WO2006053024A2 - Lactam compounds and their use as pharmaceuticals - Google Patents

Lactam compounds and their use as pharmaceuticals Download PDF

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Publication number
WO2006053024A2
WO2006053024A2 PCT/US2005/040550 US2005040550W WO2006053024A2 WO 2006053024 A2 WO2006053024 A2 WO 2006053024A2 US 2005040550 W US2005040550 W US 2005040550W WO 2006053024 A2 WO2006053024 A2 WO 2006053024A2
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Prior art keywords
diazaspiro
hydroxycyclohexyl
decan
trans
oxo
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PCT/US2005/040550
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French (fr)
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WO2006053024A3 (en
Inventor
Wenqing Yao
Chunhong He
Jincong Zhuo
Meizhong Xu
Colin Zhang
Ding-Quan Qian
David Burns
Brian W. Metcalf
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Incyte Corporation
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Priority to MX2007005527A priority Critical patent/MX2007005527A/en
Priority to EP05818772.5A priority patent/EP1812005B1/en
Application filed by Incyte Corporation filed Critical Incyte Corporation
Priority to AU2005304560A priority patent/AU2005304560C1/en
Priority to BRPI0518022-8A priority patent/BRPI0518022A/en
Priority to CA2585797A priority patent/CA2585797C/en
Priority to JP2007540189A priority patent/JP5202954B2/en
Priority to KR1020077012990A priority patent/KR101368228B1/en
Priority to NZ554906A priority patent/NZ554906A/en
Priority to ES05818772.5T priority patent/ES2547724T3/en
Priority to EA200701036A priority patent/EA019747B1/en
Publication of WO2006053024A2 publication Critical patent/WO2006053024A2/en
Priority to IL182876A priority patent/IL182876A/en
Priority to NO20072322A priority patent/NO340365B1/en
Priority to ZA2007/03754A priority patent/ZA200703754B/en
Publication of WO2006053024A3 publication Critical patent/WO2006053024A3/en
Priority to HK08100816.4A priority patent/HK1113305A1/en

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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Definitions

  • the present invention relates to modulators of 11- ⁇ hydroxyl steroid dehydrogenase type 1 (ll ⁇ HSDl) and/or mineralocorticoid receptor (MR), compositions thereof and methods of using the same.
  • ll ⁇ HSDl 11- ⁇ hydroxyl steroid dehydrogenase type 1
  • MR mineralocorticoid receptor
  • 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.
  • ACTH adrenocorticotrophic hormone
  • 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.
  • glucocorticoid receptor GR
  • mineralocorticoid receptor MR
  • Cortisol a member of the nuclear hormone receptor superfamily
  • GR glucocorticoid receptor
  • MR mineralocorticoid receptor
  • glucocorticoid action was 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.
  • tissue-specific pre-receptor metabolism by glucocorticoid-activating and -inactivating enzymes.
  • 11-beta-hydroxysteroid dehydrogenase (11- ⁇ -HSD) enzymes act as pre-receptor control enzymes that modulate activation of the GR and MR by regulation of glucocorticoid hormones.
  • l l ⁇ HSDl also known as 11-beta-HSD type 1, llbetaHSDl, HSDIlBl, HDL, and HSDI lL
  • l l ⁇ HSD2 catalyze the interconversion of hormonally active Cortisol (corticosterone in rodents) and inactive cortisone (11- dehydrocorticosterone in rodents).
  • l l ⁇ HSDl 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.
  • l l ⁇ HSDl catalyzes both 11-beta-dehydrogenation and the reverse 11-oxoreduction reaction, although l l ⁇ HSDl acts predominantly as a NADPH-dependent oxoreductase in intact cells and tissues, catalyzing the activation of Cortisol from inert cortisone (Low et al. (1994) J. MoI. Endocrin. 13: 167-174) and has been reported to regulate glucocorticoid access to the GR.
  • ll ⁇ HSD2 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) MoI. Cell. Endocrin. 105: RIl-Rl 7), 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. MoI. Biol. 75:173-216).
  • the MR binds Cortisol and aldosterone with equal affinity.
  • tissue specificity of aldosterone activity is conferred by the expression of l l ⁇ HSD2 (Funder et al. (1988), Science 242: 583-585).
  • the inactivation of Cortisol to cortisone by l l ⁇ HSD2 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.
  • sgk-1 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).
  • ACE angiotensin- converting enzyme
  • AZA angiotensin type 1 receptor
  • 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.
  • ll ⁇ HSD2 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).
  • ll ⁇ HSDl a primary regulator of tissue-specific glucocorticoid bioavailability
  • H6PD hexose 6-phosphate dehydrogenase
  • CRD cortisone reductase deficiency
  • cortisone metabolites tetrahydrocortisone
  • Cortisol metabolites tetrahydrocortisols
  • CRD patients 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).
  • PCOS polycystic ovary syndrome
  • l l ⁇ HSDl Given the ability of l l ⁇ HSDl to regenerate Cortisol from inert circulating cortisone, considerable attention has been given to its role in the amplification of glucocorticoid function.
  • l l ⁇ HSDl 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.
  • 1 l ⁇ HSDl 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. Metab. 88: 2738-2744; Wake et al. (2003) J. Clin. Endocrinol. Metab. 88: 3983-3988).
  • mice are completely devoid of 11-keto reductase activity, confirming that 1 l ⁇ HSDl encodes the only activity capable of generating active corticosterone from inert 11-dehydrocorticosterone.
  • 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 unproved lipid profile (decreased triglycerides and increased cardio-protective HDL). Additionally, these animals show resistance to high fat diet-induced obesity.
  • PEPCK hepatic gluconeogenic enzymes
  • G6P hepatic gluconeogenic enzymes
  • these animals show resistance to high fat diet-induced obesity.
  • 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.
  • ll ⁇ HSDl 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).
  • inhibition of 11 ⁇ HSD 1 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.
  • Glucocorticoids are known to inhibit the glucose-stimulated secretion of insulin from pancreatic beta-cells (Billaudel and Sutter (1979) Horm. Metab. Res. 11: 555-560). In both Cushing's syndrome and diabetic Zucker fa/ fa rats, glucose-stimulated insulin secretion is markedly reduced (Ogawa et al. (1992) J. Clin. Invest. 90: 497-504). 1 l ⁇ HSDl mKNA and activity has been reported in the pancreatic islet cells of ob/ob mice and inhibition of this activity with carbenoxolone, an 11 ⁇ HSD 1 inhibitor, improves glucose-stimulated insulin release (Davani et al. (2000) J. Biol. Chem. 275: 34841-34844). Thus, inhibition of ll ⁇ HSDl is predicted to have beneficial effects on the pancreas, including the enhancement of glucose-stimulated insulin release.
  • Mild cognitive impairment is a common feature of aging that may be ultimately related to the progression of dementia.
  • 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).
  • 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).
  • ll ⁇ HSDl 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). Treatnent of primary hippocampal cells with the l l ⁇ HSDl inhibitor carbenoxolone protects the cells from glucocorticoid-mediated exacerbation of excitatory amino acid neurotoxicity (Rajan et al. (1996) J. Neurosci. 16: 65-70). Additionally, l l ⁇ HSDl -deficient mice are protected from glucocorticoid-associated hippocampal dysfunction that is associated with aging (Yau et al.
  • 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).
  • IOP intra-ocular pressure
  • IOP intra-ocular pressure
  • Aqueous humour production occurs in the non-pigmented epithelial cells (NPE) and its drainage is through the cells of the trabecular meshwork.
  • NPE non-pigmented epithelial cells
  • l l ⁇ HSDl has been localized to NPE cells (Stokes et al. (2000) Invest. Ophthalmol. Vis.
  • 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-l l ⁇ HSDl 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.
  • renin- angiotensin system 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-ll ⁇ HSDl 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-l l ⁇ HSDl transgenic mice.
  • 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). l l ⁇ HSDl 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.
  • Small molecule inhibitors of l l ⁇ HSDl are currently being developed to treat or prevent l l ⁇ HSDl -related diseases such as those described above.
  • certain amide-based inhibitors are reported in WO 2004/089470, WO 2004/089896, WO 2004/056745, and WO 2004/065351.
  • Antagonists of 1 l ⁇ HSDl have been evaluated in human clinical trials (Kurukulasuriya , et al., (2003) Curr. Med. Chem. 10: 123-53).
  • l l ⁇ HSDl 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 1 l ⁇ HSDl are desirable.
  • the MR binds to aldosterone (its natural ligand) and Cortisol with equal affinities
  • compounds that are designed to interact with the active site of l l ⁇ HSDl which binds to cortisone/cortisol may also interact with the MR and act as antagonists.
  • 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.
  • 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.
  • the present invention provides, inter alia, compounds of Formula I:
  • compositions comprising compounds of the invention and a pharmaceutically acceptable carrier.
  • the present invention further provides methods of modulating 1 l ⁇ HSDl or MR by contacting 1 l ⁇ HSDl or MR with a compound of the invention.
  • the present invention further provides methods of inhibiting 1 l ⁇ HSDl or MR by contacting
  • the present invention further provides methods of inhibiting the conversion of cortisone to Cortisol in a cell by contacting the cell with a compound of the invention.
  • the present invention further provides methods of inhibiting the production of Cortisol in a cell by contacting the cell with a compound of the invention.
  • the present invention further provides methods of treating diseases assocated with activity or expression of 1 l ⁇ HDSl or MR.
  • the present invention further provides a compound or composition of the invention for use in therapy.
  • the present invention further provides a compound of the invention for use in the treatment of a disease associated with expression or activity of 1 l ⁇ HSDl or MR.
  • the present invention further provides a compound or composition for use in the preparation of a medicament for the treatment of a disease associated with expression or activity of 1 l ⁇ HSDl or MR.
  • the present invention provides, inter alia, compounds of Formula I:
  • Cy is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 -W-X-Y-Z;
  • L is (CR 12 R 13 V, (CR 12 R 13 ) ql O(CR 12 R 13 ) q2 , (CR 12 R 13 ) ql S(CR 12 R 13 ) q2 , (CR 12 R 13 ) ql SO 2 (CR 12 R 13 ) q2 , (CR 12 R 13 ) ql SO(CR 12 R 13 ) q2 , or (CR 12 R 13 ) ql CO(CR 12 R 13 ) q2 ;
  • A is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 -W'-X'-Y'-Z';
  • E is -(CR 3a R 3b ) n i-, -(CR 3a R 3b ) n2 CO-, -(CR 3a R 3b ) n2 OCO-, -(CR 33 R 3 ⁇ 112 SO-,
  • D 1 , D 2 , D 3 and D 4 are each N or CR 15 ;
  • R 1 and R 2 are each, independently, H or C 1-S alkyl
  • R 3a and R 3b are each, independently, H, OC(O)R a' , OC(O)OR b' , C(O)OR b' , OC(O)NR 0' R d' , NR c> R d' , NR c' C(O)R a' , NR° C(O)OR b' , S(O)R a> , S(O)NR° ' R d> , S(O) 2 R' ' , S(O) 2 NR c> R d' , OR b> , SR b> , halo, C 1-I o alkyl, C 1-I0 haloalkyl, C 2-I o alkenyl, C 2-I0 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each, independently, H, OC(O)R a> , OC(O)OR b> , C(O)OR b> , OC(O)NR c' R d' , NR 0> R d' , NR° ' C(O)R a' , NR c' C(O)OR b' , S(O)R 3' , S(O)NR° ' R d' , S(O) 2 R 3' , S(O) 2 NR°'R d> , OR b> , SR b> , halo, C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroary
  • R 12 and R 13 are each, independently, H, halo, Ci -4 alkyl, C 1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OR a> , SR a> , C(O)R b> , C(O)NRV, C(O)OR 3' , OC(O)R b' , OC(0)NR 0' R d' , NR c' R d' , NR 0' C(0)R d' , NR 0' C(0)OR a' , S(O)R b> , S(O)NRV, S(O) 2 R" ' , or S(O) 2 NR c' R d' ;
  • R 14 is halo, Cw alkyl, C 1 . 4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OR a' , SR a' , C(0)R b' , C(0)NR° ' R d> , C(O)OR 3' , OC(O)R b' , OC(O)NR c> R d' , NR° ' R d' , NR° ' C(0)R d' , NR c' C(O)OR a' , S(O)R b' , S(O)NR° ' R d> , S(O) 2 R b' , or S(O) 2 NR° ' R d' ;
  • R 15 is H, halo, C 1 . 4 alkyl, C 1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OR 3" , SR 3" , C(O)R b" , C(0)NR° “ R d” , C(O)OR 3" , OC(O)R b" , 0C(0)NR c" R d” , NR c" R d” , NR° “ C(0)R d” , NR c" C(0)0R 3" , S(O)R b” , S(O)NR 0 V, S(O) 2 R b" , or S(O) 2 NR 0 V;
  • R 16 is halo, C 1 . 4 alkyl, Ci -4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OR 3' , SR a> , C(O)R b' , C(O)NRV, C(O)OR 3' , OC(O)R b' , OC(O)NRV, NRV, NR° ' C(O)R d' , NR 0' C(O)OR 3' , S(O)R b> , S(O)NRV, S(O) 2 R b' , or S(O) 2 NRV;
  • W, W and W" are each, independently, absent, Ci -6 alkylenyl, C 2-6 alkenylenyl, C 2-6 alkynylenyl, O, S, NR e , CO, COO, C0NR e , SO
  • X, X' and X" are each, independently, absent, Ci-6 alkylenyl, C 2 - 6 alkenylenyl, C 2-6 alkynylenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said Ci -6 alkylenyl, C 2-6 alkenylenyl, C 2 -6 alkynylenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by one or more halo, oxo, CN, NO 2 , OH, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, Ci -4 alkylamino or C 2- s dialkylamino;
  • Z, Z' and Z" are each, independently, H, halo, CN, NO 2 , OH, C 1-4 alkoxy, Ci -4 haloalkoxy, amino, Ci -4 alkylamino, C 2-8 dialkylamino, Ci- ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2 or 3 halo, oxo, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ci -4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , 0R a , SR a ,
  • R a , R a and R a are each, independently, H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl; heterocycloalkyl, heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, Ci -6 alkyl, Ci -6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;
  • R b , R b and R b are each, independently, H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 haloalkyl, aryl, arylalky
  • 6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or R c and R d together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group;
  • R° and R d are each, independently, H, Ci -I0 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said Ci -I0 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 haloalkyl, aryl, arylalkyl,
  • R c and R d are each, independently, H, Ci -I0 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said Ci -I0 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 haloalkyl, aryl, arylalkyl
  • A when A is aryl optionally substituted with 1, 2, 3, 4 or 5 -W'-X'-Y'-
  • Z' or heteroaryl optionally substituted with 1, 2, 3, 4 or 5 -W'-X'-Y'-Z';
  • L is SO 2 , SO 2 CH 2 or CH 2 ; and
  • m is 0, then Cy is other than unsubstituted aryl, monosubstituted aryl, unsubstituted heteroaryl, or monosubstituted heteroaryl.
  • A is aryl optionally substituted with 1, 2, 3, 4 or 5 — W'-X'-Y'- Z' or heteroaryl optionally substituted with 1, 2, 3, 4 or 5 -W'-X'-Y'-Z';
  • L is SO 2 , SO 2 CH 2 or CH 2 ;
  • m is 0; and Cy is di-, tri-, terra- or penta-substituted aryl or di-, tri-, terra- or penta-substituted heteroaryl, then said di-, tri-, tetra- or penta-substituted aryl or di-, tri-, terra- or penta-substituted heteroaryl is substituted by at least one Q -6 alkyl and at least one halo.
  • A is aryl optionally substituted with 1, 2, 3, 4 or 5 — W'-X'-Y'- Z' or heteroaryl optionally substituted with 1, 2, 3, 4 or 5 -W'-X'-Y'-Z'; L is SO 2 , SO 2 CH 2 or CH 2 ; and m is 0, then Cy is other than 2-chloro-6-methyl-phenyl.
  • Cy is other than cyclohexyl or l,l-dioxo-tetrahydro-thien-3-yl.
  • Cy is aryl optionally substituted with 1, 2, 3, 4 or 5 -W-X-Y-Z or heteroaryl optionally substituted with 1, 2, 3, 4 or 5 -W-X-Y-Z;
  • L is SO 2 , SO 2 CH 2 or CH 2 ; and
  • m is 0, then A is other than tetrahydropyran-4-yl, 2,3-dihydroinden-2-yl or 2,2-difluoro-l,3- benzodioxol-5-yl.
  • Cy is aryl optionally substituted with 1, 2, 3, 4 or 5 -W-X-Y-Z or heteroaryl optionally substituted with 1, 2, 3, 4 or 5 -W-X-Y-Z;
  • L is SO 2 , SO 2 CH 2 or CH 2 ; and
  • m is 1, then A is other than pyridine-4-yl, phenyl, 2-chloro-6-fluoro-phenyl, 4-methoxyphenyl or 4- phenoxy-phenyl.
  • R 3a and R 3b are each, independently, H, halo, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, or C 2-4 alkynyl.
  • X, X' and X" are each, independently, absent, Ci -6 alkylenyl, C 2-6 alkenylenyl, C 2 . 6 alkynylenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said Ci -6 alkylenyl, C 2-6 alkenylenyl, C 2-6 alkynylenyl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by one or more halo, oxo, CN, NO 2 , OH, C 1-4 alkoxy, C 1 . 4 haloalkoxy, amino, C 1-4 alkylamino or C 2-8 dialkylamino.
  • Z, Z' and Z" are each, independently, H, halo, CN, NO 2 , OH, Ci -4 alkoxy, Cj -4 haloalkoxy, amino, Ci -4 alkylamino, C 2-8 dialkylamino, Ci -6 alkyl, C 2-6 alkenyl, C 2 .
  • Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2 or 3 halo, OXO, Ci-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OR a , SR 3 , C(O)R b , C(0)NR c R d , C(O)OR 3 , 0C(0)R b , OC(O)NR°R d , NR c R d , NR°C(O)R d , NR 0 C(O)OR 3 , S(O)R b
  • n 1 and R 4 and R 5 together with the carbon atom to which they are attached form a 3, 4, 5 or 6-membered heterocycloalkyl group, then m is other than 1.
  • Cy is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 -W-X-Y-Z.
  • Cy is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 -W-X-Y-Z wherein W is O or absent, X is absent, and Y is absent.
  • Cy is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, thiazolyl, pyrazinyl, purinyl, quinazolinyl, quinolinyl, isoquinolinyl, pyrrolo[2,3-d]pyrimidinyl, or 1,3-benzothiazolyl, each optionally substituted with 1, 2, 3, 4 or 5 -W-X-Y-Z.
  • Cy is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl or thienyl, each optionally substituted with 1, 2, 3, 4 or 5 -W-X-Y-Z.
  • Cy is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl thiazolyl, pyrazinyl, purinyl, quinazolinyl, quinolinyl, isoquinolinyl, pyrrolo[2,3-d]pyrimidinyl, or 1,3-benzothiazolyl, each optionally substituted with 1, 2, 3 or 4 halo, CN, NO 2 , C 1 .
  • Cy is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl thienyl, thiazolyl, pyrazinyl, purinyl, quinazolinyl, quinolinyl, isoquinolinyl, pyrrolo[2,3-d]pyrimidinyl, or 1,3-benzothiazolyl, each optionally substituted with 1, 2, 3 or 4 substituents independently selected form: halo, CN, NO 2 , C 1-4 alkoxy, pyridin-2-yloxy, pyridin-3-yloxy, pyridin-4-yloxy, C 2-6 alkynyl, C 1-4 haloalkoxy, NR°C(0)R d , NR 0 C(O)OR 3 , C(0)NR°R d , NR°R d , NR e S(O) 2 R b , C 1-4
  • Cy is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl or thienyl, each optionally substituted with 1, 2, or 3 halo, CN, Ci -4 alkoxy, C 1-4 haloalkoxy, Ci -6 alkyl or aryl, wherein said Ci -6 alkyl or aryl is optionally substituted by 1, 2 or 3 halo, Ci -6 alkyl, C 1-4 haloalkyl, CN, NO 2 , OR 3 , or SR 3 .
  • Cy is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl or thienyl, each optionally substituted with 1, 2, or 3 halo, CN, Ci -4 alkoxy, C 1-4 haloalkoxy, Ci -6 alkyl or aryl, wherein said Q -6 alkyl or aryl is optionally substituted by 1, 2 or 3 halo or Ci -6 alkyl.
  • Cy is phenyl, pyridyl, pyrimidinyl, quinolinyl, or isoquinolinyl, each optionally substituted with 1 , 2, 3, 4 or 5 -W-X-Y-Z.
  • Cy is phenyl, pyridyl, pyrimidinyl, quinolinyl, or isoquinolinyl, each optionally substituted with 1, 2, or 3 halo, CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci. 6 alkoxy, , -NR 6 C(O)O-Z, -C(O)O-Z, or NR e C(O)-Z.
  • Cy is cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 -W-X-Y-Z.
  • Cy is piperidinyl, pyrrolindinyl, 1, 2, 3,6-tetrahydropyridinyl, 2-oxo- [l,3]oxazinanyl, or piperizinyl, each optionally substituted with 1, 2, 3, 4 or 5 -W-X-Y-Z.
  • Cy is piperidinyl, pyrrolindinyl, 1,2,3,6-tetrahydropyridinyl, or piperizinyl, each optionally substituted with 1, 2, 3, 4 or 5 -W-X-Y-Z. In some embodiments, Cy is piperidinyl, pyrrolindinyl, 1, 2, 3, 6-tetrahydropyridinyl, 2-oxo-
  • Cy is piperidinyl, pyrrolindinyl, 1, 2, 3, 6-tetrahydropyridinyl, 2-oxo- [l,3]oxazinanyl, or piperizinyl, each optionally substituted with 1, 2, or 3 phenyl, pyridyl or quinolinyl, wherein each of said phenyl, pyridyl, quinolinyl is optionally substituted by 1, 2 or 3 halo, CN, C 1 - 4 alkyl, phenyl, CM alkoxy, or Ci -4 haloalkyl.
  • Cy is piperidinyl, pyrrolindinyl, 1,2,3,6-tetrahydropyridinyl, or piperizinyl, each optionally substituted with 1, 2, or 3 aryl, wherein said aryl is optionally substituted by 1, 2 or 3 halo or Ci -4 haloalkyl.
  • L is (CR 12 R 13 ) q iS(CR 12 R 13 ) q2 , (CR 12 R 13 ) q iSO 2 (CR 12 R 13 ) q2 , or (CR 12 R 13 ) ql SO(CR 12 R 13 ) q2 .
  • L is (CR 12 R 13 ) q iSO 2 (CR 12 R 13 ) q2 .
  • L is S, SO or SO 2 . In some embodiments, L is SO 2 .
  • L is CO
  • L is (CR 12 R 13 ) q i.
  • L is (CR 12 R 13 ) q i and ql is O.
  • Q is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 -W'-X'-Y'-Z'.
  • Q is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 halo, C M alkyl, CN, NR°C(O)R d or NR e S(O) 2 R b .
  • Q is phenyl, pyridyl or quinolinyl, each optionally substituted with 1 or 2 halo, C M alkyl, CN, NR c C(O)R d or NR e S(O) 2 R b .
  • Q is cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 -W'-X'-Y'-Z'. In some embodiments, Q is cycloalkyl or heterocycloalkyl, each optionally substituted with 1 or 2 -W'-X'-Y'-Z'.
  • Q is cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 OH, Q -4 alkoxy, CN, C L4 alkyl, -O-heteroaryl, -(d. 4 alkyl)-CN, COOR a , C(O)NR c R d or NR 0 C(O)OR 3 .
  • Q is cyclopropyl, cyclohexyl, cycloheptyl, adamantyl, tetrahydro-2H- pyranyl or piperidinyl, each optionally substituted with 1 OH, C 1-4 alkoxy, CN, Ci -4 alkyl, -O-heteroaryl, -(Ci -4 alkyl)-CN, COOR a , C(0)NR c R d or NR c C(O)OR a .
  • Q is cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 OH, halo, CN, Ci -4 alkyl, C 1-4 alkoxy, NR 6 COO(Ci -4 alkyl), NR e CO(C M alkyl), aryl, heteroaryl, -O-aryl, -O-heteroaryl, or -(Ci -4 alkyl)-OH.
  • Q is cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 OH, CN, -O-heteroaryl, or C(O)O-Z'.
  • Q is cycloalkyl or heterocycloalkyl, each substituted with at least two -W'-X'-Y'-Z', wherein two of said at least two -W'-X'-Y'-Z' are attached to the same atom and together with the atom to which they are attached form a 3-20 membered cycloalkyl or heterocyloalkyl group, each optionally substituted by 1, 2 or 3 -W"-X"-Y"-Z".
  • Q is phenyl, pyridyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, indanyl, or 1,2,3,4-tetrahydronaphthalene, each optionally substituted with 1, 2, 3, 4 or 5 -W'-X'-Y'-Z'.
  • Q is phenyl, pyridyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl, each optionally substituted with 1, 2, 3, 4 or 5 OH, CN, halo, Ci. 6 alkyl, - O-heteroaryl, or C(O)O-Z'.
  • Q is cyclohexyl substituted at the 4-position with at least one -W'-X'- Y'-Z'. In some embodiments, Q is cyclohexyl substituted at the 4-position with at least one OH, CN, or -O-X'-Y'-Z'.
  • Q is -(CR 1 R 2 ),, ! - A and m is 1, 2 or 3.
  • Q is -(CR 1 R 2 ) m -A and m is 2.
  • A is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 — W'-X'-Y'-Z'.
  • A is aryl optionally substituted with 1, 2, 3, 4 or 5 -W'-X'-Y'-Z'.
  • A is hteroaryl optionally substituted with 1, 2, 3, 4 or 5 -W'-X'-Y'-Z'. In some embodiments, A is cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 -W'-X'-Y'-Z ⁇
  • A is cycloalkyl or heterocycloalkyl, each optionally substituted with 1 or 2 -W-X'-Y'-Z'. In some embodiments, A is cycloalkyl optionally substituted with 1, 2, 3, 4 or 5 -W'-X'-Y'--
  • A is cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 OH, halo, CN, C 1-4 alkyl, C 1-4 alkoxy, NR 6 COO(C 1-4 alkyl), NR 6 CO(Ci -4 alkyl), aryl, heteroaryl, -O-aryl, -O-heteroaryl, or -(C 1-4 alkyl)-OH.
  • A is cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl, each optionally substituted with 1, 2, 3, 4 or 5 OH, CN, halo, Ci -6 alkyl, -O-heteroaryl, or C(O)O-Z'.
  • A is cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl, each optionally substituted with 1, 2, 3, 4 or 5 OH, CN, halo, Ci -6 alkyl, -O-heteroaryl, or C(O)O-(C 1 . 4 alkyl).
  • A is cycloalkyl or heterocycloalkyl, each optionally substituted with 1,
  • A is cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 OH, CN, -O-heteroaryl, or C(O)O-(Ci -4 alkyl).
  • A is cycloalkyl or heterocycloalkyl, each substituted with at least two -W'-X'-Y'-Z', wherein two of said at least two -W'-X'-Y'-Z' are attached to the same atom and together with the atom to which they are attached form a 3-20 membered cycloalkyl or heterocyloalkyl group, each optionally substituted by 1, 2 or 3 -W"-X"-Y"-Z".
  • A is phenyl, pyridyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, indanyl, or 1,2,3,4-tetrahydronaphthalene, each optionally substituted with 1, 2, 3, 4 or 5 -W'-X'-Y'-Z'.
  • A is phenyl, pyridyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl, each optionally substituted with 1, 2, 3, 4 or 5 OH, CN, halo, Q -6 alkyl, -O-heteroaryl, or C(O)O-Z'.
  • A is phenyl, pyridyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl, each optionally substituted with 1, 2, 3, 4 or 5 OH, CN, halo, Ci -6 alkyl, -O-heteroaryl, or C(O)O-(Ci -4 alkyl).
  • A is cyclohexyl substituted at the 4-position with at least one -W'-X'- Y'-Z'.
  • A is cyclohexyl substituted at the 4-position with at least one OH, CN, or -O-X'-Y'-Z'.
  • E is methylene, ethylene, or propylene.
  • E is ethylene. In some embodiments, E is -(CR 3a R 3b ) n3 CONR 3c - or -(CR 3a R 3b ) n2 NR 3o CO-. In some embodiments, E is -CONR 30 -.
  • E is -CONR 30 -, wherein R 3o is H, Ci -4 alkyl, or CO-(Ci -4 alkyl). In some embodiments, E is -CONH-. In some embodiments, E is a group of formula:
  • D 1 , D 2 , D 3 and D 4 are each CR 15 .
  • one or two of D 1 , D 2 , D 3 and D 4 is N.
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each, independently, H, OC(O)R 3' , OC(O)OR b' , C(O)OR b' , OC(O)NR 0 R" ' , NR 0 R d' , NR 0' C(O)R 3' , NR° ' C(O)OR b> , S(O)R 3' ,
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each, independently, H, C 1-10 alkyl or Ci -I0 haloalkyl.
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each H.
  • R 3a and R 3b are each H.
  • r is 1.
  • r is O. In some embodiments, the sum of ql and q2 is O, 1 or 2.
  • the sum of ql and q2 is 0.
  • R 12 and R 13 are each H.
  • At least one of R 1 and R 2 is C 1 . 4 alkyl.
  • n is 0. In some embodiments, m is 1 or 2.
  • nl is 1.
  • nl is 2.
  • n2 is 0.
  • n2 is 1. In some embodiments, n3 is 0.
  • n3 is 1, 2, 3 or 4;
  • p is 0.
  • each -W-X-Y-Z is, independently, -NR 6 C(O)O-Z, -C(O)O-Z, -NR 6 C(O)-Z, -CO-Z, -SO-Z, -SO 2 -Z, -SONR e -Z, -NR e CONR f -Z, halo, CN, NO 2 , OH, d -4 alkoxy, Ci -4 haloalkoxy, amino, Ci -4 alkylamino, C 2-S dialkylamino, Q -6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted
  • each -W-X-Y-Z is, independently, -NHC(O)O-Ci -4 alkyl, -NHC(O)O-Ci -4 alkynyl, -C(O)O-Cj -4 alkyl, -NHC(O)-Ci -4 alkyl, -NHC(O)-C 3-9 cycloalkyl, halo, CN, NO 2 , OH, Ci -4 alkoxy, Ci -4 haloalkoxy, amino, Ci -4 alkylamino, C 2-8 dialkylamino, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said Ci -6 alkyl, C 2-6 alkenyl, C 2 .
  • 6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2 or 3 halo, oxo, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ci -4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , 0R a , SR 3 , C(0)R b , C(0)NR c R d , C(O)OR 3 , 0C(0)R b , 0C(0)NR°R d , NR°R d , NR°C(0)R d , NR 0 C(O)OR 3 , S(O)R b , S(0)NR°R d , S(O) 2 R b , or S(0) 2 NR°R d .
  • each -W-X-Y-Z is, independently, halo, CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, -NR 0 C(O)O-Z, -C(O)O-Z, -NR 6 C(O)-Z or aryl, wherein said aryl is optionally substituted by 1, 2 or 3 halo or Ci -4 haloalkyl.
  • each -W-X-Y-Z is, independently, halo, CN, Ci -4 alkyl, Ci -4 haloalkyl,
  • Ci -4 alkoxy -NHC(O)O-(Ci -4 alkyl), -NHC(O)O-(Ci -4 alkynyl), -C(O)O-(Ci -4 alkyl), -NHC(O)-(Ci -4 alkyl), -NHC(O)-(C 3-9 cycloalkyl) or phenyl, wherein said phenyl is optionally substituted by 1, 2 or 3 halo or Ci. 4 haloalkyl.
  • each -W-X-Y-Z is, independently, halo, CN, NO 2 , Ci -4 alkoxy, heteroaryloxy, C 2-6 alkynyl, C 1-4 haloalkoxy, NR c C(0)R d , NR 0 C(O)OR 3 , C(0)NR°R d , NR°R d , NR 6 S(O) 2 R b , Ci -4 haloalkyl, Ci -6 alkyl, heterocycloalkyl, aryl or heteraryl, wherein each of said Ci -6 alkyl, aryl or heteraryl is optionally substituted by 1, 2 or 3 halo, Ci -6 alkyl, C ⁇ 4 haloalkyl, CN, NO 2 , OR 3 , SR 3 , C(O)NR 0 R 1 , NR°C(0)R d or COOR 3 .
  • each -W-X-Y-Z is, independently, halo, CN, NO 2 , Ci -4 alkoxy, pyridin-2-yloxy, pyridin-3-yloxy, pyridin-4-yloxy, C 2-6 alkynyl, Ci -4 haloalkoxy, NR°C(0)R d , NR 0 C(O)OR 3 , C(O)NR°R d , NR°R d , NR e S(O) 2 R b , Ci -4 haloalkyl, d.
  • each -W-X-Y-Z is, independently, aryl or heteroayl, wherein each of said aryl or heteroaryl is optionally substituted by 1, 2 or 3 halo, CN, Ci -4 alkyl, phenyl, pyridyl, Q -4 alkoxy, or Q -4 haloalkyl.
  • each -W-X-Y-Z is, independently, phenyl, pyridyl or quinolinyl, wherein each of said phenyl, pyridyl, quinolinyl is optionally substituted by 1, 2 or 3 halo, CN, C 1 . 4 alkyl, phenyl, C 1 ⁇ alkoxy, or Ci -4 haloalkyl.
  • each -W'-X'-Y'-Z' is, independently, OH, CN, halo, Ci -6 alkyl, Ci -6 haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -OZ', -C(O)-Z' or -C(O)O-Z', wherein said Ci -6 alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl are each optionally substituted by 1, 2 or 3 halo, 0x0, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ci -4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , 0R a , SR 3 , C(O)R b , C(0)NR°R d , C(0)0R a , 0C
  • each -W'-X'-Y'-Z' is, independently, OH, Ci -4 alkoxy, CN, Ci -4 alkyl, -O-heteroaryl, -(Ci -4 alkyl)-CN, C00R a , C(O)NR°R d or NR°C(0)0R a .
  • each -W'-X'-Y'-Z' is, independently, halo, Ci -4 alkyl, CN,
  • each -W'-X'-Y'-Z' is, independently, OH, CN, halo, Ci -6 alkyl, -O- heteroaryl, or C(O)O-Z'.
  • each -W'-X'-Y'-Z' is, independently, OH, CN, halo, Ci -6 alkyl, -O- heteroaryl, or -C(O)O-Ci -4 alkyl.
  • each -W"-X"-Y"-Z" is halo, CN, NO 2 , OH, C 1-4 alkoxy, Ci -4 haloalkoxy, amino, Ci -4 alkylamino, C 2-8 dialkylamino, NR e S(O) 2 R b , Ci -6 alkyl, C 2 .
  • Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl wherein said Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2 or 3 halo, 0x0, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ci -4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , 0R a , SR a , C(0)R b , C(0)NR°R d , C(0)0R a , 0C(0)R b , OC(O)NR 0 R 1 , NR°R d , NR°C(0)R d , NR
  • each -W"-X"-Y"-Z" is halo, CN, NO 2 , OH, Ci 4 alkoxy, Ci -4 haloalkoxy, amino, Ci -4 alkylamino, C 2-8 dialkylamino, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2 or 3 halo, oxo, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ci -4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , 0R a , SR
  • each -W"-X"-Y"-Z" is halo, CN, NO 2 , OH, C M alkoxy, Ci -4 haloalkoxy, amino, Ci -4 alkylamino, C 2-8 dialkylamino, Ci -6 alkyl, C 2-6 alkenyl, C 2 . 6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl.
  • compounds of the invention have Formula II:
  • compounds of the invention have Formula Ilia:
  • compounds of the invention have Formula IHb:
  • compounds of the invention have Formula IHc:
  • compounds of the invention have Formula IV:
  • compounds of the invention have Formula IVa:
  • compounds of the invention have Formula IVb:
  • compounds of the invention have Formula IVc:
  • compounds of the invention have Formula IV, Formula IVa, Formul IVb, or Formula IVc, wherein R 3c is H, C 1-4 alkyl, or CO-(Ci -4 alkyl). In some further embodiments, R 30 is H.
  • substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges.
  • C 1 ⁇ alkyl is specifically intended to individually disclose methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • 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.
  • 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.
  • n-membered where n is an integer typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n.
  • piperidinyl is an example of a 6-membered heterocycloalkyl ring
  • 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.
  • 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 (e.g., 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 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3 carbon atoms.
  • alkylenyl refers to a divalent alkyl linking group.
  • alkenyl refers to an alkyl group having one or more double carbon-carbon bonds.
  • Example alkenyl groups include ethenyl, propenyl, cyclohexenyl, and the like.
  • alkenylenyl refers to a divalent linking alkenyl group.
  • alkynyl refers to an alkyl group having one or more triple carbon-carbon bonds.
  • Example alkynyl groups include ethynyl, propynyl, and the like.
  • alkynylenyl refers to a divalent linking alkynyl group.
  • haloalkyl refers to an alkyl group having one or more halogen substituents.
  • Example haloalkyl groups include CF 3 , C 2 F 5 , CHF 2 , CCl 3 , CHCl 2 , C 2 Cl 5 , and the like.
  • 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.
  • cycloalkyl refers to non-aromatic cyclic hydrocarbons including cyclized alkyl, alkenyl, and alkynyl groups. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groups.
  • Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by oxo or sulfido.
  • Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohep ⁇ yl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like.
  • cycloalkyl moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of pentane, pentene, hexane, and the like.
  • heteroaryl refers 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.
  • heteroaryl groups include without limitation, pyridyl, 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.
  • 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, 4 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.
  • heterocycloalkyl refers to non-aromatic heterocycles including cyclized alkyl, alkenyl, and alkynyl groups where one or more of the ring-forming carbon atoms is replaced by a heteroatom such as an O, N, or S atom.
  • Heterocycloalkyl groups include monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) systems.
  • 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, and the like.
  • Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by oxo or sulfido.
  • 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.
  • the heterocycloalkyl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms.
  • the heterocycloalkyl group contains 3 to about 14, 4 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments, the heterocycloalkyl group contains 0 to 3 double or triple bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double or triple bonds.
  • halo or “halogen” includes fluoro, chloro, bromo, and iodo.
  • 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.
  • haloalkoxy refers to an -O-haloalkyl group.
  • An example haloalkoxy group is OCF 3 .
  • heteroaryloxy refers to -O-heteroaryl.
  • An example heteroaryloxy is pyridine-2-yloxy [i.e., -O-(pyridine-2-yl)].
  • arylalkyl refers to alkyl substituted by aryl and "cycloalkylalkyl” refers to alkyl substituted by cycloalkyl.
  • An example arylalkyl group is benzyl.
  • amino refers to NH 2 .
  • alkylamino refers to an amino group substituted by an alkyl group.
  • 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).
  • 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 camphqrsulfonic acids such as ⁇ -camphorsulfonic acid.
  • resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of ⁇ - 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).
  • 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 further include hydrates and solvates, as well as anyhydrous and non-solvated forms.
  • 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.
  • phrases "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.
  • 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.
  • 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.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p.
  • 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
  • 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.
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C) infrared spectroscopy, spectrophotometry (e.g.,
  • 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.
  • 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.
  • suitable solvents for a particular reaction step can be selected.
  • the compounds of the invention can be prepared, for example, using the reaction pathways and techniques described below.
  • Reagents of formula 1-1 (X is a leaving group such as halo) can be reacted with an amines of formula
  • a series of spirocyclyl amines of formula 2-8 can be prepared according to the procedure outlined in Scheme 2.
  • N-protected 2-1 (Pr is an amino protecting group such as Boc) can be treated with a base such as LDA at low temperature in a solvent such as tetrahydrofuran followed by addition of l-bromo-3-methyl-2-butene (2-2).
  • the resulting intermediate (2-3) can be treated with ozone and then reduced with methyl sulfide to provide the aldehyde 2-4.
  • Reductive amination of 2-4 with amines 2-5 can be conducted in a solvent such as methanol and using a reducing agent such as sodium triacetoxyborohydride, and the product 2-6 can be cyclized in the presence of a base such as isopropylmagnesium bromide to provide the lactam 2-7 which upon acidic cleavage of the Boc group yields the desired amine 2-8.
  • a solvent such as methanol
  • a reducing agent such as sodium triacetoxyborohydride
  • a series of amines of formula 3-7 can be prepared according to the procedure outlined in Scheme 3.
  • Treatment of Boc protected nipecotic ethyl ester 3-1 with a base such as LDA at low temperature in a solvent such as tetrahydrofuran followed by addition of l-bromo-3-methyl-2- butene can result in an intermediate 3-2, which can be treated with ozone followed by reduction with methyl sulfide to provide the aldehyde 3-3.
  • Reductive animation of 3-3 with amines 3-4 can be conducted in a solvent such as methanol and using a reducing agent such as sodium triacetoxyborohydride.
  • a solvent such as methanol
  • a reducing agent such as sodium triacetoxyborohydride.
  • the resulting intermediate 3-5 can be cyclized in the presence of a base such as isopropylmagnesium bromide to provide the lactam 3-6 which upon acidic cleavage of the Boc group yields the desired piperidine 3-7.
  • a series of piperdines of 4-4 can be prepared by the method outlined in Scheme 4.
  • Compound 4-1 can be readily converted to the spirohydantoin 4-2 under Bucherer-Bergs conditions, using, e.g., ammonium carbonate and either sodium cyanide or potassium cyanide in aqueous ethanol.
  • piperdines 6-6 can also be prepared by the method outlined in Scheme 6.
  • the protected amino acid 6-1 can be coupled with an amine Q-NH 2 using a coupling agent such as BOP to provide compound 6-2 which, in turn, can be hydrogenated at the presence of Pd catalyst to yield compound 6-3.
  • Compound 6-3 can be treated with methyl chloroformate and a base such as triethyl amine in CH 2 Cl 2 to complete the ring closure and form hydantoin 6-4.
  • N alkylation with R 30 X (X is a leaving group such as halo) can yield compounds of formula 6-5 and acid cleavage can yield compounds of formula 6-6.
  • Compounds of the invention can modulate activity of l l ⁇ HSDl and/or MR.
  • modulate is meant to refer to an ability to increase or decrease activity of an enzyme or receptor. Accordingly, compounds of the invention can be used in methods of modulating l l ⁇ HSDl and/or MR by contacting the enzyme or receptor with any one or more of the compounds or compositions described herein. In some embodiments, compounds of the present invention can act as inhibitors of l l ⁇ HSDl and/or MR. In further embodiments, the compounds of the invention can be used to modulate activity of l l ⁇ HSDl and/or MR in an individual in need of modulation of the enzyme or receptor by administering a modulating amount of a compound of the invention.
  • the present invention further provides methods of inhibiting the conversion of cortisone to Cortisol in a cell, or inhibiting the production of Cortisol in a cell, where conversion to or production of Cortisol is mediated, at least in part, by ll ⁇ HSDl activity.
  • Methods of measuring conversion rates of cortisone to Cortisol and vice versa, as well as methods for measuring levels of cortisone and Cortisol in cells, are routine in the art.
  • the present invention further provides methods of increasing insulin sensitivity of a cell by contacting the cell with a compound of the invention. Methods of measuring insulin sensitivity are routine in the art.
  • the present invention further provides methods of treating disease associated with activity or expression, including abnormal activity and overexpression, of ll ⁇ HSDl and/or MR in an individual (e.g., patient) by administering to the individual in need of such treatment a therapeutically effective amount or dose of a compound of the present invention or a pharmaceutical composition thereof.
  • Example diseases can include any disease, disorder or condition that is directly or indirectly linked to expression or activity of the enzyme or receptor.
  • An l l ⁇ HSDl -associated disease can also include any disease, disorder or condition that can be prevented, ameliorated, or cured by modulating enzyme activity.
  • l l ⁇ HSDl -associated diseases include obesity, diabetes, glucose intolerance, insulin resistance, hyperglycemia, hypertension, hyperlipidemia, cognitive impairment, dementia, depression (e.g., psychotic depression), glaucoma, cardiovascular disorders, osteoporosis, and inflammation.
  • 1 l ⁇ HSDl -associated diseases include metabolic syndrome, type 2 diabetes, androgen excess (hirsutism, menstrual irregularity, hyperandrogenism) and polycystic ovary syndrome (PCOS).
  • the present invention further provides methods of modulating MR activity by contacting the
  • MR with a compound of the invention, pharmaceutically acceptable salt, prodrug, or composition thereof.
  • the modulation can be inhibition.
  • methods of inhibiting aldosterone binding to the MR are provided. Methods of measuring MR activity and inhibition of aldosterone binding are routine in the art.
  • the present invention further provides methods of treating a disease associated with activity or expression of the MR.
  • diseases associated with activity or expression of the MR include, but are not limited to hypertension, as well as cardiovascular, renal, and inflammatory pathologies such as heart failure, atherosclerosis, arteriosclerosis, coronary artery disease, thrombosis, angina, peripheral vascular disease, vascular wall damage, stroke, dyslipidemia, hyperlipoproteinaemia, diabetic dyslipidemia, mixed dyslipidemia, hypercholesterolemia, hypertriglyceridemia, and those associated with type 1 diabetes, type 2 diabetes, obesity metabolic syndrome, insulin resistance and general aldosterone-related target organ damage.
  • pathologies such as heart failure, atherosclerosis, arteriosclerosis, coronary artery disease, thrombosis, angina, peripheral vascular disease, vascular wall damage, stroke, dyslipidemia, hyperlipoproteinaemia, diabetic dyslipidemia, mixed dyslipidemia, hypercholesterolemia, hypertriglyceridemia, and those associated with type 1 diabetes, type 2 diabetes, obesity metabolic syndrome, insulin resistance and general aldosterone-related target organ
  • an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal.
  • an in vitro cell can be a cell in a cell culture.
  • an in vivo cell is a cell living in an organism such as a mammal.
  • the cell is an adipocyte, a pancreatic cell, a hepatocyte, neuron, or cell comprising the eye.
  • contacting refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • "contacting" the l l ⁇ HSDl enzyme with a compound of the invention includes the administration of a compound of the present invention to an individual or patient, such as a human, having l l ⁇ HSDl, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing the l l ⁇ HSDl enzyme.
