WO2005095339A1 - Dicyanopyrrolidines as dipeptidyl peptidase iv inhibitors - Google Patents

Abstract

The invention provides compounds of formula (I), the prodrugs and stereoisomers thereof, and the pharmaceutically acceptable salts of the compounds, prodrugs, and stereoisomers, wherein wherein R is as defined herein; pharmaceutical compositions thereof; combinations thereof; and uses thereof in the treatment of diabetic complications including diabetic neuropathy, diabetic nephropathy, diabetic microangiopathy, and the like.

Description

DICYANOPYRROLIDINES AS DIPEPTIDYL PEPTIDASE IV INHIBITORS Field of the Invention The invention relates to selective inhibitors of the enzyme dipeptidyl peptidase-IV (DPP-IV), pharmaceutical compositions thereof, and uses thereof for treating diseases associated with proteins that are subject to processing by DPP-IV, such as Type 2 diabetes, metabolic syndrome (Syndrome X and/or insulin- resistance syndrome), hyperglycemia, Type 1 diabetes, obesity, and the like.

Background of the Invention DPP-IV (EC 3.4.14.5) is a serine protease that preferentially hydrolyzes an N-terminal dipeptide from proteins having proline or alanine in the 2-position. The physiological roles of DPP-IV have not been fully elucidated, but it is believed to be involved in diabetes, glucose tolerance, obesity, appetite regulation, lipidemia, osteoporosis, neuropeptide metabolism and T-cell activation, among others. DPP-IV has been implicated in the control of glucose homeostasis because its substrates include the incretin peptides glucagon-like peptide 1 (GLP-1 ) and gastric inhibitory polypeptide (GIP). Cleavage of the N-terminal amino acids from these peptides renders them functionally inactive. GLP-1 has been shown to be an effective anti-diabetic therapy in Type 2 diabetic patients and to reduce the meal- related insulin requirement in Type 1 diabetic patients. GLP-1 and/or GIP are believed to regulate satiety, lipidemia and osteogenesis. Exogenous GLP-1 has been proposed as a treatment for patients suffering from acute coronary syndrome, angina, and ischemic heart disease. Administration of DPP-IV inhibitors in vivo prevents N-terminal degradation of GLP-1 and GIP, resulting in higher circulating concentrations of these peptides, thereby increasing insulin secretion and improving glucose tolerance. On the basis of these observations, DPP-IV inhibitors are regarded as agents for the treatment of Type 2 diabetes, a disease in which glucose tolerance is impaired. In addition, treatment with DPP-IV inhibitors prevents degradation of Neuropeptide Y (NPY), a peptide associated with a variety of central nervous system disorders, and Peptide YY which has been linked to gastrointestinal conditions such as ulcers, irritable bowel disease, and inflammatory bowel disease. In spite of the early discovery of insulin and its subsequent widespread use in the treatment of diabetes, and the later discovery of and use of sulfonylureas

(e.g. chlorpropamide, tolbutamide, acetohexamide, biguanides (e.g., phenformin), metformin, thiazolidinediones (e.g., rosiglitazone), and pioglitazone as oral hypoglycemic agents, the treatment of diabetes remains less than satisfactory. The use of insulin, necessary in Type 1 diabetic patients and about 10% of Type 2 diabetic patients in whom currently available oral hypoglycemic agents are ineffective, requires multiple daily doses, usually by self-injection. Determination of the appropriate dosage of insulin necessitates frequent estimations of the glucose concentration in urine or blood. The administration of an excess dose of insulin causes hypoglycemia, with consequences ranging from mild abnormalities in blood glucose to coma, or even death. Treatment of Type 2 diabetes usually comprises a combination of diet, exercise, oral agents, and in more severe cases, insulin. However, the clinically available hypoglycemics can have side effects that limit their use. A continuing need for hypoglycemic agents, which may have fewer side effects or succeed where others fail, is clearly evident. Poorly controlled hyperglycemia is a direct cause of the multiplicity of complications (cataracts, neuropathy, nephropathy, retinopathy, cardiomyopathy) that characterize advanced Type 2 diabetes. In addition, Type 2 diabetes is a comorbid disease that frequently confounds hyperlipidemia, atherosclerosis, and hypertension, adding significantly to the overall morbidity and mortality attributable to those diseases. Epidemiological evidence has firmly established hyperlipidemia as a primary risk factor for cardiovascular disease ("CVD") due to atherosclerosis. Atherosclerosis is recognized to be a leading cause of death in the United States and Western Europe. CVD is especially prevalent among diabetic subjects, at least in part because of the existence of multiple independent risk factors such as glucose intolerance, left ventricular hypertrophy and hypertension in this population. Successful treatment of hyperlipidemia in the general population, and in diabetic subjects in particular, is therefore of exceptional medical importance. Hypertension (high blood pressure) is a condition that can occur in many patients in whom the underlying etiology is unknown. Such "essential" hypertension is often associated with disorders such as obesity, diabetes, and hypertriglyceridemia and it is known that hypertension is positively associated with heart failure, renal failure, and stroke. Hypertension can also contribute to the development of atherosclerosis and coronary disease. Hypertension, together with insulin resistance and hyperlipidemia, comprise the constellation of symptoms characterizing metabolic syndrome, also known as insulin-resistance syndrome (IRS) and Syndrome X. Metabolic syndrome, as defined herein, and according to the Adult Treatment Panel III (ATP III; National Institues of Health; Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaulation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III), Executive Summary; Bethesda, MD; National Institues of Health, National Heart, Lung, and Blood Institute; 2001 (NIH Pub. No. 01 -3670)), occurs when a person meets three or more of the following criteria: 1 ) abdominal obesity (waist circumference >102 cm in men and >88 cm in women); 2) hypertriglyceridemia (≥150 mg/dl); 3) low HDL cholesterol (<40mg/dl in men and <50 mg/dl in women); 4) high blood pressure (>130/85 mmHg); (5) high fasting glucose (>110 mg/dl). Obesity is a well-known and common risk factor for the development of atherosclerosis, hypertension, and diabetes. The incidence of obesity and its related sequelae is increasing worldwide. Currently, few pharmacological agents are available that reduce adiposity effectively and acceptably. Osteoporosis is a progressive systemic disease characterized by low bone density and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. Osteoporosis and the consequences of compromised bone strength are a significant cause of frailty, and of increased morbidity and mortality. Heart disease is a major health problem throughout the world. Myocardial infarctions are a significant source of mortality among those individuals with heart disease. Acute coronary syndrome denotes patients who have or are at high risk of developing an acute myocardial infarction (Ml). Though there are therapies available for the treatment of diabetes, hyperglycemia, hyperlipidemia, hypertension, obesity, and osteoporosis there is a continuing need for alternative and improved therapies. Various indications for DPP-IV inhibitors are discussed in the following review articles: Augustyns, et al., Curr. Medicinal Chem., 1999, 6, 311 ; Ohnuki, et al., Drugs of the Future 1999, 24, 665-670; and Villhauer, et al., Annual Reports in Medicinal Chemistry, 2001 , 36, 191-200.

SUMMARY OF INVENTION

The invention provides compounds of formula (I),

(I) the prodrugs and stereoisomers thereof, and the pharmaceutically acceptable salts of the compounds, prodrugs, and stereoisomers, wherein R is as defined hereinbelow; pharmaceutical compositions thereof; combinations thereof; and uses thereof in the treatment of diabetic complications including diabetic neuropathy, diabetic nephropathy, diabetic microangiopathy, and the like.

DETAILED DESCRIPTION OF THE INVENTION This invention is directed to compounds of formula (I),

, (I) the prodrugs and stereoisomers thereof, and the pharmaceutically acceptable salts of the compounds, prodrugs, and stereoisomers, wherein R is:

(I)

or Rι-X-Y-(CH₂)_n(C(CH₃)₂)-, wherein: X is a covalent bond, O, S, -C(O)-, -SO₂-, -NR₃C(O)-, -NR₃SO₂-, or -OC(O)-; Y is a covalent bond or -N(R₂)-, provided Y is not a covalent bond when X is either a covalent bond or -C(O)-, and Y is not -N(R₂)- when X is O or S; R_! is: (a) phenyl(C₀-C₈)alkyl; (b) phenoxy(C C₈)alkyl; or (c) heterocyclyl(C₀-C₈)alkyl, wherein said phenyl, said phenoxy, or said heterocyclyl, in the definitions of phenyl(Co-C₈)alkyl, phenoxy(C C₈)alkyl, and heterocyclyl(C₀-C₈)alkyl respectively, is optionally substituted independently with one to three (CrC₈)alkyl, (C₃-C₈)cycloalkyl, (Cι-C₈)alkoxy, cyano, halogen, (C C₈)alkylsulfonyl, (C C₈)alkylthio, -CO₂(C C₈)alkyl, -CO₂H, -CONH₂, -CHO, -CH₂OH, hydroxy, trifluoromethyl, amino, nitro, phenyl(C C₈)alkoxy, or phenyl optionally substituted independently with one to three (d- C₈)alkyl, halogen, (CrC₈)alkoxy, cyano, hydroxy, trifluoromethyl, (CrC₈)alkylsulfonyl, (C C₈)alkylthio, or phenyl(C C₈)alkoxy; (d) (CrCi₂)alkyl, optionally substituted independently with one to three hydroxy, trifluoromethyl, cyano, (Cι-C₃)hydroxyalkyl, (C C₈)alkoxy, (C

C₈)alkylsulfonyl, (CrC₈)alkylthio, phenyl, or phenyl-SO₂-, wherein said phenyl is optionally substituted independently with one to three (C C₈)alkyl, (C₃-C₈)cycloalkyl,

(CrC₈)alkoxy, cyano, halogen, (CrC₈)alkylsulfonyl, (CrC₈)a,lkylthio, -CO₂(CrC₈)alkyl,

-CO₂H, -CONH₂, -CHO, -CH₂OH, hydroxy, trifluoromethyl, amino, or nitro; or (e) (C₃-Cι₂)cycloalkyl, optionally substituted independently with one to three hydroxy, trifluoromethyl, cyano, (CrC₃)hydroxyalkyl, (Cι-C₈)alkyl, (d-C₈)alkoxy, (C

C₈)alkylsulfonyl, (C C₈)alkylthio, phenyl-SO₂(Co-C₈)alkyl, or phenyl(C₀-C₈)alkyl, wherein said phenyl is optionally substituted independently with one to three (C

C₈)alkyl, (C₃-C₈)cycloalkyl, (CrC₈)alkoxy, cyano, halogen, (C C₈)alkylsulfonyl, (C C₈)alkylthio, -CO₂(CrC₈)alkyl, -CO₂H, -CONH₂, -CHO, -CH₂OH, hydroxy, trifluoromethyl, amino, or nitro; R₂ is hydrogen, (CrC₈)alkyl, or (C₃-C₈)cycloalkyl; R₃ is hydrogen, methyl, or ethyl; or R₂ and R₃, taken together, form a five- or six-membered ring heterocyclyl group; m is two, three, or four; and n is one, two, or three; (II) (C C₁₂)alkyl, optionally substituted independently with one to three hydroxy, trifluoromethyl, cyano, or R X-Y-;

(III) (C₃-C₁₂)cycloalkyl, optionally substituted independently with one to three hydroxy, trifluoromethyl, cyano, (C|-C₃)hydroxyalkyl, (C C₈)alkyl, or R₁-X-Y-(CH₂)_P-, wherein p is zero, one, two, or three;

