KR20070022792A - ?-substituted piperidines and their use as pharmaceuticals - Google Patents

Abstract

The present invention relates to inhibitors of 11-β hydroxyl steroid dehydrogenase type 1, antagonists of mineralocorticoid receptors (MR) and pharmaceutical compositions thereof. The compounds of the present invention may be useful for the treatment of various diseases related to the expression or activity of 11-β hydroxyl steroid dehydrogenase type 1 and / or diseases related to aldosterone excess.

Inhibitor of 11-β hydroxyl steroid dehydrogenase type 1, antagonist of mineralocorticoid receptor

Description

N-substituted piperidine and its use as pharmaceuticals {N-substituted piperidines and their use as pharmaceuticals}

Field of invention

The present invention relates to modulators and / or mineralocorticoid receptors (MR) of 11-β hydroxyl steroid dehydrogenase type 1 (11-β-HSD1), compositions thereof and methods of using the same.

Background of the Invention

Glucocorticoids are steroid hormones that regulate fat metabolism, function and distribution. In vertebrates, glucocorticoids also have sufficient and diverse physiological effects in development, neurobiology, inflammation, blood pressure, metabolism and cell death. In humans, the primary endogenous-generated glucocorticoid is cortisol. Cortisol is synthesized in the regional bundles of the adrenal cortex under the control of the short-term neuroendocrine feedback circulation, referred to as the hypothalamic-pituitary-adrenal (HPA) axis. Adrenal production of cortisol proceeds under the control of the adrenal cortical stimulating hormone (ACTH), a factor produced and released by the anterior pituitary gland. The production of ACTH in the anterior pituitary gland is highly regulated and driven by corticotropin-releasing hormone (CRH) produced by the hypothalamus nucleus. The HPA axis maintains cortisol concentrations circulating at weekly maximums or within limited limits driven forward during stress times, negative feedback causing cortisol's ability to inhibit ACTH production in the anterior pituitary gland and inhibit CRH production in the hypothalamus. Reduce loops quickly

Aldosterone is another hormone produced by the adrenal cortex; Aldosterone regulates sodium and potassium homeostasis. Fifty years ago, the role of aldosterone excess in human disease was reported in the description of the syndrome of primary aldosteroneism. Conn, (1955), J. Lab. Clin. Med. 45: 6-17. Elevated levels of aldosterone are associated with detrimental effects in the heart and kidneys, and are evident in the major causative factors of morbidity and mortality in both heart failure and hypertension.

Two members of the nuclear hormone receptor family, the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR), modulate cortisol function in vivo, while the primary intracellular receptor for aldosterone is MR. Their receptors are also referred to as "ligand-dependent transcription factors" because their functionality depends on the receptor (eg cortisol) bound to its ligand; Ligand-binding phases their receptors directly regulate transcription through the DNA-binding zinc finger domain and the transcriptional activation domain.

Historically, the major determinants of glucocorticoid action are thought to be three primary factors: 1) circulation of glucocorticoid levels (mainly driven by the HPA axis), 2) protein binding of glucocorticoids in circulation and 3) targets Intracellular receptor density in tissues. Recently, a fourth determinant of glucocorticoid function has been identified: tissue-specific pre-receptor metabolism by glucocorticoid-activating and -inactivating enzymes. These 11-β-hydroxysteroid dehydrogenases (11-β-HSD) act as pro-receptor regulatory enzymes that regulate the activation of GR and MR by the regulation of glucocorticoid hormones. To date, two separate isozymes of 11-β-HSD have been cloned and characterized as: 11-β-HSD1 (11-β-HSD type 1, 11-β-HSD1, HSD11B1, HDL and HSD11L Known) and 11-β-HSD2. 11-β-HSD1 and 11-β-HSD2 catalyze the interconversion of hormones' active cortisol (corticosterone in rodents) and inactive cortisone (11-dihydrocorticosterone in rodents). 11-β-HSD1 is widely distributed in rat and human tissues; Expression of enzymes and corresponding mRNA is detected in lungs, testes, and most often in liver and adipose tissue. 11-β-HSD1 acts as a NADPH-dependent oxoriductase that catalyzes the activation of cortisol from inactive cortisone in mainly intact cells and tissues [Low et al. (1994) J. Mol. Endocrin. 13: 167-174, although it has been reported to regulate glucocorticoid access to GR, 11-β-HSD1 catalyzes both 11-β-dehydrogenation and reverse 11-redox reactions. Conversely, 11-β-HSD2 expression is mainly found in mineralocorticoid target tissues such as kidney, placenta, colon and salivary glands and acts as a NAD-dependent dehydrogenase that catalyzes the inactivation of cortisol to cortisone. And [Albiston et al. (1994) Mol. Cell. Endocrin. 105: R11-R17], has been shown to protect MR from high levels of glucocorticoids, eg, receptor-active cortisol (Blum, et al., (2003) Prog. Nucl. Acid Res. Mol. Biol. 75: 173-216.

In vitro, MR binds cortisol and aldosterone with the same affinity. However, tissue specificity of aldosterone activity is provided by expression of 11-β-HSD2. Funder et al. (1988), Science 242: 583-585. Inactivation of cortisol to cortisone by 11-β-HSD2 at the site of MR allows aldosterone to bind to this receptor in vivo. The binding of aldosterone to MR results in the separation of the ligand-activated MR from the multiprotein complex comprising the chaperone protein, the translocation of the MR to the nucleus and its binding to hormonal response elements at the regulatory site of the target gene promoter. Within the terminal elongation unit of the kidney, induction of serum and glucocorticoid-induced kinase-1 (sgk-1) expression leads to uptake of Na ⁺ ions and water through epithelial sodium channels, as well as subsequent volumetric expansion of potassium Causes excretion and hypertension (Bhargava et al., (2001), Endo 142: 1587-1594).

In humans, elevated aldosterone levels are associated with endothelial dysfunction, myocardial infarction, left ventricular atrophy and death. In attempts to modulate this adverse effect, a number of intervention strategies have been chosen to modulate aldosterone overactivity and reduce the resulting hypertension and its associated cardiovascular outcomes. Inhibition of angiotensin-converting enzyme (ACE) and blocking of angiotensin type 1 receptor (AT1R) are two strategies that directly affect the Lenin-Angiotensin-Aldosterone System (RAAS). However, although ACE inhibition and AT1R antagonism initially reduce aldosterone concentrations, the circulating concentrations of these hormones return to baseline levels with chronic treatment (known as “aldosterone deviations”). Importantly, co-administration of the MR antagonist spironolactone or eplerenone directly prevents the deleterious effects of this escape mechanism and significantly reduces patient mortality. Pitt et al., New England J. Med. (1999), 341: 709-719; Pitt et al., New England J. Med. (2003), 348: 1309-1321. Thus, MR antagonism may be an important treatment strategy for many patients with hypertension and cardiovascular disease, especially for hypertensive patients at risk of target-organ damage.

Mutations in one of the genes encoding the 11-β-HSD enzyme are associated with human pathology. For example, 11-β-HSD2 is expressed in aldosterone-sensitive tissues such as terminal elongation units, salivary glands and colonic mucosa, where its cortisol dehydrogenase activity is essentially insensitive to non-selective MR by cortisol. Protect from occupation. Edwards et al. (1988) Lancet 2: 986-989). Individuals with mutations in 11-β-HSD2 lack this cortisol-inactivating activity, thus resulting in overt mineralocorticoid hyperactivity syndrome characterized by hypertension, hypokalemia and sodium accumulation (also referred to as "SAME"). See Wilson et al. (1998) Proc. Natl. Acad. Sci. 95: 10200-10205. In addition, hexose 6-phosphate dehydrogenase (H6PD) in genes encoding mutations in 11-β-HSD1, primary regulators of tissue-specific glucocorticoid bioavailability and co-localized NADPH-producing enzymes, lack cortisone reductase (CRD), where the activation of cortisol in cortisone does not occur, leading to adrenal cortical hormone-mediated androgen hyperactivity. CRD patients secrete virtually all glucocorticoids with low or absent cortisol metabolites (tetrahydrocortisol) as cortisone metabolites (tetrahydrocortisone). When tested with oral cortisone, CRD patients have abnormally low plasma cortisol concentrations. These individuals are present in phenotypes similar to ACTH-mediated androgen hyperactivity (hiratosis, menstrual irregularities, hyperandrogenosis), polycystic ovary syndrome (PCOS). See Draper et al. (2003) Nat. Genet. 34: 434-439.

The importance of the HPA axis in glucocorticoid locomotor control is evidenced by the fact that homeostasis disruption due to excessive or deficient secretion or action in the HPA axis results in Cushing syndrome or Addison disease, respectively (Miller and Chrousos (2001). ) Endocrinology and Metabolism, eds. Felig and Frohman (McGraw-Hill, New York), 4 ^th Ed .: 387-524]. Patients receiving Cushing's syndrome (a rare disease characterized by excess systemic glucocorticoids derived from adrenal or pituitary tumors) or glucocorticoid treatment develop reversible visceral fat obesity. Interestingly, the phenotype of Cushing's syndrome patients is very similar to Reaven metabolic syndrome (also known as syndrome X or insulin resistance syndrome), and these signs are visceral obesity, glucose intolerance, insulin resistance, hypertension, type 2 diabetes and Hyperlipidemia, including Reaven (1993) Ann. Rev. Med. 44: 121-131. However, the role of glucocorticoids remains obscure in the general form of human obesity because there is no increase in circulating glucocorticoid concentrations in most patients with metabolic syndrome. In fact, glucocorticoid action in target tissues depends not only on the level of circulation but also on intracellular concentrations, and locally enhanced activity of glucocorticoids in adipose tissue and skeletal muscle has been demonstrated in metabolic syndrome. Evidence has accumulated that the enzymatic activity of 11-β-HSD1, which plays a key role in regenerating active glucocorticoids from inactive forms and regulating intracellular glucocorticoid concentrations, is generally elevated at the site of fat accumulation from obese individuals. This suggests a role for local glucocorticoid reactivation in obesity and metabolic syndrome.

Given the ability of 11-β-HSD1 to regenerate cortisol from inactive circulating cortisone, its role in the amplification of glucocorticoid function has drawn considerable attention. 11-β-HSD1 is expressed in several major GR-rich tissues including significantly important metabolic tissues such as liver, fat and skeletal muscles, which is a tissue-specific elevation of glucocorticoid-mediated antagonism in insulin function It has been claimed to help work. Considering a) phenotypic similarity between glucocorticoid hyperplasia (Cushing syndrome) and metabolic syndrome with normal circulating glucocorticoids in the latter, as well as b) the ability of 11-β-HSD1 to generate active cortisol from inactive cortisone in a tissue-specific manner. Thus, central obesity and related metabolic complications in syndrome X have been suggested to increase the activity of 11-β-HSD1 in adipose tissue, leading to "netus Cushing's disease". Bujalska et al. (1997) Lancet 349: 1210-1213. Indeed, 11-β-HSD1 has been shown to be unregulated in obese rodents and human adipose tissue. Livingstone et al. (2000) Endocrinology 131: 560-563; Rask et al. (2001) J. Clin. Endocrinol. Metab. 86: 1418-1421; Lindsay et al. (2003) J. Clin. Endocrinol. Metab. 88: 2738-2744; Wake et al. (2003) J. Clin. Endocrinol. Metab. 88: 3983-3988.

Further evidence of this idea is the study in the mouse transgenic model. Adipose-specific overexpression of 11-β-HSD1 under the control of aP2 promoters in mice produces a prominent phenotype suggestive of human metabolic syndrome. Masuzaki et al. (2001) Science 294: 2166-2170; Masuzaki et al. (2003) J. Clinical Invest. 112: 83-90. Importantly, this phenotype occurs without an increase in total circulating corticosterone, but rather is driven by local production of corticosteroids in the fat accumulation site. The increased activity (11-3 fold) of 11-β-HSD1 in these mice is very similar to that observed in obese people. Rask et al. (2001) J. Clin. Endocrinol. Metab. 86: 1418-1421. This suggests that local 11-β-HSD1-mediated conversion of inactive glucocorticoids to active glucocorticoids significantly affects systemic insulin sensitivity.

Based on these data, it can be expected that the loss of 11-β-HSD1 may cause an increase in insulin sensitivity and glucose tolerance due to tissue-specific deficiency at active glucocorticoid levels. This is, in fact, the case in 11-β-HSD1-deficient mouse studies generated by homologous recombination. Kotelevstev et al. (1997) Proc. Natl. Acad. Sci. 94: 14924-14929; Morton et al. (2001) J. Biol. Chem. 276: 41293-41300; Morton et al. (2004) Diabetes 53: 931-938. These mice lack complete 11-keto reductase activity, demonstrating that 11-β-HSD1 encodes the only activity capable of producing active corticosterone from inactive 11-dihydrocorticosterone. 11-β-HSD1-deficient mice are resistant to diet- and stress-induced hyperglycemia, exhibit reduced induction of hepatic glucose synthetase (PEPCK, G6P), show increased insulin sensitivity in fat, Have an improved lipid profile (reduced triglycerides and increased cardio-protective HDL). In addition, these animals exhibit resistance to high fat diet-induced obesity. Together, these transgenic mouse studies demonstrate a local reactivation role of glucocorticoids that regulate liver and peripheral insulin sensitivity, and the inhibition of 11-β-HSD1 activity includes obesity, insulin resistance, hyperglycemia and hyperlipidemia. It is proposed to be able to prove beneficial for treating a number of glucocorticoid-related diseases.

Data supporting this hypothesis has been published. Recently, 11-β-HSD1 has been reported to play a major role in the mechanism of invention of central obesity and the expression of metabolic syndrome. Increased expression of 11-β-HSD1 of genes is associated with metabolic abnormalities in obese women, and increased expression of these genes is thought to cause increased local transformation of cortisone to cortisol in adipose tissue of obese individuals See Engeli, et al., (2004) Obes. Res. 12: 9-17.

A new class of 11-β-HSD1 inhibitors, arylsulfonamidothiazoles, have been shown to improve hepatic insulin sensitivity and reduce blood glucose levels in mouse hyperglycemic cell lines. Barf et al. (2002) J. Med. Chem. 45: 3813-3815; Alberts et al. Endocrinology (2003) 144: 4755-4762. In addition, it has recently been reported that selective inhibitors of 11-β-HSD1 may improve severe hyperglycemia in genetic diabetic obese mice. Thus, 11-β-HSD1 is a promising pharmaceutical target for the treatment of metabolic syndrome. Masuzaki, et al., (2003) Curr. Drug Targets Immune Endocr. Metabol. Disord. 3: 255-62.

A. Obesity and Metabolic Syndrome

As noted above, evidence from a number of lines suggests that inhibition of 11-β-HSD1 activity eliminates aspects of the obesity and / or metabolic syndrome community, including glucose intolerance, insulin resistance, hyperglycemia, hypertension and / or hyperlipidemia. It is suggested that it can be effective. Glucocorticoids are known as antagonists of insulin action, and reduction of local glucocorticoid levels by inhibition of intracellular cortisone to cortisol conversion can increase liver and / or peripheral insulin sensitivity and effectively reduce visceral steatosis. . As mentioned above, 11-β-HSD1 knockout mice are resistant to hyperglycemia, exhibit reduced induction of major hepatic glucose synthase, significantly increase insulin sensitivity in fat, and improve lipids Represents a profile. In addition, these animals are resistant to high fat diet-induced obesity. Kotelevstev et al. (1997) Proc. Natl. Acad. Sci. 94: 14924-14929; Morton et al. (2001) J. Biol. Chem. 276: 41293-41300; Morton et al. (2004) Diabetes 53: 931-938. Thus, inhibition of 11-β-HSD1 is expected to have various beneficial effects associated with alleviation of metabolic syndrome and / or obesity component (s), particularly in liver, fat and / or skeletal muscle.

B. Pancreatic Function

Glucocorticoids are known to inhibit glucose-stimulated secretion of insulin from pancreatic β-cells. Billaudel and Sutter (1979) Horm. Metab. Res. 11: 555-560. In both Cushing's syndrome and diabetic Zucker fa / fa rats, glucose-stimulated insulin secretion is significantly reduced (Ogawa et al. (1992) J. Clin. Invest. 90: 497-504]. 11-β-HSD1 mRNA and activity have been reported in pancreatic islet cells of ob / ob mice, and inhibition of this activity with the carbenoxolone 11-β-HSD1 inhibitor improves glucose-stimulated insulin release. Davani et al. (2000) J. Biol. Chem. 275: 34841-34844. Thus, inhibition of 11-β-HSD1 is expected to have a beneficial effect on the pancreas, including enhancing glucose-stimulated insulin release.

C. Cognitive and Dementia

Mild cognitive impairment is a characteristic of general aging that may ultimately be involved in the development of dementia. In both aged animals and humans, individual differences in general cognitive function have been associated with variability in prolonged exposure with glucocorticoids. Lupien et al. (1998) Nat. Neurosci. 1: 69-73. In addition, the dysregulation of the HPA axis caused by chronic exposure to glucocorticoid overload in certain brain subregions has been suggested to contribute to a decrease in cognitive function. McEwen and Sapolsky (1995) Curr. Opin. Neurobiol. 5: 205-216. 11-β-HSD1 is abundant in the brain and expressed in several subregions, including the hippocampus, epithelium and cerebellum. Sandeep et al. (2004) Proc. Natl. Acad. Sci. Early Edition: 1-6]. Treatment of primary hippocampal cells with carbenoxolone, an 11-β-HSD1 inhibitor, protects cells from glucocorticoid-mediated exacerbations of stimulating amino acid neurotoxicity. Rajan et al. (1996) J. Neurosci. 16: 65-70. In addition, 11-β-HSD1-deficient mice are protected from glucocorticoid-related hippocampal dysfunction associated with aging. Yau et al. (2001) Proc. Natl. Acad. Sci. 98: 4716-4721. In two randomized, double-blind, placebo-controlled crossover studies, administration of carbenoxolone improves language fluency and language memory. Sandeep et al. (2004) Proc. Natl. Acad. Sci. Early Edition: 1-6]. Thus, inhibition of 11-β-HSD1 is expected to reduce exposure to glucocorticoids in the brain and to protect against glucocorticoid effects that are detrimental to neuronal function, including cognitive impairment, dementia and / or depression.

D. Guide Pressure

Glucocorticoids can be used locally and systemically for a wide range of conditions in clinical ophthalmology. A unique complication of this treatment regimen is corticosteroid-induced glaucoma. This pathology is characterized by a marked increase in intraocular pressure (IOP). In the most advanced and untreated form, IOP can cause partial visual field damage and eventually blindness. IOP is caused by the relationship between aqueous body fluid production and discharge. Aqueous body fluid production occurs in non-stained epithelial cells (NPE), the excretion of which is through the cells of the columnar fibrous cells. 11-β-HSD1 is localized to NPE cells [see Stokes et al. (2000) Invest. Ophthalmol. Vis. Sci. 41: 1629-1683; Rauz et al. (2001) Invest. Ophthalmol. Vis. Sci. 42: 2037-2042], its function is also involved in the amplification of glucocorticoid activity in these cells. This idea is confirmed by observations in which the free cortisol concentration significantly exceeds the concentration of cortisone in aqueous body fluids (14: 1 ratio). The functional importance of 11-β-HSD1 in the eye was assessed using the inhibitor carbenoxolone in healthy volunteers. Rauz et al. (2001) Invest. Ophthalmol. Vis. Sci. 42: 2037-2042. After 7 days of treatment with carbenoxolone, the IOP is reduced by 18%. Thus, inhibition of 11-β-HSD1 in the eye is expected to reduce local glucocorticoid concentrations and IOPs and to have a beneficial effect in the management of glaucoma and other visual diseases.

E. High Blood Pressure

Adipocyte-induced hypertensive substances, such as leptin and angiotensinogen, have been proposed to be involved in the pathogenesis of obesity-related hypertension. Matsuzawa et al. (1999) Ann. N.Y. Acad. Sci. 892: 146-154; Wajchenberg (2000) Endocr. Rev. 21: 697-738. Oversecreting leptin in aP2-11-β-HSD1 transgenic mice. Masuzaki et al. (2003) J. Clinical Invest. 112: 83-90 can activate a variety of sympathetic nervous system pathways, including those that regulate blood pressure (Mattuzawa et al. (1999) Ann. N.Y. Acad. Sci. 892: 146-154. In addition, the Lenin-Angiotensin system (RAS) has been shown to be a major determinant of blood pressure. Walker et al. (1979) Hypertension 1: 287-291. Angiotensinogen produced in liver and adipose tissue is a major substrate for renin and drives RAS activation. Plasma angiotensinogen levels are significantly elevated in aP2-11-β-HSD1 transgenic mice, thereby raising angiotensin II and aldosterone. Masuzaki et al. (2003) J. Clinical Invest. 112: 83-90. It also drives the elevated blood pressure observed in aP2-11-β-HSD1 transgenic mice. Treatment of these mice with low doses of angiotensin II receptor antagonists eliminates their hypertension. Masuzaki et al. (2003) J. Clinical Invest. 112: 83-90. These data indicate the importance of local glucocorticoid reactivation in adipose tissue and liver and suggest that hypertension may be caused or worsened by 11-β-HSD1 activity. Thus, inhibition of 11-β-HSD1 and reduction of glucocorticoid levels in fat and / or liver are expected to have beneficial effects in hypertension and hypertension-related cardiovascular disease.

F. Bone Disease

Glucocorticoids can have an adverse effect on skeletal tissue. Sequential exposure to consistently regulate glucocorticoid doses can lead to osteoporosis [Cannalis (1996) J. Clin. Endocrinol. Metab. 81: 3441-3447], can increase the risk of fracture. In vitro tests demonstrate the deleterious effects of glucocorticoids on both bone-resorbing cells (also known as osteoclasts) and osteoblasts (osteoblasts). 11-β-HSD1 has been shown to be present in culture of not only human primary osteoblasts, but also cells from adult bone, as well as a mixture of osteoclasts and osteoblasts. Cooper et al. (2000) Bone 27: 375-381], carbenoxolone, an 11-β-HSD1 inhibitor, has been shown to reduce the negative effects of glucocorticoids on bone nodule formation. Bellows et al. (1998) Bone 23: 119-125. Thus, inhibition of 11-β-HSD1 is expected to reduce local glucocorticoid concentrations in osteoblasts and osteoclasts, and have a beneficial effect in various forms of bone disease, including osteoporosis.

Small molecule inhibitors of 11-β-HSD1 have been developed to treat or prevent the above-mentioned 11-β-HSD1-associated diseases. For example, certain amide-based inhibitors have been reported in WO 2004/089470, WO 2004/089896, WO 2004/056745 and WO 2004/065351.

Antagonists of 11-β-HSD1 have been evaluated in human clinical trials. Kurukulasuriya, et al., (2003) Curr. Med. Chem. 10: 123-53.

11-β- in glucocorticoid-related diseases, metabolic syndrome, hypertension, obesity, insulin resistance, hyperglycemia, hyperlipidemia, type 2 diabetes, hyperandrogenosis (hirsutism, dysmenorrhea, hyperandrogenosis) and polycystic ovary syndrome (PCOS) In view of experimental data showing the major role of HSD1, therapeutic agents aimed at expanding or inhibiting metabolic pathways by regulating glucocorticoid signal transduction to levels of 11-β-HSD1 are preferred.

In addition, because MR binds with the same affinity to aldosterone (its native ligand) and cortisol, compounds designed to interact with the active site of 11-β-HSD1 (compounds that bind cortisone / cortisol) can also interact with MR. And act as an antagonist. MR antagonists are preferred and also hyperlipidemia because MR is associated with heart failure, hypertension, and pathologies including atherosclerosis, arteriosclerosis, coronary artery disease, thrombosis, angina, peripheral vascular disease, vascular wall damage and stroke. Or lipid metabolism diseases including hyperlipoproteinemia, diabetic dyslipidemia, mixed dyslipidemia, hypercholesterolemia, hypertriglyceridemia, as well as type 1 diabetes, type 2 diabetes, obesity, metabolic syndrome and insulin It is useful in the treatment of complex cardiovascular, renal and inflammatory pathological diseases, including diseases related to resistance, and general aldosterone-associated target-organ damage.

As demonstrated herein, there is a continuing need for new and improved drugs that target 11-β-HSD1 and / or MR. The compounds, compositions, and methods described herein help to meet these and other needs.

Summary of the Invention

The present invention particularly provides a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof, wherein the component members are defined herein.

The invention further provides a composition comprising a compound of the invention and a pharmaceutically acceptable carrier.

The invention further provides a method of regulating 11-β-HSD1 or MR by contacting 11-β-HSD1 or MR with a compound of the present invention.

The invention further provides a method of inhibiting 11-β-HSD1 or MR by contacting 11-β-HSD1 or MR with a compound of the present invention.

The invention further provides a method of inhibiting the conversion of cortisone to cortisol in a cell.

The invention further provides methods of inhibiting the production of cortisol in cells.

The invention further provides methods of increasing insulin sensitivity in cells.

The invention further provides a method of treating a disease associated with the activity or expression of 11-β-HSD1 or MR.

The present invention further provides for therapeutic use of the compounds and compositions of the present invention.

The invention further provides the use for the manufacture of a medicament for the treatment of the compounds and compositions of the invention.

details

The present invention relates in particular to a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof.

