ANTIDIABETIC SPIROCHROMAN 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, WO 2015/024448, 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

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;

X is selected from the group consisting of:

(1) oxygen,

(2) sulfur,

(3) —CR^bR^b,

(4) —C═O, and

(5) —C(R^b)OR^b, and

(6) N(R^b);

Z is selected from:

embedded image

Y is selected from the group consisting of:

(1) —C(R^g)—,

(2) —C(F)—, and

(3) —N—;

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 alkyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with one to three R^Lsubstituents, and wherein one of R¹and R²is substituted with R⁷, or R¹and R²together with the atom(s) to which they are attached form a C_3-6cycloalkyl ring or a C_2-5cycloheteroalkyl ring, wherein each R¹and R²is unsubstituted or substituted with one to three substituents selected from R^L, and wherein one of R¹and R²is substituted with R⁷;

each R³is independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) —CN,

(4) —CF₃, and

(5) —C_1-6alkyl;

R⁴is independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) —CF₃, and

(4) —C_1-6alkyl;

R⁵is independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) —CN,

(4) —CF₃,

(5) —C_1-6alkyl, and

(6) —C_1-5spirocycloalkyl,

or two R⁵groups, and the carbons they are attached to, form a —C_3-6cycloalkyl ring or a —C_2-5cycloheteroalkyl ring;

R⁶is selected from the group consisting of:

(1) aryl,

(2) aryl-SO₂—,

(3) aryl-C_1-10alkyl-,

(4) aryl-N(Rⁱ)—,

(5) aryl-C_1-10alkyl-N(Rⁱ)—,

(6) heteroaryl,

(7) heteroaryl-SO₂—,

(8) heteroaryl-C_1-10alkyl-,

(9) heteroaryl-N(Rⁱ)—, and

(10) heteroaryl-C_1-10alkyl-N(Rⁱ)—,

wherein each CH₂is unsubstituted or substituted with 1-2 substituents selected from R^a, and wherein each alkyl, aryl, and heteroaryl is unsubstituted or substituted with 1-5 substituents selected from R^a;

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_1-6alkyl,

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) —OC_1-6alkyl,

(3) halogen,

(4) —S(O)_nR^e,

(5) —S(O)_nNR^cR^d,

(6) —NR^cR^d,

(7) —C(O)R^e,

(8) —OC(O)R^e,

(9) —CO₂R^e,

(10) —CN,

(11) —C(O)NR^cR^d,

(12) —CF₃,

(13) —OCF₃,

(14) —OCHF₂,

(15) —OCH₂CF₃,

(16) aryl,

(17) heteroaryl,

(18) —C_3-6cycloalkyl, and

(19) —C_2-5cycloheteroalkyl,

wherein each alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with 1-3 substituents selected from: halogen, —C_1-6alkyl, —O—C_1-6alkyl, —CF₃, CO₂H, and —CO₂C_1-6alkyl;

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

(1) hydrogen,

(2) —C(O)R^d, and

(3) —C_1-10alkyl,

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

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 R^fsubstituents;

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;

R^gis 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 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;

R¹is independently selected from the group consisting of:

(1) hydrogen, and

(2) —C_1-6alkyl;

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) —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-;

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

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

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

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

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

each u is independently selected from: 0, 1, 2, or 3.

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 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, X is selected from the group consisting of: —C(R^b)(R^b), C═O, and —C(R^b)OR^b. In a class of this embodiment, X is selected from the group consisting of: CH₂, C═O, and —CH(OH).

In another embodiment of the present invention, X is C═O.

In another embodiment of the present invention, X is —C(R^b)OR^b. In a class of this embodiment, X is —CH(OH).

In another embodiment of the present invention, X is —C(R^b)(R^b). In a class of this embodiment, X is CH₂.

In another embodiment of the present invention, Y is selected from the group consisting of: —C(R^g)—, and —N—. In a class of this embodiment, Y is selected from the group consisting of: —C(H)—, and —N—.

In another embodiment of the present invention, Y is —C(R^g)—. In a class of this embodiment, Y is —C(H)—.

In another embodiment of the present invention, Y is —N—.

