Novel compounds of the structural formula (I), and the pharmaceutically acceptable salts thereof, are agonists of G-protein coupled receptor 40 (GPR40) and may be useful in the treatment, prevention and suppression of diseases mediated by the G-protein-coupled receptor 40. The compounds of the present invention may be useful in the treatment of Type 2 diabetes mellitus, and of conditions that are often associated with this disease, including obesity and lipid disorders, such as mixed or diabetic dyslipidemia, hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia.

BACKGROUND OF THE INVENTION

Diabetes mellitus 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 have a resistance to the effects of insulin in stimulating glucose and lipid metabolism in the main insulin-sensitive tissues, which are muscle, liver and adipose tissues. These patients often have normal levels of insulin, and may have hyperinsulinemia (elevated plasma insulin levels), as they compensate for the reduced effectiveness of insulin by secreting increased amounts of insulin. Insulin resistance is not primarily caused by a diminished number of insulin receptors but rather by a post-insulin receptor binding defect that is not yet completely understood. This lack of responsiveness to insulin results induction and secretion in the liver.

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 macrovascular 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.

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 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 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 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 macrovascular and microvascular complications that occur with Type 2 diabetes, such as atherosclerosis and coronary heart disease.

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 usual recommended first-line treatment of Type 2 diabetes and of pre-diabetic conditions associated with insulin resistance. Compliance with this treatment is generally very poor because of well-entrenched sedentary lifestyles and excess food consumption, especially of foods containing high amounts of fat and carbohydrates. Pharmacologic treatments for diabetes have largely focused on three areas of pathophysiology: (1) hepatic glucose production (biguanides, such as phenformin and metformin), (2) insulin resistance (PPAR agonists, such as rosiglitazone, troglitazone, engliazone, balaglitazone, MCC-555, netoglitazone, T-131, LY-300512, LY-818 and pioglitazone), (3) insulin secretion (sulfonylureas, such as tolbutamide, glipizide and glimipiride); (4) incretin hormone mimetics (GLP-1 derivatives and analogs, such as exenatide, liraglutide, dulaglutide, semaglutide, lixisenatide, albiglutide and taspoglutide); (5) inhibitors of incretin hormone degradation (DPP-4 inhibitors, such as sitagliptin, alogliptin, vildagliptin, linagliptin, denagliptin and saxagliptin); and SGLT2 inhibitors (canagliflozin, dapagliflozin and empagliflozin).

There has been a renewed focus on pancreatic islet-based insulin secretion that is controlled by glucose-dependent insulin secretion. This approach has the potential for stabilization and restoration of β-cell function. In this regard, several orphan G-protein coupled receptors (GPCR's) have been identified that are preferentially expressed in the β-cell and that are implicated in glucose stimulated insulin secretion (GSIS). GPR40 is a cell-surface GPCR that is highly expressed in human (and rodent) islets as well as in insulin-secreting cell lines. Several naturally-occurring medium to long-chain fatty acids (FA's) as well as synthetic compounds, including several members of the thiazolidinedione class of PPARγ agonists, have recently been identified as ligands for GPR40 [Itoh, Y. et al.,Nature,422: 173 (2003); Briscoe, C. P. et al.,J. Biol. Chem.,278: 11303 (2003); Kotarsky, K. et al.,Biochem. Biophys. Res. Comm.,301: 406 (2003)]. Under hyperglycemic conditions, GPR40 agonists are capable of augmenting the release of insulin from islet cells. The specificity of this response is suggested by results showing that the inhibition of GPR40 activity by siRNA attenuates FA-induced amplification of GSIS. These findings indicate that, in addition to the intracellular generation of lipid-derivatives of FA's that are thought to promote insulin release, FA's (and other synthetic GPR40 agonists) may also act as extracellular ligands that bind to GPR40 in mediating FA-induced insulin secretion. There are several potential advantages of GPR40 as a potential target for the treatment of Type 2 diabetes. First, since GPR40-mediated insulin secretion is glucose dependent, there is little or no risk of hypoglycemia. Second, the limited tissue distribution of GPR40 (mainly in islets) suggests that there would be less chance for side effects associated with GPR40 activity in other tissues. Third, GPR40 agonists that are active in the islets may have the potential to restore or preserve islet function. This would be highly advantageous, because long term diabetes therapy often leads to the gradual diminution of islet activity, so that after extended periods of treatment, it is often necessary to treat Type 2 diabetic patients with daily insulin injections. By restoring or preserving islet function, GPR40 agonists may delay or prevent the diminution and loss of islet function in a Type 2 diabetic patient.

Compounds that are agonists of G-protein-coupled receptor 40 (GPR40) may be useful to treat type 2 diabetes mellitus, obesity, hypertension, dyslipidemia, cancer, and metabolic syndrome, as well as cardiovascular diseases, such as myocardial infarction and stroke, by improving glucose and lipid metabolism and by reducing body weight. There is a need for potent GPR40 agonists that have pharmacokinetic and pharmacodynamic properties suitable for use as human pharmaceuticals.

SUMMARY OF THE INVENTION

The present invention relates to novel substituted compounds of structural formula I:

and pharmaceutically acceptable salts thereof. The compounds of structural formula I, and embodiments thereof, are agonists of G-protein-coupled receptor 40 (GPR40) and may be useful in the treatment, prevention and suppression of diseases, disorders and conditions mediated by agonism of the G-protein-coupled receptor 40, such as Type 2 diabetes mellitus, insulin resistance, hyperglycemia, dyslipidemia, lipid disorders, obesity, hypertension, Metabolic Syndrome and atherosclerosis.

The present invention also relates to pharmaceutical compositions comprising the compounds of the present invention and a pharmaceutically acceptable carrier. The present invention also relates to methods for the treatment, control or prevention of disorders, diseases, and conditions that may be responsive to agonism of the G-protein-coupled receptor 40 in a subject in need thereof by administering the compounds and pharmaceutical compositions of the present invention. The present invention also relates to the use of compounds of the present invention for manufacture of a medicament useful in treating diseases, disorders and conditions that may be responsive to the agonism of the G-protein-coupled receptor 40. The present invention is also concerned with treatment of these diseases, disorders and conditions by administering the compounds of the present invention in combination with a therapeutically effective amount of another agent that may be useful to treat the disease, disorder and condition. The invention is further concerned with processes for preparing the compounds of this invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is concerned with novel compounds of structural Formula I:

or a pharmaceutically acceptable salt thereof; wherein
T is selected from the group consisting of:

U is selected from the group consisting of:

V is selected from the group consisting of:

W is selected from the group consisting of:

provided that no more than two of T, U, V and W are N, further provided that if both T and W are N, then R3is absent, and further provided that both U and V are not N;

X is selected from the group consisting of:

Y is selected from the group consisting of:

Z is selected from the group consisting of:

provided that when X is N(Re), Z is not N, and further provided that when X is C(Rd)(Rd), then Y is C(Rg)(Rg);

A is selected from the group consisting of:

wherein A is unsubstituted or substituted with one to five substituents selected from Ra; B is selected from the group consisting of:

wherein B is unsubstituted or substituted with one to five substituents selected from Rb; R1and R2are each independently selected from:

wherein each alkyl and cycloalkyl is substituted with a substituent selected from R7and with one to three substituents selected from R9, provided that one of R1and R2is C1-6alkyl or C3-6cycloalkyl;

each R3is independently selected from the group consisting of:

R4is selected from the group consisting of:

wherein alkyl is unsubstituted or substituted with one to three substituents selected from Rh;

R5is selected from the group consisting of:

wherein alkyl is unsubstituted or substituted with one to three substituents selected from Rh;

R6is selected from the group consisting of:

wherein alkyl is unsubstituted or substituted with one to three substituents selected from Rh;

R7is selected from the group consisting of:

R8is selected from the group consisting of:

wherein alkyl is unsubstituted or substituted with one to three substituents selected from Ri;

each R9is independently selected from the group consisting of:

each Rais selected from the group consisting of:

wherein each alkyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with one to three substituents independently selected from —C1-6alkyl, halogen, —O—C1-6alkyl, and —CF3;

each Rbis independently selected from the group consisting of:

wherein each alkyl is unsubstituted or substituted with one to three substituents independently selected from —C1-6alkyl, halogen, —O—C1-6alkyl, and —CF3;

Rcis independently selected from the group consisting of:

wherein alkyl, alkenyl, cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted with one to three substituents independently selected from Rf;

each Rdis selected from the group consisting of:

wherein each alkyl is unsubstituted or substituted with one to five halogens;

Reis selected from the group consisting of:

wherein alkyl is unsubstituted or substituted with one to three substituents selected from —C1-6alkyl, —OC1-6alkyl, —CF3and halogen;

each Rfis selected from the group consisting of:

each Rgis selected from the group consisting of:

wherein each alkyl is unsubstituted or substituted with one to five halogens;

each Rhis independently selected from the group consisting of:

each R1is independently selected from the group consisting of:

Rjand Rkare each independently selected from the group consisting of:

wherein each alkyl, alkenyl, cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted with one to three substituents independently selected from —C1-6alkyl, halogen, or —O—C1-6alkyl; and

The invention has numerous embodiments, which are summarized below. The invention includes the compounds as shown, and also includes individual diastereoisomers, enantiomers, and epimers of the compounds, and mixtures of diastereoisomers and/or enantiomers thereof including racemic mixtures.

In one embodiment of the present invention, T is CH, U is CR1, V is CR2, and W is CH. In a class of this embodiment, T is CH, U is CR1, V is CH, and W is CH. In another class of this embodiment, T is CH, U is CH, V is CR2, and W is CH.

In another embodiment of the present invention, T is selected from the group consisting of: CH and N. In a class of this embodiment, T is CH. In another class of this embodiment, T is N. In another embodiment of the present invention, U is selected from the group consisting of: CR1and N. In a class of this embodiment, U is CR1. In another class of this embodiment, U is N. In another embodiment of the present invention, V is selected from the group consisting of: CR2and N. In a class of this embodiment, V is CR2. In another class of this embodiment, V is N.

In another embodiment of the present invention, W is selected from the group consisting of: CH and N, provided that no more than two of T, U, V and W are selected from N, further provided that if both T and W are N, then R3is absent, and further provided that both U and V are not N. In a class of this embodiment, W is CH, provided that no more than two of T, U and V are N, further provided that if two of T, U and V are N, then R3is absent, and further provided that both U and V are not N. In another class of this embodiment, W is N, provided that no more than two of T, U, V and W are N, further provided that if both T and W are N, then R3is absent, and further provided that both U and V are not N. In another class of this embodiment, W is N, provided that no more than two of T, U, V and W are N, further provided that if both T and W are N, then R3is absent, and further provided that both U and V are not N.