Formula I

In Formula I,

Cy is aryl, heteroaryl, cycloalkyl or heterocycloalkyl,

They are each optionally substituted with 1, 2, 3, 4 or 5 -W-X-Y-Z;

L is absent or is SO ₂ , C (O), C (O) O or C (O) NR ^g ;

Q is cycloalkyl or heterocycloalkyl, each of which is optionally substituted by 1, 2, 3, 4 or 5 -W'-X'-Y'-Z '; or

Q is-(CR ^1a R ^1b ) _m -A;

A is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, which are each optionally substituted by 1, 2, 3, 4 or 5 -W '-' X'-Y'-Z ';

R ^1a and R ^1b are each independently H, halo, OH, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 hydroxylalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy or C _1-4 hydroxylalkoxy;

m is 1, 2, 3 or 4;

R ^N is H, C _1-6 alkyl, aryl, heteroaryl, C _3-7 cycloalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, (C _3-7 cycloalkyl) alkyl or heterocycloalkylalkyl ;

R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently H, OC (O) R ^{a '} , OC (O) OR ^b' , C ( O) OR ^{b '} , OC (O) NR ^c' R ^{d '} , NR ^c' R ^{d '} , NR ^c' C (O) R ^{a '} , NR ^c' C (O) OR ^{b '} , S (O) R ^{a '} , S (O) NR ^c' R ^{d '} , S (O) ₂ R ^a' , S (O) ₂ NR ^{c '} R ^d' , OR ^{b '} , SR ^b' , C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, Wherein C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkyl Alkyl or heterocycloalkylalkyl is optionally substituted by R ¹⁴ ; or

R ⁴ and R ⁵ together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group, which is optionally substituted by R ¹⁴ ; or

R ⁶ and R ⁷ together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group, which is optionally substituted by R ¹⁴ ; or

R ⁸ and R ⁹ together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group, which is optionally substituted by R ¹⁴ ; or

R ¹⁰ and R ¹¹ together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group, which is optionally substituted by R ¹⁴ ; or

R ⁴ and R ⁶ together with the carbon atom to which they are attached form a 3-7 membered fused cycloalkyl group or a 3-7 membered fused heterocycloalkyl group, which is optionally substituted by R ¹⁴ ; or

R ⁶ and R ⁸ together with the carbon atom to which they are attached form a 3-7 membered fused cycloalkyl group or a 3-7 membered fused heterocycloalkyl group, which is optionally substituted by R ¹⁴ ; or

R ⁴ and R ⁹ together form a C _1-3 alkylene bridge, which is optionally substituted by R ¹⁴ ; or

R ⁴ and R ¹⁰ together form a C _1-3 alkylene bridge, which is optionally substituted by R ¹⁴ ; or

R ³ and R ⁷ together form a C _1-3 alkylene bridge, which is optionally substituted by R ¹⁴ ; or

R ³ and R ⁹ together form a C _1-3 alkylene bridge, which is optionally substituted by R ¹⁴ ; or

R ⁶ and R ¹⁰ together form a C _1-3 alkylene bridge, which is optionally substituted by R ¹⁴ ; or

R ⁹ and R ¹⁰ together form a C _1-3 alkylene bridge, which is optionally substituted by R ¹⁴ ;

R ¹⁴ is halo, C _1-4 alkyl, C _1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO ₂ , OR ^{a '} , SR ^a' , C (O) R ^{b '} , C (O) NR ^{c '} R ^d' , C (O) OR ^{a '} , OC (O) R ^b' , OC (O) NR ^{c '} R ^d' , NR ^{c '} R ^d' , NR ^{c '} C (O) R ^{d '} , NR ^c' C (O) OR ^{a '} , S (O) R ^b' , S (O) NR ^{c '} R ^d' , S (O) ₂ R ^{b '} or S (O) ₂ NR ^{c '} R ^d' ;

W, W 'and W "are each independently absent or C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynylenyl, O, S, NR ^e , CO, COO, CONR ^e , SO, SO ₂ , SONR ^e or NR ^e CONR ^f, wherein C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynylenyl are each 1, 2 or 3 halo, Optionally substituted by OH, C _1-4 alkoxy, C _1-4 haloalkoxy, amino, C _1-4 alkylamino or C _2-8 dialkylamino;

X, X 'and X "are each independently absent or are C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, Wherein C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynylenyl, cycloalkyl, heteroaryl or heterocycloalkyl is one or more halo, CN, NO ₂ , OH, C _1-4 Optionally substituted by alkoxy, C _1-4 haloalkoxy, amino, C _1-4 alkylamino or C _2-8 dialkylamino;

Y, Y 'and Y "are each independently absent or C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynylenyl, O, S, NR ^e , CO, COO, CONR ^e , SO, SO ₂ , SONR ^e or NR ^e CONR ^f , wherein C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynyleneyl are each 1, 2 or 3 halo, OH Optionally substituted by C _1-4 alkoxy, C _1-4 haloalkoxy, amino, C _1-4 alkylamino or C _2-8 dialkylamino;

Z, Z 'and Z "are each independently H, halo, CN, NO ₂ , OH, C _1-4 alkoxy, C _1-4 haloalkoxy, amino, C _1-4 alkylamino, C _2-8 dialkyl Amino, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl may be 1, 2 or 3 halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1- 4} haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO ₂ , OR ^a , SR ^a , C (O) R ^b , C (O) NR ^c R ^d , C (O) OR ^a , OC (O) R ^b , OC (O) NR ^c R ^d , NR ^c R ^d , NR ^c C (O) R ^d , NR ^c C (O) OR ^a , S (O) R ^b , S (O) Optionally substituted by NR ^c R ^d , S (O) ₂ R ^b or S (O) ₂ NR ^c R ^d ;

Wherein two -WXYZs attached to the same atom optionally form a 3- to 14-membered cycloalkyl or heterocycloalkyl group, each of which is 1, 2 or 3 -W "-X" -Y "-Z" Optionally substituted by;

Wherein two -W'-X'-Y'-Z 'attached to the same atom optionally form a 3- to 14-membered cycloalkyl or heterocycloalkyl group, each of which is 1, 2 or 3 -W Optionally substituted by "-X" -Y "-Z";

Wherein -W-X-Y-Z is not H;

Wherein -W'-X'-Y'-Z 'is not H;

Wherein -W "-X" -Y "-Z" is not H;

R ^a and R ^{a '} are each independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl Wherein C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl; Heterocycloalkyl, heterocycloalkylalkyl is selected from H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl Optionally substituted;

R ^b and R ^{b '} are each independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl , Arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cyclo Alkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 Optionally substituted by haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;

R ^c and R ^d are each independently H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, Arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl , Cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 halo Optionally substituted by alkyl, aryl, aryl alkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or

R ^c and R ^d together with the N atoms attached thereto form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;

R ^{c '} and R ^d' are each independently H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclo Alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, Heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1- Optionally substituted by ₆ haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or

R ^{c '} and R ^d' together with the N atom attached to them form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;

R ^e and R ^f are each independently H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, Arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl , Cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 halo Optionally substituted by alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or

R ^e and R ^f together with the N atoms attached to them form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;

R ^g is H, C _1-6 alkyl, aryl, heteroaryl, C _3-7 cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, (C _3-7 cycloalkyl) alkyl or heterocycloalkylalkyl.

In some embodiments, when Q is-(CR ^1a R ^1b ) _m -A, at least one R ^1a and R ^1b is not H;

In some embodiments, unsubstituted C _3-8 cycloalkyl; Adamantyl; 1,2,3,4-tetrahydro-1-naphtanenyl; Bicyclo [2.2.1] hept-2-yl; 2-methylcyclohexyl; Or 1-ethylylcyclohexyl; At least one of R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ is not H.

In some embodiments, when R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each H, Q is tetrahydrothienyl, S-oxo-tetrahydro Thienyl, S, S-dioxo-tetrahydrothienyl, 2,2,6,6-tetramethyl-4-piperidinyl, N-substituted pyrrolidin-3-yl, N-substituted piperi Din-4-yl or 3,4,5,6-tetra-substituted tetrahydropyran-2-yl.

In some embodiments, Cy is aryl or heteroaryl, which are each optionally substituted by 1, 2, 3, 4 or 5 -W-X-Y-Z.

In some embodiments, Cy is aryl or heteroaryl, each of which is optionally substituted by 1, 2, 3, 4 or 5 -W-X-Y-Z; Where W is O or absent, X is absent and Y is absent.

In some embodiments, Cy is phenyl, naphthyl, pyridyl, pyrimidinyl, quinolinyl, benzoxazolyl, pyridazinyl, pyrazinyl, triazinyl, furanyl or thienyl, respectively. Optionally substituted by 3, 4 or 5 -WXYZ.

In some embodiments, each -WXYZ is independently halo, nitro, CN, C _1-4 alkoxy, C _1-4 haloalkoxy, COOH, C (O) OC _1-4 alkyl, CONH-C _1-4 alkyl, NHC (O) C _1-4 alkyl, C _1-6 alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aryloxy, heteroaryloxy, cycloalkyloxy or heterocycloalkyloxy, wherein C _{1- 6} alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aryloxy, heteroaryloxy, cycloalkyloxy or heterocycloalkyloxy is one or more halo, nitro, CN, C _1-4 alkoxy, C _1-4 halo Optionally substituted by alkoxy, C _1-6 alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aryloxy, heteroaryloxy, cycloalkyloxy or heterocycloalkyloxy.

In some embodiments, each -WXYZ is independently aryl substituted by aryl, aryl substituted by heteroaryl, heteroaryl substituted by aryl or heteroaryl substituted by heteroaryl, each of which is one or more halo, Nitro, CN, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, COOH, C (O) OC _1-4 alkyl, Optionally substituted by CONH-C _1-4 alkyl or NHC (O) C _1-4 alkyl.

In some embodiments, Cy is phenyl, naphthyl, pyridyl, pyrimidinyl, quinolinyl, benzoxazolyl, pyridazinyl, pyrazinyl, triazinyl, furanyl or thienyl, respectively. Optionally substituted by 3 halo, CN, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-6 alkyl or aryl, wherein C _1-6 alkyl or aryl is 1, 2 or 3 halo, Optionally substituted by C _1-6 alkyl, C _1-4 haloalkyl, CN, NO ₂ , OR ^a or SR ^a .

In some embodiments, Q is cycloalkyl or heterocycloalkyl, each of which is substituted with 1, 2, 3, 4 or 5 -W'-X'-Y'-Z '.

In some embodiments, -W'-X'-Y'-Z 'are each independently halo, nitro, CN, C _1-4 alkoxy, C _1-4 haloalkoxy, COOH, C (O) OC _1-4 Alkyl, CONH-C _1-4 alkyl, NHC (O) C _1-4 alkyl, NR ^e SO ₂ (C _1-4 alkyl), C _1-6 alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, Aryloxy, heteroaryloxy, cycloalkyloxy or heterocycloalkyloxy, wherein C _1-6 alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aryloxy, heteroaryloxy, cycloalkyloxy or heterocyclo Alkyloxy is one or more halo, nitro, CN, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-6 alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aryloxy, heteroaryloxy, cyclo Optionally substituted by alkyloxy or heterocycloalkyloxy.

In some embodiments, Q is cycloalkyl or heterocycloalkyl, each of which is 1, 2, 3, 4 or 5 OH, C _1-4 alkoxy, NR ^e COO (C _1-4 alkyl), NR ^e CO ( C _1-4 alkyl), NR ^e SO ₂ (C _1-4 alkyl), aryl, heteroaryl, -O-aryl, -O-heteroaryl or-(C _1-4 alkyl) -OH .

In some embodiments, Q is cycloalkyl or heterocycloalkyl, each of which is substituted by two or more -W'-X'-Y'-Z ', wherein two or more -W'-X'-Y Two of '-Z' are attached to the same atom and together with the atoms to which they are attached form a 3- to 14-membered cycloalkyl or heterocycloalkyl group, which are each 1, 2 or 3 -W "-X; Optionally substituted by "-Y" -Z ".

In some embodiments, Q is cycloalkyl or heterocycloalkyl, each of which is substituted by two or more -W'-X'-Y'-Z ', wherein two or more -W'-X'-Y Two of '-Z' are attached to the same atom and together with the atoms to which they are attached a 3-14 membered hetero optionally substituted by 1, 2 or 3 -W "-X" -Y "-Z" To form a cycloalkyl group.

In some embodiments, -W "-X" -Y "-Z" are each independently halo, nitro, CN, C _1-4 alkoxy, C _1-4 haloalkoxy, COOH, C (O) OC _1-4 Alkyl, CONH-C _1-4 alkyl, NHC (O) C _1-4 alkyl, NR ^e SO ₂ (C _1-4 alkyl), C _1-6 alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, Aryloxy, heteroaryloxy, cycloalkyloxy or heterocycloalkyloxy, wherein C _1-6 alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aryloxy, heteroaryloxy, cycloalkyloxy or heterocyclo Alkyloxy is one or more halo, nitro, CN, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-6 alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aryloxy, heteroaryloxy, cyclo Optionally substituted by alkyloxy or heterocycloalkyloxy.

In some embodiments, Q is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, indanyl or 1,2,3,4-tetrahydronaphthalen-2-yl, each of which is optionally 1, 2, 3 , 4 or 5 -W'-X'-Y'-Z '.

In some embodiments, Q is a 3-14 membered heterocycloalkyl group comprising one or more ring-forming O atoms, wherein the 3-14 membered heterocycloalkyl group is 1, 2, 3, 4 or Optionally substituted by five -W'-X'-Y'-Z '.

In some embodiments, Q is cyclohexyl substituted by one or more -W'-X'-Y'-Z 'at the 4-position.

In some embodiments, Q is cyclohexyl substituted by one or more OH in the 4-position.

In some embodiments, L is SO ₂ .

In some embodiments, L is absent.

In some embodiments, L is C (O), C (O) O or C (O) NR ^g .

In some embodiments, L is C (O) NR ^g and R ^g is H or C _1-6 alkyl.

In some embodiments, L is C (O) NH.

In some embodiments, R ^N is H, C _1-6 alkyl, C _3-7 cycloalkyl or (C _3-7 cycloalkyl) alkyl.

In some embodiments, R ^N is H.

In some embodiments, R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently H, OC (O) R ^{a ′} , OC (O) OR ^{b '} , C (O) OR ^b' , OC (O) NR ^{c '} R ^d' , NR ^{c '} R ^d' , NR ^{c '} C (O) R ^a' , NR ^{c '} C (O) OR ^b' , S (O) R ^{a '} , S (O) NR ^c' R ^{d '} , S (O) ₂ R ^a' , S (O) ₂ NR ^{c '} R ^d' , OR ^{b '} , SR ^b' , C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or hetero Cycloalkylalkyl.

In some embodiments, R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently H, C _1-10 alkyl or C _1-10 haloalkyl .

In some embodiments, R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each H.

In some embodiments, R ³ is C _1-10 alkyl.

In some embodiments:

R ⁴ and R ⁵ together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group, which is optionally substituted by R ¹⁴ ; or

R ⁶ and R ⁷ together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group, which is optionally substituted by R ¹⁴ ; or

R ⁸ and R ⁹ together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group, which is optionally substituted by R ¹⁴ ; or

R ¹⁰ and R ¹¹ together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group, which is optionally substituted by R ¹⁴ ; or

R ⁴ and R ⁶ together with the carbon atom to which they are attached form a 3-7 membered fused cycloalkyl group or a 3-7 membered fused heterocycloalkyl group, which is optionally substituted by R ¹⁴ ; or

R ⁶ and R ⁸ together with the carbon atom to which they are attached form a 3-7 membered fused cycloalkyl group or a 3-7 membered fused heterocycloalkyl group, which is optionally substituted by R ¹⁴ ; or

R ⁴ and R ⁹ together form a C _1-3 alkylene bridge, which is optionally substituted by R ¹⁴ ; or

R ⁴ and R ¹⁰ together form a C _1-3 alkylene bridge, which is optionally substituted by R ¹⁴ ; or

R ³ and R ⁷ together form a C _1-3 alkylene bridge, which is optionally substituted by R ¹⁴ ; or

R ³ and R ⁹ together form a C _1-3 alkylene bridge, which is optionally substituted by R ¹⁴ ; or

R ⁶ and R ¹⁰ together form a C _1-3 alkylene bridge, which is optionally substituted by R ¹⁴ ; or

R ⁹ and R ¹⁰ together form a C _1-3 alkylene bridge, which is optionally substituted by R ¹⁴ .

In the present specification, substituents of the compounds of the present invention are described in groups or ranges. In particular, the invention is intended to include the subcombination of each and every individual such group and range. For example, the term “C _1-6 alkyl” is especially intended to denote individually methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl and C ₆ alkyl.

It is understood that certain features of the invention described in the context of separate embodiments for further clarity may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of the embodiments, may also be provided separately or in suitable subcombinations.

The term "n-member", where n is an integer, typically refers to the number of ring-forming atoms in the residue, where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

As used herein, the term “substituted” or “substituted” means that the hydrogen atom is replaced with a substituent other than H. For example, "n-substituted piperidin-4-yl" means that the H atom is substituted from the NH of piperidinyl with a non-hydrogen substituent, for example alkyl.

As used herein, the term "alkyl" refers to a straight or branched chain saturated hydrocarbon group. Exemplary alkyl groups include methyl (Me), ethyl (Et), propyl (eg, n-propyl and isopropyl), butyl (eg, n-butyl, isobutyl, t-butyl), pentyl (eg N-pentyl, isopentyl, neopentyl) and the like. The alkyl group may comprise 1 to about 20, 2 to about 20, 1 to about 10, 1 to about 8, 1 to about 6, 1 to about 4, or 1 to about 3 carbon atoms. The term "alkylenyl" or "alkylene bridge" refers to a divalent alkyl linking or bridging group.

The term "alkenyl" as used herein is an alkyl group having one or more carbon-carbon double bonds. Exemplary alkenyl groups include ethenyl, propenyl and the like. The term "alkenylenyl" is a divalent bonding alkenyl group.

The term "alkynyl" as used herein is an alkyl group having one or more carbon-carbon triple bonds. Exemplary alkynyl groups include ethynyl, propynyl, and the like. The term "alkynylenyl" is a divalent bonding alkynyl group.

The term "haloalkyl" as used herein is an alkyl group having one or more halogen substituents. Exemplary haloalkyl groups include CF ₃ , C ₂ F ₅ , CHF ₂ , CCl ₃ , CHCl ₂ , C ₂ Cl ₅ , and the like.

As used herein, the term “aryl” refers to monocyclic or polycyclic (eg having 2, 3 or 4 fused rings) aromatic hydrocarbons such as phenyl, naphthyl, anthracenyl, phenanthrenyl , Indanyl, indenyl, and the like. In some embodiments, the aryl group has 6 to about 20 carbon atoms.

As used herein, the term "cycloalkyl" is a non-aromatic cyclic hydrocarbon comprising cyclized alkyl, alkenyl and alkynyl groups. Cycloalkyl groups can include mono- or polycyclic (eg, having 2, 3 or 4 fused rings) ring systems, as well as spiro ring systems. Ring-forming carbon atoms of a cycloalkyl group may be optionally substituted by oxo or sulfido. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norfinyl, norcarnyl , Adamantyl and the like. In addition, the definition of cycloalkyl includes residues having one or more aromatic rings (ie, having one bond in combination) fused to a cycloalkyl ring, for example benzo or thienyl derivatives such as pentane, pentene, hexane, etc. do.

The term "heteroaryl" group, as used herein, is an aromatic heterocycle having one or more heteroatom reductions, such as sulfur, oxygen or nitrogen. Heteroaryl groups include monocyclic and polycyclic (eg, having 2, 3 or 4 fused rings) systems. Exemplary heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indole Reel, pyryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothieryl Nil, furinyl, carbazolyl, benzimidazolyl, indolinyl, and the like. In some embodiments, the heteroaryl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heteroaryl group has 3 to about 14, 3 to about 7 or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3 or 1 to 2 heteroatoms.

As used herein, the term "heterocycloalkyl" is a non-aromatic heterocycle comprising cyclized alkyl, alkenyl and alkynyl groups, wherein one or more ring-forming carbon atoms is a heteroatom, such as O, N Or replaced by an S atom. Heterocycloalkyl groups have a mono- or polycyclic [eg, two, three, four or more fusion sums or have a two-ring, three-ring, four-ring spiro system (eg, Having from 8 to 20 ring-forming atoms). Heterocycloalkyl groups include monocyclic and polycyclic groups. Exemplary “heterocycloalkyl” groups include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxol, benzo -1,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl and the like. Ring-forming carbon atoms and heteroatoms of heterocycloalkyl groups may be optionally substituted by oxo or sulfido. In addition, the definition of heterocycloalkyl is defined as residues having one or more aromatic rings (ie, having one bond in combination) fused to a non-aromatic heterocyclic ring, for example phthalimidyl, naphthalimidyl and hetero Benzo derivatives of the cycle, such as indolene and isoindolene groups. In some embodiments, the heterocycloalkyl group has 1 to about 20 carbon atoms and in further embodiments about 3 to about 20 carbon atoms. In some embodiments, the heterocycloalkyl group comprises 3 to about 14, 3 to about 7 or 5 to 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to about 4, 1 to about 3 or 1 to 2 heteroatoms. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 triple bonds.

The term "halo" or "halogen" as used herein includes fluoro, chloro, bromo and iodo.

The term "alkoxy" as used herein is an -O-alkyl group. Exemplary alkoxy groups include methoxy, ethoxy, propoxy (eg n-propoxy and isopropoxy), t-butoxy and the like.

The term "haloalkoxy" as used herein is an -O-haloalkyl group. An exemplary haloalkoxy group is OCF ₃ .

The term "aryloxy" as used herein is -O-aryl.

The term “heteroaryloxy” as used herein is —O-heteroaryl.

The term "cycloalkyloxy" as used herein is -O-cycloalkyl.

As used herein, the term “heterocycloalkyloxy” is —O-heterocycloalkyl.

As used herein, the term "arylalkyl" is alkyl substituted by aryl and "cycloalkylalkyl" is alkyl substituted by cycloalkyl. Exemplary arylalkyl groups are benzyl.

The term "amino" as used herein is NH ₂ .

As used herein, the term "alkylamino" is an amino group substituted by an alkyl group.

As used herein, the term "dialkylamino" is an amino group substituted by two alkyl groups.

The compounds described herein can be asymmetric (eg having one or more stereocenters). Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers. Compounds of the invention comprising asymmetrically substituted carbon atoms can be separated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials are known in the art and are, for example, resolution or stereoselective synthesis of racemic mixtures. Numerous geometrical isomers such as olefins, C═N double bonds and the like may also be present in the compounds described herein, and all such stable isomers are included in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be separated as a mixture of isomers or in separate isomeric forms.

Degradation of the racemic mixture of compounds can be carried out by a number of methods known in the art. Exemplary methods include fractional recrystallization using “chiral resolving acid”, an optically active, salt-forming organic acid. Suitable disintegrating agents for fractional recrystallization methods are, for example, optically active acids, for example tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid in the D and L form, mandelic acid, malic acid, lactic acid or various optically active camphors. Sulfonic acids such as β-camphorsulfonic acid. Other dissociating agents suitable for the fractional crystallization method are α-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, nord in stereoisomerically pure form. Ephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

Degradation of the racemic mixture can also be carried out by eluting on a column packed with an optically active dissolving agent (eg dinitrobenzoylphenylglycine). Suitable elution solvent compositions can be determined by those skilled in the art.

Compounds of the invention also include tautomeric forms, such as keto-enol tautomers.

The compounds of the present invention may also include all isotopes generated from atoms in intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

The phrase “pharmaceutically acceptable” herein is suitable for use in contact with tissues of humans and animals without undue toxicity, irritation, allergic reactions or other problems or complications within the scope of sound medical judgment, and at reasonable benefit / risk ratios. It is used to refer to suitable compounds, materials, compositions and / or dosage forms.

The invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, the term “pharmaceutically acceptable salts” is a derivative of the described compounds, wherein the parent compound is modified by converting the acid or base residue present in its salt form. 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. Pharmaceutically acceptable salts of the present invention include conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of the invention can be synthesized using conventional chemical methods from the parent compound comprising a basic or acidic moiety. In general, such salts can be prepared by reacting the free acid or base form of such a compound with stoichiometric amounts of a suitable base or acid in water or an organic solvent or in a mixture of two organic solvents; In general, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. A list of suitable salts is described in the literature, which is hereby incorporated by reference in its entirety. Remington's Pharmaceutical Sciences , 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science , 66, 2 (1977).

The invention also includes prodrugs of the compounds described herein. As used herein, the term “prodrug” refers to a covalently bonded carrier that releases the active parent drug when administered to a mammalian subject. Prodrugs can be prepared by modifying functional groups present in a compound, in which the modification is broken down to the parent compound in conventional processing or in vivo. Prodrugs are compounds in which a hydroxyl, amino, sulfhydryl or carboxyl group is bonded to any group of compounds and is broken down when administered to a mammalian subject to form a free hydroxyl, amino, sulfhydryl or carboxyl group, respectively. It includes. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention. The preparation and use of prodrugs is described in the literature, see T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the ACS Symposium Series, and in Bioreversible Carriers in Drug Design , ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entirety.

synthesis

The novel compounds of the present invention can be prepared by a variety of methods known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the following methods in combination with methods known in the art of synthesis of synthetic organic chemistry or modifications thereof that will be apparent to those skilled in the art.

The compounds of the present invention can be prepared eluted from the available starting materials using the following general methods and procedures. Usual but preferred process conditions (ie reaction temperature, time, mol ratio of reactants, solvent, pressure, etc.) are provided; It is understood that other process conditions may also be used, unless otherwise noted. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined in a general optimal manner by one skilled in the art.

