfonyl, chloro, 2- methoxyethyl, lH-l,2,4-triazol-l-yl, trifluoromethyl, 2-hydroxyethyl, 2-(dimethylamino)ethyl, 2-morpholinoethyl, lH-tetrazol-l-yl, oxetan-3-ylsulfonyl, cyclopropylsulfonyl, pyridazin-4-yl, and dimethylcarbamoyl; and
  • R 1 is selected from: Ci-C 6 alkoxycarbonyl, C 3 -C 7 cycloalkoxycarbonyl, and heteroaryl; each optionally substituted with one or more substituents selected from: chloro, ethyl, fluoro, 2- fluoropropan-2-yl, isopropyl, methyl, and trifluoromethyl.
  • One aspect of the present invention encompasses certain cyclohexyl derivatives selected from compounds of Formula (If) and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof:
  • Ar is selected from: pyridin-4-yl, pyridin-2-yl, phenyl, thieno[3,2-c]pyridin-4-yl, furo[3,2-c]pyridin-4-yl, pyrimidin-2-yl, pyridin-3-yl, 1 ,6-naphthyridin-4-yl, pyrazin-2-yl, isoquinolin-8-yl, quinoxalin-2-yl, benzo[d]thiazol-2-yl, lH-pyrazol-5-yl, thieno[3,2- d]pyrimidin-4-yl, and pyrimidin-4-yl; each optionally substituted with one or more substituents selected from: C 1 -C6 alkyl, C 1 -C6 alkylsulfonyl, heterocyclylsulfonyl, cyano, C3-C7 cycloalkylsulfonyl, C 2
  • C 1 -C6 alkyl is optionally substituted with one or more substituents selected from: C 1 -C6 alkoxy, hydroxyl, C 2 -C6 dialkylamino, and heterocyclyl; and
  • R 1 is selected from: Ci-C 6 alkoxycarbonyl, C 3 -C 7 cycloalkoxycarbonyl, and heteroaryl; each optionally substituted with one or more substituents selected from: chloro, ethyl, fluoro, 2- fluoropropan-2-yl, isopropyl, methyl, and trifluoromethyl.
  • One aspect of the present invention encompasses certain cyclohexyl derivatives selected from compounds of Formula (If) and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof:
  • Ar is selected from: pyridin-4-yl, pyridin-2-yl, phenyl, thieno[3,2-c]pyridin-4-yl, furo[3,2-c]pyridin-4-yl, pyrimidin-2-yl, pyridin-3-yl, 1 ,6-naphthyridin-4-yl, pyrazin-2-yl, isoquinolin-8-yl, quinoxalin-2-yl, benzo[d]thiazol-2-yl, lH-pyrazol-5-yl, thieno[3,2- d]pyrimidin-4-yl, and pyrimidin-4-yl; each optionally substituted with one or more substituents selected from: cyano, fluoro, methyl, bromo, methylsulfonyl, chloro, 2-methoxyethyl, 1H-1,2,4- triazol-l-yl, trifluoromethyl, 2-hydroxyeth
  • R 1 is selected from: teri-butoxycarbonyl, isopropoxycarbonyl, cyclopropoxycarbonyl, 1,2,4-oxadiazolyl, and pyrimidin-2-yl; each optionally substituted with one or more substituents selected from: chloro, ethyl, fluoro, 2-fluoropropan-2-yl, isopropyl, methyl, and trifluoromethyl.
  • One aspect of the present invention encompasses certain cyclohexyl derivatives selected from compounds of Formula (If) and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof:
  • Ar is selected from: 3-cyanopyridin-4-yl, 3,5-difluoropyridin-4-yl, 3-cyano-5- methylpyridin-4-yl, 3-cyano-5-fluoropyridin-4-yl, 3-cyano-5-fluoropyridin-2-yl, 4-bromo-2- cyanophenyl, 2,4-dicyanophenyl, 2-cyano-4-(methylsulfonyl)phenyl, thieno[3,2-c]pyridin-4-yl, furo[3,2-c]pyridin-4-yl, 5-bromopyrimidin-2-yl, 4-chloro-2-cyanophenyl, 2-fluoro-4- (methylsulfonyl)phenyl, 5-(methylsulfonyl)pyridin-3-yl, 2-cyano-4-fluorophenyl, 4-(2- methoxyethyl)phenyl, l,6-naphthyridin-4
  • R 1 is selected from: teri-butoxycarbonyl, (l ,l , l-trifluoropropan-2-yloxy)carbonyl, 5- chloropyrimidin-2-yl, (l-methylcyclopropoxy)carbonyl, isopropoxycarbonyl, 5-ethylpyrimidin- 2-yl, 3-isopropyl-l ,2,4-oxadiazol-5-yl, 3-(trifluoromethyl)-l ,2,4-oxadiazol-5-yl, and 3-(2- fluoropropan-2-yl)-l ,2,4-oxadiazol-5-yl.
  • One aspect of the present invention encompasses certain cyclohexyl derivatives selected from compounds of Formula (If) and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof:
  • Ar is selected from: pyridin-4-yl, pyridin-2-yl, phenyl, pyridin-3-yl, and pyrazin-2-yl; each optionally substituted with one or more substituents selected from: cyano, fluoro, methyl, bromo, methylsulfonyl, chloro, 2-methoxyethyl, lH-l ,2,4-triazol-l -yl, trifluoromethyl, 2- hydroxyethyl, 2-cyanoethyl, 2-(dimethylamino)ethyl, 2-morpholinoethyl, lH-tetrazol-l -yl, oxetan-3-ylsulfonyl, cyclopropylsulfonyl, pyridazin-4-yl, and dimethylcarbamoyl; and
  • R 1 is selected from: teri-butoxycarbonyl, (l ,l , l-trifluoropropan-2-yloxy)carbonyl, 5- chloropyrimidin-2-yl, (l-methylcyclopropoxy)carbonyl, isopropoxycarbonyl, 5-ethylpyrimidin- 2-yl, 3-isopropyl-l ,2,4-oxadiazol-5-yl, 3-(trifluoromethyl)-l ,2,4-oxadiazol-5-yl, and 3-(2- fluoropropan-2-yl)-l ,2,4-oxadiazol-5-yl.
  • Some embodiments of the present invention include every combination of one or more compounds selected from the following group shown in Table A.
  • individual compounds and chemical genera of the present invention for example those compounds found in Table A including, isomers, diastereoisomers and enantiomers thereof, encompass all pharmaceutically acceptable salts, solvates, and hydrates, thereof.
  • mesoisomers of individual compounds and chemical genera of the present invention for example those compounds found in Table A, encompass all pharmaceutically acceptable salts, solvates and particularly hydrates, thereof.
  • the compounds of the Formula (I) of the present invention may be prepared according to relevant published literature procedures that are used by one skilled in the art. Exemplary reagents and procedures for these reactions appear hereinafter in the working Examples.
  • Protection and deprotection may be carried out by procedures generally known in the art (see, for example, Greene, T. W. and Wuts, P. G. M., Protecting Groups in Organic Synthesis, 3 rd Edition, 1999 [Wiley]). It is understood that the present invention embraces, each isomer, each diastereoisomer, each enantiomer and mixtures thereof of each compound and generic formulae disclosed herein just as if they were each individually disclosed with the specific stereochemical designation for each chiral carbon.
  • compositions Compositions, Methods, Indications, Pharmaceutical Products, Combinations, and Uses of Compounds of the Present Invention.
  • compositions comprising a compound of the present invention.
  • One aspect of the present invention pertains to pharmaceutical products selected from: a pharmaceutical composition, a formulation, a unit dosage form, and a kit; each comprising a compound of the present invention.
  • One aspect of the present invention pertains to pharmaceutical compositions comprising a compound of the present invention, and a pharmaceutically acceptable carrier.
  • One aspect of the present invention pertains to methods for preparing a pharmaceutical composition comprising the step of admixing a compound of the present invention, and a pharmaceutically acceptable carrier; some embodiments pertain to pharmaceutical compositions obtained by any of the methods described herein.
  • One aspect of the present invention pertains to compositions comprising a compound of the present invention, and a second pharmaceutical agent.
  • a pharmaceutical agent and “a second pharmaceutical agent”
  • these terms in some aspects be further limited to a pharmaceutical agent that is not a compound of Formula (I) or a compounds related thereto.
  • a pharmaceutical agent and “a second pharmaceutical agent” may refer to a pharmaceutical agent that is not detectable or has an EC 50 that is greater than a value selected from: 50 ⁇ , 10 ⁇ , 1 ⁇ , and 0.1 ⁇ in a GPR119 receptor activity assay as described in Example 4.
  • One aspect of the present invention pertains to methods for preparing a composition comprising the step of admixing a compound of the present invention, and a second pharmaceutical agent; some embodiments pertain to compositions obtained by any of the methods described herein.
  • One aspect of the present invention pertains to pharmaceutical products selected from: a pharmaceutical composition, a formulation, a unit dosage form, a combined preparation, a twin pack, and a kit; each comprising a compound of the present invention, and a second pharmaceutical agent.
  • One aspect of the present invention pertains to pharmaceutical compositions comprising a compound of the present invention, a second pharmaceutical agent, and a pharmaceutically acceptable carrier.
  • One aspect of the present invention pertains to methods for preparing a pharmaceutical composition
  • methods for preparing a pharmaceutical composition comprising the step of admixing a compound of the present invention, a second pharmaceutical agent, and a pharmaceutically acceptable carrier; some embodiments pertain to pharmaceutical compositions obtained by any of the methods described herein.
  • One aspect of the present invention pertains to methods selected from one or more of the following: 1) for modulating the activity of a GPR119 receptor; 2) for agonizing a GPR119 receptor; 3) for increasing the secretion of an incretin in an individual; 4) increasing a blood incretin level in an individual; and 5) for treating/treatment of a disorder selected from: a GPR119-receptor-related disorder; a condition ameliorated by increasing secretion of an incretin; a condition ameliorated by increasing a blood incretin level; a condition characterized by low bone mass; a neurological disorder; a metabolic-related disorder; type 2 diabetes; and obesity; in an individual; comprising: A) administering to an individual in need thereof or B) prescribing to an individual in need thereof, a therapeutically effective amount of: a compound of the present invention; a composition of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention; each optionally in combination with a therapeutically effective amount of a second pharmaceutical agent
  • Some embodiments pertain to methods comprising administering to an individual in need thereof a therapeutically effective amount of: a compound of the present invention; a composition of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention. Some embodiments pertain to methods for prescribing to an individual in need thereof, a therapeutically effective amount of: a compound of the present invention; a composition of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention.
  • One aspect of the present invention pertains to the use of a compound of the present invention, optionally in combination with a second pharmaceutical agent, in the manufacture of a medicament, selected from one or more of the following: 1) for modulating the activity of a GPR119 receptor in an individual; 2) for agonizing a GPR119 receptor; 3) for increasing the secretion of an incretin in an individual; 4) increasing a blood incretin level in an individual; and 5) for treating/treatment of a disorder selected from: a GPR119-receptor-related disorder; a condition ameliorated by increasing secretion of an incretin; a condition ameliorated by increasing a blood incretin level; a condition characterized by low bone mass; a neurological disorder; a metabolic-related disorder; type 2 diabetes; and obesity.
  • One aspect of the present invention pertains to a compound of the present invention; a composition of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention; optionally in combination with a second pharmaceutical agent, for use in a method of treatment of the human or animal body by therapy.
  • One aspect of the present invention pertains to one or more of the following: methods of the present invention, compounds of the present invention; compositions of the present invention; pharmaceutical products of the present invention; and pharmaceutical compositions of the present invention; optionally in combination with a second pharmaceutical agent, for use in a method selected from one or more of the following: 1) for modulating the activity of a GPR119 receptor; 2) for agonizing a GPR119 receptor; 3) for increasing the secretion of an incretin in an individual; 4) increasing a blood incretin level in an individual; and 5) for treating/treatment of a disorder selected from: a GPR119-receptor-related disorder; a condition ameliorated by increasing secretion of an incretin; a condition ameliorated by increasing a blood incretin level; a condition characterized by low bone mass; a neurological disorder; a metabolic- related disorder; type 2 diabetes; and obesity.
  • a second pharmaceutical agent for use in a method selected from one or more of the following: 1) for modulating the activity of a GPR
  • One aspect of the present invention pertains to a pharmaceutical agent in combination with a compound of the present invention; a composition of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention; for use in a method of treatment of the human or animal body by therapy.
  • One aspect of the present invention pertains to a pharmaceutical agent in combination with a compound of the present invention; a composition of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention; for use in a method selected from one or more of the following: 1) for modulating the activity of a GPR119 receptor; 2) for agonizing a GPR119 receptor; 3) for increasing the secretion of an incretin in an individual; 4) increasing a blood incretin level in an individual; and 5) for treating/treatment of a disorder selected from: a GPR119-receptor-related disorder; a condition ameliorated by increasing secretion of an incretin; a condition ameliorated by increasing a blood incretin level; a condition characterized by low bone mass; a neurological disorder; a metabolic-related disorder; type 2 diabetes; and obesity.
  • Some embodiments pertain to methods, uses, compounds, and pharmaceutical agents, each as described herein, for modulating the activity of a GPR119 receptor. Some embodiments pertain to methods, uses, compounds, and pharmaceutical agents, each as described herein, for agonizing a GPR119 receptor. Some embodiments pertain to methods, uses, compounds, and pharmaceutical agents, each as described herein, for increasing the secretion of an incretin in an individual. Some embodiments pertain to methods, uses, compounds, and pharmaceutical agents, each as described herein, for increasing a blood incretin level in an individual.
  • Some embodiments pertain to methods, uses, compounds, and pharmaceutical agents, each as described herein, for treatment of a disorder selected from: a GPR119-receptor-related disorder; a condition ameliorated by increasing secretion of an incretin; a condition ameliorated by increasing a blood incretin level; a condition characterized by low bone mass; a neurological disorder; a metabolic-related disorder; and obesity; in an individual.
  • a disorder selected from: a GPR119-receptor-related disorder; a condition ameliorated by increasing secretion of an incretin; a condition ameliorated by increasing a blood incretin level; a condition characterized by low bone mass; a neurological disorder; a metabolic-related disorder; and obesity; in an individual.
  • the disorder is a GPR119-receptor-related disorder. In some embodiments, the disorder is a condition ameliorated by increasing secretion of an incretin. In some embodiments, the disorder is a condition ameliorated by increasing a blood incretin level. In some embodiments, the disorder is a condition characterized by low bone mass. In some embodiments, the disorder is a neurological disorder. In some embodiments, the disorder is a metabolic -related disorder. In some embodiments, the disorder is obesity. In some embodiments, the disorder is type 2 diabetes. In some embodiments, the disorder is hyperglycemia. In some embodiments, the disorder is hyperlipidemia. In some embodiments, the disorder is
  • the disorder is type 1 diabetes. In some embodiments, the disorder is dyslipidemia. In some embodiments, the disorder is syndrome X.
  • the pharmaceutical product comprises a pharmaceutical composition. In some embodiments, the pharmaceutical product comprises a formulation. In some embodiments, the pharmaceutical product comprises a unit dosage form. In some embodiments, the pharmaceutical product comprises a kit. In some embodiments, the pharmaceutical product comprises a combined preparation. In some embodiments, the pharmaceutical product comprises a twin pack.
  • the compound and pharmaceutical agent or the second pharmaceutical agent are administered simultaneously, separately, or sequentially. In some embodiments, the compound and the pharmaceutical agent or the second pharmaceutical agent are administered simultaneously. In some embodiments, the compound and the pharmaceutical agent or the second pharmaceutical agent are administered separately. In some embodiments, the compound and the pharmaceutical agent or the second pharmaceutical agent are
  • the incretin is GLP-1. In some embodiments, the incretin is GIP. In some embodiments, the incretin is PYY.
  • a DPP-IV inhibitor a biguanide
  • an alpha-glucosidase inhibitor an insulin analogue
  • a sulfonylurea an SGLT2 inhibitor
  • meglitinide a thiazolidinedione
  • anti- diabetic peptide analogue analogue
  • One aspect of the present invention pertains to compositions, methods, pharmaceutical products, pharmaceutical compositions, uses; compounds, and pharmaceutical agents, each as described herein, wherein: 1) the compound and the pharmaceutical agent or the second pharmaceutical agent are provided in amounts which give a synergistic effect in treating the disorder; 2) the amount of the compound alone is substantially therapeutically ineffective at treating the disorder; and/or 3) the amount of the pharmaceutical agent alone or the second pharmaceutical agent alone is substantially therapeutically ineffective at treating the disorder.
  • One aspect of the present invention relates to methods for preparing pharmaceutical products of the present invention comprising the steps: mixing said compound with a first pharmaceutically acceptable carrier to prepare a compound unit dosage form; mixing said second pharmaceutical agent with a second pharmaceutically acceptable carrier to prepare a second pharmaceutical agent unit dosage form; and combining said compound unit dosage form and said second pharmaceutical agent unit dosage form in a combined unit dosage form for simultaneous, separate, or sequential use.
  • the first pharmaceutically acceptable carrier is different from the second pharmaceutically acceptable carrier. In some embodiments, the different
  • pharmaceutically acceptable carriers are suitable for administration by the same route.
  • the different pharmaceutically acceptable carriers are suitable for administration by different routes.
  • the first pharmaceutically acceptable carrier is substantially the same as the second pharmaceutically acceptable carrier.
  • the substantially the same pharmaceutically acceptable carriers are suitable for oral
  • a compound as described herein or a pharmaceutical composition thereof can be utilized for modulating the activity of GPR119- receptor and therefore related diseases, conditions and/or disorders related thereto such as those described herein.
  • modulating the activity includes the treatment of a GPR119- receptor-related disorder.
  • a GPR119-receptor-related disorder is a condition ameliorated by increasing a blood incretin level.
  • a GPR119- receptor-related disorder is a condition characterized by low bone mass.
  • a GPR119-receptor-related disorder is a neurological disorder.
  • a GPR119-receptor-related disorder is a neurological disorder.
  • GPR119-receptor-related disorder is a metabolic-related disorder. In some embodiments, a GPR119-receptor-related disorder is type 2 diabetes. In some embodiments, a GPR119-receptor- related disorder is obesity
  • Some embodiments of the present invention include every combination of one or more conditions characterized by low bone mass selected from: osteopenia, osteoporosis, rheumatoid arthritis, osteoarthritis, periodontal disease, alveolar bone loss, osteotomy bone loss, childhood idiopathic bone loss, Paget' s disease, bone loss due to metastatic cancer, osteolytic lesions, curvature of the spine, and loss of height.
  • the neurological disorder selected from: stroke and
  • Some embodiments of the present invention include every combination of one or more metabolic -related disorders selected from: type 1 diabetes, type 2 diabetes mellitus, and conditions associated therewith, such as, but not limited to, coronary heart disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease, intermittent claudication, myocardial infarction (e.g.
  • necrosis and apoptosis dyslipidemia, post-prandial lipemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy, macular degeneration, cataract, 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, vascular restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, insulin resistance, impaired glucose metabolism, erectile dysfunction, skin and connective tissue disorders, foot ulcerations and ulcerative colitis, endothelial dysfunction and impaired vascular compliance.
  • ITT impaired glucose tolerance
  • impaired fasting plasma glucose glucose
  • Some embodiments of the present invention include every combination of one or more metabolic -related disorders selected from: diabetes, type 1 diabetes, type 2 diabetes, inadequate glucose tolerance, impaired glucose tolerance, insulin resistance, hyperglycemia,
  • hyperlipidemia hypertriglyceridemia, hypercholesterolemia, dyslipidemia, atherosclerosis, stroke, syndrome X, hypertension, pancreatic beta-cell insufficiency, enteroendocrine cell insufficiency, glucosuria, metabolic acidosis, cataracts, diabetic nephropathy, diabetic neuropathy, peripheral neuropathy, diabetic coronary artery disease, diabetic cerebrovascular disease, diabetic peripheral vascular disease, diabetic retinopathy, metabolic syndrome, a condition related to diabetes, myocardial infarction, learning impairment, memory impairment, a neurodegenerative disorder, a condition ameliorated by increasing a blood GLP-1 level in an individual with a neurodegenerative disorder, excitotoxic brain damage caused by severe epileptic seizures, Alzheimer's disease, Parkinson's disease, Huntington's disease, prion- associated disease, motor-neuron disease, traumatic brain injury, spinal cord injury, and obesity.
  • the disorder is type 2 diabetes. In some embodiments, the disorder is hyperglycemia. In some embodiments, the disorder is hyperlipidemia. In some embodiments, the disorder is hypertriglyceridemia. In some embodiments, the disorder is type 1 diabetes. In some embodiments, the disorder is dyslipidemia. In some embodiments, the disorder is syndrome X. In some embodiments, the disorder is obesity.
  • One aspect of the present invention pertains to methods for weight management, comprising administering to an individual in need thereof, a therapeutically effective amount of a compound of the present invention in combination with a therapeutically effective amount of a pharmaceutical agent, such as any agent described herein; wherein the compound and the pharmaceutical agent.
  • the weight management comprises weight loss. In some embodiments, the weight management comprises maintenance of weight loss. In some embodiments, the weight management further comprises a reduced-calorie diet. In some embodiments, the weight management further comprises a program of regular exercise. In some embodiments, the weight management further comprises both a reduced-calorie diet and a program of regular exercise.
  • the individual in need of weight management is a patient with an initial body mass of index > 40 kg/m 2 ; > 39 kg/m 2 ; > 38 kg/m 2 ; > 37 kg/m 2 ; > 36 kg/m 2 ; > 35 kg/m 2 ; > 34 kg/m 2 ; > 33 kg/m 2 ; > 32 kg/m 2 ; > 31 kg/m 2 ; > 30 kg/m 2 ; > 29 kg/m 2 ; > 28 kg/m 2 ; > 27 kg/m 2 ; > 26 kg/m 2 ; > 25 kg/m 2 ; > 24 kg/m 2 ; > 23 kg/m 2 ; > 22 kg/m 2 ; > 21 kg/m 2 ; or > 20 kg/m 2 ; and the patient optionally has at least one or at least two weight related comorbid condition(s).
  • the comorbid condition(s) when present are selected from:
  • hypertension hypertension, dyslipidemia, cardiovascular disease, glucose intolerance, and sleep apnea.
  • Formulations may be prepared by any suitable method, typically by uniformly mixing the active compound(s) with liquids or finely divided solid carriers, or both, in the required proportions and then, if necessary, forming the resulting mixture into a desired shape.
  • excipients such as binding agents, fillers, acceptable wetting agents, tabletting lubricants and disintegrants may be used in tablets and capsules for oral
  • Liquid preparations for oral administration may be in the form of solutions, emulsions, aqueous or oily suspensions and syrups.
  • the oral preparations may be in the form of dry powder that can be reconstituted with water or another suitable liquid vehicle before use. Additional additives such as suspending or emulsifying agents, non-aqueous vehicles (including edible oils), preservatives and flavorings and colorants may be added to the liquid preparations.
  • Parenteral dosage forms may be prepared by dissolving the compound of the invention in a suitable liquid vehicle and filter sterilizing the solution before filling and sealing an appropriate vial or ampule. These are just a few examples of the many appropriate methods well known in the art for preparing dosage forms.
  • a compound of the present invention can be formulated into pharmaceutical compositions using techniques well known to those in the art. Suitable pharmaceutically- acceptable carriers, outside those mentioned herein, are known in the art; for example, see Remington, The Science and Practice of Pharmacy, 20 th Edition, 2000, Lippincott Williams & Wilkins, (Editors: Gennaro et al.)
  • a compound of the invention may, in an alternative use, be administered as a raw or pure chemical, it is preferable however to present the compound or active ingredient as a pharmaceutical formulation or composition further comprising a pharmaceutically acceptable carrier.
  • Transdermal patches dispense a drug at a controlled rate by presenting the drug for absorption in an efficient manner with minimal degradation of the drug.
  • transdermal patches comprise an impermeable backing layer, a single pressure sensitive adhesive and a removable protective layer with a release liner.
  • the compounds of the invention may thus be placed into the form of pharmaceutical formulations and unit dosages thereof and in such form may be employed as 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 unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
  • the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid.
  • the pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient.
  • Examples of such dosage units are capsules, tablets, powders, granules or a suspension, with conventional additives such as lactose, mannitol, corn starch or potato starch; with binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators such as corn starch, potato starch or sodium carboxymethyl-cellulose; and with lubricants such as talc or magnesium stearate.
  • the active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable pharmaceutically acceptable carrier.
  • active ingredient defined in the context of a “pharmaceutical composition” refers to a component of a pharmaceutical composition that provides the primary pharmacological effect, as opposed to an "inactive ingredient” which would generally be recognized as providing no pharmaceutical benefit.
  • the dose when using the compounds of the present invention can vary within wide limits and as is customary and is known to the physician, it is to be tailored to the individual conditions in each individual case. It depends, for example, on the nature and severity of the illness to be treated, on the condition of the patient, on the compound employed or on whether an acute or chronic disease state is treated or prophylaxis conducted or on whether further active compounds are administered in addition to the compounds of the present invention.
  • Representative doses of the present invention include, but not limited to, about 0.001 mg to about 5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg to about 1000 mg, 0.001 mg to about 500 mg, 0.001 mg to about 250 mg, about 0.001 mg to 100 mg, about 0.001 mg to about 50 mg and about 0.001 mg to about 25 mg.
  • Multiple doses may be administered during the day, especially when relatively large amounts are deemed to be needed, for example 2, 3 or 4 doses. Depending on the individual and as deemed appropriate from the patient's physician or caregiver it may be necessary to deviate upward or downward from the doses described herein.
  • the amount of active ingredient, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected 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 attendant physician or clinician.
  • a model system typically an animal model
  • these extrapolations may merely be based on the weight of the animal model in comparison to another, such as a mammal, preferably a human, however, more often, these extrapolations are not simply based on weights, but rather incorporate a variety of factors.
  • compositions of this invention are selected in accordance with a variety factors as cited above.
  • the actual dosage regimen employed may vary widely and therefore may deviate from a preferred dosage regimen and one skilled in the art will recognize that dosage and dosage regimen outside these typical ranges can be tested and, where appropriate, may be used in the methods of this invention.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations.
  • the daily dose can be divided, especially when relatively large amounts are administered as deemed appropriate, into several, for example 2, 3 or 4 part administrations. If appropriate, depending on individual behavior, it may be necessary to deviate upward or downward from the daily dose indicated.
  • the compounds of the present invention can be administrated in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a compound of the invention or a pharmaceutically acceptable salt, solvate, or hydrate of a compound of the invention.
  • a suitable pharmaceutically acceptable carrier can be either solid, liquid or a mixture of both.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories and dispersible granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted to the desire shape and size.
  • the powders and tablets may contain varying percentage amounts of the active compound.
  • a representative amount in a powder or tablet may contain from 0.5 to about 90 percent of the active compound; however, an artisan would know when amounts outside of this range are necessary.
  • Suitable carriers for powders and tablets are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter and the like.
  • the term "preparation” refers to the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets and lozenges can be used as solid forms suitable for oral administration.
  • a low melting wax such as an admixture of fatty acid glycerides or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogenous mixture is then poured into convenient sized molds, allowed to cool and thereby to solidify.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Liquid form preparations include solutions, suspensions and emulsions, for example, water or water-propylene glycol solutions.
  • parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated 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 nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the compounds according to the present invention may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • parenteral administration e.g. by injection, for example bolus injection or continuous infusion
  • the pharmaceutical compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
  • a suitable vehicle e.g. sterile, pyrogen-free water
  • Aqueous formulations suitable for oral use can be prepared by dissolving or suspending the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents, as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, 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 preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents and the like.
  • the compounds according to the invention may be formulated 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 and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
  • Formulations suitable for topical administration in the mouth include lozenges comprising active agent in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray.
  • the formulations may be provided in single or multi-dose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump.
  • Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurized pack with a suitable propellant.
  • aerosol formulation in which the active ingredient is provided in a pressurized pack with a suitable propellant.
  • the compounds of the present invention or pharmaceutical compositions comprising them are administered as aerosols, for example as nasal aerosols or by inhalation, this can be carried out, for example, using a spray, a nebulizer, a pump nebulizer, an inhalation apparatus, a metered inhaler or a dry powder inhaler.
  • Pharmaceutical forms for administration of the compounds of the present invention as an aerosol can be prepared by processes well known to the person skilled in the art.
  • solutions or dispersions of the compounds of the present invention in water, water/alcohol mixtures or suitable saline solutions can be employed using customary additives, for example benzyl alcohol or other suitable preservatives, absorption enhancers for increasing the bioavailability, solubilizers, dispersants and others and, if appropriate, customary propellants, for example include carbon dioxide, CFCs, such as, dichlorodifluoromethane, trichlorofluorome thane, or dichlorotetrafluoroe thane; and the like.
  • the aerosol may conveniently also contain a surfactant such as lecithin.
  • the dose of drug may be controlled by provision of a metered valve.
  • the compound In formulations intended for administration to the respiratory tract, including intranasal formulations, the compound will generally have a small particle size for example of the order of 10 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization. When desired, formulations adapted to give sustained release of the active ingredient may be employed.
  • the active ingredients may be provided in the form of a dry powder, for example, a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
  • a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
  • the powder carrier will form a gel in the nasal cavity.
  • the powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.
  • the pharmaceutical preparations are preferably in unit dosage forms.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • Tablets or capsules for oral administration and liquids for intravenous administration are preferred compositions.
  • the compounds according to the invention may optionally exist as pharmaceutically acceptable salts including pharmaceutically acceptable acid addition salts prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids.
  • Representative acids include, but are not limited to, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic,
  • Certain compounds of the present invention which 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, aluminium, calcium, lithium, magnesium, potassium, sodium, zinc and the like. In some embodiments the pharmaceutically acceptable metal is sodium.
  • Organic bases include, but are not limited to, benzathine (N ⁇ N 2 -dibenzylethane-l,2-diamine), chloroprocaine (2- (diethylamino)ethyl 4-(chloroamino)benzoate), choline, diethanolamine, ethylenediamine, meglumine ((2R,3R,4R,5S)-6-(methylamino)hexane-l,2,3,4,5-pentaol), procaine (2- (diethylamino)ethyl 4-aminobenzoate), and the like.
  • Certain pharmaceutically acceptable salts are listed in Berge, et al., Journal of Pharmaceutical Sciences, 66:1-19 (1977).
  • the acid addition salts may be obtained as the direct products of compound synthesis.
  • the free base may 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 may form solvates with standard low molecular weight solvents using methods known to the skilled artisan.
  • Pro-drugs can be converted to "pro-drugs.”
  • the term "pro- drugs” refers to compounds that have been modified with specific chemical groups known in the art and when administered into an individual these groups undergo biotransformation to give the parent compound.
  • Pro-drugs can thus be viewed as compounds of the invention containing one or more specialized non-toxic protective groups used in a transient manner to alter or to eliminate a property of the compound.
  • the "pro-drug” approach is utilized to facilitate oral absorption.
  • T. Higuchi and V. Stella Prodrugs 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 producing a pharmaceutical composition for "combination-therapy" comprising admixing at least one compound according to any of the compound embodiments disclosed herein, together with at least one known pharmaceutical agent as described herein and a pharmaceutically acceptable carrier.
  • GPRl 19 receptor modulators are utilized as active ingredients in pharmaceutical compositions, these are not intended for use in humans only, but in non- human mammals as well.
  • active agents such as GPRl 19 receptor modulators
  • livestock animals e.g., horses, cows, etc.
  • the dosage forms described herein may comprise, as the active component, either a compound described herein or a pharmaceutically acceptable salt or as a pharmaceutically acceptable solvate or hydrate thereof.
  • various hydrates and solvates of the compounds described herein and their salts will find use as intermediates in the manufacture of pharmaceutical compositions. Typical procedures for making and identifying suitable hydrates and solvates, outside those mentioned herein, are well known to those 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. England, Vol.
  • one aspect of the present invention pertains to methods of administering hydrates and solvates of compounds described herein and/or their pharmaceutical acceptable salts, that can be isolated and characterized by methods known in the art, such as, thermogravimetric analysis (TGA), TGA-mass spectroscopy, TGA-Infrared spectroscopy, powder X-ray diffraction (XRPD), Karl Fisher titration, high resolution X-ray diffraction, and the like.
  • TGA thermogravimetric analysis
  • TGA-mass spectroscopy TGA-Infrared spectroscopy
  • powder X-ray diffraction (XRPD) powder X-ray diffraction
  • Karl Fisher titration high resolution X-ray diffraction
  • Polymorphism is the ability of a substance to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattice.
  • Polymorphs show the same properties in the liquid or gaseous state but they behave differently in the solid state.
  • drugs can also exist as salts and other multicomponent crystalline phases.
  • solvates and hydrates may contain an API host and either solvent or water molecules, respectively, as guests.
  • the guest compound is a solid at room temperature, the resulting form is often called a cocrystal.
  • Salts, solvates, hydrates, and cocrystals may show polymorphism as well. Crystalline phases that share the same API host, but differ with respect to their guests, may be referred to as
  • Solvates contain molecules of the solvent of crystallization in a definite crystal lattice. Solvates, in which the solvent of crystallization is water, are termed hydrates. Because water is a constituent of the atmosphere, hydrates of drugs may be formed rather easily.
  • Crystalline forms can be identified by their unique solid state signature with respect to, for example, differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and other solid state methods.
  • DSC differential scanning calorimetry
  • PXRD powder X-ray diffraction
  • the temperatures observed will depend upon sample purity, the rate of temperature change, as well as sample preparation technique and the particular instrument employed.
  • the values relating to DSC thermograms can vary by plus or minus about 4 °C ( ⁇ 4 °C).
  • the values relating to DSC thermograms can also vary by plus or minus about 20 joules per gram ( ⁇ 20 joules per gram).
  • DSC can be used to observe desolvation events.
  • DSC thermogram values relate to desolvation events, the values are understood to be estimates.
  • Scan rate and pan closure can influence DSC values for desolvation events, which can vary by plus or minus about 25 °C.
  • DSC values for desolvation events are typically recorded using a sample in an aluminum pan with an uncrimped lid and a scan rate of 10 °C/min.
  • the relative intensities of the peaks can vary, depending upon the sample preparation technique, the sample mounting procedure and the particular instrument employed.
  • the peak assignments of diffraction patterns can vary by plus or minus 0.2 °2 ⁇ ( ⁇ 0.2 °2 ⁇ ).
  • the features reported herein can vary by plus or minus about 5 °C ( ⁇ 5 °C).
  • the TGA features can also vary by plus or minus about 2% ( ⁇ 2%) weight change due to, for example, sample variation.
  • DMS dynamic moisture sorption
  • a compound of the invention can be administered as the sole active pharmaceutical agent ⁇ i.e. , mono-therapy), or it can be used in combination with one or more pharmaceutical agents ⁇ i.e. , combination-therapy), such as pharmaceutical agents, such as, known anti-diabetic agents, either administered together or separately for the treatment of the diseases, conditions, and disorders described herein. Therefore, another aspect of the present invention includes methods of treatment of a metabolic related disorder, including a weight-related disorder, such as obesity, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of Formula (I) and pharmaceutically acceptable salts, solvates and hydrates thereof, in combination with one or more pharmaceutical agents, such as anti-diabetic agents, as described herein.
  • a metabolic related disorder including a weight-related disorder, such as obesity
  • the combination can be used by mixing the respective active components, a compound of Formula (I) and a pharmaceutical agent, either together or independently optionally with a physiologically acceptable carrier, excipient, binder, diluent, etc. , as described herein, and administering the mixture or mixtures either orally or non- orally as a pharmaceutical composition(s).
  • a compound of Formula (I) is administered as a combination therapy with another active compound the compound of Formula (I) and the pharmaceutical agent can be formulated as separate pharmaceutical compositions given at the same time or at different times; or the compound of Formula (I) and the pharmaceutical agent can be formulated together as a single unit dosage.
  • Suitable pharmaceutical agents that can be used in combination with the compounds of the present invention include anti-obesity agents such as apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors; MCR-4 agonists, cholescystokinin-A (CCK-A) agonists; serotonin and norepinephrine reuptake inhibitors (for example, sibutramine); sympathomimetic agents; ⁇ 3 adrenergic receptor agonists; dopamine agonists (for example, bromocriptine); melanocyte-stimulating hormone receptor analogues; cannabinoid 1 receptor antagonists [for example, SR141716: N-(piperidin-l-yl)-5-(4-chlorophenyl)-l-(2,4- dichlorophenyl)-4-methyl-lH-pyrazole-3-carboxamide]; melanin concentrating hormone antagonists; leptin (
  • anorectic agents such as a bombesin agonist
  • neuropeptide -Y antagonists such as a bombesin agonist
  • thyromimetic agents such as a bombesin agonist
  • dehydroepiandrosterone or an analogue thereof such as glucocorticoid receptor agonists or antagonists
  • orexin receptor antagonists such as urocortin binding protein antagonists
  • ciliary neutrotrophic factors such as AxokineTM available from Regeneron
  • GPP human agouti-related proteins
  • H3R histamine 3 receptor
  • neuromedin U receptor agonists for example, phentermine, mazindol and the like
  • noradrenergic anorectic agents for example, phentermine, mazindol and the like
  • appetite suppressants for example, bupropion
  • anti-obesity agents including the agents set forth infra, are well known, or will be readily apparent in light of the instant disclosure, to one of ordinary skill in the art.
  • the anti-obesity agents are selected from the group consisting of orlistat, sibutramine, bromocriptine, ephedrine, leptin, and pseudoephedrine.
  • compounds of the present invention and combination therapies are administered in conjunction with exercise and/or a calorie -controlled diet.
  • combination-therapy of the compounds of the present invention with anti-obesity agents, anorectic agents, appetite suppressant and related agents is not limited to those listed above, but includes in principle any combination with any
  • combination-therapy of the compounds of the present invention with other pharmaceutical agents is not limited to those listed herein, supra or infra, but includes in principle any combination with any pharmaceutical agent or pharmaceutical composition useful for the treatment of diseases, conditions or disorders that are linked to metabolic related disorders.
  • Some embodiments of the present invention include methods of treatment of a disease, disorder, condition or complication thereof as described herein, comprising administering to an individual in need of such treatment a therapeutically effective amount or dose of a compound of Formula (I) in combination with at least one pharmaceutical agent selected from the group consisting of: sulfonylureas (for example, tolbutamide (Orinase); acetohexamide (Dymelor); tolazamide (Tolinase); chlorpropamide (Diabinese); glipizide (Glucotrol); glyburide (Diabeta, Micronase, Glynase); glimepiride (Amaryl); gliclazide (Diamicron); and sulfonylureas known in the art); meglitinides (for example, repaglinide (Prandin), nateglinide (Starlix), mitiglinide, and other meglitinides known in the art); biguanides (for example,
  • PPAR- ⁇ ) agonists for example, rosiglitazone (Avandia), pioglitazone (Actos), troglitazone (Rezulin), rivoglitazone, ciglitazone, and thiazolidinediones known in the art); insulin and insulin analogues; anti-diabetic peptide analogues (for example, exenatide, liraglutide, taspoglutide, and anti-diabetic peptides analogues know in the art); HMG- CoA reductase inhibitors (for example, 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 (for example, cholesterol
  • antiplatelet agents for example, aspirin and adenosine diphosphate receptor antagonists that include: clopidogrel, ticlopidine and the like
  • angiotensin-converting enzyme inhibitors for example, captopril, enalapril, alacepril, delapril; ramipril, lisinopril, imidapril, benazepril, ceronapril, cilazapril, enalaprilat, fosinopril, moveltopril, perindopril, quinapril, spirapril, temocapril, trandolapril, and other angiotensin converting enzyme inhibitors known in the art); angiotensin II receptor antagonists [for example, losartan (and the potassium salt form), and other angiotensin II receptor antagonists known in the art; adip
  • Suitable pharmaceutical agents that can be used in conjunction with compounds of the present invention include, but are not limited to: amylin agonists (for example, pramlintide); insulin secretagogues (for example, GLP-1 agonists, exendin-4, and insulinotropin (NN2211)); acyl CoA cholesterol acetyltransierase inhibitors (for example, ezetimibe, eflucimibe, and other acyl CoA cholesterol acetyltransierase inhibitors known in the art); cholesterol absorption inhibitors (for example, ezetimibe, pamaqueside and other cholesterol absorption inhibitors known in the art); cholesterol ester transfer protein inhibitors (for example, CP-529414, JTT- 705, CETi-1, and other cholesterol ester transfer protein inhibitors known in the art);
  • amylin agonists for example, pramlintide
  • insulin secretagogues for example, GLP-1 agonists, exendin-4, and insulinotropin (NN22
  • microsomal triglyceride transfer protein inhibitors for example, implitapide, and other microsomal triglyceride transfer protein inhibitors known in the art
  • cholesterol modulators for example, NO-1886, and other cholesterol modulators known in the art
  • bile acid modulators for example, GT 103 -279 and other bile acid modulators known in the art
  • insulin signaling pathway modulators inhibitors of protein tyrosine phosphatases (PTPases); non-small molecule mimetics and inhibitors of glutamine-fructose-6-phosphate amidotransf erase (GFAT);
  • G6Pase glucose-6- phosphatase
  • F-l,6-BPase fructose-l,6-bisphosphatase
  • GP glycogen phosphorylase
  • glucagon receptor antagonists inhibitors of phosphoenolpyruvate carboxykinase (PEPCK); pyruvate dehydrogenase kinase (PDHK) inhibitors; insulin sensitivity enhancers; insulin secretion enhancers; inhibitors of gastric emptying; ⁇ -adrenergic antagonists; retinoid X receptor (RXR) agonists; and dipeptidyl peptidase-4 (DPP-IV) inhibitors; DGAT-1 inhibitors; and the like.
  • G6Pase glucose-6- phosphatase
  • F-l,6-BPase fructose-l,6-bisphosphatase
  • GP glycogen phosphorylase
  • PEPCK phosphoenolpyruvate carboxy
  • Some aspects of the present invention include compounds of Formula (I) that can be employed in any of the methods, pharmaceutical products, uses, compounds, and
  • the two distinct pharmaceutical agents are selected from any of the pharmaceutical agents, or classes of pharmaceutical agents described herein.
  • the two distinct pharmaceutical agents are selected from: an inhibitor of DPP-IV, a biguanide, an alpha-glucosidase inhibitor, an insulin analogue, a sulfonylurea, a SGLT2 inhibitor, a meglitinide, a thiazolidinedione, and an anti-diabetic peptide analogue.
  • the two distinct pharmaceutical agents include every combination selected from pharmaceutical agents of the following group: an inhibitor of DPP-IV, a biguanide, an alpha- glucosidase inhibitor, a sulfonylurea, and a SGLT2 inhibitor.
  • Some embodiments of the present invention include every combination of one or more compounds selected from compounds of the following group and pharmaceutically acceptable salts, solvates, and hydrates thereof: an inhibitor of DPP-IV selected from: 3(R)-amino-l -[3- (trifluoromethyl)-5,6,7,8-tetrahydro[l ,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5- trifluorophenyl)butan-l -one; l-[2-(3-hydroxyadamant-l-ylamino)acetyl]pyrrolidine-2(5)- carbonitrile; (15,35,55)-2-[2(5)-amino-2-(3-hydroxyadamantan-l-yl)acetyl]-2- azabicyclo[3.1.0]hexane-3-carbonitrile; 2-[6-[3(R)-aminopiperidin-l-yl]-3-methyl-2,4-diox
  • a-glucosidase inhibitor selected from: acarbose ((2R,3R,4R,5R)-4-((2R,3R,4R,55,6R)-5-((2R,3R,45,55,6R)-3,4-dihydroxy-6-methyl-5- ((15,4R,55,65)-4,5,6-trihydroxy-3-(hydroxymethyl)cyclohex-2-enylamino)tetrahydro-2H-pyran-
  • acarbose ((2R,3R,4R,5R)-4-((2R,3R,4R,55,6R)-5-((2R,3R,45,55,6R)-3,4-dihydroxy-6-methyl-5- ((15,4R,55,65)-4,5,6-trihydroxy-3-(hydroxymethyl)cyclohex-2-enylamino)tetrahydro-2H-pyran-
  • glibenclamide also known as glyburide (Diabeta, Micronase, Glynase, 5-chloro-N-(4-(N- (cyclohexylcarbamoyl)sulfamoyl)phenethyl)-2-methoxybenzamide); glimepiride (Amaryl, 3- ethyl-4-methyl-N-(4-(N-((lr,4r)-4-methylcyclohexylcarbamoyl)sulfamoyl)phenethyl)-2-oxo- 2,5-dihydro-lH-pyrrole-l-carboxamide); and gliclazide (Diamicron, N-
  • a SGLT2 inhibitor selected from: dapagliflozin ((2S,3R,4R,5S,6R)-2-(4-chloro-3-(4- ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3 ,4,5 -triol) ; remogliflozin (ethyl ((2R,35,45,5R,65)-3,4,5-trihydroxy-6-(4-(4-isopropoxybenzyl)-l-isopropyl-5-methyl-lH- pyrazol-3-yloxy)tetrahydro-2H-pyran-2-yl)methyl carbonate); ASP1941, canagliflozin
  • LX4211 a meglitinide selected from: repaglinide (Prandin, (5)-2-ethoxy-4-(2-(3 -methyl- 1 -(2- (piperidin-l-yl)phenyl)butylamino)-2-oxoethyl)benzoic acid); nateglinide (Starlix, (R)-2- ((lr,4R)-4-isopropylcyclohexanecarboxamido)-3-phenylpropanoic acid); and mitiglinide ((5)-2- benzyl-4-((3aR,7a5)-lH-isoindol-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)-4-oxobutanoic acid); a thiazolidinedione selected from: rosiglitazone (Avandia, 5-(4-(2-(methyl(pyridin-2- yl)
  • the two distinct pharmaceutical agents include every
  • Dipeptidyl peptidase IV (DPP-IV, EC 3.4.14.5) exhibits catalytic activity against a broad range of peptide substrates that includes peptide hormones, neuropeptides, and chemokines.
  • the incretins glucagon-like peptide 1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP), which stimulate glucose-dependent insulin secretion and otherwise promote blood glucose homeostasis, are rapidly cleaved by DPP-IV at the position-2 alanine leading to inactivation of their biological activity.
  • Peptide YY is a gut peptide that has been implicated in modulating satiety (Chaudhri et al, Annu Rev Physiol (2008) 70:239- 255). PYY is released into the circulation as PYYi_ 36 and PYY 3 _ 36 (Eberlein et al, Peptides (1989) 10:797-803). PYY 3 -36 is generated from PYYi_ 36 by cleavage of the N-terminal Tyr and Pro residues by DPP-IV. Both pharmacological and genetic attenuation of DPP-IV activity is associated with enhanced incretin action, increased insulin, and lower blood glucose in vivo.
  • DPP-IV activity has been shown to provide resistance to obesity and to improve insulin sensitivity.
  • Inhibitors of DPP-IV have shown to be useful as therapeutics, for example, oral administration of vildagliptin (l-[2-(3-hydroxyadamant-l- ylamino)acetyl]pyrrolidine-2(5)-carbonitrile) or sitagliptin (3(R)-amino-l-[3-(trifluoromethyl)- 5,6,7,8-tetrahydro[l,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-l-one) to human patients suffering with type 2 diabetes has been found to reduce fasting glucose and postprandial glucose excursion in association with significantly reduced HbA lc levels.
  • 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).
  • suitable pharmaceutical agents include inhibitors of DPP-IV that can be used in conjunction with compounds of the present invention either dosed separately or together.
  • Inhibitors of DPP-IV are well-known in the art or can be readily identified and their in vitro biological activity determined using any number of methods available, for example, 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-GloTM Protease Assay Technical Bulletin #TB339.
  • 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;
  • DPP-IV inhibitors include, but are not limited to, dipeptide derivatives or dipeptide mimetics such as alanine-pyrrolidide, isoleucine-thiazolidide, and the pseudosubstrate N-valyl prolyl, O-benzoyl hydroxylamine, as described, for example, in U.S. Pat. No. 6,303,661.
  • DPP-IV inhibitors selected from the DPP-IV inhibitors found in U.S. Pat. Nos. 6,869,947, 6,867,205, 6,861,440, 6,849,622, 6,812,350, 6,803,357, 6,800,650, 6,727,261, 6,716,843, 6,710,040, 6,706,742, 6,645,995, 6,617,340, 6,699,871, 6,573,287, 6,432,969, 6,395,767, 6,380,398, 6,303,661, 6,242,422, 6,166,063, 6,100,234, and 6,040,145.
  • DPP-IV inhibitors selected from the DPP-IV inhibitors found in U.S. Pat. Nos. 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 every combination of one or more DPP-IV inhibitors selected from the DPP-IV inhibitors found in International Patent Application Publication Nos. 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 2005/044195, 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 2005/026148, WO 2005/025554, WO 2005/023762, WO 2005/020920, WO 05/19168, WO 05/12312, WO 05/12308, WO 05/122
  • Some embodiments of the present invention include every combination of one or more DPP-IV inhibitors selected from the DPP-IV inhibitors found in Patent Publication Nos. EP 1517907, EP 1513808, EP 1492777, EP 1490335, EP 1489088, EP 1480961, EP 1476435, EP 1476429, EP 1469873, EP 1465891, EP 1463727, EP 1461337, EP 1450794, EP 1446116, EP 1442049, EP 1441719, EP 1426366, EP 1412357, EP1406873, EP 1406872, EP 1406622, EP 1404675, EP 1399420, EP 1399471, EP 1399470, EP 1399469, EP 1399433, EP 1399154, EP 1385508, EP 1377288, EP 1355886, EP 1354882, EP 1338592, EP 1333025, EP 1304327, EP 1301187, EP 1296974, EP 1280797, EP 1282600, EP 126
  • JP 2003238566 JP 2002531547, JP 2002527504, JP 2002517401, JP 2002516318, JP 2002363157, JP 2002356472, JP 2002356471, JP 2002265439, JP 2001510442, JP
  • the DPP-IV inhibitor has an IC 50 of less than about 10 ⁇ , less than about 1 ⁇ , 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.
  • the DPP-IV inhibitor has an IC 50 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 about 3 nM, less than about 2 nM, or less than about 1 nM.
  • the DPP-IV inhibitor is a selective DPP-IV inhibitor, wherein the selective DPP-IV inhibitor has a selectivity for human plasma DPP-IV over one or more of
  • the DPP-IV inhibitor is a selective DPP-IV inhibitor, wherein the selective DPP-IV inhibitor has a selectivity for human plasma DPP-IV over one or more of PPCE, DPP-II, DPP-8 and DPP-9 of at least about 100-fold. In some embodiments, the DPP-IV inhibitor is a selective DPP-IV inhibitor, wherein the selective DPP-IV inhibitor has a selectivity for human plasma DPP-IV over one or more of PPCE, DPP-II, DPP-8 and DPP-9 of at least about 10-fold.
  • the DPP-IV inhibitor is a selective DPP-IV inhibitor, wherein the selective DPP-IV inhibitor has a selectivity for human plasma DPP-IV over one or more of PPCE, DPP-II, DPP-8 and DPP-9 of at least about 1000-fold.
  • the DPP-IV inhibitor is orally active.
  • the DPP-IV inhibitor is an inhibitor of human DPP-IV.
  • Some embodiments of the present invention include every combination of one or more compounds selected from compounds of the following group and pharmaceutically acceptable salts, solvates, and hydrates thereof: 3(R)-amino-l -[3-(trifluoromethyl)-5,6,7,8- tetrahydro[l ,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-l-one; l-[2-(3- hydroxyadamant-l-ylamino)acetyl]pyrrolidine-2(5)-carbonitrile; (15,35,55)-2-[2(5)-amino-2-(3- hydroxyadamantan- 1 -yl)acetyl] -2-azabicyclo [3.1.0]hexane-3-carbonitrile ; 2- [6- [3(R)- aminopiperidin-l-yl]-3-methyl-2,4-dioxo-l ,2,3,
  • Sitagliptin phosphate (Januvia®, MK-0431 , dihydrogenphosphate salt of 3(R)-amino-l - [3-(trifluoromethyl)-5,6,7,8-tetrahydro[l ,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5- trifluorophenyl)butan-l -one) is marketed by Merck & Co. for once -daily oral treatment of type 2 diabetes. Januvia was first launched in Mexico followed by commercialization in the U.S. In 2007, the product was approved by the European Medicines Evaluation Agency (EMEA) and is currently available in the U.K., Germany and Spain.
  • EMEA European Medicines Evaluation Agency
  • Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in WO2003/004498 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • the DPP-IV inhibitor is selected from 3(R)-amino-l-[3-(trifluoromethyl)-5, 6,7,8- tetrahydro[l ,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-l-one, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • the DPP-IV inhibitor is (R)-amino-l-[3-(trifluoromethyl)-5,6,7,8- tetrahydro[l ,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-l-one phosphate:
  • the DPP-IV inhibitor is crystalline (R)-amino-l -[3-(trifluoromethyl)-5,6,7,8-tetrahydro[l ,2,4]triazolo[4,3-a]pyrazin-7- yl]-4-(2,4,5-trifluorophenyl)butan-l-one phosphate monohydrate.
  • Vildagliptin (Galvus®, LAF-237, l-[2-(3-hydroxyadamant-l - ylamino)acetyl]pyrrolidine-2(5)-carbonitrile) is another DPP-IV inhibitor and was first commercialized in Brazil and Mexico by Novartis for oral, once-daily treatment of type 2 diabetes.
  • a marketing authorization application (MAA) was approved in the E.U. for this indication and launch took place in the U.K. in March, 2008.
  • An approvable letter has been received for the regulatory application filed in the U.S. Vildagliptin was approved in Japan in 2010.
  • the compound, l-[2-(3-hydroxyadamant-l-ylamino)acetyl]pyrrolidine-2(5)-carbonitrile, is disclosed in international patent publication WO 2000/034241. Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in WO2000/034241 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • the DPP-IV inhibitor is selected from l-[2-(3- hydroxyadamant- 1 -ylamino)acetyl]pyrrolidine-2(5)-carbonitrile, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • the DPP-IV inhibitor is l-[2-(3-hydroxyadamant-l-ylamino)acetyl]pyrrolidine- 2(5)-carbonitrile HCI:
  • Saxagliptin (OnglyzaTM, BMS-477118, (15,35,55)-2-[2(5)-amino-2-(3- hydroxyadamantan-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile) is another DPP-IV inhibitor, which was launched in 2009 by AstraZeneca and Bristol-Myers Squibb in the U.S. for the treatment of type 2 diabetes. In 2009, the product was approved in the E.U. for the treatment of type 2 diabetes independently or in combination with metformin. Phase 3 clinical studies are ongoing in Japan for the treatment of type 2 diabetes.
  • the DPP-IV inhibitor is selected from (15,35,55)-2-[2(5)-amino-2-(3- hydroxyadamantan-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • the compound, 2-[6-[3(R)-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-l , 2,3,4- tetrahydropyrimidin-l-ylmethyl]benzonitrile, and pharmaceutically acceptable salts thereof are disclosed in international patent publication WO 2005/095381.
  • Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in WO 2005/095381 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • the DPP-IV inhibitor is selected from 2-[6-[3(R)- aminopiperidin-l-yl]-3-methyl-2,4-dioxo-l ,2,3,4-tetrahydropyrimidin-l -ylmethyl]benzonitrile, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • the DPP-IV inhibitor is 2-[6-[3(R)-aminopiperidin- yl]-3-methyl-2,4-dioxo- -tetrahydropyrimidin-l -ylmethyl]benzonitrile benzoate:
  • Linagliptin (BI-1356, Tradjenta®, 8-[3(R)-aminopiperidin-l -yl]-7-(2-butynyl)-3- methyl-l-(4-methylquinazolin-2-ylmethyl)xanthine) is an inhibitor of DPP-IV approved by the FDA in May 2011 as an adjunct to diet and excerise to improve glycemic control in adults with type 2 diabetes.
  • the compound, 8-[3(R)-aminopiperidin-l-yl]-7-(2-butynyl)-3-methyl-l -(4- methylquinazolin-2-ylmethyl)xanthine is disclosed in international patent publication
  • WO2004/018468 Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in WO2004/018468 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • the DPP-IV inhibitor is selected from 8-[3(R)-aminopiperidin-l-yl]-7-(2-butynyl)-3-methyl-l-(4- methylquinazolin-2-ylmethyl)xanthine, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • the DPP-IV inhibitor is a crystalline form of 8-[3(R)- aminopiperidin-l-yl]-7-(2-butynyl)-3-methyl-l -(4-methylquinazolin-2-ylmethyl)xanthine.
  • Dutogliptin (PHX-1149, l-[N-[3(R)-pyrrolidinyl]glycyl]pyrrolidin-2(R)-yl boronic acid) is a DPP-IV inhibitor in phase 3 clinical trials by Phenomix and Forest for the oral, once-daily treatment of type 2 diabetes.
  • the compound, l-[N-[3(R)-pyrrolidinyl]glycyl] pyrrolidin-2(R)-yl boronic acid, and pharmaceutically acceptable salts thereof are disclosed in international patent publication WO2005/047297.
  • Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in WO2005/047297 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • the DPP-IV inhibitor is selected from l-[N-[3(R)-pyrrolidinyl]glycyl]pyrrolidin-2(R)-yl boronic acid, and pharmaceutically acceptable salts, solvates, and h drates thereof:
  • the DPP-IV inhibitor is l-[N- -pyrrolidinyl]glycyl]pyrrolidin-2(R)-yl boronic acid tartrate:
  • Melogliptin (GRC-8200, 4(5)-fluoro-l-[2-[(lR,35)-3-(lH-l ,2,4-triazol-l - ylmethyl)cyclopentylamino]acetyl]pyrrolidine-2(5)-carbonitrile) is a DPP-IV inhibitor currently undergoing phase 2 clinical trials by Glenmark Pharmaceuticals and Merck KGaA for the treatment of type 2 diabetes.
  • the compound, 4(5)-fluoro-l -[2-[(lR,35)-3-(lH-l ,2,4-triazol-l - ylmethyl)cyclopentylamino]acetyl]pyrrolidine-2(5)-carbonitrile, is disclosed in international patent publication WO2006/040625.
  • Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in WO2006/040625 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • the DPP-IV inhibitor is selected from 4(5)-fluoro-l -[2-[(lR,35)-3-(lH-l ,2,4-triazol-l - ylmethyl)cyclopentylamino] acetyl]pyrrolidine-2(S)-carbonitrile, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • Carmegliptin (R-1579, l-[(25,35, l lb5)-2-amino-9,10-dimethoxy-2,3,4,6,7,l lb- hexahydro-lH-pyrido[2,l-a]isoquinolin-3-yl]-4(5)-(fluoromethyl)pyrrolidin-2-one) is a DPP-IV inhibitor.
  • the compound, l-[(25,35, l lb5)-2-amino-9,10-dimethoxy-2,3,4,6,7,l lb-hexahydro- lH-pyrido[2, l-a]isoquinolin-3-yl]-4(5)-(fluoromethyl)pyrrolidin-2-one, is disclosed in international patent publication WO2005/000848. Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in WO2005/000848 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • the DPP-IV inhibitor is selected from l-[(2S,3S, l lbS)-2-amino-9, 10-dimethoxy- 2,3,4,6,7,11 b-hexahydro- 1 H-pyrido [2, 1 -a] isoquinolin-3-yl] -4(5)-(fluoromethyl)pyrrolidin-2- one, and pharmaceutically ac s thereof:
  • ethylamino]acetylpyrrolidine a DPP-IV inhibitor in US patent publication US 2007/0112059.
  • Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in US 2007/0112059 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • the DPP-IV inhibitor is selected from (25,45)-2-cyano-4-fluoro-l -[(2-hydroxy-l ,l- dimethyl)ethylamino]acetylpyrrolidine, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • Sanofi-Aventis disclosed a series of substituted bicyclic 8-pyrrolidineoxanthine derivatives as DPP-IV inhibitors in US publication US 2007/0167468. Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in US publication US 2007/0167468 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • the DPP-IV inhibitor is selected from 8-(cw-hexahydro-pyrrolo[3,2-b]pyrrol-l-yl)-3-methyl-7-(3-methyl-but-2-enyl)-l -(2-oxo-2- phenylethyl)-3,7-dihydro-purine-2,6-dione, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • Pfizer disclosed a series of 3-amino-pyrrolidine-4-lactam derivatives as DPP-IV inhibitors in international patent publication WO2007/148185.
  • Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in WO2007/148185 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • One such compound is l-((35,45)-4-amino-l-(4-(3,3-difluoropyrrolidin-l -yl)- l ,3,5-triazin-2-yl)pyrrolidin-3-yl)-5,5difluoropiperidin-2-one.
  • the DPP- IV inhibitor is selected from l-((35,45)-4-amino-l -(4-(3,3-difluoropyrrolidin-l -yl)-l ,3,5-triazin- 2-yl)pyrrolidin-3-yl)-5,5difluoropiperidin-2-one, and pharmaceutically acceptable salts, solvates, and hydrates thereof
  • Syrrx disclosed a series of substituted pyrimidine-2,4(lH,3H)-dione derivatives as DPP- IV inhibitors in international patent publication WO2005/095381.
  • Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in WO2005/095381 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • One such compound is (R)-2-((6-(3-aminopiperidin-l-yl)-3-methyl-2,4-dioxo- 3,4-dihydropyrimidin-l(2H)-yl)methyl)-4-fluorobenzonitrile.
  • the DPP- IV inhibitor is selected from (R)-2-((6-(3-aminopiperidin-l -yl)-3-methyl-2,4-dioxo-3,4- dihydropyrimidin-l(2H)-yl)methyl)-4-fluorobenzonitrile, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • One embodiment of the present invention pertains to any one or more crystalline forms of (R)-2-((6-(3-aminopiperidin-l-yl)-3-methyl-2,4- dioxo-3,4-dihydropyrimidin-l(2H)-yl)methyl)-4-fluorobenzonitrile succinic acid salt as described in international patent publication WO2008/067465.
  • the DPP- IV inhibitor is crystalline (R)-2-((6-(3-aminopiperidin-l -yl)-3-methyl-2,4-dioxo-3,4- dihydropyrimidin-l(2H)- salt:
  • One such compound is 5- ⁇ (S)-2-[2-((S)-2-cyano-pyrrolidin-l -yl)-2-oxo- ethylamino] -propyl ⁇ -5-( 1 H-tetrazol-5 -yl) 10,11 -dihydro-5H-dibenzo [a,d]cycloheptene-2,8- dicarboxylic acid bis-dimethylamide.
  • the DPP-IV inhibitor is selected from 5- ⁇ (5)-2-[2-((5)-2-cyano-pyrrolidin-l -yl)-2-oxo-ethylamino]-propyl ⁇ -5-(lH-tetrazol-5- yl)10,l l-dihydro-5H-dibenzo[a,d]cycloheptene-2,8-dicarboxylic acid bis-dimethylamide, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in WO2002/0014271 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • One such compound is ((25,45)-4-(4-(3-methyl-l -phenyl-lH-pyrazol-5- yl)piperazin-l -yl)pyrrolidin-2-yl)(thiazolidin-3-yl)methanone.
