GLUCOKINASE ACTIVATORS

FIELD OF THE INVENTION

Provided are compounds that are useful in the treatment and/or prevention of diseases mediated by deficient levels of glucokinase activity, such as diabetes mellitus, and methods of preparing such compounds. Also provided are methods of treating diseases and disorders characterized by underactivation of glucokinase activity or which can be treated by activating glucokinase, comprising administering an effective amount of a compound of this invention.

BACKGROUND OF THE INVENTION

Diabetes mellitus comprises a group of syndromes characterized by an inability of the body to produce adequate insulin or to properly use insulin. Most diabetes patients can be classified clinically as having either insulin-dependent diabetes mellitus (IDDM) or non-insulin-dependent diabetes mellitus (NIDDM). Nearly all forms of diabetes mellitus result from either a decrease in the secretion and blood concentration of insulin or a decrease in the response of tissues to insulin (insulin resistance), often associated with an elevated level of hormones (e.g., glucagon) that act contrary to insulin. Such abnormalities give rise to changes in carbohydrate, lipid and protein metabolism. The syndrome's hallmark is hyperglycemia; other complications can include cardiovascular disease, retinopathy, neuropathy, nephropathy, skin disorders and gastroparesis.

Diabetes mellitus affects millions of persons worldwide, including over 18 million in the United States. It is estimated that IDDM (Type I diabetes), which results from the body's failure to produce insulin, accounts for 5-10% of the cases of diabetes diagnosed in the United States. The majority of diabetes patients in the United States are diagnosed with NIDDM (Type II diabetes), which results from insulin resistance combined with the inability of the pancreas to secrete sufficient insulin to overcome such resistance. Type II diabetes occurs in at least 5% of the United States population, and in 1996 alone NIDDM affected 16 million people (Roman, S. H.; Harris, M. I., Endocrinology and Metabolism Clinics of North America, 1997, 26.3, 443-474). Impaired glucose tolerance (IGT), a syndrome characterized by impaired glucose processing that presents symptoms similar to a mild form of Type II diabetes, is even more prevalent, affecting 35 to 40 million adults in the United States.

Diabetes is most frequently diagnosed either by the presentation of a fasting plasma glucose of greater than or equal to 126 mg/dL on two occasions, or by an oral glucose tolerance test (OGTT) with a 2 hour post load value of greater than 200 mg/dL plus classic symptoms such as polydipsia, polyphagia and/or polyuria (The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, Diabetes Care, 1998, 21, S5-19). In the case of IGT, a fasting plasma glucose of less than 126 mg/dL but a 2-hour post-oral glucose challenge lever greater than 140 mg/dL is observed.

A primary goal in the treatment of each of these conditions is the reduction and control of blood glucose levels. The reduction of hyperglycemia in insulin-dependent diabetes (IDDM) can attenuate the development of many of the attendant complications of IDDM (Diabetes Control and Complications Trial Research Group, New England J. Med., 1993, 329, 977-986). For example, tight control of blood glucose levels through intensive insulin therapy can reduce the development of retinopathy, nephropathy and neuropathy by >50% each in IDDM patients. These findings, together with the similarity of the pathologies seen in IDDM and NIDDM, suggest that control of blood glucose levels would produce similar benefits in NIDDM patients (American Diabetes Association, Diabetes Care, 1998, 21, S88-90), as has been reported (Ohkubo, Y., et al., Diabetes Res. Clin. Pract. 1995, 28, 103-117).

Several methods to treat hyperglycemia have been attempted. Patients with Type I diabetes receive insulin. In patients with Type II diabetes, the pancreas secretes insulin, but in insufficient amounts to overcome the intrinsic insulin resistance of the disease. The administration of agents such as metformin (De Froinzo, R. A.; Goodman, A. M. N. Engl. J. Med., 1995, 333, 541-549; Bailey, C. J. Biguanides and NIDDM, Diabetes Care 1992, 15, 773-784) and glitazone (PPAR agonist class of drugs; Willson, T. M., et al., J. Med. Chem. 1996, 39, 665-668) can at least partially ameliorate insulin resistance, but these agents do not promote insulin secretion. Treatment with certain sulfonylureas has been shown to promote insulin secretion by affecting an ion channel; however, the increase in insulin caused by this class of drugs is not glucose dependent or even glucose sensitive, and such treatment can actually raise the risk of overt hypoglycemia. DPP-IV inhibitors, such as GLP or a GLP mimetic (such as Exedin), promote CANT secretion at the β-cell through an incretin mechanism, and administration of these agents promotes insulin release in a glucose dependent manner (Vahl, T. P., D'Alessio, D. A., Expert Opinion on Invest. Drugs 2004, 13, 177-188). However, even with these potential treatments, it is difficult to achieve tight control of blood glucose levels in NIDMM patients in accordance with the guidelines recommended by the American Diabetes Association. Accordingly, there is significant demand for novel therapeutic approaches that allow sufficient glycemic control.

Possible approaches to glycemic control include enhancing clearance of glucose from the blood and increasing the rate of glucose storage or utilization. Glucose enters most cells by a specific transport protein, where it is phosphorylated to form glucose-6-phosphate in a reaction catalyzed by a hexokinase. Inside the cell, glucose-6-phosphate has one of several fates: it can be broken down via the glycolytic pathway, converted into glycogen or it can be oxidized via the pentose phosphate pathway.

Glucokinase (GK) (ATP:D-hexose 6-phosphotransferase), one of the four types of mammalian hexokinases (hexokinase IV), plays an essential role in blood glucose homeostasis. Expression of glucokinase is largely localized in the liver and pancreatic β-cells, where several types of glucokinase are expressed: these types differ in the sequence of the 15 N-terminal amino acids due to differences in splicing, but their enzymatic properties are virtually identical. Glucokinase is also expressed in a population of neurons in the hypothalamus.

Unlike the enzymatic activities of the other three hexokinases (I, II, III), each of which becomes saturated at a glucose concentration of below 1 mM, glucokinase has a K_mfor glucose of 8 mM, which is close to the physiological glucose level (5 mM). Thus, at lower glucose levels, glucose is more rapidly utilized in brain, muscle and other peripheral tissues—through conversion by a hexokinase other than glucokinase—than in the liver. At elevated glucose levels, such as after a meal or overnutrition (the postprandial glucose level can exceed 10-15 mM), glucokinase-mediated glucose metabolism in the liver and pancreas is accelerated. Moreover, hexokinases I, II and III are inhibited by high concentrations of glucose-6-phosphate, lowering glucose utilization, whereas glucokinase continues to catalyze utilization of glucose even at high levels of glucose-6-phosphate.

In tissues where glucokinase is expressed, it plays an important role in glucose uptake and utilization: in the β-cell, the glucose-6-phosphate produced is a necessary signal for insulin release; in the hypothalamus glucose-6-phosphate acts as a satiety signal and might contribute to the secretion of enteroincretins; and in the liver, where glucose-6-phosphate production by the action of glucokinase acts as a mechanism for disposal of excessive glucose through storage as glycogen (Printz, R. L., et al., Annu. Rev. Nutr., 1993, 13, 463-496). Glucokinase-catalyzed glucose phosphorylation is the rate-limiting reaction for glycolysis in hepatocytes and pancreatic O-cells. In the liver, glucokinase determines the rates of both glucose uptake and glycogen synthesis, and it is also thought to be essential for the regulation of various glucose-responsive genes (Girard, J., et al., Annu. Rev. Nutr., 1997, 17, 325-352). In both liver and pancreatic β-cells, glucokinase is rate limiting for glucose utilization, and consequently is a major component of the regulation of insulin secretion from the β-cell and glycogen storage in the liver. The control of insulin secretion and the control of glycogen storage are deficient in diabetes (DeFronzo, R. A., Diabetes, 1988, 37, 667-687).

