WO2016092413A1

WO2016092413A1 - Indole and indazole compounds that activate ampk

Info

Publication number: WO2016092413A1
Application number: PCT/IB2015/059222
Authority: WO
Inventors: Kimberly Cameron; David James EDMONDS; Amit Kalgutkar; David Ebner; Benjamin Thuma; Kevin James Filipski; Rajesh Kumar
Original assignee: Pfizer Inc.
Priority date: 2014-12-10
Filing date: 2015-11-30
Publication date: 2016-06-16

Abstract

The present invention relates to indole and indazole compounds of Formula (I) Formula (I) that activate 5' adenosine monophosphate-activated protein kinase (AMPK). The invention also encompasses pharmaceutical compositions containing these compounds and methods for treating or preventing diseases, conditions, or disorders ameliorated by activation of AMPK.

Description

INDOLE AND INDAZOLE COMPOUNDS THAT ACTIVATE AMPK

FIELD OF THE INVENTION

The present invention relates to indole and indazole compounds that activate 5' adenosine monophosphate-activated protein kinase (AMPK), pharmaceutical compositions containing these compounds, and the use of these compounds for treating or preventing diseases, conditions, or disorders ameliorated by activation of AMPK.

BACKGROUND

Diabetes is a major public health concern because of its increasing prevalence and associated health risks. The disease is characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both. Two major forms of diabetes are recognized, type I and type II. Type I diabetes develops when the body's immune system destroys pancreatic beta cells, the only cells in the body that make the hormone insulin that regulates blood glucose. To survive, people with type 1 diabetes must have insulin delivered by injection or a pump. Type II diabetes accounts for about 90 to 95 percent of all diagnosed cases of diabetes. Type II diabetes usually begins as insulin resistance, a disorder in which the cells do not use insulin properly. Key target tissues, including liver, muscle, and adipose tissue, are resistant to the effects of insulin in stimulating glucose and lipid metabolism. As the need for insulin rises, the pancreas gradually loses its ability to produce insulin. Controlling type II diabetes with medication is essential; otherwise it can progress into pancreatic beta-cell failure requiring complete dependence on insulin.

Obesity increases the risk of type II diabetes as well as many other health conditions including coronary heart disease, stroke, and high blood pressure. More than one-third of U.S. adults (over 72 million people) and 17% of U.S. children are obese. During 1980-2008, obesity rates doubled for adults and tripled for children. During the past several decades, obesity rates for all population groups— regardless of age, sex, race, ethnicity, socioeconomic status, education level, or geographic region— have increased markedly.

Research has identified the enzyme 5' adenosine monophosphate-activated protein kinase (AMPK) as a regulator of cellular and whole-body energy homeostasis. AMPK is activated by cellular stress resulting in downstream events that serve to conserve or generate ATP. AMPK is composed of three distinct subunits, each with multiple isoforms: the alpha subunit (alpha 1 or 2); the beta subunit (beta 1 or 2); and the gamma subunit (gamma 1 , 2, or 3); for a total of twelve possible heterotrimeric isoforms.

In the liver, activated AMPK phosphorylates a variety of substrates including 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (Clarke, P.R. & Hardie, D.G., EMBO J 9, 2439-2446 (1990)) and acetyl-CoA carboxylase (Carling, D. et al. FEBS Letters 223, 217-222 (1987)) which inhibits cholesterol biosynthesis and decreases fatty acid synthesis, respectively. Therefore, activation of AMPK should lead to decreases in the levels of triglycerides and cholesterol. AMPK is also thought to regulate plasma glucose levels by decreasing hepatic gluconeogenesis through downregulation of key gene products following phosphorylation of CRTC2 (Koo S.H. et. Al., Nature 437, 1 109-1 1 1 1 (2005)). In muscle and myocardial tissues, AMPK activates the transport activity of glucose transporter 4 (GLUT4) increasing glucose uptake into cells thereby producing an additional avenue for decreasing plasma glucose (Kurth- Kraczek, E.J. et. al., Diabetes 48, 1667-1671 (1999)). AMPK activation has also been shown to enhance mitochondrial biogenesis improving fatty acid oxidation and decreasing circulating lipids (Merrill, G.M. et. al., Am. J. Physiol. 273, E1 107-E1 1 12 (1997)). Direct activation of AMPK using AICAR (5-aminoimidazole-4-carboxamide riboside) has been shown to lead to beneficial effects on several metabolic endpoints including improved glucose disposal, decreased hepatic glucose output and decreases in plasma triglycerides and free fatty acids (Song, X.M. et. al., Diabetologia 45, 56-65 (2002); Bergeron, R. et. al., Diabetes 50, 1076-1082 (2001 ); Buhl, E.S.et. al., Diabetes 50, 12-17 (2001 ); Iglesias, M.A. et. al., Diabetes 51 , 2886-2894 (2002), Fogarty, S. & Hardie, D.G., Biochim et Biophys Acta 1804, 581 -591 (2010)). Because of AMPK's pluripotent effects on carbohydrate, lipid, and cholesterol metabolism and biosynthesis, agents that activate AMPK are attractive therapeutic targets for treating metabolic syndrome disorders such as diabetes, obesity, and dyslipidemia.

Decreases in renal AMPK activation have been implicated in the etiology of diseases of the kidney, including diabetic nephropathy, acute kidney injury (AKI), and polycystic kidney disease (PKD); activation of AMPK through hormonal (adiponectin) or pharmacological (AICAR) mechanisms has been shown to be protective in rodent models of these diseases. In diabetic nephropathy decreased AMPK activation in podocytes occurs early in the disease and is associated with increased expression of the NADPH-Oxidase protein Nox4 and increased proteinuria. These effects were reduced following administration of the AMPK activators AICAR, metformin, and Adiponectin (Lee, MJ. et.al. American Journal of Physiology - Renal Physiology. 292. F61 7-F627 (2007); Sharma, K. et.al. Journal of Clinical Investigation.1 1 8. 1645-1 656. (2008)). In ischemia/reperfusion models of AKI the AMPK activators metformin and AICAR were shown to dose-dependently reduce subsequent proteinuria, oxidative tissue damage, and kidney macrophage infiltration (Lempiainen, J. et.al. British Journal of Pharmacology 1 66. 1 905-1 91 5 (201 2); Seo-Mayer, P.W. et.al. American Journal of Physiology - Renal Physiology, 301 , F1346-F1 357 (201 1 )). In two rodent models of PKD the AMPK activator metformin was shown to reduce renal cyst expansion (Takiar, V. et. al. PNAS 1 08, 2462-2467 (201 1 )). These studies suggest a broad benefit of AMPK activators in multiple renal diseases.

The compounds of the present invention activate AMPK and are, therefore, useful in treating metabolic disorders such as diabetes, obesity, and dyslipidemia as well as the renal diseases chronic kidney disease, diabetic nephropathy, acute kidney injury and polycystic kidney disease.

SUMMARY OF THE INVENTION

The present invention provides compounds of Formula (I) that activate 5' adenosine monophosphate-activated protein kinase and are useful for treating or preventing disorders ameliorated b activation of AMPK in humans,

Formula (I)

or a pharmaceutically acceptable salt thereof, wherein

X is N or CH;

Ri is -C(O)OR or -CH₂OR;

R is H or (C C₆)alkyl;

R₂, R3, and R₄ are independently H, (CrC₆)alkoxy, (CrC₆)alkyl, (CrC₆)alkylthio, carboxy, cyano, halogen, halo(CrC6)alkoxy, halo(CrC6)alkyl, hydroxy,

hydroxy(CrC8)alkyl, mercapto, nitro, -N RQRH or (NRoR^carbonyl;

RG and RH are independently H, (CrC₆)alkyl, (CrC₆)alkylcarbonyl, or R_G and RH form a ring that is azetidine, pyrrolidine, piperidine, or azepane;

R₅ is H; L is a bond, O, S, N R_A, (CrC₆)alkylene, (C₂-C₆)alkenylene, or (C₂-C₆)alkynylene;

A is phenyl, 2,3-dihydrobenzo[b][1 ,4]dioxinyl, 2,3-dihydrobenzofuranyl,

2,3-dihydro-1 H-indenyl, imidazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, or thiazolyl, wherein each is optionally substituted with 1 , 2, 3, 4, or 5 substituents that are independently (CrC₆)alkoxy, (Ci-C6)alkoxy(Ci-C₆)alkoxy, (Ci-C6)alkoxy(Ci-C₆)alkyl, (CrC₆)alkoxycarbonyl, (CrC₆)alkyl, (CrC₆)alkylcarbonyl, (CrC₆)alkylthio, aryl, aryl(CrC₆)alkoxy, aryl(CrC₆)alkyl, arylcarbonyl, aryloxy, carboxy,

carboxy(CrC6)alkoxy, carboxy(CrC6)alkyl, cyano, (C3-C8)cycloalkyl,

(C3-C8)cycloalkyl(CrC6)alkoxy, (C3-C8)cycloalkyl(CrC6)alkyl, (C3-C8)cycloalkylcarbonyl, (C₃-C₈)cycloalkyloxy, halogen, halo(CrC₆)alkoxy, halo(CrC₆)alkyl, heteroaryl, heteroaryl(CrC₆)alkoxy, heteroaryl(CrC₆)alkyl, heteroarylcarbonyl, heteroaryloxy, (C3-C7)heterocycle, (C3-C7)heterocycle(CrC6)alkoxy, (C3-C7)heterocycle(CrC6)alkyl, (C3-C7)heterocyclecarbonyl, (C3-C7)heterocyclecarbonyl(CrC6)alkyl,

(C3-C7)heterocycleoxy, hydroxy, hydroxy(Ci-C6)alkoxy, hydroxy(CrC6)alkyl, mercapto, nitro, -NRjR_K, (NRjR_K)carbonyl, -N R_MRN, -NRM N(Ci-C₆)alkoxy, (N R_MRN)carbonyl, (N R_MRN)carbonyl(CrC6)alkyl, or (N R_MRN)carbonyl(C-i-C6)alkoxy; wherein the aryl, aryl(Ci-C6)alkoxy, aryl(CrC6)alkyl, arylcarbonyl, and aryloxy are optionally substituted with 1 , 2, 3, 4, or 5 substituents that are independently (Ci-C6)alkoxy,

(CrC₆)alkoxycarbonyl, (CrC₆)alkyl, (CrC₆)alkylcarbonyl, (CrC₆)alkylthio, carboxy, cyano, halogen, halo(CrC₆)alkoxy, halo(CrC₆)alkyl, hydroxy, hydroxy(CrC₆)alkyl, mercapto, nitro, -N R_MRN, or (N R_MRN)carbonyl; wherein the halo(CrC₆)alkyl is optionally substituted with 1 or 2 hydroxy groups; wherein the (C₃-C₈)cycloalkyl,

(C3-C8)cycloalkyl(CrC6)alkoxy, (C3-C8)cycloalkyl(CrC6)alkyl, (C3-C8)cycloalkylcarbonyl, and (C3-C8)cycloalkyloxy are optionally substituted with 1 , 2, or 3 substituents that are independently (CrC₆)alkoxy, (CrC₆)alkoxycarbonyl, (CrC₆)alkyl, (CrC₆)alkylcarbonyl, (CrC₆)alkylthio, carboxy, cyano, halogen, halo(CrC₆)alkoxy, halo(CrC₆)alkyl, hydroxy, hydroxy(CrC6)alkyl, mercapto, nitro, -N RMRN, or (NRMRNi)carbonyl; wherein the heteroaryl, heteroaryl(Ci-C6)alkoxy, heteroaryl(CrC6)alkyl, heteroarylcarbonyl, and heteroaryloxy, are optionally substituted with 1 , 2, or 3 substituents that are

independently (CrC₆)alkoxy, (CrC₆)alkoxycarbonyl, (CrC₆)alkyl, (CrC₆)alkylcarbonyl, (CrC6)alkylthio, carboxy, cyano, halogen, halo(CrC6)alkoxy, halo(CrC6)alkyl, hydroxy, hydroxy(CrC6)alkyl, mercapto, nitro, -N RMRN, or (N RMRN)carbonyl; and wherein the (C₃-C₇)heterocycle, (C₃-C₇)heterocycle(Ci-C6)alkoxy, (C₃-C₇)heterocycle(Ci-C6)alkyl, (C₃-C₇)heterocyclecarbonyl, (C₃-C₇)heterocyclecarbonyl(Ci-C6)alkyl, and

(C3-C7)heterocycleoxy, are optionally substituted with 1 , 2, or 3 substituents that are independently (CrC₆)alkoxy, (CrC₆)alkoxycarbonyl, (CrC₆)alkoxysulfonyl, (CrC₆)alkyl, (CrC6)alkylcarbonyl, (CrC6)alkylsulfonyl, (Ci-C6)alkylthio, carboxy, cyano, halogen, halo(CrC6)alkoxy, halo(CrC6)alkyl, hydroxy, hydroxy(CrC6)alkyl, mercapto,

nitro, -N R_MRN, (NR_MRN)carbonyl, or oxo;

Rj and R« are independently H or (CrC₆)alkyl; and

RM and RN are independently H, (CrC₆)alkyl, (Ci-C6)alkyl(Ci-C₆)alkoxy, or (CrC₆)alkylcarbonyl; or R_M and RN together with the nitrogen they are attached to form a 3 to 8 membered ring, wherein the 3 to 8 membered ring may be optionally

substituted with 1 to 3 substituents that are (Ci-C6)alkoxy, (CrC6)alkyl, halogen, or hydroxy.

In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of Formula (I) and at least one pharmaceutically acceptable excipient, diluent, or carrier.

In another embodiment, the present invention provides a method for treating or preventing metabolic disorders in a mammal, particularly a human, where the metabolic disorder is ameliorated by activation of 5' adenosine monophosphate-activated protein kinase comprising administering to the mammal or human, in need of such treatment, a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method for treating or preventing type II diabetes in a mammal, particularly a human, comprising administering to the mammal or human, in need of such treatment, a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method for treating or preventing obesity in a mammal, particularly a human, comprising administering to the mammal or human, in need of such treatment, a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method for treating or preventing dyslipidemia in a mammal, particularly a human, comprising administering to the mammal or human, in need of such treatment, a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method for treating or preventing nonalcoholic fatty liver disease (NAFLD) in a mammal, particularly a human, comprising administering to the mammal or human, in need of such treatment, a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method for treating or preventing nonalcoholic steatohepatitis (NASH) in a mammal, particularly a human, comprising administering to the mammal or human, in need of such treatment, a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method for treating or preventing liver cirrhosis in a mammal, particularly a human, comprising administering to the mammal or human, in need of such treatment, a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method for treating or preventing renal diseases in a mammal, particularly a human, where the renal disease is ameliorated by activation of 5' adenosine monophosphate-activated protein kinase comprising administering to the mammal or human, in need of such treatment, a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method for treating or preventing chronic kidney disease in a mammal, particularly a human, comprising administering to the mammal or human, in need of such treatment, a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method for treating or preventing diabetic nephropathy in a mammal, particularly a human, comprising administering to the mammal or human, in need of such treatment, a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method for treating or preventing acute kidney injury in a mammal, particularly a human, comprising administering to the mammal or human, in need of such treatment, a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method for treating or preventing polycystic kidney disease in a mammal, particularly a human, comprising administering to the mammal or human, in need of such treatment, a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides uses for compounds of Formula (I) for preparing, or for the manufacture of, a medicament for treating metabolic disorders in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds of Formula (I) for preparing, or for the manufacture of, a medicament for treating or preventing type II diabetes in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds of Formula (I) for preparing, or for the manufacture of, a medicament for treating or preventing obesity in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds of Formula (I) for preparing, or for the manufacture of, a medicament for treating or preventing dyslipidemia in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds of Formula (I) for preparing, or for the manufacture of, a medicament for treating or preventing nonalcoholic fatty liver disease (NAFLD) in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds of Formula (I) for preparing, or for the manufacture of, a medicament for treating or preventing nonalcoholic steatohepatitis (NASH) in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds of Formula (I) for preparing, or for the manufacture of, a medicament for treating or preventing liver cirrhosis in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds of Formula (I) for preparing, or for the manufacture of, a medicament for treating renal diseases in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds of Formula (I) for preparing, or for the manufacture of, a medicament for treating or preventing chronic kidney disease in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds of Formula (I) for preparing, or for the manufacture of, a medicament for treating or preventing diabetic nephropathy in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds of Formula (I) for preparing, or for the manufacture of, a medicament for treating or preventing acute kidney injury in a mammal, particularly a human. In another aspect, the present invention provides uses for compounds of Formula (I) for preparing, or for the manufacture of, a medicament for treating or preventing polycystic kidney disease in a mammal, particularly a human.

DETAILED DESCRIPTION OF THE INVENTION

In another embodiment, the present invention provides compounds of Formula

(II)

Formula (II)

or a pharmaceutically acceptable salt thereof, wherein

X is N or CH;

L is a bond, O, S, N RA, (CrC6)alkylene, (C2-C6)alkenylene, or (C2-C6)alkynylene; A is

Ri is-C(O)OR or-CH₂OR;

R is H or (C C₆)alkyl;

hydroxy(CrC8)alkyl, mercapto, nitro, -N RQRH, or (NRoR^carbonyl;

R₅ is H; R₆, R₇, R9, and R10 are independently H, (CrC₆)alkoxy, (CrC₆)alkoxycarbonyl, (CrC6)alkyl, (CrC6)alkylcarbonyl, (Ci-C6)alkylthio, carboxy, cyano, halogen,

halo(CrC6)alkoxy, halo(CrC6)alkyl, hydroxy, hydroxy(CrC6)alkyl, mercapto,

nitro, -N RJ RK, or (NRjR_K)carbonyl;

Rj and R« are independently H or (CrC₆)alkyl;

R₈ is H, (C C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, (CrC₆)alkoxycarbonyl, (CrC₆)alkyl, (CrC₆)alkylcarbonyl, (CrC₆)alkylthio, aryl, aryl(Ci-C6)alkoxy, aryl(CrC6)alkyl, arylcarbonyl, aryloxy, carboxy,

carboxy(CrC6)alkoxy, carboxy(CrC6)alkyl, cyano, (C3-C8)cycloalkyl,

(C₃-C₈)cycloalkyl(Ci-C6)alkoxy, (C₃-C₈)cycloalkyl(Ci-C6)alkyl, (C₃-C₈)cycloalkylcarbonyl, (C₃-C₈)cycloalkyloxy, halogen, halo(CrC₆)alkoxy, halo(CrC₆)alkyl, heteroaryl, heteroaryl(Ci-C6)alkoxy, heteroaryl(CrC6)alkyl, heteroarylcarbonyl, heteroaryloxy, (C₃-C7)heterocycle, (C₃-C7)heterocycle(CrC6)alkoxy, (C₃-C7)heterocycle(CrC6)alkyl, (C₃-C7)heterocyclecarbonyl, (C₃-C7)heterocyclecarbonyl(CrC6)alkyl,

(C₃-C₇)heterocycleoxy, hydroxy, hydroxy(CrC₆)alkoxy, hydroxy(CrC₆)alkyl, mercapto, nitro, -N R_MRN, -NR_MRN(CrC₆)alkoxy, (NR_MRN)carbonyl, (NRMRN)carbonyl(Ci-C₆)alkyl, or (NRMRN)carbonyl(Ci-C6)alkoxy; wherein the aryl, aryl(Ci-C6)alkoxy, aryl(CrC6)alkyl, arylcarbonyl, and aryloxy are optionally substituted with 1 , 2, 3, 4, or 5 substituents that are independently (CrC₆)alkoxy, (CrC₆)alkoxycarbonyl, (CrC₆)alkyl,

(CrC₆)alkylcarbonyl, (CrC₆)alkylthio, carboxy, cyano, halogen, halo(CrC₆)alkoxy, halo(CrC₆)alkyl, hydroxy, hydroxy(CrC₆)alkyl, mercapto, nitro, -N R_MRN, or

(NR_MRN)carbonyl; wherein the halo(CrC₆)alkyl is optionally substituted with 1 or 2 hydroxy groups; wherein the (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(CrC6)alkoxy,

(C₃-C₈)cycloalkyl(CrC6)alkyl, (C₃-C₈)cycloalkylcarbonyl, and (C₃-C₈)cycloalkyloxy are optionally substituted with 1 , 2, or 3 substituents that are independently (C C₆)alkoxy, (CrC₆)alkoxycarbonyl, (CrC₆)alkyl, (CrC₆)alkylcarbonyl, (CrC₆)alkylthio, carboxy, cyano, halogen, halo(CrC6)alkoxy, halo(CrC6)alkyl, hydroxy, hydroxy(CrC6)alkyl, mercapto, nitro, -N RMRN, or (NRMRNi)carbonyl; wherein the heteroaryl,

heteroaryl(CrC₆)alkoxy, heteroaryl(CrC₆)alkyl, heteroarylcarbonyl, and heteroaryloxy, are optionally substituted with 1 , 2, or 3 substituents that are independently

(Ci-C6)alkoxy, (CrC6)alkoxycarbonyl, (Ci-C6)alkyl, (CrC6)alkylcarbonyl,

(CrC6)alkylthio, carboxy, cyano, halogen, halo(CrC6)alkoxy, halo(CrC6)alkyl, hydroxy, hydroxy(CrC₆)alkyl, mercapto, nitro, -N R_MRN, or (NR_MRN)carbonyl; and wherein the (C₃-C₇)heterocycle, (C₃-C₇)heterocycle(C-i-C₆)alkoxy, (C₃-C7)heterocycle(Ci-C₆)alkyl, (C₃-C7)heterocyclecarbonyl, (C₃-C7)heterocyclecarbonyl(CrC6)alkyl, and (C₃-C₇)heterocycleoxy, are optionally substituted with 1 , 2, or 3 substituents that are independently (CrC6)alkoxy, (CrC6)alkoxycarbonyl, (CrC6)alkoxysulfonyl, (CrC6)alkyl, (CrC6)alkylcarbonyl, (CrC6)alkylsulfonyl, (CrC6)alkylthio, carboxy, cyano, halogen, halo(CrC₆)alkoxy, halo(CrC₆)alkyl, hydroxy, hydroxy(CrC₆)alkyl, mercapto,

nitro, -N R_MRN, (N R_MRN)carbonyl, or oxo; and

In another embodiment, the present invention provides compounds of Formula (II), or a pharmaceutically acceptable salt thereof, wherein X is N or CH; L is a bond or -C6)alkynylene; A is

; R₁ is -C(O)OR; R is H or (C C₆)alkyl; R2, R3, and R₄ are independently H, (Ci-C6)alkyl, cyano, or halogen; R₅ is H; R₆, R7, R9, and R10 are independently H, (CrC₆)alkoxy, (CrC₆)alkyl, cyano, halogen, hydroxy, or hydroxy(C C₆)alkyl; R₈ is H, (C C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, (C C₆)alkyl, (CrC6)alkylcarbonyl, aryl, carboxy(CrC6)alkoxy, (C3-C8)cycloalkyl,

(C3-C₈)cycloalkyl(Ci-C₆)alkyl, (C₃-C₈)cycloalkyloxy, halo(C C₆)alkyl,

heteroaryl(Ci-C6)alkoxy, (C3-C₇)heterocycle, (C3-C₇)heterocycle(CrC6)alkoxy,

(C3-C₇)heterocyclecarbonyl(Ci-C₆)alkyl, (C₃-C₇)heterocycleoxy, hydroxy(CrC₆)alkoxy, hydroxy(CrC₆)alkyl, -N R_MRN, (N R_MRN)carbonyl(Ci-C₆)alkyl, or

(NRMRN)carbonyl(Ci-C6)alkoxy; wherein the aryl is optionally substituted with 1 substituent that is (Ci-C6)alkoxy or hydroxy; wherein the halo(CrC6)alkyl is optionally with 1 hydroxy group; wherein the (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(Ci-C6)alkyl, and (C₃-C₈)cycloalkyloxy are optionally substituted with 1 substituent that is carboxy, hydroxy, hydroxy(CrC6)alkyl, or (NRMRNi)carbonyl; and wherein the (C3-C₇)heterocycle and (C3-C₇)heterocycle(CrC6)alkoxy are optionally substituted with 1 substituent that is (CrC₆)alkoxycarbonyl, (CrC₆)alkyl, (CrC₆)alkylcarbonyl, (CrC₆)alkylsulfonyl, hydroxy, hydroxy(CrC₆)alkyl, or oxo; and RM and RN are independently H, (CrC₆)alkyl,

(Ci-C6)alkyl(CrC6)alkoxy, or (CrC6)alkylcarbonyl; or RM and RN together with the nitrogen they are attached to form a 3 to 8 membered ring, wherein the 3 to 8

membered ring may be optionally substituted with 1 to 3 substituents that are

(CrC₆)alkoxy, (CrC₆)alkyl, halogen, or hydroxy.