The methods described herein can be observed according to suitable methods known in the art. For example, product formation may be performed by spectroscopic methods, such as nuclear magnetic resonance spectroscopy (eg ¹ H or ¹³ C), infrared spectroscopy, spectrometer (eg UV-visible line), or mass spectrometer, or Chromatography, for example, can be observed by high performance liquid chromatography (HPLC) or thin layer chromatography.

Preparation of compounds may involve the protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of suitable protection groups can be readily determined by one skilled in the art. Chemistry of protective groups can be found in the literature, which is incorporated herein by reference in its entirety. Greene, et al., Protective Groups in Organic Synthesis, 2d. Ed., Wiley & Sons, 1991].

The reaction of the methods described herein can be carried out in a suitable solvent, which can be readily selected by those skilled in the art of organic synthesis. Suitable solvents may be substantially unreactive at the temperature at which the reaction is carried out with the starting materials (reactants), intermediates or products. That is, the temperature may range from the cooling temperature of the solvent to the boiling point of the solvent. A given reaction can be carried out in one solvent or a mixture of one or more solvents. Depending on the specific reaction step, a suitable solvent for the particular reaction step can be selected.

The compounds of the present invention can be prepared, for example, using the following reaction routes and methods.

A series of piperidine-3-carboxamides of Formula 4 are prepared by the method described in Scheme 1. 1- (tert-butoxycarbonyl) piperidine-3-carboxylic acid (1) to an amine R ^N QNH wherein Q can be cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, etc., R ^N May be coupled using a coupling reagent such as BOP with various substituents such as H, (C _3-7 cycloalkyl) alkyl, etc.) to obtain the desired product (2). The Boc protecting group (2) was removed with TFA in methylene chloride to give the amino salt (3), which was subjected to various acyl halide CyC (O) Cl, chloroformate CyOC (O) Cl or sulfonyl chloride CySO ₂ Cl, , Cy is directly coupled to a cyclic moiety such as aryl to afford the final compound of formula 4. A series of ureas of Formula 4 'is used to convert piperidine derivatives (3) to the corresponding isocyanates Cy (R ^g ) N = C = O or the corresponding amine carbonyl chloride Cy (R ^g ) NHC (O) Cl Can be prepared under treatment. Alternatively, a series of ureas of formula 4 'is treated with piperidine derivative 3 with p-nitrophenyl chloroformate in the presence of a base to form an activated carbamate species 3', which is suitable for amines. It can be prepared by subsequent reaction with R ^g NHCy.

A series of piperidine-3-carboxamides of Formula 5 are prepared by the method described in Scheme 2. Treatment of ethyl piperidine-3-carboxylate (6) with (Boc) ₂ O affords Boc-protected compound (7). Compound (7) was then treated with LiHMDS and organo halide R ³ X where X is halo and R ³ is C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, cyclo Alkyl, heterocycloalkyl, arylalkyl, etc.) to obtain the coupling product (8). Directly converts the ethyl ester (8) to the corresponding amide (9), wherein Q can be cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, etc., and R ^N can be a variety of substituents, for example H , (C _3-7 cycloalkyl) alkyl and the like). The Boc group of formula (9) was removed with TFA to give a TFA salt (10), which was converted to various acyl halides CyC (O) Cl, chloroformate CyOC (O) Cl or sulfonyl chloride CySO ₂ Cl, where Cy is Coupling with a click moiety, such as aryl, to give the desired coupling product 5. In the series of ureas of Formula 5 ', the piperidine derivative (10) is substituted with the corresponding isocyanate Cy (R ^g ) N = C = O or the corresponding amine carbonyl chloride Cy (R ^g ) NHC (O) Cl Can be prepared under treatment. Alternatively, a series of ureas of Formula 5 'is treated with piperidine derivative 10 with p-nitrophenyl chloroformate in the presence of a base to form an activated carbamate species 10', which is a suitable amine It can be prepared by subsequent reaction with R ^g NHCy.

Primary amines of formula 11 can be prepared from suitable cyclic ketones 12 under the various protocols shown in Scheme 3, wherein R ^x is, for example, H, halo, alkyl, haloalkyl, cycloalkyl, aryl , Heteroaryl, and the like; X is CH ₂ , O, S, SO ₂ , NH, N-alkyl, N-Boc, and the like; p is 1 or 2; n is 1 or 2).

Alternatively, the primary amine 11 is mesylated from a suitable alcohol 13 as described in Scheme 4, after which the mesylate 14 is converted to the corresponding azide 15 and reduced to the desired Primary amine 11 can be obtained, wherein R ^x , X, n and p are as defined in Scheme 3.

Suitable cyclic amines (11) as described in Scheme 5 can be prepared by using a suitable aldehyde R ¹ CHO, wherein R ¹ is H, C _1-10 alkyl, C _2-10 alkenyl, aryl, hetero Aryl, arylalkyl, and the like), wherein R ^x , X, n and p are as defined in Scheme 3.

Carboxamides of Formula 18 may be prepared using BOP or other suitable coupling agent as described in Scheme 6, wherein X, R ^x , n and p are as defined in Scheme 3; R ^P Is an H or amino protecting group).

Primary amines of formula 23 and secondary amines of formula 20 can be prepared according to the methods described in Scheme 7. Suitable bromide, for example compound 21, wherein A can be alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, etc., R ² is alkyl, haloalkyl, cycloalkyl , Cycloalkylalkyl, etc.) can be converted first to the corresponding azide 22 and then through hydrogenation to the desired primary amine 23. Finally, a suitable aldehyde R ¹ CHO wherein R ¹ may be H, C _1-10 alkyl, C _2-10 alkenyl, aryl, heteroaryl, arylalkyl, etc. To obtain a secondary amine.

Primary amines 24 and secondary amines 25 can be prepared according to the methods described in Scheme 8, wherein R ⁱⁱⁱ and R ^iv are, for example, halo, alkyl, haloalkyl, OH, alkoxy, Aryl, heteroaryl, and the like). Substituted indole 26 is reacted with Fmoc protected amino acid chloride 27 where R ^vi is, for example, H, halo, alkyl, haloalkyl, OH, alkoxy, aryl, heteroaryl, and the like. Compound (28) is obtained, after which the Fmoc group is digested with piperidine in DMF. Reduction of the carbonyl group of formula 28 with NaBH ₄ affords compound 24, wherein a suitable aldehyde R ¹ CHO, wherein R ¹ is H, C _1-10 alkyl, C _2-10 alkenyl, aryl, heteroaryl , Arylalkyl, etc.) to obtain compound (25) under reductive amination conditions.

A series of piperidine-3-carboxamides of Formula 29 can be prepared by the method described in Scheme 9. Piperidine-3-carboxamide (10) is a compound of the formula ArX wherein X can be a leaving group such as halo and Ar can be a cyclic moiety such as aryl or heteroaryl And Ar may be optionally substituted by one or more suitable substituents such as alkyl, alkoxy, etc.), for example bromobenzene, in a solvent such as dimethyl sulfoxide, for example Coupling in the presence of tert-butoxide yields the compound of formula 29. Alternatively, the coupling reaction is carried out under palladium catalyzed conditions, for example Hartwig conditions.

Way

Compounds of the invention can modulate the activity of 11-β-HSD1 and / or MR. The term "regulation" refers to the ability to increase or decrease the activity of an enzyme or receptor. Accordingly, the compounds of the present invention can be used in methods of modulating 11-β-HSD1 and / or MR by contacting enzymes or receptors with one or more compounds or compositions described herein. In some embodiments, the compounds of the present invention may act as inhibitors of 11-β-HSD1 and / or MR. In a further aspect, the compounds of the present invention can be used to modulate the activity of 11-β-HSD1 and / or MR by administering to the subject in need of control of an enzyme or receptor, a controlled amount of a compound of the invention.

The present invention further provides a method of inhibiting the conversion of cortisone to cortisol in a cell or a method of inhibiting the production of cortisol in a cell, wherein the conversion or production of cortisol at least partially mediates 11-β-HSD1 activity. do. Methods of measuring the rate of conversion of cortisone to cortisol and vice versa, as well as methods of measuring the levels of cortisone and cortisol in cells are common in the art.

The invention further provides a method of increasing the insulin sensitivity of a cell by contacting the cell with a compound of the invention. Insulin sensitivity measurement methods are conventional in the art.

The invention further provides an abnormality of 11-β-HSD1 and / or MR in a subject (eg, a patient) by administering to the subject in need thereof a therapeutically effective amount or dosage of a compound of the invention or a pharmaceutical composition thereof. Methods of treating diseases associated with activity or expression, including activity and overexpression, are provided. Exemplary diseases may include diseases, diseases or conditions that are directly or indirectly related to the expression or activity of an enzyme or receptor. 11-β-HSD1-associated diseases may also include diseases, diseases or conditions that can be prevented, ameliorated or treated by modulating enzyme activity. MR-related diseases may also include diseases, diseases or conditions that can be prevented, ameliorated or treated by modulating receptor activity or binding to receptors of endogenous ligands.

Examples of 11-β-HSD1-associated diseases include obesity, diabetes, glucose intolerance, insulin resistance, hyperglycemia, hypertension, hyperlipidemia, cognitive impairment, dementia, depression, glaucoma, cardiovascular disease, osteoporosis and inflammation. Further examples of 11-β-HSD1-associated diseases include metabolic syndrome, type 2 diabetes, androgen excess (hirsutism, dysmenorrhea, hyperandrogenosis) and polycystic ovary syndrome (PCOS).

The invention further provides a method of modulating MR activity by contacting MR with a compound of the invention, a pharmaceutically acceptable salt, prodrug or composition thereof. In some embodiments, the regulation can be inhibition. In a further aspect, a method of inhibiting the binding of aldosterone to MR (optionally in a cell) is provided. Methods of measuring MR activity and measuring inhibition of aldosterone binding are common in the art.

The invention further provides a method of treating a disease related to the activity or expression of MR. Examples of diseases related to the activity or expression of MR include, but are not limited to, hypertension, as well as cardiovascular, kidney, and inflammatory pathological diseases such as heart failure, atherosclerosis, arteriosclerosis, coronary artery disease, thrombosis , Angena, peripheral vascular disease, vascular wall damage, stroke, dyslipidemia, hyperlipoproteinemia, diabetes dyslipidemia, mixed dyslipidemia, hypercholesterolemia, hypertriglyceridemia, and type 1 diabetes 2 diabetes, obesity metabolic syndrome, insulin resistance and diseases associated with common aldosterone-related target organ damage.

As used herein, the term "cell" refers to a cell that is in vitro, ex vivo or in vivo. In some embodiments, the ex vivo cell may be part of a tissue sample incised from an organism, eg, a mammal. In some embodiments, the in vitro cells can be cells in cell culture. In some embodiments, the cell in vivo is a living cell in an organism, eg, a mammal. In some embodiments, the cell is an adipocyte, pancreatic cell, hepatocyte, neuron or cell including the eye.

As used herein, the term “contacting” means bringing together the residues described in an in vitro system or an in vivo system. For example, “contacting” an 11-β-HSD1 enzyme with a compound of the present invention not only administers a compound of the present invention having 11-β-HSD1 to an individual or patient, eg, a human, eg, For example, the method includes introducing a purified formulation comprising 11-β-HSD1 enzyme into a sample comprising cells.

As used herein, the term “individual” or “patient” is used interchangeably and includes mammals, preferably mice, rats, other rodents, rabbits, dogs, cows, pigs, cattle, sheep, horses or primates, most Preferably it is a person.

As used herein, the phrase “therapeutically effective amount” refers to an active compound that induces a biological or medical response sought by a researcher, veterinarian, physician or other clinician in a tissue, system, animal, individual or person comprising one or more of the following: The amount of pharmaceutical agent is:

(1) prevention of disease; For example, prevention of a disease, condition or disease in a subject who is susceptible to a disease, condition or illness but has not yet experienced or exhibited the pathology or symptom of the disease (non-limiting examples include metabolic syndrome, hypertension, obesity, insulin resistance, Hyperglycemia, hyperlipidemia, type 2 diabetes, hyperandrogenosis (hyperthyroidism, dysmenorrhea, hyperandrogenosis) and polycystic ovary syndrome (PCOS) are prevented);

(2) inhibition of disease; For example, inhibition of a disease, condition or disease (ie, the inhibition of further development of pathology and / or symptom) in an individual who is still experiencing or exhibiting the pathology or symptom of the disease, condition or disease, for example metabolic syndrome , Stabilization of viral load in case of hypertension, obesity, insulin resistance, hyperglycemia, hyperlipidemia, type 2 diabetes, hyperandrogenosis (hirsutism, dysmenorrhea, hyperandrogenosis) or polycystic ovary syndrome (PCOS), or viral infection ; And

(3) amelioration of the disease; For example, amelioration (ie, reversal of pathology and / or symptomology) of a disease, condition or condition in an individual who is still experiencing or exhibiting the pathology or symptom of the disease, condition or disease, for example metabolic syndrome, hypertension, obesity , Decreased insulin severity, hyperglycemia, hyperlipidemia, type 2 diabetes, hyperandrogenosis (hirsutism, dysmenorrhea, hyperandrogenosis) and polycystic ovary syndrome (PCOS), or decreased viral load in the case of viral infection.

Pharmaceutical Formulations and Dosage Forms

When used as a medicament, the compound of formula I can be administered in the form of a pharmaceutical composition. These compositions can be prepared by methods known in the pharmaceutical art and can be administered by a variety of routes depending on whether topical or systemic treatment is desired and on the area to be treated. Administration may be topical (including the eye and mucous membranes including intranasal, vaginal and rectal delivery), lungs (e.g., inhalation or aeration of powders or aerosols including sprays; intratracheal, nasal, epidermal and transdermal), eyes It may be oral or parenteral. Eye delivery methods can include topical administration (eye drop), introduction by subconjunctival, peri-eye or intravitreal injection or by eye implants surgically placed in a balloon catheter or conjunctival sac. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; Or intracranial, for example intradural or intraventricular administration. Parenteral administration may be in the form of a single mass administration or may be administered, for example, with a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, solutions and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

The present invention also includes pharmaceutical compositions, which comprise, as active ingredient, one or more of the compounds of the present invention in combination with one or more pharmaceutically acceptable carriers. When preparing the compositions of the present invention, the active ingredient is usually mixed with excipients and diluted with excipients or enclosed in such carriers, for example in the form of capsules, sachets, paper or other containers. When an excipient is used as a diluent, it may be a solid, semisolid or liquid substance, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the composition may comprise tablets, pills, powders, lozenges, sachets, cathay, elixirs, suspensions, emulsions, solvents, syrups, aerosols (solid or in a liquid medium), ointments (e.g., 10% by weight of the active compound) In the form of soft or hard gelatin capsules, suppositories, sterile injectables and sterile packed powders.

In preparing the formulations, the active compound may be ground to a suitable particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it may be ground to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size may be adjusted by milling to produce a substantially uniform dispersion (eg, about 40 mesh) in the formulation.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, Cellulose, water, syrup and methyl cellulose. The formulation may further comprise lubricants such as talc, magnesium stearate and mineral oil; Wetting agents; Emulsifying and suspending agents; Preservatives such as methyl- and propylhydroxy-benzoate; Sweeteners; And flavoring agents. The compositions of the present invention may be formulated to provide a patient with a rapid, sustained or prolonged release of the active ingredient after administration using methods known in the art.

The compositions may be formulated in unit dosage forms, each dosage containing about 5 to about 100 mg, more typically about 10 to about 30 mg of the active ingredient. The term “unit dosage form” is a physically discrete unit suitable for unit administration to human subjects and other mammals, each unit having a predetermined amount of a calculated amount to provide the desired therapeutic effect in connection with a suitable pharmaceutical excipient. Suitable active materials.

The active compounds can be effective over a wide range of dosages and are generally administered in pharmaceutically effective amounts. However, the amount of compound actually administered can usually be determined depending on the conditions to be treated by the physician, the route of administration chosen, the actual compound administered, age, weight and individual patient's response, the severity of the patient's symptoms, and the like.

 To prepare a solid composition, such as a tablet, the main active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition comprising a homogeneous mixture of the compounds of the invention. When referring to a preformulation composition as homogeneous, the active ingredient is usually dispersed completely in the composition so that the composition can be readily separated into equal amounts of effective unit dosage forms, such as tablets, pills and capsules. Such solid preformulations are separated, for example, in unit dosage forms of the form described above comprising from 0.1 to about 500 mg of the active ingredient of the invention.

Tablets or pills of the invention may be coated or otherwise synthesized to provide dosage forms that provide benefits with extended activity. For example, tablets or pills may include internal dosage form and external dosage form components, the latter being in the form encapsulated in the former. The two components can be separated into an intestinal layer that inhibits degradation in the stomach and allows internal components to pass through or delay release without damage to the intestine. Various materials can be used as such intestinal layers or coatings, and such materials include a plurality of polymer acids and mixtures of polymer acids together with shellac, cetyl alcohol and cellulose acetate.

Liquid forms into which the compounds and compositions of the present invention may be introduced for oral administration or injection may comprise aqueous solutions, suitable flavor syrups, aqueous or oily suspensions and flavor emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil. As well as elixirs and similar pharmaceutical vehicles.

 Inhalation or aeration compositions include solutions and suspensions, and powders in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof. Liquid or solid compositions may comprise suitable pharmaceutically acceptable excipients as described above. In some embodiments, the composition is administered for local or systemic effects by the oral or nasal breathing route. The composition can be sprayed using an inert gas. The sprayed solution can breathe directly from the spraying device, or the spraying device can be attached with a face mask tent or an intermittent positive pressure breathing machine. Solutions, suspensions or powder compositions may be administered from a device that delivers the formulation orally or nasal in a suitable manner.

The amount of compound or composition administered to a patient may vary depending on the substance to be administered, the purpose of administration, such as prevention or treatment, the condition of the patient, the method of administration, and the like. In therapeutic applications, the composition may be administered to a patient already suffering from the disease in an amount sufficient to at least partially treat or arrest the symptoms of the disease and its complications. Effective dosages may depend upon the judgment of the attending physician, as well as the disease state being treated, depending on factors such as the severity of the disease, the age, weight and general conditions of the patient.

The composition administered to the patient may be in the form of a pharmaceutical composition described above. These compositions may be sterilized by conventional sterilization techniques or may be sterile filtered. The aqueous solution may be packed for use or lyophilized and the lyophilized formulation may be combined with a sterile aqueous carrier prior to administration. The pH of the compound formulation can typically be 3-11, more preferably 5-9, most preferably 7-8. It is understood that the particular use of such excipients, carriers or stabilizers may form pharmaceutical salts.

The therapeutic dosage of a compound of the present invention may vary, for example, depending on the particular method of treatment, the method of administering the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the present invention in a pharmaceutical composition can vary depending on a number of factors, including dosage, chemical properties (eg, hydrophobicity), and route of administration. For example, the compounds of the present invention can be prepared in physiological aqueous buffer solution comprising about 0.1 to about 10% w / v of the compound by parenteral administration. Some typical dosage ranges are from about 1 μg / kg body weight to about 1 g / kg body weight per day. In some embodiments, the dosage range is about 0.01 mg / kg body weight to about 100 mg / kg body weight per day. Dosages tend to depend on such variables as the form and extent of the disease or condition, the general health of the particular patient, the relative biological potency of the selected compound, the formulation of the excipient and the route of administration thereof. Effective dosages may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

The compounds of the present invention may also be formulated in combination with one or more additional active ingredients which may include pharmaceutical agents, such as anti-viral agents, antibodies, immunosuppressive agents, anti-inflammatory agents, and the like. Exemplary agents that can be co-administered (eg, administered simultaneously, separately or sequentially) include insulin and insulin homologues; Sulfonylureas (e.g., glycbenclamide or glyphidide), dietary glucose modulators (e.g., repaglinide or nateglinide), glucagon-like peptide 1 agonists (GLP1 agonists) (e.g., Insulin secretagogues, including exenatide or liraglutide) and dipeptidyl peptidase IV inhibitors (DPP-IV inhibitors); Insulin sensitive agents (eg, pioglitazone or rosiglitazone) including PPARγ agonists; Agents that inhibit hepatic glucose production (eg, metformin); Agents intended to reduce glucose absorption from the intestine (eg acarbose); Agents intended to treat complications of prolonged hyperglycemia (eg, aldose reductatase inhibitors); Anti-diabetic agents including phosphotyrosine phosphatase inhibitors, glucose 6-phosphatase inhibitors, glucagon receptor antagonists, glucokinase activators, glycogen phosphorylase inhibitors, fructose 1,6-bisphosphatase inhibitors and glutamine: fructose- 6-phosphate amidotransferase inhibitors; Anti-obesity agents (eg sibutramine or orlistat); Anti-dyslipidemic agents (eg, statin-like pravastatin), including HMG-CoA reductase inhibitors, PPARα agonists (eg, fibrate-like gemfibrozil), bile acid separation agents (eg, kohl) Restyramine), cholesterol absorption inhibitors (eg, plant stanol or synthetic inhibitors), ileal bile acid absorption inhibitors (IBATi), cholesterol ester transfer protein inhibitors, nicotinic acid and analogs thereof (eg, niacin); antihypertensive agents (e.g. atenolol or inderal) containing β blockers, ACE inhibitors (e.g. ricinopril), calcium antagonists (e.g. nifedipine), angiotensin receptor antagonists (e.g. , Candesartan), α antagonists, diuretics (eg furosemide or benzthiazide); Antithrombotic agents, fibrinolytic activators, thrombin antagonists, factor Xa inhibitors, factor VIIa inhibitors, antiplatelet agents (e.g. aspirin or clopidogrel), anticoagulants (e.g. heparin, hirudin, homologues thereof) and warfarin Hemostatic regulators, including; And anti-inflammatory agents including non-steroidal anti-inflammatory drugs (eg aspirin) and steroidal anti-inflammatory drugs (eg cortisone).

Labeled Compounds and Assay Methods

Other aspects of the invention are not only useful for radio-imaging, but also for localizing and quantifying enzymes in tissue samples including humans in in vitro and in vivo assays, and for identifying ligands by inhibitory binding of radiolabeled compounds. It relates to a radiolabeled compound of the invention. Accordingly, the present invention includes enzyme assays comprising such radio-labeled compounds.

The present invention further includes isotope-labeled compounds of the invention. An “isotope” or “radiation-labeled” compound is a compound of the present invention, wherein one or more atoms are typically nuclear reactors having an atomic mass or mass number different from the atomic mass or mass number found in nature (ie, naturally occurring). Replaced or substituted. Suitable radionuclides that can be incorporated into the compounds of the present invention include, but are not limited to, ² H (also described as D as deuterium), ³ H (also described as T as tritium), ¹¹ C, ¹³ C , ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ¹⁸ F, ³⁵ S, ³⁶ Cl, ⁸² Br, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I and ¹³¹ Contains I Radionuclides that are immediately introduced into a radio-labeled compound may depend on the particular application of such radio-labeled compound. For example, in in vitro receptor labeling and competition assays, compounds introducing ³ H, ¹⁴ C, ⁸² Br, ¹²⁵ I, ¹³¹ I or ³⁵ S may generally be most useful. For radio-image applications, ¹¹ C, ¹⁸ F, ¹²⁵ I, ¹²³ I, ¹²⁴ I, ¹³¹ I, ⁷⁵ Br, ⁷⁶ Br or ⁷⁷ Br may generally be most useful.

A "radiolabeled" or "labeled compound" is understood to be a compound that introduces one or more radionuclides. In some embodiments, the radionuclide is selected from the group consisting of ³ H, ¹⁴ C, ¹²⁵ I, ³⁵ S and ⁸² Br.

Synthetic methods for introducing radio-isotopes into organic compounds are applied to the compounds of the present invention and are known in the art.

Radiation-labeled compounds of the invention can be used in screening assays to identify / evaluate compounds. In general terms, newly synthesized or identified compounds (ie, test compounds) can assess the ability to reduce the binding of the radiation-labeled compounds of the invention to enzymes. Thus, the ability of a test compound to compete for binding to an enzyme with a radiolabeled compound is directly related to binding affinity.

Kit

The present invention also includes pharmaceutical kits useful for the treatment or prevention of 11-β-HSD1-associated diseases or disorders, obesity, diabetes mellitus and other diseases related herein, comprising: a medicament comprising a therapeutically effective amount of a compound of the invention One or more containers containing a pharmaceutical composition. Such kits may further include, optionally, one or more of various conventional pharmaceutical kit components, such as containers with one or more pharmaceutically acceptable carriers, additional containers, and the like, It is obvious to the skilled person. Instructions such as inserts or labels indicative of the amount of ingredient administered, instructions for administration, and / or instructions for mixing ingredients may also be included in the kit.

The invention may be described in more detail by way of specific examples. The following examples are provided for illustrative purposes and are not intended to limit the invention in this way. Those skilled in the art can readily recognize various non-critical parameters that are altered or modified to achieve essentially the same results. Compounds in the example portion were found as inhibitors or antagonists of 11-β-HSD1 or MR according to one or more assays provided herein.

Example 1

N-cyclohexyl-1-[(2-nitrophenyl) sulfonyl] piperidine-3-carboxamide

Step 1.

NN-diiso in a solution of 1- (tert-butoxycarbonyl) piperidine-3-carboxylic acid (69 mg, 0.3 mmol), cyclohexanamine (30 mg, 0.3) and BOP (140 mg) in 1.0 mL of methylene chloride 68.5 μl of propylethylamine was added. The reaction mixture was stirred at rt overnight and directly purified by combi-flash eluting with EtOAc / hexanes to afford 70 mg of the desired product.