In another embodiment of the present invention, Z is selected from:

embedded image

In a class of this embodiment, Z is selected from:

embedded image

In another embodiment of the present invention, Z is selected from:

embedded image

In a class of this embodiment, Z is selected from:

embedded image

In another embodiment of the present invention, Z is

embedded image

In a class of this embodiment, Z is selected from:

embedded image

In another class of this embodiment, Z is

embedded image

In another class of this embodiment, Z is

embedded image

In another class of this embodiment, Z is

embedded image

In another class of this embodiment, Z is

embedded image

In another class of this embodiment, Z is

embedded image

In another embodiment of the present invention, Z is:

embedded image

In a class of this embodiment, Z is

embedded image

In another embodiment of the present invention, Z is:

embedded image

In a class of this embodiment, Z is selected from:

embedded image

In another class of this embodiment of the present invention, Z is:

embedded image

In another class of this embodiment, Z is:

embedded image

In another embodiment of the present invention, R¹and R²are each independently 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 one of R¹and R²is substituted with R⁷, or R¹and R²together with the atom(s) to which they are attached form a C_3-6cycloalkyl ring or a C_2-5cycloheteroalkyl ring, wherein each R¹and R²is unsubstituted or substituted with one to three substituents selected from R^L, and wherein one of R¹and R²is substituted with R⁷. In a class of this embodiment, R¹and R²are each independently 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 one of R¹and R²is substituted with R⁷.

In another embodiment of the present invention, R¹and R²are each independently selected from: a bond, hydrogen, —OH, —OC_1-6alkyl 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 substituted with R⁷, or R¹and R²together with the atom(s) to which they are attached form a C_3-6cycloalkyl ring or a C_2-5cycloheteroalkyl ring containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—R^g, wherein each R¹and R²is unsubstituted or substituted with one to three substituents selected from R^L, and wherein one of R¹and R²is substituted with R⁷. In another class of this embodiment, R¹and R²are each independently selected from: a bond, hydrogen, —OH, —OC_1-6alkyl, 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 substituted with 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 substituted with R⁷, or R¹and R²together with the atom(s) to which they are attached form a C_3-6cycloalkyl ring or a C_2-5cycloheteroalkyl ring containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—R^g, wherein each R¹and R²is unsubstituted or substituted with one to three substituents selected from R^L, and wherein one of R¹and R²is substituted with R⁷. In another class of this embodiment, R¹and R²are each independently selected from: a bond, 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 substituted with 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 substituted with R⁷, or R¹and R²together with the atom(s) to which they are attached form a C_3-6cycloalkyl ring or a C_2-5cycloheteroalkyl ring containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—R^g, wherein each R¹and R²is unsubstituted or substituted with one to three substituents selected from R^L, and wherein one of R¹and R²is substituted with R⁷. In a class of this embodiment, 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 substituted with R⁷. In another class of this embodiment, 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 substituted with 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 substituted with R⁷, or R¹and R²together with the atom(s) to which they are attached form a C_3-6cycloalkyl ring or a C_2-5cycloheteroalkyl ring containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—R^g, wherein each R¹and R²is unsubstituted or substituted with one to three substituents selected from R^L, and wherein one of R¹and R²is substituted with R⁷. In a class of this 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 substituted with R⁷.

In another embodiment of the present invention, R¹is independently 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 substituted with R⁷, or R¹and R²together with the atom(s) to which they are attached form a C_3-6cycloalkyl ring or a C_2-5cycloheteroalkyl ring containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—R^g, wherein each R¹and R²is unsubstituted or substituted with one to three substituents selected from R^L, and wherein one of R¹and R²is substituted with R⁷. In a class of this embodiment, R¹is independently 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 substituted with R⁷.

