Abstract:
The present invention is directed to novel macrocyclic compounds of formula (I) and their pharmaceutically acceptable salts, hydrates or solvates: 
     
       
                 
         
             
             
         
       
     
     wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , n 1 , m, p Z 1 , Z 2 , and Z 3  are as describe in the specification. The invention also relates to compounds of formula (I) which are antagonists of the motilin receptor and are useful in the treatment of disorders associated with this receptor and with or with motility dysfunction.

Description:
RELATED APPLICATION INFORMATION 
       [0001]    This application is a continuation under 35 U.S.C. § 120 of U.S. patent application Ser. No. 10/872,142, filed Jun. 18, 2004, currently pending, which claims the benefit of U.S. Patent Application Ser. No. 60/479,223, filed Jun. 18, 2003. The disclosure of each application is incorporated herein by reference in its entirety. 
     
    
     FIELD OF THE INVENTION 
       [0002]    The present invention relates to novel conformationally-defined macrocyclic compounds, pharmaceutical compositions comprising same and intermediates used in their manufacture. More particularly, the invention relates to macrocyclic compounds that have been demonstrated to selectively antagonize the activity of the motilin receptor. The invention further relates to macrocyclic compounds useful as therapeutics for a range of gastrointestinal disorders, in particular those in which malfunction of gastric motility or increased motilin secretion is observed, such as hypermotilinemia, irritable bowel syndrome and dyspepsia. 
       BACKGROUND OF THE INVENTION 
       [0003]    A number of peptide hormones are involved in the control of the different functions in the gastrointestinal (GI) tract, including absorption, secretion, blood flow and motility (Mulvihill, et al. in  Basic and Clinical Endocrinology,  4 th  edition, Greenspan, F. S.; Baxter, J. D., eds., Appleton &amp; Lange: Norwalk, Conn., 1994, pp 551-570). Since interactions between the brain and GI system are critical to the proper modulation of these functions, these peptides can be produced locally in the GI tract or distally in the CNS. 
         [0004]    One of these peptide hormones, motilin, a linear 22-amino acid peptide, plays a critical regulatory role in the GI physiological system though governing of fasting gastrointestinal motor activity. As such, the peptide is periodically released from the duodenal mucosa during fasting in mammals, including humans. More precisely, motilin exerts a powerful effect on gastric motility through the contraction of gastrointestinal smooth muscle to stimulate gastric emptying, decrease intestinal transit time and initiate phase III of the migrating motor complex in the small bowel (Itoh, Z., Ed.,  Motilin , Academic Press: San Diego, Calif., 1990, ASIN: 0123757304; Nelson, D. K.  Dig. Dis. Sci.  1996, 41, 2006-2015; Peeters, T. L.; Vantrappen, G.; Janssens, J.  Gastroenterology  1980, 79, 716-719). 
         [0005]    Motilin exerts these effects through receptors located predominantly on the human antrum and proximal duodenum, although its receptors are found in other regions of the GI tract as well (Peeters, T. L.; Bormans, V.; Vantrappen, G.  Regul. Pept.  1988, 23, 171-182). Therefore, motilin hormone is involved in motility of both the upper and lower parts of the GI system (Williams et al.  Am. J. Physiol.  1992, 262, G50-G55). In addition, motilin and its receptors have been found in the CNS and periphery, suggesting a physiological role in the nervous system that has not yet been definitively elucidated (Depoortere, I.; Peeters, T. L.  Am. J. Physiol.  1997, 272, G994-999 and O&#39;Donohue, T. L et al.  Peptides  1981, 2, 467-477). For example, motilin receptors in the brain have been suggested to play a regulatory role in a number of CNS functions, including feeding and drinking behavior, micturition reflex, central and brain stem neuronal modulation and pituitary hormone secretion (Itoh, Z. Motilin and Clinical Applications.  Peptides  1997, 18, 593-608; Asakawa, A.; Inui, A.; Momose, K.; et al., M.  Peptides  1998, 19, 987-990 and Rosenfeld, D. J.; Garthwaite, T. L.  Physiol. Behav.  1987, 39, 753-756). Physiological studies have provided confirmatory evidence that motilin can indeed have an effect on feeding behavior (Rosenfeld, D. J.; Garthwaite, T. L.  Phys. Behav.  1987, 39, 735-736). 
         [0006]    The recent identification and cloning of the human motilin receptor (WO 99/64436) has simplified and accelerated the search for agents which can modulate its activity for specific therapeutic purposes. 
         [0007]    Due to the critical and direct involvement of motilin in control of gastric motility, agents that either diminish (hypomotility) or enhance (hypermotility) the activity at the motilin receptor, are a particularly attractive area for further investigation in the search for new effective pharmaceuticals towards these indications. 
         [0008]    Peptidic agonists of the motilin receptor, which have clinical application for the treatment of hypomotility disorders, have been reported (U.S. Pat. Nos. 5,695,952; 5,721,353; 6,018,037; 6,380,158; 6,420,521, U.S. Appl. 2001/0041791, WO 98/42840; WO 01/00830 and WO 02/059141). Derivatives of erythromycin, commonly referred to as motilides, have also been reported as agonists of the motilin receptor (U.S. Pat. Nos. 4,920,102; 5,008,249; 5,175,150; 5,418,224; 5,470,961; 5,523,401, 5,554,605; 5,658,888; 5,854,407; 5,912,235; 6,100,239; 6,165,985; 6,403,775). 
         [0009]    Antagonists of the motilin receptor are potentially extremely useful as therapeutic treatments for diseases associated with hypermotility and hypermotilinemia, including irritable bowel syndrome, dyspepsia, gastroesophogeal reflux disorders, Crohn&#39;s disease, ulcerative colitis, pancreatitis, infantile hypertrophic pyloric stenosis, diabetes mellitus, obesity, malabsorption syndrome, carcinoid syndrome, diarrhea, atrophic colitis or gastritis, gastrointestinal dumping syndrome, postgastroenterectomy syndrome, gastric stasis and eating disorders leading to obesity. 
         [0010]    A variety of peptidic compounds have been described as antagonists of the motilin receptor (Depoortere, I.; Macielag, M. J.; Galdes, A.; Peeters, T. L.  Eur. J. Pharmacol.  1995, 286, 241-247; U.S. Pat. Nos. 5,470,830; 6,255,285; 6,586,630; 6,720,433; U.S. 2003/0176643; WO 02/64623). These peptidic antagonists suffer from the known limitations of peptides as drug molecules, in particular poor oral bioavailability and degradative metabolism. 
         [0011]    Cyclization of peptidic derivatives is a method employed to improve the properties of a linear peptide both with respect to metabolic stability and conformational freedom. Cyclic molecules tend to be more resistant to metabolic enzymes. Such cyclic tetrapeptide motilin antagonists have been reported (Haramura, M. et al  J. Med. Chem.  2002, 45, 670-675, U.S. 2003/0191053; WO 02/16404). 
         [0012]    Other motilin antagonists, which are non-peptidic and non-cyclic in nature have also been reported (U.S. Pat. Nos. 5,972,939; 6,384,031; 6,392,040; 6,423,714; 6,511,980; 6,624,165; 6,667,309; U.S. 2002/0111484; 2001/041701; 2002/0103238; 2001/0056106, 2002/0013352; 2003/0203906 and 2002/0002192) 
         [0013]    The macrocyclic motilin antagonists of the present invention comprise elements of both peptidic and non-peptidic structures in a combination which has not been pursued for this application previously. 
         [0014]    Indeed, the structural features of antagonists of the present invention are different. In particular, within the known motilin antagonists which are cyclic peptides, it was found that such derivatives containing D-amino acids were devoid of activity. In contrast, for the tripeptidomimetic compounds of the present invention, the D-stereochemistry is required for two of the three building elements. 
         [0015]    The motilin antagonists of the present invention are also distinct from the prior art in that they comprise a tether element to fulfill the dual role of controlling conformations and providing additional sites for interaction either through hydrophobic interactions, hydrogen bonding or dipole-dipole interactions. 
       SUMMARY OF THE INVENTION 
       [0016]    In a first aspect, the present invention is directed to compounds of formula (I): 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    and pharmaceutically acceptable salts, hydrates or solvates thereof wherein:
 
Z 1 , Z 2  and Z 3  are independently selected from the group consisting of O, N and NR 10 , wherein R 10  is selected from the group consisting of hydrogen, lower alkyl, and substituted lower alkyl;
 
R 1  is independently selected from the group consisting of lower alkyl substituted with aryl, lower alkyl substituted with substituted aryl, lower alkyl substituted with heteroaryl and lower alkyl substituted with substituted heteroaryl;
 
R 2  is hydrogen;
 
R 3  is independently selected from the group consisting of alkyl and cycloalkyl with the proviso that when Z 1  is N, R 3  can form a four, five, six or seven-membered heterocyclic ring together with Z 1 ;
 
R 4  is hydrogen;
 
R 5  and R 6  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl and substituted heteroaryl, with the proviso that at least one of R 5  and R 6  is hydrogen;
 
X is selected from the group consisting of O, NR 8 , and N(R 9 ) 2   + ;
       wherein R 8  is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, formyl, acyl, carboxyalkyl, carboxyaryl, amido, sulfonyl, sulfonamido and amidino; and   R 9  is selected from the group consisting of hydrogen, lower alkyl, and substituted lower alkyl;
 
m, n 1  and p are independently selected from 0, 1 or 2; and
 
T is a bivalent radical of formula II:
       
 
         [0000]      —U—(CH 2 ) d —W—Y-Z-(CH 2 ) e —  (II)       wherein d and e are independently selected from 0, 1, 2, 3, 4 or 5;   wherein U is bonded to X of formula (I) and is —CH 2 — or —C(═O)—;   wherein Y and Z are each optionally present;   W, Y and Z are independently selected from the group consisting of: —O—, —NR 28 —, —S—, —SO—, —SO 2 —, —C(═O)—, —C(═O)—O—, —O—C(═O)—, —C(═O)—NH—, —NH—C(═O)—, —SO 2 —NH—, —NH—SO 2 —, —CR 29 R 30 —, —CH═CH— with a configuration Z or E, and —C≡C—, or from a ring structure independently selected from the group         
         [0000]    
       
                 
         
             
             
         
       
       
         
           
             wherein any carbon atom contained within said ring structure, can be replaced by a nitrogen atom, with the proviso that if said ring structure is a monocyclic ring structure, it does not comprise more than four nitrogen atoms and if said ring structure is a bicyclic ring structure, it does not comprise more than six nitrogen atoms; 
             G 1  and G 2  each independently represent a covalent bond or a bivalent radical selected from the group consisting of —O—, —NR 41 —, —S—, —SO—, —SO 2 —, —C(═O)—, —C(═O)—O—, —O—C(═O)—, —C(═O)NH—, —NH—C(═O)—, —SO 2 —NH—, —NH—SO 2 —, —CR 42 R 43 —, —CH═CH— with a configuration Z or E, and —C≡C—; with the proviso that G 1  is bonded closer to U than G 2 ; 
             K 1 , K 2 , K 3 , K 4 , K 6 , K 15  and K 16  are independently selected from the group consisting of O, NR 44  and S; 
             f is selected from 1, 2, 3, 4, 5 or 6; 
             R 31 , R 32 , R 38 , R 39 , R 48  and R 49  are independently selected from hydrogen, halogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hydroxy, alkoxy, aryloxy, amino, halogen, formyl, acyl, carboxy, carboxyalkyl, carboxyaryl, amido, carbamoyl, guanidino, ureido, amidino, cyano, nitro, mercapto, sulfinyl, sulfonyl and sulfonamido; and 
             R 33 , R 34 , R 35 , R 36 , R 37 , R 47 , R 50  and R 51  are independently selected from hydrogen, halogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hydroxy, alkoxy, aryloxy, oxo, amino, halogen, formyl, acyl, carboxy, carboxyalkyl, carboxyaryl, amido, carbamoyl, guanidino, ureido, amidino, cyano, nitro, mercapto, sulfinyl, sulfonyl and sulfonamido. 
           
         
       
     
         [0029]    In a second aspect, the invention also proposes compounds of formula (1) which are antagonists of the motilin receptor. 
         [0030]    In a third aspect, the invention proposes a method of treating a disorder associated with the motilin receptor or motility dysfunction in humans and other mammals comprising administering a therapeutically effective amount of a compound of formula (1). 
         [0031]    While the invention will be described in conjunction with example embodiments, it will be understood that it is not intended to limit the scope of the invention to such embodiment. On the contrary, it is intended to cover all alternatives, modifications and equivalents as may be included as defined by the appended claims. 
       DETAILED DESCRIPTION OF THE INVENTION 
       [0032]    Preferably in formula (I), as depicted hereinabove, R 1  is selected from the group consisting of —(CH 2 ) q R 11 , and —CHR 12 R 13  
       wherein q is 0, 1, 2 or 3; and   R 11  and R 12  are independently selected from a ring structure from the following group:       
 
         [0000]    
       
                 
         
             
             
         
       
       
         
           
             wherein any carbon atom in said ring structure can be replaced a nitrogen atom, with the proviso that if said ring structure is a monocyclic ring structure, it does not comprise more than four nitrogen atoms and if said ring structure is a bicyclic ring structure, it does not comprise more than six nitrogen atoms; 
             A 1 , A 2 , A 3 , A 4  and A 5  are each optionally present and are independently selected from the group consisting of halogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hydroxy, alkoxy, aryloxy, amino, halogen, formyl, acyl, carboxy, carboxyalkyl, carboxyaryl, amido, carbamoyl, guanidino, ureido, amidino, cyano, nitro, mercapto, sulfinyl, sulfonyl and sulfonamido; 
             B 1 , B 2 , B 3 , and B 4  are independently selected from NR 14 , S or O, wherein R 14  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, formyl, acyl, carboxyalkyl, carboxyaryl, amido, sulfonyl and sulfonamido; 
             R 13  is as defined for as R 11  and R 12  or is selected from the group comprising lower alkyl, substituted lower alkyl, hydroxy, alkoxy, aryloxy, amino, carboxy, carboxyalkyl, carboxyaryl, and amido.
 
wherein A 1 , A 2 , A 3 , A 4  and A 5  are most preferably selected from halogen, trifluoromethyl, C 1-6  alkyl or C 1-6  alkoxy.
 
           
         
       
     
         [0039]    Preferably, R 11 , R 12  and R 13  are selected from the group consisting of: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein R a  and R b  are chosen from the group consisting of Cl, F, CF 3 , OCH 3 , OH, and C(CH 3 ) 3  and CH 3 . 
         [0040]    Also preferably, R 3  in formula (I), is selected from the group consisting of:
       —(CH 2 ) s CH 3 , —CH(CH 3 )(CH 2 ) t CH 3 , —CH(OR 15 )CH 3 , —CH 2 SCH 3  —CH 2 CH 2 SCH 3 , —CH 2 S(═O)CH 3 , —CH 2 CH 2 S(═O)CH 3 , —CH 2 S(═O) 2 CH 3 , —CH 2 CH 2 S(═O) 2 CH 3 , —(CH 2 ) u CH(CH 3 ) 2 , —C(CH 3 ) 3 , and —(CH 2 ) y —R 21 , wherein:
           s and u are independently selected from 0, 1, 2, 3, 4 or 5;   t is independently selected from 1, 2, 3 or 4;   y is selected from 0, 1, 2, 3 or 4;   R 15  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, formyl and acyl;   R 21  is selected from a ring structure selected from the following group:   
               
 
         [0000]    
       
                 
         
             
             
         
       
       
         
           
             
               
                 wherein any carbon atom in said ring structure can be replaced by a nitrogen atom, with the proviso that if said ring structure is a monocyclic ring structure, it does not comprise more than four nitrogen atoms and if said ring structure is a bicyclic ring structure, it does not comprise more than six nitrogen atoms; 
                 z is selected from 1, 2, 3, 4 or 5; 
                 E 1 , E 2  and E 3  are each optionally present and are independently selected from the group consisting of halogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hydroxy, alkoxy, aryloxy, amino, halogen, formyl, acyl, carboxy, carboxyalkyl, carboxyaryl, amido, carbamoyl, guanidino, ureido, amidino, cyano, nitro, mercapto, sulfinyl, sulfonyl and sulfonamido; and 
                 J is optionally present and is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hydroxy, alkoxy, aryloxy, oxo, amino, halogen, formyl, acyl, carboxy, carboxyalkyl, carboxyaryl, amido, carbamoyl, guanidino, ureido, amidino, mercapto, sulfinyl, sulfonyl and sulfonamido. 
               
