Patent Publication Number: US-2010130471-A1

Title: Renin Inhibitors

Description:
BACKGROUND OF THE INVENTION 
     Aspartic proteases, including renin, β-secretase (BACE),  Candida albicans  secreted aspartyl proteases, HIV protease, HTLV protease and plasmepsins I and II, are implicated in a number of disease states. In hypertension elevated levels of angiotensin I, the product of renin catalyzed cleavage of angioteninogen are present. Elevated levels of βamyloid, the product of BACE activity on amyloid precursor protein, are widely believed to be responsible for the amyloid plaques present in the brains of Alzheimer&#39;s disease patients. Secreted aspartyl proteases play a role in the virulence of the pathogen  Candida albicans . The viruses HIV and HTLV depend on their respective aspartic proteases for viral maturation.  Plasmodium falciparum  uses plasmepsins I and II to degrade hemoglobin. 
     In the renin-angiotensin-aldosterone system (RAAS) the biologically active peptide angiotensin II (Ang II) is generated by a two-step mechanism. The highly specific aspartic protease renin cleaves angiotensinogen to angiotensin I (Ang I), which is then further processed to Ang II by the less specific angiotensin-converting enzyme (ACE). Ang II is known to work on at least two receptor subtypes called AT 1  and AT 2 . Whereas AT 1  seems to transmit most of the known functions of Ang II, the role of AT 2  is still unknown. 
     Modulation of the RAAS represents a major advance in the treatment of cardiovascular diseases (Zaman, M. A. et al  Nature Reviews Drug Discovery  2002, 1, 621-636). ACE inhibitors and AT 1  blockers have been accepted as treatments of hypertension (Waeber B. et al., “The renin-angiotensin system: role in experimental and human hypertension”, in Berkenhager W. H., Reid J. L. (eds):  Hypertension , Amsterdam, Elsevier Science Publishing Co, 1996, 489-519; Weber M. A.,  Am. J. Hypertens.,  1992, 5, 247S). In addition, ACE inhibitors are used for renal protection (Rosenberg M. E. et al.,  Kidney International,  1994, 45, 403; Breyer J. A. et al.,  Kidney International,  1994, 45, S156), in the prevention of congestive heart failure (Vaughan D. E. et al.,  Cardiovasc. Res.,  1994, 28, 159; Fouad-Tarazi F. et al.,  Am. J. Med.,  1988, 84 (Suppl. 3A), 83) and myocardial infarction (Pfeffer M. A. et al.,  N Engl. J: Med,  1992, 327, 669). 
     Interest in the development of renin inhibitors stems from the specificity of renin (Kleinert H. D.,  Cardiovasc. Drugs,  1995, 9, 645). The only substrate known for renin is angiotensinogen, which can only be processed (under physiological conditions) by renin. In contrast, ACE can also cleave bradykinin besides Ang I and can be bypassed by chymase, a serine protease (Husain A.,  J. Hypertens.,  1993, 11, 1155). In patients, inhibition of ACE thus leads to bradykinin accumulation causing cough (5-20%) and potentially life-threatening angioneurotic edema (0.1-0.2%) (Israili Z. H. et al.,  Annals of Internal Medicine,  1992, 117, 234). Chymase is not inhibited by ACE inhibitors. Therefore, the formation of Ang II is still possible in patients treated with ACE inhibitors. Blockade of the ATI receptor (e.g., by losartan) on the other hand overexposes other AT-receptor subtypes to Ang II, whose concentration is dramatically increased by the blockade of ATI receptors. In summary, renin inhibitors are not only expected to be superior to ACE inhibitors and AT 1  blockers with regard to safety, but more importantly also with regard to their efficacy in blocking the RAAS. 
     Only limited clinical experience (Azizi M. et al.,  J. Hypertens.,  1994, 12, 419; Neutel J. M. et al.,  Am. Heart,  1991, 122, 1094) has been generated with renin inhibitors because their peptidomimetic character imparts insufficient oral activity (Kleinert H. D.,  Cardiovasc. Drugs,  1995, 9, 645). The clinical development of several compounds has been stopped because of this problem together with the high cost of goods. It appears as though only one compound has entered clinical trials (Rahuel J. et al.,  Chem. Biol.,  2000, 7, 493; Mealy N. E.,  Drugs of the Future,  2001, 26, 1139). Thus, metabolically stable, orally bioavailable and sufficiently soluble renin inhibitors that can be prepared on a large scale are not available. Recently, the first non-peptide renin inhibitors were described which show high in vitro activity (Oefner C. et al.,  Chem. Biol.,  1999, 6, 127; Patent Application WO 97/09311; Maerki H. P. et al.,  II Farmaco,  2001, 56, 21). The present invention relates to the unexpected identification of renin inhibitors of a non-peptidic nature and of low molecular weight. Orally active renin inhibitors which are active in indications beyond blood pressure regulation where the tissular renin-chymase system may be activated leading to pathophysiologically altered local functions such as renal, cardiac and vascular remodeling, atherosclerosis, and restenosis, are described. 
     All documents cited herein are incorporated by reference. 
     SUMMARY OF THE INVENTION 
     Compounds have now been found which are orally active and bind to aspartic proteases to inhibit their activity. They are useful in the treatment or amelioration of diseases associated with aspartic protease activity. 
     It will be appreciated by those skilled in the art, that the compounds of this invention contain 1, 2 or more chiral centers and may exist in different enantiomeric and/or diastereomeric forms. The following compounds are recited without reference to the relative or absolute configuration of any of the chiral centers present therein, but such recitation is intended to encompass each enantiomeric and/or diastereomeric form of these compounds and all mixtures thereof, such as enantiomerically and/or diastereomerically enriched mixtures and racemic mixtures. The following are compounds of the invention: 
                                 Cpd. No.   Name                  I-1   methyl 4-(1-(3-aminocyclopentanecarbonyl)piperidin-3-yl)-4-hydroxy-           4-(2-(pyridin-4-yl)phenyl)butylcarbamate       I-2   2-((4-(3-aminocyclopentanecarbonyl)morpholin-2-yl)(6-fluoro-3′-           methylbiphenyl-2-yl)methoxy)-N-ethylacetamide       I-3   N-(4-(1-(3-aminocyclopentanecarbonyl)piperidin-3-yl)-4-hydroxy-4-           (2-(o-tolyloxy)phenyl)butyl)acetamide       I-4   (3-aminocyclopentyl)(3-(1-(2-(2,6-dimethylphenoxy)phenyl)-1-           hydroxy-5-methoxypentyl)piperidin-1-yl)methanone       I-5   methyl 4-(1-(3-amino-4-hydroxycyclopentanecarbonyl)piperidin-3-yl)-           4-hydroxy-4-(2-(pyridin-3-yl)phenyl)butylcarbamate       I-6   (3-amino-4-hydroxycyclopentyl)(2-(1-(6-chloro-3′-ethylbiphenyl-2-yl)-           1-hydroxypent-4-enyl)morpholino)methanone       I-7   methyl 2-((4-(3-aminocyclopentanecarbonyl)morpholin-2-yl)(6-fluoro-           3′-methylbiphenyl-2-yl)methoxy)ethylcarbamate       I-8   2-((4-(3-amino-4-hydroxycyclopentanecarbonyl)morpholin-2-yl)(6-           fluoro-3′-methylbiphenyl-2-yl)methoxy)-N-ethylacetamide       I-9   (3-aminocyclopentyl)(2-(1-(4′,6-difluoro-3′-methylbiphenyl-2-yl)-1-           hydroxy-5-methoxypentyl)morpholino)methanone       I-10   (3-amino-4-hydroxycyclopentyl)(2-(1-(3-chloro-2-(pyridin-3-           yl)phenyl)-1-hydroxy-5-methoxypentyl)morpholino)methanone       I-11   (3-amino-4-hydroxycyclopentyl)(2-(1-(3-chloro-2-(3-methyl-1,2,4-           oxadiazol-5-yl)phenyl)-1-hydroxy-5-methoxypentyl)morpholino)methanone       I-12   methyl 4-(1-(3-aminocyclopentanecarbonyl)piperidin-3-yl)-4-hydroxy-           4-(2-(o-tolyloxy)phenyl)butylcarbamate       I-13   N-(4-(1-(3-amino-4-hydroxycyclopentanecarbonyl)piperidin-3-yl)-4-           hydroxy-4-(2-(o-tolyloxy)phenyl)butyl)acetamide       I-14   (3-amino-4-hydroxycyclopentyl)(3-(1-(2-(2,6-           dimethylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)piperidin-1-           yl)methanone       I-15   (3-aminocyclopentyl)(3-(1-(6-fluoro-3′-methoxy-5′-methylbiphenyl-2-           yl)-1-hydroxy-5-methoxypentyl)piperidin-1-yl)methanone       I-16   (3-aminocyclopentyl)(3-(1-(6-chloro-3′-ethylbiphenyl-2-yl)-1-hydroxy-           5-methoxypentyl)piperidin-1-yl)methanone       I-17   (3-aminocyclopentyl)(3-(1-(3-chloro-2-(2-methylbenzyl)phenyl)-1-           hydroxy-5-methoxypentyl)piperidin-1-yl)methanone       I-18   (3-aminocyclopentyl)(3-(1-(3-chloro-2-(3-methylbenzyl)phenyl)-1-           hydroxy-5-methoxypentyl)piperidin-1-yl)methanone       I-19   (3-aminocyclopentyl)(2-(1-(6-fluoro-3′-methoxy-5′-methylbiphenyl-2-           yl)-1-hydroxy-5-methoxypentyl)morpholino)methanone       I-20   (3-aminocyclopentyl)(2-(1-(6-chloro-3′-ethylbiphenyl-2-yl)-1-hydroxy-           5-methoxypentyl)morpholino)methanone       I-21   (3-aminocyclopentyl)(3-(1-(3-chloro-2-(o-tolyloxy)phenyl)-1-hydroxy-           5-methoxypentyl)piperidin-1-yl)methanone       I-22   (3-aminocyclopentyl)(3-(1-(2-(2-chloro-6-methylphenoxy)phenyl)-1-           hydroxy-5-methoxypentyl)piperidin-1-yl)methanone       I-23   (3-amino-4-hydroxycyclopentyl)(2-(1-(4′,6-difluoro-3′-methylbiphenyl-           2-yl)-1-hydroxy-5-methoxypentyl)morpholino)methanone       I-24   methyl 4-(1-(3-amino-4-hydroxycyclopentanecarbonyl)piperidin-3-yl)-           4-hydroxy-4-(2-(o-tolyloxy)phenyl)butylcarbamate       I-25   methyl 4-(1-(2-aminocyclopentanecarbonyl)piperidin-3-yl)-4-(3′-ethyl-           6-fluorobiphenyl-2-yl)-4-hydroxybutylcarbamate       I-26   methyl 4-(1-(3-aminocyclopentanecarbonyl)piperidin-3-yl)-4-(3′-ethyl-           6-fluorobiphenyl-2-yl)-4-hydroxybutylcarbamate       I-27   (4-aminocyclohexyl)(3-(1-(6-chloro-3′-ethylbiphenyl-2-yl)-1-hydroxy-           5-methoxypentyl)piperidin-1-yl)methanone       I-29   (3-amino-4-hydroxycyclopentyl)(3-(1-(6-fluoro-3′-methoxy-5′-           methylbiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)piperidin-1-           yl)methanone       I-28   1-(1-{[6-(aminomethyl)-3-pyridinyl]carbonyl}-3-piperidinyl)-1-(6-           chloro-3′-ethyl-2-biphenylyl)-5-(methyloxy)-1-pentanol       I-30   (3-amino-4-hydroxycyclopentyl)(3-(1-(6-chloro-3′-ethylbiphenyl-2-yl)-           1-hydroxy-5-methoxypentyl)piperidin-1-yl)methanone       I-31   (3-aminocyclopentyl)(3-(1-(3-chloro-2-(2-ethylphenoxy)phenyl)-1-           hydroxy-5-methoxypentyl)piperidin-1-yl)methanone       I-32   (3-aminocyclopentyl)(3-(1-(3-chloro-2-(3-ethylphenoxy)phenyl)-1-           hydroxy-5-methoxypentyl)piperidin-1-yl)methanone       I-33   (3-amino-4-hydroxycyclopentyl)(3-(1-(3-chloro-2-(2-           methylbenzyl)phenyl)-1-hydroxy-5-methoxypentyl)piperidin-1-           yl)methanone       I-34   (3-amino-4-hydroxycyclopentyl)(3-(1-(3-chloro-2-(3-           methylbenzyl)phenyl)-1-hydroxy-5-methoxypentyl)piperidin-1-           yl)methanone       I-35   (3-amino-4-hydroxycyclopentyl)(2-(1-(6-fluoro-3′-methoxy-5′-           methylbiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)morpholino)methanone       I-36   (3-amino-4-hydroxycyclopentyl)(3-(1-(3-chloro-2-(o-tolyloxy)phenyl)-           1-hydroxy-5-methoxypentyl)piperidin-1-yl)methanone       I-37   (3-amino-4-hydroxycyclopentyl)(2-(1-(6-chloro-3′-ethylbiphenyl-2-yl)-           1-hydroxy-5-methoxypentyl)morpholino)methanone       I-38   (3-amino-4-hydroxycyclopentyl)(2-(1-(6-chloro-2′-fluoro-5′-           methylbiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)morpholino)methanone       I-39   (3-aminocyclopentyl)(3-(1-(3-chloro-2-(quinolin-3-yl)phenyl)-1-           hydroxy-5-methoxypentyl)piperidin-1-yl)methanone       I-40   (3-aminocyclopentyl)(2-(1-(3-chloro-2-(naphthalen-2-yl)phenyl)-1-           hydroxy-5-methoxypentyl)morpholino)methanone       I-41   (3-aminocyclopentyl)(2-(1-(3-chloro-2-(quinolin-3-yl)phenyl)-1-           hydroxy-5-methoxypentyl)morpholino)methanone       I-42   methyl 4-hydroxy-4-(1-{[3-(methylamino)cyclopentyl]carbonyl}-3-           piperidinyl)-4-{2-[(2-methylphenyl)oxy]phenyl}butyl)carbamate       I-43   methyl 4-(6-fluoro-3′-methoxybiphenyl-2-yl)-4-hydroxy-4-(1-(3-           (methylamino)cyclopentanecarbonyl)piperidin-3-yl)butylcarbamate       I-44   N-(4-(1-(3-amino-4-hydroxycyclopentanecarbonyl)piperidin-3-yl)-4-           (6-chloro-3′-ethylbiphenyl-2-yl)-4-hydroxybutyl)acetamide       I-45   methyl 4-(1-(3-aminocyclopentanecarbonyl)piperidin-3-yl)-4-(6-           chloro-3′-ethylbiphenyl-2-yl)-4-hydroxybutylcarbamate       I-46   methyl 4-(4-(3-aminocyclopentanecarbonyl)morpholin-2-yl)-4-(6-           chloro-3′-ethylbiphenyl-2-yl)-4-hydroxybutylcarbamate       I-47   (3-amino-4-hydroxycyclopentyl)(3-(1-(3-chloro-2-(3-           ethylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)piperidin-1-           yl)methanone       I-48   (3-amino-4-hydroxycyclopentyl)(2-(1-(6-fluoro-3′,5′-           dimethoxybiphenyl-2-yl)-1-hydroxy-5-           methoxypentyl)morpholino)methanone       I-49   (3-amino-4-hydroxycyclopentyl)(2-(1-(6-chloro-3′-           (methoxymethyl)biphenyl-2-yl)-1-hydroxy-5-           methoxypentyl)morpholino)methanone       I-50   (4-(aminomethyl)cyclohexyl)(2-(1-(6-chloro-2′-fluoro-5′-           methylbiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)morpholino)methanone       I-51   (3-amino-4-hydroxycyclopentyl)(3-(1-(3-chloro-2-(quinolin-3-           yl)phenyl)-1-hydroxy-5-methoxypentyl)piperidin-1-yl)methanone       I-52   (3-amino-4-hydroxycyclopentyl)(2-(1-(3-chloro-2-(naphthalen-2-           yl)phenyl)-1-hydroxy-5-methoxypentyl)morpholino)methanone       I-53   (3-amino-4-hydroxycyclopentyl)(2-(1-(3-chloro-2-(quinolin-3-           yl)phenyl)-1-hydroxy-5-methoxypentyl)morpholino)methanone       I-54   (3-amino-4-hydroxycyclopentyl)(2-(1-(3-chloro-2-(isoquinolin-4-           yl)phenyl)-1-hydroxy-5-methoxypentyl)morpholino)methanone       I-55   methyl 4-(6-chloro-3′-ethylbiphenyl-2-yl)-4-hydroxy-4-(1-(3-           (methylamino)cyclopentanecarbonyl)piperidin-3-yl)butylcarbamate       I-56   methyl 4-(1-(3-aminocyclopentanecarbonyl)piperidin-3-yl)-4-(6-           chloro-3′-isopropylbiphenyl-2-yl)-4-hydroxybutylcarbamate       I-57   methyl 4-(1-(3-amino-4-hydroxycyclopentanecarbonyl)piperidin-3-yl)-           4-(6-chloro-3′-ethylbiphenyl-2-yl)-4-hydroxybutylcarbamate       I-58   methyl 4-(6-chloro-3′-methoxybiphenyl-2-yl)-4-hydroxy-4-(1-(3-           (methylamino)cyclopentanecarbonyl)piperidin-3-yl)butylcarbamate       I-59   (3-amino-4-hydroxycyclopentyl)(2-(1-(6-chloro-3′,5′-           dimethoxybiphenyl-2-yl)-1-hydroxy-5-           methoxypentyl)morpholino)methanone       I-60   methyl 4-(1-(4-(aminomethyl)cyclohexanecarbonyl)piperidin-3-yl)-4-           (6-chloro-3′-ethylbiphenyl-2-yl)-4-hydroxybutylcarbamate       I-61   methyl 4-(1-(3-amino-4-hydroxycyclopentanecarbonyl)piperidin-3-yl)-           4-(6-chloro-3′-isopropylbiphenyl-2-yl)-4-hydroxybutylcarbamate       I-62   (3-aminocyclopentyl)(3-(1-(3′-ethoxy-6-fluoro-5′-           (trifluoromethyl)biphenyl-2-yl)-1-hydroxy-5-methoxypentyl)piperidin-1-           yl)methanone       I-63   methyl 4-(1-(3-amino-4-hydroxycyclopentanecarbonyl)piperidin-3-yl)-           4-(3-chloro-2-(quinolin-3-yl)phenyl)-4-hydroxybutylcarbamate       I-64   (3-aminocyclopentyl)(2-(1-(3′-ethoxy-6-fluoro-5′-           (trifluoromethyl)biphenyl-2-yl)-1-hydroxy-5-           methoxypentyl)morpholino)methanone       I-65   (3-amino-4-hydroxycyclopentyl)(3-(1-(3′-ethoxy-6-fluoro-5′-           (trifluoromethyl)biphenyl-2-yl)-1-hydroxy-5-methoxypentyl)piperidin-1-           yl)methanone       I-66   (3-amino-4-hydroxycyclopentyl)(2-(1-(3′-ethoxy-6-fluoro-5′-           (trifluoromethyl)biphenyl-2-yl)-1-hydroxy-5-           methoxypentyl)morpholino)methanone       I-67   (3-aminocyclopentyl)(2-(1-(6-fluoro-3′,5′-dimethoxybiphenyl-2-yl)-1-           hydroxy-5-methoxypentyl)morpholino)methanone       I-68   (3-aminocyclopentyl)(2-(1-(3-chloro-2-(isoquinolin-4-yl)phenyl)-1-           hydroxy-5-methoxypentyl)morpholino)methanone       I-69   methyl (4-(1-{[3-aminocyclopentyl]carbonyl}-3-piperidinyl)-4-{3-           chloro-2-[(2-methylphenyl)oxy]phenyl}-4-hydroxybutyl)carbamate       I-70   methyl (4-(1-{[3-aminocyclopentyl]carbonyl}-3-piperidinyl)-4-{3-           chloro-2-[(2-ethylphenyl)oxy]phenyl}-4-hydroxybutyl)carbamate       I-71   methyl (4-(1-{[3-amino-4-hydroxycyclopentyl]carbonyl}-3-           piperidinyl)-4-{3-chloro-2-[(2-methylphenyl)oxy]phenyl}-4-           hydroxybutyl)carbamate       I-72   methyl (4-(1-{[3-amino-4-hydroxycyclopentyl]carbonyl}-3-           piperidinyl)-4-{3-chloro-2-[(2-ethylphenyl)oxy]phenyl}-4-           hydroxybutyl)carbamate       I-73   methyl [4-(1-{[3-amino-4-hydroxycyclopentyl]carbonyl}-3-           piperidinyl)-4-(3′-ethyl-6-fluoro-2-biphenylyl)-4-hydroxybutyl]carbamate       I-74   methyl {4-(6-chloro-3′-ethyl-2-biphenylyl)-4-hydroxy-4-[1-({trans-4-           [(methylamino)methyl]cyclohexyl}carbonyl)-3-           piperidinyl]butyl}carbamate       I-75   methyl [4-(1-{[2-aminocyclopentyl]carbonyl}-3-piperidinyl)-4-(3′-           ethyl-6-fluoro-2-biphenylyl)-4-hydroxybutyl]carbamate       I-76   1-(4-{[6-(aminomethyl)-3-pyridinyl]carbonyl}-2-morpholinyl)-1-(6-           chloro-3′-ethyl-2-biphenylyl)-5-(methyloxy)-1-pentanol       I-77   methyl [4-(1-{[6-(aminomethyl)-3-pyridinyl]carbonyl}-3-piperidinyl)-           4-(6-chloro-3′-ethyl-2-biphenylyl)-4-hydroxybutyl]carbamate       I-78   1-{1-[(cis-4-aminocyclohexyl)acetyl]-3-piperidinyl}-1-(6-chloro-3′-           ethyl-2-biphenylyl)-5-(methyloxy)-1-pentanol       I-79   1-{1-[(trans-4-aminocyclohexyl)acetyl]-3-piperidinyl}-1-(6-chloro-3′-           ethyl-2-biphenylyl)-5-(methyloxy)-1-pentanol       I-80   1-(1-{[-2-aminocyclopentyl]carbonyl}-3-piperidinyl)-1-(6-chloro-3′-           ethyl-2-biphenylyl)-5-(methyloxy)-1-pentanol       I-81   1-(6-chloro-3′-ethyl-2-biphenylyl)-1-(4-{[3-           (methylamino)cyclopentyl]carbonyl}-2-morpholinyl)-5-(methyloxy)-1-           pentanol       I-82   1-(6-chloro-3′-ethyl-2-biphenylyl)-1-(1-{[3-           (methylamino)cyclopentyl]carbonyl}-3-piperidinyl)-5-(methyloxy)-1-           pentanol       I-83   4-({2-[1-(6-chloro-3′-ethyl-2-biphenylyl)-1-hydroxy-5-           (methyloxy)pentyl]-4-morpholinyl}carbonyl)-2-[(2-           hydroxyethyl)amino]cyclopentanol       I-84   methyl {4-(6-chloro-3′-ethyl-2-biphenylyl)-4-hydroxy-4-{1-({3-           hydroxy-4-[(2-hydroxyethyl)amino]cyclopentyl}carbonyl)-3-           piperidinyl]butyl}carbamate       I-85   1-(6-chloro-3′-ethyl-2-biphenylyl)-1-[1-({trans-4-           [(methylamino)methyl]cyclohexyl}carbonyl)-3-piperidinyl]-5-(methyloxy)-           1-pentanol       I-86   4-({2-[1-(6-chloro-3′-ethyl-2-biphenylyl)-1-hydroxy-5-           (methyloxy)pentyl]-4-morpholinyl}carbonyl)-2-[(1,3-thiazol-2-           ylmethyl)amino]cyclopentanol       I-87   methyl [4-(1-{[3-aminocyclohexyl]carbonyl}-3-piperidinyl)-4-(6-           chloro-3′-ethyl-2-biphenylyl)-4-hydroxybutyl]carbamate       I-88   N-{4-(6-chloro-3′-methyl-2-biphenylyl)-4-hydroxy-4-[1-({trans-4-           [(methylamino)methyl]cyclohexyl}carbonyl)-3-piperidinyl]butyl}acetamide       I-89   N-[4-(6-chloro-3′-methyl-2-biphenylyl)-4-hydroxy-4-(1-{[3-           (methylamino)cyclopentyl]carbonyl}-3-piperidinyl)butyl]acetamide       I-90   1-(6-chloro-3′-ethyl-2-biphenylyl)-1-{4-[(3-{[(2,5-dimethyl-1,3-           oxazol-4-yl)methyl]amino}cyclopentyl)carbonyl]-2-morpholinyl}-5-           (methyloxy)-1-pentanol       I-91   N-[4-(1-{[trans-4-(aminomethyl)cyclohexyl]carbonyl}-3-piperidinyl)-           4-(6-chloro-3′-methyl-2-biphenylyl)-4-hydroxybutyl]acetamide       I-92   methyl {4-(4,6-difluoro-3′-methyl-2-biphenylyl)-4-hydroxy-4-[1-           ({trans-4-[(methylamino)methyl]cyclohexyl}carbonyl)-3-           piperidinyl]butyl}carbamate       I-93   methyl [4-hydroxy-4-(1-{[3-(methylamino)cyclopentyl]carbonyl}-3-           piperidinyl)-4-(2′,4,6-trifluoro-5′-methyl-2-biphenylyl)butyl]carbamate       I-94   methyl [4-hydroxy-4-[1-({trans-4-           [(methylamino)methyl]cyclohexyl}carbonyl)-3-piperidinyl]-4-(2′,4,6-           trifluoro-5′-methyl-2-biphenylyl)butyl]carbamate       I-95   methyl [4-(6-chloro-3′-methyl-2-biphenylyl)-4-hydroxy-4-(1-{[3-           (methylamino)cyclopentyl]carbonyl}-3-piperidinyl)butyl]carbamate       I-96   1-(6-chloro-3′-ethyl-2-biphenylyl)-1-[4-({trans-4-           [(methylamino)methyl]cyclohexyl}carbonyl)-2-morpholinyl]-5-           (methyloxy)-1-pentanol       I-97   methyl [4-(4-{[3-amino-4-hydroxycyclopentyl]carbonyl}-2-           morpholinyl)-4-(3′-ethyl-6-fluoro-2-biphenylyl)-4-hydroxybutyl]carbamate       I-98   methyl {4-(3′-ethyl-6-fluoro-2-biphenylyl)-4-hydroxy-4-[4-({trans-4-           [(methylamino)methyl]cyclohexyl}carbonyl)-2-           morpholinyl]butyl}carbamate       I-99   2-amino-4-({2-[1-[2-chloro-3-(3-ethylphenyl)-4-pyridinyl]-1-hydroxy-           5-(methyloxy)pentyl]-4-morpholinyl}carbonyl)cyclopentanol       I-100   1-(4-{[3-aminocyclopentyl]carbonyl}-2-morpholinyl)-1-[2-chloro-3-(3-           ethylphenyl)-4-pyridinyl]-5-(methyloxy)-1-pentanol       I-101   2-amino-4-({2-[1-[2-(1-benzothien-3-yl)-3-chlorophenyl]-1-hydroxy-5-           (methyloxy)pentyl]-4-morpholinyl}carbonyl)cyclopentanol       I-102   1-(4-{[3-aminocyclopentyl]carbonyl}-2-morpholinyl)-1-[2-(1-           benzothien-3-yl)-3-chlorophenyl]-5-(methyloxy)-1-pentanol       I-103   1-[4-chloro-3-(3-ethylphenyl)-2-pyridinyl]-1-(4-{[3-           (methylamino)cyclopentyl]carbonyl}-2-morpholinyl)-5-(methyloxy)-1-           pentanol       I-104   methyl {4-[2-chloro-3-(3-ethylphenyl)-4-pyridinyl]-4-hydroxy-4-[1-           ({trans-4-[(methylamino)methyl]cyclohexyl}carbonyl)-3-           piperidinyl]butyl}carbamate       I-105   methyl [4-[2-chloro-3-(3-ethylphenyl)-4-pyridinyl]-4-hydroxy-4-(1-           {[3-(methylamino)cyclopentyl]carbonyl}-3-piperidinyl)butyl]carbamate       I-106   methyl {4-{3-chloro-2-[4-(1-methylethyl)-2-quinazolinyl]phenyl}-4-           hydroxy-4-[1-({trans-4-[(methylamino)methyl]cyclohexyl}carbonyl)-3-           piperidinyl]butyl}carbamate       I-107   methyl [4-{3-chloro-2-[4-(1-methylethyl)-2-quinazolinyl]phenyl}-4-           hydroxy-4-(1-{[3-(methylamino)cyclopentyl]carbonyl}-3-           piperidinyl)butyl]carbamate       I-108   1-(1-{[(1R,3S)-3-aminocyclopentyl]carbonyl}-3-piperidinyl)-1-{3-           chloro-2-[(3-methylphenyl)oxy]phenyl}-5-(methyloxy)-1-pentanol       I-109   2-amino-4-({3-[1-{3-chloro-2-[(3-methylphenyl)oxy]phenyl}-1-           hydroxy-5-(methyloxy)pentyl]-1-piperidinyl}carbonyl)cyclopentanol       I-110   methyl (4-(1-{[3-aminocyclopentyl]carbonyl}-3-piperidinyl)-4-{3-           chloro-2-[(3-methylphenyl)oxy]phenyl}-4-hydroxybutyl)carbamate       I-111   methyl (4-(1-{[3-amino-4-hydroxycyclopentyl]carbonyl}-3-           piperidinyl)-4-{3-chloro-2-[(3-methylphenyl)oxy]phenyl}-4-           hydroxybutyl)carbamate       I-112   methyl (4-(1-{[3-aminocyclopentyl]carbonyl}-3-piperidinyl)-4-{2-           [(2,6-dimethylphenyl)oxy]phenyl}-4-hydroxybutyl)carbamate       I-113   methyl (4-(1-{[3-amino-4-hydroxycyclopentyl]carbonyl}-3-           piperidinyl)-4-{2-[(2,6-dimethylphenyl)oxy]phenyl}-4-           hydroxybutyl)carbamate       I-114   methyl {4-{3-chloro-2-[8-(1-methylethyl)-2-quinolinyl]phenyl}-4-           hydroxy-4-[1-({trans-4-[(methylamino)methyl]cyclohexyl}carbonyl)-3-           piperidinyl]butyl}carbamate       I-115   methyl {4-[3-chloro-2-(8-methyl-2-quinolinyl)phenyl]-4-hydroxy-4-[1-           ({trans-4-[(methylamino)methyl]cyclohexyl}carbonyl)-3-           piperidinyl]butyl}carbamate       I-116   methyl [4-[3-fluoro-2-(3-quinolinyl)phenyl]-4-hydroxy-4-(1-{[3-           (methylamino)cyclopentyl]carbonyl}-3-piperidinyl)butyl]carbamate       I-117   methyl [4-{2-chloro-3-[3-(1-methylethyl)phenyl]-4-pyridinyl}-4-           hydroxy-4-(1-{[3-(methylamino)cyclopentyl]carbonyl}-3-           piperidinyl)butyl]carbamate       I-118   methyl [4-[3-chloro-2-(5-methyl-2-furanyl)phenyl]-4-hydroxy-4-(1-           {[3-(methylamino)cyclopentyl]carbonyl}-3-piperidinyl)butyl]carbamate       I-119   methyl {4-1-{[3-amino-4-hydroxycyclopentyl]carbonyl}-3-           piperidinyl)-4-[3-chloro-2-(5-methyl-2-furanyl)phenyl]-4-           hydroxybutyl}carbamate       I-120   1-{2-chloro-3-[3-(1-methylethyl)phenyl]-4-pyridinyl}-1-[4-({trans-4-           [(methylamino)methyl]cyclohexyl}carbonyl)-2-morpholinyl]-5-           (methyloxy)-1-pentanol       I-121   1-{2-chloro-3-[3-(1-methylethyl)phenyl]-4-pyridinyl}-1-(4-{[3-           (methylamino)cyclopentyl]carbonyl}-2-morpholinyl)-5-(methyloxy)-1-           pentanol       I-122   2-amino-4-({2-[1-{2-chloro-3-[3-(1-methylethyl)phenyl]-4-pyridinyl}-           1-hydroxy-5-(methyloxy)pentyl]-4-morpholinyl}carbonyl)cyclopentanol       I-123   methyl {4-[5-chloro-4-(3-ethylphenyl)-3-pyridinyl]-4-hydroxy-4-[1-           ({trans-4-[(methylamino)methyl]cyclohexyl}carbonyl)-3-           piperidinyl]butyl}carbamate       I-124   methyl [4-[5-chloro-4-(3-ethylphenyl)-3-pyridinyl]-4-hydroxy-4-(1-           {[3-(methylamino)cyclopentyl]carbonyl}-3-piperidinyl)butyl]carbamate       I-125   methyl {4-(5-chloro-4-[3-(1-methylethyl)phenyl]-3-pyridinyl}-4-           hydroxy-4-[1-({trans-4-[(methylamino)methyl]cyclohexyl}carbonyl)-3-           piperidinyl]butyl}carbamate       I-126   methyl [4-{5-chloro-4-[3-(1-methylethyl)phenyl]-3-pyridinyl}-4-           hydroxy-4-(1-{[3-(methylamino)cyclopentyl]carbonyl}-3-           piperidinyl)butyl]carbamate       I-127   methyl {4-[6-fluoro-3′-(1-methylethyl)-2-biphenylyl]-4-hydroxy-4-{1-           ({trans-4-[(methylamino)methyl]cyclohexyl}carbonyl)-3-           piperidinyl]butyl}carbamate       I-128   methyl [4-(6-chloro-3′-fluoro-5′-methyl-2-biphenylyl)-4-hydroxy-4-(1-           {[3-(methylamino)cyclopentyl]carbonyl}-3-piperidinyl)butyl]carbamate       I-129   methyl [4-(3′,6-difluoro-5′-methyl-2-biphenylyl)-4-hydroxy-4-(1-{[3-           (methylamino)cyclopentyl]carbonyl}-3-piperidinyl)butyl]carbamate       I-130   2-amino-4-({3-[1-{3-chloro-2-[(2-ethylphenyl)oxy]phenyl}-1-hydroxy-           5-(methyloxy)pentyl]-1-piperidinyl}carbonyl)cyclopentanol       I-131   methyl {4-(3′-ethyl-6-fluoro-2-biphenylyl)-4-hydroxy-4-[1-([trans-4-           [(methylamino)methyl]cyclohexyl}carbonyl)-3-           piperidinyl]butyl}carbamate       I-132   2-amino-4-({3-[1-{2-[(2-chloro-6-methylphenyl)oxy]phenyl}-1-           hydroxy-5-(methyloxy)pentyl]-1-piperidinyl}carbonyl)cyclopentanol       I-133   2-amino-4-({3-[1-{3-fluoro-2-[(3-methylphenyl)oxy]phenyl}-1-           hydroxy-5-(methyloxy)pentyl]-1-piperidinyl}carbonyl)cyclopentanol       I-134   1-(1-{[3-aminocyclopentyl]carbonyl}-3-piperidinyl)-1-{3-fluoro-2-[(3-           methylphenyl)oxy]phenyl}-5-(methyloxy)-1-pentanol       I-135   methyl (4-(1-{[3-amino-4-hydroxycyclopentyl]carbonyl}-3-           piperidinyl)-4-{3-chloro-2-[(3-ethylphenyl)oxy]phenyl}-4-           hydroxybutyl)carbamate       I-136   methyl (4-(1-{[3-aminocyclopentyl]carbonyl}-3-piperidinyl)-4-{3-           chloro-2-[(3-ethylphenyl)oxy]phenyl}-4-hydroxybutyl)carbamate       I-137   methyl (4-(1-{[3-amino-4-hydroxycyclopentyl]carbonyl}-3-           piperidinyl)-4-{3-fluoro-2-[(3-methylphenyl)oxy]phenyl}-4-           hydroxybutyl)carbamate       I-138   methyl (4-(1-{[3-aminocyclopentyl]carbonyl}-3-piperidinyl)-4-{3-           fluoro-2-[(3-methylphenyl)oxy]phenyl}-4-hydroxybutyl)carbamate       I-139   methyl (4-(1-{[3-amino-4-hydroxycyclopentyl]carbonyl}-3-           piperidinyl)-4-{3-chloro-2-[(3-methylphenyl)methyl]phenyl}-4-           hydroxybutyl)carbamate       I-140   methyl [4-{3-chloro-2-[(3-methylphenyl)methyl]phenyl}-4-hydroxy-4-           (1-{[3-(methylamino)cyclopentyl]carbonyl}-3-piperidinyl)butyl]carbamate       I-141   methyl (4-(1-{[3-aminocyclopentyl]carbonyl}-3-piperidinyl)-4-{3-           chloro-2-[(3-methylphenyl)methyl]phenyl}-4-hydroxybutyl)carbamate       I-142   methyl (2-{[(4-{[3-amino-4-hydroxycyclopentyl]carbonyl}-2-           morpholinyl)(6-chloro-3′-ethyl-2-biphenylyl)methyl]oxy}ethyl)carbamate       I-143   methyl (2-{[(1-{[3-amino-4-hydroxycyclopentyl]carbonyl}-3-           piperidinyl)(6-chloro-3′-ethyl-2-biphenylyl)methyl]oxy}ethyl)carbamate       I-144   methyl [4-(1-{[4-(aminomethyl)-5-methyl-2-furanyl]carbonyl}-3-           piperidinyl)-4-(6-chloro-3′-ethyl-2-biphenylyl)-4-hydroxybutyl]carbamate       I-145   methyl {4-(6-chloro-3′-ethyl-2-biphenylyl)-4-hydroxy-4-[1-({6-           [(methylamino)methyl]-3-pyridinyl}carbonyl)-3-           piperidinyl]butyl}carbamate       I-146   methyl [4-{1-[(2-amino-4-oxo-1,4-dihydro-5-pyrimidinyl)carbonyl]-3-           piperidinyl}-4-(6-chloro-3′-methyl-2-biphenylyl)-4-           hydroxybutyl]carbamate       I-147   methyl [4-(6-chloro-3′-methyl-2-biphenylyl)-4-hydroxy-4-(1-{[2-           (methylamino)-5-pyrimidinyl]carbonyl}-3-piperidinyl)butyl]carbamate       I-148   methyl [4-(1-{[5-(aminomethyl)-3-isoxazolyl]carbonyl}-3-piperidinyl)-           4-(6-chloro-3′-methyl-2-biphenylyl)-4-hydroxybutyl]carbamate       I-149   methyl {4-(6-chloro-3′-ethyl-2-biphenylyl)-4-hydroxy-4-[1-({5-           [(methylamino)methyl]-2-thienyl}carbonyl)-3-piperidinyl]butyl}carbamate       I-150   methyl [4-{1-[(6-amino-3-pyridinyl)carbonyl]-3-piperidinyl}-4-(3′,6-           difluoro-5′-methyl-2-biphenylyl)-4-hydroxybutyl]carbamate       I-151   methyl [2-({(6-chloro-3′-ethyl-2-biphenylyl)[1-({trans-4-           [(methylamino)methyl]cyclohexyl}carbonyl)-3-           piperidinyl]methyl}oxy)ethyl]carbamate       I-152   methyl [2-({(6-chloro-3′-ethyl-2-biphenylyl)[-4-({trans-4-           [(methylamino)methyl]cyclohexyl}carbonyl)-2-           morpholinyl]methyl}oxy)ethyl]carbamate       I-153   N-[4-(1-{[6-(aminomethyl)-3-pyridinyl]carbonyl}-3-piperidinyl)-4-(6-           chloro-3′-methyl-2-biphenylyl)-4-hydroxybutyl]acetamide       I-154   methyl [4-(1-{[4-(aminomethyl)-1-piperidinyl]carbonyl}-3-           piperidinyl)-4-(3′-ethyl-6-fluoro-2-biphenylyl)-4-hydroxybutyl]carbamate       I-155   methyl {4-(3′-ethyl-6-fluoro-2-biphenylyl)-4-hydroxy-4-[1-((4-           [(methylamino)methyl]-1-piperidinyl}carbonyl)-3-           piperidinyl]butyl}carbamate       I-156   methyl [4-(1-{[4-(aminomethyl)-1-piperidinyl]carbonyl}-3-           piperidinyl)-4-(6-chloro-3′-ethyl-2-biphenylyl)-4-hydroxybutyl]carbamate       I-157   methyl [4-(1-{[4-(aminomethyl)-4-phenyl-1-piperidinyl]carbonyl}-3-           piperidinyl)-4-(6-chloro-3′-ethyl-2-biphenylyl)-4-hydroxybutyl]carbamate       I-158   N-[4-(1-{[4-(aminomethyl)-1-piperidinyl]carbonyl}-3-piperidinyl)-4-           (2′,6-difluoro-5′-methyl-2-biphenylyl)-4-hydroxybutyl]-2-           hydroxyacetamide       I-159   methyl {4-(6-chloro-3′-ethyl-2-biphenylyl)-4-hydroxy-4-[1-({4-           [(methylamino)methyl]-1-piperidinyl}carbonyl)-3-           piperidinyl]butyl}carbamate       I-160   methyl {4-(6-chloro-3′-ethyl-2-biphenylyl)-4-hydroxy-4-[1-({4-[(2-           propen-1-ylamino)methyl]-1-piperidinyl}carbonyl)-3-           piperidinyl]butyl}carbamate                    
or a diastereomer, enantiomer or salt thereof.
 