(IV) heterocyclyl(C₀-C₈)alkyl, optionally substituted independently with one to three hydroxy, cyano, (C C₃)hydroxyalkyl, or R X-; or

(V) -C(CH₃)R₄R₅, wherein: R₄ is: (f) (C_rC₈)alkyl, (g) (C₃-C₈)cycloalkyl, (h) heterocyclyl, or (i) phenyl(C₀-C₈)alkyl, wherein said (d-C₈)alkyl and (C₃-C₈)cycloalkyl are optionally substituted independently with one to three (Cι-C₈)alkoxy, (C C₈)(cycloalkyl)oxy, cyano, halogen, (CrC₄)alkylsulfonyl, (CrC )alkylthio, (C₃-C₈)(cycloalkyl)thio, hydroxy, trifluoromethyl, amino, or nitro; and wherein said heterocyclyl and said phenyl are optionally substituted independently with one to three (C C₈)alkyl, (C₃-C₈)cycloalkyl, (Cι-C₈)alkoxy, cyano, halogen, (C C₈)alkylsulfonyl, (C C₈)alkylthio, -CO₂(Cι-C₈)alkyl, -CO₂H, -CONH₂, -CHO, -CH₂OH, hydroxy, trifluoromethyl, amino, nitro, phenyl(C C₈)alkoxy, or phenyl optionally substituted independently with one to three (d- C₈)alkyl, halogen, (d-C₈)alkoxy, cyano, hydroxy, trifluoromethyl, (CrC₈)alkylsulfonyl, (CrC^alkylsulfonyloxy, or pheny^d-C^alkoxy; and R₅ is hydrogen, (C C₈)alkyl, or (C₃-C₈)cycloalkyl. Generally preferred compounds of formula (I), the prodrugs and stereoisomers thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs, comprise those compounds wherein both nitrile substituents on the pyrrolidine ring are s-oriented with respect thereto as depicted in the formula below. 2005/095339

A generally preferred subgroup of the compounds of formula (I), the prodrugs and stereoisomers thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs, comprises those compounds wherein R is:

(I) R X-Y-(CH₂)_m- or RrX-Y-(CH₂)_n(C(CH₃)₂)-, wherein: X is a covalent bond, O, S, -C(O)-, -SO₂-, -NR₃C(O)-, -NR₃SO₂-, or -OC(O)-; Y is a covalent bond or -N(R₂)-, provided Y is not a covalent bond when X is either a covalent bond or -C(O)-, and Y is not -N(R₂)- when X is O or S;

(a) phenyl or (c) heterocyclyl(C₀-C₈)alkyl, wherein said phenyl or said heterocyclyl, in the definition of heterocyclyl(C₀-C₈)alkyl, is optionally substituted independently with one to three (d-C₈)alkyl, (C₃-C₈)cycloalkyl, (d-C₈)alkoxy, cyano, halogen, (Cι-C₈)alkylsulfonyl, (C C₈)alkylthio, -CO₂(d-C₈)alkyl, -CO₂H, -CONH₂, - CHO, -CH₂OH, hydroxy, trifluoromethyl, amino, nitro, phenyl(d-C₈)alkoxy, or phenyl optionally substituted independently with one to three (C C₈)alkyl, halogen, (d- C₈)alkoxy, cyano, hydroxy, trifluoromethyl, (d-C₈)alkylsulfonyl, (d-C₈)alkylthio, or phenyl(d -C₈)alkoxy; (d) (Cι-Cι₂)alkyl, optionally substituted independently with one to three hydroxy, trifluoromethyl, cyano, (d-C₃)hydroxyalkyl, (d-C₈)alkoxy, (d- C₈)alkylsulfonyl, (CrC₈)alkylthio, phenyl, or phenyl-SO₂-, wherein said phenyl is optionally substituted independently with one to three (d-C₈)alkyl, (C₃-C₈)cycloalkyl, (C C₈)alkoxy, cyano, halogen, (C C₈)alkylsulfonyl, (Cι-C₈)alkylthio, -CO₂(C C₈)alkyl, -CO₂H, -CONH₂, -CHO, -CH₂OH, hydroxy, trifluoromethyl, amino, or nitro; or (e) (C₃-C₁₂)cycloalkyl, optionally substituted independently with one to three hydroxy, trifluoromethyl, cyano, (C C₃)hydroxyalkyl, (C_rC₈)alkyl, (d-C₈)alkoxy, (C C₈)alkylsulfonyl, (C C₈)alkylthio, phenyl-SO₂(C₀-C₈)alkyl, or phenyl(C₀-C₈)alkyl, wherein said phenyl is optionally substituted independently with one to three (C C₈)alkyl, (C₃-C₈)cycloalkyl, (C_rC₈)alkoxy, cyano, halogen, (C C₈)alkylsulfonyl, (C C₈)alkylthio, -CO₂(C_rC₈)alkyl, -CO₂H, -CONH₂, -CHO, -CH₂OH, hydroxy, trifluoromethyl, amino, or nitro; R₂ is hydrogen, (C₁-C₃)alkyl, or (C₃-C₅)cycloalkyl; R₃ is hydrogen, methyl, or ethyl; or R₂ and R₃, taken together, form a five- or six-membered ring heterocyclyl group; m is two or three; and n is one or two;

(II) (d-Cι₂)alkyl, optionally substituted independently with one to three hydroxy, trifluoromethyl, cyano, or R X-Y-;

(III) (C₃-Cι₂)cycloalkyl, optionally substituted independently with one to three hydroxy, trifluoromethyl, cyano, (C C₃)hydroxyalkyl, (C_rC₈)alkyl, or R X-Y-(CH₂)_p-, wherein p is zero, one, two, or three; or

(IV) heterocyclyl(C₀-C₄)alkyl, optionally substituted independently with one to three hydroxy, cyano, (d-C₃)hydroxyalkyl, or R X-. An especially preferred subgroup of the compounds of formula (I), the prodrugs and stereoisomers thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs, comprises those compounds wherein R is:

(I) RrX-Y-fCHzJm- or Rι-X-Y-(CH2)_n(C(CH₃)2)-, wherein: X is a covalent bond, O, S, -C(O)-, -SO₂-, -NR₃C(O)-, -NR₃SO₂-, or -OC(O)-; Y is a covalent bond or -N(R₂)-, provided Y is not a covalent bond when X is either a covalent bond or -C(O)-, and Y is not -N(R₂)- when X is O or S; R-, is: (a) phenyl or (c) heterocyclyl(C₀-C₈)alkyl, wherein said phenyl or said heterocyclyl, in the definition of heterocyclyl(C₀-C₈)alkyl, is optionally substituted independently with one to three (d-C )alkyl, (C₃-C₆)cycloalkyl, (C C₄)alkoxy, cyano, halogen, (C C₄)alkylsulfonyl, (C C₄)alkylthio, -CO₂(C₁-C₄)alkyl, -CO₂H, -CONH₂, - CHO, -CH₂OH, hydroxy, trifluoromethyl, amino, nitro, or phenyl optionally substituted independently with one to three (d-C₄)alkyl, halogen, (d-C₄)alkoxy, cyano, hydroxy, trifluoromethyl, (d-C )alkylsulfonyl, or (C C₄)alkylthio; 2005/095339

(d) (d-C₁₂)alkyl, optionally substituted independently with one to three hydroxy, trifluoromethyl, cyano, (C C₃)hydroxyalkyl, (C C₈)alkoxy, (d- C₈)alkylsulfonyl, (C C₈)alkylthio, phenyl, or phenyl-SO₂-, wherein said phenyl is optionally substituted independently with one to three (d-C₈)alkyl, (C₃-C₈)cycloalkyl, (CrCs)alkoxy, cyano, halogen, (CrC₈)alkylsulfonyl, (C C₈)alkylthio, -CO₂(Cι-C₈)alkyl, -CO₂H, -CONH₂, -CHO, -CH₂OH, hydroxy, trifluoromethyl, amino, or nitro; or (e) (C₃-Cι₂)cycloalkyl, optionally substituted independently with one to three hydroxy, trifluoromethyl, cyano, (Cι-C₃)hydroxyalkyl, (d-C₈)alkyl, (d-C₈)alkoxy, (d- C₈)alkylsulfonyl, (C C₈)alkylthio, phenyl-SO₂(C₀-C₈)alkyl, or phenyl(C₀-C₈)alkyl, wherein said phenyl is optionally substituted independently with one to three (C C₈)alkyl, (C₃-C₈)cycloalkyl, (CrC₈)alkoxy, cyano, halogen, (C C₈)alkylsulfonyl, (C C₈)alkylthio, -CO₂(C C₈)alkyl, -CO₂H, -CONH₂, -CHO, -CH₂OH, hydroxy, trifluoromethyl, amino, or nitro; R₂ is hydrogen or (C C₃)alkyl; R₃ is hydrogen, methyl, or ethyl; or R₂ and R₃, taken together, form a five- or six-membered ring heterocyclyl group; m is two; and n is one; (III) (C₃-C ₂)cycloalkyl, optionally substituted independently with one to three hydroxy, trifluoromethyl, cyano, (d-C₈)alkyl, or R X-Y-(CH₂)_p-, wherein p is zero, one, or two. The compounds and intermediates of the present invention may be named according to either the IUPAC (International Union for Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature systems. The carbon atom content of the various hydrocarbon-containing moieties herein may be indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, for example, the prefix (C_a-C_b)alkyl indicates an alkyl moiety of the integer "a" to "b" carbon atoms, inclusive. Thus, for example, (d-C₆)alkyl refers to an alkyl group of one to six carbon atoms inclusive. The term "alkoxy" refers to straight or branched, monovalent, saturated aliphatic chains of carbon atoms bonded to an oxygen atom that is attached to a core structure. Examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy, /so-butoxy, terf-butoxy, and the like. 2005/095339 10