The theoretical importance of glucokinase in diabetes is supported by studies of genetic populations and genetic manipulation of animal models of NIDDM. Mutation of glucokinase to a less active form of the kinase is the cause of the Maturity Onset of Diabetes in the Young (NODY-2) (Froguel, P., et al., New England J. Med., 1993, 328, 697-702; Bell, G. I., et al., Annual Rev. of Physiol., 1996, 58, 171-186). Conversely, humans with a glucokinase activation mutation are less prone to hyperglycemia and have increased insulin secretion in response to a glucose challenge (Christesen, H. B., et al., Diabetes, 2002, 51, 1240-1246; Gloyn, A. L, et al., Diabetes, 2003, 52, 2433-2440; Glaser, B., et al., New England J. Med., 1998, 338, 226-230). Also, NIDDM patients have been reported to have inappropriately low glucokinase activity. Furthermore, over expression of glucokinase in dietary or genetic animal models of diabetes either prevents, ameliorates, or reverses the progress of pathological symptoms in the disease (Caro, J. F., et al., Hormone & Metabolic Res., 1995, 27, 19-22). For these reasons, compounds that activate glucokinase have been sought by the pharmaceutical industry.

Substituted benzyl carbamoyl, substituted heterobenzyl carbamoyl, substituted phenyl carbamoyl; and substituted heteroaryl carbamoyl compounds have been disclosed as glucokinase activators. See, for example, WO 03/000267, WO 03/015774, WO 04/045614, WO 04/046139, WO 05/04480, WO 05/054200, WO 05/054233, WO 05/044801, WO 05/056530, WO 03/080585, WO 04/076420, WO 04/081001, WO 04/063194, WO 04/050645, WO 03/055482, WO 04/002481, WO 05/066145, WO 04/072031, WO 04/072066, U.S. Pat. No. 6,610,846, WO 00/058293, WO 03/095438, WO 01/44216, WO 01/083465, WO 01/083478, WO 01/085706, WO 01/085707, WO 02/008209, WO 02/014312, WO 02/046173, WO 02/048106, WO 03/095438, WO 04/031179, and WO 04/052869. These compounds either lower the K_mfor glucose and/or increase the V_maxof glucokinase. A class of glucokinase activators that can lower the K_mof glucose moderately to 2-5 mM at low activator concentrations is desirable.

SUMMARY OF THE INVENTION

The present invention relates to compounds that are activators of glucokinase which are useful in the treatment. of diseases and disorders that would benefit from activation of glucokinase.

More specifically, one aspect of this invention provides compounds of Formula I

and solvates, metabolites and pharmaceutically acceptable salts and prodrugs thereof, wherein L, Y, Z, G, R¹and R²are as defined herein.

The invention also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formula I, or a solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier.

The inventive compounds may be used advantageously in combination with other known therapeutic agents. Accordingly, this invention also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formula I or a solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof, in combination with a second therapeutic agent.

This invention also provides methods of preventing or treating a disease or disorder characterized by underactivation of glucokinase or which can be treated by activating glucokinase in a mammal, comprising administrating to said mammal one or more compounds of Formula I, or a metabolite, solvate, or pharmaceutically acceptable salt or prodrug thereof, in an amount effective to treat said disease or disorder. The compounds of the present invention can be used, for example, as prophylactics or therapeutic agents for treating diseases or disorders mediated by deficient levels of glucokinase activity, including, but not limited to, diabetes mellitus (type I and type II), impaired glucose tolerance, IFG (impaired fasting glucose) and IFG (impaired fasting glycemia), as well as other diseases and disorders characterized by underactivation of glucokinase or which can be treated by activation of glucokinase, such as those discussed below.

This invention also provides compounds of Formula I for use as medicaments in the treatment of diseases or disorders characterized by underactivation of glucokinase or which can be treated by activating glucokinase.

An additional aspect of the invention is the use of a compound of Formula I for the preparation of a medicament for the treatment or prevention of a disease or disorder characterized by underactivation of glucokinase or which can be treated by activating glucokinase in a mammal suffering from such disorder.

This invention further provides kits for the treatment or prevention of a disease or disorder characterized by underactivation of glucokinase, said kit comprising a compound of Formula I, or a solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof, a container, and optionally a package insert or label indicating a treatment. The kits may further comprise a second compound or formulation comprising a second pharmaceutical agent useful for treating said disease or disorder.

This invention further includes methods of preparing, methods of separating, and methods of purifying of the compounds of this invention.

Additional advantages and novel features of this invention shall be set forth in part in the description that follows, and in part will become apparent to those skilled in the art upon examination of the following specification or may be learned by the practice of the invention. The advantages of the invention may be realized and attained by means of the instrumentalities, combinations, compositions, and methods particularly pointed out in the appended claims.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. While the invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents which may be included within the scope of the present invention as defined by the claims. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described. In the event that one or more of the incorporated literature and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls.

DEFINITIONS

The term “alkyl” as used herein refers to a saturated linear or branched-chain monovalent hydrocarbon radical of one to twelve carbon atoms, wherein the allyl radical may be optionally substituted independently with one or more substituents described below. Examples of alkyl groups include, but are not limited to, methyl (Me, —CH₃), ethyl (Et, —CH₂CH₃), 1-propyl (n-Pr, n-propyl, —CH₂CH₂CH₃), 2-propyl (i-Pr, i-propyl, —CH(CH₃)₂), 1-butyl (n-Bu, n-butyl, —CH₂CH₂CH₂CH₃). 2-methyl-1-propyl (1-Bu, i-butyl, —CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl, —CH(CH₃)CH₂C₁H₃), 2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl (n-pentyl, —CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl (—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl (—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl (—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl (—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)), 2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl (—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂), 3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl (—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂), 3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, 1-heptyl, 1-octyl, and the like.

In certain embodiments, the term “alkyl” refers to a saturated linear or branched-chain monovalent hydrocarbon radical of one to six carbon atoms, wherein the alkyl radical may be optionally substituted independently with one or more substituents described below.

The term “alkylene” as used herein refers to a linear or branched saturated divalent hydrocarbon radical of one to twelve carbon atoms, wherein the alkylene radical may be optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, methylene, ethylene, propylene, 2-methylpropylene, pentylene, and the like.

In certain embodiments, the term “alkylene” refers to a linear or branched saturated divalent hydrocarbon radical of one to four carbon atoms, wherein the alkylene radical may be optionally substituted independently with one or more substituents described herein.

The term “alkenyl” as used herein refers to a linear or branched-chain monovalent hydrocarbon radical of two to twelve carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon sp2 double bond, wherein the alkenyl radical may be optionally substituted independently with one or more substituents described herein, and includes radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations. Examples include, but are not limited to, ethylenyl or vinyl (—CH═CH₂), allyl (—CH₂CH═CH₂), 1-buten-1-yl, 1-buten-2-yl, and the like.

In certain embodiments, the term “alkenyl” as used herein refers to a linear or branched-chain monovalent hydrocarbon radical of two to six-carbon atoms with at least one site of unsaturation, wherein the alkenyl radical may be optionally substituted independently with one or more substituents described herein, and includes radicals having “cis” and “trans” orientations.

The term “alkenylene” as used herein refers to a linear or branched divalent hydrocarbon radical of two to twelve carbons containing at least one double bond, wherein the alkenylene radical may be optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, ethenylene, propenylene, and the like.

The term “alkenylene” includes linear or branched divalent hydrocarbon radical of two to four carbons containing at least one double bond, wherein the alkenylene radical may be optionally substituted independently with one or more substituents described herein.

The term “alkynyl” as used herein refers to a linear or branched monovalent hydrocarbon radical of two to twelve carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon sp triple bond, wherein the alkynyl radical may be optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, ethynyl (—C≡CH), propynyl (propargyl, —CH₂C≡CH) and the like.

In certain embodiments, the term “alkynyl” refers to a linear or branched monovalent hydrocarbon radical of two to six carbon atoms with at least one carbon-carbon sp triple bond.

The term “alkynylene” as used herein refers to a linear or branched divalent hydrocarbon radical of two to twelve carbons containing at least one triple bond, wherein the alkynylene radical may be optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, ethynylene, propynylene, and the like.

In certain embodiments, the term “alkynylene” refers to a linear or branched divalent hydrocarbon radical of two to four carbons containing at least one triple bond.