     In another embodiment the present invention is directed to pharmaceutical compositions comprising a compound described herein or enantiomers, diastereomers, or salts thereof and a pharmaceutically acceptable carrier or excipient. 
     In another embodiment the present invention is directed to a method of inhibiting an aspartic protease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound described herein or an enantiomer, diastereomer, or salt thereof. 
     In another embodiment the present invention is directed to method for treating or ameliorating an aspartic protease mediated disorder in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a compound described herein or an enantiomer, diastereomer, or salt thereof. 
     In another embodiment the present invention is directed to a method for treating or ameliorating a renin mediated disorder in a subject in need thereof comprising administering to the subject an effective amount of a compound described herein or an enantiomer, diastereomer, or salt thereof. 
     In another embodiment the present invention is directed to a method for the treatment of hypertension in a subject in need thereof comprising administering to the subject a compound described herein in combination therapy with one or more additional agents said additional agent selected from the group consisting of α-blockers, β-blockers, calcium channel blockers, diuretics, angiotensin converting enzyme (ACE) inhibitors, dual ACE and neutral endopeptidase (NEP) inhibitors, angiotensin-receptor blockers (ARBs), aldosterone synthase inhibitors, aldosterone-receptor antagonists, and endothelin receptor antagonists. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     A description of embodiments of the compounds of the invention follows. It will be appreciated by those skilled in the art that each enantiomer and diastereomer of the compounds of this invention will likely demonstrate a different level of effectiveness of inhibiting the action of aspartic proteases, particularly renin. It will be further appreciated that for the most active compounds, all or most of the enantiomers and/or diastereomers may demonstrate some level of activity, but that for compounds with lower activity, certain enantiomers and/or diastereomers may demonstrate such low levels of activity as to be considered inactive. It is understood that the following represent the preferred relative and absolute configuration of the compounds of the invention. It will be appreciated that each of the different enantiomeric and/or diastereomeric forms of the compounds of this invention, including the stereoisomeric forms depicted below, may be separately obtained using conventional procedures (e.g. stereospecific synthesis or resolution via chiral chromatography, crystallization, etc.). 
                                     Cpd.               No.   Structure   Name                  I-1a                         methyl (S)-4-((R)-1-((1R,3S)-3- aminocyclopentanecarbonyl)piperidin- 3-yl)-4-hydroxy-4-(2-(pyridin-4-  yl)phenyl)butylcarbamate               I-2a                         2-((S)-((R)-4-((1R,3S)-3- aminocyclopentanecarbonyl)morpholin- 2-yl)(6-fluoro-3′-methylbiphenyl-2- yl)methoxy)-N-ethylacetamide               I-3a                         N-((S)-4-((R)-1-((1R,3S)-3- aminocyclopentanecarbonyl)piperidin- 3-yl)-4-hydroxy-4-(2-(o- tolyloxy)phenyl)butyl)acetamide               I-4a                         ((1R,3S)-3-aminocyclopentyl) ((R)- 3-((S)-1-(2-(2,6-dimethyl phenoxy)phenyl)-1-hydroxy-5- methoxypentyl)piperidin-1- yl)methanone               I-5a                         methyl (S)-4-((R)-1-((1S,3R,4S)-3- amino-4-hydroxycyclopentane carbonyl) piperidin-3-yl)-4-hydroxy-4- (2-(pyridin-3-yl)phenyl)butylcarbamate               I-6a                         ((1S,3R,4S)-3-amino-4- hydroxycyclopentyl)((R)-2-((R)-1-(6- chloro-3′-ethylbiphenyl-2-yl)-1- hydroxypent-4-enyl)morpholino) methanone               I-7a                         methyl 2-((S)-((R)-4-((1R,3S)-3- aminocyclopentanecarbonyl) morpholin-2-yl)(6-fluoro-3′- methylbiphenyl-2-yl)methoxy) ethylcarbamate               I-8a                         2-((S)-((R)-4-((1S,3R,4S)-3-amino- 4-hydroxycyclopentane carbonyl)morpholin-2-yl)(6-fluoro-3′- methylbiphenyl-2-yl)methoxy)-N- ethylacetamide               I-9a                         ((1R,3S)-3-aminocyclopentyl) ((R)- 2-((R)-1-(4′,6-difluoro-3′- methylbiphenyl-2-yl)-1-hydroxy-5- methoxypentyl)morpholino) methanone               I-10a                         ((1S,3R,4S)-3-amino-4- hydroxycyclopentyl)((R)-2-((R)-1-(3- chloro-2-(pyridin-3-yl)phenyl)-1- hydroxy-5-methoxypentyl) morpholino)methanone               I-11a                         ((1S,3R,4S)-3-amino-4- hydroxycyclopentyl)((R)-2-((R)-1-(3- chloro-2-(3-methyl-1,2,4-oxadiazol-5- yl)phenyl)-1-hydroxy-5- methoxypentyl)morpholino) methanone               I-12a                         methyl (S)-4-((R)-1-((1R,3S)-3- aminocyclopentanecarbonyl)piperidin- 3-yl)-4-hydroxy-4-(2-(o- tolyloxy)phenyl)butylcarbamate               I-13a                         N-((S)-4-((R)-1-((1S,3R,4S)-3- amino-4-hydroxycyclopentane carbonyl)piperidin-3-yl)-4-hydroxy-4- (2-(o-tolyloxy)phenyl)butyl) acetamide               I-14a                         ((1S,3R,4S)-3-amino-4- hydroxycyclopentyl)((R)-3-((S)-1-(2- (2,6-dimethylphenoxy)phenyl)-1- hydroxy-5-methoxypentyl) piperidin-1- yl)methanone               I-15a                         ((1R,3S)-3-aminocyclopentyl)((R)- 3-((S)-1-(6-fluoro-3′-methoxy-5′- methylbiphenyl-2-yl)-1-hydroxy-5- methoxypentyl)piperidin-1- yl)methanone               I-16a                         ((1R,3S)-3-aminocyclopentyl)((R)- 3-((S)-1-(6-chloro-3′-ethylbiphenyl-2- yl)-1-hydroxy-5-methoxypentyl) piperidin-1-yl)methanone               I-17a                         ((1R,3S)-3-aminocyclopentyl)((R)- 3-((S)-1-(3-chloro-2-(2- methylbenzyl)phenyl)-1-hydroxy-5- methoxypentyl) piperidin-1- yl)methanone               I-18a                         ((1R,3S)-3-aminocyclopentyl)((R)- 3-((S)-1-(3-chloro-2-(3- methylbenzyl)phenyl)-1-hydroxy-5- methoxypentyl) piperidin-1- yl)methanone               I-19a                         ((1R,3S)-3-aminocyclopentyl)((R)- 2-((R)-1-(6-fluoro-3′-methoxy-5′- methylbiphenyl-2-yl)-1-hydroxy-5- methoxypentyl)morpholino)methanone               I-20a                         ((1R,3S)-3-aminocyclopentyl)((R)- 2-((R)-1-(6-chloro-3′-ethylbiphenyl-2- yl)-1-hydroxy-5-methoxypentyl) morpholino) methanone               I-21a                         ((1R,3S)-3-aminocyclopentyl)((R)- 3-((S)-1-(3-chloro-2-(o- tolyloxy)phenyl)-1-hydroxy-5- methoxypentyl) piperidin-1- yl)methanone               I-22a                         ((1R,3S)-3-aminocyclopentyl)((R)- 3-((S)-1-(2-(2-chloro-6-methylphenoxy) phenyl)-1-hydroxy-5- methoxypentyl)piperidin-1- yl)methanone               I-23a                         ((1S,3R,4S)-3-amino-4- hydroxycyclopentyl)((R)-2-((R)-1-(4′,6- difluoro-3′-methylbiphenyl-2-yl)-1- hydroxy-5-methoxypentyl) morpholino) methanone               I-24a                         methyl (S)-4-((R)-1-((1S,3R,4S)-3- amino-4-hydroxycyclopentanecarbonyl) piperidin-3-yl)-4-hydroxy-4-(2-(o- tolyloxy)phenyl)butylcarbamate               I-25a                         methyl (S)-4-((R)-1-((1R,2S)-2- aminocyclopentanecarbonyl)piperidin- 3-yl)-4-(3′-ethyl-6-fluorobiphenyl-2- yl)-4-hydroxybutylcarbamate               I-26a                         methyl (S)-4-((R)-1-((1R,3S)-3- aminocyclopentanecarbonyl)piperidin- 3-yl)-4-(3′-ethyl-6-fluorobiphenyl-2- yl)-4-hydroxybutylcarbamate               I-27a                         (trans-4-aminocyclohexyl)((R)-3- ((S)-1-(6-chloro-3′-ethylbiphenyl-2-yl)- 1-hydroxy-5-methoxypentyl)piperidin- 1-yl)methanone               I-28a                         (1S)-1-((3R)-1-{[6-(aminomethyl)- 3-pyridinyl]carbonyl}-3-piperidinyl)-1- (6-chloro-3′-ethyl-2-biphenylyl)-5- (methyloxy)-1-pentanol               I-29a                         ((1S,3R,4S)-3-amino-4- hydroxycyclopentyl)((R)-3-((S)-1-(6- fluoro-3′-methoxy-5′-methylbiphenyl-2- yl)-1-hydroxy-5- methoxypentyl)piperidin-1-yl) methanone               I-30a                         ((1S,3R,4S)-3-amino-4- hydroxycyclopentyl)((R)-3-((S)-1-(6- chloro-3′-ethylbiphenyl-2-yl)-1- hydroxy-5-methoxypentyl) piperidin-1- yl)methanone               I-31a                         ((1R,3S)-3-aminocyclopentyl)((R)- 3-((S)-1-(3-chloro-2-(2- ethylphenoxy)phenyl)-1-hydroxy-5- methoxypentyl) piperidin-1- yl)methanone               I-32a                         ((1R,3S)-3-aminocyclopentyl)((R)- 3-((S)-1-(3-chloro-2-(3- ethylphenoxy)phenyl)-1-hydroxy-5- methoxypentyl) piperidin-1- yl)methanone               I-33a                         ((1S,3R,4S)-3-amino-4- hydroxycyclopentyl)((R)-3-((S)-1-(3- chloro-2-(2-methylbenzyl) phenyl)-1- hydroxy-5-methoxypentyl)piperidin-1- yl)methanone               I-34a                         ((1S,3R,4S)-3-amino-4- hydroxycyclopentyl)((R)-3-((S)-1-(3- chloro-2-(3-methylbenzyl) phenyl)-1- hydroxy-5-methoxypentyl)piperidin-1- yl)methanone               I-35a                         ((1S,3R,4S)-3-amino-4- hydroxycyclopentyl)((R)-2-((R)-1-(6- fluoro-3′-methoxy-5′-methylbiphenyl-2- yl)-1-hydroxy-5- methoxypentyl)morpholino)methanone               I-36a                         ((1S,3R,4S)-3-amino-4- hydroxycyclopentyl)((R)-3-((S)-1-(3- chloro-2-(o-tolyloxy)phenyl)-1- hydroxy-5-methoxypentyl) piperidin-1- yl)methanone               I-37a                         ((1S,3R,4S)-3-amino-4- hydroxycyclopentyl)((R)-2-((R)-1-(6- chloro-3′-ethylbiphenyl-2-yl)-1- hydroxy-5-methoxypentyl) morpholino)methanone               I-38a                         ((1S,3R,4S)-3-amino-4- hydroxycyclopentyl)((2R)-2-((1R)-1-(6- chloro-2′-fluoro-5′-methylbiphenyl-2- yl)-1-hydroxy-5- methoxypentyl)morpholino) methanone               I-39a                         ((1R,3S)-3-aminocyclopentyl) ((R)- 3-((S)-1-(3-chloro-2-(quinolin-3- yl)phenyl)-1-hydroxy-5- methoxypentyl) piperidin-1- yl)methanone               I-40a                         ((1R,3S)-3-aminocyclopentyl) ((R)- 2-((R)-1-(3-chloro-2-(naphthalen-2- yl)phenyl)-1-hydroxy-5- methoxypentyl) morpholino) methanone               I-41a                         ((1R,3S)-3-aminocyclopentyl) ((R)- 2-((R)-1-(3-chloro-2-(quinolin-3- yl)phenyl)-1-hydroxy-5- methoxypentyl) morpholino) methanone               I-42a                         methyl ((4S)-4-hydroxy-4-((3R)-1- {((1R,3S)-3-(methylamino) cyclopentyl]carbonyl}-3-piperidinyl)-4- {2-[(2-methylphenyl) oxy]phenyl}butyl)carbamate               I-43a                         methyl (S)-4-(6-fluoro-3′- methoxybiphenyl-2-yl)-4-hydroxy-4- ((R)-1-((1R,3S)-3-(methylamino) cyclopentanecarbonyl)piperidin-3- yl)butylcarbamate               I-44a                         N-((S)-4-((R)-1-((1S,3R,4S)-3- amino-4-hydroxycyclopentane carbonyl)piperidin-3-yl)-4-(6-chloro-3′- ethylbiphenyl-2-yl)-4- hydroxybutyl)acetamide               I-45a                         methyl (S)-4-((R)-1-((1R,3S)-3- aminocyclopentanecarbonyl)piperidin- 3-yl)-4-(6-chloro-3′-ethylbiphenyl-2- yl)-4-hydroxybutylcarbamate               I-46a                         methyl (R)-4-((R)-4-((1R,3S)-3- aminocyclopentanecarbonyl)morpholin- 2-yl)-4-(6-chloro-3′-ethylbiphenyl-2- yl)-4-hydroxybutylcarbamate               I-47a                         ((1S,3R,4S)-3-amino-4- hydroxycyclopentyl)((R)-3-((S)-1-(3- chloro-2-(3-ethylphenoxy) phenyl)-1- hydroxy-5-methoxypentyl)piperidin-1- yl)methanone               I-48a                         ((1S,3R,4S)-3-amino-4- hydroxycyclopentyl)((R)-2-((R)-1-(6- fluoro-3′,5′-dimethoxybiphenyl-2-yl)-1- hydroxy-5-methoxypentyl) morpholino) methanone               I-49a                         ((1S,3R,4S)-3-amino-4- hydroxycyclopentyl)((R)-2-((R)-1-(6- chloro-3′-(methoxymethyl) biphenyl-2- yl)-1-hydroxy-5- methoxypentyl)morpholino) methanone               I-50a                         (4-(aminomethyl)cyclohexyl) ((2R)-2-((1R)-1-(6-chloro-2′-fluoro-5′- methylbiphenyl-2-yl)-1-hydroxy-5- methoxypentyl) morpholino)methanone               I-51a                         ((1S,3R,4S)-3-amino-4-  hydroxycyclopentyl)((R)-3-((S)-1-(3- chloro-2-(quinolin-3-yl)phenyl)-1- hydroxy-5-methoxypentyl) piperidin-1- yl)methanone               I-52a                         ((1S,3R,4S)-3-amino-4- hydroxycyclopentyl)((R)-2-((R)-1-(3- chloro-2-(naphthalen-2-yl)phenyl)-1- hydroxy-5-methoxypentyl)morpholino)  methanone               I-53a                         ((1S,3R,4S)-3-amino-4- hydroxycyclopentyl)((R)-2-((R)-1-(3- chloro-2-(quinolin-3-yl)phenyl)-1- hydroxy-5-methoxypentyl)morpholino) methanone               I-54a                         ((1S,3R,4S)-3-amino-4- hydroxycyclopentyl)((2R)-2-((1R)-1-(3- chloro-2-(isoquinolin-4-yl)phenyl)-1- hydroxy-5-methoxypentyl)morpholino) methanone               I-55a                         methyl (S)-4-(6-chloro-3′- ethylbiphenyl-2-yl)-4-hydroxy-4-((R)- 1-((1R,3S)-3- (methylamino)cyclopentanecarbonyl) piperidin-3-yl)butylcarbamate               I-56a                         methyl (S)-4-((R)-1-((1R,3S)-3-  aminocyclopentanecarbonyl)piperidin- 3-yl)-4-(6-chloro-3′-isopropylbiphenyl- 2-yl)-4-hydroxybutylcarbamate               I-57a                         methyl (S)-4-((R)-1-((1S,3R,4S)-3- amino-4-hydroxycyclopentanecarbonyl) piperidin-3-yl)-4-(6-chloro-3′- ethylbiphenyl-2-yl)-4- hydroxybutylcarbamate               I-58a                         methyl (S)-4-(6-chloro-3′- methoxybiphenyl-2-yl)-4-hydroxy-4- ((R)-1-((1R,3S)-3-(methylamino) cyclopentanecarbonyl)piperidin-3- yl)butylcarbamate               I-59a                         ((1S,3R,4S)-3-amino-4- hydroxycyclopentyl)((R)-2-((R)-1-(6- chloro-3′,5′-dimethoxybiphenyl-2-yl)-1- hydroxy-5-methoxypentyl) morpholino) methanone               I-60a                         methyl (S)-4-((R)-1-(trans-4- (aminomethyl)cyclohexanecarbonyl) piperidin-3-yl)-4-(6-chloro-3′-  ethylbiphenyl-2-yl)-4- hydroxybutylcarbamate               I-61a                         methyl (S)-4-((R)-1-((1S,3R,4S)-3- amino-4-hydroxycyclopentanecarbonyl) piperidin-3-yl)-4-(6-chloro-3′-  isopropylbiphenyl-2-yl)-4- hydroxybutylcarbamate               I-62a                         ((1R,3S)-3-aminocyclopentyl)((R)- 3-((S)-1-(3′-ethoxy-6-fluoro-5′- (trifluoromethyl)biphenyl-2-yl)-1- hydroxy-5-methoxypentyl)piperidin-1- yl)methanone               I-63a                         methyl (S)-4-((R)-1-((1S,3R,4S)-3- amino-4-hydroxycyclopentanecarbonyl) piperidin-3-yl)-4-(3-chloro-2-(quinolin- 3-yl)phenyl)-4-hydroxybutylcarbamate               I-64a                         ((1R,3S)-3-aminocyclopentyl)((R)- 2-((R)-1-(3′-ethoxy-6-fluoro-5′- (trifluoromethyl)biphenyl-2-yl)-1- hydroxy-5-methoxypentyl)morpholino) methanone               I-65a                         ((1S,3R,4S)-3-amino-4- hydroxycyclopentyl)((R)-3-((S)-1-(3′- ethoxy-6-fluoro-5′- (trifluoromethyl)biphenyl-2-yl)-1- hydroxy-5-methoxypentyl)piperidin-1- yl)methanone               I-66a                         ((1S,3R,4S)-3-amino-4- hydroxycyclopentyl)((R)-2-((R)-1-(3′- ethoxy-6-fluoro-5′- (trifluoromethyl)biphenyl-2-yl)-1- hydroxy-5-methoxypentyl)morpholino) methanone               I-67a                         ((1R,3S)-3-aminocyclopentyl)((R)- 2-((R)-1-(6-fluoro-3′,5′- dimethoxybiphenyl-2-yl)-1-hydroxy-5- methoxypentyl)morpholino) methanone               I-68a                         ((1R,3S)-3- aminocyclopentyl)((2R)-2-((1R)-1-(3- chloro-2-(isoquinolin-4-yl)phenyl)-1- hydroxy-5-methoxypentyl) morpholino)methanone               I-69a                         methyl (4-((3R)-1-{[(1R,3S)-3- aminocyclopentyl]carbonyl}-3- piperidinyl)-4-{3-chloro-2-[(2- methylphenyl)oxy]phenyl}-4- hydroxybutyl)carbamate               I-70a                         methyl (4-((3R)-1-{[(1R,3S)-3- aminocyclopentyl]carbonyl}-3- piperidinyl)-4-{3-chloro-2-[(2- ethylphenyl)oxy]phenyl}-4- hydroxybutyl)carbamate               I-71a                         methyl (4-((3R)-1-{[(1S,3R,4S)-3- amino-4- hydroxycyclopentyl]carbonyl}-3- piperidinyl)-4-{3-chloro-2-[(2- methylphenyl)oxy]phenyl}-4- hydroxybutyl)carbamate               I-72a                         methyl (4-((3R)-1-{[(1S,3R,4S)-3- amino-4- hydroxycyclopentyl]carbonyl}-3- piperidinyl)-4-{3-chloro-2-[(2- ethylphenyl)oxy]phenyl}-4- hydroxybutyl)carbamate               I-73a                         methyl [4-((3R)-1-{[(1S,3R,4S)-3- amino-4- hydroxycyclopentyl]carbonyl}-3-  piperidinyl)-4-(3′-ethyl-6-fluoro-2- biphenylyl)-4-hydroxybutyl]carbamate               I-74a                         methyl {4-(6-chloro-3′-ethyl-2- biphenylyl)-4-hydroxy-4-[(3R)-1- ({trans-4-[(methylamino)methyl] cyclohexyl}carbonyl)-3- piperidinyl]butyl}carbamate               I-75a                         methyl [(4S)-4-((3R)-1-{[(1R,2S)- 2-aminocyclopentyl]carbonyl}-3- piperidinyl)-4-(3′-ethyl-6-fluoro-2- biphenylyl)-4-hydroxybutyl]carbamate               I-76a                         (1R)-1-((2R)-4-{(6-(aminomethyl)- 3-pyridinyl]carbonyl}-2-morpholinyl)- 1-(6-chloro-3′-ethyl-2-biphenylyl)-5- (methyloxy)-1-pentanol               I-77a                         methyl [(4S)-4-((3R)-1-{(6- (aminomethyl)-3-pyridinyl]carbonyl}- 3-piperidinyl)-4-(6-chloro-3′-ethyl-2- biphenylyl)-4-hydroxybutyl]carbamate               I-78a                         (1S)-1-{(3R)-1-[(cis-4- aminocyclohexyl)acetyl]-3- piperidinyl}-1-(6-chloro-3′-ethyl-2- biphenylyl)-5-(methyloxy)-1-pentanol               I-79a                         (1S)-1-{(3R)-1-[(trans-4- aminocyclohexyl)acetyl]-3- piperidinyl}-1-(6-chloro-3′-ethyl-2- biphenylyl)-5-(methyloxy)-1-pentanol               I-80a                         (1S)-1-((3R)-1-{((1R,2S)-2- aminocyclopentyl]carbonyl}-3- piperidinyl)-1-(6-chloro-3′-ethyl-2- biphenylyl)-5-(methyloxy)-1-pentanol               I-81a                         (1R)-1-(6-chloro-3′-ethyl-2- biphenylyl)-1-((2R)-4-{[(1R,3S)-3- (methylamino)cyclopentyl]carbonyl}-2- morpholinyl)-5-(methyloxy)-1-pentanol               I-82a                         (1S)-1-(6-chloro-3′-ethyl-2- biphenylyl)-1-((3R)-1-{((1R,3S)-3- (methylamino)cyclopentyl]carbonyl}-3- piperidinyl)-5-(methyloxy)-1-pentanol               I-83a                         (1S,2R,4S)-4-({(2R)-2-[(1R)-1-(6- chloro-3′-ethyl-2-biphenylyl)-1- hydroxy-5-(methyloxy)pentyl]-4- morpholinyl}carbonyl)-2-[(2- hydroxyethyl)amino]cyclopentanol               I-84a                         methyl {(4S)-4-(6-chloro-3′-ethyl- 2-biphenylyl)-4-hydroxy-4-[(3R)-1- ({(1S,3S,4R)-3-hydroxy-4-[(2- hydroxyethyl)amino]cyclopentyl} carbonyl)-3-piperidinyl]butyl}carbamate               I-85a                         (1S)-1-(6-chloro-3′-ethyl-2- biphenylyl)-1- [(3R)-1-({trans-4- [(methylamino)methyl]cyclohexyl} carbonyl)-3-piperidinyl]-5-(methyloxy)-1- pentanol               I-86a                         (1S,2R,4S)-4-({(2R)-2-[(1R)-1-(6- chloro-3′-ethyl-2-biphenylyl)-1- hydroxy-5-(methyloxy)pentyl]-4- morpholinyl}carbonyl)-2-[(1,3-thiazol- 2-ylmethyl)amino]cyclopentanol               I-87a                         methyl [(4S)-4-((3R)-1-{[(1R,3S)-  3-aminocyclohexyl]carbonyl}-3- piperidinyl)-4-(6-chloro-3′-ethyl-2- biphenylyl)-4-hydroxybutyl]carbamate               I-88a                         N-{(4S)-4-(6-chloro-3′-methyl-2- biphenylyl)-4-hydroxy-4-[(3R)-1- ({trans-4- [(methylamino)methyl]cyclohexyl} carbonyl)-3-piperidinyl]butyl}acetamide               I-89a                         N-[(4S)-4-(6-chloro-3′-methyl-2-  biphenylyl)-4-hydroxy-4-((3R)-1- {[(1R,3S)-3- (methylamino)cyclopentyl]carbonyl}-3- piperidinyl)butyl]acetamide               I-90a                         (1R)-1-(6-chloro-3′-ethyl-2- biphenylyl)-1-{(2R)-4-[((1R,3S)-3- {((2,5-dimethyl-1,3-oxazol-4- yl)methyl]amino}cyclopentyl)carbonyl]- 2-morpholinyl}-5-(methyloxy)-1- pentanol               I-91a                         N-[(4S)-4-((3R)-1-{[trans-4- (aminomethyl)cyclohexyl]carbonyl}-3- piperidinyl)-4-(6-chloro-3′-methyl-2- biphenylyl)-4-hydroxybutyl]acetamide               I-92a                         methyl {(4S)-4-(4,6-difluoro-3′- methyl-2-biphenylyl)-4-hydroxy-4- [(3R)-1-({trans-4- [(methylamino)methyl]cyclohexyl} carbonyl)-3-piperidinyl]butyl}carbamate               I-93a                         methyl [(4S)-4-hydroxy-4-((3R)-1- {[(1R,3S)-3-(methylamino) cyclopentyl]carbonyl}-3-piperidinyl)-4- (2′,4,6-trifluoro-5′-methyl-2- biphenylyl)butyl] carbamate               I-94a                         methyl [(4S)-4-hydroxy-4-[(3R)-1- ({trans-4-[(methylamino) methyl]cyclohexyl}carbonyl)-3- piperidinyl]-4-(2′,4,6-trifluoro-5- methyl-2-biphenylyl)butyl] carbamate               I-95a                         methyl [(4S)-4-(6-chloro-3′- methyl-2-biphenylyl)-4-hydroxy-4- ((3R)-1-{[(1R,3S)-3-(methylamino) cyclopentyl]carbonyl}-3- piperidinyl)butyl]carbamate               I-96a                         (1R)-1-(6-chloro-3′-ethyl-2- biphenylyl)-1-[(2R)-4-({trans-4- [(methylamino)methyl]cyclohexyl} carbonyl)-2-morpholinyl]-5-(methyloxy)-1- pentanol               I-97a                         methyl [(4R)-4-((2R)-4- {[(1S,3R,4S)-3-amino-4- hydroxycyclopentyl]carbonyl}-2- morpholinyl)-4-(3′-ethyl-6-fluoro-2- biphenylyl)-4-hydroxybutyl] carbamate               I-98a                         methyl {(4R)-4-(3′-ethyl-6-fluoro- 2-biphenylyl)-4-hydroxy-4-[(2R)-4- ({trans-4- [(methylamino)methyl]cyclohexyl} carbonyl)-2-morpholinyl]butyl} carbamate               I-99a                         (1S,2R,4S)-2-amino-4-({(2R)-2- [(1R)-1-[2-chloro-3-(3-ethylphenyl)-4- pyridinyl]-1-hydroxy-5- (methyloxy)pentyl]-4- morpholinyl}carbonyl) cyclopentanol               I-100a                         (1R)-1-((2R)-4-{[(1R,3S)-3- aminocyclopentyl] carbonyl}-2- morpholinyl)-1-[2-chloro-3-(3- ethylphenyl)-4-pyridinyl]-5- (methyloxy)-1-pentanol               I-101a                         (1S,2R,4S)-2-amino-4-({(2R)-2- [(1R)-1-[2-(1-benzothien-3-yl)-3- chlorophenyl]-1-hydroxy-5- (methyloxy)pentyl]-4-morpholinyl} carbonyl)cyclopentanol               I-102a                         (1R)-1-((2R)-4-{[(1R,3S)-3- aminocyclopentyl]carbonyl}-2- morpholinyl)-1-[2-(1-benzothien-3-yl)- 3-chlorophenyl]-5-(methyloxy)-1- pentanol               I-103a                         (1R)-1-[4-chloro-3-(3- ethylphenyl)-2-pyridinyl]-1-((2R)-4- {[(1R,3S)-3-(methylamino) cyclopentyl]carbonyl}-2-morpholinyl)- 5-(methyloxy)-1-pentanol               I-104a                         methyl {(4S)-4-[2-chloro-3-(3- ethylphenyl)-4-pyridinyl]-4-hydroxy-4- [(3R)-1-({trans-4- [(methylamino)methyl]cyclohexyl carbonyl)-3-piperidinyl]butyl} carbamate               I-105a                         methyl [(4S)-4-[2-chloro-3-(3- ethylphenyl)-4-pyridinyl]-4-hydroxy-4- ((3R)-1-{[(1R,3S)-3- (methylamino)cyclopentyl] carbonyl}- 3-piperidinyl)butyl] carbamate               I-106a                         methyl {(4S)-4-{3-chloro-2-[4-(1- methylethyl)-2-quinazolinyl]phenyl}-4- hydroxy-4-[(3R)-1-({trans-4- [(methylamino)methyl]cyclohexyl} carbonyl)-3-piperidinyl]butyl}carbamate               I-107a                         methyl [(4S)-4-{3-chloro-2-[4-(1- methylethyl)-2-quinazolinyl] phenyl}- 4-hydroxy-4-((3R)-1-{[(1R,3S)-3- (methylamino) cyclopentyl]carbonyl}- 3-piperidinyl)butyl]carbamate               I-108a                         (1S)-1-((3R)-1-{[(1R,3S)-3- aminocyclopentyl]carbonyl}-3- piperidinyl)-1-{3-chloro-2-[(3- methylphenyl)oxy]phenyl}-5- (methyloxy)-1-pentanol               I-109a                         (1S,2R,4S)-2-amino-4-({(3R)-3- [(1S)-1-{3-chloro-2-[(3- methylphenyl)oxy]phenyl}-1-hydroxy- 5-(methyloxy)pentyl]-1- piperidinyl}carbonyl)cyclopentanol               I-110a                         methyl ((4S)-4-((3R)-1-{[(1R,3S)- 3-aminocyclopentyl] carbonyl}-3- piperidinyl)-4-{3-chloro-2-[(3- methylphenyl)oxy] phenyl}-4- hydroxybutyl)carbamate               I-111a                         methyl ((4S)-4-((3R)-1- {[(1S,3R,4S)-3-amino-4- hydroxycyclopentyl]carbonyl}-3- piperidinyl)-4-{3-chloro-2-[(3- methylphenyl)oxy]phenyl}-4- hydroxybutyl)carbamate               I-112a                         methyl ((4S)-4-((3R)-1-{[(1R,3S)- 3-aminocyclopentyl] carbonyl}-3- piperidinyl)-4-{2-[(2,6- dimethylphenyl)oxy]phenyl}-4- hydroxybutyl)carbamate               I-113a                         methyl ((4S)-4-((3R)-1- {[(1S,3R,4S)-3-amino-4- hydroxycyclopentyl]carbonyl}-3- piperidinyl)-4-{2-[(2,6- dimethylphenyl)oxy]phenyl}-4- hydroxybutyl)carbamate               I-114a                         methyl {(4S)-4-{3-chloro-2-[8-(1- methylethyl)-2-quinolinyl] phenyl}-4- hydroxy-4-[(3R)-1-({trans-4- [(methylamino)methyl] cyclohexyl}carbonyl)-3- piperidinyl]butyl}carbamate               I-115a                         methyl {(4S)-4-[3-chloro-2-(8- methyl-2-quinolinyl)phenyl]-4- hydroxy-4-[(3R)-1-({trans-4- [(methylamino)methyl]cyclohexyl} carbonyl)-3-piperidinyl]butyl} carbamate               I-116a                         methyl [(4S)-4-[3-fluoro-2-(3- quinolinyl)phenyl]-4-hydroxy-4-((3R)- 1-{[(1R,3S)-3-(methylamino) cyclopentyl]carbonyl}-3- piperidinyl)butyl]carbamate               I-117a                         methyl [(4S)-4-{2-chloro-3-[3-(1- methylethyl)phenyl]-4-pyridinyl}-4- hydroxy-4-((3R)-1-{[(1R,3S)-3- (methylamino) cyclopentyl]carbonyl}- 3-piperidinyl)butyl]carbamate               I-118a                         methyl [(4S)-4-[3-chloro-2-(5- methyl-2-furanyl)phenyl]-4-hydroxy-4- ((3R)-1-{[(1R,3S)-3- (methylamino)cyclopentyl] carbonyl}- 3-piperidinyl)butyl] carbamate               I-119a                         methyl {(4S)-4-((3R)-1- {[(1S,3R,4S)-3-amino-4- hydroxycyclopentyl]carbonyl}-3- piperidinyl)-4- [3-chloro-2-(5-methyl-2- furanyl)phenyl]-4- hydroxybutyl}carbamate               I-120a                         (1R)-1-{2-chloro-3-[3-(1- methylethyl)phenyl]-4-pyridinyl}-1- [(2R)-4-({trans-4- [(methylamino)methyl]cyclohexyl} carbonyl)-2-morpholinyl]-5- (methyloxy)-1-pentanol               I-121a                         (1R)-1-{2-chloro-3-[3-(1- methylethyl)phenyl]-4-pyridinyl}-1- ((2R)-4-{[(1R,3S)-3- (methylamino)cyclopentyl] carbonyl}- 2-morpholinyl)-5-(methyloxy)-1- pentanol               I-122a                         (1S,2R,4S)-2-amino-4-({(2R)-2- [(1R)-1-{2-chloro-3-[3-(1- methylethyl)phenyl]-4-pyridinyl}-1- hydroxy-5-(methyloxy)pentyl]-4- morpholinyl}carbonyl) cyclopentanol               I-123a                         methyl {(4S)-4-[5-chloro-4-(3- ethylphenyl)-3-pyridinyl]-4-hydroxy-4- [(3R)-1-({trans-4- [(methylamino)methyl]cyclohexyl} carbonyl)-3-piperidinyl]butyl} carbamate               I-124a                         methyl [(4S)-4-[5-chloro-4-(3- ethylphenyl)-3-pyridinyl]-4-hydroxy-4- ((3R)-1-{[(1R,3S)-3- (methylamino)cyclopentyl] carbonyl}- 3-piperidinyl)butyl] carbamate               I-125a                         methyl {(4S)-4-{5-chloro-4-[3-(1- methylethyl)phenyl]-3-pyridinyl}-4- hydroxy-4-[(3R)-1-({trans-4- [(methylamino) methyl]cyclohexyl}carbonyl)-3- piperidinyl]butyl}carbamate               I-126a                         methyl [(4S)-4-{5-chloro-4-[3-(1- methylethyl)phenyl]-3-pyridinyl}-4- hydroxy-4-((3R)-1-{[(1R,3S)-3- (methylamino)cyclopentyl]carbonyl}- 3-piperidinyl)butyl]carbamate               I-127a                         methyl {(4S)-4-[6-fluoro-3′-(l- methylethyl)-2-biphenylyl]-4-hydroxy- 4-[(3R)-1-({trans-4- [(methylamino)methyl]cyclohexyl} carbonyl)-3-piperidinyl]butyl} carbamate               I-128a                         methyl [(4S)-4-(6-chloro-3′-fluoro- 5′-methyl-2-biphenylyl)-4-hydroxy-4- ((3R)-1-{[(1R,3S)-3- (methylamino)cyclopentyl] carbonyl}- 3-piperidinyl)butyl] carbamate               I-129a                         methyl [(4S)-4-(3′,6-difluoro-5′- methyl-2-biphenylyl)-4-hydroxy-4- ((3R)-1-{[(1R,3S)-3- (methylamino)cyclopentyl] carbonyl}- 3-piperidinyl)butyl] carbamate               I-130a                         (1S,2R,4S)-2-amino-4-({(3R)-3- [(1S)-1-{3-chloro-2-[(2- ethylphenyl)oxy]phenyl}-1-hydroxy-5- (methyloxy)pentyl]-1- piperidinyl}carbonyl)cyclopentanol               I-131a                         methyl {(4S)-4-(3′-ethyl-6-fluoro- 2-biphenylyl)-4-hydroxy-4-[(3R)-1- ({trans-4-[(methylamino) methyl]cyclohexyl}carbonyl)-3- piperidinyl]butyl}carbamate               I-132a                         (1S,2R,4S)-2-amino-4-({(3R)-3- [(1S)-1-{2-[(2-chloro-6- methylphenyl)oxy]phenyl}-1-hydroxy 5-(methyloxy)pentyl]-1- piperidinyl}carbonyl)cyclopentanol               I-133a                         (1S,2R,4S)-2-amino-4-({(3R)-3- [(1S)-1-{3-fluoro-2-[(3- methylphenyl)oxy]phenyl}-1-hydroxy 5-(methyloxy)pentyl]-1- piperidinyl}carbonyl)cyclopentanol               I-134a                         (1S)-1-((3R)-1-{[(1R,3S)-3- aminocyclopentyl]carbonyl}-3- piperidinyl)-1-{3-fluoro-2-[(3- methylphenyl)oxy]phenyl}-5- (methyloxy)-1-pentanol               I-135a                         methyl ((4S)-4-((3R)-1- {[(1S,3R,4S)-3-amino-4- hydroxycyclopentyl]carbonyl}-3- piperidinyl)-4-{3-chloro-2-[(3- ethylphenyl)oxy]phenyl}-4- hydroxybutyl)carbamate               I-136a                         methyl ((4S)-4-((3R)-1-{[(1R,3S)- 3-aminocyclopentyl]carbonyl}-3- piperidinyl)-4-{3-chloro-2-[(3- ethylphenyl)oxy] phenyl}-4- hydroxybutyl)carbamate               I-137a                         methyl ((4S)-4-((3R)-1- {[(1S,3R,4S)-3-amino-4- hydroxycyclopentyl] carbonyl}-3- piperidinyl)-4-{3-fluoro-2-[(3- methylphenyl)oxy]phenyl}-4- hydroxybutyl)carbamate               I-138a                         methyl ((4S)-4-((3R)-1-{[(1R,3S)- 3-aminocyclopentyl] carbonyl}-3- piperidinyl)-4-{3-fluoro-2-[(3- methylphenyl)oxy] phenyl}-4- hydroxybutyl)carbamate               I-139a                         methyl ((4S)-4-((3R)-1- {[(1S,3R,4S)-3-amino-4- hydroxycyclopentyl]carbonyl}-3- piperidinyl)-4-{3-chloro-2-[(3- methylphenyl)methyl]phenyl}-4- hydroxybutyl)carbamate               I-140a                         methyl [(4S)-4-{3-chloro-2-[(3- methylphenyl)methyl]phenyl}-4- hydroxy-4-((3R)-1-{[(1R,3S)-3- (methylamino)cyclopentyl] carbonyl}- 3-piperidinyl)butyl] carbamate               I-141a                         methyl ((4S)-4-((3R)-1-{[(1R,3S)- 3-aminocyclopentyl] carbonyl}-3- piperidinyl)-4-{3-chloro-2-[(3- methylphenyl)methyl] phenyl}-4- hydroxybutyl)carbamate               I-142a                         methyl (2-{[(S)-((2R)-4- {[(1S,3R,4S)-3-amino-4- hydroxycyclopentyl]carbonyl}-2- morpholinyl)(6-chloro-3′-ethyl-2- biphenylyl)methyl]oxy}ethyl) carbamate               I-143a                         methyl (2-{[(R)-((3R)-1- {[(1S,3R,4S)-3-amino-4- hydroxycyclopentyl]carbonyl}-3- piperidinyl)(6-chloro-3′-ethyl-2- biphenylyl)methyl]oxy}ethyl)carbamate               I-144a                         methyl [(4S)-4-((3R)-1-{[4- (aminomethyl)-5-methyl-2- furanyl]carbonyl}-3-piperidinyl)-4-(6- chloro-3′-ethyl-2-biphenylyl)-4- hydroxybutyl]carbamate               I-145a                         methyl {(4S)-4-(6-chloro-3′-ethyl- 2-biphenylyl)-4-hydroxy-4-[(3R)-1-({6- [(methylamino) methyl]-3- pyridinyl}carbonyl)-3- piperidinyl]butyl}carbamate               I-146a                         methyl [(4S)-4-{(3R)-1-[(2-amino- 4-oxo-1,4-dihydro-5- pyrimidinyl)carbonyl]-3-piperidinyl}-4- (6-chloro-3′-methyl-2-biphenylyl)-4- hydroxybutyl] carbamate               I-147a                         methyl [(4S)-4-(6-chloro-3′- methyl-2-biphenylyl)-4-hydroxy-4- ((3R)-1-{[2-(methylamino)-5- pyrimidinyl]carbonyl}-3- piperidinyl)butyl]carbamate               I-148a                         methyl [(4S)-4-((3R)-1-{[5- (aminomethyl)-3-isoxazolyl] carbonyl}- 3-piperidinyl)-4-(6-chloro-3′-methyl-2- biphenylyl)-4-hydroxybutyl] carbamate               I-149a                         methyl {(4S)-4-(6-chloro-3′-ethyl- 2-biphenylyl)-4-hydroxy-4-[(3R)-1-({5- [(methylamino) methyl]-2- thienyl}carbonyl)-3- piperidinyl]butyl}carbamate               I-150a                         methyl [(4S)-4-{(3R)-1-[(6-amino- 3-pyridinyl)carbonyl]-3-piperidinyl}-4- (3′,6-difluoro-5′-methyl-2-biphenylyl)- 4-hydroxybutyl]carbamate               I-151a                         methyl [2-({(R)-(6-chloro-3′-ethyl- 2-biphenylyl)[(3R)-1-({trans-4- [(methylamino)methyl] cyclohexyl}carbonyl)-3-piperidinyl] methyl}oxy)ethyl]carbamate               I-152a                         methyl [2-({(S)-(6-chloro-3′-ethyl- 2-biphenylyl)[(2R)-4-({trans-4- [(methylamino)methyl] cyclohexyl}carbonyl)-2- morpholinyl]methyl}oxy)ethyl] carbamate               I-153a                         N-[(4S)-4-((3R)-1-{[6- (aminomethyl)-3-pyridinyl] carbonyl}- 3-piperidinyl)-4-(6-chloro-3′-methyl-2- biphenylyl)-4-hydroxybutyl]acetamide               I-154a                         methyl [(4S)-4-((3R)-1-{[4- (aminomethyl)-1-piperidinyl] carbonyl}-3-piperidinyl)-4-(3′-ethyl-6- fluoro-2-biphenylyl)-4-hydroxybutyl] carbamate               I-155a                         methyl {(4S)-4-(3′-ethyl-6-fluoro- 2-biphenylyl)-4-hydroxy-4-[(3R)-1-({4- [(methylamino) methyl]-1- piperidinyl}carbonyl)-3- piperidinyl]butyl}carbamate               I-156a                         methyl [(4S)-4-((3R)-1-{[4- (aminomethyl)-1-piperidinyl] carbonyl}-3-piperidinyl)-4-(6-chloro-3′- ethyl-2-biphenylyl)-4- hydroxybutyl]carbamate               I-157a                         methyl [(4S)-4-((3R)-1-{[4- (aminomethyl)-4-phenyl-1- piperidinyl]carbonyl}-3-piperidinyl)-4- (6-chloro-3′-ethyl-2-biphenylyl)-4- hydroxybutyl]carbamate               I-158a                         N-[(4S)-4-((3R)-1-{[4- (aminomethyl)-1-piperidinyl] carbonyl}-3-piperidinyl)-4-(2′,6- difluoro-5′-methyl-2-biphenylyl)-4- hydroxybutyl]-2-hydroxyacetamide               I-159a                         methyl {(4S)-4-(6-chloro-3′-ethyl- 2-biphenylyl)-4-hydroxy-4-[(3R)-1-({4- [(methylamino) methyl]-1- piperidinyl}carbonyl)-3- piperidinyl]butyl}carbamate               I-160a                         methyl {(4S)-4-(6-chloro-3′-ethyl- 2-biphenylyl)-4-hydroxy-4-[(3R)-1-({4- [(2-propen-1-ylamino)methyl]-1- piperidinyl} carbonyl)-3- piperidinyl]butyl} carbamate                    
or the salts thereof.
 
     The following Compound Nos. represent the preferred compounds of this invention: I-3a, I-6a, I-7a, I-12a, I-15a, I-28a, I-29a, I-32a, I-33a, I-35a, I-38a, I-39a, I-40a, I-48a, I-49a, I-51a, I-53a, I-54a, I-59a, I-76a, I-77a, I-78a, I-79a, I-83a, I-85a, I-87a, I-88a, I-92a, I-95a, I-96a, I-99a, I-101a, I-102a, I-104a, I-105a, I-106a, I-107a, I-108a, I-113a, I-116a, I-117a, I-122a, I-132a, 134a, I-148a, I-150a, and I-153a, or the salts thereof. The following Compound Nos. represent the more preferred compounds of this invention: I-13a, I-20a, I-21a, I-24a, I-26a, I-30a, I-31a, I-36a, I-37a, I-42a, I-43a, I-44a, I-45a, I-46a, I-47a, I-52a, I-55a, I-56a, I-57a, I-58a, I-60a, I-61a, I-63a, I-69a, I-70a, I-72a, I-73a, I-74a, I-81a, I-82a, I-84a, I-89a, I-91a, I-93a, I-94a, I-97a, I-98a, I-109a, I-110a, I-111a, I-114a, I-115a, I-123a, I-124a, I-125a, I-126a, I-127a, I-128a, I-129a, I-130a, I-131a, I-133a, I-135a, I-136a, I-137a, I-138a, I-142a, I-143a, I-145a, I-149a, I-154a, I-155a, I-156a, I-157a, I-158a, I-159a, and I-160a, or the salts thereof. 
     The compounds of the invention (Compound #1-160) exhibit 50% renin inhibition (as determined using the method of Example 17) at concentrations of from approximately 5000 nM to approximately 0.01 nM. Preferred compounds of the invention exhibit 50% inhibition at concentrations of from approximately 50 nM to approximately 0.01 nM. More preferred compounds of the invention exhibit 50% inhibition at concentrations of from approximately 5 nM to approximately 0.01 nM. 
     Enantiomers, Diastereomers, and Salts 
     Certain compounds of this invention may exist in various stereoisomeric or tautomeric forms. The invention encompasses all such forms, including active compounds in the form of essentially pure enantiomers, racemic mixtures, and tautomers, including forms those not depicted structurally. 
     The compounds of the invention may be present in the form of pharmaceutically acceptable salts. For use in medicines, the salts of the compounds of the invention refer to non-toxic “pharmaceutically acceptable salts.” Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts. 
     Pharmaceutically acceptable acidic/anionic salts include, the acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, and triethiodide salts. 
     The compounds of the invention include pharmaceutically acceptable anionic salt forms, wherein the anionic salts include the acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, and triethiodide salts. 
     The anionic salt form of a compound of the invention includes the acetate, bromide, camsylate, chloride, edisylate, fumarate, hydrobromide, hydrochloride, iodide, isethionate, lactate, mesylate, maleate, napsylate, salicylate, sulfate, and tosylate salts. 
     When a disclosed compound or its pharmaceutically acceptable salt is named or depicted by structure, it is to be understood that solvates or hydrates of the compound or its pharmaceutically acceptable salts are also included. “Solvates” refer to crystalline forms wherein solvent molecules are incorporated into the crystal lattice during crystallization. Solvate may include water or non-aqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and EtOAc. Solvates, wherein water is the solvent molecule incorporated into the crystal lattice, are typically referred to as “hydrates”. Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. 
     When a disclosed compound or its pharmaceutically acceptable salt is named or depicted by structure, it is to be understood that the compound, including solvates thereof, may exist in crystalline forms, non-crystalline forms or a mixture thereof. 
     The compound or its pharmaceutically acceptable salts or solvates may also exhibit polymorphism (i.e. the capacity to occur in different crystalline forms). These different crystalline forms are typically known as “polymorphs.” It is to be understood that when named or depicted by structure, the disclosed compound and its pharmaceutically acceptable salts, solvates or hydrates also include all polymorphs thereof. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. One of ordinary skill in the art will appreciate that different polymorphs may be produced, for example, by changing or adjusting the conditions used in solidifying the compound. For example, changes in temperature, pressure, or solvent may result in different polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions. 
     It may be necessary and/or desirable during synthesis to protect sensitive or reactive groups on any of the molecules concerned. Representative conventional protecting groups are described in T. W. Greene and P. G. M. Wuts “Protective Groups in Organic Synthesis” John Wiley &amp; Sons, Inc., New York 1999. Protecting groups may be added and removed using methods well known in the art. 
     The invention also includes various isomers and mixtures thereof. “Isomer” refers to compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). 
     Certain of the disclosed aspartic protease inhibitors may exist in various stereoisomeric forms. Stereoisomers are compounds which differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center. “Enantiomer” means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms. The symbol “*” in a structural formula represents the presence of a chiral carbon center. “R” and “S” represent the configuration of substituents around one or more chiral carbon atoms. Thus, “R*” and “S*” denote the relative configurations of substituents around one or more chiral carbon atoms. When a chiral center is not defined as R or S, a mixture of both configurations is present. 
     “Racemate” or “racemic mixture” means a compound of equimolar quantities of two enantiomers, wherein such mixtures exhibit no optical activity; i.e., they do not rotate the plane of polarized light. 
     “Geometric isomer” means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H) on each side of a carbon-carbon double bond may be in an E (substituents are on opposite sides of the carbon-carbon double bond) or Z (substituents are oriented on the same side) configuration. 
     Atoms (other than H) attached to a carbocyclic ring may be in a cis or trans configuration. In the “cis” configuration, the substituents are on the same side in relationship to the plane of the ring; in the “trans” configuration, the substituents are on opposite sides in relationship to the plane of the ring. A mixture of “cis” and “trans” species is designated “cis/trans”. 
     The point at which a group or moiety is attached to the remainder of the compound or another group or moiety can be indicated by   which represents “ ”,  , or    
     “R,” “S,” “S*,” “R*,” “E,” “Z,” “cis,” and “trans,” indicate configurations relative to the core molecule. 
     The compounds of the invention may be prepared as individual isomers by either isomer-specific synthesis or resolved from an isomeric mixture. Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods. 
     When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight optically pure. Percent optical purity by weight is the ratio of the weight of the enantiomer over the weight of the enantiomer plus the weight of its optical isomer. 
     When a disclosed compound is named or depicted by structure without indicating the stereochemistry, and the inhibitor has at least one chiral center, it is to be understood that the name or structure encompasses one enantiomer of inhibitor free from the corresponding optical isomer, a racemic mixture of the inhibitor and mixtures enriched in one enantiomer relative to its corresponding optical isomer. 
     When a disclosed aspartic protease inhibitor is named or depicted by structure without indicating the stereochemistry and has at least two chiral centers, it is to be understood that the name or structure encompasses a diastereomer free of other diastereomers, a pair of diastereomers free from other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers in which one diastereomer is enriched relative to the other diastereomer(s) and mixtures of diastereomeric pairs in which one diastereomeric pair is enriched relative to the other diastereomeric pair(s). 
     The compounds of the invention are useful for ameliorating or treating disorders or diseases in which decreasing the levels of aspartic protease products is effective in treating the disease state or in treating infections in which the infectious agent depends upon the activity of an aspartic protease. In hypertension elevated levels of angiotensin I, the product of renin catalyzed cleavage of angiotensinogen are present. Thus, the compounds of the invention can be used in the treatment of hypertension, heart failure such as (acute and chronic) congestive heart failure; left ventricular dysfunction; cardiac hypertrophy; cardiac fibrosis; cardiomyopathy (e.g., diabetic cardiac myopathy and post-infarction cardiac myopathy); supraventricular and ventricular arrhythmias; arial fibrillation; atrial flutter; detrimental vascular remodeling; myocardial infarction and its sequelae; atherosclerosis; angina (whether unstable or stable); renal failure conditions, such as diabetic nephropathy; glomerulonephritis; renal fibrosis; scleroderma; glomerular sclerosis; microvascular complications, for example, diabetic retinopathy; renal vascular hypertension; vasculopathy; neuropathy; complications resulting from diabetes, including nephropathy, vasculopathy, retinopathy and neuropathy, diseases of the coronary vessels, proteinuria, albumenuria, post-surgical hypertension, metabolic syndrome, obesity, restenosis following angioplasty, eye diseases and associated abnormalities including raised intra-ocular pressure, glaucoma, retinopathy, abnormal vascular growth and remodeling, angiogenesis-related disorders, such as neovascular age related macular degeneration; hyperaldosteronism, anxiety states, and cognitive disorders (Fisher N. D.; Hollenberg N. K.  Expert Opin. Investig. Drugs.  2001, 10, 417-26). 
     Elevated levels of βamyloid, the product of the activity of the well-characterized aspartic protease β-secretase (BACE) activity on amyloid precursor protein, are widely believed to be responsible for the development and progression of amyloid plaques in the brains of Alzheimer&#39;s disease patients. The secreted aspartic proteases of  Candida albicans  are associated with its pathogenic virulence (Naglik, J. R.; Challacombe, S. J.; Hube, B.  Microbiology and Molecular Biology Reviews  2003, 67, 400-428). The viruses HIV and HTLV depend on their respective aspartic proteases for viral maturation.  Plasmodium falciparum  uses plasmepsins I and II to degrade hemoglobin. 
     A pharmaceutical composition of the invention may, alternatively or in addition to a compound of this invention, comprise a pharmaceutically acceptable salt of a compound of this invention or a prodrug or pharmaceutically active metabolite of such a compound or salt and one or more pharmaceutically acceptable carriers therefore. 
     The compositions of the invention are aspartic protease inhibitors. Said compositions contain compounds having a mean inhibition constant (IC 50 ) against aspartic proteases of between about 5,000 nM to about 0.01 nM; preferably between about 50 nM to about 0.01 nM; and more preferably between about 5 nM to about 0.01 nM. 
     The compositions of the invention reduce blood pressure. Said compositions include compounds having an IC 50  for renin of between about 5,000 nM to about 0.01 nM; preferably between about 50 nM to about 0.01 nM; and more preferably between about 5 nM to about 0.01 nM. 
     The invention includes a therapeutic method for treating or ameliorating an aspartic protease mediated disorder in a subject in need thereof comprising administering to a subject in need thereof an effective amount of a compound of this invention, or the enantiomers, diastereomers, or salts thereof or composition thereof. 
     Administration methods include administering an effective amount (i.e., a therapeutically effective amount) of a compound or composition of the invention at different times during the course of therapy or concurrently in a combination form. The methods of the invention include all known therapeutic treatment regimens. 
     “Prodrug” means a pharmaceutically acceptable form of an effective derivative of a compound (or a salt thereof) of the invention, wherein the prodrug may be: 1) a relatively active precursor which converts in vivo to a compound of the invention; 2) a relatively inactive precursor which converts in vivo to a compound of the invention; or 3) a relatively less active component of the compound that contributes to therapeutic activity after becoming available in vivo (i.e., as a metabolite). See “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985. 
     “Metabolite” means a pharmaceutically acceptable form of a metabolic derivative of a compound (or a salt thereof) of the invention, wherein the derivative is an active compound that contributes to therapeutic activity after becoming available in vivo. 
     “Effective amount” means that amount of active compound agent that elicits the desired biological response in a subject. Such response includes alleviation of the symptoms of the disease or disorder being treated. The effective amount of a compound of the invention in such a therapeutic method is from about 10 mg/kg/day to about 0.01 mg/kg/day, preferably from about 0.5 mg/kg/day to 5 mg/kg/day. 
     The invention includes the use of a compound of the invention for the preparation of a composition for treating or ameliorating an aspartic protease mediated chronic disorder or disease or infection in a subject in need thereof, wherein the composition comprises a mixture one or more compounds of the invention and an optional pharmaceutically acceptable carrier. 
     “Pharmaceutically acceptable carrier” means compounds and compositions that are of sufficient purity and quality for use in the formulation of a composition of the invention and that, when appropriately administered to an animal or human, do not produce an adverse reaction. 
     “Aspartic protease mediated disorder or disease” includes disorders or diseases associated with the elevated expression or overexpression of aspartic proteases and conditions that accompany such diseases. 
     An embodiment of the invention includes administering a renin inhibiting compound of this invention or composition thereof in a combination therapy (U.S. Pat. No. 5,821,232, U.S. Pat. No. 6,716,875, U.S. Pat. No. 5,663,188, Fossa, A. A.; DePasquale, M. J.; Ringer, L. J.; Winslow, R. L. “Synergistic effect on reduction in blood pressure with coadministration of a renin inhibitor or an angiotensin-converting enzyme inhibitor with an angiotensin II receptor antagonist”  Drug Development Research  1994, 33(4), 422-8) with one or more additional agents for the treatment of hypertension including α-blockers, β-blockers, calcium channel blockers, diuretics, natriuretics, saluretics, centrally acting antiphypertensives, angiotensin converting enzyme (ACE) inhibitors, dual ACE and neutral endopeptidase (NEP) inhibitors, angiotensin-receptor blockers (ARBs), aldosterone synthase inhibitor, aldosterone-receptor antagonists, or endothelin receptor antagonist. α-Blockers include doxazosin, prazosin, tamsulosin, and terazosin. β-Blockers for combination therapy are selected from atenolol, bisoprol, metoprolol, acetutolol, esmolol, celiprolol, taliprolol, acebutolol, oxprenolol, pindolol, propanolol, bupranolol, penbutolol, mepindolol, carteolol, nadolol, carvedilol, and their pharmaceutically acceptable salts. Calcium channel blockers include dihydropyridines (DHPs) and non-DHPs. The preferred DHPs are selected from the group consisting of amlodipine, felodipine, ryosidine, isradipine, lacidipine, nicardipine, nifedipine, nigulpidine, niludipine, nimodiphine, nisoldipine, nitrendipine, and nivaldipine and their pharmaceutically acceptable salts. Non-DHPs are selected from flunarizine, prenylamine, diltiazem, fendiline, gallopamil, mibefradil, anipamil, tiapamil, and verampimil and their pharmaceutically acceptable salts. A diuretic is, for example, a thiazide derivative selected from amiloride, chlorothiazide, hydrochlorothiazide, methylchlorothiazide, and chlorothalidon. ACE inhibitors include alacepril, benazepril, benazaprilat, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, lisinopril, moexipiril, moveltopril, perindopril, quinapril, quinaprilat, ramipril, ramiprilat, spirapril, temocapril, trandolapril, and zofenopril. Preferred ACE inhibitors are benazepril, enalpril, lisinopril, and ramipril. Dual ACE/NEP inhibitors are, for example, omapatrilat, fasidotril, and fasidotrilat. Preferred ARBs include candesartan, eprosartan, irbesartan, losartan, olmesartan, tasosartan, telmisartan, and valsartan. Preferred aldosterone synthase inhibitors are anastrozole, fadrozole, and exemestane. Preferred aldosterone-receptor antagonists are spironolactone and eplerenone. A preferred endothelin antagonist is, for example, bosentan, enrasentan, atrasentan, darusentan, sitaxentan, and tezosentan and their pharmaceutically acceptable salts. 
     An embodiment of the invention includes administering an HIV protease inhibiting compound of this invention or composition thereof in a combination therapy with one or more additional agents for the treatment of AIDS including reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, other HIV protease inhibitors, HIV integrase inhibitors, attachment and fusion inhibitors, antisense drugs and immune stimulators. Preferred reverse transcriptase inhibitors are zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, tenofovir, and emtricitabine. Preferred non-nucleoside reverse transcriptase inhibitors are nevirapine, delaviridine, and efavirenz. Preferred HIV protease inhibitors are saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, and fosamprenavir. Preferred HIV integrase inhibitors are L-870,810 and S-1360. A preferred attachment and fusion inhibitor is enfuvirtide. 
     An embodiment of the invention includes administering β-secretase inhibiting compound of this invention or composition thereof in a combination therapy with one or more additional agents for the treatment of Alzheimer&#39;s disease including tacrine, donepezil, rivastigmine, galantamine, and memantine. 
     An embodiment of the invention includes administering a plasmepsin inhibiting compound of this invention or composition thereof in a combination therapy with one or more additional agents for the treatment of malaria including artemisinin, chloroquine, halofantrine, hydroxychloroquine, mefloquine, primaquine, pyrimethamine, quinine, sulfadoxine 
     Combination therapy includes co-administration of the compound of the invention and said other agent, sequential administration of the compound and the other agent, administration of a composition containing the compound and the other agent, or simultaneous administration of separate compositions containing of the compound and the other agent. 
     The invention further includes the process for making the composition comprising mixing one or more of the present compounds and an optional pharmaceutically acceptable carrier; and includes those compositions resulting from such a process, which process includes conventional pharmaceutical techniques. 
     The compositions of the invention include ocular, oral, nasal, transdermal, topical with or without occlusion, intravenous (both bolus and infusion), and injection (intraperitoneally, subcutaneously, intramuscularly, intratumorally, or parenterally). The composition may be in a dosage unit such as a tablet, pill, capsule, powder, granule, liposome, ion exchange resin, sterile ocular solution, or ocular delivery device (such as a contact lens and the like facilitating immediate release, timed release, or sustained release), parenteral solution or suspension, metered aerosol or liquid spray, drop, ampoule, auto-injector device, or suppository; for administration ocularly, orally, intranasally, sublingually, parenterally, or rectally, or by inhalation or insufflation. 
     Compositions of the invention suitable for oral administration include solid forms such as pills, tablets, caplets, capsules (each including immediate release, timed release, and sustained release formulations), granules and powders; and, liquid forms such as solutions, syrups, elixirs, emulsions, and suspensions. Forms useful for ocular administration include sterile solutions or ocular delivery devices. Forms useful for parenteral administration include sterile solutions, emulsions, and suspensions. 
     The compositions of the invention may be administered in a form suitable for once-weekly or once-monthly administration. For example, an insoluble salt of the active compound may be adapted to provide a depot preparation for intramuscular injection (e.g., a decanoate salt) or to provide a solution for ophthalmic administration. 
     The dosage form containing the composition of the invention contains a therapeutically effective amount of the active ingredient necessary to provide a therapeutic effect. The composition may contain from about 5,000 mg to about 0.5 mg (preferably, from about 1,000 mg to about 0.5 mg) of a compound of the invention or salt form thereof and may be constituted into any form suitable for the selected mode of administration. The composition may be administered about 1 to about 5 times per day. Daily administration or post-periodic dosing may be employed. 
     For oral administration, the composition is preferably in the form of a tablet or capsule containing, e.g., 500 to 0.5 milligrams of the active compound. Dosages will vary depending on factors associated with the particular patient being treated (e.g., age, weight, diet, and time of administration), the severity of the condition being treated, the compound being employed, the mode of administration, and the strength of the preparation. 
     The oral composition is preferably formulated as a homogeneous composition, wherein the active ingredient is dispersed evenly throughout the mixture, which may be readily subdivided into dosage units containing equal amounts of a compound of the invention. Preferably, the compositions are prepared by mixing a compound of the invention (or pharmaceutically acceptable salt thereof) with one or more optionally present pharmaceutical carriers (such as a starch, sugar, diluent, granulating agent, lubricant, glidant, binding agent, and disintegrating agent), one or more optionally present inert pharmaceutical excipients (such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and syrup), one or more optionally present conventional tableting ingredients (such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, and any of a variety of gums), and an optional diluent (such as water). 
     Binder agents include starch, gelatin, natural sugars (e.g., glucose and beta-lactose), corn sweeteners and natural and synthetic gums (e.g., acacia and tragacanth). Disintegrating agents include starch, methyl cellulose, agar, and bentonite. 
     Tablets and capsules represent an advantageous oral dosage unit form. Tablets may be sugarcoated or filmcoated using standard techniques. Tablets may also be coated or otherwise compounded to provide a prolonged, control-release therapeutic effect. The dosage form may comprise an inner dosage and an outer dosage component, wherein the outer component is in the form of an envelope over the inner component. The two components may further be separated by a layer which resists disintegration in the stomach (such as an enteric layer) and permits the inner component to pass intact into the duodenum or a layer which delays or sustains release. A variety of enteric and non-enteric layer or coating materials (such as polymeric acids, shellacs, acetyl alcohol, and cellulose acetate or combinations thereof) may be used. 
     Compounds of the invention may also be administered via a slow release composition; wherein the composition includes a compound of the invention and a biodegradable slow release carrier (e.g., a polymeric carrier) or a pharmaceutically acceptable non-biodegradable slow release carrier (e.g., an ion exchange carrier). 
     Biodegradable and non-biodegradable slow release carriers are well known in the art. Biodegradable carriers are used to form particles or matrices which retain an active agent(s) and which slowly degrade/dissolve in a suitable environment (e.g., aqueous, acidic, basic and the like) to release the agent. Such particles degrade/dissolve in body fluids to release the active compound(s) therein. The particles are preferably nanoparticles (e.g., in the range of about 1 to 500 nm in diameter, preferably about 50-200 nm in diameter, and most preferably about 100 nm in diameter). In a process for preparing a slow release composition, a slow release carrier and a compound of the invention are first dissolved or dispersed in an organic solvent. The resulting mixture is added into an aqueous solution containing an optional surface-active agent(s) to produce an emulsion. The organic solvent is then evaporated from the emulsion to provide a colloidal suspension of particles containing the slow release carrier and the compound of the invention. 
     The compound of this invention may be incorporated for administration orally or by injection in a liquid form such as aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil and the like, or in elixirs or similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions, include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone, and gelatin. The liquid forms in suitably flavored suspending or dispersing agents may also include synthetic and natural gums. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations, which generally contain suitable preservatives, are employed when intravenous administration is desired. 
     The compounds may be administered parenterally via injection. A parenteral formulation may consist of the active ingredient dissolved in or mixed with an appropriate inert liquid carrier. Acceptable liquid carriers usually comprise aqueous solvents and other optional ingredients for aiding solubility or preservation. Such aqueous solvents include sterile water, Ringer&#39;s solution, or an isotonic aqueous saline solution. Other optional ingredients include vegetable oils (such as peanut oil, cottonseed oil, and sesame oil), and organic solvents (such as solketal, glycerol, and formyl). A sterile, non-volatile oil may be employed as a solvent or suspending agent. The parenteral formulation is prepared by dissolving or suspending the active ingredient in the liquid carrier whereby the final dosage unit contains from 0.005 to 10% by weight of the active ingredient. Other additives include preservatives, isotonizers, solubilizers, stabilizers, and pain-soothing agents. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. 
     Compounds of the invention may be administered intranasally using a suitable intranasal vehicle. 
     Compounds of the invention may also be administered topically using a suitable topical transdermal vehicle or a transdermal patch. 
     For ocular administration, the composition is preferably in the form of an ophthalmic composition. The ophthalmic compositions are preferably formulated as eye-drop formulations and filled in appropriate containers to facilitate administration to the eye, for example a dropper fitted with a suitable pipette. Preferably, the compositions are sterile and aqueous based, using purified water. In addition to the compound of the invention, an ophthalmic composition may contain one or more of: a) a surfactant such as a polyoxyethylene fatty acid ester; b) a thickening agents such as cellulose, cellulose derivatives, carboxyvinyl polymers, polyvinyl polymers, and polyvinylpyrrolidones, typically at a concentration n the range of about 0.05 to about 5.0% (wt/vol); c) (as an alternative to or in addition to storing the composition in a container containing nitrogen and optionally including a free oxygen absorber such as Fe), an anti-oxidant such as butylated hydroxyanisol, ascorbic acid, sodium thiosulfate, or butylated hydroxytoluene at a concentration of about 0.00005 to about 0.1% (wt/vol); d) ethanol at a concentration of about 0.01 to 0.5% (wt/vol); and e) other excipients such as an isotonic agent, buffer, preservative, and/or pH-controlling agent. The pH of the ophthalmic composition is desirably within the range of 4 to 8. 
     The compounds of this invention may be generically defined by the following Formula I: 
     