In another embodiment, the present invention provides compounds of Formula

(III)

Formula (III)

or a pharmaceutically acceptable salt thereof, wherein X is N or CH; L is a bond, O, S, NR_A, (CrC₆)alkylene, (C₂-C₆)alkenylene, or (C₂-C₆)alkynylene; R is -C(O)OR or -CH₂OR; R is H or (Ci-C6)alkyl; R₂, R3, and R₄ are independently H, (Ci-C6)alkoxy, (CrC₆)alkyl, (CrC₆)alkylthio, carboxy, cyano, halogen, halo(CrC₆)alkoxy,

halo(CrC₆)alkyl, hydroxy, hydroxy(CrC₈)alkyl, mercapto, nitro, -N R_GRH, or

(NRoR^carbonyl; RQ and RH are independently H, (Ci-C6)alkyl, (CrC6)alkylcarbonyl, or RG and RH form a ring that is azetidine, pyrrolidine, piperidine, or azepane; R5 is H; R₆, R₇, Rg, and R10 are independently H, (CrC₆)alkoxy, (CrC₆)alkoxycarbonyl, (CrC₆)alkyl, (CrC6)alkylcarbonyl, (Ci-C6)alkylthio, carboxy, cyano, halogen, halo(CrC6)alkoxy, halo(CrC₆)alkyl, hydroxy, hydroxy(CrC₆)alkyl, mercapto, nitro, -NRjR_K, or

(NRjR_K)carbonyl; Rj and RK are independently H or (CrC₆)alkyl; R₈ is H, (CrC₆)alkoxy, (Ci -C6)alkoxy(Ci -Ce)alkoxy, (Ci -C6)alkoxy(Ci -Ce)alkyl, (Ci -C6)alkoxycarbonyl ,

(CrC₆)alkyl, (C C₆)alkylcarbonyl, (C C₆)alkylthio, aryl, aryl(C C₆)alkoxy,

aryl(CrC₆)alkyl, arylcarbonyl, aryloxy, carboxy, carboxy(CrC₆)alkoxy,

carboxy(CrC₆)alkyl, cyano, (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(Ci-C6)alkoxy,

(C3-C₈)cycloalkyl(CrC6)alkyl, (C3-C₈)cycloalkylcarbonyl, (C3-C₈)cycloalkyloxy, halogen, halo(CrC6)alkoxy, halo(CrC6)alkyl, heteroaryl, heteroaryl(Ci-C6)alkoxy,

heteroaryl(CrC₆)alkyl, heteroarylcarbonyl, heteroaryloxy, (C₃-C₇)heterocycle,

(C₃-C₇)heterocycle(Ci-C₆)alkoxy, (C3-C₇)heterocycle(Ci-C₆)alkyl,

(C3-C₇)heterocyclecarbonyl, (C3-C₇)heterocyclecarbonyl(CrC6)alkyl,

(C3-C₇)heterocycleoxy, hydroxy, hydroxy(Ci-C6)alkoxy, hydroxy(CrC6)alkyl, mercapto, nitro, -N R_MRN, -NR_M N(Ci-C₆)alkoxy, (NR_MRN)carbonyl, (NR_MRN)carbonyl(Ci-C₆)alkyl, or (N R_MRN)carbonyl(CrC6)alkoxy; wherein the aryl, aryl(CrC₆)alkoxy, aryl(CrC₆)alkyl, arylcarbonyl, and aryloxy are optionally substituted with 1 , 2, 3, 4, or 5 substituents that are independently (Ci-C6)alkoxy, (CrC6)alkoxycarbonyl, (Ci-C6)alkyl,

(CrC₆)alkylcarbonyl, (CrC₆)alkylthio, carboxy, cyano, halogen, halo(CrC₆)alkoxy, halo(CrC₆)alkyl, hydroxy, hydroxy(CrC₆)alkyl, mercapto, nitro, -N R_MRN, or (N R_MRN)carbonyl; wherein the halo(CrC₆)alkyl is optionally substituted with 1 or 2 hydroxy groups; wherein the (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(Ci-C6)alkoxy,

(C3-C8)cycloalkyl(CrC6)alkyl, (C3-C8)cycloalkylcarbonyl, and (C3-C8)cycloalkyloxy are optionally substituted with 1 , 2, or 3 substituents that are independently (Ci-C6)alkoxy, (CrC₆)alkoxycarbonyl, (CrC₆)alkyl, (CrC₆)alkylcarbonyl, (CrC₆)alkylthio, carboxy, cyano, halogen, halo(CrC₆)alkoxy, halo(CrC₆)alkyl, hydroxy, hydroxy(CrC₆)alkyl, mercapto, nitro, -N RMRN, or (NRMRNi)carbonyl; wherein the heteroaryl,

heteroaryl(Ci-C6)alkoxy, heteroaryl(CrC6)alkyl, heteroarylcarbonyl, and heteroaryloxy, are optionally substituted with 1 , 2, or 3 substituents that are independently

(CrC₆)alkoxy, (CrC₆)alkoxycarbonyl, (CrC₆)alkyl, (CrC₆)alkylcarbonyl,

(CrC₆)alkylthio, carboxy, cyano, halogen, halo(CrC₆)alkoxy, halo(CrC₆)alkyl, hydroxy, hydroxy(CrC6)alkyl, mercapto, nitro, -N RMRN, or (NRMRNi)carbonyl; and wherein the (C3-C7)heterocycle, (C3-C7)heterocycle(CrC6)alkoxy, (C3-C7)heterocycle(CrC6)alkyl, (C₃-C₇)heterocyclecarbonyl, (C₃-C₇)heterocyclecarbonyl(Ci-C₆)alkyl, and

(C₃-C₇)heterocycleoxy, are optionally substituted with 1 , 2, or 3 substituents that are independently (CrC₆)alkoxy, (CrC₆)alkoxycarbonyl, (CrC₆)alkoxysulfonyl, (CrC₆)alkyl, (CrC₆)alkylcarbonyl, (CrC₆)alkylsulfonyl, (CrC₆)alkylthio, carboxy, cyano, halogen, halo(CrC6)alkoxy, halo(CrC6)alkyl, hydroxy, hydroxy(CrC6)alkyl, mercapto,

nitro, -N RMRN, (N RMRN)carbonyl, or oxo; and RM and RN are independently H,

(CrC₆)alkyl, (Ci-C6)alkyl(Ci-C₆)alkoxy, or (CrC₆)alkylcarbonyl; or R_M and RN together with the nitrogen they are attached to form a 3 to 8 membered ring, wherein the 3 to 8 membered ring may be optionally substituted with 1 to 3 substituents that are

(Ci-C6)alkoxy, (CrC6)alkyl, halogen, or hydroxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH or N ; L is a bond; Ri is -C(O)OR or -CH₂OR; R is H or (C C₆)alkyl; R₂, R₃, and R₄ are independently H, (Ci-C6)alkoxy, (CrC6)alkyl, (Ci-C6)alkylthio, carboxy, cyano, halogen,

halo(CrC₆)alkoxy, halo(CrC₆)alkyl, hydroxy, hydroxy(CrC₈)alkyl, mercapto,

nitro, -N RQRH, or (N R_GRi-i)carbonyl; R_G and RH are independently H, (CrC₆)alkyl, (CrC6)alkylcarbonyl, or RQ and RH form a ring that is azetidine, pyrrolidine, piperidine, or azepane; R₅ is H; R₆, R₇, R9, and R10 are independently H, (C C₆)alkoxy, (CrC6)alkoxycarbonyl, (CrC6)alkyl, (CrC6)alkylcarbonyl, (CrC6)alkylthio, carboxy, cyano, halogen, halo(CrC6)alkoxy, halo(CrC6)alkyl, hydroxy, hydroxy(CrC6)alkyl, mercapto, nitro, -NRjR_K or (NRjR_K)carbonyl; Rj and R« are independently H or

(C C₆)alkyl; R₈ is H, (C C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,

(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C C₆)alkoxycarbonyl, (C C₆)alkyl, (C C₆)alkylcarbonyl, (CrC₆)alkylthio, carboxy, carboxy(CrC₆)alkoxy, carboxy(CrC₆)alkyl, cyano, halogen, halo(CrC6)alkoxy, halo(CrC6)alkyl, hydroxy, hydroxy(Ci-C6)alkoxy,

hydroxy(CrC6)alkyl, mercapto,

nitro, -N R_MRN, -NR_MRN(CrC₆)alkoxy, -NR_MRN(CrC₆)alkyl, (NR_MR_N)carbonyl,

(NR_MRN)carbonyl(CrC6)alkyl, or (NR_MRN)carbonyl(CrC6)alkoxy; wherein the

halo(CrC6)alkyl is optionally substituted with 1 or 2 hydroxy groups; and RM and RN are independently H, (Ci-C6)alkyl, (Ci-C6)alkyl(CrC6)alkoxy, or (CrC6)alkylcarbonyl; or RM and RN together with the nitrogen they are attached to form a 3 to 8 membered ring, wherein the 3 to 8 membered ring may be optionally substituted with 1 to 3 substituents that are (C C₆)alkoxy, (CrC₆)alkyl, halogen, or hydroxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR or -CH₂OR; R is H; R₂ is H or halogen; R₃ is (CrC₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆, R₇, Rg, and R10 are independently H, (CrC₆)alkoxy, halogen, hydroxy, or hydroxy(CrC₆)alkyl; R₈ is H, (CrC₆)alkoxy, (Ci-C6)alkoxy(Ci-C₆)alkyl,

(CrC₆)alkyl, (CrC₆)alkylcarbonyl, carboxy(CrC₆)alkoxy, halo(CrC₆)alkyl,

hydroxy(Ci-C6)alkoxy, hydroxy(CrC6)alkyl, -NRMRN(C C6)alkoxy,

(NRMRN)carbonyl(CrC6)alkyl, or (NRMRN)carbonyl(Ci-C6)alkoxy; wherein the

halo(CrC₆)alkyl is optionally substituted with 1 hydroxy group; and RM and RN are independently H, (CrC₆)alkyl, (Ci-C6)alkyl(Ci-C₆)alkoxy, or (CrC₆)alkylcarbonyl; or R_M and RN together with the nitrogen they are attached to form a 3 to 8 membered ring, wherein the 3 to 8 membered ring may be optionally substituted with 1 to 3 substituents that are (C C₆)alkoxy, (CrC₆)alkyl, halogen, or hydroxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR or -CH₂OR; R is H; R₂ is H or F; R₃ is methyl, cyano, CI, or F; R₄ is H; R₅ is H; R₆, R₇, Rg, and R10 are independently H, (CrC₆)alkoxy, halogen, hydroxy, or hydroxy(C C₆)alkyl; R₈ is H, (C C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, (C C₆)alkyl, (CrC6)alkylcarbonyl, carboxy(CrC6)alkoxy, halo(CrC6)alkyl, hydroxy(Ci-C6)alkoxy, hydroxy(Ci -C₆)alkyl, -NR_MRN(Ci-C₆)alkoxy, (NR_MRN)carbonyl(Ci-C₆)alkyl, or

(NRMRN)carbonyl(CrC6)alkoxy; wherein the halo(CrC6)alkyl is optionally substituted with 1 hydroxy group; and RM and RN are independently H, (CrC6)alkyl,

(Ci -C6)alkyl(Ci-C₆)alkoxy, or (CrC₆)alkylcarbonyl; or R_M and RN together with the nitrogen they are attached to form a 3 to 8 membered ring, wherein the 3 to 8 membered ring may be optionally substituted with 1 to 3 substituents that are

(CrC₆)alkoxy, (CrC₆)alkyl, halogen, or hydroxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR or -CH₂OR; R is H; R₂ is H or F; R₃ is CI, F or CN; R₄ is H; R₅ is H; R₆, R₇, R_g, and Ri₀ are independently H, (CrC₆)alkoxy, halogen, hydroxy, or

hydroxy(CrC₆)alkyl; R₈ is H, (C C₆)alkoxy, (Ci-C₆)alkoxy(Ci-C₆)alkyl, (C C₆)alkyl, (CrC6)alkylcarbonyl, carboxy(CrC6)alkoxy, halo(CrC6)alkyl, hydroxy(Ci -C6)alkoxy, hydroxy(CrC₆)alkyl, -NR_MRN(Ci-C₆)alkoxy, (NR_MRN)carbonyl(Ci-C₆)alkyl, or

(NR_MRN)carbonyl(CrC6)alkoxy; wherein the halo(CrC₆)alkyl is optionally substituted with 1 hydroxy group; and RM and RN are independently H, (CrC₆)alkyl,

(Ci -C6)alkyl(CrC6)alkoxy, or (CrC6)alkylcarbonyl; or RM and RN together with the nitrogen they are attached to form a 3 to 8 membered ring, wherein the 3 to 8 membered ring may be optionally substituted with 1 to 3 substituents that are

(CrC₆)alkoxy, (CrC₆)alkyl, halogen, or hydroxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; Rg, and Rio are H; and Rs is hydroxy(Ci -C6)alkoxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆, R₉, and Rio are H; R₇ is H or (Ci -C6)alkoxy ; and Rs is hydroxy(Ci-C6)alkoxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆, R₉, and Rio are H; R₇ is methoxy; and Rs is hydroxy(Ci -C6)alkoxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH2OR; R is H; R₂ is H or F; R₃ is CI, F, or CN ; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; Rg, and R10 are H; and R₈ is hydroxy(Ci -C6)alkoxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH ; L is a bond; Ri is -CH2OR; R is H; R₂ is H or F; R₃ is CI, F, or CN ; R₄ is H; R₅ is H; R₆, R₉, and Ri₀ are H; R₇ is H or (C-i-C₆)alkoxy ; and R₈ is hydroxy(CrC₆)alkoxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH ; L is a bond; Ri is -CH2OR; R is H; R₂ is H or F; R₃ is CI, F, or CN ; R₄ is H; R₅ is H; R₆, R₉, and R10 are H; R₇ is methoxy; and R₈ is hydroxy(CrC₆)alkoxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; Rg, and R-io are H; and R₈ is (Ci-C6)alkoxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆, R₇, R₉, and R10 are H; and R₈ is (Ci-C6)alkoxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH ; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆, R₉, and Ri₀ are H; R₇ is methoxy; and R₈ is (CrC₆)alkoxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH ; L is a bond; Ri is -CH₂OR; R is H; R₂ is H or F; R₃ is CI, F, or CN ; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; Rg, and R10 are H; and R₈ is (CrC₆)alkoxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH₂OR; R is H; R₂ is H or F; R₃ is CI, F, or CN ; R₄ is H; R₅ is H; R₆, R₇, R₉, and Ri₀ are H; and R₈ is (CrC₆)alkoxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH₂OR; R is H; R₂ is H or F; R₃ is CI, F, or CN ; R₄ is H; R₅ is H; R₆, R₉, and Ri₀ are H; R₇ is methoxy; and R₈ is (CrC₆)alkoxy. In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is N; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or halogen; R₃ is (CrC6)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆, R₇, R9, and R10 are independently H, (CrC₆)alkoxy, halogen, hydroxy, or hydroxy(C C₆)alkyl; R₈ is H, (C C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, (C C₆)alkyl, (CrC₆)alkylcarbonyl, carboxy(CrC₆)alkoxy, halo(CrC₆)alkyl, hydroxy(CrC₆)alkoxy, hydroxy(C C₆)alkyl, -NR_MRN(C C₆)alkoxy, (NR_MRN)carbonyl(Ci-C₆)alkyl, or

(NRMRN)carbonyl(Ci-C6)alkoxy; wherein the halo(CrC6)alkyl is optionally substituted with 1 hydroxy group; and RM and RN are independently H, (Ci-C6)alkyl,

(Ci -C6)alkyl(Ci-C₆)alkoxy, or (CrC₆)alkylcarbonyl; or R_M and RN together with the nitrogen they are attached to form a 3 to 8 membered ring, wherein the 3 to 8

membered ring may be optionally substituted with 1 to 3 substituents that are

(Ci -C6)alkoxy, (CrC6)alkyl, halogen, or hydroxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is N; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is methyl, cyano, CI, or F; R₄ is H; R₅ is H; R₆, R₇, Rg, and R10 are independently H, (Ci -C6)alkoxy, halogen, hydroxy, or

hydroxy(CrC₆)alkyl; R₈ is H, (C C₆)alkoxy, (Ci-C₆)alkoxy(Ci-C₆)alkyl, (C C₆)alkyl, (CrC₆)alkylcarbonyl, carboxy(CrC₆)alkoxy, halo(CrC₆)alkyl, hydroxy(CrC₆)alkoxy, hydroxy(C C₆)alkyl, -NR_MRN(Ci-C₆)alkoxy, (NR_MRN)carbonyl(C C₆)alkyl, or

(Ci -C6)alkyl(CrC6)alkoxy, or (CrC6)alkylcarbonyl; or RM and RN together with the nitrogen they are attached to form a 3 to 8 membered ring, wherein the 3 to 8

membered ring may be optionally substituted with 1 to 3 substituents that are

(CrC₆)alkoxy, (CrC₆)alkyl, halogen, or hydroxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is N; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆, R₇, R₉, and Ri₀ are independently H, (CrC₆)alkoxy, halogen, hydroxy, or hydroxy(CrC₆)alkyl; R₈ is H, (CrC₆)alkoxy, (Ci-C₆)alkoxy(Ci-C₆)alkyl, (C C₆)alkyl, (C C₆)alkylcarbonyl,

carboxy(CrC6)alkoxy, halo(CrC6)alkyl, hydroxy(Ci-C6)alkoxy,

hydroxy(C C₆)alkyl, -NR_MRN(Ci-C₆)alkoxy, (NR_MRN)carbonyl(Ci-C₆)alkyl, or

(NR_MRN)carbonyl(CrC6)alkoxy; wherein the halo(CrC₆)alkyl is optionally substituted with 1 hydroxy group; and RM and RN are independently H, (Ci-C6)alkyl, (Ci-C6)alkyl(Ci-C₆)alkoxy, or (CrC₆)alkylcarbonyl; or R_M and RN together with the nitrogen they are attached to form a 3 to 8 membered ring, wherein the 3 to 8

membered ring may be optionally substituted with 1 to 3 substituents that are

(CrC₆)alkoxy, (CrC₆)alkyl, halogen, or hydroxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH or N; L is a bond; Ri is -C(O)OR; R is H; R₂, R₃, and R₄ are independently H, (C C₆)alkoxy, (C C₆)alkyl, (CrC6)alkylthio, carboxy, cyano, halogen, halo(CrC6)alkoxy, halo(CrC6)alkyl, hydroxy, hydroxy(CrC8)alkyl, mercapto, nitro, -N RQRH, or (NRoR^carbonyl; RQ and RH are independently H, (CrC₆)alkyl, (CrC₆)alkylcarbonyl, or R_G and RH form a ring that is azetidine, pyrrolidine, piperidine, or azepane; R₅ is H; R₆, R₇, R9, and R10 are

independently H, (Ci-C6)alkoxy, (CrC6)alkoxycarbonyl, (Ci-C6)alkyl,

(CrC6)alkylcarbonyl, (Ci-C6)alkylthio, carboxy, cyano, halogen, halo(CrC6)alkoxy, halo(CrC6)alkyl, hydroxy, hydroxy(CrC6)alkyl, mercapto, nitro, -NRjR«, or

(NRjR_K)carbonyl; Rj and R« are independently H or (CrC₆)alkyl; R₈ is aryl,

aryl(CrC₆)alkoxy, aryl(CrC₆)alkyl, arylcarbonyl, or aryloxy, wherein each is optionally substituted with 1 , 2, 3, 4, or 5 substituents that are independently (Ci-C6)alkoxy, (CrC6)alkoxycarbonyl, (Ci-C6)alkyl, (CrC6)alkylcarbonyl, (Ci-C6)alkylthio, carboxy, cyano, halogen, halo(CrC₆)alkoxy, halo(CrC₆)alkyl, hydroxy, hydroxy(CrC₆)alkyl, mercapto, nitro, -N R_MRN, or (NR_MRN)carbonyl; and RM and RN are independently H, (CrC₆)alkyl, (Ci-C6)alkyl(Ci-C₆)alkoxy, or (CrC₆)alkylcarbonyl; or R_M and RN together with the nitrogen they are attached to form a 3 to 8 membered ring, wherein the 3 to 8 membered ring may be optionally substituted with 1 to 3 substituents that are

(Ci-C6)alkoxy, (CrC6)alkyl, halogen, or hydroxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or halogen; R₃ is (CrC6)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; Rg and R10 are H; R₈ is aryl wherein the aryl is phenyl substituted with 1 substituent that is (CrC₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or halogen; R₃ is (CrC6)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆, R₇, Rg, and R10 are H; R₈ is aryl wherein the aryl is phenyl substituted with 1 substituent that is (CrC₆)alkoxy or hydroxy. In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is methyl, cyano, CI, or F; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; Rg and Ri₀ are H; R₈ is aryl wherein the aryl is phenyl substituted with 1 substituent that is (CrC₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is methyl, cyano, CI, or F; R₄ is H; R₅ is H; R₆, R₇, Rg, and R-io are H; R₈ is aryl wherein the aryl is phenyl substituted with 1 substituent that is (CrC₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; Rg and Rio are H; R₈ is aryl wherein the aryl is phenyl substituted with 1 substituent that is (CrC₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆, R₇, R₉, and Rio are H; R₈ is aryl wherein the aryl is phenyl substituted with 1 substituent that is

(C C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ and R₅ are H; R₆ and R₇ are independently H, F, or methoxy; Rg and Rio are H; R₈ is aryl wherein the aryl is phenyl substituted with 1 substituent that is hydroxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄, R₅, R₆, Rz, Rg, and Rio are H; R₈ is aryl wherein the aryl is phenyl substituted with 1 substituent that is hydroxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH₂OR; R is H; R₂ is H or halogen; R₃ is (CrC₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; Rg and Ri₀ are H; R₈ is aryl wherein the aryl is phenyl substituted with 1 substituent that is (CrC₆)alkoxy or hydroxy. In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH2OR; R is H; R₂ is H or halogen; R₃ is (CrC6)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆, R7, R9, and R10 are H; R₈ is aryl wherein the aryl is phenyl substituted with 1 substituent that is (CrC₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH2OR; R is H; R₂ is H or F; R₃ is methyl, cyano, CI, or F; R₄ is H; R₅ is H; R₆ and R7 are independently H, F, or methoxy; Rg and R10 are H; R₈ is aryl wherein the aryl is phenyl substituted with 1 substituent that is (CrC₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH2OR; R is H; R₂ is H or F; R₃ is methyl, cyano, CI, or F; R₄ is H; R₅ is H; R₆, R7, Rg, and R-io are H; R₈ is aryl wherein the aryl is phenyl substituted with 1 substituent that is (CrC₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH2OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; Rg and R10 are H; R₈ is aryl wherein the aryl is phenyl substituted with 1 substituent that is (CrC₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH2OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆, R₇, R₉, and R10 are H; R₈ is aryl wherein the aryl is phenyl substituted with 1 substituent that is

(C C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH ; L is a bond; Ri is -CH2OR; R is H; R₂ is H or F; R₃ is CI, F, or CN ; R₄ and R₅ are H; R₆ and R₇ are independently H, F, or methoxy; Rg and R10 are H; R₈ is aryl wherein the aryl is phenyl substituted with 1 substituent that is hydroxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH ; L is a bond; Ri is -CH2OR; R is H; R₂ is H or F; R₃ is CI, F, or CN ; R₄, R₅, R₆, R₇, R₉, and Ri₀ are H; R₈ is aryl wherein the aryl is phenyl substituted with 1 substituent that is hydroxy. In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is N; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or halogen; R₃ is (CrC6)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; Rg and Ri₀ are H; R₈ is aryl wherein the aryl is phenyl substituted with 1 substituent that is (CrC₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is N; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or halogen; R₃ is (CrC6)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆, R7, R9, and R-io are H; R₈ is aryl wherein the aryl is phenyl substituted with 1 substituent that is (CrC₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is N; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is methyl, cyano, CI, or F; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; Rg and R10 are H; R₈ is aryl wherein the aryl is phenyl substituted with 1 substituent that is (CrC₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is N; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is methyl, cyano, CI, or F; R₄ is H; R₅ is H; R₆, R₇, Rg, and R10 are H; R₈ is aryl wherein the aryl is phenyl substituted with 1 substituent that is (CrC₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is N; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; Rg and R10 are H; R₈ is aryl wherein the aryl is phenyl substituted with 1 substituent that is (CrC₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is N; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆, R₇, R₉, and R10 are H; R₈ is aryl wherein the aryl is phenyl substituted with 1 substituent that is

(C C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH or N; L is a bond; Ri is -C(O)OR; R is H or (C C₆)alkyl; R₂, R₃, and R₄ are independently H, (C C₆)alkoxy, (CrC₆)alkyl, (CrC₆)alkylthio, carboxy, cyano, halogen, halo(CrC₆)alkoxy,

halo(CrC6)alkyl, hydroxy, hydroxy(CrC₈)alkyl, mercapto, nitro, -N RQRH, or (NR_GRi-i)carbonyl; R_G and RH are independently H, (CrC₆)alkyl, (CrC₆)alkylcarbonyl, or RG and RH form a ring that is azetidine, pyrrolidine, piperidine, or azepane; R5 is H; R₆, R₇, R9, and R10 are independently H, (Ci-C6)alkoxy, (CrC6)alkoxycarbonyl, (CrC6)alkyl, (CrC₆)alkylcarbonyl, (CrC₆)alkylthio, carboxy, cyano, halogen, halo(CrC₆)alkoxy, halo(CrC₆)alkyl, hydroxy, hydroxy(CrC₆)alkyl, mercapto, nitro, -NRjR_K, or

(NRjR_K)carbonyl; Rj and R« are independently H or (CrC₆)alkyl; R₈ is

(C₃-C₇)heterocycle, (C₃-C₇)heterocycle(Ci-C₆)alkoxy, (C3-C₇)heterocycle(Ci-C₆)alkyl, (C3-C₇)heterocyclecarbonyl, (C3-C₇)heterocyclecarbonyl(CrC6)alkyl, or

(C3-C₇)heterocycleoxy, wherein each is optionally substituted with 1 , 2, or 3 substituents that are independently (CrC₆)alkoxy, (CrC₆)alkoxycarbonyl, (CrC₆)alkoxysulfonyl, (CrC₆)alkyl, (CrC₆)alkylcarbonyl, (CrC₆)alkylsulfonyl, (CrC₆)alkylthio, carboxy, cyano, halogen, halo(CrC6)alkoxy, halo(CrC6)alkyl, hydroxy, hydroxy(CrC6)alkyl, mercapto, nitro, -N RMRN, (NRMRN)carbonyl, or oxo; and RM and RN are independently H,

