WO2013011402A1 - Gpr 119 modulators - Google Patents

Abstract

Compounds that modulate the activity of the G-protein-coupled receptor GPR119 and their uses in the treatment of diseases linked to the modulation of the G-protein- coupled receptor GPR119 in animals are described herein.

Description

GPR 1 19 MODULATORS

FIELD OF THE INVENTION

The present invention relates to new pharmaceutical compounds, pharmaceutical compositions containing these compounds, and their use to modulate the activity of the G-protein-coupled receptor, GPR1 19.

BACKGROUND

Diabetes mellitus are disorders in which high levels of blood glucose occur as a consequence of abnormal glucose homeostasis. The most common forms of diabetes mellitus are Type I (also referred to as insulin-dependent diabetes mellitus) and Type II diabetes (also referred to as non-insulin-dependent diabetes mellitus). Type II diabetes, accounting for roughly 90% of all diabetic cases, is a serious progressive disease that results in microvascular complications (including retinopathy, neuropathy and

nephropathy) as well as macrovascular complications (including accelerated

atherosclerosis, coronary heart disease and stroke).

Currently, there is no cure for diabetes. Standard treatments for the disease are limited, and focus on controlling blood glucose levels to minimize or delay complications. Current treatments target either insulin resistance (metformin, thiazolidinediones, or insulin) release from beta cells (sulphonylureas, exenatide). Sulphonylureas and other compounds that act via depolarization of the beta cell promote hypoglycemia as they stimulate insulin secretion independent of circulating glucose concentrations. One approved drug, exenatide, stimulates insulin secretion only in the presence of high glucose, but must be injected due to a lack of oral bioavailablity. Sitagliptin, a dipeptidyl peptidase IV inhibitor, is a new drug that increases blood levels of incretin hormones, which can increase insulin secretion, reduce glucagon secretion and have other less well characterized effects. However, sitagliptin and other dipeptidyl peptidases IV inhibitors may also influence the tissue levels of other hormones and peptides, and the long-term consequences of this broader effect have not been fully investigated.

In Type II diabetes, muscle, fat and liver cells fail to respond normally to insulin.

This condition (insulin resistance) may be due to reduced numbers of cellular insulin receptors, disruption of cellular signaling pathways, or both. At first, the beta cells compensate for insulin resistance by increasing insulin output. Eventually, however, the beta cells become unable to produce sufficient insulin to maintain normal glucose levels (euglycemia), indicating progression to Type II diabetes. In Type II diabetes, fasting hyperglycemia occurs due to insulin resistance combined with beta cell dysfunction. There are two aspects of beta cell defect dysfunction: 1 ) increased basal insulin release (occurring at low, non-stimulatory glucose concentrations), which is observed in obese, insulin-resistant pre-diabetic stages as well as in Type II diabetes, and 2) in response to a hyperglycemic challenge, a failure to increase insulin release above the already elevated basal level, which does not occur in pre-diabetic stages and may signal the transition from normo-glycemic insulin-resistant states to Type II diabetes. Current therapies to treat the latter aspect include inhibitors of the beta-cell ATP-sensitive potassium channel to trigger the release of endogenous insulin stores, and administration of exogenous insulin. Neither achieves accurate normalization of blood glucose levels and both carry the risk of eliciting hypoglycemia.

Thus, there has been great interest in the discovery of agents that function in a glucose-dependent manner. Physiological signaling pathways which function in this way are well known, including gut peptides GLP-1 and GIP. These hormones signal via cognate G-protein coupled receptors to stimulate production of cAMP in pancreatic beta-cells. Increased cAMP apparently does not result in stimulation of insulin release during the fasting or pre-prandial state. However, a number of biochemical targets of cAMP, including the ATP-sensitive potassium channel, voltage-sensitive potassium channels and the exocytotic machinery, are modulated such that insulin secretion due to postprandial glucose stimulation is significantly enhanced. Therefore, agonist modulators of novel, similarly functioning, beta-cell GPCRs, including GPR1 19, would also stimulate the release of endogenous insulin and promote normalization of glucose levels in Type II diabetes patients. It has also been shown that increased cAMP, for example as a result of GLP-1 stimulation, promotes beta-cell proliferation, inhibits beta- cell death and, thus, improves islet mass. This positive effect on beta-cell mass should be beneficial in Type II diabetes where insufficient insulin is produced.

It is well known that metabolic diseases have negative effects on other physiological systems and there is often co-occurrence of multiple disease states (e.g., Type I diabetes, Type II diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia,

dyslipidemia, obesity or cardiovascular disease in "Syndrome X") or secondary diseases which occur secondary to diabetes such as kidney disease, and peripheral neuropathy. Thus, treatment of the diabetic condition should be of benefit to such interconnected disease states.

SUMMARY OF THE INVENTION

In accordance with the present invention, new GPR 1 19 modulators have been discovered. These compounds include 1 -methylcyclopropyl (3R,4R)-3-fluoro-4-({5- methyl-6-[(2-methylpyridin-3-yl)oxy]pyrimidin-4-yl}oxy)piperidine-1-carboxylate and 1- methylcyclopropyl (3S,4S)-3-fluoro-4-({5-methyl-6-[(2-methylpyridin-3-yl)oxy]pyrimidin- 4-yl}oxy)piperidine-1-carboxylate, and mixtures thereof and pharmaceutically

acceptable salts thereof.

These compounds modulate the activity of the G-protein-coupled receptor. More specifically the compounds modulate GPR1 19. As such, said compounds are useful for the treatment of diseases, such as diabetes, in which the activity of GPR1 19 contributes to the pathology or symptoms of the disease. Examples of such conditions include hyperlipidemia, Type I diabetes mellitus, Type II diabetes mellitus, idiopathic Type I diabetes (Type lb), latent autoimmune diabetes in adults (LADA), early-onset Type 2 diabetes (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, 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, obesity, 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, transient ischemic attacks, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia,

hypertrygliceridemia, insulin resistance, impaired glucose metabolism, conditions of impaired glucose tolerance, conditions of impaired fasting plasma glucose, obesity, erectile dysfunction, skin and connective tissue disorders, foot ulcerations and ulcerative colitis, endothelial dysfunction and impaired vascular compliance. The compounds may be used to treat neurological disorders such as Alzheimer's disease, schizophrenia, and impaired cognition. The compounds will also be beneficial in gastrointestinal illnesses such as inflammatory bowel disease, ulcerative colitis, Crohn's disease, irritable bowel syndrome, etc. As noted above, the compounds may also be used to stimulate weight loss in obese patients, especially those afflicted with diabetes.

A further embodiment of the invention is directed to pharmaceutical compositions containing a compound of this invention. Such formulations will typically contain a compound of this invention in admixture with at least one pharmaceutically acceptable excipient. Such formulations may also contain at least one additional pharmaceutical agent. Examples of such agents include anti-obesity agents and/or anti-diabetic agents. Additional aspects of the invention relate to the use of the compounds of this invention in the preparation of medicaments for the treatment of diabetes and related conditions as described herein.

It is to be understood that both the foregoing summary and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.

DETAILED DESCRIPTION OF THE INVENTION

The present invention may be understood even more readily by reference to the following detailed description of exemplary embodiments of the invention and the examples included therein.

It is to be understood that this invention is not limited to specific synthetic methods of making that may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. The plural and singular should be treated as interchangeable, other than the indication of number:

a. "therapeutically effective amount" means an amount of a compound of the

present invention that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein;

b. "patient" refers to warm blooded animals such as, for example, guinea pigs, mice, rats, gerbils, cats, rabbits, dogs, monkeys, chimpanzees, and humans; "treat" embraces both preventative, i.e., prophylactic, and palliative treatment, i.e., relieve, alleviate, or slow the progression of the patient's disease (or condition) or any tissue damage associated with the disease;

the terms "modulated", "modulating", or "modulate(s)", as used herein, unless otherwise indicated, refers to the activation of the G-protein-coupled receptor GPR1 19 with compounds of the present invention;

"pharmaceutically acceptable" indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith,

"salts" is intended to refer to pharmaceutically acceptable salts and to salts suitable for use in industrial processes, such as the preparation of the compound, "pharmaceutically acceptable salts" is intended to include pharmaceutically acceptable acid addition salts".

"pharmaceutically acceptable acid addition salts" is intended to apply to any nontoxic organic or inorganic acid addition salt of the base compounds or any of its intermediates. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulphuric, and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate, and potassium hydrogen sulfate. Illustrative organic acids, which form suitable salts include the mono-, di-, and tricarboxylic acids. Illustrative of such acids are for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxy-benzoic, phenylacetic, cinnamic, salicylic, 2-phenoxybenzoic, p-toluenesulfonic acid, and sulfonic acids such as methane sulfonic acid and 2-hydroxyethane sulfonic acid. Such salts can exist in either a hydrated or substantially anhydrous form. In general, the acid addition salts of these compounds are soluble in water and various hydrophilic organic solvents.

"isomer" means "stereoisomer" and "geometric isomer" as defined below.

