HETEROCYCLIC MODULATORS OF TGR5 FOR TREATMENT OF DISEASE

Disclosed herein are new heterocyclic compounds, compositions and their application as a pharmaceutical for the treatment of disease. Methods of modulation of TGR5 activity in a human or animal subject are also provided for the treatment of diseases mediated by TGR5.

Obesity is a growing threat to the global health by virtue of its association with a cluster of diseases that include insulin resistance, glucose intolerance, dyslipidemia, and hypertension, collectively known as the metabolic syndrome or syndrome X. It is well documented that patients with metabolic syndrome have a higher risk for coronary heart disease and stroke [Grundy S. M. et al. Circulation 112:e285-e290, 2005]. The treatment of obesity will require complex solutions, including increased public awareness to diminish food portions, improved food choices and increased physical activity. However, epidemiologic studies have shown that treating diabetes/insulin resistance in these patients can reduce the risk of coronary artery disease. Marketed drugs to treat diabetes and insulin resistance include biguanides (such as metformin), peroxisome proliferator activated receptor gamma (PPARγ) agonists (such as rosiglitazone and pioglitazone), sulphonylureas, and most recently GLP-1 mimetics such as Exenatide (Byetta). However, there remains a need for additional agents that can perhaps treat the root cause(s) of metabolic syndrome by treating obesity and diabetes. TGR5 modulators described herein might represent such an opportunity.

Bile acids (BA) are amphipathic molecules which are synthesized in the liver from cholesterol and stored in the gall bladder until secretion to the duodenum and intestine to play an important role in the solubilization and absorption of dietary fat and lipid-soluble vitamins. Approx. 99% of BA are absorbed again by passive diffusion and active transport in the terminal ileum and transported back to the liver via the portal vein (enterohepatic circulation). In the liver, BA decrease their own biosynthesis from cholesterol through the activation of the farnesoid X receptor alpha (FXRα) and small heterodimer partner (SHP), leading to the transcriptional repression of cholesterol 7α-hydroxylase, the rate-limiting step of BA biosynthesis from cholesterol.

Recently, two groups independently discovered the GPCR, TGR5 (aka M-BAR) which responds to bile acids [Kawamata Y. et al, J. Biol. Chem., 278:9435-9440, 2003; Maruyama T. et al. Biochem. Biophs. Res. Commun. 298, 714-719, 2002]. TGR5 is a seven transmembrane Gs-coupled GPCR and stimulation by ligand binding causes activation of adenylyl cyclase which leads to the elevation of intracellular cAMP and subsequent activation of downstream signaling pathways. The human receptor shares 86, 90, 82, and 83% amino acid identity to bovine, rabbit, rat, and mouse receptor, respectively. TGR5 is abundantly expressed in the lung, spleen, small intestine, placenta and mononuclear cells (Kawamata Y. et al, J. Biol. Chem., 278:9435-9440, 2003). Bile acids induced receptor internalization, intracellular cAMP production and activation of extracellular signal-regulated kinase in TGR5-expressing HEK293 and CHO cells. In addition, TGR5 was found to be abundantly expressed in monocytes/macrophages from humans and rabbits (Kawamata Y. et al, J. Biol. Chem., 278:9435-9440, 2003), and bile acid treatment suppressed LPS-induced cytokine production in rabbit alveolar macrophages and human THP-1 cells expressing TGR5. These data suggest that bile acids can suppress the macrophage function via activation of TGR5.

Maruyama et al. [Maruyama T. et al. Biochem. Biophs. Res. Commun. 298, 714-719, 2002] showed that TGR5 is expressed in intestinal enteroendocrine cell lines from human (NCI-H716) and murine (STC-1, GLUTag) origin, but not in the intestinal epithelial cells (CaCo-2 and HT-29). Stimulation of TGR5 by BA in NCI-H716 cells stimulated cAMP production. This suggested that bile acids may induce the secretion of glucagon-like peptide-1 (GLP-1) or cholecystokinin (CCK) from the enteroendocrine cells through TGR5 stimulation, since cAMP stimulated the secretion of GLP-1 and CCK from these cells [Reimer R. A. et al. Endocrinology 142, 4522-4528, 2001; Chang C. H. et al. Am. J. Physiol. 271, G516-G523, 1996; Brubaker P. L. et al, Endocrinology 139, 4108-4114, 1998]. This hypothesis was recently confirmed in a publication by Katsuma S. et al. who demonstrated that activation of TGR5 by BA promoted GLP-1 in STC-1 cells [Katsuma S. et al. Biochem. Biophys. Res. Commun. 329, 386-390, 2005]. RNA interference experiments revealed that reduced expression of TGR5 resulted in reduced secretion of GLP-1. GLP-1 has been shown to stimulate insulin release in a glucose dependent manner in humans [Kreymann et al. Lancet 2 (8571) 1300-1304, 1987] and studies in experimental animals demonstrated that this incretin hormone is necessary for normal glucose homeostasis. In addition, GLP-1 can exert several beneficial effects in diabetes and obesity, including 1) increased glucose disposal, 2) suppression in glucose production, 3) reduced gastric emptying, 4) reduction in food intake and 5) weight loss.

Furthermore, recently published data suggested that activation of TGR5 might be beneficial for the treatment of obesity and diabetes. Watanabe et al. (Nature, 439, 484-489, 2006) reported that mice fed high fat diet (HFD) containing 0.5% cholic acid gained less weight than control mice on HFD alone. There was no difference between the two groups in terms of food intake. These effects were independent of FXR-alpha, and instead stem from the binding of bile acids to TGR5 and the subsequent induction of the cAMP-dependent thyroid hormone activating enzyme type 2 (D2) which converts the inactive T3 into the active T4, leading to stimulation of the thyroid hormone receptor and promoting energy expenditure. Mice lacking the D2 gene (D2^−/−) were resistant to cholic acid-induced weight loss. In both rodents and humans, the most thermogenically important tissues (the brown adipose and skeletal muscle) are specifically targeted by this mechanism because they co-express D2 and TGR5. The BA-TGR5-cAMP-D2 signaling pathway is therefore a crucial mechanism for fine-tuning energy homeostasis that can be targeted to improve metabolic control.

Taken together these data indicate that, a small molecule TGR5 modulator could be used for the treatment of obesity, diabetes and a wide range of acute and chronic inflammatory diseases.

Recently, certain substituted heterocyclic compounds have been described as agonists of TGR5 for the treatment of metabolic, cardiovascular, and inflammatory diseases.

Novel compounds and pharmaceutical compositions, certain of which have been found to modulate TGR5 have been discovered, together with methods of synthesizing and using the compounds including methods for the treatment of TGR5-mediated diseases in a patient by administering the compounds.

Provided herein are compounds of structural Formula I, or a salt, ester, or prodrug thereof, wherein,

X is (CR₉R₁₀)_m;

Y is selected from the group consisting of (CR₁₁R₁₂)_n, and (CR₁₃R₁₄)_pO(CR₁₅R₁₆)_q;

m, p, and q are each independently an integer from 0 to 2;

n is an integer from 0 to 3;

R₁is selected from the group consisting of aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, any of which may be optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, alkyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, thioalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, alkenyl, arylalkenyl, heteroarylalkenyl, heterocycloalkylalkenyl, alkynyl, arylalkynyl, heteroarylalkynyl, heterocycloalkylalkynyl, alkoxy, haloalkoxy, perhaloalkoxy, acyloxy, arylalkoxy, aryloxy, heteroaryloxy, acyl, arylalkanoyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, amino, alkylamino, arylamino, C-amido, N-amido, carbamate, urea, N-sulfonamido, S-sulfonamido, alkylsulfonyl, thiol, alkylthio, arylthio, heteroarylthio, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, any of which may be optionally substituted;

R₂is selected from the group consisting of hydrogen, lower alkyl, lower perhaloalkyl, acyl, and alkylsulfonyl, any of which may be optionally substituted;

R₃is selected from the group consisting of hydrogen, amino, alkyl, perhaloalkyl, alkoxy, hydroxy, perhaloalkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aryloxy, heteroaryloxy, cycloalkoxy, heterocycloalkoxy, arylthio, cycloalkylthio, heteroarylthio, heterocycloalkylthio, arylalkyl, cycloalkylalkyl, heteroarylalkyl, and heterocycloalkylalkyl, any of which may be optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, alkyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, thioalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, alkenyl, arylalkenyl, heteroarylalkenyl, heterocycloalkylalkenyl, alkynyl, arylalkynyl, heteroarylalkynyl, heterocycloalkylalkynyl, alkoxy, haloalkoxy, perhaloalkoxy, acyloxy, arylalkoxy, aryloxy, heteroaryloxy, acyl, arylalkanoyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, amino, alkylamino, arylamino, C-amido, N-amido, carbamate, urea, N-sulfonamido, S-sulfonamido, alkylsulfonyl, thiol, alkylthio, arylthio, heteroarylthio, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, any of which may be optionally substituted;

R₄, R₅, R₆, R₇, and R₈are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, alkyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, thioalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, alkenyl, arylalkenyl, heteroarylalkenyl, heterocycloalkylalkenyl, alkynyl, arylalkynyl, heteroarylalkynyl, heterocycloalkylalkynyl, alkoxy, haloalkoxy, perhaloalkoxy, acyloxy, arylalkoxy, aryloxy, heteroaryloxy, acyl, arylalkanoyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, amino, alkylamino, arylamino, C-amido, N-amido, carbamate, urea, N-sulfonamido, S-sulfonamido, alkylsulfonyl, thiol, alkylthio, arylthio, heteroarylthio, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, any of which may be optionally substituted; and

R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, and R₁₆, are independently selected from the group consisting of hydrogen, lower alkyl, lower perhaloalkyl, and halogen, any of which may be optionally substituted, or R₉and R₁₀, R₁₁and R₁₂, R₁₃and R₁₄, or R₁₅and R₁₆, taken together, are oxy or optionally substituted cycloalkyl.

Certain compounds disclosed herein may possess useful TGR5 modulating activity, and may be used in the treatment or prophylaxis of a disease or condition in which TGR5 plays an active role. Thus, in broad aspect, certain embodiments also provide pharmaceutical compositions comprising one or more compounds disclosed herein together with a pharmaceutically acceptable carrier, as well as methods of making and using the compounds and compositions. Certain embodiments provide methods for modulating TGR5. Other embodiments provide methods for treating a TGR5-mediated disorder in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound or composition as disclosed herein. Also provided is the use of certain compounds disclosed herein for use in the manufacture of a medicament for the treatment of a disease or condition ameliorated by the modulation of TGR5 activity.

In certain embodiments provided herein,

X is CH₂;

Y is (CR₁₁R₁₂)_n;

n is an integer from 0 to 2;

R₂is hydrogen; and

R₃is selected from the group consisting of hydrogen, amino, alkyl, perhaloalkyl, alkoxy, hydroxy, perhaloalkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl containing at least one heteroatom selected from the group consisting of oxygen and sulfur, aryloxy, heteroaryloxy, cycloalkoxy, heterocycloalkoxy, arylthio, cycloalkylthio, heteroarylthio, heterocycloalkylthio, arylalkyl, cycloalkylalkyl, heteroarylalkyl, and heterocycloalkylalkyl, any of which may be optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, alkyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, thioalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, alkenyl, arylalkenyl, heteroarylalkenyl, heterocycloalkylalkenyl, alkynyl, arylalkynyl, heteroarylalkynyl, heterocycloalkylalkynyl, alkoxy, haloalkoxy, perhaloalkoxy, acyloxy, arylalkoxy, aryloxy, heteroaryloxy, acyl, arylalkanoyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, amino, alkylamino, arylamino, C-amido, N-amido, carbamate, urea, N-sulfonamido, S-sulfonamido, alkylsulfonyl, thiol, alkylthio, arylthio, heteroarylthio, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl.

In further embodiments provided herein,

Y is CH₂CH₂; and

R₄, R₇, and R₈are hydrogen.

In further embodiments provided herein,

R₁is phenyl, which may be optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, acyloxy, acyl, carboxyl, amino, alkylamino, arylamino, C-amido, N-amido, carbamate, urea, N-sulfonamido, S-sulfonamido, alkylsulfonyl, thiol, and alkylthio;

R₅and R₆are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, acyloxy, acyl, carboxyl, amino, alkylamino, thiol, and alkylthio.

In yet further embodiments provided herein,

R₁is phenyl, which may be optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, acyloxy, acyl, carboxyl, amino, alkylamino, arylamino, C-amido, N-amido, carbamate, urea, N-sulfonamido, S-sulfonamido, alkylsulfonyl, thiol, and alkylthio;

In yet further embodiments provided herein, R₃is thiophen-3-yl.

Provided herein are compounds of structural Formula II, or a salt, ester, or prodrug thereof, wherein,

Y is (CR₁₁R₁₂)_n;

n is an integer from 0 to 2;

R₃is selected from the group consisting of hydrogen, amino, alkyl, perhaloalkyl, alkoxy, hydroxy, perhaloalkoxy, aryl, heteroaryl, heterocycloalkyl containing at least one heteroatom selected from the group consisting of oxygen and sulfur, aryloxy, heteroaryloxy, cycloalkoxy, heterocycloalkoxy, arylthio, cycloalkylthio, heteroarylthio, heterocycloalkylthio, arylalkyl, cycloalkylalkyl, heteroarylalkyl, and heterocycloalkylalkyl, any of which may be optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, alkyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, thioalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, alkenyl, arylalkenyl, heteroarylalkenyl, heterocycloalkylalkenyl, alkynyl, arylalkynyl, heteroarylalkynyl, heterocycloalkylalkynyl, alkoxy, haloalkoxy, perhaloalkoxy, acyloxy, arylalkoxy, aryloxy, heteroaryloxy, acyl, arylalkanoyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, amino, alkylamino, arylamino, C-amido, N-amido, carbamate, urea, N-sulfonamido, S-sulfonamido, alkylsulfonyl, thiol, alkylthio, arylthio, heteroarylthio, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, any of which may be optionally substituted;

R₄, R₆, R₇, and R₈are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, alkyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, thioalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, alkenyl, arylalkenyl, heteroarylalkenyl, heterocycloalkylalkenyl, alkynyl, arylalkynyl, heteroarylalkynyl, heterocycloalkylalkynyl, alkoxy, haloalkoxy, perhaloalkoxy, acyloxy, arylalkoxy, aryloxy, heteroaryloxy, acyl, arylalkanoyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, amino, alkylamino, arylamino, C-amido, N-amido, carbamate, urea, N-sulfonamido, S-sulfonamido, alkylsulfonyl, thiol, alkylthio, arylthio, heteroarylthio, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, any of which may be optionally substituted;

R₅is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, alkyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, thioalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, alkenyl, arylalkenyl, heteroarylalkenyl, heterocycloalkylalkenyl, alkynyl, arylalkynyl, heteroarylalkynyl, heterocycloalkylalkynyl, C₂-C₆alkoxy, haloalkoxy, perhaloalkoxy, acyloxy, arylalkoxy, aryloxy, heteroaryloxy, acyl, arylalkanoyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, amino, alkylamino, arylamino, C-amido, N-amido, carbamate, urea, N-sulfonamido, S-sulfonamido, alkylsulfonyl, thiol, alkylthio, arylthio, heteroarylthio, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, any of which may be optionally substituted; and

R₉, R₁₀, R₁₁and R₁₂are independently selected from the group consisting of hydrogen, lower alkyl, lower perhaloalkyl, and halogen, any of which may be optionally substituted, or R₉and R₁₀, or R₁₁and R₁₂, taken together, are oxy or optionally substituted cycloalkyl.

In certain embodiments provided herein,

Y is CH₂CH₂; and

R₄, R₇, R₈, R₉, and R₁₀are hydrogen.

In further embodiments provided herein,

R₁is phenyl, which may be optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, alkyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, thioalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, alkenyl, arylalkenyl, heteroarylalkenyl, heterocycloalkylalkenyl, alkynyl, arylalkynyl, heteroarylalkynyl, heterocycloalkylalkynyl, alkoxy, haloalkoxy, perhaloalkoxy, acyloxy, arylalkoxy, aryloxy, heteroaryloxy, acyl, arylalkanoyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, amino, alkylamino, arylamino, C-amido, N-amido, carbamate, urea, N-sulfonamido, S-sulfonamido, alkylsulfonyl, thiol, alkylthio, arylthio, heteroarylthio, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; and

R₃is selected from the group consisting of phenyl and thiophenyl, any of which may be optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, alkyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, thioalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, alkenyl, arylalkenyl, heteroarylalkenylheterocycloalkylalkenyl, alkynyl, arylalkynyl, heteroarylalkynyl, heterocycloalkylalkynyl, alkoxy, haloalkoxy, perhaloalkoxy, acyloxy, arylalkoxy, aryloxy, heteroaryloxy, acyl, arylalkanoyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, amino, alkylamino, arylamino, C-amido, N-amido, carbamate, urea, N-sulfonamido, S-sulfonamido, alkylsulfonyl, thiol, alkylthio, arylthio, heteroarylthio, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl.

In further embodiments provided herein,

R₁is phenyl, which may be optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, acyloxy, acyl, carboxyl, amino, alkylamino, thiol, and alkylthio, any of which may be optionally substituted;

R₅is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, alkyl, haloalkyl, perhaloalkyl, C₂-C₆alkoxy, haloalkoxy, perhaloalkoxy, acyloxy, acyl, carboxyl, amino, alkylamino, thiol, and alkylthio; and

R₆is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, acyloxy, acyl, carboxyl, amino, alkylamino, thiol, and alkylthio.

In yet further embodiments provided herein,

R₁is phenyl, which may be optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, and perhaloalkyl; and

R₃is thiophenyl.

In yet further embodiments provided herein, R₃is thiophen-3-yl.

In yet further embodiments provided herein,

R₅is selected from the group consisting of hydrogen, hydroxy, and C₂-C₆alkoxy; and

R₆is selected from the group consisting of hydrogen, hydroxy, and alkoxy.

Provided herein are compounds of structural Formula II, or a salt, ester, or prodrug thereof, wherein,

Y is (CR₁₁R₁₂)_n;

n is an integer from 0 to 2;

R₃is selected from the group consisting of hydrogen, amino, alkyl, perhaloalkyl, alkoxy, hydroxy, perhaloalkoxy, aryl, bicyclic heteroaryl, 6-membered monocyclic heteroaryl, 5-membered heteroaryl, thiophen-2-yl, cycloalkyl, heterocycloalkyl containing at least one heteroatom selected from the group consisting of oxygen and sulfur, aryloxy, heteroaryloxy, cycloalkoxy, heterocycloalkoxy, arylthio, cycloalkylthio, heteroarylthio, heterocycloalkylthio, arylalkyl, cycloalkylalkyl, heteroarylalkyl, and heterocycloalkylalkyl, any of which may be optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, alkyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, thioalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, alkenyl, arylalkenyl, heteroarylalkenyl, heterocycloalkylalkenyl, alkynyl, arylalkynyl, heteroarylalkynyl, heterocycloalkylalkynyl, alkoxy, haloalkoxy, perhaloalkoxy, acyloxy, arylalkoxy, aryloxy, heteroaryloxy, acyl, arylalkanoyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, amino, alkylamino, arylamino, C-amido, N-amido, carbamate, urea, N-sulfonamido, S-sulfonamido, alkylsulfonyl, thiol, alkylthio, arylthio, heteroarylthio, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, any of which may be optionally substituted;

R₉, R₁₀, R₁₁and R₁₂are independently selected from the group consisting of hydrogen, lower alkyl, lower perhaloalkyl, halogen, any of which may be optionally substituted, or R₉and R₁₀, or R₁₁and R₁₂, taken together, are oxy or optionally substituted cycloalkyl.

In certain embodiments provided herein,

Y is CH₂CH₂; and

R₄, R₇, R₈, R₉, and R₁₀are hydrogen.

In further embodiments provided herein,

R₁is phenyl, which may be optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, alkyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, thioalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, alkenyl, arylalkenyl, heteroarylalkenyl, heterocycloalkylalkenyl, alkynyl, arylalkynyl, heteroarylalkynyl, heterocycloalkylalkynyl, alkoxy, haloalkoxy, perhaloalkoxy, acyloxy, arylalkoxy, aryloxy, heteroaryloxy, acyl, arylalkanoyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, amino, alkylamino, arylamino, C-amido, N-amido, carbamate, urea, N-sulfonamido, S-sulfonamido, alkylsulfonyl, thiol, alkylthio, arylthio, heteroarylthio, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; and

R₃is selected from the group consisting of phenyl and thiophen-2-yl, any of which may be optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, alkyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, thioalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, alkenyl, arylalkenyl, heteroarylalkenyl, heterocycloalkylalkenyl, alkynyl, arylalkynyl, heteroarylalkynyl, heterocycloalkylalkynyl, alkoxy, haloalkoxy, perhaloalkoxy, acyloxy, arylalkoxy, aryloxy, heteroaryloxy, acyl, arylalkanoyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, amino, alkylamino, arylamino, C-amido, N-amido, carbamate, urea, N-sulfonamido, S-sulfonamido, alkylsulfonyl, thiol, alkylthio, arylthio, heteroarylthio, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl.

In yet further embodiments provided herein,

R₅is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, acyloxy, acyl, carboxyl, amino, alkylamino, thiol, and alkylthio; and

In yet further embodiments provided herein,

R₁is phenyl, which may be optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, and perhaloalkyl.

In yet further embodiments provided herein,

R₅and R₆are independently selected from the group consisting of hydrogen, hydroxy, and alkoxy.

Provided herein are compounds of structural Formula II, or a salt, ester, or prodrug thereof, wherein,

Y is (CR₁₁R₁₂)_n;

n is an integer from 0 to 2;

R₄, R₅, R₇, and R₈are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, alkyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, thioalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, alkenyl, arylalkenyl, heteroarylalkenyl, heterocycloalkylalkenyl, alkynyl, arylalkynyl, heteroarylalkynyl, heterocycloalkylalkynyl, alkoxy, haloalkoxy, perhaloalkoxy, acyloxy, arylalkoxy, aryloxy, heteroaryloxy, acyl, arylalkanoyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, amino, alkylamino, arylamino, C-amido, N-amido, carbamate, urea, N-sulfonamido, S-sulfonamido, alkylsulfonyl, thiol, alkylthio, arylthio, heteroarylthio, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, any of which may be optionally substituted;

R₆is selected from the group consisting of halogen, hydroxy, cyano, nitro, alkyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, thioalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, alkenyl, arylalkenyl, heteroarylalkenyl, heterocycloalkylalkenyl, alkynyl, arylalkynyl, heteroarylalkynyl, heterocycloalkylalkynyl, alkoxy, haloalkoxy, perhaloalkoxy, acyloxy, arylalkoxy, aryloxy, heteroaryloxy, acyl, arylalkanoyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, amino, alkylamino, arylamino, C-amido, N-amido, carbamate, urea, N-sulfonamido, S-sulfonamido, alkylsulfonyl, thiol, alkylthio, arylthio, heteroarylthio, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, any of which may be optionally substituted; and

In certain embodiments provided herein,

Y is CH₂CH₂; and

R₄, R₇, R₈, R₉, and R₁₀are hydrogen.

In further embodiments provided herein,

R₁is phenyl, which may be optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, alkyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, thioalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, alkenyl, arylalkenyl, heteroarylalkenyl, heterocycloalkylalkenyl, alkynyl, arylalkynyl, heteroarylalkynyl, heterocycloalkylalkynyl, alkoxy, haloalkoxy, perhaloalkoxy, acyloxy, arylalkoxy, aryloxy, heteroaryloxy, acyl, arylalkanoyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, amino, alkylamino, arylamino, C-amido, N-amido, carbamate, urea, N-sulfonamido, S-sulfonamido, alkylsulfonyl, thiol, alkylthio, arylthio, heteroarylthio, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; and

R₃is selected from the group consisting of phenyl and thiophenyl, any of which may be optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, alkyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, thioalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, alkenyl, arylalkenyl, heteroarylalkenyl, heterocycloalkylalkenyl, alkynyl, arylalkynyl, heteroarylalkynyl, heterocycloalkylalkynyl, alkoxy, haloalkoxy, perhaloalkoxy, acyloxy, arylalkoxy, aryloxy, heteroaryloxy, acyl, arylalkanoyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, amino, alkylamino, arylamino, C-amido, N-amido, carbamate, urea, N-sulfonamido, S-sulfonamido, alkylsulfonyl, thiol, alkylthio, arylthio, heteroarylthio, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl.

In further embodiments provided herein,

R₆is selected from the group consisting of halogen, hydroxy, cyano, nitro, alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, acyloxy, acyl, carboxyl, amino, alkylamino, thiol, and alkylthio.

In yet further embodiments provided herein,

R₁is phenyl, which may be optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, and perhaloalkyl; and

R₃is thiophenyl.

In yet further embodiments provided herein, R₃is thiophen-3-yl.

In yet further embodiments provided herein,

R₅is selected from the group consisting of hydrogen, hydroxy, and alkoxy; and

R₆is selected from the group consisting of hydroxy and alkoxy.

