BRIDGED AND FUSED HETEROCYCLIC ANTIDIABETIC COMPOUNDS

FIELD OF THE INVENTION

The present invention relates to certain bridged and fused heterocyclic compounds that are agonists of the G-protein coupled receptor 40 (GPR40, also known as free fatty acid receptor FFAR), pharmaceutical compositions containing the compounds, and the use of these compounds to regulate insulin levels in a mammal. The compounds may be used, for example in the prevention and treatment of Type 2 diabetes mellitus and in the prevention and treatment of conditions related to Type 2 diabetes mellitus, such as insulin resistance, obesity and lipid disorders.

BACKGROUND OF THE INVENTION

Diabetes refers to a disease state or process derived from multiple causative factors and is characterized by elevated levels of plasma glucose (hyperglycemia) in the fasting state or after administration of glucose during a glucose tolerance test. Persistent or uncontrolled hyperglycemia is associated with a wide range of pathologies. Diabetes mellitus, is associated with elevated fasting blood glucose levels and increased and premature cardiovascular disease and premature mortality. It is also related directly and indirectly to various metabolic conditions, including alterations of lipid, lipoprotein, apolipoprotein metabolism and other metabolic and hemodynamic diseases. As such, the diabetic patient is at increased risk of macrovascular and microvascular complications. Such complications can lead to diseases and conditions such as coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Accordingly, therapeutic control and correction of glucose homeostasis is regarded as important in the clinical management and treatment of diabetes mellitus.

There are two generally recognized forms of diabetes. In Type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), the diabetic patient's pancreas is incapable of producing adequate amounts of insulin, the hormone which regulates glucose uptake and utilization by cells. In Type 2 diabetes, or noninsulin dependent diabetes mellitus (NIDDM), patients often produce plasma insulin levels comparable to those of nondiabetic subjects; however, the cells of patients suffering from type 2 diabetes develop a resistance to the effect of insulin, even in normal or elevated plasma levels, on glucose and lipid metabolism, especially in the main insulin-sensitive tissues (muscle, liver and adipose tissue).

Insulin resistance is not associated with a diminished number of cellular insulin receptors but rather with a post-insulin receptor binding defect that is not well understood. This cellular resistance to insulin results in insufficient insulin activation of cellular glucose uptake, oxidation, and storage in muscle, and inadequate insulin repression of lipolysis in adipose tissue, and of glucose production and secretion in the liver. A net effect of decreased sensitivity to insulin is high levels of insulin circulating in the blood without appropriate reduction in plasma glucose (hyperglycemia). Hyperinsulinemia is a risk factor for developing hypertension and may also contribute to vascular disease.

Patients who have insulin resistance often have several symptoms that together are referred to as Syndrome X, or the metabolic syndrome. According to one widely used definition, a patient having metabolic syndrome is characterized as having three or more symptoms selected from the 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 clinically in the 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 Heath, 2001, NIH Publication No. 01-3670. Patients with metabolic syndrome, whether or not they have increase risk of developing the macrovascular and microvascular complications that occur with Type 2 diabetes, such as atherosclerosis and coronary heart disease.

The available treatments for Type 2 diabetes, some of which have not changed substantially in many years, are used alone and in combination. However, many of these treatments have recognized limitations. For example, while physical exercise and reductions in dietary intake of fat, high glycemic carbohydrates, and calories can dramatically improve the diabetic condition, compliance with this treatment is very poor because of well-entrenched sedentary lifestyles and excess food consumption, especially of foods containing high amounts of saturated fat. Increasing the plasma level of insulin by administration of sulfonylureas (e.g. tolbutamide and glipizide) or meglitinide, which stimulate the pancreatic beta-cells to secrete more insulin, and/or by injection of insulin when sulfonylureas or meglitinide become ineffective, can result in insulin concentrations high enough to stimulate insulin-resistance in tissues. However, dangerously low levels of plasma glucose can result from administration of insulin or insulin secretagogues (sulfonylureas or meglitinide), and an increased level of insulin resistance due to the even higher plasma insulin levels can occur. The biguanides are a separate class of agents that can increase insulin sensitivity and bring about some degree of correction of hyperglycemia. These agents, however, can induce lactic acidosis, nausea and diarrhea.

The glitazones (i.e. 5-benzylthiazolidine-2,4-diones) are another class of compounds that have proven useful for the treatment of Type 2 diabetes. These agents increase insulin sensitivity in muscle, liver and adipose tissue in several animal models of type 2 diabetes, resulting in partial or complete correction of the elevated plasma levels of glucose without occurrence of hypoglycemia. The glitazones that are currently marketed are agonists of the peroxisome proliferator activated receptor (PPAR), primarily the PPAR-γ subtype. PPAR-γ agonism is generally believed to be responsible for the improved insulin sensititization that is observed with the glitazones. Newer PPAR agonists that are being tested for treatment of Type 2 diabetes are agonists of the alpha, gamma or delta subtype, or a combination thereof, and in many cases are chemically different from the glitazones (i.e., they are not thiazolidinediones). Serious side effects (e.g. liver toxicity) have been noted in some patients treated with glitazone drugs, such as troglitazone.

Compounds that are inhibitors of the dipeptidyl peptidase-IV (DPP-IV) enzyme are also under investigation as drugs that may be useful in the treatment of diabetes, and particularly Type 2 diabetes.

Additional methods of treating hyperglycemia and diabetes are currently under investigation. New biochemical approaches include treatment with alpha-glucosidase inhibitors (e.g. acarbose), protein tyrosine phosphatase-1B (PTP-1B) inhibitors, and glucagon receptor antagonists.

The free fatty acid receptor GPR40 (FFAR or FFAR1) is part of a family of recently deorphanized GPCRs that bind fatty acids of varying chain lengths. GPR40 binds long-chain FFA, particularly oleate, as well as the PPAR-gamma agonist rosiglitazone. GPR40 is highly expressed in the pancreas, where it functions to produce insulin release upon agonist stimulation through activation of the PKC pathway resulting in Ca++ efflux. The receptor is also expressed in throughout the brain in monkeys and humans, but not in rodents.

Initial studies in GPR40 KO mice reported that they were resistant to high-fat diet-induced insulin resistance, suggesting an antagonist mechanism would be appropriate for this target. However, given the localization and function of the receptor, as well as the fact that most groups have not replicated this initial finding, the use of an agonist appears to be the appropriate answer for increasing insulin release for the treatment of diabetes. In facts, it has been demonstrated that agonists of GPR40 stimulate glucose-dependent insulin secretion in vitro and lower an elevated blood glucose level in vivo. See for example, Diabetes 2008, 57, 2211; J. Med. Chem. 2007, 50, 2807.