             
           
         
       
     
         [0051]    The tether portion (T) of formula (I) is preferably selected from the group consisting of: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein L 1  is O, NH or NMe; L 2  is CH or N; L 3  is CH or N; L 4  is O or CH 2 ; L 5  is CH or N L 6  is CR 52 R 53  or O; R 46  is H or CH 3 ;
 
R 52 , R 53 , R 54 , R 55 , R 56  and R 57  are independently selected from hydrogen, lower alkyl, substituted lower alkyl, hydroxy, alkoxy, aryloxy, amino, and oxo; or R 52  together with R 53  or R 54  together with R 55  or R 56  together with R 57  can independently form a three to seven-membered cyclic ring comprising carbon, oxygen, sulfur and/or nitrogen atoms;
 
(X) is the site of a covalent bond to X in formula (I); and
 
(Z 3 ) is the site of a covalent bond to Z 3  in formula (I).
 
         [0052]    In a particularly preferred embodiment of the invention, there are provided compounds of formula (I) wherein m, n and p are 0, X, Z 1 , Z 2  and Z 3  are NH and R 2 , R 4  and R 5  are hydrogen, represented by formula (III): 
         [0000]    
       
                 
         
             
             
         
       
     
         [0053]    According to another aspect of the invention, there are provided compounds of formula (I) wherein when Z 1  is a nitrogen atom, R 3  forms a four, five, six or seven-membered heterocyclic ring together with Z 1 , represented by formula (IV): 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein said heterocyclic ring may contain a second nitrogen atom, or an oxygen, or sulfur atom;
 
n 2  is selected from 0, 1, 2 or 3
 
R 7  is optionally present and is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hydroxy, alkoxy, aryloxy, oxo, amino, halogen, formyl, acyl, carboxy, carboxyalkyl, carboxyaryl, amido, carbamoyl, guanidino, ureido, amidino, mercapto, sulfinyl, sulfonyl and sulfonamido.
 
         [0054]    It is to be understood, that in the context of the present invention, the terms amino, guanidine, ureido and amidino encompass substituted derivatives thereof as well. 
         [0055]    Preferably, the invention provides a method of treating a disorder associated with hypermotility or hypermotilinemia in humans and other mammals comprising administering a therapeutically effective amount of a compound of formula (I). 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0056]      FIG. 1  depicts Scheme 1 presenting a general synthetic strategy to conformationally-defined macrocycles of the present invention. 
           [0057]      FIG. 2  depicts the standard procedure for the synthesis of tether T8 of Example 16. 
           [0058]      FIG. 3  depicts the standard procedure for the synthesis of tether T9 of Example 17. 
           [0059]      FIG. 4  depicts the standard procedure for the synthesis of Ddz-propargylamine of Example 18. 
           [0060]      FIG. 5A  depicts the standard procedure for the synthesis of tether T10 of Example 19. 
           [0061]      FIG. 5B  depicts the second synthetic route to tether T10 of Example 19. 
           [0062]      FIG. 6  depicts the standard procedure for the synthesis of Tether T11 of Example 20. 
           [0063]      FIG. 7  depicts the standard procedure for the synthesis of tether T12 of Example 26. 
           [0064]      FIG. 8  depicts the procedure for synthesis of PPh 3 -DIAD adduct of Example 29-C. 
           [0065]      FIG. 9  depicts the standard procedure for attachment of tethers via reductive amination of Example 30. 
           [0066]      FIG. 10  depicts the standard procedure for the synthesis of tether T28 of Example 32. 
           [0067]      FIG. 11  the standard procedure for the synthesis of tether T32 of Example 36. 
           [0068]      FIGS. 12A ,  12 B depict the standard procedure for the synthesis of tether T33a and T33b of Example 37. 
           [0069]      FIG. 13  depicts the standard procedure for the synthesis of tether T34 of Example 38. 
           [0070]      FIG. 14  depicts the standard procedure for the synthesis of tether T35 of Example 39. 
           [0071]      FIG. 15  depicts the standard procedure for the synthesis of tether T36 of Example 40. 
           [0072]      FIG. 16  depicts the standard procedure for the synthesis of tether T37 of Example 41. 
           [0073]      FIG. 17  depicts the standard procedure for the synthesis of tether T38 of Example 42. Chiral T38 can be accessed through the use of asymmetric synthesis methods, resolution or chiral chromatography techniques available in the literature. 
           [0000]    HPLC (standard gradient) t R =8.46 min
 
Chiral material can be accessed by starting with the chiral epoxide. For example, the (S)-isomer of T38 was constructed in 89% overall yield from (S)-propylene oxide.
 
           [0074]      FIG. 18  depicts the standard procedure for the synthesis of tether T39 of Example 43. Chiral T39 can be accessed through the use of asymmetric synthesis methods, resolution or chiral chromatography techniques available in the literature. 
           [0075]      FIG. 19  depicts the standard procedure for the synthesis of tether T40 of Example 44. Chiral T40 can be accessed through the use of asymmetric synthesis methods, resolution or chiral chromatography techniques available in the literature. 
           [0076]      FIG. 20  depicts the standard procedure for the synthesis of tether T41 of Example 45. 
           [0077]      FIG. 21  depicts the standard procedure for the synthesis of tether T42 of Example 46. 
           [0078]      FIG. 22  depicts Scheme 2 of the thioester strategy for macrocyclic compounds of the present invention. 
       
    
    
     DESCRIPTION OF PREFERRED EMBODIMENTS 
       [0079]    Although preferred embodiments of the present invention have been described in detail herein and illustrated in the accompanying structures, schemes and tables, it is to be understood that the invention is not limited to these precise embodiments and that various changes and modifications may be effected therein without departing from the scope or spirit of the present invention. 
         [0080]    Specifically preferred compounds of the present invention, include, but are not limited to: 
         [0000]    
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
     
         [0081]    In addition to the preferred tethers (T) illustrated previously, other specific tethers employed for compounds of the invention are shown hereinbelow: 
         [0000]    
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
     
         [0082]    In a preferred embodiment, the present invention is directed to a method of treating irritable bowel syndrome, dyspepsia, Crohn&#39;s disease, gastroesophogeal reflux disorders, ulcerative colitis, pancreatitis, infantile hypertrophic pyloric stenosis, carcinoid syndrome, malabsorption syndrome, diarrhea, diabetes mellitus, obesity, postgastroenterectomy syndrome, atrophic colitis or gastritis, gastric stasis, gastrointestinal dumping syndrome, celiac disease and eating disorders leading to obesity in humans and other mammals comprising administering a therapeutically effective amount of a compound of formula (I). 
       Synthetic Methods 
     A. General Information 
       [0000]    
       
         
           
             Reagents and solvents were of reagent quality or better and were used as obtained from various commercial suppliers unless otherwise noted. DMF, DCM and THF used are of DriSolv® (EM Science, now EMD Chemicals, Inc., part of Merck KgaA, Darmstadt, Germany) or synthesis grade quality except for (i) deprotection, (ii) resin capping reactions and (iii) washing. NMP used for the amino acid (AA) coupling reactions is of analytical grade. DMF was adequately degassed by placing under vacuum for a minimum of 30 min prior to use. Tyr(3tBu) was synthesized following the method reported in JP2000 44595. Cpa was made using literature methods (Tetrahedron: Asymmetry 2003, 14, 3575-3580) or obtained commercially. Boc- and Fmoc-protected amino acids and side chain protected derivatives, including those of N-methyl and unnatural amino acids, were obtained from commercial suppliers or synthesized through standard methodologies known to those in the art. Ddz-amino acids were either synthesized by standard procedures or obtained commercially from Orpegen (Heidelberg, Germany) or Advanced ChemTech (Louisville, Ky., USA). Bts-amino acids were synthesized as described in Example 6. Hydroxy acids were obtained from commercial suppliers or synthesized from the corresponding amino acids by literature methods. Analytical TLC was performed on pre-coated plates of silica gel 60F254 (0.25 mm thickness) containing a fluorescent indicator. The term “concentrated/evaporated under reduced pressure” indicates evaporation utilizing a rotary evaporator under either water aspirator pressure or the stronger vacuum provided by a mechanical oil vacuum pump as appropriate for the solvent being removed. “Dry pack” indicates chromatography on silica gel that has not been pre-treated with solvent, generally applied on larger scales for purifications where a large difference in R f  exists between the desired product and any impurities. For solid phase chemistry processes, “dried in the standard manner” is that the resin is dried first in air (1 h), and subsequently under vacuum (oil pump usually) until full dryness is attained (˜30 min to O/N). 
           
         
       
     
       B. Synthetic Methods for Building Blocks of the Invention 
     Example 6 
     Standard Procedure for the Synthesis of Bts-Amino Acids 
       [0084]    
       
                 
         
             
             
         
       
       
         
           
             To a solution of the amino acid or amino acid derivative (0.1 mol, 1.0 eq) in 0.25 N sodium hydroxide (0.08 mol, 0.8 eq) with an initial pH of approximately 9.5 (pH meter) at rt, solid Bts-Cl (0.11 mol, 1.1 eq) was added in one portion. The resulting suspension was stirred vigorously for 2-3 d. The pH of the reaction should be adjusted with 5.0 N sodium hydroxide as required to remain within the range 9.5-10.0 during this time. Typically, the pH has to be adjusted every 20-30 min during the first 5 h. Once the pH stops dropping, it is an indication that the reaction is almost complete. This can be confirmed by TLC (EtOAc:MeOH, 95:5). Upon completion, the reaction mixture was washed with Et 2 O. Washing is continued until the absence of non-polar impurities in the aqueous layer is confirmed by TLC (typically 3×100 mL). The aqueous solution was then cooled to 0° C., acidified to pH 2.0 with 1 N HCl until no additional cloudiness forms, and extracted with EtOAc (3×100 mL). Alternatively, a mixture of DCM and EtOAc may be used as the extraction solvent, depending on the solubility of the product obtained from different amino acids or derivatives. Note that DCM cannot be used solely as solvent because of the emulsion formed during extraction. The combined organic phases were washed with brine (2×150 mL), dried over MgSO 4 , filtered and evaporated under reduced pressure. DCM (1×) and hexanes (2×) were evaporated from the residue in order to ensure complete removal of the EtOAc and give the desired compound as a solid in 55-98% yield. 
             The following are modifications that have proven useful for certain amino acids: 
             Gly, Ala, D-Ala, β-Ala and GABA: Use 1.5 eq of amino acid per eq of Bts-Cl, in order to prevent dibetsylation. 
             Met: Carry out the reaction under N 2  to prevent oxidation. 
             Gln and Asn: Due to the solubility of Bts-Gln and Bts-Asn, the work-up required is modified from the standard procedure: Upon completion of the reaction, the reaction mixture was washed with diethyl ether. Washing is continued until the absence of non-polar impurities in the aqueous layer is confirmed by TLC (typically 3×100 mL). The aqueous phase was then cooled to 0° C. and acidified to pH 2.0 with 6 N HCl. 6 N HCl was employed to minimize the volume of the solution due to the water solubility of Bts-Gln and Bts-Asn. (They are, in contrast, difficult to dissolve in DCM, EtOAc or chloroform.) The solution was maintained at 0° C. for 10 min and the product was collected by filtration as a white precipitate. The solid was washed with cold water (1×), cold brine (2×) and water (1×, 25° C.). The pH of this wash was taken, if it is not approximately 4, the solid was washed again with water. Finally, the solid was washed with cold EtOAc, then with cold Et 2 O (2×), and finally dried under vacuum (oil pump) (83-85% yield). 
           
         
       
     
       C. General Synthetic Strategy to Conformationally-Defined Macrocycles of the Present Invention 
       [0090]    The compounds of Formula I can be synthesized using traditional solution synthesis techniques or solid phase chemistry methods. In either, the construction involves four phases: first, synthesis of the building blocks, including one to four moieties, comprising recognition elements for the biological target receptor, plus one tether moiety, primarily for control and definition of conformation. These building blocks are assembled together, typically in a sequential fashion, in a second phase employing standard chemical transformations. The precursors from the assembly are then cyclized in the third stage to provide the macrocyclic structures. Finally, a post-cyclization processing stage involving removal of protecting groups and optional purification then provides the desired final compounds (see  FIG. 1 ). This method has been previously disclosed in WO 01/25257 and U.S. patent application Ser. No. 09/679,331. A general synthetic strategy is shown in  FIG. 1 . 
       D. Procedures for the Synthesis of Representative Tethers of the Present Invention 
       [0091]    The important tether component required for compounds of the invention are synthesized as described in WO01/25257, U.S. Provisional Pat. Appl. Ser. No. 60/491,248 or herein. A standard procedure for the synthesis of tether B is shown in  FIG. 2 .
   Step T8-1: Chlorotrimethylsilane (116 mL, 0.91 mol, 1.5 eq) was added to a suspension of 2-hydroxycinnamic acid (100 g, 0.61 mol, 1.0 eq) in MeOH (500 mL, HPLC grade) over 30 min at 0° C. The resulting mixture was stirred at rt O/N. The reaction was monitored by TLC (EtOAc/MeOH: 98/2). Heating the reaction mixture in a hot water can accelerate the process if necessary. After the reaction was completed, the reaction mixture was evaporated under reduced pressure to afford methyl 2-hydroxycinnamate as a white solid (108.5 g) in quantitative yield. The identity of this intermediate compound is confirmed by NMR. This reaction can be carried out on larger (kg) scale with similar results   Step T8-2: 3,4-Dihydro-2H-pyran (DHP, 140 mL, 1.54 mol, 2.52 eq) was added dropwise to 2-bromoethanol (108 mL, 1.51 mol, 2.5 eq) in a 2 L three-neck flask with mechanical stirring at 0° C. over 2 h. The resulting mixture was stirred for additional 1 h at rt. Methyl 2-hydroxycinnamate from Step T8-1 (108 g, 0.61 mol, 1.0 eq), potassium carbonate (92.2 g, 0.67 mol, 1-0.1 eq), potassium iodide (20 g, 0.12 mol, 0.2 eq) and DMF (300 mL, spectrometric grade) were added to the above flask. The reaction mixture was stirred at 70° C. (external temperature) for 24 h. The reaction was monitored by TLC (DCM/Et 2 O: 95/5). The reaction was allowed to cool to rt and Et 2 O (450 mL) was added. The inorganic salts were removed by filtration and washed with Et 2 O (3×50 mL). The filtrate was diluted with hexanes (400 mL) and washed with water (3×500 mL), dried over MgSO 4 , filtered and the filtrate evaporated under reduced pressure. The crude ester (desired product and excess Br—C 2 H 4 —OTHP) was used for the subsequent reduction without further purification.   Step T8-3: DIBAL (1.525 L, 1.525 mol, 2.5 eq, 1.0 M in DCM) was added slowly to a solution of the above crude ester from Step T8-2 (0.61 mol based on the theoretical yield) in anhydrous DCM (610 mL) at −35° C. with mechanical stirring over 1.5 h. The resulting mixture was stirred for 1.5 h at −35° C., then 1.5 h at 0° C. The reaction was monitored by TLC (hex/EtOAc: 50/50). When complete, Na 2 SO 4 .10H 2 O (100 g, 0.5 eq) was slowly added; hydrogen evolution was observed, when it subsided water was added (100 mL). The mixture was warmed to rt and stirred for 10 min, then warmed to 40° C. with hot water and stirred under reflux for 20 min. The mixture was cooled to rt, diluted with DCM (600 mL), and the upper solution decanted into a filter. The solid that remained in the flask was washed with dichloromethane (5×500 mL) with mechanical stirring and filtered. The filtrate from each wash was checked by TLC, and additional washes performed if necessary to recover additional product. In an alternative work-up procedure, after dilution with DCM (600 mL), the mixture was filtered. The resulting solid was then continuously extracted with 0.5% TEA in dichloromethane using a Soxhlet extractor. Higher yield was typically obtained by this alternative procedure, although it does require more time. The filtrate was concentrated under reduced pressure and the residue purified by dry pack (EtOAc/hex/Et 3 N: 20/80/0.5) to give the product alcohol as a yellowish oil (yield: 90%). The identity and purity were confirmed by NMR.   Step T8-4: To a mixture of the allylic alcohol from Step T8-3 (28 g, 0.100 mol, 1.0 eq) and collidine (0.110 mol, 1.1 eq) in 200 mL of anhydrous DMF under N 2  was added anhydrous LiCl (4.26 g, 0.100 mol, 1.0 eq.) dissolved in 100 mL of anhydrous DMF. The mixture was then cooled to 0° C., and MsCl (12.67 g, 0.110 mol, 1.1 eq., freshly distilled over P 2 O 5 ), was added dropwise. The reaction was allowed to warm to rt and monitored by TLC (3:7 EtOAc/hex). When the reaction was complete, NaN 3  (32.7 g, 0.500 mol, 5.0 eq.) was added. The reaction mixture was stirred at rt O/N with progress followed by NMR. When the reaction was complete, the mixture is poured into an ice-cooled water bath, and extracted with diethyl ether (3×). The combined organic phases were then washed sequentially with citrate buffer (2×), saturated sodium bicarbonate (2×), and finally with brine (1×). The organic layer was dried with MgSO 4 , filtered and the filtrate concentrated under reduced pressure. The allylic azide was obtained in 90% combined yield, and was of sufficient quality to use as such for the following step.   Step T8-5: PPh 3  (25.9 g, 0.099 mol, 1.5 eq) was added at 0° C. to a solution of the allylic azide from Step T8-4 (20.0 g, 0.066 mol, 1.0 eq.) in 100 mL of THF. The solution was stirred for 30 min at 0° C. and 20 h at rt. Water (12 mL) was then added and the resulting solution was heated at 60° C. for 4 h. The solution was cooled to rt, 2N HCl (15 mL) added and the mixture stirred for 90 min at 50° C. The separated organic phase was extracted with 0.05 N HCl (2×100 mL). The combined aqueous phase was washed with Et 2 O (5×150 mL) and toluene (4×150 mL) (more extraction could be necessary, follow by TLC), which were combined and back-extracted with 0.05 N HCl (1×100 mL). This acidic aqueous phase from back-extraction was combined with the main aqueous phase and washed with ether (5×150 mL) again. The pH of the aqueous phase was then adjusted to 8-9 by the addition of sodium hydroxide (5 N). Care must be exercised to not adjust the pH above 9 due to the reaction conditions required by the next step. The aqueous phase was concentrated under reduced pressure (aspirator, then oil pump) or lyophilized to dryness. Toluene (2×) was added to the residue and then also evaporated under reduced pressure to remove traces of water. The crude product (desired amino alcohol along with inorganic salt) was used for the next reaction without further purification.   Step T8-6: A mixture of the crude amino alcohol from Step T8-5 (0.5 mol based on the theoretical yield), Ddz-OPh (174 g, 0.55 mol, 1.1 eq) and Et 3 N (70 mL, 0.5 mol, 1.0 eq) in DMF (180 mL) was stirred for 24 h at 50° C. Additional DMF is added if required to solubilize all materials. The reaction was monitored by TLC (hex/EtOAc: 50/50, ninhydrin detection). After the reaction was complete, the reaction mixture was diluted with Et 2 O (1.5 L) and water (300 mL). The separated aqueous phase was extracted with Et 2 O (2×150 mL). The combined organic phase was washed with water (3×500 mL) and brine (1×500 mL), dried over MgSO 4 , filtered and the filtrate concentrated under reduced pressure. The layers were monitored by TLC to ensure no product was lost into the aqueous layer. If so indicated, perform one or more additional extractions with Et 2 O of the aqueous phase to recover this material. The crude product was purified by dry pack (recommended column conditions: EtOAc/hex/Et 3 N: 35/65/0.5 to 65/35/0.5) to give the tether Ddz-T8 as a pale yellow syrup (yield: ˜40%). The identity and purity of the product was confirmed by NMR.   
 