(CrC6)alkyl, (Ci-C6)alkyl(CrC6)alkoxy, or (CrC6)alkylcarbonyl; or RM and RN together with the nitrogen they are attached to form a 3 to 8 membered ring, wherein the 3 to 8 membered ring may be optionally substituted with 1 to 3 substituents that are

(Ci-C6)alkoxy, (CrC6)alkyl, halogen, or hydroxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or halogen; R₃ is (CrC₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; Rg and R10 are H; R₈ is

(C₃-C₇)heterocycle, (C₃-C₇)heterocycle(Ci-C₆)alkoxy,

(C3-C₇)heterocyclecarbonyl(CrC6)alkyl, or (C3-C₇)heterocycleoxy, wherein the

(C3-C₇)heterocycle is azetidinyl, morpholinyl,oxetanyl, piperazinyl, piperidinyl,

pyrrolidinyl, tetrahydrofuran, tetrahydro-2H-pyran, or triazolyl, wherein each is optionally substituted with 1 substituent that is (CrC₆)alkoxycarbonyl, (CrC₆)alkyl,

(CrC6)alkylcarbonyl, (CrC6)alkylsulfonyl, hydroxy, hydroxy(CrC6)alkyl, or oxo.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or halogen; R₃ is (CrC₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆, R7, R9, and R10 are H; R₈ is (C3-C₇)heterocycle,

(C3-C7)heterocycle(CrC6)alkoxy, (C3-C7)heterocyclecarbonyl(CrC6)alkyl, or

(C₃-C₇)heterocycleoxy, wherein the (C₃-C₇)heterocycle is azetidinyl,

morpholinyl,oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,

tetrahydro-2H-pyran, or triazolyl, wherein each is optionally substituted with 1 substituent that is (CrC₆)alkoxycarbonyl, (CrC₆)alkyl, (CrC₆)alkylcarbonyl, (CrC6)alkylsulfonyl, hydroxy, hydroxy(CrC6)alkyl, or oxo.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is methyl, cyano, CI, or F; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; Rg and Ri₀ are H; R₈ is (C₃-C₇)heterocycle, (C₃-C₇)heterocycle(Ci-C₆)alkoxy, (C3-C₇)heterocyclecarbonyl(Ci-C₆)alkyl, or

(C3-C₇)heterocycleoxy, wherein the (C3-C₇)heterocycle is azetidinyl,

morpholinyl,oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,

tetrahydro-2H-pyran, or triazolyl, wherein each is optionally substituted with 1 substituent that is (CrC₆)alkoxycarbonyl, (CrC₆)alkyl, (CrC₆)alkylcarbonyl,

(CrC6)alkylsulfonyl, hydroxy, hydroxy(CrC6)alkyl, or oxo.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is methyl, cyano, CI, or F; R₄ is H; R₅ is H; R₆, R₇, Rg, and Ri₀ are H; R₈ is (C₃-C₇)heterocycle, (C₃-C₇)heterocycle(Ci-C₆)alkoxy,

(C₃-C₇)heterocyclecarbonyl(CrC6)alkyl, or (C₃-C₇)heterocycleoxy, wherein the

(C₃-C₇)heterocycle is azetidinyl, morpholinyl,oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran, tetrahydro-2H-pyran, or triazolyl, wherein each is optionally substituted with 1 substituent that is (CrC₆)alkoxycarbonyl, (CrC₆)alkyl,

(CrC₆)alkylcarbonyl, (CrC₆)alkylsulfonyl, hydroxy, hydroxy(CrC₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; Rg and Ri₀ are H; R₈ is (C₃-C₇)heterocycle,

(C₃-C₇)heterocycle(Ci-C₆)alkoxy, (C₃-C₇)heterocyclecarbonyl(CrC₆)alkyl, or

(C₃-C₇)heterocycleoxy, wherein the (C₃-C₇)heterocycle is azetidinyl,

morpholinyl,oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,

(CrC6)alkylsulfonyl, hydroxy, hydroxy(CrC6)alkyl, or oxo.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆, R₇, R₉, and Ri₀ are H; R₈ is (C₃-C₇)heterocycle, (C₃-C₇)heterocycle(CrC6)alkoxy, (C₃-C₇)heterocyclecarbonyl(Ci -C6)alkyl, or (C₃-C₇)heterocycleoxy, wherein the

(C3-C₇)heterocycle is azetidinyl, morpholinyl,oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran, tetrahydro-2H-pyran, or triazolyl, wherein each is optionally substituted with 1 substituent that is (CrC₆)alkoxycarbonyl, (CrC₆)alkyl,

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; Rg and R-io are H; R₈ is (C3-C₇)heterocycle or

(C3-C₇)heterocycle(Ci-C₆)alkoxy, wherein the (C₃-C₇)heterocycle is azetidinyl, morpholinyl,oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,

tetrahydro-2H-pyran, or triazolyl, wherein each is optionally substituted with 1 substituent that is (CrC6)alkoxycarbonyl, (Ci -C6)alkyl, (CrC6)alkylcarbonyl,

(CrC6)alkylsulfonyl, hydroxy, hydroxy(CrC6)alkyl, or oxo.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆, R₇, R₉, and Rio are H; R₈ is (C3-C₇)heterocycle or (C3-C₇)heterocycle(CrC6)alkoxy, wherein the

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; Rg and Ri₀ are H; R₈ is (C₃-C₇)heterocycle wherein the (C₃-C₇)heterocycle is azetidinyl, morpholinyl,oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran, tetrahydro-2H-pyran, or triazolyl, wherein each is optionally substituted with 1 substituent that is (CrC₆)alkoxycarbonyl, (CrC₆)alkyl,

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; Rg and Ri₀ are H; R₈ is (C₃-C₇)heterocycle wherein the (C₃-C₇)heterocycle is tetrahydro-2H-pyran. In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆, R₇, R₈, and R₉ are H; R₈ is (C₃-C₇)heterocycle wherein the (C₃-C₇)heterocycle is tetrahydro-2H-pyran.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆, R₇, R₉, and Ri₀ are H; R₈ is (C₃-C₇)heterocycle wherein the (C₃-C₇)heterocycle is azetidinyl,

morpholinyl,oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,

(CrC6)alkylsulfonyl, hydroxy, hydroxy(CrC6)alkyl, or oxo.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; Rg and Ri₀ are H; R₈ is

(C₃-C₇)heterocycle(CrC6)alkoxy, wherein the (C₃-C₇)heterocycle is azetidinyl, morpholinyl,oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,

(CrC₆)alkylsulfonyl, hydroxy, hydroxy(CrC₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆, R₇, R₉, and Rio are H; R₈ is (C₃-C₇)heterocycle(Ci-C₆)alkoxy, wherein the (C₃-C₇)heterocycle is azetidinyl, morpholinyl,oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran, tetrahydro-2H-pyran, or triazolyl, wherein each is optionally substituted with 1 substituent that is (CrC6)alkoxycarbonyl, (Ci-C6)alkyl, (CrC6)alkylcarbonyl,

(CrC₆)alkylsulfonyl, hydroxy, hydroxy(CrC₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH₂OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; Rg and Ri₀ are H; R₈ is (C₃-C₇)heterocycle wherein the (C₃-C₇)heterocycle is azetidinyl, morpholinyl,oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran, tetrahydro-2H-pyran, or triazolyl, wherein each is optionally substituted with 1 substituent that is (CrC₆)alkoxycarbonyl, (CrC₆)alkyl, (CrC₆)alkylcarbonyl, (CrC₆)alkylsulfonyl, hydroxy, hydroxy(CrC₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH2OR; R is H; R₂ is H or F; R₃ is CI, F, or CN ; R₄ is H; R₅ is H; R₆, R₇, R₉, and Ri₀ are H; R₈ is (C₃-C₇)heterocycle wherein the (C₃-C₇)heterocycle is azetidinyl,

morpholinyl,oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,

tetrahydro-2H-pyran, or triazolyl, wherein each is optionally substituted with 1

substituent that is (CrC6)alkoxycarbonyl, (Ci-C6)alkyl, (CrC6)alkylcarbonyl,

(CrC₆)alkylsulfonyl, hydroxy, hydroxy(CrC₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH ; L is a bond; Ri is -CH2OR; R is H; R₂ is H or F; R₃ is CI, F, or CN ; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; Rg and R10 are H; R₈ is

(C₃-C₇)heterocycle(Ci-C₆)alkoxy, wherein the (C₃-C₇)heterocycle is azetidinyl, morpholinyl,oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,

substituent that is (CrC6)alkoxycarbonyl, (Ci-C6)alkyl, (CrC6)alkylcarbonyl,

(CrC₆)alkylsulfonyl, hydroxy, hydroxy(CrC₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH2OR; R is H; R₂ is H or F; R₃ is CI, F, or CN ; R₄ is H; R₅ is H; R₆, R₇, R₉, and Ri₀ are H; R₈ is (C₃-C₇)heterocycle(CrC₆)alkoxy, wherein the (C₃-C₇)heterocycle is azetidinyl, morpholinyl,oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran, tetrahydro-2H-pyran, or triazolyl, wherein each is optionally substituted with 1

substituent that is (CrC₆)alkoxycarbonyl, (CrC₆)alkyl, (CrC₆)alkylcarbonyl,

(CrC₆)alkylsulfonyl, hydroxy, hydroxy(CrC₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is N; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or halogen; R₃ is (CrC₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; Rg and R10 are H; R₈ is

(C₃-C₇)heterocycle, (C₃-C₇)heterocycle(CrC₆)alkoxy,

(C₃-C₇)heterocyclecarbonyl(CrC₆)alkyl, or (C₃-C₇)heterocycleoxy, wherein the

(C₃-C₇)heterocycle is azetidinyl, morpholinyl,oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran, tetrahydro-2H-pyran, or triazolyl, wherein each is optionally substituted with 1 substituent that is (CrC₆)alkoxycarbonyl, (CrC₆)alkyl, (CrC6)alkylcarbonyl, (CrC6)alkylsulfonyl, hydroxy, hydroxy(CrC6)alkyl, or oxo.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is N; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or halogen; R₃ is (CrC₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆, R₇, R9, and R10 are H; R₈ is (C₃-C₇)heterocycle,

(C3-C₇)heterocycle(Ci-C₆)alkoxy, (C3-C₇)heterocyclecarbonyl(Ci-C₆)alkyl, or

(C3-C₇)heterocycleoxy, wherein the (C3-C₇)heterocycle is azetidinyl,

morpholinyl,oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,

(CrC6)alkylsulfonyl, hydroxy, hydroxy(CrC6)alkyl, or oxo.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is N; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is methyl, cyano, CI, or F; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; Rg and R10 are H; R₈ is (C₃-C₇)heterocycle, (C3-C₇)heterocycle(CrC6)alkoxy, (C3-C₇)heterocyclecarbonyl(CrC6)alkyl, or

(C3-C₇)heterocycleoxy, wherein the (C3-C₇)heterocycle is azetidinyl,

morpholinyl,oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,

(CrC₆)alkylsulfonyl, hydroxy, hydroxy(CrC₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is N; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is methyl, cyano, CI, or F; R₄ is H; R₅ is H; R₆, R₇, Rg, and R10 are H; R₈ is (C₃-C₇)heterocycle, (C3-C₇)heterocycle(Ci-C₆)alkoxy,

(CrC6)alkylcarbonyl, (CrC6)alkylsulfonyl, hydroxy, hydroxy(CrC6)alkyl, or oxo.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is N; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; Rg and R-io are H; R₈ is (C3-C₇)heterocycle, (C₃-C₇)heterocycle(Ci-C6)alkoxy, (C3-C₇)heterocyclecarbonyl(Ci-C₆)alkyl, or (C3-C₇)heterocycleoxy, wherein the (C3-C₇)heterocycle is azetidinyl,

morpholinyl,oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,

(CrC₆)alkylsulfonyl, hydroxy, hydroxy(CrC₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is N; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆, R₇, R₉, and Rio are H; R₈ is (C₃-C₇)heterocycle, (C₃-C₇)heterocycle(Ci-C₆)alkoxy,

(C3-C₇)heterocyclecarbonyl(Ci-C₆)alkyl, or (C₃-C₇)heterocycleoxy, wherein the

(C3-C₇)heterocycle is azetidinyl, morpholinyl,oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran, tetrahydro-2H-pyran, or triazolyl, wherein each is optionally substituted with 1 substituent that is (CrC6)alkoxycarbonyl, (Ci-C6)alkyl,

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH or N; L is a bond; Ri is -C(O)OR or -CH₂OR; R is H or (C C₆)alkyl; R₂, R₃, and R₄ are independently H, (CrC₆)alkoxy, (CrC₆)alkyl, (CrC₆)alkylthio, carboxy, cyano, halogen,

halo(CrC₆)alkoxy, halo(CrC₆)alkyl, hydroxy, hydroxy(CrC₈)alkyl, mercapto,

nitro, -N RQRH, or (NR_GRH)carbonyl; R_G and RH are independently H, (CrC₆)alkyl, (CrC₆)alkylcarbonyl, or R_G and RH form a ring that is azetidine, pyrrolidine, piperidine, or azepane; R5 is H; R₆, R7, R9, and R10 are independently H, (Ci-C6)alkoxy,

(CrC6)alkoxycarbonyl, (Ci-C6)alkyl, (CrC6)alkylcarbonyl, (Ci-C6)alkylthio, carboxy, cyano, halogen, halo(CrC₆)alkoxy, halo(CrC₆)alkyl, hydroxy, hydroxy(CrC₆)alkyl, mercapto, nitro, -NRjR_K, or (NRjR_K)carbonyl; Rj and R« are independently H or

(CrC6)alkyl; R₈ is heteroaryl, heteroaryl(Ci-C6)alkoxy, heteroaryl(CrC6)alkyl, heteroarylcarbonyl, or heteroaryloxy, wherein each is optionally substituted with 1 , 2, or 3 substituents that are independently (CrC₆)alkoxy, (CrC₆)alkoxycarbonyl,

(CrC₆)alkyl, (CrC₆)alkylcarbonyl, (CrC₆)alkylthio, carboxy, cyano, halogen,

halo(CrC6)alkoxy, halo(CrC6)alkyl, hydroxy, hydroxy(CrC6)alkyl, mercapto,

nitro, -N RMRN, or (NRMRNi)carbonyl; and RM and RN are independently H, (Ci-C6)alkyl, (Ci-C6)alkyl(Ci-C₆)alkoxy, or (CrC₆)alkylcarbonyl; or R_M and RN together with the nitrogen they are attached to form a 3 to 8 membered ring, wherein the 3 to 8 membered ring may be optionally substituted with 1 to 3 substituents that are (CrC₆)alkoxy, (CrC₆)alkyl, halogen, or hydroxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or halogen; R₃ is (CrC₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; Rg and Ri₀ are H; R₈ is

heteroaryl(CrC₆)alkoxy wherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or halogen; R₃ is (CrC₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆, R₇, Rg, and Ri₀ are H; R₈ is heteroaryl (CrC₆)alkoxy wherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is methyl, cyano, CI, or F; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; Rg and Ri₀ are H; R₈ is heteroaryl(CrC₆)alkoxy wherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is methyl, cyano, CI, or F; R₄ is H; R₅ is H; R₆, R₇, Rg, and Ri₀ are H; R₈ is heteroaryl(CrC₆)alkoxy wherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; Rg and Ri₀ are H; R₈ is heteroaryl(CrC₆)alkoxy wherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆, R₇, R₉, and Ri₀ are H; R₈ is heteroaryl(CrC₆)alkoxy wherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH₂OR; R is H; R₂ is H or halogen; R₃ is (CrC₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; Rg and Ri₀ are H; R₈ is

heteroaryl(Ci -C6)alkoxy wherein the heteroaryl is pyridinyl. In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH2OR; R is H; R₂ is H or halogen; R₃ is (CrC6)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆, R7, R9, and R10 are H; R₈ is heteroaryl(CrC₆)alkoxy wherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH2OR; R is H; R₂ is H or F; R₃ is methyl, cyano, CI, or F; R₄ is H; R₅ is H; R₆ and R7 are independently H, F, or methoxy; Rg and R10 are H; R₈ is heteroaryl(Ci-C6)alkoxy wherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH2OR; R is H; R₂ is H or F; R₃ is methyl, cyano, CI, or F; R₄ is H; R₅ is H; R₆, R7, Rg, and R-io are H; R₈ is heteroaryl(Ci-C6)alkoxy wherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH2OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; Rg and R-io are H; R₈ is heteroaryl(Ci-C6)alkoxy wherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH2OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆, R₇, R₉, and Ri₀ are H; R₈ is heteroaryl(Ci -C6)alkoxy wherein the heteroaryl is pyridinyl.

heteroaryl(Ci -C6)alkoxy wherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is N; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or halogen; R₃ is (CrC6)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆, R7, Rg, and R10 are H; R₈ is heteroaryl (Ci-C6)alkoxy wherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is N; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is methyl, cyano, CI, or F; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; Rg and R-10 are H; R₈ is heteroaryl(Ci-C6)alkoxy wherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is N; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is methyl, cyano, CI, or F; R₄ is H; R₅ is H; R₆, R₇, Rg, and R10 are H; R₈ is heteroaryl(CrC₆)alkoxy wherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is N; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; Rg and R10 are H; R₈ is heteroaryl(CrC₆)alkoxy wherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is N; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆, R₇, R₉, and Ri₀ are H; R₈ is heteroaryl(CrC₆)alkoxy wherein the heteroaryl is pyridinyl.

halo(CrC₆)alkoxy, halo(CrC₆)alkyl, hydroxy, hydroxy(CrC₈)alkyl, mercapto,

nitro, -N RQRH, or (N R_GRH)carbonyl; R_G and RH are independently H, (CrC₆)alkyl,

(CrC6)alkylcarbonyl, or RQ and RH form a ring that is azetidine, pyrrolidine, piperidine, or azepane; R5 is H; R₆, R7, Rg, and R-io are independently H, (Ci-C6)alkoxy,

(CrC₆)alkoxycarbonyl, (CrC₆)alkyl, (CrC₆)alkylcarbonyl, (CrC₆)alkylthio, carboxy, cyano, halogen, halo(CrC₆)alkoxy, halo(CrC₆)alkyl, hydroxy, hydroxy(CrC₆)alkyl, mercapto, nitro, -NRjR«, or (NRjR_K)carbonyl; Rj and RK are independently H or

(CrC₆)alkyl; R₈ is (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(CrC₆)alkoxy,

(C₃-C₈)cycloalkyl(Ci-C₆)alkyl, (C₃-C₈)cycloalkylcarbonyl, and (C₃-C₈)cycloalkyloxy wherein each is optionally substituted with 1 , 2, or 3 substituents that are independently (Ci-C6)alkoxy, (CrC6)alkoxycarbonyl, (Ci-C6)alkyl, (CrC6)alkylcarbonyl,

(CrC6)alkylthio, carboxy, cyano, halogen, halo(CrC6)alkoxy, halo(CrC6)alkyl, hydroxy, hydroxy(CrC₆)alkyl, mercapto, nitro, -N R_MRN, or (N R_MRN)carbonyl; and RM and RN are independently H, (CrC₆)alkyl, (Ci-C6)alkyl(Ci-C₆)alkoxy, or (CrC₆)alkylcarbonyl; or R_M and RN together with the nitrogen they are attached to form a 3 to 8 membered ring, wherein the 3 to 8 membered ring may be optionally substituted with 1 to 3 substituents that are (C C₆)alkoxy, (CrC₆)alkyl, halogen, or hydroxy.

(C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionally substituted with 1 substituent that is carboxy, hydroxy, hydroxy(CrC₆)alkyl, or (NR_MRNi)carbonyl; and RM and RN are H.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or halogen; R₃ is (CrC₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆, Rg, and R-io are H; R₇ is H or methoxy; R₈ is (C₃-C₈)cycloalkyl or

(C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionally substituted with 1 substituent that is carboxy, hydroxy, hydroxy(CrC₆)alkyl, or (NR_MRNi)carbonyl; and RM and RN are H.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is methyl, cyano, CI, or F; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; Rg and Ri₀ are H; R₈ is (C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionally substituted with 1 substituent that is carboxy, hydroxy, hydroxy(CrC₆)alkyl, or (NR_MRNi)carbonyl; and RM and RN are H.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is methyl, cyano, CI, or F; R₄ is H; R₅ is H; R₆, R₉, and R-io are H; R₇ is H or methoxy; R₈ is (C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionally substituted with 1 substituent that is carboxy, hydroxy, hydroxy(CrC₆)alkyl, or (NR_MRN)carbonyl; and RM and RN are H.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; Rg and R-io are H; R₈ is (C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionally substituted with 1 substituent that is carboxy, hydroxy, hydroxy(CrC₆)alkyl, or (NR_MRN)carbonyl; and RM and RN are H.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆, R₉, and Ri₀ are H; R₇ is H or methoxy; R₈ is (C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionally substituted with 1 substituent that is carboxy, hydroxy, hydroxy(CrC₆)alkyl, or (NR_MRN)carbonyl; and RM and RN are H.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH ; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or methoxy; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; Rg and R-io are H; R₈ is (C₃-C₈)cycloalkyl wherein the (C₃-C₈)cycloalkyl is cyclopropyl or cyclobutyl substituted with hydroxy(CrC₆)alkyl.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or methoxy; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆, R₉, and R-io are H; R₇ is H or methoxy; R₈ is (C₃-C₈)cycloalkyl wherein the (C₃-C₈)cycloalkyl is cyclopropyl or cyclobutyl substituted with hydroxy(CrC₆)alkyl.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH ; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; Rg and R-io are H; R₈ is (C₃-C₈)cycloalkyl wherein the (C₃-C₈)cycloalkyl is cyclobutyl substituted with hydroxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆, R₉, and Rio are H; R₇ is H or methoxy; R₈ is (C₃-C₈)cycloalkyl wherein the (C₃-C₈)cycloalkyl is cyclobutyl substituted with hydroxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH ; L is a bond; Ri is -CH₂OR; R is H; R₂ is H or halogen; R₃ is (CrC₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; Rg and Ri₀ are H; R₈ is

(C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionally substituted with 1 substituent that is carboxy, hydroxy, hydroxy(CrC₆)alkyl, or (NR_MRN)carbonyl; and RM and RN are H.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH₂OR; R is H; R₂ is H or halogen; R₃ is (CrC₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆, Rg, and Ri₀ are H; R₇ is H or methoxy; R₈ is (C₃-C₈)cycloalkyl or

(C3-C8)cycloalkyloxy wherein the (C3-C8)cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionally substituted with 1 substituent that is carboxy, hydroxy, hydroxy(CrC₆)alkyl, or (NR_MR_N)carbonyl; and RM and RN are H.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH₂OR; R is H; R₂ is H or F; R₃ is methyl, cyano, CI, or F; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; Rg and Rio are H; R₈ is (C₃-C8)cycloalkyl or (C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionally substituted with 1 substituent that is carboxy, hydroxy, hydroxy(CrC₆)alkyl, or (NR_MRNi)carbonyl; and RM and RN are H.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH₂OR; R is H; R₂ is H or F; R₃ is methyl, cyano, CI, or F; R₄ is H; R₅ is H; R₆, Rg, and R-io are H; R₇ is H or methoxy; R₈ is (C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionally substituted with 1 substituent that is carboxy, hydroxy, hydroxy(CrC₆)alkyl, or (NR_MRN)carbonyl; and RM and RN are H.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH₂OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; Rg and R-io are H; R₈ is (C₃-C₈)cycloalkyl or

(C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionally substituted with 1 substituent that is carboxy, hydroxy, hydroxy(CrC₆)alkyl, or (NR_MRN)carbonyl; and RM and RN are H.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH₂OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆, R₉, and Ri₀ are H; R₇ is H or methoxy; R₈ is (C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionally substituted with 1 substituent that is carboxy, hydroxy, hydroxy(CrC6)alkyl, or (NR_MRN)carbonyl; and RM and RN are H.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH ; L is a bond; Ri is -CH₂OR; R is H; R₂ is H or methoxy; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; Rg and Ri₀ are H; R₈ is (C₃-C₈)cycloalkyl wherein the (C3-C8)cycloalkyl is cyclopropyl or cyclobutyl substituted with hydroxy(CrC6)alkyl.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH ; L is a bond; Ri is -CH2OR; R is H; R₂ is H or methoxy; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆, R₉, and R-io are H; R₇ is H or methoxy; Rs is (C3-C8)cycloalkyl wherein the (C3-C8)cycloalkyl is cyclopropyl or cyclobutyl substituted with hydroxy(CrC₆)alkyl.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH ; L is a bond; Ri is -CH2OR; R is H; R₂ is H or F; R₃ is CI, F, or CN ; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; Rg and R-io are H; R₈ is (C3-C8)cycloalkyl wherein the (C3-C8)cycloalkyl is cyclobutyl substituted with hydroxy.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH ; L is a bond; Ri is -CH2OR; R is H; R₂ is H or F; R₃ is CI, F, or CN ; R₄ is H; R₅ is H; R₆, R₉, and Ri₀ are H; R₇ is H or methoxy; R₈ is (C₃-C₈)cycloalkyl wherein the (C₃-C₈)cycloalkyl is cyclobutyl substituted with hydroxy.