Step 2.

5 mL of TFA was added to a solution of tert-butyl 3- (cyclohexylcarbamoyl) piperidine-1-carboxylate (70 mg) in 4.5 mL of methylene chloride and 0.5 mL of water. The reaction mixture was stirred at rt for 50 min and concentrated under reduced pressure to give a residue.

Step 3.

In a solution of 2-nitrobenzene-1-sulfonyl chloride (12.3 mg) and N-cyclohexylpiperidine-3-carboxamide (TFA salt, 18 mg) from step 2 in triethylamine ( 19.3 μl) was added. The reaction mixture was stirred at rt for 2 h and purified directly by HPLC to give 13.2 mg of the desired product. LCMS: m / z 396.1 (M + H) < + >; 813.3 (2M + Na) < + >.

Example 2

N-cyclohexyl-1- (phenylsulfonyl) piperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 1. LCMS: m / z 351.1 (M + H) < + >; 373.0 (M + Na) < + >; 723.2 (2M + Na) < + >.

Example 3

N-cyclohexyl-N-cyclopropyl-1- (phenylsulfonyl) piperidine-3-carboxamide

Step 1.

0.409 mL of benzenesulfonyl chloride was added to a solution of benzyl piperidine-3-carboxylate (TFA salt, 1.5 g) and potassium carbonate (2.2 g) in 10 mL acetonitrile. The reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine and dried over Na ₂ SO ₄ . After filtration, the filtrate was concentrated to give a residue.

Step 2.

The residue from step 1 was hydrogenated using Pd / C as catalyst.

Step 3.

1- (phenylsulfonyl) piperidine-3-carboxylic acid (20 mg), N-cyclopropylcyclohexanamine (10 mg) and benzotriazol-1-yloxytris (dimethylamino) -force in DMF (200 μl) N, N-diisopropylethylamine (26 μl) was added to a solution of phonium hexafulophosphate (36 mg). The resulting solution was stirred for 2 h at room temperature and directly purified by preparative HPLC. LCMS m / z 391.1 (M + H) < + >; 803.2 (2M + Na) < + >.

Example 4

N-cyclopentyl-1- (phenylsulfonyl) piperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 1. LCMS: m / z 337.1 (M + H) < + >; 359.0 (M + Na) < + >; 695.2 (2M + Na) < + >.

Example 5

N-[(1R) -1-phenylethyl] -1- (phenylsulfonyl) piperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 1. LCMS: m / z 373.1 (M + H) < + >; 395.0 (M + Na) < + >; 767.5 (2M + Na) < + >.

Example 6

N- (1-methyl-3-phenylpropyl) -1- (phenylsulfonyl) piperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 1. LCMS: m / z 401.0 (M + H) < + >; 423.1 (M + Na) < + >.

Example 7

N- (4-hydroxycyclohexyl) -1- (phenylsulfonyl) piperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 1. LCMS: m / z 367.0 (M + H) < + >; 755.0 (2M + Na) < + >.

Example 8

(3R) -N- (4-hydroxycyclohexyl) -1- (phenylsulfonyl) piperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 1. LCMS: m / z 367.1 (M + H) < + >; 755.2 (M + Na) < + >.

Example 9

1-[(4-chlorophenyl) sulfonyl] -N-cyclohexylpiperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 1. LCMS: 385.1 (M + H) < + >; 387.1 (M + Na) < + >; 791.2 (2M + Na) +

Example 10

1-[(5-chloro-2-fluorophenyl) sulfonyl] -N-cyclohexylpiperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 1. LCMS: m / z 403.1 (M + H) < + >; 425.1 (M + Na) < + >; 827.2 (2M + Na) < + >.

Example 11

1-[(3-chlorophenyl) sulfonyl] -N-cyclohexylpiperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 1. LCMS: m / z 385.1 (M + H) < + >; 791.2 (2M + Na) < + >.

Example 12

N-cyclohexyl-1-[(2-fluorophenyl) sulfonyl] piperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 1. LCMS: m / z 369.1 (M + H) < + >; 391.1 (M + Na) < + >; 759.2 (2M + Na) < + >.

Example 13

1-[(3-chloro-2-methylphenyl) sulfonyl] -N-cyclohexylpiperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 1. LCMS: m / z 399.1 (M + H) < + >; 819.2 (2M + Na) < + >.

Example 14

N-cyclohexyl-1-{[2- (trifluoromethyl) phenyl] sulfonyl} piperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 1. LCMS: m / z 419.1 (M + H) < + >; 441.1 (M + Na) < + >; 859.3 (2M + Na) < + >.

Example 15

(3S) -N-cyclohexyl-1-[(2-fluorophenyl) sulfonyl] piperidine-3-carboxamide

This compound was prepared according to the method described in Example 1 starting from (3S) -1- (tert-butoxycarbonyl) piperidine-3-carboxylic acid. LCMS: m / z 369.1 (M + H) +

Example 16

(3S) -N-cyclohexyl-1-[(2-methylphenyl) sulfonyl] piperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 365.1 (M + H) +

Example 17

(3S) -N-cyclohexyl-1-[(4-fluoro-2-methylphenyl) sulfonyl] piperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 383.1 (M + H) < + >

Example 18

(3S) -1-[(2-chlorophenyl) sulfonyl] -N-cyclohexylpiperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 385.1 (M + H) < + >

Example 19

(3S) -N-cyclohexyl-1-[(2,6-difluorophenyl) sulfonyl] piperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 387.1 (M + H) < + >

Example 20

(3S) -1-[(3-chloro-4-fluorophenyl) sulfonyl] -N-cyclohexylpiperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 403.1 (M + H) < + >

Example 21

(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] -N-cyclohexylpiperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 399.1 (M + H) +

Example 22

(3S) -1-[(5-chloro-2-fluorophenyl) sulfonyl] -N-cyclohexylpiperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 403.1 (M + H) < + >

Example 23

(3S) -1-[(3-chlorophenyl) sulfonyl] -N-cyclohexylpiperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 385.1 (M + H) < + >

Example 24

(3S) -1-[(3-chloro-2-fluorophenyl) sulfonyl] -N-cyclohexylpiperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 403.1 (M + H) < + >.

Example 25

N-[(1S) -1-phenylethyl] -1- (phenylsulfonyl) piperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 1. LCMS: m / z 373.0 (M + H) < + >; 395.0 (M + Na) < + >.

Example 27

(3S) -N-cyclohexyl-1- (pyridin-3-ylsulfonyl) piperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 352.1 (M + H) < + >; 725.3 (2M + Na).

Example 28

(3S) -N-cyclohexyl-1-[(3-phenoxyphenyl) sulfonyl] piperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 443.2 (M + H) < + >.

Example 29

(3S) -1-[(2-cyanophenyl) sulfonyl] -N-cyclohexylpiperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 376.1 (M + H) < + >; 773.2 (2M + Na) < + >.

Example 30

(3S) -N-cyclohexyl-1-[(2-phenoxyphenyl) sulfonyl] piperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 443.2 (M + H) < + >.

Example 31

(3S) -N-cyclohexyl-1-{[3- (pyridin-4-yloxy) phenyl] sulfonyl} piperidine-3-carboxamide trifluoroacetate

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 444.1 (M + H) < + >; 466.1 (M + Na) < + >.

Example 32

(3S) -N-cyclohexyl-1-[(4-phenoxypyridin-3-yl) sulfonyl] piperidine-3-carboxamide trifluoroacetate

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 444.1 (M + H) < + >.

Example 33

(3S) -N-cyclohexyl-1-{[3- (2-methylphenoxy) phenyl] sulfonyl} piperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 457.1 (M + H) < + >.

Example 34

(3S) -1-{[3- (2-chlorophenoxy) phenyl] sulfonyl} -N-cyclohexylpiperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 477.1 (M + H) < + >.

Example 35

(3S) -1-{[3- (4-chlorophenoxy) phenyl] sulfonyl} -N-cyclohexylpiperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 477.1 (M + H) < + >.

Example 36

(3S) -N-cyclohexyl-1-[(3-methoxyphenyl) sulfonyl] piperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 381.1 (M + H) < + >; 783.3 (2M + Na) < + >.

Example 37

(3S) -1-[(3-chloro-4-fluorophenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 419.0 (M + H) < + >; 441.1 (M + Na) < + >.

Example 38

(3S) -1-[(2,6-difluorophenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 403.1 (M + H) < + >; 425.1 (M + Na) < + >; 827.2 (2M + Na) < + >.

Example 39

(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 415.0 (M + H) < + >; 851.2 (2M + Na) < + >.

Example 40

(3S) -1-[(2-fluorophenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 385.1 (M + H) < + >; 791.3 (2M + Na) < + >.

Example 41

(3S) -1-[(5-chloro-2-fluorophenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 419.1 (M + H) < + >; 859.2 (2M + Na) < + >.

Example 42

(3S) -1-[(3-chlorophenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 401.0 (M + H) < + >; 823.2 (2M + Na) < + >.

Example 43

(3S) -1-[(3-chloro-2-fluorophenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 419.1 (M + H) < + >.

Example 44

(3S) -N- (trans-4-hydroxycyclohexyl) -1-[(2-methylphenyl) sulfonyl] piperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 381.1 (M + H) < + >; 783.3 (2M + Na) < + >.

Example 45

(3S) -1-[(4-fluoro-2-methylphenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 399.1 (M + H) < + >; 819.3 (2M + Na) < + >.

Example 46

(3S) -1-[(2-chlorophenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 401.0 (M + H) < + >; 823.2 (2M + Na) < + >.

Example 47

(3S) -1-[(2-cyanophenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 392.1 (M + H) < + >; 414.0 (M + Na) < + >.

Example 48

(3S) -N- (trans-4-hydroxycyclohexyl) -1-[(3-phenoxyphenyl) sulfonyl] piperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 459.1 (M + H) < + >.

Example 49

(3S) -N- (trans-4-hydroxycyclohexyl) -1-{[4- (pyridin-3-yloxy) phenyl] sulfonyl} piperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 460.1 (M + H) < + >.

Example 50

(3S) -N- (trans-4-hydroxycyclohexyl) -1-{[3- (2-methylphenoxy) phenyl] sulfonyl} -piperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 473.2 (M + H) < + >.

Example 51

(3S) -1-{[3- (2-chlorophenoxy) phenyl] sulfonyl} -N- (trans-4-hydroxycyclohexyl) -piperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 493.1 (M + H) < + >.

Example 52

(3S) -N- (trans-4-hydroxycyclohexyl) -1-[(2-methoxyphenyl) sulfonyl] piperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 397.2 (M + H) < + >; 815.3 (2M + Na) < + >.

Example 53

(3S) -N- (trans-4-hydroxycyclohexyl) -1-[(2-phenoxyphenyl) sulfonyl] piperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 459.1 (M + H) < + >.

Example 54

(3S) -N- (trans-4-hydroxycyclohexyl) -1-[(6-phenoxypyridin-3-yl) sulfonyl] piperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 460.1 (M + H) < + >.

Example 55

(3S) -N- (trans-4-hydroxycyclohexyl) -1-[(3-isopropylphenyl) sulfonyl] piperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 409.2 (M + H) < + >; 839.4 (2M + Na) < + >.

Example 56

(3S) -1-[(3,4-dimethoxyphenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 427.1 (M + H) < + >.

Example 57

(3S) -N- (trans-4-hydroxycyclohexyl) -1-[(2-nitrophenyl) sulfonyl] piperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 412.1 (M + H) < + >; 845.2 (2M + Na) < + >.

Example 58

(3S) -N-cyclopentyl-1- (phenylsulfonyl) piperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 337.1 (M + H) < + >.

Example 59

(3S) -N-cyclopentyl-1-[(2,6-difluorophenyl) sulfonyl] piperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 373.1 (M + H) < + >.

Example 60

(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] -N-cyclopentylpiperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 385.1 (M + H) < + >.

Example 61

(3S) -1-[(3-chlorophenyl) sulfonyl] -N-cyclopentylpiperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 371.1 (M + H) < + >; 763.1 (2M + Na) < + >.

Example 62

(3S) -N- [trans-4- (acetylamino) cyclohexyl] -1- (phenylsulfonyl) piperidine-3-carboxamide

Step 1.

At room temperature, add a solution of acetyl chloride (16.4 μl, 0.23 mmol) in acetonitrile (0.3 mL) to a solution of trans-cyclohexane-1,4-diamine (0.0261 g, 0.23 mmol) in acetonitrile (0.2 mL) And diisopropylethylamine were added slowly. The mixture was stirred at rt for 30 min.

Step 2.

To the mixture was added (3S) -1- (tert-butoxycarbonyl) piperidine-3-carboxylic acid (50 mg, 0.22 mmol) and benzotriazol-1-yloxytris (dimethyl) in acetonitrile (0.5 mL). A mixture of amino) phosphonium hexafulophosphate (101 mg, 0.23 mmol) was added slowly at room temperature with stirring, and diisopropylethylamine (55 μl) was added. After stirring for 2 hours at room temperature, the reaction mixture was concentrated. The residue was used in the next step.

Step 3.

The residue from step 2 in 4N HCl solution in dioxane (1.5 mL) was stirred at rt for 1 h. After removing the solvent, the residue was used in the next step.

Step 4.

A mixture of the residue, K ₂ CO ₃ (90 mg, 0.65 mmol) and benzenesulfonyl chloride (41.7 μl, 0.33 mmol) obtained from step 3 in acetonitrile (0.3 mL) was stirred overnight at room temperature. 5.1 mg (5.7%) of final product was obtained after purification by preparative HPLC. LCMS: m / z 408.1 (M + H) < + >.

Example 63

(3S) -N- {trans-4-[(methylsulfonyl) amino] cyclohexyl} -1- (phenylsulfonyl) piperidine-3-carboxamide

This compound was prepared according to a method analogous to Example 63. LCMS: m / z 444.1 (M + H) < + >; 466.0 (M + Na) < + >.

Example 64

Methyl [trans-4-({[(3S) -1- (phenylsulfonyl) piperidin-3-yl] carbonyl} amino) cyclohexyl] carbamate

This compound was prepared according to a method analogous to Example 63. LCMS: m / z 424.1 (M + H) < + >; 446.1 (M + Na) < + >.

Example 65

(3S) -N- (3-hydroxycyclohexyl) -1- (phenylsulfonyl) piperidine-3-carboxamide

This compound was prepared according to a method analogous to Example 15. LCMS: m / z 367.1 (M + H) < + >; 755.3 (2M + Na) < + >.

Example 66

(3S) -1-[(2-fluorophenyl) sulfonyl] -N- (3-hydroxycyclohexyl) piperidine-3-carboxamide

This compound was prepared according to a method analogous to Example 15.

LCMS: m / z 385.1 (M + H) < + >; 791.2 (2M + Na) < + >.

Example 67

(3S) -1-[(5-chloro-2-fluorophenyl) sulfonyl] -N- (3-hydroxycyclohexyl) piperidine-3-carboxamide

This compound was prepared according to a method analogous to Example 15.

LCMS: m / z 419.0 (M + H) < + >; 859.0 (2M + Na) < + >.

Example 68

(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] -N- (3-hydroxycyclohexyl) piperidine-3-carboxamide

This compound was prepared according to a method analogous to Example 15.

LCMS: m / z 415.1 (M + H) < + >; 437.0 (M + Na) < + >.

Example 69

(3S) -N- (3-hydroxycyclohexyl) -1-[(3-methoxyphenyl) sulfonyl] piperidine-3-carboxamide

This compound was prepared according to a method analogous to Example 15.

LCMS: m / z 397.1 (M + H) < + >; 815.3 (2M + Na) < + >.

Example 70

(3S) -1-[(3-chlorophenyl) sulfonyl] -N- (3-hydroxycyclohexyl) piperidine-3-carboxamide

This compound was prepared according to a method analogous to Example 15.

LCMS: m / z 401.0 (M + H) < + >; 823.0 (2M + Na) < + >.

Example 71

(3S) -1-[(2-bromophenyl) sulfonyl] -N- (3-hydroxycyclohexyl) piperidine-3-carboxamide

This compound was prepared according to a method analogous to Example 15.

LCMS: m / z 445.0 (M + H) < + >.

Example 72

(3S) -N- (3-hydroxycyclohexyl) -1-[(3-methylphenyl) sulfonyl] piperidine-3-carboxamide

This compound was prepared according to a method analogous to Example 15.

LCMS: m / z 381.1 (M + H) < + >; 783.2 (2M + Na) < + >.

Example 73

(3S) -1-[(3-fluorophenyl) sulfonyl] -N- (3-hydroxycyclohexyl) piperidine-3-carboxamide

This compound was prepared according to a method analogous to Example 15.

LCMS: m / z 385.1 (M + H) < + >; 791.2 (2M + Na) < + >.

Example 74

(3S) -1-[(2,6-dichlorophenyl) sulfonyl] -N- (3-hydroxycyclohexyl) piperidine-3-carboxamide

This compound was prepared according to a method analogous to Example 15.

LCMS: m / z 435.0 (M + H) < + >.

Example 75

(3S) -1-[(2,5-dimethylphenyl) sulfonyl] -N- (3-hydroxycyclohexyl) piperidine-3-carboxamide

This compound was prepared according to a method analogous to Example 15.

LCMS: m / z 395.1 (M + H) < + >; 811.2 (2M + Na) < + >.

Example 76

(3S) -1-[(3-bromophenyl) sulfonyl] -N- (3-hydroxycyclohexyl) piperidine-3-carboxamide

This compound was prepared according to a method analogous to Example 15.

LCMS: m / z 445.0 (M + H) < + >.

Example 77

(3S) -1-[(2,5-dichlorophenyl) sulfonyl] -N- (3-hydroxycyclohexyl) piperidine-3-carboxamide

This compound was prepared according to a method analogous to Example 1.

LCMS: m / z 435.0 (M + H) < + >; 893.0 (2M + Na) < + >.

Example 78

(3S) -1-[(2,4-difluorophenyl) sulfonyl] -N- (3-hydroxycyclohexyl) piperidine-3-carboxamide

This compound was prepared according to a method analogous to Example 15.

LCMS: m / z 403.1 (M + H) < + >; 827.2 (2M + Na) < + >.

Example 79

(3S) -1-[(3,5-dichlorophenyl) sulfonyl] -N- (3-hydroxycyclohexyl) piperidine-3-carboxamide

This compound was prepared according to a method analogous to Example 15.

LCMS: m / z 435.0 (M + H) < + >; 893.0 (2M + Na) < + >.

Example 80

(3S) -1-[(2,5-difluorophenyl) sulfonyl] -N- (3-hydroxycyclohexyl) piperidine-3-carboxamide

This compound was prepared according to a method analogous to Example 15.

LCMS: m / z 403.1 (M + H) < + >; 827.2 (2M + Na) < + >.

Example 81

(3S) -1-[(2-bromophenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide

This compound was prepared according to a method analogous to Example 15. LCMS: m / z 445.0 (M + H) < + >.

Example 82

(3S) -N- (trans-4-hydroxycyclohexyl) -1-[(3-methylphenyl) sulfonyl] piperidine-3-carboxamide

This compound was prepared according to a method analogous to Example 15. LCMS: m / z 381.1 (M + H) < + >; 783.3 (2M + Na) < + >.

Example 83

(3S) -1-[(3-fluorophenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide

This compound was prepared according to a method analogous to Example 15. LCMS: m / z 385.1 (M + H) < + >; 791.2 (2M + Na) < + >.

Example 84

(3S) -1-[(2,6-dichlorophenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide

This compound was prepared according to a method analogous to Example 15. LCMS: m / z 435.1 (M + H) < + >.

Example 85

(3S) -1-[(2,5-dimethylphenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide

This compound was prepared according to a method analogous to Example 15. LCMS: m / z 395.1 (M + H) < + >; 811.3 (2M + Na) < + >.

Example 86

(3S) -1-[(3-bromophenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide

This compound was prepared according to a method analogous to Example 15. LCMS: m / z 445.0 (M + H) < + >.

Example 87

(3S) -1-[(2,5-dichlorophenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide

This compound was prepared according to a method analogous to Example 15. LCMS: m / z 435.0 (M + H) < + >.

Example 88

(3S) -1-[(2,4-difluorophenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide

This compound was prepared according to a method analogous to Example 15. LCMS: m / z 403.1 (M + H) < + >; 827.2 (2M + Na) < + >.

Example 89

(3S) -1-[(3,5-dichlorophenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide

This compound was prepared according to a method analogous to Example 15. LCMS: m / z 435.0 (M + H) < + >.

Example 90

(3S) -1-[(2,3-dichlorophenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 15. LCMS: m / z 435.0 (M + H) < + >.

Example 91

(3S) -1-[(2,5-difluorophenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide

This compound was prepared according to a method analogous to Example 15. LCMS: m / z 403.1 (M + H) < + >; 827.2 (2M + Na) < + >.

Example 92

(3S) -N- (trans-4-hydroxycyclohexyl) -1- (2-thienylsulfonyl) piperidine-3-carboxamide

This compound was prepared according to a method analogous to Example 15. LCMS: m / z 373.1 (M + H) < + >; 767.2 (2M + Na) < + >.

Example 93

(3S) -N-cycloheptyl-1- (phenylsulfonyl) piperidine-3-carboxamide

This compound was prepared according to a method analogous to Example 15. LCMS: m / z 365.1 (M + H) < + >; 751.3 (2M + Na) < + >.

Example 94

(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] -N-cycloheptylpiperidine-3-carboxamide

This compound was prepared according to a method analogous to Example 15. LCMS: m / z 413.1 (M + H) < + >; 847.2 (2M + Na) < + >.

Example 95

(3S) -N-cycloheptyl-1-[(2-fluorophenyl) sulfonyl] piperidine-3-carboxamide

This compound was prepared according to a method analogous to Example 15. LCMS: m / z 383.1 (M + H) < + >; 787.3 (2M + Na) < + >.

Example 96

(3S) -1-[(2-bromophenyl) sulfonyl] -N-cycloheptylpiperidine-3-carboxamide

This compound was prepared according to a method analogous to Example 15. LCMS: m / z 443.1 (M + H) < + >.

Example 97

(3S) -1-[(3-chlorophenyl) sulfonyl] -N-cycloheptylpiperidine-3-carboxamide

This compound was prepared according to a method analogous to Example 15. LCMS: m / z 399.1 (M + H) < + >; 819.3 (2M + Na) < + >.

Example 98

(3S) -N-cycloheptyl-1-[(3-methylphenyl) sulfonyl] piperidine-3-carboxamide

This compound was prepared according to a method analogous to Example 15. LCMS: m / z 379.1 (M + H) < + >; 779.3 (2M + Na) < + >.

Example 99

(3S) -1- (phenylsulfonyl) -N- (tetrahydro-2H-pyran-4-yl) piperidine-3-carboxamide

This compound was prepared according to a method analogous to Example 15. LCMS: m / z 353.1 (M + H) < + >; 727.2 (2M + Na) < + >.

Example 100

(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] -N- (tetrahydro-2H-pyran-4-yl) piperidine-3-carboxamide

This compound was prepared according to a method analogous to Example 15. LCMS: m / z 401.1 (M + H) < + >; 423.0 (M + Na) < + >.

Example 101

(3S) -1-[(3-methoxyphenyl) sulfonyl] -N- (tetrahydro-2H-pyran-4-yl) piperidine-3-carboxamide

This compound was prepared according to a method analogous to Example 15. LCMS: m / z 383.1 (M + H) < + >; 787.3 (M + Na) < + >.

Example 102

(3S) -1- (phenylsulfonyl) -N- [4- (pyridin-4-yloxy) cyclohexyl] piperidine-3-carboxamide

 Under nitrogen atmosphere, (3S) -N- (trans-4-hydroxycyclohexyl) -1- (phenylsulfonyl) piperidine-3-carboxamide (25 mg, 0.068 mmol) in tetrahydrofuran (0.5 mL) ), 4-pyridinol (9.7 mg, 0.10 mmol) and triphenylphosphine (26.8 mg, 0.10 mmol) of diethyl azodicarboxylate (16 μl, 0.10 mmol) in tetrahydrofuran (0.1 mL). Solution was added. The mixture was stirred at rt overnight. The product was purified by preparative HPLC. 1.9 mg of product was obtained. Yield: 6.3%. LCMS: m / z 444.2 (M + H) < + >; 887.2 (2M + Na) < + >.

Example 103

N-cyclohexyl-3-methyl-1- (phenylsulfonyl) piperidine-3-carboxamide

Step 1.

A mixture of ethyl piperidine-3-carboxylate (1.00 g, 6.36 mmol), benzenesulfonyl chloride (0.812 mL, 6.36 mmol) and triethylamine (2.66 mL, 19.1 mmol) in methylene chloride (10.0 mL) was room temperature Stirred for 2 h. The mixture was quenched with water and extracted with ethyl acetate. The extract was washed successively with 1N HCl solution, water, saturated sodium bicarbonate solution, water and brine. The extract was then dried over sodium sulfate (anhydrous). After filtration, the filtrate was concentrated to give 1.79 g (94%) of ethyl 1- (phenylsulfonyl) piperidine-3-carboxylate.

Step 2.