Provided herein are compounds of structural Formula II, or a salt, ester, or prodrug thereof, wherein,

Y is (CR₁₁R₁₂)_n;

n is an integer from 0 to 2;

R₃is selected from the group consisting of hydrogen, amino, alkyl, perhaloalkyl, alkoxy, hydroxy, perhaloalkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl containing at least one heteroatom selected from the group consisting of oxygen and sulfur, aryloxy, heteroaryloxy, cycloalkoxy, heterocycloalkoxy arylthio, cycloalkylthio, heteroarylthio, heterocycloalkylthio, arylalkyl, cycloalkylalkyl, heteroarylalkyl, and heterocycloalkylalkyl, any of which may be optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, alkyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, thioalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, alkenyl, arylalkenyl, heteroarylalkenyl, heterocycloalkylalkenyl, alkynyl, arylalkynyl, heteroarylalkynyl, heterocycloalkylalkynyl, alkoxy, haloalkoxy, perhaloalkoxy, acyloxy, arylalkoxy, aryloxy, heteroaryloxy, acyl, arylalkanoyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, amino, alkylamino, arylamino, C-amido, N-amido, carbamate, urea, N-sulfonamido, S-sulfonamido, alkylsulfonyl, thiol, alkylthio, arylthio, heteroarylthio, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, any of which may be optionally substituted;

In certain embodiments provided herein, Y is CH₂CH₂.

In further embodiments provided herein, R₁is phenyl, which may be optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, acyloxy, acyl, carboxyl, amino, alkylamino, arylamino, C-amido, N-amido, carbamate, urea, N-sulfonamido, S-sulfonamido, alkylsulfonyl, thiol, and alkylthio.

In further embodiments provided herein R₁is phenyl, which may be optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, acyloxy, acyl, carboxyl, amino, alkylamino, thiol, and alkylthio.

In yet further embodiments provided herein, R₁is phenyl, which may be optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, and perhaloalkyl.

In certain embodiments provided herein, R₃is selected from the group consisting of phenyl and thiophenyl, any of which may be optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, acyloxy, acyl, acarboxyl, amino, alkylamino, thiol, and alkylthio.

In further embodiments provided herein, R₃is selected from the group consisting of phenyl and thiophenyl, any of which may be optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, acyloxy, acyl, carboxyl, amino, alkylamino, thiol, and alkylthio.

In yet further embodiments provided herein, R₃is thiophenyl.

In yet further embodiments provided herein, R₃is thiophen-3-yl.

In certain embodiments provided herein, R₄, R₇, and R₈are hydrogen.

In further embodiments provided herein, R₉, and R₁₀are hydrogen.

In yet further embodiments provided herein, R₄, R₇, R₈, R₉, and R₁₀are hydrogen.

In other embodiments provided herein, R₅and R₆are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, acyloxy, acyl, carboxyl, amino, alkylamino, thiol, and alkylthio.

In further embodiments provided herein, R₅and R₆are independently selected from the group consisting of hydrogen, hydroxy, and alkoxy.

As used herein, the terms below have the meanings indicated.

When ranges of values are disclosed, and the notation “from n₁. . . to n₂” is used, where n₁and n₂are the numbers, then unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. This range may be integral or continuous between and including the end values. By way of example, the range “from 2 to 6 carbons” is intended to include two, three, four, five, and six carbons, since carbons come in integer units. Compare, by way of example, the range “from 1 to 3 μM (micromolar),” which is intended to include 1 μM, 3 μM, and everything in between to any number of significant figures (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.).

The term “about,” as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term “about” should be understood to mean that range which would encompass the recited value and the range which would be included by rounding up or down to that figure as well, taking into account significant figures.

The term “acyl,” as used herein, alone or in combination, refers to a carbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocycle, or any other moiety where the atom attached to the carbonyl is carbon. An “acetyl” group refers to a —C(O)CH₃group. An “alkylcarbonyl” or “alkanoyl” group refers to an alkyl group attached to the parent molecular moiety through a carbonyl group. Examples of such groups include methylcarbonyl and ethylcarbonyl. Examples of acyl groups include formyl, alkanoyl and aroyl.

The term “acyloxy” as used herein, alone or in combination, refers to an acyl group attached to the parent moiety through an oxygen atom.

The term “alkenyl,” as used herein, alone or in combination, refers to a straight-chain or branched-chain hydrocarbon group having one or more double bonds and containing from 2 to 20 carbon atoms. In certain embodiments, said alkenyl will comprise from 2 to 6 carbon atoms. The term “alkenylene” refers to a carbon-carbon double bond system attached at two or more positions such as ethenylene [(—CH═CH—),(—C::C—)]. Examples of suitable alkenyl groups include ethenyl, propenyl, 2-methylpropenyl, 1,4-butadienyl and the like. Unless otherwise specified, the term “alkenyl” may include “alkenylene” groups.

The term “alkoxy,” as used herein, alone or in combination, refers to an alkyl ether group, wherein the term alkyl is as defined below. Examples of suitable alkyl ether groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like.

The term “alkyl,” as used herein, alone or in combination, refers to a straight-chain or branched-chain alkyl group containing from 1 to 20 carbon atoms. In certain embodiments, said alkyl will comprise from 1 to 10 carbon atoms. In further embodiments, said alkyl will comprise from 1 to 6 carbon atoms. Alkyl groups may be optionally substituted as defined herein. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, noyl and the like. The term “alkylene,” as used herein, alone or in combination, refers to a saturated aliphatic group derived from a straight or branched chain saturated hydrocarbon attached at two or more positions, such as methylene (—CH₂—). Unless otherwise specified, the term “alkyl” may include “alkylene” groups.

The term “alkylamino,” as used herein, alone or in combination, refers to an alkyl group attached to the parent molecular moiety through an amino group. Suitable alkylamino groups may be mono- or dialkylated, forming groups such as, for example, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-ethylmethylamino and the like.

The term “alkylidene,” as used herein, alone or in combination, refers to an alkenyl group in which one carbon atom of the carbon-carbon double bond belongs to the moiety to which the alkenyl group is attached.

The term “alkylthio,” as used herein, alone or in combination, refers to an alkyl thioether (R—S—) group wherein the term alkyl is as defined above and wherein the sulfur may be singly or doubly oxidized. Examples of suitable alkyl thioether groups include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like.

The term “alkynyl,” as used herein, alone or in combination, refers to a straight-chain or branched-chain hydrocarbon group having one or more triple bonds and containing from 2 to 20 carbon atoms. In certain embodiments, said alkynyl comprises from 2 to 6 carbon atoms. In further embodiments, said alkynyl comprises from 2 to 4 carbon atoms. The term “alkynylene” refers to a carbon-carbon triple bond attached at two positions such as ethynylene (—C:::C—, —C≡C—). Examples of alkynyl groups include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, 3-methylbutyn-1-yl, hexyn-2-yl, and the like. Unless otherwise specified, the term “alkynyl” may include “alkynylene” groups.

The terms “amido” and “carbamoyl,” as used herein, alone or in combination, refer to an amino group as described below attached to the parent molecular moiety through a carbonyl group, or vice versa. The term “C-amido” as used herein, alone or in combination, refers to a —C(═O)—NR₂group with R as defined herein. The term “N-amido” as used herein, alone or in combination, refers to a RC(═O)NH— group, with R as defined herein. The term “acylamino” as used herein, alone or in combination, embraces an acyl group attached to the parent moiety through an amino group. An example of an “acylamino” group is acetylamino (CH₃C(O)NH—).

The term “amino,” as used herein, alone or in combination, refers to—NRR′, wherein R and R′ are independently selected from the group consisting of hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may themselves be optionally substituted. Additionally, R and R′ may combine to form heterocycloalkyl, either of which may be optionally substituted.

The term “aryl,” as used herein, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such polycyclic ring systems are fused together. The term “aryl” embraces aromatic groups such as phenyl, naphthyl, anthracenyl, and phenanthryl.

The term “arylalkenyl” or “aralkenyl,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkenyl group.

The term “arylalkoxy” or “aralkoxy,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkoxy group.

The term “arylalkyl” or “aralkyl,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkyl group.

The term “arylalkynyl” or “aralkynyl,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkynyl group.

The term “arylalkanoyl” or “aralkanoyl” or “aroyl,” as used herein, alone or in combination, refers to an acyl group derived from an aryl-substituted alkanecarboxylic acid such as benzoyl, napthoyl, phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like.

The term aryloxy as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an oxy.

The terms “benzo” and “benz,” as used herein, alone or in combination, refer to the divalent group C₆H₄=derived from benzene. Examples include benzothiophene and benzimidazole.

The term “carbamate,” as used herein, alone or in combination, refers to an ester of carbamic acid (—NHCOO—) which may be attached to the parent molecular moiety from either the nitrogen or acid end, and which may be optionally substituted as defined herein.

The term “O-carbamyl” as used herein, alone or in combination, refers to a —OC(O)NRR′, group-with R and R′ as defined herein.

The term “N-carbamyl” as used herein, alone or in combination, refers to a ROC(O)NR′— group, with R and R′ as defined herein.

The term “carbonyl,” as used herein, when alone includes formyl [—C(O)H] and in combination is a —C(O)— group.

The term “carboxyl” or “carboxy,” as used herein, refers to —C(O)OH or the corresponding “carboxylate” anion, such as is in a carboxylic acid salt. An “O-carboxy” group refers to a RC(O)O— group, where R is as defined herein. A “C-carboxy” group refers to a —C(O)OR groups where R is as defined herein.

The term “cyano,” as used herein, alone or in combination, refers to —CN.

The term “cycloalkyl,” or, alternatively, “carbocycle,” as used herein, alone or in combination, refers to a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl group wherein each cyclic moiety contains from 3 to 12 carbon atom ring members and which may optionally be a benzo fused ring system which is optionally substituted as defined herein. In certain embodiments, said cycloalkyl will comprise from 5 to 7 carbon atoms. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronapthyl, indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl and the like.

“Bicyclic” and “tricyclic” as used herein are intended to include both fused ring systems, such as decahydronaphthalene, octahydronaphthalene as well as the multicyclic (multicentered) saturated or partially unsaturated type. The latter type of isomer is exemplified in general by, bicyclo[1,1,1]pentane, camphor, adamantane, and bicyclo[3,2,1]octane.

The term “ester,” as used herein, alone or in combination, refers to a carboxy group bridging two moieties linked at carbon atoms.

The term “ether,” as used herein, alone or in combination, refers to an oxy group bridging two moieties linked at carbon atoms.

The term “halo,” or “halogen,” as used herein, alone or in combination, refers to fluorine, chlorine, bromine, or iodine.

The term “haloalkoxy,” as used herein, alone or in combination, refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.

The term “haloalkyl,” as used herein, alone or in combination, refers to an alkyl group having the meaning as defined above wherein one or more hydrogens are replaced with a halogen. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl groups. A monohaloalkyl group, for one example, may have an iodo, bromo, chloro or fluoro atom within the group. Dihalo and polyhaloalkyl groups may have two or more of the same halo atoms or a combination of different halo groups. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. “Haloalkylene” refers to a haloalkyl group attached at two or more positions. Examples include fluoromethylene (—CFH—), difluoromethylene (—CF₂—), chloromethylene (—CHCl—) and the like.

The term “heteroalkyl,” as used herein, alone or in combination, refers to a stable straight or branched chain, or cyclic hydrocarbon group, or combinations thereof, fully saturated or containing from 1 to 3 degrees of unsaturation, consisting of the stated number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N and S may be placed at any interior position of the heteroalkyl group. Up to two heteroatoms may be consecutive, such as, for example, —CH₂—NH—OCH₃.

The term “heteroaryl,” as used herein, alone or in combination, refers to a 3 to 7 membered unsaturated heteromonocyclic ring, or a fused monocyclic, bicyclic, or tricyclic ring system in which at least one of the fused rings is aromatic, which contains at least one atom selected from the group consisting of O, S, and N. In certain embodiments, said heteroaryl will comprise from 5 to 7 carbon atoms. The term also embraces fused polycyclic groups wherein heterocyclic rings are fused with aryl rings, wherein heteroaryl rings are fused with other heteroaryl rings, wherein heteroaryl rings are fused with heterocycloalkyl rings, or wherein heteroaryl rings are fused with cycloalkyl rings. Examples of heteroaryl groups include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, benzothienyl, chromonyl, coumarinyl, benzopyranyl, tetrahydroquinolinyl, tetrazolopyridazinyl, tetrahydroisoquinolinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl and the like.

The terms “heterocycloalkyl” and, interchangeably, “heterocycle,” as used herein, alone or in combination, each refer to a saturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic, or tricyclic heterocyclic group containing at least one heteroatom as a ring member, wherein each said heteroatom may be independently selected from the group consisting of nitrogen, oxygen, and sulfur In certain embodiments, said heterocycloalkyl will comprise from 1 to 4 heteroatoms as ring members. In further embodiments, said heterocycloalkyl will comprise from 1 to 2 heteroatoms as ring members. In certain embodiments, said heterocycloalkyl will comprise from 3 to 8 ring members in each ring. In further embodiments, said heterocycloalkyl will comprise from 3 to 7 ring members in each ring. In yet further embodiments, said heterocycloalkyl will comprise from 5 to 6 ring members in each ring. “Heterocycloalkyl” and “heterocycle” are intended to include sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclic fused and benzo fused ring systems; additionally, both terms also include systems where a heterocycle ring is fused to an aryl group, as defined herein, or an additional heterocycle group. Examples of heterocycle groups include aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihy-dropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like. The heterocycle groups may be optionally substituted unless specifically prohibited.

The term “hydrazinyl” as used herein, alone or in combination, refers to two amino groups joined by a single bond, i.e., —N—N—.

The term “hydroxy,” as used herein, alone or in combination, refers to —OH.

The term “hydroxyalkyl,” as used herein, alone or in combination, refers to a hydroxy group attached to the parent molecular moiety through an alkyl group.

The term “imino,” as used herein, alone or in combination, refers to ═N—.

The term “iminohydroxy,” as used herein, alone or in combination, refers to ═N(OH) and ═N—O—.

The phrase “in the main chain” refers to the longest contiguous or adjacent chain of carbon atoms starting at the point of attachment of a group to the compounds of any one of the formulas disclosed herein.

The term “isocyanato” refers to a —NCO group.

The term “isothiocyanato” refers to a —NCS group.

The phrase “linear chain of atoms” refers to the longest straight chain of atoms independently selected from carbon, nitrogen, oxygen and sulfur.

The term “lower,” as used herein, alone or in a combination, where not otherwise specifically defined, means containing from 1 to and including 6 carbon atoms.

The term “lower aryl,” as used herein, alone or in combination, means phenyl or naphthyl, which may be optionally substituted as provided.

The term “lower heteroaryl,” as used herein, alone or in combination, means either 1) monocyclic heteroaryl comprising five or six ring members, of which between one and four said members may be heteroatoms selected from the group consisting of O, S, and N, or 2) bicyclic heteroaryl, wherein each of the fused rings comprises five or six ring members, comprising between them one to four heteroatoms selected from the group consisting of O, S, and N.

The term “lower cycloalkyl,” as used herein, alone or in combination, means a monocyclic cycloalkyl having between three and six ring members. Lower cycloalkyls may be unsaturated. Examples of lower cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The term “lower heterocycloalkyl,” as used herein, alone or in combination, means a monocyclic heterocycloalkyl having between three and six ring members, of which between one and four may be heteroatoms selected from the group consisting of O, S, and N. Examples of lower heterocycloalkyls include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, and morpholinyl. Lower heterocycloalkyls may be unsaturated.

The term “lower amino,” as used herein, alone or in combination, refers to —NRR′, wherein R and R′ are independently selected from the group consisting of hydrogen, lower alkyl, and lower heteroalkyl, any of which may be optionally substituted. Additionally, the R and R′ of a lower amino group may combine to form a five- or six-membered heterocycloalkyl, either of which may be optionally substituted.

The term “mercaptyl” as used herein, alone or in combination, refers to an RS— group, where R is as defined herein.

The term “nitro,” as used herein, alone or in combination, refers to —NO₂.

The terms “oxy” or “oxa,” as used herein, alone or in combination, refer to —O—.

The term “oxo,” as used herein, alone or in combination, refers to ═O.

The term “perhaloalkoxy” refers to an alkoxy group where all of the hydrogen atoms are replaced by halogen atoms.

The term “perhaloalkyl” as used herein, alone or in combination, refers to an alkyl group where all of the hydrogen atoms are replaced by halogen atoms.

The terms “sulfonate,” “sulfonic acid,” and “sulfonic,” as used herein, alone or in combination, refer the —SO₃H group and its anion as the sulfonic acid is used in salt formation.

The term “sulfanyl,” as used herein, alone or in combination, refers to —S—.

The term “sulfinyl,” as used herein, alone or in combination, refers to —S(O)—.

The term “sulfonyl,” as used herein, alone or in combination, refers to —S(O)₂—.

The term “N-sulfonamido” refers to a RS(═O)₂NR′— group with R and R′ as defined herein.

The term “S-sulfonamido” refers to a —S(═O)₂NRR′, group, with R and R′ as defined herein.

The terms “thia” and “thio,” as used herein, alone or in combination, refer to a —S— group or an ether wherein the oxygen is replaced with sulfur. The oxidized derivatives of the thio group, namely sulfinyl and sulfonyl, are included in the definition of thia and thio.

The term “thiol,” as used herein, alone or in combination, refers to an —SH group.

The term “thiocarbonyl,” as used herein, when alone includes thioformyl —C(S)H and in combination is a —C(S)— group.

The term “N-thiocarbamyl” refers to an ROC(S)NR′— group, with R and R′ as defined herein.

The term “O-thiocarbamyl” refers to a —OC(S)NRR′, group with R and R′ as defined herein.

The term “thiocyanato” refers to a —CNS group.

The term “trihalomethanesulfonamido” refers to a X₃CS(O)₂NR— group with X is a halogen and R as defined herein.

The term “trihalomethanesulfonyl” refers to a X₃CS(O)₂— group where X is a halogen.

The term “trihalomethoxy” refers to a X₃CO— group where X is a halogen.

The term “trisubstituted silyl,” as used herein, alone or in combination, refers to a silicone group substituted at its three free valences with groups as listed herein under the definition of substituted amino. Examples include trimethysilyl, tert-butyldimethylsilyl, triphenylsilyl and the like.

Any definition herein may be used in combination with any other definition to describe a composite structural group. By convention, the trailing element of any such definition is that which attaches to the parent moiety. For example, the composite group alkylamido would represent an alkyl group attached to the parent molecule through an amido group, and the term alkoxyalkyl would represent an alkoxy group attached to the parent molecule through an alkyl group.

When a group is defined to be “null,” what is meant is that said group is absent.

The term “optionally substituted” means the anteceding group may be substituted or unsubstituted. When substituted, the substituents of an “optionally substituted” group may include, without limitation, one or more substituents independently selected from the following groups or a particular designated set of groups, alone or in combination: lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester, lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, lower alkylamino, arylamino, amido, nitro, thiol, lower alkylthio, lower haloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonic acid, trisubstituted silyl, N₃, SH, SCH₃, C(O)CH₃, CO₂CH₃, CO₂H, pyridinyl, thiophene, furanyl, lower carbamate, and lower urea. Two substituents may be joined together to form a fused five-, six-, or seven-membered carbocyclic or heterocyclic ring consisting of zero to three heteroatoms, for example forming methylenedioxy or ethylenedioxy. An optionally substituted group may be unsubstituted (e.g., —CH₂CH₃), fully substituted (e.g., —CF₂CF₃), monosubstituted (e.g., —CH₂CH₂F) or substituted at a level anywhere in-between fully substituted and monosubstituted (e.g., —CH₂CF₃). Where substituents are recited without qualification as to substitution, both substituted and unsubstituted forms are encompassed. Where a substituent is qualified as “substituted,” the substituted form is specifically intended. Additionally, different sets of optional substituents to a particular moiety may be defined as needed; in these cases, the optional substitution will be as defined, often immediately following the phrase, “optionally substituted with.”

The term R or the term R′, appearing by itself and without a number designation, unless otherwise defined, refers to a moiety selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl and heterocycloalkyl, any of which may be optionally substituted. Such R and R′ groups should be understood to be optionally substituted as defined herein. Whether an R group has a number designation or not, every R group, including R, R′ and Rⁿwhere n=(1, 2, 3, . . . n), every substituent, and every term should be understood to be independent of every other in terms of selection from a group. Should any variable, substituent, or term (e.g. aryl, heterocycle, R, etc.) occur more than one time in a formula or generic structure, its definition at each occurrence is independent of the definition at every other occurrence. Those of skill in the art will further recognize that certain groups may be attached to a parent molecule or may occupy a position in a chain of elements from either end as written. Thus, by way of example only, an unsymmetrical group such as —C(O)N(R)— may be attached to the parent moiety at either the carbon or the nitrogen.

Asymmetric centers exist in the compounds disclosed herein. These centers are designated by the symbols “R” or “S,” depending on the configuration of substituents around the chiral carbon atom. It should be understood that the invention encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric, and epimeric forms, as well as d-isomers and 1-isomers, and mixtures thereof. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art. Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art. Additionally, the compounds disclosed herein may exist as geometric isomers. The present invention includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. Additionally, compounds may exist as tautomers; all tautomeric isomers are provided by this invention. Additionally, the compounds disclosed herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms.

The term “bond” refers to a covalent linkage between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure. A bond may be single, double, or triple unless otherwise specified. A dashed line between two atoms in a drawing of a molecule indicates that an additional bond may be present or absent at that position.

The term “disease” as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.

The term “combination therapy” means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.

“TGR5 modulator” is used herein to refer to a compound that exhibits an EC₅₀with respect to TGR5 activity of no more than about 100 μM and more typically not more than about 50 μM, as measured in the cAMP production assay and glucagon-like peptide-1 (GLP-1) secretion assays described generally hereinbelow. “EC₅₀” is that concentration of inhibitor which activates the activity of an enzyme (e.g., TGR5) to half-maximal level. Certain compounds disclosed herein have been discovered to exhibit modulatory activity against TGR5. In certain embodiments, compounds will exhibit an EC₅₀with respect to TGR5 of no more than about 10 μM; in further embodiments, compounds will exhibit an EC₅₀with respect to TGR5 of no more than about 5 μM; in yet further embodiments, compounds will exhibit an EC₅₀with respect to TGR5 of not more than about 1 μM; in yet further embodiments, compounds will exhibit an EC₅₀with respect to TGR5 of not more than about 200 nM, as measured in the TGR5 assay described herein.

The phrase “therapeutically effective” is intended to qualify the amount of active ingredients used in the treatment of a disease or disorder. This amount will achieve the goal of reducing or eliminating the said disease or disorder.

The term “therapeutically acceptable” refers to those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.

As used herein, reference to “treatment” of a patient is intended to include prophylaxis. The term “patient” means all mammals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, pigs, and rabbits. Preferably, the patient is a human.

The term “prodrug” refers to a compound that is made more active in vivo. Certain compounds disclosed herein may also exist as prodrugs, as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compounds described herein are structurally modified forms of the compound that readily undergo chemical changes under physiological conditions to provide the compound. Additionally, prodrugs can be converted to the compound by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to a compound when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because, in some situations, they may be easier to administer than the compound, or parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. A wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. An example, without limitation, of a prodrug would be a compound which is administered as an ester (the “prodrug”), but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound.

The compounds disclosed herein can exist as therapeutically acceptable salts. The present invention includes compounds listed above in the form of salts, including acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable salts may be of utility in the preparation and purification of the compound in question. Basic addition salts may also be formed and be pharmaceutically acceptable. For a more complete discussion of the preparation and selection of salts, refer to Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P. Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002).

The term “therapeutically acceptable salt,” as used herein, represents salts or zwitterionic forms of the compounds disclosed herein which are water or oil-soluble or dispersible and therapeutically acceptable as defined herein. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound in the form of the free base with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, phosphonate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluenesulfonate (p-tosylate), and undecanoate. Also, basic groups in the compounds disclosed herein can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids which can be employed to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Salts can also be formed by coordination of the compounds with an alkali metal or alkaline earth ion. Hence, the provided herein are sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, and the like.

Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxy group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine. The cations of therapeutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,N′-dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

In certain embodiments, the salts may include hydrochloride. A salt of a compound can be made by reacting the appropriate compound in the form of the free base with the appropriate acid.

While it may be possible for the compounds provided herein to be administered as raw chemicals, it is also possible to present them as pharmaceutical formulations. Accordingly, provided herein are pharmaceutical formulations which comprise one or more of certain compounds disclosed herein, or one or more pharmaceutically acceptable salts, esters, prodrugs, amides, or solvates thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients. The carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., in Remington's Pharmaceutical Sciences. The pharmaceutical compositions disclosed herein may be manufactured in any manner known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.

The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Typically, these methods include the step of bringing into association a compound or a pharmaceutically acceptable salt, ester, amide, prodrug or solvate thereof (“active ingredient”) with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

Formulations of the compounds disclosed herein suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

Pharmaceutical preparations which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner. Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.

The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.

Certain compounds disclosed herein may be administered topically, that is by non-systemic administration. This includes the application of a compound disclosed herein externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.

Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient for topical administration may comprise, for example, from 0.001% to 10% w/w (by weight) of the formulation. In certain embodiments, the active ingredient may comprise as much as 10% w/w. In other embodiments, it may comprise less than 5% w/w. In certain embodiments, the active ingredient may comprise from 2% w/w to 5% w/w. In other embodiments, it may comprise from 0.1% to 1% w/w of the formulation.