The term “heteroalkyl” as used herein refers to saturated linear or branched-chain monovalent hydrocarbon radical of one to twelve carbon atoms, wherein at least one of the carbon atoms is replaced with a heteroatom independently selected from N, O, or S, and wherein the radical may be a carbon radical or heteroatom radical. The heteroalkyl radical may be optionally substituted independently with one or more substituents described herein. The term “heteroalkyl” encompasses alkoxy and heteroalkoxy radicals.

The terms “cycloalkyl,” “carbocycle,” “carbocyclyl” and “carbocyclic ring” are used interchangeably and refer to a saturated or partially unsaturated cyclic hydrocarbon radical having from three to twelve carbon atoms. The term “cycloalkyl” includes monocyclic and polycyclic (e.g., bicyclic and tricyclic) cycloalkyl structures, wherein the polycyclic structures optionally include a saturated or partially unsaturated cycloalkyl fused to a saturated, partially unsaturated or aromatic cycloalkyl or heterocyclic ring. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, and the like. Bicyclic carbocycles include those having 7 to 12 ring atoms arranged, for example, as a bicyclo[4,5], [5,5], [5,6] or [6,6] system, or as bridged systems such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. The cycloalkyl may be optionally substituted independently with one or more substituents described herein.

“Aryl” as used herein means a monovalent aromatic hydrocarbon radical of 6-20 carbon atoms derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Aryl includes bicyclic radicals comprising an aromatic ring fused to a saturated, partially unsaturated ring, or aromatic carbocyclic or heterocyclic ring. Exemplary aryl groups include, but are not limited to, radicals derived from benzene, naphthalene, anthracene, biphenyl, indene, indane, 1,2-dihydronapthalene, 1,2,3,4-tetrahydronapthalene, and the like. Aryl groups may be optionally substituted independently with one or more substituents described herein.

The terms “heterocycle”, “heterocyclyl” and “heterocyclic ring” as used herein are used interchangeably and refer to a saturated or partially unsaturated carbocyclic radical of 3 to 12 ring atoms in which at least one ring atom is a heteroatom independently selected from nitrogen, oxygen and sulfur, the remaining ring atoms being C, where one or more ring atoms may be optionally substituted independently with one or more substituents described below. The radical may be a carbon radical or heteroatom radical. The term “heterocycle” includes heterocycloalkoxy. “Heterocyclyl” also includes radicals where heterocycle radicals are fused with a saturated, partially unsaturated, or aromatic carbocyclic or heterocyclic ring. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinylimidazolinyl, imidazolidinyl, 3-azabicyco[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3H-indolyl quinolizinyl and N-pyridyl ureas. Spiro moieties are also included within the scope of this definition. The heterocycle may be C-attached or N-attached where such is possible. For instance, a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole may be imidazol-1-yl (N-attached) or imidazol-3-yl (C-attached). Examples of heterocyclic groups wherein 2 ring carbon atoms are substituted with oxo (═O) moieties are isoindoline-1,3-dionyl and 1,1-dioxo-thiomorpholinyl. The heterocycle groups herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups described herein.

The term “heteroaryl” as used herein refers to a monovalent aromatic radical of a 5-, 6-, or 7-membered ring, and includes fused ring systems (at least one of which is aromatic) of 5-12 atoms, containing at least one heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Spiro moieties are also included within the scope of this definition. Heteroaryl groups may be optionally substituted independently at one or more substitutable positions with one or more substituents described herein.

By way of example and not limitation, carbon bonded heterocycles and heteroaryls are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline. Further examples of carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

By way of example and not limitation, nitrogen bonded heterocycles and heteroaryls are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of an isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or 3-carboline. Still more typically, nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

The term “halogen” as used herein means fluoro, chloro, bromo or iodo.

The term “a” as used herein means one or more.

As used herein, the terms “compound of this invention,” “compounds of the present invention” and “compounds of Formula I” include compounds of Formula I and tautomers, resolved enantiomers, resolved diastereomers, racemic mixtures, solvates, metabolites, and pharmaceutically acceptable salts and prodrugs thereof.

In general, the various moieties or functional groups of the compounds of this invention may be optionally substituted by one or more substituents. Examples of substituents suitable for purposes of this invention include, but are not limited to, oxo, halogen, CN, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, V_n—NR″SO₂R′, V_n—SO₂NR′R″, V_n—C(═O)R′, V_n—C(═O)OR′, V_n—OC(—O)R′, V_n—NR″C(═O)OR′, V_n—NR″C(═O)R′, V_n—C(═O)NR′R″, V_n—NR′R″, V_n—NR′″C(═O)N′R″, V_n—OR′, V_n—SR′, V_n—S(O)₂R′, V_n—S(O)₂R′, alkyl, alkenyl, alkynyl, V_n-heteroalkyl, V_n-cycloalkyl, V_n-heterocyclyl, V_n-aryl, and V_n-heteroaryl, where R′, R″ and R′″ are independently H, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

It is to be understood that in instances where two or more radicals are used in succession to define a substituent attached to a structure, the first named radical is considered to be terminal and the last named radical is considered to be attached to the structure in question. Thus, for example, an arylalkyl radical is attached to the structure in question by the alkyl group.

Glucokinase Activators

The present invention provides compounds, and pharmaceutical formulations thereof, that are useful in the treatment of diseases, conditions and/or disorders characterized by underactivation of glucokinase or which can be treated by activation of glucokinase.

One aspect of the invention provides compounds of Formula I

and tautomers, resolved enantiomers, resolved diastereomers, racemic mixtures, solvates, metabolites and pharmaceutically acceptable salts and prodrugs thereof, wherein:

L is O, S, S(═O), S(═O)₂, NR¹⁴CR¹⁴R¹⁵, or C(═O);

Y is N or CR⁴;

G is N or CR¹¹;

Z is N or CR³, wherein at least one of G or Z is not N;

R¹is a heteroaryl ring represented by the formula

D¹is S, O or N;

D²is N or CR¹²;

D³is S, O or CR¹³;

R²is aryl, heteroaryl, saturated or partially unsaturated cycloalkyl, or saturated or partially unsaturated heterocyclyl optionally substituted with oxo, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl are monocyclic or bicyclic and are further optionally substituted with one or more groups independently selected from alkyl, alkenyl, alkynyl, heteroalkyl, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, aryl, heteroaryl, F, Cl, Br, I, CF₃, CN, OR⁶, C(═O)R⁶, C(═O)OR⁶, OC(═O)R⁶, O(CH₂)_nC(═O)OR⁶, O(CH₂)_nC(═O)NR⁶R⁷, C(═O)NR⁶R⁷, NR⁶R⁷, NR⁶C(—O)R⁷, SR⁶, S(O)R⁶, S(O)₂R⁶, NO₂, and wherein said alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from oxo, alkyl, alkenyl, alkynyl, heteroalkyl, saturated and partially unsaturated V_n-cycloalkyl, saturated and partially unsaturated V_n-heterocyclyl, V_n-aryl, V_n-heteroaryl, V_n—F, V_n—Cl, V_n—Br, V_n—I, V_n—CF₃, V_n—CN, V_n—OR⁸, V_n—C(═O)R⁸, V_n—C(═O)OR⁸, V_n—OC(═O)R⁸, V_n—C(═O)NR⁸R⁹, V_n—NR⁸R⁹, V_n—NR⁸C(═O)R⁹, V_n—SR⁸, V_n—S(O)R⁸, and V_n—S(O)₂R⁸;

R³is H, alkyl, alkenyl, alkynyl, heteroalkyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, heteroaryl, F, Cl, Br, I, CN, OR⁶, C(═O)R⁶, C(═O)OR⁶, OC(—O)R⁶, C(═O)NR⁶R⁷, OC(═O)NR⁶R⁷, OC(═S)NR⁶R⁷, NR⁶R⁷, NR⁶C(═O)R⁷, SR⁶, S(O)R⁶, S(O)₂R⁶or S(O)₂NR⁶R⁷, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from oxo, alkyl, alkenyl, alkynyl, heteroalkyl, saturated and partially unsaturated V_n-cycloalkyl, saturated and partially unsaturated V_n-heterocyclyl, V_n-aryl, V_n-heteroaryl, V_n—F, V_n—Cl, V_n—Br, V_n—I, V_n—CF₃, V_n—CN, V_n—OR⁸, V_n—C(—O)R⁸, V_n—C(═O)OR⁸, V_n—OC(═O)R⁸, V_n—C(—O)NR⁸R⁹V_n—NR⁸R⁹, V_n—NR⁸C(═O)R⁹, V_n—SR⁸, V_n—S(O)R⁸V_n—S(O)₂R⁸and V_n—S(O)₂NR⁸R⁹;

