Patent Publication Number: US-2011077395-A1

Title: Inhibitors of 11-beta hydroxysteroid dehydrogenase type i

Description:
This application is a Divisional Application of copending, prior application Ser. No. 11/403,092, filed on Apr. 12, 2006, which claims the benefit of U.S. Provisional Application No. 60/671,174, filed Apr. 14, 2005. The entirety of each of these applications is incorporated herein by reference. 
    
    
     BACKGROUND OF THE INVENTION 
     The steroid hormone cortisol is a key regulator of many physiological processes. However, an excess of cortisol, as occurs in Cushing&#39;s Disease, provokes severe metabolic abnormalities including: type 2 diabetes, cardiovascular disease, obesity, and osteoporosis. Many patients with these diseases, however, do not show significant increases in plasma cortisol levels. In addition to plasma cortisol, individual tissues can regulate their glucocorticoid tone via the in situ conversion of inactive cortisone to the active hormone cortisol. Indeed, the normally high plasma concentration of cortisone provides a ready supply of precursor for conversion to cortisol via the intracellular enzyme 11-beta-hydroxysteroid dehydrogenase type I (11beta-HSD1). 
     11beta-HSD1 is a member of the short chain dehydrogenase superfamily of enzymes. By catalyzing the conversion of biologically inactive cortisone to cortisol, 11beta-HSD1 controls the intracellular glucocorticoid tone according to its expression and activity levels. In this manner, 11beta-HSD1 can determine the overall metabolic status of the organ. 11beta-HSD1 is expressed at high levels in the liver and at lower levels in many metabolically active tissues including the adipose, the CNS, the pancreas, and the pituitary. Taking the example of the liver, it is predicted that high levels of 11beta-HSD1 activity will stimulate gluconeogenesis and overall glucose output. Conversely, reduction of 11beta-HSD1 activity will downregulate gluconeogenesis resulting in lower plasma glucose levels. 
     Various studies have been conducted that support this hypothesis. For example, transgenic mice expressing 2× the normal level of 11beta-HSD1 in only the adipose tissue show abdominal obesity, hyperglycemia, and insulin resistance. (H. Masuzaki, J. Paterson, H. Shinyama, N. M. Morton, J. J. Mullins, J. R. Seckl, J. S. Flier, A Transgenic Model of Visceral Obesity and the Metabolic Syndrome,  Science  294:2166-2170 (2001). Conversely, when the 11beta-HSD1 gene is ablated by homologous recombination, the resulting mice are resistant to diet induced obesity and the accompanying dysregulation of glucose metabolism (N. M. Morton, J. M. Paterson, H. Masuzaki, M. C. Holmes, B. Staels, C. Fievet, B. R. Walker, J. S. Flier, J. J. Mullings, J. R. Seckl, Novel Adipose Tissue-Mediated Resistance to Diet-induced Visceral Obesity in 11β-Hydroxysteroid Dehydrogenase Type 1-Deficient Mice.  Diabetes  53: 931-938 (2004). In addition, treatment of genetic mouse models of obesity and diabetes (ob/ob, db/db and KKAy mice) with a specific inhibitor of 11beta-HSD1 causes a decrease in glucose output from the liver and an overall increase in insulin sensitivity (P. Alberts, C. Nilsson, G. Selen, L. O. M. Engblom, N. H. M. Edling, S, Norling, G. Klingstrom, C. Larsson, M. Forsgren, M. Ashkzari, C. E. Nilsson, M. Fiedler, E. Bergqvist, B. Ohman, E. Bjorkstrand, L. B. Abrahmsen, Selective Inhibition of 11β-Hydroxysteroid Dehydrogenase Type I Improves Hepatic Insuling Sensitivity in Hyperglycemic Mice Strains,  Endocrinology  144: 4755-4762 (2003)). Furthermore, inhibitors of 11beta-HSD1 have been shown to be effective in treating metabolic syndrome and atherosclerosis in high fat fed mice (Hermanowoki-Vosetka et. al.,  J. Eg. Med.,  2002, 202(4), 517-527). Based in part on these studies, it is believed that local control of cortisol levels is important in metabolic diseases in these model systems. In addition, the results of these studies also suggest that inhibition of 11beta-HSD1 will be a viable strategy for treating metabolic diseases such as type 2 diabetes, obesity, and the metabolic syndrome. 
     Lending further support to this idea are the results of a series of preliminary clinical studies. For example, several reports have shown that adipose tissue from obese individuals has elevated levels of 11beta-HSD1 activity. In addition, studies with carbenoxolone, a natural product derived from licorice that inhibits both 11beta-HSD1 and 11beta-HSD2 (converts cortisol to cortisone in kidney) have shown promising results. A seven day, double blind, placebo controlled, cross over study with carbenoxolone in mildly overweight individuals with type 2 diabetes showed that patients treated with the inhibitor, but not the placebo group, displayed a decrease in hepatic glucose production (R. C. Andrews, O. Rooyackers, B. R. Walker,  J. Clin. Endocrinol. Metab.  88: 285-291 (2003)). This observation is consistent with the inhibition of 11beta-HSD1 in the liver. The results of these preclinical and early clinical studies strongly support the concept that treatment with a potent and selective inhibitor of 11beta-HSD1 will be an efficacious therapy in patients afflicted with type 2 diabetes, obesity, and the metabolic syndrome. 
     SUMMARY OF THE INVENTION 
     In accordance with the present invention, aryl and heteroaryl and related compounds are provided that have the general structure of formula I: 
     
       
         
         
             
             
         
       
     
     wherein G, L, Q, Z, R 6 , R 7 , and R 8  are defined below. 
     The compounds of the present invention inhibit the activity of the enzyme 11-beta-hydroxysteroid dehydrogenase type I. Consequently, the compounds of the present invention may be used in the treatment of multiple diseases or disorders associated with 11-beta-hydroxysteroid dehydrogenase type I, such as diabetes and related conditions, microvascular complications associated with diabetes, the macrovascular complications associated with diabetes, cardiovascular diseases, Metabolic Syndrome and its component conditions, and other maladies. Examples of diseases or disorders associated with the activity of the enzyme 11-beta-hydroxysteroid dehydrogenase type I that can be prevented, inhibited, or treated according to the present invention include, but are not limited to, diabetes, hyperglycemia, impaired glucose tolerance, insulin resistance, hyperinsulinemia, retinopathy, neuropathy, nephropathy, delayed wound healing, atherosclerosis and its sequelae, abnormal heart function, myocardial ischemia, stroke, Metabolic Syndrome, hypertension, obesity, dislipidemia, dylsipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL, high LDL, non-cardiac ischemia, infection, cancer, vascular restenosis, pancreatitis, neurodegenerative disease, lipid disorders, cognitive impairment and dementia, bone disease, HIV protease associated lipodystrophy and glaucoma. 
     The present invention provides for compounds of formula I, pharmaceutical compositions employing such compounds, and for methods of using such compounds. In particular, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, alone or in combination with a pharmaceutically acceptable carrier. 
     Further, in accordance with the present invention, a method is provided for preventing, inhibiting, or treating the progression or onset of diseases or disorders associated with the activity of the enzyme 11-beta-hydroxysteroid dehydrogenase type I, such as defined above and hereinafter, wherein a therapeutically effective amount of a compound of formula I is administered to a mammalian, i.e., human, patient in need of treatment. 
     The compounds of the invention can be used alone, in combination with other compounds of the present invention, or in combination with one or more other agent(s). 
     Further, the present invention provides a method for preventing, inhibiting, or treating the diseases as defined above and hereinafter, wherein a therapeutically effective amount of a combination of a compound of formula I and another compound of formula I and/or at least one other type of therapeutic agent, is administered to a mammalian, i.e., human, patient in need of treatment. 
    
    
     DESCRIPTION OF THE INVENTION 
     In accordance with the present invention, compounds of formula I are provided 
     
       
         
         
             
             
         
       
     
     or stereoisomers or prodrugs or pharmaceutically acceptable salts thereof, wherein: 
     Z is aryl or heterocyclyl group, and may be optionally substituted with R 1 , R 2 , R 3 , R 4 , and R 5  at any available positions; 
     R 1 , R 2 , R 3 , R 4 , and R 5  are independently hydrogen, halo, cyano, haloalkyl, haloalkoxy, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, alkylamino, —C(O)R 9 , —NR 9 C(O)R 9a , —NR 9 R 9a , aryl, arylalkyl, aryloxy, or heterocyclyl, wherein the haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, alkylamino, aryl, arylalkyl, or heterocyclyl, may be optionally substituted with R 9  and R 9a ; 
     or independently any two adjoining R 1 , R 2 , R 3 , R 4 , and/or R 5  may be taken together to form a fused aryl or heterocyclyl ring, which may be may be optionally substituted with R 10 , R 10a , R 10b , and R 10c ; 
     R 10 , R 10a , R 10b , and R 10c  are independently selected from hydrogen, halo, hydroxy, nitro, cyano, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, —C(O)NR 9 R 9a , —C(O)R 9 , —NR 9 C(O)R 9a , aryl, aryloxy, or heterocyclyl, wherein the haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aryloxy, or heterocyclyl may be optionally substituted with R 9  and R 9a ; and 
     R 9  and R 9a  are independently hydrogen, alkyl, alkoxy, cycloalkyl, aryl, or heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclyl may be optionally substituted with halo, haloalkyl, alkyl, aryl, or heterocyclyl; 
     L is a bond, O, S, SO 2 , SO 2 NR 4a , NR 4a , OCR 4a R 4b , CR 4a R 4b O, SCR 4a R 4b , CR 4a R 4b S, SO 2 CR 4a R 4b , CR 4a R 4b SO 2 , CR 4a R 4b CR 4c R 4d , CR 4a ═CR 4b , or OCONR 4b ; 
     R 4a , R 4b , R 4c  and R 4d  are independently hydrogen, alkyl or haloalkyl, wherein the alkyl and haloalkyl may be optionally substituted with R 10 , R 10a , R 10b , and R 10c ; 
     G is a 5- or 6-membered heteroaryl containing at least one nitrogen; 
     R 6 , R 7 , and R 8  are independently hydrogen, halo, haloalkyl, haloalkoxy, alkyl, aryl, heterocyclyl, alkoxy, aryloxy; 
     Q is CONR 11 R 11a , SO 2 NR 11 R 11a , or OCONR 11 R 11a ; 
     R 11  and R 11a  are independently hydrogen, haloalkyl, alkyl, cycloalkyl, aryl, arylalkyl, or heterocyclyl, wherein the alkyl, cycloalkyl, aryl, arylalkyl, or heterocyclyl may be optionally substituted with R 10 , R 10a , R 10b , and R 10c ; 
     or R 11  and R 11a  may be taken together with the nitrogen to which they are attached to form a heterocyclyl ring, which may be optionally substituted with R 10 , R 10a , R 10b , and R 10c . 
     In another embodiment, compounds of formula I are those in which L is a bond, O, S, OCR 4a R 4b , SCR 4a R 4b , CR 4a R 4b S, SO 2 CR 4a R 4b , CR 4a R 4b SO 2 , CR 4a R 4b CR 4c R 4d , or CR 4a ═CR 4b . 
     In another embodiment, compounds of formula I are those in which L is a bond, OCR 4a R 4b , SCR 4a R 4b , CR 4a R 4b S, SO 2 CR 4a R 4b , CR 4a R 4b SO 2 , or CR 4a ═CR 4b . 
     In another embodiment, compounds of formula I are those in which L is OCR 4a R 4b , SCR 4a R 4b , CR 4a R 4b S, SO 2 CR 4a R 4b , CR 4a R 4b SO 2 , or CR 4a ═CR 4b . 
     In another embodiment, compounds of formula I are those in which L is CR 4a R 4b S, SO 2 CR 4a R 4b , CR 4a R 4b SO 2 , or CR 4a ═CR 4b . 
     In yet another embodiment, compounds of formula I are those in which L is CR 4a R 4b S, CR 4a R 4b SO 2 , or CR 4a ═CR 4b . 
     In another embodiment, compounds of formula I are those in which: 
     Z is aryl or heterocyclyl group, and may be optionally substituted with R 1 , R 2 , R 3 , R 4 , and R 5  at any available positions; 
     R 1 , R 2 , R 3 , R 4 , and R 5  are independently hydrogen, halo, cyano, haloalkyl, haloalkoxy, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, alkylamino, —C(O)R 9 , —NR 9 C(O)R 9a , —NR 9 R 9a , aryl, arylalkyl, aryloxy, or heterocyclyl, wherein the haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, alkylamino, aryl, arylalkyl, or heterocyclyl, may be optionally substituted with R 9  and R 9a ; 
     or independently any two adjoining R 1 , R 2 , R 3 , R 4 , and/or R 5  may be taken together to form a fused aryl or heterocyclyl ring, which may be may be optionally substituted with R 10 , R 10a , R 10b , and R 10c ; 
     L is bond, O, S, SO 2 , OCR 4a R 4b , CR 4a R 4b O, SCR 4a R 4b , CR 4a R 4b S, SO 2 CR 4a R 4b , CR 4a R 4b SO 2 , CR 4a R 4b CR 4c R 4d , CR 4a ═CR 4b , or OCONR 4b ; 
     R 4a , R 4b , R 4c , and R 4d  are independently hydrogen and alkyl, wherein the alkyl may be optionally substituted with R 10 , R 10a , R 10b , and R 10c ; 
     G is a 5- or 6-membered heteroaryl containing at least one nitrogen; 
     R 6 , R 7 , and R 8  are independently hydrogen, halo, haloalkyl, haloalkoxy, alkyl, aryl, heterocyclyl, alkoxy, aryloxy; 
     Q is CONR 11 R 11a , SO 2 NR 11 R 11a , or OCONR 11 R 11a ; 
     R 11  and R 11a  are independently hydrogen, haloalkyl, alkyl, cycloalkyl, aryl, arylalkyl, or heterocyclyl, wherein the alkyl, cycloalkyl, aryl, arylalkyl, or heterocyclyl may be optionally substituted with R 10 , R 10a , R 10b , and R 10c ; 
     or R 11  and R 11a  may be taken together with the nitrogen to which they are attached to form a heterocyclyl ring, which may be optionally substituted with R 10 , R 10a , R 10b , and R 10c ; 
     R 10 , R 10a , R 10b , and R 10c  are independently selected from hydrogen, halo, hydroxy, nitro, cyano, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, —C(O)NR 9 R 9a , —C(O)R 9 , —NR 9 C(O)R 9a , aryl, aryloxy, or heterocyclyl, wherein the haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aryloxy, or heterocyclyl may be optionally substituted with R 9  and R 9a ; and 
     R 9  and R 9a  are independently hydrogen, alkyl, alkoxy, cycloalkyl, aryl, or heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclyl may be optionally substituted with halo, haloalkyl, alkyl, aryl, or heterocyclyl. 
     In still yet another embodiment, compounds of formula I are those in which: 
     Z is aryl or heterocyclyl group, and may be optionally substituted with R 1 , R 2 , R 3 , R 4 , and R 5  at any available positions; 
     R 1 , R 2 , R 3 , R 4 , and R 5  are independently hydrogen, halo, cyano, haloalkyl, haloalkoxy, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, alkylamino, —C(O)R 9 , —NR 9 C(O)R 9a , —NR 9 R 9 , aryl, arylalkyl, aryloxy, or heterocyclyl, wherein the haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, alkylamino, aryl, arylalkyl, or heterocyclyl, may be optionally substituted with R 9  and R 9a ; 
     or independently any two adjoining R 1 , R 2 , R 3 , R 4 , and/or R 5  may be taken together to form a fused aryl or heterocyclyl ring, which may be may be optionally substituted with R 10 , R 10a , R 10b , and R 10c ; 
     L is a bond, OCR 4a R 4b , CR 4a R 4b O, SCR 4a R 4b , CR 4a R 4b S, SO 2 CR 4a R 4b , CR 4a R 4b SO 2 , CR 4a R 4b CR 4c R 4dc , or CR 4a ═CR 4b ; 
     R 4a , R 4b , R 4c , and R 4d  are independently hydrogen, alkyl or haloalkyl, wherein the alkyl or haloalkyl may be optionally substituted with R 10 , R 10a , R 10b , and R 10c ; 
     G is a 5- or 6-membered heteroaryl containing at least one nitrogen; 
     R 6 , R 7 , and R 8  are independently hydrogen, halo, haloalkyl, haloalkoxy, alkyl, aryl, heterocyclyl, alkoxy, aryloxy; 
     Q is SO 2 NR 11 R 11a  or OCONR 11 R 11a ; 
     R 11  and R 11a  are independently hydrogen, haloalkyl, alkyl, cycloalkyl, aryl, arylalkyl, or heterocyclyl, wherein the alkyl, cycloalkyl, aryl, arylalkyl, or heterocyclyl may be optionally substituted with R 10 , R 10a , R 10b , and R 10c ; 
     or R 11  and R 11a  may be taken together with the nitrogen to which they are attached to form a heterocyclyl ring, which may be optionally substituted with R 10 , R 10a , R 10b , and R 10c ; 
     R 10 , R 10a , R 10b , and R 10c  are independently selected from hydrogen, halo, hydroxy, nitro, cyano, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, —C(O)NR 9 R 9a , —C(O)R 9 , —NR 9 C(O)R 9a , aryl, aryloxy, or heterocyclyl, wherein the haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aryloxy, or heterocyclyl may be optionally substituted with R 9  and R 9a ; and 
     R 9  and R 9a  are independently hydrogen, alkyl, alkoxy, cycloalkyl, aryl, or heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclyl may be optionally substituted with halo, haloalkyl, alkyl, aryl, or heterocyclyl. 
     In one embodiment, compounds of formula I are those in which: 
     Z is aryl, and may be optionally substituted with R 1 , R 2 , R 3 , R 4 , and R 5  at any available positions; 
     R 1 , R 2 , R 3 , R 4 , and R 5  are independently hydrogen, halo, cyano, haloalkyl, haloalkoxy, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, alkylamino, —C(O)R 9 , —NR 9 C(O)R 9a , —NR 9 R 9a , aryl, arylalkyl, aryloxy, or heterocyclyl, wherein the haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, alkylamino, aryl, arylalkyl, or heterocyclyl, may be optionally substituted with R 9  and R 9a ; 
     L is a bond, OCR 4a R 4b , SCR 4a R 4b , SO 2 CR 4a R 4b , or CR 4a R 4b CR 4c R 4d ; 
     R 4a , R 4b , R 4c , and R 4d  are independently hydrogen and alkyl, wherein the alkyl may be optionally substituted with R 10 , R 10a , R 10b , and R 10c ; 
     G is a 5- or 6-membered heteroaryl containing at least one nitrogen; 
     R 6 , R 7 , and R 8  are independently hydrogen, halo, haloalkyl, haloalkoxy, alkyl, aryl, heterocyclyl, alkoxy, aryloxy; 
     Q is SO 2 NR 11 R 11a  or OCONR 11 R 11a ; 
     R 11  and R 11a  are independently hydrogen, haloalkyl, alkyl, cycloalkyl, aryl, arylalkyl, or heterocyclyl, wherein the alkyl, cycloalkyl, aryl, arylalkyl, or heterocyclyl may be optionally substituted with R 10 , R 10a , R 10b , and R 10c ; 
     or R 11  and R 11a  may be taken together with the nitrogen to which they are attached to form a heterocyclyl ring, which may be optionally substituted with R 10 , R 10a , R 10b , and R 10c ; 
     R 10 , R 10a , R 10b , and R 10c  are independently selected from hydrogen, halo, hydroxy, nitro, cyano, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, —C(O)NR 9 R 9a , —C(O)R 9 , —NR 9 C(O)R 9a , aryl, aryloxy, or heterocyclyl, wherein the haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aryloxy, or heterocyclyl may be optionally substituted with R 9  and R 9a ; and 
     R 9  and R 9a  are independently hydrogen, alkyl, alkoxy, cycloalkyl, aryl, or heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclyl may be optionally substituted with halo, haloalkyl, alkyl, aryl, or heterocyclyl. 
     In another embodiment, compounds of formula I are those in which: 
     Z is an aryl or heteroaryl of the following structure: 
     
       
         
         
             
             
         
       
     
     In yet another embodiment, compounds of formula I are those in which: 
     Z is an aryl or heteroaryl of the following structure: 
     
       
         
         
             
             
         
       
     
     In still yet another embodiment, the compounds of formula I are those in which: 
     G is a 5- or 6-membered heteroaryl containing at least one nitrogen of the following structure: 
     
       
         
         
             
             
         
       
     
     In one embodiment, compounds of formula I are those in which: 
     G is a 5- or 6-membered heteroaryl containing at least one nitrogen of the following structure: 
     
       
         
         
             
             
         
       
     
     In another embodiment, compounds of formula I are those in which: 
     Z is an aryl or heteroaryl of the following structure: 
     
       
         
         
             
             
         
       
     
     L is a bond, OCR 4a R 4b , CR 4a R 4b O, SCR 4a R 4b , CR 4a R 4b S, SO 2 CR 4a R 4b , CR 4a R 4b SO 2 , CR 4a R 4b CR 4c R 4d , or CR 4a ═CR 4b ; and 
     G is a 5- or 6-membered heteroaryl containing at least one nitrogen of the following structure: 
     
       
         
         
             
             
         
       
     
     In another embodiment, compounds of formula I are those in which: 
     Z is an aryl or heteroaryl of the following structure: 
     
       
         
         
             
             
         
       
     
     L is a bond, OCR 4 R 4b , SCR 4a R 4b , or SO 2 CR 4a R 4b ; 
     G is a 5- or 6-membered heteroaryl containing at least one nitrogen of the following structure: 
     
       
         
         
             
             
         
       
     
     In another embodiment, compounds of formula I are those in which: 
     Z is 
     
       
         
         
             
             
         
       
     
     and 
     G is a 5- or 6-membered heteroaryl containing at least one nitrogen of the following structure: 
     
       
         
         
             
             
         
       
     
     In another embodiment, compounds of formula I are those in which: 
     Z is 
     
       
         
         
             
             
         
       
     
     R 1 , R 2 , R 3 , R 4 , and R 5  are independently hydrogen, halo, cyano, haloalkyl, haloalkoxy, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, alkylamino, —C(O)R 9 , —NR 9 C(O)R 9a , —NR 9 R 9a , aryl, arylalkyl, aryloxy, or heterocyclyl, wherein the haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, alkylamino, aryl, arylalkyl, or heterocyclyl, may be optionally substituted with R 9  and R 9a ; 
     or independently any two adjoining R 1 , R 2 , R 3 , R 4 , and/or R 5  may be taken together to form a fused aryl or heterocyclyl ring, which may be may be optionally substituted with R 10 , R 10a , R 10b , and R 10c ; 
     L is a bond, OCR 4a R 4b , SCR 4a R 4b , or SO 2 CR 4a R 4b ; 
     R 4a  and R 4b  are independently hydrogen, alkyl, or haloalkyl; 
     G is a 5- or 6-membered heteroaryl containing at least one nitrogen of the following structure: 
     
       
         
         
             
             
         
       
     
     R 6 , R 7 , and R 8  are independently hydrogen, halo, haloalkyl, haloalkoxy, alkyl, aryl, heterocyclyl, alkoxy, aryloxy; 
     Q is SO 2 NR 11 R 11a  or OCONR 11 R 11a ; 
     R 11  and R 11a  are independently hydrogen, haloalkyl, alkyl, cycloalkyl, aryl, arylalkyl, or heterocyclyl, wherein the alkyl, cycloalkyl, aryl, arylalkyl, or heterocyclyl may be optionally substituted with R 10 , R 11a , R 10b , and R 10c ; 
     or R 11  and R 11a  may be taken together with the nitrogen to which they are attached to form a heterocyclyl ring, which may be optionally substituted with R 10 , R 10a , R 10b , and R 10c ; 
     R 10 , R 10a , R 10b , and R 10c  are independently selected from hydrogen, halo, hydroxy, nitro, cyano, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, —C(O)NR 9 R 9a , —C(O)R 9 , —NR 9 C(O)R 9a , aryl, aryloxy, or heterocyclyl, wherein the haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aryloxy, or heterocyclyl may be optionally substituted with R 9  and R 9a ; and 
     R 9  and R 9a  are independently hydrogen, alkyl, alkoxy, cycloalkyl, aryl, or heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclyl may be optionally substituted with halo, haloalkyl, alkyl, aryl, or heterocyclyl. 
     In yet another embodiment, compounds of formula I are those in which: 
     R 1 , R 2 , R 3 , R 4 , and R 5  are independently hydrogen, halo, cyano, haloalkyl, haloalkoxy, nitro, alkyl, cycloalkyl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, alkylamino, —C(O)R 9 , —NR 9 C(O)R 9a , —NR 9 R 9a , aryl, arylalkyl, aryloxy, or heterocyclyl, wherein the haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, alkylamino, aryl, arylalkyl, or heterocyclyl, may be optionally substituted with R 9  and R 9a ; 
     or independently any two adjoining R 1 , R 2 , R 3 , R 4 , and/or R 5  may be taken together to form a fused aryl or heterocyclyl ring, which may be may be optionally substituted with R 10 , R 10a , R 10b , and R 10c ; 
     L is OCR 4a R 4b , SCR 4a R 4b , or SO 2 CR 4a R 4b ; 
     R 4a  and R 4b  are independently hydrogen, alkyl or haloalkyl; 
     G is a 5- or 6-membered heteroaryl containing at least one nitrogen of the following structure: 
     
       
         
         
             
             
         
       
     
     R 6 , R 7 , and R 8  are independently hydrogen, halo, haloalkyl, haloalkoxy, alkyl, aryl, heterocyclyl, alkoxy, aryloxy; 
     Q is SO 2 NR 11 R 11a  or OCONR 11 R 11a ; 
     R 11  and R 11a  are independently hydrogen, haloalkyl, alkyl, cycloalkyl, aryl, arylalkyl, or heterocyclyl, wherein the alkyl, cycloalkyl, aryl, arylalkyl, or heterocyclyl may be optionally substituted with R 10 , R 10a , R 10b , and R 10c ; 
     or R 11  and R 11a  may be taken together with the nitrogen to which they are attached to form a heterocyclyl ring, which may be optionally substituted with R 10 , R 10a , R 10b , and R 10c ; 
     R 10 , R 10a , R 10b , and R 10c  are independently selected from hydrogen, halo, hydroxy, nitro, cyano, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, —C(O)NR 9 R 9a , —C(O)R 9 , —NR 9 C(O)R 9a , aryl, aryloxy, or heterocyclyl, wherein the haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aryloxy, or heterocyclyl may be optionally substituted with R 9  and R 9a ; and 
     R 9  and R 9a  are independently hydrogen, alkyl, alkoxy, cycloalkyl, aryl, or heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclyl may be optionally substituted with halo, haloalkyl, alkyl, aryl, or heterocyclyl. 
     In still yet another embodiment, compounds of formula I are those in which: 
     R 1 , R 2 , R 3 , R 4 , and R 5  are independently hydrogen, halo, cyano, haloalkyl, haloalkoxy, nitro, alkyl, cycloalkyl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, alkylamino, —C(O)R 9 , —NR 9 C(O)R 9a , —NR 9 R 9a , aryl, arylalkyl, aryloxy, or heterocyclyl, wherein the haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, alkylamino, aryl, arylalkyl, or heterocyclyl, may be optionally substituted with R 9  and R 9a ; 
     or independently any two adjoining R 1 , R 2 , R 3 , R 4 , and/or R 5  may be taken together to form a fused aryl or heterocyclyl ring, which may be may be optionally substituted with R 10 , R 10a , R 10b , and R 10c ; 
     L is OCR 4a R 4b  or SO 2 CR 4a R 4b ; 
     R 4a  and R 4b  are independently hydrogen, alkyl, or haloalkyl; 
     G is a 5- or 6-membered heteroaryl containing at least one nitrogen of the following structure: 
     
       
         
         
             
             
         
       
     
