WO2016092413A1 - Composés indoliques et indazoliques qui activent l'ampk - Google Patents

Composés indoliques et indazoliques qui activent l'ampk Download PDF

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Publication number
WO2016092413A1
WO2016092413A1 PCT/IB2015/059222 IB2015059222W WO2016092413A1 WO 2016092413 A1 WO2016092413 A1 WO 2016092413A1 IB 2015059222 W IB2015059222 W IB 2015059222W WO 2016092413 A1 WO2016092413 A1 WO 2016092413A1
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crc
alkyl
alkoxy
crc6
hydroxy
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PCT/IB2015/059222
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English (en)
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Kimberly Cameron
David James EDMONDS
Amit Kalgutkar
David Ebner
Benjamin Thuma
Kevin James Filipski
Rajesh Kumar
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Pfizer Inc.
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Publication of WO2016092413A1 publication Critical patent/WO2016092413A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/10—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals directly attached to heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • 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.
  • AMPK 5' adenosine monophosphate-activated protein kinase
  • 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.
  • AMPK 5' adenosine monophosphate-activated protein kinase
  • 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.
  • HMG-CoA 3-hydroxy-3-methylglutaryl coenzyme A reductase
  • acetyl-CoA carboxylase Carling, D. et al. FEBS Letters 223, 217-222 (1987)
  • 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)).
  • 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.
  • AICAR 5-aminoimidazole-4-carboxamide riboside
  • AMPK activation has 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.
  • AICAR pharmacological
  • 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.
  • 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.
  • 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,
  • X is N or CH
  • Ri is -C(O)OR or -CH 2 OR
  • R is H or (C C 6 )alkyl
  • R 2 , R3, and R 4 are independently H, (CrC 6 )alkoxy, (CrC 6 )alkyl, (CrC 6 )alkylthio, carboxy, cyano, halogen, halo(CrC6)alkoxy, halo(CrC6)alkyl, hydroxy,
  • RG and RH are independently H, (CrC 6 )alkyl, (CrC 6 )alkylcarbonyl, or R G and RH form a ring that is azetidine, pyrrolidine, piperidine, or azepane;
  • R 5 is H;
  • L is a bond, O, S, N R A , (CrC 6 )alkylene, (C 2 -C 6 )alkenylene, or (C 2 -C 6 )alkynylene;
  • A is phenyl, 2,3-dihydrobenzo[b][1 ,4]dioxinyl, 2,3-dihydrobenzofuranyl,
  • (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 (CrC 6 )alkoxy, (CrC 6 )alkoxycarbonyl, (CrC 6 )alkyl, (CrC 6 )alkylcarbonyl, (CrC 6 )alkylthio, carboxy, cyano, halogen, halo(CrC 6 )alkoxy, halo(CrC 6 )alkyl, hydroxy, hydroxy(CrC6)alkyl, mercapto, nitro, -N RMRN, or (NRMRNi)carbonyl; wherein the heteroaryl, heteroaryl(Ci-C6)alkoxy, heteroaryl(Cr
  • (C3-C7)heterocycleoxy are optionally substituted with 1 , 2, or 3 substituents that are independently (CrC 6 )alkoxy, (CrC 6 )alkoxycarbonyl, (CrC 6 )alkoxysulfonyl, (CrC 6 )alkyl, (CrC6)alkylcarbonyl, (CrC6)alkylsulfonyl, (Ci-C6)alkylthio, carboxy, cyano, halogen, halo(CrC6)alkoxy, halo(CrC6)alkyl, hydroxy, hydroxy(CrC6)alkyl, mercapto,
  • Rj and R « are independently H or (CrC 6 )alkyl
  • RM and RN are independently H, (CrC 6 )alkyl, (Ci-C6)alkyl(Ci-C 6 )alkoxy, or (CrC 6 )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
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I) and at least one pharmaceutically acceptable excipient, diluent, or carrier.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • NAFLD nonalcoholic fatty liver disease
  • 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.
  • NASH nonalcoholic steatohepatitis
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • NAFLD nonalcoholic fatty liver disease
  • 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.
  • NASH nonalcoholic steatohepatitis
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the present invention provides compounds of Formula
  • 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-CH 2 OR
  • R is H or (C C 6 )alkyl
  • R 2 , R3, and R 4 are independently H, (CrC 6 )alkoxy, (CrC 6 )alkyl, (CrC 6 )alkylthio, carboxy, cyano, halogen, halo(CrC6)alkoxy, halo(CrC6)alkyl, hydroxy,
  • RG and RH are independently H, (CrC 6 )alkyl, (CrC 6 )alkylcarbonyl, or R G and RH form a ring that is azetidine, pyrrolidine, piperidine, or azepane;
  • R 5 is H;
  • R 6 , R 7 , R9, and R10 are independently H, (CrC 6 )alkoxy, (CrC 6 )alkoxycarbonyl, (CrC6)alkyl, (CrC6)alkylcarbonyl, (Ci-C6)alkylthio, carboxy, cyano, halogen,
  • Rj and R « are independently H or (CrC 6 )alkyl
  • R 8 is H, (C C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (CrC 6 )alkoxycarbonyl, (CrC 6 )alkyl, (CrC 6 )alkylcarbonyl, (CrC 6 )alkylthio, aryl, aryl(Ci-C6)alkoxy, aryl(CrC6)alkyl, arylcarbonyl, aryloxy, carboxy,
  • (C 3 -C 8 )cycloalkyl(CrC6)alkyl, (C 3 -C 8 )cycloalkylcarbonyl, and (C 3 -C 8 )cycloalkyloxy are optionally substituted with 1 , 2, or 3 substituents that are independently (C C 6 )alkoxy, (CrC 6 )alkoxycarbonyl, (CrC 6 )alkyl, (CrC 6 )alkylcarbonyl, (CrC 6 )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(CrC 6 )alkoxy, heteroaryl(CrC 6 )alkyl, heteroarylcarbonyl, and heteroaryloxy are optionally substituted with 1 , 2, or 3 substituents that are independently
  • RM and RN are independently H, (CrC 6 )alkyl, (Ci-C6)alkyl(Ci-C 6 )alkoxy, or (CrC 6 )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
  • 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
  • R 1 is -C(O)OR;
  • R is H or (C C 6 )alkyl;
  • R2, R3, and R 4 are independently H, (Ci-C6)alkyl, cyano, or halogen;
  • R 5 is H;
  • R 6 , R7, R9, and R10 are independently H, (CrC 6 )alkoxy, (CrC 6 )alkyl, cyano, halogen, hydroxy, or hydroxy(C C 6 )alkyl;
  • R 8 is H, (C C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C C 6 )alkyl, (CrC6)alkylcarbonyl, aryl, carboxy(CrC6)alkoxy, (C3-C8)cycloalkyl,
  • membered ring may be optionally substituted with 1 to 3 substituents that are
  • the present invention provides compounds of Formula
  • X is N or CH;
  • L is a bond, O, S, NR A , (CrC 6 )alkylene, (C 2 -C 6 )alkenylene, or (C 2 -C 6 )alkynylene;
  • R is -C(O)OR or -CH 2 OR;
  • R is H or (Ci-C6)alkyl;
  • R 2 , R3, and R 4 are independently H, (Ci-C6)alkoxy, (CrC 6 )alkyl, (CrC 6 )alkylthio, carboxy, cyano, halogen, halo(CrC 6 )alkoxy,
  • 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;
  • R 6 , R 7 , Rg, and R10 are independently H, (CrC 6 )alkoxy, (CrC 6 )alkoxycarbonyl, (CrC 6 )alkyl, (CrC6)alkylcarbonyl, (Ci-C6)alkylthio, carboxy, cyano, halogen, halo(CrC6)alkoxy, halo(CrC 6 )alkyl, hydroxy, hydroxy(CrC 6 )alkyl, mercapto, nitro, -NRjR K , or
  • Rj and RK are independently H or (CrC 6 )alkyl;
  • R 8 is H, (CrC 6 )alkoxy, (Ci -C6)alkoxy(Ci -Ce)alkoxy, (Ci -C6)alkoxy(Ci -Ce)alkyl, (Ci -C6)alkoxycarbonyl ,
  • aryl(CrC 6 )alkyl arylcarbonyl, aryloxy, carboxy, carboxy(CrC 6 )alkoxy,
  • heteroaryl(CrC 6 )alkyl heteroarylcarbonyl, heteroaryloxy, (C 3 -C 7 )heterocycle
  • (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, (CrC 6 )alkoxycarbonyl, (CrC 6 )alkyl, (CrC 6 )alkylcarbonyl, (CrC 6 )alkylthio, carboxy, cyano, halogen, halo(CrC 6 )alkoxy, halo(CrC 6 )alkyl, hydroxy, hydroxy(CrC 6 )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
  • (C 3 -C 7 )heterocycleoxy are optionally substituted with 1 , 2, or 3 substituents that are independently (CrC 6 )alkoxy, (CrC 6 )alkoxycarbonyl, (CrC 6 )alkoxysulfonyl, (CrC 6 )alkyl, (CrC 6 )alkylcarbonyl, (CrC 6 )alkylsulfonyl, (CrC 6 )alkylthio, carboxy, cyano, halogen, halo(CrC6)alkoxy, halo(CrC6)alkyl, hydroxy, hydroxy(CrC6)alkyl, mercapto,
  • 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 -CH 2 OR; R is H or (C C 6 )alkyl; R 2 , R 3 , and R 4 are independently H, (Ci-C6)alkoxy, (CrC6)alkyl, (Ci-C6)alkylthio, carboxy, cyano, halogen,
  • R G and RH are independently H, (CrC 6 )alkyl, (CrC6)alkylcarbonyl, or RQ and RH form a ring that is azetidine, pyrrolidine, piperidine, or azepane;
  • R 5 is H;
  • R 6 , R 7 , R9, and R10 are independently H, (C C 6 )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
  • R 8 is H, (C C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy,
  • 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 C 6 )alkoxy, (CrC 6 )alkyl, halogen, or hydroxy.