The term "alkyl" means straight, or branched, monovalent chains of carbon atoms, wherein the alkyl group optionally incorporates one or more double or triple bonds, or a combination of double and triple bonds. Examples of alkyl groups include, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, vinyl, allyl, 2-methylpropenyl, 2- butenyl, 1 ,3-butadienyl, ethynyl, propargyl, and the like. The term "cycloalkyl" denotes a monocyclic or polycylic cycloalkyl group, optionally fused to an aromatic hydrocarbon group, wherein the cycloalkyl group optionally incorporates one or more double or triple bonds, or a combination of double and triple bonds. Examples of cycloalkyl groups include adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, decahydronaphthalinyl, indanyl, noradamantyl (hexahydro-2,5-methano-pentalen- 3a-yl), tetrahydronaphthyl, and the like. The term "halogen" represents chloro, bromo, fluoro, or iodo. The term "heterocyclyl", unless otherwise specified, denotes a saturated, unsaturated, or partially saturated, 5- or 6-membered, or 9- or 10-membered, monocyclic or polycyclic cycloalkyl group, in which from one to five carbon atoms have replaced with nitrogen, oxygen, or sulfur heteroatoms. If the heterocyclyl group contains more than one heteroatom, the heteroatoms may be the same or different. Examples of heterocyclyl groups include pyridyl, piperazinyl, pyranyl, pyrrolyl, imidazolyl, indolyl, furanyl, piperidinyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, quinuclidinyl, and the like. The term "mammal" means animals including, for example, dogs, cats, cows, sheep, horses, and humans. Preferred mammals include humans. The term "oxo" denotes a carbonyl substituent formed between a carbon atom and an oxygen atom. The term "perfluoroalkyl" as used herein, means a saturated monovalent straight or branched aliphatic hydrocarbon radical, in which the valences normally occupied by hydrogen have been entirely replaced by fluorine and wherein the number of carbon atoms may be defined in a parenthetical where the term is used. Examples of perfluoroalkyl groups include trifluoromethyl, pentafluoroethylethyl, heptafluoropropyl, nonafluorobutyl, and the like. The phrase "pharmaceutically acceptable" indicates that the designated carrier, vehicle, diluent, or excipient(s) is generally chemically and/or physically compatible with the other ingredients comprising the formulation, and physiologically compatible with the patient being treated therewith. The expression "pharmaceutically acceptable salt" as used herein in relation to compounds of formula (I) preferably includes pharmaceutically acceptable anionic salts. The term "pharmaceutically acceptable anion" refers to a negative ion that is compatible chemically and/or toxicologically with the other ingredients of a pharmaceutical composition and the patient being treated therewith. Suitable anions include, but are not limited to chloride, iodide, bromide, sulfate, bisulfate, nitrate, acetate, trifluoroacetate, oxalate, besylate, palmitiate, pamoate, malonate, stearate, laurate, malate, borate, benzoate, lactate, phosphate, hexafluorophosphate, benzene sulfonate, tosylate, formate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, laurylsulphonate, (d-C₁₂)alkylsulfonates (e.g., mesylate, ethylsulfonate, etc.), arylsulfonates (e.g., phenylsulfonate, tosylate, etc.), (d-Cι₂)alkylphosphonates, di(d-Cι₂)alkylphosphates (e.g., dimethylphosphate, diethylphosphate, α-diglycerol phosphate, etc.), arylphosphonates, arylphosphates, alkylarylphosphonates, alkylarylphosphates, (d-Cι₂)alkylcarboxylates (e.g., acetates, propionates, glutamates, glycerates, etc.), arylcarboxylates, and the like. The salts maybe prepared in situ during the isolation or purification step(s), or by separately reacting the compound, prodrug, or stereoisomer with a suitable organic or inorganic counterion and isolating the salt so formed. The term "prodrug" means a compound that is transformed in vivo to yield a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof. Such compounds include, but are not limited to, N-acyl and N-carboalkoxy derivatives as well as imine derivatives. The transformation may occur via various mechanisms, including hydrolysis in blood. See, for example, T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems", Vol. 14, A.C.S. Symposium Series, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987. The phrase "reaction-inert solvent" refers to a solvent, or mixture of solvents, that does not adversely interact with starting materials, reagents, intermediates, or products. The term "substituted" means that a designated atom or functional group on a molecule has been replaced with a different atom or functional group. The atom or functional group replacing the designated atom is denoted a "substituent." The terms "treating", "treated", or "treatment" as employed herein includes preventative (e.g., prophylactic), palliative, or curative use or result. A cyclic group may be bonded to another group in more than one way. If no particular bonding arrangement is specified, then all possible arrangements are intended. For example, the term "pyridyl" includes 2-, 3-, or 4-pyridyl. Some of the compounds of formula (I) contain at least one stereogenic center; consequently, those skilled in the art will appreciate that all stereoisomers (e.g., enantiomers and diasteroisomers, and racemic mixtures thereof) of the compounds of formula (I) are within the scope of the present invention. One skilled in the art will also recognize that the pyrrolidine moiety of the compounds of formula (I) may also contain stereogenic centers, such as, for example, where the configuration between the nitrile groups on the pyrollidine ring in formula (I) is trans. All stereoisomers (e.g., enantiomers and diasteroisomers, and racemic mixtures thereof) of the compounds of formula (I) are within the scope of the present invention. The compounds of formula (I) can exist in crystalline form as hydrates wherein molecules of water are incorporated within the crystal structure thereof and as solvates wherein molecules of a solvent are incorporated therein. All such hydrate and solvate forms are embraced within the scope of the invention. This invention also includes isotopically-labeled compounds of formula (I), the prodrugs and stereoisomers thereof, and the pharmaceutically acceptable salts of the compounds, prodrugs, and stereoisomers, wherein 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, sulfur and fluorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸0, ¹⁷O, ³⁵S, ³⁶CI, ¹²⁵I, ¹²⁹l, and ¹⁸F respectively. Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution 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), can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. The isotopically labeled compounds of formula (I), and the prodrugs and stereoisomers thereof, can generally be prepared according to the procedures disclosed in the instant Schemes and/or Examples by substituting isotopically labeled reagents for non-isotopically labeled reagents. In another aspect, the invention is directed to pharmaceutical compositions comprising an amount of a compound of formula (I), a prodrug or stereoisomer thereof, or a pharmaceutically acceptable salt of the compound, prodrug, or stereoisomer, and a pharmaceutically acceptable carrier, vehicle, or diluent. In another aspect, the invention is directed to pharmaceutical compositions comprising amounts of: a) a compound of formula (I), a prodrug or stereoisomer thereof, or a pharmaceutically acceptable salt of the compound, prodrug, or stereoisomer; ι b) an antidiabetic agent, a prodrug or pharmaceutically acceptable salt thereof, insulin or an analog thereof, insulinotropin, a biguanide, an α₂-antagonist, an imidazoline, a glitazone, an aldose reductase inhibitor, a glycogen phosphorylase inhibitor, a sorbitol dehydrogenase inhibitor, a fatty acid oxidation inhibitor, an α-glucosidase inhibitor, a β-agonist, a phosphodiesterase inhibitor, a lipid-lowering agent, an antiobesity agent, a vanadate, a vanadium complex, a peroxovanadium complex, an amylin antagonist, a glucagon antagonist, a growth hormone secretagogue, a gluconeogenesis inhibitor, a somatostatin analog, an antilipotic agents, or an inhibitor of renal glucose; and c) a pharmaceutically acceptable carrier, vehicle, or diluent. In another aspect, the invention is directed to methods of inhibiting DPP-IV which methods comprise administering to a mammal in need of such inhibition a DPP-IV inhibiting amount of a compound of formula (I), a prodrug or stereoisomer thereof, or a pharmaceutically acceptable salt of the compound, prodrug or stereoisomer, either alone or in combination with an antidiabetic agent described above. In another aspect, the invention is directed to methods of treating conditions mediated by DPP-IV inhibition which methods comprise administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (I), a prodrug or. stereoisomer thereof, or a pharmaceutically acceptable salt of the compound, prodrug or stereoisomer, either alone or in combination with an antidiabetic agent described above. Conditions treatable according to the instant methods are Type 2 diabetes, progression of disease in Type 2 diabetes, metabolic syndrome (Syndrome X and/or IRS), hyperglycemia, impaired glucose tolerance, glucosuria, metabolic acidosis, arthritis, cataracts, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, Type 1 diabetes, obesity, conditions exacerbated by obesity, hypertension, hyperlipidemia, atherosclerosis, osteoporosis, osteopenia, frailty, bone loss, bone fracture, short stature due to bone growth deficiency, acute coronary syndrome, infertility due to polycystic ovary syndrome, short bowel syndrome, anxiety, depression, insomnia, chronic fatigue, epilepsy, eating disorders, chronic pain, alcohol addiction, diseases associated with intestinal motility, ulcers, irritable bowel syndrome, or inflammatory bowel syndrome. Preferably, the condition is Type 2 diabetes. The compounds of formula (I), the prodrugs and stereoisomers thereof, and the . pharmaceutically acceptable salts of the compounds, prodrugs, and stereoisomers, may be administered to mammals at dosage levels in the range of 0.01 mg/kg/day to 30 mg/kg/day, preferably 0.01 mg/kg/day to 1 mg/kg/day, in single or divided doses. Some variations in dosage will necessarily occur, however, depending on the condition of the subject being treated. The individual responsible for dosing will, in any event, determine the appropriate dose for the individual subject. Preferably, a single dose is administered orally. The compounds of formula (I) may be administered to a subject in need of treatment by a variety of conventional routes of administration, including orally and parenterally, (e.g., intravenously, subcutaneously or intramedullary). Further, the pharmaceutical compositions of this invention may be administered intranasally, as a suppository, or using a "flash" formulation, i.e., allowing the medication to dissolve in the mouth without the need to use water. The appropriate dosage regimen, the amount of each dose administered and the intervals between doses of the compound will depend upon the compound of formula (I), or the prodrug or stereoisomer being used, the type of pharmaceutical compositions being used, the characteristics of the subject being treated, and/or the severity of the conditions being treated. Administration may be in single (e.g., once daily) or multiple doses or via constant infusion. The compounds may also be administered alone or, preferably, in combination with pharmaceutically acceptable carriers, vehicles, or diluents, in either single or multiple doses. Suitable pharmaceutical carriers, vehicles, and diluents include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. The pharmaceutical compositions formed by combining the compounds of this invention and the pharmaceutically acceptable carriers, vehicles or diluents are then readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions and the like. These pharmaceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. Thus, for purposes of oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and/or calcium phosphate may be employed .along with various disintegrants such as starch, alginic acid and/or certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and/or acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules. Generally preferred materials for oral include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired, the active pharmaceutical agent therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and/or combinations thereof. For parenteral administration, solutions in sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solutions may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this connection, the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art. For intranasal administration or administration by inhalation, the compounds of formula (I) are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container or nebulizer may contain a solution or suspension of a compound of this invention. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound or compounds of the invention and a suitable powder base such as lactose or starch. Methods of preparing pharmaceutical compositions with amounts of active ingredients are known, or will be apparent in light of this disclosure, to those skilled in this art. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 19th Edition (1995). The compounds of formula (I), the prodrugs and stereoisomers thereof, and the pharmaceutically acceptable salts of the compounds, prodrugs, and stereoisomers, may be prepared according to the exemplary routes disclosed in the Schemes and Examples below, as well as by other conventional preparative procedures known, or apparent in light of the instant disclosure, to one of ordinary skill in the art. The methods disclosed in the instant Schemes and Examples are are intended for purposes of exemplifying the instant invention, and are not to be construed in any manner as limitations thereon. In the discussions below, the following abbreviations are used: BOC (tert- butoxycarbonyl), Cbz (benzyloxycarbonyl), THF (tetrahydrofuran), DMF (N,N- dimethylformamide), NMP (N-methyl-2-pyrrolidinone), DMAC (N,N- dimethylacetamide), DME (dimethoxyethane), DMSO (dimethylsulfoxide), TFA (trifluoroacetic acid), TEA (triethylamine), DIPEA (diisopropylethylamine), EDC (1 - (3-dimethylaminopropyl)-3-carbodiimide)), DCC (dicyclohexylcarbodiimide), CDI (1 ,1 '-carbonyldiimidazole), HOBT (N-hydroxybenzotriazole), and EEDQ (2-ethoxy- 1 -ethoxycarbonyl-1 ,2-dihydroquinoline). The compounds of formula (I), wherein R is as defined above, may be prepared as shown in exemplary Scheme I.

Scheme I

II (I) In Scheme 1 , an appropriately-substituted amine RNH₂ is coupled with a compound of formula II, wherein Lv is a suitable leaving group, for example, halo, alkylsulfonyloxy, perfluoroalkylsulfonoxy, or phenylsulfonyloxy (wherein phenyl, phenoxy, and heterocyclyl are optionally substituted independently with from one to three (d-C₈)alkyl). The reaction is effected in a reaction-inert solvent, preferably an aprotic solvent, optionally in the presence of a base. Suitable solvents include, for example, acetonitrile, dichloromethane, DMF, THF, 1 ,4-dioxane, or chloroform. Suitable bases include, for example, DIPEA, TEA, 2,6-lutidine, sodium carbonate, or potassium carbonate. The coupling is generally conducted at ambient pressure and temperature. The amine starting material may be prepared by known procedures, by techniques that are analogous to the synthesis of known compounds, or by the procedures described in the examples hereinbelow. The compounds of formula II may be prepared by known methods or according to the methods described in Schemes II, III, and IV hereinbelow.

