Antidiabetic heterocyclic compounds

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.

G-protein-coupled receptor 40 (GPR40) agonists are disclosed in WO 2007/136572, WO 2007/136573, WO 2009/058237, WO 2006/083612, WO 2006/083781, WO 2010/085522, WO 2010/085525, WO 2010/085528, WO 2010/091176, WO 2004/041266, EP 2004/1630152, WO 2004/022551, WO 2005/051890, WO 2005/051373, EP 2004/1698624, WO 2005/086661, WO 2007/213364, WO 2005/063729, WO 2005/087710, WO 2006/127503, WO 2007/1013689, WO 2006/038738, WO 2007/033002, WO 2007/106469, WO 2007/123225, WO 2008/001931, WO 2008/030520, WO 2008/030618, WO 2008/054674, WO 2008/054675, WO 2008/066097, WO 2008/130514, WO 2009/048527, WO 2009/058237, WO 2009/111056, WO 2010/004347, WO 2010/045258, WO 2010/085522, WO 2010/085525, WO 2010/085528, WO 2010/091176, WO 2010/143733, WO 2012/0004187, WO 2012/072691, WO 2013/122028, WO2013/122029, WO2014/130608, WO2016022448, WO2016022742 and GB 2498976.

GPR40 agonists are also disclosed in Walsh et al., Bioorganic & Medicinal Chemistry Letters (2011), 21(11), 3390-3394; Zhou et al., Bioorganic & Medicinal Chemistry Letters (2010), 20(3), 1298-1301; Tan et al., Diabetes (2008), 57(8), 2211-2219; Houze et al., Bioorganic & Medicinal Chemistry Letters (2012), 22(2), 1267-1270; Brown et al., ACS Medicinal Chemistry Letters (2012), 3(9), 726-730; Lin et al., PloS One (2011), 6(11), e27270; Lou et al., PloS One (2012), 7(10), e46300; Lin et al., Molecular Pharmacology (2012), 82(5), 843-859; Yang, Lihu, Abstracts of Papers, 239th ACS Meeting, San Francisco, Calif., USA Mar. 21-25, 2010 MEDI-313; and Houze et al., Abstracts of Papers, 243rd ACS National Meeting & Exposition, San Diego, Calif., USA Mar. 25-29, 2012, MEDI-265.

SUMMARY OF THE INVENTION

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

embedded image

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:

embedded image

or a pharmaceutically acceptable salt thereof; wherein

“a” is a single bond or a double bond, provided that if “a” is a double bond, then R⁶is absent and Y is selected from the group consisting of: C—R^g, —C—OC_1-6alkyl, CF and N;

T is selected from the group consisting of:

(1) CH,

(2) N, and

(3) N-oxide;

U is selected from the group consisting of:

(1) CR¹,

(2) N, and

(3) N-oxide;

V is selected from the group consisting of:

(1) CR²,

(2) N, and

(3) N-oxide;

W is selected from the group consisting of:

(1) CH,

(2) N, and

(3) N-oxide,

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

Y is selected from the group consisting of:

(1) oxygen,

(2) sulfur,

(3) —CR^gR^g,

(4) C═O,

(5) —C(R^g)OC_1-6alkyl,

(6) —CF₂, and

(7) —NR^c;

A is selected from the group consisting of:

(1) —C_1-6alkyl-N(Rⁿ)—,

(2) —C_1-6alkyl-O—;

(3) —C_1-6alkyl-C_7-15cycloalkyl,

(4) —C_1-6alkyl-C_6-14cycloheteroalkyl,

(5) —C_7-15cycloalkyl, and

(6) —C_6-14cycloheteroalkyl,

wherein A is unsubstituted or substituted with one to five substituents selected from R^a;

B is selected from the group consisting of:

(1) hydrogen,

(2) aryl,

(3) aryl-O—,

(4) aryl-C_1-10alkyl-,

(5) aryl-C_1-10alkyl-O—,

(6) C_3-6cycloalkyl,

(7) C_3-6cycloalkyl-C_1-10alkyl-,

(8) C_3-6cycloalkyl-C_1-10alkyl-O—,

(9) C_3-6cycloalkenyl,

(10) C_3-6cycloalkenyl-C_1-10alkyl-,

(11) C_3-6cycloalkenyl-C_1-10alkyl-O—,

(12) C_2-5cycloheteroalkyl,

(13) C_3-6cycloheteroalkyl-C_1-10alkyl-,

(14) C_3-6cycloheteroalkyl-C_1-10alkyl-O—,

(15) heteroaryl,

(16) heteroaryl-O—,

(17) heteroaryl-C_1-10alkyl-, and

(18) heteroaryl-C_1-10alkyl-O—,

wherein B is unsubstituted or substituted with one to five substituents selected from R^b;

R¹and R²are each independently selected from:

(1) a bond,

(2) hydrogen,

(3) halogen,

(4) —OR^k,

(5) —CN,

(6) —C_1-6alkyl,

(7) —C_3-6cycloalkyl,

(8) —C_3-6cycloalkyl-C_1-3alkyl-,

(9) —C_2-6cycloheteroalkyl, and

(10) —C_2-6cycloheteroalkyl-C_1-3alkyl-,

wherein each —OR^k, alkyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with one to three substituents selected from R^L, and wherein one of R¹and R²is selected from a bond, —OR^k, —C_1-6alkyl, —C_3-6cycloalkyl, —C_3-6cycloalkyl-C_1-3alkyl-, —C_2-6cycloheteroalkyl, and —C_2-6cycloheteroalkyl-C_1-3alkyl-, wherein the bond, —OR^k, —C_1-6alkyl, —C_3-6cycloalkyl, —C_3-6cycloalkyl-C_1-3alkyl-, —C_2-6cycloheteroalkyl, and —C_2-6cycloheteroalkyl-C_1-3alkyl- is substituted with a substituent selected from R⁷;

R³is selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) —OR^e,

(4) —CN,

(5) —C_1-6alkyl,

(6) —C_3-6cycloalkyl, and

(7) —C_3-6cycloalkyl-C_1-3alkyl-,

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

R⁴is selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) OR^e,

(4) C_1-6alkyl,

(5) C_1-6alkyl-O—,

(6) C_3-6cycloalkyl,

(7) C_3-6cycloalkyl-O—,

(8) C_3-6cycloalkyl-C_1-10alkyl-,

(9) C_3-6cycloalkyl-C_1-10alkyl-O—,

(10) C_2-5cycloheteroalkyl,

(11) C_2-5cycloheteroalkyl-O—,

(12) C_2-5cycloheteroalkyl-C_1-10alkyl-,

(13) C_2-5cycloheteroalkyl-C_1-10alkyl-O—,

(14) aryl,

(15) aryl-O—,

(16) aryl-C_1-10alkyl-,

(17) heteroaryl,

(18) heteroaryl-O—, and

(19) heteroaryl-C_1-10alkyl-,

wherein each alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three substituents selected from R^j,

provided that when R⁴is selected from the group consisting of:

(1) OR^e,

(2) C_1-6alkyl-O—,

(3) C_3-6cycloalkyl-O—,

(4) C_3-6cycloalkyl-C_1-10alkyl-O—,

(5) C_2-5cycloheteroalkyl-O—,

(6) C_2-5cycloheteroalkyl-C_1-10alkyl-O—,

(7) aryl-O—, and

(8) heteroaryl-O—,

then Y is selected from the group consisting of:

(1) —CR^gR^g,

(2) C═O,

(3) —C(R^g)OC_1-6alkyl, and

(4) —CF₂;

R⁵is selected from the group consisting of:

(1) hydrogen,

(2) —C_1-6alkyl, and

(3) —C_3-6cycloalkyl,

wherein each alkyl and cycloalkyl is unsubstituted or substituted with one to three substituents selected from R^j;

R⁶is selected from the group consisting of:

(1) hydrogen,

(2) —C_1-6alkyl, and

(3) —C_3-6cycloalkyl,

wherein each alkyl and cycloalkyl is unsubstituted or substituted with one to three substituents selected from R^j;

R⁷is selected from the group consisting of:

(1) —CO₂R⁸,

(2) —C_1-6alkyl-CO₂R⁸,

(3) —C_1-6alkyl-CONHSO₂R^m,

(4) —C_1-6alkyl-SO₂NHCOR^m,

(5) —C_1-6alkyl-tetrazolyl, and

(6) a cycloheteroalkyl selected from the group consisting of:

embedded image

R⁸is selected from the group consisting of:

(1) hydrogen,

(2) —C_1-6alkyl,

(3) —C_3-6cycloalkyl, and

(4) aryl-C_1-6-alkyl,

wherein each alkyl, cycloalkyl and aryl is unsubstituted or substituted with one to three substituents selected from R^j;

R^ais selected from the group consisting of:

(1) —C_1-6alkyl,

(2) halogen,

(3) —OR^e,

(4) —NR^cS(O)_nR^e,

(5) —S(O)_nR^e,

(6) —S(O)_nNR^cR^d,

(7) —NR^cR^d,

(8) —C(O)R^e,

(9) —OC(O)R^e,

(10) —CO₂R^e,

(11) —CN,

(12) —C(O)NR^cR^d,

(13) —NR^cC(O)R^e,

(14) —NR^cC(O)OR^e,

(15) —NR^cC(O)NR^cR^d,

(16) —CF₃,

(17) —OCF₃,

(18) —OCHF₂,

(19) aryl,

(20) heteroaryl,

(21) —C_3-6cycloalkyl,

(22) —C_3-6cycloalkenyl, and

(23) —C_2-5cycloheteroalkyl,

wherein each alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with —C_1-6alkyl, halogen, —O—C_1-6alkyl and —CF₃;

R^bis independently selected from the group consisting of:

(1) —C_1-10alkyl,

(2) —C_2-10alkenyl,

(3) —CF₃,

(4) halogen,

(5) —CN,

(6) —OH,

(7) —OC_1-10alkyl,

(8) —OC_2-10alkenyl,

(9) —O(CH₂)_pOC_1-10alkyl,

(10) —O(CH₂)_pC_3-6cycloalkyl,

(11) —O(CH₂)_pC_3-6cycloalkyl-C_1-10alkyl-,

(12) —O(CH₂)_pC_2-5cycloheteroalkyl,

(13) —O(CH₂)_pC_2-5cycloheteroalkyl-C_1-10alkyl-,

(14) —O-aryl,

(15) —O-heteroaryl,

(16) —O-aryl-C_1-10alkyl-,

(17) —O-heteroaryl-C_1-10alkyl-,

(18) —O(CH₂)_pNR^cS(O)_mR^e,

(19) —O(CH₂)_pS(O)_mR^e,

(20) —O(CH₂)_pS(O)_mNR^cR^d,

(21) —O(CH₂)_pNR^cR^d,

(22) —C(O)R^e,

(23) —OC(O)R^e,

(24) —CO₂R^e,

(25) —C(O)NR^cR^d,

(26) —NR^cC(O)R^e,

(27) —NR^cC(O)OR^e,

(28) —NR^cC(O)NR^cR^d,

(29) —O(CH₂)_pO—C_3-6cycloalkyl,

(30) —O(CH₂)_pO—C_2-5cycloheteroalkyl,

(31) —OCF₃,

(32) —OCHF₂,

(33) —(CH₂)_pC_3-6cycloalkyl,

(34) —(CH₂)_pC_2-5cycloheteroalkyl,

(35) aryl,

(36) heteroaryl,

(37) aryl-C_1-10alkyl-, and

(38) heteroaryl-C_1-10alkyl-,

wherein each CH, CH₂, alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with —C_1-6alkyl, halogen, —O—C_1-6alkyl and —CF₃;

R^cand R^dare each independently selected from the group consisting of:

(1) hydrogen,

(2) C_1-10alkyl,

(3) C_2-10alkenyl,

(4) C_3-6cycloalkyl,

(5) C_3-6cycloalkyl-C_1-10alkyl-,

(6) C_2-5cycloheteroalkyl,

(7) C_2-5cycloheteroalkyl-C_1-10alkyl-,

(8) aryl,

(9) heteroaryl,

(10) aryl-C_1-10alkyl-, and

(11) heteroaryl-C_1-10alkyl-,

wherein each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three substituents independently selected from R^f;

each R^eis independently selected from the group consisting of:

(1) hydrogen,

(2) —C_1-10alkyl,

(3) —C_2-10alkenyl,

(4) —C_3-6cycloalkyl,

(5) —C_3-6cycloalkyl-C_1-10alkyl-,

(6) —C_2-5cycloheteroalkyl,

(7) —C_2-5cycloheteroalkyl-C_1-10alkyl-,

(8) aryl,

(9) aryl-C_1-10alkyl-,

(10) heteroaryl, and

(11) heteroaryl-C_1-10alkyl-,

wherein each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three substituents selected from R^h;

each R^fis selected from the group consisting of:

(1) halogen,

(2) C_1-10alkyl,

(3) —OH,

(4) —O—C_1-4alkyl,

(5) —S(O)_m—C_1-4alkyl,

(6) —CN,

(7) —CF₃,

(8) —OCHF₂, and

(9) —OCF₃,

wherein each alkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, halogen, C_1-6alkyl, cyano and S(O)₂C_1-6alkyl;

each R^gis selected from the group consisting of:

(1) hydrogen,

(2) —C(O)R^e, and

(3) —C_1-10alkyl,

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

each R^his selected from the group consisting of:

(1) halogen,

(2) C_1-10alkyl,

(3) —OH,

(4) —O—C_1-4alkyl,

(5) —S(O)_m—C_1-4alkyl,

(6) —CN,

(7) —CF₃,

(8) —OCHF₂, and

(9) —OCF₃,

wherein each alkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, halogen, C_1-6alkyl, cyano and S(O)₂C_1-6alkyl;

Rⁱis independently selected from the group consisting of:

(1) —C_1-6alkyl,

(2) —OR^e,

(3) —NR^cS(O)_mR^e,

(4) halogen,

(5) —S(O)_mR^e,

(6) —S(O)_mNR^cR^d,

(7) —NR^cR^d,

(8) —C(O)R^e,

(9) —OC(O)R^e,

(10) —CO₂R^e,

(11) —CN,

(12) —C(O)NR^cR^d,

(13) —NR^cC(O)R^e,

(14) —NR^cC(O)OR^e,

(15) —NR^cC(O)NR^cR^d,

(16) —CF₃,

(17) —OCF₃,

(18) —OCHF₂,

(19) —C_3-6cycloalkyl, and

(20) —C_2-5cycloheteroalkyl;

R^jis independently selected from the group consisting of:

(1) —C_1-6alkyl,

(2) —OR^e,

(3) —NR^cS(O)_mR^e,

(4) halogen,

(5) —S(O)_mR^e,

(6) —S(O)_mNR^cR^d,

(7) —NR^cR^d,

(8) —C(O)R^e,

(9) —OC(O)R^e,

(10) —CO₂R^e,

(11) —CN,

(12) —C(O)NR^cR^d,

(13) —NR^cC(O)R^e,

(14) —NR^cC(O)OR^e,

(15) —NR^cC(O)NR^cR^d,

(16) —CF₃,

(17) —OCF₃,

(18) —OCHF₂,

(19) —C_3-6cycloalkyl, and

(20) —C_2-5cycloheteroalkyl;

each R^kis independently selected from the group consisting of:

(1) hydrogen,

(2) —C_1-6alkyl,

(3) —C_1-6alkyl-SO₂C_1-6alkyl,

(4) —CF₃, and

(5) —CHF₂,

wherein each alkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, —OC_1-6alkyl, halogen, cyano, and —S(O)₂C_1-6alkyl;

each R^Lis independently selected from the group consisting of:

(1) —CO₂C_1-6alkyl,

(2) —C_1-10alkyl,

(3) —C_2-10alkenyl,

(4) —C_2-10alkynyl,

(5) —C_3-6cycloalkyl,

(6) —C_2-6cycloheteroalkyl,

(7) aryl, and

(8) heteroaryl,

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with 1-4 substituents selected from C_1-6alkyl, halogen, and —OC_1-6alkyl;

each R^mis independently selected from the group consisting of:

(1) —C_1-10alkyl,

(2) —C_2-10alkenyl,

(3) —C_3-6cycloalkyl,

(4) —C_3-6cycloalkyl-C_1-10alkyl-,

(5) —C_2-5cycloheteroalkyl,

(6) —C_2-5cycloheteroalkyl-C_1-10alkyl-,

(7) aryl,

(8) heteroaryl,

(9) aryl-C_1-10alkyl-, and

(10) heteroaryl-C_1-10alkyl-;

Rⁿis selected from the group consisting of:

(1) hydrogen, and

(2) —C_1-10alkyl,

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

each n is independently selected from: 0, 1 or 2;

each m is independently selected from: 0, 1 or 2; and

each p is independently selected from: 0, 1, 2, 3, 4, 5 or 6.

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, “a” is a single bond.

In another embodiment of the present invention, “a” is a single bond, and Y is selected from the group consisting of: oxygen, sulfur, —CR^gR^g, C═O, —C(R^g)OC_1-6alkyl, —CF₂, and —NR^c. In another embodiment of the present invention, “a” is a single bond and R⁶is present. In another embodiment of the present invention, “a” is a double bond and R⁶is absent.

In another embodiment of the present invention, “a” is a double bond, R⁶is absent and Y is selected from the group consisting of: C—R^g, CF, and N. In a class of this embodiment, Y is selected from the group consisting of: —CH, —CF, and —N. In another class of this embodiment, Y is selected from the group consisting of: —C—R^g. In a subclass of this class, Y is —CH.

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

In another embodiment of the present invention, U is selected from the group consisting of: CR¹, N and N-oxide. In a class of this embodiment, U is selected from the group consisting of: CR¹and N. In another class of this embodiment, U is CR¹. In another class of this embodiment, U is N or N-oxide. In another class of this embodiment, U is N.

In another class of this embodiment, U is N-oxide.

In another embodiment of the present invention, V is selected from the group consisting of: CR², N and N-oxide. In a class of this embodiment, V is selected from the group consisting of: CR²and N. In another class of this embodiment, V is CR². In another class of this embodiment, V is N or N-oxide. In another class of this embodiment, V is N. In another class of this embodiment, V is N-oxide.

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

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

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

In another embodiment of the present invention, T is N or N-oxide, U is CR¹, V is CR², and W is N or N-oxide. In a class of this embodiment, T is N, U is CR¹, V is CR², and W is N. In another embodiment of the present invention, T is N or N-oxide, U is CR¹, V is CR², and W is N or N-oxide; and R³is absent. In a class of this embodiment, 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 or N-oxide, V is CR², and W is N or N-oxide. In a class of this embodiment, 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 or N-oxide, and W is N or N-oxide. In a class of this embodiment, 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, N or N-oxide.

In another embodiment of the present invention, Y is selected from the group consisting of: oxygen and sulfur.

In another embodiment of the present invention, Y is selected from the group consisting of: —CR^gR^g, C═O, —CF₂, and —NR^c. In a class of this embodiment, Y is selected from the group consisting of: —CH₂, C═O, —CF₂, and —NH. In another embodiment of the present invention, Y is selected from the group consisting of: —CR^gR^g, C═O, and —CF₂. In a class of this embodiment, Y is selected from the group consisting of: —CH₂, C═O, and —CF₂. In another embodiment of the present invention, Y is selected from the group consisting of: —CR^gR^g. In a class of this embodiment, Y is —CH₂.

In another embodiment of the present invention, A is selected from the group consisting of: —C_1-6alkyl-N(Rⁿ)—, —C_1-6alkyl-C_7-15cycloalkyl, —C_1-6alkyl-C_6-14cycloheteroalkyl, —C_7-15cycloalkyl, and —C_6-14cycloheteroalkyl, wherein A is unsubstituted or substituted with one to five substituents selected from R^a.

In another embodiment of the present invention, A is selected from the group consisting of: —C_1-6alkyl-N(Rⁿ)—, —C_1-6alkyl-C_6-14cycloheteroalkyl, and —C_6-14cycloheteroalkyl, wherein A is unsubstituted or substituted with one to five substituents selected from R^a. In a class of this embodiment, A is selected from the group consisting of: —CH₂CH₂—N(CH₃)—, —CH₂-piperidine, 2-azaspiro[3.3]heptane, 3-oxa-7-azabicyclo[3.3.1]nonane, 8-azabicyclo[3.2.1]octane, 2-aza-bicyclo-[2.2.1]heptane, 3-azabicyclo[3.2.1]octane, 9-azabicyclo[3.3.1]nonane, and 2-azabicyclo[3.1.1]heptane, wherein A is unsubstituted or substituted with one to five substituents selected from R^a. In another class of this embodiment, A is selected from the group consisting of: —CH₂CH₂—N(CH₃)—, —CH₂-piperidine, 2-azaspiro[3.3]heptane, 3-oxa-7-azabicyclo[3.3.1]nonane, 8-azabicyclo[3.2.1]octane, 2-aza-bicyclo-[2.2.1]heptane, 3-azabicyclo[3.2.1]octane, 9-azabicyclo[3.3.1]nonane, and 2-azabicyclo[3.1.1]heptane.

In another embodiment of the present invention, A is selected from the group consisting of: —C_1-6alkyl-C_6-14cycloheteroalkyl, and —C_6-14cycloheteroalkyl, wherein A is unsubstituted or substituted with one to five substituents selected from R^a. In a class of this embodiment, A is selected from the group consisting of: —CH₂-piperidine, 2-azaspiro[3.3]heptane, 3-oxa-7-azabicyclo[3.3.1]nonane, 8-azabicyclo[3.2.1]octane, 2-aza-bicyclo-[2.2.1]heptane, 3-azabicyclo[3.2.1]octane, 9-azabicyclo[3.3.1]nonane, and 2-azabicyclo[3.1.1]heptane, wherein A is unsubstituted or substituted with one to five substituents selected from R^a. In another class of this embodiment, A is selected from the group consisting of: —CH₂-piperidine, 2-azaspiro[3.3]heptane, 3-oxa-7-azabicyclo[3.3.1]nonane, 8-azabicyclo[3.2.1]octane, 2-aza-bicyclo-[2.2.1]heptane, 3-azabicyclo[3.2.1]octane, 9-azabicyclo[3.3.1]nonane, and 2-azabicyclo[3.1.1]heptane.