  • the term "individual” or “patient,” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • the phrase "therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease (non-limiting examples are preventing metabolic syndrome, hypertension, obesity, insulin resistance, hyperglycemia, hyperlipidemia, type 2 diabetes, androgen excess (hirsutism, menstrual irregularity, hyperandrogenism) and polycystic ovary syndrome (PCOS);
  • preventing the disease for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease (non-limiting examples are preventing metabolic syndrome, hyper
  • inhibiting the disease for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology) such as inhibiting the development of metabolic syndrome, hypertension, obesity, insulin resistance, hyperglycemia, hyperlipidemia, type 2 diabetes, androgen excess (hirsutism, menstrual irregularity, hyperandrogenism) or polycystic ovary syndrome (PCOS), stabilizing viral load in the case of a viral infection; and
  • ameliorating the disease for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of metabolic syndrome, hypertension, obesity, insulin resistance, hyperglycemia, hyperlipidemia, type 2 diabetes, androgen excess (hirsutism, menstrual irregularity, hyperandrogenism) and polycystic ovary syndrome (PCOS), or lowering viral load in the case of a viral infection.
  • ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder i.e., reversing the pathology and/or symptomatology
  • reversing the pathology and/or symptomatology such as decreasing the severity of metabolic syndrome, hypertension, obesity, insulin resistance, hyperglycemia, hyperlipidemia, type 2 diabetes, androgen excess (hirsu
  • the compounds of Formula I can be administered in the form of pharmaceutical compositions.
  • These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), ocular, oral or parenteral.
  • topical including ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery
  • pulmonary e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal
  • ocular oral or parenteral.
  • Methods for ocular delivery can include topical administration (eye drops), subconjunctival, periocular or intravitreal injection or introduction by balloon catheter or ophthalmic inserts surgically placed in the conjunctival sac.
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration.
  • Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump.
  • Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointnents, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
  • compositions which contain, as the active ingredient, one or more of the compounds of the invention above in combination with one or more pharmaceutically acceptable carriers.
  • the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10 % by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • the compositions can be formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount.
  • the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.
  • the tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions in can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.
  • compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like.
  • compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
  • the pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.
  • the therapeutic dosage of the compounds of the present invention can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician.
  • the proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration.
  • the compounds of the invention can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w/v of the compound for parenteral adminstration. Some typical dose ranges are from about 1 ⁇ g/kg to about 1 g/kg of body weight per day.
  • the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day.
  • the dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • the compounds of the invention can also be formulated in combination with one or more additional active ingredients which can include any pharmaceutical agent such as anti-viral agents, antibodies, immune suppressants, anti-inflammatory agents and the like.
  • Labeled Compounds and Assay Methods Another aspect of the present invention relates to labeled compounds of the invention (radio ⁇ labeled, fluorescent-labeled, etc.) that would be useful not only in radio-imaging but also in assays, both in vitro and in vivo, for localizing and quantitating the enzyme in tissue samples, including human, and for identifying ligands by inhibition binding of a labeled compound. Accordingly, the present invention includes enzyme assays that contain such labeled compounds. The present invention further includes isotopically-labeled compounds of the invention. An
  • isotopically or “radio-labeled” compound is a compound of the invention where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring).
  • Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to 2 H (also written as D for deuterium), 3 H (also written as T for tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 35 S 5 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I and 131 I.
  • radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound. For example, for in vitro receptor labeling and competition assays, compounds that incorporate 3 H, 14 C, 82 Br, 125 1 , 131 1, 35 S or will generally be most useful. For radio- imaging applications 11 C, 18 F, 125 1, 123 1, 124 1, 131 1, 75 Br, 76 Br or 77 Br will generally be most useful.
  • a "radio-labeled compound” is a compound that has incorporated at least one radionuclide.
  • the radionuclide is selected from the group consisting of 3 H, 14 C, 125 I 3 35 S and 82 Br.
  • the labeled compounds of the present invention contain a fluorescent lable.
  • a labeled compound of the invention can be used in a screening assay to identify/evaluate compounds.
  • a newly synthesized or identified compound i.e., test compound
  • a test compound which is labeled can be evaluated for its ability to bind a 1 l ⁇ HSDl or MR by monitering its concentration variation when contacting with the l l ⁇ HSDl or MR, through tracking the labeling.
  • a test compound (labeled) can be evaluated for its ability to reduce binding of another compound which is known to bind to ll ⁇ HSDl or MR (i.e., standard compound).
  • test compound to compete with the standard compound for binding to the ll ⁇ HSDl or MR directly correlates to its binding affinity.
  • the standard compound is labled and test compounds are unlabeled. Accordingly, the concentration of the labled standard compound is monitored in order to evaluate the competition between the standard compound and the test compound, and the relative binding affinity of the test compound is thus ascertained.
  • Kits The present invention also includes pharmaceutical kits useful, for example, in the treatment or prevention of l l ⁇ HSDl- or MR-associated diseases or disorders, obesity, diabetes and other diseases referred to herein which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention.
  • kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art.
  • Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.
  • zso-Propylmagnesium bromide (1.0 M in THF, 1.5 mL) was slowly added to a solution of 1- tert-bxxtyl 3-ethyl 3- ⁇ 2-[(cis-4-hydroxycyclohexyl)amino]ethyl ⁇ piperidine-l,3-dicarboxylate (0.15 g, 0.38 mmol) at 0 0 C and the mixture was stirred at this temperature for 1 h. The reaction was then poured to cold water and extracted with ethyl acetate, dried and concentrated to give the desired product (0.11 g , 85 %).
  • LC-MS 353.2 (M+H) + , 297.1 (M+H-56) + .
  • This compound was prepared by using procedures that were analogous to those described for the synthesis of example 1, steps 1-3, followed by the following reductive amination/cyclization and amine/ary 1 coupling procedure :
  • LCMS indicated that most of the desired product was oxidized to the ketone so the crude reaction mixture was cooled to -10 0 C and 1.0 M of L-selectride ® in tetrahydrofuran (0.2 mL) was added and the mixture was stirred for 20 min. LCMS indicated that the ketone was converted to the alcohol. The crude mixture was purified by prep.-HPLC. to afford 5.2 mg ofthe desired product. LC-MS: 397.2 (M+H) + .
  • Step 2 isopropyl ⁇ 4-[2-(trans-4-hydroxycyclohexyl)-l-oxo-2, 7-diazaspiro[4.5]dec-7- yljphenyl ⁇ carbamate
  • isopropyl chloroformate 11 mg, 0.000087 mol
  • triethylamine 20 ⁇ L
  • Lithium diisopropylamide (1.8 M in THF, 3.9 mL) was slowly added to a solution of 1-tert-butyl 3-ethyl piperidine-l,3-dicarboxylate (1.50 g, 0.00583 mol) in tetrahydrofuran (20 mL, 0.2 mol) at -78 °C and the mixture was stirred for about 1 hour during which the temperature was allowed to rise to about -50 "C. l-Bromo-2-chloro-ethane (0.75 mL, 0.0082 mol) was slowly added to the mixture and then the resulting mixture was allowed to warm to rt (room temperature).
  • Lithium hexamethyldisilazide (1.0 M in tetrahydrofuran, 2.5 mL) was slowly added to a solution of o-chloroaniline (0.14 g, 0.0011 mol) in tetrahydrofuran (4.0 mL, 0.049 mol) at -78 0 C and stirred for 30 min. To this mixture was added a solution of l-tert-butyl 3 -ethyl 3-(2-chloroethyl)piperidine-
  • the shorter retention time peak was designated as the S-enantiomer and the longer retention time peak was designated as the R-enantiomer (the R-enantiomer was found to be active).
  • Racemic 2-(tetrahydro-2H-pyran-4-yl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7- diazaspiro[4.5]decan-l-one (9.0 mg, 0.000023 mol, the racemic mixture was prepared by using procedures analogous to those described for the synthesis of example 93) was purified by chiral column to give the pure two enantiomers. The shorter retention time peak was designated as S- enantiomer and the longer retention time peak was designated as R-enantiomer. The R-enantiomer was fount to be active. LC-MS: 384.2 (M+H) + .
  • Methyl chloroformate (4.4 ⁇ L, 0.000057 mol) was added to a solution of (5R)-7-(5-aminopyridin- 2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-l-one (15.8 mg, 0.0000478 mol), N,N- diisopropylethylamine (27 ⁇ L, 0.00016 mol) and methylene chloride (1.0 mL, 0.016 mol); and the mixture was stirred for 1 h. The volatiles were removed in-vacuo and the crude product was purified by prep-HPLC. LC-MS: 389.2 (M+H) + .
  • Methyl chloroformate (4.4 ⁇ L, 0.000057 mol) was added to a solution of 2-piperidin-4-yl-7-[5- (trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-l-one (18.3 mg, 0.0000478 mol) and NN- diisopropylethylamine (27 ⁇ L, 0.00016 mol) in methylene chloride (1.0 mL, 0.016 mol); and the mixture was stirred for 0.5 h. The volatiles were removed in-vacuo and the product was purified by prep-HPLC. LC-MS: 441.2 (M+H) + .
  • Tritylamine 180 mg, 0.00068 mol was added to a solution of 1-tert-butyl 3-ethyl 3-(2- oxoethyl)piperidine-l,3-dicarboxylate (0.170 g, 0.000568 mol, this was prepared by using procedures analogous to that described for the synthesis of example 1, steps 1-2) in 1,2-dichloroethane (4.0 mL, 0.051 mol) and followed by sodium triacetoxyborohydride (0.36 g, 0.0017 mol) and the mixture was stirred overnight. The mixture was poured into pre-cooled water, and extracted with ethyl acetate. The organic layer was separated, dried (NaSO 4 ), and concentrated in-vacuo. The product was purified by CombiFlash eluting with hexane/EtOAc (max EtOAc 20%). LC-MS: 543.3 (M+H) + ; 243.2.
  • Trifluoroacetic acid (1.0 mL, 0.013 mol) was added to a solution of 1-tert-butyl 3-ethyl 3-[2- (tritylamino)ethyl]piperidine-l,3-dicarboxylate (0.10 g, 0.00018 mol) in methylene chloride (1.0 mL, 0.016 mol) and the mixture was stirred for 1 h at rt to remove the Boc and trityl groups.
  • Step 1 1-tert-butyl 3-ethyl 3- ⁇ 2-[(4-methylpyridin-3-yl)amino]ethyl ⁇ piperidine-l,3-dicarboxylate
  • this compound was prepared by using procedures analogous to those described in example 1, steps 1-5), 2,4-dichloroiodobenzene (22.7 mg, 0.0000831 mol), potassium carbonate (20.1 mg, 0.000145 mol), copper(I) iodide (0.6 mg, 0.000003 mol), and (lS,2S)-cyclohexane-l,2-diol (16.1 mg, 0.000138 mol) in tert-butyl alcohol (1.0 mL, 0.010 mol) was heated at 100 0 C for 18 h. The crude product was purified by prep-HPLC to afford the desired product. LC-MS: 377.1 (M+H) + .

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Abstract

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

Description

LACTAM COMPOUNDS AND THEIR USE AS PHARMACEUTICALS
FIELD OF THE INVENTION
The present invention relates to modulators of 11-β hydroxyl steroid dehydrogenase type 1 (llβHSDl) 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-β-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: l lβHSDl (also known as 11-beta-HSD type 1, llbetaHSDl, HSDIlBl, HDL, and HSDI lL) and l lβHSD2. l lβHSDl and llβHSD2 catalyze the interconversion of hormonally active Cortisol (corticosterone in rodents) and inactive cortisone (11- dehydrocorticosterone in rodents). l lβHSDl 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. l lβHSDl catalyzes both 11-beta-dehydrogenation and the reverse 11-oxoreduction reaction, although l lβHSDl acts predominantly as a NADPH-dependent oxoreductase in intact cells and tissues, catalyzing the activation of Cortisol from inert cortisone (Low et al. (1994) J. MoI. Endocrin. 13: 167-174) and has been reported to regulate glucocorticoid access to the GR. Conversely, llβHSD2 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) MoI. Cell. Endocrin. 105: RIl-Rl 7), 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. MoI. 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 l lβHSD2 (Funder et al. (1988), Science 242: 583-585). The inactivation of Cortisol to cortisone by l lβHSD2 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 (ATlR) are two strategies that directly impact the rennin-angiotensin-aldosterone system (RAAS). However, although ACE inhibition and ATlR antagonism initially reduce aldosterone concentrations, circulating 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, llβHSD2 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 l lβHSD2 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 llβHSDl, 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), 4th 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 l lβHSDl, 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 l lβHSDl to regenerate Cortisol from inert circulating cortisone, considerable attention has been given to its role in the amplification of glucocorticoid function. l lβHSDl 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 1 lβHSDl 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 l lβHSDl within adipose tissue, resulting in 'Cushing's disease of the omentum' (Bujalska et al. (1997) Lancet 349: 1210-1213). Indeed, 1 lβHSDl 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. 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 l lβHSDl 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 l lβHSDl in these mice (2-3 fold) is very similar to that observed in human obesity (Rask et al. (2001) J. Clin. Endocrinol. Metab. 86: 1418-1421). This suggests that local l lβHSDl -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 1 lβHSDl 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 l lβHSDl -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 1 lβHSDl encodes the only activity capable of generating active corticosterone from inert 11-dehydrocorticosterone. l lβHSDl- 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 unproved 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 l lβHSDl 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 l lβHSDl plays a role in the pathogenesis of central obesity and the appearance of the metabolic syndrome in humans. Increased expression of the l lβHSDl 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 l lβHSDl 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 l lβHSDl can ameliorate severe hyperglycemia in genetically diabetic obese mice. Thus, l lβHSDl 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 l lβHSDl 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, llβHSDl 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 11 βHSD 1 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. 11: 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). 1 lβHSDl mKNA and activity has been reported in the pancreatic islet cells of ob/ob mice and inhibition of this activity with carbenoxolone, an 11 βHSD 1 inhibitor, improves glucose-stimulated insulin release (Davani et al. (2000) J. Biol. Chem. 275: 34841-34844). Thus, inhibition of llβHSDl 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). llβHSDl 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). Treatnent of primary hippocampal cells with the l lβHSDl inhibitor carbenoxolone protects the cells from glucocorticoid-mediated exacerbation of excitatory amino acid neurotoxicity (Rajan et al. (1996) J. Neurosci. 16: 65-70). Additionally, l lβHSDl -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 l lβHSDl 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. l lβHSDl has been localized to NPE cells (Stokes et al. (2000) Invest. Ophthalmol. Vis. ScL 41: 1629-1683; Rauz et al. (2001) Invest. Ophthalmol. Vis. Sci. 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 l lβHSDl 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, IOP was reduced by 18%. Thus, inhibition of l lβHSDl 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-l lβHSDl 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-llβHSDl 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-l lβHSDl 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 llβHSDl activity. Thus, inhibition of 1 lβHSDl 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). l lβHSDl 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 l lβHSDl 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 l lβHSDl 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 l lβHSDl are currently being developed to treat or prevent l lβHSDl -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 1 lβHSDl 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 l lβHSDl 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 1 lβHSDl 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 l lβHSDl (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 l lβHSDl 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 Formula I:
Figure imgf000010_0001
I 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 lβHSDl or MR by contacting 1 lβHSDl or MR with a compound of the invention. The present invention further provides methods of inhibiting 1 lβHSDl or MR by contacting
1 lβHSDl or MR with a compound of the invention.
The present invention further provides methods of inhibiting the conversion of cortisone to Cortisol in a cell by contacting the cell with a compound of the invention.
The present invention further provides methods of inhibiting the production of Cortisol in a cell by contacting the cell with a compound of the invention.
The present invention further provides methods of treating diseases assocated with activity or expression of 1 lβHDSl or MR.
The present invention further provides a compound or composition of the invention for use in therapy. The present invention further provides a compound of the invention for use in the treatment of a disease associated with expression or activity of 1 lβHSDl or MR.
The present invention further provides a compound or composition for use in the preparation of a medicament for the treatment of a disease associated with expression or activity of 1 lβHSDl or MR. DETAILED DESCRIPTION
The present invention provides, inter alia, compounds of Formula I:
Figure imgf000011_0001
I or pharmaceutically acceptable salt or prodrug thereof, wherein:
Cy is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 -W-X-Y-Z;
L is (CR12R13V, (CR12R13)qlO(CR12R13)q2, (CR12R13)qlS(CR12R13)q2, (CR12R13)qlSO2(CR12R13)q2, (CR12R13)qlSO(CR12R13)q2, or (CR12R13)qlCO(CR12R13)q2;
Figure imgf000011_0002
A is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 -W'-X'-Y'-Z';
E is -(CR3aR3b)ni-, -(CR3aR3b)n2CO-, -(CR3aR3b)n2OCO-, -(CR33R3^112SO-,
-(CR3aR3b)n2SO2-, -(CR3aR3b)n2NR30-, -(CR3aR3b)n3CONR3c-, -(CR3aR3b)n2NR3oCO-, or a group of formula:
Figure imgf000011_0003
D1, D2, D3 and D4 are each N or CR15;
R1 and R2 are each, independently, H or C1-S alkyl;
R3a and R3b are each, independently, H, OC(O)Ra', OC(O)ORb', C(O)ORb', OC(O)NR0'Rd', NRc>Rd', NRc'C(O)Ra', NR° C(O)ORb', S(O)Ra>, S(O)NR°'Rd>, S(O)2R'', S(O)2NRc>Rd', ORb>, SRb>, halo, C1-Io alkyl, C1-I0 haloalkyl, C2-Io alkenyl, C2-I0 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C1- io alkyl, C1-10 haloalkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by R16; R3c is H, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, or CO-(C1-4 alkyl);
R4, R5, R6, R7, R8, R9, R10 and R11 are each, independently, H, OC(O)Ra>, OC(O)ORb>, C(O)ORb>, OC(O)NRc'Rd', NR0>Rd', NR°'C(O)Ra', NRc'C(O)ORb', S(O)R3', S(O)NR°'Rd', S(O)2R3', S(O)2NR°'Rd>, ORb>, SRb>, halo, C1-10 alkyl, C1-10 haloalkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C1-1O alkyl, Ci.iohaloalkyl, C2-1O alkenyl, C2-I0 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by R14; or R4 and R5 together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group which is optionally substituted by R14; or R6 and R7 together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group which is optionally substituted by R14; or R8 and R9 together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group which is optionally substituted by R14; or R10 and R11 together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group which is optionally substituted by R14; or R4 and R6 together with the carbon atom to which they are attached form a 3-7 membered fused cycloalkyl group or 3-7 membered fused heterocycloalkyl group which is optionally substituted by R14; or R6 and R8 together with the carbon atom to which they are attached form a 3-7 membered fused cycloalkyl group or 3-7 membered fused heterocycloalkyl group which is optionally substituted by R14; or R4 and R9 together form a Ci-3 alkylene bridge which is optionally substituted by R14; or R4 and R10 together form a Ci-3 alkylene bridge which is optionally substituted by R14; or R6 and R10 together form a Ci-3 alkylene bridge which is optionally substituted by R14; or R9 and R10 together form a Ci-3 alkylene bridge which is optionally substituted by R14;
R12 and R13 are each, independently, H, halo, Ci-4 alkyl, C1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa>, SRa>, C(O)Rb>, C(O)NRV, C(O)OR3', OC(O)Rb', OC(0)NR0'Rd', NRc'Rd', NR0'C(0)Rd', NR0'C(0)ORa', S(O)Rb>, S(O)NRV, S(O)2R"', or S(O)2NRc'Rd';
R14 is halo, Cw alkyl, C1.4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa', SRa', C(0)Rb', C(0)NR°'Rd>, C(O)OR3', OC(O)Rb', OC(O)NRc>Rd', NR°'Rd', NR°'C(0)Rd', NRc'C(O)ORa', S(O)Rb', S(O)NR°'Rd>, S(O)2Rb', or S(O)2NR°'Rd';
R15 is H, halo, C1.4 alkyl, C1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, OR3", SR3", C(O)Rb", C(0)NR°"Rd", C(O)OR3", OC(O)Rb", 0C(0)NRc"Rd", NRc"Rd", NR°"C(0)Rd", NRc"C(0)0R3", S(O)Rb", S(O)NR0V, S(O)2Rb", or S(O)2NR0V;
R16 is halo, C1.4 alkyl, Ci-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, OR3', SRa>, C(O)Rb', C(O)NRV, C(O)OR3', OC(O)Rb', OC(O)NRV, NRV, NR°'C(O)Rd', NR0' C(O)OR3', S(O)Rb>, S(O)NRV, S(O)2Rb', or S(O)2NRV; W, W and W" are each, independently, absent, Ci-6 alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl, O, S, NRe, CO, COO, C0NRe, SO, SO2, SONRe, or NReC0NRf, wherein said Cw alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl are each optionally substituted by 1, 2 or 3 halo, OH, Ci-4 alkoxy, C1.4 haloalkoxy, amino, Ci-4 alkylamino or C2-S dialkylamino;
X, X' and X" are each, independently, absent, Ci-6 alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said Ci-6 alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by one or more halo, oxo, CN, NO2, OH, C1-4 alkoxy, C1-4 haloalkoxy, amino, Ci-4 alkylamino or C2-s dialkylamino;
Y, Y' and Y" are each, independently, absent, Ci-6 alkylenyl, C2-6 alkenylenyl, C2.6 alkynylenyl, O, S, NRe, CO, COO, C0NRe, SO, SO2, SONRe, or NReCONRf, wherein said Ci-6 alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl are each optionally substituted by 1, 2 or 3 halo, OH, Ci-4 alkoxy, Ci-4 haloalkoxy, amino, Ci-4 alkylamino or C2-8 dialkylamino;
Z, Z' and Z" are each, independently, H, halo, CN, NO2, OH, C1-4 alkoxy, Ci-4 haloalkoxy, amino, Ci-4 alkylamino, C2-8 dialkylamino, Ci-β alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2 or 3 halo, oxo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, 0Ra, SRa, C(0)Rb, C(0)NR°Rd, C(O)OR3, OC(O)Rb, 0C(0)NR°Rd, NRcRd, NRcC(O)Rd, NR0C(O)OR3, NReS(0)2Rb, S(O)Rb, S(O)NR°Rd, S(O)2Rb, or S(O)2NR0Rd; wherein two -W-X-Y-Z attached to the same atom optionally form a 3-20 membered cycloalkyl or heterocyloalkyl group, each optionally substituted by 1, 2 or 3 -W"-X"-Y"-Z"; wherein two -W'-X'-Y'-Z' attached to the same atom optionally form a 3-20 membered cycloalkyl or heterocyloalkyl group, each optionally substituted by 1, 2 or 3 -W"-X"-Y"-Z"; 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;
Ra, Ra and Ra are each, independently, H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl; heterocycloalkyl, heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, Ci-6 alkyl, Ci-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;
Rb, Rb and Rb are each, independently, H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; R° and R >d are each, independently, H, Ci-10 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said Ci-I0 alkyl, Ci-6 haloalkyl, C2.6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or Rc and Rd together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group;
R° and Rd are each, independently, H, Ci-I0 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said Ci-I0 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or R° and Rd together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group;
Rc and Rd are each, independently, H, Ci-I0 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said Ci-I0 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or Rc and Rd together with the N atom to which they are attached form a A-, S-, 6- or 7- membered heterocycloalkyl group; Re and Rf are each, independently, H, Ci-I0 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said Ci-I0 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or Re and Rf together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group; m is 0, 1, 2 or 3; nl is 1, 2, 3 or 4; n2 is 0, 1, 2, 3 or 4; n3 is O, 1, 2, 3 or 4; p is 0, 1 or 2; ql is 0, 1 or 2; q2 is 0, 1 or 2; and r is 0, 1 or 2.
In some embodiments, when A is aryl optionally substituted with 1, 2, 3, 4 or 5 -W'-X'-Y'-
Z' or heteroaryl optionally substituted with 1, 2, 3, 4 or 5 -W'-X'-Y'-Z'; L is SO2, SO2CH2 or CH2; and m is 0, then Cy is other than unsubstituted aryl, monosubstituted aryl, unsubstituted heteroaryl, or monosubstituted heteroaryl.
In some embodiments, when A is aryl optionally substituted with 1, 2, 3, 4 or 5 — W'-X'-Y'- Z' or heteroaryl optionally substituted with 1, 2, 3, 4 or 5 -W'-X'-Y'-Z'; L is SO2, SO2CH2 or CH2; m is 0; and Cy is di-, tri-, terra- or penta-substituted aryl or di-, tri-, terra- or penta-substituted heteroaryl, then said di-, tri-, tetra- or penta-substituted aryl or di-, tri-, terra- or penta-substituted heteroaryl is substituted by at least one Q-6 alkyl and at least one halo.
In some embodiments, when A is aryl optionally substituted with 1, 2, 3, 4 or 5 — W'-X'-Y'- Z' or heteroaryl optionally substituted with 1, 2, 3, 4 or 5 -W'-X'-Y'-Z'; L is SO2, SO2CH2 or CH2; and m is 0, then Cy is other than 2-chloro-6-methyl-phenyl.
In some embodiments, when A is phenyl or 4-phenoxyphenyl; L is SO2 or SO2CH2; and m is 0 or 1, then Cy is other than cyclohexyl or l,l-dioxo-tetrahydro-thien-3-yl.
In some embodiments, when Cy is aryl optionally substituted with 1, 2, 3, 4 or 5 -W-X-Y-Z or heteroaryl optionally substituted with 1, 2, 3, 4 or 5 -W-X-Y-Z; L is SO2, SO2CH2 or CH2; and m is 0, then A is other than tetrahydropyran-4-yl, 2,3-dihydroinden-2-yl or 2,2-difluoro-l,3- benzodioxol-5-yl.
In some embodiments, when Cy is aryl optionally substituted with 1, 2, 3, 4 or 5 -W-X-Y-Z or heteroaryl optionally substituted with 1, 2, 3, 4 or 5 -W-X-Y-Z; L is SO2, SO2CH2 or CH2; and m is 1, then A is other than pyridine-4-yl, phenyl, 2-chloro-6-fluoro-phenyl, 4-methoxyphenyl or 4- phenoxy-phenyl.
In some embodiments, R3a and R3b are each, independently, H, halo, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, or C2-4 alkynyl.
In some embodiments, X, X' and X" are each, independently, absent, Ci-6 alkylenyl, C2-6 alkenylenyl, C2.6 alkynylenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said Ci-6 alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by one or more halo, oxo, CN, NO2, OH, C1-4 alkoxy, C1.4 haloalkoxy, amino, C1-4 alkylamino or C2-8 dialkylamino.
In some embodiments, Z, Z' and Z" are each, independently, H, halo, CN, NO2, OH, Ci-4 alkoxy, Cj-4 haloalkoxy, amino, Ci-4 alkylamino, C2-8 dialkylamino, Ci-6 alkyl, C2-6 alkenyl, C2.6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2 or 3 halo, OXO, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa, SR3, C(O)Rb, C(0)NRcRd, C(O)OR3, 0C(0)Rb, OC(O)NR°Rd, NRcRd, NR°C(O)Rd, NR0C(O)OR3, S(O)Rb, S(0)NR°Rd, S(O)2Rb, or S(O)2NR°Rd.
In some embodiments, when r is 1 and R4 and R5 together with the carbon atom to which they are attached form a 3, 4, 5 or 6-membered heterocycloalkyl group, then m is other than 1.
In some embodiments, Cy is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 -W-X-Y-Z.
In some embodiments, Cy is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 -W-X-Y-Z wherein W is O or absent, X is absent, and Y is absent. In some embodiments, Cy is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, thiazolyl, pyrazinyl, purinyl, quinazolinyl, quinolinyl, isoquinolinyl, pyrrolo[2,3-d]pyrimidinyl, or 1,3-benzothiazolyl, each optionally substituted with 1, 2, 3, 4 or 5 -W-X-Y-Z.
In some embodiments, Cy is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl or thienyl, each optionally substituted with 1, 2, 3, 4 or 5 -W-X-Y-Z. In some embodiments, Cy is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl thiazolyl, pyrazinyl, purinyl, quinazolinyl, quinolinyl, isoquinolinyl, pyrrolo[2,3-d]pyrimidinyl, or 1,3-benzothiazolyl, each optionally substituted with 1, 2, 3 or 4 halo, CN, NO2, C 1.4 alkoxy, heteroaryloxy, C2-6 alkynyl, C1-4 haloalkoxy, NR°C(0)Rd, NR0C(O)OR3, C(0)NR°Rd, NR°Rd, NReS(O)2Rb, Ci-4 haloalkyl, Ci-6 alkyl, heterocycloalkyl, aryl or heteraryl, wherein each of said C1-6 alkyl, aryl or heteraryl is optionally substituted by 1, 2 or 3 halo, Ci-6 alkyl, Q-4 haloalkyl, CN, NO2, OR3, SR3, C(0)NR°Rd, NRcC(0)Rd or COOR3.
In some embodiments, Cy is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl thienyl, thiazolyl, pyrazinyl, purinyl, quinazolinyl, quinolinyl, isoquinolinyl, pyrrolo[2,3-d]pyrimidinyl, or 1,3-benzothiazolyl, each optionally substituted with 1, 2, 3 or 4 substituents independently selected form: halo, CN, NO2, C1-4 alkoxy, pyridin-2-yloxy, pyridin-3-yloxy, pyridin-4-yloxy, C2-6 alkynyl, C1-4 haloalkoxy, NR°C(0)Rd, NR0C(O)OR3, C(0)NR°Rd, NR°Rd, NReS(O)2Rb, C1-4 haloalkyl, C1-6 alkyl, phenyl, pyridyl, pyrimidinyl, isoxazolyl, pyrazolyl, 1,2,3,6-tetrahydro-pyridinyl, 2-oxo-(2H)- pyridinyl, 2-oxo-[l,3]oxazolidinyl, 2-oxo-pyrrolidinyl, pyrrolidinyl, 2-oxopiperidinyl, and 2-oxo- [l,3]oxazinanyl; wherein each of said Ci-6 alkyl, phenyl, pyridyl, pyrimidinyl, isoxazolyl, pyrazolyl, 1,2,3,6-tetrahydro-pyridinyl, 2-oxo-(2H)-pyridinyl, 2-oxo-[l,3]oxazolidinyl, 2-oxo-pyrrolidinyl, pyrrolidinyl, 2-oxopiperidinyl, or 2-oxo-[l,3]oxazinanyl is optionally substituted by 1, 2 or 3 halo, C1. 6 alkyl, Ci-4 haloalkyl, CN, NO2, OR3, SR3, C(O)NR0R1, NR°C(0)Rd or COOR3.
In some embodiments, Cy is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl or thienyl, each optionally substituted with 1, 2, or 3 halo, CN, Ci-4 alkoxy, C1-4 haloalkoxy, Ci-6 alkyl or aryl, wherein said Ci-6 alkyl or aryl is optionally substituted by 1, 2 or 3 halo, Ci-6 alkyl, C1-4 haloalkyl, CN, NO2, OR3, or SR3. In some embodiments, Cy is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl or thienyl, each optionally substituted with 1, 2, or 3 halo, CN, Ci-4alkoxy, C1-4haloalkoxy, Ci-6 alkyl or aryl, wherein said Q-6 alkyl or aryl is optionally substituted by 1, 2 or 3 halo or Ci-6 alkyl.
In some embodiments, Cy is phenyl, pyridyl, pyrimidinyl, quinolinyl, or isoquinolinyl, each optionally substituted with 1 , 2, 3, 4 or 5 -W-X-Y-Z.
In some embodiments, Cy is phenyl, pyridyl, pyrimidinyl, quinolinyl, or isoquinolinyl, each optionally substituted with 1, 2, or 3 halo, CN, Ci-6 alkyl, Ci-6haloalkyl, Ci.6 alkoxy, , -NR6C(O)O-Z, -C(O)O-Z, or NReC(O)-Z.
In some embodiments, Cy is cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 -W-X-Y-Z.
In some embodiments, Cy is piperidinyl, pyrrolindinyl, 1, 2, 3,6-tetrahydropyridinyl, 2-oxo- [l,3]oxazinanyl, or piperizinyl, each optionally substituted with 1, 2, 3, 4 or 5 -W-X-Y-Z.
In some embodiments, Cy is piperidinyl, pyrrolindinyl, 1,2,3,6-tetrahydropyridinyl, or piperizinyl, each optionally substituted with 1, 2, 3, 4 or 5 -W-X-Y-Z. In some embodiments, Cy is piperidinyl, pyrrolindinyl, 1, 2, 3, 6-tetrahydropyridinyl, 2-oxo-
[l,3]oxazinanyl, or piperizinyl, each optionally substituted with 1, 2, or 3 aryl or heteroayl, wherein each of said aryl or heteroaryl is optionally substituted by 1, 2 or 3 halo, CN, Ci-4 alkyl, phenyl, pyridyl, Cμ alkoxy, or Ci-4 haloalkyl.
In some embodiments, Cy is piperidinyl, pyrrolindinyl, 1, 2, 3, 6-tetrahydropyridinyl, 2-oxo- [l,3]oxazinanyl, or piperizinyl, each optionally substituted with 1, 2, or 3 phenyl, pyridyl or quinolinyl, wherein each of said phenyl, pyridyl, quinolinyl is optionally substituted by 1, 2 or 3 halo, CN, C 1-4 alkyl, phenyl, CM alkoxy, or Ci-4 haloalkyl.
In some embodiments, Cy is piperidinyl, pyrrolindinyl, 1,2,3,6-tetrahydropyridinyl, or piperizinyl, each optionally substituted with 1, 2, or 3 aryl, wherein said aryl is optionally substituted by 1, 2 or 3 halo or Ci-4 haloalkyl.
In some embodiments, L is (CR12R13)qiS(CR12R13)q2, (CR12R13)qiSO2(CR12R13)q2, or (CR12R13)qlSO(CR12R13)q2.
In some embodiments, L is (CR12R13)qiSO2(CR12R13)q2.
In some embodiments, L is S, SO or SO2. In some embodiments, L is SO2.
In some embodiments, L is CO.
In some embodiments, L is (CR12R13)qi.
In some embodiments, L is (CR12R13)qi and ql is O.
In some embodiments, Q is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 -W'-X'-Y'-Z'.
In some embodiments, Q is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 halo, CM alkyl, CN, NR°C(O)Rd or NReS(O)2Rb. In some embodiments, Q is phenyl, pyridyl or quinolinyl, each optionally substituted with 1 or 2 halo, CM alkyl, CN, NRcC(O)Rd or NReS(O)2Rb.
In some embodiments, Q is cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 -W'-X'-Y'-Z'. In some embodiments, Q is cycloalkyl or heterocycloalkyl, each optionally substituted with 1 or 2 -W'-X'-Y'-Z'.
In some embodiments, Q is cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 OH, Q-4 alkoxy, CN, CL4 alkyl, -O-heteroaryl, -(d.4 alkyl)-CN, COORa, C(O)NRcRd or NR0C(O)OR3. In some embodiments, Q is cyclopropyl, cyclohexyl, cycloheptyl, adamantyl, tetrahydro-2H- pyranyl or piperidinyl, each optionally substituted with 1 OH, C1-4 alkoxy, CN, Ci-4 alkyl, -O-heteroaryl, -(Ci-4 alkyl)-CN, COORa, C(0)NRcRd or NRcC(O)ORa.
In some embodiments, Q is cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 OH, halo, CN, Ci-4 alkyl, C1-4 alkoxy, NR6COO(Ci-4 alkyl), NReCO(CM alkyl), aryl, heteroaryl, -O-aryl, -O-heteroaryl, or -(Ci-4 alkyl)-OH.
In some embodiments, Q is cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 OH, CN, -O-heteroaryl, or C(O)O-Z'.
In some embodiments, Q is cycloalkyl or heterocycloalkyl, each substituted with at least two -W'-X'-Y'-Z', wherein two of said at least two -W'-X'-Y'-Z' are attached to the same atom and together with the atom to which they are attached form a 3-20 membered cycloalkyl or heterocyloalkyl group, each optionally substituted by 1, 2 or 3 -W"-X"-Y"-Z".
In some embodiments, Q is phenyl, pyridyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, indanyl, or 1,2,3,4-tetrahydronaphthalene, each optionally substituted with 1, 2, 3, 4 or 5 -W'-X'-Y'-Z'. In some embodiments, Q is phenyl, pyridyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl, each optionally substituted with 1, 2, 3, 4 or 5 OH, CN, halo, Ci.6 alkyl, - O-heteroaryl, or C(O)O-Z'.
In some embodiments, Q is cyclohexyl substituted at the 4-position with at least one -W'-X'- Y'-Z'. In some embodiments, Q is cyclohexyl substituted at the 4-position with at least one OH, CN, or -O-X'-Y'-Z'.
In some embodiments, Q is -(CR1R2),,!- A and m is 1, 2 or 3.
In some embodiments, Q is -(CR1R2)m-A and m is 2.
In some embodiments, A is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 — W'-X'-Y'-Z'.
In some embodiments, A is aryl optionally substituted with 1, 2, 3, 4 or 5 -W'-X'-Y'-Z'.
In some embodiments, A is hteroaryl optionally substituted with 1, 2, 3, 4 or 5 -W'-X'-Y'-Z'. In some embodiments, A is cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 -W'-X'-Y'-Z\
In some embodiments, A is cycloalkyl or heterocycloalkyl, each optionally substituted with 1 or 2 -W-X'-Y'-Z'. In some embodiments, A is cycloalkyl optionally substituted with 1, 2, 3, 4 or 5 -W'-X'-Y'-
Z'.
In some embodiments, A is cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 OH, halo, CN, C1-4 alkyl, C1-4 alkoxy, NR6COO(C1-4 alkyl), NR6CO(Ci-4 alkyl), aryl, heteroaryl, -O-aryl, -O-heteroaryl, or -(C1-4 alkyl)-OH. In some embodiments, A is cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl, each optionally substituted with 1, 2, 3, 4 or 5 OH, CN, halo, Ci-6 alkyl, -O-heteroaryl, or C(O)O-Z'.
In some embodiments, A is cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl, each optionally substituted with 1, 2, 3, 4 or 5 OH, CN, halo, Ci-6 alkyl, -O-heteroaryl, or C(O)O-(C1. 4 alkyl). In some embodiments, A is cycloalkyl or heterocycloalkyl, each optionally substituted with 1,
2, 3, 4 or 5 OH, CN, -O-heteroaryl, or C(O)O-Z'.
In some embodiments, A is cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 OH, CN, -O-heteroaryl, or C(O)O-(Ci-4 alkyl).
In some embodiments, A is cycloalkyl or heterocycloalkyl, each substituted with at least two -W'-X'-Y'-Z', wherein two of said at least two -W'-X'-Y'-Z' are attached to the same atom and together with the atom to which they are attached form a 3-20 membered cycloalkyl or heterocyloalkyl group, each optionally substituted by 1, 2 or 3 -W"-X"-Y"-Z".
In some embodiments, A is phenyl, pyridyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, indanyl, or 1,2,3,4-tetrahydronaphthalene, each optionally substituted with 1, 2, 3, 4 or 5 -W'-X'-Y'-Z'.
In some embodiments, A is phenyl, pyridyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl, each optionally substituted with 1, 2, 3, 4 or 5 OH, CN, halo, Q-6 alkyl, -O-heteroaryl, or C(O)O-Z'.
In some embodiments, A is phenyl, pyridyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl, each optionally substituted with 1, 2, 3, 4 or 5 OH, CN, halo, Ci-6 alkyl, -O-heteroaryl, or C(O)O-(Ci-4 alkyl).
In some embodiments, A is cyclohexyl substituted at the 4-position with at least one -W'-X'- Y'-Z'.
In some embodiments, A is cyclohexyl substituted at the 4-position with at least one OH, CN, or -O-X'-Y'-Z'.
In some embodiments, E is methylene, ethylene, or propylene.
In some embodiments, E is ethylene. In some embodiments, E is -(CR3aR3b)n3CONR3c- or -(CR3aR3b)n2NR3oCO-. In some embodiments, E is -CONR30-.
In some embodiments, E is -CONR30-, wherein R3ois H, Ci-4 alkyl, or CO-(Ci-4 alkyl). In some embodiments, E is -CONH-. In some embodiments, E is a group of formula:
Figure imgf000020_0001
In some embodiments, D1, D2, D3 and D4 are each CR15.
In some embodiments, one or two of D1, D2, D3 and D4 is N.
In some embodiments, R4, R5, R6, R7, R8, R9, R10 and R11 are each, independently, H, OC(O)R3', OC(O)ORb', C(O)ORb', OC(O)NR0 R"', NR0 Rd', NR0' C(O)R3', NR°'C(O)ORb>, S(O)R3',
S(O)NR0R"', S(O)2R3', S(O)2NR°'Rd' ; 0Rb>, SRb', C1-10 alkyl, C1-10 haloalkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl.
In some embodiments, R4, R5, R6, R7, R8, R9, R10 and R11 are each, independently, H, C1-10 alkyl or Ci-I0 haloalkyl.
In some embodiments, R4, R5, R6, R7, R8, R9, R10 and R11 are each H.
In some embodiments, R3a and R3b are each H.
In some embodiments, r is 1.
In some embodiments, r is O. In some embodiments, the sum of ql and q2 is O, 1 or 2.
In some embodiments, the sum of ql and q2 is 0.
In some embodiments, R12 and R13 are each H.
In some embodiments, at least one of R1 and R2 is C1.4 alkyl.
In some embodiments, m is 0. In some embodiments, m is 1 or 2.
In some embodiments, nl is 1.
In some embodiments, nl is 2.
In some embodiments, n2 is 0.
In some embodiments, n2 is 1. In some embodiments, n3 is 0.
In some embodiments, n3 is 1, 2, 3 or 4;
In some embodiments, p is 0.
In some embodiments, p is 1. In some embodiments, each -W-X-Y-Z is, independently, -NR6C(O)O-Z, -C(O)O-Z, -NR6C(O)-Z, -CO-Z, -SO-Z, -SO2-Z, -SONRe-Z, -NReCONRf-Z, halo, CN, NO2, OH, d-4 alkoxy, Ci-4 haloalkoxy, amino, Ci-4 alkylamino, C2-S dialkylamino, Q-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2 or 3 halo, oxo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, 0Ra, SRa, C(O)Rb, C(0)NRcRd, C(O)OR3, OC(O)Rb, 0C(0)NR°Rd, NR°Rd, NR°C(0)Rd, NR0C(O)OR3, S(O)Rb, S(0)NR°Rd, S(O)2Rb, or S(O)2NRcRd.
In some embodiments, each -W-X-Y-Z is, independently, -NHC(O)O-Ci-4 alkyl, -NHC(O)O-Ci-4 alkynyl, -C(O)O-Cj-4 alkyl, -NHC(O)-Ci-4 alkyl, -NHC(O)-C3-9 cycloalkyl, halo, CN, NO2, OH, Ci-4alkoxy, Ci-4 haloalkoxy, amino, Ci-4 alkylamino, C2-8 dialkylamino, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said Ci-6 alkyl, C2-6 alkenyl, C2.6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2 or 3 halo, oxo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, 0Ra, SR3, C(0)Rb, C(0)NRcRd, C(O)OR3, 0C(0)Rb, 0C(0)NR°Rd, NR°Rd, NR°C(0)Rd, NR0C(O)OR3, S(O)Rb, S(0)NR°Rd, S(O)2Rb, or S(0)2NR°Rd.
In some embodiments, each -W-X-Y-Z is, independently, halo, CN, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 alkoxy, -NR0C(O)O-Z, -C(O)O-Z, -NR6C(O)-Z or aryl, wherein said aryl is optionally substituted by 1, 2 or 3 halo or Ci-4 haloalkyl. In some embodiments, each -W-X-Y-Z is, independently, halo, CN, Ci-4 alkyl, Ci-4 haloalkyl,
Ci-4 alkoxy, -NHC(O)O-(Ci-4 alkyl), -NHC(O)O-(Ci-4 alkynyl), -C(O)O-(Ci-4 alkyl), -NHC(O)-(Ci-4 alkyl), -NHC(O)-(C3-9 cycloalkyl) or phenyl, wherein said phenyl is optionally substituted by 1, 2 or 3 halo or Ci.4 haloalkyl.
In some embodiments, each -W-X-Y-Z is, independently, halo, CN, NO2, Ci-4 alkoxy, heteroaryloxy, C2-6 alkynyl, C1-4 haloalkoxy, NRcC(0)Rd, NR0C(O)OR3, C(0)NR°Rd, NR°Rd, NR6S(O)2Rb, Ci-4 haloalkyl, Ci-6 alkyl, heterocycloalkyl, aryl or heteraryl, wherein each of said Ci-6 alkyl, aryl or heteraryl is optionally substituted by 1, 2 or 3 halo, Ci-6 alkyl, C^4 haloalkyl, CN, NO2, OR3, SR3, C(O)NR0R1, NR°C(0)Rd or COOR3.
In some embodiments, each -W-X-Y-Z is, independently, halo, CN, NO2, Ci-4 alkoxy, pyridin-2-yloxy, pyridin-3-yloxy, pyridin-4-yloxy, C2-6 alkynyl, Ci-4 haloalkoxy, NR°C(0)Rd, NR0C(O)OR3, C(O)NR°Rd, NR°Rd, NReS(O)2Rb, Ci-4 haloalkyl, d.6 alkyl, phenyl, pyridyl, pyrimidinyl, isoxazolyl, pyrazolyl, 1,2,3,6-tetrahydro-pyridinyl, 2-oxo-(2H)-pyridinyl, 2-oxo- [l,3]oxazolidinyl, 2-oxo-pyrrolidinyl, pyrrolidinyl, 2-oxopiperidinyl, or 2-oxo-[l,3]oxazinanyl, wherein each of said Cμ6 alkyl, phenyl, pyridyl, pyrimidinyl, isoxazolyl, pyrazolyl, 1,2,3,6-tetrahydro- pyridinyl, 2-oxo-(2H)-pyridinyl, 2-oxo-[l,3]oxazolidinyl, 2-oxo-pyrrolidinyl, pyrrolidinyl, 2- oxopiperidinyl, or 2-oxo-[l,3]oxazinanyl is optionally substituted by 1, 2 or 3 halo, C1-6 alkyl, Ci-4 haloalkyl, CN, NO2, OR3, SR3, C(O)NR°Rd, NR°C(0)Rd or C00Ra. In some embodiments, each -W-X-Y-Z is, independently, aryl or heteroayl, wherein each of said aryl or heteroaryl is optionally substituted by 1, 2 or 3 halo, CN, Ci-4 alkyl, phenyl, pyridyl, Q-4 alkoxy, or Q-4 haloalkyl.
