Disclosed are compounds represented by Formula (I): [structure] or pharmaceutically acceptable salts, enantiomers or diastereomers thereof. Also disclosed are pharmaceutical compositions comprising the compounds of Formula (I) or pharmaceutically acceptable salts, enantiomers or diastereomers thereof and methods of inhibiting 11Î²-HSD1 activity comprising the step of administering to a mammal in need of such treatment an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof. Values for the variables in Formula (I) are defined herein.

Description

422 parts

›RELATED APPLICATIONS

The present application is a U.S. national stage application claiming the benefit of International Application No. PCT/US2008/009017, filed on Jul. 25, 2008, which claims the benefit of U.S. Provisional Application No. 60/962,058, filed on Jul. 26, 2007, U.S. Provisional Application No. 61/001,253, filed Oct. 31, 2007 and U.S. Provisional Application No. 61/049,650, filed May 1, 2008. The entire teachings of the above applications are incorporated herein by reference.

›BACKGROUND OF THE INVENTION · 1 of 3

Glucocorticoids, such as cortisol (hydrocortisone), are steroid hormones that regulate fat metabolism, function and distribution, and play a role in carbohydrate, protein and fat metabolism. Glucocorticoids are also known to have physiological effects on development, neurobiology, inflammation, blood pressure, metabolism, and programmed cell death. Cortisol and other corticosteroids bind both the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR), which are members of the nuclear hormone receptor superfamily and have been shown to mediate cortisol function in vivo. These receptors directly modulate transcription via DNA-binding zinc finger domains and transcriptional activation domains.

Until recently, the major determinants of glucocorticoid action were attributed to three primary factors: (1) circulating levels of glucocorticoid (driven primarily by the hypothalamic-pituitary-adrenal (HPA) axis); (2) protein binding of glucocorticoids in circulation; and (3) intracellular receptor density inside target tissues. Recently, a fourth determinant of glucocorticoid function has been identified: tissue-specific pre-receptor metabolism by glucocorticoid-activating and -inactivating enzymes. These 11β-hydroxysteroid dehydrogenase (11β-HSD) pre-receptor control enzymes modulate activation of GR and MR by regulation of glucocorticoid hormones. To date, two distinct isozymes of 11-beta-HSD have been cloned and characterized: 11β-HSD1 (also known as 11-beta-HSD type 1, 11betaHSD1, HSD11B1, HDL, and HSD11L) and 11β-HSD2. 11β-HSD1 is a bi-directional oxidoreductase that regenerates active cortisol from inactive 11-keto forms, whereas 11β-HSD2 is a unidirectional dehydrogenase that inactivates biologically active cortisol by converting it into cortisone.

The two isoforms are expressed in a distinct tissue-specific fashion, consistent with the differences in their physiological roles. 11β-HSD1 is widely distributed in rat and human tissues; expression of the enzyme and corresponding mRNA have been detected in human liver, adipose tissue, lung, testis, bone and ciliary epithelium. In adipose tissue, increased cortisol concentrations stimulate adipocyte differentiation and may play a role in promoting visceral obesity. In the eye, 11β-HSD1 may regulate intraocular pressure and may contribute to glaucoma; some data suggest that inhibition of 11β-HSD1 may cause a drop in intraocular pressure in patients with intraocular hypertension (Kotelevstev et al. (1997), Proc. Natl. Acad. Sci. USA 94(26):14924-9). Although 11β-HSD1 catalyzes both 11-beta-dehydrogenation and the reverse 11-oxoreduction reaction, 11β-HSD1 acts predominantly as a NADPH-dependent oxoreductase in intact cells and tissues, catalyzing the formation of active cortisol from inert cortisone (Low et al. (1994) J. Mol. Endocrin. 13: 167-174). In contradistinction, 11β-HSD2 expression is found mainly in mineralocorticoid target tissues such as kidney (cortex and medulla), placenta, sigmoid and rectal colon, salivary gland and colonic epithelial cell lines. 11β-HSD2 acts as an NAD-dependent dehydrogenase catalyzing the inactivation of cortisol to cortisone (Albiston et al. (1994) Mol. Cell. Endocrin. 105: R11-R17), and has been shown to protect the MR from glucocorticoid excess (e.g., high levels of receptor-active cortisol) (Blum, et al. (2003) Prog. Nucl. Acid Res. Mol. Biol. 75:173-216).

Mutations in either the 11β-HSD1 or the 11β-HSD2 genes result in human pathology. For example, individuals with mutations in 11β-HSD2 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 (Edwards et al. (1988) Lancet 2: 986-989; Wilson et al. (1998) Proc. Natl. Acad. Sci. 95: 10200-10205). Similarly, mutations in 11β-HSD1 and in the gene encoding a co-localized NADPH-generating enzyme, hexose 6-phosphate dehydrogenase (H6PD), can result in cortisone reductase deficiency (CRD); 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).

Notably, disruption of homeostasis in the HPA axis by either deficient or excess secretion or action results in Cushing's syndrome or Addison's disease, respectively (Miller and Chrousos (2001) Endocrinology and Metabolism, eds. Felig and Frohman (McGraw-Hill, New York), 4 th Ed.: 387-524). Patients with Cushing's syndrome or receiving glucocorticoid therapy develop reversible visceral fat obesity. 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). Although the role of glucocorticoids in human obesity is not fully characterized, there is mounting evidence that 11β-HSD1 activity plays an important role in obesity and metabolic syndrome (Bujalska et al. (1997) Lancet 349: 1210-1213); (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).

Data from studies in mouse transgenic models supports the hypothesis that adipocyte 11β-HSD1 activity plays a central role in visceral obesity and metabolic syndrome (Alberts et al. (2002) Diabetologia. 45(11): 1526-32). Over-expression in adipose tissue of 11β-HSD1 under the control of the aP2 promoter in transgenic mice produced a phenotype remarkably similar to human metabolic syndrome (Masuzaki et al. (2001) Science 294: 2166-2170; Masuzaki et al. (2003) J. Clinical Invest. 112: 83-90). Moreover, the increased activity of 11β-HSD1 in these mice is very similar to that observed in human obesity (Rask et al. (2001) J. Clin. Endocrinol. Metab. 86: 1418-1421). In addition, data from studies with 11β-HSD1-deficient mice produced by homologous recombination demonstrate that the loss of 11β-HSD1 leads to an increase in insulin sensitivity and glucose tolerance due to a tissue-specific deficiency in active glucocorticoid levels (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).

›BACKGROUND OF THE INVENTION · 2 of 3

The published data supports the hypothesis that increased expression of 11β-HSD1 contributes to increased local conversion of cortisone to cortisol in adipose tissue and hence that 11β-HSD1 plays a role in the pathogenesis of central obesity and the appearance of the metabolic syndrome in humans (Engeli, et al., (2004) Obes. Res. 12: 9-17). Therefore, 1143-HSD1 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). Furthermore, inhibition of 11β-HSD1 activity may prove beneficial in treating numerous glucocorticoid-related disorders. For example, 11β-HSD1 inhibitors could be effective in combating obesity and/or aspects of the metabolic syndrome cluster, including glucose intolerance, insulin resistance, hyperglycemia, hypertension, and/or hyperlipidemia (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). In addition, inhibition of 11β-HSD1 activity may have beneficial effects on the pancreas, including the enhancement of glucose-stimulated insulin release (Billaudel and Sutter (1979) Horm. Metab. Res. 11: 555-560; Ogawa et al. (1992) J. Clin. Invest. 90: 497-504; Davani et al. (2000) J. Biol. Chem. 275: 34841-34844).

Furthermore, given that 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) and dysregulation of the HPA axis resulting in chronic exposure to glucocorticoid excess in certain brain subregions has been theorized to contribute to the decline of cognitive function (McEwen and Sapolsky (1995) Curr. Opin. Neurobiol. 5: 205-216), one might predict that inhibition of 11β-HSD1 could reduce exposure to glucocorticoids in the brain and thereby protect against deleterious glucocorticoid effects on neuronal function, including cognitive impairment, dementia, and/or depression. Notably, it is known that stress and glucocorticoids influence cognitive function (de Quervain et al. (1998) Nature 394: 787-790); and it has been shown that 11β-HSD1, through its control of glucocorticoid action in the brain, may have effects on neurotoxicity (Rajan et al. (1996) Neuroscience 16: 65-70; Seckl (2000) Neuroendocrinol. 18:49-99).

There is also evidence that glucocorticoids and 11β-HSD1 play a role in regulation of in intra-ocular pressure (IOP) (Stokes et al. (2000) Invest. Opthalmol. Vis. Sci. 41: 1629-1683; Rauz et al. (2001) Invest. Opthalmol. Vis. Sci. 42: 2037-2042); if left untreated, elevated IOP can lead to partial visual field loss and eventually blindness. Thus, inhibition of 11β-HSD1 in the eye could reduce local glucocorticoid concentrations and IOP, and 11β-HSD1 hence could potentially be used to treat glaucoma and other visual disorders.

Transgenic aP2-11βHSD1 mice exhibit high arterial blood pressure and have increased sensitivity to dietary salt. Moreover, plasma angiotensinogen levels are elevated in the transgenic mice, as are angiotensin II and aldosterone; and treatment of the mice with an angiotensin II antagonist alleviates the hypertension (Masuzaki et al. (2003) J. Clinical Invest. 112: 83-90). This suggests that hypertension may be caused or exacerbated by 11β-HSD1 activity. Thus, 11β-HSD1 inhibitors may be useful for treatment of hypertension and hypertension-related cardiovascular disorders. Inhibition of 11β-HSD1 in mature adipocytes is also expected to attenuate secretion of plasminogen activator inhibitor 1 (PAI-1), which is an independent cardiovascular risk factor (Halleux et al. (1999) J. Clin. Endocrinol. Metabl. 84: 4097-4105).

Glucocorticoids can have adverse effects on skeletal tissues; and prolonged exposure to even moderate glucocorticoid doses can result in osteoporosis (Cannalis (1996) J. Clin. Endocrinol. Metab. 81: 3441-3447). In addition, 11β-HSD1 has been shown to be present in cultures of human primary osteoblasts as well as cells from adult bone (Cooper et al. (2000) Bone 27: 375-381), and the 11β-HSD1 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 11β-HSD1 is predicted to decrease the local glucocorticoid concentration within osteoblasts and osteoclasts, thereby producing beneficial effects in various forms of bone disease, including osteoporosis.

11β-HSD1 inhibitors may also be useful for immunomodulation. Although glucocorticoids are perceived to suppress the immune system, in actuality, there is a complex, dynamic interaction between the HPA axis and the immune system (Rook (1999) Baillier's Clin. Endocrinol. Metabl. 13: 576-581). Glucocorticoids play a role in modulating the balance between cell-mediated and humoral immune response, with high glucocorticoid activity normally associated with a humoral response. Inhibition of 11β-HSD1 therefore can be used a means of shifting the immune response towards a cell-mediated response. Certain disease states, such as tuberculosis, leprosy (Hansen's disease) and psoriasis, trigger immune responses that are biased towards a humoral response whereas the more effective immune response may be a cell-mediated response. Hence, 11β-HSD1 inhibitors may be useful for treating such diseases.

It has been reported that glucocorticoids inhibit wound healing, especially in diabetic patients with ulcers (Bitar et al. (1999) J. Surg. Res. 82: 234-243; Bitar et al. (1999) Surgery 125: 594-601; Bitar (2000) Surgery 127: 687-695; Bitar (1998) Am. J. Pathol. 152: 547-554). Patients that exhibit impaired glucose tolerance and/or type 2 diabetes often also have impaired wound healing. Glucocorticoids have been shown to increase the risk of infection and delay wound healing (Anstead (1998) Adv. Wound Care 11:277-285). Moreover, there is a correlation between elevated levels of cortisol in wound fluid and non-healing wounds (EP Patent App. No. 0 902 288). Recent published patent applications have suggested that certain 11β-HSD1 inhibitors may be useful for promoting wound healing (PCT/US2006/043,951).

›BACKGROUND OF THE INVENTION · 3 of 3

As evidenced herein, there is a continuing need for new and improved drugs that inhibit 11β-HSD1. The novel compounds of the instant invention are effective inhibitors of 11β-HSD1.

›SUMMARY OF THE INVENTION · 1 of 8

It has now been found that compounds of Formula I or pharmaceutically acceptable salts or prodrugs thereof, are effective inhibitors of 11β-HSD1. The invention is a compound represented by Formula I:

In a first embodiment of the invention, Formula I and its constituent members are defined herein as follows:

R 1 is (a) absent or (b) is selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkoxy, or (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl and is optionally substituted with up to four groups independently selected from fluorine, cyano, oxo, R 4 , R 4 O—, (R 4 ) 2 N—, R 4 O 2 C—, R 4 S, R 4 S(═O)—, R 4 S(═O) 2 —, R 4 C(═O)NR 4 —, (R 4 ) 2 NC(═O)—, (R 4 ) 2 NC(═O)O—, (R 4 ) 2 NC(═O)NR 4 —, R 4 OC(═O)NR 4 —, (R 4 ) 2 NC(═NCN)NR 4 —, (R 4 O) 2 P(═O)O—, (R 4 O) 2 P(═O)NR 4 —, R 4 OS(═O) 2 NR 4 —, (R 4 ) 2 NS(═O) 2 O—, (R 4 ) 2 NS(═O) 2 NR 4 —, R 4 S(═O) 2 NR 4 —, R 4 S(═O) 2 NHC(═O)—, R 4 S(═O) 2 NHC(═O)O—, R 4 S(═O) 2 NHC(═O)NR 4 —, R 4 OS(═O) 2 NHC(═O)—, R 4 OS(═O) 2 NHC(═O)O—, R 4 OS(═O) 2 NHC(═O)NR 4 —, (R 4 ) 2 NS(═O) 2 NHC(═O)—, (R 4 ) 2 NS(═O) 2 NHC(═O)O—, (R 4 ) 2 NS(═O) 2 NHC(═O)NR 4 —, R 4 C(═O)NHS(═O) 2 —, R 4 C(═O)NHS(═O) 2 O—, R 4 C(═O)NHS(═O) 2 NR 4 —, R 4 OC(═O)NHS(═O) 2 —, R 4 OC(═O)NHS(═O) 2 O—, R 4 OC(═O)NHS(═O) 2 NR 4 —, (R 4 ) 2 NC(═O)NHS(═O) 2 —, (R 4 ) 2 NC(═O)NHS(═O) 2 O—, (R 4 ) 2 NC(═O)NHS(═O) 2 NR 4 —, heterocyclyl, heteroaryl, arylamino and heteroarylamino;

A 1 is (a) a bond, or (b) (C 1 -C 3 )alkylene, CH 2 CH 2 O, wherein the oxygen is attached to Cy 1 , or CH 2 C(═O), wherein the carbonyl carbon is attached to Cy 1 ;

Cy 1 is aryl, heteroaryl, monocyclic cycloalkyl or monocyclic heterocyclyl and is optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, hydroxy(C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl(C 2 -C 4 )alkynyl, halo(C 1 -C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl, halo(C 4 -C 7 )cycloalkylalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, (C 4 -C 7 )cycloalkylalkoxy, halo(C 1 -C 6 )alkoxy, halo(C 3 -C 6 )cycloalkoxy, halo(C 4 -C 7 )cycloalkylalkoxy, (C 1 -C 6 )alkylthio, (C 3 -C 6 )cycloalkythio, (C 4 -C 7 )cycloalkylalkylthio, halo(C 1 -C 6 )alkylthio, halo(C 3 -C 6 )cycloalkythio, halo(C 4 -C 7 )cycloalkylalkylthio, (C 1 -C 6 )alkanesulfinyl, (C 3 -C 6 )cycloalkanesulfinyl, (C 4 -C 7 )cycloalkylalkanesulfinyl, halo(C 1 -C 6 )alkanesulfinyl, halo(C 3 -C 6 )cycloalkanesulfinyl, halo(C 4 -C 7 )cycloalkylalkanesulfinyl, (C 1 -C 6 )alkanesulfonyl, (C 3 -C 6 )cycloalkanesulfonyl, (C 4 -C 7 )cycloalkylalkanesulfonyl, halo(C 1 -C 6 )alkanesulfonyl, halo(C 3 -C 6 )cycloalkanesulfonyl, halo(C 4 -C 7 )cyclo-alkylalkanesulfonyl, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, H 2 NCO, H 2 NSO 2 , (C 1 -C 6 )alkylaminocarbonyl, di(C 1 -C 6 )alkylaminocarbonyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkylaminocarbonyl, heterocyclylcarbonyl, (C 1 -C 6 )alkylaminosulfonyl, di(C 1 -C 6 )alkylaminosulfonyl, heterocyclosulfonyl, (C 1 -C 6 )alkylcarbonylamino, (C 1 -C 6 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonylamino, (C 1 -C 6 )alkyl-sulfonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkoxy, heteroaryl oxo, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl amino(C 2 -C 6 )alkoxy, (C 1 -C 6 )alkylamino(C 2 -C 6 )alkoxy, di(C 1 -C 6 )alkylamino(C 2 -C 6 )alkoxy and (C 1 -C 6 )alkylcarbonyl;

A 2 is (a) a bond, O, S or NR 4 ; or (b) (C 1 -C 3 )alkylene or (C 1 -C 2 )alkyleneoxy, each of which is optionally substituted with 1 to 4 groups independently selected from methyl, ethyl, trifluoromethyl or oxo;

Cy 2 is (a) hydrogen or (b) aryl, heteroaryl, cycloalkyl or heterocyclyl and is optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, hydroxy(C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl(C 2 -C 4 )alkynyl, halo(C 1 -C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl, halo(C 4 -C 7 )cycloalkylalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, (C 4 -C 7 )cycloalkylalkoxy, halo(C 1 -C 6 )alkoxy, halo(C 3 -C 6 )cycloalkoxy, halo(C 4 -C 7 )cycloalkylalkoxy, (C 1 -C 6 )alkylthio, (C 3 -C 6 )cycloalkythio, (C 4 -C 7 )cycloalkylalkylthio, halo(C 1 -C 6 )alkylthio, halo(C 3 -C 6 )cycloalkythio, halo(C 4 -C 7 )cycloalkylalkylthio, (C 1 -C 6 )alkanesulfinyl, (C 3 -C 6 )cycloalkanesulfinyl, (C 4 -C 7 )cycloalkylalkanesulfinyl, halo(C 1 -C 6 )alkanesulfinyl, halo(C 3 -C 6 )cycloalkanesulfinyl, halo(C 4 -C 7 )cycloalkyl-alkanesulfinyl, (C 1 -C 6 )alkanesulfonyl, (C 3 -C 6 )cycloalkanesulfonyl, (C 4 -C 7 )cycloalkyl-alkanesulfonyl, halo(C 1 -C 6 )alkanesulfonyl, halo(C 3 -C 6 )cycloalkanesulfonyl, halo(C 4 -C 7 )cyclo-alkylalkanesulfonyl, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, H 2 NCO, H 2 NSO 2 , (C 1 -C 6 )alkylaminocarbonyl, di(C 1 -C 6 )alkylaminocarbonyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkylaminocarbonyl, heterocyclylcarbonyl, (C 1 -C 6 )alkylaminosulfonyl, di(C 1 -C 6 )alkylaminosulfonyl, heterocyclosulfonyl, (C 1 -C 6 )alkylcarbonylamino, (C 1 -C 6 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonylamino, (C 1 -C 6 )alkylsulfonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkoxy, heteroaryl, oxo, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl amino(C 2 -C 6 )alkoxy, (C 1 -C 6 )alkylamino(C 2 -C 6 )alkoxy, di(C 1 -C 6 )alkylamino(C 2 -C 6 )alkoxy and (C 1 -C 6 )alkylcarbonyl. In one aspect, the heterocyclyl represented by Cy 2 is other than optionally substituted thiazolidine-2,4-dionyl;

›SUMMARY OF THE INVENTION · 2 of 8

Y is (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl or oxo;

n is 0, 1 or 2;

E is (a) a bond or (b) (C 1 -C 3 )alkylene or (C 1 -C 2 )alkylenyloxy, wherein the O is attached to R 2 , each of which is optionally substituted with 1 to 4 groups independently selected from methyl, ethyl, trifluoromethyl or oxo;

R 2 is (C 1 -C 6 )alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl and is optionally substituted with up to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, hydroxy(C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl(C 2 -C 4 )alkynyl, halo(C 1 -C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl, halo(C 4 -C 7 )cycloalkylalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, (C 4 -C 7 )cycloalkylalkoxy, halo(C 1 -C 6 )alkoxy, halo(C 3 -C 6 )cycloalkoxy, halo(C 4 -C 7 )cycloalkylalkoxy, (C 1 -C 6 )alkylthio, (C 3 -C 6 )cycloalkythio, (C 4 -C 7 )cycloalkylalkylthio, halo(C 1 -C 6 )alkylthio, halo(C 3 -C 6 )cycloalkythio, halo(C 4 -C 7 )cycloalkylalkylthio, (C 1 -C 6 )alkanesulfinyl, (C 3 -C 6 )cycloalkanesulfinyl, (C 4 -C 7 )cycloalkylalkanesulfinyl, halo(C 1 -C 6 )alkanesulfinyl, halo(C 3 -C 6 )cycloalkanesulfinyl, halo(C 4 -C 7 )cycloalkyl-alkanesulfinyl, (C 1 -C 6 )alkanesulfonyl, (C 3 -C 6 )cycloalkanesulfonyl, (C 4 -C 7 )cycloalkyl-alkanesulfonyl, halo(C 1 -C 6 )alkanesulfonyl, halo(C 3 -C 6 )cycloalkanesulfonyl, halo(C 4 -C 7 )cyclo-alkylalkanesulfonyl, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, H 2 NCO, H 2 NSO 2 , (C 1 -C 6 )alkylaminocarbonyl, di(C 1 -C 6 )alkylaminocarbonyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkylaminocarbonyl, heterocyclylcarbonyl, (C 1 -C 6 )alkylaminosulfonyl, di(C 1 -C 6 )alkylaminosulfonyl, heterocyclosulfonyl, (C 1 -C 6 )alkylcarbonylamino, (C 1 -C 6 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonylamino, (C 1 -C 6 )alkylsulfonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkoxy, heteroaryl, oxo, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl amino(C 2 -C 6 )alkoxy, (C 1 -C 6 )alkylamino(C 2 -C 6 )alkoxy, di(C 1 -C 6 )alkylamino(C 2 -C 6 )alkoxy and (C 1 -C 6 )alkylcarbonyl;

R 3 is selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 5 )cycloalkyl(C 1 -C 4 )alkyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkoxy, or (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl and is optionally substituted with up to four groups independently selected from fluorine, cyano, oxo, R 4 , R 4 O—, (R 4 ) 2 N—, R 4 O 2 C—, R 4 C(═O)O—, R 4 S, R 4 S(═O)—, R 4 S(═O) 2 —, R 4 C(═O)NR 4 —, (R 4 ) 2 NC(═O)—, (R 4 ) 2 NC(═O)O—, (R 4 ) 2 NC(═O)NR 4 —, R 4 OC(═O)NR 4 —, (R 4 ) 2 NC(═NCN)NR 4 —, (R 4 O) 2 P(═O)O—, (R 4 O) 2 P(═O)NR 4 —, R 4 OS(═O) 2 NR 4 —, (R 4 ) 2 NS(═O) 2 O—, (R 4 ) 2 NS(═O) 2 NR 4 —, R 4 S(═O) 2 NR 4 —, R 4 S(═O) 2 NHC(═O)—, R 4 S(═O) 2 NHC(═O)O—, R 4 S(═O) 2 NHC(═O)NR 4 —, R 4 OS(═O) 2 NHC(═O)—, R 4 OS(═O) 2 NHC(═O)O—, R 4 OS(═O) 2 NHC(═O)NR 4 —, (R 4 ) 2 NS(═O) 2 NHC(═O)—, (R 4 ) 2 NS(═O) 2 NHC(═O)O—, (R 4 ) 2 NS(═O) 2 NHC(═O)NR 4 —, R 4 C(═O)NHS(═O) 2 —, R 4 C(═O)NHS(═O) 2 O—, R 4 C(═O)NHS(═O) 2 NR 4 —, R 4 OC(═O)NHS(═O) 2 —, R 4 OC(═O)NHS(═O) 2 O—, R 4 OC(═O)NHS(═O) 2 NR 4 —, (R 4 ) 2 NC(═O)NHS(═O) 2 —, (R 4 ) 2 NC(═O)NHS(═O) 2 O—, (R 4 ) 2 NC(═O)NHS(═O) 2 NR 4 —, spirocycloalkyl; heterocyclyl (which in turn may be optionally substituted with alkyl, haloalkyl, halogen or oxo), heteroaryl (which in turn may be optionally substituted with alkyl, haloalkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO 2 H, CONH 2 , N-monoalkyl-substituted amido, N,N-dialkyl-substituted amido, or oxo), arylamino (which in turn may be optionally substituted with alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO 2 H, CONH 2 , N-monoalkyl-substituted amido and N,N-dialkyl-substituted amido) and heteroarylamino (which in turn may be optionally substituted with alkyl, haloalkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO 2 H, CONH 2 , N-monoalkyl-substituted amido, N,N-dialkyl-substituted amido, or oxo); and

R 4 is independently selected from H, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl and (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

In a second embodiment, Formula I and its constituent members are defined herein as follows:

R 1 is (a) absent or (b) is selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkoxy, or (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl and is optionally substituted with up to four groups independently selected from fluorine, cyano, oxo, R 4 , R 4 O—, (R 4 ) 2 N—, R 4 O 2 C—, R 4 S, R 4 S(═O)—, R 4 S(═O) 2 —, R 4 C(═O)NR 4 —, (R 4 ) 2 NC(═O)—, (R 4 ) 2 NC(═O)O—, (R 4 ) 2 NC(═O)NR 4 —, R 4 OC(═O)NR 4 —, (R 4 ) 2 NC(═NCN)NR 4 —, (R 4 O) 2 P(═O)O—, (R 4 O) 2 P(═O)NR 4 —, R 4 OS(═O) 2 NR 4 —, (R 4 ) 2 NS(═O) 2 O—, (R 4 ) 2 NS(═O) 2 NR 4 —, R 4 S(═O) 2 NR 4 —, R 4 S(═O) 2 NHC(═O)—, R 4 S(═O) 2 NHC(═O)O—, R 4 S(═O) 2 NHC(═O)NR 4 OS(═O) 2 NHC(═O)—, R 4 OS(═O) 2 NHC(═O)O—, R 4 OS(═O) 2 NHC(═O)N(R 4 ) 2 NS(═O) 2 NHC(═O)—, (R 4 ) 2 NS(═O) 2 NHC(═O)O—, (R 4 ) 2 NS(═O) 2 NHC(═O)NR 4 —, R 4 C(═O)NHS(═O) 2 —, R 4 C(═O)NHS(═O) 2 O—, R 4 C(═O)NHS(═O) 2 NR 4 —, R 4 OC(═O)NHS(═O) 2 —, R 4 OC(═O)NHS(═O) 2 O—, R 4 OC(═O)NHS(═O) 2 NR 4 —, (R 4 ) 2 NC(═O)NHS(═O) 2 —, (R 4 ) 2 NC(═O)NHS(═O) 2 O—, (R 4 ) 2 NC(═O)NHS(═O) 2 NR 4 —, heterocyclyl, heteroaryl, arylamino and heteroarylamino;

›SUMMARY OF THE INVENTION · 3 of 8

A 1 is (a) a bond, or (b) (C 1 -C 3 )alkylene, CH 2 CH 2 O, wherein the oxygen is attached to Cy 1 , or CH 2 C(═O), wherein the carbonyl carbon is attached to Cy 1 ;

Cy 1 is aryl, heteroaryl, monocyclic cycloalkyl or monocyclic heterocyclyl and is optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, hydroxy(C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl(C 2 -C 4 )alkynyl, halo(C 1 -C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl, halo(C 4 -C 7 )cycloalkylalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, (C 4 -C 7 )cycloalkylalkoxy, halo(C 1 -C 6 )alkoxy, halo(C 3 -C 6 )cycloalkoxy, halo(C 4 -C 7 )cycloalkylalkoxy, (C 1 -C 6 )alkylthio, (C 3 -C 6 )cycloalkythio, (C 4 -C 7 )cycloalkylalkylthio, halo(C 1 -C 6 )alkylthio, halo(C 3 -C 6 )cycloalkythio, halo(C 4 -C 7 )cycloalkylalkylthio, (C 1 -C 6 )alkanesulfinyl, (C 3 -C 6 )cycloalkanesulfinyl, (C 4 -C 7 )cycloalkylalkanesulfinyl, halo(C 1 -C 6 )alkanesulfinyl, halo(C 3 -C 6 )cycloalkanesulfinyl, halo(C 4 -C 7 )cycloalkylalkanesulfinyl, (C 1 -C 6 )alkanesulfonyl, (C 3 -C 6 )cycloalkanesulfonyl, (C 4 -C 7 )cycloalkylalkanesulfonyl, halo(C 1 -C 6 )alkanesulfonyl, halo(C 3 -C 6 )cycloalkanesulfonyl, halo(C 4 -C 7 )cyclo-alkylalkanesulfonyl, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, H 2 NCO, H 2 NSO 2 , (C 1 -C 6 )alkylaminocarbonyl, di(C 1 -C 6 )alkylaminocarbonyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkylaminocarbonyl, heterocyclylcarbonyl, (C 1 -C 6 )alkylaminosulfonyl, di(C 1 -C 6 )alkylaminosulfonyl, heterocyclosulfonyl, (C 1 -C 6 )alkylcarbonylamino, (C 1 -C 6 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonylamino, (C 1 -C 6 )alkyl-sulfonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkoxy, heteroaryl, oxo, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl amino(C 2 -C 6 )alkoxy, (C 1 -C 6 )alkylamino(C 2 -C 6 )alkoxy, di(C 1 -C 6 )alkylamino(C 2 -C 6 )alkoxy and (C 1 -C 6 )alkylcarbonyl;

Y is (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl or oxo;

n is 0, 1 or 2;

›SUMMARY OF THE INVENTION · 4 of 8

R 3 is selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkoxy or (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl and is optionally substituted with up to four groups independently selected from fluorine, cyano, oxo, R 4 , R 4 O—, (R 4 ) 2 N—, R 4 O 2 C—, R 4 S, R 4 S(═O)—, R 4 S(═O) 2 —, R 4 C(═O)NR 4 —, (R 4 ) 2 NC(═O)—, (R 4 ) 2 NC(═O)O—, (R 4 ) 2 NC(═O)NR 4 —, R 4 OC(═O)NR 4 —, (R 4 ) 2 NC(═NCN)NR 4 —, (R 4 O) 2 P(═O)O—, (R 4 O) 2 P(═O)NR 4 —, R 4 OS(═O) 2 NR 4 —, (R 4 ) 2 NS(═O) 2 O—, (R 4 ) 2 NS(═O) 2 NR 4 —, R 4 S(═O) 2 NR 4 —, R 4 S(═O) 2 NHC(═O)—, R 4 S(═O) 2 NHC(═O)O—, R 4 S(═O) 2 NHC(═O)NR 4 —, R 4 OS(═O) 2 NHC(═O)—, R 4 OS(═O) 2 NHC(═O)O—, R 4 OS(═O) 2 NHC(═O)NR 4 —, (R 4 ) 2 NS(═O) 2 NHC(═O)—, (R 4 ) 2 NS(═O) 2 NHC(═O)O—, (R 4 ) 2 NS(═O) 2 NHC(═O)NR 4 —, R 4 C(═O)NHS(═O) 2 —, R 4 C(═O)NHS(═O) 2 O—, R 4 C(═O)NHS(═O) 2 NR 4 —, R 4 OC(═O)NHS(═O) 2 —, R 4 OC(═O)NHS(═O) 2 O—, R 4 OC(═O)NHS(═O) 2 NR 4 —, (R 4 ) 2 NC(═O)NHS(═O) 2 —, (R 4 ) 2 NC(═O)NHS(═O) 2 O—, (R 4 ) 2 NC(═O)NHS(═O) 2 NR 4 —, heterocyclyl (which in turn may be optionally substituted with alkyl, haloalkyl or oxo), heteroaryl (which in turn may be optionally substituted with alkyl, haloalkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO 2 H, CONH 2 , N-monoalkyl-substituted amido, N,N-dialkyl-substituted amido, or oxo), arylamino (which in turn may be optionally substituted with alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO 2 H, CONH 2 , N-monoalkyl-substituted amido and N,N-dialkyl-substituted amido) and heteroarylamino (which in turn may be optionally substituted with alkyl, haloalkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO 2 H, CONH 2 , N-monoalkyl-substituted amido, N,N-dialkyl-substituted amido, or oxo); and

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

In a third embodiment, Formula I and its constituent members are defined herein as follows:

R 1 is absent or is selected from (C 1 -C 6 )alkyl or (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl or (C 1 -C 3 )alkoxy(C 1 -C 3 )alkoxy and is optionally substituted with up to four groups independently selected from fluorine, cyano, oxo, R 4 , R 4 O—, (R 4 ) 2 N—, R 4 O 2 C—, R 4 S, R 4 S(═O)—, R 4 S(═O) 2 —, R 4 C(═O)NR 4 —, (R 4 ) 2 NC(═O)—, (R 4 ) 2 NC(═O)O—, (R 4 ) 2 NC(═O)NR 4 , R 4 OC(═O)NR 4 —, (R 4 ) 2 NC(═NCN)NR 4 —, (R 4 O) 2 P(═O)O—, (R 4 O) 2 P(═O)NR 4 —, R 4 OS(═O) 2 NR 4 —, (R 4 ) 2 NS(═O) 2 O—, (R 4 ) 2 NS(═O) 2 NR 4 —, R 4 S(═O) 2 NR 4 —, R 4 S(═O) 2 NHC(═O)—, R 4 S(═O) 2 NHC(═O)O—, R 4 S(═O) 2 NHC(═O)NR 4 —, R 4 OS(═O) 2 NHC(═O)—, R 4 OS(═O) 2 NHC(═O)O—, R 4 OS(═O) 2 NHC(═O)NR 4 —, (R 4 ) 2 NS(═O) 2 NHC(═O)—, (R 4 ) 2 NS(═O) 2 NHC(═O)O—, (R 4 ) 2 NS(═O) 2 NHC(═O)NR 4 —, R 4 C(═O)NHS(═O) 2 —, R 4 C(═O)NHS(═O) 2 O—, R 4 C(═O)NHS(═O) 2 NR 4 —, R 4 OC(═O)NHS(═O) 2 —, R 4 OC(═O)NHS(═O) 2 O—, R 4 OC(═O)NHS(═O) 2 NR 4 —, (R 4 ) 2 NC(═O)NHS(═O) 2 —, (R 4 ) 2 NC(═O)NHS(═O) 2 O—, (R 4 ) 2 NC(═O)NHS(═O) 2 NR 4 —, heterocyclyl, heteroaryl, arylamino and heteroarylamino;

A 1 is (a) a bond, or (b) (C 1 -C 3 )alkylene, CH 2 CH 2 O, wherein the oxygen is attached to Cy 1 , or CH 2 C(═O), wherein the carbonyl carbon is attached to Cy 1 ;

Cy 1 is aryl, heteroaryl, monocyclic cycloalkyl or monocyclic heterocyclyl each optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl(C 2 -C 4 )alkynyl, halo(C 1 -C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl, halo(C 4 -C 7 )cycloalkylalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, (C 4 -C 7 )cycloalkylalkoxy, halo(C 1 -C 6 )alkoxy, halo(C 3 -C 6 )cycloalkoxy, halo(C 4 -C 7 )cycloalkylalkoxy, (C 1 -C 6 )alkylthio, (C 3 -C 6 )cycloalkythio, (C 4 -C 7 )cycloalkylalkylthio, halo(C 1 -C 6 )alkylthio, halo(C 3 -C 6 )cycloalkythio, halo(C 4 -C 7 )cycloalkylalkylthio, (C 1 -C 6 )alkanesulfinyl, (C 3 -C 6 )cycloalkanesulfinyl, (C 4 -C 7 )cycloalkylalkanesulfinyl, halo(C 1 -C 6 )alkanesulfinyl, halo(C 3 -C 6 )cycloalkanesulfinyl, halo(C 4 -C 7 )cycloalkylalkanesulfinyl, (C 1 -C 6 )alkanesulfonyl, (C 3 -C 6 )cycloalkanesulfonyl, (C 4 -C 7 )cycloalkylalkanesulfonyl, halo(C 1 -C 6 )alkanesulfonyl, halo(C 3 -C 6 )cycloalkanesulfonyl, halo(C 4 -C 7 )cyclo-alkylalkanesulfonyl, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, H 2 NCO, H 2 NSO 2 , (C 1 -C 6 )alkylaminocarbonyl, di(C 1 -C 6 )alkylaminocarbonyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkylaminocarbonyl, heterocyclylcarbonyl, (C 1 -C 6 )alkylaminosulfonyl, di(C 1 -C 6 )alkylaminosulfonyl, heterocyclosulfonyl, (C 1 -C 6 )alkylcarbonylamino, (C 1 -C 6 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonylamino, (C 1 -C 6 )alkylsulfonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkoxy, heteroaryl and oxo;

A 2 is (a) a bond, O, S or NR 4 ; or (b) (C 1 -C 3 )alkylene, (C 1 -C 2 )alkyleneoxy, each of which is optionally substituted with 1 to 4 groups independently selected from methyl, ethyl, trifluoromethyl or oxo;

Cy 2 is (a) hydrogen or (b) aryl, heteroaryl, cycloalkyl or heterocyclyl each optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl(C 2 -C 4 )alkynyl, halo(C 1 -C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl, halo(C 4 -C 7 )cycloalkylalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, (C 4 -C 7 )cycloalkylalkoxy, halo(C 1 -C 6 )alkoxy, halo(C 3 -C 6 )cycloalkoxy, halo(C 4 -C 7 )cycloalkylalkoxy, (C 1 -C 6 )alkylthio, (C 3 -C 6 )cycloalkythio, (C 4 -C 7 )cycloalkylalkylthio, halo(C 1 -C 6 )alkylthio, halo(C 3 -C 6 )cycloalkythio, halo(C 4 -C 7 )cycloalkylalkylthio, (C 1 -C 6 )alkanesulfinyl, (C 3 -C 6 )cycloalkanesulfinyl, (C 4 -C 7 )cycloalkylalkanesulfinyl, halo(C 1 -C 6 )alkanesulfinyl, halo(C 3 -C 6 )cycloalkanesulfinyl, halo(C 4 -C 7 )cycloalkylalkanesulfinyl, (C 1 -C 6 )alkanesulfonyl, (C 3 -C 6 )cycloalkanesulfonyl, (C 4 -C 7 )cycloalkylalkanesulfonyl, halo(C 1 -C 6 )alkanesulfonyl, halo(C 3 -C 6 )cycloalkanesulfonyl, halo(C 4 -C 7 )cyclo-alkylalkanesulfonyl, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, H 2 NCO, H 2 NSO 2 , (C 1 -C 6 )alkylaminocarbonyl, di(C 1 -C 6 )alkylaminocarbonyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkylaminocarbonyl, heterocyclylcarbonyl, (C 1 -C 6 )alkylaminosulfonyl, di(C 1 -C 6 )alkylaminosulfonyl, heterocyclosulfonyl, (C 1 -C 6 )alkylcarbonylamino, (C 1 -C 6 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonylamino, (C 1 -C 6 )alkylsulfonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkoxy, heteroaryl and oxo;

›SUMMARY OF THE INVENTION · 5 of 8

Y is (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl or oxo;

n is 0, 1 or 2;

E is (a) a bond or (b) (C 1 -C 3 )alkylene, (C 1 -C 2 )alkylenyloxy, wherein the O is attached to R 2 , each of which is optionally substituted with 1 to 4 groups independently selected from methyl, ethyl, trifluoromethyl or oxo;

R 2 is (C 1 -C 6 )alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl and is optionally substituted with up to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl(C 2 -C 4 )alkynyl, halo(C 1 -C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl, halo(C 4 -C 7 )cycloalkylalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, (C 4 -C 7 )cycloalkylalkoxy, halo(C 1 -C 6 )alkoxy, halo(C 3 -C 6 )cycloalkoxy, halo(C 4 -C 7 )cycloalkylalkoxy, (C 1 -C 6 )alkylthio, (C 3 -C 6 )cycloalkythio, (C 4 -C 7 )cycloalkylalkylthio, halo(C 1 -C 6 )alkylthio, halo(C 3 -C 6 )cycloalkythio, halo(C 4 -C 7 )cycloalkylalkylthio, (C 1 -C 6 )alkanesulfinyl, (C 3 -C 6 )cycloalkanesulfinyl, (C 4 -C 7 )cycloalkylalkanesulfinyl, halo(C 1 -C 6 )alkanesulfinyl, halo(C 3 -C 6 )cycloalkanesulfinyl, halo(C 4 -C 7 )cycloalkylalkanesulfinyl, (C 1 -C 6 )alkanesulfonyl, (C 3 -C 6 )cycloalkanesulfonyl, (C 4 -C 7 )cycloalkylalkanesulfonyl, halo(C 1 -C 6 )alkanesulfonyl, halo(C 3 -C 6 )cycloalkanesulfonyl, halo(C 4 -C 7 )cyclo-alkylalkanesulfonyl, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, H 2 NCO, H 2 NSO 2 , (C 1 -C 6 )alkylaminocarbonyl, di(C 1 -C 6 )alkylaminocarbonyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkylaminocarbonyl, heterocyclylcarbonyl, (C 1 -C 6 )alkylaminosulfonyl, di(C 1 -C 6 )alkylaminosulfonyl, heterocyclosulfonyl, (C 1 -C 6 )alkylcarbonylamino, (C 1 -C 6 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonylamino, (C 1 -C 6 )alkylsulfonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkoxy, heteroaryl or oxo;

R 3 is selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl or (C 1 -C 3 )alkoxy(C 1 -C 3 )alkoxy and is optionally substituted with up to four groups independently selected from fluorine, cyano, oxo, R 4 , R 4 O—, (R 4 ) 2 N—, R 4 O 2 C—, R 4 S, R 4 S(═O)—, R 4 S(═O) 2 —, R 4 C(═O)NR 4 —, (R 4 ) 2 NC(═O)—, (R 4 ) 2 NC(═O)O—, (R 4 ) 2 NC(═O)NR 4 —, R 4 OC(═O)NR 4 —, (R 4 ) 2 NC(═NCN)NR 4 —, (R 4 O) 2 P(═O)O—, (R 4 O) 2 P(═O)NR 4 —, R 4 OS(═O) 2 NR 4 —, (R 4 ) 2 NS(═O) 2 O—, (R 4 ) 2 NS(═O) 2 NR 4 —, R 4 S(═O) 2 NR 4 —, R 4 S(═O) 2 NHC(═O)—, R 4 S(═O) 2 NHC(═O)O—, R 4 S(═O) 2 NHC(═O)NR 4 —, R 4 OS(═O) 2 NHC(═O)—, R 4 OS(═O) 2 NHC(═O)O—, R 4 OS(═O) 2 NHC(═O)NR 4 —, (R 4 ) 2 NS(═O) 2 NHC(═O)—, (R 4 ) 2 NS(═O) 2 NHC(═O)O—, (R 4 ) 2 NS(═O) 2 NHC(═O)NR 4 —, R 4 C(═O)NHS(═O) 2 —, R 4 C(═O)NHS(═O) 2 O—, R 4 C(═O)NHS(═O) 2 NR 4 —, R 4 OC(═O)NHS(═O) 2 —, R 4 OC(═O)NHS(═O) 2 O—, R 4 OC(═O)NHS(═O) 2 NR 4 —, (R 4 ) 2 NC(═O)NHS(═O) 2 —, (R 4 ) 2 NC(═O)NHS(═O) 2 O—, (R 4 ) 2 NC(═O)NHS(═O) 2 NR 4 —, heterocyclyl (which in turn may be optionally substituted with alkyl, haloalkyl or oxo), heteroaryl which in turn may be optionally substituted with alkyl, haloalkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO 2 H, CONH 2 , N-monoalkyl-substituted amido, N,N-dialkyl-substituted amido, or oxo), arylamino (which in turn may be optionally substituted with alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO 2 H, CONH 2 , N-monoalkyl-substituted amido and N,N-dialkyl-substituted amido) and heteroarylamino (which in turn may be optionally substituted with alkyl, haloalkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO 2 H, CONH 2 , N-monoalkyl-substituted amido, N,N-dialkyl-substituted amido, or oxo); and

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

In a fourth embodiment,

R 1 is (a) absent or (b) is selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkoxy, or (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl and is optionally substituted with up to four groups independently selected from fluorine, cyano, oxo, R 4 , R 4 O—, (R 4 ) 2 N—, R 4 O 2 C—, R 4 S, R 4 S(═O)—, R 4 S(═O) 2 —, R 4 C(═O)NR 4 —, (R 4 ) 2 NC(═O)—, (R 4 ) 2 NC(═O)O—, (R 4 ) 2 NC(═O)NR 4 —, R 4 OC(═O)NR 4 —, (R 4 ) 2 NC(═NCN)NR 4 —, (R 4 O) 2 P(═O)O—, (R 4 O) 2 P(═O)NR 4 —, R 4 OS(═O) 2 NR 4 —, (R 4 ) 2 NS(═O) 2 O—, (R 4 ) 2 NS(═O) 2 NR 4 —, R 4 S(═O) 2 NR 4 —, R 4 S(═O) 2 NHC(═O)—, R 4 S(═O) 2 NHC(═O)O—, R 4 S(═O) 2 NHC(═O)NR 4 —, R 4 OS(═O) 2 NHC(═O)—, R 4 OS(═O) 2 NHC(═O)O—, R 4 OS(═O) 2 NHC(═O)NR 4 —, (R 4 ) 2 NS(═O) 2 NHC(═O)—, (R 4 ) 2 NS(═O) 2 NHC(═O)O—, (R 4 ) 2 NS(═O) 2 NHC(═O)NR 4 —, R 4 C(═O)NHS(═O) 2 —, R 4 C(═O)NHS(═O) 2 O—, R 4 C(═O)NHS(═O) 2 NR 4 , R 4 OC(═O)NHS(═O) 2 —, R 4 OC(═O)NHS(═O) 2 O—, R 4 OC(═O)NHS(═O) 2 NR 4 —, (R 4 ) 2 NC(═O)NHS(═O) 2 —, (R 4 ) 2 NC(═O)NHS(═O) 2 O—, (R 4 ) 2 NC(═O)NHS(═O) 2 NR 4 —, heterocyclyl, heteroaryl, arylamino and heteroarylamino;

A 1 is (a) a bond, or (b) (C 1 )alkylene, CH 2 CH 2 O, wherein the oxygen is attached to Cy 1 , or CH 2 C(═O), wherein the carbonyl carbon is attached to Cy 1 ;

Cy 1 is aryl, heteroaryl, monocyclic cycloalkyl or monocyclic heterocyclyl, each optionally substituted with 1 to 4 groups independently selected from nitro, amino, hydroxy, carboxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, hydroxy(C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl(C 2 -C 4 )alkynyl, halo(C 1 -C 6 )alkyl, halo(C 4 -C 7 )cycloalkylalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, (C 4 -C 7 )cycloalkylalkoxy, halo(C 1 -C 6 )alkoxy, halo(C 3 -C 6 )cycloalkoxy, halo(C 4 -C 7 )cycloalkylalkoxy, (C 1 -C 6 )alkylthio, (C 3 -C 6 )cycloalkythio, (C 4 -C 7 )cycloalkylalkylthio, halo(C 1 -C 6 )alkylthio, halo(C 3 -C 6 )cycloalkythio, halo(C 4 -C 7 )cycloalkylalkylthio, (C 1 -C 6 )alkanesulfinyl, (C 3 -C 6 )cycloalkanesulfinyl, (C 4 -C 7 )cycloalkylalkanesulfinyl, halo(C 1 -C 6 )alkanesulfinyl, halo(C 3 -C 6 )cycloalkanesulfinyl, halo(C 4 -C 7 )cycloalkylalkanesulfinyl, (C 1 -C 6 )alkanesulfonyl, (C 3 -C 6 )cycloalkanesulfonyl, (C 4 -C 7 )cycloalkylalkanesulfonyl, halo(C 1 -C 6 )alkanesulfonyl, halo(C 3 -C 6 )cycloalkanesulfonyl, halo(C 4 -C 7 )cyclo-alkylalkanesulfonyl, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, H 2 NCO, H 2 NSO 2 , (C 1 -C 6 )alkylaminocarbonyl, di(C 1 -C 6 )alkylaminocarbonyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkylaminocarbonyl, heterocyclylcarbonyl, (C 1 -C 6 )alkylaminosulfonyl, di(C 1 -C 6 )alkylaminosulfonyl, heterocyclosulfonyl, (C 1 -C 6 )alkylcarbonylamino, (C 1 -C 6 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonylamino, (C 1 -C 6 )alkylsulfonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkoxy, oxo, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl amino(C 2 -C 6 )alkoxy, (C 1 -C 6 )alkylamino(C 2 -C 6 )alkoxy, di(C 1 -C 6 )alkylamino(C 2 -C 6 )alkoxy and (C 1 -C 6 )alkylcarbonyl; or if the substitution is either meta or para to A 1 , the substituents may also include optionally substituted cycloalkyl, optionally substituted halo cycloalkyl or optionally substituted heteroaryl.

›SUMMARY OF THE INVENTION · 6 of 8

Cy 2 is meta or para to A 1 and is (a) hydrogen or (b) aryl, heteroaryl, cycloalkyl, pyrrolidine, pyrrolidin-2-one, 1-methylpyrrolidin-2-one, piperidine, piperidin-2-one, dihydropyridine, tetrahydropyridine, piperazine, 1-(2,2,2-trifluoroethyl)piperazine, 1,2-dihydro-2-oxopyridine, 1,4-dihydro-4-oxopyridine, piperazin-2-one, 3,4,5,6-tetrahydro-4-oxopyrimidine, 3,4-dihydro-4-oxopyrimidine, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, tetrahydrothiopyran, isoxazolidine, 1,3-dioxolane, 1,3-dithiolane, 1,3-dioxane, 1,4-dioxane, 1,3-dithiane, 1,4-dithiane, oxazolidin-2-one, imidazolidin-2-one, imidazolidine-2,4-dione, tetrahydropyrimidin-2(1H)-one, morpholine, N-methylmorpholine, morpholin-3-one, 1,3-oxazinan-2-one, thiomorpholine, thiomorpholine 1,1-dioxide, tetrahydro-1,2,5-thiaoxazole 1,1-dioxide, tetrahydro-2H-1,2-thiazine 1,1-dioxide, hexahydro-1,2,6-thiadiazine 1,1-dioxide, tetrahydro-1,2,5-thiadiazole 1,1-dioxide isothiazolidine 1,1-dioxide, 6-oxo-1,6-dihydropyridazin-3-yl, 6-oxo-1,6-dihydropyridazin-4-yl, 5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl and 5-oxo-4,5-dihydro-1H-imidazol-2-yl optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, hydroxy(C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl(C 2 -C 4 )alkynyl, halo(C 1 -C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl, halo(C 4 -C 7 )cycloalkylalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, (C 4 -C 7 )cycloalkylalkoxy, halo(C 1 -C 6 )alkoxy, halo(C 3 -C 6 )cycloalkoxy, halo(C 4 -C 7 )cycloalkylalkoxy, (C 1 -C 6 )alkylthio, (C 3 -C 6 )cycloalkythio, (C 4 -C 7 )cycloalkyl-alkylthio, halo(C 1 -C 6 )alkylthio, halo(C 3 -C 6 )cycloalkythio, halo(C 4 -C 7 )cycloalkylalkylthio, (C 1 -C 6 )alkanesulfinyl, (C 3 -C 6 )cycloalkanesulfinyl, (C 4 -C 7 )cycloalkylalkanesulfinyl, halo(C 1 -C 6 )alkanesulfinyl, halo(C 3 -C 6 )cycloalkanesulfinyl, halo(C 4 -C 7 )cycloalkylalkanesulfinyl, (C 1 -C 6 )alkanesulfonyl, (C 3 -C 6 )cycloalkanesulfonyl, (C 4 -C 7 )cycloalkylalkanesulfonyl, halo(C 1 -C 6 )alkanesulfonyl, halo(C 3 -C 6 )cycloalkanesulfonyl, halo(C 4 -C 7 )cyclo-alkylalkanesulfonyl, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylaminocarbonyl, di(C 1 -C 6 )alkylaminocarbonyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkylaminocarbonyl, heterocyclylcarbonyl, (C 1 -C 6 )alkylaminosulfonyl, di(C 1 -C 6 )alkylaminosulfonyl, heterocyclosulfonyl, (C 1 -C 6 )alkylcarbonylamino, (C 1 -C 6 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonylamino, (C 1 -C 6 )alkylsulfonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, halo(C 1 -C 8 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkoxy, heteroaryl, oxo, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl amino(C 2 -C 6 )alkoxy, (C 1 -C 6 )alkylamino(C 2 -C 6 )alkoxy, di(C 1 -C 6 )alkylamino(C 2 -C 6 )alkoxy and (C 1 -C 6 )alkylcarbonyl;

Y is (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl or oxo;

n is 0, 1 or 2;

R 3 is selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl(C 1 -C 4 )alkyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkoxy, or (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl and is optionally substituted with up to four groups independently selected from fluorine, cyano, oxo, R 4 , R 4 O—, (R 4 ) 2 N—, R 4 O 2 C—, R 4 C(═O)O—, R 4 S, R 4 S(═O)—, R 4 S(═O) 2 —, R 4 C(═O)NR 4 , (R 4 ) 2 NC(═O)—, (R 4 ) 2 NC(═O)O—, (R 4 ) 2 NC(═O)NR 4 —, R 4 OC(═O)NR 4 —, (R 4 ) 2 NC(═NCN)NR 4 —, (R 4 O) 2 P(═O)O—, (R 4 O) 2 P(═O)NR 4 —, R 4 OS(═O) 2 NR 4 —, (R 4 ) 2 NS(═O) 2 O—, (R 4 ) 2 NS(═O) 2 NR 4 —, R 4 S(═O) 2 NR 4 —, R 4 S(═O) 2 NHC(═O)—, R 4 S(═O) 2 NHC(═O)O—, R 4 S(═O) 2 NHC(═O)NR 4 —, R 4 OS(═O) 2 NHC(═O)—, R 4 OS(═O) 2 NHC(═O)O—, R 4 OS(═O) 2 NHC(═O)NR 4 —, (R 4 ) 2 NS(═O) 2 NHC(═O)—, (R 4 ) 2 NS(═O) 2 NHC(═O)O—, (R 4 ) 2 NS(═O) 2 NHC(═O)NR 4 —, R 4 C(═O)NHS(═O) 2 —, R 4 C(═O)NHS(═O) 2 O—, R 4 C(═O)NHS(═O) 2 NR 4 —, R 4 OC(═O)NHS(═O) 2 —, R 4 OC(═O)NHS(═O) 2 O—, R 4 OC(═O)NHS(═O) 2 NR 4 —, (R 4 ) 2 NC(═O)NHS(═O) 2 —, (R 4 ) 2 NC(═O)NHS(═O) 2 O—, (R 4 ) 2 NC(═O)NHS(═O) 2 NR 4 —, spirocycloalkyl; heterocyclyl (which in turn may be optionally substituted with alkyl, haloalkyl, halogen or oxo), heteroaryl (which in turn may be optionally substituted with alkyl, haloalkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO 2 H, CONH 2 , N-monoalkyl-substituted amido, N,N-dialkyl-substituted amido, or oxo), arylamino (which in turn may be optionally substituted with alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO 2 H, CONH 2 , N-monoalkyl-substituted amido and N,N-dialkyl-substituted amido) and heteroarylamino (which in turn may be optionally substituted with alkyl, haloalkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO 2 H, CONH 2 , N-monoalkyl-substituted amido, N,N-dialkyl-substituted amido, or oxo); and

›SUMMARY OF THE INVENTION · 7 of 8

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof; and the remainder of the variables are as defined as for the first, second or third embodiments.

In a fifth embodiment,

n is 0;

A 1 is (a) a bond, or (b) (C 1 )alkylene, CH 2 CH 2 O, wherein the oxygen is attached to Cy 1 , or CH 2 C(═O), wherein the carbonyl carbon is attached to Cy 1 ;

Cy 1 is aryl, heteroaryl, monocyclic cycloalkyl or monocyclic heterocyclyl, each optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, hydroxy(C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl(C 2 -C 4 )alkynyl, halo(C 1 -C 6 )alkyl, halo(C 4 -C 7 )cycloalkylalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, (C 4 -C 7 )cycloalkylalkoxy, halo(C 1 -C 6 )alkoxy, halo(C 3 -C 6 )cycloalkoxy, halo(C 4 -C 7 )cycloalkylalkoxy, (C 1 -C 6 )alkylthio, (C 3 -C 6 )cycloalkythio, (C 4 -C 7 )cycloalkylalkylthio, halo(C 1 -C 6 )alkylthio, halo(C 3 -C 6 )cycloalkythio, halo(C 4 -C 7 )cycloalkylalkylthio, (C 1 -C 6 )alkanesulfinyl, (C 3 -C 6 )cycloalkanesulfinyl, (C 4 -C 7 )cycloalkylalkanesulfinyl, halo(C 1 -C 6 )alkanesulfinyl, halo(C 3 -C 6 )cycloalkanesulfinyl, halo(C 4 -C 7 )cycloalkylalkanesulfinyl, (C 1 -C 6 )alkanesulfonyl, (C 3 -C 6 )cycloalkanesulfonyl, (C 4 -C 7 )cycloalkylalkanesulfonyl, halo(C 1 -C 6 )alkanesulfonyl, halo(C 3 -C 6 )cycloalkanesulfonyl, halo(C 4 -C 7 )cyclo-alkylalkanesulfonyl, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, H 2 NCO, H 2 NSO 2 , (C 1 -C 6 )alkylaminocarbonyl, di(C 1 -C 6 )alkylaminocarbonyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkylaminocarbonyl, heterocyclylcarbonyl, (C 1 -C 6 )alkylaminosulfonyl, di(C 1 -C 6 )alkylaminosulfonyl, heterocyclosulfonyl, (C 1 -C 6 )alkylcarbonylamino, (C 1 -C 6 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonylamino, (C 1 -C 6 )alkyl-sulfonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkoxy, oxo, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl amino(C 2 -C 6 )alkoxy, (C 1 -C 6 )alkylamino(C 2 -C 6 )alkoxy, di(C 1 -C 6 )alkylamino(C 2 -C 6 )alkoxy and (C 1 -C 6 )alkylcarbonyl; or if the substitution is either meta or para to A 1 , the substituents may also include optionally substituted cycloalkyl, optionally substituted halo cycloalkyl or optionally substituted heteroaryl.

Cy 2 is meta or para to A 1 and is (a) hydrogen or (b) aryl, heteroaryl, cycloalkyl pyrrolidine, pyrrolidin-2-one, 1-methylpyrrolidin-2-one, piperidine, piperidin-2-one, dihydropyridine, tetrahydropyridine, piperazine, 1-(2,2,2-trifluoroethyl)piperazine, 1,2-dihydro-2-oxopyridine, 1,4-dihydro-4-oxopyridine, piperazin-2-one, 3,4,5,6-tetrahydro-4-oxopyrimidine, 3,4-dihydro-4-oxopyrimidine, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, tetrahydrothiopyran, isoxazolidine, 1,3-dioxolane, 1,3-dithiolane, 1,3-dioxane, 1,4-dioxane, 1,3-dithiane, 1,4-dithiane, oxazolidin-2-one, imidazolidin-2-one, imidazolidine-2,4-dione, tetrahydropyrimidin-2(1H)-one, morpholine, N-methylmorpholine, morpholin-3-one, 1,3-oxazinan-2-one, thiomorpholine, thiomorpholine 1,1-dioxide, tetrahydro-1,2,5-thiaoxazole 1,1-dioxide, tetrahydro-2H-1,2-thiazine 1,1-dioxide, hexahydro-1,2,6-thiadiazine 1,1-dioxide, tetrahydro-1,2,5-thiadiazole 1,1-dioxide isothiazolidine 1,1-dioxide, 6-oxo-1,6-dihydropyridazin-3-yl, 6-oxo-1,6-dihydropyridazin-4-yl, 5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl and 5-oxo-4,5-dihydro-1H-imidazol-2-yl optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, hydroxy(C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl(C 2 -C 4 )alkynyl, halo(C 1 -C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl, halo(C 4 -C 7 )cycloalkylalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, (C 4 -C 7 )cycloalkylalkoxy, halo(C 1 -C 6 )alkoxy, halo(C 3 -C 6 )cycloalkoxy, halo(C 4 -C 7 )cycloalkylalkoxy, (C 1 -C 6 )alkylthio, (C 3 -C 6 )cycloalkythio, (C 4 -C 7 )cycloalkylalkylthio, halo(C 1 -C 6 )alkylthio, halo(C 3 -C 6 )cycloalkythio, halo(C 4 -C 7 )cycloalkylalkylthio, (C 1 -C 6 )alkanesulfinyl, (C 3 -C 6 )cycloalkanesulfinyl, (C 4 -C 7 )cycloalkylalkanesulfinyl, halo(C 1 -C 6 )alkanesulfinyl, halo(C 3 -C 6 )cycloalkanesulfinyl, halo(C 4 -C 7 )cycloalkylalkanesulfinyl, (C 1 -C 6 )alkanesulfonyl, (C 3 -C 6 )cycloalkanesulfonyl, (C 4 -C 7 )cycloalkylalkanesulfonyl, halo(C 1 -C 6 )alkanesulfonyl, halo(C 3 -C 6 )cycloalkanesulfonyl, halo(C 4 -C 7 )cyclo-alkylalkanesulfonyl, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, H 2 NCO, H 2 NSO 2 , (C 1 -C 6 )alkylaminocarbonyl, di(C 1 -C 6 )alkylaminocarbonyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkylaminocarbonyl, heterocyclylcarbonyl, (C 1 -C 6 )alkylaminosulfonyl, di(C 1 -C 6 )alkylaminosulfonyl, heterocyclosulfonyl, (C 1 -C 6 )alkylcarbonylamino, (C 1 -C 6 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonylamino, (C 1 -C 6 )alkylsulfonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkoxy, heteroaryl, oxo, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl amino(C 2 -C 6 )alkoxy, (C 1 -C 6 )alkylamino(C 2 -C 6 )alkoxy, di(C 1 -C 6 )alkylamino(C 2 -C 6 )alkoxy and (C 1 -C 6 )alkylcarbonyl;

›SUMMARY OF THE INVENTION · 8 of 8

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof; and the remainder of the variables are as defined as for the first, second, third or fourth embodiments.

In a sixth embodiment,

R 3 is selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkoxy or (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl and is substituted with one to four groups independently selected from cyano, oxo, R 4 O—, (R 4 ) 2 N—, R 4 O 2 C—, R 4 S, R 4 S(═O)—, R 4 S(═O) 2 —, R 4 C(═O)NR 4 —, (R 4 ) 2 NC(═O)—, (R 4 ) 2 NC(═O)O—, (R 4 ) 2 NC(═O)NR 4 —, R 4 C(═O)NR 4 —, (R 4 ) 2 NC(═NCN)NR 4 —, (R 4 O) 2 P(═O)O—, (R 4 O) 2 P(═O)NR 4 —, R 4 OS(═O) 2 NR 4 —, (R 4 ) 2 NS(═O) 2 O—, (R 4 ) 2 NS(═O) 2 NR 4 —, R 4 S(═O) 2 NR 4 —, R 4 SO 2 NR 4 —, R 4 S(═O) 2 NHC(═O)—, R 4 S(═O) 2 NHC(═O)O—, R 4 S(═O) 2 NHC(═O)NR 4 —, R 4 OS(═O) 2 NHC(═O)—, R 4 OS(═O) 2 NHC(═O)O—, R 4 OS(═O) 2 NHC(═O)NR 4 —, (R 4 ) 2 NS(═O) 2 NHC(═O)—, (R 4 ) 2 NS(═O) 2 NHC(═O)O—, (R 4 ) 2 NS(═O) 2 NHC(═O)NR 4 —, R 4 C(═O)NHS(═O) 2 —, R 4 C(═O)NHS(═O) 2 O—, R 4 C(═O)NHS(═O) 2 NR 4 —, R 4 OC(═O)NHS(═O) 2 —, R 4 OC(═O)NHS(═O) 2 O—, R 4 OC(═O)NHS(═O) 2 NR 4 —, (R 4 ) 2 NC(═O)NHS(═O) 2 —, (R 4 ) 2 NC(═O)NHS(═O) 2 O— and (R 4 ) 2 NC(═O)NHS(═O) 2 NR 4 —;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof; and the remainder of the variables are as defined as for the first, second, third, fourth or fifth embodiments.

In a seventh embodiment, the variables in Formula (I) are as defined in the first or second embodiment, provided that the substituents for the aryl, heteroaryl, monocyclic cycloalkyl and monocyclic heterocyclyl group represented by Cy 1 can additionally be selected from (C 3 -C 6 )cycloalkylcarbonyl, (C 3 -C 6 )cycloalkylaminocarbonyl, {(C 3 -C 6 )cycloalkyl}{(C 1 -C 6 )alkyl}aminocarbonyl, di(C 3 -C 6 )cycloalkylaminocarbonyl, (C 3 -C 6 )cycloalkylaminosulfonyl, {(C 3 -C 6 )cycloalkyl}{(C 1 -C 6 )alkyl}aminosulfonyl, di(C 3 -C 6 )cycloalkylaminosulfonyl, cyano(C 1 -C 6 )alkyl, aminocarbonyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylaminocarbonyl(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylaminocarbonyl(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkylaminocarbonyl(C 1 -C 6 )alkyl, {(C 3 -C 6 )cycloalkyl}{(C 1 -C 6 )alkyl}aminocarbonyl(C 1 -C 6 )alkyl and di(C 3 -C 6 )cycloalkylaminocarbonyl(C 1 -C 6 )alkyl;

the substituents for the aryl, heteroaryl, cycloalkyl and heterocyclyl group represented by Cy 2 can additionally be selected from (C 3 -C 6 )cycloalkylcarbonyl, (C 3 -C 6 )cycloalkylaminocarbonyl, {(C 3 -C 6 )cycloalkyl}{(C 1 -C 6 )alkyl}aminocarbonyl, di(C 3 -C 6 )cycloalkylaminocarbonyl, (C 3 -C 6 )cycloalkylaminosulfonyl, {(C 3 -C 6 )cycloalkyl}{(C 1 -C 6 )alkyl}aminosulfonyl, di(C 3 -C 6 )cycloalkylaminosulfonyl, cyano(C 1 -C 6 )alkyl, aminocarbonyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylaminocarbonyl(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylaminocarbonyl(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkylaminocarbonyl(C 1 -C 6 )alkyl, {(C 3 -C 6 )cycloalkyl}{(C 1 -C 6 )alkyl}aminocarbonyl(C 1 -C 6 )alkyl and di(C 3 -C 6 )cycloalkylaminocarbonyl(C 1 -C 6 )alkyl; and

the substituents for the aryl, heteroaryl, cycloalkyl and heterocyclyl group represented by R 2 can additionally be selected from (C 3 -C 6 )cycloalkylcarbonyl, (C 3 -C 6 )cycloalkylaminocarbonyl, {(C 3 -C 6 )cycloalkyl}{(C 1 -C 6 )alkyl}aminocarbonyl, di(C 3 -C 6 )cycloalkylaminocarbonyl, (C 3 -C 6 )cycloalkylaminosulfonyl, {(C 3 -C 6 )cycloalkyl}{(C 1 -C 6 )alkyl}aminosulfonyl, di(C 3 -C 6 )cycloalkylaminosulfonyl, cyano(C 1 -C 6 )alkyl, aminocarbonyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylaminocarbonyl(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylaminocarbonyl(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkylaminocarbonyl(C 1 -C 6 )alkyl, {(C 3 -C 6 )cycloalkyl}{(C 1 -C 6 )alkyl}aminocarbonyl(C 1 -C 6 )alkyl and di(C 3 -C 6 )cycloalkylaminocarbonyl(C 1 -C 6 )alkyl.

Another embodiment of the invention is a method of inhibiting 11β-HSD1 activity comprising the step of administering to a mammal in need of such treatment an effective amount of a compound of Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih Ii, Ij, Ik, Il or, Im 1-12 , In 1-12 , Io 1-12 , Ip 1-7 , Iq 1-21 , Ir 1-21 , Is 1-21 , It 1-7 , Iu 1-20 , Iv 1-20 , Iw 1-20 or Ix 1-7 or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment of the invention is a method of treating a subject with a disease associated with the activity or expression of 11β-HSD1, comprising the step of administering to the subject an effective amount of a compound of Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih Ii, Ij, Ik, Il, Im 1-12 , In 1-12 , Io 1-12 , Ip 1-7 , Iq 1-21 , Ir 1-21 , Is 1-21 , It 1-7 , Iu 1-20 , Iv 1-20 , Iw 1-20 or Ix 1-7 or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment of the invention is the use of a compound of Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih Ii, Ij, Ik, Il or, Im 1-12 , In 1-12 , Io 1-12 , Ip 1-7 , Iq 1-21 , Ir 1-21 , Is 1-21 , It 1-7 , Iu 1-20 , Iv 1-20 , Iw 1-20 or Ix 1-7 or a diastereomer thereof for the manufacture of a medicament for inhibiting 11β-HSD1 activity in a mammal in need of such treatment.

Another embodiment of the invention is the use of a compound of Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih Ii, Ij, Ik, Il, Im 1-12 , In 1-12 , Io 1-12 , Ip 1-7 , Iq 1-21 , Ir 1-21 , Is 1-21 , It 1-7 , Iu 1-20 , Iv 1-20 , Iw 1-20 or Ix 1-7 or a or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof for the manufacture of a medicament for treating a subject with a disease associated with the activity or expression of 11β-HSD1.

Another embodiment of the invention is a compound of Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih Ii, Ij, Ik, Il, Im 1-12 , In 1-12 , Io 1-12 , Ip 1-7 , Iq 1-21 , Ir 1-21 , Is 1-21 , It 1-7 , Iu 1-20 , Iv 1-20 , Iw 1-20 or Ix 1-7 or a or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof for use in inhibiting 11β-HSD1 activity in a mammal in need of such treatment.

Another embodiment of the invention is a compound of Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih Ii, Ij, Ik, Il, Im 1-12 , In 1-12 , Io 1-12 , Ip 1-7 , Iq 1-21 , Ir 1-21 , Is 1-21 , It 1-7 , Iu 1-20 , Iv 1-20 , Iw 1-20 or Ix 1-7 or a or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof for use in for treating a subject with a disease associated with the activity or expression of 11β-HSD1.