  • the DPP- IV inhibitor is selected from ((25,45)-4-(4-(3-methyl-l-phenyl-lH-pyrazol-5-yl)piperazin-l - yl)pyrrolidin-2-yl)(thiazolidin-3-yl)methanone, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • One embodiment of the present invention pertains to any one or more crystalline forms of ((25,45)-4-(4-(3-methyl-l - phenyl-1 H-pyrazol-5 -yl)piperazin-l -yl)pyrrolidin-2-yl)(thiazolidin-3-yl)methanone salt as described in international patent publication WO2006/088129 and US publication
  • the DPP-IV inhibitor is crystalline ((25,45)-4-(4-(3- methyl-l-phenyl-lH-pyrazol-5-yl)piperazin-l -yl)pyrrolidin-2-yl)(thiazolidin-3-yl)methanone 2.5 hydrobromide salt:
  • the DPP-IV inhibitor is crystalline
  • Kyorin disclosed a series of pyrrolidinecarbonitrile derivatives as DPP-IV inhibitors in international patent publication WO2008/114857 and US publication US 2008/0146818. Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in WO2008/114857 and US publication US 2008/0146818, and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • One such compound is (25,45)-l -[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-l -yl)amino]acetyl]-4-fluoropyrrolidine-2- carbonitrile.
  • the DPP-IV inhibitor is selected from (25,45)-l -[2-[(4- ethoxycarbonylbicyclo[2.2.2]oct-l-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in WO2006/068163 and US publication US 2009/0192129 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • One such compound is (6-[(3R)-3-amino-piperidin-l -yl]-5-(2-chloro-5-fluoro-benzyl)-l ,3-dimethyl- l ,5dihydro-pyrrolo[3,2-d]pyrimidine-2,4-dione.
  • the DPP-IV inhibitor is selected from (6-[(3R)-3-amino-piperidin-l -yl]-5-(2-chloro-5-fluoro-benzyl)-l ,3-dimethyl- l ,5dihydro-pyrrolo[3,2-d]pyrimidine-2,4-dione, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • the DPP-IV inhibitor is selected from 2-( ⁇ 6-[(3R)-3-amino-3- methylpiperidin- 1 -yl] - 1 ,3 -dimethyl-2,4-dioxo- 1 ,2,3 ,4-tetrahydro-5H-pyrrolo [3 ,2-d]pyrimidin-5 - yl ⁇ methyl)-4-fluorobenzonitrile, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • Hoffmann-La Roche 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 every combination of one or more compounds selected from compounds disclosed in WO 03/037327 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • One such compound is (25)-l- ⁇ [2-(5-methyl-2-phenyl-oxazol-4-yl)- ethylamino] -acetyl ⁇ -pyrrolidine-2-carbonitrile.
  • the DPP-IV inhibitor is selected from (25)-l- ⁇ [2-(5-methyl-2-phenyl-oxazol-4-yl)-ethylamino] -acetyl ⁇ -pyrrolidine -2- carbonitrile, and pharmaceu ates thereof:
  • the DPP-IV inhibitor is (25)-l- ⁇ [2-(5- methyl-2-phenyl-oxazol-4-yl)-ethylamino] -acetyl ⁇ -pyrrolidine -2 -carbonitrile methansulfonic acid salt (i.e. , mesylat
  • the DPP-IV inhibitor is selected from (25)- 1- ⁇ [1,1 -dimethyl-3 -(4-pyridin-3 -yl-imidazol- 1 -yl)-propylamino] -acetyl ⁇ -pyrrolidine -2- carbonitrile, and pharmac ates thereof:
  • the DPP-IV inhibitor is (25)-l- ⁇ [l,l-dimethyl-3-(4-pyridin-3-yl- imidazol- 1 -yl) nic acid:
  • the DPP-IV inhibitor is (25)- 1- ⁇ [1,1 -dimethyl-3 -(4-pyridin-3 -yl-imidazol- 1 -yl)-propylamino] -acetyl ⁇ -pyrrolidine -2- carbonitrile fumaric acid salt (i.e. , fumarate):
  • Pfizer disclosed a series of proline derivatives as DPP-IV inhibitors in international patent publication WO2005/116014.
  • Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in WO2005/116014 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • One such compound is (3,3-difluoropyrrolidin- 1 -yl)-((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin- 1 -yl)pyrrolidin-2- yl)methanone.
  • the DPP-IV inhibitor is selected from (3,3- difluoropyrrolidin- 1 -yl)-((25,45)-4-(4-(pyrimidin-2-yl)piperazin- 1 -yl)pyrrolidin-2- yl)methanone, and pharmac ates thereof:
  • GlaxoSmithKline disclosed a series of fluoropyrrolidine derivatives as DPP-IV inhibitors in international patent publication WO 03/002531.
  • Some embodiments of the present invention include every combination of one or more compounds selected from the DPP-IV inhibitors disclosed in WO 03/037327 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • One such compound is (25,45)-l-[(25)-2-amino-3,3-bis(4- fluorophenyl)propanoyl]-4-fluoropyrrolidine-2-carbonitrile (Denagliptin).
  • Denagliptin is (25,45)-l-[(25)-2-amino-3,3-bis(4- fluorophenyl)propanoyl]-4-fluoropyrrolidine-2-carbonitrile
  • the DPP-IV inhibitor is selected from (25,45)-l-[(25)-2-amino-3,3-bis(4- fluorophenyl)propanoyl]-4-fluoropyrrolidine-2-carbonitrile, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • One salt disclosed is (25,45)-l-[(25)-2- amino-3,3-bis(4-fluorophenyl)propanoyl]-4-fluoropyrrolidine-2-carbonitrile /?-toluenesulfonic acid salt (also referred to as (25,45)-4-fluoro-l -[4-fluoro- -(4-fluorophenyl)-L-phenylalanyl]-2- pyrrolidinecarbonitrile /?-toluenesulfonic acid salt, or Denagliptin tosylate).
  • the DPP-IV inhibitor is (25,45)-l-[(25)-2-amino-3,3-bis(4- fluorophenyl)propanoyl]-4-fluoropyrrolidine-2-carbonitrile /?-toluenesulfonic acid salt:
  • Abbott disclosed a series of substituted pyrrolidinyl derivatives as DPP-IV inhibitors in international patent publication WO 2004/026822.
  • Some embodiments of the present invention include every combination of one or more compounds selected from the DPP-IV inhibitors disclosed in WO 2004/026822 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • One such compound is (2S,5R)-5-ethynyl-l - ⁇ N-(4-methyl-l -(4-carboxy-pyridin-2- yl)piperidin-4-yl)glycyl ⁇ pyrrolidine-2-carbonitrile.
  • the DPP-IV inhibitor is selected from (25,5R)-5-ethynyl-l - ⁇ N-(4-methyl-l -(4-carboxy-pyridin-2-yl)piperidin-4- yl)glycyl ⁇ pyrrolidine-2-carbonitrile, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • Abbott has further disclosed a series of substituted cyclohexanyl/cyclohexenyl derivatives as DPP-IV inhibitors in international patent publication WO 2007/027651.
  • Some embodiments of the present invention include every combination of one or more compounds selected from the DPP-IV inhibitors disclosed in WO 2007/027651 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • One such compound is (15,6R)-3- ⁇ [3- (trifluoromethyl)-5,6-dihydro[l ,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl ⁇ -6-(2,4,5- trifluorophenyl)cyclohex-3-en-l -amine.
  • the DPP-IV inhibitor is selected from (15,6R)-3- ⁇ [3-(trifluoromethyl)-5,6-dihydro[l ,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl]carbonyl ⁇ -6-(2,4,5-trifluorophenyl)cyclohex-3-en-l -amine, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • the biguanides are a class of drugs that stimulate anaerobic glycolysis, increase the sensitivity to insulin in the peripheral tissues, inhibit glucose absorption from the intestine, suppress of hepatic gluconeogenesis, and inhibit fatty acid oxidation.
  • biguanides include phenformin ((phenylethyl) biguanide), metformin (dimethylbiguanide), buformin
  • the pharmaceutical agent or said second pharmaceutical agent is a biguanide selected from the following biguanide:
  • the pharmaceutical agent or the second pharmaceutical agent is a biguanide selected from (phenylethyl)biguanide (chemical structure shown below) and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • the pharmaceutical agent or the second pharmaceutical agent is a biguanide selected from dimethylbiguanide (chemical structure shown below) and
  • the pharmaceutical agent or the second pharmaceutical agent is a biguanide selected from butylbiguanide (chemical structure shown below) and pharmaceutically acceptable salts, solvates, and hydrates thereof; the chemical structure is as follows:
  • the pharmaceutical agent or the second pharmaceutical agent is a biguanide selected from l-(p-chlorophenyl)-5-isopropylbiguanide (chemical structure shown below) and pharmaceutically acceptable salts, solvates, and hydrates thereof; the chemical structure is as follows:
  • the pharmaceutical agent or said second pharmaceutical agent is a biguanide selected from the following biguanides: metformin, phenformin, buformin, and proguanil.
  • the pharmaceutical agent or the second pharmaceutical agent is metformin.
  • the pharmaceutical agent or the second pharmaceutical agent is phenformin.
  • the pharmaceutical agent is buformin.
  • the pharmaceutical agent or the second pharmaceutical agent is proguanil.
  • a-Glucosidase inhibitors belong to the class of drugs which competitively inhibit digestive enzymes such as a-amylase, maltase, a-dextrinase, sucrase, etc. in the pancreas and or small intestine.
  • the reversible inhibition by a-glucosidase inhibitors retard, diminish or otherwise reduce blood glucose levels by delaying the digestion of starch and sugars.
  • a-glucosidase inhibitors include acarbose ((2R,3R,4R,5R)-4- ((2R,3R,4R,55,6R)-5-((2R,3R,45,55,6R)-3,4-dihydroxy-6-methyl-5-((15,4R,55,65)-4,5,6- trihydroxy-3-(hydroxymethyl)cyclohex-2-enylamino)tetrahydro-2H-pyran-2-yloxy)-3,4- dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yloxy)-2,3,5,6-tetrahydroxyhexanal), miglitol ((2R,3R,4R,55)-l -(2-hydroxyethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol), voglibose ((15,25,3R,45,55)-5-(l ,3-dihydroxy
  • the pharmaceutical agent or said second pharmaceutical agent is a ⁇ -glucosidase inhibitor selected from the following ⁇ -glucosidase inhibitors:
  • the pharmaceutical agent or the second pharmaceutical agent is a ⁇ -glucosidase inhibitor selected from (2R,3R,4R,5R)-4-((2R,3R,4R,55,6R)-5-((2R,3R,45,55,6R)- 3 ,4-dihydroxy-6-methyl-5 -((15,4R,55,65)-4,5 ,6-trihydroxy-3 -(hydroxymethyl)cyclohex-2- enylamino)tetrahydro-2H-pyran-2-yloxy)-3,4-dihydroxy-6-(hydroxymethyl)tetrahydro-2H- pyran-2-yloxy)-2,3,5,6-tetrahydroxyhexanal (chemical structure shown below) and
  • the pharmaceutical agent or the second pharmaceutical agent is a a-glucosidase inhibitor selected from (2R,3R,4R,5S)-l-(2-hydroxyethyl)-2- (hydroxymethyl)piperidine-3,4,5-triol (chemical structure shown below) and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • the pharmaceutical agent or the second pharmaceutical agent is a a-glucosidase inhibitor selected from (lS,2S,3R,4S,5S)-5-(l,3-dihydroxypropan-2-ylamino)-l- (hydroxymethyl)cyclohexane-l,2,3,4-tetraol (chemical structure shown below) and
  • the pharmaceutical agent or the second pharmaceutical agent is an alpha-glucosidase inhibitor selected from: acarbose, miglitol, and voglibose.
  • the pharmaceutical agent or the second pharmaceutical agent is acarbose.
  • the pharmaceutical agent or the second pharmaceutical agent is miglitol.
  • the pharmaceutical agent or the second pharmaceutical agent is voglibose. Insulin and Insulin Analogues
  • insulin analogue refers to the naturally occurring human hormone and insulin receptor ligands (i.e., synthetic insulin analogues). Insulin receptor ligands are structurally different from the natural human hormone, but have substantially the same activity as human insulin in terms of glycemic control.
  • an insulin analogue examples include, NPH insulin (also known as Humulin N, Novolin N, NPH Lletin II, and insulin isophane), insulin lispro (28B-L -lysine -29B-L-proline -insulin, wherein insulin is human insulin), insulin aspart (28B-L-aspartic acid-insulin, wherein insulin is human insulin), insulin glulisine (3B-L -lysine - 29B-L-glutamic acid-insulin, wherein insulin is human insulin), and insulin analogues known in the art.
  • NPH insulin also known as Humulin N, Novolin N, NPH Lletin II, and insulin isophane
  • insulin lispro 28B-L -lysine -29B-L-proline -insulin, wherein insulin is human insulin
  • insulin aspart 28B-L-aspartic acid-insulin, wherein insulin is human insulin
  • insulin glulisine 3B-L -lys
  • NPH insulin is marketed by Eli Lilly and Company under the name Humulin N, and is considered as an intermediate-acting insulin analogue given to help control the blood sugar level of those with diabetes.
  • Insulin lispro is marketed by Eli Lilly and Company under the name Humalog, and is considered a rapid 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 is sold under the trade name Apidra. Insulin glulisine is considered a rapid acting insulin analogue but shorter duration of action compared to human insulin.
  • the pharmaceutical agent or the second pharmaceutical agent is an insulin analogue selected from NPH insulin and pharmaceutically acceptable salts, solvates, and hydrates thereof. In some embodiments, the pharmaceutical agent or the second
  • the pharmaceutical agent is an insulin analogue selected from insulin lispro and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • the pharmaceutical agent or the second pharmaceutical agent is an insulin analogue selected from insulin aspart and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • the pharmaceutical agent or the second pharmaceutical agent is an insulin analogue selected from insulin glulisine and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • the sulfonylureas are drugs which promote secretion of insulin from pancreatic beta cells by transmitting signals of insulin secretion via receptors in the cell membranes.
  • Examples of a sulfonylurea include tolbutamide (Orinase, N-(butylcarbamoyl)-4- methylbenzenesulfonamide); acetohexamide (Dymelor, 4-acetyl-N-
  • glibenclamide also known as glyburide (Diabeta, Micronase, Glynase, 5-chloro-N-(4-(N- (cyclohexylcarbamoyl)sulfamoyl)phenethyl)-2-methoxybenzamide); glimepiride (Amaryl, 3- ethyl-4-methyl-N-(4-(N-((l r,4r)-4-methylcyclohexylcarbamoyl)sulfamoyl)phenethyl)-2-oxo- 2,5-dihydro-lH-pyrrole-l-carboxamide); gliclazide (Diamicron, N-
  • the pharmaceutical agent or the second pharmaceutical agent is a sulfonylurea selected from sulfonylureas:
  • the pharmaceutical agent or the second pharmaceutical agent is a sulfonylurea selected from N-(butylcarbamoyl)-4-methylbenzenesulfonamide (chemical structure shown below) and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • the pharmaceutical agent or the second pharmaceutical agent is a sulfonylurea selected from 4-acetyl-N-(cyclohexylcarbamoyl)benzenesulfonamide (chemical structure shown below) and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • the pharmaceutical agent or the second pharmaceutical agent is a sulfonylurea selected from N-(azepan-l-ylcarbamoyl)-4-methylbenzenesulfonamide (chemical structure shown below) and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • the pharmaceutical agent or the second pharmaceutical agent is a sulfonylurea selected from 4-chloro-N-(propylcarbamoyl)benzenesulfonamide (chemical structure shown below) and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • the pharmaceutical agent or the second pharmaceutical agent is a sulfonylurea selected from N-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-5- methylpyrazine-2-carboxamide (chemical structure shown below) and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • the pharmaceutical agent or the second pharmaceutical agent is a sulfonylurea selected from 5-chloro-N-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-2- methoxybenzamide (chemical structure shown below) and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • the pharmaceutical agent or the second pharmaceutical agent is a sulfonylurea selected from 3-ethyl-4-methyl-N-(4-(N-((lr,4r)-4- methylcyclohexylcarbamoyl)sulfamoyl)phenethyl)-2-oxo-2,5-dihydro- lH-pyrrole- 1 - carboxamide (chemical structure shown below) and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • the pharmaceutical agent or the second pharmaceutical agent is a sulfonylurea selected from N-(hexahydrocyclopenta[c]pyrrol-2(lH)-ylcarbamoyl)-4- methylbenzenesulfonamide (chemical structure shown below) and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • the pharmaceutical agent or the second pharmaceutical agent is a sulfonylurea selected from the following sulfonylureas and pharmaceutically acceptable salts, solvates, and hydrates thereof: glipizide, glimepiride, and glibenclamide.
  • the pharmaceutical agent or the second pharmaceutical agent is tolbutamide.
  • the pharmaceutical agent or the second pharmaceutical agent is acetohexamide.
  • the pharmaceutical agent or the second pharmaceutical agent is tolazamide.
  • the pharmaceutical agent or the second pharmaceutical agent is chlorpropamide.
  • the pharmaceutical agent or the second pharmaceutical agent is glipizide.
  • the pharmaceutical agent or the second pharmaceutical agent is glyburide.
  • the pharmaceutical agent is glimepiride.
  • the pharmaceutical agent or the second pharmaceutical agent is gliclazide.
  • Sodium-glucose transporter-2 (SGLT2) inhibitors belong to the class of drugs which inhibit the protein SGLT2 and the reabsorption of glucose in the kidney. The inhibition by SGLT2 inhibitors retard, diminish, or otherwise reduce the amount of glucose that is reabsorbed and therefore is eliminated in the urine.
  • 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,35,45,5R,65)-3,4,5-trihydroxy-6-(4-(4-isopropoxybenzyl)-l -isopropyl- 5-methyl-lH-pyrazol-3-yloxy)tetrahydro-2H-pyran-2-yl)methyl carbonate, GlaxoSmithKline), ASP1941 (Kotobuki/Astellas), canagliflozin ((25,3R,4R,55,6R)-2-(3-((5-(4- fluorophenyl
  • the pharmaceutical agent or the second pharmaceutical agent is a SGLT2 inhibitor selected from the following SGLT2 inhibitors:
  • the pharmaceutical agent or the second pharmaceutical agent is a sulfonylurea selected from (25,3R,4R,55,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (chemical structure shown below) and pharmaceutically acceptable
  • the pharmaceutical agent or the second pharmaceutical agent is a sulfonylurea selected from ethyl ((2R,35,45,5R,65)-3,4,5-trihydroxy-6-(4-(4-isopropoxybenzyl)- 1 -isopropyl-5-methyl- lH-pyrazol-3-yloxy)tetrahydro-2H-pyran-2-yl)methyl carbonate
  • the pharmaceutical agent or the second pharmaceutical agent is a sulfonylurea selected from ethyl ((2R,35,45,5R,65)-3,4,5-trihydroxy-6-(2-(4- methoxybenzyl)phenoxy)tetrahydro-2H-pyran-2-yl)methyl carbonate (chemical structure shown below) and pharmaceutically s thereof:
  • the pharmaceutical agent or the second pharmaceutical agent is a SGLT2 inhibitor selected from: dapagliflozin, remigliflozin, and sergliflozin.
  • the pharmaceutical agent or the second pharmaceutical agent is dapagliflozin.
  • the pharmaceutical agent or the second pharmaceutical agent is remigliflozin.
  • the pharmaceutical agent or the second pharmaceutical agent is sergliflozin.
  • Astellas and Kotobuki disclosed a series of SGLT2 inhibitors in international patent publication WO2004/080990. Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in WO2004/080990 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in WO2004/007517 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • One such compound is (2R,35,45,5R,65)-2-(hydroxymethyl)-6-(2-(4-methoxybenzyl)thiophen-3-yloxy)tetrahydro-2H- pyran-3,4,5-triol.
  • 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 pharmaceutically accept of:
  • Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in WO2005/012326 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • One such compound is (25,3R,4R,55,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol.
  • the SGLT2 inhibitor is selected from (25,3R,4R,55,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4- methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, and pharmaceutically acceptable salts, solvates,
  • Boehringer Ingelheim disclosed a series of SGLT2 inhibitors in international patent publication WO2005/092877. Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in WO2005/092877 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • Chugai disclosed a series of SGLT2 inhibitors in international patent publication WO2006/080421. Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in WO2006/080421 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • Lexicon disclosed a series of SGLT2 inhibitors in international patent publication WO2008/109591. Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in WO2008/109591 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • meglitinides promote secretion of insulin by binding to the pancreatic beta cells in a similar manner as sulfonylureas but at an alternative binding site.
  • meglitinides include Novo Nordisk's repaglinide (Prandin, (S)-2-ethoxy-4-(2-(3-methyl-l-(2-(piperidin-l- yl)phenyl)butylamino)-2-oxoethyl)benzoic acid), nateglinide (Starlix, (R)-2-((lr,4R)-4- isopropylcyclohexanecarboxamido)-3-phenylpropanoic acid), mitiglinide ((5)-2-benzyl-4- ((3aR,7a5)-lH-isoindol-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)-4-oxobutanoic acid), and the like.
  • the pharmaceutical agent or the second pharmaceutical agent is a meglitinide selected from the following meglitinides: (5)-2-ethoxy-4-(2-(3-methyl-l-(2- (piperidin-l-yl)phenyl)butylamino)-2-oxoethyl)benzoic acid; (R)-2-((lr,4R)-4- isopropylcyclohexanecarboxamido)-3-phenylpropanoic acid; (S)-2-benzyl-4-((3aR,7aS)-lH- isoindol-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)-4-oxobutanoic acid; and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • meglitinides selected from the following meglitinides: (5)-2-ethoxy-4-(2-(3-methyl-l-(2- (piperidin-l
  • the pharmaceutical agent or the second pharmaceutical agent is (5)-2-ethoxy-4-(2-(3 -methyl- 1 -(2-(piperidin- 1 -yl)phenyl)butylamino)-2-oxoethyl)benzoic acid (chemical structure shown below) and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • the pharmaceutical agent or the second pharmaceutical agent is a sulfonylurea selected from (R)-2-((lr,4R)-4-isopropylcyclohexanecarboxamido)-3- phenylpropanoic acid (chemical structure shown below) and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • the pharmaceutical agent or the second pharmaceutical agent is a sulfonylurea selected from (S)-2-benzyl-4-((3aR,7aS)-lH-isoindol-
  • the pharmaceutical agent or the second pharmaceutical agent is a meglitinide selected from the following meglitinides: repaglinide, nateglinide, mitiglinide, and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • the pharmaceutical agent or the second pharmaceutical agent is a meglitinide selected from repaglinide and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • the pharmaceutical agent or the second pharmaceutical agent is a meglitinide selected from nateglinide and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • the pharmaceutical agent or the second pharmaceutical agent is a meglitinide selected from mitiglinide and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • Thiazolidinediones belong to the class of drugs more commonly known as TZDs. These drugs act by binding to the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARy) activate transcription of a number of specific genes leading to a decrease in insulin resistance.
  • TZDs nuclear receptor peroxisome proliferator-activated receptor gamma
  • thiazolidinediones examples 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)thiazolidine-2,4-dione),
  • rivoglitazone (5-(4-((6-methoxy-l-methyl-lH-benzo[d]imidazol-2- yl)methoxy)benzyl)thiazolidine-2,4-dione), ciglitazone(5-(4-(( 1 - methylcyclohexyl)methoxy)benzyl)thiazolidine-2,4-dione), and thiazolidinediones known in the art.
  • the pharmaceutical agent or the second pharmaceutical agent is a meglitinide selected from: 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-lH- benzo[d]imidazol-2-yl)methoxy)benzyl)thiazolidine-2,4-dione; 5-(4-((l- methylcyclohexyl)methoxy)benzyl)thiazolidine-2,4-dione; and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • the pharmaceutical agent or the second pharmaceutical agent is 5-(4-(2-(methyl(pyridin-2-yl)amino)ethoxy)benzyl)thiazolidine-2,4-dione (chemical structure shown below) and ph ates thereof:
  • the pharmaceutical agent or the second pharmaceutical agent is 5-(4-(2-(5-ethylpyridin-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione (chemical structure shown below) and pharmaceutica thereof:
  • the pharmaceutical agent or the second pharmaceutical agent is 5-(4-((6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)methoxy)benzyl)thiazolidine-2,4-dione (chemical structure shown below) and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • the pharmaceutical agent or the second pharmaceutical agent is 5-(4-((6-methoxy- 1 -methyl- 1 H-benzo [d] imidazol-2-yl)methoxy)benzyl)thiazolidine-2,4-dione (chemical structure shown below) and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • the pharmaceutical agent or the second pharmaceutical agent is 5-(4-((l-methylcyclohexyl)methoxy)benzyl)thiazolidine-2,4-dione (chemical structure shown below) and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • the pharmaceutical agent or the second pharmaceutical agent is a thiazolidinedione selected from rosiglitazone and pharmaceutically acceptable salts, solvates, and hydrates thereof. In some embodiments, the pharmaceutical agent or the second
  • the pharmaceutical agent is a thiazolidinedione selected from pioglitazone and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • the pharmaceutical agent or the second pharmaceutical agent is a thiazolidinedione selected from troglitazone and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • the pharmaceutical agent or the second pharmaceutical agent is a thiazolidinedione selected from rivoglitazone and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • the pharmaceutical agent or the second pharmaceutical agent is a
  • thiazolidinedione selected from ciglitazone and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • Anti-diabetic peptide analogues are peptides that promote secretion of insulin by acting as an incretin mimetic, such as, GLP-1 and GIP.
  • examples of an anti-diabetic peptide analog include, exenatide, liraglutide, taspoglutide, and anti-diabetic peptides analogues know in the art.
  • the pharmaceutical agent or the second pharmaceutical agent is an anti-diabetic peptide analogue selected from: exenatide; liraglutide; and taspoglutide.
  • the pharmaceutical agent or the second pharmaceutical agent is exenatide.
  • the pharmaceutical agent or the second pharmaceutical agent is liraglutide.
  • the pharmaceutical agent or the second pharmaceutical agent is taspoglutide.
  • the pharmaceutical agent or the second pharmaceutical agent is L-histidylglycyl-L-a-glutamylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-a- aspartyl-L-leucyl-L-seryl-L-lysyl-L-glutaminyl-L-methionyl-L-a-glutamyl-L-a-glutamyl-L-a-glutamyl-L-a- glutamyl-L-alanyl-L-valyl-L-arginyl-L-leucyl-L-phenylalanyl-L-isoleucyl-L-a-glutamyl-L- tryptophyl-L-leucyl-L-lysyl-L-asparaginylglycyl-L-prolyl-L-seryl-L
  • the pharmaceutical agent or the second pharmaceutical agent is L-histidyl-L-alanyl-L-a-glutamylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-a- aspartyl-L-valyl-L-seryl-L-seryl-L-tyrosyl-L-leucyl-L-a-glutamylglycyl-L-glutaminyl-L-alanyl- L-alanyl-N6- [N-( 1 -oxohexadecyl)-L-a-glutamyl] -L-lysyl-L-a-glutamyl-L-phenylalanyl-L- isoleucyl-L-alanyl-L-tryptophyl-L-leucyl-L-valyl-L-arginylglyc
  • the pharmaceutical agent or the second pharmaceutical agent is
  • Triglycerides represent the major form of energy stored in eukaryotes. Disorders and/or imbalances in triglyceride metabolism are implicated in the pathogenesis of and increased risk for metabolic related disorders, such as, obesity, insulin resistance syndrome and type 2 diabetes, nonalcoholic fatty liver disease, and coronary heart disease.
  • Triglyceride biosynthesis and the resulting TG burden on tissues are largely controlled by two major pathways in humans. Both of these pathways converge at an intermediate diacylglycerols (DAG) which are subsequently converted to triglycerides through acylation by a fatty acid acyl-CoA catalyzed by the acyl-CoA:diacylglycerol acyltransferases (DGAT).
  • DAG diacylglycerols
  • DGAT consists of DGAT-1 and DGAT-2.
  • Inhibition of acyl-CoA:diacylglycerol acyltransferase-1 (DGAT-1) is one of the most advanced targets for altering lipid biosyntheis as evidenced by on going human clinical trials.
  • the pharmaceutical agent or said second pharmaceutical agent is a DGAT-1 inhibitor known in the art.
  • the pharmaceutical agent or said second pharmaceutical agent is a DGAT-1 inhibitor selected from the DGAT-1 inhibitors described in the following patent applications and pharmaceutically acceptable salts, solvates, and hydrates thereof: WO
  • the pharmaceutical agent or said second pharmaceutical agent is a DGAT-1 inhibitor selected from the following DGAT-1 inhibitors and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • ira «i-(4- ⁇ 4-[5-(6-trifluoromethyl-pyridin-3ylamino)-pyridin-2-yl]-phenyl ⁇ -cyclohexyl)- acetic acid (see Example 5-1, WO2007/126957 and Examples 1-10, WO2012/051488 for formulations related thereto; alternative name: 2-((lr,4r)-4-(4-(5-(6-(trifluoromethyl)pyridin-3- ylamino)pyridin-2-yl)phenyl)cyclohexyl)acetic acid); and
  • Another object of the present invention relates to radio-labeled compounds of the present invention that would be useful not only in radio-imaging but also in assays, both in vitro and in vivo, for localizing and quantitating GPR119 receptors in tissue samples, including human and for identifying GPR119 receptor ligands by inhibition binding of a radio-labeled compound. It is a further object of this invention to develop novel GPR119 receptor assays of which comprise such radio-labeled compounds.
  • the present disclosure includes all isotopes of atoms occurring in the present compounds, intermediates, salts and crystalline forms thereof.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • One aspect of the present invention includes every combination of one or more atoms in the present compounds, intermediates, salts, and crystalline forms thereof that is replaced with an atom having the same atomic number but a different mass number.
  • One such example is the replacement of an atom that is the most naturally abundant isotope, such as l H or 12 C, found in one the present compounds,
  • Isotopic-labeling of the present compounds, intermediates, salts, and crystalline forms thereof can be accomplished using any one of a variety of different synthetic methods know to those of ordinary skill in the art and they are readily credited with understanding the synthetic methods and available reagents needed to conduct such isotopic- labeling.
  • isotopes of hydrogen include 2 H (deuterium) and 3 H (tritium).
  • Isotopes of carbon include n C, 13 C, and 14 C.
  • Isotopes of nitrogen include 13 N and 15 N.
  • Isotopes of oxygen include 15 O, 17 O, and 18 C.
  • An isotope of fluorine includes 18 F.
  • An isotope of sulfur includes 35 S.
  • An isotope of chlorine includes 36 C1.
  • Isotopes of bromine include 75 Br, 76 Br, 77 Br, and 82 Br.
  • Isotopes of iodine include 123 I, 124 I, 125 I, and 131 I.
  • compositions such as, those prepared during synthesis, preformulation, and the like, and pharmaceutical compositions, such as, those prepared with the intent of using in a mammal for the treatment of one or more of the disorders described herein, comprising one or more of the present compounds, intermediates, salts, and crystalline forms thereof, wherein the naturally occurring distribution of the isotopes in the composition is perturbed.
  • compositions and pharmaceutical compositions comprising compounds as described herein wherein the compound is enriched at one or more positions with an isotope other than the most naturally abundant isotope.
  • isotopically-labeled compounds of the present invention are useful in compound and/or substrate tissue distribution assays.
  • the radionuclide 3 H and/or 14 C isotopes are useful in these studies.
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability
  • Isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Drawings and Examples infra, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. Other synthetic methods that are useful are discussed infra. Moreover, it should be understood that all of the atoms represented in the compounds of the invention can be either the most commonly occurring isotope of such atoms or the scarcer radio-isotope or nonradioactive isotope.
  • Synthetic methods for incorporating radio-isotopes into organic compounds are applicable to 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 Tritium Gas: This procedure normally yields high specific activity products and requires halogenated or unsaturated precursors.
  • Tritium Gas Exposure Labeling This procedure involves exposing precursors containing exchangeable protons to tritium gas in the presence of a suitable catalyst.
  • Synthetic methods for incorporating activity levels of 125 I into target molecules include:
  • Aryl and heteroaryl bromide exchange with 125 I This method is generally a two step process.
  • the first step is the conversion of the aryl or heteroaryl bromide to the corresponding tri-alkyltin intermediate using for example, a Pd catalyzed reaction [i.e. Pd(Ph 3 P) 4 ] or through an aryl or heteroaryl lithium, in the presence of a tri-alkyltinhalide or hexaalkylditin [e.g., (CH 3 ) 3 SnSn(CH 3 )3] .
  • Pd catalyzed reaction i.e. Pd(Ph 3 P) 4
  • a tri-alkyltinhalide or hexaalkylditin e.g., (CH 3 ) 3 SnSn(CH 3 )3
  • a radiolabeled GPR119 receptor compound of Formula (I) can be used in a screening assay to identify/evaluate compounds.
  • a newly synthesized or identified compound i.e., test compound
  • test compound can be evaluated for its ability to reduce binding of the "radiolabeled compound of Formula (I)" to a GPR119 receptor. Accordingly, the ability of a test compound to compete with the "radio-labeled compound of Formula (I)" for the binding to a GPR119 receptor directly correlates to its binding affinity.
  • Certain labeled compounds of the present invention bind to certain GPR119 receptors.
  • the labeled compound has an IC 50 less than about 500 ⁇ , in another embodiment the labeled compound has an IC 50 less than about 100 ⁇ , in yet another embodiment the labeled compound has an IC 50 less than about 10 ⁇ , in yet another embodiment the labeled compound has an IC 50 less than about 1 ⁇ and in still yet another embodiment the labeled inhibitor has an IC 50 less than about 0.1 ⁇ .
  • Example 1 Syntheses of Compounds of the Present Invention.
  • TLC Thin-layer chromatography
  • PK6F silica gel 60 A 1 mm plates (Whatman) and column chromatography was carried out on a silica gel column using Kieselgel 60, 0.063-0.200 mm (Merck). Evaporation was done under reduced pressure on a Biichi rotary evaporator.
  • Example 1.1 Preparation of (lR,3s,5S)-tert-butyl 3-((ls,4S)-4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate and (IR,3s,5S)-tert-butyl 3-((lr,4/?)-4- hydroxycyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate.
  • Step A Preparation of (lR,3s,5S)-tert-Butyl 3-(4-(benzyloxy)phenoxy)-8- azabicyclo[3.2.1]octane-8-carboxylate.
  • triphenylphosphine (10.31 g, 39.30 mmol) in anhydrous THF (12 mL) was added triethylamine (4.979 mL, 35.72 mmol).
  • the reaction mixture was cooled down in an ice-water bath under an atmosphere of argon and DIAD (7.293 mL, 37.51 mmol) was added dropwise to the stirred solution.
  • the reaction mixture was slowly allowed to warm to room temperature and stirred over the weekend.
  • the white solid was filtered off to give the title compound (3.021 g).
  • the filtrate was partly concentrated and CH 3 CN was added to provide a white precipitate that was collected to give another portion of the title compound (6.468 g).
  • Step B Preparation of (lR,3s,5S)-tert-Butyl 3-(4-hydroxyphenoxy)-8- azabicyclo[3.2.1]octane-8-carboxylate.
  • Step C Preparation of (lR,3s,5S)-tert-Butyl 3-((ls,4S)-4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate and (lR,3s,5S)-tert-butyl 3-((lr,4/?)-4- hydroxycyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate.
  • Example 1.2 Preparation of (lR,3r,5S)-tert-butyl 3-(4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate.
  • Example 1.3 Preparation of (lR,3r,5S)-tert-butyl 3-(4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate.
  • Step A Preparation of l-(benzyloxy)-4-fluorobenzene.
  • Step B Preparation of (lR,3r,5S)-tert-butyl 3-(4-(benzyloxy)phenoxy)-8- azabicyclo[3.2.1]octane-8-carboxylate.
  • Residue was purified by BiotageTM column chromatography (Si0 2 , hexane/ AcOEt gradient) to give (lR,3r,55)-teri-butyl 3-(4-(benzyloxy)phenoxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (0.34 g, 0.830 mmol, 18.9%) as a white solid.
  • Step C Preparation of (lR,3r,5S)-tert-butyl 3-(4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate.
  • Example 1.4 Preparation of (l/?,3S,5S)-((S)-l,l,l-Trifluoropropan-2-yl) 3-((lr,4fl)-4-(3- Cyanopyridin-4-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 5).
  • Step A Preparation of (lR,3r,5S)-tert-butyl 3-((lr,4/?)-4-(3-cyanopyridin-4- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 2) and (lR,3r,5S)- tert-Butyl 3-((ls,4S)-4-(3-Cyanopyridin-4-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8- carboxylate.
  • Residue was purified by BiotageTM column chromatography (Si0 2 , hexane/AcOEt gradient). Fractions containing the less polar isomer were concentrated and the residue was re-purified by HPLC (CH 3 CN/H 2 0 gradient + 0.1 % TFA). Fractions containing pure product were partly concentrated and the residue was extracted with 1 M NaOH and CH 2 C1 2 .
  • Step B Preparation of 4-((l ?,4r)-4-((l ?,3r,5S)-8-Azabicyclo[3.2.1]octan-3- yloxy)cyclohexyloxy)nicotinonitrile Dihydrochloride.
  • Step C Preparation of (lfl,3S,5S)-((S)-l,l,l-Trifluoropropan-2-yl) 3-((lr,4/?)-4-(3- cyanopyridin-4-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 5).
  • Example 1.5 Preparation of (lR,3s,5S)-tert-butyl 3-((lr,4/?)-4-(3-Cyanopyridin-4- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 1).
  • Example 1.6 Preparation of (lfl,3fl,5S)-((S)-l,l,l-trifluoropropan-2-yl) 3-((lr,4fl)-4-(3- cyanopyridin-4-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 3).
  • Step A Preparation of 4-((l ?,4r)-4-((l ?,3s,5S)-8-azabicyclo[3.2.1]octan-3- yloxy)cyclohexyloxy)nicotinonitrile dihydrochloride.
  • Step B Preparation of (lfl,3fl,5S)-((S)-l,l,l-trifluoropropan-2-yl) 3-((lr,4fl)-4-(3- cyanopyridin-4-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate .
  • Example 1.7 Preparation of (lfl,3S,5S)-((fl)-l,l,l-Trifluoropropan-2-yl) 3-((lr,4/?)-4-(3- Cyanopyridin-4-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 4).
  • Example 1.8 Preparation of (lR,3s,5S)-tert-butyl 3-((lr,4fl)-4-(3,5-difluoropyridin-4- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 6).
  • Example 1.9 Preparation of 4-((l ?,4r)-4-((l ?,3s,5S)-8-(5-Chloropyrimidin-2-yl)-8- azabicyclo[3.2.1]octan-3-yloxy)cyclohexyloxy)nicotinonitrile (Compound 7).
  • Step A Preparation of 2-chloro-5-fluoronicotinonitrile.
  • Step B Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4/?)-4-(3-cyano-5-fluoropyridin- 2-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate .
  • Step A Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4/?)-4-(5-bromo-3- methylpyrazin-2-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate
  • Step B Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4fl)-4-(3-methyl-5- (methylsulfonyl)pyrazin-2-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate.
  • Step A Preparation of (lR,3s,5S)-tert-butyl 3-((lr,4fl)-4-(2-fluoro-4-
  • Step B Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4/?)-4-(4-(dimethylcarbamoyl)-2- fluorophenoxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate
  • Step A Preparation of (lR,3s,5S)-tert-butyl 3-((lr,4fl)-4-(5-bromopyridin-2- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate.
  • Step B Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4/?)-4-(5- (methylsulfonyl)pyridin-2-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate
  • Step A Preparation of (lvP,3 ⁇ f,5J)- i?/"/-Butyl 3-((l/",4v ⁇ )-4-(5-bromopyrimidin-2- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 18).
  • Step B Preparation of 3-((l/-,4A -4-(5- (methylsulfonyl)pyrimidin-2-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate
  • the mixture was stirred at room temperature for 17 h.
  • the reaction was not complete and thus more reagents (0.5 eq of 4 reagents) were added.
  • the reaction was continued to stir at room temperature for 2 h.
  • the reaction mixture was concentrated in vacuo and purified by preparative HPLC. Pure fractions were combined, neutralized with saturated sodium bicarbonate (aq), and evaporated MeCN to form a solid. The solid was collected, washed with water, and dried under reduced pressure to give the title compound (16.2 mg, 33.71 ⁇ , 11.0%) as a white solid.

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Abstract

The present invention relates to compounds of Formula (I) and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof,that are useful as single pharmaceutical agents or in combination with one or more additional pharmaceutical agents, such as, an inhibitor of DPP-IV, a biguanide, an alpha-glucosidase inhibitor, an insulin analogue, a sulfonylurea, an SGLT2 inhibitor, a meglitinide, a thiazolidinedione, or an anti-diabetic peptide analogue, in the treatment of, for example, a disorder selected from: a GPR119-receptor-related disorder; a condition ameliorated by increasing secretion of an incretin; a condition ameliorated by increasing a blood incretin level; a condition characterized by low bone mass; a neurological disorder; a metabolic-related disorder; type 2 diabetes; obesity; and complications related thereto.

Description

MODULATORS OF THE GPR119 RECEPTOR AND THE TREATMENT OF DISORDERS RELATED THERETO
FIELD OF THE INVENTION
The present invention relates to compounds of Formula (I) and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof, that are useful as single
pharmaceutical agents or in combination with one or more additional pharmaceutical agents, such as, an inhibitor of DPP-IV, a biguanide, an alpha-glucosidase inhibitor, an insulin analogue, a sulfonylurea, an SGLT2 inhibitor, a meglitinide, a thiazolidinedione, or an antidiabetic peptide analogue, in the treatment of, for example, a disorder selected from: a GPR119- receptor-related disorder; a condition ameliorated by increasing secretion of an incretin; a condition ameliorated by increasing a blood incretin level; a condition characterized by low bone mass; a neurological disorder; a metabolic -related disorder; type 2 diabetes; obesity; and complications related thereto.
BACKGROUND OF THE INVENTION
A. Diabetes Mellitus
Diabetes mellitus is a serious disease afflicting over 100 million people worldwide. In the United States, there are more than 12 million diabetics, 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. There are many types of diabetes, but the two most common are type 1 (also referred to as insulin-dependent diabetes mellitus or IDDM) and type 2 (also referred to as non-insulin-dependent diabetes mellitus or NIDDM).
The etiology of the different types of diabetes is not the same; however, everyone with diabetes has two things in common: overproduction of glucose by the liver and little or no ability to move glucose out of the blood into the cells where it becomes the body's primary fuel.
People who do not have diabetes rely on insulin, a hormone made in the pancreas, to move glucose from the blood into the cells of the body. However, people who have diabetes either don't produce insulin or can't efficiently use the insulin they produce; therefore, they can't move glucose into their cells. Glucose accumulates in the blood creating a condition called hyperglycemia, and over time, can cause serious health problems.
Diabetes is a syndrome with interrelated metabolic, vascular, and neuropathic components. The metabolic syndrome, generally characterized by hyperglycemia, comprises alterations in carbohydrate, fat and protein metabolism caused by absent or markedly reduced insulin secretion and/or ineffective insulin action. The vascular syndrome consists of abnormalities in the blood vessels leading to cardiovascular, retinal and renal complications. Abnormalities in the peripheral and autonomic nervous systems are also part of the diabetic syndrome.
About 5% to 10% of the people who have diabetes have IDDM. These individuals don't produce insulin and therefore must inject insulin to keep their blood glucose levels normal. IDDM is characterized by low or undetectable levels of endogenous insulin production caused by destruction of the insulin-producing β cells of the pancreas, the characteristic that most readily distinguishes IDDM from NIDDM. IDDM, once termed juvenile-onset diabetes, strikes young and older adults alike.
Approximately 90 to 95% of people with diabetes have type 2 (or NIDDM). NIDDM subjects produce insulin, but the cells in their bodies are insulin resistant: the cells don't respond properly to the hormone, so glucose accumulates in their blood. NIDDM is characterized by a relative disparity between endogenous insulin production and insulin requirements, leading to elevated blood glucose levels. In contrast to IDDM, there is always some endogenous insulin production in NIDDM; many NIDDM patients have normal or even elevated blood insulin levels, while other NIDDM patients have inadequate insulin production (Rotwein, R. et al. N. Engl. J.
Med. 308, 65-71 (1983)). Most people diagnosed with NIDDM are age 30 or older, and half of all new cases are age 55 and older. Compared with whites and Asians, NIDDM is more common among Native Americans, African- Americans, Latinos, and Hispanics. In addition, the onset can be insidious or even clinically unapparent, making diagnosis difficult.
The primary pathogenic lesion on NIDDM has remained elusive. Many have suggested that primary insulin resistance of the peripheral tissues is the initial event. Genetic epidemiological studies have supported this view. Similarly, insulin secretion abnormalities have been argued as the primary defect in NIDDM. It is likely that both phenomena are important contributors to the disease process (Rimoin, D. L., et. al. Emery and Rimoin's Principles and Practice of Medical Genetics 3ri Ed. 1: 1401-1402 (1996)).
Many people with NIDDM have sedentary lifestyles and are obese: they weigh approximately 20% more than the recommended weight for their height and build. Furthermore, obesity is characterized by hyperinsulinemia and insulin resistance, a feature shared with NIDDM, hypertension and atherosclerosis.
The patient with diabetes faces a 30% reduced lifespan. After age 45, people with diabetes are about three times more likely than people without diabetes to have significant heart disease and up to five times more likely to have a stroke. These findings emphasize the inter-relations between risks factors for NIDDM and coronary heart disease and the potential value of an integrated approach to the prevention of these conditions (Perry, I. J., et al, BMJ 310, 560-564 (1995)).
Diabetes has also been implicated in the development of kidney disease, eye diseases and nervous-system problems. Kidney disease, also called nephropathy, occurs when the kidney's "filter mechanism" is damaged and protein leaks into urine in excessive amounts and eventually the kidney fails. Diabetes is also a leading cause of damage to the retina at the back of the eye and increases risk of cataracts and glaucoma. Finally, diabetes is associated with nerve damage, especially in the legs and feet, which interferes with the ability to sense pain and contributes to serious infections. Taken together, diabetes complications are one of the nation's leading causes of death.
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 has increased from 25% at the end of the 1970's, to 33% at the beginning the 1990's. Obesity is one of the most important risk factors for NIDDM. Definitions of obesity differ, but in general, a subject 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 with NIDDM are overweight.
Obesity, which is the result of an imbalance between caloric intake and energy expenditure, is highly correlated with insulin resistance and diabetes in experimental animals and human.
However, the molecular mechanisms that are involved in obesity-diabetes syndromes are not clear. During early development of obesity, increased insulin secretion balances 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 non-insulin-dependent diabetes develops in about 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 its high prevalence in modern societies, obesity has thus become the leading risk factor for NIDDM (Hill, J. O., et al, Science 280, 1371-1374 (1998)). However, the factors which predispose a fraction of patients to alteration of insulin secretion in response to fat accumulation remain unknown.
Whether someone is classified as overweight or obese can be determined by a number of different methods, such as, on the basis of their body mass index (BMI) which is calculated by dividing body weight (kg) by height squared (m2). Thus, the units of BMI are kg/m2 and it is possible to calculate the BMI range associated with minimum mortality in each decade of life. Overweight is defined as a BMI in the range 25-30 kg/m2, and obesity as a BMI greater than 30 kg/m2 (see table below). There are problems with this definition in that it does not take into account the proportion of body mass that is muscle in relation to fat (adipose tissue). To account for this, alternately, obesity can be defined on the basis of body fat content: greater than 25% and 30% in males and females, respectively.
CLASSIFICATION OF WEIGHT BY BODY MASS INDEX (BMI)
BMI CLASSIFICATION
< 18.5 Underweight
18.5 - 24.9 Normal
25.0 - 29.9 Overweight 30.0 - 34.9 Obesity (Class I)
35.0 - 39.9 Obesity (Class II)
> 40 Extreme Obesity (Class III)
As the BMI increases there is an increased risk of death from a variety of causes that is independent of other risk factors. The most common diseases with obesity are cardiovascular disease (particularly hypertension), diabetes (obesity aggravates the development of diabetes), gall bladder disease (particularly cancer) and diseases of reproduction. Research has shown that even a modest reduction in body weight can correspond to a significant reduction in the risk of developing coronary heart disease.
Obesity considerably increases the risk of developing cardiovascular diseases as well. Coronary insufficiency, atheromatous disease, and cardiac insufficiency are at the forefront of the cardiovascular complication induced by obesity. It is estimated that if the entire population had an ideal weight, the risk of coronary insufficiency would decrease by 25% and the risk of cardiac insufficiency and of cerebral vascular accidents by 35%. The incidence of coronary diseases is doubled 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 cholesterol deposition and monocyte infiltration into the subendothelial space, resulting in foam cell formation. Thrombosis subsequent to atherosclerosis leads to myocardial infarction and stroke. Atherosclerosis is the leading cause of mortality in many countries, including the United States. (See, e.g., 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 the loss of bone mass and microarchitectural deterioration of skeletal structure leading to compromised bone strength, which predisposes a patient to increased risk of fragility 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 alone. In the United States, osteoporosis affects at least 25% of all post-menopausal white women, and the proportion rises to 70% in women older than 80 years. One in three women older than 50 years will have an osteoporotic fracture that causes a considerable social and financial burden on society. The disease is not limited to women; older men also can be affected. By 2050, the worldwide incidence of hip fracture in men is projected to increase by 310% and 240% in women. The combined lifetime risk for hip, forearm, and vertebral fractures presenting clinically is around 40%, equivalent to the risk for cardiovascular disease. Osteoporotic fractures therefore cause substantial mortality, morbidity, and economic cost. With an ageing population, the number of osteoporotic fractures and their costs will at least double in the next 50 years unless effective preventive strategies are developed. (See, e.g., 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 (IBD) is the general name for diseases that cause inflammation in the intestines and includes, e.g. Crohn's disease, ulcerative colitis, ulcerative proctitis. U.S. medical costs of inflammatory bowel disease for 1990 have been estimated to be $1.4 to $1.8 billion. Lost productivity has been estimated to have added an additional $0.4 to $0.8 billion, making the estimated cost of inflammatory bowel disease $1.8 to $2.6 billion. (See, e.g. , 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 intestine, especially the small intestine, a general condition that can have any of numerous different causes. Enterocolitis refers to inflammation of the small intestine and colon.
Crohn's disease (CD) is an inflammatory process that can affect any portion of the digestive tract, but is most commonly seen in the last part of the small intestine otherwise called the (terminal) ileum and cecum. Altogether this area is also known as the ileocecal region. Other cases may affect one or more of: the colon only, the small bowel only (duodenum, jejunum and/or ileum), the anus, stomach or esophagus. In contrast with ulcerative colitis, CD usually does not affect the rectum, but frequently affects the anus instead. The inflammation extends deep into the lining of the affected organ. The inflammation can cause pain and can make the intestines empty frequently, resulting in diarrhea. Crohn's disease may also be called enteritis. Granulomatous colitis is another name for Crohn's disease that affects the colon. Ileitis is CD of the ileum which is the third part of the small intestine. Crohn's colitis is CD affecting part or all of the colon.
Ulcerative colitis (UC) is an inflammatory disease of the large intestine, commonly called the colon. UC causes inflammation and ulceration of the inner lining of the colon and rectum. The inflammation of UC is usually most severe in the rectal area with severity diminishing (at a rate that varies from patient to patient) toward the cecum, where the large and small intestine join. Inflammation of the rectum is called proctitis. Inflammation of the sigmoid colon (located just above the rectum) is called sigmoiditis. Inflammation involving the entire colon is termed pancolitis. The inflammation causes the colon to empty frequently resulting in diarrhea. As the lining of the colon is destroyed ulcers form releasing mucus, pus and blood. Ulcerative proctitis is a form of UC that affects only the rectum.
F. GPR119
GPR119 is a G protein-coupled receptor (GPR119; e.g. , human GPR119, GenBank® Accession No. AAP72125 and alleles thereof; e.g. , mouse GPR119, GenBank® Accession No. AY288423 and alleles thereof) and is selectively expressed on pancreatic beta cells. GPR119 activation leads to elevation of a level of intracellular cAMP, consistent with GPR119 being coupled to Gs. Agonists to GPR119 stimulate glucose-dependent insulin secretion in vitro and lower an elevated blood glucose level in vivo; see, e.g. , International Applications WO
04/065380 and WO 04/076413, and EP 1338651, the disclosure of each of which is herein incorporated by reference in its entirety. In the literature, GPR119 has also been referred to as RUP3 (see, International Application WO 00/31258) and as 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): 1339-1359); for specific references related to GPR119 agonists and the release of:
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 αΙ., Αηη. 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 enhance incretin release and therefore can be used in treatment of disorders related to the incretins, such as, GIP, GLP-1, and PYY. However, a number of the incretins, such as, GIP and GLP-1, are substrates for the enzyme DPP-IV. Jones and co-workers (Jones, et αΙ., Αηη. Rep. Med. Chem., (2009) 44: 149-170) have demonstrated that a combined administration of a GPR119 agonist, (2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4- (3-isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin-l-yl]-5-nitro-pyrimidin-4-yl} -amine (see, compound B 111 in WO 2004/065380), and a DPP-IV inhibitor acutely increased plasma GLP-1 levels and improved glucose tolerance to a significantly greater degree than either agent alone.
G. Glucose-dependent Insulinotropic Polypeptide (GIP)
Glucose-dependent insulinotropic polypeptide (GIP, also known as gastric inhibitory polypeptide) is a peptide incretin hormone of 42 amino acids that is released from duodenal endocrine K cells after meal 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.
As GIP contains an alanine at position 2, it is an excellent substrate for dipeptidyl peptidase-4 (DPP-IV), an enzyme regulating the degradation of GIP. Full-length GIP(l-42) is rapidly converted to bioinactive GIP(3-42) within minutes of secretion from the gut K cell. Inhibition of DPP-IV has been shown to augment GIP bioactivity. (See, e.g. , 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 bioactive GIP, for example in blood, can be carried out using N-terminal-specific assays (see, e.g. , Deacon et al, J Clin Endocrinol Metab (2000) 85:3575-3581).
Recently, GIP has been shown to promote bone formation. GIP has been shown to activate osteoblastic receptors, resulting in increases in 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. GIP administration has been shown to prevent the bone loss due to ovariectomy. GIP receptor (GIPR) knockout mice evidence a decreased bone size, lower bone mass, altered bone microarchitecture and biochemical properties, and altered parameters for bone turnover, especially in bone formation. (See, e.g., Zhong et al, Am J Physiol Endocrinol Metab (2007) 292:E543-E548; Bollag et al , Endocrinology (2000) 141 : 1228-1235; Bollag et al, Mol Cell Endocrinol (2001) 177:35-41 ; Xie et al , Bone (2005) 37:759-769; and Tsukiyama et al, Mol Endocrinol (2006) 20: 1644-1651.)
The usefulness of GIP for maintaining or increasing bone density or formation has been acknowledged by the United State Trademark and Patent Office by issuance of United States Patent No. 6,410,508 for the treatment of reduced bone mineralization by administration of GIP peptide. However, current GIP peptide agonists suffer from a lack of oral bioavailability, negatively impacting patient compliance. An attractive alternative approach is to develop an orally active composition for increasing an endogenous level of GIP activity.
H. Glucagon-Like Peptide-1 (GLP-1)
Glucagon-like peptide-1 (GLP-1) is an incretin hormone derived from the
posttranslaltional modification of proglucagon and secreted by gut endocrine cells. GLP-1 mediates its actions through a specific G protein-coupled receptor (GPCR), namely GLP-1R. GLP-1 is best characterized as a hormone that regulates glucose homeostasis. GLP-1 has been shown to stimulate glucose-dependent insulin secretion and to increase pancreatic beta cell mass. GLP-1 has also been shown to reduce the rate of gastric emptying and to promote satiety. The efficacy of GLP-1 peptide agonists in controlling blood glucose in Type 2 diabetics has been demonstrated in several clinical studies [see, e.g. , Nauck et al, Drug News Perspect (2003) 16:413-422], as has its efficacy in reducing body mass [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 be cardioprotective in a rat model of myocardial infarction [Bose et al, Diabetes (2005) 54: 146- 151], and GLP-1 R 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 αΙ. , Αηη N Y Acad Sri (2004) 1035:290-315]. Certain disorders such as Type 2 diabetes are characterized by a deficiency in GLP-1 [see, e.g. , Nauck et al , Diabetes (2004) 53 Suppl 3:S190-196].
Current GLP-1 peptide agonists suffer from a lack of oral bioavailability, negatively impacting patient compliance. Efforts to develop orally bioavailable non-peptidergic, small- molecule agonists of GLP-1 R have so far been unsuccessful [Mentlein, Expert Opin Investig Drugs (2005) 14:57-64]. An attractive alternative approach is to develop an orally active composition for increasing an endogenous level of GLP-1 in the blood.
I. Peptide YY (PYY)
Peptide YY (PYY) 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 within both the large and small intestine. It has been shown that in rat and human gut concentrations of immunoreactive PYY are low in duodenum and jejunum, high in ileum and colon, and highest in 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 rat been reported to also extend to alpha cells of the islets of Langerhans and to cells in the medulla oblongata (Ekblad et al, Peptides (2002) 23:251-261 ; PYY is released into the circulation as PYYi_36 and PYY3.36 (Eberlein et al, Peptides (1989) 10:797-803). PYY3-36 is generated from PYYi_36 by cleavage of the N-terminal Tyr and Pro residues by dipeptidyl peptidase IV. PYY3.36 is the predominant form of PYY in human postprandial plasma (Grandt et al, Regul. Pept. (1994) 51 : 151-159). PYYi-36 and PYY3.36 have been reported to have comparable agonist activity at NPY Y2 receptor (Y2R), a G protein- coupled receptor (Parker et al, Br. J. Pharmacol. (2008) 153:420-431); however, PYY3.36 has been reported to be a high-affinity Y2R selective agonist (Keire et al, Am. J. Physiol.
Gastrointest. Liver Physiol. (2000) 279:G126-G131). PYY was subsequently reported to reduce high-fat food intake in rats after peripheral administration (Okada et al, Endocrinology
Supplement (1993) 180) and to cause weight loss in mice after peripheral administration (Morley et al, Life Sciences (1987) 41:2157-2165).
Peripheral administration of PYY3.36 has been reported to markedly reduce food intake and weight gain in rats, to decrease appetite and food intake in humans, and to decrease food intake in mice, but not in Y2R-null mice, which was said to suggest that the food intake effect requires the Y2R. In human studies, infusion of PYY3.36 was found to significantly decrease appetite and reduce food intake by 33% over 24 hours. Infusion of PYY3.36 to reach the normal postprandial circulatory concentrations of the peptide led to peak serum levels of PYY3.36 within 15 minutes, followed by a rapid decline to basal levels within 30 minutes. It was reported that there was significant inhibition of food intake in the 12-hour period following the PYY3.36 infusion, but was essentially no effect on food intake in the 12-hour to 24-hour period. In a rat study, repeated administration of PYY3.36 intraperitoneally (injections 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 PYY3.36 has been reported to reduce food intake, body weight gain and glycemic indices in diverse rodent models of metabolic diseases of both sexes (Pittner et al, Int. J. Obes. Relat. Metab. Disord. (2004) 28:963-971). It has been reported that blockade of Y2R with the specific antagonist BIIE-246 attenuates the effect of peripherally administered endogenous and exogenous PYY3_36 for reducing food intake (Abbott et al, Brain Res (2005) 1043: 139-144). It has been reported that peripheral administration of a novel long- acting selective Y2R polyethylene gly col-conjugated peptide agonist reduces food intake and improves glucose metabolism (glucose disposal, 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). It has been reported that peripheral administration of a long-acting, potent and highly selective Y2R agonist inhibits food intake and promotes fat metabolism in mice (Balasubramaniam et al, Peptides (2007) 28:235-240).
There is evidence that agents which stimulate PYY synthesis in vivo can confer protection against diet-induced and genetic obesity and can improve glucose tolerance (Boey et al, Neuropeptides (2008) 42: 19-30).
It has been reported that Y2R agonists such as PYY1 36 and PYY3.36 can confer protection against epileptic seizures, such as against kainate seizures (El Bahh et al, Eur. J.
Neurosci. (2005) 22: 1417-1430; Woldbye et al, Neurobiology of Disease (2005) 20:760-772).
It has been reported that Y2R agonists such as PYY1 36 and PYY3.36 act as proabsorbtive (or anti-secretory) hormones, increasing upon intravenous administration the absorption of both water and sodium in various parts of the bowel (Bilchik et al, Gastroenterol. (1993) 105: 1441- 1448; Liu et al, J. Surg. Res. (1995) 58:6-11 ; Nightingale et al, Gut (1996) 39:267-272; Liu et al, Am Surg (1996) 62:232-236; Balasubramaniam et al, J. Med. Chem. (2000) 43:3420-3427). It has been reported that Y2R agonists such as PYY analogues inhibit secretion and promote absorption and growth in the intestinal epithelium (Balasubramaniam et al, J. Med. Chem.
(2000) 43:3420-3427). It has been reported that PYY promotes intestinal growth in normal rats (Gomez et al, Am. J. Physiol. (1995) 268:G71-G81). It has been reported that Y2R agonists such as PYYi_36 and PYY3.36 inhibit bowel motility and work to prevent diarrhea (EP1902730; also see Cox, Peptides (2007) 28:345-351).
It has been reported that Y2R agonists such as PYY1 36 and PYY3.36 can confer protection against inflammatory bowel disease such as ulcerative colitis and Crohn's disease (WO 03/105763). It has been reported that PYY-deficient mice exhibit an osteopenic phenotype, i.e. that PYY can increase bone mass and/or can confer protection against loss of bone mass (e.g. , decreases loss of bone mass) (Wortley et al, Gastroenterol. (2007) 133: 1534-1543). It has been reported that PYY3.36 can confer protection in rodent models of pancreatitis (Vona-Davis et al, Peptides (2007) 28:334-338).
It has been reported that angiogenesis is impaired in Y2R-deficient mice (Lee et al, Peptides (2003) 24:99-106), i.e. that agonists of Y2R such as PYYi_36 and PYY3.36 promote angiogenesis. It has been reported that would healing is impaired in Y2R-deficient mice
(Ekstrand et al, PNAS USA (2003) 100:6033-6038), i.e. that agonists of Y2R such as PYYi_36 and PYY3.36 promote wound healing. It has been reported that ischemic angiogenesis is impaired in Y2R-deficient mice (Lee et al, J. Clin. Invest. (2003) 111 : 1853-1862), i.e. that agonists of Y2R such as PYYi_36 and PYY3.36 promotes revascularization and restoration of function of ischemic tissue. It has been reported that agonists of Y2R such as PYYi_36 and PYY3.36 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 PYY3.36 can suppress tumor growth in the cases of, e.g. , pancreatic cancer such as pancreatic ductal adenocarcinoma, breast cancer such as breast infiltrative ductal adenocarcinoma, 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).