In some embodiments, each -W-X-Y-Z is, independently, phenyl, pyridyl or quinolinyl, wherein each of said phenyl, pyridyl, quinolinyl is optionally substituted by 1, 2 or 3 halo, CN, C1.4 alkyl, phenyl, C1^ alkoxy, or Ci-4 haloalkyl.
In some embodiments, each -W'-X'-Y'-Z' is, independently, OH, CN, halo, Ci-6 alkyl, Ci-6 haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -OZ', -C(O)-Z' or -C(O)O-Z', wherein said Ci-6 alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl are each optionally substituted by 1, 2 or 3 halo, 0x0, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, 0Ra, SR3, C(O)Rb, C(0)NR°Rd, C(0)0Ra, 0C(0)Rb, 0C(0)NR°Rd, NR°Rd, NRcC(0)Rd, NR0C(O)OR3, S(O)Rb, S(0)NR°Rd, S(O)2Rb, or S(O)2NR°Rd.
In some embodiments, each -W'-X'-Y'-Z' is, independently, OH, Ci-4 alkoxy, CN, Ci-4 alkyl, -O-heteroaryl, -(Ci-4 alkyl)-CN, C00Ra, C(O)NR°Rd or NR°C(0)0Ra. In some embodiments, each -W'-X'-Y'-Z' is, independently, halo, Ci-4 alkyl, CN,
NRcC(0)Rd or NReS(0)2Rb.
In some embodiments, each -W'-X'-Y'-Z' is, independently, OH, CN, halo, Ci-6 alkyl, -O- heteroaryl, or C(O)O-Z'.
In some embodiments, each -W'-X'-Y'-Z' is, independently, OH, CN, halo, Ci-6 alkyl, -O- heteroaryl, or -C(O)O-Ci-4 alkyl.
In some embodiments, each -W"-X"-Y"-Z" is halo, CN, NO2, OH, C1-4 alkoxy, Ci-4 haloalkoxy, amino, Ci-4 alkylamino, C2-8 dialkylamino, NReS(O)2Rb, Ci-6 alkyl, C2.6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2 or 3 halo, 0x0, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, 0Ra, SRa, C(0)Rb, C(0)NR°Rd, C(0)0Ra, 0C(0)Rb, OC(O)NR0R1, NR°Rd, NR°C(0)Rd, NR0C(O)OR3, NR6S(O)2R", S(O)Rb, S(0)NR°Rd, S(O)2Rb, or S(O)2NR0R1.
In some embodiments, each -W"-X"-Y"-Z" is halo, CN, NO2, OH, Ci4 alkoxy, Ci-4 haloalkoxy, amino, Ci-4 alkylamino, C2-8 dialkylamino, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2 or 3 halo, oxo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, 0Ra, SRa, C(0)R\ C(0)NR°Rd, C(O)OR3, OC(O)Rb, 0C(0)NR°Rd, NR°Rd, NR°C(0)Rd, NR0C(O)OR3, S(O)Rb, S(O)NR°Rd, S(O)2Rb, or S(O)2NR°Rd. In some embodiments, each -W"-X"-Y"-Z" is halo, CN, NO2, OH, CM alkoxy, Ci-4 haloalkoxy, amino, Ci-4 alkylamino, C2-8 dialkylamino, Ci-6 alkyl, C2-6 alkenyl, C2.6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl. In some embodiments, compounds of the invention have Formula II:
Figure imgf000023_0001
II. In some embodiments, compounds of the invention have Formula Ilia:
Figure imgf000023_0002
Ilia.
In some embodiments, compounds of the invention have Formula IHb:
Figure imgf000023_0003
UIb.
In some embodiments, compounds of the invention have Formula IHc:
Figure imgf000023_0004
πic.
In some embodiments, compounds of the invention have Formula IV:
Figure imgf000024_0001
IV.
In some embodiments, compounds of the invention have Formula IVa:
Figure imgf000024_0002
IVa.
In some embodiments, compounds of the invention have Formula IVb:
Figure imgf000024_0003
IVb.
In some embodiments, compounds of the invention have Formula IVc:
Figure imgf000024_0004
IVc. In some embodiments, compounds of the invention have Formula IV, Formula IVa, Formul IVb, or Formula IVc, wherein R3c is H, C1-4 alkyl, or CO-(Ci-4 alkyl). In some further embodiments, R30 is H.
At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges. For example, the term "C1^ alkyl" is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. It 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.
The term "n-membered" where n is an integer typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.
As used herein, the term "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 (e.g., 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 1 to about 10, from 1 to about 8, from 1 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.
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 CF3, C2F5, CHF2, CCl3, CHCl2, C2Cl5, 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. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groups. Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by oxo or sulfido. Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohepτyl, 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 or thienyl derivatives of pentane, pentene, hexane, and the like.
As used herein, "heteroaryl" refers 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, 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, 4 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 alkynyl groups where one or more of the ring-forming carbon atoms is replaced by a heteroatom such as an O, N, or S atom. Heterocycloalkyl groups include monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) systems. 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, and the like. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by oxo or sulfido. 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. 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, 4 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments, the heterocycloalkyl group contains 0 to 3 double or triple bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double or triple bonds. 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 OCF3.
As used herein, "heteroaryloxy" refers to -O-heteroaryl. An example heteroaryloxy is pyridine-2-yloxy [i.e., -O-(pyridine-2-yl)]. As used herein, "arylalkyl" refers to alkyl substituted by aryl and "cycloalkylalkyl" refers to alkyl substituted by cycloalkyl. An example arylalkyl group is benzyl.
As used herein, "amino" refers to NH2.
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 camphqrsulfonic acids such as β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of α- 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 further include hydrates and solvates, as well as anyhydrous and non-solvated forms. 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 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., 1H or 13C) 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 of the invention can be prepared, for example, using the reaction pathways and techniques described below.
Compounds of the invention can be generally prepared by the method outlined in Scheme 1.
Reagents of formula 1-1 (X is a leaving group such as halo) can be reacted with an amines of formula
1-2 (or its salts) in an appropriate solvent (e.g., CH2Cl2) and optionally in the presence of a base such as diisopropyl ethyl amine to provide the desired products 1-3. As an example, sulfonyl chlorides of formula 1-4 can be reacted with the amines of formula 1-2 to provide sulfonyl linked compounds of formula 1-5. Scheme 1
Figure imgf000030_0001
A series of spirocyclyl amines of formula 2-8 can be prepared according to the procedure outlined in Scheme 2. N-protected 2-1 (Pr is an amino protecting group such as Boc) can be treated with a base such as LDA at low temperature in a solvent such as tetrahydrofuran followed by addition of l-bromo-3-methyl-2-butene (2-2). The resulting intermediate (2-3) can be treated with ozone and then reduced with methyl sulfide to provide the aldehyde 2-4. Reductive amination of 2-4 with amines 2-5 can be conducted in a solvent such as methanol and using a reducing agent such as sodium triacetoxyborohydride, and the product 2-6 can be cyclized in the presence of a base such as isopropylmagnesium bromide to provide the lactam 2-7 which upon acidic cleavage of the Boc group yields the desired amine 2-8.
Scheme 2
Figure imgf000031_0001
A series of amines of formula 3-7 can be prepared according to the procedure outlined in Scheme 3. Treatment of Boc protected nipecotic ethyl ester 3-1 with a base such as LDA at low temperature in a solvent such as tetrahydrofuran followed by addition of l-bromo-3-methyl-2- butene can result in an intermediate 3-2, which can be treated with ozone followed by reduction with methyl sulfide to provide the aldehyde 3-3. Reductive animation of 3-3 with amines 3-4 (where Qi is, e.g., substituted or unsubstituted cycloalkyl or aryl) can be conducted in a solvent such as methanol and using a reducing agent such as sodium triacetoxyborohydride. The resulting intermediate 3-5 can be cyclized in the presence of a base such as isopropylmagnesium bromide to provide the lactam 3-6 which upon acidic cleavage of the Boc group yields the desired piperidine 3-7. Scheme 3
Figure imgf000032_0001
3-1 3-2
Figure imgf000032_0002
3-3 3-5
Figure imgf000032_0003
A series of piperdines of 4-4 can be prepared by the method outlined in Scheme 4. Compound 4-1 can be readily converted to the spirohydantoin 4-2 under Bucherer-Bergs conditions, using, e.g., ammonium carbonate and either sodium cyanide or potassium cyanide in aqueous ethanol. Alkylation of compound 4-2 with one equivalent of alkyl halide QX (X is a leaving group such as halo) in the presence of potassium carbonate in DMF, followed by a second alkylation with R3cX (X is a leaving group such as halo) in the presence of sodium hydride in DMF provides substituted hydantoins 4-3, which upon acidic cleavage of the Boc group yields the desired piperidines 4-4.
Scheme 4
Figure imgf000032_0004
4-3 4-4 Alternatively, treatment of compound 5-1 with alkyl amines R30NH2 and sodium cyanide can provide alkylated hydantoin derivatives 5-2. Aromatic substituted hydantoins 5-4 can be obtained by coupling compounds 5-2 with aromatic boronic acids or aromatic halides 5-3 in the presence of catalyst. Acidic cleavage of the Boc group yields the desired piperidines 5-4 (Scheme 5).
Scheme 5
Figure imgf000033_0001
5-1 5-2
Figure imgf000033_0002
5-4 5-5
In a further alternative route, piperdines 6-6 can also be prepared by the method outlined in Scheme 6. The protected amino acid 6-1 can be coupled with an amine Q-NH2 using a coupling agent such as BOP to provide compound 6-2 which, in turn, can be hydrogenated at the presence of Pd catalyst to yield compound 6-3. Compound 6-3 can be treated with methyl chloroformate and a base such as triethyl amine in CH2Cl2 to complete the ring closure and form hydantoin 6-4.
As described previously, N alkylation with R30X (X is a leaving group such as halo) can yield compounds of formula 6-5 and acid cleavage can yield compounds of formula 6-6.
Scheme 6
Figure imgf000034_0001
6-1 6-2 6-3
Figure imgf000034_0002
6-4 6-5 6-6
Methods Compounds of the invention can modulate activity of l lβHSDl and/or MR. The term
"modulate" is meant to refer to an ability to increase or decrease activity of an enzyme or receptor. Accordingly, compounds of the invention can be used in methods of modulating l lβHSDl and/or MR by contacting the enzyme or receptor with any one or more of the compounds or compositions described herein. In some embodiments, compounds of the present invention can act as inhibitors of l lβHSDl and/or MR. In further embodiments, the compounds of the invention can be used to modulate activity of l lβHSDl and/or MR in an individual in need of modulation of the enzyme or receptor by administering a modulating amount of a compound of the invention.
The present invention further provides methods of inhibiting the conversion of cortisone to Cortisol in a cell, or inhibiting the production of Cortisol in a cell, where conversion to or production of Cortisol is mediated, at least in part, by llβHSDl activity. Methods of measuring conversion rates of cortisone to Cortisol and vice versa, as well as methods for measuring levels of cortisone and Cortisol in cells, are routine in the art.
The present invention further provides methods of increasing insulin sensitivity of a cell by contacting the cell with a compound of the invention. Methods of measuring insulin sensitivity are routine in the art.
The present invention further provides methods of treating disease associated with activity or expression, including abnormal activity and overexpression, of llβHSDl and/or MR in an individual (e.g., patient) by administering to the individual in need of such treatment a therapeutically effective amount or dose of a compound of the present invention or a pharmaceutical composition thereof. Example diseases can include any disease, disorder or condition that is directly or indirectly linked to expression or activity of the enzyme or receptor. An l lβHSDl -associated disease can also include any disease, disorder or condition that can be prevented, ameliorated, or cured by modulating enzyme activity.
Examples of l lβHSDl -associated diseases include obesity, diabetes, glucose intolerance, insulin resistance, hyperglycemia, hypertension, hyperlipidemia, cognitive impairment, dementia, depression (e.g., psychotic depression), glaucoma, cardiovascular disorders, osteoporosis, and inflammation. Further examples of 1 lβHSDl -associated diseases include metabolic syndrome, type 2 diabetes, androgen excess (hirsutism, menstrual irregularity, hyperandrogenism) and polycystic ovary syndrome (PCOS). The present invention further provides methods of modulating MR activity by contacting the
MR with a compound of the invention, pharmaceutically acceptable salt, prodrug, or composition thereof. In some embodiments, the modulation can be inhibition. In further embodiments, methods of inhibiting aldosterone binding to the MR (optionally in a cell) are provided. Methods of measuring MR activity and inhibition of aldosterone binding are routine in the art. The present invention further provides methods of treating a disease associated with activity or expression of the MR. Examples of diseases associated with activity or expression of the MR include, but are not limited to hypertension, as well as cardiovascular, renal, and inflammatory pathologies such as heart failure, atherosclerosis, arteriosclerosis, coronary artery disease, thrombosis, angina, peripheral vascular disease, vascular wall damage, stroke, dyslipidemia, hyperlipoproteinaemia, diabetic dyslipidemia, mixed dyslipidemia, hypercholesterolemia, hypertriglyceridemia, and those associated with type 1 diabetes, type 2 diabetes, obesity metabolic syndrome, insulin resistance and general aldosterone-related target organ damage.
As used herein, the term "cell" is meant to refer to a cell that is in vitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal. In some embodiments, an in vitro cell can be a cell in a cell culture. In some embodiments, an in vivo cell is a cell living in an organism such as a mammal. In some embodiments, the cell is an adipocyte, a pancreatic cell, a hepatocyte, neuron, or cell comprising the eye.
As used herein, the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" the l lβHSDl enzyme with a compound of the invention includes the administration of a compound of the present invention to an individual or patient, such as a human, having l lβHSDl, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing the l lβHSDl enzyme.
As used herein, the term "individual" or "patient," used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. As used herein, the phrase "therapeutically effective amount" refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease (non-limiting examples are preventing metabolic syndrome, hypertension, obesity, insulin resistance, hyperglycemia, hyperlipidemia, type 2 diabetes, androgen excess (hirsutism, menstrual irregularity, hyperandrogenism) and polycystic ovary syndrome (PCOS);
(2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology) such as inhibiting the development of metabolic syndrome, hypertension, obesity, insulin resistance, hyperglycemia, hyperlipidemia, type 2 diabetes, androgen excess (hirsutism, menstrual irregularity, hyperandrogenism) or polycystic ovary syndrome (PCOS), stabilizing viral load in the case of a viral infection; and
(3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of metabolic syndrome, hypertension, obesity, insulin resistance, hyperglycemia, hyperlipidemia, type 2 diabetes, androgen excess (hirsutism, menstrual irregularity, hyperandrogenism) and polycystic ovary syndrome (PCOS), or lowering viral load in the case of a viral infection.
Pharmaceutical Formulations and Dosage Forms
When employed as pharmaceuticals, the compounds of Formula I can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), ocular, oral or parenteral. Methods for ocular delivery can include topical administration (eye drops), subconjunctival, periocular or intravitreal injection or introduction by balloon catheter or ophthalmic inserts surgically placed in the conjunctival sac. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointnents, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
This invention also includes pharmaceutical compositions which contain, as the active ingredient, one or more of the compounds of the invention above in combination with one or more pharmaceutically acceptable carriers. In making the compositions of the invention, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10 % by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
In preparing a formulation, the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art. The compositions can be formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. The active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.
The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate. The liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.
The amount of compound or composition administered to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like.
The compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.
The therapeutic dosage of the compounds of the present invention can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, the compounds of the invention can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w/v of the compound for parenteral adminstration. Some typical dose ranges are from about 1 μg/kg to about 1 g/kg of body weight per day. In some embodiments, the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day. The dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems. The compounds of the invention can also be formulated in combination with one or more additional active ingredients which can include any pharmaceutical agent such as anti-viral agents, antibodies, immune suppressants, anti-inflammatory agents and the like.
Labeled Compounds and Assay Methods Another aspect of the present invention relates to labeled compounds of the invention (radio¬ labeled, fluorescent-labeled, etc.) that would be useful not only in radio-imaging but also in assays, both in vitro and in vivo, for localizing and quantitating the enzyme in tissue samples, including human, and for identifying ligands by inhibition binding of a labeled compound. Accordingly, the present invention includes enzyme assays that contain such labeled compounds. The present invention further includes isotopically-labeled compounds of the invention. An
"isotopically" or "radio-labeled" compound is a compound of the invention where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to 2H (also written as D for deuterium), 3H (also written as T for tritium), 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 18F, 35S5 36Cl, 82Br, 75Br, 76Br, 77Br, 123I, 124I, 125I and 131I. The radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound. For example, for in vitro receptor labeling and competition assays, compounds that incorporate 3H, 14C, 82Br, 1251 , 1311, 35S or will generally be most useful. For radio- imaging applications 11C, 18F, 1251, 1231, 1241, 1311, 75Br, 76Br or 77Br will generally be most useful.
It is understood that a "radio-labeled compound" is a compound that has incorporated at least one radionuclide. In some embodiments the radionuclide is selected from the group consisting of 3H, 14C, 125I 3 35S and 82Br.
In some embodiments, the labeled compounds of the present invention contain a fluorescent lable.
Synthetic methods for incorporating radio-isotopes and fluorescent labels into organic compounds are are well known in the art.
A labeled compound of the invention (radio-labeled, fluorescent-labeled, etc.) can be used in a screening assay to identify/evaluate compounds. For example, a newly synthesized or identified compound (i.e., test compound) which is labeled can be evaluated for its ability to bind a 1 lβHSDl or MR by monitering its concentration variation when contacting with the l lβHSDl or MR, through tracking the labeling. For another example, a test compound (labeled) can be evaluated for its ability to reduce binding of another compound which is known to bind to llβHSDl or MR (i.e., standard compound). Accordingly, the ability of a test compound to compete with the standard compound for binding to the llβHSDl or MR directly correlates to its binding affinity. Conversely, in some other screening assays, the standard compound is labled and test compounds are unlabeled. Accordingly, the concentration of the labled standard compound is monitored in order to evaluate the competition between the standard compound and the test compound, and the relative binding affinity of the test compound is thus ascertained.
Kits The present invention also includes pharmaceutical kits useful, for example, in the treatment or prevention of l lβHSDl- or MR-associated diseases or disorders, obesity, diabetes and other diseases referred to herein which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention. Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.
The invention will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of noncritical parameters which can be changed or modified to yield essentially the same results. The compound of the Examples were found to inhibitors of 1 lβHSDl and/or MR according to one or more of the assays provided herein.
EXAMPLES Example 1
Figure imgf000041_0001
7-[(3-ChIoro-2-methylphenyl)sulfonyl]-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l- one
Stepl. 1-tert-butyl 3-ethyl 3-(3-methylbut-2-en-l-yl)piperidine-l,3-dicarboxylate
Figure imgf000041_0002
To a solution of l-tør/-butyl 3-ethyl piperidine-l,3-dicarboxylate (2.6 g, 10.0 mmol) in THF (30 niL) was slowly added LDA (6.7 niL, 12.0 mmol, 1.8 M solution in heptane- /tetrahydrofuran/ethylbenzene) at -78 0C and the mixture was slowly warmed to -55 0C over 1 h. To this mixture, l-bromo-3-methyl-2-butene (1.55 g, 10.5 mmol) was slowly added and the reaction was warmed to room temperature and stirred for 4 h. The mixture was quenched with saturated NH4Cl and extract with diethyl ether and the combined extract was washed with brine, dried and concentrated. The product (2.75 g, 85%) was purified by CombiFlash eluted with Hexane/ethyl acetate.
Step 2. 1-tert-butyl 3-ethyl 3-(2-oxoethyl)piperidine-l,3-dicarboxylate
Figure imgf000041_0003
1-terf-Butyl 3-ethyl 3-(3-methylbut-2-en-l-yl)piperidine-l,3-dicarboxylate (2.75 g, 8.5 mmol) in CH2Cl2 (100 mL) was cooed to -78 0C, and ozone was passed into the reaction mixture until a light blue color was observed (ca.15 min). Nitrogen was then bubbled through the solution to remove the excess ozone. Dimethyl sulfide (10 mL) was added and the reaction was slowly warmed to room temperature and stirred overnight. The reaction was then washed with water and brine, dried and concentrated to give the product (2.5 g).
Step 3. 1-tert-butyl 3-ethyl 3-{2-[(cis-4-hydroxycyclohexyl)amino]ethyl}piperidine-l,3-dicarboxylate
Figure imgf000042_0001
DIPEA (1.05 eq.) was added to a solution of frα/ω-4-aminocyclohexanol hydrochloride
(0.080 g, 0.53 mmol) in methanol (2.0 mL) and stirred for 5 min., to this solution l-tert-tutyl 3-ethyl 3-(2-oxoethyl)-piperidine-l,3-dicarboxylate (0.15 g, 0.5 mmol) was added followed by sodium triacetoxyborohydride (0.21 g, 1.0 mmol) and the mixture was stirred for 2 h. The reaction was acidified by adding AcOH and diluted with water and extracted with ether, the aqueous phase was the basifϊed by adding 1 N NaOH and the extracted with ethyl acetate which was then washed with water, brine, dried and concentrated to give the desired product (0.17 g, 85%). LC-MS: 399.2 (M+H)+.
Step 4. tert-butyl 2-(cis-4-hydroxycyclohexyl)-l-oxo-2, 7-diazaspiro[4.5]decane-7-carboxylate
Figure imgf000042_0002
zso-Propylmagnesium bromide (1.0 M in THF, 1.5 mL) was slowly added to a solution of 1- tert-bxxtyl 3-ethyl 3-{2-[(cis-4-hydroxycyclohexyl)amino]ethyl}piperidine-l,3-dicarboxylate (0.15 g, 0.38 mmol) at 0 0C and the mixture was stirred at this temperature for 1 h. The reaction was then poured to cold water and extracted with ethyl acetate, dried and concentrated to give the desired product (0.11 g , 85 %). LC-MS: 353.2 (M+H)+, 297.1 (M+H-56)+.
Step 5. 2-(cis-4-hydroxycyclohexyl)-2, 7-diazaspiro[4,5]decan-l-one hydrochloride
Figure imgf000042_0003
H-Cl
Hydrogen chloride (2.0 mL, 4.0 M in 1,4-dioxnae) was added to a solution of tert-butyl 2- (cis-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]decane-7-carboxylate (0.10 g) in ethyl acetate (0.5 mL) at room temperature and the mixture was stirred for 1 h. the solvent was then removed under vacuum to give the product. LC-MS: 253.2 (M+H)+.
Step 6. 7-[(3-chloro-2-methylphenyl)sulfonyl]-2-(cis-4-hydroxycyclohexyl)-2, 7- diazaspiro[4.5]decan-l-one
A solution of 3-chloro-2 -methylbenzenesulfonyl chloride (0.050 g, 0.22 mmol) in CH2Cl2 (1.0 mL) was slowly added to a mixture of 2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l- one hydrochloride (0.060 g, 0.2 mmol) and DIPEA (0.10 mL, 0.6 mmol) in CH2Cl2(LO mL) at 0 0C and the reaction was stirred for 1 h. The mixture was diluted with ethyl acetate and then washed with diluted HCl, water and brine, dried and concentrated. The product was purified by CombiFlash eluted with CH2Cl2/Et0Ac. LC-MS: 441.2/443.2 (M+H)+.
Example 2
7-[(3-Chloro-2-methylphenyl)sulfonyl]-2-(/r««5-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan- 1-one
Figure imgf000043_0001
This compound was prepared using procedures analogous to those of for example 1. LC-MS: 441.1/443.1 (M+H)+.
Example 3
7-[(3-ChIoro-2-methylphenyI)sulfonyl]-2-(2-methylphenyl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000043_0002
This compound was prepared using procedures analogous to those of for example 1. LC-MS: 433.1/435.1 (M+H)+.
Example 4 7-[(3-Chloro-2-methylphenyl)suIfonyl]-2-phenyl-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000044_0001
This compound was prepared using procedures analogous to those of for example 1. LC-MS: 419.2/421.2 (M+H)+.
Example 5
7>αλi5-4-{7-[(3-chIoro-2-methylphenyl)sulfonyI]-l-oxo-2,7-diazaspiro[4.5]dec-2- yl} cyclohexanecarbonitrile
Figure imgf000044_0002
This compound was prepared using procedures analogous to those of for example 1. LC-MS: 450.2/452.2 (M+H)+.
Example 6 7-[(3-Chloro-2-methyIphenyl)sulfonyl]-2-cycloheptyl-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000044_0003
This compound was prepared using procedures analogous to those of for example 1. LC-MS:
439.1/441.1 (M+H)+.
Example 7 7-[(3-Chloro-2-methylphenyl)sulfonyl]-2-cyclohexyl-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000044_0004
This compound was prepared using procedures analogous to those of for example 1. LC-MS:
425.1/427.1 (M+K)+. Example 8 7-[(3-ChIoro-2-methylphenyl)sulfonyl]-2-(4-methylpyridin-3-yl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000045_0001
This compound was prepared using procedures analogous to those of for example 1. LC-MS: 434.1/435.1 (M+H)+.
Example 9
7-[(3-Chloro-2-methylphenyI)sulfonyl]-2-[c/5-4-(pyridin-2-yloxy)cycIohexyl]-2,7- diazaspiro [4.5] decan-1-one
Figure imgf000045_0002
This compound was prepared using procedures analogous to those of for example 1. LC-MS: 518.2/520.2 (M+H)+.
Example 10
7-[(3-Chloro-2-methylphenyl)sulfonyl]-2-[c/s'-4-(pyridiii-3-yloxy)cyclohexyl]-2,7- diazaspiro[4.5]decan-l-one
Figure imgf000045_0003
This compound was prepared using procedures analogous to those of for example 1. LC-MS:
518.2/520.2 (M+H)+.
Example 11
7-[(3-Chloro-2-methylphenyl)sulfonyl]-2-[c/5-4-(pyridin-4-yloxy)cyclohexyl]-2,7- diazaspiro [4.5] decan-1-one
Figure imgf000046_0001
This compound was prepared using procedures analogous to those of for example 1. LC-MS: 518.2/520.2 (M+H)+.
Example 12 2-(l-Adamantyl)-7-[(3-chloro-2-methylphenyl)sulfonyl]-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000046_0002
This compound was prepared using procedures analogous to those of for example 1. LC-MS: 477.2/479.2 (M+H)+.
Example 13
7-[(3-Chloro-2-methylphenyl)sulfonyl]-2-(l-methyl-2-phenylethyl)-2,7-diazaspiro[4.5]decan-l- one
Figure imgf000046_0003
This compound was prepared using procedures analogous to those of for example 1. LC-MS:
461.1/463.1 (M+H)+.
Example 14 (5iϊ)-7-[(3-Chloro-2-methylphenyl)sulfonyl]-2-cycloheptyl-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000046_0004
This compound was prepared by using a chiral column to separate the enantiomers of example 6. LC-MS: 439.1/441.1 (M+H)+. Example 15 (55)-7-[(3-Chloro-2-methyIphenyl)sulfonyl]-2-cycloheptyl-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000047_0001
This compound was prepared using procedures analogous to those for the synthesis of example 1. LC-MS: 439.1/441.1 (M+H)+.
Example 16 c/5-4-{7-[(3-Chloro-2-methylphenyl)sulfonyI]-l-oxo-2,7-diazaspiro[4.5]dec-2- yljcyclohexanecarbonitrile
Figure imgf000047_0002
This compound was prepared using procedures analogous to those for the synthesis of example 1. LC-MS: 450.2/452.2 (M+H)+.
Example 17
2-Cyclohexyl-7-(2-fluorophenyl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000047_0003
This compound was prepared by using procedures that were analogous to those described for the synthesis of example 1, steps 1-5, followed by the following microwave mediated amine/aryl coupling procedure:
A mixture of 2-cyclohexyl-2,7-diazaspiro[4.5]decan-l-one hydrochloride (0.025 g, 0.000092 mol), l-bromo-2-fluorobenzene (0.032 g, 0.00018 mol), and sodium tert-butoxide (0.026 g, 0.00027 mol) in DMSO (0.5 mL) was microwave irradiated at 180 0C for 5 min. After cooling the reaction mixture to ambient temperature the crude product was purified by prep.-HPLC. LC-MS: 331.2 (M+H)+.
Example 18 2-Cyclohexyl-7-(4-fluorophenyl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000048_0001
This compound was prepared using procedures analogous to those for the synthesis of example 17. LC-MS: 331.2 (M+H)+.
Example 19
2-Cyclohexyl-7-(3-fluorophenyl)-2,7-diazaspiro [4.5] decan- 1-one
Figure imgf000048_0002
This compound was prepared using procedures analogous to those for the synthesis of example 17. LC-MS: 331.2 (M+H)+.
Example 20 2-Cyclohexyl-7-phenyI-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000048_0003
This compound was prepared using procedures analogous to those for the synthesis of example 17. LC-MS: 313.2 (M+H)+.
Example 21 7-(4-FluorophenyI)-2-(trans-4-hydroxycyclohexyI)-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000049_0001
This compound was prepared using procedures analogous to those for the synthesis of example 17. LC-MS: 347.2 (M+H)+.
Example 22
7-(3-Fluorophenyl)-2-(trans-4-hydroxycyclohexyI)-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000049_0002
This compound was prepared using procedures analogous to those for the synthesis of example 17. LC-MS: 347.2 (M+H)+.
Example 23 2-(tfrø«s-4-HydroxycyclohexyI)-7-phenyl-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000050_0001
This compound was prepared using procedures analogous to those for the synthesis of example 17. LC-MS: 329.2 (M+H)+.
Example 26
Methyl l-[7-(2-fluorophenyl)-l-oxo-2,7-diazaspiro[4.5]dec-2-yl] cyclopropanecarboxylate
Figure imgf000050_0002
This compound was prepared by using procedures that were analogous to those described for the synthesis of example 1, steps 1-3, followed by the following reductive amination/cyclization and amine/ary 1 coupling procedure :
1-Aminocyclopropanecarboxylic acid (0.10 g, 0.00099 mol) in MeOH (3 niL) with 4 N HCl (1.5 mL) was stirred at rt for 2 h. LCMS analysis indicated that the carboxylic acid was successfully converted to methyl ester, (m/z 116.3). The volatiles were removed in-vacuo to afford 150 mg of the methyl ester HCl salt. To this methyl ester, l-tert-butyl 3-ethyl 3-(2-oxoethyl)piperidine-l,3- dicarboxylate (0.25 g, 0.00084 mol), and triethylamine (190 μL, 0.0013 mol) in 1,2-dichloroethane (1.5 mL, 0.019 mol) was stirred at .rt for 30 min. To the mixture was added sodium triacetoxyborohydride (0.35 g, 0.0017 mol) with stirring. After stirring at rt for 2 h, the reaction mixture then was heated to 70 0C and stirred for 16 h. LCMS data indicated that the spiro-ring formed and the methyl ester was hydro lyzed (m/z 283.0, (M - Bu + 2H)+). The reaction mixture was diluted with ethyl acetate and the organic solution was washed with IN HCl, water, brine, and dried over Na2SCv After filtration, the filtrate was concentrated to yield 300 mg of crude material. The residue was stirred with a solution of MeOH (2 mL) in 4 N HCl-dioxane solution for 2 h to form the methyl ester. The volatiles were removed in-vacuo to yield 268 mg of the desired product. LC-MS: 253.2 (MH-H)+. Example 27 2-(f/"α«5-4-Hydroxycyclohexyl)-7-[5-(trifluoromethyI)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-l- one H
Figure imgf000051_0001
This compound was prepared by using procedures that were analogous to those described for the synthesis of example 1, steps 1-5, and by the following microwave mediated amine/aryl coupling procedure:
A mixture of 2-(frα«s-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one hydrochloride (5 mg, 0.00002 mol), 2-chloro-5-(trifluoromethyl)pyridine (6 mg, 0.00003 mol) , and triethylamine (20 μL, 0.0001 mol) in N-methylpyrrolidinone (800 μL, 0.008 mol) was microwave irradiated at 180 0C for 10 min. After cooling, it was purified by prep.-HPLC to afford 1.7 mg of the desired product.
LC-MS: 398.3 (M+H)+.
Example 28
6-[2-(ff«n5'-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]nicotinonitrile H
Figure imgf000051_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 27. LC-MS: 355.3 (M+H)+.
Example 29 2-(//-αλis-4-Hydroxycyclohexyl)-7-(6-methoxypyridin-2-yI)-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000052_0001
This compound was prepared by using procedures that were analogous to those described for the synthesis of example 1, steps 1-5, and by the following microwave mediated amine/aryl coupling procedure:
A mixture of 2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one hydrochloride (35 mg, 0.00012 mol), 2-bromo-6-methoxypyridine (34 mg, 0.00018 mol), triethylamine (200 μL, 0.001 mol), and copper(I) iodide (28 mg, 0.00014 mol) in N-methylpyrrolidinone (1.0 mL, 0.010 mol) was microwave irradiated at 180 0C for 20 min. After allowing the reaction mixture to cool to rt the crude mixture was purified by prep.-HPLC to afford 8.3 mg of the desired product. LC-MS: 360.3 (M+H)+.
Example 30 2-(^rfl«5i-4-HydroxycyclohexyI)-7-(6-methylpyridin-2-yI)-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000052_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 29. LC-MS: 344.3 (M+H)+.
Example 31 2-(^r«/i5-4-Hydroxycyclohexyl)-7-(5-methylpyridin-2-yl)-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000053_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 29. LC-MS: 344.3 (M+H)+.
Example 32
7-(5-Fuoropyridin-2-yI)-2-(/rαns-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000053_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 29. LC-MS: 348.3 (M+H)+.
Example 33 2-(frα/is-4-Hydroxycyclohexyl)-7-[6-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-l- one H
Figure imgf000053_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 29. LC-MS: 398.3 (M+H)+.
Example 34 (55)-2-(frαns-4-Hydroxycyclohexyl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7- diazaspiro [4.5] decan- 1-one H
Figure imgf000054_0001
This compound was prepared by chiral separation of example 27. LC-MS: 398.3 (M+H)+.
Example 35
(5J?)-2-(fran5-4-HydroxycycIohexyI)-7-[5-(trifluoromethyl)pyridiii-2-yl]-2,7- diazaspiro[4.5]decan-l-one
Figure imgf000054_0002
This compound was prepared by chiral separation of example 27. LC-MS: 398.3 (M+H)+.
Example 36 7-(6-Fuoropyridin-2-yl)-2-(frαns-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan- 1-one H
Figure imgf000055_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 29. LC-MS: 348.3 (M+H)+.
Example 37
2-(t ι*αH*-4-Hydroxycyclohexyl)-7-(3-methyIpyridin-2-yl)-2,7-diazaspiro [4.5] decan- 1-one H
Figure imgf000055_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 29. LC-MS: 344.2 (M+H)+.
Example 38
2-(frm«-4-HydroxycycIohexyl)-7-(4-methoxypyridin-2-yl)-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000055_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 29. LC-MS: 360.3 (M+H)+. Example 39 2-(tfrøns-4-Hydroxycyclohexyl)-7-pyridin-2-yI-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000056_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 29. LC-MS: 330.3 (M+H)+.
Example 40 (5iϊ)-2-Cyclohexyl-7-phenyI-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000056_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 17 followed by separation of the enantiomers using a chiral column. LC-MS: 313.3 (M+H)+.
Example 41 (55)-2-Cyclohexyl-7-phenyl-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000056_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 17 followed by separation of the enantiomers using a chiral column. LC-MS: 313.3 (M+H)+. Example 42
7-[3-Chloro-5-(trifluoromethyl)pyridin-2-yI]-2-(fra«s-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one H
Figure imgf000057_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 29. LC-MS: 432.2 (M+H)+.
Example 43 4- [2-(frα«5'-4-HydroxycyclohexyI)-l-oxo-2,7-diazaspiro [4.5] dec-7-yl] benzonitrile H
Figure imgf000057_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 17, with the exception that NaO-(t-Bu) was replaced by K2CO3. LC-MS: 354.2 (M+H)+.
Example 44 2-(frans'-4-Hydroxycyclohexyl)-7-[4-(trifIuoromethyl)phenyI]-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000058_0001
This compound was prepared by using procedures that were analogous to those described for the synthesis of example 1, steps 1-5, and by the following microwave mediated amine/aryl coupling procedure: A mixture of 2-(/rørø-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one hydrochloride
(25 mg, 0.000086 mol), l-bromo-4-(trifluoromethyl)benzene (29 mg, 0.00013 mol) , sodium tert- butoxide (28 mg, 0.00029 mol), palladium acetate (0.6 mg, 0.000002 mol), and 2-{άι-tert- butylphosphino)biphenyl (0.8 mg, 0.000002 mol) in 1,4-dioxane (1.0 niL, 0.013 mol) was heated at 100 0C with stirring for 16 h. LCMS indicated that most of the desired product was oxidized to the ketone so the crude reaction mixture was cooled to -10 0C and 1.0 M of L-selectride ® in tetrahydrofuran (0.2 mL) was added and the mixture was stirred for 20 min. LCMS indicated that the ketone was converted to the alcohol. The crude mixture was purified by prep.-HPLC. to afford 5.2 mg ofthe desired product. LC-MS: 397.2 (M+H)+.
Example 45
3-Fluoro-4-[2-(ϊf««4'-4-hydroxycyclohexyI)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile H
Figure imgf000058_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 43. LC-MS: 372.2 (M+H)+.
Example 46 4-(2-CyclohexyI-l-oxo-2,7-diazaspiro[4.5]dec-7-yl)benzonitrile
Figure imgf000059_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 43. LC-MS: 338.3 (M+H)+.
Example 47 4-(2-Cyclohexyl-l-oxo-2,7-diazaspiro[4.5]dec-7-yl)-3-fluorobenzonitrile
Figure imgf000059_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 43. LC-MS: 356.3 (M+H)+.
Example 48
2-(ϊra/i5-4-HydroxycyclohexyI)-7-(piperidin-l-yIcarbonyl)-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000059_0003
This compound was prepared by using procedures that were analogous to those described for the synthesis of example 1, steps 1-5, and by the following urea coupling procedure. Step 1. 4-nitrophenyl 2-(trans-4-hydroxycyclohexyl)-l-oxo-2, 7-diazaspiro[4.5]decane-7-carboxylate A mixture of 2-(frαrø-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one hydrochloride (0.30 g, 0.0010 mol), /7-nitrophenyl chloroformate (0.25 g, 0.0012 mol), and N1N- diisopropylethylamine (540 μL, 0.0031 mol) in methylene chloride (4 mL, 0.06 mol) was stirred at it for 16 h. The crude reaction mixture was purified by flash column chromatography to afford 120 mg of the desired product.
Step 2. 2- (trans-4-hydroxycyclohexyl) - 7- (piperidin- 1 -ylcarbonyl)-2, 7-diazaspiro[4.5]decan-l-one To a solution of 4-nitrophenyl 2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7- diazaspiro[4.5]decane-7-carboxylate (30 mg, 0.00007 mol) in tetrahydrofuran (0.5 mL, 0.006 mol) was added N,N-diisopropylethylamine (25.0 μL, 0.000144 mol) and piperidine (10 μL, 0.0001 mol).
After stirring at rt for 16 h, the crude reaction mixture was purified by prep.-HPLC to afford the desired product. LC-MS: 364.3 (M+H)+.
Example 49
2-(frfl/i5-4-HydroxycyclohexyI)-7-(pyrrolidin-l-ylcarbonyl)-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000060_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 48. LC-MS: 350.3 (M+H)+.
Example 50
2-(frα«5'-4-HydroxycycIohexyl)-7-[(4-phenyl-3,6-dihydropyridin-l(2H)-yl)carbonyl]-2,7- diazaspiro[4.5]decan-l-one H
Figure imgf000061_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 48. LC-MS: 438.3 (M+H)+.
Example 51
2-(fra«*-4-Hydroxycyclohexyl)-7-[(4-phenylpiperidin-l-yl)carbonyl]-2,7-diazaspiro[4.5]decan-l- one H
Figure imgf000061_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 48. LC-MS: 440.3 (M+H)+.
Example 52
2-(frαns-4-Hydroxycyclohexyl)-7-[(4-phenylpiperazin-l-yl)carbonyl]-2,7-diazaspiro[4.5]decan-l- one H
Figure imgf000062_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 48. LC-MS: 441.2 (M+H)+.
Example 53
7-{[4-(2-Fluorophenyl)piperazin-l-yl]carbonyl}-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro [4.5] decan- 1-one H
Figure imgf000062_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 48. LC-MS: 459.2 (M+H)+.
Example 54
2-(ϊran5'-4-Hydroxycyclohexyl)-7-({4-[2-(trifluoromethyl)phenyl]piperazin-l-yl}carbonyl)-2,7- diazaspiro [4.5] decan- 1-one H
Figure imgf000063_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 48. LC-MS: 509.2 (M+H)+.
Example 55
2-Cyclohexyl-7-isonicotinoyl-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000063_0002
This compound was prepared by using procedures that were analogous to those described for the synthesis of example 1, steps 1-5, followed by the following acylation procedure:
A mixture of 2-cyclohexyl-2,7-diazaspiro[4.5]decan-l-one hydrochloride (15 mg, 0.000055 mol), isonicotinoyl chloride hydrochloride (12 mg, 0.000066 mol), and triethylamine (27 μL, 0.00019 mol) in acetonitrile (0.5 mL, 0.01 mol) was stirred at rt for 2 h. The crude reaction mixture was purified by prep.-HPLC. to afford 18 mg of the desired product. LC-MS: 342.3 (M+H)+.
Example 56 7-Benzoyl-2-cycIohexyl-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000063_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 55. LC-MS: 340.3 (M+H)+.
Example 57 2-CycIohexyI-7-(pyridin-3-ylcarbonyl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000064_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 55. LC-MS: 342.3 (M+H)+.
Example 58
2-(frø«s-4-HydroxycyclohexyI)-7-isonicotinoyl-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000064_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 55. LC-MS: 358.3 (M+H)+.
Example 59 7-Benzoyl-2-(tfr«ns-4-hydroxycycIohexyl)-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000065_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 55. LC-MS: 357.2 (M+H)+.
Example 60
2-(^flHS-4-Hydroxycyclohexyl)-7-(pyridin-3-ylcarbonyl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000065_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 55. LC-MS: 358.3 (M+H)+.
Example 61
Isopropyl {4-[2-(^rα«5'-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl] phenyl} carbamate
Figure imgf000065_0003
Step 1. 7-(4-Aminophenyl)-2-(trans-4-hydroxycyclohexyl)-2, 7-diazaspiro[4.5]decan-l-one
A mixture of 2-(trans-4-hydroxycyclohexyl)-7-(4-nitrophenyl)-2,7-diazaspiro[4.5]decan-l- one (0.13 g, 0.00028 mol, prepared by using a procedure that was analogous to that described for the synthesis of example 43), 10% Pd/C (activated) in methanol (5 mL, 0.1 mol) was stirred under a H2 atmosphere (balloon) for 1.5 hour. The catalyst was filtered and the filtrate was concentrated in-vauo to afford the desired product in quantitative yield. LC-MS: 344.3 (M+H)+.
Step 2. isopropyl {4-[2-(trans-4-hydroxycyclohexyl)-l-oxo-2, 7-diazaspiro[4.5]dec-7- yljphenyl} carbamate A mixture of 7-(4-aminophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l- one (20 mg, 0.00006 mol), isopropyl chloroformate (11 mg, 0.000087 mol), and triethylamine (20 μL,
0.0002 mol) in methylene chloride (300 μL, 0.005 mol) was stirred at rt for 2 h. The crude reaction mixture was purified by prep.-HPLC to afford 17.4 mg of the desired product. LC-MS: 430.3
(M+H)+.
Example 62
Prop-2-yn-l-yl {4-[2-(frα/w-4-hydroxycyclohexyI)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl] phenyl} carbamate
Figure imgf000066_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 61. LC-MS: 426.3 (M+H)+.
Example 63
Methyl {4-[2-(fran5-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate H
Figure imgf000067_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 61. LC-MS: 402.2 (M+H)+.
Example 64
7V-{4-[2-(^α/is'-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}acetamide H
Figure imgf000067_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 61. LC-MS: 386.3 (M+H)+.
Example 65 iV-{4-[2-(frαHS'-4-HydroxycyclohexyI)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl}cyclopropanecarboxamide H
Figure imgf000068_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 61. LC-MS: 412.3 (M+H)+.
Example 66
Isopropyl {3-fluoro-4-[2-(frø«s-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl] phenyl}carbamate
Figure imgf000068_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 61. LC-MS: 448.3 (M+H)+.
Example 67
Prop-2-yn-l-yl {3-fluoro-4-[2-(fra/w-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl] phenyl} carbamate
Figure imgf000069_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 61. LC-MS: 444.3 (M+H)+.
Example 68
Methyl {3-fluoro-4-[2-(frα/ii1-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl] phenyl}carbamate H
Figure imgf000069_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 61. LC-MS: 420.3 (M+H)+.
Example 69 iV-{3-Fluoro-4-[2-(frfl/is-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl}cyclopropanecarboxamide H
Figure imgf000070_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 61. LC-MS: 430.3 (M+H)+.
Example 70
7-(4-Chloropyrimidin-2-yl)-2-(frα/i5'-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000070_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 29. LC-MS: 365.3 (M+H)+.
Example 71 2-Cyclohexyl-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000070_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 29. LC-MS: 382.2 (M+H)+.
Example 72 2-Cyclohexyl-7-pyridin-2-yl-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000071_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 29. LC-MS: 314.3 (M+H)+.
Example 73
7-[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]-2-cycIohexyl-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000071_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 29. LC-MS: 416.2 (M+H)+.
Example 74 2-Cyclohexyl-7-(piperidin-l-ylcarbonyl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000071_0003
This compound was prepared by using procedures that were analogous to those described for the synthesis of example 1, steps 1-5, and by the following urea coupling procedure:
To a solution of 2-cyclohexyl-2,7-diazaspiro[4.5]decan-l-one hydrochloride (20 mg, 0.00007 mol) in methylene chloride (0.5 mL, 0.008 mol) was added N,N-diisopropylethylamine (14.0 μL, 0.0000806 mol) and the solution was stirred at rt for 5 min. prior to the addition of N,N- carbonyldiimidazole (24 mg, 0.00015 mol). After stirring the reaction mixture at rt for 3 h, piperidine (6.2 mg, 0.00007 mol) was added and stirring was continued for 12 h. To drive the reaction to completion the mixture was heated at 170 °C under microwave irradiation for 1 h. The crude mixture was purified by prep.-HPLC to afford the desired product. LC-MS: 348.2 (M+H)+.
