WO2009005672A1 - Antidiabetic azaindoles and diazaindoles - Google Patents

Abstract

Azaindoles and diazaindoles having aromatic substituents on the 5-membered ring are agonists or partial agonists of the PPAR receptor and are useful in the treatment and control of type 2 diabetes and of symptoms of diabetes, including hyperglycemia, dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, and obesity that are often associated with type 2 diabetes.

Description

TITLE OF THE INVENTION

ANTIDIABETIC AZATNDOLES AND DIAZAINDOLES

FIELD OF THE INVENTION

The instant invention is concerned with azaindoles and diazaindoles having an aromatic substituent, and pharmaceutically acceptable salts and prodrugs thereof, which are useful as therapeutic compounds, particularly in the treatment of Type 2 diabetes mellitus, and of conditions that are often associated with this disease, including obesity and lipid disorders.

BACKGROUND OF THE INVENTION

Diabetes is a disease derived from multiple causative factors and characterized by elevated levels of plasma glucose (hyperglycemia) in the fasting state or after administration of glucose during an oral glucose tolerance test. There are two generally recognized forms of diabetes. In type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), patients produce little or no insulin, the hormone which regulates glucose utilization. In type 2 diabetes, or noninsulin-dependent diabetes mellitus (NIDDM), insulin is still produced in the body. Patients having type 2 diabetes often have hyperinsulinemia (elevated plasma insulin levels); however, these patients are insulin resistant, which means that they have a resistance to the effect of insulin in stimulating glucose and lipid metabolism in the main insulin-sensitive tissues, which are muscle, liver and adipose tissues. Patients who are insulin resistant but not diabetic compensate for the insulin resistance by secreting more insulin, so that serum glucose levels are not elevated enough to meet the criteria of Type 2 diabetes. In patients with Type 2 diabetes, even elevated plasma insulin levels are insufficient to overcome the pronounced insulin resistance. Persistent or uncontrolled hyperglycemia that occurs with diabetes is associated with increased and premature morbidity and mortality. Often abnormal glucose homeostasis is associated both directly and indirectly with obesity, hypertension, and alterations of the lipid, lipoprotein and apolipoprotein metabolism, as well as other metabolic and hemodynamic disease. Patients with type 2 diabetes mellitus have a significantly increased risk of macro vascular and microvascular complications, including atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Therefore, therapeutic control of glucose homeostasis, lipid metabolism, obesity, and hypertension are critically important in the clinical management and treatment of diabetes mellitus.

Many patients who have insulin resistance or Type 2 diabetes often have several symptoms that together are referred to as syndrome X, or the metabolic syndrome. A patient having this syndrome is characterized as having three or more symptoms selected from the following group of five symptoms: (1) abdominal obesity; (2) hypertriglyceridemia; (3) low high-density lipoprotein cholesterol (HDL); (4) high blood pressure; and (5) elevated fasting glucose, which may be in the range characteristic of Type 2 diabetes if the patient is also diabetic. Each of these symptoms is defined in the recently released Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III, or ATP III), National Institutes of Health, 2001, NIH Publication No. 01-3670. Patients with metabolic syndrome, whether or not they have or develop overt diabetes mellitus, have an increased risk of developing the macro vascular and microvascular complications that are listed above that occur with type 2 diabetes, such as atherosclerosis and coronary heart disease.

Insulin resistance is not primarily caused by a diminished number of insulin receptors but by a post-insulin receptor binding defect that is not yet completely understood. This lack of responsiveness to insulin results in insufficient insulin-mediated activation of uptake, oxidation and storage of glucose in muscle and inadequate insulin-mediated repression of lipolysis in adipose tissue and of glucose production and secretion in the liver.

There are several available treatments for type 2 diabetes, each of which has its own limitations and potential risks. Physical exercise and a reduction in dietary intake of calories often dramatically improve the diabetic condition and are the best first line treatment of type 2 diabetes. Compliance with this treatment is very poor because of well-entrenched sedentary lifestyles and excess food consumption, especially of foods containing high amounts of fat. A widely used drug treatment involves the administration of meglitinide or a sulfonylurea (e.g. tolbutamide or glipizide), which are insulin secretagogues. These drugs increase the plasma level of insulin by stimulating the pancreatic βcells to secrete more insulin. When administration of a sulfonylurea or meglitinide becomes ineffective, the amount of insulin in the body can be supplemented by the injection of insulin so that insulin concentrations are high enough to stimulate even the very insulin-resistant tissues. However, dangerously low levels of plasma glucose can result from administration of insulin and/or insulin secretagogues, and an increased level of insulin resistance due to the even higher plasma insulin levels can occur. The biguanides are another class of drugs that are widely used to treat type 2 diabetes. The two best known biguanides, phenformin and metformin, cause some correction of hyperglycemia without risk of causing hypoglycemia. The biguanides can be used either with insulin or with an insulin secretagogue without increasing the risk of hypoglycemia. However, phenformin and metformin can induce lactic acidosis and nausea/diarrhea. Metformin has a lower risk of side effects than phenformin and is widely prescribed for the treatment of Type 2 diabetes.

The glitazones (i.e. 5-benzylthiazolidine-2,4-diones) are a newer class of compounds that can ameliorate hyperglycemia and other symptoms of type 2 diabetes. These agents substantially increase insulin sensitivity in muscle, liver and adipose tissue in several animal models of type 2 diabetes, resulting in partial or complete correction of elevated plasma glucose levels without the occurrence of hypoglycemia. The glitazones that are currently marketed (rosiglitazone and pioglitazone) are agonists of the peroxisome proliferator activated receptor (PPAR) gamma subtype. PPAR-gamma agonism is generally believed to be responsible for the improved insulin sensititization that is observed with the glitazones. New PPAR agonists are being developed for the treatment of Type 2 diabetes and/or dyslipidemia. Many of the newer PPAR compounds are agonists of one or more of the PPAR alpha, gamma and delta subtypes. Compounds that are agonists of both the PPAR alpha and PPAR gamma subtypes (PPAR alpha/gamma dual agonists) are promising because they reduce hyperglycemia and also improve lipid metabolism.

PPAR agonists, and particularly glitazones, have had shortcomings which have so far detracted from their attractiveness. Some of the compounds, especially troglitazone, have exhibited liver toxicity. Troglitazone was eventually withdrawn from the marketplace because of hepatotoxicity. Another weakness in the currently marketed PPAR agonists is that monotherapy for type 2 diabetes produces only modest efficacy - a reduction in average plasma glucose of ~ 20% and a decline from -9.0% to -8.0% in HemoglobinAlC. The currently marketed compounds also do not greatly improve lipid metabolism, and may actually have a negative effect on the lipid profile. These shortcomings have provided an incentive to develop better insulin sensitizers for Type 2 diabetes which function via similar mechanism(s) of action. Recently, there have been reports of compounds that are PPAR gamma antagonists or partial agonists. WOO 1/30343 describes a specific compound that is a PPAR gamma partial agonist/antagonist that is useful for the treatment of obesity and Type 2 diabetes. WO02/08188, WO2004/020408, WO2004/020409, WO2004/019869, WO 2006/014262, and WO 2006/022954 disclose classes of PPAR agonists and partial agonists that are indole or benzourea derivatives and that are useful in the treatment of Type 2 diabetes, with reduced side effects relating to body and heart weight gain. PPAR agonists and partial agonists having an azaindole central ring have not been described.

SUMMARY OF THE INVENTION The class of compounds described herein is a new class of PPAR-gamma agonists and partial agonists. The compounds are potent ligands of the PPAR gamma nuclear receptor. The class of compounds comprises primarily PPARγ partial agonists, but also may include PPARγ full agonists and/or PPARγ antagonists. Some compounds may also have PP ARa activity in addition to PPARγ activity. The compounds are useful in the treatment and control of hyperglycemia and insulin resistance. The compounds are efficacious in the treatment of non- insulin dependent diabetes mellitus (NIDDM) in human and other mammalian patients, particularly in the treatment of hyperglycemia, and in the treatment of conditions associated with NIDDM, including hyperlipidemia, dyslipidemia, obesity, hypercholesterolemia, hypertriglyceridemia, atherosclerosis, vascular restenosis, inflammatory conditions, and other PPAR mediated diseases, disorders and conditions.

The compounds are also useful in the treatment of one or more lipid disorders, including mixed or diabetic dyslipidemia, isolated hypercholesterolemia, which may be manifested by elevations in LDL-C and/or non-HDL-C, hyperapoBlipoproteinemia, hypertriglyceridemia, elevated triglyceride-rich-lipoproteins, and reduced HDL cholesterol. They are also useful in the treatment or amelioration of atherosclerosis, obesity, vascular restenosis, inflammatory conditions, psoriasis, polycystic ovary syndrome, and other PPAR mediated diseases, disorders and conditions.

The class of compounds is described by formula I:

I and includes pharmaceutically acceptable salts of formula I. hi the compounds of formula I, including pharmaceutically acceptable salts of formula I: A, G, D and E are each selected from CH and N, wherein (a) one of A, G, D and E is

N, and the others of A, G, D and E are CH; or (b) A and E are N, and D and G are CH; wherein when A and E are N, and D and G are CH, D and G are optionally connected to opposite ends of a 4-carbon bridging group -HC=CH-CH=CH-, so that a phenyl ring is fused to the structure of Formula I at the G and D positions, said phenyl group being optionally substituted with 1 -3 substituent groups independently selected from -CH3, -CF3, -OCH3, -OCF3, and halogen; Rl is selected from -X-Aryl-Y-Z and -X-HET-Y-Z, wherein Aryl and HET are optionally substituted with 1-3 groups independently selected from R⁹;

Aryl is phenyl or naphthyl;

HET is a 5-membered heteroaromatic ring having 1-4 heteroatoms independently selected from N, O and S; and

X is selected from the group consisting of a bond, CH2, CH(CH3), and C(CH3)2-

Y and Z have 3 alternative definitions as follows:

(1) Y is selected from the group consisting of -OCR^R^-, -SCR7R8-₅ and -CR5R6CR7R8-_; and Z is selected from the group consisting of -CO2H and -CO2Ci-C5alkyl;

(2) or alternatively, Y and Z together optionally represent a group selected from -NH2, -OH, -NO2, -NHSC-2Phenyl, -NHSO2Ci-C3alkyl, -NHC(=O)Phenyl, -NHC(=O)NHPhenyl, -NHC(=O)Ci-C3alkyl, and -Sθ2Ci-C3alkyl, wherein Phenyl in all uses is optionally substituted with 1-3 groups independently selected from Ci-C4alkyl, -OCi-C4alkyl, and halogen, and all alkyl groups in all uses are optionally substituted with 1-3 halogens;

(3) or alternatively, when Rl is -X-HET-Y-Z, -Y-Z is optionally H, -CR5R6CO2H, or -CO2H.

In these compounds, each R⁹ is independently selected from the group consisting of Ci-C4alkyl, C2-C4alkenyl, C2-C3alkynyl, -C≡C-Phenyl, -OCi-C4alkyl, -OH, halogen, and -CN, wherein Ci-C4alkyl, C2-C4alkenyl, C2-C3alkynyl, and -OCi_C4alkyl are each optionally substituted with 1-5 halogens, and Phenyl of -C≡C-Phenyl is optionally substituted with 1-3 substitutents independently selected from CH3, CF3, -OCH3, -OCF3, and halogen;

R5, R6_S R7₅ and R8 are each independently selected from the group consisting of H, halogen, C1-C5 alkyl, -OC1-C5 alkyl, C2-C5 alkenyl, and -OC2-C5 alkenyl, wherein C1-C5 alkyl, -OC1-C5 alkyl, C2-C5 alkenyl, and -OC2-C5 alkenyl are optionally substituted with 1-5 halogens; R2 is selected from the group consisting of H, -CH2S(O)2Ci-C3alkyl,

-CH2SCi-C3alkyl, and Ci-C3alkyl, wherein Ci-C3alkyl in all uses is optionally substituted with 1-3 halogens;

R.3 is selected from the group consisting of -C(=O)Aryl, -OAryl, -S(O)_nAryl, and -C(=O)C4-C6alkyl, wherein C4-C6alkyl is optionally substituted with 1-5 halogens, and Aryl is optionally substituted with 1-3 substituent groups independently selected from halogen, Ci- C3alkyl, -OCi-Csalkyl, and -SCi-C3alkyl, wherein Ci_C3alkyl, -OCiX^alkyl, and -SCi-C3alkyl are optionally substituted with 1-5 halogens;

Each R4 is independently selected from H, halogen, C1-C5 alkyl and -OC1-C5 alkyl, wherein C1-C5 alkyl and -OC1-C5 alkyl are optionally substituted with 1-5 halogens; n is an integer from 0-2; and p is an integer from 1 to 3.

In the above definitions and subsequent definitions, alkyl groups may be either linear or branched, unless otherwise specified.

DETAILED DESCRIPTION OF THE INVENTION

The invention has numerous embodiments. It provides compounds of Formula I, including pharmaceutically acceptable salts of these compounds, prodrugs of these compounds, and pharmaceutical compositions comprising these compounds and a pharmaceutically acceptable carrier.

Numerous embodiments are described below, in which the various chemical groups that are defined above have varying definitions. These alternative descriptions of the chemical substitutent groups can be substituted into the description of the invention independently of one another to yield combinations that are not explicitly described herein.

hi embodiments of the compounds of Formula I, including pharmaceutically acceptable salts thereof, Aryl is Phenyl.

In embodiments of the compounds of Formula I, including pharmaceutically acceptable salts thereof, HET is isoxazolyl, pyrazolyl, or tetrazolyl. In embodiments of the compounds of Formula I, including pharmaceutically acceptable salts thereof, Y is selected from the group consisting of -OCR^R^-, -SCR7R.8-, and -CR5R6CR7R8-.

In embodiments of the compounds of Formula I, including pharmaceutically acceptable salts thereof, Z is CO2H.

In embodiments of the compounds of Formula I, including pharmaceutically acceptable salts thereof, R2 is selected from H and C1-C3 alkyl, which is optionally substituted with 1-3 halogens.