In another embodiment of the present invention, W is selected from the group consisting of: CH and N. In a class of this embodiment, W is CH. In another class of this embodiment, W is N.

In another embodiment of the present invention, T is N, U is CR1, V is CR2, and W is CH. In another embodiment of the present invention, T is CH, U is N, V is CR2, and W is CH. In another embodiment of the present invention, T is CH, U is CR1, and V is N, and W is CH. In another embodiment of the present invention, T is CH, U is CR1, V is CR2, and W is N. In another embodiment of the present invention, T is N, U is N, V is CR2, and W is CH. In another embodiment of the present invention, T is N, U is CR1, V is N, and W is CH. In another embodiment of the present invention, T is N, U is CR1, V is CR2, and W is N. In another embodiment of the present invention, T is N, U is CR1, V is CR2, and W is N; and R3is absent. In another embodiment of the present invention, T is CH, U is N, V is CR2, and W is N. In another embodiment of the present invention, T is CH, U is CR1, V is N, and W is N. In another embodiment of the present invention, T is CH; U is CR1; V is CR2; and W is CH or N.

In another embodiment of the present invention, X is selected from the group consisting of: C(Rd)(Rd), and N(Re). In a class of this embodiment of the present invention, X is selected from the group consisting of: CH2, NH, and NCH3.

In another embodiment of the present invention, X is selected from the group consisting of: N(Re). In a class of this embodiment of the present invention, X is selected from the group consisting of: NH, and NCH3.

In another embodiment of the present invention, Y is selected from the group consisting of: oxygen, C(Rg)(Rg), and N(Rc).

In another embodiment of the present invention, Y is selected from the group consisting of: oxygen, and C(Rg)(Rg). In a class of this embodiment of the present invention, Y is selected from the group consisting of: oxygen, and CH2.

In another embodiment of the present invention, Y is oxygen.

In another embodiment of the present invention, Y is selected from the group consisting of: C(Rg)(Rg). In a class of this embodiment, Y is-CH2.

In another embodiment of the present invention, Z is selected from the group consisting of: C(R5), and N, provided that when X is N(Re), Z is not N, and further provided that when X is C(Rd)(Rd), then Y is C(Rg)(Rg). In a class of this embodiment of the present invention, Z is selected from the group consisting of: CH, and N, provided that when X is N(Re), Z is not N, and further provided that when X is C(Rd)(Rd), then Y is C(Rg)(Rg).

In another embodiment of the present invention, Z is selected from the group consisting of: C(R5) provided that when X is C(Rd)(Rd), then Y is C(Rg)(Rg). In a class of this embodiment of the present invention, Z is CH, provided that when X is C(Rd)(Rd), then Y is C(Rg)(Rg).

In another embodiment of the present invention, Z is N, provided that X is not N(Re), and further provided that when X is C(Rd)(Rd), then Y is C(Rg)(Rg).

In another embodiment of the present invention, A is selected from the group consisting of: aryl, heteroaryl, C3-8cycloalkyl, and C2-7cycloheteroalkyl, wherein A is unsubstituted or substituted with one to five substituents selected from Ra.

In another embodiment of the present invention, A is selected from the group consisting of: aryl, and C2-7cycloheteroalkyl, wherein aryl and cycloheteroalkyl are unsubstituted or substituted with one to five substituents selected from Ra. In a class of this embodiment, A is selected from the group consisting of: phenyl and piperidine, wherein phenyl and piperidine are unsubstituted or substituted with one to five substituents selected from Ra.

In another embodiment of the present invention, A is aryl, wherein aryl is unsubstituted or substituted with one to five substituents selected from Ra. In a class of this embodiment, A is phenyl, wherein phenyl is unsubstituted or substituted with one to five substituents selected from Ra.

In another embodiment of the present invention, A is selected from the group consisting of: C2-7cycloheteroalkyl, wherein cycloheteroalkyl is unsubstituted or substituted with one to five substituents selected from Ra. In a class of this embodiment, A is piperidine, wherein piperidine is unsubstituted or substituted with one to five substituents selected from Ra.

In another embodiment of the present invention, B is selected from the group consisting of: aryl, aryl-O—, aryl-C1-10alkyl-, aryl-C1-10alkyl-O—, heteroaryl, heteroaryl-O, heteroaryl-C1-10alkyl-, and heteroaryl-C1-10alkyl-O—, wherein B is unsubstituted or substituted with one to five substituents selected from Rb.

In another embodiment of the present invention, B is selected from the group consisting of: aryl, aryl-C1-10alkyl-, heteroaryl, and heteroaryl-C1-10alkyl-, wherein B is unsubstituted or substituted with one to five substituents selected from Rb.

In another embodiment of the present invention, B is selected from the group consisting of: aryl, and aryl-C1-10alkyl-, wherein B is unsubstituted or substituted with one to five substituents selected from Rb. In a class of this embodiment, B is selected from the group consisting of: phenyl, and phenyl-CH2—, wherein B is unsubstituted or substituted with one to five substituents selected from Rb.

In another embodiment of the present invention, B is selected from the group consisting of: aryl, wherein aryl is unsubstituted or substituted with one to five substituents selected from Rb. In a class of this embodiment, B is phenyl, wherein phenyl is unsubstituted or substituted with one to five substituents selected from Rb.

In another embodiment of the present invention, B is selected from the group consisting of: aryl-C1-10alkyl-, wherein B is unsubstituted or substituted with one to five substituents selected from Rb. In a class of this embodiment, B is phenyl-CH2—, wherein B is unsubstituted or substituted with one to five substituents selected from Rb.

In another embodiment of the present invention, R1and R2are each independently selected from: hydrogen, —C1-6alkyl, and —C3-6cycloalkyl, wherein alkyl and cycloalkyl is substituted with a substituent selected from R7and with one to three substituents selected from R9, provided that one of R1and R2is C1-6alkyl or C3-6cycloalkyl. In a class of this embodiment, one of R1and R2is —C1-6alkyl substituted with a substituent selected from R7and with one to two substituents selected from R9, or —C3-6cycloalkyl substituted with a substituent selected from R7and with one to two substituents selected from R9.

In another embodiment of the present invention, R1and R2are each independently selected from: hydrogen, and —C1-6alkyl, wherein alkyl is substituted with a substituent selected from R7and substituted with one to three substituents selected from R9, provided that one of R1and R2is —C1-6alkyl. In a class of this embodiment, R1and R2are each independently selected from: hydrogen, and —C1-6alkyl, wherein alkyl is substituted with a substituent selected from R7and substituted with one to two substituents selected from R9, provided that one of R1and R2is —C1-6alkyl.

In another embodiment of the present invention, R1and R2are each independently selected from: hydrogen, and —C2alkyl, wherein alkyl is substituted with a substituent selected from R7and substituted with one to three substituents selected from R9, provided that one of R1and R2is —C2alkyl. In a class of this embodiment, R1and R2are each independently selected from: hydrogen, and —C2alkyl, wherein alkyl is substituted with a substituent selected from R7and substituted with one to two substituents selected from R9, provided that one of R1and R2is —C2alkyl.

In another embodiment, R1is —C1-6alkyl, wherein alkyl is substituted with a substituent selected from R7and substituted with one to three substituents selected from R9. In a class of this embodiment, R1is —C2alkyl, wherein alkyl is substituted with a substituent selected from R7and substituted with two substituents selected from R9.

In another embodiment, R1is —C1-6alkyl, wherein alkyl is substituted with a substituent selected from R7and substituted with one to three substituents selected from R9; and R2is hydrogen. In a class of this embodiment, R1is —C2alkyl, wherein alkyl is substituted with a substituent selected from R7and substituted with two substituents selected from R9; and R2is hydrogen.

In another embodiment of the present invention, R1is hydrogen.

In another embodiment, R2is —C1-6alkyl, wherein alkyl is substituted with a substituent selected from R7and substituted with one to three substituents selected from R9. In a class of this embodiment, R2is —C2alkyl, wherein alkyl is substituted with a substituent selected from R7and substituted with two substituents selected from R9.

In another embodiment, R2is —C1-6alkyl, wherein alkyl is substituted with a substituent selected from R7and substituted with one to three substituents selected from R9; and R1is hydrogen. In a class of this embodiment, R2is —C2alkyl, wherein alkyl is substituted with a substituent selected from R7and substituted with two substituents selected from R9; and R1is hydrogen.

In another embodiment of the present invention, R2is hydrogen.

In another embodiment of the present invention, when present, each R3is independently selected from the group consisting of: hydrogen, and F.

In another embodiment of the present invention, when present, R3is hydrogen.

In another embodiment of the present invention, when present, each R3is F.

In another embodiment of the present invention, R4is selected from the group consisting of: hydrogen, halogen, and —C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from Rh.

In another embodiment of the present invention, R4is selected from the group consisting of: hydrogen, and —C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from Rh. In a class of this embodiment, R4is C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from Rh. In another class of this embodiment, R4is hydrogen.

In another embodiment of the present invention, R4is selected from the group consisting of: hydrogen, and halogen. In a class of this embodiment, R4is halogen.

In another embodiment of the present invention, R5is selected from the group consisting of: hydrogen, and —C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from Rh. In a class of this embodiment, R5is C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from Rh.

In another class of this embodiment, R5is hydrogen.

In another embodiment of the present invention, R6is selected from the group consisting of: hydrogen, and —C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from Rh. In a class of this embodiment, R6is C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from Rh.

In another class of this embodiment, R6is hydrogen.

In another embodiment of the present invention, R7is selected from the group consisting of: —CO2R8, and —C1-6alkyl-CO2R8.

In another embodiment of the present invention, R7is selected from the group consisting of: —C1-6alkyl-CO2R8.

In another embodiment of the present invention, R7is —CO2R8. In a class of this embodiment, R7is —CO2H.

In another embodiment of the present invention, R8is selected from the group consisting of: hydrogen, and —C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from Ri.

In another embodiment of the present invention, R8is selected from the group consisting of: —C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from Ri.

In another embodiment of the present invention, R8is hydrogen.

In another embodiment of the present invention, each R9is independently selected from the group consisting of: —CO2C1-6alkyl, —C1-10alkyl, —C2-10alkenyl, —C2-10alkynyl, —C3-6cycloalkyl, —C2-6cycloheteroalkyl, aryl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with 1-4 substituents selected from C1-6alkyl, halogen, and —OC1-6alkyl.