(C3-C8)cycloalkyl or (C3-C8)cycloalkyloxy wherein the (C3-C8)cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionally substituted with 1 substituent that is carboxy, hydroxy, hydroxy(CrC₆)alkyl, or (NR_MRN)carbonyl; and RM and RN are H.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is N; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or halogen; R₃ is (CrC₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆, Rg, and R-io are H; R₇ is H or methoxy; Rs is (C3-C8)cycloalkyl or (C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionally substituted with 1 substituent that is carboxy, hydroxy, hydroxy(CrC6)alkyl, or (NRMRN)carbonyl; and RM and RN are H.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is N; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is methyl, cyano, CI, or F; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; Rg and Ri₀ are H; R₈ is (C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionally substituted with 1 substituent that is carboxy, hydroxy, hydroxy(CrC₆)alkyl, or (NR_MRN)carbonyl; and RM and RN are H.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is N; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is methyl, cyano, CI, or F; R₄ is H; R₅ is H; R₆, R₉, and R-io are H; R₇ is H or methoxy; R₈ is (C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionally substituted with 1 substituent that is carboxy, hydroxy, hydroxy(CrC6)alkyl, or (NRMRNi)carbonyl; and RM and RN are H.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is N; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; Rg and Ri₀ are H; R₈ is (C₃-C₈)cycloalkyl or

(C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionally substituted with 1 substituent that is carboxy, hydroxy, hydroxy(CrC6)alkyl, or (NRMRN)carbonyl; and RM and RN are H.

In another embodiment, the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is N; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆, R₉, and Rio are H; R₇ is H or methoxy; R₈ is (C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionally substituted with 1 substituent that is carboxy, hydroxy, hydroxy(CrC₆)alkyl, or (NRMRN)carbonyl; and RM and RN are H.

In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of Formula (I II), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier. In another embodiment, the present invention provides a method for treating or preventing metabolic disorders in a mammal, particularly a human, where the metabolic disorder is ameliorated by activation of 5' adenosine monophosphate-activated protein kinase comprising administering to the mammal or human, in need of such treatment, a therapeutically effective amount of a compound of Formula (III), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method for treating or preventing type II diabetes in a mammal, particularly a human, comprising administering to the mammal or human, in need of such treatment, a therapeutically effective amount of a compound of Formula (III), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method for treating or preventing obesity in a mammal, particularly a human, comprising administering to the mammal or human, in need of such treatment, a therapeutically effective amount of a compound of Formula (III), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method for treating or preventing dyslipidemia in a mammal, particularly a human, comprising administering to the mammal or human, in need of such treatment, a therapeutically effective amount of a compound of Formula (III), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method for treating or preventing NAFLD in a mammal, particularly a human, comprising administering to the mammal or human, in need of such treatment, a therapeutically effective amount of a compound of Formula (III), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method for treating or preventing NASH in a mammal, particularly a human, comprising administering to the mammal or human, in need of such treatment, a therapeutically effective amount of a compound of Formula (III), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method for treating or preventing liver cirrhosis in a mammal, particularly a human, comprising administering to the mammal or human, in need of such treatment, a therapeutically effective amount of a compound of Formula (III), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method for treating or preventing renal diseases in a mammal, particularly a human, where the renal disease is ameliorated by activation of 5' adenosine monophosphate-activated protein kinase comprising administering to the mammal or human, in need of such treatment, a therapeutically effective amount of a compound of Formula (III), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method for treating or preventing chronic kidney disease in a mammal, particularly a human, comprising administering to the mammal or human, in need of such treatment, a therapeutically effective amount of a compound of Formula (III), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method for treating or preventing diabetic nephropathy in a mammal, particularly a human, comprising administering to the mammal or human, in need of such treatment, a therapeutically effective amount of a compound of Formula (III), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method for treating or preventing acute kidney injury in a mammal, particularly a human, comprising administering to the mammal or human, in need of such treatment, a therapeutically effective amount of a compound of Formula (III), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method for treating or preventing polycystic kidney disease in a mammal, particularly a human, comprising administering to the mammal or human, in need of such treatment, a therapeutically effective amount of a compound of Formula (III), or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides uses for compounds of Formula (III), or a pharmaceutically acceptable salt thereof, for preparing, or for the manufacture of, a medicament for treating metabolic disorders in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds of Formula (III), or a pharmaceutically acceptable salt thereof, for preparing, or for the manufacture of, a medicament for treating or preventing type II diabetes in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds of Formula (III), or a pharmaceutically acceptable salt thereof, for preparing, or for the manufacture of, a medicament for treating or preventing obesity in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds of Formula (III), or a pharmaceutically acceptable salt thereof, for preparing, or for the manufacture of, a medicament for treating or preventing dyslipidemia in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds of Formula (III), or a pharmaceutically acceptable salt thereof, for preparing, or for the manufacture of, a medicament for treating or preventing NAFLD in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds of Formula (III), or a pharmaceutically acceptable salt thereof, for preparing, or for the manufacture of, a medicament for treating or preventing NASH in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds of Formula (III), or a pharmaceutically acceptable salt thereof, for preparing, or for the manufacture of, a medicament for treating or preventing liver cirrhosis in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds of Formula (III) for preparing, or for the manufacture of, a medicament for treating renal diseases in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds of Formula (III) for preparing, or for the manufacture of, a medicament for treating or preventing chronic kidney disease in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds of Formula (III) for preparing, or for the manufacture of, a medicament for treating or preventing diabetic nephropathy in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds of Formula (III) for preparing, or for the manufacture of, a medicament for treating or preventing acute kidney injury in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds of Formula (III) for preparing, or for the manufacture of, a medicament for treating or preventing polycystic kidney disease in a mammal, particularly a human.

In another embodiment, the present invention provides compounds of Formula

(IV)

Formula (IV) or a pharmaceutically acceptable salt thereof, wherein X is N or CH; L is a bond, O, S, NR_A, (CrC₆)alkylene, (C₂-C₆)alkenylene, or (C₂-C₆)alkynylene; R is -C(O)OR

or -CH2OR; R is H or (Ci-C6)alkyl; R₂, R3, and R₄ are independently H, (Ci-C6)alkoxy, (CrC₆)alkyl, (CrC₆)alkylthio, carboxy, cyano, halogen, halo(CrC₆)alkoxy,

halo(CrC₆)alkyl, hydroxy, hydroxy(CrC₈)alkyl, mercapto, nitro, -N R_GRH, or

(NR_GRH)carbonyl; R_G and RH are independently H, (CrC₆)alkyl, (CrC₆)alkylcarbonyl, or RG and RH form a ring that is azetidine, pyrrolidine, piperidine, or azepane; R₅ is H; R₆, R7, and R-io are independently H, (Ci-C6)alkoxy, (CrC6)alkoxycarbonyl, (Ci-C6)alkyl, (CrC6)alkylcarbonyl, (Ci-C6)alkylthio, carboxy, cyano, halogen, halo(CrC6)alkoxy, halo(CrC₆)alkyl, hydroxy, hydroxy(CrC₆)alkyl, mercapto, nitro, -NRjR_K, or

aryl(CrC6)alkyl, arylcarbonyl, aryloxy, carboxy, carboxy(CrC6)alkoxy,

(C3-C₈)cycloalkyl(Ci-C₆)alkyl, (C₃-C₈)cycloalkylcarbonyl, (C₃-C₈)cycloalkyloxy, halogen, halo(CrC6)alkoxy, halo(CrC6)alkyl, heteroaryl, heteroaryl(Ci-C6)alkoxy,

heteroaryl(CrC6)alkyl, heteroarylcarbonyl, heteroaryloxy, (C₃-C7)heterocycle,

(C₃-C₇)heterocycle(C-i-C₆)alkoxy, (C₃-C₇)heterocycle(Ci-C₆)alkyl,

(C₃-C₇)heterocyclecarbonyl, (C₃-C₇)heterocyclecarbonyl(CrC₆)alkyl,

(C₃-C₇)heterocycleoxy, hydroxy, hydroxy(CrC₆)alkoxy, hydroxy(CrC₆)alkyl, mercapto, nitro, -N R_MRN, -NRMRN(C C₆)alkoxy, (NR_MRN)carbonyl, (NRMRN)carbonyl(CrC₆)alkyl, or (NRMRN)carbonyl(Ci-C6)alkoxy; wherein the aryl, aryl(Ci-C6)alkoxy, aryl(CrC6)alkyl, arylcarbonyl, and aryloxy are optionally substituted with 1 , 2, 3, 4, or 5 substituents that are independently (CrC₆)alkoxy, (CrC₆)alkoxycarbonyl, (CrC₆)alkyl,

(CrC₆)alkylcarbonyl, (CrC₆)alkylthio, carboxy, cyano, halogen, halo(CrC₆)alkoxy, halo(CrC6)alkyl, hydroxy, hydroxy(CrC6)alkyl, mercapto, nitro, -N RMRN, or

(NRMRN)carbonyl; wherein the halo(CrC6)alkyl is optionally substituted with 1 or 2 hydroxy groups; wherein the (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(CrC₆)alkoxy,

(C₃-C₈)cycloalkyl(Ci-C₆)alkyl, (C₃-C₈)cycloalkylcarbonyl, and (C₃-C₈)cycloalkyloxy are optionally substituted with 1 , 2, or 3 substituents that are independently (Ci-C6)alkoxy, (CrC6)alkoxycarbonyl, (Ci-C6)alkyl, (CrC6)alkylcarbonyl, (Ci-C6)alkylthio, carboxy, cyano, halogen, halo(CrC₆)alkoxy, halo(CrC₆)alkyl, hydroxy, hydroxy(CrC₆)alkyl, mercapto, nitro, -N R_MRN, or (NR_MRN)carbonyl; wherein the heteroaryl,

heteroaryl(Ci-C6)alkoxy, heteroaryl(CrC6)alkyl, heteroarylcarbonyl, and heteroaryloxy, are optionally substituted with 1 , 2, or 3 substituents that are independently (Ci-C6)alkoxy, (CrC6)alkoxycarbonyl, (Ci-C6)alkyl, (CrC6)alkylcarbonyl,

(CrC6)alkylthio, carboxy, cyano, halogen, halo(CrC6)alkoxy, halo(CrC6)alkyl, hydroxy, hydroxy(CrC₆)alkyl, mercapto, nitro, -N R_MRN, or (NR_MRN)carbonyl; and wherein the (C₃-C₇)heterocycle, (C3-C₇)heterocycle(Ci-C₆)alkoxy, (C3-C₇)heterocycle(Ci-C₆)alkyl, (C₃-C₇)heterocyclecarbonyl, (C₃-C₇)heterocyclecarbonyl(Ci-C₆)alkyl, and

(C₃-C₇)heterocycleoxy, are optionally substituted with 1 , 2, or 3 substituents that are independently (Ci-C6)alkoxy, (CrC6)alkoxycarbonyl, (CrC6)alkoxysulfonyl, (Ci-C6)alkyl, (CrC6)alkylcarbonyl, (CrC6)alkylsulfonyl, (Ci-C6)alkylthio, carboxy, cyano, halogen, halo(CrC₆)alkoxy, halo(CrC₆)alkyl, hydroxy, hydroxy(CrC₆)alkyl, mercapto,

nitro, -N R_MRN, (NR_MRN)carbonyl, or oxo; and RM and RN are independently H,

(CrC₆)alkoxy, (CrC₆)alkyl, halogen, or hydroxy.

In another embodiment, the present invention provides compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or halogen; R₃ is (CrC6)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆, R₇, and Ri₀ are H; R₈ is (C₃-C₇)heterocycle.

In another embodiment, the present invention provides compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is methyl, cyano, CI, or F; R₄ is H; R₅ is H; R₆, R₇, and R-io are H; R₈ is (C₃-C₇)heterocycle.

In another embodiment, the present invention provides compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆, R₇, and Ri₀ are H; R₈ is (C₃-C₇)heterocycle.

In another embodiment, the present invention provides compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆, R₇, and Ri₀ are H; R₈ is (C₃-C₇)heterocycle wherein the (C₃-C₇)heterocycle is morpholinyl.

In another embodiment, the present invention provides compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH₂OR; R is H; R₂ is H or halogen; R₃ is (CrC₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆, R7, and R-io are H; R₈ is (C₃-C₇)heterocycle. In another embodiment, the present invention provides compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH2OR; R is H; R₂ is H or F; R₃ is methyl, cyano, CI, or F; R₄ is H; R₅ is H; R₆, R7, and R-io are H; R₈ is (C₃-C₇)heterocycle.

In another embodiment, the present invention provides compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH2OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆, R₇, and Ri₀ are H; R₈ is (C3-C₇)heterocycle.

In another embodiment, the present invention provides compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH2OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆, R₇, and Ri₀ are H; R₈ is (C3-C₇)heterocycle wherein the (C3-C₇)heterocycle is morpholinyl.

In another embodiment, the present invention provides compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein X is N; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or halogen; R₃ is (CrC₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆, R₇, and R10 are H; R₈ is (C₃-C₇)heterocycle.

In another embodiment, the present invention provides compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein X is N; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is methyl, cyano, CI, or F; R₄ is H; R₅ is H; R₆, R₇, and R-io are H; R₈ is (C₃-C₇)heterocycle.

In another embodiment, the present invention provides compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein X is N; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆, R₇, and R10 are H; R₈ is (C3-C₇)heterocycle.

In another embodiment, the present invention provides compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein X is N; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄ is H; R₅ is H; R₆, R₇, and R10 are H; R₈ is (C3-C₇)heterocycle wherein the (C3-C₇)heterocycle is morpholinyl.

In another embodiment, the present invention provides compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or halogen; R₃ is (CrC6)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ are H ; Ri₀ is (Ci-C6)alkoxy; R₈ is (C3-C₇)heterocycle.

In another embodiment, the present invention provides compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or halogen; R₃ is (CrC6)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ are H ; R ₀ is H or (CrC₆)alkoxy; R₈ is (C₃-C₇)heterocycle wherein the (C3-C₇)heterocycle is pyrrolidinyl optionally substituted with (Ci-C6)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or halogen; R₃ is (CrC₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ are H ; R ₀ is H or (CrC₆)alkoxy; R₈ is (C₃-C₇)heterocycle wherein the (C₃-C₇)heterocycle is morpholinyl or pyrrolidinyl where the pyrrolidinyl is optionally substituted with (Ci-C6)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH₂OR; R is H; R₂ is H or halogen; R₃ is (CrC₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ are H ; Ri₀ is (Ci-C6)alkoxy; R₃ is (C₃-C₇)heterocycle.

In another embodiment, the present invention provides compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH2OR; R is H; R₂ is H or halogen; R₃ is (CrC₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ are H ; R ₀ is H or (CrC₆)alkoxy; R₈ is (C₃-C₇)heterocycle wherein the (C₃-C₇)heterocycle is pyrrolidinyl optionally substituted with (Ci-C6)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH2OR; R is H; R₂ is H or halogen; R₃ is (CrC₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ are H ; R ₀ is H or (CrC₆)alkoxy; R₈ is (C₃-C₇)heterocycle wherein the (C₃-C₇)heterocycle is morpholinyl or pyrrolidinyl where the pyrrolidinyl is optionally substituted with (Ci-C6)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or halogen; R₃ is (CrC₆)alkyl, cyano, or halogen; R₄, R₅, R₆, and R₇ are H; R₈ is -N RMRN; RM and RN are independently H or (Ci-C6)alkyl; and R10 is (CrC₆)alkoxy.

In another embodiment, the present invention provides compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is methyl, cyano, CI, or F; R₄, R₅, R₆, and R₇ are H; R₈ is -N RMRN; RM and RN are independently (CrC6)alkyl; and R-io is (Ci-C6)alkoxy.

In another embodiment, the present invention provides compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄, R₅, R₆, and R₇ are H; R₈ is -N RMRN; RM and RN are each methyl; and R-io is methoxy.

In another embodiment, the present invention provides compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH₂OR; R is H; R₂ is H or halogen; R₃ is (CrC₆)alkyl, cyano, or halogen; R₄, R₅, R₆, and R₇ are H; R₈ is -N R_MRN; RM and RN are independently H or (CrC₆)alkyl; and Ri₀ is (C C₆)alkoxy.

In another embodiment, the present invention provides compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH2OR; R is H; R₂ is H or F; R₃ is methyl, cyano, CI, or F; R₄, R₅, R₆, and R₇ are H; R₈ is -N R_MRN; RM and RN are independently (CrC₆)alkyl; and R10 is (CrC₆)alkoxy.

In another embodiment, the present invention provides compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH2OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄, R₅, R₆, and R₇ are H; R₈ is -N R_MRN; RM and RN are each methyl; and R10 is methoxy.

In another embodiment, the present invention provides compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein X is N; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or halogen; R₃ is (CrC6)alkyl, cyano, or halogen; R₄, R₅, R₆, and R₇ are H; R₈ is -N R_MRN; RM and RN are independently H or (CrC₆)alkyl; and R10 is (C C₆)alkoxy.

In another embodiment, the present invention provides compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein X is N; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is methyl, cyano, CI, or F; R₄, R₅, R₆, and R₇ are H; R₈ is -N RMRN; RM and RN are independently (CrC6)alkyl; and R-io is (Ci-C6)alkoxy.

In another embodiment, the present invention provides compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein X is N; L is a bond; Ri is -C(O)OR; R is H; R₂ is H or F; R₃ is CI, F, or CN; R₄, R₅, R₆, and R₇ are H; R₈ is -N RMRN; RM and RN are each methyl; and R-io is methoxy.

In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier.

In another embodiment, the present invention provides a method for treating or preventing metabolic disorders in a mammal, particularly a human, where the metabolic disorder is ameliorated by activation of 5' adenosine monophosphate-activated protein kinase comprising administering to the mammal or human, in need of such treatment, a therapeutically effective amount of a compound of Formula (IV), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method for treating or preventing type II diabetes in a mammal, particularly a human, comprising administering to the mammal or human, in need of such treatment, a therapeutically effective amount of a compound of Formula (IV), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method for treating or preventing obesity in a mammal, particularly a human, comprising administering to the mammal or human, in need of such treatment, a therapeutically effective amount of a compound of Formula (IV), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method for treating or preventing dyslipidemia in a mammal, particularly a human, comprising administering to the mammal or human, in need of such treatment, a therapeutically effective amount of a compound of Formula (IV), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method for treating or preventing NAFLD in a mammal, particularly a human, comprising administering to the mammal or human, in need of such treatment, a therapeutically effective amount of a compound of Formula (IV), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method for treating or preventing NASH in a mammal, particularly a human, comprising administering to the mammal or human, in need of such treatment, a therapeutically effective amount of a compound of Formula (IV), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method for treating or preventing liver cirrhosis in a mammal, particularly a human, comprising administering to the mammal or human, in need of such treatment, a therapeutically effective amount of a compound of Formula (IV), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method for treating or preventing renal diseases in a mammal, particularly a human, where the renal disease is ameliorated by activation of 5' adenosine monophosphate-activated protein kinase comprising administering to the mammal or human, in need of such treatment, a therapeutically effective amount of a compound of Formula (IV), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method for treating or preventing chronic kidney disease in a mammal, particularly a human, comprising administering to the mammal or human, in need of such treatment, a therapeutically effective amount of a compound of Formula (IV), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method for treating or preventing diabetic nephropathy in a mammal, particularly a human, comprising administering to the mammal or human, in need of such treatment, a therapeutically effective amount of a compound of Formula (IV), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method for treating or preventing acute kidney injury in a mammal, particularly a human, comprising administering to the mammal or human, in need of such treatment, a therapeutically effective amount of a compound of Formula (IV), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method for treating or preventing polycystic kidney disease in a mammal, particularly a human, comprising administering to the mammal or human, in need of such treatment, a therapeutically effective amount of a compound of Formula (IV), or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides uses for compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, for preparing, or for the manufacture of, a medicament for treating metabolic disorders in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, for preparing, or for the manufacture of, a medicament for treating or preventing type II diabetes in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, for preparing, or for the manufacture of, a medicament for treating or preventing obesity in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, for preparing, or for the manufacture of, a medicament for treating or preventing dyslipidemia in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, for preparing, or for the manufacture of, a medicament for treating or preventing NAFLD in a mammal, particularly a human. In another aspect, the present invention provides uses for compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, for preparing, or for the manufacture of, a medicament for treating or preventing NASH in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, for preparing, or for the manufacture of, a medicament for treating or preventing liver cirrhosis in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds of Formula (IV) for preparing, or for the manufacture of, a medicament for treating renal diseases in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds of Formula (IV) for preparing, or for the manufacture of, a medicament for treating or preventing chronic kidney disease in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds of Formula (IV) for preparing, or for the manufacture of, a medicament for treating or preventing diabetic nephropathy in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds of Formula (IV) for preparing, or for the manufacture of, a medicament for treating or preventing acute kidney injury in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds of Formula (IV) for preparing, or for the manufacture of, a medicament for treating or preventing polycystic kidney disease in a mammal, particularly a human.

Definitions

As used throughout this specification and the appended claims, the following terms have the following meanings.

The term "(C2-C8)alkenylene" means a divalent group derived from a straight or branched chain hydrocarbon of from 2 to 8 carbon atoms containing at least one double bond. Representative examples of alkenylene include, but are not limited

to, -CH=CH-, -CH=CH₂CH₂-, and -CH=C(CH₃)CH₂-.

The term "(CrC₆)alkoxy" as used herein, means a (CrC₆)alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

Representative examples of (CrC₆)alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy. The term "(Ci -C6)alkoxy(Ci-C₆)alkoxy" as used herein, means a (CrC₆)alkoxy group, as defined herein, appended to the parent molecular moiety through another (Ci -C6)alkoxy group, as defined herein. Representative examples of

(Ci -C6)alkoxy(Ci -C₆)alkoxy include, but are not limited to, tert-butoxymethoxy, 2- ethoxyethoxy, 2-methoxyethoxy, and methoxymethoxy.

The term "(Ci -C6)alkoxy(Ci-C₆)alkyl" as used herein, means a (CrC₆)alkoxy group, as defined herein, appended to the parent molecular moiety through a

(CrC6)alkyl group, as defined herein. Representative examples of

(Ci -C6)alkoxy(CrC6)alkyl include, but are not limited to, tert-butoxymethyl, 2- ethoxyethyl, 2-methoxyethyl, and methoxymethyl.

The term "(CrC₆)alkoxycarbonyl" as used herein, means a (CrC₆)alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of (CrC6)alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl.

The term "(CrC₆)alkoxysulfonyl" as used herein, means a (CrC₆)alkoxy group, as defined herein, appended appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of (CrC6)alkoxysulfonyl include, but are not limited to, methoxysulfonyl, ethoxysulfonyl and propoxysulfonyl.

The term "(C C₆)alkyl" as used herein, means a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms. Representative examples of (CrC₆)alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

The term "(CrC6)alkylcarbonyl" as used herein, means a (CrC6)alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of (C C₆)alkylcarbonyl include, but are not limited to, acetyl, 1 -oxopropyl, 2,2-dimethyl-1 -oxopropyl, 1 -oxobutyl, and 1 -oxopentyl.

The term "(CrC6)alkylene" means a divalent group derived from a straight or branched chain hydrocarbon of from 1 to 6 carbon atoms. Representative examples of (C C₈)alkylene include, but are not limited to, -CH₂-, -CH(CH₃)-, -C(CH₃)₂-, -CH₂CH₂- , -CH₂CH₂CH₂-, -CH₂CH₂CH₂CH₂-, -CH₂CH(CH3)CH₂-, and -CH₂CH₂CH₂CH₂CH₂CH₂-.

The term "(CrC6)alkylsulfonyl" as used herein, means an (Ci-C6)alkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of (CrC₆)alkylsulfonyl include, but are not limited to, methylsulfonyl and ethylsulfonyl. The term "(CrC₆)alkylthio" as used herein, means a (CrC₆)alkyl group, as defined herein, appended to the parent molecular moiety through a sulfur atom.

Representative examples of (CrC6)alkylthio include, but are not limited to, methylthio, ethylthio, tert-butylthio, and hexylthio.

The term "aryl" as used herein, means a phenyl or naphthyl group.

The term "aryl(CrC₆)alkoxy" as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an (CrC₆)alkoxy group, as defined herein.

The term "aryl(CrC6)alkyl" as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an (CrC₆)alkyl group, as defined herein. Representative examples of aryl(CrC₆)alkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and 2-naphth-2-ylethyl.

The term "arylcarbonyl" as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Examples of arylcarbonyl are benzoyl and naphthoyl.

The term "aryloxy" as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Examples of aryloxy are phenoxy and naphthalenyloxy.

The term "carbonyl" as used herein, means a -C(O)- group.

The term "carboxy" as used herein, means a -C(O)OH group.

The term "carboxy(CrC₆)alkoxy" as used herein, means a carboxy group, as defined herein, is attached to the parent molecular moiety through a (CrC₆)alkoxy group, as defined herein.

The term "carboxy(CrC6)alkyl" as used herein, means a carboxy group, as defined herein, is attached to the parent molecular moiety through a (CrC₆)alkyl group, as defined herein.

The term "cyano" as used herein, means a -CN group.

The term "(C3-C8)cycloalkyl" as used herein, means a saturated cyclic

hydrocarbon group containing from 3 to 8 carbons, examples of (C₃-C₈)cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

The term "(C3-C8)cycloalkyl(CrC6)alkoxy" as used herein, means a

(C3-C8)cycloalkyl group, as defined herein, appended to the parent molecular moiety through a (CrC₆)alkoxy group, as defined herein.

The term "(C₃-C₈)cycloalkyl(Ci -C6)alkyl" as used herein, means a

(C3-C6)cycloalkyl group, as defined herein, appended to the parent molecular moiety through a (CrC₆)alkyl group, as defined herein. Representative examples of (C3-C8)cycloalkyl(CrC6)alkyl include, but are not limited to, cyclopropylmethyl, 2- cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, and 4-cycloheptylbutyl.