     R 6 , R 7 , and R 8  are independently hydrogen, halo, haloalkyl, haloalkoxy, alkyl, aryl, heterocyclyl, alkoxy, aryloxy; 
     Q is SO 2 NR 11 R 11a  or OCONR 11 R 11a ; 
     R 11  and R 11a  are independently hydrogen, haloalkyl, alkyl, cycloalkyl, aryl, arylalkyl, or heterocyclyl, wherein the alkyl, cycloalkyl, aryl, arylalkyl, or heterocyclyl may be optionally substituted with R 10 , R 10a , R 10b , and R 10c ; 
     or R 11  and R 11a  may be taken together with the nitrogen to which they are attached to form a heterocyclyl ring, which may be optionally substituted with R 10 , R 10a , R 10b , and R 10c ; 
     R 10 , R 10a , R 10b , and R 10c  are independently selected from hydrogen, halo, hydroxy, nitro, cyano, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, —C(O)NR 9 R 9a , —C(O)R 9 , —NR 9 C(O)R 9a , aryl, aryloxy, or heterocyclyl, wherein the haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aryloxy, or heterocyclyl may be optionally substituted with R 9  and R 9a ; and 
     R 9  and R 9a  are independently hydrogen, alkyl, alkoxy, cycloalkyl, aryl, or heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclyl may be optionally substituted with halo, haloalkyl, alkyl, aryl, or heterocyclyl. 
     In one embodiment, compounds of formula I are those in which: 
     R 1 , R 2 , R 3 , R 4 , and R 5  are independently hydrogen, halo, cyano, haloalkyl, haloalkoxy, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, alkylamino, —C(O)R 9 , —NR 9 C(O)R 9a , —NR 9 R 9a , aryl, arylalkyl, aryloxy, or heterocyclyl, wherein the haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, alkylamino, aryl, arylalkyl, or heterocyclyl, may be optionally substituted with R 9  and R 9a ; 
     or independently any two adjoining R 1 , R 2 , R 3 , R 4 , and/or R 5  may be taken together to form a fused aryl or heterocyclyl ring, which may be may be optionally substituted with R 10 , R 10a , R 10b , and R 10c ; 
     L is OCR 4a R 4b  or SO 2 CR 4a R 4b ; 
     R 4a  and R 4b  are independently hydrogen or alkyl; 
     G is a 5- or 6-membered heteroaryl containing at least one nitrogen of the following structure: 
     
       
         
         
             
             
         
       
     
     R 6 , R 7 , and R 8  are independently hydrogen, halo, haloalkyl, haloalkoxy, alkyl, aryl, heterocyclyl, alkoxy, aryloxy; 
     Q is SO 2 NR 11 R 11a  or OCONR 11 R 11a ; 
     R 11  and R 11a  are independently hydrogen, haloalkyl, alkyl, cycloalkyl, aryl, arylalkyl, or heterocyclyl, wherein the alkyl, cycloalkyl, aryl, arylalkyl, or heterocyclyl may be optionally substituted with R 10 , R 10a , R 10b , and R 10c ; 
     or R 11  and R 11a  may be taken together with the nitrogen to which they are attached to form a heterocyclyl ring, which may be optionally substituted with R 10 , R 10a , R 10b , and R 10c ; 
     R 10 , R 10a , R 10b , and R 10c  are independently selected from hydrogen, halo, hydroxy, nitro, cyano, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, —C(O)NR 9 R 9a , —C(O)R 9 , —NR 9 C(O)R 9a , aryl, aryloxy, or heterocyclyl, wherein the haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aryloxy, or heterocyclyl may be optionally substituted with R 9  and R 9a ; and 
     R 9  and R 9a  are independently hydrogen, alkyl, alkoxy, cycloalkyl, aryl, or heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclyl may be optionally substituted with halo, haloalkyl, alkyl, aryl, or heterocyclyl. 
     In another embodiment, compounds of formula I are those in which: 
     R 1 , R 2 , R 3 , R 4 , and R 5  are independently hydrogen, halo, cyano, haloalkyl, haloalkoxy, nitro, alkyl, cycloalkyl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, alkylamino, —C(O)R 9 , —NR 9 C(O)R 9a , —NR 9 R 9a , aryl, arylalkyl, aryloxy, or heterocyclyl, wherein the haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, alkylamino, aryl, arylalkyl, aryloxy, or heterocyclyl, may be optionally substituted with R 9  and R 9a ; 
     or independently any two adjoining R 1 , R 2 , R 3 , R 4 , and/or R 5  may be taken together to form a fused aryl or heterocyclyl ring, which may be may be optionally substituted with R 10 , R 10a , R 10b , and R 10c ; 
     L is OCR 4a R 4b  or SO 2 CR 4a R 4b ; 
     R 4a  and R 4b  are independently hydrogen or alkyl; 
     G is a 5- or 6-membered heteroaryl containing at least one nitrogen of the following structure: 
     
       
         
         
             
             
         
       
     
     R 6 , R 7 , and R 8  are independently hydrogen, halo, haloalkyl, haloalkoxy, alkyl, aryl, heterocyclyl, alkoxy, aryloxy; 
     Q is SO 2 NR 11 R 11a  or OCONR 11 R 11a ; 
     R 11  and R 11a  are independently hydrogen, haloalkyl, alkyl, cycloalkyl, aryl, arylalkyl, or heterocyclyl, wherein the alkyl, cycloalkyl, aryl, arylalkyl, or heterocyclyl may be optionally substituted with R 10 , R 10a , R 10b , and R 10c ; 
     or R 11  and R 11a  may be taken together with the nitrogen to which they are attached to form a heterocyclyl ring, which may be optionally substituted with R 10 , R 10a , R 10b , and R 10c ; 
     R 10 , R 10a , R 10b , and R 10c  are independently selected from hydrogen, halo, hydroxy, nitro, cyano, haloalkyl, alkyl, cycloalkyl, —C(O)NR 9 R 9a , —C(O)R 9 , —NR 9 C(O)R 9a , aryl, aryloxy, or heterocyclyl, wherein the haloalkyl, alkyl, cycloalkyl, aryl, aryloxy, or heterocyclyl may be optionally substituted with R 9  and R 9a ; and 
     R 9  and R 9a  are independently hydrogen, alkyl, alkoxy, cycloalkyl, aryl, or heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclyl may be optionally substituted with halo, haloalkyl, alkyl, aryl, or heterocyclyl. 
     In yet another embodiment, compounds of formula I are those in which: 
     R 1 , R 2 , R 3 , R 4 , and R 5  are independently hydrogen, halo, cyano, haloalkyl, haloalkoxy, nitro, alkyl, cycloalkyl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, alkylamino, aryl, arylalkyl, aryloxy, or heterocyclyl, wherein the haloalkyl, haloalkoxy, alkyl, cycloalkyl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, alkylamino, aryl, arylalkyl, or heterocyclyl, may be optionally substituted with R 9  and R 9a ; 
     or independently any two adjoining R 1 , R 2 , R 3 , R 4 , and/or R 5  may be taken together to form a fused aryl or heterocyclyl ring, which may be may be optionally substituted with R 10 , R 10a , R 10b , and R 10c ; 
     L is OCR 4a R 4b  or SO 2 CR 4a R 4b ; 
     R 4a  and R 4b  are independently hydrogen or alkyl; 
     G is a 5- or 6-membered heteroaryl containing at least one nitrogen of the following structure: 
     
       
         
         
             
             
         
       
     
     R 6 , R 7 , and R 8  are independently hydrogen, halo, haloalkyl, haloalkoxy, alkyl, aryl, or heterocyclyl; 
     Q is SO 2 NR 11 R 11a  or OCONR 11 R 11a ; 
     R 11  and R 11a  are independently hydrogen, haloalkyl, alkyl, cycloalkyl, aryl, arylalkyl, or heterocyclyl, wherein the alkyl, cycloalkyl, aryl, arylalkyl, or heterocyclyl may be optionally substituted with R 10 , R 10a , R 10b , and R 10c ; 
     or R 11  and R 11a  may be taken together with the nitrogen to which they are attached to form a heterocyclyl ring, which may be optionally substituted with R 10 , R 10a , R 10b , and R 10c ; 
     R 10 , R 10a , R 10b , and R 10c  are independently selected from hydrogen, halo, hydroxy, nitro, cyano, haloalkyl, alkyl, cycloalkyl, aryl, aryloxy, or heterocyclyl, wherein the haloalkyl, alkyl, cycloalkyl, aryl, aryloxy, or heterocyclyl may be optionally substituted with R 9  and R 9a ; and 
     R 9  and R 9a  are independently hydrogen, alkyl, alkoxy, cycloalkyl, aryl, or heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclyl may be optionally substituted with halo, haloalkyl, alkyl, aryl, or heterocyclyl. 
     In still yet another embodiment, compounds of formula I are those in which: 
     R 1 , R 2 , R 3 , R 4 , and R 5  are independently hydrogen, halo, haloalkyl, haloalkoxy, alkyl, cycloalkyl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, alkylamino, aryl, arylalkyl, aryloxy, or heterocyclyl, wherein the haloalkyl, haloalkoxy, alkyl, cycloalkyl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, alkylamino, aryl, arylalkyl, or heterocyclyl, may be optionally substituted with R 9  and R 9a ; 
     or independently any two adjoining R 1 , R 2 , R 3 , R 4 , and/or R 5  may be taken together to form a fused aryl or heterocyclyl ring, which may be may be optionally substituted with R 10 , R 10a , R 10b , and R 10c ; 
     L is OCR 4a R 4b  or SO 2 CR 4a R 4b ; 
     R 4a  and R 4b  are independently hydrogen or alkyl; 
     G is a 5- or 6-membered heteroaryl containing at least one nitrogen of the following structure: 
     
       
         
         
             
             
         
       
     
     R 6 , R 7 , and R 8  are independently hydrogen, halo, alkyl, aryl, or heterocyclyl; 
     Q is SO 2 NR 11 R 11a  or OCONR 11 R 11a ; 
     R 11  and R 11a  are independently hydrogen, alkyl, cycloalkyl, aryl or heterocyclyl, wherein the alkyl, cycloalkyl, aryl, or heterocyclyl may be optionally substituted with R 10 , R 10a , R 10b , and R 10c ; 
     or R 11  and R 11a  may be taken together with the nitrogen to which they are attached to form a heterocyclyl ring, which may be optionally substituted with R 10 , R 10a ; R 10b , and R 10c ; 
     R 10 , R 10a , R 10b , and R 10c  are independently selected from hydrogen, halo, haloalkyl, alkyl, cycloalkyl, aryl, aryloxy, or heterocyclyl, wherein the haloalkyl, alkyl, cycloalkyl, aryl, aryloxy, or heterocyclyl may be optionally substituted with R 9  and R 9a ; and 
     R 9  and R 9a  are independently hydrogen, alkyl, alkoxy, cycloalkyl, aryl, or heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclyl may be optionally substituted with halo, haloalkyl, alkyl, aryl, or heterocyclyl. 
     In an additional embodiment, compounds of formula I are those in which: 
     R 1 , R 2 , R 3 , R 4 , and R 5  are independently hydrogen, halo, haloalkyl, haloalkoxy, alkyl, cycloalkyl, alkoxy, aryl, arylalkyl, aryloxy, or heterocyclyl, wherein the haloalkyl, haloalkoxy, alkyl, cycloalkyl, alkoxy, aryl, arylalkyl, aryloxy, or heterocyclyl, may be optionally substituted with R 9  and R 9a ; 
     L is OCR 4a R 4b  or SO 2 CR 4a R 4b ; 
     R 4a  and R 4b  are independently hydrogen or alkyl; 
     G is a 5- or 6-membered heteroaryl containing at least one nitrogen of the following structure: 
     
       
         
         
             
             
         
       
     
     R 6 , R 7 , and R 8  are independently hydrogen, alkyl, aryl, or heterocyclyl; 
     Q is SO 2 NR 11 R 11a  or OCONR 11 R 11a ; 
     R 11  and R 11a  are independently hydrogen, alkyl, cycloalkyl, aryl or heterocyclyl, wherein the alkyl, cycloalkyl, aryl or heterocyclyl may be optionally substituted with R 10 , R 10a , R 10b , and R 10c ; 
     or R 11  and R 11a  may be taken together with the nitrogen to which they are attached to form a heterocyclyl ring, which may be optionally substituted with R 10 , R 10a , R 10b , and R 10c ; 
     R 10 , R 10a , R 10b , and R 10c  are independently selected from hydrogen, halo, haloalkyl, alkyl, cycloalkyl, aryl, or heterocyclyl, wherein the haloalkyl, alkyl, cycloalkyl, aryl, or heterocyclyl may be optionally substituted with R 9  and R 9a ; and 
     R 9  and R 9a  are independently hydrogen, alkyl, cycloalkyl, aryl, or heterocyclyl, wherein the alkyl, cycloalkyl, aryl, or heterocyclyl may be optionally substituted with halo, haloalkyl, alkyl, aryl, or heterocyclyl. 
     In another additional embodiment, compounds of formula I are those in which: 
     R 1 , R 2 , R 3 , R 4 , and R 5  are independently hydrogen, halo, haloalkyl, alkyl, cycloalkyl, aryl, arylalkyl, aryloxy, or heterocyclyl, wherein the haloalkyl, haloalkoxy, alkyl, cycloalkyl, alkoxy, aryl, arylalkyl, aryloxy, or heterocyclyl, may be optionally substituted with R 9  and R 9a ; 
     L is OCH 2  or SO 2 CH 2 ; 
     G is a 5- or 6-membered heteroaryl containing at least one nitrogen of the following structure: 
     
       
         
         
             
             
         
       
     
     R 6 , R 7 , and R 8  are independently hydrogen or alkyl; 
     Q is SO 2 NR 11 R 11a  or OCONR 11 R 11a ; 
     R 11  and R 11a  are independently hydrogen, alkyl, cycloalkyl, aryl or heterocyclyl, wherein the alkyl, cycloalkyl, aryl or heterocyclyl may be optionally substituted with R 10 , R 10a , R 10b , and R 10c ; 
     or R 11  and R 11a  may be taken together with the nitrogen to which they are attached to form a heterocyclyl ring, which may be optionally substituted with R 10 , R 10a , R 10b , and R 10c ; 
     R 10 , R 10a , R 10b , and R 10c  are independently selected from hydrogen, halo, alkyl, cycloalkyl, aryl, or heterocyclyl, wherein the alkyl, cycloalkyl, aryl, or heterocyclyl may be optionally substituted with R 9  and R 9a ; and 
     R 9  and R 9a  are independently hydrogen, alkyl, cycloalkyl, aryl, or heterocyclyl, wherein the alkyl, cycloalkyl, aryl, or heterocyclyl may be optionally substituted with halo, haloalkyl, alkyl, aryl, or heterocyclyl. 
     In yet another additional embodiment, compounds of formula I are those in which: 
     R 1 , R 2 , R 3 , R 4 , and R 5  are independently hydrogen, halo, haloalkyl, alkyl, cycloalkyl, aryl, or heterocyclyl, wherein the haloalkyl, alkyl, cycloalkyl, aryl, or heterocyclyl, may be optionally substituted with R 9  and R 9a ; 
     G is a 5- or 6-membered heteroaryl containing at least one nitrogen of the following structure: 
     
       
         
         
             
             
         
       
     
     R 6 , R 7 , and R 8  are hydrogen; 
     Q is SO 2 NR 11 R 11a ; 
     R 11  and R 11a  are independently hydrogen, alkyl, or cycloalkyl, wherein the alkyl or cycloalkyl may be optionally substituted with R 10 , R 10a , R 10b , and R 10c ; 
     or R 11  and R 11a  may be taken together with the nitrogen to which they are attached to form a heterocyclyl ring, which may be optionally substituted with R 10 , R 10a , R 10b , and R 10c ; 
     R 10 , R 10a , R 10b , and R 10c  are independently selected from hydrogen, halo, alkyl, aryl, or heterocyclyl, wherein the alkyl, aryl, or heterocyclyl may be optionally substituted with R 9  and R 9a ; and 
     R 9  and R 9a  are independently hydrogen, alkyl, aryl, or heterocyclyl, wherein the alkyl, aryl, or heterocyclyl may be optionally substituted with halo, haloalkyl, alkyl, aryl, or heterocyclyl. 
     In still yet another embodiment, compounds of formula I are those in which: 
     R 1 , R 2 , R 3 , R 4 , and R 5  are independently hydrogen, halo, haloalkyl, alkyl, or cycloalkyl, wherein the haloalkyl, alkyl or cycloalkyl, may be optionally substituted with R 9  and R 9a ; 
     G is a 5- or 6-membered heteroaryl containing at least one nitrogen of the following structure: 
     
       
         
         
             
             
         
       
     
     R 6 , R 7 , and R 8  are hydrogen; 
     Q is SO 2 NR 11 R 11a ; 
     R 11  and R 11a  are independently hydrogen or alkyl; 
     or R 11  and R 11a  may be taken together with the nitrogen to which they are attached to form a heterocyclyl ring, which may be optionally substituted with R 10 , R 10a ; R 10b , and R 10c ; 
     R 10 , R 10a , R 10b , and R 10c  are independently selected from hydrogen, halo, or alkyl. 
     In one embodiment, compounds of formula I are those in which: 
     G is a 5- or 6-membered heteroaryl containing at least one nitrogen of the following structure: 
     
       
         
         
             
             
         
       
     
     In another embodiment, compounds of formula I are those in which: 
     G is a 5- or 6-membered heteroaryl containing at least one nitrogen of the following structure: 
     
       
         
         
             
             
         
       
     
     In another embodiment, compounds of the present invention are selected from the compounds exemplified in the examples. 
     In another embodiment, the present invention relates to pharmaceutical compositions comprised of a therapeutically effective amount of a compound of the present invention, alone or, optionally, in combination with a pharmaceutically acceptable carrier and/or one or more other agent(s). 
     In another embodiment, the present invention relates to methods of inhibiting the activity of the enzyme 11-beta-hydroxysteroid dehydrogenase type I comprising administering to a mammalian patient, for example, a human patient, in need thereof a therapeutically effective amount of a compound of the present invention, alone, or optionally, in combination with another compound of the present invention and/or at least one other type of therapeutic agent. 
     In another embodiment, the present invention relates to a method for preventing, inhibiting, or treating the progression or onset of diseases or disorders associated with the activity of the enzyme 11-beta-hydroxysteroid dehydrogenase type I comprising administering to a mammalian patient, for example, a human patient, in need of prevention, inhibition, or treatment a therapeutically effective amount of a compound of the present invention, alone, or, optionally, in combination with another compound of the present invention and/or at least one other type of therapeutic agent. 
     Examples of diseases or disorders associated with the activity of the enzyme 11-beta-hydroxysteroid dehydrogenase type I that can be prevented, inhibited, or treated according to the present invention include, but are not limited to, diabetes, hyperglycemia, impaired glucose tolerance, insulin resistance, hyperinsulinemia, retinopathy, neuropathy, nephropathy, delayed wound healing, atherosclerosis and its sequelae, abnormal heart function, myocardial ischemia, stroke, Metabolic Syndrome, hypertension, obesity, dislipidemia, dylsipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL, high LDL, non-cardiac ischemia, infection, cancer, vascular restenosis, pancreatitis, neurodegenerative disease, lipid disorders, cognitive impairment and dementia, bone disease, HIV protease associated lipodystrophy and glaucoma. 
     In another embodiment, the present invention relates to a method for preventing, inhibiting, or treating the progression or onset of diabetes, hyperglycemia, obesity, dyslipidemia, hypertension and cognitive impairment comprising administering to a mammalian patient, for example, a human patient, in need of prevention, inhibition, or treatment a therapeutically effective amount of a compound of the present invention, alone, or, optionally, in combination with another compound of the present invention and/or at least one other type of therapeutic agent. 
     In still another embodiment, the present invention relates to a method for preventing, inhibiting, or treating the progression or onset of diabetes, comprising administering to a mammalian patient, for example, a human patient, in need of prevention, inhibition, or treatment a therapeutically effective amount of a compound of the present invention, alone, or, optionally, in combination with another compound of the present invention and/or at least one other type of therapeutic agent. 
     In yet still another embodiment, the present invention relates to a method for preventing, inhibiting, or treating the progression or onset of hyperglycemia comprising administering to a mammalian patient, for example, a human patient, in need of prevention, inhibition, or treatment a therapeutically effective amount of a compound of the present invention, alone, or, optionally, in combination with another compound of the present invention and/or at least one other type of therapeutic agent. 
     In another embodiment, the present invention relates to a method for preventing, inhibiting, or treating the progression or onset of obesity comprising administering to a mammalian patient, for example, a human patient, in need of prevention, inhibition, or treatment a therapeutically effective amount of a compound of the present invention, alone, or, optionally, in combination with another compound of the present invention and/or at least one other type of therapeutic agent. 
     In one embodiment, the present invention relates to a method for preventing, inhibiting, or treating the progression or onset of dyslipidemia comprising administering to a mammalian patient, for example, a human patient, in need of prevention, inhibition, or treatment a therapeutically effective amount of a compound of the present invention, alone, or, optionally, in combination with another compound of the present invention and/or at least one other type of therapeutic agent. 
     In another embodiment, the present invention relates to a method for preventing, inhibiting, or treating the progression or onset of hypertension comprising administering to a mammalian patient, for example, a human patient, in need of prevention, inhibition, or treatment a therapeutically effective amount of a compound of the present invention, alone, or, optionally, in combination with another compound of the present invention and/or at least one other type of therapeutic agent. 
     In another embodiment, the present invention relates to a method for preventing, inhibiting, or treating the progression or onset of cognitive impairment comprising administering to a mammalian patient, for example, a human patient, in need of prevention, inhibition, or treatment a therapeutically effective amount of a compound of the present invention, alone, or, optionally, in combination with another compound of the present invention and/or at least one other type of therapeutic agent. 
     DEFINITIONS 
     The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, C═N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms, and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. 
     The term “substituted,” as used herein, means that any one or more hydrogens on the designated atom or ring is replaced with a selection from the indicated group, provided that the designated atom&#39;s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom are replaced. 
     When any variable (e.g., R a ) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R a , then said group may optionally be substituted with up to two R a  groups and R a  at each occurrence is selected independently from the definition of R a . Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. 
     When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. 
     Unless otherwise indicated, the term “lower alkyl,” “alkyl,” or “alk” as employed herein alone or as part of another group includes both straight and branched chain hydrocarbons, containing 1 to 20 carbons, preferably 1 to 10 carbons, more preferably 1 to 8 carbons, in the normal chain, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethyl-pentyl, nonyl, decyl, undecyl, dodecyl, the various branched chain isomers thereof, and the like as well as such groups may optionally include 1 to 4 substituents such as halo, for example F, Br, Cl, or I, or CF 3 , alkyl, alkoxy, aryl, aryloxy, aryl(aryl) or diaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amino, hydroxy, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, nitro, cyano, thiol, haloalkyl, trihaloalkyl, and/or alkylthio. 
     Unless otherwise indicated, the term “cycloalkyl” as employed herein alone or as part of another group includes saturated or partially unsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groups containing 1 to 3 rings, including monocyclic alkyl, bicyclic alkyl (or bicycloalkyl) and tricyclic alkyl, containing a total of 3 to 20 carbons forming the ring, preferably 3 to 10 carbons, forming the ring and which may be fused to 1 or 2 aromatic rings as described for aryl, which includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl, 
     
       
         
         
             
             
         
       
     
     any of which groups may be optionally substituted with 1 to 4 substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy, arylalkyl, cycloalkyl, alkylamido, alkanoylamino, oxo, acyl, arylcarbonylamino, amino, nitro, cyano, thiol, and/or alkylthio, and/or any of the substituents for alkyl. 
     Unless otherwise indicated, the term “lower alkenyl” or “alkenyl” as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbons, and more preferably 1 to 8 carbons in the normal chain, which include one to six double bonds in the normal chain, such as vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl, and the like, and which may be optionally substituted with 1 to 4 substituents, namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, amino, hydroxy, heteroaryl, cycloheteroalkyl, alkanoylamino, alkylamido, arylcarbonyl-amino, nitro, cyano, thiol, alkylthio, and/or any of the alkyl substituents set out herein. 
     Unless otherwise indicated, the term “lower alkynyl” or “alkynyl” as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbons and more preferably 2 to 8 carbons in the normal chain, which include one triple bond in the normal chain, such as 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl, 3-undecynyl, 4-dodecynyl, and the like, and which may be optionally substituted with 1 to 4 substituents, namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, amino, heteroaryl, cycloheteroalkyl, hydroxy, alkanoylamino, alkylamido, arylcarbonylamino, nitro, cyano, thiol, and/or alkylthio, and/or any of the alkyl substituents set out herein. 
     Where alkyl groups as defined above have single bonds for attachment to other groups at two different carbon atoms, they are termed “alkylene” groups and may optionally be substituted as defined above for “alkyl”. 
     Where alkenyl groups as defined above and alkynyl groups as defined above, respectively, have single bonds for attachment at two different carbon atoms, they are termed “alkenylene groups” and “alkynylene groups”, respectively, and may optionally be substituted as defined above for “alkenyl” and “alkynyl”. 
     The term “halogen” or “halo” as used herein alone or as part of another group refers to chlorine, bromine, fluorine, and iodine as well as CF 3 , with chlorine or fluorine being preferred. 
     Unless otherwise indicated, the term “aryl” as employed herein alone or as part of another group refers to monocyclic and bicyclic aromatic groups containing 6 to 10 carbons in the ring portion (such as phenyl or naphthyl, including 1-naphthyl and 2-naphthyl) and may optionally include 1 to 3 additional rings fused to a carbocyclic ring or a heterocyclic ring (such as aryl, cycloalkyl, heteroaryl, or cycloheteroalkyl rings 
     for example 
     
       
         
         
             
             
         
       
     
     and may be optionally substituted through available carbon atoms with 1, 2, or 3 substituents, for example, hydrogen, halo, haloalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkyl-alkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, arylthio, arylazo, heteroarylalkyl, heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro, cyano, amino, substituted amino wherein the amino includes 1 or 2 substituents (which are alkyl, aryl, or any of the other aryl compounds mentioned in the definitions), thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl, arylcarbonyl, alkyl-aminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino, or arylsulfon-aminocarbonyl, and/or any of the alkyl substituents set out herein. 
     Unless otherwise indicated, the term “lower alkoxy”, “alkoxy”, “aryloxy” or “aralkoxy” as employed herein alone or as part of another group includes any of the above alkyl, aralkyl, or aryl groups linked to an oxygen atom. 
     Unless otherwise indicated, the term “amino” as employed herein alone or as part of another group refers to amino that may be substituted with one or two substituents, which may be the same or different, such as alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or thioalkyl. These substituents may be further substituted with a carboxylic acid and/or any of the R 1  groups or substituents for R 1  as set out above. In addition, the amino substituents may be taken together with the nitrogen atom to which they are attached to form 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl, 4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl, 1-pyrrolidinyl, 1-piperidinyl, or 1-azepinyl, optionally substituted with alkyl, alkoxy, alkylthio, halo, trifluoromethyl, or hydroxy. 
     Unless otherwise indicated, the term “lower alkylthio,” “alkylthio,” “arylthio,” or “aralkylthio” as employed herein alone or as part of another group includes any of the above alkyl, aralkyl, or aryl groups linked to a sulfur atom. 
     Unless otherwise indicated, the term “lower alkylamino,” “alkylamino,” “arylamino,” or “arylalkylamino” as employed herein alone or as part of another group includes any of the above alkyl, aryl, or arylalkyl groups linked to a nitrogen atom. 
     As used herein, the term “heterocyclyl” or “heterocyclic system” is intended to mean a stable 5- to 12-membered monocyclic or bicyclic heterocyclic ring which is saturated, partially unsaturated, or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, NH, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. As used herein, the term “aromatic heterocyclic system” is intended to mean a stable 5- to 12-membered monocyclic or bicyclic heterocyclic aromatic ring, which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S. 
     Unless otherwise indicated, the term “heteroaryl” as used herein alone or as part of another group refers to a 5- or 12-membered aromatic ring, preferably, a 5- or 6-membered aromatic ring, which includes 1, 2, 3, or 4 hetero atoms such as nitrogen, oxygen, or sulfur, and such rings fused to an aryl, cycloalkyl, heteroaryl, or cycloheteroalkyl ring (e.g. benzothiophenyl, indolyl), and includes possible N-oxides. The heteroaryl group may optionally include 1 to 4 substituents such as any of the substituents set out above for alkyl. Examples of heteroaryl groups include the following: 
     
       
         
         
             
             
         
       
     
     and the like. 
     The term “heterocyclylalkyl” or “heterocyclyl” as used herein alone or as part of another group refers to heterocyclyl groups as defined above linked through a C atom or heteroatom to an alkyl chain. 
     The term “heteroarylalkyl” or “heteroarylalkenyl” as used herein alone or as part of another group refers to a heteroaryl group as defined above linked through a C atom or heteroatom to an alkyl chain, alkylene, or alkenylene as defined above. 
     The term “cyano” as used herein, refers to a —CN group. 
     The term “nitro” as used herein, refers to an —NO 2  group. 
     The term “hydroxy” as used herein, refers to an —OH group. 
     The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. 
     As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like. 
     The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in  Remington&#39;s Pharmaceutical Sciences,  17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference. 
     Any compound that can be converted in vivo to provide the bioactive agent (i.e., the compound of formula I) is a prodrug within the scope and spirit of the invention. 
     The term “prodrugs” as employed herein includes esters and carbonates formed by reacting one or more hydroxyls of compounds of formula I with alkyl, alkoxy, or aryl substituted acylating agents employing procedures known to those skilled in the art to generate acetates, pivalates, methylcarbonates, benzoates, and the like. 
     Various forms of prodrugs are well known in the art and are described in:
     a)  The Practice of Medicinal Chemistry , Camille G. Wermuth et al., Ch. 31, (Academic Press, 1996);   b)  Design of Prodrugs , edited by H. Bundgaard, (Elsevier, 1985);   c)  A Textbook of Drug Design and Development , P. Krogsgaard-Larson and H. Bundgaard, eds. Ch. 5, pgs 113-191 (Harwood Academic Publishers, 1991); and   d)  Hydrolysis in Drug and Prodrug Metabolism , Bernard Testa and Joachim M. Mayer, (Wiley-VCH, 2003).
 