In another embodiment of the present invention, R¹is selected from: a bond, hydrogen, —OH, —OC_1-6alkyl 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 R⁷, or R¹and R²together with the atom(s) to which they are attached form a C_3-6cycloalkyl ring or a C_2-5cycloheteroalkyl ring containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—R^g, wherein each R¹and R²is unsubstituted or substituted with one to three substituents selected from R^L, and wherein one of R¹and R²is substituted with R⁷. In another class of this embodiment, R¹is selected from: a bond, hydrogen, —OH, —OC_1-6alkyl, 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 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 substituted with R⁷, or R¹and R²together with the atom(s) to which they are attached form a C_3-6cycloalkyl ring or a C_2-5cycloheteroalkyl ring containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—R^g, wherein each R¹and R²is unsubstituted or substituted with one to three substituents selected from R^L, and wherein one of R¹and R²is substituted with R⁷. In a class of this embodiment, 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 substituted with R⁷. In another class of this embodiment, R¹is selected from: a bond, hydrogen and C₂alkyl-, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^L, and wherein R¹is substituted with R⁷, or R¹and R²together with the atom(s) to which they are attached form a C_3-6cycloalkyl ring or a C_2-5cycloheteroalkyl ring, wherein each R¹and R²is unsubstituted or substituted with one to three substituents selected from R^L, and wherein one of R¹and R²is substituted with R⁷. In another class of this embodiment, R¹is selected from: a bond, hydrogen and C₂alkyl-, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^L, and wherein R¹is substituted with 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 substituted with R⁷, or R¹and R²together with the atom(s) to which they are attached form a C_3-6cycloalkyl ring or a C_2-5cycloheteroalkyl ring containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—R^g, wherein each R¹and R²is unsubstituted or substituted with one to three substituents selected from R^L, and wherein one of R¹and R²is substituted with R⁷. In a class of this embodiment, 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 substituted with R⁷. In another class of this embodiment, 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 substituted with R⁷.

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

In another embodiment of the present invention, R¹is 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 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 R⁷; and R²is hydrogen. In a class of this embodiment, R¹is selected from: a bond, —OH, —OC_1-6alkyl, 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 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 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 R⁷; and R²is 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 substituted with R⁷, or R¹and R²together with the atom(s) to which they are attached form a C_3-6cycloalkyl ring or a C_2-5cycloheteroalkyl ring containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—R^g, wherein each R¹and R²is unsubstituted or substituted with one to three substituents selected from R^L, and wherein one of R¹and R²is substituted with R⁷. In a class of this 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 substituted with R⁷.

In another embodiment of the present invention, R²is independently 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 substituted with R⁷, or R¹and R²together with the atom(s) to which they are attached form a C_3-6cycloalkyl ring or a C_2-5cycloheteroalkyl ring containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—R^g, wherein each R¹and R²is unsubstituted or substituted with one to three substituents selected from R^L, and wherein one of R¹and R²is substituted with R⁷. In a class of this embodiment, 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 substituted with R⁷. In another class of this embodiment, R²is selected from: a bond, hydrogen, —OH, —OC_1-6alkyl, 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 R⁷, or R¹and R²together with the atom(s) to which they are attached form a C_3-6cycloalkyl ring or a C_2-5cycloheteroalkyl ring, wherein each R¹and R²is unsubstituted or substituted with one to three substituents selected from R^L, and wherein one of R¹and R²is substituted with R⁷. In another class of this embodiment, R²is selected from: a bond, hydrogen, —OH, —OC_1-6alkyl, 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 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 substituted with R⁷, or R¹and R²together with the atom(s) to which they are attached form a C_3-6cycloalkyl ring or a C_2-5cycloheteroalkyl ring containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—R^g, wherein each R¹and R²is unsubstituted or substituted with one to three substituents selected from R^L, and wherein one of R¹and R²is substituted with R⁷. In a class of this embodiment, 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 substituted with R⁷. In another class of this embodiment, R²is selected from: a bond, hydrogen and C₂alkyl-, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R^L, and wherein R²is substituted with 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 substituted with R⁷. In another class of this embodiment, 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 substituted with R⁷.

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

In another embodiment of the present invention, 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 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 R⁷; and R¹is hydrogen. In a class of this embodiment, R²is selected from: a bond, —OH, —OC_1-6alkyl, 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 R⁷; and R¹is hydrogen.

In another embodiment of the present invention, 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 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 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 R⁷; and R¹is hydrogen.

In another embodiment of the present invention, when present, R³is selected from the group consisting of: hydrogen, halogen, CN and —C_1-6alkyl.

In another embodiment of the present invention, when present, R³is selected from the group consisting of: hydrogen, halogen and —C_1-6alkyl.

In another embodiment of the present invention, when present, R³is selected from the group consisting of: hydrogen and halogen. In a class of this embodiment, R³is selected from the group consisting of: hydrogen and fluorine.

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

In another embodiment of the present invention, when present, R³is halogen. In a class of this embodiment, R³is F.

In another embodiment, when present, R³is selected from the group consisting of: hydrogen and —C_1-6alkyl. In another embodiment of the present invention, R³is —C_1-6alkyl.