         [0098]      1 H NMR (DMSO-d 6 ): 1.6 ppm (s, 6H, 2×CH 3 ), 3.6-3.8 ppm (wide s, 10H, 2×OCH 3 , 2×OCH 2 ), 3.95 ppm (triplet, 2H, CH 2 N), 6-6.2 ppm (m, 2H, 2×CH), 6.2-6.5 ppm (m, 3H, 3×CH, aromatic), 6.6-7.6 ppm (m, 5H, aromatic). 
         [0099]    A standard procedure for the synthesis of tether T9 is shown in  FIG. 3 . 
         [0100]    Tether T9 can also be synthesized from T8 by reduction as in step T9-3 or with other appropriate hydrogenation catalysts known to those in the art. 
         [0101]    A standard procedure for the synthesis of Ddz propargylamine is shown in  FIG. 4 . 
         [0102]    In a dried three-neck flask, a solution of propargylamine (53.7 g, 0.975 mol, 1.5 eq) in degassed DMF (Drisolv, 388 mL) was treated with Ddz-N 3  (170.9 g, 0.65 mol, 1.0 eq), tetramethylguanidine (TMG, 81.4 mL, 0.65 mol, 1.0 eq) and DIPEA (113.1 mL, 0.65 mol, 1.0 eq) and stirred at 50° C. O/N. The reaction was monitored by TLC (conditions: 25/75 EtOAc/hex. R f : 0.25; detection: UV, ninhydrin). Upon completion, DMF was evaporated under reduced pressure until dryness and the residue dissolved in Et 2 O (1 L). The organic solution was washed sequentially with citrate buffer (pH 4.5, 3×), saturated aqueous sodium bicarbonate (2×), and brine (2×), then dried with MgSO 4 , filtered and the filtrate evaporated under reduced pressure. A pale orange solid was obtained. This solid was triturated with 1% EtOAc in hex, then collected by filtration and dried under vacuum (oil pump) to provide the desired product (153.4 g, 85.2%). 
         [0103]    A standard procedure for the synthesis of tether T10 is shown in  FIG. 5A . 
         [0104]    Two alternative routes to this tether have been developed. The first synthetic approach proceeded starting from the commercially available monobenzoate of resorcinol (T10-0). Mitsunobu reaction under standard conditions with the protected amino alcohol from Example 9, followed by saponification of the benzoate provided T10-1 in good yield after recrystallization. Alkylation of the phenol with 2-bromoethanol using the optimized conditions shown permitted the desired product Ddz-T10 to be obtained after dry pack purification in 42% yield. 
         [0105]    A second synthetic route to T10 is shown in  FIG. 5B . 
         [0106]    From resorcinol, two successive Mitsunobu reactions are conducted with the appropriate two carbon synthons illustrated, themselves derived from 2-aminoethanol and ethylene glycol, respectively, through known protection methodologies. Lastly, deprotection of the silyl ether, also under standard conditions provided Boc-T10. 
         [0107]    Although the yields in the two methods are comparable, the first required less mechanical manipulation and is preferred for larger scales. 
         [0108]    A standard procedure for the synthesis of tether T11 is shown in  FIG. 6 . 
         [0109]    A standard procedure for the synthesis of tether T12 is shown in  FIG. 7 . 
         [0110]    In a 3-L flame-dried three-neck flask, a solution of (aminomethyl)phenylthiobenzyl alcohol (12-0, 96 g, 0.39 mol) in degassed DMF (1 L, 0.4 M) was prepared. To this was added DdzN 3  (0.95 eq), followed by TMG (0.39 mol, 49 mL). The reaction was stirred for 10 min, then DIPEA (68 mL, 0.39 mol) added. The mixture was heated at 50° C. under N 2  until TLC indicated no DdzN 3  remained (48 h typically). (TLC eluent: EtOAc:Hex 50:50; detection: ninhydrin). Upon completion, to the reaction mixture was added 3 L citrate buffer and the separated aqueous layer extracted with Et 2 O (3×1500 mL). The combined organic phase was washed sequentially with citrate buffer (2×200 mL), water (2×200 mL) and brine (2×200 mL). The organic layer was dried over MgSO 4 , filtered and the filtrate evaporated under reduced pressure. A dark orange oil was obtained, which was purified by dry-pack. For this procedure, the oil was first dissolved in EtOAc:Hex:DCM:TEA (20:80:1:0.5, v/v/v/v). At this point, a little extra DCM was sometimes required to ensure complete dissolution. The solution was loaded onto the column, then the column eluted with EtOAc:Hex:DCM:Et 3 N (20:80:1:0.5) until all the impurities were separated out as indicated by TLC, paying particular attention to that closest to the desired product. The elution was then continued with EtOAc:Hex:Et 3 N 30:70:0.5 (v/v/v) and finally with EtOAc:hexanes:Et 3 N (50:50:0.5) to elute the desired product. After removal of the solvent from the fractions containing the product under reduced pressure, the residue was dissolved in the minimum amount of DCM, a three-fold larger volume of hexanes added, then the solvents again evaporated under reduced pressure. This treatment was repeated until an off-white foam was obtained. The latter solidified while drying under vacuum (oil pump). Alternatively, the material yielded a solid after sequential concentration with DCM (1×) and hexanes (2×). Tether Ddz-T12 was obtained as an off-white solid (85-90% yield). 
       Example 29 
     Standard Procedure for Attachment of Tethers Utilizing the Mitsunobu Reaction 
     Example 29-A 
     Using PPh 3 -DIAD Isolated Adduct 
       [0111]    To a 0.2 M solution of the appropriate tether (1.5 eq) in THF or THF-toluene (1:1) was added the PPh 3 -DIAD (pre-formed by mixing equivalent amounts of the reagents and isolated by evaporation of solvent, see Example 29-C) adduct (1.0 eq.). The resultant mixture was manually agitated for 10 sec (the solution remained turbid), then added to the resin. Alternatively, the resin was added to the solution. The reaction suspension was agitated O/N (after ˜5 min the mixture becomes limpid). The resin was filtered and washed 2×DCM, 1× toluene, 1×EtOH, 1× toluene, 1×(DCM/MeOH), 1×(THF/MeOH), 1×(DCM/MeOH), 1×(THF/MeOH), 2×DCM, then dried in the standard manner. 
       Example 29-B 
     Using “PPh 3 -DIAD In Situ Procedure” 
       [0112]    To a 0.2 M solution of the appropriate tether (4 eq) in THF or THF-toluene (1:1) was added triphenylphosphine (4 eq). The resultant mixture was manually shaken until a homogenous solution was obtained, then added to the resin. Alternatively, the resin (or IRORI™ MiniKans® (NEXUS Biosystems, Poway, Calif.), miniaturized microreactors, containing resin) was added to the solution. To this suspension was then added DIAD (3.9 eq) and the reaction agitated O/N. Note: Since the reaction is exothermic, for larger scales, the reaction should be cooled in an ice bath. In addition, an appropriate vent must be supplied to allow any pressure build-up to be released. The resin was filtered and washed DCM (2×), toluene (1×), EtOH (1×), toluene (1×), DCM/MeOH (1×), 1×THF/MeOH (1×), DCM/MeOH (1×), THF/MeOH (1×), 2×DCM, then dried in the standard manner. 
         [0113]    A procedure for the synthesis of PPh 3 -DIAD adduct is shown in  FIG. 8 . 
         [0114]    DIAD (1 eq) was added dropwise to a well-stirred solution of triphenylphosphine (1 eq) in THF (0.4 M) at 0° C. under nitrogen. The mixture was then maintained at 0° C. with stirring for 30 min. The white solid obtained was collected by filtration (use medium sized fritted filters), washed with cold anhydrous THF until the washes were colorless, and lastly washed once with anhydrous Et 2 O. The white solid product was then vacuum-dried (oil pump) and stored under nitrogen. (Note: The PPh 3 -DIAD adduct can be made in larger than immediately required quantity and stored under nitrogen; it is very important to store this reagent under anhydrous conditions.) 
       Example 30 
     Standard Procedure for Attachment of Tethers via Reductive Amination as Shown in FIG.  9   
       [0115]    In certain instances, the Mitsunobu process of Example 29 cannot be applied or is not efficient for incorporation of the tether. Hence, reductive amination has been developed as an alternative that can be employed for tether incorporation as illustrated hereinbelow for one of the preferred tethers. Similar chemistry can be used to incorporate other tethers of the present invention. 
         [0116]    The Tether (30-2) with the amine protected as its Ddz derivative was efficiently oxidized to the corresponding aldehyde 30-2 using SO 3 .pyr in DMSO-Et 3 N-DCM. This aldehyde (0.14 mmol, 56 mg, 1.5 eq based upon loading of resin support) was dissolved in a 1:3 mixture of TMOF-MeOH (DriSolv, 4 mL) at rt. To this was added the resin containing the tripeptide (30-1, as its trifluoroacetic acid salt from the deprotection of the terminal amine), the mixture was agitated briefly to wet the resin, and then borane-pyridine complex (as the commercially available 8 M solution, 23 μL, 2 eq) was introduced to the suspension. The reaction was agitated O/N, then the resin filtered, washed with DCM (2×), THF (1×), DCM/MeOH [3:1] (1×), THF/MeOH [3:1] (1×), DCM (2×) and dried in the standard manner. Care must be taken to ensure that the desired resin bound product 30-3 is not contaminated with the dialkylated material. However, even if the reaction does not proceed to completion or if a small amount of the dialkylation side product is present, the material is of sufficient purity for the macrocyclization reaction. 
         [0117]    A standard procedure for the synthesis of tether T28 is shown in  FIG. 10 . Henry reaction of 2-hydroxybenzaldehyde 28-0 provided 28-1 in 79% yield. This was followed by reduction first with sodium borohydride, then with catalytic hydrogenation, to give the amine, which was then protected as its Boc derivative, 28-2. Yields of these first two steps were lower on larger scales. Alkylation of 28-2 with the TBDMS ether of 2-bromoethanol, itself synthesized by standard methods, gave 28-3 in 74% yield. Deprotection of the silyl ether under standard conditions yielded the desired protected tether, Boc-T28. Alternative use of ethylene carbonate for the phenol alkylation to avoid the protection/deprotection steps, gave 73% yield. 
         [0118]    A standard procedure for the synthesis of tether T32 is shown in  FIG. 11 . 
         [0119]    A standard procedure for the synthesis of tether T33a and T33b is shown in  FIGS. 12A and 12B . 
         [0120]    The construction to the (R)-isomer of this tether (T33a) was accomplished from 2-iodophenol (33-0) and (S)-methyl lactate (33-A). Mitsunobu reaction of 33-0 and 33-A proceeded with inversion of configuration in excellent yield to give 33-1. Reduction of the ester to the corresponding alcohol (33-2) also occurred in high yield and was followed by Sonagashira reaction with Ddz-propargylamine. The alkyne in the resulting coupling product, 33-3, was reduced with catalytic hydrogenation. Workup with scavenger resin provided the desired product, Ddz-T33a. 
         [0121]    The synthesis of the (S)-enantiomer (Ddz-T33b) was carried out in an identical manner in comparable yield starting from (R)-methyl lactate (33-B). See  FIG. 12B . 
         [0122]    Standard procedures for the synthesis of various tethers are shown in the figures: tether T34 ( FIG. 13 ), tether T35 ( FIG. 14 ), tether T36 ( FIG. 15 ), tether T37 ( FIG. 16 ), tether T38 ( FIG. 17 ), tether T39 ( FIG. 18 ), tether T40 ( FIG. 19 ), tether T41 ( FIG. 20 ) and tether T42 ( FIG. 21 ). 
       E. Examples of Synthetic Strategies for the Macrocyclic Compounds of the Invention 
       [0123]      FIG. 22  presents a scheme depicting a thioester strategy for macrocyclic compounds of the present invention. 
         [0124]    It should be noted that one or more of the amino acids indicated can be replaced by corresponding hydroxy acids and coupled to the next building block utilizing methods known to those in the art. 
       Example 47 
     Standard Procedure for Macrocyclization with Thioester Linker 
       [0125]    The resin containing the cyclization precursor is combined in an appropriate vessel with pre-washed MP-carbonate resin [Argonaut Technologies, Foster City, Calif., commercially supplied MP-carbonate resin was treated with 3×THF (1 L per 400 g) and dried O/N at 30° C. in a vacuum oven] (1.4 to 1.6 eq relative to the initial loading of the synthesis resin). A 0.2 M DIPEA solution in THF was then added to the combined resins (1 mL/60 mg MP-carbonate resin) and the suspension agitated O/N at rt. Subsequently, the resin was filtered and rinsed 2×THF. The combined filtrates are collected together in an appropriate vessel, then the volatile contents evaporated under reduced pressure [in addition to the standard methods, solvent can also be removed in vacuo using centrifugal evaporation (ThermoSavant Discovery®, SpeedVac® or comparable) (Thermo Electron Corporation, Waltham, Mass.)] to provide the crude macrocycles. 
       Example 48 
     Standard Procedure for Silver-Assisted Macrocyclization with Thioester Linker 
       [0126]    Except for the cyclization itself and subsequent work-up, this procedure is identical to that of Example 47. The resin containing the cyclization precursor was combined in an appropriate vessel with pre-washed MP-carbonate resin [Argonaut Technologies, commercially supplied MP-carbonate resin was treated with THF (3×, 1 L per 400 g) and dried O/N at 30° C. in a vacuum oven] (1.4 to 1.6 eq relative to the initial loading of the synthesis resin). To this was added THF (1 mL per 100 mg resin) and silver trifluoroacetate (1 eq relative to the initial loading of the resin). Finally, an amount of DIPEA sufficient to obtain a 0.2 M solution was added. The reaction mixture was agitated at rt O/N. The solution was then filtered and the resins washed 2×THF. The filtrates are collected together in an appropriate vessel, then evaporated under reduced pressure [(the volatile contents could also be removed in vacuo using centrifugal evaporation (ThermoSavant Discovery®, SpeedVac® or comparable)] to provide the crude macrocycles. For this procedure, silver trifluoroacetate should be stored in a dessicator between uses. In addition, it is recommended to use a new bottle of THF (or a bottle that has been recently opened under N 2  or Ar) to minimize formation of silver oxide. 
         [0127]    Additionally, a ring-closing metathesis (RCM) strategy, as developed by Grubbs et al. can also be used to access some of the macrocyclic compounds of the invention (see for example U.S. Pat. No. 5,811,515; Grubbs, R. H. et al. J. Org. Chem. 2001, 66, 5291-5300; Fürstner, A. Angew. Chem. Int. Ed. 2000, 39, 3012-3043). 
         [0128]    To access certain derivatives of compounds of the present invention, additional reactions from those in the general scheme were required. For some, it was advantageous to react the functionality to be derivatized prior to the formation of the macrocyclic ring. The cyclic structure can restrict access of reagents to that functionality. For example, in the synthesis of N-methyl and N-acyl derivatives of macrocycles, where the secondary nitrogen atom of the ring is the site of derivatization, the reaction is preferred to be performed prior to the application of the appropriate cyclization protocol. 
         [0129]    In other cases, for example the derivatization of side chain functionality, the reaction was best performed after formation of the macrocyclic ring. For example, further reaction of amino moieties on side chains examples was typically efficiently done by reaction of the partially protected macrocycle. In this manner, acylation, sulfonylation, alkylation (via reductive amination), guanidine and urea formation were performed via standard methods. 
         [0130]    Table 1, hereinbelow, shows a representative, but by no means exclusive, summary of the chemical synthesis of several representative compounds of the invention. 
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 Synthesis of Representative Compounds of the Present Invention 
               
