Inhibitors of 11-beta hydroxysteroid dehydrogenase type I

BACKGROUND OF THE INVENTION

The steroid hormone cortisol is a key regulator of many physiological processes. However, an excess of cortisol, as occurs in Cushing's Disease, provokes severe metabolic abnormalities including: type 2 diabetes, cardiovascular disease, obesity, and osteoporosis. Many patients with these diseases, however, do not show significant increases in plasma cortisol levels. In addition to plasma cortisol, individual tissues can regulate their glucocorticoid tone via the in situ conversion of inactive cortisone to the active hormone cortisol. Indeed, the normally high plasma concentration of cortisone provides a ready supply of precursor for conversion to cortisol via the intracellular enzyme 11-beta-hydroxysteroid dehydrogenase type I (11beta-HSD1).

11beta-HSD1 is a member of the short chain dehydrogenase superfamily of enzymes. By catalyzing the conversion of biologically inactive cortisone to cortisol, 11beta-HSD1 controls the intracellular glucocorticoid tone according to its expression and activity levels. In this manner, 11beta-HSD1 can determine the overall metabolic status of the organ. 11beta-HSD1 is expressed at high levels in the liver and at lower levels in many metabolically active tissues including the adipose, the CNS, the pancreas, and the pituitary. Taking the example of the liver, it is predicted that high levels of 11beta-HSD1 activity will stimulate gluconeogenesis and overall glucose output. Conversely, reduction of 11beta-HSD1 activity will downregulate gluconeogenesis resulting in lower plasma glucose levels.

Various studies have been conducted that support this hypothesis. For example, transgenic mice expressing 2× the normal level of 11beta-HSD1 in only the adipose tissue show abdominal obesity, hyperglycemia, and insulin resistance. (H. Masuzaki, J. Paterson, H. Shinyama, N. M. Morton, J. J. Mullins, J. R. Seckl, J. S. Flier, A Transgenic Model of Visceral Obesity and the Metabolic Syndrome, Science 294:2166-2170 (2001). Conversely, when the 11beta-HSD1 gene is ablated by homologous recombination, the resulting mice are resistant to diet induced obesity and the accompanying dysregulation of glucose metabolism (N. M. Morton, J. M. Paterson, H. Masuzaki, M. C. Holmes, B. Staels, C. Fievet, B. R. Walker, J. S. Flier, J. J. Mullings, J. R. Seckl, Novel Adipose Tissue-Mediated Resistance to Diet-induced Visceral Obesity in 11β-Hydroxysteroid Dehydrogenase Type 1-Deficient Mice. Diabetes 53: 931-938 (2004). In addition, treatment of genetic mouse models of obesity and diabetes (ob/ob, db/db and KKAy mice) with a specific inhibitor of 11beta-HSD1 causes a decrease in glucose output from the liver and an overall increase in insulin sensitivity (P. Alberts, C. Nilsson, G. Selen, L. O. M. Engblom, N. H. M. Edling, S. Norling, G. Klingstrom, C. Larsson, M. Forsgren, M. Ashkzari, C. E. Nilsson, M. Fiedler, E. Bergqvist, B. Ohman, E. Bjorkstrand, L. B. Abrahmsen, Selective Inhibition of 11β-Hydroxysteroid Dehydrogenase Type I Improves Hepatic Insuling Sensuitivity in Hyperglycemic Mice Strains, Endocrinology 144: 4755-4762 (2003)). Furthermore, inhibitors of 11beta-HSD1 have been shown to be effective in treating metabolic syndrome and atherosclerosis in high fat fed mice (Hermanowoki-Vosetka et. al., J. Eg. Med., 2002, 202(4), 517-527). Based in part on these studies, it is believed that local control of cortisol levels is important in metabolic diseases in these model systems. In addition, the results of these studies also suggest that inhibition of 11beta-HSD1 will be a viable strategy for treating metabolic diseases such as type 2 diabetes, obesity, and the metabolic syndrome.

Lending further support to this idea are the results of a series of preliminary clinical studies. For example, several reports have shown that adipose tissue from obese individuals has elevated levels of 11beta-HSD1 activity. In addition, studies with carbenoxolone, a natural product derived from licorice that inhibits both 11beta-HSD1 and 11beta-HSD2 (converts cortisol to cortisone in kidney) have shown promising results. A seven day, double blind, placebo controlled, cross over study with carbenoxolone in mildly overweight individuals with type 2 diabetes showed that patients treated with the inhibitor, but not the placebo group, displayed a decrease in hepatic glucose production (R. C. Andrews, O. Rooyackers, B. R. Walker, J. Clin. Endocrinol. Metab. 88: 285-291 (2003)). This observation is consistent with the inhibition of 11beta-HSD1 in the liver. The results of these preclinical and early clinical studies strongly support the concept that treatment with a potent and selective inhibitor of 11beta-HSD1 will be an efficacious therapy in patients afflicted with type 2 diabetes, obesity, and the metabolic syndrome.

SUMMARY OF THE INVENTION

In accordance with the present invention, aryl and heteroaryl and related compounds are provided that have the general structure of formula I:
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wherein G, L, Q, Z, R₆, R₇, and R₈are defined below.

The compounds of the present invention inhibit the activity of the enzyme 11-beta-hydroxysteroid dehydrogenase type I. Consequently, the compounds of the present invention may be used in the treatment of multiple diseases or disorders associated with 11 -beta-hydroxysteroid dehydrogenase type I, such as diabetes and related conditions, microvascular complications associated with diabetes, the macrovascular complications associated with diabetes, cardiovascular diseases, Metabolic Syndrome and its component conditions, and other maladies. Examples of diseases or disorders associated with the activity of the enzyme 11-beta-hydroxysteroid dehydrogenase type I that can be prevented, inhibited, or treated according to the present invention include, but are not limited to, diabetes, hyperglycemia, impaired glucose tolerance, insulin resistance, hyperinsulinemia, retinopathy, neuropathy, nephropathy, delayed wound healing, atherosclerosis and its sequelae, abnormal heart function, myocardial ischemia, stroke, Metabolic Syndrome, hypertension, obesity, dislipidemia, dylsipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL, high LDL, non-cardiac ischemia, infection, cancer, vascular restenosis, pancreatitis, neurodegenerative disease, lipid disorders, cognitive impairment and dementia, bone disease, HIV protease associated lipodystrophy and glaucoma.

The present invention provides for compounds of formula I, pharmaceutical compositions employing such compounds, and for methods of using such compounds. In particular, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, alone or in combination with a pharmaceutically acceptable carrier.

Further, in accordance with the present invention, a method is provided for preventing, inhibiting, or treating the progression or onset of diseases or disorders associated with the activity of the enzyme 11-beta-hydroxysteroid dehydrogenase type I, such as defined above and hereinafter, wherein a therapeutically effective amount of a compound of formula I is administered to a mammalian, i.e., human, patient in need of treatment.

The compounds of the invention can be used alone, in combination with other compounds of the present invention, or in combination with one or more other agent(s).

Further, the present invention provides a method for preventing, inhibiting, or treating the diseases as defined above and hereinafter, wherein a therapeutically effective amount of a combination of a compound of formula I and another compound of formula I and/or at least one other type of therapeutic agent, is administered to a mammalian, i.e., human, patient in need of treatment.

DESCRIPTION OF THE INVENTION

In accordance with the present invention, compounds of formula I are provided
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or stereoisomers or prodrugs or pharmaceutically acceptable salts thereof, wherein:

Z is aryl or heterocyclyl group, and may be optionally substituted with R₁, R₂, R₃, R₄, and R₅at any available positions;

R₁, R₂, R₃, R₄, and R₅are independently hydrogen, halo, cyano, haloalkyl, haloalkoxy, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, alkylamino, —C(O)R₉, —NR₉C(O)R_9a, —NR₉R_9a, aryl, arylalkyl, aryloxy, or heterocyclyl, wherein the haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, alkylamino, aryl, arylalkyl, or heterocyclyl, may be optionally substituted with R₉and R_9a; or independently any two adjoining R₁, R₂, R₃, R₄, and/or R₅may be taken together to form a fused aryl or heterocyclyl ring, which may be may be optionally substituted with R₁₀, R_10a, R_10b, and R_10c;

R₁₀, R_10a, R_10b, and R_10care independently selected from hydrogen, halo, hydroxy, nitro, cyano, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, —C(O)NR₉R_9a, —C(O)R₉, —NR₉C(O)R_9a, aryl, aryloxy, or heterocyclyl, wherein the haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aryloxy, or heterocyclyl may be optionally substituted with R₉and R_9a; and

R₉and R_9aare independently hydrogen, alkyl, alkoxy, cycloalkyl, aryl, or heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclyl may be optionally substituted with halo, haloalkyl, alkyl, aryl, or heterocyclyl;

L is a bond, O, S, SO₂, SO₂NR_4a, NR_4a, OCR_4aR_4b, CR_4aR_4bO, SCR_4aR_4b, CR_4aR_4bS, SO₂CR_4aR_4b, CR_4aR_4bSO₂, CR_4aR_4bCR_4cR_4d, CR_4a═CR_4b, or OCONR_4b;

R_4a, R_4b, R_4c, and R_4dare independently hydrogen, alkyl or haloalkyl, wherein the alkyl and haloalkyl may be optionally substituted with R₁₀, R_10a, R_10b, and R_10c;

G is a 5- or 6-membered heteroaryl containing at least one nitrogen;

R₆, R₇, and R₈are independently hydrogen, halo, haloalkyl, haloalkoxy, alkyl, aryl, heterocyclyl, alkoxy, aryloxy;

Q is CONR₁₁R_11a, SO₂NR₁₁R_11a, or OCONR₁₁R_11a;

R₁₁and R_11aare independently hydrogen, haloalkyl, alkyl, cycloalkyl, aryl, arylalkyl, or heterocyclyl, wherein the alkyl, cycloalkyl, aryl, arylalkyl, or heterocyclyl may be optionally substituted with R₁₀, R_10a, R_10b, and R_10c; or R₁₁and R_11amay be taken together with the nitrogen to which they are attached to form a heterocyclyl ring, which may be optionally substituted with R₁₀, R_10a, R_10b, and R_10c.

In another embodiment, compounds of formula I are those in which L is a bond, O, S, OCR_4aR_4b, SCR_4aR_4b, CR_4aR_4bS, SO₂CR_4aR_4b, CR_4aR_4bSO₂, CR_4aR_4bCR_4cR_4d, or CR_4a═CR_4b.

In another embodiment, compounds of formula I are those in which L is a bond, OCR_4aR_4b, SCR_4aR_4b, CR_4aR_4bS, SO₂CR_4aR_4b, CR_4aR_4bSO₂, or CR_4a═CR_4b.

In another embodiment, compounds of formula I are those in which L is OCR_4aR_4b, SCR_4aR_4b, CR_4aR_4bS, SO₂CR_4aR_4b, CR_4aR_4bSO₂, or CR_4a═CR_4b.

In another embodiment, compounds of formula I are those in which L is CR_4aR_4bS, SO₂CR_4aR_4b, CR_4aR_4bSO₂, or CR_4a═CR_4b.

In yet another embodiment, compounds of formula I are those in which L is CR_4aR_4bS, CR_4aR_4bSO₂, or CR_4a═CR_4b.

In another embodiment, compounds of formula I are those in which:

Z is aryl or heterocyclyl group, and may be optionally substituted with R₁, R₂, R₃, R₄, and R₅at any available positions;

L is bond, O, S, SO₂, OCR_4aR_4b, CR_4aR_4bO, SCR_4aR_4b, CR_4aR_4bS, SO₂CR_4aR_4b, CR_4aR_4bSO₂, CR_4aR_4bCR_4cR_4d, CR_4a═CR_4b, or OCONR_4b;

R_4a, R_4b, R_4cand R_4dare independently hydrogen and alkyl, wherein the alkyl may be optionally substituted with R₁₀, R_10a, R_10b, and R_10c;

G is a 5- or 6-membered heteroaryl containing at least one nitrogen;

R₆, R₇, and R₈are independently hydrogen, halo, haloalkyl, haloalkoxy, alkyl, aryl, heterocyclyl, alkoxy, aryloxy;

Q is CONR₁₁R_11a, SO₂NR₁₁R_11a, or OCONR₁₁R_11a;

In still yet another embodiment, compounds of formula I are those in which:

Z is aryl or heterocyclyl group, and may be optionally substituted with R₁, R₂, R₃, R₄, and R₅at any available positions;

R₁, R₂, R₃, R₄, and R₅are independently hydrogen, halo, cyano, haloalkyl, haloalkoxy, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, alkylamino, —C(O)R, —NR₉C(O)R_9a, —NR₉R_9a, aryl, arylalkyl, aryloxy, or heterocyclyl, wherein the haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, alkylamino, aryl, arylalkyl, or heterocyclyl, may be optionally substituted with R₉and R_9a; or independently any two adjoining R₁, R₂, R₃, R₄, and/or R₅may be taken together to form a fused aryl or heterocyclyl ring, which may be may be optionally substituted with R₁₀, R_10a, R_10b, and R_10c;

L is a bond, OCR_4aR_4b, CR_4aR_4bO, SCR_4aR_4b, CR_4aR_4bS, SO₂CR_4aR_4b, CR_4aR_4bSO₂, CR_4aR_4bCR_4cR_4dc, or CR_4a═CR_4b;

R_4a, R_4b, R_4c, and R_4dare independently hydrogen, alkyl or haloalkyl, wherein the alkyl or haloalkyl may be optionally substituted with R₁₀, R_10a, R_10b, and R_10c;

G is a 5- or 6-membered heteroaryl containing at least one nitrogen;

R₆, R₇, and R₈are independently hydrogen, halo, haloalkyl, haloalkoxy, alkyl, aryl, heterocyclyl, alkoxy, aryloxy;

Q is SO₂NR₁₁R_11a, or OCONR₁₁R_11a;

R₁₀, R_10a, R_10b, and R_10care independently selected from hydrogen, halo, hydroxy, nitro, cyano, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, —C(O)NR₉R_9a, —C(O)R₉, —NR₉C(O)R₉, aryl, aryloxy, or heterocyclyl, wherein the haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aryloxy, or heterocyclyl may be optionally substituted with R₉and R_9a; and

In one embodiment, compounds of formula I are those in which:

Z is aryl, and may be optionally substituted with R₁, R₂, R₃, R₄, and R₅at any available positions;

L is a bond, OCR_4aR_4b, SCR_4aR_4b, SO₂CR_4aR_4b, or CR_4aR_4bCR_4cR_4d;

R_4a, R_4b, R_4cand R_4dare independently hydrogen and alkyl, wherein the alkyl may be optionally substituted with R₁₀, R_10a, R_10b, and R_10c;

G is a 5- or 6-membered heteroaryl containing at least one nitrogen;

R₆, R₇, and R₈are independently hydrogen, halo, haloalkyl, haloalkoxy, alkyl, aryl, heterocyclyl, alkoxy, aryloxy;

Q is SO₂NR₁₁R_11aor OCONR₁₁R_11a;

In another embodiment, compounds of formula I are those in which:

Z is an aryl or heteroaryl of the following structure:
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In yet another embodiment, compounds of formula I are those in which:

Z is an aryl or heteroaryl of the following structure:
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In still yet another embodiment, the compounds of formula I are those in which:

G is a 5- or 6-membered heteroaryl containing at least one nitrogen of the following structure:
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In one embodiment, compounds of formula I are those in which:

G is a 5- or 6-membered heteroaryl containing at least one nitrogen of the following structure:
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In another embodiment, compounds of formula I are those in which:

Z is an aryl or heteroaryl of the following structure:
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L is a bond, OCR_4aR_4b, CR_4aR_4bO, SCR_4aR_4b, CR_4aR_4bS, SO₂CR_4aR_4b, CR_4aR_4bSO₂, CR_4aR_4bCR_4cR_4d, or CR_4a═CR_4b; and

G is a 5- or 6-membered heteroaryl containing at least one nitrogen of the following structure:
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In another embodiment, compounds of formula I are those in which:

Z is an aryl or heteroaryl of the following structure:
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L is a bond, OCR_4aR_4b, SCR_4aR_4b, or SO₂CR_4aR_4b;

G is a 5- or 6-membered heteroaryl containing at least one nitrogen of the following structure:
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In another embodiment, compounds of formula I are those in which:

Z is
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G is a 5- or 6-membered heteroaryl containing at least one nitrogen of the following structure:
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In another embodiment, compounds of formula I are those in which:

Z is
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L is a bond, OCR_4aR_4b, SCR_4aR_4b, or SO₂CR_4aR_4b;

R_4aand R_4bare independently hydrogen, alkyl, or haloalkyl;

G is a 5- or 6-membered heteroaryl containing at least one nitrogen of the following structure:
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R₆, R₇, and R₉are independently hydrogen, halo, haloalkyl, haloalkoxy, alkyl, aryl, heterocyclyl, alkoxy, aryloxy;

Q is SO₂NR₁₁R_11aor OCONR₁₁R_11a;

R₁₀, R_10a, R_10band R_10care independently selected from hydrogen, halo, hydroxy, nitro, cyano, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, —C(O)NR₉R_9a, —C(O)R₉, —NR₉C(O)R_9a, aryl, aryloxy, or heterocyclyl, wherein the haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aryloxy, or heterocyclyl may be optionally substituted with R₉and R_9a; and

In yet another embodiment, compounds of formula I are those in which:

R₁, R₂, R₃, R₄, and R₅are independently hydrogen, halo, cyano, haloalkyl, haloalkoxy, nitro, alkyl, cycloalkyl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, alkylamino, —C(O)R₉, —NR₉C(O)R_9a, —NR₉R_9a, aryl, arylalkyl, aryloxy, or heterocyclyl, wherein the haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, alkylamino, aryl, arylalkyl, or heterocyclyl, may be optionally substituted with R₉and R_9a; or independently any two adjoining R₁, R₂, R₃, R₄, and/or R₅may be taken together to form a fused aryl or heterocyclyl ring, which may be may be optionally substituted with R₁₀, R_10a, R_10b, and R_10c;

L is OCR_4aR_4b, SCR_4aR_4b, or SO₂CR_4aR_4b;

R_4aand R_4bare independently hydrogen, alkyl or haloalkyl;

G is a 5- or 6-membered heteroaryl containing at least one nitrogen of the following structure:
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R₆, R₇, and R₈are independently hydrogen, halo, haloalkyl, haloalkoxy, alkyl, aryl, heterocyclyl, alkoxy, aryloxy;

Q is SO₂NR₁₁R_11aor OCONR₁₁R_11a;

In still yet another embodiment, compounds of formula I are those in which:

L is OCR_4aR_4bor SO₂CR_4aR_4b;

R_4aand R_4bare independently hydrogen, alkyl, or haloalkyl;

G is a 5- or 6-membered heteroaryl containing at least one nitrogen of the following structure:
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R₆, R₇, and R₈are independently hydrogen, halo, haloalkyl, haloalkoxy, alkyl, aryl, heterocyclyl, alkoxy, aryloxy;

Q is SO₂NR₁₁R_11aor OCONR₁₁R_11a;

R₁₀, R_10a, R_10b, and R₁₀, are independently selected from hydrogen, halo, hydroxy, nitro, cyano, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, —C(O)NR₉R_9a, —C(O)R₉, —NR₉C(O)R_9a, aryl, aryloxy, or heterocyclyl, wherein the haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aryloxy, or heterocyclyl may be optionally substituted with R₉and R_9a; and

In one embodiment, compounds of formula I are those in which:

L is OCR_4aR_4bor SO₂CR_4aR_4b;

R_4aand R_4bare independently hydrogen or alkyl;

G is a 5- or 6-membered heteroaryl containing at least one nitrogen of the following structure:
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R₆, R₇, and R₈are independently hydrogen, halo, haloalkyl, haloalkoxy, alkyl, aryl, heterocyclyl, alkoxy, aryloxy;

Q is SO₂NR₁₁R_11aor OCONR₁₁R_11a;

In another embodiment, compounds of formula I are those in which:

R₁, R₂, R₃, R₄, and R₅are independently hydrogen, halo, cyano, haloalkyl, haloalkoxy, nitro, alkyl, cycloalkyl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, alkylamino, —C(O)R₉, —NR₉C(O)R_9a, —NR₉R_9a, aryl, arylalkyl, aryloxy, or heterocyclyl, wherein the haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, alkylamino, aryl, arylalkyl, aryloxy, or heterocyclyl, may be optionally substituted with R₉and R_9a; or independently any two adjoining R₁, R₂, R₃, R₄, and/or R₅may be taken together to form a fused aryl or heterocyclyl ring, which may be may be optionally substituted with R₁₀, R_10a, R_10b, and R_10c;