In embodiments of the compounds of Formula I, including pharmaceutically acceptable salts thereof, R3 is selected from the group consisting of -C(=O)Aryl, -OAryl, -S(O)_nAryl, and -C(=O)CH2C(CH3)3; wherein the Aryl of R3 is optionally substituted with 1-2 substituent groups independently selected from halogen, Ci-3alkyl, and -OCi-3alkyl, wherein Ci_3alkyl and -OCi-3alkyl are optionally substituted with 1-3 F. hi embodiments of the compounds of Formula I, including pharmaceutically acceptable salts thereof, each R4 is independently selected from H, halogen, C1-C3 alkyl and -OC1-C3 alkyl, wherein C1-C3 alkyl and -OC1-C3 alkyl are optionally substituted with 1-3 F. hi embodiments of the compounds of Formula I, including pharmaceutically acceptable salts thereof, n is an integer from 0-2. hi embodiments of the compounds of Formula I, including pharmaceutically acceptable salts thereof, p is an integer from 1 to 3. hi other embodiments, p is an integer from 1-2. In other embodiments, p is 1.

hi embodiments of the compounds of Formula I, including pharmaceutically acceptable salts thereof, R3 is selected from the group consisting -O-Phenyl and -C(=O)Phenyl, wherein Phenyl is optionally substituted with 1-2 substituents independently selected from CH3, CF3, -OCH3, -OCF3, and halogen.

hi embodiments of the compounds of Formula I, including pharmaceutically acceptable salts thereof, Rl is -X- Aryl- Y-Z, wherein Aryl is phenyl which is optionally substituted with 1-3 groups independently selected from R9.

hi embodiments of the compounds of Formula I, including pharmaceutically acceptable salts thereof, each R9 is independently selected from the group consisting of C1-C3 alkyl, C2-3 alkenyl, C2-3alkynyl, -OH, -CN, CF3, -OCH3, -OCF3, halogen, and -C≡C-Phenyl in which the phenyl group is optionally substituted with 1-3 substituents independently selected from CH3, CF3, -OCH3, -OCF3, and halogen.

hi embodiments of the compounds of Formula I, including pharmaceutically acceptable salts thereof, Y is -OCR7R.8-; R7 i_s selected from the group consisting of H and C1-C3 alkyl; and R.8 is selected from the group consisting of H, C1-C3 alkyl, and OC1-C3 alkyl, wherein Ci- C3 alkyl and OC1-C3 alkyl in all uses are optionally substituted with 1-3 F.

In embodiments of the compounds of Formula I, including pharmaceutically acceptable salts thereof, Y is -CR5R.6CHR8-; wherein R.5 and R.6 are each independently selected from H and CH3; and R.8 is selected from the group consisting of H, Ci_C3alkyl and -OC1-C3 alkyl, wherein Cl-C3alkyl and -OCl-C3alkyl are each optionally substituted with 1-3 F.

hi embodiments of the compounds of Formula I, including pharmaceutically acceptable salts thereof, X is CH2 or a bond.

hi embodiments of the compounds of Formula I, including pharmaceutically acceptable salts thereof, X is a bond.

hi embodiments of the compounds of Formula I, including pharmaceutically acceptable salts thereof, X is CH2.

hi embodiments of the compounds of Formula I, including pharmaceutically acceptable salts thereof, R.4 is selected from the group consisting of H, CH3, CF3, -OCH3, -OCF3, and halogen.

hi embodiments of the compounds of Formula I, including pharmaceutically acceptable salts thereof, R.2 is CH3.

hi embodiments of the compounds of Formula I including pharmaceutically acceptable salts thereof,

A, G, D and E are each selected from CH and N, wherein (a) one of A, G, D and E is N, and the others of A, G, D and E are CH; or (b) A and E are N, and D and G are CH; wherein when A and E are N, and D and G are CH, D and G are optionally connected to opposite ends of a 4-carbon bridging group -HC=CH-CH=CH-, so that a phenyl ring is fused to the structure of Formula I at the G and D positions, said phenyl group being optionally substituted with 1 substituent selected from the group consisting of -CH3, -CF3, -OCH3, -OCF3, and halogen;

Rl is selected from -X-Aryl-Y-Z and -X-HET-Y-Z, wherein Aryl and HET are optionally substituted with 1-2 groups independently selected from R⁹;

Aryl is Phenyl;

HET is a 5-membered heteroaromatic ring selected from the group consisting of isoxazolyl, pyrazolyl, and tetrazolyl; and

X is selected from the group consisting of a bond and CH2-

In these compounds, Y and Z have alternative definitions, as follows:

(1) Y is selected from the group consisting of -OCR^R^-, -SCR7R8-₅ and -CR5R6CR7R8-_; and Z is -CO2H or -CO2CH3;

(2) or alternatively, Y and Z together optionally represent a substituent selected from the group consisting of -NH2, -OH, -NO2, -NHSO2Phenyl, -NHSO2CH3, -NHC(=O)Phenyl, -NHC(=O)NHPhenyl, and -NHC(=O)CH3, wherein Phenyl in all uses is optionally substituted with 1-2 groups independently selected from Ci-C4alkyl, CF3, -OCH3, -OCF3, and halogen;

(3) or alternatively, when Rl is -X-HET-Y-Z, -Y-Z is optionally H, -CR5R6CC>2H, or -CO2H.

In these compounds, each R⁹ is independently selected from the group consisting of

Ci_C3alkyl, C2-C3alkenyl, C2-C3alkynyl, -C≡C-Phenyl, -OCH3, CF3, -OCF3, -OH, halogen, and -CN;

R5 and R6 are each independently selected from the group consisting of H and Ci-C3alkyl, wherein Ci-C3alkyl is optionally substituted with 1-3 F atoms;

R7 is selected from the group consisting of H and Ci-C3alkyl, wherein Ci-C3alkyl is optionally substituted with 1-3 F atoms; R.8 is selected from the group consisting of H, Ci-C3alkyl, and -OCi-C2alkyl, wherein Ci-C3alkyl and -OCi-C2alkyl are optionally substituted with 1-3 F atoms;

R2 is selected from the group consisting of H, -CH2S(O)2CH3, -CH2SCH3, and CH3;

R3 is selected from the group consisting of -C(=O)Aryl, -OAryl, and -C(=O)CH2C(CH3)3; wherein Aryl is Phenyl which is optionally substituted with 1-2 substituent groups independently selected from CH3, CF3, -OCH3, OCF3, and halogen;

Each R4 is independently selected from H, CH3, CF3, -OCH3, -OCF3, and halogen; and p is an integer from 1 to 2.

In a subset of the compounds described above, or a pharmaceutically acceptable salt thereof:

Rl is -X-HET-Y-Z, wherein HET is optionally substituted with 1-2 groups independently selected from R9;

X is selected from the group consisting of a bond and CH2; and

Y and Z have alternative definitions, as follows:

(1) Y is selected from the group consisting of -OCR^R^-, -SCR7R8-, and -CR5R6CR7R8-; and Z is -CO2H;

(2) or alternatively, Y and Z together optionally represent a substituent selected from the group consisting of H, -CR5R6C02H, and -CO2H.

hi these compounds, each R9 is independently selected from the group consisting of halogen, CH3, -OCH3, CF3, and -OCF3; and

R2 is CH3. In embodiments of the compounds of Formula I, including pharmaceutically acceptable salts thereof, A, G, D and E are each selected from CH and N, wherein (a) one of A, G, D and E is N, and the others of A, G, D and E are CH; or (b) A and E are N, and D and G are CH; wherein D and G do not have the option of being joined to a bridging -CH=CH-CH=CH-group to make a phenyl ring.

In embodiments of the compounds of Formula I, including pharmaceutically acceptable salts thereof,

A and E are N, and D and G are CH groups which are connected to opposite ends of a 4- carbon bridging groups -HC=C-C=CH-, yielding a phenyl group fused to the diaziandole moiety.

In embodiments of the compounds of Formula I, including pharmaceutically acceptable salts thereof, Rl is -X-Phenyl-Y-CO2H, wherein Phenyl is optionally substituted with 1-2 groups independently selected from R.9.

hi embodiments of the compounds of Formula I, including pharmaceutically acceptable salts thereof, each R.9 is independently selected from the group consisting of C 1.3 alkyl, C2-3alkenyl, C2-3alkynyl, -OCi -3 alkyl, -OH, halogen, and -CN, wherein alkyl, alkenyl, alkynyl, and -Oalkyl are each optionally substituted with 1-3 F.

hi embodiments of the compounds of Formula I, including pharmaceutically acceptable salts thereof, Y is -OCR7R8-, wherein R7 is selected from the group consisting of H and CH3, and R8 is selected from the group consisting of C1-C3 alkyl and -OC1-C2 alkyl.

In embodiments of the compounds of Formula I, including pharmaceutically acceptable salts thereof, R^ is selected from the group consisting of -C(=O)Phenyl and -OPhenyl, wherein Phenyl is optionally substituted with 1-2 groups independently selected from halogen, CH3, CF3, -OCH3, and -OCF3.

Structures of specific compounds are provided in Tables 1 and 2. The syntheses of the specific compounds in Table 1 are provided hereinafter in the Examples. The compounds in Table 2 were made by generally following the methods disclosed herein, which were varied to adjust for structural differences. These compounds can readily be made by a practitioner of synthetic organic chemistry using the techniques disclosed herein. Mass spectral data are also included in Table 2.

Table 2

The compounds of this invention can be used in pharmaceutical compositions comprising the compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The compounds of this invention can be used in pharmaceutical compositions in which a compound of Formula I or a pharmaceutically acceptable salt thereof is the only active ingredient, or in compositions that also include additional active ingredients.

The compounds of the invention and pharmaceutically acceptable salts thereof can be used in the manufacture of medicaments for the treatment of type 2 diabetes mellitus in a human or other mammalian patient, and in the manufacture of medicaments for other diseases described herein that are treated by the compounds.

The compounds as defined above may be used in any of the following methods to treat or control diseases, as well as methods to treat other diseases not listed below, in a mammalian patient, especially a human, by administering to the patient a therapeutically effective amount of a compound of Formula I:

(1) non-insulin dependent diabetes mellitus (type 2 diabetes);

(2) hyperglycemia;

(3) metabolic syndrome;

(4) obesity; (5) hypercholesterolemia;

(6) hypertriglyceridemia; and/or (7) one or more lipid disorders, including mixed or diabetic dyslipidemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia.

The compounds may also be used in a method for reducing the risks of adverse sequelae associated with metabolic syndrome in a human or other mammalian patient in need of such treatment which comprises administering to the patient a therapeutically effective amount of a compound of Formula I.

The compounds may also be used in a method for treating atherosclerosis, for reducing the risk of developing atherosclerosis, for delaying the onset of atherosclerosis, and/or reducing the risk of sequelae of atherosclerosis in a human or other mammalian patient in need of such treatment or at risk of developing atherosclerosis or sequelae of atherosclerosis, which comprises administering to the patient a therapeutically effective amount of a compound of Formula I. Sequelae of atherosclerosis include for example angina, claudication, heart attack, stroke, etc. PPAR agonists are potentially useful in the treatment of Alzheimer's disease.

These compounds may therefore also have utility in treating Alzheimer's disease.

The compounds are especially useful in the treatment of the following diseases, by administering a therapeutically effective amount to a patient in need of treatment:

(1) type 2 diabetes, and especially hyperglycemia resulting from type 2 diabetes;

(2) metabolic syndrome;

(3) obesity; and

(4) hypercholesterolemia.

Definitions

"Ac" is acetyl, which is CH3C(O)-.

"Alkyl" means saturated carbon chains which may be linear or branched or combinations thereof, unless the carbon chain is defined otherwise. Other groups having the prefix "alk", such as alkoxy and alkanoyl, also may be linear or branched or combinations thereof, unless the carbon chain is defined otherwise. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like.

"Alkenyl" means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2- butenyl, and the like. "Alkynyl" means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-l-pentynyl, 2-heptynyl and the like.

"Cycloalkyl" means mono- or bicyclic saturated or partially unsaturated carbocyclic rings, each having from 3 to 10 carbon atoms, unless otherwise stated. The term also includes a monocyclic ring fused to an aryl group. Examples of cycloalkyl include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

A cycloalkylidene group is a divalent cycloalkane radical in which both attachments are at the same carbon. For example, the cyclopropyl group of 1,1- dimethylcyclopropane is a cyclopropylidene group.

"Aryl" (and "arylene") when used to describe a substituent or group in a structure means a monocyclic or bicyclic compound in which all the rings are aromatic and which contains only carbon ring atoms. The term "aryl" can also refer to an aryl group that is fused to a cycloalkyl or heterocycle. More specifically, Aryl means phenyl or naphthyl. The most preferred Aryl group is phenyl.

"Heteroaryl" (and heteroarylene) means a mono- or fused bicyclic aromatic ring system containing 1-4 heteroatoms selected from N, O and S, including -S(O)- and -S(O)2-, with each ring containing 5 to 6 atoms. "HET" in this application is a 5-membered aromatic ring containing 1-4 heteroatoms independently selected from N, O, and S, wherein the ring does not contain any carbonyl, sulfoxide, or sulfone groups. Examples of heteroaryl include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, azoxazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl (including S-oxide and dioxide), furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl, and the like. Examples of HET include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, azoxazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, and thienyl. Preferred HET groups include tetrazolyl, isoxazolyl, and pyrazolyl. "Halogen" includes fluorine, chlorine, bromine and iodine. "Me" represents methyl. The term "composition," as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.

The substituent "tetrazole" means a 2//-tetrazol-5-yl substituent group and tautomers thereof.

Optical Isomers - Diastereomers - Geometric Isomers - Tautomers

Compounds of Formula I may contain one or more asymmetric centers and can thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is meant to comprehend all such isomeric forms of the compounds of Formula I.

Some of the compounds described herein may contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.

Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers. An example is a ketone and its enol form, known as keto-enol tautomers. The individual tautomers as well as mixtures thereof are encompassed with compounds of Formula I.

Compounds of Formula I having one or more asymmetric centers may be separated into diastereoisomers, enantiomers, and the like by methods well known in the art.

Alternatively, enantiomers and other compounds with chiral centers may be synthesized by stereospecific synthesis using optically pure starting materials and/or reagents of known configuration.

Salts

The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl- morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p- toluenesulfonic acid, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids. It will be understood that, as used herein, references to the compounds of Formula

I are meant to also include the pharmaceutically acceptable salts.

Metabolites - Prodrugs

Therapeutically active metabolites of other compounds, where the metabolites themselves fall within the scope of the claimed invention, are also compounds of the current invention. Prodrugs, which are compounds that are converted to the claimed compounds as they are being administered to a patient or after they have been administered to a patient, are also compounds of this invention.