In another embodiment of the present invention, R⁴is independently selected from the group consisting of: hydrogen, halogen, and —C_1-6alkyl.

In another embodiment of the present invention, R⁴is independently selected from the group consisting of: hydrogen, and —C_1-6alkyl.

In another embodiment of the present invention, R⁴is —C_1-6alkyl.

In another embodiment of the present invention, R⁴is hydrogen.

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

In another embodiment of the present invention, R⁴is halogen.

In another embodiment of the present invention, R⁵is independently selected from the group consisting of: hydrogen, halogen, —CN, —CF₃, —C_1-6alkyl, and —C_1-5spirocycloalkyl. In a class of this embodiment, the spirocycloalkyl is spirocyclopropyl.

In another embodiment of the present invention, R⁵is independently selected from the group consisting of: hydrogen, halogen, —CN, —CF₃, and —C_1-6alkyl.

In another embodiment of the present invention, R⁵is independently selected from the group consisting of: hydrogen, halogen, —CF₃, and —C_1-6alkyl.

In another embodiment of the present invention, R⁵is independently selected from the group consisting of: hydrogen, halogen, —CN, and —C_1-6alkyl.

In another embodiment of the present invention, R⁵is independently selected from the group consisting of: hydrogen, halogen, and —C_1-6alkyl.

In another embodiment of the present invention, R⁵is independently selected from the group consisting of: hydrogen, and —C_1-6alkyl.

In another embodiment of the present invention, R⁵is —C_1-6alkyl.

In another embodiment of the present invention, R⁵is hydrogen.

In another embodiment of the present invention, R⁶is selected from the group consisting of: aryl, aryl-SO₂—, aryl-C_1-10alkyl-, aryl-N(Rⁱ)—, aryl-C_1-10alkyl-N(Rⁱ)—, heteroaryl, heteroaryl-SO₂—, heteroaryl-C_1-10alkyl-, heteroaryl-N(Rⁱ)—, and heteroaryl-C_1-10alkyl-N(Rⁱ)—, wherein each CH₂is unsubstituted or substituted with 1-2 substituents selected from R^a, and wherein each alkyl, aryl, and heteroaryl is unsubstituted or substituted with 1-4 substituents selected from R^a.

In another embodiment of the present invention, R⁶is selected from the group consisting of: aryl, aryl-SO₂—, aryl-C_1-10alkyl-, aryl-N(Rⁱ)—, aryl-C_1-10alkyl-N(Rⁱ)—, heteroaryl, heteroaryl-C_1-10alkyl-, and heteroaryl-N(Rⁱ)—, wherein each CH₂is unsubstituted or substituted with 1-2 substituents selected from R^a, and wherein each alkyl, aryl, cycloheteroalkyl, and heteroaryl is unsubstituted or substituted with 1-5 substituents selected from R^a.

In a class of this embodiment, R⁶is selected from the group consisting of: phenyl, phenyl-SO₂—, phenyl-CH₂—, phenyl-NH, phenyl-N(CH₃)—, phenyl-CH₂—N(H)—, phenyl-CH₂—N(CH₃)—, pyridine, pyrimidine, pyrazine, dihydrobenzofuran, indazole, imidazo[1,2-b]pyridazine, pyridine-CH₂—, pyrazole-CH₂—, thiazole-CH₂—, and pyridine-N(Rⁱ)—, wherein each CH₂is unsubstituted or substituted with 1-2 substituents selected from R^a, and wherein each alkyl, aryl, and heteroaryl is unsubstituted or substituted with 1-5 substituents selected from R^a.

In another class of this embodiment, R⁶is selected from the group consisting of: phenyl, phenyl-SO₂—, phenyl-CH₂—, phenyl-NH, phenyl-CH₂—N(H)—, pyridine, pyrimidine, pyrazine, dihydrobenzofuran, indazole, imidazo[1,2-b]pyridazine, pyridine-CH₂—, pyrazole-CH₂—, thiazole-CH₂—, and pyridine-N(Rⁱ)—, wherein each CH₂is unsubstituted or substituted with 1-2 substituents selected from R^a, and wherein each alkyl, aryl, and heteroaryl is unsubstituted or substituted with 1-5 substituents selected from R^a.