It has been reported that stimulation of Y2R such as by PYY3.36 leads to an increase in plasma 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 exerts 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 adiponectin levels have been reported to be associated with atherogenic lipoproteins in dyslipidemia (elevated triglycerides, small dense LDL cholesterol, low HDL cholesterol) (Marso et al, Diabetes Care (2008) Feb 5 Epub ahead of print). Adiponectin has been implicated in high density lipoprotein (HDL) assembly (Oku et al, FEBS Letters (2007) 581 :5029-5033). Adiponectin has been found to ameliorate the abnormalities of metabolic syndrome, including insulin resistance, hyperglycemia, and dyslipidemia, in a mouse model of obesity-linked metabolic syndrome associated with decreased adiponectin levels (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 through endothelial nitric oxide synthase-dependent mechanisms (Nishimura et al, Circulation (2008) 117:216-223). Adiponectin has been reported to confer protection against myocardial ischemia-reperfusion injury (Shibata et al, Nat Med (2005) 11 : 1096-1103; Tao et al, Circulation (2007) 115: 1408- 1416). Adiponectin has been reported to confer protection against myocardial ischemia- reperfusion injury via AMP-activated protein kinase, Akt, and nitric oxide (Gonon et al, Cardiovasc Res. (2008) 78: 116-122). Adiponectin has been reported to confer protection against the development of systolic dysfunction following myocardial infarction, through its abilities to suppress cardiac hypertrophy and interstitial fibrosis, and protect against myocyte and capillary loss (Shibata et al, J. Mol. Cell Cardiol. (2007) 42: 1065-1074). Adiponectin has been reported to confer protection against inflammatory lung disease; adiponectin-deficient mice exhibit an emphysema-like phenotype (Summer et al, Am J. Physiol. Lung Cell Mol. Physiol (March 7, 2008)). Adiponectin has been reported to confer protection against allergic airway inflammation and airway hyperresponsiveness such as may be associated with asthma (Shore et al, J. Allergy Clin. Immunol (2006) 118:389-395). Adiponectin has been suggested to confer protection against pulmonary arterial hypertension by virtue of its insulin-sensitizing effects (Hansmann et al, Circulation (2007) 115:1275-1284). Adiponectin has been reported to ameliorate obesity- related hypertension, with said amelioration of hypertension being associated in part with upregulated prostacyclin expression (Ohashi et al, Hypertension (2006) 47: 1108-1116).
Adiponectin has been reported to decrease tumor necrosis factor (TNF)-a-induced expression of the adhesion molecules VCAM-1, E-selectin and ICAM-1 in human aortic endothelial cells (HAECs) (Ouchi et al, Circulation (1999) 100:2473-2476) and to inhibit production of TNF-a in macrophages (Yokota et al, Blood (2000) 96:1723-1732). Adiponectin has been reported to confer protection against restenosis after vascular intervention (Matsuda et al, J Biol Chem
(2002) 277:37487-37491). The central role of TNF-a in inflammation has been demonstrated by the ability of agents that block the action of TNF-a to treat a range of inflammatory conditions. TNF-a-mediated inflammatory conditions encompass 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: 149-160). See, e.g.,
Yamamoto et al, Clinical Science (2002) 103: 137-142; Behre, Scand J Clin Lab Invest (2007) 67:449-458; Guerre-Millo, Diabetes & Metabolism (2008) 34: 12-18; Parker et al, Br. J.
Pharmacol. (2008) 153:420-431. SUMMARY OF THE INVENTION
One aspect of the present invention is directed to compounds, as described herein, and pharmaceutically acceptable salts, solvates, and hydrates thereof, which bind to and modulate the activity of a GPCR, referred to herein as GPR119, and uses thereof.
One aspect of the present invention encompasses, inter alia, certain cyclohexane derivatives selected from compounds of Formula (I) and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof:
Figure imgf000013_0001
(I)
wherein:
Ar is selected from: aryl and heteroaryl; each optionally substituted with one or more substituents selected from: Ci-C6 alkyl, C1-C4 alkylcarboxamide, Ci-C6 alkylsulfinyl, Ci-C6 alkylsulfonyl, heterocyclylsulfonyl, Ci-C6 alkylthio, carboxamide, cyano, C3-C7
cycloalkylsulfinyl, C3-C7 cycloalkylsulfonyl, C3-C7 cycloalkylthio, C2-C8 dialkylcarboxamide, Ci-C6 haloalkyl, halogen, and heteroaryl; wherein said Ci-C6 alkyl is optionally substituted with one or more substituents selected from: Ci-C6 alkoxy, hydroxyl, cyano, C2-C6 dialkylamino, and heterocyclyl; and
R1 is selected from: C1-C6 alkoxycarbonyl, C3-C7 cycloalkoxycarbonyl, and heteroaryl; each optionally substituted with one or more substituents selected from: C1-C6 alkyl, C1-C6 haloalkyl, and halogen.
One aspect of the present invention encompasses, inter alia, certain cyclohexane derivatives selected from compounds of Formula (lb) and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides
Figure imgf000013_0002
(Ib)
One aspect of the present invention encompasses, inter alia, certain cyclohexane derivatives selected from compounds of Formula (If) and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides
Figure imgf000013_0003
(If)
One aspect of the present invention pertains to compositions comprising a compound of the present invention.
One aspect of the present invention pertains to a pharmaceutical product selected from: a pharmaceutical composition, a formulation, a unit dosage form, and a kit; each comprising a compound of the present invention.
One aspect of the present invention pertains to pharmaceutical compositions comprising a compound of the present invention, and a pharmaceutically acceptable carrier.
One aspect of the present invention pertains to methods for preparing a pharmaceutical composition comprising the step of admixing a compound of the present invention, and a pharmaceutically acceptable carrier. One aspect of the present invention pertains to compositions comprising a compound of the present invention, and a second pharmaceutical agent.
One aspect of the present invention pertains to methods for preparing a composition comprising the step of admixing a compound of the present invention, and a second pharmaceutical agent.
One aspect of the present invention pertains to a pharmaceutical product selected from: a pharmaceutical composition, a formulation, a unit dosage form, a combined preparation, a twin pack, and a kit; each comprising a compound of the present invention, and a second pharmaceutical agent.
One aspect of the present invention pertains to pharmaceutical compositions comprising a compound of the present invention, a second pharmaceutical agent, and a pharmaceutically acceptable carrier.
One aspect of the present invention pertains to methods for preparing a pharmaceutical composition comprising the step of admixing a compound of the present invention, a second pharmaceutical agent, and a pharmaceutically acceptable carrier.
One aspect of the present invention pertains to methods for modulating the activity of a GPRl 19 receptor, comprising administering to an individual in need thereof, a therapeutically effective amount of: a compound of the present invention; a composition of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention
One aspect of the present invention pertains to methods for modulating the activity of a GPRl 19 receptor, comprising prescribing to an individual in need thereof, a therapeutically effective amount of: a compound of the present invention; a composition of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention.
One aspect of the present invention pertains to the use of a compound of the present invention in the manufacture of a medicament for modulating the activity of a GPRl 19 receptor in an individual.
One aspect of the present invention pertains to a compound of the present invention; a composition of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention; for use in a method of treatment of the human or animal body by therapy.
One aspect of the present invention pertains to a compound of the present invention; a composition of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention; for use in a method of modulating the activity of a GPRl 19 receptor in an individual. One aspect of the present invention pertains to methods for modulating the activity of a GPRl 19 receptor, comprising administering to an individual in need thereof, a therapeutically effective amount of a compound of the present invention; a composition of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention; each in combination with a therapeutically effective amount of a second pharmaceutical agent.
One aspect of the present invention pertains to methods for modulating the activity of a GPRl 19 receptor, comprising prescribing to an individual in need thereof, a therapeutically effective amount of a compound of the present invention; a composition of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention; each in combination with a therapeutically effective amount of a second pharmaceutical agent.
One aspect of the present invention pertains 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 the activity of a GPRl 19 receptor in an individual.
One aspect of the present invention pertains to the use of a pharmaceutical agent in combination with a compound of the present invention, in the manufacture of a medicament for modulating the activity of a GPRl 19 receptor in an individual.
One aspect of the present invention pertains to a compound of the present invention; a composition of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention; each in combination with a second pharmaceutical agent for use in a method of treatment of the human or animal body by therapy.
One aspect of the present invention pertains to a compound of the present invention; a composition of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention; each in combination with a second pharmaceutical agent for use in a method of modulating the activity of a GPRl 19 receptor in an individual.
One aspect of the present invention pertains to a pharmaceutical agent in combination with a compound of the present invention; a composition of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention; for use in a method of treatment of the human or animal body by therapy.
One aspect of the present invention pertains to a pharmaceutical agent in combination with a compound of the present invention; a composition of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention; for use in modulating the activity of a GPRl 19 receptor in an individual.
In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is selected from: a DPP-IV inhibitor, a biguanide, an alpha-glucosidase inhibitor, an insulin analogue, a sulfonylurea, an SGLT2 inhibitor, a meglitinide, a thiazolidinedione, and an antidiabetic peptide analogue.
In some embodiments, modulating the activity of a GPR119 receptor is agonizing a GPR119 receptor. In some embodiments, agonizing a GPR119 receptor is selected from:
increasing the secretion of an incretin in an individual; increasing a blood incretin level in an individual; a GPR119-receptor-related disorder; a condition ameliorated by increasing secretion of an incretin; a condition ameliorated by increasing a blood incretin level; a condition characterized by low bone mass; a neurological disorder; a metabolic -related disorder; and obesity.
These and other aspects of the invention disclosed herein will be set forth in greater detail as the patent disclosure proceeds.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows the in vivo effects of Compound 5 on incretin hormone GIP release. Figure 2 shows the in vivo effects of Compound 5 on glucose homeostasis in male
129SVE mice (oral glucose tolerance test (oGTT)).
Figure 3 shows the in vivo effects of Compound 5 on glucose excursion in terms of percent glycemic inhibition (i.e., percent AUC reduction) in male 129SVE mice.
Figure 4 shows a general synthetic scheme for the preparation of intermediates useful in preparing compounds of Formula (I).
Figure 5 shows a general synthetic scheme for the preparation of intermediates useful in preparing compounds of Formula (I), and when PG2 is R1 then using either Method A or Method B provides Compounds of Formula (I).
Figure 6 shows a general synthetic scheme for the preparation of compounds of Formula (I) wherein R1 is C1-C6 alkoxycarbonyl or C3-C7 cycloalkoxycarbonyl, each optionally substituted as described herein, and wherein R1 is heteroaryl optionally substituted as described herein.
Figure 7 shows a general synthetic scheme for the preparation of compounds of Formula (I) wherein R1 is oxadiazole and Ra selected from H, C1-C6 alkyl and C1-C6 haloalkyl.
Figure 8 shows a general synthetic scheme for the preparation of cis-exo and trans-exo intermediates useful in the preparation of Compounds of Formula (If).
Figure 9 shows a general synthetic scheme for the preparation of the trans-exo intermediates useful in the preparation of Compounds of Formula (If) wherein PG2 is a protection group, and when PG2 is R1 then using either Method A or Method B provides Compounds of Formula (If).
Figure 10 shows a general synthetic scheme for the preparation of Compounds of Formula (If) wherein R1 is Ci-C6 alkoxycarbonyl or C3-C7 cycloalkoxycarbonyl, each optionally substituted as described herein, and wherein R1 is heteroaryl optionally substituted as described herein.
Figure 11 shows a general synthetic scheme for the preparation of Compounds of Formula (If) wherein R1 is oxadiazole and Ra selected from H, Ci-C6 alkyl and Ci-C6 haloalkyl.
DETAILED DESCRIPTION OF THE INVENTION
DEFINITIONS
For clarity and consistency, the following definitions will be used throughout this patent document.
The term "agonist" as used herein refers to a moiety that interacts with and activates a
G-protein-coupled receptor, for instance a GPR119-receptor, and can thereby initiate a physiological or pharmacological response characteristic 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 term "antagonist" as used herein refers to a moiety that competitively binds to the receptor at the same site as an agonist (for example, the endogenous ligand), but which does not activate the intracellular response initiated by the active form of the receptor and can thereby inhibit the intracellular responses by an agonist or partial agonist. An antagonist does not diminish the baseline intracellular response in the absence of an agonist or partial agonist.
The term "hydrate" as used herein refers to a compound of the invention or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
The term "solvate" as used herein refers to a compound of the invention or a salt, thereof, that further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic, and/or acceptable for administration to humans in trace amounts.
The term "in need of treatment" and the term "in need thereof" when referring to treatment are used interchangeably and refer to a judgment made by a caregiver (e.g. physician, nurse, nurse practitioner, etc. in the case of humans; veterinarian in the case of animals, including non-human mammals) that an individual or animal requires or will benefit from treatment. This judgment is made based on a variety of factors that are in the realm of a caregiver's expertise, but that includes the knowledge that the individual or animal is ill, or will become ill, as the result of a disease, condition or disorder that is treatable by the compounds of the invention. Accordingly, the compounds of the invention can be used in a protective or preventive manner; or compounds of the invention can be used to alleviate, inhibit or ameliorate the disease, condition or disorder. The term "individual" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
The term "inverse agonist" refers to a moiety that binds to the endogenous form of the receptor or to the constitutively activated form of the receptor and which inhibits the baseline intracellular response initiated by the active form of the receptor below the normal base level of activity which is observed in the absence of an agonist or partial agonist, or decreases GTP binding to a membrane. Preferably, the baseline intracellular response is inhibited in the presence of the inverse agonist by at least 30%, more preferably by at least 50% and most preferably by at least 75%, as compared with the baseline response in the absence of the inverse agonist.
The term "modulate or modulating" refers to an increase or decrease in the amount, quality, response or effect of a particular activity, function or molecule.
The term "pharmaceutical composition" refers to a composition comprising at least one active ingredient; including but not limited to, salts, solvates, and hydrates of compounds of the present invention, whereby the composition is amenable to investigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human). Those of ordinary skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based upon the needs of the artisan.
The term "therapeutically effective amount" refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician or caregiver or by an individual, which includes one or more of the following:
(1) Preventing the disease, for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease;
(2) Inhibiting the disease, for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or
symptomatology); and
(3) Ameliorating the disease, for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology).
The term "unit dosage form" refers to a single dose form which is capable of being administered to a subject, and which can be readily handled and packaged, remaining as a physically and chemically stable unit comprising a compound of the present invention (i.e., compound used neat, such as in a dry powder inhaler (DPI) consisting of neat drug substance or for use in sublingual or buccal administration) or a pharmaceutically acceptable composition comprising a compound of the present invention such as in a pill, capsule, tablet, and the like. CHEMICAL GROUP, MOIETY OR RADICAL
The term "C1-C6 acyl" denotes a C1-C6 alkyl radical attached to a carbonyl wherein alkyl has the same definition as described herein, some embodiments are when acyl is C1-C5 acyl; some embodiments are when acyl is C1-C4 acyl; some examples include, but are not limited to, acetyl, propionyl, «-butanoyl, wo-butanoyl, seobutanoyl, i-butanoyl (i.e., pivaloyl), pentanoyl and the like.
The term "amino" refers to the group -NH2.
The term "C1-C6 alkoxy" refers to a radical comprising a C1-C6 alkyl group attached directly to an oxygen atom, wherein C1-C6 alkyl has the same definition as found herein. Some embodiments contain 1 to 5 carbons. Some embodiments contain 1 to 4 carbons. Some embodiments contain 1 to 3 carbons. Some embodiments contain one or two carbons. Examples of an alkoxy group include, but are not limited to methoxy, ethoxy, «-propoxy, isopropoxy, n- butoxy, i-butoxy, isobutoxy, s-butoxy, and the like.
The term "Ci-C6 alkoxycarbonyl" refers to a radical consisting of a Ci-C6 alkoxy group attached to a carbonyl group, wherein Ci-C6 alkoxy has the same definition as found herein. Examples include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, and tert- butoxycarbonyl.
The term "Ci-C6 alkyl" refers to a straight or branched carbon radical containing 1 to 6 carbons. Some embodiments contain 1 to 5 carbons. Some embodiments contain 1 to 4 carbons. Some embodiments contain 1 to 3 carbons. Some embodiments contain one or two carbons.
Examples of an alkyl group include, but are not limited to, methyl, ethyl, w-propyl, isopropyl, n- butyl, s-butyl, isobutyl, i-butyl, pentyl, isopentyl, i-pentyl, neopentyl, 1-methylbutyl [i.e. , -CH(CH3)CH2CH2CH3], 2-methylbutyl [i.e. , -CH2CH(CH3)CH2CH3], ra-hexyl, and the like.
The term "C1-C4 alkylcarboxamide" refers to a radical consisting of one C1-C4 alkyl group attached to either the carbon or the nitrogen of an amide group, wherein C1-C4 alkyl has the same definition as found herein. The C1-C4 alkylcarboxamide group can be represented by the following formulae:
Figure imgf000019_0001
Examples include, but are not limited to, N-methylcarboxamide, N-ethylcarboxamide, N-n- propylcarboxamide, N-isopropylcarboxamide, N-«-butylcarboxamide, N-s-butylcarboxamide, N- isobutylcarboxamide, and N-i-butylcarboxamide. The term "Ci-C6 alkylsulfinyl" refers to a radical consisting of a Ci-C6 alkyl group attached to the sulfur of an sulfinyl group (i.e., -S(O)-), wherein Ci-C6 alkyl has the same definition as described herein. Examples include, but are not limited to, methylsulfinyl, ethylsulfinyl, «-propylsulfinyl, isopropylsulfinyl, «-butylsulfinyl, seobutylsulfinyl,
isobutylsulfinyl, and teri-butylsulfinyl.
The term "C1-C6 alkylsulfonyl" refers to a radical comprising a C1-C6 alkyl group attached to the sulfur of a sulfonyl group, wherein the C1-C6 alkyl radical has the same definition as described herein. Examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, «-propylsulfonyl, isopropylsulfonyl, «-butylsulfonyl, s-butylsulfonyl, isobutylsulfonyl, i-butylsulfonyl, and the like.
The term "C1-C6 alkylthio" denotes a C1-C6 alkyl radical attached to a sulfur atom to form the group: C1-C6 alkyl-S-, wherein the alkyl radical has the same definition as described herein. Examples include, but are not limited to, methylthio (i.e., CH3S-), ethylthio, n- propylthio, iso-propylthio, n-butylthio, sec-butylthio, iso-butylthio, t-butylthio, and the like.
The term "aryl" denotes a 6- to 12-membered mono- or bicyclic ring system containing only ring carbons wherein at least one ring is aromatic. Examples include phenyl, 1,2,3,4- tetrahydro-naphthalen-l-yl, l,2,3,4-tetrahydro-naphthalen-2-yl, 5,6,7, 8-tetrahydro-naphthalen-l- yl, 5,6,7,8-tetrahydro-naphthalen-2-yl, indan-4-yl, naphtha-l-yl, naphtha-2-yl, and the like. In some embodiments, aryl is phenyl.
The term "carbonyl" refers to a C=0 group.
The term "carboxamide" refers to the group -CONH2.
The term "cyano" refers to the group -CN.
The term "C3-C7 cycloalkoxycarbonyl" refers to a radical consisting of a C3-C7 cycloalkoxy group attached to a carbonyl group, wherein C3-C7 cycloalkoxy has the same definition as found herein. Examples include, but are not limited to, cyclopropoxycarbonyl, cyclobutoxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, and
cycloheptyloxycarbonyl.
The term "C3-C7 cycloalkylsulfinyl" refers to a radical consisting of a C3-C7 cycloalkyl group attached to the sulfur of an sulfinyl group (i.e., -S(O)-), wherein C3-C7 cycloalkyl has the same definition as described herein. Examples include cyclopropylsulfinyl, cyclobutylsulfinyl, cyclopentylsulfinyl, cyclohexylsulfinyl, and cycloheptylsulfinyl.
The term "C3-C7 cycloalkylsulfonyl" refers to a radical comprising a C3-C7 cycloalkyl group attached to the sulfur of a sulfonyl group, wherein the C3-C7 cycloalkyl radical has the same definition as described herein. Examples include cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl, and cycloheptylsulfonyl.
The term "C3-C7 cycloalkylthio" denotes a C3-C7 cycloalkyl radical attached to a sulfur atom to form the group: C3-C7 cycloalkyl-S-, wherein the C3-C7 cycloalkyl radical has the same definition as described herein. Examples include cyclopropylthio, cyclobutylthio,
cyclopentylthio, cyclohexylthio, and cycloheptylthio.
The term "C3-C7 cycloalkoxy" refers to a radical comprising a C3-C7 cycloalkyl group attached directly to an oxygen atom, wherein C3-C7 cycloalkyl has the same definition as found herein. Some embodiments contain 3 to 6 carbons. Some embodiments contain 3 to 5 carbons. Some embodiments contain 3 to 4 carbons. Examples of a cycloalkoxy group include, but are not limited to cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and cycloheptyloxy.
The term "C3-C7 cycloalkyl" refers to a saturated ring radical containing 3 to 7 carbons. Some embodiments contain 3 to 4 carbons. Some embodiments contain 3 to 5 carbons. Some embodiments contain 4 to 6 carbons. Some embodiments contain 5 to 6 carbons. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
The term "C2-C6 dialkylamino" denotes an amino group substituted with two of the same or different Ci-C3 alkyl radicals wherein alkyl has the same definition as described herein. Some embodiments are "C2-C4 dialkylamino". Some examples include, but are not limited to, dimethylamino, methylethylamino, diethylamino, methylpropylamino, methylisopropylamino, ethylpropylamino, ethylisopropylamino, dipropylamino, propylisopropylamino and the like.
The term "C2-C8 dialkylcarboxamide" refers to two alkyl radicals, that are the same or different, attached to a carboxamide group, wherein alkyl has the same definition as described herein. A C2-C8 dialkylcarboxamide may be represented by the following groups:
Figure imgf000021_0001
wherein Ci-C4 has the same definition as described herein. Examples of a dialkylcarboxamide include, but are not limited to, N,N-dimethylcarboxamide, N-methyl-N-ethylcarboxamide, N,N- diethylcarboxamide, N-methyl-N-isopropylcarboxamide, and the like.
The term "C1-C6 haloalkyl" refers to a radical comprising a C1-C6 alkyl group substituted with one or more halogens, wherein C1-C6 alkyl has the same definition as found herein. The C1-C6 haloalkyl may be fully substituted in which case it can be represented by the formula CqL2q+i, wherein L is a halogen and "q" is 1, 2, 3, 4, 5 or 6. When more than one halogen is present then they may be the same or different and selected from: fluorine, chlorine, bromine, and iodine. In some embodiments, haloalkyl contains 1 to 5 carbons. In some embodiments, haloalkyl contains 1 to 4 carbons. In some embodiments, haloalkyl contains 1 to 3 carbons. In some embodiments, haloalkyl contains one or two carbons. Examples of a haloalkyl group include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2- trifluoroethyl, pentafluoroethyl, 2-fluoropropan-2-yl, 1,1-difluoropropyl, l,3-difluoropropan-2- yl, (5)-l-fluoropropan-2-yl, (R)-l-fluoropropan-2-yl, l,l,l-trifluoropropan-2-yl, 1,1,1,3,3,3- hexafluoropropan-2-yl, and the like. The term "halogen" refers to a fluoro, chloro, bromo or iodo group.
The term "heteroaryl" refers to a ring system containing 5 to 10 ring atoms, that may contain a single ring or two fused rings, and wherein at least one ring is aromatic and at least one ring atom of the aromatic ring is a heteroatom selected from, for example: O, S and N, wherein N is optionally substituted with H, C1-C4 acyl, Ci-C alkyl, or O (i.e., forming an N- oxide) and S is optionally substituted with one or two oxygens. In some embodiments, the aromatic ring contains one heteroatom. In some embodiments, the aromatic ring contains two heteroatoms. In some embodiments, the aromatic ring contains three heteroatoms. Examples include furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolyl, isoindolyl, indazolyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl. phenazinyl, phenothiazinyl, phenoxazinyl, benzoxazolyl, benzothiazolyl, lH-benzimidazolyl, imidazopyridinyl, benzothienyl, benzofuranyl, isobenzofuran, 2,3- dihydrobenzofuranyl, 4H-benzo[l ,3]dioxinyl, 3,4-dihydro-lH-isoquinolinyl, 1 ,4,6,7-tetrahydro- imidazo[4,5-c]pyridinyl, 7,8-dihydro-5H-[l ,6]naphthyridinyl, 5,6-dihydro-8H- [l ,2,4]triazolo[4,3-a]pyrazinyl, benzo[l ,3]dioxolyl, pyrazolo[l ,5-a]pyrimidinyl, 1 ,2,3,4- tetrahydroquinolinyl, and the like. Some embodiments are directed to 5-membered heteroaryl rings. Examples of a 5-membered heteroaryl ring include furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, and the like. Some embodiments are directed to 6-membered heteroaryl rings. Examples of a 6-membered heteroaryl ring include pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and the like. Some embodiments are directed to 8 to 10-membered heteroaryl rings. Examples of a 8 to 10-membered heteroaryl ring include quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolyl, isoindolyl, indazolyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl. phenazinyl,
phenothiazinyl, phenoxazinyl, benzoxazolyl, benzothiazolyl, lH-benzimidazolyl,
imidazopyridinyl, benzothienyl, benzofuranyl, isobenzofuran, 2,3-dihydrobenzofuranyl, 4H- benzo[l ,3]dioxinyl, 3,4-dihydro-lH-isoquinolinyl, l ,4,6,7-tetrahydro-imidazo[4,5-c]pyridinyl, 7,8-dihydro-5H-[l ,6]naphthyridinyl, 5,6-dihydro-8H-[l ,2,4]triazolo[4,3-a]pyrazinyl, benzo[l ,3]dioxolyl, pyrazolo[l ,5-a]pyrimidinyl, 1 ,2,3,4-tetrahydroquinolinyl, and the like.
The term "heterocyclyl" refers to a non-aromatic ring radical containing 3 to 7 ring atoms, wherein one, two or three ring atoms are heteroatoms is selected independently from, for example: O, S, and N, wherein N is optionally substituted with Η, Ci-C acyl or Ci-C alkyl; and S is optionally substituted with one or two oxygens. Examples of a heterocyclyl group include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, [l ,3]-dioxolanyl, thiomo holinyl, [l ,4]oxazepanyl, l , l-dioxothiomo holinyl, azepanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, l-oxo-hexahydro-ΐλ4- thiopyranyl, l,l-dioxo-hexahydro-^6-thiopyranyl, and the like.
The term "heterocyclylsulfonyl" refers to a radical comprising a heterocyclyl group attached to the sulfur of a sulfonyl group, wherein the heterocyclyl radical has the same definition as described herein. Examples include aziridinylsulfonyl, azetidinylsulfonyl, oxetan- 3-ylsulfonyl, piperidinylsulfonyl, morpholinylsulfonyl, piperazinylsulfonyl,
pyrrolidinylsulfonyl, and tetrahydrofuranylsulfonyl.
The term "hydroxyl" refers to the group -OH.
The term "phenyl" refers to the group -CeH5.
COMPOUNDS OF THE INVENTION
One aspect of the present invention provides, inter alia, compounds selected from compounds of Formula (I) and pharmaceutically acceptable salts, solvates, hydrates, and N- oxides thereof:
Figure imgf000023_0001
(I)
wherein Ar and R1 have the same definitions as described herein, supra and infra.
One aspect of the present invention provides, inter alia, compounds selected from compounds of Formula (lb) and pharmaceutically acceptable salts, solvates, hydrates, and N- oxides thereof:
Figure imgf000023_0002
wherein Ar and R1 have the same definitions as described herein, supra and infra.
One aspect of the present invention provides, inter alia, compounds selected from compounds of Formula (If) and pharmaceutically acceptable salts, solvates, hydrates, and N- oxides thereof:
Figure imgf000023_0003
(If)
wherein Ar and R1 have the same definitions as described herein, supra and infra.
One aspect of the present invention provides, inter alia, compounds selected from compounds of Formulae (I), (la), (la'), (lb), (Ic), (Id), (Ie), and (If), and pharmaceutically acceptable salts, solvates, and hydrates thereof; wherein Ar and R1 have the same definitions described herein, supra and infra. It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of the embodiments pertaining to the chemical groups represented by the variables (e.g. , Ar and R1) contained within the generic chemical formulae described herein, for example, (I), (la), (la'), (lb), (Ic), (Id), (Ie), and (If) are specifically embraced by the present invention just as if each and every combination was individually and explicitly recited, to the extent that such combinations embrace compounds that result in stable compounds (i.e. , compounds that can be isolated, characterized and tested for biological activity). In addition, all subcombinations of the chemical groups listed in the embodiments describing such variables, as well as all subcombinations of methods, uses, compounds, and medical indications as described herein, are also specifically embraced by the present invention just as if each and every subcombination of chemical groups and subcombination of methods, uses, compounds, and medical indications were individually and explicitly recited herein. In addition, some embodiments include every combination of one or more pharmaceutical agents, such as an inhibitor of DPP-IV, a biguanide, an alpha-glucosidase inhibitor, and the like, either specifically disclosed herein or specifically disclosed in any reference recited herein just as if each and every combination was individually and explicitly recited. Still further, some embodiments of the present invention include every combination of one or more embodiments pertaining to the chemical groups represented by the variables and generic chemical formulae as described herein or every combination of one or more compounds of Formula (I), and related Formulae, together/in combination with every combination of one or more pharmaceutical agents, such as an inhibitor of DPP-IV, a biguanide, an alpha-glucosidase inhibitor, and the like, either specifically disclosed herein or specifically disclosed in any reference recited herein just as if each and every combination was individually and explicitly recited.
As used herein, "substituted" indicates that at least one hydrogen atom of the chemical group is replaced by a non-hydrogen substituent or group, the non-hydrogen substituent or group can be monovalent or divalent. When the substituent or group is divalent, then it is understood that this group is further substituted with another substituent or group. When a chemical group herein is "substituted" it may have up to the full valance of substitution; for example, a methyl group can be substituted by 1 , 2, or 3 substituents, a methylene group can be substituted by one or two substituents, a phenyl group can be substituted by 1 , 2, 3, 4, or 5 substituents, a naphthyl group can be substituted by 1 , 2, 3, 4, 5, 6, or 7 substituents, and the like. Likewise, "substituted with one or more substituents" refers to the substitution of a group with one substituent up to the total number of substituents physically allowed by the group. Further, when a group is substituted with more than one group they can be identical or they can be different.
Compounds of the invention can also include tautomeric forms, such as keto-enol tautomers and the like. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. It is understood that the various tautomeric forms are within the scope of the compounds of the present invention.
It is understood and appreciated that compounds of Formula (I) and formulae related thereto may have one or more chiral centers and therefore can exist as enantiomers and/or diastereoisomers. The invention is understood to extend to and embrace all such enantiomers, diastereoisomers and mixtures thereof, including but not limited to racemates. It is understood that compounds of Formula (I) and formulae used throughout this disclosure represent all individual enantiomers and mixtures thereof, unless stated or shown otherwise.
It is understood and appreciated that compounds of Formula (I) and formulae related thereto exist as meso isomers. Such meso isomers may be referred to as cis and trans. The cis meso isomers of compounds of the present invention are named herein using the designation (Is, 4s) and the trans meso isomers of compounds of the present invention are named herein using the designation (lr,4r) as shown below using Formula (la) and Formula (la')
respectively
Figure imgf000025_0001
(is, 4s)- or cis- mesoisomer (lr,4r)- or trans- mesoisomer
It is further understood and appreciated that certain compounds of Formula (I) may have the oxygen of the ether group attached to the azabicyclo[3.2.1]octane ring in either an endo or exo orientation. These compounds are named using the designations as shown below for Formulae
(Ic), (Id), (I
Figure imgf000025_0002
(iR,3r,5S) or endo and (iR,3r,5S) or endo and
(ir,4R) or trans isomers
Figure imgf000025_0003
(iR,3s,5S) or exo and (iR,3s,5S) or exo and
(is,4S) or cis isomers (lr,4R) or trans isomers One aspect of the present invention pertains to compounds selected from one or more of the following: Formula (la), Formula (la'), Formula (lb), Formula (Ic), Formula (Id), Formula (Ie), and Formula (If), and pharmaceutically acceptable salts, solvates, and hydrates thereof, wherein each variable in Formula (la), Formula (la'), Formula (lb), Formula (Ic), Formula (Id), Formula (Ie), and Formula (If) has the same meaning as described herein, supra and infra. The Group Ar:
In some embodiments, Ar is selected from: aryl and heteroaryl; each optionally substituted with one or more substituents selected from: C1-C6 alkyl, C1-C4 alkylcarboxamide, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, heterocyclylsulfonyl, C1-C6 alkylthio, carboxamide, cyano, C3-C7 cycloalkylsulfinyl, C3-C7 cycloalkylsulfonyl, C3-C7 cycloalkylthio, C2-C8 dialkylcarboxamide, C1-C6 haloalkyl, halogen, and heteroaryl; wherein said C1-C6 alkyl is optionally substituted with one or more substituents selected from: C1-C6 alkoxy, hydroxyl, cyano, C2-C6 dialkylamino, and heterocyclyl
In some embodiments, Ar is selected from: phenyl and heteroaryl; each optionally substituted with one or more substituents selected from: C1-C6 alkyl, C1-C6 alkylsulfonyl, heterocyclylsulfonyl, cyano, C3-C7 cycloalkylsulfonyl, C2-C8 dialkylcarboxamide, Ci-C6 haloalkyl, halogen, and heteroaryl; wherein said Ci-C6 alkyl is optionally substituted with one or more substituents selected from: Ci-C6 alkoxy, hydroxyl, cyano, C2-C6 dialkylamino, and heterocyclyl.
In some embodiments, Ar is selected from: pyridin-4-yl, pyridin-2-yl, phenyl, thieno[3,2-c]pyridin-4-yl, furo[3,2-c]pyridin-4-yl, pyrimidin-2-yl, pyridin-3-yl, 1,6- naphthyridin-4-yl, pyrazin-2-yl, isoquinolin-8-yl, quinoxalin-2-yl, benzo[d]thiazol-2-yl, 1H- pyrazol-5-yl, thieno[3,2-d]pyrimidin-4-yl, and pyrimidin-4-yl; each optionally substituted with one or more substituents selected from: Ci-C6 alkyl, Ci-C6 alkylsulfonyl, heterocyclylsulfonyl, cyano, C3-C7 cycloalkylsulfonyl, C2-C8 dialkylcarboxamide, C1-C6 haloalkyl, halogen, and heteroaryl; wherein said C1-C6 alkyl is optionally substituted with one or more substituents selected from: C1-C6 alkoxy, hydroxyl, cyano, C2-C6 dialkylamino, and heterocyclyl.
In some embodiments, Ar is selected from: phenyl and heteroaryl; each optionally substituted with one or more substituents selected from: cyano, fluoro, methyl, bromo, methylsulionyl, chloro, 2-methoxyethyl, lH-l,2,4-triazol-l-yl, trifluoromethyl, 2-hydroxyethyl, 2-cyanoethyl, 2-(dimethylamino)ethyl, 2-morpholinoethyl, lH-tetrazol-l-yl, oxetan-3- ylsulfonyl, cyclopropylsulfonyl, pyridazin-4-yl, and dimethylcarbamoyl.
In some embodiments, Ar is selected from: pyridin-4-yl, pyridin-2-yl, phenyl, thieno[3,2-c]pyridin-4-yl, furo[3,2-c]pyridin-4-yl, pyrimidin-2-yl, pyridin-3-yl, 1,6- naphthyridin-4-yl, pyrazin-2-yl, isoquinolin-8-yl, quinoxalin-2-yl, benzo[d]thiazol-2-yl, 1H- pyrazol-5-yl, thieno[3,2-d]pyrimidin-4-yl, and pyrimidin-4-yl; each optionally substituted with one or more substituents selected from: cyano, fluoro, methyl, bromo, methylsulionyl, chloro, 2- methoxyethyl, lH-l,2,4-triazol-l-yl, trifluoromethyl, 2-hydroxyethyl, 2-cyanoethyl, 2- (dimethylamino)ethyl, 2-morpholinoethyl, lH-tetrazol-l -yl, oxetan-3-ylsulfonyl,
cyclopropylsulfonyl, pyridazin-4-yl, and dimethylcarbamoyl.
In some embodiments, Ar is selected from: 3-cyanopyridin-4-yl, 3,5-difluoropyridin-4- yl, 3-cyano-5-methylpyridin-4-yl, 3-cyano-5-fluoropyridin-4-yl, 3-cyano-5-fluoropyridin-2-yl, 4-bromo-2-cyanophenyl, 2,4-dicyanophenyl, 2-cyano-4-(methylsulfonyl)phenyl, thieno[3,2- c]pyridin-4-yl, furo[3,2-c]pyridin-4-yl, 5-bromopyrimidin-2-yl, 4-chloro-2-cyanophenyl, 2- fluoro-4-(methylsulfonyl)phenyl, 5-(methylsulfonyl)pyridin-3-yl, 2-cyano-4-fluorophenyl, 4-(2- methoxyethyl)phenyl, 1 ,6-naphthyridin-4-yl, pyridin-4-yl, 5-(lH-l ,2,4-triazol-l -yl)pyrazin-2-yl, 2-methyl-6-( 1H- 1 ,2,4-triazol- 1 -yl)pyridin-3 -yl, isoquinolin-8 -yl, 5 -(trifluoromethyl)pyridin-2- yl, quinoxalin-2-yl, 4-cyanopyridin-2-yl, 4-(2-hydroxyethyl)phenyl, 4-bromo-3-fluorophenyl, 5- cyanopyridin-2-yl, 4-(2-cyanoethyl)phenyl, benzo[d]thiazol-2-yl, 5-(methylsulfonyl)pyrimidin- 2-yl, 4-(2-(dimethylamino)ethyl)phenyl, 4-(2-morpholinoethyl)phenyl, l-methyl-3- (trifluoromethyl)-lH-pyrazol-5-yl, 3-cyanopyridin-2-yl, thieno[3,2-d]pyrimidin-4-yl, 4-(lH- tetrazol-1 -yl)phenyl, 4-(2-methyl-6-(oxetan-3-ylsulfonyl)pyridin-3-yl, 4-(6- (cyclopropylsulfonyl)-2-methylpyridin-3-yl, 2-cyanopyridin-3-yl, 5-bromo-3-methylpyrazin-2- yl, 3-methyl-5-(methylsulfonyl)pyrazin-2-yl, 6-(trifluoromethyl)pyridin-3-yl, 4-cyanopyridin-3- yl, 5-cyanopyrimidin-4-yl, 4-cyano-2,6-difluorophenyl, 2-methyl-6-(pyridazin-4-yl)pyridin-3-yl, 4-(dimethylcarbamoyl)-2-fluorophenyl, 5-(methylsulfonyl)pyridin-2-yl, 2-methyl-6- (methylsulfonyl)pyridin-3-yl, 3-fluoro-4-(lH-l ,2,4-triazol-l -yl)phenyl, 5- (methylsulfonyl)pyrazin-2-yl, 5-(dimethylcarbamoyl)pyridin-2-yl, 4-(methylsulfonyl)phenyl, and pyrimidin-4-yl.
In some embodiments, Ar is 3-cyanopyridin-4-yl. In some embodiments, Ar is 3,5- difluoropyridin-4-yl. In some embodiments, Ar is 3-cyano-5-methylpyridin-4-yl. In some embodiments, Ar is 3-cyano-5-fluoropyridin-4-yl. In some embodiments, Ar is 3-cyano-5- fluoropyridin-2-yl. In some embodiments, Ar is 4-bromo-2-cyanophenyl. In some embodiments, Ar is 2,4-dicyanophenyl. In some embodiments, Ar is 2-cyano-4-(methylsulfonyl)phenyl. In some embodiments, Ar is thieno[3,2-c]pyridin-4-yl. In some embodiments, Ar is furo[3,2- c]pyridin-4-yl. In some embodiments, Ar is 5-bromopyrimidin-2-yl. In some embodiments, Ar is 4-chloro-2-cyanophenyl. In some embodiments, Ar is 2-fluoro-4-(methylsulfonyl)phenyl. In some embodiments, Ar is 5-(methylsulfonyl)pyridin-3-yl. In some embodiments, Ar is 2-cyano- 4-fluorophenyl. In some embodiments, Ar is 4-(2-methoxyethyl)phenyl. In some embodiments, Ar is 1 ,6-naphthyridin-4-yl. In some embodiments, Ar is pyridin-4-yl. In some embodiments, Ar is 5-(lH-l ,2,4-triazol-l -yl)pyrazin-2-yl. In some embodiments, Ar is 2-methyl-6-(lH- 1 ,2,4- triazol-l-yl)pyridin-3-yl. In some embodiments, Ar is isoquinolin-8 -yl. In some embodiments, Ar is 5-(trifluoromethyl)pyridin-2-yl. In some embodiments, Ar is quinoxalin-2-yl. In some embodiments, Ar is 4-cyanopyridin-2-yl. In some embodiments, Ar is 4-(2- hydroxyethyl)phenyl. In some embodiments, Ar is 4-bromo-3-fluorophenyl. In some embodiments, Ar is 5-cyanopyridin-2-yl. In some embodiments, Ar is 4-(2-cyanoethyl)phenyl. In some embodiments, Ar is benzo[d]thiazol-2-yl. In some embodiments, Ar is 5- (methylsulfonyl)pyrimidin-2-yl. In some embodiments, Ar is 4-(2-(dimethylamino)ethyl)phenyl. In some embodiments, Ar is 4-(2-morpholinoethyl)phenyl. In some embodiments, Ar is 1- methyl-3-(trifluoromethyl)-lH-pyrazol-5-yl. In some embodiments, Ar is 3-cyanopyridin-2-yl. In some embodiments, Ar is thieno[3,2-d]pyrimidin-4-yl. In some embodiments, Ar is 4-(lH- tetrazol-l -yl)phenyl. In some embodiments, Ar is 4-(2-methyl-6-(oxetan-3-ylsulfonyl)pyridin-3- yl. In some embodiments, Ar is 4-(6-(cyclopropylsulfonyl)-2-methylpyridin-3-yl. In some embodiments, Ar is 2-cyanopyridin-3-yl. In some embodiments, Ar is 5-bromo-3- methylpyrazin-2-yl. In some embodiments, Ar is 3-methyl-5-(methylsulfonyl)pyrazin-2-yl. In some embodiments, Ar is 6-(trifluoromethyl)pyridin-3-yl. In some embodiments, Ar is 4- cyanopyridin-3-yl. In some embodiments, Ar is 5-cyanopyrimidin-4-yl. In some embodiments, Ar is 4-cyano-2,6-difluorophenyl. In some embodiments, Ar is 2-methyl-6-(pyridazin-4- yl)pyridin-3-yl. In some embodiments, Ar is 4-(dimethylcarbamoyl)-2 -fluorophenyl. In some embodiments, Ar is 5-(methylsulfonyl)pyridin-2-yl. In some embodiments, Ar is 2-methyl-6- (methylsulfonyl)pyridin-3-yl. In some embodiments, Ar is 3-fluoro-4-(lH-l ,2,4-triazol-l - yl)phenyl. In some embodiments, Ar is 5-(methylsulfonyl)pyrazin-2-yl. In some embodiments, Ar is 5-(dimethylcarbamoyl)pyridin-2-yl. In some embodiments, Ar is 4- (methylsulfonyl)phenyl. In some embodiments, Ar is pyrimidin-4-yl.
The Group R1:
In some embodiments, R1 is selected from: Ci-C6 alkoxycarbonyl, C3-C7
cycloalkoxycarbonyl, and heteroaryl; each optionally substituted with one or more substituents selected from: C1-C6 alkyl, C1-C6 haloalkyl, and halogen.
In some embodiments, R1 is selected from: C1-C6 alkoxycarbonyl, C3-C7
cycloalkoxycarbonyl, and heteroaryl; each optionally substituted with one or more substituents selected from: chloro, ethyl, fluoro, 2-fluoropropan-2-yl, isopropyl, methyl, and trifluoromethyl.
In some embodiments, R1 is selected from: teri-butoxycarbonyl, isopropoxycarbonyl, cyclopropoxycarbonyl, 1 ,2,4-oxadiazolyl, and pyrimidin-2-yl; each optionally substituted with one or more substituents selected from: chloro, ethyl, fluoro, 2-fluoropropan-2-yl, isopropyl, methyl, and trifluoromethyl.
In some embodiments, R1 is heteroaryl optionally substituted with one or more substituents selected from: Ci-C6 alkyl, Ci-C6 haloalkyl, and halogen.
In some embodiments, R1 is selected from: 1 ,2,4-oxadiazolyl and pyrimidin-2-yl; each optionally substituted with one or more substituents selected from: Ci-C6 alkyl, Ci-C6 haloalkyl, and halogen. In some embodiments, R1 is selected from: 1 ,2,4-oxadiazolyl and pyrimidin-2-yl; each optionally substituted with one or more substituents selected from: chloro, ethyl, isopropyl, trifluoromethyl, and 2-fluoropropan-2-yl.
In some embodiments, R1 is selected from: Ci-C6 alkoxycarbonyl, and C3-C7 cycloalkoxycarbonyl; each optionally substituted with one or more substituents selected from: halogen and C1-C6 alkyl.
In some embodiments, R1 is selected from: C1-C6 alkoxycarbonyl, and C3-C7 cycloalkoxycarbonyl; each optionally substituted with one or more substituents selected from: fluoro and methyl.
In some embodiments, R1 is selected from: teri-butoxycarbonyl, isopropoxycarbonyl, and cyclopropoxycarbonyl; each optionally substituted with one or more substituents selected from: fluoro and methyl.
In some embodiments, R1 is selected from: teri-butoxycarbonyl, ( 1 ,1 ,1 -trifluoropropan- 2-yloxy)carbonyl, 5-chloropyrimidin-2-yl, (1 -methylcyclopropoxy)carbonyl,
isopropoxycarbonyl, 5-ethylpyrimidin-2-yl, 3-isopropyl-l ,2,4-oxadiazol-5-yl, 3- (trifluoromethyl)-l ,2,4-oxadiazol-5-yl, and 3-(2-fluoropropan-2-yl)-l ,2,4-oxadiazol-5-yl.
In some embodiments, R1 is teri-butoxycarbonyl. In some embodiments, R1 is (1 , 1, 1- trifluoropropan-2-yloxy)carbonyl. In some embodiments, R1 is 5-chloropyrimidin-2-yl. In some embodiments, R1 is (l-methylcyclopropoxy)carbonyl. In some embodiments, R1 is
isopropoxycarbonyl. In some embodiments, R1 is 5-ethylpyrimidin-2-yl. In some embodiments, R1 is 3-isopropyl-l ,2,4-oxadiazol-5-yl. In some embodiments, R1 is 3-(trifluoromethyl)-l ,2,4- oxadiazol-5-yl. In some embodiments, R1 is 3-(2-fluoropropan-2-yl)-l ,2,4-oxadiazol-5-yl.
Certain Combinations:
One aspect of the present invention encompasses certain cyclohexyl derivatives selected from compounds of Formula (lb) and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof:
Figure imgf000029_0001
(lb)
wherein:
Ar is selected from: phenyl and heteroaryl; each optionally substituted with one or more substituents selected from: Ci-C6 alkyl, Ci-C6 alkylsulfonyl, heterocyclylsulionyl, cyano, C3-C7 cycloalkylsulfonyl, C2-C8 dialkylcarboxamide, Ci-C6 haloalkyl, halogen, and heteroaryl;
wherein said Ci-C6 alkyl is optionally substituted with one or more substituents selected from: Ci-C6 alkoxy, hydroxyl, C2-C6 dialkylamino, and heterocyclyl; and R1 is selected from: Ci-C6 alkoxycarbonyl, C3-C7 cycloalkoxycarbonyl, and heteroaryl; each optionally substituted with one or more substituents selected from: chloro, ethyl, fluoro, 2- fluoropropan-2-yl, isopropyl, methyl, and trifluoromethyl.
One aspect of the present invention encompasses certain cyclohexyl derivatives selected from compounds of Formula (lb) and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof:
wherein:
Ar is selected from: phenyl and heteroaryl; each optionally substituted with one or more substituents selected from: cyano, fluoro, methyl, bromo, methylsulfonyl, chloro, 2- methoxyethyl, lH-l,2,4-triazol-l-yl, trifluoromethyl, 2-hydroxyethyl, 2-(dimethylamino)ethyl, 2-morpholinoethyl, lH-tetrazol-l-yl, oxetan-3-ylsulfonyl, cyclopropylsulfonyl, pyridazin-4-yl, and dimethylcarbamoyl; and
R1 is selected from: C1-C6 alkoxycarbonyl, C3-C7 cycloalkoxycarbonyl, and heteroaryl; each optionally substituted with one or more substituents selected from: chloro, ethyl, fluoro, 2- fluoropropan-2-yl, isopropyl, methyl, and trifluoromethyl.
One aspect of the present invention encompasses certain cyclohexyl derivatives selected from compounds of Formula (lb) and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof:
wherein:
Ar is selected from: pyridin-4-yl, pyridin-2-yl, phenyl, thieno[3,2-c]pyridin-4-yl, furo[3,2-c]pyridin-4-yl, pyrimidin-2-yl, pyridin-3-yl, l,6-naphthyridin-4-yl, pyrazin-2-yl, isoquinolin-8-yl, quinoxalin-2-yl, benzo[d]thiazol-2-yl, lH-pyrazol-5-yl, thieno[3,2- d]pyrimidin-4-yl, and pyrimidin-4-yl; each optionally substituted with one or more substituents selected from: C1-C6 alkyl, C1-C6 alkylsulfonyl, heterocyclylsulfonyl, cyano, C3-C7 cycloalkylsulfonyl, C2-C8 dialkylcarboxamide, C1-C6 haloalkyl, halogen, and heteroaryl;
wherein said C1-C6 alkyl is optionally substituted with one or more substituents selected from: C1-C6 alkoxy, hydroxyl, C2-C6 dialkylamino, and heterocyclyl; and
R1 is selected from: C1-C6 alkoxycarbonyl, C3-C7 cycloalkoxycarbonyl, and heteroaryl; each optionally substituted with one or more substituents selected from: chloro, ethyl, fluoro, 2- fluoropropan-2-yl, isopropyl, methyl, and trifluoromethyl.
One aspect of the present invention encompasses certain cyclohexyl derivatives selected from compounds of Formula (If) and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof:
Figure imgf000030_0001
(If)
wherein: Ar is selected from: phenyl and heteroaryl; each optionally substituted with one or more substituents selected from: Ci-C6 alkyl, Ci-C6 alkylsulfonyl, heterocyclylsulfonyl, cyano, C3-C7 cycloalkylsulfonyl, C2-C8 dialkylcarboxamide, Ci-C6 haloalkyl, halogen, and heteroaryl;
wherein said Ci-C6 alkyl is optionally substituted with one or more substituents selected from: Ci-C6 alkoxy, hydroxyl, C2-C6 dialkylamino, and heterocyclyl; and
R1 is selected from: C1-C6 alkoxycarbonyl, C3-C7 cycloalkoxycarbonyl, and heteroaryl; each optionally substituted with one or more substituents selected from: chloro, ethyl, fluoro, 2- fluoropropan-2-yl, isopropyl, methyl, and trifluoromethyl.
One aspect of the present invention encompasses certain cyclohexyl derivatives selected from compounds of Formula (If) and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof:
wherein:
Ar is selected from: phenyl and heteroaryl; each optionally substituted with one or more substituents selected from: cyano, fluoro, methyl, bromo, methylsulfonyl, chloro, 2- methoxyethyl, lH-l,2,4-triazol-l-yl, trifluoromethyl, 2-hydroxyethyl, 2-(dimethylamino)ethyl, 2-morpholinoethyl, lH-tetrazol-l-yl, oxetan-3-ylsulfonyl, cyclopropylsulfonyl, pyridazin-4-yl, and dimethylcarbamoyl; and
R1 is selected from: Ci-C6 alkoxycarbonyl, C3-C7 cycloalkoxycarbonyl, and heteroaryl; each optionally substituted with one or more substituents selected from: chloro, ethyl, fluoro, 2- fluoropropan-2-yl, isopropyl, methyl, and trifluoromethyl.
One aspect of the present invention encompasses certain cyclohexyl derivatives selected from compounds of Formula (If) and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof:
wherein:
Ar is selected from: pyridin-4-yl, pyridin-2-yl, phenyl, thieno[3,2-c]pyridin-4-yl, furo[3,2-c]pyridin-4-yl, pyrimidin-2-yl, pyridin-3-yl, 1 ,6-naphthyridin-4-yl, pyrazin-2-yl, isoquinolin-8-yl, quinoxalin-2-yl, benzo[d]thiazol-2-yl, lH-pyrazol-5-yl, thieno[3,2- d]pyrimidin-4-yl, and pyrimidin-4-yl; each optionally substituted with one or more substituents selected from: C1-C6 alkyl, C1-C6 alkylsulfonyl, heterocyclylsulfonyl, cyano, C3-C7 cycloalkylsulfonyl, C2-C8 dialkylcarboxamide, C1-C6 haloalkyl, halogen, and heteroaryl;
wherein said C1-C6 alkyl is optionally substituted with one or more substituents selected from: C1-C6 alkoxy, hydroxyl, C2-C6 dialkylamino, and heterocyclyl; and
R1 is selected from: Ci-C6 alkoxycarbonyl, C3-C7 cycloalkoxycarbonyl, and heteroaryl; each optionally substituted with one or more substituents selected from: chloro, ethyl, fluoro, 2- fluoropropan-2-yl, isopropyl, methyl, and trifluoromethyl. One aspect of the present invention encompasses certain cyclohexyl derivatives selected from compounds of Formula (If) and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof:
wherein:
Ar is selected from: pyridin-4-yl, pyridin-2-yl, phenyl, thieno[3,2-c]pyridin-4-yl, furo[3,2-c]pyridin-4-yl, pyrimidin-2-yl, pyridin-3-yl, 1 ,6-naphthyridin-4-yl, pyrazin-2-yl, isoquinolin-8-yl, quinoxalin-2-yl, benzo[d]thiazol-2-yl, lH-pyrazol-5-yl, thieno[3,2- d]pyrimidin-4-yl, and pyrimidin-4-yl; each optionally substituted with one or more substituents selected from: cyano, fluoro, methyl, bromo, methylsulfonyl, chloro, 2-methoxyethyl, 1H-1,2,4- triazol-l-yl, trifluoromethyl, 2-hydroxyethyl, 2-(dimethylamino)ethyl, 2-morpholinoethyl, 1H- tetrazol-l-yl, oxetan-3-ylsulfonyl, cyclopropylsulionyl, pyridazin-4-yl, and dimethylcarbamoyl; and
R1 is selected from: teri-butoxycarbonyl, isopropoxycarbonyl, cyclopropoxycarbonyl, 1,2,4-oxadiazolyl, and pyrimidin-2-yl; each optionally substituted with one or more substituents selected from: chloro, ethyl, fluoro, 2-fluoropropan-2-yl, isopropyl, methyl, and trifluoromethyl.
One aspect of the present invention encompasses certain cyclohexyl derivatives selected from compounds of Formula (If) and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof:
wherein:
Ar is selected from: 3-cyanopyridin-4-yl, 3,5-difluoropyridin-4-yl, 3-cyano-5- methylpyridin-4-yl, 3-cyano-5-fluoropyridin-4-yl, 3-cyano-5-fluoropyridin-2-yl, 4-bromo-2- cyanophenyl, 2,4-dicyanophenyl, 2-cyano-4-(methylsulfonyl)phenyl, thieno[3,2-c]pyridin-4-yl, furo[3,2-c]pyridin-4-yl, 5-bromopyrimidin-2-yl, 4-chloro-2-cyanophenyl, 2-fluoro-4- (methylsulfonyl)phenyl, 5-(methylsulfonyl)pyridin-3-yl, 2-cyano-4-fluorophenyl, 4-(2- methoxyethyl)phenyl, l,6-naphthyridin-4-yl, pyridin-4-yl, 5-(lH-l,2,4-triazol-l-yl)pyrazin-2-yl, 2-methyl-6-( 1H- 1 ,2,4-triazol- 1 -yl)pyridin-3 -yl, isoquinolin-8 -yl, 5 -(trifluoromethyl)pyridin-2- yl, quinoxalin-2-yl, 4-cyanopyridin-2-yl, 4-(2-hydroxyethyl)phenyl, 4-bromo-3-fluorophenyl, 5- cyanopyridin-2-yl, 4-(2-cyanoethyl)phenyl, benzo[d]thiazol-2-yl, 5-(methylsulfonyl)pyrimidin- 2-yl, 4-(2-(dimethylamino)ethyl)phenyl, 4-(2-mo holinoethyl)phenyl, l-methyl-3- (trifluoromethyl)-lH-pyrazol-5-yl, 3-cyanopyridin-2-yl, thieno[3,2-d]pyrimidin-4-yl, 4-(lH- tetrazol-1 -yl)phenyl, 4-(2-methyl-6-(oxetan-3-ylsulfonyl)pyridin-3-yl, 4-(6- (cyclopropylsulfonyl)-2-methylpyridin-3-yl, 2-cyanopyridin-3-yl, 5-bromo-3-methylpyrazin-2- yl, 3-methyl-5-(methylsulfonyl)pyrazin-2-yl, 6-(trifluoromethyl)pyridin-3-yl, 4-cyanopyridin-3- yl, 5-cyanopyrimidin-4-yl, 4-cyano-2,6-difluorophenyl, 2-methyl-6-(pyridazin-4-yl)pyridin-3-yl, 4-(dimethylcarbamoyl)-2-fluorophenyl, 5-(methylsulfonyl)pyridin-2-yl, 2-methyl-6- (methylsulfonyl)pyridin-3 -yl, 3 -fluoro-4-( 1H- 1 ,2,4-triazol- 1 -yl)phenyl, 5- (methylsulfonyl)pyrazin-2-yl, 5 -(dimethylcarbamoyl)pyridin-2-yl, 4-(methylsulfonyl)phenyl, and pyrimidin-4-yl; and
R1 is selected from: teri-butoxycarbonyl, (l ,l , l-trifluoropropan-2-yloxy)carbonyl, 5- chloropyrimidin-2-yl, (l-methylcyclopropoxy)carbonyl, isopropoxycarbonyl, 5-ethylpyrimidin- 2-yl, 3-isopropyl-l ,2,4-oxadiazol-5-yl, 3-(trifluoromethyl)-l ,2,4-oxadiazol-5-yl, and 3-(2- fluoropropan-2-yl)-l ,2,4-oxadiazol-5-yl.
One aspect of the present invention encompasses certain cyclohexyl derivatives selected from compounds of Formula (If) and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof:
wherein:
Ar is selected from: pyridin-4-yl, pyridin-2-yl, phenyl, pyridin-3-yl, and pyrazin-2-yl; each optionally substituted with one or more substituents selected from: cyano, fluoro, methyl, bromo, methylsulfonyl, chloro, 2-methoxyethyl, lH-l ,2,4-triazol-l -yl, trifluoromethyl, 2- hydroxyethyl, 2-cyanoethyl, 2-(dimethylamino)ethyl, 2-morpholinoethyl, lH-tetrazol-l -yl, oxetan-3-ylsulfonyl, cyclopropylsulfonyl, pyridazin-4-yl, and dimethylcarbamoyl; and
R1 is selected from: teri-butoxycarbonyl, (l ,l , l-trifluoropropan-2-yloxy)carbonyl, 5- chloropyrimidin-2-yl, (l-methylcyclopropoxy)carbonyl, isopropoxycarbonyl, 5-ethylpyrimidin- 2-yl, 3-isopropyl-l ,2,4-oxadiazol-5-yl, 3-(trifluoromethyl)-l ,2,4-oxadiazol-5-yl, and 3-(2- fluoropropan-2-yl)-l ,2,4-oxadiazol-5-yl.
Some embodiments of the present invention include every combination of one or more compounds selected from the following group shown in Table A.
Table A
Figure imgf000033_0001
Cmpd
Chemical Structure Chemical Name No.
(1R,35,55)-((R)-1,1,1- f trilluoropropan-2-yl) 3- ((1 r,4R)-4-(3-cyanopyridin-4-
4 cr yloxy)cyclohexyloxy)-8-
0 * azabicyclo[3.2. l]octane-8- carboxylate
(lR,35,55)-((5)-l,l,l- trilluoropropan-2-yl) 3- ((1 r,4R)-4-(3-cyanopyridin-4-
5
yloxy)cyclohexyloxy)-8-
0 = azabicyclo[3.2. l]octane-8- carboxylate
(lR,3s,5S)-tert-butyl 3- ((lr,4R)-4-(3,5- dilluoropyridin-4-
6
yloxy)cyclohexyloxy)-8-
F 0 1 azabicyclo[3.2. l]octane-8- carboxylate
4-((lR,4r)-4-((lR,3*,55)-8-(5- chloropyrimidin-2-yl)- 8 -
7 azabicyclo[3.2. l]octan-3- yloxy)cyclohexyloxy)nicotinon itrile
(lR,3s,5S)-l- methylcyclopropyl 3-((lr,4R)- 4-(3 -cy anopyridin-4-
8
yloxy)cyclohexyloxy)-8-
0 ' azabicyclo[3.2. l]octane-8- carboxylate
(lR,3s,5S)-isopropyl 3- ((1 r,4R)-4-(3-cyanopyridin-4-
9 yloxy)cyclohexyloxy)-8- azabicyclo[3.2. l]octane-8- o 1 carboxylate
(l/?,3i,55)-tert-butyl 3- ((lr,4R)-4-(3-cyano-5- methylpyridin-4-
10
yloxy)cyclohexyloxy)-8-
' 0 ' azabicyclo[3.2. l]octane-8- carboxylate
(l/?,3i,55)-tert-butyl 3- ((lr,4R)-4-(3-cyano-5- lluoropyridin-4-
11
yloxy)cyclohexyloxy)-8-
F 0 1 azabicyclo[3.2. l]octane-8- carboxylate
Figure imgf000035_0001
carboxylate
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
0 ' carboxylate
Figure imgf000039_0001
carboxylate
Figure imgf000040_0001
Figure imgf000041_0001
oxadiazole Cmpd
Chemical Structure Chemical Name No.