Utilities

Compounds of the present invention are potent ligands having agonist, partial agonist or antagonist activity on one or more of the various peroxisome proliferator activated receptor subtypes, particularly PPARγ. The compounds may also be ligands or agonists, partial agonists or antagonists of the PPARαsubtype as well as the PPARγ subtype, resulting in mixed PPARα/γ agonism or in agonism of mainly the PPARαsubtype. Some compounds (generally less preferred) may also be PPARδ ligands and have PPARδ activity in addition to their other PPAR activity. The compounds of this invention are useful in treating or controlling diseases, disorders or conditions which are mediated by one or more ligands of the individual PPAR subtypes (eg γ or α) or a combination of PPAR subtypes (e.g. α/γ). One aspect of the present invention provides a method for the treatment and control of diseases that can be mediated by administration of a PPAR agonist or partial agonist, particularly a PPAR γ agonist or partial agonist, such as type 2 diabetes, by administering to a patient in need of treatment a therapeutically effective amount of a compound of Formula I. Compounds of the present invention may be useful in treating or controlling many PPAR mediated diseases and conditions, including, but not limited to, (1) diabetes mellitus, and especially non-insulin dependent diabetes mellitus (NIDDM), (2) hyperglycemia, (3) low glucose tolerance, (4) insulin resistance, (5) obesity, (6) lipid disorders, (7) dyslipidemia, (8) hyperlipidemia, (9) hypertriglyceridemia, (10) hypercholesterolemia, (11) low HDL levels, (12) high LDL levels, (13) atherosclerosis and its sequelae, (14) vascular restenosis, (15) irritable bowel syndrome, (16) inflammatory bowel disease, including Crohn's disease and ulcerative colitis, (17) other inflammatory conditions, (18) pancreatitis, (19) abdominal obesity, (20) neurodegenerative disease, (21) retinopathy, (22) psoriasis, (23) metabolic syndrome, (24) ovarian hyperandrogenism (polycystic ovarian syndrome), and other disorders where insulin resistance is a component. They may also have utility in treating high blood pressure, neoplastic conditions, adipose cell tumors, adipose cell carcinomas, such as liposarcoma, prostate cancer and other cancers, including gastric, breast, bladder and colon cancers, angiogenesis, and Alzheimer's disease.

The present compounds can be used to lower glucose, lipids, and insulin in non- diabetic patients that have impaired glucose tolerance and/or are in a pre-diabetic condition.

The present compounds can be used to treat obesity in a patient in need of such treatment by administering to the patient a therapeutically effective amount of a compound of Formula 1.

The present compounds can be used to treat or reduce the risk of developing atherosclerosis in a patient in need of such treatment by administering to the patient a therapeutically effective amount of a compound of Formula 1. The present compounds can be used to treat or reduce hyperglycemia in a patient in need of such treatment by administering to the patient a therapeutically effective amount of a compound of Formula 1.

The compounds may have utility in treating osteoporosis. The compounds of this invention may treat osteoporosis or reduce the risk of developing osteoporosis by slowing or stopping the loss of bone density in a patient who has osteoporosis or is at risk of developing osteoporosis. The compounds of this invention may also reverse the loss of bone mass in patients who have already begun to lose bone mass.

One aspect of the invention provides a method for the treatment and control of mixed or diabetic dyslipidemia, hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, and/or hypertriglyceridemia, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound having formula I. The compound may be used alone or advantageously may be administered with a cholesterol biosynthesis inhibitor, particularly an HMG-CoA reductase inhibitor such as lovastatin, simvastatin, rosuvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, or itavastatin. The compound may also be used advantageously in combination with other lipid lowering drugs such as cholesterol absorption inhibitors (for example stanol esters, sterol glycosides such as tiqueside, and azetidinones such as ezetimibe), ACAT inhibitors (such as avasimibe), CETP inhibitors, niacin, niacin receptor agonists, bile acid sequestrants, microsomal triglyceride transport inhibitors, and bile acid reuptake inhibitors. These combination treatments may also be effective for the treatment or control of one or more related conditions selected from the group consisting of hypercholesterolemia, atherosclerosis, hyperlipidemia, hypertriglyceridemia, dyslipidemia, high LDL, and low HDL.

Another aspect of the invention provides a method of treating inflammatory conditions, including inflammatory bowel disease, Crohn's disease, and ulcerative colitis by administering an effective amount of a compound of this invention to a patient in need of treatment. Additional inflammatory diseases that may be treated with the instant invention include gout, rheumatoid arthritis, osteoarthritis, multiple sclerosis, asthma, ARDS, psoriasis, vasculitis, ischemia/reperfusion injury, frostbite, and related diseases.

Administration and Dose Ranges

Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. Preferably compounds of Formula I are administered orally.

The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art. When treating or controlling diabetes mellitus and/or hyperglycemia or hypertriglyceridemia or other diseases for which compounds of Formula I are indicated, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of from about 0.01 milligram to about 100 milligrams per kilogram of animal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form. For most large mammals, including humans (e.g. a 70 kg adult), the total daily dosage is from about 0.1 milligrams to about 1000 milligrams, is likely to be from about 0.5 milligrams to about 350 milligrams, and is often from about 1 milligram to about 50 milligrams. For a particularly potent compound, the dosage for an adult human may be as low as 0.1 mg. Examples of daily dosages for a 70 kg adult human are 0.1 mg, 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 350 mg, and 500 mg per day. The daily dosage regimen may be adjusted within the above ranges or even outside of these ranges to provide the optimal therapeutic response.

Oral administration will usually be carried out using tablets. Examples of doses in tablets which may be administered once a day or more than once a day (e.g. 2x, 3x, or (rarely) 4 or more times per day, are 0.1 mg, 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 350 mg, and 500 mg. Other oral forms (e.g. capsules or suspensions) can also be administered in doses having similar sizes.

Pharmaceutical Compositions Another aspect of the present invention provides pharmaceutical compositions which comprise a compound of Formula I and a pharmaceutically acceptable carrier. The pharmaceutical compositions of the present invention comprise a compound of Formula I or a pharmaceutically acceptable salt as an active ingredient, as well as a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term "pharmaceutically acceptable salts" refers to salts of pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids. A pharmaceutical composition may also comprise a prodrug, or a pharmaceutically acceptable salt thereof, if a prodrug is administered.

The compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy. In general, compositions suitable for oral administration are preferred. hi practical use, the compounds of Formula I can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous), hi preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.

Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained. The active compounds can also be administered intranasally as, for example, liquid drops or spray.

The tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.

Compounds of formula I may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. Combination Therapy

Compounds of Formula I may be used in combination with other drugs that may also be useful in the treatment or amelioration of the diseases or conditions for which compounds of Formula I are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of

Formula I. When a compound of Formula I is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of Formula I is preferred. However, the combination therapy also includes therapies in which the compound of Formula I and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compound of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of Formula I. Examples of other active ingredients that may be administered in combination with a compound of Formula I, and either administered separately or in the same pharmaceutical composition, include, but are not limited to:

(a) other PPAR gamma agonists and partial agonists, such as the glitazones (e.g. troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone, balaglitazone, netoglitazone, and the like), and PPAR gamma agonists and partial agonists that do not have a glitazone structure such as T- 131 ;

(b) biguanides such as metformin and phenformin;

(c) protein tyrosine phosphatase- IB (PTP-IB) inhibitors,

(d) dipeptidyl peptidase FV (DP-FV) inhibitors, such as sitagliptin, vildagliptin, saxigliptin, and NN-7201.

(e) insulin or insulin mimetics;

(f) sulfonylureas such as tolbutamide and glipizide, or related materials;

(g) α-glucosidase inhibitors (such as acarbose);

(h) agents which improve a patient's lipid profile, such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, rosuvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, and other statins), (ii) bile acid sequestrants (cholestyramine, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran), (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) niacin receptor agonists, (v) PP ARa agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate), (vi) cholesterol absorption inhibitors, such as for example ezetimibe, (vii) acyl CoAxholesterol acyltransferase (ACAT) inhibitors, such as avasimibe, (viii) CETP inhibitors, such as torcetrapib, and (ix) phenolic antioxidants, such as probucol;

(i) PPARα/γdual agonists, such as KRP-297, muraglitazar, tesaglitazar, naveglitazar (LY-818), TAK-559, LY-929, and the like; (j) PPARδ agonists such as GW501516 and compounds disclosed in

WO97/28149;

(k) antiobesity compounds such as fenfluramine, dexfenfluramine, phentiramine, subitramine, orlistat, neuropeptide Y5 inhibitors, Mc4r agonists, cannabinoid receptor 1 (CB-I) antagonists/inverse agonists, and β3 adrenergic receptor agonists; (1) ileal bile acid transporter inhibitors;

(m) agents intended for use in inflammatory conditions such as aspirin, nonsteroidal anti-inflammatory drugs, glucocorticoids, azulfidine, and cyclo-oxygenase 2 selective inhibitors;

(n) glucagon receptor antagonists; (o) GLP-I,

(p) GIP-I, and

(q) GLP-I analogs, such as exenatide and exendins.

The above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds. Non-limiting examples include combinations of compounds having Formula I with two or more active compounds selected from biguanides, sulfonylureas, HMG-CoA reductase inhibitors, other PPAR agonists, PTP-IB inhibitors, DP-IV inhibitors, and anti-obesity compounds.

Compounds of the present invention (i.e. compounds having Formula I) can be used to treat one or more diseases or conditions selected from hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia, and dyslipidemia by administering a therapeutically effective amount of a compound of Claim 1 in combination with an HMG-CoA reductase inhibitor to a patient in need of such treatment. Statins are the preferred HMG-CoA reductase inhibitors for use in this combination therapy. Preferred statins include lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, itavastatin, ZD-4522, rivastatin, and rosuvastatin. This combination treatment may be particularly desirable for treating or reducing the risk of developing atherosclerosis.

BIOLOGICAL ASSAYS A) PPAR Binding Assays For preparation of recombinant human PPARγ PPARδ and PP ARa: Human PPARy₂, human PPARδ and human PP ARa were expressed as gst-fusion proteins in E. coll The full length human cDNA for PPARy₂ was subcloned into the pGΕX-2T expression vector (Pharmacia). The full length human cDNAs for PPARδ and PP ARa were subcloned into the pGEX-KT expression vector (Pharmacia). E. coli containing the respective plasmids were propagated, induced, and harvested by centrifugation. The resuspended pellet was broken in a French press and debris was removed by centrifugation at 12,000 X g. Recombinant human PPAR receptors were purified by affinity chromatography on glutathione sepharose. After application to the column, and one wash, receptor was eluted with glutathione. Glycerol (10%) was added to stabilize the receptor and aliquots were stored at -80⁰C.

For binding to PPARγ, an aliquot of receptor was incubated in TEGM (10 mM Tris, pH 7.2, 1 mM EDTA, 10% glycerol, 7 μL/100 mL β-mercaptoethanol, 10 mM Na molybdate, 1 mM dithiothreitol, 5 μg/mL aprotinin, 2 μg/mL leupeptin, 2 μg/mL benzamidine and 0.5 mM PMSF) containing 0.1% non-fat dry milk and 10 nM [³H2] AD5075, (21 Ci/mmole), ± test compound as described in Berger et al (Novel peroxisome proliferator- activated receptor (PPARγ) and PPARδ ligands produce distinct biological effects. J. Biol. Chem. (1999), 274: 6718-6725. Assays were incubated for -16 hr at 4°C in a final volume of 150 μL. Unbound ligand was removed by incubation with 100 μL dextran/gelatin-coated charcoal, on ice, for -10 min. After centrifugation at 3000 rpm for 10 min at 4°C, 50 μL of the supernatant fraction was counted in a Topcount.

For binding to PPARδ, an aliquot of receptor was incubated in TEGM (10 mM Tris, pH 7.2, 1 mM EDTA, 10% glycerol, 7 μL/100 mL β-mercaptoethanol, 10 mM Na molybdate, 1 mM dithiothreitol, 5 μg/mL aprotinin, 2 μg/mL leupeptin, 2 μg/mL benzamide and 0.5 mM PMSF) containing 0.1% non-fat dry milk and 2.5 nM [³H2]L-783483, (17 Ci/mmole), ± test compound as described in Berger et al (Novel peroxisome proliferator-activated receptorγ (PPARγ) and PPARδ ligands produce distinct biological effects.1999 J Biol Chem 274: 6718- 6725). (L-783483 is 3-chloro-4-(3-(7-propyl-3-trifluoromethyl-6-benz-[4,5]- isoxazoloxy)propylthio)phenylacetic acid, Ex. 20 in WO 97/28137). Assays were incubated for — 16 hr at 4°C in a final volume of 150 μL. Unbound ligand was removed by incubation with 100 μL dextran/gelatin-coated charcoal, on ice, for -10 min. After centrifugation at 3000 rpm for 10 min at 4°C, 50 μL of the supernatant fraction was counted in a Topcount.

For binding to PP ARa, an aliquot of receptor was incubated in TEGM (10 mM Tris, pH 7.2, 1 mM EDTA, 10% glycerol, 7 μL/100 mL β-mercaptoethanol, 10 mM Na molybdate, 1 mM dithiothreitol, 5 μg/mL aprotinin, 2 μg/mL leupeptin, 2 μg/mL benzamide and 0.5 mM PMSF) containing 0.1% non-fat dry milk and 5.0 nM [³H2]L-797773, (34 Ci/mmole), ± test compound. (L-797733 is (3-(4-(3-phenyl-7-propyl-6-benz-[4,5]- isoxazoloxy)butyloxy))phenylacetic acid, Ex.62 in WO 97/28137). Assays were incubated for -16 hr at 4°C in a final volume of 150 μL. Unbound ligand was removed by incubation with 100 μL dextran/gelatin-coated charcoal, on ice, for -10 min. After centrifϊigation at 3000 rpm for 10 min at 4°C, 50 μL of the supernatant fraction was counted in a Topcount.

The specific compounds in this application exhibit IC50 values for PPAR gamma using this assay in the range of 390OnM to <0.5nM, and preferred compounds have IC50 values in the range of 50OnM to <0.5nM.