1.0 M lithium hexa in hexane (2.5 mL, 2.5 mmol) in a solution of ethyl 1- (phenylsulfonyl) piperidine-3-carboxylate (0.50 g, 2.0 mmol) in tetrahydrofuran (5.0 mL) at room temperature. Methyldisyl azide was added slowly with stirring. After stirring for 30 minutes, methyl iodide (157 μl, 2.5 mmol) was added to the mixture. The mixture was stirred at rt overnight, quenched with 10% citric acid and extracted with ethyl acetate. The extract was washed successively with water, saturated sodium bicarbonate solution, water and brine. The extract was dried over sodium sulfate (anhydrous). After filtration, the filtrate was concentrated to give 200 mg (40%) of ethyl 3-methyl-1- (phenylsulfonyl) piperidine-3-carboxylate.

Step 3.

At room temperature, 2.0 M of trimethylaluminum in toluene (96 μl, 0.19 mmol) was added to a solution of cyclohexaneamine (19.1 mg, 0.19 mmol) in methylene chloride (0.1 mL). After stirring for 30 minutes, a solution of ethyl 3-methyl-1- (phenylsulfonyl) piperidine-3-carboxylate (35 mg, 0.11 mmol) in methylene chloride (0.1 mL) was added. The mixture was stirred at rt for 10 min and then at 40 ° C. overnight. After cooling to room temperature, the mixture was purified by combi-flash. The product was further purified by preparative HPLC. 1.3 mg of final product was obtained. Yield: 3.2%.

LCMS: m / z 365.1 (M + H) < + >; 751.3 (2M + Na) < + >.

Example 104

(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] -N- (3-oxo-3H-spiro [2-benzofuran-1,1'-cyclohexane] -4'-yl) Piperidine-3-carboxamide

Step 1.

Under nitrogen atmosphere, a solution of 1.0 M dibutylmagnesium (2.6 mL, 2.6 mmol) in heptane was slowly added to a solution of 2-bromobenzoic acid (1.0 g, 4.97 mmol) in tetrahydrofuran (10 mL), which was -15 ° C. Cooling while stirring below. Then a solution of 1.60 M n-butyllithium (3.40 mL, 5.44 mmol) in hexane was added to the mixture under effective stirring for 20 minutes below -15 ° C. After stirring for 1 h below −15 ° C., a solution of 1,4-cyclohexanedione mono-ethylene ketal (0.932 g, 5.97 mmol) in tetrahydrofuran (3 mL) was added at −15 ° C. in the reaction mixture. After stirring at −15 ° C. for 1 hour, the reaction mixture was quenched with 2N HCl solution (10 mL). The resulting mixture was stirred at rt overnight and extracted with ethyl acetate. The extract was washed successively with 10% citric acid, water, saturated sodium bicarbonate solution, water and brine. After drying over anhydrous sodium sulfate, the solid was filtered off. The filtrate was concentrated. The obtained residue was heated under reflux in acetone (5 mL) and 3N HCl solution (6 mL) for 4 hours. After cooling, it was concentrated. The product was dissolved with ethyl acetate. The organic solution was washed with water, 1N HCl solution, water, saturated sodium bicarbonate, water and brine; Dry over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The obtained residue was purified by flash column. 0.486 g (yield: 45%) of 3H, 4'H-spiro [2-benzofuran-1,1'-cyclohexane] -3,4'-dione was obtained.

Step 2.

Sodium borohydride (35 mg, 0.92 mmol) in a solution of 3H, 4'H-spiro [2-benzofuran-1,1'-cyclohexane] -3,4'-dione (100 mg, 0.46 mmol) in methanol (1 mL) ) Was added with stirring. The mixture was stirred at rt for 2 h and then quenched with water. The mixture was then concentrated and extracted with ethyl acetate. The extract was washed successively with 10% citric acid, water and brine; Dry over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to give 101 mg (yield: 99%) of 4'-hydroxy-3H-spiro [2-benzofuran-1,1'-cyclohexane] -3-one.

Step 3.

4'-hydroxy-3H-spiro [2-benzofuran-1,1'-cyclohexane] -3-one (100 mg, 0.46 mmol) in methylene chloride (2 mL) at room temperature, triethylamine (192 μl, 1.37 To the mixture of mmol) methanesulfonyl chloride (42.6 μl, 0.55 mmol) was added with stirring. The mixture was stirred at rt overnight, then quenched with water and extracted with ethyl acetate. The extract was washed once with water followed by brine; Dry over anhydrous sodium sulfate. After removing the solid, the solution was concentrated to give 120 mg (yield: 88%) of 3-oxo-3H-spiro [2-benzofuran-1,1'-cyclohexane] -4'-yl methanesulfonate.

Step 4.

3-oxo-3H-spiro [2-benzofuran-1,1'-cyclohexane] -4'-yl methanesulfonate (120 mg, 0.40 mmol), sodium azide (263 mg, 4.05 mmol in DMF (2.0 mL) ) Was allowed to stand at 80 ° C. overnight. After cooling, it was quenched with saturated NH ₄ Cl solution and extracted with ethyl acetate. The extract was washed twice with water and once with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to give 90 mg (yield: 91%) of 4'-azido-3H-spiro [2-benzofuran-1,1'-cyclohexane] -3-one.

Step 5.

A mixture of 4'-azido-3H-spiro [2-benzofuran-1,1'-cyclohexane] -3-one (90 mg, 0.36 mmol) in methanol (5 mL) was mixed with 10% palladium (30 mg) on charcoal. The mixture was stirred for 1 hour under a hydrogen atmosphere (balloon). After filtration, the solution was concentrated to give 88 mg (yield: 90%) of 4'-amino-3H-spiro [2-benzofuran-1,1'-cyclohexane] -3-one.

Step 6.

4'-Amino-3H-spiro [2-benzofuran-1,1'-cyclohexane] -3-one (11 mg, 0.03 mmol) in acetonitrile (0.2 mL), 3-chloro-2-methylbenzenesul A mixture of polyvinyl chloride (6.8 mg, 0.03 mmol) and triethylamine (10.5 μl, 0.075 mmol) was stirred at room temperature for 2 hours. The mixture was purified by flash column to give 10.2 mg of the final product. Yield 65%.

LCMS: 517.0 (M + H) < + >; 539.1 (M + Na) < + >.

Example 105

(3S) -1-[(2,6-dichlorophenyl) sulfonyl] -N- (3-oxo-3H-spiro [2-benzofuran-1,1'-cyclohexane] -4'-yl) pi Ferridine-3-carboxamide

This compound was prepared using a method similar to Example 105. LCMS: m / z 537.0 (M + H) < + >; 559.0 (M + Na) < + >.

Example 106

(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] -N- (cyclopropylmethyl) -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide

Step 1.

After stirring for 20 minutes cyclopropane in a suspension of trans-4-aminocyclohexanol hydrochloride (1.0 g, 6.6 mmol) and triethylamine (1.84 mL, 13.2 mmol) in 1,2-dichloroethane (10 mL) Carboxaldehyde (0.49 mL, 6.6 mmol) was added slowly with vigorous stirring. After stirring for an additional 30 minutes, sodium triacetoxyborohydride (2.8 g, 13.2 mmol) was added to the mixture. The mixture was stirred at rt overnight, quenched with water and extracted with ethyl acetate. The extract was washed with water.

Step 2.

Sodium hydroxide (0.79 g, 20 mmol) was added to the extract, and 1 eq. Of di-tert-butyldicarbonate (1.44 g, 6.6 mmol) was added thereto. The mixture was stirred for 1 week at room temperature and then acidified with 1N HCl solution to pH about 7. The product was extracted with ethyl acetate. The organic solution was washed successively with 1N HCl solution, water and brine. The extract was then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to give 0.857 g (yield: 48%, 2-steps) of tert-butyl (cyclopropylmethyl) (trans-4-hydroxycyclohexyl) carbamate.

Step 3.

Tert-butyl (cyclopropylmethyl) (trans-4-hydroxycyclohexyl) carbamate (0.857 g, 3.2 mmol) in a solution of 4.0 M hydrogen chloride in methylene chloride (6 mL) and 1,4-dioxane (3 mL) The mixture was stirred at rt for 2 h. Concentration gave 0.658 g of trans-4-[(cyclopropylmethyl) amino] cyclohexanol hydrochloride (100%).

Step 4.

Trans-4-[(cyclopropylmethyl) amino] cyclohexanol hydrochloride (90 mg, 0.44 mmol), (3S) -1- (tert-butoxycarbonyl) piperidine- in methylene chloride (1.5 mL) 3-carboxylic acid (100 mg, 0.44 mmol), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafulurophosphate (193 mg, 0.44 mmol) and N, N-diisopropylethylamine (190 μl, 1.09 mmol) was stirred overnight at room temperature. The mixture was quenched with 10% citric acid and extracted with ethyl acetate. The extract was washed successively with 10% citric acid solution, water and brine; Dry over anhydrous sodium sulfate. After filtration, the filtrate was concentrated.

Step 5.

A mixture of this concentrate in 4.0 M hydrogen chloride in methylene chloride (3.0 mL) and 1,4-dioxane (6 mL) was stirred at room temperature for 3 hours. The mixture was then concentrated to 0.34 g (98%, 2 steps) of (3S) -N- (cyclopropylmethyl) -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide hydrochloride , Crude material).

Step 6.

(3S) -N- (cyclopropylmethyl) -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide hydrochloride (10 mg, 0.03 mmol) in acetonitrile (0.2 mL), 3 A mixture of chloro-2-methylbenzenesulfonyl chloride (7.1 mg, 0.03 mmol) and triethylamine (11 μl, 0.08 mmol) was stirred at room temperature for 1 hour and then purified by flash column. 5.1 mg (yield: 34%) final product were obtained. LCMS: m / z 468.9 (M + H) < + >.

Example 107

(3S) -N- (cyclopropylmethyl) -1-[(2,6-dichlorophenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide

This compound was prepared using a method similar to Example 107. LCMS: m / z 468.9 (M + H) < + >.

Example 108

(3S) -N-cycloheptyl-1-[(2,6-dichlorophenyl) sulfonyl] piperidine-3-carboxamide

This compound was prepared using a method similar to that described in Example 1. LCMS: m / z 433.1 (M + H) < + >; 889.2 (2M + Na) < + >.

Example 109

(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] -N- [trans-4- (hydroxymethyl) cyclohexyl] piperidine-3-carboxamide

Step 1.

A mixture of methylene chloride (1 mL) and tert-butyl [trans-4- (hydroxymethyl) cyclohexyl] carbamate (0.2 mg, 0.87 mmol) in 4.0 M hydrogen chloride in 1,4-dioxane (1 mL) was cooled to room temperature. Stirred for 2 h. The mixture was concentrated to give quantitative product: (trans-4-aminocyclohexyl) methanol hydrochloride.

Step 2.

(Trans-4-aminocyclohexyl) methanol hydrochloride (0.144 g, 0.87 mmol) in DMF (3 mL), (3S) -1- (tert-butoxycarbonyl) piperidine-3-carboxylic acid (0.219 g , 0.96 mmol), of benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafulurophosphate (0.423 g, 0.96 mmol) and N, N-diisopropylethylamine (0.38 mL, 2.17 mmol) The mixture was stirred at rt overnight. The mixture was quenched with 10% citric acid and extracted with ethyl acetate. The extract was washed twice with 10% citric acid and once with water and brine. The extract was then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and the obtained residue was purified by flash column.

Step 3.

The intermediate from step 2 was dissolved in methylene chloride (3.0 mL) and combined with 4.0 M hydrogen chloride in 1,4-dioxane (6 mL). The mixture was stirred at rt for 2 h. After concentration, 0.42 g (yield: 55%) of (3S) -N- [trans-4- (hydroxymethyl) cyclohexyl] piperidine-3-carboxamide hydrochloride were obtained.

Step 4.

(3S) -N- [trans-4- (hydroxymethyl) cyclohexyl] piperidine-3-carboxamide hydrochloride (170 mg, 0.61 mmol), 3-chloro-2-methyl in acetonitrile (3 mL) A mixture of benzenesulfonyl chloride (138 mg, 0.61 mmol) and triethylamine (0.21 mL, 1.54 mmol) was stirred at room temperature for 2 hours. After removing the solvent, the residue was added dropwise onto a flash column eluting with methylene chloride with ethyl acetate-hexane. 110 mg of final product was obtained (yield: 41%). LCMS: m / z 429.0 (M + H) < + >; 879.2 (2M + Na) < + >.

Example 110

(3R) -N- (trans-4-hydroxycyclohexyl) -1- (quinolin-8-ylsulfonyl) piperidine-3-carboxamide

This compound was prepared using a method similar to Example 15. LCMS: m / z 418.1 (M + H) < + >; 440.0 (M + Na) < + >; 857.2 (2M + Na) < + >.

Example 111

(3S) -N- (trans-4-hydroxycyclohexyl) -1- (1-naphthylsulfonyl) piperidine-3-carboxamide

This compound was prepared using a method similar to Example 15. LCMS: m / z 417.1 (M + H) < + >; 855.2 (2M + Na) < + >.

Example 112

(3S) -N- (trans-4-hydroxycyclohexyl) -1- (2-naphthylsulfonyl) piperidine-3-carboxamide

This compound was prepared using a method similar to Example 15. LCMS: m / z 417.1 (M + H) < + >; 439.1 (M + Na) < + >: 855.3 (2M + Na) < + >.

Example 113

(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] -N-[(1R) -1,2,3,4-tetrahydronaphthal-1-yl] piperidine-3- Carboxamide

This compound was prepared using a method similar to Example 15. LCMS: m / z 447.1 (M + H) < + >; 469.0 (M + Na) < + >.

Example 115

(3S) -1-benzoyl-N- (4-hydroxycyclohexyl) piperidine-3-carboxamide

This compound was prepared using a method similar to Example 1. LCMS: m / z 331.1 (M + H) < + >; 353.0 (M + Na) < + >.

Example 116

(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] -N- (cis-4-hydroxycyclohexyl) piperidine-3-carboxamide

This compound was prepared using a method similar to Example 15. LCMS: m / z 415.2 (M + H) < + >; 851.2 (2M + Na) < + >.

Example 117

(3S) -1-[(2-chlorophenyl) sulfonyl] -N- (cis-4-hydroxycyclohexyl) piperidine-3-carboxamide

This compound was prepared using a method similar to Example 15. LCMS: m / z 401.1 (M + H) < + >; 823.3 (2M + Na) < + >.

Example 118

(3S) -1- (biphenyl-4-ylsulfonyl) -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide

This compound was prepared using a method similar to Example 15. LCMS: m / z 443.2 (M + H) < + >.

Example 119

(3S) -N- (trans-4-hydroxycyclohexyl) -1-{[4- (trifluoromethyl) phenyl] sulfonyl} piperidine-3-carboxamide

This compound was prepared using a method similar to Example 15. LCMS: m / z 435.1 (M + H) < + >; 891.3 (2M + Na) < + >.

Example 120

(3S) -1-{[3- (difluoromethoxy) phenyl] sulfonyl} -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide

This compound was prepared using a method similar to Example 15. LCMS: m / z 433.0 (M + H) < + >; 887.2 (2M + Na) < + >.

Example 121

(3S) -1-{[3- (4-fluorophenoxy) phenyl] sulfonyl} -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide

This compound was prepared using a method similar to Example 15. LCMS: m / z 477.1 (M + H) < + >.

Example 122

(3S) -N- (trans-4-hydroxycyclohexyl) -1-{[3- (trifluoromethoxy) phenyl] sulfonyl} -piperidine-3-carboxamide

This compound was prepared using a method similar to Example 15. LCMS: m / z 451.0 (M + H) < + >.

Example 123

(3S) -1- (biphenyl-3-ylsulfonyl) -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide

This compound was prepared using a method similar to Example 15. LCMS: m / z 443.2 (M + H) < + >.

Example 124

(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] -N- (1,2,3,4-tetrahydronaphthalen-2-yl) piperidine-3-carboxamide

This compound was prepared using a method similar to Example 15. LCMS: m / z 447.0 (M + H) < + >; 469.0 (M + Na) < + >.

Example 125

(3S) -1-[(2,6-dichlorophenyl) sulfonyl] -N- (1,2,3,4-tetrahydronaphthalen-2-yl) piperidine-3-carboxamide

This compound was prepared using a method similar to Example 15. LCMS: m / z 467.0 (M + H) < + >.

Example 126

(3S) -1- (phenylsulfonyl) -N- [trans-4- (pyridin-4-yloxy) cyclohexyl] piperidine-3-carboxamide

Step 1.

At 0 ° C. tert-butyl (cis-4-hydroxycyclohexyl) carbamate (100 mg, 0.5 mmol), 4-pyridinol (106 mg, 1.11 mmol) and triphenylphosphine (2 mL) in tetrahydrofuran (2 mL) 292 mg, 1.11 mmol) was added with stirring diethyl azodicarboxylate (176 μL, 1.11 mmol). The mixture was stirred at rt overnight, quenched with saturated NH ₄ Cl solution and extracted with ethyl acetate. The extract was washed twice with water and once with brine. The extract was then dried over Na ₂ SO ₄ . After filtration, the filtrate was concentrated to give tert-butyl [trans-4- (pyridin-4-yloxy) cyclohexyl] carbamate.

Step 2.

A mixture of tert-butyl [trans-4- (pyridin-4-yloxy) cyclohexyl] carbamate in a solution of 4.0 M hydrogen chloride in methylene chloride (1 mL) and 1,4-dioxane (2 mL) was added at room temperature. Stir for hours. The mixture was concentrated to give 45% of trans-4- (pyridin-4-yloxy) cyclohexaneamine dihydrochloride (2-step).

Step 3.

Trans-4- (pyridin-4-yloxy) cyclohexaneamine dihydrochloride (70 mg, 0.3 mmol), trans-4- (pyridin-4-yloxy) cyclohexanamine dihydrochloride in methylene chloride (1.5 mL) (180 mg, 45%, 0.3 mmol), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafulurophosphate (142 mg, 0.32 mmol) and N, N-diisopropylethylamine (186 μl, 1.07 mmol) was stirred overnight at room temperature. The mixture was quenched with water and extracted with ethyl acetate. The extract was washed twice with saturated sodium bicarbonate solution and once with water and brine. The extract was then dried over Na ₂ SO ₄ . After filtration, the filtrate was concentrated.

Step 4.

(3S) -N- [trans-4- (pyridin-4-yloxy) cyclohexyl] piperidine-3-carboxamide dihydrochloride (28 mg, purity: 40%, 0.03 mmol) in acetonitrile (1 mL) ), Benzenesulfonyl chloride (6.3 mg, 0.036 mmol) and triethylamine (16 μl, 0.12 mmol) were stirred overnight at room temperature. The mixture was purified by preparative HPLC. 5.9 mg (45%) of final product was obtained. LCMS: m / z 444.1 (M + H) < + >; 466.1 (M + Na) < + >.

Example 127

(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] -N- [trans-4- (pyridin-4-yloxy) cyclohexyl] piperidine-3-carboxamide

This compound was prepared using a method similar to Example 126. LCMS: m / z 492.1 (M + H) < + >.

Example 128

(3S) -N-cyclohexyl-1-phenylpiperidine-3-carboxamide

Step 1. (3S) -N-cyclohexylpiperidine-3-carboxamide trifluoroacetate

This compound was prepared using a method similar to that used for the synthesis of Example 1, steps 1-2.

Step 2. (3S) -N-cyclohexyl-1-phenylpiperidine-3-carboxamide

Bromobenzene (13 μl, 0.00012 mol), (3S) -N-cyclohexylpiperidine-3-carboxamide trifluoroacetate (40 mg, 0.0001 mol), sodium tert-butoxide (28 mg, 0.00030 mol ), Palladium acetate (0.8 mg, 0.000004 mol) and 2- (di-tert-butylphosphino) biphenyl (1 mg, 0.000004 mol) were released and charged with nitrogen. 1,4-dioxane (1 mL, 0.01 mol) was added to the mixture, and the obtained mixture was refluxed overnight. After cooling the mixture to ambient temperature, the inorganics were filtered and the filtrate was adjusted to pH = 7.0 with TFA. The crude product was chromatographed with combiflash (ethyl acetate in hexanes: 60%) to afford the desired product. LCMS: m / z 287.3 (M + H) < + >.

Example 129

(3S) -N-1-adamantyl-1-phenylpiperidine-3-carboxamide

Step 1. (3S) -Piperidine-3-carboxylic acid hydrochloride

(3S) -1- (tert-butoxycarbonyl) piperidine-3-carboxylic acid (4.0 g, 0.017 in 4.0 M hydrogen chloride in methylene chloride (10 mL, 0.2 mol) and 1,4-dioxane (30 mL) mol) mixture was stirred at room temperature for 2 hours. The volatiles were removed in vacuo to afford the desired product in quantitative yield. The crude product was used to next step without further purification. LCMS: m / z 166.2 (M + H) < + >.

Step 2. (3S) -1-phenylpiperidine-3-carboxylic acid

Bromobenzene (0.82 mL, 0.0078 mol), (3S) -piperidine-3-carboxylic acid hydrochloride (6.5 mmol, 0.0065 mol), sodium tert-butoxide (1.2 g, 0.013 mol), palladium acetate (40 mg , 0.0002 mol) and 2- (di-tert-butylphosphino) biphenyl (60 mg, 0.0002 mol) were degassed under vacuum and filled with nitrogen. 1,4-dioxane (20 mL, 0.2 mol) was added to the mixture, and the obtained mixture was refluxed overnight. After cooling the reaction mixture to ambient temperature, the mixture was filtered and the filtrate was adjusted to pH = 3.0 with TFA and extracted with EtOAc. The crude product was used to next step without further purification.

Step 3. (3S) -N-1-adamantyl-1-phenylpiperidine-3-carboxamide

4-Methylmorpholine (43 μl, 0.00039 mol) was added to (3S) -1-phenylpiperidine-3-carboxylic acid (20 mg, 0.0001 mol) in N, N-dimethylformamide (0.5 mL, 0.006 mol) Cyclo [3.3.1.13,7] decan-1-amine (18 mg, 0.00012 mol), (benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafulurophosphate (53.2 mg, 0.000102 mol) or benzo Triazol-1-yloxytris (dimethylamino) phosphonium hexafulurophosphate (45.2 mg, 0.000102 mol) was added to the mixture. The reaction mixture was stirred at rt for 2 h and the crude reaction mixture was purified by pre-LCMS to give the desired product. LCMS: m / z 339.3 (M + H) < + >.

Example 130

(3S) -N- (3-hydroxy-1-adamantyl) -1-phenylpiperidine-3-carboxamide

This compound was prepared using a method similar to that used for the synthesis of Example 129, steps 1-3. LCMS: m / z 355.3 (M + H) < + >.

Example 131

(3S) -N- (trans-4-hydroxycyclohexyl) -1-phenylpiperidine-3-carboxamide

This compound was prepared using a method similar to that used for the synthesis of Example 129, steps 1-3. LCMS: m / z 303.3 (M + H) < + >.

Example 132

(3S) -N-cyclohexyl-1- (3-methylphenyl) piperidine-3-carboxamide

This compound was prepared using a method similar to that used for the synthesis of Example 128, steps 1 and 2. LCMS: m / z 301.3 (M + H) < + >.

Example 133

(3S) -N-cyclohexyl-1- (2-fluorophenyl) piperidine-3-carboxamide

This compound was prepared using a method similar to that used for the synthesis of Example 128, steps 1 and 2. LCMS: m / z 305.3 (M + H) < + >.

Example 134

(3S) -N-cyclohexyl-1- (4-methoxyphenyl) piperidine-3-carboxamide

This compound was prepared using a method similar to that used for the synthesis of Example 128, steps 1 and 2. LCMS: m / z 317.3 (M + H) < + >.

Example 135

(3S) -N-cyclohexyl-1- [2- (trifluoromethyl) phenyl] piperidine-3-carboxamide

This compound was prepared using a method similar to that used for the synthesis of Example 128, steps 1 and 2. LCMS: m / z 355.3 (M + H) < + >.

Example 136

(3S) -N-cyclohexyl-1- (2-methylphenyl) piperidine-3-carboxamide

This compound was prepared using a method similar to that used for the synthesis of Example 128, steps 1 and 2. LCMS: m / z 301.3 (M + H) < + >.

Example 137

(3S) -N-cyclohexyl-1- (3-methoxyphenyl) piperidine-3-carboxamide

This compound was prepared using a method similar to that used for the synthesis of Example 128, steps 1 and 2. LCMS: m / z 317.2 (M + H) < + >.

Example 138

(3S) -N-cyclohexyl-1- [3- (trifluoromethyl) phenyl] piperidine-3-carboxamide

This compound was prepared using a method similar to that used for the synthesis of Example 128, steps 1 and 2. LCMS: m / z 355.2 (M + H) < + >.

Example 139

(3S) -N-cyclohexyl-1- [4- (trifluoromethyl) phenyl] piperidine-3-carboxamide

This compound was prepared using a method similar to that used for the synthesis of Example 128, steps 1 and 2. LCMS: m / z 355.2 (M + H) < + >.

Example 140

(3S) -N-cyclohexyl-1- (4-phenoxyphenyl) piperidine-3-carboxamide

This compound was prepared using a method similar to that used for the synthesis of Example 128, steps 1 and 2. LCMS: m / z 379.3 (M + H) < + >.

Example 141

(3S) -1- (4-cyano-2-methylphenyl) -N-cyclohexylpiperidine-3-carboxamide

This compound was prepared using a method similar to that used for the synthesis of Example 128, steps 1 and 2. LCMS: m / z 326.3 (M + H) < + >.