"Stereoisomer" refers to compounds that possess one or more chiral centers and each center may exist in the R or S configuration. Stereoisomers includes all diastereomeric, enantiomeric and epimeric forms as well as racemates and mixtures thereof. "Geometric isomer" refers to compounds that may exist in cis, trans, anti, syn, entgegen (E), and zusammen (Z) forms as well as mixtures thereof. Certain of the compounds of this invention may exist as geometric isomers. The compounds may possess one or more asymmetric centers, thus existing as two, or more, stereoisomeric forms. The present invention includes all the individual

stereoisomers and geometric isomers of the compounds of this invention and mixtures thereof. Individual enantiomers can be obtained by chiral separation or using the relevant enantiomer in the synthesis. As noted above, some of the compounds exist as isomers. These isomeric mixtures can be separated into their individual isomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereoisomers and

converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers. Enantiomers can also be separated by use of a chiral HPLC column.

Alternatively, the specific stereoisomers may be synthesized by using an optically active starting material, by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one stereoisomer into the other by asymmetric transformation.

The present invention also embraces isotopically-labeled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵0, ¹⁷0, ¹⁸0, ³¹ P, ³²P, ³⁵S, ¹⁸F, ¹²³l, ¹²⁵l and ³⁶CI, respectively.

Certain isotopically-labeled compounds of the present invention (e.g., those labeled with ³H and ¹⁴C) are useful in compound and/or substrate tissue distribution assays. Certain isotopically labeled ligands including tritium, ¹⁴C, ³⁵S and ¹²⁵l could be useful in radioligand binding assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C) isotopes are particularly preferred for their ease of preparation and detectability.

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. Positron emitting isotopes such as ¹⁵0, ¹³N, ¹¹C, and ¹⁸F are useful for positron emission tomography (PET) studies to examine receptor occupancy.

Isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an isotopically labeled reagent for a non- isotopically labeled reagent.

Certain compounds of the present invention may exist in more than one crystal form (generally referred to as "polymorphs"). Polymorphs may be prepared by crystallization under various conditions, for example, using different solvents or different solvent mixtures for recrystallization; crystallization at different temperatures; and/or various modes of cooling, ranging from very fast to very slow cooling during

crystallization. Polymorphs may also be obtained by heating or melting the compound of the present invention followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.

In addition, the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention. The compounds may also exist in one or more crystalline states, i.e. as co-crystals, polymorphs, or they may exist as amorphous solids. All such forms are encompassed by the invention and claims.

In an embodiment in the composition of this invention, the composition further includes at least one additional pharmaceutical agent selected from the group consisting of an anti-obesity agent and an anti-diabetic agent. Example anti-obesity agents include dirlotapide, mitratapide, implitapide, R56918 (CAS No. 403987), CAS No. 913541-47-6, lorcaserin, cetilistat, PYY3-36, naltrexone, oleoyl-estrone, obinepitide, pramlintide, tesofensine, leptin, liraglutide, bromocriptine, orlistat, exenatide, AOD-9604 (CAS No. 221231 -10-3) and sibutramine. Example anti-diabetic agents include metformin, acetohexamide, chlorpropamide, diabinese, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone, glisolamide, tolazamide, tolbutamide, tendamistat, trestatin, acarbose, adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q, salbostatin, balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone, pioglitazone, rosiglitazone, troglitazone, exendin-3, exendin-4, trodusquemine, reservatrol, hyrtiosal extract, dapagliflozin, sitagliptin, vildagliptin, alogliptin and saxagliptin.

In another embodiment of a method of this invention, the compounds or compositions of this invention may be administered in an effective amount for treating a condition selected from the group consisting of hyperlipidemia, Type I diabetes, Type II diabetes mellitus, idiopathic Type I diabetes (Type lb), latent autoimmune diabetes in adults (LADA), early-onset Type 2 diabetes (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, 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, obesity, 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, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertrygliceridemia, insulin resistance, impaired glucose metabolism, conditions of impaired glucose tolerance, conditions of impaired fasting plasma glucose, obesity, erectile dysfunction, skin and connective tissue disorders, foot ulcerations and ulcerative colitis, endothelial dysfunction and impaired vascular compliance, hyper apo B lipoproteinemia, Alzheimer's disease, schizophrenia, impaired cognition, inflammatory bowel disease, ulcerative colitis, Crohn's disease, and irritable bowel syndrome.

In a further embodiment, the method further includes administering a second composition comprising at least one additional pharmaceutical agent selected from the group consisting of an anti-obesity agent and an anti-diabetic agent, and at least one pharmaceutically acceptable excipient. This method may be used for admistering the compositions simultaneously or sequentially and in any order.

In yet another embodiment, the compounds of this invention are useful in the manufacture of a medicament for treating a disease, condition or disorder that modulates the activity of G-protein-coupled receptor GPR1 19. Furthermore, the compounds are useful in the preparation of a medicament for the treatment of diabetes or a morbidity associated with said diabetes.

Synthesis

As is readily apparent to one skilled in the art, protection of remote functionality (e.g., primary or secondary amine) of intermediates may be necessary. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. Suitable amino-protecting groups (NH-Pg) include acetyl, trifluoroacetyl, /-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9- fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxy-protecting group" refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality.

Suitable hydroxyl-protecting groups (O-Pg) include for example, allyl, acetyl, silyl, benzyl, para-methoxybenzyl, trityl, and the like. The need for such protection is readily determined by one skilled in the art. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

As noted above, some of the compounds of this invention are acidic and they form salts with pharmaceutically acceptable cations. Some of the compounds of this invention are basic and form salts with pharmaceutically acceptable anions. All such salts are within the scope of this invention and they can be prepared by conventional methods such as combining the acidic and basic entities, usually in a stoichiometric ratio, in either an aqueous, non-aqueous or partially aqueous medium, as appropriate. The salts are recovered either by filtration, by precipitation with a non-solvent followed by filtration, by evaporation of the solvent, or, in the case of aqueous solutions, by lyophilization, as appropriate. The compounds are obtained in crystalline form according to procedures known in the art, such as by dissolution in an appropriate solvent(s) such as ethanol, hexanes or water/ethanol mixtures.

Medical Uses

Compounds of the present invention modulate the activity of G-protein-coupled receptor GPR1 19. As such, said compounds are useful for the prophylaxis and treatment of diseases, such as diabetes, in which the activity of GPR1 19 contributes to the pathology or symptoms of the disease. Consequently, another aspect of the present invention includes a method for the treatment of a metabolic disease and/or a metabolic-related disorder in an individual which comprises administering to the individual in need of such treatment a therapeutically effective amount of a compound of the invention, a salt of said compound or a pharmaceutical composition containing such compound. The metabolic diseases and metabolism-related disorders are selected from, but not limited to, hyperlipidemia, Type I diabetes, Type II diabetes mellitus, idiopathic Type I diabetes (Type lb), latent autoimmune diabetes in adults (LADA), early-onset Type 2 diabetes (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, 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, obesity, 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, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertrygliceridemia, insulin resistance, impaired glucose metabolism, conditions of impaired glucose tolerance, conditions of impaired fasting plasma glucose, obesity, erectile dysfunction, skin and connective tissue disorders, foot ulcerations, endothelial dysfunction, hyper apo B lipoproteinemia and impaired vascular compliance.

Additionally, the compounds may be used to treat neurological disorders such as Alzheimer's disease, schizophrenia, and impaired cognition. The compounds will also be beneficial in gastrointestinal illnesses such as inflammatory bowel disease, ulcerative colitis, Crohn's disease, irritable bowel syndrome, etc. As noted above the compounds may also be used to stimulate weight loss in obese patients, especially those afflicted with diabetes.

In accordance with the foregoing, the present invention further provides a method for preventing or ameliorating the symptoms of any of the diseases or disorders described above in a subject in need thereof, which method comprises administering to a subject a therapeutically effective amount of a compound of the present invention. Further aspects of the invention include the preparation of medicaments for the treating diabetes and its related co-morbidities. In order to exhibit the therapeutic properties described above, the compounds need to be administered in a quantity sufficient to modulate activation of the G-protein- coupled receptor GPR1 19. This amount can vary depending upon the particular disease/condition being treated, the severity of the patient's disease/condition, the patient, the particular compound being administered, the route of administration, and the presence of other underlying disease states within the patient, etc. When administered systemically, the compounds typically exhibit their effect at a dosage range of from about 0.1 mg/kg/day to about 100 mg/kg/day for any of the diseases or conditions listed above. Repetitive daily administration may be desirable and will vary according to the conditions outlined above.

The compounds of the present invention may be administered by a variety of routes. They may be administered orally. The compounds may also be administered parenterally (i.e., subcutaneously, intravenously, intramuscularly, intraperitoneally, or intrathecally), rectally, or topically.