       
         
         
             
             
         
       
     
     or an enantiomer, diastereomer or salt thereof, wherein R is: 
     a) (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 7 )cycloalkyl, (C 5 -C 7 )cycloalkenyl, (C 3 -C 7 )cycloalkyl(C 1 -C 3 )alkyl, (C 3 -C 7 )cycloalkyl(C 2 -C 3 )alkenyl, (C 3 -C 7 )cycloalkyl(C 2 -C 3 )alkynyl, (C 1 -C 8 )alkoxy, (C 3 -C 8 )alkenyloxy, (C 3 -C 8 )alkynyloxy, (C 3 -C 7 )cycloalkoxy, (C 5 -C 7 )cyclo-alkenyloxy, (C 3 -C 7 )cycloalkoxy(C 1 -C 3 )alkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 3 )alkoxy, (C 5 -C 7 )cycloalkenyl(C 1 -C 3 )alkoxy, (C 1 -C 8 )alkylthio, (C 3 -C 8 )alkenylthio, (C 3 -C 8 )alkynylthio, (C 3 -C 7 )cycloalkylthio(C 1 -C 3 )alkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 3 )alkylthio, (C 5 -C 7 )cycloalkenyl(C 1 -C 3 )alkylthio, (C 1 -C 8 )alkylamino, di(C 1 -C 8 )alkylamino, azepano, azetidino, piperidino, pyrrolidino, (C 3 -C 7 )cycloalkylamino, ((C 3 -C 7 )cycloalkyl(C 1 -C 3 )alkyl)amino or tri(C 1 -C 4 )alkylsilyl, each optionally substituted with up to four substituents independently selected from the group consisting of fluorine, hydroxy, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )cycloalkoxy and oxo; 
     b) aryl, heteroaryl, aryloxy, heteroaryloxy, aryl(C 1 -C 3 )alkyl, heteroaryl(C 1 -C 3 )alkyl, aryl(C 1 -C 3 )alkoxy, heteroaryl(C 1 -C 3 )alkoxy, aryl(C 2 -C 3 ))alkenyl, aryl(C 2 -C 3 )alkynyl, heteroaryl(C 2 -C 3 ))alkenyl, or heteroaryl(C 2 -C 3 ))alkynyl, each optionally substituted with up to three substituents independently selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )-cycloalkyl(C 2 -C 4 )alkynyl, halo(C 1 -C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl, halo(C 4 -C 7 )-cycloalkylalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, (C 4 -C 7 )cycloalkylalkoxy, halo(C 1 -C 6 )alkoxy, halo(C 3 -C 6 )cycloalkoxy, halo(C 4 -C 7 )cycloalkylalkoxy, (C 1 -C 6 )alkylthio, (C 3 -C 6 )cycloalkylhio, (C 4 -C 7 )cycloalkylalkylthio, halo(C 1 -C 6 )alkylthio, halo(C 3 -C 6 )cycloalkylhio, halo(C 4 -C 7 )cycloalkylalkylthio, (C 1 -C 6 )alkanesulflnyl, (C 3 -C 6 )cycloalkanesulfinyl, (C 4 -C 7 )cycloalkylalkanesulflnyl, halo(C 1 -C 6 )alkane-sulflnyl, halo(C 3 -C 6 )cycloalkanesulfinyl, halo(C 4 -C 7 )cycloalkylalkanesulfinyl, (C 1 -C 6 )alkanesulfonyl, (C 3 -C 6 )cycloalkanesulfonyl, (C 4 -C 7 )cycloalkylalkanesulfonyl, halo(C 1 -C 6 )alkanesulfonyl, halo(C 3 -C 6 )cycloalkanesulfonyl, halo(C 4 -C 7 )cycloalkylalkanesulfonyl, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, H 2 NCO, H 2 NSO 2 , (C 1 -C 6 )alkylaminocarbonyl, and di(C 1 -C 6 )alkylaminocarbonyl, (C 1 -C 6 )alkylaminosulfonyl, and di(C 1 -C 6 )alkylaminosulfonyl; or 
     c) a divalent radical selected from —(CH 2 ) 3 —, —(CH 2 ) 4 —, —(CH 2 ) 5 — or —(CH 2 ) 6 —, which is attached to R 1  to form a fused or spiro-fused ring system, and is optionally substituted with up to four substituents independently selected from the group consisting of fluorine, hydroxy, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy and oxo; 
     R 1  is phenyl, monocyclic heteroaryl, bicyclic heteroaryl, benzo-1,3-dioxole, benzo-1,3-dioxine, 2,3-dihydrobenzo-1,4-dioxine or (C 3 -C 7 )cycloalkyl, each optionally substituted with up to four substituents independently selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )-cycloalkyl(C 2 -C 4 )alkynyl, halo(C 1 -C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl, halo(C 4 -C 7 )-cycloalkylalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, (C 4 -C 7 )cycloalkylalkoxy, halo(C 1 -C 6 )alkoxy, halo(C 3 -C 6 )cycloalkoxy, halo(C 4 -C 7 )cycloalkylalkoxy, (C 1 -C 6 )alkylthio, (C 3 -C 6 )cycloalkylhio, (C 4 -C 7 )cycloalkylalkylthio, halo(C 1 -C 6 )alkylthio, halo(C 3 -C 6 )cycloalkylhio, halo(C 4 -C 7 )cycloalkylalkylthio, (C 1 -C 6 )alkanesulfinyl, (C 3 -C 6 )cycloalkanesulfinyl, (C 4 -C 7 )cycloalkylalkanesulfinyl, halo(C 1 -C 6 )alkane-sulflnyl, halo(C 3 -C 6 )cycloalkanesulfinyl, halo(C 4 -C 7 )cycloalkylalkanesulfinyl, (C 1 -C 6 )alkanesulfonyl, (C 3 -C 6 )cycloalkanesulfonyl, (C 4 -C 7 )cycloalkylalkanesulfonyl, halo(C 1 -C 6 )alkanesulfonyl, halo(C 3 -C 6 )cycloalkanesulfonyl, halo(C 4 -C 7 )cycloalkylalkanesulfonyl, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, H 2 NSO 2 , H 2 NCO, (C 1 -C 6 )alkylaminosulfonyl, di(C 1 -C 6 )alkylaminosulfonyl, (C 1 -C 6 )alkylaminocarbonyl and di(C 1 -C 6 )alkylaminocarbonyl; 
     X and Y are each independently CH 2  or a single bond; 
     R 2  is a) —H; or b) (C 1 -C 12 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl, (C 1 -C 12 )alkoxy, (C 1 -C 12 )alkylthio, (C 1 -C 12 )alkylamino, oxo(C 1 -C 12 )alkyl, oxo(C 2 -C 12 )alkenyl, oxo(C 2 -C 12 )alkynyl, oxo(C 1 -C 12 )alkoxy, oxo(C 1 -C 12 )alkylthio, oxo(C 1 -C 12 )alkylamino, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkylthio, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkylthio (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkylthio(C 1 -C 6 )alkylthio, (C 1 -C 6 )alkylamino (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylamino (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkylamino, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, amino carbonylamino (C 1 -C 12 )alkyl, amino carbonylamino (C 1 -C 12 )alkoxy, amino carbonylamino (C 1 -C 12 )alkylthio, amino carbonylamino (C 1 -C 12 )alkylamino, (C 1 -C 6 )-alkanoylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoylamino(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoylamino(C 1 -C 6 )alkylthio, (C 1 -C 6 )alkanoylamino (C 1 -C 6 )alkylamino, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkylthio, (C 1 -C 6 )alkoxy-carbonyl(C 1 -C 6 )alkylamino, (C 1 -C 6 )acyloxy(C 1 -C 6 )alkyl, (C 1 -C 6 )acyloxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )acyloxy(C 1 -C 6 )alkylthio, (C 1 -C 6 )acyloxy(C 1 -C 6 )alkylamino, amino sulfonylamino (C 1 -C 12 )alkyl, amino sulfonylamino (C 1 -C 12 )alkoxy, amino sulfonylamino (C 1 -C 12 )alkylthio, amino sulfonyl-amino (C 1 -C 12 )alkylamino, (C 1 -C 6 )alkanesulfonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkanesulfonyl-amino(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkane sulfonylamino (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkanesulfonyl-amino (C 1 -C 6 )alkylamino, formylamino(C 1 -C 6 )alkyl, formylamino(C 1 -C 6 )alkoxy, formylamino(C 1 -C 6 )alkylthio, formylamino(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkoxycarbonylamino (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonylamino(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonylamino(C 1 -C 6 )alkylthio, (C 1 -C 6 )alkoxycarbonylamino (C 1 -C 6 )alkylamino, (C 1 -C 6 )alkylaminocarbonyl-amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylaminocarbonylamino(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylamino carbonyl-amino (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkylaminocarbonylamino(C 1 -C 6 )alkylamino, amino carbonyl(C 1 -C 6 )alkyl, amino carbonyl(C 1 -C 6 )alkoxy, amino carbonyl(C 1 -C 6 )alkylthio, amino carbonyl(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkylamino carbonyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylaminocarbonyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylamino carbonyl(C 1 -C 6 )alkylthio, (C 1 -C 6 )alkylaminocarbonyl(C 1 -C 6 )alkylamino, amino carboxy(C 1 -C 6 )alkyl, aminocarboxy(C 1 -C 6 )alkoxy, aminocarboxy(C 1 -C 6 )alkylthio, aminocarboxy(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkylamino carboxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylaminocarboxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylaminocarboxy(C 1 -C 6 )alkylthio, (C 1 -C 6 )alkylaminocarboxy(C 1 -C 6 )alkylamino, (C 1 -C 12 )alkoxycarbonylamino, (C 1 -C 12 )alkylamino-carbonylamino, or (C 1 -C 12 )alkanoylamino, each optionally substituted by: 1) 1 to 5 halogen atoms; and 2) 1 group selected from cyano, hydroxyl, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkoxy, halo(C 1 -C 3 )alkyl, halo(C 1 -C 3 )alkoxy, halo(C 3 -C 6 )cycloalkyl, and halo(C 3 -C 6 )cycloalkoxy, where the divalent sulfur atoms in R 2  are independently optionally oxidized to sulfoxide or sulfone and wherein the carbonyl groups are optionally independently changed to a thiocarbonyl groups; 
     R 3  is —H, halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxyl, hydroxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoylamino, (C 1 -C 6 )alkoxycarbonylamino, (C 1 -C 6 )alkylamino-carbonylamino, di(C 1 -C 6 )alkylaminocarbonylamino, (C 1 -C 6 )alkanesulfonylamino, (C 1 -C 6 )alkylaminosulfonylamino, di(C 1 -C 6 )alkylaminosulfonyl-amino, phenylamino or heteroarylamino in which each phenylamino or heteroarylamino group is optionally substituted with 1 to 5 groups independently selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl(C 2 -C 4 )alkynyl, halo(C 1 -C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl, halo(C 4 -C 7 )cycloalkylalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, (C 4 -C 7 )cycloalkylalkoxy, halo(C 1 -C 6 )alkoxy, halo(C 3 -C 6 )cycloalkoxy, halo(C 4 -C 7 )cycloalkylalkoxy, (C 1 -C 6 )alkylthio, (C 3 -C 6 )cycloalkylhio, (C 4 -C 7 )cycloalkylalkylthio, halo(C 1 -C 6 )alkylthio, halo(C 3 -C 6 )cycloalkylhio, halo(C 4 -C 7 )cycloalkylalkylthio, (C 1 -C 6 )alkanesulfinyl, (C 3 -C 6 )cycloalkanesulfinyl, (C 4 -C 7 )cycloalkylalkanesulfinyl, halo(C 1 -C 6 )alkane-sulflnyl, halo(C 3 -C 6 )cycloalkanesulfinyl, halo(C 4 -C 7 )-cycloalkylalkanesulfinyl, (C 1 -C 6 )alkanesulfonyl, (C 3 -C 6 )cycloalkanesulfonyl, (C 4 -C 7 )cycloalkylalkanesulfonyl, halo(C 1 -C 6 )alkanesulfonyl, halo(C 3 -C 6 )-cycloalkanesulfonyl, halo(C 4 -C 7 )cycloalkylalkanesulfonyl, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, amino-carbonyl, (C 1 -C 6 )alkylaminocarbonyl, and di(C 1 -C 6 )alkylaminocarbonyl, provided that i) R 2  and R 3  are not both hydrogen; and ii) when R 3  is hydroxyl, halogen, or optionally substituted phenylamino or heteroarylamino, R 2  is not (C 1 -C 12 )alkoxy, (C 1 -C 12 )alkylthio, (C 1 -C 12 )alkylamino, oxo(C 1 -C 12 )alkoxy, oxo(C 1 -C 12 )alkylthio, oxo(C 1 -C 12 )alkylamino, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkylthio, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkylthio(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio(C 1 -C 6 )alkylamino, (C 1 -C 6 )-alkylthio (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkylamino (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkylthio, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkylamino, amino carbonylamino (C 1 -C 12 )alkoxy, amino carbonyl-amino (C 1 -C 12 )alkylthio, amino carbonylamino (C 1 -C 12 )alkylamino, (C 1 -C 6 )alkanoylamino(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoylamino (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkanoylamino (C 1 -C 6 )alkylamino, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkylthio, (C 1 -C 6 )alkoxycarbonyl-(C 1 -C 6 )alkylamino, (C 1 -C 6 )acyloxy(C 1 -C 6 )alkoxy, (C 1 -C 6 ) acyloxy(C 1 -C 6 )alkylthio, (C 1 -C 6 )-acyloxy(C 1 -C 6 )alkylamino, aminosulfonylamino(C 1 -C 12 )alkoxy, aminosulfonylamino(C 1 -C 12 )alkylthio, amino sulfonylamino (C 1 -C 12 )alkylamino, (C 1 -C 6 )alkanesulfonylamino(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanesulfonylamino(C 1 -C 6 )alkylthio, (C 1 -C 6 )alkanesulfonylamino(C 1 -C 6 )alkylamino, formylamino(C 1 -C 6 )alkoxy, formylamino(C 1 -C 6 )alkylthio, formylamino(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkoxycarbonylamino(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonylamino(C 1 -C 6 )alkylthio, (C 1 -C 6 )alkoxycarbonylamino (C 1 -C 6 )alkylamino, (C 1 -C 6 )alkylamino carbonyl-amino (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylaminocarbonylamino(C 1 -C 6 )alkylthio, (C 1 -C 6 )alkylamino-carbonylamino(C 1 -C 6 )alkylamino, aminocarbonyl(C 1 -C 6 )alkoxy, aminocarbonyl(C 1 -C 6 )alkylthio, amino carbonyl(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkylaminocarbonyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylaminocarbonyl(C 1 -C 6 )alkylthio, (C 1 -C 6 )alkylaminocarbonyl(C 1 -C 6 )alkylamino, aminocarboxy(C 1 -C 6 )alkoxy, aminocarboxy(C 1 -C 6 )alkylthio, amino carboxy(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkylaminocarboxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylamino carboxy(C 1 -C 6 )alkylthio, (C 1 -C 6 )alkylamino carboxy(C 1 -C 6 )alkylamino, (C 1 -C 12 )alkoxycarbonylamino, (C 1 -C 12 )alkylamino-carbonylamino, or (C 1 -C 12 )alkanoylamino, each optionally substituted by: 1) 1 to 5 halogen atoms; and 2) 1 group selected from cyano, hydroxyl, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkoxy, halo(C 1 -C 3 )alkyl, halo(C 1 -C 3 )alkoxy, halo(C 3 -C 6 )cycloalkyl, or halo(C 3 -C 6 )cycloalkoxy; where the divalent sulfur atoms in R 3  are independently optionally oxidized to sulfoxide or sulfone and wherein the carbonyl groups in R 3  are optionally independently changed to thiocarbonyl groups; 
     A is a saturated or unsaturated 4-, 5-, 6-, or 7-membered ring which is optionally bridged by (CH 2 ) m  via bonds to two members of said ring, wherein said ring is composed of carbon atoms and 0-2 hetero atoms selected from the group consisting of 0, 1, or 2 nitrogen atoms, 0 or 1 oxygen atoms, and 0 or 1 sulfur atoms, said ring being optionally substituted with up to four independently selected halogen atoms, (C 1 -C 6 )alkyl groups, halo(C 1 -C 6 )alkyl groups or oxo groups such that when there is substitution with one oxo group on a carbon atom it forms a carbonyl group and when there is substitution of one or two oxo groups on sulfur it forms sulfoxide or sulfone groups, respectively, where m is 1 to 3; 
     Q and Y are attached to carbon or nitrogen atoms in ring A in a 1,2 or 1,3, or 1,4 relationship; 
     Q is a divalent radical selected from 
     
       
         
         
             
             
         
       
     
     E is a saturated or unsaturated 3-, 4-, 5-, 6-, or 7-membered ring which is optionally bridged by (CH 2 ) via bonds to two members of said ring, wherein said ring is composed of carbon atoms, and 0-3 hetero atoms selected from 0, 1, 2, or 3 nitrogen atoms, 0 or 1 oxygen atoms, and 0 or 1 sulfur atoms, said ring being optionally substituted with up to four groups independently selected from halogen, hydroxy, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, aryl, and oxo groups such that when there is substitution with one oxo group on a carbon atom it forms a carbonyl group and when there is substitution of one or two oxo groups on sulfur it forms sulfoxide or sulfone groups, respectively, where n is 1 to 3; and 
     G is hydroxy, hydroxy(C 1 -C 6 )alkyl, amino, (C 1 -C 6 )alkylamino, hydroxy(C 1 -C 6 )alkylamino, amino (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenylamino(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl, C(═NH)NH 2 , C(═NH)NHR 4 , NHC(═NH)NH 2 , or NHC(═NH)NHR 4 , where R 4  is (C 1 -C 3 )alkyl, and wherein the heteroaryl moiety of the heteroaryl(C 1 -C 6 )alkyl group is optionally substituted with 1 or two substituents independently selected from the group consisting of (C 1 -C 4 )alkyl, hydroxy(C 1 -C 4 )alkyl, amino(C 1 -C 4 )alkyl, or (C 1 -C 4 )alkylamino(C 1 -C 4 )alkyl; 
     wherein Ring A in Formula I may be depicted as follows: 
     
       
         
         
             
             
         
       
     
     wherein Ring A is a benzene ring (A 1  and A 4  are CH and the bonds in ring A are aromatic bonds); or Ring A is a piperidine ring (A 1  is N, A 4  is CH 2  and the bonds in ring A are single bonds); or Ring A is a morpholine ring (A 1  is N, A 4  is O and the bonds in ring A are single bonds). 
     In the discussion below the substituent variables R, R 1 , R 2 , R 3 , X, Y, A, Q, E, and G are as defined above: 
     When any variable (e.g., aryl, alkyl, R′, R 2 , etc.) occurs more than once in a compound, its definition on each occurrence is independent of any other occurrence. 
     “Alkyl” means a saturated aliphatic branched or straight-chain mono- or divalent hydrocarbon radical having the specified number of carbon atoms. Thus, “(C 1 -C 8 )alkyl” means a radical having from 1-8 carbon atoms in a linear or branched arrangement. “(C 1 -C 6 )alkyl” includes methyl, ethyl, propyl, butyl, pentyl, and hexyl. 
     “Cycloalkyl” means a saturated aliphatic cyclic hydrocarbon radical having the specified number of carbon atoms. Thus, (C 3 -C 7 )cycloalkyl means a radical having from 3-8 carbon atoms arranged in a ring. (C 3 -C 7 )cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. 
     Haloalkyl and halocycloalkyl include mono, poly, and perhaloalkyl groups where the halogens are independently selected from fluorine, chlorine, and bromine. 
     “Heteroaryl” means a monovalent heteroaromatic monocyclic and polycylic ring radical. Heteroaryl rings are 5- and 6-membered aromatic heterocyclic rings containing 1 to 4 heteroatoms independently selected from N, O, and S, and include furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-oxadiazole, 1,2,5-thiadiazole, 1,2,5-thiadiazole 1-oxide, 1,2,5-thiadiazole 1,1-dioxide, 1,3,4-thiadiazole, pyridine, pyridine-N-oxide, pyrazine, pyrimidine, pyridazine, 1,2,4-triazine, 1,3,5-triazine, and tetrazole. Bicyclic heteroaryl rings are bicyclo[4.4.0] and bicyclo[4,3.0] fused ring systems containing 1 to 4 heteroatoms independently selected from N, O, and S, and include indolizine, indole, isoindole, benzo[b]furan, benzo[b]thiophene, indazole, benzimidazole, benzthiazole, purine, 4H-quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. 
     “Alkoxy” means an alkyl radical attached through an oxygen linking atom. “(C 1 -C 4 )-alkoxy” includes methoxy, ethoxy, propoxy, and butoxy. 
     “Aromatic” means an unsaturated cycloalkyl ring system. 
     “Aryl” means an aromatic monocyclic, or polycyclic ring system. Aryl systems include phenyl, naphthalenyl, fluorenyl, indenyl, azulenyl, and anthracenyl. 
     “Hetero” refers to the replacement of at least one carbon atom member in a ring system with at least one heteroatom selected from N, S, and O. A hetero ring may have 1, 2, 3, or 4 carbon atom members replaced by a heteroatom. 
     “Unsaturated ring” means a ring containing one or more double bonds and include cyclopentene, cyclohexene, cyclopheptene, cyclohexadiene, benzene, pyrroline, pyrazole, 4,5-dihydro-1H-imidazole, imidazole, 1,2,3,4-tetrahydropyridine, 1,2,3,6-tetrahydropyridine, pyridine and pyrimidine. 
     In cases where the synthetic intermediates and final products of this invention described below contain potentially reactive functional groups, for example amino, hydroxyl, thiol and carboxylic acid groups, that may interfere with the desired reaction, it may be advantageous to employ protected forms of the intermediate. Methods for the selection, introduction and subsequent removal of protecting groups are well known to those skilled in the art. (T. W. Greene and P. G. M. Wuts “Protective Groups in Organic Synthesis” John Wiley &amp; Sons, Inc., New York 1999). In the discussion below all intermediates are assumed to be protected when necessary and protection/deprotection are generally not described. 
     In the first process of the invention, a compound of Formula I, in which a nitrogen atom that is part of A is attached to Q, is prepared by reaction of an amine of Formula II and an intermediate of Formula III: 
     
       
         
         
             
             
         
       
     
     wherein Z 1  in III is a leaving group such as halide, alkanesulfonate, haloalkanesulfonate, carboxylate, arylsulfonate, aryloxy, heteroaryloxy, azole, azolium salt, alkoxy, alkylthio, or arylthio. 
     Intermediates of formula II wherein H is attached to a nitrogen atom that is part of A are prepared from intermediates of Formula IV: 
     
       
         
         
             
             
         
       
     
     wherein J is an amine protecting group, including carbamate, amide, and sulfonamide protecting groups known in the art (T. W. Greene and P. G. M. Wuts “Protective Groups in Organic Synthesis” John Wiley &amp; Sons, Inc., New York 1999). 
     Intermediates of Formula IV wherein R 3 ═OH are prepared from ketone intermediates of formula V by addition of an organometallic reagent of formula VI, where M is for example Li, MgCl, MgBr, or MgI, to the carbonyl group of V: 
     
       
         
         
             
             
         
       
     
     Intermediates of Formula IV wherein R 3 ═H and R 2  is a group attached by an ether linkage are prepared from alcohol intermediates of formula VII by reaction with an alkylating agent under basic conditions or by reaction with an alcohol of formula R 2 OH under acidic conditions. 
     
       
         
         
             
             
         
       
     
     Alcohol intermediates of formula VII are prepared by reduction of ketone intermediates of formula V: 
     
       
         
         
             
             
         
       
     
     or by addition of an organometallic reagent of formula VIII, wherein M is, for example Li, MgCl, MgBr, or MgI, to an aldehyde of Formula IX: 
     
       
         
         
             
             
         
       
     
     Ketone intermediates of formula V are prepared by the addition of an organometallic reagent of formula VIII, wherein M is Li, MgCl, MgBr, MgI, to a carboxylic acid derivative of formula X wherein Z 2  is an alkoxy, dialkylamino group, or an N-alkoxy-N-alkylamino group: 
     
       
         
         
             
             
         
       
     
     Intermediates of Formula III, wherein Q is Q1 attached to a carbon atom of E and Z 1  is alkanesulfonate, haloalkanesulfonate, carboxylate, arylsulfonate, or represents an active ester are prepared by activation of carboxylic acids of Formula XV: 
     
       
         
         
             
             
         
       
     
     Reagents used to effect carboxylic activation are well known in the literature and include thionyl chloride and oxalyl chloride used to prepare acid chlorides, alkanesulfonyl chlorides used to prepare mixed anhydrides, alkyl chloroformates used to prepare mixed anhydrides, and carbodiimides used to prepare active esters. Intermediates of formula III are often prepared and used in situ without isolation. 
     In another process of the invention, a compound of Formula I, in which a nitrogen atom that is part of E is attached to Q, is prepared by reaction of an intermediate of Formula XVIII and an amine of Formula XVI: 
     
       
         
         
             
             
         
       
     
     wherein Z 1  is as defined above. 
     Intermediates of Formula XVIII wherein Q is attached to a nitrogen atom of ring A and Q is Q1, Q4, Q5, Q6, Q8, Q9, or Q10 are prepared from amine intermediates of Formula II and intermediates of Formula XVII wherein Z 1  is halide, alkanesulfonate, haloalkanesulfonate, carboxylate, arylsulfonate, aryloxy, heteroaryloxy, azole, azolium salt, alkoxy, alkylthio, or arylthio: 
     
       
         
         
             
             
         
       
     
     In another process of the invention, a compound of Formula I, in which R is an alkoxy, cycloalkoxy, cycloalkylalkoxy or arylalkoxy group, is prepared by reaction of an alkylating agent of Formula XXII, in which Z 3  is chloride, bromide, iodide, methanesulfonate, arenesulfonate or trifluoromethanesulfonate and R c  is an alkyl, cycloalkyl, cycloalkylalkyl or arylalkyl, with a hydroxy compound of Formula XXIII: 
     
       
         
         
             
             
         
       
     
     Intermediates of Formula XXIII are prepared by routes analogous to those shown for compounds of Formula I in equations 1 and 16. 
     In the first process of the invention, a compound of Formula Ia, in which A 1  is a nitrogen atom is prepared by reaction of an amine of Formula IIa and an intermediate of Formula IIIa: 
     
       
         
         
             
             
         
       
     
     wherein Z 1  in III is a leaving group such as halide, alkanesulfonate, haloalkanesulfonate, carboxylate, arylsulfonate, aryloxy, heteroaryloxy, azole, azolium salt, alkoxy, alkylthio, or arylthio. 
     Intermediates of formula IIa in which A 1  is a nitrogen atom are prepared from intermediates of Formula IVa: 
     
       
         
         
             
             
         
       
     
     wherein J is an amine protecting group, including carbamate, amide and sulfonamide protecting groups known in the art (T. W. Greene and P. G. M. Wuts “Protective Groups in Organic Synthesis” John Wiley &amp; Sons, Inc., New York 1999). 
     Intermediates of Formula IVa wherein R 3 ═OH are prepared from ketone intermediates of formula Va by addition of an organometallic reagent of formula VIa, where M is for example Li, MgCl, MgBr, or MgI, to the carbonyl group of Va: 
     
       
         
         
             
             
         
       
     
     Intermediates of Formula IVa wherein R 3 ═H and R 2  is a group attached by an ether linkage are prepared from alcohol intermediates of formula VIIa by reaction with an alkylating agent under basic conditions or by reaction with an alcohol under acidic conditions. 
     
       
         
         
             
             
         
       
     
     Alcohol intermediates of formula VIIa are prepared by reduction of ketone intermediates of formula Va using reagents known in the art (Handbook of Reagents for Organic Synthesis: Oxidizing and Reducing Reagents Ed. S. D. Burke and R. L. Danheiser, John Wiley &amp; Sons, New York, 1999): 
     
       
         
         
             
             
         
       
     
     or by addition of an organometallic reagent of formula VIIIa, wherein M is, for example Li, MgCl, MgBr, or MgI, to an aldehyde of Formula IXa: 
     
       
         
         
             
             
         
       
     
     Ketone intermediates of formula Va are prepared by the addition of an organometallic reagent of formula VIIIa, wherein M is Li, MgCl, MgBr, MgI, to a carboxylic acid derivative of formula Xa wherein Z 2  is an alkoxy, dialkylamino group, or an N-alkoxy-N-alkylamino group: 
     
       
         
         
             
             
         
       
     
     Intermediates of formula Va are also prepared by oxidation of alcohol intermediates of formula VIIa using reagents known in the art (Handbook of Reagents for Organic Synthesis: Oxidizing and Reducing Reagents Ed. S. D. Burke and R. L. Danheiser, John Wiley &amp; Sons, New York, 1999): 
     
       
         
         
             
             
         
       
     
     Intermediates of Formula IVa, wherein the R is group attached to R 1  through an ether linkage, are also prepared by alkylation of intermediates of formula XIIIa, in which Z 3  is a hydroxyl group with alkylating agents of formula XIVa, wherein X is a halogen, alkanesulfonate, haloalkanesulfonate, or arenesulfonate leaving group: 
     
       
         
         
             
             
         
       
     
     The intermediates of Formula XIIIa used in equation 11a are available by processes analogous to those described for IVa (equations 3a and 4a). 
     Intermediates of Formula Ma, wherein Q is Q1 attached to a carbon atom of E and Z 1  is alkanesulfonate, haloalkanesulfonate, carboxylate, arylsulfonate, or represents an active ester are prepared by activation of carboxylic acids of Formula XVa: 
     
       
         
         
             
             
         
       
     
     Reagents used to effect carboxylic activation are well known in the literature and include thionyl chloride and oxalyl chloride used to prepare acid chlorides, alkanesulfonyl chlorides used to prepare mixed anhydrides, alkyl chloroformates used to prepare mixed anhydrides, and carbodiimides used to prepare active esters. Intermediates of formula IIIa are often prepared and used in situ without isolation. 
     In another process of the invention, a compound of Formula Ia, in which a nitrogen atom that is part of E is attached to Q, is prepared by reaction of an intermediate of Formula XVIIIa and an amine of Formula XVIa: 
     
       
         
         
             
             
         
       
     
     wherein Z 1  is as defined above. 
     Intermediates of Formula XVIIIa wherein Q is attached to a nitrogen atom of ring A and Q is Q1, Q4, Q5, Q6, Q8, Q9, or Q10 are prepared from amine intermediates of Formula IIa and intermediates of Formula XVIIa wherein Z 1  is halide, alkanesulfonate, haloalkanesulfonate, carboxylate, arylsulfonate, aryloxy, heteroaryloxy, azole, azolium salt, alkoxy, alkylthio, or arylthio: 
     
       
         
         
             
             
         
       
     
     In another process of the invention, a compound of Formula Ia, in which R is an alkoxy, cycloalkoxy, cycloalkylalkoxy or arylalkoxy group, is prepared by reaction of an alkylating agent of Formula XIVa, in which Z 3  is chloride, bromide, iodide, methanesulfonate, arenesulfonate or trifluoromethanesulfonate and Rc is an alkyl, cycloalkyl, cycloalkylalkyl or arylalkyl group, with a hydroxy compound of Formula XXIIa: 
     
       
         
         
             
             
         
       
     
     Intermediates of Formula XXIIa are prepared by routes analogous to those shown for compounds of Formula Ia in reaction schemes 1a and 16a. 
     The invention is further defined by reference to the examples, which are intended to be illustrative and not limiting. 
     Representative compounds of the invention can be synthesized in accordance with the general synthetic schemes described above and are illustrated in the examples that follow. The methods for preparing the various starting materials used in the schemes and examples are well within the knowledge of persons skilled in the art. During the course of preparing aryl 3-piperidinyl ketones, as described in the following protocols (e.g. Preparations 5-7 and 11), racemization of the stereocenter adjacent to the carbonyl group can occur and was specifically observed during the preparation of (R)-tent-butyl 3-(6-chloro-3′-ethylbiphenylcarbonyl)piperidine-1-carboxylate. In this case, the racemic product was detected when the reaction mixture was allowed to stir at room temperature for prolonged times (e.g. overnight) but was not observed when the ketone forming reaction was quenched at −78° C. (by addition of aqueous ammonium chloride). When racemization does occur, the resulting stereoisomers may be resolved using conventional methods well known to those skilled in the art. Accordingly, it will be appreciated by those skilled in the art, that in the following Experimental section, any identification of a specific stereoisomer (e.g., assignment of configuration of a chiral center) in a final or intermediate product compound name or structure is to be understood to represent the intended relative or absolute configuration of that chiral center, but not necessarily the only stereoisomer obtained. 
     The following abbreviations have the indicated meanings: 
     
       
         
           
               
               
             
               
                   
               
               
                 Abbreviation 
                 Meaning 
               
               
                   
               
             
            
               
                 Aq 
                 aqueous 
               
               
                 Boc 
                 tert-butoxy carbonyl or t-butoxy carbonyl 
               
               
                 (Boc) 2 O 
                 di-tert-butyl dicarbonate 
               
               
                 Brine 
                 saturated aqueous NaCl 
               
               
                 CH 2 Cl 2   
                 methylene chloride 
               
               
                 CH 3 CN or MeCN 
                 acetonitrile 
               
               
                 Cpd 
                 compound 
               
               
                 D 
                 day 
               
               
                 DBU 
                 1,8-diazabicyclo[5.4.0]undec-7-ene 
               
               
                 DIEA 
                 N,N-diisopropylethylamine 
               
               
                 DMAP 
                 4-(dimethylamino)pyridine 
               
               
                 DMF 
                 N,N-dimethylformamide 
               
               
                 DMPU 
                 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone 
               
               
                 EDC•HCl 
                 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide 
               
               
                   
                 hydrochloride 
               
               
                 Equiv 
                 equivalents 
               
               
                 Et 
                 ethyl 
               
               
                 Et 2 O 
                 ethyl ether 
               
               
                 EtOAc 
                 ethyl acetate 
               
               
                 Fmoc 
                 1-[[(9H-fluoren-9-ylmethoxy)carbonyl]oxy]- 
               
               
                 Fmoc-OSu 
                 1-[[(9H-fluoren-9-ylmethoxy)carbonyl]oxy]-2,5- 
               
               
                   
                 pyrrolidinedione 
               
               
                 h, hr 
                 hour 
               
               
                 HOBt 
                 1-hydroxybenzotriazole 
               
               
                 HATU 
                 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3- 
               
               
                   
                 tetramethyluronium 
               
               
                   
                 hexafluorophosphate 
               
               
                 HBTU 
                 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium 
               
               
                   
                 hexafluorophosphate 
               
               
                 KHMDS 
                 potassium hexamethyldisilazane 
               
               
                 LAH or LiAlH 4   
                 lithium aluminum hydride 
               
               
                 LC-MS 
                 liquid chromatography-mass spectroscopy 
               
               
                 LHMDS 
                 lithium hexamethyldisilazane 
               
               
                 Me 
                 methyl 
               
               
                 MeCN 
                 aceronitrile 
               
               
                 MeOH 
                 methanol 
               
               
                 MsCl 
                 methanesulfonyl chloride 
               
               
                 min 
                 minute 
               
               
                 MS 
                 mass spectrum 
               
               
                 NaH 
                 sodium hydride 
               
               
                 NaHCO 3   
                 sodium bicarbonate 
               
               
                 NaN 3   
                 sodium azide 
               
               
                 NaOH 
                 sodium hydroxide 
               
               
                 Na 2 SO 4   
                 sodium sulfate 
               
               
                 NMP 
                 N-methylpyrrolidinone 
               
               
                 P 4 -t-Bu 
                 1-tert-butyl-4,4,4-tris(dimethylamino)- 
               
               
                   
                 2,2-bis[tris(dimethylamino)- 
               
               
                   
                 phosphoranylidenamino]-2/\ 5 ,4/\ 5 - 
               
               
                   
                 catenadi(phosphazene) 
               
               
                 Pd 2 (dba) 3   
                 tris(dibenzylideneacetone)dipalladium(0) 
               
               
                 Ph 
                 phenyl 
               
               
                 rt 
                 room temperature 
               
               
                 satd 
                 saturated 
               
               
                 SOCl 2   
                 thionyl chloride 
               
               
                 TBAF 
                 tetrabutylammonium fluoride 
               
               
                 TEA 
                 triethylamine or Et 3 N 
               
               
                 TEAF 
                 tetraethylammonium fluoride 
               
               
                 TEMPO 
                 2,2,6,6-tetramethyl-1-piperidinyloxy, free radical 
               
               
                 Teoc 
                 1-[2-(trimethylsilyl)ethoxycarbonyloxy]- 
               
               
                 Teoc-OSu 
                 1-[2-(trimethylsilyl)ethoxycarbonyloxy]pyrrolidin- 
               
               
                   
                 2,5-dione 
               
               
                 TFA 
                 trifluoroacetic acid 
               
               
                 THF 
                 tetrahydrofuran 
               
               
                 TMSCl 
                 chlorotrimethylsilane or trimethylsilyl chloride 
               
               
                 t R   
                 retention time 
               
               
                   
               
            
           
         
       
     
     LC-MS Methods 
     Method 1 [Instrument 1]: Analytical LC-MS was conducted on an Agilent 1100 Series LC/MSD SL or VL using electrospray positive [ES+ve to give MH + ] equipped with a Sunfire C 18  5.0 μm column (3.050 mm×50 3.0 mm, i.d.), eluting with 0.05% TFA in water (solvent A) and 0.05% TFA in acetonitrile (solvent B), using the following elution gradient 10%±99% (solvent B) over 3.0 min and holding at 99% for 1.0 min at a flow rate of 1.0 ml/min. 
     Method 2 [Instrument 2]: Analytical LC-MS was conducted on an PE Sciex API 150 single quadrupole mass spectrometer using electrospray positive [ES+ve to give MH+] equipped with a Aquasil C18 5 μm column (1 mm×40 mm), eluting with 0.02% TFA in water (solvent A) and 0.018% TFA in acetonitrile (solvent B), using the following elution gradient 4.5%-90% (solvent B) over 3.2 min and holding at 90% for 0.4 min at a flow rate of 0.3 ml/min. 
     Method 3: Analytical LC-MS was conducted on an Agilent 1200 Series LC/MSD VL using electrospray positive [ES+ve to give MH + ] equipped with a YMC C 18  5.0 μm column (2.0 mm×50, 2.0 mm, i.d.), eluting with 0.0375% TFA in water (solvent A) and 0.01875% TFA in acetonitrile (solvent B), using the following elution gradient 10%-80% (solvent B) over 2.0 min and holding at 80% for 0.5 min at a flow rate of 1.0 ml/min. 
     Chiral HPLC Method 
     Column: Chiralpak AD-H, 0.46 cm×25 cm 
     Solvent A: 0.025% Diethylamine in Hexane 
     Solvent B: Isopropanol 
     Flow rate: 1 mL/min.
 
40 min. run
 
     Gradient: 
       
     
       
         
           
               
               
               
             
               
                   
               
               
                 Time (min) 
                 A(%) 
                 B(%) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                 0 
                 95 
                 5 
               
               
                 40 
                 90 
                 10 
               
               
                   
               
            
           
         
       
     
     The following procedures describe preparation of intermediates used in the synthesis of compounds of this invention. 
     Preparation 1 
     Weinreb Amide 
     (R)-tert-butyl 3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     (R)-1-(tent-butoxy carbonyl)piperidine-3-carboxylic acid (25 g, 0.11 mol, 1.0 equiv), N,O-dimethylhydroxylamine hydrochloride, (10.5 g, 0.14 mol, 1.25 equiv), EDC.HCl (26.3 g, 0.14 mol, 1.25 equiv) and DIEA (48 mL, 0.28 mol, 2.5 equiv) were dissolved in CH 2 Cl 2  (400 mL) and stirred overnight at rt. The reaction mixture was diluted with EtOAc, washed with 5% aq HCl (2×150 mL), satd aq NaHCO 3  (150 mL), brine (100 mL), and dried over Na 2 SO 4 . Concentration afforded (R)-tent-butyl 3-(N-methoxy-N-methylcarbamoyl)-piperidine-1-carboxylate (24.42 g, 82%) as a clear oil. 
     Preparation 2 
     Halodiphenyl Ethers from Halophenols and Benzeneboronic Acids 
     1-(3-Fluorophenoxy)-2-bromobenzene 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 3-fluorophenylboronic acid (2.10 g, 15 mmol), 2-bromophenol (1.77 g, 10 mmol) and Cu(OAc) 2  (0.93 g, 5 mmol) in anhydrous CH 2 Cl 2  (25 mL) was added activated 4 Å molecular sieves (˜0.1 g), followed by anhydrous Et 3 N (3.5 mL, 25 mmol). The resulting dark green solution was stirred at rt for 48 h. The mixture was evaporated under reduced pressure and the residue was washed several times with Et 2 O (˜150 mL). The Et 2 O solution was washed with satd aq NH 4 Cl, and 1 N aq HCl. The organic layer was evaporated and the crude product was purified by flash column chromatography to give 1-(3-fluorophenoxy)-2-bromobenzene (1.28 g, 48%) as clear oil. 
     The following halodiphenyl ethers were prepared following the procedure described above. 
     
       
         
           
               
               
               
             
               
                   
               
               
                 Halodiphenyl ether 
                 Phenol 
                 Boronic Acid 
               
               
                   
               
             
            
               
                 1-bromo-3-chloro-2-[(3- 
                 2-bromo-6- 
                 3-ethylphenylboronic acid 
               
               
                 ethylphenyl)oxy]benzene 
                 chlorophenol 
               
               
                 1-bromo-3-chloro-2-[(2- 
                 2-bromo-6- 
                 2-methylphenylboronic 
               
               
                 methylphenyl)oxy]benzene 
                 chlorophenol 
                 acid 
               
               
                 1-bromo-3-chloro-2-[(2- 
                 2-bromo-6- 
                 2-ethylphenylboronic acid 
               
               
                 ethylphenyl)oxy]benzene 
                 chlorophenol 
               
               
                 1-bromo-2-[(3- 
                 2-bromo-6- 
                 (3-methylphenyl)boronic 
               
               
                 methylphenyl)oxy]-3- 
                 fluorophenol 
                 acid 
               
               
                 fluorobenzene 
               
               
                 1-bromo-3-chloro-2-[(3- 
                 2-bromo-6- 
                 (3-methylphenyl)boronic 
               
               
                 methylphenyl)oxy]benzene 
                 chlorophenol 
                 acid 
               
               
                   
               
            
           
         
       
     
     Preparation 3 
     Halodiphenyl Ethers From Phenoxyanilines 
     1-(O-tolyloxy)-2-iodobenzene 
     
       
         
         
             
             
         
       
     
     To a solution of 2-(o-tolyloxy)aniline (40 g, 0.2 mol) in 1N aq HCl (400 mL, 0.4 mol, 2 equiv) cooled to 0° C. was added dropwise a solution of NaNO 2  (18 g, 0.26 mol, 1.3 equiv) in water (520 ml). The mixture was stirred for 1 h at 0° C. and a solution of KI (83 g, 0.5 mol, 2.5 equiv) in water (500 mL) was added dropwise with vigorous stirring. After 0.5 h the mixture was warmed to 90-100° C. for 1 h, cooled to rt and washed with satd NaHSO 3  until the aqueous layer become clear. The mixture was extracted with EtOAc (3×200 mL) and the combined organic layers were washed with aq Na 2 S 2 O 4  and dried over Na 2 SO 4 . After evaporation of the solvent, the solution was passed through a short silica gel column to afford 1-(o-tolyloxy)-2-iodobenzene (40.0 g, 65%). 
     Preparation 4 
     Halodiphenyl Ethers from Phenols and Fluoronitrobenzenes 
     1-(2-Iodophenoxy)-2-chlorobenzene 
     
       
         
         
             
             
         
       
     
     Step 1. 1-(2-Iodophenoxy)-2-nitrobenzene: To a solution of 2-iodophenol (11. 82 g, 52.7 mmol) and 1-fluoro-2-nitrobenzene (5.0 g, 35.1 mmol) in DMSO (50 mL was added K 2 CO 3  (14.5 g, 105.3 mmol), followed by CsF (8.0 g, 52.7 mmol). The resulting suspension was stirred at 50° C. until no starting material remained (˜5 h), cooled to rt and partitioned between water (50 mL) and CH 2 Cl 2  (50 mL). The water layer was separated and extracted with CH 2 Cl 2  (2×10 mL). The combined organic layers were washed with 1 aq N NaOH (10 mL) and brine, and dried over Na 2 SO 4 . Solvent was removed under vacuum to give 1-(2-iodophenoxy)-2-nitrobenzene (11.2 g, 93%) as an oil, which was used for next step without purification. 
     Step 2. 2-(2-Iodophenoxy)benzenamine: A solution of 1-(2-iodophenoxy)-2-nitrobenzene (9.60 g, 28.1 mmol) and SnCl.2H 2 O (13.0 g, 56.0 mmol) in ethanol (25 mL) and water (5 mL) was refluxed until no starting material remained (˜1 h). The ethanol was removed in vacuo and the aq layer was basified to pH&gt;10 and extracted with CH 2 Cl 2  (4×10 mL). The combined organic layers were dried over Na 2 SO 4 , and the solvent was removed to give a crude 2-(2-Iodophenoxy)benzenamine (8.57 g, 98%), which was used for the next step without purification. 
     Step 3. 1-(2-Iodophenoxy)-2-chlorobenzene: A solution of crude 2-(2-iodophenoxy)benzenamine (8.57 g, 27.6 mmol) in MeCN (60 mL) was cooled to 0° C. and treated with HBF 4  (54 wt % in Et 2 O, 4.93 mL, 35.9 mmol). The reaction mixture was stirred at 0° C. for 5 min and of t-BuONO (4.10 g, 35.9 mmol) was added dropwise. The resulting mixture was stirred at 0° C. for 10 min, cooled to −20° C., and added to a solution of CuCl (41 g, 414.1 mmol) and CuCl 2  (70 g, 414.1 mmol) in water (500 mL) at 0° C. The mixture was stirred vigorously at 25° C. for 2 h, and partitioned between EtOAc and water. The water layer was extracted with EtOAc (3×10 mL) and the combined organic layers were washed with brine, dried over Na 2 SO 4  and concentrated under vacuum. Flash column chromatography gave 1-(2-iodophenoxy)-2-chlorobenzene (5.35 g, 58%). 
     The following halodiphenyl ethers were prepared following the procedures described above using the starting materials and reagents indicated: 
     
       
         
           
               
               
               
             
               
                   
               
               
                   
                   
                 Halide 
               
               
                 Halopdiphenyl ether 
                 Phenol in Step 1 
                 in Step 3 
               
               
                   
               
             
            
               
                 2-[(2-bromophenyl)oxy]-1,3- 
                 2,6-dimethylphenol 
                 CuBr/CuBr 2   
               
               
                 dimethylbenzene 
               
               
                 2-[(2-bromophenyl)oxy]-1-chloro-3- 
                 2-chloro-6- 
                 CuBr/CuBr 2   
               
               
                 methylbenzene 
                 methylphenol 
               
               
                 1-bromo-3-chloro-2-[(2- 
                 2-methylphenol 
                 CuBr/CuBr 2   
               
               
                 methylphenyl)oxy]benzene 
               
               
                   
               
            
           
         
       
     
     Preparation 5 
     Piperidines from Weinreb Amides and Halodiphenylethers 
     1-(2-(3-Fluorophenoxy)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol 
     
       
         
         
             
             
         
       
     
     Step 1. 2-(3-Fluorophenoxy)phenyllithium: To a stirred solution of 1-(3-fluorophenoxy)-2-bromobenzene (1.27 g, 4.75 mmol) in THF (10 mL) at −70° C. was added 1.7 M t-BuLi in pentane (5.6 mL, 9.50 mmol) dropwise to keep the temperature below −70° C. The resulting solution was stirred at −70° C. for 30 min, and used for the next step directly. 
     Step 2. (3R)-1-(tent-butoxycarbonyl)-3-((3-fluorophenoxy)benzoyl)piperidine: To a solution of (R)-tent-butyl 3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate (0.65 g, 2.37 mmol) in THF (4 mL) at −20° C. was added dropwise the solution of 2-(3-fluorophenoxy)phenyllithium prepared in Step 2 above. After the addition was complete, the resulting solution was allowed to warm to rt slowly, and left at rt for 1 h. The reaction was quenched with 1N HCl (˜6 mL), and extracted with Et 2 O (4×10 mL). The combined organic layers were washed with satd aq NaHCO 3  and brine, and dried over Na 2 SO 4 . Removal of the solvent left the crude ketone (1.49 g, quantitative), which was used for next step without further purification. 
     Step 3. (3R)-tert-butyl 3-(1-(2-(3-fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate: To a solution of (3R)-1-(tert-butoxycarbonyl)-3-((3-fluorophenoxy)benzoyl)piperidine (0.95 g, 2.37 mmol) in THF (3 mL) at −20° C. was added 1.45 M 4-methoxybutyl magnesium chloride in THF (3.3 mL, 4.76 mmol) dropwise. The resulting solution was warmed to rt slowly, and the completion of reaction was confirmed by LC-MS (˜20 min). The reaction was quenched with satd aq NH 4 Cl (4 mL) and extracted with Et 2 O (4×5 mL). The combined organic layers were washed with water and brine, and the solvent was removed in vacuo to give a crude product which was purified by flash column chromatography to afford (3R)-tert-butyl 3-(1-(2-(3-fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (0.50 g, 43%). 
     Step 4. 1-(2-(3-Fluorophenoxy)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol: To a solution of (3R)-tert-butyl 3-(1-(2-(3-fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (0.50 g, 1.03 mmol) in MeCN (60 mL) was added 2 N aq HCl (60 mL) slowly at rt. The resulting solution was stirred at rt overnight, then basified to pH=10 with 10 N aq NaOH. The mixture was evaporated under reduced pressure to remove MeCN. The aq layer was extracted with CH 2 Cl 2  (4×10 mL), and the combined organic layers were washed with brine and dried over Na 2 SO 4 . The solvent was removed under vacuum to give 1-(2-(3-fluorophenoxy)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol (0.40 g, quantitative) as a free amine. 
     The following piperidines prepared using the above procedures using the halodiphenyl ethers listed below in Step 1. 
     