Scheme II

III II In Scheme II, the compounds of formula II, wherein Lv is bromo, are prepared by treating dinitrile III, prepared as disclosed in Scheme V below, with a reactive bromoacetyl compound, for example bromoacetyl bromide or bromoacetyl chloride, in a reaction-inert solvent. Suitable solvents include, for example, acetonitrile, dichloromethane, or chloroform, preferably acetonitrile. The reaction is generally conducted at ambient pressure and temperature. In Scheme III, the compounds of Formula II, wherein Lv is halo, alkylsulfonyloxy, perfluoroalkylsulfonoxy, or phenylsulfonyloxy (wherein phenyl, phenoxy, and heterocyclyl are optionally substituted independently with from one to three (Cι-C₈)alkyl), may be prepared by first coupling diamide IV with an acid of the formula LvCH₂CO₂H, or an acid chloride of the formula LvCH₂COCI, to afford V. Compound V is then treated with a dehydrating agent to furnish II. Scheme III

IV V II In Scheme ill, Step 1 , diamide IV, prepared as disclosed in Scheme VI below, and a carboxylic acid of the formula LvCH₂CO₂H are coupled in a reaction- inert solvent, at ambient temperature, in the presence of a coupling agent and an optional adjuvant. Coupling agents include EDC, DCC, EEDQ, GDI, or diethylphosphorylcyanide. Optional adjuvants include HOBT or N- hydroxysuccinimide. Preferably, EDC or DCC is the coupling agent and HOBT is the adjuvant. Suitable solvents include, for example, DMF, DMAC, NMP, or water, preferably water admixed with DMF. Alternatively, diamide IV and an acid chloride LvCH₂COCI may be reacted in a reaction-inert solvent in the presence of an organic base, such as 2,6-lutidine, 2,4,6-collidine, N-methylimidazole, N-methylmorpholine, TEA, or DIPEA. Suitable solvents include, for example, acetonitrile, dichloromethane, pyridine, and chloroform. Preferably, pyridine is employed as both the solvent and base. The starting materials LvCH₂CO₂H and LvCH COCI may be prepared by known methods or obtained commercially. Methods of coupling carboxylic acids are well-known in the art. See, for example, Houben-Weyl, Vol XV, Part II, E. Wunsch, Ed., G. Theime Verlag, 1974, Stuttgart, and those described in M. Bodansky, Principles of Peptide Synthesis, Springer-Verlag Berlin 1984, and The Peptides - Analysis, Synthesis and Biology (ed. E. Gross and J. Meienhofer), Vols 1 -5, Academic Press NY 1979-1983. In Scheme III, Step 2, compound V is reacted with a dehydrating agent in a reaction-inert solvent, optionally in the presence of a base, to afford II. Dehydrating agents useful in Step 2 include TFAA, phosphorus oxychloride, p-toluenesulfonyl chloride, cyanuric chloride, DCC, or ethylene chlorophosphite. Bases include pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, N-methylimidazole, N- methylmorpholine, TEA, or DIPEA. Preferably, TFAA or phosphorus oxychloride is used as the dehydrating agent and pyridine or imidazole is the base. Suitable solvents include, for example, acetonitrile, dichloromethane, chloroform, THF, or pyridine. Preferably, pyridine admixed with dichloromethane is used as the solvent. Step 2 is generally conducted at a temperature of between about -20 °C and about 25 °C. For a discussion of methods of dehydrating amides to nitriles, see, for example, R. Larock, Comprehensive Organic Transformations, VCH Publishers, _, 1989. Alternatively, dinitrile II may be prepared as disclosed in Scheme IV below by reacting protected dinitrile VI with a reactive chloroacetyl, bromoacetyl, or iodoacetyl compound. Scheme IV

VI II The reaction is effected by reacting dinitrile VI, prepared as disclosed in Scheme VII below, wherein Lv is chloro, bromo, or iodo, and Prot is a suitable nitrogen-protecting group, and a reactive chloroacetyl, bromoacetyl, or iodoacetyl compound, preferably chloroacetyl chloride or bromoacetyl bromide, in a reaction- inert solvent. Suitable solvents include, for example, acetonitrile, dichloromethane, and chloroform, preferably acetonitrile. Suitable nitrogen-protecting groups may include for example, but are not limited to, Boc and Cbz. The reaction is generally conducted at ambient temperature. Dinitrile III, useful in preparing intermediates of formula II in Scheme II hereinabove, may be prepared as disclosed in Scheme V.

Scheme V

In Scheme V, dinitrile III is prepared by reacting aminodiphenylmethane with a mixture of potassium cyanide and 2,5-dimethoxytetrahydrofuran in an aqueous solution of citric acid in a manner analogous to that described by Mclntosh, J. Org. Chem., 1988, 447 or Takahishi, et. al., Heterocycles, 1986, 2905. The reaction is generally conducted at ambient temperature. Diamide IV of Scheme III may be prepared as disclosed hereinbelow in Scheme VI.

Scheme VI

VII VIII IV In Scheme VI, Step 1 , protected diester VII is prepared by treating diethyl

2,5-dibromoadipate with benzylamine, which is subjected to catalytic hydrogenolysis in Step 2 to afford deprotected diester VIII. Step 1 is typically effected in a reaction-inert solvent, for example, benzene, toluene, or xylene at ambient temperature. Toluene is generally preferred. The catalytic hydrogenolysis of Step 2 is typically conducted in a reaction- inert solvent, for example, methanol, ethanol, and water, preferably methanol, in the presence of 10% palladium on carbon (Pd/C) or palladium hydroxide. The mixture is hydrogenated at a suitable hydrogen pressure, such as between about 30 psi and about 60 psi, preferably about 45 psi, for a period of time sufficient to bring the reaction to completion, usually overnight. Deprotected diester VIII is then treated with excess ammonia in Step 3 in a reaction-inert solvent. Suitable solvents include, for example, methanol, ethanol, or water, preferably methanol. The mixture is generally kept at ambient temperature and at between ambient pressure and about 30 psi. Protected dinitrile VI of Scheme IV may be prepared as disclosed hereinbelow in Scheme VII. Scheme VII

IV IX VI In Scheme VII, Step 1 , protected diamide IX is prepared by treating diamide

IV with a suitable nitrogen-protecting group, for example by treatment with di-tetf- butyl dicarbonate or benzyl chloroformate, in a reaction-inert solvent, such as THF, 1 ,4-dioxane, 1 ,2-dimethoxyethane, or water. Preferably di-tø/ -butyldicarbonate is used in a mixture of water and 1 ,4-dioxane. Methods of introducing nitrogen- protecting groups are well-known in the art. See, for example, "Protective Groups in Organic Synthesis", 2^nd. Ed., P.G.M. Wuts and T.W. Greene, p.315. Step 1 is generally conducted at ambient temperature. Step 2 is effected by treating protected diamide IX with a dehydrating agent, and an optional base, in a reaction-inert solvent to provide protected dinitrile VI. Typical dehydrating agents include TFAA, phosphorus oxychloride, p- toluenesulfonyl chloride, cyanuric chloride, DCC, or ethylene chlorophosphite. Optional bases include pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, N- methylimidazole, N-methylmorpholine, TEA, or DIPEA. Preferably, TFAA or phosphorus oxychloride is used as the dehydrating agent and pyridine or imidazole is used as the optional base. Suitable solvents include, for example, acetonitrile, dichloromethane, chloroform, THF, or pyridine, preferably pyridine admixed with dichloromethane. Step 2 is generally conducted at a temperature of between about -20 °C and about 25 °C. BIOLOGICAL PROTOCOLS The utility of the compounds of formula I, the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs, in the treatment or prevention of the conditions enumerated hereinabove in mammals may be demonstrated in conventional assays known to one of ordinary skill in the relevant art, including the in vitro and in vivo assays described below. Such assays also provide a means whereby the activities of the compounds of formula (I) can be compared with the activities of other known compounds.

In Vitro Assay for DPP-IV Inhibition DPP-IV inhibition may be demonstrated in vitro by the following assay, which is adapted from methods of Scharpe, et al., A. Clin. Chem., 1988, 2299 and Lodja, Z Czechoslovak Medicine, 1988, 181 . 150 μL of an enzyme-substrate solution is pipetted into microtiter wells of a polystyrene 96-well plate, and maintained at 4°C. The enzyme-substrate solution comprises 50 μM Gly-Pro-4-methoxy-β- naphthylamide hydrochloride in 50mM Tris assay buffer pH 7.3 containing 0.1 M sodium chloride, 0.1 % (v/v) Triton and 50 μU/mL DPP-IV (MP Biomedicals, Livermore, CA; DPP-IV 5 mU/mL stock). 5 μL per well of compounds of Formula I are added, bringing the final compound of Formula I concentrations to 3 μM - 10 nM per well. Controls. Enzyme is omitted from four (4) wells, as a reagent blank. 5 μL of 3 mM Diprotin A (Bachem Bioscience, Inc.; King of Prussia, PA) is added to four wells as a positive quality control, providing a final Diprotin A concentration of 100 μM. To measure total enzyme activity (i.e., a negative control), without the influence of any compounds of Formula I, 5 μL of distilled water is added to four wells. The entire assay is incubated overnight (about 14 to about 18 hours) at 37 °C. The reaction is quenched by adding 10 μL of Fast Blue B solution (0.5 mg/mL Fast Blue B in a buffer comprising 0.1 M sodium acetate pH 4.2 and 10% (v/v) Triton X-100 to each well, followed by shaking for approximately 5 minutes at room temperature. The plates may be analyzed on a Spectramax spectrophotometer (Molecular Devices; Sunnyvale, CA), or equivalent equipment, (absorption maximum at 525 nm). IC₅₀ data for compounds may be obtained by measuring the activity of DPP-IV over a range of compound concentrations from 10nM to 3μM. In Vivo Assay for Glucose Lowering The glucose lowering effects of DPP-IV inhibitors, such as compounds of Formula I, may be exemplified in 4-6 week old KK/H1J mice (Jackson Labs; Bar Harbor, ME) in the context of an oral glucose tolerance test. Oral glucose tolerance tests (OGTT") have been in use in humans since, at least, the 1930s, as described by Pincus, et al., Am. J. Med. Sci., 1934, 782, and are routinely used in the diagnosis of human diabetes, though not to evaluate the efficacy of therapeutic agents in patients. KK mice have been used to evaluate (i) glitazones (Fujita et al. Diabetes, 1983, 804; Fujiwara, et al., Diabetes, 1988, 1549; and Izumi, et al., Biopharm Drug. Dispos., 1997, 247); (ii) metformin (Reddi, et al. Diabet. Metabol., 1993, 44); (iii) glucosidase inhibitors (Hamada, et al., Jap. Pharmacol. Ther., 1988, 17 and Matsuo, et al., Am. J. Clin. Nutr., 1992, 314S), and (iv) extra-pancreatic effects of sulfonylureas by (Kameda, et al., Arzenim. Forsch Drug Res., 1982, 39044 and Muller et al., Horm. Metabl. Res., 1990, 469). KK mice are derived from an inbred line first established and described by

Kondo, et al., Bull. Exp. Anim., 1957, 107. These mice spontaneously develop a hereditary form of polygenic diabetes that progresses to cause renal, retinal, and neurological complications analogous to those seen in human diabetic subjects, however, they do not require insulin or other medication for survival. Another aspect of the invention is directed to the use of KK mice to evaluate the effects of insulin secretagogue agents in the context of an oral glucose tolerance test. The mice are fasted overnight (about 14 to about 18 hours), but allowed free access to water. After fasting, (time "t" = 0), 25 μL of blood is drawn from the retro- orbital sinus and added to 0.025% heparinized saline (100 μL) on ice. The mice (10 per group) are then orally dosed with a solution of a compound of formula I in 0.5% methylcellulose (0.2 mL/mouse). Two controls groups receive only 0.5% methylcellulose. At t = 15 minutes, the mice are bled, as described above, and then dosed with 1 mg/kg glucose in distilled water (0.2 mlJmouse). The first control group is dosed with glucose. The second control group is dosed with water. At t = 45 minutes, the mice are again bled, as described above. The blood samples are centrifuged, the plasma collected and analyzed for glucose content on a Roche- Hitachi 912 glucose analyzer (Roche Diagnostics Corp.; Indianpolis, IN). The data may be expressed as percent (%) inhibition of glucose excursion relative to the two control groups (i.e., the glucose level in the animals receiving glucose but no test compound representing 0% inhibition and the glucose concentration in the animals receiving only water representing 100% inhibition).