Co-Administration

The compounds of this invention may also be used in conjunction with other pharmaceutical agents for the treatment of the diseases, conditions and/or disorders described herein. Therefore, methods of treatment that include administering compounds of the present invention in combination with other pharmaceutical agents are also provided. Suitable pharmaceutical agents that may be used in combination with the compounds of the present invention include anti-obesity agents (including appetite suppressants), anti-diabetic agents, anti-hyperglycemic agents, lipid lowering agents, and anti-hypertensive agents.

Suitable anti-diabetic agents include an acetyl-CoA carboxylase- (ACC) inhibitor such as those described in WO2009144554, WO2003072197, WO2009144555 and WO2008065508, a diacylglycerol O-acyltransferase 1 (DGAT-1 ) inhibitor, such as those described in WO09016462 or WO2010086820, AZD7687 or LCQ908, diacylglycerol O- acyltransferase 2 (DGAT-2) inhibitor, monoacylglycerol O-acyltransferase inhibitors, a phosphodiesterase (PDE)-10 inhibitor, an AMPK activator, a sulfonylurea (e.g., acetohexamide, chlorpropamide, diabinese, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone, glisolamide, tolazamide, and tolbutamide), a meglitinide, an oamylase inhibitor (e.g., tendamistat, trestatin and AL-3688), an o glucoside hydrolase inhibitor (e.g., acarbose), an a-glucosidase inhibitor (e.g., adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q, and salbostatin), a PPARy agonist (e.g., balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone, pioglitazone, rosiglitazone and troglitazone), a PPAR α/γ agonist (e.g., CLX-0940, GW- 1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767 and SB-219994), a biguanide (e.g., metformin), a glucagon-like peptide 1 (GLP-1 ) modulator such as an agonist (e.g., exendin-3 and exendin-4), liraglutide, albiglutide, exenatide (Byetta®), albiglutide, taspoglutide, lixisenatide, dulaglutide, semaglutide, NN-9924,TTP-054, a protein tyrosine phosphatase-1 B (PTP-1 B) inhibitor (e.g., trodusquemine, hyrtiosal extract, and compounds disclosed by Zhang, S., et al., Drug Discovery Today, 12(9/10), 373-381 (2007)), SIRT-1 inhibitor (e.g., resveratrol, GSK2245840 or GSK184072), a dipeptidyl peptidease IV (DPP-IV) inhibitor (e.g., those in WO20051 16014, sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin and saxagliptin), an insulin secreatagogue, a fatty acid oxidation inhibitor, an A2 antagonist, a c-jun amino-terminal kinase (JNK) inhibitor, glucokinase activators (GKa) such as those described in WO2010103437, WO2010103438, WO2010013161 , WO2007122482, TTP-399, TTP-355, TTP-547, AZD1656, ARRY403, MK-0599, TAK-329, AZD5658 or GKM-001 , insulin, an insulin mimetic, a glycogen phosphorylase inhibitor (e.g. GSK1362885), a VPAC2 receptor agonist, SGLT2 inhibitors, such as those described in E.C. Chao et al. Nature Reviews Drug Discovery 9, 551-559 (July 2010) including dapagliflozin, canagliflozin, BI-10733, tofogliflozin (CSG452), ASP-1941 , THR1474, TS-071 , ISIS388626 and LX421 1 as well as those in WO2010023594, a glucagon receptor modulator such as those described in Demong, D.E. et al. Annual Reports in Medicinal Chemistry 2008, 43, 1 19-137, GPR1 19 modulators, particularly agonists, such as those described in WO2010140092, WO2010128425, WO2010128414, WO2010106457, Jones, R.M. et al. in Medicinal Chemistry 2009, 44, 149-170 (e.g. MBX-2982, GSK1292263, APD597 and PSN821 ), FGF21 derivatives or analogs such as those described in Kharitonenkov, A. et al. et al., Current Opinion in Investigational Drugs 2009, 10(4)359-364, TGR5 (also termed GPBAR1 ) receptor modulators, particularly agonists, such as those described in Zhong, M., Current Topics in Medicinal Chemistry, 2010, 10(4), 386-396 and INT777, GPR40 agonists, such as those described in Medina, J.C., Annual Reports in Medicinal

Chemistry, 2008, 43, 75-85, including but not limited to TAK-875, GPR120 modulators, particularly agonists, high affinity nicotinic acid receptor (HM74A) activators, and SGLT1 inhibitors, such as GSK1614235. A further representative listing of anti-diabetic agents that can be combined with the compounds of the present invention can be found, for example, at page 28, line 35 through page 30, line 19 of WO201 100561 1 . Preferred anti-diabetic agents are metformin and DPP-IV inhibitors (e.g., sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin and saxagliptin). Other antidiabetic agents could include inhibitors or modulators of carnitine palmitoyi transferase enzymes, inhibitors of fructose 1 ,6-diphosphatase, inhibitors of aldose reductase, mineralocorticoid receptor inhibitors, inhibitors of TORC2, inhibitors of CCR2 and/or CCR5, inhibitors of PKC isoforms (e.g. PKCa, ΡΚΟβ, PKCy), inhibitors of fatty acid synthetase, inhibitors of serine palmitoyi transferase, modulators of GPR81 , GPR39, GPR43, GPR41 , GPR105, Kv1 .3, retinol binding protein 4, glucocorticoid receptor, somatostain receptors (e.g. SSTR1 , SSTR2, SSTR3 and SSTR5), inhibitors or modulators of PDHK2 or PDHK4, inhibitors of MAP4K4, modulators of IL1 family including ILI beta, modulators of RXRalpha. In addition suitable anti-diabetic agents include mechanisms listed by Carpino, P.A., Goodwin, B. Expert Opin. Ther. Pat, 2010, 20(12), 1627-51 .

Suitable anti-obesity agents (some of which may also act as anti-diabetic agents as well) include 1 1 β-hydroxy steroid dehydrogenase-1 (1 1 β-HSD type 1 ) inhibitors, stearoyl-CoA desaturase-1 (SCD-1 ) inhibitor, MCR-4 agonists, cholecystokinin-A (CCK- A) agonists, monoamine reuptake inhibitors (such as sibutramine), sympathomimetic agents, β3 adrenergic agonists, dopamine agonists (such as bromocriptine), melanocyte-stimulating hormone analogs, 5HT2c agonists, melanin concentrating hormone antagonists, leptin (the OB protein), leptin analogs, leptin agonists, galanin antagonists, lipase inhibitors (such as tetrahydrolipstatin, i.e. orlistat), anorectic agents (such as a bombesin agonist), neuropeptide-Y antagonists (e.g., NPY Y5 antagonists such as velneperit), PYY3-36 (including analogs thereof), BRS3 modulator, mixed antagonists of opiod receptor subtypes, thyromimetic agents, dehydroepiandrosterone or an analog thereof, glucocorticoid agonists or antagonists, orexin antagonists, glucagon-like peptide-1 agonists, ciliary neurotrophic factors (such as Axokine™ available from Regeneron Pharmaceuticals, Inc., Tarrytown, NY and Procter s Gamble Company, Cincinnati, OH), human agouti-related protein (AGRP) inhibitors, histamine 3 antagonists or inverse agonists, neuromedin U agonists, MTP/ApoB inhibitors (e.g., gut-selective MTP inhibitors, such as dirlotapide, JTT130, Usistapide, SLx4090), opioid antagonist, mu opioid receptor modulators, including but not limited to GSK1521498, MetAp2 inhibitors, including but not limited to ZGN-433, agents with mixed modulatory activity at 2 or more of glucagon, GIP and GLP1 receptors, such as MAR-701 or ZP2929, norepinephrine transporter inhibitors, cannabinoid-1 -receptor antagonist/inverse agonists, ghrelin agonists/antagonists, oxyntomodulin and analogs, monoamine uptake inhibitors, such as but not limited to tesofensine, an orexin antagonist, combination agents (such as bupropion plus zonisamide, pramlintide plus metreleptin, bupropion plus naltrexone, phentermine plus topiramate), and the like.

Preferred anti-obesity agents for use in the combination aspects of the present invention include gut-selective MTP inhibitors (e.g., dirlotapide, mitratapide and implitapide, R56918 (CAS No. 403987) and CAS No. 913541 -47-6), CCKa agonists (e.g., N-benzyl-2-[4-(1 H-indol-3-ylmethyl)-5-oxo-1 -phenyl-4,5-dihydro-2,3, 6,10b- tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-acetamide described in PCT Publication No. WO 2005/1 16034 or US Publication No. 2005-0267100 A1 ), 5HT2c agonists (e.g., lorcaserin), MCR4 agonist (e.g., compounds described in US 6,818,658), lipase inhibitor (e.g., Cetilistat), PYY3-36 (as used herein "PYY₃-3₆" includes analogs, such as peglated PYY3-36 e.g., those described in US Publication 2006/0178501 ), opioid antagonists (e.g., naltrexone), oleoyl-estrone (CAS No. 180003-17-2), obinepitide (TM30338), pramlintide (Symlin®), tesofensine (NS2330), leptin, bromocriptine, orlistat, AOD-9604 (CAS No. 221231 -10-3) and sibutramine. Preferably, compounds of the present invention and combination therapies are administered in conjunction with exercise and a sensible diet.