B) Gal-4 hPPARTransactivation Assays

The chimeric receptor expression constructs, pcDNA3-hPPARγ/GAL4, pcDNA3- hPPARδ/GAL4, pcDNA3-hPPARα/GAL4 were prepared by inserting the yeast GAL4 transcription factor DBD adjacent to the ligand binding domains (LBDs) of hPPARγ, hPPARδ, hPPARα, respectively. The reporter construct, pUAS(5X)-tk-luc was generated by inserting 5 copies of the GAL4 response element upstream of the herpes virus minimal thymidine kinase promoter and the luciferase reporter gene. pCMV-lacZ contains the galactosidase Z gene under

3 the regulation of the cytomegalovirus promoter. COS-I cells were seeded at 12 X 10 cells/well in 96 well cell culture plates in high glucose Dulbecco's modified Eagle medium (DMEM) containing 10% charcoal stripped fetal calf serum (Gemini Bio-Products, Calabasas, CA), nonessential amino acids, 100 units/ml Penicillin G and 100 mg/ml Streptomycin sulfate at 37 °C in a humidified atmosphere of 10% CO2- After 24 h, transfections were performed with

Lipofectamine (GIBCO BRL, Gaithersburg, MD) according to the instructions of the manufacturer. Briefly, transfection mixes for each well contained 0.48 μl of Lipofectamine, 0.00075 μg of pcDNA3-PPAR/GAL4 expression vector, 0.045 μg of pUAS(5X)-tk-luc reporter vector and 0.0002 μg of pCMV-lacZ as an internal control for transactivation efficiency. Cells were incubated in the transfection mixture for 5 h at 37° C in an atmosphere of 10% CO2. The cells were then incubated for -48 h in fresh high glucose DMEM containing 5% charcoal stripped fetal calf serum, nonessential amino acids, 100 units/ml Penicillin G and 100 mg/ml Streptomycin sulfate ± increasing concentrations of test compound. Since the compounds were solubilized in DMSO, control cells were incubated with equivalent concentrations of DMSO; final DMSO concentrations were < 0.1%, a concentration which was shown not to effect transactivation activity. Cell lysates were produced using Reporter Lysis Buffer (Promega, Madison, WI) according to the manufacturer's instructions. Luciferase activity in cell extracts was determined using Luciferase Assay Buffer (Promega, Madison, WI) in an ML3000 luminometer (Dynatech Laboratories, Chantilly, VA). β-galactosidase activity was determined using β-D-galactopyranoside (Calbiochem, San Diego, CA).

Agonism is determined by comparison of maximal transactivation activity with a full PPAR agonist, such as rosiglitazone. Generally, if the maximal stimulation of transactivation is less than 50% of the effect observed with a full agonist, then the compound is designated as a partial agonist. If the maximal stimulation of transactivation is greater than 50% of the effect observed with a full agonist, then the compound is designated as a full agonist. The compounds of this invention have EC50 values in the range of InM to 3000 nM.

C) In Vivo Studies

Male db/db mice (10-11 week old C57B1/KFJ, Jackson Labs, Bar Harbor, ME) are housed 5/cage and allowed ad lib. access to ground Purina rodent chow and water. The animals, and their food, are weighed every 2 days and are dosed daily by gavage with vehicle (0.5% carboxymethylcellulose) ± test compound at the indicated dose. Drug suspensions are prepared daily. Plasma glucose, and triglyceride concentrations are determined from blood obtained by tail bleeds at 3-5 day intervals during the study period. Glucose and triglyceride, determinations are performed on a Boehringer Mannheim Hitachi 911 automatic analyzer (Boehringer Mannheim, Indianapolis, IN) using heparinized plasma diluted 1 :6 (v/v) with normal saline. Lean animals are age-matched heterozygous mice maintained in the same manner.

EXAMPLES

The following Examples are provided to illustrate the invention and are not to be construed as limiting the invention in any manner. The scope of the invention is defined by the appended claims. Specific compounds are presented with detailed syntheses in the following

Examples and are also summarized in Table 1. Additional specific compounds are provided in Table 2.

The compounds in the Examples and Table 1 were generally analyzed by NMR and tandem high pressure liquid chromatography - mass spectrometry (LC-MS). The compounds in Table 2 were analyzed by LC-MS, as well as NMR or other methods for many of the compounds. LC-MS samples were analyzed using an Agilent 1 100 Series high pressure liquid chromatograph coupled to a Waters Micromass ZQ mass spectrometer. The column used was a Waters XTerra and compounds were eluted using a gradient elution program (10% B to 100% B in 4.5 min) with a flow rate of 2.5 mL/min; Solvent A: water containing 0.05% trifluoroacetic acid; Solvent B: acetonitrile containing 0.05% trifluoroacetic acid. Retention times are given in minutes.

Method A: XTerra MS-C 18, 4.5 x 50 mm, 10 - 100% B in 4.5 min, flow rate 2.5 ml/min. Method B: XTerra Cl 8, 3 x 50 mm, 10 - 98% in 3.75 min, then 98% for 1 min, flow rate 1 ml/min.

General and specific procedures for making the compounds and synthetic intermediates that are disclosed herein are summarized in the following schemes and examples. Other compounds claimed herein can readily be made by one of ordinary skill in the art of medicinal and/or synthetic organic chemistry by adapting the procedures disclosed herein.

The schemes and/or examples listed below provide methodology for making the following classes of azaindoles and diazaindoles that are PPAR agonists, and particularly selective PPAR gamma modulators.

Schemes 1 and 2 (Ex. 1 and 2): 3-Aroyl-7-azaindoles

Scheme 3 (Ex. 3): 3-Phenoxy-7-azaindoles

Scheme 4 (Ex. 4): 6-Azaindoles

Scheme 5 (Ex. 5): 5-Azaindoles

Example 6: 4- Azaindoles

Scheme 6 (Ex. 7): 4,7-Diazaindoles (C2-H); 5H-pyrrolo[2,3- bjpyrazines Scheme 7 (Ex. 8): 4,7-Diazaindoles (C2-methyl); 6-methyl-5H- pyrrolo[2,3-b]pyrazines

3-Aroyl-7-Azaindoles (C3-Aroyl) SCHEME 1, EXAMPLE 1

EXAMPLE 1

Step 1. The first step in this synthesis was published in a methodology paper in

Tetrahedron Lett. 2005, 46(13) 2283.

To a solution of 2-amino-6-picoline (840mg, 7.78mmol) in CH₂Cl₂ (2OmL) at - 78°C was added a solution of tBuOCI (2 eq, 1.76mL) in CH₂Cl₂ (6mL). The reaction was stirred for 10-15 min prior to the addition of methyl thioacetone (1 eq, 0.8mL) in CH₂Cl₂ (6mL). After 90 min, a solution OfNEt₃ (1 eq, 1.2mL) in CH₂Cl₂ (6mL) was added and the mixture warmed to ambient temperature. The reaction was quenched by the addition of water and the layers allowed to separate. The organic layer was dried over Na₂SO₄ and concentrated. Purification was by flash chromatography which provided 2,6-dimethyl-3-(methylthio)-lH-pyrrolo[2,3-b]pyridine as a yellow solid. ¹H NMR (500 MHz, CDCl₃): δ 10.59 (bs, IH), 7.86 (d, IH), 6.99 (d, IH), 2.67 (s, 3H), 2.59 (s, 3H), 2.45 (s, 3H).

A solution of 2,6-dimethyl-3-(methylthio)-lH-pyrrolo[2,3-b]pyridine (225mg,

1.17mmol), Cs₂CO₃ (3eq, l.lg) and isobutyl (2S)-2-[3-(bromomethyl)phenoxy]propanoate (1.1 eq, 405mg) in DMF (6mL) was stirred at 25°C for 15h. The reaction was diluted with EtOAc and washed with water (2x) and IM HCl (Ix). The organic layer was dried over Na₂SO₄ and concentrated. The residue was purified via flash chromatography eluting with 0 to 100% EtOAc/hexanes. Isobutyl (2S)-2-(3-{[2,6-dimethyl-3-(methyltio)-lH-pyrrolo[2,3-b]pyridin-l- yl]methyl}phenoxy)propanoate. ¹H NMR (500 MHz, CDCl₃): δ 7.85 (d, IH), 7.15 (t, IH), 6.98 (d, IH), 6.71 (dd, IH), 6.68 (d, IH), 6.65 (m, IH), 5.45 (s, 2H), 4.67 (q, IH), 3.88 (dd, IH), 3.79 (dd, IH), 2.61 (s, 3H), 2.40 (s, 3H), 2.24 (s, 3H), 1.84 (m, IH), 1.57 (d, 3H), 0.82 (dd, 6H).

A slurry of isobutyl (2S)-2-(3-{[2,6-dimethyl-3-(methyltio)-lH-pyrrolo[2,3- b]pyridin-l-yl] methyl }phenoxy)propanoate (352mg, 0.83mmol) and Raney Nickel (~lg) in aqueous EtOH was stirred for 20min at 25°C. The mixture was then filtered through Celite and silica gel and concentrated. Isobutyl (2S)-2-(3-{[2,6-dimethyl-lH-pyrrolo[2,3-b]pyridin-l- yl]methyl}phenoxy)propanoate was used without further purification. ¹H NMR (500 MHz, CDCl₃): δ 7.67 (d, IH), 7.14 (t, IH), 6.89 (d, IH), 6.70 (dd, IH), 6.65 (d, IH), 6.61 (s, IH), 6.15 (s, IH), 5.44 (s, 2H), 4.66 (q, IH), 3.87 (dd, IH), 3.79 (dd, IH), 2.59 (s, 3H), 2.27 (s, 3H), 1.84 (m, IH), 1.56 (d, 3H), 0.82 (dd, 6H).

To a solution of isobutyl (2S)-2-(3-{[2,6-dimethyl-lH-pyrrolo[2,3-b]pyridin-l- yl]methyl}phenoxy)propanoate (323mg, 0.83mmol) in DCM (8.5mL) was added AlCl₃ (5eq, 566mg). The slurry stirred at 25°C for Ih before the addition of p-anisoyl chloride (2eq, 291mg). After 5h, the reaction was quenched with MeOH and concentrated. The residue was purified via flash chromatography eluding with 0 to50% EtOAc/hexanes. Isobutyl (2S)-2-(3-{[3-(4- chlorobenzoyl)-2,6-dimethyl-lH-pyrrolo[2,3-b]pyridin-l-yl]methyl}phenoxy)propanoate was isolated as colorless syrup. ¹U NMR (500 MHz, CDCl₃): δ 8.05 (d, IH), 7.77 (d, 2H), 7.53 (d, IH), 7.18 (t, IH), 6.95 (m, 3H), 6.73 (m, 2H), 6.71 (s, IH), 5.54 (dd, 2H), 4.69 (q, IH), 3.88 (s, 3H), 3.87 (m, IH), 3.81 (dd, IH), 2.60 (s, 3H), 2.50 (s, 3H), 1.85 (m, IH), 1.58 (d, 3H), 0.82 (d, 6H).

Isobutyl (2S)-2-(3 - { [3 -(4-chlorobenzoyl)-2,6-dimethyl- 1 H-pyrrolo [2,3 -b]pyridin- 1-yl] methyl }phenoxy)propanoate (21 lmg, 0.41mmol) and NaOH (1.2eq) were combined and dissolved in aqueous MeOH (1OmL). After 2h, reaction was concentrated and residue purified by prep LC. (2S)-2-(3-{[3-(4-chlorobenzoyl)-2,6-dimethyl-lH-pyrrolo[2,3-b]pyridin-l- yl]methyl}phenoxy)propanoic acid was isolated as a lyophilized powder. ¹H NMR (500 MHz, CDCl₃): δ 8.00 (d, IH), 7.77 (d, 2H), 7.20 (t, IH), 7.15 (d, IH), 6.97 (d, 2H), 6.80 (dd, IH), 6.67 (d, IH), 6.39 (s, IH), 5.66 (dd, 2H), 4.56 (q, IH), 3.90 (s, 3H), 2.74 (s, 3H), 2.45 (s, 3H), 1.54 (d, 3H).

SCHEME 2, EXAMPLE 2

Step 1 : 2-amino-6-methoxypyridine

The starting material was prepared using the procedure described by Lang, F.; Zewge, D.; Houpis, I.N.; Volante, R.P. Tetrahedron Lett., 42, 3251-3254, 2001.

Step 2: 6-methoxy-2-methyl-3-(methylthio)-l//-pyrrolo[2,3-6]pyridine

To a solution of 2-amino-6-methoxypyridine (2.07 mL, 20 mmol) and methylthioacetone (1 eq, 2.08 mL) in CH₂Cl₂ (50 mL) at -78°C was added a solution of tBuOCl (1 eq, 2.26 mL) in CH₂Cl₂ (50 mL). After 1 hour, a solution OfNEt₃ (1 eq, 2.80 mL) in CH₂Cl₂ (50 mL) was added. The reaction was warmed to 25 °C and stirred for 1 hour. The mixture was poured into water and the layers separated. The organic layer was dried over Na₂SO₄ and concentrated. The residue was purified via flash chromatography eluding with a gradient of 0 to 100% CH₂Cl₂/hexanes then 0 to 25% EtOAc/hexanes. The title compound was isolated as a slightly impure solid. H NMR (500 MHz, CDCl₃): δ 8.63 (bs, IH), 7.83 (d, IH), 6.60 (d, IH), 3.95 (s, 3H), 2.50 (s, 3H), 2.25 (s, 3H).

Step 3 : 6-methoxy-2-methyl- lH-pyrrolo[2,3-6]pyridine

A slurry of 6-methoxy-2-methyl-3-(methylthio)-lH-pyrrolo[2,3-Z?]pyridine (280 mg, 1.4 mmol) and Raney Nickel (~lg) in aqueous EtOH was stirred for 60 min at 25°C. The mixture was then filtered through Celite and silica gel and concentrated. The title compound was used without further purification. ¹H NMR (500 MHz, CDCl₃): δ 8.77 (bs, IH), 7.67 (d, IH), 6.53 (d, IH), 6.06 (m, IH), 3.95 (s, 3H), 2.39 (s, 3H). Step 4: (6-methoxy-2-methyl-l//-pyrrolo[2,3-&]pyridin-3-yl)(4-methoxyphenyl)methanone

To a solution of 6-methoxy-2-methyl-lH-pyrrolo[2,3-6]pyridine (780 mg, 4.8 mmol) and ZnCl₂ (3.2 eq, 337 mg) in CH₂Cl₂ (60 mL) was added EtMgBr (3.0 M soln, 1.1 eq, 1.77 mL). After 1 hour, p-anisoylchloride (1.1 eq, 862 mg) was added. After 1 hour, the reaction was quenched with water and extracted with CH₂Cl₂ (2x). The organic layer was washed with satd NH₄Cl (Ix). The organic layer was dried over Na₂SO₄ and concentrated. The residue was purified via flash chromatography eluding with a gradient of 0 to 100% EtOAc/hexanes. The product was then triturated with MeOH and filtered. The title compound was obtained as a white solid. ¹H NMR (500 MHz, CDCl₃): δ 9.10 (bs, IH), 7.77 (d, 2H), 7.63 (d, IH), 6.95 (d, 2H), 6.55 (d, IH), 3.96 (s, 3H), 3.89 (s, 3H), 2.57 (s, 3H).