Compounds that act as GPR40 receptor agonists are known in the art. WO2008/054674 (assigned to Merck) discloses bicyclic derivatives of the formula

embedded image

These derivatives are said to be useful in treating Type 2 diabetes mellitus and conditions associated with the disease, including insulin resistance, obesity and lipid disorders. WO2006/083781, WO2006/083612, US 2007/0265332 and WO2008/054674 (all assigned to Merck) disclose bicyclic derivatives that modulate the GPR40 receptor and are said to treat Type-2 diabetes.

Other bicyclic derivatives are known in the art to be useful in treating disease states such as diabetes, obesity and metabolic disorder. WO 2004/058174 (assigned to Bayer) discloses indane acetic acid derivatives of the formula

embedded image

and states that these derivatives are useful in treating Type-2 diabetes, obesity and atherosclerotic diseases.

US 2005/0245529 (Boehringer Ingelheim) discloses alkyne derivatives that are said to be useful in treating metabolic disorders and diabetes by antagonizing the MCH-receptor.

There is a need for new compounds, formulations, treatments and therapies to treat diseases and disorders associated with the GPR40 receptor that exhibit good safety profiles and efficacy by controlling insulin levels in a mammal. It is, therefore, an object of this invention to provide compounds that are useful in the treatment or prevention or amelioration of diseases and disorders associated with the GPR40 receptor, such as hyperglycemia, diabetes, and related metabolic diseases and indications.

SUMMARY OF THE INVENTION

In its many embodiments, the present invention provides for a novel class of bridged and fused heterocyclic compounds that are agonists of the GPR40 receptor, or metabolites, stereoisomer, salts, solvates or polymorphs thereof, methods of preparing such compounds, pharmaceutical compositions comprising one or more of such compounds, methods of preparing pharmaceutical formulations compromising one or more such compounds, and methods of treatment, prevention, inhibition or amelioration of one or more conditions associated with compounds that act as agonists of the GRP40 receptor.

In one aspect, the present application discloses a compound, or pharmaceutically acceptable salts, esters, metabolites, solvates, prodrugs or polymorphs of said compound, said compound having the general structure shown in the Formula:

embedded image

wherein:

- L is

embedded image

- A is —S(O)_q—, —[C(R^a)(R^b)]_m—, or —C(O)—;
- D is a bond, —S(O)_q—[C(R¹²)(R¹³)]_n—, —C(O)—[C(R¹²)(R¹³)]_n—, —C(═NR⁹)—[C(R¹²)(R¹³)]_n— or —[C(R¹²)(R¹³)]_n—;
- E is a bond, —S(O)_q—, —C(O)—, or —[C(R¹⁴)(R¹⁵)]_n—;
- F is —O—, —C(O)—, —S(O)_q—, or —N(R⁹)—;
- W is —C— or —N—;
- X is a bond, —O—, —C(O)—, —S(O)_q, —C(R^a)(R^b)— or —N(R⁸)—;
- Y is a bond, —[C(R^a)(R^b)]_n—O—[C(R^a)(R^b)]_n, —[C(R^a)(R^b)]_n—C(O)—[C(R^a)(R^b)]n_n, —[C(R^a)(R^b)]_n—S(O)_q—[C(R^a)(R^b)]_n, —[C(R^a)(R^b)]_m— or —N(R⁸)—;
- Z is absent, a bond, —[C(R^a)(R^b)]_n—O—[C(R^a)(R^b)]_n, —[C(R^a)(R^b)], —C(O)—[C(R^a)(R^b)]_n, —[C(R^a)(R^b)]_n—S(O)_q—[C(R^a)(R^b)]_n, —[C(R^a)(R^b)]_m— or —N(R⁸)—;
- R is a group selected from the group consisting of

embedded image

and

- (v) tetrazolyl,
  - wherein
    - Q is —CH— or —N—, and
    - J is —S—, —CH₂—, —O— or —N(R⁸)—;

R^ais independently selected from the group consisting of H, —OH, halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl;

R^bis independently selected from the group consisting of H, —OH, halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl;

R¹is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —C(O)—R⁵, —C(O)O—R⁵, —S(O)_q—R⁵, —C(O)N(R⁶)(R⁷), —C(O)-alkylene-OR⁴, —S(O)_q-alkylene-OR⁴, —S(O)_q-alkylene-N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷);

R²is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, and cycloalkylalkoxy wherein said alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, and cycloalkylalkoxy are optionally substituted with one or more (for example 1 to 5 or 1 to 3) groups selected from the group consisting of —OH, halo, alkyl, haloalkyl, alkoxy, haloalkoxy and cycloalkyl;

R³is independently selected from the group consisting of H, halogen, —SF₅, —S(O)_q-alkyl, —CN, —NO₂, —N(R⁶)(R⁷), —OH, alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, and cycloalkylalkoxy wherein said alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, and cycloalkylalkoxy are optionally substituted with one or more (for example 1 to 5 or 1 to 3) groups selected from the group consisting of —OH, halo, —S(O)_q-alkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, and cycloalkyl;

R⁴is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;

R⁵is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;

R⁶is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl;

R⁷is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;

- or R⁶and R⁷together form a 4- to 7-membered heterocycloalkyl or a 5- or 5-membered heteroaryl ring optionally having, in addition to the N atom, 1 or 2 heteroatoms selected from the group consisting of O, N(R⁸), N or S, wherein said rings are optionally substituted by one or more (for example 1 to 5 or 1 to 3) R¹⁶moieties;

R⁸is independently selected from the group consisting of

H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —C(O)—R⁵, —C(O)O—R⁵, —C(O)N(R)(R⁷), —C(O)-alkylene-OR⁴, C(O)-alkylene-N(R⁶)(R⁷), —C(O)-alkylene-S(O)_q—R⁵, —S(O)_q—R⁵, —S(O)_q-alkylene-OR⁴, —S(O)_q-alkylene-N(R⁶)(R⁷), -alkylene-OR⁴, -alkylene-S(O)_q—R⁵, -alkylene-N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷) wherein said alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl and alkylene are optionally substituted with one or more (for example 1 to 5 or 1 to 3) groups selected from the group consisting of —OH, halo, alkyl, haloalkyl, alkoxy, haloalkoxy and cycloalkyl

R⁹is independently selected from the group consisting of H, alkyl, haloalkyl;

R¹⁰is independently selected from the group consisting of H, —OH, alkyl, alkyl, cycloalkyl or alkoxy wherein said alkyl, alkyl, cycloalkyl or alkoxy groups are optionally substituted with at least one (for example 1 to 5 or 1 to 3) substituents selected from the group consisting of halo and —OR⁵;

R¹¹is independently selected from the group consisting of H, alkyl, and haloalkyl;