The term "(C₃-C₈)cycloalkylcarbonyl" as used herein, means (C₃-C₈)cycloalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of (C₃-C₈)cycloalkylcarbonyl include, but are not limited to, cyclopropylcarbonyl, 2-cyclobutylcarbonyl, and

cyclohexylcarbonyl.

The term "(C3-C8)cycloalkyloxy" as used herein, means (C3-C8)cycloalkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom, as defined herein. Representative examples of (C₃-C₈)cycloalkyloxy include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy.

The term "Formula (l-IV)" as used herein means compounds of Formula (I), (II), (II I), and (IV).

The term "halo" or "halogen" as used herein, means -CI, -Br, -I or -F.

The term "halo(CrC6)alkoxy" as used herein, means at least one halogen, as defined herein, appended to the parent molecular moiety through a (Ci-C6)alkoxy group, as defined herein. Representative examples of halo(CrC₆)alkoxy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.

The term "halo(CrC₆)alkyl" as used herein, means at least one halogen, as defined herein, appended to the parent molecular moiety through a (CrC₆)alkyl group, as defined herein. Representative examples of halo(CrC6)alkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3- fluoropentyl.

The term "heteroaryl," as used herein, means a monocyclic heteroaryl or a bicyclic heteroaryl. The monocyclic heteroaryl is a 5 or 6 membered ring. The 5 membered ring consists of two double bonds and one, two, three or four nitrogen atoms and/or optionally one oxygen or sulfur atom. The 6 membered ring consists of three double bonds and one, two, three or four nitrogen atoms. The 5 or 6 membered heteroaryl is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heteroaryl. Representative examples of monocyclic heteroaryl include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl. The bicyclic heteroaryl consists of a monocyclic heteroaryl fused to a phenyl, or a monocyclic heteroaryl fused to a cycloalkyl, or a monocyclic heteroaryl fused to a cycloalkenyl, or a monocyclic heteroaryl fused to a monocyclic heteroaryl. The bicyclic heteroaryl is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the bicyclic heteroaryl. Representative examples of bicyclic heteroaryl include, but are not limited to, benzimidazolyl, benzofuranyl, benzothienyl, benzoxadiazolyl, cinnolinyl, dihydroquinolinyl, dihydroisoquinolinyl, furopyridinyl, indazolyl, indolyl, isoquinolinyl, naphthyridinyl, quinolinyl, tetrahydroquinolinyl, and thienopyridinyl.

The term "heteroaryl(CrC₆)alkoxy" as used herein, means a heteroaryl group, as defined herein, appended to the parent molecular moiety through an (CrC₆)alkoxy group, as defined herein. Representative examples of heteroaryl(CrC₆)alkoxy include, but are not limited to, fur-3-ylmethoxy, 1 H-imidazol-2-ylmethoxy, 1 H-imidazol-4- ylmethoxy, 1 -(pyridin-4-yl)ethoxy, pyridin-3-ylmethoxy, 6-chloropyridin-3-ylmethoxy, pyridin-4-ylmethoxy, (6-(trifluoromethyl)pyridin-3-yl)methoxy, (6-(cyano)pyridin-3- yl)methoxy, (2-(cyano)pyridin-4-yl)methoxy, (5-(cyano)pyridin-2-yl)methoxy,

(2-(chloro)pyridin-4-yl)methoxy, pyrimidin-5-ylmethoxy, 2-(pyrimidin-2-yl)propoxy, thien-2-ylmethoxy, and thien-3-ylmethoxy.

The term "heteroaryl(CrC₆)alkyl" as used herein, means a heteroaryl, as defined herein, appended to the parent molecular moiety through an (CrC₆)alkyl group, as defined herein. Representative examples of heteroaryl(CrC₆)alkyl include, but are not limited to, fur-3-ylmethyl, 1 H-imidazol-2-ylmethyl, 1 H-imidazol-4-ylmethyl, 1 -(pyridin-4- yl)ethyl, pyridin-3-ylmethyl, 6-chloropyridin-3-ylmethyl, pyridin-4-ylmethyl,

(6-(trifluoromethyl)pyridin-3-yl)methyl, (6-(cyano)pyridin-3-yl)methyl, (2-(cyano)pyridin-4- yl)methyl, (5-(cyano)pyridin-2-yl)methyl, (2-(chloro)pyridin-4-yl)methyl, pyrimidin-5- ylmethyl, 2-(pyrimidin-2-yl)propyl, thien-2-ylmethyl, and thien-3-ylmethyl.

The term "heteroarylcarbonyl" as used herein, means a heteroaryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of heteroarylcarbonyl include, but are not limited to, fur-3-ylcarbonyl, 1 H-imidazol-2-ylcarbonyl, 1 H-imidazol-4-ylcarbonyl, pyridin- 3-ylcarbonyl, 6-chloropyridin-3-ylcarbonyl, pyridin-4-ylcarbonyl,

(6-(trifluoromethyl)pyridin-3-yl)carbonyl, (6-(cyano)pyridin-3-yl)carbonyl,

(2-(cyano)pyridin-4-yl)carbonyl, (5-(cyano)pyridin-2-yl)carbonyl, (2-(chloro)pyridin-4- yl)carbonyl, pyrimidin-5-ylcarbonyl, pyrimidin-2-ylcarbonyl, thien-2-ylcarbonyl, and thien- 3-ylcarbonyl. The term "heteroaryloxy" as used herein, means a heteroaryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

Representative examples of heteroaryloxy include, but are not limited to, fur-3-yloxy, 1 H-imidazol-2-yloxy, 1 H-imidazol-4-yloxy, pyridin-3-yloxy, 6-chloropyridin-3-yloxy, pyridin-4-yloxy, (6-(trifluoromethyl)pyridin-3-yl) oxy, (6-(cyano)pyridin-3-yl) oxy, (2-(cyano)pyridin-4-yl)oxy, (5-(cyano)pyridin-2-yl)oxy, (2-(chloro)pyridin-4-yl)oxy, pyrimidin-5-yloxy, pyrimidin-2-yloxy, thien-2-yloxy, and thien-3-yloxy.

The term "(C3-C7)heterocycle" or ""(C3-C7)heterocyclic" as used herein, means a 3, 4, 5, 6 or 7 membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S. The 3 or 4 membered ring contains 1 heteroatom selected from the group consisting of O, N and S. The 5 membered ring contains zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S. The 6 or 7 membered ring contains zero, one or two double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S. The heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocycle. Representative examples of heterocycle include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1 ,3-dioxanyl, 1 ,3-dioxolanyl, 1 ,3-dithiolanyl, 1 ,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1 ,1 - dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl.

The term "(C3-C7)heterocycle(CrC6)alkoxy" as used herein, means a 3-7 membered heterocycle group, as defined herein, appended to the parent molecular moiety through an (CrC₆)alkoxy group, as defined herein.

The term ""(C3-C7)heterocycle(CrC6)alkyl" as used herein, means a 3-7 membered heterocycle, as defined herein, appended to the parent molecular moiety through an (CrC₆)alkyl group, as defined herein.

The term ""(C₃-C₇)heterocyclecarbonyl" as used herein, means a 3-7 membered heterocycle, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.

The term ""(C₃-C₇)heterocycleoxy" as used herein, means a 3-7 membered heterocycle, as defined herein, appended to the parent molecular moiety through an oxygen atom. The term "hydroxy" as used herein, means an -OH group.

The term "hydroxy(CrC₆)alkoxy" as used herein, means at least one hydroxy group, as defined herein, is appended to the parent molecular moiety through a

(CrC₆)alkoxy group, as defined herein. Representative examples of

hydroxy(CrC₆)alkoxy include, but are not limited to, hydroxymethoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 2,3-dihydroxypentoxy, and 2-ethyl-4-hydroxyheptoxy.

The term "hydroxy(CrC₆)alkyl" as used herein, means at least one hydroxy group, as defined herein, is appended to the parent molecular moiety through a

(CrC₆)alkyl group, as defined herein. Representative examples of hydroxy(CrC₆)alkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl,

2,3-dihydroxypentyl, and 2-ethyl-4-hydroxyheptyl.

The term "mercapto" as used herein, means a -SH group.

The term "nitro" as used herein, means a -NO2 group.

The term "nitrogen protecting group" as used herein, means those groups intended to protect an amino group against undesirable reactions during synthetic procedures. Representative examples of a nitrogen protecting group include, but are not limited to, acetyl, benzoyl, benzyl, benzyloxycarbonyl (Cbz), formyl, phenylsulfonyl, pivaloyl, tert-butoxycarbonyl (Boc), tert-butylacetyl, ethyloxycarbonyl, trifluoroacetyl, triphenylmethyl (trityl), te/t-butyldimethylsilane, and triisopropylsilane.

The term "N R_GRH" as used herein, means two groups, RQ and RH, which are appended to the parent molecular moiety through a nitrogen atom. R_G and RH are each independently H, (CrC₆)alkyl, (CrC₆)alkylcarbonyl, or R_G and RH form a ring.

Representative examples of N RQRH include, but are not limited to, amino, methylamino, dimethylamino, ethylmethylamino, acetamido, propionamido, isobutyramido, aziridine, azetidine, pyrrolidine, piperidine, and azepane.

The term "(NR_GRH)carbonyl" as used herein, means a N R_GRH group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of (NRoR^carbonyl include, but are not limited to, aminocarbonyl, (methylamino)carbonyl, (dimethylamino)carbonyl, and

(ethylmethylamino)carbonyl.

The term "N RJ RK" as used herein, means two groups, Rj and R«, which are appended to the parent molecular moiety through a nitrogen atom. Rj and RK are each independently H or (CrC₆)alkyl. Representative examples of NRjR_K include, but are not limited to, amino, methylamino, dimethylamino, and ethylmethylamino. The term "(NRjR_K)carbonyl" as used herein, means a NRjR_K group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of (NRjR_K)carbonyl include, but are not limited to, aminocarbonyl, (methylamino)carbonyl, (dimethylamino)carbonyl, and

(ethylmethylamino)carbonyl.

The term "N R_MRN" as used herein, means two groups, RM and RN, which are appended to the parent molecular moiety through a nitrogen atom. R_M and RN are each independently H, (Ci-C6)alkyl, (Ci-C6)alkyl(CrC6)alkoxy, or (CrC6)alkylcarbonyl; or RM and RN together with the nitrogen they are attached to form a 3 to 8 membered ring, wherein the 3 to 8 membered ring may be optionally substituted with 1 to 3 substituents that are (C C₆)alkoxy, (CrC₆)alkyl, halogen, or hydroxy. Representative examples of N RMRN include, but are not limited to, amino, methylamino, dimethylamino,

ethylmethylamino, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, and azocanyl.

The term "N RMRN(C C6)alkoxy" as used herein, means a N RMRN group, as defined herein, appended to the parent molecular moiety through a (CrC₆)alkoxy group, as defined herein.

The term "N RMRN(C C6)alkyl" as used herein, means a N RMRN group, as defined herein, appended to the parent molecular moiety through a (CrC6)alkyl group, as defined herein.

The term "(N R_MRN)carbonyl" as used herein, means a N R_MRN group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of ( N R_MRN)carbonyl include, but are not limited to, aminocarbonyl, (methylamino)carbonyl, (dimethylamino)carbonyl, and

(ethylmethylamino)carbonyl.

The term "(NR_MRN)carbonyl(CrC6)alkoxy" as used herein, means a

(NR_MRN)carbonyl group, as defined herein, appended to the parent molecular moiety through a (Ci-C6)alkoxy group, as defined herein.

The term "(NR_MR_N)carbonyl(CrC6)alkyl" as used herein, means a

(NR_MR_N)carbonyl group, as defined herein, appended to the parent molecular moiety through a (CrC₆)alkyl group, as defined herein.

The term "tautomer," as used herein, means a proton shift from one atom of a molecule to another atom of the same molecule wherein two or more structurally distinct compounds are in equilibrium with each other. Compounds of the present invention may exist as tautomers. The present invention contemplates tautomers due to proton shifts from one atom to another atom of the same molecule generating two or more distinct compounds that are in equilibrium with each other.

The term "therapeutically effective amount" means an amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, that: (i) treats the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.

It is to be understood that the structure

includes all 32 stereoisomers.

The compounds of the present invention can be used in the form of

pharmaceutically acceptable salts derived from inorganic or organic acids. By

"pharmaceutically acceptable salt" is meant those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well-known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:1 -19. The salts can be prepared in situ during the final isolation and purification of the compounds of the present invention or separately by reacting a free base (basic nitrogen) with a suitable organic or inorganic acid. Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsufonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethansulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2- naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained. Examples of acids which can be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.

Compounds of the present invention may exist as stereoisomers wherein asymmetric or chiral centers are present. These stereoisomers are "R" or "S" depending on the configuration of substituents around the chiral carbon atom. The terms "R" and "S" used herein are configurations as defined in lUPAC 1974

Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., (1976), 45: 13-30. The present invention contemplates various stereoisomers and mixtures thereof and are specifically included within the scope of this invention.

Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. Individual stereoisomers of compounds of the present invention may be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution well-known to those of ordinary skill in the art. These methods of resolution include, but are not limited to (1 ) attachment of a chiral auxiliary to a mixture of enantiomers, separation of the resulting mixture of diastereomers by recrystallization or chromatography, and liberation of the optically pure product from the auxiliary or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns.

Compounds of the present invention may exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit separation of different conformers. The compounds of the present invention further include each conformational isomer of compounds of Formula (I) and mixtures thereof.

Tautomers may exist in the compounds of the present invention and are specifically included within the scope of the present invention. The present invention contemplates tautomers due to proton shifts from one atom to another atom of the same molecule generating two or more compounds that are in equilibrium with each other. The compounds of the present invention may be isolated and used per se or in the form of their pharmaceutically acceptable salts. In accordance with the present invention, compounds with multiple basic nitrogen atoms can form salts with varying number of equivalents ("eq.") of acid. It will be understood by practitioners that all such salts are within the scope of the present invention.

Compounds of the present invention may exist in more than one crystal form. Polymorphs and/or co-crystals of compounds of Formula l-IV and salts thereof

(including solvates and hydrates) form part of this invention and may be prepared by crystallization of a compound of the present invention under different conditions. For example, using different solvents or different solvent mixtures for recrystallization;

crystallization at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallization. Polymorphs may also be obtained by heating or melting a compound of the present invention followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe nuclear magnetic resonance (NMR) spectroscopy, infrared (IR) spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.

This invention also includes isotopically-labeled compounds, which are identical to those described by Formula l-IV, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur and fluorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸0, ¹⁷0, ³⁵S, ³⁶CI, ¹²⁵l, ¹²⁹l, and ¹⁸F respectively. Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated (i.e., ³H), and carbon-14 (i.e., ¹⁴C), isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ²H), can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of the present invention can generally be prepared by carrying out the procedures disclosed in the schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

Compounds of the present invention are useful for treating diseases, conditions and/or disorders ameliorated via activation of AMPK. Another embodiment of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention and a pharmaceutically acceptable excipient, diluent or carrier. The compounds of the present invention (including the compositions and processes used herein) may also be used in the manufacture of a medicament for the therapeutic applications described herein.

A typical formulation is prepared by mixing a compound of the present invention and a carrier, diluent or excipient. Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like. The particular carrier, diluent or excipient used will depend upon the means and purpose for which the compound of the present invention is being applied. Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (GRAS) to be administered to a mammal. In general, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), etc. and mixtures thereof. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or

pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., for use in the preparing a medicament).

The formulations may be prepared using conventional dissolution and mixing procedures. For example, the bulk drug substance (i.e., compound of the present invention or stabilized form of the compound (e.g., complex with a cyclodextrin derivative or other known complexation agent)) is dissolved in a suitable solvent in the presence of one or more of the excipients described above. The dissolution rate of poorly water-soluble compounds may be enhanced by the use of a spray-dried dispersion, such as those described by Takeuchi, H., et al. in "Enhancement of the dissolution rate of a poorly water-soluble drug (tolbutamide) by a spray-drying solvent deposition method and disintegrants" J. Pharm. Pharmacol., 39, 769-773 (1987); and EP0901786 B1 (US2002/009494), incorporated herein by reference. The compound of the present invention is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to give the patient an elegant and easily handleable product.

The pharmaceutical compositions also include solvates and hydrates of the compounds of the present invention. The term "solvate" refers to a molecular complex of a compound represented by Formula (l)-(IV), including pharmaceutically acceptable salts thereof, with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, ethylene glycol, and the like, The term "hydrate" refers to the complex where the solvent molecule is water. The solvates and/or hydrates preferably exist in crystalline form. Other solvents may be used as intermediate solvates in the preparation of more desirable solvates, such as methanol, methyl t-butyl ether, ethyl acetate, methyl acetate, (S)-propylene glycol, (R)-propylene glycol, 1 ,4- butyne-diol, and the like.

The pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug. Generally, an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form. Suitable containers are well- known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.

The present invention provides a method of treating diseases, conditions and/or disorders activated by the activation of AMPK in an animal, particularly a human, that includes administering to the animal or human in need of such treatment a

therapeutically effective amount of a compound of the present invention or a

pharmaceutical composition comprising an effective amount of a compound of the present invention and a pharmaceutically acceptable excipient, diluent, or carrier. The method is particularly useful for treating diseases, conditions and/or disorders that benefit from the activation of AMPK.

One aspect of the present invention is the treatment of obesity, and obesity- related disorders (e.g., overweight, weight gain, or weight maintenance). Obesity and overweight are generally defined by body mass index (BMI), which is correlated with total body fat and estimates the relative risk of disease. BMI is calculated by weight in kilograms divided by height in meters squared (kg/m²). Overweight is typically defined as a BMI of 25-29.9 kg/m², and obesity is typically defined as a BMI of 30 kg/m². See, e.g., National Heart, Lung, and Blood Institute, Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults, The Evidence Report, Washington, DC: U.S. Department of Health and Human Services, NIH publication no. 98-4083 (1998).

Another aspect of the present invention is for the treatment (e.g., delaying the progression or onset) of diabetes or diabetes-related disorders including Type 1 and Type 2 diabetes, impaired glucose tolerance, insulin resistance, hyperglycemia, and diabetic complications such as atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, nephropathy, hypertension, neuropathy, and retinopathy.

In yet another aspect of the present invention is the treatment of obesity comorbidities, such as metabolic syndrome. Metabolic syndrome includes diseases, conditions or disorders such as dyslipidemia, hypertension, insulin resistance, diabetes (e.g., Type 2 diabetes), coronary artery disease and heart failure. For more detailed information on Metabolic Syndrome, see, e.g., Zimmet, P.Z., et al., "The Metabolic Syndrome: Perhaps an Etiologic Mystery but Far From a Myth - Where Does the International Diabetes Federation Stand?," Diabetes & Endocrinology, 7(2), (2005); and Alberti, K.G., et al., "The Metabolic Syndrome - A New Worldwide Definition," Lancet, 366, 1059-62 (2005). Preferably, administration of the compounds of the present invention provides a statistically significant (p<0.05) reduction in at least one

cardiovascular disease risk factor, such as lowering of plasma leptin, C-reactive protein (CRP) and/or cholesterol, as compared to a vehicle control containing no drug. The administration of compounds of the present invention may also provide a statistically significant (p<0.05) reduction in glucose serum levels.

In yet another aspect of the invention is the treatment of nonalcoholic fatty liver disease (NAFLD) and hepatic insulin resistance.

The present invention also provides pharmaceutical compositions which comprise compounds of the present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions may be specially formulated for oral administration in solid or liquid form, for parenteral injection, or for rectal administration.

The compounds of the present invention or pharmaceutical compositions thereof can be administered to humans and other mammals orally, rectally, parenterally , intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), bucally or as an oral or nasal spray. The term "parenterally," as used herein, refers to modes of administration which include intravenous, intramuscular,

intraperitoneal, intrasternal, subcutaneous, intraarticular injection and infusion.

Pharmaceutical compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the

maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preservative agents, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form.

Alternatively, delayed absorption of a parenterally administered drug form is

accomplished by dissolving or suspending the drug in an oil vehicle.

Suspensions, in addition to the active compounds, may contain suspending agents, as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar- agar, tragacanth, and mixtures thereof.

For a normal adult human having a body weight of about 100 kg, a dosage in the range of from about 0.001 mg to about 10 mg per kilogram body weight is typically sufficient, preferably from about 0.01 mg/kg to about 5.0 mg/kg, more preferably from about 0.01 mg/kg to about 1 mg/kg. However, some variability in the general dosage range may be required depending upon the age and weight of the subject being treated, the intended route of administration, the particular compound being administered and the like. The determination of dosage ranges and optimal dosages for a particular patient is well within the ability of one of ordinary skill in the art having the benefit of the instant disclosure. It is also noted that the compounds of the present invention can be used in sustained release, controlled release, and delayed release formulations, which forms are also well known to one of ordinary skill in the art.

The compounds of this invention may also be used in conjunction with other pharmaceutical agents for the treatment of the diseases, conditions and/or disorders described herein. Therefore, methods of treatment that include administering

compounds of the present invention in combination with other pharmaceutical agents are also provided. Suitable pharmaceutical agents that may be used in combination with the compounds of the present invention include anti-obesity agents (including appetite suppressants), anti-diabetic agents, anti-hyperglycemic agents, lipid lowering agents, and anti-hypertensive agents.

Suitable lipid lowering agents that can be combined with the compounds of the present invention include, for example, those described at page 30, line 20 through page 31 , line 30 of WO 201 100561 1 . The lipid lowering agents include bile acid sequestrants, HMG-CoA reductase inhibitors, HMG-CoA synthase inhibitors, cholesterol absorption inhibitors, acyl coenzyme A-cholesterol acyl transferase (ACAT) inhibitors, CETP inhibitors, squalene synthetase inhibitors, PPAR a agonists, FXR receptor modulators, LXR receptor modulators, lipoprotein synthesis inhibitors, rennin

angiotensisn system inhibitors, PPAR d partial agonists, bile acid reabsorption inhibitors, PPAR γ agonists, triglyceride synthesis inhibitors, microsomal triglyceride transport inhibitors, transcription modulators, squalene epoxidase inhibitors, low density lipoprotein receptor inducers, platelet aggregation inhibitors, 5-LO or FLAP inhibitors, niacin bound chromium and other agents that affect lipid composition.

Suitable anti-hypertensive agents that can be combined with the compounds of the present invention include, for example, those described at page 31 , line 31 through page 32, line 18 of WO 201 100561 1 . The anti-hypertensive agents include diuretics, beta-adrenergic blockers, calcium channel blockers, angiotensin converting enzyme (ACE) inhibitors, neutral endopeptidase inhibitors, endothelin antagonists, vasodilators, angiotensin II receptor antagonists, α/β adrenergic blockers, alpha 1 blockers, alpha 2 agonists, aldosterone inhibitors, mineraocorticoid receptor inhibitors, renin inhibitors and angiopoietin-2-binding agents.

Suitable anti-diabetic agents include an acetyl-CoA carboxylase- (ACC) inhibitor such as those described in WO2009144554, WO2003072197, WO2009144555 and WO2008065508, a diacylglycerol O-acyltransferase 1 (DGAT-1 ) inhibitor, such as those described in WO09016462 or WO2010086820, AZD7687 or LCQ908, diacylglycerol O- acyltransferase 2 (DGAT-2) inhibitor, monoacylglycerol O-acyltransferase inhibitors, a phosphodiesterase (PDE)-10 inhibitor, an AMPK activator, a sulfonylurea (e.g., acetohexamide, chlorpropamide, diabinese, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone, glisolamide, tolazamide, and tolbutamide), a meglitinide, an a-amylase inhibitor (e.g., tendamistat, trestatin and AL-3688), an a- glucoside hydrolase inhibitor (e.g., acarbose), an a-glucosidase inhibitor (e.g., adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q, and salbostatin), a PPARy agonist (e.g., balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone, pioglitazone, rosiglitazone and troglitazone), a PPAR α/γ agonist (e.g., CLX-0940, GW- 1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767 and SB-219994), a biguanide (e.g., metformin), a glucagon-like peptide 1 (GLP-1 ) modulator such as an agonist (e.g., exendin-3 and exendin-4), liraglutide, albiglutide, exenatide (Byetta®), albiglutide, taspoglutide, lixisenatide, dulaglutide, semaglutide, NN-9924,TTP-054, a protein tyrosine phosphatase-1 B (PTP-1 B) inhibitor (e.g., trodusquemine, hyrtiosal extract, and compounds disclosed by Zhang, S., et al., Drug Discovery Today, 12(9/10), 373-381 (2007)), SIRT-1 inhibitor (e.g., resveratrol, GSK2245840 or GSK184072), a dipeptidyl peptidease IV (DPP-IV) inhibitor (e.g., those in WO20051 16014, sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin and saxagliptin), an insulin secreatagogue, a fatty acid oxidation inhibitor, an A2 antagonist, a c-jun amino-terminal kinase (JNK) inhibitor, glucokinase activators (GKa) such as those described in WO2010103437, WO2010103438, WO2010013161 , WO2007122482, TTP-399, TTP-355, TTP-547, AZD1656, ARRY403, MK-0599, TAK-329, AZD5658 or GKM-001 , insulin, an insulin mimetic, a glycogen phosphorylase inhibitor (e.g. GSK1362885), a VPAC2 receptor agonist, SGLT2 inhibitors, such as those described in E.C. Chao et al. Nature Reviews Drug Discovery 9, 551 -559 (July 2010) including dapagliflozin, canagliflozin, BI-10733, tofogliflozin (CSG452), ASP-1941 , THR1474, TS-071 , ISIS388626 and LX421 1 as well as those in WO2010023594, a glucagon receptor modulator such as those described in Demong, D.E. et al. Annual Reports in Medicinal Chemistry 2008, 43, 1 19-137,

GPR1 19 modulators, particularly agonists, such as those described in WO2010140092, WO2010128425, WO2010128414, WO2010106457, Jones, R.M. et al. in Medicinal Chemistry 2009, 44, 149-170 (e.g. MBX-2982, GSK1292263, APD597 and PSN821 ), FGF21 derivatives or analogs such as those described in Kharitonenkov, A. et al. et al., Current Opinion in Investigational Drugs 2009, 10(4)359-364, TGR5 (also termed GPBAR1 ) receptor modulators, particularly agonists, such as those described in Zhong, M., Current Topics in Medicinal Chemistry, 2010, 10(4), 386-396 and INT777, GPR40 agonists, such as those described in Medina, J.C., Annual Reports in Medicinal

Chemistry, 2008, 43, 75-85, including but not limited to TAK-875, GPR120 modulators, particularly agonists, high affinity nicotinic acid receptor (HM74A) activators, and SGLT1 inhibitors, such as GSK1614235. A further representative listing of anti-diabetic agents that can be combined with the compounds of the present invention can be found, for example, at page 28, line 35 through page 30, line 19 of WO201 100561 1 . Preferred anti-diabetic agents are metformin and DPP-IV inhibitors (e.g., sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin and saxagliptin). Other antidiabetic agents could include inhibitors or modulators of carnitine palmitoyi transferase enzymes, inhibitors of fructose 1 ,6-diphosphatase, inhibitors of aldose reductase, mineralocorticoid receptor inhibitors, inhibitors of TORC2, inhibitors of CCR2 and/or CCR5, inhibitors of PKC isoforms (e.g. PKCa, PKCb, PKCg), inhibitors of fatty acid synthetase, inhibitors of serine palmitoyi transferase, modulators of GPR81 , GPR39, GPR43, GPR41 , GPR105, Kv1 .3, retinol binding protein 4, glucocorticoid receptor, somatostain receptors (e.g. SSTR1 , SSTR2, SSTR3 and SSTR5), inhibitors or modulators of PDHK2 or PDHK4, inhibitors of MAP4K4, modulators of IL1 family including ILI beta, modulators of

RXRalpha. In addition suitable anti-diabetic agents include mechanisms listed by Carpino, P.A., Goodwin, B. Expert Opin. Ther. Pat, 2010, 20(12), 1627-51 .