R⁴is H, methyl, ethyl, F, Cl, Br, I, CF₃, CHF₂or CH₂F;

R⁶and R⁷are independently H, alkyl, alkenyl, alkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, heteroaryl, OR⁸, NR⁸R⁹, C(═O)NR⁸R⁹, C(═O)R⁸, or C(═O)OR⁸, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from oxo, alkyl, alkenyl, alkynyl, heteroalkyl, saturated and partially unsaturated V_n-cycloalkyl, saturated and partially unsaturated V_n-heterocyclyl optionally substituted with C(O)O(C₁-C₆alkyl), V_n-aryl, V_n-heteroaryl, V_n—F, V_n—Cl, V_n—Br, V_n—I, V_n—CF₃, V_n—CN, V_n—OR⁸, V_n—C(═O)R⁸, V_n—C(═O)OR⁸, V_n—OC(═O)R⁸, V_n—C(—O)NR⁸R⁹, V_n—NR⁸R⁹, V_n—NR⁸C(═O)R⁹, V_n—SR⁸, V_n—S(O)R⁸, V_n—S(O)₂R⁸, and V_n—S(O)₂NR⁸R⁹,

or R⁶and R⁷together with the atoms to which they are attached form a saturated or partially unsaturated heterocyclic ring, wherein said heterocyclic ring optionally comprises one or more additional ring heteroatoms independently selected from N, O or S, wherein said heterocyclic ring is optionally substituted with one or more groups independently selected from oxo, V_n—F, V_n—Cl, V_n—Br, V_n—I, V_n—OR⁸, V —C(═O)OR⁸, V_n—C(═O)NR⁸R⁹, V_n—NR⁸R⁹, V_n—NR⁸C(═O)R⁹, V_n—NR⁸C(═O)NR⁹R¹⁰, alkyl, alkenyl, and alkynyl;

R⁸, R⁹and R¹⁰are independently H, alkyl, alkenyl, alkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from oxo, alkyl, alkenyl, alkynyl, saturated and partially unsaturated V_n-cycloalkyl, saturated and partially unsaturated V_n-heterocyclyl, V_n-aryl, V_n-heteroaryl, V_n—F, V_n—Cl, V_n—Br, V_n—I, V_n—OR^a, V_n—NR^aR^b, V_n—C(═O)OR^a, V_n—C(═O)NR^aR^b, and V_n—NR^aC(═O)R^b,

or R⁸and R⁹together with the atoms to which they are attached form a saturated or partially unsaturated heterocyclic ring, wherein said heterocyclic ring optionally comprises one or more additional ring heteroatoms independently selected from N, O or S, wherein said heterocyclic ring is optionally substituted with one or more groups independently selected from oxo, alkyl, alkenyl, alkynyl, V_n—F, V_n—Cl, V_n—Br, V_n—I, V_nOR³, and V_n—CN,

or R⁹and R¹⁰together with the atoms to which they are attached form a saturated or partially unsaturated heterocyclic ring, wherein said heterocyclic ring optionally comprises one or more additional ring heteroatoms independently selected from N, O or S, wherein said heterocyclic ring is optionally substituted with one or more groups independently selected from oxo, alkyl, alkenyl, alkynyl, V_n—F, V_n—Cl, V_n—Br, V_n—I, V_n—OR^a, and V_n—CN;

R¹¹is H, methyl, ethyl, F, Cl, Br, I, CF₃, CHF₂, CH₂F, OH, O—(C₁-C₄alkyl), or NH₂;

R¹²and R¹³are independently H, alkyl, alkenyl, alkynyl, heteroalkyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, heteroaryl, F, Cl, Br, I, CF₃, CN, OR⁶, C(═O)R⁶, C(═O)OR⁶, OC(O)R⁶, C(═O)NR⁶R⁷, NR⁶R⁷, NR⁶C(═O)R⁷, SR⁶, S(O)R⁶or S(O)₂R⁶, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from oxo, V_n—F, V_n—Cl, V_n—Br, V_n—I, V_n—CF₃, V_n—CN; V_n—OR⁸, V_n—C(═O)OR⁸, V_n—OC(═O)R⁸, V_n—C(═O)NR⁸R⁹, V_n—NR⁸R⁹, V_n—NR⁸C(═O)R⁹, alkyl, alkenyl, alkynyl, saturated and partially unsaturated V_n-cycloalkyl, saturated and partially unsaturated V_n-heterocyclyl, V_n-aryl, and V_n-heteroaryl, wherein said heterocyclyl is optionally substituted with one or more oxo,

or R¹²and R¹³together with the atoms to which they are attached form a saturated, partially unsaturated or aromatic carbocyclic or heterocyclic ring, wherein said carbocyclic and heterocyclic rings are optionally substituted with one or more groups independently selected from alkyl, alkenyl, alkynyl, heteroalkyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, heteroaryl, oxo, F, Cl, Br, I, CF₃, CN, OR⁶, C(═O)R⁶, C(═O)OR⁶, OC(═O)R⁶, C(—O)NR⁶R⁷, NR⁶R⁷, NR⁶C(═O)R⁷, SR⁶, S(O)R⁶, S(O)₂R⁶and SO₂NR⁶R⁷, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from oxo, V_n—F, V_n—Cl, V_n—Br, V_n—I, V_n—CF₃, V_n—CN, V_n—OR⁸, V_n—C(═O)OR⁸, V_n—OC(═O)R⁸, V_n—C(═O)NR⁸R⁹, V_n—NR⁸R⁹, V_n—NR⁸C(═O)R⁹, alkyl, alkenyl, alkynyl, saturated and partially unsaturated V_n-cycloalkyl, saturated and partially unsaturated V_n-heterocyclyl, V_n-aryl, and V_n-heteroaryl;

R¹⁴and R¹⁵are independently H, methyl, ethyl, F, Cl, Br, I, CF₃, CHF₂, CH₂F, OH, O—(C₁-C₄alkyl), or NH₂;

R^aand R^bare independently H, alkyl, alkenyl, alkynyl, saturated or partially unsaturated V_n-cycloalkyl, saturated or partially unsaturated V_n-heterocyclyl, V_n-aryl, or V_n-heteroaryl, wherein said alkyl, alkenyl, alkynyl, saturated or partially unsaturated V_n-cycloalkyl, saturated or partially unsaturated V_n-heterocyclyl, V_n-aryl, and V_n-heteroaryl are optionally substituted with one or more OH;

V is alkylene having from 1 to 12 carbons, or alkenylene or alkynylene each having from 2 to 12 carbons, wherein said alkylene, alkenylene, or alkynylene are optionally substituted with one or more groups independently selected from alkyl, alkenyl, alkynyl, heteroalkyl, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, aryl, heteroaryl, F, Cl, Br, I, CF₃, cyano, OR⁸, C(—O)OR⁸, OC(—O)R⁸, C(═O)NR⁸R⁹, NR⁸R⁹, and NR⁸C(═O)R⁹; and

n is 0 or l.

In certain embodiments of Formula I wherein R¹and R²are each 5 membered single-ring heteroaryl groups, R¹does not have a substituent represented by C(═O)OR^dor C(═O)NR^eR^f, wherein R^dis H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, cycloalkenyl-alkyl, arylalkyl or aryl, and R^eand R^fare independently H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, cycloalkenyl-alkyl, arylalkyl, aryl heterocyclyl, or acyl, or R^eand R^ftogether with the N atom form a heterocyclic ring. The compounds according to this definition were disclosed in the provisional application from which the present invention claims priority, and are provided as an embodiment of the invention.