Gels for topical or transdermal administration may comprise, generally, a mixture of volatile solvents, nonvolatile solvents, and water. In certain embodiments, the volatile solvent component of the buffered solvent system may include lower (C₁-C₆) alkyl alcohols, lower alkyl glycols and lower glycol polymers. In further embodiments, the volatile solvent is ethanol. The volatile solvent component is thought to act as a penetration enhancer, while also producing a cooling effect on the skin as it evaporates. The nonvolatile solvent portion of the buffered solvent system is selected from lower alkylene glycols and lower glycol polymers. In certain embodiments, propylene glycol is used. The nonvolatile solvent slows the evaporation of the volatile solvent and reduces the vapor pressure of the buffered solvent system. The amount of this nonvolatile solvent component, as with the volatile solvent, is determined by the pharmaceutical compound or drug being used. When too little of the nonvolatile solvent is in the system, the pharmaceutical compound may crystallize due to evaporation of volatile solvent, while an excess may result in a lack of bioavailability due to poor release of drug from solvent mixture. The buffer component of the buffered solvent system may be selected from any buffer commonly used in the art; in certain embodiments, water is used. A common ratio of ingredients is about 20% of the nonvolatile solvent, about 40% of the volatile solvent, and about 40% water. There are several optional ingredients which can be added to the topical composition. These include, but are not limited to, chelators and gelling agents. Appropriate gelling agents can include, but are not limited to, semisynthetic cellulose derivatives (such as hydroxypropylmethylcellulose) and synthetic polymers, and cosmetic agents.

Lotions include those suitable for application to the skin or eye. An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops. Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.

Creams, ointments or pastes are semi-solid formulations of the active ingredient for external application. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy base. The base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives or a fatty acid such as steric or oleic acid together with an alcohol such as propylene glycol or a macrogel. The formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof. Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.

Drops may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and, in certain embodiments, including a surface active agent. The resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-100° C. for half an hour. Alternatively, the solution may be sterilized by filtration and transferred to the container by an aseptic technique. Examples of bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.

Formulations for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising the active ingredient in a flavored basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.

For administration by inhalation, compounds may be conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, compounds may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.

Preferred unit dosage formulations are those containing an effective dose, as herein below recited, or an appropriate fraction thereof, of the active ingredient.

It should be understood that in addition to the ingredients particularly mentioned above, the formulations described above may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

Compounds may be administered orally or via injection at a dose of from 0.1 to 500 mg/kg per day. The dose range for adult humans is generally from 5 mg to 2 g/day. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of one or more compounds which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

The compounds can be administered in various modes, e.g. orally, topically, or by injection. The precise amount of compound administered to a patient will be the responsibility of the attendant physician. The specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diets, time of administration, route of administration, rate of excretion, drug combination, the precise disorder being treated, and the severity of the indication or condition being treated. Also, the route of administration may vary depending on the condition and its severity.

In certain instances, it may be appropriate to administer at least one of the compounds described herein (or a pharmaceutically acceptable salt, ester, or prodrug thereof) in combination with another therapeutic agent. By way of example only, if one of the side effects experienced by a patient upon receiving one of the compounds herein is hypertension, then it may be appropriate to administer an anti-hypertensive agent in combination with the initial therapeutic agent. Or, by way of example only, the therapeutic effectiveness of one of the compounds described herein may be enhanced by administration of an adjuvant (i.e., by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or, by way of example only, the benefit experienced by a patient may be increased by administering one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit. By way of example only, in a treatment for diabetes involving administration of one of the compounds described herein, increased therapeutic benefit may result by also providing the patient with another therapeutic agent for diabetes. In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient may simply be additive of the two therapeutic agents or the patient may experience a synergistic benefit.

Specific, non-limiting examples of possible combination therapies include use of certain compounds disclosed herein with agents found in the following pharmacotherapeutic classifications as indicated below. These lists should not be construed to be closed, but should instead serve as illustrative examples common to the relevant therapeutic area at present. Moreover, combination regimens may include a variety of routes of administration and should include oral, intravenous, intraocular, subcutaneous, dermal, and inhaled topical.

For the treatment of metabolic disorders, compounds disclosed herein may be administered with an agent selected from the group comprising: insulin, insulin derivatives and mimetics, insulin secretagogues, insulin sensitizers, biguanide agents, alpha-glucosidase inhibitors, insulinotropic sulfonylurea receptor ligands, meglitinides, protein tyrosine phosphatase-1B (PTP-1B) inhibitors, GSK3 (glycogen synthase kinase-3) inhibitors, GLP-1 (glucagon like peptide-1), GLP-1 analogs, DPPIV (dipeptidyl peptidase IV) inhibitors, RXR ligands, sodium-dependent glucose co-transporter (SGLT2) inhibitors, glycogen phosphorylase A inhibitors, an AGE breaker, PPAR modulators, non-glitazone type PPARδ agonist, HMG-CoA reductase inhibitors, cholesterol-lowering drugs and anti-obesity agents.

For the treatment of metabolic disorders, compounds disclosed herein may be administered with an agent selected from the group comprising: insulin, metformin, Glipizide, glyburide, Amaryl, gliclazide, meglitinides, nateglinide, repaglinide, amylin mimetics (for example, pramlintide), PTP-112, SB-517955, SB-4195052, SB-216763, N,N-57-05441, N,N-57-05445, GW-0791, AGN-¹⁹4²⁰4, T-1095, BAY R3401, acarbose, miglitol, voglibose, Exendin-4, DPP728, LAF237, vildagliptin, BMS477118, PT-100, GSK-823093, PSN-9301, T-6666, SYR-322, SYR-619, Liraglutide, CJC-1134-PC, naliglutide, MK-0431, saxagliptin, GSK23A, pioglitazone, rosiglitazone, AVE2268, GW869682, GSK189075, GPR119 agonists including, but not limited to APD668, PSN-119-1 and PSN-821, HMG-CoA reductase inhibitors (for example, rosuvastatin, atrovastatin, simvastatin, lovastatin, pravastatin, fluvastatin, cerivastatin, rosuvastatin, pitavastatin and like), cholesterol-lowering drugs (for example, fibrates which include: fenofibrate, benzafibrate, clofibrate, gemfibrozil and like; cholesterol absorption inhibitors such as Ezetimibe, eflucimibe and like compounds), cholesterol ester transfer protein inhibitors (for example, CP-529414, CETi-1, JTT-705 and like compounds), bile acid sequestrants (for example, cholestyramine, colestipol, and like compounds), niacin, microsomal triglyceride transfer protein inhibitors (for example, implitapide), insulin signaling pathway modulators, like inhibitors of protein tyrosine phosphatases (PTPases) and inhibitors of glutamine-fructose-6-phosphate amidotransferase (GFAT), inhibitors of glucose-6-phosphatase (G6 Pase), inhibitors of fructose-1,6-bisphosphatase (F-1,6-BPase), inhibitors of glycogen phosphorylase, glucagon receptor antagonists, inhibitors of phosphoenolpyruvate carboxylase (PEPCK), inhibitors of pyruvate dehydrogenase kinase, activators AMP-activated protein kinase (AMPK), (R)-1-{4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonyl}2,3-dihydro-1H-indole-2-carboxylic acid described in the patent application WO 03/043985, as compound 19 of Example 4, and GI-262570.

For the treatment of obesity, compounds disclosed herein may be administered with an agent selected from the group comprising: cholescystokinin-A (CCK-A) agonists, serotonin and norepinephrine reuptake inhibitors (for example sibutramine), dopamine agonists (for example, bromocriptine and like) sympathomimetic agents, β3 adrenergic receptor agonists, leptin, leptin analogues, leptin receptor agonists, galanin antagonists, lipase inhibitors (for example Orlistat), Neuropeptide-γ antagonists, glucocorticoid receptor agonists or antagonists, cannabinoid 1 receptor antagonists (for example, rimonabant and like), ciliary neurotropic factors (CNTF, for example Axokine), human agouti-related proteins (AGRP), ghrelin receptor antagonists, histamine 3 receptor antagonists, appetite suppressants (for example, bupropion), urocortin binding protin antagonists, orexin receptor antagonists, and bombesin agonists.

For the treatment of inflammatory diseases, compounds disclosed herein may be administered with an agent selected from the group comprising: corticosteroids, non-steroidal anti-inflammatories, muscle relaxants and combinations thereof with other agents, anaesthetics and combinations thereof with other agents, expectorants and combinations thereof with other agents, antidepressants, anticonvulsants and combinations thereof, antihypertensives, opioids, topical cannabinoids, and other agents, such as capsaicin.

For the treatment of inflammatory diseases, compounds disclosed herein may be administered with an agent selected from the group comprising: betamethasone dipropionate (augmented and nonaugemnted), betamethasone valerate, clobetasol propionate, prednisone, methyl prednisolone, diflorasone diacetate, halobetasol propionate, amcinonide, dexamethasone, dexosimethasone, fluocinolone acetononide, fluocinonide, halocinonide, clocortalone pivalate, dexosimetasone, flurandrenalide, salicylates, ibuprofen, ketoprofen, etodolac, diclofenac, meclofenamate sodium, naproxen, piroxicam, celecoxib, cyclobenzaprine, baclofen, cyclobenzaprine/lidocaine, baclofen/cyclobenzaprine, cyclobenzaprine/lidocaine/ketoprofen, lidocaine, lidocaine/deoxy-D-glucose, prilocalne, EMLA Cream (Eutectic Mixture of Local Anesthetics (lidocaine 2.5% and prilocalne 2.5%), guaifenesin, guaifenesin/ketoprofen/cyclobenzaprine, amitryptiline, doxepin, desipramine, imipramine, amoxapine, clomipramine, nortriptyline, protriptyline, duloxetine, mirtazepine, nisoxetine, maprotiline, reboxetine, fluoxetine, fluvoxamine, carbamazepine, felbamate, lamotrigine, topiramate, tiagabine, oxcarbazepine, carbamezipine, zonisamide, mexiletine, gabapentin/clonidine, gabapentin/carbamazepine, carbamazepine/cyclobenzaprine, antihypertensives including clonidine, codeine, loperamide, tramadol, morphine, fentanyl, oxycodone, hydrocodone, levorphanol, butorphanol, menthol, oil of wintergreen, camphor, eucalyptus oil, turpentine oil; CB1/CB2 ligands, acetaminophen, infliximab; n) nitric oxide synthase inhibitors, particularly inhibitors of inducible nitric oxide synthase; anti-TNFα agents including, but not limited to etanerecept and infliximab, and other agents, such as capsaicin.

In any case, the multiple therapeutic agents (at least one of which is a compound disclosed herein) may be administered in any order or even simultaneously. If simultaneously, the multiple therapeutic agents may be provided in a single, unified form, or in multiple forms (by way of example only, either as a single pill or as two separate pills). One of the therapeutic agents may be given in multiple doses, or both may be given as multiple doses. If not simultaneous, the timing between the multiple doses may be any duration of time ranging from a few minutes to four weeks.

Thus, in another aspect, certain embodiments provide methods for treating TGR5-mediated disorders in a human or animal subject in need of such treatment comprising administering to said subject an amount of a compound disclosed herein effective to reduce or prevent said disorder in the subject, in combination with at least one additional agent for the treatment of said disorder that is known in the art. In a related aspect, certain embodiments provide therapeutic compositions comprising at least one compound disclosed herein in combination with one or more additional agents for the treatment of TGR5-mediated disorders.

Specific diseases to be treated by the compounds, compositions, and methods disclosed herein include: diabetes (type I and type II) and conditions associated with diabetic diseases which include, but are not limited to, hyperglycemia, hyperlipidemia, hyperinsulinemia, insulin resistance, inadequate glucose tolerance, impaired glucose metabolism, diabetic nephropathy, glomerulosclerosis, diabetic neuropathy, erectile dysfunction, macular degeneration, diabetic retinopathy, chronic microvascular complications, peripheral vascular disease, cataracts, stroke, foot ulcerations, renal failure, kidney disease, ketosis, metabolic acidosis, and related disorders, obesity, myocardial infarction, angina pectoris, coronary artery disease, atherosclerosis, cardiac hypertrophy, allergic diseases, fatty liver disease, nonalcoholic steatohepatitis, liver fibrosis, kidney fibrosis, anorexia nervosa, bulimia vervosa, autoimmune diseases, inflammatory diseases including rheumatoid arthritis, asthma, chronic obstructive pulmonary disease (COPD), psoriasis, ulcerative colitis, proliferative disorders, infectious diseases, angiogenic disorders, reperfusion/ischemia in stroke, vascular hyperplasia, organ hypoxia, cardiac hypertrophy, thrombin-induced platelet aggregation, and conditions associated with prostaglandin endoperoxidase synthetase-2 (COX-2).

In certain embodiments, the disease is obesity and the effects to be achieved in a human or animal patient include decreasing body weight and controlling weight gain.

In addition, topical application of TGR5 agonists might be useful for the treatment of cellulite and other cosmetic conditions which are characterized by subcutaneous fat accumulation. This is due to recent evidence showing that TGR5 agonists increase energy expenditure and fat burning in experimental models (Watanabe et al. Nature, 439:484-489).

In certain embodiments, the disease is associated with perturbed bile acid metabolism, including, but not limited to gall bladder stones, cholecystitis, cholangitis, choledocholithiasis, jaundice, and obstetric cholestasis and the itch associated with it.

Metabolic diseases other than Type 1 and Type 2 diabetes which may be treated or prevented include, without limitation, metabolic syndrome and insulin resistance. In addition, the compounds disclosed herein can be used to treat insulin resistance and other metabolic disorders such as atherosclerosis that are typically associated with an exaggerated inflammatory signaling.

In certain embodiments, the disease is a hyperproliferative condition of the human or animal body, including, but not limited to restenosis, inflammation, immune disorders, cardiac hypertrophy, atherosclerosis, pain, migraine, angiogenesis-related conditions or disorders, proliferation induced after medical conditions, including but not limited to surgery, angioplasty, or other conditions.

The compounds disclosed herein may be useful as anti-inflammatory agents with the additional benefit of having significantly less harmful side effects. The compositions may be used to treat arthritis, including but not limited to rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis, acute rheumatic arthritis, enteropathic arthritis, neuropathic arthritis, psoriatic arthritis, and pyogenic arthritis. The compositions may also be used in the treatment of pulmonary inflammation, such as that associated with viral infections and cystic fibrosis. In certain embodiments, the particular inflammatory disease is rheumatoid arthritis.

Further inflammatory diseases which may be prevented or treated include, without limitation: asthma, allergies, respiratory distress syndrome or acute or chronic pancreatitis. Furthermore, respiratory system diseases may be prevented or treated including but not limited to chronic obstructive pulmonary disease, pulmonary fibrosis, ulcerative colitis, inflammatory bowel disease, Crohn's disease, peptic ulceration, gastritis, psoriasis, and skin inflammation.

In certain embodiments, the disease to be treated by the methods provided herein may be an opthalmologic disorder. Opthalmologic diseases and other diseases in which angiogenesis plays a role in pathogenesis, may be treated or prevented and include, without limitation, dry eye (including Sjögren's syndrome), macular degeneration, closed and wide angle glaucoma, retinal ganglion degeneration, occular ischemia, retinitis, retinopathies, uveitis, ocular photophobia, and of inflammation and pain associated with acute injury to the eye tissue. In certain embodiments, the opthalmologic disease to be treated is glaucomatous retinopathy and/or diabetic retinopathy. In certain embodiments, the opthalmologic condition to be treated is post-operative inflammation or pain as from ophthalmic surgery such as cataract surgery and refractive surgery.

In certain embodiments, the disease to be treated by the methods provided herein may be an autoimmune disease. Autoimmune diseases which may be prevented or treated include, but are not limited to: rheumatoid arthritis, inflammatory bowel disease, inflammatory pain, ulcerative colitis, Crohn's disease, periodontal disease, temporomandibular joint disease, multiple sclerosis, diabetes, glomerulonephritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Grave's disease, hemolytic anemia, autoimmune gastritis, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis, atopic dermatitis, graft vs. host disease, and psoriasis. Inflammatory diseases which may be prevented or treated include, but are not limited to: asthma, allergies, respiratory distress syndrome or acute or chronic pancreatitis. In certain embodiments, the particular autoimmune disease is rheumatoid arthritis.

The compounds provided herein are also useful in treating tissue damage in such diseases as vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, neuromuscular junction disease including myasthenia gravis, white matter disease including multiple sclerosis, sarcoidosis, nephritis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, periodontis, hypersensitivity, swelling occurring after injury, ischemias including myocardial ischemia, cardiovascular ischemia, and ischemia secondary to cardiac arrest, and the like. These compounds can also be used to treat allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome, and atherosclerosis.

In certain embodiments, the disease to be treated by the methods of the present invention may be a cardiovascular condition. In certain embodiments, said cardiovascular condition is selected from the group consisting of atherosclerosis, cardiac hypertrophy, idiopathic cardiomyopathies, heart failure, angiogenesis-related conditions or disorders, and proliferation induced after medical conditions, including, but not limited to restenosis resulting from surgery and angioplasty.

In certain embodiments, the disease to be prevented or treated by the methods of the present invention may be autism. Recent data have shown that TGR5 agonists increase the expression and the activity of the enzyme iodothyronine deiodinase type 2 (D2) (Watanabe et al. Nature, 439:484-489). D2 converts inactive thyroxine (T4) into active 3,5,3′-tri-iodothyronine (T3). Recent data have also shown that inhibition of D2 in fetal brain causes a reduction of T3 levels and results in permanent alterations of cerebral cortical architecture reminiscent of these observed in brains of patients with autism. Therefore, a TGR5 agonist (or antagonist) might be useful for the prevention or treatment of autism.

Besides being useful for human treatment, certain compounds and formulations disclosed herein may also be useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.

All references, patents or applications, U.S. or foreign, cited in the application are hereby incorporated by reference as if written herein.

General Synthetic Methods for Preparing Compounds

The following schemes and examples can be used to practice the present invention. Starting materials are commercially available, made by known procedures, or prepared as illustrated herein.

One of the principal routes for preparation of compounds within the scope of the instant invention is depicted in Scheme 1. Starting from an appropriately substituted aniline 1-1, this is converted into the acetamide 1-2 using standard conditions. Acetamides 1-2 are then reacted with phosphorous oxychloride and DMF at elevated temperatures to give chloro quinolines 1-3. Chloro quinolines 1-3 are then coupled to appropriately substituted boronic acids (or aryl tin reagents) 1-4 using palladium catalysts under standard conditions. Coupled quinolines 1-5 are then reacted with amines 1-6 under typical reductive amination conditions to give desired quinolines 1-7. Quinolines 1-7 can be further reacted with a variety of acid chlorides, sulfonyl chlorides or aldehydes under reductive amination conditions to give desired substituted quinolines 1-8. These compounds can exist as mixtures of stereoisomers. These can be separated by a variety of methods, including by HPLC using a column with a chiral stationary phase.

Another of the principal routes for preparation of compounds within the scope of the instant invention is depicted in Scheme 2. Starting from amino quinolines 1-9, prepared as in scheme 1, these are reacted with acid chlorides 1-10 under conditions well known in the art to give quinoline amides 1-11. These compounds can exist as mixtures of stereoisomers. These can be separated by a variety of methods, including by HPLC using a column with a chiral stationary phase.

Another of the principal routes for preparation of compounds within the scope of the instant invention is depicted in Scheme 3. Starting from quinoline aldehydes 1-5, prepared as in scheme 1, these are oxidized using N-iodosuccinimide to give quinoline esters 1-12. Ester hydrolysis using standard conditions affords acids 1-13, which are reacted with amines 1-6 using standard coupling conditions to provide the desired quinoline amides 1-14. These compounds can exist as mixtures of stereoisomers. These can be separated by a variety of methods, including by HPLC using a column with a chiral stationary phase.

Another of the principal routes for preparation of compounds within the scope of the instant invention is depicted in Scheme 4. Starting from chloro quinolines 1-3, prepared as in scheme 1, these are reacted with hydroxyl or thio pyridines to give quinoline aldehydes 1-16. These are then reacted with amines 1-6 under typical reductive amination conditions to give desired quinolines 1-17. These compounds can exist as mixtures of stereoisomers. These can be separated by a variety of methods, including by HPLC using a column with a chiral stationary phase.

Another of the principal routes for preparation of compounds within the scope of the instant invention is depicted in Scheme 5. Starting from 2-methoxy-4-nitrophenol 1-18, this is reduced using hydrogen and palladium on carbon to give 2-methoxy-4-aminophenol 1-19. Acetylation of 1-19 using acetic anhydride under typical conditions gave bis-acetylated compound 1-20. This is then reacted with phosphorous oxychloride and DMF at elevated temperatures to give chloro quinoline 1-21. Chloro quinoline 1-21 is then coupled to appropriately substituted boronic acids (or aryl tin reagents) 1-4 using palladium catalysts under standard conditions. Coupled quinolines 1-22 are then reacted with amines 1-6 under typical reductive amination conditions to give desired quinolines 1-23. These compounds can exist as mixtures of stereoisomers. These can be separated by a variety of methods, including by HPLC using a column with a chiral stationary phase.

The invention is further illustrated by the following examples.

EXAMPLE 1
1-(7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine

Step 1
N-(3-Methoxyphenyl)acetamide

A mixture of 3-methoxyaniline (9.07 mL, 81.2 mmol), acetic anhydride (7.67 mL, 81.2 mmol), DIEA (21.2 mL, 122 mmol), DMAP (500 mg, 4.06 mmol) and DCM (150 mL) was stirred at room temperature for 1.5 h under nitrogen. Water (150 mL) was added and the layers were separated. The organic layer was sequentially washed with 1.0 M AcOH (150 mL), sat. aq. NaHCO₃(150 mL) and brine (150 mL). The organic layer was dried over MgSO₄, filtered and concentrated under vacuum to afford 13.2 g of N-(3-methoxyphenyl)acetamide as an tan solid. MS (ESI): 166.18 (M+H⁺).

Step 2
2-Chloro-7-methoxyquinoline-3-carbaldehyde

Phosphorus oxychloride (19.4 mL, 212 mmol) was added dropwise over a period of 10 minutes to DMF (5.91 mL, 76.3 mmol) at 0° C. under nitrogen. The mixture was stirred for 20 minutes prior to the addition of N-(3-methoxyphenyl)acetamide (5.00 g, 30.3 mmol). The suspension was heated to 110° C. for 2.5 h. The reaction mixture was cooled to room temperature then poured onto ice (200 g). The mixture was warmed to room temperature and the resulting precipitate collected by vacuum filtration. The solid was washed with water (500 mL) and dried under vacuum to afford 4.92 g of 2-chloro-7-methoxyquinoline-3-carbaldehyde as a tan solid. MS (ESI): 221.99 (M+H⁺).

Step 3
7-Methoxy-2-(thiophen-3-yl)quinoline-3-carbaldehyde

Bis(triphenylphosphine)palladium(II) dichloride (317 mg, 451 μmol) was added to a nitrogen purged mixture of 2-chloro-7-methoxyquinoline-3-carbaldehyde (1.00 g, 4.51 mmol), thiophen-3-ylboronic acid (635 mg, 4.96 mmol), 2M Na₂CO₃(6.76 mL, 13.5 mmol) and DME (15 mL) at room temperature. The suspension was heated to 90° C. for 1 h then cooled to room temperature. The mixture was concentrated under vacuum prior to addition of brine (15 mL) and ethyl acetate (15 mL). The phases were separated and the organic layer was concentrated under vacuum. The product was purified using column chromatography (hexanes to 1:1 hexanes/ethyl acetate) to give 1.14 g of 7-methoxy-2-(thiophen-3-yl)quinoline-3-carbaldehyde as a white solid. MS (ESI): 269.97 (M+H⁺).

Step 4
1-(7-Methoxy-2-(thiophen-3-yl)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine

A mixture of 7-methoxy-2-(thiophen-3-yl)quinoline-3-carbaldehyde (100 mg, 371 μmol), 2-(4-chlorophenyl)ethanamine (58 mg, 371 μmol), glacial acetic acid (100 μL) and isopropyl alcohol (2 mL) was heated to 45° C. for 30 minutes then cooled to room temperature. Sodium triacetoxyborohydride (236 mg, 1.11 mmol) was added and the vented reaction mixture was stirred for 1 h. DCM (15 mL) and 1M NaOH (15 mL) were added and the phases were separated. The organic layer was washed with brine (15 mL) and concentrated under vacuum. The product was purified using column chromatography (hexanes to ethyl acetate) to give 104 mg of 1-(7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine as a white solid. ¹H-NMR (400 MHz, CDCl₃) δ 8.13 (s, 1H), 7.82 (dd, 1H), 7.69 (d, 1H), 7.55 (d, 2H), 7.52 (dd, 1H), 7.44 (d, 1H), 7.42-7.40 (m, 3H), 7.18 (dd, 1H), 3.98 (s, 2H), 3.95 (s, 3H), 3.87 (s, 2H). MS (ESI): 428.95 (M+H⁺).

EXAMPLE 2
2-(4-Chlorophenyl)-N-((7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine

2-(4-Chlorophenyl)-N-((7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 1. H-NMR (400 MHz, CDCl₃) δ 8.03 (s, 1H), 7.72 (dd, 1H), 7.66 (d, 2H), 7.46 (dd, 1H), 7.43 (d, 1H), 7.38 (dd, 1H), 7.25 (d, 2H), 7.17 (dd, 1H), 7.09 (d, 1H), 3.94 (s, 3H), 3.93 (s, 2H), 2.87 (t, 2H), 2.76 (t, 2H). MS (ESI): 408.89 (M+H⁺).