R¹²is independently selected from the group consisting of H, halogen, —CN, —NO₂, —N(R⁶)(R⁷), —OR⁴, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;

R¹³is independently selected from the group consisting of H, halogen, —CN, —NO₂, —N(R⁶)(R⁷), —OR⁴, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;

R¹⁴is independently selected from the group consisting of H, halogen, —CN, —NO₂, —N(R⁶)(R⁷), —OR⁴, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;

R¹⁵is independently selected from the group consisting of H, halogen, —CN, —NO₂, —N(R⁶)(R⁷), —OR⁴, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl,

- or R¹²and R¹⁴are absent and R¹³and R¹⁵together form 5- or 6-membered aryl ring or a 5- or 6-membered heteroaryl ring, (“B ring”)-which has 1 or 2 heteroatoms selected from the group consisting of O, S or N, that is optionally substituted by one or more (for example 1 to 5 or 1 to 3) R¹⁶groups;
  
  wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl groups in R¹, R⁴, R⁵, R⁶, and R⁷are independently unsubstituted or substituted by one or more (for example 1 to 5 or 1 to 3) R¹⁶groups, where

R¹⁶is independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —OR⁴, —C(O)—R⁵, —C(O)O—R⁵, —S(O)_q—R⁵, —C(O)N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷), —NO₂, —SF₅, —CN, —N(R⁶)(R⁷) and halo and wherein each alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl group in R¹⁶is independently unsubstituted or substituted by one or more (for example 1 to 5 or 1 to 3) R¹⁷groups, where

R¹⁷is independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —OR⁴, —C(O)—R⁵, —C(O)O—R⁶, —S(O)_q—R⁵, —C(O)N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷), —NO₂, —SF₅, —CN, and halo;

m is independently 1, 2, or 3;

n is independently 0, 1 or 2;

p is 0, 1, 2, or 3; and

q is independently 0, 1, or 2,

provided that Y and Z cannot be a bond at the same time.

In another aspect, the present application provides for a pharmaceutical composition comprising a pharmaceutically effective amount of compound of Formula I or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof and a pharmaceutically acceptable carrier.

In yet another aspect, the present application provides for a method for controlling insulin levels in a mammal (e.g., human) in need thereof which comprises administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof to said mammal (e.g., human).

Another aspect of the present invention is to provide for a method for the prevention or treatment of Type-2 diabetis mellitus in a mammal (e.g., human) in need thereof which which comprises administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof to said mammal (e.g., human).

Another aspect of the present invention is to provide for a method for the prevention or treatment of conditions related to Type-2 diabetis mellitus (e.g., insulin resistance, obesity and lipid disorders) in a mammal (e.g., human) in need there of which which comprises administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof to said mammal (e.g., human).

Another aspect of the present invention is to provide for a method for the prevention or treatment of Syndrome X in a mammal (e.g., human) in need thereof which comprises administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof to said mammal (e.g., human).

DETAILED DISCUSSION

In an embodiment, the present invention discloses certain bridged and fused heterocyclic compounds that are represented by structural Formula I, or a pharmaceutical acceptable salt, ester, solvate or prodrug thereof, wherein the various moieties are described above.

In one embodiment, the present invention discloses compounds of Formula Ia, which are represented by the structural formula

embedded image

or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof,

- A is —S(O)_q—, —[C(R^a)(R^b)]_m—, or —C(O)—;
- D is a bond, —S(O)_q—[C(R¹²)(R¹³)]_n—, —C(O)—[C(R¹²)(R¹³)]_n—, —C(═NR⁹)—[C(R¹²)(R¹³)]_n— or —[C(R¹²)(R¹³)]_n;
- E is a bond, —S(O)_q—, —C(O)—, or —[C(R¹⁴)(R¹⁵)]_n—:
- F is —O—, —C(O)—, —S(O)_q—, or —N(R⁹)—;
- W is —C— or —N—;
- X is a bond, —O—, —C(O)—, —S(O)_q, —C(R^a)(R^b)— or —N(R⁸)—;
- Y is a bond, —[C(R^a)(R^b)]_n—O—[C(R^a)(R^b)]_n—, —[C(R^a)(R^b)]_n—C(O)—[C(R^a)(R^b)]_n, —[C(R^a)(R^b)]_n—S(O)_q—[C(R^a)(R^b)]_n, —[C(R^a)(R^b)]_m— or —N(R⁸)—;
- Z is absent, a bond, —[C(R^a)(R^b)]_n—O—[C(R^a)(R^b)]_n, —[C(R^a)(R^b)], —C(O)—[C(R^a)(R^b)]_n, —[C(R^a)(R⁶)]_n—S(O)_q—[C(R^a)(R^b)]_n, —[C(R^a)(R^b)]_m— or —N(R⁸)—;
- R is a group selected from the group consisting of

embedded image

and

- (v) tetrazolyl,
  - wherein
    - Q is —CH— or —N—, and
    - J is —S—, —CH₂—, —O— or —N(R)—;

R^ais independently selected from the group consisting of H, —OH, halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl;

R^bis independently selected from the group consisting of H, —OH, halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl;

R¹is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —C(O)—R⁵, C(O)O—R⁵, —S(O)_q—R⁵, —C(O)N(R⁶)(R⁷), —C(O)-alkylene-OR⁴, —S(O)_q-alkylene-OR⁴, —S(O)_q-alkylene-N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷);

R⁴is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;

R⁵is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;

R⁶is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl;

R⁷is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;

- or R⁶and R⁷together form a 4- to 7-membered heterocycloalkyll or a 5- or 5-membered heteroaryl ring optionally having, in addition to the N atom, 1 or 2 heteroatoms selected from the group consisting of O, N(R⁸), N or S, wherein said rings are optionally substituted by one or more (for example 1 to 5 or 1 to 3) R¹⁶moieties;

R⁸is independently selected from the group consisting of

H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —C(O)—R⁵, —C(O)O—R⁵, —C(O)N(R⁶)(R⁷), —C(O)-alkylene-OR⁴, —C(O)-alkylene-N(R⁶)(R⁷), —C(O)-alkylene-S(O)_q—R⁵, —S(O)_q—R⁵, —S(O)_q-alkylene-OR⁴, S(O)_q-alkylene-N(R⁶)(R⁷), -alkylene-OR⁴, -alkylene-S(O)_q—R⁵, -alkylene-N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷) wherein said alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl and alkylene are optionally substituted with one or more groups (for example 1 to 5 or 1 to 3) selected from the group consisting of —OH, halo, alkyl, haloalkyl, alkoxy, haloalkoxy and cycloalkyl;

R⁹is independently selected from the group consisting of H, alkyl, haloalkyl;