In certain embodiments, provided are compounds of Formula I wherein:

R²is aryl, heteroaryl, saturated or partially unsaturated cycloalkyl, or saturated or partially unsaturated heterocyclyl, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl are monocyclic or bicyclic and are further optionally substituted with one or more groups independently selected from alkyl, alkenyl, alkynyl, heteroalkyl, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, aryl, heteroaryl, F, Cl, Br, I, CF₃, CN, OR⁶, C(═O)R⁶, C(═O)OR⁶, OC(═O)R⁶, O(CH₂)_nC(═O)OR⁶, O(CH₂)_nC(═O)NR⁶R⁷, C(—O)NR⁶R⁷, NR⁶R⁷, NR⁶C(—O)R⁷, SR⁶, S(O)R⁶, and S(O)₂R⁶, and wherein said alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from oxo, alkyl, alkenyl, alkynyl, heteroalkyl, saturated and partially unsaturated V_n-cycloalkyl, saturated and partially unsaturated V_n-heterocyclyl, V_n-aryl, V_n-heteroaryl, V_n—F, V_n—Cl, V_n—Br, V_n—I, V_n—CF₃, V_n—CN, V_n—OR⁸, V_n—C(═O)R⁸, V_n—C(—O)OR⁸, V_n—OC(—O)R³, V_n—C(═O)NR⁸R⁹, V_n—NR⁸R⁹, V_n—NR⁸C(═O)R⁹V_n—SR⁸, V_n—S(O)R⁸, and V_n—S(O)₂R⁸; and

R⁶and R⁷are independently H, alkyl, alkenyl, alkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, heteroaryl, OR⁸, NR⁸R⁹, C(—O)NR¹R⁹, C(═O)R⁸, or C(═O)OR⁸, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from oxo, alkyl, alkenyl, alkynyl, heteroalkyl, saturated and partially unsaturated V_n-cycloalkyl, saturated and partially unsaturated V_n-heterocyclyl, V_n-aryl, V_n-heteroaryl, V_n—F, V_n—Cl, V_n—Br, V_n—I, V_n—CF₃, V_n—CN, V_n—OR⁸V_n—C(═O)R⁸, V_n—C(═O)OR⁸, V_n—OC(═O)R⁸, V_n—C(—O)NR⁸R⁹, V_n—NR⁸R⁹, V_n—NR⁸C(═O)R⁹, V_n—SR⁸, V_n—S(O)R⁸, V_n—S(O)₂R⁸, and V_n—S(O)₂NR⁸R⁹,

or R⁶and R⁷together with the atoms to which they are attached form a saturated or partially unsaturated heterocyclic ring, wherein said heterocyclic ring optionally comprises one or more additional ring heteroatoms independently selected from N, O or S, wherein said heterocyclic ring is optionally substituted with one or more groups independently selected from oxo, V_n—F, V_n—Cl, V_n—Br, V_n—I, V_n—OR⁸, V_n—C(═O)OR⁸, V_n—C(—O)NR⁸R⁹, V_n—NR⁸R⁹, V_n—NR⁸C(—O)R⁹, V_n—NR⁸C(═O)NR⁹R¹⁰, alkyl, alkenyl, and alkynyl.

In certain embodiments, provided are compounds of Formula I wherein G is CH or CCl, Y is CH, and Z is CR³.

In certain embodiments, L is O.

In certain embodiments, L is S.

In certain embodiments, L is SO.

In certain embodiments, L is SO₂

In certain embodiments, L is NR¹⁴. In particular embodiments, L is NH.

In certain embodiments, L is CR¹⁴R¹⁵. In particular embodiments, L is CH₂.

In certain embodiments, L is C(—O).

The compounds of Formula I include compounds having the Formula Ia

wherein:

L is O, S, SO, SO₂, CHOH, C(O), or CH₂;

D²is CR¹²or N;

R³is H, Br, OR⁶, SR⁶, C(O)OR⁶, C(O)NR⁶R⁷, C(O)R⁶, heteroaryl, or C₁-C₆alkyl substituted with one or more groups independently selected from V_n-aryl, V_n—OR⁸, V_n—C(═O)OR⁸and V_n—NR⁸R⁹;

R⁶and R⁷are independently H, C₁-C₆alkyl, saturated or partially unsaturated cycloalkyl, aryl, or heteroaryl, wherein said alkyl is optionally substituted with one or more groups independently selected from V_n-heterocyclyl [optionally substituted with C(O)O(C₁-C₆alkyl)], V_n-heteroaryl, V_n—C(═O)OR⁸,

R⁸, R⁹and R¹⁰are independently H or alkyl;

R¹¹is H or Cl;

R¹²and R¹³are independently H, C₁-C₆alkyl (optionally substituted with one or more groups independently selected from V_n—OR⁸, or V_n—C(═O)OR⁸)₃saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, or heteroaryl (optionally substituted with C₁-C₆alkyl),

or R¹²and R¹³together with the atoms to which they are attached form a saturated, partially unsaturated or aromatic heterocyclic ring;

each V is independently alkylene having from 1 to 4 carbons or alkenylene having from 2 to 4 carbons; and

each n is independently 0 or 1.

In certain embodiments of compounds of Formula I, R¹¹is hydrogen.

In certain embodiments of compounds of Formula I, R⁴is hydrogen.

In certain embodiments of compounds of Formula I, R¹is a heteroaryl ring selected from

wherein R²⁰is H, alkyl, alkenyl, alkynyl, heteroalkyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, heteroaryl, F, Cl, Br, I, CF₃, CN, OR⁶, C(═O)R⁶, C(—O)OR⁶, OC(═O)R⁶, C(═O)NR⁶R⁷, NR⁶R⁷, NR⁶C(—O)R⁷, SR⁶, S(O)R⁶, S(O)₂R⁶or SO₂NR⁶R⁷, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from oxo, V_n—F, V_n—Cl, V_n—Br, V_n—I, V_n—CF₃, V_n—CN, V_n—OR⁸, V_n—C(═O)OR⁸, V_n—OC(═O)R³, V_n—C(═O)NR⁸R⁹, V_n—NR⁸R⁹, V_n—NR⁸C(═O)R⁹, alkyl, alkenyl, alkynyl, saturated and partially unsaturated V_n-cycloalkyl, saturated and partially unsaturated V_n-heterocyclyl, V_n-aryl, and V_n-heteroaryl,

and wherein each R²⁰is independent of the other.

In particular embodiments of Formula I, R¹is selected from the structures:

wherein R¹²and R¹³are as defined herein.

In particular embodiments, R²⁰is H.

In certain embodiments, R¹²and R¹³are independently selected from H, alkyl, alkenyl, alkynyl, OR⁶, C(═O)OR⁶, C(—O)NR⁶R⁷, NR⁶R⁷, NR⁶C(═O)R⁷and heterocyclyl, wherein said alkyl, alkenyl, alkynyl, and heterocyclyl are optionally substituted with one or more groups independently selected from V_n—OR⁶, V_n—C(═O)OR⁶, V_n—C(═O)NR⁶R⁷, V_n—NR⁶R⁷, V_n—NR⁶C(═O)R⁷and V_n-heterocyclyl. For example, in certain embodiments R¹²and R¹³are independently selected from H, CH₃, CH₂CH₂OH, CH₂COOH and CH₂CH₂COOH. In certain embodiments, R¹²is H and R¹³is methyl.

In other embodiments of Formula I, R¹²and R¹³are independently selected from H, CF₃, C₁-C₆alkyl [optionally substituted with V_n—OR⁸, V_n—C(═O)OR⁸or V_n-aryl], C₃-C₆cycloalkyl, a 5-6 membered heterocyclyl having an oxygen atom, heteroaryl, and CO₂R⁶. In certain embodiments, V is C₁-C₄alkylene and n is 0 or 1.

In other embodiments of Formula I, R¹³is an N-(1-6C alkanoyl)-piperidin-4-yl group. As used herein, the term “alkanoyl” as used herein, refers to the group —C(—O)-(1-6C alkyl), wherein the alkyl portion is of the straight or branched configuration. Exemplary alkanoyl groups include, but are not limited to, acetyl (ethanoyl), n-propanoyl, n-butanoyl, 2-methylpropanoyl and n-pentanoyl.