In another embodiment of the present invention, R⁶is aryl-C_1-10alkyl-, wherein each alkyl and aryl is unsubstituted or substituted with 1-5 substituents selected from R^a.

In a class of this embodiment, R⁶is phenyl-CH₂—, wherein each CH₂is unsubstituted or substituted with 1-2 substituents selected from R^a, and wherein each phenyl is unsubstituted or substituted with 1-4 substituents selected from R^a.

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 class of this embodiment, R⁷is selected from the group consisting of: —CO₂R⁸, —C_1-6alkyl-CO₂R⁸, and a cycloheteroalkyl selected from:

embedded image

In another class of this embodiment, R⁷is selected from the group consisting of: —CO₂H, —CH₂CO₂H, —(CH₂)₂CO₂H, and a cycloheteroalkyl selected from:

embedded image

In another class of this embodiment, R⁷is selected from the group consisting of: —CO₂H, —CH₂CO₂H, and a cycloheteroalkyl selected from:

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 —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, —OC_1-6alkyl, halogen, —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, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, heteroaryl, and —C_3-6cycloalkyl, wherein each alkyl, cycloalkyl, and heteroaryl is unsubstituted or substituted with 1-3 substituents selected from: halogen, —C_1-6alkyl, —O—C_1-6alkyl, —CF₃, CO₂H, and —CO₂C_1-6alkyl.

In another embodiment of the present invention, R^ais selected from the group consisting of: —C_1-6alkyl, —OC_1-6alkyl, halogen, —CN, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, aryl, heteroaryl, and —C_2-5cycloheteroalkyl, wherein each alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with 1-3 substituents selected from: halogen, —C_1-6alkyl, —O—C_1-6alkyl, —CF₃, CO₂H, and —CO₂C_1-6alkyl.

In another class of this embodiment, R^ais selected from the group consisting of: —C_1-6alkyl, —OC_1-6alkyl, halogen, —CN, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, heteroaryl, and —C_3-6cycloalkyl, wherein each alkyl, cycloalkyl and heteroaryl is unsubstituted or substituted with 1-3 substituents selected from: —C_1-6alkyl and CO₂H.

In another embodiment of the present invention, R^ais selected from the group consisting of: —C_1-6alkyl, —OC_1-6alkyl, halogen, —CN, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, heteroaryl, and —C_3-6cycloalkyl, wherein each alkyl, cycloalkyl and heteroaryl is unsubstituted or substituted with 1-3 substituents selected from: halogen, —C_1-6alkyl, —O—C_1-6alkyl, —CF₃, CO₂H, and —CO₂C_1-6alkyl.

In a class of this embodiment, R^ais selected from the group consisting of: —CH₃, —CH₂CH₃, —C(CH₃)₃, —OCH₃, F, Cl, —CN, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, pyrazole, furan, isoxazole, thiophene, pyrrole, and cyclopropyl, wherein each alkyl, cycloalkyl and heteroaryl is unsubstituted or substituted with 1-3 substituents selected from: halogen, —C_1-6alkyl, —O—C_1-6alkyl, —CF₃, CO₂H, and —CO₂C_1-6alkyl.

In another embodiment of the present invention, R^ais selected from the group consisting of: —C_1-6alkyl, halogen, —CF₃, and —OCF₃.

In a class of this embodiment, R^ais selected from the group consisting of: —CH₃, F, Cl, —CF₃, and —OCF₃.

In another embodiment of the present invention, each R^bis independently 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^bis —C_1-10alkyl, wherein each alkyl is unsubstituted or substituted with one to five halogens.

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

In another embodiment of the present invention, R^cand R^dare each independently selected from the group consisting of: hydrogen, C_1-10alkyl, C_2-10alkenyl, C_3-6cycloalkyl, C_2-5cycloheteroalkyl, aryl and heteroaryl, wherein each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three R^fsubstituents, or R^cand R^dtogether with the atom(s) to which they are attached form a C_2-5cycloheteroalkyl ring containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—R^g, wherein each R^cand R^dis unsubstituted or substituted with one to three R^fsubstituents. In a class of this embodiment, R^cand R^dare each independently selected from the group consisting of: hydrogen, C_1-10alkyl, C_2-10alkenyl, C_3-6cycloalkyl, C_2-5cycloheteroalkyl, aryl and heteroaryl, wherein each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three R^fsubstituents.