In another embodiment of the present invention, each R9is independently selected from the group consisting of: —CO2C1-6alkyl, —C1-10alkyl, —C2-10alkenyl, —C2-10alkynyl, —C3-6cycloalkyl, and —C2-6cycloheteroalkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted with 1-4 substituents selected from C1-6alkyl, halogen, and —OC1-6alkyl.

In another embodiment of the present invention, each R9is independently selected from the group consisting of: —C1-10alkyl, —C2-10alkenyl, —C2-10alkynyl, —C3-6cycloalkyl, and —C2-6cycloheteroalkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted with 1-4 substituents selected from C1-6alkyl, halogen, and —OC1-6alkyl.

In another embodiment of the present invention, each R9is independently selected from the group consisting of: —C1-10alkyl, —C2-10alkynyl, and —C3-6cycloalkyl, wherein each alkyl, alkynyl, and cycloalkyl is unsubstituted or substituted with 1-4 substituents selected from C1-6alkyl, halogen, and —OC1-6alkyl.

In another embodiment of the present invention, each R9is independently selected from the group consisting of: —C1-10alkyl, and —C3-6cycloalkyl, wherein each alkyl and cycloalkyl is unsubstituted or substituted with 1-4 substituents selected from C1-6alkyl, halogen, and —OC1-6alkyl. In a class of this embodiment, each R9is independently selected from the group consisting of: —C1-4alkyl, and —C3-5cycloalkyl, wherein each alkyl and cycloalkyl is unsubstituted or substituted with 1-4 substituents selected from C1-6alkyl, halogen, and —OC1-6alkyl. In another class of this embodiment, each R9is independently selected from the group consisting of: —C1-4alkyl, and —C3-5cycloalkyl. In another class of this embodiment, each R9is independently selected from the group consisting of: —CH3, and -cyclopropyl, wherein each —CH3and cyclopropyl is unsubstituted or substituted with 1-4 substituents selected from C1-6alkyl, halogen, and —OC1-6alkyl. In another class of this embodiment, each R9is independently selected from the group consisting of: —CH3, and -cyclopropyl.

In another embodiment of the present invention, each R9is —C1-10alkyl, wherein each alkyl is unsubstituted or substituted with 1-4 substituents selected from C1-6alkyl, halogen, and —OC1-6alkyl.

In a class of this embodiment, each R9is —C1-4alkyl, wherein each alkyl is unsubstituted or substituted with 1-4 substituents selected from C1-6alkyl, halogen, and —OC1-6alkyl. In another class of this embodiment, each R9is —C1-4alkyl. In another class of this embodiment, each R9is CH3, wherein each —CH3is unsubstituted or substituted with 1-4 substituents selected from C1-6alkyl, halogen, and —OC1-6alkyl. In another class of this embodiment, each R9is —CH3.

In another embodiment of the present invention, each R9is —C3-6cycloalkyl,

wherein each cycloalkyl is unsubstituted or substituted with 1-4 substituents selected from C1-6alkyl, halogen, and —OC1-6alkyl.

In a class of this embodiment, each R9is —C3-5cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with 1-4 substituents selected from C1-6alkyl, halogen, and —OC1-6alkyl. In another class of this embodiment, each R9is —C3-5cycloalkyl. In another class of this embodiment, each R9is cyclopropyl is unsubstituted or substituted with 1-4 substituents selected from C1-6alkyl, halogen, and —OC1-6alkyl. In another class of this embodiment, each R9is cyclopropyl.

In another embodiment of the present invention, each Rais selected from the group consisting of: —C1-6alkyl, halogen, —C3-6cycloalkyl, —C2-5cycloheteroalkyl, and —C1-6alkylN(Rj)(Rk), wherein each alkyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with one to three substituents independently selected from —C1-6alkyl, halogen, —O—C1-6alkyl, and —CF3.

In another embodiment of the present invention, each Rais selected from the group consisting of: —C1-6alkyl, halogen, —C3-6cycloalkyl, and —C2-5cycloheteroalkyl; wherein each alkyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with one to three substituents independently selected from —C1-6alkyl, halogen, —O—C1-6alkyl and —CF3.

In another embodiment of the present invention, each Rais selected from the group consisting of: —C1-6alkyl, and halogen, wherein each alkyl is unsubstituted or substituted with one to three substituents independently selected from —C1-6alkyl, halogen, —O—C1-6alkyl and —CF3.

In another embodiment of the present invention, each Rais —C1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents independently selected from —C1-6alkyl, halogen, —O—C1-6alkyl and —CF3. In a class of this embodiment, each Rais —C1-6alkyl.

In another embodiment of the present invention, each Rais halogen.

In another embodiment of the present invention, each Rbis independently selected from the group consisting of: —C1-10alkyl, —CF3, halogen, —CN, —OH, and —OC1-10alkyl,

wherein each alkyl is unsubstituted or substituted with one to three substituents independently selected from —C1-6alkyl, halogen, —O—C1-6alkyl and —CF3.

In another embodiment of the present invention, each Rbis independently selected from the group consisting of: —C1-10alkyl, —CF3, halogen, and —OC1-10alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents independently selected from —C1-6alkyl, halogen, —O—C1-6alkyl and —CF3.

In another embodiment of the present invention, each Rbis independently selected from the group consisting of: —CF3, halogen, and —OC1-10alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents independently selected from —C1-6alkyl, halogen, —O—C1-6alkyl and —CF3. In a class of this embodiment, each Rbis independently selected from the group consisting of: —CF3, F, and —OCH3.

In another embodiment of the present invention, each Rbis —CF3.

In another embodiment of the present invention, each Rbis independently selected from the group consisting of: halogen, and —OC1-10alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents independently selected from —C1-6alkyl, halogen, —O—C1-6alkyl and —CF3. In a class of this embodiment, each Rbis independently selected from the group consisting of: F, and —OCH3.

In another embodiment of the present invention, Rcis independently selected from the group consisting of: hydrogen, C1-10alkyl, C2-10alkenyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-10alkyl-, C2-5cycloheteroalkyl, and C2-5cycloheteroalkyl-C1-10alkyl, wherein alkyl, alkenyl, cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted with one to three substituents independently selected from Rf.

In another embodiment of the present invention, Rcis independently selected from the group consisting of: hydrogen, —C1-10alkyl, and C2-10alkenyl, wherein alkyl, and alkenyl is unsubstituted or substituted with one to three substituents independently selected from Rf.

In another embodiment of the present invention, Rcis independently selected from the group consisting of: hydrogen, and —C1-10alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents independently selected from Rf. In a class of this embodiment, Rcis hydrogen. In another class of this embodiment, Rcis —C1-10alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents independently selected from Rf. In another class of this embodiment, Rcis —C1-10alkyl.

In another embodiment of the present invention, each Rdis selected from the group consisting of: hydrogen, —C1-4alkyl, and halogen, wherein each alkyl is unsubstituted or substituted with one to five halogens.

In another embodiment of the present invention, each Rdis selected from the group consisting of: hydrogen, and halogen. In a class of this embodiment, each Rdis halogen.

In another embodiment of the present invention, each Rdis selected from the group consisting of: hydrogen, and —C1-4alkyl, wherein each alkyl is unsubstituted or substituted with one to five halogens. In a class of this embodiment of the present invention, each Rdis selected from the group consisting of: hydrogen, and —C1-4alkyl.

In another embodiment of the present invention, each Rdis hydrogen.

In another embodiment of the present invention, each Rdis —C1-4alkyl, wherein each alkyl is unsubstituted or substituted with one to five halogens. In a class of this embodiment of the present invention, each Rdis —C1-4alkyl.

In another embodiment of the present invention, Reis selected from the group consisting of: hydrogen, and —C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from —C1-6alkyl, —OC1-6alkyl, —CF3and halogen. In a class of this embodiment, Reis selected from the group consisting of: hydrogen, and —C1-6alkyl.

In another embodiment of the present invention, Reis hydrogen.

In another embodiment of the present invention, Reis —C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from —C1-6alkyl, —OC1-6alkyl, —CF3and halogen. In another class of this embodiment, Reis —CH3.

In another embodiment of the present invention, each Rfis selected from the group consisting of: —C1-4alkyl, —OC1-4alkyl, and halogen.

In another embodiment of the present invention, each Rfis selected from the group consisting of: —C1-4alkyl and halogen.

In another embodiment of the present invention, each Rfis —OC1-4alkyl.

In another embodiment of the present invention, each Rfis —C1-4alkyl.

In another embodiment of the present invention, each Rfis halogen.

In another embodiment of the present invention, each Rgis selected from the group consisting of: hydrogen, —C1-4alkyl, and halogen, wherein each alkyl is unsubstituted or substituted with one to five halogens.

In another embodiment of the present invention, each Rgis selected from the group consisting of: hydrogen, and halogen. In a class of this embodiment, each Rgis halogen.

In another embodiment of the present invention, each Rgis selected from the group consisting of: hydrogen, and —C1-4alkyl, wherein each alkyl is unsubstituted or substituted with one to five halogens. In a class of this embodiment of the present invention, each Rgis selected from the group consisting of: hydrogen, and —C1-4alkyl.

In another embodiment of the present invention, each Rgis hydrogen.

In another embodiment of the present invention, each Rgis —C1-4alkyl, wherein each alkyl is unsubstituted or substituted with one to five halogens. In a class of this embodiment of the present invention, each Rgis —C1-4alkyl.

In another embodiment of the present invention, each Rhis independently selected from the group consisting of: —C1-6alkyl, —OC1-6alkyl, and halogen.

In another embodiment of the present invention, each Rhis —C1-6alkyl.

In another embodiment of the present invention, each Rhis independently selected from the group consisting of: —OC1-6alkyl, and halogen.

In another embodiment of the present invention, each Rhis —OC1-6alkyl.

In another embodiment of the present invention, each Rhis halogen.

In another embodiment of the present invention, each Riis independently selected from the group consisting of: —C1-6alkyl, —OC1-6alkyl, and halogen.

In another embodiment of the present invention, each Riis —C1-6alkyl.

In another embodiment of the present invention, each Riis independently selected from the group consisting of: —OC1-6alkyl, and halogen.

In another embodiment of the present invention, each Riis —OC1-6alkyl.

In another embodiment of the present invention, each Riis halogen.

In another embodiment of the present invention, Rjis selected from the group consisting of: hydrogen, C1-10alkyl, C2-10alkenyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-10alkyl-, C2-5cycloheteroalkyl, and C2-5cycloheteroalkyl-C1-10alkyl-, wherein each alkyl, alkenyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with one to three substituents independently selected from —C1-6alkyl, halogen, or —O—C1-6alkyl.