       
         
           
               
               
             
               
                   
               
               
                 Piperidine 
                 Halodiphenyl ether 
               
               
                   
               
             
            
               
                 1-(2-(2,6-dimethylphenoxy)phenyl)-5- 
                 2-(2-bromophenoxy)-1,3- 
               
               
                 methoxy-1-((R)-piperidin-3-yl)pentan-1-ol 
                 dimethylbenzene 
               
               
                 1-(3-chloro-2-(o-tolyloxy)phenyl)-5-methoxy- 
                 1-bromo-3-chloro-2-(o- 
               
               
                 1-((R)-piperidin-3-yl)pentan-1-ol 
                 tolyloxy)benzene 
               
               
                 1-(2-(2-chloro-6-methylphenoxy)phenyl)-5- 
                 2-(2-bromophenoxy)-1- 
               
               
                 methoxy-1-((R)-piperidin-3-yl)pentan-1-ol 
                 chloro-3-methylbenzene 
               
               
                 1-(3-chloro-2-(2-ethylphenoxy)phenyl)-5- 
                 1-bromo-3-chloro-2-(2- 
               
               
                 methoxy-1-((R)-piperidin-3-yl)pentan-1-ol 
                 ethylphenoxy)benzene 
               
               
                 1-(3-chloro-2-(3-ethylphenoxy)phenyl)-5- 
                 1-bromo-3-chloro-2-(3- 
               
               
                 methoxy-1-((R)-piperidin-3-yl)pentan-1-ol 
                 ethylphenoxy)benzene 
               
               
                 1-{3-chloro-2-[(3-methylphenyl)oxy]phenyl}- 
                 1-bromo-3-chloro-2-[(3- 
               
               
                 5-(methyloxy)-1-[(3R)-3-piperidinyl]-1- 
                 methyl- 
               
               
                 pentanol 
                 phenyl)oxy]benzene 
               
               
                 1-{3-fluoro-2-[(3-methylphenyl)oxy]phenyl}- 
                 1-bromo-3-fluoro-2-[(3- 
               
               
                 5-(methyloxy)-1-[(3R)-3-piperidinyl]-1- 
                 methyl- 
               
               
                 pentanol 
                 phenyl)oxy]benzene 
               
               
                   
               
            
           
         
       
     
     Preparation 6 
     Boc Protected Piperidines from Weinreb Amides and Iododiphenyl Ethers 
     5-(methyloxy)-1-{2-[(2-methylphenyl)oxy]phenyl}-1-[(3R)-3-piperidinyl]-1-pentanol 
     
       
         
         
             
             
         
       
     
     Step 1. (2-(O-tolyloxy)phenyl)((R)-1-(tert-butoxycarbonyl)piperidin-3-yl)methanone: To a solution of 1-(o-tolyloxy)-2-iodobenzene (40 g, 0.13 mol) in anhydrous THF (500 mL) cooled to −78° C. was added dropwise 1.6 M n-BuLi in hexanes (52 mL, 0.13 mol). After stirring for 1 h at −78° C., a solution of (R)-tent-butyl 3-(N-methoxy-N-methylcarbamoyl)-piperidine-1-carboxylate (35 g, 0.13 mol) in anhydrous THF (500 mL) was added dropwise. The mixture was allowed to warm to rt and stirred overnight. Saturated aq NH 4 Cl (500 mL) was added and the mixture was extracted with EtOAc (3×150 mL). The combined organic layers were dried over Na 2 SO 4 . Solvent removal and flash column chromatography afforded (2-(o-tolyloxy)phenyl)((R)-1-(tert-butoxycarbonyl)piperidin-3-yl)methanone (23 g, 45%). 
     Step 2. (3R)-tert-butyl 3-(1-(2-(o-tolyloxy)phenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate: A 500-mL, three-necked flask was charged with magnesium turnings (12 g, 0.5 mol) and a small crystal of iodine. The flask was evacuated and refilled with N 2 . A solution of 1-chloro-4-methoxybutane (50 g, 0.4 mol) in THF (200 mL) was added dropwise to the mixture. The reaction mixture was stirred at reflux for 2 h and most of magnesium was consumed. The solution of Grignard reagent was cooled to rt. 
     A 1000 mL, three-necked flask was charged with the (2-(o-tolyloxy)phenyl)((R)-1-(tert-butoxycarbonyl)piperidin-3-yl)methanone (20 g, 0.05 mol) and THF (250 mL). The flask was evacuated and refilled with N 2 , the mixture was cooled with a dry ice-acetone bath and the Grignard reagent was added dropwise. The mixture was allowed to warm slowly to rt and stirred overnight. After quenching with satd aq NH 4 Cl (500 mL), the mixture was extracted with EtOAc (3×150 mL) and the combined organic layers were dried over Na 2 SO 4 . The solvent was removed and the crude product was purified by flash column chromatography to afford (3R)-tert-butyl 3-(1-(2-(o-tolyloxy)phenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (20 g, 83%). 
     Step 3. 5-(methyloxy)-1-{2-[(2-methylphenyl)oxy]phenyl}-1-[(3R)-3-piperidinyl]-1-pentanol: The Boc protecting group was removed using the protocol described in Preparation 5 Step 4. 
     Preparation 6b 
     Alternate Piperidines from Weinreb Amides and Halodiphenylethers 
     methyl {4-{3-fluoro-2-[3-methylphenyl)oxy]phenyl}-4-hydroxy-4-[(3R)-3-piperidinyl]butyl}carbamate 
     
       
         
         
             
             
         
       
     
     Step 1. 1,1-dimethylethyl (3R)-3-({3-fluoro-2-[(3-methylphenyl)oxy]phenyl}carbonyl)-1-piperidinecarboxylate 
     To a solution of 1-bromo-3-fluoro-2-[(3-methylphenyl)oxy]benzene (3.27 g, 11.7 mmol) in THF at −78° C., was added n-BuLi (2.5 M, 5.5 mL, 13.8 mmol). The resulting solution was stirred at −78° C. for 1 h. A solution of 1,1-dimethylethyl (3R)-3-{[methyl(methyloxy)amino]carbonyl}-1-piperidinecarboxylate (2.89 g, 10.6 mmol) in THF was then added dropwise and the resulting mixture warmed to room temperature for 2 h before it was quenched with saturated NH 4 Cl. The organic layer was separated and aqueous layer extracted with ethyl acetate. Combined organic layers are washed with brine, concentrated in vacuo to give crude 1,1-dimethylethyl (3R)-3-({3-fluoro-2-[(3-methylphenyl)oxy]phenyl}carbonyl)-1-piperidinecarboxylate (5.1 g) which was used in the next reaction without further purification. 
     Step 2. 1,1-dimethylethyl (3R)-3-(4-amino-1-{3-fluoro-2-[(3-methylphenyl)oxy]phenyl}-1-hydroxybutyl)-1-piperidinecarboxylate 
     To a solution of 1,1-dimethylethyl (3R)-3-({3-fluoro-2-[(3-methylphenyl)oxy]phenyl}carbonyl)-1-piperidinecarboxylate (5 g, 12.1 mmol) in THF at −78° C. was added dropwise a solution of (3-(2,2,5,5-tetramethyl-1,2,5-azadisilolidin-1-yl)propyl)magnesium chloride (1.45 M, 10.5 mL, 36.5 mmol). After the addition is complete, the resulting solution is allowed to warm to rt slowly, and left at rt for 1 h. The reaction was quenched with saturated NH 4 Cl and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo to give crude 1,1-dimethylethyl (3R)-3-(4-amino-1-{3-fluoro-2-[(3-methylphenyl)oxy]phenyl}-1-hydroxybutyl)-1-piperidinecarboxylate (6.6 g) which was used in the next step without further purification. MS (E/Z): 473.1 (M+H + ) 
     Step 3. 1,1-dimethylethyl (3R)-3-(1-{3-fluoro-2-[(3-methylphenyl)oxy]phenyl}-1-hydroxy-4-{[(methyloxy)carbonyl]amino}butyl)-1-piperidinecarboxylate 
     To a solution of 1,1-dimethylethyl (3R)-3-(4-amino-1-{3-fluoro-2-[(3-methylphenyl)oxy]phenyl}-1-hydroxybutyl)-1-piperidinecarboxylate (5.93 g, 13.2 mmol) and DMAP (0.81 g, 0.6 mmol) in CH 2 Cl 2  was added Et 3 N (4.0 g, 39.6 mmol). The resulting mixture was cooled to 5° C. and methyl chloroformate (6.2 g, 66 mmol) added and the mixture maintained at 5° C. for 2 h. The reaction was quenched with water and extracted with CH 2 Cl 2 . The combined organic layers are washed with 10% citric acid and brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo to give a crude product which is purified by flash column chromatography to afford 1,1-dimethylethyl (3R)-3-(1-{3-fluoro-2-[(3-methylphenyl)oxy]phenyl}-1-hydroxy-4-{[(methyloxy)carbonyl]amino}butyl)-1-piperidinecarboxylate (3.2 g, 48%). MS (E/Z): 531.1 (M+H + ) 
     Step 4. Methyl {4-{3-fluoro-2-[(3-methylphenyl)oxy]phenyl}-4-hydroxy-4-[(3R)-3-piperidinyl]butyl}carbamate 
     To a solution of 1,1-dimethylethyl (3R)-3-(1-{3-fluoro-2-[(3-methylphenyl)oxy]phenyl}-1-hydroxy-4-{[(methyloxy)carbonyl]amino}butyl)-1-piperidinecarboxylate (3.19 g, 6.0 mmol) in CH 2 Cl 2  (31.9 mL) was added TFA (31.9 mL) slowly at rt. The resulting mixture was stirred at rt for 15 min then neutralized to pH=7 with aqueous NaHCO 3  and extracted with CH 2 Cl 2 . The combined extracts were washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo to give methyl {4-{3-fluoro-2-[(3-methylphenyl)oxy]phenyl}-4-hydroxy-4-[(3R)-3-piperidinyl]butyl}carbamate (2.9 g) which was used in the next step without further purification. MS (E/Z): 431.1 (M+H + ) 
     The following piperidines prepared using the above procedures using the halodiphenyl ethers listed below in Step 1. 
     
       
         
           
               
               
             
               
                   
               
               
                 Piperidine 
                 Halodiphenyl ether 
               
               
                   
               
             
            
               
                 methyl {4-{3-chloro-2-[(3- 
                 1-bromo-3-chloro-2-[(3- 
               
               
                 methylphenyl)oxy]phenyl}-4-hydroxy-4- 
                 methylphenyl)oxy]benzene 
               
               
                 [(3R)-3-piperidinyl]butyl}carbamate 
               
               
                 methyl {4-{2-[(2,6- 
                 2-[(2-bromophenyl)oxy]-1,3- 
               
               
                 dimethylphenyl)oxy]phenyl}-4-hydroxy-4- 
                 dimethylbenzene 
               
               
                 [(3R)-3-piperidinyl]butyl}carbamate 
               
               
                 methyl 4-(3-chloro-2-(3- 
                 1-bromo-3-fluoro-2-(m- 
               
               
                 ethylphenoxy)phenyl)-4-hydroxy-4-((R)- 
                 tolyloxy)benzene 
               
               
                 piperidin-3-yl)butylcarbamate 
               
               
                   
               
            
           
         
       
     
     Preparation 7 
     Piperidines from Weinreb Amides and Bromobiaryls 
     1-(2′-chloro-2-biphenylyl)-5-(methyloxy)-1-[(3R)-3-piperidinyl]-1-pentanol 
     
       
         
         
             
             
         
       
     
     Step 1. (3R)-1-(tent-butoxycarbonyl)-3-((2-(2-chlorophenyl))benzoyl)piperidine: To a solution of 2′-bromo-2-chloro-biphenyl (5.34 g, 20 mmol) in anhydrous THF (50 mL) cooled to −78° C. was added dropwise a solution of 1.6 M n-BuLi in hexane (12.5 mL, 20 mmol). The reaction mixture was stirred at −78° C. for 1 h and a solution of (R)-tent-butyl 3-(N-methoxy-N-methylcarbamoyl)-piperidine-1-carboxylate (5.44 g, 20 mmol) in anhydrous THF (50 mL) was added. The mixture was allowed to warm to rt and stirred overnight. The mixture was quenched with satd aq NH 4 Cl (100 mL) and extracted with EtOAc (3×75 mL). The combined organic layers were dried over Na 2 SO 4  and concentrated to give the crude product, which was purified by flash column chromatography to afford (3R)-1-(tert-butoxycarbonyl)-3-42-(2-chlorophenyl))benzoyl)piperidine (4.43 g, 55%). 
     Step 2. 1,1-dimethylethyl (3R)-3-[1-(2′-chloro-2-biphenylyl)-1-hydroxy-5-(methyloxy)pentyl]-1-piperidinecarboxylate: A 250 mL three-necked flask was charged with magnesium turning (2.88 g, 0.12 mol) and a small crystal of iodine. The flask was evacuated and refilled with N 2 . A solution of 1-chloro-4-methoxybutane (15 g, 0.12 mol) in THF (60 ml) was added dropwise to the above mixture. After heating under reflux for 2 h most of magnesium had been consumed and the Grignard solution was cooled to rt. A 250 mL three-necked flask was charged with (3R)-1-(tert-butoxycarbonyl)-3-((2-(2-chlorophenyl))benzoyl)piperidine (4.43 g, 11 mmol) and THF (50 mL), evacuated and refilled with N 2 . The mixture was cooled in a dry ice-acetone bath and the Grignard reagent was added dropwise. The mixture was allowed to warm slowly to rt and stirred overnight. The mixture was quenched with satd aq NH 4 Cl (100 mL) and extracted with EtOAc. The combined organic layers were dried over Na 2 SO 4  and concentrated to give the crude product which was purified by flash column chromatography to afford pure 1,1-dimethylethyl (3R)-3-[1-(2′-chloro-2-biphenylyl)-1-hydroxy-5-(methyloxy)pentyl]-1-piperidinecarboxylate (2.5 g, 47%). 
     Step 3. 1-(2′-chloro-2-biphenylyl)-5-(methyloxy)-1-[(3R)-3-piperidinyl]-1-pentanol: The Boc protecting group was removed using the protocol described in Preparation 5 Step 4. 
     The following piperidines were prepared using procedures analogous to those described above substituting the bromobiphenyls indicated in Step 1: 
     
       
         
           
               
               
             
               
                   
               
               
                 Piperidine 
                 Bromobiphenyl 
               
               
                   
               
             
            
               
                 1-(6-fluoro-3′-methoxy-5′-methylbiphenyl- 
                 2-bromo-6-fluoro-3′-methoxy- 
               
               
                 2-yl)-5-methoxy-1-((R)-piperidin-3- 
                 5′-methylbiphenyl 
               
               
                 yl)pentan-1-ol 
               
               
                 1-(6-chloro-3′-ethylbiphenyl-2-yl)-5- 
                 2-bromo-6-chloro-3′- 
               
               
                 methoxy-1-((R)-piperidin-3-yl)pentan-1-ol 
                 ethylbiphenyl 
               
               
                 1-(3-chloro-2-(2-methylbenzyl)phenyl)-5- 
                 1-bromo-3-chloro-2-(2- 
               
               
                 methoxy-1-((R)-piperidin-3-yl)pentan-1-ol 
                 methylbenzyl)benzene 
               
               
                 1-(3-chloro-2-(3-methylbenzyl)phenyl)-5- 
                 1-bromo-3-chloro-2-(3- 
               
               
                 methoxy-1-((R)-piperidin-3-yl)pentan-1-ol 
                 methylbenzyl)benzene 
               
               
                 1-(3-chloro-2-(quinolin-3-yl)phenyl)-5- 
                 3-(2-bromo-6- 
               
               
                 methoxy-1-((R)-piperidin-3-yl)pentan-1-ol 
                 chlorophenyl)quinoline 
               
               
                 1-(3′-ethoxy-6-fluoro-5′- 
                 2-bromo-3′-ethoxy-6-fluoro- 
               
               
                 (trifluoromethyl)biphenyl-2-yl)-5- 
                 5′-(trifluoromethyl)biphenyl 
               
               
                 methoxy-1-((R)-piperidin-3-yl)pentan-1-ol 
               
               
                   
               
            
           
         
       
     
     Preparation 8 
     Ester Hydrolysis 
     (1S,3S,4R)-3-hydroxy-4-(tert-butoxycarbonylamino)cyclopentane-1-carboxylic acid 
     
       
         
         
             
             
         
       
     
     To a solution of tert-butyl (1R,2S,4S)-4-(methoxycarbonyl)-2-hydroxycyclopentyl-carbamate (115 mg, 0.444 mmol) in THF (1 mL) and ethanol (1 mL), was added 1M aq NaOH solution (1 mL). The mixture was stirred for 1 h. The solvent was evaporated and the filtrate was redissolved in water. The solution was neutralized with 1M aq HCl and extracted with EtOAc. The organic layer was washed with brine and dried over sodium sulfate. The solvent was removed by evaporation and to afford tert-butyl (1S,3R,4S)-3-(tert-butoxycarbonylamino)-4-hydroxycyclopentanecarboxylic acid (94 mg, 87%). 
     (1S,3R,4R)-3-(tert-butoxycarbonylamino)-4-hydroxycyclopentanecarboxylic acid was prepared from (1R,2R,4S)—N—BOC-1-amino-2-hydroxycyclopentane-4-carboxylic acid methyl ester using the above procedure. 
     Preparation 9 
     Biaryl Syntheses 
     a) 6-Bromo-2-fluoro-3′-methylbiphenyl 
     
       
         
         
             
             
         
       
     
     Step 1. 1-Bromo-3-fluoro-2-iodobenzene: To a solution of diisopropylamine (76 mL, 0.4 mol) in dry THF (664 mL) and n-hexane (220 mL) was added 2.5 M n-BuLi (160 mL. 0.4 mol) dropwise at −78° C. during a period of 1 h. The mixture was stirred for 1 h at −78° C. Then a solution of 1-bromo-3-fluoro-benzene (69 g, 0.4 mol) in dry THF (300 mL) at −78° C. was added to the above mixture dropwise. After stirring for an additional 1 h at −78° C., the mixture was added a solution of iodine (101 g, 0.4 mol) in dry THF (400 mL) dropwise at −78° C. The temperature was raised from −78° C. to rt during 2 h. After stirring for 18 h at rt, the mixture was concentrated in vacuo to give crude product (120 g) which was distilled under reduced pressure to afford 1-bromo-3-fluoro-2-iodobenzene (110 g).  1 H NMR (400 MHz, DMSO): 7.24-7.19 (t, 1H), 7.38-7.32 (m, 1H), 7.55-7.53 (d, 1H). 
     Step 2. 6-Bromo-2-fluoro-3′-methylbiphenyl: Pd(Ph 3 P) 4  in a 500-mL round-bottom flask under N 2  atmosphere was treated sequentially with a solution of 1-bromo-3-fluoro-2-iodo-benzene (30 g, 0.1 mol) in toluene (250 mL), a solution of 2N aq Na 2 CO 3  (200 mL) and 3-methyl phenylboronic acid in ethanol (62 mL). This mixture was heated at reflux under N 2  for 12 h, then cooled to rt. The mixture was partitioned between water and EtOAc. The combined organic layers were washed with brine, dried over MgSO 4 , evaporated and purified by column chromatography to give 6-bromo-2-fluoro-3′-methyl-biphenyl (12 g).  1 H NMR (400 MHz, CD 3 OD): 7.03 (m, 2H), 7.48-7.04 (m, 4H), 7.50 (d, 1H). 
     b) 6-Bromo-2-chloro-3′-methyl-biphenyl 
     
       
         
         
             
             
         
       
     
     Step 1. 1-bromo-3-chloro-2-iodobenzene: To a solution of diisopropylamine (76 mL, 0.4 mol) in anhydrous THF (664 mL) and n-hexane (220 mL) was added 2.5 M n-BuLi (160 mL, 0.4 mol) dropwise at −78° C. over 1 h. The mixture was stirred for 1 h at −78° C. and a solution of 1-bromo-3-chlorobenzene (76 g, 0.4 mol) in anhydrous THF (300 mL) was added dropwise at −78° C. After stirring for an additional 1 h at the same temperature, a solution of iodine (101 g, 0.4 mol) in anhydrous THF (400 mL) was added dropwise at −78° C. The temperature was raised from −78° C. to rt during 2 h. After stirring for 18 h at rt, the mixture was concentrated in vacuo to give the crude product (120 g) which was distilled under reduced pressure to give 1-bromo-3-fluoro-2-iodobenzene (115 g, 91%).  1 H NMR (400 MHz, CDCl 3 ): 7.12-7.18 (t, 1H), 7.35-7.41 (dd, 1H), 7.49-7.54 (dd, 1H); MS (E/Z): 317 (M+H + ) 
     Step 2. 6-bromo-2-chloro-3′-methyl-biphenyl: A 500-mL round-bottom flask under N 2  atmosphere was charged sequentially with Pd(Ph 3 P) 4 , 1-bromo-3-fluoro-2-iodobenzene (10 g, 0.032 mol) in toluene (80 mL), 2N aqueous sodium carbonate (55 mL) and 3-methylphenylboronic acid (5.16 g, 0.032 mol) dissolved in ethanol (40 mL). This mixture was heated at reflux under N 2  for 12 h and cooled to rt. The mixture was partitioned between water and EtOAc. The combined organic layers were washed with brine, dried over MgSO 4 , and concentrated. The residue was purified by column chromatography to give 6-bromo-2-chloro-3′-methyl-biphenyl (6 g, 67%).  1 H NMR (400 MHz, CD 3 OD): 6.90-7.00 (t, 2H), 7.14-7.24 (m, 2H), 7.26-7.33 (t, 1H), 7.44-7.50 (d, 1H), 7.58-7.62 (d, 1H); MS (E/Z): 281 (M+H + ) 
     The following biaryls were prepared from aryl halides and the boronic acids indicated using the procedures described in Preparations 9a Step 2 and 9b Step 2: 
     
       
         
           
               
               
               
             
               
                   
               
               
                 Biaryl 
                 Aryl halide 
                 Boronic acid 
               
               
                   
               
             
            
               
                 2-bromo-6-chloro-3′- 
                 1-bromo-3-chloro- 
                 3-ethylphenylboronic acid 
               
               
                 ethylbiphenyl 
                 2-iodobenzene 
               
               
                 2-bromo-3′-ethyl-6- 
                 1-bromo-3-fluoro- 
                 3-ethylphenylboronic acid 
               
               
                 fluorobiphenyl 
                 2-iodobenzene 
               
               
                 2-bromo-6-chloro-3′- 
                 1-bromo-3-chloro- 
                 3-isopropylphenylboronic acid 
               
               
                 isopropylbiphenyl 
                 2-iodobenzene 
               
               
                 2-bromo-4′,6-difluoro-3′- 
                 1-bromo-3-fluoro- 
                 (4-fluoro-3-methylphenyl)boronic 
               
               
                 methylbiphenyl 
                 2-iodobenzene 
                 acid 
               
               
                 2-bromo-6-fluoro-4′-fluoro- 
                 1-bromo-3-fluoro- 
                 (4-fluoro-3-methylphenyl)boronic 
               
               
                 3′-methylbiphenyl 
                 2-iodobenzene 
                 acid 
               
               
                 2-bromo-6-chloro-3′,5′-bis 
                 1-bromo-3-chloro- 
                 [3,5-bis (methoxy) phenyl]boronic 
               
               
                 (methoxy) biphenyl 
                 2-iodobenzene 
                 acid 
               
               
                 2-bromo-6-fluoro-3′,5′-bis 
                 1-bromo-3-fluoro- 
                 [3,5-bis (methoxy) phenyl]boronic 
               
               
                 (methoxy) biphenyl 
                 2-iodobenzene 
                 acid 
               
               
                 2-bromo-6-chloro-3′- 
                 1-bromo-3-chloro- 
                 [3-(methoxy)phenyl]boronic acid 
               
               
                 (methoxy)biphenyl 
                 2-iodobenzene 
               
               
                 2-bromo-6-fluoro-3′- 
                 1-bromo-3-fluoro- 
                 [3-(methoxy)phenyl]boronic acid 
               
               
                 (methoxy)biphenyl 
                 2-iodobenzene 
               
               
                 2-bromo-6-fluoro-3′-methyl- 
                 1-bromo-3-fluoro- 
                 [3-methyl-5-(methoxy)phenyl]boronic 
               
               
                 5′-(methoxy)biphenyl 
                 2-iodobenzene 
                 acid 
               
               
                 2-bromo-3′-(ethyloxy)-6- 
                 1-bromo-3-fluoro- 
                 [3-(ethyloxy)-5-(trifluoromethyl)phenyl]boronic 
               
               
                 fluoro-5′- 
                 2-iodobenzene 
                 acid 
               
               
                 (trifluoromethyl)biphenyl 
               
               
                 3-(2-bromo-6- 
                 1-bromo-3-chloro- 
                 3-quinolinylboronic acid 
               
               
                 chlorophenyl)quinoline 
                 2-iodobenzene 
               
               
                 2-(2-bromo-6- 
                 1-bromo-3-chloro- 
                 2-naphthalenylboronic acid 
               
               
                 chlorophenyl)naphthalene 
                 2-iodobenzene 
               
               
                 3-(2-bromophenyl)pyridine 
                 1-bromo-2- 
                 3-pyridinylboronic acid 
               
               
                   
                 iodobenzene 
               
               
                 3-(2-bromo-6- 
                 1-bromo-3-chloro- 
                 3-pyridinylboronic acid 
               
               
                 chlorophenyl)pyridine 
                 2-iodobenzene 
               
               
                 4-(2-bromophenyl)pyridine 
                 1-bromo-2- 
                 4-pyridinylboronic acid 
               
               
                   
                 iodobenzene 
               
               
                 4-(2-bromo-6- 
                 1-bromo-3-chloro- 
                 4-isoquinolinylboronic acid 
               
               
                 chlorophenyl)isoquinoline 
                 2-iodobenzene 
               
               
                 2-bromo-6-fluoro-2′-fluoro- 
                 1-bromo-3-fluoro- 
                 (2-fluoro-5-methylphenyl)boronic 
               
               
                 5′-methylbiphenyl 
                 2-iodobenzene 
                 acid 
               
               
                 2-bromo-6-chloro-3′- 
                 1-bromo-3-chloro- 
                 {3-[(methoxy)methyl]phenyl}boronic 
               
               
                 [(methoxy)methyl]biphenyl 
                 2-iodobenzene 
                 acid 
               
               
                 2-bromo-5-fluoro-3′- 
                 1-bromo-4-fluoro- 
                 3-methylphenylboronic acid 
               
               
                 methylbiphenyl 
                 2-iodobenzene 
               
               
                 2-bromo-2′,4,6-trifluoro-5′- 
                 1-bromo-3,5- 
                 (2-fluoro-5-methylphenyl)boronic 
               
               
                 methylbiphenyl 
                 difluoro-2- 
                 acid 
               
               
                   
                 iodobenzene 
               
               
                 2-bromo-4,6-difluoro-3′- 
                 1-bromo-3,5- 
                 3-methylphenylboronic acid 
               
               
                 methylbiphenyl 
                 difluoro-2- 
               
               
                   
                 iodobenzene 
               
               
                 2-bromo-3′,6-difluoro-5′- 
                 1-bromo-3-fluoro- 
                 3-fluoro-5-methylphenylboronic 
               
               
                 methylbiphenyl 
                 2-iodobenzene 
                 acid 
               
               
                 2-bromo-6-chloro-3′-fluoro- 
                 1-bromo-3-chloro- 
                 3-fluoro-5-methylphenylboronic 
               
               
                 5′-methylbiphenyl 
                 2-iodobenzene 
                 acid 
               
               
                 3-(2-bromo-6- 
                 1-bromo-3-fluoro- 
                 3-quinolinylboronic acid 
               
               
                 fluorophenyl)quinoline 
                 2-iodobenzene 
               
               
                 2-(2-bromo-6-fluorophenyl)- 
                 1-bromo-3-chloro- 
                 5-methylfuran-2-ylboronic acid 
               
               
                 5-methylfuran 
                 2-iodobenzene 
               
               
                 2-bromo-6-fluoro-3′- 
                 1-bromo-3-chloro- 
                 3-isopropylphenylboronic acid 
               
               
                 isopropylbiphenyl 
                 2-iodobenzene 
               
               
                 3-(2-bromo-6- 
                 1-bromo-3-chloro- 
                 1-benzothien-2-ylboronic acid 
               
               
                 chlorophenyl)-1- 
                 2-iodobenzene 
               
               
                 benzothiophene 
               
               
                 4-bromo-2-chloro-3-(3- 
                 4-bromo-2-chloro- 
                 (3-ethylphenyl)boronic acid 
               
               
                 ethylphenyl)pyridine 
                 3-iodopyridine 
               
               
                 2-bromo-4-chloro-3-(3- 
                 2-bromo-4-chloro- 
                 (3-ethylphenyl)boronic acid 
               
               
                 ethylphenyl)pyridine 
                 3-iodopyridine 
               
               
                 4-bromo-2-chloro-3-[3-(1- 
                 4-bromo-2-chloro- 
                 [3-(1-methylethyl)phenyl]boronic 
               
               
                 methylethyl)phenyl]pyridine 
                 3-iodopyridine 
                 acid 
               
               
                   
               
            
           
         
       
     
     c) 2-(2-bromo-6-chlorophenyl)-8-(1-methylethyl)quinoline 
     
       
         
         
             
             
         
       
     
     Step 1. 2-bromo-6-chloro-N-[2-(1-methylethyl)phenyl]benzamide 
     To a solution of 2-bromo-6-chlorobenzoyl chloride (39.3 g, 149.1 mmol) and Na 2 CO 3  (31.4 g, 318.3 mmol) in THF (232 mL) and water (23 mL) was added [2-(1-methylethyl)phenyl]amine (22.2 g, 164.1 mmol). The resulting mixture was stirred at room temperature for 1 h. The mixture was extracted with ethyl acetate and the pH adjusted to 2. The organic layers were then washed with Na 2 CO 3 , brine, dried over Na 2 SO 4 , filtered and concentrated to give 2-bromo-6-chloro-N-[2-(1-methylethyl)phenyl]benzamide (35.5 g) which was used in the subsequent reaction without further purification. MS (E/Z): 353.9 (M+H + ) 
     Step 2. N-[(1)-1-(2-bromo-6-chlorophenyl)-3-(trimethylsilyl)-2-propyn-1-ylidene]-2-(1-methylethyl)aniline 
     To a stirred solution of 2-bromo-6-chloro-N-[2-(1-methylethyl)phenyl]benzamide (50 g, 137.8 mmol) and 2-chloropyridine (50.5 mL, 554.9 mmol) in CH 2 Cl 2  (300 mL) under argon at −78° C. was added Tf 2 O (28.2 mL, 167.6 mmol). After 5 min, the reaction mixture was warmed to 0° C. and maintained at that temperature for 20 min before recooling to −78° C. [(Trimethylsilyl)ethynyl]copper (730 mL, 383.4 mmol) was then added via cannula as a solution in THF. The resulting mixture was maintained at −78° C. for 5 min before warming to 0° C. After 10 min the crude mixture was filtered through Celite and the filtrate concentrated in vacuo. The crude material was purified via column chromatography to give N-[(1)-1-(2-bromo-6-chlorophenyl)-3-(trimethylsilyl)-2-propyn-1-ylidene]-2-(1-methylethyl)aniline (9.58 g, 16%). MS (E/Z): 433.1 (M+H + ) 
     Step 3. 2-(2-bromo-6-chlorophenyl)-8-(1-methylethyl)quinoline 
     To a mixture of Ammonium hexafluorophosphate purum (3.7 g, 22.2 mmol) and CpRu(Ph 3 P) 2 Cl (1.64 g, 2.3 mmol) in toluene (110 mL) was added N-[(1)-1-(2-bromo-6-chlorophenyl)-3-(trimethylsilyl)-2-propyn-1-ylidene]-2-(1-methylethyl)aniline (9.1 g, 21.0 mmol). The resulting mixture was then heated to 115° C. for 19 h. The reaction was then cooled to rt, diluted with CH 2 Cl 2  and the solvent removed in vacuo. The residue was then purified via column chromatography to afford 2-(2-bromo-6-chlorophenyl)-8-(1-methylethyl)quinoline (3.7 g, 49%). MS (E/Z): 360.0 (M+H + ) 
     The following biaryl was prepared from the aniline indicated using the procedures described in Preparations 9c Steps 1-3: 
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 Biaryl 
                 Aniline 
               
               
                   
                   
               
             
            
               
                   
                 2-(2-bromo-6-chlorophenyl)-8- 
                 2-methyl aniline 
               
               
                   
                 methylquinoline 
               
               
                   
                   
               
            
           
         
       
     
     d) 2-(2-bromo-6-chlorophenyl)-4-(1-methylethyl)quinazoline 
     
       
         
         
             
             
         
       
     
     Step 1. 2-bromo-6-chlorobenzoic acid 
     To a stirred solution of n-BuLi (90.0 mmol, 36 ml of a 2.5 M solution in hexanes) in 160 mL of dry THF at −78° C., was added dropwise diisopropylamine (12.4 ml, 90 mmol) in 20 mL of dry THF. The resulting solution was stirred for 0.5 h at −78° C. A solution of 1-bromo-3-chlorobenzene (14.3 g, 75.0 mmol) in 20 ml of dry THF was added and the resulting mixture was stirred for an additional hour −78° C. Then dry ice (CO 2 ) was added in small portions (large gas evolution) and after 20 min the solution was quenched with 100 mL of 2N HCl. The mixture was extracted with ethyl acetate (1000 ml) and the crude 2-bromo-6-chlorobenzoic acid (white solid) was triturated with Et 2 O and used in the next step without other purification. MS (E/Z): 234.9 (M+H + ) 
     Step 2. 2-bromo-6-chloro-N-phenylbenzamide 
     To a stirred solution of 2-bromo-6-chlorobenzoic acid (3.15 g, 13.4 mmol) in 20.0 mL of dry methylene chloride, were added DMF (catalytic amount) and oxalyl chloride (1.45 mL, 16.1 mmol) dropwise. The resulting solution was stirred for 2 h at room temperature. The solvent was removed in vacuo and the crude dissolved in 20.0 mL of dry DCM. Triethylamine (3.7 mL, 26.8 mmol) and aniline (1.78 mL, 18.7 mmol) were added and the resulting mixture was stirred over night at room temperature. HPLC/MS showed that the reaction was completed at this time. The reaction mixture was quenched with 0.6N HCl and extracted with methylene chloride. The organic layer was then dried, filtered and concentrated to afford 2-bromo-6-chloro-N-phenylbenzamide, which was used in the next step without further purification. MS (E/Z): 309.9 (M+H + ) 
     Step 3. 2-(2-bromo-6-chlorophenyl)-4-(1-methylethyl)quinazoline 
     To a stirred solution of 2-bromo-6-chloro-N-phenylbenzamide (930 mg, 3.0 mmol) and 2-chloropyridine (406 μl, 3.6 mmol) in 10 ml of dry methylene chloride was added at −78° C. followed by Tf 2 O (1015 μl, 3.6 mmol). The solution was stirred at −78° C. and then was warmed to 0° C. and i-PrCN (354 μl, 3.6 mmol) added. The resulting solution was stirred overnight 70° C. in a microwave vial. The HPLC/MS showed product as well as starting material. The reaction mixture was quenched with 0.6N HCl and extracted with methylene chloride. The organic layer was then dried, filtered, and concentrated to afford the crude material. Column chromatography then gave 2-(2-bromo-6-chlorophenyl)-4-(1-methylethyl)quinazoline (0.418 g, 40%). MS (E/Z): 361.0 (M+H + ) 
     e) 2-bromo-4-chloro-3-(3-ethylphenyl)pyridine 
     
       
         
         
             
             
         
       
     
     Step 1. 2-bromo-4-chloropyridine 
     To an aqueous solution of 48% strength hydrobromic acid (82 mL) at 0° C. was added 4-chloro-2-pyridinamine (8.9 g, 69.2 mmol) followed by addition of bromine (33.4 g, 209 mmol) over 10 min. The resulting mixture was cooled to −10° C. and a solution of NaNO 2  (10.65 g, 154 mmol) in H 2 O (20 mL) was poured in over a period of 30 min. The mixture was warmed at room temperature and stirred overnight. The mixture was recooled to 0° C. and NaOH (35%) added until the pH &gt;10. The mixture was then extracted with ethyl acetate. The organic layer was then dried, filtered, and concentrated in vacuo. The product was purified via column chromatography (0-20% ethyl acetate/hexane) to afford 2-bromo-4-chloropyridine (12.1 g, 92%). 
     Step 2. 2-bromo-4-chloro-3-iodopyridine 
     To a stirred solution of diisopropylamine (8.24 mL, 60.0 mmol) in THF (100 mL) at −78° C. was added n-BuLi (24.0 mL, 60.0 mmol) and the solution was stirred at this temperature for 30 min. Then, a solution of 2-bromo-4-chloropyridine (12.1 g, 60.0 mmol) dissolved in THF (100 mL) was added dropwise. The resulting mixture was stirred for 1 h at −78° C. Then I 2  (21.0 g, 66.0 mmol) was added in three portions. The solution was warmed to room temperature and stirred overnight. The mixture was diluted with ethyl acetate and washed with water. The organic layer was then dried, filtered, and concentrated in vacuo. The crude material was purified via column chromatography to give 2-bromo-4-chloro-3-iodopyridine (7.3 g, 38%). MS (E/Z): 317.8 (M+H + ). 
     Step 3. 2-bromo-4-chloro-3-(3-ethylphenyl)pyridine 
     To a solution of 2-bromo-4-chloro-3-iodopyridine (3.17 g, 10 mmol) in dioxane (20 mL) and water (10 mL) was added (3-ethylphenyl)boronic acid (1.9 g, 13.0 mmol) followed by Pd(Ph) 2 Cl 2  (0.350 g, 0.5 mmol). The resulting mixture was then heated at 80° C. overnight. In the morning, the reaction mixture was diluted with ethyl acetate, washed with water then brine, dried, filtered and concentrated in vacuo. The crude material was then purified via column chromatography to afford 2-bromo-4-chloro-3-(3-ethylphenyl)pyridine (1.5 g, 50%). 
     f.) 3-Bromo-5-chloro-4-[3-(1-methylethyl)phenyl]pyridine 
     
       
         
         
             
             
         
       
     
     Step 1: 3-bromo-5-chloro-4-iodopyridine 
     To a −78° C. solution of diisopropylamine (3.7 mL, 26 mmol) in anhydrous THF (50 mL) was added n-BuLi (10.4 mL, 2.5 M hexanes, 26 mmol). After stirring for 30 minutes, a solution of 3-bromo-5-chloropyridine (5.0 g, 26 mmol) in THF (10 mL) was added dropwise. After stirring for an additional 1 hour at −78° C., a solution of iodine (7.9 g, 31.2 mmol) in THF (25 mL) was added. The reaction was slowly allowed to warm to room temperature and continued to stir overnight. The reaction was quenched with water (25 ml) and a saturated sodium thiosulfate solution (25 mL). The phases were separated. The organic layer was washed with Na 2 S 2 O 3  solution (25 mL). The aqueous phase was back extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine, dried over MgSO 4 , filtered and concentrated to give 7 g of a brown solid. The crude product was triturated with Et 2 O twice and isolated 3-bromo-5-chloro-4-iodopyridine (3.3 g, 40% yield) as a brown solid (powder). 
     Step 2: 3-bromo-5-chloro-4-(3-isopropylphenyl)pyridine 
     3-Bromo-5-chloro-4-iodopyridine (1.6 g, 5.0 mmol), (3-isopropylphenyl)boronic acid (0.99 g, 6.0 mmol), Na 2 CO 3  (1.1 g, 10 mmol) and Pd(PPh 3 ) 2 Cl 2  (0.50 g, 0.50 mmol) were added to a flask with 1,4-dioxane/water (2:1) (15 mL). The reaction mixture was immersed into a preheated oil bath (85° C.) and stirred overnight (18 hours). The reaction mixture was allowed to cool to room temperature and then diluted with EtOAc and water. The phases were separated and the aqueous phase was extracted with EtOAc (2×). The combined organics were washed with brine, dried over MgSO 4 , filtered and concentrated to give 2 g of a brown oil. The crude residue was purified by flash chromatography on silica gel and isolated 0.78 g (50% yield) of 3-bromo-5-chloro-4-(3-isopropylphenyl)pyridine as a clear oil. 
     The following biaryl was prepared from the indicated boronic acid using the procedures described in Preparations 9f Steps 1-2: 
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 Biaryl 
                 Boronic Acid 
               
               
                   
                   
               
             
            
               
                   
                 3-bromo-5-chloro-4-(3- 
                 (3-ethylphenyl)boronic acid 
               
               
                   
                 ethylphenyl)pyridine 
               
               
                   
                   
               
            
           
         
       
     
     Preparation 10 
     Morpholine Synthesis 
     (R)-1-(6-Fluoro-3′-methylbiphenyl-2-yl)-5-methoxy-1-((R)-morpholin-2-yl)pentan-1-ol 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Step 1. (R)-2-(Benzyloxymethyl)morpholine: To a stirred mixture of (R)-2-(benzyloxymethyl)oxirane (10.0 g, 60.9 mmol) and NaOH (19.49 g, 487.2 mmol) in H 2 O (46 mL) and MeOH (18 mL), there was added 2-aminoethyl hydrogen sulfate (36.8 g, 255.8 mmol) in portions. After addition was complete, the reaction mixture was stirred at 40° C. for 2 h. After cooling, the mixture was treated with NaOH (15.0 g, 375.0 mmol), followed by toluene (70 mL), and stirred at 65° C. overnight. The mixture was cooled, diluted with toluene (27 mL) and H 2 O (92 mL). The toluene layer was separated and the aqueous layer was extracted with CH 2 Cl 2  (2×50 mL). The combined organic layers were concentrated to give crude (R)-2-(benzyloxymethyl)morpholine (˜14 g), which was used without purification. MS m/z 208 (M+H + ). 
     Step 2. (R)-tent-Butyl 2-(benzyloxymethyl)morpholine-4-carboxylate: To a solution of crude (R)-2-(benzyloxymethyl)morpholine (˜14 g) in acetone (100 mL) and H 2 O (30 mL) at 0° C., there was added K 2 CO 3  (25.2 g, 182.7 mmol), followed by (Boc) 2 O (14.6 g, 67.0 mmol). The resulting solution was warmed to rt, and stirred until no starting material remained (˜30 min). Acetone was removed under vacuum, and the aqueous solution was extracted with CH 2 Cl 2  (4×10 mL). The combined organic layers were washed with H 2 O (10 mL) and the solvent was removed. The residue was purified by flash column chromatography to give (R)-tent-butyl 2-(benzyloxymethyl)morpholine-4-carboxylate (8.33 g, 44% over 2 steps).  1 H NMR (400 MHz, CDCl 3 ): 7.34 (m, 5H), 4.56 (s, 2H), 3.88 (d, 2H), 3.82 (br, 1H), 3.40 (m, 1H), 3.48 (m, 3H), 2.94 (m, 1H), 2.76 (m, 1H), 1.44 (s, 9H); MS m/z 330 (M+Na + ). 
     Step 3. (R)-tent-Butyl 2-(hydroxymethyl)morpholine-4-carboxylate: To a solution of (R)-tent-butyl 2-(benzyloxymethyl)morpholine-4-carboxylate (8.33 g, 27.1 mmol) in EtOH was added Pd—C (wet, 3.6 g), and the resulting mixture was stirred at rt under a H 2  balloon overnight. After filtration, the solvent was removed under vacuum, and the residue was purified by flash column chromatography to give (R)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (5.84 g, 99%) as a clear oil.  1 H NMR (400 MHz, CDCl 3 ): 3.88 (d, 2H), 3.82 (br, 1H), 3.64 (d, 1H), 3.56 (m, 3H), 2.94 (m, 1H), 2.76 (m, 1H), 1.90 (br, 1H), 1.44 (s, 9H); MS m/z 218 (M+H + ). 
     Step 4. (R)-4-(tert-Butoxycarbonyl)morpholine-2-carboxylic acid: Satd aq NaHCO 3  (15 mL) was added to a solution of (R)-tent-butyl 2-(hydroxymethyl)-morpholine-4-carboxylate (1.09 g, 5.0 mmol) in acetone (50 mL), stirred and maintained at 0° C. Solid NaBr (0.1 g, 1 mmol) and TEMPO (0.015 g, 0.1 mmol) were added. Trichloroisocyanuric acid (2.32 g, 10.0 mmol) was then added slowly within 20 min at 0° C. After addition, the mixture was warmed to rt and stirred overnight. 2-Propanol (3 mL) was added, and the resulting solution was stirred at rt for 30 min, filtered through a pad of Celite, concentrated under vacuum, and treated with satd aq Na 2 CO 3  (15 mL). The aqueous solution was washed with EtOAc (5 mL), acidified with 6 N HCl, and extracted with EtOAc (5×10 mL). The combined organic layers were dried over Na 2 SO 4  and the solvent was removed to give (R)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (1.07 g, 92%) as a white solid.  1 H NMR (400 MHz, CDCl 3 ): 4.20 (br, 1H), 4.12 (d, 1H), 4.02 (d, 1H), 3.84 (m, 1H), 3.62 (m, 1H), 3.04 (m, 2H), 1.44 (s, 9H); MS m/z 232 (M+H). 
     Step 5. (R)-tent-Butyl 2-(methoxy(methyl)carbamoyl)morpholine-4-carboxylate: To a solution of (R)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (1.05 g, 4.54 mmol) in DMF (10 mL) at 0° C. C, was added DIEA (3.9 mL, 22.7 mmol), followed by HBTU (1.89 g, 4.99 mmol) and HOBt (0.67 g, 4.99 mmol). MeONHMe.HCl (0.48 g, 4.92 mmol) was added and the resulting solution was warmed to rt and stirred until no starting material remained (˜2 h). The mixture was diluted with H 2 O (10 mL) and extracted with EtOAc (4×10 mL). The combined organic layers were washed with 1 N aq HCl (10 mL), 1 N aq NaOH (3×10 mL), water (2×10 mL) and brine (10 mL), and dried over Na 2 SO 4 . The solvent was removed under vacuum to give (R)-tent-butyl 2-(methoxy(methyl)carbamoyl)morpholine-4-carboxylate (1.40 g, quant.), which was used without further purification.  1 H NMR (400 MHz, CDCl 3 ): 4.36 (br, 1H), 4.08 (m, 1H), 4.00 (d, 1H), 3.84 (m, 1H), 3.76 (s, 3H), 3.58 (m, 1H), 3.20 (s, 3H), 3.04 (m, 2H), 1.44 (s, 9H); MS m/z 297 (M+Na + ). 
     Step 6. (R)-tent-Butyl 2-(5-methoxypentanoyl)morpholine-4-carboxylate: To a stirred solution of (R)-tent-butyl 2-(methoxy(methyl)carbamoyl)morpholine-4-carboxylate (1.37 g, 5.0 mmol) in THF (10 mL) at −20° C., there was added 1.47 M 4-methoxybutylmagnesium chloride in THF (10.2 mL, 15.0 mmol) dropwise to keep the temperature below −20° C. After addition, the resulting solution was warmed to rt and quenched with 1 N aq HCl (10 mL). The organic layer was separated, and the aqueous layer was extracted with ether (3×5 mL). Combined organic layers were washed with satd aq NaHCO 3  (10 mL) and brine (5 mL) and dried over Na 2 SO 4 . Removal of the solvent under vacuum gave (R)-tent-butyl 2-(5-methoxypentanoyl)morpholine-4-carboxylate (1.41 g, 93%), which was used without purification. MS m/s 324 (M+Na + ). 
     Step 7. (R)-tent-Butyl 2-((R)-1-(6-fluoro-3′-methylbiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)-morpholine-4-carboxylate: To a solution of 2-bromo-6-fluoro-3′-methylbiphenyl (1.90 g, 7.17 mmol) in ether (8 mL) at −78° C., there was added t-BuLi in pentane (1.70 M, 8.43 mL, 14.33 mmol) dropwise to keep the temperature below −70° C. The resulting solution was stirred at −78° C. 
     To a solution of (R)-tert-butyl 2-(5-methoxypentanoyl)morpholine-4-carboxylate (0.68 g, 2.26 mmol) in toluene (8 mL) at −20° C. there was added the above lithium reagent dropwise to keep the solution temperature below −20° C. After addition, the resulting mixture was warmed to rt slowly, and quenched with saturated NH 4 Cl (8 mL). The organic layer was separated, and aqueous layer was extracted with ether (3×5 mL). Combined organic layers were washed with water (10 mL), concentrated, and the residue was purified by flash column chromatography to give (R)-tert-butyl 2-((R)-1-(6-fluoro-3′-methylbiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)-morpholine-4-carboxylate (0.48 g, 44%) as a foam.  1 H NMR (400 MHz, CDCl 3 ): 7.40 (m, 1H), 7.32 (m, 2H), 7.20 (d, 1H), 7.04 (m, 3H), 3.84 (m, 1H), 3.78 (m, 2H), 3.40-3.24 (ms, 7H), 2.82 (s, 3H), 1.70-1.20 (m, 5H), 1.44 (s, 9H), 0.94 (m, 1H); MS m/z 510 (M+Na + ). 
     Step 8. (R)-1-(6-Fluoro-3′-methylbiphenyl-2-yl)-5-methoxy-1-((R)-morpholin-2-yl)-pentan-1-ol: To a solution of (R)-tert-butyl 2-((R)-1-(6-fluoro-3′-methylbiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)morpholine-4-carboxylate (0.46 g, 0.96 mmol) in acetonitrile (50 mL) was added 2 N aq HCl (50 mL). The resulting solution was stirred at rt overnight and basified with 10 N aq NaOH to pH 10. Acetonitrile was removed under vacuum, and the aqueous residue was extracted with CH 2 Cl 2  (4×5 mL). The combined organic layers were washed with brine (5 mL), dried over Na 2 SO 4 , and concentrated to give (R)-1-(6-fluoro-3′-methylbiphenyl-2-yl)-5-methoxy-1-((R)-morpholin-2-yl)pentan-1-ol (0.38, quant.). MS m/z 388 (M+H + ). 
     The following morpholines were prepared using procedures analogous to those described above:
     (R)-1-(4′,6-difluoro-3′-methylbiphenyl-2-yl)-5-methoxy-1-((R)-morpholin-2-yl)pentan-1-ol using 2-bromo-4′,6-difluoro-3′-methylbiphenyl in Step 7.   (R)-1-(3-chloro-2-(pyridin-3-yl)phenyl)-5-methoxy-1-((R)-morpholin-2-yl)pentan-1-ol using 3-(2-bromo-6-chlorophenyl)pyridine in Step 7.   (R)-1-(3-chloro-2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-5-methoxy-1-((R)-morpholin-2-yl)pentan-1-ol using 5-(2-bromo-6-chlorophenyl)-3-methyl-1,2,4-oxadiazole in Step 7.   (R)-1-(6-fluoro-3′-methoxy-5′-methylbiphenyl-2-yl)-5-methoxy-1-((R)-morpholin-2-yl)pentan-1-ol using 2-bromo-6-fluoro-3′-methoxy-5′-methylbiphenyl in Step 7.   (R)-1-(6-chloro-3′-ethylbiphenyl-2-yl)-5-methoxy-1-((R)-morpholin-2-yl)pentan-1-ol using 2-bromo-6-chloro-3′-ethylbiphenyl in Step 7.   (1R)-1-(6-chloro-2′-fluoro-5′-methylbiphenyl-2-yl)-5-methoxy-1-((R)-morpholin-2-yl)pentan-1-ol using 2′-bromo-6′-chloro-2-fluoro-5-methylbiphenyl in Step 7.   (R)-1-(3-chloro-2-(naphthalen-2-yl)phenyl)-5-methoxy-1-((R)-morpholin-2-yl)pentan-1-ol using 2-(2-bromo-6-chlorophenyl)naphthalene in Step 7.   (R)-1-(3-chloro-2-(quinolin-3-yl)phenyl)-5-methoxy-1-(R)-morpholin-2-yl)pentan-1-ol using 3-(2-bromo-6-chlorophenyl)quinoline in Step 7.   (R)-1-(6-fluoro-3′,5′-dimethoxybiphenyl-2-yl)-5-methoxy-1-((R)-morpholin-2-yl)pentan-1-ol using 2-bromo-6-fluoro-3′,5′-dimethoxybiphenyl in Step 7.   (R)-1-(6-chloro-3′-(methoxymethyl)biphenyl-2-yl)-5-methoxy-1-((R)-morpholin-2-yl)pentan-1-ol using 2-bromo-6-chloro-3′-(methoxymethyl)biphenyl in Step 7.   (1R)-1-(3-chloro-2-(isoquinolin-4-yl)phenyl)-5-methoxy-1-(R)-morpholin-2-yl)pentan-1-ol using 4-(2-bromo-6-chlorophenyl)isoquinoline in Step 7.   (R)-1-(6-chloro-3′,5′-dimethoxybiphenyl-2-yl)-5-methoxy-1-(R)-morpholin-2-yl)pentan-1-ol using 2-bromo-6-chloro-3′,5′-dimethoxybiphenyl in Step 7.   (R)-1-(6-fluoro-3′,5′-dimethoxybiphenyl-2-yl)-5-methoxy-1-((R)-morpholin-2-yl)pentan-1-ol using 2-bromo-6-fluoro-3′,5′-dimethoxybiphenyl in Step 7.   (R)-1-(3′-ethoxy-6-fluoro-5′-(trifluoromethyl)biphenyl-2-yl)-5-methoxy-1-((R)-morpholin-2-yl)pentan-1-ol using 2-bromo-3′-ethoxy-6-fluoro-5′-(trifluoromethyl)biphenyl in Step 7.   (1R)-1-[2-chloro-3-(3-ethylphenyl)-4-pyridinyl]-5-(methyloxy)-1-[(2R)-2-morpholinyl]-1-pentanol using 4-bromo-2-chloro-3-(3-ethylphenyl)pyridine in Step 7.   1-[2-(1-benzothien-3-yl)-3-chlorophenyl]-5-(methyloxy)-1-[(2R)-2-morpholinyl]-1-pentanol using 3-(2-bromo-6-chlorophenyl)-1-benzothiophene in Step 7.   (1R)-1-[4-chloro-3-(3-ethylphenyl)-2-pyridinyl]-5-(methyloxy)-1-[(2R)-2-morpholinyl]-1-pentanol using 2-bromo-4-chloro-3-(3-ethylphenyl)pyridine in Step 7.   