In another embodiment of the present invention, A is —C_1-6alkyl-C_6-14cycloheteroalkyl, wherein A is unsubstituted or substituted with one to five substituents selected from R^a. In a class of this embodiment, A is —CH₂-piperidine-, wherein A is unsubstituted or substituted with one to five substituents selected from R^a. In another class of this embodiment, A is —CH₂-piperidine-.

In another embodiment of the present invention, A is —C_6-14cycloheteroalkyl-, wherein A is unsubstituted or substituted with one to five substituents selected from R^a. In a class of this embodiment, A is selected from the group consisting of: 2-azaspiro[3.3]heptane, 3-oxa-7-azabicyclo[3.3.1]nonane, 8-azabicyclo[3.2.1]octane, 2-aza-bicyclo-[2.2.1]heptane, 3-azabicyclo[3.2.1]octane, 9-azabicyclo[3.3.1]nonane, and 2-azabicyclo[3.1.1]heptane, wherein A is unsubstituted or substituted with one to five substituents selected from R^a. In another class of this embodiment, A is selected from the group consisting of: 2-azaspiro[3.3]heptane, 3-oxa-7-azabicyclo[3.3.1]nonane, 8-azabicyclo[3.2.1]octane, 2-aza-bicyclo-[2.2.1]heptane, 3-azabicyclo[3.2.1]octane, 9-azabicyclo[3.3.1]nonane, and 2-azabicyclo[3.1.1]heptane.

In another embodiment of the present invention, A is selected from the group consisting of: —C_1-6alkyl-N(Rⁿ)—, and —C_6-14cycloheteroalkyl-, wherein A is unsubstituted or substituted with one to five substituents selected from R^a. In a class of this embodiment, A is unsubstituted or substituted with one to three substituents selected from R^a. In another class of this embodiment, A is unsubstituted or substituted with one to two substituents selected from R^a.

In another embodiment of the present invention, A is selected from the group consisting of —(CH₂)₂—N(CH₃)—, 2-aza-bicyclo[2.2.1]heptane, and 2-azabicyclo-[3.1.1]heptane, wherein A is unsubstituted or substituted with one to five substituents selected from R^a. In a class of this embodiment, A is unsubstituted or substituted with one to three substituents selected from R^a. In another class of this embodiment, A is unsubstituted or substituted with one to two substituents selected from R^a.

In another embodiment of the present invention, A is —C_1-6alkyl-N(Rⁿ)—, wherein A is unsubstituted or substituted with one to five substituents selected from R^a. In a class of this embodiment, A is unsubstituted or substituted with one to three substituents selected from R^a. In another class of this embodiment, A is unsubstituted or substituted with one to two substituents selected from R^a. In another class of this embodiment, A is —(CH₂)₂—N(CH₃)—, wherein A is unsubstituted or substituted with one to five substituents selected from R^a. In a subclass of this class, A is unsubstituted or substituted with one to three substituents selected from R^a. In another subclass of this class, A is unsubstituted or substituted with one to two substituents selected from R^a.

In another embodiment of the present invention, A is —C_6-14cycloheteroalkyl-, wherein A is unsubstituted or substituted with one to five substituents selected from R^a. In a class of this embodiment, A is unsubstituted or substituted with one to three substituents selected from R^a. In another class of this embodiment, A is unsubstituted or substituted with one to two substituents selected from R^a. In another class of this embodiment, A is 2-aza-bicyclo[2.2.1]heptane or 2-azabicyclo[3.1.1]heptane, wherein A is unsubstituted or substituted with one to five substituents selected from R^a. In a subclass of this class, A is unsubstituted or substituted with one to three substituents selected from R^a. In another subclass of this class, A is unsubstituted or substituted with one to two substituents selected from R^a.

In another embodiment of the present invention, B is selected from the group consisting of aryl, aryl-O—, aryl-C_1-10alkyl-, aryl-C_1-10alkyl-O—, C_3-6cycloalkyl, C_3-6cycloalkyl-C_1-10alkyl-, C_3-6cycloalkyl-C_1-10alkyl-O—, C_3-6cycloalkenyl, C_3-6cycloalkenyl-C_1-10alkyl-, C_3-6cycloalkenyl-C_1-10alkyl-O—, C_2-5cycloheteroalkyl, C_3-6cycloheteroalkyl-C_1-10alkyl-, C_3-6cycloheteroalkyl-C_1-10alkyl-O—, heteroaryl, heteroaryl-O—, heteroaryl-C_1-10alkyl-, and heteroaryl-C_1-10alkyl-O—, wherein B is unsubstituted or substituted with one to five substituents selected from R^b.

In another embodiment of the present invention, B is selected from the group consisting of aryl, aryl-C_1-10alkyl-, C_3-6cycloalkyl, C_3-6cycloalkyl-C_1-10alkyl-, C_3-6cycloalkenyl, C_3-6cycloalkenyl-C_1-10alkyl-, C_2-5cycloheteroalkyl, C_3-6cycloheteroalkyl-C_1-10alkyl-, heteroaryl and heteroaryl-C_1-10alkyl-, wherein B is unsubstituted or substituted with one to five substituents selected from R^b.

In another embodiment of the present invention, B is selected from the group consisting of: aryl, aryl-C_1-10alkyl-, heteroaryl, and heteroaryl-C_1-10alkyl-, wherein B is unsubstituted or substituted with one to five substituents selected from R^b.

In another embodiment of the present invention, B is selected from the group consisting of: aryl-C_1-10alkyl-, and heteroaryl, wherein B is unsubstituted or substituted with one to five substituents selected from R^b. In a class of this embodiment, B is selected from the group consisting of: phenyl-CH₂—, and pyridine, wherein B is unsubstituted or substituted with one to five substituents selected from R^b.

In another embodiment of the present invention, B is heteroaryl, wherein B is unsubstituted or substituted with one to five substituents selected from R^b. In a class of this embodiment, B is pyridine, wherein pyridine is unsubstituted or substituted with one to five substituents selected from R^b.

In another embodiment of the present invention, B is aryl-C_1-10alkyl-, wherein B is unsubstituted or substituted with one to five substituents selected from R^b. In a class of this embodiment, B is unsubstituted or substituted with one to three substituents selected from R^b. In another class of this embodiment, B is unsubstituted or substituted with one to two substituents selected from R^b.

In another embodiment of the present invention, B is phenyl-C_1-10alkyl-, wherein B is unsubstituted or substituted with one to five substituents selected from R^b. In a class of this embodiment, B is unsubstituted or substituted with one to three substituents selected from R^b. In another class of this embodiment, B is unsubstituted or substituted with one to two substituents selected from R^b.

In another embodiment of the present invention, B is phenyl-CH₂—, wherein B is unsubstituted or substituted with one to five substituents selected from R^b. In a class of this embodiment, B is unsubstituted or substituted with one to three substituents selected from R^b. In another class of this embodiment, B is unsubstituted or substituted with one to two substituents selected from R^b.