R¹⁰is independently selected from the group consisting of H, —OH, alkyl, alkyl, cycloalkyl or alkoxy wherein said alkyl, alkyl, cycloalkyl or alkoxy groups are optionally substituted with at least one (for example 1 to 5 or 1 to 3) substituent selected from the group consisting of halo and —OR⁵;

R¹¹is independently selected from the group consisting of H, alkyl, and haloalkyl;

- or R¹²and R¹⁴are absent and R¹³and R¹⁵together form 5- or 6-membered aryl ring or a 5- or 6-membered heteroaryl ring, (“B ring”)—which has 1 or 2 heteroatoms selected from the group consisting of O, S or N, that is optionally substituted by one or more (for example 1 to 5 or 1 to 3) R¹⁶groups;
  
  wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl groups in R¹, R⁴, R⁵, R⁶, and R⁷are independently unsubstituted or substituted by one or more (for example 1 to 5 or 1 to 3) R¹⁶groups, where

R¹⁷is independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —OR⁴, —C(O)—R⁵, —C(O)O—R⁵, —S(O)_q—R⁵, —C(O)N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷), —NO₂, —SF₅, —CN, and halo;

m is independently 1, 2, or 3;

n is independently 0, 1 or 2;

p is 0, 1, 2, or 3; and

q is independently 0, 1, or 2,

provided that Y and Z cannot be a bond at the same time.

In another embodiment, the present invention discloses compounds of Formula I, which are represented by the structural Formula Ib

embedded image

or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof,

- A is —S(O)_q—, —[C(R^a)(R^b)]_m—, or —C(O)—;
- D is a bond, —S(O)_q, —[C(R¹²)(R¹³)]_n, —C(O)—[C(R¹²)(R¹³)]_n, —C(═NR⁹)—[C(R¹²)(R¹³)]_n— or —[C(R¹²)(R¹³)]_n—;
- E is a bond, —S(O)_q—, —C(O)—, or —[C(R¹⁴)(R¹⁸)]
- F is —O—, —C(O)—, —S(O)_q—, or —N(R⁹)—;
- W is —C— or —N—;
- X is a bond, —O—, —C(O)—, —S(O)_q, —C(R^a)(R^b)— or —N(R⁸)—;
- Y is a bond, —[C(R^a)(R^b)]_n—O—[C(R^a)(R^b)]_n, —[C(R^a)(R^b)]_n—C(O)—[C(R^a)(R^b)]_n, —[C(R^a)(R^b)]_n—S(O)_q—[C(R^a)(R^b)]_m, —[C(R^a)(R⁸)]_m— or —N(R⁸)—;
- Z is absent, a bond, —[C(R^a)(R^b)]_n—O—[C(R^a)(R^b)]_n, —[C(R^a)(R^b)]_n, —C(O)—[C(R^a)(R^b)]_n, —[C(R^a)(R^b)]_n—S(O)_q—[C(R^a)(R^b)]_m, —[C(R^a)(R^b]_m— or —N(R⁸)—;
- R is a group selected from the group consisting of

embedded image

and

- (v) tetrazolyl,
  - wherein
    - Q is —CH— or —N—, and
    - J is —S—, —CH₂—, —O— or —N(R⁸)—;

R^ais independently selected from the group consisting of H, —OH, halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl;

R^bis independently selected from the group consisting of H, —OH, halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl;

R⁴is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;

R⁵is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;

R⁶is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl;

R⁷is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;

- or R⁶and R⁷together form a 4- to 7-membered heterocycloalkyl or a 5- or 5-membered heteroaryl ring optionally having, in addition to the N atom, 1 or 2 heteroatoms selected from the group consisting of O, N(R⁸), N or S, wherein said rings are optionally substituted by one or more (for example 1 to 5 or 1 to 3) R¹⁶moieties;

R⁸is independently selected from the group consisting of

H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —C(O)—R⁵, —C(O)O—R⁵, —C(O)N(R⁶)(R⁷), —C(O)-alkylene-OR⁴, —C(O)-alkylene-N(R⁶)(R⁷), —C(O)-alkylene-S(O)_q—R⁵, —S(O)_q—R⁵, —S(O)_q-alkylene-OR⁴, —S(O)_q-alkylene-N(R⁶)(R⁷), -alkylene-OR⁴, -alkylene-S(O)_q—R⁵, -alkylene-N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷) wherein said alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl and alkylene are optionally substituted with one or more (for example 1 to 5 or 1 to 3) groups selected from the group consisting of —OH, halo, alkyl, haloalkyl, alkoxy, haloalkoxy and cycloalkyl;

R⁹is independently selected from the group consisting of H, alkyl, haloalkyl;

R¹¹is independently selected from the group consisting of H, alkyl, and haloalkyl;

- or R¹²and R¹⁴are absent and R¹³and R¹⁵together form 5- or 6-membered aryl ring or a 5- or 6-membered heteroaryl ring, (“B ring”)—which has 1 or 2 heteroatoms selected from the group consisting of O, S or N, that is optionally substituted by one or more (for example 1 to 5 or 1 to 3) R¹⁶groups;
  
  wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl groups in R¹, R⁴, R⁵, R⁶, and R⁷are independently unsubstituted or substituted by one or more (for example 1 to 5 or 1 to 3) R¹⁶groups, where

R¹⁷is independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —OR⁴, —C(O)—R⁵, —C(O)O—R⁵, —S(O)_q—R⁵, —C(O)N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷), —NO₂, —SF₅, —CN, and halo;

m is independently 1, 2, or 3;

n is independently 0, 1 or 2;

p is 0, 1, 2, or 3; and

q is independently 0, 1, or 2,

provided that Y and Z cannot both be a bond at the same time.

An embodiment of the present invention is a compound of Formula Ia where W is —CH—.

Another embodiment is a compound of Formula Ia where X is a bond.

Another embodiment is a compound of Formula Ia where X is —CH₂—.

Another embodiment is a compound of Formula Ia where X is —O—.

Another embodiment is a compound of Formula Ia where Y is a bond.

Another embodiment is a compound of Formula Ia where Y is —CH₂—.

Another embodiment is a compound of Formula Ia where Y is —CH₂CH₂—.

Another embodiment is a compound of Formula Ia where Z is a bond.

Another embodiment is a compound of Formula Ia where Z is —CH₂—.

Another embodiment is a compound of Formula Ia where Z is —CH₂CH₂—.

Another embodiment is a compound of Formula Ia where W is —CH— and R³is halogen, cyano or —SF₅and p is 1.

Another embodiment is a compound of Formula Ia where R is —CH₂—C(O)—OH.

Another embodiment is a compound of Formula Ia where R is —CH₂—C(O)—O(C₁-C₄) alkyl.