›DETAILED DESCRIPTION OF THE INVENTION · 1 of 20

In an eighth embodiment, the variables in Formula I or any one of Formulas Ia-Il are as defined in the following paragraphs:

R 1 is (a) absent or (b) (C 1 -C 6 )alkyl is optionally substituted with up to four groups independently selected from fluorine, cyano, oxo, R 4 , R 4 O—, (R 4 ) 2 N—, R 4 O 2 C—, R 4 S, R 4 S(═O)—, R 4 S(═O) 2 —, R 4 C(═O)NR 4 —, (R 4 ) 2 NC(═O)—, (R 4 ) 2 NC(═O)O—, (R 4 ) 2 NC(═O)NR 4 —, R 4 OC(═O)NR 4 —, (R 4 ) 2 NS(═O) 2 NR 4 — and R 4 S(═O) 2 NR 4 —;

A 1 is (a) a bond, or (b) (C 1 -C 2 )alkylene;

A 2 is a bond;

Cy 2 is (a) hydrogen or (b) aryl, heteroaryl, cycloalkyl or heterocyclyl and is optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, hydroxy(C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl(C 2 -C 4 )alkynyl, halo(C 1 -C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl, halo(C 4 -C 7 )cycloalkylalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, (C 4 -C 7 )cycloalkylalkoxy, halo(C 1 -C 6 )alkoxy, halo(C 3 -C 6 )cycloalkoxy, halo(C 4 -C 7 )cycloalkylalkoxy, (C 1 -C 6 )alkylthio, (C 3 -C 6 )cycloalkythio, (C 4 -C 7 )cycloalkylalkylthio, halo(C 1 -C 6 )alkylthio, halo(C 3 -C 6 )cycloalkythio, halo(C 4 -C 7 )cycloalkylalkylthio, (C 1 -C 6 )alkanesulfinyl, (C 3 -C 6 )cycloalkanesulfinyl, (C 4 -C 7 )cycloalkylalkanesulfinyl, halo(C 1 -C 6 )alkanesulfinyl, halo(C 3 -C 6 )cycloalkanesulfinyl, halo(C 4 -C 7 )cycloalkyl-alkanesulfinyl, (C 1 -C 6 )alkanesulfonyl, (C 3 -C 6 )cycloalkanesulfonyl, (C 4 -C 7 )cycloalkyl-alkanesulfonyl, halo(C 1 -C 6 )alkanesulfonyl, halo(C 3 -C 6 )cycloalkanesulfonyl, halo(C 4 -C 7 )cyclo-alkylalkanesulfonyl, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, H 2 NCO, H 2 NSO 2 , (C 1 -C 6 )alkylaminocarbonyl, di(C 1 -C 6 )alkylaminocarbonyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkylaminocarbonyl, heterocyclylcarbonyl, (C 1 -C 6 )alkylaminosulfonyl, di(C 1 -C 6 )alkylaminosulfonyl, heterocyclosulfonyl, (C 1 -C 6 )alkylcarbonylamino, (C 1 -C 6 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonylamino, (C 1 -C 6 )alkylsulfonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkoxy, heteroaryl, oxo, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl amino(C 2 -C 6 )alkoxy, (C 1 -C 6 )alkylamino(C 2 -C 6 )alkoxy, di(C 1 -C 6 )alkylamino(C 2 -C 6 )alkoxy, (C 1 -C 6 )alkylcarbonyl C 3 -C 6 )cycloalkylaminocarbonyl, {(C 3 -C 6 )cycloalkyl}{(C 1 -C 6 )alkyl}aminocarbonyl, di(C 3 -C 6 )cycloalkylaminocarbonyl, (C 3 -C 6 )cycloalkylaminosulfonyl, {(C 3 -C 6 )cycloalkyl}{(C 1 -C 6 )alkyl}aminosulfonyl and di(C 3 -C 6 )cycloalkylaminosulfonyl; In one aspect, the heterocyclyl represented by Cy 2 is other than optionally substituted thiazolidine-2,4-dionyl;

n is 0;

E is a bond;

R 4 is independently selected from H, (C 1 -C 6 )alkyl and halo(C 1 -C 6 )alkyl;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

In a ninth embodiment, the variables in Formula I or in any one of Formulas Ia-Il are defined in the following paragraphs:

R 1 (for Formulas I, Id, Ig and Ih) is absent or is methyl or ethyl;

A 1 (for Formulas I, Id, Ig and Ih) is a bond or CH 2 or CH when R 1 is present;

Cy 1 (for Formulas I, Id, Ig, Ih) is phenyl, cyclohexyl, pyridyl, N-oxo-pyridyl, thiazolyl or pyrimidinyl each optionally substituted with 1 to 4 groups independently selected from halo, methyl, trifluoromethyl, hydroxy, methoxy, methoxycarbonyl, carboxy, ethoxycarbonylmethoxy and 2-hydroxy-2-methylpropoxy;

›DETAILED DESCRIPTION OF THE INVENTION · 2 of 20

A 2 (for Formulas I, Ia-e, Ig and Ih) is a bond, O or OCH 2 CO;

Cy 2 (for Formulas I, Ia-e, Ig and Ih) is (a) hydrogen or (b) phenyl, thienyl, pyridyl, N-oxo-pyridyl, cyclopropyl, piperidinyl or piperazinyl each optionally substituted by 1 to 4 groups independently selected from halo, hydroxy, methoxy, hydroxymethyl, methoxycarbonyl, amino, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, (2-methoxyethyl)aminocarbonyl, acetylaminomethyl, methylsulfonyl, methylsulfonylamino, methylaminosulfonyl, isopropylaminosulfonyl, dimethylaminosulfonyl, pyrrolidine-1-sulfonyl, methylsulfonylaminomethyl or tetrazolyl;

n (for Formulas I, Ig and Ih) is 0;

E (for Formulas I, Ia-c and Ie-i) is a bond or CH 2 ;

R 2 (for Formulas I, Ia-c and Ie-i) is phenyl, thienyl or pyridyl each optionally substituted with halo, methyl, methylthio or (4-morpholino)methyl; and

R 3 (for Formulas I and Ia-i) is methyl, ethyl, propyl, vinyl or allyl each optionally substituted with up to two groups independently selected from HO—, MeO—, H 2 N—, MeC(═O)NH—, MeS(═O) 2 NH—, H 2 NC(═O)—, MeNHC(═O)—, HO 2 C—, (HO) 2 P(═O)O—, H 2 NS(═O) 2 O—, H 2 NS(═O) 2 NH—, MeNHC(═O)NH—, MeNHC(═O)O— oxo, cyano, HO 2 C—, HOCH 2 CH 2 NH—, 4-morpholino, HOCH 2 C(═O)NH—, H 2 NCH 2 C(═O)NH—, EtNHC(═O)NH, MeOC(═O)NH—, MeNHC(═NC≡N)NH—, or oxo;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

In a tenth embodiment, the variables in Formula I or in any one of Formulas Ia-Il are as defined in the following paragraphs:

R 1 is absent or is methyl or ethyl;

A 1 is a bond, CH 2 , CH 2 CH 2 , or CH when R 1 is present;

Cy 1 is phenyl, cyclopropyl, cyclohexyl, pyrrolidinyl, pyridyl, N-oxo-pyridyl, thiazolyl or pyrimidinyl each optionally substituted with 1 to 4 groups independently selected from halo, methyl, trifluoromethyl, hydroxy, methoxy, methoxycarbonyl, carboxy, ethoxycarbonylmethoxy, 2-hydroxy-2-methylpropoxy, cyano, difluoromethoxy, t-butoxycarbonyl, hydroxy, hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-2-propyl, methoxymethyl, methylsulfonyl and methylsulfonylamino;

A 2 is a bond, O, OCH 2 CO or C═O;

Cy 2 is (a) hydrogen or (b) phenyl, thienyl, pyridyl, N-oxo-pyridyl, cyclopropyl, piperidinyl, piperazinyl, morpholinyl, thiazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, S,S-dioxothiazinyl, 2-oxo-1,2-dihydropyridyl each optionally substituted by 1 to 4 groups independently selected from halo, hydroxy, methoxy, hydroxymethyl, methoxycarbonyl, amino, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, (2-methoxyethyl)aminocarbonyl, acetylaminomethyl, methylsulfonyl, methylsulfonylamino, methylaminosulfonyl, isopropylaminosulfonyl, dimethylaminosulfonyl, pyrrolidine-1-sulfonyl, methylsulfonylaminomethyl, tetrazolyl, methyl, trifluoromethyl, acetyl, 2-hydroxyethyl and 1-aminoethyl;

n is 0;

E is a bond or CH 2 ;

R 2 is phenyl, thienyl, pyridyl or isopropyl each optionally substituted with halo, methyl, methylthio or (4-morpholino)methyl; and

R 3 is methyl, ethyl, propyl, butyl, vinyl, allyl or ethoxyethyl each optionally substituted with up to two groups independently selected from Methyl, HO—, MeO—, H 2 N—, MeC(═O)NH—, MeS(═O) 2 NH—, H 2 NC(═O)—, MeNHC(═O)—, HO 2 C—, (HO) 2 P(═O)O—, H 2 NS(═O) 2 O—, H 2 NS(═O) 2 NH—, MeNHC(═O)NH—, MeNHC(═O)O—, oxo, cyano, HO 2 C—, HOCH 2 CH 2 NH—, 4-morpholino, HOCH 2 C(═O)NH—, H 2 NCH 2 C(═O)NH—, EtNHC(═O)NH, MeOC(═O)NH—, MeNHC(═NC≡N)NH—, Me-, MeS—, MeSO 2 -MeSO 2 N(Me)-, MeS(═O) 2 NHC(═O)—, imidazolylamino-, imidazolyl, tetrazolyl, H 2 NCONH—, H 2 NCO 2 —, HOCH 2 CH 2 O—, MeNH—, Me 2 N— and MeCONMe;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

In an eleventh embodiment, the variables in Formula I or any one of Formulas Ia-Il are as defined in the following paragraphs:

R 1 (for Formulas I, Id, Ig and Ih) is absent or is methyl or ethyl;

R 1a (for Formulas Ij and Ik) is methyl or ethyl;

A 1 (for Formulas I, Id, Ig and Ih) is a bond, CH 2 or CH 2 CH 2 or CH when R 1 is present;

Cy 1 (for Formulas I, Id, Ig, Ih) is phenyl, cyclopropyl, cyclohexyl, pyrrolidinyl, pyridyl, N-oxo-pyridyl, thiazolyl, piperidinyl or pyrimidinyl each optionally substituted with 1 to 4 groups independently selected from halo, methyl, trifluoromethyl, hydroxy, methoxy, methoxycarbonyl, carboxy, ethoxycarbonylmethoxy, 2-hydroxy-2-methylpropoxy, cyano, difluoromethoxy, t-butoxycarbonyl, hydroxy, hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-2-propyl, methoxymethyl, methylsulfonyl, methylsulfonylamino and benzyloxycarbonyl;

A 2 (for Formulas I, Ia-e, Ig and Ih) is a bond, CH 2 , O, OCH 2 CO or C═O;

Cy 2 (for Formulas I, Ia-e, Ig, Ih, Ik and Il) is (a) hydrogen or (b) phenyl, thienyl, pyridyl, N-oxo-pyridyl, cyclopropyl, piperidinyl, piperazinyl, morpholinyl, thiazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, S,S-dioxothiazinyl, 2-oxo-1,2-dihydropyridyl each optionally substituted by 1 to 4 groups independently selected from halo, hydroxy, methoxy, hydroxymethyl, methoxycarbonyl, amino, aminomethyl, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, (2-methoxyethyl)aminocarbonyl, acetylaminomethyl, methylsulfonyl, methylsulfonylamino, methylaminosulfonyl, isopropylaminosulfonyl, dimethylaminosulfonyl, pyrrolidine-1-sulfonyl, methylsulfonylaminomethyl, tetrazolyl, methyl, trifluoromethyl, acetyl, 2-hydroxyethyl and 1-aminoethyl;

n (for Formulas I, Ig and Ih) is 0;

E (for Formulas I, Ia-c and Ie-i) is a bond or CH 2 ;

R 2 (for Formulas I, Ia-c and Ie-l) is phenyl, thienyl, pyridyl, t-butyl or isopropyl each optionally substituted with halo, methyl, methylthio, hydroxymethyl or (4-morpholino)methyl; and

R 3 (for Formulas I and Ia-l) is methyl, ethyl, propyl, butyl, vinyl, allyl or ethoxyethyl each optionally substituted with up to two groups independently selected from methyl, HO—, MeO—, H 2 N—, MeC(═O)NH—, MeS(═O) 2 NH—, H 2 NC(═O)—, MeNHC(═O)—, HO 2 C—, (HO) 2 P(═O)O—, H 2 NS(═O) 2 O—, H 2 NS(═O) 2 NH—, MeNHC(═O)NH—, MeNHC(═O)O—, oxo, cyano, HO 2 C—, HOCH 2 CH 2 NH—, 4-morpholino, HOCH 2 C(═O)NH—, H 2 NCH 2 C(═O)NH—, EtNHC(═O)NH, MeOC(═O)NH—, MeNHC(═NC≡N)NH—, Me-, MeS—, MeSO 2 — MeSO 2 N(Me)-, MeS(═O) 2 NHC(═O)—, imidazolylamino-, imidazolyl, tetrazolyl, spirocyclopropyl, FCH 2 CH 2 NH, 1-pyrrolidinyl, 3-fluoro-1-pyrrolidinyl, 3-oxo-1-piperazinyl, 1-azetidinyl, 1,1-dioxo-2-isothiazolidinyl, 2-oxo-1-pyrrolidinyl, H 2 NCONH—, H 2 NCO 2 —, HOCH 2 CH 2 O—, MeNH—, Me 2 N— and MeCONMe;

›DETAILED DESCRIPTION OF THE INVENTION · 3 of 20

G (for Formulas Ia, Ie, Ii and Ij) is alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO 2 H, CONH 2 , N-monoalkyl-substituted amido and N,N-dialkyl-substituted amido;

r (for Formulas Ia, Ie, Ii and Ij) is 0, 1 or 2;

G 1 and G 2 (for Formula If) are independently alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO 2 H, CONH 2 , N-monoalkyl-substituted amido and N,N-dialkyl-substituted amido;

r (for Formulas Ia, Ie, If, Ii and Ij) is 0, 1 or 2;

s (for Formula If) is 0, 1 or 2;

t (for Formula Il) is 1 or 2;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

In a twelfth embodiment, the variables in formula I or in any one or Formulas Ia-Il are as defined in the following paragraphs:

R 1 is absent or is methyl or ethyl;

A 1 is a bond, CH 2 , CH 2 CH 2 , or CH when R 1 is present;

Cy 1 is phenyl, cyclopropyl, cyclohexyl, pyrrolidinyl, pyridyl, N-oxo-pyridyl, thiazolyl, pyrimidinyl, piperidinyl, each optionally substituted with 1 to 4 groups independently selected from halo, methyl, trifluoromethyl, hydroxy, methoxy, methoxycarbonyl, carboxy, ethoxycarbonylmethoxy, 2-hydroxy-2-methylpropoxy, cyano, difluoromethoxy, t-butoxycarbonyl, hydroxy, hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-2-propyl, methoxymethyl, methylsulfonyl, methylsulfonylamino, trifluoromethoxy, 2,2,2-trifluoroethoxy and benzyloxycarbonyl;

A 2 is a bond, O, OCH 2 CO, C═O or CH 2 ;

Cy 2 is (a) hydrogen or (b) phenyl, thienyl, pyridyl, N-oxo-pyridyl, cyclopropyl, piperidinyl, piperazinyl, morpholinyl, thiazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, S,S-dioxothiazinyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 3-oxo-2,3-dihydropyridazinyl, 4-oxo-3,4-dihydropyrimidinyl or 2-oxo-1,2-dihydropyrimidinyl each optionally substituted by 1 to 4 groups independently selected from halo, hydroxy, methoxy, hydroxymethyl, methoxycarbonyl, amino, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, (2-methoxyethyl)aminocarbonyl, acetylaminomethyl, methylsulfonyl, methylsulfonylamino, methylaminosulfonyl, isopropylaminosulfonyl, dimethylaminosulfonyl, pyrrolidine-1-sulfonyl, methylsulfonylaminomethyl, tetrazolyl, methyl, trifluoromethyl, acetyl, 2-hydroxyethyl, 1-aminoethyl, ethyl, isopropyl, 2,2,2-trifluoroethyl, cyano, ethoxy, cyclopropylcarbamoyl and t-butylcarbamoyl;

n is 0;

E is a bond or CH 2 ;

R 2 is phenyl, thienyl, pyridyl or isopropyl, t-butyl each optionally substituted with halo, methyl, methylthio or (4-morpholino)methyl; and

R 3 is methyl, ethyl, propyl, butyl, vinyl, allyl or ethoxyethyl each optionally substituted with up to two groups independently selected from methyl, HO—, MeO—, H 2 N—, MeC(═O)NH—, MeS(═O) 2 NH—, H 2 NC(═O)—, MeNHC(═O)—, HO 2 C—, (HO) 2 P(═O)O—, H 2 NS(═O) 2 O—, H 2 NS(═O) 2 NH—, MeNHC(═O)NH—, MeNHC(═O)O—, oxo, cyano, HO 2 C—, HOCH 2 CH 2 NH—, 4-morpholino, HOCH 2 C(═O)NH—, H 2 NCH 2 C(═O)NH—, EtNHC(═O)NH, MeOC(═O)NH—, MeNHC(═NC≡N)NH—, Me-, MeS—, MeSO 2 — MeSO 2 N(Me)-, MeS(═O) 2 NHC(═O)—, imidazolylamino-, imidazolyl, tetrazolyl, H 2 NCONH—, H 2 NCO 2 —, HOCH 2 CH 2 O—, MeNH—, Me 2 N—, MeCON(Me)-, 2-fluoroethylamino, azetidinyl, pyrrolidinyl, 3-fluoropyrrolidinyl, 3-oxopiperazinyl, 1,1-dioxoisothiazolidin-2-yl, methyl-1H-imidazol-2-yl, 5-methyl-1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-thiadiazol-2-yl, EtOC(═O)NH—, and fluoro;

alternatively R 3 is (1-hydroxycyclopropyl)methyl;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Formula Ia:

wherein A 2 , Cy 2 , E, R 2 , and R 3 are as defined for the first embodiment described for Formula I above, r is 0, 1, 2, 3 or 4 and substituents G are independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, hydroxy(C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl(C 2 -C 4 )alkynyl, halo(C 1 -C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl, halo(C 4 -C 7 )cycloalkylalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, (C 4 -C 7 )cycloalkylalkoxy, halo(C 1 -C 6 )alkoxy, halo(C 3 -C 6 )cycloalkoxy, halo(C 4 -C 7 )cycloalkylalkoxy, (C 1 -C 6 )alkylthio, (C 3 -C 6 )cycloalkythio, (C 4 -C 7 )cycloalkylalkylthio, halo(C 1 -C 6 )alkylthio, halo(C 3 -C 6 )cycloalkythio, halo(C 4 -C 7 )cycloalkylalkylthio, (C 1 -C 6 )alkanesulfinyl, (C 3 -C 6 )cycloalkanesulfinyl, (C 4 -C 7 )cycloalkylalkanesulfinyl, halo(C 1 -C 6 )alkanesulfinyl, halo(C 3 -C 6 )cycloalkanesulfinyl, halo(C 4 -C 7 )cycloalkylalkanesulfinyl, (C 1 -C 6 )alkanesulfonyl, (C 3 -C 6 )cycloalkanesulfonyl, (C 4 -C 7 )cycloalkylalkanesulfonyl, halo(C 1 -C 6 )alkanesulfonyl, halo(C 3 -C 6 )cycloalkane-sulfonyl, halo(C 4 -C 7 )cyclo-alkylalkanesulfonyl, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, H 2 NCO, H 2 NSO 2 , (C 1 -C 6 )alkylaminocarbonyl, di(C 1 -C 6 )alkylaminocarbonyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkylaminocarbonyl, heterocyclylcarbonyl, (C 1 -C 6 )alkylaminosulfonyl, di(C 1 -C 6 )alkylaminosulfonyl, heterocyclosulfonyl, (C 1 -C 6 )alkylcarbonylamino, (C 1 -C 6 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonylamino, (C 1 -C 6 )alkylsulfonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkoxy, heteroaryl, oxo, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl amino(C 2 -C 6 )alkoxy, (C 1 -C 6 )alkylamino(C 2 -C 6 )alkoxy, di(C 1 -C 6 )alkylamino(C 2 -C 6 )alkoxy and (C 1 -C 6 )alkylcarbonyl;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Alternatively for Formula Ia, A 2 , Cy 2 , E, R 2 , and R 3 are as defined for the second embodiment described for Formula I above, and r is 0, 1, 2, 3 or 4 and substituents G are independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, hydroxy(C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl(C 2 -C 4 )alkynyl, halo(C 1 -C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl, halo(C 4 -C 7 )cycloalkylalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, (C 4 -C 7 )cycloalkylalkoxy, halo(C 1 -C 6 )alkoxy, halo(C 3 -C 6 )cycloalkoxy, halo(C 4 -C 7 )cycloalkylalkoxy, (C 1 -C 6 )alkylthio, (C 3 -C 6 )cycloalkythio, (C 4 -C 7 )cycloalkylalkylthio, halo(C 1 -C 6 )alkylthio, halo(C 3 -C 6 )cycloalkythio, halo(C 4 -C 7 )cycloalkylalkylthio, (C 1 -C 6 )alkanesulfinyl, (C 3 -C 6 )cycloalkanesulfinyl, (C 4 -C 7 )cycloalkylalkanesulfinyl, halo(C 1 -C 6 )alkanesulfinyl, halo(C 3 -C 6 )cycloalkanesulfinyl, halo(C 4 -C 7 )cycloalkylalkanesulfinyl, (C 1 -C 6 )alkanesulfonyl, (C 3 -C 6 )cycloalkanesulfonyl, (C 4 -C 7 )cycloalkylalkanesulfonyl, halo(C 1 -C 6 )alkanesulfonyl, halo(C 3 -C 6 )cycloalkanesulfonyl, halo(C 4 -C 7 )cyclo-alkylalkanesulfonyl, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, H 2 NCO, H 2 NSO 2 , (C 1 -C 6 )alkylaminocarbonyl, di(C 1 -C 6 )alkylaminocarbonyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkylaminocarbonyl, heterocyclylcarbonyl, (C 1 -C 6 )alkylaminosulfonyl, di(C 1 -C 6 )alkylaminosulfonyl, heterocyclosulfonyl, (C 1 -C 6 )alkylcarbonylamino, (C 1 -C 6 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonylamino, (C 1 -C 6 )alkylsulfonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkoxy, heteroaryl and oxo;

›DETAILED DESCRIPTION OF THE INVENTION · 4 of 20

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

In another alternative for Formulas Ia, A 2 , Cy 2 , E, R 2 , and R 3 are as defined for the second embodiment described for Formula I above, and r is 0, 1, 2, 3 or 4 and substituents G are independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, hydroxy(C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl(C 2 -C 4 )alkynyl, halo(C 1 -C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl, halo(C 4 -C 7 )cycloalkylalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, (C 4 -C 7 )cycloalkylalkoxy, halo(C 1 -C 6 )alkoxy, halo(C 3 -C 6 )cycloalkoxy, halo(C 4 -C 7 )cycloalkylalkoxy, (C 1 -C 6 )alkylthio, (C 3 -C 6 )cycloalkythio, (C 4 -C 7 )cycloalkylalkylthio, halo(C 1 -C 6 )alkylthio, halo(C 3 -C 6 )cycloalkythio, halo(C 4 -C 7 )cycloalkylalkylthio, (C 1 -C 6 )alkanesulfinyl, (C 3 -C 6 )cycloalkanesulfinyl, (C 4 -C 7 )cycloalkylalkanesulfinyl, halo(C 1 -C 6 )alkanesulfinyl, halo(C 3 -C 6 )cycloalkanesulfinyl, halo(C 4 -C 7 )cycloalkylalkanesulfinyl, (C 1 -C 6 )alkanesulfonyl, (C 3 -C 6 )cycloalkanesulfonyl, (C 4 -C 7 )cycloalkylalkanesulfonyl, halo(C 1 -C 6 )alkanesulfonyl, halo(C 3 -C 6 )cycloalkanesulfonyl, halo(C 4 -C 7 )cyclo-alkylalkanesulfonyl, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, H 2 NCO, H 2 NSO 2 , (C 1 -C 6 )alkylaminocarbonyl, di(C 1 -C 6 )alkylaminocarbonyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkylaminocarbonyl, heterocyclylcarbonyl, (C 1 -C 6 )alkylaminosulfonyl, di(C 1 -C 6 )alkylaminosulfonyl, heterocyclosulfonyl, (C 1 -C 6 )alkylcarbonylamino, (C 1 -C 6 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonylamino, (C 1 -C 6 )alkyl-sulfonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkoxy, heteroaryl, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl amino(C 2 -C 6 )alkoxy, (C 1 -C 6 )alkylamino(C 2 -C 6 )alkoxy, di(C 1 -C 6 )alkylamino(C 2 -C 6 )alkoxy, (C 1 -C 6 )alkylcarbonyl, (C 3 -C 6 )cycloalkylcarbonyl, (C 3 -C 6 )cycloalkylaminocarbonyl, {(C 3 -C 6 )cycloalkyl}{(C 1 -C 6 )alkyl}aminocarbonyl, di(C 3 -C 6 )cycloalkylaminocarbonyl, (C 3 -C 6 )cycloalkylaminosulfonyl, {(C 3 -C 6 )cycloalkyl}{(C 1 -C 6 )alkyl}aminosulfonyl, di(C 3 -C 6 )cycloalkylaminosulfonyl, cyano(C 1 -C 6 )alkyl, aminocarbonyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylaminocarbonyl(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylaminocarbonyl(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkylaminocarbonyl(C 1 -C 6 )alkyl, {(C 3 -C 6 )cycloalkyl}{(C 1 -C 6 )alkyl}aminocarbonyl(C 1 -C 6 )alkyl and di(C 3 -C 6 )cycloalkylaminocarbonyl(C 1 -C 6 )alkyl;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Formula Ib:

wherein A 2 , Cy 2 , E, R 2 , and R 3 are as defined for the first or second embodiments described for Formula I above;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Formula Ic:

wherein A 2 , Cy 2 , E, R 2 , and R 3 are as defined for the first or second embodiments described for Formula I above;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Formula Id:

wherein, Cy 1 , A 1 , R 1 , A 2 , Cy 2 , and R 3 are as defined for the first embodiment described for Formula I above, m is 0, 1, 2, 3 or 4 and substituents X are independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, hydroxy(C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl(C 2 -C 4 )alkynyl, halo(C 1 -C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl, halo(C 4 -C 7 )cycloalkylalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, (C 4 -C 7 )cycloalkylalkoxy, halo(C 1 -C 6 )alkoxy, halo(C 3 -C 6 )cycloalkoxy, halo(C 4 -C 7 )cycloalkylalkoxy, (C 1 -C 6 )alkylthio, (C 3 -C 6 )cycloalkythio, (C 4 -C 7 )cycloalkylalkylthio, halo(C 1 -C 6 )alkylthio, halo(C 3 -C 6 )cycloalkythio, halo(C 4 -C 7 )cycloalkylalkylthio, (C 1 -C 6 )alkanesulfinyl, (C 3 -C 6 )cycloalkanesulfinyl, (C 4 -C 7 )cycloalkylalkanesulfinyl, halo(C 1 -C 6 )alkanesulfinyl, halo(C 3 -C 6 )cycloalkanesulfinyl, halo(C 4 -C 7 )cycloalkyl-alkanesulfinyl, (C 1 -C 6 )alkanesulfonyl, (C 3 -C 6 )cycloalkanesulfonyl, (C 4 -C 7 )cycloalkyl-alkanesulfonyl, halo(C 1 -C 6 )alkanesulfonyl, halo(C 3 -C 6 )cycloalkanesulfonyl, halo(C 4 -C 7 )cyclo-alkylalkanesulfonyl, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, H 2 NCO, H 2 NSO 2 , (C 1 -C 6 )alkylaminocarbonyl, di(C 1 -C 6 )alkylaminocarbonyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkylaminocarbonyl, heterocyclylcarbonyl, (C 1 -C 6 )alkylaminosulfonyl, di(C 1 -C 6 )alkylaminosulfonyl, heterocyclosulfonyl, (C 1 -C 6 )alkylcarbonylamino, (C 1 -C 6 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonylamino, (C 1 -C 6 )alkylsulfonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkoxy, heteroaryl, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl amino(C 2 -C 6 )alkoxy, (C 1 -C 6 )alkylamino(C 2 -C 6 )alkoxy, di(C 1 -C 6 )alkylamino(C 2 -C 6 )alkoxy and (C 1 -C 6 )alkylcarbonyl;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Alternatively for Formula Id, Cy 1 , A 1 , R 1 , A 2 , Cy 2 , and R 3 are as defined for the second embodiment described for Formula I above, m is 0, 1, 2, 3 or 4 and substituents X are independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, hydroxy(C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl(C 2 -C 4 )alkynyl, halo(C 1 -C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl, halo(C 4 -C 7 )cycloalkylalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, (C 4 -C 7 )cycloalkylalkoxy, halo(C 1 -C 6 )alkoxy, halo(C 3 -C 6 )cycloalkoxy, halo(C 4 -C 7 )cycloalkylalkoxy, (C 1 -C 6 )alkylthio, (C 3 -C 6 )cycloalkythio, (C 4 -C 7 )cycloalkylalkylthio, halo(C 1 -C 6 )alkylthio, halo(C 3 -C 6 )cycloalkythio, halo(C 4 -C 7 )cycloalkylalkylthio, (C 1 -C 6 )alkanesulfinyl, (C 3 -C 6 )cycloalkanesulfinyl, (C 4 -C 7 )cycloalkylalkanesulfinyl, halo(C 1 -C 6 )alkanesulfinyl, halo(C 3 -C 6 )cycloalkanesulfinyl, halo(C 4 -C 7 )cycloalkylalkanesulfinyl, (C 1 -C 6 )alkanesulfonyl, (C 3 -C 6 )cycloalkanesulfonyl, (C 4 -C 7 )cycloalkylalkanesulfonyl, halo(C 1 -C 6 )alkanesulfonyl, halo(C 3 -C 6 )cycloalkanesulfonyl, halo(C 4 -C 7 )cyclo-alkylalkanesulfonyl, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, H 2 NCO, H 2 NSO 2 , (C 1 -C 6 )alkylaminocarbonyl, di(C 1 -C 6 )alkylaminocarbonyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkylaminocarbonyl, heterocyclylcarbonyl, (C 1 -C 6 )alkylaminosulfonyl, di(C 1 -C 6 )alkylaminosulfonyl, heterocyclosulfonyl, (C 1 -C 6 )alkylcarbonylamino, (C 1 -C 6 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonylamino, (C 1 -C 6 )alkylsulfonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkoxy and heteroaryl;

›DETAILED DESCRIPTION OF THE INVENTION · 5 of 20

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

In another alternative for Formula Id, Cy 1 , A 1 , R 1 , A 2 , Cy 2 , and R 3 are as defined for the second embodiment described for Formula I above, m is 0, 1, 2, 3 or 4 and substituents X are independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, hydroxy(C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl(C 2 -C 4 )alkynyl, halo(C 1 -C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl, halo(C 4 -C 7 )cycloalkylalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, (C 4 -C 7 )cycloalkylalkoxy, halo(C 1 -C 6 )alkoxy, halo(C 3 -C 6 )cycloalkoxy, halo(C 4 -C 7 )cycloalkylalkoxy, (C 1 -C 6 )alkylthio, (C 3 -C 6 )cycloalkythio, (C 4 -C 7 )cycloalkylalkylthio, halo(C 1 -C 6 )alkylthio, halo(C 3 -C 6 )cycloalkythio, halo(C 4 -C 7 )cycloalkylalkylthio, (C 1 -C 6 )alkanesulfinyl, (C 3 -C 6 )cycloalkanesulfinyl, (C 4 -C 7 )cycloalkylalkanesulfinyl, halo(C 1 -C 6 )alkanesulfinyl, halo(C 3 -C 6 )cycloalkanesulfinyl, halo(C 4 -C 7 )cycloalkylalkanesulfinyl, (C 1 -C 6 )alkanesulfonyl, (C 3 -C 6 )cycloalkanesulfonyl, (C 4 -C 7 )cycloalkylalkanesulfonyl, halo(C 1 -C 6 )alkanesulfonyl, halo(C 3 -C 6 )cycloalkanesulfonyl, halo(C 4 -C 7 )cyclo-alkylalkanesulfonyl, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, H 2 NCO, H 2 NSO 2 , (C 1 -C 6 )alkylaminocarbonyl, di(C 1 -C 6 )alkylaminocarbonyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkylaminocarbonyl, heterocyclylcarbonyl, (C 1 -C 6 )alkylaminosulfonyl, di(C 1 -C 6 )alkylaminosulfonyl, heterocyclosulfonyl, (C 1 -C 6 )alkylcarbonylamino, (C 1 -C 6 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonylamino, (C 1 -C 6 )alkyl-sulfonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkoxy, heteroaryl, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl amino(C 2 -C 6 )alkoxy, (C 1 -C 6 )alkylamino(C 2 -C 6 )alkoxy, di(C 1 -C 6 )alkylamino(C 2 -C 6 )alkoxy, (C 1 -C 6 )alkylcarbonyl, (C 3 -C 6 )cycloalkylcarbonyl, (C 3 -C 6 )cycloalkylaminocarbonyl, {(C 3 -C 6 )cycloalkyl}{(C 1 -C 6 )alkyl}aminocarbonyl, di(C 3 -C 6 )cycloalkylaminocarbonyl, (C 3 -C 6 )cycloalkylaminosulfonyl, {(C 3 -C 6 )cycloalkyl}{(C 1 -C 6 )alkyl}aminosulfonyl, di(C 3 -C 6 )cycloalkylaminosulfonyl, cyano(C 1 -C 6 )alkyl, aminocarbonyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylaminocarbonyl(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylaminocarbonyl(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkylaminocarbonyl(C 1 -C 6 )alkyl, {(C 3 -C 6 )cycloalkyl}{(C 1 -C 6 )alkyl}aminocarbonyl(C 1 -C 6 )alkyl and di(C 3 -C 6 )cycloalkylaminocarbonyl(C 1 -C 6 )alkyl;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Formula Ie:

wherein A 2 , Cy 2 , E, R 2 , and R 3 are as defined for the first embodiment described for Formula I above; r is 0, 1, 2, 3 or 4 and substituents G are independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, hydroxy(C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl(C 2 -C 4 )alkynyl, halo(C 1 -C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl, halo(C 4 -C 7 )cycloalkylalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, (C 4 -C 7 )cycloalkylalkoxy, halo(C 1 -C 6 )alkoxy, halo(C 3 -C 6 )cycloalkoxy, halo(C 4 -C 7 )cycloalkylalkoxy, (C 1 -C 6 )alkylthio, (C 3 -C 6 )cycloalkythio, (C 4 -C 7 )cycloalkylalkylthio, halo(C 1 -C 6 )alkylthio, halo(C 3 -C 6 )cycloalkythio, halo(C 4 -C 7 )cycloalkylalkylthio, (C 1 -C 6 )alkanesulfinyl, (C 3 -C 6 )cycloalkanesulfinyl, (C 4 -C 7 )cycloalkylalkanesulfinyl, halo(C 1 -C 6 )alkanesulfinyl, halo(C 3 -C 6 )cycloalkanesulfinyl, halo(C 4 -C 7 )cycloalkyl-alkanesulfinyl, (C 1 -C 6 )alkanesulfonyl, (C 3 -C 6 )cycloalkanesulfonyl, (C 4 -C 7 )cycloalkyl-alkanesulfonyl, halo(C 1 -C 6 )alkanesulfonyl, halo(C 3 -C 6 )cycloalkanesulfonyl, halo(C 4 -C 7 )cyclo-alkylalkanesulfonyl, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, H 2 NCO, H 2 NSO 2 , (C 1 -C 6 )alkylaminocarbonyl, di(C 1 -C 6 )alkylaminocarbonyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkylaminocarbonyl, heterocyclylcarbonyl, (C 1 -C 6 )alkylaminosulfonyl, di(C 1 -C 6 )alkylaminosulfonyl, heterocyclosulfonyl, (C 1 -C 6 )alkylcarbonylamino, (C 1 -C 6 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonylamino, (C 1 -C 6 )alkylsulfonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkoxy heteroaryl, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl amino(C 2 -C 6 )alkoxy, (C 1 -C 6 )alkylamino(C 2 -C 6 )alkoxy, di(C 1 -C 6 )alkylamino(C 2 -C 6 )alkoxy and (C 1 -C 6 )alkylcarbonyl;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Formula If:

wherein E, R 2 , and R 3 are as defined for the first embodiment described for Formula I above; r and s are independently 0, 1, 2, 3 or 4, and G 1 and G 2 are independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, hydroxy(C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl(C 2 -C 4 )alkynyl, halo(C 1 -C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl, halo(C 4 -C 7 )cycloalkylalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, (C 4 -C 7 )cycloalkylalkoxy, halo(C 1 -C 6 )alkoxy, halo(C 3 -C 6 )cycloalkoxy, halo(C 4 -C 7 )cycloalkylalkoxy, (C 1 -C 6 )alkylthio, (C 3 -C 6 )cycloalkythio, (C 4 -C 7 )cycloalkylalkylthio, halo(C 1 -C 6 )alkylthio, halo(C 3 -C 6 )cycloalkythio, halo(C 4 -C 7 )cycloalkylalkylthio, (C 1 -C 6 )alkanesulfinyl, (C 3 -C 6 )cycloalkanesulfinyl, (C 4 -C 7 )cycloalkylalkanesulfinyl, halo(C 1 -C 6 )alkanesulfinyl, halo(C 3 -C 6 )cycloalkanesulfinyl, halo(C 4 -C 7 )cycloalkyl-alkanesulfinyl, (C 1 -C 6 )alkanesulfonyl, (C 3 -C 6 )cycloalkanesulfonyl, (C 4 -C 7 )cycloalkyl-alkanesulfonyl, halo(C 1 -C 6 )alkanesulfonyl, halo(C 3 -C 6 )cycloalkanesulfonyl, halo(C 4 -C 7 )cyclo-alkylalkanesulfonyl, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, H 2 NCO, H 2 NSO 2 , (C 1 -C 6 )alkylaminocarbonyl, di(C 1 -C 6 )alkylaminocarbonyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkylaminocarbonyl, heterocyclylcarbonyl, (C 1 -C 6 )alkylaminosulfonyl, di(C 1 -C 6 )alkylaminosulfonyl, heterocyclosulfonyl, (C 1 -C 6 )alkylcarbonylamino, (C 1 -C 6 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonylamino, (C 1 -C 6 )alkylsulfonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkoxy, heteroaryl, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl amino(C 2 -C 6 )alkoxy, (C 1 -C 6 )alkylamino(C 2 -C 6 )alkoxy, di(C 1 -C 6 )alkylamino(C 2 -C 6 )alkoxy and (C 1 -C 6 )alkylcarbonyl;

›DETAILED DESCRIPTION OF THE INVENTION · 6 of 20

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

In one alternative for Formula If E, R 2 , and R 3 are as defined for the first embodiment described for Formula I above; r and s are independently 0, 1, 2, 3 or 4, and G 1 and G 2 are independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, hydroxy(C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl(C 2 -C 4 )alkynyl, halo(C 1 -C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl, halo(C 4 -C 7 )cycloalkylalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, (C 4 -C 7 )cycloalkylalkoxy, halo(C 1 -C 6 )alkoxy, halo(C 3 -C 6 )cycloalkoxy, halo(C 4 -C 7 )cycloalkylalkoxy, (C 1 -C 6 )alkylthio, (C 3 -C 6 )cycloalkythio, (C 4 -C 7 )cycloalkylalkylthio, halo(C 1 -C 6 )alkylthio, halo(C 3 -C 6 )cycloalkythio, halo(C 4 -C 7 )cycloalkylalkylthio, (C 1 -C 6 )alkanesulfinyl, (C 3 -C 6 )cycloalkanesulfinyl, (C 4 -C 7 )cycloalkylalkanesulfinyl, halo(C 1 -C 6 )alkanesulfinyl, halo(C 3 -C 6 )cycloalkanesulfinyl, halo(C 4 -C 7 )cycloalkylalkanesulfinyl, (C 1 -C 6 )alkanesulfonyl, (C 3 -C 6 )cycloalkanesulfonyl, (C 4 -C 7 )cycloalkylalkanesulfonyl, halo(C 1 -C 6 )alkanesulfonyl, halo(C 3 -C 6 )cycloalkanesulfonyl, halo(C 4 -C 7 )cyclo-alkylalkanesulfonyl, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, H 2 NCO, H 2 NSO 2 , (C 1 -C 6 )alkylaminocarbonyl, di(C 1 -C 6 )alkylaminocarbonyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkylaminocarbonyl, heterocyclylcarbonyl, (C 1 -C 6 )alkylaminosulfonyl, di(C 1 -C 6 )alkylaminosulfonyl, heterocyclosulfonyl, (C 1 -C 6 )alkylcarbonylamino, (C 1 -C 6 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonylamino, (C 1 -C 6 )alkyl-sulfonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkoxy, heteroaryl, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl amino(C 2 -C 6 )alkoxy, (C 1 -C 6 )alkylamino(C 2 -C 6 )alkoxy, di(C 1 -C 6 )alkylamino(C 2 -C 6 )alkoxy, (C 1 -C 6 )alkylcarbonyl, (C 3 -C 6 )cycloalkylcarbonyl, (C 3 -C 6 )cycloalkylaminocarbonyl, {(C 3 -C 6 )cycloalkyl}{(C 1 -C 6 )alkyl}aminocarbonyl, di(C 3 -C 6 )cycloalkylaminocarbonyl, (C 3 -C 6 )cycloalkylaminosulfonyl, {(C 3 -C 6 )cycloalkyl}{(C 1 -C 6 )alkyl}aminosulfonyl, di(C 3 -C 6 )cycloalkylaminosulfonyl, cyano(C 1 -C 6 )alkyl, aminocarbonyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylaminocarbonyl(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylaminocarbonyl(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkylaminocarbonyl(C 1 -C 6 )alkyl, {(C 3 -C 6 )cycloalkyl}{(C 1 -C 6 )alkyl}aminocarbonyl(C 1 -C 6 )alkyl and di(C 3 -C 6 )cycloalkylaminocarbonyl(C 1 -C 6 )alkyl;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Formula Ig:

wherein, Cy 1 , A 1 , R 1 , A 2 , Cy 2 , R 2 , E, R 3 , Y, and n are as defined for the first or second embodiments described for Formula I above and at least one and preferably both stereocenters are in the configuration depicted. Pharmaceutically acceptable salts, enantiomers or diastereomers thereof are also included.

Another embodiment is a compound of Formula Ih:

Another embodiment is a compound of Formula Ii:

wherein E, R 2 and R 3 are as defined for the first or second embodiments described for Formula I above, r is 0, 1, 2, 3 or 4, and substituents G are independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, hydroxy(C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl(C 2 -C 4 )alkynyl, halo(C 1 -C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl, halo(C 4 -C 7 )cycloalkylalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, (C 4 -C 7 )cycloalkylalkoxy, halo(C 1 -C 6 )alkoxy, halo(C 3 -C 6 )cycloalkoxy, halo(C 4 -C 7 )cycloalkylalkoxy, (C 1 -C 6 )alkylthio, (C 3 -C 6 )cycloalkythio, (C 4 -C 7 )cycloalkylalkylthio, halo(C 1 -C 6 )alkylthio, halo(C 3 -C 6 )cycloalkythio, halo(C 4 -C 7 )cycloalkylalkylthio, (C 1 -C 6 )alkanesulfinyl, (C 3 -C 6 )cycloalkanesulfinyl, (C 4 -C 7 )cycloalkylalkanesulfinyl, halo(C 1 -C 6 )alkanesulfinyl, halo(C 3 -C 6 )cycloalkanesulfinyl, halo(C 4 -C 7 )cycloalkyl-alkanesulfinyl, (C 1 -C 6 )alkanesulfonyl, (C 3 -C 6 )cycloalkanesulfonyl, (C 4 -C 7 )cycloalkyl-alkanesulfonyl, halo(C 1 -C 6 )alkanesulfonyl, halo(C 3 -C 6 )cycloalkanesulfonyl, halo(C 4 -C 7 )cyclo-alkylalkanesulfonyl, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, H 2 NCO, H 2 NSO 2 , (C 1 -C 6 )alkylaminocarbonyl, di(C 1 -C 6 )alkylaminocarbonyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkylaminocarbonyl, heterocyclylcarbonyl, (C 1 -C 6 )alkylaminosulfonyl, di(C 1 -C 6 )alkylaminosulfonyl, heterocyclosulfonyl, (C 1 -C 6 )alkylcarbonylamino, (C 1 -C 6 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonylamino, (C 1 -C 6 )alkylsulfonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkoxy, heteroaryl, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl amino(C 2 -C 6 )alkoxy, (C 1 -C 6 )alkylamino(C 2 -C 6 )alkoxy, di(C 1 -C 6 )alkylamino(C 2 -C 6 )alkoxy and (C 1 -C 6 )alkylcarbonyl;

›DETAILED DESCRIPTION OF THE INVENTION · 7 of 20

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Alternatively, for Formula Ii:

E, R 2 and R 3 are as defined for the first or second embodiments described for Formula I above, r is 0, 1, 2, 3 or 4, and substituents G are independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, hydroxy(C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl(C 2 -C 4 )alkynyl, halo(C 1 -C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl, halo(C 4 -C 7 )cycloalkylalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, (C 4 -C 7 )cycloalkylalkoxy, halo(C 1 -C 6 )alkoxy, halo(C 3 -C 6 )cycloalkoxy, halo(C 4 -C 7 )cycloalkylalkoxy, (C 1 -C 6 )alkylthio, (C 3 -C 6 )cycloalkythio, (C 4 -C 7 )cycloalkylalkylthio, halo(C 1 -C 6 )alkylthio, halo(C 3 -C 6 )cycloalkythio, halo(C 4 -C 7 )cycloalkylalkylthio, (C 1 -C 6 )alkanesulfinyl, (C 3 -C 6 )cycloalkanesulfinyl, (C 4 -C 7 )cycloalkylalkanesulfinyl, halo(C 1 -C 6 )alkanesulfinyl, halo(C 3 -C 6 )cycloalkanesulfinyl, halo(C 4 -C 7 )cycloalkylalkanesulfinyl, (C 1 -C 6 )alkanesulfonyl, (C 3 -C 6 )cycloalkanesulfonyl, (C 4 -C 7 )cycloalkylalkanesulfonyl, halo(C 1 -C 6 )alkanesulfonyl, halo(C 3 -C 6 )cycloalkanesulfonyl, halo(C 4 -C 7 )cyclo-alkylalkanesulfonyl, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, H 2 NCO, H 2 NSO 2 , (C 1 -C 6 )alkylaminocarbonyl, di(C 1 -C 6 )alkylaminocarbonyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkylaminocarbonyl, heterocyclylcarbonyl, (C 1 -C 6 )alkylaminosulfonyl, di(C 1 -C 6 )alkylaminosulfonyl, heterocyclosulfonyl, (C 1 -C 6 )alkylcarbonylamino, (C 1 -C 6 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonylamino, (C 1 -C 6 )alkyl-sulfonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkoxy, heteroaryl, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl amino(C 2 -C 6 )alkoxy, (C 1 -C 6 )alkylamino(C 2 -C 6 )alkoxy, di(C 1 -C 6 )alkylamino(C 2 -C 6 )alkoxy, (C 1 -C 6 )alkylcarbonyl, (C 3 -C 6 )cycloalkylcarbonyl, (C 3 -C 6 )cycloalkylaminocarbonyl, {(C 3 -C 6 )cycloalkyl}{(C 1 -C 6 )alkyl}aminocarbonyl, di(C 3 -C 6 )cycloalkylaminocarbonyl, (C 3 -C 6 )cycloalkylaminosulfonyl, {(C 3 -C 6 )cycloalkyl}{(C 1 -C 6 )alkyl}aminosulfonyl, di(C 3 -C 6 )cycloalkylaminosulfonyl, cyano(C 1 -C 6 )alkyl, aminocarbonyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylaminocarbonyl(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylaminocarbonyl(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkylaminocarbonyl(C 1 -C 6 )alkyl, {(C 3 -C 6 )cycloalkyl}{(C 1 -C 6 )alkyl}aminocarbonyl(C 1 -C 6 )alkyl and di(C 3 -C 6 )cycloalkylaminocarbonyl(C 1 -C 6 )alkyl;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Formula Ij:

wherein R 2 and R 3 are as defined for the first or second embodiments described for Formula I above, R 1a is methyl or ethyl, r is 0, 1, 2, 3 or 4, and substituents G are independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, hydroxy(C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl(C 2 -C 4 )alkynyl, halo(C 1 -C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl, halo(C 4 -C 7 )cycloalkylalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, (C 4 -C 7 )cycloalkylalkoxy, halo(C 1 -C 6 )alkoxy, halo(C 3 -C 6 )cycloalkoxy, halo(C 4 -C 7 )cycloalkylalkoxy, (C 1 -C 6 )alkylthio, (C 3 -C 6 )cycloalkythio, (C 4 -C 7 )cycloalkylalkylthio, halo(C 1 -C 6 )alkylthio, halo(C 3 -C 6 )cycloalkythio, halo(C 4 -C 7 )cycloalkylalkylthio, (C 1 -C 6 )alkanesulfinyl, (C 3 -C 6 )cycloalkanesulfinyl, (C 4 -C 7 )cycloalkylalkanesulfinyl, halo(C 1 -C 6 )alkanesulfinyl, halo(C 3 -C 6 )cycloalkanesulfinyl, halo(C 4 -C 7 )cycloalkyl-alkanesulfinyl, (C 1 -C 6 )alkanesulfonyl, (C 3 -C 6 )cycloalkanesulfonyl, (C 4 -C 7 )cycloalkyl-alkanesulfonyl, halo(C 1 -C 6 )alkanesulfonyl, halo(C 3 -C 6 )cycloalkanesulfonyl, halo(C 4 -C 7 )cyclo-alkylalkanesulfonyl, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, H 2 NCO, H 2 NSO 2 , (C 1 -C 6 )alkylaminocarbonyl, di(C 1 -C 6 )alkylaminocarbonyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkylaminocarbonyl, heterocyclylcarbonyl, (C 1 -C 6 )alkylaminosulfonyl, di(C 1 -C 6 )alkylaminosulfonyl, heterocyclosulfonyl, (C 1 -C 6 )alkylcarbonylamino, (C 1 -C 6 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonylamino, (C 1 -C 6 )alkylsulfonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkoxy, heteroaryl, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl amino(C 2 -C 6 )alkoxy, (C 1 -C 6 )alkylamino(C 2 -C 6 )alkoxy, di(C 1 -C 6 )alkylamino(C 2 -C 6 )alkoxy and (C 1 -C 6 )alkylcarbonyl;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Alternatively for Formula Ij:

R 2 and R 3 are as defined for the first or second embodiments described for Formula I above, R 1a is methyl or ethyl, r is 0, 1, 2, 3 or 4, and substituents G are independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, hydroxy(C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl(C 2 -C 4 )alkynyl, halo(C 1 -C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl, halo(C 4 -C 7 )cycloalkylalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, (C 4 -C 7 )cycloalkylalkoxy, halo(C 1 -C 6 )alkoxy, halo(C 3 -C 6 )cycloalkoxy, halo(C 4 -C 7 )cycloalkylalkoxy, (C 1 -C 6 )alkylthio, (C 3 -C 6 )cycloalkythio, (C 4 -C 7 )cycloalkylalkylthio, halo(C 1 -C 6 )alkylthio, halo(C 3 -C 6 )cycloalkythio, halo(C 4 -C 7 )cycloalkylalkylthio, (C 1 -C 6 )alkanesulfinyl, (C 3 -C 6 )cycloalkanesulfinyl, (C 4 -C 7 )cycloalkylalkanesulfinyl, halo(C 1 -C 6 )alkanesulfinyl, halo(C 3 -C 6 )cycloalkanesulfinyl, halo(C 4 -C 7 )cycloalkylalkanesulfinyl, (C 1 -C 6 )alkanesulfonyl, (C 3 -C 6 )cycloalkanesulfonyl, (C 4 -C 7 )cycloalkylalkanesulfonyl, halo(C 1 -C 6 )alkanesulfonyl, halo(C 3 -C 6 )cycloalkanesulfonyl, halo(C 4 -C 7 )cyclo-alkylalkanesulfonyl, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, H 2 NCO, H 2 NSO 2 , (C 1 -C 6 )alkylaminocarbonyl, di(C 1 -C 6 )alkylaminocarbonyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkylaminocarbonyl, heterocyclylcarbonyl, (C 1 -C 6 )alkylaminosulfonyl, di(C 1 -C 6 )alkylaminosulfonyl, heterocyclosulfonyl, (C 1 -C 6 )alkylcarbonylamino, (C 1 -C 6 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonylamino, (C 1 -C 6 )alkyl-sulfonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkoxy, heteroaryl, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl amino(C 2 -C 6 )alkoxy, (C 1 -C 6 )alkylamino(C 2 -C 6 )alkoxy, di(C 1 -C 6 )alkylamino(C 2 -C 6 )alkoxy, (C 1 -C 6 )alkylcarbonyl, (C 3 -C 6 )cycloalkylcarbonyl, (C 3 -C 6 )cycloalkylaminocarbonyl, {(C 3 -C 6 )cycloalkyl}{(C 1 -C 6 )alkyl}aminocarbonyl, di(C 3 -C 6 )cycloalkylaminocarbonyl, (C 3 -C 6 )cycloalkylaminosulfonyl, {(C 3 -C 6 )cycloalkyl}{(C 1 -C 6 )alkyl}aminosulfonyl, di(C 3 -C 6 )cycloalkylaminosulfonyl, cyano(C 1 -C 6 )alkyl, aminocarbonyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylaminocarbonyl(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylaminocarbonyl(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkylaminocarbonyl(C 1 -C 6 )alkyl, {(C 3 -C 6 )cycloalkyl}{(C 1 -C 6 )alkyl}aminocarbonyl(C 1 -C 6 )alkyl and di(C 3 -C 6 )cycloalkylaminocarbonyl(C 1 -C 6 )alkyl;

›DETAILED DESCRIPTION OF THE INVENTION · 8 of 20

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Formula Ik:

wherein Cy 2 , R 2 and R 3 are as defined for the first or second embodiments described for Formula I above, and R 1a is methyl or ethyl;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Formula Ik wherein R 1a is methyl or ethyl, R 2 is phenyl optionally substituted with up to 2 groups selected from halogen, methyl, trifluoromethyl and cyano, R 3 is MeSO 2 NHCH 2 CH 2 CH 2 , H 2 NC(═O)CH 2 CH 2 , H 2 NC(═O)CMe 2 CH 2 , 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl and Cy 2 is 5-oxo-4,5-dihydro-1H-pyrazolyl, 3-oxo-2,3-dihydro-1H-pyrazolyl, 5-oxo-4,5-dihydro-1H-imidazolyl, 2-oxo-2,3-dihydro-1H-imidazolyl, 5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl, 5-oxo-4,5-dihydro-1,3,4-thiadiazolyl, 1,2-dihydro-2-oxopyridyl, 2,3-dihydro-3-oxopyridazinyl, 1,2-dihydro-2-oxopyrimidinyl, 3,4-dihydro-4-oxopyrimidinyl or 1,2-dihydro-2-oxopyrazinyl optionally substituted with up to 3 groups independently selected from fluorine, chlorine, cyano, hydroxy, amino, (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C 1 -C 2 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkoxy, CONH 2 , (C 1 -C 4 )alkylaminocarbonyl, di(C 1 -C 4 )alkylaminocarbonyl, and (C 1 -C 4 )alkylcarbonylamino;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof. In one alternative, the embodiments described in this paragraph exclude the compound exemplified in Examples 221 or 313 or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Formula Ik wherein R 1a is methyl or ethyl, R 2 is phenyl optionally substituted with up to 2 groups selected from halogen, methyl, trifluoromethyl and cyano, R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl and Cy 2 is 1,2-dihydro-2-oxopyridyl, 2,3-dihydro-3-oxopyridazinyl, 1,2-dihydro-2-oxopyrimidinyl, 3,4-dihydro-4-oxopyrimidinyl or 1,2-dihydro-2-oxopyrazinyl optionally substituted with up to 2 groups independently selected from (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl, halo(C 1 -C 4 )alkyl and halogen;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Formula Ik wherein R 1a is methyl or ethyl, R 2 is phenyl optionally substituted with up to 2 groups selected from halogen, methyl, trifluoromethyl and cyano, R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl and Cy 2 is heteroaryl optionally substituted with up 2 groups selected from (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, halogen, cyano, CONH 2 , (C 1 -C 4 )alkylaminocarbonyl, di(C 1 -C 4 )alkylaminocarbonyl and (C 3 -C 5 )cycloalkylaminocarbonyl or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof. In another embodiment, Cy 2 is heteroaryl optionally substituted with one group selected from (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, halogen, cyano, CONHMe and CONMe 2 ; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof. In an alternative embodiment CONH 2 is excluded as a permissible substituent when Cy 2 is pyridine or thiazole. In yet another embodiment, Cy 2 is heteroaryl optionally substituted with one group selected from (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, halogen, cyano;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Formula Ik wherein R 1a is methyl or ethyl, R 2 is phenyl or fluorophenyl, R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl and Cy 2 is pyridine, pyridine N-oxide, pyridazine, pyrimidine, pyrazine, thiazole, pyrazole or thiadiazole optionally substituted with methyl, fluorine, chlorine, cyano, CONH 2 , CONHMe, CONMe 2 , CONHt-Bu or CONHc-Pr;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof. In an alternative embodiment CONH 2 is excluded as a permissible substituent when Cy 2 is pyridine or thiazole.

Another embodiment is a compound of Formula Il:

wherein Cy 2 , R 2 and R 3 are as defined for the first or second embodiments described for Formula I above, and t is 1, 2 or 3;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Formula Il wherein t is 1, 2 or 3; R 2 is phenyl or fluorophenyl, R 3 is MeSO 2 NHCH 2 CH 2 CH 2 , H 2 NC(═O)CH 2 CH 2 , H 2 NC(═O)CMe 2 CH 2 , 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl and Cy 2 is heterocyclyl optionally substituted with up to 3 groups independently selected from oxo, fluorine, chlorine, cyano, hydroxy, amino, (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C 1 -C 2 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkoxy, CONH 2 , (C 1 -C 4 )alkylaminocarbonyl, di(C 1 -C 4 )alkylaminocarbonyl and (C 1 -C 4 )alkylcarbonylamino;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Formula Il wherein t is 1, 2 or 3; R 2 is phenyl or fluorophenyl, R 3 is MeSO 2 NHCH 2 CH 2 CH 2 , H 2 NC(═O)CH 2 CH 2 , H 2 NC(═O)CMe 2 CH 2 , 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl and Cy 2 is hetereoaryl optionally substituted with up to 3 groups independently selected from oxo, fluorine, chlorine, cyano, hydroxy, amino, (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C 1 -C 2 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkoxy, CONH 2 , (C 1 -C 4 )alkylaminocarbonyl, di(C 1 -C 4 )alkylaminocarbonyl and (C 1 -C 4 )alkylcarbonylamino;

›DETAILED DESCRIPTION OF THE INVENTION · 9 of 20

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Formula Il wherein t is 1, 2 or 3; R 2 is phenyl or fluorophenyl, R 3 is MeSO 2 NHCH 2 CH 2 CH 2 , H 2 NC(═O)CH 2 CH 2 , H 2 NC(═O)CMe 2 CH 2 , 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl and Cy 2 is pyridine, pyridazine, pyrimidine, pyrazine, thiadiazole, pyrazole or thiazole optionally substituted with up to 2 groups independently selected from methyl, fluorine, chlorine, cyano, CF 3 , CONH 2 , CONHMe or CONMe 2 ; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment is a compound of Formula Il wherein R 2 is phenyl or fluorophenyl, R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl and Cy 2 is pyridine, pyridazine, pyrimidine, pyrazine, thiadiazole, pyrazole or thiazole optionally substituted with up to 2 groups independently selected from methyl, fluorine, chlorine, cyano, CF 3 , CONH 2 , CONHMe or CONMe 2 ;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment of the invention is a compound of any one of Formulas Im 1-12 or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof:

In Formulas Im 1-12 , the oxodihydropyridyl, oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings in Formulas Im 1-12 are optionally substituted (substitution at ring carbons bonded to hydrogen and ring nitrogen atoms bonded to hydrogen atoms are encompassed, i.e., a “substitutable ring nitrogen atom”) with up to four substituents as described above for Cy 2 . Suitable substituents for Cy 2 and suitable values for R 1 , R 2 , R 3 , A 1 , Cy 1 and E are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiments. Alternatively, suitable substituents for Cy 1 and the oxodihydropyridyl, oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings in Formulas Im 1-12 are as described for G 1 and G 2 , respectively, in Formula If, and values for R 1 , R 2 , R 3 , A 1 , Cy 1 and E are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiments. Alternatively, suitable substituents for Cy 1 include (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )haloalkoxy, halogen, cyano and nitro; suitable substituents for a substitutable ring nitrogen atom in the oxodihydropyridyl, oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings in Formulas Im 1-12 include (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C 1 -C 2 )alkyl, and (C 1 -C 4 )haloalkyl; suitable substituents for a ring carbon atom in the oxodihydropyridyl, oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings in Formulas Im 1-12 include fluorine, chlorine, cyano, hydroxy, amino, (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C 1 -C 2 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkoxy, CONH 2 , (C 1 -C 4 )alkylaminocarbonyl, di(C 1 -C 4 )alkylaminocarbonyl and (C 1 -C 4 )alkylcarbonylamino; and suitable values for R 1 , R 2 , R 3 , A 1 , Cy 1 and E are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiments. In another alternative, the embodiments in this paragraph exclude the compound exemplified in Example 221 and Example 313 or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

For each of the embodiments described in the previous paragraph, R 1 is preferably methyl or ethyl.

For each of the embodiments described in the paragraph immediately following Formulas Im 1-12 , R 1 is preferably methyl or ethyl; and R 3 is MeSO 2 NHCH 2 CH 2 CH 2 , H 2 NC(═O)CH 2 CH 2 , H 2 NC(═O)CMe 2 CH 2 , 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediately following Formulas Im 1-12 , R 1 is preferably methyl or ethyl; and R 3 is H 2 NC(═O)CMe 2 CH 2 , 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediately following Formulas Im 1-12 , R 1 is preferably methyl or ethyl; R 2 is phenyl optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, CONH 2 , (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, and SO 2 Me; and R 3 is MeSO 2 NHCH 2 CH 2 CH 2 , H 2 NC(═O)CH 2 CH 2 , H 2 NC(═O)CMe 2 CH 2 , 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediately following Formulas Im 1-12 , R 1 is preferably methyl or ethyl; R 2 is phenyl optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, CONH 2 , (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, and SO 2 Me; and R 3 is H 2 NC(═O)CMe 2 CH 2 , 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediately following Formulas Im 1-12 , R 1 is preferably methyl or ethyl; and R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediately following Formulas Im 1-12 , R 1 is preferably methyl or ethyl; R 2 is phenyl or fluorophenyl; and R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediately following Formulas Im 1-12 , R 1 is preferably methyl or ethyl; R 2 is phenyl or fluorophenyl; R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; the substituent on the substitutable ring nitrogen atom in the oxodihydropyridyl, oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings in Formulas Im 1-12 is (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C 1 -C 2 )alkyl, or (C 1 -C 2 )haloalkyl; and one or two ring carbon atoms in the oxodihydropyridyl, oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings in Formulas Im 1-12 are optionally substituted with methyl or ethyl.

›DETAILED DESCRIPTION OF THE INVENTION · 10 of 20

Another embodiment of the invention is a compound of any one of Formulas Im 1-12 , or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof:

In Formulas In 1-12 , the oxodihydropyridyl, oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings are optionally substituted (substitution at ring carbons bonded to hydrogen and at nitrogen atoms bonded to hydrogen atoms are encompassed, i.e., a “substitutable ring nitrogen atom”) with up to four substituents as described above for Cy 2 . Suitable substituents for Cy 2 and suitable values for R 1 , R 2 , R 3 and Cy 1 are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiments. Alternatively, suitable substituents for Cy 1 and the oxodihydropyridyl, oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings in Formulas In 1-12 are as described for G 1 and G 2 , respectively, in Formula If, and values for R 1 , R 2 , R 3 and Cy 1 are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiments. Alternatively, suitable substituents for Cy 1 include (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )haloalkoxy, halogen, cyano and nitro; suitable substituents for a substitutable ring nitrogen atom in the oxodihydropyridyl, oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings in Formulas In 1-12 include (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C 1 -C 2 )alkyl and (C 1 -C 4 )haloalkyl; suitable substituents for a ring carbon atom in the oxodihydropyridyl, oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings in Formulas In 1-12 include fluorine, chlorine, cyano, hydroxy, amino, (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C 1 -C 2 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkoxy, CONH 2 , (C 1 -C 4 )alkylaminocarbonyl, di(C 1 -C 4 )alkylaminocarbonyl and (C 1 -C 4 )alkylcarbonylamino; and suitable values for R 1 , R 2 , R 3 , and Cy 1 are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiments. In another alternative, the embodiments described in this paragraph exclude the compound exemplified in Example 221 and Example 313 or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

For each of the embodiments described in the previous paragraph, R 1 is preferably methyl or ethyl.

For each of the embodiments described in the paragraph immediately following Formulas In 1-12 , R 1 is preferably methyl or ethyl; and R 3 is MeSO 2 NHCH 2 CH 2 CH 2 , H 2 NC(═O)CH 2 CH 2 , H 2 NC(═O)CMe 2 CH 2 , 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediately following Formulas In 1-12 , R 1 is preferably methyl or ethyl; and R 3 is H 2 NC(═O)CMe 2 CH 2 , 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediately following Formulas In 1-12 , R 1 is preferably methyl or ethyl; R 2 is phenyl optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, CONH 2 , (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl and SO 2 Me; and R 3 is MeSO 2 NHCH 2 CH 2 CH 2 , H 2 NC(═O)CH 2 CH 2 , H 2 NC(═O)CMe 2 CH 2 , 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediately following Formulas In 1-12 , R 1 is preferably methyl or ethyl; R 2 is phenyl optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, CONH 2 , (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl and SO 2 Me; and R 3 is H 2 NC(═O)CMe 2 CH 2 , 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediately following Formulas In 1-12 , R 1 is preferably methyl or ethyl; and R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediately following Formulas In 1-12 , R 1 is preferably methyl or ethyl; R 2 is phenyl or fluorophenyl; and R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediately following Formulas In 1-12 , R 1 is preferably methyl or ethyl; R 2 is phenyl or fluorophenyl; R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; the substituent on the substitutable ring nitrogen atom in the oxodihydropyridyl, oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings in Formulas In 1-12 is (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C 1 -C 2 )alkyl, or (C 1 -C 2 )haloalkyl; and one or two ring carbon atoms in the oxodihydropyridyl, oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings in Formulas In 1-12 are optionally substituted with methyl or ethyl.

Another embodiment of the invention is a compound of any one for Formulas Io 1-12 , or a pharmaceutically acceptable salt thereof:

In Formulas Io 1-12 , the oxodihydropyridyl, oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings in Formulas Io 1-12 are optionally substituted (substitution at ring carbons bonded to hydrogen and at nitrogen atoms bonded to hydrogen atoms are encompassed, i.e., a “substitutable ring nitrogen atom”) with up to four substituents as described above for Cy 2 ; suitable values for G 1 are as described for G 1 in Formula If; n is 0, 1, 2 or 3; and suitable substituents for Cy 2 and suitable values for R 1 , R 2 and R 3 are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiments. Alternatively, n is 0, 1, 2 or 3; suitable values for G 1 and substituents for the oxodihydropyridyl, oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings in Formulas Io 1-12 are as described for G 1 and G 2 , respectively, in Formula If, and values for R 1 , R 2 and R 3 are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiments. Alternatively, n is 0, 1, 2 or 3; suitable values for G 1 include (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )haloalkoxy, halogen, cyano and nitro; suitable substituents for a substitutable ring nitrogen atom in the oxodihydropyridyl, oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings in Formulas Io 1-12 include C 1 -C 4 alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C 1 -C 2 )alkyl and C 1 -C 4 haloalkyl; suitable substituents for a ring carbon atom in the oxopyridyl, oxopyridazinyl, oxopyrimidinyl and oxopyrazinyl rings in Formulas Io 1-12 include fluorine, chlorine, cyano, hydroxy, amino, (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C 1 -C 2 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkoxy, CONH 2 , (C 1 -C 4 )alkylaminocarbonyl, di(C 1 -C 4 )alkylaminocarbonyl and (C 1 -C 4 )alkylcarbonylamino; and suitable values for R 1 , R 2 and R 3 are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiments. In another alternative, the embodiments described in this paragraph exclude the compound exemplified in Example 221 and Example 313 or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

›DETAILED DESCRIPTION OF THE INVENTION · 11 of 20

For each of the embodiments described in the previous paragraph, R 1 is preferably methyl or ethyl.

For each of the embodiments described in the paragraph immediately following Formulas Io 1-12 , R 1 is preferably methyl or ethyl; and R 3 is MeSO 2 NHCH 2 CH 2 CH 2 , H 2 NC(═O)CH 2 CH 2 , H 2 NC(═O)CMe 2 CH 2 , 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediately following Formulas Io 1-12 , R 1 is preferably methyl or ethyl; and R 3 is H 2 NC(═O)CMe 2 CH 2 , 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediately following Formulas Io 1-12 , R 1 is preferably methyl or ethyl; R 2 is phenyl optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, CONH 2 , (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl and SO 2 Me; and R 3 is MeSO 2 NHCH 2 CH 2 CH 2 , H 2 NC(═O)CH 2 CH 2 , H 2 NC(═O)CMe 2 CH 2 , 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediately following Formulas Io 1-12 , R 1 is preferably methyl or ethyl; R 2 is phenyl optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, CONH 2 , (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl and SO 2 Me; and R 3 is H 2 NC(═O)CMe 2 CH 2 , 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediately following Formulas Io 1-12 , R 1 is preferably methyl or ethyl; and R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediately following Formulas Io 1-12 , R 1 is preferably methyl or ethyl; R 2 is phenyl or fluorophenyl; and R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediately following Formulas Io 1-12 , R 1 is preferably methyl or ethyl; R 2 is phenyl or fluorophenyl; R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; the substituent on the substitutable ring nitrogen atom in the oxodihydropyridyl, oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings in Formulas Io 1-12 is (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C 1 -C 2 )alkyl, or (C 1 -C 2 )haloalkyl; and one or two ring carbon atoms in the oxodihydropyridyl, oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings in Formulas Io 1-12 are optionally substituted with methyl or ethyl.

Another embodiment of the invention is a compound represented by any one of Formulas Ip 1-7 , or a pharmaceutically acceptable salt thereof:

In Formulas Ip 1-7 , G 1 is (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )haloalkoxy, halogen, cyano or nitro; n is 0, 1 or 2; G 2a is (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl or (C 1 -C 4 )haloalkyl; G 2b is hydrogen, fluorine, chlorine, cyano, hydroxy, amino, (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C 1 -C 2 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkoxy, CONH 2 , (C 1 -C 4 )alkylaminocarbonyl, di(C 1 -C 4 )alkylaminocarbonyl or (C 1 -C 4 )alkylcarbonylamino; and suitable values for R 1 , R 2 and R 3 are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiments. In another alternative, the embodiments in this paragraph exclude the compound exemplified in Example 221 and Example 313 or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

For each of the embodiments described in the previous paragraph, R 1 is preferably methyl or ethyl.

For each of the embodiments described in the paragraph immediately following Formulas Ip 1-7 , R 1 is preferably methyl or ethyl; and R 3 is MeSO 2 NHCH 2 CH 2 CH 2 , H 2 NC(═O)CH 2 CH 2 , H 2 NC(═O)CMe 2 CH 2 , 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediately following Formulas Ip 1-7 , R 1 is preferably methyl or ethyl; and R 3 is H 2 NC(═O)CMe 2 CH 2 , 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediately following Formulas Ip 1-7 , R 1 is preferably methyl or ethyl; R 2 is phenyl optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, CONH 2 , (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl and SO 2 Me; and R 3 is MeSO 2 NHCH 2 CH 2 CH 2 , H 2 NC(═O)CH 2 CH 2 , H 2 NC(═O)CMe 2 CH 2 , 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediately following Formulas Ip 1-7 , R 1 is preferably methyl or ethyl; R 2 is phenyl optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, CONH 2 , (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl and SO 2 Me; and R 3 is H 2 NC(═O)CMe 2 CH 2 , 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediately following Formulas Ip 1-7 , R 1 is preferably methyl or ethyl; and R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediately following Formulas Ip 1-7 , R 1 is preferably methyl or ethyl; R 2 is phenyl or fluorophenyl; and R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiment described in the paragraph immediately following Formulas Ip 1-7 , R 1 is preferably methyl or ethyl; R 2 is phenyl or fluorophenyl; R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; the substituent G 2a is selected from (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C 1 -C 2 )alkyl, and (C 1 -C 2 )haloalkyl; and G 2b is optionally selected from hydrogen, methyl or ethyl.

›DETAILED DESCRIPTION OF THE INVENTION · 12 of 20

Another embodiment of the invention is a compound of any one of Formulas Iq 1-20 or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof:

In Formulas Iq 1-21 , the pyridine, pyridazine, pyrimidine, pyrazine, pyrazole, thiazole and thiadiazole rings in Formulas Iq 1-21 are optionally substituted (substitution at ring carbons bonded to hydrogen and ring nitrogen atoms bonded to hydrogen atoms are encompassed, i.e., a “substitutable ring nitrogen atom”) with up to four substituents as described above for Cy 2 . Suitable substituents for Cy 2 and suitable values for R 1 , R 2 , R 3 , A 1 , Cy 1 and E are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiments. Alternatively, suitable substituents for Cy 1 and the pyridine, pyridazine, pyrimidine, pyrazine, pyrazole, thiazole and thiadiazole rings in Formulas Iq 1-21 are as described for G 1 and G 2 , respectively, in Formula If, and values for R 1 , R 2 , R 3 , A 1 , Cy 1 and E are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiments. Alternatively, suitable substituents for Cy 1 include (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )haloalkoxy, halogen, cyano and nitro; suitable substituents for a substitutable ring nitrogen atom in the pyrazole rings in Formulas Iq 18 , Iq 20 and Iq 21 include (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C 1 -C 2 )alkyl, and (C 1 -C 4 )haloalkyl; suitable substituents for a ring carbon atom in the pyridine, pyridazine, pyrimidine, pyrazine, pyrazole, thiazole and thiadiazole rings in Formulas Iq 1-21 include fluorine, chlorine, cyano, amino, (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C 1 -C 2 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkoxy, CONH 2 , (C 1 -C 4 )alkylaminocarbonyl, di(C 1 -C 4 )alkylaminocarbonyl, (C 3 -C 4 )cycloalkylaminocarbonyl, {(C 1 -C 4 )alkyl}{(C 3 -C 4 )cycloalkyl}aminocarbonyl and (C 1 -C 4 )alkylcarbonylamino; the ring nitrogen in the pyridine rings in Formulas Iq 1-4 is optionally substituted by oxo; and suitable values for R 1 , R 2 , R 3 , A 1 , Cy 1 and E are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiments. In another alternative, the embodiments in this paragraph exclude the compound exemplified in Example 205, Example 211, Example 214, Example 222, Example 226, Example 235, Example 236, Example 281, Example 292, Example 295, Example 298, Example 300, Example 302, Example 305, Example 304, Example 306, Example 307, Example 210, Example 296, Example 311, Example 230, Example 244, Example 258 and Example 291 or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

For each of the embodiments described in the previous paragraph, R 1 is preferably methyl or ethyl.

For each of the embodiments described in the paragraph immediately following Formulas Iq 1-21 , R 1 is preferably methyl or ethyl; and R 3 is MeSO 2 NHCH 2 CH 2 CH 2 , H 2 NC(═O)CH 2 CH 2 , H 2 NC(═O)CMe 2 CH 2 , 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediately following Formulas Iq 1-21 , R 1 is preferably methyl or ethyl; and R 3 is H 2 NC(═O)CMe 2 CH 2 , 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediately following Formulas Iq 1-21 , R 1 is preferably methyl or ethyl; R 2 is phenyl optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, CONH 2 , (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl and SO 2 Me; and R 3 is MeSO 2 NHCH 2 CH 2 CH 2 , H 2 NC(═O)CH 2 CH 2 , H 2 NC(═O)CMe 2 CH 2 , 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediately following Formulas Iq 1-21 , R 1 is preferably methyl or ethyl; R 2 is phenyl optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, CONH 2 , (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl and SO 2 Me; and R 3 is H 2 NC(═O)CMe 2 CH 2 , 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediately following Formulas Iq 1-21 , R 1 is preferably methyl or ethyl; and R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediately following Formulas Iq 1-21 , R 1 is preferably methyl or ethyl; R 2 is phenyl or fluorophenyl; and R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediately following Formulas Iq 1-21 , R 1 is preferably methyl or ethyl; R 2 is phenyl or fluorophenyl; R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; one or two ring carbon atoms in the pyridine, pyridazine, pyrimidine, pyrazine, pyrazole, thiazole and thiadiazole rings in Formulas Iq 1-21 are optionally substituted with fluoro, chloro, cyano, CONH 2 , CONHMe, CONMe 2 , CONHc-Pr, methoxy, ethoxy, methyl, ethyl or CF 3 . the substitutable ring nitrogen atom in the pyrazole rings in Formulas Iq 18 , Iq 20 and Iq 21 are optionally substituted with (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C 1 -C 2 )alkyl, or (C 1 -C 2 )haloalkyl, the ring nitrogen in the pyridine rings in Formulas Iq 1-4 is optionally substituted by oxo.

Another embodiment of the invention is a compound of any one of Formulas Ir 1-21 , or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof:

In Formulas Ir 1-21 , the pyridine, pyridazine, pyrimidine, pyrazine, pyrazole, thiazole and thiadiazole rings in Formulas Ir 1-21 are optionally substituted (substitution at ring carbons bonded to hydrogen and ring nitrogen atoms bonded to hydrogen atoms are encompassed, i.e., a “substitutable ring nitrogen atom”) with up to four substituents as described above for Cy 2 . Suitable substituents for Cy 2 and suitable values for R 1 , R 2 , R 3 , Cy 1 and E are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiments. Alternatively, suitable substituents for Cy 1 and the pyridine, pyridazine, pyrimidine, pyrazine, pyrazole, thiazole and thiadiazole rings in Formulas Ir 1-21 are as described for G 1 and G 2 , respectively, in Formula If, and values for R 1 , R 2 , R 3 , Cy 1 and E are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiments. Alternatively, suitable substituents for Cy 1 include (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )haloalkoxy, halogen, cyano and nitro; suitable substituents for a substitutable ring nitrogen atom in the pyrazole rings in Formulas Ir 18 , Ir 20 and Ir 21 include (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C 1 -C 2 )alkyl, and (C 1 -C 4 )haloalkyl; suitable substituents for a ring carbon atom in the pyridine, pyridazine, pyrimidine, pyrazine, pyrazole, thiazole and thiadiazole rings in Formulas Ir 1-21 include fluorine, chlorine, cyano, hydroxy, amino, (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C 1 -C 2 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkoxy, CONH 2 , (C 1 -C 4 )alkylaminocarbonyl, di(C 1 -C 4 )alkylaminocarbonyl, (C 3 -C 4 )cycloalkylaminocarbonyl, {(C 1 -C 4 )alkyl}{(C 3 -C 4 )cycloalkyl}aminocarbonyl and (C 1 -C 4 )alkylcarbonylamino; the ring nitrogen in pyridines Ir 1-4 is optionally substituted by oxo; and suitable values for R 1 , R 2 , R 3 , Cy 1 and E are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiments. In another alternative, the embodiments described in this paragraph exclude the compound exemplified in Example 205, Example 211, Example 214, Example 222, Example 226, Example 235, Example 236, Example 281, Example 292, Example 295, Example 298, Example 300, Example 302, Example 305, Example 304, Example 306, Example 307, Example 210, Example 296, Example 311, Example 230, Example 244, Example 258 and Example 291 or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

›DETAILED DESCRIPTION OF THE INVENTION · 13 of 20

For each of the embodiment described in the previous paragraph, R 1 is preferably methyl or ethyl.