Example 75 2-CyclohexyI-7-(pyrroIidin-l-ylcarbonyl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000072_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 74. LC-MS: 334.2 (M+H)+.
Example 76
2-Cyclohexyl-7-[(4-phenyl-3,6-dihydropyridin-l(2H)-yl)carbonyl]-2,7-diazaspiro[4.5]decan-l- one
Figure imgf000072_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 74. LC-MS: 422.2 (M+H)+.
Example 77 2-Cyclohexyl-7-[(4-phenylpiperidin-l-yl)carbonyl]-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000073_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 74. LC-MS: 424.2 (M+H)+.
Example 78 2-CyclohexyI-7-[(4-phenylpiperazin-l-yI)carbonyl]-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000073_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 74. LC-MS: 424.2 (M+H)+.
Example 79 2-Cyclohexyl-7-{[4-(2-fluorophenyl)piperazin-l-yl]carbonyl}-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000073_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 74. LC-MS: 443.2 (M+H)+. Example 80
2-CyclohexyI-7-({4-[2-(trifluoromethyI)phenyI]piperazin-l-yI}carbonyl)-2,7- diazaspiro[4.5]decan-l-one
Figure imgf000074_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 74. LC-MS: 493.2 (M+H)+.
Example 83 2-[2-(^«n5-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]nicotinonitrile H
Figure imgf000074_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 27. LC-MS: 355.2 (M+H)+.
Example 84
7-(5-Chloropyridin-2-yl)-2-(^ra/is-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000075_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 27. LC-MS: 364.2/366.2 (M+H)+.
Example 85
7-(3,5-Dichloropyridin-2-yl)-2-(fr«M5-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000075_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 27. LC-MS: 398.2/400.2/402.2 (M+H)+.
Example 86 2-(frα«*-4-HydroxycyclohexyI)-7-[4-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-l- one H
Figure imgf000075_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 27. LC-MS: 398.2 (M+H)+.
Example 87 2-(^rflH5-4-HydroxycycIohexyl)-7-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-2,7- diazaspiro[4.5]decan-l-one H
Figure imgf000076_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 27. LC-MS: 412.3 (M+H)+.
Example 88
Methyl 6-[2-(f/wιs-4~hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]nicotinate H
Figure imgf000076_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 27. LC-MS: 388.2 (M+H)+.
Example 89 2-(frα/w-4-Hydroxycyclohexyl)-7-isoquinolin-l-yl-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000077_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 27. LC-MS: 380.3 (M+H)+.
Example 90
2-(tfrø«s-4-Hydroxycyclohexyl)-7-quinoIin-2-yI-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000077_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 27. LC-MS: 380.2 (M+H)+.
Example 91 iV-{3-Fluoro-4-[2-(ϊrflHS'-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl] phenyl} acetamide
H
Figure imgf000078_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 61. LC-MS: 404.3 (M+H)+.
Example 92 (5R)-2-(2-Chlorophenyl)-7-(3,5-dichloropyridin-2-yl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000078_0002
Step 1. 1-tert-butyl 3-ethyl 3-(2-chloroethyl)piperidine-l ,3-dicarboxylate
Lithium diisopropylamide (1.8 M in THF, 3.9 mL) was slowly added to a solution of 1-tert-butyl 3-ethyl piperidine-l,3-dicarboxylate (1.50 g, 0.00583 mol) in tetrahydrofuran (20 mL, 0.2 mol) at -78 °C and the mixture was stirred for about 1 hour during which the temperature was allowed to rise to about -50 "C. l-Bromo-2-chloro-ethane (0.75 mL, 0.0082 mol) was slowly added to the mixture and then the resulting mixture was allowed to warm to rt (room temperature). After stirring for 2 h, the reaction mixture was quenched with saturated NH4CI and extracted with ethyl ether twice. The combined organic layers were dried and concentrated in-vacuo to afford the crude product, which was purified by CombiFlash eluting with hexane/EtOAc (max. EA 20%). Step 2. tert-butyl (5S)-2-(2-chlorophenyl)-l-oxo-2,7-diazaspiro[4.5]decane-7-carhoxylate and tert- butyl (5R) -2- (2-chlorophenyl)-l-oxo-2, 7-diazaspiro[4.5]decane- 7-carboxylate
Lithium hexamethyldisilazide (1.0 M in tetrahydrofuran, 2.5 mL) was slowly added to a solution of o-chloroaniline (0.14 g, 0.0011 mol) in tetrahydrofuran (4.0 mL, 0.049 mol) at -78 0C and stirred for 30 min. To this mixture was added a solution of l-tert-butyl 3 -ethyl 3-(2-chloroethyl)piperidine-
1,3-dicarboxylate (0.320 g, 0.00100 mol) in THF (0.5 mL) and the resultant mixture was stirred for additional 18 h. The reaction mixture was quenched by an addition of methanol (2 mL) and the solvent was removed in-vacuo to afford the racemic product, which was purified by CombiFlash (12 g column, eluting with hexane/EtOAc with max. EtOAc 30%) to afford the desired racemate (0.26 g, 72%). LC-MS: 309.1 (M+ H- t-B\x (56)).+ The pure enantiomers were separated by chiral column.
The shorter retention time peak was designated as the S-enantiomer and the longer retention time peak was designated as the R-enantiomer (the R-enantiomer was found to be active).
Step 3. (5R)-2-(2-chlorophenyl)-2, 7-diazaspiro[4.5]decan-l-one hydrochloride Hydrogen chloride (4.0 M in 1,4-dioxane, 2.0 mL) was added to a solution of føt-butyl (5i?)-2-(2- chloropheny^-l-oxo^J-diazaspiro^.SJdecane^-carboxylate (0.103 g, 0.000283 mol) in ethyl acetate (0.5 mL) and the mixture was stirred for 2 h. Then the solvent was removed in-vacuo to afford the desired product. LC-MS: 265.2 (M+H).+
Step 4. (5R)-2-(2-chlorophenyl)-7-(3,5-dichloropyridin-2-yl)-2, 7-diazaspiro[4.5]decan-l-one
A mixture of (5i?)-2-(2-chlorophenyl)-2,7-diazaspiro[4.5]decan-l-one hydrochloride (18.2 mg, 0.0000604 mol), 2,3,5-trichloropyridine (16 mg, 0.000091 mol) and triethylamine (0.025 mL, 0.00018 mol) in NN-dimethylformamide (0.4 mL, 0.005 mol) was irradiated with microwaves to heat the mixture to 180 "C for 20 min. The crude product was purified by prep-HPLC to afford the desired product. LC-MS: 410.1/ 412.1/ 414.0 (M+H)+.
Example 93 2-(2-ChlorophenyI)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000079_0001
A mixture of 2-(2-chlorophenyl)-2,7-diazaspiro[4.5]decan-l-one (16.0 mg, 0.0000604 mol, which was prepared by using a procedure that was analogous to that used for the synthesis of example 1, steps 1-5), 2-chloro-5-(trifiuoromethyl)pyridine (13 mg, 0.000072 mol) and N,N- diisopropylethylamine (0.032 mL, 0.00018 mol) in N-methylpyrrolidinone (0.4 niL, 0.005 mol) was irradiated with microwaves to heat the reaction mixture to 180 "C for 20 min. The crude product was purified by prep-HPLC to afford the desired product. LC-MS: 410.2/412.2 (M+H)+.
Example 94 2-(2-Chlorophenyl)-7-(3-chloropyrazin-2-yl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000080_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 377.1/379.1 (M+H)+.
Example 95 2-(2-Chlorophenyl)-7-(3-chloropyridin-2-yl)-2,7-diazaspiro [4.5] decan-1-one
Figure imgf000080_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 376.1/378.1 (M+H)+.
Example 96
2-[(5R)-2-(2-Chlorophenyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]nicotinonitrile
Figure imgf000081_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 92. LC-MS: 367.2/369.1 (M+H)+.
Example 97
(5R)-2-(2-ChIorophenyl)-7-[3-(trifluoromethyl)pyridin-2-yI]-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000081_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 92. LC-MS: 410.1/412.1 (M+H)+.
Example 98 6-[(5R)-2-(2-ChIorophenyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]nicotinonitrile
Figure imgf000081_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 92. LC-MS: 367.2/369.1 (M+H)+.
Example 99
Methyl {6-[(5R)-2-(2-chlorophenyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate
Figure imgf000082_0001
Step 1. (5R)-7-(5-aminopyridin-2-yl)-2-(2-chlorophenyl)-2, 7-diazaspiro[4,5]decan-l-one
A mixture of (5R)-2-(2-chlorophenyl)-2,7-diazaspiro[4.5]decan-l-one hydrochloride (40.0 mg, 0.000133 mol, prepared by using a procedure analogous to that used for the synthesis of example 92, steps 1-3), 2-chloro-5-nitropyridine (23 mg, 0.00015 mol), and potassium carbonate (55 mg, 0.00040 mol) in NN-dimethylformamide (1.0 mL, 0.013 mol) was stirred at 120 0C for 1.5 hours. After cooling the reaction mixture to ambient temperature the solid was filtered off and the filtrate was concentrated in-vacuo to afford the desired product. LC-MS: 387.1 (M+H)+. The resulting residue was dissolved in methanol and to this solution was added platinum [5 wt. % (dry basis) on activated carbon, wet, Degussa type FlOl, RA/W (Aldrich # 330159), 15 mg] under an atmosphere of H2 (g) at rt for 2 h. The catalyst was filtered off from the mxture and the filtrate was concentrated in- vacuo to afford the product in quantitative yield. LC-MS: 357.1 (M+H)+.
Step 2. Methyl {6-[(5R)-2-(2-chlorophenyl)-l-oxo-2, 7-diazaspiro[4.5]dec-7-yl]pyridin-3- yljcarbamate
Methyl chloroformate (4.4 μL, 0.000057 mol) was added to a solution of (5i?)-7-(5-aminopyridin-
2-yl)-2-(2-chlorophenyl)-2,7-diazaspiro[4.5]decan-l-one (18.5 mg, 0.0000478 mol) and pyridine (13 μL, 0.00016 mol) methylene chloride (1.0 mL, 0.016 mol) and the mixture was stirred for 0.5 h at rt.
The volatiles were removed in-vacuo and the crude product was purified by prep-HPLC. LC-MS: 415.1/417.1 (M+H)+.
Example 100
Ethyl {6-[(5R)-2-(2-chIorophenyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate
Figure imgf000083_0001
This compound was prepared using procedures analogous to those described for the synthesis of example 99. LC-MS: 429.1 (M+H)+.
Example 101
Propyl {6-[(5R)-2-(2-chlorophenyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate
Figure imgf000083_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 99. LC-MS: 443.1 (M+H)+.
Example 102 6-[2-(2-Chlorophenyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-N-methylnicotinamide
Figure imgf000084_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 399.2 (M+H)+.
Example 103 6-[2-(2-Chlorophenyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-N-ethylnicotinamide
Figure imgf000084_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 413.2 (M+H)+.
Example 104
(5JK)-2-(Tetrahydro-2H-pyran-4-yI)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7- diazaspiro[4.5]decan-l-one
Figure imgf000084_0003
Racemic 2-(tetrahydro-2H-pyran-4-yl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7- diazaspiro[4.5]decan-l-one (9.0 mg, 0.000023 mol, the racemic mixture was prepared by using procedures analogous to those described for the synthesis of example 93) was purified by chiral column to give the pure two enantiomers. The shorter retention time peak was designated as S- enantiomer and the longer retention time peak was designated as R-enantiomer. The R-enantiomer was fount to be active. LC-MS: 384.2 (M+H)+.
Example 105
Methyl {6-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yI)-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3- yl}carbamate
Figure imgf000085_0001
Step 1. (5R)-7-(5-aminopyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2, 7-diazaspiro[4.5]decan-l-one
A mixture of (5i?)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-l-one [90 mg, 0.0004 mol, this compound was prepared by using procedures analogous to those described for the synthesis of example 1, steps 1-5], 2-cloro-5-nitropyridine (69 mg, 0.00044 mol), and potassium carbonate (160 mg, 0.0012 mol) in N,N-dimethylformamide (2 niL, 0.02 mol) was stirred at 120 0C for 1.5 hours. After cooling the reaction mixture to ambient temperature, the solid was filtered off and the filtrate was concentrated in-vacuo to afford the desired product. LC-MS: 361.2 (M+H)+. The resulting residue was dissolved in methanol and to this solution was added 10% Pd on carbon and the reaction vessel was placed under a H2 (g) atmosphere and stirred at rt for 1.5 h. The catalyst was filtered off from the mixture and the filtrate was concentrated to afford the desired product in quantitative yield and was used in the next step without further purification. LC-MS: 331.2 (M+H)+.
Step 2. Methyl {6-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2, 7-diazaspiro[4.5]dec-7-yl]pyrϊdin-3- yljcarbamate
Methyl chloroformate (4.4 μL, 0.000057 mol) was added to a solution of (5R)-7-(5-aminopyridin- 2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-l-one (15.8 mg, 0.0000478 mol), N,N- diisopropylethylamine (27 μL, 0.00016 mol) and methylene chloride (1.0 mL, 0.016 mol); and the mixture was stirred for 1 h. The volatiles were removed in-vacuo and the crude product was purified by prep-HPLC. LC-MS: 389.2 (M+H)+.
Example 106 Ethyl {6-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3- yljcarbamate
Figure imgf000086_0001
This compound was prepared using procedures analogous to those described for the synthesis of example 105. LC-MS: 403.3 (M+H)+.
Example 107
Propyl {6-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3- yljcarbamate
Figure imgf000086_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 417.3 (M+H)+.
Example 108 Isopropyl {6-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3- yljcarbamate
Figure imgf000087_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 417.3 (M+H)+.
Example 109
Isobutyl {6-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3- yl}carbamate
Figure imgf000087_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 431.3 (M+H)+.
Example 110 (5R)-7-(3-Chloropyrazin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000088_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 351.1 (M+H)+.
Example 111
3-[(5R)-l-Oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyrazine-2-carbonitrile
Figure imgf000088_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 342.2 (M+H)+.
Example 112
(5R)-7-(3-Chloropyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000088_0003
This compound was prepared using procedures analogous to those described for the synthesis of example 93. LC-MS: 350.2 (M+H)+.
Example 113 2-[(5R)-l-Oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]nicotinonitrile
Figure imgf000089_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 341.2 (M+H)+.
Example 114
(5R)-2-(Tetrahydro-2H-pyran-4-yl)-7-[3-(trifluoromethyl)pyridin-2-yl]-2,7- diazaspiro[4.5]decan-l-one
Figure imgf000089_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 384.2 (M+H)+.
Example 115 (5R)-7-(3,5-Dichloropyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000089_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 384.1 (M+H)+.
Example 116 (5R)-7-(5-ChIoropyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000090_0001
A mixture of (5R)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-l-one hydrochloride (29.4 mg, 0.000107 mol, this compound was prepared by using procedures analogous to those described for the synthesis of example 1, steps 1-5), 5-chloro-2-fluoropyridine (17 mg, 0.00013 mol) and potassium carbonate (0.029 mL, 0.00032 mol) in N,N-dimethylformamide (0.6 mL, 0.008 mol) was heated at 120 0C for 5 h. The crude product was purified by prep-HPLC to afford the desired product. LC-MS: 350.2 (M+H)+.
Example 117
Methyl {5-chloro-6-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7- yl] pyridin-3-yl} carbamate
Figure imgf000090_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 423.1 (M+H)+.
Example 118
Ethyl {5-chloro-6-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyridin-
3-yl}carbamate
Figure imgf000091_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 437.2 (M+H)+.
Example 119
Propyl {5-chloro-6-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7- yl] pyridin-3-yl} carbamate
Figure imgf000091_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 451.2 (M+H)+.
Example 120
Isopropyl {5-chloro-6- [(5R)- l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro [4.5] dec-7- yl] pyridin-3-yl} carbamate
Figure imgf000092_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 451.2 (M+H)+.
Example 121
Isobutyl {5-chloro-6-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7- yl] pyridin-3-yl}carbamate
Figure imgf000092_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 465.2 (M+H)+.
Example 122 3-Chloro-4-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile
Figure imgf000093_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 116. LC-MS: 351.1 (M+H)+.
Example 123
6-[(5R)-l-Oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]nicotinonitrile
χ
Figure imgf000093_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 116. LC-MS: 341.2 (M+H)+.
Example 124 (5R)-7-(3,5-Difluoropyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000093_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 116. LC-MS: 352.2 (M+H)+. Example 125 (5R)-7-Isoquinolin-l-yl-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000094_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 116. LC-MS: 366.3 (M+H)+.
Example 126 (5R)-7-quinolin-2-yl-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000094_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 116. LC-MS: 366.2 (M+H)+.
Example 127
Methyl {5-methyl-6-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7- yl]pyridin-3-yl}carbamate
Figure imgf000095_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 403.2 (M+H)+.
Example 128
Ethyl {5-methyl-6-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7- yl] pyridin-3-yl}carbamate
Figure imgf000095_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 417.2 (M+H)+.
Example 129
Propyl {5-methyl-6-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7- yl]pyridin-3-yl}carbamate
Figure imgf000096_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 431.2 (M+H)+.
Example 130
Methyl {3-fluoro-4-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7- yl] phenyljcarbamate
Figure imgf000096_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 406.3 (M+H)+.
Example 131
Ethyl {3-fluoro-4-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7- yl] phenyl} carbamate
Figure imgf000097_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 420.2 (M+H)+.
Example 132
Propyl {3-fluoro-4-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7- yl]phenyl}carbamate
Figure imgf000097_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 434.2 (M+H)+.
Example 133
Isopropyl {3-fluoro-4-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7- yl] phenyl} carbamate
Figure imgf000098_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 434.3 (M+H)+.
Example 134
Isobutyl {3-fluoro-4-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7- yl] phenyl} carbamate
Figure imgf000098_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 448.3 (M+H)+.
Example 135
Methyl {4-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7- yl] phenyl} carbamate
Figure imgf000099_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 388.3 (M+H)+.
Example 136
Ethyl {4-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7- yl] phenyl}carbamate
Figure imgf000099_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 402.2 (M+H)+.
Example 137
Propyl {4- [(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yI)-2,7-diazaspiro [4.5] dec-7- yl] phenyl} carbamate
Figure imgf000100_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 416.3 (M+H)+.
Example 138
Isopropyl {4- [(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro [4.5] dec-7- yl] phenyl} carbamate
Figure imgf000100_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 416.2 (M+H)\
Example 139
Isobutyl {4-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yI)-2,7-diazaspiro[4.5]dec-7- yl] phenyl}carbamate
Figure imgf000101_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 430.3 (M+H)+.
Example 140
Methyl methyl{4-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7- yl] phenyl}carbamate
Figure imgf000101_0002
Sodium hydride (1.6 mg, 0.000041 mol) was added to a solution of methyl {4-[(5R)-l-oxo-2- (tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate (8.0 mg, 0.000021 mol) in tetrahydrofuran (1.0 mL, 0.012 mol) at it. After stirring for 5 min., methyl iodide (2.6 μL, 0.000041 mol) was added and the reaction mixture was stirred for 1 h at rt. The crude product was purified by prep- HPLC. LC-MS: 402.3 (M+H)+.
Example 141
3-Fluoro-4-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile
Figure imgf000102_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 116. LC-MS: 358.2 (M+H)+.
Example 142
2-(l-Methylpiperidin-4-yl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decaii-l-one
Figure imgf000102_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 397.2 (M+H)+.
Example 143
Methyl 4-{l-oxo-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]dec-2-yl}piperidine-l- carboxylate
Figure imgf000102_0003
Step 1. 2-piperidin-4-yl-7-[5~(trifluoromethyl)pyridin-2-yl]-2, 7-diazaspiro[4.5]decan-l-one
A mixture of tert-butyl 4-(l-oxo-2,7-diazaspiro[4.5]dec-2-yl)piperidine-l-carboxylate (36.0 mg, 0.000107 mol, this compound was prepared by using a procedure that was analogous to that described for the synthesis of example 1, steps 1-5), 2-chloro-5-(trifluoromethyl)pyridine (23 mg, 0.00013 mol) and N,N-diisopropylethylamine (0.056 niL, 0.00032 mol) in N-methylpyrrolidinone (0.8 niL, 0.008 mol) was irradiated with microwaves to heat the mixture to 180 "C for 20 min. The mixture was diluted with ethyl acetate and washed with water and brine, dried over sodium sulfate, filtered and concentrated to afford the desired Boc-protected product. LC-MS: 483.2 (M+H)+. The residue was treated with 4 Ν HCl in dioxane to afford the de-Boc product. LC-MS: 383.2 (M+H)+.
Step 2. Methyl 4-{l-oxo-7-[5-(trifluoromethyl)pyridin-2-yl]-2, 7-dia∑aspiro[4.5]dec-2-yl}piperidine- 1-carboxylate
Methyl chloroformate (4.4 μL, 0.000057 mol) was added to a solution of 2-piperidin-4-yl-7-[5- (trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-l-one (18.3 mg, 0.0000478 mol) and NN- diisopropylethylamine (27 μL, 0.00016 mol) in methylene chloride (1.0 mL, 0.016 mol); and the mixture was stirred for 0.5 h. The volatiles were removed in-vacuo and the product was purified by prep-HPLC. LC-MS: 441.2 (M+H)+.
Example 144 Ν,Ν-DimethyI-4-{l-oxo-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]dec-2- yl} piperidine- 1-carboxamide
Figure imgf000103_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 143. LC-MS: 454.2 (M+H)+.
Example 145 7-(3-Chloropyrazin-2-yl)-2-quinoIm-5-yl-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000104_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 394.2 (M+H)+.
Example 146
7-(3-Chloropyridin-2-yl)-2-quinolin-5-yl-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000104_0002
This compound was prepared usring01 procedures analogous to those described for the synthesis of example 93. LC-MS: 393.2 (M+H)+.
Example 147 7-(3,5-Dichloropyridin-2-yl)-2-quinolin-5-yl-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000104_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 427.2 (M+H)+.
Example 148 2-(2-MethyIphenyI)-7-[4-(trifluoromethyl)pyrimidin-2-yl]-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000105_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 391.2 (M+H)+.
Example 149
7-(4-Chloropyrimidin-2-yl)-2-(2-methylphenyl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000105_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 357.2 (M+H)+.
Example 150 7-(6-ChIoro-7H-purin-2-yl)-2-(2-methylphenyl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000105_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 397.2 (M+H)+.
Example 151 3-[2-(2-MethylphenyI)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyrazine-2-carbonitrile
Figure imgf000106_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 348.2 (M+H)+.
Example 152
7-(6-ChIoropyrazin-2-yl)-2-(2-methylphenyl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000106_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 357.2 (M+H)+.
Example 153 7-(3-Chloropyrazin-2-yl)-2-(2-methylphenyl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000106_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 357.2 (M+H)+.
Example 154 2-(2-MethylphenyI)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000107_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 390.2 (M+H)+.
Example 155
2-Quinolin-5-yI-7-[5-(trifluoromethyl)pyridin-2-yI]-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000107_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 427.2 (M+H)+.
Example 156 2-IsoquinoIin-5-yI-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000107_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 427.2 (M+H)+. Example 157
2-(4-Bromo-2-methylphenyI)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000108_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 468.1/470.1 (M+H)+.
Example 158 3-Methyl-4-{l-oxo-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]dec-2-yl}benzonitrile
Figure imgf000108_0002
A mixture of 2-(4-bromo-2-methylphenyl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7- diazaspiro[4.5]decan-l-one (63.6 mg, 0.000136 mol), zinc cyanide (32 mg, 0.00027 mol), potassium carbonate (0.056 g, 0.00041 mol) and tetrakis(triphenylphosphine) palladium(O) (8 mg, 0.000007 mol) in N,N-dimethylformamide (0.5 mL, 0.006 mol) was stirred at 100 0C for 2 days. The reaction mixture was cooled to ambient temperature and purified by prep-HPLC (under PH ~ 10) to afford the desired product. LC-MS : 415.2 (M+H)+.
Example 159
Ν-(3-MethyI-4-{l-oxo-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]dec-2- yl}phenyl)acetamide
Figure imgf000109_0001
To a solution of 2-(4-bromo-2-methylphenyl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7- diazaspiro[4.5]decan-l-one (38.1 mg, 0.0000814 mol), in 1,4-dioxane (0.5 niL, 0.006 mol) was added (lS,2S)-N,N'-dimethylcyclohexane-l,2-diamine (2.3 mg, 0.000016 mol), copper(I) iodide (1.6 mg, 0.0000081 mol), acetamide (9.6 mg, 0.00016 mol), and potassium carbonate (23.6 mg, 0.000171 mol) and the mixture was stirred at 100 0C overnight. The product was purified by prep-HPLC. LC-MS: 447.2 (M+H)+.
Example 160 Ν-(3-Methyl-4-{l-oxo-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]dec-2- yl} phenyl) ni ethanesull'oiiamide
Figure imgf000109_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 159. LC-MS: 483.2 (M+H)+.
Example 161 2-(3-Methylpyridin-4-yl)-7-[5-(trifluoromethyI)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000110_0001
Step 1. 1-tert-butyl 3-ethyl 3-[2-(tritylamino)ethyl]piperidine-l,3-dicarboxylate
Tritylamine (180 mg, 0.00068 mol) was added to a solution of 1-tert-butyl 3-ethyl 3-(2- oxoethyl)piperidine-l,3-dicarboxylate (0.170 g, 0.000568 mol, this was prepared by using procedures analogous to that described for the synthesis of example 1, steps 1-2) in 1,2-dichloroethane (4.0 mL, 0.051 mol) and followed by sodium triacetoxyborohydride (0.36 g, 0.0017 mol) and the mixture was stirred overnight. The mixture was poured into pre-cooled water, and extracted with ethyl acetate. The organic layer was separated, dried (NaSO4), and concentrated in-vacuo. The product was purified by CombiFlash eluting with hexane/EtOAc (max EtOAc 20%). LC-MS: 543.3 (M+H)+; 243.2.
Step 2. 2, 7-diazaspiro[4.5]decan-l-one
Trifluoroacetic acid (1.0 mL, 0.013 mol) was added to a solution of 1-tert-butyl 3-ethyl 3-[2- (tritylamino)ethyl]piperidine-l,3-dicarboxylate (0.10 g, 0.00018 mol) in methylene chloride (1.0 mL, 0.016 mol) and the mixture was stirred for 1 h at rt to remove the Boc and trityl groups. Then the solvent was removed under vacuum and to the resultant residue was added 1,4-dioxane (3.0 mL, 0.038 mol) followed by N,N-diisopropylethylamine (0.13 mL, 0.00074 mol) and the resultant mixture was stirred at 150 0C (microwave) for 1 h. The solvent from the mixture was removed under vacuum and the crude product was used in the next step without further purification. LC-MS: 155.2 (MH-H)+.
Step 3. 7-[5-(trifluoromethyl)pyridin-2-yl]-2, 7-diazaspiro[4.5]decan-l-one
A mixture of 2,7-diazaspiro[4.5]decan-l-one (50.0 mg, 0.000324 mol), 2-chloro-5- (trifluoromethyl)pyridine (71 mg, 0.00039 mol) and N,N-diisopropylethylamine (0.17 mL, 0.00097 mol) in N-methylpyrrolidinone (2 mL, 0.02 mol) was irradiated with microwaves at 180 "C for 20 min. The product was purified by prep-HPLC. LC-MS: 300.2 (M+H)+.
Step 4. 2-(3-methylpyridin-4-yl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2, 7-diazaspiro[4.5]decan-l-one
To a solution of 7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-l-one (24.4 mg, 0.0000814 mol) in 1,4-dioxane (0.5 mL, 0.006 mol) were added (lS,2S)-Ν,Ν'-dimethylcyclohexane- 1,2-diamine (2.3 mg, 0.000016 mol), copper(I) iodide (1.6 mg, 0.0000081 mol), 4-bromo-3- methylpyridine (28 mg, 0.00016 mol) and potassium carbonate (23.6 mg, 0.000171 mol); and the mixture was stirred at 100 0C overnight. The product was purified by prep-HPLC. LC-MS: 391.2 (M+H)+.
Example 162 (5R)-2-(4-Methylpyridin-3-yI)-7-[5-(trifluoromethyI)pyridin-2-yI]-2,7-diazaspiro[4.5]decan-l- one
Figure imgf000111_0001
Step 1. 1-tert-butyl 3-ethyl 3-{2-[(4-methylpyridin-3-yl)amino]ethyl}piperidine-l,3-dicarboxylate
4-methylpyridin-3 -amine (36.0 mg, 0.000333 mol) was added to a solution of
Figure imgf000111_0002
3- ethyl 3-(2-oxoethyl)piperidine-l,3-dicarboxylate (0.095 g, 0.00032 mol) in 1,2-dichloroethane (1.9 mL, 0.025 mol) and followed by sodium triacetoxyborohydride (0.20 g, 0.00095 mol) and the mixture was stirred for 24 h. The mixture was poured into pre-cooled water, extracted with ethyl acetate. The organic layer was separated, dried and concentrated. The product was purified by CombiFlash using CH2Cl2/Et0Ac (max EtOAc 50%). LC-MS: 392.3 (M+H)+.
Step 2. ethyl 3-{2-[(4-methylpyridin-3-yl)amino]ethyl}pipeήdine-3-carboxylate trihydrochloride
Hydrogen chloride in 1,4-dioxane (4.0 M, 2.0 mL) was added to a solution of \-tert-buty\ 3- ethyl 3-{2-[(4-methylpyridin-3-yl)amino]ethyl}piperidine-l,3-dicarboxylate (0.036 g, 0.000092 mol) in ethyl acetate (0.5 mL) and the mixture was stirred for 2 h. Then the solvent was removed in-vacuo to afford the product. LC-MS: 292.3 (M+H)+.
Step 3. (5R)-2-(4-methylpyridin-3-yl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2, 7-diazaspiro[4.5]decan- 1-one
A mixture of ethyl 3-{2-[(4-methylpyridin-3-yl)amino]ethyl}piperidine-3-carboxylate trihydrochloride (42.8 mg, 0.000107 mol), 2-chloro-5-(trifluoromethyl)pyridine (23 mg, 0.00013 mol) and N,N-diisopropylethylamine (0.056 mL, 0.00032 mol) in N-methylpyrrolidinone (0.8 mL, 0.008 mol) was irradiated with microwaves to 180 °C for 20 min. Sodium hydride (30.0 mg) was then added to the above solution and the mixture was stirred overnight. The product was purified by prep- HPLC. LC-MS: 391.2 (M+H)+. Example 163 7-(3-Chloropyrazin-2-yl)-2-(l-methylpiperidin-4-yl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000112_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 364.1 (M+H)+.
Example 164
Methyl [4-[(5R)-2-cyclohexyl-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-
(trifluoromethyl)phenyl] carbamate
Figure imgf000112_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 454.2 (M+H)+.
Example 165 Ethyl [4-[(5R)-2-cyclohexyl-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-
(trifluoromethyl)phenyl]carbamate
Figure imgf000113_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 468.2 (M+H)+.
Example 166
Prop-2-yn-l-yl [4-[(5R)-2-cyclohexyl-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-
(trifluoromethyl)phenyl] carbamate
Figure imgf000113_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 478.1 (M+H)+.
Example 167 N-[4-[(5R)-2-Cyclohexyl-l-oxo-2,7-diazaspiro[4.5]dec-7-yI]-3-(trifluoromethyl)phenyl]acetamide
Figure imgf000114_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 438.1 (M+H)+.
Example 168
N-[4-[(5R)-2-Cyclohexyl-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3- (trifluoromethyl)phenyl]methanesulfonamide
Figure imgf000114_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 474.1 (M+H)+.
Example 169
Methyl methyl[4-[(5R)-2-cyclohexyl-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-
(trifluoromethyl)phenyl] carbamate
Figure imgf000115_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 468.1 (M+H)+.
Example 170
Prop-2-yn-l-yl {5-chloro-6-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl] pyridin-3-yl} carbamate
Figure imgf000115_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 461.1 (MH-H)+.
Example 171
Methyl {5-chloro-6-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl] pyridin-3-yl}carbamate H
Figure imgf000116_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 437.1 (M+H)+.
Example 172
Ethyl {5-chloro-6-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yI]pyridin-3-yl}carbamate
Figure imgf000116_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 450.1 (M+H)+.
Example 173
N-{5-Chloro-6-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3- yl}acetamide
Figure imgf000117_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 421.1 (M+H)+.
Example 174
N-{5-Chloro-6-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3- yljmethanesulfonamide
Figure imgf000117_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 457.2 (M+H)+.
Example 175
4-{l-Oxo-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]dec-2- yl}cyclohexanecarbonitrile I
Figure imgf000118_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 407.2 (M+H)+.
Example 176
4-{l-Oxo-7-[4-(trifluoromethyI)phenyl]-2,7-diazaspiro[4.5]dec-2-yl}cyclohexanecarbonitriIe
Figure imgf000118_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 406.2 (M+H)+.
Example 177
4-{7-[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]-l-oxo-2,7-diazaspiro[4.5]dec-2- yl}cyclohexanecarbonitrile
Figure imgf000119_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 441.2 (M+H)+.
Example 178
4-[7-(3,5-Dichloropyridin-2-yl)-l-oxo-2,7-diazaspiro[4.5]dec-2-yI]cyclohexanecarbonitriIe
Figure imgf000119_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 407.2/409.2 (M+H)+.
Example 179
4-[7-(6-Fluoropyridin-2-yl)-l-oxo-2,7-diazaspiro[4.5]dec-2-yl]cyclohexanecarbonitrile
Figure imgf000119_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 357.1 (M+H)+.
Example 180 (5R)-7-(2-Fluoro-4-methylphenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l- one H
Figure imgf000120_0001
A mixture of (5R)-2-(frαrø-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one (20 mg, 0.00007 mol, this compound was prepared by using procedures analogous to those described in example 1, steps 1-5), 4-methyl-2-fluoro-l-iodobenzene (21 mg, 0.00009 mol), sodium tert-bvAoxide (9.98 mg, 0.000104 mol), 1,4,7,10,13,16-hexaoxacyclooctadecane (27.4 mg, 0.000104 mol) , 2-(di- tert-butylphosphino)biphenyl (0.8 mg, 0.000003 mol) , tris(diben2ylideneacetone)dipalladium(0) (1 mg, 0.000001 mol), in tert-butyl alcohol (1.0 mL, 0.010 mol) was stirred at rt for 18. The crude product was purified by prep-HPLC to afford the desired product. . LC-MS: 361.1 (MfH)+.
Example 181
(5R)-2-(frfl/i5-4-HydroxycycIohexyl)-7-(4-methoxyphenyl)-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000120_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 180. LC-MS: 359.1 (M+H)+.
Example 182 {4-[(5i-)-2-(/ransr-4-HydroxycycIohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yI]phenyl}acetonitrile H
Figure imgf000121_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 180. LC-MS: 368.1 (M+H)+.
Example 183
(5JR)-2-(fm«s-4-Hydroxycyclohexyl)-7-[3-(trifluoromethoxy)phenyI]-2,7-diazaspiro[4.5]decan-l- one
Figure imgf000121_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 180. LC-MS: 413.1 (M+H)+.
Example 184 (5J?)-2-(fm«5-4-Hydroxycycloliexyl)-7-[3-(trifluoromethyl)phenyl]-2,7-diazaspiro[4.5]decan-l- one H
Figure imgf000122_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 180. LC-MS: 397.1 (M+H)+.
Example 185
(5JR)-2-(frfl«5'-4-Hydroxycyclohexyl)-7-[2-(trifluoromethoxy)phenyl]-2,7-diazaspiro[4.5]decan-l- one H
Figure imgf000122_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 180. LC-MS: 413.1 (M+H)+.
Example 186 (5R)-7-(4-Chloro-2-methylphenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l- one H
Figure imgf000122_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 180. LC-MS: 377.1 (M+H)+.
Example 187 (5R)-7-(3-Chloro-2-methylphenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l- one H
Figure imgf000123_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 180. LC-MS: 377.1 (M+H)+.
Example 188 (5R)-7-(2-ChIoro-4-methylphenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l- one H
Figure imgf000123_0002
A mixture of (5R)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one (20 mg,
0.00007 mol, this compound was prepared by using procedures analogous to those described in example 1, steps 1-5), 2,4-dichloroiodobenzene (22.7 mg, 0.0000831 mol), potassium carbonate (20.1 mg, 0.000145 mol), copper(I) iodide (0.6 mg, 0.000003 mol), and (lS,2S)-cyclohexane-l,2-diol (16.1 mg, 0.000138 mol) in tert-butyl alcohol (1.0 mL, 0.010 mol) was heated at 100 0C for 18 h. The crude product was purified by prep-HPLC to afford the desired product. LC-MS: 377.1 (M+H)+.
Example 189 2-FIuoro-6-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile H
Figure imgf000124_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 188. LC-MS: 372.1 (M+H) .
Example 190
(5R)-7-(2,5-DichlorophenyI)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000124_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 188. LC-MS: 397.2/399.2 (M+H)+.
Example 191 (5R)-7-(2,3-Dichlorophenyl)-2-(trans-4-hydroxycyclohexyI)-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000124_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 188. LC-MS: 397.2/399.2 (M+H)+. Example 192
(5R)-7-(3,5-Difluorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000125_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 188. LC-MS: 365.1 (M+H)+.
Example 193 (5R)-7-(4-ChIoro-2-methylphenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l- one H
Figure imgf000125_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 188. LC-MS: 377.1 (M+H)+.
Example 194
(5R)-7-(3-Chloro-2-methylphenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l- one H
Figure imgf000126_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 188. LC-MS: 377.1 (M+H)+.
Example 195
(5R)-7-(2,6-Dichlorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000126_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 188. LC-MS: 397.2/399.2 (M+H)+.
Example 196
3-[(5R)-2-(fra«5-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile H
Figure imgf000126_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 188. LC-MS: 354.2 (M+H)+. Example 197
(5R)-7-(2-FIuorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000127_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 180. LC-MS: 347.1 (M+H)+.
Example 198
(5R)-7-(2-Chlorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000127_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 180. LC-MS: 363.1 (M+H)+.
Example 199 (5R)-7-(4-Chloro-2-fluorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000127_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 180. LC-MS: 381.1 (M+H)+.
Example 200 (5R)-7-(2,4-Difluorophenyl)-2-(trans-4-hydroxycyclohexyI)-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000128_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 180. LC-MS: 365.1 (M+H)+.
Example 201
(5R)-7-(3-Chloro-2-fluorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000128_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 180. LC-MS: 381.1 (M+H)+.
Example 202
(frø«5-4-{l-Oxo-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]dec-2- yl} cyclohexyl) acetonitrile
Figure imgf000129_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 421.1 (M+H)+.
Example 203
(^ffOS'-4-{l-Oxo-7-[4-(trifluoromethyl)phenyl]-2,7-diazaspiro[4.5]dec-2- yl}cyclohexyl)acetonitrile
Figure imgf000129_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 420.1 (M+H)+.
Example 204
(frαH,s-4-{7-[3-ChloiO-5-(trifluoromethyl)pyridin-2-yl]-l-oxo-2,7-diazaspiro[4.5]dec-2- yl}cyclohexyl)acetonitrile
Figure imgf000130_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 455.1 (M+H)+.
Example 205
{^rα«5-4-[7-(3,5-Dichloropyridin-2-yl)-l-oxo-2,7-diazaspiro[4.5]dec-2-yI]cyclohexyl}acetonitrile
Figure imgf000130_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 421.1 (M+H)+.
Example 206
{trans-4- [7-(6-Fluoropyridin-2-yl)-l-oxo-2,7-diazaspiro [4.5] dec-2-yl] cyclohexyl} acetonitrile
Figure imgf000130_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 371.1 (M+H)+.
Example 207 (5R)-2-(fra«5'-4-HydroxycycIohexyl)-7-(3,5,6-trifluoropyridin-2-yl)-2,7-diazaspiro[4.5]decan-l- one H
Figure imgf000131_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 384.1 (M+H)+.
Example 208 (5R)-7-(4,6-Dimethoxypyrimidin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-
1-one H
Figure imgf000131_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 391.1 (M+H)+.
Example 209
(5R)-7-[4-FIuoro-5-(trifluoromethyl)pyrimidin-2-yl]-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one H
Figure imgf000132_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 417.1 (M+H)+.
Example 210
(5R)-7-(2,5-Difluorophenyl)-2-(trans-4-hydroxycyclohexyI)-2,7-diazaspiro[4.5]decan-l-one
H
Figure imgf000132_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 180. LC-MS: 365.1 (M+H)+.
Example 211 (5R)-7-[2-(Difluoromethoxy)phenyl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l- one H
Figure imgf000132_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 180. LC-MS: 395.1 (M+H)+.
Example 212 (5R)-7-(4-Fluoropyrimidin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000133_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 349.1 (M+H)+.
Example 213 (5R)-7-[4-Chloro-5-(trifluoromethyl)pyrimidin-2-yl]-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one H
Figure imgf000133_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 433.1 (M+H)+.
Example 214 (5R)-2-(trans-4-Hydroxycyclohexyl)-7-quinazolin-4-yl-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000134_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 381.1 (M+H)+.
Example 215
(5R)-2-(trans-4-Hydroxycyclohexyl)-7-(6-methoxypyridin-3-yl)-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000134_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 180. LC-MS: 360.1 (M+H)+.
Example 216
(5R)-2-(trans-4-HydroxycyclohexyI)-7-[6-(methylamino)-9H-purin-2-yI]-2,7- diazaspiro[4.5]decan-l-one
H
Figure imgf000135_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 400.1 (M+H)+.
Example 217 tert-Butyl (/#"fl/i5-4-{l-oxo-7-[S-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]dec-2- yl}cyclohexyl)carbamate
Figure imgf000135_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 497.1 (M+H)+.
Example 218-a
7-{[4-(2-Chlorophenyl)piperazin-l-yl]carbonyl}-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one H
Figure imgf000136_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 48. LC-MS: 475.1 (M+H)+.
Example 218-b
2-(trans-4-Hydroxycyclohexyl)-7-({4-[2-(trifluoromethyl)quinolin-4-yl)piperazin-l-yl}carbonyl)-
2,7-diazaspiro[4.5]decan-l-one H
This compound was prepared by using procedures analogous to those described for the synthesis of example 48. LC-MS: 560.1 (M+H)+.
Example 219
2-(trans-4-Hydroxycyclohexyl)-7-({4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-l-yl}carbonyl)- 2,7-diazaspiro[4.5] decan-1-one H
Figure imgf000137_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 48. LC-MS: 510.1 (M+H)+.
Example 220
2-(trans-4-HydroxycycIohexyl)-7-{[4-(2-methylphenyl)piperazin-l-yl]carbonyl}-2,7- diazaspiro[4.5]decan-l-one H
Figure imgf000137_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 48. LC-MS: 455.1 (M+H)+.
Example 221
7-{[4-(3,4-Dichlorophenyl)piperazin-l-yl]carbonyl}-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one H
Figure imgf000138_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 48. LC-MS: 509.1 (M+H)+.
Example 222
2-(trans-4-Hydroxycyclohexyl)-7-({4-[3-(trifluoromethyl)phenyl]piperazin-l-yl}carbonyI)-2,7- diazaspiro[4.5]decan-l-one H
Figure imgf000138_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 48. LC-MS: 509.1 (M+H)+.
Example 223
7-[(4-Biphenyl-4-ylpiperazin-l-yl)carbonyl]-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one H
Figure imgf000139_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 48. LC-MS: 517.1 (M+H)+.
Example 224
2-(trans-4-HydroxycycIohexyl)-7-({4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-l-yl}carbonyl)- 2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000139_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 48. LC-MS: 510.1 (M+H)+.
Example 225
2-(trans-4-Hydroxycyclohexyl)-7-{[4-(2-methoxyphenyI)piperazin-l-yl]carbonyl}-2,7- diazaspiro[4.5]decan-l-one
Figure imgf000140_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 48. LC-MS: 471.1 (M+H)+.
Example 226
2-(trans-4-Hydroxycyclohexyl)-7-[(4-pyridin-2-ylpiperazin-l-yl)carbonyl]-2,7- diazaspiro [4.5] decan-1-one H
Figure imgf000140_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 48. LC-MS: 442.1 (M+H)+.
Example 227
7-{[4-(4-Chlorophenyl)piperazin-l-yl]carbonyl}-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one H
Figure imgf000141_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 48. LC-MS: 475.1 (M+H)+.
Example 228
7-{[4-(2-Ethoxyphenyl)piperazin-l-yl]carbonyI}-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro [4.5] decan-1-one H
Figure imgf000141_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 48. LC-MS: 485.1 (M+H)+.
Example 229
2-(trans-4-Hydroxycyclohexyl)-7-{[4-(3-methoxyphenyl)piperazin-l-yl]carbonyl}-2,7- diazaspiro[4.5]decan-l-one H
Figure imgf000142_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 48. LC-MS: 471.1 (M+H)+.
Example 230
2-(trans-4-Hydroxycyclohexyl)-7-{[4-(3-methylphenyl)piperazin-l-yl]carbonyl}-2,7- diazaspiro[4.5]decan-l-one H
Figure imgf000142_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 48. LC-MS: 455.1 (M+H)+.
Example 231
7-{[4-(3-ChlorophenyI)piperazin-l-yl]carbonyl}-2-(trans-4-hydroxycycIohexyl)-2,7- diazaspiro [4.5] decan- 1-one H
Figure imgf000143_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 48. LC-MS: 475.1 (M+H)+.
Example 232
2-(trans-4-HydroxycycIohexyl)-7-{[4-(4-methoxyphenyl)piperazin-l-yl]carbonyl}-2,7- diazaspiro[4.5]decan-l-one H
Figure imgf000143_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 48. LC-MS: 471.1 (M+H)+.
Example 233
4-(4-{[2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]carbonyl}piperazin-l- yl)benzonitrile H
Figure imgf000144_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 48. LC-MS: 466.1 (M+H)+.
Example 234
7-{[4-(3,5-Dichloropyridin-4-yl)piperazin-l-yl]carbonyl}-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro [4.5] decan-1-one H
Figure imgf000144_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 48. LC-MS: 510.1 (M+H)+.
Example 235
(5R)-2-(trans-4-Hydroxycyclohexyl)-7-(l,3-thiazol-2-yl)-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000144_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 336.2 (M+H)+.