In another embodiment of the present invention, B is aryl-C_1-10alkyl-, wherein aryl and alkyl are unsubstituted or substituted with one to five substituents selected from R^b. In a class of this embodiment, B is phenyl-CH₂—, wherein B is unsubstituted or substituted with one to five substituents selected from R^b.

In another embodiment of the present invention, B is heteroaryl, wherein heteroaryl is unsubstituted or substituted with one to five substituents selected from R^b. In a class of this embodiment, B is pyridine, wherein pyridine is unsubstituted or substituted with one to five substituents selected from R^b.

In another embodiment of the present invention, R¹and R²are each independently selected from: a bond, hydrogen, —OR^k, and —C_1-6alkyl, wherein each —OR^kand alkyl is unsubstituted or substituted with one to three substituents selected from R^L, and wherein one of R¹and R²is selected from a bond, —OR^k, and —C_1-6alkyl, wherein the bond, —OR^k, -and —C_1-6alkyl is substituted with R⁷.

In another embodiment of the present invention, R¹and R²are each independently selected from: hydrogen, —OR^k, and —C_1-6alkyl, wherein each —OR^kand alkyl is unsubstituted or substituted with one to three substituents selected from R^L, and wherein one of R¹and R²is selected from —OR^kand —C_1-6alkyl, wherein —OR^kand —C_1-6alkyl is substituted with a substituent selected from R⁷.

In another embodiment of the present invention, R¹and R²are each independently selected from: a bond, hydrogen, and —C_1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^L, and wherein one of R¹and R²is selected from a bond and —C_1-6alkyl, wherein the bond and —C_1-6alkyl is substituted with a substituent selected from R⁷.

In another embodiment of the present invention, R¹and R²are each independently selected from: hydrogen and —C_1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^L, and wherein at least one of R¹and R²is C_1-6alkyl, wherein —C_1-6alkyl is substituted with a substituent selected from R⁷.

In another embodiment of the present invention, R¹and R²are each independently selected from: hydrogen and —C_1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^L, and wherein one of R¹and R²is C_1-6alkyl, wherein —C_1-6alkyl is substituted with a substituent selected from R⁷.

In another embodiment of the present invention, R¹and R²are each independently selected from: hydrogen and —C₂alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^L, and wherein at least one of R¹and R²is C₂alkyl, wherein —C₂alkyl is substituted with a substituent selected from R⁷.

In another embodiment of the present invention, R¹and R²are each independently selected from: hydrogen and —C₂alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^L, and wherein one of R¹and R²is C₂alkyl, wherein —C₂alkyl is substituted with a substituent selected from R⁷.

In another embodiment of the present invention, R¹and R²are each independently selected from: hydrogen and —C₂alkyl, wherein each alkyl is substituted with one to three substituents selected from R^L, and wherein at least one of R¹and R²is C₂alkyl, wherein —C₂alkyl is substituted with a substituent selected from R⁷.

In another embodiment of the present invention, R¹and R²are each independently selected from: hydrogen and —C₂alkyl, wherein each alkyl is substituted with one to three substituents selected from R^L, and wherein one of R¹and R²is C₂alkyl, wherein —C₂alkyl is substituted with a substituent selected from R⁷.

In another embodiment, R¹is independently selected from: a bond, hydrogen, halogen, —OR^k, —CN, —C_1-6alkyl, —C_3-6cycloalkyl, —C_3-6cycloalkyl-C_1-3alkyl-, —C_2-6cycloheteroalkyl, and —C_2-6cycloheteroalkyl-C_1-3alkyl-, wherein each alkyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with one to three substituents selected from R^L, and wherein R¹is unsubstituted or substituted with a substituent selected from R⁷. In a class of this embodiment, R¹is substituted with a substituent selected from R⁷.

In another embodiment of the present invention, R¹is selected from: a bond, hydrogen, —OR^kand —C_1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^L, and wherein R¹is unsubstituted or substituted with a substituent selected from R⁷. In a class of this embodiment, R¹is substituted with a substituent selected from R⁷.

In another embodiment of the present invention, R¹is selected from: a bond, hydrogen and —C_1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^L, and wherein R¹is unsubstituted or substituted with a substituent selected from R⁷. In a class of this embodiment, R¹is substituted with a substituent selected from R⁷.

In another embodiment of the present invention, R¹is selected from: hydrogen, and —C_1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^L, and wherein R¹is unsubstituted or substituted with a substituent selected from R⁷. In a class of this embodiment, R¹is substituted with a substituent selected from R⁷.

In another embodiment of the present invention, R¹is selected from: hydrogen and —C₂alkyl-, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^L, and wherein R¹is unsubstituted or substituted with a substituent selected from R⁷. In a class of this embodiment, R¹is substituted with a substituent selected from R⁷.

In another embodiment of the present invention, R¹is —C₂alkyl-, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^L, and wherein R¹is unsubstituted or substituted with a substituent selected from R⁷. In a class of this embodiment, R¹is substituted with a substituent selected from R⁷.

In another embodiment of the present invention, R¹is hydrogen. In another embodiment, R²is independently selected from: a bond, hydrogen, halogen, —OR^k, —CN, —C_1-6alkyl, —C_3-6cycloalkyl, —C_3-6cycloalkyl-C_1-3alkyl-, —C_2-6cycloheteroalkyl, and —C_2-6cycloheteroalkyl-C_1-3alkyl-, wherein each alkyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with one to three substituents selected from R^L, and wherein R²is unsubstituted or substituted with a substituent selected from R⁷. In a class of this embodiment, R²is substituted with a substituent selected from R⁷.

In another embodiment of the present invention, R²is selected from: a bond, hydrogen, —OR^kand —C_1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^L, and wherein R²is unsubstituted or substituted with a substituent selected from R⁷. In a class of this embodiment, R²is substituted with a substituent selected from R⁷.

In another embodiment of the present invention, R²is selected from: a bond, hydrogen and —C_1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^L, and wherein R²is unsubstituted or substituted with a substituent selected from R⁷. In a class of this embodiment, R²is substituted with a substituent selected from R⁷.

In another embodiment of the present invention, R²is selected from: hydrogen and —C_1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^L, and wherein R²is unsubstituted or substituted with a substituent selected from R⁷. In a class of this embodiment, R²is substituted with a substituent selected from R⁷.

In another embodiment of the present invention, R²is selected from: hydrogen and —C₂alkyl-, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^L, and wherein R²is unsubstituted or substituted with a substituent selected from R⁷. In a class of this embodiment, R²is substituted with a substituent selected from R⁷.

In another embodiment of the present invention, R²is —C₂alkyl-, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^L, and wherein R²is unsubstituted or substituted with a substituent selected from R⁷. In a class of this embodiment, R²is substituted with a substituent selected from R⁷.

In another embodiment of the present invention, R²is hydrogen.

In another embodiment, R¹is independently selected from: a bond, halogen, —OR^k, —CN, —C_1-6alkyl, —C_3-6cycloalkyl, —C_3-6cycloalkyl-C_1-3alkyl-, —C_2-6cycloheteroalkyl, and —C_2-6cycloheteroalkyl-C_1-3alkyl-, wherein each alkyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with one to three substituents selected from R^L, and wherein R¹is substituted with a substituent selected from R⁷; and R²is hydrogen.

In another embodiment of the present invention, R¹is selected from: a bond, —OR^kand —C_1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^L, and wherein R¹is substituted with a substituent selected from R⁷; and R²is hydrogen.