(lR,3s,5S)-l- methylcyclopropyl 3-((lr,4R)- 4-(2-methyl-6-
71 (methylsulfonyl)pyridin-3 - yloxy)cyclohexyloxy)-8- o 1 azabicyclo[3.2. l]octane-8- carboxylate
3-(2-fluoropropan-2-yl)-5- ((lR,3s,5S)-3-((lr,4R)-4-(2- methyl-6-
72 (methylsulfonyl)pyridin-3 - yloxy)cyclohexyloxy)-8- azabicyclo[3.2. l]octan-8-yl)- 1 ,2,4-oxadiazole
3-isopropyl-5-((lR,3s,5S)-3-
((lr,4R)-4-(2-methyl-6- (methylsulfonyl)pyridin-3 -
73
yloxy)cyclohexyloxy)-8- o-N azabicyclo[3.2. l]octan-8-yl)- 1 ,2,4-oxadiazole
3-(2-fluoropropan-2-yl)-5- ((lR,3s,5S)-3-((lr,4R)-4-(4- (methylsulfonyl)phenoxy)cyclo
74
hexyloxy)-8- azabicyclo[3.2. l]octan-8-yl)- 1 ,2,4-oxadiazole
5-((lR,3s,5S)-3-((lr,4R)-4-(2- methyl-6- (methylsulfonyl)pyridin-3 -
75 yloxy)cyclohexyloxy)-8- azabicyclo[3.2. l]octan-8-yl)-3-
1 O-N (trifluoromethyl)- 1 ,2,4- oxadiazole
Additionally, individual compounds and chemical genera of the present invention, for example those compounds found in Table A including, isomers, diastereoisomers and enantiomers thereof, encompass all pharmaceutically acceptable salts, solvates, and hydrates, thereof. Further, mesoisomers of individual compounds and chemical genera of the present invention, for example those compounds found in Table A, encompass all pharmaceutically acceptable salts, solvates and particularly hydrates, thereof.
The compounds of the Formula (I) of the present invention may be prepared according to relevant published literature procedures that are used by one skilled in the art. Exemplary reagents and procedures for these reactions appear hereinafter in the working Examples.
Protection and deprotection may be carried out by procedures generally known in the art (see, for example, Greene, T. W. and Wuts, P. G. M., Protecting Groups in Organic Synthesis, 3rd Edition, 1999 [Wiley]). It is understood that the present invention embraces, each isomer, each diastereoisomer, each enantiomer and mixtures thereof of each compound and generic formulae disclosed herein just as if they were each individually disclosed with the specific stereochemical designation for each chiral carbon. Separation of the individual isomers and enantiomers (such as, by chiral HPLC, recrystallization of diastereoisomeric mixtures and the like) or selective synthesis (such as, by enantiomeric selective syntheses and the like) of the individual isomers can be accomplished by application of various methods which are well known to practitioners in the art.
Certain Embodiments: Compositions, Methods, Indications, Pharmaceutical Products, Combinations, and Uses of Compounds of the Present Invention.
In addition to the foregoing, without limitation, certain other embodiments are described and provided below. Certain Compositions of the Present Invention:
One aspect of the present invention pertains to compositions comprising a compound of the present invention. One aspect of the present invention pertains to pharmaceutical products selected from: a pharmaceutical composition, a formulation, a unit dosage form, and a kit; each comprising a compound of the present invention. One aspect of the present invention pertains to pharmaceutical compositions comprising a compound of the present invention, and a pharmaceutically acceptable carrier. One aspect of the present invention pertains to methods for preparing a pharmaceutical composition comprising the step of admixing a compound of the present invention, and a pharmaceutically acceptable carrier; some embodiments pertain to pharmaceutical compositions obtained by any of the methods described herein. One aspect of the present invention pertains to compositions comprising a compound of the present invention, and a second pharmaceutical agent.
In any of the embodiments that recites the terms "a pharmaceutical agent" and "a second pharmaceutical agent", it is appreciated that these terms in some aspects be further limited to a pharmaceutical agent that is not a compound of Formula (I) or a compounds related thereto. It is understood that the terms "a pharmaceutical agent" and "a second pharmaceutical agent" may refer to a pharmaceutical agent that is not detectable or has an EC50 that is greater than a value selected from: 50 μΜ, 10 μΜ, 1 μΜ, and 0.1 μΜ in a GPR119 receptor activity assay as described in Example 4.
One aspect of the present invention pertains to methods for preparing a composition comprising the step of admixing a compound of the present invention, and a second pharmaceutical agent; some embodiments pertain to compositions obtained by any of the methods described herein. One aspect of the present invention pertains to pharmaceutical products selected from: a pharmaceutical composition, a formulation, a unit dosage form, a combined preparation, a twin pack, and a kit; each comprising a compound of the present invention, and a second pharmaceutical agent. One aspect of the present invention pertains to pharmaceutical compositions comprising a compound of the present invention, a second pharmaceutical agent, and a pharmaceutically acceptable carrier. One aspect of the present invention pertains to methods for preparing a pharmaceutical composition comprising the step of admixing a compound of the present invention, a second pharmaceutical agent, and a pharmaceutically acceptable carrier; some embodiments pertain to pharmaceutical compositions obtained by any of the methods described herein.
Certain Methods, Pharmaceutical Products, Combinations, and Uses of the Present Invention:
One aspect of the present invention pertains to methods selected from one or more of the following: 1) for modulating the activity of a GPR119 receptor; 2) for agonizing a GPR119 receptor; 3) for increasing the secretion of an incretin in an individual; 4) increasing a blood incretin level in an individual; and 5) for treating/treatment of a disorder selected from: a GPR119-receptor-related disorder; a condition ameliorated by increasing secretion of an incretin; a condition ameliorated by increasing a blood incretin level; a condition characterized by low bone mass; a neurological disorder; a metabolic-related disorder; type 2 diabetes; and obesity; in an individual; comprising: A) administering to an individual in need thereof or B) prescribing to an individual in need thereof, a therapeutically effective amount of: a compound of the present invention; a composition of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention; each optionally in combination with a therapeutically effective amount of a second pharmaceutical agent.
Some embodiments pertain to methods comprising administering to an individual in need thereof a therapeutically effective amount of: a compound of the present invention; a composition of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention. Some embodiments pertain to methods for prescribing to an individual in need thereof, a therapeutically effective amount of: a compound of the present invention; a composition of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention.
One aspect of the present invention pertains to the use of a compound of the present invention, optionally in combination with a second pharmaceutical agent, in the manufacture of a medicament, selected from one or more of the following: 1) for modulating the activity of a GPR119 receptor in an individual; 2) for agonizing a GPR119 receptor; 3) for increasing the secretion of an incretin in an individual; 4) increasing a blood incretin level in an individual; and 5) for treating/treatment of a disorder selected from: a GPR119-receptor-related disorder; a condition ameliorated by increasing secretion of an incretin; a condition ameliorated by increasing a blood incretin level; a condition characterized by low bone mass; a neurological disorder; a metabolic-related disorder; type 2 diabetes; and obesity.
One aspect of the present invention pertains to a compound of the present invention; a composition of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention; optionally in combination with a second pharmaceutical agent, for use in a method of treatment of the human or animal body by therapy.
One aspect of the present invention pertains to one or more of the following: methods of the present invention, compounds of the present invention; compositions of the present invention; pharmaceutical products of the present invention; and pharmaceutical compositions of the present invention; optionally in combination with a second pharmaceutical agent, for use in a method selected from one or more of the following: 1) for modulating the activity of a GPR119 receptor; 2) for agonizing a GPR119 receptor; 3) for increasing the secretion of an incretin in an individual; 4) increasing a blood incretin level in an individual; and 5) for treating/treatment of a disorder selected from: a GPR119-receptor-related disorder; a condition ameliorated by increasing secretion of an incretin; a condition ameliorated by increasing a blood incretin level; a condition characterized by low bone mass; a neurological disorder; a metabolic- related disorder; type 2 diabetes; and obesity.
One aspect of the present invention pertains to a pharmaceutical agent in combination with a compound of the present invention; a composition of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention; for use in a method of treatment of the human or animal body by therapy.
One aspect of the present invention pertains to a pharmaceutical agent in combination with a compound of the present invention; a composition of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention; for use in a method selected from one or more of the following: 1) for modulating the activity of a GPR119 receptor; 2) for agonizing a GPR119 receptor; 3) for increasing the secretion of an incretin in an individual; 4) increasing a blood incretin level in an individual; and 5) for treating/treatment of a disorder selected from: a GPR119-receptor-related disorder; a condition ameliorated by increasing secretion of an incretin; a condition ameliorated by increasing a blood incretin level; a condition characterized by low bone mass; a neurological disorder; a metabolic-related disorder; type 2 diabetes; and obesity.
Some embodiments pertain to methods, uses, compounds, and pharmaceutical agents, each as described herein, for modulating the activity of a GPR119 receptor. Some embodiments pertain to methods, uses, compounds, and pharmaceutical agents, each as described herein, for agonizing a GPR119 receptor. Some embodiments pertain to methods, uses, compounds, and pharmaceutical agents, each as described herein, for increasing the secretion of an incretin in an individual. Some embodiments pertain to methods, uses, compounds, and pharmaceutical agents, each as described herein, for increasing a blood incretin level in an individual. Some embodiments pertain to methods, uses, compounds, and pharmaceutical agents, each as described herein, for treatment of a disorder selected from: a GPR119-receptor-related disorder; a condition ameliorated by increasing secretion of an incretin; a condition ameliorated by increasing a blood incretin level; a condition characterized by low bone mass; a neurological disorder; a metabolic-related disorder; and obesity; in an individual.
In some embodiments, the disorder is a GPR119-receptor-related disorder. In some embodiments, the disorder is a condition ameliorated by increasing secretion of an incretin. In some embodiments, the disorder is a condition ameliorated by increasing a blood incretin level. In some embodiments, the disorder is a condition characterized by low bone mass. In some embodiments, the disorder is a neurological disorder. In some embodiments, the disorder is a metabolic -related disorder. In some embodiments, the disorder is obesity. In some embodiments, the disorder is type 2 diabetes. In some embodiments, the disorder is hyperglycemia. In some embodiments, the disorder is hyperlipidemia. In some embodiments, the disorder is
hypertriglyceridemia. In some embodiments, the disorder is type 1 diabetes. In some embodiments, the disorder is dyslipidemia. In some embodiments, the disorder is syndrome X.
In some embodiments, the pharmaceutical product comprises a pharmaceutical composition. In some embodiments, the pharmaceutical product comprises a formulation. In some embodiments, the pharmaceutical product comprises a unit dosage form. In some embodiments, the pharmaceutical product comprises a kit. In some embodiments, the pharmaceutical product comprises a combined preparation. In some embodiments, the pharmaceutical product comprises a twin pack.
In some embodiments, the compound and pharmaceutical agent or the second pharmaceutical agent are administered simultaneously, separately, or sequentially. In some embodiments, the compound and the pharmaceutical agent or the second pharmaceutical agent are administered simultaneously. In some embodiments, the compound and the pharmaceutical agent or the second pharmaceutical agent are administered separately. In some embodiments, the compound and the pharmaceutical agent or the second pharmaceutical agent are
administered sequentially.
In some embodiments, the incretin is GLP-1. In some embodiments, the incretin is GIP. In some embodiments, the incretin is PYY.
One aspect of the present invention pertains to compositions, methods, pharmaceutical products, pharmaceutical compositions, uses; compounds, and pharmaceutical agents, each as described herein, wherein the pharmaceutical agent or the second pharmaceutical agent is selected from: a DPP-IV inhibitor, a biguanide, an alpha-glucosidase inhibitor, an insulin analogue, a sulfonylurea, an SGLT2 inhibitor, a meglitinide, a thiazolidinedione, and an anti- diabetic peptide analogue. As provided herein are specific non-limiting examples of each of these agents.
One aspect of the present invention pertains to compositions, methods, pharmaceutical products, pharmaceutical compositions, uses; compounds, and pharmaceutical agents, each as described herein, wherein: 1) the compound and the pharmaceutical agent or the second pharmaceutical agent are provided in amounts which give a synergistic effect in treating the disorder; 2) the amount of the compound alone is substantially therapeutically ineffective at treating the disorder; and/or 3) the amount of the pharmaceutical agent alone or the second pharmaceutical agent alone is substantially therapeutically ineffective at treating the disorder.
One aspect of the present invention relates to methods for preparing pharmaceutical products of the present invention comprising the steps: mixing said compound with a first pharmaceutically acceptable carrier to prepare a compound unit dosage form; mixing said second pharmaceutical agent with a second pharmaceutically acceptable carrier to prepare a second pharmaceutical agent unit dosage form; and combining said compound unit dosage form and said second pharmaceutical agent unit dosage form in a combined unit dosage form for simultaneous, separate, or sequential use.
In some embodiments, the first pharmaceutically acceptable carrier is different from the second pharmaceutically acceptable carrier. In some embodiments, the different
pharmaceutically acceptable carriers are suitable for administration by the same route. In some embodiments, the different pharmaceutically acceptable carriers are suitable for administration by different routes. In some embodiments, the first pharmaceutically acceptable carrier is substantially the same as the second pharmaceutically acceptable carrier. In some embodiments, the substantially the same pharmaceutically acceptable carriers are suitable for oral
administration.
Certain Indications of the Present Invention:
In the context of the present invention, a compound as described herein or a pharmaceutical composition thereof can be utilized for modulating the activity of GPR119- receptor and therefore related diseases, conditions and/or disorders related thereto such as those described herein.
In some embodiments, modulating the activity includes the treatment of a GPR119- receptor-related disorder. In some embodiments, a GPR119-receptor-related disorder is a condition ameliorated by increasing a blood incretin level. In some embodiments, a GPR119- receptor-related disorder is a condition characterized by low bone mass. In some embodiments, a GPR119-receptor-related disorder is a neurological disorder. In some embodiments, a
GPR119-receptor-related disorder is a metabolic-related disorder. In some embodiments, a GPR119-receptor-related disorder is type 2 diabetes. In some embodiments, a GPR119-receptor- related disorder is obesity
Some embodiments of the present invention include every combination of one or more conditions characterized by low bone mass selected from: osteopenia, osteoporosis, rheumatoid arthritis, osteoarthritis, periodontal disease, alveolar bone loss, osteotomy bone loss, childhood idiopathic bone loss, Paget' s disease, bone loss due to metastatic cancer, osteolytic lesions, curvature of the spine, and loss of height.
In some embodiments, the neurological disorder selected from: stroke and
Parkinsonism.
Some embodiments of the present invention include every combination of one or more metabolic -related disorders selected from: type 1 diabetes, type 2 diabetes mellitus, and conditions associated therewith, such as, but not limited to, coronary heart disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease, intermittent claudication, myocardial infarction (e.g. necrosis and apoptosis), dyslipidemia, post-prandial lipemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy, macular degeneration, cataract, 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, vascular restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, insulin resistance, impaired glucose metabolism, erectile dysfunction, skin and connective tissue disorders, foot ulcerations and ulcerative colitis, endothelial dysfunction and impaired vascular compliance.
Some embodiments of the present invention include every combination of one or more metabolic -related disorders selected from: diabetes, type 1 diabetes, type 2 diabetes, inadequate glucose tolerance, impaired glucose tolerance, insulin resistance, hyperglycemia,
hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, atherosclerosis, stroke, syndrome X, hypertension, pancreatic beta-cell insufficiency, enteroendocrine cell insufficiency, glucosuria, metabolic acidosis, cataracts, diabetic nephropathy, diabetic neuropathy, peripheral neuropathy, diabetic coronary artery disease, diabetic cerebrovascular disease, diabetic peripheral vascular disease, diabetic retinopathy, metabolic syndrome, a condition related to diabetes, myocardial infarction, learning impairment, memory impairment, a neurodegenerative disorder, a condition ameliorated by increasing a blood GLP-1 level in an individual with a neurodegenerative disorder, excitotoxic brain damage caused by severe epileptic seizures, Alzheimer's disease, Parkinson's disease, Huntington's disease, prion- associated disease, motor-neuron disease, traumatic brain injury, spinal cord injury, and obesity. In some embodiments, the disorder is type 2 diabetes. In some embodiments, the disorder is hyperglycemia. In some embodiments, the disorder is hyperlipidemia. In some embodiments, the disorder is hypertriglyceridemia. In some embodiments, the disorder is type 1 diabetes. In some embodiments, the disorder is dyslipidemia. In some embodiments, the disorder is syndrome X. In some embodiments, the disorder is obesity.
One aspect of the present invention pertains to methods for weight management, comprising administering to an individual in need thereof, a therapeutically effective amount of a compound of the present invention in combination with a therapeutically effective amount of a pharmaceutical agent, such as any agent described herein; wherein the compound and the pharmaceutical agent.
In some embodiments, the weight management comprises weight loss. In some embodiments, the weight management comprises maintenance of weight loss. In some embodiments, the weight management further comprises a reduced-calorie diet. In some embodiments, the weight management further comprises a program of regular exercise. In some embodiments, the weight management further comprises both a reduced-calorie diet and a program of regular exercise.
In some embodiments, the individual in need of weight management is a patient with an initial body mass of index > 40 kg/m2; > 39 kg/m2; > 38 kg/m2; > 37 kg/m2; > 36 kg/m2; > 35 kg/m2; > 34 kg/m2; > 33 kg/m2; > 32 kg/m2; > 31 kg/m2; > 30 kg/m2; > 29 kg/m2; > 28 kg/m2; > 27 kg/m2; > 26 kg/m2; > 25 kg/m2; > 24 kg/m2; > 23 kg/m2; > 22 kg/m2; > 21 kg/m2; or > 20 kg/m2; and the patient optionally has at least one or at least two weight related comorbid condition(s).
In some embodiments, the comorbid condition(s) when present are selected from:
hypertension, dyslipidemia, cardiovascular disease, glucose intolerance, and sleep apnea.
Formulations and Compositions
Formulations may be prepared by any suitable method, typically by uniformly mixing the active compound(s) with liquids or finely divided solid carriers, or both, in the required proportions and then, if necessary, forming the resulting mixture into a desired shape.
Conventional excipients, such as binding agents, fillers, acceptable wetting agents, tabletting lubricants and disintegrants may 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, the oral preparations may be in the form of dry powder that can be reconstituted with water or another suitable liquid vehicle before use. Additional additives such as suspending or emulsifying agents, non-aqueous vehicles (including edible oils), preservatives and flavorings and colorants may be added to the liquid preparations. Parenteral dosage forms may be prepared by dissolving the compound of the invention in a suitable liquid vehicle and filter sterilizing the solution before filling and sealing an appropriate vial or ampule. These are just a few examples of the many appropriate methods well known in the art for preparing dosage forms.
A compound of the present invention can be formulated into pharmaceutical compositions using techniques well known to those in the art. Suitable pharmaceutically- acceptable carriers, outside 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 use in the prophylaxis or treatment, a compound of the invention may, in an alternative use, be administered as a raw or pure chemical, it is preferable however to present the compound or active ingredient as a pharmaceutical formulation or composition further comprising a pharmaceutically acceptable carrier.
Pharmaceutical formulations include those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, sub- cutaneous and intravenous) administration or in a form suitable for administration by inhalation, insufflation or by a transdermal patch. Transdermal patches dispense a drug at a controlled rate by presenting the drug for absorption in an efficient manner with minimal degradation of the drug. Typically, transdermal patches comprise an impermeable backing layer, a single pressure sensitive adhesive and a removable protective layer with a release liner. One of ordinary skill in the art will understand and appreciate the techniques appropriate for manufacturing a desired efficacious transdermal patch based upon the needs of the artisan.
The compounds of the invention, together with a conventional adjuvant, carrier, or diluent, may thus be placed into the form of pharmaceutical formulations and unit dosages thereof and in such form may be employed as 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 unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient.
Examples of such dosage units are capsules, tablets, powders, granules or a suspension, with conventional additives such as lactose, mannitol, corn starch or potato starch; with binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators such as corn starch, potato starch or sodium carboxymethyl-cellulose; and with lubricants such as talc or magnesium stearate. The active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable pharmaceutically acceptable carrier.
Compounds of the present invention or a solvate, hydrate or physiologically functional derivative thereof can be used as active ingredients in pharmaceutical compositions, specifically 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 the primary pharmacological effect, as opposed to an "inactive ingredient" which would generally be recognized as providing no pharmaceutical benefit.
The dose when using the compounds of the present invention can vary within wide limits and as is customary and is known to the physician, it is to be tailored to the individual conditions in each individual case. It depends, for example, on the nature and severity of the illness to be treated, on the condition of the patient, on the compound employed or on whether an acute or chronic disease state is treated or prophylaxis conducted or on whether further active compounds are administered in addition to the compounds of the present invention.
Representative doses of the present invention include, but not limited to, about 0.001 mg to about 5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg to about 1000 mg, 0.001 mg to about 500 mg, 0.001 mg to about 250 mg, about 0.001 mg to 100 mg, about 0.001 mg to about 50 mg and about 0.001 mg to about 25 mg. Multiple doses may be administered during the day, especially when relatively large amounts are deemed to be needed, for example 2, 3 or 4 doses. Depending on the individual and as deemed appropriate from the patient's physician or caregiver it may be necessary to deviate upward or downward from the doses described herein.
The amount of active ingredient, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected 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 attendant physician or clinician. In general, one skilled in the art understands how to extrapolate in vivo data obtained in a model system, typically an animal model, to another, such as a human. In some circumstances, these extrapolations may merely be based on the weight of the animal model in comparison to another, such as a mammal, preferably a human, however, more often, these extrapolations are not simply based on weights, but rather incorporate a variety of factors. Representative factors include the type, age, weight, sex, diet and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized, on whether an acute or chronic disease state is being treated or prophylaxis conducted or on whether further active compounds are administered in addition to the compounds of the present invention and as part of a drug combination. The dosage regimen for treating a disease condition with the compounds and/or compositions of this invention is selected in accordance with a variety factors as cited above. Thus, the actual dosage regimen employed may vary widely and therefore may deviate from a preferred dosage regimen and one skilled in the art will recognize that dosage and dosage regimen outside these typical ranges can be tested and, where appropriate, may be used in the methods of this invention.
The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations. The daily dose can be divided, especially when relatively large amounts are administered as deemed appropriate, into several, for example 2, 3 or 4 part administrations. If appropriate, depending on individual behavior, it may be necessary to deviate upward or downward from the daily dose indicated.
The compounds of the present invention can be administrated in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a compound of the invention or a pharmaceutically acceptable salt, solvate, or hydrate of a compound of the invention.
For preparing pharmaceutical compositions from the compounds of the present invention, the selection of a suitable pharmaceutically acceptable carrier can be either solid, liquid or a mixture of both. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component.
In tablets, the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted to the desire shape and size.
The powders and tablets may contain varying percentage amounts of the active compound. A representative amount in a powder or tablet may contain from 0.5 to about 90 percent of the active compound; however, an artisan would know when amounts outside of this range are necessary. Suitable carriers for powders and tablets are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter and the like. The term "preparation" refers to the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association 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.
For preparing suppositories, a low melting wax, such as an admixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogenous mixture is then poured into convenient sized molds, allowed to cool and thereby to solidify.
Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
Liquid form preparations include solutions, suspensions and emulsions, for example, water or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated 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 nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds according to the present invention may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The pharmaceutical compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
Aqueous formulations suitable for oral use can be prepared by dissolving or suspending the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents, as desired.
Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, 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 preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents and the like.
For topical administration to the epidermis the compounds according to the invention may be formulated 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 and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
Formulations suitable for topical administration in the mouth include lozenges comprising active agent in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. The formulations may be provided in single or multi-dose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump.
Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurized pack with a suitable propellant. If the compounds of the present invention or pharmaceutical compositions comprising them are administered as aerosols, for example as nasal aerosols or by inhalation, this can be carried out, for example, using a spray, a nebulizer, a pump nebulizer, an inhalation apparatus, a metered inhaler or a dry powder inhaler. Pharmaceutical forms for administration of the compounds of the present invention as an aerosol can be prepared by processes well known to the person 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 employed using customary additives, for example benzyl alcohol or other suitable preservatives, absorption enhancers for increasing the bioavailability, solubilizers, dispersants and others and, if appropriate, customary propellants, for example include carbon dioxide, CFCs, such as, dichlorodifluoromethane, trichlorofluorome thane, or dichlorotetrafluoroe thane; and the like. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by provision of a metered valve.
In formulations intended for administration to the respiratory tract, including intranasal formulations, the compound will generally have a small particle size for example of the order of 10 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization. When desired, formulations adapted to give sustained release of the active ingredient may be employed.
Alternatively the active ingredients may be provided in the form of a dry powder, for example, a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
Conveniently the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.
The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
Tablets or capsules for oral administration and liquids for intravenous administration are preferred compositions.
The compounds according to the invention may optionally exist as pharmaceutically acceptable salts including pharmaceutically acceptable acid addition salts prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids.
Representative acids include, but are not limited to, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic,
methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfide, tartaric, oxalic, /?-toluenesulfonic and the like. Certain compounds of the present invention which 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, aluminium, calcium, lithium, magnesium, potassium, sodium, zinc and the like. In some embodiments the pharmaceutically acceptable metal is sodium. Representative organic bases include, but are not limited to, benzathine (N\N2-dibenzylethane-l,2-diamine), chloroprocaine (2- (diethylamino)ethyl 4-(chloroamino)benzoate), choline, diethanolamine, ethylenediamine, meglumine ((2R,3R,4R,5S)-6-(methylamino)hexane-l,2,3,4,5-pentaol), procaine (2- (diethylamino)ethyl 4-aminobenzoate), and the like. Certain pharmaceutically acceptable salts are listed in Berge, et al., Journal of Pharmaceutical Sciences, 66:1-19 (1977).
The acid addition salts may be obtained as the direct products of compound synthesis. In the alternative, the free base may 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 may form solvates with standard low molecular weight solvents using methods known to the skilled artisan.
Compounds of the present invention can be converted to "pro-drugs." The term "pro- drugs" refers to compounds that have been modified with specific chemical groups known in the art and when administered into an individual these groups undergo biotransformation to give the parent compound. Pro-drugs can thus be viewed as compounds of the invention containing one or more specialized non-toxic protective groups used in a transient manner to alter or to eliminate a property of the compound. In one general aspect, the "pro-drug" approach is utilized to facilitate oral absorption. A thorough discussion is provided in T. Higuchi and V. Stella, Prodrugs 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 producing a pharmaceutical composition for "combination-therapy" comprising admixing at least one compound according to any of the compound embodiments disclosed herein, together with at least one known pharmaceutical agent as described herein and a pharmaceutically acceptable carrier.
It is noted that when the GPRl 19 receptor modulators are utilized as active ingredients in pharmaceutical compositions, these are not intended for use in humans only, but in non- human mammals as well. Recent advances in the area of animal health-care mandate that consideration be given for the use of active agents, such as GPRl 19 receptor modulators, for the treatment of a GPRl 19 receptor-associated disease or disorder in companionship animals (e.g., cats, dogs, etc.) and in livestock animals (e.g., horses, cows, etc.) Those of ordinary skill in the art are readily credited with understanding the utility of such compounds in such settings.
Hydrates and Solvates
It is understood that when the phrase "pharmaceutically acceptable salts, solvates, and hydrates" or the phrase "pharmaceutically acceptable salt, solvate, or hydrate" is used when referring to compounds described herein, it embraces pharmaceutically acceptable solvates and/or hydrates of the compounds, pharmaceutically acceptable salts of the compounds, as well as pharmaceutically acceptable solvates and/or hydrates of pharmaceutically acceptable salts of the compounds. It is also understood that when the phrase "pharmaceutically acceptable solvates and hydrates" or the phrase "pharmaceutically acceptable solvate or hydrate" is used when referring to salts described herein, it embraces pharmaceutically acceptable solvates and/or hydrates of such salts. It will be apparent to those skilled in the art that the dosage forms described herein may comprise, as the active component, either a compound described herein or a pharmaceutically acceptable salt or as a pharmaceutically acceptable solvate or hydrate thereof. Moreover, various hydrates and solvates of the compounds described herein and their salts will find use as intermediates in the manufacture of pharmaceutical compositions. Typical procedures for making and identifying suitable hydrates and solvates, outside those mentioned herein, are well known to those 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 pertains to methods of administering hydrates and solvates of compounds described herein and/or their pharmaceutical acceptable salts, that can be isolated and characterized by methods known in the art, such as, thermogravimetric analysis (TGA), TGA-mass spectroscopy, TGA-Infrared spectroscopy, powder X-ray diffraction (XRPD), Karl Fisher titration, high resolution X-ray diffraction, and the like. There are several commercial entities that provide quick and efficient services for identifying solvates and hydrates on a routine basis. Example companies offering these services include Wilmington PharmaTech (Wilmington, DE), Avantium Technologies (Amsterdam) and Aptuit (Greenwich, CT).
Polymorphs and Pseudopolymorphs
Polymorphism is the ability of a substance to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattice.
Polymorphs show 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 host and either solvent or water molecules, respectively, as guests. Analogously, when the guest compound is a solid at room temperature, the resulting form is often called a cocrystal. Salts, solvates, hydrates, and cocrystals may show polymorphism as well. Crystalline phases that share the same API host, but differ with respect to their guests, may be referred to as
pseudopolymorphs of one another.
Solvates contain molecules of the solvent of crystallization in a definite crystal lattice. Solvates, in which the solvent of crystallization is water, are termed hydrates. Because water is a constituent of the atmosphere, hydrates of drugs may be formed rather easily.
By way of example, Stahly recently published a polymorph screen of 245 compounds consisting of a "wide variety of structural types" that revealed about 90% of the compounds exhibited multiple solid forms. Overall, approximately half the compounds were polymorphic, often having one to three forms. About one-third of the compounds formed hydrates, and about one-third formed other solvates. Data from cocrystal screens of 64 compounds showed that 60% formed cocrystals other than hydrates or solvates. (G. P. Stahly, Crystal Growth & Design
(2007), 7(6), 1007-1026).
Crystalline forms can be identified by their unique solid state signature with respect to, for example, differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and other solid state methods.
Further characterization with respect to water or solvent content of crystalline forms can be determined by any of the following methods, for example, thermogravimetric analysis
(TGA), Karl Fischer analysis, and the like.
For DSC, it is known that the temperatures observed will depend upon sample purity, the rate of temperature change, as well as sample preparation technique and the particular instrument employed. Thus, the values relating to DSC thermograms can vary by plus or minus about 4 °C (± 4 °C). The values relating to DSC thermograms can also vary by plus or minus about 20 joules per gram (± 20 joules per gram).
DSC can be used to observe desolvation events. When DSC thermogram values relate to desolvation events, the values are understood to be estimates. Scan rate and pan closure can influence DSC values for desolvation events, which can vary by plus or minus about 25 °C.
DSC values for desolvation events are typically recorded using a sample in an aluminum pan with an uncrimped lid and a scan rate of 10 °C/min.
For PXRD, the relative intensities of the peaks can vary, depending upon the sample preparation technique, the sample mounting procedure and the particular instrument employed.
Moreover, instrument variation and other factors can often affect the 2 lvalues. Therefore, the peak assignments of diffraction patterns can vary by plus or minus 0.2 °2Θ (± 0.2 °2Θ).
For TGA, the features reported herein can vary by plus or minus about 5 °C (± 5 °C). The TGA features can also vary by plus or minus about 2% (± 2%) weight change due to, for example, sample variation.
Further characterization with respect to hygroscopicity of a crystalline form can be gauged by, for example, dynamic moisture sorption (DMS). The DMS features can vary by plus or minus about 5% (± 5%) relative humidity. The DMS features can also vary by plus or minus about 5% (± 5%) weight change.
COMBINATION THERAPY
A compound of the invention can be administered as the sole active pharmaceutical agent {i.e. , mono-therapy), or it can be used in combination with one or more pharmaceutical agents {i.e. , combination-therapy), such as pharmaceutical agents, such as, known anti-diabetic agents, either administered together or separately for the treatment of the diseases, conditions, and disorders described herein. Therefore, another aspect of the present invention includes methods of treatment of a metabolic related disorder, including a weight-related disorder, such as obesity, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of Formula (I) and pharmaceutically acceptable salts, solvates and hydrates 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 components, a compound of Formula (I) and a pharmaceutical agent, either together or independently optionally with a physiologically acceptable carrier, excipient, binder, diluent, etc. , as described herein, and administering the mixture or mixtures either orally or non- orally as a pharmaceutical composition(s). When a compound of Formula (I) is administered as a combination therapy with another active compound the compound of Formula (I) and the pharmaceutical agent can be formulated as separate pharmaceutical compositions given at the same time or at different times; or the compound of Formula (I) and the pharmaceutical agent can be formulated together as a single unit dosage.
Suitable pharmaceutical agents that can be used in combination with the compounds of the present invention include anti-obesity agents such as apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors; MCR-4 agonists, cholescystokinin-A (CCK-A) agonists; serotonin and norepinephrine reuptake inhibitors (for example, sibutramine); sympathomimetic agents; β3 adrenergic receptor agonists; dopamine agonists (for example, bromocriptine); melanocyte-stimulating hormone receptor analogues; cannabinoid 1 receptor antagonists [for example, SR141716: N-(piperidin-l-yl)-5-(4-chlorophenyl)-l-(2,4- dichlorophenyl)-4-methyl-lH-pyrazole-3-carboxamide]; melanin concentrating hormone antagonists; leptin (the OB protein); leptin analogues; leptin receptor agonists; galanin antagonists; lipase inhibitors (such as tetrahydrolipstatin, i.e. , Orlistat); anorectic agents (such as a bombesin agonist); neuropeptide -Y antagonists; thyromimetic agents; dehydroepiandrosterone or an analogue thereof; glucocorticoid receptor agonists or antagonists; orexin receptor antagonists; urocortin binding protein antagonists; glucagon-like peptide- 1 (GLP-1) receptor agonists; ciliary neutrotrophic factors (such as Axokine™ available from Regeneron
Pharmaceuticals, Inc., Tarrytown, ΝΥ and Procter & Gamble Company, Cincinnati, OH);
human agouti-related proteins (AGRP); ghrelin receptor antagonists; histamine 3 receptor (H3R) antagonists or inverse agonists; neuromedin U receptor agonists; noradrenergic anorectic agents (for example, phentermine, mazindol and the like); and appetite suppressants (for example, bupropion).
Other anti-obesity agents, including the agents set forth infra, are well known, or will be readily apparent in light of the instant disclosure, to one of ordinary skill in the art. In some embodiments, the anti-obesity agents are selected from the group consisting of orlistat, sibutramine, bromocriptine, ephedrine, leptin, and pseudoephedrine. In a further embodiment, compounds of the present invention and combination therapies are administered in conjunction with exercise and/or a calorie -controlled diet.
It is understood that the scope of combination-therapy of the compounds of the present invention with anti-obesity agents, anorectic agents, appetite suppressant and related agents is not limited to those listed above, but includes in principle any combination with any
pharmaceutical agent or pharmaceutical composition useful for the treatment of overweight and obese individuals.
It is understood that the scope of combination-therapy of the compounds of the present invention with other pharmaceutical agents is not limited to those listed herein, supra or infra, but includes in principle any combination with any pharmaceutical agent or pharmaceutical composition useful for the treatment of diseases, conditions or disorders that are linked to metabolic related disorders.
Some embodiments of the present invention include methods of treatment of a disease, disorder, condition or complication thereof as described herein, comprising administering to an individual in need of such treatment a therapeutically effective amount or dose of a compound of Formula (I) in combination with at least one pharmaceutical agent selected from the group consisting of: sulfonylureas (for example, tolbutamide (Orinase); acetohexamide (Dymelor); tolazamide (Tolinase); chlorpropamide (Diabinese); glipizide (Glucotrol); glyburide (Diabeta, Micronase, Glynase); glimepiride (Amaryl); gliclazide (Diamicron); and sulfonylureas known in the art); meglitinides (for example, repaglinide (Prandin), nateglinide (Starlix), mitiglinide, and other meglitinides known in the art); biguanides (for example, phenformin, metformin, buformin, and biguanides known in the art); oc-glucosidase inhibitors (for example, acarbose, miglitol, and a-glucosidase inhibitors known in the art); thiazolidinediones - peroxisome proliferators-activated receptor-γ {i.e. , PPAR-γ) agonists (for example, rosiglitazone (Avandia), pioglitazone (Actos), troglitazone (Rezulin), rivoglitazone, ciglitazone, and thiazolidinediones known in the art); insulin and insulin analogues; anti-diabetic peptide analogues (for example, exenatide, liraglutide, taspoglutide, and anti-diabetic peptides analogues know in the art); HMG- CoA reductase inhibitors (for example, 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 (for example, fibrates that include: bezafibrate, beclobrate, binifibrate, ciplofibrate, clinofibrate, clofibrate, clofibric acid, etofibrate, fenofibrate, gemfibrozil, nicofibrate, pirifibrate, ronifibrate, simfibrate, theofibrate, and other fibrates known in the art; bile acid sequestrants which include:
cholestyramine, colestipol and the like; and niacin); antiplatelet agents (for example, aspirin and adenosine diphosphate receptor antagonists that include: clopidogrel, ticlopidine and the like); angiotensin-converting enzyme inhibitors (for example, captopril, enalapril, alacepril, delapril; ramipril, lisinopril, imidapril, benazepril, ceronapril, cilazapril, enalaprilat, fosinopril, moveltopril, perindopril, quinapril, spirapril, temocapril, trandolapril, and other angiotensin converting enzyme inhibitors known in the art); angiotensin II receptor antagonists [for example, losartan (and the potassium salt form), and other angiotensin II receptor antagonists known in the art; adiponectin; squalene synthesis inhibitors {for example, (5)-a-[bis[2,2- dimethyl- 1 -oxopropoxy)methoxy] phosphinyl]-3-phenoxybenzenebutanesulfonic acid, mono potassium salt (BMS-188494) and other squalene synthesis inhibitors known in the art} ; and the like. In some embodiments, compounds of the present invention and the pharmaceutical agents are administered separately. In further embodiments, compounds of the present invention and the pharmaceutical agents are administered simultaneously.
Suitable pharmaceutical agents that can be used in conjunction with compounds of the present invention include, but are not limited to: amylin agonists (for example, pramlintide); insulin secretagogues (for example, GLP-1 agonists, exendin-4, and insulinotropin (NN2211)); acyl CoA cholesterol acetyltransierase inhibitors (for example, ezetimibe, eflucimibe, and other acyl CoA cholesterol acetyltransierase inhibitors known in the art); cholesterol absorption inhibitors (for example, ezetimibe, pamaqueside and other cholesterol absorption inhibitors known in the art); cholesterol ester transfer protein inhibitors (for example, CP-529414, JTT- 705, CETi-1, and other cholesterol ester transfer protein inhibitors known in the art);
microsomal triglyceride transfer protein inhibitors (for example, implitapide, and other microsomal triglyceride transfer protein inhibitors known in the art); cholesterol modulators (for example, NO-1886, and other cholesterol modulators known in the art); bile acid modulators (for example, GT 103 -279 and other bile acid modulators known in the art); insulin signaling pathway modulators; inhibitors of protein tyrosine phosphatases (PTPases); non-small molecule mimetics and inhibitors of glutamine-fructose-6-phosphate amidotransf erase (GFAT);
compounds influencing a dysregulated hepatic glucose production; inhibitors of glucose-6- phosphatase (G6Pase); inhibitors of fructose-l,6-bisphosphatase (F-l,6-BPase); inhibitors of glycogen phosphorylase (GP); glucagon receptor antagonists; inhibitors of phosphoenolpyruvate carboxykinase (PEPCK); pyruvate dehydrogenase kinase (PDHK) inhibitors; insulin sensitivity enhancers; insulin secretion enhancers; inhibitors of gastric emptying; ^-adrenergic antagonists; retinoid X receptor (RXR) agonists; and dipeptidyl peptidase-4 (DPP-IV) inhibitors; DGAT-1 inhibitors; and the like.
Tripartite Combinations
Some aspects of the present invention include compounds of Formula (I) that can be employed in any of the methods, pharmaceutical products, uses, compounds, and
pharmaceutical agents, as described herein, in combination with two distinct pharmaceutical agents. In some embodiments, the two distinct pharmaceutical agents are selected from any of the pharmaceutical agents, or classes of pharmaceutical agents described herein. In some embodiments, the two distinct pharmaceutical agents are selected from: an inhibitor of DPP-IV, a biguanide, an alpha-glucosidase inhibitor, an insulin analogue, a sulfonylurea, a SGLT2 inhibitor, a meglitinide, a thiazolidinedione, and an anti-diabetic peptide analogue. In some embodiments, the two distinct pharmaceutical agents include every combination selected from pharmaceutical agents of the following group: an inhibitor of DPP-IV, a biguanide, an alpha- glucosidase inhibitor, a sulfonylurea, and a SGLT2 inhibitor.
Some embodiments of the present invention include every combination of one or more compounds selected from compounds of the following group and pharmaceutically acceptable salts, solvates, and hydrates thereof: an inhibitor of DPP-IV selected from: 3(R)-amino-l -[3- (trifluoromethyl)-5,6,7,8-tetrahydro[l ,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5- trifluorophenyl)butan-l -one; l-[2-(3-hydroxyadamant-l-ylamino)acetyl]pyrrolidine-2(5)- carbonitrile; (15,35,55)-2-[2(5)-amino-2-(3-hydroxyadamantan-l-yl)acetyl]-2- azabicyclo[3.1.0]hexane-3-carbonitrile; 2-[6-[3(R)-aminopiperidin-l-yl]-3-methyl-2,4-dioxo- 1 ,2,3 ,4-tetrahydropyrimidin- 1 -ylmethyl] benzonitrile ; 8-[3(R)-aminopiperidin- 1 -yl] -7-(2- butynyl)-3-methyl-l-(4-methylquinazolin-2-ylmethyl)xanthine; 1-[N-[3(R)- pyrrolidinyl]glycyl]pyrrolidin-2(R)-yl boronic acid; 4(5)-fluoro-l-[2-[(lR,35)-3-(lH-l ,2,4- triazol-l-ylmethyl)cyclopentylamino]acetyl]pyrrolidine-2(5)-carbonitrile; l-[(25,35, l lb5)-2- amino-9, 10-dimethoxy-2,3,4,6,7, l lb-hexahydro-lH-pyrido[2,l-a]isoquinolin-3-yl]-4(5)- (fluoromethyl)pyrrolidin-2-one ; (25,45)-2-cyano-4-fluoro- 1 - [(2-hydroxy- 1 , 1 -dimethyl) ethylamino]acetylpyrrolidine; 8-(cw-hexahydro-pyrrolo[3,2-b]pyrrol-l -yl)-3-methyl-7-(3- methyl-but-2-enyl)-l -(2-oxo-2-phenylethyl)-3,7-dihydro-purine-2,6-dione; l-((35,45)-4-amino- 1 -(4-(3 , 3 -difluoropyrrolidin- 1 -yl) - 1 , 3 ,5 -triazm
(R)-2-((6-(3 -aminopiperidin- 1 -yl)-3 -methyl -2,4-dioxo-3 ,4-dihydropyrimidin- 1 (2H)-yl)methyl)- 4-fluorobenzonitrile; 5-{ (5)-2-[2-((5)-2-cyano-pyrrolidin-l-yl)-2-oxo-ethylamino]-propyl}-5- (lH-tetrazol-5-yl)10, l l-dihydro-5H-dibenzo[a,d]cycloheptene-2,8-dicarboxylic acid bis- dimethylamide ; ((25,45)-4-(4-(3-methyl- 1 -phenyl- 1 H-pyrazol-5 -yl)piperazin- 1 -yl)pyrrolidin-2- yl)(thiazolidin-3-yl)methanone ; (25,45)- 1 -[2- [(4-ethoxycarbonylbicyclo [2.2.2] oct- 1 - yl)amino] acetyl] -4-fluoropyrrolidine-2-carbonitrile; 6-[(3R)-3-amino-piperidin-l -yl]-5-(2- chloro-5-fluoro-benzyl)- 1 ,3 -dimethyl- 1 ,5dihydro-pyrrolo [3 ,2-d]pyrimidine-2,4-dione; 2-( { 6- [(3R)-3 -amino-3 -methylpiperidin- 1 -yl] - 1 ,3 -dimethyl-2,4-dioxo- 1 ,2,3 ,4-tetrahydro-5H- pyrrolo[3,2-d]pyrimidin-5-yl}methyl)-4-fluorobenzonitrile; (25)-l -{ [2-(5-methyl-2-phenyl- oxazol-4-yl)-ethylamino] -acetyl } -pyrrolidine-2-carbonitrile ; (25)- 1 - { [ 1 , 1 -dimethyl-3-(4-pyridin- 3-yl-imidazol- 1 -yl)-propylamino] -acetyl } -pyrrolidine-2-carbonitrile; (3,3-difluoropyrrolidin- 1 - yl)-((25,45)-4-(4-(pyrimidin-2-yl)piperazin-l-yl)pyrrolidin-2-yl)methanone; (25,45)-l -[(25)-2- amino-3,3-bis(4-fluorophenyl)propanoyl]-4-fluoropyrrolidine-2-carbonitrile; (25,5R)-5-ethynyl- 1- {N-(4-methyl-l-(4-carboxy-pyridin-2-yl)piperidm^ and (15,6R)-3-{ [3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4 -a]pyrazin-7(8H)-yl]carbonyl}-6- (2,4,5-trifluorophenyl)cyclohex-3-en-l-amine; a biguanide selected from: phenformin
((phenylethyl)biguanide); metformin (dimethylbiguanide); buformin (butylbiguanide); and proguanil (l-(p-chlorophenyl)-5-isopropylbiguanide); an a-glucosidase inhibitor selected from: acarbose ((2R,3R,4R,5R)-4-((2R,3R,4R,55,6R)-5-((2R,3R,45,55,6R)-3,4-dihydroxy-6-methyl-5- ((15,4R,55,65)-4,5,6-trihydroxy-3-(hydroxymethyl)cyclohex-2-enylamino)tetrahydro-2H-pyran-
2- yloxy)-3,4-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yloxy)-2,3,5,6- tetrahydroxyhexanal); miglitol ((2R,3R,4R,5S)-1 -(2-hydroxyethyl)-2- (hydroxymethyl)piperidine-3,4,5-triol); and voglibose ((lS,2S,3R,4S,5S)-5-(l,3- dihydroxypropan-2-ylamino)-l-(hydroxymethyl)cyclohexane-l,2,3,4-tetraol); an insulin analogue selected from: ΝΡΗ insulin (also known as Humulin Ν, Novolin N, NPH Lletin II, and insulin isophane); insulin lispro (28B-L-lysine-29B-L-proline -insulin, wherein insulin is human insulin); insulin aspart (28B-L-aspartic acid-insulin, wherein insulin is human insulin); and insulin glulisine (3B-L-lysine-29B-L-glutamic acid-insulin, wherein insulin is human insulin); a sulfonylurea selected from: tolbutamide (Orinase, N-(butylcarbamoyl)-4- methylbenzenesulfonamide); acetohexamide (Dymelor, 4-acetyl-N-
(cyclohexylcarbamoyl)benzenesulfonamide); tolazamide (Tolinase, N-(azepan-l-ylcarbamoyl)- 4-methylbenzenesulfonamide); chlorpropamide (Diabinese, 4-chloro-N- (propylcarbamoyl)benzenesulfonamide); glipizide (Glucotrol, N-(4-(N-
(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-5-methylpyrazine-2-carboxamide); glibenclamide, also known as glyburide (Diabeta, Micronase, Glynase, 5-chloro-N-(4-(N- (cyclohexylcarbamoyl)sulfamoyl)phenethyl)-2-methoxybenzamide); glimepiride (Amaryl, 3- ethyl-4-methyl-N-(4-(N-((lr,4r)-4-methylcyclohexylcarbamoyl)sulfamoyl)phenethyl)-2-oxo- 2,5-dihydro-lH-pyrrole-l-carboxamide); and gliclazide (Diamicron, N-
(hexahydrocyclopenta[c]pyrrol-2(lH)-ylcarbamoyl)-4-methylbenzenesulfonamide); a SGLT2 inhibitor selected from: dapagliflozin ((2S,3R,4R,5S,6R)-2-(4-chloro-3-(4- ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3 ,4,5 -triol) ; remogliflozin (ethyl ((2R,35,45,5R,65)-3,4,5-trihydroxy-6-(4-(4-isopropoxybenzyl)-l-isopropyl-5-methyl-lH- pyrazol-3-yloxy)tetrahydro-2H-pyran-2-yl)methyl carbonate); ASP1941, canagliflozin
((25,3R,4R,55,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3, 4,5 -triol); ISIS 388626; sergliflozin (ethyl
((2R,35,45,5R,65)-3,4,5-trihydroxy-6-(2-(4-methoxybenzyl)phenoxy)tetrahydro-2H-pyran-2- yl)methyl carbonate), AVE2268 ((2R,35,45,5R,65)-2-(hydroxymethyl)-6-(2-(4- methoxybenzyl)thiophen-3-yloxy)tetrahydro-2H-pyran-3,4,5-triol), BI10773, CSG453; and
LX4211 ; a meglitinide selected from: repaglinide (Prandin, (5)-2-ethoxy-4-(2-(3 -methyl- 1 -(2- (piperidin-l-yl)phenyl)butylamino)-2-oxoethyl)benzoic acid); nateglinide (Starlix, (R)-2- ((lr,4R)-4-isopropylcyclohexanecarboxamido)-3-phenylpropanoic acid); and mitiglinide ((5)-2- benzyl-4-((3aR,7a5)-lH-isoindol-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)-4-oxobutanoic acid); a thiazolidinedione selected from: 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)thiazolidine-2,4-dione) ; rivoglitazone (5-(4-((6- methoxy- 1 -methyl- lH-benzo [d] imidazol-2-yl)methoxy)benzyl)thiazolidine-2,4-dione) ; and ciglitazone (5-(4-((l-methylcyclohexyl)methoxy)benzyl)thiazolidine-2,4-dione); an antidiabetic peptide analogue selected from: exenatide; liraglutide; and taspoglutide; and a
DGAT-1 inhibitor selected from: (lr,4r)-4-(4-(5-(3,4-difluorophenylamino)-l,3,4-oxadiazole- 2-carboxamido)-3-fluorophenyl)cyclohexanecarboxylic acid; ira«s-(4-{4-[5-(6-trifluoromethyl- pyridin-3ylamino)-pyridin-2-yl] -phenyl }-cyclohexyl)-acetic acid; and {ira«s-4-(4-(4-amino-5- oxo-7,8-dihydropyrimido[5.4-f][f]oxazepin-6(5H)yl)phenyllcyclohexyl} acetic acid.
In some embodiments, the two distinct pharmaceutical agents include every
combination selected from pharmaceutical agents of the following group: sitagliptin, vildagliptin, saxagliptin, alogliptin, linagliptin, phenformin, metformin, buformin, acarbose, miglitol, voglibose, tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide, glibenclamide, glimepiride, gliclazide, dapagliflozin, remigliflozin, and sergliflozin. Dipeptidyl Peptidase IV Inhibitors
Dipeptidyl peptidase IV (DPP-IV, EC 3.4.14.5) exhibits catalytic activity against a broad range of peptide substrates that includes peptide hormones, neuropeptides, and chemokines. The incretins glucagon-like peptide 1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP), which stimulate glucose-dependent insulin secretion and otherwise promote blood glucose homeostasis, are rapidly cleaved by DPP-IV at the position-2 alanine leading to inactivation of their biological activity. Peptide YY (PYY) is a gut peptide that has been implicated in modulating satiety (Chaudhri et al, Annu Rev Physiol (2008) 70:239- 255). PYY is released into the circulation as PYYi_36 and PYY3_36 (Eberlein et al, Peptides (1989) 10:797-803). PYY3-36 is generated from PYYi_36 by cleavage of the N-terminal Tyr and Pro residues by DPP-IV. Both pharmacological and genetic attenuation of DPP-IV activity is associated with enhanced incretin action, increased insulin, and lower blood glucose in vivo. Genetic attenuation of DPP-IV activity has been shown to provide resistance to obesity and to improve insulin sensitivity. Inhibitors of DPP-IV have shown to be useful as therapeutics, for example, oral administration of vildagliptin (l-[2-(3-hydroxyadamant-l- ylamino)acetyl]pyrrolidine-2(5)-carbonitrile) or sitagliptin (3(R)-amino-l-[3-(trifluoromethyl)- 5,6,7,8-tetrahydro[l,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-l-one) to human patients suffering with type 2 diabetes has been found to reduce fasting glucose and postprandial glucose excursion in association with significantly reduced HbAlc levels. For reviews on the application 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 inhibitors of DPP-IV that can be used in conjunction with compounds of the present invention either dosed separately or together. Inhibitors of DPP-IV are well-known in the art or can be readily identified and their in vitro biological activity determined using any number of methods available, for example, 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. , 3. 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: 1265-1268; Edmondson et al , Bioorg. Med. Chem. Lett. (2004) 14:5151-5155; and Abe et al , J. Na.t Prod. (2004) 67:999- 1004.
Specific examples of DPP-IV inhibitors include, but are not limited to, dipeptide derivatives or dipeptide mimetics such as alanine-pyrrolidide, isoleucine-thiazolidide, and the pseudosubstrate N-valyl prolyl, O-benzoyl hydroxylamine, as described, for example, in U.S. Pat. No. 6,303,661.
Some embodiments of the present invention include every combination of one or more
DPP-IV inhibitors selected from the DPP-IV inhibitors found in U.S. Pat. Nos. 6,869,947, 6,867,205, 6,861,440, 6,849,622, 6,812,350, 6,803,357, 6,800,650, 6,727,261, 6,716,843, 6,710,040, 6,706,742, 6,645,995, 6,617,340, 6,699,871, 6,573,287, 6,432,969, 6,395,767, 6,380,398, 6,303,661, 6,242,422, 6,166,063, 6,100,234, and 6,040,145.
Some embodiments of the present invention include every combination of one or more
DPP-IV inhibitors selected from the DPP-IV inhibitors found in U.S. Pat. Nos. 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 every combination of one or more DPP-IV inhibitors selected from the DPP-IV inhibitors found in International Patent Application Publication Nos. 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 2005/044195, 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 2005/026148, 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 03/22871, 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 every combination of one or more DPP-IV inhibitors selected from the DPP-IV inhibitors found in Patent Publication Nos. EP 1517907, EP 1513808, EP 1492777, EP 1490335, EP 1489088, EP 1480961, EP 1476435, EP 1476429, EP 1469873, EP 1465891, EP 1463727, EP 1461337, EP 1450794, EP 1446116, EP 1442049, EP 1441719, EP 1426366, EP 1412357, EP1406873, EP 1406872, EP 1406622, EP 1404675, EP 1399420, EP 1399471, EP 1399470, EP 1399469, EP 1399433, EP 1399154, EP 1385508, EP 1377288, EP 1355886, EP 1354882, EP 1338592, EP 1333025, EP 1304327, EP 1301187, EP 1296974, EP 1280797, EP 1282600, EP 1261586, EP 1258476, EP 1254113, EP 1248604, EP 1245568, EP 1215207, EP 1228061, EP 1137635, EP 1123272, EP 1104293, EP 1082314, EP 1050540, EP 1043328, EP 0995440, EP 0980249, EP 0975359, EP 0731789, EP 0641347, EP 0610317, EP 0528858, CA 2466870, CA 2433090, CA 2339537, CA 2289125, CA 2289124, CA 2123128, DD 296075, DE 19834591, DE 19828113, DE 19823831, DE 19616486, DE 10333935, DE 10327439, DE 10256264, DE 10251927, DE 10238477, DE 10238470, DE 10238243, DE 10143840, FR 2824825, FR 2822826, JP2005507261, JP
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In some embodiments, the DPP-IV inhibitor has an IC50 of less than about 10 μΜ, less than about 1 μΜ, less than about 100 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 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 about 3 nM, less than about 2 nM, or less than about 1 nM.
In some embodiments, the DPP-IV inhibitor is a selective DPP-IV inhibitor, wherein the selective DPP-IV inhibitor has a selectivity for human plasma DPP-IV over one or more of
PPCE, DPP-II, DPP-8 and DPP-9 of at least about 10-fold. In some embodiments, the DPP-IV inhibitor is a selective DPP-IV inhibitor, wherein the selective DPP-IV inhibitor has a selectivity for human plasma DPP-IV over one or more of PPCE, DPP-II, DPP-8 and DPP-9 of at least about 100-fold. In some embodiments, the DPP-IV inhibitor is a selective DPP-IV inhibitor, wherein the selective DPP-IV inhibitor has a selectivity for human plasma DPP-IV over one or more of PPCE, DPP-II, DPP-8 and DPP-9 of at least about 10-fold. In some embodiments, the DPP-IV inhibitor is a selective DPP-IV inhibitor, wherein the selective DPP-IV inhibitor has a selectivity for human plasma DPP-IV over one or more of PPCE, DPP-II, DPP-8 and DPP-9 of at least about 1000-fold.
In some embodiments, the DPP-IV inhibitor is orally active.
In some embodiments, the DPP-IV inhibitor is an inhibitor of human DPP-IV.
Some embodiments of the present invention include every combination of one or more compounds selected from compounds of the following group and pharmaceutically acceptable salts, solvates, and hydrates thereof: 3(R)-amino-l -[3-(trifluoromethyl)-5,6,7,8- tetrahydro[l ,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-l-one; l-[2-(3- hydroxyadamant-l-ylamino)acetyl]pyrrolidine-2(5)-carbonitrile; (15,35,55)-2-[2(5)-amino-2-(3- hydroxyadamantan- 1 -yl)acetyl] -2-azabicyclo [3.1.0]hexane-3-carbonitrile ; 2- [6- [3(R)- aminopiperidin-l-yl]-3-methyl-2,4-dioxo-l ,2,3,4-tetrahydropyrimidin-l -ylmethyl]benzonitrile; 8-[3(R)-aminopiperidin- 1 -yl] -7-(2-butynyl)-3-methyl- 1 -(4-methylquinazolin-2- ylmethyl)xanthine; l-[N-[3(R)-pyrrolidinyl]glycyl]pyrrolidin-2(R)-yl boronic acid; 4(5)-fluoro- 1 -[2- [( lR,35)-3 -( 1H- 1 ,2,4-triazol- 1 -ylmethyl)cyclopentylamino] acetyl]pyrrolidine-2(5)- carbonitrile; 1-[(25,35,1 lb5)-2-amino-9, 10-dimethoxy-2,3,4,6,7,l lb-hexahydro-lH-pyrido[2,l- a]isoquinolin-3-yl]-4(5)-(fluoromethyl)pyrrolidin-2-one; (25,45)-2-cyano-4-fluoro-l -[(2- hydroxy- 1 , 1 -dimethyl) ethylamino] acetylpyrrolidine ; 8-(c s-hexahydro-pyrrolo[3 ,2-b]pyrrol- 1 - yl)-3-methyl-7-(3-methyl-but-2-enyl)-l-(2-oxo-2-phenylethyl)-3,7-dihydro-purine-2,6-dione; 1- ((35,45)-4-amino-l -(4-(3,3-difluoropyrrolidin-l -yl)-l ,3,5-triazin-2-yl)pyrrolidin-3-yl)- 5,5difluoropiperidin-2-one; (R)-2-((6-(3-aminopiperidin-l-yl)-3-methyl-2,4-dioxo-3,4- dihydropyrimidin-1 (2H)-yl)methyl)-4-fluorobenzonitrile; 5- { (5)-2-[2-((5)-2-cyano-pyrrolidin- 1 - yl)-2-oxo-ethylamino] -propyl } -5-( lH-tetrazol-5-yl) 10, 11 -dihydro-5H- dibenzo[a,d]cycloheptene-2,8-dicarboxylic acid bis-dimethylamide; ((25,45)-4-(4-(3-methyl-l- phenyl-lH-pyrazol-5-yl)piperazin-l -yl)pyrrolidin-2-yl)(thiazolidin-3-yl)methanone; (25,45)- 1- [2- [(4-ethoxycarbonylbicyclo [2.2.2] oct- 1 -yl)amino] acetyl] -4-fluoropyrrolidine-2-carbonitrile; 6- [(3R)-3 -amino -piperidin- 1 -yl] -5 -(2-chloro-5 -fluoro-benzyl)- 1 ,3 -dimethyl- 1 ,5dihydro- pyrrolo[3,2-d]pyrimidine-2,4-dione; 2-({ 6-[(3R)-3-amino-3-methylpiperidin-l-yl]-l ,3-dimethyl- 2,4-dioxo-l ,2,3,4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl}methyl)-4-fluorobenzonitrile; (25)-l -{ [2-(5-methyl-2-phenyl-oxazol-4-yl)-ethylamino]-acetyl}-pyrrolidine -2 -carbonitrile; (25)- 1 -{ [1 ,1 -dimethyl-3 -(4-pyridin-3-yl-imidazol- 1 -yl)-propylamino] -acetyl } -pyrrolidine -2- carbonitrile; (3,3-difluoropyrrolidin-l -yl)-((25,45)-4-(4-(pyrimidin-2-yl)piperazin-l- yl)pyrrolidin-2-yl)methanone; (25,45)-l -[(25)-2-amino-3,3-bis(4-fluorophenyl)propanoyl]-4- fluoropyrrolidine -2 -carbonitrile; (25,5R)-5-ethynyl- 1 - {N-(4-methyl- 1 -(4-carboxy-pyridin-2- yl)piperidin-4-yl)glycyl}pyrrolidine-2-carbonitrile; and (15,6R)-3-{ [3-(trifluoromethyl)-5,6- dihydro[l ,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}-6-(2,4,5-trifluorophenyl)cyclohex-3- en-1 -amine. Sitagliptin phosphate (Januvia®, MK-0431 , dihydrogenphosphate salt of 3(R)-amino-l - [3-(trifluoromethyl)-5,6,7,8-tetrahydro[l ,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5- trifluorophenyl)butan-l -one) is marketed by Merck & Co. for once -daily oral treatment of type 2 diabetes. Januvia was first launched in Mexico followed by commercialization in the U.S. In 2007, the product was approved by the European Medicines Evaluation Agency (EMEA) and is currently available in the U.K., Germany and Spain. In 2009, Januvia was approved and launched in Japan. In addition, Merck has also filed for approval of Januvia in the U.S. as an adjunct to diet and exercise and in combination with other therapies to improve glycemic control in the treatment of diabetes. The compound, 3(R)-amino-l-[3-(trifluoromethyl)-5,6,7,8- tetrahydro[l ,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-l-one, and pharmaceutically acceptable salts thereof are disclosed in international patent publication WO2003/004498. Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in WO2003/004498 and pharmaceutically acceptable salts, solvates, and hydrates thereof. In some embodiments, the DPP-IV inhibitor is selected from 3(R)-amino-l-[3-(trifluoromethyl)-5, 6,7,8- tetrahydro[l ,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-l-one, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000069_0001
In some embodiments, the DPP-IV inhibitor is (R)-amino-l-[3-(trifluoromethyl)-5,6,7,8- tetrahydro[l ,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-l-one phosphate:
Figure imgf000069_0002
The crystalline form of (R)-amino-l -[3-(trifluoromethyl)-5,6,7,8-tetrahydro[l ,2,4]triazolo[4,3- a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-l -one phosphate salt monohydrate is disclosed in international patent publication WO2005/003135. In some embodiments, the DPP-IV inhibitor is crystalline (R)-amino-l -[3-(trifluoromethyl)-5,6,7,8-tetrahydro[l ,2,4]triazolo[4,3-a]pyrazin-7- yl]-4-(2,4,5-trifluorophenyl)butan-l-one phosphate monohydrate.