             
          
           
               
                   
                   
                   
                   
                   
                 Tether 
                 Additional 
               
               
                   
                 AA 1   
                 AA 2   
                 AA 3   
                 Tether 
                 Attachment 
                 Steps 
               
               
                   
                   
               
             
          
           
               
                 1 
                 Bts-D-Tyr(tBu) 
                 Boc-D-Val 
                 Boc-Nva 
                 Ddz-T8 
                 Example 29 
                 none 
               
               
                 2 
                 Bts-D-Phe 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T8 
                 Example 29 
                 none 
               
               
                 3 
                 Bts-D-Phe 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 4 
                 Bts-D-Tyr(tBu) 
                 Boc-D-Val 
                 Boc-Nva 
                 Ddz-T9 
                 Example 29 
                 none 
               
               
                 5 
                 Bts-D-Tyr(tBu) 
                 Boc-D-Ala 
                 Boc-Nva 
                 Ddz-T8 
                 Example 29 
                 none 
               
               
                 6 
                 Bts-D-Tyr(tBu) 
                 Boc-D-Val 
                 Boc-Met 
                 Ddz-T8 
                 Example 29 
                 none 
               
               
                 7 
                 Bts-D-Tyr(tBu) 
                 Boc-D-Val 
                 Boc-Nle 
                 Ddz-T8 
                 Example 29 
                 none 
               
               
                 8 
                 Bts-D-Tyr(tBu) 
                 Boc-D-Val 
                 Boc-Phe 
                 Ddz-T8 
                 Example 29 
                 none 
               
               
                 9 
                 Bts-D-Tyr(tBu) 
                 Boc-D-Val 
                 Boc-Val 
                 Ddz-T8 
                 Example 29 
                 none 
               
               
                 10 
                 Bts-D-Tyr(tBu) 
                 Boc-D-Val 
                 Boc-Leu 
                 Ddz-T9 
                 Example 29 
                 none 
               
               
                 11 
                 Bts-D-2-Nal 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T8 
                 Example 29 
                 none 
               
               
                 12 
                 Bts-D-Tyr(tBu) 
                 Boc-D-Val 
                 Boc-Abu 
                 Ddz-T8 
                 Example 29 
                 none 
               
               
                 13 
                 Bts-D-Phe 
                 Boc-D-Val 
                 Boc-Leu 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 14 
                 Bts-D-2-Nal 
                 Boc-D-Val 
                 Boc-Leu 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 15 
                 Bts-D-Phe(3Cl) 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 16 
                 Bts-D-Phe(4Cl) 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 17 
                 Bts-D-Trp(Boc) 
                 Boc-D-Val 
                 Boc-Nva 
                 Ddz-T9 
                 Example 29 
                 none 
               
               
                 18 
                 Bts-D-Tyr(tBu) 
                 Boc-D-2-Abu 
                 Boc-Nva 
                 Ddz-T9 
                 Example 29 
                 none 
               
               
                 19 
                 Bts-D-Phe(4F) 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 20 
                 Bts-D-Phe 
                 Boc-D-Val 
                 Boc-Leu 
                 Boc-T8 
                 Example 29 
                 none 
               
               
                 21 
                 Bts-D-2-Nal 
                 Boc-D-Val 
                 Boc-Leu 
                 Boc-T8 
                 Example 29 
                 none 
               
               
                 22 
                 Bts-D-Tyr(OMe) 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 23 
                 Bts-D-1-Nal 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 24 
                 Bts-D-2-Thi 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 25 
                 Bts-D-Phe(2Cl) 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 26 
                 Bts-D-Tyr(tBu) 
                 Boc-D-Val 
                 Boc-Cpa 
                 Ddz-T9 
                 Example 29 
                 none 
               
               
                 27 
                 Bts-D-4-Thz 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 28 
                 Bts-D-3-Pal 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 29 
                 Bts-D-Tyr(tBu) 
                 Boc-D-Val 
                 Ddz-Dap(Boc) 
                 Ddz-T9 
                 Example 29 
                 none 
               
               
                 30 
                 Bts-D-Tyr(tBu) 
                 Hnva(THP) 
                 Boc-Nva 
                 Ddz-T9 
                 Example 29 
                 none 
               
               
                 34 
                 Bts-D-Tyr(tBu) 
                 Ddz-D-Tyr(tBu) 
                 Boc-Nva 
                 Ddz-T8 
                 Example 29 
                 None 
               
               
                 38 
                 Bts-D-Tyr(tBu) 
                 Boc-D-Val 
                 Boc-Ala 
                 Ddz-T8 
                 Example 29 
                 none 
               
               
                 39 
                 Bts-D-Tyr(tBu) 
                 Boc-D-Val 
                 Boc-□-Ala 
                 Ddz-T8 
                 Example 29 
                 none 
               
               
                 40 
                 Bts-D-Tyr(tBu) 
                 Boc-D-Val 
                 Boc-Gly 
                 Ddz-T8 
                 Example 29 
                 none 
               
               
                 41 
                 Bts-D-Tyr(tBu) 
                 Boc-DPhe 
                 Boc-Nva 
                 Ddz-T8 
                 Example 29 
                 none 
               
               
                 52 
                 Bts-D-Tyr(tBu) 
                 Boc-D-Val 
                 Boc-Phg 
                 Ddz-T8 
                 Example 29 
                 none 
               
               
                 55 
                 Bts-D-Tyr(tBu) 
                 Ddz-D-Val 
                 Ddz-Lys(Boc) 
                 Ddz-T8 
                 Example 29 
                 none 
               
               
                 56 
                 Bts-D-Tyr(tBu) 
                 Ddz-D-Val 
                 Ddz-Orn(Boc) 
                 Ddz-T8 
                 Example 29 
                 none 
               
               
                 57 
                 Bts-D-Tyr(tBu) 
                 Ddz-D-Val 
                 Ddz-Ser(tBu) 
                 Ddz-T8 
                 Example 29 
                 none 
               
               
                 58 
                 Bts-D-Tyr(tBu) 
                 Ddz-D-Val 
                 Ddz-Tyr(tBu) 
                 Ddz-T8 
                 Example 29 
                 none 
               
               
                 59 
                 Bts-D-Tyr(tBu) 
                 Ddz--D-Val 
                 Ddz-Trp(Boc) 
                 Ddz-T8 
                 Example 29 
                 none 
               
               
                 60 
                 Bts-D-Tyr(tBu) 
                 Boc-D-Val 
                 Boc-Tyr(OMe) 
                 Ddz-T8 
                 Example 29 
                 none 
               
               
                 65 
                 Bts-D-Tyr(tBu) 
                 Boc-D-Val 
                 Boc-Nva 
                 Ddz-T2 
                 Example 29 
                 none 
               
               
                 71 
                 Bts-D-Tyr(tBu) 
                 Boc-D-Val 
                 Boc-Nva 
                 Ddz-T10 
                 Example 29 
                 none 
               
               
                 72 
                 Bts-D-Tyr(tBu) 
                 Boc-D-Val 
                 Boc-2-Nal 
                 Ddz-T8 
                 Example 29 
                 none 
               
               
                 76 
                 Bts-D-Tyr(tBu) 
                 Boc-D-2-Nal 
                 Boc-Nva 
                 Ddz-T8 
                 Example 29 
                 none 
               
               
                 77 
                 Bts-D-Tyr(tBu) 
                 Boc-D-Nle 
                 Boc-Nva 
                 Ddz-T8 
                 Example 29 
                 none 
               
               
                 80 
                 Bts-D-Tyr(tBu) 
                 Boc-D-Val 
                 Boc-Ile 
                 Ddz-T8 
                 Example 29 
                 none 
               
               
                 85 
                 Bts-D-Tyr(tBu) 
                 Boc-D-Val 
                 Boc-D-Nva 
                 Ddz-T8 
                 Example 29 
                 none 
               
               
                 87 
                 Bts-D-Bip 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 88 
                 Bts-D-Tyr(tBu) 
                 Boc-D-Val 
                 Boc-Nva 
                 Ddz-T9 
                 Example 29 
                 none 
               
               
                 89 
                 Bts-D-Hfe 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 90 
                 Bts-D-Dip 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 91 
                 Bts-D-Tyr(tBu) 
                 Boc-D-Nva 
                 Boc-Nva 
                 Ddz-T9 
                 Example 29 
                 none 
               
               
                 92 
                 Bts-D-Tyr(tBu) 
                 Boc-D-Tle 
                 Boc-Nva 
                 Ddz-T9 
                 Example 29 
                 none 
               
               
                 96 
                 Bts-D-Tyr(tBu) 
                 Boc-β-Ala 
                 Boc-Nva 
                 Ddz-T9 
                 Example 29 
                 none 
               
               
                 97 
                 Bts-D-Tyr(tBu) 
                 Boc-D-Chg 
                 Boc-Nva 
                 Ddz-T9 
                 Example 29 
                 none 
               
               
                 98 
                 Bts-D-Tyr(tBu) 
                 Boc-D-Val 
                 Boc-Nva 
                 Ddz-T18 
                 Example 29 
                 none 
               
               
                 99 
                 Bts-D-Tyr(tBu) 
                 Boc-D-Val 
                 Boc-Nva 
                 Ddz-T15 
                 Example 29 
                 none 
               
               
                 109 
                 Bts-D-Tyr(tBu) 
                 Boc-D-Val 
                 Ddz-Dab(Boc) 
                 Ddz-T9 
                 Example 29 
                 none 
               
               
                 110 
                 Bts-D-Tyr(tBu) 
                 Boc-D-Val 
                 Boc-Nva 
                 Ddz-T11 
                 Example 29 
                 none 
               
               
                 111 
                 Bts-D-Tyr(tBu) 
                 Boc-D-Val 
                 Hval(THP) 
                 Ddz-T9 
                 Example 29 
                 none 
               
               
                 112 
                 Bts-D-Tyr(tBu) 
                 Boc-D-Val 
                 Boc-Nva 
                 Ddz-T9 
                 Example 29 
                 none 
               
               
                 120 
                 Bts-D-Tyr(tBu) 
                 Boc-D-Pro 
                 Boc-Nva 
                 Ddz-T8 
                 Example 29 
                 none 
               
               
                 121 
                 Bts-D-Tyr(tBu) 
                 Boc-D-Val 
                 Boc-Nva 
                 Ac-T8-NH2 
                 Example 29 
                 none 
               
               
                 122 
                 Boc-D-3-Pal 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T9 
                 Example 30 
                 none 
               
               
                 123 
                 Boc-D-2-Pal 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T9 
                 Example 30 
                 none 
               
               
                 124 
                 Boc-D-4-Pal 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T9 
                 Example 30 
                 none 
               
               
                 125 
                 Bts-D-Tyr(tBu) 
                 Boc-D-Cpg 
                 Boc-Nva 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 126 
                 Bts-D-Tyr(tBu) 
                 Boc-D-Val 
                 Boc-NMeLeu 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 127 
                 Boc-D-His(Mts) 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T12 
                 Example 30 
                 none 
               
               
                 128 
                 Bts-D-Tyr(OMe) 
                 Boc-D-Val 
                 Boc-Leu 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 129 
                 Bts-D-1-Nal 
                 Boc-D-Val 
                 Boc-Leu 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 130 
                 Bts-D-2-Thi 
                 Boc-D-Val 
                 Boc-Leu 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 131 
                 Bts-D-Phe(3Cl) 
                 Boc-D-Val 
                 Boc-Leu 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 132 
                 Bts-D-Phe(4Cl) 
                 Boc-D-Val 
                 Boc-Leu 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 133 
                 Bts-D-Phe(4F) 
                 Boc-D-Val 
                 Boc-Leu 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 134 
                 Bts-D-Phe(3Cl) 
                 Boc-D-Val 
                 Boc-Leu 
                 Boc-T2 
                 Example 29 
                 none 
               
               
                 135 
                 Bts-D-Tyr(OMe) 
                 Boc-D-Val 
                 Boc-Leu 
                 Boc-T11 
                 Example 29 
                 none 
               
               
                 136 
                 Bts-D-1Nal 
                 Boc-D-Val 
                 Boc-Leu 
                 Boc-T11 
                 Example 29 
                 none 
               
               
                 137 
                 Bts-D-2-Thi 
                 Boc-D-Val 
                 Boc-Leu 
                 Boc-T11 
                 Example 29 
                 none 
               
               
                 138 
                 Bts-D-Phe(3Cl) 
                 Boc-D-Val 
                 Boc-Leu 
                 Boc-T11 
                 Example 29 
                 none 
               
               
                 139 
                 Bts-D-Phe(4Cl) 
                 Boc-D-Val 
                 Boc-Leu 
                 Boc-T11 
                 Example 29 
                 none 
               
               
                 140 
                 Bts-D-Phe(4F) 
                 Boc-D-Val 
                 Boc-Leu 
                 Boc-T11 
                 Example 29 
                 none 
               