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 R^fsubstituents, or R^cand R^dtogether with the atom(s) to which they are attached form a C_2-5cycloheteroalkyl ring containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—R^g, wherein each R^cand R^dis unsubstituted or substituted with one to three R^fsubstituents. In a class of this embodiment, 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 R^fsubstituents.

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 is unsubstituted or substituted with one to three R^fsubstituents, or R^cand R^dtogether with the atom(s) to which they are attached form a C_2-5cycloheteroalkyl ring containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—R^g, wherein each R^cand R^dis unsubstituted or substituted with one to three R^fsubstituents.

In a class of this embodiment, R^cand R^dare each independently selected from the group consisting of: hydrogen and C_1-10alkyl, wherein each alkyl is unsubstituted or substituted with one to three R^fsubstituents.

In another embodiment of the present invention, R^cand R^dare each independently selected from the group consisting of: C_1-10alkyl, wherein each alkyl is unsubstituted or substituted with one to three R^fsubstituents, or R^cand R^dtogether with the atom(s) to which they are attached form a C_2-5cycloheteroalkyl ring containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—R^g, wherein each R^cand R^dis unsubstituted or substituted with one to three R^fsubstituents. In a class of this embodiment, R^cand R^dare each independently selected from the group consisting of: C_1-10alkyl, wherein each alkyl is unsubstituted or substituted with one to three R^fsubstituents.

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, C_2-10alkenyl, C_3-6cycloalkyl, C_3-6cycloalkyl-C_1-10alkyl-, C_2-5cycloheteroalkyl, C_2-5cycloheteroalkyl-C_1-10alkyl-, aryl, heteroaryl, aryl-C_1-10alkyl-, and heteroaryl-C_1-10alkyl-, wherein each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three R^fsubstituents, or R^cand R^dtogether with the atom(s) to which they are attached form a C_2-5cycloheteroalkyl ring containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—R^g, wherein each R^cand R^dis unsubstituted or substituted with one to three R^fsubstituents. In a class of this embodiment, R^cis independently selected from the group consisting of: hydrogen, C_1-10alkyl, C_2-10alkenyl, C_3-6cycloalkyl, C_3-6cycloalkyl-C_1-10alkyl-, C_2-5cycloheteroalkyl, C_2-5cycloheteroalkyl-C_1-10alkyl-, aryl, heteroaryl, aryl-C_1-10alkyl- and heteroaryl-C_1-10alkyl-, wherein each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three R^fsubstituents.

In another embodiment of the present invention, R^cis selected from the group consisting of: hydrogen, C_1-10alkyl, C_2-10alkenyl, C_3-6cycloalkyl, C_2-5cycloheteroalkyl, aryl and heteroaryl, wherein each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three R^fsubstituents, or R^cand R^dtogether with the atom(s) to which they are attached form a C_2-5cycloheteroalkyl ring containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—R^g, wherein each R^cand R^dis unsubstituted or substituted with one to three R^fsubstituents. In a class of this embodiment, R^cis selected from the group consisting of: hydrogen, C_1-10alkyl, C_2-10alkenyl, C_3-6cycloalkyl, C_2-5cycloheteroalkyl, aryl and heteroaryl, wherein each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three R^fsubstituents.

In another embodiment of the present invention, R^cis 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 R^fsubstituents, or R^cand R^dtogether with the atom(s) to which they are attached form a C_2-5cycloheteroalkyl ring containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—R^g, wherein each R^cand R^dis unsubstituted or substituted with one to three R^fsubstituents. In a class of this embodiment, R^cis 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 R^fsubstituents.

In another embodiment of the present invention, R^cis selected from the group consisting of: hydrogen and C_1-10alkyl, wherein each alkyl is unsubstituted or substituted with one to three R^fsubstituents, or R^cand R^dtogether with the atom(s) to which they are attached form a C_2-5cycloheteroalkyl ring containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—R^g, wherein each R^cand R^dis unsubstituted or substituted with one to three R^fsubstituents. In a class of this embodiment, R^cis selected from the group consisting of: hydrogen and C_1-10alkyl, wherein each alkyl is unsubstituted or substituted with one to three R^fsubstituents.