Examples of R¹²and R¹³when represented by a C₁-C₆alkyl group substituted by V_n—OR⁸include groups where V is C₁-C₄alkylene, n is 1, and R⁶is C₁-C₆alkyl or H. A particular value includes —(C₁-C₆alkyl)OH.

Examples of R¹²and R¹³when represented by a C₁-C₆alkyl group substituted by V_n—CO₂R⁶include groups where V is C₁-C₄alkylene, n is 1, and R¹is C₁-C₆alkyl or H. Particular values include —(C₁-C₆alkyl)CO₂H and —(C₁-C₆alkyl)CO₂(C₁-C₆alkyl).

Examples of R¹²and R¹³when represented by a C₁-C₆alkyl group substituted by V_n-aryl include groups where V is C₁-C₄alkylene, n is 1, for example and aryl is phenyl. A particular value is a benzyl group.

A particular value for R¹²and R¹³when represented by a 5-6 membered heterocycle having an oxygen atom is a tetrahydrofuranyl ring.

Examples of R¹²and R¹³when represented by a heteroaryl ring include 5-6 membered heteroaryl rings having one to three heteroatoms independently selected from N and S. Particular values include pyridyl and thienyl rings.

Examples of R¹²and R¹³when represented by a CO₂R⁶group include groups where R⁶is H or C₁-C₆alkyl.

In particular embodiments of Formula I, R¹²and R¹³are independently H, methyl, ethyl, isopropyl, butyl, isobutyl, t-butyl, CF₃, cyclopropyl, cyclohexyl, —CH₂CH₂OH, (CH₂)₂CO₂H, —(CH₂)₂CO₂Me, —(CH₂)CO₂Et, CH₂CH₂Ph, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-thienyl, 2-tetrahydrofuranyl or CO₂Et.

In particular embodiments, R¹²is H.

In certain embodiments of Formula I, R²is an aryl or cycloalkyl ring selected from phenyl, 1-naphthyl, 2-naphthyl, 1-tetrahydronaphthalenyl, 2-tetrahydronaphthalenyl, 3-tetrahydronaphthalenyl, 4-tetrahydronaphthalenyl, 5-tetrahydronaphthalenyl, 6-tetrahydronaphthalenyl, 7-tetrahydronaphthalenyl, 8-tetrahydronaphthalenyl, cyclohexyl, and substituted forms thereof.

In certain embodiments, R²is selected from

and substituted forms thereof.

For example, in certain embodiments, R²is phenyl optionally substituted with one or more groups independently selected from F, Cl, Br, I, CN, alkyl, CF₃, OR⁶, C(═O)OR⁶, O(CH₂)_nC(═O)OR⁶, C(═O)NR⁶R⁷and NR⁶C(—O)R⁷, wherein said alkyl is optionally substituted with one or more groups independently selected from V_n—OR⁶, V_n—C(═O)OR⁶, V_n—O(CH₂)_nC(═O)OR⁶, V_n—C(═O)NR⁶R⁷and V_n—NR⁶C(═O)R⁷.

In other embodiments, R²is phenyl optionally substituted with one or more groups independently selected from F, Cl, CN, CF₃, —OR⁶, —CO₂R⁶, —O(CH₂)_nC(═O)OR⁶, —C(═O)NR⁶R⁷and C₁-C₆alkyl (optionally substituted with OH).

Examples of phenyl substituents having the formula —OR⁶include groups wherein R⁶is H or C₁-C₆alkyl.

Examples of phenyl substituents having the formula —C(—O)OR⁶include groups wherein R⁶is H or a C₁-C₆alkyl group optionally substituted with OH.

Examples of phenyl substituents having the formula —O(CH₂)C(O)OR⁶include groups wherein R⁶is H or C₁-C₆alkyl.

Examples of phenyl substituents having the formula —C(—O)NR⁶R⁷include groups wherein R⁶and R⁷are independently H or C₁-C₆alkyl. In certain embodiments the alkyl group is substituted with —NR⁸R⁹(wherein R⁸and R⁹are independently H or C₁-C₆alkyl), a 5-membered heteroaryl having 1-2 ring nitrogen atoms, or a 5-6 membered heterocycle having 1-2 ring heteroatoms independently selected from N and O.

Further examples of phenyl substituents having the formula —C(═O)NR⁶R⁷include groups wherein —NR⁶R⁷forms a 5-6 membered heterocyclic ring optionally having a ring nitrogen and optionally having a second ring N atom. Exemplary values of the heterocyclic ring include pyrrolidinyl, piperidinyl, and piperazinyl. In particular examples, NR⁶R⁷form a piperidinyl ring. In certain embodiments the heterocyclic ring is substituted with C₁-C₆alkyl, such as methyl or ethyl.

Examples of phenyl substituents represented by a C₁-C₆alkyl group substituted by V_n—OR⁶include groups wherein V is C₁-C₄alkylene, n is 0 or 1, and R⁶is H or C₁-C₆alkyl. A particular-value is CH₂CH₂OH.

In particular embodiments of Formula I, R²is phenyl optionally substituted with one or more groups independently selected from Cl, F, CN, Me, iPr, CF₃, —OCH₃, —OH, —OCH₂CH₂OH, —CH₂OH, —OCH₂CO₂H, —OCH₂CO₂(t-Bu), —CO₂Me, —CO₂Et, —CO₂H, —C(O)NHCH₂CH₂NMe₂, C(O)NHCH₂CH₂CH₂N(CH₃)₂, —C(O)N(Me)CH₂CH₂N(CH₃)₂, C(O)NHCH₂CH₂NHCH(CH₃)₂, —C(O)NH(CH₂)₃(N-morpholinyl), —C(O)(N-pyrrolidinyl), —C(O)NHCH₂CH₂(imidazolyl), —OCH₂C(O)OC(CH₃)₂, —OCH₂C(O)OH,

Further exemplary embodiments of R²include, but are not limited to, the structures:

Further exemplary embodiments of R²include the structures:

Exemplary embodiments of R²further include, but are not limited to, heteroaryl and heterocyclic rings selected from 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl, 8-quinolinyl, 2-quinoxalinyl, 3-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl, 7-quinoxalinyl, 8-quinoxalinyl, benzo[d]thiazol-2-yl, 4-benzo[d]thiazolyl, 5-benzo[d]thiazolyl, 6-benzo[d]thiazolyl, 7-benzo[d]thiazolyl, 2-1H-benzo[d]imidazolyl, 1H-benzo[d]imidazole-4-yl, 1H-benzo[d]imidazole-5-yl, 1H-benzo[d]imidazole-6-yl, 1H-benzo[d]imidazole-7-yl, 2-thiophenyl, 3-thiophenyl, 5-tetrahydroquinolinyl, 6-tetrahydroquinolinyl, 7-tetrahydroquinolinyl, 8-tetrahydroquinolinyl, 5-tetrahydroisoquinolinyl, 6-tetrahydroisoquinolinyl, 7-tetrahydroisoquinolinyl, 8-tetrahydroisoquinolinyl, 1-pyrazolyl, 2-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, and substituted forms thereof.

In other embodiments, R²is a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from N and O (provided the ring does not contain a 0-0 bond). Examples of heteroaryl rings include 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-imidazolyl, 3-furyl, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, and 2-oxazolyl.

In particular embodiments, R²is a heteroaryl ring optionally substituted with one or two groups independently selected from NO₂, Cl, Br, CN, CF₃, and C₁-C₆alkyl.

Exemplary embodiments of R²includes the structures:

and substituted forms thereof.

In particular embodiments, R²is selected from

Further exemplary embodiments of R²when represented by a heteroaryl ring include the structures:

In another embodiment, R²is a saturated or partially unsaturated 5 membered heterocyclic ring. In certain embodiments, there heterocyclic ring has one or two ring heteroatoms, for example, a 4,5-dihydro-1H-pyrazolyl ring. In certain embodiments, the heterocyclic ring is substituted with oxo. A particular example of R²is the structure:

In other embodiments, R²is a 9-10 membered heteroaryl ring having a nitrogen atom and optionally having 1 to 2 additional ring heteroatoms independently selected from N, O and S (provided the ring does not contain a O—O or S—S bond). In certain embodiments, the bicyclic heterocyclic ring is quinolyl, isoxazolo[5,4-b]pyridyl, thienopyridyl, pyrazolopyrimidyl, or 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidyl.