For each of the embodiment described in the paragraph immediately following Formulas Ir 1-21 , R 1 is preferably methyl or ethyl; and R 3 is MeSO 2 NHCH 2 CH 2 CH 2 , H 2 NC(═O)CH 2 CH 2 , H 2 NC(═O)CMe 2 CH 2 , 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiment described in the paragraph immediately following Formulas Ir 1-21 , R 1 is preferably methyl or ethyl; and R 3 is H 2 NC(═O)CMe 2 CH 2 , 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiment described in the paragraph immediately following Formulas Ir 1-21 , R 1 is preferably methyl or ethyl; R 2 is phenyl optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, CONH 2 , (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl and SO 2 Me; and R 3 is MeSO 2 NHCH 2 CH 2 CH 2 , H 2 NC(═O)CH 2 CH 2 , H 2 NC(═O)CMe 2 CH 2 , 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiment described in the paragraph immediately following Formulas Ir 1-21 , R 1 is preferably methyl or ethyl; R 2 is phenyl optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, CONH 2 , (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl and SO 2 Me; and R 3 is H 2 NC(═O)CMe 2 CH 2 , 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiment described in the paragraph immediately following Formulas Ir 1-21 , R 1 is preferably methyl or ethyl; and R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiment described in the paragraph immediately following Formulas Ir 1-21 , R 1 is preferably methyl or ethyl; R 2 is phenyl or fluorophenyl; and R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiment described in the paragraph immediately following Formulas Ir 1-21 , R 1 is preferably methyl or ethyl; R 2 is phenyl or fluorophenyl; R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; one or two ring carbon atoms in the pyridine, pyridazine, pyrimidine, pyrazine, pyrazole, thiazole and thiadiazole rings in Formulas Ir 1-21 are optionally substituted with fluoro, chloro, cyano, CONH 2 , CONHMe, CONMe 2 , CONHc-Pr, methoxy, ethoxy, methyl, ethyl or CF 3 . the substitutable ring nitrogen atom in the pyrazole rings in Formulas Ir 18 , Ir 20 and Ir 21 are optionally substituted with (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C 1 -C 2 )alkyl, or (C 1 -C 2 )haloalkyl, the ring nitrogen in the pyridine rings in Formulas Ir 1-4 is optionally substituted by oxo.

Another embodiment of the invention is a compound of any one of Formulas Is 1-21 , or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof:

In Formulas Is 1-21 , the pyridine, pyridazine, pyrimidine, pyrazine, pyrazole, thiazole and thiadiazole rings in Formulas Is 1-21 are optionally substituted (substitution at ring carbons bonded to hydrogen and ring nitrogen atoms bonded to hydrogen atoms are encompassed, i.e., a “substitutable ring nitrogen atom”) with up to four substituents as described above for Cy 2 . Suitable values for G 1 are as described in Formula If; n is 0, 1 or 2; substituents for Cy 2 and suitable values for R 1 , R 2 and R 3 are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiments. Alternatively, n is 0, 1 or 2, suitable values for G 1 in Formulas Is 1-21 and suitable substituents for the pyridine, pyridazine, pyrimidine, pyrazine, pyrazole, thiazole and thiadiazole rings in Formulas Is 1-21 are as described for G 1 and G 2 , respectively, in Formula If, and values for R 1 , R 2 , R 3 and E are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiments. Alternatively, n is 0, 1 or 2; suitable values for G 1 include (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )haloalkoxy, halogen, cyano and nitro; suitable substituents for a substitutable ring nitrogen atom in the pyrazole rings in Formulas Is 18 , Is 20 and Is 21 include (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C 1 -C 2 )alkyl, and (C 1 -C 4 )haloalkyl; suitable substituents for a ring carbon atom in the pyridine, pyridazine, pyrimidine, pyrazine, pyrazole, thiazole and thiadiazole rings in Formulas Is 1-21 include fluorine, chlorine, cyano, amino, (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C 1 -C 2 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkoxy, CONH 2 , (C 1 -C 4 )alkylaminocarbonyl, di(C 1 -C 4 )alkylaminocarbonyl, (C 3 -C 4 )cycloalkylaminocarbonyl, {(C 1 -C 4 )alkyl}{(C 3 -C 4 )cycloalkyl}aminocarbonyl and (C 1 -C 4 )alkylcarbonylamino; the ring nitrogen in pyridines Is 1-4 is optionally substituted by oxo; and suitable values for R 1 , R 2 and R 3 are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiments. In another alternative, the embodiments described in this paragraph exclude the compound exemplified in Example 205, Example 211, Example 214, Example 222, Example 226, Example 235, Example 236, Example 281, Example 292, Example 295, Example 298, Example 300, Example 302, Example 305, Example 304, Example 306, Example 307, Example 210, Example 296, Example 311, Example 230, Example 244, Example 258 and Example 291, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

For each of the embodiment described in the previous paragraph, R 1 is preferably methyl or ethyl.

For each of the embodiment described in the paragraph immediately following Formulas Is 1-21 , R 1 is preferably methyl or ethyl; and R 3 is MeSO 2 NHCH 2 CH 2 CH 2 , H 2 NC(═O)CH 2 CH 2 , H 2 NC(═O)CMe 2 CH 2 , 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

›DETAILED DESCRIPTION OF THE INVENTION · 14 of 20

For each of the embodiment described in the paragraph immediately following Formulas Is 1-21 , R 1 is preferably methyl or ethyl; and R 3 is H 2 NC(═O)CMe 2 CH 2 , 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiment described in the paragraph immediately following Formulas Is 1-21 , R 1 is preferably methyl or ethyl; R 2 is phenyl optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, CONH 2 , (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl and SO 2 Me; and R 3 is MeSO 2 NHCH 2 CH 2 CH 2 , H 2 NC(═O)CH 2 CH 2 , H 2 NC(═O)CMe 2 CH 2 , 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiment described in the paragraph immediately following Formulas Is 1-21 , R 1 is preferably methyl or ethyl; R 2 is phenyl optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, CONH 2 , (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl and SO 2 Me; and R 3 is H 2 NC(═O)CMe 2 CH 2 , 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiment described in the paragraph immediately following Formulas Is 1-21 , R 1 is preferably methyl or ethyl; and R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiment described in the paragraph immediately following Formulas Is 1-21 , R 1 is preferably methyl or ethyl; R 2 is phenyl or fluorophenyl; and R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiment described in the paragraph immediately following Formulas Is 1-21 , R 1 is preferably methyl or ethyl; R 2 is phenyl or fluorophenyl; R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; one or two ring carbon atoms in the pyridine, pyridazine, pyrimidine, pyrazine, pyrazole, thiazole and thiadiazole rings in Formulas Is 1-21 are optionally substituted with fluoro, chloro, cyano, CONH 2 , CONHMe, CONMe 2 , CONHc-Pr, methyl, ethyl or CF 3 ; the substitutable ring nitrogen atom in the pyrazole rings in Formulas Is 18 , Is 20 and Is 21 is optionally substituted with (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C 1 -C 2 )alkyl, or (C 1 -C 2 )haloalkyl, the ring nitrogen in the pyridine rings in Formulas Is 1-4 is optionally substituted by oxo.

Another embodiment of the invention is a compound represented by any one of Formulas It 1-6 , or a pharmaceutically acceptable salt thereof:

In Formulas It 1-7 , G 1 is (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkyl, (C 1 -C 4 ) haloalkoxy, halogen, cyano and nitro; n is 0 1 or 2; G 2a and G 2b are independently selected from hydrogen, fluorine, chlorine, cyano, amino, (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C 1 -C 2 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkoxy, CONH 2 , (C 1 -C 4 )alkylaminocarbonyl, di(C 1 -C 4 )alkylaminocarbonyl, (C 1 -C 4 )cycloalkylaminocarbonyl, {(C 1 -C 4 )alkyl}{(C 3 -C 4 )cycloalkyl}aminocarbonyl and (C 1 -C 4 )alkylcarbonylamino; G 2c is (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl or (C 1 -C 4 )haloalkyl; and suitable values for R 2 and R 3 are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiments. In another alternative, the embodiments in the this paragraph exclude the compound exemplified in Example 205, Example 211, Example 214, Example 222, Example 226, Example 235, Example 236, Example 281, Example 292, Example 295, Example 298, Example 300, Example 302, Example 305, Example 304, Example 306, Example 307, Example 210, Example 296, Example 311, Example 230, Example 244, Example 258, and Example 291, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

For each of the embodiment described in the previous paragraph, R 1 is preferably methyl or ethyl.

For each of the embodiment described in the paragraph immediately following Formulas It 1-7 , R 1 is preferably methyl or ethyl; and R 3 is MeSO 2 NHCH 2 CH 2 CH 2 , H 2 NC(═O)CH 2 CH 2 , H 2 NC(═O)CMe 2 CH 2 , 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiment described in the paragraph immediately following Formulas It 1-7 , R 1 is preferably methyl or ethyl; and R 3 is H 2 NC(═O)CMe 2 CH 2 , 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiment described in the paragraph immediately following Formulas It 1-7 , R 1 is preferably methyl or ethyl; R 2 is phenyl optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, CONH 2 , (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl and SO 2 Me; and R 3 is MeSO 2 NHCH 2 CH 2 CH 2 , H 2 NC(═O)CH 2 CH 2 , H 2 NC(═O)CMe 2 CH 2 , 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiment described in the paragraph immediately following Formulas It 1-7 , R 1 is preferably methyl or ethyl; R 2 is phenyl optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, CONH 2 , (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl and SO 2 Me; and R 3 is H 2 NC(═O)CMe 2 CH 2 , 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiment described in the paragraph immediately following Formulas It 1-7 , R 1 is preferably methyl or ethyl; and R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiment described in the paragraph immediately following Formulas It 1-7 , R 1 is preferably methyl or ethyl; R 2 is phenyl or fluorophenyl; and R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

Alternatively, —CHO, NH 2 —SO 2 NH 2 , —COOH, and —CONH 2 are excluded as permissible substituents for the pyridine and thiazole rings at the position corresponding to Cy 1 for all of the specific embodiments described above for Formulas Iq 1-21 , Ip 1-21 , Ir 1-21 , Is 1-21 and It 1-7 .

›DETAILED DESCRIPTION OF THE INVENTION · 15 of 20

Another embodiment of the invention is a compound of any one of Formulas Iu 1-20 or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof:

In Formulas Iu 1-20 , the pyridine, pyridazine, pyrimidine, pyrazine, pyrazole, thiazole and thiadiazole rings in Formulas Iu 1-20 are optionally substituted (substitution at ring carbons bonded to hydrogen and ring nitrogen atoms bonded to hydrogen atoms are encompassed, i.e., a “substitutable ring nitrogen atom”) with up to four substituents as described above for Cy 2 ; and the pyrrolidine, piperidine and azepane rings are optionally substituted with 0, 1 or 2 substituents as described above for Cy 1 . Suitable substituents for Cy 1 and Cy 2 and suitable values for R 2 , R 3 and E are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiments; and t is 1, 2 or 3. Alternatively, suitable substituents for the pyrrolidine, piperidine and azepane rings and the pyridine, pyridazine, pyrimidine, pyrazine, pyrazole, thiazole and thiadiazole rings in Formulas Iu 1-20 are as described for G 1 and G 2 , respectively, in Formula If; values for R 2 , R 3 and E are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiments; and t is 1, 2 or 3. Alternatively, suitable substituents for the pyrrolidine, piperidine and azepane rings include oxo, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )haloalkoxy, halogen, cyano and nitro; suitable substituents for a substitutable ring nitrogen atom in the pyrazole rings in Formulas Iu 18-20 include (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C 1 -C 2 )alkyl, and (C 1 -C 4 )haloalkyl; suitable substituents for a ring carbon atom in the pyridine, pyridazine, pyrimidine, pyrazine, pyrazole, thiazole and thiadiazole rings in Formulas Iu 1-20 include fluorine, chlorine, cyano, hydroxy, amino, (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C 1 -C 2 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkoxy, CONH 2 , (C 1 -C 4 )alkylaminocarbonyl, di(C 1 -C 4 )alkylaminocarbonyl, (C 3 -C 4 )cycloalkylaminocarbonyl, {(C 1 -C 4 )alkyl}{(C 3 -C 4 )cycloalkyl}aminocarbonyl and (C 1 -C 4 )alkylcarbonylamino; the ring nitrogen in the pyridine rings in Formulas Iu 1-4 is optionally substituted by oxo; t is 1, 2 or 3; and suitable values for R 2 , R 3 and E are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiments.

Alternatively, for each of the embodiments described in the paragraph immediately following Formulas Iu 1-20 , R 3 is preferably MeSO 2 NHCH 2 CH 2 CH 2 , H 2 NC(═O)CH 2 CH 2 , H 2 NC(═O)CMe 2 CH 2 , 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

Alternatively, for each of the embodiments described in the paragraph immediately following Formulas Iu 1-20 , R 3 is preferably H 2 NC(═O)CMe 2 CH 2 , 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

Alternatively, for each of the embodiments described in the paragraph immediately following Formulas Iu 1-20 , R 2 is preferably phenyl optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, CONH 2 , (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl and SO 2 Me; and R 3 is preferably MeSO 2 NHCH 2 CH 2 CH 2 , H 2 NC(═O)CH 2 CH 2 , H 2 NC(═O)CMe 2 CH 2 , 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

Alternatively, for each of the embodiments described in the paragraph immediately following Formulas Iu 1-20 , R 2 is preferably phenyl optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, CONH 2 , (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl and SO 2 Me; and R 3 is preferably H 2 NC(═O)CMe 2 CH 2 , 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

Alternatively, for each of the embodiments described in the paragraph immediately following Formulas Iu 1-20 , t is preferably 2; R 2 is preferably phenyl or fluorophenyl; and R 3 is preferably 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

Alternatively, for each of the embodiment described in the paragraph immediately following Formulas Iu 1-20 , wherein t is 2; R 2 is preferably phenyl or fluorophenyl; R 3 preferably is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; one or two ring carbon atoms in the pyridine, pyridazine, pyrimidine, pyrazine, pyrazole, thiazole and thiadiazole rings in Formulas Iu 1-20 are optionally substituted with fluoro, chloro, cyano, CONH 2 , CONHMe, CONMe 2 , CONHc-Pr, methyl, ethyl or CF 3 ; the substitutable ring nitrogen atom in the pyrazole rings in Formulas Iu 18-20 are optionally substituted with (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C 1 -C 2 )alkyl, and (C 1 C 2 )haloalkyl; the ring nitrogen in the pyridine rings in Formulas Iu 1-4 are optionally substituted by oxo.

Another embodiment of the invention is a compound of any one of Formulas Iv 1-20 , or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof:

In Formulas Iv 1-20 , the pyridine, pyridazine, pyrimidine, pyrazine, pyrazole, thiazole and thiadiazole rings in Formulas Iv 1-20 are optionally substituted (substitution at ring carbons bonded to hydrogen and ring nitrogen atoms bonded to hydrogen atoms are encompassed, i.e., a “substitutable ring nitrogen atom”) with up to four substituents as described above for Cy 2 . Suitable substituents for Cy 2 and suitable values for R 2 , R 3 and E are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiments. t is 1, 2 or 3. Alternatively, suitable substituents for the pyrrolidine, piperidine and azepane rings and the pyridine, pyridazine, pyrimidine, pyrazine, pyrazole, thiazole and thiadiazole rings in Formulas Iv 1-20 are as described for G 1 and G 2 , respectively, in Formula If, t is 1, 2 or 3 and values for R 2 , R 3 and E are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiments. Alternatively, suitable substituents for the pyrrolidine, piperidine and azepane rings include oxo, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkyl, (C 1 -C 4 ) haloalkoxy, halogen, cyano and nitro; suitable substituents for a substitutable ring nitrogen atom in the pyrazole rings in Formulas Iv 18-20 include (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C 1 -C 2 )alkyl, and (C 1 -C 4 )haloalkyl; suitable substituents for a ring carbon atom in the pyridine, pyridazine, pyrimidine, pyrazine, pyrazole, thiazole and thiadiazole rings in Formulas Iv 1-20 include fluorine, chlorine, cyano, hydroxy, amino, (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C 1 -C 2 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkoxy, CONH 2 , (C 1 -C 4 )alkylaminocarbonyl, di(C 1 -C 4 )alkylaminocarbonyl, (C 3 -C 4 )cycloalkylaminocarbonyl, {(C 1 -C 4 )alkyl}{(C 3 -C 4 )cycloalkyl}aminocarbonyl and (C 1 -C 4 )alkylcarbonylamino; the ring nitrogen in the pyridine rings in Formulas Iv 1-4 is optionally substituted by oxo; t is 1, 2 or 3; and suitable values for R 2 , R 3 and E are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiments.

›DETAILED DESCRIPTION OF THE INVENTION · 16 of 20

For each of the embodiments described in the paragraph immediately following Formulas Iv 1-20 , R 3 is MeSO 2 NHCH 2 CH 2 CH 2 , H 2 NC(═O)CH 2 CH 2 , H 2 NC(═O)CMe 2 CH 2 , 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediately following Formulas Iv 1-20 , R 3 is H 2 NC(═O)CMe 2 CH 2 , 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediately following Formulas Iv 1-20 , R 2 is phenyl optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, CONH 2 , (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl and SO 2 Me; and R 3 is MeSO 2 NHCH 2 CH 2 CH 2 , H 2 NC(═O)CH 2 CH 2 , H 2 NC(═O)CMe 2 CH 2 , 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediately following Formulas Iv 1-20 , R 2 is phenyl optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, CONH 2 , (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl and SO 2 Me; and R 3 is H 2 NC(═O)CMe 2 CH 2 , 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediately following Formulas Iv 1-20 , t is preferably 2; R 2 is phenyl or fluorophenyl; and R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediately following Formulas Iv 1-20 , t is preferably 2; R 2 is phenyl or fluorophenyl; R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; one or two ring carbon atoms in the pyridine, pyridazine, pyrimidine, pyrazine, pyrazole, thiazole and thiadiazole rings in Formulas Iv 1-20 are optionally substituted with fluoro, chloro, cyano, CONH 2 , CONHMe, CONMe 2 , CONHc-Pr, methyl, ethyl or CF 3 ; the substitutable ring nitrogen atom in the pyrazole rings in Formulas Iv 18-20 is optionally substituted with (C 1 -C 4 ) alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C 1 -C 2 )alkyl, and (C 1 -C 2 )haloalkyl; the ring nitrogen in the pyridine rings in Formulas Iv 1-4 is optionally substituted by oxo.

Another embodiment of the invention is a compound of any one of Formulas Iw 1-20 or a pharmaceutically acceptable salt thereof:

In Formulas Iw 1-20 , the pyridine, pyridazine, pyrimidine, pyrazine, pyrazole, thiazole and thiadiazole rings in Formulas Iw 1-20 are optionally substituted (substitution at ring carbons bonded to hydrogen and ring nitrogen atoms bonded to hydrogen atoms are encompassed, i.e., a “substitutable ring nitrogen atom”) with up to four substituents as described above for Cy 2 . Suitable substituents for Cy 2 and suitable values for R 2 and R 3 are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiments; suitable values for G 1 is as described for Formula If, n is 0, 1 or 2; and t is 1, 2 or 3. Alternatively, suitable values for G 1 are as described for Formula If; substituents for the pyridine, pyridazine, pyrimidine, pyrazine, pyrazole, thiazole and thiadiazole rings in Formulas Iw 1-20 are as described for G 2 in Formula If; n is 0, 1 or 2; t is 1, 2 or 3; and values for R 2 and R 3 are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiments. Alternatively, suitable values for G 1 include oxo, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkyl, (C 1 -C 4 ) haloalkoxy, halogen, cyano and nitro; suitable substituents for a substitutable ring nitrogen atom in the pyrazole rings in Formulas Iw 18-20 include (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C 1 -C 2 )alkyl, and (C 1 -C 4 )haloalkyl; suitable substituents for a ring carbon atom in the pyridine, pyridazine, pyrimidine, pyrazine, pyrazole, thiazole and thiadiazole rings in Formulas Iw 1-20 include fluorine, chlorine, cyano, hydroxy, amino, (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C 1 -C 2 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkoxy, CONH 2 , (C 1 -C 4 )alkylaminocarbonyl, di(C 1 -C 4 )alkylaminocarbonyl, (C 3 -C 4 )cycloalkylaminocarbonyl, {(C 1 -C 4 )alkyl}{(C 3 -C 4 )cycloalkyl}aminocarbonyl and (C 1 -C 4 )alkylcarbonylamino; the ring nitrogen in the pyridine rings in Formulas Iw 1-4 is optionally substituted by oxo; n is 0, 1 or 2; t is 1, 2 or 3; and suitable values for R 2 and R 3 are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiments.

Alternatively, for each of the embodiments described in the paragraph immediately following Formulas Iw 1-20 , R 3 is preferably MeSO 2 NHCH 2 CH 2 CH 2 , H 2 NC(═O)CH 2 CH 2 , H 2 NC(═O)CMe 2 CH 2 , 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

Alternatively, for each of the embodiments described in the paragraph immediately following Formulas Iw 1-20 , R 3 is preferably H 2 NC(═O)CMe 2 CH 2 , 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

Alternatively, for each of the embodiments described in the paragraph immediately following Formulas Iw 1-20 , R 2 is preferably phenyl optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, CONH 2 , (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl and SO 2 Me; and R 3 is preferably MeSO 2 NHCH 2 CH 2 CH 2 , H 2 NC(═O)CH 2 CH 2 , H 2 NC(═O)CMe 2 CH 2 , 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

Alternatively, for each of the embodiments described in the paragraph immediately following Formulas Iw 1-20 , R 2 is preferably phenyl optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, CONH 2 , (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl and SO 2 Me; and R 3 is preferably H 2 NC(═O)CMe 2 CH 2 , 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

›DETAILED DESCRIPTION OF THE INVENTION · 17 of 20

Alternatively, for each of the embodiments described in the paragraph immediately following Formulas Iw 1-20 , t is preferably 2; R 2 is preferably phenyl or fluorophenyl; and R 3 is preferably 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

Alternatively, for each of the embodiments described in the paragraph immediately following Formulas Iw 1-20 or a pharmaceutically acceptable salt thereof: wherein t is 2; R 2 is phenyl or fluorophenyl; R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; one or two ring carbon atoms in the pyridine, pyridazine, pyrimidine, pyrazine, pyrazole, thiazole and thiadiazole rings in Formulas Iw 1-20 are optionally substituted with fluoro, chloro, cyano, CONH 2 , CONHMe, CONMe 2 , CONHc-Pr, methyl, ethyl or CF 3 ; the substitutable ring nitrogen atom in the pyrazole rings in Formulas Iw 18-20 is optionally substituted with (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C 1 -C 2 )alkyl, and (C 1 -C 2 )haloalkyl; the ring nitrogen in the pyridine rings in Formulas Iw 1-4 is optionally substituted by oxo.

Another embodiment of the invention is a compound represented by any one of Formulas It 1-6 , or a pharmaceutically acceptable salt thereof:

In Formulas Ix 1-7 , G 1 is oxo, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )haloalkoxy, halogen, cyano and nitro; n is 0, 1 or 2; G 2a and G 2b are independently selected from hydrogen, fluorine, chlorine, cyano, hydroxy, amino, (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C 1 -C 2 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkoxy, CONH 2 , (C 1 -C 4 )alkylaminocarbonyl, di(C 1 -C 4 )alkylaminocarbonyl, (C 3 -C 4 )cycloalkylaminocarbonyl, {(C 1 -C 4 )alkyl}{(C 3 -C 4 )cycloalkyl}aminocarbonyl and (C 1 -C 4 )alkylcarbonylamino; and suitable values for R 2 and R 3 are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiments.

Alternatively, for each of the embodiments described in the paragraph immediately following Formulas Ix 1-7 , R 3 is preferably MeSO 2 NHCH 2 CH 2 CH 2 , H 2 NC(═O)CH 2 CH 2 , H 2 NC(═O)CMe 2 CH 2 , 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

Alternatively, for each of the embodiments described in the paragraph immediately following Formulas Ix 1-7 , R 3 is preferably H 2 NC(═O)CMe 2 CH 2 , 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

Alternatively, for each of the embodiments described in the paragraph immediately following Formulas Ix 1-7 , R 2 is preferably phenyl optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, CONH 2 , (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl and SO 2 Me; and R 3 is preferably MeSO 2 NHCH 2 CH 2 CH 2 , H 2 NC(═O)CH 2 CH 2 , H 2 NC(═O)CMe 2 CH 2 , 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

Alternatively, for each of the embodiments described in the paragraph immediately following Formulas Ix 1-7 , R 2 is preferably phenyl optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, CONH 2 , (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl and SO 2 Me; and R 3 is preferably H 2 NC(═O)CMe 2 CH 2 , 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

In another alternative for each of the embodiments described in the paragraph immediately following Formulas Ix 1-7 , R 2 is preferably phenyl or fluorophenyl; and R 3 preferably is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

Compounds of the invention are also disclosed in INHIBITORS OF 11β-HYDROXYSTEROID DEHYDOGENASE I, U.S. Provisional Application No. 61/135,933, filed Jul. 25, 2008, the entire teachings of which are incorporated herein by reference.

The present invention further provides methods of inhibiting 11β-HSD1 by contacting 11β-HSD1 with a compound of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, Im 1-12 , In 1-12 , Io 1-12 , Ip 1-7 , Iq 1-21 , Ir 1-21 , Is 1-21 , It 1-7 , Iu 1-20 , Iv 1-20 , Iw 1-20 or Ix 1-7 of the invention.

The present invention further provides methods of inhibiting or reducing the conversion of cortisone to cortisol in a cell using a compound of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, Im 1-12 , In 1-12 , Io 1-12 , Ip 1-7 , Iq 1-21 , Ir 1-21 , Is 1-21 , It 1-7 , Iu 1-20 , Iv 1-20 , Iw 1-20 or Ix 1-7 of the invention.

The present invention further provides methods of inhibiting or reducing production of cortisol in a cell using a compound of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, Im 1-12 , In 1-12 , Io 1-12 , Ip 1-7 , Iq 1-21 , Ir 1-21 , Is 1-21 , It 1-7 , Iu 1-20 , Iv 1-20 , Iw 1-20 or Ix 1-7 of the invention.

The present invention further provides methods of increasing insulin sensitivity in a subject in need thereof using a compound of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, Im 1-12 , In 1-12 , Io 1-12 , Ip 1-7 , Iq 1-21 , Ir 1-21 , Is 1-21 , It 1-7 , Iu 1-20 , Iv 1-20 , Iw 1-20 or Ix 1-7 of the invention.

The present invention further provides methods of treating a subject with a disease associated with activity of expression of 11β-HSD1 using a compound of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, Im 1-12 , In 1-12 , Io 1-12 , Ip 1-7 , Iq 1-21 , Ir 1-21 , Is 1-21 , It 1-7 , Iu 1-20 , Iv 1-20 , Iw 1-20 or Ix 1-7 of the invention.

Preferred values for the variables in the above-described structural formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il Im 1-12 , In 1-12 , Io 1-12 , Ip 1-7 , Iq 1-21 , Ir 1-21 , Is 1-21 , It 1-7 , Iu 1-20 , Iv 1-20 , Iw 1-20 or Ix 1-7 are provided below:

A 1 is a bond. Alternatively, A 1 is (C 1 -C 3 )alkylene. In another specific embodiment, A 1 is methylene. In another specific embodiment, A 1 is CH when R 1 is present.

R 1 is (C 1 -C 6 )alkyl. Alternatively, R 1 is methyl or ethyl.

Cy 1 is optionally substituted aryl or optionally substituted heteroaryl.

›DETAILED DESCRIPTION OF THE INVENTION · 18 of 20

Alternatively, Cy 1 is optionally substituted phenyl or optionally substituted pyridyl. In another alternative, Cy 1 is optionally substituted phenyl. In yet another specific embodiment, Cy 1 is substituted with fluorine or bromine. In another embodiment A 2 is a bond, Cy 2 is H and Cy 1 is optionally substituted monocyclic cycloalkyl. In another embodiment A 2 is a bond, Cy 2 is H and Cy 1 is optionally substituted cyclohexyl. In another embodiment A 2 is a bond, Cy 2 is H and Cy 1 is phenyl substituted with fluorine, chlorine, bromine, methyl, methoxy, trifluoromethyl, hydroxymethyl or 2-hydroxy-2-propyl. In another embodiment Cy 1 is phenyl substituted with trifluoromethoxy or 2,2,2-trifluoroethoxy. Alternatively Cy 1 is optionally substituted heterocyclyl. In another embodiment Cy 1 is optionally substituted pyrrolidinyl, piperidinyl or azepanyl.

A 2 is a bond and Cy 2 is hydrogen. Alternatively, A 2 is a bond and Cy 2 is cyclopropyl. Alternatively, A 2 is a bond and Cy 2 is (C 3 -C 7 )cycloalkyl. Alternatively, A 2 is a bond and Cy 2 is optionally substituted aryl or optionally substituted heteroaryl. In another specific embodiment, A 2 is a bond and Cy 2 is optionally substituted phenyl or optionally substituted pyridyl. In yet another specific embodiment, A 2 is a bond and Cy 2 is optionally substituted phenyl. In yet another specific embodiment, A 2 is a bond and Cy 2 is substituted with 1 to 4 groups independently selected from chlorine or fluorine. In yet another specific embodiment, A 2 is a bond and Cy 2 is difluorophenyl. In yet another specific embodiment, A 2 is a bond and Cy 2 is fluorophenyl. In yet another specific embodiment A 2 is a bond and Cy 2 is optionally substituted 2-thienyl, 1-pyrazolyl, 3-pyrazolyl, 1,2,4-thiadiazol-3-yl, thiazolyl or 2-oxo-1,2-dihydro-5-pyridyl. In yet another specific embodiment, A 2 is a bond and Cy 2 is phenyl or thienyl substituted with amino(C 1 -C 6 )alkyl. In another embodiment A 2 is a bond and Cy 2 is optionally substituted pyridazinyl, pyrimidinyl, pyrazinyl, 1,2-dihydro-2-oxopyridyl, 2,3-dihydro-3-oxopyridazinyl, 1,2-dihydro-2-oxopyrimidinyl, 3,4-dihydro-4-oxopyrimidinyl or 1,2-dihydro-2-oxopyrazinyl. In yet another embodiment A 2 is a bond and Cy 2 is unsubstituted, methyl substituted or ethyl substituted pyridazinyl, pyrimidinyl, pyrazinyl, 1,2-dihydro-2-oxopyridyl, 2,3-dihydro-3-oxopyridazinyl, 1,2-dihydro-2-oxopyrimidinyl, 3,4-dihydro-4-oxopyrimidinyl or 1,2-dihydro-2-oxopyrazinyl. In yet another specific embodiment A 2 is a bond and Cy 2 is 6-oxo-1,6-dihydropyridin-3-yl, 1-methyl-6-oxo-1,6-dihydropyridin-3-yl, 1-methyl-2-oxo-1,2-dihydropyridin-4-yl, 1-ethyl-6-oxo-1,6-dihydropyridin-3-yl or 1-methyl-6-oxo-1,6-dihydropyridazin-3-yl. In another embodiment A 2 is a bond and Cy 2 is optionally substituted heterocyclyl. In another embodiment A 2 is a bond and Cy 2 is heterocylyl substituted by one oxo group and up 3 groups independently selected from amino, fluoro, chloro, cyano, CONH 2 , CONHMe, CONMe 2 , CONHc-Pr, methyl, ethyl, isopropyl, t-butyl, cyclopropyl, methoxy, ethoxy or trifluoromethyl. In yet another specific embodiment A 2 is a bond and Cy 2 is 1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl, 1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl, 6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridin-3-yl, 1,6-dimethyl-2-oxo-1,2-dihydropyridin-4-yl, 1-ethyl-2-oxo-1,2-dihydropyridin-4-yl, 1-isopropyl-2-oxo-1,2-dihydropyridin-4-yl, 2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridin-4-yl, 1-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl, 1-ethyl-6-oxo-1,6-dihydropyridazin-3-yl, 1-ethyl-5-methyl-6-oxo-1,6-dihydropyridin-3-yl or 6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridazin-3-yl. In another specific embodiment, A 2 is a bond and Cy 2 is heteroaryl optionally substituted with by up to 2 groups independently selected from amino, halo, cyano, CONH 2 , (C 1 -C 4 )alkylaminocarbonyl, di(C 1 -C 4 )alkylaminocarbonyl, cyclo(C 3 -C 5 )alkylaminocarbonyl, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy or (C 1 -C 2 )haloalkyl, (C 1 -C 2 )haloalkoxy. In yet another embodiment A 2 is a bond and Cy 2 is pyridinyl, N-oxo-pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiadiazolyl or thiazolyl optionally substituted by up to 2 groups independently selected from amino, halo, cyano, CONH 2 , (C 1 -C 4 )alkylaminocarbonyl, di(C 1 -C 4 )alkylaminocarbonyl, cyclo(C 3 -C 5 )alkylaminocarbonyl, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy or (C 1 -C 2 )haloalkyl, (C 1 -C 2 )haloalkoxy. In yet another embodiment A 2 is a bond and Cy 2 is pyridinyl, N-oxo-pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiadiazolyl or thiazolyl optionally substituted by up to 2 groups independently selected from amino, fluoro, chloro, cyano, CONH 2 , CONHMe, CONMe 2 , CONHc-Pr, CONHt-Bu, methyl, ethyl, methoxy, ethoxy or trifluoromethyl. In yet another embodiment A 2 is a bond and Cy 2 is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-3-yl, 1,3,4-thiadiazol-2-yl, thiazol-2-yl or thiazol-5-yl optionally substituted by up to 2 groups independently selected from amino, fluoro, chloro, cyano, CONH 2 , CONHMe, CONMe 2 , CONHc-Pr, methyl, ethyl, methoxy, ethoxy or trifluoromethyl. In yet another embodiment A 2 is a bond and Cy 2 is pyridinyl or thiazolyl optionally substituted by up to 2 groups independently selected from fluoro, chloro, cyano, CONHMe, CONMe 2 , CONHc-Pr, methyl, ethyl, methoxy, ethoxy or trifluoromethyl. In yet another specific embodiment A 2 is a bond and Cy 2 is 5-fluoropyridin-2-yl, 5-(trifluoromethyl)pyridin-2-yl, 5-cyanopyridin-2-yl, 5-carbamoylpyridin-2-yl, 5-(methylcarbamoyl)pyridin-2-yl, 5-(dimethylcarbamoyl)pyridin-2-yl, 6-methoxypyridin-3-yl, 5-fluoropyridin-3-yl, 5-chloropyridin-3-yl, 2-methylpyridin-4-yl, 2,6-dimethylpyridin-4-yl, 6-methylpyridazin-3-yl, 2-methylpyrimidin-5-yl, 2-methylpyrimidin-4-yl, 5-methylpyrazin-2-yl, 5-cyanopyrazin-2-yl, 6-cyanopyrazin-2-yl, 5-(dimethylcarbamoyl)thiazol-2-yl, 6-carbamoylpyrazin-2-yl, 6-ethoxy-5-methylpyridin-3-yl, or 5-(cyclopropylcarbamoyl)pyridin-2-yl.

›DETAILED DESCRIPTION OF THE INVENTION · 19 of 20

R 3 is hydroxy(C 2 -C 4 )alkyl. Alternatively, R 3 is dihydroxy(C 3 -C 4 )alkyl. In another specific embodiment, R 3 is ω-H 2 NCO(C 1 -C 3 )alkyl. In yet another specific embodiment, R 3 is (C 1 -C 2 )alkoxy(C 1 -C 3 )alkyl. In yet another specific embodiment, R 3 is H 2 NSO 2 O(C 2 -C 4 )alkyl. In yet another specific embodiment, R 3 is H 2 NSO 2 NH(C 2 -C 4 )alkyl. In yet another specific embodiment, R 3 is oxo(C 2 -C 4 )alkyl. In yet another specific embodiment, R 3 is alkenyl. In yet another specific embodiment, R 3 is allyl. In yet another specific embodiment, R 3 is MeC(═O)NH(C 2 -C 4 )alkyl. In yet another specific embodiment R 3 is 2-hydroxy-2-methylpropyl, 3-hydroxypropyl, 2-hydroxypropyl or 2-hydroxyethyl. In yet another specific embodiment R 3 is 2,3-dihydroxypropyl. In yet another specific embodiment R 3 is H 2 NC(═O)CH 2 CH 2 —. In yet another specific embodiment R 3 is 2-(4-morpholino)ethyl. In yet another embodiment R 3 is MeSO 2 NH(C 2 -C 4 )alkyl. In yet another specific embodiment R 3 is MeSO 2 NHCH 2 CH 2 CH 2 .

R 3 is (HO) 2 P(═)O(C 1 -C 4 )alkyl. R 3 is hydroxy(C 2 -C 5 )alkyl. In yet another specific embodiment R 3 is 3-hydroxybutyl, 3-hydroxy-3-methylbutyl, 3-hydroxypropyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl, or 2-hydroxyethyl. Alternatively, R 3 is dihydroxy(C 3 -C 4 )alkyl. In yet another specific embodiment R 3 is 2,3-dihydroxypropyl. R 3 is amino(C 2 -C 5 )alkyl or methylamino(C 2 -C 5 )alkyl, each optionally substituted with hydroxy. In another specific embodiment, R 3 is ω-H 2 NCO(C 1 -C 3 )alkyl. In another specific embodiment, R 3 is H 2 NCONH(C 1 -C 3 )alkyl, optionally substituted with hydroxy. In another specific embodiment, R 3 is H 2 NCH 2 CONH(C 1 -C 3 )alkyl, optionally substituted with hydroxy. In another specific embodiment, R 3 is (C 1 -C 3 )alkylHNCONH(C 1 -C 3 )alkyl. In yet another specific embodiment, R 3 is H 2 NC(═O)C 1 -C 4 alkyl. In yet another specific embodiment, R 3 is MeC(═O)NHC 1 -C 4 alkyl. In yet another specific embodiment, R 3 is MeOC(═O)NHC 1 -C 4 alkyl. In yet another specific embodiment, R 3 is MeNHC(═O)C 1 -C 4 alkyl. In yet another specific embodiment R 3 is H 2 NC(═O)OC 1 -C 4 alkyl. In yet another specific embodiment, R 3 is MeHNC(═O)OC 1 -C 4 alkyl. In yet another specific embodiment, R 3 is (C 1 -C 2 )alkoxy(C 1 -C 3 )alkyl, optionally substituted with hydroxy. In yet another specific embodiment, R 3 is (C 1 -C 2 )alkylthio(C 1 -C 3 )alkyl, optionally substituted with hydroxy. In yet another specific embodiment, R 3 is H 2 NSO 2 O(C 2 -C 4 )alkyl. In yet another specific embodiment, R 3 is H 2 NSO 2 NH(C 2 -C 4 )alkyl. In yet another specific embodiment, R 3 is oxo(C 2 -C 4 )alkyl. In yet another specific embodiment, R 3 is MeCO(C 1 -C 2 alkyl). In yet another specific embodiment, R 3 is HOCO(C 1 -C 2 alkyl). In yet another specific embodiment, R 3 is alkenyl. In yet another specific embodiment, R 3 is alkyl. In yet another specific embodiment, R 3 is allyl. In yet another specific embodiment, R 3 is MeC(═O)NH(C 2 -C 4 )alkyl. In yet another specific embodiment, R 3 is MeOC(═O)NH(C 2 -C 4 )alkyl. In yet another specific embodiment, R 3 is cyanoalkyl. In yet another specific embodiment, R 3 is alkylsulfonylaminoalkyl. In yet another specific embodiment, R 3 is alkylsulfonylalkyl. In yet another specific embodiment R 3 is MeSO 2 NH(C 2 -C 4 )alkyl, optionally substituted with hydroxy. In yet another specific embodiment, R 3 is aminocarbonylaminoalkyl. In yet another specific embodiment, R 3 is aminocarboxyalkyl. In yet another specific embodiment R 3 is 2-(4-morpholino)ethyl. In yet another specific embodiment R 3 is 2-(1-imidazolyl)ethyl. In yet another specific embodiment R 3 is 2-(1-aminoimidazolyl)ethyl.

In another embodiment R 3 is (C 3 -C 4 )cycloalkyl(C 1 -C 2 )alkyl. In another specific embodiment R 3 is (1-hydroxycyclopropyl)methyl. In another specific embodiment R 3 is 1-(hydroxymethyl)cyclopropyl)methyl. In another specific embodiment R 3 is (1-carbamoylcyclopropyl)methyl. In another specific embodiment R 3 is 2-(1-azetidinyl)ethyl, 2-(1-pyrrolidinyl)ethyl, 2-(3-fluoro-1pyrrolidinyl)ethyl, 2-(2-oxo-1-pyrrolidinyl)ethyl, 2-(1,1-dioxo-2-isothiazolidinyl)ethyl, 2-(3-oxo-1-piperazinyl)ethyl, (5-methyl-1,3,4-thiadiazol-2-yl)methyl, 2-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl, (5-methyl-1,3,4-oxadiazol-2-yl)methyl or 2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl. In another embodiment R 3 is heterocyclyl(C 1 -C 3 )alkyl.

In another specific embodiment R 3 is H 2 NCOCHMeCH 2 —, H 2 NCOC(Me) 2 CH 2 —, NCCHMeCH 2 —, NCC(Me) 2 CH 2 —, H 2 NCH 2 C(Me) 2 CH 2 —, MeCONHCH 2 C(Me) 2 CH 2 —, MeOCONHCH 2 C(Me) 2 CH 2 —, MeSO 2 NHCH 2 C(Me) 2 CH 2 —, HOCH 2 CHMeCH 2 —, HOCH 2 C(Me) 2 CH 2 —, MeSO 2 NMeCH 2 CH 2 — or MeSO 2 NMeCH 2 CH 2 CH 2 —. In another specific embodiment R 3 is methyl, ethyl, FCMe 2 CH 2 —, MeC(═O)NHCMe 2 CH 2 —, MeOC(═O)NHCMe 2 CH 2 — or MeS(═O) 2 NHCMe 2 CH 2 —.

E is a bond.

R 2 is optionally substituted aryl, optionally substituted heteroaryl or cycloalkyl. In one specific embodiment, R 2 is optionally substituted phenyl or optionally substituted pyridyl. In another specific embodiment, R 2 is optionally substituted phenyl. In yet another specific embodiment, R 2 is fluorophenyl. R 2 is (C 3 -C 5 )alkyl. In one specific embodiment R 2 is isopropyl. In another embodiment R 2 is optionally substituted thienyl. In another specific embodiment R 2 is t-butyl.

In another embodiment of the invention, the provisos applied to pharmaceutical compositions comprising compounds of Formula I or Ia-Il or Im 1-12 , In 1-12 , Io 1-12 , Ip 1-7 , Iq 1-21 , Ir 1-21 , Is 1-21 , It 1-7 , Iu 1-20 , Iv 1-20 , Iw 1-20 or Ix 1-7 also apply to methods of treatment utilizing any one of the compounds of Formula I or Formulas Ia-Il or Im 1-12 , In 1-12 , Io 1-12 , Ip 1-7 , Iq 1-21 , Ir 1-21 , Is 1-21 , It 1-7 , Iu 1-20 , Iv 1-20 , Iw 1-20 or Ix 1-7 .

Another embodiment of the invention is a compound of Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il Im 1-12 , In 1-12 , Io 1-12 , Ip 1-7 , Iq 1-21 , Ir 1-21 , Is 1-21 , It 1-7 , Iu 1-20 , Iv 1-20 , Iw 1-20 or Ix 1-7 , or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, wherein any one of the following provisos apply or any combination thereof:

›DETAILED DESCRIPTION OF THE INVENTION · 20 of 20

Proviso 1: If (a) either R 3 or E-R 2 is (C 1 -C 4 )alkyl or benzyl substituted with halogen or (C 1 -C 2 )alkoxy, and (b) n is not zero, then Y cannot be either oxo or (C 1 -C 3 )alkyl at the position β to the nitrogen atom in the ring.

Proviso 2: If A 1 is a C 2 -C 3 alkylene, then -Cy 1 -A 2 -Cy 2 cannot be

wherein the nitrogen-containing heterocycle represented by Cy 1 is optionally substituted.

Proviso 3: If (a) A 1 and A 2 are both bonds, (b) R 3 is an alkyl optionally substituted with amino, alkyl, alkoxy, oxo, carboxy, hydroxy, fluorine, or sulfonyl, or an unsubstituted alkynyl (c) E-R 2 is (i) a optionally substituted alkyl or an optionally substituted carbocyclic aromatic group wherein the substituent is an amino, alkyl, alkenyl, alkynyl, alkoxy, carboxy, hydroxy, halogen or sulfonyl, or (ii) an unsubstituted cycloalkyl, and (d) Cy 2 is H, then Cy 1 is not (i) an unsubstituted monocyclic cycloalkyl or (ii) a substituted or unsubstituted carbocyclic aromatic group.

Proviso 4: If (a) A 1 and A 2 are both bonds, (b) R 3 is an alkyl optionally substituted with amino, alkyl, alkoxy, oxo, carboxy, hydroxy, fluorine, or sulfonyl, or an unsubstituted alkynyl (c) E-R 2 is (i) a optionally substituted alkyl or an optionally substituted carbocyclic aromatic group wherein the substituent is an amino, alkyl, alkenyl, alkynyl, alkoxy, carboxy, hydroxy, halogen or sulfonyl, or (ii) an unsubstituted cycloalkyl, and (d) Cy 1 is an optionally substituted carbocyclic aromatic group, then Cy 2 is not an unsubstituted carbocyclic aromatic group.

Proviso 5: If (a) A 1 is alkyl optionally substituted with amino, alkyl, alkoxy, oxo, carboxy, hydroxy, fluorine, or sulfonyl, (b) R 3 is an alkyl substituted with amino, alkyl, alkoxy, oxo, carboxy, hydroxy, fluorine, or sulfonyl, or an unsubstituted alkynyl (c) E-R 2 is (i) a optionally substituted alkyl or an optionally substituted carbocyclic aromatic group wherein the substituent is an amino, alkyl, alkenyl, alkynyl, alkoxy, carboxy, hydroxy, halogen or sulfonyl, or (ii) an unsubstituted cycloalkyl, then Cy 1 is a carbocyclic aromatic group optionally substituted with C 1 C 4 alkoxy or halogen.

Proviso 6: If (a) A 1 is a bond or alkylene, (b) Cy 1 is (C 3 -C 7 )cycloalkyl, aryl or heteroaryl, and (c) E is a bond, then R 2 is not 3,4-dialkoxyphenyl optionally substituted with halogen or hydroxy, or 3,4-dicycloalkoxyphenyl optionally substituted with halogen or 3,4-dialkoxyalkoxyphenyl optionally substituted with halogen.

Proviso 7: If (a) A 1 is a bond, (b) Cy 1 is phenyl, (c) A 2 is unsubstituted methylene, (d) Cy 2 is H, and (e) n is 1, then Y is not oxo adjacent to the nitrogen in the oxazinone ring.

Proviso 8: If E is a bond or C 1 alkylene, R 2 is aryl, heteroaryl or heterocyclyl, A 1 is (C 1 )alkylene, R 3 is optionally fluorinated (C 1 -C 5 )alkyl, (C 2 -C 5 )alkenyl or (C 2 -C 6 )alkynyl and Cy 1 is optionally substituted phenyl, then Cy 1 is not substituted at the ortho position by optionally substituted aryl, heteroaryl, heterocyclyl or cycloalkyl.

Another embodiment of the present invention is a compound of Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, or Il or a pharmaceutically acceptable salt, enantiomer of diastereomer thereof, wherein all of the above Provisos apply. Yet another embodiment of the present invention is a compound of Formula I or a pharmaceutically acceptable salt, enantiomer of diastereomer thereof, wherein the above Provisos 3-8 apply.

Another embodiment of the present invention is a pharmaceutical composition comprising: i) a pharmaceutically acceptable carrier or diluent; and ii) a compound of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih Ii, Ij, Ik, or Il or a pharmaceutically acceptable salt, enantiomer of diastereomer thereof, wherein the above Provisos 1, 2, 6 and 8 apply.

Another embodiment of the present invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent; and ii) a compound of Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih Ii, Ij, Ik, or Il or a pharmaceutically acceptable salt, enantiomer of diastereomer thereof, wherein Provisos 6 and 8 apply.

In one embodiment, Proviso 2 applies when the subject is being treated to lower intraocular pressure.

In one embodiment, Proviso 2 applies when the subject is being treated for cardiovascular disorders.

In one embodiment, Proviso 2 applies when the subject is being treated for dyslipidemia or hypertension.

In one embodiment, Proviso 8 applies when the subject is being treated for atherosclerosis, dyslipidemia, or cardiovascular disorders.

In one embodiment, Proviso 8 applies when the subject is being treated for diabetes, atherosclerosis, dyslipidemia, hypertension, obesity or cardiovascular disorders.

In another embodiment, Provisos 2 and 8 apply to methods of treatment utilizing any one of the compounds of Formula I or Formulas Ia-Il.

›DEFINITIONS · 1 of 6

The term “alkyl” means a straight or branched hydrocarbon radical having 1-10 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like.

The term “carbocyclic aromatic group” shall have the same meaning as the term “aryl” is used in U.S. Pat. No. 7,186,844, which is incorporated by reference herein in its entirety. For further clarity, the term “carbocyclic aromatic group,” as used in U.S. Pat. No. 7,186,844, means is an all carbon, monocyclic or polycyclic ring system which obeys Huckel's 4n+2 rule (M. B. Smith and J. March, “March's Advanced Organic Chemistry” 5th Edition, p 57, Wiley-Interscience, 2001) and includes, for example, benzene and naphthalene.

The term “cycloalkyl” means a monocyclic, bicyclic or tricyclic, saturated hydrocarbon ring having 3-10 carbon atoms and includes, for example, cyclopropyl (c-Pr), cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptyl, Spiro[4.4]nonane, adamantyl and the like.

The term “aryl” means an aromatic radical which is a phenyl group, a naphthyl group, an indanyl group or a tetrahydronaphthalene group. An aryl group is optionally substituted with 1-4 substituents. Exemplary substituents include alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO 2 H, CONH 2 , N-monoalkyl-substituted amido and N,N-dialkyl-substituted amido.

The term “heteroaryl” means a 5- and 6-membered heteroaromatic radical which may optionally be fused to a saturated or unsaturated ring containing 0-4 heteroatoms selected from N, O, and S and includes, for example, a heteroaromatic radical which is 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3-pyrrolyl, 2-, 3-, or 4-pyridyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 3- or 4-pyridazinyl, 1H-indol-6-yl, 1H-indol-5-yl, 1H-benzimidazol-6-yl, 1H-benzimidazol-5-yl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 2-, 3-, 5-, 6-, 7- or 8-quinoxalinyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 2-, 4-, or 5-thiazolyl, 2-, 3-, 4-, or 5-pyrazolyl, 2-, 3-, 4-, or 5-imidazolyl. A heteroaryl is optionally substituted. Exemplary substituents include alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO 2 H, CONH 2 , N-monoalkyl-substituted amido and N,N-dialkyl-substituted amido, or by oxo to form an N-oxide.

The term “heterocyclyl” means a 4-, 5-, 6- and 7-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S. Exemplary heterocyclyls include pyrrolidine, pyrrolidin-2-one, 1-methylpyrrolidin-2-one, piperidine, piperidin-2-one, dihydropyridine, tetrahydropyridine, piperazine, 1-(2,2,2-trifluoroethyl)piperazine, 1,2-dihydro-2-oxopyridine, 1,4-dihydro-4-oxopyridine, piperazin-2-one, 3,4,5,6-tetrahydro-4-oxopyrimidine, 3,4-dihydro-4-oxopyrimidine, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, tetrahydrothiopyran, isoxazolidine, 1,3-dioxolane, 1,3-dithiolane, 1,3-dioxane, 1,4-dioxane, 1,3-dithiane, 1,4-dithiane, oxazolidin-2-one, imidazolidin-2-one, imidazolidine-2,4-dione, tetrahydropyrimidin-2(1H)-one, morpholine, N-methylmorpholine, morpholin-3-one, 1,3-oxazinan-2-one, thiomorpholine, thiomorpholine 1,1-dioxide, tetrahydro-1,2,5-thiaoxazole 1,1-dioxide, tetrahydro-2H-1,2-thiazine 1,1-dioxide, hexahydro-1,2,6-thiadiazine 1,1-dioxide, tetrahydro-1,2,5-thiadiazole 1,1-dioxide isothiazolidine 1,1-dioxide, 6-oxo-1,6-dihydropyridazin-3-yl, 6-oxo-1,6-dihydropyridazin-4-yl, 5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl and 5-oxo-4,5-dihydro-1H-imidazol-2-yl. A heterocyclyl can be optionally substituted with 1-4 substituents. Exemplary substituents include alkyl, haloalkyl, halogen and oxo.

The term “spirocycloalkyl” means a cycloalkyl group which shares one ring carbon with another alkyl or cycloalkyl group.

As used herein the terms “subject” and “patient” may be used interchangeably, and means a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like). Typically, the subject is a human in need of treatment.

When a disclosed compound or its pharmaceutically acceptable salt is named or depicted by structure, it is to be understood that solvates or hydrates of the compound or its pharmaceutically acceptable salts are also included. “Solvates” refer to crystalline forms wherein solvent molecules are incorporated into the crystal lattice during crystallization. Solvate may include water or nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and EtOAc. Solvates, wherein water is the solvent molecule incorporated into the crystal lattice, are typically referred to as “hydrates.” Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water.

Certain of the disclosed compounds may exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center. “Enantiomer” means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms. The symbol “*” in a structural formula represents the presence of a chiral carbon center. “R” and “S” represent the configuration of substituents around one or more chiral carbon atoms. Thus, “R*” and “S*” denote the relative configurations of substituents around one or more chiral carbon atoms.

“Racemate” or “racemic mixture” means a compound of equimolar quantities of two enantiomers, wherein such mixtures exhibit no optical activity; i.e., they do not rotate the plane of polarized light.

›DEFINITIONS · 2 of 6

“Geometric isomer” means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H) on each side of a carbon-carbon double bond may be in an E (substituents are on opposite sides of the carbon-carbon double bond) or Z (substituents are oriented on the same side) configuration.

“R,” “S,” “S*,” “R*,” “E,” “Z,” “cis,” and “trans,” indicate configurations relative to the core molecule.

The compounds of the invention may be prepared as individual isomers by either isomer-specific synthesis or resolved from an isomeric mixture. Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods.

When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight optically pure. Percent optical purity by weight is the ratio of the weight of the enantiomer over the weight of the enantiomer plus the weight of its optical isomer.

When a disclosed compound is named or depicted by structure without indicating the stereochemistry, and the compound has at least one chiral center, it is to be understood that the name or structure encompasses one enantiomer of compound free from the corresponding optical isomer, a racemic mixture of the compound and mixtures enriched in one enantiomer relative to its corresponding optical isomer.

When a disclosed compound is named or depicted by structure without indicating the stereochemistry and has at least two chiral centers, it is to be understood that the name or structure encompasses a diastereomer free of other diastereomers, a pair of diastereomers free from other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers in which one diastereomer is enriched relative to the other diastereomer(s) and mixtures of diastereomeric pairs in which one diastereomeric pair is enriched relative to the other diastereomeric pair(s).

The compounds of the invention may be present in the form of pharmaceutically acceptable salts. For use in medicines, the salts of the compounds of the invention refer to non-toxic “pharmaceutically acceptable salts.” Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts.

Pharmaceutically acceptable basic/cationic salts include, the sodium, potassium, calcium, magnesium, diethanolamine, n-methyl-D-glucamine, L-lysine, L-arginine, ammonium, ethanolamine, piperazine and triethanolamine salts.

Pharmaceutically acceptable acidic/anionic salts include, the acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphospate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, hydrogensulfate, tannate, tartrate, teoclate, tosylate, and triethiodide salts.

The following abbreviations have the indicated meanings:

General Description of Synthetic Methods

Compounds of Formula I can be prepared by several processes. In the discussion below, A 1 , A 2 , Cy 1 , Cy 2 , E, R 1 , R 2 , R 3 , Y and n have the meanings indicated above unless otherwise noted. In cases where the synthetic intermediates and final products of Formulas I described below contain potentially reactive functional groups, for example amino, hydroxyl, thiol and carboxylic acid groups, that may interfere with the desired reaction, it may be advantageous to employ protected forms of the intermediate. Methods for the selection, introduction and subsequent removal of protecting groups are well known to those skilled in the art. (T. W. Greene and P. G. M. Wuts “Protective Groups in Organic Synthesis” John Wiley & Sons, Inc., New York 1999). Such protecting group manipulations are assumed in the discussion below and not described explicitly. Generally, reagents in the reaction schemes are used in equimolar amounts; however, in certain cases it may be desirable to use an excess of one reagent to drive a reaction to completion. This is especially the case when the excess reagent can be readily removed by evaporation or extraction. Bases employed to neutralize HCl in reaction mixtures are generally used in slight to substantial excess (1.05-5 equivalents).

In a first process a compound of Formula I, wherein can be prepared by reaction of an aminoalcohol intermediate of Formula II with a reagent of Formula III, wherein Z 1 and Z 2 are leaving groups such as chloride, 1-imidazolyl or aryloxide in an inert solvent such as THF, CH 2 Cl 2 , toluene or MeCN, usually in the presence of an organic or inorganic base such as triethylamine or NaHCO 3 respectively, at −10° C. to 120° C.:

Certain instances of reagent III are especially convenient because they are commercially available. For example when Z 1 and Z 2 are both chloride, III is phosgene. When Z 1 and Z 2 are both 1-imidazolyl, III is carbonyl diimidazole. When Z 1 is chloride and Z 2 is p-nitrophenoxide, III is p-nitrophenyl chloroformate. When Z 1 and Z 2 are both OCCl 3 , III is triphosgene and as little as one third of molar equivalent can be used.

›DEFINITIONS · 3 of 6

Aminoalcohol intermediates of Formula II can be prepared by reduction of amides of Formula IV using a hydride reagent such as BH 3 .THF solution, BH 3 .Me 2 S or LiAlH 4 in an inert solvent ethereal such as THF or DME at 20° C. to 100° C. for between 1 h and 48 h:

Intermediates of Formula IV can be prepared by coupling of a β-hydroxyacid of Formula V with an amine of Formula VI using standard peptide coupling reagents such as EDC in the presence of HOBt and N,N-diisopropylethylamine in an inert solvent such as CH 2 Cl 2 at 0-30° C. for between 1 h and 24 h:

Amine intermediates of Formula VI, wherein A 1 =CH 2 and R 1 is absent, can be prepared by reduction of amides of Formula VII using a hydride reagent such as BH 3 .THF solution, BH 3 .Me 2 S or LiAlH 4 in an inert solvent ethereal such as THF or DME at 20° C. to 100° C. for between 1 h and 48 h:

Amine intermediates of Formula VI, wherein A 1 is a bond, R 1 is absent and Cy 1 is not an aromatic or heteroaromatic ring, can be prepared from ketones of formula VIII via oximes of Formula IX or by reductive amination of a ketone of Formula VIII with ammonia:

Methods for the conversion of ketones to oximes are described in Smith, M. B. and March, J. “March's Advanced Organic Chemistry” pp 1194-1195, 5 th Edition, Wiley, New York, N.Y., 2001. Methods for the reduction of oximes to primary amines are described in Smith, M. B. and March, J. “March's Advanced Organic Chemistry” p 1555, 5 th Edition, Wiley, New York, N.Y., 2001. Methods for the reductive amination of ketones are described in Baxter, E. W. and Reitz, A. B. “Organic Reactions” Volume 59, Ed. Overman, L. E., Wiley Interscience, 2002.

Intermediates of Formula II, wherein n=0, can be prepared by reaction of oxetanes of Formula X with amines of Formula VI as described in Smith, M. B. and March, J. “March's Advanced Organic Chemistry” p 505, 5 th Edition, Wiley, New York, N.Y., 2001:

Intermediates of Formula II can also be prepared by reductive amination of β-hydroxyaldehydes of Formula Xa with amines of Formula VI. Methods for the reductive amination of aldehydes are described in Baxter, E. W. and Reitz, A. B. “Organic Reactions” Volume 59, Ed. Overman, L. E., Wiley Interscience, 2002.

Aldehydes of Formula Xa can be prepared from homoallylic alcohols of Formula XXI by treatment with OsO 4 and NaIO 4 .

Intermediates of Formula II, wherein A 1 =CH 2 and R 1 is absent, can be prepared by reduction of amide intermediates of formula XI using a hydride reagent such as BH 3 .THF solution, BH 3 .Me 2 S or LiAlH 4 in an inert solvent ethereal such as THF or DME at 20° C. to 100° C. for between 1 h and 48 h:

Amide intermediates of Formula XI can be prepared by reaction of an aminoalcohol intermediate of Formula XII with activated carboxylic acid of Formula XIII wherein Z 3 =chloride or an activated ester, such as an N-hydroxysuccinimide ester:

Amino-alcohol intermediates of Formula XII, wherein n=0, can be prepared by reaction of an epoxide of Formula XIV with cyanide ion followed by reduction of the resulting hydroxynitrile of Formula XV with hydrogen gas in the presence of a catalyst or with a hydride source such as LiAlH 4 :

Epoxide compounds of formula XIV can, in turn, be prepared in a number of ways including, as described in Aube, J. “Epoxidation and Related Processes” Chapter 3.2 in Volume 1 of “Comprehensive Organic Synthesis” Edited by B. M. Trost, I. Fleming and Stuart L. Schreiber, Pergamon Press, New York, 1992.

Hydroxynitrile intermediates of Formula XV can be prepared by treatment of ketones of Formula XVI with acetonitrile anion, formed by treatment of acetonitrile with n-BuLi or LDA, in an inert, anhydrous solvent such as THF at low temperature:

Amino-alcohol intermediates of Formula XII, wherein n is 0, can be prepared by treatment of sulfonate intermediates of Formula XVII, wherein R A is for example methyl, trifluoromethyl or p-methylphenyl, with ammonia:

Amino-alcohol intermediates of Formula XII can be prepared by treatment of sulfonate intermediates of Formula XVII with sodium azide to give an azide intermediate of Formula XVIII, followed by catalytic hydrogenation or by Staudinger reduction with PPh 3 in wet THF:

Sulfonate intermediates of Formula XVII can be prepared from diol intermediates of Formula XIX with a sulfonyl chloride R A SO 2 Cl:

Diol intermediates of Formula XIX can be prepared by hydroboration of allyl alcohols of Formula XX:

Diol intermediates of Formula XIX can be prepared by ozonolysis and reduction of homoallyl alcohols of Formula XXI:

Aminoalcohol intermediates of Formula II, wherein A 1 is a bond, R 1 is absent, and Cy 1 is a heteroaryl group or an aryl group bearing at least one strongly electron withdrawing group such as CF 3 , can be prepared by reaction of an aminoalcohol intermediate of Formula XII with a compound of Formula XXII, wherein Cy 1 is a heteroaryl group or an aryl group bearing at least one strongly electron withdrawing group such as CF 3 and R B is a leaving group such a fluoro, chloro, bromo or iodo:

Aminoalcohol intermediates of Formula II, wherein A 1 is (C 1 )alkylene can be prepared by reaction of an aminoalcohol of Formula XII with an aldehyde or methyl ketone of Formula XII in the presence of a reducing agent such as NaCNBH 3 or Na(OAc) 3 BH:

Methods for the reductive amination of aldehydes and ketones are described in Baxter, E. W. and Reitz, A. B. “Organic Reactions” Volume 59, Ed. Overman, L. E., Wiley Interscience, 2002.

In a second process a compound of Formula I can be prepared by reaction of a ketocarbamate of Formula XXIV, wherein R D is alkyl or arylalkyl group such as methyl, t-butyl or benzyl, with an organometallic reagent of Formula XXV wherein M includes, but is not limited to, MgCl, MgBr, MgI or Li:

In specific examples, organometallic reagent XXV is allylmagnesium bromide, allylzinc(II) bromide, (2-methylallyl)magnesium chloride or (2-methoxy-2-oxoethyl)zinc(III) bromide. In certain cases when M is MgCl, MgBr or MgI, it is advantageous to add CeCl 3 to the reaction mixture.

›DEFINITIONS · 4 of 6

Ketocarbamates of Formula XXIV can be prepared by reaction of aminoketones of Formula XXVI with intermediates of Formula XXVII wherein R E is a leaving group such as chloride, succinyloxy, imidazolyl or t-butoxycarboxycarbonyl:

Aminoketones of Formula XXVI, wherein n=0, can be prepared by reaction of α,β-unsaturated ketones of Formula XXVIII with amines of Formula VI:

Aminoketones of Formula XXVI, wherein n=0, can be prepared by reaction of β-dialkylaminoketones of Formula XXVIII, wherein R F is lower alkyl especially methyl, with amines of Formula VI:

β-Dialkylaminoketones of Formula XXVIII are in turn derived from α,β-unsaturated ketones of Formula XXVII with dialkylamines of Formula R F NHR F .

In a third process a compound of Formula I, can be prepared by reaction of a compound of Formula XVII with an isocyanate of Formula XXIX in the presence of a base:

Isocyanates of Formula XXIX can be prepared from amines of Formula VI by treatment with phosgene, diphosgene or triphosgene. This third process is described in greater detail in U.S. Provisional Application Ser. No. 61/137,013, filed Jul. 25, 2008 entitled SYNTHESIS OF INHIBITORS OF 11β-HYDROXYSTEROID DEHYDROGENASE TYPE 1, the entire teachings of which are incorporated herein by reference.

In a fourth process a compound of Formula I can be prepared by reaction of a halo compound of Formula, wherein Hal is chlorine or bromine, with an isocyanate of Formula XXIX in the presence of a base:

Halo compounds of Formula XXX can be prepared by reaction of β-haloketones of Formula XXXI with organometallic reagents of Formula XXV wherein M is a metal containing radical including MgCl, MgBr, MgI or Li. The reaction is optionally carried out in the presence of anhydrous cerium trichloride:

In a fifth process a compound of Formula I, wherein A 1 is CH 2 or CH 2 CH 2 and R 1 is absent, can be prepared by reaction of a compound of Formula XXXII, with a compound of Formula XXXIII, wherein A 1 is CH 2 or CH 2 CH 2 and R G is a leaving group such as Br, I, OSO 2 Me, OSO 2 CF 3 or OSO 2 Ph, in the presence of a base such as NaH or K 2 CO 3 :

Compounds of Formula XXXII can be prepared by treatment of compounds of Formula XII with various reagents of Formula III, wherein Z 1 and Z 2 are leaving groups such as chloride, 1-imidazolyl or aryloxide in an inert solvent such as THF, CH 2 Cl 2 , toluene or MeCN, usually in the presence of an organic or inorganic base such as triethylamine or NaHCO 3 respectively, at −10° C. to 120° C.:

In a sixth process a compound of Formula I, wherein A is a bond can be prepared by reaction of a compound of Formula XXXII, with a compound of Formula XXII, wherein R B is a leaving group such as chloro, bromo, iodo or OSO 2 CF 3 , in the presence of a base such as K 2 CO 3 and a copper or palladium catalyst in an inert solvent such as dioxane, DMF or NMP at elevated temperature:

In a seventh process a compound of Formula I can be prepared from another compound of Formula I. For example:

(1) a compound of Formula I wherein Cy 1 is substituted with bromine or iodine, A 2 is a bond and Cy 2 is hydrogen can be reacted with an optionally substituted aryl or heteroarylboronic acid or ester in the presence of a palladium catalyst to give a compound of Formula I wherein A 2 is a bond and Cy 2 is optionally substituted aryl or heteroaryl.

(2) a compound of Formula I wherein R 1 or R 3 is ω-hydroxy(C 2 -C 6 )alkyl can be oxidized to a compound of Formula I wherein R 1 or R 3 is ω-carboxy(C 1 -C 5 )alkyl using Jones reagent.

(3) a compound of Formula I wherein R 1 or R 3 is ω-carboxy(C 1 -C 6 )alkyl can be coupled with ammonia or a (C 1 -C 6 )alkylamine using a standard peptide coupling reagent such as EDC to afford a compound of Formula I wherein R 1 or R 3 is ω-H 2 NC(═O)(C 1 -C 6 )alkyl or ω-{(C 1 -C 6 )alkylNHC(═O)}(C 1 -C 6 )alkyl.

(4) a compound of Formula I wherein R 1 or R 3 is ω-hydroxy(C 1 -C 6 )alkyl can be converted to its methanesulfonate or trifluoromethanesulfonate, treated with sodium azide and reduced to give a compound of Formula I, wherein R 1 or R 3 is ω-amino(C 1 -C 6 )alkyl.

(5) a compound of Formula I wherein R 1 or R 3 is amino(C 1 -C 6 )alkyl can be reacted with acetic anhydride or acetyl chloride to give a compound of Formula I wherein R 1 or R 3 is {acetylamino}(C 1 -C 6 )alkyl.

(6) a compound of Formula I wherein R 1 or R 3 is amino(C 1 -C 6 )alkyl can be reacted with methanesulfonyl chloride to give a compound of Formula I wherein R 1 or R 3 is {methanesulfonylamino}(C 1 -C 6 )alkyl.

(7) a compound of Formula I, wherein R 1 is (C 2 -C 6 )alkenyl is hydroborated to afford a compound of Formula I wherein R 1 is hydroxy(C 2 -C 6 )alkyl.

(8) a compound of Formula I, wherein R 3 is (C 2 -C 6 )alkenyl, is hydroborated to afford a compound of Formula I wherein R 3 is hydroxy(C 2 -C 6 )alkyl.

(9) a compound of Formula I, wherein R 1 is (C 2 -C 6 )alkenyl, can be reacted with osmium tetroxide and N-methylmorpholine-N-oxide to afford a compound of Formula I wherein R 1 is vicinal dihydroxy(C 2 -C 6 )alkyl,

(10) a compound of Formula I, wherein R 3 is (C 2 -C 6 )alkenyl, can be reacted with osmium tetroxide and N-methylmorpholine-N-oxide to afford a vicinal diol compound of Formula I wherein R 3 is vicinal dihydroxy(C 2 -C 6 )alkyl,

(11) a compound of Formula I, wherein R 1 is (C 2 -C 6 )alkenyl, can be reacted with ozone followed by NaBH 4 to give a compound of Formula I wherein R 1 is ω-hydroxy(C 1 -C 5 )alkyl.

(12) a compound of Formula I, wherein R 3 is (C 2 -C 6 )alkenyl, can be reacted with ozone followed by NaBH 4 to give a compound of Formula I wherein R 3 is ω-hydroxy(C 1 -C 5 )alkyl.

(13) a compound of Formula I wherein R 1 or R 3 is amino(C 1 -C 6 )alkyl can be reacted with an (C 1 -C 6 )alkyl isocyanate to give a compound of Formula I wherein R 1 or R 3 is (C 1 -C 6 )alkylaminocarbonylamino(C 1 -C 6 )alkyl.

(14) a compound of Formula I wherein R 1 or R 3 is amino(C 1 -C 6 )alkyl can be reacted with an (C 1 -C 6 )alkyl chloroformate to give a compound of Formula I wherein R 1 or R 3 is (C 1 -C 6 )alkoxycarbonylamino(C 1 -C 6 )alkyl.

›DEFINITIONS · 5 of 6

(15) a compound of Formula I wherein R 1 or R 3 is amino(C 1 -C 6 )alkyl can be reacted with chlorosulfonyl isocyanate or sulfamide to give a compound of Formula I wherein R 1 or R 3 is aminosulfonylamino(C 1 -C 6 )alkyl.

(16) a compound of Formula I wherein R 1 or R 3 is amino(C 1 -C 6 )alkyl can be reacted with a (C 1 -C 6 )alkylsulfamoyl chloride to give a compound of Formula I wherein R 1 or R 3 is (C 1 -C 6 )alkylaminosulfonylamino(C 1 -C 6 )alkyl.

(17) a compound of Formula I wherein R 1 or R 3 is hydroxy(C 1 -C 6 )alkyl can be reacted with chlorosulfonyl isocyanate to give a compound of Formula I wherein R 1 or R 3 is aminosulfonyloxy(C 1 -C 6 )alkyl.

(18) a compound of Formula I wherein R 1 or R 3 is hydroxy(C 1 -C 6 )alkyl can be reacted with p-nitrophenyl chloroformate, pentafluorophenyl chloroformate or carbonyl diimidazole, followed by ammonia, a (C 1 -C 6 )alkylamine or a di(C 1 -C 6 )alkylamine to give a compound of Formula I wherein R 1 or R 3 is aminocarboxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl aminocarboxy(C 1 -C 6 )alkyl or di(C 1 -C 6 )alkyl aminocarboxy(C 1 -C 6 )alkyl.

(19) a compound of Formula I wherein R 1 or R 3 is hydroxy(C 1 -C 6 )alkyl can be reacted with POCl 3 to give a compound of Formula I wherein R 1 or R 3 is (HO) 2 P(═O)O(C 1 -C 6 )alkyl.

(20) a compound of Formula I wherein Cy 1 is substituted with bromine or iodine, A 2 is a bond and Cy 2 is hydrogen can be reacted with a cyclic amine in the presence of a palladium catalyst to give a compound of Formula I wherein A 2 is a bond and Cy 2 is a cyclic amino moiety attached through its nitrogen atom.

(21) a compound of Formula I wherein Cy 1 is aryl or heteroaryl substituted with bromine or iodine, A 2 is a bond and Cy 2 is hydrogen can be reacted with bis(pinacolato)diboron in the presence of a palladium catalyst to give a boronate ester which can be further reacted with (a) an aryl, heteroaryl or heterocyclyl halide again in the presence of a palladium catalyst to give a compound of Formula I wherein A 2 is a bond and Cy 2 is aryl, heteroaryl or heterocyclyl.

(22) a compound of Formula I, wherein R 3 is allyl or homoallyl can be reacted with oxygen in the presence of PdCl 2 and CuCl to afford a compound of Formula I, wherein R 3 is 2-oxopropyl or 3-oxobutyl respectively.

(23) a compound of Formula I, wherein R 3 is 2-oxopropyl or 3-oxobutyl can be reacted with MeMgX, wherein X is Cl, Br or I, to give a compound of Formula I, wherein R 3 is 2-hydroxy-2-methylpropyl or 3-hydroxy-3-methylpropyl respectively.

(24) a compound of Formula I, wherein R 3 is —CH 2 CO 2 Me can be treated with MeMgX, wherein X is Cl, Br or I, to give a compound of Formula I, wherein R 3 is 2-hydroxy-2-methylpropyl.

(25) a compound of Formula I, wherein R 3 is allyl or —CH 2 C(Me)=CH 2 can be hydrocyanated with TsCN in the presence of triphenylsilane and various cobalt catalysts to afford compounds of Formula I, wherein R 3 is —CH 2 CH(CN)Me or —CH 2 CMe 2 CN respectively.

(26) a compound of Formula I, wherein R 3 is CH 2 C(Me) 2 CN, can be treated with acetamide in the presence of PdCl 2 to give a compound of Formula I, wherein R 3 is CH 2 CMe 2 CONH 2 .

(27) a compound of Formula I, wherein R 3 is —CH 2 C(Me)=CH 2 can be treated with m-CPBA followed by lithium triethylborohydride to afford a compound of Formula I, wherein R 3 is 2-hydroxy-2-methylpropyl.

In an eighth process, compounds of the invention as prepared as follows:

Halo compounds of Formula LIII can be formed by the treatment of β-haloketones of Formula LI with organometallic reagents of Formula LII, wherein M denotes MgCl, and the reaction is performed in the presence of anhydrous cerium trichloride in an inert anhydrous solvent, such as tetrahydrofuran, at about −25 to 0° C. for about 0.5 h.

Cyclic carbamates of Formula LV can be prepared from the reaction between β-haloalcohols of Formula LIII where Hal is a chloride and Isocyanates of Formula LIV in the presence of a base, such as but not limited to DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), in a refluxing inert solvent, such as but not limited to tetrahydrofuran.

Tertiary alcohols of Formula LVII can be derived from trisubstituted alkenes of Formula LV by first epoxidizing the alkene with an epoxidation reagent, such as m-CPBA (3-chloroperbenzoic acid), in an inert solvent, such as dichloromethane to produce the corresponding epoxides of Formula LVI. The resulting epoxide is then reductively ring opened to provide the corresponding tertiary alcohol LVII via treatment with a strong hydride reagent, such as triethylborohydride, in an anhydrous inert solvent, such as tetrahydrofuran.

This eighth process is described in greater detail in U.S. Provisional Application Ser. No. 61/137,013, filed Jul. 25, 2008 entitled SYNTHESIS OF INHIBITORS OF 11β-HYDROXYSTEROID DEHYDROGENASE TYPE 1, the entire teachings of which are incorporated herein by reference.

In another variation, Id is prepared from Ia′ by using a “Suzuki” coupling reaction with Cy 2 -B(OH) 2 and (PH 3 P) 2 PdCl 2 as described in, for example, Example 111:

The 2-methyl-2-hydroxypropyl group is introduced via epoxidation and hydride ring opening as described above.