               
                 141 
                 Bts-D-Tyr(OMe) 
                 Boc-D-Val 
                 Boc-Cpa 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 142 
                 Bts-D-1-Nal 
                 Boc-D-Val 
                 Boc-Cpa 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 143 
                 Bts-D-2-Thi 
                 Boc-D-Val 
                 Boc-Cpa 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 144 
                 Bts-D-Phe(3Cl) 
                 Boc-D-Val 
                 Boc-Cpa 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 145 
                 Bts-D-Phe(4Cl) 
                 Boc-D-Val 
                 Boc-Cpa 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 146 
                 Bts-D-Phe(4F) 
                 Boc-D-Val 
                 Boc-Cpa 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 147 
                 Bts-D-Tyr(OMe) 
                 Boc-D-Val 
                 Boc-Cpa 
                 Boc-T11 
                 Example 29 
                 none 
               
               
                 148 
                 Bts-D-1-Nal 
                 Boc-D-Val 
                 Boc-Cpa 
                 Boc-T11 
                 Example 29 
                 none 
               
               
                 149 
                 Bts-D-Phe(3Cl) 
                 Boc-D-Val 
                 Boc-Cpa 
                 Boc-T11 
                 Example 29 
                 none 
               
               
                 150 
                 Bts-D-Phe(4Cl) 
                 Boc-D-Val 
                 Boc-Cpa 
                 Boc-T11 
                 Example 29 
                 none 
               
               
                 151 
                 Bts-D-Phe(4F) 
                 Boc-D-Val 
                 Boc-Cpa 
                 Boc-T11 
                 Example 29 
                 none 
               
               
                 152 
                 Bts-D-Tyr(OMe) 
                 Ddz-D-Val 
                 Ddz-Dap(Boc) 
                 Ddz-T9 
                 Example 29 
                 none 
               
               
                 153 
                 Bts-D-1-Nal 
                 Ddz-D-Val 
                 Ddz-Dap(Boc) 
                 Ddz-T9 
                 Example 29 
                 none 
               
               
                 154 
                 Bts-D-2-Thi 
                 Ddz-D-Val 
                 Ddz-Dap(Boc) 
                 Ddz-T9 
                 Example 29 
                 none 
               
               
                 155 
                 Bts-D-Phe(3Cl) 
                 Ddz-D-Val 
                 Ddz-Dap(Boc) 
                 Ddz-T9 
                 Example 29 
                 none 
               
               
                 156 
                 Bts-D-Phe(4Cl) 
                 Ddz-D-Val 
                 Ddz-Dap(Boc) 
                 Ddz-T9 
                 Example 29 
                 none 
               
               
                 157 
                 Bts-D-Phe(4F) 
                 Ddz-D-Val 
                 Ddz-Dap(Boc) 
                 Ddz-T9 
                 Example 29 
                 none 
               
               
                 158 
                 Bts-D-Phe(3Cl) 
                 Ddz-D-Val 
                 Ddz-Dap(Boc) 
                 Ddz-T11 
                 Example 29 
                 none 
               
               
                 159 
                 Bts-D-Tyr(But) 
                 Boc-D-Ile 
                 Boc-Nva 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 160 
                 Bts-D-Tyr(But) 
                 Boc-D-allolle 
                 Boc-Nva 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 161 
                 Boc-D-Phe(4CH2NHFmoc) 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T9 
                 Example 30 
                 none 
               
               
                 162 
                 Bts-D-Phe(2Me) 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 163 
                 Bts-D-Phe(3Me) 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 164 
                 Bts-D-Phe(4Me) 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 165 
                 Bts-D-Phe(3OMe) 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 166 
                 Bts-D-Phe(2OMe) 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 167 
                 Bts-D-3- 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                   
                 benzothienyl 
               
               
                 168 
                 Bts-D-3-Thi 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 169 
                 Bts-D-□-HomoPhe(3Cl) 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 170 
                 Bts-D-Phe(3,4diCl) 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 171 
                 Bts-D-Phe(3,4diF) 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 172 
                 Bts-D-Phe(3,4diOMe) 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 173 
                 Bts-D-1Nal 
                 Hnva(THP) 
                 Boc-Nva 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 174 
                 Bts-D-Tyr(OMe) 
                 Hnva(THP) 
                 Boc-Nva 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 175 
                 Bts-D-Tyr(tBu) 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T33b 
                 Example 29 
                 none 
               
               
                 176 
                 Bts-D-Tyr(tBu) 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T33a 
                 Example 29 
                 none 
               
               
                 177 
                 Bts-D-Tyr(tBu) 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T28 
                 Example 29 
                 none 
               
               
                 178 
                 Bts-D-Tyr(OMe) 
                 Ddz-D-Val 
                 Ddz-Ser(tBu) 
                 Ddz-T9 
                 Example 29 
                 none 
               
               
                 179 
                 Bts-D-1-Nal 
                 Ddz-D-Val 
                 Ddz-Ser(tBu) 
                 Ddz-T9 
                 Example 29 
                 none 
               
               
                 180 
                 Bts-D-2-Thi 
                 Ddz-D-Val 
                 Ddz-Ser(tBu) 
                 Ddz-T9 
                 Example 29 
                 none 
               
               
                 181 
                 Bts-D-Phe(3Cl) 
                 Ddz-D-Val 
                 Ddz-Ser(tBu) 
                 Ddz-T9 
                 Example 29 
                 none 
               
               
                 182 
                 Bts-D-Phe(4Cl) 
                 Ddz-D-Val 
                 Ddz-Ser(tBu) 
                 Ddz-T9 
                 Example 29 
                 none 
               
               
                 183 
                 Bts-D-Phe(4F) 
                 Ddz-D-Val 
                 Ddz-Ser(tBu) 
                 Ddz-T9 
                 Example 29 
                 none 
               
               
                 184 
                 Bts-D-1-Nal 
                 Ddz-D-Val 
                 Ddz-Dap(Boc) 
                 Ddz-T11 
                 Example 29 
                 none 
               
               
                 185 
                 Bts-D-Phe(4Cl) 
                 Ddz-D-Val 
                 Ddz-Dap(Boc) 
                 Ddz-T11 
                 Example 29 
                 none 
               
               
                 186 
                 Ddz-D-Tyr(tBu) 
                 Ddz-D-Val 
                 Ddz-His(Mts) 
                 Ddz-T9 
                 Example 30 
                 none 
               
               
                 187 
                 Bts-D-Phe(3CF3) 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 188 
                 Bts-D-Phe(3F) 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 189 
                 Bts-D-Phe(4NO2) 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 190 
                 Bts-D-3-benzothienyl 
                 Boc-D-Val 
                 Boc-Cpa 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 191 
                 Bts-D-Phe(3OMe) 
                 Boc-D-Val 
                 Boc-Cpa 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 192 
                 Bts-D-Phe(3,4diCl) 
                 Boc-D-Val 
                 Boc-Cpa 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 193 
                 Bts-D-Phe(3,4diF) 
                 Boc-D-Val 
                 Boc-Cpa 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 194 
                 Bts-D-Tyr(OMe) 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T34 
                 Example 29 
                 none 
               
               
                 195 
                 Bts-D-Tyr(OMe) 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T38 
                 Example 29 
                 none 
               
               
                 196 
                 Bts-D-Phe(3Cl) 
                 Boc-D-Val 
                 Boc-Cpa 
                 Ddz-T32(Boc) 
                 Example 29 
                 none 
               
               
                 197 
                 Bts-D-Phe(3Cl) 
                 Boc-D-Val 
                 Boc-Cpa 
                 Boc-T34 
                 Example 29 
                 none 
               
               
                 198 
                 Bts-D-Phe(3Cl) 
                 Boc-D-Val 
                 Boc-Cpa 
                 Boc-T38 
                 Example 29 
                 none 
               
               
                 199 
                 Bts-D-Phe(3Cl) 
                 Boc-D-Val 
                 Boc-Cpa 
                 Boc-T41 
                 Example 29 
                 none 
               
               
                 200 
                 Bts-D-Phe(3Cl) 
                 Boc-D-Val 
                 Boc-Cpa 
                 Boc-T8 
                 Example 29 
                 none 
               
               
                 201 
                 Bts-D-1-Nal 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T8 
                 Example 29 
                 none 
               
               
                 202 
                 Bts-D-Phe(3OMe) 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T8 
                 Example 29 
                 none 
               
               
                 203 
                 Bts-D-Phe(4Cl) 
                 Ddz-D-Val 
                 Ddz-Dap(Boc) 
                 Ddz-T9 
                 Example 29 
                 acetylation 
               
               
                 204 
                 Bts-D-Phe(4Cl) 
                 Ddz-D-Val 
                 Ddz-Dap(Boc) 
                 Ddz-T9 
                 Example 29 
                 guanidinylation 
               
               
                 205 
                 Bts-D-Phe(3Cl) 
                 Boc-D-Val 
                 Boc-NMeLeu 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 206 
                 Bts-D-Phe(4Cl) 
                 Ddz-D-Val 
                 Ddz-Dap(Boc) 
                 Ddz-T9 
                 Example 29 
                 mesylation 
               
               
                 207 
                 Bts-D-Phe(4Cl) 
                 Ddz-D-Val 
                 Ddz-Dap(Boc) 
                 Ddz-T9 
                 Example 29 
                 TMS- 
               
               
                   
                   
                   
                   
                   
                   
                 isocyanate 
               
               
                   
                   
                   
                   
                   
                   
                 followed by 
               
               
                   
                   
                   
                   
                   
                   
                 dilute acid 
               
               
                 208 
                 Bts-D-Tyr(tBu) 
                 Ddz-D-Val 
                 Ddz-Dap(Boc) 
                 Ddz-T9 
                 Example 29 
                 guanidinylation 
               
               
                 209 
                 Bts-D-Tyr(tBu) 
                 Ddz-D-Val 
                 Ddz-Dap(Boc) 
                 Ddz-T9 
                 Example 29 
                 acetylation 
               
               
                 210 
                 Bts-D-Tyr(tBu) 
                 Ddz-D-Val 
                 Ddz-Dap(Boc) 
                 Ddz-T9 
                 Example 29 
                 reductive 
               
               
                   
                   
                   
                   
                   
                   
                 amination with 
               
               
                   
                   
                   
                   
                   
                   
                 acetone 
               
               
                 211 
                 Bts-D-Phe(4Cl) 
                 Ddz-D-Val 
                 Ddz-Dap(Boc) 
                 Ddz-T9 
                 Example 29 
                 reductive 
               
               
                   
                   
                   
                   
                   
                   
                 amination with 
               
               
                   
                   
                   
                   
                   
                   
                 excess 
               
               
                   
                   
                   
                   
                   
                   
                 formaldehyde 
               
               
                 212 
                 Bts-D-Phe(4Cl) 
                 Ddz-D-Val 
                 Ddz-Dap(Boc) 
                 Ddz-T9 
                 Example 29 
                 reductive 
               
               
                   
                   
                   
                   
                   
                   
                 amination with 
               
               
                   
                   
                   
                   
                   
                   
                 acetone 
               
               
                 213 
                 Bts-D-Tyr(3,5dil) 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 214 
                 Bts-D-Tyr(OMe) 
                 Boc-D-Val 
                 Boc-Hse(Bzl) 
                 Boc-T9 
                 Example 29 
                 hydrogenolysis 
               
               
                   
                   
                   
                   
                   
                   
                 for protecting 
               
               
                   
                   
                   
                   
                   
                   
                 group removal 
               
               
                 215 
                 Bts-D-Tyr(tBu) 
                 Ddz-D-Val 
                 Ddz-Dap(Boc) 
                 Ddz-T9 
                 Example 29 
                 reductive 
               
               
                   
                   
                   
                   
                   
                   
                 amination with 
               
               
                   
                   
                   
                   
                   
                   
                 excess 
               
               
                   
                   
                   
                   
                   
                   
                 formaldehyde 
               
               
                 216 
                 Bts-D-Phe(3Cl) 
                 Boc-D-Val 
                 Boc-Cpa 
                 Boc-T40 
                 Example 29 
                 none 
               
               
                 217 
                 Bts-D-Phe(3Cl) 
                 Boc-D-Val 
                 Boc-Cpa 
                 Boc-T36 
                 Example 29 
                 none 
               
               
                 218 
                 Bts-D-Phe(3Cl) 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T39 
                 Example 29 
                 none 
               
               
                 219 
                 Bts-D-Phe(3Cl) 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T37 
                 Example 29 
                 none 
               
               
                 220 
                 Bts-D-Phe(3Cl) 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T39 
                 Example 29 
                 none 
               
               
                 221 
                 Bts-D-Phe(3Cl) 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T35 
                 Example 29 
                 none 
               
               
                 222 
                 Bts-D-Tyr(3tBu) 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T9 
                 Example 29 
                 none 
               
               
                 223 
                 Bts-D-Tyr(But) 
                 Boc-D-Val 
                 Boc-Nva 
                 Boc-T9 
                 Example 29 
                 acetylation 
               
               
                 224 
                 Bts-D-1-Nal 
                 Boc-D-Val 
                 Boc-Leu 
                 Boc-T9 
                 Example 29 
                 reductive 
               
               
                   
                   
                   
                   
                   
                   
                 amination with 
               
               
                   
                   
                   
                   
                   
                   
                 formaldehyde 
               
               
                 225 
                 Bts-D-1-Nal 
                 Boc-D-Val 
                 Boc-Leu 
                 Boc-T9 
                 Example 29 
                 acetylation 
               
               
                 226 
                 Bts-D-1-Nal 
                 Boc-D-Val 
                 Boc-Leu 
                 Boc-T9 
                 Example 29 
                 reductive 
               
               
                   
                   
                   
                   
                   
                   
                 amination with 
               
               
                   
                   
                   
                   
                   
                   
                 aldehyde 
               
               
                 227 
                 Bts-D-1-Nal 
                 Boc-D-Val 
                 Boc-Leu 
                 Boc-T9 
                 Example 29 
                 reductive 
               
               
                   
                   
                   
                   
                   
                   
                 amination with 
               
               
                   
                   
                   
                   
                   
                   
                 benzaldehyde 
               
               
                   
               
               
                 Notes 
               
               
                 Any amino acid or tether designated as the Boc derivative could be substituted with the corresponding Ddz derivative. 
               