L is OCR_4aR_4bor SO₂CR_4aR_4b;

R_4aand R_4bare independently hydrogen or alkyl;

G is a 5- or 6-membered heteroaryl containing at least one nitrogen of the following structure:
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R₆, R₇, and R₈are independently hydrogen, halo, haloalkyl, haloalkoxy, alkyl, aryl, heterocyclyl, alkoxy, aryloxy;

Q is SO₂NR₁₁R_11aor OCONR₁₁R_11a;

R₁₀, R_10a, R_10b, and R_10care independently selected from hydrogen, halo, hydroxy, nitro, cyano, haloalkyl, alkyl, cycloalkyl, —C(O)NR₉R_9a, —C(O)R₉, —NR₉C(O)R_9a, aryl, aryloxy, or heterocyclyl, wherein the haloalkyl, alkyl, cycloalkyl, aryl, aryloxy, or heterocyclyl may be optionally substituted with R₉and R_9a; and

In yet another embodiment, compounds of formula I are those in which:

or independently any two adjoining R₁, R₂, R3, R₄, and/or R₅may be taken together to form a fused aryl or heterocyclyl ring, which may be may be optionally substituted with R₁₀, R_10a, R_10b, and R_10c;

L is OCR_4aR_4bor SO₂CR_4aR_4b;

R_4aand R_4bare independently hydrogen or alkyl;

G is a 5- or 6-membered heteroaryl containing at least one nitrogen of the following structure:
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R₆, R₇, and R₈are independently hydrogen, halo, haloalkyl, haloalkoxy, alkyl, aryl, or heterocyclyl;

Q is SO₂NR₁₁R_11aor OCONR₁₁R_11a;

R₁₀, R_10a, R_10b, and R_10care independently selected from hydrogen, halo, hydroxy, nitro, cyano, haloalkyl, alkyl, cycloalkyl, aryl, aryloxy, or heterocyclyl, wherein the haloalkyl, alkyl, cycloalkyl, aryl, aryloxy, or heterocyclyl may be optionally substituted with R₉and R_9a; and

In still yet another embodiment, compounds of formula I are those in which:

R₁, R₂, R₃, R₄, and R₅are independently hydrogen, halo, haloalkyl, haloalkoxy, alkyl, cycloalkyl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, alkylamino, aryl, arylalkyl, aryloxy, or heterocyclyl, wherein the haloalkyl, haloalkoxy, alkyl, cycloalkyl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, alkylamino, aryl, arylalkyl, or heterocyclyl, may be optionally substituted with R₉and R_9a; or independently any two adjoining R₁, R₂, R₃, R₄, and/or R₅may be taken together to form a fused aryl or heterocyclyl ring, which may be may be optionally substituted with R₁₀, R_10a, R_10b, and R_10c;

L is OCR_4aR_4bor SO₂CR_4aR_4b;

R_4aand R_4bare independently hydrogen or alkyl;

G is a 5- or 6-membered heteroaryl containing at least one nitrogen of the following structure:
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R₆, R₇, and R₈are independently hydrogen, halo, alkyl, aryl, or heterocyclyl;

Q is SO₂NR₁₁R_11aor OCONR₁₁R_11a;

R₁₁and R_11aare independently hydrogen, alkyl, cycloalkyl, aryl or heterocyclyl, wherein the alkyl, cycloalkyl, aryl, or heterocyclyl may be optionally substituted with R₁₀, R_10a, R_10b, and R_10c;

or R₁₁and R_11amay be taken together with the nitrogen to which they are attached to form a heterocyclyl ring, which may be optionally substituted with R₁₀, R_10a, R_10b, and R_10c;

R₁₀, R_10a, R_10b, and R_10care independently selected from hydrogen, halo, haloalkyl, alkyl, cycloalkyl, aryl, aryloxy, or heterocyclyl, wherein the haloalkyl, alkyl, cycloalkyl, aryl, aryloxy, or heterocyclyl may be optionally substituted with R₉and R_9a; and

In an additional embodiment, compounds of formula I are those in which:

R₁, R₂, R₃, R₄, and R₅are independently hydrogen, halo, haloalkyl, haloalkoxy, alkyl, cycloalkyl, alkoxy, aryl, arylalkyl, aryloxy, or heterocyclyl, wherein the haloalkyl, haloalkoxy, alkyl, cycloalkyl, alkoxy, aryl, arylalkyl, aryloxy, or heterocyclyl, may be optionally substituted with R₉and R_9a;

L is OCR_4aR_4bor SO₂CR_4aR_4b;

R_4aand R_4bare independently hydrogen or alkyl;

G is a 5- or 6-membered heteroaryl containing at least one nitrogen of the following structure:
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R₆, R₇, and R₈are independently hydrogen, alkyl, aryl, or heterocyclyl;

Q is SO₂NR₁₁R_11aor OCONR₁₁R_11a;

R₁₁and R_11aare independently hydrogen, alkyl, cycloalkyl, aryl or heterocyclyl, wherein the alkyl, cycloalkyl, aryl or heterocyclyl may be optionally substituted with R₁₀, R_10a, R_10b, and R_10c; or R₁₁and R_11amay be taken together with the nitrogen to which they are attached to form a heterocyclyl ring, which may be optionally substituted with R₁₀, R_10a, R_10b, and R_10c;

R₁₀, R_10a, R_10b, and R_10care independently selected from hydrogen, halo, haloalkyl, alkyl, cycloalkyl, aryl, or heterocyclyl, wherein the haloalkyl, alkyl, cycloalkyl, aryl, or heterocyclyl may be optionally substituted with R₉and R_9a; and

R₉and R_9aare independently hydrogen, alkyl, cycloalkyl, aryl, or heterocyclyl, wherein the alkyl, cycloalkyl, aryl, or heterocyclyl may be optionally substituted with halo, haloalkyl, alkyl, aryl, or heterocyclyl.

In another additional embodiment, compounds of formula I are those in which:

R₁, R₂, R₃, R₄, and R₅are independently hydrogen, halo, haloalkyl, alkyl, cycloalkyl, aryl, arylalkyl, aryloxy, or heterocyclyl, wherein the haloalkyl, haloalkoxy, alkyl, cycloalkyl, alkoxy, aryl, arylalkyl, aryloxy, or heterocyclyl, may be optionally substituted with R₉and R_9a;

L is OCH₂or SO₂CH₂;

G is a 5- or 6-membered heteroaryl containing at least one nitrogen of the following structure:
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R₆, R₇, and R₈are independently hydrogen or alkyl;

Q is SO₂NR₁₁R_11aor OCONR₁₁R_11a;

R₁₀, R_10a, R_10b, and R_10care independently selected from hydrogen, halo, alkyl, cycloalkyl, aryl, or heterocyclyl, wherein the alkyl, cycloalkyl, aryl, or heterocyclyl may be optionally substituted with R₉and R_9a; and

In yet another additional embodiment, compounds of formula I are those in which:

R₁, R₂, R₃, R₄, and R₅are independently hydrogen, halo, haloalkyl, alkyl, cycloalkyl, aryl, or heterocyclyl, wherein the haloalkyl, alkyl, cycloalkyl, aryl, or heterocyclyl, may be optionally substituted with R₉and R_9a;

G is a 5- or 6-membered heteroaryl containing at least one nitrogen of the following structure:
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R₆, R₇, and R₈are hydrogen;

Q is SO₂NR₁₁R_11a;

R₁, and R_11aare independently hydrogen, alkyl, or cycloalkyl, wherein the alkyl or cycloalkyl may be optionally substituted with R₁₀, R_10a, R_10b, and R_10c; or R₁₁and R_11amay be taken together with the nitrogen to which they are attached to form a heterocyclyl ring, which may be optionally substituted with R₁₀, R_10a, R_10b, and R_10c;

R₁₀, R_10a, R_10b, and R_10care independently selected from hydrogen, halo, alkyl, aryl, or heterocyclyl, wherein the alkyl, aryl, or heterocyclyl may be optionally substituted with R₉and R_9a; and

R₉and R_9aare independently hydrogen, alkyl, aryl, or heterocyclyl, wherein the alkyl, aryl, or heterocyclyl may be optionally substituted with halo, haloalkyl, alkyl, aryl, or heterocyclyl.

In still yet another embodiment, compounds of formula I are those in which:

R₁, R₂, R₃, R₄, and R₅are independently hydrogen, halo, haloalkyl, alkyl, or cycloalkyl, wherein the haloalkyl, alkyl or cycloalkyl, may be optionally substituted with R₉and R_9a;

G is a 5- or 6-membered heteroaryl containing at least one nitrogen of the following structure:
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R₆, R₇, and R₈are hydrogen;

Q is SO₂NR₁₁R_11a;

R₁₁and R_11aare independently hydrogen or alkyl; or R₁₁and R_11amay be taken together with the nitrogen to which they are attached to form a heterocyclyl ring, which may be optionally substituted with R₁₀, R_10a, R_10b, and R_10c;

R₁₀, R_10a, R_10b, and R_10care independently selected from hydrogen, halo, or alkyl.

In one embodiment, compounds of formula I are those in which:

G is a 5- or 6-membered heteroaryl containing at least one nitrogen of the following structure:
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In another embodiment, compounds of formula I are those in which:

G is a 5- or 6-membered heteroaryl containing at least one nitrogen of the following structure:
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In another embodiment, compounds of the present invention are selected from the compounds exemplified in the examples.

In another embodiment, the present invention relates to pharmaceutical compositions comprised of a therapeutically effective amount of a compound of the present invention, alone or, optionally, in combination with a pharmaceutically acceptable carrier and/or one or more other agent(s).

In another embodiment, the present invention relates to methods of inhibiting the activity of the enzyme 11-beta-hydroxysteroid dehydrogenase type I comprising administering to a mammalian patient, for example, a human patient, in need thereof a therapeutically effective amount of a compound of the present invention, alone, or optionally, in combination with another compound of the present invention and/or at least one other type of therapeutic agent.

In another embodiment, the present invention relates to a method for preventing, inhibiting, or treating the progression or onset of diseases or disorders associated with the activity of the enzyme 11-beta-hydroxysteroid dehydrogenase type I comprising administering to a mammalian patient, for example, a human patient, in need of prevention, inhibition, or treatment a therapeutically effective amount of a compound of the present invention, alone, or, optionally, in combination with another compound of the present invention and/or at least one other type of therapeutic agent.

Examples of diseases or disorders associated with the activity of the enzyme 11-beta-hydroxysteroid dehydrogenase type I that can be prevented, inhibited, or treated according to the present invention include, but are not limited to, diabetes, hyperglycemia, impaired glucose tolerance, insulin resistance, hyperinsulinemia, retinopathy, neuropathy, nephropathy, delayed wound healing, atherosclerosis and its sequelae, abnormal heart function, myocardial ischemia, stroke, Metabolic Syndrome, hypertension, obesity, dislipidemia, dylsipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL, high LDL, non-cardiac ischemia, infection, cancer, vascular restenosis, pancreatitis, neurodegenerative disease, lipid disorders, cognitive impairment and dementia, bone disease, HIV protease associated lipodystrophy and glaucoma.

In another embodiment, the present invention relates to a method for preventing, inhibiting, or treating the progression or onset of diabetes, hyperglycemia, obesity,dyslipidemia, hypertension and cognitive impairment comprising administering to a mammalian patient, for example, a human patient, in need of prevention, inhibition, or treatment a therapeutically effective amount of a compound of the present invention, alone, or, optionally, in combination with another compound of the present invention and/or at least one other type of therapeutic agent.

In still another embodiment, the present invention relates to a method for preventing, inhibiting, or treating the progression or onset of diabetes, comprising administering to a mammalian patient, for example, a human patient, in need of prevention, inhibition, or treatment a therapeutically effective amount of a compound of the present invention, alone, or, optionally, in combination with another compound of the present invention and/or at least one other type of therapeutic agent.

In yet still another embodiment, the present invention relates to a method for preventing, inhibiting, or treating the progression or onset of hyperglycemia comprising administering to a mammalian patient, for example, a human patient, in need of prevention, inhibition, or treatment a therapeutically effective amount of a compound of the present invention, alone, or, optionally, in combination with another compound of the present invention and/or at least one other type of therapeutic agent.

In another embodiment, the present invention relates to a method for preventing, inhibiting, or treating the progression or onset of obesity comprising administering to a mammalian patient, for example, a human patient, in need of prevention, inhibition, or treatment a therapeutically effective amount of a compound of the present invention, alone, or, optionally, in combination with another compound of the present invention and/or at least one other type of therapeutic agent.

In one embodiment, the present invention relates to a method for preventing, inhibiting, or treating the progression or onset of dyslipidemia comprising administering to a mammalian patient, for example, a human patient, in need of prevention, inhibition, or treatment a therapeutically effective amount of a compound of the present invention, alone, or, optionally, in combination with another compound of the present invention and/or at least one other type of therapeutic agent.

In another embodiment, the present invention relates to a method for preventing, inhibiting, or treating the progression or onset of hypertension comprising administering to a mammalian patient, for example, a human patient, in need of prevention, inhibition, or treatment a therapeutically effective amount of a compound of the present invention, alone, or, optionally, in combination with another compound of the present invention and/or at least one other type of therapeutic agent.

In another embodiment, the present invention relates to a method for preventing, inhibiting, or treating the progression or onset of cognitive impairment comprising administering to a mammalian patient, for example, a human patient, in need of prevention, inhibition, or treatment a therapeutically effective amount of a compound of the present invention, alone, or, optionally, in combination with another compound of the present invention and/or at least one other type of therapeutic agent.

DEFINITIONS

The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, C═N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms, and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.

The term “substituted,” as used herein, means that any one or more hydrogens on the designated atom or ring is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom are replaced.

When any variable (e.g., R^a) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R^a, then said group may optionally be substituted with up to two R^agroups and R^aat each occurrence is selected independently from the definition of R^a. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

Unless otherwise indicated, the term “lower alkyl,” “alkyl,” or “alk” as employed herein alone or as part of another group includes both straight and branched chain hydrocarbons, containing 1 to 20 carbons, preferably 1 to 10 carbons, more preferably 1 to 8 carbons, in the normal chain, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethyl-pentyl, nonyl, decyl, undecyl, dodecyl, the various branched chain isomers thereof, and the like as well as such groups may optionally include 1 to 4 substituents such as halo, for example F, Br, Cl, or I, or CF₃, alkyl, alkoxy, aryl, aryloxy, aryl(aryl) or diaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amino, hydroxy, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, nitro, cyano, thiol, haloalkyl, trihaloalkyl, and/or alkylthio.

Unless otherwise indicated, the term “cycloalkyl” as employed herein alone or as part of another group includes saturated or partially unsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groups containing 1 to 3 rings, including monocyclic alkyl, bicyclic alkyl (or bicycloalkyl) and tricyclic alkyl, containing a total of 3 to 20 carbons forming the ring, preferably 3 to 10 carbons, forming the ring and which may be fused to 1 or 2 aromatic rings as described for aryl, which includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl,
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any of which groups may be optionally substituted with 1 to 4 substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy, arylalkyl, cycloalkyl, alkylamido, alkanoylamino, oxo, acyl, arylcarbonylamino, amino, nitro, cyano, thiol, and/or alkylthio, and/or any of the substituents for alkyl.

Unless otherwise indicated, the term “lower alkenyl” or “alkenyl” as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbons, and more preferably 1 to 8 carbons in the normal chain, which include one to six double bonds in the normal chain, such as vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl, and the like, and which may be optionally substituted with 1 to 4 substituents, namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, amino, hydroxy, heteroaryl, cycloheteroalkyl, alkanoylamino, alkylamido, arylcarbonyl-amino, nitro, cyano, thiol, alkylthio, and/or any of the alkyl substituents set out herein.

Unless otherwise indicated, the term “lower alkynyl” or “alkynyl” as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbons and more preferably 2 to 8 carbons in the normal chain, which include one triple bond in the normal chain, such as 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl,3-undecynyl, 4-dodecynyl, and the like, and which may be optionally substituted with 1 to 4 substituents, namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, amino, heteroaryl, cycloheteroalkyl, hydroxy, alkanoylamino, alkylamido, arylcarbonylamino, nitro, cyano, thiol, and/or alkylthio, and/or any of the alkyl substituents set out herein.

Where alkyl groups as defined above have single bonds for attachment to other groups at two different carbon atoms, they are termed “alkylene” groups and may optionally be substituted as defined above for “alkyl”.

Where alkenyl groups as defined above and alkynyl groups as defined above, respectively, have single bonds for attachment at two different carbon atoms, they are termed “alkenylene groups” and “alkynylene groups”, respectively, and may optionally be substituted as defined above for “alkenyl” and “alkynyl”.

The term “halogen” or “halo” as used herein alone or as part of another group refers to chlorine, bromine, fluorine, and iodine as well as CF₃, with chlorine or fluorine being preferred.

Unless otherwise indicated, the term “aryl” as employed herein alone or as part of another group refers to monocyclic and bicyclic aromatic groups containing 6 to 10 carbons in the ring portion (such as phenyl or naphthyl, including 1-naphthyl and 2-naphthyl) and may optionally include 1 to 3 additional rings fused to a carbocyclic ring or a heterocyclic ring (such as aryl, cycloalkyl, heteroaryl, or cycloheteroalkyl rings for example
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and may be optionally substituted through available carbon atoms with 1, 2, or 3 substituents, for example, hydrogen, halo, haloalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkyl-alkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, arylthio, arylazo, heteroarylalkyl, heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro, cyano, amino, substituted amino wherein the amino includes 1 or 2 substituents (which are alkyl, aryl, or any of the other aryl compounds mentioned in the definitions), thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl, arylcarbonyl, alkyl-aminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino, or arylsulfon-aminocarbonyl, and/or any of the alkyl substituents set out herein.

Unless otherwise indicated, the term “lower alkoxy”, “alkoxy”, “aryloxy” or “aralkoxy” as employed herein alone or as part of another group includes any of the above alkyl, aralkyl, or aryl groups linked to an oxygen atom.

Unless otherwise indicated, the term “amino” as employed herein alone or as part of another group refers to amino that may be substituted with one or two substituents, which may be the same or different, such as alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or thioalkyl. These substituents may be further substituted with a carboxylic acid and/or any of the R¹groups or substituents for R¹as set out above. In addition, the amino substituents may be taken together with the nitrogen atom to which they are attached to form 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl, 4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl, 1-pyrrolidinyl, 1-piperidinyl, or 1-azepinyl, optionally substituted with alkyl, alkoxy, alkylthio, halo, trifluoromethyl, or hydroxy.

Unless otherwise indicated, the term “lower alkylthio,” “alkylthio,” “arylthio,” or “aralkylthio” as employed herein alone or as part of another group includes any of the above alkyl, aralkyl, or aryl groups linked to a sulfur atom.

Unless otherwise indicated, the term “lower alkylamino,” “alkylamino,” “arylamino,” or “arylalkylamino” as employed herein alone or as part of another group includes any of the above alkyl, aryl, or arylalkyl groups linked to a nitrogen atom.

As used herein, the term “heterocyclyl ” or “heterocyclic system” is intended to mean a stable 5- to 12-membered monocyclic or bicyclic heterocyclic ring which is saturated, partially unsaturated, or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, NH, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. As used herein, the term “aromatic heterocyclic system” is intended to mean a stable 5- to 12-membered monocyclic or bicyclic heterocyclic aromatic ring, which consists of carbon atoms and from 1 to 4 heterotams independently selected from the group consisting of N, O, and S.

Unless otherwise indicated, the term “heteroaryl” as used herein alone or as part of another group refers to a 5- or 12-membered aromatic ring, prefereably, a 5- or 6-membered aromatic ring, which includes 1, 2, 3, or 4 hetero atoms such as nitrogen, oxygen, or sulfur, and such rings fused to an aryl, cycloalkyl, heteroaryl, or cycloheteroalkyl ring (e.g. benzothiophenyl, indolyl), and includes possible N-oxides. The heteroaryl group may optionally include 1 to 4 substituents such as any of the substituents set out above for alkyl. Examples of heteroaryl groups include the following:
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and the like.

The term “heterocyclylalkyl” or “heterocyclyl” as used herein alone or as part of another group refers to heterocyclyl groups as defined above linked through a C atom or heteroatom to an alkyl chain.

The term “heteroarylalkyl” or “heteroarylalkenyl” as used herein alone or as part of another group refers to a heteroaryl group as defined above linked through a C atom or heteroatom to an alkyl chain, alkylene, or alkenylene as defined above.

The term “cyano” as used herein, refers to a —CN group.

The term “nitro” as used herein, refers to an —NO₂group.

The term “hydroxy” as used herein, refers to an —OH group.