Example 236 2-(trans-4-Hydroxycyclohexyl)-7-({4-[4-(trifluoromethyl)phenyl]piperazin-l-yl}carbonyl)-2,7- diazaspiro [4.5] decan-1-one
Figure imgf000145_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 48. LC-MS: 509.1 (M+H)+.
Example 237
7-(3,5-DichIoropyridin-2-yl)-2-(4-hydroxy-l-adamantyl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000145_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS : 451.1 (M+H)+.
Example 238
Propyl {3-fluoro-4-[2-(4-hydroxy-l-adamantyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl}carbamate
Figure imgf000146_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 500.2 (M+H)+.
Example 239
2-(4-Hydroxy-l-adamantyI)-7-[3-(trifluoromethyl)pyridin-2-yI]-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000146_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 450.2 (M+H)+.
Example 240
Ethyl {3-fluoro-4-[2-(4-hydroxy-l-adamantyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl] phenyl}carbamate
Figure imgf000146_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 486.2 (M+H)+.
Example 241 7-(3,5-Difluoropyridin-2-yl)-2-(4-hydroxy-l-adamantyI)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000147_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 418.2 (M+H)+.
Example 242
3-Fluoro-4- [2-(4-hydroxy-l-adamantyl)-l-oxo-2,7-diazaspiro [4.5] dec-7-yl] benzonitrile
Figure imgf000147_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 424.2 (M+H)+.
Example 243
2- [2-(4-Hydroxy-l-adamantyl)-l-oxo-2,7-diazaspiro[4.5] dec-7-yl] nicotinonitrile
Figure imgf000148_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 407.2 (M+H)+.
Example 244
4-[2-(4-Hydroxy-l-adamantyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]benzonitriIe
Figure imgf000148_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 406.2 (M+H)+.
Example 245
N-{3-Fluoro-4-[2-(4-hydroxy-l-adamantyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl] phenyl} cyclopropanecarboxamide
Figure imgf000148_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 482.2 (M+H)+.
Example 246 2-(4-Hydroxy-l-adamantyl)-7-[5-(trifluoromethyl)pyridin-2-yI]-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000149_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 450.2 (M+H)+.
Example 247 7-(5-Ethylpyrimidin-2-yl)-2-(4-hydroxy-l-adamanfyl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000149_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 411.2 (M+H)+.
Example 248 7-(3-FIuoropyridin-2-yl)-2-(4-hydroxy-l-adamantyI)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000150_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 400.2 (M+H)+.
Example 249
N-{3-Fluoro-4-[2-(4-hydroxy-l-adamantyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyI}acetamide
Figure imgf000150_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 456.2 (M+H)+.
Example 250
N-{3-Fluoro-4-[2-(4-hydroxy-l-adamantyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl}propanamide
Figure imgf000150_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 470.2 (M+H)+.
Example 251
N-{3-Fluoro-4-[2-(4-hydroxy-l-adamantyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl] phenyl} methanesulfonamide
Figure imgf000151_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 492.2 (M+H)+.
Example 252 (5R)-7-(2,3-DiJB[uorophenyl)-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decau-l-one
Figure imgf000151_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 44. LC-MS: 365.2 (M+H)+.
Example 253 (5R)-7-(3-FIuorophenyl)-2-(4-hydroxycycIohexyl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000152_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 44. LC-MS: 347.3 (M+H)+.
Example 254
5R)-7-(2-Chloro-3-fluorophenyl)-2-(4-hydroxycycIohexyl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000152_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 44. LC-MS: 381.2 (M+H)+.
Example 255
(5R)-7-(4-FIuorophenyI)-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000152_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 44. LC-MS: 347.2 (M+H)+. Example 256
(5R)-7-[3-Chloro-5-(2-oxo-l,3-oxazinan-3-yl)pyridin-2-yl]-2-(4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one
Figure imgf000153_0001
3-Chloropropyl chloridocarbonate (15.1 μL, 0.000125 mol) was added to a mixture of (5R)-7- (5-amino-3-chloropyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one (37.89 mg, 0.0001000 mol, this compound was prepared by using procedures analogous to those described for the synthesis of example 105, step 1) and 4-dimethylaminopyridine (18.3 mg, 0.000150 mol) in DMF (1.00 mL). After stirring the mixture for 1 h, 1.0000 M of potassium tert-butoxide in tetrahydrofuran (0.375 mL) was added and the resultant mixture was stirred at rt for 2 h. The mixture was diluted with methanol (0.8 mL) and was adjusted to pH = 2.0 with TFA. The resulting solution was purified by prep.-HPLC to give the desired product. LC-MS: 463.1 (M+H)+.
Example 257
(5R)-7-(3,4'-Bipyridin-6-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000153_0002
Sodium carbonate (10.6 mg, 0.000100 mol) in water(0.10 niL) was added to a mixture of
(5R)-7-(5-bromopyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one (20.4 mg, 0.0000500 mol, this compound was prepared by using a procedure that was analogous to the one described for the synthesis of example 93) in NMP (0.25 mL), 4-pyridinylboronic acid (9.22 mg, 0.0000750 mol) and tetrakis(triphenylphosphine) palladium(O) (1.7 mg, 0.0000015 mol) in toluene
(200.0 μL, 0.001878 mol) and ethanol (100.000 μL, 1.71267E-3 mol). The resulting mixture was heated at 120 °C for 20 min. The mixture was filtered and the filtrate was diluted with methanol and adjusted to pH = 2 with TFA. The resulting solution was purified by prep.-HPLC to give the desired product. LC-MS: 407.2 (M+H)+.
Example 258
(5R)-2-(trans-4-HydroxycycIohexyl)-7-(6'-methoxy-3,3'-bipyridin-6-yI)-2,7- diazaspiro [4.5] decan-1-one
H
Figure imgf000154_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 257. LC-MS: 437.3 (M+H)+.
Example 259 4-{6-[(5R)-2-(frø«s-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}-N,N- dimethylbenzamide H
Figure imgf000155_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 257. LC-MS: 477.3 (M+H)+.
Example 260
4-{6-[(5R)-2-(trans-4-HydroxycycIohexyI)-l-oxo-2,7-diazaspiro[4.5]dec-7-yI]pyridin-3- yl}benzamide
H
Figure imgf000155_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 257. LC-MS: 449.3 (M+H)+.
Example 261
N-Cyclopropyl-4-{6-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl] pyridin-3-yl} benzamide H
Figure imgf000156_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 257. LC-MS: 489.3 (M+H)+.
Example 262
N-(4-{6-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3- yl}phenyl)acetamide
H
Figure imgf000156_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 257. LC-MS: 463.3 (M+H)+.
Example 263 (5R)-2-(trans-4-HydroxycyclohexyI)-7-[5-(4-methoxyphenyl)pyridin-2-yl]-2,7- diazaspiro [4.5] decan- 1-one
H
Figure imgf000157_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 257. LC-MS: 436.3 (M+H)+.
Example 264
(5R)-7-[5-(4-Fluorophenyl)pyridin-2-yl]-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one
H
Figure imgf000157_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 257. LC-MS: 424.2 (M+H)+.
Example 265
(5R)-7-(3,3'-Bipyridin-6-yI)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000158_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 257. LC-MS: 407.3 (M+H)+.
Example 266
(5R)-7-(6'-Fluoro-3,3'-bipyridin-6-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l- one H
Figure imgf000158_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 257. LC-MS: 425.3 (M+H)+.
Example 267
(5R)-2-(trans-4-Hydroxycyclohexyl)-7-(5-pyrimidin-5-ylpyridin-2-yl)-2,7-diazaspiro[4.5]decan-
1-one H
Figure imgf000159_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 257. LC-MS: 408.3 (M+H)+.
Example 268
3-{6-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yI]pyridin-3- yl}benzamide H
Figure imgf000159_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 257. LC-MS: 449.3 (M+H)+.
Example 269
N-(3-{6-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yI]pyridin-3- yl}phenyl)acetamide H
Figure imgf000160_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 257. LC-MS: 463.3 (M+H)+.
Example 270
(5R)-7-[5-(3,5-Dimethylisoxazol-4-yl)pyridin-2-yl]-2-(trans-4-hydroxycyclohexyI)-2,7- diazaspiro[4.5]decan-l-one H
Figure imgf000160_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 257. LC-MS: 425.3 (M+H)+.
Example 271
(5R)-2-(trans-4-Hydroxycyclohexyl)-7-[5-(l-methyI-lH-pyrazol-4-yl)pyridin-2-yl]-2,7- diazaspiro [4.5] decan- 1-one H
Figure imgf000161_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 257. LC-MS: 410.3 (M+H)+.
Example 272
4-{2-[(5R)-2-(trans-4-HydroxycycIohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyrimidin-5-yl}- N,N-dimethylbenzamide H
Figure imgf000161_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 257. LC-MS: 478.2 (M+H)+.
Example 273
(5R)-2-(trans-4-Methoxycyclohexyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-2,7- diazaspiro [4.5] decaii-1-oiie —
Figure imgf000162_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 412.2 (M+H)+.
Example 274
N-Cyclopropyl-4-{2-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl] pyrimidin-5-yl}benzamide
Figure imgf000162_0002
This compound was prepared using procedures analogous to those described for the synthesis of example 257. LC-MS: 490.2 (M+H)+.
Example 275
(5R)-7-(5-Chloro-3,3'-bipyridin-6-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l- one H
Figure imgf000163_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 257. LC-MS: 441.2 (M+H)+.
Example 276
(5R)-7-(5-Bromopyrimidin-2-yl)-2-(trans-4-hydroxycycIohexyl)-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000163_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 409.1/411.1 (M+H)+.
Example 277
(5R)-7-[3-ChIoro-5-(l-methyl-lH-pyrazol-4-yI)pyridin-2-yl]-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro [4.5] decan- 1-one H
Figure imgf000164_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 257. LC-MS: 444.2 (M+H)+.
Example 278
4-{2-[(5R)-2-(trans-4-HydroxycycIohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyrimidin-5- yljbenzamide H
Figure imgf000164_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 257. LC-MS: 450.2 (M+H)+.
Example 279 (5R)-7-(3,5-Difluoropyridin-2-yl)-2-(trans-4-methoxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one —
Figure imgf000165_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 380.2 (M+H)+.
Example 280
(5R)-7-(5-Chloro-3,4'-bipyridin-6-yl)-2-(trans-4-hydroxycycIohexyl)-2,7-diazaspiro[4.5]decan-l- one H
Figure imgf000165_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 257. LC-MS: 441.2 (M+H)+.
Example 281 (5R)-7-(5-Ethylpyrimidin-2-yl)-2-(trans-4-methoxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one —
Figure imgf000166_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 373.3 (M+H)+.
Example 282 tert-Butyl 5-chIoro-6-[(5ϋf)-2-(trans-4-hydroxycycIohexyI)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]- 3',6'-dihydro-3,4l-bipyridine-l'(2Η)-carboxylate
H
Figure imgf000166_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 257. LC-MS: 545.3 (M+H)+.
Example 283 (5R)-7-(5-Fluoropyrimidin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000167_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 349.2 (M+H)+.
Example 284
(5R)-2-(trans-4-Hydroxycyclohexyl)-7-[4-(2-oxo-l,3-oxazoIidin-3-yI)phenyl]-2,7- diazaspiro [4.5] decan- 1-one H
Figure imgf000167_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 256. LC-MS: 414.3 (M+H)+.
Example 285
(5R)-7-[2-Fluoro-4-(2-oxo-l,3-oxazolidin-3-yl)phenyl]-2-(trans-4-hydroxycyclohexyI)-2,7- diazaspiro[4.5]decan-l-one H
Figure imgf000168_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 256. LC-MS: 432.2 (M+H)+.
Example 286
(5R)-7-[2-Fluoro-4-(2-oxopyrrolidin-l-yl)phenyl]-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one
Figure imgf000168_0002
This compound was prepared b using procedures analogous to those described for the synthesis of example 256. LC-MS: 430.3 (M+H)+.
Example 287
(5R)-7-[3-Chloro-5-(2-oxopyrrolidin-l-yl)pyridin-2-yl]-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro [4.5] decan-1-one
Figure imgf000169_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 256. LC-MS: 447.3 (M+H)+.
Example 288
(5R)-2-(trans-4-HydroxycyclohexyI)-7-[4-(2-oxopyrroIidin-l-yl)phenyl]-2,7- diazaspiro [4.5] decan- 1-one H
Figure imgf000169_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 256. LC-MS: 412.2 (M+H)+.
Example 289
(5R)-7-[3-Chloro-5-(2-oxo-l,3-oxazolidin-3-yl)pyridin-2-yl]-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one H
Figure imgf000170_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 256. LC-MS: 449.1 (M+H)+.
Example 290
(5R)-7-(2-FIuoro-4-pyrrolidin-l-ylphenyl)-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decaii-l-one H
Figure imgf000170_0002
A mixture of 1,4-diiodobutane (13.5 μL, 0.000100 mol), (5R)-7-(4-amino-2-fluorophenyl)-2- (fraws^-hydroxycyclohexyl^J-diazaspirol^.SJdecan-l-one (28.9 mg, 0.0000800 mol, this compound was prepared by using procedures analogous to that described for the synthesis of example
105, step 1) and 4-dimethylaminopyridine (14.7 mg, 0.000120 mol) in DMF (1.00 mL), and potassium iodide (1.5 mg, 0.0000090 mol) was heated at 110 0C by microwave for 15 min. The mixture was diluted with methanol (0.8 mL) and was adjusted to be acidic with TFA ( the pH was about 2.0). The resulting solution was purified by prep-HPLC to give the desired product. LC-MS:
416.2 (M+H)+.
Example 291 (5R)-7-(3-Chloro-5-pyrrolidin-l-ylpyridin-2-yl)-2-(trans-4-hydroxycyclohexyI)-2,7- diazaspiro[4.5]decan-l-one H
Figure imgf000171_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 290. LC-MS: 433.2 (M+H)+.
Example 292 (5R)-2-(trans-4-Hydroxycyclohexyl)-7-(5-pyrrolidin-l-ylpyridin-2-yl)-2,7-diazaspiro[4.5]decan-
1-one H
Figure imgf000171_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 290. LC-MS: 499.2 (M+H)+.
Example 293 (5R)-7-[2-Fluoro-4-(2-oxo-piperidin-l-yl)-phenyl]-2-(trans-4-hydroxy-cyclohexyl)-2,7-diaza- spiro[4.5]decan-l-one H
Figure imgf000172_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 256. LC-MS: 444.3 (M+H)+.
Example 294
(5R)-7-[2-Fluoro-4-(2-oxo-l,3-oxazinan-3-yI)phenyl]-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro [4.5] decan- 1-one H
Figure imgf000172_0002
This compound was prepared b usring procedures analogous to those described for the synthesis of example 256. LC-MS: 446.3 (M+H)+.
Example 295
(5R)-2-(trans-4-hydroxycyclohexyl)-7-[4-(2-oxopiperidin-l-yl)phenyl]-2,7-diazaspiro[4.5]decan-
1-one
Figure imgf000173_0001
This compound was prepared b using procedures analogous to those described for the synthesis of example 256. LC-MS: 426.3 (M+H)+.
Example 296
(5R)-7-(l,3-BenzothiazoI-2-yI)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000173_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 386.2 (M+H)+.
Example 297 2-[(5R)-2-(trans-4-Methoxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]nicotinonitrile
Figure imgf000173_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 369.2 (M+H)+.
Example 298 (5R)-2-(trans-4-Methoxycyclohexyl)-7-[5-(trifluoromethyI)pyridin-2-yl]-2,7- diazaspiro[4.5]decan-l-one
Figure imgf000174_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 412.2 (M+H)+.
Example 299 (5R)-7-(5-Fluoropyrimidin-2-yl)-2-(trans-4-methoxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000174_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 363.2 (M+H)+.
Example 300
(5R)-7-{3-Chloro-5-[4-(trifluoromethoxy)phenyl]pyridin-2-yl}-2-(trans-4-hydroxycyclohexyl)-
2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000175_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 257. LC-MS: 524.2 (M+H)+.
Example 301
(5R)-7-(2-Chloro-9H-purin-6-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000175_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 405.2 (M+H)+.
Example 302
(5R)-7-(4-Amino-5-fluoropyrimidin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one H
Figure imgf000176_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 464.2 (M+H)+.
Example 303
N-{3-Fluoro-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl] phenyl} cyclopropanecarboxamide H
Figure imgf000176_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 430.3 (M+H)+.
Example 304
N-{3-Fluoro-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl] phenyl} cyclobutanecarboxamide H
Figure imgf000177_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 444.3 (M+H)+.
Example 305
N-{3-Fluoro-4-[(5R)-2-(trans-4-hydroxycycIohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl] phenyl} cyclopentanecarboxamide
Figure imgf000177_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS : 458.3 (M+H)+.
Example 306
N-{3-Fluoro-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl}cyclohexanecarboxamide H
Figure imgf000178_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 472.3 (M+H)+.
Example 307
Ethyl {3-fluoro-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl] phenyl} carbamate H
Figure imgf000178_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 434.3 (M+H)+.
Example 308
Propyl {3-fluoro-4-[(5R)-2-(trans-4-hydroxycycIohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl] phenyl} carbamate
Figure imgf000179_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 448.3 (M+H)+.
Example 309
Isobutyl {3-fluoro-4-[(5R)-2-(trans-4-hydroxycycIohexyI)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl] phenyl} carbamate H
Figure imgf000179_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 462.3 (M+H)+.
Example 310
N-{3-Fluoro-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl}propanamide 50
Figure imgf000180_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 418.3 (M+H)+.
Example 311
N-{3-Fluoro-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}-2- methylpropanamide
Figure imgf000180_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 432.3 (M+H)+.
Example 312
N- {3-Fluoro-4- [(5R)-2-(trans-4-hydroxycyclohexyI)- l-oxo-2,7-diazaspiro [4.5] dec-7- yl] phenyl}methanesulfonamide H
Figure imgf000181_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 440.2 (M+H)+.
Example 313
N-{3-FIuoro-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl] phenyljethanesulfonamide H
Figure imgf000181_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 454.2 (M+H)+.
Example 314
(5R)-2-(trans-4-HydroxycycIohexyI)-7-[3-(trifluoromethyl)pyridin-2-yl]-2,7- diazaspiro[4.5]decan-l-one
Figure imgf000182_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 398.2 (M+H)+.
Example 315
Ethyl [4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-
(trifluoromethyl)phenyl] carbamate H
Figure imgf000182_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 484.3 (M+H)+.
Example 316
Methyl [4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-
(trifluoromethyl)phenyl] carbamate H
Figure imgf000183_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 470.2 (M+H)+.
Example 317
Propyl [4-[(5R)-2-(trans~4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-
(trifluoromethyl)phenyl] carbamate
Figure imgf000183_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 498.3 (M+H)+.
Example 318
Isobutyl [4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-
(trifluoromethyl)phenyl] carbamate
Figure imgf000184_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 512.3 (M+H)+.
Example 319
Isopropyl [4-[(5R)-2-(trans-4-hydroxycycIohexyI)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-
(trifluoromethyl)phenyl] carbamate
Figure imgf000184_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 498.3 (M+H)+.
Example 320
N-[4-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-
(trifluoromethyl)phenyl]cyclopropanecarboxamide
Figure imgf000185_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 480.3 (M+H)+.
Example 321
N-[4-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3- (trifluoromethyl)phenyl]cyclobutanecarboxamide
Figure imgf000185_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 494.3 (M+H)+.
Example 322
N-[4-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-
(trifluoromethyl)phenyl]cyclopentanecarboxamide H
Figure imgf000186_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 508.3 (M+H)+.
Example 323
N-[4-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-
(trifluoromethyl)phenyl]methanesulfonamide
Figure imgf000186_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 490.2 (M+H)+.
Example 324
N-[4-[(5R)-2-(trans-4-HydroxycycIohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-
(trifluoromethyl)phenyl]acetamide H
Figure imgf000187_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 454.3 (M+H)+.
Example 325
N-[4-[(5R)-2-(trans-4-HydroxycycIohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3- (trifluoromethyl)phenyl]propanamide
Figure imgf000187_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 468.3 (M+H)+.
Example 326
N-[4-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-
(trifluoromethyl)phenyl]-2-methylpropanamide H
Figure imgf000188_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 482.3 (M+H)+.
Example 327
(5R)-7-[2-Fluoro-4-(pyridin-2-yIoxy)phenyl]-2-(trans-4-hydroxycyclohexyI)-2,7- diazaspiro[4.5]decan-l-one H
Figure imgf000188_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 180. LC-MS: 440.3 (M+H)+.
Example 328
Methyl {6-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3- yl} carbamate H
Figure imgf000189_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 403.3 (M+H)+.
Example 329
Ethyl {6-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3- yl}carbamate H
Figure imgf000189_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 417.3 (M+H)+.
Example 330
Propyl {6-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yI]pyridin-3- yl}carbamate
Figure imgf000190_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 431.3 (M+H)+.
Example 331
Isobutyl {6-[(5R)-2-(trans-4-hydroxycydohexyI)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3- yl} carbamate
Figure imgf000190_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 445.3 (M+H)+.
Example 332
Isopropyl {6-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3- yljcarbamate
Figure imgf000191_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 431.3 (M+H)+.
Example 333
N-{6-[(5R)-2-(trans-4-HydroxycycIohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3- yl}cyclopropanecarboxamide
OH
Figure imgf000191_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 413.3 (M+H)+.
Example 334
N-{6-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3- yl}cyclobutanecarboxamide H
Figure imgf000192_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 427.3 (M+H)+.
Example 335
N-{6-[(5R)-2-(trans-4-HydroxycyclohexyI)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3- yl} cyclopentanecarboxamide
H
Figure imgf000192_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 441.3 (M+H)+.
Example 336
N-{6-[(5R)-2-(trans-4-HydroxycycIohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3- yl}acetamide H
Figure imgf000193_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 387.3 (M+H)+.
Example 337
N-{6-[(5R)-2-(trans-4-HydroxycyclohexyI)-l-oxo-2,7-diazaspiro[4.5]dec-7-yI]pyridin-3- yl}propanamide
Figure imgf000193_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS : 401.3 (M+H)+.
Example 338
N-{6-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}-2- methylpropanamide H
Figure imgf000194_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 415.3 (M+H)+.
Example 339
N-{6-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3- yl}cyclohexanecarboxamide H
Figure imgf000194_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS : 455.3 (M+H)+.
Example 340
Methyl {6-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yI]-5- methylpyridin-3-yl}carbamate
Figure imgf000195_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 417.1 (M+H)+.
Example 341
Ethyl {6-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5- methylpyridin-3-yl}carbamate H
Figure imgf000195_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS : 431.2 (M+H)+.
Example 342
Propyl {6-[(5R)-2-(trans-4-hydroxycycIohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5- methylpyridin-3-yI} carbamate
Figure imgf000196_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 445.1 (M+H)+.
Example 343
Methyl {3-cyano-4-[(5R)-2-(trans-4-hydroxycycIohexyI)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl] phenyljcarbamate
Figure imgf000196_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 427.2 (M+H)+.
Example 344
Ethyl {3-cyano-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl] phenyl} carbamate H
Figure imgf000197_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 441.3 (M+H)+.
Example 345
Propyl {3-cyano-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl] phenyljcarbamate
Figure imgf000197_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 455.3 (M+H)+.
Example 346
Isobutyl {3-cyano-4-[(5R)-2-(trans-4-hydroxycycIohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl] phenyl} carbamate
Figure imgf000198_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 469.3 (M+H)+.
Example 347
Isopropyl {3-cyano-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl] phenyl}carbamate H
Figure imgf000198_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 455.3 (M+H)+.
Example 348
N-{3-Cyano-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl}cyclopropanecarboxamide H
Figure imgf000199_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 437.3 (M+H)+.
Example 349
N-{3-Cyano-4-[(5R)-2-(trans-4-hydroxycycIohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl] phenyl} cyclobutanecarboxamide H
Figure imgf000199_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 451.3 (M+H)+.
Example 350
N- {3-Cyano-4- [(5R)-2-(trans-4-hydroxycyclohexyl)- l-oxo-2,7-diazaspiro [4.5] dec-7- yl]phenyl}cyclopentanecarboxamide OH
Figure imgf000200_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 465.3 (M+H)+.
Example 351
N-{3-Cyano-4-[(5R)-2-(trans-4-hydroxycyclohexyI)-l-oxo-2,7-diazaspiro[4.5)dec-7- yl] phenyl} acetamide H
Figure imgf000200_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 425.3 (M+H)+.
Example 352
N-{3-Cyano-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl}propanamide H
Figure imgf000201_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 439.3 (M+H)+.
Example 353
N-{3-Cyano-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}-2- methylpropanamide H
Figure imgf000201_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 439.3 (M+H)+.
Example 354
N-{3-Cyano-4-[(5R)-2-(trans-4-hydroxycycIohexyI)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl}cyclohexanecarboxamide H
Figure imgf000202_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 479.3 (M+H)+.
Example 355
Methyl {4-[(5R)-2-(trans-4-hydroxycyclohexyI)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3- methylphenyl}carbamate H
Figure imgf000202_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 416.3 (M+H)+.
Example 356
Ethyl {4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3- methylphenyl} carbamate
Figure imgf000203_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 430.3 (M+H)+.
Example 357
Propyl {4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3- methylphenj 1} carbamate
H
Figure imgf000203_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 444.3 (M+H)+.
Example 358
Isobutyl {4-[(5R)-2-(trans-4-hydroxycyclohexyI)-l-oxo-2,7-diazaspiro[4.5]dec-7-yI]-3- methylphenyl} carbamate
Figure imgf000204_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 458.3 (M+H)+.
Example 359
Isopropyl {4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3- methylphenyl}carbamate
Figure imgf000204_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 444.3 (M+H)+.
Example 360
N-{4-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3- methylphenyl}cyclopropanecarboxamide H
Figure imgf000205_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 426.3 (M+H)+.
Example 361
N-{4-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3- methylphenyljcyclobutanecarboxamide
H
Figure imgf000205_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 440.3 (M+H)+.
Example 362
N-{4-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3- methylphenyl}cyclopentanecarboxamide H
Figure imgf000206_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 454.4 (M+H)+.
Example 363
N-{4-[(5R)-2-(trans-4-HydroxycycIohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yI]-3- methylphenyl}cyclohexanecarboxamide H
Figure imgf000206_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 468.3 (M+H)+.
Example 364
N-{4-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3- methylphenyl}acetamide H
Figure imgf000207_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 400.3 (M+H)+.
Example 365
N-{4-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3- methylphenyl} propanamide H
Figure imgf000207_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 414.3 (M+H)+.
Example 366
N-{4-[(5R)-2-(trans-4-HydroxycyclohexyI)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-methyIphenyl}-
2-methylpropanamide H
Figure imgf000208_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 428.3 (M+H)+.
Example 367
(5R)-2-(trans-4-Hydroxycyclohexyl)-7-[4-(trifluoromethyl)quinolin-2-yl]-2,7- diazaspiro [4.5] decan-1-one H
Figure imgf000208_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 448.3 (M+H)+.
Example 368 (5R)-7-(3-ChIoropyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000209_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 364.2 (M+H)+.
Example 369
(5R)-7-[3-Fluoro-4-(trifluoromethyl)pyridin-2-yl]-2-(trans-4-hydroxycycIohexyl)-2,7- diazaspiro[4.5]decan-l-one H
Figure imgf000209_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 354.2 (M+H)+.
Example 370 (5R)-2-(trans-4-Hydroxycyclohexyl)-7-(3,5,6-trifluoro-4-methyIpyridin-2-yl)-2,7- diazaspiro[4.5]decan-l-one H
Figure imgf000209_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 398.2 (M+H)+.
Example 371 2,3,5-Trifluoro-6-[(5R)-2-(trans-4-hydroxycycIohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yljisonicotinonitrile
Figure imgf000210_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 409.2 (M+H)+.
Example 372 (5R)-7-(3,5-Difluoropyridin-2-yI)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000210_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 366.2 (M+H)+.
Example 373
(5R)-2-(trans-4-hydroxycyclohexyI)-7-[4-(trifluoromethyl)pyridin-2-yl]-2,7- diazaspiro [4.5] decan-1-one H
Figure imgf000211_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 398.2 (M+H)+.
Example 374
(5R)-7-(3-FIuoropyridin-2-yI)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000211_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 29. LC-MS: 348.2 (M+H)+.
Example 375 (5R)-7-(5-Chloro-3-fluoropyridin-2-yl)-2-(trans-4-hydroxycycIohexyl)-2,7-diazaspiro[4.5]decan-
1-one H
Figure imgf000211_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 382.1 (M+H)+.
Example 376 (5R)-7-(3-Ethynylpyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000212_0001
A mixture of (5R)-2-(trans-4-hydroxycyclohexyl)-7-{3-[(trimethylsilyl)ethynyl] pyridin-2- yl}-2,7-diazaspiro[4.5]decan-l-one (10 mg, 0.00002 mol, this compound was prepared by using procedures analogous to those described for the synthesis of example 93), lithium hydroxide monohydrate (1.1 mg, 0.000026 mol) in tetrahydrofuran (0.5 mL, 0.006 mol) and a couple of drops of water was stirred at rt for 30 min. The crude reaction mixture was purified by prep-HPLC to afford 7.2 mg of the desired product. LC-MS: 354.2 (M+H)+.
Example 377 7-(2-fluoro-4-nitrophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000212_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 43. LC-MS: 392.2 (M+H)+.
Example 378
2-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-6- methylnicotinonitrile
Figure imgf000213_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 369.2 (M+H)+.
Example 379
(5R)-2-(trans-4-HydroxycycIohexyl)-7-quinolin-2-yI-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000213_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 380.3 (M+H)+.
Example 380 2-(trans-4-Hydroxycyclohexyl)-7-[6-methyl-4-(trifluoromethyI)pyridin-2-yI]-2,7- diazaspiro [4.5] decan- 1-one
Figure imgf000213_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 412.3 (M+H)+.
Example 381 (5R)-7-(3-Fluoropyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000214_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 348.2 (M+H)+.
Example 382
7-(5-EthyIpyrimidin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000214_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 29. LC-MS: 359.3 (M+H)+.
Example 383 (5R)-2-(trans-4-Hydroxycyclohexyl)-7-(3-methylquinolin-2-yl)-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000215_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 394.3 (M+H)+.
Example 384
N-{4-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl] phenyljmethanesulfonamide H
Figure imgf000215_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS : 422.2 (M+H)+.
Example 385
(5R)-7-[2-FIuoro-4-(pyridin-4-yloxy)phenyl]-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro [4.5] decan-1-one H
Figure imgf000216_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 180. LC-MS: 440.2 (M+H)+.
Example 386
(5R)-2-(trans-4-Hydroxycyclohexyl)-7-[5-(hydroxymethyl)pyridin-2-yI]-2,7- diazaspiro [4.5] decan- 1-one H
Figure imgf000216_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 180. LC-MS: 440.2 (M+H)+.
Example 387
6-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-N- methylnicotinamide H
Figure imgf000217_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 387.3 (M+H)+.
Example 388
(5R)-7-(3-FIuoropyridin-4-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000217_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 348.3 (M+H)+.
Example 389 (5R)-7-(2-ChIoropyridin-4-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000217_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS : 364.2 (M+H)+. Example 390
N-{3-Fluoro-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}-
N-methylmethanesulfonamide H
Figure imgf000218_0001
A mixture of N-{3-fluoro-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7- diazaspiro[4.5]dec-7-yl]phenyl}methanesulfonamide (20 mg, 0.00006 mol, example 312), methyl iodide (4.1 μL, 0.000066 mol), and potassium carbonate (10 mg, in excess) in acetone (2 mL, 0.03 mol) was stirred at rt for 2 h and then heated to 40 0C for 2 h. The reaction mixture was allowed to cool to rt and was purified by prep- HPLC to afford the desired product. LC-MS: 454.2 (M+H)+.
Example 391 N-{6-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}-2- methylpropanamide H
Figure imgf000218_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 415.3 (M+H)+.
Example 392 7-(2-ChIoropyrimidin-4-yl)-2-(trans-4-hydroxycycIohexyl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000219_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 29. LC-MS: 365.2 (M+H)+.
Example 393 6-[2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yI]-N,N-dimethylnicotilnamide
H
Figure imgf000219_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 29. LC-MS: 401.2 (M+H)+.
Example 394
Ethyl {2-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yI]-6- methoxypyridin-3-yl} carbamate H
Figure imgf000220_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 447.2 (M+H)+.
Example 395
Methyl {2-[(5R)-2-(trans-4-hydroxycyclohexyI)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-6- methoxypyridin-3-yl}carbamate H
Figure imgf000220_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 433.2 (M+H)+.
Example 396 N-{2-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-6-methoxypyridin-
3-yl}acetamide
Figure imgf000220_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 417.2 (M+H)+.
Example 397 5-[(5R)-2-(trans-4-HydroxycycIohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-N-methylpyridine-2- carboxamide
Figure imgf000221_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 180. LC-MS: 387.2 (M+H)+.
Example 398
(5R)-2-(trans-4-Hydroxycyclohexyl)-7-(3-methoxypyridin-2-yl)-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000221_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS : 360.2 (M+H)+.
Example 399 2-[8-(trans-4-Hydroxycyclohexyl)-7-oxo-2,8-diazaspiro[5.5]undec-2-yI]nicotinonitriIe
Figure imgf000222_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 92. LC-MS: 369.2 (M+H)+.
Example 400
2-(trans-4-Hydroxycyclohexyl)-8-[3-(trifluoromethyl)pyridin-2-yI]-2,8-diazaspiro[5.5]undecan- 1-one
Figure imgf000222_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 92. LC-MS: 412.2 (M+H)+.
Example 401
3-Cyclohexyl-7- [5-(trifluoromethyl)pyridin-2-yl] -1 ,3,7-triazaspiro [4.5] decane-2,4-dione
Figure imgf000222_0003
Step 1. tert-butyl 3-oxopiperidine-l-carboxylate
To a solution of pyridinium chlorochromate (3.21 g, 0.0149 mol) in methylene chloride (18 mL) was added another solution of fert-butyl 3-hydroxypiperidine-l-carboxylate (1.00 g, 0.00497 mol) in 7 mL methylene chloride at rt. After stirring for 18 h, the reaction mixture was diluted with diethyl ether, filtered through a bed of celite, concentrated in-vacuo, and then purified by Combiflash to afford the desired product verified by NMR.
Step 2. tert-butyl 2, 4-dioxo-l, 3, 7-triazaspiro[4.5]decane- 7-carboxylate A mixture of tert-butyl 3-oxopiperidine-l-carboxylate (0.20 g, 0.0010 mol), potassium cyanide (0.13 g, 0.0020 mol) and ammonium carbonate (0.77 g, 0.0080 mol) in ethanol (4.0 mL,
0.068 mol) and water (2.0 mL) was stirred at 70 0C for 4 h. The mixture was then diluted with ethyl acetate and washed with water, brine, dried and concentrated to give the desired product. LC-MS: 292.0 (M+Na)+.
Step 3. tert-butyl 3-cyclohexyl-2,4-dioxo-l,3, 7-triazaspiro[4.5]decane-7-carboxylate
Diethyl azodicarboxylate (0.315 mL, 0.00200 mol) was added to a mixture of tert-butyl 2,4- dioxo-l,3,7-triazaspiro[4.5]decane-7-carboxylate (269.3 mg, 0.001000 mol) , cyclohexanol (0.156 mL, 0.00150 mol), and triphenylphosphine (524 mg, 0.00200 mol) in tetrahydrofuran (6 mL, 0.08 mol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by Combiflash with ethyl acetate/heaxane. LC-MS: 296.2 (M - Bu + 2H)+.
Step 4. 3-cyclohexyl- 7-[5-(trtfluoromethyl)pyridin-2-yl]-l, 3, 7-triazaspiro[4.5]decane-2, 4-dione
This compound was prepared by using procedures analogous to those described for the synthesis of example 92, steps 3 and 4. LC-MS: 397.2 (M+H)+.
Example 402 6-(3-cyclohexyl-2,4-dioxo-l,3,7-triazaspiro[4.5]dec-7-yl)nicotinonitrile
Figure imgf000223_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 401. LC-MS: 354.2 (M+H)+.
Example 403
4-(3-CycIohexyl-2,4-dioxo-l,3,7-triazaspiro[4.5]dec-7-yl)-3-fluorobenzonitrile
Figure imgf000224_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 401. LC-MS: 393.1 (M+Na)+, 371.1 (M+H)+.
Example 404
3-CycIohexyl-7-(5-ethylpyrimidin-2-yl)-l,3,7-triazaspiro[4.5]decane-2,4-dione
Figure imgf000224_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 401. LC-MS : 358.1 (M+H)+.
Example 405 3-Cyclohexyl-7-(3-fluoropyridin-2-yI)-l,3,7-triazaspiro[4.5]decane-2,4-dione
Figure imgf000224_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 401. LC-MS: 347.1 (M+H)+.
Example 406 3-Cyclohexyl-7-(3,5-difluoropyridin-2-yl)-l,3,7-triazaspiro[4.5]decane-2,4-dione
Figure imgf000225_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 401. LC-MS: 365.2 (M+H)+.
Example 407
3-Cyclohexyl-7-(3,5-dichloropyridin-2-yl)-l,3,7-triazaspiro[4.5]decane-2,4-dione
Figure imgf000225_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 401. LC-MS: 397.1/399.1 (M+H)+.
Example 408 2-(3-Methylpyridin-2-yl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000225_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 92. LC-MS : 391.2 (M+H)+.
Example 409
N,N-Dimethyl-5-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yI]pyridine-
2-carboxamide
Figure imgf000226_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 180. LC-MS: 387.2 (M+H)+.
Example 410
3-Fluoro-4-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]benzonitriIe
Figure imgf000226_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 43. LC-MS: 358.2 (M+H)+.
Example 411
(5R)-2-(trans-4-Hydroxycyclohexyl)-7-(6-methoxy-2-methylpyridin-3-yl)-2,7- diazaspiro [4.5] decan- 1-one H
Figure imgf000227_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 180. LC-MS: 374.2 (M+H)+.
Example 412
(5R)-2-(4-HydroxycycIohexyl)-7-(6-methoxy-4-methylpyridin-3-yI)-2,7-diazaspiro[4.5]decan-l- one
Figure imgf000227_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 180. LC-MS: 374.2 (M+H)+.
Example 413 (5R)-7-(2,6-Difluorophenyl)-2-(4-hydroxycycIohexyl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000227_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 180. LC-MS: 365.2 (M+H)+.
Example 414 7-(5-Chloropyridin-2-yl)-2-(4-hydroxy-l-adamantyl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000228_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 416.2 (M+H)+.
Example 415
7-(3-Fluoropyridin-4-yl)-2-(4-hydroxy-l-adamantyl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000228_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 400.1 (M+H)+.
Example 416
N-{3-FIuoro-4-[2-(4-hydroxy-l-adamantyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl}propanamide
Figure imgf000229_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 470.1 (M+H)+.
Example 417
Methyl {3-fluoro-4-[2-(4-hydroxy-l-adamantyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl] phenyljcarbamate
Figure imgf000229_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 472.1 (M+H)+.
Example 418
Propyl {3-fluoro-4-[2-(4-hydroxy-l-adamantyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl] phenyl}carbamate
Figure imgf000230_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 500.1 (M+H)+.
Example 419
N-{3-Fluoro-4-[2-(4-hydroxy-l-adamantyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl}ethanesulfonamide
Figure imgf000230_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS : 506.1 (M+H)+.
Example 420
2-[(5R)-2-(cis-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]nicotinonitriIe
Figure imgf000230_0003
Step 1. benzyl (5R)-2-[cis-4-(benzoyloxy)cyclohexyl]-l-oxo-2, 7-diazaspiro[4.5Jdecane-7-carboxylate Diethyl azodicarboxylate (163.0 μL, 0.001035 mol) was added to a mixture of benzyl (5R)-2- (trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]decane-7-carboxylate (200.0 mg, 0.0005175 mol, this compound was prepared by using procedures analogous to those described for the synthesis of example 1, steps 1-4), and triphenylphosphine (271.4 mg, 0.001035 mol) in tetrahydrofuran (3.0 mL, 0.037 mol) at rt. The mixture was stirred at rt for 5 minutes, then benzoic acid (66.36 mg, 0.0005434 mol) was added. After stirring for additional 2 h, the volatiles in the mixture were removed in-vacuo and the residue was purified by flash chromatography to afford the desired product.
Step 2. cis-4-[(5R)-l-oxo-2, 7-diazaspiro[4.5]dec-2-yl]cyclohexyl benzoate Benzyl (5R)-2- [cis-4-(benzoyloxy)cyclohexy 1] - 1 -oxo-2,7-diazaspiro [4.5] decane-7- carboxylate (0.16 g, 0.00033 mol) in methanol (5 mL, 0.1 mol) was stirred with palladium (20 mg, 0.00002 mol) under an atmosphere of hydrogen for 2 h. The mixture was filtered and the filtrate was concentrated to afford the desired product. LC-MS: 357.2 (M+H)+.
Step 3. 2-[(5R)-2-(cis-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]nicotinonitrile
A mixture of cis-4-[(5R)-l-oxo-2,7-diazaspiro[4.5]dec-2-yl]cyclohexyl benzoate (19.0 mg, 0.0000533 mol), 2-chloronicotinonitrile (8.12 mg, 0.0000586 mol) and NN-diisopropylethylamine (20.0 μL, 0.000115 mol) in Ν-methylpyrrolidinone (0.6 mL, 0.006 mol) was irradiated by microwaves at 180 0C for 20 min. After cooling to rt, lithium hydroxide aqueous solution (1.0 M, 0.150 mL) was added, followed by methanol (0.2 mL). The mixture was heated at 100 0C for 5 h. The crude reaction mixture was then purified by prep-HPLC under basic conditions to afford the desired product. LC- MS: 355.2 (M+H)+.
Example 421 (5R)-2-(cis-4-Hydroxycyclohexyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-
1-one
Figure imgf000231_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 420. LC-MS: 398.2 (M+H)+. Example 422 (5R)-7-(3-Fluoropyridin-2-yl)-2-(cis-4-hydroxycydohexyI)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000232_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 420. LC-MS: 348.2 (M+H)+.
Example 423
(5R)-7-(3,5-Dichloropyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000232_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 420. LC-MS: 398.1/400.2 (M+H)+.
Example 424 (5R)-7-(5-Chloro-3-fluoropyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l- one
Figure imgf000233_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 420. LC-MS: 382.2 (M+H)+.
Example 425
(5R)-7-(3-Chloropyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000233_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 420. LC-MS: 364.2 (M+H)+.
Example 426
Methyl {4-[(5R)-2-(trans-4-hydroxycyclohexyI)-l-oxo-2,7-diazaspiro[4.5]dec-7-yI]-2- methylphenyl}carbamate
Figure imgf000234_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 416.2 (M+H)+.
Example 427
Ethyl {4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yI]-2- methylphenyljcarbamate H
Figure imgf000234_0002
This compound was prepared using procedures analogous to those described for the synthesis of example 105. LC-MS: 430.3 (M+H)+.
Example 428
Prop-2-yn-l-yl {4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-2- methylphenyl}carbamate
Figure imgf000235_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 440.3 (M+H)+.
Example 429
Methyl {6-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yI]-4- methylpyridin-3-yl}carbamate
Figure imgf000235_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 417.2 (M+H)+.
Example 430
Ethyl {6-[(5R)-2-(trans-4-hydroxycycIohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-4- methylpyridin-3-yl}carbamate H
Figure imgf000236_0001
This compound was prepared using procedures analogous to those described for the synthesis of example 105. LC-MS: 431.3 (M+H)+.
Example 431
Prop-2-yn-l-yl {6-[(5R)-2-(trans-4-hydroxycycIohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yI]-4- methylpyridin-3-yl}carbamate H
Figure imgf000236_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS : 441.2 (M+H)+.
Example 432
Methyl {6-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5- methoxypyridin-3-yl}carbamate
Figure imgf000237_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 433.3 (M+H)+.
Example 433
Ethyl {6-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5- methoxypy ridin-3-yl} carbamate
Figure imgf000237_0002
This compound was prepared using procedures analogous to those described for the synthesis of example 105. LC-MS: 447.3 (M+H)+.
Example 434
Prop-2-yn-l-yl {6-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5- methoxypyridin-3-yl}carbamate
Figure imgf000238_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 457.2 (M+H)+.
Example 435
Methyl {5-fluoro-2-[(5R)-2-(trans-4-hydroxycyclohexyI)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl] pyrimidin-4-yl} carbamate
Figure imgf000238_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 457.2 (M+H)+.
Example 436
Isopropyl {3-fluoro-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl] phenyl}methylcarbamate H
Figure imgf000239_0001
A mixture of isopropyl {3-fluoro-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7- diazaspiro[4.5]dec-7-yl]phenyl}carbamate (6 mg, 0.00001 mol, this compound was prepared by using procedures analogous to those described for the synthesis of example 105), methyl iodide (0.5 mL, 0.008 mol), and potassium carbonate (6 mg, 0.00004 mol) was stirred at rt for 24 h at 60 0C. After cooling, the reaction mixture was purified by prep.-HPLC to afford the desired product. LC-MS: 462.3 (M+H)+.
Example 437 (5R)-7-(3-Bromo-5-methyIpyridin-2-yI)-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro [4.5] decan- 1-one H
Figure imgf000239_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 422.2/424.2 (M+H)+.
Example 438
2- [(5R)-2-CycIohexyI-l-oxo-2,7-diazaspiro [4.5] dec-7-yI] nicotinonitrile
Figure imgf000240_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 339.2 (M+H)+.
Example 439
2-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]isonicotinonitrile H
Figure imgf000240_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 355.2 (MH-H)+.
Example 440 (5R)-7-(3-Fluoro-6-methylpyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-
1-one
Figure imgf000240_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 355.2 (M+H)+. Example 441
6-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yI]-2- methylnicotinonitrile H
Figure imgf000241_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 369.2 (M+H)+.
Example 442 2-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-4,6- dimethylnicotinonitrile
Figure imgf000241_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 383.2 (M+H)+.
Example 443
(5R)-2-(trans-4-Hydroxycyclohexyl)-7-[2-(trifluoromethyl)quinazolin-4-yl]-2,7- diazaspiro[4.5]decan-l-one H
Figure imgf000242_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 449.1 (M+H)+.