In another embodiment of the present invention, Rjis selected from the group consisting of: hydrogen, C1-10alkyl, C2-10alkenyl, C3-6cycloalkyl, and C2-5cycloheteroalkyl, wherein alkyl, alkenyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with one to three substituents independently selected from —C1-6alkyl, halogen, or —O—C1-6alkyl.

In another embodiment of the present invention, Rjis selected from the group consisting of: hydrogen, and C1-10alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents independently selected from —C1-6alkyl, halogen, or —O—C1-6alkyl.

In another embodiment of the present invention, Rjis —C1-10alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents independently selected from —C1-6alkyl, halogen, or —O—C1-6alkyl. In a class of this embodiment, Rjis —C1-10alkyl.

In another embodiment of the present invention, Rjis hydrogen.

In another embodiment of the present invention, Rkis selected from the group consisting of: hydrogen, C1-10alkyl, C2-10alkenyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-10alkyl-, C2-5cycloheteroalkyl, and C2-5cycloheteroalkyl-C1-10alkyl-, wherein alkyl, alkenyl, cycloalkyl, and cycloheteroalkyl are unsubstituted or substituted with one to three substituents independently selected from —C1-6alkyl, halogen, or —O—C1-6alkyl.

In another embodiment of the present invention, Rkis selected from the group consisting of: hydrogen, C1-10alkyl, C2-10alkenyl, C3-6cycloalkyl, and C2-5cycloheteroalkyl, wherein alkyl, alkenyl, cycloalkyl, and cycloheteroalkyl are unsubstituted or substituted with one to three substituents independently selected from —C1-6alkyl, halogen, or —O—C1-6alkyl.

In another embodiment of the present invention, Rkis selected from the group consisting of: hydrogen, and C1-10alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents independently selected from —C1-6alkyl, halogen, or —O—C1-6alkyl.

In another embodiment of the present invention, Rkis —C1-10alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents independently selected from —C1-6alkyl, halogen, or —O—C1-6alkyl. In a class of this embodiment, Rkis —C1-10alkyl.

In another embodiment of the present invention, Rkis hydrogen.

In another embodiment of the present invention, q is 0, 1, 2 or 3. In another embodiment of the present invention, q is 1, 2 or 3. In another embodiment of the present invention, q is 0, 1 or 2. In a class of this embodiment, q is 0 or 1. In another class of this embodiment, q is 1 or 2. In another class of this embodiment, q is 0. In another class of this embodiment, q is 1. In another class of this embodiment, q is 2. In another class of this embodiment, q is 3.

or a pharmaceutically acceptable salt thereof.

or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, the invention relates to compounds of structural formula Ic:

or a pharmaceutically acceptable salt thereof.

or a pharmaceutically acceptable salt thereof.

or a pharmaceutically acceptable salt thereof.

or a pharmaceutically acceptable salt thereof.

or a pharmaceutically acceptable salt thereof.

or a pharmaceutically acceptable salt thereof.

or a pharmaceutically acceptable salt thereof.

The compound of structural formula I includes the compounds of structural formulas Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and Ii, and pharmaceutically acceptable salts, hydrates and solvates thereof.

Another embodiment of the present invention relates to compounds of structural formula Id:

wherein
Y is selected from the group consisting of:

A is selected from the group consisting of:

wherein aryl and cycloheteroalkyl are unsubstituted or substituted with one to five substituents selected from Ra;

B is selected from the group consisting of:

wherein B is unsubstituted or substituted with one to five substituents selected from Rb;

wherein each alkyl is substituted with a substituent selected from R7and with one to three substituents selected from R9, provided that one of R1and R2is C1-6alkyl;

each R9is independently selected from the group consisting of:

wherein each alkyl and cycloalkyl is unsubstituted or substituted with 1-4 substituents selected from C1-6alkyl, halogen, and —OC1-6alkyl;

Reis selected from the group consisting of:

wherein each alkyl is unsubstituted or substituted with one to three substituents selected from —C1-6alkyl, —OC1-6alkyl, —CF3and halogen; and

q is 1;

or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention relates to compounds of structural Formula Id:

wherein
Y is selected from the group consisting of:

A is aryl, wherein aryl is unsubstituted or substituted with one to five substituents selected from Ra;

B is aryl, wherein aryl is unsubstituted or substituted with one to five substituents selected from Rb;

R1is —C1-6alkyl, wherein alkyl is substituted with a substituent selected from R7and with one to three substituents selected from R9;

each R9is independently selected from the group consisting of:

wherein each alkyl and cycloalkyl is unsubstituted or substituted with 1-4 substituents selected from C1-6alkyl, halogen, and —OC1-6alkyl;

Reis selected from the group consisting of:

q is 1;

or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention relates to compounds of structural Formula Ii:

wherein
A is C2-7cycloheteroalkyl, wherein cycloheteroalkyl is unsubstituted or substituted with one to five substituents selected from Ra;
B is aryl-C1-10alkyl-, wherein B is unsubstituted or substituted with one to five substituents selected from Rb;
R1is —C1-6alkyl, wherein alkyl is substituted with a substituent selected from R7and with one to three substituents selected from R9;
R2, R3, R4, R6, and R8are hydrogen;
R7is —CO2R8;
each R9is independently selected from the group consisting of:

wherein each alkyl and cycloalkyl is unsubstituted or substituted with 1-4 substituents selected from C1-6alkyl, halogen, and —OC1-6alkyl; and

q is 1;

or a pharmaceutically acceptable salt thereof.

Illustrative, but non-limiting, examples of the compounds of the present invention that are useful as agonists of G-protein-coupled receptor 40 (GPR40) are the following compounds:

and pharmaceutically acceptable salts thereof.

Although the specific stereochemistries described herein are preferred, other stereoisomers, including diastereoisomers, enantiomers, epimers, and mixtures of these may also have utility in treating GPR40 mediated diseases.

Synthetic methods for making the compounds are disclosed in the Examples shown below. Where synthetic details are not provided in the examples, the compounds are readily made by a person of ordinary skill in the art of medicinal chemistry or synthetic organic chemistry by applying the synthetic information provided herein. Where a stereochemical center is not defined, the structure represents a mixture of stereoisomers at that center. For such compounds, the individual stereoisomers, including enantiomers, diastereoisomers, and mixtures of these are also compounds of the invention.

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. In one embodiment of the present invention, alkyl is methyl.

“Alkenyl” means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched, or combinations thereof, unless otherwise defined. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like. In one embodiment of the present invention, alkenyl is 2-methyl-1-propenyl.

“Alkynyl” means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched, or combinations thereof, unless otherwise defined. Examples of alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like. In one embodiment, alkynyl is —C2alkyne-CH3.

“Cycloalkyl” means a saturated monocyclic, bicyclic or bridged carbocyclic ring, having a specified number of carbon atoms. The term may also be used to describe a carbocyclic ring fused to an aryl group. Examples of cycloalkyl include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. In one embodiment of the present invention, cycloalkyl is selected from: cyclopropane, cyclobutane and cyclohexane. In another embodiment of the present invention, cycloalkyl is cyclopropane.

“Cycloalkenyl” means a nonaromatic monocyclic or bicyclic carbocylic ring containing at least one double bond. Examples of cycloalkenyl include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooxtenyl and the like. In one embodiment of the present invention, cycloalkenyl is cyclopentenyl.

“Cycloheteroalkyl” means a saturated or partly unsaturated non-aromatic monocyclic, bicyclic or bridged carbocyclic ring or ring system containing at least one ring heteroatom selected from N, NH, S (including SO and SO2) and O. The cycloheteroalkyl ring may be substituted on the ring carbons and/or the ring nitrogen(s). Examples of cycloheteroalkyl include tetrahydrofuran, pyrrolidine, tetrahydrothiophene, azetidine, piperazine, piperidine, morpholine, oxetane and tetrahydropyran, hexose, pentose, isosorbide and isomannide, dianhydromannitol, 1, 4:3, 6-dianhydromannitol, 1, 4:3, 6-dianhydro[D]mannitol, hexahydrofuro[3,2-b]furan, and 2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan. In one embodiment of the present invention, cycloheteroalkyl is selected from: hexose, pentose, isosorbide and isomannide. In another embodiment of the present invention, cycloheteroalkyl is selected from: isosorbide and isomannide. In another embodiment of of the present invention, cycloheteroalkyl is selected from: oxetane, tetrahydropyran, azetidine, tetrahydrothiopyran and pyrrolidine. In another embodiment of the present invention cycloheteroalkyl is selected from: oxetane, -piperazine, azetidine, pyrrolidine, morpholine and spiro(indene-1,4-piperidine).

“Cycloheteroalkenyl” means a nonaromatic monocyclic, bicyclic or bridged carbocyclic ring or ring system containing at least one double bond and containing at least one heteroatom selected from N, NH, S and O.

“Aryl” means a monocyclic, bicyclic or tricyclic carbocyclic aromatic ring or ring system containing 6-14 carbon atoms, wherein at least one of the rings is aromatic. Examples of aryl include phenyl and naphthyl. In one embodiment of the present invention, aryl is phenyl. In another embodiment of the present invention, aryl-O— is phenyl-O—. In another embodiment of the present invention, aryl-C1-10alkyl-O— is phenyl-CH2—O—.

“Heteroaryl” means monocyclic, bicyclic or tricyclic ring or ring system containing 2-14 carbon atoms and containing at least one ring heteroatom selected from N, NH, S (including SO and SO2) and O, wherein at least one of the heteroatom containing rings is aromatic. Examples of heteroaryl include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzpyrazole (or indazole), benzothiophenyl (including S-oxide and dioxide), furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl, quinazolinyl, dibenzofuranyl, and the like. In one embodiment of the present invention, heteroaryl is selected from: pyridine, isoxazole, pyrimidine, thiazole, benzimidazole, benzthiazole, benzoxazole, and benzisoxazole. In another embodiment of the present invention, heteroaryl is selected from: pyridine, isoxazole and benzpyrazole. In another embodiment of the present invention, heteroaryl is pyridine or thiazole. In another embodiment of the present invention, heteroaryl is pyridine.

“Halogen” includes fluorine, chlorine, bromine and iodine. In one embodiment of the present invention, halogen is bromine, chlorine or fluorine. In another embodiment of the present invention, halogen is chlorine or fluorine. In another embodiment of the present invention, halogen is bromine. In another embodiment of the present invention, halogen is chlorine. In another embodiment of the present invention, halogen is fluorine.

When any variable (e.g., R1, Ra, etc.) occurs more than one time in any constituent or in formula I, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. A squiggly line across a bond in a substituent variable represents the point of attachment.

Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. For example, a C1-5alkylcarbonylamino C1-6alkyl substituent is equivalent to:

For example, —NRcC(O)Reis equivalent to —N(Rc)C(O)Re.

In choosing compounds of the present invention, one of ordinary skill in the art will recognize that the various substituents, i.e. R1, R2, etc., are to be chosen in conformity with well-known principles of chemical structure connectivity and stability.

The term “substituted” shall be deemed to include multiple degrees of substitution by a named substitutent. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different.

The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, salts and/or dosage forms which are, using sound medical judgment, and following all applicable government regulations, safe and suitable for administration to a human being or an animal.

The term “% enantiomeric excess” (abbreviated “ee”) shall mean the % major enantiomer less the % minor enantiomer. Thus, a 70% enantiomeric excess corresponds to formation of 85% of one enantiomer and 15% of the other. The term “enantiomeric excess” is synonymous with the term “optical purity.”

Compounds of Formula I may contain one or more asymmetric centers and can thus occur as racemates and 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.

Tautomers are defined as compounds that undergo rapid proton shifts from one atom of the compound to another atom of the compound. Some of the compounds described herein may exist as tautomers with different points of attachment of hydrogen. Such an example may be a ketone and its enol form known as keto-enol tautomers. The individual tautomers as well as mixture thereof are encompassed with compounds of Formula I.

In the compounds of general formula I, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominately found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of structural formula I. For example, different isotopic forms of hydrogen (H) include protium (1H), deuterium (2H), and tritium (3H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Tritium is radioactive and may therefore provide for a radiolabeled compound, useful as a tracer in metabolic or kinetic studies. Isotopically-enriched compounds within structural formula I, can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.

The independent syntheses of optical isomers and diastereoisomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration.

Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.

Furthermore, some of the crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of this invention.

It is generally preferable to administer compounds of the present invention as enantiomerically pure formulations. Racemic mixtures can be separated into their individual enantiomers by any of a number of conventional methods. These include chiral chromatography, derivatization with a chiral auxiliary followed by separation by chromatography or crystallization, and fractional crystallization of diastereomeric salts.

It will be understood that, as used herein, references to the compounds of the present invention are meant to also include the pharmaceutically acceptable salts, and also salts that are not pharmaceutically acceptable when they are used as precursors to the free compounds or their pharmaceutically acceptable salts or in other synthetic manipulations.

Also, in the case of a carboxylic acid (—COOH) or alcohol group being present in the compounds of the present invention, pharmaceutically acceptable esters of carboxylic acid derivatives, such as methyl, ethyl, or pivaloyloxymethyl, or acyl derivatives of alcohols, such as O-acetyl, O-pivaloyl, O-benzoyl, and O-aminoacyl, can be employed. Included are those esters and acyl groups known in the art for modifying the solubility or hydrolysis characteristics for use as sustained-release or prodrug formulations.

Solvates, and in particular the hydrates, of the compounds of the present invention are included in the present invention as well.

Utilities

The compounds of the present invention are potent agonists of the GPR40 receptor.

The compounds, and pharmaceutically acceptable salts thereof, may be efficacious in the treatment of diseases that are modulated by GPR40 ligands, which are generally agonists. Many of these diseases are summarized below.

One or more of these diseases may be treated by the administration of a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, to a patient in need of treatment. Also, the compounds of the present invention may be used for the manufacture of a medicament which may be useful for treating one or more of these diseases:(1) non-insulin dependent diabetes mellitus (Type 2 diabetes);(2) hyperglycemia;(3) insulin resistance;(4) Metabolic Syndrome;(5) obesity;(6) hypercholesterolemia;(7) hypertriglyceridemia (elevated levels of triglyceride-rich-lipoproteins);(8) mixed or diabetic dyslipidemia;(9) low HDL cholesterol;(10) high LDL cholesterol;(11) hyperapo-B liproteinemia; and(12) atherosclerosis.

Preferred uses of the compounds may be for the treatment of one or more of the following diseases by administering a therapeutically effective amount to a patient in need of treatment. The compounds may be used for manufacturing a medicament for the treatment of one or more of these diseases:(1) Type 2 diabetes, and specifically hyperglycemia associated with Type 2 diabetes;(2) Metabolic Syndrome;(3) obesity; and(4) hypercholesterolemia.

The compounds may be effective in lowering glucose and lipids in diabetic patients and in non-diabetic patients who have impaired glucose tolerance and/or are in a pre-diabetic condition. The compounds may ameliorate hyperinsulinemia, which often occurs in diabetic or pre-diabetic patients, by modulating the swings in the level of serum glucose that often occur in these patients. The compounds may also be effective in treating or reducing insulin resistance. The compounds may be effective in treating or preventing gestational diabetes.

The compounds may also be effective in treating or preventing lipid disorders. The compounds may be effective in treating or preventing diabetes related disorders. The compounds may also be effective in treating or preventing obesity related disorders.

The compounds of this invention may also have utility in improving or restoring β-cell function, so that they may be useful in treating Type 1 diabetes or in delaying or preventing a patient with Type 2 diabetes from needing insulin therapy.

The invention also includes pharmaceutically acceptable salts of the compounds, and pharmaceutical compositions comprising the compounds and a pharmaceutically acceptable carrier. The compounds may be useful in treating insulin resistance, Type 2 diabetes, hyperglycemia, and dyslipidemia that is associated with Type 2 diabetes and insulin resistance. The compounds may also be useful for the treatment of obesity

A compound of the present invention, or a pharmaceutically acceptable salt thereof, may be used in the manufacture of a medicament for the treatment of Type 2 diabetes in a human or other mammalian patient.

A method of treating Type 2 diabetes comprises the administration of a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound, to a patient in need of treatment. Other medical uses of the compounds of the present invention are described herein.

The term “diabetes,” as used herein, includes both insulin-dependent diabetes mellitus (i.e., IDDM, also known as type 1 diabetes) and non-insulin-dependent diabetes mellitus (i.e., NIDDM, also known as Type 2 diabetes). Type 1 diabetes, or insulin-dependent diabetes, is the result of an absolute deficiency of insulin, the hormone which regulates glucose utilization. Type 2 diabetes, or insulin-independent diabetes (i.e., non-insulin-dependent diabetes mellitus), often occurs in the face of normal, or even elevated levels of insulin and appears to be the result of the inability of tissues to respond appropriately to insulin. Most of the Type 2 diabetics are also obese. The compositions of the present invention may be useful for treating both Type 1 and Type 2 diabetes. The term “diabetes associated with obesity” refers to diabetes caused by obesity or resulting from obesity.

Diabetes is characterized by a fasting plasma glucose level of greater than or equal to 126 mg/dl. A diabetic subject has a fasting plasma glucose level of greater than or equal to 126 mg/dl. A pre diabetic subject is someone suffering from prediabetes. Prediabetes is characterized by an impaired fasting plasma glucose (FPG) level of greater than or equal to 110 mg/dl and less than 126 mg/dl; or impaired glucose tolerance; or insulin resistance. A prediabetic subject is a subject with impaired fasting glucose (a fasting plasma glucose (FPG) level of greater than or equal to 110 mg/dl and less than 126 mg/dl); or impaired glucose tolerance (a 2 hour plasma glucose level of ≥140 mg/dl and <200 mg/dl); or insulin resistance, resulting in an increased risk of developing diabetes.

Treatment of diabetes mellitus refers to the administration of a compound or combination of the present invention to treat a diabetic subject. One outcome of treatment may be decreasing the glucose level in a subject with elevated glucose levels. Another outcome of treatment may be decreasing insulin levels in a subject with elevated insulin levels. Another outcome of treatment may be decreasing plasma triglycerides in a subject with elevated plasma triglycerides. Another outcome of treatment is decreasing LDL cholesterol in a subject with high LDL cholesterol levels. Another outcome of treatment may be increasing HDL cholesterol in a subject with low HDL cholesterol levels. Another outcome of treatment is increasing insulin sensivity. Another outcome of treatment may be enhancing glucose tolerance in a subject with glucose intolerance. Yet another outcome of treatment may be decreasing insulin resistance in a subject with increased insulin resistance or elevated levels of insulin. Prevention of diabetes mellitus, in particular diabetes associated with obesity, refers to the administration of a compound or combination of the present invention to prevent the onset of diabetes in a subject in need thereof. A subject in need of preventing diabetes is a prediabetic subject that is overweight or obese.

The term “diabetes related disorders” should be understood to mean disorders that are associated with, caused by, or result from diabetes. Examples of diabetes related disorders include retinal damage, kidney disease, and nerve damage.

The term “atherosclerosis” as used herein encompasses vascular diseases and conditions that are recognized and understood by physicians practicing in the relevant fields of medicine. Atherosclerotic cardiovascular disease, coronary heart disease (also known as coronary artery disease or ischemic heart disease), cerebrovascular disease and peripheral vessel disease are all clinical manifestations of atherosclerosis and are therefore encompassed by the terms “atherosclerosis” and “atherosclerotic disease.” The combination comprised of a therapeutically effective amount of an anti-obesity agent in combination with a therapeutically effective amount of an anti-hypertensive agent may be administered to prevent or reduce the risk of occurrence, or recurrence where the potential exists, of a coronary heart disease event, a cerebrovascular event, or intermittent claudication. Coronary heart disease events are intended to include CHD death, myocardial infarction (i.e., a heart attack), and coronary revascularization procedures. Cerebrovascular events are intended to include ischemic or hemorrhagic stroke (also known as cerebrovascular accidents) and transient ischemic attacks. Intermittent claudication is a clinical manifestation of peripheral vessel disease. The term “atherosclerotic disease event” as used herein is intended to encompass coronary heart disease events, cerebrovascular events, and intermittent claudication. It is intended that persons who have previously experienced one or more non-fatal atherosclerotic disease events are those for whom the potential for recurrence of such an event exists. The term “atherosclerosis related disorders” should be understood to mean disorders associated with, caused by, or resulting from atherosclerosis.