  • 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 -CH 2 OR; R is H; R 2 is H or halogen; R 3 is (CrC 6 )alkyl, cyano, or halogen; R 4 is H; R 5 is H; R 6 , R 7 , Rg, and R10 are independently H, (CrC 6 )alkoxy, halogen, hydroxy, or hydroxy(CrC 6 )alkyl; R 8 is H, (CrC 6 )alkoxy, (Ci-C6)alkoxy(Ci-C 6 )alkyl,
  • halo(CrC 6 )alkyl is optionally substituted with 1 hydroxy group; and RM and RN are independently H, (CrC 6 )alkyl, (Ci-C6)alkyl(Ci-C 6 )alkoxy, or (CrC 6 )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 C 6 )alkoxy, (CrC 6 )alkyl, halogen, or hydroxy.
  • 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 -CH 2 OR; R is H; R 2 is H or F; R 3 is methyl, cyano, CI, or F; R 4 is H; R 5 is H; R 6 , R 7 , Rg, and R10 are independently H, (CrC 6 )alkoxy, halogen, hydroxy, or hydroxy(C C 6 )alkyl; R 8 is H, (C C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C C 6 )alkyl, (CrC6)alkylcarbonyl, carboxy(CrC6)alkoxy, halo(CrC6)alkyl, hydroxy(Ci-C6)alkoxy, hydroxy(Ci -C 6 )alkyl, -NR M
  • 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 -CH 2 OR; R is H; R 2 is H or F; R 3 is CI, F or CN; R 4 is H; R 5 is H; R 6 , R 7 , R g , and Ri 0 are independently H, (CrC 6 )alkoxy, halogen, hydroxy, or
  • R 8 is H, (C C 6 )alkoxy, (Ci-C 6 )alkoxy(Ci-C 6 )alkyl, (C C 6 )alkyl, (CrC6)alkylcarbonyl, carboxy(CrC6)alkoxy, halo(CrC6)alkyl, hydroxy(Ci -C6)alkoxy, hydroxy(CrC 6 )alkyl, -NR M RN(Ci-C 6 )alkoxy, (NR M RN)carbonyl(Ci-C 6 )alkyl, or
  • NR M RN carbonyl(CrC6)alkoxy; wherein the halo(CrC 6 )alkyl is optionally substituted with 1 hydroxy group; and RM and RN are independently H, (CrC 6 )alkyl,
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg, and Rio are H; and Rs is hydroxy(Ci -C6)alkoxy.
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 , R 9 , and Rio are H; R 7 is H or (Ci -C6)alkoxy ; and Rs is hydroxy(Ci-C6)alkoxy.
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 , R 9 , and Rio are H; R 7 is methoxy; and Rs is hydroxy(Ci -C6)alkoxy.
  • 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; R 2 is H or F; R 3 is CI, F, or CN ; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg, and R10 are H; and R 8 is hydroxy(Ci -C6)alkoxy.
  • 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; R 2 is H or F; R 3 is CI, F, or CN ; R 4 is H; R 5 is H; R 6 , R 9 , and Ri 0 are H; R 7 is H or (C-i-C 6 )alkoxy ; and R 8 is hydroxy(CrC 6 )alkoxy.
  • 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; R 2 is H or F; R 3 is CI, F, or CN ; R 4 is H; R 5 is H; R 6 , R 9 , and R10 are H; R 7 is methoxy; and R 8 is hydroxy(CrC 6 )alkoxy.
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg, and R-io are H; and R 8 is (Ci-C6)alkoxy.
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 , R 7 , R 9 , and R10 are H; and R 8 is (Ci-C6)alkoxy.
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 , R 9 , and Ri 0 are H; R 7 is methoxy; and R 8 is (CrC 6 )alkoxy.
  • the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH ; L is a bond; Ri is -CH 2 OR; R is H; R 2 is H or F; R 3 is CI, F, or CN ; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg, and R10 are H; and R 8 is (CrC 6 )alkoxy.
  • the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH 2 OR; R is H; R 2 is H or F; R 3 is CI, F, or CN ; R 4 is H; R 5 is H; R 6 , R 7 , R 9 , and Ri 0 are H; and R 8 is (CrC 6 )alkoxy.
  • the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH 2 OR; R is H; R 2 is H or F; R 3 is CI, F, or CN ; R 4 is H; R 5 is H; R 6 , R 9 , and Ri 0 are H; R 7 is methoxy; and R 8 is (CrC 6 )alkoxy.
  • 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; R 2 is H or halogen; R 3 is (CrC6)alkyl, cyano, or halogen; R 4 is H; R 5 is H; R 6 , R 7 , R9, and R10 are independently H, (CrC 6 )alkoxy, halogen, hydroxy, or hydroxy(C C 6 )alkyl; R 8 is H, (C C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C C 6 )alkyl, (CrC 6 )alkylcarbonyl, carboxy(CrC 6 )alkoxy, halo(CrC 6 )alkyl, hydroxy(CrC 6 )alkoxy, hydroxy(C C 6 )alkyl,
  • 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,
  • membered ring may be optionally substituted with 1 to 3 substituents that are
  • 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; R 2 is H or F; R 3 is methyl, cyano, CI, or F; R 4 is H; R 5 is H; R 6 , R 7 , Rg, and R10 are independently H, (Ci -C6)alkoxy, halogen, hydroxy, or
  • R 8 is H, (C C 6 )alkoxy, (Ci-C 6 )alkoxy(Ci-C 6 )alkyl, (C C 6 )alkyl, (CrC 6 )alkylcarbonyl, carboxy(CrC 6 )alkoxy, halo(CrC 6 )alkyl, hydroxy(CrC 6 )alkoxy, hydroxy(C C 6 )alkyl, -NR M RN(Ci-C 6 )alkoxy, (NR M RN)carbonyl(C C 6 )alkyl, or
  • NR M RN carbonyl(CrC6)alkoxy; wherein the halo(CrC 6 )alkyl is optionally substituted with 1 hydroxy group; and RM and RN are independently H, (CrC 6 )alkyl,
  • membered ring may be optionally substituted with 1 to 3 substituents that are
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 , R 7 , R 9 , and Ri 0 are independently H, (CrC 6 )alkoxy, halogen, hydroxy, or hydroxy(CrC 6 )alkyl; R 8 is H, (CrC 6 )alkoxy, (Ci-C 6 )alkoxy(Ci-C 6 )alkyl, (C C 6 )alkyl, (C C 6 )alkylcarbonyl,
  • NR M RN carbonyl(CrC6)alkoxy; wherein the halo(CrC 6 )alkyl is optionally substituted with 1 hydroxy group; and RM and RN are independently H, (Ci-C6)alkyl, (Ci-C6)alkyl(Ci-C 6 )alkoxy, or (CrC 6 )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
  • 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; R 2 , R 3 , and R 4 are independently H, (C C 6 )alkoxy, (C C 6 )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, (CrC 6 )alkyl, (CrC 6 )alkylcarbonyl, or R G and RH form a ring that is azetidine, pyrrolidine, piperidine, or azepane; R 5 is H; R 6 , R 7 ,
  • 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; R 2 is H or halogen; R 3 is (CrC6)alkyl, cyano, or halogen; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg and R10 are H; R 8 is aryl wherein the aryl is phenyl substituted with 1 substituent that is (CrC 6 )alkoxy or hydroxy.