Example 444
(5R)-2-Cyclohexyl-7-[2-fluoro-4-(2-oxo-l,3-oxazolidin-3-yl)phenyl]-2,7-diazaspiro[4.5]decan-l- one
Figure imgf000242_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 256. LC-MS: 416.1 (M+H)+.
Example 445 (5R)-2-Cyclohexyl-7-[2-fluoro-4-(2-oxopyrroIidin-l-yl)phenyl]-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000243_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 256. LC-MS: 414.1 (M+H)+.
Example 446
(5R)-7-(3-Fluoropyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000243_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 116. LC-MS: 334.1 (M+H)+.
Example 447
(5R)-7-[2-Fluoro-4-(2-oxo-l,3-oxazolidin-3-yl)phenyl]-2-(tetrahydro-2H-pyran-4-yI)-2,7- diazaspiro[4.5]decan-l-one
Figure imgf000243_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 256. LC-MS: 418.1 (M+H)+.
Example 448 (5R)-7-[2-Fluoro-4-(2-oxo-l,3-oxazinan-3-yI)phenyl]-2-(tetrahydro-2H-pyran-4-yI)-2,7- diazaspiro[4.5] decan-1-oiie
Figure imgf000244_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 256. LC-MS: 432.2 (M+H)+.
Example 449
(5R)-7-[2-Fluoro-4-(2-oxopiperidin-l-yl)phenyI]-2-(tetrahydro-2H-pyran-4-yl)-2,7- diazaspiro [4.5] decan- 1-one
Figure imgf000244_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 256. LC-MS: 430.2 (M+H)+.
Example 450
(5R)-7-[2-FIuoro-4-(2-oxopyrrolidin-l-yl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)-2,7- diazaspiro[4.5]decan-l-one
Figure imgf000245_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 256. LC-MS: 416.2 (M+H)+.
Example 451
3-FIuoro-N-methyI-4-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yI)-2,7-diazaspiro[4.5]dec-7- yljbenzamide
Figure imgf000245_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 116. LC-MS: 390.2 (M+H)+.
Example 452
3-Fluoro-N,N-dimethyl-4-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7- yl]benzamide
Figure imgf000246_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 116. LC-MS: 404.2 (M+H)+.
Example 453
2- [(5R)-l-Oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro [4.5] dec-7-yl] benzonitrile
Figure imgf000246_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 116. LC-MS: 340.2 (M+H)+.
Example 454 (5R)-7-(3,5-DichIoropyridin-2-yl)-2-(3-methylpyridin-2-yI)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000246_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 116. LC-MS: 340.2 (M+H)+. Example 455
3-Bromo-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yI]benzonitrile H
Figure imgf000247_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 44. LC-MS: 432.1/434.1 (M+H)+.
Example 456 (5R)-7-(2,5-difluorophenyI)-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000247_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 44. LC-MS: 365.2 (M+H)+.
Example 457 (5R)-7-(2-Bromo-3-fluorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000248_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 44. LC-MS: 425.1/427.1 (M+H)+.
Example 458
(5R)-7-(5-Fluoro-2-methyIphenyl)-2-(4-hydroxycycIohexyl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000248_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 44. LC-MS: 361.2 (M+H)+.
Example 459 (5R)-7-(2,3-Dichlorophenyl)-2-(4-hydroxycyclohexyI)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000248_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 44. LC-MS: 397.1/399.1 (M+H)+. Example 460
(5R)-7-(2,6-DichlorophenyI)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000249_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 44. LC-MS: 397.1/399.1 (M+H)+.
Example 461 4-Bromo-2-[(5R)-2-(cis-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile H
Figure imgf000249_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 432.1 (M+H)+.
Example 462 2-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile H
Figure imgf000249_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 44. LC-MS: 354.2 (M+H)+.
Example 463 (5R)-7-(2-FIuorophenyl)-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000250_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 44. LC-MS: 347.2 (M+H)+.
Example 464
2-[(5R)-2-(cis-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]isonicotinonitriIe
Figure imgf000250_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 420. LC-MS: 355.2 (M+H)+.
Example 465
(SR)-7-(3-Bromo-5-fluoropyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l- one
Figure imgf000251_0001
This compound was prepared b using procedures analogous to those described for the synthesis of example 420. LC-MS: 426.1/428.1 (M+H)+.
Example 466
(5R)-7-(3-Fluoro-4-methylpyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l- one
Figure imgf000251_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 420. LC-MS: 362.2 (M+H)+.
Example 467
6-[(5R)-2-(cis-4-HydroxycycIohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-2-methylnicotinonitrile
Figure imgf000251_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 420. LC-MS: 369.2 (M+H)+.
Example 468 (5R)-7-(5-ChIoro-3-methyIpyridin-2-yl)-2-(cis-4-hydroxycycIohexyl)-2,7-diazaspiro[4.5]decan-l- one
Figure imgf000252_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 420. LC-MS: 378.1 (M+H)+.
Example 469
4-Chloro-2-[(5R)-2-(cis-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile
Figure imgf000252_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 420. LC-MS: 388.1 (M+H)+.
Example 470 2-Fluoro-4-[(5R)-2-(cis-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]benzonitriIe
Figure imgf000253_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 420. LC-MS: 372.1 (M+H)+.
Example 471
4-Bromo-2-[(5R)-2-(cis-4-hydroxycycIohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile
Figure imgf000253_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 420. LC-MS: 432.1 (M+H)+.
Example 472
7-[(3-Chloro-2-methylphenyI)sulfonyl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-
1-one
Figure imgf000253_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 1. LC-MS: 441.2/443.2 (M+H)+. Example 472-a
(5R)-7-[2-Chloro-5-(trifluoromethyl)phenyl]-2-(trans-4-hydroxycycIohexyl)-2,7- diazaspiro[4.5]decan-l-one H
Figure imgf000254_0001
Step 1. Benzyl (5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2, 7-diazaspiro[4.5]decane-7-carboxylate
A mixture of 1-benzyl 3-ethyl 3-(2-oxoethyl)piperidine-l,3-dicarboxylate (1.0 g, 0.0030 mol, prepared by using procedures analogous to those described for the synthesis of example 1, steps 1 and 2) , trans-4-aminocyclohexanol hydrochloride (0.50 g, 0.0033 mol), and triethylamine (0.48 g, 0.0048 mol) in 1,2-dichloroethane (8 mL, 0.1 mol) was stirred at rt for 30 min. To the mixture was added sodium triacetoxyborohydride (1.6 g, 0.0075 mol) and the resulting mixture was stirred at rt for 1 h. The reaction mixture then was warmed to 80 0C with stirring for 16 h. After cooling to ambient temperature, the reaction mixture was diluted with dichloromethane and the solution was washed with IN HCl, water, brine, and dried over MgSU4. After filtration, the filtrate was concentrated in-vacuo and the resulting residue was purified by flash column chromatography to afford 1.04 g of the desired product. Further purification by chiral HPLC led to the isolation of both diastereoisomers. The first peak to elute was assigned the S configuration and the second peak was assigned as the R configuration. LC-MS: 387.3 (M+H)+.
Step 2. Benzyl (5R)-l-oxo-2-{trans-4-[(tιiethylsilyl)oxy]cyclohexyl}-2, 7-diazaspiro[4.5]decane-7- carboxylate
To a solution of benzyl (5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]decane-7- carboxylate (2.0 g, 0.0052 mol) in N,N-dimethylformamide (5 mL, 0.06 mol) were added IH- imidazole (0.986 g, 0.0145 mol) and chlorotriethylsilane (1.13 mL, 0.00673 mol) at rt. After stirring for 2 h ice-water was added and the resulting mixture was stirred at room temperature for 30 minutes and extracted three times with AcOEt. The combined extracts were washed with brine, dried over sodium sulfate, and concentrated. The residual oil was purified by column chromatography using 30% by volume AcOEt in hexanes.
Step 3. (5R)-2-{trans-4-[(ti"iethylsilyl)oxy]cyclohexyl}-2, 7-diazaspiro[4.5]decan-l-one To a solution of benzyl (5R)-l-oxo-2-{trans-4-[(triethylsilyi)oxy]cyclohexyl}-2,7- diazaspiro[4.5]decane-7-carboxylate (2.4 g, 0.0048 mol) in methanol (10 mL, 0.2 mol) was added Pd/C, and the suspension was stirred at rt under a H2 balloon for 1.5 h. The inorganics were filtered and the filtrate was concentrated to afford the desired product.
Step 4. (SRJ-y-^-chloroS-ftrifluoromethylJphetTylJ^-ftrans^-hydroxycyclohexyl)^, 7- dia∑aspiro[4.5]decan-l-one
A mixture of aryl bromide, tris(dibenzylideneacetone)dipalladium(0) (2 mg, 0.000002 mol), 2'-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (5 mg, 0.00001 mol) in 1,4-dioxane (0.5 mL, 0.006 mol) was stirred under N2 (g) for 20 min. To this were added (5R)-2-{trans-4- [(triethylsilyl)oxy]cyclohexyl}-2,7-diazaspiro[4.5]decan-l-one (30 mg, 0.00008 mol) and sodium te/t-butoxide (11.8 mg, 0.000123 mol), and the resulting mixture was degassed and stirred at 100 "C for 16 h. At this time IM TBAF in THF (0.3 mL) was added dropwise to the reaction mixture and the solution was stirred at rt for 1 h. The volatiles were removed in-vacuo and the residue was purified by prep-HPLC to afford the desired product. LC-MS : 431.1 (M+H)+.
Example 473 (5R)-7-[3-Fluoro-5-(trifluoromethyl)phenyl]-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one H
Figure imgf000255_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 472-a. LC-MS: 415.1 (M+H)+.
Example 474 (5R)-7-(4-Chloro-2-methylphenyI)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l- one H
Figure imgf000256_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 472-a. LC-MS: 377.4 (M+H)+.
Example 475
(5R)-7-(3-chloro-2-methylphenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000256_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 472-a. LC-MS: 377.4 (M+H)+.
Example 476 (5R)-2-(fr«H5'-4-HydroxycycIohexyl)-7-quinoIin-8-yI-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000256_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 472-a. LC-MS: 380.2 (M+H)+. Example 477
{3-[(5R)-2-(frfl«sr-4-HydroxycycIohexyI)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}acetonitriIe
Figure imgf000257_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 472-a. LC-MS: 354.2 (M+H)+.
Example 478 (5R)-7-(4-Fluoro-2-methylphenyI)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l- one H
Figure imgf000257_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 180. LC-MS: 361.2 (M+H)+.
Example 479
(5R)-2-(fm/!S'-4-Hydroxycycloliexyl)-7-[4-(2-oxopyrrolidin-l-yl)-2-(trifluoromethyl)phenyl]-2,7- diazaspiro[4.5]decan-l-one H
Figure imgf000258_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 256. LC-MS: 480.2 (M+H)+.
Example 480
(5R)-2-(frα«s-4-Hydroxycyclohexyl)-7-[4-(2-oxo-l,3-oxazolidin-3-yl)-2-(trifluoromethyl)phenyl]- 2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000258_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 256. LC-MS: 482.2 (M+H)+.
Example 481
(5R)-2-(^αns-4-Hydroxycyclohexyl)-7-[4-(2-oxo-l,3-oxazinan-3-yl)-2-(trifluoromethyI)phenyI]-
2,7-diazaspiro[4.5]decan-l-one
Figure imgf000259_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 256. LC-MS: 496.2 (M+H)+.
Example 482 (5R)-7-[3-Fluoro-4-(pyridin-2-yloxy)phenyl]-2-(4-hydroxycycIohexyl)-2,7-diazaspiro[4.5]decan-
1-one
Figure imgf000259_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 180. LC-MS: 440.3 (M+H)+.
Example 483
(5R)-7-[3-Fluoro-4-(pyridin-4-yloxy)phenyl]-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-
1-one
Figure imgf000260_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 180. LC-MS: 440.3 (M+H)+.
Example 484
(5R)-7-[3-Fluoro-4-(pyridin-3-yloxy)phenyI]-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-
1-one
Figure imgf000260_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 180. LC-MS: 440.3 (M+H)+.
Example 485
(5R)-7-[2-FIuoro-4-(pyridin-3-yIoxy)phenyI]-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-
1-one
Figure imgf000261_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 180. LC-MS: 440.3 (M+H)+.
Example 486
Methyl {3-chloro-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl] phenyljcarbamate
Figure imgf000261_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 436.3 (M+H)+.
Example 487
Ethyl {3-chloro-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl] phenyljcarbamate H
Figure imgf000262_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 450.3 (M+H)+.
Example 488
Prop-2-yn-l-yl {3-chIoro-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl] phenyljcarbamate
Figure imgf000262_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 460.3 (M+H)+.
Example 489
Propyl {3-chIoro-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl] phenyl} carbamate
Figure imgf000263_0001
This compound was prepared by using procedures analogous to those described . for the synthesis of example 105. LC-MS: 465.1 (M+H)+.
Example 490
N- {3-Chloro-4- [(5R)-2-(trans-4-hydroxycycIohexyl)- l-oxo-2,7-diazaspiro [4.5] dec-7- yl]phenyl}cyclopentanecarboxamide H
Figure imgf000263_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS : 475.1 (M+H)+.
Example 491
N-{3-Chloro-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl] phenyl} cyclohexanecarboxamide H
Figure imgf000264_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 489.1 (M+H)+.
Example 492
(5R)-7-(5-Fluoropyrimidin-2-yI)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000264_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 349.1 (M+H)+.
Example 493 (5R)-7-(5-Bromopyrimidin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000265_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 409.1/411.1 (M+H)+.
Example 494
(5R)-7-(5-Ethylpyrimidin-2-yI)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000265_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 359.1 (M+H)+.
Example 495
4-{2-[(5R)-2-(cis-4-HydroxycyclohexyI)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyrimidin-5- yl}benzamide
Figure imgf000266_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 257. LC-MS: 450.1 (M+H)+.
Example 496 N-Cyclopropyl-4-{2-[(5R)-2-(cis-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl] pyrimidin-5-yl} benzamide
Figure imgf000266_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 257. LC-MS: 490.1 (M+H)+.
Example 497
(5R)-2-(cis-4-Hydroxycyclohexyl)-7-[5-(4-methoxyphenyl)pyrimidin-2-yl]-2,7- diazaspiro[4.5]decan-l-one
Figure imgf000267_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 257. LC-MS: 437.1 (M+H)+.
Example 498
(5R)-2-(cis-4-Hydroxycyclohexyl)-7-(5-pyridin-3-ylpyrimidin-2-yl)-2,7-diazaspiro[4.5]decan-l- one
Figure imgf000267_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 257. LC-MS : 408.2 (M+H)+.
Example 499
5-{2-[(5R)-2-(cis-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyrimidin-5-yI}-N,N- dimethyIpyridine-2-carboxamide
Figure imgf000268_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 257. LC-MS: 479.1 (M+H)+.
Example 500
(5R)-2-(cis-4-Hydroxycyclohexyl)-7-(5-pyridin-4-yIpyrimidin-2-yl)-2,7-diazaspiro[4.5]decan-l- one
Figure imgf000268_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 257. LC-MS: 408.2 (M+H)+.
Example 501
4-{5-Chloro-6-[(5R)-2-(cis-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3- yl}-N-cyclopropyIbenzamide
Figure imgf000269_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 257. LC-MS: 523.2 (M+H)+.
Example 502
5'-Chloro-N-ethyl-6'-[(5R)-2-(cis-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yI]-3,3'- bipyridine-6-carboxamide
Figure imgf000269_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 257. LC-MS : 512.2 (M+H)+.
Example 503
2- [(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro [4.5] dec-7-yl] isonicotinonitrile
Figure imgf000270_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 355.2 (M+H)+.
Example 504
Methyl {4- [(5R)-2-(cis-4-hydroxy-4-methylcyclohexyl)- l-oxo-2,7-diazaspiro [4.5] dec-7-yl] -3- methylphenyl}carbamate
Figure imgf000270_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 430.1 (M+H)+.
Example 505
Prop-2-yn-l-yl {6-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5- methoxypyridin-3-yl}carbamate
Figure imgf000271_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 105. LC-MS: 457.2 (M+H)+.
Example 506
(5R)-7-(5-Fluoropyrimidin-2-yl)-2-(tetrahydro-2H-pyran-4-yI)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000271_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 116. LC-MS: 335.1 (M+H)+.
Example 507
(5R)-7-(5-Ethylpyrimidin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000271_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 116. LC-MS: 345.1 (M+H)+.
Example 508 (5R)-2-(Tetrahydro-2H-pyran-4-yl)-7-[4-(trifluoromethyl)pyrimidin-2-yl]-2,7- diazaspiro [4.5] decan-1-one
Figure imgf000272_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 116. LC-MS: 385.1 (M+H)+.
Example 509
(5R)-7-(4-Methoxypyrimidin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000272_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 116. LC-MS: 347.1 (M+H)+.
Example 510 (5R)-7-(2-Fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000273_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 180. LC-MS: 333.1 (M+H)+.
Example 511
(5R)-2-(cis-4-Hydroxycyclohexyl)-7-[5-(lH-pyrazol-l-yl)pyrimidin-2-yI]-2,7- diazaspiro[4.5]decan-l-one
Figure imgf000273_0002
To a solution of (5R)-7-(5-bromopyrimidin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7- diazasρiro[4.5]decan-l-one (30 mg, 0.00007 mol, this compound was prepared by using a procedures that were analogous to those described for the synthesis of example 420) in 1,4-dioxane (1 mL, 0.01 mol) was added lH-pyrazole (6.0 mg, 0.0000880 mol), (lS,2S)-N,N'-dimethylcyclohexane-l,2- diamine (2.3 uL, 0.000015 mol), copper(I) iodide (1.4 mg, 0.0000073 mol), and potassium carbonate
(0.0213 g, 0.000154 mol). After stirring at 150 °C for 16 h, the reaction mixture was filtered and purified by prep-HPLC to afford the desired product. LC-MS: 397.2 (M+H)+.
Example 512
(5R)-2-(cis-4-Hydroxycyclohexyl)-7-[5-(3-methyl-lH-pyrazol-l-yI)pyrimidin-2-yI]-2,7- diazaspiro [4.5] decan- 1-one
Figure imgf000274_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 511. LC-MS: 411.2 (M+H)+.
Example 513
(S^^-^is-^Hydroxycyclohexy^-T-fS-IS-^rifluoromethylJ-lH-pyrazoI-l-yllpyrimidin^-yl}^,?- diazaspiro[4.5]decan-l-one
Figure imgf000274_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 511. LC-MS : 465.2 (M+H)+.
Example 514 (5R)-2-(cis-4-HydroxycyclohexyI)-7-pyrimidin-2-yl-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000275_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 511. LC-MS: 331.2 (M+H)+.
Example 515
(5R)-2-(cis-4-HydroxycycIohexyl)-7-[5-(2-oxopyridin-l(2H)-yl)pyrimidin-2-yl]-2,7- diazaspiro[4.5]decan-l-one
Figure imgf000275_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 511. LC-MS: 424.2 (M+H)+.
Example 516
(5R)-7-(2,5-Difluoropyridin-3-yI)-2-(cis-4-hydroxycycIohexyI)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000275_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 420. LC-MS: 366.1 (M+H)+.
Example 517 (5R)-7-(3,5-Difluoropyridin-2-yl)-2-(cis-4-hydroxycyclohexyI)-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000276_0001
This compound was prepared b using procedures analogous to those described for the synthesis of example 420. LC-MS: 366.1 (M+H)+.
Example 518
(5R)-7-[3-FIuoro-4-(trifluoromethyl)pyridin-2-yl]-2-(cis-4-hydroxycycIohexyl)-2,7- diazaspiro[4.5]decan-l-one
Figure imgf000276_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 420. LC-MS: 416.1 (M+H)+.
Example 519
(5R)-7-[3-Chloro-5-(trifluoromethyl)pyridin-2-yI]-2-(cis-4-hydroxycycIohexyl)-2,7- diazaspiro[4.5]decan-l-one
Figure imgf000277_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 420. LC-MS: 432.2 (M+H)+.
Example 520
(5R)-2-(cis-4-HydroxycyclohexyI)-7-[4-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan- 1-one
Figure imgf000277_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 420. LC-MS: 398.2 (M+H)+.
Example 521
(5R)-7-(5-Bromo-2-chloropyridin-3-yl)-2-(cis-4-hydroxycyclohexyI)-2,7-diazaspiro[4.5]decan-l- one
Figure imgf000277_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 420. LC-MS: 442.2/444.2 (M+H)+.
Example 522a (5R)-7-(5-Bromo-3-fluoropyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l- one
Figure imgf000278_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 420. LC-MS: 446.2/448.2 (M+H)+.
Example 522b (5R)-7-(5-Bromo-3-chloropyridin-2-yl)-2-(cis-4-hydroxycyclohexyI)-2,7-diazaspiro[4.5]decan-l- one
Figure imgf000278_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 420. LC-MS: 442.2/444.2 (M+H)+.
Example 523 (5R)-7-(5-Bromo-3-methylpyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l- one
Figure imgf000279_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 420. LC-MS: 422.2/424.2 (M+H)+.
Example 524
Methyl {6-[(5R)-2-(cis-4-hydroxycyclohexyI)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5- methylpyridin-3-yl} carbamate
Figure imgf000279_0002
This compound was prepared by using procedures analogous to those described for the synthesis of examples 420, steps 1 and 2 followed by using procedures that were analogous to those described for the synthesis of example 105, steps 1 and 2. LC-MS: 417.2 (M+H)+.
Example 525
Ethyl {6-[(5R)-2-(cis-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5-methylpyridin- 3-yl}carbamate
Figure imgf000280_0001
This compound was prepared using procedures analogous to those described for the synthesis of example 524. LC-MS: 431.2 (M+H)+.
Example 526
Propyl {6-[(5R)-2-(cis-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5-methylpyridin- 3-yl}carbamate
Figure imgf000280_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 524. LC-MS : 445.2 (M+H)+.
Example 527
Prop-2-yn-l-yl {6-[(5R)-2-(cis-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yI]-5- methylpyridin-3-yl} carbamate
Figure imgf000281_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 524. LC-MS: 441.2 (M+H)+.
Example 528
Methyl {6-[(5R)-2-(cis-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5- methoxypyridin-3-yl}carbamate
Figure imgf000281_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 524. LC-MS: 433.2 (M+H)+.
Example 529
Ethyl {6-[(5R)-2-(cis-4-hydroxycyclohexyI)-l-oxo-2,7-diazaspiro[4.5]dec-7-yI]-5- methoxypyridin-3-yl}carbamate
Figure imgf000282_0001
This compound was prepare by using procedures analogous to those described for the synthesis of example 524. LC-MS: 447.2 (M+H)+.
Example 530
Propyl {6-[(5R)-2-(cis-4-hydroxycycIohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5- methoxypyridin-3-yl}carbamate
Figure imgf000282_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 524. LC-MS : 461.2 (M+H)+.
Example 531
Prop-2-yn-l-yl {6-[(5R)-2-(cis-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5- methoxypyridin-3-yl}carbamate
Figure imgf000283_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 524. LC-MS: 457.2 (M+H)+.
Example 532
(5R)-2-(cis-4-HydroxycycIohexyl)-7-[3-methoxy-5-(2-oxopyrrolidin-l-yl)pyridin-2-yl]-2,7- diazaspiro [4.5] decan-1-one
Figure imgf000283_0002
This compound was prepared by using procedures analogous to those described for the synthesis of examples 420, steps 1 and 2 followed by using procedures that were analogous to those described for the synthesis of example 256. LC-MS: 443.2 (M+H)+.
Example 533
(5R)-2-(cis-4-Hydroxycyclohexyl)-7-[3-methoxy-5-(2-oxo-l,3-oxazolidin-3-yl)pyridin-2-yl]-2,7- diazaspiro [4.5] decan-1-one
Figure imgf000284_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 532. LC-MS: 445.2 (M+H)+.
Example 534
(5R)-2-(cis-4-Hydroxycyclohexyl)-7-[3-methoxy-5-(2-oxo-l,3-oxazinan-3-yI)pyridin-2-yl]-2,7- diazaspiro[4.5]decan-l-one
Figure imgf000284_0002
This compound was prepared b using procedures analogous to those described for the synthesis of example 532. LC-MS: 459.1 (M+H)+.
Example 535
(5R)-7-(3-Chloro-5-phenylpyridin-2-yI)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l- one
Figure imgf000285_0001
This compound was prepared by using procedures analogous to those described for the synthesis of examples 420, steps 1 and 2 followed by using procedures that were analogous to those described for the synthesis of example 257. LC-MS: 440.2 (M+H)+.
Example 536a (5R)-7-[3-ChIoro-5-(4-methoxyphenyl)pyridin-2-yl]-2-(cis-4-hydroxycyclohexyl)-2,7- diazaspiro [4.5] decan- 1-one
Figure imgf000285_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 535. LC-MS: 471.2 (M+H)+.
Example 536b
4-{5-Chloro-6-[(5R)-2-(cis-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3- yljbenzamide
Figure imgf000286_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 535. LC-MS: 483.2 (M+H)+.
Example 537
(5R)-7-(5-Chloro-3,4'-bipyridiπ-6-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l- one
Figure imgf000286_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 535. LC-MS : 441.2 (M+H)+.
Example 538
5'-Chloro-6'-[(5R)-2-(cis-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-N,N-dimethyl-
3,3'-bipyridine-6-carboxamide
Figure imgf000287_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 535. LC-MS: 512.2 (M+H)+.
Example 539
5'-Chloro-N,N-diethyI-6'-[(5R)-2-(cis-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-
3,3'-bipyridine-6-carboxamide
Figure imgf000287_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 535. LC-MS: 540.2 (M+H)+.
Example 540
4-{5-ChIoro-6-[(5R)-2-(cis-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3- yl}-N,N-dimethylbenzamide
Figure imgf000288_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 535. LC-MS: 511.2 (M+H)+.
Example 541
Methyl {5-chloro-6-[(5R)-2-(cis-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yI]pyridin- 3-yl}carbamate
Figure imgf000288_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 524. LC-MS: 437.2 (M+H)+.
Example 542
Ethyl {5-chIoro-6-[(5R)-2-(cis-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yI]pyridin-3- yl} carbamate
Figure imgf000289_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 524. LC-MS: 451.2 (M+H)+.
Example 543
Propyl {5-chloro-6-[(5R)-2-(cis-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin- 3-yI}carbamate
Figure imgf000289_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 524. LC-MS : 465.2 (M+H)+.
Example 544
Prop-2-yn-l-yl {5-chloro-6-[(5R)-2-(cis-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl] pyridin-3-yI}carbamate
Figure imgf000290_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 524. LC-MS: 461.2 (M+H)+.
Example 545
(5R)-7-[3-Chloro-5-(2-oxo-l,3-oxazolidin-3-yl)pyridin-2-yl]-2-(cis-4-hydroxycycIohexyl)-2,7- diazaspiro[4.5]decan-l-one
Figure imgf000290_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 532. LC-MS: 449.2 (M+H)+.
Example 546
(5R)-7-[3-Chloro-5-(2-oxo-l,3-oxazinan-3-yl)pyridin-2-yl]-2-(ds-4-hydroxycyclohexyI)-2,7- diazaspiro[4.5]decan-l-one
Figure imgf000291_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 532. LC-MS: 463.2 (M+H)+.
Example 547
(5R)-7-[3-Chloro-5-(2-oxopyrroIidin-l-yl)pyridin-2-yl]-2-(ds-4-hydroxycycIohexyl)-2,7- diazaspiro [4.5] decan-1-one
Figure imgf000291_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 532. LC-MS: 447.2 (M+H)+.
Example 548
(5R)-7-(5-ChIoro-3,3'-bipyridin-6-yl)-2-(cis-4-hydroxycycIohexyl)-2,7-diazaspiro[4.5]decan-l- one
Figure imgf000292_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 535. LC-MS: 441.2 (M+H)+.
Example 549
(5R)-7-(3-Fluoro-6-methylpyridin-2-yI)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan- 1-one H
Figure imgf000292_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS : 362.2 (M+H)+.
Example 550
6- [(5R)-2-(trans-4-HydroxycycIohexyl)- l-oxo-2,7-diazaspiro [4.5] dec-7-yl] -2- methylnicotinonitrile H
Figure imgf000293_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 369.2 (M+H)+.
Example 551
2-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yI]-4,6- dimethylnicotinonitrile H
Figure imgf000293_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS : 383.2 (M+H)+.
Example 552
(5R)-2-(trans-4-Hydroxycyclohexyl)-7-[2-(trifluoromethyl)quinazoIin-4-yl]-2,7- diazaspiro[4.5]decan-l~one
Figure imgf000293_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 449.2 (M+H)+.
Example 553 (5R)-2-CyclohexyI-7-[2-fluoro-4-(2-oxopyrrolidin-l-yl)phenyI]-2,7-diazaspiro[4.5]decan-l-one
Figure imgf000294_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 256. LC-MS: 414.2 (M+H)+.
Example 554
(5R)-2-Cyclohexyl-7-[2-fluoro-4-(2-oxo-l,3-oxazolidin-3-yl)phenyl]-2,7-diazaspiro[4.5]decan-l- one
Figure imgf000294_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 256. LC-MS: 416.2 (M+H)+.
Example 555
(5R)-7-(5-Chloro-3-methylpyridin-2-yl)-2-(trans-4-hydroxycycloliexyl)-2,7- diazaspiro[4.5]decan-l-one H
Figure imgf000295_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 378.2 (M+H)+.
Example 556
(5R)-7-(3-FIuoro-4-methylpyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan- 1-one H
Figure imgf000295_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 362.2 (M+H)+.
Example 557
(5R)-7-(5-Fluoro-3-methylpyridin-2-yl)-2-(trans-4-hydroxycycIohexyl)-2,7-diazaspiro[4.5]decan-
1-one H
Figure imgf000295_0003
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 362.2 (M+H)+.
Example 558 (5R)-7-(5-Fluoro-6-methyIpyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan- 1-one H
Figure imgf000296_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 362.2 (M+H)+.
Example 559
(5R)-2-(trans-4-HydroxycycIohexyl)-7-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7- diazaspiro [4.5] decan-1-one
Figure imgf000296_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 370.2 (M+H)+.
Example 560 (5R)-2-(trans-4-Hydroxycyclohexyl)-7-(5-methyIpyridin-2-yl)-2,7-diazaspiro[4.5]decan-l-one H
Figure imgf000297_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 93. LC-MS: 344.2 (M+H)+.
Example 561
2-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5- phenylnicotinonitrile H
Figure imgf000297_0002
This compound was prepared by using procedures analogous to those described for the synthesis of example 257. LC-MS: 431.2 (M+H)+.
Example 562
(5R)-7-[3-Chloro-5-(2-oxo-l,3-oxazoIidin-3-yI)pyridin-2-yl]-2-cyclohexyl-2,7- diazaspiro[4.5]decan-l-one
Figure imgf000298_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 256. LC-MS: 433.2 (M+H)+.
Example 563
(5R)-7-[3-Chloro-5-(2-oxopyrrolidin-l-yl)pyridin-2-yl]-2-cyclohexyl-2,7-diazaspiro[4.5]decan-l- one
Figure imgf000298_0002
This compound was prepared b using procedures analogous to those described for the synthesis of example 256. LC-MS: 431.2 (M+H)+.
Example 564
(5R)-7-[3-Chloro-5-(2-oxo-l,3-oxazinan-3-yI)pyridin-2-yI]-2-cyclohexyl-2,7- diazaspiro[4.5]decan-l-one
Figure imgf000299_0001
This compound was prepared by using procedures analogous to those described for the synthesis of example 256. LC-MS: 447.2 (M+H)+.
Example 565
(5R)-7-[3-Chloro-5-(2-oxopiperidin-l-yl)pyridin-2-yl]-2-cyclohexyl-2,7-diazaspiro[4.5]decan-l- o lie
Figure imgf000299_0002
This compound was prepared b usring procedures analogous to those described for the synthesis of example 256. LC-MS: 445.2 (M+H)+.
Example A
Enzymatic assay of llβHSDl
All in vitro assays were performed with clarified lysates as the source of l lβHSDl activity. HEK-293 transient transfectants expressing an epitope-tagged version of full-length human 11 βHSDl were harvested by centrifugation. Roughly 2 x 107 cells were resuspended in 40 mL of lysis buffer (25 mM Tris-HCl, pH 7.5, 0.1 M NaCl, 1 mM MgCl2 and 250 mM sucrose) and lysed in a microfluidizer. Lysates were clarified by centrifugation and the supernatants were aliquoted and frozen. Inhibition of l lβHSDl by test compounds was assessed in vitro by a Scintillation Proximity Assay (SPA). Dry test compounds were dissolved at 5 mM in DMSO. These were diluted in DMSO to suitable concentrations for the SPA assay. 0.8 μL of 2-fold serial dilutions of compounds were dotted on 384 well plates in DMSO such that 3 logs of compound concentration were covered. 20 μL of clarified lysate was added to each well. Reactions were initiated by addition of 20 μL of substrate- cofactor mix in assay buffer (25 mM Tris-HCl, pH 7.5, 0.1 M NaCl, 1 mM MgCl2) to final concentrations of 400 μM NADPH, 25 nM 3H-cortisone and 0.007% Triton X-100. Plates were incubated at 37 0C for one hour. Reactions were quenched by addition of 40 μL of anti-mouse coated SPA beads that had been pre-incubated with 10 μM carbenoxolone and a cortisol-specifϊc monoclonal antibody. Quenched plates were incubated for a minimum of 30 minutes at RT prior to reading on a Topcount scintillation counter. Controls with no lysate, inhibited lysate, and with no mAb were run routinely. Roughly 30% of input cortisone is reduced by 11 βHSDl in the uninhibited reaction under these conditions.
Test compounds having an IC50 value less than about 20 μM according to this assay were considered active.
Example B
Cell-based assays for HSD activity
Peripheral blood mononuclear cells (PBMCs) were isolated from normal human volunteers by Ficoll density centrifugation. Cells were plated at 4x105 cells/well in 200 μL of AIM V (Gibco-
BRL) media in 96 well plates. The cells were stimulated overnight with 50 ng/ml recombinant human
IL-4 (R&D Systems). The following morning, 200 nM cortisone (Sigma) was added in the presence or absence of various concentrations of compound. The cells were incubated for 48 hours and then supernatants were harvested. Conversion of cortisone to Cortisol was determined by a commercially available ELISA (Assay Design).
Test compounds having an IC50 value less than about 20 μM according to this assay were considered active.
Example C Cellular assay to evaluate MR antagonism
Assays for MR antagonism were performed essentially as described (Jausons-Loffreda et al. J Biolumin and Chemilumin, 1994, 9: 217-221). Briefly, HEK293/MSR cells (Invitrogen Corp.) were co-transfected with three plasmids: 1) one designed to express a fusion protein of the GAL4 DNA binding domain and the mineralocorticoid receptor ligand binding domain, 2) one containing the GAL4 upstream activation sequence positioned upstream of a firefly luciferase reporter gene (pFR- LUC, Stratagene, Inc.), and 3) one containing the Renilla luciferase reporter gene cloned downstream of a thymidine kinase promoter (Promega). Transfections were performed using the FuGENEό reagent (Roche). Transfected cells were ready for use in subsequent assays 24 hours post- transfection.
In order to evaluate a compound's ability to antagonize the MR, test compounds are diluted in cell culture medium (E-MEM, 10% charcoal-stripped FBS, 2 mM L-glutamine) supplemented with 1 nM aldosterone and applied to the transfected cells for 16-18 hours. After the incubation of the cells with the test compound and aldosterone, the activity of firefly luciferase (indicative of MR agonism by aldosterone) and Renilla luciferase (normalization control) were determined using the Dual-Glo
Luciferae Assay System (Promega). Antagonism of the mineralocorticoid receptor was determined by monitoring the ability of a test compound to attenuate the aldosterone-induced firefly luciferase activity.
Compounds having an IC50 of 100 μM or less were considered active.
Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patent, patent applications, and publications, cited in the present application is incorporated herein by reference in its entirety.

Claims

What is claimed is:
1. A compound of Formula I:
Figure imgf000302_0001
I or pharmaceutically acceptable salt or prodrug thereof, wherein:
Cy is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 -W-X-Y-Z;
L is (CR12R13)ql, (CR12R13)qlO(CR12R13)q2, (CR12R13)qlS(CR12R13)q2, (CR12R13)qlSO2(CR12R13)q2, (CR12R13)qlSO(CR12R13)q2, or (CR12R13)qlCO(CR12R13)q2;
Figure imgf000302_0002
A is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 -W'-X'-Y'-Z';
E is -(CR3aR3b)nl-, -(CR3aR3b)n2CO-, -(CR3aR3b)n2OCO-, -(CR3aR3b)n2SO-,
-(CR3aR3b)n2SO2-, -(CR3aR3b)n2NR3c-, -(CR3aR3b)n3CONR3c-, -(CR33R3^112NR30CO-, or a group of formula:
Figure imgf000302_0003
D1, D2, D3 and D4 are each N or CR15;
R1 and R2 are each, independently, H or C1-8 alkyl;
R3a and R3b are each, independently, H, OC(O)R3', OC(O)ORb>, C(O)ORb>, OC(0)NR0>Rd', NR°'Rd', NR°'C(0)Ra', NR°'C(0)0Rb', S(O)R3', S(0)NR° Rd', S(O)2R3', S(O)2NR0>Rd', 0Rb', SRb', halo, C1-10 alkyl, C1-10 haloalkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C1. io alkyl, Ci-10 haloalkyl, C2-I0 alkenyl, C2-I0 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by R16;
R3c is H, Ci-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, or CO-(Ci-4 alkyl);
R4, R5, R6, R7, R8, R9, R10 and R11 are each, independently, H, OC(O)R3', 0C(0)0Rb', C(0)0Rb>, 0C(0)NR°'Rd', NR°'Rd>, NR°'C(O)Ra>, NRc'C(0)0Rb', S(O)R3', S(O)NR°'Rd', S(O)2R3', S(O)2NR°'Rd', ORb', SRb>, halo, CM0 alkyl, CM0 haloalkyl, C2-J0 alkenyl, C2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said Ci-I0 alkyl, Ci-I0 haloalkyl, C2-10 alkenyl, C2-I0 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by R14; or R4 and R5 together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group which is optionally substituted by R14; or R6 and R7 together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group which is optionally substituted by R14; or R8 and R9 together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group which is optionally substituted by R14; or R10 and R11 together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group which is optionally substituted by R14; or R and R6 together with the carbon atom to which they are attached form a 3-7 membered fused cycloalkyl group or 3-7 membered fused heterocycloalkyl group which is optionally substituted by R14; or R6 and R8 together with the carbon atom to which they are attached form a 3-7 membered fused cycloalkyl group or 3-7 membered fused heterocycloalkyl group which is optionally substituted by R14; or R4 and R9 together form a Ci-3 alkylene bridge which is optionally substituted by R14; jor R4 and R10 together form a Ci-3 alkylene bridge which is optionally substituted by R14; or R6 and R10 together form a Ci-3 alkylene bridge which is optionally substituted by R14; or R9 and R10 together form a Ci-3 alkylene bridge which is optionally substituted by R14;
R12 and R13 are each, independently, H, halo, Q.4 alkyl, Cμ haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa', SRa', C(O)Rb', C(O)NR°'Rd>, C(O)ORa>, OC(O)Rb>, OC(O)NR0'Rd', NR°'Rd>, NR°'C(0)Rd>, NR°'C(0)0Ra', S(O)Rb>, S(O)NR° Rd', S(O)2Rb', or S(O)2NRc'Rd';
R14 is halo, Ci-4 alkyl, Ci-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, OR3', SRa', C(O)Rb>, C(O)NR0 Rd>, C(O)OR3', 0C(0)Rb', 0C(0)NR° Rd', NR°'Rd', NR°'C(0)Rd', NR°'C(0)0Ra>, S(O)Rb>, S(O)NRc'Rd>, S(O)2Rb', or S(0)2NR°'Rd';
R15 is H, halo, Ci-4 alkyl, Ci-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, 0Ra", SRa", C(O)Rb", C(O)NR0V, C(O)OR3", 0C(0)Rb", 0C(0)NR°"Rd", NR°"Rd", NR°"C(0)Rd", NR°"C(0)0Ra", S(O)Rb", S(0)NR°"Rd", S(O)2Rb", or S(O)2NR°"Rd";
R16 is halo, Ci-4 alkyl, Ci-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, OR3', SR3', C(0)Rb>, C(0)NR°'Rd>, C(O)OR3', 0C(0)Rb', 0C(0)NR°'Rd', NR°'Rd', NR0>C(0)Rd>, NR°'C(0)0R3', S(O)Rb', S(0)NR°'Rd', S(O)2Rb>, or S(0)2NR°'Rd';
W, W and W" are each, independently, absent, C1.6 alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl, O, S, NRe, CO, COO, C0NRe, SO, SO2, S0NRe, or NReC0NRf, wherein said Ci-6 alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl are each optionally substituted by 1, 2 or 3 halo, OH, Ci-4 alkoxy, Ci-4haloalkoxy, amino, Q-4 alkylamino or C2-S dialkylamino;
X, X' and X" are each, independently, absent, C1-6 alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said Ci-6 alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by one or more halo, oxo, CN, NO2, OH, CM alkoxy, Ci-4haloalkoxy, amino, Q-4 alkylamino or C2-8 dialkylamino;
Y, Y' and Y" are each, independently, absent, Ci-6 alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl, O, S, NRe, CO, COO, C0NRe, SO, SO2, SONR6, or NReC0NRf, wherein said Cj-6 alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl are each optionally substituted by 1, 2 or 3 halo, OH, C^4 alkoxy, Ci-4 haloalkoxy, amino, Ci-4 alkylamino or C2-8 dialkylamino;
Z, Z' and Z" are each, independently, H, halo, CN, NO2, OH, Ci-4 alkoxy, Ci-4haloalkoxy, amino, Q-4 alkylamino, C2-8 dialkylamino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2 or 3 halo, oxo, Ci-6 alkyl, C2.6 alkenyl, C2-6 alkynyl, CL4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, 0Ra, SRa, C(O)Rb, C(0)NRcRd, C(0)0Ra, OC(O)Rb, 0C(0)NRcRd, NR°Rd, NR°C(O)Rd, NR0C(O)OR3, NReS(O)2Rb, S(O)Rb, S(0)NR°Rd, S(O)2Rb, or S(O)2NRcRd; wherein two -W-X-Y-Z attached to the same atom optionally form a 3-20 membered cycloalkyl or heterocyloalkyl group, each optionally substituted by 1, 2 or 3 -W"-X"-Y"-Z"; wherein two — W'-X'-Y'-Z' attached to the same atom optionally form a 3-20 membered cycloalkyl or heterocyloalkyl group, each optionally substituted by 1, 2 or 3 -W"-X"-Y"-Z"; 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;
Ra, Ra and Ra are each, independently, H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl; heterocycloalkyl, heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, Ci-6 alkyl, Ci-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;
Rb, Rb and Rb are each, independently, H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said Ci-6 alkyl, C]-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; Rc and Rd are each, independently, H, Ci-10 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said Ci-I0 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or Rc and Rd together with the N atom to which they are attached form a A-, 5-, 6- or 7- membered heterocycloalkyl group;
R0' and Rd are each, independently, H, Ci-I0 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said Ci-I0 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or Rc and Rd together with the N atom to which they are attached form a A-, 5-, 6- or 7- membered heterocycloalkyl group;
Rc and Rd are each, independently, H, Ci-I0 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said Ci-I0 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or Rc and Rd together with the N atom to which they are attached form a A-, 5-, 6- or 7- membered heterocycloalkyl group;
Re and Rf are each, independently, H, Q.jo alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said Ci-I0 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2.6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, Q-6 alkyl, Ci-6 haloalkyl, Ci-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or Re and Rf together with the N atom to which they are attached form a A-, 5-, 6- or 7- membered heterocycloalkyl group; m is O, 1, 2 or 3; nl is 1, 2, 3 or 4; n2 is θ, 1, 2, 3 or 4; n3 is O, 1, 2, 3 or 4; p is 0, 1 or 2; ql is 0, 1 or 2; q2 is 0, 1 or 2; and r is 0, 1 or 2; with the provisos:
(a) when A is aryl optionally substituted with 1, 2, 3, 4 or 5 -W-X'-Y'-Z' or heteroaryl optionally substituted with 1, 2, 3, 4 or 5 -W'-X'-Y'-Z'; L is SO2, SO2CH2 or CH2; and m is 0, then Cy is other than unsubstituted aryl, monosubstituted aryl, unsubstituted heteroaryl, or monosubstituted heteroaryl;
(b) when A is aryl optionally substituted with 1, 2, 3, 4 or 5 -W'-X'-Y'-Z' or heteroaryl optionally substituted with 1, 2, 3, 4 or 5 -W'-X'-Y'-Z'; L is SO2, SO2CH2 or CH2; m is 0, and Cy is di-, tri-, tetra- or penta-substituted aryl or di-, tri-, tetra- or penta-substituted heteroaryl, then said di-, tri-, tetra- or penta-substituted aryl or di-, tri-, tetra- or penta-substituted heteroaryl is substituted by at least one C1^ alkyl and at least one halo;
(c) when A is aryl optionally substituted with I5 2, 3, 4 or 5 -W'-X'-Y'-Z' or heteroaryl optionally substituted with I5 2, 3, 4 or 5 -W'-X'-Y'-Z'; L is SO2, SO2CH2 or CH2; and m is 0, then Cy is other than 2-chloro-6-methyl-phenyl;
(d) when A is phenyl or 4-phenoxyphenyl; L is SO2 or SO2CH2; and m is 0 or 1, then Cy is other than cyclohexyl or l,l-dioxo-tetrahydro-thien-3-yl;
(e) when Cy is aryl optionally substituted with 1, 2, 3, 4 or 5 -W-X-Y-Z or heteroaryl optionally substituted with 1, 2, 3, 4 or 5 -W-X-Y-Z; L is SO2, SO2CH2 or CH2; and m is 0, then A is other than tetrahydropyran-4-yl, 2,3-dihydroinden-2-yl or 2,2-difluoro-l,3-benzodioxol-5-yl; and
(f) when Cy is aryl optionally substituted with 1, 2, 3, 4 or 5 -W-X-Y-Z or heteroaryl optionally substituted with 1, 2, 3, 4 or 5 -W-X-Y-Z; L is SO2, SO2CH2 or CH2; and m is 1, then A is other than pyridine-4-yl, phenyl, 2-chloro-6-fluoro-phenyl, 4-methoxyphenyl or 4-phenoxy-phenyl.
