ZA200609236B - Amido compounds and their use as pharmaceuticals - Google Patents

Description

AMIDO COMPOUNDS AND

THEIR USE AS PHARMACEUTICALS

FIELD OF THE INVENTION

The present invention relates to modulators of 11-B hydroxyl steroid dehydrogenase type 1 (11BHSDI1) and/or mineralocorticoid receptor (MR), 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 profound and diverse physiological effects on development, neurobiology, inflammation, blood pressure, metabolism and programmed cell death. In humans, the primary endogenously-produced glucocorticoid is cortisol. Cortisol is synthesized in the zona fasciculate of the adrenal cortex under the control of a short-term neuroendocrine feedback circuit called the hypothalamic-pituitary-adrenal (HPA) axis. Adrenal production of cortisol proceeds under the control of adrenocorticotrophic hormone (ACTH), a factor produced and secreted by the anterior pituitary. Production of ACTH in the anterior pituitary is itself highly regulated, driven by corticotropin releasing hormone (CRH) produced by the paraventricular nucleus of the hypothalamus.

The HPA axis maintains circulating cortisol concentrations within restricted limits, with forward drive at the diurnal maximum or during periods of stress, and is rapidly attenuated by a negative feedback loop resulting from the ability of cortisol to suppress ACTH production in the anterior pituitary and

CRH production in the hypothalamus.

Aldosterone is another hormone produced by the adrenal cortex; aldosterone regulates sodium and potassium homeostasis. Fifty years ago, a role for aldosterone excess in human disease was reported in a description of the syndrome of primary aldosteronism (Conn, (1955), J. Lab. Clin. Med. 45: 6-17). It is now clear that elevated levels of aldosterone are associated with deleterious effects on the heart and kidneys, and are a major contributing factor to morbidity and mortality in both heart failure and hypertension.

Two members of the nuclear hormone receptor superfamily, glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), mediate cortisol function in vivo, while the primary intracellular receptor for aldosterone is the MR. These receptors are also referred to as ‘ligand-dependent transcription factors,” because their functionality is dependent on the receptor being bound to its ligand (for example, cortisol); upon ligand-binding these receptors directly modulate transcription via

DNA-binding zinc finger domains and transcriptional activation domains.

Historically, the major determinants of glucocorticoid action were attributed to three primary factors: 1) circulating levels of glucocorticoid (driven primarily by the HPA axis), 2) protein binding of glucocorticoids in circulation, and 3) intracellular receptor density inside target tissues. Recently, a fourth determinant of glucocorticoid function was identified: tissue-specific pre-receptor metabolism by glucocorticoid-activating and -inactivating enzymes. These 11-beta-hydroxysteroid dehydrogenase (11-B-HSD) enzymes act as pre-receptor control enzymes that modulate activation of the GR and MR by regulation of glucocorticoid hormones. To date, two distinct isozymes of 11-beta-HSD have been cloned and characterized: 11BHSD1 (also known as 11-beta-HSD type 1, 11betaHSD1, HSD11Bl1,

HDL, and HSDI11L) and 11BHSD2. 11BHSD! and 11BHSD2 catalyze the interconversion of hormonally active cortisol (corticosterone in rodents) and inactive cortisone (11- dehydrocorticosterone in rodents). 11BHSD1 is widely distributed in rat and human tissues; expression of the enzyme and corresponding mRNA have been detected in lung, testis, and most abundantly in liver and adipose tissue. 11BHSD1 catalyzes both 11-beta-dehydrogenation and the reverse 11-oxoreduction reaction, although 11BHSDI acts predominantly as a NADPH-dependent oxoreductase in intact cells and tissues, catalyzing the activation of cortiso! from inert cortisone (Low et al. (1994) J. Mol. Endocrin. 13: 167-174) and has been reported to regulate glucocorticoid access to the GR. Conversely, 113HSD2 expression is found mainly in mineralocorticoid target tissues such as kidney, placenta, colon and salivary gland, acts as an NAD-dependent dehydrogenase catalyzing the inactivation of cortisol to cortisone (Albiston et al. (1994) Mol. Cell. Endocrin. 105: R11-R17), and has been found to protect the MR from glucocorticoid excess, such as high levels of receptor-active cortisol (Blum, et al., (2003) Prog. Nucl. Acid Res. Mol. Biol. 75:173-216).

In vitro, the MR binds cortisol and aldosterone with equal affinity. The tissue specificity of aldosterone activity, however, is conferred by the expression of 11pHSD2 (Funder et al. (1988),

Science 242: 583-585). The inactivation of cortisol to cortisone by 11FHSD2 at the site of the MR enables aldosterone to bind to this receptor in vivo. The binding of aldosterone to the MR results in dissociation of the ligand-activated MR from a multiprotein complex containing chaperone proteins, translocation of the MR into the nucleus, and its binding to hormone response elements in regulatory regions of target gene promoters. Within the distal nephron of the kidney, induction of serum and glucocorticoid inducible kinase-1 (sgk-1) expression leads to the absorption of Na’ ions and water through the epithelial sodium channel, as well as potassium excretion with subsequent volume expansion and hypertension (Bhargava et al., (2001), Endo 142: 1587-1594).

In humans, elevated aldosterone concentrations are associated with endothelial dysfunction, myocardial infarction, left ventricular atrophy, and death. In attempts to modulate these ill effects, multiple intervention strategies have been adopted to control aldosterone overactivity and attenuate the resultant hypertension and its associated cardiovascular consequences. Inhibition of angiotensin- converting enzyme (ACE) and blockade of the angiotensin type 1 receptor (ATIR) are two strategies that directly impact the rennin-angiotensin-aldosterone system (RAAS). However, although ACE inhibition and ATIR antagonism initially reduce aldosterone concentrations, circulating 5S concentrations of this hormone return to baseline levels with chronic therapy (known as ‘aldosterone escape’). Importantly, co-administration of the MR antagonist Spironolactone or Eplerenone directly blocks the deleterious effects of this escape mechanism and dramatically 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). Therefore, MR antagonism may be an important treatment strategy for many patients with hypertension and cardiovascular disease, particularly those hypertensive patients at risk for target-organ damage.

Mutations in either of the genes encoding the 11-beta-HSD enzymes are associated with human pathology. For example, 11BHSD2 is expressed in aldosterone-sensitive tissues such as the distal nephron, salivary gland, and colonic mucosa where its cortisol dehydrogenase activity serves to protect the intrinsically non-selective MR from illicit occupation by cortisol (Edwards et al. (1988)

Lancet 2: 986-989). Individuals with mutations in | 1PHSD2 are deficient in this cortisol-inactivation activity and, as a result, present with a syndrome of apparent mineralocorticoid excess (also referred to as ‘SAME’) characterized by hypertension, hypokalemia, and sodium retention (Wilson et al. (1998) Proc. Natl. Acad. Sci. 95: 10200-10205). Likewise, mutations in 11BHSDI, a primary regulator of tissue-specific glucocorticoid bioavailability, and in the gene encoding a co-localized

NADPH-generating enzyme, hexose 6-phosphate dehydrogenase (H6PD), can result in cortisone reductase deficiency (CRD), in which activation of cortisone to cortisol does not occur, resulting in adrenocorticotropin-mediated androgen excess. CRD patients excrete virtually all glucocorticoids as cortisone metabolites (tetrahydrocortisone) with low or absent cortisol metabolites (tetrahydrocortisols). When challenged with oral cortisone, CRD patients exhibit abnormally low plasma cortisol concentrations. These individuals present with ACTH-mediated androgen excess (hirsutism, menstrual irregularity, hyperandrogenism), a phenotype resembling polycystic ovary syndrome (PCOS) (Draper et al. (2003) Nat. Genet. 34: 434-439).

The importance of the HPA axis in controlling glucocorticoid excursions is evident from the fact that disruption of homeostasis in the HPA axis by either excess or deficient secretion or action results in Cushing’s syndrome or Addison’s disease, respectively (Miller and Chrousos (2001)

Endocrinology and Metabolism, eds. Felig and Frohman (McGraw-Hill, New York), 4% Ed.: 387- 524). Patients with Cushing’s syndrome (a rare disease characterized by systemic glucocorticoid excess originating from the adrenal or pituitary tumors) or receiving glucocorticoid therapy develop reversible visceral fat obesity. Interestingly, the phenotype of Cushing’s syndrome patients closely resembles that of Reaven’s metabolic syndrome (also known as Syndrome X or insulin resistance syndrome) the symptoms of which include visceral obesity, glucose intolerance, insulin resistance, hypertension, type 2 diabetes and hyperlipidemia (Reaven (1993) Ann. Rev. Med. 44: 121-131).

However, the role of glucocorticoids in prevalent forms of human obesity has remained obscure because circulating glucocorticoid concentrations are not elevated in the majority of metabolic syndrome patients. In fact, glucocorticoid action on target tissue depends not only on circulating levels but also on intracellular concentration, locally enhanced action of glucocorticoids in adipose tissue and skeletal muscle has been demonstrated in metabolic syndrome. Evidence has accumulated that enzyme activity of 11BHSD1, which regenerates active glucocorticoids from inactive forms and plays a central role in regulating intracellular glucocorticoid concentration, is commonly elevated in fat depots from obese individuals. This suggests a role for local glucocorticoid reactivation in obesity and metabolic syndrome.

Given the ability of 11BHSDI to regenerate cortisol from inert circulating cortisone, considerable attention has been given to its role in the amplification of glucocorticoid function. 11BHSDI is expressed in many key GR-rich tissues, including tissues of considerable metabolic importance such as liver, adipose, and skeletal muscle, and, as such, has been postulated to aid in the tissue-specific potentiation of glucocorticoid-mediated antagonism of insulin function. Considering a) the phenotypic similarity between glucocorticoid excess (Cushing’s syndrome) and the metabolic syndrome with normal circulating glucocorticoids in the latter, as well as b) the ability of 11BHSD1 to _ generate active cortisol from inactive cortisone in a tissue-specific manner, it has been suggested that central obesity and the associated metabolic complications in syndrome X result from increased activity of 11BHSDI1 within adipose tissue, resulting in ‘Cushing’s disease of the omentum’ (Bujalska et al. (1997) Lancet 349: 1210-1213). Indeed, 11BHSDI1 has been shown to be upregulated in adipose tissue of obese rodents and humans (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. 75 Metab. 88: 2738-2744; Wake et al. (2003) J. Clin. Endocrinol. Metab. 88: 3983-3988).

Additional support for this notion has come from studies in mouse transgenic models.

Adipose-specific overexpression of 118HSDI under the control of the aP2 promoter in mouse produces a phenotype remarkably reminiscent 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 a local production of corticosterone within the adipose depots. The increased activity of 11BHSD1 in these mice (2-3 fold) is very similar to that observed in human obesity (Rask et al. (2001) I. Clin.

Endocrinol. Metab. 86: 1418-1421). This suggests that local 11BHSDI-mediated conversion of inert glucocorticoid to active glucocorticoid can have profound influences whole body insulin sensitivity.

Based on this data, it would be predicted that the loss of 11BHSD1 would lead to an increase in insulin sensitivity and glucose tolerance due to a tissue-specific deficiency in active glucocorticoid levels. This is, in fact, the case as shown in studies with 11BHSD1-deficient mice produced 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 are completely devoid of 11-keto reductase activity, confirming that 11HSD1 encodes the only activity capable of generating active corticosterone from inert 11-dehydrocorticosterone. 11pHSDI1- deficient mice are resistant to diet- and stress-induced hyperglycemia, exhibit attenuated induction of hepatic gluconeogenic enzymes (PEPCK, G6P), show increased insulin sensitivity within adipose, : and have an improved lipid profile (decreased triglycerides and increased cardio-protective HDL).

Additionally, these animals show resistance to high fat diet-induced obesity. Taken together, these transgenic mouse studies confirm a role for local reactivation of glucocorticoids in controlling hepatic and peripheral insulin sensitivity, and suggest that inhibition of 11BHSD1 activity may prove beneficial in treating a number of glucocorticoid-related disorders, including obesity, insulin resistance, hyperglycemia, and hyperlipidemia.

Data in support of this hypothesis has been published. Recently, it was reported that - 15 118HSD! plays a role in the pathogenesis of central obesity and the appearance of the metabolic syndrome in humans. Increased expression of the 11BHSD! gene is associated with metabolic abnormalities in obese women and that increased expression of this gene is suspected to contribute to the increased local conversion of cortisone to cortisol in adipose tissue of obese individuals (Engeli, et al., (2004) Obes. Res. 12: 9-17).

A new class of 11BHSDI inhibitors, the arylsulfonamidothiazoles, was shown to improve hepatic insulin sensitivity and reduce blood glucose levels in hyperglycemic strains of mice (Barf et al. (2002) J. Med. Chem. 45: 3813-3815; Alberts et al Endocrinology (2003) 144: 4755-4762).

Furthermore, it was recently reported that selective inhibitors of 11BHSDI1 can ameliorate severe hyperglycemia in genetically diabetic obese mice. Thus, 11BHSDI is a promising pharmaceutical target for the treatment of the Metabolic Syndrome (Masuzaki, et al., (2003) Curr. Drug Targets

Immune Endocr. Metabol. Disord. 3: 255-62).

A. Obesity and metabolic syndrome

As described above, multiple lines of evidence suggest that inhibition of 11BHSD1 activity can be effective in combating obesity and/or aspects of the metabolic syndrome cluster, including glucose intolerance, insulin resistance, hyperglycemia, hypertension, and/or hyperlipidemia.

Glucocorticoids are known antagonists of insulin action, and reductions in local glucocorticoid levels by inhibition of intracellular cortisone to cortisol conversion should increase hepatic and/or peripheral insulin sensitivity and potentially reduce visceral adiposity. As described above, 1 1BHSD1 knockout mice are resistant to hyperglycemia, exhibit attenuated induction of key hepatic gluconeogenic enzymes, show markedly increased insulin sensitivity within adipose, and have an improved lipid profile. Additionally, these animals show resistance 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 11pHSDI is predicted to have multiple beneficial effects in the liver, adipose, and/or skeletal muscle, particularly related to § alleviation of component(s) of the metabolic syndrome and/or obesity.

B. Pancreatic function

Glucocorticoids are known to inhibit the glucose-stimulated secretion of insulin from pancreatic beta-cells (Billaudel and Sutter (1979) Horm. Metab. Res. | 1: 555-560). In both Cushing’s syndrome and diabetic Zucker fa/fa rats, glucose-stimulated insulin secretion is markedly reduced (Ogawa et al. (1992) J. Clin. Invest. 90: 497-504). 11BHSD! mRNA and activity has been reported in the pancreatic islet cells of ob/ob mice and inhibition of this activity with carbenoxolone, an 11BHSDI inhibitor, improves glucose-stimulated insulin release (Davani et al. (2000) J. Biol. Chem. 275: 34841-34844). Thus, inhibition of 11BHSD1 is predicted to have beneficial effects on the pancreas, including the enhancement of glucose-stimulated insulin release.

C. Cognition and dementia

Mild cognitive impairment is a common feature of aging that may be ultimately related to the progression of dementia. In both aged animals and humans, inter-individual differences in general cognitive function have been linked to variability in the long-term exposure to glucocorticoids (Lupien et al. (1998) Nat. Neurosci. 1: 69-73). Further, dysregulation of the HPA axis resulting in chronic exposure to glucocorticoid excess in certain brain subregions has been proposed to contribute to the decline of cognitive function (McEwen and Sapolsky (1995) Curr. Opin. Neurobiol. 5: 205- 216). 11BHSD1 is abundant in the brain, and is expressed in multiple subregions including the hippocampus, frontal cortex, and cerebellum (Sandeep et al. (2004) Proc. Natl. Acad. Sci. Early

Edition: 1-6). Treatment of primary hippocampal cells with the 11BHSDI inhibitor carbenoxolone protects the cells from glucocorticoid-mediated exacerbation of excitatory amino acid neurotoxicity (Rajan et al. (1996) J. Neurosci. 16: 65-70). Additionally, 11BHSDI-deficient mice are protected from glucocorticoid-associated hippocampal dysfunction that is 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 improved verbal fluency and verbal memory (Sandeep et al. (2004) Proc. Natl. Acad. Sci. Early Edition: 1-6). Thus, inhibition of 11pHSDI is predicted to reduce exposure to glucocorticoids in the brain and protect against deleterious glucocorticoid effects on neuronal function, including cognitive impairment, dementia, and/or depression.

D. Intra-ocular pressure

Glucocorticoids can be used topically and systemically for a wide range of conditions in clinical ophthalmology. One particular complication with these treatment regimens is corticosteroid- induced glaucoma. This pathology is characterized by a significant increase in intra-ocular pressure (IOP). In its most advanced and untreated form, IOP can lead to partial visual field loss and eventually blindness. IOP is produced by the relationship between aqueous humour production and drainage. Aqueous humour production occurs in the non-pigmented epithelial cells (NPE) and its drainage is through the cells of the trabecular meshwork. 1 1BHSD1 has been localized to NPE cells (Stokes et al. (2000) Invest. Ophthalmol. Vis. Sci. 41: 1629-1683; Rauz et al. (2001) Invest.

Ophthalmol. Vis. Sei. 42: 2037-2042) and its function is likely relevant to the amplification of glucocorticoid activity within these cells. This notion has been confirmed by the observation that free cortisol concentration greatly exceeds that of cortisone in the aqueous humour (14:1 ratio). The functional significance of 11BHSDI in the eye has been evaluated using the inhibitor carbenoxolone in healthy volunteers (Rauz et al. (2001) Invest. Ophthalmol. Vis. Sci. 42: 2037-2042). After seven days of carbenoxolone treatment, 10P was reduced by 18%. Thus, inhibition of 11BHSDI in the eye is predicted to reduce local glucocorticoid concentrations and IOP, producing beneficial effects in the management of glaucoma and other visual disorders.

E. Hypertension

Adipocyte-derived 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). Leptin, which is secreted in excess in aP2-11BHSD]1 transgenic mice (Masuzaki et al. (2003) J. Clinical Invest. 112: 83-90), can activate various sympathetic nervous system pathways, including those that regulate blood pressure (Matsuzawa et al. (1999) Ann. N.Y. Acad. Sci. 892: 146-154). Additionally, the renin- angiotensin system (RAS) has been shown to be a major determinant of blood pressure (Walker et al. (1979) Hypertension 1: 287-291). Angiotensinogen, which is produced in liver and adipose tissue, is the key substrate for renin and drives RAS activation. Plasma angiotensinogen levels are markedly elevated in aP2-11BHSDI transgenic mice, as are angiotensin II and aldosterone (Masuzaki et al. (2003) J. Clinical Invest. 112: 83-90). These forces likely drive the elevated blood pressure observed in aP2-11BHSDI transgenic mice. Treatment of these mice with low doses of an angiotensin II receptor antagonist abolishes this hypertension (Masuzaki et al. (2003) J. Clinical Invest. 112: 83-90).

This data illustrates the importance of local glucocorticoid reactivation in adipose tissue and liver, and suggests that hypertension may be caused or exacerbated by 11BHSDI activity. Thus, inhibition of 11BHSDI and reduction in adipose and/or hepatic glucocorticoid levels is predicted to have beneficial effects on hypertension and hypertension-related cardiovascular disorders.

F. Bone disease

Glucocorticoids can have adverse effects on skeletal tissues. Continued exposure to even moderate glucocorticoid doses can result in osteoporosis (Cannalis (1996) J. Clin. Endocrinol. Metab. 81: 3441-3447) and increased risk for fractures. Experiments in vitro confirm the deleterious effects of glucocorticoids on both bone-resorbing cells (also known as osteoclasts) and bone forming cells (osteoblasts). 11BHSDI has been shown to be present in cultures of human primary osteoblasts as well as cells from adult bone, likely a mixture of osteoclasts and osteoblasts (Cooper et al. (2000)

Bone 27: 375-381), and the 11BHSDI inhibitor carbenoxolone has been shown to attenuate the negative effects of glucocorticoids on bone nodule formation (Bellows et al. (1998) Bone 23: 119- 125). Thus, inhibition of 11pHSDI1 is predicted to decrease the local glucocorticoid concentration within osteoblasts and osteoclasts, producing beneficial effects in various forms of bone disease, including osteoporosis.

Small molecule inhibitors of 11BHSDI1 are currently being developed to treat or prevent 11BHSDI1-related diseases such as those described above. For example, certain amide-based inhibitors are reported in WO 2004/089470, WO 2004/089896, WO 2004/056745, and WO 2004/065351.

Antagonists of 11BHSD1 have been evaluated in human clinical trials (Kurukulasuriya , et al., (2003) Curr. Med. Chem. 10: 123-53).

In light of the experimental data indicating a role for 11pHSDI1 in glucocorticoid-related disorders, metabolic syndrome, hypertension, obesity, insulin resistance, hyperglycemia, hyperlipidemia, type 2 diabetes, androgen excess (hirsutism, menstrual irregularity, hyperandrogenism) and polycystic ovary syndrome (PCOS), therapeutic agents aimed at augmentation or suppression of these metabolic pathways, by modulating glucocorticoid signal transduction at the level of 11BHSD]1 are desirable.

Furthermore, because the MR binds to aldosterone (its natural ligand) and cortisol with equal affinities, compounds that are designed to interact with the active site of 11BHSD1 (which binds to cortisone/cortisol) may also interact with the MR and act as antagonists. Because the MR is implicated in heart failure, hypertension, and related pathologies including atherosclerosis, arteriosclerosis, coronary artery disease, thrombosis, angina, peripheral vascular disease, vascular wall damage, and stroke, MR antagonists are desirable and may also be useful in treating complex cardiovascular, renal, and inflammatory pathologies including disorders of lipid metabolism including dyslipidemia or hyperlipoproteinaemia, diabetic dyslipidemia, mixed dyslipidemia, hypercholesterolemia, hypertriglyceridemia, as well as those associated with type 1 diabetes, type 2 diabetes, obesity, metabolic syndrome, and insulin resistance, and general aldosterone-related target- organ damage.

As evidenced herein, there is a continuing need for new and improved drugs that target 11BHSD1 and/or MR. The compounds, compositions and methods described herein help meet this and other needs.

SUMMARY OF THE INVENTION

The present invention provides, inter alia, compounds of Formulas I 11, III, IV, Va, Vb, VI,

VII, and VIII: 3 v |) L] rR" RZ R R' R2 > (W'-X'-Y'-Z') \ "

Cy “Rr Cy 0] 0

I 11 1 2

R R (xray R! R? G'

N_~ r N 2

Cy Cy G 0 6) 111 |AY

Q2 ALY LU

EE Ql (W-X"-Y -2")s wr [CGE

N (W"'-X"-Y"-2"),

Cy q 0

Va (W-X-Y'-Z)y =e XC

X NS Ww LX “Y"-Z");

R’ R2 [ Q? (W'-X"-Y"-Z")¢

N

Cy q 0]

Vb 1—-Q2 WwW xX" Y" z" xr Qt 9 WXYZ)

Qt

R! R? [ 4 V3

N U4 c A mm NN WXYZ, y q 0]

Vi rR! R? A'~q2

N (XYZ

PN ZN gt (W-X"-Y"-Z"),

VII

R! R? Q'~q2

N

0 A vir or pharmaceutically acceptable salts or prodrugs thereof, wherein constituent members are defined herein,

The present invention further provides compositions comprising compounds of the invention and a pharmaceutically acceptable carrier.

The present invention further provides methods of modulating 1 1BHSD1 or MR by contacting the 118HSD1 or MR with a compound of the invention.

The present invention further provides methods of treating diseases assocated with activity or expression of 11BHSD1 or MR.

The present invention further perovids use of the compounds and compositions herein in therapy.

The present invention further provides use of the compounds and compositions here for the preparation of a medicament for use in therapy. - DETAILED DESCRIPTION

The present invention provides, inter alia, compounds of Formula I:

R! R2 Re oN Re o or pharmaceutically acceptable salts or prodrugs thereof, wherein:

Cy is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, each optionally substituted by 1,2, 3, 4 or5 -W-X-Y-Z;

R' and R? together with the C atom to which they are attached form a 3-, 4-, 5-, 6- or 7- membered cycloalkyl group or a 3-, 4-, 5-, 6- or 7-membered heterocycloalky! group, each optionally substituted by 1,2 0r3 R%

R? and R? together with the N atom to which they are attached form a 4-15 membered heterocycloalkyl group optionally substituted by 1, 2, 3, or 4 -W'-X"-Y’-Z’;

R’ is halo, C4 alkyl, Cos alkenyl, Cos alkynyl, C,.4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO, OR, SR?, C(O)R", C(O)NR°RY, C(O)OR’, OC(O)R", OC(O)NRR’,

NR°RY, NR°C(O)R’, NR°C(O)OR’, S(O)R®, S(O)NR°RY, S(O)R", or S(O),NRR,

W, W’ and W’ are each, independently, absent, C5 alkylenyl, C,¢alkenylenyl, Cas alkynylenyl, O, S, NR’, CO, CS, COO, CONR’, OCONR’, SO, SO, SONR®, or NR°CONR', wherein said C14 alkylenyl, C6 alkenylenyl, Cas alkynylenyl are each optionally substituted by 1, 2 or 3 halo,

OH, C4 alkoxy, C4 haloalkoxy, amino, C4 alkylamino or Cy dialkylamino;

X, X* and X’* are each, independently, absent, C,salkylenyl, Cg alkenylenyl, Cas alkynylenyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, arylalkenyl, cycloalkylalkenyl, heteroarylalkenyl, heterocycloalkylalkenyl, arylalkynyl, cycloalkylalkynyl, heteroarylalkynyl, heterocycloalkylalkynyl, each of which is optionally substituted by one or more halo, CN, NO,, OH, C,.salkoxy, C).4 haloalkoxy, amino, C4 alkylamino or Cp dialkylamino;

Y, Y’ and Y”’ are each, independently, absent, Ci.¢ alkylenyl, Cys alkenylenyl, Ca alkynylenyl, O, S, NR*, CO, CS, COO, CONR®, OCONR®, SO, SO, SONR®, or NRECONR, wherein said C,¢alkylenyl, C,¢alkenylenyl, Cys alkynylenyl are each optionally substituted by 1,2 or 3 halo,

OH, C,.4 alkoxy, Ci.4 haloalkoxy, amino, C4 alkylamino or C,.¢ dialkylamino;

Z, Z’ and Z"’ are each, independently, H, halo, CN, NO,, OH, C,.4 alkoxy, C,., haloalkoxy, amino, C4 alkylamino or C,.s dialkylamino, C,. alkyl, Cy alkenyl, Cy alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said Cy. alkyl, Cs. alkenyl, Cy. alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalky! is optionally substituted by 1, 2 or 3 halo, Cy.¢ alkyl, Cz.¢ alkenyl, Cy alkynyl, C,., haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO,, OR’, SR? C(O)R",

C(O)NRR', C(O)OR?, OC(O)R®, OC(O)NRR?, NR°R’, NR°C(O)RY, NR°C(O)OR?, S(O)R”,

S(O)NR°RY, S(O);R®, or S(O);NR°R’; wherein two —W-X-Y-Z attached to the same atom optionally form a 3-20 membered cycloalkyl or heterocycloalkyl group optionally substituted by 1,2 or 3 “WXYZ wherein two —W’-X’-Y’-Z’ attached to the same atom optionally form a 3-20 membered cycloalkyl or heterocycloalkyl group optionally substituted by 1,2 or 3 WXYZ wherein —=W-X-Y-Z is other than H; wherein —W’-X’-Y’-Z’ is other than H;

wherein —=W”’-X’’-Y**-Z’" is other than H;

R? is H, Cy. alkyl, C,.¢ haloalkyl, Cy alkenyl, (C1. alkoxy)-Ci.c alkyl, Cos alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl;

R® is H, C1. alkyl, C,.¢ haloalkyl, Ca. alkenyl, Cy. alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl;

RC and RY are each, independently, H, Cis alkyl, C, haloalkyl, Ca.6 alkenyl, Cy alkynyl, aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl; or RC and R® together with the N atom to which they are attached form a 4-,5-,6-or7- membered heterocycloalkyl group; and

RE and Rf are each, independently, H, Cis alkyl, Cis haloalkyl, C..¢ alkenyl, Ca.¢ alkynyl, aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl; or R® and Rf together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group.