The term “hypertension” as used herein includes essential, or primary, hypertension wherein the cause is not known or where hypertension is due to greater than one cause, such as changes in both the heart and blood vessels; and secondary hypertension wherein the cause is known. Causes of secondary hypertension include, but are not limited to obesity; kidney disease; hormonal disorders; use of certain drugs, such as oral contraceptives, corticosteroids, cyclosporin, and the like. The term “hypertension” encompasses high blood pressure, in which both the systolic and diastolic pressure levels are elevated (≥140 mmHg/≥90 mmHg), and isolated systolic hypertension, in which only the systolic pressure is elevated to greater than or equal to 140 mm Hg, while the diastolic pressure is less than 90 mm Hg. Normal blood pressure may be defined as less than 120 mmHg systolic and less than 80 mmHg diastolic. A hypertensive subject is a subject with hypertension. A pre-hypertensive subject is a subject with a blood pressure that is between 120 mmHg over 80 mmHg and 139 mmHg over 89 mmHg. One outcome of treatment is decreasing blood pressure in a subject with high blood pressure. Treatment of hypertension refers to the administration of the compounds and combinations of the present invention to treat hypertension in a hypertensive subject. Treatment of hypertension-related disorder refers to the administration of a compound or combination of the present invention to treat the hypertension-related disorder. Prevention of hypertension, or a hypertension related disorder, refers to the administration of the combinations of the present invention to a pre-hypertensive subject to prevent the onset of hypertension or a hypertension related disorder. The hypertension-related disorders herein are associated with, caused by, or result from hypertension. Examples of hypertension-related disorders include, but are not limited to: heart disease, heart failure, heart attack, kidney failure, and stroke.

Dyslipidemias and lipid disorders are disorders of lipid metabolism including various conditions characterized by abnormal concentrations of one or more lipids (i.e., cholesterol and triglycerides), and/or apolipoproteins (i.e., apolipoproteins A, B, C and E), and/or lipoproteins (i.e., the macromolecular complexes formed by the lipid and the apolipoprotein that allow lipids to circulate in blood, such as LDL, VLDL and IDL). Hyperlipidemia is associated with abnormally high levels of lipids, LDL and VLDL cholesterol, and/or triglycerides. Treatment of dyslipidemia refers to the administration of the combinations of the present invention to a dyslipidemic subject. Prevention of dyslipidemia refers to the administration of the combinations of the present invention to a pre-dyslipidemic subject. A pre-dyslipidemic subject is a subject with higher than normal lipid levels, that is not yet dyslipidemic.

The terms “dyslipidemia related disorders” and “lipid disorder related disorders” should be understood to mean disorders associated with, caused by, or resulting from dyslipidemia or lipid disorders. Examples of dylipidemia related disorder and lipid disorder related disorders include, but are not limited to: hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low high density lipoprotein (HDL) levels, high plasma low density lipoprotein (LDL) levels, atherosclerosis and its sequelae, coronary artery or carotid artery disease, heart attack, and stroke.

The term “obesity” as used herein is a condition in which there is an excess of body fat. The operational definition of obesity is based on the Body Mass Index (BMI), which is calculated as body weight per height in meters squared (kg/m2). “Obesity” refers to a condition whereby an otherwise healthy subject has a Body Mass Index (BMI) greater than or equal to 30 kg/m2, or a condition whereby a subject with at least one co-morbidity has a BMI greater than or equal to 27 kg/m2. An “obese subject” is an otherwise healthy subject with a Body Mass Index (BMI) greater than or equal to 30 kg/m2or a subject with at least one co-morbidity with a BMI greater than or equal to 27 kg/m2. An overweight subject is a subject at risk of obesity. A “subject at risk of obesity” is an otherwise healthy subject with a BMI of 25 kg/m2to less than 30 kg/m2or a subject with at least one co-morbidity with a BMI of 25 kg/m2to less than 27 kg/m2.

The increased risks associated with obesity occur at a lower Body Mass Index (BMI) in Asians. In Asian countries, including Japan, “obesity” refers to a condition whereby a subject with at least one obesity-induced or obesity-related co-morbidity, that requires weight reduction or that would be improved by weight reduction, has a BMI greater than or equal to 25 kg/m2. In Asian countries, including Japan, an “obese subject” refers to a subject with at least one obesity-induced or obesity-related co-morbidity that requires weight reduction or that would be improved by weight reduction, with a BMI greater than or equal to 25 kg/m2. In Asia-Pacific, a “subject at risk of obesity” is a subject with a BMI of greater than 23 kg/m2to less than 25 kg/m2.

As used herein, the term “obesity” is meant to encompass all of the above definitions of obesity.

Treatment of obesity and obesity-related disorders refers to the administration of the compounds of the present invention to reduce or maintain the body weight of an obese subject. One outcome of treatment may be reducing the body weight of an obese subject relative to that subject's body weight immediately before the administration of the compounds of the present invention. Another outcome of treatment may be preventing body weight regain of body weight previously lost as a result of diet, exercise, or pharmacotherapy. Another outcome of treatment may be decreasing the occurrence of and/or the severity of obesity-related diseases. The treatment may suitably result in a reduction in food or calorie intake by the subject, including a reduction in total food intake, or a reduction of intake of specific components of the diet such as carbohydrates or fats; and/or the inhibition of nutrient absorption; and/or the inhibition of the reduction of metabolic rate; and in weight reduction in patients in need thereof. The treatment may also result in an alteration of metabolic rate, such as an increase in metabolic rate, rather than or in addition to an inhibition of the reduction of metabolic rate; and/or in minimization of the metabolic resistance that normally results from weight loss.

Prevention of obesity and obesity-related disorders refers to the administration of the compounds of the present invention to reduce or maintain the body weight of a subject at risk of obesity. One outcome of prevention may be reducing the body weight of a subject at risk of obesity relative to that subject's body weight immediately before the administration of the compounds of the present invention. Another outcome of prevention may be preventing body weight regain of body weight previously lost as a result of diet, exercise, or pharmacotherapy. Another outcome of prevention may be preventing obesity from occurring if the treatment is administered prior to the onset of obesity in a subject at risk of obesity. Another outcome of prevention may be decreasing the occurrence and/or severity of obesity-related disorders if the treatment is administered prior to the onset of obesity in a subject at risk of obesity. Moreover, if treatment is commenced in already obese subjects, such treatment may prevent the occurrence, progression or severity of obesity-related disorders, such as, but not limited to, arteriosclerosis, Type II diabetes, polycystic ovarian disease, cardiovascular diseases, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, and cholelithiasis.

The obesity-related disorders herein are associated with, caused by, or result from obesity. Examples of obesity-related disorders include overeating and bulimia, hypertension, diabetes, elevated plasma insulin concentrations and insulin resistance, dyslipidemias, hyperlipidemia, endometrial, breast, prostate and colon cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heart rhythms and arrythmias, myocardial infarction, congestive heart failure, coronary heart disease, sudden death, stroke, polycystic ovarian disease, craniopharyngioma, the Prader-Willi Syndrome, Frohlich's syndrome, GH-deficient subjects, normal variant short stature, Turner's syndrome, and other pathological conditions showing reduced metabolic activity or a decrease in resting energy expenditure as a percentage of total fat-free mass, e.g, children with acute lymphoblastic leukemia. Further examples of obesity-related disorders are metabolic syndrome, also known as syndrome X, insulin resistance syndrome, sexual and reproductive dysfunction, such as infertility, hypogonadism in males and hirsutism in females, gastrointestinal motility disorders, such as obesity-related gastro-esophageal reflux, respiratory disorders, such as obesity-hypoventilation syndrome (Pickwickian syndrome), cardiovascular disorders, inflammation, such as systemic inflammation of the vasculature, arteriosclerosis, hypercholesterolemia, hyperuricaemia, lower back pain, gallbladder disease, gout, and kidney cancer. The compounds of the present invention are also useful for reducing the risk of secondary outcomes of obesity, such as reducing the risk of left ventricular hypertrophy.

The term “metabolic syndrome”, also known as syndrome X, is defined 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 Health, 2001, NIH Publication No. 01-3670. E. S. Ford et al., JAMA, vol. 287 (3), Jan. 16, 2002, pp 356-359. Briefly, a person is defined as having metabolic syndrome if the person has three or more of the following disorders: abdominal obesity, hypertriglyceridemia, low HDL cholesterol, high blood pressure, and high fasting plasma glucose. The criteria for these are defined in ATP-III. Treatment of metabolic syndrome refers to the administration of the combinations of the present invention to a subject with metabolic syndrome. Prevention of metabolic syndrome refers to the administration of the combinations of the present invention to a subject with two of the disorders that define metabolic syndrome. A subject with two of the disorders that define metabolic syndrome is a subject that has developed two of the disorders that define metabolic syndrome, but has not yet developed three or more of the disorders that define metabolic syndrome.

The terms “administration of” and or “administering a” compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual or mammal in need of treatment.

The administration of the compound of structural formula I in order to practice the present methods of therapy is carried out by administering an effective amount of the compound of structural formula I to the mammal in need of such treatment or prophylaxis. The need for a prophylactic administration according to the methods of the present invention is determined via the use of well known risk factors. The effective amount of an individual compound is determined, in the final analysis, by the physician or veterinarian in charge of the case, but depends on factors such as the exact disease to be treated, the severity of the disease and other diseases or conditions from which the patient suffers, the chosen route of administration other drugs and treatments which the patient may concomitantly require, and other factors in the physician's judgment.

The usefulness of the present compounds in these diseases or disorders may be demonstrated in animal disease models that have been reported in the literature.

Administration and Dose Ranges

In the treatment or prevention of conditions which require agonism of GPR40 receptor activity, an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 mg of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.

When treating or preventing diabetes mellitus and/or hyperglycemia or hypertriglyceridemia or other diseases for which compounds of the present invention are indicated, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of from about 0.1 mg to about 100 mg 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, the total daily dosage is from about 1.0 mg to about 1000 mg, preferably from about 1 mg to about 50 mg. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 mg to about 350 mg. This dosage regimen may be adjusted to provide the optimal therapeutic response.

The compounds of this invention may be used in pharmaceutical compositions comprising (a) the compound(s) or pharmaceutically acceptable salts thereof, and (b) a pharmaceutically acceptable carrier. The compounds of this invention may be used in pharmaceutical compositions that include one or more other active pharmaceutical ingredients. The compounds of this invention may also be used in pharmaceutical compositions in which the compound of the present invention or a pharmaceutically acceptable salt thereof is the only active ingredient.

Compounds of the present invention 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 the present invention 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 the present invention. In the treatment of patients who have Type 2 diabetes, insulin resistance, obesity, metabolic syndrome, and co-morbidities that accompany these diseases, more than one drug is commonly administered. The compounds of this invention may generally be administered to a patient who is already taking one or more other drugs for these conditions. Often the compounds will be administered to a patient who is already being treated with one or more antidiabetic compound, such as metformin, sulfonylureas, and/or PPARγ agonists, when the patient's glycemic levels are not adequately responding to treatment.

When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of the present invention is preferred. However, the combination therapy also includes therapies in which the compound of the present invention 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 the present invention.