In certain embodiments, the bicyclic heterocyclic ring is substituted with C₁-C₆alkyl (for example, methyl).

Further exemplary embodiments when R²is represented by a 9-10 membered heteroaryl ring include the structures:

In certain embodiments, R²is a partially unsaturated 10 membered bicyclic heterocyclic ring having 1-3 nitrogen atoms. In certain embodiments, the bicyclic heterocyclic ring is substituted with C(O)O-tBu. Exemplary embodiments include the structures:

In certain embodiments, R²is a 5-6 membered cycloalkyl ring optionally substituted with C₁-C₆alkyl. In particular embodiments, R²is cyclopentyl, cyclohexyl or 2-methylcyclohexyl.

In certain embodiments of Formula I, Z is N.

In other embodiments of Formula I, Z is CR³.

In certain embodiments of Formula I, R³is selected from F, Cl, Br, I, CN, V_n—OR⁶, V_n—SR⁶, V_n—S(O)R⁶, V_n—S(O)₂R⁶, V_n—NR⁶R⁷, V_n—C(═O)NR⁶R⁷, V_n—C(═O)OR⁶, V_n—C(═O)R⁶, V_n-aryl, V_n-heteroaryl, alkyl, alkenyl and alkynyl, wherein said aryl, heteroaryl, alkyl, alkenyl and alkynyl are substituted or unsubstituted.

In other embodiments of Formula I, R³is H, Br, OR⁶, SR⁶, C(O)OR⁶, C(O)NR⁶R⁷, C(O)R⁶, a 5-6 membered heteroaryl group having at least one ring nitrogen atom, or a C₁-C₆alkyl group optionally substituted with V_n—CO₂R⁶, V_n—OR⁶, V_n—NR⁶R⁷or V_n—Ar. In certain embodiments, V is C₁-C₄alkylene or C₂-C₄alkenylene. In certain embodiments, n is 0 or 1.

In certain embodiments, R³is alkyl, alkenyl or alkynyl substituted with V_n—SR⁶wherein R⁶is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl or heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl and heteroaryl are optionally substituted with one or more groups independently selected from alkyl, alkenyl, alkynyl, V_n-cycloalkyl, V_n-heterocycle, V_n-aryl and V_n-heteroaryl. For example, in certain embodiments R³is S-cyclohexyl, S-phenyl, S-(4-pyridyl), SCH₂CH₂C(—O)OMe, SCH₂CH₂NMe₂, SCH₂CH₂Me₂, SCH₂-phenyl, SCH₂-(2-pyridyl), or SCH₂-(4-piperidinyl).

In other embodiments of Formula I, R³is a group having the formula SR⁶wherein R⁶is cycloalkyl, aryl, heteroaryl, a C₁-C₆alkyl group substituted with V_n—C(O)OR⁸, V_n-heteroaryl, or V_n-heterocyclyl [wherein the heterocyclyl group is optionally substituted with C(O)O(C₁-C₆alkyl)]. In certain embodiments, V is C₁-C₄alkylene. In certain embodiments, n is 0 or 1.

A particular example of SR⁶when represented by S-cycloalkyl includes S—(C₃-C₆cycloalkyl). A particular value includes S-cyclohexyl.

A particular example of SR¹when represented by S-aryl includes S-phenyl.

Particular examples of SR⁶when represented by S-heteroaryl include groups wherein the heteroaryl moiety is a 5-6 membered ring having a nitrogen atom and optionally having an additional atom selected from N and S, for example, pyridyl, pyrazinyl and thienyl rings. Particular examples include the structures:

Examples of SR⁶when R⁶represents a C₁-C₆alkyl group substituted with V_n—C(O)OR⁸include groups wherein V is C₁-C₄alkylene, n is 1 and R⁸is C₁-C₆alkyl. A particular value is S—CH₂CH₂C(O)OCH₃.

Examples of SR⁶when R⁶represents a C₁-C₆alkyl group substituted with V_n-heteroaryl include groups wherein the heteroaryl moiety is a 6 membered heteroaryl, such as a pyridyl or pyrimidyl group. A particular value includes S—CH₂-(2-pyridyl).

Examples of SR⁶when R⁶represents (C₁-C₆alkyl)-heterocyclyl include groups wherein the heterocycle is a 5-6 membered azacycle, such as a piperidyl ring. In certain embodiments the azacycle is substituted with CO₂-tBu. Particular values include:

In other embodiments, R³is alkyl, alkenyl or alkynyl substituted with V_n—OR⁶wherein R⁶is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or C(═O)OR⁸, wherein said alkyl, alkenyl, alkynyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from alkyl, alkenyl, alkynyl, V_n-aryl, V_n-heteroaryl, or V_nC(═O)OR⁸. For example, in certain embodiments R³is CH₂OH, OH, OMe OCH₂-phenyl, OCH₂-(3-pyridyl), or OCH₂C(═O)OMe.

In a particular embodiment, R³is CH₂OH.

In other embodiments of Formula I, R³is a group having the formula OR⁶. In certain embodiments, R⁶is H or C₁-C₆alkyl. In particular embodiments, R³is OH or OCH₃.

In other embodiments, R³is alkyl, alkenyl or alkynyl, wherein said alkyl, alkenyl and alkynyl are optionally substituted with one or more groups independently selected from alkyl, alkenyl, alkynyl, V_n-cycloalkyl, V_n-heterocyclyl, V_n-aryl and V_n-heteroaryl. For example, in certain embodiments R³is CH₂CH(CH₃)₂, CH₂-(1-piperidinyl), CH₂CH₂(4-piperidinyl), or CH₂CH₂(2-pyridyl).

In other embodiments of Formula I, R³is a C₁-C₆alkyl group substituted with Ar. In certain embodiments, Ar is phenyl. A particular value of R³includes a benzyl group.

In other embodiments, R³is alkyl, alkenyl or alkynyl substituted with V_n—NR⁶R⁷. For example, in certain embodiments R³is CH₂NMe₂, CH₂NH-cyclohexyl, or CH₂NHCH₂CH₂NMe₂.

In other embodiments of Formula I, R³is a C₁-C₆alkyl group or a C₂-C₆alkene group substituted with V_n—NR⁶R⁷. In certain embodiments, V is C₂-C₄alkenylene, and n is 0 or 1. In certain embodiments, R⁶and R⁷are independently H, (3-6C)cycloalkyl, C₁-C₆alkyl or (C₁-C₆alkyl)N(C₁-C₆alkyl)₂]. Particular values of R³include CH═CHCH₂CH₂N(CH)₃, CH₂NMe₂, CH₂NH-cyclohexyl, and CH₂NHCH₂CH₂NMe₂. In other embodiments, R³is a C₁-C₆alkyl group substituted with V_n—NR⁶R⁷wherein NR⁶R⁷forms a 5-6 membered azacyclic ring, for example a piperidyl ring. A particular value for R³includes CH₂-(1-piperidyl).

In other embodiments, R³is optionally substituted aryl or heteroaryl. For example, in certain embodiments R³is selected from phenyl, 3-pyridyl, 4-pyridyl and substituted forms thereof.

A particular value for R³is 2-pyridyl.

In other embodiments, R³is alkyl, alkenyl or alkynyl substituted with one or more groups independently selected from V_n—C(═O)NR⁶R⁷or V_n—C(═O)OR⁶. In certain embodiments, V is C₁-C₄alkylene or C₂-C₄alkenylene, and n is 0 or 1. For example, in certain embodiments R³is CH₂CH₂CO₂Me, or CH═CHC(O)OCH₃.

In certain embodiments of Formula I, R³is a group having the formula CO₂R⁶. In certain embodiments, R⁶is H or C₁-C₆alkyl. Particular values of R³include CO₂H and CO₂Et.