Another embodiment is a compound of Formula Ia where R is —CH₂—C(O)—NH₂.

Another embodiment is a compound of Formula Ia where R is

embedded image

and R⁸is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia where R is

embedded image

and R⁸is independently H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia where R is

embedded image

and R⁸is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia where R is

embedded image

and R⁸is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia where R is

embedded image

and R⁸is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia where R is

embedded image

R⁸is H or —(C₁-C₄)alkyl and R¹¹is R⁸is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia where R is

embedded image

R⁸is independently H or —(C₁-C₄)alkyl and R¹¹is R⁸is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia where R is

embedded image

R⁸is H or —(C₁-C₄)alkyl and R¹¹is R⁸is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia where R is

embedded image

R⁸is H or —(C₁-C₄)alkyl and R¹¹is R⁸is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia where R is tetrazolyl.

Another embodiment is a compound of Formula Ia where F is —O—.

Another embodiment is a compound of Formula Ia where R¹is H or (C₁-C₄)alkyl or halo-(C₁-C₄)-alkyl.

Another embodiment is a compound of Formula Ia where R¹is heteroaryl optionally substituted by halo (e.g. F or Cl), —OH, —NO₂, —SF₅, —CN, —O—(C₁-C₄)alkyl or alkyl.

Another embodiment is a compound of Formula Ia where R¹is heteroaryl optionally substituted by halo (e.g. F or Cl), —OH, —NO₂, —SF₅, —CN, —O—(C₁-C₄)alkyl or alkyl and the heteroaryl is pyridyl or pyrimidinyl.

Another embodiment is a compound of Formula Ia where A is —[C(R^a)(R^b)]_m—, D is —[C(R¹²)(R¹³)]_n—, E is —[C(R¹⁴)(R¹⁵)]_n—.

Another embodiment is a compound of Formula Ia where ring B is absent.

Another embodiment is a compound of Formula Ia wherein D is —C(N═R⁹)— and E is —C(R¹²)(R¹³)—.

Another embodiment is a compound of Formula Ia wherein D is —C(N═R⁹)—CH₂C(R¹²)(R¹³)— and E is —C(R¹⁴)(R¹⁵)—, where R¹²and R¹⁴are absent and R¹³and R¹⁵together form a 6-membered aryl ring which is independently, optionally substituted by 1 or 2 R¹⁶groups.

Another embodiment is a compound of Formula Ia where R²is H.

An embodiment of the present invention is a compound of Formula Ib where W is —CH—.

Another embodiment is a compound of Formula Ib where X is a bond.

Another embodiment is a compound of Formula Ib where X is —CH₂—.

Another embodiment is a compound of Formula Ib where X is —O—.

Another embodiment is a compound of Formula Ib where Y is a bond.

Another embodiment is a compound of Formula Ib where Y is —CH₂—.

Another embodiment is a compound of Formula Ib where Y is —CH₂CH₂—.

Another embodiment is a compound of Formula Ib where Z is a bond.

Another embodiment is a compound of Formula Ib where Z is —CH₂—.

Another embodiment is a compound of Formula Ia where Z is —CH₂CH₂

Another embodiment is a compound of Formula Ib where W is —CH— and R³is halogen, cyano or —SF₅and p is 1.

Another embodiment is a compound of Formula Ib where R is —CH₂—C(O)—OH.

Another embodiment is a compound of Formula Ib where R is —CH₂—C(O)—O(C₁-C₄alkyl.

Another embodiment is a compound of Formula Ib where R is —CH₂—C(O)—NH₂.

Another embodiment is a compound of Formula Ib where R is

embedded image

and R⁸is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ib where R is

embedded image

and R⁸is independently H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ib where R is

embedded image

and R⁸is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ib where R is

embedded image

and R⁸is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ib where R is

embedded image

and R⁸is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ib where R is

embedded image

R⁸is H or —(C₁-C₄)alkyl and R¹¹is R⁸is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ib where R is

embedded image

R⁸is independently H or —(C₁-C₄)alkyl and R¹¹is R⁸is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ib where R is

embedded image

R⁸is H or —(C₁-C₄)alkyl and R¹¹is R⁸is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ib where R is

embedded image

R⁸is H or —(C₁-C₄)alkyl and R¹¹is R⁸is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ib where R is tetrazolyl.

Another embodiment is a compound of Formula Ib where F is —O—.

Another embodiment is a compound of Formula Ib where R¹is H or (C₁-C₄)alkyl or halo-(C₁-C₄)-alkyl.

Another embodiment is a compound of Formula Ib where R¹is heteroaryl optionally substituted by halo (e.g. F or Cl), —OH, —NO₂, —SF₅, —CN, —O—(C₁-C₄)alkyl or alkyl.

Another embodiment is a compound of Formula Ib where R¹is heteroaryl optionally substituted by halo (e.g. F or Cl), —OH, —NO₂, —SF₅, —CN, —O—(C₁-C₄)alkyl or alkyl and the heteroaryl is pyridyl or pyrimidinyl.

Another embodiment is a compound of Formula Ib where A is —[C(R^a)(R^b)]_m—, D is —[C(R¹²)(R¹³)]_n—, E is —[C(R¹⁴)(R¹⁵)]_n—.

Another embodiment is a compound of Formula Ib where ring B is absent.

Another embodiment is a compound of Formula Ib where R²is H.

Another embodiment is a compound of Formula Ia wherein D is —C(N═R⁹)— and E is —C(R¹²)(R¹³)—.

Another embodiment of the present invention is a compound of Formula Ia-1 of the formula

embedded image

or a pharmaceutically acceptable ester, salt, solvate or prodrug thereof

wherein:

- A is —S(O)_q—, —[C(R^a)(R^b)]_m—, or —C(O)—;
- F is —O—, —C(O)—, —S(O)_q—, or —N(R⁹)—;
- W is —C— or —N—;
- X is a bond, —O—, —C(O)—, —S(O)_q, —C(R^a)(R^b)— or —N(R⁸)—;
- Y is a bond, —[C(R^a)(R^b)]_n—O—[C(R^a)(R^b)]_n, —[C(R^a)(R^b)]_n—C(O)—[C(R^a)(R^b)]_n, —[C(R^a)(R^b)]_n—S(O)_q—[C(R^a)(R^b)]_n, —[C(R^a)(R^b)]_m— or —N(R⁸)—;
- R is a group selected from the group consisting of

embedded image

and

- (v) tetrazolyl,
  - wherein
    - Q is —CH— or —N—, and
    - J is —S—, —CH₂—, —O— or —N(R⁸)—;

R^ais independently selected from the group consisting of H, —OH, halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl;

R^bis independently selected from the group consisting of H, —OH, halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl;