In another embodiment of the present invention, R¹is selected from: a bond and —C_1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^L, and wherein R¹is substituted with a substituent selected from R⁷; and R²is hydrogen. In a class of this embodiment, R¹is selected from: a bond and —C₂alkyl-, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^L, and wherein R¹is substituted with a substituent selected from R⁷; and R²is hydrogen.

In another embodiment of the present invention, R¹is selected from: —C_1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^L, and wherein R¹is substituted with a substituent selected from R⁷; and R²is hydrogen. In a class of this embodiment, R¹is selected from: —C₂alkyl-, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^L, and wherein R¹is substituted with a substituent selected from R⁷; and R²is hydrogen.

In another embodiment, R²is independently selected from: a bond, halogen, —OR^k, —CN, —C_1-6alkyl, —C_3-6cycloalkyl, —C_3-6cycloalkyl-C_1-3alkyl-, —C_2-6cycloheteroalkyl, and —C_2-6cycloheteroalkyl-C_1-3alkyl-, wherein each alkyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with one to three substituents selected from R^L, and wherein R²is substituted with a substituent selected from R⁷; and R¹is hydrogen.

In another embodiment of the present invention, R²is selected from: a bond, —OR^kand —C_1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^L, and wherein R²is substituted with a substituent selected from R⁷; and R¹is hydrogen.

In another embodiment of the present invention, R²is selected from: a bond and —C_1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^L, and wherein R²is substituted with a substituent selected from R⁷; and R¹is hydrogen. In a class of this embodiment, R²is selected from: a bond and —C₂alkyl-, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^L, and wherein R²is substituted with a substituent selected from R⁷; and R¹is hydrogen.

In another embodiment of the present invention, R²is selected from: —C_1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^L, and wherein R²is substituted with a substituent selected from R⁷; and R¹is hydrogen. In a class of this embodiment, R²is selected from: —C₂alkyl-, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^L, and wherein R²is substituted with a substituent selected from R⁷; and R¹is hydrogen.

In another embodiment, R³is absent or when present is selected from the group consisting of: hydrogen, halogen, —OR^e, —CN, —C_1-6alkyl, —C_3-6cycloalkyl, and —C_3-6cycloalkyl-C_1-3alkyl-, wherein each alkyl and cycloalkyl is unsubstituted or substituted with one to three substituents selected from Rⁱ.

In another embodiment of the present invention, when present, R³is selected from the group consisting of: hydrogen, halogen, —OR^e, —CN and —C_1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from Rⁱ.

In another embodiment of the present invention, when present, R³is selected from the group consisting of: hydrogen, halogen and —C_1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from Rⁱ. In a class of this embodiment, when present, R³is selected from the group consisting of: hydrogen and —C_1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from Rⁱ. In another class of this embodiment, when present, R³is selected from the group consisting of: —C_1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from Rⁱ. In another class of this embodiment, when present R³is hydrogen.

In another embodiment of the present invention, R⁴is selected from the group consisting of: hydrogen, halogen, OR^e, C_1-6alkyl, and C_1-6alkyl-O—, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^j, provided that when R⁴is selected from the group consisting of: OR^e, and —C_1-6alkyl-O—, then Y is selected from the group consisting of: —CR^gR^g, C═O, —C(R^g)OC_1-6alkyl, and —CF₂. In a class of this embodiment, R⁴is selected from the group consisting of: hydrogen, halogen, OR^e, C_1-6alkyl, and C_1-6alkyl-O—, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^j, provided that when R⁴is selected from the group consisting of: OR^e, and —C_1-6alkyl-O—, then Y is selected from the group consisting of: —CR^gR^g, C═O and —CF₂. In another class of this embodiment, R⁴is selected from the group consisting of: hydrogen, halogen, OR^e, C_1-6alkyl, and C_1-6alkyl-O—, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^j, provided that when R⁴is selected from the group consisting of: OR^eand —C_1-6alkyl-O—, then Y is selected from the group consisting of: —CH₂, C═O, and —CF₂.

In another embodiment of the present invention, R⁴is selected from the group consisting of: hydrogen, halogen and C_1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^j.

In another embodiment of the present invention, R⁴is selected from the group consisting of: hydrogen and C_1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^j.

In another embodiment of the present invention, R⁴is selected from the group consisting of: —C_1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^j.

In another embodiment of the present invention, R⁴is hydrogen.

In another embodiment of the present invention, R⁵is selected from the group consisting of: hydrogen, —C_1-6alkyl and —C_3-6cycloalkyl, wherein each alkyl and cycloalkyl is unsubstituted or substituted with one to three substituents selected from R^j.

In another embodiment of the present invention, R⁵is selected from the group consisting of: hydrogen and —C_1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^j. In another embodiment of the present invention, R⁵is selected from the group consisting of: —C_1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^j. In another embodiment of the present invention, R⁵is hydrogen.

In another embodiment of the present invention, R⁶is absent, or when present R⁶is selected from the group consisting of: hydrogen, —C_1-6alkyl, and —C_3-6cycloalkyl, wherein each alkyl and cycloalkyl is unsubstituted or substituted with one to three substituents selected from R^j.

In another embodiment of the present invention, R⁶is absent, or when present R⁶is selected from the group consisting of: hydrogen and —C_1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^j. In a class of this embodiment, R⁶is absent, or when present R⁶is selected from the group consisting of: —C_1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^j. In another class of this embodiment, R⁶is absent, or when present R⁶is hydrogen.

In another embodiment of the present invention, R⁶is selected from the group consisting of: hydrogen, —C_1-6alkyl, and —C_3-6cycloalkyl, wherein each alkyl and cycloalkyl is unsubstituted or substituted with one to three substituents selected from R^j.

In another embodiment of the present invention, R⁶is selected from the group consisting of: hydrogen and —C_1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^j. In a class of this embodiment, R⁶is selected from the group consisting of: —C_1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^j. In another class of this embodiment, R⁶is hydrogen.

In another embodiment of the present invention, R⁷is selected from the group consisting of: —CO₂R⁸, —C_1-6alkyl-CO₂R⁸, and a cycloheteroalkyl selected from the group consisting of:

embedded image

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, —C_1-6alkyl and —C_3-6cycloalkyl, wherein each alkyl and cycloalkyl is unsubstituted or substituted with one to three substituents selected from R^j. In a class of this embodiment, R⁸is selected from the group consisting of: hydrogen and —C_1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^j. In another class of this embodiment, R⁸is selected from the group consisting of: hydrogen and —C_1-6alkyl. In another class of this embodiment, R⁸is —C_1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^j. In another class of this embodiment, R⁸is hydrogen.

In another embodiment of the present invention, R^ais selected from the group consisting of: —C_1-6alkyl, halogen, —OR^e, —NR^cS(O)_nR^e, —S(O)_nR^e, —S(O)_nNR^cR^d, —NR^cR^d, —C(O)R^e, —OC(O)R^e, —CO₂R^e, —CN, —C(O)NR^cR^d, —NR^cC(O)R^e, —NR^cC(O)OR^e, —NR^cC(O)NR^cR^d, —CF₃, —OCF₃, and —OCHF₂, wherein each alkyl is unsubstituted or substituted with —C_1-6alkyl, halogen, —O—C_1-6alkyl and —CF₃. In another embodiment of the present invention, R^ais selected from the group consisting of: —C_1-6alkyl, halogen, —OR^e, —NR^cR^d, —CN, —CF₃, —OCF₃, and —OCHF₂, wherein each alkyl is unsubstituted or substituted with —C_1-6alkyl, halogen, —O—C_1-6alkyl and —CF₃. In another embodiment of the present invention, R^ais selected from the group consisting of: —C_1-6alkyl, and halogen, wherein each alkyl is unsubstituted or substituted with —C_1-6alkyl, halogen, —O—C_1-6alkyl and —CF₃. In another embodiment of the present invention, R^ais —C_1-6alkyl, wherein each alkyl is unsubstituted or substituted with —C_1-6alkyl, halogen, —O—C_1-6alkyl and —CF₃. In another embodiment of the present invention, R^ais halogen.