In some embodiments, when R® and R* together with the N-atom to which they are attached form piperidinyl, the piperidinyl is unsubstituted or substituted by other than: 0 v—

Ne $ >

RTC

F wherein:

V is CH,CH,, CH=CH, or CHO; and

R is H, halo or Cs alkyl.

In some embodiments, when R? and R* together with the N-atom to which they are attached form piperazinyl, the Cy is substituted by at least one -W-X-Y-Z.

In some embodiments, Cy is aryl or heteroaryl, each optionally substituted by 1,2,3,40r5 —

W-X-Y-Z.

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

In some embodiments, Cy is aryl optionally substituted by 1, 2 or 3 halo, Cy.4 alkyl, C4 alkoxy, C;.4 haloalkyl, or C, 4 haloalkoxy.

In some embodiments, Cy is phenyl optionally substituted by 1, 2 or 3 halo, Ciaalkyl, Cia alkoxy, Cys haloalkyl, or C4 haloalkoxy.

In some embodiments, R' and R? together with the C atom to which they are attached form a 3-,4-, 5-, 6- or 7-membered cycloalkyl group.

In some embodiments, R' and R? together with the C atom to which they are attached forma cyclopropyl group.

In some embodiments, R® and R* together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted by 1, 2,3, 0r 4 WXYZ.

In some embodiments, R® and R* together with the N atom to which they are attached form a piperidiny] or pyrrolidinyl group, each optionally substituted by 1,2, 3, or 4 -W-X-Y-2’.

In some embodiments, R® and R* together with the N atom to which they are attached form a piperidinyl or pyrrolidiny! group, each substituted by 2,3, or 4 _W’-X'-Y'-Z’; wherein two —W’-X’- v’-Z’ are attached to the same atom and optionally form a 3-20 membered cycloalkyl or heterocycloalkyl group optionally substituted by 1,2 or 3 -W*-X""-Y’-Z".

In some embodiments, —W-X-Y-Z is halo, cyano, C,.4 cyanoalkyl, nitro, Cy.galkyl, Cas alkenyl, Cy.g haloalkyl, Ci. alkylthio, C.4 haloalkylthio, C,.s alkoxy, Cz.s alkenyloxy, Ci. haloalkoxy,

OH, (C,4alkoxy)-C;.4alkyl, amino, C.4alkylamino, Cys dialkylamino, OC(O)NR°R®, NRC(O)RY,

NR‘C(O)OR’, NR°S(O),R®, C(O)OR®, C(O)R*, C(O)NR®NR'R’, S(O)R’, SR, C(O)NRRY,

C(S)NR°R!, aryloxy, heteroaryloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, arylalkyloxy, heteroarylalkyloxy, cycloalkylalkyloxy, heterocycloalkylalkyloxy, heteroaryloxyalkyl, aryloxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl , heteroarylalkynyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein each of said Cz alkyl, Cys alkenyl, C5 haloalkyl, C4 alkylthio, Ci haloalkylthio,

C,.s alkoxy, aryloxy, heteroaryloxy, arylalkyloxy, heteroarylalkyloxy, heteroaryloxyalkyl, aryloxy, heteroaryloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, arylalkyloxy, heteroarylalkyloxy, cycloalkylalkyloxy, heteracycloalkylalkyloxy, heteroaryloxyalkyl, aryloxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl , heteroarylalkynyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted by 1, 2, or 3 halo, cyano, nitro, hydroxyl-(C,.¢ alkyl), aminoalkyl, dialkylaminoalkyl, Ci alkyl, Cj.s haloalkyl, C4 cyanoalkyl, Cis alkoxy, Ci.4 haloalkoxy, OH, OR?, (C4 alkoxy)-C;4 alkyl, amino, C4 alkylamino, C,5 dialkylamino, C(O)NR°R?, C(O)OR?, C(O)R’, (cyclocalkylalkyl)-C(O)-,

NR°C(O)R?, NR°C(O)OR’, NR°S(O),R’, C(S)NRR?, S(0).R’, SR’, (C14 alkyl)sulfonyl, arylsulfonyl, aryl optionally substituted by halo, heteroaryl, cycloalkylalkyl, cycloalkyl, or heterocycloalkyl.

In some embodiments, ~-W-X-Y-Z is halo, cyano, Cy. cyanoalkyl, nitro, Cis alkyl, Cis alkenyl, C,.5 haloalkyl, C,.jo alkoxy, C,4haloalkoxy, OH, Cs alkoxyalkyl, amino, C4 alkylamino, C,. dialkylamino, OC(O)NR°R’, NR°C(O)R?, NR°C(O)OR’, aryloxy, heteroaryloxy, arylalkyloxy, heteroarylalkyloxy, heteroaryloxyalkyl, aryloxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl , heteroarylalkynyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein each of said Cs alkyl, Cy.salkenyl, Cs haloalkyl, C,.3 alkoxy, aryloxy, heteroaryloxy, arylalkyloxy, heteroarylalkyloxy, heteroaryloxyalkyl, aryloxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl , heteroarylalkynyl, cycloalkylalkyl, or heterocycloalkylalky! is optionally substituted by 1, 2, or 3 halo, cyano, nitro, hydroxyl{Ci.¢ alkyl), aminoalkyl, dialkylaminoalkyl, Ci.4 alkyl, Cis haloalkyl, Ci. alkoxy, Ci haloalkoxy, OH, Ci.s alkoxyalkyl, amino, C,4alkylamino, C,.3 dialkylamino, C(O)NR'R’,

C(O)OR® , NR°C(O)R?, NR°S(O)RY, (C\.salkyl)sulfonyl, arylsulfonyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl. 12. The compound of claim 1 wherein —-W-X-Y-Z is halo, cyano, Cis cyanoalkyl, nitro,

C4nitroalky), Ci4alkyl, Ci4 haloalkyl, C\.4alkoxy, C;.4haloalkoxy, OH, (C,.; alkoxy)-Ci4 alkyl, amino, Cy. alkylamino, Cag dialkylamino, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl.

In some embodiments, —-W-X-Y-Z is halo, C;.4 alkyl, or C,_4alkoxy.

In some embodiments, -W’-X’-Y’-Z’ is halo, OH, cyano, CHO, COOH, C(0)O~« C4 alkyD),

C(O) C4 alkyl), SO»( Ci alkyl), Cy.s alkyl, Cis alkoxy or -L-R’, wherein said C4 alkyl or Ci4 alkoxy is optionally substituted by one or more halo, OH, COOH or C(0)O-( C4 alkyl);

In some embodiments, ~-W’-X’-Y’-Z’ is halo; Cis alkyl; Cis haloalkyl; OH; C,4 alkoxy; Ci.4 haloalkoxy; hydroxyalkyl; alkoxyalkyl; aryl; heteroaryl, aryl substituted by halo, Cis alkyl, Cia alkoxy, aryl, heteroaryl, or aryloxy; or heteroaryl substituted by halo, C, 4 alkyl, C4 alkoxy, aryl, or © heteroaryl.

In some embodiments, —~W’-X’-Y’-Z’ are attached to the same atom and optionally form a 3- membered cycloalky! or heterocycioalkyl group optionally substituted by 1,2 or 3 “WX Y-

Zz’. . 20 In some embodiments, —-W”-X”-Y”-Z” is halo, cyano, Cy4 cyanoalkyl, nitro, C4 nitroalkyl,

Ci alkyl, C;.4 haloalkyl, C4 alkoxy, Ci. haloalkoxy, OH, (C.4alkoxy)-C,4 alkyl, amino, Cia alkylamino, C, dialkylamino, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl.

In some embodiments: —W'-X’-Y"-Z’ is halo, OH, cyano, CHO, COOH, C(O)O~( Cy.salkyl), C(O)-( C14 alkyl), SO,- ( CisalkyD), C4 alkyl, C14 alkoxy or —L-R’, wherein said C4 alkyl or C4 alkoxy is optionally substituted by one or more halo, OH, COOH or C(0)O-( Cy.« alkyl);

L is absent, O, CH,, NHSO,, N{C(0)-( Cis alkyD)]; and

R’ is aryl or heteroaryl, each is optionally substituted by 1, 2, or 3 halo, OH, cyano, CHO,

COOH, C(0)O~( C14 alkyl), C(O) Ci.4 alkyl), SO2-( C14 alkyl), SO:-NH( Cy.salky), Ciaalkyl, Cis alkoxy, Cy haoalkyl, Cys hydroxyalkyl, aryl, heteroaryl or aryloxy.

In some embodiments, the compounds of the invention have Formula II:

R!' RZ [x WXYZ,

N <

Cy 0] 11 including pharmaceutically acceptable salts or prodrugs thereof, wherein constituent variables are defined herein above, and gis 0, 1, 2,3 or 4.

In some embodiments, Cy is aryl or heteroaryl, each optionally substituted by 1, 2,3,40r5 —

W-X-Y-Z.

In some embodiments, q is 1,2,3 or 4.

In some embodiments, q is 2, 3 or 4.

In some embodiments, two —W’-X’-Y’-Z’ attached to the same atom form a 3-20 membered cycloalkyl or heterocycloalky! group optionally substituted by 1, 2 or 3 -W*-X"*-Y"’-Z>".

The present invention further provides compounds of Formula III:

R! R? 1's WXN-Z) oN 0) m or pharmaceutically acceptable salts or prodrugs thereof, wherein constituent variables are defined hereinabove; and ris0,1,2,3 0r4.

In some embodiments, when U is CHa, then —W’-X’-Y’-Z’ forms a group other than: 0 v— 3

CY

RT

HF wherein:

V is CH,CH,, CH=CH, or CH,0; and

Ris H, halo or Cs alkyl.

In some embodiments, when U is NH, Cy is substituted by at least one —W-X-Y-Z.

In some embodiments, ris 1,2, 3 or 4.

In some embodiments, ris 2, 3 or 4.

In some embodiments, U is CH,.

In some embodiments, two —W*-X’-Y’-Z’ attached to the same atom form a 3-20 membered cycloalkyl! or heterocycloalky! group optionally substituted by 1,2 or 3 ~W>-X">-Y**-Z"’.

The present invention further provides compounds of Formula IV: (W'-X'-Y'-2)y

R! R? he oN 0) 1\Y or pharmaceutically acceptable salts or prodrugs thereof, wherein constituent variables are defined hereinabove:

G' and G? together with the carbon atom to which they are attached form a 3-20 membered cycloalkyl! or heterocycloalkyl group optional substituted by 1,2 or 3 ~W-X"-Y-Z”,; and vis 0, 1 or 2.

In some embodiments, v is 0.

In some embodiments, v is 1.

In some embodiments, G' and G? together with the carbon atom to which they are attached form a 9-14 membered cycloalkyl or heterocycloalkyl group optional substituted by 1,2 or 3 -W*’-

XYZ, :

In some embodiments, —W”-X”-Y”-Z” is halo, cyano, C,.4 cyanoalkyl, nitro, Cy nitroalkyl,

C14 alkyl, C4 haloalkyl, C,4 alkoxy, C,4haloalkoxy, OH, (C,4alkoxy)-Cy.4 alkyl, amino, C4 alkylamino, C.s dialkylamino, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalky]l, cycloalkylalkyl, or heterocycloalkylalkyl

The present invention further provides compounds of Formula Va or Vb: (WXYZ), Qt=@ (WXYZ)

N (WXYZ), oO

Va (XA Zh rps

RR? i Qt WXYZ) " ih) oN 0

Vb or pharmaceutically acceptable salts or prodrugs thereof, wherein contstituent variables are defined herein above: ring B is a fused 5 or 6-membered aryl or heteroaryl group;

Q' is 0, S, NH, CH,, CO, CS, SO, SO, OCH,, SCH,, NHCH,, CH,CH,, CH=CH, COCH;,

CONH, COO, SOCH,, SONH, SO,CHy, or SO,NH,;

Q?is 0, S$, NH, CH,, CO, CS, SO, SO,, OCH,, SCH,, NHCH,, CH;CH, CH=CH, COCH,,

CONH, COO, SOCH;, SONH, SO;CH, or SO,NH; qisQorl; vis 0,1 or2; ris0,1or2; sis 0, 1 or2; and the sum of rand s is 0, 1 or 2.

In some embodiments, Q' and Q? are selected to form a 1-, 2-, or 3- atom spacer. In further embodiments, Q' and Q” when bonded together form a spacer group having other than an O-O or O-S ring-forming bond.

In some embodiments, Q' is 0, 8, NH, CH; or CO, wherein each of said NH and CH; is optionally substituted by WXYZ".

Tn some embodiments, Q' is O, NH, CH, or CO, wherein each of said NH and CH, is optionally substituted by “Wr X-Y”-Z7,

In some embodiments, Q” is O, S, NH, CH,, CO, or SO, wherein each of said NH and CH; is optionally substituted by ~-W”-X>-Y”-Z".

In some embodiments, one of Q' and Q’ is O and the other is CO or CONH, wherein said

CONH is optionally substituted by —-W"-X"-Y"-Z".

In some embodiments, one of Q' and Q? is CO and the other is O, NH, or CH,, and wherein 95 each of said NH and CH, is optionally substituted by ~-W”-X"-Y”-Z”.

In some embodiments, one of Q' and Q? is CH, and the other is O, S, NH, or CH, and wherein each of said NH and CH, is optionally substituted by ~W"-X"-Y"-Z".

In some embodiments, one of Q' and Q’is CO.

In some embodiments, the compound has Formula Va wherein one of Q' and Q?is CO and the other is O, NH, or CH,, and wherein each of said NH and CH, is optionally substituted by —W”- xX -Y”-Z”,

In some embodiments, the compound has Formula Va wherein one of Q' and Q’is CH, and the other is O, S, NH, or CH,, and wherein each of said NH and CH; is optionally substituted by —W"-

X»-Y”-27,

In some embodiments, the compound has Formula Vb wherein one of Q' and Q* is CO.

In some embodiments, the compound has Formula Va.

In some embodiments, the compound has Formula Vb.

In some embodiments, ring B is phenyl or pyridyl.

In some embodiments, ring B is phenyl.

In some embodiments, r is 0.

In some embodiments, ris 0 or 1.

In some embodiments, s is 0 or 1.

The present invention further provides compounds of F ormula VI:

WXYZ) qQ! 7 (W'-X"-Y"-Z")s

X J

R! R? f Ye

A N = wey zy,

Cy q 0

VI pharmaceutically acceptable salt forms and prodrugs thereof, wherein constituent variables are defined hereinabove, and Q*and Q* are each, independently, CH or N. :

In some embodiments, Q’ is CH optionally substituted by “WXYZ.

In some embodiments, Q’ is N.

In some embodiments, Q* is CH optionally substituted by “W»-X>-Y”-Z27.

In some embodiments, Q* is N.

In some embodiments, Q° is CH and Q* is CH, each optionally substituted by -W2-X7-Y”-2”

In some embodiments, Q’ is CH and Q'is N, wherein said Q’ is optionally substituted by —

W2-X>-Y”-Z7.

In some embodiments, Q is N and Q* is CH optionally substituted by -W7-X"-Y-Z",

In some embodiments, Q' is O, NH, CH, or CO, wherein each of said NH and CH; is optionally substituted by ~-W”-X"-Y"-Z".

In some embodiments, Q is O, S, NH, CHa, CO, or SO, wherein each of said NH and CH, is optionally substituted by —W”-X”-Y”-Z”".

In some embodiments, one of Q' and Q? is CO and the other is O, NH, or CH,, wherein each of said NH and CH, is optionally substituted by —-W”-X"-Y”-Z” .

In some embodiments, one of Q' and Q? is CH, and the other is O, S, NH, or CH,, wherein each of said NH and CH, is optionally substituted by —W”-X"-Y"-Z”.

In some embodiments, one of Q' and Q? is O and the other is CO or CONH, wherein said

CONH is optionally substituted by —W”-X"-Y”-Z".

In some embodiments, risQ or 1.

In some embodiments, sis O or 1.

The present invention further provides compounds of Formula VII:

R! R? Aq

N (WXYZ)

AN ZN ge (W'-X"-Y"-Z");

VII, pharmaceutically acceptable salts and prodrugs thereof, wherein constituent variables are defined hereinabove.

The present invention further provides compounds of having Formula VII:

R! R? Q'~q2

N ahte; : VIII; pharmaceutically acceptable salts and prodrugs thereof, wherein constituent variables are defined hereinabove.

In some embodiments, Q' is O, NH, CH, or CO, wherein each of said NH and CH, is optionally substituted by “WXYZ.

In some embodiments, Q° is O, S, NH, CH,, CO, or SO, wherein each of said NH and CH, is optionally substituted by —W”-X"-Y”-Z".

In some embodiments, one of Q' and Q* is CO and the other is O, NH, or CH,, wherein each of said NH and CH, is optionally substituted by —W”-X*-Y”-Z” .

In some embodiments, one of Q' and Q? is CH; and the other is O, 5, NH, or CH,, wherein each of said NH and CH, is optionally substituted by —W”-X"-Y>-Z"

In some embodiments, one of Q' and Q’ is O and the other is CO or CONH, wherein said

CONH is optionally substituted by —-W”-X"-Y"-Z”.

In some embodiments, Q° is CH optionally substituted by “WXYZ.

In some embodiments, Q* is N.

In some embodiments, Q* is CH optionally substituted by WXYZ.

In some embodiments, Q* is N.

In some embodiments, ris 0 or 1.

In some embodiments, s is 0 or 1.

At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. Itis specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges. For example, the term “Cre alkyl” is specifically intended to individually disclose methyl, ethyl, Cs alkyl, C4 alkyl, Cs alkyl, and Cealkyl

For compounds of the invention in which a variable appears more than once, each variable can be a different moiety selected from the Markush group defining the variable. For example, where a structure is described having two R groups that are simultaneously present on the same compound; the two R groups can represent different moieties selected from the Markush group defined for R. In another example, when an optionally multiple substituent is designated in the form:

Re o/ then it is understood that substituent R can occur s number of times on the ring, and R can be a different moiety at each occurrence. Further, in the above example, should the variable Q be defined to include hydrogens, such as when Q is said to be CHa, NH, etc., any floating substituent such as R in the above example, can replace a hydrogen of the Q variable as well as a hydrogen in any other non- variable component of the ring.

It is further intended that the compounds of the invention are stable. As used herein “stable” refers to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and preferably capable of formulation into an efficacious therapeutic agent.

Tt is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment.

Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

As used herein, the term “alkyl” is meant to refer to a saturated hydrocarbon group which is straight-chained or branched. Example alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n- propyl and isopropyl), butyl (eg., n-butyl, isobutyl, t-butyl), pentyl (e.g. n-pentyl, isopentyl, neopentyl), and the like. An alkyl group can contain from 1 to about 20, from 2 to about 20, from | to about 10, from 1 to about 8, from | to about 6, from 1 to about 4, or from 1 to about 3 carbon atoms.

The term “alkylenyl” refers to a divalent alkyl linking group.

As used herein, “alkenyl” refers to an alkyl group having one or more double carbon-carbon bonds. Example alkenyl groups include ethenyl, propenyl, cyclohexenyl, and the like. The term “alkenylenyl” refers to a divalent linking alkenyl group. An example C, alkenylenyl is -CH=.

As used herein, “alkynyl” refers to an alkyl group having one or more triple carbon-carbon bonds. Example alkynyl groups include ethynyl, propynyl, and the like. The term “alkynylenyl” refers to a divalent linking alkynyl group.

As used herein, “haloalkyl” refers to an alkyl group having one or more halogen substituents.

Example haloalkyl groups include CFs, C;Fs, CHF, CCl3, CHCl, C,Cls, and the like.

As used herein, “aryl” refers to monocyclic or polycyclic (e.g, having 2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, aryl groups have from 6 to about 20 carbon atoms.

As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbons including cyclized alkyl, alkenyl, and alkynyl groups. Cycloalky! groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems as well as 2-ring, 3-ring, 4-ring spiro system (e.g., having 8 to 20 ring-forming atoms). Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo, pryido or thieno derivatives of pentane, pentene, hexane, and the like.

Carbon atoms of the cycloalky! group can be optionally oxidized, e. g. bear an oxo or sulfildo group to form CO or CS.

As used herein, “heteroaryl” groups refer to an aromatic heterocycle having at least one heteroatom ring member such as sulfur, oxygen, or nitrogen. Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) systems. Examples of heteroaryl groups include without limitation, pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, 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 contains 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, “heterocycloalkyl” refers to non-aromatic heterocycles including cyclized alkyl, alkenyl, and alkyny! groups where one or more of the ring-forming carbon atoms is replaced by a heteroatom such as an O, N, or S atom. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the nonaromatic heterocyclic ring, for example phthalimidyl, naphthalimidyl, and benzo derivatives of heterocycles such as indolene and isoindolene groups. Heterocycloalky! groups can be mono- or polycyclic (e.g., having 2, 3, 4 or more fused rings or having a 2-ring, 3-ring, 4-ring spiro system (e.g., having 8 to 20 ring-forming atoms)). Heteroatoms or carbon atoms of the heterocycloalkyl group can be optionally oxidized, e. g., bearing one or two oxo or sulfildo groups to form SO, SO,

CO, NO, etc. In some embodiments, the heterocycloalkyl 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 heterocycloalkyl group contains 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, | to about 3, or 1 to 2 heteroatoms. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalky! group contains 0 to 2 triple bonds. Example “heterocycloalkyl” groups include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, ~~ 2,3- dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, as well as radicals of 3H- isobenzofuran-1-one, 1,3-dihydro-isobenzofuran, 2,3-dihydro-benzo[d]isothiazole 1,1-dioxide, and the like.

As used herein, “halo” or “halogen” includes fluoro, chloro, bromo, and iodo.

As used herein, “alkoxy” refers to an -O-alkyl group. Example alkoxy groups include methoxy, ethoxy, propoxy {(e.g., n-propoxy and isopropoxy), t-butoxy, and the like.

As used here, “haloalkoxy” refers to an ~O-haloalkyl group. An example haloalkoxy group is

OCF;.

As used herein, “arylalkyl!” refers to alkyl substituted by ary! and “cycloalkylalkyl” refers to. alkyl substituted by cycloalkyl. An example arylalkyl group is benzyl.

As used herein, “amino” refers to NH,. -

As used herein, “alkylamino” refers to an amino group substituted by an alkyl group.

As used herein, “dialkylamino” refers to an amino group substituted by two alkyl groups.

The compounds described herein can be asymmetric (e.g. having one or more stereocenters).

All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.

Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. An example method includes fractional recrystallizaion using a “chiral resolving acid” which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as B-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of a- methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol,

norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g. dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art.

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

Compounds of the invention can also include all isotopes of atoms occurring in the 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" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to 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. The pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting 95 the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

The present invention also includes prodrugs of the compounds described herein. As used herein, “prodrugs” refer to any covalently bonded carriers which release the active parent drug when administered to a mammalian subject. Prodrugs can be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds wherein hydroxyl, amino, sulfhydryl, or carboxyl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, sulfhydryl, or carboxyl group respectively. 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 invention. Preparation and use of prodrugs is discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems,"

Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference in their entirety.

Synthesis

The novel compounds of the present invention can be prepared in a variety of ways known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods as hereinafter described below, together with synthetic methods known in the art of synthetic organic chemistry or variations thereon as appreciated by those skilled in the art.

The compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given; other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

The processes described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g. 'H or °C) infrared spectroscopy, spectrophotometry (e.g.

UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatograpy (HPLC) or thin layer chromatography.

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

The reactions of the processes described herein can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, i.e., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected.

The compounds described herein can be asymmetric (e.g. having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis.

Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. An example method includes fractional recrystallizaion using a “chiral resolving acid” which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids. Resolution of racemic mixtures can also be carried out by clution on a column packed with an optically active resolving agent (e.g, dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art.

The compounds of the invention can be prepared, for example, using the reaction pathways and techniques as described below.

A series of cycloalkylcarboxmides of formula 2 can be prepared by the method outlined in

Scheme 1. The carboxylic acids 1 can be coupled to an amine using coupling reagents such as BOP to provide the desired product 2.

Scheme 1

AVA R3R*NH NS i

BOP, iProNEt, CHCl 0 0) 1 2

A series of cycloalkylcarboxylic acids formula 3 can be prepared by the method outlined in

Scheme 2. Mono-alkylation of alpha-substituted methyl 4 with an alkylenedihalide such as ethylene bromide, 1,3-dibromopropane, and 1,4-dibromobutane provides mono-alkylated product 5, followed by treatment with either 1) sodium hydride in DMSO or DMF or 2) LDA in THF provides the cycloalkylcarboxylic acid esters 6. Hydrolysis of 6 gives the corresponding acid 3.

Claims (44)

What is claimed is:

1. A compound of Formula I: R! R? RY oN N- R* 0) 1 or pharmaceutically acceptable salt or prodrug thereof, wherein: Cy is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or5 -W-X-Y-Z; "R' and R? together with the C atom to which they are attached form a 3-, 4-, 5-,6-or 7- membered cycloalkyl group or a 3-, 4-, 5-, 6- or 7.membered heterocycloalky! group, each optionally substituted by 1,2 or 3 R%; R’ and R* together with the N atom to which they are attached form a 4-15 membered heterocycloalkyl group optionally substituted by 1, 2,3, 0r4-W*-X'-Y’-Z’; R’ is halo, C6 alkyl, C,.¢ alkenyl, C». alkynyl, Cy haloalkyl, aryl, cycloalkyl, heteroary], heterocycloalkyl, CN, NO,, OR’, SR®, C(O)R®, C(O)NR'R’, C(O)OR’, OC(O)R®, OC(O)NR'R®, NRR?, NR'C(O)R?, NR°C(O)OR?, S(O)R®, S(O)NR'R?, S(0)R", or S(O):NR'R%; W, W’ and W*’ are each, independently, absent, Cy. alkylenyl, Cy alkenylenyl, Cz alkynylenyt, O, S, NR®, CO, CS, COO, CONR®, OCONR?®, SO, SO,, SONR’, or NR°CONR/, wherein said Cy alkylenyl, Cys alkenylenyl, Cy alkynylenyl are each optionally substituted by 1, 2 or 3 halo, ‘OH, C,.4 alkoxy, C,.q haloalkoxy, amino, C,.4 alkylamino or Ca dialkylamino; X, X* and X'* are each, independently, absent, Cg alkylenyl, Cag alkenylenyl, Cag alkynylenyl, aryl, cycloalkyl, heteroaryl, heteracycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, arylalkenyl, cycloalkylalkenyl, heteroarylalkenyl, heterocycloalkylalkenyl, arylalkynyl, cycloalkylalkynyl, heteroarylalkynyl, heterocycloalkylalkynyl, each of which is optionally substituted by one or more halo, CN, NO,, OH, C,.salkoxy, C,_, haloalkoxy, amino, C,.4 alkylamino or Cy dialkylamino; Y, Y’ and Y*’ are each, independently, absent, C, alkylenyl, Ca.6 alkenylenyl, Cy.6 alkynyleny!, O, S, NR¢, CO, CS, COO, CONR®, OCONRS, SO, SO,, SONR’, or NR°CONR, wherein said C.alkylenyl, Cy. alkenylenyl, Co alkynylenyl are each optionally substituted by 1, 2 or 3 halo, OH, C,.4alkoxy, C4 haloalkoxy, amino, C,_4 alkylamino or C,gdialkylamino; Z,Z’ and Z*’ are each, independently, H, halo, CN, NO,, OH, C4 alkoxy, Ci. haloalkoxy, amino, C4 alkylamino or Cy.z dialkylamino, Cy.c alkyl, Cac alkenyl, Caos alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said C;salkyl, Cs alkenyl, Cy6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2 or 3 halo, Cy. alkyl, Cy. alkenyl, C,.6 alkynyl, C,.4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO, OR?, SR?, C(O)R”,

C(O)NRR¢, C(O)OR?, OC(O)R”, OC(O)NR°RY, NR°R¢, NR°C(O)R’, NR"C(O)OR’, S(O)R®, S(O)NRR’, S(O),R®, or S(O):NRR’;

wherein two —W-X-Y-Z attached to the same atom optionally form a 3-20 membered cycloalkyl or heterocycloalkyl group optionally substituted by 1,2 or 3 WXYZ wherein two —W?-X’-Y’-Z’ attached to the same atom optionally form a 3-20 membered cycloalky! or heterocycloalkyl group optionally substituted by 1,2 or 3 “WXYZ wherein —W-X-Y-Z is other than H; wherein —W’-X’-Y’-2’ is other than H; wherein —W?**-X?’-Y*'-Z"" is other than H; R? is H, C6 alkyl, Cy. haloalkyl, C,.¢ alkenyl, (C.¢ alkoxy)-Cy.¢ alkyl, Cy6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl; RY is H, C, alkyl, Cy. haloalkyl, C;6 alkenyl, Cae alkynyl, aryl, cycloalkyl, heteroary! or heterocycloalkyl; RE and RY are each, independently, H, C,.c alkyl, Cis haloalkyl, Cs. alkenyl, Cy. alkynyl, aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl; : or R® and R" together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group; and R® and Rf are each, independently, H, Cy alkyl, Cys haloalkyl, C,¢ alkenyl, Cas alkynyl, aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl; : or R® and R' together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group; with the provisos: a) when R® and R? together with the N-atom to which they are attached form piperidinyl, said piperidinyl is unsubstituted or substituted by other than: 0 v— 3 > RC wherein: V is CH,CH,, CH=CH, or CH;O; and R is H, halo or C,.salkyl; and b) when R® and R* together with the N-atom to which they are attached form piperazinyl, said Cy is substituted by at least one —W-X-Y-Z.