EXAMPLE 3
1-(7-Methoxy-2-(thiophen-3-yl)quinolin-3-yl)-N-(3-(trifluoromethyl)benzyl)methanamine

1-(7-Methoxy-2-(thiophen-3-yl)quinolin-3-yl)-N-(3-(trifluoromethyl)benzyl)methanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.33 (s, 1H), 8.03 (t, 1H), 7.84 (d, 1H), 7.70 (s, 1H), 7.63 (d, 1H), 7.58-7.50 (m, 4H), 7.34 (d, 1H), 7.20 (dd, 1H), 3.89 (s, 3H), 3.86 (s, 2H), 3.84 (s, 2H). MS (ESI): 429.15 (M+H⁺).

EXAMPLE 4
2-(4-Chlorophenyl)-N-((8-methyl-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine

2-(4-Chlorophenyl)-N-((8-methyl-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, CDCl₃) δ 8.07 (s, 1H), 7.88 (dd, 1H), 7.65 (dd, 1H), 7.61 (d, 1H), 7.52 (s, 1H), 7.40 (d, 1H), 7.38 (dd, 1H), 7.25 (d, 2H), 7.10 (d, 2H), 4.02 (s, 2H), 2.92 (t, 2H), 2.81 (s, 3H), 2.78 (t, 2H). MS (ESI): 392.96 (M+H⁺).

EXAMPLE 5
1-(8-Methyl-2-(thiophen-3-yl)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine

1-(8-Methyl-2-(thiophen-3-yl)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, CDCl₃) δ 8.16 (s, 1H), 7.96 (dd, 1H), 7.70 (dd, 1H), 7.64 (d, 1H), 7.58 (d, 2H), 7.54 (d, 1H), 7.45-7.39 (m, 4H), 4.08 (s, 2H), 3.91 (s, 2H), 2.83 (s, 3H). MS (ESI): 413.56 (M+H⁺).

EXAMPLE 6
1-(7-Methoxy-2-(pyridin-3-yl)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine

1-(7-Methoxy-2-(pyridin-3-yl)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, CDCl₃) δ 8.93 (d, 1H), 8.69 (dd, 1H), 8.23 (s, 1H), 8.00 (dt, 1H), 7.74 (d, 2H), 7.55 (d, 2H), 7.46 (d, 1H), 7.40-7.35 (m, 2H), 7.24 (dd, 1H), 3.95 (s, 3H), 3.89 (s, 2H), 3.83 (s, 2H)MS (ESI): 424.84 (M+H⁺).

EXAMPLE 7
2-(4-Chlorophenyl)-N-((7-methoxy-2-(pyridin-3-yl)quinolin-3-yl)methyl)ethanamine

2-(4-Chlorophenyl)-N-((7-methoxy-2-(pyridin-3-yl)quinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, CDCl₃) δ 8.89 (d, 1H), 8.67 (dd, 1H), 8.12 (s, 1H), 7.94 (dt, 1H), 7.70 (d, 2H), 7.44 (d, 1H), 7.37 (dd, 1H), 7.26-7.21 (m, 2H), 7.08 (d, 2H), 3.94 (s, 3H), 3.86 (s, 2H), 2.83 (t, 2H), 2.73 (t, 2H). MS (ESI): 403.98 (M+H⁺).

EXAMPLE 8
2-(4-Fluorophenyl)-N-((7-methoxy-2-(pyridin-3-yl)quinolin-3-yl)methyl)ethanamine

2-(4-Fluorophenyl)-N-((7-methoxy-2-(pyridin-3-yl)quinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.86 (d, 1H), 8.64 (dd, 1H), 8.31 (s, 1H), 8.10 (dt, 1H), 7.86 (d, 2H), 7.46 (dd, 1H), 7.40 (d, 1H), 7.23 (dd, 1H), 7.21-7.20 (m, 1H), 7.06 (d, 2H), 3.90 (s, 3H), 3.75 (s, 2H), 2.74-2.65 (m, 4H). MS (ESI): 387.97 (M+H⁺).

EXAMPLE 9
2-(4-Bromophenyl)-N-((7-methoxy-2-(pyridin-3-yl)quinolin-3-yl)methyl)ethanamine

2-(4-Bromophenyl)-N-((7-methoxy-2-(pyridin-3-yl)quinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.85 (dd, 1H), 8.64 (dd, 1H), 8.30 (s, 1H), 8.10 (dt, 1H), 7.85 (d, 2H), 7.47-7.39 (m, 3H), 7.25 (dd, 1H), 7.13 (d, 2H), 3.90 (s, 3H), 3.76 (s, 2H), 2.71 (t, 2H), 2.66 (t, 2H). MS (ESI): 449.87, 451.20 (M+H⁺).

EXAMPLE 10
1-(7-Methoxy-2-(pyridin-3-yl)quinolin-3-yl)-N-(4-(trifluoromethoxy)benzyl)methanamine

1-(7-Methoxy-2-(pyridin-3-yl)quinolin-3-yl)-N-(4-(trifluoromethoxy)benzyl)methanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.85 (d, 1H), 8.62 (dd, 1H), 8.42 (s, 1H), 8.09 (dt, 1H), 7.91 (d, 2H), 7.46-7.36 (m, 4H), 7.28-7.22 (m, 2H), 3.90 (s, 3H), 3.72 (s, 2H), 3.70 (s, 2H). MS (ESI): 440.58 (M+H⁺).

EXAMPLE 11
4-(((7-Methoxy-2-(pyridin-3-yl)quinolin-3-yl)methylamino)methyl)-N,N-dimethylaniline

4-(((7-Methoxy-2-(pyridin-3-yl)quinolin-3-yl)methylamino)methyl)-N,N-dimethylaniline was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.86 (d, 1H), 8.66 (dd, 1H), 8.40 (s, 1H), 8.10 (dt, 1H), 7.95 (d, 2H), 7.55-7.40 (m, 2H), 7.26 (d, 2H), 7.06 (d, 1H), 6.62 (d, 1H), 3.91 (s, 3H), 3.90 (s, 2H), 3.89 (s, 2H), 3.31 (s, 6H). MS (ESI): 399.09 (M+H⁺).

EXAMPLE 12
1-(2-(Thiophen-3-yl)-7-(trifluoromethoxy)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine

1-(2-(Thiophen-3-yl)-7-(trifluoromethoxy)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.54 (s, 1H), 8.14 (d, 1H), 8.08 (dd, 1H), 7.88 (s, 1H), 7.66-7.54 (m, 7H), 3.92 (s, 2H), 3.85 (s, 2H). MS (ESI): 483.63 (M+H⁺).

EXAMPLE 13
2-(4-Chlorophenyl)-N-((2-(thiophen-3-yl)-7-(trifluoromethoxy)quinolin-3-yl)methyl)ethanamine

2-(4-Chlorophenyl)-N-((2-(thiophen-3-yl)-7-(trifluoromethoxy)quinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.42 (s, 1H), 8.09 (s, 1H), 8.07 (t, 1H), 7.87 (s, 1H), 7.63-7.50 (m, 3H), 7.30 (d, 2H), 7.24 (d, 2H), 3.89 (s, 2H), 2.80 (t, 2H), 2.73 (t, 2H). MS (ESI): 464.70 (M+H⁺).

EXAMPLE 14
2-(4-Chlorophenyl)-N-((2-(pyridin-3-yl)-7-(trifluoromethoxy)quinolin-3-yl)methyl)ethanamine

2-(4-Chlorophenyl)-N-((2-(pyridin-3-yl)-7-(trifluoromethoxy)quinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.86 (dd, 1H), 8.67 (dd, 1H), 8.50 (s, 1H), 8.14 (d, 1H), 8.11 (dt, 1H), 7.95 (s, 1H), 7.63 (dd, 1H), 7.48 (dd, 1H), 7.29 (d, 2H), 7.20 (d, 2H), 3.81 (s, 2H), 2.72-2.66 (m, 4H). MS (ESI): 458.00 (M+H⁺).

EXAMPLE 15
1-(2-(Pyridin-3-yl)-7-(trifluoromethoxy)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)-methanamine

1-(2-(Pyridin-3-yl)-7-(trifluoromethoxy)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine was prepared following the procedures described in preparation of Example 1. ¹H NMR (400 MHz, DMSO) 8.85 (t, 1H), 8.65 (q, 1H), 8.62 (s, 1H), 8.20 (d, 1H), 8.10 (m, 1H), 7.95 (s, 1H), 7.66 (m, 1H), 7.61 (s, 1H), 7.59 (s, 1H), 7.50-7.46 (m, 3H), 3.80 (s, 2H), 3.77 (s, 2H). MS (ESI): 477.87 (M+H⁺).

EXAMPLE 16
2-(4-Bromophenyl)-N-((2-(pyridin-3-yl)-7-(trifluoromethoxy)quinolin-3-yl)methyl)ethanamine

2-(4-Bromophenyl)-N-((2-(pyridin-3-yl)-7-(trifluoromethoxy)quinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 1. ¹H NMR (400 MHz, DMSO) 8.86 (q, 1H), 8.67 (q, 1H), 8.49 (1H), 8.14 (d, 1H), 8.11 (dt, 1H), 7.95 (s, 1H), 7.63 (dd, 1H), 7.50-7.46 (m, 1H), 7.44-7.41 (m, 2H), 7.15-7.20 (m, 2H), 3.81 (s, 2H), 2.71-2.64 (m, 4H). MS (ESI): 502.19 (M+H⁺).

EXAMPLE 17
N-((7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)-4-(trifluoromethyl)benzamide

Step 1
(7-Methoxy-2-(thiophen-3-yl)quinolin-3-yl)methanamine

(7-Methoxy-2-(thiophen-3-yl)quinolin-3-yl)methanamine was prepared following the procedures described in preparation of Example 1. MS (ESI): 271.43 (M+H⁺).

Step 2
N-((7-Methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)-4-(trifluoromethyl)benzamide

4-(Trifluoromethyl)benzoyl chloride (30.2 μL, 203 μmol) was added to a solution of (7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methanamine (55 mg, 203 μmol), TEA (43 μL, 305 μmol) and DCM (2 mL) at room temperature under nitrogen. The reaction mixture was stirred for 17 h prior to concentrating under vacuum. The residue was purified using column chromatography (hexanes to ethyl acetate) to afford 44 mg of N-((7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)-4-(trifluoromethyl)benzamide as a white solid. ¹H-NMR (400 MHz, DMSO) δ 8.51 (s, 1H), 8.11 (d, 2H), 7.95 (d, 1H), 7.93 (d, 1H), 7.87 (d, 2H), 7.66 (dd, 1H), 7.57 (dd, 1H), 7.40 (d, 1H), 7.26 (dd, 1H), 5.60 (s, 2H), 3.92 (s, 3H). MS (ESI): 443.43 (M+H⁺).

EXAMPLE 18
7-methoxy-2-(thiophen-3-yl)-N-(4-(trifluoromethyl)benzyl)quinoline-3-carboxamide

Step 1
Methyl 7-methoxy-2-(thiophen-3-yl)quinoline-3-carboxylate

A mixture of NIS (835 mg, 3.71 mmol), 7-methoxy-2-(thiophen-3-yl)quinoline-3-carbaldehyde (400 mg, 1.49 mmol), K₂CO₃(514 mg, 3.71 mmol) and MeOH (15 mL) was stirred at room temperature in the dark for 4 h. DCM (50 mL) and sat. aq. Na₂S₂O₃(50 mL) were added and the phases were separated. The organic layer was concentrated under vacuum to afford 424 mg of methyl 7-methoxy-2-(thiophen-3-yl)quinoline-3-carboxylate as an orange solid. MS (ESI): 300.12 (M+H⁺).

Step 2
7-Methoxy-2-(thiophen-3-yl)quinoline-3-carboxylic acid

A mixture of 10M LiOH (3.54 mL, 3.54 mmol), methyl 7-methoxy-2-(thiophen-3-yl)quinoline-3-carboxylate (424 mg, 1.42 mmol) and THF (10 mL) was heated to 50° C. for 40 h. 1M HCl (3.54 mL) was added and the phases were separated. The organic layer was concentrated under vacuum and the residue was purified using column chromatography (DCM to 9:1 DCM/MeOH) to afford 381 mg of 7-methoxy-2-(thiophen-3-yl)quinoline-3-carboxylic acid as a white solid. MS (ESI): 286.03 (M+H⁺).

Step 3
7-Methoxy-2-(thiophen-3-yl)-N-(4-(trifluoromethyl)benzyl)quinoline-3-carboxamide

A mixture of 7-methoxy-2-(thiophen-3-yl)quinoline-3-carboxylic acid (70 mg, 245 μmol), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (140 mg, 368 μmol), TEA (69 μL, 726 μmol) and DMF (3 mL) was stirred at room temperature for 30 min prior to the addition of (4-(trifluoromethyl)phenyl)methanamine (35 μL, 245 μmol). The reaction mixture was stirred for an additional 13 h then water (30 mL) and Et₂O (5 mL) were added. The phases were separated and the organic layer was concentrated under vacuum. The residue was purified using column chromatography (hexanes to ethyl acetate) to afford 68 mg of 7-methoxy-2-(thiophen-3-yl)-N-(4-(trifluoromethyl)benzyl)quinoline-3-carboxamide as a white solid. ¹H-NMR (400 MHz, DMSO) δ 9.20 (s, 1H), 8.34 (s, 1H), 7.94 (d, 1H), 7.77 (t, 1H), 7.68 (d, 2H), 7.56-7.48 (m, 4H), 7.39 (d, 1H), 7.27 (dd, 1H), 4.50 (d, 2H), 3.93 (s, 3H). MS (ESI): 442.82 (M+H⁺).

EXAMPLE 19
N-(4-Chlorophenethyl)-7-methoxy-2-(thiophen-3-yl)quinoline-3-carboxamide

N-(4-Chlorophenethyl)-7-methoxy-2-(thiophen-3-yl)quinoline-3-carboxamide was prepared following the procedures described in preparation of Example 18. ¹H-NMR (400 MHz, DMSO) δ 8.67 (t, 1H), 8.17 (s, 1H), 7.90 (d, 1H), 7.71 (dd, 1H), 7.55 (d, 1H), 7.54 (d, 1H), 7.50 (dd, 1H), 7.37 (d, 1H), 7.34 (d, 2H), 7.25 (d, 2H), 3.92 (s, 3H), 3.49 (m, 2H), 2.80 (t, 2H). MS (ESI): 422.78 (M+H⁺).

EXAMPLE 20
1-(7-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine

1-(7-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.24 (s, 1H), 8.01 (d, 1H), 7.80 (d, 1H), 7.67 (d, 2H), 7.60 (d, 2H), 7.29 (d, 1H), 7.15 (d, 1H), 7.13 (d, 1H), 3.94-3.86 (m, 4H), 3.89 (s, 3H), 3.88 (s, 3H). MS (ESI): 426.84 (M+H⁺).

EXAMPLE 21
2-(4-Chlorophenyl)-N-((7-methoxy-2-(1-methyl-1H-pyrazol-4-yl)quinolin-3-yl)methyl)ethanamine

2-(4-Chlorophenyl)-N-((7-methoxy-2-(1-methyl-1H-pyrazol-4-yl)quinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.21 (s, 1H), 8.15 (s, 1H), 8.00 (d, 1H), 7.74 (d, 1H), 7.32-7.24 (m, 4H), 7.15 (d, 1H), 7.12 (d, 1H), 3.90 (s, 2H), 3.89 (s, 3H), 3.87 (s, 3H), 2.85 (t, 2H), 2.77 (t, 2H). MS (ESI): 407.06 (M+H⁺).

EXAMPLE 22
2-(4-Chlorophenyl)-N-((7-methoxy-2-(pyridin-4-yl)quinolin-3-yl)methyl)ethanamine

2-(4-Chlorophenyl)-N-((7-methoxy-2-(pyridin-4-yl)quinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.63 (dd, 2H), 8.31 (s, 1H), 7.86 (d, 1H), 7.66 (dd, 2H), 7.40 (d, 1H), 7.32-7.24 (m, 3H), 7.20 (d, 2H), 3.87 (s, 3H), 3.74 (s, 2H), 2.74-2.64 (m, 4H). MS (ESI): 404.02 (M+H⁺).

EXAMPLE 23
1-(7-Methoxy-2-(pyridin-4-yl)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine

1-(7-Methoxy-2-(pyridin-4-yl)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.63 (dd, 2H), 8.43 (s, 1H), 7.91 (d, 1H), 7.65 (dd, 2H), 7.61 (d, 2H), 7.47 (d, 2H), 7.40 (d, 1H), 7.27 (dd, 1H), 3.90 (s, 3H), 3.77 (s, 2H), 3.72 (s, 2H). MS (ESI): 423.92 (M+H⁺).

EXAMPLE 24
1-(2-(2-Fluorophenyl)-7-methoxyquinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine

1-(2-(2-Fluorophenyl)-7-methoxyquinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.43 (s, 1H), 7.92 (d, 1H), 7.53 (d, 2H), 7.52-7.38 (m, 5H), 7.32-7.24 (m, 3H), 3.89 (s, 3H), 3.69 (s, 2H), 3.61 (s, 2H). MS (ESI): 441.07 (M+H⁺).

EXAMPLE 25
2-(4-Chlorophenyl)-N-((2-(2-fluorophenyl)-7-methoxyquinolin-3-yl)methyl)ethanamine

2-(4-Chlorophenyl)-N-((2-(2-fluorophenyl)-7-methoxyquinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.27 (s, 1H), 7.84 (d, 2H), 7.60-7.46 (m, 1H), 7.43 (dt, 1H), 7.37 (d, 1H), 7.33-7.24 (m, 4H), 7.14 (d, 2H), 3.88 (s, 3H), 3.63 (s, 2H), 3.15 (m, 2H), 2.60 (m, 2H). MS (ESI): 421.01 (M+H⁺).

EXAMPLE 26
1-(6-Methoxy-2-(thiophen-3-yl)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine

1-(6-Methoxy-2-(thiophen-3-yl)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.34 (s, 1H), 7.96 (dd, 1H), 7.86 (d, 1H), 7.65 (d, 2H), 7.60-7.54 (m, 4H), 7.38-7.32 (m, 2H), 3.89 (s, 3H), 3.88 (s, 2H), 3.84 (s, 2H). MS (ESI): 429.72 (M+H⁺).

EXAMPLE 27
2-(4-Chlorophenyl)-N-((6-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine

2-(4-Chlorophenyl)-N-((6-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.19 (s, 1H), 7.95 (dd, 1H), 7.85 (d, 1H), 7.58-7.52 (m, 2H), 7.34 (d, 1H), 7.34-7.22 (m, 5H), 3.89 (s, 3H), 3.86 (s, 2H), 2.80 (t, 2H), 2.73 (t, 2H). MS (ESI): 410.75 (M+H⁺).

EXAMPLE 28
1-(2-(Thiophen-3-yl)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)-methanamine

1-(2-(Thiophen-3-yl)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.14 (s, 1H), 8.04 (dd, 1H), 7.98-7.94 (m, 2H), 7.71 (dt, 1H), 7.65 (d, 2H), 7.62-7.54 (m, 5H), 3.90 (s, 2H), 3.85 (s, 2H). MS (ESI): 399.92 (M+H⁺).

EXAMPLE 29
2-(4-Chlorophenyl)-N-((2-(thiophen-3-yl)quinolin-3-yl)methyl)-ethanamine

2-(4-Chlorophenyl)-N-((2-(thiophen-3-yl)quinolin-3-yl)methyl)-ethanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.40 (s, 1H), 8.02 (dd, 1H), 7.96 (d, 1H), 7.89 (d, 1H), 7.70 (dt, 1H), 7.61-7.54 (m, 3H), 7.31 (d, 2H), 7.25 (d, 2H), 3.87 (s, 2H), 2.80 (t, 2H), 2.73 (t, 2H). MS (ESI): 379.08 (M+H⁺).

EXAMPLE 30
1-(7-methoxy-2-(thiazol-2-yl)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine

Step 1
7-Methoxy-2-(thiazol-2-yl)quinoline-3-carbaldehyde

Bis(triphenylphosphine)palladium(II) dichloride (94.0 mg, 134 μmol) was added to a nitrogen purged mixture of 2-chloro-7-methoxyquinoline-3-carbaldehyde (410 mg, 1.85 mmol), 2-(tributylstannyl)thiazole (610 μL, 1.94 mmol) and DMF (6.2 mL) at room temperature under nitrogen. The solution was heated to 90° C. for 3 h, then cooled to room temperature. KF (10 mL of a saturated aqueous solution) was added and the mixture stirred for 1 h. Ethyl acetate (10 mL) was added and the layers were separated. The organic layer was washed with brine and concentrated under vacuum. The product was purified using column chromatography (hexanes to ethyl acetate) to give 280 mg of 7-methoxy-2-(thiazol-2-yl)quinoline-3-carbaldehyde as a tan solid. MS (ESI): 271.04 (M+H⁺).

Step 2
1-(7-Methoxy-2-(thiazol-2-yl)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine

1-(7-Methoxy-2-(thiazol-2-yl)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.45 (s, 1H), 8.03 (d, 1H), 7.93 (s, 1H), 7.91 (d, 1H), 7.65 (d, 2H), 7.58 (d, 2H), 7.37 (d, 1H), 7.27 (dd, 1H), 4.32 (s, 2H), 3.94 (s, 3H), 3.85 (s, 2H). MS (ESI): 429.73 (M+H⁺).

EXAMPLE 31
2-(4-Chlorophenyl)-N-((7-methoxy-2-(thiazol-2-yl)quinolin-3-yl)methyl)ethanamine

2-(4-Chlorophenyl)-N-((7-methoxy-2-(thiazol-2-yl)quinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 30. ¹H-NMR (400 MHz, DMSO) δ 8.48 (s, 1H), 8.00-7.92 (m, 3H), 7.41 (d, 1H), 7.35 (d, 2H), 7.33 (d, 1H), 7.29 (d, 2H), 4.57 (s, 2H), 3.96 (s, 3H), 3.31 (s, 2H), 3.16 (t, 2H), 2.94 (t, 2H). MS (ESI): 411.67 (M+H⁺).

EXAMPLE 32
N-(4-Chlorophenethyl)-N-((7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)acetamide

A mixture of 2-(4-chlorophenyl)-N-((7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine (24.5 mg, 59.9 μmol), acetic anhydride (6.24 μL, 66.0 μmol), TEA (12.5 μL, 89.7 μmol), DMAP (2 mg, 16.4 μmol) and DCM (1 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum and the residue was purified using column chromatography (hexanes to ethyl acetate) to afford 12 mg of N-(4-chlorophenethyl)-N-((7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)acetamide as a white solid. MS (ESI): 450.86 (M+H⁺).

EXAMPLE 33
N-(4-Chlorophenethyl)-N-((7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)methanesulfonamide

A mixture of 2-(4-chlorophenyl)-N-((7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine (24.5 mg, 59.9 μmol), methanesulfonyl chloride (5.13 μL, 66.0 μmol), TEA (12.5 μL, 89.7 μmol) and DCM (1 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum and the residue was purified using column chromatography (hexanes to ethyl acetate) to afford 24 mg of N-(4-chlorophenethyl)-N-((7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)methanesulfonamide as a white solid. MS (ESI): 488.80 (M+H⁺).

EXAMPLE 34
2-(4-Bromophenyl)-N-((7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine

2-(4-Bromophenyl)-N-((7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.22 (s, 1H), 8.01 (t, 1H), 7.80 (d, 1H), 7.57 (d, 1H), 7.44 (d, 2H), 7.33 (d, 1H), 7.21-7.16 (m, 4H), 3.89 (s, 3H), 3.82 (s, 2H), 2.80 (t, 2H), 2.71 (t, 2H). MS (ESI): 454.83, 456.28 (M+H⁺).

EXAMPLE 35
2-(4-Chlorophenyl)-N-((7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)-N-methylethanamine

A mixture of 2-(4-chlorophenyl)-N-((7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine (10.0 mg, 24.0 μmol), formalin (35 μL, 432 μmol), AcOH (50 μL) and MeOH (500 μL) was stirred at room temperature for 30 min prior to the addition of sodium triacetoxyborohydride (16 mg, 73.0 μmol). The vented reaction mixture was stirred for an additional 30 minutes then 1M NaOH (5 mL) and ethyl acetate (5 mL) were added. The phases were separated and the organic layer was concentrated under vacuum. The residue was purified using column chromatography (hexanes to ethyl acetate) to afford 11 mg of 2-(4-chlorophenyl)-N-((7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)-N-methylethanamine as a white solid. ¹H-NMR (400 MHz, DMSO) δ 8.12 (s, 1H), 7.91 (dd, 1H), 7.77 (d, 1H), 7.63-7.54 (m, 2H), 7.32 (d, 1H), 7.30 (d, 2H), 7.22-7.18 (m, 3H), 3.90 (s, 3H), 3.61 (s, 2H), 2.76 (t, 2H), 2.62 (t, 2H), 2.23 (s, 3H). MS (ESI): 422.97 (M+H⁺).