In another embodiment, R^ais —C_1-6alkyl, wherein each alkyl is unsubstituted or substituted with —C_1-6alkyl, halogen, —O—C_1-6alkyl and —CF₃.

In another embodiment, R^ais —C_1-6alkyl. In a class of this embodiment, R^ais —CH₃.

In another embodiment of the present invention, R^bis independently selected from the group consisting of: —C_1-10alkyl, —C_2-10alkenyl, —CF₃, halogen, —CN, —OH, —OC_1-10alkyl, —OC_2-10alkenyl, —O(CH₂)_pOC_1-10alkyl, —O(CH₂)_pNR^cS(O)_mR^e, —O(CH₂)_pS(O)_mR^e, —O(CH₂)_pS(O)_mNR^cR^d, —O(CH₂)_pNR^cR^d, —C(O)R^e, —OC(O)R^e, —CO₂R^e, —C(O)NR^cR^d, —NR^cC(O)R^e, —NR^cC(O)OR^e, —NR^cC(O)NR^cR^d, —OCF₃, and —OCHF₂, wherein each CH, CH₂, alkyl and alkenyl is unsubstituted or substituted with —C_1-6alkyl, halogen, —O—C_1-6alkyl and —CF₃.

In another embodiment of the present invention, R^bis independently selected from the group consisting of: —C_1-10alkyl, —C_2-10alkenyl, —CF₃, halogen, —CN, —OH, —OC_1-10alkyl, —OC_2-10alkenyl, —OCF₃, and —OCHF₂, wherein each CH, alkyl and alkenyl is unsubstituted or substituted with —C_1-6alkyl, halogen, —O—C_1-6alkyl and —CF₃.

In another embodiment of the present invention, R^bis independently selected from the group consisting of: —C_1-10alkyl, —CF₃, halogen, —CN, —OH, —OCF₃, and —OCHF₂. In another embodiment of the present invention, R^bis independently selected from the group consisting of: —C_1-10alkyl, —CF₃, halogen, —OCF₃and —OC_1-10alkyl, wherein each alkyl is unsubstituted or substituted with —C_1-6alkyl, halogen, —O—C_1-6alkyl and —CF₃. In a class of this embodiment, each alkyl is unsubstituted or substituted with —C_1-6alkyl. In a subclass of this class, each alkyl is unsubstituted or substituted with —CH₃.

In another embodiment of the present invention, R^bis independently selected from the group consisting of: —C_1-10alkyl, —CF₃, halogen, and —OCF₃, wherein each alkyl is unsubstituted or substituted with —C_1-6alkyl, halogen, —O—C_1-6alkyl and —CF₃. In a class of this embodiment of the present invention, R^bis independently selected from the group consisting of: —C_1-10alkyl, —CF₃, halogen, and —OCF₃. In another class of this embodiment, R^bis independently selected from the group consisting of: —CH₃, —CF₃, F, Cl and —OCF₃.

In another embodiment, R^bis independently selected from the group consisting of: —C_1-10alkyl, —CF₃, halogen, and —OCF₃, wherein alkyl is unsubstituted or substituted with —C_1-6alkyl, halogen, —O—C_1-6alkyl and —CF₃. In another embodiment, R^bis independently selected from the group consisting of: —CH₃, —CF₃, F, and —OCF₃.

In another embodiment of the present invention, R^cand R^dare each independently selected from the group consisting of: hydrogen, C_1-10alkyl, and C_2-10alkenyl, wherein each alkyl and alkenyl is unsubstituted or substituted with one to three substituents independently selected from R^f. In another embodiment of the present invention, R^cand R^dare each independently selected from the group consisting of hydrogen and C_1-10alkyl, wherein each alkyl and alkenyl is unsubstituted or substituted with one to three substituents independently selected from R^f. In another embodiment of the present invention, R^cand R^dare each —C_1-10alkyl, wherein each alkyl and alkenyl is unsubstituted or substituted with one to three substituents independently selected from R^f. In another embodiment of the present invention, R^cand R^dare each hydrogen.

In another embodiment of the present invention, R^cis independently selected from the group consisting of: hydrogen, C_1-10alkyl, and C_2-10alkenyl, wherein each alkyl and alkenyl is unsubstituted or substituted with one to three substituents independently selected from R^f. In another embodiment of the present invention, R^cis independently selected from the group consisting of: hydrogen and C_1-10alkyl, wherein each alkyl and alkenyl is unsubstituted or substituted with one to three substituents independently selected from R^f. In another embodiment of the present invention, R^cis —C_1-10alkyl, wherein each alkyl and alkenyl is unsubstituted or substituted with one to three substituents independently selected from R^f. In another embodiment of the present invention, R^cis hydrogen.

In another embodiment of the present invention, R^dis independently selected from the group consisting of: hydrogen, C_1-10alkyl, and C_2-10alkenyl, wherein each alkyl and alkenyl is unsubstituted or substituted with one to three substituents independently selected from R^f. In another embodiment of the present invention, R^dis independently selected from the group consisting of: hydrogen and C_1-10alkyl, wherein each alkyl and alkenyl is unsubstituted or substituted with one to three substituents independently selected from R^f. In another embodiment of the present invention, R^dis —C_1-10alkyl, wherein each alkyl and alkenyl is unsubstituted or substituted with one to three substituents independently selected from R^f. In another embodiment of the present invention, R^dis hydrogen.

In another embodiment of the present invention, each R^eis independently selected from the group consisting of: hydrogen, —C_1-10alkyl and —C_2-10alkenyl, wherein each alkyl, and alkenyl is unsubstituted or substituted with one to three substituents selected from R^h. In another embodiment of the present invention, each R^eis independently selected from the group consisting of: hydrogen, and —C_1-10alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^h. In another embodiment, each R^eis —C_1-10alkyl-, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^h. In a class of this embodiment, each R^eis —CH₃.

In another embodiment of the present invention, each R^eis hydrogen.

In another embodiment of the present invention, each R^fis selected from the group consisting of: halogen, C_1-10alkyl, —OH, —O—C_1-4alkyl, —CN, —CF₃, —OCHF₂and —OCF₃, wherein each alkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, halogen, C_1-6alkyl, cyano and S(O)₂C_1-6alkyl.

In another embodiment of the present invention, each R^fis selected from the group consisting of: halogen, C_1-10alkyl and —OH, wherein each alkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, halogen, C_1-6alkyl, cyano and S(O)₂C_1-6alkyl.

In another embodiment of the present invention, each R^fis selected from the group consisting of: halogen and C_1-10alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, halogen, C_1-6alkyl, cyano and S(O)₂C_1-6alkyl. In a class of this embodiment, each R^fis C_1-10alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, halogen, C_1-6alkyl, cyano and S(O)₂C_1-6alkyl. In a subclass of this class, each R^fis selected from the group consisting of: C_1-10alkyl. In another class of this embodiment, each R^fis halogen.