Examples of other active ingredients/pharmaceutical agents that may be administered in combination with a compound of the present invention, and either administered separately or in the same pharmaceutical composition, include, but are not limited to:

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 with two or more active compounds selected from biguanides, sulfonylureas, HMG-CoA reductase inhibitors, PPARγ agonists, DPP-4 inhibitors, anti-diabetic compounds, anti-obesity compounds and anti-hypertensive agents.

The present invention also provides a method for the treatment or prevention of a G-protein coupled receptor 40 (GPR40) mediated disease, which method comprises administration to a patient in need of such treatment or at risk of developing a GPR40 mediated disease of an amount of a GPR40 agonist and an amount of one or more active ingredients, such that together they give effective relief.

In a further aspect of the present invention, there is provided a pharmaceutical composition comprising a GPR40 agonist and one or more active ingredients, together with at least one pharmaceutically acceptable carrier or excipient.

Thus, according to a further aspect of the present invention there is provided the use of a GPR40 agonist and one or more active ingredients for the manufacture of a medicament for the treatment or prevention of a GPR40 mediated disease. In a further or alternative aspect of the present invention, there is therefore provided a product comprising a GPR40 agonist and one or more active ingredients as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of a GPR40 mediated disease. Such a combined preparation may be, for example, in the form of a twin pack.

It will be appreciated that for the treatment or prevention of diabetes, obesity, hypertension, Metabolic Syndrome, dyslipidemia, cancer, atherosclerosis, and related disorders thereof, a compound of the present invention may be used in conjunction with another pharmaceutical agent effective to treat that disorder.

The present invention also provides a method for the treatment or prevention of diabetes, obesity, hypertension, Metabolic Syndrome, dyslipidemia, cancer, atherosclerosis, and related disorders thereof, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an amount of another pharmaceutical agent effective to threat that disorder, such that together they give effective relief.

The present invention also provides a method for the treatment or prevention of diabetes, obesity, hypertension, Metabolic Syndrome, dyslipidemia, cancer, atherosclerosis, and related disorders thereof, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an amount of another pharmaceutical agent useful in treating that particular condition, such that together they give effective relief.

The term “therapeutically effective amount” means the amount the compound of structural formula I that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disorder being treated. The novel methods of treatment of this invention are for disorders known to those skilled in the art. The term “mammal” includes humans, and companion animals such as dogs and cats.

Methods of Synthesis of the Compounds of the Present Invention:

The following reaction schemes and Examples illustrate methods which may be employed for the synthesis of the compounds of structural formula I described in this invention. These reaction schemes and Examples are provided to illustrate the invention and are not to be construed as limiting the invention in any manner. All substituents are as defined above unless indicated otherwise. Several strategies based upon synthetic transformations known in the literature of organic synthesis may be employed for the preparation of the compounds of structural formula I. The scope of the invention is defined by the appended claims.

The compounds of the present invention can be prepared according to the procedures of the following Examples, using appropriate materials. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. The Examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of protecting groups, as well as of the conditions and processes of the following preparative procedures, can be used to prepare these compounds. It is also understood that whenever a chemical reagent such as a boronic acid or a boronate is not commercially available, such a chemical reagent can be readily prepared following one of numerous methods described in the literature. All temperatures are degrees Celsius unless otherwise noted. Mass spectra (MS) were measured either by electrospray ion-mass spectroscopy (ESMS) or by atmospheric pressure chemical ionization mass spectroscopy (APCI).

List of Abbreviations

Several methods for preparing the compounds of this invention are illustrated in the following Schemes, Intermediates and Examples. Starting materials are either commercially available or made by known procedures in the literature or as illustrated. The present invention further provides processes for the preparation of compounds of structural formula I as defined above. In some cases the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. The following Schemes and Examples are provided for the purpose of illustration only and are not to be construed as limitations on the disclosed invention. All temperatures are degrees Celsius unless otherwise noted.

A mixture of bis-pinacolatodiboron (325 mg, 1.3 mmol), tert-butyl-7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (200 mg, 0.6 mmol), KOAc (189 mg, 1.9 mmol) and PdCl2(dppf) (94 mg, 0.13 mmol) in DMSO (2 mL) was stirred at 60° C. for 3 h. Then the reaction mixture was cooled to rt and diluted with water (30 mL). The resulting mixture was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4and filtered. The filtrate was concentrated under reduced pressure to give the title compound. MS (ESI) m/z: 345 [M-t-butyl+MeCN+H]+.

To a solution of intermediate 3 (320 mg, 0.86 mmol) in DCM (3 mL) was added TFA (0.6 mL, 7.8 mmol) at 0° C. The reaction was stirred at rt for 1.5 h, then concentrated, washed with saturated aqueous NaHCO3(20 mL), and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (20 mL) dried over anhydrous MgSO4and filtered. The filtrate was concentrated to give the title compound. MS (ESI) m/z: 274 [M+H]+.

To a mixture of intermediate 6 (3.00 g, 7.52 mmol) in EtOH (30 mL) and H2O (12 mL) was added iron power (1.26 g, 22.5 mmol) and NH4Cl (4.02 g, 75 mmol). The reaction was stirred at 78° C. for 1.5 h, then concentrated, diluted with EtOAc (50 mL) and filtered. To the filtrate was added water (30 mL), followed by extraction with EtOAc (40 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous MgSO4, filtered and concentrated to give the title compound. MS (ESI) m/z: 295 [M−56+H]+.

To a solution of intermediate 8 (2.6 g, 7.4 mmol) in DCM (15 mL) was added TFA (4 mL, 52 mmol) at 0° C. The reaction was stirred at 20° C. for 1.5 h, then concentrated and saturated aqueous NaHCO3(20 mL) and EtOAc (20 mL) were added. The reaction mixture was extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous MgSO4, filtered and concentrated to the title compound.

Step B: To a solution of tert-butyl 4-(7-(4,4,5-trimethyl-1,3,2-dioxa borolan-2-yl)-quinolin-2-yl)piperidine-1-carboxylate (200 mg, 0.5 mmol, Step A), (E)-methyl 3-cyclopropyl-2-methyl-3-(tosyloxy)acrylate (170 mg, 0.5 mmol) and K2CO3(126 mg, 0.9 mmol) in THF (16 mL) and water (4.0 mL) was added Pd(PPh3)2Cl2(32.0 mg, 0.0456 mmol). The mixture was stirred at 70° C. for 1.5 h under N2. Then water (10 mL) was added and the resulting aqueous layer was extracted with EtOAc (10 mL×3). The combined organic layers were dried over sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by column chromatography (SiO2, PE:ethyl acetate=3:1, v/v) to give the title compound.

To a solution of intermediate 16 (1.58 g, 4.4 mmol) was added BOC-anhydride (1.03 mL, 4.43 mmol) and Et3N (0.927 mL, 6.65 mmol) in DCM (20 mL). The solution was stirred at 20° C. for 30 min. Then the mixture was concentrated under reduced pressure to give rise to the crude product, which was purified by column chromatography (SiO2, PE:ethyl acetate=3:1, v/v) to give the title compound. LCMS (ESI) m/z: 457.3 [M+H]+

To a solution of intermediate 20 (180 mg, 0.31 mmol) in MeOH (10 mL) was added paraformaldehyde (400 mg, 0.31 mmol), H2O (100 μl, 5.5 mmol), and AcOH (100 μl, 1.7 mmol). The mixture was stirred at 20° C. for 10 min, then NaCNBH4(194 mg, 3.1 mmol) was added. The reaction mixture was stirred at 20° C. for 12 h, then H2O (3.0 mL) was added. The aqueous phase was extracted with EtOAc (10 mL×3). The combined organic layers were dried over sodium sulfate, then filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by prep-TLC (SiO2, PE:ethyl acetate=10:1, v/v) to give the title compound. LCMS (ESI) m/z: 597.4 [M+H]+

To a solution of (E)-methyl-3-cyclopropyl-3-(2-(2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-yl)quinolin-7-yl)-2-methylacrylate (2.00 g, 4.28 mmol) in MeOH (18 mL) and DCM (2 mL) was added Josiphos (0.232 g, 0.428 mmol), bis(2-methylallyl)(1,5-cyclooctadiene) ruthenium(II) (0.137 g, 0.428 mmol) and tetrafluoroboric acid-diethyl ether complex (0.277 g, 0.856 mmol) at rt. The mixture was stirred at 80° C. for 48 h under 4 Mpa pressure of hydrogen in an autoclave. Then the mixture was concentrated under reduced pressure and the resulting residue was purified by column chromatography (silica gel, PE to PE:EtOAc=10:1, v/v) to give the title compound. MS (ESI) m/z: 474.6 [M+H]+.

To a solution of intermediate 22 (10.0 g, 40.9 mmol) in DCM (180 mL) was added bromine (2.00 mL, 38.9 mmol) in DCM (30 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h, then the mixture was poured into saturated sodium thiosulfate solution (150 mL). The aqueous layer was separated and extracted with DCM (100 mL×2). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound.

To a solution of intermediate 28 (4.00 g, 9.62 mmol) in EtOH (40 mL) and H2O (10 mL) was added Fe powder (2.15 g, 38.5 mmol) and NH4Cl (4.12 g, 77 mmol) at rt. The mixture was stirred at 90° C. for 2.5 h, then filtered and diluted with H2O (50 mL) and dichloromethane (50 mL). The organic layer was separated. The aqueous layer was extracted with dichloromethane (30 mL×3). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give the title compound. MS (ESI) m/z: 368.1 [M+H]+.

Step A: To a solution of intermediate 30 (1.20 g, 3.24 mmol) and bis-pinacolatodiboron (0.989 g, 3.89 mmol) in dioxane (15 mL) was added dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (0.155 g, 0.324 mmol), tris(dibenzylideneacetone) dipalladium(0) (0.297 g, 0.324 mmol) and KOAc (0.955 g, 9.73 mmol) at rt. The reaction mixture was degassed and refilled with N2three times. The reaction mixture was heated to 105° C. for 8 h. Then the mixture was diluted with H2O (50 mL) and EtOAc (30 mL). The organic layer was separated. The aqueous layer was extracted with EtOAc (30 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product, which was purified by column chromatography (silica gel, PE to PE:EtOAc=10:1, v/v) to give 3-(2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine.

Step A: A mixture of intermediate 4 (22.0 mg, 0.080 mmol) and intermediate 5 (29 mg, 0.09 mmol) in DCM (2 mL) was added sodium triacetoxyborohydride (25.6 mg, 0.121 mmol). The reaction was stirred at 20° C. for 16 h. Then the mixture was diluted with water (30 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous MgSO4and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by prep-TLC (SiO2, PE:EtOAc=5:1, v/v) to give (2S,3R)-methyl 3-(2-(1-(2,5-bis-(trifluoromethyl)-benzyl)piperidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyclopropyl-2-methylpropanoate. LC/MS (ESI) m/z: 583 [M+H]+.