In a ninth process, compounds of Formula Ie 1 can be prepared according to the following scheme:

A methoxymethyl ketone of Formula LVIII is reacted with an organometallic allyl reagent of Formula LIX wherein M includes, but is not limited to, MgCl, MgBr, MgI or Li to yield an allyl compound of Formula LX. In specific examples, organometallic reagent LIX is allylmagnesium chloride, allylmagnesium bromide or allylzinc(II) bromide. In certain cases when M is MgCl, MgBr or MgI, it is advantageous to add CeCl 3 to the reaction mixture.

Allyl compound of Formula LX is converted to the aldehyde of Formula LXII by ozonolysis or by OsO 4 catalysed dihydroxylation followed by cleavage of the glycol of Formula LXI by periodates like sodium periodate. Aminocarbinol of Formula LXIV can be prepared by reductive amination with an amine of Formula LXIII using sodium cyanoborohydride or sodium triacetoxyborohydride as reducing agent. Cyclisation of the aminocarbinol of Formula LXIV to the compounds of Formula Ie 1 can be achieved by reacting with activated carbonic acid derivates such as phosgene, diphosgene, triphosgene or 1,1′-carbonyl-diimidazol.

›DEFINITIONS · 6 of 6

Purification Methods

Compounds of the invention can be purified by high pressure liquid chromatography (prep HPLC). Unless otherwise specified, prep HPLC refers to preparative reverse phase HPLC on a C-18 column eluted with a water/acetonitrile gradient containing 0.01% TFA run on a Gilson 215 system.

LC-MS Methods

Method 1 [LC-MS (3 min)]

Column: Chromolith SpeedRod, RP-18e, 50×4.6 mm; Mobil phase: A: 0.01% TFA/water, B: 0.01% TFA/CH 3 CN; Flow rate: 1 mL/min; Gradient:

Time (min) A % B % 0.0 90 10 2.0 10 90 2.4 10 90 2.5 90 10 3.0 90 10

Method 2 (10-80)

Column YMC-PACK ODS-AQ, 50 × 2.0 mm 5 μm Mobile A: water (4 L) + TFA (1.5 mL)) Phase B: acetonitrile (4 L) + TFA (0.75 mL)) TIME (min) A % B % 0 90 10 2.2 20 80 2.5 20 80 Flow Rate 1 mL/min Wavelength UV 220 nm Oven Temp 50° C. MS ESI ionization

Method 3 (30-90)

Column YMC-PACK ODS-AQ, 50 × 2.0 mm 5 μm Mobile A: water (4 L) + TFA (1.5 mL)) Phase B: acetonitrile (4 L) + TFA (0.75 mL)) TIME (min) A % B % 0 70 30 2.2 10 90 2.5 10 90 Flow Rate 1 mL/min Wavelength UV220 Oven Temp 50° C. MS ESI ionization

Method 4 [50-100]

›Example 1

6-methyl-6-phenyl-3-m-tolyl-1,3-oxazinan-2-one

›Step 1. 2-Phenylpent-4-en-2-ol

To a solution of acetophenone (30 g, 0.25 mol) in dry THF (250 mL) at −78° C. was added dropwise 1M allylmagnesium bromide (1.25 L, 1.25 mol). After addition was complete, the mixture was allowed to stir at rt for 3 h. The reaction was quenched with satd aq NH 4 Cl solution (30 mL). The mixture was extracted with EtOAc (200 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na 2 SO 4 and concentrated to give 2-phenylpent-4-en-2-ol (40.2 g), which was used for the next step without purification.

›Step 2. 3-Phenylbutane-1,3-diol

A solution of 2-phenylpent-4-en-2-ol (74 g, 0.457 mol) in dry CH 2 Cl 2 (1 L) was treated with ozone at −78° C. until the mixture turned blue. The system was then flushed with oxygen to remove excess ozone. NaBH 4 (42.8 g, 1.143 mol) was added to the mixture in portions at −20° C. The mixture was stirred overnight at rt. The mixture was quenched with water and the layers were separated. The aqueous layer was extracted with CH 2 Cl 2 (2×). The organic layers were combined, washed with brine, dried over anhydrous Na 2 SO 4 and concentrated to give 3-phenylbutane-1,3-diol (67.8 g), which was used for the next step without purification.

›Step 3. 3-Hydroxy-3-phenylbutyl 4-methylbenzenesulfonate

To a solution of 3-phenylbutane-1,3-diol (68 g, 0.41 mol) in dry CH 2 Cl 2 (500 mL) was added dropwise a solution of TsCl (78 g, 0.41 mol) and triethylamine (71 mL, 0.45 mol) in dry CH 2 Cl 2 (500 mL) at 0° C. The mixture was stirred overnight. The mixture was poured into water and separated. The aqueous layer was extracted with CH 2 Cl 2 (200 mL) twice. The organic layer was combined, washed with brine, dried over anhydrous Na 2 SO 4 and concentrated to give the crude product. The crude product was purified by column chromatography to give 3-hydroxy-3-phenylbutyl 4-methylbenzenesulfonate (62 g, 42%). 1 H NMR (400 MHz, CDCl 3 ): δ=1.55 (s, 3H), 1.93 (w, 1H), 2.19˜2.24 (q, 2H), 2.45 (s, 3H), 3.87˜4.01 (m, 1H), 4.09˜4.16 (m, 1H), 7.19˜7.34 (m, 7H), 7.68˜7.76 (d, 2H).

›Step 4. 6-methyl-6-phenyl-3-m-tolyl-1,3-oxazinan-2-one

To a solution of 3-hydroxy-3-phenylbutyl 4-methylbenzenesulfonate (1 g, 3.12 mmol) and DBU (1.4 g, 9.26 mmol) in CH 2 Cl 2 (15 mL) was added a solution of 3-methylphenyl isocyanate (623 mg, 4.68 mmol) in CH 2 Cl 2 (5 mL) at 0° C. over 0.5 h. The mixture was stirred at rt overnight. The mixture was concentrated to give the crude product, which was purified by column chromatography and then by preparative HPLC to afford 6-methyl-6-phenyl-3-m-tolyl-1,3-oxazinan-2-one. LC-MS Method 2, t R =2.706 min, m/z=282. 1 H NMR (CDCl 3 ) 1.75 (s, 3H), 2.30 (s, 3H), 2.35-2.50 (m, 2H), 3.30 (m, 1H), 3.50 (m, 1H), 6.95 (m, 2H), 7.05 (m, 1H), 7.20-7.30 (m, 1H), 7.35 (m, 1H), 7.42-7.50 (m, 4H).

›Step 5. Enantiomers of 6-methyl-6-phenyl-3-m-tolyl-1,3-oxazinan-2-one

Chiral preparative SFC using a ChiralPak-AD, 400×25 mm I.D, 20 μm (Daicel Chemical Industries, Ltd) column maintained at 35 C eluted with 70:30 supercritical CO 2 /0.1% diethylamine in MeOH at a flow rate of 70 mL min −1 and a nozzle pressure of 100 bar afforded two isomers.

Isomer 1 (90 mg) gave the following spectral data: 1 H NMR (400 MHz, CDCl 3 ): δ=1.62 (m, 1H), 1.76 (s, 3H), 2.31 (s, 3H), 2.48 (m, 2H), 3.28 (m, 1H), 3.50 (m, 1H), 6.95 (m, 1H), 7.04 (m, 1H), 7.23 (t, 1H), 7.35 (m, 1H), 7.44 (m, 4H);

Isomer 2 (100 mg) gave the following spectral data: (400 MHz, CDCl 3 ): δ=1.62 (m, 1H), 1.76 (s, 3H), 2.31 (s, 3H), 2.48 (m, 2H), 3.28 (m, 1H), 3.50 (m, 1H), 6.95 (m, 1H), 7.04 (m, 1H), 7.23 (t, 1H), 7.35 (m, 1H), 7.44 (m, 4H).

›Examples52

›Example 2

3-(4-chlorophenyl)-6-methyl-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to those described in Example 1 Steps 1-4 using 4-chlorophenyl isocyanate in Step 4. LC-MS Method 2, t R =2.798 min, m/z=324. 1 H NMR (CD 3 OD) 1.75 (s, 3H), 2.45 (m, 1H), 2.65 (m, 1H), 3.27 (m, 1H), 3.60 (m, 1H), 7.15 (d, 2H), 7.35 (dd, 3H), 7.47 (m, 4H).

›Example 3

3-(2-chlorophenyl)-6-methyl-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to those described in Example 1 Steps 1-4 using 2-chlorophenyl isocyanate in Step 4. LC-MS Method 3, t R =1.14 min, m/z=625.1. 1 H NMR (CD 3 OD) 1.80 (d, 3H), 2.50 (m, 1H), 2.62 (m, 1H), 3.20-3.30 (m, 1H), 3.42 (m, 1H), 3.50-3.60 (m, 2H), 7.03 (d, 1H), 7.30-7.50 (m, 5H), 7.50-7.60 (m, 4H).

›Example 4

3-(3-chlorophenyl)-6-methyl-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to those described in Example 1 Steps 1-4 using 3-chlorophenyl isocyanate in Step 4. LC-MS Method 2, t R =2.291 min, m/z=301. 1 H NMR (CD 3 OD) 1.75 (s, 3H), 2.50 (m, 1H), 2.70 (m, 1H), 3.30 (m, 1H), 3.68 (m, 1H), 7.12 (d, 1H), 7.30-7.45 (m, 4H), 7.50 (d, 4H).

›Example 5

6-methyl-6-phenyl-3-(4-(trifluoromethyl)phenyl)-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to those described in Example 1 Steps 1-4 using 4-(trifluoromethyl)phenyl isocyanate in Step 4. LC-MS Method 2, t R =2.903 min, m/z=336. 1 H NMR (CD 3 OD) 1.75 (s, 3H), 2.50 (m, 1H), 2.70 (m, 1H), 3.40 (m, 1H), 3.70 (m, 1H), 7.32-7.42 (m, 3H), 7.45-7.50 (m, 4H), 7.70 (d, 2H).

›Example 6

3-(3-bromophenyl)-6-methyl-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to those described in Example 1 Steps 1-4 using 3-bromophenyl isocyanate in Step 4. LC-MS Method 3, t R =1.232 min, m/z=367.9. 1 H NMR (CDCl 3 ) 1.70 (s, 2H), 2.30-2.40 (m, 1H), 3.45 (m, 1H), 7.07 (d, 1H), 7.12 (t, 1H), 7.22-7.30 (m, 3H), 7.35-7.40 (m, 4H).

›Example 7

6-methyl-3,6-diphenyl-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to those described in Example 1 Steps 1-4 using phenyl isocyanate in Step 4. LC-MS Method 2, t R =1.99 min, m/z=268. 1 H NMR (CD 3 OD) 1.75 (s, 3H), 2.45 (m, 1H), 2.65 (m, 1H), 3.25 (m, 1H), 3.60 (m, 1H), 7.12 (d, 2H), 7.25 (t, 1H), 7.35 (m, 3H), 7.45-7.53 (m, 4H).

›Example 8

3-cyclohexyl-6-methyl-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to those described in Example 1 Steps 1-4 using cyclohexyl isocyanate in Step 4. LC-MS Method 3, t R =1.529 min, m/z=274.1. 1 H NMR (CDCl 3 ) 0.97-1.15 (m, 3H), 1.20-1.37 (m, 2H), 1.55 (d, 1H), 1.65 (m, 2H), 1.80-1.90 (m, 2H), 2.05 (s, 1H), 2.75 (m, 2H), 3.40 (b, 1H), 4.10 (t, 2H), 5.08 (s, 1H), 7.18 (m, 1H), 7.25 (m, 2H), 7.34 (dd, 2H).

›Example 9

3-(biphenyl-3-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one

To a solution of 3-(3-bromophenyl)-6-methyl-6-phenyl-1,3-oxazinan-2-one (50 mg, 0.14 mmol) and phenylboronic acid (35 mg, 0.29 mmol) in THF (2 mL) was added a solution of NaHCO 3 (31 mg, 0.29 mmol) in H 2 O (2 mL) followed by Pd(PPh 3 )Cl 2 (9 mg, 0.01 mmol). The mixture was refluxed overnight. The mixture was concentrated to give the crude product, which was purified by column chromatography, followed by preparative HPLC to afford 3-(biphenyl-3-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one (10 mg, 20%). 1 H NMR: (400 MHz, CDCl 3 ): δ 1.71 (s, 3H), 2.40 (m, 1H), 2.48 (m, 1H), 3.31 (m, 1H), 3.54 (m, 1H), 7.08 (m, 1H), 7.30 (m, 3H), 7.7.32-7.42 (m, 8H), 7.46 (m, 2H). LC-MS Method 3, t R =1.362 min, m/z=344. 1 H NMR (CDCl 3 ) 1.75 (s, 3H), 2.32-2.43 (m, 1H), 2.50 (m, 1H), 3.20 (m, 1H), 3.52 (m, 1H), 7.10 (d, 1H), 7.25-7.45 (m, 11H), 7.50 (d, 2H).

›Example 10

3-(2′-chlorobiphenyl-3-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to those in Example 9 using 2-chlorophenylboronic acid. LC-MS Method 3, t R =1.479 min, m/z=378.1. 1 H NMR (CDCl 3 ) 1.63 (s, 3H), 2.38 (m, 1H), 2.67 (m, 1H), 3.18-3.26 (m, 1H), 3.59 (m, 1H), 7.09 (m, 2H), 7.24 (m, 5H), 7.38 (m, 6H).

›Example 11

3-(4′-Methanesulfonyl-biphenyl-3-yl)-6-methyl-6-phenyl-[1,3]oxazinan-2-one

The title compound was prepared following procedures analogous to those in Example 9 using 4-(methylsulfonyl)phenylboronic acid. LC-MS Method 3, t R =2.042 min, m/z=422.1. 1 H NMR (CD 3 OD) 1.69 (s, 3H), 2.40-2.50 (m, 1H), 2.50-2.60 (m, 1H), 3.20 (s, 1H), 3.51-3.60 (m, 1H), 4.5 (m, 1H), 7.05-7.11 (m, 2H), 7.20-7.30 (m, 5H), 7.30-7.45 (m, 6H).

›Example 12

3′-(6-Methyl-2-oxo-6-phenyl-[1,3]oxazinan-3-yl)-biphenyl-2-carbonitrile

The title compound was prepared following procedures analogous to those in Example 9 using 2-cyanophenylboronic acid. LC-MS Method 3, t R =1.376 min, m/z=369.1. 1 H NMR (CD 3 OD) 1.73 (s, 3H), 2.38-2.60 (m, 1H), 2.62-2.78 (m, 1H), 3.38-3.52 (m, 1H), 3.65-3.78 (m, 1H), 7.22-7.28 (m, 1H), 7.32-7.39 (m, 2H), 7.40-7.52 (m, 6H), 7.53-7.62 (m, 2H), 7.68-7.85 (m, 2H).

›Example 13

N-isopropyl-3′-(6-methyl-2-oxo-6-phenyl-1,3-oxazinan-3-yl)biphenyl-4-sulfonamide

The title compound was prepared following procedures analogous to those in Example 9 using 4-(isopropylaminosulfonyl)phenylboronic acid. LC-MS Method 3, t R =1.566 min, m/z=465.1. 1 H NMR (CDCl 3 ) 1.11-1.15 (m, 6H), 1.79 (s, 3H), 2.40-2.50 (m, 1H), 2.50-2.60 (m, 1H), 3.40 (s, 4H), 3.45-3.62 (m, 2H), 7.15-7.20 (m, 1H), 7.32-7.55 (m, 8H), 7.60-7.68 (m, 2H), 7.92-7.96 (m, 2H).

›Example 14

N,N-dimethyl-3′-(6-methyl-2-oxo-6-phenyl-1,3-oxazinan-3-yl)biphenyl-3-sulfonamide

The title compound was prepared following procedures analogous to those in Example 9 using 3-(dimethylaminosulfonyl)phenylboronic acid. LC-MS Method 3, t R =1.459 min, m/z=451.1. 1 H NMR (CDCl 3 ) 1.71 (s, 3H), 2.40-2.50 (m, 1H), 2.50-2.58 (m, 1H), 3.25-3.35 (m, 1H), 3.51-3.65 (m, 1H), 7.10-7.12 (m, 1H), 7.25-7.40 (m, 8H), 7.50-7.60 (m, 1H), 7.65-7.70 (m, 2H), 7.80-7.85 (m, 1H).

›Example 15

6-methyl-3-(2′-(methylsulfonyl)biphenyl-3-yl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to those in Example 9 using 2-(methylsulfonyl)phenylboronic acid. LC-MS Method 3, t R =1.464 min, m/z=422. 1 H NMR (CDCl 3 ) 1.77 (s, 3H), 2.40-2.50 (m, 1H), 2.50-2.60 (m, 1H), 2.60-2.68 (m, 3H), 3.38-3.48 (m, 1H), 3.62-3.70 (m, 1H), 4.90-5.02 (s, 2H), 7.30-7.45 (m, 5H), 7.45-7.50 (m, 5H), 7.52-7.70 (m, 2H), 8.20-8.25 (m, 1H).

›Example 16

6-methyl-6-phenyl-3-(4′-(pyrrolidin-1-ylsulfonyl)biphenyl-3-yl)-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to those in Example 9 using 4-(pyrrolidin-1-ylsulfonyl)phenylboronic acid. LC-MS Method 3, t R =1.504 min, m/z=477.2. 1 H NMR (CDCl 3 ) 1.72-1.75 (m, 7H), 2.35-2.42 (m, 1H), 2.45-2.52 (m, 1H), 3.20-3.28 (m, 6H), 3.30-3.35 (m, 1H), 3.50-3.58 (m, 1H), 7.10-7.15 (m, 1H), 7.26-7.40 (m, 4H), 7.52-7.60 (m, 2H), 7.60-7.70 (m, 2H), 7.80-7.90 (m, 3H).

›Example 17

3′-(6-methyl-2-oxo-6-phenyl-1,3-oxazinan-3-yl)biphenyl-3-carbonitrile

The title compound was prepared following procedures analogous to those in Example 9 using 3-cyanophenylboronic acid. LC-MS Method 3, t R =1.487 min, m/z=369.1. 1 H NMR (CDCl 3 ) 1.72 (s, 3H), 2.32-2.58 (m, 2H), 3.25-3.38 (m, 1H), 3.45-3.57 (m, 1H), 7.12-7.18 (m, 1H), 7.25-7.32 (m, 2H), 7.33-7.42 (m, 6H), 7.42-7.50 (m, 1H), 7.52-7.58 (m, 1H), 7.66-7.75 (m, 2H).

›Example 18

N-(2-methoxyethyl)-3′-(6-methyl-2-oxo-6-phenyl-1,3-oxazinan-3-yl)biphenyl-3-carboxamide

The title compound was prepared following procedures analogous to those in Example 9 using 3-(2-methoxyethylcarbamoyl)phenylboronic acid. LC-MS Method 3, t R =1.328 min, m/z=445.2. 1 H NMR (CDCl 3 ) 1.70 (s, 3H), 2.45 (m, 2H), 3.27 (m, 1H), 3.33 (s, 3H), 3.50 (m, 3H), 3.65 (m, 2H), 6.52 (m, 1H), 7.10 (m, 1H), 7.30-7.47 (m, 10H), 7.60 (m, 1H), 7.68 (m, 1H), 7.90 (s, 1H).

›Example 19

N-((3′-(6-methyl-2-oxo-6-phenyl-1,3-oxazinan-3-yl)biphenyl-4-yl)methyl)methanesulfonamide

The title compound was prepared following procedures analogous to those in Example 9 using 4-(methylsulfonamidomethyl)phenylboronic acid. LC-MS Method 3, t R =1.19 min, m/z=450.9. 1 H NMR (CDCl 3 ) 1.70 (s, 3H), 2.35-2.60 (m, 2H), 2.95 (s, 3H), 3.35 (m, 1H), 3.60 (m, 1H), 4.40 (m, 2H), 4.65 (b, 1H), 6.95-7.20 (m, 3H), 7.30-7.60 (m, 11H).

›Example 20

6-methyl-6-phenyl-3-(3-(pyridin-3-yl)phenyl)-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to those in Example 9 using 3-pyridylboronic acid. LC-MS Method 2, t R =1.819 min, m/z=345.1. 1 H NMR (CDCl 3 ) 1.80 (s, 3H), 2.45-2.65 (m, 2H), 3.40 (m, 1H), 3.62 (m, 1H), 7.30-7.60 (m, 8H), 7.85 (m, 1H), 8.40 (m, 1H), 8.75 (m, 1H), 9.00 (m, 1H), 9.30-9.50 (b, 2H).

›Example 21

3-(2′-methoxybiphenyl-3-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to those in Example 9 using 2-methoxyphenylboronic acid. LC-MS Method 3, t R =1.55 min, m/z=374.1. 1H NMR (CDCl3) 1.69 (s, 3H), 2.36 (m, 1H), 2.46 (m, 1H), 3.31 (m, 1H), 3.52 (m, 1H), 4.5 (m, 1H), 5.17 (m, 1H), 7.06 (m, 1H), 7.12 (m, 1H), 7.18 (m, 1H), 7.28 (m, 3H), 7.33 (m, 2H), 7.38 (m, 4H), 7.45 (m, 1H).

›Example 22

3-(2′,6′-dichlorobiphenyl-3-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to those in Example 9 using 2,6-dichlorophenylboronic acid. LC-MS Method 3, t R =1.676 min, m/z=412. 1H NMR (CDCl3) 1.69 (s, 3H), 2.36 (m, 1H), 2.45 (m, 1H), 3.30 (m, 1H), 3.50 (m, 1H), 7.05 (m, 2H), 7.16 (m, 1H), 7.25 (m, 2H), 7.30 (m, 1H), 7.32 (m, 1H), 7.40 (m, 5H).

›Example 23

3-(2′,4′-difluorobiphenyl-3-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to those in Example 9 using 2,4-difluorophenylboronic acid. LC-MS Method 3, t R =1.595 min, m/z=380.1. 1 H NMR (CDCl 3 ) 1.69 (s, 3H), 2.30-2.50 (m, 2H), 3.28 (m, 1H), 3.50 (m, 1H), 6.86 (m, 2H), 7.13 (m, 1H), 7.21 (m, 1H), 7.28 (m, 3H), 7.35 (m, 5H).

›Example 24

3-(3′-chlorobiphenyl-3-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to those in Example 9 using 3-chlorophenylboronic acid. LC-MS Method 3, t R =1.67 min, m/z=378. 1 H NMR (CDCl 3 ) (s, 3H), 2.36 (m, 1H), 2.48 (m, 1H), 3.28 (m, 1H), 3.49 (m, 1H), 7.12 (m, 1H), 7.27 (m, 4H), 7.32 (m, 3H), 7.38 (m, 4H), 7.42 (m, 1H).

›Example 25

3-(3′-fluorobiphenyl-3-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to those in Example 9 using 3-fluorophenylboronic acid. LC-MS Method 3, t R =1.69 min, m/z=362.1. 1H NMR (CDCl3) 1.68 (s, 3H), 2.46 (m, 1H), 2.57 (m, 1H), 3.38 (m, 1H), 3.62 (m, 1H), 7.06 (m, 1H), 7.17 (m, 1H), 7.23 (m, 1H), 7.32 (m, 2H), 7.38 (m, 2H), 7.48 (m, 6H).

›Example 26

3-(2′,5′-difluorobiphenyl-3-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to those in Example 9 using 2,5-difluorophenylboronic acid. LC-MS Method 3, t R =1.686 min, m/z=380.1. 1H NMR (CDCl3) 1.77 (s, 3H), 2.42 (m, 1H), 2.55 (m, 1H), 3.35 (m, 1H), 3.58 (m, 1H), 6.98 (m, 1H), 7.08 (m, 2H), 7.23 (m, 1H), 7.35 (m, 2H), 7.43 (m, 6H).

›Example 27

3-(3′,5′-difluorobiphenyl-3-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to those in Example 9 using 3,5-difluorophenylboronic acid. LC-MS Method 3, t R =1.468 min, m/z=379.9. 1H NMR (CDCl3) 1.78 (s, 3H), 2.42 (m, 1H), 2.56 (m, 1H), 3.37 (m, 1H), 3.58 (m, 1H), 6.78 (m, 1H), 7.03 (m, 2H), 7.23 (m, 1H), 7.32 (m, 1H), 7.38 (m, 1H), 7.42 (m, 2H), 7.48 (m, 4H).

›Example 28

3-(4′-fluorobiphenyl-3-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to those in Example 9 using 4-fluorophenylboronic acid. LC-MS Method 3, t R =1.38 min, m/z=362.1. 1 H NMR (CDCl 3 ) 1.77 (s, 3H), 2.42 (m, 1H), 2.55 (m, 1H), 3.35 (m, 1H), 3.58 (m, 1H), 7.13 (m, 3H), 7.32 (m, 1H), 7.36 (m, 1H), 7.39 (m, 2H), 7.48 (m, 6H).

Chiral preparative SFC using a ChiralCel-AS, 400×25 mm I.D, 20 μm (Daicel Chemical Industries, Ltd) column maintained at 35 C eluted with 60:40 supercritical CO 2 /0.1% diethylamine in MeOH at a flow rate of 70 mL min −1 and a nozzle pressure of 100 bar afforded the two enantiomers.

Isomer 1: LC-MS Method 3, t R =1.38 min, m/z=362.1. 1H NMR (CDCl3) 1.81 (s, 3H), 2.41-2.50 (m, 2H), 3.35 (m, 1H), 3.51 (m, 1H), 7.15 (m, 3H), 7.33-7.52 (m, 10H).

Isomer 2: LC-MS Method 3, t R =1.392 min, m/z=362.1. 1H NMR (CDCl3) 1.70 (s, 3H), 2.32-2.50 (m, 2H), 3.28 (m, 1H), 3.51 (m, 1H), 7.05 (m, 3H), 7.22-7.45 (m, 10H).

›Example 29

N-(3′-(6-methyl-2-oxo-6-phenyl-1,3-oxazinan-3-yl)biphenyl-3-yl)methanesulfonamide

The title compound was prepared following procedures analogous to those in Example 9 using 3-(methylsulfonylamino)phenylboronic acid. LC-MS Method 3, t R =1.626 min, m/z=437.1. 1H NMR (CDCl3) 1.70 (s, 3H), 2.34-2.50 (m, 2H), 2.98 (s, 3H), 3.21 (m, 1H), 3.51 (m, 1H), 6.48 (m, 1H), 7.05 (m, 1H), 7.18 (m, 1H), 7.25-7.40 (m, 11H).

›Example 30

N-methyl-3′-(6-methyl-2-oxo-6-phenyl-1,3-oxazinan-3-yl)biphenyl-3-sulfonamide

The title compound was prepared following procedures analogous to those in Example 9 using 3-(methylaminosulfonyl)phenylboronic acid. LC-MS Method 3, t R =1.184 min, m/z=437.1. 1 H NMR (CDCl 3 ) 1.11-1.13 (m, 6H), 1.70 (m, 3H), 2.40-2.50 (m, 1H), 2.50-2.60 (m, 1H), 3.20-3.49 (s, 4H), 3.49-3.65 (m, 2H), 7.15-7.21 (m, 1H), 7.31-7.56 (m, 8H), 7.62-7.68 (m, 2H), 7.90-7.96 (m, 2H).

›Example 31

N-methyl-3′-(6-methyl-2-oxo-6-phenyl-1,3-oxazinan-3-yl)biphenyl-3-carboxamide

The title compound was prepared following procedures analogous to those in Example 9 using 3-(methylcarbamoyl)phenylboronic acid. LC-MS Method 3, t R =1.11 min, m/z=401.1. 1 H NMR (CDCl 3 ) 1.70 (s, 3H), 2.35 (m, 1H), 2.46 (m, 1H), 2.95 (s, 3H), 3.30 (m, 1H), 3.50 (m, 1H), 6.45 (m, 1H), 7.17 (m, 1H), 7.30 (m, 2H), 7.38 (m, 6H), 7.55 (m, 1H), 7.65 (m, 1H), 7.80 (s, 1H).

›Example 32

3-(3′-aminobiphenyl-3-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to those in Example 9 using 3-aminophenylboronic acid. LC-MS Method 2, t R =1.761 min, m/z=359.1. 1 H NMR (CDCl 3 ) 1.70 (s, 3H), 2.30-2.50 (m, 2H), 3.30 (m, 1H), 3.50 (m, 1H), 6.62 (m, 1H), 6.80-6.90 (m, 2H), 7.05-7.47 (m, 10H).

›Example 33

6-methyl-6-phenyl-3-(3-(pyridin-4-yl)phenyl)-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to those in Example 9 using 4-pyridylboronic acid. LC-MS Method 2, t R =1.329 min, m/z=345.1. 1 H NMR (CDCl 3 ) 1.70 (s, 3H), 2.30-2.50 (m, 2H), 3.30 (m, 1H), 3.50 (m, 1H), 4.10 (m, 2H), 7.27-7.50 (m, 9H), 8.60 (b, 1H).

›Example 34

3-(3′-methoxybiphenyl-3-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to those in Example 9 using 3-methoxyphenylboronic acid. LC-MS Method 3, t R =1.392 min, m/z=374.1. 1 H NMR (CDCl 3 ) 1.70 (s, 3H), 2.30-2.50 (m, 2H), 3.30 (m, 1H), 3.50 (m, 1H), 3.80 (s, 3H), 6.85 (m, 1H), 7.00-7.45 (m, 12H).

›Example 35

3-(2′-(hydroxymethyl)biphenyl-3-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to those in Example 9 using 2-hydroxymethylphenylboronic acid. LC-MS Method 3, t R =1.375 min, m/z=769.3. 1H NMR (CDCl3) 1.69 (s, 3H), 2.36 (m, 1H), 2.46 (m, 1H), 3.31 (m, 1H), 3.52 (m, 1H), 4.5 (m, 1H), 5.17 (m, 1H), 7.06 (m, 1H), 7.12 (m, 1H), 7.18 (m, 1H), 7.28 (m, 3H), 7.33 (m, 2H), 7.38 (m, 4H), 7.45 (m, 1H).

›Example 36

6-methyl-6-phenyl-3-(3-(thiophen-2-yl)phenyl)-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to those in Example 9 using 2-thienylboronic acid. LC-MS Method 3, t R =1.721 min, m/z=350. 1H NMR (CDCl3) 1.69 (s, 3H), 2.33-2.50 (m, 2H), 3.27 (m, 1H), 3.52 (m, 1H), 3.71 (S, 3H), 6.94 (m, 1H), 7.09 (m, 1H), 7.21-7.40 (m, 11H).

›Example 37

3-(2′-fluorobiphenyl-3-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to those in Example 9 using 2-fluorophenylboronic acid. LC-MS Method 3, t R =1.772 min, m/z=362.1. 1 H NMR (CDCl 3 ) 1.15 (s, 3H), 2.30-2.53 (m, 2H), 3.30 (m, 1H), 3.50 (m, 1H), 7.08 (m, 3H), 7.25 (m, 2H), 7.32 (m, 3H), 7.38 (m, 5H).

›Example 38

methyl 3′-(6-methyl-2-oxo-6-phenyl-1,3-oxazinan-3-yl)biphenyl-3-carboxylate

The title compound was prepared following procedures analogous to those in Example 9 using 3-methoxycarbonylphenylboronic acid. LC-MS Method 3, t R =1.745 min, m/z=402.1. 1 H NMR (CDCl 3 ) 1.20 (s, 3H), 2.32-2.50 (m, 2H), 3.30 (m, 1H), 3.55 (m, 1H), 3.89 (s, 3H), 7.10 (m, 1H), 7.30-7.47 (m, 9H), 7.65 (m, 1H), 7.95 (m, 1H), 8.12 (m, 1H).

›Example 39

3-(3′-(hydroxymethyl)biphenyl-3-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to those in Example 9 using 3-hydroxymethylphenylboronic acid. LC-MS Method 3, t R =1.35 min, m/z=374.1. 1 H NMR (CDCl 3 ) 1.70 (s, 3H), 2.30-2.50 (m, 2H), 3.30 (m, 1H), 4.70 (d, 2H), 7.05 (m, 1H), 7.27-7.55 (m, 13H).

›Example 40

6-methyl-3-(3′-(methylsulfonyl)biphenyl-3-yl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to those in Example 9 using 3-(methylsulfonyl)phenylboronic acid. LC-MS Method 3, t R =1.172 min, m/z=422.1. 1 H NMR (CDCl 3 ) 1.71 (s, 3H), 2.37-2.44 (m, 1H), 2.46-2.52 (m, 1H), 3.02 (s, 3H), 3.27-3.35 (m, 1H), 3.51-3.58 (m, 1H), 7.11 (d, 1H), 7.26 (m, 1H), 7.35-7.42 (m, 6H), 7.52-7.58 (t, 2H), 7.75 (d, 1H), 7.88 (d, 1H), 8.01 (s, 1H).

›Example 41

N-((3′-(6-methyl-2-oxo-6-phenyl-1,3-oxazinan-3-yl)biphenyl-3-yl)methyl)acetamide

The title compound was prepared following procedures analogous to those in Example 9 using 3-(acetamidomethyl)phenylboronic acid. LC-MS Method 3, t R =1.329 min, m/z=415.2. 1H NMR (CDCl3) 1.70 (s, 3H), 2.00 (s, 3H), 2.38 (m, 1H), 2.50 (m, 1H), 3.30 (m, 1H), 3.52 (m, 1H), 4.40 (m, 2H), 6.35 (m, 1H), 7.27-7.62 (m, 19H).

›Example 42

N,N-dimethyl-3′-(6-methyl-2-oxo-6-phenyl-1,3-oxazinan-3-yl)biphenyl-4-carboxamide

The title compound was prepared following procedures analogous to those in Example 9 using 4-(dimethylcarbamoyl)phenylboronic acid. LC-MS Method 3, t R =1.157 min, m/z=415.1. 1H NMR (CDCl3) 1.70 (s, 2H), 2.30-2.50 (m, 2H), 2.85 (m, 1H), 2.97 (s, 3H), 3.10 (s, 3H), 3.30 (m, 1H), 3.50 (m, 1H), 7.00-7.60 (m, 14H).

›Example 43

3-(4′-hydroxybiphenyl-3-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to those in Example 9 using 4-hydroxyphenylboronic acid. LC-MS Method 3, t R =1.381 min, m/z=360.1. 1H NMR (CDCl3) 1.70 (s, 3H), 2.35-2.50 (m, 2H), 3.30 (m, 1H), 3.50 (m, 1H), 6.80 (m, 2H), 7.0 (m, 1H), 7.20-7.65 (m, 12H).

›Example 44

3′-(6-methyl-2-oxo-6-phenyl-1,3-oxazinan-3-yl)biphenyl-4-carboxamide

The title compound was prepared following procedures analogous to those in Example 9 using 4-(carbamoyl)phenylboronic acid. LC-MS Method 2, t R =1.999 min, m/z=386.9. 1 H NMR (CDCl 3 ) 1.79 (s, 3H), 1.930 (s, 3H), 2.46 (m, 1H), 2.52 (m, 1H), 3.38 (m, 1H), 3.62 (m, 1H), 6.46 (m, 1H), 7.26 (m, 1H), 7.2 (m, 1H), 7.38 (m, 2H), 7.43 (m, 5H), 7.48 (m, 1H), 7.13 (m, 2H), 7.17 (m, 1H), 7.88 (m, 1H).

›Example 45

N-(3′-(6-methyl-2-oxo-6-phenyl-1,3-oxazinan-3-yl)biphenyl-2-yl)methanesulfonamide

The title compound was prepared following procedures analogous to those in Example 9 using 2-(methylsulfonylamino)phenylboronic acid. LC-MS Method 3, t R =1.167 min, m/z=437.1. 1 H NMR (CDCl 3 ) 1.69 (s, 3H), 2.32-2.41 (m, 1H), 2.46-2.52 (m, 1H), 2.86 (s, 2H), 3.30-3.40 (m, 1H), 3.40-3.60 (m, 1H), 6.50 (s, 1H), 7.10-7.18 (m, 4H), 7.20-7.40 (m, 8H), 7.51-7.59 (m, 1H).

›Example 46

methyl 3′-(6-methyl-2-oxo-6-phenyl-1,3-oxazinan-3-yl)biphenyl-4-carboxylate

The title compound was prepared following procedures analogous to those in Example 9 using 4-(methoxycarbonyl)phenylboronic acid. LC-MS Method 3, t R =1.359 min, m/z=402.1. 1H NMR (CDCl3) 1.80 (s, 3H), 2.42-2.62 (m, 2H), 3.38-3.44 (m, 1H), 3.60 (m, 1H), 3.95 (s, 3H), 7.19 (d, 1H), 7.34-7.53 (m, 8H), 7.60 (d, 2H), 8.10 (d, 2H).

›Example 47

N-methyl-3′-(6-methyl-2-oxo-6-phenyl-1,3-oxazinan-3-yl)biphenyl-4-sulfonamide

The title compound was prepared following procedures analogous to those in Example 9 using 4-(methylaminosulfonyl)phenylboronic acid. LC-MS Method 3, t R =1.403 min, m/z=437.1. 1H NMR (CDCl3) 1.70 (s, 3H), 2.40-2.50 (m, 1H), 2.50-2.60 (m, 1H), 3.20 (s, 3H), 3.32-3.42 (m, 1H), 3.52-3.62 (m, 1H), 7.15-7.20 (m, 1H), 7.30-7.50 (m, 8H), 7.60-7.70 (m, 2H), 7.86-7.95 (m, 2H).

›Example 48

3-(4′-(hydroxymethyl)biphenyl-3-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to those in Example 9 using 4-(hydroxmethyl)phenylboronic acid. LC-MS Method 3, t R =1.123 min, m/z=374.1. 1H NMR (CDCl3) 1.80 (s, 3H), 2.40-2.60 (m, 2H), 3.35 (m, 1H), 3.60 (m, 1H), 4.75 (d, 2H), 7.15 (m, 1H), 7.34-7.62 (m, 13H).

›Example 49

3-(3′-(1H-tetrazol-5-yl)biphenyl-3-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to those in Example 9 using 3-(2H-tetrazol-5-yl)phenylboronic acid. LC-MS Method 3, t R =1.341 min, m/z=412.2. 1 H NMR (CDCl 3 ) 1.85 (s, 3H), 2.50-2.70 (m, 2H), 3.40 (m, 1H), 3.65 (m, 1H), 7.05 (d, 1H), 7.20-7.35 (m, 3H), 7.40-7.50 (m, 3H), 7.52 (m, 4H), 7.80 (s, 1H), 7.90 (d, 1H).

›Example 50

3-(6-(2-chloro-4-fluorophenyl)pyridin-2-yl)-6-(2-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one

The title compound was prepared by application of procedures analogous to those described in Example 63 using o-fluoroacetophenone in Step 1 and 2-amino-6-bromopyridine in Step 2, followed by Example 74 and Example 75 Step 1 using 2-chloro-4-fluorophenylboronic acid. LC-MS Method 3, t R =1.381 min, m/z=444.11. 1 H NMR (CD 3 OD) δ=2.20-2.60 (m, 3H), 2.75 (dd, 1H), 3.42 (m, 2H), 3.72 (m, 1H), 4.15 (m, 1H), 7.03-7.30 (m, 4H), 7.42 (m, 3H), 7.55 (m, 1H), 7.75 (m, 2H).

›Example 51

2-(3-((1S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)acetamide

The title compound was prepared from 3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one by application of procedures analogous to those described in Example 70 followed by Example 76. Two isomers were isolated.

Isomer 1: 2-((S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)acetamide LC-MS Method 1, t R =1.71 min, m/z=469. 1 H NMR (CDCl 3 ) 7.25-7.33 (m, 5H), 6.86-7.06 (m, 6H), 5.66 (q, 1H), 2.95-2.99 (m, 1H), 2.83 (d, 1H), 2.72 (d, 1H), 2.30-2.50 (m, 3H), 2.55 (d, 3H).

Isomer 2: 2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)acetamide LC-MS Method 1 t R =1.75 min, m/z=469 (M+1); 1 H NMR (CDCl 3 ) 7.49-6.88 (m, 11H), 6.19 (br s, 1H), 5.75 (q, J=6.8 Hz, 1H), 5.46 (br s, 1H), 2.85-2.69 (m, 4H), 2.43-2.38 (m, 1H), 2.29-2.21 (m, 1H), 1.33 (d, J=6.8 Hz, 3H).

›Example 52

(6S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(2,3-dihydroxypropyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one

A mixture of (R)-6-allyl-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (1.2722 g, 2.82 mmol), 4-methylmorpholine N-oxide monohydrate (0.8926 g, 6.60 mmol), and OsO 4 (2.5 wt. % solution in t-BuOH, 0.2800 g, 0.0275 mmol) in CH 2 Cl 2 (25 mL) was stirred at rt for 16 h. The mixture was treated with EtOAc and washed with 0.5 N HCl, brine, dried (Na 2 SO 4 ), filtered, and concentrated under reduced pressure to give 1.3462 g of the crude diol as a foam. The crude diol was directly used in the next step without further purification. LC-MS t R =1.71 min in 3 min chromatography, m/z 486 (MH + ).

Analytical samples were purified by reversed-phase HPLC (SunFire™ Prep C 18 OBD™ 5 μm 19×50 mm column, 10%→90% CH 3 CN/H 2 O, 0.1% CF 3 COOH over 8 min and then 90% CH 3 CN/H 2 O, 0.1% CF 3 COOH over 2 min, flow rate 20 mL/min) to afford two diastereoisomers.

Isomer 1: (6S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(2,3-dihydroxypropyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one. LC-MS Method 1, t R =1.7 min, m/z=486. 1 H NMR (CD 3 OD) 7.35-7.29 (m, 3H), 7.18 (d, J=7.0 Hz, 2H), 7.04-6.88 (m, 6H), 5.48 (q, J=7.0 Hz, 1H), 3.36-3.27 (m, 3H), 3.09-3.04 (m, 1H), 2.67-2.61 (m, 1H), 2.37-2.30 (m, 1H), 2.23-2.15 (m, 1H), 2.02-1.91 (m, 2H), 1.47 (d, J=7.0 Hz, 3H).

Isomer 2: (6S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(2,3-dihydroxypropyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one. LC-MS Method 1, t R =1.71 min, m/z=486. 1 H NMR (CD 3 OD) 7.36-7.19 (m, 5H), 7.04-6.91 (m, 6H), 5.51 (q, J=7.0 Hz, 1H), 3.76-3.71 (m, 1H), 3.06-3.01 (m, 1H), 2.44-2.37 (m, 2H), 2.25-2.18 (m, 1H), 1.98 (dd, J=14.9, 2.6 Hz, 1H), 1.84 (dd, J=15.2, 7.9 Hz, 1H), 1.48 (d, J=7.0 Hz, 3H).

›Example 53

6-(3-chlorophenyl)-6-methyl-3-(6-(piperidin-1-yl)pyridin-2-yl)-1,3-oxazinan-2-one

›Step 1. 3-(3-chlorophenyl)-3-hydroxybutanenitrile

Dry THF (15 mL) was cooled to −78° C. and 2.5M n-BuLi (5.18 mL, 2.0 equiv.) was added. A solution of acetonitrile (680 μL, 2.0 equiv.) in dry THF (2 mL) was added dropwise over 2 min. The mixture was stirred at −78° C. for 1 h. A solution of 3-chloroacetophenone (835 μL, 6.468 mmol) in dry THF (2 mL) was added dropwise over 2 min. 30 min. The mixture was stirred at −78° C. for 30 min. and was warmed to rt slowly. After being stirred at rt for 15 min., the mixture was quenched with water (10 mL), diluted by ether (20 mL), washed with 2% aq HCl (15 mL). The aqueous layer was extracted with ether (2×10 mL). The combined organic layers were washed with satd aq NaHCO 3 (5 mL) and brine (10 mL), and dried over Na 2 SO 4 . After filtration and concentration, the crude product (1.4 g, quant. yield) was used for next step without further purification. LC-MS Method 1 t R =1.40 min., m/z=219, 221 (M+Na).

›Step 2. 4-amino-2-(3-chlorophenyl)butan-2-ol

A solution of 3-(3-chlorophenyl)-3-hydroxybutanenitrile (400 mg, 2.04 mmol) in dry THF (10 mL) was cooled to 0° C. LiAlH 4 powder (155 mg, 2 equiv.) was added. After 5 min, the mixture was warmed to rt and stirred for 4 h. The mixture was then heated to reflux for 6 h. The mixture was diluted with 1 M aq NaOH (30 mL) and extracted with CH 2 Cl 2 (2×100 mL). The combined CH 2 Cl 2 extracts were washed with brine, dried over Na2SO4 and concentrated to afford crude 4-amino-2-(3-chlorophenyl)butan-2-ol (550 mg, quant) which was used without purification. LC-MS Method 1, t R =0.88 min, m/z=200, 202.

›Step 3. 6-(3-chlorophenyl)-6-methyl-1,3-oxazinan-2-one

A stirred solution of crude 4-amino-2-(3-chlorophenyl)butan-2-ol (550 mg) and i-Pr 2 NEt (1 mL, 5.5 mmol) in CH 2 Cl 2 was cooled in an ice bath and solid triphosgene (286 mg, 0.96 mmol) was added. The ice bath was allowed to melt and the mixture was stirred overnight at rt. The mixture was diluted with ether (150 mL), washed with 5% aq HCl (50 mL) and satd aq NaHCO3 (50 mL) and dried over MgSO 4 . Removal of the solvent left a brown oil (590 mg) which was purified by chromatography on a 12-g silica cartridge eluted with a 0-100% EtOAc in hexanes gradient to afford 6-(3-chlorophenyl)-6-methyl-1,3-oxazinan-2-one (57 mg).

›Step 4. 6-(3-chlorophenyl)-6-methyl-3-(6-(piperidin-1-yl)pyridin-2-yl)-1,3-oxazinan-2-one

A mixture of 6-(3-chlorophenyl)-6-methyl-1,3-oxazinan-2-one (28 mg, 0.12 mmol), 2-bromo-6-piperidinopyridine (33 mg, 0.14 mmol), CuI (7 mg, 0.037 mmol), powdered K2CO3 (19 mg, 0.14 mmol) and CH 2 Cl 2 (0.25 mL) was heated to 130 C under a stream of N 2 such that the CH 2 Cl 2 evaporated. The vessel was sealed and the mixture was heated at 130° C. for 1 h under N 2 . The residue was dissolved in MeCN (0.5 mL) and DMSO (0.5 mL) and purified by prep HPLC to afford 6-(3-chlorophenyl)-6-methyl-3-(6-(piperidin-1-yl)pyridin-2-yl)-1,3-oxazinan-2-one (20 mg) as a brown oil. LC-MS Method 1, t R =2.08 min, m/z=386, 388. 1 H NMR (CDCl 3 ) 1.62 (6H), 1.73 (s, 3H), 2.35 (m, 1H), 2.48 (m, 1H), 3.43 (5H), 4.11 (m, 1H), 6.50 (d, 1H), 7.20-7.60 (6H).

›Example 54

3-(2-(3-chlorophenyl)pyrimidin-4-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one

›Step 1. 3-hydroxy-3-phenylbutanenitrile

Dry THF was cooled to −20° C. and 2.5 M n-Bull (100 mL, 0.25 mol) was added. A solution of CH 3 CN (11.25 g, 0.25 mol) in dry THF was added dropwise over 10 min. Then the mixture was stirred for 1 h at −20° C. and a solution of acetophenone (30 g, 0.25 mol) in THF was added dropwise over 10 min. The mixture was stirred at −20° C. for 15 min and warmed to rt over 15 min. Aq NH 4 Cl was added to quench the reaction. The solution was extract with EtOAc. The organic layer washed with brine, dried over anhydrous Na 2 SO 4 and concentrated to give 3-hydroxy-3-phenylbutanenitrile (30 g, yield 75%). 1 H NMR (CDCl 3 , 400 MH Z ): δ=1.76 (s, 3H), 2.83 (s, 2H), 7.34 (m, 1H), 7.41 (m, 2H), 7.5 (m, 2H).

›Step 2. 4-amino-2-phenylbutan-2-ol

To a solution of 3-hydroxy-3-phenylbutanenitrile (1 g, 6.2 mmol) in THF (10 mL) was added dropwise BH 3 .Me 2 S (32 mL, 62 mmol) under a N 2 atmosphere. The mixture was stirred at rt overnight. The reaction was quenched with MeOH (10 mL). The mixture was concentrated to give crude 4-amino-2-phenylbutan-2-ol (1.2 g, crude), which was used in the next step without further purification.

›Step 3. 4-(2-chloropyrimidin-4-ylamino)-2-phenylbutan-2-ol

To a solution of 4-amino-2-phenyl-butan-2-ol (1.2 g, 0.0072 mmol) and DIEA in CH 2 Cl 2 (15 ml) was added dropwise a solution of 2,4-dichloro-pyrimidine (980 mg, 0.0072 mmol) in CH 2 Cl 2 slowly at 0° C. under N 2 . The mixture was stirred at rt overnight. The mixture was concentrated to give the crude product, which was purified by preparative TLC to afford a mixture of 4-(2-chloro-pyrimidin-4-ylamino)-2-phenyl-butan-2-ol and 4-(4-chloropyrimidin-2-ylamino)-2-phenylbutan-2-ol (450 mg, 23%). 1 H NMR (CDCl 3 , 400 MH Z ): δ=1.55 (s, 3H), 2.05 (m, 2H), 3.03 (m, 2H), 3.6 (m, 1H), 6.02 (m, 2H), 7.28 (m, 1H), 7.28 (m, 2H), 7.28 (m, 2H).

›Step 4. 3-(2-chloropyrimidin-4-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one

To a solution of 4-(4-chloro-pyrimidin-2-ylamino)-2-phenyl-butan-2-ol (450 mg, 1.6 mmol) and Et 3 N (508 mg, 4.8 mmol) in CH 2 Cl 2 (2 ml) was added dropwise a solution of triphosgene (159 mg, 0.54 mmol) in CH 2 Cl 2 slowly at 0° C. under nitrogen atmosphere. The mixture was stirred at rt overnight. The mixture was concentrated to give the crude product, which was purified by TLC and preparative HPLC to afford 3-(2-chloropyrimidin-4-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one (250 mg, 52%) 1 H NMR (CDCl 3 , 400 MH Z ): δ=1.73 (s, 3H), 2.38 (m, 1H), 2.63 (m, 1H), 3.49 (m, 1H), 4.2 (m, 1H), 7.36 (m, 5H), 8.28 (m, 1H), 8.52 (m, 1H) and 3-(4-chloropyrimidin-2-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one (20 mg, 9%) [Example 57]. 1 H NMR (CDCl 3 , 400 MH Z ): δ=1.73 (s, 3H), 2.4 (m, 1H), 2.58 (m, 1H), 3.47 (m, 1H), 4.13 (m, 1H), 7.06 (m, 5H), 7.16-7.55 (m, 5H), 8.54 (m, 1H).

›Step 5. 3-(2-chloropyrimidin-4-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one

To a solution of 3-(2-chloropyrimidin-4-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one (100 mg, 0.33 mmol) and 3-chlorophenylboronic acid (0.53 mmol) in 2M aq K 2 CO 3 (1 mL, 2 mmol) and 1,4-dioxane (3 mL) was slowly added Pd(Ph 3 ) 2 Cl 2 (20 mg, 10%) at 0° C. under N 2 . The mixture was refluxed overnight. The mixture was concentrated to give crude product, which was purified by TLC and preparative HPLC to afford 3-(2-chloropyrimidin-4-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one (13 mg). 1 H NMR (CDCl 3 , 400 MH Z ): δ=1.78 (s, 3H), 2.43 (m, 1H), 2.57 (m, 1H), 3.6 (m, 1H), 4.4 (m, 1H), 7.3-7.5 (m, 6H), 8.2-8.4 (m, 3H), 8.65 (m, 1H). LC-MS Method 3, t R =1.655 min, m/z=380.

›Examples9

›Example 55

3-(2-(4-fluorophenyl)pyrimidin-4-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one

To a solution of 3-(2-chloropyrimidin-4-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one (50 mg, 0.165 mmol) and 4-fluorophenylboronic acid (32 mg, 0.33 mmol), K 2 CO 3 (0.5 mL, 2 M) in 1,4-dioxane (1.5 ml) at 0° C. under N 2 was slowly added Pd(Ph 3 ) 2 Cl 2 (10 mg, 20%). The mixture was refluxed overnight. The mixture was concentrated to give the crude product, which was purified by TLC and preparative HPLC to afford 3-(2-(4-fluorophenyl)pyrimidin-4-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one (15 mg, yield 25%). 1 H NMR (CDCl 3 , 400 MH Z ): δ=1.75 (s, 3H), 2.4 (m, 1H), 2.54 (m, 1H), 3.6 (m, 1H), 4.4 (m, 1H), 7.1 (m, 2H), 7.25-7.4 (m, 5H), 8.08 (m, 1H), 8.34 (m, 2H), 8.62 (m, 1H). LC-MS Method 3, t R =1.519 min, m/z=364.1. 1 H NMR (CDCl3) 1.80 (s, 3H), 2.40 (m, 1H), 2.60-2.70 (d, 1H), 3.60 (m, 1H), 4.40 (t, 1H), 7.10 (t, 2H), 7.20-7.45 (m, 5H), 8.17 (d, 1H), 8.35 (t, 2H), 8.65 (d, 1H).

›Example 56

3-(2-(3-fluorophenyl)pyrimidin-4-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one

To a solution of 3-(2-chloropyrimidin-4-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one (100 mg, 0.33 mmol) and 3-fluorophenylboronic acid (80 mg, 0.53 mmol), K 2 CO 3 (1 mL, 2 M) in 1,4-dioxane (3 ml) at 0° C. under N 2 was slowly added Pd(Ph 3 ) 2 Cl 2 (20 mg, 20%). The mixture was refluxed overnight. The mixture was concentrated to give the crude product, which was purified by TLC and preparative HPLC to afford 3-(2-(3-fluorophenyl)pyrimidin-4-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one (20 mg, yield 17%). 1 H NMR (CDCl 3 , 400 MH Z ): δ=1.71 (s, 3H), 2.37 (m, 1H), 2.6 (m, 1H), 3.54 (m, 1H), 4.34 (m, 1H), 7.08 (m, 1H), 7.25 (m, 1H), 7.34 (m, 5H), 7.96 (m, 1H), 8.09 (m, 1H), 8.16 (m, 1H), 8.6 (m, 1H). LC-MS Method 3, t R =1.46 min, m/z=364.

›Example 57

3-(4-chloropyrimidin-2-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one

The title compound was isolated as described in Example 54 Step 3. LC-MS Method 3, t R =1.007 min, m/z=304. 1 H NMR (CDCl 3 ) 1.73 (s, 3H), 2.4 (m, 1H), 2.58 (m, 1H), 3.47 (m, 1H), 4.13 (m, 1H), 7.06 (m, 5H), 7.16-7.55 (m, 5H), 8.54 (m, 1H).

›Example 58

3-(4-(3-chlorophenyl)pyrimidin-2-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to those in Example 56 using 3-(4-chloropyrimidin-2-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one and 3-chlorophenylboronic acid. LC-MS Method 3, t R =1.354 min, m/z=781.1. 1 H NMR (CDCl 3 ) 1.80 (s, 3H), 2.48-2.53 (m, 1H), 2.62-2.71 (m, 1H), 3.55-3.67 (m, 1H), 4.30-4.40 (m, 1H), 7.30-7.60 (m, 8H), 7.90-7.95 (m, 1H), 8.05 (s, 1H), 8.80-8.85 (m, 1H).

›Example 59

3-(4-(2,4-difluorophenyl)pyrimidin-2-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to those in Example 56 using 3-(4-chloropyrimidin-2-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one and 2,4-difluorophenylboronic acid. LC-MS Method 3, t R =1.238 min, m/z=785. 1 H NMR (CDCl 3 ) 1.80 (s, 3H), 2.48-2.53 (m, 1H), 2.62-2.71 (m, 1H), 3.58-3.67 (m, 1H), 4.35-4.45 (m, 1H), 6.93-7.08 (m, 2H), 7.30-7.48 (m, 5H), 7.62-7.65 (m, 1H), 8.15-8.23 (m, 1H), 8.78-8.81 (m, 1H).

›Example 60

3-(4-(2,6-dichlorophenyl)pyrimidin-2-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to those in Example 56 using 3-(4-chloropyrimidin-2-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one and 2,6-dichlorophenylboronic acid. LC-MS Method 3, t R =1.317 min, m/z=414. 1 H NMR (CDCl 3 ) 1.70 (s, 3H), 2.30-2.40 (m, 1H), 2.48-2.52 (m, 1H), 3.47-3.51 (m, 1H), 4.10-4.15 (m, 1H), 7.10-7.40 (m, 10H), 8.78-8.79 (m, 1H).

›Example 61

3-(4-(4-fluorophenyl)pyrimidin-2-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to those in Example 56 using 3-(4-chloropyrimidin-2-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one and 4-fluorophenylboronic acid. LC-MS Method 3, t R =1.193 min, m/z=363.9. 1 H NMR (CDCl 3 ) 1.60 (s, 1H), 1.80 (s, 3H), 2.48-2.53 (m, 1H), 2.62-2.71 (m, 1H), 3.60-3.67 (m, 1H), 4.30-4.40 (m, 1H), 7.20-7.55 (m, 10H), 7.60-7.62 (m, 1H), 8.05-8.15 (m, 3H), 8.80-8.85 (m, 1H).

›Example 62

3-(4-(3-fluorophenyl)pyrimidin-2-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to those in Example 56 using 3-(4-chloropyrimidin-2-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one and 3-fluorophenylboronic acid. LC-MS Method 3, t R =1.215 min, m/z=749. 1 H NMR (CDCl 3 ) 1.80 (s, 3H), 2.48-2.53 (m, 1H), 2.62-2.71 (m, 1H), 3.58-3.67 (m, 1H), 4.30-4.40 (m, 1H), 7.30-7.65 (m, 10H), 7.80-7.90 (m, 2H), 8.90-8.95 (m, 1H).

›Example 63

6-allyl-3-(3-bromophenyl)-6-phenyl-1,3-oxazinan-2-one

›Step 1. 3-(dimethylamino)-1-phenylpropan-1-one

The solution of acetophenone (30 g, 0.25 mol) and Me 2 NH.HCl (0.28 mol) in EtOH (400 mL) was heated at 70° C. overnight. The resulting mixture was concentrated and the residue was washed with EtOAc to give 3-(dimethylamino)-1-phenylpropan-1-one (17.7 g, 40%). 1 H NMR (400 MHz, CDCl 3 ): δ=2.36 (m, 6H), 2.74 (m, 2H), 3.14 (m, 2H), 7.43 (m, 2H), 7.52 (m, 1H), 7.94 (m, 2H).

›Step 2. 3-(3-bromophenylamino)-1-phenylpropan-1-one

A mixture of 3-(dimethylamino)-1-phenylpropan-1-one (0.1 mol) and 3-bromoaniline (0.1 mol) in 1:1 EtOH/H 2 O (100 mL) was heated at 80° C. overnight. The resulting mixture was concentrated and the residue was washed with H 2 O and then EtOH several times to give to give 3-(3-bromophenylamino)-1-phenylpropan-1-one (27 g, 90%). 1 H NMR (400 MHz, CDCl 3 ): δ=3.52 (m, 2H), 4.33 (m, 2H), 4.51 (m, 1H), 6.8 (m, 1H), 7.05 (m, 2H), 7.28 (m, 1H), 7.72 (m, 2H), 7.80 (m, 1H), 8.2 (m, 2H).

›Step 3. Methyl 3-bromophenyl(3-oxo-3-phenylpropyl)carbamate

To the solution of 3-(3-bromophenylamino)-1-phenylpropan-1-one (0.03 mol) in anhydrous THF (30 mL) was added K 2 CO 3 (0.06 mol) and methyl chloroformate (0.033 mol) at 0° C. under N 2 atmosphere. Then the reaction mixture was stirred at rt for 2 h. The resulting mixture was filtered and the filtrate was concentrated. The residue was washed with H 2 O, 1N HCl and brine and then extracted with EtOAc. The combined organic layers were concentrated to give crude product, which was purified by column chromatography to afford methyl 3-bromophenyl(3-oxo-3-phenylpropyl)carbamate (30.5 g, 95%). 1 H NMR (400 MHz, CDCl 3 ): δ=3.22 (m, 2H), 3.62 (s, 3H), 4.02 (m, 2H), 7.05-7.20 (m, 2H), 7.3-7.5 (m, 4H), 7.8 (m, 1H).

›Step 4. 6-allyl-3-(3-bromophenyl)-6-phenyl-1,3-oxazinan-2-one

To a solution of methyl 3-bromophenyl(3-oxo-3-phenylpropyl)carbamate (250 mg, 0.69 mmol) in dry THF (2 mL) was added dropwise 1 M allylmagnesium bromide (10 mL) −78° C. The reaction mixture was stirred at rt for 3 h. The resulting mixture was quenched with sattd aq NH 4 Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and concentrated to give 6-allyl-3-(3-bromophenyl)-6-phenyl-1,3-oxazinan-2-one (120 mg, 47%). 1 H NMR (400 MHz, CDCl 3 ): δ=2.48 (m, 2H), 2.55-2.7 (m, 2H), 3.23 (m, 1H), 3.51 (m, 1H), 5.04 (m, 2H), 5.72 (m, 1H), 7.01 (m, 1H), 7.11 (m, 1H), 7.23 (m, 1H), 7.3 (m, 1H), 7.35 (m, 6H).

›Example 64

6-allyl-3-(2′,4′-difluorobiphenyl-3-yl)-6-phenyl-1,3-oxazinan-2-one

›Step 1. 6-allyl-3-(2′,4′-difluorobiphenyl-3-yl)-6-phenyl-1,3-oxazinan-2-one

To a solution of 6-allyl-3-(3-bromophenyl)-6-phenyl-1,3-oxazinan-2-one (50 mg, 0.134 mmol) and 2,4-difluorophenylboronic acid (40 mg, 0.215 mmol), K 2 CO 3 (0.5 mL, 2 M) in 1,4-dioxane (1.5 ml) was slowly added Pd(Ph 3 ) 2 Cl 2 (10 mg, 20%) at 0° C. under N 2 . The mixture was refluxed overnight. The mixture was concentrated to give the crude product, which was purified by TLC and preparative HPLC to afford 6-allyl-3-(2′,4′-difluorobiphenyl-3-yl)-6-phenyl-1,3-oxazinan-2-one (10 mg, 18%). 1 H NMR (400 MHz, CDCl 3 ): δ=2.40 (m, 2H), 2.55-2.72 (m, 2H), 3.26 (m, 1H), 3.47 (m, 1H), 5.05 (m, 2H), 5.76 (m, 1H), 6.76-6.90 (m, 2H), 7.04 (m, 1H), 7.28 (m, 4H), 7.36 (m, 2H).

›Example 65

3-(2′,4′-difluorobiphenyl-3-yl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one

›Step 1. 3-(2′,4′-difluorobiphenyl-3-yl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one

A solution of 6-allyl-3-(2′,4′-difluorobiphenyl-3-yl)-6-phenyl-1,3-oxazinan-2-one (600 mg, 1.47 mmol) in dry CH 2 Cl 2 (10 mL) was treated with ozone at −78° C. until the mixture turned blue. The system was then flushed with oxygen to remove excess ozone. NaBH 4 (450 mg, 11.7 mmol) was added to the mixture in portions at −20° C. The mixture was stirred overnight at rt. The mixture was quenched with water and the layers were separated. The aqueous layer was extracted with CH 2 Cl 2 (2×). The organic layers were combined, washed with brine, dried over anhydrous Na 2 SO 4 and concentrated to give 3-(2′,4′-difluorobiphenyl-3-yl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one (150 mg, 25%). 1 H NMR (400 MHz, CDCl 3 ): δ=2.12-2.35 (m, 2H), 2.51 (m, 2H), 3.26 (m, 1H), 3.47-3.6 (m, 2H), 4.25 (m, 1H), 6.83 (m, 2H), 7.06 (m, 1H), 7.26-7.51 (m, 8H).

Preparative HPLC on a Chiralpak IA, 4.6×250 mm, 5 micron column eluted with 10% EtOH in hexanes at a flow rate of 1 mL min −1 afforded two isomers.

Isomer 1: LC-MS Method 1, t R =min, m/z=410 (M+1). 1 H NMR (CDCl 3 ) 7.47-7.33 (m, 8H), 7.27-7.26 (m, 1H), 7.16-7.13 (m, 1H), 6.96-6.86 (m, 2H), 3.86-3.80 (m, 1H), 3.64-3.61 (m, 1H), 3.58-3.53 (m, 1H), 3.35-3.28 (m, 1H), 2.58-2.52 (m, 2H), 2.37-2.23 (m, 2H).

Isomer 2 was not characterized.

›Examples5

›Example 66

3-(4′,6-difluorobiphenyl-3-yl)-6-(2-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one

The title compound was prepared by application of procedures analogous to those described in Example 63 using p-fluoroacetophenone in Step 1 and 3-bromo-4-fluoroaniline in Step 2 followed by procedures analogous to those described in Example 64 using 4-fluorophenylboronic acid followed by procedures analogous to those described in Example 65. LC-MS Method 3, t R =1.234 min, m/z=428. 1 H NMR (CDCl 3 ) 1.62-1.70 (m, 1H), 2.2-2.38 (m, 2H), 2.5-2.6 (m, 2H), 3.22-3.35 (m, 1H), 3.50-3.65 (m, 2H), 3.80-3.90 (m, 1H), 7.05-7.2 (m, 7H), 7.5-7.6 (m, 4H).

›Example 67

3-(4′,6-difluorobiphenyl-3-yl)-6-(2-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one

The title compound was prepared by application of procedures analogous to those described in Example 63 using o-fluoroacetophenone in Step 1 and 3-bromo-4-fluoroaniline in Step 2 followed by procedures analogous to those described in Example 64 using 4-fluorophenylboronic acid followed by procedures analogous to those described in Example 65. LC-MS Method 3, t R =1.263 min, m/z=428.1. 1 H NMR (CDCl 3 ) 2.35-2.6 (m, 3H), 2.79-2.85 (m, 1H), 3.28-3.40 (m, 2H), 3.52-3.60 (m, 1H), 3.63-3.72 (m, 1H), 3.80-3.88 (m, 1H), 7.05-7.20 (m, 6H), 7.22-7.3 (m, 1H), 7.38-7.50 (m, 3H), 7.52-7.61 (m, 1H).

›Example 68

3-(2′-chloro-4′-fluorobiphenyl-3-yl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared by application of procedures analogous to those described in Example 64 using 2-chloro-4-fluorophenylboronic acid in Step 1 followed by procedures analogous to those described in Example 65. LC-MS Method 3, t R =1.268 min, m/z=426. 1 H NMR (CD3OD) 2.2-2.30 (m, 2H), 2.45-2.60 (m, 1H), 2.60-2.70 (m, 1H), 3.15-3.25 (m, 1H), 3.3-3.40 (m, 1H), 3.5-3.65 (m, 1H), 3.65-3.77 (m, 1H), 7.0-7.2 (m, 3H), 7.3-7.48 (m, 9H).

›Example 69

3-(2′,6′-dichlorobiphenyl-3-yl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared by application of procedures analogous to those described in Example 64 using 2,6-dichlorophenylboronic acid in Step 1 followed by procedures analogous to those described in Example 65. LC-MS Method 3, t R =1.28 min, m/z=441.9. 1 H NMR (CDCl 3 ) 2.26-2.44 (m, 2H), 2.60 (m, 2H), 3.37-3.48 (m, 1H), 3.60-3.70 (m, 1H), 3.88 (m, 1H), 7.11 (m, 1H), 7.19 (m, 1H), 7.29 (m, 1H), 7.45 (m, 4H), 7.50 (m, 4H).

›Example 70

2-(3-(2′,4′-difluorobiphenyl-3-yl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)acetic acid

›Step 1. 2-(3-(2′,4′-difluorobiphenyl-3-yl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)acetic acid

Jones reagent was prepared by addition of CrO 3 (1 g) to H 2 SO 4 (1 mL) and addition of water to bring the total volume to 4 mL. 3-(2′,4′-difluorobiphenyl-3-yl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one (100 mg, 0.24 mmol) was dissolved in acetone (2 mL), and cooled in an ice bath. Jones reagent (0.2 mL) was slowly added to the mixture and the reaction mixture was stirred overnight. Solvent was removed in vacuo and the obtained residue was purified by preparative HPLC to afford 2-(3-(2′,4′-difluorobiphenyl-3-yl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)acetic acid (20 mg, yield 19%). 1 H NMR (400 MHz, CDCl 3 ): δ=2.7-2.9 (m, 4H), 3.55 (m, 2H), 6.86 (m, 2H), 7.05 (m, 1H), 7.19 (m, 1H), 7.33 (m, 5H), 7.44 (m, 3H).

›Example 71

3-(3-bromobenzyl)-6-methyl-6-phenyl-1,3-oxazinan-2-one

›Step 1. 4-amino-2-phenylbutan-2-ol

To a solution of 3-hydroxy-3-phenylbutanenitrile (13 g, 0.081 mol) in THF (150 mL) was added BH 3 .Me 2 S (2 M, 122 mL) at 0° C. The mixture was refluxed overnight. The reaction mixture was quenched with MeOH and extracted with EtOAc. The organic layer was washed with brine, dried over Na 2 SO 4 and concentrated to obtain crude. 4-amino-2-phenylbutan-2-ol (15 g, 100%). 1 H NMR (CDCl 3 ): 1.60 (s, 3H), 1.60 (s, 3H), 2.10-2.20 (m, 1H), 2.30-2.40 (m, 1H), 2.90-3.00 (m, 1H), 3.65-3.85 (m, 1H), 7.20-7.40 (m, 5H).

›Step 2. 6-methyl-6-phenyl-1,3-oxazinan-2-one

A solution of 4-amino-2-phenylbutan-2-ol (5.0 g, 0.03 mol) in CH 2 Cl 2 (50 mL) was added triphosgene (2.97 g, 0.01 mol) and Et 3 N (9.09 g, 0.09 mol) at 0° C. After stirring for 1 h, the mixture was diluted with water and extracted with CH 2 Cl 2 . The organic layer was washed with brine, dried over Na 2 SO 4 , concentrated and purified by chromatography to afford 6-methyl-6-phenyl-1,3-oxazinan-2-one (1.14 g, 20%). 1 H NMR (CDCl 3 ): 1.60 (s, 3H), 1.80-2.00 (m, 1H), 2.30-2.40 (m, 1H), 3.15-3.21 (m, 1H), 6.00 (s, 1H), 7.30-7.45 (m, 5H), 8.90-9.01 (m, 1H).

›Step 3. 3-(3-bromobenzyl)-6-methyl-6-phenyl-1,3-oxazinan-2-one

A solution of 6-methyl-6-phenyl-1,3-oxazinan-2-one (500 mg, 2.62 mmol) and NaH (189 mg, 7.86 mmol) in dry THF (10 mL) was stirred for 1 h. A solution of m-bromobenzyl bromide (1.31 g, 5.24 mmol) in dry THF (3 mL) was added. The mixture was stirred overnight at rt. The reaction mixture was quenched water and extracted with EtOAc. The organic layer was washed with brine, dried over Na 2 SO 4 , concentrated and purified by preparative TLC to afford 3-(3-bromobenzyl)-6-methyl-6-phenyl-1,3-oxazinan-2-one (300 mg, 32%). 1 H NMR (CDCl 3 ): 1.60-1.70 (s, 3H), 2.15-2.30 (m, 1H), 2.35-2.48 (m, 1H), 2.79-2.90 (m, 1H), 3.00-3.10 (m, 1H), 4.30-4.40 (m, 1H), 4.50-4.60 (m, 1H), 6.90-7.00 (m, 1H), 7.00-7.10 (m, 1H), 7.20-7.45 (m, 7H).

›Examples4

›Example 72

3-(2-bromobenzyl)-6-methyl-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to those described in Example 71 using o-bromobenzyl bromide in Step 3. LC-MS Method 3, t R =1.305 min, m/z=362. 1 H NMR (CDCl3) 1.60-1.65 (s, 3H), 2.15-2.26 (m, 1H), 2.30-2.40 (m, 1H), 2.81-2.92 (m, 1H), 3.00-3.08 (m, 1H), 4.45-4.65 (m, 2H), 6.80-6.90 (m, 1H), 7.00-7.10 (m, 1H), 7.21-7.38 (m, 5H), 7.40-7.45 (m, 1H).

›Example 73

3-(4-bromobenzyl)-6-methyl-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to those described in Example 71 using p-bromobenzyl bromide in Step 3. LC-MS Method 3, t R =1.317 min, m/z=361.8. 1 H NMR (CDCl 3 ) 1.55-1.65 (s, 3H), 2.10-2.20 (m, 1H), 2.30-2.40 (m, 1H), 2.79-2.80 (m, 1H), 2.90-3.00 (m, 1H), 4.25-4.50 (m, 2H), 6.80-6.90 (m, 1H), 7.21-7.38 (m, 7H).

›Example 74

3-(3-bromophenyl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one

A solution of 6-allyl-3-(3-bromophenyl)-6-phenyl-1,3-oxazinan-2-one (200 mg, 0.54 mmol) in dry CH 2 Cl 2 (10 mL) was treated with ozone at −78° C. until the mixture turned blue. The system was then flushed with oxygen to remove excess ozone. NaBH 4 (207 mg, 5.4 mmol) was added to the mixture in portions at −20° C. The mixture was stirred overnight at rt. The mixture was quenched with water and the layers were separated. The aqueous layer was extracted with CH 2 Cl 2 (2×). The organic layers were combined, washed with brine, dried over anhydrous Na 2 SO 4 and concentrated to give 3-(3-bromophenyl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one (75 mg, 37%). 1 H NMR (400 MHz, CDCl 3 ): δ=2.12-2.30 (m, 2H), 2.47 (m, 2H), 3.19 (m, 1H), 3.40 (m, 1H), 3.53 (m, 1H), 3.76 (m, 1H), 7.06 (m, 1H), 7.13 (m, 1H), 7.22 (m, 1H), 7.25-7.40 (m, 6H).

›Example 75

6-(2-aminoethyl)-3-(2′,4′-difluorobiphenyl-3-yl)-6-phenyl-1,3-oxazinan-2-one

›Step 1. 3-(2′,4′-difluorobiphenyl-3-yl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one

To a solution of 3-(3-bromophenyl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one (200 mg, 0.538 mmol), 4-fluorophenylboronic acid (128 mg, 0.806 mmol), and aq. K 2 CO 3 (1 mL, 2 M) in 1,4-dioxane (3 ml) was slowly added Pd(Ph 3 ) 2 Cl 2 (20 mg, 10%) at 0° C. under N 2 . The mixture was refluxed overnight. The mixture was concentrated to give the crude product, which was purified by TLC and preparative HPLC to afford 3-(2′,4′-difluorobiphenyl-3-yl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one (200 mg, 91%). 1 H-NMR (400 MHz, CDCl 3 ): δ=2.12-2.35 (m, 2H), 2.51 (m, 2H), 3.26 (m, 1H), 3.47-3.6 (m, 2H), 4.25 (m, 1H), 6.83 (m, 2H), 7.06 (m, 1H), 7.26-7.51 (m, 8H).

›Step 2. 2-(3-(2′,4′-difluorobiphenyl-3-yl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)ethyl methanesulfonate

To a solution of 3-(2′,4′-difluorobiphenyl-3-yl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one (200 mg, 0.49 mmol) in dry CH 2 Cl 2 (4 mL) was added Et 3 N (0.234 mL, 1.46 mmol) at 0˜5° C. A solution of methanesulfonyl chloride (67 mg, 0.59 mmol) in dry CH 2 Cl 2 (1 mL) was added dropwise at the same temperature. After addition, the mixture was allowed to warm to it gradually. When the reaction was complete, water (10 mL) was added and the mixture was extracted with CH 2 Cl 2 (3×10 mL). The combined organic layers were washed with 10% aq citric acid, satd aq NaHCO 3 and brine, then dried over Na 2 SO 4 , filtered and concentrated to give 2-(3-(2′,4′-difluorobiphenyl-3-yl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)ethyl methanesulfonate (230 mg, 97%), which was used in the next step without purification.

