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 Sensitivity 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_4cand 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_4c, and 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;

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 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)R₉, —NR₉C(O)R_9a, —NR₉R₉, 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;

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_11aor OCONR₁₁R_11a;

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 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_4c, and 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;

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:

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, OCR₄R_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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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

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

Q is SO₂NR₁₁R_11aor OCONR₁₁R_11a;

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 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;

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;

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 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;

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 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;

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:

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;

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;

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, 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:

R₁, R₂, R₃, R₄, and R₅are independently hydrogen, halo, cyano, haloalkyl, haloalkoxy, nitro, 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;

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;

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, 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;

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;

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, 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;

R₁₁and 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 heteroatoms 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, preferably, 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, 2^ndEd., 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 III 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 III.

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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; α-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), N,N-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 KAD 1229 (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; 642-(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 farnesyl 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, CI-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 ApoB100-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 1 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, bleomycins, 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 intrasternal 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 3 h. 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(Method A): 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), 2.82-2.70 (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 (⅗) 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 5 u C18 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 1

HPLC

Mass
Purity

Example
Structure
[M + H]
(%)

10

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347
99

11

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381
95

12

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330
97

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 SOCl₂(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 (3.2 g). 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 2

HPLC

Mass
Purity

Example
Structure
[M + H]
(%)