  • 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; R 2 is H or halogen; R 3 is (CrC6)alkyl, cyano, or halogen; R 4 is H; R 5 is H; R 6 , R 7 , Rg, and R10 are H; R 8 is aryl wherein the aryl is phenyl substituted with 1 substituent that is (CrC 6 )alkoxy or hydroxy.
  • 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; R 2 is H or F; R 3 is methyl, cyano, CI, or F; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg and Ri 0 are H; R 8 is aryl wherein the aryl is phenyl substituted with 1 substituent that is (CrC 6 )alkoxy or hydroxy.
  • 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; R 2 is H or F; R 3 is methyl, cyano, CI, or F; R 4 is H; R 5 is H; R 6 , R 7 , Rg, and R-io are H; R 8 is aryl wherein the aryl is phenyl substituted with 1 substituent that is (CrC 6 )alkoxy or hydroxy.
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg and Rio are H; R 8 is aryl wherein the aryl is phenyl substituted with 1 substituent that is (CrC 6 )alkoxy or hydroxy.
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 , R 7 , R 9 , and Rio are H; R 8 is aryl wherein the aryl is phenyl substituted with 1 substituent that is
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 and R 5 are H; R 6 and R 7 are independently H, F, or methoxy; Rg and Rio are H; R 8 is aryl wherein the aryl is phenyl substituted with 1 substituent that is hydroxy.
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 , R 5 , R 6 , Rz, Rg, and Rio are H; R 8 is aryl wherein the aryl is phenyl substituted with 1 substituent that is hydroxy.
  • the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH 2 OR; R is H; R 2 is H or halogen; R 3 is (CrC 6 )alkyl, cyano, or halogen; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg and Ri 0 are H; R 8 is aryl wherein the aryl is phenyl substituted with 1 substituent that is (CrC 6 )alkoxy or hydroxy.
  • 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; R 2 is H or halogen; R 3 is (CrC6)alkyl, cyano, or halogen; R 4 is H; R 5 is H; R 6 , R7, R9, and R10 are H; R 8 is aryl wherein the aryl is phenyl substituted with 1 substituent that is (CrC 6 )alkoxy or hydroxy.
  • 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; R 2 is H or F; R 3 is methyl, cyano, CI, or F; R 4 is H; R 5 is H; R 6 and R7 are independently H, F, or methoxy; Rg and R10 are H; R 8 is aryl wherein the aryl is phenyl substituted with 1 substituent that is (CrC 6 )alkoxy or hydroxy.
  • 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; R 2 is H or F; R 3 is methyl, cyano, CI, or F; R 4 is H; R 5 is H; R 6 , R7, Rg, and R-io are H; R 8 is aryl wherein the aryl is phenyl substituted with 1 substituent that is (CrC 6 )alkoxy or hydroxy.
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg and R10 are H; R 8 is aryl wherein the aryl is phenyl substituted with 1 substituent that is (CrC 6 )alkoxy or hydroxy.
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 , R 7 , R 9 , and R10 are H; R 8 is aryl wherein the aryl is phenyl substituted with 1 substituent that is
  • 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; R 2 is H or F; R 3 is CI, F, or CN ; R 4 and R 5 are H; R 6 and R 7 are independently H, F, or methoxy; Rg and R10 are H; R 8 is aryl wherein the aryl is phenyl substituted with 1 substituent that is hydroxy.
  • 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; R 2 is H or F; R 3 is CI, F, or CN ; R 4 , R 5 , R 6 , R 7 , R 9 , and Ri 0 are H; R 8 is aryl wherein the aryl is phenyl substituted with 1 substituent that is hydroxy.
  • 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; R 2 is H or halogen; R 3 is (CrC6)alkyl, cyano, or halogen; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg and Ri 0 are H; R 8 is aryl wherein the aryl is phenyl substituted with 1 substituent that is (CrC 6 )alkoxy or hydroxy.
  • 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; R 2 is H or halogen; R 3 is (CrC6)alkyl, cyano, or halogen; R 4 is H; R 5 is H; R 6 , R7, R9, and R-io are H; R 8 is aryl wherein the aryl is phenyl substituted with 1 substituent that is (CrC 6 )alkoxy or hydroxy.
  • 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; R 2 is H or F; R 3 is methyl, cyano, CI, or F; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg and R10 are H; R 8 is aryl wherein the aryl is phenyl substituted with 1 substituent that is (CrC 6 )alkoxy or hydroxy.
  • 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; R 2 is H or F; R 3 is methyl, cyano, CI, or F; R 4 is H; R 5 is H; R 6 , R 7 , Rg, and R10 are H; R 8 is aryl wherein the aryl is phenyl substituted with 1 substituent that is (CrC 6 )alkoxy or hydroxy.
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg and R10 are H; R 8 is aryl wherein the aryl is phenyl substituted with 1 substituent that is (CrC 6 )alkoxy or hydroxy.
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 , R 7 , R 9 , and R10 are H; R 8 is aryl wherein the aryl is phenyl substituted with 1 substituent that is
  • 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 C 6 )alkyl; R 2 , R 3 , and R 4 are independently H, (C C 6 )alkoxy, (CrC 6 )alkyl, (CrC 6 )alkylthio, carboxy, cyano, halogen, halo(CrC 6 )alkoxy,
  • R G and RH are independently H, (CrC 6 )alkyl, (CrC 6 )alkylcarbonyl, or RG and RH form a ring that is azetidine, pyrrolidine, piperidine, or azepane;
  • R5 is H;
  • R 6 , R 7 , R9, and R10 are independently H, (Ci-C6)alkoxy, (CrC6)alkoxycarbonyl, (CrC6)alkyl, (CrC 6 )alkylcarbonyl, (CrC 6 )alkylthio, carboxy, cyano, halogen, halo(CrC 6 )alkoxy, halo(CrC 6 )alkyl, hydroxy, hydroxy(CrC 6
  • (C3-C 7 )heterocycleoxy wherein each is optionally substituted with 1 , 2, or 3 substituents that are independently (CrC 6 )alkoxy, (CrC 6 )alkoxycarbonyl, (CrC 6 )alkoxysulfonyl, (CrC 6 )alkyl, (CrC 6 )alkylcarbonyl, (CrC 6 )alkylsulfonyl, (CrC 6 )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,
  • 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; R 2 is H or halogen; R 3 is (CrC 6 )alkyl, cyano, or halogen; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg and R10 are H; R 8 is
  • (C3-C 7 )heterocycle is azetidinyl, morpholinyl,oxetanyl, piperazinyl, piperidinyl,
  • 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; R 2 is H or halogen; R 3 is (CrC 6 )alkyl, cyano, or halogen; R 4 is H; R 5 is H; R 6 , R7, R9, and R10 are H; R 8 is (C3-C 7 )heterocycle,
  • 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; R 2 is H or F; R 3 is methyl, cyano, CI, or F; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg and Ri 0 are H; R 8 is (C 3 -C 7 )heterocycle, (C 3 -C 7 )heterocycle(Ci-C 6 )alkoxy, (C3-C 7 )heterocyclecarbonyl(Ci-C 6 )alkyl, or
  • 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; R 2 is H or F; R 3 is methyl, cyano, CI, or F; R 4 is H; R 5 is H; R 6 , R 7 , Rg, and Ri 0 are H; R 8 is (C 3 -C 7 )heterocycle, (C 3 -C 7 )heterocycle(Ci-C 6 )alkoxy,
  • (C 3 -C 7 )heterocycle is azetidinyl, morpholinyl,oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran, tetrahydro-2H-pyran, or triazolyl, wherein each is optionally substituted with 1 substituent that is (CrC 6 )alkoxycarbonyl, (CrC 6 )alkyl,
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg and Ri 0 are H; R 8 is (C 3 -C 7 )heterocycle,
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 , R 7 , R 9 , and Ri 0 are H; R 8 is (C 3 -C 7 )heterocycle, (C 3 -C 7 )heterocycle(CrC6)alkoxy, (C 3 -C 7 )heterocyclecarbonyl(Ci -C6)alkyl, or (C 3 -C 7 )heterocycleoxy, wherein the
  • (C3-C 7 )heterocycle is azetidinyl, morpholinyl,oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran, tetrahydro-2H-pyran, or triazolyl, wherein each is optionally substituted with 1 substituent that is (CrC 6 )alkoxycarbonyl, (CrC 6 )alkyl,
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg and R-io are H; R 8 is (C3-C 7 )heterocycle or
  • (C3-C 7 )heterocycle(Ci-C 6 )alkoxy wherein the (C 3 -C 7 )heterocycle is azetidinyl, morpholinyl,oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 , R 7 , R 9 , and Rio are H; R 8 is (C3-C 7 )heterocycle or (C3-C 7 )heterocycle(CrC6)alkoxy, wherein the
  • (C 3 -C 7 )heterocycle is azetidinyl, morpholinyl,oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran, tetrahydro-2H-pyran, or triazolyl, wherein each is optionally substituted with 1 substituent that is (CrC 6 )alkoxycarbonyl, (CrC 6 )alkyl,
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg and Ri 0 are H; R 8 is (C 3 -C 7 )heterocycle wherein the (C 3 -C 7 )heterocycle is azetidinyl, morpholinyl,oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran, tetrahydro-2H-pyran, or triazolyl, wherein each is optionally substituted with 1 substituent that is (CrC 6 )alkoxycarbonyl, (CrC 6 )alkyl,
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg and Ri 0 are H; R 8 is (C 3 -C 7 )heterocycle wherein the (C 3 -C 7 )heterocycle is tetrahydro-2H-pyran.