R³is independently selected from the group consisting of H, halogen, —SF₅, —S(O)_q-alkyl, —CN, —NO₂, —N(R⁶)(R⁷), —OH, alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, and cycloalkylalkoxy wherein said alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, and cycloalkylalkoxy are optionally substituted with one or more groups selected from the group consisting of —OH, halo, —S(O)_q-alkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, and cycloalkyl;

R⁴is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;

R⁵is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;

R⁶is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl;

R⁷is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;

- or R⁶and R⁷together form a 4- to 7-membered heterocycloalkyl or a 5- or 5-membered heteroaryl ring optionally having, in addition to the N atom, 1 or 2 heteroatoms selected from the group consisting of O, N(R⁸), N or S, wherein said rings are optionally substituted by one or more R¹⁶moieties;

R⁸is independently selected from the group consisting of

H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —C(O)—R⁵, —C(O)O—R⁵, —C(O)N(R⁶)(R⁷), —C(O)-alkylene-OR⁴, —C(O)-alkylene-N(R⁶)(R⁷), —C(O)-alkylene-S(O)_q—R⁵, —S(O)_q—R⁵, —S(O)_q-alkylene-OR⁴, S(O)_q-alkylene-N(R⁶)(R⁷), -alkylene-OR⁴, -alkylene-S(O)_q—R⁵, -alkylene-N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R′) wherein said alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl and alkylene are optionally substituted with one or more groups selected from the group consisting of —OH, halo, alkyl, haloalkyl, alkoxy, haloalkoxy and cycloalkyl

R⁹is independently selected from the group consisting of H, alkyl, haloalkyl;

R¹⁰is independently selected from the group consisting of H, —OH, alkyl, alkyl, cycloalkyl or alkoxy wherein said alkyl, alkyl, cycloalkyl or alkoxy groups are optionally substituted with at least one substituents selected from the group consisting of halo and —OR⁵;

R¹¹is independently selected from the group consisting of H, alkyl, and haloalkyl;

R¹²is independently selected from the group consisting of H, halogen, —CN, —NO₂, —N(R⁶)(R⁷), —OR⁴and alkyl;

R¹³is independently selected from the group consisting of H, halogen, —CN, —NO₂, —N(R⁶)(R⁷), —OR⁴, and alkyl;

R¹⁴is independently selected from the group consisting of H, halogen, —CN, —NO₂, —N(R⁶)(R⁷), —OR⁴, and alkyl;

wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl groups in R¹, R⁴, R⁵, R⁶, and R⁷are independently unsubstituted or substituted by one or more R¹⁶groups, where

R¹⁷is independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —OR⁴, —C(O)—R⁵, —C(O)O—R⁵, —S(O)_q—R⁵, —C(O)N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷), —NO₂, —SF₅, —CN, and halo;

m is independently 1, 2, or 3;

n is independently 0, 1 or 2;

p is 0, 1, 2, or 3; and

q is independently 0, 1, or 2.

An embodiment of the present invention is a compound of Formula Ia-1 where W is —CH—.

Another embodiment is a compound of Formula Ia-1 where X is a bond.

Another embodiment is a compound of Formula Ia-1 where X is —CH₂—.

Another embodiment is a compound of Formula Ia-1 where X is —O—.

Another embodiment is a compound of Formula Ia-1 where Y is a bond.

Another embodiment is a compound of Formula Ia-1 where Y is —CH₂—.

Another embodiment is a compound of Formula Ia-1 where Y is —CH₂CH₂—.

Another embodiment is a compound of Formula Ia-1 where W is —CH— and R³is halogen, cyano or —SF₅and p is 1.

Another embodiment is a compound of Formula Ia-1 where R is —CH₂—C(O)—OH.

Another embodiment is a compound of Formula Ia-1 where R is —CH₂—C(O)—O(C₁-C₄) alkyl.

Another embodiment is a compound of Formula Ia-1 where R is —CH₂—C(O)—NH₂.

Another embodiment is a compound of Formula Ia-1 where R is

embedded image

and R⁸is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia-1 where R is

embedded image

and R⁸is independently H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia-1 where R is

embedded image

and R⁸is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia-1 where R is

embedded image

and R⁸is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia-1 where R is

embedded image

and R⁸is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia-1 where R is

embedded image

R⁸is H or —(C₁-C₄)alkyl and R¹¹is R⁸is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia-1 where R is

embedded image

R⁸is independently H or —(C₁-C₄)alkyl and R¹¹is R⁸is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia-1 where R is

embedded image

R⁸is H or —(C₁-C₄)alkyl and R¹¹is R⁸is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia-1 where R is

embedded image

R⁸is H or —(C₁-C₄)alkyl and R¹¹is R⁸is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia-1 where R is tetrazolyl.

Another embodiment is a compound of Formula Ia-1 where F is —O—.

Another embodiment is a compound of Formula Ia-1 where R¹is H or (C₁-C₄)alkyl or halo-(C₁-C₄)-alkyl.

Another embodiment is a compound of Formula Ia-1 where R¹is heteroaryl optionally substituted by halo (e.g. F or Cl), —OH, —NO₂, —SF₅, —CN, —O—(C₁-C₄)alkyl or alkyl.

Another embodiment is a compound of Formula Ia-1 where R¹is heteroaryl optionally substituted by halo (e.g. F or Cl), —OH, —NO₂, —SF₅, —CN, —O—(C₁-C₄)alkyl or alkyl and the heteroaryl is pyridyl or pyrimidinyl.

Another embodiment is a compound of Formula Ia-1 where R¹²is H, halogen, —CN, —NO₂, —OH, —O—(C₁-C₄)alkyl, or alkyl.

Another embodiment is a compound of Formula Ia-1 where R¹³is H, halogen, —CN, —NO₂, —OH, —O—(C₁-C₄)alkyl, or alkyl.

Another embodiment is a compound of Formula Ia-1 where R¹⁴is H, halogen, —CN, —NO₂, —OH, —O—(C₁-C₄)alkyl, or alkyl.