20

embedded image

409.37
100

21

embedded image

353.32
100

22

embedded image

367.35
100

23

embedded image

396.35
100

24

embedded image

381.35
100

25

embedded image

409.37
100

26

embedded image

409.37
99

27

embedded image

480.4
100

28

embedded image

424.37
100

29

embedded image

409.37
100

30

embedded image

397.35
100

31

embedded image

457.34
100

32

embedded image

395.4
100

33

embedded image

449.32
100

34

embedded image

435.42
100

35

embedded image

429.34
94

36

embedded image

395.4
100

37

embedded image

487.37
97

38

embedded image

341.36
100

39

embedded image

398.38
100

40

embedded image

395.4
97

41

embedded image

367.35
100

42

embedded image

397.35
82

43

embedded image

423.42
98

44

embedded image

423.41
100

45

embedded image

424.37
100

46

embedded image

485.25
100

47

embedded image

435.36
100

48

embedded image

439.36
94

49

embedded image

438.39
81

50

embedded image

445.38
100

51

embedded image

341.22
88

52

embedded image

369.23
95

53

embedded image

369.24
89

54

embedded image

355.19
85

55

embedded image

369.23
84

56

embedded image

369.23
87

57

embedded image

417.21
92

58

embedded image

355.21
97

59

embedded image

355.22
88

60

embedded image

383.23
100

61

embedded image

409.25
100

62

embedded image

355.21
86

63

embedded image

429.04
100

64

embedded image

415.04
88

65

embedded image

443.06
98

66

embedded image

443.06
100

67

embedded image

443.07
100

68

embedded image

431.05
100

69

embedded image

429.05
100

70

embedded image

457.07
96

71

embedded image

429.05
100

72

embedded image

429.05
100

73

embedded image

411.16
100

74

embedded image

425.16
100

75

embedded image

425.18
100

76

embedded image

425.15
100

77

embedded image

425.17
100

78

embedded image

473.16
88

79

embedded image

411.15
100

80

embedded image

439.19
100

81

embedded image

465.19
100

82

embedded image

395.1
85

83

embedded image

381.09
93

84

embedded image

409.1
82

85

embedded image

409.11
85

86

embedded image

395.12
90

87

embedded image

409.1
87

88

embedded image

409.1
98

89

embedded image

395.09
86

90

embedded image

449.12
90

91

embedded image

395.1
83

92

embedded image

375.15
100

93

embedded image

389.15
99

94

embedded image

347.14
95

95

embedded image

376.12
98

96

embedded image

363.13
96

97

embedded image

361.15
96

98

embedded image

389.18
85

99

embedded image

389.17
99

100

embedded image

460.19
100

101

embedded image

404.15
97

102

embedded image

375.15
91

103

embedded image

389.17
99

104

embedded image

389.15
93

105

embedded image

377.14
91

106

embedded image

437.17
94

107

embedded image

375.17
99

108

embedded image

375.16
95

109

embedded image

403.17
81

110

embedded image

375.15
100

111

embedded image

395.1
85

112

embedded image

409.1
100

113

embedded image

367.07
97

114

embedded image

381.07
95

115

embedded image

409.09
100

116

embedded image

409.1
100

117

embedded image

424.07
95

118

embedded image

395.07
100

119

embedded image

409.08
99

120

embedded image

409.1
100

121

embedded image

397.07
85

122

embedded image

395.1
100

123

embedded image

395.01
100

124

embedded image

395.09
100

125

embedded image

369.08
81

126

embedded image

423.11
100

127

embedded image

449.13
96

128

embedded image

395.09
100

129

embedded image

405.2
100

130

embedded image

361.28
100

131

embedded image

395.23
100

132

embedded image

357.32
94

133

embedded image

369.35
98

134

embedded image

341.35
100

135

embedded image

361.3
100

136

embedded image

395.24
97

137

embedded image

357.34
100

138

embedded image

341.35
100

139

embedded image

405.2
98

140

embedded image

345.33
100

141

embedded image

361.28
98

142

embedded image

384.33
98

143

embedded image

357.35
100

144

embedded image

341.35
100

145

embedded image

372.31
100

146

embedded image

405.2
100

147

embedded image

355.38
97

148

embedded image

355.38
100

149

embedded image

355.38
100

150

embedded image

355.38
96

151

embedded image

429.17
100

152

embedded image

383.41
96

153

embedded image

377.35
92

154