All of the above recited U.S. patents and publications are incorporated herein by reference.

Pharmaceutical Formulations

The present invention also provides pharmaceutical compositions which comprise a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, in admixture with at least one pharmaceutically acceptable excipient. The compositions include those in a form adapted for oral, topical or parenteral use and can be used for the treatment of diabetes and related conditions as described above.

The composition can be formulated for administration by any route known in the art, such as subdermal, inhalation, oral, topical, parenteral, etc. The compositions may be in any form known in the art, including but not limited to tablets, capsules, powders, granules, lozenges, or liquid preparations, such as oral or sterile parenteral solutions or suspensions. Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats,

emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerin, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavoring or coloring agents.

For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle or other suitable solvent. In preparing solutions, the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, agents such as local anesthetics, preservatives and buffering agents etc. can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound. The compositions may contain, for example, from about 0.1 % to about 99 by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will contain, for example, from about 0.1 to 900 mg of the active ingredient, more typically from 1 mg to 250mg.

Compounds of the invention can be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other antidiabetic agents. Such methods are known in the art and have been summarized above. For a more detailed discussion regarding the preparation of such formulations; the reader's attention is directed to Reminqton"s Pharmaceutical Sciences, 21^st Edition, by University of the Sciences in Philadelphia.

Embodiments of the present invention are illustrated by the following Examples. It is to be understood, however, that the embodiments of the invention are not limited to the specific details of these Examples, as other variations thereof will be known, or apparent in light of the instant disclosure, to one of ordinary skill in the art.

EXAMPLES

Unless specified otherwise, starting materials are generally available from commercial sources such as Aldrich Chemicals Co. (Milwaukee, Wl), Lancaster Synthesis, Inc. (Windham, NH), Acros Organics (Fairlawn, NJ), Maybridge Chemical Company, Ltd. (Cornwall, England), Tyger Scientific (Princeton, NJ), and AstraZeneca Pharmaceuticals (London, England), Mallinckrodt Baker (Phillipsburg NJ); EMD

(Gibbstown, NJ).

General Experimental Procedures

NMR spectra were recorded on a Varian Unity™ 400 (DG400-5 probe) or 500 (DG500-5 probe - both available from Varian Inc., Palo Alto, CA) at room temperature at 400 MHz or 500 MHz respectively for proton analysis. Chemical shifts are expressed in parts per million (delta) relative to residual solvent as an internal reference. The peak shapes are denoted as follows: s, singlet; d, doublet; dd, doublet of doublet; t, triplet; q, quartet; m, multiplet; bs, broad singlet; 2s, two singlets.

Atmospheric pressure chemical ionization mass spectra (APCI) were obtained on a Waters™ Spectrometer (Micromass ZMD, carrier gas: nitrogen) (available from Waters Corp., Milford, MA, USA) with a flow rate of 0.3 mL/minute and utilizing a 50:50 water/acetonitrile eluent system. Electrospray ionization mass spectra (ES) were obtained on a liquid chromatography mass spectrometer from Waters™ (Micromass ZQ or ZMD instrument (carrier gas: nitrogen) (Waters Corp., Milford, MA, USA) utilizing a gradient of 95:5 - 0:100 water in acetonitrile with 0.01 % formic acid added to each solvent. These instruments utilized a Varian Polaris 5 C18-A20x2.0mm column (Varian Inc., Palo Alto, CA) at flow rates of 1 mL/minute for 3.75 minutes or 2 mL/minute for 1 .95 minutes.

Column chromatography was performed using silica gel with either Flash 40 Biotage™ columns (ISC, Inc., Shelton, CT) or Biotage™ SNAP cartridge KPsil or Redisep Rf silica (from Teledyne Isco Inc) under nitrogen pressure. Preparative HPLC was performed using a Waters FractionLynx system with photodiode array (Waters 2996) and mass spectrometer (Waters/Micromass ZQ) detection schemes. Analytical HPLC work was conducted with a Waters 2795 Alliance HPLC or a Waters ACQUITY UPLC with photodiode array, single quadrupole mass and evaporative light scattering detection schemes.

Optical rotations were determined using a Perkin-Elmer model 343 polarimeter. Concentration in vacuo refers to evaporation of solvent under reduced pressure using a rotary evaporator.

Unless otherwise noted, chemical reactions were performed at room temperature (about 23 degrees Celsius). Also, unless otherwise noted chemical reactions were run under an atmosphere of nitrogen.

PHARMACOLOGICAL DATA

The practice of the invention for the treatment of diseases modulated by the agonist activation of G-protein-coupled receptor GPR1 19 with compounds of the invention can be evidenced by activity in one or more of the functional assays described herein below. The source of supply is provided in parenthesis.

In- Vitro Functional Assays

cAMP:

GPR1 19 agonist activity was determined with a cell-based assay utilizing an HTRF (Homogeneous Time-Resolved Fluorescence) cAMP detection kit (cAMP dynamic 2 Assay Kit; Cis Bio cat # 62AM4PEC) that measures cAMP levels in a HEK293-CRE beta-lactamase reporter cell line expressing human GPR1 19. The method is a competitive immunoassay between native cAMP produced by the cells and the cAMP labeled with the dye d2. The tracer binding is visualized by a Mab anti-cAMP labeled with Cryptate. The specific signal (i.e. energy transfer) is inversely proportional to the concentration of cAMP in either standard or sample.

Specifically, hGPR1 19 HEK-CRE beta-lactamase cells (Invitrogen 2.5 x 10⁷/ml_) are removed from cryopreservation and diluted in growth medium (Dulbecco's modified Eagle medium high glucose (DMEM; Gibco Cat # 1 1995-065), 1 % charcoal dextran treated fetal bovine serum (CD serum; HyClone Cat # SH30068.03), 1x MEM

Nonessential amino acids (Gibco Cat # 15630-080) and 25 mM HEPES pH 7.0 (Gibco Cat # 15630-080)). The cell concentration was adjusted to 1 .5 x 10⁵ cells/mL and 30 mLs of this suspension was added to a T-175 flask and incubated at 37 degrees Celsius in a humidified environment in 5% carbon dioxide. After 16 hours (overnight), the cells were removed from the T-175 flask (by rapping the side of the flask), centrifuged at 800 x g and then re-suspended in assay medium (1 x HBSS +CaCI₂ + MgCI₂ (Gibco Cat # 14025-092) and 25 mM HEPES pH 7.0 (Gibco Cat # 15630-080)). The cell

concentration was adjusted to 6.25 x 10⁵ cells/mL with assay medium and 8 μΙ of this cell suspension (5000 cells) was added to each well of a white Greiner 384-well, low- volume assay plate (VWR cat # 82051 -458).

Varying concentrations of each compound to be tested were diluted in assay buffer containing 3-isobutyl-1 -methylxanthin (IBMX; Sigma cat # I5879) and added to the assay plate wells in a volume of 2 microL (final IBMX concentration was 400 microM and final DMSO concentration was 0.58%). Following 30 minutes incubation at room temperature, 5 microL of labeled d2 cAMP and 5 microL of anti-cAMP antibody (both diluted 1 :20 in cell lysis buffer; as described in the manufacturers assay protocol) were added to each well of the assay plate. The plates were then incubated at room temperature and after 60 minutes, changes in the HTRF signal were read with an Envision 2104 multilabel plate reader using excitation of 330 nm and emissions of 615 and 665 nm. Raw data were converted to nM cAMP by interpolation from a cAMP standard curve (as described in the manufacturer's assay protocol) and EC50 determinations were made from an agonist-response curves analyzed with a curve fitting program using a 4-paramter logistic dose response equation.

It is recognized that cAMP responses due to activation of GPR1 19 could be generated in cells other than the specific cell line used herein. The following results were obtained for the cAMP assay

^*The intrinsic activity is the percent of maximal activity of the test compound, relative to the activity of a standard GPR1 19 agonist, 4-[[6-[(2-fluoro-4 methylsulfonylphenyl) amino]pyrimidin-4-yl]oxy]piperidine-1 -carboxylic acid isopropyl ester (WO2005121 121 ), or (S)-1-methylcyclopropyl 4-(1 -fluoro-2-(2-(2,3,6- trifluorophenyl)acetamido)ethyl)piperidine-1 -carboxylate (see Figure below; disclosed in Bioorganic & Medicinal Chemistry Letters 2011 , 21, 1306-1309), at a final concentration of 10 micromolar.