In certain embodiments of Formula I, R³is a group having the formula COR⁶. A particular value of R³is C(O)H.

In certain embodiments of Formula I, R³is a group having the formula C(O)NR⁶R⁷. In certain embodiments, R⁶and R⁷are independently H or C₁-C₆alkyl optionally substituted with N(C₁-C₆alkyl)₂. In other embodiments, NR⁶R⁷forms a 5-6 membered azacyclic ring optionally substituted with C₁-C₆alkyl, for example an optionally substituted piperidyl ring. Particular values of R³include C(O)NHCH₂CH₂N(CH₃)₂and C(O)(N-ethylpiperazin-4-yl).

In certain embodiments of Formula I, R³is Br.

In certain embodiments of Formula I, R³is H.

The compounds of Formula I include compounds having the Formula Ib

wherein R¹³is N-(1-6C alkanoyl)-piperidin-4-yl and R², R³, R¹¹, and D²are as defined for Formula Ia.

In one embodiment of Formula Ib, L is O, S, SO, SO₂, CHOH, C(O), or CH₂;

In one embodiment of Formula Ib, D²is CR¹²or N.

In one embodiment of Formula Ib, R²is aryl, 3-pyridyl or 8-quinolinyl, wherein said aryl, pyridyl and quinolinyl are optionally substituted with one or more groups independently selected from 1-6C alkyl, Cl, CN, and C(—O)NR⁶R⁷.

In one embodiment of Formula Ib, R³is H, Br, S-aryl, O-aryl, CH₂-aryl, S-heteroaryl, O-heteroaryl or CH₂-heteroaryl, wherein said aryl and heteroaryl portions are optionally substituted with one or more groups independently selected from (1-3C) alkyl, F, Cl, Br, CN, CF₃, and O-(1-3C alkyl).

In one embodiment of Formula Ib, R⁶and R⁷are independently H, 1-6C alkyl, -(1-6C alkyl)NH₂, -(1-6C alkyl)NH(1-6C alkyl), -(1-6C alkyl)N(1-6C alkyl)₂, -(1-6C alkyl)-heteroaryl and -(1-6C alkyl)-heterocycle.

In one embodiment of Formula Ib, R⁸and R⁹are independently H or 1-6C alkyl;

In one embodiment of Formula Ib, R¹¹is H or Cl.

In one embodiment of Formula Ib, R¹²is H or 1-6C alkyl.

In certain embodiments of Formula Ib, D²is CR¹².

In certain embodiments of Formula Ib, D²is N.

In certain embodiments of Formula Ib, L is O.

In certain embodiments of Formula Ib, L is S.

In certain embodiments of Formula Ib, L is SO.

In certain embodiments of Formula Ib, L is SO₂.

In certain embodiments of Formula Ib, L is CHOH.

In certain embodiments of Formula Ib, L is C(O).

In certain embodiments of Formula Ib, L is CH₂.

In certain embodiments of Formula Ib, R¹¹is H.

In certain embodiments of Formula Ib R¹²is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or t-butyl.

In particular embodiments of Formula Ib, R¹²is H.

In certain embodiments of Formula Ib, R²is aryl optionally substituted with one or more groups independently selected from Cl, 1-6C alkyl, and C(═O)NR⁶R⁷.

Examples of aryl substituents for Formula Ib having the formula —C(═O)NR⁶R⁷include groups wherein R⁶and R⁷are independently H, 1-6C alkyl, -(1-6C alkyl)NH₂, -(1-6C alkyl)NH(1-6C alkyl), -(1-6C alkyl)N(1-6C alkyl)₂, -(1-6C alkyl)-heteroaryl and -(1-6C alkyl)-heterocycle.

Examples of R⁶and R⁷for Formula Ib when represented by -(1-6C alkyl)-heterocycle include groups wherein the heterocycle is a 5-6 membered ring having 1-2 atoms independently selected from N and O. A particular example of the heterocyclic ring is a morpholinyl group.

Examples, of R⁶and R⁷for Formula Ib when represented by -(1-6C alkyl)-heteroaryl include groups wherein the heteroaryl is a 5-membered ring having 1-2 nitrogen atoms. A particular value for the heteroaryl is an imidazolyl group.

In certain embodiments of Formula Ib, R²is a phenyl group optionally substituted with one or more groups independently selected from Cl, Me, —C(O)NHCH₂CH₂NMe₂, —C(O)NHCH₂CH₂CH₂N(CH₃)₂, —C(O)NMe)CH₂CH₂N(CH₃)₂, —C(O)N—HCH₂CH₂NHCH(CH₃)₂, —C(O)NH(CH₂)₃(N-morpholinyl), —C(O)(N-pyrrolidinyl) and —C(O)NHCH₂CH₂(imidazolyl).

In particular embodiments of Formula Ib, R²is phenyl optionally substituted with one or two groups independently selected from Cl, Me and —C(O)NHCH₂CH₂NMe₂.

Particular values of R²for Formula Ib include the structures:

In other embodiments of Formula Ib, R²is 3-pyridyl optionally substituted with one or more groups independently selected from (1-6C alkyl), CN, and C(═O)NR⁶R⁷, wherein the C(═O)NR⁶R⁷group is as defined above.

Exemplary embodiments of R²for Formula Ib include 3-pyridyl optionally substituted with one or more groups independently selected from methyl, CN, —C(O)NHCH₂CH₂NMe₂, —C(O)NHCH₂CH₂CH₂N(CH₃)₂, —C(O)N(Me)CH₂CH₂N(CH₃)₂, —C(O)NHCH₂CH₂NHCH(CH₃)₂, —C(O)NH(CH₂)₃(N-morpholinyl), —C(O)(N-pyrrolidinyl) and —C(O)NHCH₂CH₂(imidazolyl).

In particular embodiments of Formula Ib, R²is 3-pyridyl optionally substituted with one or two groups independently selected from methyl, CN and —C(O)NHCH₂CH₂NMe₂.

Particular values for R²of Formula Ib include the structures:

In certain embodiments of Formula Ib, R²is 8-quinolinyl.

In certain embodiments of Formula Ib, R³is S-aryl optionally substituted with one or more groups independently selected from (1-3C) alkyl, F, Cl, Br, CN, CF₃, and O-(1-3C alkyl).

A particular value for R³of Formula Ib is S-phenyl.

In certain embodiments of Formula Ib, R³is S-heteroaryl optionally substituted with one or more groups independently selected from (1-3C) alkyl, F, Cl, Br, CN, CF₃, and O-(1-3C alkyl). Exemplary embodiments of R³of Formula Ib when represented by S-heteroaryl include groups wherein the heteroaryl moiety is a 5-6 membered ring having a nitrogen atom and optionally having an additional atom selected from N and S, for example, pyridyl, pyrimidyl and thiazolyl rings.

Particular values of R³for Formula Ib include the structures:

In other embodiments of Formula Ib, R³is O-aryl optionally substituted with one or more groups independently selected from (1-3C) alkyl, F, Cl, Br, CN, CF₃, and O-(1-3C alkyl). A particular value is O-phenyl.

In certain embodiments of Formula Ib, R³is O-heteroaryl optionally substituted with one or more groups independently selected from (1-3C) alkyl, F, Cl, Br, CN, CF₃, and O-(1-3C alkyl) A particular value of the heteroaryl is a 2-pyridyl, 3-pyridyl or 4-pyridyl group;

In certain embodiments of Formula Ib, R³is CH₂-aryl optionally substituted with one or more groups independently selected from (1-3C) alkyl, F, Cl, Br, CN, CF₃, and O-(1-3C alkyl). A particular value is CH₂-phenyl.

In certain embodiments of Formula Ib, R³is CH₂-heteroaryl optionally substituted with one or more groups independently selected from (1-3C) alkyl, F, Cl, Br, CN, CF₃, and O-(1-3C alkyl). A particular value of the heteroaryl is a 2-pyridyl, 3-pyridyl or 4-pyridyl group.

Exemplary embodiments of compounds of Formula I include, but are not limited to, compounds of the general formulas

and substituted forms thereof, wherein L, R¹, R², R³, R⁴and R¹¹are as defined above.