     Preparation 10b 
     Alternate Morpholines 
     Methyl {(4R)-4-(3′-ethyl-6-fluoro-2-biphenylyl)-4-hydroxy-4-[(2R)-2-morpholinyl]butyl}carbamate 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Step 1. 1,1-dimethylethyl (2R)-2-[4,4-bis(methyloxy)butanoyl]-4-morpholinecarboxylate 
     To a stirred solution of Mg° (960 mg, 40.0 mmol) in 35.0 mL of dry THF, was added at reflux 0.3 mL of BrCH 2 CH 2 Br (0.3 mL, 3.5 mmol) and 3-bromo-1,1-bis(methyloxy)propane (6.45 g, 35.0 mmol). The resulting mixture was then heated at reflux for 1 h. Then the solution was cooled to room temperature and added to a solution of 1,1-dimethylethyl (2R)-2-{[methyl(methyloxy)amino]carbonyl}-4-morpholinecarboxylate (5.46 g, 20.0 mmol) dissolved in 20.0 mL of dry THF at −30° C. The mixture was warmed to room temperature and stirred over night. The mixture was quenched with NH 4 Cl and extracted with ethyl acetate. The organic layer was then dried, filtered, and concentrated in vacuo. The crude material was then purified via column chromatography to afford 1,1-dimethylethyl (2R)-2-[4,4-bis(methyloxy)butanoyl]-4-morpholinecarboxylate (5.06 g, 81%). 
     Step 2. 1,1-dimethylethyl (2R)-2-[(1R)-1-(3′-ethyl-6-fluoro-2-biphenylyl)-1-hydroxy-4,4-bis(methyloxy)butyl]-4-morpholinecarboxylate 
     To a stirred solution of 2-bromo-3′-ethyl-6-fluorobiphenyl (6.6 g, 23.6 mmol) in 15.0 mL of dry THF at −78° C., was added n-BuLi (10 mL, 25 mmol). The resulting mixture was stirred for 30 min at −78° C. Then, a solution of 1,1-dimethylethyl (2R)-2-[4,4-bis(methyloxy)butanoyl]-4-morpholinecarboxylate (5.0 g, 15.7 mmol) dissolved in 15.0 ml of dry THF was added. The resulting solution was warmed to room temperature over 3 h and quenched with 0.5N HCl. The mixture was then extracted with ethyl acetate. The organic layer was then dried, filtered, and concentrated in vacuo. The crude residue was purified via column chromatography to give 1,1-dimethylethyl (2R)-2-[(1R)-1-(3′-ethyl-6-fluoro-2-biphenylyl)-1-hydroxy-4,4-bis(methyloxy)butyl]-4-morpholinecarboxylate (6.7 g, 82%). 
     Step 3. Mixture of 1,1-dimethylethyl (2R)-2-[(1R)-1-(3′-ethyl-6-fluoro-2-biphenylyl)-1-hydroxy-4-oxobutyl]-4-morpholinecarboxylate and 1,1-dimethylethyl (2R)-2-[(2R)-2-(3′-ethyl-6-fluoro-2-biphenylyl)-5-hydroxytetrahydro-2-furanyl]-4-morpholinecarboxylate 
     To a microwave vial containing 1,1-dimethylethyl (2R)-2-[(1R)-1-(3′-ethyl-6-fluoro-2-biphenylyl)-1-hydroxy-4,4-bis(methyloxy)butyl]-4-morpholinecarboxylate (180 mg, 0.35 mmol) dissolved in acetone (2 mL) and H 2 O (0.8 mL), a catalytic amount of pyridinium p-toluenesulfonate (22 mg, 0.088 mmol) was added and the mixture was stirred under microwave irradiation for 30 min 100° C. The mixture was quenched with NaHCO 3  and then extracted with ethyl acetate. The organic layer was then dried, filtered, and concentrated in vacuo. The crude mixture of 1,1-dimethylethyl (2R)-2-[(1R)-1-(3′-ethyl-6-fluoro-2-biphenylyl)-1-hydroxy-4-oxobutyl]-4-morpholinecarboxylate and 1,1-dimethylethyl (2R)-2-[(2R)-2-(3′-ethyl-6-fluoro-2-biphenylyl)-5-hydroxytetrahydro-2-furanyl]-4-morpholinecarboxylate was used in the next step without other purification. 
     Step 4. 1,1-dimethylethyl (2R)-2-((1R)-1-(3′-ethyl-6-fluoro-2-biphenylyl)-1-hydroxy-4-{[(methyloxy)carbonyl]amino}butyl)-4-morpholinecarboxylate 
     To a microwave vial containing the mixture of 1,1-dimethylethyl (2R)-2-[(1R)-1-(3′-ethyl-6-fluoro-2-biphenylyl)-1-hydroxy-4-oxobutyl]-4-morpholinecarboxylate and 1,1-dimethylethyl (2R)-2-[(2R)-2-(3′-ethyl-6-fluoro-2-biphenylyl)-5-hydroxytetrahydro-2-furanyl]-4-morpholinecarboxylate (500 mg, 1.1 mmol) dissolved in dry MeOH (8 mL), (NH 4 ) + CH 3 COO −  (3.0 g) was added followed by NaCNBH 3  (135 mg, 2.2 mmol). The mixture was then stirred for 30 min at 100° C. under microwave irradiation. The solvent was removed in vacuo and the residue redissolved in methylene chloride and washed with NaHCO 3 . The organic layer was then dried, filtered, and concentrated in vacuo. The crude material was then purified via SCX (10 g) column. The amine was then dissolved in methylene chloride (8.0 mL) and Et 3 N (0.300 g, 3.0 mmol) and (COOMe) 2 O (0.328 g, 2.0 mmol) added. The resulting mixture was stirred for 20 min at room temperature. The reaction was diluted with methylene chloride and washed with NaHCO 3 . The organic layer was then dried, filtered, and concentrated in vacuo. The crude material was then purified by flash chromatography to afford 1,1-dimethylethyl (2R)-241R)-1-(3′-ethyl-6-fluoro-2-biphenylyl)-1-hydroxy-4-{[(methyloxy)carbonyl]amino}butyl)-4-morpholinecarboxylate (0.135 g, 23%). MS (E/Z): 431.2 (M-Boc+H + ) 
     Step 5. Methyl {(4R)-4-(3′-ethyl-6-fluoro-2-biphenylyl)-4-hydroxy-4-[(2R)-2-morpholinyl]butyl}carbamate 
     To a solution of 1,1-dimethylethyl (2R)-2-41R)-1-(3′-ethyl-6-fluoro-2-biphenylyl)-1-hydroxy-4-{[(methyloxy)carbonyl]amino}butyl)-4-morpholinecarboxylate (135 mg, 0.25 mmol) in methylene chloride (4 mL) at 0° C., was added TFA (1.0 mL, 25% v/v). The solution was stirred for 1.5 h at room temperature before the solvent was removed in vacuo and the crude material filtered through an SCX column (5 g) to afford methyl {(4R)-4-(3′-ethyl-6-fluoro-2-biphenylyl)-4-hydroxy-4-[(2R)-2-morpholinyl]butyl}carbamate (0.100 g, &gt;99%). 
     The following morpholines were prepared using procedures analogous to those described above: 
     Methyl (R)-4-(3-fluoro-2-(quinolin-3-yl)phenyl)-4-hydroxy-4-((R)-morpholin-2-yl)butylcarbamate using 3-(2-bromo-6-fluorophenyl)quinoline in Step 2 
     Preparation 11 
     Methyl {4-(6-chloro-3′-methyl-2-biphenylyl)-4-hydroxy-4-[(3R)-3-piperidinyl]butyl}carbamate 
     
       
         
         
             
             
         
       
     
     Step 1. (R)-tert-butyl 3-(6-chloro-3′-methylbiphenylcarbonyl)piperidine-1-carboxylate: To a solution of 6-bromo-2-fluoro-3′-methylbiphenyl (2 g, 7.14 mmol) in anhydrous THF (30 mL) cooled to ±78° C. was added dropwise a solution of 1.6 M of n-BuLi in hexane (4.46 mL). The reaction mixture was stirred at −78° C. for 1 h and a solution of (R)-tent-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (1.94 g, 7.14 mmol) in anhydrous THF (20 mL)was added. The mixture was allowed to warm to rt and stirred overnight. The mixture was quenched with satd aq NH 4 Cl (40 mL) and extracted with EtOAc (40 mL). The combined organic layers were dried over Na 2 SO 4  and concentrated to give crude product, which was purified by flash column chromatography to afford (R)-tent-butyl 3-(6-chloro-3′-methylbiphenylcarbonyl)piperidine-1-carboxylate (1 g, 34%).  1 H NMR (400 MHz, CD 3 OD): 0.80-1.20 (m, 8H), 1.30 (s, 1H), 1.40 (s, 1H), 1.40-1.60 (m, 2H), 2.00-2.18 (s, 1H), 2.30-2.40 (s, 3H), 2.60-2.80 (m, 2H), 3.50-3.80 (m, 2H), 7.00-7.15 (s, 2H), 7.20-7.30 (d, 1H), 7.30-7.40 (t, 2H), 7.39-7.48 (t, 1H), 7.60-7.70 (d, 1H); MS (E/Z): 414 (M+H + ) 
     Step 2. 1,1-dimethylethyl (3R)-3-[4-amino-1-(6-chloro-3′-methyl-2-biphenylyl)-1-hydroxybutyl]-1-piperidinecarboxylate: To a solution of (R)-tent-butyl 3-(6-chloro-3′-methylbiphenylcarbonyl)piperidine-1-carboxylate (800 mg, 1.94 mmol) in anhydrous THF (15 mL) cooled to ±78° C. was added dropwise a solution of 2 M (3-(2,2,5,5-tetramethyl-1,2,5-azadisilolidin-1-yl)propyl)magnesium chloride in THF (0.968 mL, 1.94 mmol). After addition, the reaction mixture was allowed to warm slowly to rt while stirring overnight. The mixture was quenched with satd aq NH 4 Cl (15 mL) and extracted with CH 2 Cl 2  (3×). The combined organic layers were dried over Na 2 SO 4  and concentrated to give crude 1,1-dimethylethyl (3R)-3-[4-amino-1-(6-chloro-3′-methyl-2-biphenylyl)-1-hydroxybutyl]-1-piperidinecarboxylate (900 mg), which was used in the next step without further purification. 
     Step 3. 1,1-dimethylethyl (3R)-3-(1-(6-chloro-3′-methyl-2-biphenylyl)-1-hydroxy-4-{[(methyloxy)carbonyl]amino}butyl)-1-piperidinecarboxylate: To a solution of 1,1-dimethylethyl (3R)-3-[4-amino-1-(6-chloro-3′-methyl-2-biphenylyl)-1-hydroxybutyl]-1-piperidinecarboxylate (800 mg, 1.69 mmol) in anhydrous CH 2 Cl 2  (15 mL) were added 4-dimethyaminopyridine (1.24 g, 10.17 mmol) and Et 3 N (2.35 mL, 16.95 mmol). The mixture was cooled with an ice bath and methyl chloroformate (0.65 mL, 8.47 mmol) in CH 2 Cl 2  (5 mL) was added. The reaction mixture was allowed to warm slowly to rt while stirring overnight. The solvent was removed in vacuo and the residue was purified by column chromatography to afford 1,1-dimethylethyl (3R)-3-(1-(6-chloro-3′-methyl-2-biphenylyl)-1-hydroxy-4-{[(methyloxy)carbonyl]amino}butyl)-1-piperidinecarboxylate (700 mg, 78%).  1 H NMR (400 MHz, CD 3 OD): 1.00-1.70 (m, 17H), 2.30-2.50 (d, 3H), 2.50-2.70 (s, 1H), 2.90-2.31 (m, 2H), 3.50-3.52 (m, 3H), 3.80-4.20 (m, 2H), 6.0-7.15 (m, 3H), 7.15-7.40 (m, 3H), 7.50-7.70 (m, 1H); MS (E/Z): 531 (M+H + ) 
     Step 4. Methyl {4-(6-chloro-3′-methyl-2-biphenylyl)-4-hydroxy-4-[(3R)-3-piperidinyl]butyl}carbamate: To a solution of 1,1-dimethylethyl (3R)-3-(1-(6-chloro-3′-methyl-2-biphenylyl)-1-hydroxy-4-{[(methyloxy)carbonyl]amino}butyl)-1-piperidinecarboxylate (600 mg, 1.13 mg) in CH 3 CN (18 mL) was added 2N aq HCl (15 mL) and the reaction mixture was vigorously stirred overnight at rt. The solvents were removed in vacuo to give methyl {4-(6-chloro-3′-methyl-2-biphenylyl)-4-hydroxy-4-[(3R)-3-piperidinyl]butyl}carbamate as its hydrochloride salt (500 mg, 95.8%).  1 H NMR (400 MHz, CD 3 OD): 1.00-1.20 (m, 1H), 1.30-1.80 (m, 8H), 1.80-2.00 (m, 2H), 2.40-2.50 (d, 3H), 2.75-2.90 (t, 1H), 2.90-3.05 (m, 3H), 3.05-3.12 (t, 1H), 3.20-3.30 (m, 1H), 3.30-3.40 (m, 1H), 3.60-3.70 (d, 4H), 6.90-6.98 (d, 1H), 7.00-7.12 (m, 1H), 7.25-7.50 (m, 4H), 7.75-7.85 (d, 1H); MS (E/Z): 431 (M+H + ) 
     The following piperidines were prepared using procedures analogous to those described above:
     Methyl 4-hydroxy-4-((R)-piperidin-3-yl)-4-(2-(pyridin-4-yl)phenyl)butylcarbamate using 4-(2-bromophenyl)pyridine in Step 1.   N-(4-hydroxy-4-((R)-piperidin-3-yl)-4-(2-(o-tolyloxy)phenyl)butyl)acetamide using 1-bromo-2-(o-tolyloxy)benzene in Step 1 and acetyl chloride in place of methyl chloroformate in Step 3.   Methyl 4-hydroxy-4-((R)-piperidin-3-yl)-4-(2-(o-tolyloxy)phenyl)butylcarbamate using 1-bromo-2-(o-tolyloxy)benzene in Step 1.   Methyl 4-(3′-ethyl-6-fluorobiphenyl-2-yl)-4-hydroxy-4-((R)-piperidin-3-yl)butylcarbamate using 2-bromo-3′-ethyl-6-fluorobiphenyl in Step 1.   Methyl 4-(6-fluoro-3′-methoxybiphenyl-2-yl)-4-hydroxy-4-((R)-piperidin-3-yl)butylcarbamate using 2-bromo-6-fluoro-3′-methoxybiphenyl in Step 1.   Methyl 4-(6-chloro-3′-isopropylbiphenyl-2-yl)-4-hydroxy-4-((R)-piperidin-3-yl)butylcarbamate using 2-bromo-6-chloro-3′-isopropylbiphenyl in Step 1.   Methyl 4-(6-chloro-3′-methoxybiphenyl-2-yl)-4-hydroxy-4-((R)-piperidin-3-yl)butylcarbamate using 2-bromo-6-chloro-3′-methoxybiphenyl in Step 1.   Methyl 4-(3-chloro-2-(quinolin-3-yl)phenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butylcarbamate using 3-(2-bromo-6-chlorophenyl)quinoline in Step 1.   Methyl 4-(6-chloro-3′-ethylbiphenyl-2-yl)-4-hydroxy-4-((R)-piperidin-3-yl)butylcarbamate using 2-bromo-6-chloro-3′-ethylbiphenyl in Step 1.   N-(4-(6-chloro-3′-ethylbiphenyl-2-yl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)acetamide using 2-bromo-6-chloro-3′-ethylbiphenyl in Step 1 and acetyl chloride in place of methyl chloroformate in Step 3.   Methyl 4-(3-chloro-2-(o-tolyloxy)phenyl)-4-hydroxy-4-(R)-piperidin-3-yl)butylcarbamate using 1-bromo-3-chloro-2-(o-tolyloxy)benzene in Step 1.   Methyl 4-(3-chloro-2-(2-ethylphenoxy)phenyl)-4-hydroxy-4-(R)-piperidin-3-yl)butylcarbamate using 1-bromo-3-chloro-2-(2-ethylphenoxy)benzene in Step 1.   N-(4-(6-chloro-3′-methylbiphenyl-2-yl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)acetamide using 2-bromo-6-chloro-3′ methylbiphenyl in Step 1 and acetyl chloride in place of methyl chloroformate in Step 3.   Methyl 4-(4,6-difluoro-3′-methylbiphenyl-2-yl)-4-hydroxy-4-((R)-piperidin-3-yl)butylcarbamate using 2-bromo-4,6-difluoro-3′-methylbiphenyl in Step 1.   Methyl 4-hydroxy-4-((R)-piperidin-3-yl)-4-(2′,4,6-trifluoro-5′-methylbiphenyl-2-yl)butylcarbamate using 2-bromo-2′,4,6-trifluoro-5′-methylbiphenyl in Step 1.   Methyl 4-(6-fluoro-3′-isopropylbiphenyl-2-yl)-4-hydroxy-4-((R)-piperidin-3-yl)butylcarbamate using 2-bromo-6-fluoro-3′-isopropylbiphenyl in Step 1.   Methyl 4-(6-chloro-3′-fluoro-5′-methylbiphenyl-2-yl)-4-hydroxy-4-((R)-piperidin-3-yl)butylcarbamate using 2-bromo-6-chloro-3′-fluoro-5′-methylbiphenyl in Step 1.   Methyl 4-(3′,6-difluoro-5′-methylbiphenyl-2-yl)-4-hydroxy-4-((R)-piperidin-3-yl)butylcarbamate using 2-bromo-3′,6-difluoro-5′-methylbiphenyl in Step 1.   Methyl 4-(3-chloro-2-(3-methylbenzyl)phenyl)-4-hydroxy-4-(R)-piperidin-3-yl)butylcarbamate using 1-bromo-3-chloro-2-(3-methylbenzyl)benzene in Step 1.   Methyl {4-{3-chloro-2-[4-(1-methylethyl)-2-quinazolinyl]phenyl}-4-hydroxy-4-[(3R)-3-piperidinyl]butyl}carbamate using 2-(2-bromo-6-chlorophenyl)-4-(1-methylethyl)quinazoline in Step 1.   Methyl {4-[2-chloro-3-(3-ethylphenyl)-4-pyridinyl]-4-hydroxy-4-[(3R)-3-piperidinyl]butyl}carbamate using 4-bromo-2-chloro-3-(3-ethylphenyl)pyridine in Step 1.   Methyl {4-{3-chloro-2-[8-(1-methylethyl)-2-quinolinyl]phenyl}-4-hydroxy-4-[(3R)-3-piperidinyl]butyl}carbamate using 2-(2-bromo-6-chlorophenyl)-8-(1-methylethyl)quinoline in Step 1.   Methyl {4-[3-fluoro-2-(3-quinolinyl)phenyl]-4-hydroxy-4-[(3R)-3-piperidinyl]butyl}carbamate using 3-(2-bromo-6-fluorophenyl)quinoline in Step 1.   Methyl {4-[3-chloro-2-(5-methyl-2-furanyl)phenyl]-4-hydroxy-4-[(3R)-3-piperidinyl]butyl}carbamate using 2-(2-bromo-6-chlorophenyl)-5-methylfuran in Step 1.   Methyl {4-{2-chloro-3-[3-(1-methylethyl)phenyl]-4-pyridinyl}-4-hydroxy-4-[(3R)-3-piperidinyl]butyl}carbamate using 4-bromo-2-chloro-3-[3-(1-methylethyl)phenyl]pyridine in Step 1.   Methyl {4-[3-chloro-2-(8-methyl-2-quinolinyl)phenyl]-4-hydroxy-4-[(3R)-3-piperidinyl]butyl}carbamate using 2-(2-bromo-6-chlorophenyl)-8-methylquinoline in Step 1.   

     Preparation 11b 
     Methyl {4-{5-chloro-4-[3-(1-methylethyl)phenyl]-3-pyridinyl}-4-hydroxy-4-[(3R)-3-piperidinyl]butyl}carbamate 
     
       
         
         
             
             
         
       
     
     Step 1: 1,1-dimethylethyl (3R)-3-({5-chloro-4-[3-(1-methylethyl)phenyl]-3-pyridinyl}carbonyl)-1-piperidinecarboxylate 
     To a cold (0° C.) solution of 3-bromo-5-chloro-4-(3-isopropylphenyl)pyridine (0.78 g, 2.51 mmol) in THF (1.5 mL) was added a i-PrMgCl.LiCl solution (2.6 mL, 1.0 M in THF, 2.6 mmol). After stirring for 45 minutes at 0° C., a solution 1,1-dimethylethyl (3R)-3-{[methyl(methyloxy)amino]carbonyl}-1-piperidinecarboxylate (0.53 g, 1.93 mmol) in THF (1.5 mL) was added. The reaction was stirred at 0° C. for 2 hours and then room temperature for 22 hours. The reaction was quenched with a sat. NH 4 Cl solution (3 mL). EtOAc (10 mL) and water (2 mL) were added and then the phases separated. The organic phase was washed with brine, dried over MgSO 4 , filtered and concentrated to give 1.3 g of a dark brown oil. The crude ketone was used without purification in the subsequent reaction. 
     Step 2: 1,1-dimethylethyl (3R)-3-(4-amino-1-{5-chloro-4-[3-(1-methylethyl)phenyl]-3-pyridinyl}-1-hydroxybutyl)-1-piperidinecarboxylate 
     To a solution of 1,1-dimethylethyl (3R)-3-({5-chloro-4-[3-(1-methylethyl)phenyl]-3-pyridinyl}carbonyl)-1-piperidinecarboxylate (1.93 mmol) in THF (3 mL) at −50° C. was added a hot solution of the alkyl Grignard (9 mL, 0.72 M THF, 5.80 mmol) quickly. The reaction was slowly allowed to warm to room temperature and stirred overnight. The reaction was quenched with a sat. NH 4 Cl solution (3 mL). EtOAc and water was added and then the phases were separated. The organic phase was washed with brine, dried over MgSO 4 , filtered and concentrated to give 1.6 g of a dark brown oil. The crude 1,1-dimethylethyl (3R)-3-(4-amino-1-{5-chloro-4-[3-(1-methylethyl)phenyl]-3-pyridinyl}-1-hydroxybutyl)-1-piperidinecarboxylate was used without further purification in the subsequent reaction. 
     Step 3. 1,1-dimethylethyl (3R)-3-(1-{5-chloro-4-[3-(1-methylethyl)phenyl]-3-pyridinyl}-1-hydroxy-4-{[(methyloxy)carbonyl]amino}butyl)-1-piperidinecarboxylate 
     To a cold (0° C.) solution of the 1,1-dimethylethyl (3R)-3-(4-amino-1-{5-chloro-4-[3-(1-methylethyl)phenyl]-3-pyridinyl}-1-hydroxybutyl)-1-piperidinecarboxylate (1.93 mmol) in CH 2 Cl 2  were added i-Pr 2 NEt (1.3 mL, 7.72 mmol) and then dimethyldicarbonate (0.62 mL, 5.79 mmol). After stirring for 1.5 hour at 0° C., the reaction was quenched with a sat. NH 4 Cl solution (2 mL). The reaction was diluted with CH 2 Cl 2  and phases separated. The aqueous phase was extracted with CH 2 Cl 2 . The combined organic extracts were washed with brine, dried over MgSO 4 , filtered and concentrated to give 2 g of a dark brown oil. The crude residue was purified by flash chromatography on silica gel and isolated 350 mg (33% yield, 3 steps) of the desired 1,1-dimethylethyl (3R)-3-(1-{5-chloro-4-[3-(1-methylethyl)phenyl]-3-pyridinyl}-1-hydroxy-4-{[(methyloxy)carbonyl]amino}butyl)-1-piperidinecarboxylate as a dark yellow solid. 
     Step 4. Methyl {4-{5-chloro-4-[3-(1-methylethyl)phenyl]-3-pyridinyl}-4-hydroxy-4-[(3R)-3-piperidinyl]butyl}carbamate 
     To a solution of 1,1-dimethylethyl (3R)-3-(1-{5-chloro-4-[3-(1-methylethyl)phenyl]-3-pyridinyl}-1-hydroxy-4-{[(methyloxy)carbonyl]amino}butyl)-1-piperidinecarboxylate (0.35 g, 0.62 mmol) in CH 2 Cl 2  (5 mL) was added trifluoroacetic acid (1 mL). After stirring for 2 hours at room temperature, the reaction was concentrated to give a yellow oil. The crude residue was purified with a 5 gm Strata SCX ion exchange resin eluting with 0.6 M NH 3  in MeOH and isolated 278 mg (97% yield) of methyl {4-{5-chloro-4-[3-(1-methylethyl)phenyl]-3-pyridinyl}-4-hydroxy-4-[(3R)-3-piperidinyl]butyl}carbamate as a yellow oil. 
     The following piperidine was prepared using procedures analogous to those described above: 
     Methyl {4-[5-chloro-4-(3-ethylphenyl)-3-pyridinyl]-4-hydroxy-4-[(3R)-3-piperidinyl]butyl}carbamate using 3-bromo-5-chloro-4-(3-ethylphenyl)pyridine in Step 1 
     Preparation 11c 
     N-{4-(6-chloro-3′-ethyl-2-biphenylyl)-4-hydroxy-4-[(3R)-3-piperidinyl]butyl}-2-hydroxyacetamide 
     
       
         
         
             
             
         
       
     
     Step 1. 1,1-dimethylethyl (3R)-3-{1-(6-chloro-3′-ethyl-2-biphenylyl)-1-hydroxy-4-[(hydroxyacetyl)amino]butyl}-1-piperidine carboxylate 
     A solution of 1,1-dimethylethyl (3R)-3-[4-amino-1-(6-chloro-3′-ethyl-2-biphenylyl)-1-hydroxybutyl]-1-piperidinecarboxylate (75 mg, 0.14 mmol) in 0.5 mL of DMF at 25° C. was treated with glycolic acid (13 mg, 0.17 mmol), i-Pr 2 NEt (0.122 mL, 0.7 mmol), and HBTU (64 mg, 0.17 mmol). After 24 h, H 2 O was added and the mixture was extracted with EtOAc. The organic extracts were washed (1N aq HCl, 1N aq NaOH, H 2 O, brine), dried (Na 2 SO 4 ), concentrated under reduced pressure, and subjected to flash chromatography to provide 1,1-dimethylethyl (3R)-3-{1-(6-chloro-3′-ethyl-2-biphenylyl)-1-hydroxy-4-[(hydroxyacetyl)amino]butyl}-1-piperidinecarboxylate as a colorless oil (39 mg, 51%). MS (m/z) 567.2 (M+Na + ). 
     Step 2. N-{4-(6-chloro-3′-ethyl-2-biphenylyl)-4-hydroxy-4-[(3R)-3-piperidinyl]butyl}-2-hydroxyacetamide 
     A solution of 1,1-dimethylethyl (3R)-3-{1-(6-chloro-3′-ethyl-2-biphenylyl)-1-hydroxy-4-(hydroxyacetyl)amino)butyl}-1-piperidinecarboxylate (45 mg, 0.08 mmol) in 3 mL of CH 3 CN at 25° C. was treated with 3 mL of aq 2N HCl. After 24 h, the mixture was concentrated under reduced pressure to provide N-{4-(6-chloro-3′-ethyl-2-biphenylyl)-4-hydroxy-4-[(3R)-3-piperidinyl]butyl}-2-hydroxyacetamide as a white solid (41 mg, quantitative). MS (m/z) 445.2 (M+H + ). 
     The following piperidines were prepared following procedures analogous to those described above using the appropriate piperidine and the indicated acid: 
     
       
         
           
               
               
               
             
               
                   
               
               
                 Structure 
                 Name 
                 Acid Used in Step 1 
               
               
                   
               
             
            
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-(4-(2′,6-difluoro-5′- methylbiphenyl-2-yl)-4-hydroxy-4- ((3R)-piperidin-3-yl)butyl)-2- hydroxyacetamide 
                 glycolic acid 
               
               
                   
               
            
           
         
       
     
     Preparation 12 
     N-(2-((S)-(6-fluoro-3′-methylbiphenyl-2-yl)((R)-morpholin-2-yl)methoxy)ethyl)acetamide 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Step 1. (R)-tent-butyl 2-(S)-(2-ethoxy-2-oxoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)morpholine-4-carboxylate: To a slurry of 60% NaH in oil (0.75 g, 18.7 mmol) in THF (30 mL) was added a solution of (R)-tent-butyl 2-((S)-(6-fluoro-3′-methylbiphenyl-2-yl)(hydroxy)methyl)morpholine-4-carboxylate (2.5 g, 6.23 mmol) in THF (20 mL) dropwise at and then the reaction mixture was stirred for about 1 h at rt. A solution of ethyl 3-bromopropionate (1.55 g, 9.35 mmol) in THF (20 mL) was added dropwise while the temperature was maintained at −15 to −5° C. The mixture was allowed to warm slowly to rt and stirred for ±2 h until the reaction was complete by tlc analysis. The reaction was cooled in an ice bath, quenched with satd aq NH 4 Cl (120 mL) and extracted with EtOAc. The combined organic extracts were washed with brine, dried over NaSO 4 , concentrated and purified by flash chromatography to afford (R)-tent-butyl 2-(S)-(2-ethoxy-2-oxoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)morpholine-4-carboxylate (570 mg, 19%). MS (E/Z): 488 (M+H + ) 
     Step 2. (R)-tent-butyl 2-(S)-(6-fluoro-3′-methylbiphenyl-2-yl)(2-hydroxyethoxy)methyl)morpholine-4-carboxylate: To a solution of (R)-tent-butyl 2-((S)-(2-ethoxy-2-oxoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)morpholine-4-carboxylate (570 mg, 1.17 mmol) in CH 3 OH (20 mL) at rt, NaBH 4  (355 mg, 9.36 mmol) was added in portions. The mixture was stirred for ±0.5 h at rt and then evaporated. The residue was partitioned between water and EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO 4  and evaporated to give semi-crude (R)-tent-butyl 2-(S)-(6-fluoro-3′-methylbiphenyl-2-yl)(2-hydroxyethoxy)methyl)morpholine-4-carboxylate (498 mg, 96%), which was used in the next step reaction without further purification. MS (E/Z): 446 (M+H + ) 
     Step 3. (R)-tent-butyl 2-(S)-(6-fluoro-3′-methylbiphenyl-2-yl)(2-(methylsulfonyloxy)ethoxy)methyl)morpholine-4-carboxylate: To a solution of (R)-tert-butyl 2-(S)-(6-fluoro-3′-methylbiphenyl-2-yl)(2-hydroxyethoxy)methyl) morpholine-4-carboxylate (498 mg, 1.12 mmol) in dry CH 2 Cl 2 (15 mL) was added Et 3 N (472 mg, 4.68 mmol) at −0 to −5° C. A solution of MsCl (267 mg, 2.34 mmol) in dry CH 2 Cl 2  (10 mL) was added dropwise at the same temperature. The mixture was allowed to warm to room temperature gradually. Water (10 mL) was added and the aqueous layer was extracted with CH 2 Cl 2  (3×20 mL). The combined organic layers were washed with 10% aq citric acid, satd aq NaHCO 3  and brine, dried over Na 2 SO 4 , filtered and concentrated to afford crude (R)-tent-butyl 2-(S)-(6-fluoro-3′-methylbiphenyl-2-yl)(2-(methylsulfonyloxy)ethoxy)methyl)morpholine-4-carboxylate (554 mg, 95%). which was used in the next step without further purification. MS (E/Z): 524 (M+H + ) 
     Step 4. (R)-tent-butyl 2-((S)-(2-azidoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)morpholine-4-carboxylate: To a solution of (R)-tent-butyl 2-45)-(6-fluoro-3′-methylbiphenyl-2-yl)(2-(methylsulfonyloxy)ethoxy)methyl)morpholine-4-carboxylate (554 mg, 1.0 mmol) in anhydrous DMF (18 mL), solid NaN 3  (230 mg, 3.51 mmol) was added and the reaction mixture was heated to 70° C. for overnight. The reaction mixture was cooled to rt and diluted with EtOAc (110 mL), and water (30 ml). The organic phase was washed with water (3×30 mL), dried over Na 2 SO 4  and evaporated to give (R)-tent-butyl 2-(S)-(2-azidoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)morpholine-4-carboxylate (423 mg, 90%). MS (E/Z): 471 (M+H + ) 
     Step 5. (R)-tent-butyl 2-((S)-(2-aminoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)morpholine-4-carboxylate: To a solution of (R)-tent-butyl 2-((S)-(2-azidoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)morpholine-4-carboxylate (423 mg, 0.9 mmol) in EtOAc (20 mL) was added wetted Pd/C (42 mg) and the mixture was hydrogenated overnight using a balloon of hydrogen. The mixture was filtered through a pad of Celite and the solvent was removed to give (R)-tent-butyl 2-((S)-(2-aminoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)morpholine-4-carboxylate (430 mg, 100%). MS (E/Z): 445 (M+H + ) 
     Step 6. (R)-tent-butyl 2-((S)-(2-acetamidoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)morpholine-4-carboxylate: To a round-bottom flask were added (R)-tert-butyl 2-(S)-(2-aminoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)morpholine-4-carboxylate (280 mg, 0.63 mmol), triethylamine (0.19 mL, 1.89 mmol) and anhydrous CH 2 Cl 2  (15 mL). The mixture was cooled in an ice bath and a solution of acetyl chloride (49.2 mg, 0.045 mL, 0.63 mmol) was added. The reaction mixture was allowed to warm slowly to rt and stirred until the reaction was complete (ca 1-2 h). The solvent was removed by evaporation, and the residue was purified by preparative tlc to give (R)-tent-butyl 2-45)-(2-acetamidoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)morpholine-4-carboxylate (202 mg, 66%).  1 H NMR (300 MHz, CDCl 3 ): δ=1.45 (s, 9H), 1.93 (s, 3H), 2.38 (s, 3H), 2.87˜3.2 (m, 6H), 3.32-3.92 (m, 5H), 4.28 (d, 1H), 7.01-7.25 (m, 3H), 7.28-7.37 (m, 4H), 9.41-9.54 (s, 1H). MS (E/Z): 487 (M+H + ) 
     Step 7. N-(2-(S)-(6-fluoro-3′-methylbiphenyl-2-yl)((R)-morpholin-2-yl)methoxy)ethyl)acetamide: (R)-tert-butyl 2-(S)-(2-acetamidoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)morpholine-4-carboxylate (202 mg, 0.42 mmol) was dissolved in 20% TFA in CH 2 Cl 2  (8 mL) and stirred for about 1 h at rt. The mixture was neutralized with satd aq NaHCO 3  and the product was extracted with CH 2 Cl 2 . The combined organic layers were washed with brine, dried over Na 2 SO 4  and concentrated to give N-(2-(S)-(6-fluoro-3′-methylbiphenyl-2-yl)((R)-morpholin-2-yl)methoxy)ethyl)acetamide (130 mg, 82%).  1 H NMR (300 MHz, CDCl 3 ): δ=1.98 (s, 3H), 2.39 (s, 3H), 2.90˜3.3 (m, 6H), 3.31˜3.41 (m, 2H), 3.6˜4.0 (m, 3H), 4.33 (d, 1H), 6.56-6.57 (s, 1H), 6.97˜7.14 (m, 3H), 7.27˜7.40 (m, 4H), 9.40˜9.55 (s, 1H). MS (E/Z): 387 (M+H + ). 
     The following compounds were prepared using procedures analogous to those described above: 
     methyl 2-45)-(6-fluoro-3′-methylbiphenyl-2-yl)((R)-morpholin-2-yl)methoxy)ethylcarbamate using methyl chloroformate in place of acetyl chloride in Step 6 
     Preparation 13 
     1-bromo-3-chloro-2-[(3-methylphenyl)methyl]benzene 
     
       
         
         
             
             
         
       
     
     Step 1. (2-bromo-6-chlorophenyl)(m-tolyl)methanol: To a −78° C. solution of diisopropylamine (9.9 mL, 70 mmol) in anhydrous THF (80 mL) was added dropwise a n-BuLi solution (31.5 mL, 50 mmol, 1.6M hexanes). The reaction was stirred for 20 min at −78° C. and 1-chloro-3-bromobenzene (5.9 mL, 50 mmol) was added. After stirring for 30 min at −78° C., m-tolualdehyde (5.9 mL, 50 mmol) was added. The reaction was gradually allowed to warm to rt and then stirred overnight. The reaction was quenched with the addition of water and then extracted with EtOAc. The organic extracts were dried over MgSO 4 , filtered and concentrated. The crude residue was purified by flash chromatography on silica gel (ISCO Combiflash, 120 gm column, Hexane/EtOAc 0→10%) and isolated 10.7 g of (2-bromo-6-chlorophenyl)(m-tolyl)methanol. 
     Step 2. 1-bromo-3-chloro-2-[(3-methylphenyl)methyl]benzene: (2-bromo-6-chlorophenyl)(m-tolyl)methanol (10.7 g, 34.4 mmol) was dissolved in CH 2 Cl 2  (50 mL) and then Et 3 SiH (22 mL, 138 mmol) and trifluoroacetic acid (10.6 mL, 138 mmol) were added. After stirring at rt overnight, the reaction was concentrated to remove solvent. The crude residue was purified by flash chromatography on silica gel (ISCO Combiflash, 120 gm column, Hexane/EtOAc 0→10%) and isolated 8.7 g of 1-bromo-3-chloro-2-[(3-methylphenyl)methyl]benzene as a white solid. 
     1-bromo-3-chloro-2-[(2-methylphenyl)methyl]benzene was prepared using procedures analogous to those described above using o-tolualdehyde in Step 1. 
     Preparation 14 
     5-(2-bromo-6-chlorophenyl)-3-methyl-1,2,4-oxadiazole 
     
       
         
         
             
             
         
       
     
     Step 1. 2-bromo-6-chlorobenzoic acid: To a −78° C. solution of n-BuLi (10 mL, 25 mmol, 2.5M Hexanes) in anhydrous THF (70 mL) was added diisopropylamine (3.5 mL, 25 mmol). After stirring for 15 min, 1-chloro-3-bromobenzene (4.32 g, 25 mmol) was added and stirred for 2 h at −78° C. Dry ice (CO 2 ) was added and after 15 min a 2N aq HCl solution (100 mL) was added. The reaction mixture was extracted with EtOAc. The product was re-crystallized from hexanes and isolated 5 g (85%) of 2-bromo-6-chlorobenzoic acid. 
     Step 2. 5-(2-bromo-6-chlorophenyl)-3-methyl-1,2,4-oxadiazole: To a solution of 2-bromo-6-chlorobenzoic acid (1 g, 4.25 mmol) in anhydrous CH 2 Cl 2  were added dropwise oxalyl chloride (0.45 mL, 5.1 mmol) and 2-3 drops of DMF. The solution was stirred at rt for 2 h and then the solvent was evaporated. The crude residue was added dropwise to a stirred suspension of the acetamide oxime (315 mg, 4.25 mmol) in pyridine (6 mL). After the addition the mixture was refluxed overnight. The solvent was evaporated and the crude residue purified by flash chromatography to afford 376 mg (32%) of 5-(2-bromo-6-chlorophenyl)-3-methyl-1,2,4-oxadiazole. 
     Preparation 15 
     3,5-dimethoxyphenylboronic acid 
     
       
         
         
             
             
         
       
     
     To a solution of 1-bromo-3,5-dimethoxybenzene (5 g, 23 mmol) in THF (100 mL) at −78° C. was added n-Bu-Li (2.5M in hexane, 10 mL, 25 mmol). The mixture was stirred at −78° C. for 30 min and transferred to a solution of B(OCH 3 ) 3  (3.1 ml) in THF at −78° C. The resulting mixture was warmed up to rt and allowed to stir overnight. The reaction was quenched with 2N aq HCl and extracted with EtOAc. The combined organic extracts were dried over Na 2 SO 4  and concentrated. The residue was washed with hexane to give 2.2 g (53% yield) of 3,5-dimethoxyphenylboronic acid as a solid. MS m/z=182.2 (M+H) + . 
     Preparation 16 
     3-methoxy-5-methylphenylboronic acid 
     
       
         
         
             
             
         
       
     
     Step 1. 4-bromo-2-methoxy-6-methylaniline: 2-methoxy-6-methylaniline (24.2 g, 182 mmol) was dissolved in MeOH (81 mL) and acetic acid (27 mL) and a solution of bromine (28 g, 182 mmol) in acetic acid (81 mL) was added dropwise. The reaction was allowed to stand at rt for 2 h and concentrated to remove solvents. The crude product was recrystallized from hexanes to give 36 g of 4-bromo-2-methoxy-6-methylaniline as a brown solid. 
     Step 2. 1-bromo-3-methoxy-5-methylbenzene: To a cold (0° C.) solution of 4-bromo-2-methoxy-6-methylaniline (36 g, 167 mmol) in a mixture of acetic acid (280 mL), water (120 mL) and concentrated HCl (32 mL) was added dropwise a solution of NaNO 2  (13.8 g, 200 mmol) in water (40 mL). The reaction mixture was stirred for 30 min at 0° C. and 50% aq H 3 PO 2  (320 mL) was added. After stirring for 8 h at 0° C., the reaction mixture was allowed to stand at rt for 48 h. The reaction mixture was extracted with EtOAc/Et 2 O. The crude residue was purified by flash chromatography on silica gel (ISCO Combiflash, 330 g column, 100% hexane) to afford 27.5 g of 1-bromo-3-methoxy-5-methylbenzene as a colorless oil. 
     Step 3. 3-methoxy-5-methylphenylboronic acid: To a −78° C. solution of 1-bromo-3-methoxy-5-methylbenzene (10 g, 49.8 mmol) in anhydrous THF (200 mL) was added dropwise a n-BuLi solution (37.3 mL, 59.7 mmol, 1.6 M Hexane). After stirring for 30 min at −78° C., trimethyl borate (13.9 mL, 124.3 mmol) was added. The resulting mixture was stirred at −78° C. for 30 min and then warmed to rt and stirred for an additional 60 min. The reaction mixture was poured into an ice/H 2 O mixture and acidified with 2N HCl to pH=3. The aqueous solution was extracted with Et 2 O. The combined organic extracts were dried over Na 2 SO 4 , filtered and concentrated in vacuo. The crude residue (13 g) was washed with hexanes. The precipitate was collected and recrystallized from hexanes to give 6.5 g (79%) of 3-methoxy-5-methylphenylboronic acid as a white solid. 
     Preparation 17 
     4-((tert-butoxycarbonyl(methyl)amino)methyl)benzoic acid 
     
       
         
         
             
             
         
       
     
     Step 1. Methyl 4-((tert-butoxycarbonyl(methyl)amino)methyl)benzoate: A solution of 4-((tert-butoxycarbonylamino)methyl)benzoic acid (1.01 g, 4.0 mmol) in 10 mL of DMF at 0° C. was treated with NaH (60% in oil, 400 mg, 10 mmol) and warmed to 25° C. After 10 min, methyl iodide (3 mL) was added and the mixture was stirred at 25° C. for 16 h before being concentrated under reduced pressure. The residue was treated with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were washed (brine), dried (Na 2 SO 4 ), concentrated, and subjected to flash chromatography to provide methyl 4-((tert-butoxycarbonyl(methyl)amino)methyl)benzoate as a clear oil (849 mg, 76%). MS (m/z) 280.3 (M+H + ). 
     Step 2. 4-((tert-butoxycarbonyl(methyl)amino)methyl)benzoic acid: A solution of methyl 4-((tert-butoxycarbonyl(methyl)amino)methyl)benzoate (300 mg, 1.08 mmol) in EtOH (10 ml) at 25° C. was treated with aqueous 1N NaOH (2.16 mL, 2.16 mmol) and the mixture was stirred for 16 h before being extracted with EtOAc (2×5 mL). The aqueous layer was acidified by the addition of aqueous 1N HCl and then extracted with EtOAc (3×10 ml). The combined organic extracts were washed (brine), dried (Na 2 SO 4 ), and concentrated to provide 4-((tert-butoxycarbonyl(methyl)amino)methyl)benzoic acid as a white solid (215 mg, 75%). MS (m/z) 266.1 (M+H + ). 
     The following benzoic acids were prepared following procedures analogous to those described above by using the indicated starting material and alkylating agent in Step 1: 
     
       
         
           
               
               
               
               
             
               
                   
               
               
                   
                   
                   
                 Alkylating 
               
               
                 Structure 
                 Name 
                 Starting Material 
                 Agent 
               
               
                   
               
             
            
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 trans-4-{[{[(1,1- dimethylethyl)oxy]carbonyl} (methyl)amino]methyl} cyclohexanecarboxylic acid 
                 trans-4-[({[(1,1- dimethylethyl)oxy] carbonyl}amino)methyl] cyclohexanecarboxylic acid 
                 Methyl iodide 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (1R,3S)-3-[{[(1,1- dimethylethyl)oxy] carbonyl}(methyl)amino] cyclopentanecarboxylic acid 
                 (1R,3S)-3-({[(1,1- dimethylethyl)oxy] carbonyl}amino) cyclopentanecarboxylic acid 
                 Methyl iodide 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-{[{[(1,1- dimethylethyl)oxy]carbonyl} (methyl)amino]methyl}-3- pyridinecarboxylic acid 
                 6-[({[(1,1- dimethylethyl)oxy]carbonyl} amino)methyl]-3- pyridinecarboxylic acid 
                 Methyl iodide 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 5-[({[(1,1- dimethylethyl)oxy]carbonyl} amino)methyl]-3- isoxazolecarboxylic acid 
                 ethyl 5-[({[(1,1- dimethylethyl)oxy]carbonyl} amino)methyl]-3- isoxazolecarboxylate 
                 Omit Step 1 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-amino-4-oxo-1,4-dihydro- 5-pyrimidinecarboxylic acid 
                 ethyl 2-amino-4-oxo- 1,4-dihydro-5- pyrimidinecarboxylate 
                 Omit Step 1 
               
               
                   
               
            
           
         
       
     
     Preparation 18 
     (R)-1-(6-chloro-3′-ethylbiphenyl-2-yl)-1-((R)-morpholin-2-yl)pent-4-en-1-ol 
     
       
         
         
             
             
         
       
     
     Step 1. (R)-tent-butyl 2-pent-4-enoylmorpholine-4-carboxylate: To a solution of (R)-tent-butyl 2-(methoxy(methyl)carbamoyl)morpholine-4-carboxylate (1.2 g, 4.38 mmol) in 50 mL of THF at −78° C. under a nitrogen atmosphere was slowly added 26 mL (13.3 mmol, 0.5M) of (4-penten-1-yl)magnesium bromide in THF using a syringe. The solution was stirred overnight, allowing it to slowly warm to rt. A saturated solution of NH 4 Cl in water (50 mL) was added to the reaction flask. The solution was extracted using EtOAc (3×25 mL). The combined organic extracts were dried over Na 2 SO 4  and filtered, followed by concentration under reduced pressure to give 810 mg of (R)-tent-butyl 2-pent-4-enoylmorpholine-4-carboxylate. 
     Step 2. (R)-tent-butyl 2-((R)-1-(6-chloro-3′-ethylbiphenyl-2-yl)-1-hydroxypent-4-enyl)morpholine-4-carboxylate: To a solution of 2-bromo-6-chloro-3′-ethylbiphenyl, 2.2 g (7.44 mmol) in 20 mL of THF at −78° C. under a nitrogen atmosphere was slowly added a hexane solution of n-BuLi (3.7 ml, 2.5M) using a syringe. The resulting solution was stirred for 0.5 h. 1,1-dimethylethyl (2R)-2-(4-pentenoyl)-4-morpholinecarboxylate (0.8 g, 2.97 mmol) in 20 mL of THF was slowly added to the above solution using a syringe. The reaction was then allowed to stir and warm to rt overnight. A saturated solution of NH 4 Cl in water (50 mL) was added to the reaction flask. The solution was extracted using EtOAc (3×25 mL). The combined organic extracts were dried over Na 2 SO 4  and filtered, followed by concentration under reduced pressure. This afforded 550 mg of (R)-tent-butyl 2-((R)-1-(6-chloro-3′-ethylbiphenyl-2-yl)-1-hydroxypent-4-enyl)morpholine-4-carboxylate which was used without purification. LC-MS t R =3.74 min, (m/z) 508.2 (M+H + ). 
     Step 3. (R)-1-(6-chloro-3′-ethylbiphenyl-2-yl)-1-((R)-morpholin-2-yl)pent-4-en-1-ol; To a solution of 1,1-dimethylethyl (2R)-2-[(1R)-1-(6-chloro-3′-ethyl-2-biphenylyl)-1-hydroxy-4-penten-1-yl]-4-morpholinecarboxylate (73 mg, 0.15 mmol) in 5 ml of acetonitrile was added 5 ml of 2N aqueous HCl. The reaction was stirred overnight. It was basified with 10N aqueous NaOH to pH=14 and extracted with DCM (3×10 ml). The combined organic extracts were dried over Na 2 SO 4  and filtered, followed by concentration under reduced pressure. This afforded (R)-1-(6-chloro-3′-ethylbiphenyl-2-yl)-1-((R)-morpholin-2-yl)pent-4-en-1-ol which was used without purification. 
     Preparation 19 
     (R)-1-(6-chloro-3′-ethylbiphenyl-2-yl)-1-((R)-morpholin-2-yl)pent-4-en-1-ol 
     
       
         
         
             
             
         
       
     
     Step 1. (R)-tent-butyl 2-((R)-1-(6-chloro-3′-ethylbiphenyl-2-yl)-1-hydroxy-4-oxobutyl)morpholine-4-carboxylate: To a solution of (R)-tent-butyl 2-((R)-1-(6-chloro-3′-ethylbiphenyl-2-yl)-1-hydroxypent-4-enyl)morpholine-4-carboxylate (350 mg, 0.72 mmol) in 10 mL of THF and 5 mL of water was added NMO (255 mg, 2.18 mmol), followed by NaIO 4  (310 mg, 1.44 mmol) and a few small crystals of OsO 4 . The reaction was stirred overnight. The solution was diluted with 10 mL of water and extracted with CH 2 Cl 2  (3×10 ml). The combined organic extracts were dried over Na 2 SO 4  and filtered, followed by concentration under reduced pressure. This afforded (R)-tent-butyl 2-((R)-1-(6-chloro-3′-ethylbiphenyl-2-yl)-1-hydroxy-4-oxobutyl)morpholine-4-carboxylate which was used without purification. LC-MS t R =3.36 min, (m/z) 510.2 (M+Na + ). 
     Step 2. (R)-tent-butyl 2-((R)-4-amino-1-(6-chloro-3′-ethylbiphenyl-2-yl)-1-hydroxybutyl)morpholine-4-carboxylate: To a refluxing solution of (R)-tent-butyl 2-((R)-1-(6-chloro-3′-ethylbiphenyl-2-yl)-1-hydroxy-4-oxobutyl)morpholine-4-carboxylate (350 mg, 0.7 mmol) in 20 mL of MeOH was added NH 3 .AcOH (550 mg, 7.2 mmol), followed by NaCNBH 3  (135 mg, 2.2 mmol). After a few h at reflux the reaction was cooled to rt and diluted with 20 mL of water. The solution was extracted using EtOAc (3×10 ml). The combined organic extracts were dried over Na 2 SO 4  and filtered, followed by concentration under reduced pressure. This afforded (R)-tert-butyl 2-((R)-4-amino-1-(6-chloro-3′-ethylbiphenyl-2-yl)-1-hydroxybutyl)morpholine-4-carboxylate which was used without purification. LC-MS t R =2.56 min, (m/z) 489.2 (M+H + ). 
     Preparation 20 
     
       
         
         
             
             
         
       
     
     Step 1. 2-44-(tert-butoxycarbonyl)morpholin-2-yl)(6-fluoro-3′-methylbiphenyl-2-yl)methoxy)acetic acid: To a solution of tert-butyl 2-((2-ethoxy-2-oxoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)morpholine-4-carboxylate (450 mg, 0.924 mmol) in THF (4 mL) were added water (1 mL) and LiOH (78 mg, 1.86 mmol). The reaction mixture was stirred at rt for 3 h. LC-MS indicated complete hydrolysis of the ester. The reaction mixture was concentrated and redissolved in water. The resulting solution was neutralized with 1N aq HCl. The precipitate was collected and dried to give 350 mg of 2-(4-(tert-butoxycarbonyl)morpholin-2-yl)(6-fluoro-3′-methylbiphenyl-2-yl)methoxy)acetic acid as a white solid. 
     Step 2. tert-butyl 2-42-(ethylamino)-2-oxoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)morpholine-4-carboxylate: To a solution of 2-((4-(tert-butoxycarbonyl)morpholin-2-yl)(6-fluoro-3′-methylbiphenyl-2-yl)methoxy)acetic acid (250 mg, 0.545 mmol), HOBT (147 mg, 1.09 mmol) and BOP (481 mg, 1.09 mmol) in DMF (3 mL) were added i-Pr 2 NEt (0.76 mL, 4.36 mmol) and ethylamine hydrochloride (266 mg, 3.27 mmol). The reaction mixture was stirred overnight at rt. LC-MS indicated complete conversion. EtOAc was added to the reaction and then washed with water and brine. The organic phase was dried over MgSO 4 , filtered and concentrated to give 0.6 g of an oil. The crude residue was purified by flash chromatography on silica gel [ISCO Combiflash, 40 g column, Hexanes/EtOAc 0%→50%] and isolated 300 mg of tent-butyl 2-((2-(ethylamino)-2-oxoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)morpholine-4-carboxylate as a white foam. 
     Preparation 21 
     4-((tert-butoxycarbonylamino)methyl)-2-fluorobenzoic acid 
     
       
         
         
             
             
         
       
     
     Step 1. 4-(aminomethyl)-2-fluorobenzoic acid 
     A solution of 4-cyano-2-fluorobenzoic acid (1.0 g, 6.06 mmol) in 20 mL of MeOH at 25° C. was treated with of 20% Pd(OH) 2 /C (300 mg, wet) and stirred overnight under an atmosphere of hydrogen. The reaction mixture was filtered and concentrated under reduced pressure to provide 4-(aminomethyl)-2-fluorobenzoic acid (1.0 g, quantitative). 
     Step 2. 4-((tert-butoxycarbonylamino)methyl)-2-fluorobenzoic acid 
     A solution of 4-(aminomethyl)-2-fluorobenzoic acid (1.0 g, 6.0 mmol) in 50 mL of THF at 25° C. was treated with 50 mL of 1N aq NaOH and Boc 2 O (1.5 g, 6.9 mmol) and the mixture was stirred overnight before being diluted with the addition of 25 mL of water and 10 mL of brine, acidified slowly to pH 3 using 1N aq HCl, and extracted with EtOAc (3×20 ml). The combined organic extracts were dried (Na 2 SO 4 ) and concentrated under reduced pressure to provide 4-((tert-butoxycarbonylamino)methyl)-2-fluorobenzoic acid. 
     The following benzoic acids were prepared following procedures analogous to those described above by using the indicated starting material and catalyst in Step 1: 
     
       
         
           
               
               
               
               
             
               
                   
               
               
                 Structure 
                 Name 
                 Starting Material 
                 Catalyst 
               
               
                   
               
             
            
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-[({[(1,1-dimethylethyl)oxy] carbonyl}amino)methyl]-3- pyridinecarboxylic acid 
                 6-cyano-3- pyridinecarboxylic acid 
                 Pd/C 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 4-[({[(1,1-dimethylethyl)oxy] carbonyl}amino)methyl]-5- methyl-2-furancarboxylic acid 
                 4-(aminomethyl)-5- methyl-2-furancarboxylic acid 
                 Omit Step 1 
               
               
                   
               
            
           
         
       
     
     Preparation 22 
     methyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide 
     
       
         
         
             
             
         
       
     
     Step 1. Methyl (2-hydroxyethyl)carbamate 
     To a stirred solution of 2-aminoethanol (6.11 g, 100 mmol) in dry dichloromethane (120 mL) at room temperature was added dropwise a solution of dimethyl dicarbonate (14.1 g, 105 mmol) in 20 mL. The resulting mixture was stirred for 5 hours before the solvent was removed in vacuo to afford methyl (2-hydroxyethyl)carbamate (12.1 g) as a colorless oil.  1 H NMR (400 MHz, CDCl 3 ): 2.21 (broad, 1H), 3.37 (q, 2H), 3.70-3.73 [s (3H)+q (2H)], 5.20 (broad, 1H). 
     Step 2. Methyl 1,2,3-oxathiazolidine-3-carboxylate 2-oxide 
     To a stirred suspension of methyl (2-hydroxyethyl)carbamate (100 mmol, 12.1 g) in dry dichloromethane (700 mL) at −78° C. was added triethylamine (30.4 g, 42 ml, 300 mmol) followed by thionyl chloride (17.9 g, 11 mL, 150 mmol). The resulting yellow suspension was stirred at −78° C. for 3 hours before it was quenched with methanol (3.2 g, 4 ml, 100 mmol) and warmed to room temperature. The reaction mixture was filtered and the Filtrate concentrated to remove all the dichloromethane before being re-dissolved in 900 ml Et 2 O, filtered and concentrated again. The resulting crude was purified by passing through a 15 cm silica plug eluted with 30% ethyl acetate in hexane to afford methyl 1,2,3-oxathiazolidine-3-carboxylate 2-oxide (7.905 g, 48%) as a yellowish oil.  1 H NMR (400 MHz, CDCl 3 ): 3.64 (m, 1H), 3.88 (s, 3H), 3.97 (m, 1H), 4.77 (m, 1H), 5.03 (m, 1H). 
     Step 3. Methyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide 
     To a stirred solution of methyl 1,2,3-oxathiazolidine-3-carboxylate 2-oxide (7.905 g, 47.9 mmol) in acetonitrile (45 mL) at 0° C. was added RuCl 3 H 2 O (54 mg, 0.24 mmol) followed by NaIO 4  (15.4 g, 71.8 mmol) and water (45 mL). The resulting mixture was allowed to warm to room temperature and stir for two hours before it was filtered. The filtrate was concentrated in vacuo and then redistributed in 800 mL MTBE and filtered again. The resulting solution was washed with water (50 mL), brine (2×100 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo to provide methyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (6.5 g, 75%) as an off-white solid.  1 H NMR (400 MHz, CDCl 3 ): 3.95 (s, 3H), 4.14 (t, 2H), 4.69 (t, 2H). 
     Preparation 23 
     methyl [2-({(S)-(6-chloro-3′-ethyl-2-biphenylyl)[(2R)-2-morpholinyl]methyl}oxy)ethyl]carbamate 
     