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 , R 7 , R 8 , and R 9 are H; R 8 is (C 3 -C 7 )heterocycle wherein the (C 3 -C 7 )heterocycle is tetrahydro-2H-pyran.
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 , R 7 , R 9 , and Ri 0 are H; R 8 is (C 3 -C 7 )heterocycle wherein the (C 3 -C 7 )heterocycle is azetidinyl,
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg and Ri 0 are H; R 8 is
  • (C 3 -C 7 )heterocycle(CrC6)alkoxy wherein the (C 3 -C 7 )heterocycle is azetidinyl, morpholinyl,oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 , R 7 , R 9 , and Rio are H; R 8 is (C 3 -C 7 )heterocycle(Ci-C 6 )alkoxy, wherein the (C 3 -C 7 )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)alkylcarbon
  • the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH 2 OR; R is H; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg and Ri 0 are H; R 8 is (C 3 -C 7 )heterocycle wherein the (C 3 -C 7 )heterocycle is azetidinyl, morpholinyl,oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran, tetrahydro-2H-pyran, or triazolyl, wherein each is optionally substituted with 1 substituent that is (CrC 6 )alkoxycarbonyl, (CrC 6 )alkyl, (CrC 6 )alkylcarbony
  • 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; R 2 is H or F; R 3 is CI, F, or CN ; R 4 is H; R 5 is H; R 6 , R 7 , R 9 , and Ri 0 are H; R 8 is (C 3 -C 7 )heterocycle wherein the (C 3 -C 7 )heterocycle is azetidinyl,
  • 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; R 2 is H or F; R 3 is CI, F, or CN ; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg and R10 are H; R 8 is
  • (C 3 -C 7 )heterocycle(Ci-C 6 )alkoxy wherein the (C 3 -C 7 )heterocycle is azetidinyl, morpholinyl,oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,
  • 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; R 2 is H or F; R 3 is CI, F, or CN ; R 4 is H; R 5 is H; R 6 , R 7 , R 9 , and Ri 0 are H; R 8 is (C 3 -C 7 )heterocycle(CrC 6 )alkoxy, wherein the (C 3 -C 7 )heterocycle is azetidinyl, morpholinyl,oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran, tetrahydro-2H-pyran, or triazolyl, wherein each is optionally substituted with 1
  • 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; R 2 is H or halogen; R 3 is (CrC 6 )alkyl, cyano, or halogen; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg and R10 are H; R 8 is
  • (C 3 -C 7 )heterocycle is azetidinyl, morpholinyl,oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran, tetrahydro-2H-pyran, or triazolyl, wherein each is optionally substituted with 1 substituent that is (CrC 6 )alkoxycarbonyl, (CrC 6 )alkyl, (CrC6)alkylcarbonyl, (CrC6)alkylsulfonyl, hydroxy, hydroxy(CrC6)alkyl, or oxo.
  • 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; R 2 is H or halogen; R 3 is (CrC 6 )alkyl, cyano, or halogen; R 4 is H; R 5 is H; R 6 , R 7 , R9, and R10 are H; R 8 is (C 3 -C 7 )heterocycle,
  • 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; R 2 is H or F; R 3 is methyl, cyano, CI, or F; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg and R10 are H; R 8 is (C 3 -C 7 )heterocycle, (C3-C 7 )heterocycle(CrC6)alkoxy, (C3-C 7 )heterocyclecarbonyl(CrC6)alkyl, or
  • 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; R 2 is H or F; R 3 is methyl, cyano, CI, or F; R 4 is H; R 5 is H; R 6 , R 7 , Rg, and R10 are H; R 8 is (C 3 -C 7 )heterocycle, (C3-C 7 )heterocycle(Ci-C 6 )alkoxy,
  • (C3-C 7 )heterocycle is azetidinyl, morpholinyl,oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran, tetrahydro-2H-pyran, or triazolyl, wherein each is optionally substituted with 1 substituent that is (CrC 6 )alkoxycarbonyl, (CrC 6 )alkyl,
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg and R-io are H; R 8 is (C3-C 7 )heterocycle, (C 3 -C 7 )heterocycle(Ci-C6)alkoxy, (C3-C 7 )heterocyclecarbonyl(Ci-C 6 )alkyl, or (C3-C 7 )heterocycleoxy, wherein the (C3-C 7 )heterocycle is azetidinyl,
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 , R 7 , R 9 , and Rio are H; R 8 is (C 3 -C 7 )heterocycle, (C 3 -C 7 )heterocycle(Ci-C 6 )alkoxy,
  • (C3-C 7 )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,
  • 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 -CH 2 OR; R is H or (C C 6 )alkyl; R 2 , R 3 , and R 4 are independently H, (CrC 6 )alkoxy, (CrC 6 )alkyl, (CrC 6 )alkylthio, carboxy, cyano, halogen,
  • R G and RH are independently H, (CrC 6 )alkyl, (CrC 6 )alkylcarbonyl, or R G and RH form a ring that is azetidine, pyrrolidine, piperidine, or azepane;
  • R5 is H;
  • R 6 , R7, R9, and R10 are independently H, (Ci-C6)alkoxy,
  • R 8 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 (CrC 6 )alkoxy, (CrC 6 )alkoxycarbonyl,
  • RM and RN are independently H, (Ci-C6)alkyl, (Ci-C6)alkyl(Ci-C 6 )alkoxy, or (CrC 6 )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 (CrC 6 )alkoxy, (CrC 6 )alkyl, halogen, or hydroxy.
  • 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; R 2 is H or halogen; R 3 is (CrC 6 )alkyl, cyano, or halogen; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg and Ri 0 are H; R 8 is
  • 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; R 2 is H or halogen; R 3 is (CrC 6 )alkyl, cyano, or halogen; R 4 is H; R 5 is H; R 6 , R 7 , Rg, and Ri 0 are H; R 8 is heteroaryl (CrC 6 )alkoxy wherein the heteroaryl is pyridinyl.
  • 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; R 2 is H or F; R 3 is methyl, cyano, CI, or F; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg and Ri 0 are H; R 8 is heteroaryl(CrC 6 )alkoxy wherein the heteroaryl is pyridinyl.
  • 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; R 2 is H or F; R 3 is methyl, cyano, CI, or F; R 4 is H; R 5 is H; R 6 , R 7 , Rg, and Ri 0 are H; R 8 is heteroaryl(CrC 6 )alkoxy wherein the heteroaryl is pyridinyl.
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg and Ri 0 are H; R 8 is heteroaryl(CrC 6 )alkoxy wherein the heteroaryl is pyridinyl.
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 , R 7 , R 9 , and Ri 0 are H; R 8 is heteroaryl(CrC 6 )alkoxy wherein the heteroaryl is pyridinyl.
  • the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH 2 OR; R is H; R 2 is H or halogen; R 3 is (CrC 6 )alkyl, cyano, or halogen; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg and Ri 0 are H; R 8 is
  • 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; R 2 is H or halogen; R 3 is (CrC6)alkyl, cyano, or halogen; R 4 is H; R 5 is H; R 6 , R7, R9, and R10 are H; R 8 is heteroaryl(CrC 6 )alkoxy wherein the heteroaryl is pyridinyl.
  • 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; R 2 is H or F; R 3 is methyl, cyano, CI, or F; R 4 is H; R 5 is H; R 6 and R7 are independently H, F, or methoxy; Rg and R10 are H; R 8 is heteroaryl(Ci-C6)alkoxy wherein the heteroaryl is pyridinyl.
  • 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; R 2 is H or F; R 3 is methyl, cyano, CI, or F; R 4 is H; R 5 is H; R 6 , R7, Rg, and R-io are H; R 8 is heteroaryl(Ci-C6)alkoxy wherein the heteroaryl is pyridinyl.