Another embodiment of the present invention is a compound of Formula Ia of the formula

embedded image

or a pharmaceutically acceptable ester, salt, solvate of prodrug thereof

wherein:

- F is —O—, —C(O)—, —S(O)_q—, or —N(R⁹)—;
- W is —C— or —N—;
- X is a bond, —O—, —C(O)—, —S(O)_q, —C(R^a)(R^b)— or —N(R⁸)—;
- Y is a bond, —[C(R^a)(R^b)]_n, —[C(R^a)(R^b)]_m, —[C(R^a)(R^b)]_n—C(O)—[C(R^a)(R^b)]_n, —[C(R^a)(R^b)]_n—S(O)_q—[C(R^a)(R^b)]_n, —[C(R^a)(R^b)]_m— or —N(R⁸)—;
- R is a group selected from the group consisting of

embedded image

and

- (v) tetrazolyl,
  - wherein
    - Q is —CH— or —N—, and
    - J is —S—, —CH₂—, —O— or —N(R⁸)—;

R^ais independently selected from the group consisting of H, —OH, halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl;

R^bis independently selected from the group consisting of H, —OH, halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl;

R³is independently selected from the group consisting of H, halogen, —SF₅, —S(O)_q-alkyl, —CN, —NO₂, —N(R⁶)(R⁷), —OH, alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, and cycloalkylalkoxy wherein said alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, and cycloalkylalkoxy are optionally substituted with one or more groups selected from the group consisting of —OH, halo, —S(O)_q-alkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, and cycloalkyl;

R⁴is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;

R⁵is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;

R⁶is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl;

R⁷is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;

- or R⁶and R⁷together form a 4- to 7-membered heterocycloalkyl or a 5- or 5-membered heteroaryl ring optionally having, in addition to the N atom, 1 or 2 heteroatoms selected from the group consisting of O, N(R⁸), N or S, wherein said rings are optionally substituted by one or more R¹⁶moieties;

R⁸is independently selected from the group consisting of

H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —C(O)—R⁵, —C(O)O—R⁵, —C(O)N(R⁶)(R⁷), —C(O)-alkylene-OR⁴, —C(O)-alkylene-N(R⁶)(R⁷), —C(O)-alkylene-S(O)_q—R⁵, —S(O)_q—R⁵, —S(O)_q-alkylene-OR⁴, —S(O)_q-alkylene-N(R⁶)(R⁷), -alkylene-OR⁴, -alkylene-S(O)_q—R⁵, -alkylene-N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷) wherein said alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl and alkylene are optionally substituted with one or more groups selected from the group consisting of —OH, halo, alkyl, haloalkyl, alkoxy, haloalkoxy and cycloalkyl;

R⁹is independently selected from the group consisting of H, alkyl, haloalkyl;

R¹⁰is independently selected from the group consisting of H, —OH, alkyl, alkyl, cycloalkyl or alkoxy wherein said alkyl, alkyl, cycloalkyl or alkoxy groups are optionally substituted with at least one substituent selected from the group consisting of halo and —OR⁵;

R¹¹is independently selected from the group consisting of H, alkyl, and haloalkyl;

R¹²is independently selected from the group consisting of H, halogen, —CN, —NO₂, —N(R)(R⁷), —OR⁴, and alkyl;

R¹³is independently selected from the group consisting of H, halogen, —CN, —NO₂, —N(R⁶)(R⁷), —OR⁴, and alkyl;

R¹⁷is independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —OR⁴, —C(O)—R⁵, —C(O)O—R⁵, —S(O)_q—R⁵, —C(O)N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷), —NO₂, —SF₅, —CN, and halo;

m is independently 1, 2, or 3;

n is independently 0, 1 or 2;

p is 0, 1, 2, or 3; and

q is independently 0, 1, or 2.

An embodiment of the present invention is a compound of Formula Ia-2 where W is —CH—.

Another embodiment is a compound of Formula Ia-2 where X is a bond.

Another embodiment is a compound of Formula Ia-2 where X is

Another embodiment is a compound of Formula Ia-2 where X is —O—.

Another embodiment is a compound of Formula Ia-2 where Y is a bond.

Another embodiment is a compound of Formula Ia-2 where Y is

Another embodiment is a compound of Formula Ia-2 where Y is —CH₂CH₂—.

Another embodiment is a compound of Formula Ia-2 where W is —CH— and R³is halogen, cyano or —SF₅and p is 1.

Another embodiment is a compound of Formula Ia-2 where R is —CH₂—C(O)—OH.

Another embodiment is a compound of Formula Ia-2 where R is —CH₂—C(O)—O(C₁-C₄) alkyl.

Another embodiment is a compound of Formula Ia-2 where R is —CH₂—C(O)—NH₂.

Another embodiment is a compound of Formula Ia-2 where R is

embedded image

and R⁸is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia-2 where R is

embedded image

and R⁸is independently H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia-2 where R is

embedded image

and R⁸is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia-2 where R is

embedded image

and R⁸is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia-2 where R is

embedded image

and R⁸is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia-2 where R is

embedded image

R⁸is H or —(C₁-C₄)alkyl and R¹¹is R⁸is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia-2 where R is

embedded image

R⁸is independently H or —(C₁-C₄)alkyl and R¹¹is R⁸is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia-2 where R is

embedded image

R⁸is H or —(C₁-C₄)alkyl and R¹¹is R⁸is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia-2 where R is

embedded image

R⁸is H or —(C₁-C₄)alkyl and R¹¹is R⁸is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia-2 where R is tetrazolyl.

Another embodiment is a compound of Formula Ia-2 where F is —O—.

Another embodiment is a compound of Formula Ia-2 where R¹is H or (C₁-C₄)alkyl or halo-(C₁-C₄)-alkyl.

Another embodiment is a compound of Formula Ia-2 where R¹is heteroaryl optionally substituted by halo (e.g. F or Cl), —OH, —NO₂, —SF₅, —CN, —O—(C₁-C₄)alkyl or alkyl.

Another embodiment is a compound of Formula Ia-2 where R¹is heteroaryl optionally substituted by halo (e.g. F or Cl), —OH, —NO₂, —SF₅, —CN, —O—(C₁-C₄)alkyl or alkyl and the heteroaryl is pyridyl or pyrimidinyl.

Another embodiment is a compound of Formula Ia-2 where R¹²is H, halogen, —CN, —NO₂, —OH, —O—(C₁-C₄)alkyl, or alkyl.

Another embodiment is a compound of Formula Ia-2 where R¹³is H, halogen, —CN, —NO₂, —OH, —O—(C₁-C₄)alkyl, or alkyl.