The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington 's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.

Any compound that can be converted in vivo to provide the bioactive agent (i.e., the compound of formula I) is a prodrug within the scope and spirit of the invention.

The term “prodrugs” as employed herein includes esters and carbonates formed by reacting one or more hydroxyls of compounds of formula I with alkyl, alkoxy, or aryl substituted acylating agents employing procedures known to those skilled in the art to generate acetates, pivalates, methylcarbonates, benzoates, and the like.

Various forms of prodrugs are well known in the art and are described in:

a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Ch. 31, (Academic Press, 1996);

b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985);

c) A Textbook of Drug Design and Development, P. Krogsgaard-Larson and H. Bundgaard, eds. Ch. 5, pgs 113-191 (Harwood Academic Publishers, 1991); and

d) Hydrolysis in Drug and Prodrug Metabolism, Bernard Testa and Joachim M. Mayer, (Wiley-VCH, 2003). Said references are incorporated herein by reference.

In addition, compounds of the formula I are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 99% formula I compound (“substantially pure” compound I), which is then used or formulated as described herein. Such “substantially pure” compounds of the formula I are also contemplated herein as part of the present invention.

All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form. The compounds of the present invention can have asymmetric centers at any of the carbon atoms including any one of the R substituents and/or exhibit polymorphism. Consequently, compounds of formula I can exist in enantiomeric, or diastereomeric forms, or in mixtures thereof. The processes for preparation can utilize racemates, enantiomers, or diastereomers as starting materials. When diastereomeric or enantiomeric products are prepared, they can be separated by conventional methods for example, chromatographic or fractional crystallization.

“Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. The present invention is intended to embody stable compounds.

“Therapeutically effective amount” is intended to include an amount of a compound of the present invention alone or an amount of the combination of compounds claimed or an amount of a compound of the present invention in combination with other active ingredients effective to inhibit MIP-1α or effective to treat or prevent inflammatory disorders.

As used herein, “treating” or “treatment” cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, i.e., arresting it development; and/or (c) relieving the disease-state, i.e., causing regression of the disease state.

Synthesis

Compounds of formula I of may be prepared as shown in the following reaction schemes and description thereof, as well as relevant literature procedures that may be used by one skilled in the art. Exemplary reagents and procedures for these reactions appear hereinafter and in the working Examples.
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Scheme I describes a method for preparing compounds of formula IA (a subset of compounds of formula I). An acid intermediate II can be obtained commercially, prepared by methods known in the literature or other methods used by one skilled in the art. Formation of an amide IV can be obtained from an acid II and an amine III using appropriate amide coupling reagents, such as EDAC/HOBT, EDAC/HOAT, PyBOP, or those reagents described in “The Practice of Peptide Synthesis” (Spring-Verlag, 2nd Ed., Bodanszy, Miklos, 1993), to yield an amide intermediate IV. Carbonylation of an intermediate IV with an appropriate catalyst and ligand provides an ester intermediate V. Reduction of an ester V using an appropriate reducing reagent such as sodium borohydride or other reagents used by one skilled in the art provides an alcohol VI. Mitsunobu Reaction of an alcohol VI with a phenol VII provides compounds of formula IA.
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Scheme II describes another method for preparing compounds of formula IA (a subset of compounds of formula I). An intermediate VIII can be obtained commercially, prepared by methods known in the literature or other methods used by one skilled in the art. Bromination of an intermediate VIII can be obtained using NBS with an appropriate radical reaction initiator such as AIBN to provide a bromo-intermediate IX. Alkylation of a phenol intermediate VII with a bromo-intermediate IX provides an ester intermediate X. Hydrolysis of an ester X under basic condition followed by amide formation with an amine III provides compounds of formula IA.
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Scheme III describes a method for preparing compounds of formula IB and IC (subsets of compounds of formula I). A diester intermediate XI can be obtained commercially, prepared by methods known in the literature or other methods used by one skilled in the art. Reduction of one ester group can be obtained using an appropriate reducing reagent such as sodium borohydride or other reagents used by one skilled in the art. Chlorination of an alcohol intermediate XII using thionyl chloride or carbon tetrachloride/triphenyl phosphine provides an intermediate XIII. Alkylation of a thiophenol XIV with an intermediate XIII provides an ester intermediate XV. Hydrolysis of an ester XV under basic conditions followed by amide formation with an amine III provides compounds of formula IB. Subsequent oxidation of compounds IB with an appropriate oxidizing reagent such as mCPBA, Oxone®, p-toluenesulfonic peracid generated in situ (Tetrahedron, 1996, 52, 5773-5787), or other reagents used by one skilled in the art provides compounds of formula IC.
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Scheme IV describes a method for preparing compounds of formula ID (a subset of compounds of formula I). A cross-coupling reaction of a bromo-intermediate IV (Scheme I) with a boronic acid XVI, an organostannane XVII, or an organozinc reagent XVIII using an appropriate catalyst and ligand provides compounds of formula ID.
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Scheme V describes a method for preparing compounds of formula IE (a subset of compounds of formula I). Nucleophilic aromatic substitution of an intermediate IV (Scheme I) by a phenol intermediate VII provides compounds of formula IE.
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Scheme VI describes a method for preparing compounds of formula IF and IG (subsets of compounds of formula I). Nucleophilic aromatic substitution of an intermediate IV (Scheme I) by a thiophenol intermediate XIV provides compounds of formula IF. Subsequent oxidation of a compound IF with an appropriate oxidizing reagent such as mCPBA, Oxone® p-toluenesulfonic peracid generated in situ (Tetrahedron, 1996, 52, 5773-5787), or other reagents used by one skilled in the art provides a compound of formula IG.
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Scheme VII describes a method for preparing compounds of formula IH and IJ (subsets of compounds of formula I). An alcohol intermediate XIX can be obtained commercially, prepared by methods known in the literature, or by other methods used by one skilled in the art. Chlorination of an alcohol intermediate XIX using thionyl chloride or carbon tetrachloride/triphenyl phosphine provides an intermediate XX. Alkylation of a phenol XII with an intermediate XX provides an intermediate XXI. Demethylation of an intermediate XXI can be obtained using tribromoborane or other reagents used by one skilled in the art to provide an intermediate XXII. Reaction of an intermediate XXII with phosgene followed by reaction with an amine III provides compounds of formula IH.
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Scheme VIII describes a method for preparing compounds of formula IK and IL (subsets of compounds of formula I where G is a thiazole group). Alkylation of a thiophenol XIV with a 2-bromoacetoamide XXIII provides an amide intermediate XXIV. Reaction of an amide XXIV with Lawesson Reagent provides a thioamide intermediate XXV. Thiazole formation can be obtained from reaction of a thioamide XXV and a bromopyruvate XXVI or by other methods used by one skilled in the art. Hydrolysis of an ester XXVII under basic conditions followed by amide formation with an amine III provides compounds of formula IK. Subsequent oxidation of compounds IK with an appropriate oxidizing reagent such as mCPBA, Oxone®, p-toluenesulfonic peracid generated in situ (Tetrahedron, 1996, 52, 5773-5787), or other reagents used by one skilled in the art provides compounds of formula IL.
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Scheme IX describes a method for preparing compounds of formula IM. Monolithiation (Tetrahedron Lett., 1996, 37, 2537-2540) of commerically available (XXVIII) followed by sulfinylation of the lithiated species and subsequent oxidative sulfonylation with sulfuryl chloride provides intermediate (XXIX). Reaction of amine with intermediate (XXIX) provides intermediate (XXX). Suzuki cross-coupling with bromo intermediate (XXX) using the appropriate ligand and catalyst provides compounds of formula (IM).

Utilities and Combinations

A. Utilities

The compounds of the present invention possess activity as inhibitors of the enzyme 11-beta-hydroxysteroid dehydrogenase type I, and, therefore, may be used in the treatment of diseases associated with 11-beta-hydroxysteroid dehydrogenase type I activity. Via the inhibition of 11-beta-hydroxysteroid dehydrogenase type I, the compounds of the present invention may preferably be employed to inhibit glucocorticoid, thereby interrupting or modulating cortisone or cortisol production.

Accordingly, the compounds of the present invention can be administered to mammals, preferably humans, for the treatment of a variety of conditions and disorders, including, but not limited to, treating, preventing, or slowing the progression of diabetes and related conditions, microvascular complications associated with diabetes, macrovascular complications associated with diabetes, cardiovascular diseases, Metabolic Syndrome and its component conditions, and other maladies. Consequently, it is believed that the compounds of the present invention may be used in preventing, inhibiting, or treating diabetes, hyperglycemia, impaired glucose tolerance, insulin resistance, hyperinsulinemia, retinopathy, neuropathy, nephropathy, delayed wound healing, atherosclerosis and its sequelae, abnormal heart function, myocardial ischemia, stroke, Metabolic Syndrome, hypertension, obesity, dislipidemia, dylsipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL, high LDL, non-cardiac ischemia, infection, cancer, vascular restenosis, pancreatitis, neurodegenerative disease, lipid disorders, cognitive impairment and dementia, bone disease, HIV protease associated lipodystrophy and glaucoma.

Metabolic Syndrome or “Syndrome X” is described in Ford, et al., J. Am. Med. Assoc. 2002, 287, 356-359 and Arbeeny, et al., Curr. Med. Chem.—Imm., Endoc. & Metab. Agents 2001, 1, 1-24.

B. Combinations

The present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, a therapeutically effective amount of at least one of the compounds of formula I, alone or in combination with a pharmaceutical carrier or diluent. Optionally, compounds of the present invention can be used alone, in combination with other compounds of the invention, or in combination with one or more other therapeutic agent(s), e.g., an antidiabetic agent or other pharmaceutically active material.

The compounds of the present invention may be employed in combination with other 11-beta-hydroxysteroid dehydrogenase type I inhibitors or one or more other suitable therapeutic agents useful in the treatment of the aforementioned disorders including: anti-diabetic agents, anti-hyperglycemic agents, anti-hyperinsulinemic agents, anti-retinopathic agents, anti-neuropathic agents, anti-nephropathic agents, anti-atherosclerotic agents, anti-infective agents, anti-ischemic agents, anti-hypertensive agents, anti-obesity agents, anti-dislipidemic agents, anti-dylsipidemic agents, anti-hyperlipidemic agents, anti-hypertriglyceridemic agents, anti-hypercholesterolemic agents, anti-ischemic agents, anti-cancer agents, anti-cytotoxic agents, anti-restenotic agents, anti-pancreatic agents, lipid lowering agents, appetite suppressants, memory enhancing agents and cognitive agents.

Examples of suitable anti-diabetic agents for use in combination with the compounds of the present invention include insulin and insulin analogs: LysPro insulin, inhaled formulations comprising insulin; glucagon-like peptides; sulfonylureas and analogs: chlorpropamide, glibenclamide, tolbutamide, tolazamide, acetohexamide, glypizide, glyburide, glimepiride, repaglinide, meglitinide; biguanides: metformin, phenformin, buformin; alpha2-antagonists and imidazolines: midaglizole, isaglidole, deriglidole, idazoxan, efaroxan, fluparoxan; other insulin secretagogues: linogliride, insulinotropin, exendin-4, BTS-67582, A-4166; thiazolidinediones: ciglitazone, pioglitazone, troglitazone, rosiglitazone; PPAR-gamma agonists; PPAR-alpha agonists; PPAR alpha/gamma dual agonists; SGLT2 inhibitors; dipeptidyl peptidase-IV (DPP4) inhibitors; aldose reductase inhibitors; RXR agonists: JTT-501, MCC-555, MX-6054, DRF2593, GI-262570, KRP-297, LG100268; fatty acid oxidation inhibitors: clomoxir, etomoxir; αx-glucosidase inhibitors: precose, acarbose, miglitol, emiglitate, voglibose, MDL-25,637, camiglibose, MDL-73,945; beta-agonists: BRL 35135, BRL 37344, Ro 16-8714, ICI D7114, CL 316,243, TAK-667, AZ40140; phosphodiesterase inhibitors, both cAMP and cGMP type: sildenafil, L686398: L-386,398; amylin antagonists: pramlintide, AC-137; lipoxygenase inhibitors: masoprocal; somatostatin analogs: BM-23014, seglitide, octreotide; glucagon antagonists: BAY 276-9955; insulin signaling agonists, insulin mimetics, PTP1B inhibitors: L-783281, TER17411, TER17529; gluconeogenesis inhibitors: GP3034; somatostatin analogs and antagonists; antilipolytic agents: nicotinic acid, acipimox, WAG 994; glucose transport stimulating agents: BM-130795; glucose synthase kinase inhibitors: lithium chloride, CT98014, CT98023; and galanin receptor agonists.

Other suitable thiazolidinediones include Mitsubishi's MCC-555 (disclosed in U.S. Pat. No. 5,594,016), Glaxo-Wellcome's GL-262570, englitazone (CP-68722, Pfizer), or darglitazone (CP-86325, Pfizer, isaglitazone (MIT/J&J), JTT-501 (JPNT/P&U), L-895645 (Merck), R-119702 (Sankyo/WL), NN-2344 (Dr. Reddy/NN), or YM-440 (Yamanouchi).

Suitable PPAR alpha/gamma dual agonists include AR-HO39242 (Astra/Zeneca), GW-409544 (Glaxo-Wellcome), KRP297 (Kyorin Merck), as well as those disclosed by Murakami et al, “A Novel Insulin Sensitizer Acts As a Coligand for Peroxisome Proliferation—Activated Receptor Alpha (PPAR alpha) and PPAR gamma; Effect of PPAR alpha Activation on Abnormal Lipid Metabolism in Liver of Zucker Fatty Rats”, Diabetes 47, 1841-1847 (1998), and WO 01/21602, the disclosure of which is incorporated herein by reference, employing dosages as set out therein, which compounds designated as preferred are preferred for use herein.

Suitable alpha2 antagonists also include those disclosed in WO 00/59506, employing dosages as set out herein.

Suitable SGLT2 inhibitors include T-1095, phlorizin, WAY-123783, and those described in WO 01/27128.

Suitable DPP4 inhibitors include those disclosed in WO99/38501, WO99/46272, WO99/67279 (PROBIODRUG), WO99/67278 (PROBIODRUG), WO99/61431 (PROBIODRUG), NVP-DPP728A (1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine) (Novartis) as disclosed by Hughes et al, Biochemistry, 38 (36), 11597-11603, 1999, TSL-225 (tryptophyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (disclosed by Yamada et al, Bioorg. & Med. Chem. Lett. 8 (1998) 1537-1540, 2-cyanopyrrolidides and 4-cyanopyrrolidides, as disclosed by Ashworth et al, Bioorg. & Med. Chem. Lett., Vol. 6, No. 22, pp 1163-1166 and 2745-2748 (1996), employing dosages as set out in the above references.

Suitable aldose reductase inhibitors include those disclosed in WO 99/26659.

Suitable meglitinides include nateglinide (Novartis) or KAD1229 (PF/Kissei).

Examples of glucagon-like peptide-1 (GLP-1) include GLP-1(1-36) amide, GLP-1(7-36) amide, GLP-1(7-37) (as disclosed in U.S. Pat. No. 5,614,492 to Habener), as well as AC2993 (Amylen), and LY-315902 (Lilly).

Other anti-diabetic agents that can be used in combination with compounds of the invention include ergoset and D-chiroinositol.

Suitable anti-ischemic agents include, but are not limited to, those described in the Physician's Desk Reference and NHE inhibitors, including those disclosed in WO 99/43663.

Examples of suitable anti-infective agents are antibiotic agents, including, but not limited to, those described in the Physicians' Desk Reference.

Examples of suitable lipid lowering agents for use in combination with the compounds of the present invention include one or more MTP inhibitors, HMG CoA reductase inhibitors, squalene synthetase inhibitors, fibric acid derivatives, ACAT inhibitors, lipoxygenase inhibitors, cholesterol absorption inhibitors, ileal Na⁺/bile acid cotransporter inhibitors, upregulators of LDL receptor activity, bile acid sequestrants, cholesterol ester transfer protein inhibitors (e.g., CP-529414 (Pfizer)), and/or nicotinic acid and derivatives thereof.

MTP inhibitors which may be employed as described above include those disclosed in U.S. Pat. No. 5,595,872, U.S. Pat. No. 5,739,135, U.S. Pat. No. 5,712,279, U.S. Pat. No. 5,760,246, U.S. Pat. No. 5,827,875, U.S. Pat. No. 5,885,983, and U.S. Pat. No. 5,962,440.

The HMG CoA reductase inhibitors which may be employed in combination with one or more compounds of formula I include mevastatin and related compounds, as disclosed in U.S. Pat. No. 3,983,140, lovastatin, (mevinolin) and related compounds, as disclosed in U.S. Pat. No. 4,231,938, pravastatin, and related compounds, such as disclosed in U.S. Pat. No. 4,346,227, simvastatin, and related compounds, as disclosed in U.S. Pat. Nos. 4,448,784 and 4,450,171. Other HMG CoA reductase inhibitors which may be employed herein include, but are not limited to, fluvastatin, disclosed in U.S. Pat. No. 5,354,772; cerivastatin, as disclosed in U.S. Pat. Nos. 5,006,530 and 5,177,080; atorvastatin, as disclosed in U.S. Pat. Nos. 4,681,893, 5,273,995, 5,385,929 and 5,686,104; atavastatin (Nissan/Sankyo's nisvastatin (NK-104)), as disclosed in U.S. Pat. No. 5,011,930; visastatin (Shionogi-Astra/Zeneca (ZD-4522)) as disclosed in U.S. Pat. No. 5,260,440; and related statin compounds disclosed in U.S. Pat. No. 5,753,675; pyrazole analogs of mevalonolactone derivatives, as disclosed in U.S. Pat. No. 4,613,610; indene analogs of mevalonolactone derivatives, as disclosed in PCT application WO 86/03488; 6-[2-(substituted-pyrrol-1-yl)alkyl)pyran-2-ones and derivatives thereof, as disclosed in U.S. Pat. No. 4,647,576; Searle's SC-45355 (a 3-substituted pentanedioic acid derivative) dichloroacetate; imidazole analogs of mevalonolactone, as disclosed in PCT application WO 86/07054; 3-carboxy-2-hydroxy-propane-phosphonic acid derivatives, as disclosed in French Patent No. 2,596,393; 2,3-disubstituted pyrrole, furan and thiophene derivatives, as disclosed in European Patent Application No. 0221025; naphthyl analogs of mevalonolactone, as disclosed in U.S. Pat. No. 4,686,237; octahydronaphthalenes, such as disclosed in U.S. Pat. No. 4,499,289; keto analogs of mevinolin (lovastatin), as disclosed in European Patent Application No.0142146 A2; and quinoline and pyridine derivatives, as disclosed in U.S. Pat. Nos. 5,506,219 and 5,691,322.

Preferred hypolipidemic agents are pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, atavastatin, and ZD-4522.

In addition, phosphinic acid compounds useful in inhibiting HMG CoA reductase, such as those disclosed in GB 2205837, are suitable for use in combination with the compounds of the present invention.

The squalene synthetase inhibitors suitable for use herein include, but are not limited to, α-phosphono-sulfonates disclosed in U.S. Pat. No. 5,712,396, those disclosed by Biller et al, J. Med. Chem., 1988, Vol. 31, No. 10, pp 1869-1871, including isoprenoid (phosphinyl-methyl)phosphonates, as well as other known squalene synthetase inhibitors, for example, as disclosed in U.S. Pat. Nos. 4,871,721 and 4,924,024 and in Biller, S. A., Neuenschwander, K., Ponpipom, M. M., and Poulter, C. D., Current Pharmaceutical Design, 2, 1-40 (1996).

In addition, other squalene synthetase inhibitors suitable for use herein include the terpenoid pyrophosphates disclosed by P. Ortiz de Montellano et al, J. Med. Chem., 1977, 20, 243-249, the famesyl diphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs as disclosed by Corey and Volante, J. Am. Chem. Soc., 1976, 98, 1291-1293, phosphinylphosphonates reported by McClard, R. W. et al, J.A.C.S., 1987, 109, 5544 and cyclopropanes reported by Capson, T. L., Ph.D. dissertation, June, 1987, Dept. Med. Chem. U of Utah, Abstract, Table of Contents, pp. 16, 17, 40-43, 48-51, Summary.