Example 142

(3S) -N-cyclohexyl-1- (4-fluoro-2-methylphenyl) piperidine-3-carboxamide

This compound was prepared using a method similar to that used for the synthesis of Example 128, steps 1 and 2. LCMS: m / z 319.2 (M + H) < + >.

Example 143

(3S) -N-cycloheptyl-1-phenylpiperidine-3-carboxamide

This compound was prepared using a method similar to that used for the synthesis of Example 129, steps 1-3. LCMS: m / z 301.2 (M + H) < + >.

Example 144

(3S) -N-cyclohexyl-1-pyridin-2-ylpiperidine-3-carboxamide

This compound was prepared using a method similar to that used for the synthesis of Example 128, steps 1 and 2. LCMS: m / z 388.3 (M + H) < + >.

Example 145

(3S) -N-cyclohexyl-1- [5- (trifluoromethyl) pyridin-2-yl] piperidine-3-carboxamide

This compound was prepared using a method similar to that used for the synthesis of Example 128, steps 1 and 2. LCMS: m / z 356.3 (M + H) < + >.

Example 146

(3S) -N-cyclohexyl-1-pyrazin-2-ylpiperidine-3-carboxamide

This compound was prepared using a method similar to that used for the synthesis of Example 128, steps 1 and 2. LCMS: m / z 289.2 (M + H) < + >.

Example 147

(3S) -N-cyclohexyl-1-pyrimidin-2-ylpiperidine-3-carboxamide

This compound was prepared using a method similar to that used for the synthesis of Example 128, steps 1 and 2. LCMS: m / z 289.2 (M + H) < + >.

Example 148

(3S) -1- (1,3-benzoxazol-2-yl) -N-cyclohexylpiperidine-3-carboxamide

This compound was prepared using a method similar to that used for the synthesis of Example 128, steps 1 and 2. LCMS: m / z 328.2 (M + H) < + >.

Example 149

Methyl 6-((3S) -3-{[(4-hydroxycyclohexyl) amino] carbonyl} piperidin-1-yl) nicotinate

(3S) -N- (4-hydroxycyclohexyl) piperidine-3-carboxamide hydrochloride (19.7 mg, 0.0000750 mol, Example 1 in N, N-dimethylformamide (0.75 mL, 0.0097 mol) Prepared using a method similar to that described in the synthesis of steps 1 and 2), methyl 6-chloronicotinate (15.4 mg, 0.0000900 mol) and N, N-diisopropylethylamine (37.5 μl, 0.000216 mol) The mixture of was spun at microwave at 200 ° C. for 15 minutes. The mixture was adjusted to pH 2.0 with TFA and diluted with methanol (0.8 mL). The resulting solution was purified by prep-HPLC to give the desired product. LCMS: m / z 362.2 (M + H) ⁺ .

Example 150

(3S) -N- (4-hydroxycyclohexyl) -1-quinolin-4-ylpiperidine-3-carboxamide

The title compound was prepared using a method similar to that described in the synthesis of Example 149. LCMS: m / z 354.2 (M + H) ⁺ .

Example 151

(3S) -N- (4-hydroxycyclohexyl) -1- (2-methylquinolin-4-yl) piperidine-3-carboxamide

The title compound was prepared using a method similar to that described in the synthesis of Example 149. LCMS: m / z 368.2 (M + H) ⁺ .

Example 152

6-((3S) -3-{[(4-hydroxycyclohexyl) amino] carbonyl} piperidin-1-yl) nicotinic acid

The title compound was prepared using a method similar to that described in the synthesis of Example 149. LCMS: m / z 348.2 (M + H) ⁺ .

Example 153

(3S) -N- (4-hydroxycyclohexyl) -1- (6-phenylpyridazin-3-yl) piperidine-3-carboxamide

This compound was prepared using a method similar to that described in the synthesis of Example 149. LCMS: m / z 381.2 (M + H) ⁺ .

Example 154

(3S) -1- (5-bromopyridin-2-yl) -N- (4-hydroxycyclohexyl) piperidine-3-carboxamide

The title compound was prepared using a method similar to that described in the synthesis of Example 149. LCMS: m / z 382.1 / 384.2 (M + H) ⁺ .

Example 155

(3S) -N- (4-hydroxycyclohexyl) -1- (5-phenylpyridin-2-yl) piperidine-3-carboxamide

Sodium carbonate (21.2 mg, 0.000200 mol) in water (0.10 mL) was dissolved in toluene (200.0 μl, 0.001878 mol) and (3S) -1- (5-bromopyridin-2-yl) in ethanol (100.0 μl, 0.001713 mol). -N- (4-hydroxycyclohexyl) piperidine-3-carboxamide (38.2 mg, 0.000100 mol, prepared in Example 154), phenylboronic acid (14.6 mg, 0.000120 mol) and tetrakis (tri To a mixture of phenylphosphine) palladium (0) (3.5 mg, 0.0000030 mol). The resulting mixture was spun at microwave at 150 ° C. for 20 minutes. Ethyl acetate (5 mL) was added and the mixture was washed with water and brine. The organic layer was dried over Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The residue was dissolved in DMF and purified by prep-HPLC to give the desired product. LCMS: m / z 380.2 (M + H) ⁺ .

Example 156

(3S) -1- [5- (4-chlorophenyl) pyridin-2-yl] -N- (4-hydroxycyclohexyl) piperidine-3-carboxamide

The title compound was prepared using a method similar to that described in the synthesis of Example 155. LCMS: m / z 414.2 / 416.2 (M + H) ⁺ .

Example 157

(3S) -1- [5- (3,4-difluorophenyl) pyridin-2-yl] -N- (4-hydroxycyclohexyl) piperidine-3-carboxamide

The title compound was prepared using a method similar to that described in the synthesis of Example 155. LCMS: m / z 416.2 (M + H) ⁺ .

Example 158

(3S) -1- {2-bromo-5-[(methylamino) carbonyl] phenyl} -N- (4-hydroxycyclohexyl) piperidine-3-carboxamide

The title compound was prepared using a method similar to that described in the synthesis of Example 128. LCMS: m / z 439.1 (M + H) ⁺ .

Example 159

Tert-butyl 6-((3S) -3-{[(4-hydroxycyclohexyl) amino] carbonyl} piperidin-1-yl) -3 ', 6'-dihydro-3,4' Bipyridine-1 '(2'H) -carboxylate

The title compound was prepared using a method similar to that described in the synthesis of Example 128. LCMS: m / z 485.3 (M + H) ⁺ .

Example 160

(3S) -N- (4-hydroxycyclohexyl) -1- [5- (4-methoxyphenyl) pyridin-2-yl] piperidine-3-carboxamide

The title compound was prepared using a method similar to that described in the synthesis of Example 128. LCMS: m / z 410.2 (M + H) ⁺ .

Example 161

(3S) -1- [5- (2-fluorophenyl) pyridin-2-yl] -N- (4-hydroxycyclohexyl) piperidine-3-carboxamide

The title compound was prepared using a method similar to that described in the synthesis of Example 128. LCMS: m / z 398.2 (M + H) ⁺ .

Example 162

(3S) -1- {5- [4- (acetylamino) phenyl] pyridin-2-yl} -N- (4-hydroxycyclohexyl) piperidine-3-carboxamide

The title compound was prepared using a method similar to that described in the synthesis of Example 128. LCMS: m / z 437.2 (M + H) ⁺ .

Example 163

(3S) -1- {5- [3- (acetylamino) phenyl] pyridin-2-yl} -N- (4-hydroxycyclohexyl) piperidine-3-carboxamide

The title compound was prepared using a method similar to that described in the synthesis of Example 128. LCMS: m / z 437.2 (M + H) ⁺ .

Example 164

(3S) -N- (4-hydroxycyclohexyl) -1- (6'-methoxy-3,3'-bipyridin-6-yl) piperidine-3-carboxamide

The title compound was prepared using a method similar to that described in the synthesis of Example 128. LCMS: m / z 411.2 (M + H) ⁺ .

Example 165

(3S) -N- (4-hydroxycyclohexyl) -1- (5'-methoxy-3,3'-bipyridin-6-yl) piperidine-3-carboxamide

The title compound was prepared using a method similar to that described in the synthesis of Example 128. LCMS: m / z 411.2 (M + H) ⁺ .

Example 166

(3S) -N- (4-hydroxycyclohexyl) -1- [5- (1-methyl-1H-pyrazol-4-yl) pyridin-2-yl] piperidine-3-carboxamide

The title compound was prepared using a method similar to that described in the synthesis of Example 128. LCMS: m / z 384.2 (M + H) ⁺ .

Example 167

(3S) -1-biphenyl-4-yl-N- (4-hydroxycyclohexyl) piperidine-3-carboxamide

The title compound was prepared using a method similar to that described in the synthesis of Example 128. LCMS: m / z 379.2 (M + H) ⁺ .

Example 168

Methyl 4- [4-((3S) -3-{[(4-hydroxycyclohexyl) amino] carbonyl} piperidin-1-yl) phenyl] -3,6-dihydropyridine-1 (2H ) -Carboxylate

The title compound was prepared using a method similar to that described in the synthesis of Example 128. LCMS: m / z 442.2 (M + H) ⁺ .

Example 169

(3S) -N-cyclohexyl-1- (2-fluoro-4-pyridin-4-ylphenyl) piperidine-3-carboxamide

Step 1. 4- (4-Bromo-3-fluorophenyl) pyridine

Sodium carbonate (0.86 g, 0.0081 mol) in water (3.0 mL, 0.17 mol) to 4-pyridinylboronic acid (0.5 g, 0.004 mol) in toluene (6.0 mL, 0.056 mol) and ethanol (3.0 mL, 0.051 mol), To a mixture of 1-bromo-2-fluoro-4-iodobenzene (1.5 g, 0.0049 mol) and tetrakis (triphenylphosphine) palladium (0) (0.02 g, 0.00002 mol) was added. The resulting mixture was spun at microwave at 120 ° C. for 30 minutes. The reaction mixture was extracted with EtOAc and the combined organic layers were dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo. The residue was purified by combiflash (EtOAc in hexanes: 40%) to afford the desired product.

Step 2. Ethyl (3S) -1- (2-fluoro-4-pyridin-4-ylphenyl) piperidine-3-carboxylate

4- (4-Bromo-3-fluorophenyl) pyridine (190 mg, 0.00075 mol), ethyl (3S) -piperidine-3-carboxylate hydrochloride (180 mg, 0.00090 mol), sodium tert-butoxide (140 mg, 0.0015 mol), a mixture of palladium acetate (5 mg, 0.00002 mol) and 2- (di-tert-butylphosphino) biphenyl (7 mg, 0.00002 mol) was withdrawn and nitrogen and 1,4-dioxane (5 mL, 0.06 mol). The resulting mixture was refluxed overnight. After cooling to ambient temperature, the mixture was filtered, the filtrate was adjusted to pH 7.0 with TFA and purified by combiflash (ethyl acetate in hexanes: 60%) to afford the desired product. LCMS: m / z 329.2 (M + H) ⁺ .

Step 3. (3S) -1- (2-Fluoro-4-pyridin-4-ylphenyl) piperidine-3-carboxylic acid

Lithium hydroxide monohydrate (0.013 g, 0.00030 mol) was converted to ethyl (3S) -1- (2) in methanol (0.5 mL, 0.01 mol), tetrahydrofuran (0.5 mL, 0.006 mol) and water (0.5 mL, 0.03 mol). -Fluoro-4-pyridin-4-ylphenyl) piperidine-3-carboxylate (0.050 g, 0.00015 mol) was added. The mixture was spun at microwave at 100 ° C. for 30 minutes. The reaction mixture was diluted with water and adjusted to pH = 5 by addition of 1N HCl. The volatiles were removed in vacuo to afford the desired product and LiCl, which was used as a mixture in the next step.

Step 4. (3S) -N-cyclohexyl-1- (2-fluoro-4-pyridin-4-ylphenyl) piperidine-3-carboxamide

The title compound was prepared using a method similar to that described in Synthesis of Example 129, step 3. LCMS: m / z 382.2 (M + H) ⁺ .

Example 170

(3S) -1- (2-fluoro-4-pyridin-4-ylphenyl) -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide

The compound was prepared using a method similar to that described in the synthesis of Example 169, steps 1-4. LCMS: m / z 398.2 (M + H) ⁺ .

Example 171

(3S) -N- (4-oxocyclohexyl) -1-phenylpiperidine-3-carboxamide

Ethyl (3S) -piperidine-3-carboxylate hydrochloride (0.1 g, 0.0005 mol), bromobenzene (0.16 g, 0.0010 mol) and potassium tert-butoxide in dimethyl sulfoxide (4 mL, 0.06 mol) (0.12 g, 0.0010 mol) was heated to 200 ° C. for 10 minutes under microwave irradiation. BOP-mediated coupling to crude (3S) -1-phenylpiperidine-3-carboxylic acid was performed using a method similar to that described in Example 129, synthesis of step 3. LCMS: m / z 301.2 (M + H) ⁺ .

Example 172

(3S) -1- [3- (benzyloxy) phenyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide

The compound was prepared using a method similar to that described in the synthesis of Example 128, steps 1 and 2. LCMS: m / z 409.2 (M + H) ⁺ .

Example 173

(3S) -1-acetyl-N- (3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-ylpiperidine-3-carboxamide

Step 1. Tert-butyl {(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} carbamate

A solution of 3-chloro-2-methylbenzenesulfonyl chloride (0.75 g, 0.0033 mol) in 5 mL acetonitrile was added to tert-butyl (3S) -piperidin-3-ylcarbamate (0.67 g, 5 mL in acetonitrile). 0.0033 mol) was added to the solution at 0 ° C. After stirring at room temperature for 1.5 hours, the reaction mixture is filtered and concentrated to give the desired product which is used without further purification in the next step.

Step 2. Tert-Butyl (3S) -3-[({(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} amino) carbonyl] piperi Dean-1-carboxylate

Tert-butyl {(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} carbamate (58.34 mg, 0.0001500 mol) was converted to 1,4-dioxane (1.0 mL) and treated with 4.0 M hydrogen chloride for 30 min at room temperature. The solvent was evaporated under reduced pressure, and the residue was dissolved in DMF (1.0 mL), to which benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafulurophosphate (69.6 mg, 0.000157 mol), 4 Methylmorpholine (100.0 μl, 0.0009096 mol) and (3S) -1- (tert-butoxycarbonyl) piperidine-3-carboxylic acid (34.4 mg, 0.000150 mol) were added at room temperature. After stirring for 1 hour, the reaction mixture was diluted with ethyl acetate (5 mL) and washed with NaHCO ₃ (7.5%, ₃ × 2 mL) and brine (3 × 20 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the desired product which was used directly in the next step without further purification.

Step 3. (3S) -1-acetyl-N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} piperidine-3-carboxamide

Tert-butyl (3S) -3-[((3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-ylamino) -carbonyl] -piperidine-1 Carboxylate (10.0 mg, 200 μmol) was treated with 4.0 M hydrogen chloride in 1,4-dioxane (0.5 mL) for 1 hour at room temperature. The volatiles were removed under vacuum and the residue was dissolved in acetonitrile (0.8 mL) and treated with diisopropylethylamine (20.0 μL) and acetyl chloride (5.0 μL). The crude reaction mixture was diluted with MeOH (1.3 mL), adjusted to pH 2 using TFA and purified by prep-HPLC to give the desired product. LCMS: (M + H) ⁺ = 442.1 / 444.1.

Example 174

Methyl (3S) -3-[((3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-ylamino) carbonyl] piperidine-1-carboxylate

This compound was prepared using a method similar to that described in the synthesis of Example 173. LCMS: (M + H) ⁺ = 458.1 / 460.1.

Example 175

(3S) -1- (cyclohexylcarbonyl) -N- (4-hydroxycyclohexyl) piperidine-3-carboxamide

The compound was prepared using a method similar to that described in the synthesis of Example 1. LCMS: (M + H) ⁺ = 337.2; (M + Na) ⁺ = 359.2.

Example 176

(3S) -N- (4-hydroxycyclohexyl) -1- (piperidin-1-ylcarbonyl) piperidine-3-carboxamide

The compound was prepared using a method similar to that described in the synthesis of Example 1. LCMS: (M + H) ⁺ = 338.1; (M + Na) ⁺ = 360.1.

Example 177

(3S) -N (1) -cyclohexyl-N (3)-(4-hydroxycyclohexyl) piperidine-1,3-dicarboxamide

The compound was prepared using a method analogous to that described in the synthesis of Example 1 starting from cyclohexyl isocyanate and (3S) -N- (4-hydroxycyclohexyl) piperidine-3-carboxamide. LCMS: (M + H) ⁺ = 352.2; (M + Na) ⁺ = 374.2.

Example 178

(3S) -N (3)-(4-hydroxycyclohexyl) -N (1) -phenylpiperidine-1,3-dicarboxamide

This compound was prepared using a method similar to that described in the synthesis of Example 177. LCMS: (M + H) ⁺ = 346.1; (M + Na) ⁺ = 368.1.

Example 179

(3S) -N- (7-oxoasepan-4-yl) -1-phenylpiperidine-3-carboxamide

A solution of (3S) -N- (4-oxocyclohexyl) -1-phenylpiperidine-3-carboxamide (10 mg, 0.00003 mol, prepared in Example 171) in concentrated aqueous HCl (0.5 mL) To sodium azide (2.27 mg, 0.0000350 mol) was added in small portions with gentle stirring for 3 minutes. The temperature was slowly increased to 50 ° C. The reaction temperature was maintained at 50 ° C. for 8.5 hours and then poured into 50 g of crushed ice and water. The solution was basified with cold 50% NaOH and the resulting solution was extracted with EtOAc (× 3). EtOAc extracts were combined, dried over MgSO ₄ , filtered and evaporated to afford the crude product which was purified by prep-HPLC. LCMS: (M + H) ⁺ = 316.2.

Example 180

(3S) -1- [4- (benzyloxy) phenyl] -N- (4-hydroxycyclohexyl) piperidine-3-carboxamide

The compound was prepared using a method similar to that described in the synthesis of Example 128, steps 1 and 2. LCMS: m / z 409.2 (M + H) ⁺ .

Example 181

(3S) -N- (1-methylcyclohexyl) -1-phenylpiperidine-3-carboxamide

The compound was prepared using a method similar to that described in the synthesis of Example 128, steps 1 and 2. LCMS: m / z 301.1 (M + H) ⁺ .

Example 182

(3S) -N- (1-methyl-1-phenylethyl) -1-phenylpiperidine-3-carboxamide

The compound was prepared using a method similar to that described in the synthesis of Example 128, steps 1 and 2. LCMS: m / z 323.2 (M + H) ⁺ .

Example 183

(3S) -N- [2- (4-chlorophenyl) -1-methylethyl] -1-phenylpiperidine-3-carboxamide

The compound was prepared using a method similar to that described in the synthesis of Example 128, steps 1 and 2. LCMS: m / z 357.2 / 359.2 (M + H) ⁺ .

Example A

Enzyme Assay of 11-β-HSD1

All in vitro assays were performed with clear lysate as a source of 11-β-HSD1 activity. HEK-293 transient transfectants expressing epitope-tag versions of sufficient-length human 11-β-HSD1 were obtained by centrifugation. About 2 × 10 ⁷ cells were resuspended in 40 mL of lysis buffer (25 mM Tris-HCl, pH 7.5, 0.1 M NaCl, 1 mM MgCl ₂ and 250 mM sucrose) and lysed in a microfluidizer. The lysate was purified by centrifugation, the supernatant was aliquoted and cooled.

Inhibition of 11-β-HSD1 by the test compound is assayed in vitro with the Scintillation Proximity Assay (SPA). Anhydrous test compound was dissolved at 5 mM in DMSO. It was diluted in DMSO to a concentration suitable for the SPA assay. Two-fold serial dilutions of 0.8 μl of compound were spotted onto 384 well plates in DMSO to 3 log of compound concentration. 20 μl of purified lysate was added to each well. The reaction was added to 20 μl of substrate-cofactor mixture in assay buffer (25 mM Tris-HCl, pH 7.5, 0.1 M NaCl, 1 mM MgCl ₂ ) to give a final concentration of 400 μM NADPH, 25 nM ³ H-cortisone and 0.007% Triton X-100. It started with. Plates were incubated at 37 ° C. for 1 hour. The reaction was quenched by addition of 40 μl of anti-mouse coated SPA beads pre-incubated with 10 μM carbenoxolone and cortisol-specific monoclonal antibodies. The quenched plates were incubated at room temperature for at least 30 minutes prior to reading with a Topcount scintillation counter. Controls without lysate, controls with inhibited lysate and controls without mAb were routinely performed. About 30% of injected cortisone is reduced under these conditions in a response that is not inhibited by 11-β-HSD1.

According to this assay a test compound with an IC ₅₀ value of less than about 20 μM was considered active.

Example B

Cell-Based Assays for HSD Activity

Peripheral blood mononuclear cells (PBMCs) were isolated from normal human volunteers by Ficoll density centrifugation. Cells were plated in 96 well plates in 200 μl of AIM V (Gibco-BRL) medium at 4 × 10 ⁵ cells / well. Cells were stimulated with 50ng / mL recombination human IL-4 (R & D Systems) overnight. The next morning, 200 nM Cortisone (Sigma) was added in the presence or absence of various concentrations of compound. Cells were incubated for 48 hours and supernatants were obtained. Cortisone to cortisol conversion was measured by commercial ELISA (Assay Design).

According to this assay a test compound with an IC ₅₀ value of less than about 20 μM was considered active.

Example C

Cell assays to assess MR antagonism

Assays for MR antagonism were performed essentially as described in Jausons-Loffreda et al. J Biolumin and Chemilumin, 1994, 9: 217-221. Briefly, HEK293 / MSR cells (Invitrogen Corp.) were co-transfected with three plasmids: 1) plasmid designed to express a fusion protein of the GAL4 DNA binding domain and the mineralocorticoid receptor ligand binding domain, 2) firefly lucifer Plasmids comprising a GAL4 upstream activation sequence located upstream of the laze receptor gene (pFR-LUC, Stratagene, Inc.) and 3) the Renilla luciferase receptor gene cloned downstream of thymidine kinase promoter (Promega). Plasmid comprising a. Transfection is performed with FuGENE6 reagent (Roche). Transfected cells were prepared for use in subsequent assays 24 hours after transfection.

To assess the ability of compounds to antagonize MR, cell culture media (E-MEM, 10% charcoal-striped FBS, 2 mM L-glutamine) were subjected to test compounds fed 1 nM aldosterone and applied to transfected cells for 16-18 hours. Dilution). After incubating the cells with the test compound and aldosterone, the activity of firefly luciferase (indicating MR antagonism by aldosterone) and Renilla luciferase (normalization control) were determined using a dual-glo luciferase assay system (Promega). Measured. Antagonism of the mineralocorticoid receptor is measured by observing the test compound's ability to reduce aldosterone-induced firefly luciferase activity.

Test compounds with IC ₅₀ values of less than 100 μM were considered active.

In addition to those described herein, various modifications of the invention are apparent to those skilled in the art from the above description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patent applications and publications cited herein, is incorporated herein by reference in its entirety.