2. The compound of claim 1 wherein Cy is aryl or heteroaryl, each optionally substituted by 1, 2,3,40t5 ~W-X-Y-Z.

3. The compound of claim 1 wherein Cy is aryl optionally substituted by 1,2,3,4 or 5 -W-X- Y-Z

4. The compound of claim 1 wherein Cy is aryl optionally substituted by 1,2 or 3 halo, Cis alkyl, C4 alkoxy, Ci4 haloalkyl, or Cy. haloalkoxy.

5. The compound of claim 1 wherein Cy is phenyl optionally substituted by 1,2 or 3 halo, Cia alkyl, C,.4 alkoxy, Cj.4 haloalkyl, or Cy.4 haloalkoxy.

6. The compound of claim 1 wherein R' and R? together with the C atom to which they are attached form a 3-, 4-, 5-, 6- or 7-membered cycloalkyl group.

7. The compound of claim 1 wherein R' and R? together with the C atom to which they are attached form a cyclopropyl group.

8. The compound of claim 1 wherein R? and R* together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted by 1, 2, 3,or4 -W-X’- Y'-Z'.

9. The compound of claim 1 wherein R? and R? together with the N atom to which they are attached form a piperidinyl or pyrrolidinyl group optionally substituted by 1, 2,3, 0r4-W-X-Y'-Z’.

10. The compound of claim 1 wherein R?® and R* together with the N atom to which they are attached form a piperidinyl or pyrrolidinyl group substituted by 2, 3, or 4 ~-W-X’-Y*-Z’; wherein two

~W’.-X’-Y’-Z’ are attached to the same atom and optionally form a 3-20 membered cycloalkyl or heterocycloalky! group optionally substituted by 1,2 or 3 “WXYZ

11. The compound of claim 1 wherein —~W-X-Y-Z is halo, cyano, Cy. cyanoalkyl, nitro, Cg alkyl,

C,.s alkenyl, Cg haloalkyl, Cy. alkylthio, C,.4 haloalkylthio, C,.s alkoxy, C;.¢alkenyloxy, Ci haloalkoxy, OH, (C1.4 alkoxy)-C).4 alkyl, amino, C,4 alkylamino, C,.¢ dialkylamino, OC(O)NR°RY, NR°C(O)R?, NR°C(O)OR?, NR°S(0),R?, C(O)OR?, C(O)R* , C(O)NR’NR'R’, S(O);R", SRY, C(O)NR°RY, C(S)NR°R!, aryloxy, heteroaryloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, arylalkyloxy, heteroarylalkyloxy, cycloalkylalkyloxy, heterocycloalkylalkyloxy, heteroaryloxyalkyl, aryloxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, arylalkeny!,

arylalkyny), heteroarylalkyl, heteroarylalkenyl , heteroarylalkynyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein each of said Cy.salkyl, Cog alkenyl, C,.shaloalkyl, Ci.4 alkylthio, Cy.¢ haloalkylthio,

C,.s alkoxy, aryloxy, heteroaryloxy, arylalkyloxy, heteroarylalkyloxy, heteroaryloxyalkyl, aryloxy, heteroaryloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, arylalkyloxy, heteroarylalkyloxy, cycloalkylalkyloxy, heterocycloalkylalkyloxy, heteroaryloxyalkyl, aryloxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl , heteroarylalkynyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted by 1, 2, or 3 halo, cyano, nitro, hydroxyl(C1.5 alkyl), aminoalkyl, dialkylaminoalkyl, C4 alkyl, C,.4 haloalkyl, C4 cyanoalkyl, Ci. alkoxy, Cy haloalkoxy, OH, OR? (Ci alkoxy)-C,4 alkyl, amino, C, alkylamino, C,.¢ dialkylamino, C(O)NR°RY, C(O)OR?, C(O)R’, (cyclocalkylalkyl)-C(O)-, NR°C(O)R, NR“C(O)OR?, NR*S(O);R’, C(S)NR°RY, S(0);RY, SR, (C1. alkyl)sulfonyl, arylsulfonyl, ary! optionally substituted by halo, heteroaryl, cycloalkylalkyl, cycloalkyl, or heterocycloalkyl.

12. The compound of claim 1 wherein ~-W-X-Y-Z is halo, cyano, C4 cyanoalkyl, nitro, Cys alkyl,

C,.s alkenyl, C, ghaloalkyl, Cy.;0 alkoxy, Ci. haloalkoxy, OH, Cs alkoxyalkyl, amino, C,.4 alkylamino, Cys diatkylamino, OC(O)NR°R?, NR“C(O)R’, NR°C(O)OR’, aryloxy, heteroaryloxy, arylalkyloxy, heteroarylalkyloxy, heteroaryloxyalkyl, aryloxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl , heteroarylalkynyl, cycloalkylalkyl, or heterocycloalkylalkyl, wherein each of said Cs alkyl, Cy.salkenyl, C,ghaloalkyl, Cys alkoxy, aryloxy, heteroaryloxy, arylalkyloxy, heteroarylalkyloxy, heteroaryloxyalkyl, aryloxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl , heteroarylalkynyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted by 1,2, or 3 halo, cyano, nitro, hydroxyl-(C,.s alkyl), aminoalkyl, dialkylaminoalkyl, C, 4 alkyl, C4 haloalkyl, C,4 alkoxy, Cy.4 haloalkoxy, OH, Cig alkoxyalkyl, amino, C4 alkylamino, C,.g dialkylamino, C(O)NR°R!, C(O)OR* , NR°C(O)R?, NR°S(O):R?, (C14 alkyDsulfonyl, arylsulfonyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl.

13. The compound of claim 1 wherein —-W-X-Y-Z is halo, cyano, C4 cyanoalkyl, nitro, C;.4 nitroalkyl, Cy. alkyl, C,.q haloalkyl, Cys alkoxy, Cy. haloalkoxy, OH, (Ci alkoxy)-Ci.4alkyl, amino,

Ci. alkylamino, C,.5 dialkylamino, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl.

14. The compound of claim 1 wherein -W-X-Y-Z is halo, C4 alkyl, or C,., alkoxy.

15. The compound of claim 1 wherein: 20S

—W-X’-Y*-Z’ is halo, OH, cyano, CHO, COOH, C(0)O-( Ci alkyD, C(O) Cy4 alkyl), SO»- ( Cy alkyl), Cys alkyl, Ci alkoxy or —L-R’, wherein said C4 alkyl or Ci alkoxy is optionally substituted by one or more halo, OH, COOH or C(0)O~( Cis alkyl); L is absent, O, CH,, NHSO,, N[C(0O)-( C,.4alkyl)]; and R’ is aryl or heteroaryl, each is optionally substituted by 1, 2, or 3 halo, OH, cyano, CHO, COOH, C(0)O-( C14 alkyl), C(O) C14 alkyl), SO-( Ci alkyl), SO,-NH( Cr. alkyl), Ciaalkyl, Cia alkoxy, Ci haoalkyl, C14 hydroxyalkyl, aryl, heteroaryl or aryloxy.

16. The compound of claim 1 wherein _W'-X’-Y’-Z’ is halo; C,.s alkyl; C,4 haloalkyl; OH; C,. alkoxy; C,.4 haloalkoxy; hydroxyalkyl; alkoxyalkyl; aryl; heteroaryl; ary! substituted by halo, C4 alkyl, C14 alkoxy, aryl, heteroaryl, or aryloxy; or heteroaryl substituted by halo, Cy alkyl, C4 alkoxy, aryl, or heteroaryl.

17. The compound of claim 1 wherein two —W'-X’-Y’-Z' are attached to the same atom and optionally form a 3-20 membered cycloalkyl or heterocycloalky! group optionally substituted by 1, 2 or3 -W»-X-Y.Z”,

18. The compound of claim 1 wherein —-W”-X”-Y”-Z” is halo, cyano, C4 cyanoalkyl, nitro, Ci.4 nitroalkyl, C,4 alkyl, Cy. haloalkyl, C4 alkoxy, C).« haloalkoxy, OH, (Ci alkoxy)-Ci.4 alkyl, amino,

Ci. alkylamino, C, 3 dialkylamino, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl.

19. A compound of claim 1 having Formula II: R! RZ? [WX 2)q Xe N < Cy 0] 11 or pharmaceutically acceptable salt or prodrug thereof, wherein: Cy is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, each optionally substituted by 1, 2,3, 4 or5 -W-X-Y-Z; . R' and R? together with the C atom to which they are attached form a 3-, 4-, 5-,6-or7- membered cycloalkyl group or a 3-, 4-, 5-, 6- or 7-membered heterocycloalkyl group, each optionally substituted by 1, 2 or 3 R’; R? is halo, Cy. alkyl, Cos alkenyl, Cs. alkynyl, C1 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO,, OR? SR®, C(O)R®, C(O)NRR?, C(O)OR?, OC(O)R®, OC(O)NR'RY, NRERY, NR°C(O)R?, NR°C(O)OR?, S(O)R®, S(O)NR°R®, S(0):R”, or S(0):NRR’;

W, W’ and W*’ are each, independently, absent, Cy. alkylenyl, Cis alkenylenyl, Cy alkynylenyl, O, S, NR®, CO, CS, COO, CONR?, OCONR¢, SO, SO, SONR’, or NR°CONR', wherein said C,.salkylenyl, Cys alkenylenyl, Cy¢ alkynylenyl are each optionally substituted by 1,2 or 3 halo, OH, C4 alkoxy, Cy. haloalkoxy, amino, Ci. alkylamino or Cs dialkylamino; X, X’ and X'’ are each, independently, absent, Cy.g alkylenyl, Cy.g alkenylenyl, Cy. alkynylenyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, arylalkenyl, cycloalkylalkenyl, heteroarylalkenyl, heterocycloalkylalkenyl, arylalkynyl, cycloalkylalkynyl, heteroarylalkynyl, heterocycloalkylalkynyl, each of which is optionally substituted by one or more halo, CN, NO,, OH, C4 alkoxy, C4 haloalkoxy, amino, C4 alkylamino or Cys dialkylamino; Y, Y* and Y** are each, independently, absent, C,.salkylenyl, Cys alkenylenyl, Cz6 alkynylenyl, O, S, NR®, CO, CS, COO, CONR®, OCONRS, SO, SO,, SONR®, or NRSCONR', wherein said Cys alkylenyl, C».¢ alkenylenyl, Cy. alkynylenyl are each optionally substituted by 1, 2 or 3 halo, OH, C4 alkoxy, C,.4 haloalkoxy, amino, C, alkylamino or C,.gdialkylamino;

7.7’ and Z’ are each, independently, H, halo, oxo, sulfido, CN, NO,, OH, C,. alkoxy, Ci4 haloalkoxy, amino, Cy. alkylamino or Cygdialkylamino, C.¢alkyl, Cr alkenyl, Ca alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said Cy. alkyl, Cy alkenyl, Cy alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2 or 3 halo, C,.¢ alkyl, Cas

. alkenyl, Cy. alkynyl, C, 4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO,, OR? SR®, C(O)R®, C(O)NR°R®, C(O)OR®, OC(O)R®, OC(O)NR'R’, NR°R¢, NR°C(O)R!, NR°C(O)OR?, S(O)R®, S(O)NRR?, S(0)R”, or S(O),NRR; wherein two —W-X-Y-Z attached to the same atom optionally form a 3-20 membered cycloalkyl or heterocycloalkyl group optionally substituted by 1, 2 or 3 WXYZ wherein two —~-W’-X’-Y’-Z’ attached to the same atom optionally form a 3-20 membered cycloalkyl or heterocycloalky! group optionally substituted by 1,2 or 3 WXYZ wherein —-W-X-Y-Z is other than H; wherein —W’-X'-Y’-Z’ is other than H; wherein =W?’-X’.Y’’-Z”’ is other than H; R® is H, Cy. alkyl, C\.¢ haloalkyl, C,. alkenyl, (Cy.¢ alkoxy)-C. alkyl, Cy alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl; R® is H, C,.s alkyl, C,. haloalkyl, Cy. alkenyl, Cy. alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl; R® and RY are each, independently, H, C, alkyl, C,.¢ haloalkyl, Cs alkenyl, C,.¢ alkynyl, aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl; or R® and RY together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group;

RE and Rf are each, independently, H, Cy alkyl, C,.¢ haloalkyl, Cas alkenyl, Cs. alkynyl, aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl; : or R® and Rf together with the N atom to which they are attached form a 4-, 5-, 6-or 7- membered heterocycloalky! group; and qis0,1,2,30r4.

20. A compound of claim 1 having Formula III: RF (YL wor, oN 0] 1m or pharmaceutically acceptable salt or prodrug thereof, wherein: Cy is aryl, heteroaryl, cycloalkyl! or heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 —-W-X-Y-Z; UisNH,CHyor 0; R' and R? together with the C atom to which they are attached form a 3-, 4-, 5-, 6-or 7- membered cycloalkyl group or a 3-, 4-, 5-, 6- or 7-membered heterocycloalkyl group, each optionally substituted by 1, 2 or 3 R; R’ is halo, Cy alkyl, C,.¢ alkenyl, Ca alkynyl, Cy4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO, OR’, SR? C(O)R®, C(O)NRR, C(O)OR®, OC(O)R®, OC(O)NR'R®, NR°R?, NR°C(O)RY, NR°C(O)OR?, S(O)R?, S(O)NRR!, S(O);:R", or S(O);NR°R%; W, W’ and W*’ are each, independently, absent, Cy alkylenyl, Cy alkenylenyl, Cy alkynylenyl, O, S, NR, CO, CS, COO, CONR‘, OCONR?®, SO, SO, SONR®, or NR°CONR', wherein said C,.s alkylenyl, Css alkenylenyl, C,.¢alkynylenyl are each optionally substituted by 1, 2 or 3 halo, OH, C, alkoxy, C,., haloalkoxy, amino, C,_4 alkylamino or Cy ¢ dialkylamino; X, X’ and X’’ are each, independently, absent, Cys alkylenyl, C.salkenylenyl, Cy.5 alkynylenyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylaikyl, heterocycloalkylalkyl, arylalkenyl, cycloalkylalkenyl, heteroarylalkenyl, heterocycloalkylalkenyl, arylalkynyl, cycloalkylalkynyl, heteroarylalkynyl, heterocycloalkylalkynyl, each of which is optionally substituted by one or more halo, CN, NO,, OH, C,4alkoxy, Ci. haloalkoxy, amino, C4 alkylamino or C,¢ dialkylamino; Y, Y’ and Y”’ are each, independently, absent, Cys alkylenyl, Ca alkenylenyl, Co6 alkynylenyl, O, S, NR", CO, CS, COO, CONR®, OCONR’, SO, SO,, SONR’, or NR°CONR, whercin said C, salkylenyl, C,¢alkenylenyl, C,.¢ alkynylenyl are each optionally substituted by 1,2 or 3 halo, OH, C4 alkoxy, C,4 haloalkoxy, amino, C4 alkylamino or C,.3 dialkylamino;

7,2’ and 2° are each, independently, H, halo, oxo, sulfido, CN, NO,, OH, C4 alkoxy, C,.4 haloalkoxy, amino, C4 alkylamino or Cy dialkylamino, Cy. alkyl, C2 alkenyl, Cos alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said C4 alkyl, Cac alkenyl, Cy alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1,2 or 3 halo, C,¢ alkyl, Ca. alkenyl, Cy.6 alkynyl, Cys haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO, OR’, SR?, C(O)R?, C(O)NR°RY, C(O)OR’, OC(O)R", OC(O)NR'R’, NRRY, NR°C(O)R?, NR°C(O)OR?, S(O)R", S(O)NR°R, S(O).R", or S(O);NR°RY; _ wherein two —W-X-Y-Z attached to the same atom optionally form a 3-20 membered cycloalkyl or heterocycloalkyl group optionally substituted by 1,2 or 3 “WXYZ wherein two —W’-X’-Y’-Z attached to the same atom optionally form a 3-20 membered cycloalkyl or heterocycloalkyl group optionally substituted by 1, 2 or 3 -W-X*'-Y’-2"’; wherein —-W-X-Y-Z is other than H; wherein ~W?*-X’-Y’-Z’ is other than H; wherein—W?’-X’’-Y”’-Z’’ is other than H; Ris H, C, alkyl, Cys haloalky], Cy alkenyl, (Cs alkoxy)-C,.¢ alkyl, Cy alkynyl, aryl, cycloalkyl, heteroaryl! or heterocycloalkyl; Ris H, C, alkyl, C,.¢ haloalkyl, C, alkenyl, C,. alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl; R and R are each, independently, H, Ci alkyl, Cys haloalkyl, C,.6 alkenyl, Cas alkynyl, aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl; or R® and R® together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group; R* and Rf are each, independently, H, C, alkyl, C,.¢ haloalkyl, Cy alkenyl, Cy. alkynyl, aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl; or R® and Rf together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group; and : ris0,1,2,30r4; with the provisos: a) when U is CH,, then —W’*-X’-Y’-Z’ forms a group other than: 0 v— 3 > RUC =z wherein: V is CH,CH,, CH=CH, or CH,0; and

R is H, halo or C,.s alkyl; and b) when U is NH, said Cy is substituted by at least one -W-X-Y-Z.

21. A compound of claim | having Formula IV: (W'-X'-Y'-2"), R! R2 0% oe O Iv or pharmaceutically acceptable salt or prodrug thereof, wherein: Cy is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, each optionally substituted by 1,2, 3, 4 or5 -W-X-Y-Z, R' and R? together with the C atom to which they are attached form a 3-, 4-,5-,6-or 7- membered cycloalkyl group or a 3-, 4-, 5-, 6- or 7-membered heterocycloalky! group, each optionally ’ substituted by 1, 2 or 3 Rr G' and G? together with the carbon atom to which they are attached form a 3-20 membered cycloalky! or heterocycloalkyl group optional substituted by 1,2 or 3 WXYZ R? is halo, Cys alkyl, Ca. alkenyl, Cy alkynyl, Cy haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO,, OR?, SR®, C(O)R®, C(O)NR'R’, C(O)OR*, OC(O)R", OC(O)NR°RY, NR°RY, NRC(O)R®, NR°C(O)OR?, S(O)R?, S(O)NR°RY, S(O);R®, or S(0),NRRY; W, W’and W”’ are each, independently, absent, C.salkylenyl, Ci. alkenylenyl, Ca alkynylenyl, O, S, NR, CO, COO, CONRS, SO, SO, SONR’, or NR°CONR’, wherein said Cy. alkylenyl, C,.alkenylenyl, C4 alkynylenyl are each optionally substituted by 1, 2 or 3 halo, OH, C,., alkoxy, Cy.4 haloalkoxy, amino, C4 alkylamino or C;4 dialkylamino; X, X* and X* are each, independently, absent, C; gs alkylenyl, C, galkenylenyl, Cy. alkynylenyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, arylalkenyl, cycloalkylalkenyl, heteroarylalkenyl, heterocycloalkylalkenyl, arylalkynyl, cycloalkylalkynyl, heteroarylalkynyl, heterocycloalkylalkynyl, each of which is optionally substituted by one or more halo, CN, NO,, OH, Cs alkoxy, C4 haloalkoxy, amino, C4 alkylamino or Cy gdialkylamino; Y, Y’ and Y?? are each, independently, absent, C,.¢alkylenyl, Cy alkenylenyl, Cz. alkynylenyl, O, S, NR, CO, CS, COO, CONR®, OCONR?, SO, SO,, SONR?, or NR°CONR, wherein said Cy alkylenyl, Cs alkenylenyl, C,salkynylenyl are each optionally substituted by 1, 2 or 3 halo, OH, Cs alkoxy, C,.4 haloalkoxy, amino, C 4 alkylamino or C, dialkylamino; Z, 27’ and 2”’ are each, independently, H, halo, oxo, sulfido, CN, NO,, OH, C,.4alkoxy, Ci haloalkoxy, amino, C,.4 alkylamino or Cy dialkylamino, Cs alkyl, C6 alkenyl, C;.s alkynyl, aryl,

cycloalkyl, heteroaryl or heterocycloalkyl, wherein said Cysalkyl, Cy. alkenyl, C,.¢ alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2 or 3 halo, Cy alkyl, Ca. alkenyl, Cys alkynyl, Ci4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO,, OR’, SR®, C(O)R®, C(O)NR°R?, C(O)OR?, OC(O)R®, OC(O)NRR', NR'R’, NRC(O)R?, NR°C(O)OR’, S(O)R®, S(O)NR°R’, S(O):R”, or S(O),NRRY, wherein two ~W-X-Y-Z attached to the same atom optionally form a 3-20 membered cycloalky! or heterocycloalkyl group optionally substituted by 1, 2 or 3 WXYZ wherein —W-X-Y-Z is other than H; wherein —W?’’-X*’-Y*’-Z" is other than H; R® is H, Cy alkyl, C). haloalkyl, C,.¢ alkenyl, (Ci alkoxy)-Cy.¢ alkyl, Cy alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl; R® is H, C, alkyl, C,. haloalkyl, Co alkenyl, Cp alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl; R® and R? are each, independently, H, Cy. alkyl, C,.¢ haloalkyl, C,.¢ alkenyl, Cy alkynyl, aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl; or R°and R* together with the N atom to which they are attached form a 4-, 5-, 6- or 7- ‘membered heterocycloalkyl group; R® and RF are each, independently, H, Cys alkyl, Cy. haloalkyl, Cy alkenyl, Cs. alkynyl, aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl; or R® and R' together with the N atom to which they are attached form a 4-, 5-,6-0r7- membered heterocycloalkyl group; and vis 0, lor2.

22. A compound of claim 1 having Formula Va or Vb: (WXYZ), qQ! ~Q¢_ (W'-X"-Y"-Z") po Te N (WXYZ), oN a o Va TEEN Drea Rl R? (J (WXYZ), N PN q 0]

Vb or pharmaceutically acceptable salt or prodrug thereof, wherein: ring B is a fused 5 or 6-membered aryl or heteroaryl group; Q'is 0, S, NH, CH,, CO, CS, SO, SO,, OCH, SCH,, NHCH,, CH,CH,, CH=CH, COCH;, CONH, COO, SOCH,, SONH, SO,CH;,, or SO,NH;

Q*is 0, S, NH, CH,, CO, CS, SO, SO, OCH, SCH,, NHCH,, CH,CH,, CH=CH, COCH,, CONH, COO, SOCH,, SONH, SO,CH,, or SO;NH;

Cy is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, each optionally substituted by 1,2, 3,4 or5 -W-X-Y-Z,

R! and R? together with the C atom to which they are attached form a 3-, 4-, 5-,6-o0r7- membered cycloalkyl group or a 3-, 4-, 5-, 6- or 7-membered heterocycloalkyl group, each optionally substituted by 1,2 or 3 R%;

R? is halo, C,.¢ alkyl, Ca. alkenyl, Ca. alkynyl, Ci haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO, OR?, SR®, C(O)R", C(O)NRR?, C(O)OR?, OC(O)R®, OC(O)NR'R’, NR°R®, NR°C(O)R®, NR°C(O)OR’, S(O)R®, S(O)NR'R’, S(0).R’, or S(0),NR°R’;

W, W’ and W”’ are each, independently, absent, Cy alkylenyl, C,.¢ alkenylenyl, Ca alkynylenyl, O, 8, NR*, CO, CS, COO, CONR, OCONRS, SO, SO,, SONR®, or NR°CONR', wherein said Ci alkylenyl, Cys alkenylenyl, Cas alkynylenyl are each optionally substituted by 1,2 or 3 halo, OH, C,.4 alkoxy, C,4haloalkoxy, amino, C4 alkylamino or Cys diatkylamino;

X, X’ and X’’ are each, independently, absent, Cys alkylenyl, Ca.¢ atkenylenyl, Cys alkynylenyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, arylalkenyl, cycloalkylalkenyl, heteroarylalkenyl, heterocycloalkylalkenyl, arylalkynyl, cycloalkylalkynyl, heteroarylalkynyl, heterocycloalkylalkynyl, each of which is optionally substituted by one or more halo, CN, NO, OH, C,.4 alkoxy, C,.4 haloalkoxy, amino, C4 alkylamino or C,.g dialkylamino;

Y,Y’ and Y’ are each, independently, absent, Cy.¢ alkylenyl, C,¢ alkenylenyl, Cy alkynylenyl, O, S, NR, CO, CS, COO, CONR®, OCONRS, SO, SO,, SONR®, or NR°CONR', wherein said C..¢ alkylenyl, Cys alkenylenyl, Cy. alkynylenyl are each optionally substituted by 1, 2 or 3 halo, OH, C,. alkoxy, C,.4 haloalkoxy, amino, C4 alkylamino or Cy dialkylamino;

Z,Z’ and 2”’ are each, independently, H, halo, oxo, sulfido, CN, NO, OH, C,4alkoxy, C4 haloalkoxy, amino, Cy.4 alkylamino or Cys dialkylamino, Cys alkyl, Cz.6 alkenyl, Cp. alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said Cy alkyl, Ca alkenyl, Cp. alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1,2 or 3 halo, Cy.¢ alkyl, Cy6 alkenyl, Ca.6 alkynyl, Cy haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO,, OR’, SR?, C(O)R®, C(O)NR'R!, C(O)OR®, OC(O)R®, OC(ONR'R’, NR°RY, NR"C(O)R’, NR‘C(O)OR", S(O)R®, S(O)NRR?, S(O),R®, or S(0),NRR’;

wherein two —~W-X-Y-Z attached to the same atom optionally form a 3-20 membered cycloalkyl or heterocycloalkyl group optionally substituted by 1,2 or 3-WrX-Y-2 wherein —W-X-Y-Z is other than H; wherein —-W’-X’*-Y’*-Z"" is other than H; R® is H, C,. alkyl, C;.¢ haloalkyl, Cz alkenyl, (Cis alkoxy)-C. alkyl, Ca alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl; R® is H, C,.¢ alkyl, C,.¢ haloalkyl, Cy. alkenyl, Co. alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl; RE and RY are each, independently, H, C, 4 alkyl, Ci. haloalkyl, Cy. alkenyl, Cy alkynyl, aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl; or R® and R® together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group; R® and Rf are each, independently, H, Cy. alkyl, Ci.¢ haloalkyl, Cy. alkenyl, Ca. alkynyl, aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl; or R® and Rf together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group; / qisOorl; vis0,1o0r2; ris0,1or2; sis 0, 1 or 2; and the sum ofrandsis 0, ! or2. :

23. A compound of claim 1 having Formula VI: (W-X-Y'-Z'), QQ (WXYZ), 4 R! R2 < / 3, oN = Swexevz) q 0) Vi wherein Q*and Q* are each, independently, CH or N.