       
         
         
             
             
         
       
     
     Step 1. (1,1-dimethylethyl (2R)-2-[(S)-(6-chloro-3′-ethyl-2-biphenylyl)(hydroxy)methyl]-4-morpholinecarboxylate 
     To a stirred solution of 1,1-dimethylethyl (2R)-2-[(6-chloro-3′-ethyl-2-biphenylyl)carbonyl]-4-morpholinecarboxylate (2.87 g, 6.7 mmol) in TBME (75 mL) under argon at room temperature was added drop-wise borane-methyl sulfide complex (2M in toluene, 4.5 mL, 9 mmol) and (R)-2-methyl-CBS-oxazaborolidine (1 M in toluene, 0.7 mL, 0.7 mmol). The resulting solution was heated at 40° C. for 4 hours at which time TLC analysis showed complete consumption of the ketone. The reaction was quenched with 2 mL of water added slowly and then partitioned between 700 mL Et 2 O and 150 mL brine. The organic layer was washed with brine (1×50 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude was purified by flash chromatography (ISCO, 120 g column, EtOAc Hexane, 0-25%) to provide (1,1-dimethylethyl (2R)-2-[(S)-(6-chloro-3′-ethyl-2-biphenylyl)(hydroxy)methyl]-4-morpholinecarboxylate (1.392 g, 48%, the less polar diastereomer). 
     Step 2. 1,1-dimethylethyl (2R)-2-{(S)-(6-chloro-3′-ethyl-2-biphenylyl)[(2-{[(methyloxy) carbonyl]amino}ethyl)oxy]methyl}-4-morpholinecarboxylate 
     To a stirred solution of (1,1-dimethylethyl (2R)-2-[(S)-(6-chloro-3′-ethyl-2-biphenylyl)(hydroxy)methyl]-4-morpholinecarboxylate (0.432 g, 1 mmol) in 6 mL of dry DMF at room temperature was added phosphazene base P 4 -t-Bu (1.0M in n-hexane, 2 ml, 2 mmol). The resulting mixture was stirred for 10 minutes under argon before a solution of methyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (0.362 g, 2 mmol) in 2 mL dry DMF was added. The resulting solution was stirred at room temperature overnight (18 hours). The crude reaction mixture was purified via HPLC (Gilson, C 18  column, 5 um, 50×100 mm), CH 3 CN/water (w/0.1% TFA) 65-95%) to provide 1,1-dimethylethyl (2R)-2-{(S)-(6-chloro-3′-ethyl-2-biphenylyl)[(2-{[(methyloxy) carbonyl]amino}ethyl)oxy]methyl}-4-morpholinecarboxylate as colorless oil. MS (E/Z): 533.4 (M+H + ). 
     Step 3. Methyl [2-({(S)-(6-chloro-3′-ethyl-2-biphenylyl)[(2R)-2-morpholinyl]methyl}oxy)ethyl]carbamate 
     To a stirred solution of 1,1-dimethylethyl (2R)-2-{(S)-(6-chloro-3′-ethyl-2-biphenylyl)[(2-{[(methyloxy) carbonyl]amino}ethyl)oxy]methyl}-4-morpholinecarboxylate in DCM (4 mL) at room temperature was added TFA (4 mL). The resulting mixture was stirred at room temperature for 1.5 h. The crude was concentrated under reduced pressure and then partitioned between 450 mL DCM and 50 mL saturated Na 2 CO 3  solution. The organic layer was washed with brine, dried over Na 2 SO 4 , filtered and concentrated to provide methyl [2-{(S)-(6-chloro-3′-ethyl-2-biphenylyl)[(2R)-2-morpholinyl]methyl}oxy)ethyl]carbamate (407 mg, 68% for steps 2 and 3). MS (E/Z): 433.0 (M+H + ). 
     Preparation 24 
     Methyl [2-({(R)-(6-chloro-3′-ethyl-2-biphenylyl)[(3R)-3-piperidinyl]methyl}oxy)ethyl]carbamate 
     
       
         
         
             
             
         
       
     
     Step 1. 1,1-dimethylethyl (3R)-3-[(R)-(6-chloro-3′-ethyl-2-biphenylyl)(hydroxy)methyl]-1-piperidinecarboxylate 
     To a stirred solution of 1,1-dimethylethyl (3R)-3-[(6-chloro-3′-ethyl-2-biphenylyl) carbonyl]-1-piperidinecarboxylate (1.6 g, 3.74 mmol) in TBME (60 mL) under argon at room temperature was added drop-wise simultaneously borane-methyl sulfide complex (2M in toluene, 2.5 ml, 5 mmol) and (R)-2-methyl-CBS-oxazaborolidine (1 M in toluene, 0.4 ml, 0.4 mmol). The resulting solution was heated at 40° C. for 3 h at which time TLC showed that the reaction was complete. The reaction was quenched with 1 mL water added slowly and then partitioned between 600 mL Et 2 O and 50 mL water. The organic layer was washed with brine (1×50 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude was purified by flash chromatography (ISCO, 120 g column, 0-30% ethyl acetate/hexane) to provide 1,1-dimethylethyl (3R)-3-[(R)-(6-chloro-3′-ethyl-2-biphenylyl)(hydroxy)methyl]-1-piperidinecarboxylate (1.2 g, 74.6%, less polar diastereomer). MS (E/Z): 430.4 (M+H + ) 
     Step 2. 1,1-dimethylethyl (3R)-3-{(R)-(6-chloro-3′-ethyl-2-biphenylyl)[(2-{[(methyloxy) carbonyl]amino}ethyl)oxy]methyl}-1-piperidinecarboxylate 
     To a stirred solution of 1,1-dimethylethyl (3R)-3-[(R)-(6-chloro-3′-ethyl-2-biphenylyl)(hydroxy)methyl]-1-piperidinecarboxylate (0.354 g, 0.82 mmol) in 8 mL of dry DMF at room temperature was added phosphazene base P 4 -t-Bu (1.0M in n-hexane, 1.64 mL, 1.64 mmol). The resulting mixture was stirred for 10 minutes under argon before a solution of methyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (0.298 g, 1.64 mmol) in 2 ml dry DMF was added. The resulting solution was stirred at room temperature overnight (18 hours) before it was quenched with 10 mL saturated NH 4 Cl solution. The product was extracted with 300 mL EtOAc and the organic layer was washed with saturated NH 4 Cl solution (3×50 mL), HCl (2M, 3×50 mL), brine, and dried over Na 2 SO 4 , filtered and concentrated in vacuo to provide 1,1-dimethylethyl (3R)-3-{(R)-(6-chloro-3′-ethyl-2-biphenylyl)[(2-{[(methyloxy) carbonyl]amino}ethyl)oxy]methyl}-1-piperidinecarboxylate (452 mg), which was directly used in the next step without further purification. MS (E/Z): 531.4 (M+H + ) 
     Step 3. Methyl [2-({(R)-(6-chloro-3′-ethyl-2-biphenylyl)[(3R)-3-piperidinyl]methyl}oxy)ethyl]carbamate 
     To a solution of 1,1-dimethylethyl (3R)-3-{(R)-(6-chloro-3′-ethyl-2-biphenylyl)[(2-{[(methyloxy) carbonyl]amino}ethyl)oxy]methyl}-1-piperidinecarboxylate (0.452 g, 0.82 mmol) in DCM (14 mL) at room temperature was added TFA (4 mL). The resulting solution was stirred for 1.5 h. At this time the solvent was removed under reduced pressure and the crude material partitioned between 200 mL DCM and 50 mL 5% Na 2 CO 3  solution. The organic layer was washed with water (50 mL), brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to provide methyl [2-({(R)-(6-chloro-3′-ethyl-2-biphenylyl)[(3R)-3-piperidinyl]methyl}oxy)ethyl]carbamate (0.35 g, 99%). MS (E/Z): 431.5 (M+H + ). 
     Preparation 25 
     5-{[{[(1,1-dimethylethyl)oxy]carbonyl}(methyl)amino]methyl}-2-thiophenecarboxylic acid 
     
       
         
         
             
             
         
       
     
     Step 1. Methyl 5-formyl-2-thiophenecarboxylate 
     A mixture of 5-formyl-2-thiophene carboxylic acid (2.34 g, 15 mmol) and sodium carbonate (5.57 g, 52.5 mmol) in DMF (25 ml) at 25° C. was treated with iodomethane (1.15 ml, 18 mmol) and the mixture was stirred for 20 h before being quenched with the addition of water and saturated aqueous NH 4 Cl. The resulting solid precipitate was collected by filtration to give methyl 5-formyl-2-thiophenecarboxylate as a solid. The filtrate was extracted with EtOAc (3×30 ml) and the combined organic extracts were washed with water and brine, dried (Na 2 SO 4 ), concentrated under reduced pressure, and subjected to flash chromatography to give solid material that was combined with the solid collected by precipitation to give methyl 5-formyl-2-thiophenecarboxylate as a white solid (1.60 g, 62%): ESI-MS (m/z): 171.2 (M+H + ). 
     Step 2. Methyl 5-[(methylamino)methyl]-2-thiophenecarboxylate 
     A solution of methyl 5-formyl-2-thiophenecarboxylate (1.58 g, 9.3 mmol), methyl amine (5.6 ml, 2N, 11.2 mmol) and glacial acetic acid (3.0 ml) in THF (30 ml) at 25° C. was treated with sodium triacetoxyborohydride (11.83 g, 55.8 mmol) and the mixture was stirred for 18 h. Aqueous 2N NaOH was added until the solution reached pH 5. The resulting mixture was extracted with Et 2 O (3×50 ml), and the combined organic extracts were washed with brine, dried (Na 2 SO 4 ), concentrated under reduced pressure, and subjected to flash chromatography to give methyl 5-[(methylamino)methyl]-2-thiophenecarboxylate as a white solid (650 mg, 41%): ESI-MS (m/z): 186.0 (M+H + ). 
     Step 3. Methyl 5-{[{[(1,1-dimethylethyl)oxy]carbonyl}(methyl)amino]methyl}-2-thiophenecarboxylate 
     A solution of methyl 5-[(methylamino)methyl]-2-thiophenecarboxylate (640 mg, 3.5 mmol) in THF (10 ml) at 25° C. was treated with saturated aqueous NaHCO 3  (15 ml) and (Boc) 2 O (802 mg, 3.7 mmol) and the mixture was stirred vigorously for 16 h before being diluted with EtOAc. The organic phase was separated, washed with water and brine, dried (Na 2 SO 4 ), and concentrated under reduced pressure to give methyl 5-{[{[(1,1-dimethylethyl)oxy]carbonyl}(methyl)amino]methyl}-2-thiophenecarboxylate as a clear oil (957 mg, 95%): ESI-MS (m/z): 286.3 (M+H + ). 
     Step 4. 5-{[{[(1,1-dimethylethyl)oxy]carbonyl} (methyl)amino]methyl}-2-thiophenecarboxylic acid 
     A solution of methyl 5-{[{[(1,1-dimethylethyl)oxy]carbonyl}(methyl)amino]methyl}-2-thiophenecarboxylate (939 mg, 3.3 mmol) in EtOH (10 ml) at 25° C. was treated with aqueous NaOH (6.6 ml of 1N, 6.6 mmol) and the mixture was stirred for 18 h before being concentrated under reduced pressure. The residue was dissolved in water (10 ml), washed with EtOAc (2×5 ml), and the aqueous layer was acidified by addition of 1N aqueous HCl and then extracted with EtOAc (3×10 ml). The combined organic extracts were washed with brine, dried (MgSO 4 ), and concentrated under reduced pressure to give 5-{[{[(1,1-dimethylethyl)oxy]carbonyl} (methyl)amino]methyl}-2-thiophenecarboxylic acid as an amber oil (626 mg, 70%). ESI-MS (m/z): 272.4 (M+H + ). 
     Preparation 26 
     1,1-dimethylethyl [(4-phenyl-4-piperidinyl)methyl]carbamate 
     
       
         
         
             
             
         
       
     
     Step 1. 1[4-phenyl-1-(phenylmethyl)-4-piperidinyl]methanamine: A solution of 4-phenyl-1-(phenylmethyl)-4-piperidinecarbonitrile (4 g, 12.8 mmol) in dry Et 2 O (60 ml) at 0° C. was treated with LiAlH 4  (0.585 g, 15.3 mmol) and the suspension was stirred at 25° C. overnight before being filtered through celite and concentrated under reduced pressure. The residue was treated with a cold saturated NaHCO 3  solution (gas and heat evolved) and then extracted with CH 2 Cl 2  (2×40 mL). The combined organic extracts were dried over MgSO 4  and concentrated under reduced pressure to give 1-[4-phenyl-1-(phenylmethyl)-4-piperidinyl]methanamine as a colorless oil (3.4 g, 92%): ESI-MS (m/z): 281.2 (M+H + ). 
     Step 2. 1,1-dimethylethyl {[4-phenyl-1-(phenylmethyl)-4-piperidinyl]methyl}carbamate: A solution of 1-[4-phenyl-1-(phenylmethyl)-4-piperidinyl]methanamine (3.4 g, 12.13 mmol) in 28 mL of 2N NaOH (aq) and 12 mL of THF was treated with BOC 2 O, and the mixture was stirred at 25° C. overnight before being partitioned between 40 mL of water and 60 mL of dichloromethane. The organic layer was dried over MgSO 4  and concentrated under reduced pressure to give 1,1-dimethylethyl {[4-phenyl-1-(phenylmethyl)-4-piperidinyl]methyl}carbamate as an oil (4.32 g, 91%): LCMS (m/z): 381.2 (M+W). 
     Step 3. 1,1-dimethylethyl [(4-phenyl-4-piperidinyl)methyl]carbamate: A solution of 1,1-dimethylethyl {[4-phenyl-1-(phenylmethyl)-4-piperidinyl]methyl}carbamate (4.3 g, 11.3 mmol) in EtOH (60 mL) was treated with 10% Pd/C (1.0 g) and hydrazine hydrate (0.660 ml, 22.6 mmol), and the mixture was heated at 78° C. for 5 h before being cooled, filtered through celite, and concentrated under reduced pressure to give 1,1-dimethylethyl [(4-phenyl-4-piperidinyl)methyl]carbamate as a colorless oil (3.6 g, 99%): ESI-MS (m/z): 291.2 (M+H + ). 
     The following procedures describe preparation of compounds of this invention. 
     Example 1 
     1-((3R)-1-{[(1R,3S)-3-aminocyclopentyl]carbonyl}-3-piperidinyl)-5-(methyloxy)-1-[2-(phenyloxy)phenyl]-1-pentanol 
     
       
         
         
             
             
         
       
     
     Step 1. ((1R,3S)-3-(tert-butoxycarbonylamino)cyclopentyl)((3R)-3-(1-hydroxy-5-methoxy-1-(2-phenoxyphenyl)pentyl)piperidin-1-yl)methanone: To a solution of 5-methoxy-1-(2-phenoxyphenyl)-1-((R)-piperidin-3-yl)pentan-1-ol (18.5 mg, 0.05 mmol) and (1R,3S)-3-(t-butoxycarbonylamino)cyclopentanecarboxylic acid (12.1 mg, 0.05 mmol) in DMF (0.5 mL) were added DIEA (26 μL. 0.15 mmol), HBTU (19.0 mg, 0.05 mmol), and HOBt (6.8 mg, 0.05 mmol). The resulting solution was stirred at rt for 20 min. Preparative HPLC gave ((1R,3S)-3-(tert-butoxycarbonylamino)cyclopentyl)((3R)-3-(1-hydroxy-5-methoxy-1-(2-phenoxyphenyl)pentyl)piperidin-1-yl)methanone (19.5 mg, 67%) as a oil. LC-MS (3 min) m/z 581 (M+H + ). 
     Step 2. ((1R,3S)-3-Aminocyclopentyl)((3R)-3-(1-hydroxy-5-methoxy-1-(2-phenoxy phenyl)pentyl)piperidin-1-yl)methanone: To a stirred solution of ((1R,3S)-3-(tert-butoxycarbonylamino)cyclopentyl)((3R)-3-(1-hydroxy-5-methoxy-1-(2-phenoxyphenyl)pentyl)piperidin-1-yl)methanone (19.5 mg) in MeCN (2 mL) was added 5% aq HCl (2 mL). The resulting solution was stirred at rt until no starting material remained (˜16 h), basified to pH=10 with 10 N aq NaOH, and evaporated under reduced pressure to remove MeCN. The aq layer was extracted with CH 2 Cl 2  (4×10 mL). The combined organic layers were washed with brine and dried over Na 2 SO 4 . The crude product was purified by preparative HPLC to give ((1R,3S)-3-Aminocyclopentyl)((3R)-3-(1-hydroxy-5-methoxy-1-(2-phenoxy phenyl)pentyl)piperidin-1-yl)methanone (I-4A, 17.4 mg) as its TFA salt.  1 H NMR (400 MHz, CD 3 OD): 7.64 (m, 1H), 7.38 (m, 2H), 7.08-7.24 (m, 3H), 6.92 (m, 2H), 6.80 (two d, 1H), 4.44, 4.86 (m, 1H), 3.96, 4.26 (m, 1H), 3.68 (m, 1H), 3.36, 3.44 (m, 1H), 3.28 (t, 2H), 3.24 (s, 3H), 2.94, 3.14 (m, 1H), 2.63 (m, 1H), 2.40 (m, 1H), 1.8-2.2 (m, 6H), 1.0-1.8 (m, 8H), 0.92 (m, 1H); LC-MS (3 min) m/z 481 (M+H). 
     Example 2 
     The compounds below were prepared by coupling the appropriate piperidines and Boc protected amino acids followed by deprotection according to the procedures described in Example 1.
     #1 methyl 4-((R)-1-((1R,3S)-3-aminocyclopentanecarbonyl)piperidin-3-yl)-4-hydroxy-4-(2-(pyridin-4-yl)phenyl)butylcarbamate   #2 2-((R)-((R)-4-((1R,3S)-3-aminocyclopentanecarbonyl)morpholin-2-yl)(6-fluoro-3′-methylbiphenyl-2-yl)methoxy)-N-ethylacetamide   #3 N-(4-((R)-1-((1R,3S)-3-aminocyclopentanecarbonyl)piperidin-3-yl)-4-hydroxy-4-(2-(o-tolyloxy)phenyl)butyl)acetamide   #4 ((1R,3S)-3-aminocyclopentyl)((3R)-3-(1-(2-(2,6-dimethylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)piperidin-1-yl)methanone   #7 methyl 2-((4-((1R,3S)-3-aminocyclopentanecarbonyl)morpholin-2-yl)(6-fluoro-3′-methylbiphenyl-2-yl)methoxy)ethylcarbamate   #9 ((1R,3S)-3-aminocyclopentyl)((R)-2-((R)-1-(4′,6-difluoro-3′-methylbiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)morpholino)methanone   #12 methyl 4-((R)-1-((1R,3S)-3-aminocyclopentanecarbonyl)piperidin-3-yl)-4-hydroxy-4-(2-(o-tolyloxy)phenyl)butylcarbamate   #15 ((1R,3S)-3-aminocyclopentyl)((3R)-3-(1-(6-fluoro-3′-methoxy-5′-methylbiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)piperidin-1-yl)methanone   #16 ((1R,3S)-3-aminocyclopentyl)((3R)-3-(1-(6-chloro-3′-ethylbiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)piperidin-1-yl)methanone   #17 ((1R,3S)-3-aminocyclopentyl)((3R)-3-(1-(3-chloro-2-(2-methylbenzyl)phenyl)-1-hydroxy-5-methoxypentyl)piperidin-1-yl)methanone   #18 ((1R,3S)-3-aminocyclopentyl)((3R)-3-(1-(3-chloro-2-(3-methylbenzyl)phenyl)-1-hydroxy-5-methoxypentyl)piperidin-1-yl)methanone   #19 ((1R,3S)-3-aminocyclopentyl)(2-(1-(6-fluoro-3′-methoxy-5′-methylbiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)morpholino)methanone   #20 ((1R,3S)-3-aminocyclopentyl)((2R)-2-(1-(6-chloro-3′-ethylbiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)morpholino)methanone   #21 ((1R,3S)-3-aminocyclopentyl)((3R)-3-(1-(3-chloro-2-(o-tolyloxy)phenyl)-1-hydroxy-5-methoxypentyl)piperidin-1-yl)methanone   #22 ((1R,3S)-3-aminocyclopentyl)((3R)-3-(1-(2-(2-chloro-6-methylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)piperidin-1-yl)methanone   #26 methyl 4-((R)-1-((1R,3S)-3-aminocyclopentanecarbonyl)piperidin-3-yl)-4-(3′-ethyl-6-fluorobiphenyl-2-yl)-4-hydroxybutylcarbamate   #31 ((1R,3S)-3-aminocyclopentyl)((3R)-3-(1-(3-chloro-2-(2-ethylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)piperidin-1-yl)methanone   #32 ((1R,3S)-3-aminocyclopentyl)((3R)-3-(1-(3-chloro-2-(3-ethylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)piperidin-1-yl)methanone   #39 ((1R,3S)-3-aminocyclopentyl)((R)-3-((S)-1-(3-chloro-2-(quinolin-3-yl)phenyl)-1-hydroxy-5-methoxypentyl)piperidin-1-yl)methanone   #40 ((1R,3S)-3-aminocyclopentyl)((R)-2-((R)-1-(3-chloro-2-(naphthalen-2-yl)phenyl)-1-hydroxy-5-methoxypentyl)morpholino)methanone   #41 ((1R,3S)-3-aminocyclopentyl)(2-(1-(3-chloro-2-(quinolin-3-yl)phenyl)-1-hydroxy-5-methoxypentyl)morpholino)methanone   #45 methyl 4-((R)-1-((1R,3S)-3-aminocyclopentanecarbonyl)piperidin-3-yl)-4-(6-chloro-3′-ethylbiphenyl-2-yl)-4-hydroxybutylcarbamate   #46 methyl 4-((R)-4-((1R,3S)-3-aminocyclopentanecarbonyl)morpholin-2-yl)-4-(6-chloro-3′-ethylbiphenyl-2-yl)-4-hydroxybutylcarbamate   #56 methyl 4-((R)-1-((1R,3S)-3-aminocyclopentanecarbonyl)piperidin-3-yl)-4-(6-chloro-3′-isopropylbiphenyl-2-yl)-4-hydroxybutylcarbamate   #62 ((1R,3S)-3-aminocyclopentyl)((3R)-3-(1-(3′-ethoxy-6-fluoro-5′-(trifluoromethyl)biphenyl-2-yl)-1-hydroxy-5-methoxypentyl)piperidin-1-yl)methanone   #64 ((1R,3S)-3-aminocyclopentyl)((R)-2-((R)-1-(3′-ethoxy-6-fluoro-5′-(trifluoromethyl)biphenyl-2-yl)-1-hydroxy-5-methoxypentyl)morpholino)methanone   #67 ((1R,3S)-3-aminocyclopentyl)((R)-2-((R)-1-(6-fluoro-3′,5′-dimethoxybiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)morpholino)methanone   #68 ((1R,3S)-3-aminocyclopentyl)((2R)-2-((1R)-1-(3-chloro-2-(isoquinolin-4-yl)phenyl)-1-hydroxy-5-methoxypentyl)morpholino)methanone   #69 methyl (4-((3R)-1-{[(1R,3S)-3-aminocyclopentyl]carbonyl}-3-piperidinyl)-4-{3-chloro-2-[(2-methylphenyl)oxy]phenyl}-4-hydroxybutyl)carbamate   #70 methyl (4-((3R)-1-{[(1R,3S)-3-aminocyclopentyl]carbonyl}-3-piperidinyl)-4-{3-chloro-2-[(2-ethylphenyl)oxy]phenyl}-4-hydroxybutyl)carbamate   #100 (1R)-1-((2R)-4-{[(1R,3S)-3-aminocyclopentyl]carbonyl}-2-morpholinyl)-1-[2-chloro-3-(3-ethylphenyl)-4-pyridinyl]-5-(methyloxy)-1-pentanol   #102 (1R)-1-((2R)-4-{[(1R,3S)-3-aminocyclopentyl]carbonyl}-2-morpholinyl)-1-[2-(1-benzothien-3-yl)-3-chlorophenyl]-5-(methyloxy)-1-pentanol   #108 1-((3R)-1-{[(1R,3S)-3-aminocyclopentyl]carbonyl}-3-piperidinyl)-1-{3-chloro-2-[(3-methylphenyl)oxy]phenyl}-5-(methyloxy)-1-pentanol   #110 methyl (4-((3R)-1-{[(1R,3S)-3-aminocyclopentyl]carbonyl}-3-piperidinyl)-4-{3-chloro-2-[(3-methylphenyl)oxy]phenyl}-4-hydroxybutyl)carbamate   #112 methyl (4-((3R)-1-{[(1R,3S)-3-aminocyclopentyl]carbonyl}-3-piperidinyl)-4-{2-[(2,6-dimethylphenyl)oxy]phenyl}-4-hydroxybutyl)carbamate   #134 1-((3R)-1-{[(1R,3S)-3-aminocyclopentyl]carbonyl}-3-piperidinyl)-1-{3-fluoro-2-[(3-methylphenyl)oxy]phenyl}-5-(methyloxy)-1-pentanol   #136 methyl (4-((3R)-1-{[(1R,3S)-3-aminocyclopentyl]carbonyl}-3-piperidinyl)-4-{3-chloro-2-[(3-ethylphenyl)oxy]phenyl}-4-hydroxybutyl)carbamate   #138 methyl (4-((3R)-1-{[(1R,3S)-3-aminocyclopentyl]carbonyl}-3-piperidinyl)-4-{3-fluoro-2-[(3-methylphenyl)oxy]phenyl}-4-hydroxybutyl)carbamate   #141 methyl (4-((3R)-1-{[(1R,3S)-3-aminocyclopentyl]carbonyl}-3-piperidinyl)-4-{3-chloro-2-[(3-methylphenyl)methyl]phenyl}-4-hydroxybutyl)carbamate   

     Example 3 
     N—((S)-4-(6-chloro-3′-ethylbiphenyl-2-yl)-4-hydroxy-4-((R)-1-(4-((methylamino)methyl)benzoyl)piperidin-3-yl)butyl)acetamide 
     
       
         
         
             
             
         
       
     
     Step 1. tert-butyl 4-((R)-3-((S)-4-acetamido-1-(6-chloro-3′-ethylbiphenyl-2-yl)-1-hydroxybutyl)piperidine-1-carbonyl)benzyl(methyl)carbamate: A solution of N—((S)-4-(6-chloro-3′-ethylbiphenyl-2-yl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)acetamide (48 mg, 0.10 mmol) in 1 mL of DMF at 25° C. was treated with 4-((tert-butoxycarbonyl(methyl)amino)methyl)benzoic acid (33 mg, 0.12 mmol), i-Pr 2 NEt (0.089 mL, 0.5 mmol), and HBTU (47 mg, 0.12 mmol). After 24 h, H 2 O was added and the mixture was extracted with EtOAc. The organic extracts were washed (1N aq HCl, 1N aq NaOH, H 2 O, brine), dried (Na 2 SO 4 ), concentrated under reduced pressure, and subjected to flash chromatography to provide tent-butyl 4-((R)-3-((S)-4-acetamido-1-(6-chloro-3′-ethylbiphenyl-2-yl)-1-hydroxybutyl)piperidine-1-carbonyl)benzyl(methyl)carbamate as a colorless oil (50 mg, 71%). MS (m/z) 676.3 (M+H + ). 
     Step 2. N—((S)-4-(6-chloro-3′-ethylbiphenyl-2-yl)-4-hydroxy-4-4R)-1-(4-((methylamino)methyl)benzoyl)piperidin-3-yl)butyl)acetamide: A solution of tert-butyl 4-((R)-3-((S)-4-acetamido-1-(6-chloro-3′-ethylbiphenyl-2-yl)-1-hydroxybutyl)piperidine-1-carbonyl)benzyl(methyl)carbamate (50 mg, 0.074 mmol) in 3 mL of CH 3 CN at 25° C. was treated with 3 mL of aqueous 2N HCl. After 24 h, the mixture was concentrated under reduced pressure to provide N-[(4S)-4-(6-chloro-3′-ethyl-2-biphenylyl)-4-hydroxy-4-[(3R)-1-([4-[(methylamino)methyl]phenyl]carbonyl)-3-piperidinyl]butyl]acetamide as a white solid (39 mg, quantitative). MS (m/z) 576.2 (M+H + ). 
     Example 4 
     The following compounds were prepared following procedures analogous to those described in Example 3.
     #28 (6-(aminomethyl)pyridine-3-yl)((3R)-3-(1-(6-chloro-3′-ethylbiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)piperidin-1-yl)methanone   #42 methyl (4-hydroxy-4-((3R)-1-{[(1R,3S)-3-(methylamino)cyclopentyl]carbonyl}-3-piperidinyl)-4-{2-[(2-methylphenyl)oxy]phenyl}butyl)carbamate   #43 methyl 4-(6-fluoro-3′-methoxybiphenyl-2-yl)-4-hydroxy-4-(R)-1-((1R,3S)-3-(methylamino)cyclopentanecarbonyl)piperidin-3-yl)butylcarbamate   #58 methyl 4-(6-chloro-3′-methoxybiphenyl-2-yl)-4-hydroxy-4-(R)-1-41R,3S)-3-(methylamino)cyclopentanecarbonyl)piperidin-3-yl)butylcarbamate   #76 (6-(aminomethyl)pyridine-3-yl)((R)-2-(R)-1-(6-chloro-3′-ethylbiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)morpholino)methanone   #77 methyl 4-((R)-1-(6-(aminomethyl)nicotinoyl)piperidin-3-yl)-4-(6-chloro-3′-ethylbiphenyl-2-yl)-4-hydroxybutylcarbamate   

     Example 5 
     Methyl (S)-4-(6-chloro-3′-ethylbiphenyl-2-yl)-4-hydroxy-4-((R)-1-(4-((methylamino)methyl)benzoyl)piperidin-3-yl)butylcarbamate 
     
       
         
         
             
             
         
       
     
     Step 1. methyl (S)-4-(6-chloro-3′-ethylbiphenyl-2-yl)-4-hydroxy-4-((R)-1-(4-(((N-t-butoxycarbonyl-N-methyl)amino)methyl)benzoyl)piperidin-3-yl)butylcarbamate: A solution of methyl (S)-4-(6-chloro-3′-ethylbiphenyl-2-yl)-4-hydroxy-4-((R)-piperidin-3-yl)butylcarbamate (30 mg, 0.07 mmol) in 1 mL of DMF at 25° C. was treated with 4-((tert-butoxycarbonyl(methyl)amino)methyl)benzoic acid (21 mg, 0.08 mmol), i-Pr 2 NEt (0.063 mL, 0.37 mmol), and HBTU (30 mg, 0.08 mmol). After 1 h, H 2 O was added and the mixture was extracted with EtOAc. The organic extracts were washed (1N HCl, 1N NaOH, H 2 O, brine), dried (Na 2 SO 4 ), concentrated under reduced pressure, and subjected to flash chromatography to provide methyl (S)-4-(6-chloro-3′-ethylbiphenyl-2-yl)-4-hydroxy-4-((R)-1-(4-(((N-t-butoxycarbonyl-N-methyl)amino)methyl)benzoyl)piperidin-3-yl)butylcarbamate as a colorless oil (24 mg, 51%). MS (m/z) 692.3 (M+H + ). 
     Step 2. methyl {(4S)-4-(6-chloro-3′-ethyl-2-biphenylyl)-4-hydroxy-4-[(3R)-1-({4-[(methylamino)methyl]phenyl}carbonyl)-3-piperidinyl]butyl}carbamate: A solution of methyl (S)-4-(6-chloro-3′-ethylbiphenyl-2-yl)-4-hydroxy-4-((R)-1-(4-(((N-t-butoxycarbonyl-N-methyl)amino)methyl)benzoyl)piperidin-3-yl)butylcarbamate (24 mg, 0.034 mmol) in 3 mL of CH 3 CN at 25° C. was treated with 3 mL of aqueous 2N HCl. After 24 h, the mixture was concentrated under reduced pressure to provide methyl {(4S)-4-(6-chloro-3′-ethyl-2-biphenylyl)-4-hydroxy-4-[(3R)-1-({4-[(methylamino)methyl]phenyl}carbonyl)-3-piperidinyl]butyl}carbamate as a white solid (17 mg, 81%). MS (m/z) 592.2 (M+H + ). 
     Example 6 
     The following piperidines were prepared following procedures analogous to those described in Example 5 using the appropriate amine intermediate and the indicated acid in place of 4-((tert-butoxycarbonyl(methyl)amino)methyl)benzoic acid in Step 1. 
     
       
         
           
               
               
               
             
               
                   
               
               
                 Cpd. No. 
                 Product 
                 Acid used in Step 1 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                 #25 
                 methyl 4-((R)-1-((1R,2S)-2- 
                 (1R,2S)-2-({[(1,1- 
               
               
                   
                 aminocyclopentanecarbonyl)piperidin-3-yl)- 
                 dimethylethyl)oxy]carbonyl}amino)cyclopentanecarboxylic 
               
               
                   
                 4-(3′-ethyl-6-fluorobiphenyl-2-yl)-4- 
                 acid 
               
               
                   
                 hydroxybutylcarbamate 
               
               
                 #27 
                 (trans-4-aminocyclohexyl)((3R)-3-(1- 
                 trans-4-({[(1,1- 
               
               
                   
                 (6-chloro-3′-ethylbiphenyl-2-yl)-1-hydroxy- 
                 dimethylethyl)oxy]carbonyl}amino)cyclohexanecarboxylic 
               
               
                   
                 5-methoxypentyl)piperidin-1-yl)methanone 
                 acid 
               
               
                 #50 
                 (4-(aminomethyl)cyclohexyl)((2R)-2- 
                 4-[({[(1,1-dimethylethyl)oxy]carbonyl}amino)methyl]cyclohexanecarboxylic 
               
               
                   
                 ((1R)-1-(6-chloro-2′-fluoro-5′- 
                 acid 
               
               
                   
                 methylbiphenyl-2-yl)-1-hydroxy-5- 
               
               
                   
                 methoxypentyl)morpholino)methanone 
               
               
                 #55 
                 methyl 4-(6-chloro-3′-ethylbiphenyl-2- 
                 (1R,3S)-3-[{[(1,1-dimethylethyl)oxy]carbonyl}(methyl)amino]cyclopentanecarboxylic 
               
               
                   
                 yl)-4-hydroxy-4-((R)-1-((1R,3S)-3- 
                 acid 
               
               
                   
                 (methylamino)cyclopentanecarbonyl)piperidin- 
               
               
                   
                 3-yl)butylcarbamate 
               
               
                 #60 
                 methyl 4-((R)-1-(trans-4- 
                 trans-4-[({[(1,1-dimethylethyl)oxy]carbonyl}amino)methyl]cyclohexanecarboxylic 
               
               
                   
                 (aminomethyl)cyclohexanecarbonyl)piperidin- 
                 acid 
               
               
                   
                 3-yl)-4-(6-chloro-3′-ethylbiphenyl-2-yl)- 
               
               
                   
                 4-hydroxybutylcarbamate 
               
               
                 #74 
                 methyl {4-(6-chloro-3′-ethyl-2- 
                 trans-4-{[{[(1,1-dimethylethyl)oxy]carbonyl}(methyl)amino]methyl}cyclohexanecarboxylic 
               
               
                   
                 biphenylyl)-4-hydroxy-4-[(3R)-1- 
                 acid 
               
               
                   
                 ({trans-4- 
               
               
                   
                 [(methylamino)methyl]cyclohexyl}carbonyl)- 
               
               
                   
                 3-piperidinyl]butyl}carbamate 
               
               
                 #75 
                 methyl [4-((3R)-1-{[(1R,2S)-2- 
                 (1R,2S)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)cyclopentanecarboxylic 
               
               
                   
                 aminocyclopentyl]carbonyl}-3- 
                 acid 
               
               
                   
                 piperidinyl)-4-(3′-ethyl-6-fluoro-2- 
               
               
                   
                 biphenylyl)-4-hydroxybutyl]carbamate 
               
               
                 #78 
                 1-{(3R)-1-[(cis-4- 
                 [cis-4-({[(1,1- 
               
               
                   
                 aminocyclohexyl)acetyl]-3-piperidinyl}- 
                 dimethylethyl)oxy]carbonyl}amino)cyclohexyl]acetic 
               
               
                   
                 1-(6-chloro-3′-ethyl-2-biphenylyl)-5- 
                 acid 
               
               
                   
                 (methyloxy)-1-pentanol 
               
               
                 #79 
                 1-{(3R)-1-[(trans-4- 
                 [trans-4-({[(1,1- 
               
               
                   
                 aminocyclohexyl)acetyl]-3-piperidinyl}- 
                 dimethylethyl)oxy]carbonyl}amino)cyclohexyl]acetic 
               
               
                   
                 1-(6-chloro-3′-ethyl-2-biphenylyl)-5- 
                 acid 
               
               
                   
                 (methyloxy)-1-pentanol 
               
               
                 #80 
                 1-((3R)-1-{[(1R,2S)-2- 
                 (1R,2S)-2-(tert- 
               
               
                   
                 aminocyclopentyl]carbonyl}-3- 
                 butoxycarbonylamino)cyclopentanecarboxylic 
               
               
                   
                 piperidinyl)-1-(6-chloro-3′-ethyl-2- 
                 acid 
               
               
                   
                 biphenylyl)-5-(methyloxy)-1-pentanol 
               
               
                 #81 
                 (1R)-1-(6-chloro-3′-ethyl-2- 
                 (1R,3S)-3-(tert- 
               
               
                   
                 biphenylyl)-1-((2R)-4-{[(1R,3S)-3- 
                 butoxycarbonyl(methyl)amino)cyclopentanecarboxylic 
               
               
                   
                 (methylamino)cyclopentyl]carbonyl}-2- 
                 acid 
               
               
                   
                 morpholinyl)-5-(methyloxy)-1-pentanol 
               
               
                 #82 
                 1-(6-chloro-3′-ethyl-2-biphenylyl)- 
                 (1R,3S)-3-(tert- 
               
               
                   
                 1-((3R)-1-{[(1R,3S)-3- 
                 butoxycarbonyl(methyl)amino)cyclopentanecarboxylic 
               
               
                   
                 (methylamino)cyclopentyl]carbonyl}-3- 
                 acid 
               
               
                   
                 piperidinyl)-5-(methyloxy)-1-pentanol 
               
               
                 #85 
                 1-(6-chloro-3′-ethyl-2-biphenylyl)- 
                 (1R,4R)-4-((tert- 
               
               
                   
                 1-[(3R)-1-({trans-4- 
                 butoxycarbonyl(methyl)amino)methyl)cyclohexanecarboxylic 
               
               
                   
                 [(methylamino)methyl]cyclohexyl}carbonyl)- 
                 acid 
               
               
                   
                 3-piperidinyl]-5-(methyloxy)-1- 
               
               
                   
                 pentanol 
               
               
                 #87 
                 methyl [4-((3R)-1-{[(1R,3S)-3- 
                 (1R,3S)-3-(tert- 
               
               
                   
                 aminocyclohexyl]carbonyl}-3- 
                 butoxycarbonylamino)cyclohexanecarboxylic 
               
               
                   
                 piperidinyl)-4-(6-chloro-3′-ethyl-2- 
                 acid 
               
               
                   
                 biphenylyl)-4-hydroxybutyl]carbamate 
               
               
                 #88 
                 N-{4-(6-chloro-3′-methyl-2- 
                 (1R,4R)-4-((tert- 
               
               
                   
                 biphenylyl)-4-hydroxy-4-[(3R)-1- 
                 butoxycarbonyl(methyl)amino)methyl)cyclohexanecarboxylic 
               
               
                   
                 ({trans-4- 
                 acid 
               
               
                   
                 [(methylamino)methyl]cyclohexyl}carbonyl)- 
               
               
                   
                 3-piperidinyl]butyl}acetamide 
               
               
                 #89 
                 N-[4-(6-chloro-3′-methyl-2- 
                 (1R,3S)-3-(tert- 
               
               
                   
                 biphenylyl)-4-hydroxy-4-((3R)-1- 
                 butoxycarbonyl(methyl)amino)cyclopentanecarboxylic 
               
               
                   
                 {[(1R,3S)-3- 
                 acid 
               
               
                   
                 (methylamino)cyclopentyl]carbonyl}-3- 
               
               
                   
                 piperidinyl)butyl]acetamide 
               
               
                 #91 
                 N-[4-((3R)-1-{[trans-4- 
                 (1R,4R)-4-((tert- 
               
               
                   
                 (aminomethyl)cyclohexyl]carbonyl}-3- 
                 butoxycarbonylamino)methyl)cyclohexanecarboxylic 
               
               
                   
                 piperidinyl)-4-(6-chloro-3′-methyl-2- 
                 acid 
               
               
                   
                 biphenylyl)-4-hydroxybutyl]acetamide 
               
               
                 #92 
                 methyl {4-(4,6-difluoro-3′-methyl- 
                 (1R,4R)-4-((tert- 
               
               
                   
                 2-biphenylyl)-4-hydroxy-4-[(3R)-1- 
                 butoxycarbonyl(methyl)amino)methyl)cyclohexanecarboxylic 
               
               
                   
                 ({trans-4- 
                 acid 
               
               
                   
                 [(methylamino)methyl]cyclohexyl}carbonyl)- 
               
               
                   
                 3-piperidinyl]butyl}carbamate 
               
               
                 #93 
                 methyl [4-hydroxy-4-((3R)-1- 
                 (1R,3S)-3-(tert- 
               
               
                   
                 {[(1R,3S)-3- 
                 butoxycarbonyl(methyl)amino)cyclopentanecarboxylic 
               
               
                   
                 (methylamino)cyclopentyl]carbonyl}-3- 
                 acid 
               
               
                   
                 piperidinyl)-4-(2′,4,6-trifluoro-5′- 
               
               
                   
                 methyl-2-biphenylyl)butyl]carbamate 
               
               
                 #94 
                 methyl [4-hydroxy-4-[(3R)-1- 
                 (1R,4R)-4-((tert- 
               
               
                   
                 ({trans-4- 
                 butoxycarbonyl(methyl)amino)methyl)cyclohexanecarboxylic 
               
               
                   
                 [(methylamino)methyl]cyclohexyl}carbonyl)- 
                 acid 
               
               
                   
                 3-piperidinyl]-4-(2′,4,6-trifluoro- 
               
               
                   
                 5′-methyl-2-biphenylyl)butyl]carbamate 
               
               
                 #95 
                 methyl [4-(6-chloro-3′-methyl-2- 
                 (1R,3S)-3-(tert- 
               
               
                   
                 biphenylyl)-4-hydroxy-4-((3R)-1- 
                 butoxycarbonyl(methyl)amino)cyclopentanecarboxylic 
               
               
                   
                 {[(1R,3S)-3- 
                 acid 
               
               
                   
                 (methylamino)cyclopentyl]carbonyl}-3- 
               
               
                   
                 piperidinyl)butyl]carbamate 
               
               
                 #96 
                 (1R)-1-(6-chloro-3′-ethyl-2- 
                 (1R,4R)-4-((tert- 
               
               
                   
                 biphenylyl)-1-[(2R)-4-({trans-4- 
                 butoxycarbonyl(methyl)amino)methyl)cyclohexanecarboxylic 
               
               
                   
                 [(methylamino)methyl]cyclohexyl}carbonyl)- 
                 acid 
               
               
                   
                 2-morpholinyl]-5-(methyloxy)-1- 
               
               
                   
                 pentanol 
               
               
                 #98 
                 methyl {(4R)-4-(3′-ethyl-6-fluoro- 
                 (1R,4R)-4-((tert- 
               
               
                   
                 2-biphenylyl)-4-hydroxy-4-[(2R)-4- 
                 butoxycarbonyl(methyl)amino)methyl)cyclohexanecarboxylic 
               
               
                   
                 ({trans-4- 
                 acid 
               
               
                   
                 [(methylamino)methyl]cyclohexyl}carbonyl)- 
               
               
                   
                 2-morpholinyl]butyl}carbamate 
               
               
                 #103 
                 (1R)-1-[4-chloro-3-(3-ethylphenyl)- 
                 (1R,3S)-3-(tert- 
               
               
                   
                 2-pyridinyl]-1-((2R)-4-{[(1R,3S)-3- 
                 butoxycarbonyl(methyl)amino)cyclopentanecarboxylic 
               
               
                   
                 (methylamino)cyclopentyl]carbonyl}-2- 
                 acid 
               
               
                   
                 morpholinyl)-5-(methyloxy)-1-pentanol 
               
               
                 #104 
                 methyl {4-[2-chloro-3-(3- 
                 (1R,4R)-4-((tert- 
               
               
                   
                 ethylphenyl)-4-pyridinyl]-4-hydroxy-4- 
                 butoxycarbonyl(methyl)amino)methyl)cyclohexanecarboxylic 
               
               
                   
                 [(3R)-1-({trans-4- 
                 acid 
               
               
                   
                 [(methylamino)methyl]cyclohexyl}carbonyl)- 
               
               
                   
                 3-piperidinyl]butyl}carbamate 
               
               
                 #105 
                 methyl [4-[2-chloro-3-(3- 
                 (1R,3S)-3-(tert- 
               
               
                   
                 ethylphenyl)-4-pyridinyl]-4-hydroxy-4- 
                 butoxycarbonyl(methyl)amino)cyclopentanecarboxylic 
               
               
                   
                 ((3R)-1-{[(1R,3S)-3- 
                 acid 
               
               
                   
                 (methylamino)cyclopentyl]carbonyl}-3- 
               
               
                   
                 piperidinyl)butyl]carbamate 
               
               
                 #106 
                 methyl {4-{3-chloro-2-[4-(1- 
                 (1R,4R)-4-((tert- 
               
               
                   
                 methylethyl)-2-quinazolinyl]phenyl}-4- 
                 butoxycarbonyl(methyl)amino)methyl)cyclohexanecarboxylic 
               
               
                   
                 hydroxy-4-[(3R)-1-({trans-4- 
                 acid 
               
               
                   
                 [(methylamino)methyl]cyclohexyl}carbonyl)- 
               
               
                   
                 3-piperidinyl]butyl}carbamate 
               
               
                 #107 
                 methyl [4-{3-chloro-2-[4-(1- 
                 (1R,3S)-3-(tert- 
               
               
                   
                 methylethyl)-2-quinazolinyl]phenyl}-4- 
                 butoxycarbonyl(methyl)amino)cyclopentanecarboxylic 
               
               
                   
                 hydroxy-4-((3R)-1-{[(1R,3S)-3- 
                 acid 
               
               
                   
                 (methylamino)cyclopentyl]carbonyl}-3- 
               
               
                   
                 piperidinyl)butyl]carbamate 
               
               
                 #114 
                 methyl {4-{3-chloro-2-[8-(1- 
                 (1R,4R)-4-((tert- 
               
               
                   
                 methylethyl)-2-quinolinyl]phenyl}-4- 
                 butoxycarbonyl(methyl)amino)methyl)cyclohexanecarboxylic 
               
               
                   
                 hydroxy-4-[(3R)-1-({trans-4- 
                 acid 
               
               
                   
                 [(methylamino)methyl]cyclohexyl}carbonyl)- 
               
               
                   
                 3-piperidinyl]butyl}carbamate 
               
               
                 #115 
                 methyl {4-[3-chloro-2-(8-methyl-2- 
                 (1R,4R)-4-((tert- 
               
               
                   
                 quinolinyl)phenyl]-4-hydroxy-4-[(3R)- 
                 butoxycarbonyl(methyl)amino)methyl)cyclohexanecarboxylic 
               
               
                   
                 1-({trans-4- 
                 acid 
               
               
                   
                 [(methylamino)methyl]cyclohexyl}carbonyl)- 
               
               
                   
                 3-piperidinyl]butyl}carbamate 
               
               
                 #116 
                 methyl [4-[3-fluoro-2-(3- 
                 (1R,3S)-3-(tert- 
               
               
                   
                 quinolinyl)phenyl]-4-hydroxy-4-((3R)- 
                 butoxycarbonyl(methyl)amino)cyclopentanecarboxylic 
               
               
                   
                 1-{[(1R,3S)-3- 
                 acid 
               
               
                   
                 (methylamino)cyclopentyl]carbonyl}-3- 
               
               
                   
                 piperidinyl)butyl]carbamate 
               
               
                 #117 
                 methyl [4-{2-chloro-3-[3-(1- 
                 (1R,3S)-3-(tert- 
               
               
                   
                 methylethyl)phenyl]-4-pyridinyl}-4- 
                 butoxycarbonyl(methyl)amino)cyclopentanecarboxylic 
               
               
                   
                 hydroxy-4-((3R)-1-{[(1R,3S)-3- 
                 acid 
               
               
                   
                 (methylamino)cyclopentyl]carbonyl}-3- 
               
               
                   
                 piperidinyl)butyl]carbamate 
               
               
                 #118 
                 methyl [4-[3-chloro-2-(5-methyl-2- 
                 (1R,3S)-3-(tert- 
               
               
                   
                 furanyl)phenyl]-4-hydroxy-4-((3R)-1- 
                 butoxycarbonyl(methyl)amino)cyclopentanecarboxylic 
               
               
                   
                 {[(1R,3S)-3- 
                 acid 
               
               
                   
                 (methylamino)cyclopentyl]carbonyl}-3- 
               
               
                   
                 piperidinyl)butyl]carbamate 
               
               
                 #120 
                 (1R)-1-{2-chloro-3-[3-(1- 
                 (1R,4R)-4-((tert- 
               
               
                   
                 methylethyl)phenyl]-4-pyridinyl}-1- 
                 butoxycarbonyl(methyl)amino)methyl)cyclohexanecarboxylic 
               
               
                   
                 [(2R)-4-({trans-4- 
                 acid 
               
               
                   
                 [(methylamino)methyl]cyclohexyl}carbonyl)- 
               
               
                   
                 2-morpholinyl]-5-(methyloxy)-1- 
               
               
                   
                 pentanol 
               
               
                 #121 
                 (1R)-1-{2-chloro-3-[3-(1- 
                 (1R,3S)-3-(tert- 
               
               
                   
                 methylethyl)phenyl]-4-pyridinyl}-1- 
                 butoxycarbonyl(methyl)amino)cyclopentanecarboxylic 
               
               
                   
                 ((2R)-4-{[(1R,3S)-3- 
                 acid 
               
               
                   
                 (methylamino)cyclopentyl]carbonyl}-2- 
               
               
                   
                 morpholinyl)-5-(methyloxy)-1-pentanol 
               
               
                 #123 
                 methyl {4-[5-chloro-4-(3- 
                 (1R,4R)-4-((tert- 
               
               
                   
                 ethylphenyl)-3-pyridinyl]-4-hydroxy-4- 
                 butoxycarbonyl(methyl)amino)methyl)cyclohexanecarboxylic 
               
               
                   
                 [(3R)-1-({trans-4- 
                 acid 
               
               
                   
                 [(methylamino)methyl]cyclohexyl}carbonyl)- 
               
               
                   
                 3-piperidinyl]butyl}carbamate 
               
               
                 #124 
                 methyl [4-[5-chloro-4-(3- 
                 (1R,3S)-3-(tert- 
               
               
                   
                 ethylphenyl)-3-pyridinyl]-4-hydroxy-4- 
                 butoxycarbonyl(methyl)amino)cyclopentanecarboxylic 
               
               
                   
                 ((3R)-1-{[(1R,3S)-3- 
                 acid 
               
               
                   
                 (methylamino)cyclopentyl]carbonyl}-3- 
               
               
                   
                 piperidinyl)butyl]carbamate 
               
               
                 #125 
                 methyl {4-{5-chloro-4-[3-(1- 
                 (1R,4R)-4-((tert- 
               
               
                   
                 methylethyl)phenyl]-3-pyridinyl}-4- 
                 butoxycarbonyl(methyl)amino)methyl)cyclohexanecarboxylic 
               
               
                   
                 hydroxy-4-[(3R)-1-({trans-4- 
                 acid 
               
               
                   
                 [(methylamino)methyl]cyclohexyl}carbonyl)- 
               
               
                   
                 3-piperidinyl]butyl}carbamate 
               
               
                 #126 
                 methyl [4-{5-chloro-4-[3-(1- 
                 (1R,3S)-3-(tert- 
               
               
                   
                 methylethyl)phenyl]-3-pyridinyl}-4- 
                 butoxycarbonyl(methyl)amino)cyclopentanecarboxylic 
               
               
                   
                 hydroxy-4-((3R)-1-{[(1R,3S)-3- 
                 acid 
               
               
                   
                 (methylamino)cyclopentyl]carbonyl}-3- 
               
               
                   
                 piperidinyl)butyl]carbamate 
               
               
                 #127 
                 methyl {4-[6-fluoro-3′-(1- 
                 (1R,4R)-4-((tert- 
               
               
                   
                 methylethyl)-2-biphenylyl]-4-hydroxy- 
                 butoxycarbonyl(methyl)amino)methyl)cyclohexanecarboxylic 
               
               
                   
                 4-[(3R)-1-({trans-4- 
                 acid 
               
               
                   
                 [(methylamino)methyl]cyclohexyl}carbonyl)- 
               
               
                   
                 3-piperidinyl]butyl}carbamate 
               
               
                 #128 
                 methyl [4-(6-chloro-3′-fluoro-5′- 
                 (1R,3S)-3-(tert- 
               
               
                   
                 methyl-2-biphenylyl)-4-hydroxy-4- 
                 butoxycarbonyl(methyl)amino)cyclopentanecarboxylic 
               
               
                   
                 ((3R)-1-{[(1R,3S)-3- 
                 acid 
               
               
                   