Said references are incorporated herein by reference.
   

     In addition, compounds of the formula I are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 99% formula I compound (“substantially pure” compound I), which is then used or formulated as described herein. Such “substantially pure” compounds of the formula I are also contemplated herein as part of the present invention. 
     All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form. The compounds of the present invention can have asymmetric centers at any of the carbon atoms including any one of the R substituents and/or exhibit polymorphism. Consequently, compounds of formula I can exist in enantiomeric, or diastereomeric forms, or in mixtures thereof. The processes for preparation can utilize racemates, enantiomers, or diastereomers as starting materials. When diastereomeric or enantiomeric products are prepared, they can be separated by conventional methods for example, chromatographic or fractional crystallization. 
     “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. The present invention is intended to embody stable compounds. 
     “Therapeutically effective amount” is intended to include an amount of a compound of the present invention alone or an amount of the combination of compounds claimed or an amount of a compound of the present invention in combination with other active ingredients effective to inhibit MIP-1α or effective to treat or prevent inflammatory disorders. 
     As used herein, “treating” or “treatment” cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, i.e., arresting it development; and/or (c) relieving the disease-state, i.e., causing regression of the disease state. 
     SYNTHESIS 
     Compounds of formula I of may be prepared as shown in the following reaction schemes and description thereof, as well as relevant literature procedures that may be used by one skilled in the art. Exemplary reagents and procedures for these reactions appear hereinafter and in the working Examples. 
     
       
         
         
             
             
         
       
     
     Scheme I describes a method for preparing compounds of formula IA (a subset of compounds of formula I). An acid intermediate II can be obtained commercially, prepared by methods known in the literature or other methods used by one skilled in the art. Formation of an amide IV can be obtained from an acid II and an amine III using appropriate amide coupling reagents, such as EDAC/HOBT, EDAC/HOAT, PyBOP, or those reagents described in “The Practice of Peptide Synthesis” (Spring-Verlag, 2 nd  Ed., Bodanszy, Miklos, 1993), to yield an amide intermediate IV. Carbonylation of an intermediate IV with an appropriate catalyst and ligand provides an ester intermediate V. Reduction of an ester V using an appropriate reducing reagent such as sodium borohydride or other reagents used by one skilled in the art provides an alcohol VI. Mitsunobu Reaction of an alcohol VI with a phenol VII provides compounds of formula IA. 
     
       
         
         
             
             
         
       
     
     Scheme II describes another method for preparing compounds of formula IA (a subset of compounds of formula I). An intermediate VIII can be obtained commercially, prepared by methods known in the literature or other methods used by one skilled in the art. Bromination of an intermediate VIII can be obtained using NBS with an appropriate radical reaction initiator such as AIBN to provide a bromo-intermediate IX. Alkylation of a phenol intermediate VII with a bromo-intermediate IX provides an ester intermediate X. Hydrolysis of an ester X under basic condition followed by amide formation with an amine III provides compounds of formula IA. 
     
       
         
         
             
             
         
       
     
     Scheme III describes a method for preparing compounds of formula IB and IC (subsets of compounds of formula I). A diester intermediate XI can be obtained commercially, prepared by methods known in the literature or other methods used by one skilled in the art. Reduction of one ester group can be obtained using an appropriate reducing reagent such as sodium borohydride or other reagents used by one skilled in the art. Chlorination of an alcohol intermediate XII using thionyl chloride or carbon tetrachloride/triphenyl phosphine provides an intermediate XIII Alkylation of a thiophenol XIV with an intermediate XIII provides an ester intermediate XV. Hydrolysis of an ester XV under basic conditions followed by amide formation with an amine III provides compounds of formula IB. Subsequent oxidation of compounds IB with an appropriate oxidizing reagent such as mCPBA, Oxone®, p-toluenesulfonic peracid generated in situ ( Tetrahedron,  1996, 52, 5773-5787), or other reagents used by one skilled in the art provides compounds of formula IC. 
     
       
         
         
             
             
         
       
     
     Scheme IV describes a method for preparing compounds of formula ID (a subset of compounds of formula I). A cross-coupling reaction of a bromo-intermediate IV (Scheme I) with a boronic acid XVI, an organostannane XVII, or an organozinc reagent XVIII using an appropriate catalyst and ligand provides compounds of formula ID. 
     
       
         
         
             
             
         
       
     
     Scheme V describes a method for preparing compounds of formula IE (a subset of compounds of formula I). Nucleophilic aromatic substitution of an intermediate IV (Scheme I) by a phenol intermediate VII provides compounds of formula IE. 
     
       
         
         
             
             
         
       
     
     Scheme VI describes a method for preparing compounds of formula IF and IG (subsets of compounds of formula I). Nucleophilic aromatic substitution of an intermediate IV (Scheme I) by a thiophenol intermediate XIV provides compounds of formula IF. Subsequent oxidation of a compound IF with an appropriate oxidizing reagent such as mCPBA, Oxone®, p-toluenesulfonic peracid generated in situ ( Tetrahedron,  1996, 52, 5773-5787), or other reagents used by one skilled in the art provides a compound of formula IG. 
     
       
         
         
             
             
         
       
     
     Scheme VII describes a method for preparing compounds of formula III and IJ (subsets of compounds of formula I). An alcohol intermediate XIX can be obtained commercially, prepared by methods known in the literature, or by other methods used by one skilled in the art. Chlorination of an alcohol intermediate XIX using thionyl chloride or carbon tetrachloride/triphenyl phosphine provides an intermediate XX. Alkylation of a phenol XII with an intermediate XX provides an intermediate XXI. Demethylation of an intermediate XXI can be obtained using tribromoborane or other reagents used by one skilled in the art to provide an intermediate XXII. Reaction of an intermediate XXII with phosgene followed by reaction with an amine III provides compounds of formula III. 
     
       
         
         
             
             
         
       
     
     Scheme VIII describes a method for preparing compounds of formula IK and IL (subsets of compounds of formula I where G is a thiazole group). Alkylation of a thiophenol XIV with a 2-bromoacetoamide XXIII provides an amide intermediate XXIV. Reaction of an amide XXIV with Lawesson Reagent provides a thioamide intermediate XXV. Thiazole formation can be obtained from reaction of a thioamide XXV and a bromopyruvate XXVI or by other methods used by one skilled in the art. Hydrolysis of an ester XXVII under basic conditions followed by amide formation with an amine III provides compounds of formula IK. Subsequent oxidation of compounds IK with an appropriate oxidizing reagent such as mCPBA, Oxone®, p-toluenesulfonic peracid generated in situ (Tetrahedron, 1996, 52, 5773-5787), or other reagents used by one skilled in the art provides compounds of formula IL. 
     
       
         
         
             
             
         
       
     
     Scheme IX describes a method for preparing compounds of formula IM. Monolithiation ( Tetrahedron Lett.,  1996, 37, 2537-2540) of commerically available (XXVIII) followed by sulfinylation of the lithiated species and subsequent oxidative sulfonylation with sulfuryl chloride provides intermediate (XXIX). Reaction of amine with intermediate (XXIX) provides intermediate (XXX). Suzuki cross-coupling with bromo intermediate (XXX) using the appropriate ligand and catalyst provides compounds of formula (IM). 
     Utilities and Combinations 
     A. Utilities 
     The compounds of the present invention possess activity as inhibitors of the enzyme 11-beta-hydroxysteroid dehydrogenase type I, and, therefore, may be used in the treatment of diseases associated with 11-beta-hydroxysteroid dehydrogenase type I activity. Via the inhibition of 11-beta-hydroxysteroid dehydrogenase type I, the compounds of the present invention may preferably be employed to inhibit glucocorticoid, thereby interrupting or modulating cortisone or cortisol production. 
     Accordingly, the compounds of the present invention can be administered to mammals, preferably humans, for the treatment of a variety of conditions and disorders, including, but not limited to, treating, preventing, or slowing the progression of diabetes and related conditions, microvascular complications associated with diabetes, macrovascular complications associated with diabetes, cardiovascular diseases, Metabolic Syndrome and its component conditions, and other maladies. Consequently, it is believed that the compounds of the present invention may be used in preventing, inhibiting, or treating diabetes, hyperglycemia, impaired glucose tolerance, insulin resistance, hyperinsulinemia, retinopathy, neuropathy, nephropathy, delayed wound healing, atherosclerosis and its sequelae, abnormal heart function, myocardial ischemia, stroke, Metabolic Syndrome, hypertension, obesity, dislipidemia, dylsipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL, high LDL, non-cardiac ischemia, infection, cancer, vascular restenosis, pancreatitis, neurodegenerative disease, lipid disorders, cognitive impairment and dementia, bone disease, HIV protease associated lipodystrophy and glaucoma. 
     Metabolic Syndrome or “Syndrome X” is described in Ford, et al.,  J. Am. Med. Assoc.  2002, 287, 356-359 and Arbeeny, et al.,  Curr. Med. Chem.—Imm., Endoc . &amp;  Metab. Agents  2001, 1, 1-24. 
     B. Combinations 
     The present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, a therapeutically effective amount of at least one of the compounds of formula I, alone or in combination with a pharmaceutical carrier or diluent. Optionally, compounds of the present invention can be used alone, in combination with other compounds of the invention, or in combination with one or more other therapeutic agent(s), e.g., an antidiabetic agent or other pharmaceutically active material. 
     The compounds of the present invention may be employed in combination with other 11-beta-hydroxysteroid dehydrogenase type I inhibitors or one or more other suitable therapeutic agents useful in the treatment of the aforementioned disorders including: anti-diabetic agents, anti-hyperglycemic agents, anti-hyperinsulinemic agents, anti-retinopathic agents, anti-neuropathic agents, anti-nephropathic agents, anti-atherosclerotic agents, anti-infective agents, anti-ischemic agents, anti-hypertensive agents, anti-obesity agents, anti-dislipidemic agents, anti-dylsipidemic agents, anti-hyperlipidemic agents, anti-hypertriglyceridemic agents, anti-hypercholesterolemic agents, anti-ischemic agents, anti-cancer agents, anti-cytotoxic agents, anti-restenotic agents, anti-pancreatic agents, lipid lowering agents, appetite suppressants, memory enhancing agents and cognitive agents. 
     Examples of suitable anti-diabetic agents for use in combination with the compounds of the present invention include insulin and insulin analogs: LysPro insulin, inhaled formulations comprising insulin; glucagon-like peptides; sulfonylureas and analogs: chlorpropamide, glibenclamide, tolbutamide, tolazamide, acetohexamide, glypizide, glyburide, glimepiride, repaglinide, meglitinide; biguanides: metformin, phenformin, buformin; alpha2-antagonists and imidazolines: midaglizole, isaglidole, deriglidole, idazoxan, efaroxan, fluparoxan; other insulin secretagogues: linogliride, insulinotropin, exendin-4, BTS-67582, A-4166; thiazolidinediones: ciglitazone, pioglitazone, troglitazone, rosiglitazone; PPAR-gamma agonists; PPAR-alpha agonists; PPAR alpha/gamma dual agonists; SGLT2 inhibitors; dipeptidyl peptidase-IV (DPP4) inhibitors; aldose reductase inhibitors; RXR agonists: JTT-501, MCC-555, MX-6054, DRF2593, GI-262570, KRP-297, LG100268; fatty acid oxidation inhibitors: clomoxir, etomoxir; α-glucosidase inhibitors: precose, acarbose, miglitol, emiglitate, voglibose, MDL-25,637, camiglibose, MDL-73,945; beta-agonists: BRL 35135, BRL 37344, Ro 16-8714, ICI D7114, CL 316,243, TAK-667, AZ40140; phosphodiesterase inhibitors, both cAMP and cGMP type: sildenafil, L686398: L-386,398; amylin antagonists: pramlintide, AC-137; lipoxygenase inhibitors: masoprocal; somatostatin analogs: BM-23014, seglitide, octreotide; glucagon antagonists: BAY 276-9955; insulin signaling agonists, insulin mimetics, PTP1B inhibitors: L-783281, TER17411, TER17529; gluconeogenesis inhibitors: GP3034; somatostatin analogs and antagonists; antilipolytic agents: nicotinic acid, acipimox, WAG 994; glucose transport stimulating agents: BM-130795; glucose synthase kinase inhibitors: lithium chloride, CT98014, CT98023; and galanin receptor agonists. 
     Other suitable thiazolidinediones include Mitsubishi&#39;s MCC-555 (disclosed in U.S. Pat. No. 5,594,016), Glaxo-Wellcome&#39;s GL-262570, englitazone (CP-68722, Pfizer), or darglitazone (CP-86325, Pfizer, isaglitazone (MIT/J&amp;J), JTT-501 (JPNT/P&amp;U), L-895645 (Merck), R-119702 (Sankyo/WL), N,N-2344 (Dr. Reddy/NN), or YM-440 (Yamanouchi). 
     Suitable PPAR alpha/gamma dual agonists include AR-HO39242 (Astra/Zeneca), GW-409544 (Glaxo-Wellcome), KRP297 (Kyorin Merck), as well as those disclosed by Murakami et al, “A Novel Insulin Sensitizer Acts As a Coligand for Peroxisome Proliferation—Activated Receptor Alpha (PPAR alpha) and PPAR gamma; Effect of PPAR alpha Activation on Abnormal Lipid Metabolism in Liver of Zucker Fatty Rats”, Diabetes 47, 1841-1847 (1998), and WO 01/21602, the disclosure of which is incorporated herein by reference, employing dosages as set out therein, which compounds designated as preferred are preferred for use herein. 
     Suitable alpha2 antagonists also include those disclosed in WO 00/59506, employing dosages as set out herein. 
     Suitable SGLT2 inhibitors include T-1095, phlorizin, WAY-123783, and those described in WO 01/27128. 
     Suitable DPP4 inhibitors include those disclosed in WO99/38501, WO99/46272, WO99/67279 (PROBIODRUG), WO99/67278 (PROBIODRUG), WO99/61431 (PROBIODRUG), NVP-DPP728A (1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine) (Novartis) as disclosed by Hughes et al, Biochemistry, 38 (36), 11597-11603, 1999, TSL-225 (tryptophyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (disclosed by Yamada et al, Bioorg. &amp; Med. Chem. Lett. 8 (1998) 1537-1540, 2-cyanopyrrolidides and 4-cyanopyrrolidides, as disclosed by Ashworth et al, Bioorg. &amp; Med. Chem. Lett., Vol. 6, No. 22, pp 1163-1166 and 2745-2748 (1996), employing dosages as set out in the above references. 
     Suitable aldose reductase inhibitors include those disclosed in WO 99/26659. 
     Suitable meglitinides include nateglinide (Novartis) or KAD 1229 (PF/Kissei). 
     Examples of glucagon-like peptide-1 (GLP-1) include GLP-1 (1-36) amide, GLP-1(7-36) amide, GLP-1(7-37) (as disclosed in U.S. Pat. No. 5,614,492 to Habener), as well as AC2993 (Amylen), and LY-315902 (Lilly). 
     Other anti-diabetic agents that can be used in combination with compounds of the invention include ergoset and D-chiroinositol. 
     Suitable anti-ischemic agents include, but are not limited to, those described in the Physician&#39;s Desk Reference and NHE inhibitors, including those disclosed in WO 99/43663. 
     Examples of suitable anti-infective agents are antibiotic agents, including, but not limited to, those described in the Physicians&#39; Desk Reference. 
     Examples of suitable lipid lowering agents for use in combination with the compounds of the present invention include one or more MTP inhibitors, HMG CoA reductase inhibitors, squalene synthetase inhibitors, fibric acid derivatives, ACAT inhibitors, lipoxygenase inhibitors, cholesterol absorption inhibitors, ileal Na + /bile acid cotransporter inhibitors, upregulators of LDL receptor activity, bile acid sequestrants, cholesterol ester transfer protein inhibitors (e.g., CP-529414 (Pfizer)), and/or nicotinic acid and derivatives thereof. 
     MTP inhibitors which may be employed as described above include those disclosed in U.S. Pat. No. 5,595,872, U.S. Pat. No. 5,739,135, U.S. Pat. No. 5,712,279, U.S. Pat. No. 5,760,246, U.S. Pat. No. 5,827,875, U.S. Pat. No. 5,885,983, and U.S. Pat. No. 5,962,440. 
     The HMG CoA reductase inhibitors which may be employed in combination with one or more compounds of formula I include mevastatin and related compounds, as disclosed in U.S. Pat. No. 3,983,140, lovastatin, (mevinolin) and related compounds, as disclosed in U.S. Pat. No. 4,231,938, pravastatin, and related compounds, such as disclosed in U.S. Pat. No. 4,346,227, simvastatin, and related compounds, as disclosed in U.S. Pat. Nos. 4,448,784 and 4,450,171. Other HMG CoA reductase inhibitors which may be employed herein include, but are not limited to, fluvastatin, disclosed in U.S. Pat. No. 5,354,772; cerivastatin, as disclosed in U.S. Pat. Nos. 5,006,530 and 5,177,080; atorvastatin, as disclosed in U.S. Pat. Nos. 4,681,893, 5,273,995, 5,385,929 and 5,686,104; atavastatin (Nissan/Sankyo&#39;s nisvastatin (NK-104)), as disclosed in U.S. Pat. No. 5,011,930; visastatin (Shionogi-Astra/Zeneca (ZD-4522)) as disclosed in U.S. Pat. No. 5,260,440; and related statin compounds disclosed in U.S. Pat. No. 5,753,675; pyrazole analogs of mevalonolactone derivatives, as disclosed in U.S. Pat. No. 4,613,610; indene analogs of mevalonolactone derivatives, as disclosed in PCT application WO 86/03488; 642-(substituted-pyrrol-1-yl)alkyl)pyran-2-ones and derivatives thereof, as disclosed in U.S. Pat. No. 4,647,576; Searle&#39;s SC-45355 (a 3-substituted pentanedioic acid derivative) dichloroacetate; imidazole analogs of mevalonolactone, as disclosed in PCT application WO 86/07054; 3-carboxy-2-hydroxy-propane-phosphonic acid derivatives, as disclosed in French Patent No. 2,596,393; 2,3-disubstituted pyrrole, furan and thiophene derivatives, as disclosed in European Patent Application No. 0221025; naphthyl analogs of mevalonolactone, as disclosed in U.S. Pat. No. 4,686,237; octahydronaphthalenes, such as disclosed in U.S. Pat. No. 4,499,289; keto analogs of mevinolin (lovastatin), as disclosed in European Patent Application No. 0142146 A2; and quinoline and pyridine derivatives, as disclosed in U.S. Pat. Nos. 5,506,219 and 5,691,322. 
     Preferred hypolipidemic agents are pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, atavastatin, and ZD-4522. 
     In addition, phosphinic acid compounds useful in inhibiting HMG CoA reductase, such as those disclosed in GB 2205837, are suitable for use in combination with the compounds of the present invention. 
     The squalene synthetase inhibitors suitable for use herein include, but are not limited to, α-phosphono-sulfonates disclosed in U.S. Pat. No. 5,712,396, those disclosed by Biller et al, J. Med. Chem., 1988, Vol. 31, No. 10, pp 1869-1871, including isoprenoid (phosphinyl-methyl)phosphonates, as well as other known squalene synthetase inhibitors, for example, as disclosed in U.S. Pat. Nos. 4,871,721 and 4,924,024 and in Biller, S. A., Neuenschwander, K., Ponpipom, M. M., and Poulter, C. D., Current Pharmaceutical Design, 2, 1-40 (1996). 
     In addition, other squalene synthetase inhibitors suitable for use herein include the terpenoid pyrophosphates disclosed by P. ortiz de Montellano et al, J. Med. Chem., 1977, 20, 243-249, the farnesyl diphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs as disclosed by Corey and Volante, J. Am. Chem. Soc., 1976, 98, 1291-1293, phosphinylphosphonates reported by McClard, R. W. et al, J.A.C.S., 1987, 109, 5544 and cyclopropanes reported by Capson, T. L., Ph.D. dissertation, June, 1987, Dept. Med. Chem. U of Utah, Abstract, Table of Contents, pp. 16, 17, 40-43, 48-51, Summary. 
     The fibric acid derivatives which may be employed in combination with one or more compounds of formula I include fenofibrate, gemfibrozil, clofibrate, bezafibrate, ciprofibrate, clinofibrate, and the like, probucol, and related compounds, as disclosed in U.S. Pat. No. 3,674,836, probucol and gemfibrozil being preferred, bile acid sequestrants, such as cholestyramine, colestipol and DEAE-Sephadex (Secholex®, Policexide®), as well as lipostabil (Rhone-Poulenc), Eisai E-5050 (an N-substituted ethanolamine derivative), imanixil (HOE-402), tetrahydrolipstatin (THL), istigmastanylphosphorylcholine (SPC, Roche), aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814 (azulene derivative), melinamide (Sumitomo), Sandoz 58-035, American Cyanamid CL-277,082 and CL-283,546 (disubstituted urea derivatives), nicotinic acid, acipimox, acifran, neomycin, p-aminosalicylic acid, aspirin, poly(diallylmethylamine) derivatives, such as disclosed in U.S. Pat. No. 4,759,923, quaternary amine poly(diallyldimethylammonium chloride) and ionenes, such as disclosed in U.S. Pat. No. 4,027,009, and other known serum cholesterol lowering agents. 
     The ACAT inhibitor which may be employed in combination with one or more compounds of formula I include those disclosed in Drugs of the Future 24, 9-15 (1999), (Avasimibe); “The ACAT inhibitor, CI-1011 is effective in the prevention and regression of aortic fatty streak area in hamsters”, Nicolosi et al, Atherosclerosis (Shannon, Irel). (1998), 137(1), 77-85; “The pharmacological profile of FCE 27677: a novel ACAT inhibitor with potent hypolipidemic activity mediated by selective suppression of the hepatic secretion of ApoB100-containing lipoprotein”, Ghiselli, Giancarlo, Cardiovasc. Drug Rev. (1998), 16(1), 16-30; “RP 73163: a bioavailable alkylsulfinyl-diphenylimidazole ACAT inhibitor”, Smith, C., et al, Bioorg. Med. Chem. Lett. (1996), 6(1), 47-50; “ACAT inhibitors: physiologic mechanisms for hypolipidemic and anti-atherosclerotic activities in experimental animals”, Krause et al, Editor(s): Ruffolo, Robert R., Jr.; Hollinger, Mannfred A., Inflammation: Mediators Pathways (1995), 173-98, Publisher: CRC, Boca Raton, Fla.; “ACAT inhibitors: potential anti-atherosclerotic agents”, Sliskovic et al, Curr. Med. Chem. (1994), 1(3), 204-25; “Inhibitors of acyl-CoA:cholesterol O-acyl transferase (ACAT) as hypocholesterolemic agents. 6. The first water-soluble ACAT inhibitor with lipid-regulating activity. Inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). 7. Development of a series of substituted N-phenyl-N′-[(1-phenylcyclopentyl)methyl]ureas with enhanced hypocholesterolemic activity”, Stout et al, Chemtracts: org. Chem. (1995), 8(6), 359-62, or TS-962 (Taisho Pharmaceutical Co. Ltd.). 
     The hypolipidemic agent may be an upregulator of LD2 receptor activity, such as MD-700 (Taisho Pharmaceutical Co. Ltd) and LY295427 (Eli Lilly). 
     Examples of suitable cholesterol absorption inhibitors for use in combination with the compounds of the invention include SCH48461 (Schering-Plough), as well as those disclosed in Atherosclerosis 115, 45-63 (1995) and J. Med. Chem. 41, 973 (1998). 
     Examples of suitable ileal Na + /bile acid cotransporter inhibitors for use in combination with the compounds of the invention include compounds as disclosed in Drugs of the Future, 24, 425-430 (1999). 
     The lipoxygenase inhibitors which may be employed in combination with one or more compounds of formula I include 15-lipoxygenase (15-LO) inhibitors, such as benzimidazole derivatives, as disclosed in WO 97/12615, 15-LO inhibitors, as disclosed in WO 97/12613, isothiazolones, as disclosed in WO 96/38144, and 15-LO inhibitors, as disclosed by Sendobry et al “Attenuation of diet-induced atherosclerosis in rabbits with a highly selective 15-lipoxygenase inhibitor lacking significant antioxidant properties”, Brit. J. Pharmacology (1997) 120, 1199-1206, and Cornicelli et al, “15-Lipoxygenase and its Inhibition: A Novel Therapeutic Target for Vascular Disease”, Current Pharmaceutical Design, 1999, 5, 11-20. 
     Examples of suitable anti-hypertensive agents for use in combination with the compounds of the present invention include beta adrenergic blockers, calcium channel blockers (L-type and T-type; e.g. diltiazem, verapamil, nifedipine, amlodipine and mybefradil), diuretics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone), renin inhibitors, ACE inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril), AT-1 receptor antagonists (e.g., losartan, irbesartan, valsartan), ET receptor antagonists (e.g., sitaxsentan, atrsentan, and compounds disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265), Dual ET/AII antagonist (e.g., compounds disclosed in WO 00/01389), neutral endopeptidase (NEP) inhibitors, vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., omapatrilat and gemopatrilat), and nitrates. 
     Examples of suitable anti-obesity agents for use in combination with the compounds of the present invention include a cannabinoid receptor 1 antagonist or inverse agonist, a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroid receptor beta drug, and/or an anorectic agent. 
     Cannabinoid receptor 1 antagonists and inverse agonists which may be optionally employed in combination with compounds of the present invention include rimonabant, SLV 319, and those discussed in D. L. Hertzog, Expert Opin. Ther. Patents 2004, 14, 1435-1452. 
     The beta 3 adrenergic agonists which may be optionally employed in combination with compounds of the present invention include AJ9677 (Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer,) or other known beta 3 agonists, as disclosed in U.S. Pat. Nos. 5,541,204, 5,770,615, 5,491,134, 5,776,983, and 5,488,064, with AJ9677, L750,355, and CP331648 being preferred. 
     Examples of lipase inhibitors which may be optionally employed in combination with compounds of the present invention include orlistat or ATL-962 (Alizyme), with orlistat being preferred. 
     The serotonin (and dopoamine) reuptake inhibitor which may be optionally employed in combination with a compound of formula I may be sibutramine, topiramate (Johnson &amp; Johnson), or axokine (Regeneron), with sibutramine and topiramate being preferred. 
     Examples of thyroid receptor beta compounds which may be optionally employed in combination with compounds of the present invention include thyroid receptor ligands, such as those disclosed in WO97/21993 (U. Cal SF), WO99/00353 (KaroBio), and WO00/039077 (KaroBio), with compounds of the KaroBio applications being preferred. 
     The anorectic agent which may be optionally employed in combination with compounds of the present invention include dexamphetamine, phentermine, phenylpropanolamine, or mazindol, with dexamphetamine being preferred. 
     Other compounds that can be used in combination with the compounds of the present invention include CCK receptor agonists (e.g., SR-27895B); galanin receptor antagonists; MCR-4 antagonists (e.g., HP-228); leptin or mimentics; 11-beta-hydroxysteroid dehydrogenase type-1 inhibitors; urocortin mimetics, CRF antagonists, and CRF binding proteins (e.g., RU-486, urocortin). 
     Further, the compounds of the present invention may be used in combination with anti-cancer and cytotoxic agents, including but not limited to alkylating agents such as nitrogen mustards, alkyl sulfonates, nitrosoureas, ethylenimines, and triazenes; antimetabolites such as folate antagonists, purine analogues, and pyrimidine analogues; antibiotics such as anthracyclines, bleomycins, mitomycin, dactinomycin, and plicamycin; enzymes such as L-asparaginase; farnesyl-protein transferase inhibitors; 5α reductase inhibitors; inhibitors of 17β-hydroxy steroid dehydrogenase type 3; hormonal agents such as glucocorticoids, estrogens/antiestrogens, androgens/antiandrogens, progestins, and luteinizing hormone-releasing hormone antagonists, octreotide acetate; microtubule-disruptor agents, such as ecteinascidins or their analogs and derivatives; microtubule-stabilizing agents such as taxanes, for example, paclitaxel (Taxol®), docetaxel (Taxotere), and their analogs, and epothilones, such as epothilones A-F and their analogs; plant-derived products, such as vinca alkaloids, epipodophyllotoxins, taxanes; and topiosomerase inhibitors; prenyl-protein transferase inhibitors; and miscellaneous agents such as hydroxyurea, procarbazine, mitotane, hexamethylmelamine, platinum coordination complexes such as cisplatin and carboplatin; and other agents used as anti-cancer and cytotoxic agents such as biological response modifiers, growth factors; immune modulators; and monoclonal antibodies. Additional anti-cancer agents are disclosed in EP 1177791. The compounds of the invention may also be used in conjunction with radiation therapy. 
     Examples of suitable memory enhancing agents, anti-dementia agents, or cognitive agents for use in combination with the compounds of the present invention include, but are not limited to, donepezil, rivastigmine, galantamine, memantine, tacrine, metrifonate, muscarine, xanomelline, deprenyl and physostigmine. 
     The aforementioned patents and patent applications are incorporated herein by reference. 
     The above other therapeutic agents, when employed in combination with the compounds of the present invention may be used, for example, in those amounts indicated in the Physician&#39;s Desk Reference, as in the patents set out above, or as otherwise determined by one of ordinary skill in the art. 
     The compounds of formula I can be administered for any of the uses described herein by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; bucally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection, or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to the nasal membranes, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories; in dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents. 
     In carrying out the method of the invention for treating diabetes and related diseases, a pharmaceutical composition will be employed containing the compounds of formula I, with or without other antidiabetic agent(s) and/or antihyperlipidemic agent(s) and/or other type therapeutic agents in association with a pharmaceutical vehicle or diluent. The pharmaceutical composition can be formulated employing conventional solid or liquid vehicles or diluents and pharmaceutical additives of a type appropriate to the mode of desired administration, such as pharmaceutically acceptable carriers, excipients, binders, and the like. The compounds can be administered to a mammalian patient, including humans, monkeys, dogs, etc. by an oral route, for example, in the form of tablets, capsules, beads, granules or powders. The dose for adults is preferably between 1 and 2,000 mg per day, which can be administered in a single dose or in the form of individual doses from 1-4 times per day. 
     A typical capsule for oral administration contains compounds of structure I (250 mg), lactose (75 mg), and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and packed into a No. 1 gelatin capsule. 
     A typical injectable preparation is produced by aseptically placing 250 mg of compounds of structure I into a vial, aseptically freeze-drying and sealing. For use, the contents of the vial are mixed with 2 mL of physiological saline, to produce an injectable preparation. 
     Assay(S) for 11-Beta-Hydroxysteroid Dehydrogenase Activity 
     The in vitro inhibition of recombinant human 11beta-HSD1 was determined as follows. 
     Recombinant human 11beta-HSD1 was expressed stably in HEK 293 EBNA cells. Cells were grown in DMEM (high glucose) containing MEM non-essential amino acids, L-glutamine, hygromycine B (200 ug/ml), and G418(200 ug/ml). 
     The cell pellets were homogenized, and the microsomal fraction was obtained by differential centrifugation. 11beta-HSD1 over expressed microsomes were used as the enzyme source for the Scintillation Proximity Assay (SPA). The test compounds at the desired concentration were incubated at room temperature with 12.5 μg of microsomal enzyme, 250 nM [ 3 H]-cortisone, 500 μM NADPH, 50 mM MES, pH 6.5, and 5 mM EDTA in 96-well OptiPlates. The reaction was terminated with the addition of 1 mM 18β-glycerrhentic acid. SPA reagent mixture (YSi anti-rabbit IgG, anti-cortisol antibody in 50 mM Tris, pH 8.0 containing 1% CHAPS and 1% glycerol) was added and the reaction was further incubated at room temperature over night and counted in TopCount. The IC 50  (concentration of compound required for 50% inhibition of cortisol formation) was determined using XLfit. 
     As a means of confirming selectivity for 11betaHSD1, the compounds of the present invention were also screened for 11betaHSD2 activity. The in vitro inhibition of recombinant human 11betaHSD2 was determined as follows: 
     Recombinant human 11betaHSD2 was expressed stably in HEK 293 EBNA cells. The microsomal fraction over expressing 11betaHSD2 was prepared from the cell homogenate. The test compounds at the desired concentration were incubated at 37° C. with 10 μg of microsomal enzyme, 100 nM-cortisol, 1 mM NAD, and 20 mM Tris, pH 7.5 in 96-well plates for 3 h. The reaction was stopped with the addition of equal volume of acetonitrile containing 200 ng/mL triamcinolone (internal standard). The plate was centrifuged and the supernatant was transferred to another 96-well assay plate. Cortisone in the samples was analyzed by LC/MS/MS (Micromass Quattro Ultima Triple Quadrupole Mass Spectrometer). From the MS response (ratio of compound to the internal standard), cortisone formation was calculated using the cortisone standard curve determined on each plate. The IC 50  (concentration of compound required for 50% inhibition of cortisone formation) was determined using XLfit. 
     In general, preferred compounds of the present invention, such as particular compounds disclosed in the following examples, have been identified to inhibit the catalytic activity of 11-beta-hydroxysteroid dehydrogenase type I at concentrations equivalent to, or more potently than, 10 μM, preferably 5 μM, more preferably 3 μM, thereby demonstrating compounds of the present invention as especially effective inhibitors of 11-beta-hydroxysteroid dehydrogenase type I. Potencies can be calculated and expressed as either inhibition constants (Ki values) or as IC50 (inhibitory concentration 50%) values, and refer to activity measured employing the assay system described above. 
     EXAMPLES 
     The following working Examples serve to better illustrate, but not limit, some of the preferred embodiments of the present invention. 
     General 
     The term HPLC refers to a Shimadzu high performance liquid chromatography with one of following methods: 
     Method A: YMC or Phenomenex C18 5 micron 4.6×50 mm column using a 4 minute gradient of 0-100% solvent B [90% MeOH:10% H 2 O:0.2% H 3 PO 4 ] and 100-0% solvent A [10% MeOH:90% H 2 O:0.2% H 3 PO 4 ] with 4 mL/min flow rate and a 1 min. hold, an ultra violet (uv) detector set at 220 nm. 
     Method B: Phenomenex S5 ODS 4.6×30 mm column, gradient elution 0-100% B/A over 2 min (solvent A=10% MeOH/H 2 O containing 0.1% TFA, solvent B=90% MeOH/H 2 O containing 0.1% TFA), flow rate 5 mL/min, UV detection at 220 nm. 
     Method C: YMC S7 ODS 3.0×50 mm column, gradient elution 0-100% B/A over 2 min (solvent A=10% MeOH/H 2 O containing 0.1% TFA, solvent B=90% MeOH/H 2 O containing 0.1% TFA), flow rate 5 mL/min, UV detection at 220 nm. 
     The term prep HPLC refers to an automated Shimadzu HPLC system using a mixture of solvent A (10% MeOH/90% H 2 O/0.2% TFA) and solvent B (90% MeOH/10% H 2 O/0.2% TFA). The preparative columns are packed with YMC or Phenomenex ODS C18 5 micron resin or equivalent. 
     ABBREVIATIONS 
     The following abbreviations are employed in the Examples and elsewhere herein:
     Ph=phenyl   Bn=benzyl   i-Bu=iso-butyl   Me=methyl   Et=ethyl   Pr=propyl   Bu=butyl   AIBN=2,2′-Azobisisobutyronitrile   TMS=trimethylsilyl   FMOC=fluorenylmethoxycarbonyl   Boc or BOC=tert-butoxycarbonyl   Cbz=carbobenzyloxy or carbobenzoxy or benzyloxycarbonyl   HOAc or AcOH=acetic acid   DCM=dichloromethane   DIEA=N,N-diisopropylethylamine   DMA=N,N-dimethylacetylamide   DMF=N,N-dimethylformamide   DMSO=dimethylsulfoxide   EtOAc=ethyl acetate   THF=tetrahydrofuran   TFA=trifluoroacetic acid   mCPBA=3-Chloroperoxybenzoic acid   NMM=N-methyl morpholine   NBS═N-Bromosuccinimide   n-BuLi=n-butyllithium   Oxone®=Monopersulfate   Pd/C=palladium on carbon   PtO 2 =platinum oxide   TEA=triethylamine   EDAC=3-ethyl-3′-(dimethylamino)propyl-carbodiimide hydrochloride (or 1-[(3-(dimethyl)amino)propyl])-3-ethylcarbodiimide hydrochloride)   HOBT or HOBT.H 2 O=1-hydroxybenzotriazole hydrate   HOAT=1-hydroxy-7-azabenzotriazole   PyBOP reagent=benzotriazol-1-yloxy-tripyrrolidino phosphonium hexafluorophosphate   equiv=equivalent(s)   min=minute(s)   h or hr=hour(s)   L=liter   mL=milliliter   μL=microliter   g=gram(s)   mg=milligram(s)   mol=mole(s)   mmol=millimole(s)   meq=milliequivalent   RT or R.T.=room temperature   sat or sat&#39;d=saturated   aq.=aqueous   TLC=thin layer chromatography   HPLC=high performance liquid chromatography   HPLC R t =HPLC retention time   LC/MS=high performance liquid chromatography/mass spectrometry   MS or Mass Spec=mass spectrometry   NMR=nuclear magnetic resonance   mp=melting point   PXPd 2 =Dichloro(chlorodi-tert-butylphosphine)palladium (II) dimer or [PdCl 2 (t-Bu) 2 PCl] 2      