embedded image

355.38
84

155

embedded image

345.35
100

156

embedded image

355.38
100

157

embedded image

395.32
95

158

embedded image

345.35
100

159

embedded image

395.25
94

160

embedded image

395.25
100

161

embedded image

375.32
100

162

embedded image

395.25
88

163

embedded image

369.4
98

164

embedded image

395.32
92

165

embedded image

378.33
100

166

embedded image

379.29
100

167

embedded image

379.29
100

168

embedded image

385.32
100

169

embedded image

395.32
100

170

embedded image

373.33
100

171

embedded image

397.42
92

172

embedded image

463.09
97

173

embedded image

489.14
100

174

embedded image

363.33
100

175

embedded image

369.4
94

176

embedded image

411.3
100

177

embedded image

385.35
100

178

embedded image

464.1
96

179

embedded image

395.2
97

180

embedded image

409.21
97

181

embedded image

409.2
93

182

embedded image

409.19
100

183

embedded image

395.2
92

184

embedded image

409.21
89

185

embedded image

409.21
90

186

embedded image

457.21
89

187

embedded image

395.18
93

188

embedded image

395.19
94

189

embedded image

423.22
98

190

embedded image

449.22
97

191

embedded image

355.23
98

192

embedded image

369.25
99

193

embedded image

369.25
93

194

embedded image

369.24
92

195

embedded image

440.28
96

196

embedded image

355.24
95

197

embedded image

369.25
92

198

embedded image

369.24
100

199

embedded image

357.22
94

200

embedded image

417.25
94

201

embedded image

355.24
94

202

embedded image

355.25
92

203

embedded image

329.25
100

204

embedded image

383.27
100

205

embedded image

409.28
100

206

embedded image

355.22
100

207

embedded image

377.22
94

208

embedded image

391.21
96

209

embedded image

363.2
91

210

embedded image

391.24
90

211

embedded image

391.22
92

212

embedded image

406.2
93

213

embedded image

377.19
87

214

embedded image

391.24
94

215

embedded image

391.24
92

216

embedded image

379.19
98

217

embedded image

377.22
90

218

embedded image

377.21
89

219

embedded image

405.24
94

220

embedded image

431.26
93

221

embedded image

377.2
87

222

embedded image

381.1
100

223

embedded image

395.11
100

224

embedded image

409.13
100

225

embedded image

409.13
100

226

embedded image

409.13
100

227

embedded image

409.14
100

228

embedded image

437.17
100

229

embedded image

409.14
100

230

embedded image

423.15
100

231

embedded image

409.11
100

232

embedded image

468.12
90

233

embedded image

379.08
95

234

embedded image

381.11
100

235

embedded image

395.12
100

236

embedded image

409.12
100

237

embedded image

409.11
100

238

embedded image

480.13
100

239

embedded image

424.09
100

240

embedded image

395.11
100

241

embedded image

409.12
100

242

embedded image

409.13
100

243

embedded image

457.13
100

244

embedded image

395.13
100

245

embedded image

449.09
100

246

embedded image

458.14
100

247

embedded image

429.1
100

248

embedded image

435.15
92

249

embedded image

429.09
100

250

embedded image

395.12
100

251

embedded image

487.14
92

252

embedded image

395.11
100

253

embedded image

369.12
81

254

embedded image

435.16
93

255

embedded image

381.1
100

256

embedded image

423.14
100

257

embedded image

423.13
99

258

embedded image

424.08
100

259

embedded image

423.13
100

260

embedded image

409.11
96

261

embedded image

449.15
100

262

embedded image

435.13
99

263

embedded image

435.15
90

264

embedded image

439.1
90

265

embedded image

457.13
100

266

embedded image

447.14
100

267

embedded image

377.32
100

268

embedded image

405.17
100

269

embedded image

361.21
100

270

embedded image

395.19
100

271

embedded image

362.25
99

272

embedded image

361.28
99

273

embedded image

421.2
99

274

embedded image

341.32
100

275

embedded image

409.25
95

276

embedded image

363.34
99

277

embedded image

341.38
100

278

embedded image

372.34
100

279

embedded image

405.24
100

280

embedded image

355.4
100

281

embedded image

355.41
100

282

embedded image

355.41
100

283

embedded image

355.41
100

284

embedded image

429.22
100

285

embedded image