                 (methylamino)cyclopentyl]carbonyl}-3- 
               
               
                   
                 piperidinyl)butyl]carbamate 
               
               
                 #129 
                 methyl [4-(3′,6-difluoro-5′-methyl- 
                 (1R,3S)-3-(tert- 
               
               
                   
                 2-biphenylyl)-4-hydroxy-4-((3R)-1- 
                 butoxycarbonyl(methyl)amino)cyclopentanecarboxylic 
               
               
                   
                 {[(1R,3S)-3- 
                 acid 
               
               
                   
                 (methylamino)cyclopentyl]carbonyl}-3- 
               
               
                   
                 piperidinyl)butyl]carbamate 
               
               
                 #131 
                 methyl {4-(3′-ethyl-6-fluoro-2- 
                 (1R,4R)-4-((tert- 
               
               
                   
                 biphenylyl)-4-hydroxy-4-[(3R)-1- 
                 butoxycarbonyl(methyl)amino)methyl)cyclohexanecarboxylic 
               
               
                   
                 ({trans-4- 
                 acid 
               
               
                   
                 [(methylamino)methyl]cyclohexyl}carbonyl)- 
               
               
                   
                 3-piperidinyl]butyl}carbamate 
               
               
                 #144 
                 methyl [4-((3R)-1-{[4- 
                 4-((tert- 
               
               
                   
                 (aminomethyl)-5-methyl-2- 
                 butoxycarbonylamino)methyl)-5- 
               
               
                   
                 furanyl]carbonyl}-3-piperidinyl)-4-(6- 
                 methylfuran-2-carboxylic acid 
               
               
                   
                 chloro-3′-ethyl-2-biphenylyl)-4- 
               
               
                   
                 hydroxybutyl]carbamate 
               
               
                 #145 
                 methyl {4-(6-chloro-3′-ethyl-2- 
                 6-((tert- 
               
               
                   
                 biphenylyl)-4-hydroxy-4-[(3R)-1-({6- 
                 butoxycarbonyl(methyl)amino)methyl)nicotinic 
               
               
                   
                 [(methylamino)methyl]-3- 
                 acid 
               
               
                   
                 pyridinyl}carbonyl)-3- 
               
               
                   
                 piperidinyl]butyl}carbamate 
               
               
                 #146 
                 methyl [4-{(3R)-1-[(2-amino-4- 
                 2-amino-4-hydroxypyrimidine-5- 
               
               
                   
                 oxo-1,4-dihydro-5- 
                 carboxylic acid 
               
               
                   
                 pyrimidinyl)carbonyl]-3-piperidinyl}-4- 
               
               
                   
                 (6-chloro-3′-methyl-2-biphenylyl)-4- 
               
               
                   
                 hydroxybutyl]carbamate 
               
               
                 #147 
                 methyl [4-(6-chloro-3′-methyl-2- 
                 2-(methylamino)pyrimidine-5- 
               
               
                   
                 biphenylyl)-4-hydroxy-4-((3R)-1-{[2- 
                 carboxylic acid 
               
               
                   
                 (methylamino)-5- 
               
               
                   
                 pyrimidinyl]carbonyl}-3- 
               
               
                   
                 piperidinyl)butyl]carbamate 
               
               
                 #148 
                 methyl [4-((3R)-1-{[5- 
                 5-((tert- 
               
               
                   
                 (aminomethyl)-3-isoxazolyl]carbonyl}- 
                 butoxycarbonylamino)methyl)isoxazole- 
               
               
                   
                 3-piperidinyl)-4-(6-chloro-3′-methyl-2- 
                 3-carboxylic acid 
               
               
                   
                 biphenylyl)-4-hydroxybutyl]carbamate 
               
               
                 #149 
                 methyl {4-(6-chloro-3′-ethyl-2- 
                 5-((tert- 
               
               
                   
                 biphenylyl)-4-hydroxy-4-[(3R)-1-({5- 
                 butoxycarbonyl(methyl)amino)methyl)thiophene- 
               
               
                   
                 [(methylamino)methyl]-2- 
                 2-carboxylic acid 
               
               
                   
                 thienyl}carbonyl)-3- 
               
               
                   
                 piperidinyl]butyl}carbamate 
               
               
                 #150 
                 methyl [4-{(3R)-1-[(6-amino-3- 
                 6-aminonicotinic acid 
               
               
                   
                 pyridinyl)carbonyl]-3-piperidinyl}-4- 
               
               
                   
                 (3′,6-difluoro-5′-methyl-2-biphenylyl)- 
               
               
                   
                 4-hydroxybutyl]carbamate 
               
               
                 #151 
                 methyl [2-({(R)-(6-chloro-3′-ethyl- 
                 4-{[{[(1,1- 
               
               
                   
                 2-biphenylyl)[(3R)-1-({trans-4- 
                 dimethylethyl)oxy]carbonyl}-trans- 
               
               
                   
                 [(methylamino)methyl]cyclohexyl}carbonyl)- 
                 (methyl)amino]methyl}cyclohexanecarboxylic 
               
               
                   
                 3-piperidinyl]methyl}oxy)ethyl]carbamate 
                 acid 
               
               
                 #152 
                 methyl [2-({(S)-(6-chloro-3′-ethyl- 
                 4-{[{[(1,1- 
               
               
                   
                 2-biphenylyl)[(2R)-4-({trans-4- 
                 dimethylethyl)oxy]carbonyl}-trans- 
               
               
                   
                 [(methylamino)methyl]cyclohexyl}carbonyl)- 
                 (methyl)amino]methyl}cyclohexanecarboxylic 
               
               
                   
                 2-morpholinyl]methyl}oxy)ethyl]carbamate 
                 acid 
               
               
                 #153 
                 N-[4-((3R)-1-{[6-(aminomethyl)-3- 
                 6-((tert- 
               
               
                   
                 pyridinyl]carbonyl}-3-piperidinyl)-4-(6- 
                 butoxycarbonylamino)methyl)nicotinic 
               
               
                   
                 chloro-3′-methyl-2-biphenylyl)-4- 
                 acid 
               
               
                   
                 hydroxybutyl]acetamide 
               
               
                   
               
            
           
         
       
     
     Example 7 
     ((1S,3R,4S)-3-amino-4-hydroxycyclopentyl)((R)-2-((R)-1-(6-chloro-3′-ethylbiphenyl-2-yl)-1-hydroxypent-4-enyl)morpholino)methanone (#6) 
     
       
         
         
             
             
         
       
     
     Step 1. tert-butyl (1R,2S,4S)-4-((R)-2-((R)-1-(6-chloro-3′-ethylbiphenyl-2-yl)-1-hydroxypent-4-enyl)morpholine-4-carbonyl)-2-hydroxycyclopentylcarbamate: To a solution of (R)-1-(6-chloro-3′-ethylbiphenyl-2-yl)-1-((R)-morpholin-2-yl)pent-4-en-1-ol (55 mg, 0.14 mmol), (1S,3R,4S)-3-(tert-butoxycarbonylamino)-4-hydroxycyclopentanecarboxylic acid (35 mg, 0.14 mmol), and i-Pr 2 NEt (54 mg, 0.42 mmol) in 2 mL of DMF was added HBTU (64 mg, 0.17 mmol). The reaction was stirred for 2 h and diluted with 10 mL water. It was extracted with EtOAc (3×10 mL). The combined organic extracts were dried over Na 2 SO 4  and filtered, followed by concentration under reduced pressure. This afforded tert-butyl (1R,2S,4S)-4-((R)-2-((R)-1-(6-chloro-3′-ethylbiphenyl-2-yl)-1-hydroxypent-4-enyl)morpholine-4-carbonyl)-2-hydroxycyclopentylcarbamate which was used without purification. 
     Step 2. ((1S,3R,4S)-3-amino-4-hydroxycyclopentyl)((R)-2-((R)-1-(6-chloro-3′-ethylbiphenyl-2-yl)-1-hydroxypent-4-enyl)morpholino)methanone: To a solution of tent-butyl (1R,2S,4S)-4-((R)-2-((R)-1-(6-chloro-3′-ethylbiphenyl-2-yl)-1-hydroxypent-4-enyl)morpholine-4-carbonyl)-2-hydroxycyclopentylcarbamate (85 mg, 0.14 mmol) in 10 mL of MeCN was added 10 mL of 2N aq HCl. The reaction was stirred overnight. It was basified with 10N aq NaOH to pH=14 and extracted with CH 2 Cl 2  (3×10 ml). The combined organic extracts were dried over Na 2 SO 4  and filtered, followed by concentration under reduced pressure. This afforded ((1S,3R,4S)-3-amino-4-hydroxycyclopentyl)((R)-2-((R)-1-(6-chloro-3′-ethylbiphenyl-2-yl)-1-hydroxypent-4-enyl)morpholino)methanone which was purified by reverse phase HPLC. LC-MS t R =2.52 min, (m/z) 513.2 (M+H + ). 
     Example 8 
     The following compounds were prepared following procedures analogous to those described in Example 7.
     #5 methyl 4-(1-((1S,3R,4S)-3-amino-4-hydroxycyclopentanecarbonyl)piperidin-3-yl)-4-hydroxy-4-(2-(pyridin-3-yl)phenyl)butylcarbamate   #8 2-((S)-((R)-4-((1S,3R,4S)-3-amino-4-hydroxycyclopentanecarbonyl)morpholin-2-yl)(6-fluoro-3′-methylbiphenyl-2-yl)methoxy)-N-ethylacetamide   #10 ((1S,3R,4S)-3-amino-4-hydroxycyclopentyl)((R)-2-((R)-1-(3-chloro-2-(pyridin-3-yl)phenyl)-1-hydroxy-5-methoxypentyl)morpholino)methanone   #11 ((1S,3R,4S)-3-amino-4-hydroxycyclopentyl)(2-(1-(3-chloro-2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-1-hydroxy-5-methoxypentyl)morpholino)methanone   #13 N-(4-((R)-1-((1S,3R,4S)-3-amino-4-hydroxycyclopentanecarbonyl)piperidin-3-yl)-4-hydroxy-4-(2-(o-tolyloxy)phenyl)butyl)acetamide   #14 ((1S,3R,4S)-3-amino-4-hydroxycyclopentyl)((3R)-3-(1-(2-(2,6-dimethylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)piperidin-1-yl)methanone   #23 ((1S,3R,4S)-3-amino-4-hydroxycyclopentyl)((R)-2-((R)-1-(4′,6-difluoro-3′-methylbiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)morpholino)methanone   #24 methyl 4-((R)-1-((1S,3R,4S)-3-amino-4-hydroxycyclopentanecarbonyl)piperidin-3-yl)-4-hydroxy-4-(2-(o-tolyloxy)phenyl)butylcarbamate   #29 ((1S,3R,4S)-3-amino-4-hydroxycyclopentyl)((3R)-3-(1-(6-fluoro-3′-methoxy-5′-methylbiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)piperidin-1-yl)methanone   #30 ((1S,3R,4S)-3-amino-4-hydroxycyclopentyl)((3R)-3-(1-(6-chloro-3′-ethylbiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)piperidin-1-yl)methanone   #33 ((1S,3R,4S)-3-amino-4-hydroxycyclopentyl)((3R)-3-(1-(3-chloro-2-(2-methylbenzyl)phenyl)-1-hydroxy-5-methoxypentyl)piperidin-1-yl)methanone   #34 ((1S,3R,4S)-3-amino-4-hydroxycyclopentyl)((3R)-3-(1-(3-chloro-2-(3-methylbenzyl)phenyl)-1-hydroxy-5-methoxypentyl)piperidin-1-yl)methanone   #35 ((1S,3R,4S)-3-amino-4-hydroxycyclopentyl)(2-(1-(6-fluoro-3′-methoxy-5′-methylbiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)morpholino)methanone   #36 ((1S,3R,4S)-3-amino-4-hydroxycyclopentyl)((3R)-3-(1-(3-chloro-2-(o-tolyloxy)phenyl)-1-hydroxy-5-methoxypentyl)piperidin-1-yl)methanone   #37 ((1S,3R,4S)-3-amino-4-hydroxycyclopentyl)(2-(1-(6-chloro-3′-ethylbiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)morpholino)methanone   #38 ((1S,3R,4S)-3-amino-4-hydroxycyclopentyl)((2R)-2-((1R)-1-(6-chloro-2′-fluoro-5′-methylbiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)morpholino)methanone   #44 N-(4-((R)-1-((1S,3R,4S)-3-amino-4-hydroxycyclopentanecarbonyl)piperidin-3-yl)-4-(6-chloro-3′-ethylbiphenyl-2-yl)-4-hydroxybutyl)acetamide   #47 ((1S,3R,4S)-3-amino-4-hydroxycyclopentyl)((3R)-3-(1-(3-chloro-2-(3-ethylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)piperidin-1-yl)methanone   #48 ((1S,3R,4S)-3-amino-4-hydroxycyclopentyl)((R)-2-((R)-1-(6-fluoro-3′,5′-dimethoxybiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)morpholino)methanone   #49 ((1S,3R,4S)-3-amino-4-hydroxycyclopentyl)((R)-2-((R)-1-(6-chloro-3′-(methoxymethyl)biphenyl-2-yl)-1-hydroxy-5-methoxypentyl)morpholino)methanone   #51 ((1S,3R,4S)-3-amino-4-hydroxycyclopentyl)((R)-3-((R)-1-(3-chloro-2-(quinolin-3-yl)phenyl)-1-hydroxy-5-methoxypentyl)piperidin-1-yl)methanone   #52 ((1S,3R,4S)-3-amino-4-hydroxycyclopentyl)((R)-2-((R)-1-(3-chloro-2-(naphthalen-2-yl)phenyl)-1-hydroxy-5-methoxypentyl)morpholino)methanone   #53 ((1S,3R,4S)-3-amino-4-hydroxycyclopentyl)(2-(1-(3-chloro-2-(quinolin-3-yl)phenyl)-1-hydroxy-5-methoxypentyl)morpholino)methanone   #54 ((1S,3R,4S)-3-amino-4-hydroxycyclopentyl)((2R)-2-((1R)-1-(3-chloro-2-(isoquinolin-4-yl)phenyl)-1-hydroxy-5-methoxypentyl)morpholino)methanone   #57 methyl 4-((R)-1-((1S,3R,4S)-3-amino-4-hydroxycyclopentanecarbonyl)piperidin-3-yl)-4-(6-chloro-3′-ethylbiphenyl-2-yl)-4-hydroxybutylcarbamate   #59 ((1S,3R,4S)-3-amino-4-hydroxycyclopentyl)((R)-2-((R)-1-(6-chloro-3′,5′-dimethoxybiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)morpholino)methanone   #61 methyl 4-((R)-1-((1S,3R,4S)-3-amino-4-hydroxycyclopentanecarbonyl)piperidin-3-yl)-4-(6-chloro-3′-isopropylbiphenyl-2-yl)-4-hydroxybutylcarbamate   #63 methyl 4-((R)-1-((1S,3R,4S)-3-amino-4-hydroxycyclopentanecarbonyl)piperidin-3-yl)-4-(3-chloro-2-(quinolin-3-yl)phenyl)-4-hydroxybutylcarbamate   #65 ((1S,3R,4S)-3-amino-4-hydroxycyclopentyl)((R)-3-45)-1-(3′-ethoxy-6-fluoro-5′-(trifluoromethyl)biphenyl-2-yl)-1-hydroxy-5-methoxypentyl)piperidin-1-yl)methanone   #66 ((1S,3R,4S)-3-amino-4-hydroxycyclopentyl)(2-(1-(3′-ethoxy-6-fluoro-5′-(trifluoromethyl)biphenyl-2-yl)-1-hydroxy-5-methoxypentyl)morpholino)methanone   #71 methyl (4-((3R)-1-{[(1S,3R,4S)-3-amino-4-hydroxycyclopentyl]carbonyl}-3-piperidinyl)-4-{3-chloro-2-[(2-methylphenyl)oxy]phenyl}-4-hydroxybutyl)carbamate   #72 methyl (4-((3R)-1-{[(1S,3R,4S)-3-amino-4-hydroxycyclopentyl]carbonyl}-3-piperidinyl)-4-{3-chloro-2-[(2-ethylphenyl)oxy]phenyl}-4-hydroxybutyl)carbamate   #73 methyl [4-((3R)-1-{[(1S,3R,4S)-3-amino-4-hydroxycyclopentyl]carbonyl}-3-piperidinyl)-4-(3′-ethyl-6-fluoro-2-biphenylyl)-4-hydroxybutyl] carbamate   #97 methyl [(4R)-4-((2R)-4-{[(1S,3R,4S)-3-amino-4-hydroxycyclopentyl]carbonyl}-2-morpholinyl)-4-(3′-ethyl-6-fluoro-2-biphenylyl)-4-hydroxybutyl]carbamate   #99 (1S,2R,4S)-2-amino-4-({(2R)-2-[(1R)-1-[2-chloro-3-(3-ethylphenyl)-4-pyridinyl]-1-hydroxy-5-(methyloxy)pentyl]-4-morpholinyl}carbonyl)cyclopentanol   #101 (1S,2R,4S)-2-amino-4-({(2R)-2-[(1R)-1-[2-(1-benzothien-3-yl)-3-chlorophenyl]-1-hydroxy-5-(methyloxy)pentyl]-4-morpholinyl}carbonyl)cyclopentanol   #109 (1S,2R,4S)-2-amino-4-({(3R)-3-[1-{3-chloro-2-[(3-methylphenyl)oxy]phenyl}-1-hydroxy-5-(methyloxy)pentyl]-1-piperidinyl}carbonyl)cyclopentanol   #111 methyl (4-((3R)-1-{[(1S,3R,4S)-3-amino-4-hydroxycyclopentyl]carbonyl}-3-piperidinyl)-4-{3-chloro-2-[(3-methylphenyl)oxy]phenyl}-4-hydroxybutyl)carbamate   #113 methyl (4-((3R)-1-{[(1S,3R,4S)-3-amino-4-hydroxycyclopentyl]carbonyl}-3-piperidinyl)-4-{2-[(2,6-dimethylphenyl)oxy]phenyl}-4-hydroxybutyl)carbamate   #119 methyl {4-((3R)-1-{[(1S,3R,4S)-3-amino-4-hydroxycyclopentyl]carbonyl}-3-piperidinyl)-4-[3-chloro-2-(5-methyl-2-furanyl)phenyl]-4-hydroxybutyl}carbamate   #122 (1S,2R,4S)-2-amino-4-({(2R)-2-[(1R)-1-{2-chloro-3-[3-(1-methylethyl)phenyl]-4-pyridinyl}-1-hydroxy-5-(methyloxy)pentyl]-4-morpholinyl}carbonyl)cyclopentanol   #130 (1S,2R,4S)-2-amino-4-({(3R)-3-[1-{3-chloro-2-[(2-ethylphenyl)oxy]phenyl}-1-hydroxy-5-(methyloxy)pentyl]-1-piperidinyl}carbonyl)cyclopentanol   #132 (1S,2R,4S)-2-amino-4-({(3R)-3-[1-{2-[(2-chloro-6-methylphenyl)oxy]phenyl}-1-hydroxy-5-(methyloxy)pentyl]-1-piperidinyl}carbonyl)cyclopentanol   #133 (1S,2R,4S)-2-amino-4-({(3R)-3-[1-{3-fluoro-2-[(3-methylphenyl)oxy]phenyl}-1-hydroxy-5-(methyloxy)pentyl]-1-piperidinyl}carbonyl)cyclopentanol   #135 methyl (4-((3R)-1-{[(1S,3R,4S)-3-amino-4-hydroxycyclopentyl]carbonyl}-3-piperidinyl)-4-{3-chloro-2-[(3-ethylphenyl)oxy]phenyl}-4-hydroxybutyl)carbamate   #137 methyl (4-((3R)-1-{[(1S,3R,4S)-3-amino-4-hydroxycyclopentyl]carbonyl}-3-piperidinyl)-4-{3-fluoro-2-[(3-methylphenyl)oxy]phenyl}-4-hydroxybutyl)carbamate   #139 methyl (4-((3R)-1-{[(1S,3R,4S)-3-amino-4-hydroxycyclopentyl]carbonyl}-3-piperidinyl)-4-{3-chloro-2-[(3-methylphenyl)methyl]phenyl}-4-hydroxybutyl)carbamate   #140 methyl [4-{3-chloro-2-[(3-methylphenyl)methyl]phenyl}-4-hydroxy-4-((3R)-1-{[(1R,3S)-3-(methylamino)cyclopentyl]carbonyl}-3-piperidinyl)butyl]carbamate   #142 methyl (2-{[(S)-((2R)-4-{[(1S,3R,4S)-3-amino-4-hydroxycyclopentyl]carbonyl}-2-morpholinyl)(6-chloro-3′-ethyl-2-biphenylyl)methyl]oxy}ethyl)carbamate   #143 methyl (2-{[(R) — ((3R)-1-{[(1S,3R,4S)-3-amino-4-hydroxycyclopentyl]carbonyl}-3-piperidinyl)(6-chloro-3′-ethyl-2-biphenylyl)methyl]oxy}ethyl)carbamate   

     Example 9 
     (1S,2R,4S)-4-({(3R)-3-[1-(6-chloro-3′-ethyl-2-biphenylyl)-1-hydroxy-5-methyloxy)pentyl]-1-piperidinyl}carbonyl)-2-[(2-hydroxyethyl)amino]cyclopentanol (#84) 
     
       
         
         
             
             
         
       
     
     To a solution of (1S,2R,4S)-2-amino-4-({(3R)-3-[1-(6-chloro-3′-ethyl-2-biphenylyl)-1-hydroxy-5-(methyloxy)pentyl]-1-piperidinyl}carbonyl)cyclopentanol (44 mg, 0.064 mmol) in 1,2-dichloroethane (2 ml) was added hydroxyacetaldehyde (16 mg, 0.13 mmol) and sodium cyanoborohydride (20 mg, 0.32 mmol). The reaction mixture was stirred at room temperature overnight. To the mixture was added 2N HCl solution and the organic products were extracted into methylene chloride. The organic materials were dried and concentrated. The product was purified by reverse phase HPLC to give (1S,2R,4S)-4-({(3R)-3-[1-(6-chloro-3′-ethyl-2-biphenylyl)-1-hydroxy-5-(methyloxy)pentyl]-1-piperidinyl}carbonyl)-2-[(2-hydroxyethyl)amino]cyclopentanol (6.2 mg). 
     Example 10 
     The following compounds were prepared following procedures analogous to those described in Example 9 using the indicated aldehyde. 
     
       
         
           
               
               
               
             
               
                   
               
               
                 Cpd. No. 
                 Product 
                 Aldehyde 
               
               
                   
               
             
            
               
                 #83 
                 (1S,2R,4S)-4-({(2R)-2-[(1R)-1-(6-chloro-3′- 
                 hydroxyacetaldehyde 
               
               
                   
                 ethyl-2-biphenylyl)-1-hydroxy-5- 
               
               
                   
                 (methyloxy)pentyl]-4-morpholinyl}carbonyl)-2- 
               
               
                   
                 [(2-hydroxyethyl)amino]cyclopentanol 
               
               
                 #86 
                 (1S,2R,4S)-4-({(2R)-2-[(1R)-1-(6-chloro-3′- 
                 thiazole-2-carbaldehyde 
               
               
                   
                 ethyl-2-biphenylyl)-1-hydroxy-5- 
               
               
                   
                 (methyloxy)pentyl]-4-morpholinyl}carbonyl)-2- 
               
               
                   
                 [(1,3-thiazol-2-ylmethyl)amino]cyclopentanol 
               
               
                 #90 
                 (1R)-1-(6-chloro-3′-ethyl-2-biphenylyl)-1- 
                 2,5-dimethyloxazole-4- 
               
               
                   
                 {(2R)-4-[((1R,3S)-3-{[(2,5-dimethyl-1,3-oxazol-4- 
                 carbaldehyde 
               
               
                   
                 yl)methyl]amino}cyclopentyl)carbonyl]-2- 
               
               
                   
                 morpholinyl}-5-(methyloxy)-1-pentanol 
               
               
                   
               
            
           
         
       
     
     Example 11 
     methyl [4-((3R)-1-{[4-(aminomethyl)-1-piperidinyl]carbonyl}-3-piperidinyl)-4-(6-chloro-3′-ethyl-2-biphenylyl)-4-hydroxybutyl]carbamate (#156) 
     
       
         
         
             
             
         
       
     
     Step 1. 1-({4-[({[(1,1-dimethylethyl)oxy]carbonyl}amino)methyl]-1-piperidinyl}carbonyl)-3-methyl-1H-imidazol-3-ium: A solution of 1,1-dimethylethyl (4-piperidinylmethyl)carbamate (3.0 g, 14.0 mmol), CDI (2.72 g, 16.8 mmol), and Et 3 N (5.85 ml, 42.0 mmol) in CH 2 Cl 2  (20 ml) was stirred at 25° C. for 60 hours before being concentrated under reduced pressure and subjected to flash chromatography to give a colorless solid. The solid was dissolved in 20 mL of CH 3 CN and the mixture was treated with iodomethane (3.49 ml, 56.0 mmol) and stirred overnight. The solvent was removed to give 1-({4-[({[(1,1-dimethylethyl)oxy]carbonyl}amino)methyl]-1-piperidinyl}carbonyl)-3-methyl-1H-imidazol-3-ium as a colorless solid (2.75 g, 60%) which was used without purification. ESI-MS (m/z): 323.2 (M + ). 
     Step 2. Methyl [4-((3R)-1-{[4-(aminomethyl)-1-piperidinyl]carbonyl}-3-piperidinyl)-4-(6-chloro-3′-ethyl-2-biphenylyl)-4-hydroxybutyl]carbamate: A solution of methyl {4-(6-chloro-3′-ethyl-2-biphenylyl)-4-hydroxy-4-[(3R)-3-piperidinyl]butyl}carbamate (0.25 g, 0.562 mmol) in CH 3 CN (5 ml) was treated with 1-({4-[({[(1,1-dimethylethyl)oxy]carbonyl} amino)methyl]-1-piperidinyl}carbonyl)-3-methyl-1H-imidazol-3-ium (0.363 g, 1.124 mmol) and stirred at 50° C. for 1 h before being subjected to reverse phase HPLC to give a solid. The solid was treated with 5 mL of 10% 4N HCl/dioxane in MeCN and the resulting solution was stirred at 25° C. overnight before being concentrated to give a tan solid, which was dissolved in water and lyophilized to give methyl [4-((3R)-1-{[4-(aminomethyl)-1-piperidinyl]carbonyl}-3-piperidinyl)-4-(6-chloro-3′-ethyl-2-biphenylyl)-4-hydroxybutyl]carbamate as a tan solid (0.31 g, 92%): LCMS (m/z): 585.2 (M+H + ). 
     Example 12 
     The following compounds were prepared following procedures analogous to those described in Example 11:
     #154 methyl 4-((R)-1-(4-(aminomethyl)piperidine-1-carbonyl)piperidin-3-yl)-4-(3′-ethyl-6-fluorobiphenyl-2-yl)-4-hydroxybutylcarbamate using methyl (R)-4-(3′-ethyl-6-fluorobiphenyl-2-yl)-4-hydroxy-4-((R)-piperidin-3-yl)butylcarbamate instead of methyl {4-(6-chloro-3′-ethyl-2-biphenylyl)-4-hydroxy-4-[(3R)-3-piperidinyl]butyl}carbamate in Step 2.   #157 methyl [4-((3R)-1-{[4-(aminomethyl)-4-phenyl-1-piperidinyl]carbonyl}-3-piperidinyl)-4-(6-chloro-3′-ethyl-2-biphenylyl)-4-hydroxybutyl]carbamate using 1,1-dimethylethyl [(4-phenyl-4-piperidinyl)methyl]carbamate instead of 1,1-dimethylethyl (4-piperidinylmethyl)carbamate in Step 1.   #158 N-(4-((R)-1-(4-(aminomethyl)piperidine-1-carbonyl)piperidin-3-yl)-4-(2′,6-difluoro-5′-methylbiphenyl-2-yl)-4-hydroxybutyl)-2-hydroxyacetamide using N-44R)-4-(2′,6-difluoro-5′-methylbiphenyl-2-yl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)-2-hydroxyacetamide instead of methyl {4-(6-chloro-3′-ethyl-2-biphenylyl)-4-hydroxy-4-[(3R)-3-piperidinyl]butyl}carbamate in Step 2.   

     Example 13 
     methyl {4-(6-chloro-3′-ethyl-2-biphenylyl)-4-hydroxy-4-[(3R)-1-({4-[(methylamino)methyl]-1-piperidinyl}carbonyl)-3-piperidinyl]butyl}carbamate (#159) 
     
       
         
         
             
             
         
       
     
     Step 1. methyl [4-(6-chloro-3′-ethyl-2-biphenylyl)-4-hydroxy-4-43R)-1-{[4-({[(2-nitrophenyl)sulfonyl]amino}methyl)-1-piperidinyl]carbonyl}-3-piperidinyl)butyl]carbamate: A solution of methyl [4-((3R)-1-{[4-(aminomethyl)-1-piperidinyl]carbonyl}-3-piperidinyl)-4-(6-chloro-3′-ethyl-2-biphenylyl)-4-hydroxybutyl]carbamate (0.25 g, 0.42 mmol) in CH 2 Cl 2  (10 ml) at 0° C. was treated with 2-nitrobenzenesulfonyl chloride (0.114 g, 0.51 mmol) and Et 3 N (0.179 ml, 1.28 mmol), and the mixture was stirred at for 45 min before being concentrated under reduced pressure to give methyl [4-(6-chloro-3′-ethyl-2-biphenylyl)-4-hydroxy-4-((3R)-1-{[4-({[(2-nitrophenyl)sulfonyl]amino}methyl)-1-piperidinyl]carbonyl}-3-piperidinyl)butyl]carbamate as a tan solid. ESI-MS (m/z): 770.3 (M+H + ). 
     Step 2. methyl {4-(6-chloro-3′-ethyl-2-biphenylyl)-4-hydroxy-4-[(3R)-1-({4-[(methylamino)methyl]-1-piperidinyl}carbonyl)-3-piperidinyl]butyl}carbamate: A solution of methyl [4-(6-chloro-3′-ethyl-2-biphenylyl)-4-hydroxy-4-43R)-1-{[4-({[(2-nitrophenyl)sulfonyl]amino}methyl)-1-piperidinyl]carbonyl}-3-piperidinyl)butyl]carbamate (0.10 g, 0.13 mmol) in DMF (2 ml) at 25° C. was treated with iodomethane (0.032 ml, 0.52 mmol) and K 2 CO 3  (0.036 g, 0.260 mmol) and stirred overnight before being filtered through celite and subjected to reverse phase HPLC to give methyl [4-(6-chloro-3′-ethyl-2-biphenylyl)-4-hydroxy-4-43R)-1-{[4-({methyl [(2-nitrophenyl)sulfonyl]amino}methyl)-1-piperidinyl]carbonyl}-3-piperidinyl)butyl]carbamate a solid. This material was dissolved in DMF (2 ml) and treated with thiophenol (0.053 ml, 0.52 mmol) and K 2 CO 3  (0.036 g, 0.260 mmol) and the mixture was stirred at 25° C. overnight before being filtered and subjected to reverse phase HPLC to give methyl {4-(6-chloro-3′-ethyl-2-biphenylyl)-4-hydroxy-4-[(3R)-1-({4-[(methylamino)methyl]-1-piperidinyl}carbonyl)-3-piperidinyl]butyl}carbamate as a solid (0.056 g, 57%). ESI-MS (m/z): 599.3 (M+H + ). 
     Example 14 
     The following compounds were prepared following procedures analogous to those described in Example 13:
     #155 methyl 4-(3′-ethyl-6-fluorobiphenyl-2-yl)-4-hydroxy-4-((R)-1-(4-((methylamino)methyl)piperidine-1-carbonyl)piperidin-3-yl)butylcarbamate using methyl (R)-4-((R)-1-(4-(aminomethyl)piperidine-1-carbonyl)piperidin-3-yl)-4-(3′-ethyl-6-fluorobiphenyl-2-yl)-4-hydroxybutylcarbamate instead of methyl [4-((3R)-1-{[4-(aminomethyl)-1-piperidinyl]carbonyl}-3-piperidinyl)-4-(6-chloro-3′-ethyl-2-biphenylyl)-4-hydroxybutyl]carbamate in Step 1.   #160 methyl {4-(6-chloro-3′-ethyl-2-biphenylyl)-4-hydroxy-4-[(3R)-1-({4-[(2-propen-1-ylamino)methyl]-1-piperidinyl}carbonyl)-3-piperidinyl]butyl}carbamate by replacing methyl iodide with allyl bromide in Step 2.   

     
       
         
           
               
            
               
                   
               
               
                 The following is a compound of the invention: 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                 Synthetic 
                 LC_MS 
                   
                   
               
               
                   
                   
                 Method 
                 Method 1 
                 Mass 
               
               
                 Cpd. #. 
                 Name 
                 Example No. 
                 t R (min) 
                 observed 
                 Selected 1H NMR resonances a   
               
               
                   
               
               
                 37 
                 ((1S,3R,4S)-3-amino-4- 
                 8 
                   
                 567 
                 0.8-1.0 (m, 1H), 1.20-1.40 (m, 6H), 1.40- 
               
               
                   
                 hydroxycyclopentyl)(2-(1-(6-chloro-3′- 
                   
                   
                   
                 1.55 (m, 3H), 1.60-1.80 (m, 1H), 1.90-2.15 
               
               
                   
                 ethylbiphenyl-2-yl)-1-hydroxy-5- 
                   
                   
                   
                 (m, 2H), 2.20-2.35 (m, 1H), 2.60-2.80 (m, 
               
               
                   
                 methoxypentyl)morpholino)methanone 
                   
                   
                   
                 3H), 3.10-3.25 (m, 2H), 3.25-3.35 (m, 5H), 
               
               
                   
                   
                   
                   
                   
                 3.50 (m, 1H), 3.65-3.90 (m, 2H), 4.20-4.37 
               
               
                   
                   
                   
                   
                   
                 (m, 2H), 6.90-7.00 (m, 2H), 7.20-7.42 (m, 
               
               
                   
                   
                   
                   
                   
                 4H), 7.80 (m, 1H). 
               
               
                   
               
               
                   a1 H NMR spectra were acquired in CD 3 OD unless otherwise indicated. 
               
            
           
         
       
     
     The following are compounds of the invention: 
     
       
         
           
               
               
               
               
               
               
             
               
                   
               
               
                   
                   
                 Synthetic 
                   
                   
                   
               
               
                   
                   
                 Method 
                 LC_MS 
                   
                 Mass 
               
               
                 Cpd. #. 
                 Name 
                 Example No. 
                 Method 
                 t R (min) 
                 observed 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 1 
                 methyl 4-((R)-1-((1R,3S)-3- 
                 2 
                 1 
                 1.76 
                 495.3 
               
               
                   
                 aminocyclopentanecarbonyl)piperidin-3-yl)-4- 
               
               
                   
                 hydroxy-4-(2-(pyridin-4- 
               
               
                   
                 yl)phenyl)butylcarbamate 
               
               
                 2 
                 2-((R)-((R)-4-((1R,3S)-3- 
                 2 
                 1 
                 2.22 
                 498.2 
               
               
                   
                 aminocyclopentanecarbonyl)morpholin-2- 
               
               
                   
                 yl)(6-fluoro-3′-methylbiphenyl-2-yl)methoxy)- 
               
               
                   
                 N-ethylacetamide 
               
               
                 3 
                 N-(4-((R)-1-((1R,3S)-3- 
                 2 
                 1 
                 2.11 
                 508.3 
               
               
                   
                 aminocyclopentanecarbonyl)piperidin-3-yl)-4- 
               
               
                   
                 hydroxy-4-(2-(o- 
               
               
                   
                 tolyloxy)phenyl)butyl)acetamide 
               
               
                 4 
                 ((1R,3S)-3-aminocyclopentyl)((3R)-3-(1- 
                 2 
                   
                   
                 509.2 
               
               
                   
                 (2-(2,6-dimethylphenoxy)phenyl)-1-hydroxy-5- 
               
               
                   
                 methoxypentyl)piperidin-1-yl)methanone 
               
               
                 5 
                 methyl 4-(1-((1S,3R,4S)-3-amino-4- 
                 8 
                 1 
                 1.72 
                 511.2 
               
               
                   
                 hydroxycyclopentanecarbonyl)piperidin-3-yl)- 
               
               
                   
                 4-hydroxy-4-(2-(pyridin-3- 
               
               
                   
                 yl)phenyl)butylcarbamate 
               
               
                 6 
                 ((1S,3R,4S)-3-amino-4- 
                 7 
                 1 
                 2.52 
                 513.2 
               
               
                   
                 hydroxycyclopentyl)((R)-2-((R)-1-(6-chloro-3′- 
               
               
                   
                 ethylbiphenyl-2-yl)-1-hydroxypent-4- 
               
               
                   
                 enyl)morpholino)methanone 
               
               
                 7 
                 methyl 2-((4-((1R,3S)-3- 
                 2 
                 1 
                 2.31 
                 514.2 
               
               
                   
                 aminocyclopentanecarbonyl)morpholin-2- 
               
               
                   
                 yl)(6-fluoro-3′-methylbiphenyl-2- 
               
               
                   
                 yl)methoxy)ethylcarbamate 
               
               
                 8 
                 2-((S)-((R)-4-((1S,3R,4S)-3-amino-4- 
                 8 
                 1 
                 2.18 
                 514.2 
               
               
                   
                 hydroxycyclopentanecarbonyl)morpholin-2- 
               
               
                   
                 yl)(6-fluoro-3′-methylbiphenyl-2-yl)methoxy)- 
               
               
                   
                 N-ethylacetamide 
               
               
                 9 
                 ((1R,3S)-3-aminocyclopentyl)((R)-2-((R)- 
                 2 
                 1 
                 2.26 
                 517.2 
               
               
                   
                 1-(4′,6-difluoro-3′-methylbiphenyl-2-yl)-1- 
               
               
                   
                 hydroxy-5- 
               
               
                   
                 methoxypentyl)morpholino)methanone 
               
               
                 10 
                 ((1S,3R,4S)-3-amino-4- 
                 8 
                 1 
                 1.87 
                 518.2 
               
               
                   
                 hydroxycyclopentyl)((R)-2-((R)-1-(3-chloro-2- 
               
               
                   
                 (pyridin-3-yl)phenyl)-1-hydroxy-5- 
               
               
                   
                 methoxypentyl)morpholino)methanone 
               
               
                 11 
                 ((1S,3R,4S)-3-amino-4- 
                 8 
                 1 
                 2.12 
                 523.2 
               
               
                   
                 hydroxycyclopentyl)(2-(1-(3-chloro-2-(3- 
               
               
                   
                 methyl-1,2,4-oxadiazol-5-yl)phenyl)-1- 
               
               
                   
                 hydroxy-5- 
               
               
                   
                 methoxypentyl)morpholino)methanone 
               
               
                 12 
                 methyl 4-((R)-1-((1R,3S)-3- 
                 2 
                 1 
                 2.35 
                 524.3 
               
               
                   
                 aminocyclopentanecarbonyl)piperidin-3-yl)-4- 
               
               
                   
                 hydroxy-4-(2-(o- 
               
               
                   
                 tolyloxy)phenyl)butylcarbamate 
               
               
                 13 
                 N-(4-((R)-1-((1S,3R,4S)-3-amino-4- 
                 8 
                 1 
                 2.07 
                 524.3 
               
               
                   
                 hydroxycyclopentanecarbonyl)piperidin-3-yl)- 
               
               
                   
                 4-hydroxy-4-(2-(o- 
               
               
                   
                 tolyloxy)phenyl)butyl)acetamide 
               
               
                 14 
                 ((1S,3R,4S)-3-amino-4- 
                 8 
                   
                   
                 525.4 
               
               
                   
                 hydroxycyclopentyl)((3R)-3-(1-(2-(2,6- 
               
               
                   
                 dimethylphenoxy)phenyl)-1-hydroxy-5- 
               
               
                   
                 methoxypentyl)piperidin-1-yl)methanone 
               
               
                 15 
                 ((1R,3S)-3-aminocyclopentyl)((3R)-3-(1- 
                 2 
                 1 
                 2.41 
                 527.3 
               
               
                   
                 (6-fluoro-3′-methoxy-5′-methylbiphenyl-2-yl)- 
               
               
                   
                 1-hydroxy-5-methoxypentyl)piperidin-1- 
               
               
                   
                 yl)methanone 
               
               
                 16 
                 ((1R,3S)-3-aminocyclopentyl)((3R)-3-(1- 
                 2 
                 1 
                 2.56 
                 527.3 
               
               
                   
                 (6-chloro-3′-ethylbiphenyl-2-yl)-1-hydroxy-5- 
               
               
                   
                 methoxypentyl)piperidin-1-yl)methanone 
               
               
                 17 
                 ((1R,3S)-3-aminocyclopentyl)((3R)-3-(1- 
                 2 
                 1 
                 2.56 
                 527.3 
               
               
                   
                 (3-chloro-2-(2-methylbenzyl)phenyl)-1- 
               
               
                   
                 hydroxy-5-methoxypentyl)piperidin-1- 
               
               
                   
                 yl)methanone 
               
               
                 18 
                 ((1R,3S)-3-aminocyclopentyl)((3R)-3-(1- 
                 2 
                 1 
                 2.47 
                 527.3 
               
               
                   
                 (3-chloro-2-(3-methylbenzyl)phenyl)-1- 
               
               
                   
                 hydroxy-5-methoxypentyl)piperidin-1- 
               
               
                   
                 yl)methanone 
               
               
                 19 
                 ((1R,3S)-3-aminocyclopentyl)(2-(1-(6- 
                 2 
                 1 
                 2.31 
                 529.3 
               
               
                   
                 fluoro-3′-methoxy-5′-methylbiphenyl-2-yl)-1- 
               
               
                   
                 hydroxy-5- 
               
               
                   
                 methoxypentyl)morpholino)methanone 
               
               
                 20 
                 ((1R,3S)-3-aminocyclopentyl)((2R)-2-(1- 
                 2 
                 1 
                 2.45 
                 529.2 
               
               
                   
                 (6-chloro-3′-ethylbiphenyl-2-yl)-1-hydroxy-5- 
               
               
                   
                 methoxypentyl)morpholino)methanone 
               
               
                 21 
                 ((1R,3S)-3-aminocyclopentyl)((3R)-3-(1- 
                 2 
                 3 
                 2.94; 3.03 
                 529.2 
               
               
                   
                 (3-chloro-2-(o-tolyloxy)phenyl)-1-hydroxy-5- 
               
               
                   
                 methoxypentyl)piperidin-1-yl)methanone 
               
               
                 22 
                 ((1R,3S)-3-aminocyclopentyl)((3R)-3-(1- 
                 2 
                 3 
                 1.97 
                 529.3 
               
               
                   
                 (2-(2-chloro-6-methylphenoxy)phenyl)-1- 
               
               
                   
                 hydroxy-5-methoxypentyl)piperidin-1- 
               
               
                   
                 yl)methanone 
               
               
                 23 
                 ((1S,3R,4S)-3-amino-4- 
                 8 
                 1 
                 2.26 
                 533.3 
               
               
                   
                 hydroxycyclopentyl)((R)-2-((R)-1-(4′,6- 
               
               
                   
                 difluoro-3′-methylbiphenyl-2-yl)-1-hydroxy-5- 
               
               
                   
                 methoxypentyl)morpholino)methanone 
               
               
                 24 
                 methyl 4-((R)-1-((1S,3R,4S)-3-amino-4- 
                 8 
                 1 
                 2.31 
                 540.2 
               
               
                   
                 hydroxycyclopentanecarbonyl)piperidin-3-yl)- 
               
               
                   
                 4-hydroxy-4-(2-(o 
               
               
                   
                 tolyloxy)phenyl)butylcarbamate 
               
               
                 25 
                 methyl 4-((R)-1-((1R,2S)-2- 
                 6 
                 1 
                 2.40 
                 540.3 
               
               
                   
                 aminocyclopentanecarbonyl)piperidin-3-yl)-4- 
               
               
                   
                 (3′-ethyl-6-fluorobiphenyl-2-yl)-4- 
               
               
                   
                 hydroxybutylcarbamate 
               
               
                 26 
                 methyl 4-((R)-1-((1R,3S)-3- 
                 2 
                 1 
                 2.32 
                 540.3 
               
               
                   
                 aminocyclopentanecarbonyl)piperidin-3-yl)-4- 
               
               
                   
                 (3′-ethyl-6-fluorobiphenyl-2-yl)-4- 
               
               
                   
                 hydroxybutylcarbamate 
               
               
                 27 
                 (trans-4-aminocyclohexyl)((3R)-3-(1-(6- 
                 6 
                 1 
                 2.60 
                 555.3 
               
               
                   
                 chloro-3′-ethylbiphenyl-2-yl)-1-hydroxy-5- 
               
               
                   
                 methoxypentyl)piperidin-1-yl)methanone 
               
               
                 28 
                 1-((3R)-1-{[6-(aminomethyl)-3- 
                 4 
                 1 
                 2.51 
                 550.2 
               
               
                   
                 pyridinyl]carbonyl}-3-piperidinyl)-1-(6-chloro- 
               
               
                   
                 3′-ethyl-2-biphenylyl)-5-(methyloxy)-1- 
               
               
                   
                 pentanol 
               
               
                 29 
                 ((1S,3R,4S)-3-amino-4- 
                 8 
                 1 
                 2.35 
                 543.3 
               
               
                   
                 hydroxycyclopentyl)((3R)-3-(1-(6-fluoro-3′- 
               
               
                   
                 methoxy-5′-methylbiphenyl-2-yl)-1-hydroxy-5- 
               
               
                   
                 methoxypentyl)piperidin-1-yl)methanone 
               
               
                 30 
                 ((1S,3R,4S)-3-amino-4- 
                 8 
                 1 
                 2.52 
                 543.2 
               
               
                   
                 hydroxycyclopentyl)((3R)-3-(1-(6-chloro-3′- 
               
               
                   
                 ethylbiphenyl-2-yl)-1-hydroxy-5- 
               
               
                   
                 methoxypentyl)piperidin-1-yl)methanone 
               
               
                 31 
                 ((1R,3S)-3-aminocyclopentyl)((3R)-3-(1- 
                 2 
                 3 
                 3.14; 3.38 
                 543.3 
               
               
                   
                 (3-chloro-2-(2-ethylphenoxy)phenyl)-1- 
               
               
                   
                 hydroxy-5-methoxypentyl)piperidin-1- 
               
               
                   
                 yl)methanone 
               
               
                 32 
                 ((1R,3S)-3-aminocyclopentyl)((3R)-3-(1- 
                 2 
                 3 
                 2.05 
                 543.1 
               
               
                   
                 (3-chloro-2-(3-ethylphenoxy)phenyl)-1- 
               
               
                   
                 hydroxy-5-methoxypentyl)piperidin-1- 
               
               
                   
                 yl)methanone 
               
               
                 33 
                 ((1S,3R,4S)-3-amino-4- 
                 8 
                 1 
                 2.48 
                 543.2 
               
               
                   
                 hydroxycyclopentyl)((3R)-3-(1-(3-chloro-2-(2- 
               
               
                   
                 methylbenzyl)phenyl)-1-hydroxy-5- 
               
               
                   
                 methoxypentyl)piperidin-1-yl)methanone 
               
               
                 34 
                 ((1S,3R,4S)-3-amino-4- 
                 8 
                 1 
                 2.44 
                 543.2 
               
               
                   
                 hydroxycyclopentyl)((3R)-3-(1-(3-chloro-2-(3- 
               
               
                   
                 methylbenzyl)phenyl)-1-hydroxy-5- 
               
               
                   
                 methoxypentyl)piperidin-1-yl)methanone 
               
               
                 35 
                 ((1S,3R,4S)-3-amino-4- 
                 8 
                 1 
                 2.27 
                 545.2 
               
               
                   
                 hydroxycyclopentyl)(2-(1-(6-fluoro-3′- 
               
               
                   
                 methoxy-5′-methylbiphenyl-2-yl)-1-hydroxy-5- 
               
               
                   
                 methoxypentyl)morpholino)methanone 
               
               
                 36 
                 ((1S,3R,4S)-3-amino-4- 
                 8 
                 3 
                 2.89; 2.92 
                 545.3 
               
               
                   
                 hydroxycyclopentyl)((3R)-3-(1-(3-chloro-2-(o- 
               
               
                   
                 tolyloxy)phenyl)-1-hydroxy-5- 
               
               
                   
                 methoxypentyl)piperidin-1-yl)methanone 
               
               
                 38 
                 ((1S,3R,4S)-3-amino-4- 
                 8 
                 1 
                 2.32 
                 549.3 
               
               
                   
                 hydroxycyclopentyl)((2R)-2-((1R)-1-(6-chloro- 
               
               
                   
                 2′-fluoro-5′-methylbiphenyl-2-yl)-1-hydroxy-5- 
               
               
                   
                 methoxypentyl)morpholino)methanone 
               
               
                 39 
                 ((1R,3S)-3-aminocyclopentyl)((R)-3-((S)- 
                 2 
                 1 
                 2.20 
                 550.3 
               
               
                   
                 1-(3-chloro-2-(quinolin-3-yl)phenyl)-1-hydroxy- 
               
               
                   
                 5-methoxypentyl)piperidin-1-yl)methanone 
               
               
                 40 
                 ((1R,3S)-3-aminocyclopentyl)((R)-2-((R)- 
                 2 
                 1 
                 2.44 
                 551.2 
               
               
                   
                 1-(3-chloro-2-(naphthalen-2-yl)phenyl)-1- 
               
               
                   
                 hydroxy-5- 
               
               
                   
                 methoxypentyl)morpholino)methanone 
               
               
                 41 
                 ((1R,3S)-3-aminocyclopentyl)(2-(1-(3- 
                 2 
                 1 
                 2.10 
                 552.2 
               
               
                   
                 chloro-2-(quinolin-3-yl)phenyl)-1-hydroxy-5- 
               
               
                   
                 methoxypentyl)morpholino)methanone 
               
               
                 42 
                 methyl (4-hydroxy-4-((3R)-1-{[(1R,3S)-3- 
                 4 
                 1 
                 2.36 
                 538.2 
               
               
                   
                 (methylamino)cyclopentyl]carbonyl}-3- 
               
               
                   
                 piperidinyl)-4-{2-[(2- 
               
               
                   
                 methylphenyl)oxy]phenyl}butyl)carbamate 
               
               
                 43 
                 methyl 4-(6-fluoro-3′-methoxybiphenyl-2- 
                 4 
                 1 
                 2.41 
                 556.3 
               
               
                   
                 yl)-4-hydroxy-4-((R)-1-((1R,3S)-3- 
               
               
                   
                 (methylamino)cyclopentanecarbonyl)piperidin- 
               
               
                   
                 3-yl)butylcarbamate 
               
               
                 44 
                 N-(4-((R)-1-((1S,3R,4S)-3-amino-4- 
                 8 
                 1 
                 2.27 
                 556.3 
               
               
                   
                 hydroxycyclopentanecarbonyl)piperidin-3-yl)- 
               
               
                   
                 4-(6-chloro-3′-ethylbiphenyl-2-yl)-4- 
               
               
                   
                 hydroxybutyl)acetamide 
               
               
                 45 
                 methyl 4-((R)-1-((1R,3S)-3- 
                 2 
                 1 
                 2.42 
                 556.2 
               
               
                   
                 aminocyclopentanecarbonyl)piperidin-3-yl)-4- 
               
               
                   
                 (6-chloro-3′-ethylbiphenyl-2-yl)-4- 
               
               
                   
                 hydroxybutylcarbamate 
               
               
                 46 
                 methyl 4-((R)-4-((1R,3S)-3- 
                 2 
                 1 
                 2.31 
                 558.2 
               
               
                   
                 aminocyclopentanecarbonyl)morpholin-2-yl)- 
               
               
                   
                 4-(6-chloro-3′-ethylbiphenyl-2-yl)-4- 
               
               
                   
                 hydroxybutylcarbamate 
               
               
                 47 
                 ((1S,3R,4S)-3-amino-4- 
                 8 
                 3 
                 1.82 
                 559.0 
               
               
                   
                 hydroxycyclopentyl)((3R)-3-(1-(3-chloro-2-(3- 
               
               
                   
                 ethylphenoxy)phenyl)-1-hydroxy-5- 
               
               
                   
                 methoxypentyl)piperidin-1-yl)methanone 
               
               
                 48 
                 ((1S,3R,4S)-3-amino-4- 
                 8 
                 1 
                 2.17 
                 561.2 
               
               
                   
                 hydroxycyclopentyl)((R)-2-((R)-1-(6-fluoro- 
               
               
                   
                 3′,5′-dimethoxybiphenyl-2-yl)-1-hydroxy-5- 
               
               
                   
                 methoxypentyl)morpholino)methanone 
               
               
                 49 
                 ((1S,3R,4S)-3-amino-4- 
                 8 
                 2 
                 1.64 
                 561.3 
               
               
                   
                 hydroxycyclopentyl)((R)-2-((R)-1-(6-chloro-3′- 
               
               
                   
                 (methoxymethyl)biphenyl-2-yl)-1-hydroxy-5- 
               
               
                   
                 methoxypentyl)morpholino)methanone 
               
               
                 50 
                 (4-(aminomethyl)cyclohexyl)((2R)-2- 
                 6 
                 1 
                 3.03 
                 561.3 
               
               
                   
                 ((1R)-1-(6-chloro-2′-fluoro-5′-methylbiphenyl- 
               
               
                   
                 2-yl)-1-hydroxy-5- 
               
               
                   
                 methoxypentyl)morpholino)methanone 
               
               
                 51 
                 ((1S,3R,4S)-3-amino-4- 
                 8 
                 1 
                 2.12 
                 566.2 
               
               
                   
                 hydroxycyclopentyl)((R)-3-((R)-1-(3-chloro-2- 
               
               
                   
                 (quinolin-3-yl)phenyl)-1-hydroxy-5- 
               
               
                   
                 methoxypentyl)piperidin-1-yl)methanone 
               
               
                 52 
                 ((1S,3R,4S)-3-amino-4- 
                 8 
                 1 
                 2.41 
                 567.2 
               
               
                   
                 hydroxycyclopentyl)((R)-2-((R)-1-(3-chloro-2- 
               
               
                   
                 (naphthalen-2-yl)phenyl)-1-hydroxy-5- 
               
               
                   
                 methoxypentyl)morpholino)methanone 
               
               
                 53 
                 ((1S,3R,4S)-3-amino-4- 
                 8 
                 1 
                 2.07 
                 568.2 
               