Suitable anti-obesity agents (some of which may also act as anti-diabetic agents as well) include 1 1 β-hydroxy steroid dehydrogenase-1 (1 Ι β-HSD type 1 ) inhibitors, stearoyl-CoA desaturase-1 (SCD-1 ) inhibitor, MCR-4 agonists, cholecystokinin-A (CCK- A) agonists, monoamine reuptake inhibitors (such as sibutramine), sympathomimetic agents, β₃ adrenergic agonists, dopamine agonists (such as bromocriptine), melanocyte-stimulating hormone analogs, 5HT2c agonists, melanin concentrating hormone antagonists, leptin (the OB protein), leptin analogs, leptin agonists, galanin antagonists, lipase inhibitors (such as tetrahydrolipstatin, i.e. orlistat), anorectic agents (such as a bombesin agonist), neuropeptide-Y antagonists (e.g., NPY Y5 antagonists such as velneperit), PYY3-36 (including analogs thereof), BRS3 modulator, mixed antagonists of opiod receptor subtypes, thyromimetic agents, dehydroepiandrosterone or an analog thereof, glucocorticoid agonists or antagonists, orexin antagonists, glucagon-like peptide-1 agonists, ciliary neurotrophic factors (such as Axokine™ available from Regeneron Pharmaceuticals, Inc., Tarrytown, NY and Procter & Gamble Company, Cincinnati, OH), human agouti-related protein (AGRP) inhibitors, histamine 3 antagonists or inverse agonists, neuromedin U agonists, MTP/ApoB inhibitors (e.g., gut-selective MTP inhibitors, such as dirlotapide, JTT130, Usistapide, SLx4090), opioid antagonist, mu opioid receptor modulators, including but not limited to GSK1521498, MetAp2 inhibitors, including but not limited to ZGN-433, agents with mixed modulatory activity at 2 or more of glucagon, GIP and GLP1 receptors, such as MAR-701 or ZP2929, norepinephrine transporter inhibitors, cannabinoid-1 -receptor

antagonist/inverse agonists, ghrelin agonists/antagonists, oxyntomodulin and analogs, monoamine uptake inhibitors, such as but not limited to tesofensine, an orexin antagonist, combination agents (such as bupropion plus zonisamide, pramlintide plus metreleptin, bupropion plus naltrexone, phentermine plus topiramate), and the like.

Preferred anti-obesity agents for use in the combination aspects of the present invention include gut-selective MTP inhibitors (e.g., dirlotapide, mitratapide and implitapide, R56918 (CAS No. 403987) and CAS No. 913541 -47-6), CCKa agonists (e.g., N-benzyl-2-[4-(1 H-indol-3-ylmethyl)-5-oxo-1 -phenyl-4,5-dihydro-2,3,6,10b- tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-acetamide described in PCT Publication No. WO 2005/1 16034 or US Publication No. 2005-0267100 A1 ), 5HT2c agonists (e.g., lorcaserin), MCR4 agonist (e.g., compounds described in US 6,818,658), lipase inhibitor (e.g., Cetilistat), PYY_3-3₆ (as used herein "PYY_3-3₆" includes analogs, such as peglated PYY3-36 e.g., those described in US Publication 2006/0178501 ), opioid antagonists (e.g., naltrexone), oleoyl-estrone (CAS No. 180003-17-2), obinepitide (TM30338), pramlintide (Symlin®), tesofensine (NS2330), leptin, bromocriptine, orlistat, AOD-9604 (CAS No. 221231 -10-3) and sibutramine. Preferably, compounds of the present invention and combination therapies are administered in conjunction with exercise and a sensible diet.

All of the recited U.S. patents and publications (including all technical bulletins referenced in the Examples) are incorporated herein by reference in their entireties.

Abbreviations which have been used in the descriptions of the schemes and the examples that follow are: n-BuLi for n-butyllithium; DMAP for 4-dimethylaminopyridine; DME for dimethoxyethane; DMF for Ν,Ν-dimethylformamide; EtOAc for ethyl acetate; LAH for lithium aluminum hydride; MeOH for methanol; TFA for trifluoroacetic acid; and THF for tetrahydrofuran. The present invention encompasses compounds of Formula (I), (II), (III), (IV) ,(V), (VI), (VII), (VIII), and (IX) when prepared by synthetic processes or by metabolic processes. Preparation of the compounds of the invention by metabolic processes include those occurring in the human or animal body (in vivo) or processes occurring in vitro.

Compounds of the present invention may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein. The starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, Wl) or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1 -19, Wiley, New York (1967-1999 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements (also available v/^'a the Beilstein online database)).

For illustrative purposes, the reaction schemes depicted below provide potential routes for synthesizing the compounds of the present invention as well as intermediates for preparing compounds of the present invention. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although specific starting materials and reagents are depicted in the schemes and discussed below, other starting materials and reagents can be substituted to provide a variety of derivatives and/or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

In the preparation of compounds of the present invention protection of remote functionalities such as carboxylic acids, amines, and/or hydroxy groups of intermediates may be necessary. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. Suitable amino- protecting groups (NH-PG) include acetyl, trifluoroacetyl, f-butoxycarbonyl (BOC), benzyloxycarbonyl (Cbz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxy-protecting group" refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable hydroxyl-protecting groups (O-PG) include for example, allyl, acetyl, silyl, benzyl, para-methoxybenzyl, trityl, and the like.

Carboxylic acid protecting groups include alkyl esters such as methy, ethyl, propyl, and tert-butyl. The need for such protection is readily determined by one skilled in the art. For a general description of protecting groups and their use, see T. W. Greene,

Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991 .

EXAMPLES

Example 1

1 -O-[(4,6-difluoro-5-{4-[(2S)-tetrahydro-2H-pyran-2-yl]phenyl}-1 H-indol-3-yl)carbonyl]- beta-D-glucopyranuronic acid

Step 1

1 -Acetyl-4,6-difluoro-5-{4-[(2S)-tetrahydro-2H-pyran-2-yl]phenyl}-1 H-indole-3-carboxylic acid

To a solution of the 4,6-difluoro-5-{4-[(2S)-tetrahydro-2H-pyran-2-yl]phenyl}-1 H-indole- 3-carboxylic acid (3730 mg, 10.44 mmol) in A/,A/-dimethylformamide (35 mL) at room temperature was added sodium hydride (60% dispersion in oil, 918 mg, 23 mmol). The reaction was stirred at room temperature for 30 minutes and was cooled to 0°C. Acetyl chloride (4.54 mL, 15.7 mmol) was added drop wise to the stirring solution and the reaction was allowed to warm slowly to room temperature overnight (18 hours). After 18 hours, the reaction was quenched with 1 N hydrochloric acid (30 mL) and water (50 mL) which resulted in precipitate which was dissolved in dichloromethane (50 mL). The layers were separated and the aqueous layer was extracted two additional times with dichloromethane (50 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. To the resulting crude material was added methanol (60 mL) and the resulting mixture was stirred at room temperature overnight. The following morning the mixture was filtered and the filter cake washed with methanol (10 mL) and dried in vacuo for 1 hour yielding 1 .75g (42% yield) of the desired product as a white solid. Method C: MassLynx\Acid_3Min.olp - LRMS [M-1 = 398]; ¹ H NMR (DMSO-d₆) δ: 8.48 (s, 1 H), 8.1 1 (d, J=10.5 Hz, 1 H), 7.34- 7.52 (m, 4H), 4.39 (d, J=9.8 Hz, 1 H), 4.05 (d, J=10.9 Hz, 1 H), 3.47-3.66 (m, 1 H), 2.76 (s, 3H), 1 .82-1 .93 (m, 2H), 1 .62-1 .75 (m, 1 H), 1 .54-1 .61 (m, 2H), 1 .41 -1 .53 (m, 1 H).

Step 2

Methyl 2,3,4-tri-O-acetyl-1 -O-[(4,6-difluoro-5-{4-[(2S)-tetrahydro-2H-pyran-2-yl]phenyl}- 1 H-indol-3-yl)carbonyl]-beta-D-glucopyranuronate

To a solution of 1 -acetyl-4,6-difluoro-5-{4-[(2S)-tetrahydro-2H-pyran-2-yl]phenyl}- 1 H-indole-3-carboxylic acid (754 mg, 1 .99 mmol) in dimethysulfoxide (14 mL) was added cesium carbonate (1 100 mg, 3.3 mmol). The reaction was stirred at room temperature for 5 minutes before the addition of acetobromo-alpha-D-glucuronic acid methyl ester (1 .03 g, 2.58 mmol). The reaction was allowed to stir for 18 hours at room temperature. After 18 hours, the reaction was quenched by the addition of saturated sodium bicarbonate aqueous (50 mL) and extracted three times with ethyl acetate (30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified using the Biotage Isolera One (SNAP 100g silica gel column), eluting with 0-100% ethyl acetate/heptane) to yield 738 mg of the desired product which was dissolved in hot methanol (20 mL) and was allowed to cool to room temperature and was stirred for 1 hour. The resulting precipitate was filtered and the filter cake was washed with methanol (2 mL) and dried for 30 minutes in vacuo yielding 421 mg (31 % yield) of the desired product as a white solid. The filtrate was concentrated under reduced pressure yielding 250 mg of crude desired product. The concentrated filtrate was purified using the Biotage Isolera One (SNAP 25g silica gel column) and eluting with a gradient of 0- 20% methanol/dichloromethane yielding 105 mg (8% yield) of the desired product as a solid. Method C: MassLynx\Acid_3Min.olp - LRMS [M-1 = 672];

1H NMR (METHANOL-d₄) δ: 8.03 (s, 1 H), 7.35-7.51 (m, 4H), 7.16 (d, J=9.4 Hz, 1 H), 6.06 (d, J=8.2 Hz, 1 H), 5.42-5.56 (m, 1 H), 5.16-5.29 (m, 2H), 4.50 (d, J=10.1 Hz, 1 H), 4.40-4.46 (m, 1 H), 4.06-4.18 (m, 1 H), 3.69 (s, 3H), 3.66-3.69 (m, 1 H), 2.03 (s, 3H), 2.02 (s, 3H), 1 .98 (s, 3H), 1 .94-1 .97 (m, 1 H), 1 .87-1 .94 (m, 1 H), 1 .57-1 .80 (m, 4H)

Step 3

Methyl 1 -O-[(4,6-difluoro-5-{4-[(2S)-tetrahydro-2H-pyran-2-yl]phenyl}-1 H-indol-3- yl)carbonyl]-beta-D-glucopyranuronate

To a solution of sodium citrate (pH 5.0, 20 mM buffer, 200 ml_) heated to 40°C, was added Lipase A (2.0 g, CAS# = 9001 -62-1 , Sigma Aldrich - 534781 -50g). A solution of methyl 2,3,4-tri-O-acetyl-1 -O-[(4,6-difluoro-5-{4-[(2S)-tetrahydro-2H-pyran-2- yl]phenyl}-1 H-indol-3-yl)carbonyl]-beta-D-glucopyranuronate (200 mg, 0.297 mmol) in dimethylsulfoxide (25 imL) was added to the stirring mixture drop wise. The reaction was stirred at 40°C for 64 hours. After 64 hours, the reaction was diluted with brine (250 imL) and the aqueous layer was extracted with ethyl acetate (250 imL) which resulted in an emulsion. The layers were separated and the organic layer was washed with water (200 imL) and brine (200 imL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The previous aqueous layers were washed with ethyl acetate (250 imL) and the ethyl acetate layer dried over sodium sulfate, filtered and concentrated under reduced pressure. The combined crude material was purified using the Biotage Isolera One (SNAP 25g silica gel

column), eluting with a gradient of 0-20% methanol/dichloromethane. The tubes containing the second major spot were concentrated under reduced pressure. The material was dissolved in ethyl acetate (5 imL) followed by the addition of heptane (20 imL) and concentrated under reduced pressure yielding 1 18 mg (73% yield) of the desired product as a white solid. Method C: MassLynx\Acid_3Min.olp - LRMS [M-1 = 546]; ¹ H NMR (METHANOL-d₄) δ: 8.17 (s, 1 H), 7.33-7.55 (m, 4H), 7.15 (d, J=9.4 Hz, 1 H), 5.69 (d, J=7.4 Hz, 1 H), 4.36-4.49 (m, 1 H), 4.08-4.16 (m, 1 H), 4.02 (d, J=9.4 Hz, 1 H), 3.76 (s, 3H), 3.64-3.71 (m, 1 H), 3.56-3.63 (m, 1 H), 3.53 (t, J=6.8 Hz, 2H), 1 .94- 2.03 (m, 1 H), 1 .86-1 .94 (m, 1 H), 1 .58-1 .82 (m, 4H).

Step 4

An aqueous solution of sodium citrate (pH = 5.0, 20 imM, 50 mL) was heated to 40°C and CAL-B (0.750 mL, solution, Lypozyme CAL-B, LCN02102, Novozyme) was added. A solution of methyl 1 -O-[(4,6-difluoro-5-{4-[(2S)-tetrahydro-2H-pyran-2- yl]phenyl}-1 H-indol-3-yl)carbonyl]-beta-D-glucopyranuronate (100 mg, 0.183 mmol) in dimethylsulfoxide (8 mL) was added to the stirring mixture drop wise. The reaction was stirred at 40°C for 6.5 hours. After 6.5 hours, the reaction was added to brine (100 mL) and extracted with ethyl acetate (100 mL). The layers were separated and the organic layer was washed with water (100 mL). The organic solution was diluted with ethyl acetate (100 mL) and washed with water (100 mL) which resulted in clear layers. The organic layer was washed with brine (200 mL). The first aqueous layer was washed an additional time with ethyl acetate (100 mL) and washed with both water and brine from previous washes. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The concentrated material was dissolved in 2-methyl tetrahydrofuran (25 mL) and passed through a Life Science Acrodisc 13mm syringe filter (0.2 micrometer Nylon membrane) and concentrated under reduced pressure yielding 89 mg of the crude desired product. The crude material was diluted with 2-methyl tetrahydrofuran (3 mL) and to this solution was added heptane (-10 mL) which produced a precipitate followed by the addition of 4 mL of 2- methyl

tetrahydrofuran. The mixture was stirred at room temperature for 48 hours. After 48 hours, the mixture was concentrated under reduced pressure. The material was diluted with dichloromethane (10 mL) and the resulting precipitate was filtered, washed with dichloromethane (5 mL), and dried in vacuo for 1 hour yielding 58 mg (59% yield) of the desired product as a white solid. Method C: MassLynx\Acid_3Min.olp - LRMS [M-1 = 532]; ¹ H NMR (METHANOL-d₄) δ: 8.18 (s, 1 H), 7.43 (q, J=7.8 Hz, 4H), 7.15 (d, J=9.4 Hz, 1 H), 5.70 (d, J=7.6 Hz, 1 H), 4.36-4.47 (m, 1 H), 4.12 (d, J=1 1 .2 Hz, 1 H), 3.97 (d, J=10.0 Hz, 1 H), 3.64-3.73 (m, 1 H), 3.57-3.62 (m, 1 H), 3.54-3.57 (m, 1 H), 3.50-3.54 (m, 1 H), 1 .95-2.02 (m, 1 H), 1 .87-1 .94 (m, 1 H), 1 .58-1 .81 (m, 4H).

Exam le 2

1 -O-({6-Chloro-5-[6-(dimethylamino)-2-methoxypyridin-3-yl]-1 H-indol-3-yl}carbonyl)- beta-D-glucopyranuronic acid

Step 1

1 -Acetyl-6-chloro-5-[6-(dimethylamino)-2-methoxypyridin-3-yl]-1 H-indole-3-carboxylic acid

To a solution of 6-chloro-5-[6-(dimethylamino)-2-methoxypyridin-3-yl]-1 H-indole- 3-carboxylic acid (965 mg, 2.79 mmol) in A/,A/-dimethylformamide (19 mL) at room temperature was added sodium hydride (60% dispersion in oil, 335 mg,

8.37 mmol). The reaction was stirred at room temperature for 30 minutes and was cooled to 0°C. Acetyl chloride (1 .62 mL, 5.58 mmol) was added drop wise to the stirring solution. The reaction was allowed to warm to room temperature slowly and was stirred for 18 hours. The reaction was quenched with 1 N hydrochloric acid (30 mL) and water (50 mL) and the resulting mixture was stirred for 3 hours. After 3 hours, dichloromethane was added and the mixture was stirred for 24 hour at room

temperature. The following morning the layers were separated. The aqueous layer was washed two additional times with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced

pressure. The crude material was purified using the Biotage Isolera One (SNAP 50g silica gel column) and eluting with a gradient of 20-100% ethyl acetate/heptane followed by a gradient of 0-20% methanol/dichloromethane yielding 920 mg (85% yield) of the desired product. Method C: MassLynx\Acid_3Min.olp - LRMS [M+1 = 388]; ¹H NMR (DMSO-de) δ: 8.49 (s, 1 H), 8.42 (s, 1 H), 7.92 (s, 1 H), 7.35 (d, J=8.2 Hz, 1 H), 6.23 (d, J=8.2 Hz, 1 H), 3.77 (s, 3H), 3.07 (s, 6H), 2.75 (s, 3H).

Ste 2

Methyl 2,3,4-tri-O-acetyl-1 -O-({6-chloro-5-[6-(dimethylamino)-2-methoxypyridin

indol-3-yl}carbonyl)-beta-D-glucopyranuronate

To a solution of 1 -acetyl-6-chloro-5-[6-(dimethylamino)-2-methoxypyridin-3-yl]- 1 H-indole-3-carboxylic acid (731 mg, 1 .88 mmol) in dimethysulfoxide (14 mL) was added cesium carbonate (1000 mg, 3.2 mmol). The reaction was stirred at room temperature for 5 minutes before the addition of the acetobromo-alpha-D-glucuronic acid methyl ester (973 mg, 2.45 mmol). The reaction was stirred for 18 hours at room temperature. After 18 hours, the reaction was quenched by the addition of aqueous saturated sodium bicarbonate (50 mL) and extracted three times with ethyl acetate (30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified using the Biotage Isolera One (SNAP 100g silica gel column) and eluting with 0-100% ethyl acetate/heptane). The tubes containing the desired product were concentrated under reduced pressure. The resulting gum was diluted with ethyl acetate (1 mL) and heptane (10 mL) and was concentrated under reduced pressure yielding 645 mg the crude material. The crude material was diluted with ethyl acetate (8 mL) and heated with hot air followed by the addition of heptane (20 mL). The solution was allowed to cool to room temperature and was stirred for 30 minutes. The resulting precipitate was filtered, washed with heptane and dried in vacuo for 30 minutes to yield 206 mg (16.5% yield) of the desired product as a solid. The filtrate was concentrated under reduced pressure and was purified using the Biotage Isolera One (SNAP 25g silica gel column) and eluting with a gradient of 0-20% methanol/dichloromethane. The fractions containing the major spot was concentrated under reduced pressure resulting in a gum which was diluted with ethyl acetate (1 mL) and heptane (10 mL) and was concentrated under reduced pressure yielding 289 mg (23% yield) of the desired product as a solid. Method C: MassLynx\Acid_3Min.olp - LRMS [M+1 = 662]; ¹ H NMR (DMSO-d₆) δ: 12.18 (br. s., 1 H), 8.10 (d, J=2.7 Hz, 1 H), 7.78 (s, 1 H), 7.62 (s, 1 H), 7.33 (d, J=8.2 Hz, 1 H), 6.16-6.29 (m, 2H), 5.59 (t, J=9.6 Hz, 1 H), 5.15 (t, J=8.8 Hz, 1 H), 5.06 (t, J=9.6 Hz, 1 H), 4.74 (d, J=9.8 Hz, 1 H), 3.77 (s, 3H), 3.62 (s, 3H), 3.07 (s, 6H), 2.00 (s, 3H), 1 .99 (s, 3H), 1 .93 (s, 3H).

Ste 3

methyl 1 -O-({6-chloro-5-[6-(dimethylamino)-2-methoxypyridin-3-yl]-1 H-indol-3- yl}carbonyl)-beta-D-glucopyranuronate

To a sodium citrate solution (pH = 5.0, 20 mM, 230 mL) heated to 40°C, was added Lipase A (CAS# = 9001 -62-1 , Sigma Aldrich - 534781 -50g) (1 .2 g). A solution of methyl 2,3,4-tri-O-acetyl-1 -O-({6-chloro-5-[6-(dimethylamino)-2-methoxypyridin-3-yl]-1 H- indol-3-yl}carbonyl)-beta-D-glucopyranuronate (230 mg, 0.347 mmol) in

dimethylsulfoxide (30 mL) was added to the stirring mixture drop wise. The reaction was heated to 40°C for 54 hours. After 54 hours, the reaction was diluted with brine (250 mL) and extracted with ethyl acetate (200 mL) which resulted in a large

emulsion. The emulsion was passed through a plug of celite and the layers were separated. The aqueous layer was extracted an additional time with ethyl acetate (200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure yielding 325 mg of crude material. The crude material was purified using the Biotage Isolera One (SNAP 25g silica gel column),eluting with a gradient of 0-20% methanol/dichloromethane. The tubes containing the second major spot (tubes containing the desired spot from TLC (10% methanol/dichloromethane, stained with cerium molybdate then burned)) were concentrated under reduced pressure and dissolved in 1 mL of ethyl acetate followed by the addition of heptane (10 mL) and concentrated under reduced pressure yielding 98 mg (53% yield) of the desired product as a solid. Method C: MassLynx\Acid_3Min.olp - LRMS [M+1 = 536]; ¹H NMR (METHANOL-d₄) δ: 8.10 (s, 1 H), 7.95 (s, 1 H), 7.54 (s, 1 H), 7.32 (d, J=8.2 Hz, 1 H), 6.20 (d, J=8.2 Hz, 1 H), 5.73 (d, J=7.8 Hz, 1 H), 4.02 (d, J=9.4 Hz, 1 H), 3.84 (s, 3H), 3.76 (s, 3H), 3.58-3.64 (m, 1 H), 3.47-3.57 (m, 2H), 3.12 (s, 6H).

Step 4

Two separate reactions were run and combined for purification.

Reaction 1 : A sodium citrate solution (pH = 5.0, 20 imM, 10 mL) was heated to 40°C before the addition of CAL-B (250 uL, solution, Lypozyme CAL-B, LCN02102, Novozyme). A solution of methyl 1 -O-({6-chloro-5-[6-(dimethylamino)-2-methoxypyridin- 3-yl]-1 H-indol-3-yl}carbonyl)-beta-D-glucopyranuronate (45 mg, 0.084 mmol) in dimethylsulfoxide (1 .5 mL) was added to the stirring mixture drop wise. The reaction was stirred for 56 hours at 40°C. After 56 hours, the reaction was diluted with brine (50 mL) and extracted three times with ethyl acetate (50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was diluted with ethyl acetate (5 mL) andheptane (20 mL) and was concentrated under reduced pressure to yield 31 mg of crude material.

Reaction 2: A sodium citrate solution (pH = 5.0, 20 imM, 50 mL) was heated to 40°C before the addition of CAL-B (1 .0 mL, solution, Lypozyme CAL-B, LCN02102, Novozyme). A solution of methyl 1 -O-({6-chloro-5-[6-(dimethylamino)-2-methoxypyridin- 3-yl]-1 H-indol-3-yl}carbonyl)-beta-D-glucopyranuronate (166 mg, 0.310 mmol) in dimethylsulfoxide (7 mL) was added to the stirring mixture drop wise. The reaction was stirred for 54 hours at 40°C. The reaction was cooled to room temperature before the reaction was diluted with brine (100 mL) and the aqueous solution was extracted three times with ethyl acetate (50 mL). The combined organic layers were washed with water (100 mL) and the resulting emulsion was passed through a pad of celite. The layers were separated and the organic layer was washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was diluted with ethyl acetate (5 mL) followed by heptane (20 mL) and was

concentrated under reduced pressure to yield 179 mg of crude material which showed starting material remaining.