377.39
100

286

embedded image

391
100

287

embedded image

395
96

288

embedded image

395
98

289

embedded image

395
95

290

embedded image

395
96

291

embedded image

355.41
100

292

embedded image

345.39
100

293

embedded image

395.29
100

294

embedded image

395.29
100

295

embedded image

375.32
100

296

embedded image

379.32
100

297

embedded image

379.32
100

298

embedded image

395.36
100

299

embedded image

373.38
100

300

embedded image

397.43
98

301

embedded image

463.16
100

302

embedded image

489.22
100

303

embedded image

363.36
100

304

embedded image

369.44
100

305

embedded image

464.2
100

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 3

Mass

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

306

embedded image

441.12
84

307

embedded image

413.14
96

308

embedded image

441.13
97

309

embedded image

441.12
100

310

embedded image

427.17
99

311

embedded image

441.19
100

312

embedded image

489.14
100

313

embedded image

427.17
100

314

embedded image

422.13
98

315

embedded image

481.12
98

316

embedded image

467.17
98

317

embedded image

461.16
97

318

embedded image

427.17
100

319

embedded image

519.18
100

320

embedded image

427.21
100

321

embedded image

455.22
100

322

embedded image

455.22
100

323

embedded image

517.04
100

324

embedded image

481.19
83

325

embedded image

477.18
100

326

embedded image

437.12
100

327

embedded image

393.24
96

328

embedded image

427.17
95

329

embedded image

373.28
100

330

embedded image

393.22
100

331

embedded image

427.17
100

332

embedded image

389.3
93

333

embedded image

373.3
100

334

embedded image

437.18
100

335

embedded image

377.29
83

336

embedded image

393.25
100

337

embedded image

373.35
100

338

embedded image

404.3
100

339

embedded image

437.19
100

340

embedded image

387.37
100

341

embedded image

387.37
100

342

embedded image

387.37
100

343

embedded image

461.16
100

344

embedded image

409.34
100

345

embedded image

387.37
100

346

embedded image

377.35
100

347

embedded image

387.37
100

348

embedded image

377.35
100

349

embedded image

427.24
100

350

embedded image

427.24
100

351

embedded image

407.34
100

352

embedded image

427.24
100

353

embedded image

411.3
100

354

embedded image

411.29
100

355

embedded image

427.35
100

356

embedded image

429.44
100

357

embedded image

495.14
100

358

embedded image

521.19
100

359

embedded image

395.36
100

360

embedded image

401.4
100

361

embedded image

401.26
100

362

embedded image

401.26
88

363

embedded image

387.3
93

364

embedded image

401.26
86

365

embedded image

449.24
97

366

embedded image

421.24
98

367

embedded image

415.3
97

368

embedded image

415.3
96

369

embedded image

401.27
97

370

embedded image

449.28
97

371

embedded image

415.3
86

372

embedded image

475.09
100

373

embedded image

447.09
97

374

embedded image

461.06
100

375

embedded image

475.09
100

376

embedded image

475.09
100

377

embedded image

461.06
100

378

embedded image

475.09
98

379

embedded image

477.1
95

380

embedded image

495.07
100

381

embedded image

501.08
100

382

embedded image

495.06
93

383

embedded image

461.06
100

384

embedded image

461.06
100

385

embedded image

489.08
100

386

embedded image

489.08
91

387

embedded image

475.09
93

388

embedded image

523.07
97

389

embedded image

483.04
100

390

embedded image

489.13
100

391

embedded image

441.22
81

392

embedded image

427.19
100

393

embedded image

441.22
93

394

embedded image

441.222
100

395

embedded image

441.22
100

396

embedded image

441.22
100

397

embedded image

467.21
100

398

embedded image

455.25
100

399

embedded image

455.25
94

400

embedded image

441.29
94

401

embedded image

489.26
100

402

embedded image

455.32
100

403

embedded image

441.22
100

404

embedded image

427.36
95

405

embedded image

441.22
97

406

embedded image

441.22
98

407

embedded image

427.38
100

408

embedded image

441.22
100

409

embedded image

441.22
98

410

embedded image

427.12
87

411

embedded image

475.14
100

412

embedded image

441.15
100

413