             
          
         
       
     
       D. Analytical Data for Selected Compounds of the Invention 
       [0131]      1 H and  13 C NMR spectra were recorded on a Varian Mercury 300 MHz spectrometer (Varian, Inc., Palo Alto, Calif.) and are referenced internally with respect to the residual proton signals of the solvent. Information about the conformation of the molecules in solution can be determined utilizing appropriate two-dimensional NMR techniques known to those skilled in the art. HPLC purifications were run on a Waters Xterra® MS C18 column, using the Waters FractionLynx® system (Waters Corporation, Milford, Mass.). Automated medium pressure chromatographic purifications were performed on an Isco CombiFlash® 16× system with disposable silica or C18 cartridges that permitted up to sixteen (16) samples to be run simultaneously (Teledyne Isco, Inc., Lincoln, Nebr.). MS spectra were recorded on a Waters Micromass® Platform II or ZQ™ system. HRMS spectra were recorded with a VG Micromass ZAB-ZF spectrometer. Chemical and biological information were stored and analyzed utilizing the ActivityBase® database software (ID Business Solutions Ltd., Guildford, Surrey, UK). 
       General Methods for Analytical HPLC Analyses 
       [0132]    HPLC analyses are performed on a Waters Alliance® system 2695 running at 1 mL/min using an Xterra MS C18 column 4.6×50 mm (3.5 μm). A Waters 996 PDA provided UV data for purity assessment (Waters Corporation, Milford, Mass.). An LCPackings (Dionex Corporation, Sunnyvale, Calif.) splitter (50:40:10) allowed the flow to be separated in three parts. The first part (50%) went to a Micromass® Platform II MS equipped with an APCI probe for identity confirmation. The second part (40%) went to an evaporative light scattering detector (ELSD, Polymer Laboratories, now part of Varian, Inc., Palo Alto, Calif., PL-ELS-1000™) for purity assessment and the last portion (10%) to a chemiluminescence nitrogen detector (CLND, Antek® Model 8060, Antek Instruments, Houston, Tex., part of Roper Industries, Inc., Duluth, Ga.) for quantitation and purity assessment. Data was captured and processed utilizing the most recent version of the Waters Millenium® software package (Milford, Mass.). 
         [0133]    An example LC method suitable for compounds of the present invention uses MeOH as solvent A, H 2 O as solvent B and 1% TFA/H 2 O as solvent D. Initial mobile-phase composition is 5% A, 85% B and 10% D. Details of the standard gradient method are shown below: 
         [0000]    
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 Time 
                 A % 
                 B % 
                 D % 
                 Curve 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 0.00 
                 5 
                 85 
                 10 
                 6 
               
               
                 1.00 
                 5 
                 85 
                 10 
                 6 
               
               
                 6.00 
                 50 
                 40 
                 10 
                 6 
               
               
                 9.00 
                 50 
                 40 
                 10 
                 6 
               
               
                 14.00 
                 90 
                 0 
                 10 
                 6 
               
               
                 17.00 
                 90 
                 0 
                 10 
                 6 
               
               
                 17.50 
                 5 
                 85 
                 10 
                 6 
               
               
                 20.00 
                 5 
                 85 
                 10 
                 6 
               
               
                   
               
             
          
         
       
     
         [0134]    Compounds 2-6, 8-10, 56, 65 and 144 are as defined in Table (3), hereinbelow. 
       Compound 2 
       [0135]    Yield: 12 mg pure macrocycle was obtained (CLND quantification). 
         [0136]      1 H NMR (300 MHz, DMSO-d 6 ) δ 8.83 (m, 1H); 8.53 (m, 1H); 7.63 (m, 1H); 7.4-7.08 (m, 7H); 7.00-6.84 (m, 2H); 6.60 (d, 15 Hz, 1H); 6.41 (dt, 15 Hz, 5.4 Hz, 1H); 4.35 (m, 1H); 4.25-4.05 (m, 3H); 3.94 (dt, 1H, 6 Hz, 15 Hz); 3.79 (dd, 1H, 3.6 Hz, 8.4 Hz); 3.60 (m, 1H); 3.52-3.40 (bd, 1H); 3.22-3.06 (m, 4H); 1.88 (m, 2H); 1.54-1.28 (m, 2H); 1.25 (d, 3H, 4.8 Hz); 1.22 (d, 3H, 2.7 Hz); 0.92-0.80 (m, 6H). 
         [0137]    HRMS calc. for C 30 H 40 N 4 O 4 : 520.3049; found 520.3057±0.0016 
         [0138]    HPLC [standard gradient method (refers to that presented in General Methods for Analytical HPLC Analyses)] t R =9.55 min. 
       Compound 4 
       [0139]    Yield: 12 mg pure macrocycle was obtained (CLND quantification). 
         [0140]      1 H NMR (300 MHz, DMSO-d 6 ) δ 9.35 (b, 1H); 8.98 (b, 1H); 5.52 (d, 1H, 8.4 Hz); 8.38 (b, 1H); 7.25 (b, 1H); 7.13-7.07 (m, 4H); 6.86 (t, 2H, 7.5 Hz); 6.57 (d, 2H, 8.7 Hz); 4.33 (b, 1H); 4.21-4.02 (m, 3H); 3.78 (dd, 1H, 3.3 Hz; 8.1 Hz); 3.65-3.54 (m, 1H); 3.31-3.23 (m, 1H); 3.13-3.02 (m, 4H); 2.78-2.2.28-2.18 (m, 1H); 2.0-1.80 (m, 2H); 1.50-1.30 (m, 3H); 1.25 (d, 3H, 4.5 Hz); 1.22 (d, 3H, 4.5 Hz); 1.01 (d, 3H, 6.6 Hz); 0.90 (d, 3H, 6.6 Hz); (t, 3H, 7.5 Hz). 
         [0141]      13 C NMR (75.5 MHz, DMSO-d 6 ) δ 172.22; 171.37; 157.77; 157.44; 156.04; 131.76; 130.80; 130.70; 127.88; 121.82; 115.83; 111.71; 62.13; 60.62; 54.21; 52.81; 47.13; 42.47; 33.31; 29.69; 29.30; 28.61; 20.36; 19.44; 18.72; 17.60; 13.97. 
         [0142]    HRMS calc. for C 30 H 42 N 4 O 5 : 538.3155; found: 538.3145±0.0016 
         [0143]    HPLC (standard gradient) t R =8.12 min. 
       Compound 5 
       [0144]    Yield: 17 mg pure macrocycle was obtained (CLND quantification). 
         [0145]      1 H NMR (300 MHz, DMSO-d 6 ) δ 9.02 (b, 1H); 8.47 (d, 1H, 8.4 Hz); 7.7 (b, 1H); 7.58 (d, 1H, 5.4 Hz); 7.28 (dd, 1H, 7.8 Hz, 0.8 Hz); 7.20 (t, 1H, 9.0 Hz, 0.8 Hz); 7.14 (d, 2H, 8.4 Hz); 6.98-6.91 (m, 3H); 6.66 (d, 8.7 Hz); 6.63 (d, 1H, 15.0 Hz); 6.43 (dt, 1H, 6.0 Hz, 15.0 Hz); 4.28-3.86 (m, 6H); 3.60-3.40 (m, 2H); 3.22-3.12 (m, 1H0; 3.05 (d, 2H, 5.4 Hz); 1.92-1.80 (m, 1H); 1.56-1.40 (m, 1H); 1.36-1.20 (m, 2H); 1.25 (d, 3H, 6.6 Hz); 0.84 (t, 3H, 7.2 Hz). 
         [0146]      13 C NMR (75.5 MHz, DMSO-d 6 ) δ 172.54; 171.86; 158.97; 158.56; 127.39; 155.84; 131.62; 129.73; 129.20; 129.02; 128.43; 126.30; 124.51; 122.01; 115.85; 112.88; 61.23; 52.90; 51.23; 47.08; 42.66; 36.13; 33.30; 21.14; 19.57; 17.07; 14.14; 11.49. 
         [0147]    HRMS calc. for C 28 H 36 N 4 O 5 : 508.2685; found: 508.2681±0.0015 
         [0148]    HPLC (standard gradient) t R =7.67 min. 
       Compound 6 
       [0149]    Yield: 16 mg pure macrocycle was obtained (CLND quantification). 
         [0150]      1 H NMR (300 MHz, DMSO-d 6 ) δ 9.37 (b, 1H); 8.87 (b, 1H); 8.61 (d, 1H, 8.7 Hz); 7.62 (b, 1H); 7.27 (d, 1H, 7.8 Hz); 7.21 (t, 1H, 8.4 Hz); 7.14 (d, 2H, 8.4 Hz); 6.98-6.87 (m, 3H); 6.64 (d, 2H, 8.1 Hz); 6.70 (d, 1H, 15.6 Hz); 6.39 (dt, 1H, 6.3 Hz, 15.6 Hz); 4.44-4.36 (m, 1H); 4.34-4.08 (m, 2 Hz); 4.45-3.92 (dt, 1H, 6.9 Hz, 15.6 Hz); 3.74 (dd, 1H, 3.6 Hz, 8.4 Hz); 3.54-3.26 (m, 3H); 3.22-3.02 (m, 3H); 2.60-2.36 (m, 4H); 2.24-2.14 (m, 1H); 2.02 (s, 3H); 1.96-1.89 (m, 1H); 1.80-1.66 (m, 1H); 1.01 (d, 3H, 6.3 Hz); 0.90 (d, 3H, 6.6 Hz). 
         [0151]      13 C NMR (75.5 MHz, DMSO-d 6 ) δ 171.51; 171.26; 158.90; 158.49; 157.38; 155.86; 131.63; 129.82; 129.21; 128.86; 128.63; 126.21; 121.98; 115.83; 112.83; 62.11; 61.06; 51.97; 47.10; 42.78; 30.91; 30.67; 29.34; 20.37; 19.39; 15.06. 
         [0152]    HRMS calc. for C 30 H 40 N 4 O 5 S: 568.2719; found: 568.2711±0.0017 
         [0153]    HPLC R t  (general method) 7.92 min. 
       Compound 8 
       [0154]    Yield: 27 mg pure macrocycle was obtained (CLND quantification). 
         [0155]      1 H NMR (300 MHz, DMSO-d 6 ) δ 9.05 (b, 1H); 8.43 (b, 1H); 8.34 (d, 1H, 9.3 Hz); 7.40 (b, 1H); 6.97 (d, 1H, 7.5 Hz); 6.92-6.74 (m, 9H); 6.67-6.54 (m, 2H); 6.33-6.25 (m, 3H); 6.10 (dt, 1H, 5.7 Hz, 16.2 Hz); 4.22 (dt, 1H, 0.9 Hz, 12 Hz); 3.94-6.66 (m, 4H); 3.30 (dd, 1H, 3.6 Hz, 7.8 Hz); 3.24 (m, 1H); 3.18 (m, 1H); 2.85-2.68 (m, 3H); 2.44-2.23 (m, 2H); 1.32 (o, 1H, 7.5 Hz); 0.97-0.89 (m, 1H); 0.42 (d, 3H, 6.6 Hz); 0.01 (d, 3H, 6.6 Hz). 
         [0156]      13 C NMR (75.5 MHz, DMSO-d 6 ) δ 171.20; 157.35; 155.88; 139.12; 131.61; 130.87; 129.74; 129.21; 128.77; 128.88; 126.85; 126.19; 121.97; 115.82; 112.84; 62.04; 61.10; 55.07; 50.01; 47.09; 42.85; 37.42; 29.11. 
         [0157]    HRMS calc. For C 34 H 42 N 4 O 5 : 586.3155; found: 586.3145±0.0017 
         [0158]    HPLC R t  (general method) 9.34 min. 
       Compound 9 
       [0159]    Yield: 17 mg pure macrocycle was obtained (CLND quantification). 
         [0160]      1 H NMR (300 MHz, DMSO-d 6 ) δ 9.39 (b, 1H); 8.83 (b, 1H); 8.29 (d, 1H, 9.3 Hz); 7.62 (b, 1H); 7.28 (d, 1H, 6.6 Hz); 7.20 (t, 1H, 6.9 Hz); 7.12 (d, 2H, 7.8 Hz); 6.98-6.91 (m, 2H); 6.63 (d, 2H, 8.4 Hz); 6.58 (d, 1H, 16.2 Hz); 6.40 (dt, 1H, 5.7 Hz, 16.2 Hz); 4.29-4.13 (m, 3H); 4.03-3.92 (m, 2H); 3.52 (m, 1H); 3.15-3.05 (m, 3H); 2.45-2.37 (m, 1H); 1.96-1.88 (m, 1H); 1.25 (dd, 2H, 4.5 Hz; 6 Hz); 1.01 (d, 3H, 6.3 Hz); 0.91 (d, 3H, 6.6 Hz); 0.86 (d, 3H, 7.2 Hz); 0.81 (d, 3H, 6.6 Hz). 
         [0161]      13 C NMR (75.5 MHz, DMSO-d 6 ) δ 171.85; 171.17; 157.37; 155.87; 131.59; 129.88; 129.18; 128.97; 128.78; 128.51; 126.16; 121.97; 115.83; 112.85; 61.55; 61.18; 58.15; 54.22; 47.08; 42.89; 36.32; 29.35; 29.00; 20.34; 19.56; 18.73; 17.44. 
         [0162]    HRMS calc. for C 30 H 40 N 4 O 5  536.2998; found: 536.2990±0.0017. 
         [0163]    HPLC (standard gradient) t R =8.15 min. 
       Compound 10 
       [0164]    Yield: 24 mg pure macrocycle was obtained (CLND quantification). 
         [0165]      1 H NMR (300 MHz, DMSO-d 6 ) δ 9.33 (b, 1H); 8.82 (b, 1H); 8.56 (d, 1H, 8.3 Hz); 7.60 (b, 1H); 7.27 (d, 2H, 7.8 Hz); 7.20 (t, 1H, 7.8 Hz); 7.13 (d, 2H, 8.4 Hz); 6.95 (t, 2H, 7.8 Hz); 6.64 (d, 2H, 8.4 Hz); 6.57 (d, 1H, 15.4 Hz); 6.38 (dt, 1H, 15.4 Hz, 5.8 Hz); 4.26-4.10 (m, 3H); 3.96 (dt, 1H, 5.4 Hz, 8.4 Hz); 3.77 (dd, 1H, 3.7 Hz, 7.8 Hz); 3.51-3.24 (m, 3H); 3.18-3.02 (m, 3H); 1.90 (h, 1H, 6.4 Hz); 1.73-1.54 (m, 2H); 1.45 (dt, 1H, 6.7 Hz, 0.9 Hz); 0.99 (d, 3H, 6.6 Hz); 0.89 (d, 3H, 6.3 Hz); 0.87 (d, 3H, 6.0 Hz); 0.80 (d, 3H, 6.3 Hz). 
         [0166]      13 C NMR (75.5 MHz, DMSO-d 6 ) δ 172.23; 171.17; 157.37; 155.88; 131.62; 129.82; 129.19; 128.95; 128.59; 126.24; 121.99; 115.84; 112.88; 64.23; 61.98; 61.14; 51.43; 61.14; 51.43; 47.07; 42.81; 29.38; 24.85; 24.11; 21.00; 20.32; 19.30. 
         [0167]    HRMS calc. for C 31 H 42 N 4 O 5  550.3155; found: 550.3150±0.0016. 
         [0168]    HPLC (standard gradient) t R =8.91 min. 
       Compound 56 
       [0169]    Yield: 16 mg pure macrocycle was obtained (CLND quantification). 
         [0170]      1 H NMR (300 MHz, DMSO-d 6 ) δ 9.39 (b, 1H); 8.90 (b, 1H); 8.67 (d, 1H, 8.4 Hz); 7.74 (b, 4H); 7.29-7.08 (m, 4H); 6.99-6.87 (m, 2H); 6.64 (d, 2H, 8.1 Hz); 6.61 (d, 1H, 16.5 Hz); 6.40 (dt, 1H, 5.7 Hz, 16.5 Hz); 4.40-4.06 (m, 4H); 4.02-3.95 (m, 1H); 3.79 (dd, 1H, 3.6 Hz, 7.8 Hz); 3.55-3.30 (m, 2H); 3.16-3.05 (m, 3H); 2.82-2.69 (m, 2H); 2.02-1.85 (m, 2H); 1.64-1.43 (m, 3H); 1.29-1.23 (m, 1H); 1.01 (d, 3H, 6.3 Hz); 0.91 (d, 3H, 6.3 Hz); 0.86-0.84 (m, 2H). 
         [0171]    HPLC (standard gradient) t R =5.71 min. 
       Compound 65 
       [0172]    Yield: 17 mg pure macrocycle was obtained (CLND quantification). 
         [0173]      1 H NMR (300 MHz, DMSO-d 6 ) δ 9.60 (b, 1H); 9.39 (b, 1H); 8.88 (b, 1H); 8.70 (d, 1H, 7.5 Hz); 8.57 (d, 1H, 4.2 Hz); 7.27 (t, 6 Hz); 6.96 (d, 2H, 8.4 Hz); 6.66 (d, 2H, 8.4 Hz); 5.78-5.68 (m, 1H); 5.42-5.33 (m, 1H); 3.96-3.89 (m, 1H); 3.80-3.57 (m, 5H); 3.41-3.34 (m, 1H); 3.10-2.90 (m, 1H); 2.78-2.66 (m, 1H); 2.21-2.10 (m, 1H); 2.06-1.93 (m, 1H); 1.70-1.60 (m, 1H); 1.52-1.41 (m, 1H); 1.39-1.26 (m, 1H); 1.25 (d, 3H, 4.8 Hz); 1.23 (d, 3H, 4.5 Hz); 0.83 (dd, 3H, 3 Hz, 4.5 Hz). 
         [0174]      13 C NMR (75.5 MHz, DMSO-d 6 ) δ 172.68; 172.63; 159.15; 158.73; 157.38; 157.25; 130.89; 124.99; 116.03; 62.51; 62.12; 54.29; 49.27; 42.47; 32.77; 30.43; 28.85; 20.46; 19.59; 18.72; 17.39; 13.90; 13.09. 
         [0175]    HRMS calc. for C 24 H 36 N 4 O 4 : 444.2736; found: 444.2726±0.0013 
         [0176]    HPLC (standard gradient) t R =6.80 min. 
       Compound 144 
       [0177]      1 H NMR (300 MHz, CD 3 OD) δ 7.4 (m, 1H); 7.27 (dt, 1H, 1.5 Hz, 6.6 Hz); 7.22-7.14 (m, 2H); 7.08-6.98 (m, 2H); 6.78 9t, 2H, 6.6 Hz); 4.45-4.39 (m, 2H); 4.15 (d, 2H, 8.1 Hz); 7.74 (d, 1H, 9.3 Hz); 3.54 (d, 1H, 10.8 Hz); 3.35-3.22 (m, 2H); 3.20 (q, 1H, 1.5 Hz); 2.82-2.71 (m, 1H); 2.61-2.55 (m, 1H); 2.21-2.11 (m, 1h); 2.02-1.94 (m, 1H); 1.74-1.40 (m, 5H); 1.04 (d, 3H, 6.6 Hz); 0.93 (d, 3H, 6.6 Hz); 0.74-0.64 9m, 1H); 0.45-0.28 (m, 2H); 0.15-0.08 (m, 1H); 0.06-0.02 (m, 1H). 
         [0178]      13 C NMR (75.5 MHz, CD 3 OD) δ 173.29; 172.14; 167.51; 155.47; 134.86; 134.81; 130.38; 130.31; 128.81; 128.25; 127.44; 121.63; 110.39; 107.71; 105.02; 67.10; 66.66; 62.81; 62.06; 60.10; 53.99; 41.44; 36.07; 31.91; 30.01; 29.18; 28.94; 27.79; 23.68; 23.15; 19.08; 18.25; 8.17; 4.98; 3.16. 
         [0179]    HRMS: calc. for C 31 H 41 N 4 O 4 Cl 568.2816; found 568.2802±0.0017 
       F. Mass Spectral Data for Selected Compounds of the Invention 
       [0180]      
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 Analysis of selected compounds of the invention 
               