     Example 1 
     (5-((2,6-Dichlorophenylthio)methyl)pyridin-3-yl)(4-methylpiperidin-1-yl)methanone 
     
       
         
         
             
             
         
       
     
     To a solution of 5-bromonicotinic acid (4.7 g, 23.27 mmol) in THF (90 mL) was added 4-methylmorpholine (2.56 ml, 23.27 mmol) and isobutyl chloroformate (3.03 ml, 23.27 mmol) at 0° C. The mixture was stirred at 0° C. for 1.5 hours and then 4-methyl piperidine (9.7 g, 97.73 mmol) was added at 0° C. The suspension was stirred at 0° C. to room temperature for 2 hours. The white precipitate was filtered off, and the liquid portion was concentrated under vacuum. The residue was purified by column chromatography to yield compound 1A (5.36 g) as a white powder. HPLC R t  (Method A): 2.75 min. LCMS: m/z 283 (M+H + ). 
     
       
         
         
             
             
         
       
     
     To a solution of compound 1A (2 g, 7.063 mmol) in DMF (14 mL) was added palladium acetate (791 mg, 3.53 mmol), 1,3-bis(diphenylphosphino)-propane (1.163 g, 2.83 mmol), DBU (1.29 g, 8.48 mmol), and methanol (14 mL) in a steel auto clave container. The mixture was stirred and heated at 85° C. for 14 hours under carbon monoxide (70 psi). After cooling the container, the methanol was concentrated via vacuum, and the residue was diluted with ethyl acetate. The powders were filtered off, and the mixture was washed with brine and water. Drying over MgSO 4 , followed by concentration and column chromatography purification yielded compound 1B (1.6 g) as a yellow oil. HPLC R t  (Method A) 2.497 min. LCMS: m/z 263 (M+H + ). 
     
       
         
         
             
             
         
       
     
     Compound 1B (1.6 g, 6.1 mmol) in ethanol (20 mL) was treated with sodium borohydride (462 mg, 12.2 mmol) at room temperature and stirred for 1 hour. The solution was quenched with water and neutralized to pH=7. The mixture was stripped of most of the ethanol, basified with 1N NaOH solution, and extracted 3 times with ethyl acetate. The combined organic extracts were dried over MgSO 4 , filtered, and concentrated via vacuum to yield compound 1C (310 mg) as a yellow oil. HPLC R t  (Method A): 1.218 min, LCMS: m/z 235 (M+H + ). 
     Example 1 
     Compound 1C (200 mg, 0.853 mmol) in DCM (10 mL) was treated with 1N PBr 3  (0.64 mL, 0.64 mmol) at 0° C. for 1.5 hours. The mixture was quenched with 5 mL saturated NaHCO 3  solution at 0° C. The solution was diluted with DCM. The organic layer was separated, washed with brine, and dried over MgSO 4 . The drying agent was filtered, and the filtrate was concentrated via vacuum to yield the bromide as a colorless oil. The bromide was dissolved in THF (10 mL) and treated with 2,6-dichlorothiophenol (153 mg, 0.853 mmol) and N,N-diisopropyl-ethylamine (331 mg, 2.56 mmol) at room temperature overnight. The mixture was concentrated and purified by column chromatography to yield Example 1 (76.7 mg) as a white powder. HPLC R t  (Method A: 3.618 min. LCMS: m/z 395 (M+H + ). HPLC purity: 99%.  1 H NMR: δ 8.42 (s, 1H), 8.31 (s, 1H), 7.58 (s, 1H), 7.30 (d, J=8.2 Hz, 2H), 7.15 (t, J=8.2 Hz, 1H), 4.70-4.55 (m, 1H), 4.08 (s, 2H), 3.60-3.48 (m, 1H), 3.08-2.86 (m, 1H), 2.85-2.70 (m, 1H), 1.80-1.57 (m, 3H), 1.30-1.09 (m, 2H), 0.97 (d, J=6 Hz, 3H). 
     Example 2 
     (5-((2,6-Dichlorophenylsulfonyl)methyl)pyridin-3-yl)(4-methylpiperidin-1-yl)methanone 
     
       
         
         
             
             
         
       
     
     To a solution of Example 1 (58 mg, 0.147 mmol) in THF (2 mL) and MeOH (2 mL) was added 1-(p-toluenesulfonyl)imidazole (261 mg, 1.18 mmol), 30% aqueous H 2 O 2  (240 μL, 2.352 mmol), and 1 N NaOH (2.7 mL, 2.7 mmol). The mixture was stirred at room temperature for 2.5 hours. The organic solvents were removed in vacuo, and the aqueous portion was diluted with brine and ethyl acetate. The organic portion was separated, and the aqueous layer was extracted again with ethyl acetate. The organic extracts were combined, dried over MgSO 4 , and concentrated. The residue was subjected to preparative HPLC to yield Example 2 (41 mg) as a white powder. HPLC R t  (Method A): 2.868 min. LCMS: m/z 427 (M+H + ). HPLC purity: 99%.  1 H NMR δ 8.57 (s, 1H), 8.33 (s, 1H), 7.82 (s, 1H), 7.40-7.32 (m, 3H), 4.64 (s, 2H), 4.57-4.54 (m, 1H), 3.62-3.48 (m, 1H), 3.05-2.97 (m, 1H), 2.82-2.70 (m, 1H), 1.80-1.70 (m, 1H), 1.70-1.52 (m, 2H), 1.27-0.99 (m, 2H), 0.97 (d, J=6 Hz, 3H). 
     Example 3 
     2-((2,6-Dichlorophenylthio)methyl)-5-(4-methylpiperidin-1-ylsulfonyl)-pyridine 
     
       
         
         
             
             
         
       
     
     To a solution of 6-chloropyridine-3-sulfonyl chloride (600 mg, 2.83 mmol) in DCM (10 mL) was added DIEA (1.5 mL, 8.49 mmol) and 4-methylpiperidine (281 mg, 2.83 mmol) at RT. The mixture stirred for 2 hours. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to yield compound 3A (746 mg) as a white powder. HPLC R t  (Method A): 2.982 min. LCMS: m/z 275 (M+H + ). 
     
       
         
         
             
             
         
       
     
     Compound 3B was prepared in a similar manner as compound 1B. Carbonylation of compound 3A (550 mg) gave compound 3B (580 mg) as a white powder. HPLC R t  (Method A): 2.682 min. LCMS: m/z 299 (M+H + ). 
     
       
         
         
             
             
         
       
     
     To a solution of compound 3B (400 mg, 1.34 mmol) in THF (8 mL) was added 1N LiAlH 4  (0.67 mL, 0.67 mmol) solution in THF at RT. The mixture stirred for 2 hours, was quenched with H 2 O, and was extracted 3 times with ethyl acetate. The combined organic extracts were dried over MgSO 4 , filtered, and concentrated. The residue was purified by silical gel chromatography to yield compound 3C (120 mg) as a light pink powder. HPLC R t  (Method A): 2.315 min. LCMS: m/z 271 (M+H + ). 
     Example 3 
     To a solution of compound 3C (80 mg, 0.296 mmol) in THF (2 mL) at RT was added 2,6-dichlorobenzenethiol (212 mg, 1.184 mmol), and PPh 3  (233 mg, 0.888 mmol). After the solution became homogeneous, diisopropyl azodicarboxylate (180 mg, 0.888 mmol) was added via syringe. After 5 minutes of stirring at RT, the mixture became cloudy. DCM (1.5 mL) was added and stirring was continued for another 2 hours. The precipitate was filtered off, and the solvents were removed at reduced pressure. The residue was purified by silical gel chromatography, followed by prep HPLC to give Example 3. HPLC R t  (Method A): 3.788 min. LCMS: m/z 431 (M+H + ). HPLC purity: 97%.  1 H NMR: δ 8.80 (s, 1H), 7.93-7.88 (m, 1H), 7.36-7.20 (m, 4H), 4.28 (s, 2H), 3.80-3.73 (m, 2H), 2.36-2.22 (m, 2H), 1.81-1.63 (m, 2H), 1.45-1.26 (m, 3H), 0.97 (d, J=5.1 Hz, 3H). 
     Example 4 
     2-((2,6-Dichlorophenylsulfonyl)methyl)-5-(4-methylpiperidin-1-ylsulfonyl)pyridine 
     
       
         
         
             
             
         
       
     
     Example 4 was prepared in a similar manner as Example 2, and obtained as a white powder. HPLC R t  (Method A): 3.127 min. LCMS: m/z 463 (M+H + ). HPLC purity: 95%.  1 H NMR: δ 8.61 (s, 1H), 7.96-7.93 (m, 1H), 7.63-7.61 (m, 1H), 7.34-7.31 (m, 3H), 4.83 (s, 2H), 3.64 (d, J=11.6 Hz, 2H), 2.22-2.10 (m, 2H), 1.69-1.52 (m, 2H), 1.31-1.12 (m, 3H), 0.85 (d, J=5.7 Hz, 3H) 
     Example 5 
     2-((2,6-Dichlorophenoxy)methyl)-5-(4-methylpiperidin-1-ylsulfonyl)-pyridine 
     
       
         
         
             
             
         
       
     
     To a solution of compound 3C (10 mg, 0.037 mmol) in THF (1 mL) was added 2,6-dichlorophenol (18.1 mg, 0.111 mmol) and PPh 3  (29 mg, 0.111 mmol). After 1 minute of stirring, diisopropyl azodicarboxylate (22.4 mg, 0.111 mmol) was added. The mixture was stirred at room temperature for 1.5 hours. The solvent was removed at reduced pressure, and the mixture was purified by preparative HPLC (solvent: CH 3 OH—H 2 O-TFA) to yield Example 5 (17 mg) as a white powder. HPLC R t  (Method A): 3.923 min. LCMS: m/z 415 (M+H + ). HPLC purity: 98%.  1 H NMR: δ 8.95 (d, J=1.7 Hz, 1H), 8.18-8.16 (m, 1H), 8.07-8.05 (m, 1H), 7.39-7.37 (m, 2H), 7.12-7.08 (m, 1H), 5.29 (s, 2H), 3.84 (d, J=11.7 Hz, 2H), 2.40-2.34 (m, 2H), 1.75-1.72 (m, 2H), 1.37-1.32 (m, 3H), 0.96 (d, J=5.7 Hz, 3H). 
     Example 6 
     5-((2,6-Dichlorophenylthio)methyl)-2-(4-methylpiperidin-1-ylsulfonyl)-pyridine 
     
       
         
         
             
             
         
       
     
     To a solution of 2,5-dibromopyridine (5 g, 21.10 mmol) in toluene (300 mL) at −78° C. was added 2.5 N (in hexane) n-BuLi solution (10.1 mL, 25.33 mmol). After the addition, the solution was stirred at −78° C. for 2.5 hours. The reaction mixture was added slowly, via a steel cannula, to a saturated SO 2  solution in THF (200 mL) at −78° C. After the addition, the solution was stirred at −78° C. for 20 minutes, then was warmed to RT over 1 hour. The solution was concentrated under reduced pressure to about 100 mL, and was then treated with sulfuryl chloride (2.85 g, 21.10 mmol) at 0° C. to RT for 20 minutes. The solution was concentrated under reduced pressure to yield 5-bromopyridine-2-sulfonyl chloride. A portion (⅗) of the crude intermediate was dissolved in DCM (100 mL) and was treated with 4-methylpiperidine (10 g, 101.3 mmol) at room temperature for 20 minutes. The solution was concentrated and purified by column chromatography to yield compound 6A (1.86 g) as a white powder. HPLC R t  (Method A): 3.108 min. LCMS: m/z 319 (M+H + ). 
     
       
         
         
             
             
         
       
     
     Compound 6B was prepared in a similar manner as compound 1B. Carbonylation of compound 6A (1.10 g) gave compound 6B (960 mg) as a white power. LC/MS m/z 299 (M+H + ). 
     
       
         
         
             
             
         
       
     
     To a solution of compound 6B (801 mg, 2.69 mmol) in EtOH (12 mL) and THF (20 mL) was added NaBH 4  (203 mg, 5.38 mmol). The mixture stirred at RT overnight. The reaction was quenched with water and was neutralized to pH=7 using 1N HCl. The mixture was stripped of the organic solvents, was made slightly basic using 1N NaOH, and was extracted several times with ethyl acetate. The organic extracts were combined, dried over MgSO 4 , concentrated, and purified by column chromatography to yield compound 6C (507 mg) as a white powder. HPLC R t  (Method A): 2.297 min. LCMS: m/z 271 (M+H + ). 
     Example 6 
     To a solution of compound 6C (250 mg, 0.925 mmol) in DCM (10 mL) was added thionyl chloride (0.547 mL, 7.40 mmol). The solution was stirred at room temperature for 3.5 hours and was then concentrated to yield a white powder. The powder was dissolved in DCM (10 mL) and was treated with 2,6-dichlorobenzenethiol (166 mg, 0.925 mmol) and N,N-diisopropylethylamine (0.644 mL, 3.7 mmol) at RT for 40 minutes. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to yield Example 6 (385 mg) as a white powder. HPLC R t  (Method A): 3.785 min. LCMS: m/z 431 (M+H + ). HPLC purity: 96%.  1 H NMR: δ 8.43 (s, 1H), 7.77-7.75 (m, 1H), 7.64-7.62 (m, 1H), 7.35-7.33 (m, 2H), 7.22-7.18 (m, 1H), 4.15 (s, 2H), 3.84 (d, J=12.1 Hz, 2H), 2.61-2.55 (m, 2H), 1.70-1.67 (m, 2H), 1.50-1.26 (m, 3H), 0.96 (d, J=6.3 Hz, 3H). 
     Example 7 
     5-((2,6-Dichlorophenylsulfonyl)methyl)-2-(4-methylpiperidin-1-ylsulfonyl)pyridine 
     
       
         
         
             
             
         
       
     
     Example 7 was prepared in a similar manner as Example 2. Oxidation of Example 6 (188 mg) gave Example 7 (205 mg) as a white powder. HPLC R t  (Method A): 3.030 min. LCMS: m/z 463 (M+H + ). HPLC purity: 97%.  1 H NMR: δ 8.42 (s, 1H), 7.91-7.72 (m, 2H), 7.48-7.32 (m, 3H), 4.68 (s, 2H), 3.76 (d, J=11.3 Hz, 2H), 2.52 (t, J=11.7 Hz, 2H), 1.70-1.49 (m, 2H), 1.40-1.09 (m, 3H), 0.86 (d, J=6.2 Hz, 3H) 
     Example 8 
     5-((2,6-Dichlorophenoxy)methyl)-2-(4-methylpiperidin-1-ylsulfonyl)-pyridine 
     
       
         
         
             
             
         
       
     
     Example 8 was prepared in a similar manner as Example 5. Reaction of compound 6C (32 mg) and other appropriate reagents gave Example 8 (54.9 mg) as a white powder. HPLC R t  (Method A): 3.842 min. LCMS: m/z 415 (M+H + ). HPLC purity: 97%.  1 H NMR: δ 8.88 (d, J=1.6 Hz, 1H), 8.16-8.13 (m, 1H), 8.01-7.99 (m, 1H), 7.38-7.36 (m, 2H), 7.09 (t, J=8.1 Hz, 1H), 5.17 (s, 2H), 3.94 (d, J=12.2 Hz, 2H), 2.75-2.68 (m, 2H), 1.73-1.69 (m, 2H), 1.50-1.23 (m, 3H), 0.96 (d, J=6.3 Hz, 3H). 
     Example 9 
     (6-(2-Chlorophenoxy)pyridin-2-yl)(4-methylpiperidin-1-yl)methanone 
     
       
         
         
             
             
         
       
     
     To a solution of 6-chloropyridine-2-carboxylic acid (1.0 g, 6.3 mmol) and 4-methylpiperidine (1.1 mL, 9.5 mmol) in DCM (20 mL) was added EDAC (1.8 g, 9.5 mmol), HOAT (0.5M in DMF, 1.9 mL, 0.95 mmol), and 4-DMAP (116 mg, 0.95 mmol). The solution was stirred at RT for 18 hr, and then was concentrated in vacuo. The residue was partitioned between EtOAc and Brine. The organic phase was dried (MgSO 4 ) and concentrated in vacuo. The crude product was purified via column chromatography (30% EtOAc/70% Hexane, flow rate: 30 mL/min, detection wavelength: 254 nm) to provide compound 9A (1.3 g, 88% yield) as a white solid. HPLC R t  (Method A): 2.91 min. LCMS: m/z 239 (M+H + ). HPLC purity: 95%. 
     Example 9 
     To a solution of compound 9A (100 mg, 0.42 mmol) in DMF (4 mL) was added 2-chlorophenol (81 mg, 0.63 mmol) and cesium carbonate (409 mg, 1.26 mmol). The reaction mixture was placed on the microwave reactor at 200° C. for 40 min and was then partitioned between EtOAc and a 10% LiCl solution. The organic phase was dried (MgSO 4 ) and concentrated in vacuo. The residue was purified via preparative HPLC (Phenomenex LUNA 5 u C18 21.1×100 mm column; detection at 220 nm; flow rate=25 mL/min; continuous gradient from 80% A to 100% B over 8 min, where A=90:10:0.1 H 2 O:MeOH:TFA and B=90:10:0.1 MeOH:H 2 O:TFA) to provide Example 9 (44.7 mg, 32% yield) as an oil  1 H NMR (400 MHz, CD 3 OD): δ 0.68-0.78 (m, 1H), 0.84 (d, J=6.6 Hz, 3H), 0.95-1.05 (m, 1H), 1.34 (d, J=13.2 Hz, 1H), 1.50-1.60 (m, 1H), 1.65 (d, J=13.2 Hz, 1H), 2.65-2.75 (m, 1H), 2.78-2.88 (m, 1H), 3.74 (d, J=13.2 Hz, 1H), 4.45 (d, J=13.2 Hz, 1H), 7.13-7.51 (m, 6H), 7.93 (d, J=8.4 Hz, 1H). 
     Examples 10 to 12 
     Examples 10 to 12 in Table 1 were synthesized according to the procedures described in Example 9 utilizing the appropriate starting materials. 
     