Reaction 3: A sodium citrate solution (pH = 5.0, 20 imM, 50 mL) was heated to 40°C before the addition of CAL-B (0.5 mL, solution, Lypozyme CAL-B, LCN02102, Novozyme). A solution of the crude material (120 mg) in dimethylsulfoxide (7 mL) was added to the stirring mixture drop wise. The reaction was stirred for 24 hours at 40°C. The reaction was cooled to room temperature before the reaction was diluted with brine (100 mL) and the aqueous solution was extracted three times with ethyl acetate (100 mL). The combined organic layers were washed with water (100 mL), the resulting emulsion was passed through a pad of celite. The layers were separated and the organic layer was washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was diluted with ethyl acetate (5 mL) followed by heptane (20 mL) and was concentrated under reduced pressure to yield 95 mg of crude desired material. The crude material was diluted with 2-methyl tetrahydrofuran (15 mL) and was passed through a Life Science Acrodisc 13mm syringe filter (0.2 micrometer Nylon membrane) and concentrated to ~3 mL of volume. To this solution was added heptane (-10 mL) which produced a

precipitate. The mixture was heated with hot air and 1 .5 mL of 2- methyl

tetrahydrofuran was added. The mixture was allowed to cool to room temperature and was stirred for 48 hours at room temperature. After 48 hours, the resulting precipitate was filtered, washed with heptane (10 mL), dried for 1 hour in vacuo to yield 69 mg of the desired product as a white solid.

Crude material from the second reaction (35 mg) was partitioned between water (5 mL), 1 N sodium hydroxide (3 mL) and ethyl acetate (5 mL). The layers were separated and the aqueous layer was acidified to a pH~4 using 1 N hydrochloric acid and was extracted two times with ethyl acetate. The organic layers from the acidic aqueous wash were combined and washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure yielding 38 mg. The 38 mg was partitioned between pH 5 sodium citrate buffer and ethyl acetate. The aqueous layer separated and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with water (50 mL), brine (50 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to yield 36 mg of crude desired product. The 36 mg was combined with the 31 mg of crude material from the first reaction and was diluted with 2-methyl tetrahydrofuran (10 mL) which was passed through a Life Science Acrodisc 13mm syringe filter (0.2 micrometer Nylon membrane) and concentrated to ~1 .5 mL of volume. To this solution was added heptane (~7 mL) which produced a precipitate. The mixture was heated with hot air and 0.5 mL of 2- methyl

tetrahydrofuran was added. The mixture was allowed to cool to room temperature and was stirred for 24 hours. After 24 hours, the resulting precipitate was filtered, washed with heptane (10 mL), dried for 1 hour in vacuo to yield 54.4 mg of the desired product as a white solid. This material was combined with the 69 mg of desired product from reaction 3 and was placed under high vacuum at 50°C for 1 hour yielding 1 10 mg (53% yield) of the desired product as a white solid. Method C: MassLynx\Acid_3Min.olp - LRMS [M+1 = 522]; ¹H NMR (METHANOL-d₄) δ: 8.10 (s, 1 H), 7.95 (s, 1 H), 7.54 (s, 1 H), 7.32 (d, J=7.6 Hz, 1 H), 6.20 (d, J=8.2 Hz, 1 H), 5.74 (d, J=7.6 Hz, 1 H), 3.97 (d, J=9.4 Hz, 1 H), 3.84 (s, 3H), 3.57-3.61 (m, 1 H), 3.53-3.57 (m, 1 H), 3.48-3.53 (m, 1 H), 3.12 (s, 6H).

Exam le 3

1 -O-({6-Chloro-5-[4-(1 -hydroxycyclobutyl)phenyl]-1 H-indol-3-yl}carbonyl)-beta-D- glucopyranuronic acid 1

1 -Acetyl-6-chloro-5-(4-(1 -hydroxycyclobutyl)phenyl)-1 H-indole-3-carboxylic acid

To a stirring solution of 6-chloro-5-[4-(1 -hydroxycyclobutyl)phenyl]-1 H-indole-3- carboxylic acid (25.0 g, 73.14 mmol) in N,N-dimethylformamide (300 mL) at 0°C was added sodium hydride (60% dispersion in mineral oil, 7.31 g, 183 mmol). The reaction was stirred for 30 minutes. After 30 minutes, acetyl chloride (53.1 mL, 183 mmol) was added drop wise over 60 minutes. The reaction was stirred at 0°C for 1 hour. After 1 hour, the reaction was quenched by addition of a solution of saturated aqueous ammonium chloride (1400 mL) and the aqueous solution was extracted two times with ethyl acetate (1000 mL). The combined organic layers were washed with water (1000 mL), brine (1000 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified using the CombiFlash Rf (ISCO RediSep Gold 330g silica gel column), eluting with a gradient of 0-20%

methanol/dichloromethane to yield 25.75 g of crude product. A portion of the crude material (15.23 g) was purified using the CombiFlash Rf (ISCO RediSep Gold 330g silica gel column),eluting with a gradient of 0-20% methanol/dichloromethane to yield 1 1 .53 g. This material was dissolved in dichloromethane (100 mL) and the solution was stirred overnight at room temperature. The following morning the resulting precipitate was filtered and the filter cake was washed with dichloromethane (10 mL) and dried to yield 8.06 g (28.7% yield) of the desired product as a white solid.

The remaining material from the first column (10.52 g) was dissolved in dichloromethane (50 mL) and was stirred overnight at room temperature. The following morning, the resulting white precipitate was filtered. The filter cake was washed with dichloromethane to yield 2.71 g (9.3% yield) of the desired product as a white solid which was birefringent under the microscope. Method C: MassLynx\Acid_3Min.olp - LRMS (mass not observed); ¹ H NMR (DMSO-d₆) δ: 12.95 (br. s., 1 H), 8.53 (s, 1 H), 8.49 (s, 1 H), 8.03 (s, 1 H), 7.59 (d, J=8.2 Hz, 2H), 7.43 (d, J=8.2 Hz, 2H), 2.77 (s, 3H), 2.39- 2.48 (m, 2H), 2.22-2.37 (m, 2H), 1 .88-2.00 (m, 1 H), 1 .62-1 .78 (m, 1 H). Ste 2a

Methyl 2,3,4-tri-O-acetyl-1 -0-({6-chloro-5-[4-(1 -hydroxycyclobutyl)phenyl]-1 H-indol-3- yl}carbonyl)-beta-D-glucopyranuronate

To a solution of 1 -Acetyl-6-chloro-5-(4-(1 -hydroxycyclobutyl)phenyl)-1 H-indole-3- carboxylic acid (2.355 g, 4.9 mmol) in dimethysulfoxide (30 imL) was added cesium carbonate (2.72 g, 8.34 mmol). The reaction was stirred at room temperature for 5 minutes before the addition of acetobromo-alpha-D-glucuronic acid methyl ester (2920 mg, 7.36 mmol). The reaction was stirred for 60 minutes. The reaction was quenched with saturated sodium bicarbonate aqueous (450 imL) which resulted in a

precipitate. The precipitate was filtered and the filter cake was washed with water (50 imL) and heptane (50 imL) and dried. The solids were dissolved in ethyl acetate (300 imL) and methanol (20 imL) and concentrated under reduced pressure. The resulting crude material was purified using the Biotage Isolera One (SNAP 100g silica gel column), eluting with a gradient of 0-100% ethyl acetate/heptane yielding 2.32 g (72% yield) of the desired product as a solid. Method C: MassLynx\Acid_3Min.olp - LRMS [M-1 = 656]; ¹ H NMR (METHANOL-d₄) δ: 8.05 (s, 1 H), 8.00 (s, 1 H), 7.61 (s, 1 H), 7.60 (d, J=8.6 Hz, 2H), 7.46 (d, J=8.2 Hz, 2H), 6.1 1 (d, J=7.8 Hz, 1 H), 5.46-5.55 (m, 1 H), 5.24-5.29 (m, 1 H), 5.21 (t, J=9.6 Hz, 1 H), 4.50 (d, J=9.8 Hz, 1 H), 3.68 (s, 3H), 2.55-2.70 (m, 2H), 2.34-2.48 (m, 2H), 2.05-2.1 1 (m, 1 H), 2.03 (s, 3H), 2.01 (s, 3H), 1 .96 (s, 3H), 1 .71 -1 .85 (m, 1 H).

Step 2b

Alternative reparation:

To a solution of 1 -Acetyl-6-chloro-5-(4-(1 -hydroxycyclobutyl)phenyl)-1 H-indole-3- carboxylic acid (10.0 g, 20.84 mmol) in dimethysulfoxide (130 imL) was added cesium carbonate (1 1 .5 g, 35.4 mmol). The reaction was stirred at room temperature for 5 minutes before the addition of the acetobromo-alpha-D-glucuronic acid methyl ester (12.4g, 31 .3 mmol) and the reaction was stirred for 60 minutes. The reaction was quenched by the addition of saturated sodium bicarbonate aqueous (1000 imL) which resulted in a precipitate and the mixture was stirred for 30 minutes before being filtered. The filtercake was washed with water (200 imL). The solids were dissolved in ethyl acetate (1500 imL) and washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude material was purified using the CombiFlash Rf (ISCO RediSep Gold 330g silica gel column), eluting with a gradient of 0-100% ethyl acetate/heptane to provide 10.4 g (75.8%) of a mixture (2.3:1 ) of acyl : H (nonacyl). The mixture was used without further purification. H = Method C: MassLynx\Acid_3Min.olp - LRMS [M-1 = 656]; Ac = Method C:

MassLynx\Acid_3Min.olp - LRMS [M-1 = 698].

Ste 3

Methyl 1 -O-({6-chloro-5-[4-(1 -hydroxycyclobutyl)phenyl]-1 H-indol-3-yl}carbonyl)-beta-D- glucopyranuronate

A sodium citrate solution (pH = 5.0, 20 imM , 2000 imL) was heated to 40°C before the addition of Lipase A (CAS# = 9001 -62-1 , Sigma Aldrich - 534781 -1 Og) (19.23 g). The Lipase solution was stirred for -10 minutes until large clumps of the enzyme were dissolved. A solution of the starting material (a 2.3:1 mixture of methyl 2,3,4-tri-O- acetyl-1 -O-({1 -acetyl-6-chloro-5-[4-(1 -hydroxycyclobutyl)phenyl]-1 H-indol-3-yl}carbonyl)- beta-D-glucopyranuronate and methyl 2,3,4-tri-O-acetyl-1 -O-({6-chloro-5-[4-(1 - hydroxycyclobutyl)phenyl]-1 H-indol-3-yl}carbonyl)-beta-D-glucopyranuronate (2000 mg, 3.04 mmol) in dimethylsulfoxide (260 imL) was added to the stirring mixture using an addition funnel. The mixture was stirred at 40°C overnightand was diluted with ethyl acetate and brine. The resulting layers were separated and the emulsion portion was washed into the organic layer. The aqueous layer was washed an additional time with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude desired product was purified by column chromatography (40 g silica gel column

cartridge), eluting with a gradient of 0-10% MeOH/dichloromethane yielding 1 .10 g (68% yield) of the desired product. ¹H NMR (METHANOL-d₄) δ: 8.14 (s, 1 H), 8.05 (s, 1 H), 7.60 (s, 1 H), 7.59 (d, J=8.6 Hz, 2H), 7.45 (d, J=8.2 Hz, 2H), 5.74 (d, J=7.4 Hz, 1 H), 4.03 (d, J=9.8 Hz, 1 H), 3.76 (s, 3H), 3.58-3.65 (m, 1 H), 3.47-3.57 (m, 2H), 2.54-2.69 (m, 2H), 2.34-2.49 (m, 2H), 2.03-2.12 (m, 1 H), 1 .70-1 .85 (m, 1 H).

Step 4a

1 -O-({6-Chloro-5-[4-(1 -hydroxycyclobutyl)phenyl]-1 H-indol-3-yl}carbonyl)-beta-D- glucopyranuronic acid

Two 1 gram scale reactions were set up in parallel. A sodium citrate buffer (pH -5.05, 375ml_ 0.005M) was transferred to a 1 L round bottom flask fitted with a stirring bar. The solution was heated to an internal temperature of 40°C +/-1 °C. CAL-B (8 imL (solution, Lypozyme CAL-B, LCN02102, Novozyme)) was added to the mixture. A solution of methyl 1 -O-({6-chloro-5-[4-(1 -hydroxycyclobutyl)phenyl]-1 H-indol-3- yl}carbonyl)-beta-D-glucopyranuronate (1000 mg, 1 .88 mmol) in dimethylsulfoxide (50 imL) was added using a syringe at a rate such that the internal temperature of the reaction mixture remained below 43°C. Reactions were stirred at 40°C for 6 hours. After 6 hours, the reactions were allowed to cool slowly to room temperature and were stirred at room temperature overnight. The following morning, the reactions were cooled in an ice bath and brine was added. The two reaction mixtures were combined into a separatory funnel and the aqueous solution wasextracted with ethyl

acetate (1 x500 imL, 3x300 imL). The combined organic layers were washed with water (300 imL) and brine (200 imL), and were dried over sodium sulfate by stirring for ~15 minutes over the salt. The mixture was filtered and concentrated under reduced pressure. The crude material was dissolved in 2-methyl tetrahydrofuran and was filtered in batches through 5 Life Science Acrodisc, 13 mm syringe filters, washing with 2- methyl tetrahydrofuran. The resulting pale yellow solution was concentrated to give a gum. The crude material was dissolved in 2-methyl tetrahydrofuran (15 imL) and was cooled to 0°C with stirring. Heptane (30 imL) was added and the resulting suspension was stirred at 0°C for 2 h. The mixture was filtered and dried on the filter paper for 15 minutes. The solid was dried in vacuo to remove residual solvents for about 6 hours to yield 1 .5 g (77% yield) of the desired product as a white solid. ¹H NMR (DMSO-d₆) δ: 12.20 (d, J=2.3 Hz, 1 H), 8.27 (d, J=3.1 Hz, 1 H), 7.95 (s, 1 H), 7.69 (s, 1 H), 7.58 (d, J=8.2 Hz, 2H), 7.43 (d, J=8.2 Hz, 2H), 5.60 (d, J=7.8 Hz, 1 H), 5.53 (s, 1 H), 5.43 (d, J=4.3 Hz, 1 H), 5.26 (br. s., 1 H), 3.79 (d, J=9.0 Hz, 1 H), 3.39 (s, 1 H), 3.23-3.47 (m, 2H), 2.40-2.48 (m, 2H), 2.21 -2.35 (m, 2H), 1 .93-2.01 (m, 1 H), 1 .65-1 .75 (m, 1 H).

Ste 4b

A sodium citrate solution ((pH = 5.0, 20 mM, 105 ml_) was heated to 40°C before the addition of CAL-B (2.2 imL, solution, Lypozyme CAL-B, LCN02102, Novozyme). A solution of methyl 1 -O-({6-chloro-5-[4-(1 -hydroxycyclobutyl)phenyl]-1 H-indol-3- yl}carbonyl)-beta-D-glucopyranuronate (280 mg, 0.526 mmol) in dimethylsulfoxide (14 imL) was added to the stirring mixture drop wise. The reaction was stirred for 6 hours at 40°C. After 6 hours, the heat was turned off and the reaction was allowed to cool slowly to room temperature without stirring. The following morning, brine (300 imL) was added and the aqueous solution was extracted two times with ethyl acetate (200 imL). The combined organic layers were washed with water (300 imL). The combined organic layers were washed with brine (200 imL), dried over sodium sulfate, filtered and concentrated under reduced pressure (with the bath at room temperature). The resulting gum was dissolved in ethyl acetate (5 mL), heptane (30 mL) was added, and the mixture was concentrated under reduced pressure (with the bath at room

temperature) to yield 309 mg of the desired product. The concentrated material was dissolved in 2-methyl tetrahydrofuran (25 mL) and passed through a Life Science Acrodisc 13mm syringe filter (0.2 micrometer Nylon membrane) and concentrated under reduced pressure without heating. The crude material was diluted with 2-methyl- tetrahydrofuran (5 mL) and to this solution was added heptane (20 mL) which produced a precipitate. The mixture was stirred at room temperature for 18 hours. The following morning the mixture was filtered, washed with heptane (5 mL) and dried in vacuo for 1 hour to yield 217 mg (79% yield) of the desired product as a white solid. Method C: MassLynx\Acid_3Min.olp - LRMS [M-1 = 516]; ¹ H NMR (METHANOL-d₄) δ: 8.14 (s, 1 H), 8.07 (s, 1 H), 7.61 (s, 1 H), 7.59 (d, J=8.2 Hz, 2H), 7.46 (d, J=8.2 Hz, 2H), 5.76 (d, J=7.8 Hz, 1 H), 3.98 (d, J=9.4 Hz, 1 H), 3.56-3.63 (m, 1 H), 3.53 (t, J=7.4 Hz, 2H), 2.56- 2.64 (m, 2H), 2.35-2.46 (m, 2H), 1 .99-2.1 1 (m, 1 H), 1 .72-1 .83 (m, 1 H).

AMPK in vitro biochemical assay

Expression and purification of AMPK:

We designed a tricistronic AMPK expression construct that included open reading frames encoding the full-length γΐ , β ΐ and l subunits of human AMPK with a ribosome-binding site (RBS) ahead of each coding region and subcloned this into pET- 14b expression vector (Novagen, Madison, Wisconsin) using standard molecular biology techniques . AMPK tricistronic construct was transformed into E. coli BL21 - CodonPlus™ (DE3)-RIPL strain (Stratagene) and transformants were selected on LB (Luria-Bertani) agar plates containing ampicillin (100 μg/ml). Ten liters of LB medium (MP Biomedical LB broth #1 1 -3002-032) containing 100ug/ml carbenicillin was inoculated with 100 ml E. coli shake flask culture (BL-21 , pET-14b, AMPK 1 1 1 ) in a BF4 10 L working volume bioreactor (New Brunswick Scientific Co.) at 37 ^QC, 600rpm, 6L/minute aeration. Optical density sample measurements were made on an UltroSpec 2000 spectrophotometer (Pharmacia Biotech) at 600nm. When the cell density reached -0.9 OD, the temperature was reduced to 18 ^QC and the culture was induced at 18 ^QC with 0.1 mM Isopropylthiogalactoside (IPTG). The cell paste was collected at -18 hours post induction by refrigerated continuous flow centrifugation (Heraeus, rotor #8575) at 15,000 rpm at 4 ^QC. The cell pellets were aliquoted into four portions, flash frozen in liquid nitrogen and were stored at -80 ^QC until purification. For purification, frozen cell paste was thawed and resuspended in 50 ml lysis buffer (50 imM Tris, pH 8.0, 150 imM NaCI, 10% glycerol, 2 imM Tris-2-carboxyethyl phosphine (TCEP), 20 imM imidazole and 0.001 % Triton X-100). After sonication, insoluble material was removed by

centrifugation at 15,000 rpm in a Sorvall^® RC5 plus centrifuge for 30 min at 4 °C and the supernatant was loaded onto a 5 ml HisTrap™ HP column (GE Healthcare, Piscataway, NJ) and washed with five column volumes of lysis buffer. Bound proteins were eluted using an elution buffer containing 300 imM imidazole. Fractions containing AMPK subunits were pooled based on SDS-10% PAGE analysis and dialyzed overnight in dialysis buffer (50 imM Tris, pH 8.0, 150 imM NaCI, 10% glycerol, 2 imM TCEP, and 0.001 % Triton X-100). The purified AMPK was phosphorylated on its activation loop Thr 172 by incubating 1 .0 μΜ AMPK complex in the presence of 200 nM CaMKK

(calmodulin-dependent protein kinase kinase β obtained from the University of Dundee) in phosphorylation buffer for 30 min at 30 °C. The phosphorylated AMPK complex was re-purified on HisTrap™ HP column as before, dialyzed over night in dialysis buffer. The phosphorylated AMPK complex was further purified by gel filtration chromatography with a Superdex 200 HiLoad 16/60 column (GE Healthcare) in SEC buffer (50 imM Tris, pH 8.0, 150 mM NaCI, 10% glycerol, 2 mM TCEP, and 0.001 % Triton X-100). The final samples were stored at -20 °C with 25% glycerol.

Expression and purification of PP2A

We cloned human recombinant Protein Phosphatase 2A catalytic subunit (PP2A C; 309 aa, NM_004156.2) into pFastBac HT-A expression vector and expressed in insect cells (Sf9) with a N-terminal 10X-His Tag. The Sf9 cells were cultured in SF-900- III SFM medium (Invitrogen #12658-027) in a Wave cellbag disposable bioreactor (GE Healthcare #CB0050L10-02) at 27 ^QC under 0.3L/min aeration. 2x1 ml aliquots of baculovirus infected insect cells (BIIC1 ) were removed from -80 ^QC preservation, rapidly thawed and used to infect 20 liters of log phase Sf-9 cells at a viable cell density ~1 .5x106 vc/ml at >95% viability. The harvest time (72 hours post infection) was indicated by percent cell viability (to 85-90%) and increaased cell diameter (3-4 μιη). The cell paste was collected by refrigerated continuous flow centrifugation at 3500xg (Heraeus/Thermo Scientific model Contifuge 28rs and #8575 rotor), aliquoted, flash frozen in liquid nitrogen and stored at -80 ^QC. For purification, the cell paste was resuspended in 500 imL lysis buffer (50 mM Tris pH 8.0, 150 mM NaCI, 25 mM imidazole, 10% glycerol, 2 mM MgCI2, 2 mM TCEP + protease inhibitor cocktail. After lysis, cellular debris was removed by centrifugation at 36K x g for 1 hour. The resulting supernatant was filtered at 0.2 micron before applying to a 1 imL nickel charged IMAC column (HisTrap, GE). The bound resin was washed to baseline with 50 CV of 50 mM Tris pH 8.0, 150 mM NaCI, 25 mM imidazole, 10% glycerol, 2 mM MgCI2, 2 mM TCEP before eluting over a 20 CV gradient to 1 00% with wash buffer containing 500 mM imidazole. Pooled fractions containing PP2A were combined and diluted 10x with 50 mM Tris pH 8.0, 10% glycerol, 1 mM TCEP and applied to a 1 imL AIEX resin (HiTrap QFF, GE). The bound resin was washed with dilution buffer and PP2A was eluted over a 20 CV gradient to 100% 50 mM Tris pH 8.0, 500 mM NaCI, 10% glycerol, 1 mM TCEP and was further diluted 1 :1 with 50 mM Tris pH 8.0, 150 mM NaCI, 10% glycerol, and 1 mM TCEP buffer.

Biochemical Profiling of AMPK Activators

The biochemical EC₅₀ (half-maximal concentration required for full activation) of compounds for the activation of AMPK was evaluated by ³³P-based assay using SAMS peptide (commercially available) derived from ACC-1 . Twenty μΙ of phosphorylated AMPK diluted in assay buffer, (50 mM HEPES, 1 mM EGTA, 10 mM MgCI2, 0.25 mM DTT, 0.01 % Tween-20, 0.01 % BSA (pH 7.5)) was added to 384 well plates containing 1 μΙ_ of test compound. Following a fifteen minute room temperature incubation, 10 μΙ_ of protein phosphatase PP2A was added to the plate to dephosphorylate pThr172 of AMPK. After incubation for 90 minutes, 10 μΙ_ of substrate mixture containing 41 nM okadaic acid, 82 μΜ SAMS peptide, 82 μΜ ATP and tracer amounts (6.8 nM) of ³³P- containing ATP was added to the plate. The reaction was terminated after 60 minutes incubation at room temperature by the addition of 15 μΙ_ of 2% H₃PO₄. Subsequently, 45 μΙ of reaction mix was transferred to 384 well Millipore MZPH filter plates

(MZPHNO50) pre-treated with 25 μΙ_ of 2% H₃PO₄ and the plates were washed three times with assay buffer. 20 μΙ of Ready Safe scintillation fluid was added to dried plates followed by detection on the Trilux detector. Counts from basal wells (enzyme, diluent, PP2A and substrate) were subtracted from each well. Counts were expressed as a % of positive control wells (enzyme, allosteric activator or AMP, PP2A and substrate). EC50 values were determined from this data using a 4-parameter fit algorithm and are presented in Table 1 . Table 1

In Table 1 , n represents the number of times a particular assay was conducted and AMPK 1 1 1 means the AMPK 1 1 1 isoform. Human Podocyte Assay

Conditionally immortalized human podocytes are seeded at a density of 10⁴ cells/well onto a collagen I coated 24 well plate and allowed to differentiate at 37° C for 7-10 days in glucose free RPMI with 10% FBS and the medium is replaced with fresh medium every other day. Upon differentiation, the cells are treated with the test compounds (1 imM AICAR and Ex 1 ) in serum free RPMI with 30mM glucose. The medium in the negative control wells is replaced with glucose free RPMI containing 0.2% serum and the medium in positive control wells is replaced with serum free RPMI containing 30mM glucose and DMSO. After 48 hours, apoptotic cell death is assessed using Cell Death ELISA (Roche, Inc) according to the manufacturer's instructions. Briefly, podocytes are lysed in lysis buffer provided in the kit, followed by centrifugation for 10 min at 200 X G. 20μΙ of the supernatant are added to streptavidin-coated microtiter plates followed by incubation with Anti-histone biotin and anti-DNA

peroxidase-labeled antibodies for 2 hrs. After incubation and washing, color is developed using the provided substrate to the wells. Absorbance is measured at 405 nm. Parallel cells are lysed with Cell Lysis Buffer (Cell Signaling Technology), separated on 4-12% gradient SDS-PAGE gels (Invitrogen), transferred to nitrocellulose membrane, and probed using antibodies specific to phospho-T172 AMPK alpha, total AMPK alpha, phospho-79 Acetyl-CoA-Carboxylase, and total Acetyl-CoA-Carboxylase.