Vildagliptin (Galvus®, LAF-237, l-[2-(3-hydroxyadamant-l - ylamino)acetyl]pyrrolidine-2(5)-carbonitrile) is another DPP-IV inhibitor and was first commercialized in Brazil and Mexico by Novartis for oral, once-daily treatment of type 2 diabetes. In 2008, a marketing authorization application (MAA) was approved in the E.U. for this indication and launch took place in the U.K. in March, 2008. An approvable letter has been received for the regulatory application filed in the U.S. Vildagliptin was approved in Japan in 2010. The compound, l-[2-(3-hydroxyadamant-l-ylamino)acetyl]pyrrolidine-2(5)-carbonitrile, is disclosed in international patent publication WO 2000/034241. Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in WO2000/034241 and pharmaceutically acceptable salts, solvates, and hydrates thereof. In some embodiments, the DPP-IV inhibitor is selected from l-[2-(3- hydroxyadamant- 1 -ylamino)acetyl]pyrrolidine-2(5)-carbonitrile, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000070_0001
Certain salts of the compound, l-[2-(3-hydroxyadamant-l-ylamino)acetyl]pyrrolidine-2(5)- carbonitrile, are disclosed in international patent publication WO2007/019255. In some embodiments, the DPP-IV inhibitor is l-[2-(3-hydroxyadamant-l-ylamino)acetyl]pyrrolidine- 2(5)-carbonitrile HCI:
Figure imgf000070_0002
Saxagliptin (Onglyza™, BMS-477118, (15,35,55)-2-[2(5)-amino-2-(3- hydroxyadamantan-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile) is another DPP-IV inhibitor, which was launched in 2009 by AstraZeneca and Bristol-Myers Squibb in the U.S. for the treatment of type 2 diabetes. In 2009, the product was approved in the E.U. for the treatment of type 2 diabetes independently or in combination with metformin. Phase 3 clinical studies are ongoing in Japan for the treatment of type 2 diabetes. The compound, (15,35,55)-2-[2(5)-amino- 2-(3-hydroxyadamantan-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile, is disclosed in international patent publication WO2001/068603. Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in
WO2001/068603 and pharmaceutically acceptable salts, solvates, and hydrates thereof. In some embodiments, the DPP-IV inhibitor is selected from (15,35,55)-2-[2(5)-amino-2-(3- hydroxyadamantan-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000070_0003
Takeda has filed for regulatory approval of the DPP-IV inhibitor, alogliptin (SYR-322, 2-[6-[3(R)-aminopiperidin- 1 -yl] -3-methyl-2,4-dioxo- 1 ,2,3,4-tetrahydropyrimidin- 1 - ylmethyl]benzonitrile) in Japan and the U.S for the once-daily, oral treatment of type 2 diabetes. The compound, 2-[6-[3(R)-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-l , 2,3,4- tetrahydropyrimidin-l-ylmethyl]benzonitrile, and pharmaceutically acceptable salts thereof are disclosed in international patent publication WO 2005/095381. Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in WO 2005/095381 and pharmaceutically acceptable salts, solvates, and hydrates thereof. In some embodiments, the DPP-IV inhibitor is selected from 2-[6-[3(R)- aminopiperidin-l-yl]-3-methyl-2,4-dioxo-l ,2,3,4-tetrahydropyrimidin-l -ylmethyl]benzonitrile, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000071_0001
The crystalline form of 2-[6-[3(R)-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-l ,2,3,4- tetrahydropyrimidin-l-ylmethyl]benzonitrile is disclosed in international patent publication WO2007/035372. In some embodiments, the DPP-IV inhibitor is 2-[6-[3(R)-aminopiperidin- yl]-3-methyl-2,4-dioxo- -tetrahydropyrimidin-l -ylmethyl]benzonitrile benzoate:
Figure imgf000071_0002
Linagliptin (BI-1356, Tradjenta®, 8-[3(R)-aminopiperidin-l -yl]-7-(2-butynyl)-3- methyl-l-(4-methylquinazolin-2-ylmethyl)xanthine) is an inhibitor of DPP-IV approved by the FDA in May 2011 as an adjunct to diet and excerise to improve glycemic control in adults with type 2 diabetes. The compound, 8-[3(R)-aminopiperidin-l-yl]-7-(2-butynyl)-3-methyl-l -(4- methylquinazolin-2-ylmethyl)xanthine, is disclosed in international patent publication
WO2004/018468. Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in WO2004/018468 and pharmaceutically acceptable salts, solvates, and hydrates thereof. In some embodiments, the DPP-IV inhibitor is selected from 8-[3(R)-aminopiperidin-l-yl]-7-(2-butynyl)-3-methyl-l-(4- methylquinazolin-2-ylmethyl)xanthine, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000072_0001
Certain polymorphs of the compound, 8-[3(R)-aminopiperidin-l -yl]-7-(2-butynyl)-3-methyl-l - (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-l-yl]-7-(2-butynyl)-3-methyl-l -(4-methylquinazolin-2-ylmethyl)xanthine.
Dutogliptin (PHX-1149, l-[N-[3(R)-pyrrolidinyl]glycyl]pyrrolidin-2(R)-yl boronic acid) is a DPP-IV inhibitor in phase 3 clinical trials by Phenomix and Forest for the oral, once-daily treatment of type 2 diabetes. The compound, l-[N-[3(R)-pyrrolidinyl]glycyl] pyrrolidin-2(R)-yl boronic acid, and pharmaceutically acceptable salts thereof are disclosed in international patent publication WO2005/047297. Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in WO2005/047297 and pharmaceutically acceptable salts, solvates, and hydrates thereof. In some embodiments, the DPP-IV inhibitor is selected from l-[N-[3(R)-pyrrolidinyl]glycyl]pyrrolidin-2(R)-yl boronic acid, and pharmaceutically acceptable salts, solvates, and h drates thereof:
Figure imgf000072_0002
The crystalline form of l-[N-[3(R)-pyrrolidinyl]glycyl]pyrrolidin-2(R)-yl boronic acid tartrate is disclosed in international patent publication WO2008/027273. In some embodiments, the DPP-IV inhibitor is l-[N- -pyrrolidinyl]glycyl]pyrrolidin-2(R)-yl boronic acid tartrate:
Figure imgf000072_0003
Melogliptin (GRC-8200, 4(5)-fluoro-l-[2-[(lR,35)-3-(lH-l ,2,4-triazol-l - ylmethyl)cyclopentylamino]acetyl]pyrrolidine-2(5)-carbonitrile) is a DPP-IV inhibitor currently undergoing phase 2 clinical trials by Glenmark Pharmaceuticals and Merck KGaA for the treatment of type 2 diabetes. The compound, 4(5)-fluoro-l -[2-[(lR,35)-3-(lH-l ,2,4-triazol-l - ylmethyl)cyclopentylamino]acetyl]pyrrolidine-2(5)-carbonitrile, is disclosed in international patent publication WO2006/040625. Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in WO2006/040625 and pharmaceutically acceptable salts, solvates, and hydrates thereof. In some embodiments, the DPP-IV inhibitor is selected from 4(5)-fluoro-l -[2-[(lR,35)-3-(lH-l ,2,4-triazol-l - ylmethyl)cyclopentylamino] acetyl]pyrrolidine-2(S)-carbonitrile, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000073_0001
Carmegliptin (R-1579, l-[(25,35, l lb5)-2-amino-9,10-dimethoxy-2,3,4,6,7,l lb- hexahydro-lH-pyrido[2,l-a]isoquinolin-3-yl]-4(5)-(fluoromethyl)pyrrolidin-2-one) is a DPP-IV inhibitor. The compound, l-[(25,35, l lb5)-2-amino-9,10-dimethoxy-2,3,4,6,7,l lb-hexahydro- lH-pyrido[2, l-a]isoquinolin-3-yl]-4(5)-(fluoromethyl)pyrrolidin-2-one, is disclosed in international patent publication WO2005/000848. Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in WO2005/000848 and pharmaceutically acceptable salts, solvates, and hydrates thereof. In some embodiments, the DPP-IV inhibitor is selected from l-[(2S,3S, l lbS)-2-amino-9, 10-dimethoxy- 2,3,4,6,7,11 b-hexahydro- 1 H-pyrido [2, 1 -a] isoquinolin-3-yl] -4(5)-(fluoromethyl)pyrrolidin-2- one, and pharmaceutically ac s thereof:
Figure imgf000073_0002
Taisho disclosed (25,45)-2-cyano-4-fluoro- 1 - [(2-hydroxy- 1 , 1 -dimethyl)
ethylamino]acetylpyrrolidine, a DPP-IV inhibitor in US patent publication US 2007/0112059. Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in US 2007/0112059 and pharmaceutically acceptable salts, solvates, and hydrates thereof. In some embodiments, the DPP-IV inhibitor is selected from (25,45)-2-cyano-4-fluoro-l -[(2-hydroxy-l ,l- dimethyl)ethylamino]acetylpyrrolidine, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000073_0003
Sanofi-Aventis disclosed a series of substituted bicyclic 8-pyrrolidineoxanthine derivatives as DPP-IV inhibitors in US publication US 2007/0167468. Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in US publication US 2007/0167468 and pharmaceutically acceptable salts, solvates, and hydrates thereof. In some embodiments, the DPP-IV inhibitor is selected from 8-(cw-hexahydro-pyrrolo[3,2-b]pyrrol-l-yl)-3-methyl-7-(3-methyl-but-2-enyl)-l -(2-oxo-2- phenylethyl)-3,7-dihydro-purine-2,6-dione, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000074_0001
Pfizer disclosed a series of 3-amino-pyrrolidine-4-lactam derivatives as DPP-IV inhibitors in international patent publication WO2007/148185. Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in WO2007/148185 and pharmaceutically acceptable salts, solvates, and hydrates thereof. One such compound is l-((35,45)-4-amino-l-(4-(3,3-difluoropyrrolidin-l -yl)- l ,3,5-triazin-2-yl)pyrrolidin-3-yl)-5,5difluoropiperidin-2-one. In some embodiments, the DPP- IV inhibitor is selected from l-((35,45)-4-amino-l -(4-(3,3-difluoropyrrolidin-l -yl)-l ,3,5-triazin- 2-yl)pyrrolidin-3-yl)-5,5difluoropiperidin-2-one, and pharmaceutically acceptable salts, solvates, and hydrates thereof
Figure imgf000074_0002
Syrrx disclosed a series of substituted pyrimidine-2,4(lH,3H)-dione derivatives as DPP- IV inhibitors in international patent publication WO2005/095381. Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in WO2005/095381 and pharmaceutically acceptable salts, solvates, and hydrates thereof. One such compound is (R)-2-((6-(3-aminopiperidin-l-yl)-3-methyl-2,4-dioxo- 3,4-dihydropyrimidin-l(2H)-yl)methyl)-4-fluorobenzonitrile. In some embodiments, the DPP- IV inhibitor is selected from (R)-2-((6-(3-aminopiperidin-l -yl)-3-methyl-2,4-dioxo-3,4- dihydropyrimidin-l(2H)-yl)methyl)-4-fluorobenzonitrile, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000074_0003
Various crystalline forms of (R)-2-((6-(3-aminopiperidin-l -yl)-3-methyl-2,4-dioxo-3,4- dihydropyrimidin-l(2H)-yl)methyl)-4-fluorobenzonitrile succinic acid salt are disclosed in international patent publication WO2008/067465. One embodiment of the present invention pertains to any one or more crystalline forms of (R)-2-((6-(3-aminopiperidin-l-yl)-3-methyl-2,4- dioxo-3,4-dihydropyrimidin-l(2H)-yl)methyl)-4-fluorobenzonitrile succinic acid salt as described in international patent publication WO2008/067465. In some embodiments, the DPP- IV inhibitor is crystalline (R)-2-((6-(3-aminopiperidin-l -yl)-3-methyl-2,4-dioxo-3,4- dihydropyrimidin-l(2H)- salt:
Figure imgf000075_0001
Alantos disclosed a series of substituted 2-cyano-pyrrolidine derivatives as DPP-IV inhibitors in international patent publication WO2006/116157. Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in WO2006/116157 and pharmaceutically acceptable salts, solvates, and hydrates thereof. One such compound is 5-{ (S)-2-[2-((S)-2-cyano-pyrrolidin-l -yl)-2-oxo- ethylamino] -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-{ (5)-2-[2-((5)-2-cyano-pyrrolidin-l -yl)-2-oxo-ethylamino]-propyl }-5-(lH-tetrazol-5- yl)10,l l-dihydro-5H-dibenzo[a,d]cycloheptene-2,8-dicarboxylic acid bis-dimethylamide, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000075_0002
Mitsubishi disclosed a series of 2,4-disubstituted pyrrolidine derivatives as DPP-IV inhibitors in international patent publication WO2002/0014271. Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in WO2002/0014271 and pharmaceutically acceptable salts, solvates, and hydrates thereof. One such compound is ((25,45)-4-(4-(3-methyl-l -phenyl-lH-pyrazol-5- yl)piperazin-l -yl)pyrrolidin-2-yl)(thiazolidin-3-yl)methanone. In some embodiments, the DPP- IV inhibitor is selected from ((25,45)-4-(4-(3-methyl-l-phenyl-lH-pyrazol-5-yl)piperazin-l - yl)pyrrolidin-2-yl)(thiazolidin-3-yl)methanone, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000076_0001
Various crystalline forms of ((25,45)-4-(4-(3-methyl-l -phenyl-lH-pyrazol-5-yl)piperazin-l- yl)pyrrolidin-2-yl)(thiazolidin-3-yl)methanone salts are disclosed in international patent publication WO2006/088129 and US publication 2009/0216016. One embodiment of the present invention pertains to any one or more crystalline forms of ((25,45)-4-(4-(3-methyl-l - phenyl-1 H-pyrazol-5 -yl)piperazin-l -yl)pyrrolidin-2-yl)(thiazolidin-3-yl)methanone salt as described in international patent publication WO2006/088129 and US publication
2009/0216016. In some embodiments, the DPP-IV inhibitor is crystalline ((25,45)-4-(4-(3- methyl-l-phenyl-lH-pyrazol-5-yl)piperazin-l -yl)pyrrolidin-2-yl)(thiazolidin-3-yl)methanone 2.5 hydrobromide salt:
Figure imgf000076_0002
or a mono or a dihydrate thereof. In some embodiments, the DPP-IV inhibitor is crystalline
((25,45)-4-(4-(3-methyl- 1 -phenyl- 1 H-pyrazol-5 -yl)piperazin- 1 -yl)pyrrolidin-2-yl)(thiazolidin-3- yl)methanone di-hydrobromide salt.
Kyorin disclosed a series of pyrrolidinecarbonitrile derivatives as DPP-IV inhibitors in international patent publication WO2008/114857 and US publication US 2008/0146818. Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in WO2008/114857 and US publication US 2008/0146818, and pharmaceutically acceptable salts, solvates, and hydrates thereof. One such compound is (25,45)-l -[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-l -yl)amino]acetyl]-4-fluoropyrrolidine-2- carbonitrile. In some embodiments, the DPP-IV inhibitor is selected from (25,45)-l -[2-[(4- ethoxycarbonylbicyclo[2.2.2]oct-l-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000077_0001
Dainippon Sumitomo disclosed a series of bicyclic pyrrole derivatives as DPP-IV inhibitors in international patent publication WO2006/068163 and US publication US
2009/0192129. Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in WO2006/068163 and US publication US 2009/0192129 and pharmaceutically acceptable salts, solvates, and hydrates thereof. One such compound is (6-[(3R)-3-amino-piperidin-l -yl]-5-(2-chloro-5-fluoro-benzyl)-l ,3-dimethyl- l ,5dihydro-pyrrolo[3,2-d]pyrimidine-2,4-dione. In some embodiments, the DPP-IV inhibitor is selected from (6-[(3R)-3-amino-piperidin-l -yl]-5-(2-chloro-5-fluoro-benzyl)-l ,3-dimethyl- l ,5dihydro-pyrrolo[3,2-d]pyrimidine-2,4-dione, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000077_0002
Dainippon Sumitomo disclosed 2-({ 6-[(3R)-3-amino-3-methylpiperidin-l-yl]-l ,3- dimethyl-2,4-dioxo-l ,2,3,4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl}methyl)-4- fluorobenzonitrile as a DPP-IV inhibitor in international patent publication WO2009/084497. In some embodiments, the DPP-IV inhibitor is selected from 2-({ 6-[(3R)-3-amino-3- methylpiperidin- 1 -yl] - 1 ,3 -dimethyl-2,4-dioxo- 1 ,2,3 ,4-tetrahydro-5H-pyrrolo [3 ,2-d]pyrimidin-5 - yl}methyl)-4-fluorobenzonitrile, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000077_0003
Hoffmann-La Roche 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 every combination of one or more compounds selected from compounds disclosed in WO 03/037327 and pharmaceutically acceptable salts, solvates, and hydrates thereof. One such compound is (25)-l-{ [2-(5-methyl-2-phenyl-oxazol-4-yl)- ethylamino] -acetyl }-pyrrolidine-2-carbonitrile. In some embodiments, the DPP-IV inhibitor is selected from (25)-l-{ [2-(5-methyl-2-phenyl-oxazol-4-yl)-ethylamino] -acetyl} -pyrrolidine -2- carbonitrile, and pharmaceu ates thereof:
Figure imgf000078_0001
Various crystalline forms of (25)-l-{ [2-(5-methyl-2-phenyl-oxazol-4-yl)-ethylamino]-acetyl}- pyrrolidine -2 -carbonitrile methansulfonic acid salt are disclosed in international patent publication WO2006/ 100181. In some embodiments, the DPP-IV inhibitor is (25)-l-{ [2-(5- methyl-2-phenyl-oxazol-4-yl)-ethylamino] -acetyl } -pyrrolidine -2 -carbonitrile methansulfonic acid salt (i.e. , mesylat
Figure imgf000078_0002
Other compounds disclosed by Hoffmann-La Roche in international patent publication WO 03/037327 include (25)-l-{ [l,l-dimethyl-3-(4-pyridin-3-yl-imidazol-l-yl)-propylamino]- acetyl} -pyrrolidine -2 -carbonitrile, and pharmaceutically acceptable salts thereof, such as the methansulfonic acid salt. In some embodiments, the DPP-IV inhibitor is selected from (25)- 1- { [1,1 -dimethyl-3 -(4-pyridin-3 -yl-imidazol- 1 -yl)-propylamino] -acetyl } -pyrrolidine -2- carbonitrile, and pharmac ates thereof:
Figure imgf000078_0003
In some embodiments, the DPP-IV inhibitor is (25)-l-{ [l,l-dimethyl-3-(4-pyridin-3-yl- imidazol- 1 -yl) nic acid:
Figure imgf000078_0004
Various crystalline forms of (25)-l-{ [l,l-dimethyl-3-(4-pyridin-3-yl-imidazol-l-yl)- propylamino] -acetyl }-pyrrolidine-2-carbonitrile fumaric acid salt are disclosed in international patent publication WO2007/071576. In some embodiments, the DPP-IV inhibitor is (25)- 1- { [1,1 -dimethyl-3 -(4-pyridin-3 -yl-imidazol- 1 -yl)-propylamino] -acetyl } -pyrrolidine -2- carbonitrile fumaric acid salt (i.e. , fumarate):
Figure imgf000079_0001
Pfizer disclosed a series of proline derivatives as DPP-IV inhibitors in international patent publication WO2005/116014. Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in WO2005/116014 and pharmaceutically acceptable salts, solvates, and hydrates thereof. 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 (3,3- difluoropyrrolidin- 1 -yl)-((25,45)-4-(4-(pyrimidin-2-yl)piperazin- 1 -yl)pyrrolidin-2- yl)methanone, and pharmac ates thereof:
Figure imgf000079_0002
GlaxoSmithKline disclosed a series of fluoropyrrolidine derivatives as DPP-IV inhibitors in international patent publication WO 03/002531. Some embodiments of the present invention include every combination of one or more compounds selected from the DPP-IV inhibitors disclosed in WO 03/037327 and pharmaceutically acceptable salts, solvates, and hydrates thereof. One such compound is (25,45)-l-[(25)-2-amino-3,3-bis(4- fluorophenyl)propanoyl]-4-fluoropyrrolidine-2-carbonitrile (Denagliptin). In some
embodiments, the DPP-IV inhibitor is selected from (25,45)-l-[(25)-2-amino-3,3-bis(4- fluorophenyl)propanoyl]-4-fluoropyrrolidine-2-carbonitrile, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000079_0003
Various crystalline forms of (25,45)-l-[(25)-2-amino-3,3-bis(4- fluorophenyl)propanoyl]-4-fluoropyrrolidine-2-carbonitrile and salts have been disclosed in international patent publication WO 2005/009956. One salt disclosed is (25,45)-l-[(25)-2- amino-3,3-bis(4-fluorophenyl)propanoyl]-4-fluoropyrrolidine-2-carbonitrile /?-toluenesulfonic acid salt (also referred to as (25,45)-4-fluoro-l -[4-fluoro- -(4-fluorophenyl)-L-phenylalanyl]-2- pyrrolidinecarbonitrile /?-toluenesulfonic acid salt, or Denagliptin tosylate). In some embodiments, the DPP-IV inhibitor is (25,45)-l-[(25)-2-amino-3,3-bis(4- fluorophenyl)propanoyl]-4-fluoropyrrolidine-2-carbonitrile /?-toluenesulfonic acid salt:
Figure imgf000080_0001
Abbott disclosed a series of substituted pyrrolidinyl derivatives as DPP-IV inhibitors in international patent publication WO 2004/026822. Some embodiments of the present invention include every combination of one or more compounds selected from the DPP-IV inhibitors disclosed in WO 2004/026822 and pharmaceutically acceptable salts, solvates, and hydrates thereof. One such compound is (2S,5R)-5-ethynyl-l -{N-(4-methyl-l -(4-carboxy-pyridin-2- yl)piperidin-4-yl)glycyl}pyrrolidine-2-carbonitrile. In some embodiments, the DPP-IV inhibitor is selected from (25,5R)-5-ethynyl-l -{N-(4-methyl-l -(4-carboxy-pyridin-2-yl)piperidin-4- yl)glycyl}pyrrolidine-2-carbonitrile, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000080_0002
Abbott has further disclosed a series of substituted cyclohexanyl/cyclohexenyl derivatives as DPP-IV inhibitors in international patent publication WO 2007/027651. Some embodiments of the present invention include every combination of one or more compounds selected from the DPP-IV inhibitors disclosed in WO 2007/027651 and pharmaceutically acceptable salts, solvates, and hydrates thereof. One such compound is (15,6R)-3-{ [3- (trifluoromethyl)-5,6-dihydro[l ,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}-6-(2,4,5- trifluorophenyl)cyclohex-3-en-l -amine. In some embodiments, the DPP-IV inhibitor is selected from (15,6R)-3-{ [3-(trifluoromethyl)-5,6-dihydro[l ,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl]carbonyl}-6-(2,4,5-trifluorophenyl)cyclohex-3-en-l -amine, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000081_0001
Biguanides
The biguanides are a class of drugs that stimulate anaerobic glycolysis, increase the sensitivity to insulin in the peripheral tissues, inhibit glucose absorption from the intestine, suppress of hepatic gluconeogenesis, and inhibit fatty acid oxidation. Examples of biguanides include phenformin ((phenylethyl) biguanide), metformin (dimethylbiguanide), buformin
(butylbiguanide), proguanil (l-(p-chlorophenyl)-5-isopropylbiguanide), and biguanides known in the art.
In some embodiments, the pharmaceutical agent or said second pharmaceutical agent is a biguanide selected from the following biguanide:
(phenylethyl)biguanide, dimethylbiguanide, butylbiguanide, l-(p-chlorophenyl)-5- isopropylbiguanide, and pharmaceutically acceptable salts, solvates, and hydrates thereof.
In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is a biguanide selected from (phenylethyl)biguanide (chemical structure shown below) and pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000081_0002
In some embodiments, the pharmaceutical agent or the 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:
Figure imgf000081_0003
In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is a biguanide selected from butylbiguanide (chemical structure shown below) and pharmaceutically acceptable salts, solvates, and hydrates thereof; the chemical structure is as follows:
Figure imgf000081_0004
In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is a biguanide selected from l-(p-chlorophenyl)-5-isopropylbiguanide (chemical structure shown below) and pharmaceutically acceptable salts, solvates, and hydrates thereof; the chemical structure is as follows:
Figure imgf000082_0001
In some embodiments, the pharmaceutical agent or said second pharmaceutical agent is a biguanide selected from the following biguanides: metformin, phenformin, buformin, and proguanil. In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is metformin. In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is phenformin. In some embodiments, the pharmaceutical agent or the second
pharmaceutical agent is buformin. In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is proguanil.
Alpha-Gluocosidase Inhibitors
a-Glucosidase inhibitors belong to the class of drugs which competitively inhibit digestive enzymes such as a-amylase, maltase, a-dextrinase, sucrase, etc. in the pancreas and or small intestine. The reversible inhibition by a-glucosidase inhibitors retard, diminish or otherwise reduce blood glucose levels by delaying the digestion of starch and sugars. Some representative examples of a-glucosidase inhibitors include acarbose ((2R,3R,4R,5R)-4- ((2R,3R,4R,55,6R)-5-((2R,3R,45,55,6R)-3,4-dihydroxy-6-methyl-5-((15,4R,55,65)-4,5,6- trihydroxy-3-(hydroxymethyl)cyclohex-2-enylamino)tetrahydro-2H-pyran-2-yloxy)-3,4- dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yloxy)-2,3,5,6-tetrahydroxyhexanal), miglitol ((2R,3R,4R,55)-l -(2-hydroxyethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol), voglibose ((15,25,3R,45,55)-5-(l ,3-dihydroxypropan-2-ylamino)-l -(hydroxymethyl)cyclohexane-l , 2,3,4- tetraol), and α-glucosidase inhibitors known in the art.
In some embodiments, the pharmaceutical agent or said second pharmaceutical agent is a α-glucosidase inhibitor selected from the following α-glucosidase inhibitors:
(2R,3R,4R,5R)-4-((2R,3R,4R,55,6R)-5-((2R,3R,45,55,6R)-3,4-dihydroxy-6-methyl-5- ((15,4R,55,65)-4,5,6-trihydroxy-3-(hydroxymethyl)cyclohex-2-enylamino)tetrahydro-2H-pyran- 2-yloxy)-3,4-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yloxy)-2,3,5,6- tetrahydroxyhexanal; (2R,3R,4R,55)-l -(2-hydroxyethyl)-2-(hydroxymethyl)piperidine-3,4,5- triol; (15,25,3R,45,55)-5-(l ,3-dihydroxypropan-2-ylamino)-l -(hydroxymethyl)cyclohexane- 1 ,2,3,4-tetraol; and pharmaceutically acceptable salts, solvates, and hydrates thereof.
In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is a α-glucosidase inhibitor selected from (2R,3R,4R,5R)-4-((2R,3R,4R,55,6R)-5-((2R,3R,45,55,6R)- 3 ,4-dihydroxy-6-methyl-5 -((15,4R,55,65)-4,5 ,6-trihydroxy-3 -(hydroxymethyl)cyclohex-2- enylamino)tetrahydro-2H-pyran-2-yloxy)-3,4-dihydroxy-6-(hydroxymethyl)tetrahydro-2H- pyran-2-yloxy)-2,3,5,6-tetrahydroxyhexanal (chemical structure shown below) and
pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000083_0001
In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is a a-glucosidase inhibitor selected from (2R,3R,4R,5S)-l-(2-hydroxyethyl)-2- (hydroxymethyl)piperidine-3,4,5-triol (chemical structure shown below) and pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000083_0002
In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is a a-glucosidase inhibitor selected from (lS,2S,3R,4S,5S)-5-(l,3-dihydroxypropan-2-ylamino)-l- (hydroxymethyl)cyclohexane-l,2,3,4-tetraol (chemical structure shown below) and
pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000083_0003
In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is an alpha-glucosidase inhibitor selected from: acarbose, miglitol, and voglibose. In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is acarbose. In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is miglitol. In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is voglibose. Insulin and Insulin Analogues
The term "insulin analogue" refers to the naturally occurring human hormone and insulin receptor ligands (i.e., synthetic insulin analogues). Insulin receptor ligands are structurally different from the natural human hormone, but have substantially the same activity as human insulin in terms of glycemic control. Examples of an insulin analogue include, NPH insulin (also known as Humulin N, Novolin N, NPH Lletin II, and insulin isophane), insulin lispro (28B-L -lysine -29B-L-proline -insulin, wherein insulin is human insulin), insulin aspart (28B-L-aspartic acid-insulin, wherein insulin is human insulin), insulin glulisine (3B-L -lysine - 29B-L-glutamic acid-insulin, wherein insulin is human insulin), and insulin analogues known in the art.
NPH insulin is marketed by Eli Lilly and Company under the name Humulin N, and is considered as an intermediate-acting insulin analogue given to help control the blood sugar level of those with diabetes. Insulin lispro is marketed by Eli Lilly and Company under the name Humalog, and is considered a rapid 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 is sold under the trade name Apidra. Insulin glulisine is considered a rapid acting insulin analogue but shorter duration of action compared to human insulin.
In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is an insulin analogue selected from NPH insulin and pharmaceutically acceptable salts, solvates, and hydrates thereof. In some embodiments, the pharmaceutical agent or the 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 the 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 the second pharmaceutical agent is an insulin analogue selected from insulin glulisine and pharmaceutically acceptable salts, solvates, and hydrates thereof.
Sulfonylureas
The sulfonylureas are drugs which promote secretion of insulin from pancreatic beta cells by transmitting signals of insulin secretion via receptors in the cell membranes. Examples of a sulfonylurea include tolbutamide (Orinase, N-(butylcarbamoyl)-4- methylbenzenesulfonamide); acetohexamide (Dymelor, 4-acetyl-N-
(cyclohexylcarbamoyl)benzenesulfonamide); tolazamide (Tolinase, N-(azepan-l-ylcarbamoyl)- 4-methylbenzenesulfonamide); chlorpropamide (Diabinese, 4-chloro-N- (propylcarbamoyl)benzenesulfonamide); glipizide (Glucotrol, N-(4-(N-
(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-5-methylpyrazine-2-carboxamide); glibenclamide, also known as glyburide (Diabeta, Micronase, Glynase, 5-chloro-N-(4-(N- (cyclohexylcarbamoyl)sulfamoyl)phenethyl)-2-methoxybenzamide); glimepiride (Amaryl, 3- ethyl-4-methyl-N-(4-(N-((l r,4r)-4-methylcyclohexylcarbamoyl)sulfamoyl)phenethyl)-2-oxo- 2,5-dihydro-lH-pyrrole-l-carboxamide); gliclazide (Diamicron, N-
(hexahydrocyclopenta[c]pyrrol-2(lH)-ylcarbamoyl)-4-methylbenzenesulfonamide); and sulfonylureas known in the art. In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is a sulfonylurea selected from sulfonylureas:
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-((l r,4r)-4- methylcyclohexylcarbamoyl)sulfamoyl)phenethyl)-2-oxo-2,5-dihydro- lH-pyrrole- 1 - carboxamide; and pharmaceutically acceptable salts, solvates, and hydrates thereof.
In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is a sulfonylurea selected from N-(butylcarbamoyl)-4-methylbenzenesulfonamide (chemical structure shown below) and pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000085_0001
In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is a sulfonylurea selected from 4-acetyl-N-(cyclohexylcarbamoyl)benzenesulfonamide (chemical structure shown below) and pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000085_0002
In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is a sulfonylurea selected from N-(azepan-l-ylcarbamoyl)-4-methylbenzenesulfonamide (chemical structure shown below) and pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000085_0003
In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is a sulfonylurea selected from 4-chloro-N-(propylcarbamoyl)benzenesulfonamide (chemical structure shown below) and pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000085_0004
In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is a sulfonylurea selected from N-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-5- methylpyrazine-2-carboxamide (chemical structure shown below) and pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000086_0001
In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is a sulfonylurea selected from 5-chloro-N-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-2- methoxybenzamide (chemical structure shown below) and pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000086_0002
In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is a sulfonylurea selected from 3-ethyl-4-methyl-N-(4-(N-((lr,4r)-4- methylcyclohexylcarbamoyl)sulfamoyl)phenethyl)-2-oxo-2,5-dihydro- lH-pyrrole- 1 - carboxamide (chemical structure shown below) and pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000086_0003
In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is a sulfonylurea selected from N-(hexahydrocyclopenta[c]pyrrol-2(lH)-ylcarbamoyl)-4- methylbenzenesulfonamide (chemical structure shown below) and pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000086_0004
In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is a sulfonylurea selected from the following sulfonylureas and pharmaceutically acceptable salts, solvates, and hydrates thereof: glipizide, glimepiride, and glibenclamide. In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is tolbutamide. In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is acetohexamide. In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is tolazamide. In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is chlorpropamide. In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is glipizide. In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is glyburide. In some embodiments, the pharmaceutical agent or the second
pharmaceutical agent is glimepiride. In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is gliclazide.
SGLT2 inhibitors
Sodium-glucose transporter-2 (SGLT2) inhibitors belong to the class of drugs which inhibit the protein SGLT2 and the reabsorption of glucose in the kidney. The inhibition by SGLT2 inhibitors retard, diminish, or otherwise reduce the amount of glucose that is reabsorbed and therefore is eliminated 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,35,45,5R,65)-3,4,5-trihydroxy-6-(4-(4-isopropoxybenzyl)-l -isopropyl- 5-methyl-lH-pyrazol-3-yloxy)tetrahydro-2H-pyran-2-yl)methyl carbonate, GlaxoSmithKline), ASP1941 (Kotobuki/Astellas), canagliflozin ((25,3R,4R,55,6R)-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 (an antisense oligonucleotide, Isis Pharmaceuticals), sergliflozin (ethyl ((2R,35,45,5R,65)-3,4,5-trihydroxy-6-(2-(4- methoxybenzyl)phenoxy)tetrahydro-2H-pyran-2-yl)methyl carbonate, GlaxoSmithKline), AVE2268 ((2R,35,45,5R,65)-2-(hydroxymethyl)-6-(2-(4-methoxybenzyl)thiophen-3- yloxy)tetrahydro-2H-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 the second pharmaceutical agent is a SGLT2 inhibitor selected from the following SGLT2 inhibitors:
(25,3R,4R,55,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro- 2H-pyran-3,4,5-triol; ethyl ((2R,35,45,5R,65)-3,4,5-trihydroxy-6-(4-(4-isopropoxybenzyl)-l- isopropyl-5-methyl-lH-pyrazol-3-yloxy)tetrahydro-2H-pyran-2-yl)methyl carbonate; ethyl ((2R,35,45,5R,65)-3,4,5-trihydroxy-6-(2-(4-methoxybenzyl)phenoxy)tetrahydro-2H-pyran-2- yl)methyl carbonate; (2R,35,45,5R,65)-2-(hydroxymethyl)-6-(2-(4-methoxybenzyl)thiophen-3- yloxy)tetrahydro-2H-pyran-3,4,5-triol; (25,3R,4R,55,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2- yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; and pharmaceutically acceptable salts, solvates, and hydrates thereof.
In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is a sulfonylurea selected from (25,3R,4R,55,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (chemical structure shown below) and pharmaceutically acceptable
Figure imgf000088_0001
In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is a sulfonylurea selected from ethyl ((2R,35,45,5R,65)-3,4,5-trihydroxy-6-(4-(4-isopropoxybenzyl)- 1 -isopropyl-5-methyl- lH-pyrazol-3-yloxy)tetrahydro-2H-pyran-2-yl)methyl carbonate
(chemical structure shown below) and pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000088_0002
In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is a sulfonylurea selected from ethyl ((2R,35,45,5R,65)-3,4,5-trihydroxy-6-(2-(4- methoxybenzyl)phenoxy)tetrahydro-2H-pyran-2-yl)methyl carbonate (chemical structure shown below) and pharmaceutically s thereof:
Figure imgf000088_0003
In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is a SGLT2 inhibitor selected from: dapagliflozin, remigliflozin, and sergliflozin. In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is dapagliflozin. In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is remigliflozin. In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is sergliflozin.
Astellas and Kotobuki disclosed a series of SGLT2 inhibitors in international patent publication WO2004/080990. Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in WO2004/080990 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
Aventis disclosed a series of SGLT2 inhibitors in international patent publication WO2004/007517. Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in WO2004/007517 and pharmaceutically acceptable salts, solvates, and hydrates thereof. One such compound is (2R,35,45,5R,65)-2-(hydroxymethyl)-6-(2-(4-methoxybenzyl)thiophen-3-yloxy)tetrahydro-2H- pyran-3,4,5-triol. 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 pharmaceutically accept of:
Figure imgf000089_0001
Tanabe disclosed a series of SGLT2 inhibitors in international patent publication WO2005/012326. Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in WO2005/012326 and pharmaceutically acceptable salts, solvates, and hydrates thereof. One such compound is (25,3R,4R,55,6R)-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 (25,3R,4R,55,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4- methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, and pharmaceutically acceptable salts, solvates,
Figure imgf000089_0002
Boehringer Ingelheim disclosed a series of SGLT2 inhibitors in international patent publication WO2005/092877. Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in WO2005/092877 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
Chugai disclosed a series of SGLT2 inhibitors in international patent publication WO2006/080421. Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in WO2006/080421 and pharmaceutically acceptable salts, solvates, and hydrates thereof. Lexicon disclosed a series of SGLT2 inhibitors in international patent publication WO2008/109591. Some embodiments of the present invention include every combination of one or more compounds selected from compounds disclosed in WO2008/109591 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
Meglitinides
The meglitinides promote secretion of insulin by binding to the pancreatic beta cells in a similar manner as sulfonylureas but at an alternative binding site. Examples of meglitinides include Novo Nordisk's repaglinide (Prandin, (S)-2-ethoxy-4-(2-(3-methyl-l-(2-(piperidin-l- yl)phenyl)butylamino)-2-oxoethyl)benzoic acid), nateglinide (Starlix, (R)-2-((lr,4R)-4- isopropylcyclohexanecarboxamido)-3-phenylpropanoic acid), mitiglinide ((5)-2-benzyl-4- ((3aR,7a5)-lH-isoindol-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)-4-oxobutanoic acid), and the like.
In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is a meglitinide selected from the following meglitinides: (5)-2-ethoxy-4-(2-(3-methyl-l-(2- (piperidin-l-yl)phenyl)butylamino)-2-oxoethyl)benzoic acid; (R)-2-((lr,4R)-4- isopropylcyclohexanecarboxamido)-3-phenylpropanoic acid; (S)-2-benzyl-4-((3aR,7aS)-lH- isoindol-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)-4-oxobutanoic acid; and pharmaceutically acceptable salts, solvates, and hydrates thereof.
In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is (5)-2-ethoxy-4-(2-(3 -methyl- 1 -(2-(piperidin- 1 -yl)phenyl)butylamino)-2-oxoethyl)benzoic acid (chemical structure shown below) and pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000090_0001
In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is a sulfonylurea selected from (R)-2-((lr,4R)-4-isopropylcyclohexanecarboxamido)-3- phenylpropanoic acid (chemical structure shown below) and pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000090_0002
In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is a sulfonylurea selected from (S)-2-benzyl-4-((3aR,7aS)-lH-isoindol-
2(3H,3aH,4H,5H,6H,7H,7aH)-yl)-4-oxobutanoic acid (chemical structure shown below) and pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000091_0001
In some embodiments, the pharmaceutical agent or the 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 the second pharmaceutical agent is a meglitinide selected from repaglinide and pharmaceutically acceptable salts, solvates, and hydrates thereof. In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is a meglitinide selected from nateglinide and pharmaceutically acceptable salts, solvates, and hydrates thereof. In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is a meglitinide selected from mitiglinide and pharmaceutically acceptable salts, solvates, and hydrates thereof.
Thiazolidinediones
Thiazolidinediones belong to the class of drugs more commonly known as TZDs. These drugs act by binding to the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARy) activate 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)thiazolidine-2,4-dione),
rivoglitazone (5-(4-((6-methoxy-l-methyl-lH-benzo[d]imidazol-2- yl)methoxy)benzyl)thiazolidine-2,4-dione), ciglitazone(5-(4-(( 1 - methylcyclohexyl)methoxy)benzyl)thiazolidine-2,4-dione), and thiazolidinediones known in the art.
In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is a meglitinide selected from: 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-lH- benzo[d]imidazol-2-yl)methoxy)benzyl)thiazolidine-2,4-dione; 5-(4-((l- methylcyclohexyl)methoxy)benzyl)thiazolidine-2,4-dione; and pharmaceutically acceptable salts, solvates, and hydrates thereof. In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is 5-(4-(2-(methyl(pyridin-2-yl)amino)ethoxy)benzyl)thiazolidine-2,4-dione (chemical structure shown below) and ph ates thereof:
Figure imgf000092_0001
In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is 5-(4-(2-(5-ethylpyridin-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione (chemical structure shown below) and pharmaceutica thereof:
Figure imgf000092_0002
In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is 5-(4-((6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)methoxy)benzyl)thiazolidine-2,4-dione (chemical structure shown below) and pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000092_0003
In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is 5-(4-((6-methoxy- 1 -methyl- 1 H-benzo [d] imidazol-2-yl)methoxy)benzyl)thiazolidine-2,4-dione (chemical structure shown below) and pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000092_0004
In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is 5-(4-((l-methylcyclohexyl)methoxy)benzyl)thiazolidine-2,4-dione (chemical structure shown below) and pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000093_0001
In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is a thiazolidinedione selected from rosiglitazone and pharmaceutically acceptable salts, solvates, and hydrates thereof. In some embodiments, the pharmaceutical agent or the second
pharmaceutical agent is a thiazolidinedione selected from pioglitazone and pharmaceutically acceptable salts, solvates, and hydrates thereof. In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is a thiazolidinedione selected from troglitazone and pharmaceutically acceptable salts, solvates, and hydrates thereof. In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is a thiazolidinedione selected from rivoglitazone and pharmaceutically acceptable salts, solvates, and hydrates thereof. In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is a
thiazolidinedione selected from ciglitazone and pharmaceutically acceptable salts, solvates, and hydrates thereof. Anti-Diabetic Peptide Analogues
Anti-diabetic peptide analogues are peptides that promote secretion of insulin by acting as an incretin mimetic, such as, GLP-1 and GIP. Examples of an anti-diabetic peptide analog include, exenatide, liraglutide, taspoglutide, and anti-diabetic peptides analogues know in the art.
In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is an anti-diabetic peptide analogue selected from: exenatide; liraglutide; and taspoglutide. In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is exenatide. In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is liraglutide. In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is taspoglutide.
In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is L-histidylglycyl-L-a-glutamylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-a- aspartyl-L-leucyl-L-seryl-L-lysyl-L-glutaminyl-L-methionyl-L-a-glutamyl-L-a-glutamyl-L-a- glutamyl-L-alanyl-L-valyl-L-arginyl-L-leucyl-L-phenylalanyl-L-isoleucyl-L-a-glutamyl-L- tryptophyl-L-leucyl-L-lysyl-L-asparaginylglycylglycyl-L-prolyl-L-seryl-L-serylglycyl-L-alanyl- L-prolyl-L -prolyl -L -prolyl- L-serinamide (i.e., exenatide) and pharmaceutically acceptable salts, solvates, and hydrates thereof.
In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is L-histidyl-L-alanyl-L-a-glutamylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-a- aspartyl-L-valyl-L-seryl-L-seryl-L-tyrosyl-L-leucyl-L-a-glutamylglycyl-L-glutaminyl-L-alanyl- L-alanyl-N6- [N-( 1 -oxohexadecyl)-L-a-glutamyl] -L-lysyl-L-a-glutamyl-L-phenylalanyl-L- isoleucyl-L-alanyl-L-tryptophyl-L-leucyl-L-valyl-L-arginylglycyl-L-arginyl-glycine
(liraglutide) and pharmaceutically acceptable salts, solvates, and hydrates thereof.
In some embodiments, the pharmaceutical agent or the second pharmaceutical agent is
H2N-His-2-methyl-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala- Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-2-methyl-Ala-Arg-CONH2 (taspoglutide) and pharmaceutically acceptable salts, solvates, and hydrates thereof. Acyl-CoA:Diacylglycerol Acyltransferases (DGAT-1) Inhibitors
Triglycerides (TG) represent the major form of energy stored in eukaryotes. Disorders and/or imbalances in triglyceride metabolism are implicated in the pathogenesis of and increased risk for metabolic related disorders, such as, obesity, insulin resistance syndrome and type 2 diabetes, nonalcoholic fatty liver disease, and coronary heart disease.
Triglyceride biosynthesis and the resulting TG burden on tissues are largely controlled by two major pathways in humans. Both of these pathways converge at an intermediate diacylglycerols (DAG) which are subsequently converted to triglycerides through acylation by a fatty acid acyl-CoA catalyzed by the acyl-CoA:diacylglycerol acyltransferases (DGAT). DGAT consists of DGAT-1 and DGAT-2. Inhibition of acyl-CoA:diacylglycerol acyltransferase-1 (DGAT-1) is one of the most advanced targets for altering lipid biosyntheis as evidenced by on going human clinical trials.
In some embodiments, the pharmaceutical agent or said second pharmaceutical agent is a DGAT-1 inhibitor known in the art.
In some embodiments, the pharmaceutical agent or said second pharmaceutical agent is a DGAT-1 inhibitor selected from the DGAT-1 inhibitors described in the following patent applications and pharmaceutically acceptable salts, solvates, and hydrates thereof: WO
2004/047755, WO 2004/100881 , WO 2005/0727401, WO 2006/044775, WO 2006/06019020, WO 2006/082010, WO2006/113919, WO 2006/134317, WO2007/126957, WO2012/051488, WO2009/016462.
In some embodiments, the pharmaceutical agent or said second pharmaceutical agent is a DGAT-1 inhibitor selected from the following DGAT-1 inhibitors and pharmaceutically acceptable salts, solvates, and hydrates thereof:
(l r,4r)-4-(3-fluoro-4-(5-(4-(trifluoromethyl)phenylamino)-l ,3,4-oxadiazole-2- carboxamido)phenyl)cyclohexanecarboxylic acid (see Example 1 , WO2010/070343);
(1 r,4r)-4-(4-(5-(4-(difluoromethoxy)phenylamino)- 1 ,3 ,4-oxadiazole-2-carboxamido)-3- fluorophenyl)cyclohexanecarboxylic acid (see Example 2, WO2010/070343); (lr,4r)-4-(3-fluoro-4-(5-(4-(trifluoromethoxy)phenylamino)-l,3,4-oxadiazole-2- carboxamido)phenyl)cyclohexanecarboxylic acid (see Example 3, WO2010/070343);
(lr,4r)-4-(4-(5-(3-chlorophenylamino)-l,3,4-oxadiazole-2-carboxamido)-3- fluorophenyl)cyclohexanecarboxylic acid (see Example 4, WO2010/070343);
(1 r,4r)-4-(4-(5 -(3 ,4-difluorophenylamino)- 1 ,3 ,4-oxadiazole-2-carboxamido)-3 - fluorophenyl)cyclohexanecarboxylic acid (see Example 5, WO2010/070343);
(lr,4r)-4-(3-fluoro-4-(5-(2,4,5-trifluorophenylamino)-l,3,4-oxadiazole-2- carboxamido)phenyl)cyclohexanecarboxylic acid (see Example 6, WO2010/070343);
( 1 s ,4s)-4-(4-(5 -(3 ,4-difluorophenylamino)- 1 ,3 ,4-oxadiazole-2-carboxamido)-3 - fluorophenyl)cyclohexanecarboxylic acid (see Example 7, WO2010/070343);
(li,4i)-4-(3-fluoro-4-(5-(2,4,5-trifluorophenylamino)-l,3,4-oxadiazole-2- carboxamido)phenyl)cyclohexanecarboxylic acid (see Example 8, WO2010/070343);
ira«i-(4-{4-[5-(6-trifluoromethyl-pyridin-3ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)- acetic acid (see Example 5-1, WO2007/126957 and Examples 1-10, WO2012/051488 for formulations related thereto; alternative name: 2-((lr,4r)-4-(4-(5-(6-(trifluoromethyl)pyridin-3- ylamino)pyridin-2-yl)phenyl)cyclohexyl)acetic acid); and
{ira«i-4-(4-(4-amino-5-oxo-7,8-dihydropyrimido[5.4-f] [f]oxazepin- 6(5H)yl)phenyllcyclohexyl} acetic acid (see Example 2, WO2009/016462; alternative name: 2- ((lr,4r)-4-(4-(4-amino-5-oxo-7,8-dihydropyrimido[5,4-f][l,4]oxazepin-6(5H)- yl)phenyl)cyclohexyl)acetic acid).
Other Utilities
Another object of the present invention relates to radio-labeled compounds of the present invention that would be useful not only in radio-imaging but also in assays, both in vitro and in vivo, for localizing and quantitating GPR119 receptors in tissue samples, including human and for identifying GPR119 receptor ligands by inhibition binding of a radio-labeled compound. It is a further object of this invention to develop novel GPR119 receptor assays of which comprise such radio-labeled compounds.
The present disclosure includes all isotopes of atoms occurring in the present compounds, intermediates, salts and crystalline forms thereof. Isotopes include those atoms having the same atomic number but different mass numbers. One aspect of the present invention includes every combination of one or more atoms in the present compounds, intermediates, salts, and crystalline forms thereof that is replaced with an atom having the same atomic number but a different mass number. One such example is the replacement of an atom that is the most naturally abundant isotope, such as lH or 12C, found in one the present compounds,
intermediates, salts, and crystalline forms thereof, with a different atom that is not the most naturally abundant isotope, such as 2 H or 3 H (replacing 1 H), or 11 C, 13 C, or 14 C (replacing 12 C). A compound wherein such a replacement has taken place is commonly referred to as being an isotopically-labeled compound. Isotopic-labeling of the present compounds, intermediates, salts, and crystalline forms thereof can be accomplished using any one of a variety of different synthetic methods know to those of ordinary skill in the art and they are readily credited with understanding the synthetic methods and available reagents needed to conduct such isotopic- labeling. By way of general example, and without limitation, isotopes of hydrogen include 2H (deuterium) and 3H (tritium). Isotopes of carbon include nC, 13C, and 14C. Isotopes of nitrogen include 13 N and 15 N. Isotopes of oxygen include 15 O, 17 O, and 18 C. An isotope of fluorine includes 18F. An isotope of sulfur includes 35S. An isotope of chlorine includes 36C1. Isotopes of bromine include 75Br, 76Br, 77Br, and 82Br. Isotopes of iodine include 123I, 124I, 125I, and 131I.
Another aspect of the present invention includes compositions, such as, those prepared during synthesis, preformulation, and the like, and pharmaceutical compositions, such as, those prepared with the intent of using in a mammal for the treatment of one or more of the disorders described herein, comprising one or more of the present compounds, intermediates, salts, and crystalline forms thereof, wherein the naturally occurring distribution of the isotopes in the composition is perturbed. Another aspect of the present invention includes compositions and pharmaceutical compositions comprising compounds as described herein wherein the compound is enriched at one or more positions with an isotope other than the most naturally abundant isotope. Methods are readily available to measure such isotope perturbations or enrichments, such as, mass spectrometry, and for isotopes that are radio-isotopes additional methods are available, such as, radio-detectors used in connection with HPLC or GC.
Certain isotopically-labeled compounds of the present invention are useful in compound and/or substrate tissue distribution assays. In some embodiments the radionuclide 3H and/or 14C isotopes are useful in these studies. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability
(e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Drawings and Examples infra, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. Other synthetic methods that are useful are discussed infra. Moreover, it should be understood that all of the atoms represented in the compounds of the invention can be either the most commonly occurring isotope of such atoms or the scarcer radio-isotope or nonradioactive isotope.
Synthetic methods for incorporating radio-isotopes into organic compounds are applicable to 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 Tritium Gas: This procedure normally yields high specific activity products and requires halogenated or unsaturated precursors.
B. Reduction with Sodium Borohydride [3H]: This procedure is rather inexpensive and requires precursors containing reducible functional groups such as aldehydes, ketones, lactones, esters and the like.
C. Reduction with Lithium Aluminum Hydride [3H]: This procedure offers products at almost theoretical specific activities. It also requires precursors containing reducible functional groups such as aldehydes, ketones, lactones, esters and the like.
D. Tritium Gas Exposure Labeling: This procedure involves exposing precursors containing exchangeable protons to tritium gas in the presence of a suitable catalyst.
E. N-Methylation using Methyl Iodide [3H] : This procedure is usually employed to prepare O-methyl or N-methyl (3H) products by treating appropriate precursors with high specific activity methyl iodide (3H). This method in general allows for higher specific activity, such as for example, about 70-90 Ci/mmol.
Synthetic methods for incorporating activity levels of 125I into target molecules include:
A. Sandmeyer and like reactions: This procedure transforms an aryl amine or a heteroaryl amine into a diazonium salt, such as a diazonium tetrafluoroborate salt and subsequently to 125I labeled compound using Na125I. A represented procedure was reported by Zhu, G-D. and co-workers in . Org. Chem. , 2002, 67, 943-948.
B. Ortho 125Iodination of phenols: This procedure allows for the incorporation of 125I at the ortho position of a phenol as reported by Collier, T. L. and co-workers in . Labelled Compd. Radiopharm. , 1999, 42, S264-S266.
C. Aryl and heteroaryl bromide exchange with 125I: This method is generally a two step process. The first step is the conversion of the aryl or heteroaryl bromide to the corresponding tri-alkyltin intermediate using for example, a Pd catalyzed reaction [i.e. Pd(Ph3P)4] or through an aryl or heteroaryl lithium, in the presence of a tri-alkyltinhalide or hexaalkylditin [e.g., (CH3)3SnSn(CH3)3] . A representative procedure was reported by Le Bas, M.-D. and co-workers in . Labelled Compd. Radiopharm. 2001, 44, S280-S282.
A radiolabeled GPR119 receptor compound of Formula (I) can be used in a screening assay to identify/evaluate compounds. In general terms, a newly synthesized or identified compound (i.e., test compound) can be evaluated for its ability to reduce binding of the "radiolabeled compound of Formula (I)" to a GPR119 receptor. Accordingly, the ability of a test compound to compete with the "radio-labeled compound of Formula (I)" for the binding to a GPR119 receptor directly correlates to its binding affinity.
Certain labeled compounds of the present invention bind to certain GPR119 receptors.
In one embodiment the labeled compound has an IC50 less than about 500 μΜ, in another embodiment the labeled compound has an IC50 less than about 100 μΜ, in yet another embodiment the labeled compound has an IC50 less than about 10 μΜ, in yet another embodiment the labeled compound has an IC50 less than about 1 μΜ and in still yet another embodiment the labeled inhibitor has an IC50 less than about 0.1 μΜ.
Other uses of the disclosed receptors and methods will become apparent to those skilled in the art based upon, inter alia, a review of this disclosure.
As will be recognized, the steps of the methods of the present invention need not be performed any particular number of times or in any particular sequence. Additional objects, advantages and novel features of this invention will become apparent to those skilled in the art upon examination of the following examples thereof, which are intended to be illustrative and not intended to be limiting.
EXAMPLES
Example 1: Syntheses of Compounds of the Present Invention.
Illustrated syntheses for compounds of the present invention are shown in Figures 4 through 11 where the variables have the same definitions as used throughout this disclosure.
The compounds of the invention and their syntheses are further illustrated by the following examples. The following examples are provided to further define the invention without, however, limiting the invention to the particulars of these examples. The compounds described herein, supra and infra, 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 certain instances common names are used and it is understood that these common names would be recognized by those skilled in the art.
Chemistry: Proton nuclear magnetic resonance (lYl NMR) spectra were recorded on a Bruker Avance-400 equipped with a QNP (Quad Nucleus Probe) or a BBI (Broad Band Inverse) and z-gradient. Chemical shifts are given in parts per million (ppm) with the residual solvent signal used as reference. NMR abbreviations are used as follows: s = singlet, d = doublet, dd = doublet of doublets, ddd = doublet of doublet of doublets, dt = doublet of triplets, t = triplet, td = triplet of doublets, tt = triplet of triplets, q = quartet, m = multiplet, bs = broad singlet, bt = broad triplet. Microwave irradiations were carried out using a Smith Synthesizer™ or an Emrys Optimizer™ (Biotage™). Thin-layer chromatography (TLC) was performed on silica gel 60 F254 (Merck), preparatory thin-layer chromatography (prep TLC) was preformed on PK6F silica gel 60 A 1 mm plates (Whatman) and column chromatography was carried out on a silica gel column using Kieselgel 60, 0.063-0.200 mm (Merck). Evaporation was done under reduced pressure on a Biichi rotary evaporator.
LCMS spec: HPLC-pumps: LC-10AD VP, Shimadzu Inc.; HPLC system controller:
SCL-IOA VP, Shimadzu Inc; UV-Detector: SPD-10A VP, Shimadzu Inc; Autosampler: CTC 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 (lR,3s,5S)-tert-butyl 3-((ls,4S)-4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate and (IR,3s,5S)-tert-butyl 3-((lr,4/?)-4- hydroxycyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate.
Step A: Preparation of (lR,3s,5S)-tert-Butyl 3-(4-(benzyloxy)phenoxy)-8- azabicyclo[3.2.1]octane-8-carboxylate.
To a solution of (lR,3r,5S)-tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8- carboxylate (8.12 g, 35.72 mmol), 4-(benzyloxy)phenol (7.868 g, 39.30 mmol) and
triphenylphosphine (10.31 g, 39.30 mmol) in anhydrous THF (12 mL) was added triethylamine (4.979 mL, 35.72 mmol). The reaction mixture was cooled down in an ice-water bath under an atmosphere of argon and DIAD (7.293 mL, 37.51 mmol) was added dropwise to the stirred solution. The reaction mixture was slowly allowed to warm to room temperature and stirred over the weekend. The white solid was filtered off to give the title compound (3.021 g). The filtrate was partly concentrated and CH3CN was added to provide a white precipitate that was collected to give another portion of the title compound (6.468 g). The filtrate was concentrated and the residue was purified by column chromatography with 20% ethyl acetate/hexanes to provide an additional amount of the title compound (0.978 g). The total amount of title compound was 10.46 g (25.54 mmol, 71.5% yield). Exact mass calculated for CzsI^NC : 409.2, found LCMS m/z = 410.2 [M+H]+; 'H NMR (CDC13 , 400 MHz) δ ppm 1.49 (s, 9H), 1.64-1.85 (m, 4H), 1.97- 2.10 (m, 4H), 4.20-4.40 (m, 2H), 4.47-4.52 (m, 1H), 5.01 (s, 2H), 6.82-6.90 (m, 4H), 7.30-7.45 (m, 5H).
Step B: Preparation of (lR,3s,5S)-tert-Butyl 3-(4-hydroxyphenoxy)-8- azabicyclo[3.2.1]octane-8-carboxylate.
To a solution of (lR,3s,5S)-tert-butyl 3-(4-(benzyloxy)phenoxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (3.56 g, 8.693 mmol) in THF/EtOH (1 :1, 30 mL) was added 10% palladium on activated carbon (0.925 g, 0.869 mmol). The reaction mixture was degassed and charged with H2. The resulting mixture was shaken for 3 h at room temperature under hydrogen at 1.5 atm. The solid was filtered off and washed with ethanol. The filtrate was concentrated to give the title compound (2.75 g, 8.610 mmol, 99.0% yield) as an off-white solid. Exact mass calculated for Ci8H25N04: 319.2, found LCMS m/z = 320.2 [M+H]+; !H NMR (CDC13 , 400 MHz) δ ppm 1.49 (s, 9H), 1.64-1.85 (m, 4H), 1.97-2.10 (m, 4H), 4.20-4.40 (m, 2H), 4.45-4.55 (m, 1H), 4.78 (s, 1H), 6.72-6.82 (m, 4H).
Step C: Preparation of (lR,3s,5S)-tert-Butyl 3-((ls,4S)-4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate and (lR,3s,5S)-tert-butyl 3-((lr,4/?)-4- hydroxycyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate. A reaction mixture of (lR,3s,5S)-tert-butyl 3-(4-hydroxyphenoxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (2.75 g, 8.610 mmol), 10% palladium on activated carbon (0.458 g, 0.431 mmol) and sodium tetraborate decahydrate (0.328 g, 0.861 mmol) in IPA (15 mL) (in a steel bomb) was heated at 80 °C under H2 atmosphere at 12 bar for 1 day. The reaction was filtered though Celite®, and washed with IPA. The filtrate was concentrated to give (lR,3s,5S)-tert-butyl 3-(4-hydroxycyclohexyloxy)-8-azabicyclo[3.2. l]octane-8-carboxylate (2.75 g, 8.450 mmol, 98.1% yield) in a mixture of cisltrans. About 1.94 g (5.961 mmol) of the mixture was separated by silica gel chromatography with 75% ethyl acetate/hexanes to give (\R,3s,5S)-tert-bvAy\ 3-((ls,4S)-4-hydroxycyclohexyloxy)-8-azabicyclo[3.2.1]octane-8- carboxylate (1.175 g, 3.610 mmol, 60.6% yield) (cis, less polar on reverse phase LCMS and faster eluting product on silica gel TLC), {\R,3s,5S)-tert-bv y\ 3-((lr,4R)-4- hydroxycyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (425 mg, 1.306 mmol, 21.9% yield) (trans, more polar on reverse phase LCMS and slower eluting product on silica gel TLC) and the mixture of both (206 mg, 0.633 mmol, 10.6% yield). Cis isomer: Exact mass calculated for Ci8H3iN04: 325.2, found LCMS mJz = 326.2 [M+H]+; !H NMR (CDC13, 400 MHz) δ ppm 1.30 (d, = 4.6 Hz, 1H), 1.46 (s, 9H), 1.46-1.80 (m, 12H), 1.85-2.00 (m, 4H), 3.42-3.48 (m, 1H), 3.70-3.84 (m, 2H), 4.12-4.32 (m 2H), OH was not observed. Trans isomer: Exact mass calculated for Ci8H31N04: 325.2, found LCMS m/z = 326.2 [M+H]+; 'll NMR (CDC13, 400 MHz) δ ppm 1.25-1.40 (m, 5H), 1.45 (s, 9H), 1.50-1.62 (m, 4H), 1.85-1.98 (m, 8H), 3.30-3.38 (m, 1H), 3.62-3.68 (m, 1H), 3.75-3.84 (m, 1H), 4.12-4.30 (m, 2H), -OH was not observed.
Example 1.2: Preparation of (lR,3r,5S)-tert-butyl 3-(4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate.
The title compound was obtained in a similar manner to the one described in Example 1.1 using (lR,3s,5S)-tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate and 4- (benzyloxy)phenol.
Example 1.3: Preparation of (lR,3r,5S)-tert-butyl 3-(4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate.
Step A: Preparation of l-(benzyloxy)-4-fluorobenzene.