Structure of (S)-1-methylcvclopropyl 4-(1 -fluoro-2-(2-(2,3,6-trifluorophenyl)acetamido)- ethyl)piperidine-1 -carboxylate

Preparation of 1-Methylcvclopropyl 4-nitrophenyl carbonate

A) 1 -Methylcvclopropanol

A 1 L flask was charged with titanium methoxide (100 g), cyclohexanol (232 g), and toluene (461 ml_). The flask was equipped with a Dean-Stark trap and condenser. The mixture was heated at 140 degrees Celsius until the methanol was removed. The toluene was removed at 180 degrees Celsius. More toluene was added and this process was repeated twice. After all the toluene was removed the flask was dried under high vacuum. Diethyl ether (580 mL) was added to the flask to prepare a 1 M solution in diethyl ether. A 5 L, 3-neck flask was equipped with an overhead stirrer, inert gas inlet and a pressure-equalizing addition funnel. The flask was flushed with nitrogen gas and charged with methyl acetate (60.1 mL, 756 mmol), titanium cyclohexyloxide (1 M solution in ether 75.6 mL), and diethyl ether (1500 mL). The solution was stirred while keeping the reaction flask in a room temperature water bath. The addition funnel was charged with the 3 M ethylmagnesium bromide solution (554 mL, 1 .66 moles). The Grignard reagent was added drop-wise over 3 hours at room temperature. The mixture became a light yellow solution, and then gradually a precipitate formed which eventually turned to a dark green/brown/black colored mixture. After stirring for an additional 15 minutes, following the addition of the Grignard, the mixture was carefully poured into a mixture of 10% concentrated sulfuric acid in 1 L of water. The resulting mixture was stirred until all the solids dissolved. The aqueous layer was separated and extracted with diethyl ether 2 x 500 mL. The combined organic extracts were washed sequentially with water, brine, dried over potassium carbonate (500 g) for 30 minutes, filtered and the filtrate was concentrated in vacuo to an oil. Sodium bicarbonate (200 mg) was added and the crude material was distilled, collecting fractions boiling around 100 degrees Celsius to give the title compound (23 grams) with methyl ethyl ketone and 2- butanol as minor impurities. ¹ H NMR (500 MHz, deuterochloroform) delta 0.45 (app. t, J=6.59 Hz, 2 H), 0.77 (app. t, J=5.61 Hz, 2 H), 1.46 (s, 3 H). The preparation of the title compound is also described in WO09105717.

B) 1 -Methylcvclopropyl 4-nitrophenyl carbonate

A solution of 1 -methylcyclopropanol (10 g, 137 mmol), 4-nitrophehyl chloroformate (32 g, 152 mmol), and a few crystals of 4-dimethylaminopyridine (150 mg, 1 .2 mmol) in dichloromethane (462 mL), was cooled to zero degree Celsius. Triethylamine (36.5 g, 361 mmol) was added drop-wise. After 10 minutes, the ice bath was removed and the reaction was allowed to stir at room temperature for 14 hours. The reaction mixture was washed twice with saturated aqueous sodium carbonate. The aqueous phase was extracted with dichloromethane. The combined organic extracts were washed with water, dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by flash silica gel chromatography, eluting with a gradient mixture of ethyl acetate in heptane (0 to 5% ethyl acetate over the first 10 minutes, then isocratic at 5% ethyl acetate to heptane) to give 20.8 g of the desired carbonate as a clear oil. This oil solidified upon standing.

¹ H NMR (500 MHz, deuterochloroform) delta 0.77 (app. t, =6.59 Hz, 2 H), 1 .09 (app. t, J=7.07 Hz, 2 H), 1.67 (s, 3 H), 7.40 (app. dt, J=9.27, 3.17 Hz, 2 H), 8.29 (app. dt, J=9.27, 3.17 Hz, 2 H).

Alternatively the 1 -methylcyclopropanol can be prepared as follows:

1 -Methylcvclopropanol

A 2000 mL 4-neck flask was equipped with a mechanical stirrer, inert gas inlet, thermometer, and two pressure - equalizing addition funnels. The flask was flushed with nitrogen and charged with 490 mL of diethyl ether followed by 18.2 mL (30 mmol) of titanium tetra(2-ethylhexyloxide). One addition funnel was charged with a solution prepared from 28.6 mL (360 mmol) of methyl acetate diluted to 120 mL with ether. The second addition funnel was charged with 200 mL of 3 M ethylmagnesium bromide in ether solution. The reaction flask was cooled in an ice water bath to keep the internal temperature at 10 degrees Celsius or below. Forty milliliters of the methyl acetate solution was added to the flask. The Grignard reagent was then added drop-wise from the addition funnel at a rate of about 2 drops every second, and no faster than 2 mL per minute. After the first 40 mL of Grignard reagent had been added, another 20 mL portion of methyl acetate in ether solution was added. After the second 40 mL of Grignard reagent had been added, another 20 mL portion of methyl acetate in diethyl ether solution was added. After the third 40 mL of Grignard reagent had been added, another 20 mL portion of methyl acetate in ether solution was added. After the fourth 40 mL of Grignard reagent had been added, the last 20 mL portion of methyl acetate in ether solution was added.

The mixture was stirred for an additional 15 minutes following the completion of the addition of Grignard reagent. The mixture was then poured into a mixture of 660 g of ice and 60 mL of concentrated sulfuric acid with rapid stirring to dissolve all solids. The phases were separated and the aqueous phase was extracted again with 50 mL of diethyl ether. The combined ether extracts were washed with 15 mL of 10% aqueous sodium carbonate, 15 mL of brine, and dried over 30 grams magnesium sulfate for 1 hour with stirring. The ether solution was then filtered. Tri-n-butylamine (14.3 mL, 60 mmol) and mesitylene (10 mL were added. Most of the diethyl ether was removed by distillation at atmospheric pressure using a 2.5 cm x 30 cm jacketed Vigreux column. The remaining liquid was transferred to a smaller distillation flask using two 10 mL portions of hexane to facilitate the transfer. Distillation at atmospheric pressure was continued through a 2 cm x 20 cm jacketed Vigreux column. The liquid distilling at 98 - 105 °C was collected to provide 14 g of the title compound as a colorless liquid. ¹ H NMR (400 MHz, deuterochloroform) delta 0.42 - 0.48 (m, 2 H), 0.74 - 0.80 (m, 2 H), 1 .45 (s, 3 H), 1.86 (br. s., 1 H).

Preparation of Isomers of ferf-Butyl-3-fluoro-4-hvdroxypiperidine-1-carboxylate (B and C)

The experimental details are described in detail in Scheme 1 below.

Scheme 1

step c

E D B C

Step A) fert-Butyl-4-r(trimethylsilyl)oxyl-3,6-dihvdropyridine-1 (2H)-carboxylate

To a solution of A/-terf-butoxycarbonyl-4-piperidone (30.0 g, 0.15 mol) in dry N,N- dimethylformamide (300 mL) at room temperature was added trimethylsilyl chloride (22.9 mL, 0.18 mol) and triethylamine (50.4 mL, 0.36 mol) successively via addition funnels. The resulting solution was heated at 80 degrees Celsius overnight and then cooled to room temperature. The reaction mixture was diluted with water and heptane. The layers were separated, and the aqueous layer was extracted with heptane. The combined heptane layers were washed sequentially with water and brine and then dried over magnesium sulfate. The mixture was filtered, and the filtrate concentrated under reduced pressure to give the crude product as a yellow oil. The oil was purified by passing it through a plug of silica gel eluting with 9:1 heptane/ethyl acetate to give the title compound as a colorless oil (33.6 g, 82%). ¹H NMR (400 MHz, deuterochloroform) delta 4.78 (br s, 1 H), 3.86 (br s, 2H), 3.51 (t, 2H), 2.09 (br s, 2H), 1 .45 (s, 9H), 0.18 (s, 9H).

Step B) tert-Butyl-3-fluoro-4-oxopiperidine-1 -carboxylate

To a stirred solution of iert-butyl-4-[(trimethylsilyl)oxy]-3,6-dihydropyridine-1 (2H)- carboxylate (28.8 g, 0.1 1 mol) in acetonitrile (300 mL) at room temperature was added Selectfluor™ (41.4 g, 0.12 mol). The resulting pale yellow suspension was stirred at room temperature for 1 .5 hours. Saturated aqueous sodium bicarbonate (300 mL) and ethyl acetate (300 mL) were added, and the layers were separated. The aqueous layer was extracted twice with ethyl acetate, and all the organic layers were combined and washed sequentially with saturated aqueous sodium bicarbonate and brine and then dried over magnesium sulfate. The mixture was filtered, and the filtrate was

concentrated under reduced pressure to give the crude product as a pale yellow oil. Purification of this material by repeated column chromatography on silica gel with heptane/ethyl acetate gradient (2:1 to 1 :1 ) gave the title compound as a white solid (15.5 g, 67%). ¹ H NMR (400 MHz, deuterochloroform): delta 4.88 (dd, 0.5 H), 4.77 (dd, 0.5H), 4.47 (br s, 1 H), 4.17 (ddd, 1 H), 3.25 (br s, 1 H), 3.23 (ddd, 1 H), 2.58 (m, 1 H), 2.51 (m, 1 H), 1 .49 (s, 9H).