  • Formula (III) is CH
  • L is a bond
  • Ri is -CH2OR
  • R is H
  • R 2 is H or F
  • R 3 is methyl, cyano, CI, or F
  • R 4 is H
  • R 5 is H
  • R 6 , R7, Rg, and R-io are H
  • R 8 is heteroaryl(Ci-C6)alkoxy wherein the heteroaryl is pyridinyl.
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg and R-io are H; R 8 is heteroaryl(Ci-C6)alkoxy wherein the heteroaryl is pyridinyl.
  • Formula (III) is CH
  • L is a bond
  • Ri is -CH2OR
  • R is H
  • R 2 is H or F
  • R 3 is CI, F, or CN
  • R 4 is H
  • R 5 is H
  • R 6 and R 7 are independently H, F, or methoxy
  • Rg and R-io are H
  • R 8 is heteroaryl(Ci-C6)alkoxy wherein the heteroaryl is pyridinyl.
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 , R 7 , R 9 , and Ri 0 are H; R 8 is heteroaryl(Ci -C6)alkoxy wherein the heteroaryl is pyridinyl.
  • 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; R 2 is H or halogen; R 3 is (CrC 6 )alkyl, cyano, or halogen; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg and R10 are H; R 8 is
  • 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; R 2 is H or halogen; R 3 is (CrC6)alkyl, cyano, or halogen; R 4 is H; R 5 is H; R 6 , R7, Rg, and R10 are H; R 8 is heteroaryl (Ci-C6)alkoxy wherein the heteroaryl is pyridinyl.
  • 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; R 2 is H or F; R 3 is methyl, cyano, CI, or F; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg and R-10 are H; R 8 is heteroaryl(Ci-C6)alkoxy wherein the heteroaryl is pyridinyl.
  • 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; R 2 is H or F; R 3 is methyl, cyano, CI, or F; R 4 is H; R 5 is H; R 6 , R 7 , Rg, and R10 are H; R 8 is heteroaryl(CrC 6 )alkoxy wherein the heteroaryl is pyridinyl.
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg and R10 are H; R 8 is heteroaryl(CrC 6 )alkoxy wherein the heteroaryl is pyridinyl.
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 , R 7 , R 9 , and Ri 0 are H; R 8 is heteroaryl(CrC 6 )alkoxy wherein the heteroaryl is pyridinyl.
  • 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 -CH 2 OR; R is H or (C C 6 )alkyl; R 2 , R 3 , and R 4 are independently H, (CrC 6 )alkoxy, (CrC 6 )alkyl, (CrC 6 )alkylthio, carboxy, cyano, halogen,
  • R G and RH are independently H, (CrC 6 )alkyl,
  • (CrC6)alkylcarbonyl, or RQ and RH form a ring that is azetidine, pyrrolidine, piperidine, or azepane;
  • R5 is H;
  • R 6 , R7, Rg, and R-io are independently H, (Ci-C6)alkoxy,
  • R 8 is (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(CrC 6 )alkoxy,
  • 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; R 2 is H or halogen; R 3 is (CrC 6 )alkyl, cyano, or halogen; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg and Ri 0 are H; R 8 is
  • 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; R 2 is H or halogen; R 3 is (CrC 6 )alkyl, cyano, or halogen; R 4 is H; R 5 is H; R 6 , Rg, and R-io are H; R 7 is H or methoxy; R 8 is (C 3 -C 8 )cycloalkyl or
  • (C 3 -C 8 )cycloalkyloxy wherein the (C 3 -C 8 )cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionally substituted with 1 substituent that is carboxy, hydroxy, hydroxy(CrC 6 )alkyl, or (NR M RNi)carbonyl; and RM and RN are H.
  • 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; R 2 is H or F; R 3 is methyl, cyano, CI, or F; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg and Ri 0 are H; R 8 is (C 3 -C 8 )cycloalkyl or (C 3 -C 8 )cycloalkyloxy wherein the (C 3 -C 8 )cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionally substituted with 1 substituent that is carboxy, hydroxy, hydroxy(CrC 6 )alkyl, or (NR M RNi)carbonyl; and RM and RN are H.
  • 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; R 2 is H or F; R 3 is methyl, cyano, CI, or F; R 4 is H; R 5 is H; R 6 , R 9 , and R-io are H; R 7 is H or methoxy; R 8 is (C 3 -C 8 )cycloalkyl or (C 3 -C 8 )cycloalkyloxy wherein the (C 3 -C 8 )cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionally substituted with 1 substituent that is carboxy, hydroxy, hydroxy(CrC 6 )alkyl, or (NR M RN)carbonyl; and RM and RN are H.
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg and R-io are H; R 8 is (C 3 -C 8 )cycloalkyl or (C 3 -C 8 )cycloalkyloxy wherein the (C 3 -C 8 )cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionally substituted with 1 substituent that is carboxy, hydroxy, hydroxy(CrC 6 )alkyl, or (NR M RN)carbonyl; and RM and RN are H.
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 , R 9 , and Ri 0 are H; R 7 is H or methoxy; R 8 is (C 3 -C 8 )cycloalkyl or (C 3 -C 8 )cycloalkyloxy wherein the (C 3 -C 8 )cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionally substituted with 1 substituent that is carboxy, hydroxy, hydroxy(CrC 6 )alkyl, or (NR M RN)carbonyl; and RM and RN are H.
  • 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; R 2 is H or methoxy; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg and R-io are H; R 8 is (C 3 -C 8 )cycloalkyl wherein the (C 3 -C 8 )cycloalkyl is cyclopropyl or cyclobutyl substituted with hydroxy(CrC 6 )alkyl.
  • 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; R 2 is H or methoxy; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 , R 9 , and R-io are H; R 7 is H or methoxy; R 8 is (C 3 -C 8 )cycloalkyl wherein the (C 3 -C 8 )cycloalkyl is cyclopropyl or cyclobutyl substituted with hydroxy(CrC 6 )alkyl.
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg and R-io are H; R 8 is (C 3 -C 8 )cycloalkyl wherein the (C 3 -C 8 )cycloalkyl is cyclobutyl substituted with hydroxy.
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 , R 9 , and Rio are H; R 7 is H or methoxy; R 8 is (C 3 -C 8 )cycloalkyl wherein the (C 3 -C 8 )cycloalkyl is cyclobutyl substituted with hydroxy.
  • the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH ; L is a bond; Ri is -CH 2 OR; R is H; R 2 is H or halogen; R 3 is (CrC 6 )alkyl, cyano, or halogen; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg and Ri 0 are H; R 8 is
  • the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH 2 OR; R is H; R 2 is H or halogen; R 3 is (CrC 6 )alkyl, cyano, or halogen; R 4 is H; R 5 is H; R 6 , Rg, and Ri 0 are H; R 7 is H or methoxy; R 8 is (C 3 -C 8 )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(CrC 6 )alkyl, or (NR M R N )carbonyl; and RM and RN are H.
  • the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH 2 OR; R is H; R 2 is H or F; R 3 is methyl, cyano, CI, or F; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg and Rio are H; R 8 is (C 3 -C8)cycloalkyl or (C 3 -C 8 )cycloalkyloxy wherein the (C 3 -C 8 )cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionally substituted with 1 substituent that is carboxy, hydroxy, hydroxy(CrC 6 )alkyl, or (NR M RNi)carbonyl; and RM and RN are H.
  • the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH 2 OR; R is H; R 2 is H or F; R 3 is methyl, cyano, CI, or F; R 4 is H; R 5 is H; R 6 , Rg, and R-io are H; R 7 is H or methoxy; R 8 is (C 3 -C 8 )cycloalkyl or (C 3 -C 8 )cycloalkyloxy wherein the (C 3 -C 8 )cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionally substituted with 1 substituent that is carboxy, hydroxy, hydroxy(CrC 6 )alkyl, or (NR M RN)carbonyl; and RM and RN are H.
  • the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH 2 OR; R is H; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg and R-io are H; R 8 is (C 3 -C 8 )cycloalkyl or
  • (C 3 -C 8 )cycloalkyloxy wherein the (C 3 -C 8 )cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionally substituted with 1 substituent that is carboxy, hydroxy, hydroxy(CrC 6 )alkyl, or (NR M RN)carbonyl; and RM and RN are H.
  • the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH 2 OR; R is H; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 , R 9 , and Ri 0 are H; R 7 is H or methoxy; R 8 is (C 3 -C 8 )cycloalkyl or (C 3 -C 8 )cycloalkyloxy wherein the (C 3 -C 8 )cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionally substituted with 1 substituent that is carboxy, hydroxy, hydroxy(CrC6)alkyl, or (NR M RN)carbonyl; and RM and RN are H.