Step 5 Isobutyl (25)-2-(3-{[6-methoxy-3-(4-methoxybenzoyl)-2-methyl-lH-pyrrolo[2,3- 6]pyridin-l-yl]methyl}phenoxy)propanoate

To a solution of (6-methoxy-2-methyl-lH-pyrrolo[2,3-δ]pyridin-3-yl)(4- methoxyphenyl)methanone (20 mg, 0.067mmol), Cs₂CO₃ (3eq, 65 mg) and isobutyl (2S)-2-[3- (bromomethyl)phenoxy]propanoate (1.2 eq, 26 mg) in DMF (1 mL) was stirred at 25°C for 15h. The reaction was diluted with dichloromethane and washed with water (2x). The organic layer was dried over Na₂SO₄ and concentrated. The residue was purified via thin layer chromatography (25% EtOAc/hexanes). The title compound was isolated as a film. ¹H NMR (500 MHz, CDCl₃): δ 7.76 (d, 2H), 7.53 (d, IH), 7.20 (m, IH), 6.94 (d, 2H), 6.79 (d, IH), 6.74 (m, IH), 6.55 (d, IH), 5.45 (dd, 2H), 4.70 (q, IH), 3.96 (s, 3H), 3.88 (s, 3H), 3.87 (m, 2H), 2.48 (s, 3H), 1.84 (m, IH), 1.59 (d, 3H), 0.82 (d, 6H).

Step 6 (2S)-2-(3-{[6-methoxy-3-(4-methoxybenzoyl)-2-methyl-lH-pyrrolo[2,3-ό]pyridin-l- yl] methyl }phenoxy)propanoic acid:

Isobutyl (25)-2-(3 - { [6-methoxy-3 -(4-methoxybenzoyl)-2-methyl- 1 H-pyrrolo [2,3-ό]pyridin- 1 - yl]methyl}phenoxy)propanoate (33 mg) and 1.0 M KaOH (1.2eq) were combined and dissolved in aqueous MeOH (5 mL). After 2h, reaction was concentrated and residue purified by prep LC. The title compound was isolated as a lyophilized powder. ¹H NMR (500 MHz, CDCl₃): δ 7.80 (d, 2H), 7.52 (d, IH), 7.23 (t, IH), 6.94 (d, 2H), 6.87 (d, IH), 6.80 (dd, IH), 6.57 (d, IH), 6.35 (bs, IH), 5.67 (d, IH), 5.33 (d, IH), 4.80 (bs, IH), 4.54 (q, IH), 3.94 (s, 3H), 3.89 (s, 3H), 2.39 (s, 3H), 1.57 (d, 3H).

3-Phenoxy-7-azaindoles

SCHEME 3, EXAMPLE 3

Scheme 3

A solution of 4-chlorophenol (35g, 0.273mol), chloroacetone (25g, l.leq), and cesium carbonate (11Og 1.5eq) in DMF (10OmL) was stirred for 12 hrs at ambient temperature. To the reaction was added water (10OmL) and diluted with EtOAc (20OmL). The layers were allowed to separate and the organic layer was dried over Na₂SO₄ and concentrated. The desired product was purified by silica gel column using 4:1 hexane/EtOAc that gave l-(4-chlorophenoxy)acetone as a colorless oil. ¹H NMR (500 MHz, CDCl₃): δ 9 7.19 (d, J = 7.0Hz, 2H), 6.84 (d, J = 5Hz, 2H), 4.54 (s, 2H), 2.29 (s, 3H)

To a solution of l-(4-chlorophenoxy)acetone (0.77g, 4.19mmol) was added 2-pyridyl, 3-chloro hydrazine (0.6g, leq) in benzene (2mL) at ambient temperature. The solution was heated at 60⁰C for 5 minutes. To the instantly generated hydrazone intermediate was added H₃PO₄ (4mL). The solution was heated to 76°C for 12 hrs. The reaction was concentrated down and washed with H₂O, followed by saturated Na₂CO₃ and EtOAc extraction. Silica gel chromatography eluding with 2:1 hexane:EtOAc and 1:1 hexane:EtOAc afforded 6-chloro-3-(4-chlorophenoxy)-2-methyl- lH-pyrrolo[2,3ό]pyridine as a dark brown solid. ¹H NMR (500 MHz, CDCl₃): δ 9.55 (bs, 1H);7.54 (d, J=8Hz, IH); 7.27 (m, 2H); 7.05 (d, 8Hz, IH); 6.91 (d, J=IOHz, 2H); 2.44 (s, 3H).

Step 3:

To a solution of 2-chloro-5-methylphenol (8g , 56mmol), (i?)-methyl lactate (7.7g, l.leq), triphenylphosphine (19g, 1.3 eq) in THF (6OmL) was added DIAD (14.7g, 1.3 eq) at 0°C. The reaction was stirred for 12 hrs at ambient temperature. The reaction diluted with EtOAc and washed with Na₂CO₃, HCl, brine. The aqueous layers were reextracted with EtOAc. The organic layers were concentrated and the residue purified using silica gel chromatography eluding with 9:1 hexane/EtOAc which afforded methyl-2(S)-(2-chloro-5- methylphenoxy)proponate as a colorless oil. ¹H NMR (SOO MHZ₅ CDCI₃): δ 7.26 (d, J = 8.0Hz, IH), 6.78 (d, J = 6.5Hz, IH), 6.69 (s, IH), 3.79 (s, 3H), 2.31 (s, 3H), 1.69 (d, J = 6.5, 3H)

A solution of methyl-2(5)-(2-chloro-5-methylphenoxy)proponate (2.4g, 10.5mmol), NBS (1.87g, 0.95eq), AIBN (cat.) in CCl₄ (1OmL), was heated under reflux at 78°C for 12 hrs. The reaction was washed with NaHCO₃, extracted with CH₂Cl₂. The organic layer was reconcentrated and purified using silica gel column chromatography eluding with 9:1 hexane/EtOAc to gave methyl- 2(5)-2-[5-(bromomethyl)-2-chlorophenoxy]propionate as a colorless oil. ¹H NMR (500 MHz, CDCl₃): δ 7.33 (d, J = 3.5Hz, IH), 6.97 (d, J = 7Hz, IH), 6.87 (s, IH), 4.41 (q, J=3.5Hz, 2H), 3.78 (s, 3H), 1.70 (s, 3H).

To a solution of 6-chloro-3-(4-chlorophenoxy)-2-methyl-lH-pyrrolo[2,36]pyridine (0.44g, 1.51mmol) in DMF (2mL) was added methyl-2(S)-2-[5-(bromomethyl)-2- chlorophenoxyjpropionate (0.45g, 1.48mmol) and Cs₂COs (1.46g, 4.5mmol). The reaction was allowed to stir for 12 hrs at ambient temperature. The reaction was quenched with H₂O and extracted with EtOAc, the layers were allowed to separate. The organic layer was dried over Na₂SO₄, and concentrated. To the ester intermediate was added IN NaOH (2ml) in MeOH (2mL). Stirring was continued for 2 hrs at ambient temperature. The reaction was acidified by IN HCl and extracted with EtOAc, and dried over Na₂SO₄. The organic layer was concentrated and purified by preparatory HPLC to afford (2<S)-2-(2-chloro-5-{ [6-chloro-3-(4-chlorophenoxy)- 2-methyl-lH-pyrrolo[2,3ό]pyridine-l-yl]methyl}phenoxy)propanoic acid as a white solid. ¹H NMR (500 MHz, CDCl₃): δ 7.52 (d, J=8.0Hz, IH); 7.34 (d, J=8Hz, IH); 7.24 (dd, J=2.5,6.8Hz, 2H); 7.04 (d, J=8.5Hz, IH); 6.87 (d, J=12.5Hz, 2H); 6.75 (d, J=8.5Hz, 2H); 5.46 (d, J=16.5Hz, IH); 5.43 (d, J=16.5Hz, IH); 4.15 (q, J=6.5Hz, IH); 2.24 (s, 3H); 1.68 (d, J=7Hz, 3H).

6-azaindoles

SCHEME 4, EXAMPLE 4

then 180C

Step l A solution of 2-methoxy-5-aminopyridine (1 g, 8.1 mmol) in EtOAc (2 ml) was added to a solution of BoC₂O (1.6 eq, 2.8 g) in hexanes (7 niL) at reflux. After 1 hour, the reaction was cooled to 25 °C and concentrated. Purification via flash chromatography eluding with a gradient of 0 to 25% EtOAc/hexanes provided tert-butyl (6-methoxypyridin-3- yl)carbamate.

¹H NMR (600 MHz, CDCl₃): δ 8.02 (d, IH), 7.79 (bs, IH), 6.84 (bs, IH), 6.68 (d, IH), 3.89 (s, 3H), 1.50 (s, 9H).

Step 2

To a solution of tert-butyl (6-methoxypyridin-3-yl)carbamate (7.75g, 34.6mmol) in THF (14OmL) at -78°C was added a solution of tBuLi (1.5M, 2.5eq) in hexanes. After 3h, a solution of MeI (1.2eq,2.6mL) in THF (1OmL) was added via cannula and the mixture warmed to -40°C. After Ih, the reaction was quenched with water and extracted with EtOAc (2x). The combined organic layers were washed with water (2x), satd NH₄Cl (2x) and brine (Ix). The organic layer was dried over Na₂SO₄ and concentrated. Purification via flash chromatography eluding with a gradient of 0 to 25% EtOAc/hexanes provided tert-butyl (6-methoxy-4- methylpyridin-3-yl)carbamate as a colorless syrup. 1H NMR (600 MHz, CDCl₃): δ 8.15 (bs, IH), 6.57 (s, IH), 6.11 (bs, IH), 3.89 (s, 3H), 2.22 (s, 3H), 1.49 (s, 9H).

Step 3

To a solution of tert-butyl (6-methoxy-4-methylpyridin-3-yl)carbamate (3.78g, 15.9mmol) in THF (10OmL) at -40⁰C was added a solution of tBuLi (1.5M, 2.2eq) in hexanes over 3 min. After Ih, added N-methoxy-N-methylacetamide (1.2eq, 2.ImL) and warmed to 25°C. After Ih, the reaction was quenched with IM HCl and neutralized to pH7 with 50% NaOH. The mixture was extracted with EtOAc (3x). The combined organic layers were dried over Na₂SO₄ and concentrated. Purification via flash chromatography eluding with a gradient of 0 to 100% EtOAc/hexanes provided tert-butyl 5-methoxy-2-methyl-lH-pyrrolo[2,3-c]pyridine and 5-methoxy-2-methyl-lH-pyrrolo[2,3-c]pyridine. The tert-butyl 5-methoxy-2-methyl-lH- pyrrolo[2,3-c]pyridine was converted to 5-methoxy-2-methyl-lH-pyrrolo[2,3-c]pyridine upon heating to 180°C for 20 minutes.

¹H NMR (600 MHz, CDCl₃): δ 12.31 (s, IH), 8.57 (s, IH), 6.87 (s, IH), 6.32 (s, 3H), 3.98 (s, 3H), 2.54 (s, 3H).

A solution of 5-methoxy-2-methyl-lH-pyrτolo[2,3-c]pyridine (530mg, 3.3mmol), Cs₂CO₃ (3eq) and methyl (2R)-2-[3-(bromomethyl)-4-chlorophenoxy]propanoate (1.2eq) in DMF (2OmL) was stirred at 25 °C for 8 hours. The reaction mixture was diluted with EtOAc, washed with water (2x) and satd NH₄Cl (Ix). The organic layer was dried over Na₂SO₄ and concentrated. Purification via flash chromatography eluding with a gradient of 0 to 100% EtOAc/hexanes provided methyl (2R)-2-{4-chloro-3-[(5-methoxy-2-methyl-lH-pyrrolo[2,3- c]pyridin-l-yl)methyl]phenoxy}propanoate as a yellow syrup.

¹H NMR (500 MHz, CDCl₃): δ 8.02 (s, IH), 7.25 (d, IH), 6.82 (s, IH), 6.68 (dd, IH), 6.25 (s, IH), 5.76 (d, IH), 5.26 (s, 2H), 4.36 (q, IH), 3.91 (s, 3H), 3.54 (s, 3H), 2.31 (s, 3H), 1.42 (d, 3H).

To a slurry OfAlCl₃ (5eq, 1.33g) in DCM (1OmL) was added a solution of methyl (2R)-2-{4-chloro-3-[(5-methoxy-2-methyl-lH-pyrrolo[2,3-c]pyridin-l- yl)methyl]phenoxy}propanoate (780mg, 2mmol) in DCM (1OmL). After 45 min, p-anisoyl chloride (2eq, 0.684g) was added. After 15h at 25°C, the reaction was quenched with MeOH and concentrated. Purification via preparatory LC provided methyl (2R)-2-(4-chloro-3-{[5-methoxy- 3-(4-methoxybenzoyl)-2-methyl-lH-pyrrolo[2,3-c]pyridin-l-yl)methyl]phenoxy}propanoate. ¹H NMR (500 MHz, CDCl₃): δ 8.75 (bs, IH), 7.79 (bs, 2H), 7.35 (d, IH), 7.08 (s, IH), 7.02 (bs, 2H), 6.73 (d, IH), 6.02 (s, IH), 5.25 (bs, 2H), 4.55 (s, IH), 3.98 (s, 3H), 3.91 (s, 3H), 3.65 (s, 3H), 2.53 (s, 3H), 1.52 (d, 3H).

Methyl (2R)-2-(4-chloro-3-{[5-methoxy-3-(4-methoxybenzoyl)-2-methyl-lH- pyrrolo[2,3-c]pyridin-l-yl)methyl]phenoxy}propanoate (500mg, .96mmol) and 1.0M NaOH (2eq) in aqueous methanol were stirred at 25⁰C for 2 hours. The solution was concentrated then purified via reverse phase preparatory LC.

The sodium salt was prepared upon treatment of the free acid with NaHCO₃ (0.95eq). Sodium (2R)-2-(4-chloro-3-{[5-methoxy-3-(4-methoxybenzoyl)-2-methyl-lH- pyrrolo[2,3-c]pyridin-l-yl)methyl]phenoxy}propanoate was isolated as a lyopholized white powder.