GENERAL EXPERIMENTAL PROCEDURES Melting points were determined on a capillary melting point apparatus by Thomas Scientific (Swedesboro, NJ), and are uncorrected. Flash chromatography was performed according to the method described by Still et al., J. Org. Chem., 1978, 2923. Hydrogenations were performed in a Parr (Parr Instrument Co.; Moline, IL) 3911 shaker type hydrogenation apparatus (hereafter referred to as a Parr hydrogenator) at the pressures indicated. Proton NMR chemical shifts are given in parts per million downfield from tetramethylsilane and were recorded on a Varian Unity 400 MHz spectrometer (Varian Inc.; Palo Alto, CA). Mass Spectra were recorded on a Waters (Waters Corp.; Milford, MA) Micromass Platform II spectrometer. The following Preparations describe the preparation of certain intermediates used in the Examples below. The Preparations and Examples below are intended to illustrate particular embodiments of the invention and preparations thereto and are not intended to limit the specification, including the claims, in any manner. Unless noted otherwise, all reactants were obtained commercially. Unless indicated otherwise, the following abbreviations have the indicated meanings: APCI - atmospheric pressure chemical ionization br - broad peaks °C - degree Celsius CDCI₃ - deuterated chloroform CD₃CN- deuterated acetonitrile CD₃OD- deuterated methanol d - doublet dd - double doublet peak D₂O - deuterium oxide dt - double triplet peak EtOAc - ethyl acetate g - gram(s) 2005/095339 26

H (e.g., 1 H, 2 H) - hydrogen(s) hr(s) - hour(s) Hz - hertz m - multiplet M - molar mg(s) - milligram(s) min(s) - minute(s) mL - milliliter(s) mmol - milimole(s) mp - melting point MS - mass spectrum NMR - nuclear magnetic resonance pH - negative logarithm of hydronium ion concentration psi - pounds per square inch q - quartet peak s - singlet peak t - triplet peak

Preparation 1 1 -Benzhvdryl-pyrrolidine-2,5-dicarbonitrile To 900 mL of 0.1 M aqueous citric acid solution was added 8.24 g (45 mmol) of aminodiphenylmethane, followed by 4.00 g (61 mmol) of potassium cyanide. The mixture was stirred at 20 °C until the reactants had dissolved, after which 11.00 g (83 mmol) of 2,5-dimethoxytetrahydrofuran was added in one portion. The mixture was stirred at 20 °C for about 72 hrs, after which 14.9 g of precipitate was collected by filtration, washed with water and dried. The precipitate was dissolved in a minimum of acetonitrile with heating and allowed to cool, whereupon 3.90 g (30%) of (1 -benzhydryl-pyrrolidine-2,5-c/s-dicarbonitrile) precipitated and was collected by filtration. Evaporation of the mother liquor gave a residue that was flash chromatographed on silica gel eluting with 4:1 hexane/ethyl acetate to provide 0.80 g (6%) of 1-benzhydryl-pyrrolidine-2,5-trat7s-dicarbonitrile. 1 -Benzhydryl-pyrrolidine-2,5-c/s-dicarbonitrile NMR (CDCI₃): 7.53 (m, 4 H); 7.30 (m, 4 H); 7.24 (m, 2 H); 5.11 (s, 1 H); 3.98 (m, 2 H); 2.35 (m, 4 H). APCI MS: 167 (Ph₂CH⁺ fragment), mp: 194 - 197 °C. 1-Benzhvdryl-pyrrolidine-2,5-frat?s-dicarbonitrile NMR (CDCI3): 7.53 (m, 4 H); 7.34 (m, 4 H); 7.25 (m, 2 H); 4.89 (s, 1 H); 3.86 (m, 2 H); 2.48 (m, 2 H); 2.28 (m, 2 H). APCI MS: 167 (Ph₂CH⁺ fragment), mp: 187 - 188 °C

Preparation 2 Pyrrolidine-2.5-dicarboxylic acid c/s-diamide Step l A solution of 253 g (700 mmol) of diethyl meso-2,5-dibromoadipate in 1000 mL of toluene was stirred at 80 °C while 253 mL (2300 mmol) of benzylamine was added over the course of 1 hr. Upon completion of the addition of benzylamine, the solution was kept at 80 °C with stirring for about 16 hrs. The mixture was allowed to cool to about 25 ^°C and the precipitate was removed by filtration and washed twice with toluene. The washings were combined with the filtrate and washed sequentially with water, then twice with pH = 7 5% potassium phosphate solution, brine, and dried over anhydrous magnesium sulfate. The drying agent was filtered and the toluene was evaporated to afford an amber oil. This was dissolved in 900 mL of ethyl acetate and to this solution at 20 °C was added 150 mL of a 4 M solution of hydrogen chloride in 1 ,4-dioxane. The mixture was cooled with stirring in ice for 20 mins, after which the white precipitate that formed was filtered, washed with ethyl acetate and dried to afford 164 g (70%) of the hydrochloride salt of 1 -benzyl- pyrrolidine-2,5-c/s-dicarboxylic acid diethyl ester hydrochloride. NMR (D₂O): 7.34 (m, 5 H); 4.50 (s, 2 H); 4.46 (m, 2 H); 3.99 (q, 4 H); 2.43 (m, 2 H); 2.09 (m, 2 H); 1.04 (t, 6 H). APCI MS: 306 (MH⁺). mp 120 - 122 °C. Step 2 A solution of 164 g (480 mmol) of the product of Step 1 in 250 mL of dichloromethane was stirred vigorously with 250 mL of 5 M ammonium hydroxide for 15 mins at 20 °C. The dichloromethane solution was separated, washed with brine, dried over sodium sulfate, and concentrated to give a colorless oil. The oil was dissolved in 500 mL of methanol, 4.8 g of 10% Pd/C was added, and the mixture was shaken under 50 psi of hydrogen at 20 °C for about 18 hrs. The reaction mixture was then filtered through diatomaceous earth and the solvent evaporated to provide 98 g (95%) of pyrrolidine-2,5-c/s-dicarboxylic acid diethyl ester as an oil. NMR (D₂O): 4.44 (m, 2H); 4.13 (q, 4H); 2.31 (m, 2H); 2.09 (m, 2H); 1.12 (t, 6H). APCI MS: 216 (MH⁺) Step 3 96 g (448 mmol) of the product of Step 2 was dissolved in 1300 mL of 7 M ammonia in methanol. The reaction vessel was closed tightly and the mixture was allowed to stand at 20 °C for about 7 days until the reaction was complete. The was filtered, washed with ethanol, and dried to afford 65 g (93%) of pyrrolidine-2,5-c/s- dicarboxylic acid diamide as a white solid. NMR (D₂O): 3.69 (m, 2H); 2.03 (m, 2H); 1.67 (m, 2H). APCI MS: 158 (MH⁺). mp: 229 - 230 °C.

Preparation 3 2.5-cis-Dicvano-pyrrolidine-1 -carboxylic acid fetf-butyl ester Step l A solution of 3.73 g (24 mmol) of the title compound of Preparation 2 in 30 mL of water was treated with a solution of 5.70 g (26 mmol) of

butyldicarbonate in 60 mL of 1 ,4-dioxane. The mixture was stirred at 20 °C for about 16 hrs, after which the solvents were evaporated to provide 5.98 g (24 mmol) of 2,5-c/s-dicarbamoyl-pyrrolidine-1 -carboxylic acid te/f-butyl ester as a white solid. NMR (CD₃OD): 4.26 (m, 2 H); 2.30 (m, 2 H); 1.99 (m, 2 H); 1.42 (s, 9 H). APCI MS: 258 (MH⁺). mp: 196 - 197 °C. Step 2 A solution of 6.70 g (26 mmol) of the product of Step 1 was dissolved in 65 mL of pyridine. The solution was diluted with 260 mL of dichloromethane and imidazole (7.08 g, 104 mmol) was added. The solution was cooled to 0 °C and 19 mL (208 mmol) of phosphorus oxychloride was added dropwise. The mixture was stirred at 0 ^CC for 30 mins and at 20 °C for 1 hr. Water (4 mL) was added dropwise with stirring and ice cooling. The mixture was then evaporated and the residue was triturated with THF and filtered. The filtrate was stirred for 10 mins with 50 g of Amberlite IR-120 hydrogen ion form ion exchange resin (Aldrich Chemical Co.; Milwaukee, Wl) and filtered through a pad of anhydrous magnesium sulfate. The filtrate was evaporated and the residue was recrystallized from diisopropyl ether to afford 4.24 g (74%) of the title compound as a white solid. NMR (CD₃OD): 4.68 (m, 2 H); 2.49 - 2.32 (m, 4 H); 1.52 (s, 9 H). APCI MS: 222 (MH⁺). mp: 106 - 107 °C. Preparation 4 1 -Bromoacetyl-pyrrolidine-2.5-CAS-dicarbonitrile To a solution of 3.00 g (10.4 mmol) of c s-1 -benzhydryl-pyrrolidine-2,5- dicarbonitrile (Preparation 1 ) in 40 mL of acetonitrile was added 1.1 mL (12.5 mmol) of bromoacetyl bromide with stirring at 70 °C. The mixture was stirred at 70 °C for about

16 hrs, after which the solvent was removed by evaporation. The residue was flash chromatographed on silica gel eluting with 1 :1 hexanes/ethyl acetate to afford 2.47 g

(99%) of the title compound as an oil that crystallized upon storage below 0 °C. NMR

(CD₃CN): 4.94 (m, 1 H); 4.68 (m, 1 H); 4.09 (dd, 2 H); 2.52 (m, 1 H); 2.40 (m, 3 H). APCI MS: 242, 244 (MH⁺, Br isotope pattern), mp 49 - 50 °C.