The fibric acid derivatives which may be employed in combination with one or more compounds of formula I include fenofibrate, gemfibrozil, clofibrate, bezafibrate, ciprofibrate, clinofibrate, and the like, probucol, and related compounds, as disclosed in U.S. Pat. No. 3,674,836, probucol and gemfibrozil being preferred, bile acid sequestrants, such as cholestyramine, colestipol and DEAE-Sephadex (Secholex®, Policexide®), as well as lipostabil (Rhone-Poulenc), Eisai E-5050 (an N-substituted ethanolamine derivative), imanixil (HOE-402), tetrahydrolipstatin (THL), istigmastanylphosphorylcholine (SPC, Roche), aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814 (azulene derivative), melinamide (Sumitomo), Sandoz 58-035, American Cyanamid CL-277,082 and CL-283,546 (disubstituted urea derivatives), nicotinic acid, acipimox, acifran, neomycin, p-aminosalicylic acid, aspirin, poly(diallylmethylamine) derivatives, such as disclosed in U.S. Pat. No. 4,759,923, quaternary amine poly(diallyldimethylammonium chloride) and ionenes, such as disclosed in U.S. Pat. No. 4,027,009, and other known serum cholesterol lowering agents.

The ACAT inhibitor which may be employed in combination with one or -more compounds of formula I include those disclosed in Drugs of the Future 24, 9-15 (1999), (Avasimibe); “The ACAT inhibitor, Cl-1011 is effective in the prevention and regression of aortic fatty streak area in hamsters”, Nicolosi et al, Atherosclerosis (Shannon, Irel). (1998), 137(1), 77-85; “The pharmacological profile of FCE 27677: a novel ACAT inhibitor with potent hypolipidemic activity mediated by selective suppression of the hepatic secretion of ApoB 100-containing lipoprotein”, Ghiselli, Giancarlo, Cardiovasc. Drug Rev. (1998), 16(1), 16-30; “RP 73163: a bioavailable alkylsulfinyl-diphenylimidazole ACAT inhibitor”, Smith, C., et al, Bioorg. Med. Chem. Lett. (1996), 6(1), 47-50; “ACAT inhibitors: physiologic mechanisms for hypolipidemic and anti-atherosclerotic activities in experimental animals”, Krause et al, Editor(s): Ruffolo, Robert R., Jr.; Hollinger, Mannfred A., Inflammation: Mediators Pathways (1995), 173-98, Publisher: CRC, Boca Raton, Fla.; “ACAT inhibitors: potential anti-atherosclerotic agents”, Sliskovic et al, Curr. Med. Chem. (1994), 1(3), 204-25; “Inhibitors of acyl-CoA:cholesterol O-acyl transferase (ACAT) as hypocholesterolemic agents. 6. The first water-soluble ACAT inhibitor with lipid-regulating activity. Inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). 7. Development of a series of substituted N-phenyl-N′-[(1-phenylcyclopentyl)methyl]ureas with enhanced hypocholesterolemic activity”, Stout et al, Chemtracts: Org. Chem. (1995), 8(6), 359-62, or TS-962 (Taisho Pharmaceutical Co. Ltd.).

The hypolipidemic agent may be an upregulator of LD2 receptor activity, such as MD-700 (Taisho Pharmaceutical Co. Ltd) and LY295427 (Eli Lilly).

Examples of suitable cholesterol absorption inhibitors for use in combination with the compounds of the invention include SCH48461 (Schering-Plough), as well as those disclosed in Atherosclerosis 115, 45-63 (1995) and J. Med. Chem. 41, 973 (1998).

Examples of suitable ileal Na⁺/bile acid cotransporter inhibitors for use in combination with the compounds of the invention include compounds as disclosed in Drugs of the Future, 24, 425-430 (1999).

The lipoxygenase inhibitors which may be employed in combination with one or more compounds of formula I include 15-lipoxygenase (15-LO) inhibitors, such as benzimidazole derivatives, as disclosed in WO 97/12615, 15-LO inhibitors, as disclosed in WO 97/12613, isothiazolones, as disclosed in WO 96/38144, and 15-LO inhibitors, as disclosed by Sendobry et al “Attenuation of diet-induced atherosclerosis in rabbits with a highly selective 15-lipoxygenase inhibitor lacking significant antioxidant properties”, Brit. J. Pharmacology (1997) 120, 1199-1206, and Cornicelli et al, “15-Lipoxygenase and its Inhibition: A Novel Therapeutic Target for Vascular Disease”, Current Pharmaceutical Design, 1999, 5, 11-20.

Examples of suitable anti-hypertensive agents for use in combination with the compounds of the present invention include beta adrenergic blockers, calcium channel blockers (L-type and T-type; e.g. diltiazem, verapamil, nifedipine, amlodipine and mybefradil), diuretics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone), renin inhibitors, ACE inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril), AT-1 receptor antagonists (e.g., losartan, irbesartan, valsartan), ET receptor antagonists (e.g., sitaxsentan, atrsentan, and compounds disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265), Dual ET/AII antagonist (e.g., compounds disclosed in WO 00/01389), neutral endopeptidase (NEP) inhibitors, vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., omapatrilat and gemopatrilat), and nitrates.

Examples of suitable anti-obesity agents for use in combination with the compounds of the present invention include a cannabinoid receptor 1 antagonist or inverse agonist, a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroid receptor beta drug, and/or an anorectic agent.

Cannabinoid receptor I antagonists and inverse agonists which may be optionally employed in combination with compounds of the present invention include rimonabant, SLV 319, and those discussed in D. L. Hertzog, Expert Opin. Ther. Patents 2004, 14, 1435-1452.

The beta 3 adrenergic agonists which may be optionally employed in combination with compounds of the present invention include AJ9677 (Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer,) or other known beta 3 agonists, as disclosed in U.S. Pat. Nos. 5,541,204, 5,770,615, 5,491,134, 5,776,983, and 5,488,064, with AJ9677, L750,355, and CP331648 being preferred.

Examples of lipase inhibitors which may be optionally employed in combination with compounds of the present invention include orlistat or ATL-962 (Alizyme), with orlistat being preferred.

The serotonin (and dopoamine) reuptake inhibitor which may be optionally employed in combination with a compound of formula I may be sibutramine, topiramate (Johnson & Johnson), or axokine (Regeneron), with sibutramine and topiramate being preferred.

Examples of thyroid receptor beta compounds which may be optionally employed in combination with compounds of the present invention include thyroid receptor ligands, such as those disclosed in WO97/21993 (U. Cal SF), WO99/00353 (KaroBio), and WO00/039077 (KaroBio), with compounds of the KaroBio applications being preferred.

The anorectic agent which may be optionally employed in combination with compounds of the present invention include dexamphetamine, phentermine, phenylpropanolamine, or mazindol, with dexamphetamine being preferred.

Other compounds that can be used in combination with the compounds of the present invention include CCK receptor agonists (e.g., SR-27895B); galanin receptor antagonists; MCR-4 antagonists (e.g., HP-228); leptin or mimentics; 11-beta-hydroxysteroid dehydrogenase type-1 inhibitors; urocortin mimetics, CRF antagonists, and CRF binding proteins (e.g., RU-486, urocortin).

Further, the compounds of the present invention may be used in combination with anti-cancer and cytotoxic agents, including but not limited to alkylating agents such as nitrogen mustards, alkyl sulfonates, nitrosoureas, ethylenimines, and triazenes; antimetabolites such as folate antagonists, purine analogues, and pyrimidine analogues; antibiotics such as anthracyclines, bleomyciris, mitomycin, dactinomycin, and plicamycin; enzymes such as L-asparaginase; farnesyl-protein transferase inhibitors; 5α reductase inhibitors; inhibitors of 17β-hydroxy steroid dehydrogenase type 3; hormonal agents such as glucocorticoids, estrogens/antiestrogens, androgens/antiandrogens, progestins, and luteinizing hormone-releasing hormone antagonists, octreotide acetate; microtubule-disruptor agents, such as ecteinascidins or their analogs and derivatives; microtubule-stabilizing agents such as taxanes, for example, paclitaxel (Taxol®), docetaxel (Taxotere®), and their analogs, and epothilones, such as epothilones A-F and their analogs; plant-derived products, such as vinca alkaloids, epipodophyllotoxins, taxanes; and topiosomerase inhibitors; prenyl-protein transferase inhibitors; and miscellaneous agents such as hydroxyurea, procarbazine, mitotane, hexamethylmelamine, platinum coordination complexes such as cisplatin and carboplatin; and other agents used as anti-cancer and cytotoxic agents such as biological response modifiers, growth factors; immune modulators; and monoclonal antibodies. Additional anti-cancer agents are disclosed in EP 1177791. The compounds of the invention may also be used in conjunction with radiation therapy.

Examples of suitable memory enhancing agents, anti-dementia agents, or cognitive agents for use in combination with the compounds of the present invention include, but are not limited to, donepezil, rivastigmine, galantamine, memantine, tacrine, metrifonate, muscarine, xanomelline, deprenyl and physostigmine.

The aforementioned patents and patent applications are incorporated herein by reference.

The above other therapeutic agents, when employed in combination with the compounds of the present invention may be used, for example, in those amounts indicated in the Physician's Desk Reference, as in the patents set out above, or as otherwise determined by one of ordinary skill in the art.

The compounds of formula I can be administered for any of the uses described herein by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; bucally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrastemal injection, or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to the nasal membranes, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories; in dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents.

In carrying out the method of the invention for treating diabetes and related diseases, a pharmaceutical composition will be employed containing the compounds of formula I, with or without other antidiabetic agent(s) and/or antihyperlipidemic agent(s) and/or other type therapeutic agents in association with a pharmaceutical vehicle or diluent. The pharmaceutical composition can be formulated employing conventional solid or liquid vehicles or diluents and pharmaceutical additives of a type appropriate to the mode of desired administration, such as pharmaceutically acceptable carriers, excipients, binders, and the like. The compounds can be administered to a mammalian patient, including humans, monkeys, dogs, etc. by an oral route, for example, in the form of tablets, capsules, beads, granules or powders. The dose for adults is preferably between 1 and 2,000 mg per day, which can be administered in a single dose or in the form of individual doses from 1-4 times per day.

A typical capsule for oral administration contains compounds of structure I (250 mg), lactose (75 mg), and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and packed into a No. 1 gelatin capsule.

A typical injectable preparation is produced by aseptically placing 250 mg of compounds of structure I into a vial, aseptically freeze-drying and sealing. For use, the contents of the vial are mixed with 2 mL of physiological saline, to produce an injectable preparation.

Assay(s) for 11-Beta-Hydroxysteroid Dehydrogenase Activity

The in vitro inhibition of recombinant human 11beta-HSD1 was determined as follows.

Recombinant human 11beta-HSD1 was expressed stably in HEK 293 EBNA cells. Cells were grown in DMEM (high glucose) containing MEM non-essential amino acids, L-glutamine, hygromycine B (200 ug/ml), and G418(200 ug/ml). The cell pellets were homogenized, and the microsomal fraction was obtained by differential centrifugation. 11beta-HSD1 over expressed microsomes were used as the enzyme source for the Scintillation Proximity Assay (SPA). The test compounds at the desired concentration were incubated at room temperature with 12.5 μg of microsomal enzyme, 250 nM [³H]-cortisone, 500 μM NADPH, 50 mM MES, pH 6.5, and 5 mM EDTA in 96-well OptiPlates. The reaction was terminated with the addition of 1 mM 18β-glycerrhentic acid. SPA reagent mixture (YSi anti-rabbit IgG, anti-cortisol antibody in 50 mM Tris, pH 8.0 containing 1% CHAPS and 1% glycerol) was added and the reaction was further incubated at room temperature over night and counted in TopCount. The IC₅₀(concentration of compound required for 50% inhibition of cortisol formation) was determined using XLfit.

As a means of confirming selectivity for 11betaHSD1, the compounds of the present invention were also screened for 11betaHSD2 activity. The in vitro inhibition of recombinant human 11betaHSD2 was determined as follows:

Recombinant human 11betaHSD2 was expressed stably in HEK 293 EBNA cells. The microsomal fraction over expressing 11betaHSD2 was prepared from the cell homogenate. The test compounds at the desired concentration were incubated at 37° C. with 10 μg of microsomal enzyme, 100 nM-cortisol, 1 mM NAD, and 20 mM Tris, pH 7.5 in 96-well plates for 3h. The reaction was stopped with the addition of equal volume of acetonitrile containing 200 ng/mL triamcinolone (internal standard). The plate was centrifuged and the supernatant was transferred to another 96-well assay plate. Cortisone in the samples was analyzed by LC/MS/MS (Micromass Quattro Ultima Triple Quadrupole Mass Spectrometer). From the MS response (ratio of compound to the internal standard), cortisone formation was calculated using the cortisone standard curve determined on each plate. The IC₅₀(concentration of compound required for 50% inhibition of cortisone formation) was determined using XLfit.

In general, preferred compounds of the present invention, such as particular compounds disclosed in the following examples, have been identified to inhibit the catalytic activity of 11-beta-hydroxysteroid dehydrogenase type I at concentrations equivalent to, or more potently than, 10 μM, preferably 5 μM, more preferably 3 μM, thereby demonstrating compounds of the present invention as especially effective inhibitors of 11-beta-hydroxysteroid dehydrogenase type I. Potencies can be calculated and expressed as either inhibition constants (Ki values) or as IC50 (inhibitory concentration 50%) values, and refer to activity measured employing the assay system described above.

EXAMPLES

The following working Examples serve to better illustrate, but not limit, some of the preferred embodiments of the present invention.

General

The term HPLC refers to a Shimadzu high performance liquid chromatography with one of following methods:

Method A: YMC or Phenomenex C18 5 micron 4.6×50 mm column using a 4 minute gradient of 0-100% solvent B [90% MeOH: 10% H₂O:0.2% H₃PO₄] and 100-0% solvent A [10% MeOH:90% H₂O:0.2% H₃PO₄] with 4 mL/min flow rate and a 1 min. hold, an ultra violet (uv) detector set at 220 nm.

Method B: Phenomenex S5 ODS 4.6×30 mm column, gradient elution 0-100% B/A over 2 min (solvent A =10% MeOH/H₂O containing 0.1% TFA, solvent B=90% MeOH/H₂O containing 0.1% TFA), flow rate 5 mL/min, UV detection at 220 nm.

Method C: YMC S7 ODS 3.0×50 mm column, gradient elution 0-100% B/A over 2 min (solvent A=10% MeOH/H₂O containing 0.1% TFA, solvent B=90% MeOH/H₂O containing 0.1% TFA), flow rate 5 mL/min, UV detection at 220 nm.

The term prep HPLC refers to an automated Shimadzu HPLC system using a mixture of solvent A (10% MeOH/90% H₂O/0.2%TFA) and solvent B (90% MeOH/10% H₂O/0.2% TFA). The preparative columns are packed with YMC or Phenomenex ODS C18 5 micron resin or equivalent.

ABBREVIATIONS

The following abbreviations are employed in the Examples and elsewhere herein:

Ph=phenyl
Bn=benzyl
i-Bu=iso-butyl
Me=methyl
Et=ethyl
Pr=propyl
Bu=butyl
AIBN=2,2′-Azobisisobutyronitrile
TMS=trimethylsilyl
FMOC=fluorenylmethoxycarbonyl
Boc or BOC=tert-butoxycarbonyl
Cbz=carbobenzyloxy or carbobenzoxy or benzyloxycarbonyl
HOAc or AcOH=acetic acid
DCM=dichloromethane
DIEA=N,N-diisopropylethylamine
DMA=N,N-dimethylacetylamide
DMF=N,N-dimethylformamide
DMSO=dimethylsulfoxide
EtOAc=ethyl acetate
THF=tetrahydrofuran
TFA=trifluoroacetic acid
mCPBA=3-Chloroperoxybenzoic acid
NMM=N-methyl morpholine
NBS=N-Bromosuccinimide
n-BuLi=n-butyllithium
Oxone®=Monopersulfate
Pd/C=palladium on carbon
PtO₂=platinum oxide
TEA=triethylamine
EDAC=3-ethyl-3′-(dimethylamino)propyl-carbodiimide hydrochloride (or 1-[(3-(dimethyl)amino)propyl])-3-ethylcarbodiimide hydrochloride)
HOBT or HOBT.H₂O=1-hydroxybenzotriazole hydrate
HOAT=1-hydroxy-7-azabenzotriazole
PyBOP reagent=benzotriazol-1-yloxy-tripyrrolidino phosphonium hexafluorophosphate
equiv=equivalent(s)
min=minute(s)
h or hr=hour(s)
L=liter
mL=milliliter
μL=microliter
g=gram(s)
mg=milligram(s)
mol=mole(s)
mmol=millimole(s)
meq=milliequivalent
RT or R.T.=room temperature
sat or sat'd=saturated
aq.=aqueous
TLC=thin layer chromatography
HPLC=high performance liquid chromatography
HPLC R_t=HPLC retention time
LC/MS=high performance liquid chromatography/mass spectrometry
MS or Mass Spec=mass spectrometry
NMR=nuclear magnetic resonance
mp=melting point
PXPd₂=Dichloro(chlorodi-tert-butylphosphine)palladium (II) dimer or [PdCl₂(t-Bu)₂PCl]₂

Example 1
(5-((2,6-Dichlorophenylthio)methyl)pyridin-3-yl)(4-methylpiperidin-1-yl)methanone

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To a solution of 5-bromonicotinic acid (4.7 g, 23.27 mmol) in THF (90 mL) was added 4-methylmorpholine (2.56 ml, 23.27 mmol) and isobutyl chloroformate (3.03 ml, 23.27 mmol) at 0° C. The mixture was stirred at 0° C for 1.5 hours and then 4-methyl piperidine (9.7 g, 97.73 mmol) was added at 0° C. The suspension was stirred at 0° C. to room temperature for 2 hours. The white precipitate was filtered off, and the liquid portion was concentrated under vacuum. The residue was purified by column chromatography to yield compound 1A (5.36 g) as a white powder. HPLC R_t(Method A): 2.75 min. LCMS: m/z 283 (M+H⁺).
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To a solution of compound 1A (2 g, 7.063 mmol) in DMF (14 mL) was added palladium acetate (791 mg, 3.53 mmol), 1,3-bis(diphenylphosphino)-propane (1.163 g, 2.83 mmol), DBU (1.29 g, 8.48 mmol), and methanol (14 mL) in a steel auto clave container. The mixture was stirred and heated at 85° C. for 14 hours under carbon monoxide (70 psi). After cooling the container, the methanol was concentrated via vacuum, and the residue was diluted with ethyl acetate. The powders were filtered off, and the mixture was washed with brine and water. Drying over MgSO₄, followed by concentration and column chromatography purification yielded compound 1B (1.6 g) as a yellow oil. HPLC R_t(Method A) 2.497 min. LCMS: m/z 263 (M+H⁺).
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Compound 1B (1.6 g, 6.1 mmol) in ethanol (20 mL) was treated with sodium borohydride (462 mg, 12.2 mmol) at room temperature and stirred for 1 hour. The solution was quenched with water and neutralized to pH=7. The mixture was stripped of most of the ethanol, basified with 1N NaOH solution, and extracted 3 times with ethyl acetate. The combined organic extracts were dried over MgSO₄, filtered, and concentrated via vacuum to yield compound 1C (310 mg) as a yellow oil. HPLC R_t(Method A): 1.218 min, LCMS: m/z 235 (M+H⁺).

Example 1

Compound 1C (200 mg, 0.853 mmol) in DCM (10 mL) was treated with 1N PBr₃(0.64 mL, 0.64 mmol) at 0° C. for 1.5 hours. The mixture was quenched with 5 mL saturated NaHCO₃solution at 0° C. The solution was diluted with DCM. The organic layer was separated, washed with brine, and dried over MgSO₄. The drying agent was filtered, and the filtrate was concentrated via vacuum to yield the bromide as a colorless oil. The bromide was dissolved in THF (10 mL) and treated with 2,6-dichlorothiophenol (153 mg, 0.853 mmol) and N,N-diisopropyl-ethylamine (331 mg, 2.56 mmol) at room temperature overnight. The mixture was concentrated and purified by column chromatography to yield Example 1 (76.7 mg) as a white powder. HPLC R_t(Method A: 3.618 min. LCMS: m/z 395 (M+H⁺). HPLC purity: 99%. ¹H NMR: δ 8.42 (s, 1H), 8.31 (s, 1H), 7.58 (s, 1H), 7.30 (d, J=8.2 Hz, 2H), 7.15 (t, J=8.2 Hz, 1H), 4.70-4.55 (m, 1H), 4.08 (s, 2H), 3.60-3.48 (m, 1H), 3.08-2.86 (m, 1H), 2.85-2.70 (m, 1H), 1.80-1.57 (m, 3H), 1.30-1.09 (m, 2H), 0.97 (d, J=6 Hz, 3H).