24. A compound of claim 1 having Formula VII:

R' R? '~q2 N T— (WXYZ) oN = Q? (W"-X"-Y"-Z"); VIL — 25. A compound of claim 1 having Formula VIII: R! R? Q'~q2 N PN “2 0 \ VIII

26. A compound of claim 1 selected from: 1-((1-(4-Chloropheny!) cyclopropyl) carbonyl)pyrrolidin-3-ol; 1-[(1-Phenylcyclopropyl) carbonyl] pyrrolidin-3-ol; 1-[(1-Phenylcyclopropy!) carbonyl] pyrrolidin-3-ol; 1-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl}-2-phenylpyrrolidine; 1'-{[14-Chlorophenyl)cyclopropyl] carbonyl}-2,3-dihydrospiro[indene-1,4"-piperidine]; 1-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl}-3-phenylpiperidine; 1-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl}-4-phenylpiperidine-4-carbonitri le; 1-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl}-4-phenoxypiperidine; 1'-{[1-(4-chlorophenyl)cyclopropyl] carbonyl}-1 -methylspiro[indole-3,4"-piperidin]-2(1 H)- one; 1-{[1-(4-Chlorophenyl)cyclopropy!] carbonyl}-4-phenylpiperidin-4-ol; Methyl 3-(1-{[1-(4-chlorophenyl) cyclopropyllcarbonyl} piperidin-4-yl)benzoate; 4-Benzyl-1-{[1-(4-chlorophenyl) cyclopropyl]carbonyl} piperidin-4-ol; 4-(4-tert-Buty|-1,3-thiazol-2-y1)-1-{[1-(4-chlorophenyl)cyclopropyl] carbonyl} piperidine; Methyl 4-(1-{[1-(4-chlorophenyl) cyclopropyllcarbonyl} piperidin-4-yl)benzoate, tert-Butyl 1'-{[1-(4-chlorophenyl) cyclopropyljcarbonyl}spiro[indole-3,4'-piperidine]-1(2H)- carboxylate; 1'-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl}-2,3-dihydro-1H-spiro [isoquinoline-4,4'- piperidine]; 8-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl}-3-phenyl-1-oxa-2,8-diazaspiro[4.5]dec-2-ene;

1-{[1-(4-Chlorophenyl)cyclopropyl] carbonyi}-4-[3 (trifluoromethyl) phenyl] piperidine; 1-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl}-4-(4-phenyl-1 ,3-thiazol-2-yl)piperidine;

: tert-Butyl 7-{[1-(4-chlorophenyl) cyclopropyl]carbonyl}-2,7-diazaspiro [4.5]decane-2- carboxylate; tert-Butyl 1'-{[1-(4-chlorophenyl) cyclopropyt]carbonyl}-1H-spiro [isoquinoline-4,4'- piperidine]-2(3H)-carboxylate; tert-Butyl 7-{[1-(4-chlorophenyl Yeyclopropyljcarbonyl}-2,7-diazaspiro [3.5]nonane-2- . carboxylate; 4-(1-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl} pyrrolidin-3-yl)pyridine; 4-(1-{[144-Chlorophenyl) cyclopropyljcarbonyl} pyrrolidin-3-yl)pyridine; 4-(1-{[1 (4-Chlorophenyl) cyclopropyl]carbony!}pyrrolidin-3-yl)pyridine; 1-{[1-(4-Chlorophenyl) cyclopropyl] carbonyl}-3-phenylpyrrolidine; 2-(1-{[1-(4-Chlorophenyl)cyclopropy!] carbonyl} pyrrolidin-3-yl)pyrazine; 3-(1-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl} pyrrolidin-3-yl)pyridine; 1-{[1-(4-Chloropheny!) cyclopropyl]carbonyl}-3-phenylpyrrolidine; 3-(3-Chlorophenyl)-1-{[1 -(4-chlorophenyl)cyclopropyllcarbonyl} pyrrolidine; 1-{[1<(4-Chlorophenyl)cyclopropyl] carbonyl}-3-[3-(triflucromethyl) phenyl]pyrrolidine; 2-(1-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl}pyrrolidin-3-yDpyridine; 1-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl}-3 -phenylpyrrolidin-3-ol; 1-{[1-(4-Chlorophenyl)cyclopropyl]} carbonyl}-3 -(2-naphthyl)pyrrolidine; 3-Benzyl-1-{[1-(4-chlorophenyl) cyclopropyljcarbonyl} pyrrolidine; 1-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl}-3 -(phenylsulfonyl)pyrrolidine, 2-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl}-5-(4-fluorophenyl)-2,5- diazabicyclo{2.2.1]heptane; 1-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl} -3-(4-phenoxyphenyl) pyrrolidine; Methyl 1-{[1-(4-chlorophenyl) cyclopropyl]carbonyl}-4-phenyl pyrrolidine-3-carboxylate; 1-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl}-3-(4-methoxypheny! )pyrrolidine; 1-((1-(4-Chlorophenyl)cyclopropyl carbonyl)-3-(4-trifluoropheny!) pyrrolidine; 3-(4-Chlorophenyl)-1-{[1-(4-chlorophenyl)cyclopropyljcarbonyl} pyrrolidine; 4-(1-{[1-(2,4-Dichlorophenyl) cyclopropyl]carbonyl} pyrrolidin-3-yDpyridine; 4-(1-{[1-(4-Methoxyphenyl) cyclopropyl] carbonyl} pyrrolidin-3-yl)pyridine; 4-(1-{[1-(4-Methylphenyl)cyclopropyl] carbonyl} pyrrolidin-3-yl)pyridine; 1-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl}-4-phenylpiperidine; 3-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl}-1,2,3,4,4a,5,6,1 0b-octa- hydrobenzo|[f]isoquinoline; 2-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl}-2,3,3a,4,5,9b-hexahydro-1H- benzofelisoindole;

2-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl}-1 2.3,3a,8,8a-hexahydroindeno(1,2-c]pyrrole; 1'-{[1-(4-Chlorophenylcyclopropyl] carbonyl}-1 ,3-dihydrospiro[indene-2,4"-piperidine]; 3-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl} -2,3,4,4a,5,6-hexahydro-1 H-pyrazino(1,2- ajquinoline; 2-{[t -(4-Chlorophenyl)cyclopropyl] carbonyl}-1,2,3,4,1 0,10a-hexahydro pyrazino[1,2- alindole; 1'-{[1 -(4-Chlorophenyl)cyclopropyl] carbonyl }spiro[chromene-2,4'-piperidine];

: 1'-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl }-3H-spiro[2-benzofuran-1 ,4'-piperidine}; 1'-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl! yspiro[indole-3,4"-piperidin]-2(1 H)-one; 8-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl}-2,8-diazaspiro[4.5]decan-3-one; 2-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl}-1,2,3,4-tetrahydro isoquinoline; 6-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl}-4,5,6,7-tetrahydrothieno [2,3-c]pyridine; 1-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl}indoline; 2-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl}isoindoline;

8-{[1 -(4-Chlorophenyl)cyciopropyi] carbonyl}-1-phenyl-1,3,8-triazaspiro [4.5]decan-4-one; 4-Benzylidene-1-{[1-(4-chlorophenyl) cyclopropyl]carbonyl} piperidine; 1'-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl} -1,4'-bipiperidine; 4-(1-{[1(4-Chlorophenyl)cyclopropyl] carbonyl} piperidin-4-yl)pyridine; 1-{[1-(4-Chlorophenyl)cyclopropyl] carbonyi}-3 -(4-fluorophenyl) pyrrolidine; 1-{[1(4-Chlorophenyl)cyclopropyl] carbony 1}-3-(3-fluorophenyl) pyrrolidine; N-~(1-{{1-(4-Chlorophenyl) cyclopropy [Jcarbonyl}piperidin-4-yl)-N-phenylpropanamide; 2-{[1-(4-Chlarophenyl)cyclopropyl] carbonyl} octahydropyrrolo[1,2-a]pyrazine; 4-{[1-(4-Chloropheny!)cyclopropyl] carbonyl} piperazine-1 -carbaldehyde; 4-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl}-2-methyl-1-phenyl iperazine; 1-{[1 (4-Chlorophenyl)cyclopropy!] carbonyl}-4-(pyridin-4-ylmethyl) piperazine; 1-{[1<(4-Chlorophenyl)cyclopropyl] carbonyl}-4-(2-thienylsulfonyl) piperazine; 2-(1-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl} piperidin-2-yl)ethanol, 2-(1-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl} piperidin-4-yl)ethanol; 1-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl}-4-(4-fluorophenyl) piperidine; 4-(4-Chlorophenyl)-1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-1,2,3 ,6-tetrahydropyridine; (1-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl} piperidin-2-y!)methanol; 2-(1-{[1-(4-Chloropheny!)cyclopropyl] carbonyl} pyrrolidin-2 -yDethanol; (1-{[1-(4-Chlorophenyl) cyclopropy!]carbonyl}pyrrolidin-2-yhmethanol; (1-{[1-(4-Chloropheny}) cyclopropyljcarbonyl}pyrrolidin-2-yl)methanol; 1'-{[1-(4-Chlorophenyl)cyclopropyl] carbony!}spiro[1,2-benzisothiazole-3,3-pyrrolidine] 1,1-dioxide;

1-{[1 -(4-Chlorophenyi)cyclopropyl] carbonyl} -3H-spiro[2-benzofuran-1 ,3"-pyrrolidin]-3- : one; 1'-({1-[4-(Pyridin-2-yloxy) phenylicyclopropyl}carbonyl)-3 H-spiro{2-benzofuran-1,3'- pyrrolidin]-3-one; 1'-{[1-(4-Chlorophenyl)cyclobutyl] carbonyl} -3H-spiro[2-benzofuran-1 ,3-pyrrolidin]-3-one; 1'-{[1-(4-Methylphenyl)cyclopropyl] carbonyl}-3H-spiro[2-benzofuran-1,3"-pyrrolidin]-3- one; _ 1'-{[1 -(4-Methoxyphenyl)cyclopropyl) carbonyl} -3H-spiro[2-benzofuran-1 ,3"-pyrrolidin]-3- one; oo 1'-{[1«(2,4-Dichlorophenyl) cyclopropy!]carbonyl} -3H-spiro[2-benzofuran-1 ,3-pyrrolidin}-3- one; : 1'-{[1-(4-Chiorophenyl)cyclopropyl] carbonyl }-3H-spiro[2-benzofuran-1 ,3'-pyrrolidine]; 1'-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl}-7H-spiro{furo[3,4-b]pyridine-5,3'-pyrrolidin]- 7-one; 1'-{[1-(4-Chloropheny!)cyclopropyl] carbonyl}-3 H-spiro[furo[3,4-c]pyridine-1,3"-pyrrolidin]- 3-one; 1'-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl}-1H-spiro[furo(3 ,4-c]pyridine-3,3"-pyrrolidin]- 1-one; 1'-{[1<4-Chlorophenyl)cyclopropyl] carbonyl} spiro[indole-3,3'-pyrrolidin]-2(1H)-one; 1'-({ 1-[4-(1H-Pyrazol-1-yl)phenyl] cyclopropyl} carbonyl)-3 H-spiro[furo[3,4-c}pyridine-1,3"- pyrrolidin]-3-one; 1'-({1-[4-(Difluoromethoxy) phenyljcyclopropyl}carbonyl)-3H-spiro[furo[3,4-c] pyridine- 1,3"-pyrrolidin]-3-one; 1'-{[1-(6-Phenylpyridin-3-yl)cyclopropyl]carbonyl}-3 H-spiro[2-benzofuran-1,3"-pyrrolidin]- 3-one; 1'-{[1-(6-Phenylpyridin-3-yl) cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c] pyridine-1,3'- pyrrolidin}-3-one; 1'-{{1«(4-Pyrrolidin-1-ylphenyl) cyclopropyl]carbonyl}-3H-spiro[ furo[3,4-c]pyridine-1,3'- pyrrolidin}-3-one; 1'-{[1-(4-Pyrrolidin-1-ylphenyl) cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3'- pyrrolidin]-3-one; and 1'-{[146-Pyrrolidin-1-ylpyridin-3-yl)cyclopropyljcarbonyl} -3H-spiro[furo[3,4-c]pyridine- 1,3"-pyrrolidin]-3-one, or pharmaceutically acceptable salt thereof.

27. A compound of claim 1 selected from: 1-{[1-(6-Pyrrolidin-1-ylpyridin-3-yl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3'- pyrrolidin]-3-one;

1'-({1-[4-(2-Oxo0-1 3-oxazolidin-3-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran- 1,3'-pyrrolidin}-3-one; 1'-({1-[4-(2-Oxopyrrolidin-1 -yl)phenylJcyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1 »3- pyrrolidin]-3-one; 1'-({1 -[4-(2-Phenylethoxy)phenyl] cyclopropyi}carbonyl)-3H-spiro[furo[3,4-c] pyridine-1,3'- pyrrolidin]-3-one; 1'-[(1-{4-[(1-Methylcyclopropyl) methoxy]phenyl}cyclopropyl)-carbony 1]-3H-spiro[furo(3,4- _ ¢}pyridine-1,3"-pyrrolidin]-3-one; 1'-{(1 -{4-[(2-Fluorobenzyl)oxy) phenyl} cyclopropyl)carbonyl]-3H-spiroffuro[3,4-c] pyridine- 1,3'-pyrrolidin]-3-one; 1'-({1-[4-(Quinolin-2-ylmethoxy) phenyljcyclopropyl}carbonyl)-3H-spirof furo[3 A- c]pyridine-1,3'-pyrrolidin]-3-one; 1'-[(1-{4-[(3-Fluorobenzyl)oxy} phenyl} cyclopropyl)carbonyl}-3H-spiro[furof3 ,4-c]pyridine- 1,3'-pyrrolidin]-3-one; 1'<({1-[4-(1 ,3-Benzothiazol-2-ylmethoxy)phenyl]cyclopropyl}- carbonyl)-3H-spiro[furo[3,4- c]pyridine-1,3'-pyrrolidin]-3-one; 1'-{[1-(4-{[3,5-Bis(trifluoromethy!) benzyljoxy} phenyl)-cyclopropyl] carbonyl}-3H- spiro[furo[3,4-c]pyridine-1,3'-pyrrolidin]-3-one; ) 1'-[(1-{4-[2-(4-Fluorophenyl)ethoxy] phenyl}cyclopropyl)-carbonyl}-3H-spiro furo(3,4- c]pyridine-1,3'-pyrrolidin]-3-one; 4-[(4-{1-[(3-Oxo0-1'H,3H-spiro [furo[3,4-c]pyridine-1,3"-pyrrolidin]-1'-y [Ycarbonyl] cyclopropyl} phenoxy)methyl]benzonitrile; 1'-{[1-(4-Phenoxyphenyl)cyclopropyl] carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3'- pyrrolidin]-3-one; 1'-({1-[{4-(Pyridin-4-ylmethoxy) phenyl]cyclopropy!}-carbonyl)-3H-spiro[2-benzofuran-1 »3'- pyrrolidin]-3-one; 1'-({ 1 -[4-(Pyridin-2-ylmethoxy) phenyl]cyclopropyl}-carbonyl)-3H-spiro[2-benzofuran-1 3 pyrrolidin]-3-one; 1'-{[1-(4-Pyridin-4-yIpheny!) cyclopropyl]carbonyl }-3H-spiro[2-benzofuran-1,3'-pyrrolidin]- 3-one; 1'-{[1-(4-Cyclopropylphenyl) cyclopropyljcarbonyl}-3H-spiro[2-benzofuran-1 ,3'-pyrrolidin]- 3-one; 1'-{[1-(2-Fluoro-4-pyridin-2-ylphenyl)cyclopropyl]-carbonyl} -3H-spiro{2-benzofuran-1,3'- pyrrolidin}-3-one; 1'-[(1-{4-[(E)-2-(4-Methylphenyl)vinyl]phenyl} -cyclopropyl)carbony!}-3 H-spiro[2- benzofuran-1,3"-pyrrolidin]-3-one;

1-({1 -[4-(2-Pyridin-2-ylethoxy)phenyl]cyclopropyl}-carbonyl)-3H-spiro[2-benzofuran-1 ,3- pyrrolidin]-3-one; 1'-({1-[4-(2-Pyridin-2-ylethoxy) phenyl]cyclopropy!}carbonyl)-3H-spiro[furo(3 ,4-c]pyridine- 1,3'-pyrrolidin]-3-one; 1'-[(1-{4-[(E)-2-Pyridin-4-ylvinyl]phenyl} cyclopropyl)-carbonyl]-3H-spiro[2-benzofuran- 1,3'-pyrrolidin]-3-one; 1'-({1 -[4-(3,5-Dimethylisoxazol-4-yl)phenyl]cyclopropyl} carbonyl)-3H-spiro[2-benzofuran- } 1,3'-pyrrolidin]-3-one; 1'-({1 [4 1-Methyl-1H-pyrazol-4-yl)phenyljcyclopropyl} carbonyl)-3H-spiro[2-benzofuran- 1,3"-pyrrolidin]-3-one; 1'-({1-[4'-(Methylsulfonyl) biphenyl-4-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1 3 pyrrolidin}-3-one; 1'-({1-[4-(3-Methyl-1H-pyrazol-1-yl)phenyl]cyclopropyl} carbonyl)-3H-spiroffuro[3,4- c}pyridine-1,3"-pyrrolidin]-3-one; 1'-[(1-{4-[3-(Trifluoromethyl)-1H-pyrazol-1 -yl]phenyl} cyclopropyl) carbonyl]-3H- spiro[fure[3,4-c]pyridine-1,3'-pyrrolidin]-3-one; 1'-({1-[4-(4-Methyl-1H-pyrazol-1-yl)phenyl]cyclopropy!} carbonyl)-3H-spiro [furo[3,4- c]pyridine-1,3"-pyrrolidin}-3-one; 1'-({1-[4-(2H-Indazol-2-yl)phenyl] cyclopropyl} carbonyl)-3H-spiro[furo [3,4-c]pyridine-1,3- pyrrolidin]-3-one; 1'<({1-[4-(1H-Benzimidazol-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4- c]pyridine-1,3"-pyrrolidin}-3-one; 1'~({1-[4-(2-Methyl-1H-imidazol-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro [furo[3,4- c]pyridine-1,3"-pyrrolidin}-3-one; 1'({1-[4-(10-1,2,4-Triazol-1-yl)phenyl]cyclopropyl}carbonyl)-3 H-spiro[2-benzofuran-1,3'- pyrrolidin]-3-one; 1'({1-[4-(1-Hydroxycyclopentyl) phenyljcyclopropyl} carbonyl)-3H-spiro[2-benzofuran-1,3'- pyrrolidin]-3-one; 1'-{[1-(4-Cyclopentylphenyl) cyclopropyl]carbony!} -3H-spiro[furo[3,4-c]pyridine-1,3'- pyrrolidin}-3-one; 1'<({ 1-[4-(1-Hydroxycyclopentyl) phenyl]cyclopropyl}carbony 1)-3H-spiro[furof3,4- c]pyridine-1,3"-pyrrolidin]-3-one; 1'-({1-[4-(1-Hydroxycyclobutyl) phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3'- pyrrolidin}-3-one; 1'-({1-{4-(1-Hydroxycyclobuty!) phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine- 1,3'-pyrrolidin]-3-one;

1'-({1-[4-(Tetrahydro-2H-pyran-4-y Iphenyl]cyclopropyl} carbonyl)-3H-spiro[furo [3.4- c]pyridine-1,3'"-pyrrolidin}-3-one; 1'-{{1-(4-Cyclobutylphenyl) cyclopropy!Jcarbonyl}-3H-spiro[furo[3,4-c]pyridine-1 3 pyrrolidin]-3-one; 1'-({! -[4-(4-Hydroxytetrahydro-2H-pyran-4-yl)phenyl] cyclopropy!}carbonyl)-3H-spiro(2- benzofuran-1,3"-pyrrolidin}-3-one; 1'-({1-[4-(4-Hydroxytetrahydro-2H-pyran-4-yi)phenyl] cyclopropyl} carbonyl)-3H- _ spiro[furo[3,4-c]pyridine-1 ,3'-pyrrolidin]-3-one; 1'-({1-[4-(2-Amino-1,3 -thiazol-4-yl)phenyljcyclopropyl}carbonyl)-3H-spiro[2-benzofuran- - 1,3'-pyrrolidin]-3-one; 1'-({1-[4«(2-Methyl-1 3-thiazol-4-yl)phenyl]cyclopropy|}carbonyl)-3H-spiro[2-benzofuran- 1,3'-pyrrolidin}-3-one; 1'-({1-[4~(2-Ethyl-1 ,3-thiazol-4-yl)phenyl]cyclopropyl} carbonyl)-3H-spiro [2-benzofuran- 1,3'-pyrrolidin}-3-one, 1'-({1-[4«2-Amino-1 ,3-thiazol-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4- ¢]pyridine-1,3'-pyrrolidin]-3-one; 1'-({1-[4-(2-Methyl-1,3-thiazol-4-yl)phenyljcyclopropyl} carbony!)-3H-spiro{furo[3,4- c]pyridine-1,3'-pyrrolidin}-3-one; 1'-({1-[4-(1 ,3-Thiazol-4-yl)phenyl]cyclopropy!}carbonyl)-3H-spiro[2-benzofuran-1,3"- pyrrolidin}-3-one; 4-(1-¢ [1-(4-Chlorophenyl)-3-(methoxymethoxy)cyclobutyl]carbonyl} pyrrolidin-3- yDpyridine; 3-(3-Chloropheny!)-1-{[1-(4-chlorophenyl)-3-(methoxymethoxy} cyclobutyl] carbonyl}pyrrolidine; 1'-{[trans-1-(4-Chlorophenyl)-3-hydroxycyclobutyl]Jcarbonyl} -3H-spiro[2-benzofuran-1,3'- pyrrolidin}-3-one; 1'-{[cis-1-(4-Chlorophenyi)-3-fluorocyclobutyl]carbony!} -3H-spiro[2-benzofuran-1,3'- pyrrolidin}-3-one; 1'-{[cis-1-(4-Chloropheny!)-3-fluorocyciobutyl]carbony!}-3 H-spiro[2-benzofuran-1,3'- pyrrolidine]; 1'-{[cis-1-(4-Chloropheny!)-3-fluorocyclobutyl]carbonyl}-3 H-spiro[furo[3,4-c]pyridine-1,3'- pyrrolidin]-3-one; 1'-{[cis-1-(4-Chlorophenyl)-3-fluorocyclobutyljcarbonyl} -7H-spiro[ furo[3,4-bjpyridine-5,3'"- pyrrolidin]-7-one; 3-(1-{[1-(4-Chlorophenyl)cyclobutyl] carbonyl} pyrrolidin-3-yl)pyridine; I'-{[1-(4-Chlorophenyl)cyclobutyl] carbony!}-7H-spiro[furo[3,4-b]pyridine-5,3"-pyrrolidin}- 7-one;

1'-({1-[4-(1H-Indazol-i-yl)phenyl] cyclobutyl}carbonyl)-3H-spiro[furo [3,4-c)pyridine-1,3'"- pyrrolidin]-3-one; 1'-[(1-{4-[3-(Trifluoromethyl)-1 H-pyrazol-1-yl]pheny!}cyclobutyl) carbonyl}-3H- spiro[furo(3,4-c]pyridine-1 ,3'-pyrrolidin]-3-one; 1'-({1-[4-(1 H-Benzimidazol-1 -ylyphenyljcyclobutyl} carbonyl)-3H-spiroffuro[3,4-c]pyrid ine- 1,3'-pyrrolidin}-3-one; 1'-({1-[4-(2-Ox0-1,3 -oxazolidin-3-yl)phenyl]cyclobuty!}carbonyl)-3 H-spiro{2-benzofuran- 1,3'-pyrrolidin]-3-one; 1'-[(1-Pyridin-4-ylcyclobutyl) carbonyl]-3 H-spiro[2-benzofuran-1,3'-pyrrolidin}-3-one; B 1'-{[1-(4-Pyridin-4-ylphenyl) cyclobutyl]carbonyl}-3H-spiro[2-benzofuran-1,3"-pyrrolidin)-3- one; N,N-Dimethyl-4-[5-(1-{[3-0x0-1'H,3 H-spiro[2-benzofuran-1,3"-pyrrolidin]-1 '-yljcarbonyl} cyclopropyl)pyridin-2-yl]piperazine-1 -carboxamide; 1'-[(1-{6-[4-(Methylsulfonyl) piperazin-1-yl]pyridin-3-yl}cyclopropy!)carbonyl}-3H-spiro[2- benzofuran-1,3'-pyrrolidin]-3-one; 1'-[(1-{6-[4-(2-Fluoropheny!)piperazin-1-yl]pyridin-3 -yl}cyclopropyl)carbonyl]-3H-spiro[2- benzofuran-1,3'-pyrrolidin]-3-one; 1'-({1-[6-(3,3-Difluoropyrrolidin-1-yl)pyridin-3 -yl]cyclopropyl}carbonyl)-3H-spiro[2- benzofuran-1,3'-pyrrolidin]-3-one; 1'-[(1-{6-[3-Hydroxypyrrolidin-1-yl]pyridin-3 -yl}cyclopropyl)carbonyl]-3H-spiro[2- benzofuran-1,3'-pyrrolidin]-3-one; N-{1-[5-(1-{[3-Oxo0-1'H,3H-spiro[2-benzofuran-1 ,3'-pyrrolidin]-1'- yl]carbonyl} cyclopropyl)pyridin-2-yl]pyrrolidin-3-yl} acetamide; 1'-({1-[6-(1 ,3-Dihydro-2H-isoindol-2-yl)pyridin-3-yl]cyclo-propyl} carbonyl)-3H-spiro[2- benzofuran-1,3'-pyrrolidin]-3-one; 1'-({1-[6-(3,4-Dihydro-isoquinolin-2(1 H)-yl)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro{2- benzofuran-1,3'-pyrrolidin]-3-one; 1’-{[ 1 (6-Morpholin-4-ylpyridin-3-yl)cyclopropyljcarbonyl}-3 H-spiro[2-benzofuran-1,3°- pyrrolidin]-3-one; 1'-({1-[6-(4-Hydroxypiperidin-1-yl)pyridin-3-yllcyclopropy!} carbonyl)-3H-spiro[2- benzofuran-1,3'-pyrrolidin}-3-one; N-{4-[5-(1-{[3-Oxo-1'H,3H-spirof2-benzofuran-1 ,3-pyrrolidin]-1'- . yl]carbonyl}cyclopropyl)pyridin-2-yl]phenyl} acetamide; 1'-({1-[6-(2-Fluorophenyl) pyridin-3-ylJcyclopropyl} carbonyl)-3H-spiro[2-benzofuran-1,3'- pyrrolidin]-3-one; 1'-({1-[6-(1-Benzothien-3-yl)pyridin-3-yl]cyclopropyl} carbonyl)-3H-spiro[2-benzofuran-1,3"- pyrrolidin]-3-one;