2. The compound of claim 1 wherein Cy is aryl or heteroaryl, each optionally substituted with I5
2. 3, 4 or 5 -W-X-Y-Z.
3. The compound of claim 1 wherein Cy is aryl or heteroaryl, each optionally substituted with I5 2, 3, 4 or 5 -W-X-Y-Z wherein W is O or absent, X is absent, and Y is absent.
4. The compound of claim 1 wherein Cy is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, thiazolyl, pyrazinyl, purinyl, quinazolinyl, quinolinyl, isoquinolinyl, pyrrolo[2,3- d]pyrimidinyl, or 1,3-benzothiazolyl, each optionally substituted with 1, 2, 3, 4 or 5 -W-X-Y-Z.
5. The compound of claim 1 wherein Cy is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl or thienyl, each optionally substituted with 1, 2, 3, 4 or 5 -W-X-Y-Z.
6. The compound of claim 1 wherein Cy is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl thiazolyl, pyrazinyl, purinyl, quinazolinyl, quinolinyl, isoquinolinyl, pyrrolo[2,3- d]pyrimidinyl, or 1,3-benzothiazolyl, each optionally substituted with 1, 2, 3 or 4 halo, CN, NO2, Q-4 alkoxy, heteroaryloxy, C2-6 alkynyl, C1-4 haloalkoxy, NR°C(O)Rd, NR°C(O)ORa, C(O)NR°Rd, NRcRd, NReS(O)2Rb, C1-4 haloalkyl, Ci.6alkyl, heterocycloalkyl, aryl or heteraryl, wherein each of said Ci-6 alkyl, aryl or heteraryl is optionally substituted by 1, 2 or 3 halo, Ci-6 alkyl, C1-4 haloalkyl, CN, NO2, ORa, SRa, C(O)NR°Rd, NR°C(0)Rd or COORa.
7. The compound of claim 1 wherein Cy is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl thienyl, thiazolyl, pyrazinyl, purinyl, quinazolinyl, quinolinyl, isoquinolinyl, pyrrolo[2,3- d]pyrimidinyl,or 1,3-benzothiazolyl, each optionally substituted with 1, 2, 3 or 4 substituents independently selected form: halo, CN, NO2, C1-4 alkoxy, pyridin-2-yloxy, pyridin-3-yloxy, pyridin-4-yloxy, C2-6 alkynyl, Ci-4 haloalkoxy, NR°C(0)Rd, NRcC(O)ORa, C(O)NR°Rd, NR°Rd, NReS(O)2Rb, Ci-4 haloalkyl, Cj-6 alkyl, phenyl, pyridyl, pyrimidinyl, isoxazolyl, pyrazolyl, 1,2,3,6-tetrahydro-pyridinyl, 2-oxo-(2H)- pyridinyl, 2-oxo-[l,3]oxazolidinyl, 2-oxo-pyrrolidinyl, pyrrolidinyl, 2-oxopiperidinyl, and 2-oxo- [l,3]oxazinanyl; wherein each of said Ci-6 alkyl, phenyl, pyridyl, pyrimidinyl, isoxazolyl, pyrazolyl, 1,2,3,6-tetrahydro-pyridinyl, 2-oxo-(2H)-pyridinyl, 2-oxo-[l,3]oxazolidinyl, 2-oxo-pyrrolidinyl, pyrrolidinyl, 2-oxopiperidinyl, or 2-oxo-[l,3]oxazinanyl is optionally substituted by 1, 2 or 3 halo, C1. 6 alkyl, Ci-4 haloalkyl, CN, NO2, ORa, SRa, C(0)NR°Rd, NR°C(0)Rd or COORa.
8. The compound of claim 1 wherein Cy is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl or thienyl, each optionally substituted with 1, 2, or 3 halo, CN, Ci-4 alkoxy, Ci-4 haloalkoxy, Ci-6 alkyl or aryl, wherein said Ci-6 alkyl or aryl is optionally substituted by 1, 2 or 3 halo, Ci-6 alkyl, Ci-4 haloalkyl, CN, NO2, 0Ra, or SRa.
9. The compound of claim 1 wherein Cy is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl or thienyl, each optionally substituted with 1, 2, or 3 halo, CN, Ci-4 alkoxy, Ci-4 haloalkoxy, Ci-6 alkyl or aryl, wherein said Ci-6 alkyl or aryl is optionally substituted by 1, 2 or 3 halo or Ci.6 alkyl.
10. The compound of claim 1 wherein Cy is phenyl, pyridyl, pyrimidinyl, quinolinyl, or isoquinolinyl, each optionally substituted with 1, 2, 3, 4 or 5 -W-X-Y-Z.
11. The compound of claim 1 wherein Cy is phenyl, pyridyl, pyrimidinyl, quinolinyl, or isoquinolinyl, each optionally substituted with 1, 2, or 3 halo, CN, Ci-6 alkyl, C1-6 haloalkyl, Ci-6 alkoxy, -NR6C(O)O-Z, -C(O)O-Z, or NR6C(O)-Z.
12. The compound of claim 1 wherein Cy is cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 -W-X-Y-Z.
13. The compound of claim 1 wherein Cy is piperidinyl, pyrrolindinyl, 1, 2, 3,6- tetrahydropyridinyl, 2-oxo-[l,3]oxazinanyl, or piperizinyl, each optionally substituted with 1, 2, 3, 4 or 5 -W-X-Y-Z.
14. The compound of claim 1 wherein Cy is piperidinyl, pyrrolindinyl, 1, 2, 3,6- tetrahydropyridinyl, or piperizinyl, each optionally substituted with 1, 2, 3, 4 or 5 -W-X-Y-Z.
15. The compound of claim 1 wherein Cy is piperidinyl, pyrrolindinyl, 1, 2, 3, 6- tetrahydropyridinyl, 2-oxo-[l,3]oxazinanyl, or piperizinyl, each optionally substituted with 1, 2, or 3 aryl or heteroayl, wherein each of said aryl or heteroaryl is optionally substituted by 1, 2 or 3 halo, CN, Ci-4 alkyl, phenyl, pyridyl, Ci-4 alkoxy, or Ci-4 haloalkyl.
16. The compound of claim 1 wherein Cy is piperidinyl, pyrrolindinyl, 1, 2, 3, 6- tetrahydropyridinyl, 2-oxo-[l,3]oxazinanyl, or piperizinyl, each optionally substituted with 1, 2, or 3 phenyl, pyridyl or quinolinyl, wherein each of said phenyl, pyridyl, quinolinyl is optionally substituted by 1, 2 or 3 halo, CN, Ci.4 alkyl, phenyl, Ci-4 alkoxy, or Ci-4 haloalkyl.
17. The compound of claim 1 wherein Cy is piperidinyl, pyrrolindinyl, 1, 2, 3, 6- tetrahydropyridinyl, or piperizinyl, each optionally substituted with 1, 2, or 3 aryl, wherein said aryl is optionally substituted by 1, 2 or 3 halo or Ci-4 haloalkyl.
18. The compound of cla mimi 1 i w wihiceirceiiini L L, i iss K (^CR 1122rR> l1:OK qIS o r(rCrRD 1122ϋR 113O^q2, / (rCiϋR 1122rR> 1u3N)qiS °^O2( '™CR 1122rR> 113J)q2,
Figure imgf000308_0001
19. The compound of claim 1 wherein L is (CR12R13)qiSO2(CR12R13)q2.
20. The compound of claim 1 wherein L is S, SO or SO2.
21. The compound of claim 1 wherein L is SO2.
22. The compound of claim 1 wherein L is CO.
23. The compound of claim 1 wherein L is (CR12R13)qi .
24. The compound of claim 1 wherein L is (CR12R13)qi and ql is 0.
25. The compound of claim 1 wherein Q is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 -W'-X'-Y'-Z'.
26. The compound of claim 1 wherein Q is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 halo, C1-4 alkyl, CN, NRcC(O)Rd or NReS(O)2Rb.
27. The compound of claim 1 wherein Q is phenyl, pyridyl or quinolinyl, each optionally substituted with 1 or 2 halo, Cx-4 alkyl, CN, NR°C(O)Rd or NReS(O)2Rb.
28. The compound of claim 1 wherein Q is cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 -W'-X'-Y'-Z'.
29. The compound of claim 1 wherein Q is cycloalkyl or heterocycloalkyl, each optionally substituted with 1 or 2 -W'-X'-Y'-Z'.
30. The compound of claim 1 wherein Q is cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 OH, CM alkoxy, CN, Ci-4 alkyl, -0-heteroaryl, -(C1-4 alkyl)-CN, COORa, C(O)NR°Rd or NRcC(O)ORa.
31. The compound of claim 1 wherein Q is cyclopropyl, cyclohexyl, cycloheptyl, adamantyl, tetrahydro-2H-pyranyl or piperidinyl, each optionally substituted with 1 OH, C1.4 alkoxy, CN, Ci-4 alkyl, -O-heteroaryl, -(C1-4 alkyl)-CN, COORa, C(O)NR°Rd or NR0C(O)OR3.
32. The compound of claim 1 wherein Q is cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 OH, halo, CN, Ci-4 alkyl, C1-4 alkoxy, NR6COO(C1-4 alkyl), NR6CO(Ci-4 alkyl), aryl, heteroaryl, -O-aryl, -O-heteroaryl, or -(Ci-4 alkyl)-OH.
33. The compound of claim 1 wherein Q is cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 OH, CN, -O-heteroaryl, or C(O)O-Z'.
34. The compound of claim 1 wherein Q is cycloalkyl or heterocycloalkyl, each substituted with at least two -W'-X'-Y'-Z', wherein two of said at least two -W'-X'-Y'-Z' are attached to the same atom and together with the atom to which they are attached form a 3-20 membered cycloalkyl or heterocyloalkyl group, each optionally substituted by 1, 2 or 3 -W"-X"-Y"-Z".
35. The compound of claim 1 wherein Q is phenyl, pyridyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, indanyl, or 1,2,3,4-tetrahydronaphthalene, each optionally substituted with 1, 2, 3, 4 or 5 -W'-X'-Y'-Z'.
36. The compound of claim 1 wherein Q is phenyl, pyridyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl, each optionally substituted with 1, 2, 3, 4 or 5 OH, CN, halo,
Figure imgf000310_0001
alkyl, -O-heteroaryl, or C(O)O-Z.
37. The compound of claim 1 wherein Q is cyclohexyl substituted at the 4-position with at least one -W'-X'-Y'-Z'.
38. The compound of claim 1 wherein Q is cyclohexyl substituted at the 4-position with at least one OH, CN, or -O-X'-Y'-Z'.
39. The compound of claim 1 wherein Q is -(CR^R^m-A and m is 1, 2 or 3.
40. The compound of claim 1 wherein Q is -(CR1R2)m-A and m is 2.
41. The compound of claim 30 wherein A is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 -W'-X'-Y'-Z'.
42. The compound of claim 30 wherein A is aryl optionally substituted with 1, 2, 3, 4 or 5 —W'- X'-Y'-Z'.
43. The compound of claim 1 wherein E is methylene, ethylene, or propylene.
44. The compound of claim 1 wherein E is ethylene.
45. The compound of claim 1 wherein E is -CONR30-.
46. The compound of claim 1 wherein E is a group of formula:
Figure imgf000310_0002
47. The compound of claim 1 wherein D1, D2, D3 and D4 are each CR15.
48. The compound of claim 1 wherein one or two or D1, D2, D3 and D4 is N.
49. The compound of claim 1 wherein R4, R5, R6, R7, R8, R9, R10 and R11 are each, independently, H, OC(O)R3', OC(O)ORb', C(O)ORb>, OC(O)NRcRd', NR° Rd>, NR°'C(O)Ra>, NRcC(O)ORb', S(O)R3', S(O)NR°'Rd>, S(O)2R3', S(O)2NR°'Rd', 0Rb', SRb>, C^o alkyl, Ci-10 haloalkyl, C2-10 alkenyl, C2-I0 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl.
50. The compound of claim 1 wherein R4, R5, R6, R7, R8, R9, R10 and R11 are each, independently, H, Ci-I0 alkyl or Ci.iohaloalkyl.
51. The compound of claim 1 wherein R4, R5, R6, R7, R8, R9, R10 and R11 are each H.
52. The compound of claim 1 wherein R3a and R3b are each H.
53. The compound of claim 1 wherein r is 1.
54. The compound of claim 1 wherein r is 0.
55. The compound of claim 1 wherein the sum of ql and q2 is 0, 1 or 2.
56. The compound of claim 1 wherein the sum of ql and q2 is 0.
57. The compound of claim 1 wherein R12 and R13 are each H.
58. The compound of claim 1 wherein at least one of R1 andR2 is Ci-4 alkyl.
59. The compound of claim 1 wherein m is 0.
60. The compound of claim 1 wherein m is 1 or 2.
61. The compound of claim 1 wherein nl is 2.
62. The compound of claim 1 having Formula II:
Figure imgf000312_0001
II.
63. The compound of claim 1 having Formula IV:
Figure imgf000312_0002
IV.
64. A compound of claim 1 selected from:
7-[(3-Chloro-2-methylphenyl)sulfonyl]-2-(cis-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one;
7-[(3-Chloro-2-methylphenyl)sulfonyl]-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5] decan- 1 -one;
7-[(3-Chloro-2-methylphenyl)sulfonyl]-2-(2-methylphenyl)-2,7-diazaspiro[4.5]decan-l-one;
7-[(3-Chloro-2-methylphenyl)sulfonyl]-2-phenyl-2,7-diazaspiro[4.5]decan-l-one;
Trans-4-{7-[(3-chloro-2-methylphenyl)sulfonyl]-l-oxo-2,7-diazaspiro[4.5]dec-2- yl} cyclohexanecarbonitrile;
7-[(3-Chloro-2-methylphenyl)sulfonyl]-2-cycloheptyl-2,7-diazaspiro[4.5]decan-l-one;
7-[(3-Chloro-2-methylphenyl)sulfonyl]-2-cyclohexyl-2,7-diazaspiro[4.5]decan-l-one;
7- [(3 -Chloro-2-methylpheny l)sulfony 1] -2-(4-methylpyr idin-3 -yl)-2,7-diazaspiro [4.5] decan- 1 - one;
7-[(3-Chloro-2-methylphenyl)sulfonyl]-2-[cis-4-(pyridin-2-yloxy)cyclohexyl]-2,7- diazaspiro[4.5]decan-l-one;
7-[(3-Chloro-2-methylphenyl)sulfonyl]-2-[cis-4-(pyridin-3-yloxy)cyclohexyl]-2,7- diazaspiro[4.5] decan- 1 -one; 7-[(3-Chloro-2-methylphenyl)sulfonyl]-2-[cis-4-(pyridin-4-yloxy)cyclohexyl]-2,7- diazaspiro[4.5]decan-l -one;
2-(l-Adamantyl)-7-[(3-chloro-2-methylphenyl)sulfonyl]-2,7-diazaspiro[4.5]decan-l-one;
7-[(3-Chloro-2-methylphenyl)sulfonyl]-2-(l-methyl-2-phenylethyl)-2,7-diazaspiro[4.5]decan- 1-one;
(5R)-7-[(3-Chloro-2-methylphenyl)sulfonyl]-2-cycloheptyl-2,7-diazaspiro[4.5]decan-l-one;
(5S)-7-[(3-Chloro-2-methylphenyl)sulfonyl]-2-cycloheptyl-2,7-diazaspiro[4.5]decan-l-one; cis-4-{7-[(3-Chloro-2-methylphenyl)sulfonyl]-l-oxo-2,7-diazaspiro[4.5]dec-2- yl} cyclohexanecarbonitrile;
2-Cyclohexyl-7-(2-fluorophenyl)-2,7-diazaspiro[4.5]decan-l-one;
2-Cyclohexyl-7-(4-fluorophenyl)-2,7-diazaspiro[4.5]decan-l-one;
2-Cyclohexyl-7-(3 -fluorophenyl)-2,7-diazaspiro[4.5] decan- 1 -one;
2-Cyclohexyl-7-phenyl-2,7-diazaspiro[4.5]decan-l-one;
7-(4-Fluorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one;
7-(3-Fluorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one;
2-(trans-4-Hydroxycyclohexyl)-7-phenyl-2,7-diazaspiro[4.5]decan-l-one;
Methyl l-[7-(2-fluorophenyl)-l-oxo-2,7-diazaspiro[4.5]dec-2-yl] cyclopropanecarboxylate ;
2-(trans-4-Hydroxycyclohexyl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5] decan- 1-one;
6-[2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]nicotinonitrile;
2-(trans-4-Hydroxycyclohexyl)-7-(6-methoxypyridin-2-yl)-2,7-diazaspiro[4.5]decan-l-one;
2-(trans-4-Hydroxycyclohexyl)-7-(6-methylpyridin-2-yl)-2,7-diazaspiro[4.5]decan-l-one;
2-(trans-4-Hydroxycyclohexyl)-7-(5-methylpyridin-2-yl)-2,7-diazaspiro[4.5]decan-l-one;
7-(5-Fuoropyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one;
2-(trans-4-Hydroxycyclohexyl)-7-[6-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5] decan- 1-one;
(5S)-2-(trans-4-Hydroxycyclohexyl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7- diazaspiro [4.5] decan- 1 -one;
(5R)-2-(trans-4-Hydroxycyclohexyl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7- diazaspiro[4.5]decan-l-one;
7-(6-Fuoropyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one;
2-(trans-4-Hydroxycyclohexyl)-7-(3 -methylpyridin-2-yl)-2,7-diazaspiro [4.5] decan- 1 -one;
2-(trans-4-Hydroxycyclohexyl)-7-(4-methoxypyridin-2-yl)-2,7-diazaspiro[4.5]decan-l-one;
2-(trans-4-Hydroxycyclohexyl)-7-pyridin-2-yl-2,7-diazaspiro[4.5]decan-l-one;
(5R)-2-Cyclohexyl-7-phenyl-2,7-diazaspiro[4.5]decan-l-one;
(5S)-2-Cyclohexyl-7-phenyl-2,7-diazaspiro[4.5]decan-l-one; 7-[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one;
4-[2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile;
2-(trans-4-Hydroxycyclohexyl)-7- [4-(trifluoromethyl)pheny 1] -2,7-diazaspiro [4.5] decan- 1 - one;
3-Fluoro-4-[2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile;
4-(2-Cyclohexyl-l-oxo-2,7-diazaspiro[4.5]dec-7-yl)benzonitrile;
4-(2-Cyclohexyl- 1 -oxo-2,7-diazaspiro [4.5] dec-7-yl)-3 -fluorobenzonitrile;
2-(trans-4-Hydroxycyclohexyl)-7-(piperidin-l-ylcarbonyl)-2,7-diazaspiro[4.5]decan-l-one;
2-(trans-4-Hydroxycyclohexyl)-7-(pyrrolidin-l-ylcarbonyl)-2,7-diazaspiro[4.5]decan-l-one;
2-(trans-4-Hydroxycyclohexyl)-7-[(4-phenyl-3,6-dihydropyridin-l(2H)-yl)carbonyl]-2,7- diazaspiro[4.5]decan-l-one;
2-(trans-4-Hydroxycyclohexyl)-7-[(4-phenylpiperidin-l-yl)carbonyl]-2,7- diazaspiro[4.5]decan-l-one;
2-(trans-4-Hydroxycyclohexyl)-7-[(4-phenylpiperazin-l-yl)carbonyl]-2,7- diazaspiro[4.5]decan-l-one;
7- { [4-(2-Fluorophenyl)piperazin-l -yl] carbonyl} -2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one;
2-(trans-4-Hydroxycyclohexyl)-7-({4-[2-(trifluoromethyl)phenyl]piperazin-l-yl}carbonyl)- 2,7-diazaspiro[4.5]decan-l-one;
2-Cyclohexyl-7-isonicotinoyl-2,7-diazaspiro[4.5]decan-l-one;
7-Benzoyl-2-cyclohexyl-2,7-diazaspiro[4.5]decan-l-one;
2-Cyclohexyl-7-(pyridin-3 -ylcarbonyl)-2,7-diazaspiro[4.5] decan- 1 -one;
2-(trans-4-Hydroxycyclohexyl)-7-isonicotinoyl-2,7-diazaspiro[4.5]decan-l-one;
7-Benzoyl-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one;
2-(trans-4-Hydroxycyclohexyl)-7-(pyridin-3-ylcarbonyl)-2,7-diazaspiro[4.5]decan-l-one;
Isopropyl {4-[2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl} carbamate;
Prop-2-yn-l-yl {4-[2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl} carbamate;
Methyl {4-[2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl} carbamate;
N-{4-[2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}acetamide;
N-{4-[2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl}cyclopropanecarboxamide;
Isopropyl {3-fluoro-4-[2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl} carbamate; Prop-2-yn-l-yl {3-fluoro-4-[2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl} carbamate;
Methyl { 3 -fluoro-4- [2-(trans-4-hydroxycyclohexyl)- 1 -oxo-2,7-diazaspiro [4.5] dec-7- yljphenyl} carbamate;
N-{3-Fluoro-4-[2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl}cyclopropanecarboxamide;
7-(4-Chloropyrimidin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one;
2-Cyclohexyl-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-l-one;
2-Cyclohexyl-7-pyridin-2-yl-2,7-diazaspiro[4.5]decan-l-one;
7-[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]-2-cyclohexyl-2,7-diazaspiro[4.5]decan-l-one;
2-Cyclohexyl-7-(piperidin- 1 -ylcarbonyl)-2,7-diazaspiro[4.5] decan- 1 -one;
2-Cyclohexyl-7-(pyrrolidin-l-ylcarbonyl)-2,7-diazaspiro[4.5]decan-l-one;
2-Cyclohexyl-7-[(4-phenyl-3,6-dihydropyridin-l(2H)-yl)carbonyl]-2,7-diazaspiro[4.5]decan- 1-one;
2-Cyclohexyl-7-[(4-phenylpiperidin-l-yl)carbonyl]-2,7-diazaspiro[4.5]decan-l-one;
2-Cyclohexyl-7-[(4-phenylpiperazin-l-yl)carbonyl]-2,7-diazaspiro[4.5]decan-l-one;
2-Cyclohexyl-7-{[4-(2-fluorophenyl)piperazin-l-yl]carbonyl}-2,7-diazaspiro[4.5]decan-l- one;
2-Cyclohexyl-7-({4-[2-(trifluoromethyl)phenyl]piperazin-l-yl}carbonyl)-2,7- diazaspiro[4.5]decan-l-one;
2-[2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]nicotinonitrile ;
7-(5-Chloropyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one;
7-(3,5-Dichloropyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one;
2-(trans-4-Hydroxycyclohexyl)-7-[4-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan- 1-one;
2-(trans-4-HydiOxycyclohexyl)-7-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-2,7- diazaspiro[4.5]decan-l-one;
Methyl 6-[2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]nicotinate;
2-(trans-4-Hydroxycyclohexyl)-7-isoquinolin-l-yl-2,7-diazaspiro[4.5]decan-l-one;
2-(trans-4-Hydroxycyclohexyl)-7-quinolin-2-yl-2,7-diazaspiro[4.5]decan-l-one;
N-IS-Fluoro^-P-^ans^-hydroxycyclohexy^-l-oxo^J-diazaspiro^.SJdec^- yl]phenyl} acetamide;
(5R)-2-(2-Chlorophenyl)-7-(3,5-dichloropyridin-2-yl)-2,7-diazaspiro[4.5]decan-l-one;
2-(2-Chlorophenyl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-l-one;
2-(2-Chlorophenyl)-7-(3-chloropyrazin-2-yl)-2,7-diazaspiro[4.5]decan-l-one;
2-(2-Chlorophenyl)-7-(3 -chloropyridin-2-yl)-2,7-diazaspiro [4.5] decan- 1 -one;
2-[(5R)-2-(2-Chlorophenyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]nicotinonitrile; (5R)-2-(2-Chlorophenyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-l-one;
6-[(5R)-2-(2-Chlorophenyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]nicotinonitrile;
Methyl {6-[(5R)-2-(2-chlorophenyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3- yl} carbamate;
Ethyl {6-[(5R)-2-(2-chlorophenyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3- yl} carbamate;
Propyl {6-[(5R)-2-(2-chlorophenyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3- yl} carbamate;
6-[2-(2-Chloropheny I)- 1 -oxo-2,7-diazaspiro [4.5] dec-7-yl] -N-methy lnicotinamide;
6-[2-(2-Chlorophenyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-N-ethylnicotinamide;
(5R)-2-(Tetrahydro-2H-pyran-4-yl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7- diazaspiro [4.5] decan- 1 -one;
Methyl {6-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3- yl} carbamate;
Ethyl {6-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3- yl} carbamate;
Propyl {6-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3- yl} carbamate;
Isopropyl {6-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyridin- 3-yl}carbamate;
Isobutyl {6-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3- yl} carbamate;
(5R)-7-(3-Chloropyrazin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-l-one;
3-[(5R)-l-Oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyrazine-2- carbonitrile;
(5R)-7-(3-Chloropyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-l-one;
2-[(5R)-l-Oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]nicotinonitrile;
(5R)-2-(Tetrahydro-2H-pyran-4-yl)-7-[3-(trifluoromethyl)pyridin-2-yl]-2,7- diazaspiro [4.5] decan- 1 -one;
(5R)-7-(3,5-Dichloropyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-l- one;
(5R)-7-(5-Chloropyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-l-one;
Methyl { 5-chloro-6-[(5R)- 1 -oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7- yl]pyridin-3-yl} carbamate;
Ethyl {5-chloro-6-[(5R)-l-oxo-2-(teti-ahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7- yl]pyridin-3 -yl} carbamate; Propyl {5-chloro-6-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7- yl]pyridin-3-yl}carbamate;
Isopropyl { 5 -chloro-6- [(5R)-I -oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro [4.5] dec-7- yl]pyridin-3-yl}carbamate;
Isobutyl {5-chloro-6-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7- yl]pyridin-3-yl}carbamate;
3-Chloro-4-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7- yl]benzonitrile;
6-[(5R)-l-Oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]nicotinonitrile;
(5R)-7-(3,5-Difluoropyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-l- one;
(5R)-7-Isoquinolin-l-yl-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-l-one;
(5R)-7-quinolin-2-yl-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-l-one;
Methyl {5-methyl-6-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7- y 1] pyridin-3 -yl} carbamate;
Ethyl {5-methyl-6-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7- yl]pyridin-3 -yl} carbamate;
Propyl {5-methyl-6-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7- yl]pyridin-3-yl}carbamate;
Methyl {3-fluoro-4-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7- yl]phenyl} carbamate;
Ethyl {3-fluoro-4-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7- yl]phenyl} carbamate;
Propyl {3-fluoro-4-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7- yl]phenyl} carbamate;
Isopropyl {3-fluoro-4-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7- yl]phenyl} carbamate;
Isobutyl {3-fluoro-4-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7- yljphenyl} carbamate;
Methyl {4-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7- yljphenyl} carbamate;
Ethyl {4-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7- yljphenyl} carbamate;
Propyl {4-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7- yl]phenyl} carbamate;
Isopropyl {4-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7- yl]phenyl} carbamate; Isobutyl {4-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7- yljphenyl} carbamate;
Methyl methyl{4-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7- yljphenyl} carbamate;
3-Fluoro-4-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7- yl]benzonitrile;
2-( 1 -Methy lpiperidin-4-yl)-7- [5 -(trifluoromethyl)pyridin-2-y 1] -2,7-diazaspiro [4.5] decan- 1 - one;
Methyl 4-{ 1 -oxo-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]dec-2-yl}piperidine- 1-carboxylate;
N,N-Dimethyl-4-{l-oxo-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]dec-2- y 1 } piperidine- 1 -carboxamide;
7-(3-Chloropyrazin-2-yl)-2-quinolin-5-yl-2,7-diazaspiro[4.5]decan-l-one;
7-(3 -Chloropyridin-2-yl)-2-quinolin-5-yl-2,7-diazaspiro[4.5] decan- 1 -one;
7-(3,5-Dichloropyridin-2-yl)-2-quinolin-5-yl-2,7-diazaspiro[4.5]decan-l-one;
2-(2-Methy lphenyl)-7- [4-(trifluoromethy l)pyrimidin-2-yl] -2,7-diazaspiro [4.5] decan- 1 -one;
7-(4-Chloropyrimidin-2-yl)-2-(2-methylphenyl)-2,7-diazaspiro[4.5]decan-l-one;
7-(6-Chloro-7H-purin-2-yl)-2-(2-methylphenyl)-2,7-diazaspiro [4.5] decan- 1 -one;
3-[2-(2-Methylphenyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyrazine-2-carbonitrile;
7-(6-Chloropyrazin-2-yl)-2-(2-methylphenyl)-2,7-diazaspiro[4.5]decan-l-one;
7-(3-Chloropyraziη-2-yl)-2-(2-methylphenyl)-2,7-diazaspiro[4.5]decan-l-one;
2-(2-Methylphenyl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-l-one;
2-Quinolin-5-yl-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-l-one;
2-Isoquinolin-5-yl-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-l-one;
2-(4-Bromo-2-methylphenyl)-7- [5 -(trifluoromethyl)pyridin-2-y 1] -2,7-diazaspiro [4.5] decan- 1 - one;
3-Methyl-4-{l-oxo-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]dec-2- yl}benzonitrile;
N-(3-Methyl-4-{l-oxo-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]dec-2- yl}phenyl)acetamide;
N-(3-Methyl-4-{l-oxo-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]dec-2- yl}phenyl)methanesulfonamide;
2-(3 -Methy lpyridin-4-yl)-7- [5 -(trifluoromethyl)pyridin-2-yl] -2,7-diazaspiro [4.5] decan- 1 -one;
(5R)-2-(4-Methylpyridin-3-yl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan- 1-one;
7-(3-Chloropyrazin-2-yl)-2-(l-methylpiperidin-4-yl)-2,7-diazaspiro[4.5]decan-l-one; Methyl [4-[(5R)-2-cyclohexyl-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3- (trifluoromethyl)phenyl]carbamate;
Ethyl ^-[(SR^-cyclohexyl-l-oxo^J-diazaspiro^.Sjdec^-yl]^- (trifluoromethyl)phenyl]carbamate;
Prop-2-yn-l-yl [4-[(5R)-2-cyclohexyl-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3- (trifluoromethyl)phenyl]carbamate;
N-[4-[(5R)-2-Cyclohexyl-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3- (trifluoromethyl)phenyl]acetamide;
N-[4-[(5R)-2-Cyclohexyl-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3- (trifluoromethyl)phenyl]methanesulfonamide;
Methyl methyl[4-[(5R)-2-cyclohexyl-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3- (trifluoromethyl)phenyl]carbamate;
Prop-2-yn-l-yl {5-chloro-6-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7- diazaspiro [4.5] dec-7-y 1] pyridin-3 -yl} carbamate;
Methyl {5-chloro-6-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]pyridin-3 -yl} carbamate;
Ethyl {5-chloro-6-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]pyridin-3-yl} carbamate;
N-{5-Chloro-6-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]pyridin-3 -yl} acetamide;
N- { 5 -Chloro-6-[(5R)-2-(trans-4-hy droxycyclohexy I)- 1 -oxo-2,7-diazaspiro [4.5] dec-7- y l]pyridin-3 -y 1} methanesulfonamide;
4-{l-Oxo-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]dec-2- yl} cyclohexanecarbonitrile;
4-{ 1 -Oxo-7-[4-(trifluoromethyl)phenyl]-2,7-diazaspiro[4.5]dec-2-yl} cyclohexanecarbonitrile;
4-{7-[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]-l-oxo-2,7-diazaspiro[4.5]dec-2- yl} cyclohexanecarbonitrile;
4-[7-(3,5-Dichloropyridin-2-yl)-l-oxo-2,7-diazaspiro[4.5]dec-2-yl]cyclohexanecarbonitrile;
4-[7-(6-Fluoropyridin-2-yl)-l-oxo-2,7-diazaspiro[4.5]dec-2-yl]cyclohexanecarbonitrile;
(5R)-7-(2-Fluoro-4-methylphenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro [4.5] decan- 1-one;
(5R)-2-(trans-4-Hydroxycyclohexyl)-7-(4-methoxyphenyl)-2,7-diazaspiro[4.5]decan-l-one;
{4-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl} acetonitrile;
(5R)-2-(trans-4-Hydroxycyclohexyl)-7-[3-(trifluoromethoxy)phenyl]-2,7- diazaspiro[4.5]decan-l-one; (5R)-2-(trans-4-Hydroxycyclohexyl)-7-[3-(trifluoromethyl)phenyl]-2,7-diazaspiro[4.5]decan- 1-one;
(5R)-2-(trans-4-Hydroxycyclohexyl)-7-[2-(trifluoromethoxy)phenyl]-2,7- diazaspiro[4.5]decan-l -one;
(5R)-7-(4-Chloro-2-methylphenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan- 1-one;
(5R)-7-(3-Chloro-2-methylphenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan- 1-one;
(5R)-7-(2-Chloro-4-methylphenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan- 1-one;
2-Fluoro-6- [(5R)-2-(trans-4-hydroxycyclohexy I)- 1 -oxo-2,7-diazaspiro [4.5] dec-7- yl]benzonitrile;
(5R)-7-(2,5-Dichlorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one;
(5R)-7-(2,3-Dichlorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one;
(5R)-7-(3,5-Difluorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one;
(5R)-7-(4-Chloro-2-methylphenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan- 1-one;
(5R)-7-(3-Chloro-2-methylphenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan- 1-one;
(5R)-7-(2,6-Dichlorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one;
3-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile;
(5R)-7-(2-Fluorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one;
(5R)-7-(2-Chlorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one;
(5R)-7-(4-Chloro-2-fluorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l- one;
(5R)-7-(2,4-Difluorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one;
(5R)-7-(3 -Chloro-2-fluorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro [4.5]decan- 1 - one;
(trans-4-{l-Oxo-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]dec-2- yl} cyclohexyl)acetonitrile;
(trans-4-{l-Oxo-7-[4-(trifluoromethyl)phenyl]-2,7-diazaspiro[4.5]dec-2- yl} cyclohexyl)acetonitrile;
(trans-4-{7-[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]-l-oxo-2,7-diazaspiro[4.5]dec-2- yl} cyclohexyl)acetonitrile;
{trans-4- [7-(3 , 5 -Dichloropyridin-2-yl)- 1 -oxo-2,7-diazaspiro [4.5] dec-2- y 1] cyclohexyl} acetonitrile;
{trans-4- [7-(6-Fluoropyridin-2-yl)- 1 -oxo-2,7-diazaspiro [4.5] dec-2-yl] cyclohexyl} acetonitrile; (5R)-2-(trans-4-Hydroxycy clohexyl)-7-(3 , 5 ,6-trifluoropyridin-2-yl)-2,7-diazaspiro [4.5] decan- 1-one;
(5R)-7-(4,6-Dimethoxypyrimidin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one;
(5R)-7-[4-Fluoro-5-(trifluoromethyl)pyrimidin-2-yl]-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5] decan- 1 -one;
(5R)-7-(2,5-Difluorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one;
(5R)-7-[2-(Difluoromethoxy)phenyl]-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one;
(5R)-7-(4-Fluoropyrimidin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l- one;
(5R)-7-[4-Chloro-5-(trifluoromethyl)pyrimidin-2-yl]-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5] decan- 1 -one;
(5R)-2-(trans-4-Hydroxycyclohexyl)-7-quinazolin-4-yl-2,7-diazaspiro[4.5]decan-l-one;
(5R)-2-(trans-4-Hydroxycyclohexyl)-7-(6-methoxypyridin-3-yl)-2,7-diazaspiro[4.5]decan-l- one;
(5R)-2-(trans-4-Hydroxycyclohexyl)-7-[6-(methylamino)-9H-purin-2-yl]-2,7- diazaspiro[4.5]decan-l-one; tert-Butyl (trans-4-{l-oxo-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]dec-2- yl} cyclohexyl)carbamate;
7-{[4-(2-Chlorophenyl)piperazin-l-yl]carbonyl}-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one;
2-(trans-4-Hydroxycyclohexyl)-7-({4-[2-(trifluoromethyl)quinolin-4-yl]piperazin-l- yl}carbonyl)-2,7-diazaspiro[4.5]decan-l-one;
2-(trans-4-Hydroxycyclohexyl)-7-({4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-l- yl} carbonyl)-2,7-diazaspiro[4.5] decan- 1 -one;
2-(trans-4-Hydroxycyclohexyl)-7- { [4-(2-methylphenyl)piperazin- 1 -yljcarbonyl} -2,7- diazaspiro[4.5]decan-l-one;
7- { [4-(3 ,4-Dichloropheny l)piperazin- 1 -yl] carbonyl} -2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one;
2-(trans-4-Hydroxycyclohexyl)-7-({4-[3-(trifluoromethyl)phenyl]piperazin-l-yl}carbonyl)- 2,7-diazaspiro [4.5] decan- 1 -one;
7-[(4-Biphenyl-4-ylpiperazin-l-yl)carbonyl]-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one;
2-(trans-4-Hydroxycyclohexyl)-7-({4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-l- yl}carbonyl)-2,7-diazaspiro[4.5]decan-l-one; 2-(trans-4-Hydroxycyclohexyl)-7- { [4-(2-methoxyphenyl)piperazin- 1 -yljcarbonyl} -2,7- diazaspiro[4.5]decan-l-one;
2-(trans-4-Hydroxycyclohexyl)-7-[(4-pyridin-2-ylpiperazm-l-yl)carbonyl]-2,7- diazaspiro[4.5]decan-l-one;
7-{[4-(4-Chlorophenyl)piperazin-l-yl]carbonyl}-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro [4.5] decan- 1 -one;
7- { [4-(2-Ethoxyphenyl)piperazin- 1 -yl] carbonyl} -2-(trans-4-hydroxy cyclohexyl)-2,7- diazaspiro[4.5]decan-l-one;
2-(trans-4-Hydroxycyclohexyl)-7-{[4-(3-methoxyphenyl)piperazin-l-yl]carbonyl}-2,7- diazaspiro[4.5]decan-l-one;
2-(trans-4-Hydroxycyclohexyl)-7- { [4-(3 -methylphenyl)piperazin- 1 -yljcarbonyl} -2,7- diazaspiro [4.5] decan- 1 -one;
7- { [4-(3 -Chloropheny l)piperazin- 1 -y 1] carbonyl} -2-(trans-4-hydroxycy clohexyl)-2,7- diazaspiro[4.5]decan-l-one;
2-(trans-4-Hydroxycyclohexyl)-7- { [4-(4-methoxyphenyl)piperazin-l -yl] carbonyl} -2,7- diazaspiro[4.5]decan-l-one;
4-(4- { [2-(trans-4-Hydroxycyclohexyl)- 1 -oxo-2,7-diazaspiro[4.5] dec-7-yl] carbonyl}piperazin- l-yl)benzonitrile;
7- { [4-(3 ,5-Dichloropyridin-4-yl)piperazin- 1 -yljcarbonyl} -2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one;
(5R)-2-(trans-4-Hydroxycyclohexyl)-7-(l,3-thiazol-2-yl)-2,7-diazaspiro[4.5]decan-l-one;
2-(trans-4-Hydroxycyclohexyl)-7-({4-[4-(trifluoromethyl)phenyl]piperazin-l-yl}carbonyl)- 2,7-diazaspiro[4.5]decan- 1 -one;
7-(3,5-Dichloropyridin-2-yl)-2-(4-hydroxy-l-adamantyl)-2,7-diazaspiro[4.5]decan-l-one;
Propyl {3-fluoro-4-[2-(4-hydroxy-l-adamantyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl} carbamate;
2-(4-Hydroxy-l-adamantyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-l- one;
Ethyl {3-fluoro-4-[2-(4-hydroxy-l-adamantyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl} carbamate;
7-(3,5-Difluoropyridin-2-yl)-2-(4-hydroxy-l-adamantyl)-2,7-diazaspiro[4.5]decan-l-one;
3-Fluoro-4-[2-(4-hydroxy-l-adamantyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile;
2-[2-(4-Hydroxy-l-adamantyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]nicotinonitrile;
4-[2-(4-Hydroxy-l-adamantyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile;
N-{3-Fluoro-4-[2-(4-hydroxy-l-adamantyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl}cyclopropanecarboxamide; 2-(4-Hydroxy-l-adamantyl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-l- one;
7-(5-Ethylpyrimidin-2-yl)-2-(4-hydroxy-l-adamantyl)-2,7-diazaspiro[4.5]decan-l-one;
7-(3-Fluoropyridin-2-yl)-2-(4-hydroxy-l-adamantyl)-2,7-diazaspiro[4.5]decan-l-one;
N- { 3 -Fluoro-4- [2-(4-hydroxy- 1 -adamantyl)- 1 -oxo-2,7-diazaspiro [4.5] dec-7- yl]phenyl} acetamide;
N-{3-Fluoro-4-[2-(4-hydroxy-l-adamantyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl} propanamide;
N- { 3 -Fluoro-4- [2-(4-hydroxy- 1 -adamantyl)- 1 -oxo-2,7-diazaspiro [4.5] dec-7- yl]phenyl} methanesulfonamide;
(5R)-7-(2,3-Difluorophenyl)-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one;
(5R)-7-(3-Fluorophenyl)-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one;
5R)-7-(2-Chloro-3-fluorophenyl)-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one;
(5R)-7-(4-Fluorophenyl)-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one;
(5R)-7- [3 -Chloro-5 -(2-oxo- 1 ,3 -oxazinan-3 -y l)pyridin-2-y 1] -2-(4-hy droxy cy clohexy l)-2,7- diazaspiro[4.5]decan-l-one;
(5R)-7-(3,4'-Bipyridin-6-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one;
(5R)-2-(trans-4-Hydroxycyclohexyl)-7-(6'-methoxy-3,3'-bipyridin-6-yl)-2,7- diazaspiro[4.5]decan- 1 -one;
4-{6-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}- N,N-dimethylbenzamide;
4-{6-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3- yl}benzamide;
N-Cyclopropyl-4-{6-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]pyridin-3-yl}benzamide;
N-(4-{6-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3- yl} phenyl)acetamide;
5R)-2-(trans-4-Hydroxycyclohexyl)-7-[5-(4-methoxyphenyl)pyridin-2-yl]-2,7- diazaspiro[4.5]decan-l-one;
(5R)-7-[5-(4-Fluorophenyl)pyridin-2-yl]-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5] decan- 1 -one;
(5R)-7-(3,3'-Bipyridin-6-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one;
(5R)-7-(6'-Fluoro-3,3'-bipyridin-6-yl)-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5] decan-1 -one;
(5R)-2-(trans-4-Hydroxycyclohexyl)-7-(5-pyrimidin-5-ylpyridin-2-yl)-2,7- diazaspiro[4.5]decan-l-one; 3 - { 6-[(5R)-2-(trans-4-Hydroxycyclohexyl)- 1 -oxo-2,7-diazaspiro [4.5] dec-7-yl]pyridin-3 - yl}benzamide;
^(S-lo-KS^^^trans^-Hydroxycyclohexy^-l-oxo^jT-diazaspiro^.SJdec-V-yllpyridin-S- yl} phenyl)acetamide;
(5R)-7-[5-(3,5-Dimethylisoxazol-4-yl)pyridin-2-yl]-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one;
(5R)-2-(trans-4-Hydroxycyclohexyl)-7-[5-(l-methyl-lH-pyrazol-4-yl)pyridin-2-yl]-2,7- diazaspiro[4.5]decan-l-one;
4-{2-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyrimidin-5- yl} -N,N-dimethylbenzamide;
5R)-2-(trans-4-Methoxycyclohexyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-2,7- diazaspiro[4.5]decan-l -one;
N-Cyclopropyl-4-{2-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]pyrimidin-5-yl}benzamide;
(5R)-7-(5-Chloro-3,3'-bipyridin-6-yl)-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro [4.5] decan- 1 -one;
(5R)-7-(5-Bromopyrimidin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l- one;
(5R)-7-[3-Chloro-5-(l-methyl-lH-pyrazol-4-yl)pyridin-2-yl]-2-(trans-4-hydroxycyclohexyl)- 2,7-diazaspiro[4.5]decan-l-one;
4-{2-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyrimidin-5- yl}benzamide;
(5R)-7-(3,5-Difluoropyridin-2-yl)-2-(trans-4-methoxycyclohexyl)-2,7-diazaspiro[4.5]decan- 1-one;
(5R)-7-(5-Chloro-3,4'-bipyridin-6-yl)-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l -one;
(5R)-7-(5-Ethylpyrimidin-2-yl)-2-(trans-4-methoxycyclohexyl)-2,7-diazaspiro[4.5]decan-l- one; tert-Butyl 5-chloro-6-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]-3',6'-dihydro-3,4'-bipyridine-r(2Η)-carboxylate;
(5R)-7-(5-Fluoropyrimidin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l- one;
(5R)-2-(trans-4-Hydroxycyclohexyl)-7-[4-(2-oxo-l,3-oxazolidin-3-yl)phenyl]-2,7- diazaspiro[4.5]decan-l-one;
(5R)-7-[2-Fluoro-4-(2-oxo-l,3-oxazolidin-3-yl)phenyl]-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one; (5R)-7-[2-Fluoro-4-(2-oxopyrrolidin-l-yl)phenyl]-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one;
(5R)-7-[3-Chloro-5-(2-oxopyrrolidin-l-yl)pyridin-2-yl]-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one;
(5R)-2-(trans-4-Hydroxycyclohexyl)-7-[4-(2-oxopyrrolidin-l-yl)phenyl]-2,7- diazaspiro[4.5]decan-l-one;
(5R)-7-[3-Chloro-5-(2-oxo-l,3-oxazolidin-3-yl)pyridin-2-yl]-2-(trans-4-hydroxycyclohexyl)- 2,7-diazaspiro[4.5]decan-l-one;
(5R)-7-(2-Fluoro-4-pyrrolidin-l-ylphenyl)-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one;
(5R)-7-(3-Chloro-5-pyrrolidin-l-ylpyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one;
(5R)-2-(trans-4-Hydroxycyclohexyl)-7-(5-pyrrolidin-l-ylpyridin-2-yl)-2,7- diazaspiro[4.5]decan-l-one;
(5R)-7-[2-Fluoro-4-(2-oxo-piperidin-l-yl)-phenyl]-2-(trans-4-hydroxy-cyclohexyl)-2,7-diaza- spiro[4.5]decan-l-one;
(5R)-7-[2-Fluoro-4-(2-oxo-l,3-oxazinan-3-yl)phenyl]-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one;
(5R)-2-(trans-4-hydroxycyclohexyl)-7-[4-(2-oxopiperidin-l-yl)phenyl]-2,7- diazaspiro[4.5]decan-l-one;
(5R)-7-(l,3-Benzothiazol-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l- one;
2-[(5R)-2-(trans-4-Methoxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]nicotinonitrile;
(5R)-2-(trans-4-Methoxycyclohexyl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7- diazaspiro[4.5]decan-l -one;
(5R)-7-(5-Fluoropyrimidin-2-yl)-2-(trans-4-methoxycyclohexyl)-2,7-diazaspiro[4.5]decan-l- one;
(5R)-7- {3 -Chloro-5-[4-(trifluoromethoxy)phenyl]pyridin-2-yl} -2-(trans-4- hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one;
(5R)-7-(2-Chloro-9H-purin-6-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l- one;
(5R)-7-(4-Amino-5-fluoropyrimidin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5] decan- 1 -one;
N-{3-Fluoro-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yrjphenylj-cyclopropanecarboxamide;
N-{3-Fluoro-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl}cyclobutanecarboxamide; N-{3-Fluoro-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl}cyclopentanecarboxamide;
N- {3 -Fluoro-4- [(5R)-2-(trans-4-hydroxycyclohexyl)- 1 -oxo-2,7-diazaspiro [4.5] dec-7- yl]phenyl}cyclohexanecarboxamide;
Ethyl {3-fluoro-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- y 1] phenyl} carbamate;
Propyl {3-fluoro-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- y 1] phenyl} carbamate;
Isobutyl {3 -fluoro-4-[(5R)-2-(trans-4-hydroxycyclohexyl)- 1 -oxo-2,7-diazaspiro [4.5] dec-7- yl]phenyl} carbamate;
N-{3-Fluoro-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl}propanamide;
N-{3-Fluoro-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl}-2-methylpropanamide;
N-{3-Fluoro-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl}methanesulfonamide;
N-{3-Fluoro-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl} ethanesulfonamide;
(5R)-2-(trans-4-Hydroxycyclohexyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-2,7- diazaspiro[4.5]decan-l-one;
Ethyl [4-[(5R)-2-(trans-4-hydroxycyclohexyl)- 1 -oxo-2,7-diazaspiro [4.5]dec-7-yl]-3 - (trifluoromethyl)phenyl]carbamate;
Methyl [4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3- (trifluoromethyl)phenyl]carbamate;
Propyl [4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3- (trifluoromethyl)phenyl]carbamate;
Isobutyl [4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3- (trifluoromethyl)phenyl]carbamate;
Isopropyl [4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3- (trifluoromethyl)phenyl]carbamate;
N- [4-[(5R)-2-(trans-4-Hydroxycy clohexyl)- 1 -oxo-2,7-diazaspiro [4.5] dec-7-yl] -3 - (trifluoromethytyphenyljcyclopropanecarboxamide;