Example 2
(5-((2,6-Dichlorophenylsulfonyl)methyl)pyridin-3-yl)(4-methylpiperidin-1-yl)methanone

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To a solution of Example 1 (58 mg, 0.147 mmol) in THF (2 mL) and MeOH (2 mL) was added 1-(p-toluenesulfonyl)imidazole (261 mg, 1.18 mmol), 30% aqueous H₂O₂(240 μL, 2.352 mmol), and 1 N NaOH (2.7 mL, 2.7 mmol). The mixture was stirred at room temperature for 2.5 hours. The organic solvents were removed in vacuo, and the aqueous portion was diluted with brine and ethyl acetate. The organic portion was separated, and the aqueous layer was extracted again with ethyl acetate. The organic extracts were combined, dried over MgSO₄, and concentrated. The residue was subjected to preparative HPLC to yield Example 2 (41 mg) as a white powder. HPLC/R_t): 2.868 min. LCMS: m/z 427 (M+H₊). HPLC purity: 99%. ¹H NMR δ 8.57 (s, 1H), 8.33 (s, 1H), 7.82 (s, 1H), 7.40-7.32 (m, 3H), 4.64 (s, 2H), 4.57-4.54 (m, 1H), 3.62-3.48 (m, 1H), 3.05-2.97 (m, 1H), 2.82-270 (m, 1H), 1.80-1.70 (m, 1H), 1.70-1.52 (m, 2H), 1.27-0.99 (m, 2H), 0.97 (d, J=6 Hz, 3H).

Example 3
2-((2,6-Dichlorophenylthio)methyl)-5-(4-methylpiperidin-1-ylsulfonyl)-pyridine

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To a solution of 6-chloropyridine-3-sulfonyl chloride (600 mg, 2.83 mmol) in DCM (10 mL) was added DIEA (1.5 mL, 8.49 mmol) and 4-methylpiperidine (281 mg, 2.83 mmol) at RT. The mixture stirred for 2 hours. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to yield compound 3A (746 mg) as a white powder. HPLC R_t(Method A): 2.982 min. LCMS: m/z 275 (M+H⁺).
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Compound 3B was prepared in a similar manner as compound 1B. Carbonylation of compound 3A (550 mg) gave compound 3B (580 mg) as a white powder. HPLC R_t(Method A): 2.682 min. LCMS: m/z 299 (M+H⁺).
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To a solution of compound 3B (400 mg, 1.34 mmol) in THF (8 mL) was added 1N LiAlH₄(0.67 mL, 0.67 mmol) solution in THF at RT. The mixture stirred for 2 hours, was quenched with H₂O, and was extracted 3 times with ethyl acetate. The combined organic extracts were dried over MgSO₄, filtered, and concentrated. The residue was purified by silical gel chromatography to yield compound 3C (120 mg) as a light pink powder. HPLC R_t(Method A): 2.315 min. LCMS: m/z 271 (M+H⁺).

Example 3

To a solution of compound 3C (80 mg, 0.296 mmol) in THF (2 mL) at RT was added 2,6-dichlorobenzenethiol (212 mg, 1.184 mmol), and PPh₃(233 mg, 0.888 mmol). After the solution became homogeneous, diisopropyl azodicarboxylate (180 mg, 0.888 mmol) was added via syringe. After 5 minutes of stirring at RT, the mixture became cloudy. DCM (1.5 mL) was added and stirring was continued for another 2 hours. The precipitate was filtered off, and the solvents were removed at reduced pressure. The residue was purified by silical gel chromatography, followed by prep HPLC to give Example 3. HPLC R_t(Method A): 3.788 min. LCMS: m/z 431 (M+H⁺). HPLC purity: 97%. ¹H NMR: δ 8.80 (s, 1H), 7.93-7.88 (m, 1H), 7.36-7.20 (m, 4H), 4.28 (s, 2H), 3.80-3.73 (m, 2H), 2.36-2.22 (m, 2H), 1.81-1.63 (m, 2H), 1.45-1.26 (m, 3H), 0.97 (d, J=5.1 Hz, 3H).

Example 4
2-((2,6-Dichlorophenylsulfonyl)methyl)-5-(4-methylpiperidin-1-ylsulfonyl)pyridine

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Example 4 was prepared in a similar manner as Example 2, and obtained as a white powder. HPLC R_t(Method A): 3.127 min. LCMS: m/z 463 (M+H⁺). HPLC purity: 95%. ¹H NMR: δ 8.61 (s, 1H), 7.96-7.93 (m, 1H), 7.63-7.61 (m, 1H), 7.34-7.31 (m, 3H), 4.83 (s, 2H), 3.64 (d, J=11.6 Hz, 2H), 2.22-2.10 (m, 2H), 1.69-1.52 (m, 2H), 1.31-1.12 (m, 3H), 0.85 (d, J=5.7 Hz, 3H)

Example 5
2-((2,6-Dichlorophenoxy)methyl)-5-(4-methylpiperidin-1-ylsulfonyl)-pyridine

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To a solution of compound 3C (10 mg, 0.037 mmol) in THF (1 mL) was added 2,6-dichlorophenol (18.1 mg, 0.111 mmol) and PPh₃(29 mg, 0.111 mmol). After 1 minute of stirring, diisopropyl azodicarboxylate (22.4 mg, 0.111 mmol) was added. The mixture was stirred at room temperature for 1.5 hours. The solvent was removed at reduced pressure, and the mixture was purified by preparative HPLC (solvent: CH₃OH—H₂O-TFA) to yield Example 5 (17 mg) as a white powder. HPLC R_t(Method A): 3.923 min. LCMS: m/z 415 (M+H⁺). HPLC purity: 98%. ¹H NMR: δ 8.95 (d, J=1.7 Hz, 1H), 8.18-8.16 (m, 1H), 8.07-8.05 (m, 1H), 7.39-7.37 (m, 2H), 7.12-7.08 (m, 1H), 5.29 (s, 2H), 3.84 (d, J=11.7 Hz, 2H), 2.40-2.34 (m, 2H), 1.75-1.72 (m, 2H), 1.37-1.32 (m, 3H), 0.96 (d, J=5.7 Hz, 3H).

Example 6
5-((2,6-Dichlorophenylthio)methyl)-2-(4-methylpiperidin-1-ylsulfonyl)-pyridine

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To a solution of 2,5-dibromopyridine (5 g, 21.10 mmol) in toluene (300 mL) at −78° C. was added 2.5 N (in hexane) n-BuLi solution (10.1 mL, 25.33 mmol). After the addition, the solution was stirred at −78° C. for 2.5 hours. The reaction mixture was added slowly, via a steel cannula, to a saturated SO₂solution in THF (200 mL) at −78° C. After the addition, the solution was stirred at −78° C.° for 20 minutes, then was warmed to RT over 1 hour. The solution was concentrated under reduced pressure to about 100 mL, and was then treated with sulfuryl chloride (2.85 g, 21.10 mmol) at 0° C. to RT for 20 minutes. The solution was concentrated under reduced pressure to yield 5-bromopyridine-2-sulfonyl chloride. A portion (3/5) of the crude intermediate was dissolved in DCM (100 mL) and was treated with 4-methylpiperidine (10 g, 101.3 mmol) at room temperature for 20 minutes. The solution was concentrated and purified by column chromatography to yield compound 6A (1.86 g) as a white powder. HPLC R_t(Method A): 3.108 min. LCMS: m/z 319 (M+H⁺).
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Compound 6B was prepared in a similar manner as compound 1B. Carbonylation of compound 6A (1.10 g) gave compound 6B (960 mg) as a white power. LC/MS m/z 299 (M+H⁺).
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To a solution of compound 6B (801 mg, 2.69 mmol) in EtOH (12 mL) and THF (20 mL) was added NaBH₄(203 mg, 5.38 mmol). The mixture stirred at RT overnight. The reaction was quenched with water and was neutralized to pH=7 using 1N HCl. The mixture was stripped of the organic solvents, was made slightly basic using 1N NaOH, and was extracted several times with ethyl acetate. The organic extracts were combined, dried over MgSO₄, concentrated, and purified by column chromatography to yield compound 6C (507 mg) as a white powder. HPLC R_t(Method A): 2.297 min. LCMS: m/z 271 (M+H⁺).

Example 6

To a solution of compound 6C (250 mg, 0.925 mmol) in DCM (10 mL) was added thionyl chloride (0.547 mL, 7.40 mmol). The solution was stirred at room temperature for 3.5 hours and was then concentrated to yield a white powder. The powder was dissolved in DCM (10 mL) and was treated with 2,6-dichlorobenzenethiol (166 mg, 0.925 mmol) and N,N-diisopropylethylamine (0.644 mL, 3.7 mmol) at RT for 40 minutes. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to yield Example 6 (385 mg) as a white powder. HPLC R_t(Method A): 3.785 min. LCMS: m/z 431 (M+H⁺). HPLC purity: 96%. ¹H NMR: δ 8.43 (s, 1H), 7.77-7.75 (m, 1H), 7.64-7.62 (m, 1H), 7.35-7.33 (m, 2H), 7.22-7.18 (m, 1H), 4.15 (s, 2H), 3.84 (d, J=12.1 Hz, 2H), 2.61-2.55 (m, 2H), 1.70-1.67 (m, 2H), 1.50-1.26 (m, 3H), 0.96 (d, J=6.3 Hz, 3H).

Example 7
5-((2,6-Dichlorophenylsulfonyl)methyl)-2-(4-methylpiperidin-1-ylsulfonyl)pyridine

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Example 7 was prepared in a similar manner as Example 2. Oxidation of Example 6 (188 mg) gave Example 7 (205 mg) as a white powder. HPLC R_t(Method A): 3.030 min. LCMS: m/z 463 (M+H⁺). HPLC purity: 97%. ¹H NMR: δ 8.42 (s, 1H), 7.91-7.72 (m, 2H), 7.48-7.32 (m, 3H), 4.68 (s, 2H), 3.76 (d, J=11.3 Hz, 2H), 2.52 (t, J=11.7 Hz, 2H), 1.70-1.49 (m, 2H), 1.40-1.09 (m, 3H), 0.86 (d, J=6.2 Hz, 3H)

Example 8
5-((2,6-Dichlorophenoxy)methyl)-2-(4-methylpiperidin-1-ylsulfonyl)-pyridine

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Example 8 was prepared in a similar manner as Example 5. Reaction of compound 6C (32 mg) and other appropriate reagents gave Example 8 (54.9 mg) as a white powder. HPLC R_t(Method A): 3.842 min. LCMS: m/z 415 (M+H⁺). HPLC purity: 97%. ¹H NMR: δ 8.88 (d, J=1.6 Hz,1H), 8.16-8.13 (m, 1H), 8.01-7.99 (m, 1H), 7.38-7.36 (m, 2H), 7.09 (t, J=8.1 Hz, 1H), 5.17 (s, 2H), 3.94 (d, J=12.2 Hz, 2H), 2.75-2.68 (m, 2H), 1.73-1.69 (m, 2H), 1.50-1.23 (m, 3H), 0.96 (d, J=6.3 Hz, 3H).

Example 9
(6-(2—Chlorophenoxy)pyridin-2-yl)(4-methylpiperidin-1-yl)methanone

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To a solution of 6-chloropyridine-2-carboxylic acid (1.0 g, 6.3 mmol) and 4-methylpiperidine (1.1 mL, 9.5 mmol) in DCM (20 mL) was added EDAC (1.8 g, 9.5 mmol), HOAT (0.5M in DMF, 1.9 mL, 0.95 mmol), and 4-DMAP (116 mg, 0.95 mmol). The solution was stirred at RT for 18 hr, and then was concentrated in vacuo. The residue was partitioned between EtOAc and Brine. The organic phase was dried (MgSO₄) and concentrated in vacuo. The crude product was purified via column chromatography (30% EtOAc/70% Hexane, flow rate: 30 mL/min, detection wavelength: 254 nm) to provide compound 9A (1.3 g, 88% yield) as a white solid. HPLC R_t(Method A): 2.91 min. LCMS: m/z 239 (M+H⁺). HPLC purity: 95%.

Example 9

To a solution of compound 9A (100 mg, 0.42 mmol) in DMF (4 mL) was added 2-chlorophenol (81 mg, 0.63 mmol) and cesium carbonate (409 mg, 1.26 mmol). The reaction mixture was placed on the microwave reactor at 200° C. for 40 min and was then partitioned between EtOAc and a 10% LiCl solution. The organic phase was dried (MgSO₄) and concentrated in vacuo. The residue was purified via preparative HPLC (Phenomenex LUNA 5u C 18 21.1×100 mm column; detection at 220 nm; flow rate=25 mL/min; continuous gradient from 80% A to 100% B over 8 min, where A=90:10:0.1 H₂O:MeOH:TFA and B=90:10:0.1 MeOH:H₂O:TFA) to provide Example 9 (44.7 mg, 32% yield) as an oil ¹H NMR (400 MHz, CD₃OD): δ 0.68-0.78 (m, 1H), 0.84 (d, J=6.6 Hz, 3H), 0.95-1.05 (m,1H), 1.34 (d, J=13.2 Hz, 1H), 1.50-1.60 (m, 1H), 1.65 (d, J=13.2 Hz, 1H), 2.65-2.75 (m, 1H), 2.78-2.88 (m,1H), 3.74 (d, J=13.2 Hz, 1H), 4.45 (d, J=13.2 Hz, 1H), 7.13-7.51 (m, 6H), 7.93 (d, J=8.4 Hz, 1H).

Examples 10 to 12

Examples 10 to 12 in Table 1 were synthesized according to the procedures described in Example 9 utilizing the appropriate starting materials.

TABLE 1ExampleStructureMass [M + H]HPLC Purity (%)10 embedded image

3479911

3819512

33097

Example 13
(6-((2,6-Dichlorophenylthio)methyl)pyridin-2-yl)(4-(trifluoromethyl)piperidin-1-yl)methanone

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A solution of diethyl 2,6-pyridine dicarboxylate (25 g, 112 mmol) in ethanol (250 mL) was treated with sodium borohydride (2.33 g, 0.55 equiv) and was refluxed for 2 h. After being cooled to RT, the solution was concentrated to a volume of 50 mL and water (50 mL) was added. The solution was further concentrated to a final volume of about 50 mL and extracted with several 50 mL portions of DCM. The combined DCM extracts were dried with sodium sulfate and concentrated by rotary evaporation to yield compound 13A (18.3 g of). HPLC purity 95%. LC/MS m/z 182 (M+H⁺).
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To a solution of compound 13A (2.86 g, 15.74 mmol) in DCM (100 mL) was added phosphorus tribromide (3.20 g, 11.80 mmol) at 0° C. The solution was stirred for 2 h at 0° C. under nitrogen, then quenched with 100 mL of saturated NaHCO₃solution. The DCM layer was separated, and the aqueous layer was extracted with DCM (3×100 mL). The combined extracts were washed with brine, dried over MgSO₄, and evaporated to yield compound 13B (2.65 g). HPLC purity 93%. LC/MS: m/z 244 (M+H).
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To a solution of compound 13B in THF (10 mL/mmol) was added thiophenol (1 equiv.), DIEA (2 equiv.), and CsCO₃(1 equiv). The sealed reaction mixture was heated for 2-10 h at 60° C. to push the reaction to completion. The reaction was cooled to RT and diluted with hexane. The solid CsCO₃was removed by filtration, and the THF solvent was removed by rotary evaporation to yield compound 13C. LC/MS: m/z 342 (M+H).
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Compound 13C was dissolved in a 1:1 mixture of THF and 1N NaOH solution. The mixture stirred for 2 h at RT. The THF was removed by evaporation, and the mixture was adjusted to pH 3 by the addition of HCl. A white solid precipitated out. The precipitate was filtered and dried to give compound 13D. LC/MS m/z 313 (M+H).

Example 13

To a solution of compound 13D (0.1 mmol) in DMF (2 mL) was added 4-(trifluoromethyl)piperidine (0.12 mmol), PyAOP (0.1 mmol), and DIEA (0.15 mmol). The reaction was stirred vigorously for 10 h. After the DMF solvent was removed by Speed Vac, the residue was purified by Prep-HPLC to give Example 13. LC/MS m/z 449 (M+H). ¹H NMR (500 MHz, CDCl₃): δ 1.57 (m, 2H), 1.80 (dd, 2H), 2.23 (m, 1H), 2.78 (t, 2H), 4.14 (s, 2H), 4.35 (dd, 2H), 7.09 (m, 2H), 7.25 (d, 2H), 7.43 (d, 1H), 7.58 (t, 1H).

Example 14
N-Cyclopentyl-5-((2,6-dichlorophenylthio)methyl)nicotinamide

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To a solution of methyl 5-methylnicotinate (5 g, 33 mmol) in carbon tetrachloride (200 mL) was added NBS (5.9 g, 1 equiv) and dibenzoyl peroxide (1.2 g, 0.15 equiv). The reaction was refluxed for 3 h, then was cooled to RT to give compound 14A. The carbon tetrachloride solution containing compound 14A was used without further purification.

Example 14

Example 14 was prepared in three steps in a similar manner as compounds 13C to Example 13: Alkylation of compound 14A with 2,6-dichlorothiophenol, basic hydrolysis of the methyl ester, followed by amide formation provided Example 14. LC/MS m/z 381 (M+H⁺) ¹H NMR (500 MHz, CDCl₃): δ 1.47 (m, 2H), 1.72 (m, 6H), 2.08 (m, 2H), 4.11 (s, 2H), 4.36 (q, 1H), 5.93 (bs, 1H), 7.14 (t, 1H), 7.31 (d, 2H), 7.84 (s, 1H), 8.41 (s, 1H), 8.75 (s, 1H).

Example 15
(4-Methylpiperidin-1-yl)(5-(m-tolylthiomethyl)pyridin-3-yl)methanone

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To a stirred solution of pyridine-3,5-dicarboxylic acid (25 g) in EtOH (200 mL) was added concentrated H₂SO₄(5 mL). The reaction was stirred until all pyridine-3,5-dicarboxylic acid was gone. The reaction formed a 1:1 mixture of compound 15A and diethyl pyridine-3,5-dicarboxylate. EtOH was removed via vacuum, and the residue was dissolved in saturated NaHCO₃solution (100 mL). Diethyl pyridine-3,5-dicarboxylate was extracted out by EtOAc (3×). The aqueous layer was adjusted to pH 3, and the product was precipitated out as a white solid. The solid was filtered and dried to give compound 15A (ca 50%). LC/MS m/z 196 (M+H⁺).
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To a stirred solution of compound 15A (4.31 g) in anhydrous THF (150 mL) was added NMM (4.84 mL, 2 equiv) and isobutyl chloroformate (3.17 mL, 1.1 equiv) at 0° C. The reaction was stirred for 1 h at 0° C., followed by addition of 4-methylpiperidine (5.2 mL, 2 equiv). The stirring was continued to for another 10 h. The white precipitated solid was filtered off, and the solvent was removed by evaporation. The crude product was purified by silica gel column chromatography (ISCO) to give compound 15B (3.56 g). LC/MS m/z 276 (M+H⁺).
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Compound 15C was prepared in a similar manner as compound 1C. Sodium borohydride reduction of compound 15B (3.56 g) gave compound 15C (2.5 g). LC/MS m/z 235 (M+H⁺). ¹H NMR (CDCl₃): δ 0.96 (d, 3H), 1.15 (m, 2H), 1.70 (m, 3H), 2.76 (t, 1H), 3.01 (t, 1H), 3.60 (d, 1H), 4.60 (d, 1H), 4.66 (s, 2H), 7.67 (s, 1H), 8.45 (s, 1H), 8.49 (s, 1H). ¹³C NMR (CDCl₃): δ 21.55, 30.95, 33.62, 34.63, 42.66, 48.18, 61.77, 131.86, 133.27, 137.09, 146.01, 148.90, 167.65.
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To a stirred solution of compound 15C (2.5 g, 10.6 mmol) in DCM (100 mL) was added SOC1₂(3.9 mL, 5 equiv). The mixture stirred for 1 h at RT. DCM solvent was removed by evaporation, and a white solid was obtained as compound 15D (3.2g). LC/MS m/z 253 (M+H⁺).

Example 15

Example 15 was prepared in a similar manner as Example 1: alkylation of compound 15D with 3-methylthiophenoyl provided Example 15. HPLC purity 99%. LC/MS: m/z 341 (M+H⁺). ¹H NMR (400 MHz, DMSO/CDCl₃): δ 0.95 (d, 3H), 1.42-1.80(m, 3H), 2.66-2.83 (m, 1H), 2.86-3.06 (m, 1H), 3.25-3.60 (m, 2H), 3.73 (s, 3H), 4.29 (s, 2H), 4.36-4.55 (m, 1H), 6.75 (d, 1H), 6.83-6.92 (m, 2H), 7.18 (t, 1H), 7.69 (s, 1H), 8.41 (s, 1H), 8.57 (s, 1H).