1'-{[1-(2,3"-Bipyridin-S-yl)cyclopropyljcarbonyl }-3H-spiro[2-benzofuran-1,3"-pyrrolidin}-3- one; 1'-({1-[6-(1 -Methyl-1H-indo}-5-yl)pyridine-3-yl]cyclopropy!} carbonyl)-3H-spiro[2- benzofuran-1,3’-pyrrolidin]-3-one; 1°-[(1-{6-[3-(Trifluoromethoxy)phenyl]pyridine-3 -yl}cyclopropyl)carbonyl]-3H-spiro[2- benzofuran-1,3’-pyrrolidin]-3-one; 1°-({ 1-[6-(3-Thienyl)pyridine-3-yljcyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1 3 pyrrolidin]-3-one; 1 »[(1-{6-[3-(Trifluoromethyl)phenyl]pyridine-3-yl}cyclopropyl)carbonyl]-3H-spiro[2- benzofuran-1,3’-pyrrolidin}-3-one; 1’-({1-[6-(1 -Methy!-1H-pyrazol-4-yl)pyridine-3-yl]cyclopropyl}carbonyl)-3 H-spiro[2- benzofuran-1,3’-pyrrolidin]-3-one; 1'-{[1-(6-Chloropyridin-3 -ylcyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1 ,3'-pyrrolidin)- 3-one; 1'({ 1-{6-(Benzyloxy)pyridin-3-yljcyclopropyl}carbonyl)-3H-spiro[2-benzofuran- 1,3"- pyrrolidin]-3-one; 1'-[(1-Quinolin-3 -ylcyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1 ,3'-pyrrolidin}-3-one; 1'-({1-[6-(1-Methy!-1H-pyrazol-4-yl)pyridin-3 -yl]cyclopropyl}carbonyl)-3H-spiro[ furo(3,4- c]pyridine-1,3"-pyrrolidin]-3-one; 1'«({1-[6-(Benzyloxy)pyridin-3-ylJcyclopropyl }carbonyl)-3H-spiro[ uro[3,4-c]pyridine-1,3"- pyrrolidin]-3-one; 1'-{[1-(6-Chloropyridin-3-yl)cyclopropyl)carbonyl}-3H-spiro{furo[3 ,4-c]pyridine-1,3'- pyrrolidin]-3-one; 1'-({1-[6-(3,4-Dihydroisoquinolin-2(1 H)-yl)pyridin-3 -ylleyclopropyl}carbonyl)-3H- spiro[furo[3,4-c]pyridine-1,3'-pyrrolidin]-3-one; 1'-({1-[6-(1 ,3-Dihydro-2H-isoindol-2-yl)pyridin-3-yl]cyclopropy!} carbonyl)-3H- spiro[furo{3,4-c}pyridine-1,3'-pyrrolidin]-3-one; 1'-({1-[6-(3,3-Diflucropyrrolidin-1-yl)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro[ furo[ 3,4- ¢]pyridine-1,3'-pyrrolidinj-3-one; Isobutyl 4-(5-{1-[(3-ox0-1'H,3H-spiro[furo[3,4-c]pyridine-1,3"-pyrrolidin]-1'- yl)carbonyl]cyclopropyl} pyridin-2-yi)piperazine-1-carboxylate; 2-[4-(5-{1-[(3-Oxo0-1'H,3H-spiro[furo[3,4-c]pyridine-1,3'-pyrrolidin]-1'- yl)carbonyl]cyclopropyl} pyridin-2-yl)piperazin-1-yl]benzonitrile; 1'-[(1-{6-[4-(4-Fluorophenyl) piperazin-1-yl]pyridin-3-yl}cyclopropyl)carbonyl]-3H- spiro[furo[3,4-c]pyridine-1,3'-pyrrolidin]-3-one; 1'-[(1-{6-[3-(Trifluoromethyl)phenyl] pyridin-3-yl}cyclopropyl)carbonyl]-3H-spiro[furo(3,4- c)pyridine-1,3'-pyrrolidin}-3-one;

1'-[(1-{6-[3-(Trifluoromethoxy) phenyljpyridin-3-yl}cyclopropyl) carbonyl]-3H- spiro[furo[3,4-c]pyridine-1 ,3'-pyrrolidin]-3-one; 4-(5-{1-[(3-Oxo-1 'H,3H-spiro[furo[3,4-c]pyridine-1 ,3"-pyrrolidin}-1'-yl)carbonyl] cyclopropyl} pyridin-2-yl)benzonitrile; 1'-({1-[6-(3 -Chloro-4-fluoropheny!)pyridin-3-yljcyclopropy!} carbonyl)-3H-spiro[furo[3,4- c)pyridine-1,3"-pyrrolidin}-3-one; 1'-[(1-{6-[4-(Methoxymethyl) phenyl]pyridin-3-yl}cyclopropy!) carbonyl}-3H-spiro[furo[3,4- _ ¢]pyridine-1,3"-pyrrolidin]-3-one; N-[3-(5-{1-[(3-Ox0-1 'H,3H-spiro[ furo{3,4-c]pyridine-} ,3'-pyrrolidin}-1'-yl)carbonyl] cyclopropyl} pyridin-2-yl)phenyl]acetamide; and 4-(5-{1-[(3-Oxo-1'H,3H-spiro[furo[3,4-c]pyridine-1 ,3"-pyrrolidin]-1'-yl)carbonyl] cyclopropyl} pyridin-2-yl)benzamide, or pharmaceutically acceptable salt thereof.

28.. A compound of claim | selected from: 1-[(1-{6-[4(Methylsulfonyl)phenyl] pyridin-3-yl}cyclopropyl)carbonyl]-3H-spiro [furo[3,4- c)pyridine-1,3'-pyrrolidin}-3-one; 1-({1-[6-(1-Methyl-1H-indol-5-yl)pyridin-3 -ylJcyclopropyl}carbonyl)-3H-spiro[furo[3,4- c]pyridine-1,3'-pyrrolidin]-3-one; 1-({1-[6-(1-Benzothien-5-yl)pyridin-3 -yllcyclopropyl}carbonyl)-3H-spiro[ furo[3,4- c]pyridine-1,3"-pyrrolidin]-3-one; 1'-{[1-(6-Quinolin-3 -ylpyridin-3-yl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c] pyridine-1,3'- pyrrolidin]-3-one; 1'-({1-[6-(3-Thienyl)pyridin-3-yl] cyclopropyl} carbonyl)-3H-spiro[furo[3 ,4-clpyridine-1,3'- pyrrolidin}-3-one; 1'-({1-[4-(2-Oxo0-2,3-dihydro-1H-indol-1-yl)phenyl]cyclopropyl} carbonyl)-3H- spiro[furo[3,4-c]pyridine-1,3'"-pyrrolidin]-3-one; 1'-({1-[4-(3-Methyl-2-0x0-2,3-dihydro-1H-benzimidazol-1-yl)phenyl]cyclopropyl} carbonyl)-3H-spiro[furo{3,4-c]pyridine-1,3"-pyrrolidin}-3-one; 4-{14{(3-Oxo-1"H,3H-spiro[furo[3,4-c]pyridine-1,3'-pyrrolidin]-1 "-yl)carbonyl] cyclopropyl} benzonitrile; 4-{1-[(3-Oxo-1"H,3H-spiro[furo[3,4-c]pyridine-1,3'-pyrrolidin]-1"-yl)carbonyl] cyclopropyl} benzenecarbothioamide; 1'-[(1-{4-[1-(Methylsulfonyl)-1,2,3 ,6-tetrahydropyridin-4-yl}pheny!}cyclopropyl)carbonyl]- 3H-spiro[furo{3,4-c]pyridine-1,3'-pyrrolidin]-3-one; 1'-[(1-{4-[(E)-2-Pyridin-4-ylvinyl] phenyl} cyclopropyl)carbonyl]-3H-spiro[furo[3,4- c]pyridine-1,3'-pyrrolidin}-3-one;

1'-[(1-{4-[Cyclopentyl(fluoro)methyl] phenyl} cyclopropyl)carbonyl}-3H-spiro[furo(3,4- c]pyridine-1,3-pyrrolidin]-3-one; 1'-({1 {4-(Tetrahydro-2H-pyran-4-yloxy)phenyl]cyclopropy!} carbony!)-3H-spiro {furo[3,4- clpyridine-1,3-pyrrolidin}-3-one; tert-Butyl (4-{1-[(3-oxo0-1 'H,3H-spiro[furo[3,4-c]pyridine-1 ,3"-pyrrolidin]-1'-yl)carbonyl] cyclopropyl} phenoxy)acetate; “-{1-[3 -Oxo-1'H,3H-spiro[furo[3,4-c]pyridine-1 ,3"-pyrrolidin]-1'-yl)carbonyl] cyclopropyl} _ phenoxy)acetonitrile; 1-[(1-{4-[(5-Methylisoxazol-3-yl)methoxy]phenyl} cyclopropyl)carbony!]-3H-spiro[furo[3,4- ¢]pyridine-1,3"-pyrrolidin]-3-one; 1'-({1-[4«(Cyclopentylmethoxy) phenyl]cyclopropy!}carbonyl)-3H-spiro [furo[3,4-c]pyridine- 1,3'-pyrrolidin}-3-ong; : 1'<({1-[4«(Quinolin-3-ylmethoxy) phenyl]cyclopropyl} carbony!)-3H-spiro [furo[3,4- ¢]pyridine-1,3'-pyrrolidin]-3-one; 1'-({1-[4Quinolin-4-ylmethoxy) phenyl]cyclopropyl} carbony!)-3H-spiro[furo(3,4- c¢]pyridine-1,3'-pyrrolidin}-3-one; 1'-({1-[4-(Quinolin-6-ylmethoxy) phenyljcyclopropyl} carbonyl)-3H-spiro[furo[3,4- c]pyridine-1,3"-pyrrolidin}-3-one; 1'-( {1-[4-(Pyridin-3-ylmethoxy) phenyl]cyclopropyl}carbonyl)-3H-spiro{furof3,4-c]pyridine- 1,3'-pyrrolidin]-3-one; 6-(Trifluoromethyl)-1'-({1 -[4-(trifluoromethy!)phenyl]cyclopropyl}carbonyl)-3H- spiro furo[3,4-c]pyridine-1,3'-pyrrolidin]-3-one; 1'«({ 1-[4~(Trifluoromethoxy)phenyl] cyclopropyl} carbonyl)-6-(trifluoromethyl)-3H- spiro[furo[3,4-c]pyridine-1,3'-pyrrolidin]-3-one; 1'-{[1-(2,4-Difluorophenyl) cyclopropyljcarbonyl}-6-(triflucromethyl)-3H-spiro[furo(3,4- c]pyridine-1,3"-pyrrolidin]-3-one; 1'-{[1-(1 ,3-Benzothiazol-2-yl)cyclopropyl]carbonyl}-6-(trifluoromethyl)-3 H-spiro[furo[3,4- ¢]pyridine-1,3'-pyrrolidin]-3-one; 1'-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl}-6-(trifluoromethyl)-3H-spiro[furo[3,4- c}pyridine-1,3'-pyrrolidin]-3-one; 4-Fluoro-1'-[(1 -quinolin-4-ylcyclopropyl)carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3'- pyrrolidin}-3-one; 1"-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl}-4-fluoro-3H-spiro{furo[3 A-clpyridine-1,3'- pyrrolidin]-3-one; 7-Fluoro-1'-[(1-{4-[(trifluoromethyl) thio]phenyl} cyclopropyl)carbonyl]-3H-spiro[furo{3,4- cJpyridine-1,3"-pyrrolidin]-3-one;

1'- ([1-(4-Bromophenyl)cyclopropyl] carbonyl} -7-fluoro-3H-spiroffuro[3,4-c]pyridine-1 3 pyrrolidin]-3-one; 1'-{[1-(1,3-Benzothiazol-2-y Deyclopropylicarbonyl} -3H-spiro[furo{3,4-c]pyridine-1,3'- pyrrolidin]-3-one; r-{t-(l ,3-Benzothiazol-2-yl)cyclopropyl]carbony!} -6-chloro-3H-spiro[furo[3,4-c]pyridine- 1,3'-pyrrolidin]-3-one; 6-Chloro-1'-({1-[4-(trifluoromethoxy) phenyl]cyclopropyl}carbonyl)-3H-spiro[ furof3,4- c]pyridine-1,3'-pyrrolidin]-3-one; 6-Chloro-1'-{[ 1-(2-fluoropheny!) cyclopropyljcarbonyl}-3H-spiro( furo[3 ,A-c]pyridine-1,3'- pyrrolidin}-3-one, 1'-({1-[4-(4-Chlorophenyl)-1,3 -thiazol-2-yl]cyclopropy!} carbonyl)-3H-spiro {furo[3.4- c]pyridine-1,3'-pyrrolidin]-3-one; 4-(1-{[3-Oxo-1'H,3H-spiro[2-benzofuran-1 ,3'-pyrrolidin]-1'-yl]carbonyl} cyclopropyl)benzonitrile; 1'-{[1-(3-(Hydroxymethyl)phenyl) cyclopropyljcarbonyl} -3H-spiro[2-benzofuran-1,3'- pyrrolidin]-3-one; : 1'-{[1-(4-Bromophenyl) cyclopropy!]carbonyl}-3H-spiro[2-benzofuran-1,3 '-pyrrolidin]-3- : one; 1'-({1-[4-(Pyrrolidin-1-ylcarbonyl)phenyljcyclopropy!} carbony!)-3H-spiro[2-benzofuran- 1,3'-pyrrolidin}-3-one; 4-(1-{[3-Oxo-1'H,3H-spiro[2-benzofuran-1,3"-pyrrolidin]-1'-yl]carbonyl} cyclopropyl) benzohydrazide; N-Methyl-4-(1-{[3-oxo-1'H,3H-spiro[2-benzofuran-1,3"-pyrrolidin}-1'- yljcarbony!}cyclopropyl)benzamide; 4-(1-{[3-Oxo-1'H,3H-spiro[2-benzofuran-1,3"-pyrrolidin]-1 ‘.yljcarbony!} cyclopropyl) benzenecarbothioamide; : 1'-[(1-{4-[2-(Trifluoromethyl)-1H-imidazol-4-yl]phenyl} cyclopropyl) carbonyl]-3H-spiro[2- benzofuran-1,3'-pyrrolidin]-3-one; 1'-({1-[4-(1-Methyl-1H-pyrazol-3-yl)phenyl]cyclopropyl} carbonyl)-3H-spiro[2-benzofuran- 1,3'-pyrrolidin}-3-one ; N-Cyclopropyl-4'-(1-{[3-oxo0-1'H,3H-spiro[2-benzofuran-1,3'-pyrrolidin]-1 "-yl]carbonyl} cyclopropyl)biphenyl-4-carboxamide; 1'-[(1-{4-[5-(Trifluoromethyl)-1H-1,2 4-triazol-3-yl)phenyl} cyclopropy!)carbonyl}-3H- spiro[2-benzofuran-1,3"-pyrrolidin]-3-one; : 1'-({1-[4-(1-Methyl-1H-tetrazol-5-yl)phenyl]cyclopropyl} carbonyl)-3H-spiro[2-benzofuran- 1,3'-pyrrolidin}-3-one;

1'-({1-[4-(2-Amino-1 ,3-oxazol-4-yl)phenyl]cyclopropyl}carbonyl)-3 H-spiro[2-benzofuran- 1,3"-pyrrolidin}-3-one; 1'-{[1<(4-Pyrimidin-5-ylphenyl) cyclopropyl]carbonyl}-3H-spiro{2-benzofuran-1 ,3- pyrrolidin]-3-one; 1'-({1 _[4-(6-Fluorapyridin-3-yl)phenyljcyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1 3- pyrrolidin}-3-one; 1'-({1-[4-(6-Pyrrolidin-1 -ylpyridin-3-yl)phenyl]cyclopropyl} carbonyl)-3H-spiro[2- _ benzofuran-1,3'-pyrrolidinj-3-one; : N-Cyclopropyl-5-{4-(1-{[3 -ox0-1'H,3H-spiro[2-benzofuran-1 ,3'-pyrrolidin]-1 "_yl]carbonyl} cyclopropyl)phenyl] pyridine-2-carboxamide; N-Methyl-5-[4-(1-{[3-0x0-] 'H,3H-spiro[2-benzofuran-1 3-pyrrolidin}- 1'-yljcarbonyl} cyclopropyl)phenyl] pyridine-2-carboxamide; 1'-({1-[4-(Methylsulfonyl)pheny!] cyclopropyl} carbonyl)-3H-spiro[2-benzofuran-1,3"- - pyrrolidin]-3-one; 1'-[(1-{4-[(Trifluoromethyl)thio] phenyl} cyclopropyl)carbonyi]-3H-spiro[2-benzofuran-1 ,3- pyrrolidin]-3-one; 1'-{[1-(4-Chloro-2-fluorophenyl) cyclopropyl]carbonyl} -3H-spiro[2-benzofuran-1,3'- pyrrolidin]-3-one; 1'-({ 1-[4-(2-Oxopyridin-1(2H)-yl)phenyljcyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3'- pyrrolidin]-3-one; Methyl 4-[4-(1-{[3-ox0-1'H,3H-spiro[2-benzofuran-1 ,3-pyrrolidin]-1'- yl]carbonyl}cyclopropyl)phenyl] piperazine-1 -carboxylate; 1'-[(1- {4-[4-(Methylsulfonyl)-2-oxopiperazin-1-yl] phenyl}cyclopropyl) carbonyl]-3H- spiro[2-benzofuran-1,3'-pyrrolidin]-3-one; 7-Fluoro-1'-[(1- {4-[3-(trifluoromethyl)-1H-pyrazal-1-yl]phenyl} cyclopropyl)carbonyl}-3H- spiro[2-benzofuran-1,3'-pyrrolidin]-3-one; N-[4-(1-{[3-Oxo-1'H,3H-spiro[2-benzofuran-1 ,3"-pyrrolidin}-1'- yl]carbonyl}cyclopropyl)phenyl]cyclopropanecarboxamide; N-[4-(1-{[3-Oxo0-1'H,3H-spiro[2-benzofuran-1 ,3"-pyrrolidin}-1'- yl]carbonyl}cyclopropyl)phenyl]benzenesulfonamide; Methyl] allyl[4-(1-{[3-0x0-1'H,3H-spiro[2-benzofuran-1,3'-pyrrolidin]-1'- yl]carbonyl}cyclopropyl)phenyl] carbamate; 1'-({1-{4-(1H-1,2,4-Triazol-1 -yl)phenyl]cyclopropyl} carbonyl)-3H-spiro[2-benzofuran-1,3'- pyrrolidin]-3-one; 1'-[(1-Quinolin-6-ylcyclopropyl)carbonyl}-3H-spiro[ 2-benzofuran-1,3"-pyrrolidin]-3-one; 1'-[(1-Pyridin-4-ylcyclopropyl) carbonyl]-3H-spiro[2-benzofuran-1,3"-pyrrolidin]-3-one; 1'-[(1-Quinolin-4-ylcyclopropyl) carbonyl]-3H-spiro[2-benzofuran-1,3'-pyrrolidin]-3-one;

1-[(1 -Quinolin-2-ylcyclopropyl)carbonyt]-3H-spiro[2-benzofuran-1 ,3"-pyrrolidin]-3-one¢; 1'-{(1-Pyridin-2-ylcyclopropyl) carbonyl] -3H-spiro[2-benzofuran-1,3"-pyrrol idin]-3-one; 1-{[1-(1,3 -Benzothiazol-2-yl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran- ,3'-pyrrolidin]-

3-one; 2-(1-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl} pyrrolidine-3-y!)-1,3-thiazole; 1'-{[1-(4-Methylphenyl)cyclopropyl] carbonyl} spiro[pyrido[3,4-d][1 ,3]oxazine-4,3'- pyrrolidin}-2(1H)-one trifluoroacetate; 1-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl} -3-pyridin-4-ylpyrrolidin-3-ol; 1-{[1 -(4-Chlorophenyl)cyclopropyl] carbonyl}-3-(3 fluoropyridin-4-yl)pyrrolidin-3-ol; 1-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl}-3-(2-flucrophenyl) pyrrolidin-3 -ol; 1-{[1-(4-Chlorophenyl)cyclopropy!] carbonyl}-3-[2-(hydroxymethyl) phenyl]pyrrolidin-3-ol; 1-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl} -3 -pyridin-2-ylpyrrolidin-3-ol; 1'-({1-[4-(Pyrrolidin-1 -ylmethylyphenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran- 1,3 pyrrolidin]-3-one; [4-(1-{[3-Oxo-1'H,3H-spiro[2-benzofuran-1 ,3"-pyrrolidin]-1'-yl]carbonyl} cyclopropyl) phenyl] cyclopropyl acetic acid; 6-Chloro-1'<({1-[4-(Trifluoromethyl)phenyl]cyclopropyl} carbonyl)-3H-spiro[furof3,4- . ¢]pyridine-1,3"-pyrrolidin]-3-one; 6-Chloro-1'-{[1-(4-methylphenyl) cyclopropyl]carbonyl}-3H-spirof furo[3,4-c]pyridine-1,3'- pyrrolidin]-3-one; 1'-({1-{4-(3-Thienyl)phenyl] cyclopropyl}carbonyl)-3 H-spiro{2-benzofuran-1,3'-pyrrolidin}- 3-one; 1-{[1(4-Chlorophenyl)cyclopropyl] carbonyl}-3-(1 ,3-thiazol-2-yl)pyrrolidin-3-ol; 1'-{[1-(2-Naphthyl)cyclopropyl] carbonyl}-3H-spiro[furo [3,4-c]pyridine-1,3"-pyrrolidin]-3- one; 1'-({1-[4-(Pyridin-4-ylmethoxy) phenyl]cyclopropy!}carbonyl)-3H-spiro[furo[3,4-c]pyridine- 1,3'-pyrrolidin]-3-one; 2-{[1-(4-Chloropheny!) cyclopropyl]carbonyl}octahydro-1H-isoindole; 1'-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl} spiro[isochromene-3,3'-pyrrolidin}-1(4H)-one; Ne(tert-Butyl)-2-(1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl} -3-hydroxypyrrolidin-3- yl)benzenesulfonamide; 2-[(1-{[1 -{4-Chlorophenyl) cyclopropyl]carbonyl}-3-hydroxypymolidin-3 -y)methyl]nicotinic acid; 1-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl}-3-phenylpyrrolidine-3,4-diol; I'-{[1 -(2-Fluoro-4-pyridin-4-ylphenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3'- pyrrolidin]-3-one;

5-Methoxy-1'-{[1-(4-methylphenyl) cyclopropy {carbonyl} -3H-spiro{2-benzofuran-1,3'- pyrrolidin]-3-one; I'-{[1-(4-Methylphenyl)cyclopropyl] carbonyl} -3-ox0-3H-spiro[2-benzofuran-1,3"- pyrrolidine]-5-carbonitrile; 1'-({1-[3"-(Hydroxymethyl) biphenyl-4-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3'- pyrrolidin]-3-one; 1'(§ 1-[2'-(Methylthio)biphenyl-4-yl]cyclopropyl} carbonyi)-3 H-spiro[2-benzofuran-1,3'- pyrrolidin]-3-one; 1-{[1-(1,3 -Benzothiazol-2-yl)cyclopropyl]carbony!}-7H-spiro[furo[3,4-b]pyridine-5,3" pyrrolidin]-7-one; 1°-{[1-(2-Naphthyl)cyclopropyl] carbonyl}-7H-spirof furo{3,4-blpyridine-5,3 >-pyrrolidin}-7- one; 1'-({1-[4-(Difluoromethoxy)phenyl] cyclopropyl} carbonyl)-7H-spiro[furo[3 ,4-b]pyridine- 5,3'-pyrrolidin}-7-one; 1'-{[1-(4-{{4-(Trifluoromethoxy) benzyl]oxy}phenyl)cyclopropyljcarbonyl}-3H- spiro[furo[3,4-c]pyridine-1,3’-pyrrolidin}-3-one; and 17-[(1-{4-[1-(4-Bromopheny!)ethoxy] phenyl} cyclopropyl)carbonyl]-3H-spiro[furo[3,4- c]pyridine-1,3’-pyrrolidin]-3-one, or pharmaceutically acceptable salt thereof.