To a solution of 4-fluorophenol (5.0 g, 44.60 mmol) and (bromomethyl)benzene (5.3 mL, 44.62 mmol) in 100 mL CH3CN, potassium carbonate (15.4 g, 111.4 mmol) was added. After stirring at room temperature over night, mixture was concentrated. Residue was extracted with water and CH2C12. Organic phase was dried over MgS04, filtered, and concentrated to give l-(benzyloxy)-4-fluorobenzene (8.4 g, 41.54 mmol, 93%) as a white solid. lH NMR (400 MHz, CDC13) δ ppm 5.07 (s, 2H), 6.92-7.02 (m, 4H), 7.33-7.46 (m, 5H). Step B: Preparation of (lR,3r,5S)-tert-butyl 3-(4-(benzyloxy)phenoxy)-8- azabicyclo[3.2.1]octane-8-carboxylate.
To a suspension of 60% sodium hydride dispersion (0.270 g, 6.75 mmol) in 20 mL DMSO, (lR,3r,5S)-tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (1.0 g, 4.399 mmol) was added. After stirring at room temperature for 20 min, l-(benzyloxy)-4-fluorobenzene (0.89 g, 4.401 mmol) was added and mixture was stirred at 90°C (oil bath). After 2.5 d, dark mixture was extracted with water and AcOEt (3x). Combined organic phases were dried over MgS04, filtered, and concentrated. Residue (ca. 3 g) was dissolved in 40 mL CH2C12 and triethylamine (1 mL, 7.175 mmol) and di-teri-butyl dicarbonate (0.961 g, 4.401 mmol) were added. After 10 min, mixture was transferred into a separatory funnel and extracted with water and CH2C12. Organic phases was dried over MgSO/t, filtered, and concentrated. Residue was purified by Biotage™ column chromatography (Si02, hexane/ AcOEt gradient) to give (lR,3r,55)-teri-butyl 3-(4-(benzyloxy)phenoxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (0.34 g, 0.830 mmol, 18.9%) as a white solid. Exact mass calculated for C25H31F6N04: 409.23, found: LCMS m/z = 410.2 [M+H]+; lU NMR (400 MHz, CDC13) δ ppm 1.47 (s, 9H), 1.93-1.97 (m, 4H), 2.07-2.17 (m, 4H), 4.49-4.53 (m, 2H), 4.50-4.52 (m, 1H), 5.01 (s, 2H), 6.75-6.77 (m, 2H), 6.89-6.91 (m, 2H), 7.31-7.43 (m, 5H).
Step C: Preparation of (lR,3r,5S)-tert-butyl 3-(4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate.
A suspension of (lR,3r,55)-teri-butyl 3-(4-(benzyloxy)phenoxy)-8-azabicyclo[3.2.1]octane- 8-carboxylate (335 mg, 0.818 mmol), sodium tetraborate decahydrate (0.312 g, 0.818 mmol), and palladium on carbon (10%, 50% water, Degussa type, 105 mg, 0.049 mmol) in 15 mL iPrOH was stirred in a steel bomb at 80°C (oil bath) under hydrogen pressure (ca. 15 bar). After 18 h, more Pd/C (100 mg) and sodium tetraborate decahydrate (110 mg) were added and continued to be stirred at 80°C under ca. 15 bar hydrogen. After one additional day, solids were filtered off though Celite®, washed with additional iPrOH, and filtrate was concentrated to give (lR,3r,5S)-tert-butyl 3-(4- hydroxycyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (298 mg, 0.815 mmol, 99.6%) as an viscous oil. Exact mass calculated for Ci8H31N04: 325.23, found: LCMS m/z = 326.2 [M+H]+.
Example 1.4: Preparation of (l/?,3S,5S)-((S)-l,l,l-Trifluoropropan-2-yl) 3-((lr,4fl)-4-(3- Cyanopyridin-4-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 5).
Step A: Preparation of (lR,3r,5S)-tert-butyl 3-((lr,4/?)-4-(3-cyanopyridin-4- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 2) and (lR,3r,5S)- tert-Butyl 3-((ls,4S)-4-(3-Cyanopyridin-4-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8- carboxylate.
To a solution of (lR,3r,5S)-tert-butyl 3-(4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (291 mg, 0.796 mmol) and 4-chloronicotinonitrile (160 mg, 1.155 mmol) in 3 mL THF, 1 M potassium 2-methylpropan-2-olate in THF (1 mL, 1.000 mmol) was added slowly (over ca. 15 min). After stirring for 10 min, mixture was extracted with water and CH2C12. Organic phases were dried over MgS04, filtered, and concentrated. Residue was purified by Biotage™ column chromatography (Si02, hexane/AcOEt gradient). Fractions containing the less polar isomer were concentrated and the residue was re-purified by HPLC (CH3CN/H20 gradient + 0.1 % TFA). Fractions containing pure product were partly concentrated and the residue was extracted with 1 M NaOH and CH2C12. Organic phases were dried over MgS04, filtered, and concentrated to give (lR,3r,5S)-tert-butyl 3-((l r,4R)-4-(3-cyanopyridin-4-yloxy)cyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (50 mg, 0.117 mmol, 14.7%) as a white solid. Fractions containing the more polar isomer were concentrated and the residue was re -purified by HPLC
(CH3CN/H20 gradient + 0.1 % TFA). Fractions containing the pure product were partly concentrated and residue was extracted with 1 M NaOH and CH2C12. Organic phases were dried over MgS04, filtered, and concentrated to give cis-isomer of the title compound (210 mg, 0.491 mmol, 61.7%) as a white solid. Exact mass calculated for C24H33N304: 427.3, found: LCMS m/z = 428.4 [M+H]+; lH NMR (400 MHz, CDCl3) 5 ppm 1.46 (s, 9H), 1.50-1.56 (m, 2H), 1.71-1.79 (m, 4H), 1.88-2.14 (m, 10H), 3.51-3.56 (m, 1H), 3.68-3.70 (m, 1H), 4.13-4.20 (m, 2H), 4.62-4.67 (m, 1H), 6.87 (d, J = 6.0 Hz, 1H), 8.58 (d, J = 6.0 Hz, 1H), 8.67 (s, 1H).
Step B: Preparation of 4-((l ?,4r)-4-((l ?,3r,5S)-8-Azabicyclo[3.2.1]octan-3- yloxy)cyclohexyloxy)nicotinonitrile Dihydrochloride.
To a solution of (lR,3r,5S)-tert-butyl 3-((l r,4R)-4-(3-cyanopyridin-4- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (47 mg, 0.110 mmol) in CH2C12 (0.5 mL), 4 M hydrogen chloride in dioxane (1 mL, 4.000 mmol) was added. After stirring at room temperature for 1 h, the mixture was concentrated and dried under reduced pressure to give 4- ((lR,4r)-4-((lR,3r,55)-8-azabicyclo[3.2.1]octan-3-yloxy)cyclohexyloxy)nicotinonitrile
dihydrochloride (44 mg, 0.110 mmol, 100.0%) as a white solid. Exact mass calculated for
Ci9H25N302: 327.2, found: LCMS m/z = 328.4 [M+H]+.
Step C: Preparation of (lfl,3S,5S)-((S)-l,l,l-Trifluoropropan-2-yl) 3-((lr,4/?)-4-(3- cyanopyridin-4-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 5).
A solution of (5)-l ,l , l-trifluoropropan-2-ol (0.074 mL, 0.389 mmol) and di(lH- imidazol-l-yl)methanone (16.20 mg, 99.91 μιηοΐ) in THF (2 mL) was stirred at 60°C. After 3 h, 4-((lR,4r)-4-((lR,3r,55)-8-azabicyclo[3.2.1]octan-3-yloxy)cyclohexyloxy)nicotinonitrile dihydrochloride (40 mg, 99.91 μιηοΐ) and triethylamine (71 μΐ, 0.509 mmol) were added. The mixture was stirred at 80°C (oil bath) for 1 h and then at 120°C under microwave irradiation for 6 h. The mixture was extracted with water and CH2C12. The organic phases were dried over MgS04, filtered, and concentrated. The residue was purified by Biotage™ column
chromatography (hexane/AcOEt gradient) to give the title compound (39 mg, 83.43 μιηοΐ,
83.5%) as a white solid. Exact mass calculated for C23H28F3N304: 467.2, found: LCMS m/z = 468.4 [M+H]+; lU NMR (400 MHz, CDC13) δ ppm 1.40 (d, = 6.6 Hz, 3H), 1.51-1.61 (m , 2H), 1.72-1.82 (m, 4H), 1.92-2.18 (m, 10H), 3.52-3.56 (m, 1H), 3.70-3.72 (m, 1H), 4.24-4.29 (m, 2H), 4.63-4.66 (m, 1H), 5.23-5.30 (m, 1H), 6.87 (d, = 6.0 Hz, 1H), 8.58 (d, = 6.0 Hz, 1H), 8.67 (s, 1H).
Example 1.5: Preparation of (lR,3s,5S)-tert-butyl 3-((lr,4/?)-4-(3-Cyanopyridin-4- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 1).
To a solution of (lR,3s,5S)-tert-butyl 3-(4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (0.5 g, 1.536 mmol), 4-chloronicotinonitrile (0.255 g, 1.844 mmol) in THF (5 mL) at ice-water bath under nitrogen was added 1M potassium tert- butoxide in THF (1.997 mL, 1.997 mmol) dropwise. The reaction mixture was stirred at that temperature for 30 min, quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2S04, filtered then concentrated. The residue was purified by silica gel column chromatography with 90% ethyl acetate/hexanes (1% Et3N) to give {\R, >s,5S)-tert-bv y\ 3-((lr,4R)-4-(3-cyanopyridin-4-yloxy)cyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (0.112 g, 0.262 mmol, 17.1% yield) {trans isomer: less polar on reverse phase LCMS), and \R, >s,5S)-tert-bv y\ 3-((ls,4S)-4-(3-cyanopyridin-4- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (0.264 g, 0.617 mmol, 40.2% yield) (cis isomer: more polar on reverse phase LCMS) and the mixture of both (0.163 g, 0.381 mmol, 24.8% yield). Exact mass calculated for C24H33N3O4: 427.2, found LCMS m/z = 428.4 [M+H]+; trans isomer: 'H NMR (CDC13 , 400 MHz) 5 ppm 1.45 (s, 9H), 1.42-1.72 (m, 8H), 1.85-2.00 (m, 6H), 2.05-2.12 (m, 2H), 3.50-3.56 (m, 1H), 3.76-3.83 (m, 1H), 4.14-4.29 (m, 2H), 4.52-4.58 (m, 1H), 6.87 (d, = 6.0 Hz, 1H), 8.56 (d, = 6.0 Hz, 1H), 8.65 (s, 1H). Example 1.6: Preparation of (lfl,3fl,5S)-((S)-l,l,l-trifluoropropan-2-yl) 3-((lr,4fl)-4-(3- cyanopyridin-4-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 3).
Step A: Preparation of 4-((l ?,4r)-4-((l ?,3s,5S)-8-azabicyclo[3.2.1]octan-3- yloxy)cyclohexyloxy)nicotinonitrile dihydrochloride.
(lR,3s,5S)-tert-Butyl 3-((lr,4R)-4-(3-cyanopyridin-4-yloxy)cyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (60 mg, 0.140 mmol) was dissolved in dioxane (1 mL), 4 M HCl in dioxane (1.754 mL, 7.017 mmol) was added. The reaction mixture was stirred at room temperature for 20 h. The white solid was collected, washed with dioxane, and dried to give the title compound (52 mg, 0.130 mmol, 92.6% yield). Exact mass calculated for C19H25N3O2: 327.2, found LCMS m/z = 328.4 [M+H]+.
Step B: Preparation of (lfl,3fl,5S)-((S)-l,l,l-trifluoropropan-2-yl) 3-((lr,4fl)-4-(3- cyanopyridin-4-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate . (S)-l,l,l-Trifluoropropan-2-ol (77.89 mg, 0.410 mmol) and di(lH-imidazol-l- yl)methanone (64.81 mg, 0.400 mmol) in THF was stirred for 1 h at room temperature, then 4- ((lR,4r)-4-((lR,3i,55)-8-azabicyclo[3.2.1]octan-3-yloxy)cyclohexyloxy)nicotinonitrile dihydrochloride (40 mg, 99.93 μιηοΐ) was added, followed by triethylamine (83.57 μΐ, 0.600 mmol). The reaction mixture was stirred at reflux overnight. The mixture was then heated at 120 °C for 2 h under microwave irradiation, then concentrated. The residue was purified by silica gel preparative TLC plate (90% ethyl acetate/hexanes with 1 % Et3N) to give the title compound (29 mg, 62.03 μιηοΐ, 62.1% yield) as white solid. Exact mass calculated for C23H28F3N3O4: 467.2, found LCMS m/z = 468.4 [M+H]+; 'H NMR (CDC13 , 400 MHz) δ ppm 1.38-1.43 (m, 3H), 1.45- 1.58 (m, 3H), 1.60-1.75 (m, 5H), 1.89-2.12 (m, 8H), 3.50-3.60 (m, 1H), 3.76-3.86 (m, 1H), 4.28- 4.38 (m, 2H), 4.52-4.60 (m, 1H), 5.20-5.30 (m, 1H), 6.87 (d, = 6.0 Hz, 1H), 8.56 (d, = 6.0 Hz, 1H), 8.65 (s, 1H).
Example 1.7: Preparation of (lfl,3S,5S)-((fl)-l,l,l-Trifluoropropan-2-yl) 3-((lr,4/?)-4-(3- Cyanopyridin-4-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 4).
(R)-l,l,l-Trifluoropropan-2-ol (27.82 mg, 0.102 mmol) and di(lH-imidazol-l- yl)methanone (16.20 mg, 99.93 μιηοΐ) in THF was stirred for 1 h at room temperature, then 4- ((lR,4r)-4-((lR,3i,55)-8-azabicyclo[3.2.1]octan-3-yloxy)cyclohexyloxy)nicotinonitrile dihydrochloride (10 mg, 24.98 μιηοΐ) was added, followed by triethylamine (20.89 μΐ, 0.150 mmol). The reaction mixture was stirred at reflux overnight. The mixture was then heated at 120 °C for 3 h under microwave irradiation, then concentrated. The residue was purified by silica gel preparative TLC plate (90% ethyl acetate/hexanes with 1 % Et3N) to give the title compound (7 mg, 14.97 μιηοΐ, 59.9% yield) as white solid. Exact mass calculated for C23H28F3N3O4: 467.2, found LCMS m/z = 468.4 [M+H]+; 'll NMR (CDCI3 , 400 MHz) δ ppm 1.38-1.43 (m, 3H), 1.45- 1.58 (m, 3H), 1.60-1.75 (m, 5H), 1.89-2.12 (m, 8H), 3.52-3.60 (m, 1H), 3.78-3.88 (m, 1H), 4.28- 4.38 (m, 2H), 4.54-4.60 (m, 1H), 5.20-5.30 (m, 1H), 6.87 (d, = 6.0 Hz, 1H), 8.58 (d, = 6.0 Hz, 1H), 8.67 (s, 1H). Example 1.8: Preparation of (lR,3s,5S)-tert-butyl 3-((lr,4fl)-4-(3,5-difluoropyridin-4- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 6).
To a solution of (lR,3s,5S)-tert-butyl 3-(4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (350 mg, 1.075 mmol) and 3,4,5-trifluoropyridine (0.172 g, 1.291 mmol) in THF (5 mL) at ice -water bath under nitrogen was slowly added 1 M potassium teri-butoxide in THF (1.291 mL, 1.291 mmol) dropwise. The mixture was stirred for 30 min at that temperature, quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered then concentrated. The residue was purified by silica gel column chromatography with 40% ethyl acetate/hexanes to give the mixture of cis/trans products, which was then separated by preparative Chiralcel OD column to give (lR,3s,5S)-tert-butyl 3-((li,45)-4-(3,5-difluoropyridin-4-yloxy)cyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (218 mg, 0.497 mmol, 46.2% yield) (cis, more polar on reverse phase LCMS, faster eluting on Chiralcel OD column), (lR,3s,5S)-tert-butyl 3-((lr,4R)- 4-(3 ,5 -difluoropyridin-4-yloxy)cyclohexyloxy)-8-azabicyclo [3.2.1] octane-8 -carboxylate (71 mg, 0.162 mmol, 15.1 % yield) (trans, less polar on reverse phase LCMS, slower eluting on Chiralcel OD column) and the mixture of both (100 mg, 0.228 mmol, 21.2% yield).
Resolution Via Chiral HPLC:
Column: Chiralcel OD column, 5cm ID x 50cm L
Flow: 10% IPA/hexanes with 0.1 % diethyl amine
Gradient: Isocratic
Detection: UV 214 nm
Retention time: cis-isomer at 20.0 min, traras-isomer at 23.1 min
Exact mass calculated for Czs^F^O^ 438.2, found LCMS m/z = 439.4 [M+H]+; trans- isomer: !H NMR (CDC13 , 400 MHz) δ ppm 1.40-1.50 (m, 2H), 1.45 (s, 9H), 1.50-1.68 (m, 6H), 1.85-1.90 (m, 2H), 1.90-2.00 (m, 4H), 2.02-2.10 (m, 2H), 3.45-3.52 (m, IH), 3.76-3.83 (m, IH), 4.14-4.30 (m, 2H), 4.54-4.60 (m, IH), 8.25 (s, 2H). Example 1.9: Preparation of 4-((l ?,4r)-4-((l ?,3s,5S)-8-(5-Chloropyrimidin-2-yl)-8- azabicyclo[3.2.1]octan-3-yloxy)cyclohexyloxy)nicotinonitrile (Compound 7).
The reaction mixture of 4-((lR,4r)-4-((lR,3s,5S)-8-azabicyclo[3.2.1]octan-3- yloxy)cyclohexyloxy)nicotinonitrile dihydrochloride (60 mg, 0.150 mmol), 2,5- dichloropyrimidine (44.66 mg, 0.300 mmol) and triethylamine (60.67 mg, 0.600 mmol) in IPA (2 mL) was heated at 120 °C for 3 h under microwave irradiation. Solvent was evaporated, and the residue was purified by semi preparative HPLC (30-90% CH3CN/H20 with 0.1% TFA). The combined fractions were neutralized with saturated NaHC03 aqueous solution, extracted with DCM. The combined organics were dried over anhydrous Na2S04, filtered then concentrated to give the title compound (51 mg, 0.116 mmol, 77.3%) as white solid. Exact mass calculated for C23H26CIN5O2: 439.2, found LCMS m/z = 440.2 [M+H]+; lU NMR (CDC13 , 400 MHz) δ ppm
1.42-1.52 (m, 2H), 1.60-1.80 (m, 6H), 1.92-2.00 (m, 4H), 2.00-2.10 (m, 4H), 3.54-3.60 (m, IH), 3.90-3.98 (m, IH), 4.52-4.58 (m, IH), 4.68-4.72 (m, 2H), 6.86 (d, = 6.0 Hz, IH), 8.24 (s, 2H), 8.57 (d, = 6.0 Hz, IH), 8.66 (s, IH). Example 1.10: Preparation of (lfl,3s,5S)-l-Methylcyclopropyl 3-((lr,4fl)-4-(3-
Cyanopyridin-4-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 8). 1-Methylcyclopropanol (64.85 mg, 0.899 mmol) and di(lH-imidazol-l-yl)methanone (0.146 g, 0.899 mmol) in THF (2 mL) was stirred for 1 h at room temperature, then 4-((lR,4r)- 4-((lR,3*,55)-8-azabicyclo[3.2.1]octan-3-yloxy)cyclohexyloxy)nicotinonitrile dihydrochloride (120 mg, 0.300 mmol) was added, followed by triethylamine (0.209 mL, 1.499 mmol). The reaction mixture was heated at 120 °C for 4 h under microwave irradiation, diluted with water, extracted with ethyl acetate. The combined organics were dried over anhydrous Na2S04, filtered then concentrated. The residue was purified by silica gel column chromatography (90% ethyl acetate/hexanes with 1% Et3N) to give (lR,3s,5S)-l-methylcyclopropyl 3-((lr,4R)-4-(3- cyanopyridin-4-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (94 mg, 0.221 mmol, 73.7% yield). Exact mass calculated for C24H31N3O4: 425.2, found: LCMS mJz = 426.4 [M+H]+; 'H NMR (CDC13 , 400 MHz) ppm 0.61 (t, = 6.5 Hz, 2H), 0.86 (t, = 6.5 Hz, 2H), 1.55 (s, 3H), 1.42-1.72 (m, 8H), 1.85-2.00 (m, 6H), 2.02-2.12 (m, 2H), 3.50-3.58 (m, IH), 3.74- 3.84 (m, IH), 4.10-4.35 (m, 2H), 4.52-4.58 (m, IH), 6.86 (d, = 6.0 Hz, IH), 8.56 (d, = 6.0 Hz, IH), 8.65 (s, IH).
The compound (94 mg, 0.221 mmol) obtained was then dissolved in anhydrous dioxane (1 mL), 4 N HC1 in dioxane (55 μί, 0.235 mmol) was added. The mixture was stirred at room temperature for 30 min, the white precipitate was collected and washed with dioxane to give its HC1 salt. Example 1.11: Preparation of (lfl,3s,5S)-Isopropyl 3-((lr,4/?)-4-(3-Cyanopyridin-4- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 9).
To a solution of 4-((lR,4r)-4-((lR,3i,55)-8-azabicyclo[3.2.1]octan-3- yloxy)cyclohexyloxy)nicotinonitrile dihydrochloride (180 mg, 0.450 mmol) in DCM (3 mL) at room temperature under nitrogen was added triethylamine (0.313 mL, 2.248 mmol), then 1 M isopropyl chloroformate in toluene (0.719 mL, 0.719 mmol) slowly. The mixture was stirred at room temperature for 30 min. The mixture was concentrated in vacuo to dryness and purified by semi preparative HPLC (25-90% CH3CN/H20 over 30 min, neutralized with saturated sodium bicarbonate, concentrated in vacuo to remove MeCN, extracted with DCM, and dried over anhydrous sodium sulfate) to give (lR,3s,5S)-Isopropyl 3-((lr,4R)-4-(3-cyanopyridin-4- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (143 mg, 0.346 mmol, 76.9% yield). Exact mass calculated for C23H31N3O4: 413.2, found LCMS m/z = 414.4 [M+H]+; lU NMR (CDCI3 , 400 MHz) ppm 1.25 (d, = 6.3 Hz„ 6H), 1.45-1.55 (m, 2H), 1.60-1.75 (m, 6H), 1.88-2.03 (m, 6H), 2.05-2.14 (m, 2H), 3.52-3.58 (m, IH), 3.77-3.86 (m, IH), 4.22-4.35 (m, 2H), 4.52-4.60 (m, IH), 4.88-4.96 (m, IH), 6.86 (d, = 6.0 Hz, IH), 8.58 (d, = 6.0 Hz, IH), 8.66 (s, IH).
The compound obtained above (130 mg, 0.314 mmol) was dissolved in anhydrous dioxane (2 mL), 4M hydrogen chloride in dioxane (82.53 μΐ, 0.330 mmol) was added slowly at room temperature. The reaction mixture was stirred for 30 min, the white precipitate was collected to give its HC1 salt.
Example 1.12: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4/?)-4-(3-cyano-5-methylpyridin- 4-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 10).
To a solution of (lR,3s,5S)-tert-butyl 3-((lr,4R)-4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (50 mg, 0.154 mmol), 4-chloro-5-methylnicotinonitrile (28.13 mg, 0.184 mmol) in THF (5 mL) at ice -water bath under nitrogen was added 1M potassium teri-butoxide in THF (0.200 mL, 0.200 mmol) dropwise. The reaction mixture was stirred at that temperature for 30 min, quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2S04, filtered then concentrated. The residue was purified by silica gel chromatography with 60% ethyl acetate/hexanes (1% Et3N) to give the title compound (54 mg, 0.122 mmol, 79.6% yield). Exact mass calculated for
C25H35N3O4: 441.3, found LCMS m/z = 442.4 [M+H]+; 'H NMR (CDC13 , 400 MHz) δ ppm 1.45 (s, 9H), 1.42-1.72 (m, 8H), 1.85-2.00 (m, 6H), 2.10-2.18 (m, 2H), 2.23 (s, 3H), 3.45-3.54 (m, 1H), 3.76-3.85 (m, 1H), 4.14-4.29 (m, 2H), 4.78-4.85 (m, 1H), 8.45 (s, 1H), 8.57 (s, 1H).
Example 1.13: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4/?)-4-(3-cyano-5-fluoropyridin- 4-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 11).
To a solution of (lR,3s,5S)-tert-butyl 3-((lr,4R)-4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (50 mg, 0.154 mmol), 4-chloro-5-fluoronicotinonitrile (26.46 mg, 0.169 mmol) in THF (5 mL) at ice -water bath under nitrogen was added 1M potassium teri-butoxide in THF (0.200 mL, 0.200 mmol) dropwise. The reaction mixture was stirred at that temperature for 30 min, quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2S04, filtered then concentrated. The residue was purified by semi preparative HPLC (30-90% CH3CN/H20 with 0.1% TFA over 30 min). The combined fractions were neutralized with saturated NaHC03, extracted with ethyl acetate, then concentrated to give the title compound (51 mg, 0.114 mmol, 74.5% yield). Exact mass calculated for C24H32FN3O4: 445.2, found LCMS m/z = 446.6 [M+H]+; 'H NMR (CDCI3 , 400 MHz) δ ppm 1.45 (s, 9H), 1.42-1.75 (m, 8H), 1.85-2.00 (m, 6H), 2.05-2.10 (m, 2H), 3.53- 3.58 (m, 1H), 3.76-3.85 (m, 1H), 4.14-4.30 (m, 2H), 4.88-4.92 (m, 1H), 8.50 (s, 1H), 8.52 (d, = 4.0 Hz, 1H).
Example 1.14: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4/?)-4-(3-cyano-5-fluoropyridin- 2-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 12).
Step A: Preparation of 2-chloro-5-fluoronicotinonitrile.
To a solution of hydroxylamine hydrochloride (0.410 g, 5.902 mmol) in H20 (7.5 mL) was added a solution of 2-chloro-5-fluoronicotinaldehyde (0.856 g, 5.365 mmol) in EtOH (10 mL) in one portion. White solid came out. After stirring at room temperature for 1 h, water (10 mL) was added. The white solid was filtered off to give the intermediate (0.92 g).
To a suspension of the solid obtained above in CH2C12 (15 mL) under nitrogen was added carbonyl diimidazole (1.044 g, 6.438 mmol) and the suspension became a clear solution. The mixture was heated at reflux for 1 h and concentrated. The residue was purified by silica gel chromatography (15% hexanes/EtOAc) to give the title compound (0.752 g, 4.804 mmol, 89.5% yield) as white solid. 'H NMR (CDC13 , 400 MHz) δ ppm 7.75 (dd, / = 6.8 and 3.0 Hz, IH), 8.49 (d, 7 = 3.0 Hz, IH).
Step B: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4/?)-4-(3-cyano-5-fluoropyridin- 2-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate .
To a solution of (lR,3s,5S)-tert-butyl 3-((lr,4R)-4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (25 mg, 76.82 μιηοΐ), 2-chloro-5-fluoronicotinonitrile (13.23 mg, 84.50 μιηοΐ) in THF (5 mL) at ice -water bath under nitrogen was added 1M potassium teri-butoxide in THF (99.86 μΐ, 99.86 μιηοΐ) dropwise. The reaction mixture was stirred at that temperature for 2 h, quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2S04, filtered then concentrated. The residue was purified by semipreparative HPLC (40-90% CH3CN/H20 with 0.1% TFA over 30 min), then silica gel preparative TLC plate (25% ethyl acetate/hexanes) to give the title compound (9 mg, 20.2 μιηοΐ, 26.3 yield). Exact mass calculated for C24H32FN304: 445.2, found LCMS m/z = 446.6 [M+H]+; lU NMR (CDC13 , 400 MHz) δ ppm 1.48 (s, 9H), 1.42-1.75 (m,
8H), 1.85-2.00 (m, 6H), 2.05-2.12 (m, 2H), 3.45-3.52 (m, IH), 3.78-3.85 (m, IH), 4.14-4.30 (m, 2H), 5.05-5.12 (m, IH), 7.61 (dd, / = 7.0 and 3.0 Hz, IH), 8.19 (d, = 3.0 Hz, IH).
Example 1.15: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4fl)-4-(5- (trifluoromethyl)pyridin-2-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 29).
To a solution of (lR,3s,5S)-tert-butyl 3-((lr,4R)-4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (40 mg, 0.123 mmol) in THF (1 mL) at ice-water bath under nitrogen was added 1M potassium teri-butoxide in THF (0.160 mL, 0.160 mmol) dropwise. The reaction mixture was stirred at that temperature for 10 min, added 2-chloro-5-
(trifluoromethyl)pyridine (26.78 mg, 0.147 mmol), and stirred for one more hour while warmed to room temperature. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2S04, filtered then concentrated. The residue was purified by silica gel column chromatography with 30% ethyl acetate/hexanes to give the title compound (42 mg, 89.26 μιηοΐ, 72.6%) as white solid. Exact mass calculated for C24H33F3N204: 470.2, found LCMS m/z = 471.6 [M+H]+; 'H NMR (CDC13 , 400 MHz) δ ppm 1.48 (s, 9H), 1.42-1.75 (m, 8H), 1.85-2.00 (m, 6H), 2.12-2.16 (m, 2H), 3.42-3.48 (m, IH), 3.78- 3.86 (m, IH), 4.14-4.30 (m, 2H), 5.05-5.12 (m, IH), 6.78 (d, / = 8.7 Hz, IH), 7.73 (dd, / = 8.8 and 2.4 Hz, IH), 8.40-8.42 (m, IH).
Example 1.16: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4/?)-4-(quinoxalin-2- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 30).
The title compound was obtained in a similar manner to the one described in Example 1.15. Exact mass calculated for C26H35N3O4: 453.3, found LCMS m/z = 454.4
[M+H]+; 'H NMR (CDC13 , 400 MHz) δ ppm 1.47 (s, 9H), 1.50-1.70 (m, 8H), 1.90-2.08 (m, 6H), 2.20-2.28 (m, 2H), 3.45-3.52 (m, IH), 3.80-3.86 (m, IH), 4.10-4.30 (m, 2H), 5.20-5.28 (m, IH), 7.56-7.57 (m, IH), 7.62-7.68 (m, IH), 7.81 (dd, = 8.3 and 1.2 Hz, IH), 7.99 (dd, / = 8.2 and 1.2 Hz, IH), 8.41 (s, IH).
Example 1.17: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4fl)-4-(benzo[d]thiazol-2- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 36).
The title compound was obtained in a similar manner to the one described in
Example 1.15. Exact mass calculated for C25H34N2O4S: 458.2, found LCMS m/z = 459.4 [M+H]+; 'H NMR (CDCI3 , 400 MHz) δ ppm 1.48 (s, 9H), 1.50-1.70 (m, 8H), 1.85-2.00 (m, 6H), 2.20-2.26 (m, 2H), 3.42-3.50 (m, IH), 3.75-3.86 (m, IH), 4.10-4.30 (m, 2H), 5.14-5.20 (m, IH), 7.20 (t, = 7.5 Hz, IH), 7.35 (t, = 7.4 Hz, IH), 7.60-7.68 (m, 2H).
Example 1.18: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4fl)-4-(4-cyanopyridin-2- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 31).
The title compound was obtained in a similar manner to the one described in Example 1.15. Exact mass calculated for C24H33N3O4: 427.3, found LCMS m/z = 428.4
[M+H]+; 'H NMR (CDCI3 , 400 MHz) δ ppm 1.48 (s, 9H), 1.50-1.70 (m, 8H), 1.85-2.00 (m,
6H), 2.08-2.14 (m, 2H), 3.42-3.49 (m, IH), 3.80-3.88 (m, IH), 4.10-4.30 (m, 2H), 5.00-5.08 (m, IH), 6.91 (dd, = 1.3 and 0.7 Hz, IH), 7.01 (dd, = 5.2 and 1.3 Hz, IH), 8.27 (dd, = 5.2 and 0.7 Hz, IH). Example 1.19: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4fl)-4-(6-
(trifluoromethyl)pyridin-3-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 49).
The title compound was obtained in a similar manner to the one described in Example 1.15. Exact mass calculated for C24H33F3N2O4: 470.2, found LCMS m/z = 471.6 [M+H]+; 'H NMR (CDC13 , 400 MHz) δ ppm 1.48 (s, 9H), 1.42-1.75 (m, 8H), 1.85-2.00 (m,
6H), 2.05-2.16 (m, 2H), 3.42-3.48 (m, IH), 3.75-3.86 (m, IH), 4.10-4.30 (m, 2H), 4.32-4.40 (m, IH), 7.25 (dd, = 8.7 and 2.7 Hz, IH), 7.58 (dd, = 8.7 Hz, IH), 8.34 (d, = 2.7 Hz, IH). Example 1.20: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4fl)-4-(3-methyl-5- (methylsulfonyl)pyrazin-2-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 48).
Step A: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4/?)-4-(5-bromo-3- methylpyrazin-2-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate
(Compound 47).
To a solution of (lR,3s,5S)-tert-butyl 3-((ls,4S)-4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.307 mmol), 5-bromo-3-methylpyrazin-2-ol (69.69 mg, 0.369 mmol), triethylamine (42.83 μΐ, 0.307 mmol) and triphenylphosphine (88.65 mg, 0.338 mmol) in THF (2 mL) at ice -water bath under nitrogen was added DIAD (0.123 mL, 0.369 mmol) dropwise. The reaction mixture was slowly warmed to room temperature and stirred overnight, then concentrated. The residue was purified by semi preparative HPLC (35- 95% CH3CN/H20 over 30 min) then neutralized to give the title compound (36 mg, 72.52 μιηοΐ, 23.6% yield) as oil. Exact mass calculated for CzsI^Br^C^: 495.2, found LCMS m/z = 497.6 [M+H]+; 'H NMR (CDC13 , 400 MHz) δ ppm 1.48 (s, 9H), 1.42-1.65 (m, 8H), 1.82-1.96 (m, 6H), 2.05-2.12 (m, 2H), 2.41 (d, = 0.6 Hz, 3H), 3.42-3.48 (m, 1H), 3.75-3.86 (m, 1H), 4.10- 4.30 (m, 2H), 4.92-5.00 (m, 1H), 7.97 (d, = 0.6 Hz, 1H).
Step B: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4fl)-4-(3-methyl-5- (methylsulfonyl)pyrazin-2-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate.
The mixture of (lR,3s,5S)-tert-butyl 3-((lr,4R)-4-(5-bromo-3-methylpyrazin-2- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (30 mg, 60.43 μιηοΐ), sodium methanesulfinate (15.42 mg, 0.151 mmol), copper (I) trifluoromethanesulfonate benzene complex (4.563 mg, 9.1 μιηοΐ) and Nl,N2-dimethylethane-l,2-diamine (1.951 μί, 18.13 μιηοΐ) in DMSO (1 mL) was heated at 120 °C overnight, diluted with water, extracted with ethyl acetate. The combined organics were dried over anhydrous Na2S04, filtered then concentrated. The residue was purified by silica gel chromatography with 50% ethyl acetate/hexanes to give the title compound (27 mg, 54.48 μιηοΐ, 90.1% yield) as white solid. Exact mass calculated for C24H37N306S: 495.2, found LCMS m/z = 496.4 [M+H]+; 'll NMR (CDCI3 , 400 MHz) δ ppm 1.48 (s, 9H), 1.42-1.65 (m, 8H), 1.82-1.96 (m, 6H), 2.10-2.15 (m, 2H), 2.50 (s, 3H), 3.17 (s,
3H), 3.45-3.52 (m, 1H), 3.78-3.86 (m, 1H), 4.10-4.30 (m, 2H), 5.12-5.20 (m, 1H), 8.62 (s, 1H).
Example 1.21: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4/?)-4-(4-(dimethylcarbamoyl)-2- fluorophenoxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 54).
Step A: Preparation of (lR,3s,5S)-tert-butyl 3-((lr,4fl)-4-(2-fluoro-4-
(methoxycarbonyl)phenoxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate. To a solution of (lR,3s,5S)-tert-butyl 3-((ls,4S)-4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (150 mg, 0.461 mmol), methyl 3-fluoro-4- hydroxybenzoate (94.10 mg, 0.553 mmol), triethylamine (64.24 μί, 0.461 mmol) and triphenylphosphine (0.133 g, 0.507 mmol) in THF (5 mL) at ice -water bath under nitrogen was added DIAD (0.123 mL, 0.553 mmol) dropwise. The reaction mixture was slowly warmed to room temperature and stirred overnight, then concentrated. The residue was purified by semi preparative HPLC (35-95% CH3CN/H20 over 30 min) then neutralized to give the title compound (23 mg, 48.16 μιηοΐ, 10.4% yield). Exact mass calculated for C26H36FN06: 477.2, found LCMS m/z = 478.4 [M+H]+; 'H NMR (CDC13 , 400 MHz) δ ppm 1.48 (s, 9H), 1.38-1.48 (m, 2H), 1.50-1.65 (m, 6H), 1.82-2.00 (m, 6H), 2.05-2.13 (m, 2H), 3.42-3.50 (m, 1H), 3.75-3.85 (m, 1H), 3.88 (s, 3H), 4.10-4.30 (m, 2H), 4.30-4.40 (m, 1H), 6.94-7.00 (m, 1H), 7.70-7.78 (m, 2H).
Step B: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4/?)-4-(4-(dimethylcarbamoyl)-2- fluorophenoxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate
A solution of (lR,3s,5S)-tert-butyl 3-((lr,4R)-4-(2-fluoro-4-
(methoxycarbonyl)phenoxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (23 mg, 48.16 μιηοΐ) in methanol (1 mL) was added lithium hydroxide in H20 (0.144 mL, 0.144 mmol). The reaction was stirred overnight at room temperature, acidified to pH 4 with IN HC1 aqueous solution. The white precipitate was collected and dried to give 4-((lR,4r)-4-((lR,3s,5S)-8-(teri- butoxycarbonyl)-8-azabicyclo[3.2.1]octan-3-yloxy)cyclohexyloxy)-3-fluorobenzoic acid. Exact mass calculated for C25H34FNO6: 463.2, found LCMS m/z = 464.4 [M+H]+.
A mixture of 4-((lR,4r)-4-((lR,3i,55)-8-(teri-butoxycarbonyl)-8-azabicyclo[3.2.1]octan-3- yloxy)cyclohexyloxy)-3-fluorobenzoic acid obtained above, HATU (13.93 mg, 57.79 μιηοΐ) and DIEA (16.78 μΐ, 96.32 μιηοΐ) in acetonitrile (1 mL) was stirred for 10 min at room temperature, then 2 M dimethylamine in methanol (24.08 μΐ, 48.16 μιηοΐ) was added. The reaction was stirred at room temperature overnight, then purified by semi preparative HPLC (35-95%
CH3CN/H2O over 30 min) then neutralized to give the title compound (10 mg, 20.38 μιηοΐ, 42.3% yield). Exact mass calculated for C27H39FN2O5: 490.3, found LCMS m/z = 491.4 [M+H]+; 'H NMR (CDC13 , 400 MHz) δ ppm 1.48 (s, 9H), 1.38-1.48 (m, 2H), 1.50-1.65 (m, 6H), 1.85- 2.02 (m, 6H), 2.05-2.12 (m, 2H), 3.05 (s, 6H), 3.42-3.50 (m, 1H), 3.75-3.85 (m, 1H), 4.10-4.32 (m, 3H), 6.94-7.00 (m, 1H), 7.10-7.20 (m, 2H).
Example 1.22: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4/?)-4-(5-(methylsulfonyl)pyridin- 2-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 55).
Step A: Preparation of (lR,3s,5S)-tert-butyl 3-((lr,4fl)-4-(5-bromopyridin-2- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate. To a solution of (lR,3s,5S)-tert-butyl 3-((lr,4R)-4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (40 mg, 0.123 mmol) in THF (0.5 mL) at ice -water bath under nitrogen was added 1M potassium teri-butoxide in THF (0.160 mL, 0.160 mmol) dropwise. The reaction mixture was stirred at that temperature for 10 min, 5-bromo-2- chloropyridine (23.65 mg, 0.123 mmol) in THF (0.5 mL) was then added. The reaction was stirred for 1 h while slowly warmed to room temperature then stirred overnight. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2S04, filtered then concentrated. The residue was purified by silica gel column chromatography with 25% ethyl acetate/hexanes to give the title compound (35 mg, 72.70 μιηοΐ, 59.2% yield). Exact mass calculated for C23H33BrN204: 481.2, found LCMS m/z = 482.4 [M+H]+.
Step B: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4/?)-4-(5- (methylsulfonyl)pyridin-2-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate
The mixture of (lR,3s,5S)-tert-butyl 3-((lr,4R)-4-(5-bromopyridin-2- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (35 mg, 72.70 μιηοΐ), sodium methanesulfinate (18.55 mg, 0.182 mmol), copper (I) trifluoromethanesulfonate benzene complex (5.489 mg, 10.91 μιηοΐ) and Nl,N2-dimethylethane-l,2-diamine (2.348 μΐ, 21.81 μιηοΐ) in DMSO (1 mL) was heated at 120 °C overnight, diluted with water, extracted with ethyl acetate. The combined organics were dried over anhydrous Na2S04, filtered then concentrated. The residue was purified by silica gel chromatography with 50% ethyl acetate/hexanes to give the title compound (30 mg, 62.42 μιηοΐ, 85.9% yield) as white solid. Exact mass calculated for C24H36N206S: 480.2, found LCMS m/z = 481.4 [M+H]+; 'H NMR (CDC13 , 400 MHz) δ ppm 1.48 (s, 9H), 1.42-1.65 (m, 8H), 1.85-2.00 (m, 6H), 2.10-2.15 (m, 2H), 3.06 (s, 3H), 3.40-3.48 (m, 1H), 3.78-3.88 (m, 1H), 4.10-4.30 (m, 2H), 5.12-5.18 (m, 1H), 6.78 (d, = 8.8 Hz, 1H), 8.00 (dd, = 8.8 and 2.6 Hz, 1H), 8.69 (d, = 2.4 Hz, 1H).
Example 1.23: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4/?)-4-(thieno[3,2-c]pyridin-4- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 16).
To a solution of (lR,3s,5S)-tert-butyl 3-((lr,4R)-4-(thieno[3,2-c]pyridin-4- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (25 mg, 0.077 mmol) in THF (1 mL) was added 1M potassium teri-butoxide in THF (0.115 mL, 0.115 mmol) at room temperature under N2. After the reaction mixture was stirred for 10 min, 4-chlorothieno[3,2- c]pyridine (15.64 mg, 92.18 μιηοΐ) was added into the solution. The reaction mixture was stirred overnight at room temperature, quenched with 1N-HC1, and concentrated. The residue was purified by silica gel column chromatography with (hexane: EtOAc = 100: 0 to 50: 50) to give the title compound (11 mg, 0.024 mmol, 31.2% yield). Exact mass calculated for C25H34N204S: 458.2, found LCMS m/z = 459.4 [M+H]+; 'H NMR (CDC13 , 400 MHz) δ ppm 1.47 (s, 9H), 1.48-1.57 (m, 2H), 1.58-1.67 (m, 6H), 1.88-2.04 (m, 6H), 2.19-2.23 (m, 2H), 3.44-3.52 (m, IH), 3.80-3.90 (m, IH), 4.15-4.35 (m, 2H), 5.20-5.31 (m, IH), 7.33 (d, / = 5.56 Hz, 2H), 7.47 (d, = 5.56 Hz, IH), 7.95 (d, = 5.56 Hz, IH). Example 1.24: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4/?)-4-(furo[3,2-c]pyridin-4- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 17).
To a solution of (lR,3s,5S)-tert-butyl 3-((lr,4R)-4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (25 mg, 0.077 mmol) in THF (1 mL) was added 1M potassium teri-butoxide in THF (0.115 mL, 0.115 mmol) at room temperature under N2. After the reaction mixture was stirred for 10 min, 4-chlorofuro[3,2-c]pyridine (14.16 mg, 0.092 mmol) was added into the solution. The reaction mixture was stirred overnight at room temperature, quenched with 1N-HC1, and concentrated. The residue was purified by silica gel column chromatography with (hexane: EtOAc = 100: 0 to 50: 50) to give the title compound (5.5 mg, 0.012 mmol, 16.2% yield). Exact mass calculated for C25H34N2O5: 442.3, found LCMS m/z = 443.6 [M+H]+; ^ NMR (CDC13 , 400 MHz) δ ppm 1.47 (s, 9H), 1.49-1.55 (m, 2H), 1.55-1.69 (m, 6H), 1.87-2.03 (m, 6H), 2.16-2.24 (m, 2H), 3.41-3.50 (m, IH), 3.80-3.89 (m, IH), 4.13-4.34 (m, 2H), 5.18-5.26 (m, IH), 6.81 (d, = 2.27 Hz, IH), 7.05 (d, = 6.06 Hz, IH), 7.53 (d, = 2.27 Hz, IH), 7.96 (d, = 6.06 Hz, IH). Example 1.25: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4fl)-4-(5-
(methylsulfonyl)pyrimidin-2-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 37).
Step A: Preparation of (lvP,3<f,5J)- i?/"/-Butyl 3-((l/",4v¥)-4-(5-bromopyrimidin-2- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 18).
To a solution of (lR,3s,5S)-tert-butyl 3-((lr,4R)-4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (0.12 g, 0.369 mmol) in THF (3 mL) was added 1M potassium teri-butoxide in THF (0.553 mL, 0.553 mmol) at room temperature under N2. After the reaction mixture was stirred for 15 min, 5-bromo-2-chloropyrimidine (85.59 mg, 0.442 mmol) in THF (1 mL) was added into the solution. The reaction mixture was stirred at 40°C for 4 h, quenched with 1N-HC1, and concentrated. The residue was purified by silica gel column chromatography with (hexane: EtOAc = 100: 0 to 50: 50) to give the title compound (150 mg, 0.311 mmol, 84.3% yield). Exact mass calculated for C22H32BrN304: 481.2, found LCMS m/z = 482.2 [M+H]+; 'll NMR (CDCI3 , 400 MHz) δ ppm 1.46 (s, 9H), 1.48-1.55 (m, 2H), 1.55-1.68 (m, 6H), 1.86-2.03 (m, 6H), 2.09-2.17 (m, 2H), 3.41-3.49 (m, IH), 3.78-3.87 (m, IH), 4.12-4.33 (m, 2H), 4.90-4.99 (m, IH), 8.50 (s, 2H). Step B: Preparation of
Figure imgf000114_0001
3-((l/-,4A -4-(5- (methylsulfonyl)pyrimidin-2-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate
To a mixture of (lR,3s,5S)-tert-butyl 3-((lr,4R)-4-(5-bromopyrimidin-2- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (35 mg, 0.073 mmol), sodium methanesulfinate (14.81 mg, 0.145 mmol), and Copper (I) trifluoromethanesulfonate benzene complex (3.287 mg, 6.5 μηιοΐ) in DMSO (1.5 mL), Nl,N2-dimethylethane-l,2-diamine (1.562 μΐ, 0.015 mmol) was added and the mixture was stirred at 105 °C overnight. Reaction mixture was filtered and purified by HPLC to give the title compound (8 mg, 0.017 mmol, 22.9% yield). Exact mass calculated for C23H35N3O6S: 481.2, found LCMS m/z = 482.4 [M+H]+. lU NMR (400 MHz, CDCI3) δ ppm 1.47 (s, 9H), 1.48-1.54 (m, 2H), 1.59-1.71 (m, 6H), 1.86-2.05 (m, 6H), 2.11-2.20 (m, 2H), 3.13 (s, 3H), 3.45-3.53 (m, 1H), 3.78-3.88 (m, 1H), 4.13-4.34 (m, 2H), 5.11-5.13 (m, 1H), 8.97 (s, 2H).
Example 1.26: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4/?)-4-(l-methyl-3- (trifluoromethyl)-lH-pyrazol-5-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8- carboxylate (Compound 40).
To a mixture of (lR,3s,5S)-tert-butyl 3-((ls,4S)-4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (65 mg, 0.200 mmol), l-methyl-3-(trifluoromethyl)-lH- pyrazol-5-ol (36.49 mg, 0.220 mmol), triphenylphosphine (57.62 mg, 0.220 mmol), and triethylamine (29.25 μΐ, 0.220 mmol) in THF (3 mL), was added diisopropyl diazene-1,2- dicarboxylate (48.46 mg, 0.240 mmol) dropwisely. The reaction was stirred overnight at room temperature under N2. After removal of the volatile solvent, the residue was purified by HPLC to give the title compound (15 mg, 0.032 mmol, 15.9% yield). Exact mass calculated for
C23H34F3N3O4: 473.3, found LCMS m/z = 474.4 [M+H]+. lU NMR (400 MHz, CDC13) δ ppm 1.38-1.50 (m, 2H) 1.47 (s, 9H), 1.53-1.67 (m, 7H), 1.84-1.99 (m, 6H), 2.06-2.16 (m, 2H), 3.45- 3.52 (m, 1H), 3.66 (s, 3H), 3.76-3.86 (m, 1H), 4.14-4.22 (m, 2H), 5.74 (s, 1H).
Example 1.27: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4fl)-4-(thieno[3,2-d]pyrimidin-4- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 42).
To a solution of (lR,3s,5S)-tert-butyl 3-((lr,4R)-4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (44 mg, 0.135 mmol) in THF (2.5 mL) was added 1M potassium teri-butoxide in THF (0.203 mL, 0.203 mmol) at room temperature under N2. After the reaction mixture was stirred for 15 min, 4-chlorothieno[3,2-J]pyrimidine (27.68 mg, 0.162 mmol) in THF (0.5 mL) was added into the solution. The reaction mixture was stirred at 40°C for 2 h, quenched with 1N-HC1, and concentrated. The residue was purified by silica gel column chromatography to give the title compound (45 mg, 0.098 mmol, 72.4% yield). Exact mass calculated for C24H33N3O4S: 459.2, found LCMS m/z = 460.4 [M+H]+; 'H NMR (CDC13 , 400 MHz) δ ppm 1.47 (s, 9H), 1.49-1.55 (m, 2H), 1.58-1.71 (m, 6H), 1.87-2.04 (m, 6H), 2.17-2.25 (m, 2H), 3.46-3.53 (m, IH), 3.80-3.89 (m, IH), 4.15-4.33 (m, 2H), 5.33-5.42 (m, IH), 7.48 (d, = 5.3 Hz, IH), 7.83 (d, = 5.3 Hz, IH), 8.72 (s, IH).
Example 1.28: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4/?)-4-(5-cyanopyridin-2- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 34).
To a solution of (lR,3s,5S)-tert-butyl 3-((l r,4R)-4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (20 mg, 0.062 mmol) in THF (0.615 mL) was added 1M potassium teri-butoxide in THF (73.75 μΐ, 73.75 μιηοΐ) was added 6-chloronicotinonitrile (10.22 mg, 0.074 mmol) at room temperature . After the reaction mixture was stirred for 1 h and then concentrated. The crude was purified by TLC (silica gel, 20% EtOAc in hexanes) to give the title compound (16.3 mg, 0.038 mmol, 62% yield). Exact mass calculated for C24H33N3O4: 427.3, found LCMS m/z = 428.4 [M+H]+; 'll NMR (CDCI3 , 400 MHz) δ ppm 1.42-1.67 (m, 8H), 1.47 (s, 9H), 1.86-2.00 (m, 6H), 2.07-2.16 (m, 2H), 3.41-3.49 (m, IH), 3.78-3.88 (m, IH), 4.14-4.33 (m, 2H), 5.05-5.13 (m, IH), 6.73 (d, = 8.6 Hz, IH), 7.74 (dd, / = 8.6, 2.3 Hz, IH), 8.45 (d, = 2.3 Hz, IH).
Example 1.29: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4fl)-4-(3-cyanopyridin-2- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 41).
To a solution of (lR,3s,5S)-tert-butyl 3-((l r,4R)-4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (20 mg, 0.061 mmol) in THF (0.615 mL) was added 1M potassium teri-butoxide in THF (73.75 μΐ, 73.75 μιηοΐ) was added 2-fluoronicotinonitrile (9.004 mg, 0.074 mmol) at room temperature . After the reaction mixture was stirred for 16 h and then concentrated. The crude was purified twice by TLC (1st: silica gel, 25% EtOAc in hexanes; 2nd: silica gel, 50% DCM in hexanes) to give the title compound (11.6 mg, 0.027 mmol, 44.1 % yield). Exact mass calculated for C24H33N3O4: 427.3, found LCMS m/z = 428.4 [M+H]+; lU NMR (CDCI3 , 400 MHz) 5 ppm 1.42-1.54 (m, 2H), 1.47 (s, 9H), 1.54-1.70 (m, 6H), 1.87-2.03 (m, 6H), 2.08-2.16 (m, 2H), 3.45-3.53 (m, IH), 3.78-3.88 (m, IH), 4.24 (br s, 2H), 5.13-5.23 (m, IH), 6.93 (dd, / = 7.58, 5.05 Hz, IH), 7.84 (dd, / = 7.58, 5.05 Hz, IH), 8.32 (dd, = 5.05, 2.02 Hz, IH).
Example 1.30: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4/?)-4-(2-cyanopyridin-3- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 46).
To a solution of (lR,3s,5S)-tert-butyl 3-((l r,4R)-4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (20 mg, 0.061 mmol) in THF (0.615 mL) was added 1M potassium teri-butoxide in THF (73.75 μΐ, 73.75 μιηοΐ) was added 3-chloropicolinonitrile (10.22 mg, 0.074 mmol) at room temperature . After the reaction mixture was stirred for 48 h and then concentrated. The crude was purified by TLC (silica gel, 1 : 1 EtOAc/hexanes) to give the title compound (13.2 mg, 0.031 mmol, 50.2% yield). Exact mass calculated for C24H33N3O4: 427.3, found LCMS m/z = 428.4 [M+H]+; !H NMR (CDC13 , 400 MHz) δ ppm 1.44-1.53 (m, 2H), 1.47 (s, 9H), 1.54-1.75 (m, 7H), 1.85-2.13 (m, 6H), 3.52-3.59 (m, IH), 3.78-3.85 (m, IH), 4.24 (br s, IH), 4.43-4.50 (m, IH), 4.24 (br s, 2H), 5.13-5.23 (m, IH), 7.32-7.76 (m, IH), 7.41-7.46 (m, IH).
Example 1.31: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4/?)-4-(4-cyanopyridin-3- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 50).
To a solution of (lR,3s,5S)-tert-butyl 3-((lr,4R)-4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (20 mg, 0.061 mmol) in THF (0.615 mL) was added 1M potassium teri-butoxide in THF (73.75 μΐ, 73.75 μιηοΐ) was added 3-chloroisonicotinonitrile (10.22 mg, 73.75 μιηοΐ) at room temperature . The reaction mixture was stirred for 16 h and then concentrated. The residue was purified by TLC (silica gel, 50% EtOAc/hexanes) to give the title compound (14.1 mg, 0.033 mmol, 53.7% yield). Exact mass calculated for C24H33N3O4: 427.3, found LCMS m/z = 428.4 [M+H]+; 'll NMR (CDCI3 , 400 MHz) δ ppm 1.44-1.75 (m, 8H), 1.47 (s, 9H), 1.87-2.03 (m, 6H), 2.09-2.16 (m, 2H), 3.51-3.58 (m, IH), 3.78-3.87 (m, IH), 4.15-4.33 (m, 2H), 4.57-4.63 (m, IH), 7.45 (d, = 5.0 Hz, IH), 8.32 (d, = 5.0 Hz, IH), 8.47 (s, IH).
Example 1.32: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4fl)-4-(4-bromo-2- cyanophenoxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 13).
To a solution of (lR,3s,5S)-tert-butyl 3-((ls,4S)-4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (246 mg, 0.756 mmol), 5-bromo-2-hydroxybenzonitrile (165 mg, 0.833 mmol), triphenylphosphine (218 mg, 0.831 mmol), and triethylamine (0.115 mL, 0.826 mmol) in 2 mL THF, diisopropyl diazene-l,2-dicarboxylate (0.167 mL, 0.848 mmol) was added slowly. After stirring at room temperature over night, solution was extracted with 1 M NaOH and CH2C12. Organic phases were dried over MgS04, filtered, and concentrated. Residue was purified by Biotage™ column chromatography (Si02, hexane/AcOEt gradient) to give (lR,3s,5S)-tert-butyl 3-((lr,4R)-4-(4-bromo-2-cyanophenoxy)cyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (ca. 80% pure, 113 mg, 0.179 mmol, 23.7%) as a thick oil. Exact mass calculated for C25H33BrN204: 504.16, found: LCMS m/z = 505.4 [M+H]+; lU NMR (400 MHz, CDC13) δ ppm 1.42-1.70 (m, 7H), 1.47 (s, 9H), 1.87-2.09 (m, 8H), 3.51-3.56 (m, IH), 3.76-3.85 (m, IH), 4.15-4.31 (m, 2H), 4.38-4.44 (m, IH), 4.93-5.02 (m, IH), 6.86 (d, = 9.1 Hz, IH), 7.58 (dd, = 9.1 Hz, 2.5 Hz, IH), 7.64 (d, = 2.5 Hz, IH). Example 1.33: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4/?)-4-(2,4- dicyanophenoxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 14).
A mixture of (lR,3s,5S)-tert-butyl 3-((lr,4R)-4-(4-bromo-2-cyanophenoxy)cyclohexyloxy)- 8-azabicyclo[3.2.1]octane-8-carboxylate (33 mg, 52.23 μιηοΐ) and dicyanonickel (15 mg, 0.135 mmol) in 0.5 mL DMF, was bubbled in nitrogen. After 1 min, tetrakis(triphenylphosphine)palladium (5 mg, 4.3 μιηοΐ) was added and mixture was stirred at 90 °C (oil bath). After stirring over night, mixture was extracted with water and CH2C12. Organic phases were concentrated and residue was purified by HPLC (H20/CH3CN gradient + 0.1 % TFA). Fractions containing pure product were partly concentrated and residue was extracted with 1 M NaOH and CH2C12. Organic phases were dried over MgS04, filtered, and concentrated to give (lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(2,4- dicyanophenoxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (9.5 mg, 21.04 μιηοΐ, 40.3%) as a white solid. Exact mass calculated for C26H33N304: 451.3, found: LCMS m/z = 452.4 [M+H]+; lU NMR (400 MHz, CDC13) δ ppm 1.46-1.75 (m, 8H), 1.47 (s, 9H), 1.86-2.06 (m, 6H), 2.05-2.13 (m, 2H), 3.55-3.58 (m, 1H), 3.78-3.83 (m, 1H), 4.16-4.31 (m, 2H), 4.54-4.58 (m, 1H), 7.05 (d, 7 = 8.9 Hz, 1H), 7.78 (dd, 7 = 8.9 Hz, 2.2 Hz, 1H), 7.85 (d, 7 = 2.2 Hz, 1H).
Example 1.34: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4fl)-4-(2-cyano-4- (methylsulfonyl)phenoxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate
(Compound 15).
A mixture of (lR,3s,5S)-tert-butyl 3-((lr,4R)-4-(4-bromo-2-cyanophenoxy)cyclohexyloxy)-
8-azabicyclo[3.2.1]octane-8-carboxylate (40 mg, 63.31 μιηοΐ), sodium methanesulfinate (50 mg, 0.490 mmol), copper (I) trifluoromethanesulfonate benzene complex (16 mg, 31.79 μιηοΐ), and Nl ,N2-dimethylethane-l ,2-diamine (10 μΐ, 92.91 μηιοΐ) in 0.5 mL DMSO was stirred at 90°C (oil bath). After stirring over night, mixture was extracted with water and CH2C12. Organic phases were concentrated and residue was purified by HPLC (H20/CH3CN gradient + 0.1 % TFA). Fractions containing product were partly concentrated and residue was extracted with 1 M NaOH and CH2C12. Organic phases were dried over MgS04, filtered, and concentrated to give (lR,3s,5S)-tert-butyl 3- (( 1 r,4R)-4-(2-cyano-4-(methylsulfonyl)phenoxy)cyclohexyloxy)-8 -azabicyclo [3.2.1 ] octane-8- carboxylate (19.9 mg, 39.43 μιηοΐ, 62.3%) as a white solid. Exact mass calculated for C26H36N206S: 504.2, found: LCMS m/z = 505.4 [M+H]+; lU NMR (400 MHz, CDC13) δ ppm 1.46-1.76 (m, 8H), 1.47 (s, 9H), 1.87-2.03 (m, 6H), 2.07-2.14 (m, 2H), 3.05 (s, 3H), 3.55-3.59 (m, 1H), 3.79-3.84 (m, 1H), 4.16-4.31 (m, 2H), 4.57-4.61 (m, 1H), 7.11 (d, 7 = 9.0 Hz, 1H), 8.06 (dd, 7 = 9.0 Hz, 2.4 Hz, 1H), 8.14 (d, J = 2.4 Hz, 1H). Example 1.35: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4fl)-4-(2-cyano-4- fluorophenoxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 22). To a solution of (lR,3s,5S)-tert-butyl 3-((lr,4R)-4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (33 mg, 0.101 mmol) and 2,5-difluorobenzonitrile (18 mg, 0.129 mmol) in 0.5 mL THF, 1 M potassium teri-butoxide (0.150 mL, 0.150 mmol) was added slowly. After stirring at room temperature for 1 h, mixture was extracted with water and CH2C12. Organic phases were concentrated and residue was purified by HPLC (H20/CH3CN gradient + 0.1% TFA). Fractions containing product were partly concentrated and residue was extracted with 1 M NaOH and CH2C12. Organic phases were dried over MgS04, filtered, and concentrated to give (lR,3s,5S)-tert-butyl 3-((lr,4R)-4-(2-cyano-4-fluorophenoxy)cyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (37.9 mg, 85.26 μιηοΐ, 84.1%) as a white solid. Exact mass calculated for C25H33FN204: 444.2, found: LCMS m/z = 445.6 [M+H]+; lU NMR (400 MHz, CDC13) 5 ppm 1.41-1.69 (m, 8H), 1.47 (s, 9H), 1.87-2.10 (m, 8H), 3.50-3.56 (m, 1H), 3.77-3.85 (m, 1H), 4.16-4.31 (m, 2H), 4.33-4.39 (m, 1H), 6.92-7.00 (m, 1H), 7.20-7.26 (m, 2.4 Hz, 2H).
Example 1.36: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4/?)-4-(4-(2- methoxyethyl)phenoxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate
(Compound 23).