Example 16
(2,5-Dimethylpyrrolidin-1-yl)(6-((naphthalen-1-ylsulfonyl)methyl)pyridin-2-yl)methanone

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Compound 16A was prepared in a similar manner as compound 13C using appropriate starting materials. LC/MS: m/z 324 (M+H⁺).
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To a solution of compound 16A (1 mmol) in DCM (10 mL) was added mCPBA (4 equiv.). The mixture was stirred at RT overnight. The reaction mixture was then cooled to 0° C., followed by addition of PBr₃(4 equiv.). The stirring was continued for 6 h at 0° C., and the reaction was then quenched with saturated NaHCO₃solution. The DCM layer was separated, and the aqueous layer was extracted with DCM (3×100 mL). The combined DCM extracts were washed with brine, dried over MgSO₄, and evaporated to give compound 16B. LC/MS: m/z 356 (M+H⁺).

Example 16

Example 16 was prepared in two steps in a similar manner as compounds 13D to Example 13: basic hydrolysis of compound 16B, followed by amide formation provided Example 16. LC/MS: m/z 409 (M+H⁺). ¹H NMR (400 MHz, DMSO/CDCl₃): δ 0.80 (d, 3H), 1.12 (d, 3H), 0.95-4.08 (m, 6H), 5.0 (m, 2H), 7.10-7.95 (m, 7H), 8.20 (d, 1H), 8.32 (t, 1H), 8.68 (d, 1H).

Example 17
(4-Methylpiperidin-1-yl)(5-(o-tolyloxymethyl)pyridin-3-yl)methanone

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To a solution of compound 14A (ca. 1 mmol) in CCl₄(6 mL) was added 2-methylphenol (1 equiv.) and DIEA (2 equiv). The reaction was refluxed for 1 h and then cooled to RT. The crude product was purified by silica gel column chromatography (ISCO) to give compound 17A. LC/MS: m/z 258 (M+H⁺).

Example 17

Example 17 was prepared in two steps in a similar manner as compounds 13C to Example 13: basic hydrolysis of compound 17A, followed by amide formation provided Example 17. LC/MS: m/z 325 (M+H⁺). ¹H NMR (400 MHz, DMSO/CDCl₃): δ 1.00 (d, 3H), 2.25 (s, 3H), 1.18-4.50 (m, 9H), 5.26 (s, 2H), 6.90 (t, 1H), 7.04 (d, 1H), 7.20 (m, 2H), 7.90 (s, 1H), 8.59 (s, 1H), 8.78 (s, 1H).

Example 18
(6-(2—Chlorophenyl)pyridin-2-yl)(4-methylpiperidin-1-yl)methanone

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A solution of 6-bromopicolinic acid (250 mg, 1.24 mmol) in thionyl chloride (1.7 mL) was refluxed for 1.0 h, cooled, concentrated, and dried in vacuo for 1.0 h. The crude product was dissolved in dry DCM (15 mL), was treated with 4-methylpiperidine (96%, 0.3 mL, 2.29 mmol), and was stirred at room temperature for 20 h. The reaction mixture was concentrated and dried in vacuo. The solids obtained were chromatographed (ISCO, 40 g. column; CH₃OH:CH₂Cl₂gradient—0% to 10%) to yield compound 18A (332.9 mg, 94.8%) as a white solid (m.p. 90-92° C.). HPLC: 96.6% at 1.97 and 2.07 min (retention times for rotamer mixture) (Conditions: YMC S-5 C-18 (4.6×50 mm), eluting with 0-100% B, 4 min gradient. (A=90% H₂O—10% CH₃CN—0.1% TFA and B=10% H₂O—90% CH₃CN—0.1% TFA); Flow rate at 4 mL/min. UV detection at 220 nm. MS (ES+): m/z 283 [M+H]⁺.

Example 18

A solution of compound 18A (100 mg, 0.35 mmol) in dry toluene (0.8 mL) was treated with tetrakis(triphenylphosphine)palladium(0) (14.3 mg, 0.012 mmol). The mixture stirred at room temperature for 15 min and was then treated with 2-chlorophenyl-boronic acid (70.4 mg, 0.45 mmol), 2.0 M Na₂CO₃(0.4 mL) and absolute ethanol (0.4 mL). The reaction mixture was stirred at 80° C. (oil bath) for 25 h, was cooled, and then was partitioned between H₂O (1.5 mL) and EtOAc (3×15 mL). The combined organic extracts were washed with brine (1.5 mL), dried over MgSO₄, filtered, and concentrated under pressure. The crude product was chromatographed (ISCO, 40 g silica gel column; EtOAc:Hexane—0% to 50% gradient), followed by purification via preparative HPLC (YMC S5 ODS 20×100 mm; CH₃CN/H₂O+0.1% TFA—0% to 100%) to yield Example 18 as a white solid (73.6 mg, 49%). HPLC: 98% purity at 2.10 min (retention time) (Conditions: YMC S-5 C-18 (4.6×50 mm), eluting with 0-100% B, 4 min gradient. (A=90% H₂O—10% CH₃CN—0.1% TFA and B=10% H₂O—90% CH₃CN—0.1% TFA); Flow rate at 4 mL/min. UV detection at 220 nm. MS (ES+): m/z 315 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ 0.98 (d, J=6.6 Hz, 3H), 1.20-1.27 (m, 2H), 1.62-1.80 (m, 3H), 2.84-2.88 (m, 1H), 3.09-3.13 (m, 1H), 3.81 (d, J=13.2 Hz, 1H), 4.62 (d, J=13.2 Hz, 1H), 7.40-7.45 (m, 2H), 7.52-7.57 (m, 3H), 7.71 (d, J=8.8 Hz, 1H), 8.02 (t, J=7.7 Hz, 1H).

Example 19
(6-(2-Chlorophenyl)pyridin-2-yl)(3,4-dihydroquinolin-1(2H)-yl)methanone

embedded image

To a solution of 6-bromopicolinic acid (2.5 g) in MeOH (100 mL) was added concentrated H₂SO₄(5 mL). The reaction was refluxed until the 6-bromopicolinic acid was gone. The mixture was dried by evaporation and then purified by silica gel column chromatography (ISCO) to give compound 19A (ca 90% yield). LC/MS: m/z 216/218 (M+H⁺).
embedded image

To a solution of compound 19A (300 mg) in DMA (10 mL) was added K₃PO₄(3 equiv). Nitrogen was bubbled through the solution, and then catalyst Pd(PPh₃)₄(0.1 equiv) was added. The mixture was placed in a sealed microwave tube, which was put on the Microwave for 30 min. at 120° C. The extra solid residues were filtered off and DMA solvent was removed by Speed-Vac. The crude product was purified by silica gel column chromatography to give compound 19B (ca 60%). LC/MS: m/z 248 (M+H⁺).

Example 19

Example 19 was prepared in two steps in a similar manner as compounds 13D to Example 13: basic hydrolysis of compound 19B, followed by amide formation provided Example 19. LC/MS: m/z 349 (M+H⁺). ¹H NMR (400 MHz, DMSO/CDCl₃): δ 2.05 (t, 2H), 2.86 (m, 2H), 3.86 (t, 2H), 7.00 (m, 1H), 7.05 (m, 2H), 7.24 (t, 2H), 7.37 (t, 1H), 7.42 (t, 1H), 7.52 (d, 1H), 7.64 (d, 1H), 7.73 (d, 1H), 8.03 (t, 1H).

Examples 20 to 305

Examples 20 to 305 in Table 2 were prepared according to the procedures described in the proceeding examples, or by other similar methods used by one skilled in the art, utilizing other appropriate reagents.

TABLE 2MassExampleStructure[M + H]HPLC Purity (%)20 embedded image

409.3710021 embedded image

353.3210022 embedded image

367.3510023 embedded image

396.3510024 embedded image

381.3510025 embedded image

409.3710026 embedded image

409.379927 embedded image

480.410028 embedded image

424.3710029 embedded image

409.3710030 embedded image

397.3510031 embedded image

457.3410032 embedded image

395.410033 embedded image

449.3210034 embedded image

435.4210035 embedded image

429.349436 embedded image

395.410037 embedded image

487.379738 embedded image

341.3610039 embedded image

398.3810040 embedded image

395.49741

367.3510042 embedded image

397.358243 embedded image

423.429844 embedded image

423.4110045 embedded image

424.3710046 embedded image

485.2510047 embedded image

435.3610048 embedded image

439.369449 embedded image

438.398150 embedded image

445.3810051 embedded image

341.228852 embedded image

369.239553 embedded image

369.248954 embedded image

355.198555 embedded image

369.238456 embedded image

369.238757 embedded image

417.219258 embedded image

355.219759 embedded image

355.228860 embedded image

383.2310061 embedded image

409.2510062 embedded image

355.218663 embedded image

429.0410064 embedded image

415.048865 embedded image

443.069866 embedded image

443.0610067 embedded image

443.0710068 embedded image

431.0510069 embedded image

429.0510070 embedded image

457.079671 embedded image

429.0510072 embedded image

429.0510073 embedded image

411.1610074 embedded image

425.1610075 embedded image

425.1810076 embedded image

425.1510077 embedded image

425.1710078 embedded image

473.168879 embedded image

411.1510080 embedded image

439.1910081 embedded image

465.1910082 embedded image

395.18583

381.099384 embedded image

409.18285

409.118586 embedded image

395.129087 embedded image

409.18788

409.19889

395.098690 embedded image

449.129091 embedded image

395.18392

375.1510093 embedded image

389.159994 embedded image

347.149595 embedded image

376.129896 embedded image

363.139697 embedded image

361.159698 embedded image

389.188599 embedded image

389.1799100 embedded image

460.19100101 embedded image

404.1597102 embedded image

375.1591103 embedded image

389.1799104 embedded image

389.1593105 embedded image

377.1491106 embedded image

437.1794107 embedded image

375.1799108 embedded image

375.1695109 embedded image

403.1781110 embedded image

375.15100111 embedded image

395.185112 embedded image

409.1100113 embedded image

367.0797114 embedded image

381.0795115 embedded image

409.09100116 embedded image

409.1100117 embedded image

424.0795118 embedded image

395.07100119 embedded image

409.0899120 embedded image

409.1100121 embedded image

397.0785122 embedded image

395.1100123 embedded image

395.01100124 embedded image

395.09100125 embedded image

369.0881126 embedded image

423.11100127 embedded image

449.1396128 embedded image

395.09100129 embedded image

405.2100130 embedded image

361.28100131 embedded image

395.23100132 embedded image

357.3294133 embedded image

369.3598134 embedded image

341.35100135 embedded image

361.3100136 embedded image

395.2497137 embedded image

357.34100138 embedded image

341.35100139 embedded image

405.298140 embedded image

345.33100141 embedded image

361.2898142 embedded image

384.3398143 embedded image

357.35100144 embedded image

341.35100145 embedded image

372.31100146 embedded image

405.2100147 embedded image

355.3897148 embedded image

355.38100149 embedded image

355.38100150 embedded image

355.3896151 embedded image

429.17100152 embedded image

383.4196153 embedded image

377.3592154 embedded image

355.3884155 embedded image

345.35100156 embedded image

355.38100157 embedded image

395.3295158 embedded image

345.35100159 embedded image

395.2594160 embedded image

395.25100161 embedded image

375.32100162 embedded image

395.2588163 embedded image

369.498164 embedded image

395.3292165 embedded image

378.33100166 embedded image

379.29100167 embedded image

379.29100168 embedded image

385.32100169 embedded image

395.32100170 embedded image

373.33100171 embedded image

397.4292172 embedded image

463.0997173 embedded image

489.14100174 embedded image

363.33100175 embedded image

369.494176 embedded image

411.3100177 embedded image

385.35100178 embedded image

464.196179 embedded image

395.297180 embedded image

409.2197181 embedded image

409.293182 embedded image

409.19100183 embedded image

395.292184 embedded image

409.2189185 embedded image

409.2190186 embedded image

457.2189187 embedded image

395.1893188 embedded image

395.1994189 embedded image

423.2298190 embedded image

449.2297191 embedded image

355.2398192 embedded image

369.2599193 embedded image

369.2593194 embedded image

369.2492195 embedded image

440.2896196 embedded image

355.2495197 embedded image

369.2592198 embedded image

369.24100199 embedded image

357.2294200 embedded image

417.2594201 embedded image

355.2494202 embedded image

355.2592203 embedded image

329.25100204 embedded image

383.27100205 embedded image

409.28100206 embedded image

355.22100207 embedded image

377.2294208 embedded image

391.2196209 embedded image

363.291210 embedded image

391.2490211 embedded image

391.2292212 embedded image

406.293213 embedded image

377.1987214 embedded image

391.2494215 embedded image

391.2492216 embedded image

379.1998217 embedded image

377.2290218 embedded image

377.2189219 embedded image

405.2494220 embedded image

431.2693221 embedded image

377.287222 embedded image

381.1100223 embedded image

395.11100224 embedded image

409.13100225 embedded image

409.13100226 embedded image

409.13100227 embedded image

409.14100228 embedded image

437.17100229 embedded image

409.14100230 embedded image

423.15100231 embedded image

409.11100232 embedded image

468.1290233 embedded image

379.0895234 embedded image

381.11100235 embedded image

395.12100236 embedded image

409.12100237 embedded image

409.11100238 embedded image

480.13100239 embedded image

424.09100240 embedded image

395.11100241 embedded image

409.12100242 embedded image

409.13100243 embedded image

457.13100244 embedded image

395.13100245 embedded image

449.09100246 embedded image

458.14100247 embedded image

429.1100248 embedded image

435.1592249 embedded image

429.09100250 embedded image

395.12100251 embedded image

487.1492252 embedded image

395.11100253 embedded image

369.1281254 embedded image

435.1693255 embedded image

381.1100256 embedded image

423.14100257 embedded image

423.1399258 embedded image

424.08100259 embedded image

423.13100260 embedded image

409.1196261 embedded image

449.15100262 embedded image

435.1399263 embedded image

435.1590264 embedded image

439.190265 embedded image

457.13100266 embedded image

447.14100267 embedded image

377.32100268 embedded image

405.17100269 embedded image

361.21100270 embedded image

395.19100271 embedded image

362.2599272 embedded image

361.2899273 embedded image

421.299274 embedded image

341.32100275 embedded image

409.2595276 embedded image

363.3499277 embedded image

341.38100278 embedded image

372.34100279 embedded image

405.24100280 embedded image

355.4100281 embedded image

355.41100282 embedded image

355.41100283 embedded image

355.41100284 embedded image

429.22100285 embedded image

377.39100286 embedded image

391100287

39596288

39598289

39595290

39596291

355.41100292 embedded image

345.39100293 embedded image

395.29100294 embedded image

395.29100295 embedded image

375.32100296 embedded image

379.32100297 embedded image

379.32100298 embedded image

395.36100299 embedded image

373.38100300 embedded image

397.4398301 embedded image

463.16100302 embedded image

489.22100303 embedded image

363.36100304 embedded image

369.44100305 embedded image

464.2100

Examples 306 to 534

Examples 306 to 534 were prepared according to the procedures described in Examples 2 and 16 or other similar methods used by one skilled in the art, utilizing other appropriate reagents.

TABLE 3MassExampleStructure[M + H]HPLC Purity (%)306 embedded image

441.1284307 embedded image

413.1496308 embedded image

441.1397309 embedded image

441.12100310 embedded image

427.1799311 embedded image

441.19100312 embedded image

489.14100313 embedded image

427.17100314 embedded image

422.1398315 embedded image

481.1298316 embedded image

467.1798317 embedded image

461.1697318 embedded image

427.17100319 embedded image

519.18100320 embedded image

427.21100321 embedded image

455.22100322 embedded image

455.22100323 embedded image

517.04100324 embedded image

481.1983325 embedded image

477.18100326 embedded image

437.12100327 embedded image

393.2496328 embedded image

427.1795329 embedded image

373.28100330 embedded image

393.22100331 embedded image

427.17100332 embedded image

389.393333 embedded image

373.3100334 embedded image

437.18100335 embedded image

377.2983336 embedded image

393.25100337 embedded image

373.35100338 embedded image

404.3100339 embedded image

437.19100340 embedded image

387.37100341 embedded image

387.37100342 embedded image

387.37100343 embedded image

461.16100344 embedded image

409.34100345 embedded image

387.37100346 embedded image

377.35100347 embedded image

387.37100348 embedded image

377.35100349 embedded image

427.24100350 embedded image

427.24100351 embedded image

407.34100352 embedded image

427.24100353 embedded image

411.3100354 embedded image

411.29100355 embedded image

427.35100356 embedded image

429.44100357 embedded image

495.14100358 embedded image

521.19100359 embedded image

395.36100360 embedded image

401.4100361 embedded image

401.26100362 embedded image

401.2688363 embedded image

387.393364 embedded image

401.2686365 embedded image

449.2497366 embedded image

421.2498367 embedded image

415.397368 embedded image

415.396369 embedded image

401.2797370 embedded image

449.2897371 embedded image

415.386372 embedded image

475.09100373 embedded image

447.0997374 embedded image

461.06100375 embedded image

475.09100376 embedded image

475.09100377 embedded image

461.06100378 embedded image

475.0998379 embedded image

477.195380 embedded image

495.07100381 embedded image

501.08100382 embedded image

495.0693383 embedded image

461.06100384 embedded image

461.06100385 embedded image

489.08100386 embedded image

489.0891387 embedded image

475.0993388 embedded image

523.0797389 embedded image

483.04100390 embedded image

489.13100391 embedded image

441.2281392 embedded image

427.19100393 embedded image

441.2293394 embedded image

441.22100395 embedded image

441.22100396 embedded image

441.22100397 embedded image

467.21100398 embedded image

455.25100399 embedded image

455.2594400 embedded image

441.2994401 embedded image

489.26100402 embedded image

455.32100403 embedded image

441.22100404 embedded image

427.3695405 embedded image

441.2297406 embedded image

441.2298407 embedded image

427.38100408 embedded image

441.22100409 embedded image

441.2298410 embedded image

427.1287411 embedded image

475.14100412 embedded image

441.15100413 embedded image

421.24100414 embedded image

393.2489415 embedded image

421.24100416 embedded image

407.28100417 embedded image

421.24100418 embedded image

421.24100419 embedded image

469.25100420 embedded image

441.2297421 embedded image

447.3100422 embedded image

441.22100423 embedded image

407.2888424 embedded image

407.28100425 embedded image

435.27100426 embedded image

435.27100427 embedded image

455.25100428 embedded image

421.3190429 embedded image

469.28100430 embedded image

487.26100431 embedded image

435.2796432 embedded image

401.33100433 embedded image

387.3392434 embedded image

401.33100435 embedded image

387.35100436 embedded image

401.33100437 embedded image

401.33100438 embedded image

449.32100439 embedded image

421.31100440 embedded image

427.34100441 embedded image

421.31100442 embedded image

387.3496443 embedded image

387.3396444 embedded image

415.3692445 embedded image

415.36100446 embedded image

435.3483447 embedded image

477.23100448 embedded image

441.1593449 embedded image

427.2894450 embedded image

447.09100451 embedded image

423.31100452 embedded image

409.35100453 embedded image

423.31100454 embedded image

423.33100455 embedded image

409.35100456 embedded image

423.33100457 embedded image

423.33100458 embedded image

471.36100459 embedded image

472.3397460 embedded image

443.29100461 embedded image

449.38100462 embedded image

443.29100463 embedded image

409.35100464 embedded image

409.3595465 embedded image

437.35100466 embedded image

437.35100467 embedded image

423.32100468 embedded image

471.36100469 embedded image

431.26100470 embedded image

481.3194471 embedded image

461.396472 embedded image

441.3695473 embedded image

497.2497474 embedded image

481.296475 embedded image

481.2194476 embedded image

427.0692477 embedded image

441.0897478 embedded image

441.0897479 embedded image

441.0895480 embedded image

441.0991481 embedded image

441.0795482 embedded image

441.0795483 embedded image

413.04100484 embedded image

427.0397485 embedded image

258.1784486 embedded image

441.0696487 embedded image

427.03100488 embedded image

441.0596489 embedded image

441.0695490 embedded image

489.0894491 embedded image

427.01100492 embedded image

481.0495493 embedded image

490.0696494 embedded image

461.08100495 embedded image

467.1196496 embedded image

515.2988497 embedded image

427.02100498 embedded image

427.02100499 embedded image

467.1295500 embedded image

413.02100501 embedded image

455.184502 embedded image

455.0987503 embedded image

455.0996504 embedded image

515.28100505 embedded image

481.1100506 embedded image

467.1193507 embedded image

467.1196508 embedded image

479.09100509 embedded image

427100510

42795511

42798512

437.191513 embedded image

393.2191514 embedded image

427.15100515 embedded image

373.2487516 embedded image

393.21100517 embedded image

437.1100518 embedded image

437.17100519 embedded image

387.3100520 embedded image

387.31100521 embedded image

387.34100522 embedded image

387.33100523 embedded image

461.15100524 embedded image

409.3100525 embedded image

377.3100526 embedded image

427.22100527 embedded image

427.22100528 embedded image

407.24100529 embedded image

427.22100530 embedded image

429.36100531 embedded image

495.1100532 embedded image

521.16100533 embedded image

395.2996534 embedded image

401.35100

Examples 535 To 742

Examples 535 to 1 and 17 or other similar methods used by one skilled in art, a utilizing or other appropriate reggnts.