›Step 3. 6-(2-azidoethyl)-3-(2′,4′-difluorobiphenyl-3-yl)-6-phenyl-1,3-oxazinan-2-one

To a solution of 2-(3-(2′,4′-difluorobiphenyl-3-yl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)ethyl methanesulfonate (230 mg, 0.47 mmol) in anhydrous DMF (5 mL) was added NaN 3 (92 mg, 1.42 mmol). The reaction mixture was heated to 70° C. overnight. The reaction mixture was cooled to rt and diluted with EtOAc (30 mL), and water (20 ml). The organic phase was washed with water (3×20 mL), dried over Na 2 SO 4 and evaporated to give 6-(2-azidoethyl)-3-(2′,4′-difluorobiphenyl-3-yl)-6-phenyl-1,3-oxazinan-2-one (100 mg, 49%).

›Step 4. 3-(2′,4′-difluorobiphenyl-3-yl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one

To a solution of 6-(2-azidoethyl)-3-(2′,4′-difluorobiphenyl-3-yl)-6-phenyl-1,3-oxazinan-2-one (100 mg, 0.23 mmol) in 20:1 THF/H 2 O (3 mL) was added PPh 3 (72 mg, 0.28 mmol). The reaction mixture was stirred at rt overnight. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel to afford 6-(2-aminoethyl)-3-(2′,4′-difluorobiphenyl-3-yl)-6-phenyl-1,3-oxazinan-2-one (30 mg, 31%). 1 H NMR (400 MHz, CDCl 3 ): δ=2.20-2.51 (m, 2H), 2.51-2.60 (m, 2H), 2.72 (m, 1H), 3.00 (m, 1H), 3.24 (m, 1H), 3.53 (m, 1H), 6.85-6.99 (m, 2H), 7.14 (m, 1H), 7.31-7.50 (m, 8H).

›Example 76

2-(3-(2′,4′-difluorobiphenyl-3-yl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)acetamide

A solution of 2-(3-(2′,4′-difluorobiphenyl-3-yl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)acetic acid (30 mg, 0.072 mmol), HOBt (18 mg, 0.144 mmol), EDCl (30 mg, 0.144 mmol) and DIEA (0.2 ML) in anhydrous CH 2 Cl 2 (3 mL) was stirred at 0° C. under NH 3 . Then the solution was stirred at rt overnight. Solvent was removed in vacuo, the residue was purified by HPLC to get 2-(3-(2′,4′-difluorobiphenyl-3-yl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)acetamide (1.68 mg, 6%). 1 H-NMR (400 MHz, CDCl 3 ): δ=2.58 (m, 2H), 2.80-3.00 (m, 2H), 3.27 (m, 1H), 3.50 (m, 1H), 6.00 (s, 1H), 6.36 (s, 1H), 6.78-6.90 (m, 2H), 7.05 (m, 1H), 7.23-7.55 (m, 9H).

›Example 77

3-(2′,4′-difluorobiphenyl-3-yl)-6-(2,3-dihydroxypropyl)-6-phenyl-1,3-oxazinan-2-one

›Step 1. 3-(2′,4′-difluorobiphenyl-3-yl)-6-(2,3-dihydroxypropyl)-6-phenyl-1,3-oxazinan-2-one

To a solution of 6-allyl-3-(2′,4′-difluorobiphenyl-3-yl)-6-phenyl-1,3-oxazinan-2-one (7.1 mg, 0.018 mmol) in acetone (0.5 mL) was added NMO.H 2 O (6 mg, 0.044 mmol), then OsO 4 (10 μL, 2.5 wt % in 2-Me-2-propanol). The reaction was stirred overnight at rt. The solvent was evaporated and the residue was redissolved in EtOAc. The organic layer was washed with 10% aq Na 2 S 2 O 3 (2×), 1M aq HCl (2×) and brine (1×). The organic layer was dried over Na 2 SO 4 , filtered, evaporated, and purified by prep HPLC to afford 3-(2′,4′-difluorobiphenyl-3-yl)-6-(2,3-dihydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (6.53 mg). LC-MS Method 1, m/z=440 (M+H) + . 1 H NMR (CDCl 3 ) 7.47-7.33 (m), 7.15-7.12 (m), 6.96-6.86 (m), 3.51 (br m), 3.37-3.26 (m), 2.69 (br m), 2.58-2.48 (m), 2.29-2.23 (m), 2.14 (d), 2.06 (d).

›Example 78

3-(2′,4′-difluorobiphenyl-3-yl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one

›Step 1. 3-(2′,4′-difluorobiphenyl-3-yl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one

To a 0° C. solution of 6-allyl-3-(2′,4′-difluorobiphenyl-3-yl)-6-phenyl-1,3-oxazinan-2-one (18 mg, 0.045 mmol) in THF (1 mL) was added BH 3 .THF (60 μL, 1M THF solution) and the mixture was stirred overnight at rt. The reaction was cooled to 0° C. and NaBO 3 .H 2 O (19 mg, 0.20 mmol) was added and stirred for 2 h warming to rt. The solvent was removed in vacuo and the residue was redissolved in CH 3 CN (4 mL). The solution was filtered and purified by prep HPLC to afford 3-(2′,4′-difluorobiphenyl-3-yl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (4.44 mg). LC-MS Method 1, t R =1.97 min, m/z=424 (M+H). 1 H NMR (CDCl 3 ) 7.47-7.33 (m), 7.32-7.26 (m), 7.16-7.12 (m), 6.96-6.85 (m), 4.28 (t), 3.52-3.13 (m), 3.36-3.27 (m), 2.5-2.47 (m), 2.15-1.99 (m).

›Examples4

›Example 79

3-(biphenyl-3-yl)-6-(3-chlorophenyl)-6-methyl-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to those described in Example 53 using 3-bromobiphenyl in Step 4. LC-MS Method 1, t R =1.99 min, m/z=378, 380. 1 H NMR (CDCl 3 ) 1.78 (s, 3H), 2.43 (m, 2H), 3.38 (m, 1H), 3.61 (m, 1H), 7.10-7.60 (13H).

›Example 80

3-(2′,4′-difluorobiphenyl-3-yl)-6-methyl-6-(pyridin-2-yl)-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to those described in Example 82 using 2′,4′-difluorobiphenyl-3-amine in Step 1 and 2-pyridylmagnesium bromide in Step 2. LC-MS Method 1, t R =1.72 min, m/z=381 (M+1). 1 H NMR (CD 3 OD) 8.55-8.54 (m, 1H), 7.91-7.87 (m, 1H), 7.62-7.60 (m, 1H), 7.44-7.32 (m, 4H), 7.26-7.25 (m, 1H), 7.14-7.11 (m, 1H), 7.00-6.94 (m, 2H), 3.66-3.60 (m, 1H), 3.25-3.18 (m, 1H), 2.78-2.72 (m, 1H), 2.43-2.35 (m, 1H), 1.69 (s, 3H).

›Example 81

6-methyl-3-(3-phenoxyphenyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to those described in Example 82 using 3-phenoxyaniline in Step 1. LC-MS Method 1, t R =1.9 min, m/z=360 (M+1). 1 H NMR (CD 3 OD) 7.37-7.22 (m, 8H), 7.08-7.04 (m, 1H), 6.92-6.90 (m, 2H), 6.81-6.78 (m, 2H), 6.68-6.67 (m, 1H), 3.55-3.50 (m, 1H), 3.18-3.11 (m, 1H), 2.58-2.53 (m, 1H), 2.39-2.31 (m, 1H), 1.63 (s, 3H).

›Example 82

6-methyl-6-phenyl-3-((S)-1-phenylethyl)-1,3-oxazinan-2-one

›Step 1. (S)-tert-Butyl 3-oxobutyl(1-phenylethyl)carbamate

A solution of (S)-1-phenylethanamine (0.1901 g, 1.57 mmol, 1.0 equiv) and methyl vinyl ketone (0.1117 g, 1.59 mmol, 1.02 equiv) in THF (5 mL) was allowed to stand in a refrigerator (ca. 3.3° C.) for 2 d. Boc 2 O (0.6700 g, 3.07 mmol, 1.95 equiv) was added to the solution at rt. The solution was stirred for 2 h and the solvent was removed under reduced pressure. The residue was purified by chromatography on silica gel eluted with hexanes/EtOAc to give (S)-tert-butyl 3-oxobutyl(1-phenylethyl)carbamate (0.3235 g, 71% over two steps) as a colorless oil.

›Step 2. tert-Butyl 3-hydroxy-3-phenylbutyl((S)-1-phenylethyl)carbamate

A solution of phenylmagnesium bromide (1.0 M in THF, 1.0 mL) was added dropwise to a solution of (S)-tert-butyl 3-oxobutyl(1-phenylethyl)carbamate (0.0421 g, 0.144 mmol in THF (4 mL) under N 2 at rt. After the solution was stirred for 14 h, the reaction was quenched with 10% aq Na 2 CO 3 (0.5 mL) and diluted with CH 2 Cl 2 . The organic layer was dried over Na 2 SO 4 . After the solvents were evaporated, the crude product was directly used in the next step without further purification.

›Step 3. 6-Methyl-6-phenyl-3-((S)-1-phenylethyl)-1,3-oxazinan-2-one

A mixture of crude tert-butyl 3-hydroxy-3-phenylbutyl((S)-1-phenylethyl)carbamate, obtained as described above, 60% NaH in oil (0.320 g) and THF (5 mL) was heated to reflux for 21 h. The reaction was then quenched with H 2 O (1.5 mL) and diluted with CH 2 Cl 2 . The organic layer was dried over Na 2 SO 4 . After the solvents were evaporated, the residue was purified by reversed-phase HPLC to afford 6-methyl-6-phenyl-3-((S)-1-phenylethyl)-1,3-oxazinan-2-one. After the solvents were evaporated, the residue was purified by reversed-phase HPLC (Phenomenex® Luna 5μ C18(2) 100 A, 250×21.20 mm, 5 micron, 10%→90% CH 3 CN/H 2 O, 0.1% CF 3 COOH over 13 min and then 90% CH 3 CN/H 2 O, 0.1% CF 3 COOH over 4 min, flow rate 25 mL/min) to afford 6-methyl-6-phenyl-3-((S)-1-phenylethyl)-1,3-oxazinan-2-one as a mixture of diastereomers. LC-MS Method 1 t R =1.71, 1.75 min, m/z=296 (MW); 1 H NMR (400 MHz, CD 3 OD) δ 7.36-7.18 (m), 7.06-7.02 (m), 6.89-6.85 (m), 5.54 (q, J=7.1 Hz), 5.47 (q, J=7.0 Hz), 3.00-2.95 (m), 2.73-2.69 (m), 2.40-2.34 (m), 2.26-2.19 (m), 2.13-2.05 (m), 2.00-1.92 (m), 1.53 (s), 1.52 (s), 1.45 (d, J=7.0 Hz), 1.23 (d, J=7.0 Hz). A fraction containing on the less polar diastereomer was also isolated (Isomer 1). LC-MS Method 1 t R =1.75 min, m/z=296 (MH + ); 1 H NMR (400 MHz, CD 3 OD) δ 7.35-7.18 (m, 10H), 5.54 (q, J=7.0 Hz, 1H), 2.72-2.69 (m, 2H), 2.39-2.33 (m, 1H), 1.99-1.92 (m, 1H), 1.52 (s, 3H), 1.23 (d, J=7.0 Hz, 3H).

›Examples12

›Example 83

6-methyl-6-phenyl-3-((R)-1-phenylethyl)-1,3-oxazinan-2-one

The two diastereomers of the title compound were prepared and separated following procedures analogous to those described in Example 82 using (R)-1-phenylethanamine in Step 1.

Isomer 1: LC-MS Method 1, t R =1.75 min, m/z=296 (M+1). 1 H NMR (CD 3 OD) 7.35-7.18 (m, 10H), 5.54 (q, J=7.1 Hz, 1H), 2.72-2.69 (m, 2H), 2.39-2.34 (m, 1H), 2.00-1.92 (m, 1H), 1.52 (s, 3H), 1.23 (d, J=7.0 Hz, 3H).

Isomer 2: LC-MS Method 1, tR==1.71 min, m/z=296 (M+1). 1 H NMR (CD 3 OD) 7.37-7.18 (m), 7.06-7.01 (m), 6.89-6.85 (m), 5.54 (q, J=7.2 Hz), 5.47 (q, J=7.0 Hz), 3.00-2.95 (m), 2.72-2.69 (m), 2.40-2.34 (m), 2.25-2.18 (m), 2.13-2.05 (m), 2.00-1.92 (m), 1.53 (s), 1.52 (s), 1.45 (d, J=7.0 Hz), 1.23 (d, J=7.0 Hz).

›Example 84

3-((S)-1-(3-methoxyphenyl)ethyl)-6-methyl-6-phenyl-1,3-oxazinan-2-one

The two diastereomers of the title compound were prepared and separated following procedures analogous to those described in Example 82 using (S)-1-(3-methoxyphenyl)ethanamine in Step 1.

Isomer 1: LC-MS Method 1, t R =1.72 min, m/z=326 (M+1). 1 H NMR (CDCl 3 ) 7.40-7.23 (m, 6H), 6.91-6.80 (m, 3H), 5.78 (q, J=7.0 Hz, 1H), 3.80 (s, 3H), 2.70-2.67 (m, 2H), 2.29-2.23 (m, 1H), 2.06-1.98 (m, 1H), 1.64 (s, 3H), 1.27 (d, J=7.3 Hz, 3H).

Isomer 2: LC-MS Method 1, t R =1.68 min, m/z=326 (M+1). 1 H NMR (CDCl 3 ) 7.34-7.25 (m, 5H), 7.06-7.02 (m, 1H), 6.70-6.67 (m, 1H), 6.57-6.54 (m, 2H), 5.68 (q, J=7.0 Hz, 1H), 3.63 (s, 3H), 2.92-2.87 (m, 1H), 2.39-2.26 (m, 2H), 2.17-2.10 (m, 1H), 1.64 (s, 3H), 1.52 (d, J=7.0 Hz, 3H).

›Example 85

3-((S)-1-(4-methoxyphenyl)ethyl)-6-methyl-6-phenyl-1,3-oxazinan-2-one

The two diastereomers of the title compound were prepared and separated following procedures analogous to those described in Example 82 (S)-1-(4-methoxyphenyl)ethanamine in Step 1.

Isomer 1: LC-MS Method 1, t R =1.72 min, m/z=326 (M+1). 1 H NMR (CDCl 3 ) 7.40-7.21 (m, 7H), 6.88-6.84 (m, 2H), 5.76 (q, J=7.1 Hz, 1H), 3.80 (s, 3H), 2.68-2.65 (m, 2H), 2.27-2.22 (m, 1H), 2.02-1.95 (m, 1H), 1.62 (s, 3H), 1.26 (d, J=7.3 Hz, 3H).

Isomer 2: LC-MS Method 1, t R =1.68 min, m/z=326 (M+1). 1 H NMR (CDCl 3 ) 7.37-7.27 (m, 5H), 6.88-6.84 (m, 2H), 6.66-6.62 (m, 2H), 5.65 (q, J=7.1 Hz, 1H), 3.73 (s, 3H), 2.90-2.85 (m, 1H), 2.32-2.25 (m, 2H), 2.16-2.09 (m, 1H), 1.64 (s, 3H), 1.50 (d, J=7.0 Hz, 3H).

›Example 86

6-methyl-3-((S)-1-phenylethyl)-6-o-tolyl-1,3-oxazinan-2-one

The two diastereomers of the title compound were prepared and separated following procedures analogous to those described in Example 82 using o-tolylmagnesium bromide in Step 2.

Isomer 1: LC-MS Method 1, t R =1.83 min, m/z=310 (M+1). 1 H NMR (CDCl 3 ) 7.42-7.16 (m, 9H), 5.77 (q, J=7.1 Hz, 1H), 2.79-2.66 (m, 2H), 2.61-2.55 (m, 1H), 2.47 (s, 3H), 2.03-1.95 (m, 1H), 1.70 (s, 3H), 1.27 (d, J=7.3 Hz, 3H).

Isomer 2: LC-MS Method 1, t R =1.79 min, m/z=310 (M+1). 1 H NMR (CDCl 3 ) 7.35-7.33 (m, 1H), 7.23-7.06 (m, 6H), 6.86-6.84 (m, 2H), 5.66 (q, J=7.0 Hz, 1H), 2.96-2.91 (m, 1H), 2.62-2.56 (m, 1H), 2.48 (s, 3H), 2.43-2.36 (m, 1H), 2.16-2.08 (m, 1H), 1.71 (s, 3H), 1.53 (d, J=7.0 Hz, 3H).

›Example 87

6-methyl-3-((S)-1-phenylethyl)-6-m-tolyl-1,3-oxazinan-2-one

The two diastereomers of the title compound were prepared and separated following procedures analogous to those described in Example 82 using m-tolylmagnesium bromide in Step 2.

Isomer 1: LC-MS Method 1, t R =1.84 min, m/z=310 (M+1). 1 H NMR (CDCl 3 ) 7.36-7.24 (m, 6H), 7.16-7.10 (m, 3H), 5.81 (q, J=7.1 Hz, 1H), 2.74-2.63 (m, 2H), 2.37 (s, 3H), 2.26-2.21 (m, 1H), 2.03-1.95 (m, 1H), 1.62 (s, 3H), 1.31 (d, J=7.0 Hz, 3H).

Isomer 2: LC-MS Method 1, t R =1.80 min, m/z=310 (M+1). 1 H NMR (CDCl 3 ) 7.24-7.20 (m, 1H), 7.14-7.09 (m, 6H), 6.98-6.95 (m, 2H), 5.73 (q, J=7.0 Hz, 1H), 2.93-2.87 (m, 1H), 2.35 (s, 3H), 2.34-2.23 (m, 2H), 2.17-2.09 (m, 1H), 1.64 (s, 3H), 1.53 (d, J=7.0 Hz, 3H).

›Example 88

6-methyl-3-((S)-1-phenylethyl)-6-p-tolyl-1,3-oxazinan-2-one

The two diastereomers of the title compound were prepared and separated following procedures analogous to those described in Example 82 using p-tolylmagnesium bromide in Step 2.

Isomer 1: LC-MS Method 1, t R =1.86 min, m/z=310 (M+1). 1 H NMR (CDCl 3 ) 7.36-7.17 (m, 9H), 5.81 (q, J=7.2 Hz, 1H), 2.74-2.63 (m, 2H), 2.35 (s, 3H), 2.25-2.20 (m, 1H), 2.03-1.95 (m, 1H), 1.61 (s, 3H), 1.31 (d, J=7.3 Hz, 3H).

Isomer 2: LC-MS Method 1, t R =1.80 min, m/z=310 (M+1). 1 H NMR (CDCl 3 ) 7.22-7.19 (m, 2H), 7.16-7.08 (m, 5H), 6.96-6.93 (m, 2H), 5.71 (q, J=7.0 Hz, 1H), 2.92-2.87 (m, 1H), 2.36 (s, 3H), 2.35-2.23 (m, 2H), 2.16-2.08 (m, 1H), 1.62 (s, 3H), 1.53 (d, J=7.0 Hz, 3H).

›Example 89

3-((S)-1-(3-hydroxyphenyl)ethyl)-6-methyl-6-phenyl-1,3-oxazinan-2-one

A mixture of 3-((S)-1-(3-methoxyphenyl)ethyl)-6-methyl-6-phenyl-1,3-oxazinan-2-one Isomer 1 (0.1240 g, 0.381 mmol) and EtSNa (0.2115 g, 2.51 mmol) in DMF (2 mL) was heated at 170° C. for 2.5 h under nitrogen. The mixture was diluted with EtOAc, washed with 1 N aq HCl. The aqueous phase was extracted with EtOAc (2×). The combined organic phase was dried over Na 2 SO 4 . After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc to afford of 3-((S)-1-(3-hydroxyphenyl)ethyl)-6-methyl-6-phenyl-1,3-oxazinan-2-one (0.1036 g, 87%). LC-MS Method 1 t R =1.49 min, m/z 312 (MH + ); 1 H NMR (400 MHz, CDCl 3 ) δ 7.59-7.53 (m, 1H), 7.40-7.28 (m, 5H), 7.19-7.15 (m, 1H), 6.98 (m, 1H), 6.83-6.75 (m, 2H), 5.74 (q, J=7.1 Hz, 1H), 2.80-2.67 (m, 2H), 2.30-2.25 (m, 1H), 2.09-2.01 (m, 1H), 1.62 (s, 3H), 1.25 (d, J=7.0 Hz, 3H).

›Example 90

6-methyl-6-(4-(methylthio)phenyl)-3-((S)-1-phenylethyl)-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to those described in Example 82 using p-(methylthio)phenylmagnesium bromide in Step 2. LC-MS Method 1, t R =1.84 min, m/z=342 (M+1). 1 H NMR (CDCl 3 ) 7.37-7.24 (m, 9H), 5.81 (q, J=7.2 Hz, 1H), 2.75-2.65 (m, 2H), 2.50 (s, 3H), 2.25-2.19 (m, 1H), 2.04-1.96 (m, 1H), 1.61 (s, 3H), 1.33 (d, J=7.0 Hz, 3H).

›Example 91

ethyl 2-(3-((1S)-1-(6-methyl-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenoxy)acetate

A mixture of (R/S)-3-((S)-1-(3-hydroxyphenyl)ethyl)-6-methyl-6-phenyl-1,3-oxazinan-2-one (0.0955 g, 0.31 mmol, 1.0 equiv), Cs 2 CO 3 (0.3307 g, 1.01 mmol, 3.3 equiv), and ethyl bromoacetate (0.1468 g, 0.88 mmol, 2.8 equiv) in CH 3 CN (1.5 mL) was stirred at rt for 3 d. The mixture was diluted with CH 2 Cl 2 , treated with H 2 O (2 mL), dried over Na 2 SO 4 . After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc to afford 0.1025 g (84%) of ethyl 2-(3-((S)-1-((R/S)-6-methyl-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenoxy)acetate. LC-MS Method 1, t R =1.75 min, m/z=398 (M+1). 1 H NMR (CDCl 3 ) 7.40-7.23 (m, 6H), 6.95-6.93 (m, 1H), 6.88 (m, 1H), 6.81-6.78 (m, 1H), 5.76 (q, J=7.1 Hz, 1H), 4.61 (s, 2H), 4.27 (q, J=7.1 Hz, 2H), 2.68-2.65 (m, 2H), 2.28-2.23 (m, 1H), 2.06-1.98 (m, 1H), 1.63 (s, 3H), 1.30 (t, J=7.2 Hz, 3H), 1.26 (d, J=7.3 Hz, 3H).

›Example 92

6-methyl-6-(4-(morpholinomethyl)phenyl)-3-((S)-1-phenylethyl)-1,3-oxazinan-2-one

The title compound was prepared following procedures analogous to those described in Example 82 using (4-(morpholinomethyl)phenyl)magnesium bromide in Step 2. LC-MS Method 1, t R =1.12 min, m/z=395 (M+1). 1 H NMR (CD 3 OD) 7.48 (d, J=8.5 Hz, 2H), 7.42 (d, J=8.5 Hz, 2H), 7.27-7.16 (m, 5H), 5.51 (q, J=7.2 Hz, 1H), 4.28 (s, 2H), 3.95-3.92 (m, 2H), 3.66-3.60 (m, 2H), 3.28-3.25 (m, 2H), 3.13-3.08 (m, 2H), 2.72-2.69 (m, 2H), 2.36-2.30 (m, 1H), 2.02-1.94 (m, 1H), 1.49 (s, 3H), 1.22 (d, J=7.0 Hz, 3H).

›Example 93

(R/S)-3-(S)-1-(3-(2-hydroxy-2-methylpropoxy)phenyl)ethyl)-6-methyl-6-phenyl-1,3-oxazinan-2-one

To a solution of ethyl 2-(3-((S)-1-((R/S)-6-methyl-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenoxy)acetate (0.0369 g, 0.0928 mmol) in THF (5 mL) was added methylmagnesium bromide (1.4 M in toluene/THF, 1.0 mL, 1.4 mmol) at rt under nitrogen. After stirring for 1 h, the mixture was quenched with saturated NH 4 Cl (1 mL), diluted with CH 2 Cl 2 , and dried over Na 2 SO 4 . After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc to afford 0.0268 g (75%) of (R/S)-3-((S)-1-(3-(2-hydroxy-2-methylpropoxy)phenyl)ethyl)-6-methyl-6-phenyl-1,3-oxazinan-2-one. LC-MS Method 1, t R =1.64 min, m/z=384 (M+1). 1 H NMR (CDCl 3 ) 7.41-7.23 (m, 6H), 6.92-6.88 (m, 2H), 6.84-6.81 (m, 1H), 5.77 (q, J=7.0 Hz, 1H), 3.78 (s, 2H), 2.70-2.67 (m, 2H), 2.29-2.24 (m, 1H), 2.23 (s, 1H), 2.06-1.98 (m, 1H), 1.64 (s, 3H), 1.35 (s, 6H), 1.27 (d, J=7.0 Hz, 3H).

›Example 94

(R/S)-6-methyl-3-((S)-1-(3-(2-oxo-2-(piperazin-1-yl)ethoxy)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

›Step 1. 2-(3-((S)-1-((R/S)-6-methyl-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenoxy)-acetic acid

A mixture of ethyl 2-(3-((S)-1-((R/S)-6-methyl-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenoxy)acetate (0.0587 g, 0.148 mmol) and lithium hydroxide monohydrate (0.4275 g, 10.2 mmol) in THF (10 mL) and H 2 O (10 mL) was vigorously stirred at rt for 2 d. The mixture was treated with 1 N HCl (30 mL), extracted with EtOAc (3×), dried over Na 2 SO 4 . After the solvents were evaporated, the crude product was directly used in the next step without further purification. LC-MS t R =1.48 min in 3 min chromatography, m/z 370 (MH + ).

Step 2. (R/S)-6-methyl-3-((S)-1-(3-(2-oxo-2-(piperazin-1-yl)ethoxy)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

A mixture of 2-(3-((S)-1-((R/S)-6-methyl-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenoxy)acetic acid (0.0178 g, 0.0481 mmol), piperazine (0.0575 g, 0.67 mmol), HATU (0.1136 g, 0.30 mmol), and i-Pr 2 NEt (0.5 mL, 2.87 mmol) in DMF (1 mL) was stirred overnight at rt. After the solvents were removed in vacuo, the residue was purified by reversed-phase HPLC (Phenomenex® Luna 5μ C18(2) 100 A, 250×21.20 mm, 5 micron, 10%→90% CH 3 CN/H 2 O, 0.1% CF 3 COOH over 13 min, flow rate 25 mL/min) to give 0.0207 g of TFA salt of (R/S)-6-methyl-3-((S)-1-(3-(2-oxo-2-(piperazin-1-yl)ethoxy)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one. LC-MS Method 1, t R =1.17 min, m/z=438 (M+1). 1 H NMR (CD 3 OD) 7.34-7.17 (m, 6H), 6.84-6.80 (m, 3H), 5.47 (q, J=7.1 Hz, 1H), 4.78 (m, 2H), 3.78-3.75 (m, 4H), 3.18 (m, 4H), 2.72-2.69 (m, 2H), 2.40-2.34 (m, 1H), 2.01-1.93 (m, 1H), 1.52 (s, 3H), 1.20 (d, J=7.3 Hz, 3H).

›Example 95

6-allyl-6-(4-fluorophenyl)-3-((S)-1-phenylethyl)-1,3-oxazinan-2-one

›Step 1. 1-Chloro-3-(4-fluorophenyl)hex-5-en-3-ol

To a solution of 1,1′-bi-2-naphthol (0.2280 g, 0.80 mmol, 0.26 equiv), CH 2 Cl 2 (5 mL) and titanium(IV) isopropoxide (0.2243 g, 0.79 mmol, 0.26 equiv) were added 2-propanol (3.1620 g, 52.6 mmol, 17 equiv), tetraallylstannane (1.2538 g, 4.43 mmol, 1.43 equiv), and 3-chloro-1-(4-fluorophenyl)propan-1-one (0.5760 g, 3.09 mmol, 1.0 equiv) successively. The reaction mixture was stirred at rt under nitrogen for 22 h. The reaction was quenched with satd aq NH 4 Cl and extracted with EtOAc. The organic layer was dried over Na 2 SO 4 . After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc to afford 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol as an oil.

›Step 2. 6-Allyl-6-(4-fluorophenyl)-3-((S)-1-phenylethyl)-1,3-oxazinan-2-one

A mixture of 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol (0.0889 g, 0.39 mmol, 1.0 equiv), (S)-(−)α-methylbenzyl isocyanate (0.0823 g, 0.56 mmol, 1.44 equiv), and DBU (0.1397 g, 0.92 mmol, 2.36 equiv) in THF (2 mL) was heated to reflux for 17 h. After the solvent was removed, the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc to give 0.0990 g (75%) of the product as a mixture of diastereomers. Selected fractions contained the individual diastereomers.

Isomer 1: (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-phenylethyl)-1,3-oxazinan-2-one. LC-MS Method 1, t R =1.89 min, m/z=340 (M+1). 1 H NMR (CDCl 3 ) 7.36-7.27 (m, 7H), 7.10-7.05 (m, 2H), 5.79-5.67 (m, 2H), 5.09-4.98 (m, 2H), 2.72-2.68 (m, 2H), 2.64-2.53 (m, 2H), 2.22-2.16 (m, 1H), 2.09-2.01 (m, 1H), 1.26 (d, J=7.3 Hz, 3H).

Isomer 2: (S)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-phenylethyl)-1,3-oxazinan-2-one. LC-MS Method 1, t R =1.86 min, m/z=340 (M+1). 1 H NMR (CDCl 3 ) 7.29-7.24 (m, 2H), 7.14-7.08 (m, 3H), 7.05-7.00 (m, 2H), 6.88-6.85 (m, 2H), 5.77-5.63 (m, 2H), 5.10-5.00 (m, 2H), 2.93-2.88 (m, 1H), 2.65-2.52 (m, 2H), 2.32-2.17 (m, 3H), 1.51 (d, J=7.0 Hz, 3H).

›Examples15

›Example 96

3-(4′,6-difluorobiphenyl-3-yl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared by application of procedures analogous to those described in Example 63 using 4′,6-difluorobiphenyl-3-amine in Step 2 followed by Example 65. LC-MS Method 3, t R =1.215 min, m/z=410. 1 H NMR (CDCl 3 ) 2.12-2.30 (m, 2H), 2.47 (m, 2H), 3.21 (m, 1H), 3.42 (m, 1H), 3.54 (m, 1H), 3.75 (m, 2H), 7.06-7.11 (m, 5H), 7.26-7.40 (m, 7H).

Chiral preparative SFC using a ChiralCel-AS, 400×25 mm I.D, 20 μm (Daicel Chemical Industries, Ltd) column maintained at 35° C. eluted with 70:30 supercritical CO 2 /0.1% diethylamine in MeOH at a flow rate of 70 mL min −1 and a nozzle pressure of 100 bar afforded the two enantiomers.

Isomer 1: (S)-3-(4′,6-difluorobiphenyl-3-yl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one. LC-MS Method 3, t R =1.214 min, m/z=410. 1 H NMR (CDCl 3 ) δ=2.12-2.30 (m, 2H), 2.47 (m, 2H), 3.21 (m, 1H), 3.42 (m, 1H), 3.54 (m, 1H), 3.75 (m, 2H), 7.06-7.11 (m, 5H), 7.26-7.40 (m, 7H).

Isomer 2: (R)-3-(4′,6-difluorobiphenyl-3-yl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one. LC-MS Method 3, t R =1.207 min, m/z=410. 1 H NMR (CDCl 3 ) δ=2.20-2.40 (m, 2H), 2.57 (m, 2H), 3.30 (m, 1H), 3.53 (m, 2H), 3.64 (m, 1H), 3.84 (m, 1H), 7.06-7.20 (m, 5H), 7.39 (m, 1H), 7.45 (m, 6H).

›Example 97

6-(4-fluorophenyl)-6-(2-hydroxyethyl)-3-((S)-1-phenylethyl)-1,3-oxazinan-2-one

To a solution of 6-allyl-6-(4-fluorophenyl)-3-((S)-1-phenylethyl)-1,3-oxazinan-2-one (0.1016 g, 0.30 mmol, 1.0 equiv) in THF-H 2 O (1:1, 6 mL) were added NaIO 4 (0.3240 g, 1.5 mmol, 5 equiv) and OsO 4 (2.5 wt. % solution in t-BuOH, 0.0507 g, 0.0049 mmol, 0.016 equiv), and the mixture was stirred at rt for 2 h. The mixture was diluted with EtOAc, dried over Na 2 SO 4 , and concentrated under reduced pressure. The residue was dissolved in MeOH (3 mL) and NaBH 4 (0.100 g) was added. After the mixture was stirred for 1.5 h at rt, acetone was added. The solvents were removed in vacuo, the residue was treated with saturated brine, extracted with CH 2 Cl 2 , and dried over Na 2 SO 4 . After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc to afford the two diastereomers of 6-(4-fluorophenyl)-6-(2-hydroxyethyl)-3-((S)-1-phenylethyl)-1,3-oxazinan-2-one.

Isomer 1: (R)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-3-((S)-1-phenylethyl)-1,3-oxazinan-2-one. LC-MS Method 1 t R =1.51 min, m/z=344 (MH + ); 1 H NMR (400 MHz, CDCl 3 ) δ 7.36-7.27 (m, 7H), 7.12-7.07 (m, 2H), 5.76 (q, J=7.1 Hz, 1H), 3.78-3.74 (m, 1H), 3.58-3.51 (m, 1H), 2.72-2.62 (m, 2H), 2.28-2.08 (m, 4H), 1.80 (br s, 1H), 1.28 (d, J=7.3 Hz, 3H); 19 F NMR (376 MHz, CDCl 3 ) δ −114.84 (m).

Isomer 2: (S)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-3-((S)-1-phenylethyl)-1,3-oxazinan-2-one. LC-MS Method 1 t R =1.48 min, m/z=344 (MH + ); 1 H NMR (400 MHz, CDCl 3 ) δ 7.29-7.25 (m, 2H), 7.16-7.10 (m, 3H), 7.07-7.02 (m, 2H), 6.93-6.90 (m, 2H), 5.66 (q, J=7.0 Hz, 1H), 3.80-3.74 (m, 1H), 3.58-3.53 (m, 1H), 2.94-2.88 (m, 1H), 2.32-2.07 (m, 5H), 1.79 (br s, 1H), 1.52 (d, J=7.0 Hz, 3H); 19 F NMR (376 MHz, CDCl 3 ) δ −115.03 (m).

›Example 98

N-(2-(3-(2′,4′-difluorobiphenyl-3-yl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)ethyl)acetamide

In a 5 dram vial, sodium acetate (3 mg, 0.04 mmol) was added to 6-(2-aminoethyl)-3-(2′,4′-difluorobiphenyl-3-yl)-6-phenyl-1,3-oxazinan-2-one (5.13 mg, 0.013 mmol) in acetic anhydride (0.5 mL). The reaction was stirred for 2 h. The solvent was evaporated and the crude residue purified via prep HPLC to afford 1.88 mg of N-(2-(3-(2′,4′-difluorobiphenyl-3-yl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)ethyl)acetamide. LC-MS Method 1 m/z=451 (M+H) + .

›Example 99

N-(2-(3-(2′,4′-difluorobiphenyl-3-yl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)ethyl)methanesulfonamide

In a 5 dram vial, methanesulfonyl chloride (5 drops) was added to 6-(2-aminoethyl)-3-(2′,4′-difluorobiphenyl-3-yl)-6-phenyl-1,3-oxazinan-2-one (5 mg, 0.012 mmol) and TEA (5 drops) dissolved in methylene chloride (0.5 mL). The reaction was stirred for 2 h. The solvent was evaporated and the crude residue purified via prep HPLC to afford 3.56 mg of N-(2-(3-(2′,4′-difluorobiphenyl-3-yl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)ethyl)methanesulfonamide. LC-MS Method 1 m/z=487 (M+H) + .

›Example 100

3-(2′-chloro-4′,6-difluorobiphenyl-3-yl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one

The title compound was prepared by sequential application of procedures analogous to those described in Example 63 using p-fluoroacetophenone in Step 1 and 3-bromo-4-fluoroaniline in Step 2, Example 74 and Example 75 Step 1 using 2-chloro-4-fluorophenylboronic acid. LC-MS Method 3, t R =1.265 min, m/z=462. 1 H NMR (CDCl 3 ) 2.10-2.30 (m, 2H), 2.45-2.51 (m, 2H), 3.20-3.31 (m, 1H), 3.55-3.60 (m, 2H), 3.70-3.80 (m, 1H), 6.90-7.16 (m, 6H), 7.20-7.40 (m, 4H).

›Example 101

3-(2′-chloro-4′,6-difluorobiphenyl-3-yl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared by sequential application of procedures analogous to those described in Example 63 using 3-bromo-4-fluoroaniline in Step 2, Example 74 and Example 75 Step 1 using 2-chloro-4-fluorophenylboronic acid. LC-MS Method 3, t R =1.367 min, m/z=466.1. 1 H NMR (CD 3 OD) δ=2.17 (m, 2H), 2.47 (m, 1H), 2.58 (m, 1H), 3.16 (m, 1H), 3.25 (m, 1H), 3.54 (m, 1H), 3.63 (m, 1H), 6.98 (m, 1H), 7.08 (m, 3H), 7.26 (m, 3H), 7.37 (m, 4H).

›Example 102

3-(6-(4-fluorophenyl)pyridin-2-yl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared by application of procedures analogous to those described in Example 63 using 2-amino-6-bromopyridine in Step 2, followed by Example 74 and Example 75 Step 1 using 4-fluorophenylboronic acid. LC-MS Method 3, t R =1.217 min, m/z=393. 1 H NMR (CD 3 OD) δ=2.29 (m, 2H), 2.51 (m, 1H), 2.73 (m, 1H), 3.47 (m, 2H), 3.75 (m, 1H), 4.21 (m, 1H), 7.14 (m, 2H), 7.35 (m, 1H), 7.46 (m, 4H), 7.63 (m, 1H), 7.68 (m, 1H), 7.72 (m, 1H), 8.00 (m, 2H).

Chiral preparative SFC using a ChiralCel-AS, 400×25 mm I.D, 20 μm (Daicel Chemical Industries, Ltd) column maintained at 35° C. eluted with 65:35 supercritical CO 2 /0.1% diethylamine in MeOH at a flow rate of 70 mL min −1 and a nozzle pressure of 100 bar afforded the two enantiomers.

Isomer 1: (R)-3-(6-(4-fluorophenyl)pyridin-2-yl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one. LC-MS Method 3, t R =1.2 min, m/z=393. 1 H NMR (CD 3 OD) δ=2.29 (m, 2H), 2.51 (m, 1H), 2.68 (m, 1H), 3.42 (m, 2H), 3.75 (m, 1H), 4.16 (m, 1H), 7.11 (m, 2H), 7.33 (m, 1H), 7.46 (m, 4H), 7.53 (m, 1H), 7.72 (m, 2H), 7.98 (m, 2H).

Isomer 2: (S)-3-(6-(4-fluorophenyl)pyridin-2-yl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one. LC-MS Method 3, t R =1.183 min, m/z=393. 1 H NMR (CD 3 OD) δ=2.27 (m, 2H), 2.48 (m, 1H), 2.63 (m, 1H), 3.45 (m, 2H), 3.75 (m, 1H), 4.18 (m, 1H), 7.08 (m, 2H), 7.31 (m, 1H), 7.44 (m, 4H), 7.50 (m, 1H), 7.68 (m, 2H), 7.91 (m, 2H).

›Example 103

6-(4-fluorophenyl)-3-(6-(4-fluorophenyl)pyridin-2-yl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one

The title compound was prepared by application of procedures analogous to those described in Example 63 using p-fluoroacetophenone in Step 1 and 2-amino-6-bromopyridine in Step 2, followed by Example 74 and Example 75 Step 1 using 4-fluorophenylboronic acid. LC-MS Method 2, t R =2.25 min, m/z=411. 1 H NMR (CD 3 OD) 25 (m, 2H), 2.55 (m, 1H), 2.60 (m, 1H), 3.40 (m, 1H), 3.50 (m, 1H), 3.75 (m, 1H), 4.20 (m, 1H), 7.15 (m, 4H), 7.50 (m, 2H), 7.65 (m, 2H), 7.80 (m, 1H), 8.00 (m, 2H).

›Example 104

6-(2-fluorophenyl)-3-(6-(4-fluorophenyl)pyridin-2-yl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one

The title compound was prepared by application of procedures analogous to those described in Example 63 using o-fluoroacetophenone in Step 1 and 2-amino-6-bromopyridine in Step 2, followed by Example 74 and Example 75 Step 1 using 4-fluorophenylboronic acid. LC-MS Method 3, t R =1.26 min, m/z=410.14. 1 H NMR (CD 3 OD) δ=2.20-2.40 (m, 2H), 2.45 (m, 1H), 2.75 (m, 1H), 3.42 (m, 2H), 3.72 (m, 1H), 4.15 (m, 1H), 7.03-7.20 (m, 4H), 7.35 (m, 2H), 7.55 (m, 1H), 7.65 (m, 1H), 7.75 (m, 1H), 7.95 (m, 2H).

Chiral preparative SFC using a ChiralCel-AS, 400×25 mm I.D, 20 μm (Daicel Chemical Industries, Ltd) column maintained at 35° C. eluted with 75:25 supercritical CO 2 /0.1% diethylamine in MeOH at a flow rate of 70 mL min −1 and a nozzle pressure of 100 bar afforded the two enantiomers.

Isomer 1: (R)-6-(2-fluorophenyl)-3-(6-(4-fluorophenyl)pyridin-2-yl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one. LC-MS Method 3, t R =1.255 min, m/z=410.14. 1 H NMR (CD 3 OD) δ=2.20-2.40 (m, 2H), 2.45 (m, 1H), 2.75 (m, 1H), 3.35 (m, 2H), 3.72 (m, 1H), 4.15 (m, 1H), 7.03-7.20 (m, 4H), 7.35 (m, 2H), 7.55 (m, 1H), 7.65 (m, 1H), 7.75 (m, 1H), 7.95 (m, 2H).

Isomer 2: (S)-6-(2-fluorophenyl)-3-(6-(4-fluorophenyl)pyridin-2-yl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one. LC-MS Method 3, t R =1.262 min, m/z=410.14. 1 H NMR (CD 3 OD) δ=2.20-2.40 (m, 2H), 2.45 (m, 1H), 2.75 (m, 1H), 3.42 (m, 2H), 3.72 (m, 1H), 4.15 (m, 1H), 7.03-7.20 (m, 4H), 7.45 (m, 2H), 7.55 (m, 1H), 7.65 (m, 1H), 7.75 (m, 1H), 7.95 (m, 2H).

›Example 105

6-(4-fluorophenyl)-6-(2-hydroxyethyl)-3-(2′,4′,6-trifluorobiphenyl-3-yl)-1,3-oxazinan-2-one

The title compound was prepared by sequential application of procedures analogous to those described in Example 63 using p-fluoroacetophenone in Step 1 and 3-bromo-4-fluoroaniline in Step 2, Example 74 and Example 75 Step 1 using 2,4-difluorophenylboronic acid. LC-MS Method 3, t R =1.225 min, m/z=446. 1 H NMR (CDCl 3 ) δ=2.15-2.30 (m, 2H), 2.50-2.60 (m, 2H), 3.22-3.37 (m, 1H), 3.50-3.65 (m, 2H), 3.75-3.85 (m, 1H), 6.89-6.92 (m, 2H), 7.10-7.20 (m, 5H), 7.30-7.40 (m, 3H).

›Example 106

6-(2-fluorophenyl)-6-(2-hydroxyethyl)-3-(2′,4′,6-trifluorobiphenyl-3-yl)-1,3-oxazinan-2-one

The title compound was prepared by sequential application of procedures analogous to those described in Example 63 using o-fluoroacetophenone in Step 1 and 3-bromo-4-fluoroaniline in Step 2, Example 74 and Example 75 Step 1 using 2,4-difluorophenylboronic acid. LC-MS Method 3, t R =1.237 min, m/z=446. 1 H NMR (CDCl 3 ) δ=2.30-2.50 (m, 3H), 2.70-2.80 (m, 1H), 3.20-3.30 (m, 1H), 3.40-3.50 (m, 1H), 3.55-3.65 (m, 1H), 3.70-3.80 (m, 1H), 6.85-6.90 (m, 2H), 7.00-7.10 (m, 4H), 7.20-7.38 (m, 3H), 7.45-7.52 (m, 1H).

›Example 107

3-(6-(2,4-difluorophenyl)pyridin-2-yl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared by application of procedures analogous to those described in Example 63 using 2-amino-6-bromopyridine in Step 2, followed by Example 74 and Example 75 Step 1 using 2,4-difluorophenylboronic acid. LC-MS Method 3, t R =1.25 min, m/z=411. 1 H NMR (CD 3 OD) δ=2.27 (m, 2H), 2.53 (m, 1H), 2.72 (m, 1H), 3.38 (m, 2H), 3.74 (m, 1H), 4.15 (m, 1H), 7.02 (m, 2H), 7.32 (m, 1H), 7.42 (m, 4H), 7.55 (m, 1H), 7.71 (m, 1H), 7.78 (m, 1H), 7.91 (m, 1H).

›Example 108

3-(6-(2,4-difluorophenyl)pyridin-2-yl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one

The title compound was prepared by application of procedures analogous to those described in Example 63 using p-fluoroacetophenone in Step 1 and 2-amino-6-bromopyridine in Step 2, followed by Example 74 and Example 75 Step 1 using 2,4-difluorophenylboronic acid. LC-MS Method 2, t R =2.311 min, m/z=429.4. 1 H NMR (CD 3 OD) 2.25 (m, 2H), 2.55 (m, 1H), 2.60 (m, 1H), 3.40 (m, 2H), 3.50 (m, 1H), 3.75 (m, 1H), 7.15 (m, 3H), 7.30 (m, 1H), 7.45 (m, 3H), 7.75 (m, 1H), 7.80 (m, 1H).

›Example 109

3-(6-(2,4-difluorophenyl)pyridin-2-yl)-6-(2-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one

The title compound was prepared by application of procedures analogous to those described in Example 63 using o-fluoroacetophenone in Step 1 and 2-amino-6-bromopyridine in Step 2, followed by Example 74 and Example 75 Step 1 using 2,4-difluorophenylboronic acid. LC-MS Method 2, t R =2.311 min, m/z=429. 1 H NMR (CD 3 OD) 2.35 (m, 2H), 2.55 (m, 1H), 2.80 (m, 1H), 3.45 (m, 2H), 3.75 (m, 1H), 4.20 (m, 1H), 7.05 (m, 2H), 7.20 (m, 2H), 7.40 (m, 2H), 7.60 (m, 1H), 7.80 (m, 2H), 7.90 (m, 1H).

The isomers were separated by

Isomer 1: (R)-3-(6-(2,4-difluorophenyl)pyridin-2-yl)-6-(2-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one.

Isomer 2: (S)-3-(6-(2,4-difluorophenyl)pyridin-2-yl)-6-(2-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one.

›Example 110

6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one

›Step 1. 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol

A 250-mL flask was charged with anhydrous CeCl 3 (5.58 g, 22.6 mmol) and THF (40 mL). The mixture was vigorously stirred for 3.5 h at rt. The suspension was then cooled to −78° C. and a solution of allylmagnesium bromide (1.0 M in THF, 21 mL, 21.0 mmol) was added. After stirring for 2 h at −78° C., a solution of 3-chloro-1-(4-fluorophenyl)propan-1-one (2.522 g, 13.5 mmol) in THF (30 mL) was added via cannula. The reaction mixture was allowed to slowly warm to 8° C. while stirring overnight (18 h). The reaction was then quenched with satd aq NaHCO 3 , extracted with EtOAc, and dried over Na 2 SO 4 . After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc to afford of 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol (3.0049 g, 97%) as an oil. LC-MS Method 1 t R =1.79 min, m/z 213, 211 (M-OH) + ; 1 H NMR (400 MHz, CDCl 3 ) δ 7.37-7.32 (m, 2H), 7.07-7.02 (m, 2H), 5.57-5.47 (m, 1H), 5.20-5.19 (m, 1H), 5.16 (m, 1H), 3.59-3.52 (m, 1H), 3.24-3.18 (m, 1H), 2.70 (dd, J=13.8, 5.9 Hz, 1H), 2.50 (dd, J=13.8, 8.5 Hz, 1H), 2.29 (t, J=7.9 Hz, 2H), 2.22 (s, 1H); 19 F NMR (376 MHz, CDCl 3 ) δ −116.52 (m).

Step 2. (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one and (S)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one

A mixture of 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol (0.4129 g, 1.8 mmol, 1.0 equiv), (S)-(−)-1-(4-bromophenyl)ethyl isocyanate (0.5005 g, 2.2 mmol, 1.2 equiv), and DBU (0.7375 g, 4.8 mmol, 2.7 equiv) in THF (10 mL) was heated to reflux for 25 h. The mixture was diluted with EtOAc and washed with 1 N aq HCl. The aqueous phase was extracted with EtOAc (2×). The combined organic phase was dried over Na 2 SO 4 . After the solvents were evaporated, the crude product was directly used in the next step without further purification.

An analytical sample was purified by chromatography on silica gel eluted with hexanes/EtOAc to afford the two diastereomers of 6-allyl-3-((S)-1-(4-bromo-phenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one.

Isomer 1: (S)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one. LC-MS Method 1 t R =2.03 min, m/z 420, 418 (MH + ); 1 H NMR (400 MHz, CDCl 3 ) δ 7.46 (d, J=8.2 Hz, 2H), 7.31-7.28 (m, 2H), 7.17 (d, J=8.2 Hz, 2H), 7.07 (t, J=8.5 Hz, 2H), 5.76-5.66 (m, 2H), 5.10-4.99 (m, 2H), 2.75-2.52 (m, 4H), 2.23-2.19 (m, 1H), 2.08-2.00 (m, 1H), 1.24 (d, J=7.0 Hz, 3H); 19 F NMR (376 MHz, CDCl 3 ) δ −115.07 (m).

Isomer 2: (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one. LC-MS Method 1 t R =1.98 min, m/z 420, 418 (MH + ); 1 H NMR (400 MHz, CDCl 3 ) δ 7.25-7.20 (m, 4H), 7.05-7.01 (m, 2H), 6.71 (d, J=8.5 Hz, 2H), 5.74-5.64 (m, 1H), 5.58 (q, J=7.0 Hz, 1H), 5.09-4.99 (m, 2H), 2.92-2.87 (m, 1H), 2.63-2.50 (m, 2H), 2.33-2.16 (m, 3H), 1.47 (d, J=7.0 Hz, 3H); 19 F NMR (376 MHz, CDCl 3 ) δ −114.91 (m).

(R)-6-allyl-3-((S)-1-(4-chlorophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one was prepared following procedures analogous to those described above using 3-chloro-1-phenylpropan-1-one in Step 1 and (S)-1-chloro-4-(1-isocyanatoethyl)benzene in Step 2.

›Example 111

6-allyl-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one

›Step 1. 6-allyl-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one

To a solution of 6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (0.3860 g, 0.92 mmol, 1.0 equiv) in THF (10 mL) were added, under a nitrogen atmosphere, 2,4-difluorophenylboronic acid (0.2708 g, 1.71 mmol, 1.86 equiv), 2 M aq Na 2 CO 3 (8 mL), and (Ph 3 P) 2 PdCl 2 (0.0308 g, 0.0438 mmol, 0.047 equiv). The mixture was stirred for 2 d at 100° C. Brine was then added, the mixture was extracted with Et 2 O (3×), and the combined ether extracts were dried over Na 2 SO 4 . After the solvents were evaporated, the crude product was directly used in the next step without further purification. LC-MS t R =2.13, 2.17 min in 3 min chromatography, m/z 452 (MH + ).

Analytical samples were separated by silica gel chromatography.

Isomer 1: (S)-6-allyl-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one. LC-MS Method 1, t R =2.17 min, m/z=452. 1 H NMR (CDCl 3 ) 7.47 (d, J=8.2 Hz, 2H), 7.42-7.30 (m, 5H), 7.08 (t, J=8.2 Hz, 2H), 6.98-6.88 (m, 2H), 5.82-5.68 (m, 2H), 5.08 (d, J=10.2 Hz, 1H), 5.02 (d, J=17.0 Hz, 1H), 2.78-2.71 (m, 2H), 2.66-2.54 (m, 2H), 2.25-2.20 (m, 1H), 2.13-2.05 (m, 1H), 1.30 (d, J=7.0 Hz, 3H).

Isomer 2: (R)-6-allyl-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one. LC-MS Method 1, t R =2.13 min, m/z=452. 1 H NMR (CDCl 3 ) 7.33-7.23 (m, 5H), 7.03 (t, J=8.2 Hz, 2H), 6.96-6.86 (m, 4H), 5.77-5.67 (m, 2H), 5.10 (d, J=10.3 Hz, 1H), 5.04 (d, J=17.3 Hz, 1H), 2.99-2.94 (m, 1H), 2.66-2.54 (m, 2H), 2.41-2.34 (m, 1H), 2.30-2.17 (m, 2H), 1.55 (d, J=7.0 Hz, 3H).

›Examples6

›Example 112

3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one

Step 1. (S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one and (R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one

To a solution of 6-allyl-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (obtained as described in Example 111) in THF-H 2 O (1:1, 20 mL) were added NaIO 4 (1.0148 g, 4.74 mmol, 5 equiv) and OsO 4 (2.5 wt. % solution in t-BuOH, 0.1708 g, 0.0167 mmol, 0.018 equiv), and the mixture was stirred at rt for 2 h. The mixture was diluted with EtOAc, dried over Na 2 SO 4 , and concentrated under reduced pressure. The residue was dissolved in MeOH (10 mL) and NaBH 4 (0.200 g) was added. After the mixture was stirred for 1 h at rt, acetone was added. The solvents were removed in vacuo, the residue was treated with saturated brine, extracted with CH 2 Cl 2 , and dried over Na 2 SO 4 . After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc to afford the two diastereomers of 3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one.

Isomer 1: (R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one, less polar isomer, LC-MS Method 1 t R =1.86 min, m/z 456 (MH + ); 1 H NMR (400 MHz, CDCl 3 ) δ 7.48-7.30 (m, 7H), 7.13-6.88 (m, 4H), 5.78 (q, J=7.0 Hz, 1H), 3.78-3.74 (m, 1H), 3.57-3.50 (m, 1H), 2.79-2.67 (m, 2H), 2.31-2.11 (m, 4H), 1.81 (br s, 1H), 1.31 (d, J=7.3 Hz, 3H); 19 F NMR (376 MHz, CDCl 3 ) δ −111.48 (m), −113.88 (m), −114.67 (m).

Isomer 2: (S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one, more polar isomer, LC-MS Method 1 t R =1.80 min, m/z 456 (MH + ); 1 H NMR (400 MHz, CDCl 3 ) δ 7.24-7.17 (m, 5H), 7.00-6.79 (m, 6H), 5.62 (q, J=7.0 Hz, 1H), 3.74-3.68 (m, 1H), 3.51-3.45 (m, 1H), 2.91-2.88 (m, 1H), 2.30-2.01 (m, 5H), 1.96 (br s, 1H), 1.48 (d, J=7.0 Hz, 3H); 19 F NMR (376 MHz, CDCl 3 ) δ −111.61 (m), −114.05 (m), −114.90 (m). The absolute configuration was determined by X-ray crystallography.

›Example 113

6-(4-fluorophenyl)-3-((S)-1-phenylethyl)-6-vinyl-1,3-oxazinan-2-one

The title compound was prepared by application of procedures analogous to those described in Example 110 using vinylmagnesium bromide in Step 1 and (S)-(1-isocyanatoethyl)benzene in Step 2. The isomers were separated by chromatography on silica gel.

Isomer 1: LC-MS Method 1, t R =1.8 min, m/z=348 (M+23), 326 (M+1). 1 H NMR (CDCl 3 ) 7.39-7.28 (m, 7H), 7.06 (t, J=8.6 Hz, 2H), 5.96 (dd, J=17.3, 10.8 Hz, 1H), 5.80 (q, J=7.0 Hz, 1H), 5.32 (d, J=17.3 Hz, 1H), 5.21 (d, J=10.8 Hz, 1H), 2.87-2.81 (m, 1H), 2.74-2.68 (m, 1H), 2.31-2.24 (m, 1H), 2.18-2.11 (m, 1H), 1.41 (d, J=7.3 Hz, 3H).

Isomer 2: LC-MS Method 1, t R =1.79 min, m/z=348 (M+23), 326 (M+1). 1 H NMR (CDCl 3 ) 7.39-7.35 (m, 2H), 7.25-7.22 (m, 3H), 7.12-7.10 (m, 2H), 7.03 (t, J=8.6 Hz, 2H), 6.00 (dd, J=17.3, 10.8 Hz, 1H), 5.78 (q, J=7.0 Hz, 1H), 5.34 (d, J=17.3 Hz, 1H), 5.27 (d, J=10.5 Hz, 1H), 3.10-3.04 (m, 1H), 2.59-2.53 (m, 1H), 2.24-2.20 (m, 2H), 1.53 (d, J=7.3 Hz, 3H).

›Example 114

6-(4-fluorophenyl)-6-(hydroxymethyl)-3-((S)-1-phenylethyl)-1,3-oxazinan-2-one

The title compound was prepared from 6-(4-fluorophenyl)-3-((S)-1-phenylethyl)-6-vinyl-1,3-oxazinan-2-one by application of procedures analogous to those described in Example 112. The isomers were separated by chromatography on silica gel.

Isomer 1 of 6-(4-fluorophenyl)-6-(hydroxymethyl)-3-((S)-1-phenylethyl)-1,3-oxazinan-2-one: LC-MS Method 1, t R =1.5 min, m/z=330. 1 H NMR (CDCl 3 ) 7.34-7.25 (m, 7H), 7.07 (t, 2H), 7.73 (q, 1H), 3.76 (d, 1H), 3.62 (d, 1H), 2.75 (m, 2H), 2.39 (m, 1H), 2.13 (dt, 1H), 1.30 (d, 3H).

Isomer 2 of 6-(4-fluorophenyl)-6-(hydroxymethyl)-3-((S)-1-phenylethyl)-1,3-oxazinan-2-one: LC-MS Method 1, t R =1.48 min, m/z=330. 1 H NMR (CDCl 3 ) 7.27 (m, 2H), 7.12 (m, 3H), 7.02 (t, 2H), 7.90 (m, 2H), 5.63 (q, 1H), 3.78 (d, 1H), 3.61 (d, 1H), 2.96 (m, 1H), 2.54 (m, 1H), 2.29 (m, 1H), 2.18 (m, 1H), 1.51 (d, 3H).

›Example 115

3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one

The title compound was prepared from 6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one by application of procedures analogous to those described in Example 112. The isomers were separated by chromatography on silica gel.

Isomer 1: (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one: LC-MS Method 1, t R =1.67 min, m/z=423. 1 H NMR (CDCl 3 ) 7.44-7.48 (ad, 2H), 7.28-7.32 (m, 2H), 7.16-7.19 (ad, 7.09 (at, 2H), 5.69 (q, 1H), 3.73-3.79 (m, 1H), 3.51-3.57 (m, 1H), 2.67 (dd, 2H), 2.28 (dt, 1H), 2.22-2.07 (m, 3H), 1.25 (d, 3H).

Isomer 2: (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one: LC-MS Method 1, t R =1.63 min, m/z=423. 1 H NMR (CDCl 3 ) 7.23-7.29 (m, 4H), 7.02-7.08 (m, 2H), 6.77 9d, 2H), 5.58 (q, 1H), 3.73-3.79 (m, 1H), 3.51-3.57 (m, 1H), 2.86-2.94 (m, 1H), 2.25-2.34 (m, 3H), 2.06-2.21 (m, 2H), 1.49 (d, 3H).

›Example 116

3-(6-(2-chloro-4-fluorophenyl)pyridin-2-yl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared by application of procedures analogous to those described in Example 63 using acetophenone in Step 1 and 2-amino-6-bromopyridine in Step 2, followed by Example 74 and Example 75 Step 1 using 2-chloro-4-fluorophenylboronic acid. LC-MS Method 3, t R =1.267 min, m/z=427. 1 H NMR (CD 3 OD) δ=2.28 (m, 2H), 2.53 (m, 1H), 2.72 (m, 1H), 3.41 (m, 2H), 3.76 (m, 1H), 4.13 (m, 1H), 7.15 (m, 1H), 7.32 (m, 2H), 7.44 (m, 5H), 7.55 (m, 1H), 7.76 (m, 1H), 7.85 (m, 1H).

›Example 117

3-(2′,4′-difluorobiphenyl-3-yl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one

›Step 1. 2-(3-(2′,4′-difluorobiphenyl-3-yl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)acetic acid

A 100-mL of flask was charged with 3-(2′,4′-difluorobiphenyl-3-yl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one (1 g, 2.4 mmol) dissolved in acetone (10 mL). Jones reagent (CrO 3 : 1 g; H 2 SO 4 : 1 mL, H 2 O: 4 mL) was added at 0° C. under N 2 protection. The mixture was stirred overnight at rt. Aqueous K 2 CO 3 (5 mL) was added and the mixture was extracted with EtOAc (3×15 mL). The organic layers were combined, washed with brine, dried over Na 2 SO 4 , filtered and concentrated. The residue (1.03 g) was used directly for the next step.

›Step 2. methyl 2-(3-(2′,4′-difluorobiphenyl-3-yl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)acetate

A 100-mL of flask was charged with 2-(3-(2′,4′-difluorobiphenyl-3-yl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)acetic acid (1.02 g, 2.4 mmol) dissolved in MeOH (15 mL). Then thionyl chloride (418 mg, 3.5 mmol) was added dropwise slowly at 0° C. under N 2 protection. The mixture was stirred overnight under reflux. The mixture was concentrated to give the crude product, which was purified by chromatography to give the pure product (230 mg, 23%).

›Step 3. 3-(2′,4′-difluorobiphenyl-3-yl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one

A 25-mL of flask was charged with methyl 2-(3-(2′,4′-difluorobiphenyl-3-yl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)acetate (100 mg, 0.23 mmol) dissolved in dry THF (3 mL) under N 2 protection at −78° C. Then methylmagnesium bromide (3.0 M, 1 mL, 3 mmol) was added dropwise slowly at −78° C. and stirred overnight. The mixture was quenched with water and extracted with EtOAc (3×5 mL). The organic layers were combined, washed with brine, dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by preparative HPLC to give the pure product (2.38 mg, 2%). LC-MS Method 3, t R =1.267 min, m/z=897.3. 1 H NMR (CD 3 OD): 1.0 (s, 3H), 1.30 (s, 3H), 2.30 (s, 2H), 2.60 (m, 1H), 2.80 (m, 1H), 3.17 (m, 1H), 3.60 (m, 1H), 7.02 (m, 2H), 7.10 (m, 1H), 7.23 (s, 1H), 7.30-7.50 (m, 6H).

›Examples4

›Example 118

3-(6-(2-chloro-4-fluorophenyl)pyridin-2-yl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one

The title compound was prepared by application of procedures analogous to those described in Example 63 using p-fluoroacetophenone in Step 1 and 2-amino-6-bromopyridine in Step 2, followed by Example 74 and Example 75 Step 1 using 2-chloro-4-fluorophenylboronic acid. LC-MS Method 3, t R =1.347 min, m/z=445.1. 1 H NMR (CD 3 OD) 2.25 (m, 2H), 2.55 (m, 1H), 2.60 (m, 1H), 3.40 (m, 2H), 3.50 (m, 1H), 3.75 (m, 1H), 7.15 (m, 3H), 7.30 (m, 1H), 7.45 (m, 3H), 7.75 (m, 1H), 7.80 (m, 1H).

›Example 119

3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one

The title compound was prepared from 3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one by application of procedures analogous to those described in Example 75 Step 1 using 4-fluorophenylboronic acid. The isomers were separated by chromatography on silica gel.

Isomer 1: (S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one. LC-MS Method 1, t R =1.79 min, m/z=438. 1 H NMR (CDCl 3 ) 7.47-7.44 (m, 2H), 7.32-7.27 (m, 4H), 7.13-7.04 (m, 4H), 6.98 (d, J=7.9 Hz, 2H), 5.69 (q, J=7.0 Hz, 1H), 3.80-3.74 (m, 1H), 3.60-3.54 (m, 1H), 2.99-2.95 (m, 1H), 2.38-2.28 (m, 3H), 2.24-2.19 (m, 1H), 2.18-2.08 (m, 1H), 1.56 (d, J=7.0 Hz, 3H).

Isomer 2: (R)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one. LC-MS Method 1, t R =1.84 min, m/z=438.

›Example 120

6-allyl-3-((S)-1-cyclohexylethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one

1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol (126 mg, 0.55 mmol), (S)-(+)-1-cyclohexylethyl isocyanate (160 mg, 1.44 equiv.) and proton sponge (271 mg, 2.3 equiv.) were dissolved in dry THF (5 mL) and heated to reflux for 3 h. The mixture was then cooled to 0° C. and NaH (22 mg, 1.0 equiv.) was added slowly. After 5 min, the mixture was heated to reflux overnight. LC-MS showed the reaction was complete. The mixture was diluted with EtOAc (50 mL) and washed with 1% aq HCl (2×15 mL), satd aq NaHCO 3 (10 mL) and brine (10 mL), and dried over Na 2 SO 4 . After filtration and concentration, the residue was purified by chromatography on a 12-g silica cartridge eluted with a 10-45% EtOAc in hexanes gradient to afford two isomeric products.

Isomer 1: (R)-6-allyl-3-((S)-1-cyclohexylethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (57.5 mg, 30%). LC-MS Method 1, t R =2.05 min, m/z=346. 1 H NMR (CDCl 3 ) 7.29 (m, 2H), 7.02 (m, 2H), 5.70 (m, 1H), 5.05 (dd, 2H), 3.94 (m, 1H), 3.06 (m, 1H), 2.68-2.49 (m, 3H), 2.33 (m, 1H), 2.14 (m, 1H), 1.17 (d, 3H), 0.78 (m, 2H).

Isomer 2: (S)-6-allyl-3-((S)-1-cyclohexylethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (56 mg, 29%). LC-MS Method 1, t R =2.06 min, m/z=346. 1 H NMR (CDCl 3 ) 7.27 (m, 2H), 7.03 (t, 2H), 5.71 (m, 1H), 5.05 (dd, 2H), 3.95 (m, 1H), 2.92 (m, 1H), 2.72 (m, 1H), 2.57 (m, 2H), 2.22 (m, 2H), 1.49 (d, 1H), 1.32 (m, 1H), 0.86 (d, 3H).

›Example 121

6-methyl-6-phenyl-3-(4-phenylthiazol-2-yl)-1,3-oxazinan-2-one

›Step 1. 1-Phenyl-2-thiocyanatoethanone

To a solution of 2-bromo-1-phenylethanone (20 g, 0.1 mol) in acetone (170 mL) was added NaSCN (8.1 g, 0.1 mol). The mixture was stirred till the reaction was complete. The mixture was filtered, and the filtrate was concentrated to give the crude 1-phenyl-2-thiocyanato-ethanone (20 g), which was used for the next step without further purification.

›Step 2. 4-Phenylthiazol-2(3H)-one

To a solution of 1-phenyl-2-thiocyanato-ethanone (20 g, 113 mmol) in HOAc (100 mL) was added 50% aqueous H 2 SO 4 (20 mL). The mixture was refluxed for 10 min. The mixture was poured into water. The solid formed was collected by filtration to give crude 4-phenyl-3H-thiazol-2-one (20 g) which was used for the next step without further purification.

›Step 3. 2-Chloro-4-phenylthiazole

4-Phenyl-3H-thiazol-2-one (5 g, 28.2 mmol) was dissolved in POCl 3 (30 mL), and the mixture was refluxed overnight. The mixture was concentrated in vacuum, and the residue was purified by column chromatography to give 2-chloro-4-phenylthiazole (3.1 g, 57%).

›Step 4. 2-Phenyl-4-(4-phenylthiazol-2-ylamino)butan-2-ol

A mixture of 2-chloro-4-phenylthiazole (300 mg, 1.5 mmol), 4-amino-2-phenyl-butan-2-ol (294 mg, 1.5 mmol) and DBU (1.5 mL) was heated to 100° C. under N 2 in a microwave for 2 h. After the material was consumed, the mixture was neutralized with 1 N HCl solution (5 mL), extracted with CH 2 Cl 2 (3×5 mL). The combined organic extracts were dried over Na 2 SO 4 and concentrated to leave a residue, which was purified by column chromatography (1:2 petroleum ether/EtOAc) to afford 2-phenyl-4-(4-phenylthiazol-2-ylamino)butan-2-ol (100 mg, 20%).

›Step 5. 6-methyl-6-phenyl-3-(4-phenylthiazol-2-yl)-1,3-oxazinan-2-one

To a solution of 2-phenyl-4-(4-phenylthiazol-2-ylamino)butan-2-ol (50 mg, 0.15 mmol) and Et 3 N (80 mg, 0.75 mmol) in CH 2 CH 2 (5 mL) was added triphosgene (15 mg, 0.05 mmol) at 0° C. Then, the mixture was stirred at rt overnight. The reaction solution was concentrated to give an oil, which was purified by column chromatography (1:2 petroleum ether/EtOAc) to afford 6-methyl-6-phenyl-3-(4-phenylthiazol-2-yl)-1,3-oxazinan-2-one (20 mg, 37%). LC-MS Method 3, t R =1.446 min, m/z=351. 1 H NMR (CDCl 3 , 400 Hz): 1.80 (s, 3H), 2.45 (m, 1H), 2.65 b (m, 1H), 3.70 (m, 1H), 4.42 (m, 1H), 7.18 (s, 1H), 7.20-7.40 (m, 8H), 7.80 (d, 2H).

›Examples9

›Example 122

(R)-3-((S)-1-cyclohexylethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one

The title compound was prepared from (R)-6-allyl-3-((S)-1-cyclohexylethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one using a procedure analogous to that described in Example 78. LC-MS Method 1, t R =1.72 min, m/z=364. 1 H NMR (CDCl 3 ) 7.29 (m, 2H), 7.06 (m, 2H), 3.98 (m, 1H), 3.57 (t, 2H), 3.07 (m, 1H), 2.64 (m, 1H), 2.16 (m, 1H), 1.95 (m, 2H), 1.09 (d, 3H), 0.66 (m, 1H).

›Example 123

(R)-6-allyl-3-((S)-1-(4-cyclopropylphenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one

A mixture of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (15 mg, 0.036 mmol), cyclopropylboronic acid (5.5 mg, 1.78 equiv.), Pd(OAc) 2 (2 mg, 25% mol), tricyclohexylphosphine (5 mg, 50% mol), K 3 PO 4 (20 mg, excess), water (1 mL) and DMF (1 mL) were heated in a microwave oven for 45 min at 100° C. The mixture was diluted with EtOAc (10 mL), washed with water (4 mL) and brine (5 mL), and dried over Na 2 SO 4 . After filtration and concentration, the residue was purified by preparative HPLC to afford (R)-6-allyl-3-((S)-1-(4-cyclopropylphenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (6.2 mg, 45%). LC-MS Method 1, t R =2.02 min, m/z=380. 1 H NMR (CDCl 3 ) 7.24 (m, 2H), 7.02 (t, 2H), 6.76 (q, 4H), 5.75-5.56 (m, 2H), 5.10-4.98 (dd, 2H), 2.57 (m, 2H), 1.48 (d, 3H), 0.92 (m, 2H), 0.60 (m, 2H).

›Example 124

Methyl 4-((S)-1-((R)-6-allyl-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)benzoate

To a 16 mm culture tube with a Teflon-coated stirring bar, a solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (87 mg, 0.209 mmol) in dry DMSO (4 mL) and dry methanol (1.5 mL), triethylamine (60 μL, 2 equiv), Pd(OAc) 2 (10 mg, 0.2 equiv) and 1,3-bis(diphenylphosphino)propane (35 mg, 0.4 equiv) were added. The tube was sealed with a septum and Parafilm tape. The reaction mixture was purged with CO gas through a long needle for 1 min. A balloon filled with CO gas was attached to maintain a CO atmosphere. The reaction mixture was submerged in an oil bath preheated to 85° C. and stirred vigorously. After 12 h, LC-MS showed the reaction was complete. The mixture was filtered through a thin pad of Celite. The Celite was washed with EtOAc (35 mL). The filtrate was washed with 3% aq HCl (10 mL), water (2×8 mL) and brine (2×7 mL), and dried over Na 2 SO 4 . After filtration and concentration, the residue was purified by chromatography on a 12-g silica gel cartridge eluted with a 10-60% EtOAc in hexanes gradient to afford methyl 4-((S)-1-((R)-6-allyl-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)benzoate (68.4 mg, 83%). LC-MS Method 1, t R =1.79 min, m/z=398. 1 H NMR (CDCl 3 ) 7.79 (d, 2H), 7.26 (m, 2H), 7.04 (t, 2H), 6.94 (d, 2H), 5.69 (m, m, 2H), 5.07 (dd, 2H), 3.89 (s, 3H), 2.94 (m, 1H), 2.58 (m, 2H), 1.54 (d, 3H).

›Example 125

(R)-3-((S)-1-(4-cyclopropylphenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one

The title compound was prepared from (R)-6-allyl-3-((S)-1-(4-cyclopropyl-phenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one using a procedure analogous to that described in Example 78. LC-MS Method 1, t R =1.71 min, m/z=420. 1 H NMR (CDCl 3 ) 7.31 (m, 4H), 7.07 (m, 2H), 6.82 (d, 2H), 5.65 (m, 1H), 3.96 (m, 1H), 3.58 (t, 2H), 1.48 (t, 3H), 1.12 (d, 2H), 0.92 (d, 2H).

›Example 126

(S)-2-(4-fluorophenyl)-6-(6-(2-hydroxyethyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)pyridine 1-oxide

The title compound was prepared from (S)-3-(6-(4-fluorophenyl)pyridin-2-yl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one using a procedure analogous to that described in Example 129. LC-MS Method 2, t R =1.637 min, m/z=409.1. 1 H NMR (CD 3 OD) 2.25-2.40 (m, 2H), 2.56-2.70 (m, 2H), 3.05-3.14 (m, 1H), 3.32-3.40 (m, 1H), 3.62-3.80 (m, 2H), 7.15-7.26 (m, 2H), 7.30-7.68 (m, 7H), 7.70-7.88 (m, 2H).

›Example 127

Methyl 4-((S)-1-((R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)benzoate

The title compound was prepared from methyl 4-((S)-1-((R)-6-allyl-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)benzoate using a procedure analogous to that described in Example 78. LC-MS Method 1, t R =1.49 min, m/z=416. 1 H NMR (CDCl 3 ) 7.80 (d, 2H), 7.23 (m, 2H), 7.02 (m, 4H), 5.67 (m, 1H), 3.88 (s, 3H), 3.576 (t, 2H), 2.94 (m, 1H), 1.65 (m, 1H), 1.53 (d, 3H), 1.35 (m, 1H).

›Example 128

6-allyl-3-((S)-1-(5-bromopyridin-2-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one

The title compound was prepared following using a procedure analogous to that described in Example 95 using (S)-5-bromo-2-(1-isocyanatoethyl)pyridine in Step 2.

Isomer 1: (R)-6-allyl-3-((S)-1-(5-bromopyridin-2-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one. LC-MS Method 3, t R =1.281 min, m/z=419. 1 H NMR (CDCl 3 ) 1.25 (s, 1H), 1.60 (m, 3H), 2.25-2.33 (m, 1H), 2.35 (s, 3H), 2.46-2.55 (m, 2H), 2.60-2.70 (m, 1H), 3.80 (s, 1H), 4.48-4.59 (m, 2H), 5.06-5.14 (m, 2H), 5.52-5.65 (m, 1H), 6.30 (d, 2H), 6.95 (m, 3H), 7.27 (m, 1H), 7.35 (m, 2H).