29, A compound of claim 1 selected from: 1'-{[1 -(4-Pyridin-3-yliphenyl) cyclopropyl]carbonyl}-3H-spiro[furo[3,4-¢] pyridine-1,3"- pyrrolidin]-3-one; [4-(4-{1-[(3-Oxo-1'H,3H-spiro{furo [3,4-c]pyridine-1,3"-pyrrolidin]-1'-yl)carbonyl] cyclopropyl} phenyl)-1,3-thiazol-2-yl]acetonitrile; 1'-({1-[4-(2-Pyridin-3-yl-1,3-thiazol-4-yl)phenyljcyclopropyl} carbonyl)-3H-spiro[furo[3,4- c]pyridine-1,3'-pyrrolidin]-3-one; 1'-({1-[4-(1-Propionyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]cyclopropyl} carbonyl)-3H- spiro[furo[3,4-c]pyridine-1,3'-pyrrolidin}-3-one; Ethyl 4-{4-(1-{[3-ox0-1'H,3H-spiro[furo[3,4-c]pyridine-1,3'-pyrrolidin]-1"-yl]carbony!} cyclopropyl)phenyl]}-3,6-dihydropyridine-1(2H)-carboxylate; 4-[(E)-2-(4-{1-[(3-Oxo0-1'H,3H-spiro[furo[3,4-c]pyridine-1,3"-pyrrolidin]-1'-yl)carbonyl] cyclopropyl} phenyl)vinyljbenzonitrile; 1'={{1<2-Fluoro-4-pyridin-4-ylphenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine- 1,3'-pyrrolidin]-3-one; 1'-[(1-{2-Fluoro-4-{3-(triflucromethyl)- 1 H-pyrazol-1-yl]phenyl} cyclopropyl)carbonyl}-3H- spiro[furo{3,4-c]pyridine-1,3"-pyrrolidin}-3-one;

1'-({1-[4-(2H-Indazol-2-yl)phenyl] cyclopropy}carbonyl)-3H-spiro {furo(3 ,A-c]pyridine-1,3'- ‘pyrrolidin]-3-one; 1'-({1-[4-(3,3-Difluoropyrrolidin-1 -yl)pheny!]cyclopropy!}carbonyl)-3 H-spiro[furo[3,4- ¢]pyridine-1,3"-pyrrolidin}-3-one; 1'-({1-[2-Fluoro-4-(2-oxopyrrolidin-1 -yl)phenyt]cyclopropyl}carbonyi)-3 H-spiro[furo[3,4- c]pyridine-1,3-pyrrolidin]-3-one; '({1 -[4-(2-Oxopyrrolidin-1-yl)phenyl]cyclopropyl} carbonyl)-3H-spiro[furo[3,4-c]pyridine- 1,3"-pyrrolidin]-3-one; 1'«({1-[4-(2-Ox0-1,3 -oxazolidin-3-yl)phenyl]cyclopropyl } carbonyl)-3H-spiro[furo{3 ,4- c]pyridine-1,3'-pyrrolidin}-3-one; 1'-[(1-{4-[4-Isopropyl-2-oxo-1 ,3-oxazolidin-3-yl]phenyl} cyclopropy!)carbonyl])-3H-spiro olidin}-3-one; 1'-({1-[4-(2-Oxoimidazolidin-1 -yl)phenyl]cyclopropyl} carbonyl)-3 H-spiro[furo[3,4- c]pyridine-1,3"-pyrrolidin}-3-one; 1'-({1-[4-(2-Oxoimidazolidin-1-y l)phenylicyclopropyl!} carbonyl)-3H-spiro[2-benzofuran- 1,3'-pyrrolidin]-3-one; 1'-[(1-{4-[4-Tsopropy}-2-0xo-1,3-0xazolidin-3-y!] phenyl} cyclopropy!)carbony!}-3H-spiro[2- benzofuran-1,3'-pyrrolidin]-3-one; 1'-({1-[2-Fluoro-4-(2-oxopyrrolidin-1-yl)phenyl} cyclopropyl} carbonyl)-3H-spiro[2- benzofuran-1,3'-pyrrolidin]-3-one; 1'-({1-[2-Fluoro-4-(2-oxo-1,3-0xazolidin-3-yl)phenyl] cyclopropyl}carbonyl)-3H-spiro[2- benzofuran-1,3'-pyrrolidin]-3-one; Methyl 3-0x0-4-[4-(1-{[3-0x0-1'H,3H-spiro[2-benzofuran-1,3 ‘-pyrrolidin]-1'-yl]carbony!} cyclopropyl)phenyllpiperazine-1-carboxylate; 1'-[(1-{6-[4-(Cyclopropyl carbonyl)piperazin-1 -yl]pyridin-3-yl}cyclopropyl) carbonyl]-3H- spiro[2-benzofuran-1,3"-pyrrolidin]-3-one; 1'-[(1-{6-[4-(Pyridin-4-yloxy)piperidin-1 -yl]pyridin-3-y1}cyclopropyl)carbonyl]-3H-spiro[2- benzofuran-1,3-pyrrolidin]-3-one; I'{(1 -{6-[3-(Pyridin-4-yloxy)pyrrolidin-1-yl}pyridin-3-yl} cyclopropyl) carbonyl]-3H- spiro{2-benzofuran-1,3"-pyrrolidin}-3-one; 1'-({1-[4-(6-Methoxypyridin-3-yl)phenyl]cyclopropy!}carbonyl)-3H-spiro [2-benzofuran-1,3'- pyrrolidin]-3-one; [4'-(1-{[3-Oxo0-1'H,3H-spiro[2-benzofuran-1,3'-pyrrolidin]-1 "-yl]carbonyl} cyclopropyl)biphenyl-3-yljacetonitrile; 1'-({1-[4-(6-Aminopyridin-3-yl)phenyl]cyclopropyl} carbonyl)-3H-spiro[2-benzofuran-1 3 pyrrolidin]-3-one;

1'-({1 _[4-(6-Hydroxypyridin-3-y )phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran- 1,3'- pyrrolidin]-3-one; ‘ 1-({1 -[4<(5-Methylpyridin-2-y)phenyl}cyclopropyl }carbonyl)-3H-spiro[2-benzofuran-1 3 pyrrolidin}-3-one; 1'-{(1-{4-[(Pyridin-2-yloxy) methyl]phenyl} cyclopropyl)carbonyl}-3H-spiro[2-benzofuran- 1,3'-pyrrolidin]-3-one; 1*-[(1-{4-[(Pyridin-3-yloxy)methy!]phenyl} cyclopropyl)carbonyl}-3H-spiro[2-benzofuran- 1,3'-pyrrolidin]-3-one; 1'-[(1 -{4-[(Pyridin-4-yloxy)methyl]phenyl} cyclopropyl)carbonyl]-3H-spiro[2-benzofuran- B 1,3'-pyrrolidin}-3-one; 3-(1-{[3-Oxo-1'H,3H-spiro[2-benzofuran-1,3 *-pyrrolidin]-1'-yl]carbonyl} cyclopropyl)benzonitrile; 1'-[(1-Biphenyl-3 -ylcyclopropy!)carbony!]-3H-spiro[2-benzofuran- 1,3'-pyrrolidin]-3-one; 1'-{[1-(1-Naphthyl)cyclopropy!] carbonyl}-3H-spiro[2-benzofuran-1 J3"-pyrrolidin}-3-one; 1'-[(1-Quinolin-6-ylcyclopropyl) carbonyl]-3H-spiro[2-benzofuran-1 ,3-pyrrolidin]-3-one; : 1'-[(1-{4-[(5-Methylisoxazol-3 -yDmethoxy]phenyl} cyclopropyl)carbonyl]-3H-spiro[2- _benzofuran-1,3'-pyrrolidin}-3-one; 1'-({1-[4-(2-Pyridin-3-yl-1,3 -thiazol-4-yl)phenyl]cyclopropyl} carbonyl)-3 H-spiro[2- benzofuran-1,3'-pyrrolidin]-3-one; 1'-[(1-{4-[5-(Trifluoromethyi)-1,3 .4-oxadiazol-2-yl]phenyl} cyclopropyl)carbonyl]-3H- spiro[2-benzofuran-1,3'-pyrrolidin]-3-one; 1'-{[1-(4-tert-Butyl-1,3-thiazol-2-yl)cyclopropyl] carbonyl} -3H-spiro[2-benzofuran-1,3'- pyrrolidin]-3-one; 1'-({1-[4-(4-Chlorophenyl)-1 ,3-thiazol-2-ylJcyclopropyl}carbonyl)-3H-spiro[2-benzofuran- 1,3'-pyrrolidin]-3-one; 1',1"-[1,4-Phenylenebis(cyclopropane-1,1 -diylcarbonyl)]bis(3H-spiro[2-benzofuran-1,3'- pyrrolidin]-3-one); 4-Hydroxy-1'-[(1 -quinolin-4-ylcyclopropyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1 3 . pyrrolidin]-3-one; 4-Methoxy-1'[(1-quinolin-4-ylcyclopropyl)carbonyl] -3H-spiro[furo[3,4-c]pyridine-1,3'- pyrrolidin]-3-one; 1'-[(1-Pyridin-3-ylcyclobutyl) carbonyi}-3H-spiro[2-benzofuran-1 ,3-pyrrolidin]-3-one; 1'-{[1-(4-Chlorophenyl)cyclobutyl] carbony1}-3 H-spiro[2-benzofuran-1,3'-pyrrolidin}-3-one; 1'-{[1-(4-Chlorophenyl) cyclobutyl]carbony1}-7 H-spiro[furo[3,4-b]pyridine-5,3"-pyrrolidin]- 7-one; 1-{[1<(4-Chlorophenyl)cyclopropyl] carbony!}-4-phenylpyrrolidin-3-ol; 6-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl}-1 ,3,3-trimethyl-6-azabicyclo[3.2.1]octane;

(1-{[1-(4-Chloropheny?) cyclopropyl]carbonyl} -3-phenylpyrrolidin-2-yl)methanol; (1-{[1-(4-Chlorophenyl) cyclopropyl] carbonyl} -4-phenylpyrrolidin-2-yl)methanol; (1-{[1-(4-Chlorophenyl) cyclopropyljcarbo nyl}-4-phenylpyrrolidin-2-yl)methanol;

1-{[! (4-Chlorophenyl)cyclopropyl] carbonyl}pyrrolidine;

1-{{1 (4-Chlorophenyl)cyclopentyl] carbonyl}azepane;

3-Chloro-N-(1-{[1 ~(4-chlorophenyl)cyclopropyljcarbonyl} pyrrolidin-3-yl)-2-methylbenzene sulfonamide; - 1-{[1-(4-Chlorophenyl) cyclopropyl]carbonyl}-4-phenylpyrrolidine-3-carboxylic acid;

(1-{{1-(4-Chloropheny!) cyclopropyl]carbonyl} -4-phenylpyrrolidin-3 -yl)methanol;

2-[1-{[1 -(4-Chlorophenyl)cyclopropyl] carbonyl}-4-(hydroxymethyl) pyrrolidin-3-yl]phenol; 2-{[1-(4-Chlorophenyl)cyclopropyl} carbonyl}-1,2,3,3a,4,9b-hexahydro chromeno(3,4-

c]pyrrole;

2-{[1-(4-Chlorophenyl)cyclopropyl) carbonyl}-8-(methylsulfonyl)-2,8-diazaspiro[4.5]decane; 8-Acetyl-2-{[1-(4-chlorophenyl) cyclopropyljcarbonyl}-2,8-diazaspiro[4.5]decane; 31-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl} pyrrolidin-3-yl)pyridine; 3-(1-{[1-(4-Phenoxypheny!) cyclopropyl]carbony!} pyrrolidin-3-yl)pyridine; 3-[1-({1-[4-(Cyclopentyloxy)phenyl] cyclopropyl} carbonyl)pyrrolidin-3-yljpyridine; tert-Butyl 4-(5-{1-[(3-pyridin-3-ylpyrrolidin-1-yl)carbonyl] cyclopropyl} pyridine-2-

yl)piperazine-1-carboxylate;

1-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl }-3-isopropylpyrrolidine; Methyl 3-(1-{[1-(4-chlorophenyl) cyciopropyljcarbonyl} pyrrolidin-3-yl)benzoate; 1-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl} -3-(2-methylphenyl) pyrrolidine; 1-{[1-(4-Chloropheny!)cyclopropyl] carbonyl}-3-(2 -methoxyphenyl) pyrrolidine; 1-{[1-(4-Chloropheny!)cyclopropyl] carbonyl} -3-(2,6-dimethylphenyl) pyrrolidine;

; 1-(4-{1-[(3-Pyridin-4-ylpyrrolidin-1-yl)carbonyl]cyclopropyl} phenyl)pyrrolidin-2-one; 3-(4-{1-[(3-Pyridin-4-ylpyrrolidin-1-yl)carbonyl]cyclopropy!} phenyl)-1 ,3-oxazolidin-2-one; 4-{1-[(3-Pyridin-4-ylpyrrolidin-1 -yDcarbonyl]cyclopropyl} phenol; 4-[1-({1-[4-(Benzyloxy)phenyl] cyclopropyl} carbony)pyrrolidin-3-yl]pyridine; 4-[1-({1-[4-(Allyloxy)phenyl] cyclopropyl} carbonyl)pyrrolidin-3-yljpyridine; 4-[1«{1-[4-(Pyridin-4-yloxy)phenyl] cyclopropyl }carbony!)pyrrolidin-3-yl]pyridine; 4-{14({1-[4-(3-Furyloxy)phenyl]cyclopropyl} carbonyl)pyrrolidin-3 -yl)pyridine; 4-[1({1-[4-(Cyclopentyloxy)phenyl] cyclopropyl}carbonyl) pyrrolidine-3-yl]pyridine; 4-[1({1-[4-(Cyclohex-2-en-1-yloxy)phenyl]jcyclopropyl} carbonyl) pyrrolidine-3-yl]pyridine;

3-[(4-{1-[(3-Pyridin-4-ylpyrrolidin-1-yl)carbonyl]cyclopropyl} phenoxy) methyl]pyridine; 2-[(4-{1-[(3-Pyridin-4-ylpyrrolidin-1-yl)carbonyl]cyclopropyl} phenoxy) methyl]pyridine; 4-[2-(4-{1 -[(3-Pyridin-4-ylpyrrolidin-1 -yl)carbonyl]cyclopropyl} phenoxy) ethyljmorpholine; 4-(1-{[1-(4-Chlorophenyl) cyclopropyl]carbonyl} pyrrolidin-3-yl)pyridine 1-oxide;

4-(1-{{1 -(4-Chlorophenyl)cyclopropyl] carbonyl} pyrrolidin-3-yl)-3-fluoropyridine; 1-{[1-(4-Chlorophenyl)cyclopropy! carbonyl} -3-isopropylpyrrolidin-3-ol; 3-tert-Butyl-1- {[1-(4-chlorophenyl) cyclopropyljcarbonyl} pyrrolidine-3-ol; 1-{[1-(4-Chlorophenyl)cyclopropyl} carbonyl}-3-(2-methylphenyl) pyrrolidin-3-o}; Methyl [(1-{[1«4-chlorophenyl) cyclopropyl]carbonyl}-3-phenylpyrrolidin-3-yljoxyJacetate; [{(1-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl}-3-phenylpyrrolidin-3-yloxyJacetic acid; 1-{[1{4-Chlorophenyl)cyclopropyl] carbonyl}-3-(3 -chloropyridin-4-yl)pyrrolidine-3-ol; - 1’-{[1-(4-Chlorophenyl)cyciopropyl] carbonyl} spiro[pyrido[3,4-d][1,3]oxazine-4,3’- pyrrolidin]-2(1H)-one trifluoroacetate; 1'-{[1-(2,4-Dichlorophenyl) cyclopropy!icarbonyl} spiro[pyrido([3,4-d][1,3)oxazine-4,3'- pyrrolidin)-2(1H)-one trifluoroacetate; 1'-{[1<(4-Bromophenyl)cyclopropyl] carbonyl} spiro[pyrido[3.4-d][1,3]oxazine-4,3"- pyrrolidin]-2(1 H)-one trifluoroacetate; 1'-{[1-(4-Methoxyphenyl)cyclopropyl] carbonyl} spiro[pyrido[3,4-d][1,3)oxazine-4,3'- pyrrolidin]-2(1H)-one trifluoroacetate; 1'-{[1-(4-Phenoxyphenyl)cyclopropyl] carbonyl} spiro[pyrido[3,4-d][1,3]oxazine-4,3’- pyrrolidin}-2(1 H)-one trifluoroacetate; . . 1'“[(1-{4-[(Trifluoromethyl)thio] phenyl}cyclopropyl)carbonyl]spiro[pyrido[3,4- d][1,3]oxazine-4,3’-pyrrolidin]-2(1H)-one trifluoroacetate; 1'-{[1-(3-Bromophenyl)cyclopropyl] carbonyl} spiro[pyrido[3,4-d][1,3Joxazine-4,3'- pyrrolidin]-2(1H)-one trifluoroacetate; 1'-{[1-(3-Methoxyphenyl)cyclopropyl] carbonyl} spiro[pyrido[3,4-d}{1,3Joxazine-4,3'- pyrrolidin]-2(1H)-one trifluoroacetate; 1'-{[1-(6-Chloropyridin-3 -yD)cyclopropyl]carbony!}-7H-spiro[furo[3,4-b] pyridine-5,3'- pyrrolidin]-7-one; 1'-{[1-(4-Methylphenyl)cyclopropyl] carbonyl} -7H-spiro[furo[3,4-b]pyridine-5,3’- pyrrolidin}-7-one; and 1'-({1-[4-(Trifluoromethyl)phenyl] cyclopropyl} carbony!)-7H-spiro[furo[3,4-b]pyridine-5,3'- pyrrolidin]-7-one, or pharmaceutically acceptable salt thereof.

30. A compound of claim 1 selected from: 1'-{[1-(4-Methoxyphenyl)cyclopropyl] carbonyl }-7H-spiro[furo[3,4-b]pyridine-5,3’- pyrrolidin]-7-one; 1°-({1-[4-(Trifluoromethoxy)pheny!] cyclopropyl} carbonyl)-7H-spiro[furo[3,4-b]pyridine- 5,3’-pyrrolidin]-7-one; 1'-{[1-(4-Fluorophenyl)cyclopropyl] carbonyl}-7H-spiro[furo[3,4-b] pyridine-5,3'-pyrrolidin]- 7-one;

1-{[1 {(2-Chloro-4-fluoropheny}) cyclopropyl]carbonyl}-7H-spirof furo[3,4-b]pyridine-5,3"- pyrrolidin]-7-one; 1'-{[1+(2,4-Difluorophenyl) cyclopropyljcarbonyl}-7H-spiro[furo[3,4-b]pyridine-5,3"- pyrrolidin]-7-one; 1'-{{1-(3-Chlorophenyl)cyclopropy!] carbonyl}-7H-spiro[furo[3,4-b]pyridine-5,3’- pyrrolidin]-7-one; 1'-{[1-(3,4-Dichloropheny!) cyclopropyl]carbonyl}-7H-spiro[furo[3,4-b]pyridine-5,3"- pyrrolidin]-7-one; 1'-{[1-(2,3-Difluorophenyl) cyclopropyllcarbonyl}-7H-spiro{furo(3 ,A-blpyridine-5,3"- pyrrolidin]-7-one; 1'-{[1-(2,4-Dichlorophenyl) cyclopropyl]carbonyl}-7H-spiroffuro[3,4-b]pyridine-5,3"- pyrrolidin}-7-one; ) Ethyl 4-[5-(1-{[3-0x0-1 'H,3H-spiro[2-benzofuran-1,3-pyrrolidin]-1'- yl]carbonyl}cyclopropyl)pyridin-2-yl]piperazine-1-carboxylate; 1'-[(1-{6-[4-(ethylsulfonyl) piperazin-1 -yl]pyridin-3-yl} cyclopropylcarbonyl]-3H-spiro[2- benzofuran-1,3'-pyrrolidin}-3-one; 1'-({1-[6-(4-Methylpiperazin-1 -yl)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro[2- benzofuran-1,3'-pyrrolidin}-3-one; 1'-({1-[6-(4-Pheny!piperazin-1-yl)pyridin-3 -yl]cyclopropyl} carbonyl)-3H-spiro[2- benzofuran-1,3'-pyrrolidin]-3-one; 1'-[(1-{6-[4~(3-Methylbutanoyl) piperazin-1 -ylpyridin-3-yl} cyclopropylcarbonyl]-3H- spiro[2-benzofuran-1,3'-pyrrolidin]-3-one; 1'-[(1-{6-[4-(Cyclopropylmethyl) piperazin-1 -ylJpyridin-3-yl} cyclopropyl)carbonyl]-3H- spiro[2-benzofuran-1,3"-pyrrolidin]-3-one; 1'-({1-[6-(2,5-Dihydro-1H-pyrrol-1-yl)pyridin-3-yljcyclopropyl} carbonyl)-3H-spiro[2- benzofuran-1,3'-pyrrolidin}-3-one; 1'-{[1«(6-Piperidin-1-ylpyridin-3-yl)cyclopropyl]carbonyl}-3 H-spiro[2-benzofuran-1,3'- pyrrolidin}-3-one; 1'-({1-[4-(4-Methyl-2-oxopiperazin-1-yl)phenyl]cyclopropyl} carbonyl)-3 H-spiro[2- benzofuran-1,3'-pyrrolidin]-3-one; : 1'-({1-[4-(4-Acety]-2-oxo-piperazin-1-yl)phenyl]cyclopropy!} carbonyl)-3H-spiro[2- benzofuran-1,3’-pyrrolidin]-3-one; tert-Butyl 4-[4-(1-{[3-ox0-1'H,3H-spiro[2-benzofuran-1,3'-pyrrolidin]-1 *-yl]Jcarbonyl} cyclopropyl)phenyl]piperazine-1-carboxylate; 1'-({1-{4-(4-Isobutyrylpiperazin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro [2-benzofuran- 1,3"-pyrrolidin]-3-one;

1'-[(1-{4-[4-(Cyclopropyl carbonyl)piperazin-1-yljphenyl} cyclopropyl)carbonyl}-3H- spiro[2-benzofuran-1 ,3'-pyrrolidin]-3-one; 1'-[(1-{4-[4-(Methylsulfonyl) piperazin-1 -yl}phenyl}cyclopropyl carbonyl}-3H-spiro[2- benzofuran-1,3"-pyrrolidin}-3-one; 1'-({1-[4-(4-Methylpiperazin-1 -yl)phenyl]cyclopropyl}carbonyl)-3 H-spiro[2-benzofuran-1,3'- pyrrolidin}-3-one; N-Methyl-N-{4-(1-{[3-oxo0-1 'H,3H-spiro[2-benzofuran-1,3'-pyrrolidin]-1 '-yl]carbonyl} cyclopropy [)phenyl]cyclopropanecarboxamide; N-[4-(1-{[3-Oxo-1'H,3H-spiro[2-benzofuran-1 3-pyrrolidin]- 1'-yijcarbonyl} cyclopropyl) phenyl]acetamide; 1-({1-[4-(2-Oxopyrrolidin-1 -yl)phenyl]cyclopropyl} carbonyl)-3H-spiro[2-benzofuran-1 ,3'- pyrrolidin]-3-one; 1-({1-[4-(2-Ox0-1,3-0oxazolidin-3 -yl)phenyl]cyclopropyl} carbonyl)-3H-spiro[2-benzofuran- 1,3'-pyrrolidin}-3-one; 1'-({1-{4-(1H-Pyrazol-1-yl) phenyl]cyclopropyl} carbonyl)-3H-spiro[2-benzofuran-1,3" pyrrolidin]-3-one; 1'-({1-[4«2-Oxopiperidin-1-yl)phenyl]cyclopropy!} carbonyl)-3H-spiro[2-benzofuran-1,3'- pyrrolidin]-3-one; 1-Methyl-3-[4-(1-{[3-oxo0-1'H,3H-spiro[2-benzofuran-1,3'-pyrrolidin]-1'- } yl]carbonyl}cyclopropyl)phenyl] imidazolidine-2,4-dione; 1'-{[1-(4-Morpholin-4-ylphenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3'- pyrrolidin]-3-one; 1-[4-(1-{[3-Phenylpyrrolidin-1-yl]jcarbonyl} cyclopropyl)phenyl] pyrrolidine-2-one; * 3-[4-(1-{[3-Phenylpyrrolidin-1-yl]carbonyl}cyclopropyl)phenyl]-1 ,3-oxazolidin-2-one; Methyl 4-(4-{1-[(3-phenylpyrrolidin-1-yl)carbonyl]cyclopropyl} phenyl)piperazine-1- carboxylate; Ethyl 4-(4-{1-[(3-phenylpyrrolidin-1 -yl)carbonyl]cyclopropyl} phenyl)piperazine-1- carboxylate; 1-Isobutyryl-4-(4-{1-[(3-phenylpyrrolidin-1-yl)carbonyl] cyclopropyl} phenyl)piperazine; 1-Acetyl-4-(4- {1-{(3-phenylpyrrolidin-1-yl)carbonyijcyclopropy!} phenyl) piperazine; 1-(Cyclopropylcarbonyl)-4-(4-{1-{(3-phenylpyrrolidin-1-yl)carbonyl] cyclopropyl} phenyl)piperazine; 1-Isobutyryl-4-(5-{1-[(3-phenylpyrrolidin-1-yl)carbonyl] cyclopropyl} pyridin-2- yl)piperazine; 1-(Cyclopropylcarbonyl)-4-(5-{1-[(3-phenylpyrrolidin-1-yl)carbonyl]cyclopropyl} pyridin-2- yl)piperazine; 1'-{(1-Pyridin-3-ylcyclopropyl) carbonyl]-3H-spiro[2-benzofuran-1,3'-pyrrolidin}-3-one;

N-Methyl-4-[5-(1-{{3-oxo0-1'H,3H-spiro[2-benzofuran-1 ,3-pyrrolidin]-1'-yl]carbonyl} cyclopropyl)pyridin-2-yl]benzamide; N,N-Dimethyl-4-[5-(1-{[3-0x0-1'H,3H-spiro[2-benzofuran-1 3'-pyrrolidin]-1'-yl]carbonyl} cyclopropyl)pyridin-2-yl]benzamide; 1"-[(1-{6-[4-(Methylsulfonyl) phenyl}pyridin-3-yl} cyclopropyl) carbonyl]-3H-spiro[2- benzofuran-1,3'-pyrrolidin]-3-one; 1'-{[1-4-Methoxyphenyl) cyclopropyl]carbonyl} -3H-spiro[2-benzofuran-1,3"-pyrrolidin}-3- one; 1'-({1-{4-(Pyridin-2-yloxy)phenyl] cyclopropyl }carbonyl)-3H-spiro[2-benzofuran-1 3 pyrrolidin}-3-one; 1 ( {1-[4-(Pyridin-3-ylmethoxy) phenyl]cyclopropyl} carbonyl)-3H-spiro[2-benzofuran-1,3'- pyrrolidin]-3-one; 1'-({1-[4-(Isoquinolin-] -ylmethoxy)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran- 1,3'-pyrrolidin]-3-one; 1'-{[1-(4-Vinylpheny!) cyclopropyl]carbony!}-3 H-spiro[2-benzofuran-1 ,3'-pyrrolidin}-3-one; Methyl 4-[4-(1-{[3-0x0-1"H,3H-spiro[2-benzofuran-1,3'-pyrrolidin]-1 ‘-yl]carbonyl} cyclopropyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxy late; Ethyl 4-[4-(1-{[3-0x0-1'H,3H-spiro[2-benzofuran-1,3"-pyrrolidin]-1 *-yl]carbonyl} cyclopropyl)phenyl}-3,6-dihydropyridine-1(2H)-carboxylate; 1'-({1-[4-(1-Acetyl-1,2,3 6-tetrahydropyridin-4-yl)phenyl] cyclopropyl} carbonyl)-3H- spiro[2-benzofuran-1,3"-pyrrolidin]-3-one; 1'-[(1-{4-[1-(3-Methylbutanoyl)-1,2,3,6-tetrahydropyridin-4- yl)phenyl} cyclopropyl)carbonyl]-3H-spiro{2-benzofuran-1,3'-pyrrolidin}-3-one; 5-Hydroxy-1'-{[1-(4-methylphenyl) cyclopropyljcarbonyl}-3H-spiro[2-benzofuran-1,3'- pyrrolidin}-3-one; 1'-{[1-(4-Methylphenyl)cyclopropyl]carbony!}-3H-spiro[2-benzofuran-1,3'-pyrrol idin}-5-0l; 1'|({1-[4-(Pyrrolidin-1-ylmethyl)phenyl]cyclopropyl} carbonyl)-3H-spiro[2-benzofuran-1,3'- pyrrolidin]-3-one; . 1'-{[1-(6-Pyrrolidin-1-ylpyridin-3-yl)cyclopropy!]carbony1}-3H-spiro[ furo[3,4-c]pyridine- 1,3'-pyrrolidin]-3-one; 1'<({1-[6-(4-Phenylpiperazin-1-yl)pyridin-3-yl]cyclopropyl} carbonyl)-3H-spiro{ furo[3,4- c]pyridine-1,3'-pyrrolidin]-3-one; Methyl 4-[5-(1-{[3-0x0-1'H,3H-spiro{furo[3,4-c]pyridine-1,3"-pyrrolidin}]-1'- ylJcarbonyl}cyclopropyl)pyridin-2-yl]piperazine-1-carboxylate ; Ethyl 4-(5-{1-[(3-0x0-1'H,3H-spiro[furo[3,4-c]pyridine-1,3'-pyrrolidin]-1'-yl)carbonyl] cyclopropyl} pyridin-2-yl)piperazine-1-carboxylate;