EXAMPLE 36
2-(4-Bromophenyl)-N-((7-methoxy-2-(pyridin-4-yl)quinolin-3-yl)methyl)ethanamine

2-(4-Bromophenyl)-N-((7-methoxy-2-(pyridin-4-yl)quinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 1. ¹H NMR (400 MHz, DMSO) 8.64-8.62 (m, 2H), 8.31 (s, 1H), 7.87 (d, 1H), 7.67-7.65 (m, 2H), 7.44-7.42 (m, 2H), 7.40 (d, 1H), 7.27 (dd, 1H), 7.15-7.13 (m, 2H), 3.90 (s, 3H), 3.74 (s, 2H), 2.69 (dd, 4H). MS (ESI): 449.89 (M+H⁺).

EXAMPLE 37
1-(7-Methoxy-2-(oxazol-2-yl)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine

1-(7-Methoxy-2-(oxazol-2-yl)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine was prepared following the procedures described in preparation of Example 30. ¹H-NMR (400 MHz, DMSO) δ 8.46 (s, 1H), 8.34 (s, 1H), 7.93 (d, 1H), 7.64 (d, 2H), 7.56 (d, 2H), 7.50 (s, 1H), 7.47 (d, 1H), 7.31 (dd, 1H), 4.22 (s, 2H), 3.93 (s, 3H), 3.83 (s, 2H). MS (ESI): 414.07 (M+H⁺).

EXAMPLE 38
2-(4-Chlorophenyl)-N-((7-methoxy-2-(oxazol-2-yl)quinolin-3-yl)methyl)ethanamine

2-(4-Chlorophenyl)-N-((7-methoxy-2-(oxazol-2-yl)quinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 30. MS (ESI): 394.54 (M+H⁺).

EXAMPLE 39
2-(4-Bromophenyl)-N-((7-(methylthio)-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine

2-(4-Bromophenyl)-N-((7-(methylthio)-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.24 (s, 1H), 8.01 (dd, 1H), 7.79 (d, 1H), 7.66 (d, 1H), 7.60-7.57 (m, 2H), 7.45 (d, 2H), 7.41 (d, 1H), 7.17 (d, 2H), 3.84 (s, 2H), 2.80 (t, 2H), 2.71 (t, 2H), 2.59 (s, 3H). MS (ESI): 470.87, 472.38 (M+H⁺).

EXAMPLE 40
1-(7-(Methylthio)-2-(thiophen-3-yl)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine

1-(7-(Methylthio)-2-(thiophen-3-yl)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.37 (s, 1H), 8.03 (dd, 1H), 7.85 (d, 1H), 7.67 (d, 1H), 7.64 (d, 2H), 7.61-7.52 (m, 4H), 7.42 (dd, 1H), 3.86 (s, 2H), 3.84 (s, 2H), 2.60 (s, 3H). MS (ESI): 445.02 (M+H⁺).

EXAMPLE 41
1-(7-Chloro-2-(thiophen-3-yl)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine

1-(7-Chloro-2-(thiophen-3-yl)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.50 (s, 1H), 8.06-8.00 (m, 4H), 7.68-7.54 (m, 6H), 3.90 (s, 2H), 3.85 (s, 2H). MS (ESI): 432.96 (M+H⁺).

EXAMPLE 42
2-(4-Bromophenyl)-N-((7-chloro-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine

2-(4-Bromophenyl)-N-((7-chloro-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.37 (s, 1H), 8.05 (dd, 1H), 8.00 (d, 1H), 7.96 (d, 1H), 7.61 (d, 1H), 7.58 (d, 1H), 7.56 (d, 1H), 7.43 (d, 2H), 7.17 (d, 2H), 3.87 (s, 2H), 2.80 (t, 2H), 2.71 (t, 2H). MS (ESI): 458.82, 460.64 (M+H⁺).

EXAMPLE 43
2-(4-Bromophenyl)-N-((7-methyl-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine

2-(4-Bromophenyl)-N-((7-methyl-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.24 (s, 1H), 8.00 (dd, 1H), 7.78 (d, 1H), 7.75 (d, 1H), 7.60-7.55 (m, 2H), 7.45 (d, 2H), 7.39 (dd, 1H), 7.18 (d, 2H), 3.84 (s, 2H), 2.80 (t, 2H), 2.71 (t, 2H), 2.50 (s, 3H). MS (ESI): 438.86, 440.32 (M+H⁺).

EXAMPLE 44
1-(7-Methyl-2-(thiophen-3-yl)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine

1-(7-Methyl-2-(thiophen-3-yl)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.37 (s, 1H), 8.02 (dd, 1H), 7.84 (d, 1H), 7.76 (s, 1H), 7.65 (d, 2H), 7.62-7.54 (m, 4H), 7.40 (dd, 1H), 3.87 (s, 2H), 3.84 (s, 2H), 2.50 (s, 3H). MS (ESI): 413.09 (M+H⁺).

EXAMPLE 45
2-(4-Bromophenyl)-N-((7-ethoxy-2-(pyridin-3-yl)quinolin-3-yl)methyl)ethanamine

2-(4-Bromophenyl)-N-((7-ethoxy-2-(pyridin-3-yl)quinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.89 (d, 1H), 8.68 (dd, 1H), 8.11 (s, 1H), 7.94 (dt, 1H), 7.69 (d, 1H), 7.38 (m, 4H), 7.22 (dd, 1H), 7.01 (d, 2H), 3.86 (s, 2H), 2.83 (t, 2H), 2.71 (t, 2H). MS (ESI): 462.90 (M+H⁺).

EXAMPLE 46
1-(7-Ethoxy-2-(pyridin-3-yl)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine

1-(7-Ethoxy-2-(pyridin-3-yl)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, CDCl₃) δ 8.94 (s, 1H), 8.69 (dd, 1H), 8.21 (s, 1H), 8.00 (dt, 1H), 7.73 (d, 1H), 7.55 (d, 2H), 7.43 (d, 1H), 7.38 (m, 3H), 7.22 (dd, 1H), 4.19 (q, 2H), 3.88 (s, 1H), 3.83 (s, 1H), 1.50 (t, 3H). MS (ESI): 438.06 (M+H⁺).

EXAMPLE 47
2-(4-Bromophenyl)-N-((7-methoxy-2-phenylquinolin-3-yl)methyl)ethanamine

2-(4-Bromophenyl)-N-((7-methoxy-2-phenylquinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 1. ¹H NMR (400 MHz, DMSO) 8.05 (s, 1H), 7.62 (d, 1H), 7.40 (dd, 2H), 7.23-7.21 (m, 5H), 7.16 (d, 1H), 7.02 (dd, 1H), 6.92 (d, 2H), 3.68 (s, 3H), 3.55 (S, 2H), 2.46 (dd, 4H). MS (ESI): 448.88 (M+H⁺).

EXAMPLE 48
1-(7-Methoxy-2-phenylquinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine

1-(7-Methoxy-2-phenylquinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine was prepared following the procedures described in preparation of Example 1. ¹H NMR (400 MHz, DMSO) 8.20 (s, 1H), 7.68 (d, 1H), 7.41 (d, 4H), 7.28 (d, 2H), 7.22 (d, 3H), 7.17 (d, 1H), 7.03 (dd, 1H), 3.69 (s, 3H), 3.54 (d, 4H). MS (ESI): 423.22 (M+H⁺).

EXAMPLE 49
2-(4-Bromophenyl)-N-((7-ethoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine

2-(4-Bromophenyl)-N-((7-ethoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.01 (s, 1H), 7.79 (s, 1H), 7.57 (d, 1H), 7.37 (s, 2H), 7.22 (d, 1H), 7.04 (s, 1H), 6.98 (d, 2H), 3.98 (q, 2H), 3.59 (s, 2H), 2.59 (dt, 4H), 1.20 (t, 3H). MS (ESI): 467.86 (M+H⁺).

EXAMPLE 50
2-(4-Chlorophenyl)-N-((7-ethoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine

2-(4-Chlorophenyl)-N-((7-ethoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 7.99 (s, 1H), 7.79 (s, 1H), 7.57 (d, 1H), 7.34 (s, 2H), 7.09 (m, 3H), 7.02 (d, 2H), 6.94 (d, 1H), 3.93 (q, 2H), 3.59 (s, 2H), 2.59 (dt, 4H), 1.16 (t, 3H). MS (ESI): 423.02 (M+H⁺).

EXAMPLE 51
1-(7-Ethoxy-2-(thiophen-3-yl)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine

1-(7-Ethoxy-2-(thiophen-3-yl)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.10 (s, 1H), 7.79 (s, 1H), 7.61 (d, 1H), 7.41 (m, 2H), 7.34 (m, 4H), 7.09 (s, 1H), 6.95 (d, 1H), 3.98 (q, 2H), 3.59 (s, 2H), 2.59 (dt, 4H), 1.20 (t, 3H). MS (ESI): 467.86 (M+H⁺).

EXAMPLE 52
N-(4-Bromobenzyl)-1-(7-methoxy-2-(pyridin-4-yl)quinolin-3-yl)methanamine

N-(4-Bromobenzyl)-1-(7-methoxy-2-(pyridin-4-yl)quinolin-3-yl)methanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.64 (d, 2H), 8.42 (s, 1H), 7.91 (d, 1H), 7.65 (d, 2H), 7.44 (d, 2H), 7.40 (s, 1H), 7.27 (d, 1H), 7.21 (d, 2H), 3.90 (s, 3H), 3.70 (s, 2H), 3.65 (s, 2H). MS (ESI): 436.49, 438.23 (M+H⁺).

EXAMPLE 53
1-(5,7-Dimethoxy-2-(thiophen-3-yl)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine

1-(5,7-Dimethoxy-2-(thiophen-3-yl)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine was prepared following the procedures described in preparation of Example 1. MS (ESI): 458.98 (M+H⁺).

EXAMPLE 54
2-(4-Bromophenyl)-N-((5,7-dimethoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine

2-(4-Bromophenyl)-N-((5,7-dimethoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 1. MS (ESI): 484.82 (M+H⁺).

EXAMPLE 55
1-(7-Methoxy-2-(4-methylthiophen-3-yl)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine

1-(7-Methoxy-2-(4-methylthiophen-3-yl)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.36 (s, 1H), 7.88 (d, 1H), 7.64-7.59 (m, 3H), 7.47 (d, 2H), 7.34 (d, 1H), 7.24 (d, 1H), 7.21 (d, 1H), 3.88 (s, 3H), 3.74 (s, 2H), 3.64 (s, 2H), 2.04 (s, 3H). MS (ESI): 443.56 (M+H⁺).

EXAMPLE 56
2-(4-Bromophenyl)-N-((7-methoxy-2-(4-methylthiophen-3-yl)quinolin-3-yl)methyl)ethanamine

2-(4-Bromophenyl)-N-((7-methoxy-2-(4-methylthiophen-3-yl)quinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.21 (s, 1H), 7.81 (d, 1H), 7.56 (d, 1H), 7.41 (d, 2H), 7.32 (d, 1H), 7.24 (dd, 1H), 7.20 (d, 1H), 7.11 (d, 2H), 3.88 (s, 3H), 3.64 (s, 2H), 2.70-2.60 (m, 4H), 2.04 (s, 3H). MS (ESI): 469.51, 471.32 (M+H⁺).

EXAMPLE 57
2-(4-Bromophenyl)-N-((7-methoxy-2-(thiophen-2-yl)quinolin-3-yl)methyl)ethanamine

2-(4-Bromophenyl)-N-((7-methoxy-2-(thiophen-2-yl)quinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 1. ¹H NMR (400 MHz, DMSO) 8.24 (s, 1H), 7.78 (d, 1H), 7.76 (dd, 1H), 7.68 (dd, 1H), 7.46-7.42 (m, 2H), 7.28 (d, 1H), 7.21-7.17 (m, 3H), 7.11 (dd, 1H), 3.97 (s, 2H), 3.91 (s, 3H), 2.85 (t, 2H), 2.75 (t, 2H). MS (ESI): 454.82 (M+H⁺).

EXAMPLE 58
2-(4-Bromophenyl)-N-((2-(furan-2-yl)-7-methoxyquinolin-3-yl)methyl)ethanamine

2-(4-Bromophenyl)-N-((2-(furan-2-yl)-7-methoxyquinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 1. ¹H NMR (400 MHz, DMSO) 8.21 (s, 1H), 8.19 (s, 1H), 7.78 (d, 1H), 7.52 (t, 1H), 7.45-7.42 (m, 2H), 7.32 (d, 1H), 7.20-7.18 (m, 3H), 7.07 (t, 1H), 3.90 (s, 3H), 3.87 (s, 2H), 2.82 (t, 2H), 2.74 (t, 2H). MS (ESI): 438.84 (M+H⁺).

EXAMPLE 59
2-(3-Bromophenyl)-N-((7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine

2-(3-Bromophenyl)-N-((7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.22 (s, 1H), 8.02 (dd, 1H), 7.79 (d, 1H), 7.60-7.58 (m, 3H), 7.44 (s, 1H), 7.40-7.36 (m, 1H), 7.33 (d, 1H), 7.24-7.18 (m, 2H), 3.89 (s, 3H), 3.83 (s, 2H), 2.81 (t, 2H), 2.74 (t, 2H). MS (ESI): 455.05, 456.98 (M+H⁺).

EXAMPLE 60
1-(7-Methoxy-2-(thiophen-3-yl)quinolin-3-yl)-N-(4-methylbenzyl)methanamine

1-(7-Methoxy-2-(thiophen-3-yl)quinolin-3-yl)-N-(4-methylbenzyl)methanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.31 (s, 1H), 8.05 (dd, 1H), 7.84 (d, 1H), 7.62-7.58 (m, 2H), 7.34 (d, 1H), 7.21 (d, 2H), 7.18 (d, 1H), 7.09 (d, 2H), 3.89 (s, 3H), 3.82 (s, 2H), 3.70 (s, 2H), 2.26 (s, 3H). MS (ESI): 375.16 (M+H⁺).

EXAMPLE 61
2-(3,4-Dichlorophenyl)-N-((7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine

2-(3,4-Dichlorophenyl)-N-((7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.21 (s, 1H), 8.00 (dd, 1H), 7.78 (d, 1H), 7.58-7.48 (m, 4H), 7.33 (d, 1H), 7.24-7.18 (m, 2H), 3.89 (s, 3H), 3.81 (s, 2H), 2.81 (t, 2H), 2.73 (t, 2H). MS (ESI): 443.07 (M+H⁺).

EXAMPLE 62
N-Benzyl-1-(7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methanamine

N-Benzyl-1-(7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.33 (s, 1H), 8.06 (dd, 1H), 7.85 (d, 1H), 7.62-7.58 (m, 2H), 7.36-7.18 (m, 7H), 3.89 (s, 3H), 3.84 (s, 2H), 3.75 (s, 2H). MS (ESI): 361.16 (M+H⁺).

EXAMPLE 63
1-(7-Methoxy-2-(thiophen-3-yl)quinolin-3-yl)-N-(4-methoxybenzyl)methanamine

1-(7-Methoxy-2-(thiophen-3-yl)quinolin-3-yl)-N-(4-methoxybenzyl)methanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.31 (s, 1H), 8.06 (dd, 1H), 7.84 (s, 1H), 7.62-7.58 (m, 2H), 7.34 (d, 1H), 7.24 (d, 2H), 7.20 (dd, 1H), 6.85 (d, 2H), 3.89 (s, 3H), 3.82 (s, 2H), 3.71 (s, 3H), 3.68 (s, 2H). MS (ESI): 391.13 (M+H⁺).

EXAMPLE 64
1-(Benzo[d][1,3] dioxol-5-yl)-N-((7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)methanamine

1-(Benzo[d][1,3]dioxol-5-yl)-N-((7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)methanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.31 (s, 1H), 8.05 (d, 1H), 7.85 (d, 1H), 7.59 (d, 2H), 7.34 (d, 1H), 7.20 (dd, 1H), 6.93 (d, 1H), 6.80 (t, 1H), 6.76 (t, 1H), 5.96 (s, 2H), 3.90 (s, 3H), 3.81 (s, 2H), 3.66 (s, 2H). MS (ESI): 405.12 (M+H⁺).

EXAMPLE 65
2-(3-Bromo-4-methoxyphenyl)-N-((7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine

2-(3-Bromo-4-methoxyphenyl)-N-((7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.22 (s, 1H), 8.03 (dd, 1H), 7.80 (d, 1H), 7.60-7.57 (m, 2H), 7.43 (d, 1H), 7.33 (d, 1H), 7.20 (dd, 1H), 7.17 (dd, 1H), 6.99 (d, 1H), 3.89 (s, 3H), 3.82 (s, 2H), 3.79 (s, 3H), 2.78 (t, 2H), 2.67 (t, 2H). MS (ESI): 485.06, 487.01 (M+H⁺).

EXAMPLE 66
N-(3,4-Dichlorobenzyl)-1-(7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methanamine

N-(3,4-Dichlorobenzyl)-1-(7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methanamine was prepared following the procedures described in preparation of Example 1. ¹H NMR (400 MHz, DMSO) 8.32 (s, 1H), 8.02 (dd, 1H), 7.86 (d, 1H), 7.61-7.57 (m, 3H), 7.54 (d, 1H), 7.35-7.31 (m, 2H), 7.20 (dd, 1H), 3.90 (s, 3H), 3.87 (s, 2H), 3.75 (s, 2H). MS (ESI): 429.06 (M+H⁺).

EXAMPLE 67
1-(7-Methoxy-2-(thiophen-3-yl)quinolin-3-yl)-N-(4-nitrobenzyl)methanamine

1-(7-Methoxy-2-(thiophen-3-yl)quinolin-3-yl)-N-(4-nitrobenzyl)methanamine was prepared following the procedures described in preparation of Example 1. MS (ESI): 406.11 (M+H⁺).

EXAMPLE 68
N-((7-Methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)aniline

N-((7-Methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)aniline was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.26 (s, 1H), 7.98 (dd, 1H), 7.81 (d, 1H), 7.66 (dd, 1H), 7.63 (dd, 1H), 7.37 (d, 1H), 7.18 (dd, 1H), 7.30-7.00 (m, 2H), 6.58-6.50 (m, 3H), 6.27 (t, 1H), 4.40 (d, 2H), 3.90 (s, 3H). MS (ESI): 347.15 (M+H⁺).

EXAMPLE 69
4-Chloro-N-((7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)aniline

4-Chloro-N-((7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)aniline was prepared following the procedures described in preparation of Example 1. MS (ESI): 381.15 (M+H⁺).

EXAMPLE 70
1-(7-Methoxy-2-(thiophen-3-yl)quinolin-3-yl)-N-(pyridin-4-ylmethyl)methanamine

1-(7-Methoxy-2-(thiophen-3-yl)quinolin-3-yl)-N-(pyridin-4-ylmethyl)methanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.47 (d, 1H), 8.35 (s, 1H), 8.04 (dd, 1H), 7.86 (d, 1H), 7.62-7.58 (m, 2H), 7.36-7.32 (m, 4H), 7.20 (dd, 1H), 3.90 (s, 3H), 3.85 (s, 2H), 3.78 (s, 2H). MS (ESI): 362.15 (M+H⁺).

EXAMPLE 71
1-(7-Methoxy-2-(thiophen-3-yl)quinolin-3-yl)-N-((5-methylpyrazin-2-yl)methyl)methanamine

1-(7-Methoxy-2-(thiophen-3-yl)quinolin-3-yl)-N-((5-methylpyrazin-2-yl)methyl)methanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.55 (d, 1H), 8.43 (d, 1H), 8.33 (s, 1H), 8.06 (dd, 1H), 7.85 (d, 1H), 7.59 (d, 2H), 7.34 (d, 1H), 7.20 (dd, 1H), 3.90-3.84 (m, 7H), 2.45 (s, 3H). MS (ESI): 377.13 (M+H⁺).

EXAMPLE 72
1-(7-Methoxy-2-(thiophen-3-yl)quinolin-3-yl)-N-(pyridin-3-ylmethyl)methanamine

1-(7-Methoxy-2-(thiophen-3-yl)quinolin-3-yl)-N-(pyridin-3-ylmethyl)methanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.54 (d, 1H), 8.42 (dd, 1H), 8.37 (s, 1H), 8.05 (t, 1H), 7.85 (d, 1H), 7.74 (td, 1H), 7.59 (d, 2H), 7.34 (d, 1H), 7.32 (dd, 1H), 7.20 (dd, 1H), 3.90 (s, 3H), 3.85 (s, 2H), 3.77 (s, 2H). MS (ESI): 362.14 (M+H⁺).

EXAMPLE 73
N-((2-(Benzo[b]thiophen-3-yl)-7-methoxyquinolin-3-yl)methyl)-2-(4-bromophenyl)ethanamine

N-((2-(Benzo[b]thiophen-3-yl)-7-methoxyquinolin-3-yl)methyl)-2-(4-bromophenyl)ethanamine was prepared following the procedures described in preparation of Example 1. ¹H NMR (400 MHz, DMSO) 8.31 (s, 1H), 8.07-8.05 (m, 2H), 7.87 (d, 1H), 7.74 (dd, 1H), 7.43-7.34 (m, 5H), 7.26 (dd, 1H), 7.09 (m, 2H), 3.90 (s, 3H), 3.71 (s, 2H), 2.68 (t, 2H), 2.61 (t, 2H). MS (ESI): 505.10 (M+H⁺).

EXAMPLE 74
1-(7-Methoxy-2-(pyridin-4-yl)quinolin-3-yl)-N-(2,4,6-trimethoxybenzyl)methanamine

1-(7-Methoxy-2-(pyridin-4-yl)quinolin-3-yl)-N-(2,4,6-trimethoxybenzyl)methanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, CDCl₃) δ 8.84 (d, 2H), 8.54 (s, 1H), 7.85 (m, 2H), 7.79 (d, 1H), 7.42 (d, 1H), 7.35 (dd, 1H), 6.06 (s, 2H), 4.27 (bs, 2H), 4.18 (bs, 2H), 3.97 (s, 3H), 3.83 (s, 3H), 3.71 (s, 6H). MS (ESI): 446.19 (M+H⁺).

EXAMPLE 75
N-(4-tert-Butylbenzyl)-1-(7-methoxy-2-(pyridin-4-yl)quinolin-3-yl)methanamine

N-(4-tert-Butylbenzyl)-1-(7-methoxy-2-(pyridin-4-yl)quinolin-3-yl)methanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, CDCl₃) δ 8.81 (d, 2H), 8.48 (s, 1H), 7.99 (d, 2H), 7.59 (d, 1H), 7.35 (m, 2H), 7.32 (s, 1H), 7.21 (dd, 1H), 7.14 (d, 2H), 4.16 (bs, 2H), 3.93 (s, 3H), 3.87 (bs, 2H), 1.23 (s, 9H). MS (ESI): 412.22 (M+H⁺).

EXAMPLE 76
N-((7-Methoxy-2-(pyridin-4-yl)quinolin-3-yl)methyl)-2-(pyridin-3-yl)ethanamine

N-((7-Methoxy-2-(pyridin-4-yl)quinolin-3-yl)methyl)-2-(pyridin-3-yl)ethanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 9.08 (bs, 2H), 8.80 (dd, 2H), 8.61 (s, 1H), 8.57 (m, 2H), 7.96 (d, 1H), 7.90 (m, 1H), 7.72 (dd, 2H), 7.57 (m, 1H), 7.47 (d, 1H), 7.38 (dd, 1H), 4.36 (bs, 2H), 3.93 (s, 3H), 3.27 (bs, 2H), 2.97 (t, 2H). MS (ESI): 371.20 (M+H⁺).

EXAMPLE 77
1-(2-(Furan-2-yl)-7-methoxyquinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine

1-(2-(Furan-2-yl)-7-methoxyquinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine was prepared following the procedures described in preparation of Example 1. ¹H NMR (400 MHz, DMSO) 8.29 (s, 1H), 8.25 (t, 1H), 8.66 (d, 1H), 7.77 (t, 1H), 7.66 (d, 2H), 7.59 (d, 2H), 7.33 (d, 1H), 7.19 (dd, 1H), 7.09 (d, 1H), 3.90 (s, 7H). MS (ESI): 513.14 (M+H⁺).

EXAMPLE 78
1-(Furan-2-yl)-N-((7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)methanamine

1-(Furan-2-yl)-N-((7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)methanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.30 (s, 1H), 8.08 (dd, 1H), 7.79 (d, 1H), 7.62-7.57 (m, 3H), 7.34 (d, 1H), 7.21 (dd, 1H), 6.37 (dd, 1H), 6.25 (d, 1H), 3.90 (s, 3H), 3.83 (s, 2H), 3.75 (s, 2H). MS (ESI): 351.14 (M+H⁺).