Step A: To a solution of intermediate 33 (80 mg, 0.137 mmol) in MeOH (1 mL), THF (1 mL) and H2O (1 mL) was added LiOH (65.5 mg, 2.74 mmol). The reaction was stirred at 52° C. for 20 h. Then the reaction mixture was acidified with saturated citric acid to adjust the pH to pH=5. The reaction mixture was extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (40 mL), dried over anhydrous MgSO4and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by prep-HPLC to give (2S,3R)-methyl 3-((R or S)-3-(1-(2,5-bis(trifluoromethyl)-benzyl)-piperidin-4-yl)-3,4-dihydro-2H-Benzo-[b][1,4]oxazin-6-yl)-3-cyclopropyl-2-methylpropanoic acid.

Step B: Sodium Salt Formation

To a solution of intermediate 33 (140 mg, 0.239 mmol) in MeOH (5 mL) was added paraformaldehyde (14.3 mg, 0.479 mmol), acetic acid (10 μL, 0.239 mmol), sodium cyanotrihydroborate (45.1 mg, 0.718 mmol) and water (10 μL, 0.239 mmol). The reaction was stirred at 25° C. for 15 h. Then the reaction was concentrated, and diluted with water (20 mL) and EtOAc (30 mL). The mixture was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous MgSO4and filtered. The filtrate was concentrated to give the title compound. MS (ESI) m/z: 599[M+H]+.

(2S,3R)-Methyl 3-((R or S)-3-(1-(2,5-bis(trifluoromethyl)benzyl)piperidin-4-yl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-cyclopropyl-2-methylpropanoate (170 mg, 0.284 mmol) was dissolved in MeOH (1.5 mL), THF (1.5 mL) and H2O (1.5 mL) and treated with LiOH (136 mg, 5.68 mmol). The reaction was stirred at 50° C. for 44 h. Then the reaction mixture was acidified with saturated citric acid to adjust the pH to pH 5. The mixture was extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (40 mL), dried over anhydrous MgSO4and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (neutral) to give (2S,3S)-3-((R or S)-3-(1-(2,5-bis(trifluoromethyl)benzyl)piperidin-4-yl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-cyclopropyl-2-methylpropanoic acid.

Step C: Sodium Salt Formation

TABLE 2The compound of Example 5 was prepared according to the procedure of Example 4 starting from intermediate 34.LC/MS(ESI)observedExampleStructureM.W.Compound Name[M + 1]+5584.59Sodium (2S,3S)-3-((S or R)-3-(1-(2,5-bis(trifluoro- methyl)-benzyl)piperidin- 4-yl)-4-methyl-3,4- dihydro-2H-benzo[b]- [1,4]oxazin-6-yl)-3- cyclopropyl-2-methyl propanoate585.2

To a solution of Intermediate 20 (90.0 mg, 0.154 mmol) in MeOH (1.0 mL), THF (1.0 mL) and water (1.0 mL) was added LiOH (324 mg, 7.72 mmol). The mixture was stirred at 60° C. for 12 h, then ice (2.00 g) was added and the reaction mixture was treated with citric acid to adjust the pH to pH 8. The aqueous layer was extracted with EtOAc (10 mL×3). The combined organic layers were dried over sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by preparative-HPLC (0.05% ammonia hydroxide, v/v) to give the title compound.

Step B: Sodium Salt Formation

TABLE 3The compound of Example 7 was prepared according to the procedure of Example 6 starting from intermediate 19LC/MS(ESI)observedExampleStructureM.W.Compound Name[M + 1]+7568.59Sodium (2S,3R)-3-((S or R)-2-(1-(2,5-bis(tri- fluoromethyl)- benzyl)-piperidin-4- yl)-1,2,3,4- tetrahydroquin-olin-7- yl)-3-cyclo-propyl-2- methyl propanoate569.2

TABLE 4The compound of Example 9 was prepared according to the procedure of Example 8 starting from intermediate 19.LC/MS(ESI)observedExampleStructureM.W.Compound Name[M + 1]+9582.62(2S,3R)-3-((S or R)-2-(1- (2,5-bis(trifluoromethyl)- benzyl)piperidin-4-yl)-1- methyl-1,2,3,4- tetrahydroquinolin-7-yl)- 3-cyclopropyl-2-methyl propanoic acid583.2

Examples 11 and 12

Step A: Chiral Separation

The compounds in the mixture of Example 10 (350 mg, 0.762 mmol) were separated by SFC (Instrument SFC-80-(8) Method Column OJ (250 mm*30 mm, 10 um) Condition Base-EtOH Begin B 45% End B 45% Gradient Time (min) 100% B Hold Time (min) Flow Rate (mL/min) 80 Injections 270) to give (2S,3R)-3-cyclopropyl-3-((R or S)-2-(2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-yl)-1,2,3,4-tetrahydro-quinolin-7-yl)-2-methylpropanoic acid (Example 11), and (2S,3R)-3-cyclopropyl-3-((S or R)-2-(2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-yl)-1,2,3,4-tetrahydroquinolin-7-yl)-2-methylpropanoic acid (Example 12).

Step B: Sodium Salt Formation

TABLE 5The sodium salt of the compound of Example 12 was prepared according to Step B of the procedure of Examples 11 and 12 starting from the free acidLC/MS(ESI)observedExampleStructureM.W.Compound Name[M + 1]+12582.62Sodium (2S,3R)-3-((S or R)-2-(1-(2,5- bis(trifluoromethyl)- benzyl)piperidin-4-yl)-1- methyl-1,2,3,4- tetrahydroquinolin-7-yl)- 3-cyclopropyl-2-methyl propanoate583.2

To a solution of intermediate 26 (200 mg, 0.410 mmol) in MeOH (2 mL), THF (2 mL) and water (1.5 mL) was added LiOH (98 mg, 4.10 mmol) at rt. The mixture was stirred at 50° C. for 24 h, then the pH of the mixture was adjusted to pH 6 with aqueous HCl (2 M). The mixture was treated with water (10 mL) and EtOAc (10 mL). The organic layer was separated. The aqueous layer was extracted with EtOAc (10 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a mixture of diastereomers. MS (ESI) m/z: 474.3 [M+H]+.

Examples 14 and 15

Chiral Separation

To a solution of Intermediate 31 (200 mg, 0.410 mmol) in MeOH (2 mL), THF (2 mL) and water (1.5 mL) was added LiOH (98 mg, 4.10 mmol) at rt. The mixture was stirred at 50° C. for 24 h, then the pH of the mixture was adjusted to pH=6 with aqueous HCl (2M). The mixture was diluted with water (10 mL) and EtOAc (10 mL). The organic layer was separated. The aqueous layer was extracted with EtOAc (10 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a mixture of diastereomers. MS (ESI) m/z: 474.3 [M+H]+.

Examples 17 and 18

Step A: Chiral Separation

Step B: Sodium Salt of Example 17

Step C: Sodium Salt of Example 18

Examples 20 and 21

Step A: Chiral Separation

Step B: Sodium Salt of Example 20

Step C: Sodium Salt of Example 21

Example of a Pharmaceutical Composition

As a specific embodiment of an oral pharmaceutical composition, a 100 mg potency tablet is composed of 100 mg of any one of Examples, 268 mg microcrystalline cellulose, 20 mg of croscarmellose sodium, and 4 mg of magnesium stearate. The active, microcrystalline cellulose, and croscarmellose are blended first. The mixture is then lubricated by magnesium stearate and pressed into tablets.

Biological Assays

Generation of GPR40-Expressing Cells:

Human GPR40 stable cell-lines were generated in HEK cells. The expression plasmids were transfected using lipofectamine (Life Technologies) following manufacturer's instructions. Stable cell-lines were generated following drug selection and single cell cloning.

The assay was performed in 384-well format. HEK cells stably expressing human GPR40 were plated at 7500 cells per well in growth medium (DMEM/10% fetal calf serum). Cell plates were then incubated 16 hours at 37 degrees in a 5% CO2incubator. Measurement of Inositol Phosphate Turnover (IP1) was performed using the CisBio IP-One kit (Part number 62IPAPEB). After the 16 hour incubation, the growth media was removed by centrifugation using the BlueWasher (AusWasher GUI Ver. v1.0.1.8) Protocol #21-“Light Dry” and 10 ul of stimulation buffer (prepared as described in the kit) was added to each well. In a separate plate, compounds were diluted in DMSO (200-fold over the final concentration in the assay well) and 50 nl was acoustically transferred to the appropriate well in the assay cell plate. The plates were then incubated for 60 minutes at 37 degrees in a 5% CO2incubator. 10 ul of detection buffer (also prepared as described in the IP-One kit) was added to each well and the plates were incubated at room temperature for 60 minutes in the dark. The plates were then read in a Perkin Elmer EnVision or equivalent reader able to measure FRET. Fluorescent ratio of emission at 665 and 620 nm was then converted to IP1 concentration by back calculating from an IP1 standard curve prepared at the time of the assay. Data was normalized to % activity using a reference compound and EC50s determined using a standard 4-paramter fit.

The compounds of the present invention, including the compounds in Examples 1-21, have EC50values less than 6000 nanomolar (nM) in the Inositol Phophate Turnover Assay 1 described above. Inositol Phophate Turnover (IP1) Assay 1 EC50values for specific compounds are shown in Table 1.

Male C57BL/6N mice (7-12 weeks of age) are housed 10 per cage and given access to normal diet rodent chow and water ad libitum. Mice are randomly assigned to treatment groups and fasted 4 to 6 h. Baseline blood glucose concentrations are determined by glucometer from tail nick blood. Animals are then treated orally with vehicle (0.25% methylcellulose) or test compound. Blood glucose concentration is measured at a set time point after treatment (t=0 min) and mice are then intraperitoneally-challenged with dextrose (2 g/kg). One group of vehicle-treated mice is challenged with saline as a negative control. Blood glucose levels are determined from tail bleeds taken at 20, 40, 60 min after dextrose challenge. The blood glucose excursion profile from t=0 to t=60 min is used to integrate an area under the curve (AUC) for each treatment. Percent inhibition values for each treatment are generated from the AUC data normalized to the saline-challenged controls.

While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention. For example, effective dosages other than the particular dosages as set forth herein above may be applicable as a consequence of variations in responsiveness of the mammal being treated for any of the indications with the compounds of the invention indicated above. The specific pharmacological responses observed may vary according to and depending upon the particular active compounds selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be defined by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.