  • the present invention provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH ; L is a bond; Ri is -CH 2 OR; R is H; R 2 is H or methoxy; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg and Ri 0 are H; R 8 is (C 3 -C 8 )cycloalkyl wherein the (C3-C8)cycloalkyl is cyclopropyl or cyclobutyl substituted with hydroxy(CrC6)alkyl.
  • 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; R 2 is H or methoxy; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 , R 9 , and R-io are H; R 7 is H or methoxy; Rs is (C3-C8)cycloalkyl wherein the (C3-C8)cycloalkyl is cyclopropyl or cyclobutyl substituted with hydroxy(CrC 6 )alkyl.
  • 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; R 2 is H or F; R 3 is CI, F, or CN ; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg and R-io are H; R 8 is (C3-C8)cycloalkyl wherein the (C3-C8)cycloalkyl is cyclobutyl substituted with hydroxy.
  • 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; R 2 is H or F; R 3 is CI, F, or CN ; R 4 is H; R 5 is H; R 6 , R 9 , and Ri 0 are H; R 7 is H or methoxy; R 8 is (C 3 -C 8 )cycloalkyl wherein the (C 3 -C 8 )cycloalkyl is cyclobutyl substituted with hydroxy.
  • 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; R 2 is H or halogen; R 3 is (CrC 6 )alkyl, cyano, or halogen; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg and R10 are H; R 8 is
  • 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; R 2 is H or halogen; R 3 is (CrC 6 )alkyl, cyano, or halogen; R 4 is H; R 5 is H; R 6 , Rg, and R-io are H; R 7 is H or methoxy; Rs is (C3-C8)cycloalkyl or (C 3 -C 8 )cycloalkyloxy wherein the (C 3 -C 8 )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.
  • 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; R 2 is H or F; R 3 is methyl, cyano, CI, or F; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg and Ri 0 are H; R 8 is (C 3 -C 8 )cycloalkyl or (C 3 -C 8 )cycloalkyloxy wherein the (C 3 -C 8 )cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionally substituted with 1 substituent that is carboxy, hydroxy, hydroxy(CrC 6 )alkyl, or (NR M RN)carbonyl; and RM and RN are H.
  • 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; R 2 is H or F; R 3 is methyl, cyano, CI, or F; R 4 is H; R 5 is H; R 6 , R 9 , and R-io are H; R 7 is H or methoxy; R 8 is (C 3 -C 8 )cycloalkyl or (C 3 -C 8 )cycloalkyloxy wherein the (C 3 -C 8 )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.
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 and R 7 are independently H, F, or methoxy; Rg and Ri 0 are H; R 8 is (C 3 -C 8 )cycloalkyl or
  • (C 3 -C 8 )cycloalkyloxy wherein the (C 3 -C 8 )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.
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 , R 9 , and Rio are H; R 7 is H or methoxy; R 8 is (C 3 -C 8 )cycloalkyl or (C 3 -C 8 )cycloalkyloxy wherein the (C 3 -C 8 )cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionally substituted with 1 substituent that is carboxy, hydroxy, hydroxy(CrC 6 )alkyl, or (NRMRN)carbonyl; and RM and RN are H.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the present invention provides compounds of Formula
  • Formula (IV) or a pharmaceutically acceptable salt thereof wherein X is N or CH; L is a bond, O, S, NR A , (CrC 6 )alkylene, (C 2 -C 6 )alkenylene, or (C 2 -C 6 )alkynylene; R is -C(O)OR
  • R is H or (Ci-C6)alkyl
  • R 2 , R3, and R 4 are independently H, (Ci-C6)alkoxy, (CrC 6 )alkyl, (CrC 6 )alkylthio, carboxy, cyano, halogen, halo(CrC 6 )alkoxy,
  • R G and RH are independently H, (CrC 6 )alkyl, (CrC 6 )alkylcarbonyl, or RG and RH form a ring that is azetidine, pyrrolidine, piperidine, or azepane;
  • R 5 is H;
  • R 6 , 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(CrC 6 )alkyl, hydroxy, hydroxy(CrC 6 )alkyl, mercapto, nitro, -NRjR K , or
  • Rj and RK are independently H or (CrC 6 )alkyl;
  • R 8 is H, (CrC 6 )alkoxy, (Ci -C6)alkoxy(Ci -Ce)alkoxy, (Ci -C6)alkoxy(Ci -Ce)alkyl, (Ci -C6)alkoxycarbonyl ,
  • aryl(CrC6)alkyl arylcarbonyl, aryloxy, carboxy, carboxy(CrC6)alkoxy,
  • heteroaryl(CrC6)alkyl heteroarylcarbonyl, heteroaryloxy, (C 3 -C7)heterocycle
  • (C 3 -C 8 )cycloalkyl(Ci-C 6 )alkyl, (C 3 -C 8 )cycloalkylcarbonyl, and (C 3 -C 8 )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(CrC 6 )alkoxy, halo(CrC 6 )alkyl, hydroxy, hydroxy(CrC 6 )alkyl, mercapto, nitro, -N R M RN, or (NR M RN)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,
  • (C 3 -C 7 )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(CrC 6 )alkoxy, halo(CrC 6 )alkyl, hydroxy, hydroxy(CrC 6 )alkyl, mercapto,
  • RM and RN are independently H,
  • 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; R 2 is H or halogen; R 3 is (CrC6)alkyl, cyano, or halogen; R 4 is H; R 5 is H; R 6 , R 7 , and Ri 0 are H; R 8 is (C 3 -C 7 )heterocycle.
  • 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; R 2 is H or F; R 3 is methyl, cyano, CI, or F; R 4 is H; R 5 is H; R 6 , R 7 , and R-io are H; R 8 is (C 3 -C 7 )heterocycle.
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 , R 7 , and Ri 0 are H; R 8 is (C 3 -C 7 )heterocycle.
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 , R 7 , and Ri 0 are H; R 8 is (C 3 -C 7 )heterocycle wherein the (C 3 -C 7 )heterocycle is morpholinyl.
  • the present invention provides compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH 2 OR; R is H; R 2 is H or halogen; R 3 is (CrC 6 )alkyl, cyano, or halogen; R 4 is H; R 5 is H; R 6 , R7, and R-io are H; R 8 is (C 3 -C 7 )heterocycle.
  • 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; R 2 is H or F; R 3 is methyl, cyano, CI, or F; R 4 is H; R 5 is H; R 6 , R7, and R-io are H; R 8 is (C 3 -C 7 )heterocycle.
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 , R 7 , and Ri 0 are H; R 8 is (C3-C 7 )heterocycle.
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 , R 7 , and Ri 0 are H; R 8 is (C3-C 7 )heterocycle wherein the (C3-C 7 )heterocycle is morpholinyl.
  • 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; R 2 is H or halogen; R 3 is (CrC 6 )alkyl, cyano, or halogen; R 4 is H; R 5 is H; R 6 , R 7 , and R10 are H; R 8 is (C 3 -C 7 )heterocycle.
  • 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; R 2 is H or F; R 3 is methyl, cyano, CI, or F; R 4 is H; R 5 is H; R 6 , R 7 , and R-io are H; R 8 is (C 3 -C 7 )heterocycle.
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 , R 7 , and R10 are H; R 8 is (C3-C 7 )heterocycle.
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 is H; R 5 is H; R 6 , R 7 , and R10 are H; R 8 is (C3-C 7 )heterocycle wherein the (C3-C 7 )heterocycle is morpholinyl.
  • 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; R 2 is H or halogen; R 3 is (CrC6)alkyl, cyano, or halogen; R 4 is H; R 5 is H; R 6 and R 7 are H ; Ri 0 is (Ci-C6)alkoxy; R 8 is (C3-C 7 )heterocycle.
  • 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; R 2 is H or halogen; R 3 is (CrC6)alkyl, cyano, or halogen; R 4 is H; R 5 is H; R 6 and R 7 are H ; R 0 is H or (CrC 6 )alkoxy; R 8 is (C 3 -C 7 )heterocycle wherein the (C3-C 7 )heterocycle is pyrrolidinyl optionally substituted with (Ci-C6)alkoxy or hydroxy.
  • 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; R 2 is H or halogen; R 3 is (CrC 6 )alkyl, cyano, or halogen; R 4 is H; R 5 is H; R 6 and R 7 are H ; R 0 is H or (CrC 6 )alkoxy; R 8 is (C 3 -C 7 )heterocycle wherein the (C 3 -C 7 )heterocycle is morpholinyl or pyrrolidinyl where the pyrrolidinyl is optionally substituted with (Ci-C6)alkoxy or hydroxy.
  • the present invention provides compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH 2 OR; R is H; R 2 is H or halogen; R 3 is (CrC 6 )alkyl, cyano, or halogen; R 4 is H; R 5 is H; R 6 and R 7 are H ; Ri 0 is (Ci-C6)alkoxy; R 3 is (C 3 -C 7 )heterocycle.