Isopropyl 4-(5-{1-{(3-0x0-1'"H,3H-spiro[furo[3,4-c]pyridine-1,3"-pyrrolidin]-1'-yl)carbonyl] cyclopropyl} pyridin-2-yl)piperazine-1-carboxylate; 1'-({1-[6-(4-Chlorophenyl)pyridin-3-yl]cyclopropyl} carbonyl)-3H-spiro {furo[3,4-c]pyridine- 1 ,3'-pyrrolidin]-3-one; 1'-({1 -[6-(4-Fluorophenyl)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiroffuro([3 ,4-c]pyridine- 1,3'-pyrrolidin}-3-one; 1'-({1-[6-(4-Fluoro-2-methylphenyl)pyridin-3-yl] cyclopropy!}carbonyl)-3 H-spiro[ furof3,4- : c]pyridine-1,3'-pyrrolidin]-3-one; 1'-[(1-Quinolin-4-ylcyclopropyl) carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3'-pyrrolidin}-3- B one; 4-Chloro-1'-[{1 -quinolin-4-ylcyclopropyl)carbonyl}-3H-spiro[ furo (3,4-c]pyridine-1,3'- pyrrolidin]-3-one; 4-Hydroxy-1'-[(1-quinolin-4-ylcyclopropyl)carbonyl]-3H-spiro[furo[3,4-c] pyridine-1,3'- pyrrolidin]-3-one; 4-Methoxy-1'-[(1-quinolin-4-yicyclopropyl)carbonyl]-3H-s piro[ furo[3,4-c]pyridine-1,3'- pyrrolidin}-3-one; 1'-[(1-{4-[(4-Fluorobenzyl)oxy]phenyl} cyclopropyl)carbonyl]-3H-spiroffuro [3,4-c]pyridine- 1,3'"-pyrrolidin}-3-one; 1'-{[1-(4-{[4(Trifluoromethyl)benzyl] oxy} phenyl)cyclopropyl]carbonyl}-3 H-spiro|furo{3,4- c]pyridine-1,3"-pyrrolidin]-3-one; 1'4{(1-{4-[(2-Chioro-4-fluorobenzyl) oxy]phenyl} cyclopropyl)carbonyl}-3H-spiro[furo[3,4- c]pyridine-1,3"-pyrrolidin]-3-one; 1'-[(1-{4-[(4-Bromo-2-fluorobenzyl) oxy|phenyl}cyclopropyl)carbonyl}-3H-spiro[furo[3,4- c]pyridine-1,3'-pyrrolidin}-3-one; 3-Fluoro-4-[(4-{ 1 -[(3-0x0-1H,3H-spiro[furo[3,4-c]pyridine-1 ,3'-pyrrolidin]-1'-yl)carbonyl] cyclopropyl} phenoxy)methyl]benzonitrile; 1-[(1-{4-[1«2-Fluorophenyl)ethoxy] phenyl} cyclopropyl)carbonyl]-3H-spiro[furo[3,4- c]pyridine-1,3"-pyrrolidin}-3-one; 4-[1-(4-{1-[(3-Oxo-1'H,3H-spiro[furo[3,4-c]pyridine-1 ,3'-pyrrolidin]-1'-yl)carbenyljcyclo- propyl} phenoxy)ethyljbenzonitrile; 1'«({1-[4-(Quinolin-2-ylmethoxy) phenyl]cyclopropyl} carbony )-3H-spiroffuro[3,4- c]pyridine-1,3"-pyrrolidin]-3-one; 1'-{[1-(4-Methoxyphenyl)cyclopropyl] carbonyl}-3H-spiro[furo[3,4-c] pyridine-1,3'- pyrrolidin]-3-one; 6-Chloro-1'-{[1-(4-methoxyphenyl) cyclopropyl]carbonyl}-3H-spiro[furo{3,4-c]pyridine-1,3'"- pyrrolidin}-3-one;

1'-{[1 -(4-Methoxyphenylycyclopropyl] carbonyl}-6-(trifluoromethyl)-3H-spiro{furo[3,4- c]pyridine-1,3"-pyrrolidin}-3-one; 1'-({1-[4-(Cyclopentyloxy)phenyl] cyclopropyl}carbonyl)-3H-spiro [furo[3,4-c]pyridine-1,3'- pyrrolidin]-3-one; 1'-({1-[4-(Allyloxy)phenyl]cyclo-propyl} carbonyl)-3H-spiro[ furo[3,4-c] pyridine-1,3'- pyrrolidin]-3-oney 1'({1-[4-(2-Methoxyethoxy)phenyl] cyclopropyl} carbonyl)-3H-spiro[furo[3,4-c]pyridine- . 1,3"-pyrrolidin]-3-one; 1'({1-[4-(Cyclopropylmethoxy) phenyljcyclopropyi}carbonyl)-3H-spiro[furo[3,4-c]pyridine- 1,3'-pyrrolidin}-3-one; 1'-{[1-(4-Methylpheny cyclopropyl] carbonyl} -6-(trifluoromethyl)-3H-spiro[furo(3,4- c]pyridine-1,3'-pyrrolidin]-3-one; 1'-{[1-(4-Methylphenyt)cyclopropyl] carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3'- pyrrolidin]-3-one; 1'-({1-[4-(Triflucromethyl)pheny!] cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3'- pyrrolidin]-3-one; 1'-{[1-(4-Vinylphenyl)cyclopropyl] carbony!}-3H-spiro[ furo[3,4-c]pyridine-1 ,3'-pyrrolidin]- 3-one; 1'-[(1-{4-[(E)-2-Pyridin-2-ylvinyl] phenyl}cyclopropyl)carbonyl}-3H-spirof furo[3,4- ¢]pyridine-1,3'-pyrrolidin]-3-one; 1'-({1-[4-(1-Isobutyryl-1,2,3 6-tetrahydropyridin-4-yl)phenyl] cyclopropyl} carbonyl)-3H- spiro[furo[3,4-c]pyridine-1,3"-pyrrolidin}-3-one; 1'({1-[4-(1-Acetylpiperidin-4-y1) phcnyl]cyclopropyi} carbonyl)-3H-spiroffuro{3,4- c]pyridine-1,3'-pyrrolidin]-3-one; Ethyl 4-(4-{1 -[G -oxo0-1'H,3H-spiro[furo[3,4-c]pyridine-1,3"-pyrrolidin]-1 ‘.ybhcarbonyl] cyclopropyl} phenyl)piperidine-1-carboxylate; 1-({1 -[4-(1-Isobutyrylpiperidin-4-yl)pheny!]Jcyclopropyl}carbonyl)-3H-spiro[ furo[3,4- ¢]pyridine-1,3"-pyrrolidin]-3-one; 1'-({1 -[4-(1-Propionylpiperidin-4-yl)phenyl]cyclopropyl} carbonyl)-3H-spiro[furo(3,4- c]pyridine-1,3'-pyrrolidinj-3-one; 1-[(1-{4-[1-(3-Methylbutanoyl) piperidin-4-yl]phenyl} cyclopropyl) carbonyl]-3H- spiro[furo[3,4-c]pyridine-1,3"-pyrrolidin]-3-one; 1'-({1-[4-(2-Isopropyl-1 ,3-thiazol-4-yl)phenyljcyclopropyl} carbonyl)-3H-spiro[furo{3,4- c]pyridine-1,3'-pyrrolidin]-3-one; 1'-[(1-{4-[2-(Dimethylamino)-1 ,3-thiazol-4-y{}phenyl} cyclopropyl) carbonyl]-3H- spiro[furo[3,4-c]pyridine-1,3'-pyrrolidin]-3-one;

1’-({1-[4-(2-Amino-1,3-thiazol-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[ furo[3,4- c]pyridine-1,3’-pyrrolidin]-3-one; 3-Fluoro-4-{1-[(3-0x0-1'H,3H-spiro[furo[3,4-¢]pyridine-1,3'-pyrrolidin}-1'-yl)carbonyl]cyclo- propyl}benzonitrile; : 1'«({1-[2-Fluoro-4-(4-methyl-1,3-thiazol-2-y)phenyl}cyclopropyl} carbonyl)-3H- spiro[furo[3,4-c]pyridine-1,3"-pyrrolidin]-3-one; and 1'-[(1-{4-[5-(Triflucromethyi)-1,3,4-oxadiazol-2-yl]phenyl} cyclo-propyl)carbonyl]-3H- _ spiro[furo[3,4-clpyridine-1,3'-pyrrolidin]-3-one, or pharmaceutically acceptable salt thereof. _

31. A compound of claim 1 selected from: 1'-({1-[4-(3-Methylisoxazol-4-yl)phenyl}cyclopropyl}carbonyl)-3H-spiro[ furo[3,4- ¢]pyridine-1,3'-pyrrolidin]-3-one; 1'<({1-[4<2-Pyridin-2-ylethyl) phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine- 1,3'-pyrrolidin]-3-one; 1'-({1-[2-Fluoro-4-(1H-pyrazol-1-yl)phenyl]cyclopropyl} carbonyl)-3 H-spiroffurof3,4- c]pyridine-1,3"-pyrrolidin]-3-one; 1'-({1-[2-Fluoro-4-(3-methyl-1H-pyrazol-1-yl)phenyl]cyclopropyl} carbonyl)-3H- spiro[furo[3,4-c]pyridine-1,3"-pyrrolidin]-3-one; 1'-({1-[4-(3-Amino-1H-pyrazol-1 -yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4- c]pyridine-1,3"-pyrrolidin]-3-one; 1'-({1-[4-(1H-Benzimidazol-1-y I)-2-fluorophenyli]cyclopropyl}carbonyl)-3H-spiro [furo[3,4- c]pyridine-1,3'-pyrrolidin]-3-one; 1'-[(1-{2-Fluoro-4-[2-(trifluoro-methyl)-1H-benzimidazol-1- yi] phenyl}cyclopropyl)carbonyl]-3H-spiro[furo[3,4-c}pyridine- 1,3'-pyrrolidin]-3-one; 1'-({1-[4-(2-Methoxy-1H-benzimidazol-1-yl)phenyl} cyclopropyl}carbonyl)-3H- spiro[furo(3,4-c]pyridine-1,3'-pyrrolidin]-3-one; Ethyl 4-(4-{1-[(3-oxo-1"H,3H-spiro{furo{3,4-c]pyridine-1,3 pyrrolidin]-1 "-yhcarbonyl]cyclo- propy!} phenyl)piperazine-1-carboxylate; Isopropyl 4-[4-(1-{[3-ox0-1'H,3H-spiro{furo[3,4-c]pyridine- 1 ,3-pyrrolidin]-1'- yl]carbonyl}cyclo-propyl)phenyl]piperazine-1 -carboxylate; 1'-({1-[4-(4-Propionylpiperazin-1-yl)phenyI] cyclopropyl} carbonyl)-3H-spiro[furo{3,4- ¢]pyridine-1,3"-pyrrolidin}-3-one; 1'({1 -[4-(4-Isobutyrylpiperazin-1-yl)phenyl]cyclopropy!}carbonyl)-3H-spiro[furo[3,4- c]pyridine-1,3'-pyrrolidin]-3-one; 1'-[(1-{4-[4-(Cyclopropy! carbonyl)piperazin-1-ylJphenyl} cyclopropyl)carbonyl]-3H- spiro[furo[3,4-c]pyridine-1,3'-pyrrolidin]-3-one;

1'-[(1-{4-[4-(Methylsulfony!) piperazin-1-yl]phenyl}cyclopropyl) carbonyl]-3H- spiro[furo[3,4-c]pyridine-1,3'-pyrrolidin}-3-one; 1'-({1-[4-(2-Oxopyridin-1 (2H)-yl)phenyl]cyclopropy!}carbonyl)-3H-spiro[furo[3,4- ¢]pyridine-1,3"-pyrrolidin]-3-one; Methyl [{4-(1-{[3-0x0-1"H,3H-spiro[furo[3,4-c]pyridine-1 ,3'-pyrrolidin}-1"-ylJcarbonyl}cyclo- propyl)phenyljcarbamate; N-[4-(1-{[3-Ox0-1'H,3 H-spiro[furo[3,4-c]pyridine-1,3"-pyrrolidin}-1 ‘-yl}carbonyl}cyclo- propyl)phenyl]methanesulfonamide; 1'-{[1-(2-Fluorophenyl)cyclo-propy [Jcarbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3'-pyrrolidin]- 3-one; 1'-{[1-(2-Chlorophenyl)cyclopropyl] carbonyl}-3H-spiro[furo[3,4-c]pyridine-1 ,3'-pyrrolidin]- 3-one; 1'-{[1-(2-Bromophenyl)cyclopropyl] carbonyl} -3H-spiro[furo[3,4-c]pyridine-1,3"-pyrrolidin]- 3-one; 1'«({1-[2-(Trifluoromethyl)phenyl] cyclopropyl} carbony!)-3H-spiro[furo[3,4-c]pyridine-1 3 pyrrolidin]-3-one; 1'-{[1-(2-Methoxyphenyl)cyclopropyl] carbonyl} -3H-spiro[furo[3,4-c]pyridine-1,3"- pyrrolidin]-3-one; 1-{[1 (2-Methylphenyl)cyc lopropyl] carbonyl}-3H-spiro[furo(3,4-c]pyridine-1,3'- pyrrolidin}-3-one; I-{{1 -(2,3-Difluorophenyl)cyclo-propyljcarbonyl}-3H-spiro[ furo[3,4] pyridine-1,3'- pyrrolidin]-3-one; 1'-{[1-(2-Chloro-6-fluorophenyl)cyclo-propyljcarbonyl} -3H-spiro[furo[3,4-c]pyridine-1,3'- pyrrolidin]-3-one; 1'-{[1-(1-Naphthyl)cyclopropyl] carbonyl}-3H-spiro[furo[3,4-c]pyridine-1 ,3"-pyrrolidin]-3- one; 1'-{[1<2-Fluorophenyl)cyclopropyl] carbonyl} -6-(trifluoromethyl)-3H-spiro[furo[3,4- ¢]pyridine-1,3'-pytrolidin]-3-one; 6-Chloro-1'-{[1-(4-methylphenyl) cyclopropyljcarbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3'- pyrrolidin]-3-one; 6-Chloro-1'-({1-[4-(trifluoro-methyl)phenyl]cyclopropyl} carbonyl)-3 H-spiro[furo[3,4- c]pyridine-1,3'-pyrrolidin]-3-one; 6-Chloro-1'-{{1 -(2,4-difluoropheny I) cyclopropyl]carbony!}-3H-spiro[furo[3,4-c]pyridine- 1,3'-pyrrolidin}-3-one; 6-Chloro-1'-( { 1-[3-(difluoromethoxy )phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4- ¢]pyridine-1,3'-pyrrolidin]-3-one;

1'-{[1-(2,4-Dichlorophenyl)cyclo-propyl]carbonyl} -3H-spiroffuro[3,4-c]pyridine-1,3'- pyrrolidin}-3-one; 1'-{[1-(4-Chlorophenyl)cyclopropyl] carbonyl}-4-methoxy-3H-spiro{ furo[3,4-c]pyridine- 1,3’-pyrrolidin]-3-one; 1'-{[1-(4-Chloropheny!)cyclopropyl] carbony!}-4-hydroxy-3H-spiro[furo[3,4-c]pyridine-1,3"- pyrrolidin}-3-one; 6-Chloro-1'-{[1-(3,4-dichlorophenyl) cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine- : 1,3'-pyrrolidin]-3-one; 1'-{[1-(4-Chloro-2-fluorophenyl) cyclopropy!]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3'- pyrrolidin]-3-one; 6-Chloro-1'-{[1-(2,4-difluoropheny!) cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine- 1,3'-pyrrolidin]-3-one; 1-§ [1-(2-Chloro-4-fluorophenyl)cyclo-propyl]carbonyl}-3H-spiroffuro[3 ,4-c]pyridine-1,3'- pyrrolidin}-3-one; 1'-{[1-(2,4-Difluorophenyl)cyclo-propyl]carbony!}-3H-spiro{furo[3 ,4-c]pyridine-1,3'- ~~ pyrrolidin]-3-one, 1'-({1-[4-(Methylthio)phenyl]cyclo-propyl}arbonyl)-3 H-spiro[furo[3,4-c]pyridine-1,3"- pyrrolidin]-3-one; 1'-[(1-{4-[(Trifluoromethyl)thio] phenyl} yclopropyl)carbony!]-3H-spiro[furo[3 ,4-c]pyridine- 1,3'-pyrrolidin]-3-one; 1'-{[1-(4-Chlorophenyl)cyclo-pentyl]carbonyl}-3 H-spiro[2-benzofuran-1,3'-pyrrolidin}-3- one; 1-{[1-(4-Chlarophenyl)cyclohexyl] carbonyl} azepane; Methyl 4-[5-(1-{[3-0xo0-1'H,3H-spiro[2-benzofuran-1 ,3'-pyrrolidin]-1'- yl]carbonyl}cyclopropyl)pyridin-2-yl]piperazine-1 -carboxy late; N,N-Dimethyl-4-[4-(1-{[3-0xo0-1'H,3H-spiro[2-benzofuran-1,3"-pyrrolidin}-1'- yl]carbonyl}cyclo-propy I)phenyl]piperazine-1-carboxamide; Methyl 4-[3-fluoro-4-(1-{[3-oxo-1'H,3H-spiro[2-benzofuran-1 ,3"-pyrrolidin]-1'- yl]carbonyl}cyclo-propyl)phenyl]piperazine-1 -carboxylate; 1'-({1-[2-Fluoro-4-(4-propionylpiperazin-1-yl)phenyl]cyclo-propyl} carbonyl)-3H-spiro[2- benzofuran-1,3'-pyrrolidin]-3-one; 1'<({1-[2-Fluoro-4-(4-isobutyrylpiperazin-1 -yl)phenyl]cyclo-propyl}carbonyl)-3H-spiro[2- benzofuran-1,3'-pyrrolidin]-3-one; 1'-[(1-{4-[4-(Cyclopropy| carbonyl)piperazin-1 -yl]-2-fluoro-phenyl} cyclopropyl) carbonyl] 3H-spiro[2-benzofuran-1,3-pyrrolidin]-3-one; 1'-({1-[4-(4-Acetylpiperazin-1 -yl)-2-fluorophenyl]jcyclopropyl} carbonyl)-3 H-spiro{2- benzofuran-1,3"-pyrrolidin}-3-one;

4-[3-Fluoro-4-(1-{[3-oxo-1'H,3H-spiro[2-benzofuran-1,3'-pyrrolidin]-1'- ylJcarbonyl} cyclopropyl)phenyl]-N,N-dimethylpiperazine-1-carboxamide; 1'({1-[4-(4-Hydroxypiperidin-1-yl)phenyl}cyclopropyl} carbonyl)-3H-spiro[2-benzofuran- 1 3-pyrrolidin]-3-one; N,N-Dimethy!-1-[4-(1-{[3-0ox0-1"H,3H-spiro[2-benzofuran-1,3 >-pyrrolidin]-1’- ylJcarbonyl}cyclo-propy!)phenyl]piperidine-4-carboxamide; Methyl 4-[4-(1-{[3-0x0-1"H,3H-spirof2-benzofuran-1 ,3'-pyrrolidin]-1'- _ yl]carbonyl} cyclopropyl) phenyl]piperidine- 1 carboxylate; Ethyl 4-[4-(1-{[3-ox0-1'H,3H-spiro[2-benzofuran-1 J3-pyrrolidin]-1'- yl]carbonyl} cyclopropyl) phenyljpiperidine-1 -carboxylate; 1'-({1-[4-(1-Acetylpiperidin-4-yl)phenyl]cyclopropyl} carbonyl)-3H-spiro[2-benzofuran-1,3'- pyrrolidin]-3-one; 1'-({1-[4-(1-Isobutyry Ipiperidin-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro [2-benzofuran- 1,3'-pyrrolidin]-3-one; 1'-({1-[4-(1-Propionylpiperidin-4-yl)phenyljcyclopropyl} carbonyl)-3H-spiro[2-benzofuran- 1,3"-pyrrolidin}-3-one; 1'-[(1-{4-[1-(3-Methylbutanoy!) piperidin-4-yljphenyl} cyclopropyl) carbonyl]-3H-spirof{2- benzofuran-1,3'-pyrrolidin]-3-one; 1'-({1-[4-(1-Acetylpiperidin-4-yl)phenyl] cyclopropyl} carbonyl)-3H-spiro[furo(3,4- c]pyridine-1,3"-pyrrolidin]-3-one; 1'-({1-[4-(1-Isobutyrylpiperidin-4-yl)phenyl]cyclopropyl} carbonyl)-3H-spiroffuro{3,4- c]pyridine-1,3"-pyrrolidin]-3-one; 1-({1-{4-(1 -Propionylpiperidin-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo(3,4- ¢]pyridine-1,3'-pyrrolidin}-3-one; : 1-[(1-{4-[1 -(3-Methylbutanoy!) piperidin-4-yl]phenyl} cyclo-propyl)carbonyl]-3H- spiro[furo[3,4-c]pyridine-1,3'-pyrrolidin]-3-one; Methyl 4-[4-(1-{[3-0x0-1"H,3H-spiro[furo[3,4-c]pyridine-1,3'-pyrrolidin]-1'- yl]carbonyl}cyclopropyl)phenyllpiperidine-1-carboxylate; Ethyl 4-[4-(1-{[3-0oxo-1'H,3H-spiro[furo[3,4-c]pyridine-1 ,3'-pyrrolidin]-1'- ylcarbonyl} cyclopropyl)phenyl]piperidine-1-carboxylate; Isopropyl 4-[4-(1-{[3-0x0-1'H,3H-spiro[furo[3,4-¢]pyridine-1 ,3-pyrrolidin]-1'- yl]carbonyl}cyclo-propyl)phenyl]piperidine-1-carboxylate; Methy! 4-hydroxy-4-[4-(1-{[3-0x0-1'H,3H-spiro[2-benzofuran-1,3'-pyrrolidin]-1'- yl]carbonyl}cyclo-propyl)phenyl]piperidine- 1 -carboxylate; Ethyl 4-hydroxy-4-[4-(1-{[3-0x0-1'H,3H-spiro[2-benzofuran-1 ,3'-pyrrolidin]-1'- yl]carbony1}cyclo-propyl)phenyl]piperidine-1-carboxylate;

Methyl 4-(5-{1-[(3-pyridin-3-ylpyrrolidin-1-yl)carbonyl]cyclo-propy!} pyridin-2- yDpiperazine-1-carboxylate; Ethyl 4-(5-{1-[(3-pyridin-3-ylpyrrolidin-1-yl)carbonyl]cyclo-propyl} pyridin-2-yl)piperazine- 1-carboxylate; 1-Acetyl-4-(5-{1-[(3-pyridin-3-ylpyrrolidin-1 -yl)carbonyl]jcyclo-propyl}pyridin-2- yl)piperazine; 1-Isobutyryl-4-(5-{1-[(3-pyridin-3-ylpyrrolidin-1-yl)carbonyl] cyclo-propyl} pyridin-2- _ yl)piperazine; 1-(Cyclopropylcarbonyl)-4-(5-{1-[(3-pyridin-3-ylpyrrolidin-1-yl) carbonyl]cyclopropyl} pyridin-2-yl)piperazine; Isopropy! 4-{4-(1-{[3-ox0-1"H,3H-spiro[2-benzofuran-1 ,3"-pyrrolidin]-1'-yl]Jcarbonyl}cyclo- propyl)phenyl]piperazine-1-carboxylate; 1'-[(1-{4-[6-(Pyrrolidin-1-ylcarbonyl)pyridin-3-yl} phenyl} cyclo-propyl)carbonyl}-3H- spiro[2-benzofuran-1,3'-pyrrolidin}-3-one; N-Ethyl-N-methyl-5-{4-(1-{[3-0x0-1 'H,3H-spiro[2-benzofuran-1,3"-pyrrolidin]-1"- yl]carbonyl} cyclo-propyl)pheny!]pyridine-2-carboxamide; N,N-Diethyl-5-[4-(1-{[3-0x0-1'H,3H-spiro{2-benzofuran-1 ,3'-pyrrolidin}-1'- yljcarbonyl} cyclo-propyl)phenyl]pyridine-2-carboxamide; tert-Buty!l {4-[5-(1-{[3-0x0-1 *H,3H-spiro[2-benzofuran-1,3'-pyrrolidin]-1'-yl]carbonyl} cyclo- propyl)pyridin-2-yl]phenyl} carbamate; N,N-Dimethyl-1-[5-(1-{[3-0xo0-1'H,3H-spiro[2-benzofuran- 1,3"-pyrrolidin]-1'- yl]carbonyl}cyclo-propyl)pyridin-2-yllpiperidine-4-carboxamide; and 1'-{[1 (6-Piperidin-1-ylpyridin-3-yl)cyclopropyllcarbonyl}-3H-spiro[furo[3,4-c]pyridine-1 J'- pyrrolidin}-3-one, or pharmaceutically acceptable salt thereof.

32. A compound of claim 1 selected from: 1'-({1-[2-Fluoro-4-(2-oxopyrrolidin-1 -yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2- benzofuran-1,3'-pyrrolidin]-3-one; 1'<({1-[2-Fluoro-4-(2-oxo0-1,3-0xazolidin-3 -yl)phenyljcyclopropyl}carbonyl)-3H- spiroffuro[3,4-c}pyridine-1,3"-pyrrolidin]-3-one; 1'-({1-[4-(2-Oxoazetidin-1-yl)phenyl]cyc lopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3'- pyrrolidin]-3-one; 1'-({1-[2-Fluoro-4-(2-oxoazetidin-1 -yl)phenyljcyclopropyl}carbonyl)-3H-spiro(2- benzofuran-1,3'-pyrrolidin]-3-one; ’ 1'-({1-[4-(2-Oxoazetidin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo (3,4-c]pyridine- 1,3'-pyrrolidin]-3-one;

1'-({1-[2-Fluoro-4-(2-oxoazetidin-1-yl)phenyl]cyclopropyl} carbonyl)-3H-spiro[furo[3,4- c]pyridine-1,3"-pyrrolidin]-3-one; Propyl 4-[5-(1-{[3-0x0-1"H,3H-spiro[2-benzofuran-1,3'-pyrrolidin]-1'- yl]carbonyl}cyclopropyl)pyridin-2-yl]piperazine-1-carboxylate; 1sobutyl 4-[5-(1-{[3-ox0-1"H,3H-spiro[2-benzofuran-1,3"-pyrrolidin]-1'- yl)carbonyl}cyclopropyl)pyridin-2-yl]piperazine-1-carboxylate; - Isopropyl 4-[5-(1-{[3-0x0-1'H,3H-spiro[2-benzofuran-1 ,3'-pyrrolidin]-1'- yl]carbonyl}cyclopropyl)pyridin-2-yl]piperazine-1-carboxylate; Ethyl 4-[4-(1-{[3-0x0-1'H,3H-spiro[2-benzofuran-1 ,3'-pyrrolidin]-1'- yl]carbonyl} cyclopropy!l)phenyl]piperazine-1-carboxylate; Propyl 4-[4-(1-{[3-0ox0-1"H,3H-spiro[2-benzofuran-1 ,3'-pyrrolidin]-1'- yl]carbonyl} cyclopropyl)phenyl]piperazine-1-carboxylate; Isobutyl 4-[4-(1-{[3-0x0-1'H,3H-spiro[2-benzofuran-1 ,3"-pyrrolidin]-1'- yl]carbonyl}cyclopropyl)pheny!jpiperazine-1-carboxylate; 1'-[(1-{4-[4-(Cyclopropylacetyl)piperazin-1-yl]phenyl} cyclopropyl)carbonyl]-3H-spiro[2- benzofuran-1,3"-pyrrolidin}-3-one; 1'-[(1- {4-[4-(Cyclopropylacetyl)piperazin-1-yl)-2-fluorophenyl} cyclopropyl) carbonyl}-3H- spiro[2-benzofuran-1,3'-pyrrolidin]-3-one; 1'-[(1-{4-[4-(3-Methylbutanoyl)piperazin-1 -ylphenyl}cyclopropyli)carbonyl]-3H-spiro{2- benzofuran-1,3"-pyrrolidin]-3-one; 1'-{(1-{2-Fluoro-4-[4-(3-methylbutanoyl)piperazin-1 -yl]phenyi} cyclopropyl) carbonyl]-3H- spiro[2-benzofuran-1,3'-pyrrolidin}-3-one; 1'-[(1-{4-[4«Tetrahydro-2H-pyran-4-ylcarbonyl)piperazin-1- yl}phenyl} cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3'-pyrrolid in}-3-one; Ethyl 4-[3-fluoro-4-( 1-{[3-oxo-1'H,3H-spiro[2-benzofuran-1 ,3'-pyrrolidin]-1'- yl]carbonyl}cyclopropyl)phenyl]piperazine-1-carboxylate; Propyl 4-[3-fluoro-4-(1-{[3-oxo-1'H,3H-spiro[2-benzofuran-1 ,3"-pyrrolidin]-1'- yl]carbonyl} cyclopropyl)phenyl]piperazine-1-carboxylate; 4-[3-Fluoro-4-(1-{[3-oxo0-1'H,3H-spiro[2-benzofuran-1,3"-pyrrolidin]-1'- yl]carbonyl}cyclopropyl)phenyl]-N-methylpiperazine-1-carboxamide; 1'-({ 1-[2-Fluoro-4-(4-isobutyrylpiperazin-1-yl)phenyl]cyclopropyl} carbonyl)-3H-spiro[2- benzofuran-1,3'-pyrrolidin]-3-one; 1'-[(1-{4-[4-(Cyclopropylacetyl)piperazin-1-yl]-2-fluorophenyl} cyclopropyl) carbonyl]-3H- spiro[2-benzofuran-1,3'-pyrrolidin]-3-one; Methyl 4-[3-fluoro-4-(1- {[3-ox0-1"H,3H-spiro[furo[3,4-c]pyridine-1,3'-pyrrolidin]-1'- yllearbonyl}cyclopropyl)phenyl]piperazine-1-carboxylate;