To a solution of (lR,3s,5S)-tert-butyl 3-((ls,4S)-4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.922 mmol), 4-(2-methoxyethyl)phenol (153 mg, 1.005 mmol), triphenylphosphine (270 mg, 1.029 mmol), and triethylamine (0.128 mL, 0.922 mmol) in 3 mL THF, diisopropyl diazene-l,2-dicarboxylate (0.218 mL, 1.107 mmol) was added slowly. After stirring at room temperature over night, solution was extracted with 1 M NaOH and CH2C12. Organic phases were concentrated and residue was purified by HPLC (H20/CH3CN gradient + 0.1% TFA). Fractions containing product were partly concentrated and residue was extracted with 1 M NaOH and CH2C12. Organic phases were dried over MgS04, filtered, and concentrated to give (lR,3s,5S)-tert-butyl 3-((lr,4R)-4-(4-(2-methoxyethyl)phenoxy)cyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (130 mg, 0.283 mmol, 30.7%) as an thick oil. Exact mass calculated for C27H41N05: 459.3, found: LCMS m/z = 460.6 [M+H]+; lU NMR (400 MHz, CDC13) δ ppm 1.35-1.63 (m, 8H), 1.46 (s, 9H), 1.86-2.00 (m, 6H), 2.0-2.12 (m, 2H), 2.81 (t, = 7.1 Hz, 2H), 3.35 (s, 3H), 3.40-3.47 (m, 1H), 3.56 (t, = 7.1 Hz, 2H), 3.79-3.84 (m, 1H), 4.17-4.28 (m, 3H), 6.79-6.83 (m, 2H), 7.09-7.13 (m, 2H).
Example 1.37: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4fl)-4-(4-(2- hydroxyethyl)phenoxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate
(Compound 32).
To a solution of (lR,3s,5S)-tert-butyl 3-((lr,4R)-4-(4-(2- methoxyethyl)phenoxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (125 mg, 0.272 mmol) in 3 mL CH2C12, iodotrimethylsilane (200 μΐ, 1.405 mmol) was added. After stirring at room temperature over night, ammonium hydrate (ca. 2 mL) was added and stirred for 10 min. Mixture was transferred into a separatory funnel and extracted with water and CH2C12. Organic phases were dried over MgS04, filtered, and concentrated. Residue was dissolved in 3 mL CH2C12 and triethylamine (120 μΐ, 0.861 mmol) and di-teri-butyl dicarbonate (100 mg, 0.458 mmol) were added. After stirring at room temperature for 15 min, mixture was extracted with CH2C12 and water.
Organic phases were concentrated and residue was purified by HPLC (H20/CH3CN gradient + 0.1% TFA). Fractions containing product were partly concentrated and residue was extracted with 1 M NaOH and CH2C12. Organic phases were dried over MgS04, filtered, and concentrated to give (lR,3s,5S)-tert-butyl 3-((lr,4R)-4-(4-(2-hydroxyethyl)phenoxy)cyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (75 mg, 0.168 mmol, 61.9%) as an thick oil. Exact mass calculated for C26H39N05: 445.3, found: LCMS m/z = 446.4 [M+H]+; lU NMR (400 MHz, CDC13) δ ppm 1.32-1.63 (m, 9H), 1.46 (s, 9H), 1.86-2.00 (m, 6H), 2.05-2.12 (m, 2H), 2.80 (t, = 6.5 Hz, 2H), 3.42-3.46 (m, 1H), 3.79-3.85 (m, 3H), 4.17-4.28 (m, 3H), 6.82-6.86 (m, 2H), 7.10-7.14 (m, 2H).
Example 1.38: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4/?)-4-(4-(2- cyanoethyl)phenoxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 35).
A mixture of (lR,3s,5S)-tert-butyl 3-((lr,4R)-4-(4-(2- (methylsulfonyloxy)ethyl)phenoxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (25 mg, 47.74 μιηοΐ) and tetrabutylammonium cyanide (50 mg, 0.186 mmol) in 1 mL THF was stirred at room temperature over night. Mixture was extracted with CH2C12 and water. Organic phases were concentrated and residue was purified by HPLC (H20/CH3CN gradient + 0.1%
TFA). Fractions containing pure product were partly concentrated and residue was extracted with 1 M NaOH and CH2C12. Organic phases were dried over MgS04, filtered, and concentrated to give (lR,3s,5S)-tert-butyl 3-((lr,4R)-4-(4-(2-cyanoethyl)phenoxy)cyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (9.5 mg, 20.90 μιηοΐ, 43.8%) as a solid. Exact mass calculated for C27H38N204: 454.3, found: LCMS m/z = 455.2 [M+H]+; lU NMR (400 MHz, CDC13) 5 ppm 1.35-1.63 (m, 8H), 1.46 (s, 9H), 1.86-2.00 (m, 6H), 2.05-2.11 (m, 2H), 2.58 (t, = 7.3 Hz, 2H), 2.89 (t, = 7.3 Hz, 2H), 3.41-3.47 (m, 1H), 3.78-3.86 (m, 1H), 4.16-4.31 (m, 3H), 6.84-6.87 (m, 2H), 7.10-7.13 (m, 2H).
Example 1.39: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4fl)-4-(4-(2- (dimethylamino)ethyl)phenoxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 38).
To a solution of (lR,3s,5S)-tert-butyl 3-((lr,4R)-4-(4-(2-
(methylsulfonyloxy)ethyl)phenoxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (25 mg, 47.74 μιηοΐ) in 1 mL THF, 2 M dimethylamine in THF (100 μΐ, 0.200 mmol) was added. After stirring at 60°C (oil bath) over night, mixture was extracted with CH2C12 and water.
Organic phases were concentrated and residue was purified by HPLC (H20/CH3CN gradient + 0.1 % TFA). Fractions containing pure product were partly concentrated and residue was extracted with 1 M NaOH and CH2C12. Organic phases were dried over MgS04, filtered, and concentrated to give (lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(4-(2-
(dimethylamino)ethyl)phenoxy)cyclohexyloxy)-8-azabicyclo [3.2.1] octane-8 -carboxylate (13.7 mg, 28.98 μιηοΐ, 60.7%) as a white solid. Exact mass calculated for C28H44N204: 472.3, found: LCMS m/z = 473.6 [M+H]+; lU NMR (400 MHz, CDC13) δ ppm 1.34-1.63 (m, 8H), 1.46 (s, 9H), 1.86-2.00 (m, 6H), 2.05-2.11 (m, 2H), 2.28 (s, 6H), 3.41-3.56 (m, 2H), 3.79-3.84 (m, 2H), 3.40-3.47 (m, 1H), 3.78-3.85 (m, 1H), 4.15-4.30 (m, 3H), 6.79-6.83 (m, 2H), 7.07-7.11 (m, 2H).
Example 1.40: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4/?)-4-(4-(2- morpholinoethyl)phenoxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate
(Compound 39).
To a solution of (lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(4-(2-
(methylsulfonyloxy)ethyl)phenoxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (25 mg, 47.74 μιηοΐ) in 1 mL THF, morpholine (20 μΐ, 0.229 mmol) was added. After stirring at 60°C (oil bath) over night, mixture was extracted with CH2C12 and water. Organic phases were concentrated and residue was purified by HPLC (H20/CH3CN gradient + 0.1 % TFA). Fractions containing pure product were partly concentrated and residue was extracted with 1 M NaOH and CH2C12. Organic phases were dried over MgS04, filtered, and concentrated to give (lR,3s,5S)- tert-b tyl 3-((l r,4R)-4-(4-(2-morpholinoethyl)phenoxy)cyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (10.1 mg, 19.62 μιηοΐ, 41.1 %) as a white solid. Exact mass calculated for C3oH46N205: 514.3, found: LCMS m/z = 515.6 [M+H]+; lU NMR (400 MHz, CDC13) 5 ppm 1.34-1.63 (m, 8H), 1.46 (s, 9H), 1.86-2.00 (m, 6H), 2.05-2.11 (m, 2H), 2.50-2.58 (m, 6H), 2.71-2.75 (m, 2H), 3.40-3.47 (m, 1H), 3.73-3.86 (m, 5H), 4.16-4.22 (m, 3H), 6.80-6.83 (m, 2H), 7.08-7.10 (m, 2H).
Example 1.41: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4fl)-4-(4-chloro-2- cyanophenoxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 19).
To a solution of (lR,3s,5S)-tert-butyl 3-((ls,4S)-4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.307 mmol), 5-chloro-2-hydroxybenzonitrile (49.55 mg, 0.323 mmol), and triphenylphosphine (84.62 mg, 0.323 mmol) in THF (3 mL) at room temperature under nitrogen was added triethylamine (44.97 μΐ, 0.323 mmol), followed by dropwise addition of diisopropyl diazene-l ,2-dicarboxylate (63.71 μΐ, 0.323 mmol). The mixture was stirred at room temperature for 17 h. The reaction was not complete and thus more reagents (0.5 eq of 4 reagents) were added. The reaction was continued to stir at room temperature for 5 h. The mixture was concentrated in vacuo and purified by preparative HPLC. Pure fractions were combined, neutralized with saturated sodium bicarbonate (aq), and evaporated MeCN. The aqueous residue was extracted with DCM (twice) and the combined organics were dried over anhydrous sodium sulfate. After removal of drying agent by filtration, the filtrate was concentrated in vacuo and dried under reduced pressure to give the title compound (33.1 mg, 71.80 μιηοΐ, 23.4%) as an off-white gum. Exact mass calculated for C25H33CIN2O4: 460.2, found: LCMS mJz = 461.4 [M+H]+; lU NMR (400 MHz, CDC13) δ ppm 1.40-1.51 (m, 2H), 1.47 (s, 9H), 1.57-1.72 (m, 6H), 1.84-2.13 (m, 8H), 3.48-3.58 (m, 1H), 3.75- 3.86 (m, 1H), 4.19 (br s, 1H), 4.28 (br s, 1H), 4.36-4.46 (m, 1H), 6.91 (d, = 8.8 Hz, 1H), 7.45 (dd, = 9.0, 2.7 Hz, 1H), 7.50 (d, = 2.8 Hz, 1H).
Example 1.42: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4fl)-4-(2-fluoro-4- (methylsulfonyl)phenoxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate
(Compound 20).
To a solution of (lR,3s,5S)-tert-butyl 3-((ls,4S)-4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.307 mmol), 2-fluoro-4- (methylsulfonyl)phenol (61.36 mg, 0.323 mmol), and triphenylphosphine (84.62 mg, 0.323 mmol) in THF (3 mL) at room temperature under nitrogen was added triethylamine (44.97 μΐ, 0.323 mmol), followed by dropwise addition of diisopropyl diazene-l,2-dicarboxylate (63.71 μΐ, 0.323 mmol). The mixture was stirred at room temperature for 17 h. The reaction was not complete and thus more reagents (0.5 eq of 4 reagents) were added. The mixture was continued to stir at room temperature for an additional day. The mixture was concentrated in vacuo and purified by preparative HPLC. Pure fractions were combined, neutralized with saturated sodium bicarbonate (aq), and evaporated MeCN to form a solid. The solid was collected, washed with water, and dried under reduced pressure to give the title compound (12.9 mg, 25.92 μιηοΐ, 8.4%) as a white solid. Exact mass calculated for C25H36FNO6S: 497.2, found: LCMS m/z = 498.4 [M+H]+; lU NMR (400 MHz, CDC13) δ ppm 1.39-1.51 (m, 2H), 1.47 (s, 9H), 1.57-1.73 (m, 6H), 1.83-2.04 (m, 6H), 2.05-2.17 (m, 2H), 3.04 (s, 3H), 3.45-3.56 (m, 1H), 3.75-3.89 (m, 1H), 4.19 (br s, 1H), 4.28 (br. s., 1H), 4.38-4.49 (m, 1H), 7.08 (t, = 8.2 Hz, 1H), 7.60-7.71 (m, 2H).
Example 1.43: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4/?)-4-(5-(methylsulfonyl)pyridin- 3-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 21).
To a solution of (lR,3s,5S)-tert-butyl 3-((ls,4S)-4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.307 mmol), 5-(methylsulfonyl)pyridin-3-ol (55.88 mg, 0.323 mmol), and triphenylphosphine (84.62 mg, 0.323 mmol) in THF (3 mL) at room temperature under nitrogen was added triethylamine (44.97 μΐ, 0.323 mmol), followed by dropwise addition of diisopropyl diazene-l,2-dicarboxylate (63.71 μΐ, 0.323 mmol). The mixture was stirred at room temperature for 17 h. The reaction was not complete and thus more reagents (0.5 eq of 4 reagents) were added. The reaction was continued to stir at room temperature for 2 h. The reaction mixture was concentrated in vacuo and purified by preparative HPLC. Pure fractions were combined, neutralized with saturated sodium bicarbonate (aq), and evaporated MeCN to form a solid. The solid was collected, washed with water, and dried under reduced pressure to give the title compound (16.2 mg, 33.71 μιηοΐ, 11.0%) as a white solid. Exact mass calculated for Cz-OLeNzOsS: 480.2, found: LCMS mJz = 481.4 [M+H]+; lU NMR (400 MHz, CDC13) δ ppm 1.41-1.52 (m, 2H), 1.47 (s, 9H), 1.55-1.68 (m, 6H), 1.85-2.02 (m, 6H), 2.05-2.16 (m, 2H), 3.11 (s, 3H), 3.46-3.55 (m, 1H), 3.76-3.88 (m, 1H), 4.19 (br s, 1H), 4.29 (br s, 1H), 4.38-4.46 (m, 1H), 7.62-7.66 (m, 1H), 8.52 (d, = 2.8 Hz, 1H), 8.71 (d, = 2.0 Hz, 1H).
Example 1.44: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4/?)-4-(l,6-naphthyridin-4- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 24).
To a suspension of (lR,3s,5S)-tert-butyl 3-((lr,4R)-4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (50 mg, 0.154 mmol) and 4-chloro-l,6-naphthyridine (27.82 mg, 0.169 mmol) in THF (3 mL) at 0°C under nitrogen was added 1 M potassium tert- butoxide in THF (0.200 mL, 0.200 mmol) dropwise. The mixture was stirred at room temperature for 1 h. The mixture was quenched with water and extracted with DCM (twice). The combined organic layers were concentrated in vacuo to dryness and purified by preparative HPLC. Pure fractions were combined, neutralized with saturated sodium bicarbonate (aq), and evaporated MeCN. The aqueous residue was extracted with DCM (twice) and the combined organics were dried over anhydrous sodium sulfate. After removal of drying agent by filtration, the filtrate was concentrated in vacuo and dried under reduced pressure to give the title compound (61.8 mg, 0.136 mmol, 88.7%) as a light yellow gum. Exact mass calculated for
C26H35N3O4: 453.3, found: LCMS mJz = 454.4 [M+H]+; lU NMR (400 MHz, CDC13) δ ppm 1.48 (s, 9H), 1.50-1.70 (m, 6H), 1.71-1.83 (m, 2H), 1.86-2.09 (m, 6H), 2.15-2.25 (m, 2H), 3.52-3.65 (m, 1H), 3.78-3.90 (m, 1H), 4.21 (br s, 1H), 4.31 (br s, 1H), 4.61-4.71 (m, 1H), 6.82 (d, = 5.6 Hz, 1H), 7.81 (d, = 5.0 Hz, 1H), 8.73 (d, = 5.8 Hz, 1H), 8.86 (d, = 5.3 Hz, 1H), 9.60 (s, 1H).
Example 1.45: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4fl)-4-(pyridin-4- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 25).
To a suspension of (lR,3s,5S)-tert-butyl 3-((lr,4R)-4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (50 mg, 0.154 mmol) and 4-chloropyridine hydrochloride (25.35 mg, 0.169 mmol) in THF (2 mL) at 0°C under nitrogen was added 1 M potassium tert- butoxide in THF (0.399 mL, 0.399 mmol) dropwise. The mixture was stirred at room temperature for 2 h. No reaction was observed. The mixture was heated at 100°C under microwave irradiation for 2 h. LC/MS was taken at 1 h and 2 h but no difference was observed (13% and 11 % of Rl were remained, respectively). Thus, more 4-chloropyridine hydrochloride (11.5 mg, 0.0768 mmol, 0.5 eq) and 1 M potassium teri-butoxide in THF (0.2 mL, 0.2 mmol, 1.3 eq) were added and the mixture was heated at 100°C under microwave irradiation for 1 h. The reaction was almost finished and thus stopped. The mixture was quenched with water and extracted with DCM (twice). The combined organic layers were concentrated in vacuo to dryness and purified by preparative HPLC. Pure fractions were combined, neutralized with saturated sodium bicarbonate (aq), and evaporated MeCN to form a solid. The solid was collected by vacuum filtration, washed with water, and dried under reduced pressure to give the title compound (29.4 mg, 73.04 μιηοΐ, 47.5%). Exact mass calculated for C23H34N2O4: 402.3, found: LCMS mJz = 403.6 [M+H]+; lU NMR (400 MHz, CDC13) δ ppm 1.38-1.50 (m, 2H), 1.47 (s, 9H), 1.50-1.71 (m, 6H), 1.84-2.03 (m, 6H), 2.04-2.16 (m, 2H), 3.39-3.54 (m, IH), 3.75-3.88 (m, IH), 4.18 (br s, IH), 4.27 (br s, IH), 4.32-4.41 (m, IH), 6.77 (dd, = 4.9, 1.4 Hz, 2H), 8.40 (d, = 6.3 Hz, 2H).
Example 1.46: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4fl)-4-(5-(lH-l,2,4-triazol-l- yl)pyrazin-2-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 26).
To a suspension of (lR,3s,5S)-tert-butyl 3-((l r,4R)-4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (50 mg, 0.154 mmol) and 2-chloro-5-(lH-l ,2,4-triazol-l - yl)pyrazine (30.69 mg, 0.169 mmol) in THF (2 mL) at 0°C under nitrogen was added 1 M potassium teri-butoxide in THF (0.200 mL, 0.200 mmol) dropwise. The mixture was stirred at room temperature for 1 h. The mixture was quenched with water and extracted with DCM (twice). The combined organic layers were concentrated in vacuo to dryness and purified by preparative HPLC. Pure fractions were combined, neutralized with saturated sodium bicarbonate (aq), and evaporated MeCN to form a solid. The solid was collected by vacuum filtration, washed with water, and dried under reduced pressure to give the title compound (20.3 mg, 43.14 μιηοΐ, 28.1 %) as an off-white solid. Exact mass calculated for C24H34N6O4: 470.3, found: LCMS m/z = 471.4 [M+H]+; lU NMR (400 MHz, CDC13) δ ppm 1.43-1.51 (m, 2H), 1.47 (s, 9H), 1.51- 1.72 (m, 6H), 1.86-2.04 (m, 6H), 2.10-2.20 (m, 2H), 3.42-3.53 (m, IH), 3.78-3.91 (m, IH), 4.19 (br s, IH), 4.30 (br s, IH), 5.00-5.10 (m, IH), 7.98 (d, = 1.3 Hz, IH), 8.10 (s, IH), 8.69 (d, = 1.3 Hz, IH), 8.97 (s, IH). Example 1.47: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4fl)-4-(2-methyl-6-(lH-l,2,4- triazol-l-yl)pyridin-3-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 27). To a solution of (lR,3s,5S)-tert-butyl 3-((ls,4S)-4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.307 mmol), 2-methyl-6-(lH-l,2,4-triazol-l- yl)pyridin-3-ol (64.96 mg, 0.369 mmol), and triphenylphosphine (96.71 mg, 0.369 mmol) in THF (2 mL) at room temperature under nitrogen was added triethylamine (51.39 μΐ, 0.369 mmol). To this was slowly added diisopropyl diazene-l,2-dicarboxylate (72.81 μΐ, 0.369 mmol) dropwise. The reaction mixture was stirred at room temperature for 19 h. The reaction was complete. The reaction mixture was directly concentrated in vacuo to dryness and the residue was purified by preparative HPLC. Pure fractions were combined, neutralized with saturated sodium bicarbonate (aq), and evaporated MeCN to form a solid. The solid was collected by vacuum filtration, washed with water, and dried under reduced pressure to give the title compound (31.3 mg, 64.72 μιηοΐ, 21.1%) as a light yellow solid. Exact mass calculated for C26H37N5O4: 483.3, found: LCMS m/z = 484.4 [M+H]+; lU NMR (400 MHz, CDC13) δ ppm 1.40-1.51 (m, 2H), 1.46 (s, 9H), 1.52-1.69 (m, 6H), 1.81-2.03 (m, 6H), 2.03-2.16 (m, 2H), 2.47 (s, 3H), 3.47-3.57 (m, 1H), 3.75-3.90 (m, 1H), 4.19 (br s, 1H), 4.24-4.36 (m, 2H), 7.25 (d, = 8.6 Hz, 1H), 7.63 (d, = 8.6 Hz, 1H), 8.04 (s, 1H), 9.05 (s, 1H).
Example 1.48: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4/?)-4-(isoquinolin-8- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 28).
To a solution of (lR,3s,5S)-tert-butyl 3-((ls,4S)-4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.307 mmol), isoquinolin-8-ol (53.52 mg, 0.369 mmol), and triphenylphosphine (96.71 mg, 0.369 mmol) in THF (2 mL) at room temperature under nitrogen was added triethylamine (51.39 μΐ, 0.369 mmol), followed by dropwise addition of diisopropyl diazene-l,2-dicarboxylate (72.81 μΐ, 0.369 mmol). After 19 h stirring at room temperature, the mixture was concentrated in vacuo and purified by preparative HPLC. Pure fractions were combined, neutralized with saturated sodium bicarbonate (aq), and evaporated MeCN. The aqueous residue was extracted with DCM (twice) and the combined organics were dried over anhydrous sodium sulfate. After removal of drying agent by filtration, the filtrate was concentrated in vacuo and dried under reduced pressure to give the title compound (22.5 mg, 49.71 μιηοΐ, 16.2%) as a grapefruit color solid. Exact mass calculated for C27H36N2O4: 452.3, found: LCMS m/z = 453.4 [M+H]+; lU NMR (400 MHz, CDC13) δ ppm 1.47 (s, 9H), 1.49-1.82 (m, 8H), 1.87-1.99 (m, 4H), 2.00-2.11 (m, 2H), 2.14-2.25 (m, 2H), 3.51-3.63 (m, 1H), 3.78-3.92 (m, 1H), 4.20 (br s, 1H), 4.30 (br s, 1H), 4.50-4.61 (m, 1H), 6.91 (d, = 7.8 Hz, 1H), 7.34 (d, = 8.3 Hz, 1H), 7.52-7.61 (m, 2H), 8.51 (d, = 5.8 Hz, 1H), 9.62 (s, 1H). Example 1.49: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4fl)-4-(4-bromo-3- fluorophenoxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 33). To a solution of (lR,3s,5S)-tert-butyl 3-((ls,4S)-4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.615 mmol), 4-bromo-3-fluorophenol (0.141 g, 0.737 mmol), and triphenylphosphine (0.193 g, 0.737 mmol) in THF (3 mL) at room temperature under nitrogen was added triethylamine (0.103 mL, 0.737 mmol), followed by dropwise addition of diisopropyl diazene-l,2-dicarboxylate (0.146 mL, 0.737 mmol). After 16 h stirring at room temperature, the mixture was concentrated in vacuo and purified by preparative HPLC. Pure fractions were combined, neutralized with saturated sodium bicarbonate (aq), and evaporated MeCN to form a solid. The solid was collected by vacuum filtration, washed with water, and dried under reduced pressure to give the title compound (84.1 mg, 0.169 mmol, 27.5%) as a light yellow solid. Exact mass calculated for Cz-OLsBrFNC : 497.2, found: LCMS m/z = 498.4 [M+H]+; lU NMR (400 MHz, CDC13) δ ppm 1.35-1.44 (m, 2H), 1.46 (s, 9H), 1.49- 1.71 (m, 6H), 1.83-2.01 (m, 6H), 2.01-2.12 (m, 2H), 3.40-3.51 (m, IH), 3.74-3.89 (m, IH), 4.14- 4.23 (m, 2H), 4.29 (br s, IH), 6.58 (dt, = 8.8, 1.4 Hz, IH), 6.67 (dd, = 10.6, 2.8 Hz, IH), 7.37 (t, = 8.5 Hz, IH).
Example 1.50: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4/?)-4-(4-(lH-tetrazol-l- yl)phenoxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 43).
To a solution of (lR,3s,5S)-tert-butyl 3-((ls,4S)-4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.307 mmol), 4-(lH-tetrazol-l-yl)phenol (59.79 mg, 0.369 mmol), and triphenylphosphine (96.71 mg, 0.369 mmol) in THF (2 mL) at room temperature under nitrogen was added triethylamine (51.39 μΐ, 0.369 mmol), followed by dropwise addition of diisopropyl diazene-l,2-dicarboxylate (72.81 μΐ, 0.369 mmol). After 19 h stirring at room temperature, the mixture was concentrated in vacuo and purified by preparative HPLC. Pure fractions were combined, neutralized with saturated sodium bicarbonate (aq), and evaporated MeCN to form a solid. The solid was collected by vacuum filtration, washed with water, and dried under reduced pressure to give the title compound (27.9 mg, 59.42 μιηοΐ, 19.3%) as a white solid. Exact mass calculated for C25H35N5O4: 469.3, found: LCMS m/z = 470.2 [M+H]+; lU NMR (400 MHz, CDC13) δ ppm 1.37-1.50 (m, 2H), 1.47 (s, 9H), 1.51-1.74 (m, 6H), 1.83-2.05 (m, 6H), 2.06-2.20 (m, 2H), 3.41-3.55 (m, IH), 3.75-3.91 (m, IH), 4.19 (br s, IH), 4.24-4.42 (m, 2H), 7.04 (dd, = 9.0 Hz, 2H), 7.57 (d, = 9.1 Hz, 2H), 8.87 (s, IH).
Example 1.51: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4fl)-4-(2-methyl-6-(oxetan-3- ylsulfonyl)pyridin-3-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate
(Compound 44).
Step A: Preparation of oxetan-3-yl methanesulfonate.
To a solution of oxetan-3-ol (5 g, 67.5 mmol) and triethylamine (14.11 mL, 101 mmol) in DCM (150 mL) at 0°C was added methanesulfonyl chloride (6.79 mL, 88 mmol) dropwise. The mixture was stirred at RT for 3 hr. The solid was filtered off and the filtrate was washed with ice -water and brine solution. The organic phase was dried over anhydrous Na2S04 and concentrated in vacuo to afford the title compound (11.7 g, 67.5 mmol, 100% yield) as an oil (containing 12.2 wt% of DCM). lU NMR (400 MHz, CDC13) δ 3.06 (s, 3H), 4.79-4.82 (m, 2H), 4.86-4.90 (m, 2H), 5.52-5.49 (m, 1H).
Step B: Preparation of S-Oxetan-3-yl ethanethioate.
To a solution of oxetan-3-yl methanesulfonate (9.43 g, 62.0 mmol) and ethanethioic S- acid (6.55 mL, 93 mmol) in DMF (100 mL) was added cesium carbonate (30.3 g, 93 mmol). The mixture was heated at 60°C for 19.5 hr. The mixture was quenched with water and extracted with EtOAc. The organic layer was concentrated in vacuo (bath 25 °C / 150 mmHg). The residue was distilled under vacuum (bp 45 °C/ 10 mmHg). The product had DMF and thus the product was dissolved in ether and washed with water. The organic layer was dried over anhydrous MgS04, filtered, and concentrated in vacuo (bath 25 °C / 150 mmHg) to afford the title compound (4.17 g, 11.51 mmol, 18.58% yield) as a light yellow oil (containing solvents such as DMF, EtOAc, and Et20). lU NMR (400 MHz, CDC13) δ 2.32 (s, 3H), 4.56-4.59 (m, 2H), 4.62-4.69 (m, 1H), 5.03-5.06 (m, 2H).
Step C: Preparation of Oxetane-3-sulfonyl Chloride.
To an ice cold solution of l-chloropyrrolidine-2,5-dione (6.15 g, 46.1 mmol) and 2 N hydrochloric acid (aq) (8.64 mL, 17.27 mmol) in MeCN (50 mL) was added a solution of S- oxetan-3-yl ethanethioate (4.17 g, 11.51 mmol) in MeCN (10 mL) over 20 min. The mixture was concentrated in vacuo to remove MeCN (25 °C bath / 50 mm Hg) and the residue was partitioned between Et20 and saturated NaHC03 (aq). The organic layer was separated, washed with saturated Na2S203 (aq) and brine, dried over anhydrous MgS04, filtered, and concentrated in vacuo (25 °C bath / 50 mmHg) to afford the crude title compound (0.69 g, 4.41 mmol, 38.3% yield) as an off-white oil/solid. lU NMR (400 MHz, CDC13) δ 4.99-5.06 (m, 5H).
Step D: Preparation of Sodium Oxetane-3-sulfinate.
A solution of sodium sulfite (555 mg, 4.41 mmol) in water (2 mL) was vigorously stirred at RT for 10 min. To this was added sodium bicarbonate (740 mg, 8.81 mmol) and the mixture was heated at 50°C for 1 hr. Oxetane-3-sulfonyl chloride (690 mg, 4.41 mmol) was carefully added and the mixture was continued to heat at 50°C overnight. The mixture was concentrated in vacuo and the residue was triturated with MeOH. The solid was collected by vacuum filtration to afford the title compound (476.8 mg, 3.31 mmol, 75% yield) as an off-white solid. !H NMR (400 MHz, CDC13) δ 2.97-3.04 (m, 1H), 4.45-4.49 (m, 2H), 4.53-4.58 (m, 2H).
Step E: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4fl)-4-(6-bromo-2- methylpyridin-3-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate.
To a solution of (lR,3s,5S)-tert-butyl 3-((ls,4S)-4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (500 mg, 1.536 mmol), 6-bromo-2-methylpyridin-3-ol (0.347 g, 1.844 mmol), and triphenylphosphine (0.484 g, 1.844 mmol) in THF (5 mL) at room temperature under nitrogen was added triethylamine (0.257 mL, 1.844 mmol), followed by dropwise addition of diisopropyl diazene-l,2-dicarboxylate (0.364 mL, 1.844 mmol). After 18 h stirring at room temperature, the mixture was concentrated in vacuo and purified by preparative HPLC. Pure fractions were combined, neutralized with saturated sodium bicarbonate (aq), and evaporated MeCN to form a solid. The solid was collected by vacuum filtration, washed with water, and dried under reduced pressure to give the title compound (175.1 mg, 0.353 mmol, 23.0%) as a white solid. Exact mass calculated for C24H35BrN204: 494.2, found: LCMS m/z = 495.6 [M+H]+; lU NMR (400 MHz, CDC13) δ ppm 1.37-1.45 (m, 2H), 1.47 (s, 9H), 1.50-1.71 (m, 6H), 1.84-1.99 (m, 6H), 2.00-2.11 (m, 2H), 2.42 (s, 3H), 3.44-3.55 (m, 1H), 3.76-3.88 (m, 1H), 4.12-4.35 (m, 3H), 6.97 (d, = 8.6 Hz, 1H), 7.21 (d, = 8.6 Hz, 1H).
Step F: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4fl)-4-(2-methyl-6-(oxetan-3- ylsulfonyl)pyridin-3-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate.
A mixture of (lR,3s,5S)-tert-butyl 3-((lr,4R)-4-(6-bromo-2-methylpyridin-3- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (50 mg, 0.101 mmol), sodium oxetane-3-sulfinate (21.82 mg, 0.151 mmol), and copper(I) trifluoromethanesulfonate benzene complex (5.080 mg, 10.09 μιηοΐ) in a sealed tube was added DMSO (0.4 mL) and N1,N2- dimethylethane-l,2-diamine (2.172 μΐ, 20.18 μιηοΐ) (skipped nitorgen purging). The mixture was heated at 100°C under microwave irradiation for 2 h. The reaction was not complete and thus more sodium oxetane-3-sulfinate (21.82 mg, 0.151 mmol), copper(I)
trifluoromethanesulfonate (5.080 mg, 10.09 μιηοΐ), and Nl,N2-dimethylethane-l,2-diamine (2.172 μΐ, 20.18 μιηοΐ) were added. The mixture was heated at 100°C under microwave irradiation for another 2 h. The reaction was complete. The mixture was purified by semi- preparative HPLC. Pure fractions were combined, neutralized with saturated sodium bicarbonate (aq), and evaporated MeCN to form a solid. The solid was collected by vacuum filtration, washed with water, and dried under reduced pressure to give the title compound (21.2 mg, 39.50 μιηοΐ, 39.1%) as a white solid. Exact mass calculated for C27H40N2O7S: 536.3, found: LCMS m/z = 537.6 [M+H]+; lU NMR (400 MHz, CDC13) δ ppm 1.39-1.52 (m, 2H), 1.47 (s, 9H), 1.56- 1.71 (m, 6H), 1.82-2.03 (m, 6H), 2.03-2.16 (m, 2H), 2.46 (s, 3H), 3.48-3.60 (m, 1H), 3.75-3.89 (m, 1H), 4.20 (br s, 1H), 4.30 (br s, 1H), 4.36-4.49 (m, 1H), 4.74-4.91 (m, 3H), 5.10 (t, = 5.8 Hz, 2H), 7.17 (d, = 8.6 Hz, 1H), 7.89 (d, = 8.6 Hz, 1H).
Example 1.52: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4fl)-4-(6-(cyclopropylsulfonyl)-2- methylpyridin-3-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 45).
To a solution of (lR,3s,5S)-tert-butyl 3-((ls,4S)-4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.307 mmol), 6-(cyclopropylsulfonyl)-2- methylpyridin-3-ol (78.63 mg, 0.369 mmol), and triphenylphosphine (96.71 mg, 0.369 mmol) in THF (2 mL) at room temperature under nitrogen was added triethylamine (51.39 μΐ, 0.369 mmol), followed by dropwise addition of diisopropyl diazene-l,2-dicarboxylate (72.81 μΐ, 0.369 mmol). The mixture was stirred at room temperature for 15.5 h. The reaction was not complete but stopped. The mixture was concentrated in vacuo to dryness and purified by preparative
HPLC. Pure fractions were combined, neutralized with saturated sodium bicarbonate (aq), and evaporated MeCN to form a solid. The solid was collected by vacuum filtration, washed with water, and dried under reduced pressure to give the title compound (18.8 mg, 36.11 μιηοΐ, 11.8%) as an off-white solid. Exact mass calculated for C27H40N2O6S: 520.3, found: LCMS m/z = 521.6 [M+H]+; lU NMR (400 MHz, CDC13) δ ppm 0.95-1.08 (m, 2H), 1.29-1.40 (m, 2H),
1.41-1.52 (m, 2H), 1.47 (s, 9H), 1.57-1.73 (m, 6H), 1.83-2.01 (m, 6H), 2.03-2.17 (m, 2H), 2.51 (s, 3H), 2.73-2.87 (m, 1H), 3.46-3.59 (m, 1H), 3.76-3.90 (m, 1H), 4.20 (br s, 1H), 4.30 (br s, 1H), 4.36-4.47 (m, 1H), 7.14 (d, = 8.6 Hz, 1H), 7.80 (d, = 8.3 Hz, 1H). Example 1.53: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4/?)-4-(2-methyl-6-
(methylsulfonyl)pyridin-3-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 56).
A mixture of (lR,3s,5S)-tert-butyl 3-((lr,4R)-4-(6-bromo-2-methylpyridin-3- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (50 mg, 0.101 mmol), sodium methanesulfinate (15.45 mg, 0.151 mmol), copper(I) trifluoromethanesulfonate benzene complex (5.080 mg, 10.09 μιηοΐ), and Nl,N2-dimethylethane-l,2-diamine (2.172 μΐ, 20.18 μιηοΐ) in DMSO (1 mL) under N2 was heated at 100°C under microwave irradiation for 2 h and purified by semi-preparative HPLC, neutralized with sat. NaHC03, evaporated MeCN, and the solid was collected to give the title compound (30.8 mg, 62.27 μιηοΐ, 61.7%) as an off-white solid. Exact mass calculated for CzsHssNzOsS: 494.3, found: LCMS m/z = 495.6 [M+H]+; lU NMR (400 MHz, CDC13) δ ppm 1.46 (s, 9H), 1.55-1.70 (m, 8H), 1.84-2.00 (m, 6H), 2.03-2.13 (m, 2H), 2.49 (s, 3H), 3.17 (s, 3H), 3.49-3.57 (m, 1H), 3.75-3.87 (m, 1H), 4.12-4.33 (m, 2H), 4.36-4.46 (m, 1H), 7.16 (d, = 8.3 Hz, 1H), 7.88 (d, = 8.3 Hz, 1H). Example 1.54: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4/?)-4-(5-cyanopyrimidin-4- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 51).
To a solution of (lR,3s,5S)-tert-butyl 3-((lr,4R)-4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (50 mg, 0.154 mmol) in THF (2 mL) at 0°C was added 1 M potassium teri-butoxide in THF (0.200 mL, 0.200 mmol). After stirring at 0°C for 10 min, a solution of 4-chloropyrimidine-5-carbonitrile (23.58 mg, 0.169 mmol) in THF (1 mL) was added. The mixture was stirred at room temperature for 1 h. The reaction was not complete but stopped (Any longer reaction time seems to cause a decomposition of desired product). The reaction was quenched with water and extracted with DCM (twice). The combined organic layers were concentrated in vacuo to dryness and purified by semi -preparative HPLC. There was no pure fraction. Fractions containing product were combined, neutralized with saturated sodium bicarbonate (aq), evaporated MeCN, and extracted with DCM. The organics were concentrated in vacuo and purified by Biotage™ column chromatography to give the title compound (8.8 mg, 20.54 μιηοΐ, 13.4%) as a light brown solid. Exact mass calculated for C23H32N4O4: 428.2, found: LCMS m/z = 429.6 [M+H]+; lU NMR (400 MHz, CDC13) δ ppm 1.41-1.55 (m, 2H), 1.49 (s, 9H), 1.55-1.74 (m, 6H), 1.80-2.04 (m, 6H), 2.04-2.23 (m, 2H), 3.43- 3.59 (m, 1H), 3.74-3.91 (m, 1H), 4.19 (br s, 1H), 4.28 (br s, 1H), 5.23-5.38 (m, 1H), 8.71 (s, 1H), 8.86 (s, 1H).
Example 1.55: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4/?)-4-(4-cyano-2,6- difluorophenoxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 52).
To a solution of (lR,3s,5S)-tert-butyl 3-((ls,4S)-4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.307 mmol), 3,5-difluoro-4- hydroxybenzonitrile (57.19 mg, 0.369 mmol), and triphenylphosphine (96.71 mg, 0.369 mmol) in THF (2 mL) at room temperature under nitrogen was added triethylamine (51.39 μΐ, 0.369 mmol), followed by dropwise addition of diisopropyl diazene-l,2-dicarboxylate (72.81 μΐ, 0.369 mmol). After 15.5 h stirring at room temperature, the mixture was concentrated in vacuo and purified by preparative HPLC. Pure fractions were combined, neutralized with saturated sodium bicarbonate (aq), and evaporated MeCN to form a solid. The solid was collected by vacuum filtration, washed with water, and dried under reduced pressure to give the title compound (36.8 mg, 79.56 μιηοΐ, 25.9%) as a white solid. Exact mass calculated for C25H32F2N2O4: 462.2, found: LCMS m/z = 463.6 [M+H]+; lU NMR (400 MHz, CDC13) δ ppm 1.34-1.45 (m, 2H), 1.46 (s, 9H), 1.56-1.69 (m, 6H), 1.83-1.91 (m, 2H), 1.91-2.01 (m, 4H), 2.01-2.11 (m, 2H), 3.43-3.54 (m, 1H), 3.74-3.86 (m, 1H), 4.17 (br s, 1H), 4.28 (br s, 1H), 4.34-4.44 (m, 1H), 7.22 (d, = 7.8 Hz, 2H).
Example 1.56: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4fl)-4-(2-methyl-6-(pyridazin-4- yl)pyridin-3-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 53).
To a mixture of (lR,3s,5S)-tert-butyl 3-((lr,4R)-4-(6-bromo-2-methylpyridin-3- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (50 mg, 0.101 mmol) and trans- dichlorobis(triphenylphosphine)palladium (II) (7.083 mg, 10.09 μιηοΐ) in Dioxane (3 mL) under nitrogen was added 4-(tributylstannyl)pyridazine (0.112 g, 0.303 mmol). The mixture was heated at 110°C for 16 h. The mixture was filtered, concentrated in vacuo, and purified by
Biotage™ column chromatography to give the title compound (44.7 mg, 90.37 μιηοΐ, 89.5%) a light yellow solid. Exact mass calculated for 494.3, found: LCMS m/z = 495.6 [M+H]+; lU NMR (400 MHz, CDC13) δ ppm 1.43-1.51 (m, 2H), 1.47 (s, 9H), 1.52-1.73 (m, 6H), 1.85-2.02 (m, 6H), 2.06-2.19 (m, 2H), 2.53 (s, 3H), 3.45-3.63 (m, 1H), 3.76-3.94 (m, 1H), 4.20 (br s, 1H), 4.29 (br s, 1H), 4.33-4.47 (m, 1H), 7.18 (d, / = 8.6 Hz, 1H), 7.67 (d, = 8.6 Hz, 1H), 8.02 (dd, = 5.4, 2.4 Hz, 1H), 9.21 (dd, = 5.3, 1.0 Hz, 1H), 9.75 (d, = 1.3 Hz, 1H).
Example 1.57: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4/?)-4-(3-fluoro-4-(lH-l,2,4- triazol-l-yl)phenoxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 57).
To a solution of (lR,3s,5S)-tert-butyl 3-((ls,4S)-4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (50 mg, 0.154 mmol), 3-fluoro-4-(lH-l ,2,4-triazol-l- yl)phenol (28.90 mg, 0.161 mmol), and triphenylphosphine (48.36 mg, 0.184 mmol) in THF (1 mL) at room temperature under nitrogen was added triethylamine (25.70 μΐ, 0.184 mmol), followed by dropwise addition of diisopropyl diazene-l ,2-dicarboxylate (36.41 μΐ, 0.184 mmol). After 17 h stirring at room temperature, the mixture was concentrated and purified by preparative HPLC, neutralized with sat. NaHC03, evaporated MeCN to give the title compound (19.8 mg, 40.69 μιηοΐ, 26.5%) as a white solid. Exact mass calculated for C26H35FN4O4: 486.3, found: LCMS m/z = 487.2 [M+H]+; lU NMR (400 MHz, CDC13) δ ppm 1.39-1.50 (m, 2H), 1.47 (s, 9H), 1.51-1.73 (m, 7H), 1.86-2.03 (m, 6H), 2.06-2.15 (m, 2H), 3.44-3.52 (m, 1H), 3.77-3.87 (m, 1H), 4.25-4.34 (m, 2H), 6.75-6.83 (m, 2H), 7.64-7.71 (m, 1H), 8.09 (s, 1H), 8.51 (d, = 2.5 Hz, 1H).
Example 1.58: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4fl)-4-(5- (methylsulfonyl)pyrazin-2-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 58).
To a solution of 5-(methylsulfonyl)pyrazin-2-ol (0.963 g, 5.531 mmol), (lR,5S)-tert- butyl 3-((li,45)-4-hydroxycyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.5 g, 4.609 mmol), and triphenylphosphine (1.451 g, 5.531 mmol) in THF (15.0 mL), triethylamine (0.771 mL, 5.531 mmol) was added. (Z) -diisopropyl diazene-l ,2-dicarboxylate (1.092 mL, 5.531 mmol) was then added slowly at room temperature. The reaction was allowed to stir for 25.5 h. The reaction mixture was diluted in EtOAc and water and the EtOAc layer was removed. The water was extracted with EtOAc and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 10-25-50% EtOAc in hexanes) to give the title compound (0.972 g, 2.02 mmol, 43.8%). Exact mass calculated for C23H35N3O6S: 481.2, found: LCMS m/z = 482.2 [M+H]+; lU NMR (500 MHz, CDCI3) δ ppm 1.43-1.54 (m, 1H), 1.47 (s, 9H), 1.53-1.65 (m, 7H), 1.87-1.93 (m,
2H), 1.93-2.01 (m, 4H), 2.09-2.17 (m, 2H), 3.18 (s, 3H), 3.44-3.52 (m, 1H), 3.78-3.87 (m, 1H), 4.24 (br s, 2H), 5.11-5.19 (m, 1H), 8.19 (s, 1H), 8.78 (s, 1H). Example 1.59: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4/?)-4-(5- (dimethylcarbamoyl)pyridin-2-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8- carboxylate (Compound 59).
To the mixture of 6-((lR,4r)-4-((lR,3s,5S)-8-(te^butoxycarbonyl)-8- azabicyclo[3.2.1]octan-3-yloxy)cyclohexyloxy)nicotinic acid (14 mg, 31.35 μιηοΐ) and HATU (14.31 mg, 37.62 μιηοΐ) in CH3CN was added DIEA (10.92 μΐ, 62.70 μιηοΐ) at room
temperature. The reaction was stirred for 10 min, dimethylamine in methanol (18.81 μΐ, 37.62 μιηοΐ) was added. The mixture was stirred overnight and purified by semi preparative HPLC (35-90% CH3CN/H20 with 0.1 % TFA). The combined fractions were neutralized with saturated NaHC03 and partially concentrated. The white precipitate was collected and dried to give the title compound (7.2 mg, 15.20 μιηοΐ, 48.5%). Exact mass calculated for C26H39N3O5: 473.3, found: LCMS m/z = 474.6 [M+H]+; lU NMR (400 MHz, CDC13) δ ppm 1.40-1.67 (m, 8H), 1.47 (s, 9H), 1.80-2.00 (m, 6H), 2.09-2.18 (m, 2H), 3.08 (s, 6H), 3.40-3.48 (m, IH), 3.78- 3.88 (m, IH), 4.14-4.33 (m, 2H), 5.01-5.09 (m, IH), 6.69 (d, = 8.59 Hz, IH), 7.67 (dd, = 8.59, 2.27 Hz, IH), 8.25 (d, = 2.27 Hz, IH).
Example 1.60: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4fl)-4-(4- (methylsulfonyl)phenoxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate
(Compound 60).
To a solution of (lR,3s,5S)-tert-butyl 3-((ls,4S)-4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (1 g, 3.073 mmol), 4-(methylsulfonyl)phenol (0.635 g, 3.687 mmol), triethylamine (0.428 mL, 3.073 mmol) and triphenylphosphine (0.887 g, 3.380 mmol) in THF (5 mL) at ice -water bath under nitrogen was added DIAD - Diisopropyl azodicarboxylate (0.746 g, 3.687 mmol) dropwise. The reaction mixture was slowly warmed to room temperature and stirred for 4 days, then concentrated. The residue was purified by semi preparative HPLC (40-95% CH3CN/H20). The combined fractions were neutralized with saturated NaHC03 and partially concentrated. The white solid was collected and dried to give the title compound (372 mg, 0.776 mmol, 25.2%). Exact mass calculated for C25H37NO6S: 479.2, found: LCMS m/z = 480.6 [M+H]+; lU NMR (400 MHz, CDC13) δ ppm 1.39-1.50 (m, 2H), 1.47 (s, 9H), 1.51-1.64 (m, 6H), 1.86-2.02 (m, 6H), 2.06-2.14 (m, 2H), 3.02 (s, 3H), 3.44- 3.52 (m, IH), 3.77-3.87 (m, IH), 4.13-4.33 (m, 2H), 4.34-4.42 (m, IH), 6.96-7.00 (m, 2H), 7.82- 7.86 (m, 2H). Example 1.61: Preparation of (lfl,3s,5S)-l-Methylcyclopropyl 3-((lr,4fl)-4-(5-
(methylsulfonyl)pyrazin-2-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 61). To a mixture of (lR,3s,5S)-3-((lr,4R)-4-(5-(methylsulfonyl)pyrazin-2- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane hydrochloride (0.02 g, 47.85 μιηοΐ) in CH2C12 (0.48 mL), triethylamine (46.69 μΐ, 0.335 mmol) and 2,5-dioxopyrrolidin-l-yl 1- methylcyclopropyl carbonate (12.24 mg, 57.42 μιηοΐ) were added at room temperature. The reaction was stirred for 16 h at room temperature and then loaded on a TLC plate and eluted with 50% EtOAc in hexanes to give the title compound (20.3 mg, 42.33 μιηοΐ, 88.5%). Exact mass calculated for C23H33N3O6S: 479.2, found: LCMS m/z = 480.6 [M+H]+; lU NMR (400 MHz, CDCI3) δ ppm 0.59-0.65 (m, 2H), 0.85-0.91 (m, 2H), 1.42-1.66 (m, 11H), 1.85-2.01 (m, 6H), 2.09-2.18 (m, 2H), 3.18 (s, 3H), 3.43-3.51 (m, 1H), 3.74-3.87 (m, 1H), 4.09-4.37 (m, 2H), 5.11-5.19 (m, 1H), 8.18 (d, = 1.26 Hz, 1H), 8.78 (d, = 1.26 Hz, 1H).
Example 1.62: Preparation of (lfl,3s,5S)-Isopropyl 3-((lr,4fl)-4-(5- (methylsulfonyl)pyrazin-2-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 62).
To a mixture of (lR,3s,5S)-3-((lr,4R)-4-(5-(methylsulfonyl)pyrazin-2- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane hydrochloride (0.02 g, 47.85 μιηοΐ) in CH2C12 (0.479 mL), triethylamine (33.90 mg, 0.335 mmol) and isopropyl carbonochloridate (57.42 μΐ, 57.42 μιηο1)-1Μ in toluene were added at room temperature. The reaction was stirred for 16 h and then loaded on a TLC plate and eluted with 50% EtOAc in hexanes to give the title compound (14.3mg, 30.58 μιηοΐ, 63.9%). Exact mass calculated for C22H33N3O6S: 467.2, found: LCMS m/z = 468.6 [M+H]+; lU NMR (400 MHz, CDC13) δ ppm 1.25 (d, = 6.32 Hz, 6H), 1.43- 1.71 (m, 8H), 1.87-2.02 (m, 6H), 2.09-2.18 (m, 2H), 3.18 (s, 3H), 3.44-3.52 (m, 1H), 3.79-3.88 (m, 1H), 4.20-4.38 (m, 2H), 4.87-4.98 (m, 1H), 5.11-5.19 (m, 1H), 8.18 (d, = 1.26 Hz, 1H), 8.78 (d, = 1.26 Hz, 1H).
Example 1.63: Preparation of (l/?,3s,5S)-8-(5-Ethylpyrimidin-2-yl)-3-((lr,4/?)-4-(5- (methylsulfonyl)pyrazin-2-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane (Compound 63).
To a mixture of (lR,3s,5S)-3-((lr,4R)-4-(5-(methylsulfonyl)pyrazin-2- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane hydrochloride (0.02 g, 47.85 μιηοΐ) and triethylamine (66.70 μΐ, 0.479 mmol) in IPA (0.80 mL), 2-chloro-5-ethylpyrimidine (11.62 μΐ, 95.71 μιηοΐ) was added and the reaction was heated to 100 °C for 16 h. The reaction was concentrated to dryness, taken up in DCM, and loaded on a TLC plate. The desired compound was eluted with 50% EtOAc in hexanes. This partially purified material was triturated with EtOAc and hexanes to give the title compound (7.4 mg, 15.18 μιηοΐ, 31.7%). Exact mass calculated for C24H33N5O4S: 487.2, found: LCMS m/z = 488.4 [M+H]+; lU NMR (400 MHz, CDCI3) δ ppm 1.20 (t, = 7.58 Hz, 3H), 1.40-1.80 (m, 8H), 1.90-2.01 (m, 4H), 2.04-2.16 (m, 4H), 2.47 (q, = 7.58 Hz, 2H), 3.18 (s, 3H), 3.45-3.54 (m, IH), 3.91-4.01 (m, IH), 4.69-4.75 (m, 2H), 5.09-5.17 (m, IH), 8.18 (s, 3H), 8.77 (d, = 1.26 Hz, IH).
Example 1.64: Preparation of 3-Isopropyl-5-((lfl,3s,5S)-3-((lr,4fl)-4-(5- (methylsulfonyl)pyrazin-2-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octan-8-yl)-l,2,4- oxadiazole (Compound 67).
To a mixture of (lR,3s,5S)-3-((lr,4R)-4-(5-(methylsulfonyl)pyrazin-2- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carbonitrile (0.05 g, 0.123 mmol) and (Z)- N'-hydroxyisobutyrimidamide (25.13 mg, 0.246 mmol) in CH2C12 (1.5 mL), zinc(II) chloride (0.492 mL, 0.246 mmol)-0.5M in THF was added. The reaction was stirred at room temperature for 2 h then 4M HCL in dioxane (0.20 mL) was added. The reaction was warmed to 100 °C and stirred for 1 h. The reaction was concentrated to dryness, taken up in EtOAc, and washed with water. The EtOAc layer was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by reverse phase HPLC to give the title compound (3.5mg) as a colorless foam/film. Exact mass calculated for C24H33N5O4S: 491.2, found: LCMS mJz = 492.4 [M+H]+; lU NMR (500 MHz, CDC13) δ ppm 1.31 (d, = 6.90 Hz, 6H), 1.42-1.53 (m, 2H), 1.55-1.64 (m, 2H), 1.67-1.75 (m, 2H), 1.76-1.82 (m, 2H), 1.93-2.04 (m, 4H), 2.08-2.16 (m, 4H), 2.90-2.99 (m, IH), 3.18 (s, 3H), 3.46-3.53 (m, IH), 3.85-3.94 (m, IH), 4.46 (br s, 2H), 5.12-5.19 (m, IH), 8.19 (s, IH), 8.78 (s, IH).
Example 1.65: Preparation of (lR,3s,5S)-tert-Butyl 3-((lr,4fl)-4-(pyrimidin-4- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 64).
To a solution of (lR,3s,5S)-tert-butyl 3-((lr,4R)-4-hydroxycyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (50 mg, 0.154 mmol) and 4-chloropyrimidine (21.12 mg, 0.184 mmol) in THF (2 mL) at room temperature was added 1 M potassium teri-butoxide in THF (0.399 mL, 0.399 mmol). The mixture was stirred at room temperature for 30 min. The reaction was quenched with water and extracted with CH2C12 (twice) and CH2C12/IPA (8:2) (twice). Organic layers were concentrated in vacuo to dryness and purified by Biotage™ column chromatography and semi-preparative HPLC. Fractions were neutralized with saturated sodium bicarbonate (aq) and concentrated in vacuo to remove MeCN. The solid was collected by vacuum filtration to give the title compound (51.5 mg, 0.128 mmol, 83.1%). Exact mass calculated for C22H33N304: 403.3, found: LCMS m/z = 404.6 [M+H]+; lU NMR (400 MHz, CDCI3) δ ppm 1.47 (s, 9H), 1.40-1.63 (m, 8H), 1.88-1.96 (m, 6H), 2.11-2.15 (m, 2H), 3.41-3.48 (m, IH), 3.79-3.87 (m, IH), 4.19-4.28 (m, 2H), 5.08-5.15 (m, IH), 6.66 (dd, = 5.81, 1.01 Hz, IH), 8.39 (d, = 5.81 Hz, IH), 8.74 (s, IH). Example 1.66: Preparation of (lfl,3s,5S)-Isopropyl 3-((lr,4/?)-4-(4- (methylsulfonyl)phenoxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate
(Compound 65).
To a solution of (lR,3*,55)-3-((l r,4R)-4-(4-(methylsulfonyl)phenoxy)cyclohexyloxy)-8- azabicyclo[3.2.1]octane hydrochloride (20 mg, 48.08 μιηοΐ) in CH2C12 (1 mL) at room temperature under nitrogen was added triethylamine (33.51 μΐ, 0.240 mmol), then 1 M isopropyl chloroformate in toluene (76.93 μΐ, 76.93 μιηοΐ) was added slowly. The reaction mixture was stirred at room temperature for 1 h and then concentrated. The residue was purified by silica gel column chromatography with 50% ethyl acetate/hexanes to give the title compound (19 mg, 40.81 μιηοΐ, 84.9%). Exact mass calculated for C24H35N06S: 465.2, found: LCMS mJz = 466.4 [M+H]+; lU NMR (400 MHz, CDC13) δ ppm 1.25 (d, 6H), 1.53-1.63 (m, 8H), 1.87-2.01 (m, 6H), 2.05-2.14 (m, 2H), 3.02 (s, 3H), 3.44-3.52 (m, 1H), 3.78-3.88 (m, 1H), 4.22-4.34 (m, 2H), 4.34-4.42 (m, 1H), 4.87-4.98 (m, 1H), 6.97-7.00 (m, 2H), 7.83-7.85 (m, 2H). Example 1.67: Preparation of (lfl,3s,5S)-l-Methylcyclopropyl 3-((lr,4fl)-4-(4-
(methylsulfonyl)phenoxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate
(Compound 66).
To a solution of (lR,3i,55)-3-((l r,4R)-4-(4-(methylsulfonyl)phenoxy)cyclohexyloxy)-8- azabicyclo[3.2.1]octane hydrochloride (20 mg, 48.08 μιηοΐ) in anhydrous DCM (1 mL) was added triethylamine (23.45 μΐ, 0.168 mmol). The reaction mixture was cooled down at ice-water bath, 2,5-dioxopyrrolidin-l-yl 1 -methylcyclopropyl carbonate (11.28 mg, 52.89 μιηοΐ) was added. The reaction mixture was slowly warmed to room temperature and stirred for 1 h and concentrated. The residue was purified by silica gel chromatography with 50% ethyl acetate/hexanes and then purified again by semi preparative HPLC (35-90% CH3CN/H20 with 0.1 % TFA). The combined fractions were neutralized with saturated NaHC03, partially concentrated, extracted with CH2C12 then concentrated to give the title compound (18 mg, 37.69 μιηοΐ, 78.4%). Exact mass calculated for Cz-OLsNOsS: 477.2, found: LCMS m/z = 478.4
[M+H]+; lU NMR (400 MHz, CDC13) δ ppm 0.59-0.66 (m, 2H), 0.84-0.91 (m, 2H), 1.38-1.70 (m, 11H), 1.85-2.02 (m, 6H), 2.04-2.15 (m, 2H), 3.02 (s, 3H), 3.43-3.52 (m, 1H), 3.75-3.88 (m, 1H), 4.12-4.40 (m, 2H), 4.32-4.42 (m, 1H), 6.96-7.01 (m, 2H), 7.81-7.87 (m, 2H).
Example 1.68: Preparation of (lfl,3s,5S)-Isopropyl 3-((lr,4fl)-4-(2-methyl-6- (methylsulfonyl)pyridin-3-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 68).
To a solution of (lR,3i,55)-3-((l r,4R)-4-(2-methyl-6-(methylsulfonyl)pyridin-3- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane hydrochloride (30 mg, 64.04 μιηοΐ) in CH2C12 (2 mL) at 0 °C under nitrogen was added triethylamine (44.63 μΐ, 0.320 mmol). After stirring for 3 min, 1 M isopropyl chloroformate in toluene (7.848 mg, 64.04 μιηοΐ) was added. The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo to dryness and purified by Biotage™ column chromatography and semi-preparative HPLC.
Fractions were neutralized with saturated sodium bicarbonate (aq) and concentrated in vacuo to remove MeCN and the solid was collected by vacuum filtration to give the title compound (17.6 mg, 36.62 μηιοΐ, 57.2%). Exact mass calculated for C^Hse^OeS: 480.2, found: LCMS mJz = 481.4 [M+H]+; lU NMR (400 MHz, CDC13) δ ppm 1.25 (d, = 6.32 Hz, 6H), 1.43-1.71 (m, 8H), 1.86-2.01 (m, 6H), 2.03-2.13 (m, 2H), 2.50 (s, 3H), 3.17 (s, 3H), 3.50-3.57 (m, 1H), 3.78-3.88 (m, 1H), 4.21-4.37 (m, 2H), 4.38-4.46 (m, 1H), 4.86-4.98 (m, 1H), 7.16 (d, = 8.59 Hz, 1H), 7.88 (d, 7 = 8.59 Hz, 1H).
Example 1.69: Preparation (lfl,3s,5S)-l-Methylcyclopropyl 3-((lr,4/?)-4-(2-methyl-6- (methylsulfonyl)pyridin-3-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 71).
To a solution of (lR,3i,55)-3-((lr,4R)-4-(2-methyl-6-(methylsulfonyl)pyridin-3- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane hydrochloride (30 mg, 64.04 μιηοΐ) in CH2C12 (2 mL) at 0 °C under nitrogen was added triethylamine (44.63 μΐ, 0.320 mmol). After stirring for 3 min, 2,5-dioxopyrrolidin-l-yl 1-methylcyclopropyl carbonate (17.75 mg, 83.25 μιηοΐ) was added. The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo to dryness and purified by Biotage™ column chromatography and semi- preparative HPLC. Fractions were neutralized with saturated sodium bicarbonate (aq) and concentrated in vacuo to remove MeCN and the solid was collected by vacuum filtration to give the title compound (20.7 mg, 42.02 μιηοΐ, 65.6%). Exact mass calculated for C25H36N206S: 492.2, found: LCMS m/z = 493.6 [M+H]+; lU NMR (400 MHz, CDC13) δ ppm 0.59-0.66 (m, 2H), 0.84-0.91 (m, 2H), 1.41-1.71 (m, 8H), 1.56 (s, 3H), 1.85-1.99 (m, 6H), 2.04-2.13 (m, 2H), 2.50 (s, 3H), 3.17 (s, 3H), 3.48-3.56 (m, 1H), 3.75-3.86 (m, 1H), 4.11-4.36 (m, 2H), 4.37-4.45 (m, 1H), 7.16 (d, 7 = 8.59 Hz, 1H), 7.88 (d, 7 = 8.59 Hz, 1H).
Example 1.70: Preparation of 3-(2-Fluoropropan-2-yl)-5-((l ?,3s,5S)-3-((lr,4/?)-4-(2- methyl-6-(methylsulfonyl)pyridin-3-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octan-8-yl)- 1,2,4-oxadiazole (Compound 72).
To a solution of (lR,3i,55)-3-((lr,4R)-4-(2-methyl-6-(methylsulfonyl)pyridin-3- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carbonitrile (50 mg, 0.119 mmol) and (Z)-2- fluoro-N'-hydroxy-2-methylpropanimidamide (25.77 mg, 0.215 mmol) in THF (1 mL) under nitrogen was added 0.5 M zinc(II) chloride in THF (0.477 mL, 0.238 mmol). The mixture was stirred at room temperature for 3 h. To the above solution was added THF (1 mL) and 4 N hydrogen chloride in dioxane (0.179 mL, 0.715 mmol). The mixture was heated at 120 °C for 2 h under microwave irradiation. The mixture was concentrated in vacuo to dryness and purified by semi-preparative HPLC. Fractions were neutralized with saturated sodium bicarbonate (aq) and concentrated in vacuo to remove MeCN and the solid was collected by vacuum filtration to give the title compound (45.5 mg, 87.06 μιηοΐ, 73.0%). Exact mass calculated for
C25H35FN4O5S: 522.2, found: LCMS m/z = 523.6 [M+H]+; lU NMR (400 MHz, CDC13) δ ppm 1.43-1.82 (m, 6H), 1.72 (s, 4H), 1.78 (s, 4H), 1.89-2.16 (m, 8H), 2.50 (s, 3H), 3.17 (s, 3H), 3.50- 3.59 (m, 1H), 3.83-3.94 (m, 1H), 4.38-4.46 (m, 1H), 4.45-4.52 (m, 2H), 7.16 (d, = 8.59 Hz, 1H), 7.88 (d, = 8.59 Hz, 1H).