       
         
           
               
               
               
               
             
               
                 TABLE 1 
               
               
                   
               
               
                   
                   
                   
                 HPLC 
               
               
                   
                   
                 Mass 
                 Purity 
               
               
                 Example 
                 Structure 
                 [M + H] 
                 (%) 
               
               
                   
               
             
            
               
                 10 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 347 
                 99 
               
               
                   
               
               
                 11 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 381 
                 95 
               
               
                   
               
               
                 12 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 330 
                 97 
               
               
                   
               
            
           
         
       
     
     Example 13 
     (6-((2,6-Dichlorophenylthio)methyl)pyridin-2-yl)(4-(trifluoromethyl)piperidin-1-yl)methanone 
     
       
         
         
             
             
         
       
     
     A solution of diethyl 2,6-pyridine dicarboxylate (25 g, 112 mmol) in ethanol (250 mL) was treated with sodium borohydride (2.33 g, 0.55 equiv) and was refluxed for 2 h. After being cooled to RT, the solution was concentrated to a volume of 50 mL and water (50 mL) was added. The solution was further concentrated to a final volume of about 50 mL and extracted with several 50 mL portions of DCM. The combined DCM extracts were dried with sodium sulfate and concentrated by rotary evaporation to yield compound 13A (18.3 g of). HPLC purity 95%. LC/MS m/z 182 (M+H + ). 
     
       
         
         
             
             
         
       
     
     To a solution of compound 13A (2.86 g, 15.74 mmol) in DCM (100 mL) was added phosphorus tribromide (3.20 g, 11.80 mmol) at 0° C. The solution was stirred for 2 h at 0° C. under nitrogen, then quenched with 100 mL of saturated NaHCO 3  solution. The DCM layer was separated, and the aqueous layer was extracted with DCM (3×100 mL). The combined extracts were washed with brine, dried over MgSO 4 , and evaporated to yield compound 13B (2.65 g). HPLC purity 93%. LC/MS: m/z 244 (M+H). 
     
       
         
         
             
             
         
       
     
     To a solution of compound 13B in THF (10 mL/mmol) was added thiophenol (1 equiv.), DIEA (2 equiv.), and CsCO 3  (1 equiv). The sealed reaction mixture was heated for 2-10 h at 60° C. to push the reaction to completion. The reaction was cooled to RT and diluted with hexane. The solid CsCO 3  was removed by filtration, and the THF solvent was removed by rotary evaporation to yield compound 13C. LC/MS: m/z 342 (M+H). 
     
       
         
         
             
             
         
       
     
     Compound 13C was dissolved in a 1:1 mixture of THF and 1N NaOH solution. The mixture stirred for 2 h at RT. The THF was removed by evaporation, and the mixture was adjusted to pH 3 by the addition of HCl. A white solid precipitated out. The precipitate was filtered and dried to give compound 13D. LC/MS m/z 313 (M+H). 
     Example 13 
     To a solution of compound 13D (0.1 mmol) in DMF (2 mL) was added 4-(trifluoromethyl)piperidine (0.12 mmol), PyAOP (0.1 mmol), and DIEA (0.15 mmol). The reaction was stirred vigorously for 10 h. After the DMF solvent was removed by Speed Vac, the residue was purified by Prep-HPLC to give Example 13. LC/MS m/z 449 (M+H).  1 H NMR (500 MHz, CDCl 3 ): δ 1.57 (m, 2H), 1.80 (dd, 2H), 2.23 (m, 1H), 2.78 (t, 2H), 4.14 (s, 2H), 4.35 (dd, 2H), 7.09 (m, 2H), 7.25 (d, 2H), 7.43 (d, 1H), 7.58 (t, 1H). 
     Example 14 
     N-Cyclopentyl-5-((2,6-dichlorophenylthio)methyl)nicotinamide 
     
       
         
         
             
             
         
       
     
     To a solution of methyl 5-methylnicotinate (5 g, 33 mmol) in carbon tetrachloride (200 mL) was added NBS (5.9 g, 1 equiv) and dibenzoyl peroxide (1.2 g, 0.15 equiv). The reaction was refluxed for 3 h, then was cooled to RT to give compound 14A. The carbon tetrachloride solution containing compound 14A was used without further purification. 
     Example 14 
     Example 14 was prepared in three steps in a similar manner as compounds 13C to Example 13: Alkylation of compound 14A with 2,6-dichlorothiophenol, basic hydrolysis of the methyl ester, followed by amide formation provided Example 14. LC/MS m/z 381 (M+H + )  1 H NMR (500 MHz, CDCl 3 ): δ 1.47 (m, 2H), 1.72 (m, 6H), 2.08 (m, 2H), 4.11 (s, 2H), 4.36 (q, 1H), 5.93 (bs, 1H), 7.14 (t, 1H), 7.31 (d, 2H), 7.84 (s, 1H), 8.41 (s, 1H), 8.75 (s, 1H). 
     Example 15 
     (4-Methylpiperidin-1-yl)(5-(m-tolylthiomethyl)pyridin-3-yl)methanone 
     
       
         
         
             
             
         
       
     
     To a stirred solution of pyridine-3,5-dicarboxylic acid (25 g) in EtOH (200 mL) was added concentrated H 2 SO 4  (5 mL). The reaction was stirred until all pyridine-3,5-dicarboxylic acid was gone. The reaction formed a 1:1 mixture of compound 15A and diethyl pyridine-3,5-dicarboxylate. EtOH was removed via vacuum, and the residue was dissolved in saturated NaHCO 3  solution (100 mL). Diethyl pyridine-3,5-dicarboxylate was extracted out by EtOAc (3×). The aqueous layer was adjusted to pH 3, and the product was precipitated out as a white solid. The solid was filtered and dried to give compound 15A (ca 50%). LC/MS m/z 196 (M+H + ). 
     
       
         
         
             
             
         
       
     
     To a stirred solution of compound 15A (4.31 g) in anhydrous THF (150 mL) was added NMM (4.84 mL, 2 equiv) and isobutyl chloroformate (3.17 mL, 1.1 equiv) at 0° C. The reaction was stirred for 1 h at 0° C., followed by addition of 4-methylpiperidine (5.2 mL, 2 equiv). The stirring was continued to for another 10 h. The white precipitated solid was filtered off, and the solvent was removed by evaporation. The crude product was purified by silica gel column chromatography (ISCO) to give compound 15B (3.56 g). LC/MS m/z 276 (M+H + ). 
     
       
         
         
             
             
         
       
     
     Compound 15C was prepared in a similar manner as compound 1C. Sodium borohydride reduction of compound 15B (3.56 g) gave compound 15C (2.5 g). LC/MS m/z 235 (M+H + ).  1 H NMR (CDCl 3 ): δ 0.96 (d, 3H), 1.15 (m, 2H), 1.70 (m, 3H), 2.76 (t, 1H), 3.01 (t, 1H), 3.60 (d, 1H), 4.60 (d, 1H), 4.66 (s, 2H), 7.67 (s, 1H), 8.45 (s, 1H), 8.49 (s, 1H).  13 C NMR (CDCl 3 ): δ 21.55, 30.95, 33.62, 34.63, 42.66, 48.18, 61.77, 131.86, 133.27, 137.09, 146.01, 148.90, 167.65. 
     
       
         
         
             
             
         
       
     
     To a stirred solution of compound 15C (2.5 g, 10.6 mmol) in DCM (100 mL) was added SOCl 2  (3.9 mL, 5 equiv). The mixture stirred for 1 h at RT. DCM solvent was removed by evaporation, and a white solid was obtained as compound 15D (3.2 g). LC/MS m/z 253 (M+H + ). 
     Example 15 
     Example 15 was prepared in a similar manner as Example 1: alkylation of compound 15D with 3-methylthiophenoyl provided Example 15. HPLC purity 99%. LC/MS: m/z 341 (M+H + ).  1 H NMR (400 MHz, DMSO/CDCl 3 ): δ 0.95 (d, 3H), 1.42-1.80 (m, 3H), 2.66-2.83 (m, 1H), 2.86-3.06 (m, 1H), 3.25-3.60 (m, 2H), 3.73 (s, 3H), 4.29 (s, 2H), 4.36-4.55 (m, 1H), 6.75 (d, 1H), 6.83-6.92 (m, 2H), 7.18 (t, 1H), 7.69 (s, 1H), 8.41 (s, 1H), 8.57 (s, 1H). 
     Example 16 
     (2,5-Dimethylpyrrolidin-1-yl)(6-((naphthalen-1-ylsulfonyl)methyl)pyridin-2-yl)methanone 
     
       
         
         
             
             
         
       
     
     Compound 16A was prepared in a similar manner as compound 13C using appropriate starting materials. LC/MS: m/z 324 (M+H + ). 
     
       
         
         
             
             
         
       
     
     To a solution of compound 16A (1 mmol) in DCM (10 mL) was added mCPBA (4 equiv.). The mixture was stirred at RT overnight. The reaction mixture was then cooled to 0° C., followed by addition of PBr 3  (4 equiv.). The stirring was continued for 6 h at 0° C., and the reaction was then quenched with saturated NaHCO 3  solution. The DCM layer was separated, and the aqueous layer was extracted with DCM (3×100 mL). The combined DCM extracts were washed with brine, dried over MgSO 4 , and evaporated to give compound 16B. LC/MS: m/z 356 (M+H + ). 
     Example 16 
     Example 16 was prepared in two steps in a similar manner as compounds 13D to Example 13: basic hydrolysis of compound 16B, followed by amide formation provided Example 16. LC/MS: m/z 409 (M+H).  1 H NMR (400 MHz, DMSO/CDCl 3 ): δ 0.80 (d, 3H), 1.12 (d, 3H), 0.95-4.08 (m, 6H), 5.0 (m, 2H), 7.10-7.95 (m, 7H), 8.20 (d, 1H), 8.32 (t, 1H), 8.68 (d, 1H). 
     Example 17 
     (4-Methylpiperidin-1-yl)(5-(o-tolyloxymethyl)pyridin-3-yl)methanone 
     
       
         
         
             
             
         
       
     
     To a solution of compound 14A (ca. 1 mmol) in CCl 4  (6 mL) was added 2-methylphenol (1 equiv.) and DIEA (2 equiv). The reaction was refluxed for 1 h and then cooled to RT. The crude product was purified by silica gel column chromatography (ISCO) to give compound 17A. LC/MS: m/z 258 (M+H + ). 
     Example 17 
     Example 17 was prepared in two steps in a similar manner as compounds 13C to Example 13: basic hydrolysis of compound 17A, followed by amide formation provided Example 17. LC/MS: m/z 325 (M+H).  1 H NMR (400 MHz, DMSO/CDCl 3 ): δ 1.00 (d, 3H), 2.25 (s, 3H), 1.18-4.50 (m, 9H), 5.26 (s, 2H), 6.90 (t, 1H), 7.04 (d, 1H), 7.20 (m, 2H), 7.90 (s, 1H), 8.59 (s, 1H), 8.78 (s, 1H). 
     Example 18 
     (6-(2-Chlorophenyl)pyridin-2-yl)(4-methylpiperidin-1-yl)methanone 
     
       
         
         
             
             
         
       
     
     A solution of 6-bromopicolinic acid (250 mg, 1.24 mmol) in thionyl chloride (1.7 mL) was refluxed for 1.0 h, cooled, concentrated, and dried in vacuo for 1.0 h. The crude product was dissolved in dry DCM (15 mL), was treated with 4-methylpiperidine (96%, 0.3 mL, 2.29 mmol), and was stirred at room temperature for 20 h. The reaction mixture was concentrated and dried in vacuo. The solids obtained were chromatographed (ISCO, 40 g. column; CH 3 OH:CH 2 Cl 2  gradient-0% to 10%) to yield compound 18A (332.9 mg, 94.8%) as a white solid (m.p. 90-92° C.). HPLC: 96.6% at 1.97 and 2.07 min (retention times for rotamer mixture) (Conditions: YMC S-5 C-18 (4.6×50 mm), eluting with 0-100% B, 4 min gradient. (A=90% H 2 O—10% CH 3 CN—0.1% TFA and B=10% H 2 O—90% CH 3 CN—0.1% TFA); Flow rate at 4 mL/min. UV detection at 220 nm. MS (ES + ): m/z 283 [M+H] + . 
     Example 18 
     A solution of compound 18A (100 mg, 0.35 mmol) in dry toluene (0.8 mL) was treated with tetrakis(triphenylphosphine)palladium(0) (14.3 mg, 0.012 mmol). The mixture stirred at room temperature for 15 min and was then treated with 2-chlorophenyl-boronic acid (70.4 mg, 0.45 mmol), 2.0 M Na 2 CO 3  (0.4 mL) and absolute ethanol (0.4 mL). The reaction mixture was stirred at 80° C. (oil bath) for 25 h, was cooled, and then was partitioned between H 2 O (1.5 mL) and EtOAc (3×15 mL). The combined organic extracts were washed with brine (1.5 mL), dried over MgSO 4 , filtered, and concentrated under pressure. The crude product was chromatographed (ISCO, 40 g silica gel column; EtOAc:Hexane-0% to 50% gradient), followed by purification via preparative HPLC(YMC S5 ODS 20×100 mm; CH 3 CN/H 2 O+0.1% TFA-0% to 100%) to yield Example 18 as a white solid (73.6 mg, 49%). HPLC: 98% purity at 2.10 min (retention time) (Conditions: YMC S-5 C-18 (4.6×50 mm), eluting with 0-100% B, 4 min gradient. (A=90% H 2 O—10% CH 3 CN—0.1% TFA and B=10% H 2 O—90% CH 3 CN—0.1% TFA); Flow rate at 4 mL/min. UV detection at 220 nm. MS (ES + ): m/z 315 [M+H] + .  1 H NMR (500 MHz, CD 3 OD): δ 0.98 (d, J=6.6 Hz, 3H), 1.20-1.27 (m, 2H), 1.62-1.80 (m, 3H), 2.84-2.88 (m, 1H), 3.09-3.13 (m, 1H), 3.81 (d, J=13.2 Hz, 1H), 4.62 (d, J=13.2 Hz, 1H), 7.40-7.45 (m, 2H), 7.52-7.57 (m, 3H), 7.71 (d, J=8.8 Hz, 1H), 8.02 (t, J=7.7 Hz, 1H). 
     Example 19 
     (6-(2-Chlorophenyl)pyridin-2-yl)(3,4-dihydroquinolin-1(2H)-yl)methanone 
     
       
         
         
             
             
         
       
     
     To a solution of 6-bromopicolinic acid (2.5 g) in MeOH (100 mL) was added concentrated H 2 SO 4  (5 mL). The reaction was refluxed until the 6-bromopicolinic acid was gone. The mixture was dried by evaporation and then purified by silica gel column chromatography (ISCO) to give compound 19A (ca 90% yield). LC/MS: m/z 216/218 (M+H&#39;). 
     
       
         
         
             
             
         
       
     
     To a solution of compound 19A (300 mg) in DMA (10 mL) was added K 3 PO 4  (3 equiv). Nitrogen was bubbled through the solution, and then catalyst Pd(PPh 3 ) 4  (0.1 equiv) was added. The mixture was placed in a sealed microwave tube, which was put on the Microwave for 30 min. at 120° C. The extra solid residues were filtered off and DMA solvent was removed by Speed-Vac. The crude product was purified by silica gel column chromatography to give compound 19B (ca 60%). LC/MS: m/z 248 (M+H + ). 
     Example 19 
     Example 19 was prepared in two steps in a similar manner as compounds 13D to Example 13: basic hydrolysis of compound 19B, followed by amide formation provided Example 19. LC/MS: m/z 349 (M+H + ).  1 H NMR (400 MHz, DMSO/CDCl 3 ): δ 2.05 (t, 2H), 2.86 (m, 2H), 3.86 (t, 2H), 7.00 (m, 1H), 7.05 (m, 2H), 7.24 (t, 2H), 7.37 (t, 1H), 7.42 (t, 1H), 7.52 (d, 1H), 7.64 (d, 1H), 7.73 (d, 1H), 8.03 (t, 1H). 
     Examples 20 to 305 
     Examples 20 to 305 in Table 2 were prepared according to the procedures described in the proceeding examples, or by other similar methods used by one skilled in the art, utilizing other appropriate reagents. 
     
       
         
           
               
               
               
               
             
               
                 TABLE 2 
               
               
                   
               
               
                   
                   
                   
                 HPLC 
               
               
                   
                   
                 Mass 
                 Purity 
               
               
                 Example 
                 Structure 
                 [M + H] 
                 (%) 
               
               
                   
               
             
            
               
                  20 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 409.37 
                 100 
               
               
                   
               
               
                  21 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 353.32 
                 100 
               
               
                   
               
               
                  22 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 367.35 
                 100 
               
               
                   
               
               
                  23 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 396.35 
                 100 
               
               
                   
               
               
                  24 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 381.35 
                 100 
               
               
                   
               
               
                  25 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 409.37 
                 100 
               
               
                   
               
               
                  26 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 409.37 
                  99 
               
               
                   
               
               
                  27 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 480.4  
                 100 
               
               
                   
               
               
                  28 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 424.37 
                 100 
               
               
                   
               
               
                  29 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 409.37 
                 100 
               
               
                   
               
               
                  30 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 397.35 
                 100 
               
               
                   
               
               
                  31 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 457.34 
                 100 
               
               
                   
               
               
                  32 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395.4  
                 100 
               
               
                   
               
               
                  33 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 449.32 
                 100 
               
               
                   
               
               
                  34 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 435.42 
                 100 
               
               
                   
               
               
                  35 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 429.34 
                  94 
               
               
                   
               
               
                  36 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395.4  
                 100 
               
               
                   
               
               
                  37 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 487.37 
                  97 
               
               
                   
               
               
                  38 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 341.36 
                 100 
               
               
                   
               
               
                  39 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 398.38 
                 100 
               
               
                   
               
               
                  40 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395.4  
                  97 
               
               
                   
               
               
                  41 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 367.35 
                 100 
               
               
                   
               
               
                  42 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 397.35 
                  82 
               
               
                   
               
               
                  43 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 423.42 
                  98 
               
               
                   
               
               
                  44 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 423.41 
                 100 
               
               
                   
               
               
                  45 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 424.37 
                 100 
               
               
                   
               
               
                  46 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 485.25 
                 100 
               
               
                   
               
               
                  47 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 435.36 
                 100 
               
               
                   
               
               
                  48 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 439.36 
                  94 
               
               
                   
               
               
                  49 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 438.39 
                  81 
               
               
                   
               
               
                  50 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 445.38 
                 100 
               
               
                   
               
               
                  51 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 341.22 
                  88 
               
               
                   
               
               
                  52 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 369.23 
                  95 
               
               
                   
               
               
                  53 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 369.24 
                  89 
               
               
                   
               
               
                  54 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 355.19 
                  85 
               
               
                   
               
               
                  55 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 369.23 
                  84 
               
               
                   
               
               
                  56 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 369.23 
                  87 
               
               
                   
               
               
                  57 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 417.21 
                  92 
               
               
                   
               
               
                  58 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 355.21 
                  97 
               
               
                   
               
               
                  59 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 355.22 
                  88 
               
               
                   
               
               
                  60 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 383.23 
                 100 
               
               
                   
               
               
                  61 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 409.25 
                 100 
               
               
                   
               
               
                  62 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 355.21 
                  86 
               
               
                   
               
               
                  63 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 429.04 
                 100 
               
               
                   
               
               
                  64 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 415.04 
                  88 
               
               
                   
               
               
                  65 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 443.06 
                  98 
               
               
                   
               
               
                  66 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 443.06 
                 100 
               
               
                   
               
               
                  67 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 443.07 
                 100 
               
               
                   
               
               
                  68 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 431.05 
                 100 
               
               
                   
               
               
                  69 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 429.05 
                 100 
               
               
                   
               
               
                  70 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 457.07 
                  96 
               
               
                   
               
               
                  71 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 429.05 
                 100 
               
               
                   
               
               
                  72 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 429.05 
                 100 
               
               
                   
               
               
                  73 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 411.16 
                 100 
               
               
                   
               
               
                  74 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 425.16 
                 100 
               
               
                   
               
               
                  75 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 425.18 
                 100 
               
               
                   
               
               
                  76 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 425.15 
                 100 
               
               
                   
               
               
                  77 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 425.17 
                 100 
               
               
                   
               
               
                  78 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 473.16 
                  88 
               
               
                   
               
               
                  79 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 411.15 
                 100 
               
               
                   
               
               
                  80 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 439.19 
                 100 
               
               
                   
               
               
                  81 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 465.19 
                 100 
               
               
                   
               
               
                  82 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395.1  
                  85 
               
               
                   
               
               
                  83 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 381.09 
                  93 
               
               
                   
               
               
                  84 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 409.1  
                  82 
               
               
                   
               
               
                  85 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 409.11 
                  85 
               
               
                   
               
               
                  86 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395.12 
                  90 
               
               
                   
               
               
                  87 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 409.1  
                  87 
               
               
                   
               
               
                  88 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 409.1  
                  98 
               
               
                   
               
               
                  89 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395.09 
                  86 
               
               
                   
               
               
                  90 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 449.12 
                  90 
               
               
                   
               
               
                  91 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395.1  
                  83 
               
               
                   
               
               
                  92 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 375.15 
                 100 
               
               
                   
               
               
                  93 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 389.15 
                  99 
               
               
                   
               
               
                  94 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 347.14 
                  95 
               
               
                   
               
               
                  95 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 376.12 
                  98 
               
               
                   
               
               
                  96 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 363.13 
                  96 
               
               
                   
               
               
                  97 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 361.15 
                  96 
               
               
                   
               
               
                  98 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 389.18 
                  85 
               
               
                   
               
               
                  99 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 389.17 
                  99 
               
               
                   
               
               
                 100 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 460.19 
                 100 
               
               
                   
               
               
                 101 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 404.15 
                  97 
               
               
                   
               
               
                 102 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 375.15 
                  91 
               
               
                   
               
               
                 103 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 389.17 
                  99 
               
               
                   
               
               
                 104 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 389.15 
                  93 
               
               
                   
               
               
                 105 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 377.14 
                  91 
               
               
                   
               
               
                 106 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 437.17 
                  94 
               
               
                   
               
               
                 107 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 375.17 
                  99 
               
               
                   
               
               
                 108 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 375.16 
                  95 
               
               
                   
               
               
                 109 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 403.17 
                  81 
               
               
                   
               
               
                 110 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 375.15 
                 100 
               
               
                   
               
               
                 111 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395.1  
                  85 
               
               
                   
               
               
                 112 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 409.1  
                 100 
               
               
                   
               
               
                 113 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 367.07 
                  97 
               
               
                   
               
               
                 114 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 381.07 
                  95 
               
               
                   
               
               
                 115 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 409.09 
                 100 
               
               
                   
               
               
                 116 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 409.1  
                 100 
               
               
                   
               
               
                 117 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 424.07 
                  95 
               
               
                   
               
               
                 118 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395.07 
                 100 
               
               
                   
               
               
                 119 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 409.08 
                  99 
               
               
                   
               
               
                 120 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 409.1  
                 100 
               
               
                   
               
               
                 121 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 397.07 
                  85 
               
               
                   
               
               
                 122 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395.1  
                 100 
               
               
                   
               
               
                 123 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395.01 
                 100 
               
               
                   
               
               
                 124 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395.09 
                 100 
               
               
                   
               
               
                 125 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 369.08 
                  81 
               
               
                   
               
               
                 126 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 423.11 
                 100 
               
               
                   
               
               
                 127 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 449.13 
                  96 
               
               
                   
               
               
                 128 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395.09 
                 100 
               
               
                   
               
               
                 129 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 405.2  
                 100 
               
               
                   
               
               
                 130 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 361.28 
                 100 
               
               
                   
               
               
                 131 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395.23 
                 100 
               
               
                   
               
               
                 132 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 357.32 
                  94 
               
               
                   
               
               
                 133 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 369.35 
                  98 
               
               
                   
               
               
                 134 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 341.35 
                 100 
               
               
                   
               
               
                 135 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 361.3  
                 100 
               
               
                   
               
               
                 136 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395.24 
                  97 
               
               
                   
               
               
                 137 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 357.34 
                 100 
               
               
                   
               
               
                 138 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 341.35 
                 100 
               
               
                   
               
               
                 139 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 405.2  
                  98 
               
               
                   
               
               
                 140 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 345.33 
                 100 
               
               
                   
               
               
                 141 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 361.28 
                  98 
               
               
                   
               
               
                 142 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 384.33 
                  98 
               
               
                   
               
               
                 143 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 357.35 
                 100 
               
               
                   
               
               
                 144 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 341.35 
                 100 
               
               
                   
               
               
                 145 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 372.31 
                 100 
               
               
                   
               
               
                 146 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 405.2  
                 100 
               
               
                   
               
               
                 147 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 355.38 
                  97 
               
               
                   
               
               
                 148 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 355.38 
                 100 
               
               
                   
               
               
                 149 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 355.38 
                 100 
               
               
                   
               
               
                 150 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 355.38 
                  96 
               
               
                   
               
               
                 151 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 429.17 
                 100 
               
               
                   
               
               
                 152 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 383.41 
                  96 
               
               
                   
               
               
                 153 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 377.35 
                  92 
               
               
                   
               
               
                 154 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 355.38 
                  84 
               
               
                   
               
               
                 155 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 345.35 
                 100 
               
               
                   
               
               
                 156 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 355.38 
                 100 
               
               
                   
               
               
                 157 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395.32 
                  95 
               
               
                   
               
               
                 158 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 345.35 
                 100 
               
               
                   
               
               
                 159 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395.25 
                  94 
               
               
                   
               
               
                 160 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395.25 
                 100 
               
               
                   
               
               
                 161 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 375.32 
                 100 
               
               
                   
               
               
                 162 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395.25 
                  88 
               
               
                   
               
               
                 163 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 369.4  
                  98 
               
               
                   
               
               
                 164 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395.32 
                  92 
               
               
                   
               
               
                 165 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 378.33 
                 100 
               
               
                   
               
               
                 166 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379.29 
                 100 
               
               
                   
               
               
                 167 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379.29 
                 100 
               
               
                   
               
               
                 168 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 385.32 
                 100 
               
               
                   
               
               
                 169 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395.32 
                 100 
               
               
                   
               
               
                 170 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 373.33 
                 100 
               
               
                   
               
               
                 171 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 397.42 
                  92 
               
               
                   
               
               
                 172 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 463.09 
                  97 
               
               
                   
               
               
                 173 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 489.14 
                 100 
               
               
                   
               
               
                 174 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 363.33 
                 100 
               
               
                   
               
               
                 175 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 369.4  
                  94 
               
               
                   
               
               
                 176 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 411.3  
                 100 
               
               
                   
               
               
                 177 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 385.35 
                 100 
               
               
                   
               
               
                 178 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 464.1  
                  96 
               
               
                   
               
               
                 179 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395.2  
                  97 
               
               
                   
               
               
                 180 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 409.21 
                  97 
               
               
                   
               
               
                 181 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 409.2  
                  93 
               
               
                   
               
               
                 182 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 409.19 
                 100 
               
               
                   
               
               
                 183 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395.2  
                  92 
               
               
                   
               
               
                 184 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 409.21 
                  89 
               
               
                   
               
               
                 185 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 409.21 
                  90 
               
               
                   
               
               
                 186 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 457.21 
                  89 
               
               
                   
               
               
                 187 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395.18 
                  93 
               
               
                   
               
               
                 188 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395.19 
                  94 
               
               
                   
               
               
                 189 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 423.22 
                  98 
               
               
                   
               
               
                 190 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 449.22 
                  97 
               
               
                   
               
               
                 191 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 355.23 
                  98 
               
               
                   
               
               
                 192 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 369.25 
                  99 
               
               
                   
               
               
                 193 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 369.25 
                  93 
               
               
                   
               
               
                 194 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 369.24 
                  92 
               
               
                   
               
               
                 195 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 440.28 
                  96 
               
               
                   
               
               
                 196 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 355.24 
                  95 
               
               
                   
               
               
                 197 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 369.25 
                  92 
               
               
                   
               
               
                 198 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 369.24 
                 100 
               
               
                   
               
               
                 199 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 357.22 
                  94 
               
               
                   
               
               
                 200 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 417.25 
                  94 
               
               
                   
               
               
                 201 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 355.24 
                  94 
               
               
                   
               
               
                 202 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 355.25 
                  92 
               
               
                   
               
               
                 203 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 329.25 
                 100 
               
               
                   
               
               
                 204 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 383.27 
                 100 
               
               
                   
               
               
                 205 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 409.28 
                 100 
               
               
                   
               
               
                 206 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 355.22 
                 100 
               
               
                   
               
               
                 207 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 377.22 
                  94 
               
               
                   
               
               
                 208 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 391.21 
                  96 
               
               
                   
               
               
                 209 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 363.2  
                  91 
               
               
                   
               
               
                 210 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 391.24 
                  90 
               
               
                   
               
               
                 211 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 391.22 
                  92 
               
               
                   
               
               
                 212 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 406.2  
                  93 
               
               
                   
               
               
                 213 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 377.19 
                  87 
               