Claims

We Claim:

1 . A compound of Formula I)

Formula (I)

or a pharmaceutically acceptable salt thereof, wherein

X is N or CH;

Ri is -C(O)OR or -CH₂OR;

R is H or (CrC₆)alkyl;

R₂, R3, and R₄ are independently H, (CrC₆)alkoxy, (CrC₆)alkyl, (CrC₆)alkylthio, carboxy, cyano, halogen, halo(CrC₆)alkoxy, halo(CrC₆)alkyl, hydroxy,

hydroxy(CrC8)alkyl, mercapto, nitro, -N RQRH or (NRoR^carbonyl;

RG and RH are independently H, (Ci-C6)alkyl, (CrC6)alkylcarbonyl, or RQ and RH form a ring that is azetidine, pyrrolidine, piperidine, or azepane;

R₅ is H;

L is a bond, O, S, NR_A, (CrC₆)alkylene, (C₂-C₆)alkenylene, or (C₂-C₆)alkynylene;

A is phenyl, 2,3-dihydrobenzo[b][1 ,4]dioxinyl, 2,3-dihydrobenzofuranyl,

2,3-dihydro-1 H-indenyl, imidazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, or thiazolyl, wherein each is optionally substituted with 1 , 2, 3, 4, or 5 substituents that are independently (Ci-C6)alkoxy, (Ci-C6)alkoxy(CrC6)alkoxy, (Ci-C6)alkoxy(CrC6)alkyl, (CrC₆)alkoxycarbonyl, (CrC₆)alkyl, (CrC₆)alkylcarbonyl, (CrC₆)alkylthio, aryl, aryl(CrC₆)alkoxy, aryl(CrC₆)alkyl, arylcarbonyl, aryloxy, carboxy,

carboxy(CrC6)alkoxy, carboxy(CrC6)alkyl, cyano, (C3-C8)cycloalkyl,

(C3-C8)cycloalkyl(CrC6)alkoxy, (C3-C8)cycloalkyl(CrC6)alkyl, (C3-C8)cycloalkylcarbonyl, (C₃-C₈)cycloalkyloxy, halogen, halo(CrC₆)alkoxy, halo(CrC₆)alkyl, heteroaryl, heteroaryl(CrC₆)alkoxy, heteroaryl(CrC₆)alkyl, heteroarylcarbonyl, heteroaryloxy,

(C3-C7)heterocycle, (C3-C7)heterocycle(CrC6)alkoxy, (C3-C7)heterocycle(CrC6)alkyl, (C3-C7)heterocyclecarbonyl, (C3-C7)heterocyclecarbonyl(CrC6)alkyl,

(C₃-C₇)heterocycleoxy, hydroxy, hydroxy(CrC₆)alkoxy, hydroxy(CrC₆)alkyl, mercapto, nitro, -NRjR_K, (NRjR_K)carbonyl, -N R_MRN, -N RM N(Ci-C₆)alkoxy, (NR_MRN)carbonyl, (NRMRN)carbonyl(CrC6)alkyl, or (NRMRN)carbonyl(Ci-C6)alkoxy; wherein the aryl, aryl(CrC₆)alkoxy, aryl(CrC₆)alkyl, arylcarbonyl, and aryloxy are optionally substituted with 1 , 2, 3, 4, or 5 substituents that are independently (Ci-C6)alkoxy,

(CrC6)alkoxycarbonyl, (Ci-C6)alkyl, (CrC6)alkylcarbonyl, (Ci-C6)alkylthio, carboxy, cyano, halogen, halo(CrC₆)alkoxy, halo(CrC₆)alkyl, hydroxy, hydroxy(CrC₆)alkyl, mercapto, nitro, -N R_MRN, or (N R_MRN)carbonyl; wherein the halo(CrC₆)alkyl is optionally substituted with 1 or 2 hydroxy groups; wherein the (C₃-C₈)cycloalkyl,

(C₃-C₈)cycloalkyl(Ci-C6)alkoxy, (C₃-C₈)cycloalkyl(Ci-C6)alkyl, (C₃-C₈)cycloalkylcarbonyl, and (C₃-C₈)cycloalkyloxy are optionally substituted with 1 , 2, or 3 substituents that are independently (Ci-C6)alkoxy, (CrC6)alkoxycarbonyl, (Ci-C6)alkyl, (CrC6)alkylcarbonyl, (CrC₆)alkylthio, carboxy, cyano, halogen, halo(CrC₆)alkoxy, halo(CrC₆)alkyl, hydroxy, hydroxy(CrC₆)alkyl, mercapto, nitro, -N R_MRN, or (N R_MRN)carbonyl; wherein the heteroaryl, heteroaryl(Ci-C6)alkoxy, heteroaryl(CrC6)alkyl, heteroarylcarbonyl, and heteroaryloxy, are optionally substituted with 1 , 2, or 3 substituents that are

independently (Ci-C6)alkoxy, (CrC6)alkoxycarbonyl, (Ci-C6)alkyl, (CrC6)alkylcarbonyl, (CrC₆)alkylthio, carboxy, cyano, halogen, halo(CrC₆)alkoxy, halo(CrC₆)alkyl, hydroxy, hydroxy(CrC₆)alkyl, mercapto, nitro, -N R_MRN, or (N R_MRN)carbonyl; and wherein the (C₃-C7)heterocycle, (C₃-C7)heterocycle(CrC6)alkoxy, (C₃-C7)heterocycle(CrC6)alkyl, (C₃-C7)heterocyclecarbonyl, (C₃-C7)heterocyclecarbonyl(CrC6)alkyl, and

(C₃-C₇)heterocycleoxy, are optionally substituted with 1 , 2, or 3 substituents that are independently (CrC₆)alkoxy, (CrC₆)alkoxycarbonyl, (CrC₆)alkoxysulfonyl, (CrC₆)alkyl, (CrC₆)alkylcarbonyl, (CrC₆)alkylsulfonyl, (CrC₆)alkylthio, carboxy, cyano, halogen, halo(CrC₆)alkoxy, halo(CrC₆)alkyl, hydroxy, hydroxy(CrC₆)alkyl, mercapto,

nitro, -N RMRN, (NRMRNi)carbonyl, or oxo;

Rj and RK are independently H or (Ci-C6)alkyl; and

2. A compound of Formula II)

Formula (II)

or a pharmaceutically acceptable salt thereof, wherein

X is N or CH;

L is a bond, O, S, NR_A, (CrC₆)alkylene, (C₂-C₆)alkenylene, or (C₂-C₆)alkynylene; A is

Ri is -C(O)OR or -CH₂OR;

R is H or (CrC₆)alkyl;

R2, R3, and R₄ are independently H, (Ci-C6)alkoxy, (CrC6)alkyl, (Ci-C6)alkylthio, carboxy, cyano, halogen, halo(CrC₆)alkoxy, halo(CrC₆)alkyl, hydroxy,

hydroxy(CrC₈)alkyl, mercapto, nitro, -N R_GRH, or (NR_GRi-i)carbonyl;

R₅ is H;

R₆, R7, R9, and R10 are independently H, (CrC₆)alkoxy, (CrC₆)alkoxycarbonyl, (CrC6)alkyl, (CrC6)alkylcarbonyl, (Ci-C6)alkylthio, carboxy, cyano, halogen,

halo(CrC6)alkoxy, halo(CrC6)alkyl, hydroxy, hydroxy(CrC6)alkyl, mercapto,

nitro, -N RJ RK, or (NRjR_K)carbonyl;

Rj and RK are independently H or (CrC₆)alkyl; R₈ is H, (C C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,

(CrC6)alkoxycarbonyl, (Ci-C6)alkyl, (CrC6)alkylcarbonyl, (CrC6)alkylthio, aryl, aryl(Ci-C6)alkoxy, aryl(CrC6)alkyl, arylcarbonyl, aryloxy, carboxy,

carboxy(CrC₆)alkoxy, carboxy(CrC₆)alkyl, cyano, (C₃-C₈)cycloalkyl,

(C₃-C₈)cycloalkyl(Ci-C6)alkoxy, (C₃-C₈)cycloalkyl(Ci-C6)alkyl, (C₃-C₈)cycloalkylcarbonyl,

(C₃-C₈)cycloalkyloxy, halogen, halo(CrC₆)alkoxy, halo(CrC₆)alkyl, heteroaryl, heteroaryl(CrC₆)alkoxy, heteroaryl(CrC₆)alkyl, heteroarylcarbonyl, heteroaryloxy,

(C₃-C7)heterocycle, (C₃-C7)heterocycle(CrC6)alkoxy, (C₃-C7)heterocycle(CrC6)alkyl,

(C₃-C7)heterocyclecarbonyl, (C₃-C7)heterocyclecarbonyl(CrC6)alkyl,

(C₃-C₇)heterocycleoxy, hydroxy, hydroxy(CrC₆)alkoxy, hydroxy(CrC₆)alkyl, mercapto, nitro, -N RMRN, -N RMRN(C C₆)alkoxy, (N R_MRN)carbonyl, (N RMRN)carbonyl(CrC₆)alkyl, or (N RMRN)carbonyl(CrC6)alkoxy; wherein the aryl, aryl(Ci-C6)alkoxy, aryl(CrC6)alkyl, arylcarbonyl, and aryloxy are optionally substituted with 1 , 2, 3, 4, or 5 substituents that are independently (Ci-C6)alkoxy, (CrC6)alkoxycarbonyl, (Ci-C6)alkyl,

(N RMRN)carbonyl; wherein the halo(CrC₆)alkyl is optionally substituted with 1 or 2 hydroxy groups; wherein the (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(CrC6)alkoxy,

(C₃-C₈)cycloalkyl(Ci-C₆)alkyl, (C₃-C₈)cycloalkylcarbonyl, and (C₃-C₈)cycloalkyloxy are optionally substituted with 1 , 2, or 3 substituents that are independently (C C₆)alkoxy,

(CrC₆)alkoxycarbonyl, (CrC₆)alkyl, (CrC₆)alkylcarbonyl, (CrC₆)alkylthio, carboxy, cyano, halogen, halo(CrC₆)alkoxy, halo(CrC₆)alkyl, hydroxy, hydroxy(CrC₆)alkyl, mercapto, nitro, -N RMRN, or (NRMRNi)carbonyl; wherein the heteroaryl,

(CrC₆)alkoxy, (CrC₆)alkoxycarbonyl, (CrC₆)alkyl, (CrC₆)alkylcarbonyl,

(CrC₆)alkylthio, carboxy, cyano, halogen, halo(CrC₆)alkoxy, halo(CrC₆)alkyl, hydroxy, hydroxy(CrC₆)alkyl, mercapto, nitro, -N RMRN, or (N RMRN)carbonyl; and wherein the

(C₃-C₇)heterocycle, (C₃-C7)heterocycle(Ci-C₆)alkoxy, (C₃-C7)heterocycle(Ci-C₆)alkyl,

(C₃-C₇)heterocyclecarbonyl, (C₃-C₇)heterocyclecarbonyl(Ci-C₆)alkyl, and

(C₃-C7)heterocycleoxy, are optionally substituted with 1 , 2, or 3 substituents that are independently (Ci-C6)alkoxy, (CrC6)alkoxycarbonyl, (CrC6)alkoxysulfonyl, (Ci-C6)alkyl,

(CrC₆)alkylcarbonyl, (CrC₆)alkylsulfonyl, (CrC₆)alkylthio, carboxy, cyano, halogen, halo(CrC₆)alkoxy, halo(CrC₆)alkyl, hydroxy, hydroxy(CrC₆)alkyl, mercapto,

nitro, -N RMRN, (N RMRN)carbonyl, or oxo; and RM and RN are independently H, (CrC₆)alkyl, (Ci-C6)alkyl(Ci-C₆)alkoxy, or

(CrC6)alkylcarbonyl; or RM and RN together with the nitrogen they are attached to form a 3 to 8 membered ring, wherein the 3 to 8 membered ring may be optionally

substituted with 1 to 3 substituents that are (CrC₆)alkoxy, (CrC₆)alkyl, halogen, or hydroxy.

3. A compound of Formula III)

Formula (III)

or a pharmaceutically acceptable salt thereof, wherein

X is N or CH;

L is a bond, O, S, N RA, (CrC6)alkylene, (C2-C6)alkenylene, or (C2-C6)alkynylene; Ri is -C(O)OR or -CH₂OR;

R is H or (C C₆)alkyl;

R2, R3, and R₄ are independently H, (Ci-C6)alkoxy, (CrC6)alkyl, (Ci-C6)alkylthio, carboxy, cyano, halogen, halo(CrC6)alkoxy, halo(CrC6)alkyl, hydroxy,

hydroxy(CrC₈)alkyl, mercapto, nitro, -N R_GRH, or (NR_GRi-i)carbonyl;

R₅ is H;

R₆, R₇, R9, and R10 are independently H, (Ci-C6)alkoxy, (CrC6)alkoxycarbonyl, (CrC6)alkyl, (CrC6)alkylcarbonyl, (Ci-C6)alkylthio, carboxy, cyano, halogen,

halo(CrC₆)alkoxy, halo(CrC₆)alkyl, hydroxy, hydroxy(CrC₆)alkyl, mercapto,

nitro, -NRjR_K, or (NRjR_K)carbonyl; Rj and R« are independently H or (CrC₆)alkyl;

R₈ is H, (CrC₆)alkoxy, (Ci-C₆)alkoxy(Ci-C₆)alkoxy, (Ci-C₆)alkoxy(Ci-C₆)alkyl, (CrC6)alkoxycarbonyl, (Ci-C6)alkyl, (CrC6)alkylcarbonyl, (Ci-C6)alkylthio, aryl, aryl(CrC₆)alkoxy, aryl(CrC₆)alkyl, arylcarbonyl, aryloxy, carboxy,

carboxy(CrC₆)alkoxy, carboxy(CrC₆)alkyl, cyano, (C₃-C₈)cycloalkyl,

(C3-C8)cycloalkyl(CrC6)alkoxy, (C3-C8)cycloalkyl(CrC6)alkyl, (C3-C8)cycloalkylcarbonyl, (C3-C8)cycloalkyloxy, halogen, halo(CrC6)alkoxy, halo(CrC6)alkyl, heteroaryl, heteroaryl(CrC₆)alkoxy, heteroaryl(CrC₆)alkyl, heteroarylcarbonyl, heteroaryloxy, (C₃-C₇)heterocycle, (C3-C₇)heterocycle(Ci-C₆)alkoxy, (C3-C₇)heterocycle(Ci-C₆)alkyl, (C3-C₇)heterocyclecarbonyl, (C3-C₇)heterocyclecarbonyl(CrC6)alkyl,

(C3-C₇)heterocycleoxy, hydroxy, hydroxy (Ci-C6)alkoxy, hydroxy(CrC6)alkyl, mercapto, nitro, -N RMRN, -N RM N(Ci-C₆)alkoxy, (N R_MRN)carbonyl, (N RMRN)carbonyl(Ci-C₆)alkyl, or (N R_MRN)carbonyl(CrC6)alkoxy; wherein the aryl, aryl(CrC₆)alkoxy, aryl(CrC₆)alkyl, arylcarbonyl, and aryloxy are optionally substituted with 1 , 2, 3, 4, or 5 substituents that are independently (CrC₆)alkoxy, (CrC₆)alkoxycarbonyl, (CrC₆)alkyl,

(CrC6)alkylcarbonyl, (Ci-C6)alkylthio, carboxy, cyano, halogen, halo(CrC6)alkoxy, halo(CrC6)alkyl, hydroxy, hydroxy(CrC6)alkyl, mercapto, nitro, -N RMRN, or

(NR_MRN)carbonyl; wherein the halo(CrC₆)alkyl is optionally substituted with 1 or 2 hydroxy groups; wherein the (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(Ci-C6)alkoxy,

(C3-C8)cycloalkyl(CrC6)alkyl, (C3-C8)cycloalkylcarbonyl, and (C3-C8)cycloalkyloxy are optionally substituted with 1 , 2, or 3 substituents that are independently (Ci-C6)alkoxy, (CrC6)alkoxycarbonyl, (Ci-C6)alkyl, (CrC6)alkylcarbonyl, (Ci-C6)alkylthio, carboxy, cyano, halogen, halo(CrC₆)alkoxy, halo(CrC₆)alkyl, hydroxy, hydroxy(CrC₆)alkyl, mercapto, nitro, -N R_MRN, or (N R_MRN)carbonyl; wherein the heteroaryl,

(CrC₆)alkoxy, (CrC₆)alkoxycarbonyl, (CrC₆)alkyl, (CrC₆)alkylcarbonyl,

(CrC₆)alkylthio, carboxy, cyano, halogen, halo(CrC₆)alkoxy, halo(CrC₆)alkyl, hydroxy, hydroxy(CrC₆)alkyl, mercapto, nitro, -N R_MRN, or (N R_MRN)carbonyl; and wherein the (C₃-C₇)heterocycle, (C3-C₇)heterocycle(Ci-C₆)alkoxy, (C3-C₇)heterocycle(Ci-C₆)alkyl, (C3-C₇)heterocyclecarbonyl, (C3-C₇)heterocyclecarbonyl(CrC6)alkyl, and

(C3-C₇)heterocycleoxy, are optionally substituted with 1 , 2, or 3 substituents that are independently (CrC₆)alkoxy, (CrC₆)alkoxycarbonyl, (CrC₆)alkoxysulfonyl, (CrC₆)alkyl, (CrC₆)alkylcarbonyl, (CrC₆)alkylsulfonyl, (CrC₆)alkylthio, carboxy, cyano, halogen, halo(CrC6)alkoxy, halo(CrC6)alkyl, hydroxy, hydroxy(CrC6)alkyl, mercapto,

nitro, -N RMRN, (NRMRNi)carbonyl, or oxo; and

4. The compound according to claim 3 wherein

X is CH;

L is a bond;

Ri is -C(O)OR;

R is H;

R₂ is H or F;

R₃ is CI, F, or CN;

R₄ and R5 are H;

R6 and R7 are independently H, F, or methoxy;

Rg and R10 are H;

R₈ is (C₃-C₈)cycloalkyl wherein the (C₃-C₈)cycloalkyl is cyclobutyl substituted with hydroxy.

5. A compound of structure

or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 3 wherein

X is CH;

L is a bond;

Ri is -C(O)OR;

R is H;

R₂ is H or F;

R₃ is CI, F, or CN;

R₄ is H;

R₅ is H;

R₆ and R₇ are independently H, F, or methoxy;

Rg and R10 are H;

Rs is (C₃-C₇)heterocycle wherein the (C₃-C₇)heterocycle is tetrahydro-2H-pyran.

7. A compound of structure

or a pharmaceutically acceptable salt thereof. 8. A compound of Formula IV)

Formula (IV)

or a pharmaceutically acceptable salt thereof, wherein

X is N or CH;

L is a bond, O, S, N RA, (CrC6)alkylene, (C2-C6)alkenylene, or (C2-C6)alkynylene; Ri is -C(O)OR or -CH₂OR; R is H or (C C₆)alkyl;

hydroxy(CrC8)alkyl, mercapto, nitro, -N RQRH, or (NRoR^carbonyl;

R₅ is H;

R6, R7, and R10 are independently H, (Ci-C6)alkoxy, (CrC6)alkoxycarbonyl, (CrC₆)alkyl, (CrC₆)alkylcarbonyl, (CrC₆)alkylthio, carboxy, cyano, halogen,

halo(CrC₆)alkoxy, halo(CrC₆)alkyl, hydroxy, hydroxy(CrC₆)alkyl, mercapto,

nitro, -N RJ RK, or (NRjRK)carbonyl; Rj and RK are independently H or (Ci-C6)alkyl;

R₈ is H, (CrC₆)alkoxy, (Ci-C₆)alkoxy(Ci-C₆)alkoxy, (Ci-C₆)alkoxy(Ci-C₆)alkyl, (CrC₆)alkoxycarbonyl, (CrC₆)alkyl, (CrC₆)alkylcarbonyl, (CrC₆)alkylthio, aryl, aryl(CrC₆)alkoxy, aryl(CrC₆)alkyl, arylcarbonyl, aryloxy, carboxy, carboxy(CrC₆)alkoxy, carboxy(CrC₆)alkyl, cyano, (C₃-C₈)cycloalkyl,

(C3-C8)cycloalkyl(CrC6)alkoxy, (C3-C8)cycloalkyl(CrC6)alkyl, (C3-C8)cycloalkylcarbonyl,

(C3-C8)cycloalkyloxy, halogen, halo(CrC6)alkoxy, halo(CrC6)alkyl, heteroaryl, heteroaryl(CrC₆)alkoxy, heteroaryl(CrC₆)alkyl, heteroarylcarbonyl, heteroaryloxy,

(C₃-C₇)heterocycle, (C3-C₇)heterocycle(Ci-C₆)alkoxy, (C3-C₇)heterocycle(Ci-C₆)alkyl,

(C₃-C₇)heterocyclecarbonyl, (C₃-C₇)heterocyclecarbonyl(Ci-C₆)alkyl,

(C₃-C₇)heterocycleoxy, hydroxy, hydroxy(CrC₆)alkoxy, hydroxy(CrC₆)alkyl, mercapto, nitro, -N RMRN, -N R_MRN(Ci-C6)alkoxy, (N R_MRN)carbonyl, (N R_MRN)carbonyl(CrC6)alkyl, or (N RMRN)carbonyl(CrC6)alkoxy; wherein the aryl, aryl(Ci-C6)alkoxy, aryl(CrC6)alkyl, arylcarbonyl, and aryloxy are optionally substituted with 1 , 2, 3, 4, or 5 substituents that are independently (CrC₆)alkoxy, (CrC₆)alkoxycarbonyl, (CrC₆)alkyl,

(N RMRN)carbonyl; wherein the halo(CrC6)alkyl is optionally substituted with 1 or 2 hydroxy groups; wherein the (C₃-C₈)cycloalkyl, (C3-C8)cycloalkyl(C-i-C₆)alkoxy,

(C3-C8)cycloalkyl(Ci-C₆)alkyl, (C₃-C₈)cycloalkylcarbonyl, and (C₃-C₈)cycloalkyloxy are optionally substituted with 1 , 2, or 3 substituents that are independently (Ci-C6)alkoxy,

(CrC6)alkoxycarbonyl, (Ci-C6)alkyl, (CrC6)alkylcarbonyl, (Ci-C6)alkylthio, carboxy, cyano, halogen, halo(CrC₆)alkoxy, halo(CrC₆)alkyl, hydroxy, hydroxy(CrC₆)alkyl, mercapto, nitro, -N R_MRN, or (N R_MRN)carbonyl; wherein the heteroaryl,

(Ci-C6)alkoxy, (CrC6)alkoxycarbonyl, (Ci-C6)alkyl, (CrC6)alkylcarbonyl,

(CrC₆)alkylthio, carboxy, cyano, halogen, halo(CrC₆)alkoxy, halo(CrC₆)alkyl, hydroxy, hydroxy(CrC₆)alkyl, mercapto, nitro, -N R_MRN, or (N R_MRN)carbonyl; and wherein the

(C3-C₇)heterocyclecarbonyl, (C3-C₇)heterocyclecarbonyl(CrC6)alkyl, and

(C3-C₇)heterocycleoxy, are optionally substituted with 1 , 2, or 3 substituents that are independently (CrC₆)alkoxy, (CrC₆)alkoxycarbonyl, (CrC₆)alkoxysulfonyl, (CrC₆)alkyl,

(CrC₆)alkylcarbonyl, (CrC₆)alkylsulfonyl, (CrC₆)alkylthio, carboxy, cyano, halogen, halo(CrC6)alkoxy, halo(CrC6)alkyl, hydroxy, hydroxy(CrC6)alkyl, mercapto,

nitro, -N RMRN, (NRMRNi)carbonyl, or oxo; and

RM and RN are independently H, (CrC₆)alkyl, (Ci-C6)alkyl(Ci-C₆)alkoxy, or

(CrC₆)alkylcarbonyl; or R_M and RN together with the nitrogen they are attached to form a 3 to 8 membered ring, wherein the 3 to 8 membered ring may be optionally substituted with 1 to 3 substituents that are (CrC₆)alkoxy, (CrC₆)alkyl, halogen, or hydroxy.

9. The compound according to claim XX wherein

X is CH;

L is a bond;

Ri is -C(O)OR;

R is H;

R₂ is H or halogen;

R₃ is (CrC₆)alkyl, cyano, or halogen;

R₄, R₅, R₆, and R₇ are H;

R₈ is -N R_MRN;

RM and RN are independently H or (Ci-C6)alkyl; and

Rio is (Ci-C₆)alkoxy.

A compound of structure

or a pharmaceutically acceptable salt thereof.

1 1 . A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier.

12. A method of treating or preventing metabolic disorders in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, where the metabolic disorder is ameliorated by activation of 5' adenosine monophosphate-activated protein kinase.

13. The method according to claim 12 wherein the metabolic disorder is type II diabetes, obesity, dyslipidemia, NAFLD, NASH, or liver cirrhosis.

14. A method of treating or preventing chronic kidney disease, diabetic nephropathy, acute kidney injury or polycystic kidney disease in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

15. A method of treating or preventing diabetic nephropathy in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.