embedded image

421.24
100

414

embedded image

393.24
89

415

embedded image

421.24
100

416

embedded image

407.28
100

417

embedded image

421.24
100

418

embedded image

421.24
100

419

embedded image

469.25
100

420

embedded image

441.22
97

421

embedded image

447.3
100

422

embedded image

441.22
100

423

embedded image

407.28
88

424

embedded image

407.28
100

425

embedded image

435.27
100

426

embedded image

435.27
100

427

embedded image

455.25
100

428

embedded image

421.31
90

429

embedded image

469.28
100

430

embedded image

487.26
100

431

embedded image

435.27
96

432

embedded image

401.33
100

433

embedded image

387.33
92

434

embedded image

401.33
100

435

embedded image

387.35
100

436

embedded image

401.33
100

437

embedded image

401.33
100

438

embedded image

449.32
100

439

embedded image

421.31
100

440

embedded image

427.34
100

441

embedded image

421.31
100

442

embedded image

387.34
96

443

embedded image

387.33
96

444

embedded image

415.36
92

445

embedded image

415.36
100

446

embedded image

435.34
83

447

embedded image

477.23
100

448

embedded image

441.15
93

449

embedded image

427.28
94

450

embedded image

447.09
100

451

embedded image

423.31
100

452

embedded image

409.35
100

453

embedded image

423.31
100

454

embedded image

423.33
100

455

embedded image

409.35
100

456

embedded image

423.33
100

457

embedded image

423.33
100

458

embedded image

471.36
100

459

embedded image

472.33
97

460

embedded image

443.29
100

461

embedded image

449.38
100

462

embedded image

443.29
100

463

embedded image

409.35
100

464

embedded image

409.35
95

465

embedded image

437.35
100

466

embedded image

437.35
100

467

embedded image

423.32
100

468

embedded image

471.36
100

469

embedded image

431.26
100

470

embedded image

481.31
94

471

embedded image

461.3
96

472

embedded image

441.36
95

473

embedded image

497.24
97

474

embedded image

481.2
96

475

embedded image

481.21
94

476

embedded image

427.06
92

477

embedded image

441.08
97

478

embedded image

441.08
97

479

embedded image

441.08
95

480

embedded image

441.09
91

481

embedded image

441.07
95

482

embedded image

441.07
95

483

embedded image

413.04
100

484

embedded image

427.03
97

485

embedded image

258.17
84

486

embedded image

441.06
96

487

embedded image

427.03
100

488

embedded image

441.05
96

489

embedded image

441.06
95

490

embedded image

489.08
94

491

embedded image

427.01
100

492

embedded image

481.04
95

492

embedded image

481.04
95

493

embedded image

490.06
96

494

embedded image

461.08
100

495

embedded image

467.11
96

496

embedded image

515.29
88

497

embedded image

427.02
100

498

embedded image

427.02
100

499

embedded image

467.12
95

500

embedded image

413.02
100

501

embedded image

455.1
84

502

embedded image

455.09
87

503

embedded image

455.09
96

504

embedded image

515.28
100

505

embedded image

481.1
100

506

embedded image

467.11
93

507

embedded image

467.11
96

508

embedded image

479.09
100

509

embedded image

427
100

510

embedded image

427
95

511

embedded image

427
98

512

embedded image

437.1
91

513

embedded image

393.21
91

514

embedded image

427.15
100

515

embedded image

373.24
87

516

embedded image

393.21
100

517

embedded image

437.1
100

518

embedded image

437.17
100

519

embedded image

387.3
100

520

embedded image

387.31
100

521

embedded image

387.34
100

522

embedded image

387.33
100

523

embedded image

461.15
100

524

embedded image

409.3
100

525

embedded image

377.3
100

526

embedded image

427.22
100

527

embedded image

427.22
100

528

embedded image

407.24
100

529

embedded image

427.22
100

530

embedded image

429.36
100

531

embedded image

495.1
100

532

embedded image

521.16
100

533

embedded image

395.29
96

534

embedded image

401.35
100

Examples 535 to 742

Examples 535 to 742 in Table 4 were prepared according to the procedures described in Examples 1 and 17 or other similar methods used by one skilled in the art, utilizing other appropriate reagents.

TABLE 4

HPLC

Mass
Purity

Example
Structure
[M + H]⁺
(%)