               
                   
               
               
                 214 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 391.24 
                  94 
               
               
                   
               
               
                 215 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 391.24 
                  92 
               
               
                   
               
               
                 216 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379.19 
                  98 
               
               
                   
               
               
                 217 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 377.22 
                  90 
               
               
                   
               
               
                 218 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 377.21 
                  89 
               
               
                   
               
               
                 219 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 405.24 
                  94 
               
               
                   
               
               
                 220 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 431.26 
                  93 
               
               
                   
               
               
                 221 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 377.2  
                  87 
               
               
                   
               
               
                 222 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 381.1  
                 100 
               
               
                   
               
               
                 223 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395.11 
                 100 
               
               
                   
               
               
                 224 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 409.13 
                 100 
               
               
                   
               
               
                 225 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 409.13 
                 100 
               
               
                   
               
               
                 226 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 409.13 
                 100 
               
               
                   
               
               
                 227 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 409.14 
                 100 
               
               
                   
               
               
                 228 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 437.17 
                 100 
               
               
                   
               
               
                 229 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 409.14 
                 100 
               
               
                   
               
               
                 230 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 423.15 
                 100 
               
               
                   
               
               
                 231 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 409.11 
                 100 
               
               
                   
               
               
                 232 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 468.12 
                  90 
               
               
                   
               
               
                 233 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379.08 
                  95 
               
               
                   
               
               
                 234 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 381.11 
                 100 
               
               
                   
               
               
                 235 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395.12 
                 100 
               
               
                   
               
               
                 236 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 409.12 
                 100 
               
               
                   
               
               
                 237 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 409.11 
                 100 
               
               
                   
               
               
                 238 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 480.13 
                 100 
               
               
                   
               
               
                 239 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 424.09 
                 100 
               
               
                   
               
               
                 240 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395.11 
                 100 
               
               
                   
               
               
                 241 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 409.12 
                 100 
               
               
                   
               
               
                 242 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 409.13 
                 100 
               
               
                   
               
               
                 243 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 457.13 
                 100 
               
               
                   
               
               
                 244 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395.13 
                 100 
               
               
                   
               
               
                 245 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 449.09 
                 100 
               
               
                   
               
               
                 246 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 458.14 
                 100 
               
               
                   
               
               
                 247 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 429.1  
                 100 
               
               
                   
               
               
                 248 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 435.15 
                  92 
               
               
                   
               
               
                 249 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 429.09 
                 100 
               
               
                   
               
               
                 250 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395.12 
                 100 
               
               
                   
               
               
                 251 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 487.14 
                  92 
               
               
                   
               
               
                 252 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395.11 
                 100 
               
               
                   
               
               
                 253 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 369.12 
                  81 
               
               
                   
               
               
                 254 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 435.16 
                  93 
               
               
                   
               
               
                 255 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 381.1  
                 100 
               
               
                   
               
               
                 256 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 423.14 
                 100 
               
               
                   
               
               
                 257 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 423.13 
                  99 
               
               
                   
               
               
                 258 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 424.08 
                 100 
               
               
                   
               
               
                 259 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 423.13 
                 100 
               
               
                   
               
               
                 260 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 409.11 
                  96 
               
               
                   
               
               
                 261 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 449.15 
                 100 
               
               
                   
               
               
                 262 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 435.13 
                  99 
               
               
                   
               
               
                 263 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 435.15 
                  90 
               
               
                   
               
               
                 264 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 439.1  
                  90 
               
               
                   
               
               
                 265 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 457.13 
                 100 
               
               
                   
               
               
                 266 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 447.14 
                 100 
               
               
                   
               
               
                 267 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 377.32 
                 100 
               
               
                   
               
               
                 268 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 405.17 
                 100 
               
               
                   
               
               
                 269 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 361.21 
                 100 
               
               
                   
               
               
                 270 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395.19 
                 100 
               
               
                   
               
               
                 271 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 362.25 
                  99 
               
               
                   
               
               
                 272 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 361.28 
                  99 
               
               
                   
               
               
                 273 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 421.2  
                  99 
               
               
                   
               
               
                 274 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 341.32 
                 100 
               
               
                   
               
               
                 275 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 409.25 
                  95 
               
               
                   
               
               
                 276 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 363.34 
                  99 
               
               
                   
               
               
                 277 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 341.38 
                 100 
               
               
                   
               
               
                 278 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 372.34 
                 100 
               
               
                   
               
               
                 279 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 405.24 
                 100 
               
               
                   
               
               
                 280 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 355.4  
                 100 
               
               
                   
               
               
                 281 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 355.41 
                 100 
               
               
                   
               
               
                 282 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 355.41 
                 100 
               
               
                   
               
               
                 283 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 355.41 
                 100 
               
               
                   
               
               
                 284 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 429.22 
                 100 
               
               
                   
               
               
                 285 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 377.39 
                 100 
               
               
                   
               
               
                 286 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 391   
                 100 
               
               
                   
               
               
                 287 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395   
                  96 
               
               
                   
               
               
                 288 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395   
                  98 
               
               
                   
               
               
                 289 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395   
                  95 
               
               
                   
               
               
                 290 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395   
                  96 
               
               
                   
               
               
                 291 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 355.41 
                 100 
               
               
                   
               
               
                 292 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 345.39 
                 100 
               
               
                   
               
               
                 293 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395.29 
                 100 
               
               
                   
               
               
                 294 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395.29 
                 100 
               
               
                   
               
               
                 295 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 375.32 
                 100 
               
               
                   
               
               
                 296 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379.32 
                 100 
               
               
                   
               
               
                 297 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379.32 
                 100 
               
               
                   
               
               
                 298 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395.36 
                 100 
               
               
                   
               
               
                 299 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 373.38 
                 100 
               
               
                   
               
               
                 300 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 397.43 
                  98 
               
               
                   
               
               
                 301 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 463.16 
                 100 
               
               
                   
               
               
                 302 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 489.22 
                 100 
               
               
                   
               
               
                 303 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 363.36 
                 100 
               
               
                   
               
               
                 304 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 369.44 
                 100 
               
               
                   
               
               
                 305 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 464.2  
                 100 
               
               
                   
               
            
           
         
       
     
     Examples 306 to 534 
     Examples 306 to 534 were prepared according to the procedures described in Examples 2 and 16 or other similar methods used by one skilled in the art, utilizing other appropriate reagents. 
     
       
         
           
               
               
               
               
             
               
                 TABLE 3 
               
               
                   
               
               
                   
                   
                 Mass 
                   
               
               
                 Example 
                 Structure 
                 [M + H] 
                 HPLC Purity (%) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                 306 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 441.12 
                 84 
               
               
                   
               
               
                 307 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 413.14 
                 96 
               
               
                   
               
               
                 308 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 441.13 
                 97 
               
               
                   
               
               
                 309 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 441.12 
                 100 
               
               
                   
               
               
                 310 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 427.17 
                 99 
               
               
                   
               
               
                 311 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 441.19 
                 100 
               
               
                   
               
               
                 312 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 489.14 
                 100 
               
               
                   
               
               
                 313 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 427.17 
                 100 
               
               
                   
               
               
                 314 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 422.13 
                 98 
               
               
                   
               
               
                 315 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 481.12 
                 98 
               
               
                   
               
               
                 316 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 467.17 
                 98 
               
               
                   
               
               
                 317 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 461.16 
                 97 
               
               
                   
               
               
                 318 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 427.17 
                 100 
               
               
                   
               
               
                 319 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 519.18 
                 100 
               
               
                   
               
               
                 320 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 427.21 
                 100 
               
               
                   
               
               
                 321 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 455.22 
                 100 
               
               
                   
               
               
                 322 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 455.22 
                 100 
               
               
                   
               
               
                 323 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 517.04 
                 100 
               
               
                   
               
               
                 324 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 481.19 
                 83 
               
               
                   
               
               
                 325 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 477.18 
                 100 
               
               
                   
               
               
                 326 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 437.12 
                 100 
               
               
                   
               
               
                 327 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 393.24 
                 96 
               
               
                   
               
               
                 328 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 427.17 
                 95 
               
               
                   
               
               
                 329 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 373.28 
                 100 
               
               
                   
               
               
                 330 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 393.22 
                 100 
               
               
                   
               
               
                 331 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 427.17 
                 100 
               
               
                   
               
               
                 332 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 389.3 
                 93 
               
               
                   
               
               
                 333 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 373.3 
                 100 
               
               
                   
               
               
                 334 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 437.18 
                 100 
               
               
                   
               
               
                 335 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 377.29 
                 83 
               
               
                   
               
               
                 336 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 393.25 
                 100 
               
               
                   
               
               
                 337 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 373.35 
                 100 
               
               
                   
               
               
                 338 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 404.3 
                 100 
               
               
                   
               
               
                 339 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 437.19 
                 100 
               
               
                   
               
               
                 340 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 387.37 
                 100 
               
               
                   
               
               
                 341 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 387.37 
                 100 
               
               
                   
               
               
                 342 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 387.37 
                 100 
               
               
                   
               
               
                 343 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 461.16 
                 100 
               
               
                   
               
               
                 344 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 409.34 
                 100 
               
               
                   
               
               
                 345 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 387.37 
                 100 
               
               
                   
               
               
                 346 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 377.35 
                 100 
               
               
                   
               
               
                 347 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 387.37 
                 100 
               
               
                   
               
               
                 348 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 377.35 
                 100 
               
               
                   
               
               
                 349 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 427.24 
                 100 
               
               
                   
               
               
                 350 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 427.24 
                 100 
               
               
                   
               
               
                 351 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 407.34 
                 100 
               
               
                   
               
               
                 352 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 427.24 
                 100 
               
               
                   
               
               
                 353 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 411.3 
                 100 
               
               
                   
               
               
                 354 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 411.29 
                 100 
               
               
                   
               
               
                 355 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 427.35 
                 100 
               
               
                   
               
               
                 356 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 429.44 
                 100 
               
               
                   
               
               
                 357 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 495.14 
                 100 
               
               
                   
               
               
                 358 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 521.19 
                 100 
               
               
                   
               
               
                 359 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395.36 
                 100 
               
               
                   
               
               
                 360 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 401.4 
                 100 
               
               
                   
               
               
                 361 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 401.26 
                 100 
               
               
                   
               
               
                 362 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 401.26 
                 88 
               
               
                   
               
               
                 363 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 387.3 
                 93 
               
               
                   
               
               
                 364 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 401.26 
                 86 
               
               
                   
               
               
                 365 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 449.24 
                 97 
               
               
                   
               
               
                 366 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 421.24 
                 98 
               
               
                   
               
               
                 367 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 415.3 
                 97 
               
               
                   
               
               
                 368 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 415.3 
                 96 
               
               
                   
               
               
                 369 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 401.27 
                 97 
               
               
                   
               
               
                 370 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 449.28 
                 97 
               
               
                   
               
               
                 371 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 415.3 
                 86 
               
               
                   
               
               
                 372 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 475.09 
                 100 
               
               
                   
               
               
                 373 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 447.09 
                 97 
               
               
                   
               
               
                 374 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 461.06 
                 100 
               
               
                   
               
               
                 375 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 475.09 
                 100 
               
               
                   
               
               
                 376 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 475.09 
                 100 
               
               
                   
               
               
                 377 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 461.06 
                 100 
               
               
                   
               
               
                 378 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 475.09 
                 98 
               
               
                   
               
               
                 379 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 477.1 
                 95 
               
               
                   
               
               
                 380 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 495.07 
                 100 
               
               
                   
               
               
                 381 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 501.08 
                 100 
               
               
                   
               
               
                 382 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 495.06 
                 93 
               
               
                   
               
               
                 383 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 461.06 
                 100 
               
               
                   
               
               
                 384 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 461.06 
                 100 
               
               
                   
               
               
                 385 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 489.08 
                 100 
               
               
                   
               
               
                 386 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 489.08 
                 91 
               
               
                   
               
               
                 387 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 475.09 
                 93 
               
               
                   
               
               
                 388 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 523.07 
                 97 
               
               
                   
               
               
                 389 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 483.04 
                 100 
               
               
                   
               
               
                 390 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 489.13 
                 100 
               
               
                   
               
               
                 391 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 441.22 
                 81 
               
               
                   
               
               
                 392 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 427.19 
                 100 
               
               
                   
               
               
                 393 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 441.22 
                 93 
               
               
                   
               
               
                 394 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 441.222 
                 100 
               
               
                   
               
               
                 395 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 441.22 
                 100 
               
               
                   
               
               
                 396 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 441.22 
                 100 
               
               
                   
               
               
                 397 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 467.21 
                 100 
               
               
                   
               
               
                 398 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 455.25 
                 100 
               
               
                   
               
               
                 399 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 455.25 
                 94 
               
               
                   
               
               
                 400 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 441.29 
                 94 
               
               
                   
               
               
                 401 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 489.26 
                 100 
               
               
                   
               
               
                 402 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 455.32 
                 100 
               
               
                   
               
               
                 403 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 441.22 
                 100 
               
               
                   
               
               
                 404 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 427.36 
                 95 
               
               
                   
               
               
                 405 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 441.22 
                 97 
               
               
                   
               
               
                 406 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 441.22 
                 98 
               
               
                   
               
               
                 407 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 427.38 
                 100 
               
               
                   
               
               
                 408 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 441.22 
                 100 
               
               
                   
               
               
                 409 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 441.22 
                 98 
               
               
                   
               
               
                 410 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 427.12 
                 87 
               
               
                   
               
               
                 411 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 475.14 
                 100 
               
               
                   
               
               
                 412 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 441.15 
                 100 
               
               
                   
               
               
                 413 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 421.24 
                 100 
               
               
                   
               
               
                 414 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 393.24 
                 89 
               
               
                   
               
               
                 415 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 421.24 
                 100 
               
               
                   
               
               
                 416 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 407.28 
                 100 
               
               
                   
               
               
                 417 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 421.24 
                 100 
               
               
                   
               
               
                 418 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 421.24 
                 100 
               
               
                   
               
               
                 419 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 469.25 
                 100 
               
               
                   
               
               
                 420 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 441.22 
                 97 
               
               
                   
               
               
                 421 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 447.3 
                 100 
               
               
                   
               
               
                 422 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 441.22 
                 100 
               
               
                   
               
               
                 423 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 407.28 
                 88 
               
               
                   
               
               
                 424 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 407.28 
                 100 
               
               
                   
               
               
                 425 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 435.27 
                 100 
               
               
                   
               
               
                 426 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 435.27 
                 100 
               
               
                   
               
               
                 427 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 455.25 
                 100 
               
               
                   
               
               
                 428 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 421.31 
                 90 
               
               
                   
               
               
                 429 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 469.28 
                 100 
               
               
                   
               
               
                 430 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 487.26 
                 100 
               
               
                   
               
               
                 431 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 435.27 
                 96 
               
               
                   
               
               
                 432 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 401.33 
                 100 
               
               
                   
               
               
                 433 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 387.33 
                 92 
               
               
                   
               
               
                 434 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 401.33 
                 100 
               
               
                   
               
               
                 435 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 387.35 
                 100 
               
               
                   
               
               
                 436 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 401.33 
                 100 
               
               
                   
               
               
                 437 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 401.33 
                 100 
               
               
                   
               
               
                 438 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 449.32 
                 100 
               
               
                   
               
               
                 439 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 421.31 
                 100 
               
               
                   
               
               
                 440 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 427.34 
                 100 
               
               
                   
               
               
                 441 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 421.31 
                 100 
               
               
                   
               
               
                 442 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 387.34 
                 96 
               
               
                   
               
               
                 443 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 387.33 
                 96 
               
               
                   
               
               
                 444 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 415.36 
                 92 
               
               
                   
               
               
                 445 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 415.36 
                 100 
               
               
                   
               
               
                 446 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 435.34 
                 83 
               
               
                   
               
               
                 447 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 477.23 
                 100 
               
               
                   
               
               
                 448 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 441.15 
                 93 
               
               
                   
               
               
                 449 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 427.28 
                 94 
               
               
                   
               
               
                 450 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 447.09 
                 100 
               
               
                   
               
               
                 451 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 423.31 
                 100 
               
               
                   
               
               
                 452 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 409.35 
                 100 
               
               
                   
               
               
                 453 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 423.31 
                 100 
               
               
                   
               
               
                 454 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 423.33 
                 100 
               
               
                   
               
               
                 455 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 409.35 
                 100 
               
               
                   
               
               
                 456 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 423.33 
                 100 
               
               
                   
               
               
                 457 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 423.33 
                 100 
               
               
                   
               
               
                 458 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 471.36 
                 100 
               
               
                   
               
               
                 459 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 472.33 
                 97 
               
               
                   
               
               
                 460 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 443.29 
                 100 
               
               
                   
               
               
                 461 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 449.38 
                 100 
               
               
                   
               
               
                 462 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 443.29 
                 100 
               
               
                   
               
               
                 463 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 409.35 
                 100 
               
               
                   
               
               
                 464 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 409.35 
                 95 
               
               
                   
               
               
                 465 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 437.35 
                 100 
               
               
                   
               
               
                 466 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 437.35 
                 100 
               
               
                   
               
               
                 467 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 423.32 
                 100 
               
               
                   
               
               
                 468 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 471.36 
                 100 
               
               
                   
               
               
                 469 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 431.26 
                 100 
               
               
                   
               
               
                 470 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 481.31 
                 94 
               
               
                   
               
               
                 471 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 461.3 
                 96 
               
               
                   
               
               
                 472 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 441.36 
                 95 
               
               
                   
               
               
                 473 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 497.24 
                 97 
               
               
                   
               
               
                 474 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 481.2 
                 96 
               
               
                   
               
               
                 475 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 481.21 
                 94 
               
               
                   
               
               
                 476 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 427.06 
                 92 
               
               
                   
               
               
                 477 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 441.08 
                 97 
               
               
                   
               
               
                 478 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 441.08 
                 97 
               
               
                   
               
               
                 479 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 441.08 
                 95 
               
               
                   
               
               
                 480 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 441.09 
                 91 
               
               
                   
               
               
                 481 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 441.07 
                 95 
               
               
                   
               
               
                 482 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 441.07 
                 95 
               
               
                   
               
               
                 483 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 413.04 
                 100 
               
               
                   
               
               
                 484 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 427.03 
                 97 
               
               
                   
               
               
                 485 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 258.17 
                 84 
               
               
                   
               
               
                 486 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 441.06 
                 96 
               
               
                   
               
               
                 487 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 427.03 
                 100 
               
               
                   
               
               
                 488 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 441.05 
                 96 
               
               
                   
               
               
                 489 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 441.06 
                 95 
               
               
                   
               
               
                 490 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 489.08 
                 94 
               
               
                   
               
               
                 491 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 427.01 
                 100 
               
               
                   
               
               
                 492 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 481.04 
                 95 
               
               
                   
               
               
                 492 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 481.04 
                 95 
               
               
                   
               
               
                 493 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 490.06 
                 96 
               
               
                   
               
               
                 494 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 461.08 
                 100 
               
               
                   
               
               
                 495 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 467.11 
                 96 
               
               
                   
               
               
                 496 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 515.29 
                 88 
               
               
                   
               
               
                 497 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 427.02 
                 100 
               
               
                   
               
               
                 498 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 427.02 
                 100 
               
               
                   
               
               
                 499 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 467.12 
                 95 
               
               
                   
               
               
                 500 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 413.02 
                 100 
               
               
                   
               
               
                 501 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 455.1 
                 84 
               
               
                   
               
               
                 502 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 455.09 
                 87 
               
               
                   
               
               
                 503 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 455.09 
                 96 
               
               
                   
               
               
                 504 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 515.28 
                 100 
               
               
                   
               
               
                 505 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 481.1 
                 100 
               
               
                   
               
               
                 506 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 467.11 
                 93 
               
               
                   
               
               
                 507 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 467.11 
                 96 
               
               
                   
               
               
                 508 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 479.09 
                 100 
               
               
                   
               
               
                 509 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 427 
                 100 
               
               
                   
               
               
                 510 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 427 
                 95 
               
               
                   
               
               
                 511 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 427 
                 98 
               
               
                   
               
               
                 512 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 437.1 
                 91 
               
               
                   
               
               
                 513 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 393.21 
                 91 
               
               
                   
               
               
                 514 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 427.15 
                 100 
               
               
                   
               
               
                 515 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 373.24 
                 87 
               
               
                   
               
               
                 516 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 393.21 
                 100 
               
               
                   
               
               
                 517 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 437.1 
                 100 
               
               
                   
               
               
                 518 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 437.17 
                 100 
               
               
                   
               
               
                 519 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 387.3 
                 100 
               
               
                   
               
               
                 520 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 387.31 
                 100 
               
               
                   
               
               
                 521 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 387.34 
                 100 
               
               
                   
               
               
                 522 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 387.33 
                 100 
               
               
                   
               
               
                 523 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 461.15 
                 100 
               
               
                   
               
               
                 524 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 409.3 
                 100 
               
               
                   
               
               
                 525 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 377.3 
                 100 
               
               
                   
               
               
                 526 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 427.22 
                 100 
               
               
                   
               
               
                 527 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 427.22 
                 100 
               
               
                   
               
               
                 528 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 407.24 
                 100 
               
               
                   
               
               
                 529 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 427.22 
                 100 
               
               
                   
               
               
                 530 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 429.36 
                 100 
               
               
                   
               
               
                 531 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 495.1 
                 100 
               
               
                   
               
               
                 532 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 521.16 
                 100 
               
               
                   
               
               
                 533 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395.29 
                 96 
               
               
                   
               
               
                 534 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 401.35 
                 100 
               
               
                   
               
            
           
         
       
     
     Examples 535 to 742 
     Examples 535 to 742 in Table 4 were prepared according to the procedures described in Examples 1 and 17 or other similar methods used by one skilled in the art, utilizing other appropriate reagents. 
     
       
         
           
               
               
               
               
             
               
                 TABLE 4 
               
               
                   
               
               
                   
                   
                   
                 HPLC  
               
               
                   
                   
                 Mass 
                 Purity 
               
               
                 Example 
                 Structure 
                 [M + H] +   
                 (%) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                 535 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 336.48 
                 100 
               
               
                   
               
               
                 536 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 329.47 
                 98 
               
               
                   
               
               
                 537 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379.38 
                 100 
               
               
                   
               
               
                 538 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 413.34 
                 96 
               
               
                   
               
               
                 539 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379.38 
                 99 
               
               
                   
               
               
                 540 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 387.52 
                 100 
               
               
                   
               
               
                 541 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379.46 
                 100 
               
               
                   
               
               
                 542 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 325.51 
                 98 
               
               
                   
               
               
                 543 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 339.52 
                 100 
               
               
                   
               
               
                 544 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 339.53 
                 98 
               
               
                   
               
               
                 545 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 339.52 
                 100 
               
               
                   
               
               
                 546 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 329.47 
                 100 
               
               
                   
               
               
                 547 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 345.44 
                 99 
               
               
                   
               
               
                 548 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379.42 
                 100 
               
               
                   
               
               
                 549 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 329.47 
                 98 
               
               
                   
               
               
                 550 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 345.46 
                 99 
               
               
                   
               
               
                 551 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 359.47 
                 100 
               
               
                   
               
               
                 552 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 387.53 
                 98 
               
               
                   
               
               
                 553 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379.5 
                 100 
               
               
                   
               
               
                 554 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 353.53 
                 90 
               
               
                   
               
               
                 555 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 377.51 
                 98 
               
               
                   
               
               
                 556 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 362.51 
                 100 
               
               
                   
               
               
                 557 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 362.51 
                 100 
               
               
                   
               
               
                 558 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 359.47 
                 98 
               
               
                   
               
               
                 559 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 359.47 
                 100 
               
               
                   
               
               
                 560 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379.43 
                 100 
               
               
                   
               
               
                 561 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 393.45 
                 100 
               
               
                   
               
               
                 562 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 393.45 
                 100 
               
               
                   
               
               
                 563 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 393.45 
                 100 
               
               
                   
               
               
                 564 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 441.4 
                 100 
               
               
                   
               
               
                 565 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 407.46 
                 100 
               
               
                   
               
               
                 566 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 433.45 
                   
               
               
                   
               
               
                 567 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 373.42 
                 100 
               
               
                   
               
               
                 568 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 373.42 
                 100 
               
               
                   
               
               
                 569 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 421.37 
                 100 
               
               
                   
               
               
                 570 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 387.43 
                 100 
               
               
                   
               
               
                 571 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 375.33 
                 100 
               
               
                   
               
               
                 572 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 375.33 
                 81 
               
               
                   
               
               
                 573 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 361.29 
                 90 
               
               
                   
               
               
                 574 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 375.33 
                 100 
               
               
                   
               
               
                 575 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 375.33 
                 100 
               
               
                   
               
               
                 576 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 423.27 
                 94 
               
               
                   
               
               
                 577 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 361.29 
                 100 
               
               
                   
               
               
                 578 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 389.34 
                 93 
               
               
                   
               
               
                 579 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 415.31 
                 95 
               
               
                   
               
               
                 580 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 359.34 
                 84 
               
               
                   
               
               
                 581 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 359.25 
                 100 
               
               
                   
               
               
                 582 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 373.3 
                 100 
               
               
                   
               
               
                 583 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 359.39 
                 100 
               
               
                   
               
               
                 584 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 373.42 
                 100 
               
               
                   
               
               
                 585 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 373.42 
                 100 
               
               
                   
               
               
                 586 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 421.37 
                 100 
               
               
                   
               
               
                 587 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 359.39 
                 100 
               
               
                   
               
               
                 588 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 359.34 
                 91 
               
               
                   
               
               
                 589 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 359.39 
                 84 
               
               
                   
               
               
                 590 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 387.43 
                 100 
               
               
                   
               
               
                 591 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 387.41 
                 89 
               
               
                   
               
               
                 592 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 413.42 
                 100 
               
               
                   
               
               
                 593 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 359.39 
                 100 
               
               
                   
               
               
                 594 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379.11 
                 100 
               
               
                   
               
               
                 595 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 393.13 
                 100 
               
               
                   
               
               
                 596 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 365.11 
                 89 
               
               
                   
               
               
                 597 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 393.13 
                 100 
               
               
                   
               
               
                 598 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 393.13 
                 96 
               
               
                   
               
               
                 599 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379.11 
                 100 
               
               
                   
               
               
                 600 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 393.13 
                 100 
               
               
                   
               
               
                 601 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 393.13 
                 100 
               
               
                   
               
               
                 602 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379.11 
                 100 
               
               
                   
               
               
                 603 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 433.16 
                 100 
               
               
                   
               
               
                 604 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379.13 
                 100 
               
               
                   
               
               
                 605 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 413.08 
                 100 
               
               
                   
               
               
                 606 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 399.07 
                 92 
               
               
                   
               
               
                 607 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 427.1 
                 99 
               
               
                   
               
               
                 608 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 427.08 
                 99 
               
               
                   
               
               
                 609 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 413.09 
                 99 
               
               
                   
               
               
                 610 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 427.09 
                 100 
               
               
                   
               
               
                 611 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 427.07 
                 100 
               
               
                   
               
               
                 612 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 413.07 
                 99 
               
               
                   
               
               
                 613 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 413.08 
                 100 
               
               
                   
               
               
                 614 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 441.11 
                 100 
               
               
                   
               
               
                 615 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 467.12 
                 100 
               
               
                   
               
               
                 616 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 413.06 
                 100 
               
               
                   
               
               
                 617 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 359.19 
                 100 
               
               
                   
               
               
                 618 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 373.2 
                 95 
               
               
                   
               
               
                 619 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 345.2 
                 100 
               
               
                   
               
               
                 620 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 373.21 
                 100 
               
               
                   
               
               
                 621 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 373.2 
                 100 
               
               
                   
               
               
                 622 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 359.19 
                 100 
               
               
                   
               
               
                 623 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 373.19 
                 100 
               
               
                   
               
               
                 624 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 373.2 
                 100 
               
               
                   
               
               
                 625 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 421.2 
                 100 
               
               
                   
               
               
                 626 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 359.19 
                 100 
               
               
                   
               
               
                 627 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 359.19 
                 100 
               
               
                   
               
               
                 628 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 387.2 
                 100 
               
               
                   
               
               
                 629 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 413.25 
                 100 
               
               
                   
               
               
                 630 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 359.19 
                 100 
               
               
                   
               
               
                 631 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379.11 
                 100 
               
               
                   
               
               
                 632 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 393.12 
                 100 
               
               
                   
               
               
                 633 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 365.1 
                 92 
               
               
                   
               
               
                 634 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 393.13 
                 82 
               
               
                   
               
               