Alternatively Step B can be performed as follows, isolating the hydrate of the ketone. To a stirred solution of ieri-butyl-4-[(trimethylsilyl)oxy]-3,6-dihydropyridine-1 (2H)- carboxylate (41 .3 g, 0.15 mol) in acetonitrile (500 mL) at room temperature was added Selectfluor™ (56.9 g, 0.16 mol). The resulting pale yellow suspension was stirred at room temperature for 4 hours 10 minutes. Saturated aqueous sodium bicarbonate and ethyl acetate were added, and the layers were separated. The aqueous layer was extracted twice with ethyl acetate, and all the organic layers were combined and washed sequentially with saturated aqueous sodium bicarbonate and brine and then dried over magnesium sulfate. The mixture was filtered, and the filtrate was

concentrated under reduced pressure to give the crude tert-butyl-3-fluoro-4- oxopiperidine-1 -carboxylate as white solid. The crude terf-butyl-3-fluoro-4- oxopiperidine-1 -carboxylate was suspended in tetrahydrofuran (120 mL) and water (120 mL) was added. The resulting solution was stirred at room temperature for 5.5 hours and then concentrated under reduced pressure. The residue was dried under high vacuum, transferred to an Erlenmeyer flask, and suspended in dichloromethane (250 mL). The resulting suspension was stirred for 5 minutes and the solids collected by filtration using a sintered glass funnel. The resulting filter cake was thoroughly washed with dichloromethane (200 mL), a 1 :1 mixture of dichloromethane (200 mL) and heptane (100 mL). The solid was then dried under high vacuum to provide tert-butyl 3-fluoro-4,4- dihydroxypiperidine-1 -carboxylate (26.4 g). 1 H NMR (500 MHz, deutero dimethyl sulfoxide) delta 1 .38 (s, 9 H), 1.49-1 .52 (m, 1 H), 1.63-1 .68 (m, 1 H), 2.82 -3.20 (m, 2 H) 3.75 (br, 1 H), 3.97 (br, 1 H), 4.12 (d, J = 45, 1 H), 5.92 (s, 1 H), 5.97 (s, 1 H).

Step C) Isomers of (f?^*)-fert-Butyl-3-(S)-fluoro-4-(/^:?)-hvdroxypiperidine-1-carboxylate (racemic)

To a solution of iert-butyl-3-fluoro-4-oxopiperidine-1 -carboxylate (15.5 g, 71.3 mmol) in methanol (150 mL) at 0 degrees Celsius was added sodium borohydride (3.51 g, 93.7 mmol). The resulting mixture was stirred at 0 degrees Celsius for 2 hours and then allowed to warm to room temperature. Saturated aqueous ammonium chloride (200 mL) was added, and the mixture was extracted three times with ethyl acetate. The combined extracts were washed with brine and dried over magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude product mixture which was purified by column chromatography on silica gel eluting with heptane-ethyl acetate (3:2 - 1 :1 ) to give the first eluting product, terf-butyl- (3,4-frans)-3-fluoro-4-hydroxypiperidine-1-carboxylate (compound C, Scheme 1 ) (3.81 g, 24%), as a pale yellow oil which solidified on standing to a white solid. 1 H NMR (400 MHz, deuterochloroform) delta 4.35 (ddd, 0.5 H), 4.18 (ddd, 0.5 H), 4.15 (br s, 1 H), 3.89-3.74 (m, 2H), 2.97 (br s, 1 H), 2.93 (ddd, 1 H), 2.47 (s, 1 H), 2.05-1 .92 (m, 1 H), 1.58- 1 .46 (m, 1 H), 1 .44 (s, 9H).

The second eluting compound, iert-butyl-(3,4-c/^'s)-3-fluoro-4-hydroxy-piperidine-

1 -carboxylate (compound B, Scheme 1 ) (10.57 g, 68%) was then isolated as a white solid. 1 H NMR (400 MHz, deuterochloroform) delta 4.69 - 4.65 (m, 0.5H), 4.53-4.49 (m, 0.5H), 3.92 - 3.86 (m, 2H), 3.69 (br s, 1 H), 3.39 (br s, 1 H), 3.16 (br s, 1 H), 2.13 (s, 1 H), 1 .88 - 1.73 (m, 2H), 1.44 (s, 9H).

Alternatively Step C can be performed starting with the hydrate tert-butyl 3-fluoro-

4, 4-dihydroxypiperidine-1 -carboxylate (Step 2) as follows.

To a stirred solution of tert-butyl 3-fluoro-4,4-dihydroxypiperidine-1-carboxylate (20.0 g, 85 mmol) in tetrahydrofuran (500 mL) at -35 degrees Celsius was added a solution of L-Selectride® in tetrahydrofuran (170 mL, 1 M, 170 mmol) drop-wise over 30 minutes. The reaction mixture was warmed to 0 degree Celsius over 1.5 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (150 mL) and vigorously stirred for 15 minutes. To this 0 degree Celsius mixture was added pH 7 phosphate buffer (150 mL), followed by drop-wise addition of a 35% aqueous hydrogen peroxide solution (150 mL). The resulting mixture was stirred for 30 minutes and diluted with ethyl acetate. The organic layer was separated and sequentially with water, saturated aqueous sodium thiosulfate and brine. The organic layer was then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure give the crude product mixture which was purified by column chromatography on silica gel [ combiflash ISCO 330 g column] eluting with heptane-ethyl acetate (10 to 60% gradient) to give ieri-butyl-(3,4-c/^'s)-3-fluoro-4-hydroxypiperidine-1 -carboxylate (13.9 g). Step D) Enantiomers of fert-butyl-(3,4-c/^'s)-3-fluoro-4-hvdroxy-piperidine-1-carboxylate

A 1 gram sample of racemic ieri-butyl-(3,4-c/^'s)-3-fluoro-4-hydroxy-piperidine-1 - carboxylate was purified into its enantiomers via preparatory high pressure liquid chromatography utilizing a Chiralpak AD-H column (10 x 250 mm) with a mobile phase of 90:10 carbon dioxide and ethanol respectively at a flow rate of 10 mL/minute. The wavelength for monitoring the separation was 210 nm. The analytical purity of each enantiomer was determined using analytical high pressure chromatography using a Chiralpak AD-H (4.6 mm x 25 cm) column with an isocratic mobile phase of 90:10 carbon dioxide and ethanol respectively at a flow rate of 2.5 mL/minute. The wavelength for monitoring the peaks was 210 nm. The following two isomers were obtained:

Compound E, Scheme 1 , (3S,4f?)-fert-butyl 3-fluoro-4-hvdroxypiperidine-1 -carboxylate, enantiomer 1 (363 mg): R, = 2.67 min (100% ee); [a]_D ²¹ = +21 .2 degrees (c 0.64, dichloromethane); and

Compound D, Scheme 1 , (3R4S)-tert-butyl 3-fluoro-4-hvdroxypiperidine-1 -carboxylate, enantiomer 2 (403 mg): R_f = 2.99 min (88% ee); [a]_D ²¹ = -17.8 degrees (c O.64, dichloromethane).

Preparation of te/t-butyl (3,4-frans)-3-fluoro-4-({5-methyl-6-r(2-methylpyridin-3- yl)oxylpyrimidin-4-yl}oxy)piperidine-1 -carboxylate (racemic)

To the racemic iert-butyl(3,4-irans)-3-fluoro-4-hydroxypiperidine-1-carboxylate

(Compound C, Scheme 1 ) (977 mg, 4.46 mmol) dissolved in THF (6 mL) was added 1 M potassium te/t-butoxide in THF (5.95 mL, 5.95 mmol). After stirring for 20 minutes, the solution was added drop-wise to 4-chloro-5-methyl-6-[(2-methylpyridin-3- yl)oxy]pyrimidine (1000 mg, 4.23 mmol) that had been dissolved in THF (15 mL) and cooled by ice/water bath. After 35 minutes the ice bath was removed and the reaction was stirred for an additional 2.5 hours. The mixture was diluted with water and brine and was extracted with ethyl acetate (3 x 40 mL). The organics were pooled, washed with brine, dried over sodium sulfate, filtered and the filtrate was concentrated. The residue was pre-adsorbed onto 25 g silica and purified by chromatography on 100 g silica eluting with ethyl acetate/heptanes to give the title compound as a clear, sticky solid (1.23 g, 69%). ¹ H NMR (500 MHz, deuterochloroform) delta ppm 1 .50 (s, 9 H) 1.67 - 1 .83 (m, 1 H) 2.18 - 2.32 (m, 4 H) 2.43 (s, 3 H) 3.39 (s, 1 H) 3.53 (s, 1 H) 3.65 - 3.79 (m, 1 H) 3.98 (br. s, 1 H) 4.54 - 4.86 (m, 1 H) 5.38 - 5.52 (m, 1 H) 7.27 (s, 1 H) 7.38 - 7.46 (m, 1 H) 8.21 (s, 1 H) 8.43 (d, J=4.15 Hz, 1 H). LCMS (ES+): 419.1 (M+1 ). TLC: Rf: 0.27 in 60% ethyl acetate/heptane. Preparation of enantiomers of te/t-butyl (3,4-frans)-3-fluoro-4-({5-methyl-6-r(2- methylpyridin-3-yl)oxylpyrimidin-4-yl}oxy)piperidine-1 -carboxylate