EXAMPLE 79
2-(Thiophen-3-yl)-3-((4-(trifluoromethyl)benzylamino)methyl)quinolin-7-ol

A mixture of 1-(7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine (50.0 mg, 117 μmol), sodium sulphide (45 mg, 583 μmol) and NMP (2 mL) was heated to 140° C. for 16 h. The reaction mixture was cooled to room temperature then DCM (2 mL) and sat. aq. NH₄Cl (2 mL) were added. The phases were separated and the organic layer was concentrated under vacuum. The residue was purified using column chromatography (hexanes to ethyl acetate) to afford 18 mg of 2-(thiophen-3-yl)-3-((4-(trifluoromethyl)benzylamino)methyl)quinolin-7-ol as a white solid. ¹H-NMR (400 MHz, DMSO) δ 10.07 (s, 1H), 8.26 (s, 1H), 8.00 (dd, 1H), 7.78 (d, 1H), 7.65 (d, 2H), 7.59-7.51 (m, 4H), 7.18 (d, 1H), 7.11 (dd, 1H), 3.83 (s, 2H), 3.81 (s, 2H). MS (ESI): 415.12 (M+H⁺).

EXAMPLE 80
N-((7-Methoxy-2-(pyridin-4-yl)quinolin-3-yl)methyl)-2-(pyridin-2-yl)ethanamine

N-((7-Methoxy-2-(pyridin-4-yl)quinolin-3-yl)methyl)-2-(pyridin-2-yl)ethanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 9.12 (bs, 2H), 8.85 (dd, 2H), 8.65 (s, 1H), 8.51 (dd, 2H), 7.98 (d, 1H), 7.81 (m, 3H), 7.47 (d, 1H), 7.38 (dd, 1H), 7.34 (m, 2H), 4.41 (bs, 2H), 3.93 (s, 3H), 3.36 (bs, 2H), 3.10 (t, 2H). MS (ESI): 371.19 (M+H⁺).

EXAMPLE 81
N-((7-Methoxy-2-(pyridin-4-yl)quinolin-3-yl)methyl)-3-phenylpropan-1-amine

N-((7-Methoxy-2-(pyridin-4-yl)quinolin-3-yl)methyl)-3-phenylpropan-1-amine was prepared following the procedures described in preparation of Example 1.

¹H-NMR (400 MHz, DMSO) δ 8.82 (bs, 1H), 8.79 (dd, 2H), 8.59 (s, 1H), 7.59 (d, 1H), 7.70 (dd, 2H), 7.47 (d, 1H), 7.37 (dd, 2H), 7.28 (m, 2H), 7.19 (d, 1H), 7.15 (d, 2H), 4.30 (t, 2H), 3.93 (s, 3H), 2.88 (bs, 2H), 2.58 (t, 2H), 1.82 (quin, 2H). MS (ESI): 384.23 (M+H⁺).

EXAMPLE 82
3-((4-Bromophenethylamino)methyl)-2-(thiophen-3-yl)quinolin-7-ol

3-((4-Bromophenethylamino)methyl)-2-(thiophen-3-yl)quinolin-7-ol was prepared following the procedures described in preparation of Example 79. ¹H-NMR (400 MHz, DMSO) δ 10.06 (s, 1H), 8.14 (s, 1H), 7.97 (dd, 1H), 7.72 (d, 1H), 7.59-7.52 (m, 2H), 7.44 (d, 2H), 7.20-7.15 (m, 3H), 7.10 (dd, 1H), 3.79 (s, 2H), 2.79 (t, 2H), 2.71 (t, 2H). MS (ESI): 439.02, 441.04 (M+H⁺).

EXAMPLE 83
1-(7-methoxy-2-(pyridin-3-yloxy)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine

Step 1
7-Methoxy-2-(pyridin-3-yloxy)quinoline-3-carbaldehyde

A mixture of pyridin-3-ol (107 mg, 1.13 mmol), KO^tBu (119 mg, 1.24 mmol) and DMSO (4 mL) was stirred at room temperature under nitrogen for 30 min prior to the addition of 2-chloro-7-methoxyquinoline-3-carbaldehyde (250 mg, 1.13 mmol). The reaction mixture was heated to 90° C. for 10 min then cooled to room temperature. Water (50 mL) and ethyl acetate (10 mL) were added and the phases were separated. The organic layer was concentrated under vacuum and the residue was purified using column chromatography (hexanes to ethyl acetate) to afford 142 mg of 7-methoxy-2-(pyridin-3-yloxy)quinoline-3-carbaldehyde as a tan solid. MS (ESI): 281.11 (M+H⁺).

Step 2
1-(7-Methoxy-2-(pyridin-3-yloxy)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine

1-(7-Methoxy-2-(pyridin-3-yloxy)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.51 (d, 1H), 8.45 (dd, 1H), 8.30 (s, 1H), 7.82 (d, 1H), 7.74-7.62 (m, 5H), 7.50 (dd, 1H), 7.08 (dd, 1H), 6.94 (d, 1H), 3.92 (s, 2H), 3.91 (s, 2H), 3.80 (s, 3H). MS (ESI): 440.16 (M+H⁺).

EXAMPLE 84
2-(4-Bromophenyl)-N-((7-methoxy-2-(pyridin-3-yloxy)quinolin-3-yl)methyl)ethanamine

2-(4-Bromophenyl)-N-((7-methoxy-2-(pyridin-3-yloxy)quinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 83. ¹H-NMR (400 MHz, DMSO) δ 8.49 (d, 1H), 8.45 (dd, 1H), 8.18 (s, 1H), 7.76 (d, 1H), 7.65 (ddd, 1H), 7.50 (dd, 1H), 7.43 (d, 2H), 7.20 (d, 2H), 7.08 (dd, 1H), 6.93 (d, 1H), 3.94 (s, 2H), 3.79 (s, 3H), 2.84 (t, 2H), 2.76 (t, 2H). MS (ESI): 464.02, 466.04 (M+H⁺).

EXAMPLE 85
(R)—N-((7-Methoxy-2-(pyridin-4-yl)quinolin-3-yl)methyl)-1-p-tolylethanamine

(R)—N-((7-Methoxy-2-(pyridin-4-yl)quinolin-3-yl)methyl)-1-p-tolylethanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, CDCl₃) δ 8.73 (d, 2H), 8.50 (s, 1H), 7.85 (d, 2H), 7.67 (d, 1H), 7.33 (d, 1H), 7.23 (dd, 1H), 7.06 (dd, 4H), 3.90 (s, 3H), 3.49 (s, 2H), 2.34 (s, 3H), 1.10 (d, 3H). MS (ESI): 384.21 (M+H⁺).

EXAMPLE 86
(±)-N-((7-Methoxy-2-(pyridin-4-yl)quinolin-3-yl)methyl)-2,3-dihydro-1H-inden-1-amine

(±)-N-((7-Methoxy-2-(pyridin-4-yl)quinolin-3-yl)methyl)-2,3-dihydro-1H-inden-1-amine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, CDCl₃) δ 8.78 (d, 2H), 8.56 (s, 1H), 7.97 (d, 2H), 7.63 (d, 1H), 7.36 (d, 1H), 7.31 (t, 1H), 7.21 (dd, 1H), 7.15 (d, 1H), 7.07 (t, 1H), 4.48 (d, 1H), 4.18 (d, 1H), 3.99 (t, 1H), 3.92 (s, 3H), 2.95 (quin, 1H), 2.77 (m, 1H), 2.16 (m, 2H). MS (ESI): 382.16 (M+H⁺).

EXAMPLE 87
N-(2,4-Difluorobenzyl)-1-(7-methoxy-2-(pyridin-4-yl)quinolin-3-yl)methanamine

N-(2,4-Difluorobenzyl)-1-(7-methoxy-2-(pyridin-4-yl)quinolin-3-yl)methanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, CDCl₃) δ 8.84 (d, 2H), 8.55 (s, 1H), 8.06 (d, 2H), 7.70 (d, 1H), 7.36 (d, 1H), 7.29 (d, 1H), 6.78 (m, 2H), 4.31 (bs, 2H), 4.02 (bs, 2H), 3.93 (s, 3H). MS (ESI): 392.14 (M+H⁺).

EXAMPLE 88
N,N-Dimethyl-2-(thiophen-3-yl)-3-((4-(trifluoromethyl)benzylamino)methyl)quinolin-7-amine

N,N-Dimethyl-2-(thiophen-3-yl)-3-((4-(trifluoromethyl)benzylamino)methyl)quinolin-7-amine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.27-8.24 (m, 2H), 7.89 (d, 1H), 7.80-7.76 (m, 2H), 7.70-7.61 (m, 5H), 7.41 (d, 1H), 4.22 (s, 2H), 3.99 (s, 2H), 2.83 (s, 6H). MS (ESI): 442.13 (M+H⁺).

EXAMPLE 89
3-((4-Bromophenethylamino)methyl)-N,N-dimethyl-2-(thiophen-3-yl)quinolin-7-amine

3-((4-Bromophenethylamino)methyl)-N,N-dimethyl-2-(thiophen-3-yl)quinolin-7-amine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.44 (d, 1H), 8.39 (d, 1H), 8.02 (d, 1H), 7.98 (d, 1H), 7.93 (d, 1H), 7.72 (dd, 1H), 7.58 (d, 1H), 7.42 (d, 2H), 7.16 (d, 2H), 4.83 (s, 2H), 3.26 (t, 2H), 2.96 (t, 2H), 2.76 (s, 6H). MS (ESI): 466.02, 468.05 (M+H⁺).

EXAMPLE 90
1-(2-(Furan-3-yl)-7-methoxyquinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine

1-(2-(Furan-3-yl)-7-methoxyquinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.29 (s, 1H), 8.25 (d, 1H), 7.83 (d, 1H), 7.77 (dd, 1H), 7.66 (d, 2H), 7.59 (d, 2H), 7.33 (d, 1H), 7.19 (dd, 1H), 7.09 (dd, 1H), 3.92-3.88 (m, 7H). MS (ESI): 413.21 (M+H⁺).

EXAMPLE 91
2-(4-Bromophenyl)-N-((2-(furan-3-yl)-7-methoxyquinolin-3-yl)methyl)ethanamine

2-(4-Bromophenyl)-N-((2-(furan-3-yl)-7-methoxyquinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.21 (d, 1H), 8.19 (s, 1H), 7.78 (d, 1H), 7.76 (t, 1H), 7.43 (d, 2H), 7.32 (d, 1H), 7.22-7.16 (m, 3H), 7.07 (d, 1H), 3.90 (s, 3H), 3.88 (s, 2H), 2.83 (t, 2H), 2.74 (t, 2H). MS (ESI): 437.15, 439.16 (M+H⁺).

EXAMPLE 92
N-(3-Chloro-4-fluorobenzyl)-1-(7-methoxy-2-(pyridin-4-yl)quinolin-3-yl)methanamine

N-(3-Chloro-4-fluorobenzyl)-1-(7-methoxy-2-(pyridin-4-yl)quinolin-3-yl)methanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 9.39 (bs, 2H), 8.82 (bs, 1H), 8.73 (d, 2H), 8.62 (s, 1H), 8.54 (s, 1H), 8.07 (d, 1H), 7.94 (d, 1H), 7.80 (m, 1H), 7.69 (dd, 1H), 7.63 (dd, 2H), 7.43 (m, 4H), 7.34 (m, 2H), 4.32 (bs, 2H), 4.20 (bs, 2H), 3.92 (s, 3H). MS (ESI): 408.12 (M+H⁺).

EXAMPLE 93
3-(2-((7-Methoxy-2-(pyridin-4-yl)quinolin-3-yl)methylamino)ethyl)-1H-indol-5-ol

3-(2-((7-Methoxy-2-(pyridin-4-yl)quinolin-3-yl)methylamino)ethyl)-1H-indol-5-ol was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 10.75 (s, 1H), 10.62 (s, 1H), 9.71 (bs, 1H), 9.36 (bs, 1H), 8.92 (m, 4H), 8.81 (dd, 4H), 8.61 (s, 1H), 8.48 (s, 1H), 8.34 (s, 1H), 8.00 (m, 4H), 7.84 (d, 1H), 7.74 (d, 1H), 7.44 (m, 5H), 7.11 (m, 3H), 6.82 (dd, 2H), 6.62 (dt, 2H), 5.84 (bs, 1H), 4.61 (s, 1H), 4.38 (t, 3H), 3.93 (s, 3H), 3.20 (bs, 1H), 3.15 (s, 6H), 2.90 (t, 3H). MS (ESI): 424.17 (M+H⁺).

EXAMPLE 94
1-(7-Methoxy-2-(pyridin-4-ylthio)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine

1-(7-Methoxy-2-(pyridin-4-ylthio)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)methanamine was prepared following the procedures described in preparation of Example 83. ¹H-NMR (400 MHz, DMSO) δ 8.50 (dd, 2H), 8.28 (s, 1H), 7.87 (d, 1H), 7.65 (d, 2H), 7.59 (d, 2H), 7.43 (dd, 2H), 7.21 (dd, 1H), 7.13 (d, 1H), 3.88-3.34 (m, 7H). MS (ESI): 456.14 (M+H⁺).

EXAMPLE 95
2-(4-Chlorophenyl)-N-((7-methoxy-2-(pyridin-4-ylthio)quinolin-3-yl)methyl)ethanamine

2-(4-Chlorophenyl)-N-((7-methoxy-2-(pyridin-4-ylthio)quinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 83. ¹H-NMR (400 MHz, DMSO) δ 8.50 (dd, 2H), 8.17 (s, 1H), 7.81 (d, 1H), 7.42 (dd, 2H), 7.29 (d, 2H), 7.24-7.19 (m, 3H), 7.12 (d, 1H), 3.87 (d, 2H), 3.84 (s, 3H), 2.78 (t, 2H), 2.73 (t, 2H). MS (ESI): 436.15 (M+H⁺).

EXAMPLE 96
3-((4-Bromophenethylamino)methyl)-2-(pyridin-4-yl)quinolin-7-ol

3-((4-Bromophenethylamino)methyl)-2-(pyridin-4-yl)quinolin-7-ol was prepared following the procedures described in preparation of Example 79. ¹H-NMR (400 MHz, DMSO) δ 10.18 (s, 1H), 8.61 (dd, 2H), 8.22 (s, 1H), 7.78 (d, 1H), 7.63 (dd, 2H), 7.42 (d, 2H), 7.22-7.10 (m, 3H), 3.70 (s, 2H), 2.70 (t, 2H), 2.65 (t, 2H). MS (ESI): 436.05, 438.02 (M+H⁺).

EXAMPLE 97
2-(4-Bromophenyl)-N-((6,7-dimethoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine

2-(4-Bromophenyl)-N-((6,7-dimethoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 1. MS (ESI): 485.07 (M+H⁺).

EXAMPLE 98
3-((4-Bromophenethylamino)methyl)-2-(thiophen-3-yl)quinoline-6,7-diol

3-((4-Bromophenethylamino)methyl)-2-(thiophen-3-yl)quinoline-6,7-diol was prepared following the procedures described in preparation of Example 79. MS (ESI): 457.02 (M+H⁺).

EXAMPLE 99
3-((4-bromophenethylamino)methyl)-7-methoxy-2-(thiophen-3-yl)quinolin-6-ol

Step 1
4-Amino-2-methoxyphenol

10% Pd/C (10.0 g) was added to a nitrogen purged solution of 2-methoxy-4-nitrophenol (10.0 g. 59.0 mmol) and EtOH (200 mL) at room temperature. The reaction mixture was purged with H₂then shaken under 60 psi of H₂for 14 h. The reaction mixture was filtered through Celite® (50 g) and washed with EtOH (50 mL). The filtrate was concentrated under vacuum to afford 4.82 g of 4-amino-2-methoxyphenol as a tan solid. ¹H-NMR (400 MHz, DMSO) δ 6.44 (d, 1H), 6.21 (d, 1H), 5.96 (dd, 1H), 4.44 (bs, 2H), 3.65 (s, 3H).

Step 2
4-Acetamido-2-methoxyphenyl acetate

4-Acetamido-2-methoxyphenyl acetate was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 9.97 (s, 1H), 7.40 (d, 1H), 7.09 (dd, 1H), 6.95 (d, 1H), 3.70 (s, 3H), 2.21 (s, 3H), 2.02 (s, 3H). MS (ESI): 223.46 (M+H⁺).

Step 3
2-Chloro-6-hydroxy-7-methoxyquinoline-3-carbaldehyde

2-Chloro-6-hydroxy-7-methoxyquinoline-3-carbaldehyde was prepared following the procedures described in preparation of Example 1. MS (ESI): 238.36 (M+H⁺).

Step 4
6-Hydroxy-7-methoxy-2-(thiophen-3-yl)quinoline-3-carbaldehyde

6-Hydroxy-7-methoxy-2-(thiophen-3-yl)quinoline-3-carbaldehyde was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 10.18 (s, 1H), 10.15 (s, 1H), 8.60 (s, 1H), 7.89 (dd, 1H), 7.70 (q, 1H), 7.53 (dd, 1H), 7.42 (s, 1H), 7.36 (s, 1H), 3.98 (s, 3H). MS (ESI): 286.43 (M+H⁺).

Step 5
3-((4-Bromophenethylamino)methyl)-7-methoxy-2-(thiophen-3-yl)quinolin-6-ol

A mixture of 6-hydroxy-7-methoxy-2-(thiophen-3-yl) quinoline-3-carbaldehyde (1.14 g, 4.00 mmol), 2-(4-bromophenyl)ethanamine (620 μL, 4.00 mmol) and DCE (20 mL) was heated to 80° C. for 1 h. The reaction mixture was cooled to room temperature and sodium cyanoborohydride (753 mg, 12.0 mmol) was added. The vented reaction mixture was stirred for 14 h prior to the addition of DCM (50 mL) and sat. aq. NaHCO₃(50 mL). The phases were separated and the organic layer was concentrated under vacuum. The residue was purified using column chromatography (hexanes to ethyl acetate) to afford 1.08 g of 3-((4-bromophenethylamino)methyl)-7-methoxy-2-(thiophen-3-yl)quinolin-6-ol as a white solid. ¹H-NMR (400 MHz, DMSO) δ 9.76 (s, 1H), 8.02 (s, 1H), 7.91 (dd, 1H), 7.56-7.51 (m, 2H), 7.43 (d, 2H), 7.29 (s, 1H), 7.18 (d, 2H), 7.09 (s, 1H), 3.91 (s, 3H), 3.79 (s, 2H), 2.80 (t, 2H), 2.71 (t, 2H). MS (ESI): 469.09, 471.11 (M+H⁺).

EXAMPLE 100
3-((4-Bromophenethylamino)methyl)-2-phenylquinolin-7-ol was prepared

3-((4-Bromophenethylamino)methyl)-2-phenylquinolin-7-ol was prepared following the procedures described in preparation of Example 79. ¹H-NMR (400 MHz, CDCl₃) δ 9.02 (s, 1H), 7.81 (d, 1H), 7.65 (t, 1H), 7.54 (m, 2H), 7.47 (m, 2H), 7.41 (dd, 2H), 7.13 (dd, 1H), 7.07 (d, 2H), 6.72 (bs, 1H), 4.25 (bs, 2H), 3.20 (bs, 2H), 3.02 (t, 3H). MS (ESI): 434.05 (M+H⁺).

EXAMPLE 101
3-((3,4-Dichlorophenethylamino)methyl)-2-(thiophen-3-yl)quinolin-7-ol

3-((3,4-Dichlorophenethylamino)methyl)-2-(thiophen-3-yl)quinolin-7-ol was prepared following the procedures described in preparation of Example 79. ¹H-NMR (400 MHz, MeOH) δ 8.87 (d, 1H), 8.00 (m, 2H), 7.72 (m, 1H), 7.40 (m, 4H), 7.10 (m, 2H), 4.43 (d, 2H), 3.20 (bs, 2H), 3.07 (m, 2H), 2.82 (m, 2H). MS (ESI): 428.09 (M+H⁺).

EXAMPLE 102
N-(4-bromophenethyl)-2-(7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)ethanamine

Step 1
3-(2-Chloroethyl)-7-methoxy-2-(thiophen-3-yl)quinoline

3-(2-Chloroethyl)-7-methoxy-2-(thiophen-3-yl)quinoline was prepared following the procedures described in preparation of Example 1. MS (ESI): 304.03 (M+H⁺).

A mixture of 3-(2-chloroethyl)-7-methoxy-2-(thiophen-3-yl)quinoline (58 mg, 190 μmol), 2-(4-bromophenyl)ethanamine (30 μL, 190 μmol) and EtOH (1 mL) was heated to 120° C. in a sealed tube for 17 h. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was purified using column chromatography (DCM to 9:1 DCM/MeOH) to afford 77 mg of N-(4-bromophenethyl)-2-(7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)ethanamine as a white solid. ¹H-NMR (400 MHz, DMSO) δ 8.13 (s, 1H), 7.83 (dd, 1H), 7.79 (d, 1H), 7.65 (dd, 1H), 7.46 (dd, 1H), 7.41 (d, 2H), 7.32 (d, 1H), 7.20 (dd, 1H), 7.11 (d, 2H), 3.89 (s, 3H), 2.98 (t, 2H), 2.80 (t, 2H), 2.73 (t, 2H), 2.62 (t, 2H). MS (ESI): 467.09, 469.06 (M+H⁺).

EXAMPLE 103
3-((4-Bromophenethylamino)methyl)-2-(furan-2-yl)quinolin-7-ol

3-((4-Bromophenethylamino)methyl)-2-(furan-2-yl)quinolin-7-ol was prepared following the procedures described in preparation of Example 79. ¹H-NMR (400 MHz, DMSO) δ 10.05 (s, 1H), 8.18 (s, 1H), 8.11 (s, 1H), 7.74 (d, 1H), 7.72 (d, 1H), 7.43 (d, 2H), 7.21-7.14 (m, 3H), 7.08 (dd, 1H), 7.03 (d, 1H), 3.84 (s, 2H), 2.82 (t, 2H), 2.73 (t, 2H). MS (ESI): 423.05, 425.05 (M+H⁺).

EXAMPLE 104
3-(2-(4-Bromophenethylamino)ethyl)-2-(thiophen-3-yl)quinolin-7-ol

3-(2-(4-Bromophenethylamino)ethyl)-2-(thiophen-3-yl)quinolin-7-ol was prepared following the procedures described in preparation of Example 79. ¹H-NMR (400 MHz, DMSO) δ 10.06 (s, 1H), 8.06 (s, 1H), 7.79 (dd, 1H), 7.72 (d, 1H), 7.63 (dd, 1H), 7.44-7.40 (m, 3H), 7.16 (d, 1H), 7.14-7.10 (m, 3H), 2.95 (t, 2H), 2.80 (t, 2H), 2.75 (t, 2H), 2.63 (t, 2H). MS (ESI): 453.05, 455.05 (M+H⁺).

EXAMPLE 105
3-((4-Chlorophenethylamino)methyl)-2-(thiophen-3-yl)quinolin-6-ol

3-((4-Chlorophenethylamino)methyl)-2-(thiophen-3-yl)quinolin-6-ol was prepared following the procedures described in preparation of Example 79. ¹H-NMR (400 MHz, DMSO) δ 9.96 (s, 1H), 8.09 (s, 1H), 7.92 (dd, 1H), 7.79 (d, 1H), 7.55 (dd, 1H), 7.52 (dd, 1H), 7.31 (d, 2H), 7.26 (d, 1H), 7.24 (d, 2H), 7.08 (d, 1H), 3.82 (s, 2H), 2.80 (t, 2H), 2.73 (t, 2H). MS (ESI): 395.10 (M+H⁺).

EXAMPLE 106
2-(7-Methoxy-2-(thiophen-3-yl)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)ethanamine

2-(7-Methoxy-2-(thiophen-3-yl)quinolin-3-yl)-N-(4-(trifluoromethyl)benzyl)ethanamine was prepared following the procedures described in preparation of Example 102. ¹H-NMR (400 MHz, DMSO) δ 8.13 (s, 1H), 7.82-7.79 (m, 2H), 7.63-7.59 (m, 3H), 7.47-7.40 (m, 3H), 7.31 (d, 1H), 7.19 (dd, 1H), 3.88 (s, 3H), 3.72 (s, 2H), 3.00 (t, 2H), 2.70 (t, 2H). MS (ESI): 443.16 (M+H⁺).

EXAMPLE 107
2-(Thiophen-3-yl)-3-(2-(4-(trifluoromethyl)benzylamino)ethyl)quinolin-7-ol

2-(Thiophen-3-yl)-3-(2-(4-(trifluoromethyl)benzylamino)ethyl)quinolin-7-ol was prepared following the procedures described in preparation of Example 79. ¹H-NMR (400 MHz, DMSO) δ 10.04 (s, 1H), 8.06 (s, 1H), 7.76 (dd, 1H), 7.72 (d, 1H), 7.63-7.60 (m, 3H), 7.46 (d, 2H), 7.42 (dd, 1H), 7.15 (d, 1H), 7.10 (dd, 1H), 3.75 (s, 2H), 2.98 (t, 2H), 2.71 (t, 2H). MS (ESI): 429.15 (M+H⁺).

EXAMPLE 108
3-((4-Bromophenethylamino)methyl)-2-(thiophen-2-yl)quinolin-7-ol

3-((4-Bromophenethylamino)methyl)-2-(thiophen-2-yl)quinolin-7-ol was prepared following the procedures described in preparation of Example 79. ¹H-NMR (400 MHz, DMSO) δ 10.12 (s, 1H), 8.17 (s, 1H), 7.74 (d, 1H), 7.72 (d, 1H), 7.65 (dd, 1H), 7.43 (d, 2H), 7.19 (d, 2H), 7.14 (d, 1H), 7.11-7.08 (m, 2H), 3.94 (s, 2H), 2.84 (t, 2H), 2.74 (t, 2H). MS (ESI): 439.01, 441.02 (M+H⁺).