TABLE 4MassExampleStructure[M + H]⁺HPLC Purity (%)535 embedded image

336.48100536 embedded image

329.4798537 embedded image

379.38100538 embedded image

413.3496539 embedded image

379.3899540 embedded image

387.52100541 embedded image

379.46100542 embedded image

325.5198543 embedded image

339.52100544 embedded image

339.5398545 embedded image

339.52100546 embedded image

329.47100547 embedded image

345.4499548 embedded image

379.42100549 embedded image

329.4798550 embedded image

345.4699551 embedded image

359.47100552 embedded image

387.5398553 embedded image

379.5100554 embedded image

353.5390555 embedded image

377.5198556 embedded image

362.51100557 embedded image

362.51100558 embedded image

359.4798559 embedded image

359.47100560 embedded image

379.43100561 embedded image

393.45100562 embedded image

393.45100563 embedded image

393.45100564 embedded image

441.4100565 embedded image

407.46100566 embedded image

433.45567

373.42100568 embedded image

373.42100569 embedded image

421.37100570 embedded image

387.43100571 embedded image

375.33100572 embedded image

375.3381573 embedded image

361.2990574 embedded image

375.33100575 embedded image

375.33100576 embedded image

423.2794577 embedded image

361.29100578 embedded image

389.3493579 embedded image

415.3195580 embedded image

359.3484581 embedded image

359.25100582 embedded image

373.3100583 embedded image

359.39100584 embedded image

373.42100585 embedded image

373.42100586 embedded image

421.37100587 embedded image

359.39100588 embedded image

359.3491589 embedded image

359.3984590 embedded image

387.43100591 embedded image

387.4189592 embedded image

413.42100593 embedded image

359.39100594 embedded image

379.11100595 embedded image

393.13100596 embedded image

365.1189597 embedded image

393.13100598 embedded image

393.1396599 embedded image

379.11100600 embedded image

393.13100601 embedded image

393.13100602 embedded image

379.11100603 embedded image

433.16100604 embedded image

379.13100605 embedded image

413.08100606 embedded image

399.0792607 embedded image

427.199608 embedded image

427.0899609 embedded image

413.0999610 embedded image

427.09100611 embedded image

427.07100612 embedded image

413.0799613 embedded image

413.08100614 embedded image

441.11100615 embedded image

467.12100616 embedded image

413.06100617 embedded image

359.19100618 embedded image

373.295619 embedded image

345.2100620 embedded image

373.21100621 embedded image

373.2100622 embedded image

359.19100623 embedded image

373.19100624 embedded image

373.2100625 embedded image

421.2100626 embedded image

359.19100627 embedded image

359.19100628 embedded image

387.2100629 embedded image

413.25100630 embedded image

359.19100631 embedded image

379.11100632 embedded image

393.12100633 embedded image

365.192634 embedded image

393.1382635 embedded image

393.12100636 embedded image

379.1392637 embedded image

393.1282638 embedded image

441.1294639 embedded image

433.09100640 embedded image

419.14100641 embedded image

413.0894642 embedded image

379.1292643 embedded image

325.194644 embedded image

379.11100645 embedded image

353.188646 embedded image

381.0897647 embedded image

407.15100648 embedded image

407.1499649 embedded image

433.14100650 embedded image

423.1100651 embedded image

393.1288652 embedded image

379.1191653 embedded image

339.27100654 embedded image

353.2787655 embedded image

353.27100656 embedded image

339.2694657 embedded image

393.28100658 embedded image

339.2698659 embedded image

339.25100660 embedded image

353.2698661 embedded image

353.2783662 embedded image

353.2697663 embedded image

339.2697664 embedded image

353.2695665 embedded image

353.2797666 embedded image

401.25100667 embedded image

339.2596668 embedded image

339.2797669 embedded image

367.28100670 embedded image

393.398671 embedded image

339.25100672 embedded image

379100673

41399.1674 embedded image

413100675

37996676

37995677

389.2100678 embedded image

467.1100679 embedded image

347.32100680 embedded image

345.32100681 embedded image

379.25100682 embedded image

379.25100683 embedded image

413.22100684 embedded image

379.25100685 embedded image

689.198686 embedded image

379.38100687 embedded image

325.4298688 embedded image

353.42100689 embedded image

339.45100690 embedded image

379.32100691 embedded image

389.28100692 embedded image

359.39100693 embedded image

437.27100694 embedded image

387.41100695 embedded image

379.39100696 embedded image

353.4796697 embedded image

359.3996698 embedded image

390.3397699 embedded image

412.43100700 embedded image

363.36100701 embedded image

365.15100702 embedded image

379.1893703 embedded image

393.1698704 embedded image

393.19100705 embedded image

393.19100706 embedded image

393.2199707 embedded image

421.1897708 embedded image

393.16100709 embedded image

407.18100710 embedded image

393.18100711 embedded image

377.16100712 embedded image

363.13100713 embedded image

365.15100714 embedded image

379.18100715 embedded image

393.16100716 embedded image

393.1799717 embedded image

464.1593718 embedded image

379.17100719 embedded image

393.1899720 embedded image

393.15100721 embedded image

441.14100722 embedded image

433.10100723 embedded image

442.11100724 embedded image

413.1199725 embedded image

419.18100726 embedded image

413.1199727 embedded image

379.18100728 embedded image

471.1297729 embedded image

379.16100730 embedded image

353.15100731 embedded image

419.1893732 embedded image

365.15100733 embedded image

407.18100734 embedded image

407.18100735 embedded image

407.18100736 embedded image

393.1789737 embedded image

433.15100738 embedded image

419.1497739 embedded image

419.16100740 embedded image

459.11100741 embedded image

365.15100742 embedded image

379.1893

TABLE 5

Mass

Example
Structure
[M + H]
HPLC Purity (%)

743

embedded image

315.25
100

744

embedded image

311
100

745

embedded image

326.21
95

746

embedded image

331.25
100

747

embedded image

299.22
91

748

embedded image

315.18
87

749

embedded image

295.28
88

750

embedded image

311.26
88

751

embedded image

295.27
96

752

embedded image

333.16
100

753

embedded image

357.24
92

754

embedded image

373.24
96

755

embedded image

295.26
100

756

embedded image

357.28
96

757

embedded image

287.2
92

758

embedded image

287.19
88

759

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349.21
100

760

embedded image

349.23
97

761

embedded image

315.18
100

762

embedded image

311.24
100

763

embedded image

309.25
97

764

embedded image

299.21
94

765

embedded image

331.23
100

766

embedded image

349.23
100

767

embedded image

299.24
89

768

embedded image

279.18
93

769

embedded image

317.2
88

770

embedded image

329.23
100

771

embedded image

317.2
100

772

embedded image

373.24
97

773

embedded image

309.29
99

774

embedded image

325.23
95

775

embedded image

337.3
99

776

embedded image

279.18
89

777

embedded image

341.21
85

778

embedded image

323.27
81

779

embedded image

383.1
89

780

embedded image

323.27
89

781

embedded image

310.28
92

782

embedded image

324.26
100

783

embedded image

349.13
100

784

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365.2
100

785

embedded image

349.1
100

786

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355.21
86

787

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317.26
100

788

embedded image

345.22
98

789

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306.28
100

790

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306.29
100

791

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317.26
96

792

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320.3
91

793

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301.24
84

794

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365.21
100

795

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417.2
92

796

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306.27
90

797

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317.26
97

798

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317.26
100

799

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349.15
85

800

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309.31
87

801

embedded image

312.26
100

802

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313.28
100

803

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309.3
100

804

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329.26
83

805

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325.28
100

806

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329.26
82

807

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332.27
100

808

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323.27
89

809

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329.23
86

810

embedded image

329.23
82

811

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313.27
100

812

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325.26
83

813

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332.26
100

814

embedded image

313.29
100

815

embedded image

301.22
100

816

embedded image

315.22
100

817

embedded image

329.26
100

818

embedded image

329.23
100

819

embedded image

329.23
100

820

embedded image

329.24
100

821

embedded image

357.23
100

822

embedded image

329.26
80

823

embedded image

343.26
100

824

embedded image

329.23
100

825

embedded image

313.23
100

826

embedded image

287.2
100

827

embedded image

299.2
84

828

embedded image

301.16
100

829

embedded image

315.23
100

830

embedded image

329.23
100

831

embedded image

329.24
100

832

embedded image

315.25
100

833

embedded image

329.21
100

834

embedded image

329.25
100

835

embedded image

377.22
100

836

embedded image

369.2
100

837

embedded image

378.23
100

838

embedded image

349.17
100

839

embedded image

355.21
100

840

embedded image

349.18
100

841

embedded image

315.25
100

842

embedded image

407.22
100

843

embedded image

289.22
88

844

embedded image

355.24
100

845

embedded image

301.25
100

846

embedded image

343.23
100

847

embedded image

343.26
100

848

embedded image

344.21
100

849

embedded image

343.24
100

850

embedded image

329.25
100

851

embedded image

369.26
100

852

embedded image

355.24
100

853

embedded image

355.24
100

854

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377.22
100

855

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335.19
100

856

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358.19
100

857

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395.2
100

858

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281
99.0

859

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281
100

860

embedded image

281
100

861

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383.14
100

862

embedded image

343.21
94

863

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325.32
93

864

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281.3
92

865

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312.3
92

866

embedded image

351.28
100

867

embedded image

363.29
100

868

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363.36
91

869

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401.3
94

870

embedded image

367.3
95

871

embedded image

351.33
100

872

embedded image

377.32
90

873

embedded image

334.34
97

874

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384.37
94

875

embedded image

369.37
83

876

embedded image

384.37
100

877

embedded image

384.37
88

878

embedded image

384.37
92

879

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321.41
94

880

embedded image

366.39
97

881

embedded image

389.27
91

882

embedded image

371.38
100

883

embedded image

355.35
89

884

embedded image

335.44
100

885

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397.43
100

886

embedded image

397.43
85

887

embedded image

389.34
91

888

embedded image

351.4
90

889

embedded image

339.24
88

890

embedded image

357.23
83

891

embedded image

365.22
88

892

embedded image

385.29
96

893

embedded image

349.28
87

894

embedded image

369.08
100

895

embedded image

363.31
82

896

embedded image

372.3
95

897

embedded image

372.3
83

898

embedded image

335.32
97

899

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380.32
94

900

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353.3
100

901

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369.26
100

902

embedded image

411.39
100

903

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349.44
100

904

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411.43
99

905

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403.37
100

906

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365.43
100

907

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403.37
100

908

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353.41
100

909

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371.37
97

910

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379.39
100

911

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336.41
98

912

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386.44
100

913

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371.37
100

914

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374.41
91

915

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399.43
100

916

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360.39
100

917

embedded image

367.43
98

918

embedded image

363.43
100

919

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383.4
100

920

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386.44
100

921

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377.39
100

922

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383.4
100

923

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386.44
100

Example 924
2-((2,6-Dichlorophenoxy)methyl)-6-(4-methylpiperidin-1-ylsulfonyl)pyridine

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To a solution of 2-fluoro-6-methylpyridne (6.4 mmol) in carbontetrachloride (30 mL) was added NBS (7.6 mmol). Upon completion of addition, the mixture was stirred at reflux and benzoylperoxide (0.7 mmol) was added. The resulting mixture was stirred for 4 h at 90° C. and then cool to RT. Once at the prescribed temperature, the solution was diluted with DCM and washed with brine, dried over MgSO₄and concentrated to provide a residue. The residue was dissolved in acetonitrile (20 mL) and K₂CO₃(6.4 mmol) and 2,6-dichlorophenol (6.4 mmol) were added. The resulting mixture was stirred for 2 h at 90 ° C. and then cooled to RT. Once at RT, the mixture was concentrated to provide a residue. The residue was taken up with ethyl acetate washed with brine, dried ove MgSO₄and concentrated to provide crude product. The crude product was purified via silica gel to provide Compound 924A (1.4 g, 81%). LC/MS m/z 273 (M+H)

Example 924

A mixture Compound 924A (4 mmol) and Na₂SO₃(5.2 mmol) in a 1:3 ethanol/H₂O solution (20 mL) was stirred for 4 days at 166 ° C. After this time, the mixture was cooled to RT and then concentrated to provide a residue. The residue was filtered and filtrate was purified using HPLC to give 0.12 g of a yellow solid. The yellow solid was taken up in DCM (10 mL) and DMF (0.2 mL) and then thionyl chloride (3 mmol) was added. Upon completion of addition, the resulting mixture was stirred for 2 h at 56 ° C. and cooled to RT. Once at RT, the mixture was concentrated to provide another residue. This residue was dissolved in DCM (10 mL) and 4-methylpiperidine (6 mmol) was added. The resulting mixture was concentrated and purified via HPLC to provide Example 924 as a white lyophillate (12 mg, 6%). ¹H NMR (500 MHz, CD₃OD): δ 0.92 (d, 3H), 1.15-1.23 (m, 2H), 1.35-1.45 (m, 1H), 1.65 (d, 2H), 2.66 (t, 2H), 3.80 (d, 2H), 5.22 (s, 2H), 7.15 (d, 1H), 7.42 (d, 2H), 7.91 (d, 1h), 8.00 (d, 1H), 8.13 (t, 1H). LC/MS m/z 416 (M+H).

Example 925
Methyl 6-(4-methylpiperidin-1-ylsulfonyl)picolinate

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To a mixture of 6-sulfopicolinic acid (2.4 mmol) in methanol (20 mL) was added 4 N HCl in dioxane (5 mL). The resulting mixture was stirred for 1 h to effect dissolution. After this time, the mixture was stirred for 18 h at RT and then concentrated to provide a residue. The residue was dissolved in DCM (15 mL) and DMF (0.5 mL) and then SOCl₂(24 mmol) was added. The resulting mixture was stirred for 2 h at 56° C. and then cooled to RT. Once at RT, the mixture was concentrated to provide another residue. This residue was dissolved in DCM (10 mL) and then 4-methylpiperidine (36 mmol) was added. Upon completion of addition, the resulting mixture was washed with brine, dried ove MgSO₄and concentrated to provide crude product. The crude product was purified via silica gel to provide Example 925 as a pale yellow solid (0.22 g, 30%). ¹H NMR (400 MHz, CD₃OD): δ 0.96 (d,3H), 1.20-1.35 (m, 2H), 1.40-1.51(m, 1H), 1.73 (d,2H), 2.87 (t, 2H), 3.93 (d,2H), 4.01 (s, 3H), 8.15 (d, 1H), 8.23 (t, 1H), 8.31 (d, 1H). LC/MS m/z 299 (M+H)

Example 926
2-((2,6-Dichlorophenylthio)methyl)-6-(4-methylpiperidin-1-ylsulfonyl)pyridine

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To a solution of Example 925 (0.67 mmol) in THF (5 mL) was added LAH in THF (0.8 mmol) at RT. The resulting solution was stirred for 2 h at RT and then ethyl acetate (5 mL) was added. Upon completion of addition, the solution was concentrated to yield a residue. The residue was taken up in ethyl aceate, washed with 1 N HCl, dried over MgSO₄and concentrated to provide another residue. This residue was taken up in DCM (10 mL) and then methanesulfonyl chloride (0.67 mmol) and triethylamine (0.67 mmol) were added. The resulting solution was stirred for 2 h at RT and then diluted with DCM (10 mL). Upon completion of dilution, the solution was washed with sat NaHCO₃, dried ove MgSO₄and concentrated to yield a yellow mesylate residue that was used in the next reaction without further characterization.

Example 926

To a solution of the mesylate from 926A (0.29 mmol) in acetonitrile (10 mL) was added 2,6 dichlorothiophenol (0.37 mmol) and K₂CO₃(0.37 mmol). The resulting mixture was stirred for 2 h at 90° C., cooled to RT and then filtered. The filtrate was concentrated and purified via HPLC to provide Example 926 as a pale yellow lyophillate (38 mg. 13%). ¹H NMR (400 MHz, CD₃OD): δ 0.94 (d, 3H), 1.11-1.25 (m, 2H), 1.40-1.42 (m, 1H), 1.65 (d, 2H), 2.52 (t, 2H), 3.69 (d, 2H), 4.26 (s, 2H), 7.25-7.41 (m, 3H), 7.48 (d, 1H), 7.72 (d, 1H), 7.86 (t, 1H). LC/MS m/z 432 (M+H).

Example 927
2-((2,6-Dichlorophenylsulfonyl)methyl)-6-(4-methylpiperidin-1-ylsulfonyl)pyridine

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To a mixture of Example 926 (0.046 mmol) in THF (4 mL), methanol (4 mL) and 1 N NaOH (1 mL) was added p-toluenesulfonylimidazole (0.092 mmol) followed by H₂O₂(0.19 mmol). The resulting mixture was stirred for 2 h at RT and then filtered. The filtrate was concentrated and purified via HPLC to provide Example 927 as a white lyophillate (7 mg, 33%). ¹H NMR (400 MHz, CD₃OD): δ 0.93 (d, 3H), 1.08-1.20 (m, 2H), 1.30-1.41 (m, 1H), 1.62 (d, 2H), 2.49 (t, 2H), 3.58 (d, 2H), 5.05 (s, 2H), 7.54 (m, 3H), 7.47 (d, 1H), 8.03 (t, 1H). LC/MS m/z 464 (M+H).

Example 928
3-(2-chlorophenyl)-5-(4-methylpiperidin-1-ylsulfonyl)pyridine

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To a solution of 5-bromopyridin-3-ylboronic acid (1.2 mmol) in dioxane (20 mL) was added 2-iodo-chlorobenzene (1.8 mmol), Na₂CO₃(1.8 mmol) and Pd(PPh₃)₄(0.09 mmol). The resulting mixture was stirred for 13 h at 90 ° C., cooled to RT and then concentrated to yield a residue. The residue was taken up with ethyl acetate, washed with brine, dried over MgSO₄and concentrated to yield a crude material. The crude material was purified via silica gel to provide Compound 928A (45 mg, 14%). LC/MS m/z 269 (M+H).

Example 928

To a solution of Compound 928A (0.17 mmol0 in THF (2 mL) was added BuLi in hexane (0.21 mmol) at −78° C. Upon completion of addition, the solution was stirred for 1 h at −78° C. and then transferred into a solution of THF saturated with SO₂(5 mL). The resulting solution was stirred for 20 min at −78° C. and then warmed to RT, where it stirred for 1 h. After this time, the reaction mixture was cooled to 0° C. and sulfuryl chloride (0.78 mmol) was added. The resulting solution was stirred for 30 min and then concentrated to yield a residue. The residue was dissolved in DCM (10 mL) and then 4-methylpiperidine (1.35 mmol) was added. Upon completion of addition, the mixture was stirred for 30 min and then concentrated to yield a residue. The residue was purified via HPLC to provide Example 928 as an off-white lyophillate (5 mg, 8%). ¹H NMR (400 MHz, CD₃OD): δ 0.83 (d, 3H), 1.10-1.20 (m, 2H), 1.25-1.38 (m, 1H), 1.62 (d, 2H), 2.34 (t, 2H), 3.71(d, 2H), 7.39 (m, 3H), 7.49 (m, 1H), 8.13 (s, 1H), 8.76 (s, 1H), 8.84 (s, 1H). LC/MS m/z 351 (M+H).

Example 929
3-(4-methylpiperidin-1-ylsulfonyl)-5-phenylpyridine

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Example 929 was prepared according to the procedures described in Example 928 or other similar methods used by one skilled in the art, utilizing other appropriate reagents. ¹H NMR (400 MHz, CD₃OD): δ 0.92 (d, 3H), 1.20-1.29 (m, 2H), 1.32-1.38 (m, 1H), 1.73 (d, 2H), 2.39 (t, 2H), 3.82 (d, 2H), 7.47-7.58 (m, 3H), 7.72 (d, 2H), 8.31 (s, 1H), 8.87 (s, 1H), 9.08 (s, 1H). LC/MS m/z 317 (M+H).