In another embodiment of the present invention, R^cis selected from the group consisting of: C_1-10alkyl, wherein each alkyl is unsubstituted or substituted with one to three R^fsubstituents, or R^cand R^dtogether with the atom(s) to which they are attached form a C_2-5cycloheteroalkyl ring containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—R^g, wherein each R^cand R^dis unsubstituted or substituted with one to three R^fsubstituents. In a class of this embodiment, R^cis selected from the group consisting of: C_1-10alkyl, wherein each alkyl is unsubstituted or substituted with one to three R^fsubstituents.

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, C_2-10alkenyl, C_3-6cycloalkyl, C_3-6cycloalkyl-C_1-10alkyl-, C_2-5cycloheteroalkyl, C_2-5cycloheteroalkyl-C_1-10alkyl-, aryl, heteroaryl, aryl-C_1-10alkyl- and heteroaryl-C_1-10alkyl-, wherein each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three R^fsubstituents, or R^cand R^dtogether with the atom(s) to which they are attached form a C_2-5cycloheteroalkyl ring containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—R^g, wherein each R^cand R^dis unsubstituted or substituted with one to three R^fsubstituents.

In another embodiment of the present invention, R^dis selected from the group consisting of: hydrogen, C_1-10alkyl, C_2-10alkenyl, C_3-6cycloalkyl, C_2-5cycloheteroalkyl, aryl and heteroaryl, wherein each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three R^fsubstituents, or R^cand R^dtogether with the atom(s) to which they are attached form a C_2-5cycloheteroalkyl ring containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—R^g, wherein each R^cand R^dis unsubstituted or substituted with one to three R^fsubstituents. In a class of this embodiment, R^dis selected from the group consisting of: hydrogen, C_1-10alkyl, C_2-10alkenyl, C_3-6cycloalkyl, C_2-5cycloheteroalkyl, aryl and heteroaryl, wherein each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three R^fsubstituents.

In another embodiment of the present invention, R^dis 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 R^fsubstituents, or R^cand R^dtogether with the atom(s) to which they are attached form a C_2-5cycloheteroalkyl ring containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—R^g, wherein each R^cand R^dis unsubstituted or substituted with one to three R^fsubstituents. In a class of this embodiment, R^dis 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 R^fsubstituents.

In another embodiment of the present invention, R^dis selected from the group consisting of: hydrogen and C_1-10alkyl, wherein each alkyl is unsubstituted or substituted with one to three R^fsubstituents, or R^cand R^dtogether with the atom(s) to which they are attached form a C_2-5cycloheteroalkyl ring containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—R^g, wherein each R^cand R^dis unsubstituted or substituted with one to three R^fsubstituents. In a class of this embodiment, R^dis selected from the group consisting of: hydrogen and C_1-10alkyl, wherein each alkyl is unsubstituted or substituted with one to three R^fsubstituents.

In another class of this embodiment, R^dis selected from the group consisting of: C_1-10alkyl, wherein each alkyl is unsubstituted or substituted with one to three R^fsubstituents, or R^cand R^dtogether with the atom(s) to which they are attached form a C_2-5cycloheteroalkyl ring containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—R^g, wherein each R^cand R^dis unsubstituted or substituted with one to three R^fsubstituents. In a class of this embodiment, R^dis selected from the group consisting of: C_1-10alkyl, wherein each alkyl is unsubstituted or substituted with one to three R^fsubstituents.

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, —C_2-10alkenyl, aryl, aryl-C_1-10alkyl-, heteroaryl and heteroaryl-C_1-10alkyl-, wherein each alkyl, alkenyl, aryl and heteroaryl is unsubstituted or substituted with one to three R^hsubstituents.

In another embodiment of the present invention, each R^eis independently selected from the group consisting of: hydrogen, —C_1-10alkyl and aryl-C_1-10alkyl-, wherein each alkyl and aryl is unsubstituted or substituted with one to three R^hsubstituents. In a class of this embodiment, each R^eis independently selected from the group consisting of: hydrogen, —C_1-10alkyl and phenyl-C_1-10alkyl-, wherein each alkyl and phenyl is unsubstituted or substituted with one to three R^hsubstituents. In another class of this embodiment, each R^eis independently selected from the group consisting of: hydrogen, —CH₃and —CH₂-phenyl wherein each alkyl and phenyl is unsubstituted or substituted with one to three R^hsubstituents.