             
          
           
               
                   
                   
                 Molecular Weight 
                 Monoisotopic 
                 M + H 
               
               
                   
                 Molecular Formula 
                 (calculated) 
                 Mass 
                 Found 
               
               
                   
                   
               
             
          
           
               
                 1 
                 C30H40N4O5 
                 536.7 
                 536 
                 537 
               
               
                 2 
                 C30H40N4O4 
                 520.7 
                 520 
                 521 
               
               
                 3 
                 C30H42N4O4 
                 522.7 
                 522 
                 523 
               
               
                 4 
                 C30H42N4O5 
                 538.7 
                 538 
                 539 
               
               
                 5 
                 C28H36N4O5 
                 508.6 
                 508 
                 509 
               
               
                 6 
                 C30H40N4O5S 
                 568.7 
                 568 
                 569 
               
               
                 7 
                 C31H42N4O5 
                 550.7 
                 550 
                 551 
               
               
                 8 
                 C34H42N4O5 
                 586.7 
                 586 
                 587 
               
               
                 9 
                 C30H40N4O5 
                 536.7 
                 536 
                 537 
               
               
                 10 
                 C31H42N4O5 
                 550.7 
                 550 
                 551 
               
               
                 11 
                 C34H44N4O4 
                 572.7 
                 572 
                 573 
               
               
                 12 
                 C29H38N4O5 
                 522.6 
                 522 
                 523 
               
               
                 13 
                 C31H44N4O4 
                 536.7 
                 536 
                 537 
               
               
                 14 
                 C35H46N4O4 
                 586.8 
                 586 
                 587 
               
               
                 15 
                 C30H41N4O4Cl 
                 557.1 
                 556 
                 557 
               
               
                 16 
                 C30H41N4O4Cl 
                 557.1 
                 556 
                 557 
               
               
                 17 
                 C32H43N5O4 
                 561.7 
                 561 
                 562 
               
               
                 18 
                 C29H40N4O5 
                 524.7 
                 524 
                 525 
               
               
                 19 
                 C30H41N4O4F 
                 540.7 
                 540 
                 541 
               
               
                 20 
                 C31H42N4O4 
                 534.7 
                 534 
                 535 
               
               
                 21 
                 C35H44N4O4 
                 584.7 
                 584 
                 585 
               
               
                 22 
                 C31H44N4O5 
                 552.7 
                 552 
                 553 
               
               
                 23 
                 C34H44N4O4 
                 572.7 
                 572 
                 573 
               
               
                 24 
                 C28H40N4O4S 
                 528.7 
                 528 
                 529 
               
               
                 25 
                 C30H41N4O4Cl 
                 557.1 
                 556 
                 557 
               
               
                 26 
                 C31H42N4O5 
                 550.7 
                 550 
                 551 
               
               
                 27 
                 C27H39N5O4S 
                 529.7 
                 529 
                 530 
               
               
                 28 
                 C29H41N5O4 
                 523.7 
                 523 
                 524 
               
               
                 29 
                 C28H39N5O5 
                 525.6 
                 525 
                 526 
               
               
                 30 
                 C30H41N3O6 
                 539.7 
                 539 
                 540 
               
               
                 34 
                 C34H40N4O6 
                 600.7 
                 600 
                 601 
               
               
                 38 
                 C28H36N4O5 
                 508.6 
                 508 
                 509 
               
               
                 39 
                 C28H36N4O5 
                 508.6 
                 508 
                 509 
               
               
                 40 
                 C27H34N4O5 
                 494.6 
                 494 
                 495 
               
               
                 41 
                 C34H40N4O5 
                 584.7 
                 584 
                 585 
               
               
                 52 
                 C33H38N4O5 
                 570.7 
                 570 
                 571 
               
               
                 55 
                 C31H43N5O5 
                 565.7 
                 565 
                 566 
               
               
                 56 
                 C30H41N5O5 
                 551.7 
                 551 
                 552 
               
               
                 57 
                 C28H36N4O6 
                 524.6 
                 524 
                 525 
               
               
                 58 
                 C34H40N4O6 
                 600.7 
                 600 
                 601 
               
               
                 59 
                 C36H41N5O5 
                 623.7 
                 623 
                 624 
               
               
                 60 
                 C35H42N4O6 
                 614.7 
                 614 
                 615 
               
               
                 65 
                 C24H36N4O4 
                 444.6 
                 444 
                 445 
               
               
                 71 
                 C29H40N4O6 
                 540.7 
                 540 
                 541 
               
               
                 72 
                 C38H42N4O5 
                 634.8 
                 634 
                 635 
               
               
                 76 
                 C38H42N4O5 
                 634.8 
                 634 
                 635 
               
               
                 77 
                 C31H42N4O5 
                 550.7 
                 550 
                 551 
               
               
                 80 
                 C31H42N4O5 
                 550.7 
                 550 
                 551 
               
               
                 85 
                 C30H40N4O5 
                 536.7 
                 536 
                 537 
               
               
                 87 
                 C36H46N4O4 
                 598.8 
                 598 
                 599 
               
               
                 88 
                 C34H50N4O5 
                 594.8 
                 594 
                 595 
               
               
                 89 
                 C31H44N4O4 
                 536.7 
                 536 
                 537 
               
               
                 90 
                 C36H46N4O4 
                 598.8 
                 598 
                 599 
               
               
                 91 
                 C30H42N4O5 
                 538.7 
                 538 
                 539 
               
               
                 92 
                 C31H44N4O5 
                 552.7 
                 552 
                 553 
               
               
                 96 
                 C28H38N4O5 
                 510.6 
                 510 
                 511 
               
               
                 97 
                 C33H46N4O5 
                 578.7 
                 578 
                 579 
               
               
                 98 
                 C24H39N5O4 
                 461.6 
                 461 
                 462 
               
               
                 99 
                 C24H39N5O4 
                 461.6 
                 461 
                 462 
               
               
                 109 
                 C29H41N5O5 
                 539.7 
                 539 
                 540 
               
               
                 110 
                 C29H41N5O5 
                 539.7 
                 539 
                 540 
               
               
                 111 
                 C30H41N3O6 
                 539.7 
                 539 
                 540 
               
               
                 112 
                 C31H44N4O5 
                 552.7 
                 552 
                 553 
               
               
                 120 
                 C30H38N4O5 
                 534.6 
                 534 
                 535 
               
               
                 121 
                 C32H45N5O6 
                 595.7 
                 595 
                 596 
               
               
                 122 
                 C31H43N4O4Cl 
                 571.2 
                 570 
                 571 
               
               
                 123 
                 C29H41N5O4 
                 523.7 
                 523 
                 524 
               
               
                 124 
                 C29H41N5O4 
                 523.7 
                 523 
                 524 
               
               
                 125 
                 C30H40N4O5 
                 536.7 
                 536 
                 537 
               
               
                 126 
                 C32H46N4O5 
                 566.7 
                 566 
                 567 
               
               
                 127 
                 C30H38N6O3S 
                 562.7 
                 562 
                 563 
               
               
                 128 
                 C32H46N4O5 
                 566.7 
                 566 
                 567 
               
               
                 129 
                 C35H46N4O4 
                 586.8 
                 586 
                 587 
               
               
                 130 
                 C29H42N4O4S 
                 542.7 
                 542 
                 543 
               
               
                 131 
                 C31H43N4O4Cl 
                 571.2 
                 570 
                 571 
               
               
                 132 
                 C31H43N4O4Cl 
                 571.2 
                 570 
                 571 
               
               
                 133 
                 C31H43N4O4F 
                 554.7 
                 554 
                 555 
               
               
                 134 
                 C25H37N4O3Cl 
                 477.0 
                 476 
                 477 
               
               
                 135 
                 C31H45N5O5 
                 567.7 
                 567 
                 568 
               
               
                 136 
                 C34H45N5O4 
                 587.8 
                 587 
                 588 
               
               
                 137 
                 C28H41N5O4S 
                 543.7 
                 543 
                 544 
               
               
                 138 
                 C30H42N5O4Cl 
                 572.1 
                 571 
                 572 
               
               
                 139 
                 C30H42N5O4Cl 
                 572.1 
                 571 
                 572 
               
               
                 140 
                 C30H42N5O4F 
                 555.7 
                 555 
                 556 
               
               
                 141 
                 C32H44N4O5 
                 564.7 
                 564 
                 565 
               
               
                 142 
                 C35H44N4O4 
                 584.7 
                 584 
                 585 
               
               
                 143 
                 C29H40N4O4S 
                 540.7 
                 540 
                 541 
               
               
                 144 
                 C31H41N4O4Cl 
                 569.1 
                 568 
                 569 
               
               
                 145 
                 C31H41N4O4Cl 
                 569.1 
                 568 
                 569 
               
               
                 146 
                 C31H41N4O4F 
                 552.7 
                 552 
                 553 
               
               
                 147 
                 C31H43N5O5 
                 565.7 
                 565 
                 566 
               
               
                 148 
                 C34H43N5O4 
                 585.7 
                 585 
                 586 
               
               
                 149 
                 C30H40N5O4Cl 
                 570.1 
                 569 
                 570 
               
               
                 150 
                 C30H40N5O4Cl 
                 570.1 
                 569 
                 570 
               
               
                 151 
                 C30H40N5O4F 
                 553.7 
                 553 
                 554 
               
               
                 152 
                 C29H41N5O5 
                 539.7 
                 539 
                 540 
               
               
                 153 
                 C32H41N5O4 
                 559.7 
                 559 
                 560 
               
               
                 154 
                 C26H37N5O4S 
                 515.7 
                 515 
                 516 
               
               
                 155 
                 C28H38N5O4Cl 
                 544.1 
                 543 
                 544 
               
               
                 156 
                 C28H38N5O4Cl 
                 544.1 
                 543 
                 544 
               
               
                 157 
                 C28H38N5O4F 
                 527.6 
                 527 
                 528 
               
               
                 158 
                 C27H37N6O4Cl 
                 545.1 
                 544 
                 545 
               
               
                 159 
                 C31H44N4O5 
                 552.7 
                 552 
                 553 
               
               
                 160 
                 C31H44N4O5 
                 552.7 
                 552 
                 553 
               
               
                 161 
                 C31H45N5O4 
                 551.7 
                 551 
                 552 
               
               
                 162 
                 C31H44N4O4 
                 536.7 
                 536 
                 537 
               
               
                 163 
                 C31H44N4O4 
                 536.7 
                 536 
                 537 
               
               
                 164 
                 C31H44N4O4 
                 536.7 
                 536 
                 537 
               
               
                 165 
                 C31H44N4O5 
                 552.7 
                 552 
                 553 
               
               
                 166 
                 C31H44N4O5 
                 552.7 
                 552 
                 553 
               
               
                 167 
                 C32H42N4O4S 
                 578.8 
                 578 
                 579 
               
               
                 168 
                 C28H40N4O4S 
                 528.7 
                 528 
                 529 
               
               
                 169 
                 C31H43N4O4Cl 
                 571.2 
                 570 
                 571 
               
               
                 170 
                 C30H40N4O4Cl2 
                 591.6 
                 590 
                 591 
               
               
                 171 
                 C30H40N4O4F2 
                 558.7 
                 558 
                 559 
               
               
                 172 
                 C32H46N4O6 
                 582.7 
                 582 
                 583 
               
               
                 173 
                 C34H43N3O5 
                 573.7 
                 573 
                 574 
               
               
                 174 
                 C31H43N3O6 
                 553.7 
                 553 
                 554 
               
               
                 175 
                 C31H44N4O5 
                 552.7 
                 552 
                 553 
               
               
                 176 
                 C31H44N4O5 
                 552.7 
                 552 
                 553 
               
               
                 177 
                 C29H40N4O5 
                 524.7 
                 524 
                 525 
               
               
                 178 
                 C29H40N4O6 
                 540.7 
                 540 
                 541 
               
               
                 179 
                 C32H40N4O5 
                 560.7 
                 560 
                 561 
               
               
                 180 
                 C26H36N4O5S 
                 516.7 
                 516 
                 517 
               
               
                 181 
                 C28H37N4O5Cl 
                 545.1 
                 544 
                 545 
               
               
                 182 
                 C28H37N4O5Cl 
                 545.1 
                 544 
                 545 
               
               
                 183 
                 C28H37N4O5F 
                 528.6 
                 528 
                 529 
               
               
                 184 
                 C31H40N6O4 
                 560.7 
                 560 
                 561 
               
               
                 185 
                 C27H37N6O4Cl 
                 545.1 
                 544 
                 545 
               
               
                 186 
                 C31H40N6O5 
                 576.7 
                 576 
                 577 
               
               
                 187 
                 C31H41N4O4F3 
                 590.7 
                 590 
                 591 
               
               
                 188 
                 C30H41N4O4F 
                 540.7 
                 540 
                 541 
               
               
                 189 
                 C30H41N5O6 
                 567.7 
                 567 
                 568 
               
               
                 190 
                 C33H42N4O4S 
                 590.8 
                 590 
                 591 
               
               
                 191 
                 C32H44N4O5 
                 564.7 
                 564 
                 565 
               
               
                 192 
                 C31H40N4O4Cl2 
                 603.6 
                 602 
                 603 
               
               
                 193 
                 C31H40N4O4F2 
                 570.7 
                 570 
                 571 
               
               
                 194 
                 C32H48N6O6 
                 612.8 
                 612 
                 613 
               
               
                 195 
                 C32H46N4O5 
                 566.7 
                 566 
                 567 
               
               
                 196 
                 C32H43N6O4Cl 
                 611.2 
                 610 
                 611 
               
               
                 197 
                 C32H45N6O5Cl 
                 629.2 
                 628 
                 629 
               
               
                 198 
                 C32H43N4O4Cl 
                 583.2 
                 582 
                 583 
               
               
                 199 
                 C27H39N4O6Cl 
                 551.1 
                 550 
                 551 
               
               
                 200 
                 C31H39N4O4Cl 
                 567.1 
                 566 
                 567 
               
               
                 201 
                 C34H42N4O4 
                 570.7 
                 570 
                 571 
               
               
                 202 
                 C31H42N4O5 
                 550.7 
                 550 
                 551 
               
               
                 203 
                 C30H40N5O5Cl 
                 586.1 
                 585 
                 586 
               
               
                 204 
                 C29H40N7O4Cl 
                 586.1 
                 585 
                 586 
               
               
                 205 
                 C32H45N4O4Cl 
                 585.2 
                 584 
                 585 
               
               
                 206 
                 C29H40N5O6SCl 
                 622.2 
                 621 
                 622 
               
               
                 207 
                 C29H39N6O5Cl 
                 587.1 
                 586 
                 587 
               
               
                 208 
                 C29H41N7O5 
                 567.7 
                 567 
                 568 
               
               
                 209 
                 C30H41N5O6 
                 567.7 
                 567 
                 568 
               
               
                 210 
                 C31H45N5O5 
                 567.7 
                 567 
                 568 
               
               
                 211 
                 C30H42N5O4Cl 
                 572.1 
                 571 
                 572 
               
               
                 212 
                 C31H44N5O4Cl 
                 586.2 
                 585 
                 586 
               
               
                 213 
                 C30H40N4O5I2 
                 790.5 
                 790 
                 791 
               
               
                 214 
                 C30H42N4O6 
                 554.7 
                 554 
                 555 
               
               
                 215 
                 C30H43N5O5 
                 553.7 
                 553 
                 554 
               
               
                 216 
                 C32H43N4O4Cl 
                 583.2 
                 582 
                 583 
               
               
                 217 
                 C31H40N4O4FCl 
                 587.1 
                 586 
                 587 
               
               
                 218 
                 C31H43N4O4Cl 
                 571.2 
                 570 
                 571 
               
               
                 219 
                 C30H40N4O4Cl2 
                 591.6 
                 590 
                 591 
               
               
                 220 
                 C31H43N4O4F 
                 554.7 
                 554 
                 555 
               
               
                 221 
                 C30H40N4O4FCl 
                 575.1 
                 574 
                 575 
               
               
                 222 
                 C34H50N4O5 
                 594.8 
                 594 
                 595 
               
               
                 223 
                 C32H44N4O6 
                 580.7 
                 580 
                 581 
               
               
                 224 
                 C36H48N4O4 
                 600.8 
                 600 
                 601 
               
               
                 225 
                 C37H48N4O5 
                 628.8 
                 628 
                 629 
               
               
                 226 
                 C39H49N5O4S 
                 683.9 
                 683 
                 684 
               
               
                 227 
                 C42H52N4O4 
                 676.9 
                 676 
                 677 
               
               
                   