A 1 .1 gram sample of racemic te/t-butyl (3,4-/rans)-3-fluoro-4-({5-methyl-6-[(2- methylpyridin-3-yl)oxy]pyrimidin-4-yl}oxy)piperidine-1 -carboxylate was purified into its enantiomers via preparatory high pressure liquid chromatography utilizing a Chiralcel OD-H column (10 x 250 mm) with a mobile phase of 90:10 carbon dioxide and ethanol respectively at a flow rate of 10 mL/minute with a loading of 5.5 mg/injection. The wavelength for monitoring the separation was 210 nm. The analytical purity of each enantiomer was determined using analytical high pressure chromatography using a Chiralcel OD-H column (4.6 mm x 25 cm) with a mobile phase of 90:10 carbon dioxide and ethanol respectively at a flow rate of 2.5 mL/minute. The wavelength for monitoring the peaks was 210 nm. The following two isomers were obtained:

Enantiomer 1 , tert-butyl (3f?,4f?)-3-fluoro-4-({5-methyl-6-[(2-methylpyridin-3- yl)oxy]pyrimidin-4-yl}oxy)piperidine-1 -carboxylate as a pale yellow sticky solid (509 mg): R, = 4.19 min (97% ee); and

Enantiomer 2, tert-butyl (3S,4S)-3-fluoro-4-({5-methyl-6-[(2-methylpyridin-3- yl)oxy]pyrimidin-4-yl}oxy)piperidine-1 -carboxylate as a pale yellow sticky solid (569 mg): R_f = 4.68 min (93% ee).

The absolute stereochemical assignment for the above precursors to Examples 1 and 2 was made using the literature Mosher ester method (Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512-519). All absolute structure assignments herein follow from the Mosher ester analysis. This work is described below.

Preparation of the enantiomers of fert-butyl (3,4-/rans)-3-fluoro-4-hvdroxypiperidine-1 - carboxylate

A 400 mg sample of racemic tert-butyl (3,4-frans)-3-fluoro-4-hydroxypiperidine-1- carboxylate (Compound C, Scheme 1 ), was purified into its enantiomers via preparatory high pressure liquid chromatography utilizing a Chiralpak AD-H column (10 x 250 mm) with a mobile phase of 80:20 carbon dioxide and methanol respectively at a flow rate of 10 mL/minute with a loading of 6.7 mg/injection. The wavelength for monitoring the separation was 210 nm. The analytical purity of each enantiomer was determined using analytical high pressure chromatography using a Chiralpak AD-H column (4.6 mm x 25 cm) with a mobile phase of 80:20 carbon dioxide and methanol respectively at a flow rate of 2.5 mL/minute. The wavelength for monitoring the peaks was 210 nm. The following two isomers were obtained:

Enantiomer 1 ; terf-butyl (3f?,4f?)-3-fluoro-4-hydroxypiperidine-1 -carboxylate as a pale yellow solid (178 mg): R, = 3.17 min (99% ee); and Enantiomer 2: terf-butyl (3S,4S)-3-fluoro-4-hydroxypiperidine-1-carboxylate as a pale yellow solid (159 mg): R, = 5.69 min (99% ee).

These enantiomers were further purified by silica gel chromatography, eluting with ethyl acetate/heptanes to give white solids.

Preparation of te/t-butyl (3S,4SV3-fluoro-4-fr(2S)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoylloxy}piperidine-1 -carboxylate

To a stirred, cold (degrees Celsius) solution of the tert-butyl (3S,4S)-3-fluoro-4- hydroxypiperidine-1-carboxylate (Enantiomer 2 from above) (20 mg, 0.09 mmol) and pyridine (22 μΙ_, 0.27 mmol) in dichloromethane (0.3 mL) was added (2f?)-3,3,3-trifluoro- 2-methoxy-2-phenylpropanoyl chloride (34 μΙ_, 0.18 mmol) via microsyringe. The ice bath was then removed and the suspension was stirred for 22 hours at room

temperature. The mixture was diluted with dichloromethane and aqueous sodium bicarbonate solution before it was extracted with dichloromethane (3 x 10 mL). The combined organic extracts were dried over sodium sulfate, filtered and the filtrate was concentrated under vacuum. The clear residue was pre-adsorbed onto 5 g of silica and purified by chromatography on 4 g silica, eluting with a gradient mixture of 0-20% ethyl acetate in heptane to give the title compound as a clear, colorless, viscous oil (41 mg, 100%). ¹ H NMR (500 MHz, deuterochloroform) delta ppm 1.45 (s, 9 H) 1 .52 - 1.64 (m, 1 H) 2.06 - 2.13 (m, 1 H) 3.04 - 3.16 (m, 1 H) 3.22 (br. s., 1 H) 3.58 (d, J=0.98 Hz, 3 H) 3.70 - 3.81 (m, 1 H) 3.91 - 4.28 (m, 1 H) 4.39 - 4.61 (m, 1 H) 5.18 - 5.28 (m, 1 H) 7.38 - 7.46 (m, 3 H) 7.49 - 7.56 (m, 2 H). TLC: R_f: 0.27 in 15% ethyl acetate/heptane. Preparation of te/t-butyl (3S,4SV3-fluoro-4-fr(2ffl-3,3,3-trifluoro-2-methoxy-2- phenylpropanoylloxy}piperidine-1 -carboxylate

The title compound was prepared from terf-butyl (3S,4S)-3-fluoro-4-hydroxypiperidine-1- carboxylate (Enantiomer 2 from above) (20 mg, 0.09 mmol) and (2S)-3,3,3-trifluoro-2- methoxy-2-phenylpropanoyl chloride (34 μΙ_, 0.18 mmol) in a manner similar to that used to prepare tert-butyl (3S,4S)-3-fluoro-4-{[(2S)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoyl]oxy}piperidine-1 -carboxylate. The title compound was obtained as a clear, colorless, viscous residue (41 mg, 100%). ¹H NMR (500 MHz,

deuterochloroform) delta ppm 1 .46 (s, 9 H) 1 .66 - 1.78 (m, 1 H) 2.10 - 2.21 (m, 1 H)

3.27 (br. s., 1 H) 3.37 (br. s., 1 H) 3.54 (d, J=0.98 Hz, 3 H) 3.60 - 3.71 (m, 1 H) 3.85 (br. s., 1 H) 4.34 - 4.56 (m, 1 H) 5.23 - 5.31 (m, 1 H) 7.39 - 7.46 (m, 3 H) 7.49 - 7.56 (m, 2 H). TLC: R_f: 0.24 in 15% ethyl acetate/heptane.

Preparation of 4-{r(3R4/^:?)-3-fluoropiperidin-4-ylloxy}-5-methyl-6-r(2-methylpyridin-3- vDoxylpyrimidine

A solution of tert-butyl (3R,4R)-3-fluoro-4-({5-methyl-6-[(2-methylpyridin-3- yl)oxy]pyrimidin-4-yl}oxy)piperidine-1 -carboxylate (496 mg, 1 .19 mmol) in methanol (6 mL) was treated with 4 N hydrogen chloride in dioxane (3.0 mL, 12 mmol) and stirred for 3.5 hours. The mixture was concentrated to dryness under vacuum. The resulting tan foam was dissolved in methanol (5 mL) and made basic by the addition of ~7 N ammonia in methanol (1 .2 mL). This solution was then pre-adsorbed onto 2 g of silica and purified by chromatography on 25 g of silica, eluting with a gradient mixture of 0-9% of a solution of concentrated aqueous ammonium hydroxide in methanol (1 :9) in methylene chloride. The title compound was isolated as a white solid (358 mg, 95%). ¹ H NMR (500 MHz, deuterochloroform) delta ppm 1.62 - 1 .81 (m, 2 H) 2.21 - 2.32 (m, 4 1-1) 2.42 (s, 3 1-1) 2.83 (ddd, J=12.81 , 9.03, 3.29 Hz, 1 H) 2.93 (dt, =12.87, 7.59 Hz, 1 H) 3.03 - 3.14 (m, 1 H) 3.38 (ddd, J=16.59, 12.81 , 3.78 Hz, 1 H) 4.55 - 4.76 (m, 1 H) 5.35 - 5.47 (m, 1 H) 7.22 (dd, J=8.05, 4.88 Hz, 1 H) 7.40 (dd, J=8.05, 1 .22 Hz, 1 H) 8.21 (d, J=0.49 Hz, 1 H) 8.42 (dd, J=4.88, 1 .46 Hz, 1 H). LCMS (ES+): 319.6 (M+1 ).