EXAMPLE 109
3-((4-Bromophenethylamino)methyl)-2-(furan-3-yl)quinolin-7-ol

3-((4-Bromophenethylamino)methyl)-2-(furan-3-yl)quinolin-7-ol was prepared following the procedures described in preparation of Example 79. ¹H-NMR (400 MHz, DMSO) δ 10.04 (s, 1H), 8.18 (s, 1H), 8.11 (s, 1H), 7.74 (d, 1H), 7.71 (d, 1H), 7.44 (d, 2H), 7.20-7.16 (m, 3H), 7.08 (dd, 1H), 7.03 (d, 1H), 3.84 (s, 2H), 2.81 (t, 2H), 2.73 (t, 2H). MS (ESI): 423.41, 425.12 (M+H⁺).

EXAMPLE 110
2-(4-Bromophenyl)-N-((6-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine

2-(4-Bromophenyl)-N-((6-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.19 (s, 1H), 7.95 (dd, 1H), 7.85 (d, 1H), 7.57 (dd, 1H), 7.54 (dd, 1H), 7.44 (d, 2H), 7.33 (dd, 1H), 7.26 (d, 1H), 7.18 (d, 2H), 3.89 (s, 3H), 3.85 (s, 2H), 2.79 (t, 2H), 2.71 (t, 2H). MS (ESI): 453.05, 455.05 (M+H⁺).

EXAMPLE 111
2-(Thiophen-3-yl)-3-((4-(trifluoromethyl)benzylamino)methyl)quinolin-6-ol

2-(Thiophen-3-yl)-3-((4-(trifluoromethyl)benzylamino)methyl)quinolin-6-ol was prepared following the procedures described in preparation of Example 79. ¹H-NMR (400 MHz, DMSO) δ 9.97 (s, 1H), 8.19 (s, 1H), 7.93 (dd, 1H), 7.80 (d, 1H), 7.65 (d, 2H), 7.58-7.50 (m, 4H), 7.25 (dd, 1H), 7.11 (d, 1H), 3.86-3.82 (m, 4H). MS (ESI): 415.10 (M+H⁺).

EXAMPLE 112
3-((4-Bromophenethylamino)methyl)-2-(thiophen-3-yl)quinolin-6-ol

3-((4-Bromophenethylamino)methyl)-2-(thiophen-3-yl)quinolin-6-ol was prepared following the procedures described in preparation of Example 79. ¹H-NMR (400 MHz, DMSO) δ 9.95 (s, 1H), 8.09 (s, 1H), 7.92 (dd, 1H), 7.79 (d, 1H), 7.57-7.51 (m, 2H), 7.44 (d, 2H), 7.25 (dd, 1H), 7.17 (d, 2H), 7.07 (d, 1H), 3.81 (s, 2H), 2.79 (t, 2H), 2.71 (t, 2H). MS (ESI): 439.11, 441.10 (M+H⁺).

EXAMPLE 113
3-((4-Bromophenethylamino)methyl)-6-methoxy-2-(thiophen-3-yl)quinolin-7-ol

3-((4-Bromophenethylamino)methyl)-6-methoxy-2-(thiophen-3-yl)quinolin-7-ol was prepared following the procedures described in preparation of Example 99. ¹H-NMR (400 MHz, CDCl₃) δ 10.02 (s, 1H), 7.81 (s, 1H), 7.59 (dd, 1H), 7.37-7.29 (m, 5H), 6.96 (d, 2H), 6.85 (s, 1H), 3.94 (s, 3H), 3.86 (s, 2H), 2.80 (t, 2H), 2.68 (t, 2H). MS (ESI): 469.05, 471.07 (M+H⁺).

EXAMPLE 114
3-((4-Bromophenethylamino) methyl)-2-(thiophen-3-yl)quinoline-7-thiol

3-((4-Bromophenethylamino)methyl)-2-(thiophen-3-yl)quinoline-7-thiol was prepared following the procedures described in preparation of Example 79. ¹H-NMR (400 MHz, DMSO) δ 8.30 (s, 1H), 8.06 (d, 1H), 7.98 (d, 1H), 7.94 (d, 1H), 7.73 (dd, 1H), 7.55 (d, 1H), 7.52 (d, 1H), 7.41 (d, 2H), 7.15 (d, 2H), 3.83 (s, 2H), 2.76 (t, 2H), 2.68 (t, 2H), 2.65 (s, 1H). MS (ESI): 455.06, 457.02 (M+H⁺).

EXAMPLE 115
7-Methoxy-2-(thiophen-3-yl)-N-(4-(trifluoromethyl)benzyl)quinolin-3-amine

A mixture of 7-methoxy-2-(thiophen-3-yl)quinolin-3-amine (74 mg, 290 μmol), 4-(trifluoromethyl)benzaldehyde (39 μL, 290 μmol), glacial acetic acid (100 μL) and isopropyl alcohol (2 mL) was heated to 60° C. for 30 minutes then cooled to room temperature. Sodium triacetoxyborohydride (180 mg, 860 μmol) was added and the vented reaction mixture was stirred for 1 h. DCM (5 mL) and 1M NaOH (5 mL) were added and the phases were separated. The organic layer was washed with brine (5 mL) and concentrated under vacuum. The product was purified using column chromatography (hexanes to ethyl acetate) to give 18 mg of 7-methoxy-2-(thiophen-3-yl)-N-(4-(trifluoromethyl)benzyl)quinolin-3-amine as a white solid. ¹H-NMR (400 MHz, DMSO) δ 8.11 (dd, 1H), 7.72-7.63 (m, 6H), 7.49 (d, 2H), 7.19 (d, 1H), 7.07 (s, 1H), 7.02 (dd, 1H), 4.50 (d, 2H), 3.81 (s, 3H). MS (ESI): 415.15 (M+H⁺).

EXAMPLE 116
N-(4-Bromophenethyl)-7-methoxy-2-(thiophen-3-yl)quinolin-3-amine

N-(4-Bromophenethyl)-7-methoxy-2-(thiophen-3-yl)quinolin-3-amine was prepared following the procedures described in preparation of Example 115. ¹H-NMR (400 MHz, DMSO) δ 7.86 (dd, 1H), 7.67-7.64 (m, 2H), 7.50-7.46 (m, 3H), 7.35 (s, 1H), 7.25 (d, 2H), 7.20 (d, 1H), 7.08 (dd, 1H), 4.98 (t, 1H), 3.83 (s, 3H), 3.36 (dt, 2H), 2.92 (t, 2H). MS (ESI): 439.08, 441.03 (M+H⁺).

EXAMPLE 117
2-(4-Chlorophenyl)-N-((2-(furan-3-yl)-7-methoxyquinolin-3-yl)methyl)ethanamine

2-(4-Chlorophenyl)-N-((2-(furan-3-yl)-7-methoxyquinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.21 (s, 1H), 8.19 (s, 1H), 7.78 (d, 1H), 7.75 (dd, 1H), 7.33 (d, 1H), 7.29 (d, 2H), 7.25 (d, 2H), 7.18 (dd, 1H), 7.07 (d, 1H), 3.90 (s, 3H), 3.88 (s, 2H), 2.83 (t, 2H), 2.76 (t, 2H). MS (ESI): 393.15 (M+H⁺).

EXAMPLE 118
3-((4-Chlorophenethylamino)methyl)-2-(furan-3-yl)quinolin-7-ol

3-((4-Chlorophenethylamino)methyl)-2-(furan-3-yl)quinolin-7-ol was prepared following the procedures described in preparation of Example 79. ¹H-NMR (400 MHz, DMSO) δ 10.05 (s, 1H), 8.18 (s, 1H), 8.12 (s, 1H), 7.74 (d, 1H), 7.71 (d, 1H), 7.30 (d, 2H), 7.25 (d, 2H), 7.17 (d, 1H), 7.08 (dd, 1H), 7.03 (d, 1H), 3.84 (s, 2H), 2.82 (t, 2H), 2.75 (t, 2H). MS (ESI): 379.14 (M+H⁺).

EXAMPLE 119
N-((7-Methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)-2-(quinolin-5-yloxy)acetamide

N-((7-Methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)-2-(quinolin-5-yloxy)acetamide was prepared following the procedures described in preparation of Example 1. MS (ESI): 456.01 (M+H⁺).

EXAMPLE 120
3-((4-Bromophenethylamino)methyl)-4-methyl-2-(thiophen-3-yl)quinolin-7-ol

3-((4-Bromophenethylamino)methyl)-4-methyl-2-(thiophen-3-yl)quinolin-7-ol was prepared following the procedures described in preparation of Example 79. ¹H-NMR (400 MHz, CDCl₃) δ 7.67 (bs, 1H), 7.54 (m, 5H), 7.31 (m, 1H), 7.02 (d, 2H), 6.94 (bs, 1H), 6.72 (bs, 1H), 3.91 (bs, 2H), 2.87 (t, 2H), 2.74 (t, 2H). MS (ESI): 453.16 (M+H⁺).

EXAMPLE 121
N-((7-Methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)-2-(quinolin-5-yloxy)ethanamine

N-((7-Methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)-2-(quinolin-5-yloxy)ethanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, CDCl₃) δ 8.92 (dd, 1H), 8.52 (d, 1H), 8.19 (s, 1H), 7.89 (d, 1H), 7.72-7.55 (m, 4H), 7.45-7.35 (m, 3H), 7.24 (dd, 1H), 6.85 (d, 1H), 4.28 (t, 2H), 4.11 (s, 2H), 3.94 (s, 3H), 3.20 (t, 2H). MS (ESI): 442.30 (M+H⁺).

EXAMPLE 122
7-Methoxy-2-(thiophen-3-yl)-3-((4-(trifluoromethyl)benzylamino)methyl)quinolin-6-ol

7-Methoxy-2-(thiophen-3-yl)-3-((4-(trifluoromethyl)benzylamino)methyl)quinolin-6-ol was prepared following the procedures described in preparation of Example 99. ¹H-NMR (400 MHz, DMSO) δ 9.77 (s, 1H), 8.11 (s, 1H), 7.93 (dd, 1H), 7.65 (d, 1H), 7.58-7.50 (m, 5H), 7.30 (s, 1H), 7.12 (s, 1H), 3.92 (s, 3H), 3.83 (s, 2H), 3.81 (s, 2H). MS (ESI): 445.21 (M+H⁺).

EXAMPLE 123
2-(4-Bromophenyl)-N-((7-chloro-6-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine

2-(4-Bromophenyl)-N-((7-chloro-6-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.25 (s, 1H), 8.03 (s, 1H), 7.97 (s, 1H), 7.59 (m, 2H), 7.54 (m, 1H), 7.46 (t, 1H), 7.18 (m, 2H), 3.99 (s, 3H), 3.87 (s, 2H), 2.80 (m, 2H), 2.72 (m, 2H). MS (ESI): 487.16 (M+H⁺).

EXAMPLE 124
3-((4-Bromophenethylamino)methyl)-7-chloro-2-(thiophen-3-yl)quinolin-6-ol

3-((4-Bromophenethylamino)methyl)-7-chloro-2-(thiophen-3-yl)quinolin-6-ol was prepared following the procedures described in preparation of Example 79. ¹H-NMR (400 MHz, DMSO) δ 11.08 (s, 1H), 9.02 (bs, 2H), 8.39 (s, 1H), 8.06 (s, 1H), 7.87 (dd, 1H), 7.71 (q, 1H), 7.51 (dd, 2H), 7.47 (dd, 1H), 7.35 (s, 1H), 7.20 (dd, 2H), 4.45 (t, 2H), 3.25 (m, 2H), 2.88 (t, 2H). MS (ESI): 473.12 (M+H⁺).

EXAMPLE 125
2-(4-Bromophenyl)-N-((7-fluoro-6-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine

2-(4-Bromophenyl)-N-((7-fluoro-6-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.24 (s, 1H), 7.96 (s, 1H), 7.71 (d, 1H), 7.56 (m, 3H), 7.49 (d, 1H), 7.44 (d, 2H), 7.18 (d, 2H), 3.98 (s, 3H), 3.85 (s, 2H), 2.78 (m, 2H), 2.72 (m, 2H). MS (ESI): 471.18 (M+H⁺).

EXAMPLE 126
3-((4-Bromophenethylamino)methyl)-7-fluoro-2-(thiophen-3-yl)quinolin-6-ol

3-((4-Bromophenethylamino)methyl)-7-fluoro-2-(thiophen-3-yl)quinolin-6-ol was prepared following the procedures described in preparation of Example 79. ¹H-NMR (400 MHz, DMSO) δ 10.89 (bs, 1H), 9.02 (bs, 2H), 8.40 (s, 1H), 7.86 (dd, 1H), 7.76 (d, 1H), 7.73 (q, 3H), 7.51 (dd, 3H), 7.47 (dd, 1H), 7.35 (d, 1H), 7.20 (dd, 2H), 4.45 (t, 2H), 3.95 (m, 2H), 3.23 (m, 2H), 2.88 (t, 2H). MS (ESI): 457.18 (M+H⁺).

EXAMPLE 127
2-(4-bromophenyl)-N-((7-nitro-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine

Step 1
Methyl 2-chloro-7-nitroquinoline-3-carboxylate

A mixture of methyl 7-nitro-2-oxo-1,2-dihydroquinoline-3-carboxylate (3.20 g, 12.9 mmol) and phosphorus oxychloride (44.0 mL, 481 mmol) was heated to 110° C. for 16 h. The reaction mixture was cooled to room temperature then concentrated under vacuum. Water (100 mL) was added and the resulting precipitate was collected by vacuum filtration. The solid was washed with water (50 mL) and dried under vacuum to afford 3.09 g of methyl 2-chloro-7-nitroquinoline-3-carboxylate as a yellow solid. MS (ESI): 267.08 (M+H⁺).

Step 2
Methyl 7-nitro-2-(thiophen-3-yl)quinoline-3-carboxylate

Methyl 7-nitro-2-(thiophen-3-yl)quinoline-3-carboxylate was prepared following the procedures described in preparation of Example 1. MS (ESI): 315.18 (M+H⁺).

Step 3
(7-Nitro-2-(thiophen-3-yl)quinolin-3-yl)methanol

DIBAL (2.44 mL of a 1.0M solution in toluene, 2.44 mmol) was added dropwise over 15 minutes to a −78° C. solution of methyl 7-nitro-2-(thiophen-3-yl)quinoline-3-carboxylate (350 mg, 1.11 mmol) and DCM (5 mL) under nitrogen. The reaction mixture was stirred at −78° C. for 20 min prior to the addition of ethyl acetate (1 mL). The reaction mixture was warmed to room temperature and 1M HCl (10 mL) was added. The phases were separated and the aqueous layer extracted with ethyl acetate (10 mL). The combined organic layers were concentrated under vacuum and the residue was purified using column chromatography (hexanes to ethyl acetate) to afford 208 mg of (7-nitro-2-(thiophen-3-yl)quinolin-3-yl)methanol as a yellow solid. MS (ESI): 287.16 (M+H⁺).

Step 4
7-Nitro-2-(thiophen-3-yl)quinoline-3-carbaldehyde

A suspension of MnO₂(303 mg, 3.49 mmol), (7-nitro-2-(thiophen-3-yl)quinolin-3-yl)methanol (200 mg, 699 μmol) and DCM (10 mL) was stirred at room temperature for 5 h. The reaction mixture was filtered through Celite® (50 g) and washed with DCM (50 mL). The filtrate was concentrated under vacuum to afford 183 mg of 7-nitro-2-(thiophen-3-yl)quinoline-3-carbaldehyde as a yellow solid. MS (ESI): 285.13 (M+H⁺).

Step 5
2-(4-Bromophenyl)-N-((7-nitro-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine

2-(4-Bromophenyl)-N-((7-nitro-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.76 (d, 1H), 8.53 (s, 1H), 8.29 (dd, 1H), 8.18 (d, 1H), 8.12 (dd, 1H), 7.67-7.62 (m, 2H), 7.45 (dd, 2H), 7.18 (dd, 2H), 3.93 (s, 2H), 2.76-2.56 (m, 4H). MS (ESI): 468.16, 470.17 (M+H⁺).

EXAMPLE 128
3-((4-Bromophenethylamino)methyl)-2-(thiophen-3-yl)quinolin-7-amine

Step 1
Methyl 7-amino-2-(thiophen-3-yl)quinoline-3-carboxylate

Sodium borohydride (1.23 g, 32.5 mmol) was added to a stirred solution of methyl 7-nitro-2-(thiophen-3-yl)quinoline-3-carboxylate (2.04 g, 6.49 mmol), THF (23 mL) and MeOH (23 mL) at room temperature under nitrogen. The reaction mixture was stirred for 2 h prior to the addition of 1M HCl (50 mL). The phases were separated and the aqueous layer was extracted with ethyl acetate (25 mL). The combined organic layers were concentrated under vacuum and the residue was purified using column chromatography (hexanes to ethyl acetate) to afford 1.08 g of methyl 7-amino-2-(thiophen-3-yl)quinoline-3-carboxylate as a yellow solid. MS (ESI): 285.13 (M+H⁺).

Step 2
(7-Amino-2-(thiophen-3-yl)quinolin-3-yl)methanol

(7-Amino-2-(thiophen-3-yl)quinolin-3-yl)methanol was prepared following the procedures described in preparation of Example 127. MS (ESI): 257.12 (M+H⁺).

Step 3
7-Amino-2-(thiophen-3-yl)quinoline-3-carbaldehyde

7-Amino-2-(thiophen-3-yl)quinoline-3-carbaldehyde was prepared following the procedures described in preparation of Example 127. MS (ESI): 255.08 (M+H⁺).

Step 4
3-((4-Bromophenethylamino)methyl)-2-(thiophen-3-yl)quinolin-7-amine

3-((4-Bromophenethylamino)methyl)-2-(thiophen-3-yl)quinolin-7-amine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 7.98 (s, 1H), 7.92 (dd, 1H), 7.56-7.50 (m, 3H), 7.43 (d, 2H), 7.17 (d, 2H), 6.94 (dd, 1H), 6.88 (d, 1H), 5.75 (br s, 2H), 3.76 (s, 2H), 2.85-2.70 (m, 4H). MS (ESI): 438.10, 440.12 (M+H⁺).

EXAMPLE 129
2-(4-Bromophenyl)-N-((7-methoxy-4-methyl-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine

2-(4-Bromophenyl)-N-((7-methoxy-4-methyl-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 1. MS (ESI): 467.92 (M+H⁺).

EXAMPLE 130
(R)-1-(4-Bromophenyl)-N-((7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine

(R)-1-(4-Bromophenyl)-N-((7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 1. MS (ESI): 455.12 (M+H⁺).

EXAMPLE 131
2-(4-Bromophenyl)-N-((6-methoxy-7-methyl-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine

2-(4-Bromophenyl)-N-((6-methoxy-7-methyl-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.24 (s, 1H), 8.05 (m, 1H), 7.61 (m, 2H), 7.52 (d, 3H), 7.49 (d, 1H), 7.44 (d, 2H), 7.18 (d, 2H), 4.06 (s, 3H), 3.87 (s, 2H), 2.81 (t, 2H), 2.72 (t, 2H), 2.38 (s, 3H). MS (ESI): 467.17 (M+H⁺).

EXAMPLE 132
3-((4-Bromophenethylamino)methyl)-7-methyl-2-(thiophen-3-yl)quinolin-6-ol

3-((4-Bromophenethylamino)methyl)-7-methyl-2-(thiophen-3-yl)quinolin-6-ol was prepared following the procedures described in preparation of Example 79.

¹H-NMR (400 MHz, DMSO) δ 9.36 (bs, 1H), 9.07 (bs, 2H), 8.47 (s, 1H), 8.05 (dd, 1H), 7.77 (dd, 1H), 7.72 (m, 3H), 7.52 (d, 2H), 7.44 (d, 1H), 7.34 (d, 1H), 7.21 (d, 2H), 4.54 (bs, 2H), 3.27 (m, 2H), 2.91 (t, 2H), 2.37 (s, 3H). MS (ESI): 453.12 (M+H⁺).

EXAMPLE 133
(S)-1-(4-Bromophenyl)-N-((7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine

(S)-1-(4-Bromophenyl)-N-((7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 1. MS (ESI): 453.48 (M+H⁺).

EXAMPLE 134
(R)-3-((1-(4-Bromophenyl)ethylamino)methyl)-2-(thiophen-3-yl)quinolin-7-ol

(R)-3-((1-(4-Bromophenyl)ethylamino)methyl)-2-(thiophen-3-yl)quinolin-7-ol was prepared following the procedures described in preparation of Example 79. MS (ESI): 441.43 (M+H⁺).

EXAMPLE 135
(S)-3-((1-(4-Bromophenyl)ethylamino)methyl)-2-(thiophen-3-yl)quinolin-7-ol

(S)-3-((1-(4-Bromophenyl)ethylamino)methyl)-2-(thiophen-3-yl)quinolin-7-ol was prepared following the procedures described in preparation of Example 79. MS (ESI): 441.46 (M+H⁺).

EXAMPLE 136
3-((4-Bromophenethylamino)methyl)-2-(thiophen-3-yl)quinoline-7-carbonitrile

3-((4-Bromophenethylamino)methyl)-2-(thiophen-3-yl)quinoline-7-carbonitrile was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.51 (d, 1H), 8.45 (s, 1H), 8.11 (d, 1H), 8.07 (dd, 1H), 7.86 (dd, 1H), 7.63 (dd, 1H), 7.58 (dd, 1H), 7.43 (d, 2H), 7.18 (d, 2H), 3.91 (s, 2H), 2.80 (t, 2H), 2.72 (t, 2H). MS (ESI): 448.42, 450.43 (M+H⁺).

EXAMPLE 137
Ethyl 3-((4-bromophenethylamino)methyl)-2-(thiophen-3-yl)quinoline-7-carboxylate

Ethyl 3-((4-bromophenethylamino)methyl)-2-(thiophen-3-yl)quinoline-7-carboxylate was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.54 (d, 1H), 8.40 (s, 1H), 8.08 (dd, 1H), 8.03-8.01 (m, 2H), 7.63-7.60 (m, 2H), 7.44 (d, 2H), 7.18 (d, 2H), 4.37 (q, 2H), 3.91 (s, 2H), 2.80 (t, 2H), 2.72 (t, 2H), 1.37 (t, 3H). MS (ESI): 495.50, 497.51 (M+H⁺).

EXAMPLE 138
3-((4-Bromophenethylamino)methyl)-2-(thiophen-3-yl)quinoline-7-carboxylic acid

A mixture of 1.0M LiOH (351 μL, 351 μmol), ethyl 3-((4-bromophenethylamino)methyl)-2-(thiophen-3-yl)quinoline-7-carboxylate (158 mg, 319 μmol) and THF (4 mL) was heated to 50° C. for 6 h. 1M HCl (351 μL) was added and the phases were separated. The organic layer was concentrated under vacuum and the residue was purified using column chromatography (DCM to 9:1 DCM/MeOH) to afford 89 mg of 3-((4-bromophenethylamino)methyl)-2-(thiophen-3-yl)quinoline-7-carboxylic acid as a white solid. ¹H-NMR (400 MHz, DMSO) δ 9.49 (br s, 2H), 8.79 (s, 1H), 8.56 (dd, 1H), 8.13-8.07 (m, 2H), 8.02 (dd, 1H), 7.75 (dd, 1H), 7.58 (dd, 1H), 7.53 (d, 2H), 7.21 (d, 2H), 4.52 (s, 2H), 3.26 (t, 2H), 2.96 (t, 2H). MS (ESI): 467.44, 469.48 (M+H⁺).

EXAMPLE 139
3-((4-Bromophenethylamino)methyl)-2-(thiophen-3-yl)quinoline-7-carboxamide

A mixture of ethyl 3-((4-bromophenethylamino)methyl)-2-(thiophen-3-yl)quinoline-7-carboxylate (57 mg, 120 μmol) and NH₃(6.00 mL of a 2.0M solution in MeOH, 11.5 mmol.) was heated to 50° C. in a sealed tube for 24 h. The reaction mixture was cooled to room temperature then concentrated under vacuum. The residue was purified using column chromatography (DCM to 9:1 DCM/MeOH) to afford 13 mg of 3-((4-bromophenethylamino)methyl)-2-(thiophen-3-yl)quinoline-7-carboxamide as a white solid. ¹H-NMR (400 MHz, DMSO) δ 8.52 (s, 1H), 8.35 (s, 1H), 8.25 (br s, 1H), 8.05 (dd, 1H), 7.99 (dd, 1H), 7.94 (d, 1H), 7.63-7.58 (m, 2H), 7.54 (br s, 1H), 7.44 (d, 2H), 7.18 (d, 2H), 3.89 (s, 2H), 2.81 (t, 2H), 2.65 (t, 2H). MS (ESI): 466.42, 468.48 (M+H⁺).