               
                   
                 hydroxycyclopentyl)(2-(1-(3-chloro-2- 
               
               
                   
                 (quinolin-3-yl)phenyl)-1-hydroxy-5- 
               
               
                   
                 methoxypentyl)morpholino)methanone 
               
               
                 54 
                 ((1S,3R,4S)-3-amino-4- 
                 8 
                 1 
                 2.09 
                 568.2 
               
               
                   
                 hydroxycyclopentyl)((2R)-2-((1R)-1-(3-chloro- 
               
               
                   
                 2-(isoquinolin-4-yl)phenyl)-1-hydroxy-5- 
               
               
                   
                 methoxypentyl)morpholino)methanone 
               
               
                 55 
                 methyl 4-(6-chloro-3′-ethylbiphenyl-2-yl)- 
                 6 
                 2 
                 1.80 
                 570.5 
               
               
                   
                 4-hydroxy-4-((R)-1-((1R,3S)-3- 
               
               
                   
                 (methylamino)cyclopentanecarbonyl)piperidin- 
               
               
                   
                 3-yl)butylcarbamate 
               
               
                 56 
                 methyl 4-((R)-1-((1R,3S)-3- 
                 2 
                 1 
                 2.40 
                 570.2 
               
               
                   
                 aminocyclopentanecarbonyl)piperidin-3-yl)-4- 
               
               
                   
                 (6-chloro-3′-isopropylbiphenyl-2-yl)-4- 
               
               
                   
                 hydroxybutylcarbamate 
               
               
                 57 
                 methyl 4-((R)-1-((1S,3R,4S)-3-amino-4- 
                 8 
                 1 
                 2.35 
                 572.3 
               
               
                   
                 hydroxycyclopentanecarbonyl)piperidin-3-yl)- 
               
               
                   
                 4-(6-chloro-3′-ethylbiphenyl-2-yl)-4- 
               
               
                   
                 hydroxybutylcarbamate 
               
               
                 58 
                 methyl 4-(6-chloro-3′-methoxybiphenyl-2- 
                 4 
                 1 
                 2.40 
                 572.2 
               
               
                   
                 yl)-4-hydroxy-4-((R)-1-((1R,3S)-3- 
               
               
                   
                 (methylamino)cyclopentanecarbonyl)piperidin- 
               
               
                   
                 3-yl)butylcarbamate 
               
               
                 59 
                 ((1S,3R,4S)-3-amino-4- 
                 8 
                 1 
                 2.31 
                 577.3 
               
               
                   
                 hydroxycyclopentyl)((R)-2-((R)-1-(6-chloro- 
               
               
                   
                 3′,5′-dimethoxybiphenyl-2-yl)-1-hydroxy-5- 
               
               
                   
                 methoxypentyl)morpholino)methanone 
               
               
                 60 
                 methyl 4-((R)-1-(trans-4- 
                 6 
                 1 
                 2.43 
                 584.3 
               
               
                   
                 (aminomethyl)cyclohexanecarbonyl)piperidin- 
               
               
                   
                 3-yl)-4-(6-chloro-3′-ethylbiphenyl-2-yl)-4- 
               
               
                   
                 hydroxybutylcarbamate 
               
               
                 61 
                 methyl 4-((R)-1-((1S,3R,4S)-3-amino-4- 
                 8 
                 1 
                 2.37 
                 586.2 
               
               
                   
                 hydroxycyclopentanecarbonyl)piperidin-3-yl)- 
               
               
                   
                 4-(6-chloro-3′-isopropylbiphenyl-2-yl)-4- 
               
               
                   
                 hydroxybutylcarbamate 
               
               
                 62 
                 ((1R,3S)-3-aminocyclopentyl)((R)-3-((S)- 
                 2 
                 1 
                 2.61 
                 595.3 
               
               
                   
                 1-(3′-ethoxy-6-fluoro-5′- 
               
               
                   
                 (trifluoromethyl)biphenyl-2-yl)-1-hydroxy-5- 
               
               
                   
                 methoxypentyl)piperidin-1-yl)methanone 
               
               
                 63 
                 methyl 4-((R)-1-((1S,3R,4S)-3-amino-4- 
                 8 
                 1 
                 2.34 
                 595.2 
               
               
                   
                 hydroxycyclopentanecarbonyl)piperidin-3-yl)- 
               
               
                   
                 4-(3-chloro-2-(quinolin-3-yl)phenyl)-4- 
               
               
                   
                 hydroxybutylcarbamate 
               
               
                 64 
                 ((1R,3S)-3-aminocyclopentyl)((R)-2-((R)- 
                 2 
                 1 
                 2.54 
                 597.2 
               
               
                   
                 1-(3′-ethoxy-6-fluoro-5′- 
               
               
                   
                 (trifluoromethyl)biphenyl-2-yl)-1-hydroxy-5- 
               
               
                   
                 methoxypentyl)morpholino)methanone 
               
               
                 65 
                 ((1S,3R,4S)-3-amino-4- 
                 8 
                 1 
                 2.54 
                 611.3 
               
               
                   
                 hydroxycyclopentyl)((R)-3-((S)-1-(3′-ethoxy-6- 
               
               
                   
                 fluoro-5′-(trifluoromethyl)biphenyl-2-yl)-1- 
               
               
                   
                 hydroxy-5-methoxypentyl)piperidin-1- 
               
               
                   
                 yl)methanone 
               
               
                 66 
                 ((1S,3R,4S)-3-amino-4- 
                 8 
                 1 
                 2.50 
                 613.2 
               
               
                   
                 hydroxycyclopentyl)(2-(1-(3′-ethoxy-6-fluoro- 
               
               
                   
                 5′-(trifluoromethyl)biphenyl-2-yl)-1-hydroxy-5- 
               
               
                   
                 methoxypentyl)morpholino)methanone 
               
               
                 67 
                 ((1R,3S)-3-aminocyclopentyl)((R)-2-((R)- 
                 2 
                 1 
                 2.21 
                 545.2 
               
               
                   
                 1-(6-fluoro-3′,5′-dimethoxybiphenyl-2-yl)-1- 
               
               
                   
                 hydroxy-5- 
               
               
                   
                 methoxypentyl)morpholino)methanone 
               
               
                 68 
                 ((1R,3S)-3-aminocyclopentyl)((2R)-2- 
                 2 
                 1 
                 2.07 
                 552.2 
               
               
                   
                 ((1R)-1-(3-chloro-2-(isoquinolin-4-yl)phenyl)- 
               
               
                   
                 1-hydroxy-5- 
               
               
                   
                 methoxypentyl)morpholino)methanone 
               
               
                 69 
                 methyl (4-((3R)-1-{[(1R,3S)-3- 
                 2 
                 3 
                 2.65; 2.78 
                 558.2 
               
               
                   
                 aminocyclopentyl]carbonyl}-3-piperidinyl)-4- 
               
               
                   
                 {3-chloro-2-[(2-methylphenyl)oxy]phenyl}-4- 
               
               
                   
                 hydroxybutyl)carbamate 
               
               
                 70 
                 methyl (4-((3R)-1-{[(1R,3S)-3- 
                 2 
                 3 
                 2.78; 2.92 
                 572.3 
               
               
                   
                 aminocyclopentyl]carbonyl}-3-piperidinyl)-4- 
               
               
                   
                 {3-chloro-2-[(2-ethylphenyl)oxy]phenyl}-4- 
               
               
                   
                 hydroxybutyl)carbamate 
               
               
                 71 
                 methyl (4-((3R)-1-{[(1S,3R,4S)-3-amino- 
                 8 
                 3 
                 2.61; 2.70 
                 574.2 
               
               
                   
                 4-hydroxycyclopentyl]carbonyl}-3-piperidinyl)- 
               
               
                   
                 4-{3-chloro-2-[(2-methylphenyl)oxy]phenyl}-4- 
               
               
                   
                 hydroxybutyl)carbamate 
               
               
                 72 
                 methyl (4-((3R)-1-{[(1S,3R,4S)-3-amino- 
                 8 
                 3 
                 2.75; 2.86 
                 588.2 
               
               
                   
                 4-hydroxycyclopentyl]carbonyl}-3-piperidinyl)- 
               
               
                   
                 4-{3-chloro-2-[(2-ethylphenyl)oxy]phenyl}-4- 
               
               
                   
                 hydroxybutyl)carbamate 
               
               
                 73 
                 methyl [4-((3R)-1-{[(1S,3R,4S)-3-amino- 
                 8 
                 1 
                 2.36 
                 556.3 
               
               
                   
                 4-hydroxycyclopentyl]carbonyl}-3-piperidinyl)- 
               
               
                   
                 4-(3′-ethyl-6-fluoro-2-biphenylyl)-4- 
               
               
                   
                 hydroxybutyl]carbamate 
               
               
                 74 
                 methyl {4-(6-chloro-3′-ethyl-2-biphenylyl)- 
                 6 
                 1 
                 2.46 
                 598.3 
               
               
                   
                 4-hydroxy-4-[(3R)-1-({trans-4- 
               
               
                   
                 [(methylamino)methyl]cyclohexyl}carbonyl)-3- 
               
               
                   
                 piperidinyl]butyl}carbamate 
               
               
                 75 
                 methyl [4-((3R)-1-{[(1R,2S)-2- 
                 6 
                 1 
                 2.39 
                 540.3 
               
               
                   
                 aminocyclopentyl]carbonyl}-3-piperidinyl)-4- 
               
               
                   
                 (3′-ethyl-6-fluoro-2-biphenylyl)-4- 
               
               
                   
                 hydroxybutyl]carbamate 
               
               
                 76 
                 (1R)-1-((2R)-4-{[6-(aminomethyl)-3- 
                 4 
                 1 
                 2.42 
                 552.2 
               
               
                   
                 pyridinyl]carbonyl}-2-morpholinyl)-1-(6-chloro- 
               
               
                   
                 3′-ethyl-2-biphenylyl)-5-(methyloxy)-1- 
               
               
                   
                 pentanol 
               
               
                 77 
                 methyl [4-((3R)-1-{[6-(aminomethyl)-3- 
                 4 
                 1 
                 2.40 
                 579.2 
               
               
                   
                 pyridinyl]carbonyl}-3-piperidinyl)-4-(6-chloro- 
               
               
                   
                 3′-ethyl-2-biphenylyl)-4- 
               
               
                   
                 hydroxybutyl]carbamate 
               
               
                 78 
                 1-{(3R)-1-[(cis-4- 
                 6 
                 1 
                 2.55 
                 555.3 
               
               
                   
                 aminocyclohexyl)acetyl]-3-piperidinyl}-1-(6- 
               
               
                   
                 chloro-3′-ethyl-2-biphenylyl)-5-(methyloxy)-1- 
               
               
                   
                 pentanol 
               
               
                 79 
                 (1S)-1-{(3R)-1-[(trans-4- 
                 6 
                 1 
                 2.55 
                 555.3 
               
               
                   
                 aminocyclohexyl)acetyl]-3-piperidinyl}-1-(6- 
               
               
                   
                 chloro-3′-ethyl-2-biphenylyl)-5-(methyloxy)-1- 
               
               
                   
                 pentanol 
               
               
                 80 
                 1-((3R)-1-{[(1R,2S)-2- 
                 6 
                 1 
                 2.63 
                 527.3 
               
               
                   
                 aminocyclopentyl]carbonyl}-3-piperidinyl)-1- 
               
               
                   
                 (6-chloro-3′-ethyl-2-biphenylyl)-5-(methyloxy)- 
               
               
                   
                 1-pentanol 
               
               
                 81 
                 (1R)-1-(6-chloro-3′-ethyl-2-biphenylyl)-1- 
                 6 
                 1 
                 2.48 
                 543.2 
               
               
                   
                 ((2R)-4-{[(1R,3S)-3- 
               
               
                   
                 (methylamino)cyclopentyl]carbonyl}-2- 
               
               
                   
                 morpholinyl)-5-(methyloxy)-1-pentanol 
               
               
                 82 
                 1-(6-chloro-3′-ethyl-2-biphenylyl)-1-((3R)- 
                 6 
                 1 
                 2.52 
                 541.3 
               
               
                   
                 1-{[(1R,3S)-3- 
               
               
                   
                 (methylamino)cyclopentyl]carbonyl}-3- 
               
               
                   
                 piperidinyl)-5-(methyloxy)-1-pentanol 
               
               
                 83 
                 (1S,2R,4S)-4-({(2R)-2-[(1R)-1-(6-chloro- 
                 10 
                 1 
                 2.39 
                 589.2 
               
               
                   
                 3′-ethyl-2-biphenylyl)-1-hydroxy-5- 
               
               
                   
                 (methyloxy)pentyl]-4-morpholinyl}carbonyl)-2- 
               
               
                   
                 [(2-hydroxyethyl)aminolcyclopentanol 
               
               
                 84 
                 methyl {4-(6-chloro-3′-ethyl-2-biphenylyl)- 
                 9 
                 1 
                 2.49 
                 616.2 
               
               
                   
                 4-hydroxy-4-[(3R)-1-({(1S,3S,4R)-3-hydroxy- 
               
               
                   
                 4-[(2- 
               
               
                   
                 hydroxyethyl)amino]cyclopentyl}carbonyl)-3- 
               
               
                   
                 piperidinyl]butyl}carbamate 
               
               
                 85 
                 1-(6-chloro-3′-ethyl-2-biphenylyl)-1-[(3R)- 
                 6 
                 1 
                 2.45 
                 569.3 
               
               
                   
                 1-({trans-4- 
               
               
                   
                 [(methylamino)methyl]cyclohexyl}carbonyl)-3- 
               
               
                   
                 piperidinyl]-5-(methyloxy)-1-pentanol 
               
               
                 86 
                 (1S,2R,4S)-4-({(2R)-2-[(1R)-1-(6-chloro- 
                 10 
                 1 
                 2.53 
                 642.2 
               
               
                   
                 3′-ethyl-2-biphenylyl)-1-hydroxy-5- 
               
               
                   
                 (methyloxy)pentyl]-4-morpholinyl}carbonyl)-2- 
               
               
                   
                 [(1,3-thiazol-2-ylmethyl)amino]cyclopentanol 
               
               
                 87 
                 methyl [4-((3R)-1-{[(1R,3S)-3- 
                 6 
                 1 
                 2.47 
                 570.2 
               
               
                   
                 aminocyclohexyl]carbonyl}-3-piperidinyl)-4-(6- 
               
               
                   
                 chloro-3′-ethyl-2-biphenylyl)-4- 
               
               
                   
                 hydroxybutyl]carbamate 
               
               
                 88 
                 N-{4-(6-chloro-3′-methyl-2-biphenylyl)-4- 
                 6 
                 1 
                 2.46 
                 568.3 
               
               
                   
                 hydroxy-4-[(3R)-1-({trans-4- 
               
               
                   
                 [(methylamino)methyl]cyclohexyl}carbonyl)-3- 
               
               
                   
                 piperidinyl]butyl}acetamide 
               
               
                 89 
                 N-[4-(6-chloro-3′-methyl-2-biphenylyl)-4- 
                 6 
                 1 
                 2.44 
                 540.3 
               
               
                   
                 hydroxy-4-((3R)-1-{[(1R,3S)-3- 
               
               
                   
                 (methylamino)cyclopentyl]carbonyl}-3- 
               
               
                   
                 piperidinyl)butyl]acetamide 
               
               
                 90 
                 (1R)-1-(6-chloro-3′-ethyl-2-biphenylyl)-1- 
                 10 
                 1 
                 2.53 
                 638.3 
               
               
                   
                 {(2R)-4-[((1R,3S)-3-{[(2,5-dimethyl-1,3-oxazol- 
               
               
                   
                 4-yl)methyl]amino}cyclopentyl)carbonyl]-2- 
               
               
                   
                 morpholinyl}-5-(methyloxy)-1-pentanol 
               
               
                 91 
                 N-[4-((3R)-1-{[trans-4- 
                 6 
                 1 
                 2.42 
                 554.3 
               
               
                   
                 (aminomethyl)cyclohexyl]carbonyl}-3- 
               
               
                   
                 piperidinyl)-4-(6-chloro-3′-methyl-2- 
               
               
                   
                 biphenylyl)-4-hydroxybutyl]acetamide 
               
               
                 92 
                 methyl {4-(4,6-difluoro-3′-methyl-2- 
                 6 
                 1 
                 2.43 
                 586.3 
               
               
                   
                 biphenylyl)-4-hydroxy-4-[(3R)-1-({trans-4- 
               
               
                   
                 [(methylamino)methyl]cyclohexyl}carbonyl)-3- 
               
               
                   
                 piperidinyl]butyl}carbamate 
               
               
                 93 
                 methyl [4-hydroxy-4-((3R)-1-{[(1R,3S)-3- 
                 6 
                 1 
                 2.51 
                 576.3 
               
               
                   
                 (methylamino)cyclopentyl]carbonyl}-3- 
               
               
                   
                 piperidinyl)-4-(2′,4,6-trifluoro-5′-methyl-2- 
               
               
                   
                 biphenylyl)butyl]carbamate 
               
               
                 94 
                 methyl [4-hydroxy-4-[(3R)-1-({trans-4- 
                 6 
                 1 
                 2.38 
                 604.3 
               
               
                   
                 [(methylamino)methyl]cyclohexyl}carbonyl)-3- 
               
               
                   
                 piperidinyl]-4-(2′,4,6-trifluoro-5′-methyl-2- 
               
               
                   
                 biphenylyl)butyl]carbamate 
               
               
                 95 
                 methyl [4-(6-chloro-3′-methyl-2- 
                 6 
                 1 
                 2.39 
                 556.3 
               
               
                   
                 biphenylyl)-4-hydroxy-4-((3R)-1-{[(1R,3 S)-3- 
               
               
                   
                 (methylamino)cyclopentyl]carbonyl}-3- 
               
               
                   
                 piperidinyl)butyl]carbamate 
               
               
                 96 
                 (1R)-1-(6-chloro-3′-ethyl-2-biphenylyl)-1- 
                 6 
                 1 
                 2.53 
                 571.3 
               
               
                   
                 [(2R)-4-({trans-4- 
               
               
                   
                 [(methylamino)methyl]cyclohexyl}carbonyl)-2- 
               
               
                   
                 morpholinyl]-5-(methyloxy)-1-pentanol 
               
               
                 97 
                 methyl [(4R)-4-((2R)-4-{[(1S,3R,4S)-3- 
                 8 
                 1 
                 2.44 
                 558.3 
               
               
                   
                 amino-4-hydroxycyclopentyl]carbonyl}-2- 
               
               
                   
                 morpholinyl)-4-(3′-ethyl-6-fluoro-2-biphenylyl)- 
               
               
                   
                 4-hydroxybutyl]carbamate 
               
               
                 98 
                 methyl {(4R)-4-(3′-ethyl-6-fluoro-2- 
                 6 
                 1 
                 2.18 
                 584.3 
               
               
                   
                 biphenylyl)-4-hydroxy-4-[(2R)-4-({trans-4- 
               
               
                   
                 [(methylamino)methyl]cyclohexyl}carbonyl)-2- 
               
               
                   
                 morpholinyl]butyl}carbamate 
               
               
                 99 
                 (1S,2R,4S)-2-amino-4-({(2R)-2-[(1R)-1- 
                 8 
                 1 
                 2.3 
                 546.2 
               
               
                   
                 [2-chloro-3-(3-ethylphenyl)-4-pyridinyl]-1- 
               
               
                   
                 hydroxy-5-(methyloxy)pentyl]-4- 
               
               
                   
                 morpholinyl}carbonyl)cyclopentanol 
               
               
                 100 
                 (1R)-1-((2R)-4-{[(1R,3S)-3- 
                 2 
                 1 
                 2.37 
                 530.2 
               
               
                   
                 aminocyclopentyl]carbonyl}-2-morpholinyl)-1- 
               
               
                   
                 [2-chloro-3-(3-ethylphenyl)-4-pyridinyl]-5- 
               
               
                   
                 (methyloxy)-1-pentanol 
               
               
                 101 
                 (1S,2R,4S)-2-amino-4-({(2R)-2-[(1R)-1- 
                 8 
                 1 
                 2.43 
                 573.2 
               
               
                   
                 [2-(1-benzothien-3-yl)-3-chlorophenyl]-1- 
               
               
                   
                 hydroxy-5-(methyloxy)pentyl]-4- 
               
               
                   
                 morpholinyl}carbonyl)cyclopentanol 
               
               
                 102 
                 (1R)-1-((2R)-4-{[(1R,3S)-3- 
                 2 
                 1 
                 2.42 
                 557.2 
               
               
                   
                 aminocyclopentyl]carbonyl}-2-morpholinyl)-1- 
               
               
                   
                 [2-(1-benzothien-3-yl)-3-chlorophenyl]-5- 
               
               
                   
                 (methyloxy)-1-pentanol 
               
               
                 103 
                 (1R)-1-[4-chloro-3-(3-ethylphenyl)-2- 
                 6 
                 1 
                 2.14 
                 544.3 
               
               
                   
                 pyridinyl]-1-((2R)-4-{[(1R,3S)-3- 
               
               
                   
                 (methylamino)cyclopentyl]carbonyl}-2- 
               
               
                   
                 morpholinyl)-5-(methyloxy)-1-pentanol 
               
               
                 104 
                 methyl {4-[2-chloro-3-(3-ethylphenyl)-4- 
                 6 
                 1 
                 2.33 
                 599.3 
               
               
                   
                 pyridinyl]-4-hydroxy-4-[(3R)-1-({trans-4- 
               
               
                   
                 [(methylamino)methyl]cyclohexyl}carbonyl)-3- 
               
               
                   
                 piperidinyl]butyl}carbamate 
               
               
                 105 
                 methyl [4-[2-chloro-3-(3-ethylphenyl)-4- 
                 6 
                 1 
                 2.49 
                 571.2 
               
               
                   
                 pyridinyl]-4-hydroxy-4-((3R)-1-{[(1R,3S)-3- 
               
               
                   
                 (methylamino)cyclopentyl]carbonyl}-3- 
               
               
                   
                 piperidinyl)butyl]carbamate 
               
               
                 106 
                 methyl {4-{3-chloro-2-[4-(1-methylethyl)- 
                 6 
                 1 
                 2.42 
                 664.3 
               
               
                   
                 2-quinazolinyl]phenyl}-4-hydroxy-4-[(3R)-1- 
               
               
                   
                 ({trans-4- 
               
               
                   
                 [(methylamino)methyl]cyclohexyl}carbonyl)-3- 
               
               
                   
                 piperidinyl]butyl}carbamate 
               
               
                 107 
                 methyl [4-{3-chloro-2-[4-(1-methylethyl)- 
                 6 
                 1 
                 2.45 
                 636.3 
               
               
                   
                 2-quinazolinyl]phenyl}-4-hydroxy-4-((3R)-1- 
               
               
                   
                 {[(1R,3S)-3- 
               
               
                   
                 (methylamino)cyclopentyl]carbonyl}-3- 
               
               
                   
                 piperidinyl)butyl]carbamate 
               
               
                 108 
                 1-((3R)-1-{[(1R,3S)-3- 
                 2 
                 3 
                 3.01 
                 529.2 
               
               
                   
                 aminocyclopentyl]carbonyl}-3-piperidinyl)-1- 
               
               
                   
                 {3-chloro-2-[(3-methylphenyl)oxy]phenyl}-5- 
               
               
                   
                 (methyloxy)-1-pentanol 
               
               
                 109 
                 (1S,2R,4S)-2-amino-4-({(3R)-3-[1-{3- 
                 8 
                 3 
                 2.87 
                 545.2 
               
               
                   
                 chloro-2-[(3-methylphenyl)oxy]phenyl}-1- 
               
               
                   
                 hydroxy-5-(methyloxy)pentyl]-1- 
               
               
                   
                 piperidinyl}carbonyl)cyclopentanol 
               
               
                 110 
                 methyl (4-((3R)-1-{[(1R,3S)-3- 
                 2 
                 3 
                 3.4 
                 558.1 
               
               
                   
                 aminocyclopentyl]carbonyl}-3-piperidinyl)-4- 
               
               
                   
                 {3-chloro-2-[(3-methylphenyl)oxy]phenyl}-4- 
               
               
                   
                 hydroxybutyl)carbamate 
               
               
                 111 
                 methyl (4-((3R)-1-{[(1S,3R,4S)-3-amino- 
                 8 
                 3 
                 3.31 
                 574.1 
               
               
                   
                 4-hydroxycyclopentyl]carbonyl}-3-piperidinyl)- 
               
               
                   
                 4-{3-chloro-2-[(3-methylphenyl)oxy]phenyl}-4- 
               
               
                   
                 hydroxybutyl)carbamate 
               
               
                 112 
                 methyl (4-((3R)-1-{[(1R,3S)-3- 
                 2 
                 3 
                 3.52 
                 538.3 
               
               
                   
                 aminocyclopentyl]carbonyl}-3-piperidinyl)-4- 
               
               
                   
                 {2-[(2,6-dimethylphenyl)oxy]phenyl}-4- 
               
               
                   
                 hydroxybutyl)carbamate 
               
               
                 113 
                 methyl (4-((3R)-1-{[(1S,3R,4S)-3-amino- 
                 8 
                 3 
                 3.41 
                 554.2 
               
               
                   
                 4-hydroxycyclopentyl]carbonyl}-3-piperidinyl)- 
               
               
                   
                 4-{2-[(2,6-dimethylphenyl)oxy]phenyl}-4- 
               
               
                   
                 hydroxybutyl)carbamate 
               
               
                 114 
                 methyl {4-{3-chloro-2-[8-(1-methylethyl)- 
                 6 
                 3 
                 1.88 
                 663.2 
               
               
                   
                 2-quinolinyl]phenyl}-4-hydroxy-4-[(3R)-1- 
               
               
                   
                 ({trans-4- 
               
               
                   
                 [(methylamino)methyl]cyclohexyl}carbonyl)-3- 
               
               
                   
                 piperidinyl]butyl}carbamate 
               
               
                 115 
                 methyl {4-[3-chloro-2-(8-methyl-2- 
                 6 
                 3 
                 1.67 
                 635.2 
               
               
                   
                 quinolinyl)phenyl]-4-hydroxy-4-[(3R)-1-({trans- 
               
               
                   
                 4-[(methylamino)methyl]cyclohexyl}carbonyl)- 
               
               
                   
                 3-piperidinyl]butyl}carbamate 
               
               
                 116 
                 methyl [4-[3-fluoro-2-(3- 
                 6 
                 1 
                 2.28 
                 577.3 
               
               
                   
                 quinolinyl)phenyl]-4-hydroxy-4-((3R)-1- 
               
               
                   
                 {[(1R,3S)-3- 
               
               
                   
                 (methylamino)cyclopentyl]carbonyl}-3- 
               
               
                   
                 piperidinyl)butyl]carbamate 
               
               
                 117 
                 methyl [4-{2-chloro-3-[3-(1- 
                 6 
                 1 
                 2.37 
                 585.3 
               
               
                   
                 methylethyl)phenyl]-4-pyridinyl}-4-hydroxy-4- 
               
               
                   
                 ((3R)-1-{[(1R,3S)-3- 
               
               
                   
                 (methylamino)cyclopentyl]carbonyl}-3- 
               
               
                   
                 piperidinyl)butyl]carbamate 
               
               
                 118 
                 methyl [4-[3-chloro-2-(5-methyl-2- 
                 6 
                 1 
                 2.52 
                 546.2 
               
               
                   
                 furanyl)phenyl]-4-hydroxy-4-((3R)-1-{[(1R,3S)- 
               
               
                   
                 3-(methylamino)cyclopentyl]carbonyl}-3- 
               
               
                   
                 piperidinyl)butyl]carbamate 
               
               
                 119 
                 methyl {4-((3R)-1-{[(1S,3R,4S)-3-amino- 
                 8 
                 1 
                 2.36 
                 548.2 
               
               
                   
                 4-hydroxycyclopentyl]carbonyl}-3-piperidinyl)- 
               
               
                   
                 4-[3-chloro-2-(5-methyl-2-furanyl)phenyl]-4- 
               
               
                   
                 hydroxybutyl}carbamate 
               
               
                 120 
                 (1R)-1-{2-chloro-3-[3-(1- 
                 6 
                 1 
                 2.27 
                 586.2 
               
               
                   
                 methylethyl)phenyl]-4-pyridinyl}-1-[(2R)-4- 
               
               
                   
                 ({trans-4- 
               
               
                   
                 [(methylamino)methyl]cyclohexyl}carbonyl)-2- 
               
               
                   
                 morpholinyl]-5-(methyloxy)-1-pentanol 
               
               
                 121 
                 (1R)-1-{2-chloro-3-[3-(1- 
                 6 
                 1 
                 2.27 
                 558.2 
               
               
                   
                 methylethyl)phenyl]-4-pyridinyl}-1-((2R)-4- 
               
               
                   
                 {[(1R,3S)-3- 
               
               
                   
                 (methylamino)cyclopentyl]carbonyl}-2- 
               
               
                   
                 morpholinyl)-5-(methyloxy)-1-pentanol 
               
               
                 122 
                 (1S,2R,4S)-2-amino-4-({(2R)-2-[(1R)-1- 
                 8 
                 1 
                 2.2 
                 560.2 
               
               
                   
                 {2-chloro-3-[3-(1-methylethyl)phenyl]-4- 
               
               
                   
                 pyridinyl}-1-hydroxy-5-(methyloxy)pentyl]-4- 
               
               
                   
                 morpholinyl}carbonyl)cyclopentanol 
               
               
                 123 
                 methyl {4-[5-chloro-4-(3-ethylphenyl)-3- 
                 6 
                 1 
                 2.14 
                 599.3 
               
               
                   
                 pyridinyl]-4-hydroxy-4-[(3R)-1-({trans-4- 
               
               
                   
                 [(methylamino)methyl]cyclohexyl}carbonyl)-3- 
               
               
                   
                 piperidinyl]butyl}carbamate 
               
               
                 124 
                 methyl [4-[5-chloro-4-(3-ethylphenyl)-3- 
                 6 
                 1 
                 2.14 
                 571.2 
               
               
                   
                 pyridinyl]-4-hydroxy-4-((3R)-1-{[(1R,3S)-3- 
               
               
                   
                 (methylamino)cyclopentyl]carbonyl}-3- 
               
               
                   
                 piperidinyl)butyl]carbamate 
               
               
                 125 
                 methyl {4-{5-chloro-4-[3-(1- 
                 6 
                 1 
                 2.2 
                 613.2 
               
               
                   
                 methylethyl)phenyl]-3-pyridinyl}-4-hydroxy-4- 
               
               
                   
                 [(3R)-1-({trans-4- 
               
               
                   
                 [(methylamino)methyl]cyclohexyl}carbonyl)-3- 
               
               
                   
                 piperidinyl]butyl}carbamate 
               
               
                 126 
                 methyl [4-{5-chloro-4-[3-(1- 
                 6 
                 1 
                 2.21 
                 585.3 
               
               
                   
                 methylethyl)phenyl]-3-pyridinyl}-4-hydroxy-4- 
               
               
                   
                 ((3R)-1-{[(1R,3S)-3- 
               
               
                   
                 (methylamino)cyclopentyl]carbonyl}-3- 
               
               
                   
                 piperidinyl)butyl]carbamate 
               
               
                 127 
                 methyl {4-[6-fluoro-3′-(1-methylethyl)-2- 
                 6 
                 1 
                 2.44 
                 596.3 
               
               
                   
                 biphenylyl]-4-hydroxy-4-[(3R)-1-({trans-4- 
               
               
                   
                 [(methylamino)methyl]cyclohexyl}carbonyl)-3- 
               
               
                   
                 piperidinyl]butyl}carbamate 
               
               
                 128 
                 methyl [4-(6-chloro-3′-fluoro-5′-methyl-2- 
                 6 
                 1 
                 2.26 
                 574.3 
               
               
                   
                 biphenylyl)-4-hydroxy-4-((3R)-1-{[(1R,3S)-3- 
               
               
                   
                 (methylamino)cyclopentyl]carbonyl}-3- 
               
               
                   
                 piperidinyl)butyl]carbamate 
               
               
                 129 
                 methyl [4-(3′,6-difluoro-5′-methyl-2- 
                 6 
                 1 
                 2.36 
                 558.3 
               
               
                   
                 biphenylyl)-4-hydroxy-4-((3R)-1-{[(1R,3S)-3- 
               
               
                   
                 (methylamino)cyclopentyl]carbonyl}-3- 
               
               
                   
                 piperidinyl)butyl]carbamate 
               
               
                 130 
                 (1S,2R,4S)-2-amino-4-({(3R)-3-[1-{3- 
                 8 
                 3 
                 3.23 
                 559.2 
               
               
                   
                 chloro-2-[(2-ethylphenyl)oxy]phenyl}-1- 
               
               
                   
                 hydroxy-5-(methyloxy)pentyl]-1- 
               
               
                   
                 piperidinyl}carbonyl)cyclopentanol 
               
               
                 131 
                 methyl {4-(3′-ethyl-6-fluoro-2-biphenylyl)- 
                 6 
                 1 
                 2.43 
                 582.3 
               
               
                   
                 4-hydroxy-4-[(3R)-1-({trans-4- 
               
               
                   
                 [(methylamino)methyl]cyclohexyl}carbonyl)-3- 
               
               
                   
                 piperidinyl]butyl}carbamate 
               
               
                 132 
                 (1S,2R,4S)-2-amino-4-({(3R)-3-[1-{2-[(2- 
                 8 
                 3 
                 3.21 
                 545.1 
               
               
                   
                 chloro-6-methylphenyl)oxy]phenyl}-1-hydroxy- 
               
               
                   
                 5-(methyloxy)pentyl]-1- 
               
               
                   
                 piperidinyl}carbonyl)cyclopentanol 
               
               
                 133 
                 (1S,2R,4S)-2-amino-4-({(3R)-3-[1-{3- 
                 8 
                 3 
                 1.66 
                 529.2 
               
               
                   
                 fluoro-2-[(3-methylphenyl)oxy]phenyl}-1- 
               
               
                   
                 hydroxy-5-(methyloxy)pentyl]-1- 
               
               
                   
                 piperidinyl}carbonyl)cyclopentanol 
               
               
                 134 
                 1-((3R)-1-{[(1R,3S)-3- 
                 2 
                 3 
                 1.71 
                 513.3 
               
               
                   
                 aminocyclopentyl]carbonyl}-3-piperidinyl)-1- 
               
               
                   
                 {3-fluoro-2-[(3-methylphenyl)oxy]phenyl}-5- 
               
               
                   
                 (methyloxy)-1-pentanol 
               
               
                 135 
                 methyl (4-((3R)-1-{[(1S,3R,4S)-3-amino- 
                 8 
                 3 
                 1.71 
                 588.2 
               
               
                   
                 4-hydroxycyclopentyl]carbonyl}-3-piperidinyl)- 
               
               
                   
                 4-{3-chloro-2-[(3-ethylphenyl)oxy]phenyl}-4- 
               
               
                   
                 hydroxybutyl)carbamate 
               
               
                 136 
                 methyl (4-((3R)-1-{[(1R,3S)-3- 
                 2 
                 3 
                 1.74 
                 572.2 
               
               
                   
                 aminocyclopentyl]carbonyl}-3-piperidinyl)-4- 
               
               
                   
                 {3-chloro-2-[(3-ethylphenyl)oxy]phenyl}-4- 
               
               
                   
                 hydroxybutyl)carbamate 
               
               
                 137 
                 methyl (4-((3R)-1-{[(1S,3R,4S)-3-amino- 
                 8 
                 3 
                 1.57 
                 558.2 
               
               
                   
                 4-hydroxycyclopentyl]carbonyl}-3-piperidinyl)- 
               
               
                   
                 4-{3-fluoro-2-[(3-methylphenyl)oxy]phenyl}-4- 
               
               
                   
                 hydroxybutyl)carbamate 
               
               
                 138 
                 methyl (4-((3R)-1-{[(1R,3S)-3- 
                 2 
                 3 
                 1.62 
                 542.3 
               
               
                   
                 aminocyclopentyl]carbonyl}-3-piperidinyl)-4- 
               
               
                   
                 {3-fluoro-2-[(3-methylphenyl)oxy]phenyl}-4- 
               
               
                   
                 hydroxybutyl)carbamate 
               
               
                 139 
                 methyl (4-((3R)-1-{[(1S,3R,4S)-3-amino- 
                 8 
                 1 
                 2.33 
                 572.2 
               
               
                   
                 4-hydroxycyclopentyl]carbonyl}-3-piperidinyl)- 
               
               
                   
                 4-{3-chloro-2-[(3- 
               
               
                   
                 methylphenyl)methyl]phenyl}-4- 
               
               
                   
                 hydroxybutyl)carbamate 
               
               
                 140 
                 methyl [4-{3-chloro-2-[(3- 
                 8 
                 1 
                 2.36 
                 570.2 
               
               
                   
                 methylphenyl)methyl]phenyl}-4-hydroxy-4- 
               
               
                   
                 ((3R)-1-{[(1R,3S)-3- 
               
               
                   
                 (methylamino)cyclopentyl]carbonyl}-3- 
               
               
                   
                 piperidinyl)butyl]carbamate 
               
               
                 141 
                 methyl (4-((3R)-1-{[(1R,3S)-3- 
                 2 
                 1 
                 2.4 
                 556.2 
               
               
                   
                 aminocyclopentyl]carbonyl}-3-piperidinyl)-4- 
               
               
                   
                 {3-chloro-2-[(3-methylphenyl)methyl]phenyl}- 
               
               
                   
                 4-hydroxybutyl)carbamate 
               
               
                 142 
                 methyl (2-{[(S)-((2R)-4-{[(1S,3R,4S)-3- 
                 8 
                 2 
                 1.77 
                 560.4 
               
               
                   
                 amino-4-hydroxycyclopentyl]carbonyl}-2- 
               
               
                   
                 morpholinyl)(6-chloro-3′-ethyl-2- 
               
               
                   
                 biphenylyl)methyl]oxy}ethyl)carbamate 
               
               
                 143 
                 methyl (2-{[(R)-((3R)-1-{[(1S,3R,4S)-3- 
                 8 
                 2 
                 1.84 
                 558.8 
               
               
                   
                 amino-4-hydroxycyclopentyl]carbonyl}-3- 
               
               
                   
                 piperidinyl)(6-chloro-3′-ethyl-2- 
               
               
                   
                 biphenylyl)methyl]oxy}ethyl)carbamate 
               
               
                 144 
                 methyl [4-((3R)-1-{[4-(aminomethyl)-5- 
                 6 
                 1 
                 2.5 
                 582.2 
               
               
                   
                 methyl-2-furanyl]carbonyl}-3-piperidinyl)-4-(6- 
               
               
                   
                 chloro-3′-ethyl-2-biphenylyl)-4- 
               
               
                   
                 hydroxybutyl]carbamate 
               
               
                 145 
                 methyl {4-(6-chloro-3′-ethyl-2-biphenylyl)- 
                 6 
                 1 
                 2.36 
                 593.3 
               
               
                   
                 4-hydroxy-4-[(3R)-1-({6- 
               
               
                   
                 [(methylamino)methyl]-3-pyridinyl}carbonyl)-3- 
               
               
                   
                 piperidinyl]butyl}carbamate 
               
               
                 146 
                 methyl [4-{(3R)-1-[(2-amino-4-oxo-1,4- 
                 6 
                 1 
                 2.29 
                 569.4 
               
               
                   
                 dihydro-5-pyrimidinyl)carbonyl]-3-piperidinyl}- 
               
               
                   
                 4-(6-chloro-3′-methyl-2-biphenylyl)-4- 
               
               
                   
                 hydroxybutyl]carbamate 
               
               
                 147 
                 methyl [4-(6-chloro-3′-methyl-2- 
                 6 
                 1 
                 2.67 
                 566.2 
               
               
                   
                 biphenylyl)-4-hydroxy-4-((3R)-1-{[2- 
               
               
                   
                 (methylamino)-5-pyrimidinyl]carbonyl}-3- 
               
               
                   
                 piperidinyl)butyl]carbamate 
               
               
                 148 
                 methyl [4-((3R)-1-{[5-(aminomethyl)-3- 
                 6 
                 1 
                 2.47 
                 555.2 
               
               
                   
                 isoxazolyl]carbonyl}-3-piperidinyl)-4-(6-chloro- 
               
               
                   
                 3′-methyl-2-biphenylyl)-4- 
               
               
                   
                 hydroxybutyl]carbamate 
               
               
                 149 
                 methyl {4-(6-chloro-3′-ethyl-2-biphenylyl)- 
                 6 
                 2 
                 1.32 
                 598.6 
               
               
                   
                 4-hydroxy-4-[(3R)-1-({5- 
               
               
                   
                 [(methylamino)methyl]-2-thienyl}carbonyl)-3- 
               
               
                   
                 piperidinyl]butyl}carbamate 
               
               
                 150 
                 methyl [4-{(3R)-1-[(6-amino-3- 
                 6 
                 1 
                 2.46 
                 553.2 
               
               
                   
                 pyridinyl)carbonyl]-3-piperidinyl}-4-(3′,6- 
               
               
                   
                 difluoro-5′-methyl-2-biphenylyl)-4- 
               
               
                   
                 hydroxybutyl]carbamate 
               
               
                 151 
                 methyl [2-({(R)-(6-chloro-3′-ethyl-2- 
                 6 
                 2 
                 1.46 
                 584.6 
               
               
                   
                 biphenylyl)[(3R)-1-({trans-4- 
               
               
                   
                 [(methylamino)methyl]cyclohexyl}carbonyl)-3- 
               
               
                   
                 piperidinyl]methyl}oxy)ethyl]carbamate 
               
               
                 152 
                 methyl [2-({(S)-(6-chloro-3′-ethyl-2- 
                 6 
                 2 
                 1.69 
                 586.5 
               
               
                   
                 biphenylyl)[(2R)-4-({trans-4- 
               
               
                   
                 [(methylamino)methyl]cyclohexyl}carbonyl)-2- 
               
               
                   
                 morpholinyl]methyl}oxy)ethyl]carbamate 
               
               
                 153 
                 N-[4-((3R)-1-{[6-(aminomethyl)-3- 
                 6 
                 1 
                 2.42 
                 549.2 
               
               
                   
                 pyridinyl]carbonyl}-3-piperidinyl)-4-(6-chloro- 
               
               
                   
                 3′-methyl-2-biphenylyl)-4- 
               
               
                   
                 hydroxybutyl]acetamide 
               
               
                 154 
                 methyl 4-((R)-1-(4- 
                 12 
                 1 
                 2.47 
                 569.3 
               
               
                   
                 (aminomethyl)piperidine-1-carbonyl)piperidin- 
               
               
                   
                 3-yl)-4-(3′-ethyl-6-fluorobiphenyl-2-yl)-4- 
               
               
                   
                 hydroxybutylcarbamate 
               
               
                 155 
                 methyl 4-(3′-ethyl-6-fluorobiphenyl-2-yl)- 
                 14 
                 1 
                 2.47 
                 583.3 
               
               
                   
                 4-hydroxy-4-((R)-1-(4- 
               
               
                   
                 ((methylamino)methyl)piperidine-1- 
               
               
                   
                 carbonyl)piperidin-3-yl)butylcarbamate 
               
               
                 156 
                 methyl [4-((3R)-1-{[4-(aminomethyl)-1- 
                 11 
                 1 
                 2.5 
                 585.3 
               
               
                   
                 piperidinyl]carbonyl}-3-piperidinyl)-4-(6-chloro- 
               
               
                   
                 3′-ethyl-2-biphenylyl)-4- 
               
               
                   
                 hydroxybutyl]carbamate 
               
               
                 157 
                 methyl [4-((3R)-1-{[4-(aminomethyl)-4- 
                 12 
                 1 
                 2.5 
                 661.3 
               
               
                   
                 phenyl-1-piperidinyl]carbonyl}-3-piperidinyl)-4- 
               
               
                   
                 (6-chloro-3′-ethyl-2-biphenylyl)-4- 
               
               
                   
                 hydroxybutyl]carbamate 
               
               
                 158 
                 N-(4-((R)-1-(4-(aminomethyl)piperidine- 
                 12 
                 1 
                 2.42 
                 573.3 
               
               
                   
                 1-carbonyl)piperidin-3-yl)-4-(2′,6-difluoro-5′- 
               
               
                   
                 methylbiphenyl-2-yl)-4-hydroxybutyl)-2- 
               
               
                   
                 hydroxyacetamide 
               
               
                 159 
                 methyl {4-(6-chloro-3′-ethyl-2-biphenylyl)- 
                 13 
                 1 
                 2.4 
                 599.3 
               
               
                   
                 4-hydroxy-4-[(3R)-1-({4- 
               
               
                   
                 [(methylamino)methyl]-1-piperidinyl}carbonyl)- 
               
               
                   
                 3-piperidinyl]butyl}carbamate 
               
               
                 160 
                 methyl {4-(6-chloro-3′-ethyl-2-biphenylyl)- 
                 14 
                 1 
                 2.51 
                 625.3 
               
               
                   
                 4-hydroxy-4-[(3R)-1-({4-[(2-propen-1- 
               
               
                   
                 ylamino)methyl]-1-piperidinyl}carbonyl)-3- 
               
               
                   
                 piperidinyl]butyl}carbamate 
               
               
                   
               
               
                   a Minor isomer separated by chromatography 
               
            
           
         
       
     
     Example 15 
     In Vitro Activity Studies 
     The compounds of the invention have enzyme-inhibiting properties. In particular, they inhibit the action of the natural enzyme renin. The latter passes from the kidneys into the blood where it affects the cleavage of angiotensinogen, releasing the decapeptide angiotensin I which is then cleaved in the blood, lungs, the kidneys and other organs by angiotensin converting enzyme to form the octapeptide angiotensin II. The octapeptide increases blood pressure both directly by binding to its receptor, causing arterial vasoconstriction, and indirectly by liberating from the adrenal glands the sodium-ion-retaining hormone aldosterone, accompanied by an increase in extracellular fluid volume. That increase can be attributed to the action of angiotensin II. Inhibitors of the enzymatic activity of renin bring about a reduction in the formation of angiotensin I. As a result a smaller amount of angiotensin II is produced. The reduced concentration of that active peptide hormone is the direct cause of the hypotensive effect of renin inhibitors. 
     The action of renin inhibitors in vitro is demonstrated experimentally by means of a test which measures the increase in fluorescence of an internally quenched peptide substrate. The sequence of this peptide corresponds to the sequence of human angiotensinogen. The following test protocol is used: All reactions are carried out in a flat bottom white opaque microtiter plate. A 4 μL aliquot of 400 μM renin substrate (DABCYL-γ-Abu-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Thr-EDANS) in 192 μL assay buffer (50 mM BES, 150 mM NaCl, 0.25 mg/mL bovine serum albumin, pH7.0) is added to 4 μL of test compound in DMSO at various concentrations ranging from 10 μM to 1 nM final concentrations. Next, 100 μL of trypsin-activated recombinant human renin (final enzyme concentration of 0.2-2 nM) in assay buffer is added, and the solution is mixed by pipetting. The increase in fluorescence at 495 nm (excitation at 340 nm) is measured for 60-360 min at rt using a Perkin-Elmer Fusion microplate reader. The slope of a linear portion of the plot of fluorescence increase as a function of time is then determined, and the rate is used for calculating percent inhibition in relation to uninhibited control. The percent inhibition values are plotted as a function of inhibitor concentration, and the IC 50  is determined from a fit of this data to a four parameter equation. The IC 50  is defined as the concentration of a particular inhibitor that reduces the formation of product by 50% relative to a control sample containing no inhibitor. (Wang G. T. et al.  Anal. Biochem.  1993, 210, 351; Nakamura, N. et al.  J. Biochem.  (Tokyo) 1991, 109, 741; Murakami, K. et al.  Anal Biochem.  1981, 110, 232). 
     In this in vitro systems the compounds of the invention (Compound #1-160) exhibit 50% inhibition at concentrations of from approximately 5000 nM to approximately 0.01 nM. Preferred compounds of the invention exhibit 50% inhibition at concentrations of from approximately 50 n M to approximately 0.01 nM. More preferred compounds of the invention exhibit 50% inhibition at concentrations of from approximately 5 nM to approximately 0.01 nM. Highly preferred compounds of the invention exhibit 50% inhibition at concentrations of from approximately 5 nM to approximately 0.01 nM and exhibit 50% inhibition at concentrations of from approximately 10 nM to approximately 0.01 nM in the in vitro assay in the presence of human plasma described below. 
     Example 16 
     In Vitro Activity Studies 
     All reactions are carried out in a low volume, black, 384 well microtiter plate (greiner bio-one). Compounds were diluted in 100% DMSO, and a 100mL aliquot of each compound concentration was stamped into the plate using a Hummingbird (Genomic Solutions). 5 μL of 600 pM renin (trypsin-activated recombinant human renin) was then added to the plate, followed by 5 μL of 2 μM substrate (Arg-Glu-Lys(5-FAM)-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Thr-Lys(5,6-TAMRA)-Arg-CONH 2 ). Both renin and substrate were made up in buffer containing 50 mM HEPES, 125 mM NaCl, 0.1% CHAPS, with the pH adjusted to 7.4. After 2 hours of reaction at room temperature, the plates were read on a Viewlux (PerkinElmer) with an excitation/emission of 485/530 nm, and using a 505 nm cutoff filter. The percent inhibition values are plotted as a function of inhibitor concentration, and the IC 50  is determined from a fit of this data to a four parameter equation. The IC 50  is defined as the concentration of a particular inhibitor that reduces the formation of product by 50% relative to a control sample containing no inhibitor. In the in vitro systems the compounds of the invention exhibit inhibiting activities at minimum concentrations of from approximately 5×10 −5  M to approximately 10 −12  M. Preferred compounds of the invention exhibit inhibiting activities at minimum concentrations of from approximately 10 −7  M to approximately 10 −12  M. 
     Example 17 
     In Vitro Activity Studies 
     The potency of renin inhibitors was measured using an in vitro renin assay. In this assay, renin-catalyzed proteolysis of a fluorescently labeled peptide converts the peptide from a weakly fluorescent to a strongly fluorescent molecule. The following test protocol was used. Substrate solution (5 μl; 2 μM Arg-Glu-Lys(5-Fam)-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Thr-Lys(5,6 Tamra)-Arg-CONH 2  in 50 mM Hepes, 125 mM NaCl, 0.1% CHAPS, pH 7.4) then trypsin-activated recombinant human renin (Scott, Martin J. et. al. Protein Expression and Purification 2007, 52(1), 104-116; 5 μL; 600 μM renin in 50 mM Hepes, 125 mM NaCl, 0.1% CHAPS, pH 7.4) were added sequentially to a black Greiner low volume 384-well plate (cat.#784076) pre-stamped with a 100 nl DMSO solution of compound at the desired concentration. The assay plates were incubated at room temperature for 2 hours with a cover plate then quenched by the addition of a stop solution (2 μL; 5 μM of Bachem C-3195 in 50 mM Hepes, 125 mM NaCl, 0.1% CHAPS, pH 7.4, 10% DMSO). The assay plates were read on an LJL Acquest using a 485 nm excitation filter, a 530 nm emission filter, and a 505 nm dichroic filter. Compounds were initially prepared in neat DMSO at a concentration of 10 mM. For inhibition curves, compounds were diluted using a three fold serial dilution and tested at 11 concentrations (e.g. 50 μM-0.8 nM or 25 μM-0.42 nM or 2.5 μM to 42 μM). Curves were analyzed using ActivityBase and XLfit, and results were expressed as pIC 50  values. 
     Example 18 
     In Vitro Activity of the Disclosed Compounds in Human Plasma 
     The action of renin inhibitors in vitro in human plasma is demonstrated experimentally by the decrease in plasma renin activity (PRA) levels observed in the presence of the compounds. Incubations mixtures contain in the final volume of 250 μL 95.5 mM N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid, pH 7.0, 8 mM EDTA, 0.1 mM neomycin sulfate, 1 mg/ml sodium azide, 1 mM phenylmethanesulfonyl fluoride, 2% DMSO and 87.3% of pooled mixed-gender human plasma stabilized with EDTA. For plasma batches with low PRA (less than 1 ng/ml/hr) ˜2 μM of recombinant human renin IS added to achieve PRA of 3-4 ng/ml/hr. The cleavage of endogenous angiotensinogen in plasma is carried out at 37° C. for 90 min and the product angiotensin I is measured by competitive radioimmunoassay using DiaSorin PRA kit. Uninhibited incubations containing 2% DMSO and fully inhibited controls with 2 μM of isovaleryl-Phe-Nle-Sta-Ala-Sta-OH are used for deriving percent of inhibition for each concentration of inhibitors and fitting dose-response data into a four parametric model from which IC 50  values, defined as concentrations of inhibitors at which 50% inhibition occurs, is determined. 
     Example 19 
     Efficacy of the Disclosed Inhibitors in a Transgenic Rat Model 
     The efficacy of the renin inhibitors is also evaluated in vivo in double transgenic rats engineered to express human renin and human angiotensinogen (Bohlender J, Fukamizu A, Lippoldt A, Nomura T, Dietz R, Menard J, Murakami K, Luft F C, Ganten D. High human renin hypertension in transgenic rats.  Hypertension  1997, 29, 428-434). 
     Experiments are conducted in 5-10 week-old double transgenic rats (dTGRs). The model has been described in detail earlier. Briefly, the human renin construct are used to generate transgenic animals (hRen) made up the entire genomic human renin gene (10 exons and 9 introns), with 3.0 kB of the 5′-promoter region and 1.2 kB of 3′ additional sequences. The human angiotensinogen construct made up the entire human angiotensinogen gene (5 exons and 4 introns), with 1.3 kB of 5′-flanking and 2.4 kB of 3′-flanking sequences are used to generate rats producing human angiotensinogen (hAogen). The hRen and hAogen rats are rederived using embryo transfer from breeding pairs obtained under license from Ascencion Gmbh (Germany). The hAogen and hRen are then crossed to produce the double transgenic dTGR) off-spring. The dTGr rats are maintained on irradiated rodent chow (5VO2, Purina Mills Inc) and normal water. Radio telemetry transmitters (TA11PAC40, Data Sciences International) are surgically implanted at 5-6 weeks of age. The telemetry system provided 24-h recordings of systolic, mean, diastolic arterial pressure (SAP, MAP, DAP, respectively) and heart rate (HR). Prior to dosing, baseline hemodynamic measures are obtained for 24 hours. Rats are then dosed orally with vehicle or drug and monitored up to 48 hours post-dose. 
     While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.