535

embedded image

336.48
100

536

embedded image

329.47
98

537

embedded image

379.38
100

538

embedded image

413.34
96

539

embedded image

379.38
99

540

embedded image

387.52
100

541

embedded image

379.46
100

542

embedded image

325.51
98

543

embedded image

339.52
100

544

embedded image

339.53
98

545

embedded image

339.52
100

546

embedded image

329.47
100

547

embedded image

345.44
99

548

embedded image

379.42
100

549

embedded image

329.47
98

550

embedded image

345.46
99

551

embedded image

359.47
100

552

embedded image

387.53
98

553

embedded image

379.5
100

554

embedded image

353.53
90

555

embedded image

377.51
98

556

embedded image

362.51
100

557

embedded image

362.51
100

558

embedded image

359.47
98

559

embedded image

359.47
100

560

embedded image

379.43
100

561

embedded image

393.45
100

562

embedded image

393.45
100

563

embedded image

393.45
100

564

embedded image

441.4
100

565

embedded image

407.46
100

566

embedded image

433.45

567

embedded image

373.42
100

568

embedded image

373.42
100

569

embedded image

421.37
100

570

embedded image

387.43
100

571

embedded image

375.33
100

572

embedded image

375.33
81

573

embedded image

361.29
90

574

embedded image

375.33
100

575

embedded image

375.33
100

576

embedded image

423.27
94

577

embedded image

361.29
100

578

embedded image

389.34
93

579

embedded image

415.31
95

580

embedded image

359.34
84

581

embedded image

359.25
100

582

embedded image

373.3
100

583

embedded image

359.39
100

584

embedded image

373.42
100

585

embedded image

373.42
100

586

embedded image

421.37
100

587

embedded image

359.39
100

588

embedded image

359.34
91

589

embedded image

359.39
84

590

embedded image

387.43
100

591

embedded image

387.41
89

592

embedded image

413.42
100

593

embedded image

359.39
100

594

embedded image

379.11
100

595

embedded image

393.13
100

596

embedded image

365.11
89

597

embedded image

393.13
100

598

embedded image

393.13
96

599

embedded image

379.11
100

600

embedded image

393.13
100

601

embedded image

393.13
100

602

embedded image

379.11
100

603

embedded image

433.16
100

604

embedded image

379.13
100

605

embedded image

413.08
100

606

embedded image

399.07
92

607

embedded image

427.1
99

608

embedded image

427.08
99

609

embedded image

413.09
99

610

embedded image

427.09
100

611

embedded image

427.07
100

612

embedded image

413.07
99

613

embedded image

413.08
100

614

embedded image

441.11
100

615

embedded image

467.12
100

616

embedded image

413.06
100

617

embedded image

359.19
100

618

embedded image

373.2
95

619

embedded image

345.2
100

620

embedded image

373.21
100

621

embedded image

373.2
100

622

embedded image

359.19
100

623

embedded image

373.19
100

624

embedded image

373.2
100

625

embedded image

421.2
100

626

embedded image

359.19
100

627

embedded image

359.19
100

628

embedded image

387.2
100

629

embedded image

413.25
100

630

embedded image

359.19
100

631

embedded image

379.11
100

632

embedded image

393.12
100

633

embedded image

365.1
92

634

embedded image

393.13
82

635

embedded image

393.12
100

636

embedded image

379.13
92

637

embedded image

393.12
82

638

embedded image

441.12
94

639

embedded image

433.09
100

640

embedded image

419.14
100

641

embedded image

413.08
94

642

embedded image

379.12
92

643

embedded image

325.1
94

644

embedded image

379.11
100

645

embedded image

353.1
88

646

embedded image

381.08
97

647

embedded image

407.15
100

648

embedded image

407.14
99

649

embedded image

433.14
100

650

embedded image

423.1
100

651

embedded image

393.12
88

652

embedded image

379.11
91

653

embedded image

339.27
100

654

embedded image

353.27
87

655

embedded image

353.27
100

656

embedded image

339.26
94

657

embedded image

393.28
100

658

embedded image

339.26
98

659

embedded image

339.25
100

660

embedded image

353.26
98

661

embedded image

353.27
83

662

embedded image

353.26
97

663

embedded image

339.26
97

664

embedded image

353.26
95

665

embedded image

353.27
97

666

embedded image

401.25
100

667

embedded image

339.25
96

668

embedded image

339.27
97

669

embedded image

367.28
100

670

embedded image

393.3
98

671

embedded image

339.25
100

672

embedded image

379
100

673

embedded image

413
99.1

674

embedded image

413
100

675

embedded image

379
96

676

embedded image

379
95

677

embedded image

389.2
100

678

embedded image

467.1
100

679

embedded image

347.32
100

680

embedded image

345.32
100

681

embedded image

379.25
100

682

embedded image

379.25
100

683

embedded image

413.22
100

684

embedded image

379.25
100

685

embedded image

689.1
98

686

embedded image

379.38
100

687

embedded image

325.42
98

688

embedded image

353.42
100

689

embedded image