EXAMPLE 140
3-((4-Bromophenethylamino)methyl)-N-methyl-2-(thiophen-3-yl)quinoline-7-carboxamide

3-((4-Bromophenethylamino)methyl)-N-methyl-2-(thiophen-3-yl)quinoline-7-carboxamide was prepared following the procedures described in preparation of Example 139. ¹H-NMR (400 MHz, DMSO) δ 8.72 (q, 1H), 8.46 (s, 1H), 8.35 (s, 1H), 8.05 (dd, 1H), 7.98-7.95 (m, 2H), 7.63-7.57 (m, 2H), 7.44 (d, 2H), 7.18 (d, 2H), 3.89 (s, 2H), 2.82 (d, 3H), 2.79 (t, 2H), 2.70 (t, 2H). MS (ESI): 480.55, 482.51 (M+H⁺).

EXAMPLE 141
(3-((4-Bromophenethylamino)methyl)-2-(thiophen-3-yl)quinolin-7-yl)methanol

(3-((4-Bromophenethylamino)methyl)-2-(thiophen-3-yl)quinolin-7-yl)methanol was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.26 (s, 1H), 8.02 (dd, 1H), 7.87 (d, 1H), 7.84 (d, 1H), 7.60-7.56 (m, 2H), 7.49 (dd, 1H), 7.44 (d, 2H), 7.18 (d, 2H), 5.33 (t, 1H), 4.68 (d, 2H), 3.86 (s, 2H), 2.80 (t, 2H), 2.72 (t, 2H). MS (ESI): 453.42, 455.47 (M+H⁺).

EXAMPLE 142
N-(3-((4-bromophenethylamino)methyl)-2-(thiophen-3-yl)quinolin-7-yl)acetamide

Step 1
N-(3-Formyl-2-(thiophen-3-yl)quinolin-7-yl)acetamide

N-(3-Formyl-2-(thiophen-3-yl)quinolin-7-yl)acetamide was prepared following the procedures described in preparation of Example 1. MS (ESI): 297.47 (M+H⁺).

Step 2
N-(3-((4-Bromophenethylamino)methyl)-2-(thiophen-3-yl)quinolin-7-yl)acetamide

N-(3-((4-Bromophenethylamino)methyl)-2-(thiophen-3-yl)quinolin-7-yl)acetamide was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 10.24 (s, 1H), 8.37 (s, 1H), 8.19 (s, 1H), 8.01 (dd, 1H), 7.80 (d, 1H), 7.62-7.56 (m, 3H), 7.44 (d, 2H), 7.17 (d, 2H), 3.83 (s, 2H), 2.80 (t, 2H), 2.71 (t, 2H), 2.11 (s, 3H). MS (ESI): 480.54, 482.51 (M+H⁺).

EXAMPLE 143
(±)-N-(4-Bromophenethyl)-1-(7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)ethanamine

Prepared in a similar fashion to Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.31 (s, 1H), 7.79 (d, 1H), 7.67 (d, 2H), 7.41-7.34 (m, 4H), 7.21 (d, 1H), 7.07 (d, 2H), 4.07 (q, 1H), 3.90 (s, 3H), 2.59-2.50 (m, 4H), 1.26 (d, 3H). MS (ESI): 467.20, 469.20 (M+H⁺).

EXAMPLE 144
(±)-3-(1-(4-Bromophenethylamino)ethyl)-2-(thiophen-3-yl)quinolin-7-ol

(±)-3-(1-(4-Bromophenethylamino)ethyl)-2-(thiophen-3-yl)quinolin-7-ol was prepared following the procedures described in preparation of Example 79. ¹H-NMR (400 MHz, DMSO) δ 10.06 (s, 1H), 8.21 (s, 1H), 7.70 (d, 1H), 7.65-7.60 (m, 2H), 7.37 (d, 2H), 7.30 (dd, 1H), 7.12 (d, 1H), 7.09 (dd, 1H), 7.04 (d, 2H), 4.00 (q, 1H), 2.58-2.50 (m, 4H), 1.22 (d, 3H). MS (ESI): 453.57, 455.46 (M+H⁺).

EXAMPLE 145
1-(4-Bromophenyl)-N-((7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)propan-2-amine

1-(4-Bromophenyl)-N-((7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)propan-2-amine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.27 (s, 1H), 7.97 (s, 1H), 7.83 (d, 1H), 7.57 (d, 2H), 7.46 (d, 2H), 7.36 (s, 1H), 7.22 (d, 1H), 7.16 (d, 2H), 4.05-3.90 (m, 5H), 2.90-2.73 (m, 3H), 1.17 (d, 3H). MS (ESI): 469.15, 471.11 (M+H⁺).

EXAMPLE 146
2-(4-Bromophenyl)-N-((6-fluoro-7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)-ethanamine

2-(4-Bromophenyl)-N-((6-fluoro-7-methoxy-2-(thiophen-3-yl)quinolin-3-yl)methyl)ethanamine was prepared following the procedures described in preparation of Example 1. ¹H-NMR (400 MHz, DMSO) δ 8.21 (s, 1H), 7.99 (dd, 1H), 7.72 (d, 1H), 7.56 (m, 2H), 7.52 (d, 1H), 7.44 (d, 2H), 7.17 (d, 2H), 3.98 (s, 3H), 3.82 (bs, 2H), 2.78 (t, 2H), 2.71 (t, 2H). MS (ESI): 471.49 (M+H⁺).

EXAMPLE 147
3-((4-Bromophenethylamino)methyl)-6-fluoro-2-(thiophen-3-yl)quinolin-7-ol

3-((4-Bromophenethylamino)methyl)-6-fluoro-2-(thiophen-3-yl)quinolin-7-ol was prepared following the procedures described in preparation of Example 79. ¹H-NMR (400 MHz, DMSO) δ 9.09 (bs, 1H), 8.45 (m, 1H), 7.89 (m, 1H), 7.74 (m, 1H), 7.50 (m, 3H), 7.45 (d, 1H), 7.42 (s, 1H), 7.19 (d, 2H), 4.43 (bs, 2H), 3.20 (m, 2H), 2.87 (t, 2H), 2.88 (t, 2H). MS (ESI): 457.46 (M+H⁺).

EXAMPLE 148
2-(4-Bromophenyl)-N-((2,7-dimethoxyquinolin-3-yl)methyl)ethanamine

A mixture of 2,7-dimethoxyquinoline-3-carbaldehyde (217 mg, 1.00 mmol), 2-(4-bromophenyl)ethanamine (310 μL, 2.00 mmol), DCM (100 μL), acetic acid (250 μL) and isopropanol (4.75 mL) was heated to 45° C. for 30 minutes then cooled to room temperature. Sodium triacetoxyborohydride (1.05 g, 5.00 mmol) was added and the vented reaction mixture was stirred for 17 h. DCM (15 mL) and sat. aq. NaHCO₃(15 mL) were added and the phases were separated. The organic layer was washed with brine (15 mL) and concentrated under vacuum. The product was purified using column chromatography (hexanes to ethyl acetate to DCM to 9:1 DCM/methanol) to give 294 mg of 2-(4-bromophenyl)-N-((2,7-dimethoxyquinolin-3-yl)methyl)ethanamine as a white solid. ¹H-NMR (400 MHz, DMSO) δ 7.47 (s, 1H), 7.54 (d, 1H), 7.39 (dt, 2H), 7.20 (d, 1H), 7.06 (dt, 1H), 7.01 (dd, 1H), 4.00 (s, 3H), 3.92 (s, 3H), 3.84 (s, 2H), 2.85 (t, 2H), 2.79 (t, 2H). MS (ESI): 401.36 (M+H⁺).

EXAMPLE 149
3-((4-Bromophenethylamino)methyl)-7-methoxyquinolin-2(1H)-one hydrochloride

A mixture of 2-(4-bromophenyl)-N-((2,7-dimethoxyquinolin-3-yl)methyl)ethanamine (100 mg, 250 μmol), THF (2 mL) and 3N HCl (2 mL) was heated at 60° C. for 17 h then cooled to room temperature. The precipitate was collected by vacuum filtration, washed with diethyl ether (15 mL) and dried under vacuum to afford 90 mg of 3-((4-bromophenethylamino)methyl)-7-methoxyquinolin-2-ol hydrochloride as a white solid. ¹H-NMR (400 MHz, DMSO) δ 12.06 (s, 1H), 8.86 (bs, 2H), 8.04 (s, 1H), 7.62 (d, 1H), 7.51 (dd, 2H), 7.23 (dd, 2H), 6.87 (d, 1H), 6.85 (s, 1H), 4.04 (bs, 2H), 3.81 (s, 3H), 3.16 (m, 2H), 2.94 (t, 2H). MS (ESI): 387.38 (M+H⁺).

The following compounds can generally be made using methods well known in the art. It is expected that these compounds when made will have activity similar to those that have been made in the examples above. The following compounds are represented herein using the Simplified Molecular Input Line Entry System, or SMILES. SMILES is a modern chemical notation system, developed by David Weininger and Daylight Chemical Information Systems, Inc., that is built into all major commercial chemical structure drawing software packages. Software is not needed to interpret SMILES text strings, and an explanation of how to translate SMILES into structures can be found in Weininger, D., J. Chem. Inf. Comput. Sci. 1988, 28, 31-36. All SMILES strings used herein, as well as many IUPAC names, were generated using CambridgeSoft's ChemDraw 10.0.

BrC(C=C1)=CC=C1CCNCC2=CC3=CC=C(OC)C=C3N=C2C4=CSC(C)=C4
BrC(C=C5)=CC=C5CCNCC6=CC7=CC=C(OC)C=C7N=C6C8=CSC(C(OCC)=O)=C
BrC(C=C9)=CC=C9CCNCC % 10=CC % 11=CC=C(OC)C=C % 11N=C % 10C % 12=CSC (C(O)=O)=C %12
BrC(C=C %13)=CC=C %13CCNCC %14=CC % 15=CC=C(OC)C=C % 15N=C % 14C % 16=CSC(C(NC)=O)=C % 16
COC % 17=CC=C % 18C(N=C(C % 19=CSC(C(OCC)=O)=C % 19)C(CNCC %20=CC=C(C(F)(F)F)C=C %20)=C % 18)=C % 17
COC %21=CC=C %22C(N=C(C %23=CSC(C)=C %23)C(CNCC %24=CC=C(C(F)(F)F) C=C %24)=C %22)=C %21
OC %25=CC=C %26C(N=C(C %27=CSC(C)=C %27)C(CNCCC %28=CC=C(Br)C=C % 28)=C %26)=C %25
OC %29=CC=C %30C(N=C(C %31=CSC(C(OCC)=O)=C %31)C(CNCCC %32=CC=C(Br)C=C %32)=C %30)=C %29
OC %33=CC=C %34C(N=C(C %35=CSC(C(O)=O)=C %35)C(CNCCC %36=CC=C(Br) C=C %36)=C %34)=C %33

OC %37=CC=C %38C(N=C(C %39=CSC(C(NC)=O)=C %39)C(CNCCC %40=CC=C(B r)C=C %40)=C %38)=C %37

OC %41=CC=C %42C(N=C(C %43=CSC(C(OCC)=O)=C %43)C(CNCC %44=CC=C(C (F)(F)F)C=C %44)=C %42)=C %41
OC %45=CC=C %46C(N=C(C %47=CSC(C)=C %47)C(CNCC %48=CC=C(C(F)(F)F)C=C %48)=C %46)=C %45
CC1=NC2=CC(OC)=CC=C2C=C1 CNCC3=CC=C(C(F)(F)F)C=C3
COC4=CC=C5CN=C(OC)C(CNCC6=CC=C(C(F)(F)F)C═C6)=C5)=C4
BrC(C=C7)=CC=C7CCNCC8=CC9=CC=C(OC)C=C9N=C8
CC % 10=NC % 11=CC(OC)=CC=C % 11C=C % 10CNCCC % 12=CC=C(Br)C=C % 12
BrC(C=C % 13)=CC=C % 13CCNCC % 14=CC % 15=CC=C(OC)C=C % 15N=C % 14C(C)C
BrC(C=C % 16)=CC=C % 16CCNCC % 17=CC % 18=CC=C(OC)C=C % 18N=C % 17OC OC % 19=CC=C %20C(N=C(C)C(CNCC %21=CC=C(C(F)(F)F)C=C %21)=C %20)=C % 19
OC %22=CC=C %23 CN=C(OC)C(CNCC %24=CC=C(C(F)(F)F)C=C %24)=C %23)=C %22
OC %25=CC=C %26C(N=CC(CNCCC %27=CC=C(Br)C=C %27)=C %26)=C %25
OC %28=CC=C %29C(N=C(C)C(CNCCC %30=CC=C(Br)C=C %30)=C %29)=C %28
OC %31=CC=C %32C(N=C(C(C)C)C(CNCCC %33=CC=C(Br)C=C %33)=C %32)=C %
OC %34=CC=C %35C(N=C(OC)C(CNCCC %36=CC=C(Br)C=C %36)=C %35)=C %34
BrC(C=C1)=CC=C1CCNCC2=CC3=CC=C(OC)C=C3N=C2C4=CSC=N4
BrC(C=C5)=CC=C5CCNCC6=CC7=CC=C(OC)C=C7N=C6C8=COC=N8
BrC(C=C9)=CC=C9CCNCC % 10=CC % 11=CC=C(OC)C=C % 11N=C % 10C % 12=CN=CC(OC)=C %12

The activity of the compounds in Examples 1 through 149 as TGR5 modulators is illustrated in the following assays. The other compounds listed above, which have not yet been made and/or tested, are predicted to have activity in these assays as well.

Biological Activity Assay

cAMP Production Assay:

HEK293 cells stably expressing TGR5 (HEK293-TGR5) were established by stably transfecting HEK-293 cells with an expression vector (pcDNA 3.1, Invetrogen) inserted with human TGR5 cDNA using Fugene6 (Roche, Indianapolis, Ind.) according to conventional methods. Cells were grown in DMEM (invitrogen, Carlsbad, Calif.) supplemented with 10% FBS, 1% penicillin/streptomycin under geneticin selection. The presence of TGR5 transcripts in these cells was confirmed using branched DNA (bDNA, Genospectra, Inc., Fremont Calif.) following the manufacturer's protocol and using specific probes for human TGR5. cAMP production assay was performed in high throughput 1536 well format using LANCE cAMP detection kit (Perkin Elmer Inc., Boston, Mass.) according to the manufacturer's protocol. Briefly, HEK293-TGR5 cells were harvested using non-enzymatic cell dissociation buffer (Invitrogen, Carlsbad, Calif.) and suspended in DMEM supplemented with 0.1% FBS at a density of 800,000 cells/ml. Alexa antibody was added to the cell suspension, and 4 ul of the mixture was dispensed in white opaque tissue culture treated Greiner 1536 well plates (USA Scientific, Inc., Ocala, Fla.). After an overnight incubation at 37C in an atmosphere of 10% CO₂and 95% humidity, 1 ul of 5 mM IBMX (Sigma, St. Louis, Mo.) solution in DMEM was dispensed for a final concentration of 1 mM. Cells were then stimulated with test compounds for 30 minutes, after which time 5 ul of detection reagent was added and incubated for 1-7 hrs at room temperature. TR-FRET signal was detected using the Viewlux (Perkin Elmer Inc., Boston Mass.). EC₅₀values were determined using Graph Pad Prizm analysis (GraphPad Software, Inc). The EC₅₀values for a wide range of bile acids generated from this assay were in agreement with the values published in the scientific literature. None of the compounds induced cAMP in HEK-293 cells that were transfected with an empty vector alone, confirming a TGR5 mechanism of action for cAMP production. The symbol (+) denotes an EC₅₀value of <10 μM while the symbol (−) denotes an EC₅₀value of ≧10 μM (see Table 1).

TABLE 1

In Vitro Biological Activity Assays

cAMP Production

in 293-TGR5 Cells

EC₅₀:

(+): ≦10 μM;

Example No.
(−): >10 μM

1
−

2
+

3
+

4
−

5
+

6
+

7
+

8
+

9
−

10
−

11
+

12
+

13
−

14
−

15
+

16
−

17
−

18
−

19
+

20
+

21
+

22
+

23
+

24
−

25
+

26
−

27
−

28
+

29
−

30
−

31
−

32
−

33
−

34
−

35
−

36
+

37
−

38
+

39
+

40
−

41
−

42
+

43
−

44
+

45
−

46
−

47
−

48
+

49
−

50
+

51
+

52
+

53
+

54
+

55
−

56
−

57
+

58
−

59
+

60
−

61
+

62
+

63
−

64
−

65
+

66
+

67
+

68
+

69
+

70
−

71
+

72
−

73
+

74
−

75
+

76
+

77
−

78
+

79
+

80
−

81
+

82
+

83
+

84
−

85
+

86
+

87
+

88
−

89
−

90
−

91
−

92
+

93
−

94
−

95
−

96
+

97
−

98
+

99
−

100
+

101
+

102
−

103
−

104
−

105
+

106
−

107
−

108
−

109
−

110
+

111
−

112
+

113
−

114
+

115
−

116
+

117
−

118
−

119
+

120
−

121
+

122
−

123
−

124
−

125
−

126
+

127
−

128
−

129
−

130
+

131
+

132
−

133
+

134
+

135
+

136
+

137
−

138
+

139
+

140
+

141
+

142
−

143
−

144
−

145
−

146
+

147
−

148
−

149
−

In Vivo Assays
Evaluation of Pharmacological Efficacy of a Compound of the Invention in a Model of Diet-Induced Obesity (DIO) in Mice

The DIO model in mice exhibits several features that are hallmark of metabolic syndrome in humans. Metabolic syndrome in humans is characterized by abdominal obesity, high triglycerides, impaired fasting glucose and hyperinsulinemia. In the DIO model, mice are fed high fat diet (HFD, Research diet D12492, Research Diet, NJ) diet (58% lard) for the entire period of the study. Compared to normal chow (NC, Harlan-Tekland #8604, WI) fed animals the HF fed mice develop several features of metabolic syndrome such as, hypertriglyceridemia, hyperinsulinemia and mild hyperglycemia on this diet. Body mass analyses demonstrate that the mice also develop a striking increase in visceral obesity by weeks 3-4 of HF feeding. This model was used to evaluate the pharmacological effects of Example 82 in mitigating several features of HFD induced metabolic syndrome in rodents.

C57B1/6j mice (n=6) were fed ad libitu with either the HFD (58% fat) or NC (5%) diet for 4 weeks prior to start of experiment, and throughout the course of the experiment (28 days). Starting on Day 1, mice were dosed BID with either Example 82+vehicle or vehicle alone. Animals were the assessed for body weight gain, food intake, triglyceride (TG), insulin, HDL, cholesterol, and glucose levels under either fasting or postprandial (PP) conditions. Animals were weighed twice weekly to determine body weight gain. Plasma or serum was separated from whole blood (Sarstedt) and TG levels were assayed. Plasma insulin levels were assayed using the ultrasensitive mouse Insulin ELISA immunoassay (American Laboratory Products Company). Total cholesterol and HDLc was measured to evaluate pharmacological efficacy at various time points during the study.

Dosages

Vehicle is CMC-Tween: 0.5% CMC+0.25% Tween 20 at an appropriate ml/kg. Dextrose dose per mouse=2 g dextrose/kg made from 0.5 g/ml stock dextrose solution. Example 82 dose per mouse=30 mg/kg in CMC/Tween vehicle made from 4 mg/mL stock solution by adding 50 μL DMSO to 20 mg Compound I, stirring to make a paste, adding 1 ml CMC/Tween with stirring, sonicating for 8 minutes on energy 05, and adjusting to 5 ml with CMC/Tween.

Glucose Tolerance Test (GTT)/Insulin Test

Mice (5 per group) were fasted at 6 am for an experiment at noon. Blood glucose was measured from tail nick blood using an Accucheck—Compact Monitoring Kit (Roche Diagnostics, Indianapolis Ind.). Baseline (time=−15 min) blood glucose concentration was determined for all mice and tail nick blood samples were collected. 2 g/kg dextrose (Hospira, Lake Forest, Ill.) was administered orally at time 0. Blood samples were collected from the following mice via tail nick blood draw (˜100 μL) into EDTA microtainer tubes at the following time points: 0, 5, 10, 15, 30, 60, and 120 min. Terminal blood samples were collected from portal vein draws in three mice at t=20. Blood plasma was harvested from blood collected in EDTA microvettes by centrifugation (10 min at 8.6 rpm). Plasma was stored in −80° C. freezer to be analyzed for other chemistry measurements.

Insulin ELISA Assay

A Mercodia ultrasensitive mouse insulin ELISA kit (Mercodia AB, Uppsala, Sweden) was used in a 96-well coated plate. All reagents and samples were brought to room temperature before use, Calibrator concentrations were 0.07, 0.13, 0.25, 0.63, 1.9, 5.2, 13.0, and 64.0 μg/L, and a calibration curve was prepared for each assay run. To 25 μL calibrator 0 in each well was added 5 μL calibrators and 5 μL of samples/standards in duplicate, then 50 μL dilute enzyme conjugate 11× in enzyme conjugate buffer. This was incubated on a shaker for 2 hours at room temperature (18-25° C.), and each well was washed 5 times in 350 μL wash buffer and aspirated completely. After final wash, plate was inverted and tapped firmly against absorbent paper. 200 μL substrate TMB was added to each well and incubated for 30 minutes. 50 μL stop solution was added to each well, and the plate was placed on the shaker for about 5 seconds to ensure mixing of substrate and stop Solution. Absorbance was measured at 450 nm.

TABLE 2

Glucose Tolerance Test

Plasma Glucose, mg/dL:

Ex. 82
Ex. 82
Ex. 82

Time,
Vehicle
3 mg/kg
30 mg/kg
100 mg/kg

min
Mean
SE
Mean
SE
Mean
SE
Mean
SE

0
470.67
17.61
307.00
23.88
351.00
35.71
288.17
40.99

5
635.08
41.72
442.17
31.40
423.33
28.25
493.00
25.85

10
806.67
41.70
649.75
47.88
543.50
28.43
627.75
39.62

15
936.58
57.24
736.58
30.00
628.33
28.11
641.08
37.81

30
930.42
18.63
659.42
40.46
625.00
38.70
596.00
36.23

60
808.67
68.72
503.25
39.34
406.08
17.43
464.75
33.48

120
685.33
62.35
385.67
52.53
397.83
38.87
420.00
60.25

TABLE 3

Fasting Glucose Levels on Day 15 Post-Initiation of Treatment

Glucose Disposal at t = 360 minutes

Plasma Glucose,
Plasma Glucose,

mg/dL: Mean
mg/dL: SE

Vehicle
470.67
17.61

Example 82, 3 mg/kg
307.00
23.88

Example 82, 30 mg/kg
351.00
35.71

Example 82, 100 mg/kg
288.17
40.99

TABLE 4

Glucose-Stimulated Insulin Secretion

Plasma Insulin, ng/mL:

Ex. 82
Ex. 82
Ex. 82

Time,
Vehicle
3 mg/kg
30 mg/kg
100 mg/kg

min
Mean
SE
Mean
SE
Mean
SE
Mean
SE

0
7.13
1.13
5.37
0.58
13.64
2.03
12.50
1.36

5
6.04
0.70
6.61
1.65
12.76
1.48
24.40
0.61

10
7.99
1.08
13.44
3.57
15.84
2.81
31.50
1.88

15
8.38
1.25
22.32
3.15
24.80
5.19
60.07
3.07

30
20.45
4.98
12.38
1.36
32.07
4.79
44.99
4.35

60
10.77
1.46
11.85
2.99
23.65
3.90
23.03
2.82

120
10.89
2.03
11.86
2.19
28.74
1.01
20.53
1.85

Plasma Triglyceride and HDL Assays:

The post-prandial blood samples were collected in EDTA coated microvettes and centrifuged at 10,000 rpm for 10 minutes. Plasma samples were collected and analyzed for Triglycerides and HDL on chemistry analyzer “Olympus AU 600”. Samples were diluted with phosphate buffer saline in a 1:1 ratio before loading (4 μL total volume) onto the machine and appropriate calculations were done to generate the results. The optical densities (O.D.) for triglycerides and HDL were measured at 520 and 600 nanometers with calibrator setpoints at 107 mg/dL and 62 mg/dL respectively. The quality control (QC) values were as follows:

Triglycerides:

Level 1=82.4 mg/dL (Range 53-109 mg/dL)

Level 2=146.1 mg/dL (Range 120-180 mg/dL)

HDL:

Level 1=32.5 mg/dL (Range 26-144 mg/dL)

Level 2=90.3 mg/dL (Range 86-122 mg/dL)

All reagents, calibrators and quality controls for these assays were obtained from JAS diagnostics, Miami, Fla.

TABLE 5

Post-Prandial Triglyceride Levels on

Day 15 Post-Initiation of Treatment

Plasma Triglyceride,
Plasma Triglyceride,

mg/dL: Mean
mg/dL: SE

Vehicle
528.00
39.22

Example 82, 3 mg/kg
532.67
81.98

Example 82, 30 mg/kg
371.00
44.48

Example 82, 100 mg/kg
275.60
14.74

TABLE 6

Post-Prandial HDL Levels on Day 28 Post-Initiation of Treatment

Plasma HDL,
Plasma HDL,

mg/dL: Mean
mg/dL: SE

Vehicle
76
7.18

Example 82, 3 mg/kg
111
11.84

Example 82, 30 mg/kg
117
13.36

Example 82, 100 mg/kg
112
16.73

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

	Number	Date	Country
	60889181	Feb 2007	US
	60957516	Aug 2007	US

HETEROCYCLIC MODULATORS OF TGR5 FOR TREATMENT OF DISEASE

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