Example 1.71: Preparation of 3-Isopropyl-5-((l ?,3s,5S)-3-((lr,4/?)-4-(4- (methylsulfonyl)phenoxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octan-8-yl)-l,2,4-oxadiazole (Compound 69).
To a mixture of (lR,3i,55)-3-((lr,4R)-4-(4-(methylsulfonyl)phenoxy)cyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carbonitrile (30 mg, 74.16 μιηοΐ) and (Z)-N'- hydroxyisobutyrimidamide (12.12 mg, 0.119 mmol) in CH2C12 (1 mL) was added 0.5 M zinc(II) chloride in THF (0.445 mL, 0.222 mmol) at room temperature under N2. The reaction was stirred overnight at room temperature. The mixture was concentrated, re -dissolved in ethanol (1 mL), 1.25 M HQ in ethanol (0.593 mL, 0.742 mmol) was added. The reaction mixture was heated at 80 °C for 2 h, diluted with water, neutralized with saturated NaHC03, extracted with ethyl acetate. Organic layers were dried, filtered and concentrated. The residue was purified by silica gel column chromatography with 60% ethyl acetate/hexanes to give the title compound (23 mg, 46.97 μιηοΐ, 63.3%). Exact mass calculated for C25H35N3O5S: 489.2, found: LCMS m/z = 490.4 [M+H]+; lU NMR (400 MHz, CDC13) δ ppm 1.30 (d, = 7.07 Hz, 6H), 1.38-1.64 (m, 3H), 1.66-1.81 (m, 4H), 1.92-2.02 (m, 4H), 2.04-2.15 (m, 4H), 2.91 (quin, = 7.07 Hz, 1H), 3.02 (s, 3H), 3.45-3.54 (m, 2H), 3.82-3.93 (m, 1H), 4.34-4.42 (m, 1H), 4.41-4.45 (m, 2H), 6.91- 7.01 (m, 2H), 7.81-7.87 (m, 2H).
Example 1.72: Preparation of 5-((l ?,3s,5S)-3-((lr,4/?)-4-(4- (Methylsulfonyl)phenoxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octan-8-yl)-3- (trifluoromethyl)-l,2,4-oxadiazole (Compound 70).
To a mixture of (lR,3i,55)-3-((lr,4R)-4-(4-(methylsulfonyl)phenoxy)cyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carbonitrile (60 mg, 0.148 mmol) and (Z)-2,2,2-trifluoro-N'- hydroxyacetimidamide (1.216 g, 0.237 mmol) in CH2C12 (2 mL) was added 0.5 M zinc(II) chloride in THF (0.890 mL, 0.445 mmol) at room temperature under N2. The reaction was stirred overnight at 40 °C. The mixture was concentrated, redissolved in ethanol (1 mL), 1.25 M HC1 in ethanol (1.187 mL, 1.483 mmol) was added. The reaction mixture was heated at 80 °C for 2 h. Reaction was purified by semi preparative HPLC (35-90% CH3CN/H20 with 0.1% TFA). Fractions were neutralized with saturated NaHC03, partially concentrated. The white solid was collected and dried to give the title compound (2.5 mg, 4.8 μιηοΐ, 3.3%). Exact mass calculated for CzsH^^OsS: 515.2, found: LCMS mJz = 516.4 [M+H]+; lU NMR (400 MHz, CDC13) δ ppm 1.40-1.50 (m, 2H), 1.52-1.64 (m, 2H), 1.67-1.76 (m, 2H), 1.80-1.87 (m, 2H), 1.92-2.01 (m, 2H), 2.02-2.12 (m, 4H), 2.12-2.18 (m, 2H), 3.02 (s, 3H), 3.46-3.54 (m, 1H), 3.85- 3.96 (m, 1H), 4.36-4.43 (m, 1H), 4.48-4.54 (m, 2H), 6.95-7.01 (m, 2H), 7.81-7.87 (m, 2H).
Example 1.73: Preparation of 3-Isopropyl-5-((l ?,3s,5S)-3-((lr,4/?)-4-(2-methyl-6- (methylsulfonyl)pyridin-3-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octan-8-yl)-l,2,4- oxadiazole (Compound 73).
To a solution of (lR,3i,55)-3-((lr,4R)-4-(2-methyl-6-(methylsulfonyl)pyridin-3- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carbonitrile (50 mg, 0.119 mmol) and (Z)- N'-hydroxyisobutyrimidamide (21.91 mg, 0.215 mmol) in THF (1 mL) under nitrogen was added 0.5 M zinc(II) chloride in THF (0.477 mL, 0.238 mmol). The mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo to dryness. To the above residue were added EtOH (2 mL) and 1.25 N-hydrogen chloride in EtOH (0.953 mL, 1.192 mmol). The mixture was heated at 80 °C for 5 h. The mixture was concentrated in vacuo to dryness and purified by semi-preparative HPLC. Fractions were neutralized with saturated sodium bicarbonate (aq), concentrated in vacuo to remove MeCN, and the solid was collected by vacuum filtration to give the title compound (44.2 mg, 87.59 μιηοΐ, 73.5%). Exact mass calculated for Czs^N^S: 504.2, found: LCMS m/z = 505.4 [M+H]+; lU NMR (400 MHz, CDCI3) δ ppm 1.30 (d, = 6.82 Hz, 6H), 1.43-1.54 (m, 2H), 1.55-1.80 (m, 6H), 1.90-2.02 (m, 4H), 2.02-2.14 (m, 4H), 2.50 (s, 3H), 2.91 (sep, = 6.82 Hz, 1H), 3.17 (s, 3H), 3.51-3.58 (m, 1H), 3.83-3.92 (m, 1H), 4.38-4.46 (m, 3H), 7.16 (d, = 8.59 Hz, 1H), 7.88 (d, = 8.59 Hz, 1H).
Example 1.74: Preparation of 5-((l ?,3s,5S)-3-((lr,4/?)-4-(2-Methyl-6- (methylsulfonyl)pyridin-3-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octan-8-yl)-3- (trifluoromethyl)-l,2,4-oxadiazole (Compound 75).
To a solution of (lR,3i,55)-3-((lr,4R)-4-(2-methyl-6-(methylsulfonyl)pyridin-3- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carbonitrile (50 mg, 0.119 mmol) and (Z)- 2,2,2-trifluoro-N'-hydroxyacetimidamide (28.17 mg, 0.215 mmol) in THF (2 mL) under nitrogen was added 0.5 M zinc(II) chloride in THF (0.477 mL, 0.238 mmol). The mixture was stirred at room temperature for 4 h. To the above solution was added 4 N hydrogen chloride in dioxane (0.179 mL, 0.715 mmol), and the mixture was heated at 120 °C for 8 h under microwave irradiation. The mixture was quenched with saturated sodium bicarbonate (aq) and extracted with CH2C12 (twice). The organic layers were concentrated in vacuo to dryness and purified by semi-preparative HPLC. Fractions were neutralized with saturated sodium bicarbonate (aq), evaporated MeCN, and the solid was collected by vacuum filtration to give the title compound (25.5 mg, 48.06 μιηοΐ, 40.3%). Exact mass calculated for C23H29F3N4O5S: 530.2, found: LCMS mJz = 531.4 [M+H]+; lU NMR (400 MHz, CDC13) δ ppm 1.43-1.58 (m, 2H), 1.58-1.67 (m, 2H), 1.67-1.77 (m, 2H), 1.79-1.87 (m, 2H), 1.88-1.99 (m, 2H), 2.01-2.12 (m, 4H), 2.12-2.19 (m, 2H), 2.50 (s, 3H), 3.17 (s, 3H), 3.52-3.59 (m, 1H), 3.86-3.96 (m, 1H), 4.40-4.47 (m, 1H), 4.48-4.54 (m, 2H), 7.16 (d, = 8.59 Hz, 1H), 7.88 (d, = 8.59 Hz, 1H).
Example 1.75: Preparation of 3-(2-Fluoropropan-2-yl)-5-((l ?,3s,5S)-3-((lr,4/?)-4-(4- (methylsulfonyl)phenoxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octan-8-yl)-l,2,4-oxadiazole (Compound 74).
To a mixture of (lR,3i,55)-3-((lr,4R)-4-(4-(methylsulfonyl)phenoxy)cyclohexyloxy)-8- azabicyclo[3.2.1]octane-8-carbonitrile (50 mg, 0.124 mmol) and (Z)-2-fluoro-N'-hydroxy-2- methylpropanimidamide (23.76 mg, 0.198 mmol) in THF (1.5 mL) was added 0.5 M zinc(II) chloride in THF (0.742 mL, 0.371 mmol) at room temperature under N2. The reaction mixture was stirred overnight at room temperature. Crude LCMS showed complete conversion to the intermediate. 4 M HC1 in dioxane (0.309 mL, 1.236 mmol) was then added. The reaction was heated at 120 °C for 2 h under microwave irradiation. The mixture was purified by semi preparative HPLC (35-90% CH3CN/H20 with 0.1% TFA). The combined fractions were neutralized with saturated NaHC03, partially concentrated. The white solid was collected and dried to give the title compound (34 mg, 66.98 μιηοΐ, 54.2%). Exact mass calculated for
C25H34FN3O5S: 507.2, found: LCMS m/z = 508.4 [M+H]+; lU NMR (400 MHz, CDC13) δ ppm 1.40-1.50 (m, 2H), 1.52-1.64 (m, 2H), 1.68-1.81 (m, 10H), 1.92-2.04 (m, 4H), 2.04-2.14 (m, 4H), 3.02 (s, 3H), 3.46-3.53 (m, 1H), 3.84-3.93 (m, 1H), 4.35-4.42 (m, 1H), 4.45-4.50 (m, 2H), 6.96-7.01 (m, 2H), 7.81-7.86 (m, 2H).
Example 2: In vivo Effects of a Compound of the Present Invention on Incretin Hormone GIP release.
Male 129SVE mice (approximately 8-week old) were fasted for 18 h and randomly grouped (n = 6) to receive a GPR119 agonist (Compound 5) at 3 mpk and 30 mpk dose (mg/kg body weight). Compounds were delivered orally via a gavage needle (p.o., volume 4 mL/kg), and after 45 min a blood sample was collected to determine plasma total GIP levels. A separate group received vehicle (PET: 80%PEG: 10%Ethanol: 10%Tween80™) as control. Plasma GIP levels were determined using a Total GIP ELISA kit from Millipore. The results are given in Figure 1 and Table 1. Table 1 (Total Plasma GIP in Mice)
Figure imgf000139_0002
Example 3: In vivo effects of a Representative Compound of the Present Invention on Glucose Homeostasis (oral glucose tolerance test (oGTT)) in male 129SVE mice.
Male 129SVE mice (approximately 8-week old) were fasted for 18 h and randomly grouped (n = 6) to receive a GPR119 agonist (Compound 5) at 3, or 30 mg/kg (mg/kg body weight). The compound was delivered orally via a gavage needle (p.o., volume 4 mL/kg) 30 minutes prior to glucose bolus (3g/kg) (time = -30 min in Figure 2), with a separate group receiving vehicle (20% hydroxypropyl-beta-cyclodextrin) as control. At time 0 min. the glucose bolus was administered. Levels of blood glucose were assessed using a glucometer (One -Touch Ultra™, LifeScan) at time -30 minute (prior to compound administration), at 0 min (at time when glucose bolus was given), and at 20, 40, 60, 120 minutes post glucose bolus. The plasma glucose and excursion curve are shown in Table 2 and Figure 2 respectively. Glucose excursion AUC (area under the curve) reduction in compound treated animals relative to vehicle control is given in Figure 3, and in Table 3.
Table 2 (Plasma glucose levels)
Figure imgf000139_0003
Table 3 (Glycemic Suppression in oGTT in Mice)
Figure imgf000139_0001
Example 4: Homogeneous Time-Resolved Fluorescence (HTRF®) Assay For Direct cAMP Measurement.
GPR119 agonists were evaluated in an HTRF® cAMP detection assay according to the manufacturer's instructions (Cisbio, cAMP Dynamic 2 Assay Kit; #62AM4PEJ) using CHO-K1 cells stably expressing the GPR119 receptor. Briefly, CHO-K1 cells were transduced with a lenti viral vector encoding the nucleotide sequence of GPR119 (NCBI mRNA and protein reference sequences: NM_178471.2 & NP_848566, (GPR119 has also been referred to as Glucose-Dependent Insulinotropic Receptor (GDIR)). The N-terminus of the GPR119 nucleotide sequence was modified to replace the first, methionine -coding codon with a nucleotide sequence coding for a standard, nine amino acid, hemagglutinin tag. Following transduction, cells expressing the GPR119 receptor were isolated and a single clone was isolated following standard dilution-cloning procedures. On the day of the assay, cultured CHO-GPR119 cells were harvested, suspended in assay buffer and plated into 384-well assay plates
(PerkinElmer Proxiplate #6008280) at a density of 2,000 cells per well. A cAMP standard curve was added to each plate. Test compounds were solubilized in DMSO, serially diluted in DMSO and then diluted in assay buffer before adding to the cells. Test compounds were evaluated in triplicate, using 10-point, 5-fold serial dilutions starting at 10 μΜ. The final DMSO
concentration in the assay was 0.5%. Compounds and cells were incubated for 1 h at room temperature and then detection reagents were added to each well (cAMP-D2 in cell lysis buffer, followed by europium cryptate -labeled anti-cAMP antibody). Plates were then incubated at room temperature for 1 h prior to reading. Time -resolved fluorescence measurements were collected on PerkinElmer Envision™ or BMG Pherastar™ microplate readers. The compound N-(2-fluoro-4-(methylsulfonyl) phenyl)-6-(4-(3-isopropyl-l,2,4-oxadiazol-5-yl)piperidin-l-yl)- 5-nitropyrimidin-4-amine was used as a positive control in each runset while assay buffer containing 0.5% DMSO was used as the negative control. The HTRF® assay was used to determine EC50 values for GPR119 agonists. Certain representative compounds of the present invention and their corresponding EC50 values are shown in Table B.
Table B
Figure imgf000140_0001
Each of the Compounds 1 to 75 as shown in Table A was observed to have an hGPR119 EC50 value ranging from about 0.5 nM to about 100 μΜ. Those skilled in the art will recognize that various modifications, additions, and substitutions to the illustrative examples set forth herein can be made without departing from the spirit of the invention and are, therefore, considered within the scope of the invention.
Citation of any reference throughout this application is not to be construed as an admission that such reference is prior art to the present application.

Claims

We claim:
1. A compound selected from compounds of Formula (I) and pharmaceutically acceptable salts, solvates, hydrates,
Figure imgf000142_0001
wherein:
Ar is selected from: aryl and heteroaryl; each optionally substituted with one or more substituents selected from: Ci-C6 alkyl, C1-C4 alkylcarboxamide, Ci-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, heterocyclylsulfonyl, C1-C6 alkylthio, carboxamide, cyano, C3-C7 cycloalkylsulfinyl, C3-C7 cycloalkylsulfonyl, C3-C7 cycloalkylthio, C2-C8 dialkylcarboxamide, C1-C6 haloalkyl, halogen, and heteroaryl; wherein said C1-C6 alkyl is optionally substituted with one or more substituents selected from: C1-C6 alkoxy, hydroxyl, cyano, C2-C6 dialkylamino, and heterocyclyl; and
R1 is selected from: C1-C6 alkoxycarbonyl, C3-C7 cycloalkoxycarbonyl, and heteroaryl; each optionally substituted with one or more substituents selected from: d- (, alkyl, C1-C6 haloalkyl, and halogen.
2. The compound according to claim 1 , selected from compounds of Formula (lb) and pharmaceutically accept N-oxides thereof:
Figure imgf000142_0002
(lb)
3. The compound according to claim 1 or 2, wherein Ar is selected from: phenyl and
heteroaryl; each optionally substituted with one or more substituents selected from: Q- C6 alkyl, Ci-C6 alkylsulfonyl, heterocyclylsulfonyl, cyano, C3-C7 cycloalkylsulfonyl, C2-C8 dialkylcarboxamide, Ci-C6 haloalkyl, halogen, and heteroaryl; wherein said Ci-C6 alkyl is optionally substituted with one or more substituents selected from: Ci-C6 alkoxy, hydroxyl, cyano, C2-C6 dialkylamino, and heterocyclyl.
4. The compound according to claim 1 or 2, wherein Ar is selected from: pyridin-4-yl, pyridin-2-yl, phenyl, thieno[3,2-c]pyridin-4-yl, furo[3,2-c]pyridin-4-yl, pyrimidin-2-yl, pyridin-3-yl, l ,6-naphthyridin-4-yl, pyrazin-2-yl, isoquinolin-8-yl, quinoxalin-2-yl, benzo[d]thiazol-2-yl, lH-pyrazol-5-yl, thieno[3,2-d]pyrimidin-4-yl, and pyrimidin-4-yl; each optionally substituted with one or more substituents selected from: Ci-C6 alkyl, Q- C6 alkylsulfonyl, heterocyclylsulfonyl, cyano, C3-C7 cycloalkylsulfonyl, C2-C8 dialkylcarboxamide, Ci-C6 haloalkyl, halogen, and heteroaryl; wherein said Ci-C6 alkyl is optionally substituted with one or more substituents selected from: Ci-C6 alkoxy, hydroxyl, cyano, C2-C6 dialkylamino, and heterocyclyl.
5. The compound according to claim 1 or 2, wherein Ar is selected from: phenyl and
heteroaryl; each optionally substituted with one or more substituents selected from: cyano, fluoro, methyl, bromo, methylsulionyl, chloro, 2-methoxyethyl, lH-l ,2,4-triazol- 1-yl, trifluoromethyl, 2-hydroxyethyl, 2-cyanoethyl, 2-(dimethylamino)ethyl, 2- morpholinoethyl, lH-tetrazol-l-yl, oxetan-3-ylsulfonyl, cyclopropylsulfonyl, pyridazin- 4-yl, and dimethylcarbamoyl.
6. The compound according to claim 1 or 2, wherein Ar is selected from: pyridin-4-yl, pyridin-2-yl, phenyl, thieno[3,2-c]pyridin-4-yl, furo[3,2-c]pyridin-4-yl, pyrimidin-2-yl, pyridin-3-yl, l ,6-naphthyridin-4-yl, pyrazin-2-yl, isoquinolin-8-yl, quinoxalin-2-yl, benzo[d]thiazol-2-yl, lH-pyrazol-5-yl, thieno[3,2-d]pyrimidin-4-yl, and pyrimidin-4-yl; each optionally substituted with one or more substituents selected from: cyano, fluoro, methyl, bromo, methylsulionyl, chloro, 2-methoxyethyl, lH-l ,2,4-triazol-l-yl, trifluoromethyl, 2-hydroxyethyl, 2-cyanoethyl, 2-(dimethylamino)ethyl, 2- morpholinoethyl, lH-tetrazol-l-yl, oxetan-3-ylsulfonyl, cyclopropylsulfonyl, pyridazin- 4-yl, and dimethylcarbamoyl.
7. The compound according to claim 1 or 2, wherein Ar is selected from: 3-cyanopyridin- 4-yl, 3,5-difluoropyridin-4-yl, 3-cyano-5-methylpyridin-4-yl, 3-cyano-5-fluoropyridin- 4-yl, 3-cyano-5-fluoropyridin-2-yl, 4-bromo-2-cyanophenyl, 2,4-dicyanophenyl, 2- cyano-4-(methylsulfonyl)phenyl, thieno[3,2-c]pyridin-4-yl, furo[3,2-c]pyridin-4-yl, 5- bromopyrimidin-2-yl, 4-chloro-2-cyanophenyl, 2-fluoro-4-(methylsulfonyl)phenyl, 5- (methylsulfonyl)pyridin-3-yl, 2-cyano-4-fluorophenyl, 4-(2-methoxyethyl)phenyl, 1 ,6- naphthyridin-4-yl, pyridin-4-yl, 5-(lH-l ,2,4-triazol-l -yl)pyrazin-2-yl, 2-methyl-6-(lH- l ,2,4-triazol-l-yl)pyridin-3-yl, isoquinolin-8-yl, 5-(trifluoromethyl)pyridin-2-yl, quinoxalin-2-yl, 4-cyanopyridin-2-yl, 4-(2-hydroxyethyl)phenyl, 4-bromo-3- fluorophenyl, 5-cyanopyridin-2-yl, 4-(2-cyanoethyl)phenyl, benzo[d]thiazol-2-yl, 5- (methylsulfonyl)pyrimidin-2-yl, 4-(2-(dimethylamino)ethyl)phenyl, 4-(2- mo holinoethyl)phenyl, 1 -methyl-3 -(trifluoromethyl)- lH-pyrazol-5 -yl, 3 - cyanopyridin-2-yl, thieno[3,2-d]pyrimidin-4-yl, 4-(lH-tetrazol-l -yl)phenyl, 4-(2- methyl-6-(oxetan-3-ylsulfonyl)pyridin-3-yl, 4-(6-(cyclopropylsulfonyl)-2- methylpyridin-3-yl, 2-cyanopyridin-3-yl, 5-bromo-3-methylpyrazin-2-yl, 3-methyl-5- (methylsulfonyl)pyrazin-2-yl, 6-(trifluoromethyl)pyridin-3-yl, 4-cyanopyridin-3-yl, 5- cyanopyrimidin-4-yl, 4-cyano-2,6-difluorophenyl, 2-methyl-6-(pyridazin-4-yl)pyridin- 3-yl, 4-(dimethylcarbamoyl)-2 -fluorophenyl, 5-(methylsulfonyl)pyridin-2-yl, 2-methyl- 6-(methylsulfonyl)pyridin-3-yl, 3-fluoro-4-(lH-l,2,4-triazol-l-yl)phenyl, 5-
(methylsulfonyl)pyrazin-2-yl, 5 -(dimethylcarbamoyl)pyridin-2-yl, 4- (methylsulfonyl)phenyl, and pyrimidin-4-yl.
The compound according to any one of claims 1 to 7, wherein R1 is selected from: C1-C6 alkoxycarbonyl, C3-C7 cycloalkoxycarbonyl, and heteroaryl; each optionally substituted with one or more substituents selected from: chloro, ethyl, fluoro, 2-fluoropropan-2-yl, isopropyl, methyl, and trifluoromethyl.
The compound according to any one of claims 1 to 7, wherein R1 is selected from: tert- butoxycarbonyl, isopropoxycarbonyl, cyclopropoxycarbonyl, 1 ,2,4-oxadiazolyl, and pyrimidin-2-yl; each optionally substituted with one or more substituents selected from: chloro, ethyl, fluoro, 2-fluoropropan-2-yl, isopropyl, methyl, and trifluoromethyl.
10. The compound according to any one of claims 1 to 7, wherein R1 is heteroaryl
optionally substituted with one or more substituents selected from: Ci-C6 alkyl, Ci-C6 haloalkyl, and halogen.
11. The compound according to any one of claims 1 to 7, wherein R1 is selected from:
1 ,2,4-oxadiazolyl and pyrimidin-2-yl; each optionally substituted with one or more substituents selected from: C1-C6 alkyl, C1-C6 haloalkyl, and halogen.
12. The compound according to any one of claims 1 to 7, wherein R is selected from:
1 ,2,4-oxadiazolyl and pyrimidin-2-yl; each optionally substituted with one or more substituents selected from: chloro, ethyl, isopropyl, trifluoromethyl, and 2-fluoropropan- 2-yl.
13. The compound according to any one of claims 1 to 7, wherein R1 is selected from: C1-C6 alkoxycarbonyl, and C3-C7 cycloalkoxycarbonyl; each optionally substituted with one or more substituents selected from: halogen and Ci-C6 alkyl.
14. The compound according to any one of claims 1 to 7, wherein R1 is selected from: Ci-C6 alkoxycarbonyl, and C3-C7 cycloalkoxycarbonyl; each optionally substituted with one or more substituents selected from: fluoro and methyl.
15. The compound according to any one of claims 1 to 7, wherein R1 is selected from: tert- butoxycarbonyl, isopropoxycarbonyl, and cyclopropoxycarbonyl; each optionally substituted with one or more substituents selected from: fluoro and methyl.
16. The compound according to any one of claims 1 to 7, wherein R1 is selected from: tert- butoxycarbonyl, (l,l,l-trifluoropropan-2-yloxy)carbonyl, 5-chloropyrimidin-2-yl, (1- methylcyclopropoxy)carbonyl, isopropoxycarbonyl, 5-ethylpyrimidin-2-yl, 3-isopropyl- l,2,4-oxadiazol-5-yl, 3-(trifluoromethyl)-l,2,4-oxadiazol-5-yl, and 3-(2-fluoropropan-2- yl)-l,2,4-oxadiazol-5-yl.
17. The compound according to claim 1 or 2, selected from compounds of Formula (lb) and pharmaceutically accept N-oxides thereof:
Figure imgf000145_0001
(lb)
wherein:
Ar is selected from: phenyl and heteroaryl; each optionally substituted with one or more substituents selected from: C1-C6 alkyl, C1-C6 alkylsulfonyl,
heterocyclylsulfonyl, cyano, C3-C7 cycloalkylsulfonyl, C2-C8 dialkylcarboxamide, C1-C6 haloalkyl, halogen, and heteroaryl; wherein said C1-C6 alkyl is optionally substituted with one or more substituents selected from: C1-C6 alkoxy, hydroxyl, C2-C6
dialkylamino, and heterocyclyl; and
R1 is selected from: C1-C6 alkoxycarbonyl, C3-C7 cycloalkoxycarbonyl, and heteroaryl; each optionally substituted with one or more substituents selected from: chloro, ethyl, fluoro, 2-fluoropropan-2-yl, isopropyl, methyl, and trifluoromethyl.
18. The compound according to claim 1 or 2, selected from compounds of Formula (lb) and pharmaceutically accept N-oxides thereof:
Figure imgf000145_0002
(lb)
wherein: Ar is selected from: phenyl and heteroaryl; each optionally substituted with one or more substituents selected from: cyano, fluoro, methyl, bromo, methylsulfonyl, chloro, 2-methoxyethyl, lH-l,2,4-triazol-l-yl, trifluoromethyl, 2-hydroxyethyl, 2- (dimethylamino)ethyl, 2-morpholinoethyl, lH-tetrazol-l-yl, oxetan-3-ylsulfonyl, cyclopropylsulfonyl, pyridazin-4-yl, and dimethylcarbamoyl; and
R1 is selected from: C1-C6 alkoxycarbonyl, C3-C7 cycloalkoxycarbonyl, and heteroaryl; each optionally substituted with one or more substituents selected from: chloro, ethyl, fluoro, 2-fluoropropan-2-yl, isopropyl, methyl, and trifluoromethyl.
The compound according to claim 1 or 2, selected from compounds of Formula (lb) and pharmaceutically accept N-oxides thereof:
Figure imgf000146_0001
(lb)
wherein:
Ar is selected from: pyridin-4-yl, pyridin-2-yl, phenyl, thieno[3,2-c]pyridin-4- yl, furo[3,2-c]pyridin-4-yl, pyrimidin-2-yl, pyridin-3-yl, l,6-naphthyridin-4-yl, pyrazin- 2-yl, isoquinolin-8-yl, quinoxalin-2-yl, benzo[d]thiazol-2-yl, lH-pyrazol-5-yl, thieno[3,2-d]pyrimidin-4-yl, and pyrimidin-4-yl; each optionally substituted with one or more substituents selected from: Ci-C6 alkyl, Ci-C6 alkylsulfonyl, heterocyclylsulfonyl, cyano, C3-C7 cycloalkylsulfonyl, C2-C8 dialkylcarboxamide, Ci-C6 haloalkyl, halogen, and heteroaryl; wherein said C1-C6 alkyl is optionally substituted with one or more substituents selected from: C1-C6 alkoxy, hydroxyl, C2-C6 dialkylamino, and heterocyclyl; and
R1 is selected from: C1-C6 alkoxycarbonyl, C3-C7 cycloalkoxycarbonyl, and heteroaryl; each optionally substituted with one or more substituents selected from: chloro, ethyl, fluoro, 2-fluoropropan-2-yl, isopropyl, methyl, and trifluoromethyl.
The compound according to claim 1 or 2, selected from compounds of Formula (If) and pharmaceutically accept N-oxides thereof:
Figure imgf000146_0002
(If)
wherein:
Ar is selected from: phenyl and heteroaryl; each optionally substituted with one or more substituents selected from: Ci-C6 alkyl, Ci-C6 alkylsulfonyl,
heterocyclylsulfonyl, cyano, C3-C7 cycloalkylsulfonyl, C2-C8 dialkylcarboxamide, C1-C6 haloalkyl, halogen, and heteroaryl; wherein said Ci-C6 alkyl is optionally substituted with one or more substituents selected from: Ci-C6 alkoxy, hydroxyl, C2-C6 dialkylamino, and heterocyclyl; and
R1 is selected from: Ci-C6 alkoxycarbonyl, C3-C7 cycloalkoxycarbonyl, and heteroaryl; each optionally substituted with one or more substituents selected from: chloro, ethyl, fluoro, 2-fluoropropan-2-yl, isopropyl, methyl, and trifluoromethyl.
The compound according to claim 1 or 2, selected from compounds of Formula (If) and pharmaceutically accept N-oxides thereof:
Figure imgf000147_0001
(If)
wherein:
Ar is selected from: phenyl and heteroaryl; each optionally substituted with one or more substituents selected from: cyano, fluoro, methyl, bromo, methylsulfonyl, chloro, 2-methoxyethyl, lH-l,2,4-triazol-l-yl, trifluoromethyl, 2-hydroxyethyl, 2- (dimethylamino)ethyl, 2-morpholinoethyl, lH-tetrazol-l-yl, oxetan-3-ylsulfonyl, cyclopropylsulfonyl, pyridazin-4-yl, and dimethylcarbamoyl; and
R1 is selected from: Ci-C6 alkoxycarbonyl, C3-C7 cycloalkoxycarbonyl, and heteroaryl; each optionally substituted with one or more substituents selected from: chloro, ethyl, fluoro, 2-fluoropropan-2-yl, isopropyl, methyl, and trifluoromethyl.
The compound according to claim 1 or 2, selected from compounds of Formula (If) and pharmaceutically accept N-oxides thereof:
Figure imgf000147_0002
(If)
wherein:
Ar is selected from: pyridin-4-yl, pyridin-2-yl, phenyl, thieno[3,2-c]pyridin-4- yl, furo[3,2-c]pyridin-4-yl, pyrimidin-2-yl, pyridin-3-yl, l,6-naphthyridin-4-yl, pyrazin- 2-yl, isoquinolin-8-yl, quinoxalin-2-yl, benzo[d]thiazol-2-yl, lH-pyrazol-5-yl, thieno[3,2-d]pyrimidin-4-yl, and pyrimidin-4-yl; each optionally substituted with one or more substituents selected from: Ci-C6 alkyl, Ci-C6 alkylsulfonyl, heterocyclylsulfonyl, cyano, C3-C7 cycloalkylsulfonyl, C2-C8 dialkylcarboxamide, Ci-C6 haloalkyl, halogen, and heteroaryl; wherein said Ci-C6 alkyl is optionally substituted with one or more substituents selected from: Ci-C6 alkoxy, hydroxyl, C2-C6 dialkylamino, and heterocyclyl; and R1 is selected from: Ci-C6 alkoxycarbonyl, C3-C7 cycloalkoxycarbonyl, and heteroaryl; each optionally substituted with one or more substituents selected from: chloro, ethyl, fluoro, 2-fluoropropan-2-yl, isopropyl, methyl, and trifluoromethyl.
The compound according to claim 1 or 2, selected from compounds of Formula (If) and pharmaceutically accept N-oxides thereof:
Figure imgf000148_0001
(If)
wherein:
Ar is selected from: pyridin-4-yl, pyridin-2-yl, phenyl, thieno[3,2-c]pyridin-4- yl, furo[3,2-c]pyridin-4-yl, pyrimidin-2-yl, pyridin-3-yl, l,6-naphthyridin-4-yl, pyrazin- 2-yl, isoquinolin-8-yl, quinoxalin-2-yl, benzo[d]thiazol-2-yl, lH-pyrazol-5-yl, thieno[3,2-d]pyrimidin-4-yl, and pyrimidin-4-yl; each optionally substituted with one or more substituents selected from: cyano, fluoro, methyl, bromo, methylsulfonyl, chloro, 2-methoxyethyl, lH-l,2,4-triazol-l-yl, trifluoromethyl, 2-hydroxyethyl, 2- (dimethylamino)ethyl, 2-morpholinoethyl, lH-tetrazol-l-yl, oxetan-3-ylsulfonyl, cyclopropylsulfonyl, pyridazin-4-yl, and dimethylcarbamoyl; and
R1 is selected from: teri-butoxycarbonyl, isopropoxycarbonyl, cyclopropoxycarbonyl, 1,2,4-oxadiazolyl, and pyrimidin-2-yl; each optionally substituted with one or more substituents selected from: chloro, ethyl, fluoro, 2- fluoropropan-2-yl, isopropyl, methyl, and trifluoromethyl.
24. The compound according to claim 1 or 2, selected from compounds of Formula (If) and pharmaceutically accept N-oxides thereof:
Figure imgf000148_0002
(If)
wherein:
Ar is selected from: 3-cyanopyridin-4-yl, 3,5-difluoropyridin-4-yl, 3-cyano-5- methylpyridin-4-yl, 3-cyano-5-fluoropyridin-4-yl, 3-cyano-5-fluoropyridin-2-yl, 4- bromo-2-cyanophenyl, 2,4-dicyanophenyl, 2-cyano-4-(methylsulfonyl)phenyl, thieno[3,2-c]pyridin-4-yl, furo[3,2-c]pyridin-4-yl, 5-bromopyrimidin-2-yl, 4-chloro-2- cyanophenyl, 2-fluoro-4-(methylsulfonyl)phenyl, 5-(methylsulfonyl)pyridin-3-yl, 2- cyano-4-fluorophenyl, 4-(2-methoxyethyl)phenyl, l,6-naphthyridin-4-yl, pyridin-4-yl, 5-( 1H- 1 ,2,4-triazol- 1 -yl)pyrazin-2-yl, 2-methyl-6-( 1 H- 1 ,2,4-triazol- 1 -yl)pyridin-3-yl, isoquinolin-8-yl, 5-(trifluoromethyl)pyridin-2-yl, quinoxalin-2-yl, 4-cyanopyridin-2-yl, 4-(2-hydroxyethyl)phenyl, 4-bromo-3-fluorophenyl, 5-cyanopyridin-2-yl, 4-(2- cyanoethyl)phenyl, benzo[d]thiazol-2-yl, 5-(methylsulfonyl)pyrimidin-2-yl, 4-(2- (dimethylamino)ethyl)phenyl, 4-(2-morpholinoethyl)phenyl, 1 -methyl-3- (trifluoromethyl)-lH-pyrazol-5-yl, 3-cyanopyridin-2-yl, thieno[3,2-d]pyrimidin-4-yl, 4- (lH-tetrazol-l-yl)phenyl, 4-(2-methyl-6-(oxetan-3-ylsulfonyl)pyridin-3-yl, 4-(6- (cyclopropylsulfonyl)-2-methylpyridin-3-yl, 2-cyanopyridin-3-yl, 5-bromo-3- methylpyrazin-2-yl, 3-methyl-5-(methylsulfonyl)pyrazin-2-yl, 6-
(trifluoromethyl)pyridin-3-yl, 4-cyanopyridin-3-yl, 5-cyanopyrimidin-4-yl, 4-cyano-2,6- difluorophenyl, 2-methyl-6-(pyridazin-4-yl)pyridin-3-yl, 4-(dimethylcarbamoyl)-2- fluorophenyl, 5-(methylsulfonyl)pyridin-2-yl, 2-methyl-6-(methylsulfonyl)pyridin-3-yl, 3-fluoro-4-(lH-l ,2,4-triazol-l-yl)phenyl, 5-(methylsulfonyl)pyrazin-2-yl, 5- (dimethylcarbamoyl)pyridin-2-yl, 4-(methylsulfonyl)phenyl, and pyrimidin-4-yl; and
R1 is selected from: teri-butoxycarbonyl, ( 1 ,1 , 1 -trifluoropropan-2- yloxy)carbonyl, 5-chloropyrimidin-2-yl, (l-methylcyclopropoxy)carbonyl,
isopropoxycarbonyl, 5-ethylpyrimidin-2-yl, 3-isopropyl-l ,2,4-oxadiazol-5-yl, 3- (trifluoromethyl)-l ,2,4-oxadiazol-5-yl, and 3-(2-fluoropropan-2-yl)-l ,2,4-oxadiazol-5- yi-
The compound according to claim 1 or 2, selected from compounds of Formula (If) and pharmaceutically accept N-oxides thereof:
Figure imgf000149_0001
(If)
wherein:
Ar is selected from: pyridin-4-yl, pyridin-2-yl, phenyl, pyridin-3-yl, and pyrazin-2-yl; each optionally substituted with one or more substituents selected from: cyano, fluoro, methyl, bromo, methylsulfonyl, chloro, 2-methoxyethyl, lH-l ,2,4-triazol- 1-yl, trifluoromethyl, 2-hydroxyethyl, 2-cyanoethyl, 2-(dimethylamino)ethyl, 2- morpholinoethyl, lH-tetrazol-l-yl, oxetan-3-ylsulfonyl, cyclopropylsulfonyl, pyridazin- 4-yl, and dimethylcarbamoyl; and
R1 is selected from: teri-butoxycarbonyl, ( 1 ,1 , 1 -trifluoropropan-2- yloxy)carbonyl, 5-chloropyrimidin-2-yl, (l-methylcyclopropoxy)carbonyl,
isopropoxycarbonyl, 5-ethylpyrimidin-2-yl, 3-isopropyl-l ,2,4-oxadiazol-5-yl, 3- (trifluoromethyl)-l ,2,4-oxadiazol-5-yl, and 3-(2-fluoropropan-2-yl)-l ,2,4-oxadiazol-5- yi-
26. A compound according to claim 1 or 2 selected from the following compounds and pharmaceutically acceptable salts, solvates, and hydrates thereof:
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(3-cyanopyridin-4-yloxy)cyclohexyloxy)-8- azabicyclo [3.2.1] octane- 8 -carboxylate ;
(lR,3r,5S)-tert-butyl 3-((l r,4R)-4-(3-cyanopyridin-4-yloxy)cyclohexyloxy)-8- azabicyclo [3.2.1] octane- 8 -carboxylate ;
( IR,3R,5S)-((S)- 1 ,1 , 1 -trifluoropropan-2-yl) 3-(( 1 r,4R)-4-(3 -cyanopyridin-4- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate;
( 1R,35,55)-((R)- 1 ,1 , 1 -trifluoropropan-2-yl) 3-(( 1 r,4R)-4-(3 -cyanopyridin-4- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate;
( 1R,3S,5S)-((S)- 1 ,1 , 1 -trifluoropropan-2-yl) 3-(( 1 r,4R)-4-(3 -cyanopyridin-4- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(3,5-difluoropyridin-4-yloxy)cyclohexyloxy)- 8-azabicyclo[3.2.1]octane-8-carboxylate;
4-((lR,4r)-4-((lR,3i,55)-8-(5-chloropyrimidin-2-yl)-8-azabicyclo[3.2.1]octan- 3-yloxy)cyclohexyloxy)nicotinonitrile;
(lR,3s,5S)-l-methylcyclopropyl 3-((l r,4R)-4-(3-cyanopyridin-4- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate;
(lR,3i,55)-isopropyl 3-((l r,4R)-4-(3-cyanopyridin-4-yloxy)cyclohexyloxy)-8- azabicyclo [3.2.1] octane- 8 -carboxylate ;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(3-cyano-5-methylpyridin-4- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(3-cyano-5-fluoropyridin-4- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(3-cyano-5-fluoropyridin-2- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(4-bromo-2-cyanophenoxy)cyclohexyloxy)- 8-azabicyclo[3.2.1]octane-8-carboxylate;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(2,4-dicyanophenoxy)cyclohexyloxy)-8- azabicyclo [3.2.1] octane- 8 -carboxylate ;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(2-cyano-4- (methylsulfonyl)phenoxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(thieno[3,2-c]pyridin-4- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(furo[3,2-c]pyridin-4-yloxy)cyclohexyloxy)- 8-azabicyclo[3.2.1]octane-8-carboxylate; (lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(5-bromopyrimidin-2-yloxy)cyclohexyloxy)- 8-azabicyclo[3.2.1]octane-8-carboxylate;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(4-chloro-2-cyanophenoxy)cyclohexyloxy)- 8-azabicyclo[3.2.1]octane-8-carboxylate;
(lR,3*,55)-teri-butyl 3-((l r,4R)-4-(2-fluoro-4- (methylsulfonyl)phenoxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(5-(methylsulfonyl)pyridin-3- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(2-cyano-4-fluorophenoxy)cyclohexyloxy)-8 azabicyclo [3.2.1] octane- 8 -carboxylate ;
(lR,3*,55)-teri-butyl 3-((l r,4R)-4-(4-(2- methoxyethyl)phenoxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(l ,6-naphthyridin-4-yloxy)cyclohexyloxy)-8 azabicyclo [3.2.1] octane- 8 -carboxylate ;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(pyridin-4-yloxy)cyclohexyloxy)-8- azabicyclo [3.2.1] octane- 8 -carboxylate ;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(5-(lH-l ,2,4-triazol-l-yl)pyrazin-2- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(2-methyl-6-(lH-l ,2,4-triazol-l -yl)pyridin-3 yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(isoquinolin-8-yloxy)cyclohexyloxy)-8- azabicyclo [3.2.1] octane- 8 -carboxylate ;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(5-(trilluoromethyl)pyridin-2- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(quinoxalin-2-yloxy)cyclohexyloxy)-8- azabicyclo [3.2.1] octane- 8 -carboxylate ;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(4-cyanopyridin-2-yloxy)cyclohexyloxy)-8- azabicyclo [3.2.1] octane- 8 -carboxylate ;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(4-(2-hydroxyethyl)phenoxy)cyclohexyloxy) 8-azabicyclo[3.2.1]octane-8-carboxylate;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(4-bromo-3-lluorophenoxy)cyclohexyloxy)- 8-azabicyclo[3.2.1]octane-8-carboxylate;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(5-cyanopyridin-2-yloxy)cyclohexyloxy)-8- azabicyclo [3.2.1] octane- 8 -carboxylate ;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(4-(2-cyanoethyl)phenoxy)cyclohexyloxy)-8 azabicyclo [3.2.1] octane- 8 -carboxylate ; (lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(benzo[d]thiazol-2-yloxy)cyclohexyloxy)-8- azabicyclo [3.2.1] octane- 8 -carboxylate ;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(5-(methylsulfonyl)pyrimidin-2- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(4-(2-
(dimethylamino)ethyl)phenoxy)cyclohexyloxy)-8-azabicyclo [3.2.1] octane-8 - carboxylate;
(lR,3*,55)-teri-butyl 3-((l r,4R)-4-(4-(2- mo holinoethyl)phenoxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(l-methyl-3-(triiluoromethyl)-lH-pyrazol-5- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(3-cyanopyridin-2-yloxy)cyclohexyloxy)-8- azabicyclo [3.2.1] octane- 8 -carboxylate ;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(thieno[3,2-d]pyrimidin-4- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate;
( lR,3s ,5S)-te7f -butyl 3-(( 1 r,4R)-4-(4-( 1 H-tetrazol- 1 - yl)phenoxy)cyclohexyloxy)-8 -azabicyclo [3.2.1 ] octane-8-carboxylate;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(2-methyl-6-(oxetan-3-ylsulfonyl)pyridin-3- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(6-(cyclopropylsulfonyl)-2-methylpyridin-3- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(2-cyanopyridin-3-yloxy)cyclohexyloxy)-8- azabicyclo [3.2.1] octane- 8 -carboxylate ;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(5-bromo-3-methylpyrazin-2- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(3-methyl-5-(methylsulfonyl)pyrazin-2- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(6-(trilluoromethyl)pyridin-3- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(4-cyanopyridin-3-yloxy)cyclohexyloxy)-8- azabicyclo [3.2.1] octane- 8 -carboxylate ;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(5-cyanopyrimidin-4-yloxy)cyclohexyloxy)- 8-azabicyclo[3.2.1]octane-8-carboxylate;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(4-cyano-2,6- dilluorophenoxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(2-methyl-6-(pyridazin-4-yl)pyridin-3- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate; (lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(4-(dimethylcarbamoyl)-2- fluorophenoxy)cyclohexyloxy) - 8 -azabicyclo [3.2.1 ] octane- 8 -carboxylate ;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(5-(methylsulfonyl)pyridin-2- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(2-methyl-6-(methylsulfonyl)pyridin-3- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate;
( lR,3s ,5S)-tert-butyl 3-(( 1 r,4R)-4-(3 -fluoro-4-( 1 H- 1 ,2,4-triazol- 1 - yl)phenoxy)cyclohexyloxy)-8 -azabicyclo [3.2.1 ] octane-8-carboxylate;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(5-(methylsulfonyl)pyrazin-2- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate;
(lR,3s,5S)-tert-butyl 3-((lr,4R)-4-(5-(dimethylcarbamoyl)pyridin-2- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate;
(lR,3s,5S)-tert-butyl 3-((lr,4R)-4-(4-(methylsulfonyl)phenoxy)cyclohexyloxy)- 8-azabicyclo[3.2.1]octane-8-carboxylate;
(lR,3s,5S)-l-methylcyclopropyl 3-((l r,4R)-4-(5-(methylsulfonyl)pyrazin-2- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate;
(lR,3s,5S)-isopropyl 3-((l r,4R)-4-(5-(methylsulfonyl)pyrazin-2- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate;
(lR,3*,55)-8-(5-ethylpyrimidin-2-yl)-3-((lr,4R)-4-(5-(methylsulfonyl)pyrazin- 2-yloxy)cyclohexyloxy)-8 -azabicyclo[3.2.1 ] octane;
(lR,3s,5S)-tert-butyl 3-((l r,4R)-4-(pyrimidin-4-yloxy)cyclohexyloxy)-8- azabicyclo [3.2.1] octane- 8 -carboxylate ;
(lR,3s,5S)-isopropyl 3-((l r,4R)-4-(4-(methylsulfonyl)phenoxy)cyclohexyloxy)- 8-azabicyclo[3.2.1]octane-8-carboxylate;
(lR,3s,5S)-l-methylcyclopropyl 3-((l r,4R)-4-(4- (methylsulfonyl)phenoxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate;
3-isopropyl-5-((lR,3*,55)-3-((l r,4R)-4-(5-(methylsulfonyl)pyrazin-2- yloxy)cyclohexyloxy)-8 -azabicyclo[3.2.1 ] octan-8 -yl) - 1 ,2,4-oxadiazole;
(lR,3s,5S)-isopropyl 3-((l r,4R)-4-(2-methyl-6-(methylsulfonyl)pyridin-3- yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate;
3-isopropyl-5-((lR,3*,55)-3-((l r,4R)-4-(4- (methylsulfonyl)phenoxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octan-8-yl)-l ,2,4- oxadiazole;
5-((lR,3i,55)-3-((l r,4R)-4-(4-(methylsulfonyl)phenoxy)cyclohexyloxy)-8- azabicyclo [3.2.1 ]octan-8 -yl)-3 -(trilluoromethyl)- 1 ,2,4-oxadiazole ; (lR,3s,5S)-l-methylcyclopropyl 3-((lr,4R)-4-(2-methyl-6- (methylsulfonyl)pyridin-3-yloxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octane-8- carboxylate;
3-(2-fluoropropan-2-yl)-5-((lR,3i,55)-3-((lr,4R)-4-(2-methyl-6- (methylsulfonyl)pyridin-3 -yloxy)cyclohexyloxy)-8 -azabicyclo[3.2.1 ] octan-! oxadiazole;
3-isopropyl-5-((lR,3*,55)-3-((lr,4R)-4-(2-methyl-6-(methylsulfonyl)pyridin-3- yloxy)cyclohexyloxy)-8 -azabicyclo[3.2.1 ] octan-8 -yl) - 1 ,2,4-oxadiazole;
3-(2-fluoropropan-2-yl)-5-((lR,3i,55)-3-((lr,4R)-4-(4- (methylsulfonyl)phenoxy)cyclohexyloxy)-8-azabicyclo[3.2.1]octan-8-yl)-l,2,4- oxadiazole; and
5-((lR,3i,55)-3-((lr,4R)-4-(2-methyl-6-(methylsulfonyl)pyridin-3- yloxy)cyclohexyloxy)-8 -azabicyclo[3.2.1 ] octan-8 -yl) -3-(trifluoromethyl)- 1 ,2,4- oxadiazole.
27. A composition comprising a compound according to any one of claims 1 to 26.
A pharmaceutical product selected from: a pharmaceutical composition, a formulation, unit dosage form, and a kit; each comprising a compound according to any one of claims 1 to 26.
29. A pharmaceutical composition comprising a compound according to any one of claims 1 to 26, and a pharmaceutically acceptable carrier. 30. A method for preparing a pharmaceutical composition comprising the step of admixing a compound according to any one of claims 1 to 26, and a pharmaceutically acceptable carrier.
31. A pharmaceutical product selected from: a pharmaceutical composition, a formulation, a unit dosage form, a combined preparation, a twin pack, and a kit; each comprising a compound according to any one of claims 1 to 26, and a second pharmaceutical agent.
32. A method for preparing a pharmaceutical composition comprising the step of admixing a compound according to any one of claims 1 to 26, a second pharmaceutical agent, and a pharmaceutically acceptable carrier.
33. A method for the treatment of a disorder selected from: a GPR119-receptor-related disorder; a condition ameliorated by increasing secretion of an incretin; a condition ameliorated by increasing a blood incretin level; a condition characterized by low bone mass; a neurological disorder; a metabolic -related disorder; type 2 diabetes; and obesity; in an individual; comprising administering to said individual in need thereof, a therapeutically effective amount of: a compound according to any one of claims 1 to 26; a composition according to claim 27; a pharmaceutical product according to claim 28 or 31 ; or a pharmaceutical composition according to claim 29.
Use of a compound according to any one of claims 1 to 26 or a composition according to claim 27; in the manufacture of a medicament for treating a disorder in an individual, wherein said disorder is selected from: a GPR119-receptor-related disorder; a condition ameliorated by increasing secretion of an incretin; a condition ameliorated by increasing a blood incretin level; a condition characterized by low bone mass; a neurological disorder; a metabolic-related disorder; type 2 diabetes; and obesity.
A compound according to any one of claims 1 to 26; a composition according to claim 27; a pharmaceutical product according to claim 28 or 31 ; or a pharmaceutical composition according to claim 29; for use in a method of treatment of the human or animal body by therapy.
A compound according to any one of claims 1 to 26; a composition according to claim 27; a pharmaceutical product according to claim 28 or 31 ; or a pharmaceutical composition according to claim 29; for use in a method of treating a disorder in an individual, wherein said disorder is selected from: a GPR119-receptor-related disorder; a condition ameliorated by increasing secretion of an incretin; a condition ameliorated by increasing a blood incretin level; a condition characterized by low bone mass; a neurological disorder; a metabolic -related disorder; type 2 diabetes; and obesity.
A pharmaceutical product selected from the group consisting of: a pharmaceutical composition, a formulation, a dosage form, a combined preparation, a twin pack, and a kit; comprising a compound according to any one of claims 1 to 26 for the treatment of a disorder selected from: a GPR119-receptor-related disorder; a condition ameliorated by increasing a blood incretin level; a condition characterized by low bone mass; a neurological disorder; a metabolic -related disorder; type 2 diabetes; and obesity; in an individual.
38. A method for the treatment of a disorder selected from: a GPR119-receptor-related disorder; a condition ameliorated by increasing secretion of an incretin; a condition ameliorated by increasing a blood incretin level; a condition characterized by low bone mass; a neurological disorder; a metabolic -related disorder; type 2 diabetes; and obesity; in an individual; comprising administering to said individual in need thereof, a therapeutically effective amount of a compound according to any one of claims 1 to 26; a composition according to claim 27; a pharmaceutical product according to claim 28; or a pharmaceutical composition according to claim 29; each in combination with a therapeutically effective amount of a second pharmaceutical agent.
39. Use of a compound according to any one of claims 1 to 26 in combination with a second pharmaceutical agent, in the manufacture of a medicament for the treatment of a disorder selected from: a GPR119-receptor-related disorder; a condition ameliorated by increasing secretion of an incretin; a condition ameliorated by increasing a blood incretin level; a condition characterized by low bone mass; a neurological disorder; a metabolic -related disorder; type 2 diabetes; and obesity.
Use of a pharmaceutical agent in combination with a compound according to any one claims 1 to 26, in the manufacture of a medicament for the treatment of a disorder selected from: a GPR119-receptor-related disorder; a condition ameliorated by increasing secretion of an incretin; a condition ameliorated by increasing a blood incretin level; a condition characterized by low bone mass; a neurological disorder; a metabolic -related disorder; type 2 diabetes; and obesity.
A compound according to any one of claims 1 to 26; a composition according to claim 27; a pharmaceutical product according to claim 28; or a pharmaceutical composition according to claim 29; in combination with a second pharmaceutical agent for use in a method of treatment of the human or animal body by therapy.
A compound according to any one of claims 1 to 26; a composition according to claim 27; a pharmaceutical product according to claim 28; or a pharmaceutical composition according to claim 29; in combination with a second pharmaceutical agent for use in a method of treating a disorder selected from: a GPR119-receptor-related disorder; a condition ameliorated by increasing secretion of an incretin; a condition ameliorated by increasing a blood incretin level; a condition characterized by low bone mass; a neurological disorder; a metabolic -related disorder; type 2 diabetes; and obesity; in an individual. A pharmaceutical agent in combination with a compound according to any one of claims 1 to 26; a composition according to claim 27; a pharmaceutical product according to claim 28; or a pharmaceutical composition according to claim 29; for use in a method of treatment of the human or animal body by therapy.
A pharmaceutical agent in combination with a compound according to any one of claims 1 to 26; a composition according to claim 27; a pharmaceutical product according to claim 28; or a pharmaceutical composition according to claim 29; for use in a method of treating a disorder selected from: a GPR119-receptor-related disorder; a condition ameliorated by increasing secretion of an incretin; a condition ameliorated by increasing a blood incretin level; a condition characterized by low bone mass; a neurological disorder; a metabolic -related disorder; type 2 diabetes; and obesity; in an individual.
A pharmaceutical product selected from the group consisting of: a pharmaceutical composition, a formulation, a dosage form, a combined preparation, a twin pack, and a kit; comprising a compound according to any one of claims 1 to 26 and a second pharmaceutical agent; for use in a method of treating the human or animal by therapy.
A pharmaceutical product selected from the group consisting of: a pharmaceutical composition, a formulation, a dosage form, a combined preparation, a twin pack, and a kit; comprising a compound according to any one of claims 1 to 26 and a second pharmaceutical agent for the treatment of a disorder selected from: a GPR119-receptor- related disorder; a condition ameliorated by increasing a blood incretin level; a condition characterized by low bone mass; a neurological disorder; a metabolic -related disorder; type 2 diabetes; and obesity; in an individual.
The method according to claim 32 or 38; the pharmaceutical product according to any one of claims 31, 41, 42, 45, and 46; the use according to claim 39 or 40, the compound according to claim 41 or 42; the composition according to claim 41 or 42; the pharmaceutical composition according to claim 41 or 42; or the pharmaceutical agent according to claim 43 or 44; wherein said pharmaceutical agent and said second pharmaceutical agent is selected from the group consisting of:
A. an inhibitor of DPP-IV selected from the following inhibitors of DPP- IV and pharmaceutically acceptable salts, solvates, and hydrates thereof: 3(R)-amino-l-[3-(trilluoromethyl)-5,6,7,8-tetrahydro[l ,2,4]triazolo[4,3- a]pyrazin-7-yl]-4-(2,4,5-trilluorophenyl)butan-l -one;
1 -[2-(3-hydroxyadamant- 1 -ylamino)acetyl]pyrrolidine-2(5)- carbonitrile;
( 1 ,35,55)-2- [2(S)-amino-2-(3-hydroxyadamantan- 1 -yl)acetyl] -2- azabicyclo[3.1.0]hexane-3-carbonitrile;
2-[6-[3(R)-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-l , 2,3,4- tetrahydropyrimidin- 1 -ylmethyl]benzonitrile;
8-[3(R)-aminopiperidin- 1 -yl] -7-(2-butynyl)-3-methyl- 1 -(4- methylquinazolin-2-ylmethyl)xanthine;
l-[N-[3(R)-pyrrolidinyl]glycyl]pyrrolidin-2(R)-yl boronic acid;
4(5)-fluoro-l -[2-[(lR,35)-3-(lH-l ,2,4-triazol-l- ylmethyl)cyclopentylamino]acetyl]pyrrolidine-2(5)-carbonitrile;
l-[(25,35, l lb5)-2-amino-9, 10-dimethoxy-2,3,4,6,7,l lb-hexahydro-lH- pyrido [2, 1 -a] isoquinolin-3 -yl] -4(5) -(fluoromethyl)pyrrolidin-2-one ;
(25,45)-2-cyano-4-fluoro- 1 -[(2-hydroxy-l , 1 -dimethyl)
ethylamino] acetylpyrrolidine ;
8-(c i-hexahydro-pyrrolo[3,2-b]pyrrol-l-yl)-3-methyl-7-(3-methyl-but- 2-enyl)-l-(2-oxo-2-phenylethyl)-3,7-dihydro-purine-2,6-dione;
1- ((35,45)-4-amino-l-(4-(3,3-dilluoropyrrolidin-l -yl)-l ,3,5-triazin-2- yl)pyrrolidin-3 -yl) -5 , 5dilluoropiperidin-2-one ;
(R)-2-((6-(3-aminopiperidin-l-yl)-3-methyl-2,4-dioxo-3,4- dihydropyrimidin-l(2H)-yl)methyl)-4-fluorobenzonitrile;
5- { (5)-2-[2-((5)-2-cyano-pyrrolidin- 1 -yl)-2-oxo-ethylamino] -propyl } -5- ( 1 H-tetrazol-5-yl) 10, 11 -dihydro-5H-dibenzo [a,d] cycloheptene-2,8 -dicarboxylic acid bis-dimethylamide;
((25,45)-4-(4-(3-methyl- 1 -phenyl- 1 H-pyrazol-5 -yl)piperazin- 1 - yl)pyrrolidin-2-yl)(thiazolidin-3-yl)methanone;
(25,45)-l -[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-l -yl)amino]acetyl]-4- lluoropyrrolidine-2-carbonitrile;
6- [(3R)-3-amino-piperidin-l-yl]-5-(2-chloro-5-lluoro-benzyl)-l ,3- dimethyl-l ,5dihydro-pyrrolo[3,2-d]pyrimidine-2,4-dione;
2- ({ 6-[(3R)-3-amino-3-methylpiperidin-l -yl]-l ,3-dimethyl-2,4-dioxo- l ,2,3,4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl}methyl)-4- lluorobenzonitrile ;
(25)-l -{ [2-(5-methyl-2-phenyl-oxazol-4-yl)-ethylamino]-acetyl}- pyrrolidine-2-carbonitrile; (25)- 1 -{ [1,1 -dimethyl-3 -(4-pyridin-3-yl-imidazol- 1 -yl)-propylamino] - acetyl } -pyrrolidine -2 -carbonitrile;
(3,3-difluoropyrrolidin-l-yl)-((25,45)-4-(4-(pyrimidin-2-yl)piperazin-l yl)pyrrolidin-2-yl)methanone ;
(25,45)-l-[(25)-2-amino-3,3-bis(4-lluorophenyl)propanoyl]-4- lluoropyrrolidine -2 -carbonitrile;
(2S,5R)-5 -ethynyl- 1 - { N-(4-methyl- 1 -(4-carboxy-pyridin-2-yl)piperidin 4-yl)glycyl {pyrrolidine -2 -carbonitrile; and
(15,6R)-3-{ [3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl]carbonyl}-6-(2,4,5-trilluorophenyl)cyclohex-3-en-l -amine;
B. a biguanide selected from the following biguanides, and
pharmaceutically acceptable salts, solvates, and hydrates thereof:
(phenylethyl)biguanide ;
dimethylbiguanide ;
butylbiguanide; and
1 -(p-chlorophenyl) -5 -isopropylbiguanide ;
C. an alpha-glucosidase inhibitor selected from the following alpha- glucosidase inhibitors, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
(2R,3R,4R,5R)-4-((2R,3R,4R,55,6R)-5-((2R,3R,45,55,6R)-3,4- dihydroxy-6-methyl-5-((15,4R,55,65)-4,5,6-trihydroxy-3- (hydroxymethyl)cyclohex-2-enylamino)tetrahydro-2H-pyran-2-yloxy)-3,4- dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yloxy)-2,3,5,6- tetrahydroxyhexanal ;
(2R,3R,4R,55)-l-(2-hydroxyethyl)-2-(hydroxymethyl)piperidine-3,4,5- triol; and
( 1 S,2S,3R,4S,5S)-5 -( 1 ,3 -dihydroxypropan-2-ylamino)- 1 - (hydroxymethyl)cyclohexane- 1 ,2,3 ,4-tetraol;
D. a sulfonylurea selected from the following sulfonylureas, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
N-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-5- methylpyrazine-2-carboxamide) ;
5-chloro-N-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-2- methoxybenzamide; and
3-ethyl-4-methyl-N-(4-(N-(( 1 r,4r)-4- methylcyclohexylcarbamoyl)sulfamoyl)phenethyl)-2-oxo-2,5-dihydro-lH- pyrrole-1 -carboxamide; E. a SGLT2 inhibitor selected from the following SGLT2 inhibitors, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
(25,3R,4R,55,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3 ,4,5 -triol;
ethyl ((2R,35,45,5R,65)-3,4,5-trihydroxy-6-(4-(4-isopropoxybenzyl)-l - isopropyl-5-methyl-lH-pyrazol-3-yloxy)tetrahydro-2H-pyran-2-yl)methyl carbonate; and
ethyl ((2R,35,45,5R,65)-3,4,5-trihydroxy-6-(2-(4- methoxybenzyl)phenoxy)tetrahydro-2H-pyran-2-yl)methyl carbonate; and
F. a meglitinide selected from the following meglitinides, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
(5)-2-ethoxy-4-(2-(3 -methyl- 1 -(2-(piperidin- 1 -yl)phenyl)butylamino)- 2-oxoethyl)benzoic acid;
(R)-2-((l r,4R)-4-isopropylcyclohexanecarboxamido)-3- phenylpropanoic acid; and
(5)-2-benzyl-4-((3aR,7a5)-lH-isoindol-2(3H,3aH,4H,5H,6H,7H,7aH)- yl)-4-oxobutanoic acid.
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