¹K NMR (500 MHz, CD₃OD): δ 8.25 (s, IH), 7.80 (d, 2H), 7.33 (d, IH), 7.06 (s, IH), 7.01 (d, 2H), 6.96 (dd, IH), 6.24 (s, IH), 5.52 (d, IH), 5.42 (d, IH), 4.37 (q, IH), 3.96 (s, 3H), 3.92 (s, 3H), 2.62 (s, 3H), 1.56 (d, 3H).

5-Azaindoles

SCHEME 5, EXAMPLE 5

To a solution of 3-prop-l-yn-lylpyridin-4-amine* (1.7g, 12.9mmol) and NEt₃ (2eq, 3.6mL) in DCM (65mL) at ambient temperature was added TFAA (1.2eq, 2.2mL). After lhr, the reaction was diluted with water and the layers allowed to separate. The organic layer was dried over Na₂SO₄ and concentrated. 2,2,2-trifluoro-N-(3-prop-l-yn-l-ylpyridin-4-yl)acetamide (2.5g) was used without further purification.

¹H NMR (500 MHz, CD₃OD): δ 8.07 (bs, IH); 7.95 (bs, IH); 6.67 (bs, IH); 2.10 (s, 3H). *3-prop-l-yn-lylpyridin-4-amine is a known compound (J. Org. Chem. 2002, 67(15), 5412- 5415).

2,2,2-trifluoro-N-(3-prop-l-yn-l-ylpyridin-4-yl)acetamide (2.5g, 11.5mmol), 4- iodoanisole (1.2eq, 3.2g), Pd(PPh₃)₄ (0.05eq, 664mg), and K₂CO₃ (5eq, 8g) were stirred vigorously in MeCN (115mL) under an atmosphere of CO at 45°C. After 18hr, the mixture was concentrated, redissolved in EtOAc and washed with pH4 buffer. The organic layer was dried over Na₂SO₄ and concentrated. The residue was triturated with MeOH to provide (4- methoxyphenyl)(2-methyl-lH-pyrrolo[3,2c]pyridin-3-yl)methanone (250mg) as an off-white solid. The mother liquor was concentrated and purified via flash chromatography eluding with a gradient of 0 to 15% MeOH/DCM to provide an additional 250mg of desired product (16% yield) plus 3-(4-methoxyphenyl)-2-methyl-lH-pyrrolo[3,2c]pyridine. 1H NMR (500 MHz, CDCl₃): δ 8.83 (s, IH); 8.23 (d, J=5.9Hz, IH); 7.76 (dd, J=1.9, 6.8Hz, 2H); 7.65 (d, J=6.0Hz, IH); 6.97 (dd, J=2.1, 6.9Hz, 2H); 3.89 (s, 3H); 2.62 (s, 3H). LC/MS t_R = 1.43, mwt = 267.2

Side product 3-(4-methoxyphenyl)-2-methyl-l//-pyrrolo[3,2c]pyridine

¹H NMR (500 MHz, CDCl₃): δ 8.89 (s, IH); 8.23 (d. J=5.5Hz, IH); 7.42 (dd, J=2, 6.6Hz, 2H); 7.31 (d, J=5.7Hz, IH); 7.02 (dd, J=2, 6.6Hz, 2H); 3.86 (s, 3H); 2.52 (s, 3H). LC/MS t_R = 1.65, mwt = 239.2

To a solution of (4-methoxyphenyl)(2-methyl-lH-pyrrolo[3,2c]pyridin-3- yl)methanone (lOOmg, 0.376mmol), Cs₂CO₃ (3 eq, 370mg) in DMF (4mL) at ambient temperature was added 3-(bromomethyl)-4-chlorophenyl acetate (l.leq, 109mg). After 3 hrs, the reaction was diluted with EtOAc and washed with pΗ4 buffer (2x). The organic layer was dried over Na₂SO₄ and concentrated. Trituration with MeOH provided 4-chloro-3-{[3-(4- methoxybenzoyl)-2-methyl-lH-pyrrolo [3, 2c]pyridine-l-yl]methyl} phenyl acetate as a pinkish solid.

¹H NMR (500 MHz, DMSOdό): δ 9.12 (s, IH); 8.57 (dd, J=I.1,6.8Hz, IH); 8.11 (bm, IH); 8.05 (d, J=6.8Hz, IH); 7.73 (d, J=8.7, 2H); 7.62 (d, J=8.7Hz, IH); 7.48 (m, IH); 7.27 (dd, J=2.7,8.7Hz, IH); 7.03 (dd, J=3,8.7Hz, 2H); 5.94 (s, 2H); 3.85 (s, 3H); 2.48 (s, 3H); 2.23 (s, 3H).

4-chloro-3 - { [3 -(4-methoxybenzoyl)-2-methyl- 1 H-pyrrolo [3 ,2c]pyridine- 1 - yljmethyl} phenyl acetate (1 lOmg, 0.25mmol) and K₂CO₃ (2eq, 70mg) in MeOH (5mL) were stirred at ambient temperature. Once all starting material was consumed as noted by TLC, the reaction mixture was diluted with EtOAc and washed with pΗ7 buffer. The organic layer was dried over Na₂SO₄ and concentrated. Purification of the residue via flash chromatography eluding with a gradient of 0 to 25% MeOH/DCM provided [l-(2-chloro-5-hydroxybenzyl)-2- methyl- 1 H-pyrrolo [3,2c] pyridine-3 -yl] (4-methoxyphenyl)methanone. ¹H NMR (600 MHz, CD₃OD): δ 8.59 (s, IH); 8.20 (d, J=5.4Hz, IH); 7.78 (d, J=8.7Hz, 2H); 7.42 (d, J=5.9Hz, IH); 7.14 (d, J=8.6Hz, IH); 7.05 (d, J=8.7Hz, 2H); 6.57 (d, J=8.8Hz, IH); 5.75 (s, IH); 5.49 (s, 2H); 3.89 (s, 3H); 2.45 (s, 3H).

To a solution of [l-(2-chloro-5-hydroxybenzyl)-2-rnethyl-lH- pyrrolo[3,2c]pyridine-3-yl](4-methoxyphenyl)methanone (7mg, 0.017mmol), R-methyl lactate

(2eq, 0.004mL), PPh₃ (2eq, lOmg) in TΗF (0.5mL) was added DEAD (2eq, 0.007mL). After 4 h, the reaction was purified via preparatory TLC (50% EtOAc/hexanes) to provide methyl (2S)-

2-(4-chloro-3 - { [3-(4-methoxybenzoyl)-2-methyl- 1 H-pyrrolo [3 ,2-c]pyridin- 1 - yl]methyl}phenoxy)propanoate. 1H NMR (500 MHz, CDCl₃): δ 8.69 (bs, IH); 8.33 (bs, IH); 7.85 (d, J=8.7Hz, 2H); 7.35 (d,

J=8.8Hz, IH); 7.20 (bs, IH); 6.99 (d, J=8.8Hz, 2H); 6.74 (dd, J=2.9,8.8Hz, IH); 5.85 (s, IH);

5.41 (s, 2H); 4.42 (q, J=6.7Hz, IH); 3.91 (s, 3H); 3.53 (s, 3H); 2.56 (s, 3H); 1.48 (d, J=6.8Hz,

3H).

Methyl (2S)-2-(4-chloro-3-{[3-(4-methoxybenzoyl)-2-methyl-lH-pyrrolo[3,2- c]pyridin-l-yl]methyl}phenoxy)propanoate (4.4 mg, 0.0089 mmol) and l.OM NaOH (2eq) in aqueous methanol were stirred at 25 °C for 2 hours. The solution was concentrated then purified via reverse phase preparatory LC. (2S)-2-(4-chloro-3-{[3-(4-methoxybenzoyl)-2-methyl-lH- pyrrolo[3,2-c]pyridin-l-yl]methyl}phenoxy)propanoic acid was isolated as a pale yellow film. ¹H NMR (500 MHz, CD₃OD): δ 9.00 (s, IH); 8.45 (d, J=6.9Hz, IH); 8.05 (d, J=6.9Hz, IH); 7.84 (d, J=8.9Hz, 2H); 7.43 (d, J=8.9Hz, IH); 7.10 (d, J=8.7Hz, 2H); 6.89 (dd, J=3,8.9Hz, IH); 6.02 (d, J=2.7Hz, IH); 5.77 (s, 2H); 4.59 (q, J=6.9Hz, IH); 3.90 (s, 3H); 2.46 (s, 3H); 1.46 (d, J=6.9Hz, 3H).

The sodium salt was prepared upon treatment of the free acid with NaHCO₃ (0.95eq).

4-azaindoles

EXAMPLE 6

To a solution of 3-amino-6-chloropyridine (lOOmg, 0.77mmol) in DCM (3mL) at -78°C was added a solution of tBuOCl (leq, 87μL) in DCM (ImL) via cannula. After 10 min, a solution of thiomethylacetone (leq, 80 uL) in DCM (ImL) was added via cannula. The reaction stirred for 90 min before the addition of a solution OfNEt₃ (leq, 108uL) in DCM (ImL). The mixture was warmed to 25°C. After 2 h, the reaction was quenched with water and extracted with DCM (2x). The organic layer was dried over Na₂SO₄ and concentrated. Purification via flash chromatography eluding with a gradient of 0 to 100% EtOAc/hexanes provided 5-chloro-2- methyl-3-(methylthio)-lH-pyrrolo[3,2-b]pyridine as a tan solid.

¹H NMR (500 MHz, CDCl₃): δ 6.89 (bs, IH), 7.51 (d, IH), 7.08 (d, IH), 2.59 (s, 3H), 2.36 (s,

3H).

A slurry of 5-chloro-2-methyl-3-(methylthio)-lH-pyrrolo[3,2-b]pyridine (114mg, 70%), AcOH (ImL) and Raney Nickel (~2g) in aqueous EtOH was stirred for 1 hour. Raney Ni was removed by filtration through Celite and the reaction mixture was concentrated. Purification via flash chromatography eluding with 50%EtOAc/hexanes provided 5-chloro-2-methyl-lH- pyrrolo[3,2-b]pyridine.

¹U NMR (500 MHz, CDCl₃): δ 8.38 (bs, IH), 7.50 (d, IH), 7.02 (d, IH), 6.37 (s, IH), 2.50 (s, 3H).

To a slurry of AlCl₃ (5eq, 150mg) in DCM (6mL) was added 5-chloro-2-methyl- lH-pyrrolo[3,2-b]pyridine (37mg, 0.22mmol). The suspension was stirred for Ih at 25°C before the addition of p-anisoyl chloride (5eq, 190mg). After 15h, the reaction was quenched with MeOH and concentrated. Purification via flash chromatography eluding with a gradient of 0- 10% MeOH/DCM provided product contaiminated with p-anisoyl chloride. Further purification with preparatory LC provided (5-chloro-2 -methyl- lH-pyrrolo[3,2-b]pyridin-3-yl)(4- methoxypehnyl)methanone.

¹H NMR (500 MHz, CD₃OD): δ 7.87 (d, 2H), 7.65 (d, IH), 7.11 (bd, IH), 6.95 (d, 2H), 3.90 (s, 3H), 2.59 (s, 3H).

Step 4:

(5-chloro-2-methyl-lH-pyiτolo[3,2-b]pyridin-3-yl)(4-methoxypehnyl)methanone (6mg, 0.02mmol), Cs₂CO₃ (3eq, 20mg) and isobutyl (2S)-2-[3-

(bromomethyl)phenoxy]propanoate (1.2eq, lOmg) were combined in DMF (ImL). The reaction stirred at 25⁰C for 15h. The mixture was diluted with DCM and washed with water (Ix). The organic layer was concentrated and purified via preparatory TLC (33% EtOAc/hexanes). Isobutyl (2S)-2-(3- { [5-chloro-3-(4-methoxybenzoyl)-2-methyl- lH-pyrrolo[3 ,2-b]pyridin- 1 - yl] methyl }phenoxy)propanoate was isolated as a colorless film.

¹H NMR (500 MHz, CDCl₃): δ 7.87 (d, 2H), 7.48 (d, IH), 7.26 (m, IH), 7.08 (d, IH), 6.96 (d, 2H), 6.76 (dd, IH), 6.59 (d, IH), 6.56 (s, IH), 5.35 (s, 2H), 4.74 (q, IH), 3.92 (s, 3H), 3.91 (m, 2H), 2.64 (s, 3H), 1.90 (m, IH), 1.60 (d, 3H), 0.85 (d, 6H).

Isobutyl (2S)-2-(3 - { [5-chloro-3 -(4-methoxybenzoyl)-2-methyl- 1 H-pyrrolo [3 ,2- b]pyridin-l-yl]methyl}phenoxy)propanoate (lmg) and 1.0M NaOH (2eq) in aqueous methanol were stirred at 25°C for 2 hours. The solution was concentrated then purified via preparatory LC. The sodium salt was prepared upon treatment of the free acid with NaHCO₃ (0.95eq). Sodium (2S)-2-(3-{ [5-chloro-3-(4-methoxybenzoyl)-2 -methyl- lH-pyrrolo[3,2-b]pyridin- 1 - yl] methyl }phenoxy)propanoate was isolated as a lyopholized white powder. ¹H NMR (500 MHz, CDCl₃) of free acid: δ 7.95 (d, 2H), 7.53 (d, IH), 7.26 (d, IH), 7.12 (d, IH), 6.95 (d, 2H), 6.85 (dd, IH), 6.81 (d, IH), 5.94 (s, IH), 5.45 (d, IH), 5.28 (d, IH), 4.39 (q, IH), 3.90 (s, 3H), 2.43 (s, 3H), 1.50 (d, 3H).

4,7-DiazaindoIes (C2-H)

SCHEME 6, EXAMPLE 7

Step l :

Step 1 : A solution of 5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (75mg, 0.51mmol), Cs₂CO₃ (3eq, 500mg), and 3-methoxybenzyl bromide (1.2eq, 0.087mL) in DMF (6mL) was stirred at 25°C for 15h. The reaction was diluted with EtOAc and washed with pΗ7 buffer (2x). The organic layer was dried over Na₂SO₄ and concentrated. The residue was purified via flash chromatography eluding with a gradient of 0 - 100% EtOAc/hexanes. 5-(3- methoxybenzyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde was isolated as a yellow solid. ¹H NMR (500 MHz, CDCl₃): δ 10.25 (s, IH), 8.65 (d, IH), 8.40 (d. IH), 8.12 (s, IH), 7.29 (t, IH), 6.80 (d, IH), 6.83 (m, IH), 5.48 (d, 2H), 3.78 (s, 3H).