Isomer 2: (S)-6-allyl-3-((S)-1-(5-bromopyridin-2-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one. LC-MS Method 3, t R =1.242 min, m/z=419. 1 H NMR (CDCl 3 ) 2.05 (m, 1H), 2.13 (d, 3H), 2.24 (m, 1H), 2.36 (m, 3H), 2.52 (m, 1H), 3.63 (m, 1H), 3.85 (m, 1H), 4.09 (m, 1H), 4.99 (m, 2H), 5.55 (m, 1H), 6.13 (d, 1H), 6.48 (m, 1H), 6.83 (m, 1H), 6.98 (m, 1H), 7.22 (m, 2H), 7.33 (m, 1H).

›Example 129

2-(4-fluorophenyl)-6-(6-(2-fluorophenyl)-6-(2-hydroxyethyl)-2-oxo-1,3-oxazinan-3-yl)pyridine 1-oxide

6-(2-fluorophenyl)-3-(6-(4-fluorophenyl)pyridin-2-yl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one (680 mg, 1.66 mmol) was added to acetic acid (20 mL), 30% aq hydrogen peroxide (50 mL) was added at rt and the reaction mixture was stirred for about 5 h at 80° C. The mixture was extracted with CH 2 Cl 2 and the organic phase washed with Na 2 SO 3 solution, then dried over Na 2 SO 4 . Removal of the solvent gave the crude product, which was purified by HPLC and give 2-(4-fluorophenyl)-6-(6-(2-fluorophenyl)-6-(2-hydroxyethyl)-2-oxo-1,3-oxazinan-3-yl)pyridine 1-oxide (80 mg, 11%). LC-MS Method 2, t R =1.704 min, m/z=427.1. 1 H NMR (CD 3 OD) 2.33-2.50 (m, 2H), 2.60-2.77 (m, 2H), 3.08-3.20 (m, 1H), 3.32-3.40 (m, 1H), 3.40-3.52 (m, 1H), 3.70-3.85 (m, 1H), 7.08-7.37 (m, 5H), 7.40-7.69 (m, 4H), 7.70-7.86 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ): δ=2.5 (s, 2H), 2.6 (m, 2H), 3.05 (m, 1H), 3.3 (m, 1H), 3.35-3.6 (m, 1H), 3.75 (m, 1H), 7.0-7.8 (m, 11H).

The enantiomers were separated by chiral SFC.

Isomer 1: LC-MS Method 2, t R =1.843 min, m/z=427.1. 1 H NMR (CD 3 OD) 2.40-2.52 (m, 2H), 2.62-2.80 (m, 2H), 3.12-3.23 (m, 1H), 3.35-3.45 (m, 1H), 3.58-3.65 (m, 1H), 3.72-3.88 (m, 1H), 7.12-7.49 (m, 5H), 7.50-7.70 (m, 4H), 7.72-7.90 (m, 2H).

Isomer 2: LC-MS Method 2, t R =1.841 min, m/z=427.1. 1 H NMR (CD 3 OD) 2.26-2.40 (m, 2H), 2.50-2.70 (m, 2H), 3.06 (m, 1H), 3.23-3.32 (m, 1H), 3.23-3.58 (m, 1H), 3.62-3.75 (m, 1H), 6.98-7.30 (m, 1H), 7.30-7.60 (m, 4H), 7.62-7.78 (m, 2H).

›Example 130

6-allyl-3-((S)-1-(4-bromophenyl)propyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one

The title compound was prepared following using a procedure analogous to that described in Example 95 using (S)-1-bromo-4-(1-isocyanatopropyl)benzene in Step 2.

Isomer 1: (R)-6-allyl-3-((S)-1-(4-bromophenyl)propyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one. LC-MS Method 3, t R =1.415 min, m/z=432. 1 H NMR (CD 3 OD) 0.94 (t, 3H), 1.96 (m, 2H), 2.28 (m, 2H), 2.46 (m, 1H), 2.62 (m, 2H), 3.10 (m, 1H), 5.06 (m, 1H), 5.28 (m, 1H), 5.68 (m, 1H), 6.92 (m, 2H), 7.06 (m, 2H), 7.29 (m, 4H)

Isomer 2: (S)-6-allyl-3-((S)-1-(4-bromophenyl)propyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one. LC-MS Method 3, t R =1.454 min, m/z=432. 1 H NMR (CD 3 OD) 0.56 (d, 3H), 1.65-1.75 (m, 1H), 1.76-1.88 (m, 1H), 1.98-2.08 (m, 1H), 2.46-2.55 (m, 1H), 2.60 (m, 2H), 2.72-2.86 (m, 2H), 4.98-5.08 (m, 2H), 5.30 (m, 1H), 5.62-5.72 (m, 1H), 7.11-7.18 (m, 1H), 7.25 (m, 2H), 7.39 (m, 2H), 7.50 (m, 2H).

(S)-1-bromo-4-(1-isocyanatopropyl)benzene was prepared as follows.

›Step 1

TFAA (27 mL) was dissolved in methylene chloride (121 mL) and cooled in ice water bath. A solution of (S)-1-phenylpropan-1-amine (25 g, 0.1851 mol) in methylene chloride (41 mL) was added and the ice water removed. The reaction mixture was stirred at rt for 3 h. The reaction mixture was cooled in ice water and MsOH (32.5 mL) was added followed by 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (DBDMH) (26.16 g, 0.09255 mol). The mixture was stirred overnight. The mixture was quenched with water, and the precipitate was filtered to give (S)—N-(1-(4-bromophenyl)propyl)-2,2,2-trifluoroacetamide (45.24 g, 79%).

›Step 2

To a solution of (S)—N-(1-(4-bromophenyl)propyl)-2,2,2-trifluoroacetamide (45.24 g, 0.1464 mol) in methanol (317 mL) was added a solution of NaOH (188 mL, 13%) at 0° C. The mixture was stirred for 2 h. The mixture was concentrated and extracted with methylene chloride. The solvent was removed to give (S)-1-(4-bromophenyl)propan-1-amine (29.65 g, 95%). 1 H NMR (CDCl 3 ): 084 (t, 3H), 1.63 (m, 2H), 3.79 (m, 1H), 7.19 (m, 2H), 7.45 (m, 2H).

›Step 3

(S)-1-(4-bromophenyl)propan-1-amine was used in a procedure analogous to that described in Example 392 Step 1 to afford (S)-1-bromo-4-(1-isocyanatopropyl)benzene.

›Examples18

›Example 131

6-allyl-3-(1-(5-(2,4-difluorophenyl)pyridin-2-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one

A solution of 6-allyl-3-(1-(5-bromopyridin-2-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (100 mg, 0.24 mmol), 2,4-difluorophenylboronic acid (56.9 mg, 0.36 mmol), PdCl 2 (PPh 3 ) 2 (10 mg, 10%) and aqueous solution of Cs 2 CO 3 (2 M, 0.2 mL) in 1,4-dioxane (3 mL) was heated to reflux overnight. After the solvents were evaporated, the crude product was purified by preparative TLC to give 6-allyl-3-(1-(5-(2,4-difluorophenyl)pyridin-2-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (50 mg, 46%). LC-MS Method 3, tR=1.336 min, m/z=453.1. 1 H NMR (CDCl 3 ): 2.30-2.40 (m, 1H), 2.39-2.42 (d, 3H), 2.50-2.60 (m, 2H), 2.60-2.70 (m, 2H), 4.10-4.20 (m, 1H), 4.50-4.65 (m, 2H), 5.55-5.70 (m, 2H), 6.40-6.50 (d, 1H), 6.80-7.00 (m, 4H), 7.10-7.15 (m, 1H), 7.22-7.30 (m, 2H), 7.30-7.40 (m, 3H).

›Example 132

2-(2,4-difluorophenyl)-6-(6-(2-fluorophenyl)-6-(2-hydroxyethyl)-2-oxo-1,3-oxazinan-3-yl)pyridine 1-oxide

The title compound was prepared from 3-(6-(2,4-difluorophenyl)pyridin-2-yl)-6-(2-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one following a procedure analogous to that described in Example 129. LC-MS Method 2, t R =1.724 min, m/z=445. 1 H NMR (CD 3 OD) 2.32-2.50 (m, 3H), 2.78-2.86 (m, 1H), 3.33-3.53 (m, 1H), 3.63 (m, 1H), 3.80 (m, 1H), 4.25 (m, 1H), 7.05-7.13 (m, 3H), 7.18 (m, 1H), 7.32 (m, 1H), 7.50 (m, 1H), 7.65-7.70 (m, 5H).

›Example 133

3-(5-chloro-6-(4-fluorophenyl)pyridin-2-yl)-6-(2-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one

A mixture of 6-(2-fluorophenyl)-3-(6-(4-fluorophenyl)pyridin-2-yl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one (30 mg, 0.07 mmol), NaOAc (9 mg, 0.11 mmol) in HOAc (4 mg, 0.07 mmol), CH 3 CN (2 mL), H 2 O (0.1 mL) and CH 2 Cl 2 (2 mL) was stirred at rt for 5 min. A solution of 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione (37 mg, 0.11 mmol) in CH 3 CN (0.5 mL) was added slowly. The mixture was stirred for 20 min and heated to 40° C. for 2 h. The reaction was quenched with aq NaHSO 3 and extracted with CH 2 Cl 2 . The organic layer was dried with Na 2 SO 4 , concentrated to afford the crude product. Purification afforded 3-(5-chloro-6-(4-fluorophenyl)pyridin-2-yl)-6-(2-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one (15 mg, 48%). LC-MS Method 3, t R =1.331 min, m/z=445. 1 H NMR (CDCl 3 , 400 Hz): 2.40 (m, 3H), 2.84 (m, 1H), 3.40 (m, 1H), 3.66 (m, 1H), 3.82 (m, 1H), 4.26 (m, 1H), 7.10 (m, 3H), 7.18 (m, 1H), 7.34 (m, 1H), 7.50 (m, 1H), 7.68 (m, 2H), 7.76 (m, 1H), 8.01 (m, 1H).

›Example 134

(R)-6-(2-aminoethyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one

The title compound was prepared from (S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one following procedures analogous to those described in Example 75 Steps 2, 3 and 4. LC-MS Method 2, t R =1.981 min, m/z=455.2. 1 H NMR (CDCl 3 ) 1.50 (m, 3H), 2.29 (m, 3H), 2.34-2.50 (m, 1H), 2.80-3.18 (m, 5H), 5.60 (m, 1H), 6.85-7.09 (m, 6H), 7.21 (m, 2H), 7.30 (m, 2H), 8.05-8.35 (m, 2H).

›Example 135

3-(5-chloro-6-(2,4-difluorophenyl)pyridin-2-yl)-6-(2-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one

The title compound was prepared from 3-(6-(2,4-difluorophenyl)pyridin-2-yl)-6-(2-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one using a procedure analogous to that described in Example 133. LC-MS Method 3, t R =1.314 min, m/z=463. 1 H NMR (CDCl 3 ) 2.42-2.53 (m, 3H), 2.64-2.86 (m, 1H), 3.29-3.40 (m, 1H), 3.65 (m, 1H), 3.78 (m, 1H), 4.20 (m, 1H), 4.30-4.58 (m, 1H), 6.83-6.95 (m, 2H), 7.09 (m, 1H), 7.18 (m, 1H), 7.30-7.40 (m, 2H), 7.42-7.51 (m, 1H), 7.76 (m, 1H), 8.05 (m, 1H).

›Example 136

(R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one

The title compound was prepared from (R)-6-allyl-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one using a procedure analogous to that described in Example 78. LC-MS Method 1, t R =1.84 min, m/z=470. 1 H NMR (CDCl 3 ) 7.34-7.22 (m, 4H), 7.07-6.98 (m, 4H), 6.96-6.85 (m, 3H), 5.69 (m, 1H), 3.58 (t, 1H), 1.56 (d, 3H).

›Example 137

(6S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxypropyl)-1,3-oxazinan-2-one

Step 1. 2-((S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)acetaldehyde

To a stirred solution of crude (6S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(2,3-dihydroxypropyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (0.2726 g, 0.56 mmol) in acetone/water (4:1, 5 mL) was added NaIO 4 (0.3070 g, 1.43 mmol) at rt. The white suspension was stirred for 1 h and treated with EtOAc, dried (Na 2 SO 4 ), filtered, and concentrated under reduced pressure to give crude aldehyde (0.2669 g) as a foam. The crude aldehyde was directly used in the next step without further purification. LC-MS Method 1 t R =1.93 min, m/z 454 (MH + ).

Step 2. (6S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxypropyl)-1,3-oxazinan-2-one

To a stirred solution of 2-((S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)acetaldehyde in THF (3 mL) was added MeMgBr (1.4 M in toluene/THF, 3 mL, 4.2 mmol) at 0° C. The mixture was warmed up to rt and stirred for 1.5 h before quenching with satd aq NH 4 Cl (3 mL). The mixture was diluted with CH 2 Cl 2 and dried over Na 2 SO 4 . Removal of the solvent gave the crude alcohol as a mixture of diastereomers.

Isomer 1: (S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxypropyl)-1,3-oxazinan-2-one. LC-MS Method 1, t R =1.87 min, m/z=470. 1 H NMR (CD 3 OD) 7.34-7.16 (m, 5H), 7.03-6.87 (m, 6H), 5.47 (q, J=7.0 Hz, 1H), 3.47-3.43 (m, 1H), 3.07-3.02 (m, 1H), 2.63-2.58 (m, 1H), 2.35-2.28 (m, 1H), 2.19-2.12 (m, 1H), 2.01 (dd, J=14.3, 7.6 Hz, 1H), 1.86 (dd, J=14.3, 4.4 Hz, 1H), 1.46 (d, J=7.0 Hz, 3H), 1.04 (d, J=6.4 Hz, 3H).

Isomer 2: (S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxypropyl)-1,3-oxazinan-2-one. LC-MS Method 1, t R =1.88 min, m/z=470. 1 H NMR (CD 3 OD) 7.35-7.19 (m, 5H), 7.03-6.92 (m, 6H), 5.50 (q, J=7.0 Hz, 1H), 3.90-3.86 (m, 1H), 3.04-2.99 (m, 1H), 2.40-2.36 (m, 2H), 2.23-2.16 (m, 1H), 1.95 (dd, J=15.1, 7.5 Hz, 1H), 1.85 (dd, J=15.1, 3.4 Hz, 1H), 1.48 (d, J=7.0 Hz, 3H), 0.95 (d, J=6.4 Hz, 3H).

›Example 138

(S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-oxopropyl)-1,3-oxazinan-2-one

A mixture of the above alcohol (0.1830 g, 0.39 mmol) and Dess-Martin periodinane (0.1760 g, 0.41 mmol) in CH 2 Cl 2 was stirred at rt for 2 h. The mixture was treated with satd aq NaHCO 3 , diluted with EtOAc, and dried over Na 2 SO 4 . After the solvent was evaporated under reduced pressure, the residue was purified by preparative HPLC (SunFire™ Prep C 18 OBD™ 5 μm 19×50 mm column, 10%→90% CH 3 CN/H 2 O, 0.1% CF 3 COOH over 8 min and then 90% CH 3 CN/H 2 O, 0.1% CF 3 COOH over 2 min, flow rate 20 mL/min) to afford (S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-oxopropyl)-1,3-oxazinan-2-one. LC-MS Method 1 t R =1.94 min, m/z 468 (MH + ); 1 H NMR (400 MHz, CD 3 OD) δ 7.34-7.27 (m, 3H), 7.19 (d, J=7.6 Hz, 2H), 7.01-6.90 (m, 6H), 5.49 (q, J=7.0 Hz, 1H), 3.06-3.02 (m, 1H), 2.99 (s, 2H), 2.54-2.49 (m, 1H), 2.38-2.24 (m, 2H), 1.97 (s, 3H), 1.46 (d, J=7.3 Hz, 3H); 19 F NMR (376 MHz, CD 3 OD) δ −113.66 (m), −115.74 (m), −116.72 (m).

›Example 139

(S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-one

To a stirred solution of (S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-oxopropyl)-1,3-oxazinan-2-one (0.0303 g, 0.0648 mmol) in THF (5 mL) was added MeMgBr (1.4 M in toluene/THF, 1 mL, 1.4 mmol) at 0° C. The mixture was warmed to it and stirred for 1 h before quenching with satd aq NH 4 Cl (1 mL). The mixture was diluted with CH 2 Cl 2 and dried over Na 2 SO 4 . After the solvent was evaporated under reduced pressure, the residue was purified by preparative HPLC (SunFire™ Prep C 18 OBD™ 5 μm 19×50 mm column, 10%→90% CH 3 CN/H 2 O, 0.1% CF 3 COOH over 8 min and then 90% CH 3 CN/H 2 O, 0.1% CF 3 COOH over 2 min, flow rate 20 mL/min) to afford (S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-one. LC-MS Method 1 t R =1.91 min, m/z 484 (MH + ), 426; 1 H NMR (400 MHz, CD 3 OD) δ 7.36-7.20 (m, 5H), 7.02-6.92 (m, 6H), 5.52 (q, J=7.0 Hz, 1H), 3.05-3.00 (m, 1H), 2.49-2.35 (m, 2H), 2.22-2.15 (m, 1H), 2.06 (s, 2H), 1.48 (d, J=7.0 Hz, 3H), 1.19 (s, 3H), 0.90 (s, 3H); 19 F NMR (376 MHz, CD 3 OD) δ −113.78 (m), −115.82 (m), −117.50 (m).

›Example 140

(S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-methoxyethyl)-1,3-oxazinan-2-one

A mixture of NaH 6 mg, 0.21 mmol in THF (2 mL) was added dropwise to a mixture of (S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one (80 mg, 0.196 mmol) in THF (5 mL) at −20° C. The mixture was stirred at −20° C. for 1 h, then iodomethane (30 mg, 0.21 mmol) was added dropwise. The mixture was refluxed overnight. The reaction was quenched with water and the mixture was extracted with EtOAc (3×10 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give the residue, which was purified by preparative TLC to give (S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one (30 mg, 37%. 1 H NMR (400 MHz, CD 3 OD): δ=1.5 (m, 3H), 2.1 (m, 2H), 2.3 (m, 2H), 2.5 (m, 1H), 3.1 (m, 2H), 3.2 (s, 3H), 3.53 (m, 1H), 5.5 (m, 1H), 7.0 (m, 4H), 7.15 (m, 2H), 7.30 (m, 2H), 7.42 (m, 2H), 7.50 (m, 1H); LC-MS Method 3, t R =1.393 min, m/z=470.2.

›Example 141

1-(2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl)-3-methylurea

To a solution of methylamine (11 mg, 0.11 mmol) and CDI (20 mg, 0.13 mmol) in anhydrous CH 2 Cl 2 (3 mL) was added DIEA (130 mg, 1.00 mmol) at 0° C. under nitrogen. The resulting mixture was stirred at ambient temperature for 1 h. (R)-6-(2-aminoethyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (40 mg, 0.088 mmol) was added to the above mixture, and the mixture was stirred at rt overnight. The mixture was concentrated in vacuo to give a residue, which was purified by preparative HPLC to afford 1-(2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl)-3-methylurea (5 mg, 12%). 1 H NMR (CDCl 3 ): 1.56 (m, 3H), 2.10-2.30 (m, 4H), 2.35 (m, 1H), 2.75 (s, 3H), 3.01 (m, 1H), 3.09 (m, 1H), 3.30 (m, 1H), 5.69 (m, 1H), 6.86-6.96 (m, 2H), 7.08 (m, 4H), 7.25 (m, 2H), 7.30 (m, 3H).

›Example 142

4-((S)-1-((R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)benzoic acid

The title compound was prepared following a procedure analogous to that described in Example 94 Step 1. LC-MS Method 1 t R =1.18 min, m/z=424 (M+Na); 1 H NMR (CD 3 OD) 7.79 (d, 2H), 7.32 (m, 2H), 7.13-6.97 (m, 4H), 5.57 (q, 1H), 3.47 (t, 2H), 3.14 (m, 2H), 2.48 (d, 1H), 2.34 (td, 1H), 2.23 (m, 1H), 1.55 (d, 3H).

›Example 143

3-((S)-1-(4-bromophenyl)propyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one

The title compound was prepared from 6-allyl-3-((S)-1-(4-bromophenyl)propyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one following a procedure analogous to that described in Example 74. The isomers were separated to afford:

Isomer 1: (R)-3-((S)-1-(4-bromophenyl)propyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one. LC-MS Method 3 t R =1.206 min, m/z=435.9; 1 H NMR (CD 3 OD) 0.58 (m, 3H), 1.67-1.87 (m, 2H), 2.08 (m, 3H), 2.56 (m, 1H), 2.71-2.89 (m, 2H), 3.69 (m, 1H), 5.30 (m, 1H), 7.15-7.25 (m, 2H), 7.28 (m, 2H), 7.43 (m, 2H), 7.50 (m, 2H).

Isomer 2: (S)-3-((S)-1-(4-bromophenyl)propyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one. LC-MS Method 3 t R =1.287 min, m/z=460.1; 1 H NMR (CD 3 OD) 0.97 (m, 3H), 1.94-2.04 (m, 2H), 2.12 (m, 2H), 2.30 (m, 2H), 2.49 (m, 1H), 3.09 (m, 1H), 3.66 (m, 1H), 5.28 (m, 1H), 6.94 (m, 2H), 7.05 (m, 2H), 7.28 (m, 4H).

›Example 144

(6S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2,3-dihydroxypropyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one

The title compound was prepared from (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one following a procedure analogous to that described in Example 77. The two isomers were separated by chromatography.

Isomer 1: LC-MS Method 1 t R =1.55 min, m/z=452, 454; 1 H NMR (CD 3 OD) 7.27-7.24 (m, 2H), 7.21 (d, J=8.2 Hz, 2H), 7.04 (t, J=8.8 Hz, 2H), 6.80 (d, J=8.5 Hz, 2H), 5.42 (q, J=7.0 Hz, 1H), 3.75-3.71 (m, 1H), 3.22 (m, 2H), 3.04-2.99 (m, 1H), 2.44-2.39 (m, 2H), 2.21-2.14 (m, 1H), 2.00-1.95 (m, 1H), 1.87-1.81 (m, 1H), 1.44 (d, J=7.0 Hz, 3H).

Isomer 2: LC-MS Method 1 t R =1.52 min, m/z=452, 454; 1 H NMR (CD 3 OD) 7.34-7.30 (m, 2H), 7.19 (d, J=8.5 Hz, 2H), 7.04 (t, J=8.6 Hz, 2H), 6.75 (d, J=8.8 Hz, 2H), 5.40 (q, J=7.0 Hz, 1H), 3.38-3.27 (m, 3H), 3.08-3.04 (m, 1H), 2.67-2.61 (m, 1H), 2.34-2.27 (m, 1H), 2.23-2.15 (m, 1H), 2.03-1.91 (m, 2H), 1.43 (d, J=7.0 Hz, 3H).

›Example 145

3-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propanamide

The title compound was prepared from 3-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propanoic acid following a procedure analogous to that described in Example 76. LC-MS Method 3 t R =1.212 min, m/z=483.1; 1 H NMR (CD 3 OD) 1.50 (m, 3H), 1.92-2.08 (m, 1H), 2.10-2.39 (m, 5H), 2.43 (m, 1H), 5.63 (m, 1H), 5.85 (s, 1H), 6.02 (s, 1H), 6.84 (m, 2H), 6.98 (m, 4H), 7.20 (m, 2H), 7.26 (m, 3H).

›Example 146

3-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)-N-methylpropanamide

The title compound was prepared from 3-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propanoic acid following a procedure analogous to that described in Example 76 using methylamine in place of ammonia. LC-MS Method 3 t R =1.249 min, m/z=497.2; 1 H NMR (CD 3 OD) 1.51 (m, 3H), 1.97 (s, 1H), 2.07-2.31 (m, 6H), 2.64-2.74 (s, 3H), 2.94 (d, 1H), 5.62 (m, 1H), 6.13 (s, 1H), 6.79-6.89 (m, 2H), 6.97 (m, 4H), 7.15 (s, 2H), 7.23 (m, 3H).

›Example 147

N-(2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl)acetamide

The title compound was prepared from (R)-6-(2-aminoethyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one following a procedure analogous to that described in Example 98. LC-MS Method 3 t R =1.252 min, m/z=497.1; 1 H NMR (CD 3 OD) 1.57 (m, 3H), 1.80-1.96 (s, 3H), 2.13 (m, 2H), 2.23 (s, 2H), 2.35 (m, 1H), 2.99 (m, 1H), 3.08 (m, 1H), 3.40 (m, 1H), 5.68 (m, 1H), 6.26 (s, 1H), 6.90 (m, 2H), 7.04 (m, 4H), 7.22-7.33 (m, 6H).

›Example 148

2-((S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl methylcarbamate

›Step 1

A solution of 4-nitrophenyl chloroformate (133 mg, 0.66 mmol) in dichloromethane (1 mL) was added to a solution of (S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one (100 mg, 0.22 mmol) and pyridine (608 mg, 7.7 mmol) in dichloromethane (2.8 mL). The mixture was stirred at it overnight. The reaction was quenched with 1 N HCl (7 mL), and the mixture was extracted with EtOAc (3×10 mL). The combined organic layer was washed with brine, dried and concentrated to give 2-((S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl 4-nitrophenyl carbonate (70 mg, crude), which was used for the next step without purification.

›Step 2

Methylamine (15 mg, 0.22 mmol) and TEA (2 mL) was added to a solution of 2-((S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl 4-nitrophenyl carbonate (70 mg, crude) in 8 mL of THF. The mixture was stirred at rt overnight. The reaction was quenched with saturated NH 4 Cl. The mixture was extracted with EtOAc for 3 times, washed with brine, dried over anhydrous Na 2 SO 4 and concentrated to give the residue, which was purified by preparative HPLC to give 2-((S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl methylcarbamate (5 mg, 9%). 1 H NMR (CDCl 3 ): 1.55 (m, 3H), 2.36 (m, 5H), 2.74 (m, 3H), 2.99 (m, 1H), 4.09 (m, 2H), 5.71 (m, 1H), 6.92 (m, 2H), 7.04 (m, 4H), 7.33 (m, 5H). LC-MS Method 3 t R =1.32 min, m/z=513, 535.

›Examples4

›Example 149

(6S)-6-(2-(aminosulfonylamino)ethyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one

A mixture of (R)-6-(2-aminoethyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluoro phenyl)-1,3-oxazinan-2-one (40 mg, 0.09 mmol) and sulfamide (44 mg, 0.45 mmol) in 1,4-dioxane (10 mL) was heated to reflux overnight. When the reaction was over, the solvent was removed to give the residue, which was purified by preparative HPLC to give the desired product (12 mg, 25%). 1 H NMR (CDCl 3 ): 1.54 (m, 3H), 2.26 (m, 5H), 3.08 (m, 3H), 4.56 (s, 2H), 5.67 (m, 1H), 6.89 (m, 2H), 7.05 (m, 4H), 7.28 (m, 5H). LC-MS Method 3 t R =1.24 min, m/z=534.

›Example 150

2-((S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl sulfamate

To a solution of chlorosulfonyl isocyanate (64 mg, 0.45 mmol) in MeCN (2 mL) was added dropwise a solution of formic acid (20 mg, 0.45 mmol) in MeCN (1 mL) at 0° C. After stirring at rt for 3 h, the reaction mixture was cooled to 0° C. A solution of (S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxy ethyl)-1,3-oxazinan-2-one (40 mg, 0.09 mmol) and DIEA (58 mg, 0.45 mmol) in MeCN (1 mL) was added, and the mixture was stirred at rt overnight. The mixture was concentrated, and the residue was dissolved in EtOAc (50 mL). The mixture was washed with water, 2 N aq HCl and brine, dried over anhydrous sodium sulfate and concentrated to give the residue, which was purified by preparative HPLC to give 2-((S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethylsulfamate (6 mg, 12%). 1 H NMR (CDCl 3 ): 1.49 (m, 3H), 2.35 (m, 5H), 2.92 (m, 1H), 4.02 (m, 1H), 4.29 (m, 1H), 5.16 (s, 2H), 5.61 (m, 1H), 6.82 (m, 2H), 7.01 (m, 4H), 7.22 (m, 5H). LC-MS Method 3 t R =1.28 min, 535, 557.

›Example 151

2-((S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl dihydrogen phosphate

To a solution of (S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-2-hydroxyethyl)-1,3-oxazinan-2-one (500 mg, 1.1 mmol) and Et 3 N (222 mg, 2.2 mmol) in THF (20 mL) was added POCl 3 (340 mg, 2.2 mmol) in THF at 0° C. The mixture was quenched with NaHCO 3 and treated with 1 N HCl. The organic phase was separated, and concentrated to give the crude product, which was purified by preparative HPLC to give 2-((S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl dihydrogen phosphate (120 mg, 20%). 1 H NMR: (400 MHz, CD 3 OD): δ=1.55 (d, 3H), 2.30 (m, 4H), 2.55 (m, 1H), 3.10 (m, 1H), 3.75 (m, 1H), 4.10 (m, 1H), 5.50 (m, 1H), 7.00 (m, 4H), 7.10 (m, 2H), 7.25 (m, 2H), 7.35 (m, 2H), 7.40 (m, 1H).

›Example 152

2-amino-N-(2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl)acetamide

›Step 1

A solution of (R)-6-(2-aminoethyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (100 mg, 0.22 mmol), 2-(tert-butoxy-carbonyl-amino)acetic acid (58 mg, 0.33 mmol), HOBt (60 mg, 0.44 mmol), EDC (87 mg, 0.44 mmol) and i-Pr 2 NEt (142 mg, 1.1 mmol) in CH 2 Cl 2 (5 mL) was stirred at rt overnight. After the solvents were evaporated, the crude product was purified by preparative TLC to give tert-butyl 2-(2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethylamino)-2-oxoethylcarbamate (98 mg, 74%).

›Step 2

A solution of tert-butyl 2-(2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethylamino)-2-oxoethylcarbamate (98 mg, 0.16 mmol) in TFA/CH 2 Cl 2 (20%, 5 mL) was stirred at 0° C. for 2 h. The solvent was evaporated to give the crude product, which was purified by preparative HPLC to afford 2-amino-N-(2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl)acetamide (50 mg, 60%). 1 H NMR (CDCl 3 ): 1.41-1.49 (d, 3H), 2.15-2.29 (m, 5H), 2.80-2.94 (m, 2H), 3.25-3.36 (m, 1H), 3.70-3.85 (m, 2H), 5.50 (m, 1H), 6.75-6.97 (m, 7H), 7.00-7.14 (m, 3H), 7.26-7.29 (m, 1H).

›Examples6

›Example 153

4-((S)-1-((R)-6-allyl-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)benzamide

4-((S)-1-((R)-6-allyl-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)benzoic acid (12 mg, 0.03 mmol), ammonia in methanol (c.a. 7N, 1 mL, excess), HATU (12 mg, 1.1 equiv.), and DIEPA (11 μL, 2 equiv.) were mixed in 4:1 CH 2 Cl 2 and DMF (2 mL). The mixture was stirred overnight at rt, diluted with EtOAc (5 mL), washed with 5% aq HCl (2×2 mL). The organic layer was concentrated and purified by prep HPLC to afford 4-((S)-1-((R)-6-allyl-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)benzamide (2 mg, 17.5%) product. LC-MS Method 1 t R =1.4 min, m/z=383 (M+1); 1 H NMR (CDCl 3 ) 7.55 (d, 2H), 7.25 (t, 2H), 7.03 (t, 2H), 6.94 (d, 2H), 6.03 (br d, 2H), 5.68 (m, 2H), 5.05 (dd, 2H), 2.95 (m, 1H), 1.54 (d, 3H).

›Example 154

(R)-6-(4-fluorophenyl)-3-((S)-1-(4-(hydroxymethyl)phenyl)ethyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one

Methyl 4-((S)-1-((R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)benzoate (10 mg, 0.024 mmol) was dissolved in dry THF (4 mL) and cooled to 0° C. LiAlH 4 (2 mg, excess) was added slowly. After 10 min, the mixture was warmed to rt and stirred for 2 h. LC-MS found reaction completed. The mixture was quenched with water, diluted with EtOAc (5 mL), washed with 1% aq HCl (2 mL). After concentration, the residue was purified by prep HPLC to afford (R)-6-(4-fluorophenyl)-3-((S)-1-(4-(hydroxymethyl)phenyl)ethyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (3.0 mg, 32%). LC-MS Method 1 t R =1.2 min, m/z=410 (M+Na); 1 H NMR (CDCl 3 ) 7.23 (m, 2H), 7.14 (d, 2H), 7.03 (q, 2H), 6.95 (t, 2H), 5.66 (m, 1H), 4.61 (s, 2H), 3.59 (t, 2H), 1.53 (d, 3H).

›Example 155

4-((S)-1-((R)-6-allyl-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)-N-methylbenzamide

The title compound was prepared following a procedure analogous to that described in Example 153, using methylamine in place of ammonia. LC-MS Method 1 t R =1.47 min, m/z=397 (M+1); 1 H NMR (CDCl 3 ) 7.49 (d, 2H), 7.24 (dd, 2H), 7.04 (t, 2H), 6.92 (d, 2H), 6.29 (br s, 1H), 5.65 (m, 2H), 5.06 (dd, 2H), 3.03 (s, 3H), 2.59 (m, 2H), 1.53 (d, 3H).

›Example 156

(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(2-hydroxypropan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one

Methyl 4-((S)-1-((R)-6-allyl-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)benzoate (34.5 mg, 0.087 mmol) and CuI (2 mg, cat. amount) were mixed with dry THF (3 mL). The mixture was degassed and refilled with N 2 gas for 3 times. The mixture was then cooled to −78° C. A solution of methyl lithium (1.0M in diethyl ether, 500 μL, excess) was added slowly. After 15 min, the mixture was warmed up to rt slowly and stirred overnight at rt. The mixture was quenched with satd aq NH 4 Cl (5 mL), diluted with EtOAc (8 mL), washed with 1% aq HCl (3 mL), brine (2 mL), and dried over Na 2 SO 4 . After filtration and concentration, the residue was purified by prep HPLC to afford (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(2-hydroxypropan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (7.1 mg, 21% yield). LC-MS Method 1 t R =1.65 min, m/z=398 (M+1); 1 H NMR (CDCl 3 ) 7.24-7.18 (m, 4H), 7.00 (q, 2H), 6.83 (dd, 2H), 5.63 (m, 2H), 5.03 (dd, 2H), 2.92 (m, 1H), 2.57 (m, 2H), 1.50 (d, 9H).

›Example 157

6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(thiophen-2-yl)-1,3-oxazinan-2-one

The title compound was prepared following a procedure analogous to that described in Example 95 using 3-chloro-1-(thiophen-2-yl)propan-1-one in place of 3-chloro-1-(4-fluorophenyl)propan-1-one. The diastereomers were separated by chromatography on silica gel.

Isomer 1: (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(thiophen-2-yl)-1,3-oxazinan-2-one (10 g, 32.6%). 1 H NMR (CD 3 OD): 1.52 (t, 3H), 2.25 (m, 1H), 240 (m, 1H), 2.58 (m, 1H), 2.68 (t, 2H), 3.14 (m, 1H), 5.19 (t, 2H), 5.48 (m, 1H), 5.70 (m, 1H), 6.86 (d, 3H), 6.98 (t, 1H), 7.28 (d, 2H), 741 (d, 1H). LC-MS Method 3 t R =1.33 min, m/z=406, 408.

Isomer 2: (S)-6-Allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(thiophen-2-yl)-1,3-oxazinan-2-one (10 g, 32.6%). 1 H NMR (CD 3 OD): 1.38 (t, 3H), 2.10 (m, 1H), 2.38 (m, 1H), 2.68 (m, 2H), 2.75 (m, 1H), 3.04 (m, 1H), 5.19 (t, 2H), 5.50 (m, 1H), 5.70 (m, 1H), 6.96 (d, 1H), 7.08 (t, 1H), 7.22 (d, 2H), 738 (d, 1H), 7.48 (d, 2H). LC-MS Method 3 t R =1.35 min, m/z=406, 408.

›Example 158

6-allyl-6-(4-fluorophenyl)-3-((1-phenylpiperidin-4-yl)methyl)-1,3-oxazinan-2-one

›Step 1

1-Chloro-3-(4-fluorophenyl)hex-5-en-3-ol (223 mg, 0.97 mmol), (1-phenylpiperidin-4-yl)methanamine (295 mg, 1.6 equiv.), potassium iodide (178 mg, 1.1 equiv.) and DIEPA (186 μL, 1.1 equiv.) were mixed with DMF (5 mL) and heated at 80° C. for overnight. The mixture was diluted with EtOAc (50 mL), washed by water (2×15 mL), brine (2×10 mL), and dried over Na 2 SO 4 . After filtration and concentration, the residue was purified by chromatography on a 12-g silica gel cartridge eluted with a 0˜20% methanol in CH 2 Cl 2 gradient to afford 3-(4-fluorophenyl)-1-((1-phenylpiperidin-4-yl)methylamino)hex-5-en-3-ol (245 mg. 66%).

›Step 2

3-(4-fluorophenyl)-1-((1-phenylpiperidin-4-yl)methylamino)hex-5-en-3-ol (120 mg, 0.314 mmol) was dissolved in THF (30 mL) and pyridine (c.a. 500 μL, excess). A solution of triphosgene (60 mg, excess) in THF (5 mL) was added slowly in 4 batches. After stirring 4 h at rt, DBU (94 μL, 2 equiv.) was added and the mixture was heated to reflux for overnight. There was still a lot of starting material on LC-MS spectra. The mixture was concentrated, redissolved in EtOAc (40 mL), washed with 5% aq HCl (2×8 mL), brine (8 mL), and dried over Na 2 SO 4 . After filtration and concentration, the residue was purified by prep HPLC to afford 6-allyl-6-(4-fluorophenyl)-3-((1-phenylpiperidin-4-yl)methyl)-1,3-oxazinan-2-one (17 mg, 13%). LC-MS Method 1 t R =1.32 min, m/z=409 (M+1); 1 H NMR (CD 3 OD) 7.62-7.53 (m, 4H), 7.39 (m, 2H), 7.13 (t, 2H), 5.67 (m, 1H), 5.04 (dd, 2H), 3.05 (m, 2H), 2.63 (d, 2H), 2.57 (d, 1H), 2.32 (m, 1H), 2.06 (m, 1H).

›Examples3

›Example 159

(S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared following a procedure analogous to that described in Example 74. 1 H NMR (CDCl 3 ): 1.53 (m, 3H), 2.29 (m, 5H), 2.91 (m, 1H), 3.56 (m, 1H), 3.75 (m, 1H), 6.56 (m, 1H), 6.93 (m, 2H), 7.06 (m, 2H), 7.35 (m, 7H), 7.43 (m, 2H). LC-MS Method 3 t R =1.23 min, m/z=420, 442.

›Example 160

6-allyl-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(thiophen-2-yl)-1,3-oxazinan-2-one

The two diastereomers of the title compound were prepared separately from the diastereomers of 6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(thiophen-2-yl)-1,3-oxazinan-2-one following a procedure analogous to that described in Example 111 using 4-fluorophenylboronic acid. The diastereomers were separated.

Isomer 1: 1 H NMR (CD 3 OD): 1.38 (t, 3H), 2.10 (m, 1H), 238 (m, 1H), 2.68 (m, 2H), 2.85 (m, 1H), 3.04 (m, 1H), 5.09 (t, 2H), 5.55-5.80 (m, 2H), 6.98 (d, 2H), 7.15 (t, 2H), 7.22-7.42 (m, 4H), 758 (m, 3H).

Isomer 2: 1 H NMR (CD 3 OD): 1.52-1.60 (d, 3H), 2.20-2.26 (m, 2H), 2.58-2.62 (m, 3H), 2.95-3.04 (m, 1H), 5.05-5.47 (m, 2H), 5.68-5.80 (m, 2H), 6.90 (m, 1H), 6.94 (m, 1H), 7.00-7.05 (m, 2H), 7.05-7.14 (m, 2H), 7.23 (m, 1H), 7.29-7.34 (m, 2H), 7.42-7.54 (m, 2H).

›Example 161

6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-4-methyl-1,3-oxazinan-2-one

›Step 1

To a solution of 1-bromo-4-fluorobenzene (28 g, 0.162 mol) in THF (90 mL) was added n-BuLi (70 mL, 2.5 M) at −78° C. and stirred for 1 h under nitrogen. Then to a premixed solution of CuCl (18 g, 0.16 mol) and LiCl (15 g, 0.354 mol) in THF (160 mL) at −78° C. was added the above solution quickly. The formed solution was stirred for 20 minutes, and was treated with crotonyl chloride (21 g, 0.176 mol). The resulting solution was stirred for 30 minutes. The mixture was quenched with aq NH 4 Cl, the organic phase was separated, concentrated to give the crude product which was purified by column chromatography to afford 1-(4-fluorophenyl)but-2-en-1-one (2.6 g, 10%). 1 H NMR (400 MHz, CDCl 3 ): δ=2.02 (d, 3H), 6.88 (m, 1H), 7.10 (m, 3H), 7.98 (m, 2H).

›Step 2

A solution of 1-(4-fluorophenyl)but-2-en-1-one (13 g, 79.2 mmol) in EtOH (150 mL) was added (S)-1-(4-bromophenyl)ethanamine (32 g, 158 mmol), and the resulting mixture was stirred overnight. The solvent was removed in vacuo to give the crude 3-((S)-1-(4-bromophenyl)ethylamino)-1-(4-fluorophenyl)butan-1-one which was used for the next step without purification.

›Step 3

A solution of 3-((S)-1-(4-bromophenyl)ethylamino)-1-(4-fluorophenyl)butan-1-one (28.8 g, 79.2 mmol) and K 2 CO 3 (100 g, 0.79 mol) in methylene chloride (1000 mL) was added methyl carbonochloridate (100 g, 0.72 mol) at 0° C. The formed mixture was stirred at rt overnight. The mixture was filtered and concentrated to give the crude product, which was purified by preparative HPLC to give methyl (S)-1-(4-bromophenyl)ethyl(4-(4-fluorophenyl)-4-oxobutan-2-yl)carbamate (7.5 g, 23%). 1 H NMR (400 MHz, CDCl 3 ): δ=1.28 (d, 3H), 1.52 (d, 3H), 2.59 (m, 1H), 3.72 (m, 5H), 5.43 (m, 1H), 6.98 (m, 3H), 7.16 (m, 2H), 7.31 (m, 2H), 7.60 (m, 2H).

›Step 4

To a solution of methyl (S)-1-(4-bromophenyl)ethyl((S)-4-(4-fluorophenyl)-4-oxobutan-yl)carbamate (0.5 g, 1.18 mmol) in THF (10 mL) was added allylmagnesium bromide (3 mL, 1 M) under nitrogen at −78° C. The mixture was stirred overnight at rt. The mixture was quenched by water and extracted with EtOAc, the combined organic phase was concentrated to give the crude methyl (S)-1-(4-bromophenyl)ethyl(4-(4-fluorophenyl)-4-hydroxyhept-6-en-2-yl)carbamate, which was used for the next step without purification.

›Step 5

To a solution of methyl (S)-1-(4-bromophenyl)ethyl(4-(4-fluorophenyl)-4-hydroxyhept-6-en-2-yl)carbamate (20 mg, 0.043 mmol) was added NaH at 0° C. The mixture was stirred and heated to reflux for 1 h. The mixture was cooled to rt and quenched with water. The organic phase was extracted by EtOAc and concentrated to give the crude product which was purified by preparative TLC to give three isomers of 6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-4-methyl-1,3-oxazinan-2-one.

Isomer 1: 1 H NMR (400 MHz, CDCl 3 ): δ=0.78 (d, 3H), 1.56 (d, 3H), 2.04 (m, 1H), 2.13 (m, 1H), 2.50 (m, 2H), 3.25 (m, 1H), 4.94 (m, 1H), 5.03 (m, 1H), 5.38 (m, 1H), 5.60 (m, 1H), 6.96 (m, 2H), 7.18 (m, 2H), 7.30 (m, 2H), 7.43 (m, 2H).

Isomer 2: 1 H NMR (400 MHz, CDCl 3 ): δ=1.02 (d, 3H), 1.43 (d, 3H), 2.00 (m, 1H), 2.50 (m, 3H), 3.32 (m, 1H), 4.76 (m, 1H), 4.95-5.08 (m, 2H), 5.68 (m, 1H), 6.88 (m, 2H), 7.00 (m, 2H), 7.18 (m, 2H), 7.28 (m, 2H).

Isomer 3: 1 H NMR (400 MHz, CDCl 3 ): δ=0.52 (d, 3H), 1.62 (d, 3H), 2.08 (m, 1H), 2.36 (m, 1H), 2.52 (d, 2H), 3.65 (m, 1H), 4.90 (m, 1H), 5.00 (m, 1H), 5.29 (m, 1H), 5.53 (m, 1H), 6.96 (m, 2H), 7.20 (m, 2H), 7.30 (m, 2H), 7.35 (m, 2H).

›Examples17

›Example 162

(R)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared following a procedure analogous to that described in Example 78 starting with (R)-6-allyl-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-phenyl-1,3-oxazinan-2-one. 1 H NMR (CDCl 3 ): δ=1.34 (m, 1H), 1.48 (m, 3H), 1.63 (m, 1H), 1.91 (m, 2H), 2.12 (m, 1H), 2.22 (m, 2H), 2.83 (m, 1H), 3.50 (m, 2H), 5.61 (m, 1H), 6.87 (m, 2H), 7.02 (m, 2H), 7.25 (m, 5H), 7.29 (m, 2H), 7.37 (m, 2H). LC-MS Method 3 tR=1.28 min, m/z=434, 456.

›Example 163

3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-4-methyl-1,3-oxazinan-2-one

Isomer 1 of the title compound was prepared from 6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-4-methyl-1,3-oxazinan-2-one isomer 1 following a procedure analogous to that described in Example 74. 1 H NMR (400 MHz, DCCl 3 ): δ=0.78 (d, 3H), 1.59 (d, 3H), 2.00-2.06 (m, 4H), 3.30 (m, 1H), 3.40 (m, 1H), 3.61 (m, 1H), 5.40 (m, 1H), 7.00 (m, 2H), 7.18 (m, 2H), 7.28 (m, 2H), 7.42 (m, 2H).

Isomer 2 of the title compound was prepared from 6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-4-methyl-1,3-oxazinan-2-one isomer 2 following a procedure analogous to that described in Example 74.

Isomer 3 of the title compound was prepared from 6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-4-methyl-1,3-oxazinan-2-one isomer 3 following a procedure analogous to that described in Example 74.

›Example 164

(S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared following a procedure analogous to that described in Example 74. 1 H NMR (CDCl 3 ): 1.49 (m, 3H), 2.14-2.32 (m, 2H), 2.28 (m, 3H), 2.89 (m, 1H), 3.50 (m, 0.6H), 3.70 (m, 0.6H), 4.18 (m, 0.4H), 4.44 (m, 0.4H), 5.61 (m, 1H), 6.76-6.89 (m, 4H), 7.18 (m, 2H), 7.20-7.30 (m, 6H). LC-MS Method 3 t R =1.25 min, m/z=438, 460.

›Example 165

(S)-6-allyl-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(thiophen-2-yl)-1,3-oxazinan-2-one

The title compound was prepared following a procedure analogous to that described in Example 111. 1 H NMR (CD 3 OD): 1.42 (t, 3H), 2.16 (m, 1H), 238 (m, 1H), 2.68 (m, 2H), 2.80 (m, 1H), 3.04 (m, 1H), 5.09 (t, 2H), 5.58-5.70 (m, 2H), 6.98 (d, 2H), 7.15 (t, 2H), 7.30 (m, 1H), 7.42 (m, 3H), 748 (m, 3H). LC-MS Method 4 tR=1.1 min, m/z=440, 462.

›Example 166

(S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(3-hydroxypropyl)-6-(thiophen-2-yl)-1,3-oxazinan-2-one

The title compound was prepared following a procedure analogous to that described in Example 78 starting with (S)-6-allyl-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(thiophen-2-yl)-1,3-oxazinan-2-one. 1 H NMR (CDCl 3 ): 1.32 (m, 3H), 1.45 (m, 1H), 1.73 (m, 2H), 1.89-2.18 (m, 4H), 2.72 (m, 1H), 2.86 (m, 1H), 3.52 (m, 2H), 5.75 (m, 1H), 6.90 (m, 2H), 7.15 (m, 2H), 7.25 (m, 4H), 748 (m, 3H).

›Example 167

(6R)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(2-hydroxypropyl)-6-(thiophen-2-yl)-1,3-oxazinan-2-one

The title compound was isolated as a byproduct following a procedure analogous to that described in Example 78 starting with (S)-6-allyl-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(thiophen-2-yl)-1,3-oxazinan-2-one. The alcohol epimers were separated by preparative TLC.

Isomer 1: 1 H NMR (CDCl 3 ): 1.18 (m, 3H), 1.30 (m, 3H), 1.90-2.18 (m, 3H), 2.28 (m, 1H), 2.63-2.96 (m, 2H), 4.04 (m, 1H), 4.56 (m, 1H), 5.72 (m, 1H), 6.90 (m, 2H), 7.05 (m, 2H), 7.25 (m, 4H), 748 (m, 3H).

Isomer 2: 1 H NMR (CDCl 3 ): 1.14 (m, 3H), 1.34 (m, 3H), 1.96 (m, 1H), 2.05-2.20 (m, 3H), 2.68-2.96 (m, 2H), 3.86-4.02 (m, 1H), 4.60 (s, 1H), 5.74 (m, 1H), 6.90 (m, 2H), 7.05 (m, 2H), 7.25 (m, 3H), 748 (m, 4H).

›Example 168

(6S)-6-(2,3-dihydroxypropyl)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared following a procedure analogous to that described in Example 52 starting with (S)-6-allyl-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(thiophen-2-yl)-1,3-oxazinan-2-one. The secondary alcohol epimers were separated.

Isomer 1: 1 H NMR (CDCl 3 ): 1.48 (m, 3H), 1.95 (m, 1H), 2.09 (m, 1H), 2.35 (m, 5H), 2.87 (m, 1H), 3.41 (m, 1H), 3.52 (m, 1H), 3.73 (m, 1H), 5.61 (m, 1H), 6.84 (m, 2H), 7.03 (m, 2H), 7.19 (m, 3H), 7.29 (m, 5H), 7.37 (m, 2H).

Isomer 2: 1 H NMR (CDCl 3 ): 1.49 (m, 3H), 1.89 (m, 1H), 2.08 (m, 1H), 2.25 (m, 3H), 2.82 (m, 1H), 3.27 (m, 1H), 3.38 (m, 1H), 3.77 (m, 1H), 5.61 (m, 1H), 6.89 (m, 2H), 7.03 (m, 2H), 7.19 (m, 1H), 7.25 (m, 6H), 7.43 (m, 2H).

›Example 169

(R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from (R)-6-allyl-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-phenyl-1,3-oxazinan-2-one following a procedure analogous to that described in Example 78. 1 H NMR (CDCl 3 ): 1.32 (m, 1H), 1.49 (m, 3H), 1.68 (m, 1H), 1.90 (m, 2H), 2.14 (m, 1H), 2.28 (m, 2H), 2.88 (m, 1H), 3.50 (m, 2H), 5.53 (m, 1H), 6.77-6.90 (m, 4H), 7.15 (m, 2H), 7.26 (m, 6H).

›Example 170

(6S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(2-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was isolated as a byproduct following a procedure analogous to that described in Example 78. 1 H NMR (CDCl 3 ): 0.97-1.13 (m, 3H), 1.49 (m, 3H), 1.85-1.96 (m, 1H), 2.04 (m, 1H), 2.17-2.94 (m, 3H), 2.86 (m, 1H), 3.79-4.00 (m, 1H), 5.52 (m, 1H), 6.79-6.92 (m, 4H), 7.16 (m, 2H), 7.21-7.35 (m, 5H).

›Example 171

3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(3-hydroxypropyl)-6-(thiophen-2-yl)-1,3-oxazinan-2-one

Isomer 1: (R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(3-hydroxypropyl)-6-(thiophen-2-yl)-1,3-oxazinan-2-one was prepared following a procedure analogous to that described in Example 78. 1 H NMR (CD 3 OD): 1.40 (m, 1H), 1.50 (m, 3H), 1.65 (m, 1H), 2.00 (m, 2H), 2.35 (m, 1H), 2.40 (m, 1H), 2.60 (m, 1H), 3.15 (m, 1H), 3.50 (m, 2H), 5.60 (m, 1H), 6.90 (m, 1H), 7.00 (m, 3H), 7.10 (m, 2H), 7.40 (m, 4H). LC-MS Method 3 t R =1.42 min, m/z=458, 480.

Isomer 2: (S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(3-hydroxypropyl)-6-(thiophen-2-yl)-1,3-oxazinan-2-one was prepared following a procedure analogous to that described in Example 78. 1 H NMR (CDCl 3 ) 1.38 (m, 4H), 1.64 (m, 1H), 1.98 (m, 2H), 2.13 (m, 1H), 2.35 (m, 1H), 2.86 (m, 1H), 3.02 (m, 1H), 3.45 (m, 2H), 5.62 (m, 1H), 6.98 (m, 4H), 7.34 (m, 3H), 7.42 (m, 3H).

›Example 172

To a solution of 3-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl) propanamide (80 mg, 0.166 mmol) in anhydrous CH 2 Cl 2 (5 mL) and DIEA (0.5 mL) was added TFAA (72 mg, 0.332 mmol) at 0° C. The mixture was stirred for 2 h. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC to afford 3-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl) propanenitrile (40 mg, yield 54%). 1 H NMR (CDCl 3 ): 1.98-2.18 (m, 1H), 2.11-2.40 (m, 4H), 2.51-2.60 (m, 1H), 2.92 (m, 1H), 5.53 (m, 1H), 6.80-6.90 (m, 2H), 6.94 (m, 2H), 7.01 (m, 2H), 7.19 (m, 2H), 7.21 (m, 2H). LC-MS Method 3 t R =1.22 min, m/z=488.

›Example 173

(6S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(2,3-dihydroxypropyl)-6-phenyl-1,3-oxazinan-2-one

A solution of (R)-6-allyl-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-phenyl-1,3-oxazinan-2-one (200 mg, 0.46 mmol) in tert-BuOH (7 mL) was added dropwise to an ice-cooled solution of AD-mix-β (800 mg) in H 2 O (7 mL). The reaction mixture was stirred for 3 days. Na 2 SO 3 was added, and the mixture was stirred at rt for 1 h. The mixture was extracted with EtOAc. The organic phase was dried over Na 2 SO 4 , filtered and concentrated to give the residue, which was purified by preparative HPLC to afford two isomers.

Isomer 1: (20 mg, 9%). 1 H NMR (CDCl 3 ): 1.48 (m, 3H), 1.96 (m, 1H), 2.08 (m, 1H), 2.15-2.42 (m, 5H), 2.89 (m, 1H), 3.41 (m, 1H), 3.55 (m, 1H), 3.74 (m, 1H), 5.60 (m, 1H), 6.79-6.90 (m, 4H), 7.17 (m, 2H), 7.20-7.35 (m, 6H).

Isomer 2: (13 mg, 7%). 1 H NMR (CDCl 3 ): 1.49 (m, 3H), 1.85-1.95 (m, 1H), 2.10 (m, 2H), 2.30 (m, 2H), 2.71-2.96 (m, 1H), 3.21-3.45 (m, 2H), 3.79 (m, 1H), 5.61 (m, 1H), 6.78-6.94 (m, 4H), 7.19 (m, 2H), 7.20-7.48 (m, 6H).

›Example 174

2-((S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)acetic acid

The title compound was prepared following a procedure analogous to that described in Example 70. 1 H NMR (CDCl 3 ): 1.56 (m, 3H), 2.39 (m, 1H), 2.55 (m, 1H), 2.69 (m, 1H), 2.82-2.94 (m, 2H), 3.14 (m, 1H), 5.06 (m, 1H), 6.93-7.11 (m, 6H), 7.26 (m, 2H), 7.50 (m, 3H). LC-MS

›Example 175

3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)propyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one

To a solution of (S)-3-((S)-1-(4-bromophenyl)propyl)-6-(4-fluorophenyl)-6-(2-hydroxy ethyl)-1,3-oxazinan-2-one (60 mg, 0.14 mmol), 2,4-difluorophenylboronic acid (26 mg, 0.17 mmol) and Pd(PPh 3 ) 4 (16 mg, 0.01 mmol) in dioxane (5 mL) was added a solution of CsCO 3 (2 M, 1 mL) at 0° C. Then the reaction mixture was refluxed overnight under nitrogen. The reaction mixture was washed with water and then extract with CH 2 Cl 2 twice. The combined organic phases were dried over Na 2 SO 4 , filtered and concentrated to give the residue, which was purified by preparative HPLC to afford (S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)propyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one (17 mg, 26%). 1 H NMR (CD 3 OD): 0.96 (m, 3H), 2.01 (m, 2H), 2.12 (m, 2H), 2.30 (m, 2H), 2.48 (m, 1H), 3.10 (m, 1H), 3.33 (m, 1H), 3.65 (m, 1H), 5.38 (m, 1H), 7.02 (m, 4H), 7.08 (m, 2H), 7.28 (m, 4H), 7.42 (m, 1H). 443-114-3.

(R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)propyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one was prepared from (R)-3-((S)-1-(4-bromophenyl)propyl)-6-(4-fluorophenyl)-6-(2-hydroxy ethyl)-1,3-oxazinan-2-one following a procedure analogous to that described immediately above. 1 H NMR (CD 3 OD): 0.62 (m, 3H), 1.76 (m, 1H), 1.92 (m, 1H), 2.12 (m, 3H), 2.56 (m, 1H), 2.78 (m, 1H), 2.89 (m, 1H), 3.33 (m, 1H), 3.71 (m, 1H), 5.38 (m, 1H), 7.05 (m, 2H), 7.16 (m, 2H), 7.44 (m, 7H).

›Example 176

(R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(2-(dimethylamino)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one

(R)-6-(2-aminoethyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (50 mg, 0.11 mmol) was added to form acid, followed by the addition of 30% aqueous solution of formaldehyde at 0° C. The solution was then heated to 90° C. and stirred for 24 h. After leaving to cool, 0.1 mol of 1 M HCl was added and the mixture was extracted with dichloromethane for 3 times. Aqueous NaOH solution (20%) was then added to the thus purified aqueous phase until the pH was basic. The alkaline water was extracted with dichloromethane. The organic solution was dried over Na 2 SO 4 , filtered off and evaporated under reduced pressure to give the crude product, which was purified by preparative TLC and separated by preparative HPLC to give (R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(2-(dimethylamino)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (2.78 mg, 5%). 1 H NMR (CDCl 3 ): 6.60 (s, 1H), 7.35 (d, 1H), 7.70 (m, 1H), 7.82 (m, 1H), 7.95 (d, 1H), 8.60 (d, 1H).

›Example 177

3-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propanoic acid

The title compound was prepared following a procedure analogous to that described in Example 70. 1 H NMR (CDCl 3 ): 1.56 (m, 3H), 2.05 (m, 1H), 2.10-2.28 (m, 3H), 2.29-2.50 (m, 3H), 3.12 (m, 1H), 5.09 (m, 1H), 6.98-7.10 (m, 6H), 7.29 (m, 4H), 7.39 (m, 1H). LC-MS Method 3 t R =1.27 min, m/z=484, 506.

›Example 178

(R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-(2-hydroxyethylamino)ethyl)-1,3-oxazinan-2-one

›Step 1

To a solution of (S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one (50 mg, 0.11 mmol) in dry CH 2 Cl 2 (2 mL) was added Et 3 N (33 mg, 0.33 mmol) at 0˜−5° C. Then a solution of MsCl (12 mg, 0.13 mmol) in dry CH 2 Cl 2 (1 mL) was added dropwise at the same temperature. After addition, the mixture was allowed to warm to rt gradually. When the reaction was over, water (10 mL) was added. The layers were separated, and the aqueous layer was extracted with CH 2 Cl 2 (3×10 mL). The combined organic layers was washed with 10% citric acid, aqueous NaHCO 3 and brine respectively, dried over Na 2 SO 4 , filtered and concentrated to give 2-((S)-3-((S)-1-(2′,4′-difluorobi-phenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl methanesulfonate (58 mg, crude), which was used for the next step without purification.

›Step 2

To a solution of 2-((S)-3-((S)-1-(2′,4′-difluorobi-phenyl-4-yl)ethyl)-6-(4-fluorophenyl)2-oxo 1,3-oxazinan-6-yl)ethyl methanesulfonate (58 mg, 0.11 mmol) in anhydrous MeOH was added 2-amino-ethanol (54 mg, 0.88 mmol). Then the reaction mixture was refluxed overnight. When the reaction was over, solvent was removed in vacuo. The residue was purified by preparative HPLC to give (R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-(2-hydroxyethylamino)ethyl)-1,3-oxazinan-2-one (2 mg, 3%). 1 H NMR (CDCl 3 ): 1.53 (m, 3H), 2.25-2.36 (m, 4H), 2.51 (m, 1H), 2.87-3.24 (m, 5H), 3.75-4.02 (m, 2H), 5.60 (m, 1H), 6.85-6.96 (m, 2H), 6.96-7.10 (m, 4H), 7.22 (m, 2H), 7.38 (m, 4H).

›Examples5

›Example 179

N-(2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl)-2-hydroxyacetamide

To a solution of (R)-6-(2-aminoethyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluoro-phenyl)-1,3-oxazinan-2-one stirred in anhydrous CH 2 Cl 2 (5 ml) was added HOBT (36 mg, 0.264 mmol), EDCl (52 mg, 0.264 mmol), DIEA (0.5 ml) and hydroxy-acetic acid (50.1 mg, 0.66 mmol) at 0° C. under N 2 atmosphere. The solution was stirred at rt overnight. Then the solvent was removed under reduced pressure to give the residue, which was purified by preparative HPLC to afford N-(2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl)-2-hydroxyacetamide (19.2 mg, 28.6%). 1 H NMR (CDCl 3 ): 1.49-1.50 (d, 3H), 2.01-2.13 (m, 1H), 2.14-2.15 (m, 3H), 2.17 (m, 1H), 2.97-2.98 (m, 2H), 3.46-3.52 (m, 4H), 4.01-4.02 (m, 2H), 5.60-5.61 (m, 1H), 6.82-6.88 (m, 2H), 6.98-7.04 (m, 3H), 7.17 (s, 1H), 7.19-7.22 (m, 3H), 7.25-7.27 (m, 3H).

›Example 180

Methyl 2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethylcarbamate

To a solution of (R)-6-(2-aminoethyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (40 mg, 0.088 mmol) and DMAP (4 mg, 10%) in dry CH 2 Cl 2 (3 mL), was added Et 3 N (27 mg, 0.264 mmol). The resulting mixture was cooled to 0-5° C. under ice-water bath, and a solution of methyl chloroformate (41 mg, 0.44 mmol) in dry CH 2 Cl 2 (1 mL) was added dropwise. After addition, the reaction mixture was stirred for 1-2 h at 0˜5° C. After the starting material was disappeared, water (5 mL) was added. The layers were separated, and the aqueous layer was extracted with CH 2 Cl 2 (3×5 mL). The combined organic layers were washed with 10% citric acid (2×10 mL) and brine, dried over Na 2 SO 4 , filtered and concentrated to give the residue, which was purified by preparative HPLC to afford methyl 2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethylcarbamate (10 mg, 22%). 1 H NMR (CDCl 3 ): 1.50 (m, 3H), 2.06 (m, 2H), 2.10-2.32 (m, 4H), 3.10 (m, 1H), 3.05-3.20 (m, 2H), 3.55 (s, 3H), 4.88 (s, 1H), 5.63 (m, 1H), 6.80-6.90 (m, 2H), 6.92-7.01 (m, 4H), 7.21 (m, 1H), 7.25 (m, 4H).

›Example 181

(R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-morpholinoethyl)-1,3-oxazinan-2-one

The title compound was prepared following a procedure analogous to that described in Example 178 using morpholine in place of ethanolamine. 1 H NMR (CDCl 3 ): 1.50 (m, 3H), 2.06-2.29 (m, 3H), 2.30-2.51 (m, 3H), 2.61-2.82 (m, 3H), 2.90 (m, 1H), 3.10-3.29 (m, 2H), 3.49 (m, 1H), 3.79-3.98 (m, 4H), 5.62 (m, 2H), 6.80-6.89 (m, 2H), 7.00 (m, 4H), 7.16 (m, 2H), 7.23 (m, 3H).

›Example 182

1-(2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl)-3-ethylurea

The title compound was prepared following a procedure analogous to that described in Example 141. 1 H NMR (400 MHz, CDCl 3 ): 1.46 (t, 3H), 1.56 (m, 3H), 2.14 (m, 2H), 2.25 (m, 2H), 2.37 (m, 1H), 2.98 (m, 3H), 3.14 (q, 2H), 3.30 (m, 2H), 5.67 (m, 1H), 6.87 (m, 2H), 7.04 (m, 4H), 7.21 (m, 2H), 7.30 (m, 3H).

›Example 183

2-cyano-1-(2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl)-3-methylguanidine

›Step 1

A mixture of (R)-6-(2-aminoethyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluoro phenyl)-1,3-oxazinan-2-one (40 mg, 0.09 mmol) and dimethyl cyanocarbonimidodithioate (40 mg, 0.27 mmol) in acetonitrile (4 mL) was heated to reflux overnight. The solvent was removed to give methyl N′-cyano-N-(2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl)carbamimidothioate (50 mg, crude), which was used for the next step without purification.

›Step 2

A mixture of (Z)-methyl N′-cyano-N-(2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-luorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl)carbamimidothioate (50 mg, crude) in the solution of methylamine in ethanol (10 mL) was heated to reflux overnight. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC to give 2-cyano-1-(2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl)-3-methylguanidine (10 mg, 21%). 1 H NMR (CDCl 3 ): 1.49 (m, 3H), 2.15 (m, 4H), 2.26 (m, 2H), 2.71 (s, 3H), 2.95 (m, 1H), 3.08 (s, 1H), 3.28 (s, 1H), 5.60 (m, 2H), 6.85 (m, 2H), 7.01 (m, 4H), 7.19 (m, 2H), 7.23 (m, 3H). LC-MS Method 3 t R =1.28 min, m/z=536.

›Examples3

›Example 184

3-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)-N-(methylsulfonyl)propanamide

A mixture of 3-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propanoic acid (60 mg, 0.13 mmol), methanesulfonamide (24 mg, 0.26 mmol), HOBt (53 mg, 0.39 mmol), EDCl (75 mg, 0.39 mmol) and DIEA (1 mL) in CH 2 Cl 2 was stirred at rt overnight. The solvent was removed to give the crude product. It was purified by preparative HPLC to give 3-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)-N-(methylsulfonyl)propanamide (7 mg, 10%). 1 H NMR (CDCl 3 ): 1.50 (m, 3H), 2.21 (m, 6H), 2.54 (m, 1H), 2.93 (m, 1H), 3.15 (s, 3H), 5.59 (m, 1H), 6.83 (m, 2H), 6.98 (m, 4H), 7.18 (m, 2H), 7.24 (m, 3H), 9.58 (s, 1H). LC-MS Method 3, t R =1.26 min, m/z=561.

›Example 185

N-(3-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propyl)methanesulfonamide

The title compound was prepared from (R)-6-(3-aminopropyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one following a procedure analogous to that described in Example 99. LC-MS Method 3 t R =1.47 min, m/z=547; 1 H NMR (CDCl 3 ) 1.44-1.53 (d, 3H), 1.59-1.68 (m, 1H), 2.17-2.20 (m, 1H), 2.22-2.33 (m, 2H), 2.76 (s, 3H), 2.89-2.97 (m, 1H), 2.09-3.05 (m, 2H), 4.18-4.32 (m, 1H), 5.58-5.67 (m, 1H), 6.76-6.89 (m, 2H), 6.91-7.03 (m, 4H), 7.13-7.18 (m, 2H), 7.22-7.27 (m, 3H).

›Example 186

6-(3-hydroxypropyl)-3-phenethyl-6-phenyl-1,3-oxazinan-2-one

›Step 1

A 1000-mL flask was charged with anhydrous CeCl 3 (50 g, 0.2 mol) and THF (360 mL). The mixture was vigorously stirred for 3.5 h at rt. The suspension was then cooled to −78° C., and a solution of allylmagnesium bromide (1.0 M in THF, 200 mL) was added. After stirring for 2 h at −78° C., a solution of 3-chloro-1-phenyl-propan-1-one (25 g, 149 mmol) in THF (269 mL) was added dropwise. The reaction mixture was allowed to slowly warm to rt while stirring overnight. The reaction was then quenched with satd aq NaHCO 3 , extracted with EtOAc, and dried over Na 2 SO 4 . After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc to afford of 1-chloro-3-phenyl-hex-5-en-3-ol (25 g, 82%) as an oil. 1 H NMR (CDCl 3 ): 2.30 (m, 2H), 2.51 (m, 1H), 2.72 (m, 1H), 3.20 (m, 1H), 3.54 (m, 1H), 5.16 (m, 2H), 5.51 (m, 1H), 7.24 (m, 1H), 7.35 (m, 4H).

›Step 2

A mixture of 1-chloro-3-phenyl-hex-5-en-3-ol (500 mg, 2.38 mmol), phenethylamine (348 mg, 2.862.24 mmol), and K 2 CO 3 (643 mg, 4.76 mmol) in anhydrous CH 3 CN (10 mL) were stirred at rt under N 2 . Then the solution was refluxing at 80-90° C. overnight. The solid was filtered, and the filtrate was condensed under reduced pressure to give the residue, which was purified by preparative TLC to afford 1-phenethylamino-3-phenyl-hex-5-en-3-ol (320 mg, 45%). 1 H NMR (CDCl 3 ): 2.07-2.15 (m, 1H), 2.28-2.39 (m, 1H), 2.51-2.69 (m, 3H), 2.81 (m, 1H), 2.90-3.01 (m, 3H), 3.09 (m, 1H), 5.04 (m, 2H), 5.47-5.58 (m, 1H), 7.17-7.38 (m, 11H).

›Step 3

To a solution of 1-phenethylamino-3-phenyl-hex-5-en-3-ol (120 mg, 0.41 mmol) and Et 3 N (0.5 mL) in anhydrous CH 2 Cl 2 (5 mL) was added triphosgene (40 mg, 0.134 mmol) in portions at 0° C. under N 2 . Then the solution was refluxing at 80-90° C. overnight. The solvent was removed under reduced pressure, and the residue was purified by preparative TLC to afford 6-allyl-3-phenethyl-6-phenyl-[1,3]oxazinan-2-one (234 mg, yield: 19%). 1 H NMR (CDCl 3 ): 2.07-2.17 (m, 2H), 2.44-2.60 (m, 2H), 2.62-2.84 (m, 4H), 3.25 (m, 1H), 3.52 (m, 1H), 3.09 (m, 1H), 5.04 (m, 2H), 5.47-5.58 (m, 1H), 6.94 (m, 2H), 7.10 (m, 3H), 7.27 (m, 3H), 7.31 (m, 2H).

›Step 4

To a solution of 6-allyl-3-phenethyl-6-phenyl-[1,3]oxazinan-2-one (100 mg, 0.31 mmol) in dry THF (4 mL) was added dropwise BH 3 .THF (0.6 mL, 0.62 mmol, 1 M) at 0° C. After 2 h at rt, the reaction mixture was cooled to 0° C., and water (1 mL), aqueous NaOH (1 mL, 3 M) and H 2 O 2 (0.5 mL, 30%) were successively added. The mixture was stirred for 2-3 h at rt, and then diluted with water (8 mL). The pH of the mixture was adjusted to 6-7 with 0.5 N HCl. The layers were separated, and the aqueous phase was extracted with EtOAc (3×6 mL). The combined organic layers were washed with a saturated aqueous NaHCO 3 solution (10 mL) and brine (10 mL), dried over Na 2 SO 4 , and concentrated in vacuo to give the crude product, which was purified by preparative TLC to afford two isomers of 6-(3-hydroxypropyl)-3-phenethyl-6-phenyl-1,3-oxazinan-2-one.

Isomer 1 (12 mg, 11%). LC-MS Method 3 t R =1.13, min, m/z=340, 362; 1 H NMR (CDCl 3 ): 1.21-1.33 (m, 1H), 1.64 (m, 1H), 1.81-1.98 (m, 2H), 2.06 (m, 2H), 2.15 (m, 1H), 2.61-2.83 (m, 4H), 3.29 (m, 1H), 3.51 (m, 3H), 6.99 (m, 2H), 7.12 (m, 3H), 7.21 (m, 1H), 7.25 (m, 1H), 7.28 (m, 1H), 7.30 (m, 2H).

Isomer 2: (12 mg, 17%). LC-MS Method 3 t R =1.13, min, m/z=340, 362; 1 H NMR (CDCl 3 ): 1.20-1.38 (m, 2H), 1.67 (m, 2H), 1.86-2.00 (m, 2H), 2.02-2.34 (m, 2H), 2.64-2.88 (m, 4H), 3.31 (m, 1H), 3.50-3.62 (m, 3H), 7.02 (m, 2H), 7.15 (m, 3H), 7.21 (m, 1H), 7.28 (m, 2H), 7.33 (m, 2H).

›Example 187

3-((S)-1-(4-chlorophenyl)ethyl)-6-(3-hydroxypropyl)-6-isopropyl-1,3-oxazinan-2-one

›Step 1

In a 10 mL glass tube was placed 6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-1,3-oxazinan-2-one (50 mg, 0.14 mmol), nickel(II) chloride (18 mg, 0.14 mmol) and DMF (0.5 mL). The vessel was sealed with a spectrum and placed into the microwave cavity. Microwave irradiation of 100 W was used, the temperature being ramped from rt to 170° C. Once this temperature was reached, the reaction mixture was held at this temperature for 8 minutes. After the mixture cooled to rt, the reaction vessel was opened and the contents were poured into a separating funnel, and the tube was washed with water and then EtOAc, these washings being added to the separatory funned. The mixture was partitioned. The aqueous layer was extracted with EtOAc for 3 times, the combined organic layer was washed with brine, dried over Na 2 SO 4 , and concentrated to give 6-allyl-3-((S)-1-(4-chlorophenyl)ethyl)-6-isopropyl-1,3-oxazinan-2-one (45 mg, crude).

›Step 2

To a solution of 6-allyl-3-((S)-1-(4-chlorophenyl)ethyl)-6-isopropyl-1,3-oxazinan-2-one (45 mg, 0.14 mmol) in dry THF (5 mL) was added dropwise 1 M BH 3 .THF (0.28 mL, 0.28 mmol) at 0° C. After 2 h at rt, the reaction mixture was cooled to 0° C., and water (1 mL), 3 M aqueous NaOH (1 mL, 3 M) and 30% H 2 O 2 (0.5 mL) were successively added. The mixture was stirred for 2-3 h at rt and was then diluted with water (6 mL). The pH of the mixture was adjusted to 6-7 with 0.5 N HCl. The layers were separated, and the aqueous phase was extracted with EtOAc (3×5 mL). The combined organic layers were washed with a saturated aqueous NaHCO 3 solution (8 mL) and brine (8 mL), dried over Na 2 SO 4 , and concentrated in vacuo to give the crude product, which was purified by preparative TLC followed by preparative HPLC to afford two isomers.

Isomer 1: (5 mg, 10%) LC-MS Method 3 t R =1.22, min, m/z=340, 362; 1 H NMR (CDCl 3 ) 0.86 (m, 6H), 1.46 (m, 3H), 1.58-1.74 (m, 6H), 1.94 (m, 1H), 2.66 (m, 1H), 3.08 (m, 1H), 3.61 (m, 2H), 5.70 (m, 1H), 7.19 (m, 2H), 7.27 (m, 2H).

Isomer 2 (5 mg, 10%): LC-MS Method 3 t R =1.19, min, m/z=340, 362; 1 H NMR (CDCl 3 ) 0.91 (m, 6H), 1.49 (m, 3H), 1.62 (m, 5H), 1.87 (m, 1H), 2.07 (m, 1H), 2.68 (m, 1H), 3.03 (m, 1H), 3.59 (m, 2H), 5.74 (m, 1H), 7.22 (m, 2H), 7.29 (m, 2H).