N-[4-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3- (trifluoromethyl)phenyl]cyclobutanecarboxamide;
N-[4-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3- (trifluoromethyl)phenyl]cyclopentanecarboxamide; N-[4-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3- (trifluoromethyl)phenyl]methanesulfonamide;
N-[4-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3- (trifluoromethyl)phenyl]acetamide;
N-[4-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3- (trifluoromethyl)phenyl]propanamide;
N-[4-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3- (trifluoromethyl)phenyl]-2-methylpropanamide;
(5R)-7-[2-Fluoro-4-(pyridin-2-yloxy)phenyl]-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one;
Methyl {6-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3- yl} carbamate;
Ethyl {6-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3- yl} carbamate;
Propyl {6-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3- yl} carbamate;
Isobutyl {6-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin- 3-yl}carbamate;
Isopropyl {6-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin- 3-yl} carbamate;
N-{6-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3- yl} cyclopropanecarboxamide;
N- {6-[(5R)-2-(trans-4-Hydroxycyclohexyl)- 1 -oxo-2,7-diazaspiro[4.5] dec-7-yl]pyridin-3 - yl} cyclobutanecarboxamide;
N-{6-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3- yl} cyclopentanecarboxamide;
N-{6-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3- yl}acetamide;
N-{6-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3- yl}propanamide;
N-{6-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}- 2-methylpropanamide;
N- { 6- [(5R)-2-(trans-4-Hydroxycy clohexy I)- 1 -oxo-2,7-diazaspiro [4.5] dec-7-yl]pyridin-3 - yl} cyclohexanecarboxamide;
Methyl { 6- [(5R)-2-(trans-4-hydroxycyclohexy I)- 1 -oxo-2,7-diazaspiro [4.5] dec-7-y 1] -5- methylpyridin-3 -yl} carbamate; Ethyl {6-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5- methylpyridin-3-yl} carbamate;
Propyl {6-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5- methy lpyridin-3 -y 1 } carbamate;
Methyl {3-cyano-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yljphenyl} carbamate;
Ethyl {3-cyano-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yljphenyl} carbamate;
Propyl {3-cyano-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl} carbamate;
Isobutyl {3-cyano-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl} carbamate;
Isopropyl {3-cyano-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl} carbamate;
N- { 3 -Cyano-4- [(5R)-2-(trans-4-hydroxycyclohexy I)- 1 -oxo-2,7-diazaspiro [4.5] dec-7- yl]phenyl}cyclopropanecarboxamide;
N-{3-Cyano-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yljphenyl} cyclobutanecarboxamide;
N-{3-Cyano-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl}cyclopentanecarboxamide;
N-{3-Cyano-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl} acetamide;
N- { 3 -Cyano-4- [(5R)-2-(trans-4-hydroxycyclohexyl)- 1 -oxo-2,7-diazaspiro [4.5] dec-7- yl]phenyl}propanamide;
N-{3-Cyano-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl}-2-methylpropanamide;
N- { 3 -Cyano-4- [(5R)-2-(trans-4-hydroxycyclohexyl)- 1 -oxo-2,7-diazaspiro [4.5] dec-7- yl]phenyl}cyclohexanecarboxamide;
Methyl {4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3- methylphenyl} carbamate;
Ethyl {4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3- methylphenyl} carbamate;
Propyl {4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3- methylphenyl} carbamate;
Isobutyl {4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3- methylphenyl} carbamate; Isopropyl {4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3- methylphenyl} carbamate;
N-{4-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3- methylphenyl}cyclopropanecarboxamide;
N-{4-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3- methylphenyl}cyclobutanecarboxamide;
N-{4-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3- methylphenyl}cyclopentanecarboxamide;
N- {4-[(5R)-2-(trans-4-Hydroxycyclohexyl)- 1 -oxo-2,7-diazaspiro[4.5]dec-7-yl] -3 - methylphenytycyclohexanecarboxamide;
N-{4-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3- methylphenyl} acetamide;
N-{4-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3- methylphenyl}propanamide;
N-{4-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3- methylphenyl}-2-methylpropanamide;
(5R)-2-(trans-4-Hydroxycyclohexyl)-7-[4-(trifluoromethyl)quinolin-2-yl]-2,7- diazaspiro[4.5]decan-l-one;
(5R)-7-(3-Chloropyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l- one;
(5R)-7-[3-Fluoro-4-(trifluoromethyl)pyridin-2-yl]-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one;
(5R)-2-(trans-4-Hydroxycyclohexyl)-7-(3,5,6-trifluoro-4-methylpyridin-2-yl)-2,7- diazaspiro[4.5] decan- 1 -one;
2,3,5-Trifluoro-6-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]isonicotinonitrile;
(5R)-7-(3 ,5-Difluoropyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro [4.5] decan- 1 - one;
(5R)-2-(trans-4-hydroxycyclohexyl)-7-[4-(trifluoromethyl)pyridin-2-yl]-2,7- diazaspiro[4.5]decan-l-one;
(5R)-7-(3 -Fluoropyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro [4.5]decan- 1 - one;
(5R)-7-(5-Chloro-3-fluoropyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one;
(5R)-7-(3-Ethynylpyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l- one;
7-(2-fluoro-4-nitrophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one; 2-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-6- methylnicotinonitrile;
(5R)-2-(trans-4-Hydroxycyclohexyl)-7-quinolin-2-yl-2,7-diazaspiro[4.5]decan-l-one;
2-(trans-4-Hydroxycyclohexyl)-7-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-2,7- diazaspiro[4.5]decan-l-one;
(5R)-7-(3-Fluoropyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l- one;
7-(5-Ethylpyrimidin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one;
(5R)-2-(trans-4-Hydroxycyclohexyl)-7-(3-methylquinolin-2-yl)-2,7-diazaspiro[4.5]decan-l- one;
N-{4-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl] phenyl} methanesulfonamide;
(5R)-7-[2-Fluoro-4-(pyridin-4-yloxy)phenyl]-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro [4.5] decan- 1 -one;
(5R)-2-(trans-4-Hydroxycyclohexyl)-7-[5-(hydroxymethyl)pyridin-2-yl]-2,7- diazaspiro [4.5] decan- 1 -one;
6-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-N- methylnicotinamide;
(5R)-7-(3-Fluoropyridin-4-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l- one;
(5R)-7-(2-Chloropyridin-4-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l- one;
N-{3-Fluoro-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl}-N-methylmethanesulfonamide;
N-{6-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}- 2-methylpropanamide;
7-(2-Chloropyrimidin-4-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one;
6-[2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-N,N- dimethylnicotinamide;
Ethyl {2-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-6- methoxypyridin-3-yl}carbamate;
Methyl {2-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-6- methoxypyridin-3 -yl} carbamate;
N-{2-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-6- methoxypyridin-3 -yl} acetamide;
5-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-N- methylpyridine-2-carboxamide; (5R)-2-(trans-4-Hydroxycyclohexyl)-7-(3-methoxypyridin-2-yl)-2,7-diazaspiro[4.5]decan-l- one;
2-[8-(trans-4-Hydroxycyclohexyl)-7-oxo-2,8-diazaspiro[5.5]undec-2-yl]nicotinonitrile;
2-(trans-4-Hydroxycyclohexyl)-8-[3-(trifluoromethyl)pyridin-2-yl]-2,8- diazaspiro[5.5]undecan-l-one;
3-Cyclohexyl-7-[5-(trifluoiOmethyl)pyridin-2-yl]-l,3,7-triazaspiro[4.5]decane-2,4-dione;
6-(3-cyclohexyl-2,4-dioxo-l,3J-triazaspiro[4.5]dec-7-yl)nicotinonitrile;
4-(3-Cyclohexyl-2,4-dioxo-l,3,7-triazaspiro[4.5]dec-7-yl)-3-fluorobenzonitrile;
3-Cyclohexyl-7-(5-ethylpyrimidin-2-yl)-l,3,7-triazaspiro[4.5]decane-2,4-dione;
3-Cyclohexyl-7-(3-fluoropyridin-2-yl)-l,3,7-triazaspiro[4.5]decane-2,4-dione;
3 -Cyclohexyl-7-(3 , 5 -difluoropyridin-2-yl)- 1 ,3 ,7-triazaspiro [4.5] decane-2,4-dione;
3-Cyclohexyl-7-(3,5-dichloropyridin-2-yl)-l,3,7-triazaspiro[4.5]decane-2,4-dione;
2-(3-Methylpyridin-2-yl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-l-one;
N,N-Dimethyl-5-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7- yl]pyridine-2-carboxamide;
3 -Fluoro-4-[(5R)- 1 -oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5] dec-7- yl]benzonitrile;
(5R)-2-(trans-4-Hydroxycyclohexyl)-7-(6-methoxy-2-methylpyridin-3-yl)-2,7- diazaspiro [4.5] decan- 1 -one;
(5R)-2-(4-Hydroxycyclohexyl)-7-(6-methoxy-4-methylpyridin-3-yl)-2,7- diazaspiro[4.5]decan-l-one;
(5R)-7-(2,6-Difluorophenyl)-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one;
7-(5-Chloropyridin-2-yl)-2-(4-hydroxy-l-adamantyl)-2,7-diazaspiro[4.5]decan-l-one;
7-(3-Fluoropyridin-4-yl)-2-(4-hydroxy-l-adamantyl)-2,7-diazaspiro[4.5]decan-l-one;
N-{3-Fluoro-4-[2-(4-hydroxy-l-adamantyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl}propanamide;
Methyl {3-fluoro-4-[2-(4-hydroxy-l-adamantyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl} carbamate;
Propyl {3-fluoro-4-[2-(4-hydroxy-l-adamantyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl} carbamate;
N-{3-Fluoro-4-[2-(4-hydroxy-l-adamantyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl} ethanesulfonamide;
2-[(5R)-2-(cis-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]nicotinonitrile;
(5R)-2-(cis-4-Hydroxycyclohexyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-2,7- diazaspiro[4.5]decan-l-one;
(5R)-7-(3-Fluoropyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one; (5R)-7-(3,5-Dichloropyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l- one;
(5R)-7-(5-Chloro-3-fluoropyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7- diazaspiro [4.5] decan- 1 -one;
(5R)-7-(3-Chloropyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one;
Methyl {4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-2- methy lphenyl } carbamate;
Ethyl {4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-2- methy lphenyl} carbamate;
Prop-2-yn-l-yl {4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]- 2-methy lphenyl} carbamate;
Methyl {6-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-4- methylpyridin-3-yl} carbamate;
Ethyl {6-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-4- methylpyridin-3 -yl} carbamate;
Prop-2-yn-l-yl {6-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]- 4-methylpyridin-3 -yl} carbamate;
Methyl {6-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5- methoxypyridin-3-yl} carbamate;
Ethyl {6-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5- methoxypyridin-3 -yl} carbamate;
Prop-2-yn-l-yl {6-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]- 5-methoxypyridin-3-yl}carbamate;
Methyl {5-fluoro-2-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]pyrimidin-4-yl} carbamate;
Isopropyl {3-fluoro-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl}methylcarbamate;
(5R)-7-(3-Bromo-5-methylpyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one;
2-[(5R)-2-Cyclohexyl-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]nicotinonitrile;
2-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]isonicotinonitrile;
(5R)-7-(3-Fluoro-6-methylpyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro [4.5] decan- 1 -one;
6-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-2- methylnicotinonitrile;
2-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-4,6- dimethylnicotinonitrile; (5R)-2-(trans-4-Hydroxycyclohexyl)-7-[2-(trifluoromethyl)quinazolin-4-yl]-2,7- diazaspiro[4.5]decan-l -one;
(5R)-2-Cyclohexyl-7-[2-fluoro-4-(2-oxo-l,3-oxazolidin-3-yl)phenyl]-2,7- diazaspiro[4.5]decan-l-one;
(5R)-2-Cyclohexyl-7-[2-fluoro-4-(2-oxopyrrolidin-l-yl)phenyl]-2,7-diazaspiro[4.5]decan-l- one;
(5R)-7-(3-Fluoropyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-l-one;
(5R)-7-[2-Fluoro-4-(2-oxo-l,3-oxazolidin-3-yl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)-2,7- diazaspiro[4.5]decan-l-one;
(5R)-7-[2-Fluoro-4-(2-oxo-l,3-oxazinan-3-yl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)-2,7- diazaspiro[4.5]decan-l -one;
(5R)-7-[2-Fluoro-4-(2-oxopiperidin-l-yl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)-2,7- diazaspiro[4.5]decan-l -one;
(5R)-7-[2-Fluoro-4-(2-oxopyrrolidin-l-yl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)-2,7- diazaspiro [4.5] decan- 1 -one;
3-Fluoro-N-methyl-4-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7- yl]benzamide;
3-Fluoro-N,N-dimethyl-4-[(5R)-l-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec- 7-yl]benzamide;
2-[(5R)-l-Oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile;
(5R)-7-(3,5-Dichloropyridin-2-yl)-2-(3-methylpyridin-2-yl)-2,7-diazaspiro[4.5]decan-l-one;
3-Bromo-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]benzonitrile;
(5R)-7-(2,5-difluorophenyl)-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one;
(5R)-7-(2-Bromo-3 -fluorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro [4.5]decan- 1 - one;
(5R)-7-(5-Fluoro-2-methylphenyl)-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one;
(5R)-7-(2,3-Dichlorophenyl)-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one;
(5R)-7-(2,6-Dichlorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one;
4-Bromo-2-[(5R)-2-(cis-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]benzonitrile;
2-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile;
(5R)-7-(2-Fluorophenyl)-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one;
2-[(5R)-2-(cis-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]isonicotinonitrile;
(5R)-7-(3-Bromo-5-fluoropyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one; (5R)-7-(3-Fluoro-4-methylpyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one;
6-[(5R)-2-(cis-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-2- methylnicotinonitrile;
(5R)-7-(5-Chloro-3-methylpyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one;
4-Chloro-2-[(5R)-2-(cis-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]benzonitrile;
2-Fluoro-4-[(5R)-2-(cis-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]benzonitrile;
4-Bromo-2-[(5R)-2-(cis-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]benzonitrile;
7-[(3-Chloro-2-methylphenyl)sulfonyl]-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one;
(5R)-7-[2-Chloro-5-(trifluoromethyl)phenyl]-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one;
(5R)-7-[3-Fluoro-5-(trifluoromethyl)phenyl]-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one;
(5R)-7-(4-Chloro-2-methylphenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan- 1-one;
(5R)-7-(3-chloro-2-methylphenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan- 1-one;
(5R)-2-(trans-4-Hydroxycyclohexyl)-7-quinolin-8-yl-2,7-diazaspiro[4.5]decan-l-one;
{3-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yljphenyl} acetonitrile;
(5R)-7-(4-Fluoro-2-methylphenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan- 1-one;
(5R)-2-(trans-4-Hydroxycyclohexyl)-7-[4-(2-oxopyrrolidin-l-yl)-2-(trifluoromethyl)phenyl]- 2,7-diazaspiro[4.5]decan-l-one;
(5R)-2-(trans-4-Hydroxycyclohexyl)-7-[4-(2-oxo-l,3-oxazolidin-3-yl)-2- (trifluoromethyl)pheny 1] -2,7-diazaspiro [4.5] decan- 1 -one;
(5R)-2-(trans-4-Hydroxycyclohexyl)-7-[4-(2-oxo-l,3-oxazinan-3-yl)-2- (trifluoromethyl)phenyl]-2,7-diazaspiro[4.5]decan-l-one;
(5R)-7-[3-Fluoro-4-(pyridin-2-yloxy)phenyl]-2-(4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one;
(5R)-7-[3-Fluoro-4-(pyridin-4-yloxy)phenyl]-2-(4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one; (5R)-7-[3-Fluoro-4-(pyridin-3-yloxy)phenyl]-2-(4-hydroxycyclohexyl)-2,7- diazaspiro [4.5] decan- 1 -one;
(5R)-7-[2-Fluoro-4-(pyridin-3-yloxy)phenyl]-2-(4-hydroxycyclohexyl)-2,7- diazaspiro [4.5] decan- 1 -one;
Methyl { 3 -chloro-4- [(5R)-2-(trans-4-hy droxycy clohexy I)- 1 -oxo-2,7-diazaspiro [4.5] dec-7- yl]phenyl}carbamate;
Ethyl {3-chloro-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl} carbamate;
Prop-2-yn-l-yl {3-chloro-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7- diazaspiro[4.5] dec-7-yl]phenyl} carbamate;
Propyl {3-chloro-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl} carbamate;
N-{3-Chloro-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl}cyclopentanecarboxamide;
N-{3-Chloro-4-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]phenyl}cyclohexanecarboxamide;
(5R)-7-(5-Fluoropyrimidin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l- one;
(5R)-7-(5-Bromopyrimidin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l- one;
(5R)-7-(5-Ethylpyrimidin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l-one;
4-{2-[(5R)-2-(cis-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyrimidin-5- yl}benzamide;
N-Cyclopropyl-4-{2-[(5R)-2-(cis-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]pyrimidin-5-yl}benzamide;
(5R)-2-(cis-4-Hydroxycyclohexyl)-7-[5-(4-methoxyphenyl)pyrimidin-2-yl]-2,7- diazaspiro[4.5]decan-l-one;
(5R)-2-(cis-4-Hydroxycyclohexyl)-7-(5-pyridin-3-ylpyrimidin-2-yl)-2,7- diazaspiro[4.5]decan-l-one;
5-{2-[(5R)-2-(cis-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyrimidin-5-yl}- N,N-dimethylpyridine-2-carboxamide;
(5R)-2-(cis-4-Hydroxycyclohexyl)-7-(5-pyridin-4-ylpyrimidin-2-yl)-2,7- diazaspiro[4.5]decan-l-one;
4-{5-Chloro-6-[(5R)-2-(cis-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin- 3-yl} -N-cyclopropylbenzamide;
5'-Chloro-N-ethyl-6'-[(5R)-2-(cis-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]- 3,3'-bipyridine-6-carboxamide; 2-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]isonicotinonitrile;
Methyl {4-[(5R)-2-(cis-4-hydroxy-4-methylcyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]- 3-methylphenyl} carbamate;
Prop-2-yn-l-yl {6-[(5R)-2-(trans-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]- 5-methoxypyridin-3 -yl} carbamate;
(5R)-7-(5-Fluoropyrimidin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-l- one;
(5R)-7-(5-Ethylpyrimidin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-l-one;
(5R)-2-(Tetrahydro-2H-pyran-4-yl)-7-[4-(trifluoromethyl)pyrimidin-2-yl]-2,7- diazaspiro[4.5] decan- 1 -one;
(5R)-7-(4-Methoxypyrimidin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-l- one;
(5R)-7-(2-Fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-l-one;
(5R)-2-(cis-4-HydiOxycyclohexyl)-7-[5-(lH-pyrazol-l-yl)pyrimidin-2-yl]-2,7- diazaspiro[4.5]decan-l-one;
(5R)-2-(cis-4-Hydroxycyclohexyl)-7-[5-(3-methyl-lH-pyrazol-l-yl)pyrimidin-2-yl]-2,7- diazaspiro[4.5]decan-l-one;
(5R)-2-(cis-4-Hydroxycyclohexyl)-7-{5-[3-(trifluoromethyl)-lH-pyrazol-l-yl]pyrimidin-2- yl}-2,7-diazaspiro[4.5]decan-l-one;
(5R)-2-(cis-4-Hydroxycyclohexyl)-7-pyrimidin-2-yl-2,7-diazaspiro[4.5]decan-l-one;
(5R)-2-(cis-4-Hydroxycyclohexyl)-7-[5-(2-oxopyridin-l(2H)-yl)pyrimidin-2-yl]-2,7- diazaspiro [4.5] decan- 1 -one;
(5R)-7-(2,5-Difluoropyridin-3-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l- one;
(5R)-7-(3,5-Difluoropyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-l- one;
(5R)-7-[3-Fluoro-4-(trifluoromethyl)pyridin-2-yl]-2-(cis-4-hydroxycyclohexyl)-2,7- diazaspiro [4.5] decan- 1 -one;
(5R)-7-[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]-2-(cis-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one;
(5R)-2-(cis-4-Hydroxycyclohexyl)-7-[4-(trifluoromethyl)pyridin-2-yl]-2,7- diazaspiro [4.5] decan- 1 -one;
(5R)-7-(5-Bromo-2-chloropyridin-3-yl)-2-(cis-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one;
(5R)-7-(5-Bromo-3-fluoropyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7- diazaspiro [4.5] decan- 1 -one; (5R)-7-(5-Bromo-3-chloropyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l -one;
(5R)-7-(5-Bromo-3-methylpyridm-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one;
Methyl {6-[(5R)-2-(cis-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5- methy lpyridin-3 -y 1} carbamate;
Ethyl {6-[(5R)-2-(cis-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5- methy lpyridin-3 -yl} carbamate;
Propyl {6-[(5R)-2-(cis-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5- methy lpyridin-3 -yl} carbamate;
Prop-2-yn-l-yl {6-[(5R)-2-(cis-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5- methy lpyridin-3 -yl} carbamate;
Methyl {6-[(5R)-2-(cis-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5- methoxypyridin-3 -yl} carbamate;
Ethyl {6-[(5R)-2-(cis-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5- methoxypyridin-3 -yl} carbamate;
Propyl {6-[(5R)-2-(cis-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5- methoxypyridin-3 -yl} carbamate;
Prop-2-yn-l-yl {6-[(5R)-2-(cis-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5- methoxypyridin-3 -yl} carbamate;
(5R)-2-(cis-4-Hydroxycyclohexyl)-7-[3-methoxy-5-(2-oxopyrrolidin-l-yl)pyridin-2-yl]-2,7- diazaspiro[4.5]decan-l-one;
(5R)-2-(cis-4-Hydroxycyclohexyl)-7-[3-methoxy-5-(2-oxo-l,3-oxazolidin-3-yl)pyridin-2-yl]- 2,7-diazaspiro[4.5]decan-l-one;
(5R)-2-(cis-4-Hydroxycyclohexyl)-7-[3-methoxy-5-(2-oxo-l,3-oxazinan-3-yl)pyridin-2-yl]- 2,7-diazaspiro[4.5]decan-l-one;
(5R)-7-(3-Chloro-5-phenylpyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5] decan- 1 -one;
(5R)-7-[3-Chloro-5-(4-methoxyphenyl)pyridin-2-yl]-2-(cis-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l -one;
4-{5-Chloro-6-[(5R)-2-(cis-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin- 3-yl}benzamide;
(5R)-7-(5-Chloro-3,4'-bipyridin-6-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan- 1-one;
5'-Chloro-6'-[(5R)-2-(cis-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-N,N- dimethyl-3 ,3 '-bipyridine-6-carboxamide; 5'-Chloro-N,N-diethyl-6'-[(5R)-2-(cis-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]-3,3'-bipyridine-6-carboxamide;
4-{5-Chloro-6-[(5R)-2-(cis-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin- 3-yl} -N,N-dimethylbenzamide;
Methyl { 5 -chloro-6- [(5R)-2-(cis-4-hydroxycyclohexy I)- 1 -oxo-2,7-diazaspiro [4.5] dec-7- yl]pyridin-3-yl} carbamate;
Ethyl {5-chloro-6-[(5R)-2-(cis-4-hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7- yl]pyridin-3-yl}carbamate;
Propyl { 5 -chloro-6- [(5R)-2-(cis-4-hydroxycyclohexyl)- 1 -oxo-2,7-diazaspiro [4.5] dec-7- yl]pyridin-3-yl}carbamate;
Prop-2-yn- 1 -yl { 5-chloro-6-[(5R)-2-(cis-4-hydroxycyclohexyl)- 1 -oxo-2,7-diazaspiro[4.5] dec- 7-yl]pyridin-3 -yl} carbamate;
(5R)-7-[3-Chloro-5-(2-oxo-l,3-oxazolidin-3-yl)pyridin-2-yl]-2-(cis-4-hydroxycyclohexyl)- 2,7-diazaspiro[4.5]decan-l-one;
(5R)-7-[3-Chloro-5-(2-oxo-l,3-oxazinan-3-yl)pyridin-2-yl]-2-(cis-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one;
(5R)-7-[3-Chloro-5-(2-oxopyrrolidin-l-yl)pyridin-2-yl]-2-(cis-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan- 1 -one;
(5R)-7-(5-Chloro-3,3'-bipyridin-6-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan- 1-one;
(5R)-7-(3-Fluoro-6-methylpyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro [4.5] decan- 1 -one;
6-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-2- methylnicotinonitrile;
2-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-4,6- dimethylnicotinonitrile;
(5R)-2-(trans-4-Hydroxycyclohexyl)-7-[2-(trifluoromethyl)quinazolin-4-yl]-2,7- diazaspiro[4.5]decan- 1 -one;
(5R)-2-Cyclohexyl-7-[2-fluoro-4-(2-oxopyrrolidin-l-yl)phenyl]-2,7-diazaspiro[4.5]decan-l- one;
(5R)-2-Cyclohexyl-7-[2-fluoro-4-(2-oxo-l,3-oxazolidin-3-yl)phenyl]-2,7- diazaspiro[4.5]decan-l-one;
(5R)-7-(5-Chloro-3-methylpyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l -one;
(5R)-7-(3-Fluoro-4-methylpyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one; (5R)-7-(5-Fluoro-3-methylpyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one;
(5R)-7-(5-Fluoro-6-methylpyridin-2-yl)-2-(frans-4-hydroxycyclohexyl)-2,7- diazaspiro[4.5]decan-l-one;
(5R)-2-(trans-4-Hydroxycyclohexyl)-7-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7- diazaspiro[4.5]decan-l-one;
(5R)-2-(trans-4-Hydroxycyclohexyl)-7-(5-methylpyridin-2-yl)-2,7-diazaspiro[4.5]decan-l- one;
2-[(5R)-2-(trans-4-Hydroxycyclohexyl)-l-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5- phenylnicotinonitrile;
(5R)-7-[3 -Chloro-5-(2-oxo- 1 ,3-oxazolidin-3 -yl)pyridin-2-yl] -2-cyclohexy 1-2,7- diazaspiro [4.5] decan- 1 -one;
(5R)-7-[3-Chloro-5-(2-oxopyrrolidin-l-yl)pyridin-2-yl]-2-cyclohexyl-2,7- diazaspiro[4.5]decan-l -one;
(5R)-7-[3-Chloro-5-(2-oxo-l,3-oxazinan-3-yl)pyridin-2-yl]-2-cyclohexyl-2,7- diazaspiro[4.5]decan-l-one; and
(5R)-7-[3-Chloro-5-(2-oxopiperidin-l-yl)pyridin-2-yl]-2-cyclohexyl-2,7- diazaspiro[4.5]decan-l-one, or a pharmaceutically acceptable salt thereof.
65. A composition comprising a compound of any one of claims 1 to 64 and a pharmaceutically acceptable carrier.
66. A method of modulating activity of 11 βHSDl or MR comprising contacting said llβHSDl or said MR with a compound of Formula I:
Figure imgf000339_0001
I or pharmaceutically acceptable salt or prodrug thereof, wherein:
Cy is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 -W-X-Y-Z;
L is (CR12R13),,, (CR12R13VO(CR12R1V, (CR12R13)qlS(CR12R13)q2, (CR12R13)qiSO2(CR12R13)q2, (CR12R13)qlSO(CR12R13)q2, or (CR12R13)qlCO(CR12R13)q2;
Figure imgf000340_0001
A is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 -W'-X'-Y'-Z';
E is -(CR3aR3b)nl-, -(CR3V)112CO-, -(CR3aR3b)n2OCO-, -(CR33R3^112SO-,
-(CR3aR3b)n2SO2-, -(CR3aR3b)n2NR3c-, -(CR3aR3b)n3CONR3°-, -(CR3aR3b)n2NR3oCO-, or a group of formula:
Figure imgf000340_0002
D1, D2, D3 and D4 are each N or CR15;
R1 and R2 are each, independently, H or Ci-8 alkyl;
R3a and R3b are each, independently, H, OC(O)R1', 0C(0)0Rb', C(O)ORb>, OC(0)NR0>Rd>, NR°'Rd', NR°'C(0)Ra>, NRc'C(0)0Rb>, S(O)R3', S(O)NR°'Rd', S(O)2R3', S(O)2NR°'Rd', ORb>, SRb', halo, C1-I0 alkyl, Ci-iohaloalkyl, C2-io alkenyl, C2-Io alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said Ci- io alkyl, CMO haloalkyl, C2-I0 alkenyl, C2-I0 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by R16;
R3cis H, Ci-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C24 alkynyl, or CO-(CL4 alkyl);
R4, R5, R6, R7, R8, R9, R10 and R11 are each, independently, H, OC(O)R3', OC(O)ORb>, C(O)ORb', OC(O)NR°'Rd', NRc Rd>, NRC'C(O)R3', NRc'C(O)ORb>, S(O)R3', S(0)NR°'Rd', S(O)2R3', S(0)2NRc'Rd>, ORb', SRb', halo, Ci-I0 alkyl, CM0 haloalkyl, C2-I0 alkenyl, C2-I0 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said Ci-I0 alkyl, Ci-I0 haloalkyl, C2-I0 alkenyl, C2-1O alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by R14; or R4 and R5 together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group which is optionally substituted by R14; or R6 and R7 together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group which is optionally substituted by R14; or R8 and R9 together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group which is optionally substituted by R14; or R10 and R11 together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group which is optionally substituted by R14; or R4 and R6 together with the carbon atom to which they are attached form a 3-7 membered fused cycloalkyl group or 3-7 membered fused heterocycloalkyl group which is optionally substituted by R14; or R6 and R8 together with the carbon atom to which they are attached form a 3-7 membered fused cycloalkyl group or 3-7 membered fused heterocycloalkyl group which is optionally substituted by R14; or R4 and R9 together form a Cu alkylene bridge which is optionally substituted by R14; or R4 and R10 together form a C1^ alkylene bridge which is optionally substituted by R14; or R6 and R10 together form a C1^ alkylene bridge which is optionally substituted by R14; or R9 and R10 together form a C1^ alkylene bridge which is optionally substituted by R14;
R12 and R13 are each, independently, H, halo, Ci-4 alkyl, Ci-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, OR3', SR3', C(O)Rb', C(O)NR°'Rd', C(O)OR3', 0C(0)Rb', 0C(0)NR°'Rd', NR°'Rd', NR°'C(O)Rd', NRC'C(O)OR3', S(O)Rb>, S(O)NR°'Rd', S(O)2Rb>, or S(O)2NR°'Rd';
R14 is halo, Ci-4 alkyl, Ci-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, OR3', SR3', C(O)Rb', C(O)NRc Rd', C(O)OR3', OC(O)Rb', 0C(0)NR°'Rd>, NRc Rd>, NRc C(O)Rd', NR0' C(O)OR3', S(O)Rb', S(0)NR°'Rd', S(O)2Rb', or S(0)2NR° Rd';
R15 is H, halo, Ci-4 alkyl, Ci-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, OR3", SR3", C(0)Rb", C(0)NR°"Rd", C(O)OR3", 0C(0)Rb", 0C(0)NR°"Rd", NRc"Rd", NR°"C(0)Rd", NR°"C(0)0R3", S(O)Rb", S(0)NR°"Rd", S(O)2Rb", or S(0)2NR°"Rd";
R16 is halo, Ci-4 alkyl, Ci-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, OR3', SR3', C(O)Rb>, C(O)NR°'Rd', C(O)OR3', 0C(0)Rb>, 0C(0)NRcRd', NR°'Rd', NR°'C(0)Rd', NR0 C(O)OR3', S(O)Rb', S(0)NR°'Rd', S(O)2Rb', or S(0)2NR°'Rd';
W, W and W" are each, independently, absent, Ci-6 alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl, O, S, NRe, CO, COO, C0NRe, SO, SO2, SONRe, or NReC0NRf, wherein said Ci-6 alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl are each optionally substituted by 1, 2 or 3 halo, OH, Ci-4 alkoxy, Ci-4 haloalkoxy, amino, Ci-4 alkylamino or C2-g dialkylamino;
X, X' and X" are each, independently, absent, Ci-6 alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said Ci-6 alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by one or more halo, oxo, CN, NO2, OH, Ci-4 alkoxy, Ci-4 haloalkoxy, amino, Ci-4 alkylamino or C2-8 dialkylamino;
Y, Y' and Y" are each, independently, absent, Ci-6 alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl, O, S, NRe, CO, COO, C0NRe, SO, SO2, SONRe, or NReC0NRf, wherein said Ci-6 alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl are each optionally substituted by 1, 2 or 3 halo, OH, Ci-4 alkoxy, Ci-4 haloalkoxy, amino, Ci-4 alkylamino or C2-8 dialkylamino;
Z, Z' and Z" are each, independently, H, halo, CN, NO2, OH, Ci-4 alkoxy, Ci-4 haloalkoxy, amino, Ci-4 alkylamino, C2-8 dialkylamino, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2 or 3 halo, oxo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NR°Rd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NR°Rd, NR°C(0)Rd, NRcC(O)ORa, NReS(O)2Rb, S(O)Rb, S(O)NR°Rd, S(O)2Rb, or S(O)2NRcRd; wherein two -W-X-Y-Z attached to the same atom optionally form a 3-20 membered cycloalkyl or heterocyloalkyl group, each optionally substituted by 1, 2 or 3 -W"-X"-Y"-Z"; wherein two -W'-X'-Y'-Z' attached to the same atom optionally form a 3-20 membered cycloalkyl or heterocyloalkyl group, each optionally substituted by 1, 2 or 3 -W"-X"-Y"-Z"; 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;
Ra, Ra and Ra are each, independently, H, C1-6 alkyl, C1-O haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl; heterocycloalkyl, heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, Ci-6 alkyl, Ci-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;
Rb, Rb'and Rb" are each, independently, H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;
Rc and Rd are each, independently, H, Cno alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said Ci_io alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or Rc and Rd together with the N atom to which they are attached form a A-, 5-, 6- or 7- membered heterocycloalkyl group;
Rc and Rd are each, independently, H, Ci-I0 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C1-1O alkyl, C1^ haloalkyl, C2.6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or R0 and Rd together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group; R° and Rd are each, independently, H, C1-1O alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said Ci-I0 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, Q-6 alkyl, C1^ haloalkyl, Ci-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or R°" and Rd" together with the N atom to which they are attached form a A-, 5-, 6- or 7- membered heterocycloalkyl group;
Re and Rf are each, independently, H, Cwo alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said CMO alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or Re and Rf together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group; m is 0, 1, 2 or 3; nl is 1, 2, 3 or 4; n2 is θ, 1, 2, 3 or 4; n3 is O, 1, 2, 3 or 4; p is 0, 1 or 2; ql is 0, 1 or 2; q2 is 0, 1 or 2; and r is 0, 1 or 2.
67. The method of claim 66 wherein said modulating is inhibiting.
68. A method of treating a disease in a patient, wherein said disease is associated with expression or activity of 1 lβHSDl or MR, comprising administering to said patient a therapeutically effective amount of a compound of of Formula I:
Figure imgf000343_0001
I or pharmaceutically acceptable salt or prodrug thereof, wherein:
Cy is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 -W-X-Y-Z;
L is (CR12R13)ql, (CR12R13)qlO(CR12R13)q2, (CR12R13)qlS(CR12R13)q2, (CR12R13)qlSO2(CR12R13)q2, (CR12R13)qlSO(CR12R13)q2, or (CR12R13)qlCO(CR12R13)q2;
Figure imgf000344_0001
A is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 -W'-X'-Y'-Z';
E is -(CR3aR3b)nl-, -(CR3aR3b)n2CO-, -(CR33R3^112OCO-, -(CR33R3^112SO-,
-(CR33R3^112SO2-, -(CR33R31^)112NR30-, -(CR3aR3b)n3CONR3c-, -(CR33R315^NR30CO-, or a group of formula:
Figure imgf000344_0002
D1, D2, D3 and D4 are each N or CR15;
R1 and R2 are each, independently, H or Ci-8 alkyl;
R3a and R3b are each, independently, H, OC(O)R3', OC(O)ORb>, C(0)0Rb', 0C(0)NR°'Rd', NRc'Rd', NR°'C(0)Ra', NR0'C(0)ORb', S(O)R3', S(0)NR°'Rd', S(O)2R3', S(0)2NRc>Rd', 0Rb', SRb', halo, Ci-io alkyl, Ci-I0 haloalkyl, C2-io alkenyl, C2-io alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said Ci- io alkyl, Ci-I0 haloalkyl, C2-I0 alkenyl, C2-io alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by R16;
R3cis H, Ci-4 alkyl, Ci-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, or CO-(Ci-4 alkyl);
R4, R5, R6, R7, R8, R9, R10 and R11 are each, independently, H, OC(O)R3', OC(O)ORb', C(0)0Rb', 0C(0)NRc'Rd', NR°'Rd>, NR0 C(O)R3', NRc'C(0)0Rb', S(O)R3', S(O)NR0 R"', S(O)2R3', S(0)2NR°'Rd', 0Rb>, SRb>, halo, CM0 alkyl, Ci-I0 haloalkyl, C2-I0 alkenyl, C2-I0 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said CMO alkyl, Ci-I0 haloalkyl, C2-I0 alkenyl, C2-io alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by R14; or R4 and R5 together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group which is optionally substituted by R14; or R6 and R7 together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group which is optionally substituted by R14; or R8 and R9 together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group which is optionally substituted by R14; or R10 and R11 together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group which is optionally substituted by R14; or R4 and R6 together with the carbon atom to which they are attached form a 3-7 membered fused cycloalkyl group or 3-7 membered fused heterocycloalkyl group which is optionally substituted by R14; or R6 and R8 together with the carbon atom to which they are attached form a 3-7 membered fused cycloalkyl group or 3-7 membered fused heterocycloalkyl group which is optionally substituted by R14; or R4 and R9 together form a Cj-3 alkylene bridge which is optionally substituted by R14; or R4 and R10 together form a Ci-3 alkylene bridge which is optionally substituted by R14; or R6 and R10 together form a C1-3 alkylene bridge which is optionally substituted by R14; or R9 and R10 together form a Ci-3 alkylene bridge which is optionally substituted by R14;
R12 and R13 are each, independently, H, halo, C1-4 alkyl, C1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa', SR3', C(O)Rb', C(O)NR°'Rd', C(O)ORa>, OC(O)Rb>, OC(O)NR°'Rd', NRc'Rd', NRc'C(O)Rd', NR°'C(O)ORa', S(O)Rb>, S(O)NRc>Rd>, S(O)2Rb', or S(O)2NR°'Rd';
R14 is halo, C1-4 alkyl, Ci-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa>, SRa', C(O)Rb', C(0)NR°'Rd', C(O)OR3', OC(O)Rb', OC(O)NRc'Rd', NR°'Rd', NRc'C(O)Rd', NRc'C(0)0Ra>, S(O)Rb', S(O)NR°'Rd', S(O)2Rb>, or S(O)2NR°'Rd';
R15 is H, halo, Ci-4 alkyl, C1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, 0Ra ", SRa ", C(O)Rb ", C(O)NR0V", C(O)ORa", OC(O)Rb", 0C(0)NR°"Rd ', NR°"Rd", NR°"C(0)Rd", NR0" C(O)OR3", S(O)Rb", S(O)NR0V5 S(O)2Rb", or S(O)2NR0V;
R16 is halo, Ci-4 alkyl, Ci-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, OR3', SRa>, C(0)Rb>, C(O)NR°'Rd', C(O)OR3', 0C(0)Rb', OC(0)NR°'Rd', NR0'Rd', NR°'C(0)Rd', NR°'C(0)0Ra', S(O)Rb', S(0)NRc'Rd', S(O)2Rb', or S(0)2NRc Rd>;
W, W and W" are each, independently, absent, Ci-6 alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl, O, S, NRe, CO, COO, C0NRe, SO, SO2, SONR6, or NReC0NRf, wherein said Ci-6 alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl are each optionally substituted by 1, 2 or 3 halo, OH, Ci-4 alkoxy, Ci-4haloalkoxy, amino, C1-4 alkylamino or C2-8 dialkylamino;
X, X' and X" are each, independently, absent, Ci-6 alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said Ci-6 alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by one or more halo, oxo, CN, NO2, OH, Ci-4 alkoxy, Ci-4haloalkoxy, amino, Ci-4 alkylamino or C2-8 dialkylamino; Y, Y' and Y" are each, independently, absent, Cμ6 alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl, O5 S, NRe, CO, COO, CONRe, SO, SO2, SONRe, or NReC0NRf, wherein said Cw alkylenyl, C2.6 alkenylenyl, C2-6 alkynylenyl are each optionally substituted by 1, 2 or 3 halo, OH, C1.4 alkoxy, Ci-4haloalkoxy, amino, Cy alkylamino or C2-S dialkylamino;
Z, Z' and Z" are each, independently, H, halo, CN, NO2, OH, Ci-4 alkoxy, Ci-4haloalkoxy, amino, Ci-4 alkylamino, C2-s dialkylamino, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2 or 3 halo, oxo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, 0Ra, SRa, C(O)Rb, C(0)NRcRd, C(O)OR3, OC(O)Rb, 0C(0)NR°Rd, NR°Rd, NR°C(O)Rd, NR0C(O)OR3, NReS(0)2Rb, S(O)Rb, S(O)NR°Rd, S(O)2Rb, or S(O)2NR°Rd; wherein two -W-X-Y-Z attached to the same atom optionally form a 3-20 membered cycloalkyl or heterocyloalkyl group, each optionally substituted by 1, 2 or 3 -W"-X"-Y"-Z"; wherein two -W'-X'-Y'-Z' attached to the same atom optionally form a 3-20 membered cycloalkyl or heterocyloalkyl group, each optionally substituted by 1, 2 or 3 — W"-X"-Y"-Z"; 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;
Ra, Ra and Ra are each, independently, H, Ci-6 alkyl, Q-6 haloalkyl, C2.6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl; heterocycloalkyl, heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, Ci-6 alkyl, Ci-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;
Rb, Rb and Rb are each, independently, H, Ci-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;
Rc and Rd are each, independently, H, Cμio alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said Cn0 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or Rc and Rd together with the N atom to which they are attached form a A-, 5-, 6- or 7- membered heterocycloalkyl group; R0' and Rd are each, independently, H, Ci-10 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said Cn0 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2.6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or Rc and Rd together with the N atom to which they are attached form a A-, 5-, 6- or 7- membered heterocycloalkyl group;
Rc" and Rd" are each, independently, H, Ci-I0 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said Cn0 alkyl, Ci-6 haloalkyl, C2.6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or R° and Rd together with the N atom to which they are attached form a A-, 5-, 6- or 7- membered heterocycloalkyl group;
Re and Rf are each, independently, H, Ci-I0 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said Ci-I0 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or Re and Rf together with the N atom to which they are attached form a A-, 5-, 6- or 7- membered heterocycloalkyl group; m is 0, 1, 2 or 3; nl is 1, 2, 3 or 4; ii2 is 0, 1, 2, 3 or 4; n3 is O, 1, 2, 3 or 4; p is 0, 1 or 2; ql is 0, 1 or 2; q2 is 0, 1 or 2; and r is 0, 1 or 2.
69. The method of claim 68 wherein said disease is obesity, diabetes, glucose intolerance, insulin resistance, hyperglycemia, hypertension, hyperlipidemia, cognitive impairment, depression, dementia, glaucoma, cardiovascular disorders, osteoporosis, inflammation, 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, metabolic syndrome or general aldosterone-related target organ damage.
PCT/US2005/040550 2004-11-10 2005-11-09 Lactam compounds and their use as pharmaceuticals WO2006053024A2 (en)

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