Step 2: To a solution of 5-(3-methoxybenzyl)-5H-pyrrolo[2,3-b]pyrazine-7- carbaldehyde (113mg, 0.423mmol) in TΗF (2.2mL) at 0⁰C was added p-chlorophenylmagnesium bromide (IM soln, l.leq, 0.466mL). After 30min, the reaction was quenched with IM HCl, neutralized to pΗ6 and extracted with EtOAc. The organic layer was concentrated then purified via flash chromatography eluding with a gradient of 0 tol00% EtOAc/hexanes. (4- chlorophenyl)[5-(3-methoxybenzyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]methanol was isolated as a mixture of product and starting material.

¹H NMR (500 MHz, CDCl₃): δ 8.37 (d, IH), 8.30 (d, IH), 7.45 (d, 2H), 7.31 (d, 2H), 7.21 (t, IH), 7.12 (s, IH), 6.80 (dd, IH), 6.75 (d, IH), 6.72 (m, IH), 6.29 (s, IH), 5.36 (s, 2H), 3.74 (s, 3H).

Step 3: A solution of TPAP (0.2eq, 26mg), NMO (64mg, 1.5eq), 4A molecular sieves and (4-chlorophenyl)[5-(3-methoxybenzyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]methanol (138mg, 0.364mmol) in DCM (ImL) and MeCN (ImL) were stirred at 25°C for lhr. The mixture was filtered through silica gel and concentrated. The filtrated was concentrated and purified via prep TLC (50% EtOAc/hexanes). (4-chlorophenyl)[5-(3-methoxybenzyl)-5H- pyrrolo[2,3-b]pyrazin-7-yl]methanone was isolated as a colorless film.

¹H NMR (500 MHz, CDCl₃): δ 8.62 (d, IH), 8.37 (d, IH), 8.13 (s, IH), 7.90 (d, 2H), 7.45 (d, 2H), 7.28 (t, IH), 6.87 (m, 3H), 5.50 (s, 2H), 3.77 (s, 3H).

Step 4: To a solution of (4-chlorophenyl)[5-(3-methoxybenzyl)-5//-pyrrolo[2,3- b]pyrazin-7-yl]methanone (30mg, 0.08mmol) in DCM (0.5mL) at 0°C was added BBr₃ (IM soln, 1.2eq, 0.095mL). After 30min, the reaction was warmed to 25°C and stirred for lhr. More BBr₃ (2eq) was added over the next 2h. The reaction was quenched with pH7 buffer and extracted with DCM (2x) and EtOAc (Ix). The organic layers were dried over Na₂SO₄ and concentrated. The residue was purified via prep TLC (5% MeOH/DCM). (4-chlorophenyl)[5-(3- hydroxybenzyl)-5i/-pyrrolo[2,3-b]pyrazin-7-yl]methanone was isolated as a white solid.

¹H NMR (500 MHz, CDCl₃): δ 8.59 (d, IH), 8.35 (d, IH), 8.12 (s, IH), 7.89 (m, 2H), 7.45 (m,

IH), 7.23 (t, IH), 6.87 (d, IH), 6.79 (dd, IH), 6.73 (m, IH), 5.49 (s, 2H).

Step 5: To a solution of (4-chlorophenyl)[5-(3-hydroxybenzyl)-5H-pyrrolo[2,3- b]pyrazin-7-yl]methanone (20mg, 0.055mmol), R-methyl lactate (1.5eq, 7.9uL) and PPh₃ (1.5eq, 22mg) in DCM (55uL) and TΗF (55uL) was added DEAD (1.5eq, 13.IuL). After 4h at 25⁰C, more DEAD (0.5eq) was added. The reaction stirred for 15h then diluted with EtOAc, washed with pΗ7 buffer (2x). The organic layer was dried over Na₂SO₄ and concentrated. Purification via prep TLC (50% EtOAc/hexanes) provided methyl 2-(3-{[7-(4-chlorobenzoyl)-5H- pyrrolo [2,3 -b]pyrazin-5-yl]methyl } phenoxy)propanoate.

¹H NMR (600 MHz, CDCl₃): δ 8.63 (d, IH), 8.37 (d, IH), 8.12 (s, IH), 7.91 (d, 2H), 7.46 (d, 2H), 7.25 (m, IH), 6.91 (d, IH), 6.82 (bs, IH), 6.79 (dd, IH), 6.52 (bs, IH), 5.49 (s, IH), 4.71 (q, IH), 3.69 (s, 3H), 1.59 (s, 3H).

Step 6: Methyl 2-(3-{[7-(4-chlorobenzoyl)-5H-pyrrolo[2,3-b]pyrazin-5- yl]methyl}phenoxy)propanoate (30.6mg, 0.068mmol), IM KOH (2eq, 0.136mL) and aqueous MeOH (ImL) were stirred at 25°C for 4h. The mixture was concentrated and purified via preparatory LC. The product 2-(3-{[7-(4-chlorobenzoyl)-5H-pyrrolo[2,3-b]pyrazin-5- yl] methyl }phenoxy)propanoic acid was isolated as a white lyophilized powder. ¹H NMR (500 MHz, CDCl₃): δ 8.60 (d, IH), 8.39 (d, IH), 8.11 (s, IH), 7.87 (d, 2H), 7.43 (d, 2H), 7.27 (m, IH), 6.97 (d, IH), 6.89 (dd, IH), 6.77 (s, IH), 6.44 (bs, IH), 5.53 (d, IH), 5.48 (d, IH), 4.71 (q, IH), 1.63 (d, 3H). 4,7-Diazaindoles (C2-Me)

SCHEME 7, EXAMPLE 8

To a solution of ethyl 6-methyl-5H-pyrrolo[2,3-6]pyrazine-7-carboxylate (3.5g, 17.1mmol), Cs₂CO₃ (2eq, 1 Ig) in DMF (6OmL) was added 2-chloro-5-methoxybenzyl bromide (1.05eq, 4.2g). After 4 hours, the reaction mixture was diluted with EtOAc and washed with water (2x). The organic layer was dried over Na₂SO₄ and concentrated. Purification via flash chromatography eluding with a gradient of 0% to 100% EtOAc/hexanes provided ethyl 5-(2- chloro-5-methoxybenzyl)-6-methyl-5H-pyrrolo[2,3-i]pyrazine-7-carboxylate. ¹H NMR (500 MHz, CDCl₃): δ 8.62 (d, J=2.5Hz, IH); 8.22 (d, J=2.5Hz, IH); 7.32 (d, J=9Hz, IH); 6.73 (dd, J=3,9Hz, IH); 5.92 (d, J=3Hz, IH); 5.60 (s, 2H); 4.51 (q, J=7Hz, 2H); 3.56 (s, 3H); 2.76 (s, 3H); 1.46 (t, J=7Hz, 3H).

Ethyl 5-(2-chloro-5-methoxybenzyl)-6-methyl-5H-pyrrolo[2,3-δ]pyrazine-7- carboxylate (3.7g, 10.5 mmol) was dissolved in THF (4OmL), MeOH (4OmL) and water (2OmL) before the addition of IM NaOH (2ImL, 2eq). The reaction was heated to reflux for 4hr then concentrated. The residue was diluted with EtOAc and washed with pH 7 buffer. The aqueous layer was back extracted with CH₂Cl₂. The organic layers were dried over Na₂SO₄ and concentrated. 5-(2-chloro-5-methoxybenzyl)-6-methyl-5//-pyrrolo[2,3-ό]pyrazine-7-carboxylate was isolated as an orange solid. ¹H NMR (500 MHz, DMSO): δ 8.37 (d, J=2.5Hz, IH); 8.08 (d, J=2.5Hz, IH); 7.44 (d, J=9Hz, IH); 6.88 (dd, J=3,9Hz, IH); 5.69 (d, J=3Hz, IH); 5.47 (s, 2H); 3.53 (s, 3H); 2.49 (s, 3H).

Step 3:

To a solution of 5-(2-chloro-5-memoxybenzyl)-6-methyl-5H-pyrrolo[2,3- 6]pyrazine-7-carboxylate (140mg, 0.42mmol) in CH₂Cl₂ (5mL) was added DMF (1 drop) and oxalyl chloride (1. leq, 0.04ImL). After 1 hour, Me(MeO)NH-HCl (1.2eq, 50mg) and pyridine (2.2eq, 0.075mL) was added. The reaction stirred 18hr before dilution with EtOAc and washed with pH 7 buffer. The organic layers were dried over Na₂SO₄ and concentrated. Purification by preparative TLC (10% acetone/EtOAc) provided 5-(2-chloro-5-methoxybenzyl)-iV-methoxy-7V,6- dimethyl-5H-pyrrolo[2,3-6]pyrazine-7-carboxamide. ¹H NMR (500 MHz, CDCl₃): δ 8.50 (d, J=2.5Hz, IH); 8.20 (d, J=2.5Hz, IH); 7.32 (d, J=8.5Hz, IH); 6.73 (dd, J=3,9Hz, IH); 5.99 (d, J=2.5Hz, IH); 5.57 (s, 2H); 3.70 (bs, 3H); 3.57 (s, 3H); 3.42 (s, 3H); 2.54 (s, 3H).

p-Chlorophenylmagnesium bromide (1.0M, 2eq, 0.6mL) was added to a solution of 5-(2-chloro-5-methoxybenzyl)-iV-methoxy-N,6-dimethyl-5H-pyrrolo[2,3-6]pyrazine-7- carboxamide (113mg, 0.30 mmol) in TΗF (3mL) at -78°C. After 2 hr, more p- chlorophenylmagnesium bromide (leq) was added. After 2 hr, reaction was quenched with IM HCl. Stir 5 min before dilution with EtOAc and washed with pΗ7 buffer, brine. The organic layers were dried over Na₂SO₄ and concentrated. Purification by preparative TLC (33% EtOAc/hexanes) provided [5-(2-chloro-5-methoxybenzyl)-6-methyl-5H-pyrrolo[2,3-ό]pyrazin-7- yl](4-chlorophenyl)methanone. ¹H NMR (500 MHz, CDCl₃): δ 8.41 (d, J=3Hz, IH); 8.24 (d, J=3Hz, IH); 7.83 (d, J=8.5Hz, 2H); 7.41 (d, J=8.5Hz, 2H); 7.34 (d, J=8.5Hz, IH); 6.75 (dd, J=3,9Hz, IH); 6.07 (d, J=2.5Hz, IH); 5.65 (s, 2H); 3.62 (s, 3H); 2.68 (s, 3H).

BBr₃ (IM, 3eq, 0.6mL) was added to a solution of [5-(2-chloro-5- methoxybenzyl)-6-methyl-5H-pyrrolo[2,3-Z)]pyrazin-7-yl](4-chlorophenyl)methanone (86mg, 0.2mmol) in CH₂Cl₂ (2mL). After 2 hr, diluted with CH₂Cl₂ and washed with pH7 buffer and water. The organic layers were dried over Na₂SO₄ and concentrated. Purification by preparative TLC (33% EtOAc/hexanes) provided [5-(2-chloro-5-hydroxybenzyl)-6-methyl-5H-pyrrolo[2,3- 6]pyrazin-7-yl](4-chlorophenyl)methanone. ¹H NMR (500 MHz, CDCl₃): δ 8.17 (d, J=2.5Hz, IH); 8.13 (d, J=2.5Hz, IH); 7.55 (d, J=8.5Hz, 2H); 7.29 (d, J=8.5Hz, 2H); 7.24 (d, J=8.5Hz, IH); 6.65 (dd, J=2.5,8.5Hz, IH); 5.77 (d, J=2.5Hz, IH); 5.59 (s, 2H); 2.58 (s, 3H).

To a solution of [5-(2-chloro-5-hydroxybenzyl)-6-methyl-5H-pyrrolo[2,3- ό]pyrazin-7-yl](4-chlorophenyl)methanone (24mg, 0.058mmol), R-methyl lactate (2eq, 1 lμL) and PPh₃ (2eq, 31mg) in DCM (ImL) and THF (ImL) was added DEAD (2eq, 22μL). After 4h at 25°C, more DEAD (0.5eq) was added. The reaction stirred for 15h then diluted with EtOAc, washed with pH7 buffer (2x). The organic layer was dried over Na₂SO₄ and concentrated. Purification via prep TLC (33% EtOAc/hexanes) provided methyl (25)-2-(4-chloro-3-{[7-(4- chlorophenyl)-5H-pyrrolo[2,3-ό]pyrazin-5-yl]methyl}phenoxy)propionate as a yellow film contaiminated with excess DEAD. ¹H NMR (500 MHz, CDCl₃): δ 8.44 (d, J=2.5Hz, IH); 8.23 (d, J=2.5Hz, IH); 7.88 (d, J=8.5Hz, 2H); 7.44 (d, J=8.5Hz, 2H); 7.33 (d, J=9Hz, IH); 6.71 (dd, J=3,9Hz, IH); 6.04 (d, J=3Hz, IH); 5.67 (d, J=17Hz, IH); 5.62 (d, J=17Hz, IH); 4.47 (q, J=6.5Hz, IH); 3.58 (s, 3H); 2.69 (s, 3H); 1.44 (d, J=6.5Hz, 3H).

Methyl (2S)-2-(4-chloro-3-{[7-(4-chlorophenyl)-5H-pyrrolo[2,3-ό]pyrazin-5- yl] methyl }phenoxy)propionate (17.3mg, 0.04mmol) was dissolved in aq MeOH (ImL) and IM NaOH (2 eq, 0.07mL). After 3hr at rt, the mixture was concentrated and purified via preparatory ΗPLC to provide (2₁S)-2-(4-chloro-3-{[7-(4-chlorophenyl)-5/f-pyrrolo[2,3-ό]pyrazin-5- yl]methyl}phenoxy)propanoic acid. ¹H NMR (500 MHz, CD₃OD): δ 8.36 (bs, IH); 8.27 (bs, IH); 7.83 (d, J=8.5Hz, 2H); 7.47 (d, J=8.5Hz, 2H); 7.37 (d, J=8.5Hz, IH); 6.82 (dd, J=3,8.5Hz, IH); 6.00 (d, J=2.5Hz, IH); 5.69 (s, 2H); 4.50 (q, J=6.5Hz, IH); 2.62 (s, 3H); 1.42 (d, J=6.5Hz, 3H).