Another embodiment of the present invention is a compound of Formula Ia-3 of the formula

embedded image

or a pharmaceutically acceptable ester, salt, solvate or prodrig thereof

wherein:

- F is —O—, —C(O)—, —S(O)_q—, or —N(R³)—;
- W is —C— or —N—;
- X is a bond, —O—, —C(O)—, —S(O)_q, —C(R^a)(R^b)— or —N(R⁸)—;
- Y is a bond, —[C(R^a)(R^b)]_n—O—[C(R^a)(R^b)]_n, —[C(R^a)(R^b)]_n—C(O)—[C(R^a)(R^b)]_n, —[C(R^a)(R^b)]_n—S(O)_q—[C(R^a)(R^b)]_n, —[C(R^a)(R^b)]_n— or —N(R⁸)—;
- R is a group selected from the group consisting of

embedded image

and

- (v) tetrazolyl,
  - wherein
    - Q is —CH— or —N—, and
    - J is —S—, —CH₂—, —O— or —N(R⁸)—;

R^ais independently selected from the group consisting of H, —OH, halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl;

R^bis independently selected from the group consisting of H, —OH, halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl;

R¹is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —C(O)—R⁵, —C(O)O—R⁵—S(O)_q—R⁵, —C(O)N(R⁶)(R⁷), —C(O)-alkylene-OR⁴, —S(O)_q-alkylene-OR⁴, —S(O)_q-alkylene-N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷);

R³is independently selected from the group consisting of H, halogen, —SF₅, —S(O)_q-alkyl, —CN, —NO₂, —N(R⁶)(R⁷), —OH, alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, and cycloalkylalkoxy wherein said alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, and cycloalkylalkoxy are optionally substituted with one or more groups selected from the group consisting of —OH, halo, —S(O)_q-alkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, and cycloalkyl;

R⁴is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;

R⁵is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;

R⁶is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl;

R⁷is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;

- or R⁶and R⁷together form a 4- to 7-membered heterocycloalkyl or a 5- or 5-membered heteroaryl ring optionally having, in addition to the N atom, 1 or 2 heteroatoms selected from the group consisting of O, N(R⁸), N or S, wherein said rings are optionally substituted by one or more R¹⁶moieties;

R⁸is independently selected from the group consisting of

H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —C(O)—R⁵, —C(O)O—R⁵, —C(O)N(R⁶)(R⁷), —C(O)-alkylene-OR⁴, C(O)-alkylene-N(R⁶)(R⁷), —C(O)-alkylene-S(O)_q—R⁵, —S(O)_q—R⁵, —S(O)_q-alkylene-OR⁴, —S(O)_q-alkylene-N(R⁶)(R⁷), -alkylene-OR⁴, -alkylene-S(O)_q—R⁵, -alkylene-N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷) wherein said alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl and alkylene are optionally substituted with one or more groups selected from the group consisting of —OH, halo, alkyl, haloalkyl, alkoxy, haloalkoxy and cycloalkyl;

R⁹is independently selected from the group consisting of H, alkyl, haloalkyl;

R¹⁰is independently selected from the group consisting of H, —OH, alkyl, alkyl, cycloalkyl or alkoxy wherein said alkyl, alkyl, cycloalkyl or alkoxy groups are optionally substituted with at least one substituent selected from the group consisting of halo and —OR⁵;

R¹¹is independently selected from the group consisting of H, alkyl, and haloalkyl;

R¹⁷is independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —OR⁴, —C(O)—R⁵, —C(O)O—R⁵, —S(O)_q—R⁵, —C(O)N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷), —NO₂, —SF₅, —CN, and halo;

m is independently 1, 2, or 3;

n is independently 0, 1 or 2;

p is 0, 1, 2, or 3; and

q is independently 0, 1, or a

An embodiment of the present invention is a compound of Formula Ia-3 where W is —CH—.

Another embodiment is a compound of Formula Ia-3 where X is a bond.

Another embodiment is a compound of Formula Ia-3 where X is —CH₂—.

Another embodiment is a compound of Formula Ia-3 where X is

Another embodiment is a compound of Formula Ia-3 where Y is a bond.

Another embodiment is a compound of Formula Ia-3 where Y is —CH₂—.

Another embodiment is a compound of Formula Ia-3 where Y is —CH₂CH₂—.

Another embodiment is a compound of Formula Ia-3 where W is —CH— and R³is halogen, cyano or —SF₅and p is 1.

Another embodiment is a compound of Formula Ia-3 where R is —CH₂—C(O)—OH.

Another embodiment is a compound of Formula Ia-3 where R is —CH₂—C(O)—O(C₁-C₄) alkyl.

Another embodiment is a compound of Formula Ia-3 where R is —CH₂—C(O)—NH₂.

Another embodiment is a compound of Formula Ia-3 where R is

embedded image

and R⁸is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia-3 where R is

embedded image

and R⁸is independently H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia-3 where R is

embedded image

and R⁸is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia-3 where R is

embedded image

and R⁸is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia-3 where R is

embedded image

and R⁸is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia-3 where R is

embedded image

R⁸is H or —(C₁-C₄)alkyl and R¹¹is R⁸is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia-3 where R is

embedded image

R⁸is independently H or —(C₁-C₄)alkyl and R¹¹is R⁸is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia-3 where R is

embedded image

R⁸is H or —(C₁-C₄)alkyl and R¹¹is R⁸is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia-3 where R is

embedded image

R⁸is H or —(C₁-C₄)alkyl and R¹¹is R⁸is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia-3 where R is tetrazolyl.

Another embodiment is a compound of Formula Ia-3 where F is —O—.

Another embodiment is a compound of Formula Ia-3 where R¹is H or (C₁-C₄)alkyl or halo-(C₁-C₄)-alkyl.

Another embodiment is a compound of Formula Ia-3 where R¹is heteroaryl optionally substituted by halo (e.g. F or Cl), —OH, —NO₂, —SF₅, —CN, —O—(C₁-C₄)alkyl or alkyl.

Another embodiment is a compound of Formula Ia-3 where R¹is heteroaryl optionally substituted by halo (e.g. F or Cl), —OH, —NO₂, —SF₅, —CN, —O—(C₁-C₄)alkyl or alkyl and the heteroaryl is pyridyl or pyrimidinyl.

Another embodiment is a compound of Formula Ia-3 where R¹⁶independently is H, halogen, —CN, —NO₂, —OH, —O—(C₁-C₄)alkyl, or alkyl.

Another embodiment of the present invention is a compound of Formula Ia of the formula

embedded image

or a pharmaceutically acceptable ester, salt, solvate or prodrug thereof

wherein:

- F is —O—, —C(O)—, —S(O)_q—, or —N(R⁹)—;
- W is —C— or —N—;
- X is a bond, —O—, —C(O)—, —S(O)_q, —C(R^a)(R^b)— or —N(R⁸)—;
- Y is a bond, —[C(R^a)(R^b)]_n—O—[C(R^a)(R^b)]_n, —[C(R^a)(R^b)]_n—C(O)—[C(R^a)(R^b)]_n, —[C(R^a)(R^b)]_n—S(O)_q—[C(R^a)(R^b)]_n, —[C(R^a)(R^b)]_n— or —N(R⁸)—;
- R is a group selected from the group consisting of

embedded image

and

- (v) tetrazolyl,
  - wherein
    - Q is —CH— or —N—, and
    - J is —S—, —CH₂—, —O— or —N(R⁸)—;