Preparation 5 1-Bromoacetyl-pyrrolidine-2,5-c/s-dicarbonitrile A solution of 0.66 g (3 mmol) of the title compound of Preparation 3 was dissolved in 12 mL of acetonitrile. To this solution was added 0.61 g (3 mmol) of bromoacetyl bromide with stirring at 20 ^°C. The mixture was stirred at 20 °C for about 1 hrs, after which the solvent was removed by evaporation. The residue was dissolved in dichloromethane and washed with sodium bicarbonate, water, brine, dried over anhydrous sodium sulfate, and concentrated to afford 0.58 g (80%) of the ^■ title compound as an oil that crystallized upon standing. NMR (CD₃CN): 4.94 (m, 1 H); 4.68 (m, 1 H); 4.09 (dd, 2 H); 2.52 (m, 1 H); 2.40 (m, 3 H). APCI MS: 242, 244 (MH⁺, Br isotope pattern), mp 49 - 50 °C.

Preparation 6 1 -Bromoacetyl-pyrrolidine-2,5-fraπs-dicarbonitrile A solution of 700 mg (2.4 mmol) of _rans-1 -benzhydryl-pyrrolidine-2,5- dicarbonitrile (Preparation 1 ) was dissolved in 10 mL of acetonitrile. To this solution was added 0.25 mL (2.9 mmol) of bromoacetyl bromide with stirring at 20 °C. The mixture was stirred at 20 °C for about 16 hrs, after which the solvent was removed by evaporation. The residue was flash chromatographed on silica gel eluting with 1 :1 hexane/ethyl acetate to afford 591 mg (100%) of 1 -bromoacetyl-pyrrolidine-2,5-fraπs- dicarbonitrile as an oil. NMR (CDCI₃): 5.01 (d, 1 H); 4.84 (d, 1 H); 3.98 (dd, 2 H); 2.71 - 2.46 (m, 4 H). APCI MS: 242, 244 (MH⁺, Br isotope pattern). Preparation 7 1 -Chloroacetyl-pyrrolidine-2,5-cis-dicarbonitrile A solution of 0.66 g (3 mmol) of the title compound of Preparation 3 was dissolved in 12 mL of acetonitrile. To this solution was added 0.34 g (3 mmol) of chloroacetyl chloride with stirring at 20 °C. The mixture was stirred at 20 °C for about 3 hrs, after which the solvent was removed by evaporation. The residue was dissolved in dichloromethane and the dichloromethane was washed with sodium bicarbonate solution and dried over anhydrous sodium sulfate. The solvent was evaporated to afford 0.56 g (94%) of 1 -chloroacetyl-pyrrolidine-2,5-c s-dicarbonitrile as an oil. NMR (CDCI₃): 4.96 (m, 1 H); 4.78 (m, 1 H); 4.23 (dd, 2 H); 2.66 - 2.52 (m,

4 H). APCI MS: 196, 198 (M-H⁺, CI isotope pattern).

Preparation 8 1 -Methyl-cyclopentylamine hydrochloride A solution of 2.00 g (20 mmol) of 1 -methylcyclopentanol in 25 mL of benzene was treated with 3.18 mL (24 mmol) of azidotrimethylsilane and 3.04 mL (24 mmol) of boron trifluoride etherate as described by Zwierzak, et al., Tetrahedron Letters, 1987, 6513. After about 24 hrs, the solution was poured into 50 mL of 1 M sodium bicarbonate solution and stirred for 30 minutes, adding solid sodium bicarbonate as needed to maintain pH > 7. The benzene layer was separated and dried over anhydrous calcium chloride. The benzene solution was diluted with 25 mL of methanol hydrogenated over 0.45 g of 10% Pd/C catalyst for 90 minutes at 45 psi and 20 °C. The reaction mixture was then filtered through diatomaceous earth, 1.7 mL of 12 M hydrochloric acid was added to the filtrate, and the solvent was evaporated to provide 1.92 g (71 %) of the title compound as a white solid. NMR (D₂O): 1 .59 (m, 8 H); 1.22 (s, 3 H). APCI MS: 100 (MH⁺). mp: 261 - 262 °C. 1 -Methyl-cyclohexylamine hydrochloride and 3-methyl-tetrahydro-thiophen- 3-ylamine hydrochloride were also prepared' from the corresponding alcohols according to the procedure described in Preparation 8. Preparation 9 N-(6-Methoxy-3-nitro-pyridin-2-yl)-cyclohexane-1.4-diamine Step l To a solution of 1.28 g (6 mmol) of (4-amino-cyclohexyl)-carbamic acid tert- butyl ester (prepared as described by Anslyn, et al., J. Org. Chem., 1996, 881 1 ) in

40 mL of acetonitrile was added TEA (0.87 mL, 6 mmol) and 2-chloro-6-methoxy-3- nitropyridine (1.13 g, 6 mmol). The mixture was heated at 90 ^°C for 3 days. The mixture was cooled, filtered, and the filtrate was concentrated. The residue was digested with 50 mL of hot ethyl acetate, filtered, and concentrated to afford 1.80 g (82%) of [4-(6-methoxy-3-nitro-pyridin-2-ylamino)-cyclohexyl]-carbamic acid tert- butyl ester. NMR (CD₃OD): 8.55 (br d, 1 H); 8.28 (d, 1 H); 6.61 (br d, 1 H); 6.08 (d,

1 H); 4.14 (m, 1 H); 3.95 (s, 3 H); 3.31 (m, 1 H); 2.15 (m, 2 H); 1.94 (m, 2 H); 1.55 -

1.20 (m, 4 H); 1.42 (s, 9 H). APCI MS: 367 (MH⁺)

Step 2 A suspension of 1.40 g (3.8 mmol) of the product of Step 1 in 30 mL of dichloromethane was treated with 15 mL of TFA with cooling in ice. After 15 mins, the reaction mixture was concentrated to dryness. The residue was treated with 40 mL of dichloromethane and 8 mL of 2 M sodium hydroxide solution. The mixture was stirred for 5 minutes and separated. The dichloromethane was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to afford

0.75 g (74%) of the title compound. NMR (CD₃OD): 8.27 (d, 1 H); 6.07 (d, 2 H); 4.1 1

(m, 1 H); 3.95 (s, 3 H); 2.72 (m, 1 H); 2.16 (m, 2 H); 1.97 (m, 2 H); 1.46 - 1 .22 (m, 4

H). APCI MS: 267 (MH⁺). The following amines were prepared from (4-amino-cyclohexyl)-carbamic acid te/t-butyl ester in a manner analogous to that described in Preparation 9 using appropriate starting materials. 3-(4-amino-cyclohexylamino)-pyrazine-2-carbonitrile; 6-(4-amino-cyclohexylamino)-nicotinonitrile; N-(2-chloro-pyrimidin-4-yl)-cyclohexane-1 ,4-diamine; N-(4,6-dimethoxy-[1 ,3,5]triazin-2-yl)-cyclohexane-1 ,4-diamine; N-(5-trifluoromethyl-pyridin-2-yl)-cyclohexane-1 ,4-diamine; 1 -(4-amino-cyclohexyl)-3-pentyl-urea; N-(3-methanesulfonyl-pyridin-2-yl)-cyclohexane-1 ,4-diamine; N-(4-amino-cyclohexyl)-4-methyl-benzenesulfonamide; 1 -(4-amino-cyclohexyl)-3-phenyl-urea; N-pyrimidin-2-yl-cyclohexane-1 ,4-diamine; (4-amino-cyclohexyl)-carbamic acid benzyl ester; N-(4-amino-cyclohexyl)-benzamide; 1 -adamantan-1 -yl-3-(4-amino-cyclohexyl)-urea; N-(4-phenyl-[1 ,3,5]triazin-2-yl)-cyclohexane-1 ,4-diamine; and 2-(4-amino-cyclohexylamino)-nicotinonitrile. C-(6'-Methoxy-3'-nitro-3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-4-yl)- methylamine and 4-aminomethyl-piperidine-1 -carboxylic acid phenylamide were prepared from piperidin-4-ylmethyl-carbamic acid te/f-butyl ester (Steffan, et al., Bioorg. Med. Chem. Lett., 2002; 2957) in a manner analogous to that described in Preparation 9 using appropriate starting materials. 5'-Methoxy-3'-nitro-3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-4-ylamine and 1 -

(4,6-dimethoxy-[1 ,3,5]triazin-2-yl)-piperidin-4-ylamine were prepared from piperidin- 4-yl-carbamic acid terf-butyl ester (Carling, et al., J .Med. Chem., 1999, 2706) in a manner analogous to that described in Preparation 9 using appropriate starting materials.

EXAMPLES The Examples set forth hereinbelow are intended only to exemplify various aspects and embodiments of the invention, and are not intended to limit the scope of the claimed invention in any way.

General Procedure A solution of the appropriately-substituted amine, RNH₂, in acetonitrile (about

5 mL per mmol of RNH₂) was treated with 1 -bromoacetyl-pyrrolidine-2,5-c s- dicarbonitrile (the c/s-isomer of Compound II in which Lv is bromo). The mixture was stirred for 24 - 48 hrs at 25 °C. The solvent was evaporated and the residue was flash chromatographed on silica gel eluting with 95:5 dichloromethane /methanol to afford the title compound. In this manner, the title compound of Example 8, 1 -[(1 -hydroxymethyl- cyclopentylamino)-acetyl]-pyrrolidine-2,5-c/s-dicarbonitrile, was prepared from 20 g (173 mol) of 1 -hydroxymethyl-cyclohexylamine (Aldrich Chemical Co.; Milwaukee, Wl) and 14 g (57 mmol) of 1 -bromoacetyl-pyrrolidine-2,5-cis-dicarbonitrile to afford 11.4 g of a white solid. This solid was taken up in 400 mL of EtOAc and washed sequentially with two 40 mL portions of 10% pH 10.5 phosphate buffer solution, brine, dried over magnesium sulfate, filtered, and concentrated to afford 9.3 g (59% yield) of the title compound as a white solid. NMR (CD₃OD): 5.32 (m, 2H), 4.98 (m, 1 H), 4.42 (d, J = 16 Hz, 1 H), 4.15 (d. J = 16 Hz, 1 H), 3.71 (overlapping d, J = 13 Hz, 2H), 2.71 - 2.64 (m, 1 H), 2.61 -2.50 (m, 2H), 2.49-2.44 (m, 1 H), 2.01 -1.76 (m, 8H). APCI MS: 277 (m-H⁺). This product was dissolved in 150 mL of methanol and treated with 54.3 mL of 0.6 M hydrogen chloride in methanol. The solution was stirred for 10 min. and concentrated to a white solid which was recrystallized from 85 mL of acetonitrile. The resulting solid was triturated with a small amount of methanol, filtered, and dried to afford 6.5 g (64% yield) of the hydrochloride salt, m.p. 173 ^°C. Calculated for C₁₄H₂oN₄O₂ ^• HCI: C, 53.75%; H, 6.77%; N, 17.91%; CI, 11.33%. Found: C, 53.80%; H, 6.71%; N, 17.80%; CI, 11.22%. The following compounds of formula (I) were prepared as described above using appropriate reactants.