Claims (29)

A compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof. Formula I

In Formula I, Cy is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, each of which is optionally substituted by 1, 2, 3, 4 or 5 -W-X-Y-Z; L is absent or is SO ₂ , C (O), C (O) O or C (O) NR ^g ; Q is cycloalkyl or heterocycloalkyl, each of which is optionally substituted by 1, 2, 3, 4 or 5 -W '-' X'-Y'-Z '; or Q is-(CR ^1a R ^1b ) _m -A; A is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, which are each optionally substituted by 1, 2, 3, 4 or 5 -W '-' X'-Y'-Z '; R ^1a and R ^1b are each independently H, halo, OH, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 hydroxylalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy or C _1-4 hydroxylalkoxy; Wherein at least one R ^1a and R ^1b is not H; m is 1, 2, 3 or 4; R ^N is H, C _1-6 alkyl, aryl, heteroaryl, C _3-7 cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, (C _3-7 cycloalkyl) alkyl or heterocycloalkylalkyl; R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently H, OC (O) R ^{a '} , OC (O) OR ^b' , C ( O) OR ^{b '} , OC (O) NR ^c' R ^{d '} , NR ^c' R ^{d '} , NR ^c' C (O) R ^{a '} , NR ^c' C (O) OR ^{b '} , S (O) R ^{a '} , S (O) NR ^c' R ^{d '} , S (O) ₂ R ^a' , S (O) ₂ NR ^{c '} R ^d' , OR ^{b '} , SR ^b' , C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, Wherein C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkyl Alkyl or heterocycloalkylalkyl is optionally substituted by R ¹⁴ ; or R ⁴ and R ⁵ together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group, which is optionally substituted by R ¹⁴ ; or R ⁶ and R ⁷ together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group, which is optionally substituted by R ¹⁴ ; or R ⁸ and R ⁹ together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group, which is optionally substituted by R ¹⁴ ; or R ¹⁰ and R ¹¹ together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group, which is optionally substituted by R ¹⁴ ; or R ⁴ and R ⁶ together with the carbon atom to which they are attached form a 3-7 membered fused cycloalkyl group or a 3-7 membered fused heterocycloalkyl group, which is optionally substituted by R ¹⁴ ; or R ⁶ and R ⁸ together with the carbon atom to which they are attached form a 3-7 membered fused cycloalkyl group or a 3-7 membered fused heterocycloalkyl group, which is optionally substituted by R ¹⁴ ; or R ⁴ and R ⁹ together form a C _1-3 alkylene bridge, which is optionally substituted by R ¹⁴ ; or R ⁴ and R ¹⁰ together form a C _1-3 alkylene bridge, which is optionally substituted by R ¹⁴ ; or R ³ and R ⁷ together form a C _1-3 alkylene bridge, which is optionally substituted by R ¹⁴ ; or R ³ and R ⁹ together form a C _1-3 alkylene bridge, which is optionally substituted by R ¹⁴ ; or R ⁶ and R ¹⁰ together form a C _1-3 alkylene bridge, which is optionally substituted by R ¹⁴ ; or R ⁹ and R ¹⁰ together form a C _1-3 alkylene bridge, which is optionally substituted by R ¹⁴ ; R ¹⁴ is halo, C _1-4 alkyl, C _1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO ₂ , OR ^{a '} , SR ^a' , C (O) R ^{b '} , C (O) NR ^{c '} R ^d' , C (O) OR ^{a '} , OC (O) R ^b' , OC (O) NR ^{c '} R ^d' , NR ^{c '} R ^d' , NR ^{c '} C (O) R ^{d '} , NR ^c' C (O) OR ^{a '} , S (O) R ^b' , S (O) NR ^{c '} R ^d' , S (O) ₂ R ^{b '} or S (O) ₂ NR ^{c '} R ^d' ; W, W 'and W "are each independently absent or C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynylenyl, O, S, NR ^e , CO, COO, CONR ^e , SO, SO ₂ , SONR ^e or NR ^e CONR ^f , wherein C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynylenyl are each 1, 2 or 3 halo, OH Optionally substituted by C _1-4 alkoxy, C _1-4 haloalkoxy, amino, C _1-4 alkylamino or C _2-8 dialkylamino; X, X 'and X "are each independently absent or are C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, Wherein C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynylenyl, cycloalkyl, heteroaryl or heterocycloalkyl is one or more halo, CN, NO ₂ , OH, C _1-4 Optionally substituted by alkoxy, C _1-4 haloalkoxy, amino, C _1-4 alkylamino or C _2-8 dialkylamino; Y, Y 'and Y "are each independently absent or C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynylenyl, O, S, NR ^e , CO, COO, CONR ^e , SO, SO ₂ , SONR ^e or NR ^e CONR ^f , wherein C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynyleneyl are each 1, 2 or 3 halo, OH Optionally substituted by C _1-4 alkoxy, C _1-4 haloalkoxy, amino, C _1-4 alkylamino or C _2-8 dialkylamino; Z, Z 'and Z "are each independently H, halo, CN, NO ₂ , OH, C _1-4 alkoxy, C _1-4 halo alkoxy, amino, C _1-4 alkylamino, C _2-8 dialkyl Amino, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl may be 1, 2 or 3 halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1- 4} haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO ₂ , OR ^a , SR ^a , C (O) R ^b , C (O) NR ^c R ^d , C (O) OR ^a , OC (O) R ^b , OC (O) NR ^c R ^d , NR ^c R ^d , NR ^c C (O) R ^d , NR ^c C (O) OR ^a , S (O) R ^b , S (O) Optionally substituted by NR ^c R ^d , S (O) ₂ R ^b or S (O) ₂ NR ^c R ^d ; Wherein two -WXYZs attached to the same atom optionally form a 3- to 14-membered cycloalkyl or heterocycloalkyl group, each of which is 1, 2 or 3 -W "-X" -Y "-Z" Optionally substituted by; Wherein two -W'-X'-Y'-Z 'attached to the same atom optionally form a 3- to 14-membered cycloalkyl or heterocycloalkyl group, each of which is 1, 2 or 3 -W Optionally substituted by "-X" -Y "-Z"; Wherein -W-X-Y-Z is not H; Wherein -W'-X'-Y'-Z 'is not H; Wherein -W "-X" -Y "-Z" is not H; R ^a and R ^{a '} are each independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl Wherein C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl; Heterocycloalkyl, heterocycloalkylalkyl is selected from H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl Optionally substituted; R ^b and R ^{b '} are each independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl , Arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cyclo Alkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 Optionally substituted by haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; R ^c and R ^d are each independently H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, Arylalkyl, hetero arylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl , Cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 halo Optionally substituted by alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or R ^c and R ^d together with the N atoms attached thereto form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; R ^{c '} and R ^d' are each independently H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclo Alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, Heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1- Optionally substituted by ₆ haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or R ^{c '} and R ^d' together with the N atom attached to them form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; R ^e and R ^f are each independently H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, Arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl , Cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 halo Optionally substituted by alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or R ^e and R ^f together with the N atoms attached to them form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; R ^g is H, C _1-6 alkyl, aryl, heteroaryl, C _3-7 cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, (C _3-7 cycloalkyl) alkyl or heterocycloalkylalkyl; only, a) C _3-8 cycloalkyl unsubstituted by Q; Adamantyl; 1,2,3,4-tetrahydro-1-naphtanenyl; Bicyclo [2.2.1] hept-2-yl; 2-methylcyclohexyl; Or 1-ethylyl cyclohexyl; At least one of R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ is not H; b) when R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each H, Q is tetrahydrothienyl, S-oxo-tetrahydrothienyl, S, S-dioxo-tetrahydrothienyl, 2,2,6,6-tetramethyl-4-piperidinyl, N-substituted pyrrolidin-3-yl, N-substituted piperidine-4 -Yl or 3,4,5,6-tetra-substituted tetrahydropyran-2-yl. The compound of claim 1, wherein Cy is aryl or heteroaryl, each of which is optionally substituted by 1, 2, 3, 4 or 5 -W-X-Y-Z. The compound of claim 1, wherein Cy is aryl or heteroaryl, each of which is optionally substituted by 1, 2, 3, 4 or 5 -W-X-Y-Z; Wherein W is O or absent, X is absent and Y is absent. The compound of claim 1, wherein Cy is phenyl, naphthyl, pyridyl, pyrimidinyl, quinolinyl, benzoxazolyl, pyridazinyl, pyrazinyl, triazinyl, furanyl or thienyl, respectively. , Optionally substituted by 3, 4 or 5 -WXYZ. The compound of claim 1, wherein Cy is phenyl, naphthyl, pyridyl, pyrimidinyl, quinolinyl, benzoxazolyl, pyridazinyl, pyrazinyl, triazinyl, furanyl or thienyl, respectively. Or optionally substituted by 3 halo, CN, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-6 alkyl or aryl, wherein C _1-6 alkyl or aryl is 1, 2 or 3 halo , Optionally substituted by C _1-6 alkyl, C _1-4 haloalkyl, CN, NO ₂ , OR ^a or SR ^a . The compound of claim 1, wherein Q is cycloalkyl or heterocycloalkyl, each of which is substituted with 1, 2, 3, 4 or 5 -W'-X'-Y'-Z '. The compound of claim 1, wherein Q is cycloalkyl or heterocycloalkyl, each of which is 1, 2, 3, 4 or 5 OH, C _1-4 alkoxy, NR ^e COO (C _1-4 alkyl), NR ^e CO Optionally substituted by (C _1-4 alkyl), NR ^e SO ₂ (C _1-4 alkyl), aryl, heteroaryl, -O-aryl, -O-heteroaryl or-(C _1-4 alkyl) -OH Compound. The compound of claim 1, wherein Q is cycloalkyl or heterocycloalkyl, each of which is substituted by two or more -W'-X'-Y'-Z ', wherein two or more -W'-X'- Two of Y'-Z 'are attached to the same atom and together with the atoms to which they are attached form a 3- to 14-membered cycloalkyl or heterocycloalkyl group, each of which is 1, 2 or 3 -W "; A compound optionally substituted by -X "-Y" -Z ". The compound of claim 1, wherein Q is cycloalkyl or heterocycloalkyl, each of which is substituted by two or more -W'-X'-Y'-Z ', wherein two or more -W'-X'- Two of Y'-Z 'are attached to the same atom and together with the atoms to which they are attached a 3- to 14-membered member, optionally substituted by 1, 2 or 3 -W "-X" -Y "-Z" Compounds that form heterocycloalkyl groups. The compound of claim 1 wherein Q is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, indanyl or 1,2,3,4-tetrahydronaphthalen-2-yl, each of which is optionally 1, 2, A compound substituted by 3, 4 or 5 -W'-X'-Y'-Z '. The compound of claim 1, wherein Q is a 3-14 membered heterocycloalkyl group comprising at least one ring-forming O atom, wherein the 3-14 membered heterocycloalkyl group is optionally 1, 2, 3, A compound substituted by 4 or 5 -W'-X'-Y'-Z '. The compound of claim 1, wherein Q is cyclohexyl substituted by one or more -W'-X'-Y'-Z 'at the 4-position. The compound of claim 1, wherein Q is cyclohexyl substituted by one or more —OH at the 4-position. The compound of claim 1, wherein L is SO ₂ . The compound of claim 1, wherein L is absent. The compound of claim 1, wherein L is C (O), C (O) O or C (O) NR ^g . The compound of claim 1, wherein R ^N is H, C _1-6 alkyl, C _3-7 cycloalkyl or (C _3-7 cycloalkyl) alkyl. The compound of claim 1, wherein R ^N is H. 7. The compound of claim 1, wherein R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently H, OC (O) R ^{a ′} , OC (O) OR ^{b '} , C (O) OR ^b' , OC (O) NR ^{c '} R ^d' , NR ^{c '} R ^d' , NR ^{c '} C (O) R ^a' , NR ^{c '} C (O) OR ^{b '} , S (O) R ^a' , S (O) NR ^{c '} R ^d' , S (O) ₂ R ^{a '} , S (O) ₂ NR ^c' R ^{d '} , OR ^b' , SR ^{b '} , C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or Heterocycloalkylalkyl. The compound of claim 1, wherein R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently H, C _1-10 alkyl or C _1-10 haloalkyl Phosphorus compounds. The compound of claim 1, wherein R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each H. 7. The compound of claim 1, wherein R ³ is C _1-10 alkyl. N-cyclohexyl-1-[(2-nitrophenyl) sulfonyl] piperidine-3-carboxamide; N-cyclohexyl-N-cyclopropyl-1- (phenylsulfonyl) piperidine-3-carboxamide; N-[(1R) -1-phenylethyl] -1- (phenylsulfonyl) piperidine-3-carboxamide; N- (1-methyl-3-phenylpropyl) -1- (phenylsulfonyl) piperidine-3-carboxamide; N- (4-hydroxycyclohexyl) -1- (phenylsulfonyl) piperidine-3-carboxamide; (3R) -N- (4-hydroxycyclohexyl) -1- (phenylsulfonyl) piperidine-3-carboxamide; 1-[(4-chlorophenyl) sulfonyl] -N-cyclohexylpiperidine-3-carboxamide; 1-[(5-chloro-2-fluorophenyl) sulfonyl] -N-cyclohexylpiperidine-3-carboxamide; 1-[(3-chlorophenyl) sulfonyl] -N-cyclohexylpiperidine-3-carboxamide; N-cyclohexyl-1-[(2-fluorophenyl) sulfonyl] piperidine-3-carboxamide; 1-[(3-chloro-2-methylphenyl) sulfonyl] -N-cyclohexylpiperidine-3-carboxamide; N-cyclohexyl-1-{[2- (trifluoromethyl) phenyl] sulfonyl} piperidine-3-carboxamide; (3S) -N-cyclohexyl-1-[(2-fluorophenyl) sulfonyl] piperidine-3-carboxamide; (3S) -N-cyclohexyl-1-[(2-methylphenyl) sulfonyl] piperidine-3-carboxamide; (3S) -N-cyclohexyl-1-[(4-fluoro-2-methylphenyl) sulfonyl] piperidine-3-carboxamide; (3S) -1-[(2-chlorophenyl) sulfonyl] -N-cyclohexylpiperidine-3-carboxamide; (3S) -N-cyclohexyl-1-[(2,6-difluorophenyl) sulfonyl] piperidine-3-carboxamide; (3S) -1-[(3-chloro-4-fluorophenyl) sulfonyl] -N-cyclohexylpiperidine-3-carboxamide; (3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] -N-cyclohexylpiperidine-3-carboxamide; (3S) -1-[(5-chloro-2-fluorophenyl) sulfonyl] -N-cyclohexylpiperidine-3-carboxamide; (3S) -1-[(3-chlorophenyl) sulfonyl] -N-cyclohexylpiperidine-3-carboxamide; (3S) -1-[(3-chloro-2-fluorophenyl) sulfonyl] -N-cyclohexylpiperidine-3-carboxamide; N-[(1S) -1-phenylethyl] -1- (phenylsulfonyl) piperidine-3-carboxamide; (3S) -N-cyclohexyl-1- (pyridin-3-ylsulfonyl) piperidine-3-carboxamide; (3S) -N-cyclohexyl-1-[(3-phenoxyphenyl) sulfonyl] piperidine-3-carboxamide; (3S) -1-[(2-cyanophenyl) sulfonyl] -N-cyclohexylpiperidine-3-carboxamide; (3S) -N-cyclohexyl-1-[(2-phenoxyphenyl) sulfonyl] piperidine-3-carboxamide; (3S) -N-cyclohexyl-1-{[3- (pyridin-4-yloxy) phenyl] sulfonyl} piperidine-3-carboxamide trifluoroacetate; (3S) -N-cyclohexyl-1-[(4-phenoxypyridin-3-yl) sulfonyl] piperidine-3-carboxamide trifluoroacetate; (3S) -N-cyclohexyl-1-{[3- (2-methylphenoxy) phenyl] sulfonyl} piperidine-3-carboxamide; (3S) -1-{[3- (2-chlorophenoxy) phenyl] sulfonyl} -N-cyclohexylpiperidine-3-carboxamide; (3S) -1-{[3- (4-chlorophenoxy) phenyl] sulfonyl} -N-cyclohexylpiperidine-3-carboxamide; (3S) -N-cyclohexyl-1-[(3-methoxyphenyl) sulfonyl] piperidine-3-carboxamide; (3S) -1-[(3-chloro-4-fluorophenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -1-[(2,6-difluorophenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -1-[(2-fluorophenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -1-[(5-chloro-2-fluorophenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -1-[(3-chlorophenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -1-[(3-chloro-2-fluorophenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -N- (trans-4-hydroxycyclohexyl) -1-[(2-methylphenyl) sulfonyl] piperidine-3-carboxamide; (3S) -1-[(4-fluoro-2-methylphenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -1-[(2-chlorophenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -1-[(2-cyanophenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -N- (trans-4-hydroxycyclohexyl) -1-[(3-phenoxyphenyl) sulfonyl] piperidine-3-carboxamide; (3S) -N- (trans-4-hydroxycyclohexyl) -1-{[4- (pyridin-3-yloxy) -phenyl] -sulfonyl} -piperidine-3-carboxamide; (3S) -N- (trans-4-hydroxycyclohexyl) -1-{[3- (2-methylphenoxy) -phenyl] sulfonyl} -piperidine-3-carboxamide; (3S) -1-{[3- (2-Chlorophenoxy) -phenyl] sulfonyl} -N- (trans-4-hydroxycyclohexyl) -piperidine-3-carboxamide; (3S) -N- (trans-4-hydroxycyclohexyl) -1-[(2-methoxyphenyl) sulfonyl] piperidine-3-carboxamide; (3S) -N- (trans-4-hydroxycyclohexyl) -1-[(2-phenoxyphenyl) sulfonyl] piperidine-3-carboxamide; (3S) -N- (trans-4-hydroxycyclohexyl) -1-[(6-phenoxypyridin-3-yl) sulfonyl] piperidine-3-carboxamide; (3S) -N- (trans-4-hydroxycyclohexyl) -1-[(3-isopropylphenyl) sulfonyl] piperidine-3-carboxamide; (3S) -1-[(3,4-dimethoxyphenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -N- (trans-4-hydroxycyclohexyl) -1-[(2-nitrophenyl) sulfonyl] piperidine-3-carboxamide;  (3S) -N-cyclopentyl-1-[(2,6-difluorophenyl) sulfonyl] piperidine-3-carboxamide; (3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] -N-cyclopentylpiperidine-3-carboxamide; (3S) -1-[(3-chlorophenyl) sulfonyl] -N-cyclopentylpiperidine-3-carboxamide; (3S) -N- [trans-4- (acetylamino) cyclohexyl] -1- (phenylsulfonyl) piperidine-3-carboxamide; (3S) -N- {trans-4-[(methylsulfonyl) amino] cyclohexyl} -1- (phenylsulfonyl) piperidine-3-carboxamide; Methyl [trans-4-({[(3S) -1- (phenylsulfonyl) piperidin-3-yl] carbonyl} amino) cyclohexyl] carbamate; (3S) -N- (3-hydroxycyclohexyl) -1- (phenylsulfonyl) piperidine-3-carboxamide; (3S) -1-[(2-fluorophenyl) sulfonyl] -N- (3-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -1-[(5-chloro-2-fluorophenyl) sulfonyl] -N- (3-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] -N- (3-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -N- (3-hydroxycyclohexyl) -1-[(3-methoxyphenyl) sulfonyl] piperidine-3-carboxamide; (3S) -1-[(3-chlorophenyl) sulfonyl] -N- (3-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -1-[(2-bromophenyl) sulfonyl] -N- (3-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -N- (3-hydroxycyclohexyl) -1-[(3-methylphenyl) sulfonyl] piperidine-3-carboxamide; (3S) -1-[(3-fluorophenyl) sulfonyl] -N- (3-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -1-[(2,6-dichlorophenyl) sulfonyl] -N- (3-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -1-[(2,5-dimethylphenyl) sulfonyl] -N- (3-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -1-[(3-bromophenyl) sulfonyl] -N- (3-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -1-[(2,5-dichlorophenyl) sulfonyl] -N- (3-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -1-[(2,4-difluorophenyl) sulfonyl] -N- (3-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -1-[(3,5-dichlorophenyl) sulfonyl] -N- (3-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -1-[(2,5-difluorophenyl) sulfonyl] -N- (3-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -1-[(2-bromophenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -N- (trans-4-hydroxycyclohexyl) -1-[(3-methylphenyl) sulfonyl] piperidine-3-carboxamide; (3S) -1-[(3-fluorophenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -1-[(2,6-dichlorophenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -1-[(2,5-dimethylphenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -1-[(3-bromophenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -1-[(2,5-dichlorophenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -1-[(2,4-difluorophenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -1-[(3,5-dichlorophenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -1-[(2,3-dichlorophenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -1-[(2,5-difluorophenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -N- (trans-4-hydroxycyclohexyl) -1- (2-thienylsulfonyl) piperidine-3-carboxamide; (3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] -N-cycloheptylpiperidine-3-carboxamide; (3S) -N-cycloheptyl-1-[(2-fluorophenyl) sulfonyl] piperidine-3-carboxamide; (3S) -1-[(2-bromophenyl) sulfonyl] -N-cycloheptylpiperidine-3-carboxamide; (3S) -1-[(3-chlorophenyl) sulfonyl] -N-cycloheptylpiperidine-3-carboxamide; (3S) -N-cycloheptyl-1-[(3-methylphenyl) sulfonyl] piperidine-3-carboxamide; (3S) -1- (phenylsulfonyl) -N- (tetrahydro-2H-pyran-4-yl) piperidine-3-carboxamide; (3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] -N- (tetrahydro-2H-pyran-4-yl) piperidine-3-carboxamide; (3S) -1-[(3-methoxyphenyl) sulfonyl] -N- (tetrahydro-2H-pyran-4-yl) piperidine-3-carboxamide; (3S) -1- (phenylsulfonyl) -N- [4- (pyridin-4-yloxy) cyclohexyl] piperidine-3-carboxamide; N-cyclohexyl-3-methyl-1- (phenylsulfonyl) piperidine-3-carboxamide; (3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] -N- (3-oxo-3H-spiro [2-benzofuran-1,1'-cyclohexane] -4'-yl) Piperidine-3-carboxamide; (3S) -1-[(2,6-dichlorophenyl) sulfonyl] -N- (3-oxo-3H-spiro [2-benzofuran-1,1'-cyclohexane] -4'-yl) pi Ferridine-3-carboxamide; (3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] -N- (cyclopropylmethyl) -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -N- (cyclopropylmethyl) -1-[(2,6-dichlorophenyl) sulfonyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -N-cycloheptyl-1-[(2,6-dichlorophenyl) sulfonyl] piperidine-3-carboxamide; (3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] -N- [trans-4- (hydroxymethyl) cyclohexyl] piperidine-3-carboxamide; (3R) -N- (trans-4-hydroxycyclohexyl) -1- (quinolin-8-ylsulfonyl) piperidine-3-carboxamide; (3S) -N- (trans-4-hydroxycyclohexyl) -1- (1-naphthylsulfonyl) piperidine-3-carboxamide; (3S) -N- (trans-4-hydroxycyclohexyl) -1- (2-naphthylsulfonyl) piperidine-3-carboxamide; (3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] -N-[(1R) -1,2,3,4-tetrahydronaphthalen-1-yl] piperidine-3-car Boxamide; (3S) -1-benzoyl-N- (4-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] -N- (cis-4-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -1-[(2-chlorophenyl) sulfonyl] -N- (cis-4-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -1- (biphenyl-4-ylsulfonyl) -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -N- (trans-4-hydroxycyclohexyl) -1-{[4- (trifluoromethyl) phenyl] sulfonyl} piperidine-3-carboxamide; (3S) -1-{[3- (difluoromethoxy) phenyl] sulfonyl} -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -1-{[3- (4-fluorophenoxy) phenyl] sulfonyl} -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -N- (trans-4-hydroxycyclohexyl) -1-{[3- (trifluoromethoxy) phenyl] sulfonyl} piperidine-3-carboxamide; (3S) -1- (biphenyl-3-ylsulfonyl) -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] -N- (1,2,3,4-tetrahydronaphthalen-2-yl) piperidine-3-carboxamide; (3S) -1-[(2,6-dichlorophenyl) sulfonyl] -N- (1,2,3,4-tetrahydronaphthalen-2-yl) piperidine-3-carboxamide; (3S) -1- (phenylsulfonyl) -N- [trans-4- (pyridin-4-yloxy) cyclohexyl] piperidine-3-carboxamide; (3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] -N- [trans-4- (pyridin-4-yloxy) cyclohexyl] piperidine-3-carboxamide; (3S) -N-cyclohexyl-1-phenylpiperidine-3-carboxamide; (3S) -N-1-adamantyl-1-phenylpiperidine-3-carboxamide; (3S) -N- (3-hydroxy-1-adamantyl) -1-phenylpiperidine-3-carboxamide; (3S) -N- (trans-4-hydroxycyclohexyl) -1-phenylpiperidine-3-carboxamide; (3S) -N-cyclohexyl-1- (3-methylphenyl) piperidine-3-carboxamide; (3S) -N-cyclohexyl-1- (2-fluorophenyl) piperidine-3-carboxamide; (3S) -N-cyclohexyl-1- (4-methoxyphenyl) piperidine-3-carboxamide; (3S) -N-cyclohexyl-1- [2- (trifluoromethyl) phenyl] piperidine-3-carboxamide; (3S) -N-cyclohexyl-1- (2-methylphenyl) piperidine-3-carboxamide; (3S) -N-cyclohexyl-1- (3-methoxyphenyl) piperidine-3-carboxamide; (3S) -N-cyclohexyl-1- [3- (trifluoromethyl) phenyl] piperidine-3-carboxamide; (3S) -N-cyclohexyl-1- [4- (trifluoromethyl) phenyl] piperidine-3-carboxamide; (3S) -N-cyclohexyl-1- (4-phenoxyphenyl) piperidine-3-carboxamide; (3S) -1- (4-cyano-2-methylphenyl) -N-cyclohexylpiperidine-3-carboxamide; (3S) -N-cyclohexyl-1- (4-fluoro-2-methylphenyl) piperidine-3-carboxamide; (3S) -N-cycloheptyl-1-phenylpiperidine-3-carboxamide; (3S) -N-cyclohexyl-1-pyridin-2-ylpiperidine-3-carboxamide; (3S) -N-cyclohexyl-1- [5- (trifluoromethyl) pyridin-2-yl] piperidine-3-carboxamide; (3S) -N-cyclohexyl-1-pyrazin-2-ylpiperidine-3-carboxamide; (3S) -1- (1,3-benzoxazol-2-yl) -N-cyclohexylpiperidine-3-carboxamide; Methyl 6-((3S) -3-{[(4-hydroxycyclohexyl) amino] carbonyl} piperidin-1-yl) nicotinate; (3S) -N- (4-hydroxycyclohexyl) -1-quinolin-4-ylpiperidine-3-carboxamide; (3S) -N- (4-hydroxycyclohexyl) -1- (2-methylquinolin-4-yl) piperidine-3-carboxamide; 6-((3S) -3-{[(4-hydroxycyclohexyl) amino] carbonyl} piperidin-1-yl) nicotinic acid; (3S) -N- (4-hydroxycyclohexyl) -1- (6-phenylpyridazin-3-yl) piperidine-3-carboxamide; (3S) -1- (5-bromopyridin-2-yl) -N- (4-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -N- (4-hydroxycyclohexyl) -1- (5-phenylpyridin-2-yl) piperidine-3-carboxamide; (3S) -1- [5- (4-chlorophenyl) pyridin-2-yl] -N- (4-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -1- [5- (3,4-difluorophenyl) pyridin-2-yl] -N- (4-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -1- {2-bromo-5-[(methylamino) carbonyl] phenyl} -N- (4-hydroxycyclohexyl) piperidine-3-carboxamide; Tert-butyl 6-((3S) -3-{[(4-hydroxycyclohexyl) amino] carbonyl} piperidin-1-yl) -3 ', 6'-dihydro-3,4' Bipyridine-1 '(2'H) -carboxylate; (3S) -N- (4-hydroxycyclohexyl) -1- [5- (4-methoxyphenyl) pyridin-2-yl] piperidine-3-carboxamide; (3S) -1- [5- (2-fluorophenyl) pyridin-2-yl] -N- (4-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -1- {5- [4- (acetylamino) phenyl] pyridin-2-yl} -N- (4-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -1- {5- [3- (acetylamino) phenyl] pyridin-2-yl} -N- (4-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -N- (4-hydroxycyclohexyl) -1- (6'-methoxy-3,3'-bipyridin-6-yl) piperidine-3-carboxamide; (3S) -N- (4-hydroxycyclohexyl) -1- (5'-methoxy-3,3'-bipyridin-6-yl) piperidine-3-carboxamide; (3S) -N- (4-hydroxycyclohexyl) -1- [5- (1-methyl-1H-pyrazol-4-yl) pyridin-2-yl] piperidine-3-carboxamide; (3S) -1-biphenyl-4-yl-N- (4-hydroxycyclohexyl) piperidine-3-carboxamide; Methyl 4- [4-((3S) -3-{[(4-hydroxycyclohexyl) amino] carbonyl} piperidin-1-yl) phenyl] -3,6-dihydropyridine-1 (2H ) -Carboxylate or a pharmaceutically acceptable salt thereof; (3S) -N-cyclohexyl-1- (2-fluoro-4-pyridin-4-ylphenyl) piperidine-3-carboxamide; (3S) -1- (2-fluoro-4-pyridin-4-ylphenyl) -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -N- (4-oxocyclohexyl) -1-phenylpiperidine-3-carboxamide; (3S) -1- [3- (benzyloxy) phenyl] -N- (trans-4-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -1-acetyl-N- (3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-ylpiperidine-3-carboxamide; Methyl (3S) -3-[((3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-ylamino) carbonyl] piperidine-1-carboxylate; (3S) -1- (cyclohexylcarbonyl) -N- (4-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -N- (4-hydroxycyclohexyl) -1- (piperidin-1-ylcarbonyl) piperidine-3-carboxamide; (3S) -N (1) -cyclohexyl-N (3)-(4-hydroxycyclohexyl) piperidine-1,3-dicarboxamide; (3S) -N (3)-(4-hydroxycyclohexyl) -N (1) -phenylpiperidine-1,3-dicarboxamide; (3S) -N- (7-oxoasepan-4-yl) -1-phenylpiperidine-3-carboxamide; (3S) -1- [4- (benzyloxy) phenyl] -N- (4-hydroxycyclohexyl) piperidine-3-carboxamide; (3S) -N- (1-methylcyclohexyl) -1-phenylpiperidine-3-carboxamide; (3S) -N- (1-methyl-1-phenylethyl) -1-phenylpiperidine-3-carboxamide; And A compound selected from (3S) -N- [2- (4-chlorophenyl) -1-methylethyl] -1-phenylpiperidine-3-carboxamide, or a pharmaceutically acceptable salt thereof. A composition comprising the compound of claim 1 or 23 and a pharmaceutically acceptable carrier. A method of modulating 11-β-HSD1 or MR, comprising contacting 11-β-HSD1 or MR with a compound of Formula (I) or a pharmaceutically acceptable salt or prodrug thereof. Formula I