In another embodiment, each R^eis —C_1-10alkyl-, wherein each alkyl is unsubstituted or substituted with one to three R^hsubstituents. In a class of this embodiment, each R^eis —CH₃.

In another embodiment of the present invention, each R^eis independently selected from the group consisting of: aryl-C_1-10alkyl-, wherein each alkyl and aryl is unsubstituted or substituted with one to three R^hsubstituents. In a class of this embodiment, each R^eis —CH₂-phenyl, wherein each CH₂and phenyl is unsubstituted or substituted with one to three R^hsubstituents.

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

In another embodiment of the present invention, each R^his 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^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 selected from the group consisting of: C_1-10alkyl. In another class of this embodiment, each R^his halogen.

In another embodiment of the present invention, R¹is hydrogen.

In another embodiment of the present invention, R¹is —C_1-6alkyl.

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 independently selected from the group consisting of: —C_1-6alkyl.

In another embodiment of the present invention, each R^kis 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^kis independently selected from the group consisting of: —C_1-10alkyl and —C_2-10alkenyl.

In another embodiment of the present invention, each R^kis independently selected from the group consisting of: —C_1-10alkyl.

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, —C_3-6cycloalkyl, aryl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1-4 substituents selected from C_1-6alkyl, halogen, and —OC_1-6alkyl. In a class of this embodiment, each R^Lis independently selected from the group consisting of: —C_1-10alkyl, —C_2-10alkenyl, —C_2-10alkynyl, —C_3-6cycloalkyl, phenyl and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, phenyl and heteroaryl are unsubstituted or substituted with 1-4 substituents selected from C_1-6alkyl, halogen, and —OC_1-6alkyl. In another class of this embodiment, each R^Lis independently selected from the group consisting of: —C_1-10alkyl, —C_2-10alkenyl, —C_2-10alkynyl, —C_3-6cycloalkyl, phenyl, and pyridine, wherein alkyl, alkenyl, alkynyl, cycloalkyl, phenyl and pyridine are unsubstituted or substituted with 1-4 substituents selected from C_1-6alkyl, halogen, and —OC_1-6alkyl. In another class of this embodiment, each R^Lis independently selected from the group consisting of: —CH₃, —CH═C(CH₃)₂, —C₂alkynyl-CH₃, cyclopropyl, phenyl —OCH₃and pyridine, wherein alkyl, alkenyl, alkynyl, cyclopropyl, phenyl and pyridine are unsubstituted or substituted with 1-4 substituents selected from C_1-6alkyl, halogen and —OC_1-6alkyl. In another class of this embodiment, each R^Lis independently selected from the group consisting of: —CH₃, —CH═C(CH₃)₂, —C₂alkynyl-CH₃, cyclopropyl, phenyl —OCH₃and pyridine.

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

In another class of this embodiment, each R^Lis independently selected from the group consisting of: —CH₃, and cyclopropyl.

In another embodiment of the present invention, each R^Lis independently selected from the group consisting of: —C_2-10alkynyl, wherein alkynyl is unsubstituted or substituted with 1-4 substituents selected from C_1-6alkyl, halogen, and —OC_1-6alkyl. In a class of this embodiment, each R^Lis independently selected from the group consisting of: —C_2-6alkynyl, wherein alkynyl is unsubstituted or substituted with 1-4 substituents selected from C_1-6alkyl, halogen, and —OC_1-6alkyl. In another class of this embodiment, each R^Lis independently selected from the group consisting of: —C_2-10alkynyl, wherein alkynyl is unsubstituted or substituted with 1-4 substituents selected from —CH₃. In another class of this embodiment, each R^Lis —C₂alkynyl-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 a class of this embodiment, n is 0 or 2. 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 a class of this embodiment, m is 0 or 2. 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, p is 0, 1 or 2. In a class of this embodiment, p is 0 or 1. In a class of this embodiment, p is 0 or 2. In another class of this embodiment, p is 1 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 embodiment of the present invention, q is 0, 1 or 2. In a class of this embodiment, q is 0 or 1. In a class of this embodiment, q is 0 or 2. 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 embodiment of the present invention, t is 0, 1 or 2. In a class of this embodiment, t is 0 or 1. In a class of this embodiment, t is 0 or 2. In another class of this embodiment, t is 1 or 2. In another class of this embodiment, t is 0. In another class of this embodiment, t is 1. In another class of this embodiment, t is 2.

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

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

embedded image