›Example 188

6-(3-hydroxypropyl)-6-phenyl-3-(2-phenylcyclopropyl)-1,3-oxazinan-2-one

›Step 1

To a solution of 2-phenylcyclopropanecarboxylic acid (1.0 g, 6.17 mmol) in dry toluene (20 mL) was added triethylamine (934 mg, 9.26 mmol) and DPPA (2.0 g, 7.41 mmol) under N 2 , and the reaction mixture was refluxed for 3 h. The solution was concentrated to give (2-isocyanatocyclopropyl)benzene (800 mg), which was used for the next step without further purification.

›Step 2

To a solution of (2-isocyanatocyclopropyl)benzene (800 mg, 5.03 mmol) in THF (15 mL) was added DBU (1.61 g, 10.48 mmol) and 1-chloro-3-phenylhex-5-en-3-ol (880 mg, 4.19 mmol), and the mixture was refluxed overnight. The solution was diluted with EtOAc, and washed with 1 N HCl (2×15 mL). The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give crude product, which was purified by preparative TLC to afford 6-allyl-6-phenyl-3-(2-phenylcyclopropyl)-1,3-oxazinan-2-one (100 mg, 6%). 1 H NMR (CDCl 3 ): 1.05-1.21 (m, 3H), 1.36-1.42 (m, 1H), 2.13-2.34 (m, 1H), 2.39-2.61 (m, 2H), 2.92-3.15 (m, 1H), 3.76-4.01 (m, 1H), 4.95-5.10 (m, 2H), 5.42-5.73 (m, 1H), 6.95-6.99 (m, 1H), 7.10-7.24 (m, 10H).

›Step 3

To a solution of 6-allyl-6-phenyl-3-(2-phenylcyclopropyl)-1,3-oxazinan-2-one (200 mg, 0.60 mmol) in dry THF (5 mL) was added dropwise 1 M of BH 3 /THF (1.8 mL, 1.8 mmol) at 0° C. under N 2 . After stirring at rt for 2 h, the reaction mixture was cooled to 0° C. again, and water (0.1 mL), 3 M of aqueous NaOH solution (0.1 mL), and 30% H 2 O 2 (0.3 mL) were added sequentially. After the mixture was stirred at rt for another 2 h, 1 N aqueous HCl (0.5 mL) was added. The mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give the crude product, which was purified by preparative TLC followed by preparative HPLC to afford two isomers.

Isomer 1 (20 mg, 9%): LC-MS Method 3 t R =1.151, min, m/z=352.2; 1 H NMR (CDCl 3 ) 0.83 (m, 2H), 1.12 (m, 1H), 1.23 (m, 4H), 1.68 (m, 1H), 1.97 (m, 2H), 2.16 (m, 1H), 2.21 (m, 1H), 2.84 (m, 1H), 3.13 (m, 1H), 3.52 (m, 2H), 4.14 (m, 1H), 7.03 (m, 2H), 7.11 (m, 1H), 7.17 (m, 2H), 7.29 (m, 4H), 7.46-7.63 (m, 1H).

Isomer 2 (15 mg, 7%): LC-MS Method 3 t R =1.149, min, m/z=352.2; 1 H NMR (CDCl 3 ) 0.85 (m, 2H), 1.11 (m, 1H), 1.26 (m, 3H), 1.67 (m, 2H), 1.96 (m, 2H), 2.18 (m, 1H), 2.27 (m, 1H), 2.83 (m, 1H), 3.13 (m, 1H), 3.52 (m, 2H), 4.15 (m, 1H), 7.02 (m, 2H), 7.11 (m, 1H), 7.15 (m, 2H), 7.26 (m, 3H), 7.29 (m, 2H), 7.46-7.63 (m, 1H).

›Examples6

›Example 189

6-allyl-6-(4-fluorophenyl)-3-((S)-1-p-tolylethyl)-1,3-oxazinan-2-one

The title compound was prepared following a procedure analogous to that described in Example 110 Step 2 using (S)-1-(1-isocyanatoethyl)-4-methylbenzene. Two isomers were isolated.

Isomer 1: LC-MS Method 1 t R =1.94, min, m/z=354; 1 H NMR (CDCl 3 ) 7.31-7.27 (m, 2H), 7.19-7.13 (m, 4H), 7.10-7.05 (m, 2H), 5.75-5.63 (m, 2H), 5.09-4.97 (m, 2H), 2.73-2.52 (m, 4H), 2.34 (s, 3H), 2.22-2.16 (dt, 1H), 2.07-1.99 (m, 1H), 1.25 (d, 3H).

Isomer 2: LC-MS Method 1 t R =1.99, min, m/z=354; 1 H NMR (CDCl 3 ) 7.26-7.22, 7.03-6.95, 5.75-5.57, 5.08-4.98, 2.3, 1.47.

›Example 190

(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-hydroxyphenyl)ethyl)-1,3-oxazinan-2-one

A solution of (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-methoxyphenyl)ethyl)-1,3-oxazinan-2-one (0.1094 g, 0.30 mmol, 1.0 equiv) in 6 mL of dry CH 2 Cl 2 was cooled to −78° C. At this temperature, BBr 3 (1.0 M solution in CH 2 Cl 2 , 0.6 mL, 0.60 mmol, 2.0 equiv) was added under N 2 atmosphere. After 1 h, the reaction mixture was stirred at an ice bath for further 3 h. After the reaction mixture was cooled with a dry ice—acetone bath, surplus of BBr 3 was hydrolyzed with methanol (3 mL). The mixture was then treated with brine, diluted with CH 2 Cl 2 , and dried over Na 2 SO 4 . After the solvent was evaporated under reduced pressure, the residue was purified by reversed-phase HPLC (SunFire™ Prep C 18 OBD™ 5 μm 19×50 mm column, 10%→90% CH 3 CN/H 2 O, 0.1% CF 3 COOH over 8 min and then 90% CH 3 CN/H 2 O, 0.1% CF 3 COOH over 2 min, flow rate 20 ml/min) to afford 0.0669 g (64%) of (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-hydroxyphenyl)ethyl)-1,3-oxazinan-2-one. LC-MS Method 1 t R =1.57 min, m/z 356 (MH + ); 1 H NMR (400 MHz, CD 3 OD) δ 7.23-7.18 (m, 2H), 7.00-6.96 (m, 2H), 6.63 (d, J=8.8 Hz, 2H), 6.43 (d, J=8.2 Hz, 2H), 5.64-5.54 (m, 1H), 5.34 (q, J=7.0 Hz, 1H), 4.96-4.89 (m, 2H), 2.93-2.88 (m, 1H), 2.50 (d, J=7.0 Hz, 2H), 2.34-2.29 (m, 1H), 2.18-2.03 (m, 2H), 1.36 (d, J=7.0 Hz, 3H); 19 F NMR (376 MHz, CD 3 OD) δ −117.48 (m).

›Example 191

(S)-6-(2-hydroxyethyl)-3-((S)-1-(4-methoxyphenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-methoxyphenyl)ethyl)-1,3-oxazinan-2-one following a procedure analogous to that described in Example 74. LC-MS Method 3 t R =0.893, min, m/z=355.9; 1 H NMR (CDCl 3 ) 1.43 (d, 3H), 2.02-2.23 (m, 5H), 2.73 (m, 1H), 3.51 (m, 1H), 3.68 (s, 3H), 3.72 (m, 1H), 5.53 (m, 1H), 6.57 (d, 1H), 6.76 (d, 1H), 7.19-7.33 (m, 5H).

›Example 192

4-((S)-1-((R)-6-allyl-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)benzonitrile

The title compound was prepared from 4-((S)-1-((R)-6-allyl-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)benzamide using a procedure analogous to that described in Example 172. LC-MS Method 1 t R =1.74, min, m/z=365; 1 H NMR (CDCl 3 ) 7.39 (d, 2H), 7.26 (t, 2H), 7.05 (t, 2H), 6.93 (d, 2H), 5.74-5.62 (m, 2H), 5.06 (dd, 2H), 2.99 (m, 2H), 2.59 (m, 2H), 1.53 (d, 3H).

›Example 193

6-allyl-6-(4-fluorophenyl)-3-((1S)-1-(4-methoxyphenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared following a procedure analogous to that described in Example 110 Step 2 using (S)-1-(1-isocyanatoethyl)-4-methoxybenzene. Two isomers were isolated.

Isomer 1: LC-MS Method 1 t R =1.82, min, m/z=370; 1 H NMR (CDCl 3 ) 7.28-7.23 (m, 2H), 7.04-7.00 (m, 2H), 6.79 (d, J=8.8 Hz, 2H), 6.64 (d, J=8.8 Hz, 2H), 5.77-5.66 (m, 1H), 5.60 (q, J=7.0 Hz, 1H), 5.10-5.00 (m, 2H), 3.74 (s, 3H), 2.90-2.85 (m, 1H), 2.64-2.52 (m, 2H), 2.30-2.13 (m, 3H), 1.48 (d, J=7.0 Hz, 3H).

Isomer 2: LC-MS Method 1 t R =1.88, min, m/z=370; 1 H NMR (CDCl 3 ) 7.32-7.27 (m, 2H), 7.22 (d, J=8.5 Hz, 2H), 7.09-7.05 (m, 2H), 6.86 (d, J=8.5 Hz, 2H), 5.77-5.66 (m, 2H), 5.08-4.98 (m, 2H), 3.80 (s, 3H), 2.70-2.66 (m, 2H), 2.63-2.52 (m, 2H), 2.20-2.15 (m, 1H), 2.06-1.98 (m, 1H), 1.23 (d, J=7.0 Hz, 3H).

›Example 194

(R)-3-((S)-1-(4-(hydroxymethyl)phenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one

›Step 1

A mixture of (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (80 mg, 0.19 mmol), Pd(PPh 3 ) 2 Cl 2 (14 mg, 0.02 mmol) and TEA (38 mg, 0.38 mmol) in methanol (10 mL) was stirred in a sealed tube under 50 Psi carbon monoxide atmosphere at 80° C. overnight. The mixture was filtered, and the filtrate was concentrated to give the crude product, which was purified by preparative TLC to give methyl 4-((S)-1-((R)-6-(3-hydroxypropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)benzoate (60 mg, crude).

›Step 2

To a solution of methyl 4-((S)-1-((R)-6-(3-hydroxypropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)benzoate (60 mg, 0.25 mmol) in THF (5 mL) was added NaBH 4 (48 mg, 1.25 mmol). The mixture was heated to reflux for 15 minutes. Then methanol (3 mL) was added. The mixture was heated to reflux overnight. The reaction was quenched with water, and the solvent was removed. The aqueous layer was extracted with EtOAc for 3 times. The combined organic layer was washed with brine, dried over Na 2 SO 4 , and concentrated to give the crude product, which was purified by preparative TLC to give (R)-3-((S)-1-(4-(hydroxymethyl)phenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (5 mg, 5%). LC-MS Method 2 t R =1.29, min, m/z=370, 392; 1 H NMR (CDCl 3 ): 1.33 (m, 1H), 1.45 (m, 3H), 1.64 (m, 1H), 1.90 (m, 2H), 2.11-2.24 (m, 2H), 2.81 (m, 1H), 3.50 (m, 2H), 4.52 (s, 2H), 5.58 (m, 1H), 6.82 (m, 2H), 7.03 (m, 2H), 7.25 (m, 5H).

›Examples4

›Example 195

(S)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-3-((S)-1-(4-methoxyphenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-methoxyphenyl)ethyl)-1,3-oxazinan-2-one following a procedure analogous to that described in Example 97. LC-MS Method 1 t R =1.45, min, m/z=374; 1 H NMR (CD 3 OD) 7.28-7.24 (m, 2H), 7.06-7.02 (m, 2H), 6.82 (d, J=8.5 Hz, 2H), 6.62 (d, J=8.5 Hz, 2H), 5.44 (q, J=7.0 Hz, 1H), 3.67 (s, 3H), 3.66-3.60 (m, 1H), 3.31-3.25 (m, 1H), 3.02-2.95 (m, 1H), 2.44-2.38 (m, 1H), 2.24-2.10 (m, 2H), 2.07 (t, J=7.3 Hz, 2H), 1.44 (d, J=7.0 Hz, 3H).

›Example 196

6-allyl-3-((1S)-1-(4-chlorophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one

The title compound was prepared following a procedure analogous to that described in Example 110 Step 2 using (S)-1-chloro-4-(1-isocyanatoethyl)benzene. Two isomers were isolated.

Isomer 1: (R)-6-allyl-3-((S)-1-(4-chlorophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one: LC-MS Method 1 tR=1.97, min, m/z=374; 1H NMR (CDCl3) 7.28-7.24 (m, 2H), 7.09-7.02 (m, 4H), 6.78 (d, 2H), 5.75-5.64 (m, 1H), 5.64-5.59 (q, 1H), 5.11-5.00 (m, 2H), 2.94-2.89 (m, 1H), 2.64-2.52 (m, 2H), 2.34-2.15 (m, 3H), 1.49 (d, 3H).

Isomer 2: (S)-6-allyl-3-((S)-1-(4-chlorophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one: LC-MS Method 1 tR=2.01, m/z=374 (M+1); 1H NMR (CDCl3) 7.32-7.21 (m, 6H), 7.10-7.04 (t, 2H, J=9.0 Hz), 5.75-5.65 (m, 2H), 5.09-4.98 (m, 2H), 2.75-2.64 (m, 2H), 2.62-2.52 (m, 2H), 2.24-2.19 (m, 1H), 2.08-2.00 (m, 1H), 1.24 (d, 3H, J=7.3 Hz).

›Example 197

(6S)-3-((1S)-1-cyclohexylethyl)-6-(2,3-dihydroxypropyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one

The title compound was prepared from (R)-6-allyl-3-((S)-1-cyclohexylethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one using AD-mix-β following a procedure analogous to that described in Example 173. Two isomers were isolated.

Isomer 1: LC-MS Method 2 t R =2.183, min, m/z=402.2; 1 H NMR (CDCl 3 ) 1.01-1.13 (m, 6H), 1.42-1.71 (m, 5H), 1.92-2.43 (m, 8H), 2.51-2.71 (m, 2H), 3.08 (m, 1H), 3.47 (m, 1H), 3.61 (m, 1H), 3.75 (m, 1H), 3.97 (m, 1H), 7.02-7.09 (m, 2H), 7.22-7.39 (m, 2H).

Isomer 2: LC-MS Method 2 t R =2.215, min, m/z=402.2; 1 H NMR (CDCl 3 ) 0.96-1.03 (m, 6H), 1.38-1.71 (m, 8H), 1.73 (m, 1H), 2.01-2.09 (m, 1H), 2.29 (m, 3H), 2.53 (m, 1H), 3.01 (m, 1H), 3.22 (m, 1H), 3.48 (m, 1H), 3.73 (m, 1H), 3.89 (m, 1H), 7.03 (m, 2H), 7.22 (m, 2H).

›Example 198

(R)-3-((S)-1-(4-(2-hydroxyethyl)phenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one

›Step 1

A solution of (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (200 mg, 0.462 mmol), tributyl-vinyl-stannane (198 mg, 0.624 mmol), Pd 2 (dba) 3 (23 mg, 0.005 mmol) and BINAP (6.84 mg, 0.011 mmol) in toluene (20 mL) was heated to reflux overnight. The reaction mixture was filtered, and the filtrate was concentrated to give the crude product, which was purified by preparative TLC to give (R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-vinylphenyl)ethyl)-1,3-oxazinan-2-one (50 mg, 30%). 1 H NMR (CDCl 3 ): 0.81 (m, 2H), 1.07-1.28 (m, 5H), 1.53 (d, 3H), 1.83-1.97 (m, 4H), 2.22 (m, 3H), 2.83 (m, 1H), 3.55 (m, 2H), 5.09 (m, 1H), 5.21 (m, 1H), 5.58 (m, 1H), 6.63-6.77 (m, 2H), 7.04-28 (m, 13H), 7.43 (m, 2H), 7.68 (m, 1H).

›Step 2

To a solution of (R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-vinylphenyl)ethyl)-1,3-oxazinan-2-one (50 mg, 0.137 mmol) and imidazole (11.2 mg 0.165 mmol) in CH 2 Cl 2 (10 mL) was added a solution of TBSCl (24.6 mg, 0.164 mmol) in CH 2 Cl 2 (15 mL) dropwise at 0° C. The mixture was stirred overnight at rt. The mixture was filtered, and the solvent was evaporated to give (R)-6-(3-(tert-butyldimethylsilyloxy)propyl)-6-phenyl-3-((S)-1-(4-vinylphenyl)ethyl)-1,3-oxazinan-2-one (40 mg, 60%). 1 H NMR (CDCl 3 ): 0.02 (s, 6H), 0.87 (m, 9H), 1.23 (m, 1H), 1.52 (d, 3H), 1.62 (m, 1H), 1.98 (m, 2H), 2.14-2.38 (m, 3H), 2.97 (m, 1H), 3.58 (m, 2H), 5.28 (m, 1H), 5.71 (m, 1H), 6.68 (m, 1H), 6.88 (m, 1H), 7.16 (m, 1H), 7.22-7.38 (m, 7H).

›Step 3

To a solution of (R)-6-(3-(tert-butyldimethylsilyloxy)propyl)-6-phenyl-3-((S)-1-(4-vinylphenyl)ethyl)-1,3-oxazinan-2-one (20 mg, 0.042 mmol) in dry THF (10 mL) was added BH 3 THF (0.5 ml, 0.5 mmol) dropwise at 0° C. After stirring for 2 h at rt, the mixture was cooled to 0° C., and H 2 O (0.5 mL), 3 M aqueous NaOH (0.5 mL) and 30% H 2 O 2 (0.5 mL) were added successively added. The mixture was stirred overnight at rt. The mixture was diluted with 1 M HCl, and the pH of the mixture was adjusted to 6-7 with 1 M HCl. The layers were separated, and the aqueous phase was extracted with EtOAc (3×5 mL). The combined organic layer was washed with a saturated aqueous NaHCO 3 solution (5 mL) and brine (5 mL), dried over Na 2 SO 4 , and concentrated in vacuo to give the crude product, which was purified by TLC and preparative HPLC to afford (R)-3-((S)-1-(4-(2-hydroxyethyl)phenyl)ethyl)-6-(3-hydroxy propyl)-6-phenyl-1,3-oxazinan-2-one (7.02 mg, 20%). LC-MS Method 2 t R =1.757, min, m/z=406.2; 1 H NMR (CDCl 3 ): 1.31 (m, 1H), 1.47 (d, 3H), 1.68 (m, 1H), 1.89 (m, 2H), 2.18 (m, 2H), 2.70 (m, 1H), 2.83 (m, 1H), 3.49 (m, 2H), 3.71 (m, 2H), 5.58 (m, 1H), 6.75 (m, 2H), 6.88 (m, 2H), 7.23 (m, 5H).

›Example 199

(R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(methoxymethyl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

›Step 1

To a solution of (R)-6-(3-(tert-butyldimethylsilyloxy)propyl)-6-phenyl-3-((S)-1-(4-vinylphenyl)ethyl)-1,3-oxazinan-2-one (40 mg, 0.08 mmol) in CH 2 Cl 2 (15 mL) was treated with ozone at −78° C. until the mixture turned blue. The system was then flushed with oxygen to move excess ozone. NaBH 4 (12.2 mg, 0.32 mmol) was added to the mixture in portions at rt, and the mixture was stirred overnight at rt. The reaction was quenched by water, and the layers were separated. The aqueous layer was extracted with CH 2 Cl 2 (2×). The organic layer was combined, washed with brine, dried over anhydrous Na 2 SO 4 and concentrated to give the crude product, which was purified by preparative TLC to give (R)-6-(3-(tert-butyldimethylsilyloxy)propyl)-3-((S)-1-(4-(hydroxylmethyl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (10 mg, 25%). 1 H NMR (CDCl 3 ): 0.00 (s, 4H), 0.09 (s, 2H), 0.87 (s, 8H), 1.28 (s, 4H), 1.53 (d, 3H), 1.98 (d, 2H), 3.53 (m, 2H), 4.25 (m, 1H), 4.98 (m, 1H), 4.61 (m, 1H), 5.71 (m, 1H), 6.90 (m, 1H), 7.12-7.38 (m, 10H).

›Step 2

To a solution of (R)-6-(3-(tert-butyldimethylsilyloxy)propyl)-3-((S)-1-(4-(hydroxymethyl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (10 mg, 0.02 mmol) in THF (5 mL) was added NaH (1.4 mg) at 0° C. After stirring for 1 h at rt, the mixture was cooled to 0° C., and CH 3 I (90 mg 0.78 mmol) was added. The mixture was stirred overnight at rt. The reaction was quenched with H 2 O, and the layers were separated. The aqueous layer was extracted with CH 2 Cl 2 for two times. The organic layer was combined, washed with brine, dried over Na 2 SO 4 and concentrated to give the crude product, which was purified by preparative TLC to give (R)-6-(3-(tert-butyldimethylsilyloxy)propyl)-3-((S)-1-(4-(methoxymethyl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (10 mg, 71%).

›Step 3

To a solution of (R)-6-(3-(tert-butyldimethylsilyloxy)propyl)-3-((S)-1-(4-(methoxymethyl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (7 mg, 0.02 mmol) in EtOAc (5 mL) was added TBAF (26.1 mg, 0.10 mmol) at rt, and the mixture was stirred at rt overnight. The mixture was concentrated in vacuo to give the crude product, which was purified by preparative TLC followed by preparative HPLC to afford (R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(methoxymethyl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (1.63 mg). LC-MS Method 3 t R =0.96, min, m/z=406; 1 H NMR (CDCl 3 ): 1.39 (m, 1H), 1.49 (m, 3H), 1.71 (m, 1H), 1.89 (m, 3H), 2.01 (m, 1H), 2.18 (m, 2H), 2.75-2.88 (m, 3H), 3.23 (m, 1H), 3.48 (m, 1H), 3.70 (m, 1H) □4.19 (m, 1H), 5.58 (m, 1H), 6.73-6.86 (m, 2H), 7.08-7.29 (m, 6H).

›Examples8

›Example 200

3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-isopropyl-1,3-oxazinan-2-one

The title compound was prepared from 6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-1,3-oxazinan-2-one following a procedure analogous to that described in Example 78. Two isomers were isolated.

Isomer 1: LC-MS Method 3 t R =1.28, min, m/z=384, 386; 1 H NMR (CDCl 3 ) 0.90 (m, 6H), 1.51 (m, 3H), 1.62-1.94 (m, 6H), 2.02 (m, 1H), 2.73 (m, 1H), 3.15 (m, 1H), 3.66 (m, 2H), 5.73 (m, 1H), 7.18 (m, 2H), 7.46 (m, 2H).

LC-MS Method 3 t R =1.24, min, m/z=384, 386; 1 H NMR (CDCl 3 ) 0.92 (m, 6H), 1.51 (m, 3H), 1.62 (m, 5H), 1.87 (m, 1H), 2.05 (m, 1H), 2.69 (m, 1H), 3.04 (m, 1H), 3.61 (m, 2H), 5.73 (m, 1H), 7.18 (m, 2H), 7.46 (m, 2H).

›Example 201

6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((1S)-1-(4-methoxyphenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from 6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-methoxyphenyl)ethyl)-1,3-oxazinan-2-one following a procedure analogous to that described in Example 78. Two isomers were isolated.

Isomer 1: (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-methoxyphenyl)ethyl)-1,3-oxazinan-2-one. LC-MS Method 1 t R =1.49, min, m/z=388; 1 H NMR (CD 3 OD) 7.24-7.21 (m, 2H), 7.03-6.99 (m, 2H), 6.80 (d, J=8.8 Hz, 2H), 6.60 (d, J=8.5 Hz, 2H), 5.42 (q, J=7.0 Hz, 1H), 3.64 (s, 3H), 3.39 (t, J=6.2 Hz, 2H), 2.98-2.94 (m, 1H), 2.39-2.31 (m, 1H), 2.19-2.06 (m, 2H), 1.88-1.81 (m, 2H), 1.57-1.49 (m, 1H), 1.42 (d, J=7.0 Hz, 3H), 1.27-1.18 (m, 1H).

Isomer 2: (S)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-methoxyphenyl)ethyl)-1,3-oxazinan-2-one. LC-MS Method 1 t R =1.55, min, m/z=388; 1 H NMR (CD 3 OD) 7.31-7.27 (m, 2H), 7.15 (d, J=8.8 Hz, 2H), 7.10-7.06 (m, 2H), 6.83 (d, J=8.5 Hz, 2H), 5.49 (q, J=7.0 Hz, 1H), 3.71 (s, 3H), 3.40-3.36 (m, 2H), 2.74-2.63 (m, 3H), 2.35-2.30 (m, 1H), 2.04-1.91 (m, 1H), 1.89-1.83 (m, 2H), 1.59-1.50 (m, 1H), 1.20 (d, J=7.0 Hz, 3H).

›Example 202

(R)-3-((1S)-1-(4-chlorophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one

The title compound was prepared from (R)-6-allyl-3-((S)-1-(4-chlorophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one following a procedure analogous to that described in Example 78. LC-MS Method 1 t R =1.64, min, m/z=414; 1 H NMR (CDCl 3 ) 7.25-7.22 (m, 2H), 7.12-7.02 (m, 4H), 6.86-6.84 (d, 2H), 5.65-5.59 (m, 1H), 3.58 (t, 2H), 2.95-2.89 (m, 1H), 2.31-2.17 (m, 3H), 2.01-1.91 (m, 2H), 1.77-1.63 (m, 1H), 1.50 (d, 3H), 1.42-1.31 (m, 1H).

›Example 203

(6S)-3-((S)-1-(4-chlorophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxypropyl)-1,3-oxazinan-2-one

The title compound was prepared from (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one using a procedure analogous to that described in Example 187 Step 1, followed by a procedure analogous to that described in Example 408 Step 1, followed by a procedure analogous to that described in Example 372 Step 3. Two isomers were isolated.

Isomer 1: LC-MS Method 1 t R =1.69, m/z=414.

Isomer 2: LC-MS Method 2 t R =1.337 min, m/z=391.14; 1 H NMR (CDCl 3 ) 1.05 (d, 3H), 1.48 (d, 3H), 1.55-1.71 (s, 1H), 1.84 (d, 1H), 2.00 (m, 1H), 2.15 (m, 2H) 2.30 (m, 1H) 2.83 (m, 1H), 3.85 (m, 1H), 5.56 (m, 1H), 6.79 (d, 2H), 7.03 (m, 2H) 7.21 (m, 2H).

The title compound was also isolated as a byproduct from the procedure used to prepare Example 202. LC-MS Method 1 t R =1.7, min, m/z=392.

›Example 204

6-allyl-3-((1S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from 3-chloro-1-phenylpropan-1-one following a procedure analogous to that described in Example 110. Two isomers were isolated.

Isomer 1: (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one LC-MS Method 3 t R =1.55, min, m/z=400, 402; 1 H NMR (CDCl 3 ) 1.41 (m, 3H), 2.09-2.29 (m, 3H), 2.48-2.59 (m, 2H), 2.80 (m, 1H), 5.02 (m, 2H), 5.49 (m, 1H), 5.69 (m, 1H), 6.57 (m, 2H), 7.08 (m, 2H), 7.20-7.30 (m, 6H).

Isomer 2: (S)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one LC-MS Method 2 t R =1.56 min, m/z=401.9; 1 H NMR (CDCl 3 ) 1.18-1.26 (d, 3H), 1.99-2.12 (m, 1H), 2.24 (m, 1H), 2.52-2.79 (m, 4H), 4.97-5.13 (m, 2H), 5.62-5.86 (m, 2H), 7.18 (d, 2H), 7.31 (m, 3H), 7.38 (m, 2H), 7.43 (d, 2H).

›Example 205

(S)-6-(2-hydroxyethyl)-6-phenyl-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one and pyridine-3-boronic acid using a procedure analogous to that described in Example 64 followed by a procedure analogous to that described in Example 74. LC-MS Method 2 t R =1.44, min, m/z=403; 1 H NMR (CDCl 3 ) 1.50 (t, 3H), 1.68 (m, 2H), 1.91 (m, 2H), 2.05 (m, 1H), 2.26 (m, 2H), 2.83 (m, 1H), 3.53 (m, 2H), 5.62 (q, 1H), 6.93 (d, 2H), 7.20-7.32 (m, 8H), 7.73 (m, 1H), 8.51 (s, 1H), 8.72 (s, 1H).

›Example 206

(6S)-6-(2,3-dihydroxypropyl)-6-(4-fluorophenyl)-3-((1S)-1-(4-methoxyphenyl)ethyl)-1,3-oxazinan-2-one

Isomer 1: LC-MS Method 1 t R =1.34, min, m/z=404; 1 H NMR (CD 3 OD) 7.30-7.27 (m, 2H), 7.03-6.99 (m, 2H), 6.74 (d, J=8.8 Hz, 2H), 6.58 (d, J=8.8 Hz, 2H), 5.39 (q, J=7.0 Hz, 1H), 3.63 (s, 3H), 3.35-3.28 (m, 3H), 3.00-2.95 (m, 1H), 2.60-2.56 (m, 1H), 2.25-2.10 (m, 2H), 2.00-1.86 (m, 2H), 1.40 (d, J=7.0 Hz, 3H).

Isomer 2: LC-MS Method 1 t R =1.37, min, m/z=404; 1 H NMR (CD 3 OD) 7.25-7.21 (m, 2H), 7.02-6.98 (m, 2H), 6.79 (d, J=8.8 Hz, 2H), 6.59 (d, J=8.5 Hz, 2H), 5.40 (q, J=7.0 Hz, 1H), 3.74-3.68 (m, 1H), 3.63 (s, 3H), 3.23-3.16 (m, 2H), 2.95-2.90 (m, 1H), 2.39-2.32 (m, 2H), 2.11-2.04 (m, 1H), 1.95 (dd, J=14.9, 2.6 Hz, 1H), 1.82 (dd, J=15.2, 7.9 Hz, 1H), 1.40 (d, J=7.0 Hz, 3H).

›Example 207

3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(2-hydroxyethyl)-6-isopropyl-1,3-oxazinan-2-one

›Step 1

To a solution of 4-methyl-3-oxo-pentanoic acid ethyl ester (79 g, 0.5 mol) and ethane-1,2-diol (62 g, 1 mol) in toluene (1600 mL) was added TsOH (1.9 g, 0.1 mol). The mixture was refluxed till the reaction was over. The mixture was concentrated in vacuum to give the crude (2-isopropyl-[1,3]dioxolan-2-yl)-acetic acid ethyl ester (83 g, crude), which was used for the next step without further purification.

›Step 2

To a solution of (2-isopropyl-[1,3]dioxolan-2-yl)-acetic acid ethyl ester (83 g, 0.41 mol) in MeOH (1600 mL) was added NaBH 4 (78 g, 2.05 mol) and ZnCl 2 (8.3 g). The mixture was stirred overnight. The mixture was concentrated, and the residue was dissolved in the mixture of EtOAc and water. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic phase was dried over Na 2 SO 4 , and concentrated to give the crude product, which was purified by column to give 2-(2-isopropyl-[1,3]dioxolan-2-yl)-ethanol (30 g, crude).

›Step 3

To a solution of 2-(2-isopropyl-[1,3]dioxolan-2-yl)-ethanol (11 g, 0.069 mol) and TEA (20.91 g, 0.207 mol) in dried CH 2 Cl 2 (110 mL) was added MsCl (15.8 g, 0.138 mol) dropwise at 0° C. The mixture was stirred till the reaction was over. The reaction was quenched with water. The layers were separated, and the aqueous layer was extracted with CH 2 Cl 2 . The combined organic phase was dried over Na 2 SO 4 , and concentrated to give the crude methanesulfonic acid 2-(2-isopropyl-[1,3]dioxolan-2-yl)-ethyl ester (19 g, crude), which was used for the next step without further purification.

›Step 4

To a solution of methanesulfonic acid 2-(2-isopropyl-[1,3]dioxolan-2-yl)-ethyl ester (19 g, 0.08 mol) was added 1-(4-bromo-phenyl)-ethylamine (48 g, 0.24 mol). The mixture was refluxed overnight. The mixture was condensed to give the crude product, which was purified by column to give [1-(4-bromo-phenyl)-ethyl]-[2-(2-isopropyl-[1,3]dioxolan-2-yl)-ethyl]-amine (22 g, crude). 1 H NMR (CDCl 3 ): 0.88 (m, 6H), 1.32 (m, 3H), 1.83 (m, 3H), 2.51 (m, 2H), 3.69 (m, 1H), 3.87 (m, 4H), 7.18 (m, 2H), 7.43 (m, 2H).

›Step 5

To a solution of [1-(4-bromo-phenyl)-ethyl]-[2-(2-isopropyl-[1,3]dioxolan-2-yl)-ethyl]-amine (14.5 g, 0.042 mol) in MeOH (70 mol) was added HCl (36%, 70 mol). The mixture was stirred at 65° C. till the reaction was over. The mixture was cooled to 0° C. The pH of the mixture was adjusted to 7. The mixture was condensed, and the residue was extracted with EtOAc. The organic phase was dried over Na 2 SO 4 , and concentrated to give the crude 1-[1-(4-bromo-phenyl)-ethylamino]-4-methyl-pentan-3-one (10.3 g, crude), which was used for the next step without further purification. 1 H NMR (CDCl 3 ): 1.08 (m, 6H), 1.35 (m, 3H), 2.51-2.70 (m, 6H), 3.72 (m, 1H), 7.19 (m, 2H), 7.42 (m, 2H).

›Step 6

To a solution of 1-[1-(4-bromo-phenyl)-ethylamino]-4-methyl-pentan-3-one (3.42 g, 0.01 mol) and K 2 CO 3 (6.9 g, 0.05 mol) in dried CH 2 Cl 2 (50 mL) was added chloroformate (1.41 g, 0.015 mol). The mixture was refluxed overnight. The solvent was removed to give the crude product, which was purified by column to give [1-(4-bromo-phenyl)-ethyl]-(4-methyl-3-oxo-pentyl)-carbamic acid methyl ester (2.8 g, 79%). 1 H NMR (CDCl 3 ): 1.01 (m, 6H), 1.48 (m, 3H), 2.25-2.47 (m, 2H), 2.62 (m, 1H), 3.24 (m, 2H), 5.46 (s, 1H), 7.17 (m, 2H), 7.45 (m, 2H).

›Step 7

To a solution of [1-(4-bromo-phenyl)-ethyl]-(4-methyl-3-oxo-pentyl)-carbamic acid methyl ester (1.78 g, 5 mmol) in dried THF (20 mL) was added allymagnesium bromide (1 M, 25 mL, 25 mmol) dropwise at −78° C. The mixture was stirred overnight. The reaction was quenched with aqueous sat. NH 4 Cl. The mixture was extracted with EtOAc. The organic phase was dried over Na 2 SO 4 , and condensed to give 3-{2-[1-(4-bromo-phenyl)-ethylamino]-ethyl}-2-methyl-hex-5-en-3-ol (2.2 g, crude).

›Step 8

To a solution of 3-{2-[1-(4-bromo-phenyl)-ethylamino]-ethyl}-2-methyl-hex-5-en-3-ol (2.2 g, crude) and TEA (4 eq) in dried CH 2 Cl 2 (60 mL) at 0° C. was added triphosgene (2.12 g, 7.12 mmol). The mixture was stirred at rt till the reaction was over. Water was added, and the layers were separated. The aqueous layer was extracted with CH 2 Cl 2 . The combined organic phase was washed with water, dried over Na 2 SO 4 , and condensed to give the crude product, which was purified by column to give 6-allyl-3-[1-(4-bromo-phenyl)-ethyl]-6-isopropyl-[1,3]oxazinan-2-one (500 mg, crude).

›Step 9

A mixture of 6-allyl-3-[1-(4-bromo-phenyl)-ethyl]-6-isopropyl-[1,3]oxazinan-2-one (200 mg, 0.55 mmol), 2,4-difluorophenylboronic acid (104 mg, 0.66 mmol), PdCl 2 (PPh 3 ) 2 (20 mg), aqueous Cs 2 CO 3 solution (2 M, 2 mL) in 1,4-dioxane (8 mL) was heated to reflux for 2 h. The mixture was filtered, and the filtrate was extracted with EtOAc for 3 times. The combined organic layer was washed with brine, dried over Na 2 SO 4 and concentrated to give the crude product, which was purified by preparative TLC to give 6-allyl-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-isopropyl-1,3-oxazinan-2-one (160 mg, 73%). 1 H NMR (CDCl 3 ): 0.96 (m, 6H), 1.61 (m, 3H), 1.68-2.09 (m, 3H), 2.32-2.47 (m, 2H), 2.84 (m, 1H), 3.18 (m, 1H), 5.02-5.19 (m, 2H), 5.84 (m, 2H), 6.93 (m, 2H), 7.41 (m, 3H), 7.50 (m, 2H).

›Step 10

A solution of 6-allyl-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-isopropyl-1,3-oxazinan-2-one (60 mg, crude) in dry CH 2 Cl 2 (10 mL) was treated with ozone at −78° C. until the mixture turned blue. The system was then flushed with oxygen to remove excess ozone. NaBH 4 (29 mg, 0.75 mmol) was added to the mixture in portions at rt. The mixture was stirred overnight at rt. The mixture was quenched with water, and the layers were separated. The aqueous layer was extracted with CH 2 Cl 2 (2×). The organic layers were combined, washed with brine, dried over anhydrous Na 2 SO 4 and concentrated to give the crude product, which was purified by preparative TLC to give two isomers.

Isomer 1 (30 mg, 49%): LC-MS Method 3 t R =1.37, min, m/z=404, 426; 1H NMR (CDCl 3 ) 0.89 (m, 6H), 1.53 (d, 3H), 1.74 (m, 4H), 2.11 (m, 1H), 2.81 (m, 1H), 3.15 (m, 1H), 3.76-4.02 (m, 2H), 5.78 (m, 1H), 6.88 (m, 2H), 7.33 (m, 3H), 7.45 (m, 2H).

Isomer 2 (10 mg, 17%): LC-MS Method 3 t R =1.38, min, m/z=404, 426; 1 H NMR (CDCl 3 ) 0.95 (m, 6H), 1.52 (d, 3H), 1.72 (m, 2H), 1.84 (m, 2H), 2.05 (m, 1H), 2.79 (m, 1H), 3.08 (m, 1H), 3.77 (m, 2H), 5.76 (m, 1H), 6.86 (m, 2H), 7.35 (m, 3H), 7.42 (m, 2H).

›Examples8

›Example 208

tert-butyl 3-(6-(3-hydroxypropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)pyrrolidine-1-carboxylate

(3S)-tert-butyl 3-(6-(3-hydroxypropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)pyrrolidine-1-carboxylate was prepared using a procedure analogous to that described in Example 110 using 3-chloro-1-phenylpropan-1-one in Step 1 and (S)-tert-butyl 3-isocyanatopyrrolidine-1-carboxylate in Step 2 followed by a procedure analogous to that described in Example 78. Two isomers were isolated.

Isomer 1: LC-MS Method 2 t R =2.033, min, m/z=305.2; 1 H NMR (CDCl 3 ) 1.18 (m, 1H), 1.33 (s, 9H), 1.64 (m, 1H), 1.81-2.09 (m, 4H), 2.16 (m, 1H), 2.29 (m, 1H), 2.73 (m, 1H), 2.80-2.97 (m, 1H), 3.04 (m, 1H), 3.22 (m, 1H), 3.35 (m, 2H), 3.51 (t, 2H), 4.78 (m, 1H), 7.20 (m, 3H), 7.31 (m, 2H).

Isomer 2: LC-MS Method 2 t R =1.244, min, m/z=304.9; 1 H NMR (CDCl 3 ) 1.28 (m, 1H), 1.46 (s, 9H), 1.39 (m, 1H), 1.63 (m, 2H), 1.81 (m, 1H), 1.92 (m, 2H), 2.14 (m, 1H), 2.31 (m, 1H), 2.71 (m, 1H), 3.03 (m, 1H), 3.16 (m, 2H), 3.48-3.58 (m, 3H), 4.78 (m, 1H), 7.20-7.27 (m, 3H), 7.29-7.36 (m, 2H).

(3R)-tert-butyl 3-(6-(3-hydroxypropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)pyrrolidine-1-carboxylate was prepared as described immediately above using (R)-tert-butyl 3-isocyanatopyrrolidine-1-carboxylate to afford two isomers.

Isomer 3: LC-MS Method 3 tR=1.09, min, m/z=305, 427; 1H NMR (CDCl3) 1.38 (s, 9H), 1.63-1.70 (m, 2H), 1.80 (m, 1H), 1.95 (m, 2H), 2.16 (m, 1H), 2.30 (m, 1H), 2.71 (m, 1H), 3.0-3.30 (m, 3H), 3.52 (m, 3H), 4.82 (m, 1H), 7.20-7.27 (m, 3H), 7.28-7.39 (m, 2H).

Isomer 4: LC-MS Method 2 tR=2.03, min, m/z=405, 427; 1H NMR (CDCl3) 1.29 (m, 1H), 1.33 (s, 9H), 1.68 (m, 1H), 1.81-2.09 (m, 4H), 2.10-2.22 (m, 1H), 2.31 (m, 1H), 2.72 (m, 1H), 2.78-2.99 (m, 1H), 2.99-3.12 (m, 1H), 3.21 (m, 1H), 3.30-3.48 (m, 2H), 3.50 (m, 2H), 4.79 (m, 1H), 7.22 (m, 3H), 7.32 (m, 2H).

›Example 209

N-(2-((S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl)methanesulfonamide

The title compound was prepared from (R)-6-(2-aminoethyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one following a procedure analogous to that described in Example 99. LC-MS Method 3 t R =1.45, min, m/z=533; 1 H NMR (CDCl 3 ) 1.52-1.57 (d, 3H), 2.10-2.34 (m, 5H), 2.86 (s, 3H), 2.92-2.99 (m, 1H), 3.00-3.08 (m, 1H), 3.11-3.21 (m, 1H), 4.48-4.57 (s, 1H), 5.63-5.71 (m, 1H), 6.83-6.94 (m, 2H), 6.98-7.09 (m, 4H), 7.17-7.21 (m, 1H), 7.24-7.32 (m, 3H).

›Example 210

(R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(pyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one and pyridine-4-boronic acid using a procedure analogous to that described in Example 64 followed by a procedure analogous to that described in Example 74. LC-MS Method 2 t R =2.2, min, m/z=417; 1 H NMR (CDCl 3 ) 1.48 (m, 2H), 1.50 (t, 2H), 1.92 (m, 2H), 2.28 (m, 3H), 2.89 (m, 1H), 3.53 (m, 3H), 5.66 (m, 1H), 6.99 (m, 2H), 7.28 (q, 8H), 7.52 (d, 2H), 8.51 (m, 1H), 8.63 (m, 1H).

›Example 211

(R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one and pyridine-3-boronic acid using a procedure analogous to that described in Example 64 followed by a procedure analogous to that described in Example 78. LC-MS Method 2 t R =1.5, min, m/z=417; 1 H NMR (CDCl 3 ) 1.32 (m, 2H), 1.50 (t, 3H), 1.68 (m, 2H), 1.91 (m, 2H), 2.15 (m, 1H), 2.26 (m, 2H), 2.83 (m, 1H), 3.51 (m, 2H), 5.62 (q, 1H), 6.93 (d, 2H), 7.20-7.32 (m, 8H), 7.73 (m, 1H), 8.51 (s, 1H), 8.72 (s, 1H).

›Example 212

3-((1S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(3-hydroxypropyl)-6-isopropyl-1,3-oxazinan-2-one

The title compound was prepared from 6-allyl-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-isopropyl-1,3-oxazinan-2-one following a procedure analogous to that described in Example 211. Two isomers were isolated.

Isomer 1: LC-MS Method 3 t R =1.42, min, m/z=418; 1 H NMR (CDCl 3 ) 0.91 (m, 6H), 1.58 (m, 3H), 1.62-1.95 (m, 6H), 2.03 (m, 1H), 2.82 (m, 1H), 3.19 (m, 1H), 3.67 (m, 2H), 5.82 (m, 1H), 6.93 (m, 2H), 7.39 (m, 3H), 7.47 (m, 2H).

Isomer 2: LC-MS Method 3 tR=1.42, min, m/z=418; 1H NMR (CDCl3) 0.89 (m, 6H), 1.52 (m, 3H), 1.62 (m, 5H), 1.84 (m, 1H), 2.03 (m, 1H), 2.72 (m, 1H), 3.03 (m, 1H), 3.57 (m, 2H), 5.79 (m, 1H), 6.86 (m, 2H), 7.32 (m, 3H), 7.43 (m, 2H).

›Example 213

3-((1S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(2-hydroxypropyl)-6-isopropyl-1,3-oxazinan-2-one

The title compound was isolated as a byproduct from the procedure described in Example 212. LC-MS Method 3 t R =1.48, min, m/z=418; 1 H NMR (CDCl 3 ) 0.83-0.97 (m, 6H), 1.13 (m, 3H), 1.33-1.46 (m, 1H), 1.52 (m, 3H), 1.56 (m, 1H), 1.73-1.94 (m, 3H), 2.09 (m, 1H), 2.81 (m, 1H), 3.02-3.14 (m, 1H), 3.98-4.15 (m, 1H), 5.76 (m, 1H), 6.88 (m, 2H), 7.35 (m, 3H), 7.44 (m, 2H).

›Example 214

(S)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one and pyridine-3-boronic acid using a procedure analogous to that described in Example 64 followed by a procedure analogous to that described in Example 74. LC-MS Method 2 t R =1.412, min, m/z=421.2; 1 H NMR (CDCl 3 ) 1.52 (d, 3H), 2.03-2.17 (m, 3H), 2.22-2.32 (m, 3H), 2.81 (m, 1H), 3.47-3.52 (m, 1H), 3.72 (m, 1H), 5.63 (m, 1H), 6.93-7.01 (m, 4H), 7.21-7.26 (m, 2H), 7.28-7.33 (m, 3H), 7.73 (m, 1H), 8.51 (m, 1H), 8.68 (m, 1H).

›Example 215

(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one

›Step 1

4-((S)-1-((R)-6-allyl-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)benzoic acid (40 mg, 0.104 mmol) was dissolved in CH 2 Cl 2 (6 mL). At 0° C., thionyl chloride (1 mL, excess) was added slowly. After 10 min., the mixture was warmed up to rt and stirred 1 h at rt The mixture was concentrated and redissolved in CH 2 Cl 2 (6 mL). NaHCO 3 (22 mg, 2.5 equiv.) and acetohydrazide (12 mg, 1.5 equiv.) were added slowly. After stirring 1 h at rt, LC-MS found reaction completed. The mixture was diluted with CH 2 Cl 2 (10 mL), filtered NaHCO 3 and washed by water (5 mL), 5% aq HCl (2×5 mL), satd aq NaHCO 3 (4 mL), brine (4 mL) and dried over Na 2 SO 4 . After filtration and concentration, the crude N′-acetyl-4-((S)-1-((R)-6-allyl-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)benzohydrazide (34 mg, 74%) was used for next step without further purification.

›Step 2

Crude N′-acetyl-4-((S)-1-((R)-6-allyl-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)benzohydrazide (5 mg, 0.0114 mmol) was mixed with Burgess reagent (˜4 mg, excess), dry THF (1 mL) and put into Microwave Oven, heated to 180° C. for 10 min. at 100 W. LC-MS found reaction completed. The mixture was diluted with EtOAc (8 mL), washed with water (2×3 mL), concentrated and purified by prep HPLC to afford (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (1.4 mg, 29%). LC-MS Method 1 t R =1.61, min, m/z=422; 1 H NMR (CDCl 3 ) 7.77 (d, 2H), 7.26 (m, 3H), 7.01 (m, 3H), 5.70 (m, 2H), 5.07 (dd, 2H), 2.98 (m, 1H), 2.62 (s, 3H), 1.55 (d, 3H).

›Examples3

›Example 216

(R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(thiophen-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from (R)-6-allyl-6-phenyl-3-((S)-1-(4-(thiophen-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and thiophene-2-boronic acid using a procedure analogous to that described in Example 64 followed by a procedure analogous to that described in Example 78. LC-MS Method 2 t R =2.47, min, m/z=422; 1 H NMR (CDCl 3 ) 1.49 (d, 3H), 1.84-1.92 (m, 2H), 2.0-2.15 (m, 4H), 2.25 (m, 2H), 2.84 (m, 1H), 3.52 (m, 1H), 4.20 (m, 1H), 5.60 (m, 1H), 6.82 (dd, 2H), 7.0 (m, 1H), 7.15-7.38 (m, 9H).

›Example 217

(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-morpholinophenyl)ethyl)-1,3-oxazinan-2-one

A flask was charged with (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (400 mg, 0.96 mmol), morpholine (100 mg, 1.15 mmol) and t-BuONa (129 mg, 1.34 mmol) and Pd 2 (dba) 3 (9 mg, 0.01 mmol) and BINAP (6 mg, 0.01 mmol) and toluene. The flask was heated to 80° C. and stirred overnight. The reaction mixture was concentrated to leave a residue, which was purified by preparative TLC to give (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-morpholinophenyl)ethyl)-1,3-oxazinan-2-one (162 mg, 0.4 mmol). LC-MS Method 3 t R =1.29, min, m/z=425; 1 H NMR (CD 3 OD): 1.50 (m, 3H), 2.20 (m, 2H), 2.40 (m, 1H), 2.60 (m, 2H), 3.00 (m, 5H), 3.85 (m, 4H), 5.00 (m, 2H), 5.45 (m, 1H), 5.65 (m, 1H), 6.70 (m, 2H), 6.90 (m, 2H), 7.05 (m, 2H), 7.30 (m, 2H).

›Example 218

(S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(2-hydroxyethyl)-6-(thiophen-2-yl)-1,3-oxazinan-2-one

›Step 1

Pd(PPh 3 ) 2 Cl 2 (100 mg) was added to the solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(thiophen-2-yl)-1,3-oxazinan-2-one (1.0 g, 2.5 mmol), 4-fluorophenylboronic acid (420 mg, 3.0 mmol) in 1,4-dioxane. Cs 2 CO 3 (5 mL) was slowly added. The mixture was heated to reflux for 2 h. The mixture was quenched with water and separated, extracted with EtOAc twice, dried over anhydrous Na 2 SO 4 and concentrated to afford the residue, which was purified by TLC to give (R)-6-allyl-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(thiophen-2-yl)-1,3-oxazinan-2-one (768 mg, 73%).

›Step 2

To a solution of (R)-6-allyl-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(thiophen-2-yl)-1,3-oxazinan-2-one (300 mg, 0.71 mmol) was added aqueous solution of KMnO 4 (66 mg, 0.42 mmol) and NaIO 4 (537 mg, 2.52 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was filtered and concentrated, then extracted with CH 2 Cl 2 . The organic phases was dried over Na 2 SO 4 , filtered and concentrated to afford 2-((S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-2-oxo-6-(thiophen-2-yl)-1,3-oxazinan-6-yl)acetic acid (218 mg, 70%).

›Step 3

A solution of 2-((S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-2-oxo-6-(thiophen-2-yl)-1,3-oxazinan-6-yl)acetic acid (218 mg, 0.5 mmol) in THF anhydrous (10 mL) was added BH 3 (3.0 mL) at 0□ and then stirred at reflux for 2 h. Then the reaction mixture quenched by water and separated, extracted with EtOAc twice. The organic phases was dried over Na 2 SO 4 , filtered and concentrated to afford the residue, which was purified by TLC to give (S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(2-hydroxyethyl)-6-(thiophen-2-yl)-1,3-oxazinan-2-one (85 mg, 40%). LC-MS Method 3 t R =1.35, min, m/z=426, 448; 1 H NMR (CD 3 OD): 1.50 (m, 3H), 2.15 (m, 2H), 2.30 (m, 1H), 2.40 (m, 1H), 2.60 (m, 1H), 3.15 (m, 1H), 3.45 (m, 1H), 3.70 (m, 1H), 5.60 (m, 1H), 6.90 (m, 1H), 7.00 (m, 1H), 7.10 (m, 4H), 7.35 (m, 3H), 7.55 (m, 2H).

(R)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(2-hydroxyethyl)-6-(thiophen-2-yl)-1,3-oxazinan-2-one was prepared following a procedure analogous to that described immediately above. LC-MS Method 3 t R =1.4, min, m/z=426, 448; 1 H NMR (CD 3 OD) 1.38 (d, 3H), 2.01 (m, 1H), 2.18 (m, 3H), 2.41 (m, 1H), 2.86 (m, 1H), 3.02 (m, 1H), 3.41 (m, 1H), 3.72 (m, 1H), 5.62 (m, 1H), 6.98 (m, 1H), 7.03 (m, 1H), 7.15 (m, 1H), 7.36 (m, 3H), 7.58 (m, 4H).

›Example 219

3-((R)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanenitrile

To a solution of 3-((R)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanamide (110 mg, 0.25 mmol) and DIEA (170 mg, 1.05 mmol) in anhydrous CH 2 Cl 2 (5 mL) was added TFAA (158 mg, 0.75 mmol) at 0° C. The mixture was stirred for 2 h. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC to afford 3-((R)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanenitrile (8 mg, yield 10%). LC-MS Method 3 t R =1.458, min, m/z=429.2; 1 H NMR (CDCl 3 ): 1.52 (d, 3H), 2.01 (m, 1H), 2.14 (m, 2H), 2.29 (m, 3H), 2.53 (m, 2H), 2.90 (m, 1H), 5.62 (m, 1H), 6.93 (m, 2H), 7.04 (m, 2H), 7.16-7.25 (m, 2H), 7.30-7.47 (m, 5H).

›Example 220

(R)-3-((S)-1-(4-bromophenyl)propyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one

›Step 1

To a solution of (S)-1-phenylpropan-1-amine (3.00 g, 14 mmol) in the mixture of methylene chloride (50 mL) and saturated NaHCO 3 (50 mL) was added triphosgene (1.40 g, 4.60 mmol) at 0° C. The mixture was stirred for 15 minutes. The organic phase was separated, dried and concentrated to give (S)-(1-isocyanatopropyl)benzene (3.0 g, 88%). 1 H NMR (CDCl 3 ): δ=0.93 (q, 3H), 1.81 (m, 2H), 4.50 (m, 1H), 7.13 (m, 2H), 7.22 (m, 1H), 7.50 (m, 2H).

›Step 2

A mixture of (S)-(1-isocyanatopropyl)benzene (3.0 g, 12.5 mmol), 1-chloro-3-phenylhex-5-en-3-ol (3.6 g, 12.5 mmol) and DBU (3.80 g, 25 mmol) in tetrahydrofuran (20 mL) was heated to reflux overnight. The mixture was washed by 1 N HCl and extracted with EtOAc. The organic phase was concentrated to give the crude product which was purified by column chromatography to give (R)-6-allyl-3-((S)-1-(4-bromophenyl)propyl)-6-phenyl-1,3-oxazinan-2-one (1.0 g, 20%). 1 H NMR (400 MHz, CDCl 3 ): δ=0.92 (t, 3H), 1.72-2.00 (m, 4H), 2.06-2.31 (m, 4H), 2.53 (m, 2H), 2.82 (m, 1H), 4.99 (m, 2H), 5.32 (m, 1H), 5.69 (m, 1H), 6.72 (m, 1H), 7.12 (m, 4H), 7.25 (m, 4H).

›Step 3

To a solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)propyl)-6-phenyl-1,3-oxazinan-2-one (100 mg, 0.242 mmol) in tetrahydrofuran (10 mL) was added BH 3 THF (3 mL, 1 mol/L) at 0° C. under nitrogen. The formed mixture was stirred for 2 h. Then the reaction was quenched by water, followed by 3 mol/L NaOH and H 2 O 2 (3 mL). The PH of the mixture was adjusted to <7 with 5% HCl. The organic phase was separated, extracted by EtOAc, and concentrated to give the crude product, which was purified by preparative HPLC to give (R)-3-((S)-1-(4-bromophenyl)propyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (15 mg, 15%). LC-MS Method 3 t R =1.36, min, m/z=432, 434; 1 H NMR (CDCl 3 ): δ=0.99 (t, 3H), 1.29 (m, 1H), 1.63 (m, 1H), 1.98 (m, 4H), 2.20-2.42 (m, 2H), 2.48 (m, 1H), 3.08 (m, 1H), 3.49 (m, 1H), 5.30 (m, 1H), 6.92 (m, 2H), 7.26 (m, 4H), 7.35 (m, 2H).

›Example 221

(R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

›Step 1

A mixture of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (150 mg, 0.375 mmol) and 6-aminopyridin-3-ylboronic acid (56 mg, 0.45 mmol), Pd(Ph 3 P) 2 Cl 2 (15 mg), and aqueous Cs 2 CO 3 solution (0.5 mL, 2 M) in 1,4-dioxane (10 mL) was stirred and heated to reflux for 2 h. The organic phase was separated, and concentrated to give the crude product, which was purified by preparative HPLC to give (R)-6-allyl-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (90 mg, 60%).

›Step 2

To a solution of (R)-6-allyl-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (90 mg, 0.23 mmol) in tetrahydrofuran (10 mL) was added BH 3 THF (3.0 mL, 1 mol/L, 4 mmol) at 0° C. under nitrogen atmosphere. The formed mixture was stirred for 2 h. The reaction was quenched by water. Then NaOH (2 mL, 3 mol/L) and H 2 O 2 (1 mL) was added to the above mixture. When the reaction was over, the mixture was extracted with EtOAc. The combined organic phase was concentrated to give the crude product, which was purified by preparative HPLC to give (R)-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (40 mg, 41%).

›Step 3

(R)-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (40 mg, 0.09 mmoL) was dissolved in 3.5 M H 2 SO 4 (10 mL), and 2 M NaNO 2 (10 mL) was added at 0° C. The reaction mixture was stirred at rt for 2 h and treated with NaOH solution. The mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na 2 SO 4 , and concentrated to afford the residue, which was purified by preparative HPLC to give (R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (10 mg, 20%). LC-MS Method 2 t R =1.66, min, m/z=433, 455; 1 H NMR (CDCl 3 ): 1.36 (m, 2H), 1.50 (m, 3H), 1.68 (m, 2H), 1.92 (m, 2H), 2.10-2.30 (m, 3H), 2.84 (m, 1H), 3.50 (m, 2H), 5.12 (m, 1H), 6.62 (m, 1H), 6.86 (m, 2H), 7.08 (m, 2H), 7.18-7.32 (m, 5H), 7.46 (m, 1H), 7.62 (m, 1H).

›Examples13

›Example 222

3-(4-((S)-1-((R)-6-(3-hydroxypropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)pyridine 1-oxide

A mixture of (R)-1-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-4-(4-fluorophenyl)-4-(3-hydroxypropyl)tetra-hydropyrimidin-2(1H)-one (30 mg, 0.07 mmol) and 3-chloro-perbenzoic acid (84 mg, 0.49 mmol) in THF (1.5 mL) was stirred at rt for 3 h. Satd aq NaHCO 3 was added to the reaction mixture, and the organic layer was separated. The organic layer was washed with brine, dried over Na 2 SO 4 and concentrated to give the crude product, which was purified by preparative HPLC to give 3-(4-((S)-1-((R)-6-(3-hydroxypropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)pyridine 1-oxide (2.83 mg, 9%). LC-MS Method 2 t R =1.623, min, m/z=433.2; 1 H NMR (400 MHz, CDCl 3 ): δ=1.54 (t, 3H), 1.94 (m, 2H), 2.21-2.24 (m, 2H), 2.35-2.39 (m, 2H), 2.49 (m, 1H), 3.1 (m, 1H), 3.44 (m, 1H), 5.57 (m, 1H), 7.07 (m, 2H), 7.28-7.42 (m, 6H), 7.58 (m, 1H), 7.77 (m, 1H), 8.19 (m, 1H), 8.28 (m, 1H), 8.49 (m, 1H).

›Example 223

3-((1S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(2,3-dihydroxypropyl)-6-isopropyl-1,3-oxazinan-2-one

Isomer 1: LC-MS Method 2 t R =1.34 min, m/z=456; 1 H NMR (CDCl 3 ) 0.87 (m, 6H), 1.53 (m, 3H), 1.65 (m, 2H), 1.82 (m, 2H), 2.05 (m, 1H), 2.75 (m, 1H), 3.13 (m, 1H), 3.39 (m, 1H), 3.59 (m, 1H), 4.03 (m, 1H), 5.74 (m, 1H), 6.88 (m, 2H), 7.34 (m, 3H), 7.43 (m, 2H).

Isomer 2: LC-MS Method 2 t R =1.336 min, m/z=456.1; 1 H NMR (CDCl 3 ) 0.83 (m, 3H), 0.95 (m, 3H), 1.52 (m, 3H), 1.64 (m, 1H), 1.76-1.87 (m, 3H), 2.05 (m, 1H), 2.75 (m, 1H), 3.13 (m, 1H), 3.45 (m, 1H), 3.58 (m, 1H), 3.95 (m, 1H), 5.74 (m, 1H), 6.88 (m, 2H), 7.34 (m, 3H), 7.43 (m, 2H).

Isomer 3: LC-MS Method 2 t R =1.335, min, m/z=456.1; 1 H NMR (CDCl 3 ) 0.89-0.96 (m, 6H), 1.51 (d, 3H), 1.57 (m, 2H), 1.81-1.94 (m, 2H), 2.13 (m, 1H), 2.73 (m, 1H), 3.07 (m, 1H), 3.36 (m, 1H), 3.57 (m, 1H), 3.98 (m, 1H), 5.76 (m, 1H), 6.81-6.92 (m, 2H), 7.28-7.37 (m, 3H), 7.43 (m, 2H).

Isomer 4: LC-MS Method 2 t R =2.328 min, m/z=456.2; 1 H NMR (CDCl 3 ) 0.87 (m, 3H), 0.94 (m, 3H), 1.57 (m, 3H), 1.79-1.94 (m, 3H), 2.11 (m, 1H), 2.41 (m, 1H), 2.79 (m, 1H), 3.11 (m, 1H), 3.45 (m, 1H), 3.54 (m, 1H), 4.23 (m, 1H), 5.75 (m, 1H), 6.82-6.93 (m, 2H), 7.33 (m, 3H), 7.43 (m, 2H).

›Example 224

(6S)-3-((1S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(2-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was isolated as a byproduct of hydroboration of (R)-6-allyl-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-phenyl-1,3-oxazinan-2-one following a procedure analogous to that described in Example 78. LC-MS Method 3 t R =1.47, min, m/z=434; 1 H NMR (CDCl 3 ) 1.06 (m, 3H), 1.19 (s, 1H), 1.48 (m, 3H), 1.82-2.11 (m, 2H), 2.14-2.45 (m, 3H), 2.84 (m, 1H), 3.72-3.96 (m, 1H), 5.58 (m, 1H), 6.81 (m, 1H), 6.90 (m, 1H), 7.03 (m, 2H), 7.15-7.38 (m, 9H).

Two isomers were separated by preparative HPLC.

Isomer 1: LC-MS Method 1 t R =1.84, min, m/z=434; 1 H NMR (CD 3 OD) 7.45-7.41 (m, 2H), 7.33-7.24 (m, 5H), 7.22 (d, J=8.5 Hz, 2H), 7.08-7.03 (m, 2H), 6.84 (d, J=8.2 Hz, 2H), 5.46 (q, J=7.0 Hz, 1H), 3.49-3.45 (m, 1H), 3.03-2.98 (m, 1H), 2.64-2.59 (m, 1H), 2.34-2.27 (m, 1H), 2.19-2.12 (m, 1H), 2.04 (dd, J=14.3, 7.3 Hz, 1H), 1.88 (dd, J=14.3, 4.7 Hz, 1H), 1.46 (d, J=7.0 Hz, 3H), 1.06 (d, J=6.2 Hz, 3H).

Isomer 2: LC-MS Method 1 t R =1.88, min, m/z=434; 1 H NMR (CD 3 OD) 7.45-7.41 (m, 2H), 7.32-7.22 (m, 7H), 7.08-7.03 (m, 2H), 6.90 (d, J=8.2 Hz, 2H), 5.48 (q, J=7.1 Hz, 1H), 3.91-3.86 (m, 1H), 2.99-2.94 (m, 1H), 2.39-2.35 (m, 2H), 2.20-2.13 (m, 1H), 1.97 (dd, J=14.9, 7.3 Hz, 1H), 1.87 (dd, J=14.9, 3.5 Hz, 1H), 1.47 (d, J=7.3 Hz, 3H), 0.93 (d, J=6.2 Hz, 3H).

›Example 225

(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one following a procedure analogous to that described in Example 78. LC-MS Method 2 t R =1.463, min, m/z=435.2; 1 H NMR (CDCl 3 ) 1.51 (d, 3H), 1.82-1.98 (m, 3H), 2.11-2.21 (m, 2H), 2.22-2.32 (m, 2H), 2.93 (m, 1H), 3.53 (m, 2H), 5.66 (m, 1H), 6.93-7.01 (m, 4H), 7.22 (m, 1H), 7.28 (m, 2H), 7.33 (m, 1H), 7.79 (m, 1H), 8.52 (m, 1H), 8.68 (m, 1H).

›Example 226

(R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-phenyl-6-propyl-1,3-oxazinan-2-one

To a solution of (R)-6-allyl-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-phenyl-1,3-oxazinan-2-one (0.2475 g, 0.57 mmol, 1.0 equiv) in 6 mL of dry THF was added 9-BBN (0.5 M solution in THF, 2.3 mL, 1.15 mmol, 2.0 equiv). The mixture was stirred for 3 h at rt. It was then subjected to oxidative workup by adding 3 N aqueous NaOH (6 mL) followed by careful and dropwise addition of 50% aq H 2 O 2 (4 mL) with vigorous stirring. The reaction mixture was stirred for 1 h, extracted with CH 2 Cl 2 , and dried over Na 2 SO 4 . Surprisingly, the reductive product was observed instead of hydroboration-oxidation. After the solvent was evaporated under reduced pressure, the residue was purified by reversed-phase HPLC (SunFire™ Prep C 18 OBD™ 5 μm 19×50 mm column, 10%→90% CH 3 CN/H 2 O, 0.1% CF 3 COOH over 8 min and then 90% CH 3 CN/H 2 O, 0.1% CF 3 COOH over 2 min, flow rate 20 mL/min) to afford 0.0902 g of (R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-phenyl-6-propyl-1,3-oxazinan-2-one LC-MS Method 1 tR=2.22, min, m/z=436; 1 H NMR (400 MHz, CD 3 OD) δ 7.33-7.14 (m, 8H), 6.96-6.87 (m, 4H), 5.48 (q, J=7.0 Hz, 1H), 3.01-2.96 (m, 1H), 2.41-2.36 (m, 1H), 2.29-2.21 (m, 1H), 2.14-2.07 (m, 1H), 1.81-1.72 (m, 2H), 1.46 (d, J=7.0 Hz, 3H), 1.39-1.29 (m, 1H), 1.08-0.98 (m, 1H), 0.76 (t, J=7.5 Hz, 3H); 19 F NMR (376 MHz, CD 3 OD) δ −113.79 (m), −115.77 (m).

›Example 227

3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one

(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one was prepared from (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one following a procedure analogous to that described in Example 78. LC-MS Method 3 t R =1.287, min, m/z=458.1; 1 H NMR (CDCl 3 ) 1.43 (d, 3H), 1.58-1.69 (m, 2H), 1.81-1.97 (m, 2H), 2.11-2.24 (m, 3H), 2.82 (m, 1H), 3.51 (m, 2H), 5.52 (m, 1H), 6.71 (d, 2H), 6.98 (m, 2H), 7.22 (m, 4H).

(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one was prepared from (S)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one following a procedure analogous to that described in Example 78. LC-MS Method 3 t R =1.27, min, m/z=436, 458; 1 H NMR (CDCl 3 ) 1.48 (d, 3H), 1.55-1.65 (m, 2H), 1.82-1.94 (m, 2H), 2.08-2.24 (m, 3H), 2.84 (m, 1H), 3.50 (m, 2H), 5.53 (m, 1H), 6.72 (d, 2H), 6.96 (m, 2H), 7.19 (m, 4H).

›Example 228

N-(4-((S)-1-((S)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)methanesulfonamide

Step 1. (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-(tert-butyldimethylsilyloxy)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one

A mixture of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one (0.4300 g, 1.02 mmol), 4-dimethylaminopyridine (0.0783 g, 0.64 mmol), triethylamine (0.8 mL, 5.74 mmol), and tert-butyldimethylsilyl chloride (0.2870 g, 1.90 mmol) in CH 2 Cl 2 was stirred for 16 h at rt. After the solvents were removed in vacuo, the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc to give 0.2856 g of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-(tert-butyldimethylsilyloxy)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one as a solid. LC-MS Method 1 t R =2.49 min, m/z 560, 558 (MNa + ), 538, 536 (MH + ), 494, 492; 1 H NMR (400 MHz, CDCl 3 ) δ 7.34-7.25 (m, 4H), 7.10-7.05 (m, 2H), 6.78 (d, J=8.5 Hz, 2H), 5.63 (q, J=7.0 Hz, 1H), 3.84-3.78 (m, 1H), 3.44-3.38 (m, 1H), 2.96-2.90 (m, 1H), 2.78-2.27 (m, 3H), 2.18-2.04 (m, 2H), 1.52 (d, J=7.3 Hz, 3H), 0.87 (s, 9H), 0.02 (s, 3H), 0.00 (s, 3H); 19 F NMR (376 MHz, CDCl 3 ) δ −114.99 (m).

Step 2. N-(4-((S)-1-((S)-6-(2-(tert-butyldimethylsilyloxy)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)methanesulfonamide

A mixture of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-(tert-butyldimethylsilyloxy)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (0.0465 g, 0.0866 mmol), methanesulfonamide (0.0945 g), K 3 PO 4 (0.2753 g), N,N-dimethylglycine (0.0686 g), and CuI (0.0687 g) in DMF (2 mL) was heated at 120° C. for 17 h. The mixture was diluted with EtOAc, filtered, washed with CH 2 Cl 2 . After the solvent was evaporated under reduced pressure, the residue was purified by reversed-phase HPLC (SunFire™ Prep C 18 OBD™ 5 μm 19×50 mm column, 10%→90% CH 3 CN/H 2 O, 0.1% CF 3 COOH over 8 min and then 90% CH 3 CN/H 2 O, 0.1% CF 3 COOH over 2 min, flow rate 20 mL/min) to afford N-(4-((S)-1-((S)-6-(2-(tert-butyldimethylsilyloxy)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)methanesulfonamide. LC-MS t R =2.10 min in 3 min chromatography, m/z 551 (MH + ), 507.

Step 3. N-(4-((S)-1-((S)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)methanesulfonamide

To a solution of N-(4-((S)-1-((S)-6-(2-(tert-butyldimethylsilyloxy)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)methanesulfonamide in acetonitrile—water, obtained as described above, was added 15 mL of 2 N HCl. The mixture was vigorously stirred at rt for 20 h. After the solvents were removed in vacuo, the residue was purified by reversed-phase HPLC (SunFire™ Prep C 18 OBD™ 5 μm 19×50 mm column, 10%→90% CH 3 CN/H 2 O, 0.1% CF 3 COOH over 8 min and then 90% CH 3 CN/H 2 O, 0.1% CF 3 COOH over 2 min, flow rate 20 mL/min) to afford N-(4-((S)-1-((S)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)methanesulfonamide. LC-MS Method 1 tR=1.17, min, m/z=437; 1 H NMR (400 MHz, CD 3 OD) δ 7.25-7.22 (m, 2H), 7.03-6.99 (m, 2H), 6.94 (d, J=8.5 Hz, 2H), 6.84 (d, J=8.5 Hz, 2H), 5.43 (q, J=7.0 Hz, 1H), 3.63-3.56 (m, 1H), 3.27-3.21 (m, 1H), 3.03-2.96 (m, 1H), 2.79 (s, 3H), 2.44-2.37 (m, 1H), 2.22-2.12 (m, 2H), 2.03 (t, J=7.2 Hz, 2H), 1.42 (d, J=7.0 Hz, 3H); 19 F NMR (376 MHz, CD 3 OD) δ −117.03 (m).

›Example 229

(S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-(methylsulfonyl)ethyl)-1,3-oxazinan-2-one

To a solution of (S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-(methylthio)ethyl)-1,3-oxazinan-2-one (30 mg, 0.062 mmol) in methylene chloride (5 mL) was added m-CPBA (25 mg, 0.12 mmol). The formed mixture was stirred for 1 h and then washed with saturated Na 2 CO 3 . The organic phase was separated, and concentrated to give the crude product which was purified by preparative HPLC to afford (S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-(methylsulfonyl)ethyl)-1,3-oxazinan-2-one (6 mg, 18%). LC-MS Method 3 t R =1.44, min, m/z=518; 1 H NMR (400 MHz, CDCl 3 ): δ=1.52 (d, 3H), 2.13-2.36 (m, 4H), 2.42 (m, 1H), 2.58 (m, 1H), 3.01 (m, 1H), 3.29 (m, 1H), 5.63 (m, 1H), 6.35 (m, 2H), 7.00 (m, 4H), 7.18 (m, 2H), 7.22 (m, 3H).

›Example 230

(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one

N′-acetyl-4-((S)-1-((R)-6-allyl-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)benzohydrazide (4 mg, 0.009 mmol) was dissolved in 5:1 toluene/pyridine (1.5 mL). Phosphorous pentasulfide (8.1 mg, 2 equiv.) was added and the mixture was heated in Microwave Oven for 25 min at 130° C. LC-MS found reaction completed. The mixture was diluted with EtOAc (8 mL), washed with 5% HCl (2×5 mL), satd aq NaHCO 3 solution (4 mL), brine (4 mL) and dried over Na 2 SO 4 . After filtration and concentration, the residue was purified by prep HPLC to afford 2.43 mg (61% yield). LC-MS Method 1 t R =1.7, min, m/z=438; 1 H NMR (CDCl 3 ) 7.66 (d, 2H), 7.26 (t, 2H), 7.02 (t, 2H), 6.97 (d, 2H), 5.69 (m, 2H), 5.07 (dd, 2H), 2.98 (m, 1H), 2.83 (s, 3H), 1.56 (d, 3H).

›Example 231

(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-1,3-oxazinan-2-one

A mixture of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (400 mg, 0.96 mmol), 1-methylpiperazine (100 mg, 1.0 mmol), t-BuONa (129 mg, 1.34 mmol), Pd 2 (dba) 3 (9 mg, 0.01 mmol), BINAP (6 mg, 0.01 mmol) in toluene. was heated to 80° C. and stirred overnight. Then the reaction mixture was concentrated to afford the residue, which was purified by preparative TLC to give (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-1,3-oxazinan-2-one (162 mg, 0.4 mmol). LC-MS Method 2 t R =1.77, min, m/z=438; 1 H NMR (CD 3 OD) 1.50 (m, 3H), 2.20 (m, 2H), 2.30 (m, 3H), 2.35 (m, 1H), 2.60 (m, 6H), 3.00 (m, 1H), 3.10 (m, 4H), 5.00 (m, 2H), 5.45 (m, 1H), 5.65 (m, 1H), 6.70 (m, 2H), 6.80 (m, 2H), 7.05 (m, 2H), 7.25 (m, 2H).

›Example 232

(R)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(3-hydroxypropyl)-6-(thiophen-2-yl)-1,3-oxazinan-2-one

The title compound was prepared from (R)-6-allyl-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(thiophen-2-yl)-1,3-oxazinan-2-one following a procedure analogous to that described in Example 78. LC-MS Method 3 t R =1.39, min, m/z=440; 1 H NMR (CD 3 OD) 1.40 (m, 1H), 1.50 (m, 3H), 1.65 (m, 1H), 2.00 (m, 2H), 2.35 (m, 1H), 2.40 (m, 1H), 2.60 (m, 1H), 3.15 (m, 1H), 3.45 (m, 2H), 5.60 (m, 1H), 6.90 (m, 1H), 7.00 (m, 1H), 7.10 (m, 4H), 7.35 (m, 3H), 7.55 (m, 2H).