  • 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; R 2 is H or halogen; R 3 is (CrC 6 )alkyl, cyano, or halogen; R 4 is H; R 5 is H; R 6 and R 7 are H ; R 0 is H or (CrC 6 )alkoxy; R 8 is (C 3 -C 7 )heterocycle wherein the (C 3 -C 7 )heterocycle is pyrrolidinyl optionally substituted with (Ci-C6)alkoxy or hydroxy.
  • 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; R 2 is H or halogen; R 3 is (CrC 6 )alkyl, cyano, or halogen; R 4 is H; R 5 is H; R 6 and R 7 are H ; R 0 is H or (CrC 6 )alkoxy; R 8 is (C 3 -C 7 )heterocycle wherein the (C 3 -C 7 )heterocycle is morpholinyl or pyrrolidinyl where the pyrrolidinyl is optionally substituted with (Ci-C6)alkoxy or hydroxy.
  • 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; R 2 is H or halogen; R 3 is (CrC 6 )alkyl, cyano, or halogen; R 4 , R 5 , R 6 , and R 7 are H; R 8 is -N RMRN; RM and RN are independently H or (Ci-C6)alkyl; and R10 is (CrC 6 )alkoxy.
  • 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; R 2 is H or F; R 3 is methyl, cyano, CI, or F; R 4 , R 5 , R 6 , and R 7 are H; R 8 is -N RMRN; RM and RN are independently (CrC6)alkyl; and R-io is (Ci-C6)alkoxy.
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 , R 5 , R 6 , and R 7 are H; R 8 is -N RMRN; RM and RN are each methyl; and R-io is methoxy.
  • the present invention provides compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein X is CH; L is a bond; Ri is -CH 2 OR; R is H; R 2 is H or halogen; R 3 is (CrC 6 )alkyl, cyano, or halogen; R 4 , R 5 , R 6 , and R 7 are H; R 8 is -N R M RN; RM and RN are independently H or (CrC 6 )alkyl; and Ri 0 is (C C 6 )alkoxy.
  • 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; R 2 is H or F; R 3 is methyl, cyano, CI, or F; R 4 , R 5 , R 6 , and R 7 are H; R 8 is -N R M RN; RM and RN are independently (CrC 6 )alkyl; and R10 is (CrC 6 )alkoxy.
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 , R 5 , R 6 , and R 7 are H; R 8 is -N R M RN; RM and RN are each methyl; and R10 is methoxy.
  • 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; R 2 is H or halogen; R 3 is (CrC6)alkyl, cyano, or halogen; R 4 , R 5 , R 6 , and R 7 are H; R 8 is -N R M RN; RM and RN are independently H or (CrC 6 )alkyl; and R10 is (C C 6 )alkoxy.
  • 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; R 2 is H or F; R 3 is methyl, cyano, CI, or F; R 4 , R 5 , R 6 , and R 7 are H; R 8 is -N RMRN; RM and RN are independently (CrC6)alkyl; and R-io is (Ci-C6)alkoxy.
  • 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; R 2 is H or F; R 3 is CI, F, or CN; R 4 , R 5 , R 6 , and R 7 are H; R 8 is -N RMRN; RM and RN are each methyl; and R-io is methoxy.
  • the present invention provides a pharmaceutical composition
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • (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.
  • alkenylene include, but are not limited
  • (CrC 6 )alkoxy means a (CrC 6 )alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • (CrC 6 )alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.
  • (Ci -C6)alkoxy(Ci-C 6 )alkoxy means a (CrC 6 )alkoxy group, as defined herein, appended to the parent molecular moiety through another (Ci -C6)alkoxy group, as defined herein.
  • (Ci -C6)alkoxy(Ci -C 6 )alkoxy include, but are not limited to, tert-butoxymethoxy, 2- ethoxyethoxy, 2-methoxyethoxy, and methoxymethoxy.
  • (Ci -C6)alkoxy(Ci-C 6 )alkyl as used herein, means a (CrC 6 )alkoxy group, as defined herein, appended to the parent molecular moiety through a
  • (Ci -C6)alkoxy(CrC6)alkyl include, but are not limited to, tert-butoxymethyl, 2- ethoxyethyl, 2-methoxyethyl, and methoxymethyl.
  • (CrC 6 )alkoxycarbonyl as used herein, means a (CrC 6 )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.
  • (CrC 6 )alkoxysulfonyl as used herein, means a (CrC 6 )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.
  • (C C 6 )alkyl as used herein, means a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms.
  • Representative examples of (CrC 6 )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.
  • (CrC6)alkylcarbonyl 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 C 6 )alkylcarbonyl include, but are not limited to, acetyl, 1 -oxopropyl, 2,2-dimethyl-1 -oxopropyl, 1 -oxobutyl, and 1 -oxopentyl.
  • (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 C 8 )alkylene include, but are not limited to, -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 - , -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH(CH3)CH 2 -, and -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -.
  • (CrC6)alkylsulfonyl 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 (CrC 6 )alkylsulfonyl include, but are not limited to, methylsulfonyl and ethylsulfonyl.
  • (CrC 6 )alkylthio as used herein, means a (CrC 6 )alkyl group, as defined herein, appended to the parent molecular moiety through a sulfur atom.
  • (CrC6)alkylthio include, but are not limited to, methylthio, ethylthio, tert-butylthio, and hexylthio.
  • aryl as used herein, means a phenyl or naphthyl group.
  • aryl(CrC 6 )alkoxy as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an (CrC 6 )alkoxy group, as defined herein.
  • aryl(CrC6)alkyl as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an (CrC 6 )alkyl group, as defined herein.
  • Representative examples of aryl(CrC 6 )alkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and 2-naphth-2-ylethyl.
  • arylcarbonyl as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • arylcarbonyl examples are benzoyl and naphthoyl.
  • 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.
  • carbonyl as used herein, means a -C(O)- group.
  • carboxy(CrC 6 )alkoxy means a carboxy group, as defined herein, is attached to the parent molecular moiety through a (CrC 6 )alkoxy group, as defined herein.
  • carboxy(CrC6)alkyl as used herein, means a carboxy group, as defined herein, is attached to the parent molecular moiety through a (CrC 6 )alkyl group, as defined herein.
  • cyano as used herein, means a -CN group.
  • (C3-C8)cycloalkyl as used herein, means a saturated cyclic
  • hydrocarbon group containing from 3 to 8 carbons examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • (C3-C8)cycloalkyl(CrC6)alkoxy means a
  • (C 3 -C 8 )cycloalkyl(Ci -C6)alkyl means a
  • (C3-C6)cycloalkyl group as defined herein, appended to the parent molecular moiety through a (CrC 6 )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.
  • (C 3 -C 8 )cycloalkylcarbonyl means (C 3 -C 8 )cycloalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of (C 3 -C 8 )cycloalkylcarbonyl include, but are not limited to, cyclopropylcarbonyl, 2-cyclobutylcarbonyl, and
  • (C3-C8)cycloalkyloxy means (C3-C8)cycloalkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom, as defined herein.
  • Representative examples of (C 3 -C 8 )cycloalkyloxy include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy.
  • Form (l-IV) as used herein means compounds of Formula (I), (II), (II I), and (IV).
  • halo or halogen as used herein, means -CI, -Br, -I or -F.
  • halo(CrC6)alkoxy 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(CrC 6 )alkoxy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.
  • halo(CrC 6 )alkyl means at least one halogen, as defined herein, appended to the parent molecular moiety through a (CrC 6 )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.
  • heteroaryl 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.
  • 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.
  • bicyclic heteroaryl include, but are not limited to, benzimidazolyl, benzofuranyl, benzothienyl, benzoxadiazolyl, cinnolinyl, dihydroquinolinyl, dihydroisoquinolinyl, furopyridinyl, indazolyl, indolyl, isoquinolinyl, naphthyridinyl, quinolinyl, tetrahydroquinolinyl, and thienopyridinyl.
  • heteroaryl(CrC 6 )alkoxy means a heteroaryl group, as defined herein, appended to the parent molecular moiety through an (CrC 6 )alkoxy group, as defined herein.
  • heteroaryl(CrC 6 )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,
  • heteroaryl(CrC 6 )alkyl as used herein, means a heteroaryl, as defined herein, appended to the parent molecular moiety through an (CrC 6 )alkyl group, as defined herein.
  • Representative examples of heteroaryl(CrC 6 )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,
  • heteroarylcarbonyl 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,
  • heteroaryloxy means a heteroaryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • 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.
  • (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.
  • 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, pyrrolin
  • (C3-C7)heterocycle(CrC6)alkoxy means a 3-7 membered heterocycle group, as defined herein, appended to the parent molecular moiety through an (CrC 6 )alkoxy group, as defined herein.