Example 930
4-(2-chlorophenyl)-2-(4-methylpiperidin-1-ylsulfonyl)pyridine

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To a solution of 4-bromopyridine (1.7 mmol) and 2-chlorophenylboronic acid (2.1 mmol) in EtOH (20 mL) was added PXPd₂(0.01 mmol) and K₂CO₃(6.3 mmol). The resulting mixture was stirred for 4 h at 90° C., cooled to RT and then concentrated to yield a residue. The residue was taken up in ethyl acetate, washed with 1 N NaOH, dried over MgSO₄, and concentrated to yield a residue. This residue was purified via silica gel to provide Compound 930A as a yellow oil (0.31 g, 96%). LC/MS m/z 190 (M+H).

Example 930

To a solution of dimethylaminoethanol (1.6 mmol) in hexane (5 mL) at −5° C. was added BuLi in hexane (3.2 mmol). Upon completion of addition, the solution was stirred for 20 min at −5° C. and then a solution of Compound 930A (0.8 mmol) in hexane (5 mL) was added. The resulting solution was stirred for 1 h at −5° C. After this time, the solution was cooled to −78° C. and then added into a solution of THF saturated with SO₂(5 mL). The resulting mixture was stirred for 20 min at −78° C. and then warmed to −5° C. Once at the prescribed temperature, sulfuryl chloride (4.2 mmol) was added. Upon completion of addition, the mixture was stirred for 30 min, warmed to RT and then concentrated to yield a residue. The residue was taken up in DCM (10 mL) and then 4-methylpiperidine (4.2 mmol) was added. The resulting mixture was stirred for 1 h. After this time, ther mixture was diluted with DCM (10 mL), washed with brine, dried over MgSO₄, and concentrated to yield a residue. The residue was purified via silica gel to yield a yellow oil. The yellow oil was further purified via HPLC to provide Example 930 as a pale yellow lyophillate (10 mg, 4%). ¹H NMR (400 MHz, CD₃OD): δ 0.95 (d, 3H), 1.15-1.29 (m, 2H), 1.40-1.52 (m, 1H), 1.73 (d, 2H), 2.75 (t, 2H), 3.89 (d, 2H), 7.50 (m, 3H), 7.62 (m, 1H), 7.73 (d, 1H), 8.04 (s, 1H), 8.81 (d, 1H). LC/MS m/z 351 (M+H).

Example 931
2-(4-methylpiperidin-1-ylsulfonyl)4-phenylpyridine

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Example 931 was prepared according to the procedures described in Example 930 or other similar methods used by one skilled in the art, utilizing other appropriate reagents. ¹H NMR (400 MHz, CD₃OD): δ 0.92 (d, 3H), 1.20 (dq, 2H), 1.35-1.47 (m, 1H), 1.69 (d, 2H), 2.69 (dt, 2H), 3.87 (d, 2H), 7.53-7.60 (m, 3H), 7.79 (d, 2H), 7.90 (d, 1H), 8.15 (s, 1H), 8.72 (d, 1H). LC/MS m/z 117 (M+H).

Example 932
2-(4-methylpiperidin-1-ylsulfonyl)-6-phenoxypyridine

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To a solution BuLi (15.2 mmol) in THF (15 mL) at −78° C. was added a solution of 2,6-dibromopyridine (12.7 mmol) in THF (10 mL). Upon completion of addition, the solution was stirred for 40 min at −78° C. and transferred into a solution of THF saturated with SO₂(10 mL). The resulting yellow solution was stirred for 15 min at −78° C. and then warmed to −5° C. over a 45 min period. Once at the prescribed temperature sulfuryl chloride (15.2 mmol) was added. The resulting mixture was stirred for 30 min at RT and then sat NH₄Cl (20 mL) was added. Upon completion of addition, the mixture was concentrated to yield a residual mixture. The residual mixture was taken up in ethyl acetate. The organic layer was separated, dried over MgSO₄, and concentrated to yield a residue. The residue was purified via silica gel to provide Compound 932A as a yellow solid (1.5 g, 50%). LC/MS m/z 257 (M+H).
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To a solution of Compound 932A (0.39 mmol) in DCM (5 mL) was added 4-methylpiperidine (1 mmol). The resulting solution was stirred for 30 min and then washed with sat NaHCO₃, dried over MgSO₄, and concentrated to yield Compound 932B as a pale yellow oil (0.1 g, 80%). LC/MS m/z 320 (M+H).

Example 932

A mixture of Compound 932B (0.31 mmol), phenol (0.94 mmol), and K₂CO₃(0.94 mmol) in DMF (5 mL) was stirred for 8 h at 150° C. with microwave irradiation. At the conclusion of this period, the mixture was taken up in ethyl aceate, washed with 10% LiCl, dried over MgSO₄, and concentrated to yield a residue. The residue was purified via HPLC to provide Example 932 as an off-white lyophillate (9 mg, 9%). ¹H NMR (400 MHz, CD₃OD): δ 0.91 (d, 3H), 1.08 (dq, 2H), 1.22-1.40 (m, 1H), 1.53 (d, 2H), 2.43 (t, 2H), 3.54 (d, 2H), 7.18 (d, 2H), 7.25-7.31 (m, 2H), 7.41-7.50 9 m, 2H), 7.58 (d, 1H), 8.03 (t,1H). LC/MS m/z 333 (M+H).

Example 933
4-Methoxy-2-(4-methylpiperidin-1-ylsulfonyl)-6-phenylpyridine

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To a solution of dimethylaminoethanol (18.3 mmol) in hexane (20 mL) was added BuLi in hexane (36.6 mmol) at −5° C. The resulting dark red solution was stirred for 20 min and then 4-methoxypyridine (9.2 mmol) was added. Upon completion of addition, the reaction mixture was stirred for 1 h at −5° C. After this time, the dark brown solution was cooled to −78° C. and then a solution of carbontetrabromide (36.6 mmol) in THF (10 mL) was added. The resulting solution was stirred for 30 min at −78° C. and then sat NH₄Cl was added. Upon completion of addition, the resulting mixture was warmed to RT and then extracted with ethyl acetated. The organic layer was dried overMgSO₄and concentrated to yield a residue. The residue was purified by silica gel to yield Compound 933A as a brown oil (0.15 g, 9%). LC/MS m/z 189 (M+H).
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A mixture of Compound 933A (0.5 mmol), phenylboronic acid (0.57 mmol), PXPd₂(0.0057 mmol), and K₂CO₃(1.4 mmol) in EtOH (10 mL) was stirred for 2 h at 90° C. After this time, the mixture was cooled to RT and then concentrated to yield a residue. The residue was taken up in ethyl acetate, washed with brine, dried over MgSO₄and concentrated to yield a residue. The residue was purified by silica gel to give Compound 933B as a pale yellow oil (25 mg, 27%). LC/MS m/z 186 (M+H).

Example 933

To a solution of dimethylaminoethanol (0.27 mmol) in hexane (5 mL) was added BuLi in hexane (0.54 mmol). The resulting solution was stirred for 20 min at −5° C. and then a solution of Compound 933B (0.14 mmol) in hexane (5 mL) was added. The resulting mixture was for stirred for 1 h at −5° C. At the conclusion of this period, the mixture was cooled to −78° C. and then transferred into a solution of THF saturated with SO₂(5 mL). The resuting mixture was stirred for 10 min at −78° C. and then warmed to −5° C. Once at the prescribed temperature, sulfuryl chloride (0.54 mmol) was added, and the resulting mixture was stirred for 30 min at −5° C. and then concentrated to yield a residue. The residue was dissolved in DCM (5 mL) and then 4-methylpiperidine (1.1 mmol) of was added. The resulting solution was stirred for 10 min at RT and then concentrated to yield a residue. This residue was purified by HPLC to provide Example 933 as an off-white lyophillate (5 mg, 10%). ¹H NMR (400 MHz, CD₃OD): δ 0.81 (d, 3H), 1.12 (dq, 2H), 1.30-1.40 (m, 1H), 1.60 (d, 2H), 2.70 (t, 2H), 3.81 (d, 2H), 3.92 (s, 3H), 7.30 (d, 1H), 7.32-7.42 (m, 5H), 7.50 (d, 1H), 7.99 (t,1H). LC/MS m/z 347 (M+H).

Example 934
2-(2-(1H-tetrazol-5-yl)piperidin-1-ylsulfonyl)-6-phenylpyridine

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A mixture 2-(1H-tetrazol-5-yl)pyridine (0.68 mmol) and Pt₂O (0.068 mmol) in 37% HCl (5 mL) and EtOH (30 mL) was hydrogenated at 60 psi for 5 h. At the conclusion of this period, the mixture was filtered and concentrated to yield a residue. The residue was taken up in DMF (5 mL) and DCM (5 mL) and then Et₃N (1.36 mmol) followed by a mixture of Compound 932A (0.39 mmol) in DCM (5 mL) was added. The resulting mixture was stirred for 2 h and then concentrated to yield a residue. The residue was purified by HPLC to give Compound 934A as a yellow oil (49 mg, 19%). LC/MS m/z 374 (M+H).

Example 934

A mixture of Compound 934A (0.13 mmol), phenylboronic acid (0.16 mmol), PXPd₂(0.0032 mmol) and K₂CO₃(0.40 mmol) in EtOH (10 mL) was stirred for 2 h at 90° C. At the conclusion of this period, the reaction mixture was cooled to RT, filtered and then concentrated to yield a residue. The residue was purified by HPLC to provide Example 934 as a pale yellow lyophillate (13 mg, 27%). ¹H NMR (400 MHz, CD₃OD): δ 1.30-1.67 (m, 4H), 1.80-1.97 (m, 1H), 2.05 (d, 1H), 3.30 (t, 1H), 3.98 (d, 1H), 5.64 (m, 1H), 7.42 (m, 3H), 7.75 (m, 1H), 7.89-8.05 (m, 4H). LC/MS m/z 371 (M+H).

Examples 935 and 936
(R)-2-(2-(1H-tetrazol-5-yl)piperidin-1-ylsulfonyl)-6-phenylpyridine (S)-2-(2-(1H-tetrazol-5-yl)piperidin-1-ylsulfonyl)-6phenylpyridine

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Example 934 (31 mg) was resolved using a Chiralcel AD column (eluting with Hepane: ethanol, 9:1, with 0.1% TFA additive) to provide Example 935 (13.6 mg) and Example 936 (12.4 mg).

Examples 937 to 955

Examples 937 to 955 in Table 6 were prepared according to the procedures described in Example 934 or other similar methods used by one skilled in the art, utilizing other appropriate reagents.

TABLE 6ExampleStructureMS [M + H]Purity937 embedded image

38391938

37198939

37198940

36993941

36995942

36995943

37098944

39797945

37093946

41496947

39590948

38690949

38590950

39992951

35790952

38890953

31492954

36195955

35798

Example 956
2-(2-Chlorophenyl)-6-(4-methylpiperidin-1-ylsulfonyl)pyridine

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To an oven dried 250 mL three-neck flask equipped with a magnetic stirrer was added anhydrous THF (100 mL) under Ar. The solution was cooled to −78° C. and n-BuLi (16.2 mL, 2.5 N in hexanes, 40.5 mmol) was added. Upon completion of addition, a solution of 2,6-dibromopyridine (8.0 g, 33.8 mmol) dissolved in dry THF (20 mL) was added dropwise via addition funnel over a period of 15 min. At the conclusion of this period, the mixture was allowed to stir for 0.75 h during which time the clear, homogenous solution turned dark green. To a separate 500 mL oven dried round bottom flask was added anhydrous THF (100 mL). The solution was saturated with SO₂gas and then cooled to −78° C. The lithium salt generated previously was then slowly cannulated into the saturated SO₂solution and the resulting mixture was stirred at −78° C. for 0.5 h. After this time, the reaction mixture was slowly warmed to RT, during which time a light brown precipitate formed. The solvent was concentrated under vacuum to yield a residue. The residue was suspended in dry THF (100 mL) and the resulting suspensaion was cooled to 0° C. Once at the prescribed temperature, a solution of SO₂Cl₂(3.3 mL, 40.5 mmol) was slowly added and the suspension became homogenous. The resulting mixture was warmed to R.T., and then the solvent was removed under vacuum to yield a residue. The residue was dissolved in DCM (100 mL) and triethylamine (18.8 mL, 135.2 mmol) was added. A solution of 4-methylpiperidine (4.0 g, 40.5 mmol) was added dropwise under Ar and the resulting solution was stirred for 2.5 h. At the conclusion of this period, the solution was washed with citric acid (75 mL, 10% w/v aq.), brine (75 mL) and dried over Na₂SO₄. The solvent was concentrated and the resulting residue was purified by silica gel (15% EtOAc:Hexanes) to yield Compound 956A (4.24 g, 13.3 mmol, 39%) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 7.88 (d, 1H), 7.73 (t, 1H), 7.63 (d, 1H), 3.93-3.87 (m, 2H), 2.84-2.75 (m, 2H), 1.71-1.65 (m, 2H), 1.50-1.43 (m, 1H), 1.35-1.23 (m, 2H), 0.98 (d, 3H). LC/MS m/z 320 [M+H].

Example 956

To a 25 mL round bottom flask was added Compound 956A (120 mg, 0.376 mmol), MeOH (5 mL), K₂CO₃(182 mg, 1.32 mmol) and PXPd₂(8.1 mg, 0.0113 mmol). To the resulting mixture was added 2-chlorophenylboronic acid (82 mg, 0.527 mmol). Upon completion of addition, the solution was heated at 55° C. for 3 h and then cooled to RT. Once at R.T., water (40 mL) was added and the aqueous layer extracted with EtOAc (25 mL). The organic phase was washed with brine, dried over MgSO₄and the solvent concentrated under vacuum to yield a residue. The residue was purified by silica get to yield Example 956 (100 mg, 0.285 mmol, 76%) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 7.99-7.90 (m, 2H), 7.86-7.79 (m, 1H), 7.63-7.56 (m, 1H), 7.51-7.43 (m, 1H), 7.41-7.35 (m, 2H), 3.97-3.88 (m, 2H), 2.91-2.77 (m, 2H), 1.72-1.64 (m, 2H), 1.49-1.37 (m, 1H), 1.36-1.22 (m, 2H), 0.93 (d, 3H). LC/MS m/z 351 [M+H].

Examples 957 to 978

Examples 957 to 978 in Table 7 were prepared according to the procedures described in Example 956 or other similar methods used by one skilled in the art, utilizing other appropriate reagents.

TABLE 7ExampleStructureMS [M + H]Purity957 embedded image

33198958

35294959

36799960

35297961

34297962

40199963

35297964

37098965

39498966

36198967

34999968

34799969

36099970

33599971

36594972

36899973

36299974

33399975

36195976

33599977

34898978

31899

Example 979
4-(6-(3,3-dimethylpiperidin-1-ylsulfonyl)pyridin-2-yl)benzonitrile

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To an oven dried 250 mL three neck flask equipped with a magnetic stirrer was added anhydrous THF (100 mL) under Ar. The solution was cooled to −78° C. and n-BuLi (16.2 mL, 2.5 N in hexanes, 40.5 mmol) was added. A solution of 2,6-dibromopyridine (9.6 g, 40.5 mmol) dissolved in dry THF (30 mL) was added dropwise via addition funnel over a period of 15 min. The mixture was allowed to stir for 0.75 h during which time the clear, homogenous solution turned dark green. To a separate 500 mL oven dried round bottom flask was added anhydrous THF (100 mL). The solution was saturated with SO₂gas and then cooled to −78° C. The lithium salt generated previously was then slowly cannulated into the saturated SO₂solution, stirred at −78° C. for 0.5 h and slowly warmed to R.T. during which time a light brown precipitate formed. The solvent was concentrated under vacuum to yield a residue. The residue was suspended in dry THF (100 mL) and then cooled to 0° C. Once at the prescribed temperature, a solution of SO₂C₂(3.94 mL, 48.6 mmol) was slowly added and the suspension became homogenous. The resulting suspension was warmed to R.T., and the solvent was removed under vacuum to yield a residue. The residue was dissolved in THF (100 mL), and then pyridine was added (11.5 mL, 141.7 mmol), followed by DMAP (0.1 equiv). A solution of neopentyl alcohol (4.3 g, 48.6 mmol) was then added dropwise at 0° C. and the mixture was allowed to warm to R.T. where it stirred for 1 h. After this time, the solvent was removed under vacuum to yield a crude mixture. The crude mixture was dissolved in EtOAc (250 mL), washed with citric acid (150 mL, 10% w/v aq) and brine (150 mL) and then dried over MgSO₄. The solvent was concentrated under vacuum to yield a residue, which was purified by silica gel (15% EtOAc:Hexanes) to yielded Compound 979A (6.13 g, 19.9 mmol, 49%) as a white solid. ¹H NMR (400 MHz, CDCl₃): 6 7.98 (d, 1H), 7.77 (t, 1H), 7.74 (d, 1H), 4.11 (s, 2H), 0.97 (s, 9H). LC/MS m/z 293 [M+H].
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To a 25 mL round bottom flask was added Compound 979A (2.0 g, 6.49 mmol), MeOH (80 mL), K₂CO₃(2.7 g, 19.5 mmol) and PXPd₂(140 mg, 0.195 mmol). To the mixture was added 4-cyanophenylboronic acid (1.14 mg, 7.79 mmol). The resulting solution was heated at 55° C. for 3 h and then cooled to R.T. Once at R.T., water (200 mL) was added, and the aqueous layer was extracted with EtOAc (150 mL). The organic phase was washed with brine, dried over MgSO₄and the solvent was concentrated under vacuum to yield a residue. The residue was purified by silica get to yield Compound 979B (1.65 g, 5.25 mmol, 81%) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 8.18 (d, 2H), 8.10-8.01 (m, 3H), 7.81 (d, 2H), 4.09 (s, 2H), 0.94 (s, 9H). LC/MS m/z 315 [M+H].
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To a 250 mL round bottom flask was added Compound 979B (1.64 g, 4.96 mmol), DMF (60 mL) followed by tetramethylammonium chloride (2.2 g, 19.9 mmol). The resulting mixture was heated at 160° C. for 1 h and then cooled to R.T. The resulting solid was filtered, washed with DMF (30 mL) and the combined filtrate was concentrated under vacuum to yield a crude solid. The crude solid was triturated with EtOAc and then dried in vacuo to yield a beige solid that was suitably clean for the next step. The beige solid was suspended in DMF (20 mL) to which was slowly added SOCl₂(0.9 mL, 12.4 mmol). Upon completion of addition, the mixture was stirred for 1 h, during which time the mixture became mostly homogenous. At the conclusion of this period, the solution was diluted with EtOAc (150 mL), washed with water (2×75 mL) and brine (75 mL), dried over MgSO₄and then concentrated to yield Comopund 979C (1.07 g, 3.38 mmol, 77%) as a tan solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.30 (d, 2H), 8.06 (d, 1H), 8.01-7.93 (m, 3H), 7.78 (d, 1H).

Example 979

To a 25 mL round bottom flask was added Compound 979C (96 mg, 0.34 mg), polyvinylpyridine (145 mg, 1.38 mmol), DCM (5 mL) followed by 3,3-dimethylpiperidine (47 mg, 0.41 mmol) in a single portion. The resulting mixture was allowed to stir for 2 h. After this time, the mixture was filtered and then concentrated to yield a residue. The residue was purified by silica gel to yield Example 979 (33.3 mg, 0.094 mmol, 28%) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 8.16 (d, 2H), 8.01 (t, 1H), 7.97-7.93 (m, 2H), 7.81 (d, 2H), 3.35 (t, 2H), 2.97 (s, 2H), 1.72 (pentet, 2H), 1.31 (t, 2H), 0.99 (s, 6H). LC/MS m/z 356 [M+H].

Examples 980 to 1055

Examples 980 to 1055 in Table 8 were prepared according to the procedures described in Example 979 or other similar methods used by one skilled in the art, utilizing other appropriate reagents.

TABLE 8ExampleStructureMS [M + H]Purity980 embedded image

36698981

36698982

38699983

40598984

37096985

39698986

39899987

40796988

38797989

36999990

35597991

34496992

40597993

42196994

41097995

40695996

37996997

34499998

33096999

372951000

343981001

339951002

422961003

371991004

330981005

385991006

357991007

415951008

421961009

405951010

358991011

358881012

358991013

376991014

437991015

357991016

405991017

405981018

386971019

400981020

344991021

358981022

372931023

492981024

412971025

371991026

371951028

411981029

371991030

414981031

426991032

412981033

398991034

449991035

328971036

454981037

399981038

383961039

314941040

446991041

412971042

466991043

426971044

398971045

414981046

426981047

386991048

369981049

380991050

380991051

389991052

467981053

318981054

343961055

33298

Inhibitors of 11-beta hydroxysteroid dehydrogenase type I

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