                 635 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 393.12 
                 100 
               
               
                   
               
               
                 636 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379.13 
                 92 
               
               
                   
               
               
                 637 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 393.12 
                 82 
               
               
                   
               
               
                 638 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 441.12 
                 94 
               
               
                   
               
               
                 639 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 433.09 
                 100 
               
               
                   
               
               
                 640 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 419.14 
                 100 
               
               
                   
               
               
                 641 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 413.08 
                 94 
               
               
                   
               
               
                 642 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379.12 
                 92 
               
               
                   
               
               
                 643 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 325.1 
                 94 
               
               
                   
               
               
                 644 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379.11 
                 100 
               
               
                   
               
               
                 645 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 353.1 
                 88 
               
               
                   
               
               
                 646 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 381.08 
                 97 
               
               
                   
               
               
                 647 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 407.15 
                 100 
               
               
                   
               
               
                 648 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 407.14 
                 99 
               
               
                   
               
               
                 649 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 433.14 
                 100 
               
               
                   
               
               
                 650 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 423.1 
                 100 
               
               
                   
               
               
                 651 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 393.12 
                 88 
               
               
                   
               
               
                 652 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379.11 
                 91 
               
               
                   
               
               
                 653 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 339.27 
                 100 
               
               
                   
               
               
                 654 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 353.27 
                 87 
               
               
                   
               
               
                 655 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 353.27 
                 100 
               
               
                   
               
               
                 656 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 339.26 
                 94 
               
               
                   
               
               
                 657 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 393.28 
                 100 
               
               
                   
               
               
                 658 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 339.26 
                 98 
               
               
                   
               
               
                 659 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 339.25 
                 100 
               
               
                   
               
               
                 660 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 353.26 
                 98 
               
               
                   
               
               
                 661 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 353.27 
                 83 
               
               
                   
               
               
                 662 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 353.26 
                 97 
               
               
                   
               
               
                 663 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 339.26 
                 97 
               
               
                   
               
               
                 664 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 353.26 
                 95 
               
               
                   
               
               
                 665 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 353.27 
                 97 
               
               
                   
               
               
                 666 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 401.25 
                 100 
               
               
                   
               
               
                 667 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 339.25 
                 96 
               
               
                   
               
               
                 668 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 339.27 
                 97 
               
               
                   
               
               
                 669 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 367.28 
                 100 
               
               
                   
               
               
                 670 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 393.3 
                 98 
               
               
                   
               
               
                 671 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 339.25 
                 100 
               
               
                   
               
               
                 672 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379 
                 100 
               
               
                   
               
               
                 673 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 413 
                 99.1 
               
               
                   
               
               
                 674 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 413 
                 100 
               
               
                   
               
               
                 675 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379 
                 96 
               
               
                   
               
               
                 676 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379 
                 95 
               
               
                   
               
               
                 677 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 389.2 
                 100 
               
               
                   
               
               
                 678 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 467.1 
                 100 
               
               
                   
               
               
                 679 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 347.32 
                 100 
               
               
                   
               
               
                 680 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 345.32 
                 100 
               
               
                   
               
               
                 681 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379.25 
                 100 
               
               
                   
               
               
                 682 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379.25 
                 100 
               
               
                   
               
               
                 683 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 413.22 
                 100 
               
               
                   
               
               
                 684 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379.25 
                 100 
               
               
                   
               
               
                 685 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 689.1 
                 98 
               
               
                   
               
               
                 686 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379.38 
                 100 
               
               
                   
               
               
                 687 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 325.42 
                 98 
               
               
                   
               
               
                 688 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 353.42 
                 100 
               
               
                   
               
               
                 689 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 339.45 
                 100 
               
               
                   
               
               
                 690 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379.32 
                 100 
               
               
                   
               
               
                 691 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 389.28 
                 100 
               
               
                   
               
               
                 692 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 359.39 
                 100 
               
               
                   
               
               
                 693 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 437.27 
                 100 
               
               
                   
               
               
                 694 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 387.41 
                 100 
               
               
                   
               
               
                 695 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379.39 
                 100 
               
               
                   
               
               
                 696 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 353.47 
                 96 
               
               
                   
               
               
                 697 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 359.39 
                 96 
               
               
                   
               
               
                 698 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 390.33 
                 97 
               
               
                   
               
               
                 699 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 412.43 
                 100 
               
               
                   
               
               
                 700 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 363.36 
                 100 
               
               
                   
               
               
                 701 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 365.15 
                 100 
               
               
                   
               
               
                 702 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379.18 
                 93 
               
               
                   
               
               
                 703 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 393.16 
                 98 
               
               
                   
               
               
                 704 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 393.19 
                 100 
               
               
                   
               
               
                 705 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 393.19 
                 100 
               
               
                   
               
               
                 706 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 393.21 
                 99 
               
               
                   
               
               
                 707 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 421.18 
                 97 
               
               
                   
               
               
                 708 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 393.16 
                 100 
               
               
                   
               
               
                 709 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 407.18 
                 100 
               
               
                   
               
               
                 710 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 393.18 
                 100 
               
               
                   
               
               
                 711 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 377.16 
                 100 
               
               
                   
               
               
                 712 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 363.13 
                 100 
               
               
                   
               
               
                 713 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 365.15 
                 100 
               
               
                   
               
               
                 714 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379.18 
                 100 
               
               
                   
               
               
                 715 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 393.16 
                 100 
               
               
                   
               
               
                 716 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 393.17 
                 99 
               
               
                   
               
               
                 717 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 464.15 
                 93 
               
               
                   
               
               
                 718 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379.17 
                 100 
               
               
                   
               
               
                 719 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 393.18 
                 99 
               
               
                   
               
               
                 720 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 393.15 
                 100 
               
               
                   
               
               
                 721 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 441.14 
                 100 
               
               
                   
               
               
                 722 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 433.10 
                 100 
               
               
                   
               
               
                 723 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 442.11 
                 100 
               
               
                   
               
               
                 724 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 413.11 
                 99 
               
               
                   
               
               
                 725 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 419.18 
                 100 
               
               
                   
               
               
                 726 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 413.11 
                 99 
               
               
                   
               
               
                 727 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379.18 
                 100 
               
               
                   
               
               
                 728 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 471.12 
                 97 
               
               
                   
               
               
                 729 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379.16 
                 100 
               
               
                   
               
               
                 730 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 353.15 
                 100 
               
               
                   
               
               
                 731 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 419.18 
                 93 
               
               
                   
               
               
                 732 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 365.15 
                 100 
               
               
                   
               
               
                 733 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 407.18 
                 100 
               
               
                   
               
               
                 734 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 407.18 
                 100 
               
               
                   
               
               
                 735 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 407.18 
                 100 
               
               
                   
               
               
                 736 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 393.17 
                 89 
               
               
                   
               
               
                 737 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 433.15 
                 100 
               
               
                   
               
               
                 738 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 419.14 
                 97 
               
               
                   
               
               
                 739 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 419.16 
                 100 
               
               
                   
               
               
                 740 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 459.11 
                 100 
               
               
                   
               
               
                 741 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 365.15 
                 100 
               
               
                   
               
               
                 742 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379.18 
                 93 
               
               
                   
               
            
           
         
       
     
     Examples 743 to 923 
     Examples 743 to 923 in Table 5 were prepared according to the procedures described in Examples 18 and 19 or other similar methods used by one skilled in the art, utilizing other appropriate reagents. 
     
       
         
           
               
               
               
               
             
               
                 TABLE 5 
               
               
                   
               
               
                   
                   
                 Mass 
                   
               
               
                 Example 
                 Structure 
                 [M + H] 
                 HPLC Purity (%) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                 743 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 315.25 
                 100 
               
               
                   
               
               
                 744 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 311 
                 100 
               
               
                   
               
               
                 745 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 326.21 
                 95 
               
               
                   
               
               
                 746 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 331.25 
                 100 
               
               
                   
               
               
                 747 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 299.22 
                 91 
               
               
                   
               
               
                 748 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 315.18 
                 87 
               
               
                   
               
               
                 749 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 295.28 
                 88 
               
               
                   
               
               
                 750 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 311.26 
                 88 
               
               
                   
               
               
                 752 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 333.16 
                 100 
               
               
                   
               
               
                 753 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 357.24 
                 92 
               
               
                   
               
               
                 754 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 373.24 
                 96 
               
               
                   
               
               
                 755 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 295.26 
                 100 
               
               
                   
               
               
                 756 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 357.28 
                 96 
               
               
                   
               
               
                 757 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 287.2 
                 92 
               
               
                   
               
               
                 758 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 287.19 
                 88 
               
               
                   
               
               
                 759 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 349.21 
                 100 
               
               
                   
               
               
                 760 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 349.23 
                 97 
               
               
                   
               
               
                 761 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 315.18 
                 100 
               
               
                   
               
               
                 762 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 311.24 
                 100 
               
               
                   
               
               
                 763 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 309.25 
                 97 
               
               
                   
               
               
                 764 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 299.21 
                 94 
               
               
                   
               
               
                 765 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 331.23 
                 100 
               
               
                   
               
               
                 766 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 349.23 
                 100 
               
               
                   
               
               
                 767 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 299.24 
                 89 
               
               
                   
               
               
                 768 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 279.18 
                 93 
               
               
                   
               
               
                 769 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 317.2 
                 88 
               
               
                   
               
               
                 770 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 329.23 
                 100 
               
               
                   
               
               
                 771 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 317.2 
                 100 
               
               
                   
               
               
                 772 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 373.24 
                 97 
               
               
                   
               
               
                 773 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 309.29 
                 99 
               
               
                   
               
               
                 774 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 325.23 
                 95 
               
               
                   
               
               
                 775 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 337.3 
                 99 
               
               
                   
               
               
                 776 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 279.18 
                 89 
               
               
                   
               
               
                 777 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 341.21 
                 85 
               
               
                   
               
               
                 778 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 323.27 
                 81 
               
               
                   
               
               
                 779 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 383.1 
                 89 
               
               
                   
               
               
                 780 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 323.27 
                 89 
               
               
                   
               
               
                 781 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 310.28 
                 92 
               
               
                   
               
               
                 782 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 324.26 
                 100 
               
               
                   
               
               
                 783 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 349.13 
                 100 
               
               
                   
               
               
                 784 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 365.2 
                 100 
               
               
                   
               
               
                 785 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 349.1 
                 100 
               
               
                   
               
               
                 786 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 355.21 
                 86 
               
               
                   
               
               
                 787 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 317.26 
                 100 
               
               
                   
               
               
                 788 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 345.22 
                 98 
               
               
                   
               
               
                 789 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 306.28 
                 100 
               
               
                   
               
               
                 790 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 306.29 
                 100 
               
               
                   
               
               
                 791 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 317.26 
                 96 
               
               
                   
               
               
                 792 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 320.3 
                 91 
               
               
                   
               
               
                 793 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 301.24 
                 84 
               
               
                   
               
               
                 794 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 365.21 
                 100 
               
               
                   
               
               
                 795 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 417.2 
                 92 
               
               
                   
               
               
                 796 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 306.27 
                 90 
               
               
                   
               
               
                 797 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 317.26 
                 97 
               
               
                   
               
               
                 798 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 317.26 
                 100 
               
               
                   
               
               
                 799 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 349.15 
                 85 
               
               
                   
               
               
                 800 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 309.31 
                 87 
               
               
                   
               
               
                 801 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 312.26 
                 100 
               
               
                   
               
               
                 802 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 313.28 
                 100 
               
               
                   
               
               
                 803 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 309.3 
                 100 
               
               
                   
               
               
                 804 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 329.26 
                 83 
               
               
                   
               
               
                 805 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 325.28 
                 100 
               
               
                   
               
               
                 806 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 329.26 
                 82 
               
               
                   
               
               
                 807 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 332.27 
                 100 
               
               
                   
               
               
                 808 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 323.27 
                 89 
               
               
                   
               
               
                 809 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 329.23 
                 86 
               
               
                   
               
               
                 810 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 329.23 
                 82 
               
               
                   
               
               
                 811 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 313.27 
                 100 
               
               
                   
               
               
                 812 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 325.26 
                 83 
               
               
                   
               
               
                 813 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 332.26 
                 100 
               
               
                   
               
               
                 814 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 313.29 
                 100 
               
               
                   
               
               
                 815 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 301.22 
                 100 
               
               
                   
               
               
                 816 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 315.22 
                 100 
               
               
                   
               
               
                 817 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 329.26 
                 100 
               
               
                   
               
               
                 818 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 329.23 
                 100 
               
               
                   
               
               
                 819 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 329.23 
                 100 
               
               
                   
               
               
                 820 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 329.24 
                 100 
               
               
                   
               
               
                 821 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 357.23 
                 100 
               
               
                   
               
               
                 822 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 329.26 
                 80 
               
               
                   
               
               
                 823 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 343.26 
                 100 
               
               
                   
               
               
                 824 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 329.23 
                 100 
               
               
                   
               
               
                 825 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 313.23 
                 100 
               
               
                   
               
               
                 826 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 287.2 
                 100 
               
               
                   
               
               
                 827 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 299.2 
                 84 
               
               
                   
               
               
                 828 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 301.16 
                 100 
               
               
                   
               
               
                 829 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 315.23 
                 100 
               
               
                   
               
               
                 830 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 329.23 
                 100 
               
               
                   
               
               
                 831 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 329.24 
                 100 
               
               
                   
               
               
                 832 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 315.25 
                 100 
               
               
                   
               
               
                 833 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 329.21 
                 100 
               
               
                   
               
               
                 834 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 329.25 
                 100 
               
               
                   
               
               
                 835 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 377.22 
                 100 
               
               
                   
               
               
                 836 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 369.2 
                 100 
               
               
                   
               
               
                 837 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 378.23 
                 100 
               
               
                   
               
               
                 838 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 349.17 
                 100 
               
               
                   
               
               
                 839 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 355.21 
                 100 
               
               
                   
               
               
                 840 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 349.18 
                 100 
               
               
                   
               
               
                 841 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 315.25 
                 100 
               
               
                   
               
               
                 842 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 407.22 
                 100 
               
               
                   
               
               
                 843 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 289.22 
                 88 
               
               
                   
               
               
                 844 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 355.24 
                 100 
               
               
                   
               
               
                 845 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 301.25 
                 100 
               
               
                   
               
               
                 846 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 343.23 
                 100 
               
               
                   
               
               
                 847 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 343.26 
                 100 
               
               
                   
               
               
                 848 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 344.21 
                 100 
               
               
                   
               
               
                 849 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 343.24 
                 100 
               
               
                   
               
               
                 850 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 329.25 
                 100 
               
               
                   
               
               
                 851 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 369.26 
                 100 
               
               
                   
               
               
                 852 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 355.24 
                 100 
               
               
                   
               
               
                 853 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 355.24 
                 100 
               
               
                   
               
               
                 854 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 377.22 
                 100 
               
               
                   
               
               
                 855 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 335.19 
                 100 
               
               
                   
               
               
                 856 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 358.19 
                 100 
               
               
                   
               
               
                 857 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395.2 
                 100 
               
               
                   
               
               
                 858 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 281 
                 99.0 
               
               
                   
               
               
                 859 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 281 
                 100 
               
               
                   
               
               
                 860 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 281 
                 100 
               
               
                   
               
               
                 861 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 383.14 
                 100 
               
               
                   
               
               
                 862 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 343.21 
                 94 
               
               
                   
               
               
                 863 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 325.32 
                 93 
               
               
                   
               
               
                 864 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 281.3 
                 92 
               
               
                   
               
               
                 865 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 312.3 
                 92 
               
               
                   
               
               
                 866 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 351.28 
                 100 
               
               
                   
               
               
                 867 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 363.29 
                 100 
               
               
                   
               
               
                 868 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 363.36 
                 91 
               
               
                   
               
               
                 869 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 401.3 
                 94 
               
               
                   
               
               
                 870 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 367.3 
                 95 
               
               
                   
               
               
                 871 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 351.33 
                 100 
               
               
                   
               
               
                 872 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 377.32 
                 90 
               
               
                   
               
               
                 873 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 334.34 
                 97 
               
               
                   
               
               
                 874 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 384.37 
                 94 
               
               
                   
               
               
                 875 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 369.37 
                 83 
               
               
                   
               
               
                 876 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 384.37 
                 100 
               
               
                   
               
               
                 877 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 384.37 
                 88 
               
               
                   
               
               
                 878 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 384.37 
                 92 
               
               
                   
               
               
                 879 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 321.41 
                 94 
               
               
                   
               
               
                 880 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 366.39 
                 97 
               
               
                   
               
               
                 881 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 389.27 
                 91 
               
               
                   
               
               
                 882 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 371.38 
                 100 
               
               
                   
               
               
                 883 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 355.35 
                 89 
               
               
                   
               
               
                 884 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 335.44 
                 100 
               
               
                   
               
               
                 885 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 397.43 
                 100 
               
               
                   
               
               
                 886 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 397.43 
                 85 
               
               
                   
               
               
                 887 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 389.34 
                 91 
               
               
                   
               
               
                 888 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 351.4 
                 90 
               
               
                   
               
               
                 889 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 339.24 
                 88 
               
               
                   
               
               
                 890 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 357.23 
                 83 
               
               
                   
               
               
                 891 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 365.22 
                 88 
               
               
                   
               
               
                 892 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 385.29 
                 96 
               
               
                   
               
               
                 893 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 349.28 
                 87 
               
               
                   
               
               
                 894 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 369.08 
                 100 
               
               
                   
               
               
                 895 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 363.31 
                 82 
               
               
                   
               
               
                 896 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 372.3 
                 95 
               
               
                   
               
               
                 897 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 372.3 
                 83 
               
               
                   
               
               
                 898 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 335.32 
                 97 
               
               
                   
               
               
                 899 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 380.32 
                 94 
               
               
                   
               
               
                 900 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 353.3 
                 100 
               
               
                   
               
               
                 901 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 369.26 
                 100 
               
               
                   
               
               
                 902 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 411.39 
                 100 
               
               
                   
               
               
                 903 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 349.44 
                 100 
               
               
                   
               
               
                 904 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 411.43 
                 99 
               
               
                   
               
               
                 905 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 403.37 
                 100 
               
               
                   
               
               
                 906 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 365.43 
                 100 
               
               
                   
               
               
                 907 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 403.37 
                 100 
               
               
                   
               
               
                 908 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 353.41 
                 100 
               
               
                   
               
               
                 909 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 371.37 
                 97 
               
               
                   
               
               
                 910 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379.39 
                 100 
               
               
                   
               
               
                 911 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 336.41 
                 98 
               
               
                   
               
               
                 912 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 386.44 
                 100 
               
               
                   
               
               
                 913 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 371.37 
                 100 
               
               
                   
               
               
                 914 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 374.41 
                 91 
               
               
                   
               
               
                 915 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 399.43 
                 100 
               
               
                   
               
               
                 916 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 360.39 
                 100 
               
               
                   
               
               
                 917 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 367.43 
                 98 
               
               
                   
               
               
                 918 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 363.43 
                 100 
               
               
                   
               
               
                 919 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 383.4 
                 100 
               
               
                   
               
               
                 920 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 386.44 
                 100 
               
               
                   
               
               
                 921 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 377.39 
                 100 
               
               
                   
               
               
                 922 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 383.4 
                 100 
               
               
                   
               
               
                 923 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 386.44 
                 100 
               
               
                   
               
            
           
         
       
     
     Example 924 
     2-((2,6-Dichlorophenoxy)methyl)-6-(4-methylpiperidin-1-ylsulfonyl)pyridine 
     
       
         
         
             
             
         
       
     
     To a solution of 2-fluoro-6-methylpyridine (6.4 mmol) in carbontetrachloride (30 mL) was added NBS (7.6 mmol). Upon completion of addition, the mixture was stirred at reflux and benzoylperoxide (0.7 mmol) was added. The resulting mixture was stirred for 4 h at 90° C. and then cool to RT. Once at the prescribed temperature, the solution was diluted with DCM and washed with brine, dried over MgSO 4  and concentrated to provide a residue. The residue was dissolved in acetonitrile (20 mL) and K 2 CO 3  (6.4 mmol) and 2,6-dichlorophenol (6.4 mmol) were added. The resulting mixture was stirred for 2 h at 90° C. and then cooled to RT. Once at RT, the mixture was concentrated to provide a residue. The residue was taken up with ethyl acetate washed with brine, dried over MgSO 4  and concentrated to provide crude product. The crude product was purified via silica gel to provide Compound 924A (1.4 g, 81%). LC/MS m/z 273 (M+H) 
     Example 924 
     A mixture Compound 924A (4 mmol) and Na 2 SO 3  (5.2 mmol) in a 1:3 ethanol/H 2 O solution (20 mL) was stirred for 4 days at 166° C. After this time, the mixture was cooled to RT and then concentrated to provide a residue. The residue was filtered and filtrate was purified using HPLC to give 0.12 g of a yellow solid. The yellow solid was taken up in DCM (10 mL) and DMF (0.2 mL) and then thionyl chloride (3 mmol) was added. Upon completion of addition, the resulting mixture was stirred for 2 h at 56° C. and cooled to RT. Once at RT, the mixture was concentrated to provide another residue. This residue was dissolved in DCM (10 mL) and 4-methylpiperidine (6 mmol) was added. The resulting mixture was concentrated and purified via HPLC to provide Example 924 as a white lyophillate (12 mg, 6%).  1 H NMR (500 MHz, CD 3 OD): δ 0.92 (d, 3H), 1.15-1.23 (m, 2H), 1.35-1.45 (m, 1H), 1.65 (d, 2H), 2.66 (t, 2H), 3.80 (d, 2H), 5.22 (s, 2H), 7.15 (d, 1H), 7.42 (d, 2H), 7.91 (d, 1 h), 8.00 (d, 1H), 8.13 (t, 1H). LC/MS m/z 416 (M+H). 
     Example 925 
     Methyl 6-(4-methylpiperidin-1-ylsulfonyl)picolinate 
     
       
         
         
             
             
         
       
     
     To a mixture of 6-sulfopicolinic acid (2.4 mmol) in methanol (20 mL) was added 4 N HCl in dioxane (5 mL). The resulting mixture was stirred for 1 h to effect dissolution. After this time, the mixture was stirred for 18 h at RT and then concentrated to provide a residue. The residue was dissolved in DCM (15 mL) and DMF (0.5 mL) and then SOCl 2  (24 mmol) was added. The resulting mixture was stirred for 2 h at 56° C. and then cooled to RT. Once at RT, the mixture was concentrated to provide another residue. This residue was dissolved in DCM (10 mL) and then 4-methylpiperidine (36 mmol) was added. Upon completion of addition, the resulting mixture was washed with brine, dried over MgSO 4  and concentrated to provide crude product. The crude product was purified via silica gel to provide Example 925 as a pale yellow solid (0.22 g, 30%).  1 H NMR (400 MHz, CD 3 OD): δ 0.96 (d, 3H), 1.20-1.35 (m, 2H), 1.40-1.51 (m, 1H), 1.73 (d, 2H), 2.87 (t, 2H), 3.93 (d, 2H), 4.01 (s, 3H), 8.15 (d, 1H), 8.23 (t, 1H), 8.31 (d, 1H). LC/MS m/z 299 (M+H) 
     Example 926 
     2-((2,6-Dichlorophenylthio)methyl)-6-(4-methylpiperidin-1-ylsulfonyl)pyridine 
     
       
         
         
             
             
         
       
     
     To a solution of Example 925 (0.67 mmol) in THF (5 mL) was added LAH in THF (0.8 mmol) at RT. The resulting solution was stirred for 2 h at RT and then ethyl acetate (5 mL) was added. Upon completion of addition, the solution was concentrated to yield a residue. The residue was taken up in ethyl aceate, washed with 1 N HCl, dried over MgSO 4  and concentrated to provide another residue. This residue was taken up in DCM (10 mL) and then methanesulfonyl chloride (0.67 mmol) and triethylamine (0.67 mmol) were added. The resulting solution was stirred for 2 h at RT and then diluted with DCM (10 mL). Upon completion of dilution, the solution was washed with sat NaHCO 3 , dried over MgSO 4  and concentrated to yield a yellow mesylate residue that was used in the next reaction without further characterization. 
     Example 926 
     To a solution of the mesylate from 926A (0.29 mmol) in acetonitrile (10 mL) was added 2,6 dichlorothiophenol (0.37 mmol) and K 2 CO 3  (0.37 mmol). The resulting mixture was stirred for 2 h at 90° C., cooled to RT and then filtered. The filtrate was concentrated and purified via HPLC to provide Example 926 as a pale yellow lyophillate (38 mg. 13%).  1 H NMR (400 MHz, CD 3 OD): δ 0.94 (d, 3H), 1.11-1.25 (m, 2H), 1.40-1.42 (m, 1H), 1.65 (d, 2H), 2.52 (t, 2H), 3.69 (d, 2H), 4.26 (s, 2H), 7.25-7.41 (m, 3H), 7.48 (d, 1H), 7.72 (d, 1H), 7.86 (t, 1H). LC/MS m/z 432 (M+H). 
     Example 927 
     2-((2,6-Dichlorophenylsulfonyl)methyl)-6-(4-methylpiperidin-1-ylsulfonyl)pyridine 
     
       
         
         
             
             
         
       
     
     To a mixture of Example 926 (0.046 mmol) in THF (4 mL), methanol (4 mL) and 1 N NaOH (1 mL) was added p-toluenesulfonylimidazole (0.092 mmol) followed by H 2 O 2  (0.19 mmol). The resulting mixture was stirred for 2 h at RT and then filtered. The filtrate was concentrated and purified via HPLC to provide Example 927 as a white lyophillate (7 mg, 33%).  1 H NMR (400 MHz, CD 3 OD): δ 0.93 (d, 3H), 1.08-1.20 (m, 2H), 1.30-1.41 (m, 1H), 1.62 (d, 2H), 2.49 (t, 2H), 3.58 (d, 2H), 5.05 (s, 2H), 7.54 (m, 3H), 7.47 (d, 1H), 8.03 (t, 1H). LC/MS m/z 464 (M+H). 
     Example 928 
     3-(2-chlorophenyl)-5-(4-methylpiperidin-1-ylsulfonyl)pyridine 
     
       
         
         
             
             
         
       
     
     To a solution of 5-bromopyridin-3-ylboronic acid (1.2 mmol) in dioxane (20 mL) was added 2-iodo-chlorobenzene (1.8 mmol), Na 2 CO 3  (1.8 mmol) and Pd(PPh 3 ) 4  (0.09 mmol). The resulting mixture was stirred for 13 h at 90° C., cooled to RT and then concentrated to yield a residue. The residue was taken up with ethyl acetate, washed with brine, dried over MgSO 4  and concentrated to yield a crude material. The crude material was purified via silica gel to provide Compound 928A (45 mg, 14%). LC/MS m/z 269 (M+H). 
     Example 928 
     To a solution of Compound 928A (0.17 mmol0 in THF (2 mL) was added BuLi in hexane (0.21 mmol) at −78° C. Upon completion of addition, the solution was stirred for 1 h at −78° C. and then transferred into a solution of THF saturated with SO 2  (5 mL). The resulting solution was stirred for 20 min at −78° C. and then warmed to RT, where it stirred for 1 h. After this time, the reaction mixture was cooled to 0° C. and sulfuryl chloride (0.78 mmol) was added. The resulting solution was stirred for 30 min and then concentrated to yield a residue. The residue was dissolved in DCM (10 mL) and then 4-methylpiperidine (1.35 mmol) was added. Upon completion of addition, the mixture was stirred for 30 min and then concentrated to yield a residue. The residue was purified via HPLC to provide Example 928 as an off-white lyophillate (5 mg, 8%).  1 H NMR (400 MHz, CD 3 OD): δ 0.83 (d, 3H), 1.10-1.20 (m, 2H), 1.25-1.38 (m, 1H), 1.62 (d, 2H), 2.34 (t, 2H), 3.71 (d, 2H), 7.39 (m, 3H), 7.49 (m, 1H), 8.13 (s, 1H), 8.76 (s, 1H), 8.84 (s, 1H). LC/MS m/z 351 (M+H). 
     Example 929 
     3-(4-methylpiperidin-1-ylsulfonyl)-5-phenylpyridine 
     
       
         
         
             
             
         
       
     