Ethyl 4-[3-fluoro-4-(1-{[3-oxo-1'H,3H-spiro[furo{3,4-c]pyridine-1,3'-pyrrolidin]-1'- yllcarbonyl}cyclopropyl)phenyl]piperazine-1-carboxylate; Propyl 4-[3-fluoro-4-(1-{[3-oxo-1'H,3H-spiro[furo[3,4-c]pyridine-1,3"-pyrrolidin]-1'- yljcarbonyl}cyclopropyl)phenyl]piperazine-1-carboxylate; iso-Propyl 4-[3-fluoro-4-(1-{[3-oxo-1"H,3H-spiro[furo[3,4-c]pyridine-1,3"-pyrrolidin]-1'- yljcarbonyl} cyclopropyl)phenyl]piperazine-1 -carboxylate; iso-Butyl 4-[3-fluoro-4-(1-{[3-o0x0-1'H,3H-spiro[furo[3,4-c]pyridine-1,3"-pyrrolidin]-1'- yl]carbonyl}cyclopropyl)phenyl]piperazine-1-carboxylate; 1'-[(1-{4-[4-(Cyclopropylcarbonyl)piperazine-1-yl]-2-fluorophenyl}cyclopropyl) carbonyl]- 3H-spiro[furo{3,4-c]pyridine-1,3’-pyrrolidin]-3-one; 1'-[(1-{2-Fluoro-4-[4-(3-methylbutanoyl)piperazin-1-yl]phenyl} cyclopropyl) carbonyl]-3H- spiro[furo[3,4-c]pyridine-1,3'-pyrrolidin]-3-one; N,N-Dimethyl-5-[4-(1-{[3-0x0-1'H,3H-spiro[2-benzofuran-1,3"-pyrrolidin]-1'- yllcarbony!}cyclopropyl)phenyl]pyridine-2-carboxamide; N-Ethyl-5-[4-(1-{[3-0x0-1'H,3H-spiro[2-benzofuran-1,3"-pyrrolidin]-1'- yl]carbony!} cyclopropyl) phenyl]pyridine-2-carboxamide; N-Tsopropyl-5-[4-(1-{[3-0x0-1'H,3H-spiro[2-benzofuran-1,3'-pyrrolidin]-1'- yllcarbonyl}cyclopropyl)phenyllpyridine-2-carboxamide; 5-[3-Fluoro-4-(1-{[3-oxo-1'H,3H-spiro[2-benzofuran-1,3'-pyrrolidin]-1'- yljcarbonyl!}cyclopropyl)phenyl]-N-methylpyridine-2-carboxamide; 5-[3-Fluoro-4-(1-{[3-oxo-1'H,3H-spiro[2-benzofuran-1,3"-pyrrolidin}-1'- ylJcarbonyl}cyclopropyl)phenyl]-N-ethylpyridine-2-carboxamide; 5-[3-Fluoro-4-(1-{[3-oxo-1'H,3H-spiro[2-benzofuran-1,3'-pyrrolidin}-1'- yl]carbonyl} cyclopropyl)phenyl]-N-i-propylpyridine-2-carboxamide; 5-[3-Fluoro-4-(1-{[3-oxo0-1"H,3H-spiro[2-benzofuran-1,3"-pyrrolidin}-1'- yl]carbonyl}cyclopropyl)phenyl]-N,N-dimethylpyridine-2-carboxamide; 5-{3-Fluoro-4-(1- {[3-oxo-1'H,3H-spiro[furo[3,4-c]pyridine-1,3'-pyrrolidin]-1'- yl]carbony!}cyclopropyl)pheny!]-N-methy Ipyridine-2-carboxamide; N-Ethy!-5-[3-fluoro-4-(1-{[3-oxo0-1'H,3H-spiro{furo[3,4-c]pyridine-1,3"-pyrrolidin]-1'- yl]carbonyl}cyclopropyl)phenyl]pyridine-2-carboxamide; 5-[3-Fluoro-4-(1- {[3-oxo-1'H,3H-spiro[furo[3,4-c]pyridine-1,3-pyrrolidin]-1'- yljcarbony!}cyclopropyl)phenyl]-N-isopropylpyridine-2-carboxamide; 5-[3-Fluoro-4-(1-{[3-oxo-1'H,3H-spiro[furo[3,4-c] pyridine-1,3'-pyrrolidin]-1'- : yljcarbony!}cyclopropyl)pheny!]-N,N-dimethylpyridine-2-carboxamide; 6-[3-Fluoro-4-(1-{[3-oxo-1"H,3H-spiro[2-benzofuran-1 ,3'-pyrrolidin]-1'- yljcarbonyl} cyclopropyl)phenyl]-N-methyInicotinamide;

6-[3-Fluoro-4-(1-{[3-0x0-1'H,3H-spiro[2-benzofuran-1,3'-pyrrolidin]-1'- yllcarbonyl}cyclopropyl)phenyl]-N,N-dimethylnicotinamide; N-Methyl-6-[4-(1-{[3-0ox0-1'H,3H-spiro[2-benzofuran-1,3'-pyrrolidin}-1'- yl]carbonyl}cyclopropyl)phenyi]nicotinamide; N,N-Dimethyl-6-{4-(1-{[3-0x0-1'H,3H-spiro[2-benzofuran-1,3"-pyrrolidin]}-1'- yllcarbonyl}cyclopropyl)phenyl]nicotinamide; 1'-({1-{4-(1 -Isobutyryl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]cyclopropyl} carbonyl)-3H- spiro[2-benzofuran-1,3'-pyrrolidin]-3-one; : 1'-({1-{4-(1-Propiony!-1,2,3,6-tetrahydropyridin-4-yl)phenyl}cyclopropyl} carbonyl)-3H- spiro[2-benzofuran-1,3"-pyrrolidin}-3-one; 1'«({1-[3-Fluoro-4-(3-methyl-1H-pyrazol-1-yl)phenyl]cyclopropyl}carbonyl)-3H- spiro furo{3,4-c]pyridine-1,3'-pyrrolidin]-3-one; Methy! 4-(4-{1-[(4,4-dimethyl-2-0x0-1-0xa-7-azaspiro[4.4]non-7-yl)carbonyl] cyclopropyl}- 3-fluorophenyl)piperazine- I -carboxylate; Ethyl 4-(4-{1-[(4,4-dimethy]-2-ox0-1-0xa-7-azaspiro{4.4]non-7-yl)carbonyl]cyclopropyl}-3- fluorophenyl)piperazine-1-carboxylate; 7-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl} -4,4-dimethyl-1-oxa-7-azaspiro[4.4]nonan-2- one; Methyl 4-(3-fluoro-4-{ 1-[(3-pyridin-3-yipyrrolidin-1-yl)carbonyl]cyclopropyl} phenyl)piperazine-1-carboxylate; Methyl 4-(5-{1-[(3-pyridin-3-ylpyrrolidin-1-yl)carbonyljcyclopropyl} pyridin-2- yl)piperazine-1-carboxylate; Ethyl 4-(5-{1-[(3-pyridin-3-ylpyrrolidin-1 -yl)carbonyl]cyclopropyl} pyridin-2-yl)piperazine- 1-carboxylate; 1-Acetyl-4-(5-{1-[(3-pyridin-3-ylpyrrolidin-1-yl)carbonyl]cyclopropyl} pyridin-2- yl)piperazine; 1-(3-Methylbutanoy!)-4-(5-{1-[(3-pyridin-3-ylpyrrolidin-1 -yl)carbonyl]cyclopropyl} pyridin- 2-yl)piperazine; 1-(Cyclopropylcarbonyl)-4-(5-{1-[(3-pyridin-3-ylpyrrolidin-1 -yl)carbonyljcyclopropyl} pyridin-2-yl)piperazine; Methyl 4-(3-fluoro-4-{1-{(1,3,3-trimethyl-6-azabicyclo[3.2. 1Joct-6-yl)carbonyl] cyclopropyl} phenyl)piperazine-1-carboxylate; 1-{[1-(6-Azetidin-1-ylpyridin-3-yl)cyclopropyljcarbonyi}-3H-spiro [furo[3,4-c]pyridine-1,3'"- pyrrolidin]-3-one; 1'-({1-{6-(2-Oxoazetidin-1-yDpyridin-3-yljcyclopropy!} carbonyl)-3 H-spiro[2-benzofuran- 1,3'-pyrrolidin]-3-one;

Methy! {3-fluoro-4-(1-{[3-oxo-1'H,3H-spiro[furo[3,4-c]pyridine-1,3'-pyrrolidin]-1'- yl]carbonyl}cyclopropyl)phenyl]carbamate; Methyl [3-fluoro-4-(1-{[3-0x0-1"H,3H-spiro[2-benzofuran-1,3"-pyrrolidin]-1'- yl]carbonyl}cyclopropyl)phenyljcarbamate; 1'-({1-[4-(2-Oxopyrrolidin-1-yl)phenyl]cyclopropyl} carbonyl)-3H-spiro[ furo[3,4-c]pyridine- 1,3'-pyrrolidin]-3-one; 1'-[(1-{4-[4-(Cyclopropylcarbonyl)piperazin-1-yl]phenyl} cyclobutyl)carbonyl]-3H-spiro[2- benzofuran-1,3'-pyrrolidin]-3-one; Ethyl 4-[4-(1-{[3-0oxo-1"H,3H-spiro[furo[3,4-c]pyridine-1,3'-pyrrolidin]-1'- ylJcarbonyl}cyclopropyl)phenyl]piperazine-1-carboxylate; 1-{[1-(4-Chlorophenyl)cyclopropyljcarbonyl}-3-(1,1 -dimethylpropy)pyrrolidin-3-ol; 7-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-4,4-dimethyl-1-oxa-7-azaspiro[4.4]nonane; Methyl 4-(4-{1-[(3-tert-butyl-3-hydroxypyrrolidin-1-yl)carbonyl]cyclopropyl}-3- fluorophenyl)piperazine-1-carboxylate; N,N-Diethyl-5-[3-fluoro-4-(1-{[3-oxo-1'H,3H-spiro[2-benzofuran-1,3"-pyrrolidin]-1'- yl}carbonyl}cyclopropyl)phenyl]pyridine-2-carboxamide; 1'-({1-[4-(2-Oxopyrrolidin-1-yl)phenyl]cyclopropyl} carbony 1)-3H-spiro[2-benzofuran-1,3'- pyrrolidin]-3-one; 1-({1-[2-Fluoro-4-(1H-1,2,3-triazol-1-yl)phenyl]cyclopropyl} carbonyl)-3H-spiro[2- benzofuran-1,3'-pyrrolidin]-3-one; 1'-({1-[2-Fluoro-4-(2H-1 ,2,3-triazol-2-yl)phenyl]cyclopropy!}carbonyl)-3H-spiro [2- benzofuran-1,3'-pyrrolidin]-3-one; 1'-({1-[2-Fluoro-4-(1H-1,2,4-triazol-1 -yl)phenylicyclopropyl} carbony!)-3H-spiro[2- benzofuran-1,3'-pyrrolidin]-3-one; 1'-({1-[2-Fluoro-4-(4H-1 2,4-triazol-4-yl)phenyl]cyclopropy!} carbonyl)-3H-spiro[2- benzofuran-1,3'-pyrrolidin}-3-one; N-Ethyl-5-[3-fluoro-4-(1-{{3-oxo-1'H,3 H-spirof2-benzofuran-1,3'-pyrrolidin]-1'- yl]carbonyl}cyclopropyl)phenyl]pyridine-2-carboxamide; and 5-[3-Fluoro-4-(1-{[3-0ox0-1 'H,3H-spiro[2-benzofuran-1,3"-pyrrolidin]-1'- yljcarbonyl}cyclopropyl)phenyl]-N-isopropylpyridine-2-carboxamide; or pharmaceutically acceptable salt thereof.

33. A method of modulating activity of 11BHSD1 or MR comprising contacting said 11pHSD!1 or said MR with a compound of Formula I:

R! R2 3 oN Nope 0) 1 or pharmaceutically acceptable salt or prodrug thereof, wherein:

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

R' and R? together with the C atom to which they are attached form a 3-, 4-,'5-, 6- or 7- membered cycloalkyl group or a 3-, 4-, 5-, 6- or 7-membered heterocycloalkyl group, each optionally substituted by 1, 2 or 3 R’;

R’® and R* together with the N atom to which they are attached form a 4-15 membered heterocycloalkyl group optionally substituted by 1,2, 3 or 4 -W-X'-Y’-Z',

R® is halo, C, alkyl, Cy. alkenyl, Cy. alkynyl, Cy. haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO,, OR’, SR?, C(O)R®, C(O)NR'R’, C(O)OR?, OC(O)R®, OC(O)NR'R’, NRCR?, NR°C(O)RY, NR°C(O)OR?, S(O)R®, S(OYNR'R?, S(OX.R’, or S(O),NR°R%;

W, W’ and W*’ are each, independently, absent, C6 alkylenyl, Ci. alkenylenyl, Cis alkynylenyl, O, S, NR®, CO, CS, COO, CONR’, QCONR¢, SO, SO,, SONR®, or NRCONR', wherein said Cy. alkylenyl, Cy alkenylenyl, Ca alkynyleny! are each optionally substituted by 1, 2 or 3 halo, OH, C,., alkoxy, C,. haloalkoxy, amino, C, alkylamino or C,s dialkylamino;

X, X’ and X*’ are each, independently, absent, Cys alkylenyl, Cys alkenylenyl, Cy.3 alkynylenyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, arylalkenyl, cycloalkylatkenyl, heteroarylalkenyl, heterocycloalkylalkenyl, arylalkynyl, cycloalkylalkynyl, heteroarylalkynyl, heterocycloalkylalkynyl, each of which is optionally substituted by one or more halo, CN, NO,, OH, C,.4alkoxy, C;.4 haloalkoxy, amino, Ci4 alkylamino or Cys dialkylamino;

Y, Y’ and Y’’ are each, independently, absent, Cs alkylenyl, Cs ¢alkenylenyl, Ca alkynylenyl, O, $, NR¢, CO, CS, COO, CONR’, OCONR?®, SO, SO,, SONR’, or NRCONR', wherein said C,.¢ alkylenyl, C.s alkenylenyl, Ca alkynylenyl are each optionally substituted by 1, 2 or 3 halo, OH, C,.s alkoxy, Cy.4 haloalkoxy, amino, C4 alkylamino or C4 dialkylamino;

Z,Z’ and Z"’ are each, independently, absent, H, halo, oxo, sulfido, CN, NO,, OH, C,., alkoxy, Ci.4 haloalkoxy, amino, C;.4 alkylamino or C,.g dialkylamino, C,.salkyl, C,¢alkenyl, Cag alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said Cs alkyl, Cos alkenyl, Ca alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2 or 3 halo, Cy. alkyl, C,.¢ alkenyl, Cy. alkynyl, Ci haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO,, OR’, SR’, C(O)R”, C(O)NR°RY, C(O)OR®, OC(O)R®, OC(O)NRR?, NRR’, NRC(O)RY, NRC(O)OR®, S(O)R®, S(O)NRR, S(O):R”, or S(O)2NRR’,;

PCT/US2005/015539 wherein two ~W-X-Y-Z attached to the same atom optionally form a 3-14 membered cycloalkyl or heterocycloalkyl group optionally substituted by 1,20r3 -W».X>.Y>.2": wherein two —-W’-X’-Y’-Z" attached to the same atom optionally form a 3-14 membered cycloalkyl or heterocycloalky! group optionally substituted by 1, 2 or 3 -W».X’-Y"*.2""; wherein —~W-X-Y-Z is other than H; wherein —W’-X’-Y’-Z’ is other than H; wherein -W’’-X"’-Y"’-Z" is other than H; R®is H, C,¢ alkyl, Cy haloalkyl, Cy alkenyl, (C,.¢ alkoxy)-C,.s alkyl, Cy. alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl: Ris H, C4 alkyl, Cy haloalkyl, C, 4 alkenyl, Cy alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl; R® and R? are each, independently, H, C4 alkyl, C,¢ haloalkyl, Cy alkenyl, C4 alkynyl, aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl; or R° and RY together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group; and R® and Rf are each, independently, H, C,; alkyl, C, haloalkyl, Cy. alkenyl, Cy. alkynyl, aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl; or R® and R together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group.

34. The method of claim 33 wherein said modulating is inhibiting.

35. Use of a compound of Formula I: R! R2 Rr?

I . or pharmaceutically acceptable salt or prodrug thereof, wherein: Cy is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 ors -W-X-Y-Z; R' and R? together with the C atom to which they are attached form a 3-, 4-,5-,6- or 7- membered cycloalkyl group or a 3-, 4-, 5-, 6- or 7-membered heterocycloalkyl group, each optionally substituted by 1, 2 or 3 RY; 248 AMENDED SHEET

: PCT/US2005/015559 R’ and R* together with the N atom to which they are attached form a 4-15 membered heterocycloalky! group optionally substituted by 1, 2,30r4-W-X'-Y*-2Z’; Riis halo, C,¢ alkyl, C,4 alkenyl, Cy alkynyl, C4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO,, OR, SR, C(O)R®, C(O)NR'RY, C(O)OR’, OC(O)R®, OC(O)NRRY, NRR’, NR°C(O)R?, NR°C(O)OR?, S(O)R?, S(O)NR°R?, S(0),R", or S(O),NR°R: W, Wand W*’ are each, independently, absent, Cygalkylenyl, Cis alkenylenyl, Cp alkynylenyl, O, S, NR*, CO, CS, COO, CONR?, OCONR?S, SO, SO, SONR®, or NR‘CONR', wherein : said Cy alkylenyl, Cy alkenylenyl, Cy alkynyleny! are each optionally substituted by 1, 2 or 3 halo, OH, C4 alkoxy, C4 haloalkoxy, amino, C4 alkylamino or C,.4 dialkylamino; X, X’ and X’* are each, independently, absent, C, 4 alkylenyl, Cg alkenylenyl, C,4 - alkynylenyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, arylalkeny!, cycloalkylalkenyl, heteroarylalkenyl, heterocycloalkylalkenyl, arylalkynyl, cycloalkylalkynyt, heteroarylalkynyl, heterocycloalkylalkynyl, each of which is optionally substituted by one or more halo, CN, NO,, OH, C,, alkoxy, C4 haloalkoxy, amino, C, 4 alkylamino or C,.4 dialkylamino; Y,Y’ and YY" are each, independently, absent, C, 4 alkylenyl, Cy alkenylenyl, C,. alkynylenyl, O, S, NR¢, CO, CS, COO, CONR’, OCONR®, SO, SO,, SONR®, or NR°CONR', wherein said Cig alkylenyl, Cy alkenylenyl, Cy. alkynylenyl are each optionally substituted by 1, 2 or 3 halo, OH, C4 alkoxy, C4 haloalkoxy, amino, C,, alkylamino or Cy 4 dialkylamino; Z,Z’ and Z”’ are each, independently, absent, H, halo, oxo, sulfido, CN, NO,, OH, C4 alkoxy, C4 haloalkoxy, amino, C, 4 alkylamino or C,.4 dialkylamino, C4 alkyl, Cy alkenyl, Cy alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said Cis alkyl, Cys alkenyl, Cy alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2 or 3 halo, C, alkyl, Cy alkenyl, Cp alkynyl, C4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO,, OR, SR*, C(O)R’, C(O)NR°RY, C(O)OR?, OC(O)R?, OC(O)NR‘RY, NR°RY, NR°C(O)RY, NR*C(O)OR", S(O)R®, S(O)NR°RY, S(O),R?, or S(0),NR°R?: wherein two —W-X-Y-Z attached to the same atom optionally form a 3-14 membered cycloalkyl or heterocycloalkyl group optionally substituted by 1, 2 or 3 Wr XLylz, wherein two —-W’-X’-Y’-Z" attached to the same atom optionally form a 3-14 membered cycloalkyl or heterocycloalkyl group optionally substituted by 1, 2 or 3 -W». XYZ wherein -W-X-Y-Z is other than H; wherein —W’-X’-Y’-Z’ is other than H; : wherein —-W”’-X*’-Y**-Z*’ is other than H; Ris H, C4 alkyl, C,.¢ haloalkyl, Cs alkenyl, (Cy. alkoxy)-C, 4 alkyl, Cy. alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl; R®is H, Cis alkyl, Cy haloalkyl, Cy alkenyl, C,.4 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, 249 AMENDED SHEET

PCT/US2005/015559 R® and R* are each, independently, H, Cis alkyl, Cy haloalkyl, Cy alkenyl, C,4 alkynyl, ! aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl; or R® and R¢ together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalky! group; and R® and Rare each, independently, H, Ci. alkyl, C4 haloalkyl, Cy. alkenyl, Cas alkynyl, aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl; or R°and Rf together with the N atom to which they are attached form a 4-,5-,6-or7- BN membered heterocycloatkyl group, in the manufacture of a medicament for treating a disease In a patient, wherein said disease is associated with expression of activity of 11BHSDI or

MR. oo

36. Use of claim 35 wherein said disease is obesity, diabetes, glucose intolerance, insulin resistance, hyperglycemia, hypertension, hyperlipidemia, cognitive impairment, dementia, glaucoma, hypertension, cardiovascular disorders, osteoporosis, or inflammation.

37. Use ofclaim 35 wherein said disease is hypertension, a cardiovascular, renal or inflammatory disease, heart failure, atherosclerosis, arteriosclerosis, coronary artery disease, thrombosis, angina, peripheral vascular disease, vascular wall damage, stroke, dyslipidemia, hyperlipoproteinaemia, diabetic dyslipidemia, mixed dyslipidemia, hypercholesterolemia, hypertriglyceridemia, type 1 diabetes, type 2 diabetes, obesity, metabolic syndrome, insulin resistance or general aldosterone-related target organ damage.

38. A composition comprising a compound of claim | and a pharmaceutically acceptable carrier,

39. Use of a compound of Formula I: R! R2 i N 0 I or pharmaceutically acceptable salt or prodrug thereof, wherein: 250 : AMENDED SHEET :

PCT/US2005/015559 Cy is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, each optionally substituted by 1,2,3,4 or5 -W-X-Y-Z; R' and R? together with the C atom to which they are attached form a 3-,4-,5-,6-0r7- membered cycloalkyl group or a 3-, 4-, 5-, 6~ or 7-membered heterocycloalkyl group, each optionally substituted by 1, 2 or 3 R®; R’ and R* together with the N atom to which they are attached form a 4-15 membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 ~W-X-Y'.Z’; R’ is halo, C4 alkyl, Cy.6 alkenyl, Cy6 alkynyl, C,., haloalkyl, aryl, cycloalkyl, heteroaryl, + heterocycloalkyl, CN, NO,, OR?, SR?, C(O)R, C(O)NR'R!, C(O)OR?, OC(O)R", OC(O)NR°R’, NR‘R’, NR‘C(O)R", NR°C(O)OR?, S(O)R®, S(O)NRR', S(O);R", or S(O),NRR; W, W’ and W*” are each, independently, absent, C4 alkylenyl, C4 alkenylenyl, C, alkynylenyl, O, S, NR", CO, CS, COO, CONR®, OCONR®, SO, SO,, SONR®, or NR°CONR', wherein said Cg alkylenyl, C,4 alkenylenyl, C; 4 alkynylenyl are each optionally substituted by 1, 2 or 3 halo, OH, C4 alkoxy, Cy, haloalkoxy, amino, C, alkylamino or C,. dialkylamino; X, X" and X’ are each, independently, absent, C4 alkylenyl, C, 4 alkenylenyl, C,4 alkynylenyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, hetercarylalkyl, heterocycloalkylalky!, arylalkenyl, cycloalkylalkenyl, heteroarylalkenyl, heterocycloalkylalkenyl, arylalkynyl, cycloalkylalkynyl, heteroarylalkynyl, heterocycloalkylalkynyl, each of which is optionally substituted by one or more halo, CN, NO,, OH, C,, alkoxy, Cy, haloalkoxy, amino, Cis alkylamino or C, 4 dialkylamino; Y,Y’ and Y” are each, independently, absent, C, alkylenyl, Cy alkenylenyi, Cy alkynylenyl, O, S, NR*, CO, CS, COQ, CONR®, OCONRS, SO, SO,, SONR?, or NR°CONR', wherein said Cy galkylenyl, Cy4 alkenylenyl, C,.¢alkynylenyl are each optionally substituted by 1, 2 or 3 halo,

.- OH, C,., alkoxy, C4 haloalkoxy, amino, C, 4 alkylamino or C, 4 dialkylamino; Z,Z and Z*’ are each, independently, absent, H, halo, oxo, sulfido, CN, NO,, OH, Cig alkoxy, C4 haloalkoxy, amino, C14 alkylamino or Cag dialkylamino, C, 4 alkyl, C4 alkenyl, Cp alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said Cisalkyl, Cygalkenyl, Cp alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2 or 3 halo, C4 : alkyl, Cy alkenyl, Cy.6 alkynyl, C,, haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO, OR, SR*, C(O)R®, C(O)NR°RY, C(O)OR?, OC(O)R’, OC(O)NRR?, NR°R*, NRC(O)R, NR'C(O)OR, S(O)R®, S(O)NRR?, S(O),R®, or S(0),NR°RY; 251 AMENDED SHEET

PCT/US2005/015559 wherein two —W-X-Y-Z attached to the same atom optionally form a 3-14 membered cycloalkyl or heterocycloalkyl group optionally substituted by 1, 2 or 3 “WXYZ wherein two ~W’-X’-Y’-Z’ attached to the same atom optionally form a 3-14 membered cycloalkyl or heterocycloalkyl group optionally substituted by I,20r3 -W».X.¥.2; wherein ~W-X-Y-Z is other than H; wherein —W’-X’-Y’-Z’ is other than H; wherein ~W"-X"’-Y>>-Z"" is other than H; : Ris H, Cg alky!, C4 haloalkyl, Cy alkenyl, (C6 alkoxy)-C 6 alkyl, Cy alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl; R" is H, Cig alkyl, C,¢ haloalkyl, Cy alkenyl, Cy alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl; R® and R? are each, independently, H, C, 4 alkyl, C,.¢ haloalkyl, C,. alkenyl, Cy alkynyl, aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl; : or R® and R¢ together with the N atom to which they are attached form a 4-, 5-,6-or 7- membered heterocycloalkyl group; and R° and Rf are each, independently, H, C,¢ alkyl, C4 haloalkyl, Cs. alkenyl, C,.¢ alkynyl, aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl; or R® and R together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group, in the manufacture of a preparation for modulating activity of 11BHSDI or MR.

40. Use of claim 39 wherein said modulating is inhibiting,

41. A compound of any one of claims | to 32, substantially as herein described with reference to and as illustrated in any of the examples.

42. A method of claim 33 or claim 34, substantially as herein described with reference to and as illustrated in any of the examples.

43. Use of any one of claims 35 to 37 or 39 or 40, substantially as herein described with reference to and as illustrated in any of the examples.

44. A composition of claim 38, substantial ly as herein described with reference to and as illustrated in any of the examples. 252 AMENDED SHEET