In another embodiment of the present invention, each R^gis selected from the group consisting of: hydrogen and —C_1-10alkyl, wherein each alkyl is unsubstituted or substituted with one to five halogens. In another embodiment of the present invention, each R^gis selected from the group consisting of: —C_1-10alkyl, wherein each alkyl is unsubstituted or substituted with one to five halogens. In another embodiment of the present invention, each R^gis selected from the group consisting of: —C_1-10alkyl. In another embodiment of the present invention, each R^gis hydrogen.

In another embodiment of the present invention, each R^his selected from the group consisting of: halogen, C_1-10alkyl and —OH, wherein each alkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, halogen, C_1-6alkyl, cyano and S(O)₂C_1-6alkyl.

In another embodiment of the present invention, each R^his selected from the group consisting of: halogen and C_1-10alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, halogen, C_1-6alkyl, cyano and S(O)₂C_1-6alkyl. In a class of this embodiment, each R^his selected from the group consisting of: C_1-10alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, halogen, C_1-6alkyl, cyano and S(O)₂C_1-6alkyl. In another class of this embodiment, each R^his halogen.

In another embodiment of the present invention, R¹is independently selected from the group consisting of: —C_1-6alkyl, —OR^e, —NR^cS(O)_mR^e, halogen, —S(O)_mR^e, —S(O)_mNR^cR^d, —NR^cR^d, —C(O)R^e, —OC(O)R^e, —CO₂R^e, —CN, —C(O)NR^cR^d, —NR^cC(O)R^e, —NR^cC(O)OR^e, —NR^cC(O)NR^cR^d, —CF₃, —OCF₃and —OCHF₂. In another embodiment of the present invention, R¹is independently selected from the group consisting of: —C_1-6alkyl, —OR^e, —NR^cS(O)_mR^e, halogen, —NR^cR^d, —C(O)R^e, —OC(O)R^e, —CO₂R^e, —CN, —CF₃, —OCF₃and —OCHF₂. In another embodiment of the present invention, R¹is independently selected from the group consisting of: —C_1-6alkyl, —OR^e, and halogen. In another embodiment of the present invention, R¹is independently selected from the group consisting of: —C_1-6alkyl and halogen. In another embodiment of the present invention, R¹is —C_1-6alkyl. In another embodiment of the present invention, R¹is halogen.

In another embodiment of the present invention, R^jis independently selected from the group consisting of: —C_1-6alkyl, —OR^e, —NR^cS(O)_mR^e, halogen, —S(O)_mR^e, —S(O)_mNR^cR^d, —NR^cR^d, —C(O)R^e, —OC(O)R^e, —CO₂R^e, —CN, —C(O)NR^cR^d, —NR^cC(O)R^e, —NR^cC(O)OR^e, —NR^cC(O)NR^cR^d, —CF₃, —OCF₃and —OCHF₂. In another embodiment of the present invention, R^jis independently selected from the group consisting of: —C_1-6alkyl, —OR^e, halogen, —NR^cR^d, —C(O)R^e, —OC(O)R^e, —CO₂R^e, —CN, —CF₃, —OCF₃, and —OCHF₂. In another embodiment of the present invention, R^jis independently selected from the group consisting of: —C_1-6alkyl, —OR^e, and halogen. In another embodiment of the present invention, R^jis independently selected from the group consisting of: —C_1-6alkyl and halogen. In another embodiment of the present invention, R^jis —C_1-6alkyl. In another embodiment of the present invention, R^jis halogen.

In another embodiment of the present invention, each R^kis independently selected from the group consisting of: hydrogen, —C_1-6alkyl, —CF₃and —CHF₂, wherein each alkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, —OC_1-6alkyl, halogen, cyano, and —S(O)₂C_1-6alkyl.

In another embodiment of the present invention, each R^kis independently selected from the group consisting of: hydrogen and —C_1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, —OC_1-6alkyl, halogen, cyano, and —S(O)₂C_1-6alkyl.

In another embodiment of the present invention, each R^kis independently selected from the group consisting of: —C_1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, —OC_1-6alkyl, halogen, cyano, and —S(O)₂C_1-6alkyl. In a class of this embodiment, each R^kis independently selected from the group consisting of: —C_1-6alkyl.

In another embodiment of the present invention, each R^kis hydrogen.

In another embodiment of the present invention, each R^Lis independently selected from the group consisting of: —C_1-10alkyl, —C_2-10alkenyl, —C_2-10alkynyl, and —C_3-6cycloalkyl, wherein each alkyl, alkenyl, alkynyl, and cycloalkyl is unsubstituted or substituted with 1-4 substituents selected from C_1-6alkyl, halogen, and —OC_1-6alkyl.

In another embodiment of the present invention, each R^Lis independently selected from the group consisting of: —C_1-10alkyl and —C_3-6cycloalkyl, wherein each alkyl and cycloalkyl is unsubstituted or substituted with 1-4 substituents selected from C_1-6alkyl, halogen, and —OC_1-6alkyl.

In another embodiment of the present invention, each R^Lis independently selected from the group consisting of: —C_1-10alkyl and —C_3-6cycloalkyl. In a class of this embodiment, each R^Lis independently selected from the group consisting of: —CH₃and cyclopropyl.

In another embodiment of the present invention, R^Lis —C_1-10alkyl. In a class of this embodiment, each R^Lis —CH₃.

In another embodiment of the present invention, R^Lis —C_3-6cycloalkyl. In a class of this embodiment, each R^Lis cyclopropyl.

In another embodiment of the present invention, each R^mis independently selected from the group consisting of: —C_1-10alkyl, —C_2-10alkenyl, —C_3-6cycloalkyl, —C_2-5cycloheteroalkyl, aryl and heteroaryl. In another embodiment of the present invention, each R^mis independently selected from the group consisting of: —C_1-10alkyl and —C_2-10alkenyl. In another embodiment of the present invention, each R^mis independently selected from the group consisting of: —C_1-10alkyl.

In another embodiment of the present invention, Rⁿis selected from the group consisting of: hydrogen, and —C_1-10alkyl, wherein each alkyl is unsubstituted or substituted with one to five halogens. In a class of this embodiment, Rⁿis selected from the group consisting of: hydrogen and —CH₃. In another class of this embodiment, Rⁿis hydrogen. In another class of this embodiment, Rⁿis —CH₃.

In another embodiment, Rⁿis —C_1-10alkyl, wherein each alkyl is unsubstituted or substituted with one to five halogens. In a class of this embodiment, Rⁿis —CH₃.

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

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

In another embodiment of the present invention, each p is independently selected from: 0, 1, 2, 3, 4, 5 or 6. In another embodiment of the present invention, p is 0, 1, 2, 3 or 4. In a class of this embodiment, p is 0, 1, 2 or 3. In a class of this embodiment, p is 0, 1 or 2. In another embodiment of the present invention, p is 1, 2, 3 or 4. In a class of this embodiment, p is 1, 2 or 3. In a class of this embodiment, p is 1 or 2. In another class of this embodiment, p is 0 or 1. In another class of this embodiment, p is 0 or 2. In another class of this embodiment, p is 0. In another class of this embodiment, p is 1. In another class of this embodiment, p is 2. In another class of this embodiment, p is 3. In another class of this embodiment, p is 4. In another class of this embodiment, p is 5. In another class of this embodiment, p is 6.

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