     Example 929 was prepared according to the procedures described in Example 928 or other similar methods used by one skilled in the art, utilizing other appropriate reagents.  1 H NMR (400 MHz, CD 3 OD): δ 0.92 (d, 3H), 1.20-1.29 (m, 2H), 1.32-1.38 (m, 1H), 1.73 (d, 2H), 2.39 (t, 2H), 3.82 (d, 2H), 7.47-7.58 (m, 3H), 7.72 (d, 2H), 8.31 (s, 1H), 8.87 (s, 1H), 9.08 (s, 1H). LC/MS m/z 317 (M+H). 
     Example 930 
     4-(2-chlorophenyl)-2-(4-methylpiperidin-1-ylsulfonyl)pyridine 
     
       
         
         
             
             
         
       
     
     To a solution of 4-bromopyridine (1.7 mmol) and 2-chlorophenylboronic acid (2.1 mmol) in EtOH (20 mL) was added PXPd 2  (0.01 mmol) and K 2 CO 3  (6.3 mmol). The resulting mixture was stirred for 4 h at 90° C., cooled to RT and then concentrated to yield a residue. The residue was taken up in ethyl acetate, washed with 1 N NaOH, dried over MgSO 4 , and concentrated to yield a residue. This residue was purified via silica gel to provide Compound 930A as a yellow oil (0.31 g, 96%). LC/MS m/z 190 (M+H). 
     Example 930 
     To a solution of dimethylaminoethanol (1.6 mmol) in hexane (5 mL) at −5° C. was added BuLi in hexane (3.2 mmol). Upon completion of addition, the solution was stirred for 20 min at −5° C. and then a solution of Compound 930A (0.8 mmol) in hexane (5 mL) was added. The resulting solution was stirred for 1 h at −5° C. After this time, the solution was cooled to −78° C. and then added into a solution of THF saturated with SO 2  (5 mL). The resulting mixture was stirred for 20 min at −78° C. and then warmed to −5° C. Once at the prescribed temperature, sulfuryl chloride (4.2 mmol) was added. Upon completion of addition, the mixture was stirred for 30 min, warmed to RT and then concentrated to yield a residue. The residue was taken up in DCM (10 mL) and then 4-methylpiperidine (4.2 mmol) was added. The resulting mixture was stirred for 1 h. After this time, their mixture was diluted with DCM (10 mL), washed with brine, dried over MgSO 4 , and concentrated to yield a residue. The residue was purified via silica gel to yield a yellow oil. The yellow oil was further purified via HPLC to provide Example 930 as a pale yellow lyophillate (10 mg, 4%).  1 H NMR (400 MHz, CD 3 OD): δ 0.95 (d, 3H), 1.15-1.29 (m, 2H), 1.40-1.52 (m, 1H), 1.73 (d, 2H), 2.75 (t, 2H), 3.89 (d, 2H), 7.50 (m, 3H), 7.62 (m, 1H), 7.73 (d, 1H), 8.04 (s, 1H), 8.81 (d, 1H). LC/MS m/z 351 (M+H). 
     Example 931 
     2-(4-methylpiperidin-1-ylsulfonyl)-4-phenylpyridine 
     
       
         
         
             
             
         
       
     
     Example 931 was prepared according to the procedures described in Example 930 or other similar methods used by one skilled in the art, utilizing other appropriate reagents.  1 H NMR (400 MHz, CD 3 OD): δ 0.92 (d, 3H), 1.20 (dq, 2H), 1.35-1.47 (m, 1H), 1.69 (d, 2H), 2.69 (dt, 2H), 3.87 (d, 2H), 7.53-7.60 (m, 3H), 7.79 (d, 2H), 7.90 (d, 1H), 8.15 (s, 1H), 8.72 (d, 1H). LC/MS m/z 117 (M+H). 
     Example 932 
     2-(4-methylpiperidin-1-ylsulfonyl)-6-phenoxypyridine 
     
       
         
         
             
             
         
       
     
     To a solution BuLi (15.2 mmol) in THF (15 mL) at −78° C. was added a solution of 2,6-dibromopyridine (12.7 mmol) in THF (10 mL). Upon completion of addition, the solution was stirred for 40 min at −78° C. and transferred into a solution of THF saturated with SO 2  (10 mL). The resulting yellow solution was stirred for 15 min at −78° C. and then warmed to −5° C. over a 45 min period. Once at the prescribed temperature sulfuryl chloride (15.2 mmol) was added. The resulting mixture was stirred for 30 min at RT and then sat NH 4 Cl (20 mL) was added. Upon completion of addition, the mixture was concentrated to yield a residual mixture. The residual mixture was taken up in ethyl acetate. The organic layer was separated, dried over MgSO 4 , and concentrated to yield a residue. The residue was purified via silica gel to provide Compound 932A as a yellow solid (1.5 g, 50%). LC/MS m/z 257 (M+H). 
     
       
         
         
             
             
         
       
     
     To a solution of Compound 932A (0.39 mmol) in DCM (5 mL) was added 4-methylpiperidine (1 mmol). The resulting solution was stirred for 30 min and then washed with sat NaHCO 3 , dried over MgSO 4 , and concentrated to yield Compound 932B as a pale yellow oil (0.1 g, 80%). LC/MS m/z 320 (M+H). 
     Example 932 
     A mixture of Compound 932B (0.31 mmol), phenol (0.94 mmol), and K 2 CO 3  (0.94 mmol) in DMF (5 mL) was stirred for 8 h at 150° C. with microwave irradiation. At the conclusion of this period, the mixture was taken up in ethyl aceate, washed with 10% LiCl, dried over MgSO 4 , and concentrated to yield a residue. The residue was purified via HPLC to provide Example 932 as an off-white lyophillate (9 mg, 9%).  1 H NMR (400 MHz, CD 3 OD): δ 0.91 (d, 3H), 1.08 (dq, 2H), 1.22-1.40 (m, 1H), 1.53 (d, 2H), 2.43 (t, 2H), 3.54 (d, 2H), 7.18 (d, 2H), 7.25-7.31 (m, 2H), 7.41-7.50 9 m, 2H), 7.58 (d, 1H), 8.03 (t, 1H). LC/MS m/z 333 (M+H). 
     Example 933 
     4-Methoxy-2-(4-methylpiperidin-1-ylsulfonyl)-6-phenylpyridine 
     
       
         
         
             
             
         
       
     
     To a solution of dimethylaminoethanol (18.3 mmol) in hexane (20 mL) was added BuLi in hexane (36.6 mmol) at −5° C. The resulting dark red solution was stirred for 20 min and then 4-methoxypyridine (9.2 mmol) was added. Upon completion of addition, the reaction mixture was stirred for 1 h at −5° C. After this time, the dark brown solution was cooled to −78° C. and then a solution of carbontetrabromide (36.6 mmol) in THF (10 mL) was added. The resulting solution was stirred for 30 min at −78° C. and then sat NH 4 Cl was added. Upon completion of addition, the resulting mixture was warmed to RT and then extracted with ethyl acetated. The organic layer was dried over MgSO 4  and concentrated to yield a residue. The residue was purified by silica gel to yield Compound 933A as a brown oil (0.15 g, 9%). LC/MS m/z 189 (M+H). 
     
       
         
         
             
             
         
       
     
     A mixture of Compound 933A (0.5 mmol), phenylboronic acid (0.57 mmol), PXPd 2  (0.0057 mmol), and K 2 CO 3  (1.4 mmol) in EtOH (10 mL) was stirred for 2 h at 90° C. After this time, the mixture was cooled to RT and then concentrated to yield a residue. The residue was taken up in ethyl acetate, washed with brine, dried over MgSO 4  and concentrated to yield a residue. The residue was purified by silica gel to give Compound 933B as a pale yellow oil (25 mg, 27%). LC/MS m/z 186 (M+H). 
     Example 933 
     To a solution of dimethylaminoethanol (0.27 mmol) in hexane (5 mL) was added BuLi in hexane (0.54 mmol). The resulting solution was stirred for 20 min at −5° C. and then a solution of Compound 933B (0.14 mmol) in hexane (5 mL) was added. The resulting mixture was for stirred for 1 h at −5° C. At the conclusion of this period, the mixture was cooled to −78° C. and then transferred into a solution of THF saturated with SO 2  (5 mL). The resulting mixture was stirred for 10 min at −78° C. and then warmed to −5° C. Once at the prescribed temperature, sulfuryl chloride (0.54 mmol) was added, and the resulting mixture was stirred for 30 min at −5° C. and then concentrated to yield a residue. The residue was dissolved in DCM (5 mL) and then 4-methylpiperidine (1.1 mmol) of was added. The resulting solution was stirred for 10 min at RT and then concentrated to yield a residue. This residue was purified by HPLC to provide Example 933 as an off-white lyophillate (5 mg, 10%).  1 H NMR (400 MHz, CD 3 OD): δ 0.81 (d, 3H), 1.12 (dq, 2H), 1.30-1.40 (m, 1H), 1.60 (d, 2H), 2.70 (t, 2H), 3.81 (d, 2H), 3.92 (s, 3H), 7.30 (d, 1H), 7.32-7.42 (m, 5H), 7.50 (d, 1H), 7.99 (t, 1H). LC/MS m/z 347 (M+H). 
     Example 934 
     2-(2-(1H-tetrazol-5-yl)piperidin-1-ylsulfonyl)-6-phenylpyridine 
     
       
         
         
             
             
         
       
     
     A mixture 2-(1H-tetrazol-5-yl)pyridine (0.68 mmol) and Pt 2 O (0.068 mmol) in 37% HCl (5 mL) and EtOH (30 mL) was hydrogenated at 60 psi for 5 h. At the conclusion of this period, the mixture was filtered and concentrated to yield a residue. The residue was taken up in DMF (5 mL) and DCM (5 mL) and then Et 3 N (1.36 mmol) followed by a mixture of Compound 932A (0.39 mmol) in DCM (5 mL) was added. The resulting mixture was stirred for 2 h and then concentrated to yield a residue. The residue was purified by HPLC to give Compound 934A as a yellow oil (49 mg, 19%). LC/MS m/z 374 (M+H). 
     Example 934 
     A mixture of Compound 934A (0.13 mmol), phenylboronic acid (0.16 mmol), PXPd 2  (0.0032 mmol) and K 2 CO 3  (0.40 mmol) in EtOH (10 mL) was stirred for 2 h at 90° C. At the conclusion of this period, the reaction mixture was cooled to RT, filtered and then concentrated to yield a residue. The residue was purified by HPLC to provide Example 934 as a pale yellow lyophillate (13 mg, 27%).  1 H NMR (400 MHz, CD 3 OD): δ 1.30-1.67 (m, 4H), 1.80-1.97 (m, 1H), 2.05 (d, 1H), 3.30 (t, 1H), 3.98 (d, 1H), 5.64 (m, 1H), 7.42 (m, 3H), 7.75 (m, 1H), 7.89-8.05 (m, 4H). LC/MS m/z 371 (M+H). 
     Examples 935 and 936 
     (R)-2-(2-(1H-tetrazol-5-yl)piperidin-1-ylsulfonyl)-6-phenylpyridine 
     (S)-2-(2-(1H-tetrazol-5-yl)piperidin-1-ylsulfonyl)-6-phenylpyridine 
     
       
         
         
             
             
         
       
     
     Example 934 (31 mg) was resolved using a Chiralcel AD column (eluting with Hepane: ethanol, 9:1, with 0.1% TFA additive) to provide Example 935 (13.6 mg) and Example 936 (12.4 mg). 
     Examples 937 to 955 
     Examples 937 to 955 in Table 6 were prepared according to the procedures described in Example 934 or other similar methods used by one skilled in the art, utilizing other appropriate reagents. 
     
       
         
           
               
               
               
               
             
               
                 TABLE 6 
               
               
                   
               
               
                 Example 
                 Structure 
                 MS [M + H] 
                 Purity 
               
               
                   
               
             
            
               
                 937 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 383 
                 91 
               
               
                   
               
               
                 938 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 371 
                 98 
               
               
                   
               
               
                 939 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 371 
                 98 
               
               
                   
               
               
                 940 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 369 
                 93 
               
               
                   
               
               
                 941 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 369 
                 95 
               
               
                   
               
               
                 942 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 369 
                 95 
               
               
                   
               
               
                 943 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 370 
                 98 
               
               
                   
               
               
                 944 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 397 
                 97 
               
               
                   
               
               
                 945 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 370 
                 93 
               
               
                   
               
               
                 946 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 414 
                 96 
               
               
                   
               
               
                 947 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395 
                 90 
               
               
                   
               
               
                 948 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 386 
                 90 
               
               
                   
               
               
                 949 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 385 
                 90 
               
               
                   
               
               
                 950 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 399 
                 92 
               
               
                   
               
               
                 951 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 357 
                 90 
               
               
                   
               
               
                 952 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 388 
                 90 
               
               
                   
               
               
                 953 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 314 
                 92 
               
               
                   
               
               
                 954 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 361 
                 95 
               
               
                   
               
               
                 955 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 357 
                 98 
               
               
                   
               
            
           
         
       
     
     Example 956 
     2-(2-Chlorophenyl)-6-(4-methylpiperidin-1-ylsulfonyl)pyridine 
     
       
         
         
             
             
         
       
     
     To an oven dried 250 mL three-neck flask equipped with a magnetic stirrer was added anhydrous THF (100 mL) under Ar. The solution was cooled to −78° C. and n-BuLi (16.2 mL, 2.5 N in hexanes, 40.5 mmol) was added. Upon completion of addition, a solution of 2,6-dibromopyridine (8.0 g, 33.8 mmol) dissolved in dry THF (20 mL) was added dropwise via addition funnel over a period of 15 min. At the conclusion of this period, the mixture was allowed to stir for 0.75 h during which time the clear, homogenous solution turned dark green. To a separate 500 mL oven dried round bottom flask was added anhydrous THF (100 mL). The solution was saturated with SO 2  gas and then cooled to −78° C. The lithium salt generated previously was then slowly cannulated into the saturated SO 2  solution and the resulting mixture was stirred at −78° C. for 0.5 h. After this time, the reaction mixture was slowly warmed to RT, during which time a light brown precipitate formed. The solvent was concentrated under vacuum to yield a residue. The residue was suspended in dry THF (100 mL) and the resulting suspension was cooled to 0° C. Once at the prescribed temperature, a solution of SO 2 Cl 2  (3.3 mL, 40.5 mmol) was slowly added and the suspension became homogenous. The resulting mixture was warmed to R.T., and then the solvent was removed under vacuum to yield a residue. The residue was dissolved in DCM (100 mL) and triethylamine (18.8 mL, 135.2 mmol) was added. A solution of 4-methylpiperidine (4.0 g, 40.5 mmol) was added dropwise under Ar and the resulting solution was stirred for 2.5 h. At the conclusion of this period, the solution was washed with citric acid (75 mL, 10% w/v aq.), brine (75 mL) and dried over Na 2 SO 4 . The solvent was concentrated and the resulting residue was purified by silica gel (15% EtOAc:Hexanes) to yield Compound 956A (4.24 g, 13.3 mmol, 39%) as a white solid.  1 H NMR (400 MHz, CDCl 3 ): δ 7.88 (d, 1H), 7.73 (t, 1H), 7.63 (d, 1H), 3.93-3.87 (m, 2H), 2.84-2.75 (m, 2H), 1.71-1.65 (m, 2H), 1.50-1.43 (m, 1H), 1.35-1.23 (m, 2H), 0.98 (d, 3H). LC/MS m/z 320 [M+H]. 
     Example 956 
     To a 25 mL round bottom flask was added Compound 956A (120 mg, 0.376 mmol), MeOH (5 mL), K 2 CO 3  (182 mg, 1.32 mmol) and PXPd 2  (8.1 mg, 0.0113 mmol). To the resulting mixture was added 2-chlorophenylboronic acid (82 mg, 0.527 mmol). Upon completion of addition, the solution was heated at 55° C. for 3 h and then cooled to RT. Once at R.T., water (40 mL) was added and the aqueous layer extracted with EtOAc (25 mL). The organic phase was washed with brine, dried over MgSO 4  and the solvent concentrated under vacuum to yield a residue. The residue was purified by silica get to yield Example 956 (100 mg, 0.285 mmol, 76%) as a white solid.  1 H NMR (400 MHz, CDCl 3 ): δ 7.99-7.90 (m, 2H), 7.86-7.79 (m, 1H), 7.63-7.56 (m, 1H), 7.51-7.43 (m, 1H), 7.41-7.35 (m, 2H), 3.97-3.88 (m, 2H), 2.91-2.77 (m, 2H), 1.72-1.64 (m, 2H), 1.49-1.37 (m, 1H), 1.36-1.22 (m, 2H), 0.93 (d, 3H). LC/MS m/z 351 [M+H]. 
     Examples 957 to 978 
     Examples 957 to 978 in Table 7 were prepared according to the procedures described in Example 956 or other similar methods used by one skilled in the art, utilizing other appropriate reagents. 
     
       
         
           
               
               
               
               
             
               
                 TABLE 7 
               
               
                   
               
               
                 Example 
                 Structure 
                 MS [M + H] 
                 Purity 
               
               
                   
               
             
            
               
                 957 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 331 
                 98 
               
               
                   
               
               
                 958 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 352 
                 94 
               
               
                   
               
               
                 959 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 367 
                 99 
               
               
                   
               
               
                 960 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 352 
                 97 
               
               
                   
               
               
                 961 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 342 
                 97 
               
               
                   
               
               
                 962 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 401 
                 99 
               
               
                   
               
               
                 963 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 352 
                 97 
               
               
                   
               
               
                 964 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 370 
                 98 
               
               
                   
               
               
                 965 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 394 
                 98 
               
               
                   
               
               
                 966 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 361 
                 98 
               
               
                   
               
               
                 967 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 349 
                 99 
               
               
                   
               
               
                 968 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 347 
                 99 
               
               
                   
               
               
                 969 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 360 
                 99 
               
               
                   
               
               
                 970 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 335 
                 99 
               
               
                   
               
               
                 971 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 365 
                 94 
               
               
                   
               
               
                 972 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 368 
                 99 
               
               
                   
               
               
                 973 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 362 
                 99 
               
               
                   
               
               
                 974 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 333 
                 99 
               
               
                   
               
               
                 975 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 361 
                 95 
               
               
                   
               
               
                 976 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 335 
                 99 
               
               
                   
               
               
                 977 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 348 
                 98 
               
               
                   
               
               
                 978 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 318 
                 99 
               
               
                   
               
            
           
         
       
     
     Example 979 
     4-(6-(3,3-dimethylpiperidin-1-ylsulfonyl)pyridin-2-yl)benzonitrile 
     
       
         
         
             
             
         
       
     
     To an oven dried 250 mL three neck flask equipped with a magnetic stirrer was added anhydrous THF (100 mL) under Ar. The solution was cooled to −78° C. and n-BuLi (16.2 mL, 2.5 N in hexanes, 40.5 mmol) was added. A solution of 2,6-dibromopyridine (9.6 g, 40.5 mmol) dissolved in dry THF (30 mL) was added dropwise via addition funnel over a period of 15 min. The mixture was allowed to stir for 0.75 h during which time the clear, homogenous solution turned dark green. To a separate 500 mL oven dried round bottom flask was added anhydrous THF (100 mL). The solution was saturated with SO 2  gas and then cooled to −78° C. The lithium salt generated previously was then slowly cannulated into the saturated SO 2  solution, stirred at −78° C. for 0.5 h and slowly warmed to R.T. during which time a light brown precipitate formed. The solvent was concentrated under vacuum to yield a residue. The residue was suspended in dry THF (100 mL) and then cooled to 0° C. Once at the prescribed temperature, a solution of SO 2 Cl 2  (3.94 mL, 48.6 mmol) was slowly added and the suspension became homogenous. The resulting suspension was warmed to R.T., and the solvent was removed under vacuum to yield a residue. The residue was dissolved in THF (100 mL), and then pyridine was added (11.5 mL, 141.7 mmol), followed by DMAP (0.1 equiv). A solution of neopentyl alcohol (4.3 g, 48.6 mmol) was then added dropwise at 0° C. and the mixture was allowed to warm to R.T. where it stirred for 1 h. After this time, the solvent was removed under vacuum to yield a crude mixture. The crude mixture was dissolved in EtOAc (250 mL), washed with citric acid (150 mL, 10% w/v aq) and brine (150 mL) and then dried over MgSO 4 . The solvent was concentrated under vacuum to yield a residue, which was purified by silica gel (15% EtOAc:Hexanes) to yielded Compound 979A (6.13 g, 19.9 mmol, 49%) as a white solid.  1 H NMR (400 MHz, CDCl 3 ): δ 7.98 (d, 1H), 7.77 (t, 1H), 7.74 (d, 1H), 4.11 (s, 2H), 0.97 (s, 9H). LC/MS m/z 293 [M+H]. 
     
       
         
         
             
             
         
       
     
     To a 25 mL round bottom flask was added Compound 979A (2.0 g, 6.49 mmol), MeOH (80 mL), K 2 CO 3  (2.7 g, 19.5 mmol) and PXPd 2  (140 mg, 0.195 mmol). To the mixture was added 4-cyanophenylboronic acid (1.14 mg, 7.79 mmol). The resulting solution was heated at 55° C. for 3 h and then cooled to R.T. Once at R.T., water (200 mL) was added, and the aqueous layer was extracted with EtOAc (150 mL). The organic phase was washed with brine, dried over MgSO 4  and the solvent was concentrated under vacuum to yield a residue. The residue was purified by silica get to yield Compound 979B (1.65 g, 5.25 mmol, 81%) as a white solid.  1 H NMR (400 MHz, CDCl 3 ): δ 8.18 (d, 2H), 8.10-8.01 (m, 3H), 7.81 (d, 2H), 4.09 (s, 2H), 0.94 (s, 9H). LC/MS m/z 315 [M+H]. 
     
       
         
         
             
             
         
       
     
     To a 250 mL round bottom flask was added Compound 979B (1.64 g, 4.96 mmol), DMF (60 mL) followed by tetramethylammonium chloride (2.2 g, 19.9 mmol). The resulting mixture was heated at 160° C. for 1 h and then cooled to R.T. The resulting solid was filtered, washed with DMF (30 mL) and the combined filtrate was concentrated under vacuum to yield a crude solid. The crude solid was triturated with EtOAc and then dried in vacuo to yield a beige solid that was suitably clean for the next step. The beige solid was suspended in DMF (20 mL) to which was slowly added SOCl 2  (0.9 mL, 12.4 mmol). Upon completion of addition, the mixture was stirred for 1 h, during which time the mixture became mostly homogenous. At the conclusion of this period, the solution was diluted with EtOAc (150 mL), washed with water (2×75 mL) and brine (75 mL), dried over MgSO 4  and then concentrated to yield Compound 979C (1.07 g, 3.38 mmol, 77%) as a tan solid.  1 H NMR (400 MHz, DMSO-d 6 ): δ 8.30 (d, 2H), 8.06 (d, 1H), 8.01-7.93 (m, 3H), 7.78 (d, 1H). 
     Example 979 
     To a 25 mL round bottom flask was added Compound 979C (96 mg, 0.34 mg), polyvinylpyridine (145 mg, 1.38 mmol), DCM (5 mL) followed by 3,3-dimethylpiperidine (47 mg, 0.41 mmol) in a single portion. The resulting mixture was allowed to stir for 2 h. After this time, the mixture was filtered and then concentrated to yield a residue. The residue was purified by silica gel to yield Example 979 (33.3 mg, 0.094 mmol, 28%) as a white solid.  1 H NMR (400 MHz, CDCl 3 ): δ 8.16 (d, 2H), 8.01 (t, 1H), 7.97-7.93 (m, 2H), 7.81 (d, 2H), 3.35 (t, 2H), 2.97 (s, 2H), 1.72 (pentet, 2H), 1.31 (t, 2H), 0.99 (s, 6H). LC/MS m/z 356 [M+H]. 
     Examples 980 to 1055 
     Examples 980 to 1055 in Table 8 were prepared according to the procedures described in Example 979 or other similar methods used by one skilled in the art, utilizing other appropriate reagents. 
     
       
         
           
               
               
               
               
             
               
                 TABLE 8 
               
               
                   
               
               
                 Example 
                 Structure 
                 MS [M + H] 
                 Purity 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                 980 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 366 
                 98 
               
               
                   
               
               
                 981 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 366 
                 98 
               
               
                   
               
               
                 982 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 386 
                 99 
               
               
                   
               
               
                 983 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 405 
                 98 
               
               
                   
               
               
                 984 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 370 
                 96 
               
               
                   
               
               
                 985 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 396 
                 98 
               
               
                   
               
               
                 986 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 398 
                 99 
               
               
                   
               
               
                 987 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 407 
                 96 
               
               
                   
               
               
                 988 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 387 
                 97 
               
               
                   
               
               
                 989 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 369 
                 99 
               
               
                   
               
               
                 990 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 355 
                 97 
               
               
                   
               
               
                 991 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 344 
                 96 
               
               
                   
               
               
                 992 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 405 
                 97 
               
               
                   
               
               
                 993 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 421 
                 96 
               
               
                   
               
               
                 994 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 410 
                 97 
               
               
                   
               
               
                 995 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 406 
                 95 
               
               
                   
               
               
                 996 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379 
                 96 
               
               
                   
               
               
                 997 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 344 
                 99 
               
               
                   
               
               
                 998 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 330 
                 96 
               
               
                   
               
               
                 999 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 372 
                 95 
               
               
                   
               
               
                 1000 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 343 
                 98 
               
               
                   
               
               
                 1001 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 339 
                 95 
               
               
                   
               
               
                 1002 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 422 
                 96 
               
               
                   
               
               
                 1003 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 371 
                 99 
               
               
                   
               
               
                 1004 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 330 
                 98 
               
               
                   
               
               
                 1005 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 385 
                 99 
               
               
                   
               
               
                 1006 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 357 
                 99 
               
               
                   
               
               
                 1007 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 415 
                 95 
               
               
                   
               
               
                 1008 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 421 
                 96 
               
               
                   
               
               
                 1009 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 405 
                 95 
               
               
                   
               
               
                 1010 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 358 
                 99 
               
               
                   
               
               
                 1011 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 358 
                 88 
               
               
                   
               
               
                 1012 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 358 
                 99 
               
               
                   
               
               
                 1013 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 376 
                 99 
               
               
                   
               
               
                 1014 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 437 
                 99 
               
               
                   
               
               
                 1015 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 357 
                 99 
               
               
                   
               
               
                 1016 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 405 
                 99 
               
               
                   
               
               
                 1017 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 405 
                 98 
               
               
                   
               
               
                 1018 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 386 
                 97 
               
               
                   
               
               
                 1019 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 400 
                 98 
               
               
                   
               
               
                 1020 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 344 
                 99 
               
               
                   
               
               
                 1021 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 358 
                 98 
               
               
                   
               
               
                 1022 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 372 
                 93 
               
               
                   
               
               
                 1023 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 492 
                 98 
               
               
                   
               
               
                 1024 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 412 
                 97 
               
               
                   
               
               
                 1025 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 371 
                 99 
               
               
                   
               
               
                 1026 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 371 
                 95 
               
               
                   
               
               
                 1028 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 411 
                 98 
               
               
                   
               
               
                 1029 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 371 
                 99 
               
               
                   
               
               
                 1030 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 414 
                 98 
               
               
                   
               
               
                 1031 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 426 
                 99 
               
               
                   
               
               
                 1032 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 412 
                 98 
               
               
                   
               
               
                 1033 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 398 
                 99 
               
               
                   
               
               
                 1034 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 449 
                 99 
               
               
                   
               
               
                 1035 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 328 
                 97 
               
               
                   
               
               
                 1036 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 454 
                 98 
               
               
                   
               
               
                 1037 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 399 
                 98 
               
               
                   
               
               
                 1038 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 383 
                 96 
               
               
                   
               
               
                 1039 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 314 
                 94 
               
               
                   
               
               
                 1040 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 446 
                 99 
               
               
                   
               
               
                 1041 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 412 
                 97 
               
               
                   
               
               
                 1042 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 466 
                 99 
               
               
                   
               
               
                 1043 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 426 
                 97 
               
               
                   
               
               
                 1044 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 398 
                 97 
               
               
                   
               
               
                 1045 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 414 
                 98 
               
               
                   
               
               
                 1046 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 426 
                 98 
               
               
                   
               
               
                 1047 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 386 
                 99 
               
               
                   
               
               
                 1048 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 369 
                 98 
               
               
                   
               
               
                 1049 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 380 
                 99 
               
               
                   
               
               
                 1050 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 380 
                 99 
               
               
                   
               
               
                 1051 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 389 
                 99 
               
               
                   
               
               
                 1052 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 467 
                 98 
               
               
                   
               
               
                 1053 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 318 
                 98 
               
               
                   
               
               
                 1054 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 343 
                 96 
               
               
                   
               
               
                 1055 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 332 
                 98