  • (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 (CrC 6 )alkyl group, as defined herein.
  • heterocyclecarbonyl means a 3-7 membered heterocycle, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • hydroxy(CrC 6 )alkoxy means at least one hydroxy group, as defined herein, is appended to the parent molecular moiety through a
  • hydroxy(CrC 6 )alkoxy include, but are not limited to, hydroxymethoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 2,3-dihydroxypentoxy, and 2-ethyl-4-hydroxyheptoxy.
  • hydroxy(CrC 6 )alkyl as used herein, means at least one hydroxy group, as defined herein, is appended to the parent molecular moiety through a
  • (CrC 6 )alkyl group as defined herein.
  • Representative examples of hydroxy(CrC 6 )alkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl,
  • mercapto as used herein, means a -SH group.
  • nitro as used herein, means a -NO2 group.
  • nitrogen protecting group 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.
  • N R G RH 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, (CrC 6 )alkyl, (CrC 6 )alkylcarbonyl, or R G and RH form a ring.
  • N RQRH include, but are not limited to, amino, methylamino, dimethylamino, ethylmethylamino, acetamido, propionamido, isobutyramido, aziridine, azetidine, pyrrolidine, piperidine, and azepane.
  • (NR G RH)carbonyl means a N R G RH 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
  • N RJ RK 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 (CrC 6 )alkyl.
  • Representative examples of NRjR K include, but are not limited to, amino, methylamino, dimethylamino, and ethylmethylamino.
  • (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
  • N R M RN 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 C 6 )alkoxy, (CrC 6 )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.
  • N RMRN(C C6)alkoxy means a N RMRN group, as defined herein, appended to the parent molecular moiety through a (CrC 6 )alkoxy group, as defined herein.
  • N RMRN(C C6)alkyl means a N RMRN group, as defined herein, appended to the parent molecular moiety through a (CrC6)alkyl group, as defined herein.
  • (N R M RN)carbonyl means a N R M RN group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of ( N R M RN)carbonyl include, but are not limited to, aminocarbonyl, (methylamino)carbonyl, (dimethylamino)carbonyl, and
  • (NR M RN)carbonyl(CrC6)alkoxy means a
  • NR M RN carbonyl group, as defined herein, appended to the parent molecular moiety through a (Ci-C6)alkoxy group, as defined herein.
  • (NR M R N )carbonyl(CrC6)alkyl means a
  • tautomer 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.
  • terapéuticaally 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.
  • the compounds of the present invention can be used in the form of
  • salts 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 undecano
  • 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.
  • 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
  • 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.
  • Stereoisomers 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.
  • R and S used herein are configurations as defined in lUPAC 1974
  • 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.
  • 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
  • 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.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur and fluorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 35 S, 36 CI, 125 l, 129 l, and 18 F respectively.
  • isotopically-labeled compounds of the present invention for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated (i.e., 3 H), and carbon-14 (i.e., 14 C), isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H), 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.
  • GRAS solvents recognized by persons skilled in the art as safe
  • 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
  • the formulations may be prepared using conventional dissolution and mixing procedures.
  • 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)
  • 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.
  • 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.
  • compositions also include solvates and hydrates of the compounds of the present invention.
  • 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.
  • 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
  • hydrate refers to the complex where the solvent molecule is water.
  • the solvates and/or hydrates preferably exist in crystalline form.
  • 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.
  • 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.
  • 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
  • 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/m 2 ).
  • Overweight is typically defined as a BMI of 25-29.9 kg/m 2
  • obesity is typically defined as a BMI of 30 kg/m 2 . 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.
  • 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.
  • 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.
  • diabetes e.g., Type 2 diabetes
  • 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).
  • 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.
  • CRP C-reactive protein
  • the administration of compounds of the present invention may also provide a statistically significant (p ⁇ 0.05) reduction in glucose serum levels.
  • NASH nonalcoholic fatty liver disease
  • hepatic insulin resistance 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.
  • parenterally refers to modes of administration which include intravenous, intramuscular,
  • intraperitoneal, intrasternal, subcutaneous, intraarticular injection and infusion are intraperitoneal, intrasternal, subcutaneous, intraarticular injection and infusion.
  • 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.
  • 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
  • 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.
  • delayed absorption of a parenterally administered drug form is
  • 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.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar- agar, tragacanth, and mixtures thereof.
  • 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.
  • 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.
  • 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
  • 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 ⁇ 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, ⁇ / ⁇ adrenergic blockers, alpha 1 blockers, alpha 2 agonists, aldosterone inhibitors, mineraocorticoid receptor inhibitors, renin inhibitors and angiopoietin-2-binding agents.
  • ACE angiotensin converting enzyme
  • 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, gliquid
  • 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.
  • TGR5 also termed GPBAR1
  • GPBAR1 GPBAR1 receptor modulators
  • 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
  • anti-diabetic agents include metformin and DPP-IV inhibitors (e.g., sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin and saxagliptin).
  • 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
  • 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 include 1 1 ⁇ -hydroxy steroid dehydrogenase-1 (1 ⁇ ⁇ -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, ⁇ 3 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.
  • 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 AxokineTM 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, J
  • antagonist/inverse agonists 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.
  • CCKa agonists e.g., N-benzyl-2-[4-(1 H-indol-3-ylmethyl)-5-oxo-1 -phenyl-4,5-dihydro-2,3,6,10b-
  • PYY 3- 3 6 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.
  • compounds of the present invention and combination therapies are administered in conjunction with exercise and a sensible diet.
  • n-BuLi for n-butyllithium
  • DMAP for 4-dimethylaminopyridine
  • DME dimethoxyethane
  • DMF for ⁇ , ⁇ -dimethylformamide
  • EtOAc for ethyl acetate
  • LAH for lithium aluminum hydride
  • MeOH for methanol
  • TFA trifluoroacetic acid
  • 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)).
  • 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.
  • intermediates for preparing compounds of the present invention.
  • synthetic routes may be used to synthesize the inventive compounds.
  • 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.
  • 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.
  • Suitable amino- protecting groups include acetyl, trifluoroacetyl, f-butoxycarbonyl (BOC), benzyloxycarbonyl (Cbz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc).
  • a "hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality.
  • Suitable hydroxyl-protecting groups 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,
  • 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
  • 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 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.
  • 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 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.
  • CAL-B 250 uL, solution, Lypozyme CAL-B, LCN02102, Novozyme.
  • 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
  • CAL-B 0.5 mL, solution, Lypozyme CAL-B, LCN02102, Novozyme
  • 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
  • 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 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.
  • 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.
  • AMPK tricistronic AMPK expression construct that included open reading frames encoding the full-length ⁇ , ⁇ ⁇ 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 - CodonPlusTM (DE3)-RIPL strain (Stratagene) and transformants were selected on LB (Luria-Bertani) agar plates containing ampicillin (100 ⁇ g/ml).
  • the temperature was reduced to 18 Q C and the culture was induced at 18 Q C with 0.1 mM Isopropylthiogalactoside (IPTG).
  • IPTG Isopropylthiogalactoside
  • the cell paste was collected at -18 hours post induction by refrigerated continuous flow centrifugation (Heraeus, rotor #8575) at 15,000 rpm at 4 Q C.
  • the cell pellets were aliquoted into four portions, flash frozen in liquid nitrogen and were stored at -80 Q C until 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
  • 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.
  • the biochemical EC 50 (half-maximal concentration required for full activation) of compounds for the activation of AMPK was evaluated by 33 P-based assay using SAMS peptide (commercially available) derived from ACC-1 .
  • SAMS peptide commercially available
  • n represents the number of times a particular assay was conducted and AMPK 1 1 1 means the AMPK 1 1 1 isoform.
  • Conditionally immortalized human podocytes are seeded at a density of 10 4 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.
  • 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.
  • apoptotic cell death is assessed using Cell Death ELISA (Roche, Inc) according to the manufacturer's instructions.
  • podocytes are lysed in lysis buffer provided in the kit, followed by centrifugation for 10 min at 200 X G. 20 ⁇ 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.
  • Cell Lysis Buffer Cell Signaling Technology

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Abstract

La présente invention concerne des composés indoliques et indazoliques de formule (I) Formule (I) qui activent la protéine kinase activée par le 5'-adénosine monophosphate (AMPK). L'invention concerne également des compositions pharmaceutiques contenant ces composés ainsi que des procédés de traitement ou de prévention de maladies, d'affections ou de troubles améliorés par l'activation de l'AMPK.
PCT/IB2015/059222 2014-12-10 2015-11-30 Composés indoliques et indazoliques qui activent l'ampk WO2016092413A1 (fr)

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