›Example 233

3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(2-hydroxyethyl)-6-(thiophen-2-yl)-1,3-oxazinan-2-one

(S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(2-hydroxyethyl)-6-(thiophen-2-yl)-1,3-oxazinan-2-one was prepared from (R)-6-allyl-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(thiophen-2-yl)-1,3-oxazinan-2-one following a procedure analogous to that described in Example 218. LC-MS Method 3 t R =1.38, min, m/z=444, 466; 1 H NMR (CD 3 OD) 1.55 (m, 3H), 2.18 (m, 2H), 2.30 (m, 1H), 2.45 (m, 1H), 2.60 (m, 1H), 3.15 (m, 1H), 3.45 (m, 1H), 3.70 (m, 1H), 5.60 (m, 1H), 6.90 (m, 1H), 7.00 (m, 5H), 7.30 (m, 2H), 7.40 (m, 2H).

(R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(2-hydroxyethyl)-6-(thiophen-2-yl)-1,3-oxazinan-2-one was prepared from (S)-6-allyl-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(thiophen-2-yl)-1,3-oxazinan-2-one following a procedure analogous to that described in Example 218. LC-MS Method 3 t R =1.26, min, m/z=444, 466; 1 H NMR (CD 3 OD) 1.38 (d, 3H), 2.17 (m, 2H), 2.21 (m, 1H), 2.41 (m, 1H), 2.86 (m, 1H), 3.02 (m, 1H), 3.45 (m, 1H), 3.71 (m, 1H), 5.62 (m, 1H), 6.98 (m, 4H), 7.36 (m, 3H), 7.45 (m, 3H).

›Example 234

3-((R)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanamide

›Step 1

CrO 3 (1 g) was added to H 2 SO 4 (1 mL) and water was added to bring the total volume to 4 mL. (R)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (600 mg, 1.4 mmol) was dissolved in 10 mL acetone, and cooled in an ice bath. The Jones reagent (0.5 mL) was slowly added to the mixture and stirred overnight. Solvent was removed in vacuo, the residue was dissolved in CH 2 Cl 2 (10 mL) and water (10 mL). The layers were separated, and the aq layer was extracted with CH 2 Cl 2 (3×10 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give 3-((R)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanoic acid (500 mg, crude), which was not purified.

›Step 2

A mixture of 3-((R)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanoic acid (500 mg, 1.12 mmol), HOBT (302 mg, 2.24 mmol), EDCl (440 mg, 2.24 mmol) and DIEA (1 mL) in anhydrous CH 2 Cl 2 (10 mL) were stirred at 0□ under NH 3 . Then the solution was stirred at rt overnight. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC to afford 3-((R)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanamide (234 mg, yield 48%). 1 H NMR (CDCl 3 ): 1.49 (m, 3H), 1.91-2.02 (m, 1H), 1.87-1.98 (m, 1), 2.10-2.31 (m, 5H), 2.39-2.5 (m, 1H), 2.87 (m, 1H), 5.27 (s, 1H), 5.51 (s, 1H), 5.64 (m, 1H), 6.94 (m, 2H), 7.04 (m, 2H), 7.21-7.35 (m, 6H), 7.39 (m, 2H). LC-MS Method 3 t R =1.3, min, m/z=447, 469; 1 H NMR (CDCl 3 ) 1.49 (m, 3H), 1.91-2.02 (m, 1H), 1.87-1.98 (m, 1), 2.10-2.31 (m, 5H), 2.39-2.5 (m, 1H), 2.87 (m, 1H), 5.27 (s, 1H), 5.51 (s, 1H), 5.64 (m, 1H), 6.94 (m, 2H), 7.04 (m, 2H), 7.21-7.35 (m, 6H), 7.39 (m, 2H).

›Examples4

›Example 235

(R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-methoxypyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one and 2-methoxypyridine-5-boronic acid using a procedure analogous to that described in Example 64 followed by a procedure analogous to that described in Example 78. LC-MS Method 3 t R =1.22, min, m/z=447; 1 H NMR (CDCl 3 ) 1.01 (d, 1H), 1.10 (d, 1H), 1.49 (s, 3H), 1.85-1.95 (m, 1H), 2.00-2.07 (m, 1H), 2.21-2.30 (m, 2H), 2.40 (m, 1H), 2.35 (m, 1H), 3.87 (m, 1H), 3.90 (s, 3H), 3.95 (m, 1H), 5.61 (m, 1H), 6.71 (d, 1H), 6.83 (d, 1H), 6.91 (m, 1H), 7.16 (m, 2H), 7.25 (m, 2H), 7.31 (m, 3H), 7.61 (d, 1H), 8.22 (s, 1H).

›Example 236

3-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanamide

The title compound was prepared from (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one following a procedure analogous to that described in Example 234. LC-MS Method 2 t R =1.372, min, m/z=448.3; 1 H NMR (CDCl 3 ) 1.52 (d, 3H), 1.97 (m, 2H), 2.27-2.33 (m, 4H), 2.43 (m, 1H), 2.97 (m, 1H), 5.13 (s, 1H), 5.24 (s, 1H), 5.66 (m, 1H), 6.92-7.08 (m, 4H), 7.22 (m, 2H), 7.31 (m, 2H), 7.48 (m, 1H), 7.97 (m, 1H), 8.57 (m, 1H), 8.74 (m, 1H).

›Example 237

(R)-3-((S)-1-(4′-fluorobiphenyl-4-yl)propyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from (R)-6-allyl-3-((S)-1-(4-bromophenyl)propyl)-6-phenyl-1,3-oxazinan-2-one and 4-fluorobenzeneboronic acid using a procedure analogous to that described in Example 64 followed by a procedure analogous to that described in Example 78. LC-MS Method 3 tR=1.48, min, m/z=448; 1H NMR (CDCl3) 0.99 (t, 3H), 1.28 (m, 1H), 1.62 (m, 1H), 1.91-2.08 (m, 4H), 2.25 (m, 1H), 2.34 (m, 1H), 2.42 (m, 1H), 3.08 (m, 1H), 3.46 (m, 2H), 5.39 (m, 1H), 7.02-7.16 (m, 4H), 7.22-7.42 (m, 7H), 7.51 (m, 2H).

›Example 238

(S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one

›Step 1

A mixture of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (5.83 g, 15 mmol), 4-fluorophenylboronic acid (3 g, 22 mmol), PdCl 2 (PPh 3 ) 2 (1 g, 1.4 mmol), and aqueous Cs 2 CO 3 solution (2 M, 8.0 mL) in 1,4-dioxane (50 mL) was heated to reflux for 2 h. The mixture was filtered, and the filtrate was extracted with EtOAc (3×). The combined organic layer was washed with brine, dried over Na 2 SO 4 and concentrated to give the crude product, which was purified by preparative TLC to give (R)-6-allyl-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-phenyl-1,3-oxazinan-2-one (5.3 g, 88%).

›Step 2

To a solution of (R)-6-allyl-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-phenyl-1,3-oxazinan-2-one (3 g, 7.23 mmol) in acetone (20 mL) was added a solution of KMnO 4 (685 mg, 4.34 mmol) and NaIO 4 (5.6 g, 26 mmol) in H 2 O (15 mL) dropwise at 0° C. The mixture was stirred for 4 h. When TLC showed that the starting material had disappeared, the precipitate was removed by filtration, and the acetone was removed under reduced pressure. The resulting mixture was basified to pH=13 by the addition of 1 M aq NaOH, and then washed with ether (3×50 mL). The aqueous phase was acidified to pH=1 by addition of 1 N aq HCl, and extracted with CH 2 Cl 2 (3×15 mL). The organic layers were combined, washed with brine, dried over Na 2 SO 4 and concentrated in vacuo to give 2-((S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)acetic acid (2.8 g, 90%).

›Step 3

To a solution of 2-((S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)acetic acid (1 g, 2.3 mmol) in MeOH (15 mL) was added thionyl chloride (408 mg, 3.5 mmol) dropwise at 0° C. under N 2 atmosphere. After refluxing overnight, the mixture was concentrated to give the crude product, which was purified by chromatography to give methyl 2-((S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)acetate (680 mg, 68%).

›Step 4

To a solution of methyl 2-((S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)acetate (180 mg, 0.4 mmol) in dry THF (5 mL) under N 2 at −78° C. was added methylmagnesium bromide (1.5 mL, 3 M, 4.5 mmol) dropwise at −78° C. After addition, the mixture was stirred for 1 h at rt. Then the reaction was quenched with water and the mixture was extracted with ethyl acetate for three times (3×5 mL). The organic layers were combined, washed with brine, dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by preparative HPLC to give (S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (2.48 mg, 1%). 1 H NMR (CDCl 3 ): 1.05 (s, 1H), 1.13 (s, 3H), 1.50 (d, 3H), 2.14-2.23 (m, 2H), 2.25-2.40 (m, 1H), 2.80 (m, 1H), 5.63 (m, 1H), 6.94 (m, 2H), 7.02 (m, 2H), 7.18-7.30 (m, 7H), 7.38 (m, 2H). LC-MS Method 3 t R =1.51, min, m/z=448, 470.

›Examples8

›Example 239

(6S)-3-((1S)-1-(4-bromophenyl)propyl)-6-(2,3-dihydroxypropyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from (R)-6-allyl-3-((S)-1-(4-bromophenyl)propyl)-6-phenyl-1,3-oxazinan-2-one using AD-mix-beta following a procedure analogous to that described in Example 173. Two isomers were isolated.

Isomer 1: LC-MS Method 3 t R =1.2, min, m/z=448, 472; 1 H NMR (CDCl 3 ) 0.96 (d, 3H), 1.93 (m, 2H), 2.04 (m, 2H), 2.22-2.41 (m, 2H), 2.50 (m, 2H), 3.04 (m, 1H), 3.38 (m, 1H), 3.42 (m, 2H), 5.28 (m, 1H), 6.85 (m, 2H), 7.24 (m, 2H), 7.35 (m, 5H).

Isomer 2: LC-MS Method 3 tR=1.18, min, m/z=448, 472; 1H NMR (CDCl3) 0.99 (d, 3H), 1.93 (m, 2H), 2.04 (m, 2H), 2.22-2.41 (m, 2H), 2.70 (m, 1H), 3.04 (m, 1H), 3.32 (m, 1H), 3.42 (m, 2H), 5.27 (m, 1H), 6.85 (m, 2H), 7.24 (m, 2H), 7.35 (m, 5H).

›Example 240

3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propanamide

The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one following a procedure analogous to that described in Example 234. LC-MS Method 3 t R =1.18, min, m/z=449, 451; 1 H NMR (CDCl 3 ) 1.49 (m, 3H), 1.91-2.00 (m, 1H), 2.11-2.32 (m, 5H), 2.46 (m, 1H), 2.90 (m, 1H), 5.31-5.55 (s, 2H), 5.61 (m, 1H), 6.81 (m, 2H), 7.02 (m, 2H), 7.22 (m, 2H), 7.28 (m, 2H).

›Example 241

(R)-3-((S)-1-(4-bromophenyl)propyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one

The title compound was prepared from (R)-6-allyl-3-((S)-1-(4-bromophenyl)propyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one following a procedure analogous to that described in Example 78. LC-MS Method 3 t R =1.37, min, m/z=450, 452, 472, 474; 1 H NMR (CDCl 3 ) 0.99 (t, 3H), 1.34 (m, 1H), 1.67 (m, 1H), 1.81-2.02 (m, 4H), 2.21 (m, 1H), 2.32 (m, 1H), 2.92 (m, 1H), 3.56 (t, 2H), 5.39 (m, 1H), 6.87 (d, 2H), 6.98 (m, 2H), 7.19 (m, 2H), 7.25 (d, 2H).

›Example 242

2-((S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)acetonitrile

To a solution of 2-((S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)acetamide (60 mg, 0.128 mmol) in anhydrous CH 2 Cl 2 (4 mL) and DIEA (0.3 mL) was added TFAA (55 mg, 0.256 mmol) at 0□. The mixture was stirred for 2 h. The solvent was removed under reduced pressure, and the residue was purified by preparative TLC to afford 2-((S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)acetonitrile (40 mg, 82%). LC-MS Method 3 tR=1.52, min, m/z=451, 473; 1 H NMR (CDCl 3 ): 1.56 (m, 3H), 2.40 (m, 2H), 2.54 (m, 1H), 2.82-2.98 (m, 2H), 3.04 (m, 1H), 5.64 (m, 1H), 6.83-6.94 (m, 5H), 7.09 (m, 2H), 7.21 (m, 1H), 7.28 (m, 1H), 7.37 (m, 2H).

›Example 243

(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(piperidine-1-carbonyl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from 4-((S)-1-((R)-6-allyl-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)benzoic acid following a procedure analogous to that described in Example 153. LC-MS Method 1 t R =1.72, min, m/z=451; 1 H NMR (CDCl 3 ) 7.26 (t, 2H), 7.13 (d, 2H), 7.04 (t, 2H), 5.73-5.60 (m, 2H), 5.07 (dd, 2H), 3.71 (br s, 2H), 3.26 (br s, 2H), 2.91 (m, 1H), 2.59 (m, 2H), 1.52 (d, 5H).

›Example 244

(R)-6-allyl-3-((S)-1-(4-(2,4-dimethylthiazol-5-yl)phenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one

The title compound was prepared from (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one and 2,4-dimethylthiazole-5-boronic acid following a procedure analogous to that described in Example 64. LC-MS Method 1 t R =1.82, min, m/z=451; 1 H NMR (CDCl 3 ) 7.26 (t, 2H), 7.13 (d, 2H), 7.03 (t, 2H), 6.91 (d, 2H), 5.76-5.64 (m, 2H), 5.06 (dd, 2H), 2.98 (m, 1H), 2.74 (s, 3H), 2.42 (s, 3H), 1.53 (d, 3H).

›Example 245

(R)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one

The title compound was prepared from (R)-6-allyl-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one following a procedure analogous to that described in Example 78. LC-MS Method 3 t R =1.45, min, m/z=452, 474; 1 H NMR (CDCl 3 ) 1.30 (m, 1H), 1.50 (m, 3H), 1.66 (m, 1H), 1.91 (m, 2H), 2.20 (m, 3H), 2.88 (m, 1H), 3.50 (m, 2H), 5.63 (m, 1H), 6.90-7.09 (m, 6H), 7.18 (m, 1H), 7.23 (m, 3H), 7.40 (m, 2H).

›Example 246

(R)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(2-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one

›Step 1

1-(2-Fluorophenyl)ethanone (170 g, 1.23 mol), dimethylamine (137 g, 1.72 mol), and paraformaldehyde (55 g, 1.85 mol) were suspended in ethanol (500 mL), then concentrated HCl (3 mL) was added, and the mixture was heated to reflux overnight. The solvent was removed under vacuum. The residue was washed with EtOAc for 3 times to give 3-(dimethylamino)-1-(2-fluorophenyl)propan-1-one (207 g, 88%), which was used for the next step without purification. 1 H NMR (CDCl 3 ): δ=2.69 (s, 6H), 2.52 (m, 4H), 7.30 (m, 2H), 7.66 (m, 1H), 7.96 (m, 1H).

›Step 2

A solution of 3-dimethylamino-1-(2-fluoro-phenyl)-propan-1-one (17 g, 0.087 mol) and (S)-1-(4-bromophenyl)ethanamine (17 g, 0.087 mol) in EtOH (50 mL)/H 2 O (50 mL) was refluxed at 80° C. over night. The solvent was removed under vacuum. The residue was purified by column chromatography to afford (S)-3-(1-(4-bromophenyl)ethylamino)-1-(2-fluorophenyl)propan-1-one (1 g, 3%).

›Step 3

To a solution of (S)-3-(1-(4-bromophenyl)ethylamino)-1-(2-fluorophenyl)propan-1-one (500 mg, 1.43 mmol) in anhydrous CH 3 CN (15 mL) was added K 2 CO 3 and methyl carbonochloridate (403 mg, 4.29 mmol), and the mixture was stirred at rt for 2 h. The solution was concentrate, and the residue was purified by preparative TLC to afford (S)-methyl 1-(4-bromophenyl)ethyl(3-(2-fluorophenyl)-3-oxopropyl)carbamate (400 mg, 70%). 1 H NMR (CDCl 3 ): δ=1.50 (m, 3H), 3.00 (m, 2H), 3.36 (m, 2H), 3.78 (m, 3H), 5.40 (m, 1H), 7.11 (m, 4H), 7.28-7.50 (m, 3H), 7.71 (m, 1H).

›Step 4

To a solution of (S)-methyl-1-(4-bromophenyl)ethyl(3-(2-fluorophenyl)-3-oxopropyl)carbamate (400 mg, 1 mmol) in dry THF (10 mL) was added dropwise 1 M allylmagnesium bromide (20 mL)-78° C. After addition completely, the mixture was allowed to stir at rt for 3 h. The reaction was quenched with saturated aq NH 4 Cl solution, and the solution was extract with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and concentrated to give methyl (S)-1-(4-bromophenyl)ethyl (3-(2-fluorophenyl)-3-hydroxyhex-5-enyl)carbamate (300 mg, 67%).

›Step 5

To a suspension of NaH (55 g, 1.4 mmol) in THF (10 mL) at 0° C. was added a solution of methyl (S)-1-(4-bromophenyl)ethyl(3-(2-fluorophenyl)-3-hydroxyhex-5-enyl)carbamate (300 mg, 0.68 mmol) in THF (10 mL). The resulting mixture was stirred for 10 minutes, and then was refluxed for 1 h. The reaction was quenched with saturated aq NH 4 Cl solution, and the solution was extract with EtOAc. The combine organic layer washed with brine, dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by preparative TLC to afford (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-fluorophenyl)-1,3-oxazinan-2-one (100 mg, 35%) and (S)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-fluorophenyl)-1,3-oxazinan-2-one (100 mg, 35%).

›Step 6

A mixture of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-fluorophenyl)-1,3-oxazinan-2-one (100 mg, 0.24 mmol) and 4-fluorophenylboronic acid (55 mg, 0.36 mmol), Pd(Ph 3 P) 2 Cl 2 (20 mg), and aq Cs 2 CO 3 solution (0.5 mL, 2 M) in 1,4-dioxane (10 mL) was stirred and heated to reflux for 2 h. The organic phase was separated, and concentrated to give the crude product, which was purified by preparative TLC to give (R)-6-allyl-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(2-fluorophenyl)-1,3-oxazinan-2-one (80 mg, 80%). 1 H NMR (CDCl 3 ): δ=1.49 (m, 3H), 2.13 (m, 1H), 2.32 (m, 1H), 2.50 (m, 1H), 2.69 (m, 2H), 2.89 (m, 1H), 5.00 (m, 2H), 5.75 (m, 2H), 6.91-7.10 (m, 6H), 7.15 (m, 1H), 7.22 (m, 2H), 7.38 (m, 2H), 7.48 (m, 1H).

›Step 7

To a solution of (R)-6-allyl-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(2-fluorophenyl)-1,3-oxazinan-2-one (80 mg, 0.18 mmol) in THF (10 mL) was added BH 3 THF (1.5 mL, 1 mol/L) at 0° C. under nitrogen. The formed mixture was stirred for 2 h. The reaction was quenched by water. Then aq NaOH (0.3 mL, 3 mol/L) solution and H 2 O 2 (3 mL) was added to the above mixture. The resulting mixture was stirred for 1.5 h. The mixture was extracted with EtOAc, and the combined organic phase was concentrated to give the crude product, which was purified by preparative HPLC to give (R)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(2-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (15 mg, 17%). LC-MS Method 2 t R =1.48, min, m/z=452.2; 1 H NMR (CD 3 OD) 1.22-1.34 (m, 2H), 1.53 (d, 3H), 1.62-1.73 (m, 1H), 1.98-2.33 (m, 4H), 2.61 (d, 1H), 3.13 (m, 1H), 3.51 (m, 2H), 5.61 (m, 1H), 7.01-7.19 (m, 5H), 7.23 (m, 1H), 7.31-7.43 (m, 4H), 7.53 (m, 2H).

(S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(2-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one was prepared from (S)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-fluorophenyl)-1,3-oxazinan-2-one following procedures analogous to those described in Steps 6 and 7 immediately above. LC-MS Method 3 t R =1.531, min, m/z=452.2; 1 H NMR (CD 3 OD) 1.18-1.30 (m, 2H), 1.33 (d, 3H), 1.62-1.73 (m, 1H), 1.97-2.21 (m, 3H), 2.57-2.62 (d, 1H), 2.73-2.92 (m, 2H), 3.42-3.52 (m, 2H), 5.63 (m, 1H), 7.04-7.18 (m, 3H), 7.26 (m, 1H), 7.32-7.46 (m, 4H), 7.56-7.63 (m, 4H).

›Examples11

›Example 247

(R)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(3-fluorophenyl)-6-(3-hydroxypropy-1)-1,3-oxazinan-2-one

The title compound was prepared from 3-chloro-1-(3-fluorophenyl)propan-1-one using a procedure analogous to that described in Example 95 followed by a procedure analogous to that described in Example 78. LC-MS Method 3 t R =1.214, min, m/z=452.1; 1 H NMR (CDCl 3 ) 1.36-1.42 (m, 1H), 1.53 (d, 3H), 1.92-2.08 (m, 2H), 2.17-2.38 (m, 3H), 2.96 (m, 1H), 3.58 (m, 1H), 3.78-3.93 (m, 2H), 4.23 (m, 1H), 5.69 (m, 1H), 6.92-7.13 (m, 7H), 7.21-7.37 (m, 4H), 7.41-7.47 (m, 2H).

›Example 248

(R)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(3-hydroxy-3-methylbutyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from (R)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one using a procedure analogous to that described in Example 117. LC-MS Method 3 t R =1.284, min, m/z=484.1; 1 H NMR (CDCl 3 ) 1.03 (s, 3H), 1.04 (s, 3H), 1.11-1.21 (m, 1H), 1.46 (d, 3H), 1.58-1.67 (m, 1H), 1.84-2.02 (m, 2H), 2.09-2.31 (m, 3H), 2.84 (m, 1H), 5.61-5.68 (m, 1H), 6.84-6.89 (m, 2H), 7.01-7.08 (m, 2H), 7.21 (m, 1H), 7.23 (m, 3H), 7.29 (m, 2H), 7.38 (m, 2H).

›Example 249

(R)-3-((S)-1-(4-(5-acetylthiophen-2-yl)phenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one and 5-acetylthiophene-2-boronic acid using a procedure analogous to that described in Example 64 followed by a procedure analogous to that described in Example 78. LC-MS Method 3 t R =1.26, min, m/z=464, 486; 1 H NMR (CDCl 3 ) 1.46 (d, 3H), 1.63 (m, 2H), 1.92 (m, 2H), 2.12 (m, 1H), 2.26 (t, 2H), 2.49 (s, 3H), 2.85 (m, 1H), 3.50 (t, 2H), 5.60 (q, 1H), 6.85 (d, 2H), 7.20 (m, 8H), 7.56 (d, 1H).

›Example 250

3-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanamide

The title compound was prepared from (R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one using a procedure analogous to that described in Example 234. LC-MS Method 3 t R =1.3, min, m/z=465; 1 H NMR (CDCl 3 ): 1.51-1.60 (d, 3H), 1.91-2.03 (m, 1H), 2.12-2.38 (m, 5H), 2.46-2.57 (m, 1H), 2.88-2.97 (m, 1H), 5.32-5.54 (d, 2H), 5.63-5.74 (m, 1H), 6.82-6.93 (m, 2H), 6.94-7.02 (m, 2H), 7.19-7.22 (m, 1H), 7.27-7.38 (m, 6H).

›Example 251

(6R)-3-((1S)-1-(4-(5-(1-aminoethyl)thiophen-2-yl)phenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one

(R)-3-((S)-1-(4-(5-acetylthiophen-2-yl)phenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxa-zinan-2-one (40 mg, 0.086 mmol) and tetraisopropoxytitanium (49 mg, 0.17 mmol) are stirred overnight in the solution of NH 3 in EtOH. To this solution/paste was added NaBH 4 and stirring another 24 h. The reaction was diluted with NH 4 OH and stirred for 1 h. The mixture was filtered through celite and rinsed with EtOAc. Water and EtOAc were added and the organic layer was separated. The aq layer is extracted with EtOAc for three times. The combined organic layer was dried over Na 2 SO 4 , filtered and concentrated to afford (6R)-3-((1S)-1-(4-(5-(1-aminoethyl)thiophen-2-yl)phenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (1.26 mg, 3%). LC-MS Method 2 t R =1.014, min, m/z=448.1; 1 H NMR (CDCl 3 , 400 MHz): 1.33 (m, 1H), 1.47 (q, 6H), 1.90 (m, 2H), 2.13 (m, 1H), 2.22 (m, 2H), 2.82 (m, 1H), 3.50 (m, 2H), 4.33 (q, 1H), 5.58 (q, 1H), 6.81 (m, 3H), 6.98 (d, 1H), 7.25 (m, 7H).

›Example 252

(R)-3-((S)-1-(4′-fluorobiphenyl-4-yl)propyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one

The title compound was prepared from (R)-6-allyl-3-((S)-1-(4′-fluorobiphenyl-4-yl)propyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one using a procedure analogous to that in Example 78. LC-MS Method 3 t R =1.48, min, m/z=466, 488; 1 H NMR (CDCl 3 ) 1.02 (t, 3H), 1.44 (m, 1H), 1.68 (m, 2H), 1.90-2.06 (m, 4H), 2.23 (m, 2H), 2.34 (m, 1H), 2.98 (m, 1H), 3.58 (t, 2H), 5.5-48 (m, 1H), 6.97 (m, 2H), 7.02-7.12 (m, 4H), 7.18-7.23 (m, 2H), 7.31 (d, 2H), 7.46 (m, 2H).

›Example 253

(R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)propyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from (R)-6-allyl-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)propyl)-6-phenyl-1,3-oxazinan-2-one using a procedure analogous to that in Example 78. LC-MS Method 3 tR=1.5, min, m/z=466; 1H NMR (CDCl3) 1.02 (t, 3H), 1.31 (m, 1H), 1.63 (m, 1H), 1.96-2.11 (m, 4H), 2.25 (m, 1H), 2.36 (m, 1H), 2.48 (m, 1H), 3.12 (m, 1H), 3.49 (m, 2H), 5.39 (m, 1H), 7.00-7.11 (m, 4H), 7.22-7.36 (m, 7H), 7.42 (m, 1H).

›Example 254

(6R)-3-((1S)-1-(4-(5-(1-hydroxyethyl)thiophen-2-yl)phenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one

LC-MS Method 2 t R =2.13, min, m/z=466, 488; 1 H NMR (CDCl 3 ) 1.45 (d, 2H), 1.56 (d, 2H), 1.64 (m, 2H), 1.90 (m, 2H), 2.11 (m, 1H), 2.21 (m, 2H), 2.31 (s, 1H), 2.80 (m, 1H), 3.49 (t, 2H), 5.03 (q, 1H), 5.57 (q, 1H), 6.80 (d, 2H), 6.84, (d, 1H), 6.98 (d, 1H), 7.24 (m, 7H).

›Example 255

(6S)-3-((1S)-1-(4-bromophenyl)propyl)-6-(2,3-dihydroxypropyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one

The title compound was prepared from (R)-6-allyl-3-((S)-1-(4-bromophenyl)propyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one using a procedure analogous to that described in Example 173. Two isomers were isolated.

Isomer 1: LC-MS Method 3 t R =1.175, min, m/z=488.1; 1 H NMR (CDCl 3 ) 0.99 (t, 3H), 1.82-2.01 (m, 3H), 2.22-2.31 (m, 3H), 2.33-2.43 (m, 1H), 2.96 (m, 1H), 3.33 (m, 1H), 3.48 (m, 1H), 3.79 (m, 1H), 5.38 (m, 1H), 6.88 (m, 2H), 7.03 (m, 2H), 7.19 (m, 2H), 7.28 (m, 2H).

Isomer 2: LC-MS Method 3 tR=1.186, min, m/z=490.1; 1H NMR (CDCl3) 0.97-1.02 (m, 3H), 1.82-1.98 (m, 3H), 2.21-2.32 (m, 3H), 2.33-2.45 (m, 1H), 2.89-2.94 (m, 1H), 3.32 (m, 1H), 3.48 (m, 1H), 3.78 (m, 1H), 5.88 (m, 1H), 6.89 (m, 2H), 7.02 (m, 2H), 7.18 (m, 2H), 7.27 (m, 2H).

›Example 256

(R)-6-(3-aminopropyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one

The title compound was prepared from (R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one using procedures analogous to those described in Example 75 Steps 2 to 4. LC-MS Method 2 t R =2.15, min, m/z=469; 1 H NMR (CDCl 3 ) 1.42-1.51 (d, 3H), 1.51-1.54 (m, 1H), 1.73-1.82 (m, 1H), 1.96-2.06 (m, 2H), 2.13-2.26 (m, 3H), 2.82-2.96 (m, 3H), 5.46-5.53 (m, 1H), 6.79-6.98 (m, 6H), 7.10-7.14 (m, 2H), 7.22-7.27 (m, 2H), 8.13-8.29 (m, 2H).

›Example 257

(R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-(methylamino)ethyl)-1,3-oxazinan-2-one

›Step 1

To a solution of (R)-6-(2-aminoethyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (150 mg, 0.33 mmol) and Et 3 N (83.3 mg, 0.825 mmol) in dichloromethane (5 mL) was added di-tert-butyl dicarbonate (85.5 mg, 0.4 mmol) at 0-5° C. The resulting mixture was stirred at rt overnight. The solid was filtered and the resulting filtrate was washed with 5% HCl, extracted with CH 2 Cl 2 give the organic layer which was concentrated to give tert-butyl 2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethylcarbamate (53 mg, 29%).

›Step 2

To a solution of tert-butyl 2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethylcarbamate (53 mg, 0.1 mmol) in tetrahydrofuran was added NaH (300 mg, 12.5 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h. Then iodomethane (1.3 g, 9.15 mmol) was added to the above mixture and the mixture was stirred for 2 h. The reaction was quenched with H 2 O and extracted with EtOAc to give the organic layer which was washed with brine, dried over Na 2 SO 4 and filtered. The filtrate was concentrated to give tert-butyl 2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl(methyl)carbamate (36 mg, 66%).

›Step 3

A solution of tert-butyl 2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl(methyl)carbamate (73 mg, 0.13 mmol) in TFA/CH 2 Cl 2 (20%, 6 mL) was stirred at 0° C. for 1 h. After the material was consumed, the solution was concentrated to give residue, which was purified by preparative TLC followed by preparative HPLC to give (R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-(methylamino)ethyl)-1,3-oxazinan-2-one (13 mg, 21%). LC-MS Method 3 t R =1.10, min, m/z=469; 1 H NMR (CDCl 3 ): 1.50 (d, 3H), 2.25 (m, 4H), 2.37 (m, 1H), 2.60 (m, 3H), 2.81 (m, 1H), 2.98 (m, 2H) 6.85 (m, 2H), 7.00 (m, 4H), 7.18 (m, 2H), 7.28 (m, 3H).

›Examples5

›Example 258

(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)ethyl)-1,3-oxazinan-2-one

(R)-6-Allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (20 mg, 0.048 mmol), 3-(trifluoromethyl)-1H-pyrazole (20 mg, 3 equiv.), CuI (1.4 mg, 15% mol), (1R,2R)-(−)-1,2-transcyclohexanediamine (2 mg, 30% mol), K 3 PO 4 (20 mg, 2 equiv.) were mixed with dry toluene (2 mL) and heated in Microwave Oven for 1 h at 130° C. LC-MS found product peak. The mixture was diluted with EtOAc (8 mL), washed by water (2 mL), brine (3 mL) and dried over Na 2 SO 4 . After filtration and concentration, the residue was purified chromatography on a 4-g silica gel cartridge eluted with a gradient from 5 to 55% EtOAc in gexanes to afford (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)ethyl)-1,3-oxazinan-2-one (9.7 mg, 43%) product. LC-MS Method 1 t R =2.05, min, m/z=474; 1 H NMR (CDCl 3 ) 7.86 (s, 1H), 7.43 (d, 2H), 7.26 (t, 2H), 7.01 (dd, 2H), 6.69 (d, 1H), 5.76-5.64 (m, 2H), 5.05 (dd, 2H), 2.95 (m, 1H), 2.65-2.51 (m, 2H), 1.54 (d, 3H).

›Example 259

(S)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-3-((S)-1-(4-(1,1-dioxo-hexahydro-1,2-thiazin-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one and 1,1-dioxo-hexahydro-1,2-thiazine following a procedure analogous to that described in Example 228. LC-MS Method 1 t R =1.35, min, m/z=477; 1 H NMR (CD 3 OD) 7.26-7.22 (m, 2H), 7.05-7.01 (m, 4H), 6.87 (d, J=8.5 Hz, 2H), 5.45 (q, J=7.0 Hz, 1H), 3.61-3.55 (m, 4H), 3.15-3.12 (m, 2H), 3.05-3.01 (m, 1H), 2.44-2.40 (m, 1H), 2.24-2.17 (m, 4H), 2.04 (t, J=72 Hz, 2H), 1.83-1.77 (m, 2H), 1.44 (d, J=7.0 Hz, 3H).

›Example 260

(R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(3-hydroxy-3-methylbutyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from (R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one following a procedure analogous to that described in Example 117. LC-MS Method 3 t R =1.561, min, m/z=436.3; 1 H NMR (CDCl3) 1.11 (s, 3H), 1.13 (s, 3H), 1.18-1.27 (m, 1H), 1.53 (d, 3H), 1.61-1.72 (m, 1H), 1.91-2.06 (m, 2H), 2.16-2.24 (m, 1H), 2.27-2.38 (m, 2H), 2.91 (m, 1H), 5.68-5.72 (m, 1H), 6.82-6.97 (m, 4H), 7.19 (m, 2H), 7.23-7.36 (m, 6H).

›Example 261

(R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)propyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one

The title compound was prepared from (R)-6-allyl-3-((S)-1-(4-bromophenyl)propyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one and 2,4-difluorobenzeneboronic acid using a procedure analogous to that described in Example 64 followed by a procedure analogous to that described in Example 78. LC-MS Method 3 t R =1.49, min, m/z=484; 1 H NMR (CDCl 3 ) 1.01 (t, 3H), 1.34 (m, 1H), 1.68 (m, 2H), 1.89-2.04 (m, 4H), 2.23 (m, 2H), 2.34 (m, 1H), 2.98 (m, 1H), 3.58 (t, 2H), 5.49 (t, 1H), 6.85-6.98 (m, 4H), 7.09 (d, 2H), 7.21 (m, 2H), 7.25-7.31 (m, 3H).

›Example 262

(S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-(methylthio)ethyl)-1,3-oxazinan-2-one

›Step 1

To a solution of (S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one (250 mg, 0.55 mmol) in methylene chloride (10 mL) was added pyridine (0.5 mL) and PBr 3 (75 mg). The formed mixture was stirred for 2 h. The mixture was washed with water. The organic phase was separated, and concentrated to give the crude product, which was purified by preparative TLC to afford (S)-6-(2-bromoethyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (60 mg, 23%). 1 H NMR: (400 MHz, CDCl 3 ): δ=1.45 (d, 3H), 2.12-2.38 (d, 4H), 2.43 (m, 1H), 2.94 (m, 2H), 3.49 (m, 1H), 5.22 (m, 1H), 6.83 (m, 2H), 6.95 (m, 4H), 7.19 (m, 1H), 7.22 (m, 2H).

›Step 2

To a solution of (S)-6-(2-bromoethyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (30 mg, 0.058 mmol) in tetrahydrofuran (10 mL) was added CH 3 SNa (0.5 mL). The formed mixture was stirred overnight. The mixture was washed with water. The organic phase was separated, and concentrated to give the crude product, which was purified by preparative TLC to afford (S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-(methylthio)ethyl)-1,3-oxazinan-2-one (20 mg, 71%). LC-MS Method 3 t R =1.74, min, m/z=486, 508; 1 H NMR: (400 MHz, CDCl 3 ): δ=1.48 (d, 3H), 1.96 (m, 2H), 2.02 (m, 1H), 2.11-2.31 (m, 6H), 2.61 (m, 1H), 2.90 (m, 1H), 5.64 (q, 1H), 6.80-6.90 (m, 2H), 6.92-6.98 (m, 4H), 7.18 (m, 2H), 7.26 (m, 2H).

›Example 263

1-(2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl)urea

To a solution of (R)-6-(2-aminoethyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluoro-phenyl)-1,3-oxazinan-2-one (30 mg, 0.065 mmol) and urea (16 mg, 0.26 mmol) in H 2 O (3 mL) was added concentrated HCl (0.05 mL), and the mixture was refluxed overnight. The reaction mixture was crystallized by standing at rt. The precipitate was filtered and rinsed well with water to give 1-(2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl)urea (20 mg, 68%). LC-MS Method 3 tR=1.3, min, m/z=498; 1 H NMR (CDCl 3 ): 1.54-1.60 (d, 3H), 2.01-2.09 (m, 1H), 2.22-2.41 (m, 4H), 2.91-3.14 (m, 2H), 3.35-3.44 (m, 1H), 5.56-5.62 (s, 1H), 5.63-5.71 (m, 1H), 6.87-6.99 (m, 2H), 7.01-7.12 (m, 3H), 7.22-7.31 (m, 2H), 7.32-7.48 (m, 3H).

›Example 264

2-((S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl carbamate

(S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one (50 mg, 0.11 mmol) was dissolved in CH 2 Cl 2 (3 mL), followed by the addition of TEA (1 mL) and 4-nitrophenyl carbonochloridate (88 mg, 0.44 mmol). The mixture was stirred at rt overnight. Aqueous ammonia (2 mL) was added and the mixture was stirred at rt for 3 h. After separation of the water layer, the organic layer was washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo to give the crude product, which was purified by preparative TLC to afford 2-((S)-3-((S)

›Tables in the description — 4

Abbreviation	Meaning
A %	Area percentage
Boc	tert-butoxy carbonyl or t-butoxy carbonyl
(Boc) 2 O	di-tert-butyl dicarbonate
Cbz	Benzyloxycarbonyl
CbzCl	Benzyl chloroformate
c-Pr	cyclopropyl
DAST	diethylaminosulfur trifluoride
DBU	1,8-diazabicyclo[5.4.0]undec-7-ene
DCC	N,N′-dicyclohexylcarbodiimide
DCU	N,N′-dicyclohexylurea
DIAD	diisopropyl azodicarboxylate
DIBAL-H	diisobutylaluminum hydride
DIEA	N,N-diisopropylethylamine
DMAP	4-(dimethylamino)pyridine
DMF	N,N-dimethylformamide
DMPU	1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
2,4-DNP	2,4-dinitrophenylhydrazine
DPTBS	Diphenyl-t-butylsilyl
dr	diastereomer ratio
EDC•HCl, EDCl	1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
	hydrochloride
Equiv	equivalents
EtOAc	ethyl acetate
Fmoc	1-[[(9H-fluoren-9-ylmethoxy)carbonyl]oxy]-
Fmoc—OSu	1-[[(9H-fluoren-9-ylmethoxy)carbonyl]oxy]-2,5-
	pyrrolidinedione
h, hr	hour(s)
HOBt	1-hydroxybenzotriazole
HATU	2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-
	tetramethyluronium hexafluorophosphate
HBTU	2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
	hexafluorophosphate
KHMDS	potassium hexamethyldisilazane
LAH or LiAlH 4	lithium aluminum hydride
LC-MS	liquid chromatography-mass spectroscopy
LHMDS	lithium hexamethyldisilazane
m-CPBA	meta-chloroperoxybenzoic acid
Me	methyl
MsCl	methanesulfonyl chloride
Min	minute
MS	mass spectrum
NaH	sodium hydride
NaHCO 3	sodium bicarbonate
NaN 3	sodium azide
NaOH	sodium hydroxide
Na 2 SO 4	sodium sulfate
NMM	N-methylmorpholine
NMP	N-methylpyrrolidinone
Pd 2 (dba) 3	tris(dibenzylideneacetone)dipalladium(0)
PE	petroleum ether
Quant	quantitative yield
rt	room temperature
Satd	saturated
SOCl 2	thionyl chloride
SFC	supercritical fluid chromatography
SPA	scintillation proximity assay
SPE	solid phase extraction
TBAF	tetrabutylammonium fluoride
TBS	t-butyldimethylsilyl
TBDPS	t-butyldiphenylsilyl
TBSCl	t-butyldimethylsilyl chloride
TBDPSCl	t-butyldiphenylsilyl chloride
TEA	triethylamine or Et 3 N
TEMPO	2,2,6,6-tetramethyl-1-piperidinyloxy free radical
Teoc	1-[2-(trimethylsilyl)ethoxycarbonyloxy]-
Teoc-OSu	1-[2-(trimethylsilyl)ethoxycarbonyloxy]pyrrolidin-
	2,5-dione
T ext	External temperature
T int	Internal temperature
TFA	trifluoroacetic acid
Tlc, TLC	thin layer chromatography
TMS	trimethylsilyl
TMSCl	chlorotrimethylsilane or trimethylsilyl chloride
t R	retention time
TsOH	p-toluenesulfonic acid

TABLE OF BIOLOGICAL ASSAY RESULTS Biological Test Example 1 a ++ means IC 50 = <100 nM, + means IC 50 = 100-1000 nM, # means IC 50 > 100 nM, − means IC 50 > 1000 nM.

		Average %	Average %
		inhibition at	inhibition at
Compound	IC 50 Range a	100 nM	111.1 nM
EXAMPLE 1	++		62.7
EXAMPLE 1 Isomer 1	++		78.7
EXAMPLE 1 Isomer 2	+		32.6
EXAMPLE 2	+		28.8
EXAMPLE 3	++		74.3
EXAMPLE 4	+		56.2
EXAMPLE 5	+		34.4
EXAMPLE 6	++		78.1
EXAMPLE 7	+		37.3
EXAMPLE 8	+		6.4
EXAMPLE 9	++		93.8
EXAMPLE 10	++		90.5
EXAMPLE 11	+		28.4
EXAMPLE 12	++		86.4
EXAMPLE 13	+		19.2
EXAMPLE 14	+		21.9
EXAMPLE 15	+		38.5
EXAMPLE 16	+		35.7
EXAMPLE 17	++		58.8
EXAMPLE 18	+		7.2
EXAMPLE 19	+		24.0
EXAMPLE 20	++		54.8
EXAMPLE 21	++		76.7
EXAMPLE 22	++		88.9
EXAMPLE 23	++	94.0	88.3
EXAMPLE 24	++	93.4	86.0
EXAMPLE 25	++	91.7	84.2
EXAMPLE 26	++	88.2	87.0
EXAMPLE 27	++		67.0
EXAMPLE 28	++	93.6	82.3
EXAMPLE 28 Isomer 1	++		72.3
EXAMPLE 28 Isomer 2	++		96.6
EXAMPLE 29	+		29.8
EXAMPLE 30	+		23.1
EXAMPLE 31	+		27.5
EXAMPLE 32	+		46.0
EXAMPLE 33	+		37.1
EXAMPLE 34	++		72.0
EXAMPLE 35	+		26.7
EXAMPLE 36	++		63.3
EXAMPLE 37	++		81.0
EXAMPLE 38	+		17.8
EXAMPLE 39	+		24.8
EXAMPLE 40	+		28.8
EXAMPLE 41	+		19.9
EXAMPLE 42	+		36.7
EXAMPLE 43	++		77.7
EXAMPLE 44	+		35.0
EXAMPLE 45	+		31.2
EXAMPLE 46	+		46.4
EXAMPLE 47	+		36.3
EXAMPLE 48	+		37.0
EXAMPLE 49	+		15.4
EXAMPLE 50	++		96.3
EXAMPLE 51 Isomer 1	++		93.7
EXAMPLE 51 Isomer 2	+		38.6
EXAMPLE 52	++	98.6
EXAMPLE 52 Isomer 1	++	92.8
EXAMPLE 52 Isomer 2	++	90.8	97.0
EXAMPLE 53	++		57.1
EXAMPLE 54	+		15.5
EXAMPLE 55	+		3.7
EXAMPLE 56	+		5.6
EXAMPLE 57	+		10.4
EXAMPLE 58	+		34.8
EXAMPLE 59	+		18.0
EXAMPLE 60	+		51.3
EXAMPLE 61	+		17.7
EXAMPLE 62	+		20.5
EXAMPLE 63	++		59.0
EXAMPLE 64	++		94.0
EXAMPLE 65	++	95.9	98.4
EXAMPLE 65 Isomer 1	++	94.8	97.6
EXAMPLE 65 Isomer 2	++	48.8	57.1
EXAMPLE 66	++	90.8	93.0
EXAMPLE 67	++	93.1	96.6
EXAMPLE 68	++	92.0	92.9
EXAMPLE 69	++	94.7	94.8
EXAMPLE 70	+		9.3
EXAMPLE 71	+
EXAMPLE 72	++		77.5
EXAMPLE 73	+		48.4
EXAMPLE 74	++		70.0
EXAMPLE 75	++		57.8
EXAMPLE 76	++	81.0
EXAMPLE 77	++	88.7	89.2
EXAMPLE 78	++		93.8
EXAMPLE 79	++		75.3
EXAMPLE 80	++		77.8
EXAMPLE 81	++		72.2
EXAMPLE 82 Isomer 1	++		87.6
EXAMPLE 82 Isomer 2	++		89.2
EXAMPLE 83 Isomer 1	+		50.3
EXAMPLE 83 Isomer 2	+		45.8
EXAMPLE 84	++		94.6
EXAMPLE 84 Isomer 1	++		74.8
EXAMPLE 85	++		102.0
EXAMPLE 85 Isomer 1	++		93.1
EXAMPLE 86	++		85.7
EXAMPLE 86 Isomer 1	+		43.3
EXAMPLE 87	++
EXAMPLE 87 Isomer 1	+		13.3
EXAMPLE 88	++		97.1
EXAMPLE 88 Isomer 1	+		74.4
EXAMPLE 89	++		71.4
EXAMPLE 90	++		83.1
EXAMPLE 91	+		39.8
EXAMPLE 92	+		35.0
EXAMPLE 93	+		45.3
EXAMPLE 94	+		16.2
EXAMPLE 95	++		97.3
EXAMPLE 95 Isomer 1	++		91.0
EXAMPLE 96	++		91.9
EXAMPLE 96 Isomer 1	++	88.3	98.5
EXAMPLE 96 Isomer 2	−		9.7
EXAMPLE 97 Isomer 1	+		52.8
EXAMPLE 97 Isomer 2	++		88.2
EXAMPLE 98	++		73.4
EXAMPLE 99	++		75.3
EXAMPLE 100	++		93.7
EXAMPLE 101	++		84.4
EXAMPLE 102	++		91.7
EXAMPLE 102 Isomer 1	+		35.4
EXAMPLE 102 Isomer 2	++	94.0	95.5
EXAMPLE 103	++		86.9
EXAMPLE 104	++		85.7
EXAMPLE 104 Isomer 1	+		44.3
EXAMPLE 104 Isomer 2	++		98.1
EXAMPLE 105	++		87.4
EXAMPLE 106	++		88.7
EXAMPLE 107	++	90.9	97.0
EXAMPLE 108	++		55.4
EXAMPLE 109	++	94.1	94.0
EXAMPLE 109 Isomer 1	++		67.0
EXAMPLE 109 Isomer 2	++	98.4	93.7
EXAMPLE 110 Isomer 1	++	90.5
EXAMPLE 110 Isomer 2	++	96.6	95.0
EXAMPLE 111 Isomer 1	++		90.9
EXAMPLE 111 Isomer 2	++		58.9
EXAMPLE 112 Isomer 1	++		34.7
EXAMPLE 112 Isomer 2	++	95.2	99.9
EXAMPLE 113 Isomer 1	++		83.2
EXAMPLE 113 Isomer 2	++		82.6
EXAMPLE 114 Isomer 1	−	17.4
EXAMPLE 114 Isomer 2	++	66.6
EXAMPLE 115 Isomer 1	+		54.7
EXAMPLE 115 Isomer 2	++	99.3	104.2
EXAMPLE 116	++		97.6
EXAMPLE 117	++		82.8
EXAMPLE 118	++		96.8
EXAMPLE 119 Isomer 1	++	95.4
EXAMPLE 119 Isomer 2	++		56.3
EXAMPLE 120 Isomer 1	++	91.8	91.5
EXAMPLE 120 Isomer 2	++	90.6
EXAMPLE 121	+		34.2
EXAMPLE 122	++	94.1	95.6
EXAMPLE 123	++		97.6
EXAMPLE 124	++	95.2	96.8
EXAMPLE 125	++	98.3	94.0
EXAMPLE 126	++	79.0	80.7
EXAMPLE 127	++	86.3
EXAMPLE 128 Isomer 1	+	26.1	27.5
EXAMPLE 128 Isomer 2	−		6.5
EXAMPLE 129	+		32.1
EXAMPLE 129 Isomer 1	+		29.2
EXAMPLE 129 Isomer 2	+		20.9
EXAMPLE 130 Isomer 1	++	92.2
EXAMPLE 130 Isomer 2	++		87.7
EXAMPLE 131	−	6.6	11.3
EXAMPLE 132	+		30.4
EXAMPLE 133	++	85.8	95.4
EXAMPLE 134	++	93.9	96.2
EXAMPLE 135	++	88.9	93.8
EXAMPLE 136	++	96.4	97.3
EXAMPLE 137 Isomer 1	++		96.7
EXAMPLE 137 Isomer 2	++	96.4	95.5
EXAMPLE 138	++	95.9	95.4
EXAMPLE 139	++	93.8	96.2
EXAMPLE 140	++	95.6	97.1
EXAMPLE 141	++	90.6	92.2
EXAMPLE 142	+	34.4	27.4
EXAMPLE 143 Isomer 1	++		54.4
EXAMPLE 143 Isomer 2	++	95.4
EXAMPLE 144 Isomer 1	++		90.6
EXAMPLE 144 Isomer 2	++	95.3	96.6
EXAMPLE 145	++	96.5
EXAMPLE 146	++		79.9
EXAMPLE 147	++		89.5
EXAMPLE 148	++		85.0
EXAMPLE 149	++	95.3
EXAMPLE 150	++		92.9
EXAMPLE 151	++		77.0
EXAMPLE 152	++		79.0
EXAMPLE 153	+	27.0	26.6
EXAMPLE 154	++		79.0
EXAMPLE 155	+		45.6
EXAMPLE 156	++		93.8
EXAMPLE 157 Isomer 1	++	97.4
EXAMPLE 157 Isomer 2	++	92.9	90.7
EXAMPLE 158	+		23.8
EXAMPLE 159	++	98.6
EXAMPLE 160 Isomer 1	++		93.5
EXAMPLE 160 Isomer 2	++	95.9	95.2
EXAMPLE 161 Isomer 1	++		81.7
EXAMPLE 161 Isomer 2	+		60.5
EXAMPLE 161 Isomer 3	++	93.2	89.8
EXAMPLE 162	++	96.5
EXAMPLE 163 Isomer 1	++		66.8
EXAMPLE 163 Isomer 2	++	96.9
EXAMPLE 163 Isomer 3	#	11.3
EXAMPLE 164	++	95.9
EXAMPLE 165	++		92.9
EXAMPLE 166	++		81.8
EXAMPLE 167 Isomer 1	++	73.7	79.0
EXAMPLE 167 Isomer 2	++		77.2
EXAMPLE 168 Isomer 1	++	97.2
EXAMPLE 168 Isomer 2	++	95.6
EXAMPLE 169	++	97.0
EXAMPLE 170	++	97.0
EXAMPLE 171 Isomer 1	++	95.7
EXAMPLE 171 Isomer 2	++	68.6
EXAMPLE 172	++	95.8
EXAMPLE 173 Isomer 1	++	96.7
EXAMPLE 173 Isomer 2	++	94.5
EXAMPLE 174	+		48.0
EXAMPLE 175 Isomer 1	++	94.3	93.7
EXAMPLE 175 Isomer 2	+		25.8
EXAMPLE 176	+		54.8
EXAMPLE 177	++		77.4
EXAMPLE 178	++		77.7
EXAMPLE 179	++		79.4
EXAMPLE 180	++	85.2	84.9
EXAMPLE 181	++	101.0	90.7
EXAMPLE 182	++		79.5
EXAMPLE 183	++		88.6
EXAMPLE 184	+		65.4
EXAMPLE 185	++	98.4
EXAMPLE 186 Isomer 1	++	64.5
EXAMPLE 186 Isomer 2	#	33.5
EXAMPLE 187 Isomer 1	++	98.7
EXAMPLE 187 Isomer 2	++	46.4
EXAMPLE 188 Isomer 1	++	77.0
EXAMPLE 188 Isomer 2	#	31.7
EXAMPLE 189 Isomer 1	++	95.2
EXAMPLE 189 Isomer 2	++	90.1
EXAMPLE 190	++	76.0
EXAMPLE 191 Isomer 1	++	98.9
EXAMPLE 191 Isomer 2	++	69.0
EXAMPLE 192	++	70.7
EXAMPLE 193 Isomer 1	++	95.6
EXAMPLE 193 Isomer 2	++	94.3
EXAMPLE 194	++	89.5
EXAMPLE 195	++	96.8
EXAMPLE 196 Isomer 1	++	101.1
EXAMPLE 196 Isomer 2	++	98.9
EXAMPLE 197 Isomer 1	++	90.4
EXAMPLE 197 Isomer 2	++	82.1
EXAMPLE 198	++	88.2
EXAMPLE 199	++	90.3
EXAMPLE 200 Isomer 1	++	96.4
EXAMPLE 200 Isomer 2	++	73.1
EXAMPLE 201 Isomer 1	++	93.2
EXAMPLE 201 Isomer 2	#	27.0
EXAMPLE 202	++	95.9
EXAMPLE 203 Isomer 1	++	88.6
EXAMPLE 203 Isomer 2	++	93.8
EXAMPLE 204 Isomer 1	++	97.4
EXAMPLE 204 Isomer 2	++	99.4
EXAMPLE 205	++	98.0
EXAMPLE 206 Isomer 1	++	90.3
EXAMPLE 206 Isomer 2	++	85.9
EXAMPLE 207 Isomer 1	++	89.9
EXAMPLE 207 Isomer 2	++	89.3
EXAMPLE 208 Isomer 1	++	76.6
EXAMPLE 208 Isomer 2	#	38.5
EXAMPLE 208 Isomer 3	++	64.6
EXAMPLE 208 Isomer 4	++	29.3
EXAMPLE 209	++	88.8
EXAMPLE 210	++	96.3
EXAMPLE 211	++	93.3
EXAMPLE 212 Isomer 1	++	96.8
EXAMPLE 212 Isomer 2	++	82.6
EXAMPLE 213	++	79.1
EXAMPLE 214	++	94.3
EXAMPLE 215	++	72.1
EXAMPLE 216	++	92.6
EXAMPLE 217	++	88.0
EXAMPLE 218 Isomer 1	++	97.4
EXAMPLE 218 Isomer 2	++	60.3
EXAMPLE 219	++	92.7
EXAMPLE 220	++	85.5
EXAMPLE 221	++	94.1
EXAMPLE 222	++	87.3
EXAMPLE 223 Isomer 1	++	94.2
EXAMPLE 223 Isomer 2	++	97.1
EXAMPLE 223 Isomer 3	#	27.8
EXAMPLE 223 Isomer 4	#	52.5
EXAMPLE 224	++	97.3
EXAMPLE 224 Isomer 1	++	100.4
EXAMPLE 224 Isomer 2	++	95.6
EXAMPLE 225	++	96.5
EXAMPLE 226	++	90.7
EXAMPLE 227 Isomer 1	++	95.0
EXAMPLE 227 Isomer 2	++	60.7
EXAMPLE 228	+	30.6	19.6
EXAMPLE 229	++	81.6
EXAMPLE 230	++	73.6
EXAMPLE 231	++	57.0
EXAMPLE 232	++	96.9
EXAMPLE 233 Isomer 1	++	98.9
EXAMPLE 233 Isomer 2	++	64.1
EXAMPLE 234	++	93.4
EXAMPLE 235	++	93.4
EXAMPLE 236	++	96.8
EXAMPLE 237	++	92.6
EXAMPLE 238	++	98.0
EXAMPLE 239 Isomer 1	++	91.5
EXAMPLE 239 Isomer 2	++	89.5
EXAMPLE 240	++	94.6
EXAMPLE 241	++	96.7
EXAMPLE 242	++	91.4
EXAMPLE 243	++	38.9
EXAMPLE 244	++	90.9
EXAMPLE 245	++	92.6
EXAMPLE 246 Isomer 1	++	94.8
EXAMPLE 246 Isomer 2	++	92.9
EXAMPLE 247	++	96.8
EXAMPLE 248	++	96.7
EXAMPLE 249	++	96.3
EXAMPLE 250	++	97.1
EXAMPLE 251	++	90.9
EXAMPLE 252	++	99.0
EXAMPLE 253	++	93.3
EXAMPLE 254	++	96.0
EXAMPLE 255 Isomer 1	++	92.5
EXAMPLE 255 Isomer 2	++	89.3
EXAMPLE 256	++	93.1
EXAMPLE 257	++	78.5
EXAMPLE 258	++	86.2
EXAMPLE 259	++	43.1
EXAMPLE 260	++	94.1
EXAMPLE 261	++	96.2
EXAMPLE 262	++	86.5
EXAMPLE 263	++	92.3
EXAMPLE 264	++	99.9
EXAMPLE 265	++	56.8
EXAMPLE 266	++	93.5
EXAMPLE 267	++	88.0
EXAMPLE 268	++	50.8
EXAMPLE 269	++	92.8
EXAMPLE 270	++	96.1
EXAMPLE 271	++	94.6
EXAMPLE 272	++	93.8
EXAMPLE 273 Isomer 1	++	53.6
EXAMPLE 273 Isomer 2	#	17.9
EXAMPLE 274	++	96.2
EXAMPLE 275	++	91.5
EXAMPLE 276 Isomer 1	++	83.1
EXAMPLE 276 Isomer 2	#	35.4
EXAMPLE 277 Isomer 1	++	91.1
EXAMPLE 277 Isomer 2	++	65.6
EXAMPLE 278 Isomer 1	++	86.6
EXAMPLE 278 Isomer 2	++	65.5
EXAMPLE 279 Isomer 1	#	11.9
EXAMPLE 279 Isomer 2	++	42.5
EXAMPLE 280	++	82.4
EXAMPLE 281	++	100.1
EXAMPLE 282 Isomer 1	++	94.0
EXAMPLE 282 Isomer 2	++	77.8
EXAMPLE 283	++	92.6
EXAMPLE 284	++	97.7
EXAMPLE 285	++	96.2
EXAMPLE 286 Isomer 1	++	94.1
EXAMPLE 286 Isomer 2	++	94.5
EXAMPLE 286 Isomer 3	++	70.5
EXAMPLE 286 Isomer 4	#	29.3
EXAMPLE 287	++	89.8
EXAMPLE 288	++	72.4
EXAMPLE 289	++	94.1
EXAMPLE 290	++	91.8
EXAMPLE 291	++	96.7
EXAMPLE 292	++	93.4
EXAMPLE 293	++	94.0
EXAMPLE 294	++	97.2
EXAMPLE 295	++	91.0
EXAMPLE 296	++	94.3
EXAMPLE 297	++	86.6
EXAMPLE 298	++	96.7
EXAMPLE 299	++	71.7
EXAMPLE 300	++	81.2
EXAMPLE 301	++	86.7
EXAMPLE 302	++	96.1
EXAMPLE 303	++	98.4
EXAMPLE 304	++	94.5
EXAMPLE 305	++	98.7
EXAMPLE 306	++	97.1
EXAMPLE 307	++	96.5
EXAMPLE 308	−	25.0	8.6
EXAMPLE 309	++	97.2
EXAMPLE 310	++	77.5
EXAMPLE 311	++	96.7
EXAMPLE 312	++	85.7
EXAMPLE 313	++	96.7
EXAMPLE 314	++	96.5
EXAMPLE 315	++	93.2
EXAMPLE 316	++	88.8
EXAMPLE 317	++	87.5
EXAMPLE 318	++	83.8
EXAMPLE 319	++	93.4
EXAMPLE 320	++	97.5
EXAMPLE 321	++	96.1
EXAMPLE 322	++	96.3
EXAMPLE 323 Isomer 1	++	85.9
EXAMPLE 323 Isomer 2	++	100.9
EXAMPLE 324	++	94.3
EXAMPLE 325	++	97.1
EXAMPLE 326	++	97.7
EXAMPLE 327	++	97.2
EXAMPLE 328	++	98.8
EXAMPLE 329	++	99.8
EXAMPLE 330	++	97.8
EXAMPLE 331	++	97.1
EXAMPLE 332 Isomer 1	++	97.8
EXAMPLE 332 Isomer 2	#	32.2
EXAMPLE 333 Isomer 1	++	96.2
EXAMPLE 333 Isomer 2	#	9.1
EXAMPLE 334 Isomer 1	++	96.6
EXAMPLE 334 Isomer 2	#	31.9
EXAMPLE 335 Isomer 1	++	48.2
EXAMPLE 335 Isomer 2	++	96.7
EXAMPLE 336 Isomer 1	++	50.8
EXAMPLE 336 Isomer 2	++	94.6
EXAMPLE 337	++	59.4
EXAMPLE 338 Isomer 1	++	89.1
EXAMPLE 338 Isomer 2	#	30.5
EXAMPLE 339	++	65.9
EXAMPLE 340	++	75.9
EXAMPLE 341	++	82.0
EXAMPLE 342	++	64.2
EXAMPLE 343	++	82.3
EXAMPLE 344	++	65.7
EXAMPLE 345	++	74.7
EXAMPLE 346	++	94.0
EXAMPLE 347	++	96.0
EXAMPLE 348	++	48.9
EXAMPLE 349	++	89.8
EXAMPLE 350	++	91.8
EXAMPLE 351	++	83.1
EXAMPLE 352	++	60.8
EXAMPLE 353	++	90.7
EXAMPLE 354	++	95.2
EXAMPLE 355	++	95.5
EXAMPLE 356	++	92.0
EXAMPLE 357	++	60.7
EXAMPLE 358	++	84.0
EXAMPLE 359	++	67.5
EXAMPLE 360	++	97.0
EXAMPLE 361	++	67.4
EXAMPLE 362	++	93.4
EXAMPLE 363	++	74.5
EXAMPLE 364	++	66.3
EXAMPLE 365 Isomer 1	++	97.5
EXAMPLE 365 Isomer 2	++	61.1
EXAMPLE 366	++	95.1
EXAMPLE 367	++	44.8
EXAMPLE 368	++	96.9
EXAMPLE 369	++	100.1
EXAMPLE 370	++	97.0
EXAMPLE 371 Isomer 1	++	98.4
EXAMPLE 371 Isomer 2	++	97.4
EXAMPLE 372 Isomer 1	++	97.7
EXAMPLE 372 Isomer 2	++	98.8
EXAMPLE 373	++	89.1
EXAMPLE 374	++	52.2
EXAMPLE 375	++	70.9
EXAMPLE 376	++	50.3
EXAMPLE 377	++	72.0
EXAMPLE 378	++	70.0
EXAMPLE 379	++	57.7
EXAMPLE 380	++	97.2
EXAMPLE 381	++	97.2
EXAMPLE 382	++	81.3
EXAMPLE 383 Isomer 1	++	94.7
EXAMPLE 383 Isomer 2	++	95.3
EXAMPLE 384	++	89.2
EXAMPLE 385	++	95.3
EXAMPLE 386	++	52.5
EXAMPLE 387	++	95.8
EXAMPLE 388 Isomer 1	++	92.8
EXAMPLE 388 Isomer 2	++	94.7
EXAMPLE 389	++	96.4
EXAMPLE 390	++	96.3
EXAMPLE 391	++	94.5
EXAMPLE 392	++	97.9
EXAMPLE 393	++	99.2
EXAMPLE 394	++	99.1
EXAMPLE 395	++	98.8
EXAMPLE 396	++	98.6
EXAMPLE 397	++	94.7
EXAMPLE 398	++	97.7
EXAMPLE 399	++	97.9
EXAMPLE 400	++	96.8
EXAMPLE 401	++	98.6
EXAMPLE 402	++	96.8
EXAMPLE 403	++	99.5
EXAMPLE 404	++	91.2
EXAMPLE 405	++	55.7
EXAMPLE 406	++	86.4
EXAMPLE 407	++	94.7
EXAMPLE 408	++	90.2
EXAMPLE 409	++	91.6
EXAMPLE 410	++	52.0
EXAMPLE 411 Isomer 1	++	88.7
EXAMPLE 411 Isomer 2	++	93.1
EXAMPLE 412	++	94.7
EXAMPLE 413	++	95.3
EXAMPLE 414	++	94.4
EXAMPLE 415	++	87.6
EXAMPLE 416	++	55.1
EXAMPLE 417	++	97.1
EXAMPLE 418	++	99.2
EXAMPLE 419	++	96.9
EXAMPLE 420	++	97.3
EXAMPLE 421	++	96.1
EXAMPLE 422	++	100.3
EXAMPLE 423	++	97.6
EXAMPLE 424	++	97.0
EXAMPLE 425	++	96.2
EXAMPLE 426	++	82.5
EXAMPLE 427	++	97.8
EXAMPLE 428	++	82.0
EXAMPLE 429 Isomer 1	++	77.9
EXAMPLE 429 Isomer 2	#	23.0
EXAMPLE 430	++	99.4
EXAMPLE 431	++	97.4
EXAMPLE 432	++	100.5
EXAMPLE 433	++	91.9
EXAMPLE 434	++	96.2
EXAMPLE 435	++	97.9
EXAMPLE 436	++	101.1
EXAMPLE 437	++	99.6
EXAMPLE 438	++	99.0
EXAMPLE 439	++	95.6
EXAMPLE 440	++	100.9
EXAMPLE 441	++	50.0
EXAMPLE 442	++	98.3
EXAMPLE 443	++	49.7
EXAMPLE 444	++	68.7
EXAMPLE 445	++	64.8
EXAMPLE 446	++	65.3
EXAMPLE 447	++	95.7
EXAMPLE 448	++	97.7
EXAMPLE 449	++	98.7	99.4
EXAMPLE 450	++	79.9
EXAMPLE 451	++	95.8
EXAMPLE 452	++	76.9
EXAMPLE 453	++	96.0
EXAMPLE 454	++	99.3
EXAMPLE 455	++	98.1
EXAMPLE 456	++	94.7
EXAMPLE 457	++	93.3
EXAMPLE 458	++	90.1
EXAMPLE 459	++	96.4
EXAMPLE 460	++	95.9
EXAMPLE 461	++	95.0
EXAMPLE 462	++	72.3
EXAMPLE 463	++	81.3
EXAMPLE 464	++	80.2
EXAMPLE 465	++	65.0
EXAMPLE 466	++	55.3
EXAMPLE 467	++	81.2
EXAMPLE 468	++	94.3
EXAMPLE 469	++	99.6
EXAMPLE 470	++	99.8
EXAMPLE 471	++	98.3
EXAMPLE 472	++	98.9
EXAMPLE 473	++	96.7
EXAMPLE 474	++	90.2
EXAMPLE 475	++	97.3
EXAMPLE 476	++	101.5
EXAMPLE 477	++	98.7
EXAMPLE 478	++	93.9
EXAMPLE 479	++	99.8
EXAMPLE 480	++	98.8
EXAMPLE 481	++	97.8
EXAMPLE 482	++	98.5
EXAMPLE 483	++	93.1
EXAMPLE 484	++	95.8
EXAMPLE 485	++	95.0
EXAMPLE 486	++	96.5
EXAMPLE 487	++	74.3
EXAMPLE 488	++	99.1
EXAMPLE 489	++	98.3
EXAMPLE 490	++	94.8
EXAMPLE 491	++	99.3
EXAMPLE 492	++	87.7
EXAMPLE 493	++	89.1
EXAMPLE 494	++	100.1
EXAMPLE 495	++	95.8
EXAMPLE 496	++	87.7
EXAMPLE 497 Isomer 1	++
EXAMPLE 497 Isomer 2	++
EXAMPLE 497 Isomer 3	#
EXAMPLE 497 Isomer 4	++
EXAMPLE 498	++	97.8
EXAMPLE 499	++	95.9
EXAMPLE 500	++	98.2
EXAMPLE 501	++	88.7
EXAMPLE 502	++	100.4
EXAMPLE 503	++	90.1
EXAMPLE 504 Isomer 1	++	49.9
EXAMPLE 504 Isomer 2	++	94.4
EXAMPLE 505	++	96.3
EXAMPLE 506	++	97.7
EXAMPLE 507	++	96.1
EXAMPLE 508	++	94.9
EXAMPLE 509	++	83.1
EXAMPLE 510	++	94.3
EXAMPLE 511	++	98.5
EXAMPLE 512	++	88.0
EXAMPLE 513	++	84.4
EXAMPLE 514	++	93.1
EXAMPLE 515	++	86.3
EXAMPLE 516	++	91.3
EXAMPLE 517	++	79.6
EXAMPLE 518 Isomer 1	++	92.2
EXAMPLE 518 Isomer 2	++	98.0
EXAMPLE 519 Isomer 1	++	95.5
EXAMPLE 519 Isomer 2	++	93.6
EXAMPLE 520	++	98.0
EXAMPLE 521	++	98.1
EXAMPLE 522	++	97.5
EXAMPLE 523 Isomer 1	++	94.5
EXAMPLE 523 Isomer 2	++	85.4
EXAMPLE 524	++	97.9
EXAMPLE 525	++	86.0
EXAMPLE 526	++	54.6
EXAMPLE 527	++	89.7
EXAMPLE 528	++	98.6
EXAMPLE 529	++	93.7
EXAMPLE 530	++	73.3
EXAMPLE 531	++	73.5
EXAMPLE 532	++	96.3
EXAMPLE 533	++	94.5
EXAMPLE 534	++	98.5
EXAMPLE 535	++	96.8
EXAMPLE 536	++	95.7
EXAMPLE 537	++	94.7
EXAMPLE 538	++	88.4
EXAMPLE 539	++	73.4
EXAMPLE 540	++	96.6
EXAMPLE 541	++	102.0
EXAMPLE 542	++	98.1
EXAMPLE 543	++	91.5
EXAMPLE 544	++	93.9
EXAMPLE 545	++	97.6
EXAMPLE 546	++	95.2
EXAMPLE 547	++	92.4
EXAMPLE 548	++	98.9
EXAMPLE 549	++	95.1
EXAMPLE 550	++	99.6
EXAMPLE 551	++	93.9
EXAMPLE 552	++
EXAMPLE 553	++	90.8
EXAMPLE 554	++	93.1
EXAMPLE 555	++	97.3
EXAMPLE 556	++	94.5
EXAMPLE 557	++	93.6	89.7
EXAMPLE 558	++	88.1
EXAMPLE 559	++	98.6
EXAMPLE 560	++	97.9
EXAMPLE 561	++	96.7
EXAMPLE 562	++	93.7
EXAMPLE 563	++	96.5
EXAMPLE 564	++	93.9
EXAMPLE 565	++	94.8
EXAMPLE 566	++	100.1
EXAMPLE 567	++	78.3
EXAMPLE 568	++	97.7
EXAMPLE 569	++	97.9
EXAMPLE 570	++	98.5
EXAMPLE 571	++	95.2
EXAMPLE 572	++	99.2
EXAMPLE 573	++	97.6
EXAMPLE 574	++	97.3
EXAMPLE 575	++	97.8	99.9
EXAMPLE 576	++	99.0
EXAMPLE 577 Isomer 1	++	99.5
EXAMPLE 577 Isomer 2	++	94.7
EXAMPLE 578	++	97.7
EXAMPLE 579	++	91.8
EXAMPLE 580	++	53.3
EXAMPLE 581	++	96.4
EXAMPLE 582	++	61.2
EXAMPLE 583	++	100.0
EXAMPLE 584	++	81.6	77.0
EXAMPLE 585	++	97.6
EXAMPLE 586	++	98.0
EXAMPLE 587	++	98.7
EXAMPLE 588	++	95.0
EXAMPLE 589	++	101.9
EXAMPLE 590	++	92.3
EXAMPLE 591	++	89.0
EXAMPLE 592	++	96.5
EXAMPLE 593	++	97.4
EXAMPLE 594	++	97.1
EXAMPLE 595	++	90.6
EXAMPLE 596	++	55.2
EXAMPLE 597	++	96.4
EXAMPLE 598	++	97.6	98.3
EXAMPLE 599	++	98.6
EXAMPLE 600	++	72.5
EXAMPLE 601	++	89.4
EXAMPLE 602	++	98.6
EXAMPLE 603	++	93.4
EXAMPLE 604	++	72.4
EXAMPLE 605	++	85.8
EXAMPLE 606	++	96.2
EXAMPLE 607	++	78.9
EXAMPLE 608	++	84.7
EXAMPLE 609	++	98.7
EXAMPLE 610	++	97.4
EXAMPLE 611	++	94.7
EXAMPLE 612	++	80.7
EXAMPLE 613	++	53.9
EXAMPLE 614	++	95.4
EXAMPLE 615	++	96.6
EXAMPLE 616	++	96.0
EXAMPLE 617	++	96.4
EXAMPLE 618	++	96.6
EXAMPLE 619	++	95.5
EXAMPLE 620	++	68.7
EXAMPLE 621	++	78.3
EXAMPLE 622	++	102.8
EXAMPLE 623	++	102.2
EXAMPLE 624	++	104.7
EXAMPLE 625	++	103.4
EXAMPLE 626	++	94.8
EXAMPLE 627	++	97.0
EXAMPLE 628	++	95.9
EXAMPLE 629	++	97.0
EXAMPLE 630	++	94.5
EXAMPLE 631	++	65.4
EXAMPLE 632	++	94.7
EXAMPLE 633	++	90.7
EXAMPLE 634	++	94.7
EXAMPLE 635	++	96.4
EXAMPLE 636	++	93.9
EXAMPLE 637	++	96.2
EXAMPLE 638	++	96.9
EXAMPLE 639	++	96.2
EXAMPLE 640	++	96.3
EXAMPLE 641	++	94.9
EXAMPLE 642	++	96.1
EXAMPLE 643	++	96.0
EXAMPLE 644	++	95.7
EXAMPLE 645	++	94.6
EXAMPLE 646	++	97.7
EXAMPLE 647	++	95.6
EXAMPLE 648	++	69.8
EXAMPLE 649 Isomer 1	++	72.2
EXAMPLE 649 Isomer 2	++	56.5
EXAMPLE 650	++	94.5
EXAMPLE 651	++	98.1
EXAMPLE 652	++	94.7
EXAMPLE 653	++	95.5
EXAMPLE 654 Isomer 1	#	18.5
EXAMPLE 654 Isomer 2	++	81.5
EXAMPLE 655	++	96.5
EXAMPLE 656	++	95.0
EXAMPLE 657	++	95.1
EXAMPLE 658	++	92.2
EXAMPLE 659	++	95.6
EXAMPLE 660	++	87.2
EXAMPLE 661	++	90.3
EXAMPLE 662	++	99.4
EXAMPLE 663	++	94.5
EXAMPLE 664	++	99.2
EXAMPLE 665	++	96.5

TABLE OF BIOLOGICAL ASSAY RESULTS FOR BIOLOGICAL TEST 3 Average % control inhibition at

Example	100 nM
666	14
667	63
668	−3
669	3
670	−5
671	−19
672	10
673	9
674	−14
676	17
677	43
678	59
679	58
680	−32
681	−19
682	−8
683	−1
684	−13
685	34
686	23
687	28
688	88

TABLE OF BIOLOGICAL ASSAY RESULTS FOR EXAMPLES 690-694 Biological Test Example 1 a ++ means IC 50 = <100 nM, + means IC 50 = 100-1000 nM, # means IC 50 > 100 nM, − means IC 50 > 1000 nM.

		Average %	Average %
		inhibition at	inhibition at
Compound	IC 50 Range a	100 nM	111.1 nM
EXAMPLE 690	++	94.9
EXAMPLE 691	++	90.1
EXAMPLE 692	++	80.65
EXAMPLE 693	#	17.65
EXAMPLE 694	++	91.5

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9 codes

IPC · International Patent Classification

Section A — Human necessities

A61K31/5377
A61K31/675
A61K31/541

Section C — Chemistry; metallurgy

C07D241/04
C07D413/04
C07D413/10

USPC · US Patent Classification

514/228.8544/97544/96

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