Preparation of 4-{r(3S,4S)-3-fluoropiperidin-4-ylloxy}-5-methyl-6-r(2-methylpyridin-3- vDoxylpyrimidine

The title compound was prepared from terf-butyl (3S,4S)-3-fluoro-4-({5-methyl-6-[(2- methylpyridin-3-yl)oxy]pyrimidin-4-yl}oxy)piperidine-1-carboxylate (550 mg, 1 .32 mmol) in a manner similar to that used to prepare 4-{[(3f?,4/^:?)-3-fluoropiperidin-4-yl]oxy}-5- methyl-6-[(2-methylpyridin-3-yl)oxy]pyrimidine. The title compound was obtained as a white solid (374 mg, 89%). ¹ H NMR (500 MHz, deuterochloroform) delta ppm 1.64 - 1 .76 (m, 2 H) 2.20 - 2.31 (m, 4 H) 2.42 (s, 3 H) 2.82 (ddd, J=12.81 , 9.15, 3.42 Hz, 1 H) 2.93 (dt, J=12.99, 7.65 Hz, 1 H) 3.03 - 3.13 (m, 1 H) 3.31 - 3.46 (m, 1 H) 4.56 - 4.75 (m, 1 H) 5.35 - 5.47 (m, 1 H) 7.22 (dd, J=8.05, 4.88 Hz, 1 H) 7.40 (dd, J=8.05, 1 .46 Hz, 1 H) 8.21 (s, 1 H) 8.42 (dd, J=4.76, 1.34 Hz, 1 H). LCMS (ES+): 319.2 (M+1 ).

Example 1

1 -Methylcvclopropyl (3R4ffl-3-fluoro-4-({5-methyl-6-r(2-methylpyridin-3- yl)oxylpyrimidin-4-yl}oxy)piperidine-1 -carboxylate

To a solution of 4-{[(3f?,4/^:?)-3-fluoropiperidin-4-yl]oxy}-5-methyl-6-[(2-methylpyridin-3- yl)oxy]pyrimidine (125 mg, 0.39 mmol) and 1 -methylcyclopropyl 4-nitrophenyl carbonate (1 12 mg, 0.47 mmol) in dichloromethane (2 mL) was added triethylamine (0.1 1 mL, 0.77 mmol) and the reaction mixture was stirred at room temperature for 18 hours followed by a period of 4 hours at 35 degrees Celsius. The reaction was cooled to room temperature and 1 N aqueous sodium hydroxide was added. After stirring for 20 minutes, the mixture was extracted with dichloromethane (3 x 15 ml_). The combined organics were washed with a mixture of half saturated brine and 1 N aqueous sodium hydroxide, dried over sodium sulphate, filtered and the filtrate was concentrated under vacuum to give a light yellow residue. It was pre-adsorbed onto 5 g silica and purified on 10 g silica, eluting with an ethyl acetate/heptane gradient to give the title compound as a clear, colorless sticky solid (163 mg, 99%). ¹H NMR (500 MHz, deuterochloroform) delta ppm 0.63 - 0.69 (m, 2 H) 0.88 - 0.94 (m, 2 H) 1.58 (s, 3 H) 1.76 (br. s., 1 H) 2.19 - 2.31 (m, 4 H) 2.42 (s, 3 H) 3.27 - 3.72 (m, 3 H) 3.74 - 4.10 (m, 1 H) 4.52 - 4.82 (m, 1 H) 5.39 - 5.51 (m, 1 H) 7.22 (dd, J=7.81 , 4.88 Hz, 1 H) 7.40 (d, J=8.29 Hz, 1 H) 8.20 (s, 1 H) 8.42 (d, J=3.90 Hz, 1 H). LCMS (ES+): 417.2 (M+1 ). [a]_D ²¹ = -39.8 degrees (c 0.475, methanol).

Example 2

1 -Methylcvclopropyl (3S,4SV3-fluoro-4-({5-methyl-6-r(2-methylpyridin-3- yl)oxylpyrimidin-4-yl}oxy)piperidine-1 -carboxylate

The title compound was prepared from 4-{[(3S,4S)-3-fluoropiperidin-4-yl]oxy}-5-methyl- 6-[(2-methylpyridin-3-yl)oxy]pyrimidine (125 mg, 0.39 mmol) in a manner similar to that used to prepare 1 -methylcyclopropyl (3f?,4f?)-3-fluoro-4-({5-methyl-6-[(2-methylpyridin- 3-yl)oxy]pyrimidin-4-yl}oxy)piperidine-1 -carboxylate. The title compound was obtained as a white solid (160 mg, 98%). ¹ H NMR (500 MHz, deuterochloroform) delta ppm 0.63 - 0.69 (m, 2 H) 0.87 - 0.95 (m, 2 H) 1.58 (s, 3 H) 1.76 (br. s, 1 H) 2.20 - 2.29 (m, 4 H) 2.42 (s, 3 H) 3.30 - 3.71 (m, 3 H) 3.75 - 4.09 (m, 1 H) 4.53 - 4.82 (m, 1 H) 5.40 - 5.50 (m, 1 H) 7.22 (dd, J=8.05, 4.88 Hz, 1 H) 7.40 (d, J=8.05 Hz, 1 H) 8.20 (s, 1 H) 8.42 (d,

J=3.90 Hz, 1 H). LCMS (ES+): 417.2 (M+1 ). [a]_D ²¹ = +41 .1 degrees (c 0.470, methanol).

Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application for all purposes. It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

Claims

What is claimed is:

1 . A compound selected from the group consisting of -Methylcyclopropyl (3R,4R)-3-fluoro-4-({5-methyl-6-[(2-methylpyridin-3-yl)oxy]pyrimidin-4-yl}oxy)piperidine- 1 -carboxylate and 1 -Methylcyclopropyl (3S,4S)-3-fluoro-4-({5-methyl-6-[(2- methylpyridin-3-yl)oxy]pyrimidin-4-yl}oxy)piperidine-1 -carboxylate, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

2. 1 -Methylcyclopropyl (3R,4R)-3-fluoro-4-({5-methyl-6-[(2-methylpyridin-3- yl)oxy]pyrimidin-4-yl}oxy)piperidine-1 -carboxylate or a pharmaceutically acceptable salt thereof.

3. 1 -Methylcyclopropyl (3S,4S)-3-fluoro-4-({5-methyl-6-[(2-methylpyridin-3- yl)oxy]pyrimidin-4-yl}oxy)piperidine-1 -carboxylate or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition comprising a compound according to any of claims 1 -3, present in a therapeutically effective amount, in admixture with at least one pharmaceutically acceptable excipient.

5. The composition of claim 4 further comprising at least one additional pharmaceutical agent selected from the group consisting of an anti-obesity agent and an anti-diabetic agent.

6. The composition of Claim 5 wherein said anti-obesity agent is selected from the group consisting of dirlotapide, mitratapide, implitapide, R56918 (CAS No. 403987), CAS No. 913541 -47-6, lorcaserin, cetilistat, PYY3-36, naltrexone, oleoyl-estrone, obinepitide, pramlintide, tesofensine, leptin, bromocriptine, orlistat, AOD-9604 (CAS No. 221231 -10-3) and sibutramine.

7. The composition of Claim 5 wherein said anti-diabetic agent is selected from the group consisting of metformin, acetohexamide, chlorpropamide, diabinese, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone, glisolamide, tolazamide, tolbutamide, tendamistat, trestatin, acarbose, adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q, salbostatin, balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone, pioglitazone, rosiglitazone, troglitazone, exenatide, exendin-3, exendin-4, liraglutide,trodusquemine, reservatrol, hyrtiosal extract, sitagliptin, vildagliptin, alogliptin and saxagliptin.

8. A method for the treatment of diabetes comprising the administration of an effective amount of a compound according to claim 1 , 2 or 3 to a patient in need thereof.

9. A method for treating a metabolic or metabolic-related disease, condition or disorder comprising the step of administering to a patient a therapeutically effective amount of a compound of claim 1 , 2 or 3.

10. A method for treating a condition selected from the group consisting of hyperlipidemia, Type I diabetes, Type II diabetes mellitus, idiopathic Type I diabetes (Type lb), latent autoimmune diabetes in adults, early-onset Type 2 diabetes, youth- onset atypical diabetes, maturity onset diabetes of the young, malnutrition-related diabetes, gestational diabetes, 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, conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, obesity, 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, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertrygliceridemia, insulin resistance, impaired glucose metabolism, conditions of impaired glucose tolerance, conditions of impaired fasting plasma glucose, obesity, erectile dysfunction, skin and connective tissue disorders, foot ulcerations and ulcerative colitis, endothelial dysfunction and impaired vascular compliance, hyper apo B lipoproteinemia, Alzheimer's disease, schizophrenia, impaired cognition, inflammatory bowel disease, ulcerative colitis, Crohn's disease, and irritable bowel syndrome, comprising the administration of an effective amount of a compound of claim 1 , 2 or 3.

1 1. A method for treating a metabolic or metabolic-related disease, condition or disorder comprising the step of administering to a patient in need of such treatment two separate pharmaceutical compositions comprising

(i) a first composition according to claim 4; and

(ii) a second composition comprising at least one additional pharmaceutical agent selected from the group consisting of an anti-obesity agent and an anti-diabetic agent, and at least one pharmaceutically acceptable excipient.

12. The method of claim 1 1 wherein said first composition and said second composition are administered simultaneously.

13. The method of claim 1 1 wherein said first composition and said second composition are administered sequentially and in any order.