Claims

WHAT IS CLAIMED IS:

1. A compound of formula I:

I or a pharmaceutically acceptable salt thereof, wherein:

A, G, D and E are each selected from CH and N, wherein (a) one of A, G, D and E is N, and the others of A, G, D and E are CH; or (b) A and E are N, and D and G are CH; wherein when A and E are N, and D and G are CH, D and G are optionally connected to opposite ends of a 4-carbon bridging group -HC=CH-CH=CH-, so that a phenyl ring is fused to the structure of Formula I at the G and D positions, said phenyl group being optionally substituted with 1-3 substituent groups independently selected from -CH3, -CF3, -OCH3, -OCF3, and halogen;

Rl is selected from -X-Aryl-Y-Z and -X-HET-Y-Z, wherein Aryl and HET are optionally substituted with 1-3 groups independently selected from R⁹;

Aryl is phenyl or naphthyl;

HET is a 5-membered heteroaromatic ring having 1-4 heteroatoms independently selected from N, O and S;

X is selected from the group consisting of a bond, CH2, CH(CH3), and C(CH3)2;

Y is selected from the group consisting of -OCR^R^-, -SCR7R8-₅ and -CR5R6CR7R8-;

Z is selected from the group consisting of -CO2H and -Cθ2Ci-Csalkyl;

or alternatively, Y and Z together optionally represent a group selected from -NH2, -OH, -NO2, -NHSO2Phenyl, -NHSO2Ci-C3alkyl, -NHC(=O)Phenyl, -NHC(=O)NHPhenyl, -NHC(=O)Ci-C3alkyl, and -SO2Ci-C3alkyl, wherein Phenyl in all uses is optionally substituted with 1-3 groups independently selected from Ci-C4alkyl, -OCi-C4alkyl, and halogen, and all alkyl groups in all uses are optionally substituted with 1-3 halogens;

or alternatively, when Rl is -X-HET-Y-Z, -Y-Z is optionally H, -CR5R6CO2H, or

-CO2H;

Each R is independently selected from the group consisting of Ci_C4alkyl, C2-C4alkenyl, C2-C3alkynyl, -C≡C-Phenyl, -OCi_C4alkyl, -OH, halogen, and -CN, wherein Ci-C4alkyl, C2-C4alkenyl, C2-C3alkynyl, and -OCi-C4alkyl are each optionally substituted with 1-5 halogens, and Phenyl of -C≡C-Phenyl is optionally substituted with 1-3 substitutents independently selected from CH3, CF3, -OCH3, -OCF3, and halogen;

R5, R6, R7_? and R8 are each independently selected from the group consisting of H, halogen, C 1 -C5 alkyl, -OC 1 -C5 alkyl, C2-C5 alkenyl, and -OC2-C5 alkenyl, wherein C 1 -C5 alkyl, -OC1-C5 alkyl, C2-C5 alkenyl, and -OC2-C5 alkenyl are optionally substituted with 1-5 halogens;

R2 is selected from the group consisting of H, -CH2S(O)2Ci-C3alkyl, -CH2SCi-C3alkyl, and Ci-C3alkyl, wherein Ci-C3alkyl in all uses is optionally substituted with 1-3 halogens;

R3 is selected from the group consisting of -C(=O)Aryl, -OAryl, -S(O)_nAryl, and -C(=O)C4-C6alkyl, wherein C4-C6alkyl is optionally substituted with 1-5 halogens, and Aryl is optionally substituted with 1-3 substituent groups independently selected from halogen, Ci- C3alkyl, -OCi-Csalkyl, and -SCi-C3alkyl, wherein Ci-C3alkyl, -OCi-Csalkyl, and -SCi-C3alkyl are optionally substituted with 1-5 halogens;

Each R4 is independently selected from H, halogen, C1-C5 alkyl and -OC1-C5 alkyl, wherein C1-C5 alkyl and -OC1-C5 alkyl are optionally substituted with 1-5 halogens; n is an integer from 0-2; and p is an integer from 1 to 3.

2. The compound of Claim 1 or a pharmaceutically acceptable salt thereof, wherein: Aryl is Phenyl; HET is selected from the group consisting of isoxazolyl, pyrazolyl, and tetrazolyl;

Y is selected from the group consisting Of -OCR⁷R⁸-, -SCR7R8-, and -CR5R6CR7R8-_;

Z is CO2H;

R2 is selected from H and C1-C3 alkyl, which is optionally substituted with 1-3 halogens;

R3 is selected from the group consisting of -C(=O)Aryl, -OAryl, -S(O)_nAryl, and -C(=O)CH₂C(CH₃)3; wherein the Aryl of R3 is optionally substituted with 1-2 substituent groups independently selected from halogen, Ci_3alkyl, and -0Ci-3alkyl, wherein Ci_3alkyl and -OCi- 3alkyl are optionally substituted with 1-3 F;

each R4 is independently selected from H, halogen, C1-C3 alkyl and -OC1-C3 alkyl, wherein C1-C3 alkyl and -OC1-C3 alkyl are optionally substituted with 1-3 F; n is an integer from 0-2; and p is an integer from 1 to 3.

3. The compound of Claim 1 , or a pharmaceutically acceptable salt thereof, wherein R3 is selected from the group consisting -O-Phenyl and -C(=O)Phenyl, wherein Phenyl is optionally substituted with 1-2 substituents independently selected from CH3, CF3, -OCH3, -OCF3, and halogen.

4. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein Rl is -X- Aryl- Y-Z, wherein Aryl is phenyl which is optionally substituted with 1-3 groups independently selected from R9; wherein each R9 is independently selected from the group consisting of C1-C3 alkyl, C2-3 alkenyl, C2-3alkynyl, -OH, -CN, CF3, -OCH3, -OCF3, halogen, and -C≡C-Phenyl in which the phenyl group is optionally substituted with 1 -3 substituents independently selected from CH3, CF3, -OCH3, -OCF3, and halogen.

5. The compound of Claim 4, or a pharmaceutically acceptable salt thereof, wherein Y is -OCR7R8-; R7 is selected from the group consisting of H and C1-C3 alkyl; and R8 is selected from the group consisting of H, C1-C3 alkyl, and OC1-C3 alkyl, wherein C1-C3 alkyl and OC1-C3 alkyl in all uses are optionally substituted with 1-3 F; and Z is -CO2H.

6. The compound of Claim 4, or a pharmaceutically acceptable salt thereof, wherein Y is -CR5R6CHR8-; wherein R⁵ and R⁶ are each independently selected from H and CH3; and R8 is selected from the group consisting of H, Cl-C3alkyl and -OC1-C3 alkyl, wherein Ci-C3alkyl and -OCl-C3alkyl are each optionally substituted with 1-3 F; and Z is -CO2H.

7. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein X is a bond.

8. The compound of Claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is CH2.

9. The compound of Claim 1 , or a pharmaceutically acceptable salt thereof, wherein p is an integer from 1-2; and R4 is selected from the group consisting of H, CH3, CF3, -OCH3, -OCF3, and halogen.

10. The compound of Claim 1 , or a pharmaceutically acceptable salt thereof, wherein R2 is CH3.

11. The compound of Claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

A, G, D and E are each selected from CH and N, wherein (a) one of A, G, D and E is N, and the others of A, G, D and E are CH; or (b) A and E are N, and D and G are CH; wherein when A and E are N, and D and G are CH, D and G are optionally connected to opposite ends of a 4-carbon bridging group -HC=CH-CH=CH-, so that a phenyl ring is fused to the structure of Formula I at the G and D positions, said phenyl group being optionally substituted with 1 substituent selected from the group consisting of -CH3, -CF3, -OCH3, -OCF3, and halogen;

Rl is selected from -X-Aryl-Y-Z and -X-HET-Y-Z, wherein Aryl and HET are optionally substituted with 1 -2 groups independently selected from R⁹;

Aryl is Phenyl;

HET is a 5-membered heteroaromatic ring selected from the group consisting of isoxazolyl, pyrazolyl, and tetrazolyl; X is selected from the group consisting of a bond and CH2;

Y is selected from the group consisting of -OCR^R^~, -SCR7R.8-, and -CR5R6CR7R8-_;

Z is -CO2H or -CO2CH3;

or alternatively, Y and Z together optionally represent a substituent selected from the group consisting of -NH2, -OH, -NO2, -NHSO2Phenyl, -NHSO2CH3, -NHC(=O)Phenyl, -NHC(=O)NHPhenyl, and -NHC(=O)CH3, wherein Phenyl in all uses is optionally substituted with 1-2 groups independently selected from Ci-C4alkyl, CF3, -OCH3, -OCF3, and halogen; or alternatively, when Rl is -X-HET-Y-Z, -Y-Z is optionally H, -CR5R6CC"2H, or -CO₂H;

Each R⁹ is independently selected from the group consisting of Ci-C3alkyl,

C2-C3alkenyl, C2-C3alkynyl, -C≡C-Phenyl, -OCH3, CF3, -OCF3, -OH, halogen, and -CN;

R5 and R6 are each independently selected from the group consisting of H and Ci-C3alkyl, wherein Ci-C3alkyl is optionally substituted with 1-3 F atoms;

R? is selected from the group consisting of H and Ci-C3alkyl, wherein Ci-C3alkyl is optionally substituted with 1-3 F atoms;

R8 is selected from the group consisting of H, Ci-C3alkyl, and -OCi-C2alkyl, wherein Ci-C3alkyl and -OCi-C2alkyl are optionally substituted with 1-3 F atoms;

R2 is selected from the group consisting of H, -CH2S(O)2CH3, -CH2SCH3, and CH3;

R3 is selected from the group consisting of -C(=O)Aryl, -OAryl, and -C(=O)CH2C(CH3)3; wherein Aryl is Phenyl which is optionally substituted with 1-2 substituent groups independently selected from CH3, CF3, -OCH3, OCF3, and halogen;

Each R4 is independently selected from H, CH3, CF3, -OCH3, -OCF3, and halogen; and p is an integer from 1 to 2.

12. The compound of Claim 11 , or a pharmaceutically acceptable salt thereof, wherein:

Rl is -X-HET-Y-Z, wherein HET is optionally substituted with 1-2 groups independently selected from R9;

X is selected from the group consisting of a bond and CH2;

Y is selected from the group consisting of

-SCR7R8-, and

-CR5R6CR7R8-;

Z is -CO2H;

or alternatively, Y and Z together optionally represent a substituent selected from the group consisting of H, -CR5R6CO2H, and -CO2H;

Each R9 is independently selected from the group consisting of halogen, CH3₅ -OCH3, CF3, and -OCF3; and

R2 is CH3.

13. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein A, G, D and E are each selected from CH and N, wherein (a) one of A, G, D and E is N, and the others of A, G, D and E are CH; or (b) A and E are N, and D and G are CH;

Rl is -X-Phenyl-Y-Cθ2H, wherein Phenyl is optionally substituted with 1-2 groups independently selected from R9;

X is selected from a bond and CH2;

Each R9 is independently selected from the group consisting of Cj -.3 alkyl, C2-3alkenyl, C2-3alkynyl, -OC 1.3 alkyl, -OH, halogen, and -CN, wherein alkyl, alkenyl, alkynyl, and -Oalkyl are each optionally substituted with 1-3 F; Y is -OCR⁷R⁸-;

R7 is selected from the group consisting of H and CH3;

R8 is selected from the group consisting of C1-C3 alkyl and -OC1-C2 alkyl;

R2 is CH3;

R4 is selected from the group consisting of H, -CH3, -CF3, -OCH3, -OCF3, and halogen; p is 1 ; and

R3 is selected from the group consisting of -C(=O)Phenyl and -OPhenyl, wherein Phenyl is optionally substituted with 1-2 groups independently selected from halogen, CH3, CF3, -OCH3, and -OCF3.

14. The compound of Claim 11, or a pharmaceutically acceptable salt thereof, selected from the compounds shown below:

15. The compound of Claim 11 , or a pharmaceutically acceptable salt thereof, selected from the compounds shown below:

16. A pharmaceutical composition comprising the compound of Claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

17. The use of the compound of Claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of Type 2 diabetes mellitus.

18. A method of treating one or more diseases, disorders, or conditions selected from the group consisting of (1) non-insulin dependent diabetes mellitus (NIDDM), (2) hyperglycemia, (3) low glucose tolerance, (4) insulin resistance, (5) obesity, (6) lipid disorders, (7) dyslipidemia, (8) hyperlipidemia, (9) hypertriglyceridemia, (10) hypercholesterolemia, (11) low HDL levels, (12) high LDL levels, (13) atherosclerosis and its sequelae, (14) vascular restenosis, (15) irritable bowel syndrome, (16) inflammatory bowel disease, (17) Crohn's disease, (18) ulcerative colitis, (19) abdominal obesity, (20) retinopathy, (21) psoriasis, (22) high blood pressure, (23) metabolic syndrome, (24) ovarian hyperandrogenism (polycystic ovarian syndrome), and other diseases, disorders or conditions where insulin resistance is a component, said method comprising the administration of an effective amount of a compound of Claim 1, or a pharmaceutically acceptable salt thereof, to a patient in need of such treatment.

19. A method of treating non-insulin dependent (Type 2) diabetes mellitus in a patient in need of such treatment which comprises administering to said patient a therapeutically effective amount of the compound of Claim 1, or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition comprising

(1) a compound of Claim 1, or a pharmaceutically acceptable salt thereof, (2) one or more compounds selected from the group consisting of :

(a) PPAR gamma agonists and partial agonists;

(b) biguanides;

(c) protein tyrosine phosphatase- IB (PTP-IB) inhibitors;

(d) dipeptidyl peptidase IV (DP-IV) inhibitors; (e) insulin or an insulin mimetic;

(f) sulfonylureas;

(g) α-glucosidase inhibitors;

(h) agents which improve a patient's lipid profile, said agents being selected from the group consisting of (i) HMG-CoA reductase inhibitors, (ii) bile acid sequestrants, (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PP ARa agonists, (v) cholesterol absorption inhibitors, (vi) acyl CoAxholesterol acyltransferase (ACAT) inhibitors, (vii) CETP inhibitors, and (viii) phenolic anti-oxidants; (i) PPARα/γ dual agonists, Q) PP ARδ agonists, (k) antiobesity compounds, (1) ileal bile acid transporter inhibitors; (m) anti-inflammatory agents; (n) glucagon receptor antagonists; (o) GLP-I; (p) GIP-I; and (q) GLP-I analogs; and (3) a pharmaceutically acceptable carrier.