339.45
100

690

embedded image

379.32
100

691

embedded image

389.28
100

692

embedded image

359.39
100

693

embedded image

437.27
100

694

embedded image

387.41
100

695

embedded image

379.39
100

696

embedded image

353.47
96

697

embedded image

359.39
96

698

embedded image

390.33
97

699

embedded image

412.43
100

700

embedded image

363.36
100

701

embedded image

365.15
100

702

embedded image

379.18
93

703

embedded image

393.16
98

704

embedded image

393.19
100

705

embedded image

393.19
100

706

embedded image

393.21
99

707

embedded image

421.18
97

708

embedded image

393.16
100

709

embedded image

407.18
100

710

embedded image

393.18
100

711

embedded image

377.16
100

712

embedded image

363.13
100

713

embedded image

365.15
100

714

embedded image

379.18
100

715

embedded image

393.16
100

716

embedded image

393.17
99

717

embedded image

464.15
93

718

embedded image

379.17
100

719

embedded image

393.18
99

720

embedded image

393.15
100

721

embedded image

441.14
100

722

embedded image

433.10
100

723

embedded image

442.11
100

724

embedded image

413.11
99

725

embedded image

419.18
100

726

embedded image

413.11
99

727

embedded image

379.18
100

728

embedded image

471.12
97

729

embedded image

379.16
100

730

embedded image

353.15
100

731

embedded image

419.18
93

732

embedded image

365.15
100

733

embedded image

407.18
100

734

embedded image

407.18
100

735

embedded image

407.18
100

736

embedded image

393.17
89

737

embedded image

433.15
100

738

embedded image

419.14
97

739

embedded image

419.16
100

740

embedded image

459.11
100

741

embedded image

365.15
100

742

embedded image

379.18
93

Examples 743 to 923

Examples 743 to 923 in Table 5 were prepared according to the procedures described in Examples 18 and 19 or other similar methods used by one skilled in the art, utilizing other appropriate reagents.

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

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

embedded image

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

embedded image

365.2
100

785

embedded image

349.1
100

786

embedded image

355.21
86

787

embedded image

317.26
100

788

embedded image

345.22
98

789

embedded image

306.28
100

790

embedded image

306.29
100

791

embedded image

317.26
96

792

embedded image

320.3
91

793

embedded image

301.24
84

794

embedded image

365.21
100

795

embedded image

417.2
92

796

embedded image

306.27
90

797

embedded image

317.26
97

798

embedded image

317.26
100

799

embedded image

349.15
85

800

embedded image

309.31
87

801

embedded image

312.26
100

802

embedded image

313.28
100

803

embedded image

309.3
100

804

embedded image

329.26
83

805

embedded image

325.28
100

806

embedded image

329.26
82

807

embedded image

332.27
100

808

embedded image

323.27
89

809

embedded image

329.23
86

810

embedded image

329.23
82

811

embedded image

313.27
100

812

embedded image

325.26
83

813

embedded image

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

embedded image

377.22
100

855

embedded image

335.19
100

856

embedded image

358.19
100

857

embedded image

395.2
100

858

embedded image

281
99.0

859

embedded image

281
100

860

embedded image

281
100

861

embedded image

383.14
100

862

embedded image

343.21
94

863

embedded image

325.32
93

864

embedded image

281.3
92

865

embedded image

312.3
92

866

embedded image

351.28
100

867

embedded image

363.29
100

868

embedded image

363.36
91

869

embedded image

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

embedded image

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

embedded image

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

embedded image

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

embedded image

380.32
94

900

embedded image

353.3
100

901

embedded image

369.26
100

902

embedded image

411.39
100

903

embedded image

349.44
100

904

embedded image

411.43
99

905

embedded image

403.37
100

906

embedded image

365.43
100

907

embedded image

403.37
100

908

embedded image

353.41
100

909

embedded image

371.37
97

910

embedded image

379.39
100

911

embedded image

336.41
98

912

embedded image

386.44
100

913

embedded image

371.37
100

914

embedded image

374.41
91

915

embedded image

399.43
100

916

embedded image

360.39
100

917

embedded image

367.43
98

918

embedded image

363.43
100

919

embedded image

383.4
100

920

embedded image

386.44
100

921

embedded image

377.39
100

922

embedded image

383.4
100

923

embedded image

386.44
100

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

embedded image

To a solution of 2-fluoro-6-methylpyridine (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 over 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, 1 h), 8.00 (d, 1H), 8.13 (t, 1H). LC/MS m/z 416 (M+H).