In Formula I, Cy is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, each of which is optionally substituted by 1, 2, 3, 4 or 5 -W-X-Y-Z; L is absent or is SO ₂ , C (O), C (O) O or C (O) NR ^g ; Q is cycloalkyl or heterocycloalkyl, each of which is optionally substituted by 1, 2, 3, 4 or 5 -W'-X'-Y'-Z '; or Q is-(CR ^1a R ^1b ) _m -A; A is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, which are each optionally substituted by 1, 2, 3, 4 or 5 -W '-' X'-Y'-Z '; R ^1a and R ^1b are each independently H, halo, OH, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 hydroxylalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy or C _1-4 hydroxylalkoxy; Wherein at least one R ^1a and R ^1b is not H; m is 1, 2, 3 or 4; R ^N is H, C _1-6 alkyl, aryl, heteroaryl, C _3-7 cycloalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, (C _3-7 cycloalkyl) alkyl or heterocycloalkylalkyl ; R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently H, OC (O) R ^{a '} , OC (O) OR ^b' , C ( O) OR ^{b '} , OC (O) NR ^c' R ^{d '} , NR ^c' R ^{d '} , NR ^c' C (O) R ^{a '} , NR ^c' C (O) OR ^{b '} , S (O) R ^{a '} , S (O) NR ^c' R ^{d '} , S (O) ₂ R ^a' , S (O) ₂ NR ^{c '} R ^d' , OR ^{b '} , SR ^b' , C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, Wherein C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkyl Alkyl or heterocycloalkylalkyl is optionally substituted by R ¹⁴ ; or R ⁴ and R ⁵ together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group, which is optionally substituted by R ¹⁴ ; or R ⁶ and R ⁷ together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group, which is optionally substituted by R ¹⁴ ; or R ⁸ and R ⁹ together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group, which is optionally substituted by R ¹⁴ ; or R ¹⁰ and R ¹¹ together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group, which is optionally substituted by R ¹⁴ ; or R ⁴ and R ⁶ together with the carbon atom to which they are attached form a 3-7 membered fused cycloalkyl group or a 3-7 membered fused heterocycloalkyl group, which is optionally substituted by R ¹⁴ ; or R ⁶ and R ⁸ together with the carbon atom to which they are attached form a 3-7 membered fused cycloalkyl group or a 3-7 membered fused heterocycloalkyl group, which is optionally substituted by R ¹⁴ ; or R ⁴ and R ⁹ together form a C _1-3 alkylene bridge, which is optionally substituted by R ¹⁴ ; or R ⁴ and R ¹⁰ together form a C _1-3 alkylene bridge, which is optionally substituted by R ¹⁴ ; or R ³ and R ⁷ together form a C _1-3 alkylene bridge, which is optionally substituted by R ¹⁴ ; or R ³ and R ⁹ together form a C _1-3 alkylene bridge, which is optionally substituted by R ¹⁴ ; or R ⁶ and R ¹⁰ together form a C _1-3 alkylene bridge, which is optionally substituted by R ¹⁴ ; or R ⁹ and R ¹⁰ together form a C _1-3 alkylene bridge, which is optionally substituted by R ¹⁴ ; R ¹⁴ is halo, C _1-4 alkyl, C _1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO ₂ , OR ^{a '} , SR ^a' , C (O) R ^{b '} , C (O) NR ^{c '} R ^d' , C (O) OR ^{a '} , OC (O) R ^b' , OC (O) NR ^{c '} R ^d' , NR ^{c '} R ^d' , NR ^{c '} C (O) R ^{d '} , NR ^c' C (O) OR ^{a '} , S (O) R ^b' , S (O) NR ^{c '} R ^d' , S (O) ₂ R ^{b '} or S (O) ₂ NR ^{c '} R ^d ; W, W 'and W "are each independently absent or C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynylenyl, O, S, NR ^e , CO, COO, CONR ^e , SO, SO ₂ , SONR ^e or NR ^e CONR ^f , wherein C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynylenyl are each 1, 2 or 3 halo, OH Optionally substituted by C _1-4 alkoxy, C _1-4 haloalkoxy, amino, C _1-4 alkylamino or C _2-8 dialkylamino; X, X 'and X "are each independently absent or are C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, Wherein C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynylenyl, cycloalkyl, heteroaryl or heterocycloalkyl is one or more halo, CN, NO ₂ , OH, C _1-4 Optionally substituted by alkoxy, C _1-4 haloalkoxy, amino, C _1-4 alkylamino or C _2-8 dialkylamino; Y, Y 'and Y "are each independently absent or C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynylenyl, O, S, NR ^e , CO, COO, CONR ^e , SO, SO ₂ , SONR ^e or NR ^e CONR ^f , wherein C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynyleneyl are each 1, 2 or 3 halo, OH Optionally substituted by C _1-4 alkoxy, C _1-4 haloalkoxy, amino, C _1-4 alkylamino or C _2-8 dialkylamino; Z, Z 'and Z "are each independently H, halo, CN, NO ₂ , OH, C _1-4 alkoxy, C _1-4 haloalkoxy, amino, C _1-4 alkylamino, C _2-8 dialkyl Amino, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl may be 1, 2 or 3 halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1- 4} haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO ₂ , OR ^a , SR ^a , C (O) R ^b , C (O) NR ^c R ^d , C (O) OR ^a , OC (O) R ^b , OC (O) NR ^c R ^d , NR ^c R ^d , NR ^c C (O) R ^d , NR ^c C (O) OR ^a , S (O) R ^b , S (O) Optionally substituted by NR ^c R ^d , S (O) ₂ R ^b or S (O) ₂ NR ^c R ^d ; Wherein two -WXYZs attached to the same atom optionally form a 3- to 14-membered cycloalkyl or heterocycloalkyl group, each of which is 1, 2 or 3 -W "-X" -Y "-Z" Optionally substituted by; Wherein two -W'-X'-Y'-Z 'attached to the same atom optionally form a 3- to 14-membered cycloalkyl or heterocycloalkyl group, each of which is 1, 2 or 3 -W Optionally substituted by "-X" -Y "-Z"; Wherein -W-X-Y-Z is not H; Wherein -W'-X'-Y'-Z 'is not H; Wherein -W "-X" -Y "-Z" is not H; R ^a and R ^{a '} are each independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl Wherein C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl; Heterocycloalkyl, heterocycloalkylalkyl is selected from H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl Optionally substituted; R ^b and R ^{b '} are each independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl , Arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cyclo Alkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 Optionally substituted by haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; R ^c and R ^d are each independently H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, Arylalkyl, hetero arylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl , Cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 halo Optionally substituted by alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or R ^c and R ^d together with the N atoms attached thereto form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; R ^{c '} and R ^d' are each independently H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclo Alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, Heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1- Optionally substituted by ₆ haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or R ^{c '} and R ^d' together with the N atom attached to them form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; R ^e and R ^f are each independently H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, Arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl , Cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 halo Optionally substituted by alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or R ^e and R ^f together with the N atoms attached to them form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; R ^g is H, C _1-6 alkyl, aryl, heteroaryl, C _3-7 cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, (C _3-7 cycloalkyl) alkyl or heterocycloalkylalkyl. The method of claim 25, wherein the regulation is inhibition. A method of inhibiting the conversion of cortisone to cortisol in a cell comprising contacting the cell with a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof. Formula I

In Formula I, Cy is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, each of which is optionally substituted by 1, 2, 3, 4 or 5 -W-X-Y-Z; L is absent or is SO ₂ , C (O), C (O) O or C (O) NR ^g ; Q is cycloalkyl or heterocycloalkyl, each of which is optionally substituted by 1, 2, 3, 4 or 5 -W'-X'-Y'-Z '; or Q is-(CR ^1a R ^1b ) _m -A; A is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, which are each optionally substituted by 1, 2, 3, 4 or 5 -W '-' X'-Y'-Z '; R ^1a and R ^1b are each independently H, halo, OH, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 hydroxylalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy or C _1-4 hydroxylalkoxy; Wherein at least one R ^1a and R ^1b is not H; m is 1, 2, 3 or 4; R ^N is H, C _1-6 alkyl, aryl, heteroaryl, C _3-7 cycloalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, (C _3-7 cycloalkyl) alkyl or heterocycloalkylalkyl ; R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently H, OC (O) R ^{a '} , OC (O) OR ^b' , C ( O) OR ^{b '} , OC (O) NR ^c' R ^{d '} , NR ^c' R ^{d '} , NR ^c' C (O) R ^{a '} , NR ^c' C (O) OR ^{b '} , S (O) R ^{a '} , S (O) NR ^c' R ^{d '} , S (O) ₂ R ^a' , S (O) ₂ NR ^{c '} R ^d' , OR ^{b '} , SR ^b' , C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, Wherein C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkyl Alkyl or heterocycloalkylalkyl is optionally substituted by R ¹⁴ ; or R ⁴ and R ⁵ together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group, which is optionally substituted by R ¹⁴ ; or R ⁶ and R ⁷ together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group, which is optionally substituted by R ¹⁴ ; or R ⁸ and R ⁹ together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group, which is optionally substituted by R ¹⁴ ; or R ¹⁰ and R ¹¹ together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group, which is optionally substituted by R ¹⁴ ; or R ⁴ and R ⁶ together with the carbon atom to which they are attached form a 3-7 membered fused cycloalkyl group or a 3-7 membered fused heterocycloalkyl group, which is optionally substituted by R ¹⁴ ; or R ⁶ and R ⁸ together with the carbon atom to which they are attached form a 3-7 membered fused cycloalkyl group or a 3-7 membered fused heterocycloalkyl group, which is optionally substituted by R ¹⁴ ; or R ⁴ and R ⁹ together form a C _1-3 alkylene bridge, which is optionally substituted by R ¹⁴ ; or R ⁴ and R ¹⁰ together form a C _1-3 alkylene bridge, which is optionally substituted by R ¹⁴ ; or R ³ and R ⁷ together form a C _1-3 alkylene bridge, which is optionally substituted by R ¹⁴ ; or R ³ and R ⁹ together form a C _1-3 alkylene bridge, which is optionally substituted by R ¹⁴ ; or R ⁶ and R ¹⁰ together form a C _1-3 alkylene bridge, which is optionally substituted by R ¹⁴ ; or R ⁹ and R ¹⁰ together form a C _1-3 alkylene bridge, which is optionally substituted by R ¹⁴ ; R ¹⁴ is halo, C _1-4 alkyl, C _1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO ₂ , OR ^{a '} , SR ^a' , C (O) R ^{b '} , C (O) NR ^{c '} R ^d' , C (O) OR ^{a '} , OC (O) R ^b' , OC (O) NR ^{c '} R ^d' , NR ^{c '} R ^d' , NR ^{c '} C (O) R ^{d '} , NR ^c' C (O) OR ^{a '} , S (O) R ^b' , S (O) NR ^{c '} R ^d' , S (O) ₂ R ^{b '} or S (O) ₂ NR ^{c '} R ^d' ; W, W 'and W "are each independently absent or C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynylenyl, O, S, NR ^e , CO, COO, CONR ^e , SO, SO ₂ , SONR ^e or NR ^e CONR ^f , wherein C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynylenyl are each 1, 2 or 3 halo, OH Optionally substituted by C _1-4 alkoxy, C _1-4 haloalkoxy, amino, C _1-4 alkylamino or C _2-8 dialkylamino; X, X 'and X "are each independently absent or are C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, Wherein C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynylenyl, cycloalkyl, heteroaryl or heterocycloalkyl is one or more halo, CN, NO ₂ , OH, C _1-4 Optionally substituted by alkoxy, C _1-4 haloalkoxy, amino, C _1-4 alkylamino or C _2-8 dialkylamino; Y, Y 'and Y "are each independently absent or C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynylenyl, O, S, NR ^e , CO, COO, CONR ^e , SO, SO ₂ , SONR ^e or NR ^e CONR ^f , wherein C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynyleneyl are each 1, 2 or 3 halo, OH Optionally substituted by C _1-4 alkoxy, C _1-4 haloalkoxy, amino, C _1-4 alkylamino or C _2-8 dialkylamino; Z, Z 'and Z "are each independently H, halo, CN, NO ₂ , OH, C _1-4 alkoxy, C _1-4 halo alkoxy, amino, C _1-4 alkylamino, C _2-8 dialkyl Amino, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl may be 1, 2 or 3 halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1- 4} haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO ₂ , OR ^a , SR ^a , C (O) R ^b , C (O) NR ^c R ^d , C (O) OR ^a , OC (O) R ^b , OC (O) NR ^c R ^d , NR ^c R ^d , NR ^c C (O) R ^d , NR ^c C (O) OR ^a , S (O) R ^b , S (O) Optionally substituted by NR ^c R ^d , S (O) ₂ R ^b or S (O) ₂ NR ^c R ^d ; Wherein two -WXYZs attached to the same atom optionally form a 3- to 14-membered cycloalkyl or heterocycloalkyl group, each of which is 1, 2 or 3 -W "-X" -Y "-Z" Optionally substituted by; Wherein two -W'-X'-Y'-Z 'attached to the same atom optionally form a 3- to 14-membered cycloalkyl or heterocycloalkyl group, each of which is 1, 2 or 3 -W Optionally substituted by "-X" -Y "-Z"; Wherein -W-X-Y-Z is not H; Wherein -W'-X'-Y'-Z 'is not H; Wherein -W "-X" -Y "-Z" is not H; R ^a and R ^{a '} are each independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl Wherein C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl; Heterocycloalkyl, heterocycloalkylalkyl is selected from H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl Optionally substituted; R ^b and R ^{b '} are each independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl , Arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cyclo Alkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 Optionally substituted by haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; R ^c and R ^d are each independently H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, Arylalkyl, hetero arylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl , Cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 halo Optionally substituted by alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or R ^c and R ^d together with the N atoms attached thereto form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; R ^{c '} and R ^d' are each independently H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclo Alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, Heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1- Optionally substituted by ₆ haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or R ^{c '} and R ^d' together with the N atom attached to them form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; R ^e and R ^f are each independently H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, Arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl , Cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 halo Optionally substituted by alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or R ^e and R ^f together with the N atoms attached to them form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; R ^g is H, C _1-6 alkyl, aryl, heteroaryl, C _3-7 cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, (C _3-7 cycloalkyl) alkyl or heterocycloalkylalkyl. A method of treating a disease in a patient in which the disease is involved in the expression or activity of 11-β-HSD1 or MR, comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof. Formula I

In Formula I, Cy is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, each of which is optionally substituted by 1, 2, 3, 4 or 5 -W-X-Y-Z; L is absent or is SO ₂ , C (O), C (O) O or C (O) NR ^g ; Q is cycloalkyl or heterocycloalkyl, each of which is optionally substituted by 1, 2, 3, 4 or 5 -W'-X'-Y'-Z '; or Q is-(CR ^1a R ^1b ) _m -A; A is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, which are each optionally substituted by 1, 2, 3, 4 or 5 -W '-' X'-Y'-Z '; R ^1a and R ^1b are each independently H, halo, OH, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 hydroxylalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy or C _1-4 hydroxylalkoxy; Wherein at least one R ^1a and R ^1b is not H; m is 1, 2, 3 or 4; R ^N is H, C _1-6 alkyl, aryl, heteroaryl, C _3-7 cycloalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, (C _3-7 cycloalkyl) alkyl or heterocycloalkylalkyl ; R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently H, OC (O) R ^{a '} , OC (O) OR ^b' , C ( O) OR ^{b '} , OC (O) NR ^c' R ^{d '} , NR ^c' R ^{d '} , NR ^c' C (O) R ^{a '} , NR ^c' C (O) OR ^{b '} , S (O) R ^{a '} , S (O) NR ^c' R ^{d '} , S (O) ₂ R ^a' , S (O) ₂ NR ^{c '} R ^d' , OR ^{b '} , SR ^b' , C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, Wherein C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkyl Alkyl or heterocycloalkylalkyl is optionally substituted by R ¹⁴ ; or R ⁴ and R ⁵ together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group, which is optionally substituted by R ¹⁴ ; or R ⁶ and R ⁷ together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group, which is optionally substituted by R ¹⁴ ; or R ⁸ and R ⁹ together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group, which is optionally substituted by R ¹⁴ ; or R ¹⁰ and R ¹¹ together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group, which is optionally substituted by R ¹⁴ ; or R ⁴ and R ⁶ together with the carbon atom to which they are attached form a 3-7 membered fused cycloalkyl group or a 3-7 membered fused heterocycloalkyl group, which is optionally substituted by R ¹⁴ ; or R ⁶ and R ⁸ together with the carbon atom to which they are attached form a 3-7 membered fused cycloalkyl group or a 3-7 membered fused heterocycloalkyl group, which is optionally substituted by R ¹⁴ ; or R ⁴ and R ⁹ together form a C _1-3 alkylene bridge, which is optionally substituted by R ¹⁴ ; or R ⁴ and R ¹⁰ together form a C _1-3 alkylene bridge, which is optionally substituted by R ¹⁴ ; or R ³ and R ⁷ together form a C _1-3 alkylene bridge, which is optionally substituted by R ¹⁴ ; or R ³ and R ⁹ together form a C _1-3 alkylene bridge, which is optionally substituted by R ¹⁴ ; or R ⁶ and R ¹⁰ together form a C _1-3 alkylene bridge, which is optionally substituted by R ¹⁴ ; or R ⁹ and R ¹⁰ together form a C _1-3 alkylene bridge, which is optionally substituted by R ¹⁴ ; R ¹⁴ is halo, C _1-4 alkyl, C _1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO ₂ , OR ^{a '} , SR ^a' , C (O) R ^{b '} , C (O) NR ^{c '} R ^d' , C (O) OR ^{a '} , OC (O) R ^b' , OC (O) NR ^{c '} R ^d' , NR ^{c '} R ^d' , NR ^{c '} C (O) R ^{d '} , NR ^c' C (O) OR ^{a '} , S (O) R ^b' , S (O) NR ^{c '} R ^d' , S (O) ₂ R ^{b '} or S (O) ₂ NR ^{c '} R ^d' ; W, W 'and W "are each independently absent or C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynylenyl, O, S, NR ^e , CO, COO, CONR ^e , SO, SO ₂ , SONR ^e or NR ^e CONR ^f , wherein C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynylenyl are each 1, 2 or 3 halo, OH Optionally substituted by C _1-4 alkoxy, C _1-4 haloalkoxy, amino, C _1-4 alkylamino or C _2-8 dialkylamino; X, X 'and X "are each independently absent or are C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, Wherein C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynylenyl, cycloalkyl, heteroaryl or heterocycloalkyl is one or more halo, CN, NO ₂ , OH, C _1-4 Optionally substituted by alkoxy, C _1-4 haloalkoxy, amino, C _1-4 alkylamino or C _2-8 dialkylamino; Y, Y 'and Y "are each independently absent or C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynylenyl, O, S, NR ^e , CO, COO, CONR ^e , SO, SO ₂ , SONR ^e or NR ^e CONR ^f , wherein C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynyleneyl are each 1, 2 or 3 halo, OH Optionally substituted by C _1-4 alkoxy, C _1-4 haloalkoxy, amino, C _1-4 alkylamino or C _2-8 dialkylamino; Z, Z 'and Z "are each independently H, halo, CN, NO ₂ , OH, C _1-4 alkoxy, C _1-4 halo alkoxy, amino, C _1-4 alkylamino, C _2-8 dialkyl Amino, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl may be 1, 2 or 3 halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1- 4} haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO ₂ , OR ^a , SR ^a , C (O) R ^b , C (O) NR ^c R ^d , C (O) OR ^a , OC (O) R ^b , OC (O) NR ^c R ^d , NR ^c R ^d , NR ^c C (O) R ^d , NR ^c C (O) OR ^a , S (O) R ^b , S (O) Optionally substituted by NR ^c R ^d , S (O) ₂ R ^b or S (O) ₂ NR ^c R ^d ; Wherein two -WXYZs attached to the same atom optionally form a 3- to 14-membered cycloalkyl or heterocycloalkyl group, each of which is 1, 2 or 3 -W "-X" -Y "-Z" Optionally substituted by;  Wherein two -W'-X'-Y'-Z 'attached to the same atom optionally form a 3- to 14-membered cycloalkyl or heterocycloalkyl group, each of which is 1, 2 or 3 -W Optionally substituted by "-X" -Y "-Z"; Wherein -W-X-Y-Z is not H; Wherein -W'-X'-Y'-Z 'is not H; Wherein -W "-X" -Y "-Z" is not H; R ^a and R ^{a '} are each independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl Wherein C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl; Heterocycloalkyl, heterocycloalkylalkyl is selected from H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl Optionally substituted; R ^b and R ^{b '} are each independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl , Arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cyclo Alkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 Optionally substituted by haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; R ^c and R ^d are each independently H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, Arylalkyl, hetero arylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl , Cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 halo Optionally substituted by alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or R ^c and R ^d together with the N atoms attached thereto form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; R ^{c '} and R ^d' are each independently H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclo Alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, Heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1- Optionally substituted by ₆ haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or R ^{c '} and R ^d' together with the N atom attached to them form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; R ^e and R ^f are each independently H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, Arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl , Cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 halo Optionally substituted by alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or R ^e and R ^f together with the N atoms attached to them form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; R ^g is H, C _1-6 alkyl, aryl, heteroaryl, C _3-7 cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, (C _3-7 cycloalkyl) alkyl or heterocycloalkylalkyl. 29. The disease according to claim 28, wherein the disease is obesity, diabetes, glucose intolerance, insulin resistance, hyperglycemia, hypertension, hyperlipidemia, cognitive impairment, depression, dementia, glaucoma, cardiovascular disease, osteoporosis, inflammation, cardiovascular, kidney or inflammatory disease, Heart failure, atherosclerosis, arteriosclerosis, coronary artery disease, thrombosis, angina, peripheral vascular disease, vascular wall damage, stroke, dyslipidemia, hyperlipoproteinemia, diabetic dyslipidemia, mixed dyslipidemia, hypercholesterol Hypertension, hypertriglyceridemia, metabolic syndrome or general aldosterone-related target organ damage.