Claims

CLAIMS 1. A compound of formula (I),

(I) a prodrug or stereoisomer thereof, or a pharmaceutically acceptable salt of said compound, prodrug, or stereoisomer, wherein R is:

(I) R_rX-Y-(CH₂)_m- or Rι-X-Y-(CH2)_n(C(CH₃)2)-, wherein: X is a covalent bond, O, S, -C(O)-, -SO₂-, -NR₃C(O)-, -NR₃SO₂-, or -OC(O)-; Y is a covalent bond or -N(R₂)-, provided Y is not a covalent bond when X is either a covalent bond or -C(O)-, and Y is not -N(R₂)- when X is O or S; (a) phenyl(C₀-C₈)alkyl; (b) phenoxy(C C₈)alkyl; or (c) heterocyclyl(C₀-C₈)alkyl, wherein said phenyl, said phenoxy, or said heterocyclyl, in the definitions of phenyl(C₀-C₈)alkyl, phenoxy(Cι-C₈)alkyl, and heterocyclyl(C₀-C₈)alkyl respectively, is optionally substituted independently with one to three (Cι-C₈)alkyl, (C₃-C₈)cycloalkyl, (C C₈)alkoxy, cyano, halogen, (C C₈)alkylsulfonyl, (C C₈)alkylthio, -CO₂(C C₈)alkyl, -CO₂H, -CONH₂, -CHO, -CH₂OH, hydroxy, trifluoromethyl, amino, nitro, phenyl(C C₈)alkoxy, or phenyl optionally substituted independently with one to three (d- C₈)alkyl, halogen, (C C₈)alkoxy, cyano, hydroxy, trifluoromethyl, (C C₈)alkylsulfonyl, (Ci-C₈)alkylthio, or phenyl(C C₈)alkoxy; (d) (Cι-Cι )alkyl, optionally substituted independently with one to three hydroxy, trifluoromethyl, cyano, (C C₃)hydroxyalkyl, (C C₈)alkoxy, (d- C₈)alkylsulfonyl, (C C₈)alkylthio, phenyl, or phenyl-SO₂-, wherein said phenyl is optionally substituted independently with one to three (d-C₈)alkyl, (C₃-C₈)cycloalkyl, (CrC₈)alkoxy, cyano, halogen, (CrC₈)alkylsulfonyl, (C C₈)alkylthio, -CO₂(C C₈)alkyl, -CO₂H, -CONH₂, -CHO, -CH₂OH, hydroxy, trifluoromethyl, amino, or nitro; or (e) (C₃-C₁₂)cycloalkyl, optionally substituted independently with one to three hydroxy, trifluoromethyl, cyano, (C₁-C₃)hydroxyalkyl, (C C₈)alkyl, (C C₈)alkoxy, (C C₈)alkylsulfonyl, (C C₈)alkylthio, phenyl-SO₂(C₀-C₈)alkyl, or phenyl(C₀-C₈)alkyl, wherein said phenyl is optionally substituted independently with one to three (d- C₈)alkyl, (C₃-C₈)cycloalkyl, (d-C₈)alkoxy, cyano, halogen, (Cι-C₈)alkylsulfonyl, (d~ C₈)alkylthio, -CO₂(C C₈)alkyl, -CO₂H, -CONH₂, -CHO, -CH₂OH, hydroxy, trifluoromethyl, amino, or nitro; R₂ is hydrogen, (Cι-C₈)alkyl, or (C₃-C₈)cycloalkyl; R₃ is hydrogen, methyl, or ethyl; or R₂ and R₃, taken together, form a five- or six-membered ring heterocyclyl group; m is two, three, or four; and n is one, two, or three;

(II) (d-Cι₂)alkyl, optionally substituted independently with one to three hydroxy, trifluoromethyl, cyano, or R X-Y-;

(III) (C₃-C₁₂)cycloalkyl, optionally substituted independently with one to three hydroxy, trifluoromethyl, cyano, (d-C₃)hydroxyalkyl, (Cι-C₈)alkyl, or R X-Y-(CH₂)_p-, wherein p is zero, one, two, or three;

(IV) heterocyclyl(C₀-C₈)alkyl, optionally substituted independently with one to three hydroxy, cyano, (CrC₃)hydroxyalkyl, or RrX-; or

(V) -C(CH₃)R₄R₅, wherein: R₄ is: (f) (Ci-C₈)alkyl, (g) (C₃-C₈)cycloalkyl, (h) heterocyclyl, or (i) phenyl(C₀-C₈)alkyl, wherein said (CrC₈)alkyl and (C₃-C₈)cycloalkyl are optionally substituted independently with one to three (d-C₈)alkoxy, (d-C₈)(cycloalkyl)oxy, cyano, halogen, (C C₄)alkylsulfonyl, (d-C₄)alkylthio, (C₃-C₈)(cycloalkyl)thio, hydroxy, trifluoromethyl, amino, or nitro; and wherein said heterocyclyl and said phenyl are optionally substituted independently with one to three (Cι-C₈)alkyl, (C₃-C₈)cycloalkyl, (C C₈)alkoxy, cyano, halogen, (Cι-C₈)alkylsulfonyl, (d-C₈)alkylthio, -CO₂(d-C₈)alkyl, -CO₂H, -CONH₂, -CHO, -CH∑OH, hydroxy, trifluoromethyl, amino, nitro, phenyl(C C₈)alkoxy, or phenyl optionally substituted independently with one to three (d- C₈)alkyl, halogen, (Cι-C₈)alkoxy, cyano, hydroxy, trifluoromethyl, (C C₈)alkylsulfonyl, (Cι-C₈)alkylsulfonyloxy, or phenyl(C_rC₈)alkoxy; and R₅ is hydrogen, (Cι-C₈)alkyl, or (C₃-C₈)cycloalkyl.

2. A compound of claim 1, a prodrug or stereoisomer thereof, or a pharmaceutically acceptable salt of said compound, prodrug, or stereoisomer, wherein R is:

(I) R_rX-Y-(CH₂)_m- or Rι-X-Y-(CH₂)n(C(CH₃)2)-, wherein: X is a covalent bond, O, S, -C(O)-, -SO₂-, -NR₃C(O)-, -NR₃SO₂-, or -OC(O)-; Y is a covalent bond or -N(R₂)-, provided Y is not a covalent bond when X is either a covalent bond or -C(O)-, and Y is not -N(R₂)- when X is O or S; ₍ (a) phenyl or (c) heterocyclyl(C₀-C₈)alkyl, wherein said phenyl or said heterocyclyl, in the definition of heterocyclyl(C₀-C₈)alkyl, is optionally substituted independently with one to three (Cι-C₈)alkyl, (C₃-C₈)cycloalkyl, (d-C₈)alkoxy, cyano, halogen, (Cι-C₈)alkylsulfonyl, (d-C₈)alkylthio, -CO₂(d-C₈)alkyl, -CO₂H, -CONH₂, - CHO, -CH₂OH, hydroxy, trifluoromethyl, amino, nitro, phenyl(d-C₈)alkoxy, or phenyl optionally substituted independently with one to three (C C₈)alkyl, halogen, (d- C₈)alkoxy, cyano, hydroxy, trifluoromethyl, (d-C₈)alkylsulfonyl, (Cι-C₈)alkylthio, or phenyl(Cι -C₈)alkoxy ; (d) (d-d₂)alkyl, optionally substituted independently with one to three hydroxy, trifluoromethyl, cyano, (d-C₃)hydroxyalkyl, (d-C₈)alkoxy, (d- C₈)alkylsulfonyl, (d-C₈)alkylthio, phenyl, or phenyl-SO₂-, wherein said phenyl is optionally substituted independently with one to three (d-C₈)alkyl, (C₃-C₈)cycloalkyl, (Cι-C₈)alkoxy, cyano, halogen, (Cι-C₈)alkylsulfonyl, (d-C₈)alkylthio, -CO₂(d-C₈)alkyl, -CO₂H, -CONH₂, -CHO, -CH₂OH, hydroxy, trifluoromethyl, amino, or nitro; or (e) (C₃-Cι₂)cycloalkyl, optionally substituted independently with one to three hydroxy, trifluoromethyl, cyano, (C C₃)hydroxyalkyl, (C C₈)alkyl, (C C₈)alkoxy, (d-

C₈)alkylsulfonyl, (C C₈)alkylthio, phenyl-SO₂(C₀-C₈)alkyl, or phenyl(C₀-C₈)alkyl, wherein said phenyl is optionally substituted independently with one to three (d- C₈)alkyl, (C₃-C₈)cycloalkyl, (C_rC₈)alkoxy, cyano, halogen, (C C₈)alkylsulfonyl, (d- C₈)alkylthio, -C0₂(C₁-Cβ)alkyl_l -CO₂H, -CONH₂, -CHO, -CH₂OH, hydroxy, trifluoromethyl, amino, or nitro; R₂ is hydrogen, (CrC₃)alkyl, or (C₃-C₅)cycloalkyl; R₃ is hydrogen, methyl, or ethyl; or R₂ and R₃, taken together, form a five- or six-membered ring heterocyclyl group; m is two or three; and n is one or two;

(II) (d-Cι₂)alkyl, optionally substituted independently with one to three hydroxy, trifluoromethyl, cyano, or R X-Y-;

(III) (C₃-Cι₂)cycloalkyl, optionally substituted independently with one to three hydroxy, trifluoromethyl, cyano, (Cι-C₃)hydroxyalkyl, (d-C₈)alkyl, or Rι-X-Y-(CH₂)_P-, wherein p is zero, one, two, or three; or

(IV) heterocyclyl(C₀-C )alkyl, optionally substituted independently with one to three hydroxy, cyano, (d-C₃)hydroxyalkyl, or R X. 3. A compound of claim 1 , a prodrug or stereoisomer thereof, or a pharmaceutically acceptable salt of said compound, prodrug, or stereoisomer, wherein R is:

(I) R₁-X-Y-(CH₂)m- or R X-Y-(CH2)n(C(CH₃)₂)-, wherein: X is a covalent bond, O, S, -C(O)-, -SO₂-, -NR₃C(O)-, -NR₃SO₂-, or -OC(O)-; Y is a covalent bond or -N(R₂)-, provided Y is not a covalent bond when X is either a covalent bond or -C(O)-, and Y is not -N(R₂)- when X is O or S; R-, is: (a) phenyl or (c) heterocyclyl(C₀-C₈)alkyl, wherein said phenyl or said heterocyclyl, in the definition of heterocyclyl(C₀-C₈)alkyl, is optionally substituted independently with one to three (d-C₄)alkyl, (C₃-C₆)cycloalkyl, (C C )alkoxy, cyano, halogen, (C C₄)alkylsulfonyl, (Cι-C₄)alkylthio, -CO₂(C C₄)alkyl, -CO₂H, -CONH₂, -

CHO, -CH₂OH, hydroxy, trifluoromethyl, amino, nitro, or phenyl optionally substituted independently with one to three (C_rC₄)alkyl, halogen, (d-C₄)alkoxy, cyano, hydroxy, trifluoromethyl, (d-C₄)alkylsulfonyl, or (Cι-C₄)alkylthio; (d) (Cι-Cι₂)alkyl, optionally substituted independently with one to three hydroxy, trifluoromethyl, cyano, (d-C₃)hydroxyalkyl, (d-C₈)alkoxy, (Ci- C₈)alkylsulfonyl, (CrC₈)alkylthio, phenyl, or phenyl-SO₂-, wherein said phenyl is optionally substituted independently with one to three (C C₈)alkyl, (C₃-C₈)cycloalkyl, (C C₈)alkoxy, cyano, halogen, (C C₈)alkylsulfonyl, (C_rC₈)alkylthio, -CO₂(C C₈)alkyl, -CO≥H, -CONH₂, -CHO, -CH₂OH, hydroxy, trifluoromethyl, amino, or nitro; or (e) (C₃-Cι₂)cycloalkyl, optionally substituted independently with one to three hydroxy, trifluoromethyl, cyano, (Cι-C₃)hydroxyalkyl, (Cι-C₈)alkyl, (CrC₈)alkoxy, (Cι-