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

embedded image

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 over 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

embedded image

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 over 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, their 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 over MgSO₄and 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 resulting 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)-6-phenylpyridine

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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 6

Example
Structure
MS [M + H]
Purity

937

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383
91

938

embedded image

371
98

939

embedded image

371
98

940

embedded image

369
93

941

embedded image

369
95

942

embedded image

369
95

943

embedded image

370
98

944

embedded image

397
97

945

embedded image

370
93

946

embedded image

414
96

947

embedded image

395
90

948

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386
90

949

embedded image

385
90

950

embedded image

399
92

951

embedded image

357
90

952

embedded image

388
90

953

embedded image

314
92

954

embedded image

361
95

955

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357
98

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 suspension 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 7

Example
Structure
MS [M + H]
Purity

957

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331
98

958

embedded image

352
94

959

embedded image

367
99

960

embedded image

352
97

961

embedded image

342
97

962

embedded image

401
99

963

embedded image

352
97

964

embedded image

370
98

965

embedded image

394
98

966

embedded image

361
98

967

embedded image

349
99

968

embedded image

347
99

969

embedded image

360
99

970

embedded image

335
99

971

embedded image

365
94

972

embedded image

368
99

973

embedded image

362
99

974

embedded image

333
99

975

embedded image

361
95

976

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335
99

977

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348
98

978

embedded image

318
99

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 SO₂Cl₂(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): δ 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 Compound 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 8

Example
Structure
MS [M + H]
Purity

980

embedded image

366
98

981

embedded image

366
98

982

embedded image

386
99

983

embedded image

405
98

984

embedded image

370
96

985

embedded image

396
98

986

embedded image

398
99

987

embedded image

407
96

988

embedded image

387
97

989

embedded image

369
99

990

embedded image

355
97

991

embedded image

344
96

992

embedded image

405
97

993

embedded image

421
96

994

embedded image

410
97

995

embedded image

406
95

996

embedded image

379
96

997

embedded image

344
99

998

embedded image

330
96

999

embedded image

372
95

1000

embedded image

343
98

1001

embedded image

339
95

1002

embedded image

422
96

1003

embedded image

371
99

1004

embedded image

330
98

1005

embedded image

385
99

1006

embedded image

357
99

1007

embedded image

415
95

1008

embedded image

421
96

1009

embedded image

405
95

1010

embedded image

358
99

1011

embedded image

358
88

1012

embedded image

358
99

1013

embedded image

376
99

1014

embedded image

437
99

1015

embedded image

357
99

1016

embedded image

405
99

1017

embedded image

405
98

1018

embedded image

386
97

1019

embedded image

400
98

1020

embedded image

344
99

1021

embedded image

358
98

1022

embedded image

372
93

1023

embedded image

492
98

1024

embedded image

412
97

1025

embedded image

371
99

1026

embedded image

371
95

1028

embedded image

411
98

1029

embedded image

371
99

1030

embedded image

414
98

1031

embedded image

426
99

1032

embedded image

412
98

1033

embedded image

398
99

1034

embedded image

449
99

1035

embedded image

328
97

1036

embedded image

454
98

1037

embedded image

399
98

1038

embedded image

383
96

1039

embedded image

314
94

1040

embedded image

446
99

1041

embedded image

412
97

1042

embedded image

466
99

1043

embedded image

426
97

1044

embedded image

398
97

1045

embedded image

414
98

1046

embedded image

426
98

1047

embedded image

386
99

1048

embedded image

369
98

1049

embedded image

380
99

1050

embedded image

380
99

1051

embedded image

389
99

1052

embedded image

467
98

1053

embedded image

318
98

1054

embedded image

343
96

1055

embedded image

332
98

	Number	Date	Country
Parent	11403092	Apr 2006	US
Child	12958706		US

INHIBITORS OF 11-BETA HYDROXYSTEROID DEHYDROGENASE TYPE I

Information

Publication Number

Date Filed

Date Published

Inventors

Original Assignees

CPC

US Classifications

International Classifications

Abstract

Description

Claims

Parent Case Info

Provisional Applications (1)

Divisions (1)