C₈)alkylsulfonyl, (C_rC₈)alkylthio, phenyl-SO₂(C₀-C₈)alkyl, or phenyl(C₀-C₈)alkyl, wherein said phenyl is optionally substituted independently with one to three (Cι- C₈)alkyl, (C₃-C₈)cycloalkyl, (C_rC₈)alkoxy, cyano, halogen, (Cι-C₈)alkylsulfonyl, (C C₈)alkylthio, -CO₂(Cι-C₈)alkyl, -CO₂H, -CONH₂, -CHO, -CH₂OH, hydroxy, trifluoromethyl, amino, or nitro; R₂ is hydrogen or (d-C₃)alkyl; R₃ is hydrogen, methyl, or ethyl; or R₂ and R₃, taken together, form a five- or six-membered ring heterocyclyl group; m is two; and n is one; (III) (C₃-Cι₂)cycloalkyl, optionally substituted independently with one to three hydroxy, trifluoromethyl, cyano, (C C₈)alkyl, or Rι-X-Y-(CH₂)_P-, wherein p is zero, one, or two. 4. The compound: 1 -[(3-hydroxy-adamantan-1 -ylamino)-acetyl]-pyrrolidine-2,5-c/s- dicarbonitrile; 1-[(adamantan-2-ylamino)-acetyl]-pyrrolidine-2,5-c/s-dicarbonitrile; 1 -{[2-(5-nitro-pyridin-2-ylamino)-ethylamino]-acetyl}-pyrrolidine-2,5-c/s- dicarbonitrile; 1 -{[2-(4-fluoro-phenyl)-1 ,1 -dimethyl-ethylamino]-acetyl}-pyrrolidine-2,5-c/s- dicarbonitrile; 1 -{[2-(5-cyano-pyridin-2-ylamino)-ethylamino]-acetyl}-pyrrolidine-2,5-c/s- dicarbonitrile; 1 -te/t-butylaminoacetyl-pyrrolidine-2,5-c/s-dicarbonitrile; 1 -[(2-hydroxy-1 ,1 -dimethyl-ethylamino)-acetyl]-pyrrolidine-2,5-c/s- dicarbonitrile; 1 -[(1 -hydroxymethyl-cyclopentylamino)-acetyl]-pyrrolidine-2,5-c/s- dicarbonitrile; 1 -[(indan-2-ylamino)-acetyl]-pyrrolidine-2,5-c/s-dicarbonitrile; 1 -[(4-trans-hydroxy-cyclohexylamino)-acetyl]-pyrrolidine-2,5-c/s- dicarbonitrile; 1 -[(1 ,1 ,3,

3-tetramethyl-butylamino)-acetyl]-pyrrolidine-2,5-c/s-dicarbonitrile; 1 -[(bicyclo[2.2.1 ]hept-2-ylamino)-acetyl]-pyrrolidine-2,5-c/s-dicarbonitrile; 1 -[(1 -methyl-1 -phenyl-ethylamino)-acetyl]-pyrrolidine-2,5-c/s-dicarbonitrile; 1-[(1 -methyl-cyclopentylamino)-acetyl]-pyrrolidine-2,5-c/s-dicarbonitrile; 1-[(2-hydroxymethyl-indan-2-ylamino)-acetyl]-pyrrolidine-2,5-c/s-dicarbonitrile; 1 -[(1 -benzyl-cyclobutylamino)-acetyl]-pyrrolidine-2,5-c/s-dicarbonitrile; 1 -[(1 ,7,7-trimethyl-bicyclo[2.2.1 ]hept-2-ylamino)-acetyl]-pyrrolidine-2,5-c/s- dicarbonitrile; 1 -[(adamantan-2-ylamino)-acetyl]-pyrrolidine-2,5-c/s-dicarbonitrile; 1 -{[4-(6-methoxy-3-nitro-pyridin-2-ylamino)-cyclohexylamino]-acetyl}- pyrrolidine-2,5-cis-dicarbonitrile; 1 -[(hexahydro-2,5-methano-pentalen-3a-ylamino)-acetyl]-pyrrolidine-2,5-c/s- dicarbonitrile; 1 -{[4-(3-cyano-pyrazin-2-ylamino)-cyclohexylamino]-acetyl}-pyrrolidine-2,5- c s-dicarbonitrile; 1 -[(1 -methyl-cyclohexylamino)-acetyl]-pyrrolidine-2,5-cs-dicarbonitrile; 1 -[(1 -hydroxymethyl-cyclohexylamino)-acetyl]-pyrrolidine-2,5-c s-dicarbonitrile; 1 -{[(6'-methoxy-3'-nitro-3,

4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-4-ylmethyl)- amino]-acetyl}-pyrrolidine-2,5-c/s-dicarbonitrile; 1-{[4-(5-cyano-pyridin-2-ylamino)-cyclohexylamino]-acetyl}-pyrrolidine-2,5-c/s- dicarbonitrile; 1 -{[4-(2-chloro-pyrimidin-4-ylamino)-cyclohexylamino]-acetyl}-pyrrolidine-2,5- c/s-dicarbonitrile; 1 -{[4-(4,6-dimethoxy-[1 ,3,5]triazin-2-ylamino)-cyclohexylamino]-acetyl}- pyrrolidine-2,5-c/s-dicarbonitrile; 1 -[(1 -phenyl-cyclobutylamino)-acetyl]-pyrrolidine-2,5-c/s-dicarbonitrile; 1 -{[4-(5-trifluoromethyl-pyridin-2-ylamino)-cyclohexylamino]-acetyl}- pyrrolidine-2,5-c/s-dicarbonitrile; 1 -[(dicyclopropylmethyl-amino)-acetyl]-pyrrolidine-2,5-c/s-dicarbonitrile; 1 -cyclopentylaminoacetyl-pyrrolidine-2,5-c/s-dicarbonitrile; 1 -{4-[2-(2,5-c/s-dicyano-pyrrolidin-1 -yl)-2-oxo-ethylamino]-cyclohexyl}-3- pentyl-urea; 1 -{[4-(3-methanesulfonyl-pyridin-2-ylamino)-cyclohexylamino]-acetyl}- pyrrolidine-2,5-c/s-dicarbonitrile; ^[(δ'-methoxy-S'-nitro-S^^.e-tetrahydro^H-CI ^'jbipyridinyl^-ylamino)- acetyl]-pyrrolidine-2,5-c/s-dicarbonitrile; N-{4-[2-(2,5-c/s-dicyano-pyrrolidin-1 -yl)-2-oxo-ethylamino]-cyclohexyl}-4- methyl-benzenesulfonamide; 1 -{4-[2-(2,5-c/s-dicyano-pyrrolidin-1 -yl)-2-oxo-ethylamino]-cyclohexyl}-3- phenyl-urea; 1 -{[4-(pyrimidin-2-ylamino)-cyclohexylamino]-acetyl}-pyrrolidine-2,5-c/s- dicarbonitrile; 1 -[(4-hydroxymethyl-tetrahydro-pyran-4-ylamino)-acetyl]-pyrrolidine-2,5-c/s- dicarbonitrile; 4-{[2-(2,5-c/s-dicyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-methyl}-piperidine-1- carboxylic acid phenylamide; 1 -{[1 -(4,6-dimethoxy-[1 ,3,5]triazin-2-yl)-piperidin-4-ylamino]-acetyl}- pyrrolidine-2,5-cis-dicarbonitrile; {4-[2-(2,5-c/s-dicyano-pyrrolidin-1 -yl)-2-oxo-ethylamino]-cyclohexyl}-carbamic acid benzyl ester; 1 -{[2-(6-methoxy-3-nitro-pyridin-2-ylamino)-1 ,1 -dimethyl-ethylamino]-acetyl}- pyrrolidine-2,5-c/s-dicarbonitrile; 1 -{4-[2-(2,5-c/s-dicyano-pyrrolidin-1 -yl)-2-oxo-ethylamino]-cyclohexyl}-1 - methyl-3-phenyl-urea; {4-[2-(2,5-c/s-dicyano-pyrrolidin-1 -yl)-2-oxo-ethylamino]-cyclohexyl}-carbamic acid tert-butyl ester; N-{4-[2-(2_I5-c s-dicyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-cyclohexyl}- benzamide; 1 -adamantan-1 -yl-3-{4-[2-(2,5-c/s-dicyano-pyrrolidin-1 -yl)-2-oxo-ethylamino]- cyclohexyl}-urea; 1 -{[4-(4-phenyl-[1 ,3,5]triazin-2-ylamino)-cyclohexylamino]-acetyl}-pyrrolidine- 2,5-c s-dicarbonitrile; 1 -[(1 -methoxymethyl-cyclopentylamino)-acetyl]-pyrrolidine-2,5-cis- dicarbonitrile; 1 -{[4-(3-cyano-pyridin-2-ylamino)-cyclohexylamino]-acetyl}-pyrrolidine-2,5-c/s- dicarbonitrile; a prodrug thereof, or a pharmaceutically acceptable salt of said compound or prodrug.

5. A pharmaceutical composition comprising an amount of a compound of formula (I) of claim 1 , a prodrug or stereoisomer thereof, or a pharmaceutically acceptable salt of said compound, prodrug, or stereoisomer, and a pharmaceutically acceptable carrier, vehicle, or diluent.

6. A method of inhibiting DPP-IV which method comprises administering to a mammal in need of such inhibition a DPP-IV inhibiting amount of a compound of formula (I) of claim 1 , a prodrug or stereoisomer thereof, or a pharmaceutically acceptable salt of said compound, prodrug, or stereoisomer.

7. A method of treating a condition mediated by DPP-IV inhibition which method comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) of claim 1 , a prodrug or stereoisomer thereof, or a pharmaceutically acceptable salt of said compound, prodrug, or stereoisomer.

8. The method of claim 7, wherein said condition is Type 2 diabetes, profression of disease in Type 2 diabetes, metabolic syndrome (Syndrome X and/or IRS), hyperglycemia, impaired glucose tolerance, glucosuria, metabolic acidosis, arthritis, cataracts, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, Type 1 diabetes, obesity, conditions exacerbated by obesity, hypertension, hyperlipidemia, atherosclerosis, osteoporosis, osteopenia, frailty, bone loss, bone fracture, short stature due to bone growth deficiency, acute coronary syndrome, infertility due to polycystic ovary syndrome, short bowel syndrome, anxiety, depression, insomnia, chronic fatigue, epilepsy, eating disorders, chronic pain, alcohol addiction, diseases associated with intestinal motility, ulcers, irritable bowel syndrome, or inflammatory bowel syndrome.

9. The method of claim 8, wherein said condition is Type 2 diabetes.

10. A pharmaceutical composition comprising: a) an amount of a compound of formula (I) of claim 1 , a prodrug or stereoisomer thereof, or a pharmaceutically acceptable salt of said compound, prodrug, or stereoisomer; b) an amount of an antidiabetic agent, a prodrug or pharmaceutically acceptable salt thereof, insulin or an analog thereof, insulinotropin, a biguanide, an α₂-antagonist, an imidazoline, a glitazone, an aldose reductase inhibitor, a glycogen phosphorylase inhibitor, a sorbitol dehydrogenase inhibitor, a fatty acid oxidation inhibitor, an α-glucosidase inhibitor, a β-agonist, a phosphodiesterase inhibitor, a lipid-lowering agent, an antiobesity agent, a vanadate, a vanadium complex, a peroxovanadium complex, an amylin antagonist, a glucagon antagonist, a growth hormone secretagogue, a gluconeogenesis inhibitor, a somatostatin analog, an antilipotic agents, or an inhibitor of renal glucose; and c) a pharmaceutically acceptable carrier, vehicle, or diluent.