               
               
                 Notes 
               
               
                 1. Molecular formulas and molecular weights (MW) are calculated automatically from the structure via ActivityBase ® software (IDBS, Guildford, Surrey, UK) or, for MW only, from the freeware program Molecular Weight Calculator v. 6.32 
               
               
                 2. M + H obtained from LC-MS analysis using the General Method as described 
               
               
                 3. All analyses conducted on material after preparative HPLC purification 
               
             
          
         
       
     
       Biological Methods and Results 
       [0181]    The compounds of the present invention were evaluated for their ability to interact at the human motilin receptor utilizing a competitive radioligand binding assay as described in Method B1. Further characterization of the interaction can be performed utilizing the functional assays described in Methods B2, B3 and B4. Some of these methods can be conducted, if so desired, in a high throughput manner to permit the simultaneous evaluation of many compounds. Other assays have also been described that are suitable for HTS, such as that based upon the stable expression of a synthetic gene for the human motilin receptor. 
         [0182]    Results for the examination of representative compounds of the present invention using Method B1 are presented in Table 3. The binding activity is listed as ranges with the following levels: A=0.001-0.10 μM; B=0.10-1.0 μM; C=1.0-10.0 μM. In addition, the assay results of two additional compounds using this Method are shown below. As can be observed, this demonstrates the activity of a representative bicyclic compound of Formula IV of the invention, which resulted from incorporation of D-proline as the second recognition building block. Significantly, the lack of binding activity obtained with compound 121, which is the linear analogue of compound 1 (K i =level B), illustrates the critical importance of the cyclic structure to attaining the desired interaction. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0183]    Competitive binding curves for two representative compounds of the invention (Compounds 8 and 11) are presented hereinbelow: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0184]    For determination of functional significance of the binding, the compounds are preferably tested in the Aequorin assay as described in Method B2, although the procedure of Method B3 is also applicable. As can be seen from the data presented in Table 4, the representative compounds examined act as antagonists at the motilin receptor and are devoid of agonist activity at the concentrations studied. The functional activity is listed as ranges with the following levels: A=0.001-0.10 μM; B=0.10-1.0 μM. The higher sensitivity of the assay of Method B2, almost 100 times that of Method C, makes it the preferred one for this assessment. This is evident in the EC 50  values obtained in each for the positive agonist standard, motilin. Additionally, Method B2 measures the actual signaling event, which makes it more relevant to the effect that is desired, whereas the assay of Method B3 simply measures GTP turnover. 
         [0000]    
       
         
               
             
               
               
               
             
               
               
               
             
           
               
                 TABLE 4 
               
             
             
               
                   
               
               
                 Demonstration of Antagonist Activity at the Motilin Receptor 
               
             
          
           
               
                   
                 Aequorin (Method B2) 1   
                   
               
             
          
           
               
                 Compound 
                 Binding (K i ) 
                 IC 50   
               
               
                   
               
               
                 142 
                 A 
                 B 
               
               
                 149 
                 A 
                 B 
               
               
                 167 
                 A 
                 A 
               
               
                 168 
                 A 
                 A 
               
               
                 212 
                 A 
                 A 
               
               
                 Motilin 
                 0.6 
                 not applicable 
               
               
                 (human, porcine) 2   
               
               
                   
               
               
                   1 Activity is listed as ranges with the following levels: A = 0.001-0.10 μM; B = 0.10-1.0 μM 
               
               
                   2 Human and porClne motilin are the same peptide. 
               
             
          
         
       
     
         [0185]    In addition, a common and scientifically-accepted ex vivo assay for the measurement of agonist or antagonist activity at the motilin receptor is the contraction of rabbit duodenum or other gastrointestinal smooth muscle tissue. A2-A4  Agonists are defined as compounds that induce &gt;50% contraction relative to the motilin peptide, whereas antagonists are defined as compounds that cause &gt;50% inhibition of the response to motilin. Compounds of the present invention have shown significant antagonist activity in this assay. For example, compound 144 exhibited a pA 2 =6.95, while compound 165 had a pA 2 =7.17, as calculated from the Schild plots of the response obtained at various concentrations as described in Method B4. 
         [0186]    Gastric motility is generally measured in the clinical setting as the time required for gastric emptying and subsequent transit time through the GI tract. Gastric emptying scans are well known to those skilled in the art an, briefly, comprise use of an oral contrast agent, such as barium, or a radiolabeled meal. Solid and liquids can be measured independently. A test food or liquid is radiolabeled with an isotope ( 99m Tc) and after ingestion or administration, transit time through the GI tract and gastric emptying are measured by visualization using gamma cameras. These studies are performed before and after the administration of the therapeutic agent to quantify the efficacy of the compound. 
       Example Method B1 
     Competitive Radioligand Binding Assay (Motilin Receptor) 
     Materials: 
       [0000]    
       
         
           
             Membranes were prepared from CHO cells stably transfected with the human motilin receptor and utilized at a quantity of 1.5 μg/assay point. [PerkinElmer™ SignalScreen®) Product #6110544, PerkinElmer, Inc., Wellesley, Mass.] 
             [ 125 I]-Motilin (PerkinElmer, #NEX-378); final concentration: 0.04-0.06 nM 
             Motilin (Bachem™, #H-4385, Bachem Bioscience Inc., King of Prussia, Pa.); final concentration: 1 μM 
             Multiscreen® Harvest plates-GF/B (Millipore™, #MAHFB1H60, Billerica, Mass.) 
             Deep-well polypropylene titer plate (Beckman Coulter™, #267006, Fullerton, Calif.) 
             TopSeal-A™ (PerkinElmer, #6005185, Wellesley, Mass.) 
             Bottom seal (Millipore™, #MATAH0P00, Billerica, Mass.) 
             MicroScint-0™ (PerkinElmer, #6013611, Wellesley, Mass.) 
             Binding Buffer: 50 mM Tris-HCl (pH 7.4), 10 mM MgCl 2 , 1 mM EDTA, 0.1% BSA 
           
         
       
     
       Assay Volumes: 
       [0000]    
       
         
           
             150 μL of membranes diluted in binding buffer 
             10 μL of compound diluted in binding buffer 
             10 μL of radioligand ([ 125 I]-Motilin) diluted in binding buffer 
           
         
       
     
       Final Test Concentrations (N=11) for Compounds: 
       [0000]    
       
         
           
             10, 5, 2, 1, 0.5, 0.2, 0.1, 0.05, 0.02, 0.01, 0.005 μM. 
           
         
       
     
       Compound Handling: 
       [0200]    Compounds were provided frozen on dry ice at a stock concentration of 10 mM diluted in 100% DMSO and stored at −20° C. until the day of testing. On the test day, compounds were allowed to thaw at room temperature and than diluted in assay buffer according to the desired test concentrations. Under these conditions, the maximum final DMSO concentration in the assay was 0.5%. 
       Assay Protocol: 
       [0201]    In deep-well plates, diluted cell membranes (1.5 μg/mL) are combined with 10 μL of either binding buffer (total binding, N=5), 1 μM motilin (non-specific binding, N=3) or the appropriate concentration of test compound. The reaction is initiated by addition of 10 μl of [ 125 I]-motilin (final conc. 0.04-0.06 nM) to each well. Plates are sealed with TopSeal-A, vortexed gently and incubated at room temperature for 2 hours. The reaction is arrested by filtering samples through pre-soaked (0.3% polyethyleneimine, 2 h) Multiscreen Harvest plates using a Tomtec® Harvester (Tomtec, Hamden, Conn.)), washed 9 times with 500 μL of cold 50 mM Tris-HCl (pH 7.4), and than plates are air-dried in a fumehood for 30 minutes. A bottom seal is applied to the plates prior to the addition of 25 μL of MicroScint-0™ to each well. Plates are then sealed with TopSeal-A® and counted for 30 sec per well on a TopCount® Microplate Scintillation and Luminescence Counter (PerkinElmer, Wellesley, Mass.) where results are expressed as counts per minute (cpm). 
         [0202]    Data are analyzed by GraphPad™ Prism (GraphPad Software, San Diego, Calif.) using a variable slope non-linear regression analysis. K i  values were calculated using a K d  value of 0.16 nM for [ 125 I]-motilin (previously determined during membrane characterization). 
         [0000]    
       
         
           
             
               D 
               max 
             
             = 
             
               1 
               - 
               
                 
                   
                     
                       
                         
                           
                             test 
                              
                             
                                 
                             
                              
                             concentration 
                              
                             
                                 
                             
                              
                             with 
                              
                             
                                 
                             
                              
                             maximal 
                              
                             
                                 
                             
                              
                             displacement 
                           
                           - 
                         
                       
                     
                     
                       
                         
                           non 
                            
                           
                             - 
                           
                            
                           specific 
                            
                           
                               
                           
                            
                           binding 
                         
                       
                     
                   
                   
                     
                       total 
                        
                       
                           
                       
                        
                       binding 
                     
                      
                     
                         
                     
                     - 
                     
                         
                     
                      
                     
                       non 
                        
                       
                         - 
                       
                        
                       specific 
                        
                       
                           
                       
                        
                       binding 
                     
                   
                 
                 × 
                 100 
               
             
           
         
       
     
         [0000]    where total and non-specific binding represent the cpm obtained in the absence or presence of 1 μM motilin, respectively. 
       Example Method B2 
     Aequorin Functional Assay (Motilin Receptor) 
     Materials: 
       [0000]    
       
         
           
             Membranes were prepared using AequoScreen™ (EUROSCREEN, Belgium) cell lines expressing the human motilin receptor (cell line ES-380-A; receptor accession #AF034632). This cell line is constructed by transfection of the human motilin receptor into CHO-K1 cells co-expressing G α16  and the mitochondrially targeted Aequorin (Ref #ES-WT-A5). 
             Motilin (Bachem™, #H-4385, Bachem Bioscience Inc., King of Prussia, Pa.) 
             Assay buffer: DMEM-F12 (Dulbeccoe&#39;s Modified Eagles Medium) with 15 mM HEPES and 0.1% BSA (pH 7.0) 
             Coelenterazine (Molecular Probes™, Leiden, The Netherlands) 
           
         
       
     
       Final Test Concentrations (N=5) for Compounds: 
       [0000]    
       
         
           
             10, 3.16, 1, 0.316, 0.1 μM. 
           
         
       
     
       Compound Handling: 
       [0208]    Compounds were provided as dry films at a quantity of approximately 1.2 mmol in pre-formatted 96-well plates. Compounds were dissolved in 100% DMSO at a concentration of 10 mM and stored at −20° C. until further use. Daughter plates were prepared at a concentration of 500 μM in 30% DMSO with 0.1% BSA and stored at −20° C. until testing. On the test day, compounds were allowed to thaw at room temperature and than diluted in assay buffer according to the desired test concentrations. Under these conditions, the maximum final DMSO concentration in the assay was 0.6%. 
       Cell Preparation: 
       [0209]    Cells are collected from culture plates with Ca 2+  and Mg 2+ -free phosphate buffered saline (PBS) supplemented with 5 mM EDTA, pelleted for 2 minutes at 1000×g, resuspended in assay buffer (see above) at a density of 5×10 6  cells/mL and incubated overnight in the presence of 5 μM coelenterazine. After loading, cells were diluted with assay buffer to a concentration of 5×10 5  cells/mL. 
       Assay Protocol: 
       [0210]    For agonist testing, 50 μl of the cell suspension was mixed with 50 μl of the appropriate concentration of test compound or motilin (reference agonist) in 96-well plates (duplicate samples). The emission of light resulting from receptor activation was recorded using the Functional Drug Screening System 6000 ‘FDSS 6000’ (Hamamatsu Photonics K.K., Japan). 
         [0211]    For antagonist testing, an approximate EC80 concentration of motilin (i.e. 0.5 nM; 100 μL) was injected onto the cell suspension containing the test compounds (duplicate samples) 15-30 minutes after the end of agonist testing and the consequent emission of light resulting from receptor activation was measured as described in the paragraph above. 
         [0212]    Results are expressed as Relative Light Units (RLU). Concentration response curves were analyzed using GraphPad™ Prism® (GraphPad Software, San Diego, Calif.) by non-linear regression analysis (sigmoidal dose-response) based on the equation E=E max /(1+EC 50 /C)n where E is the measured RLU value at a given agonist concentration (C), E max  is the maximal response, EC 50  is the concentration producing 50% stimulation and n is the slope index. For agonist testing, results for each concentration of test compound were expressed as percent activation relative to the signal induced by motilin at a concentration equal to the EC 80  (i.e. 0.5 nM). For antagonist testing, results for each concentration of test compound were expressed as percent inhibition relative to the signal induced by motilin at a concentration equal to the EC 80  (i.e. 0.5 nM). 
       Example Method B3 
     FlashPlate® Motilin [ 35 S]-GTPγS Functional Assay 
     Materials: 
       [0000]    
       
         
           
             Membranes were prepared from CHO cells stably transfected with the human motilin receptor and utilized at a quantity of 1.5 μg/assay point. 
             [PerkinElmer™ SignalScreen® Product #6110544, PerkinElmer, Inc. Wellesley, Mass.] 
             GTPγS Guanosine 5′-[γ-thio]triphosphate tetralithium salt (Sigma, #G-8634, Sigma-Aldrich, St. Louis, Mo.) 
             [ 35 S]-GTPγS (PerkinElmer, #NEX-030H) 
             Motilin (Bachem™, #H-4385, Bachem Bioscience Inc., King of Prussia, Pa.) 
             96-well FlashPlate® white polystyrene microplates (PerkinElmer, #SMP200, Wellesley, Mass.) 
             Deep-well polypropylene titer plate (Beckman Coulter™, #267006, Fullerton, Calif.) 
             TopSeal-A™ (PerkinElmer, #6005185, Wellesley, Mass.) 
             Assay Buffer: 50 mM Tris (pH 7.4), 100 mM NaCl, 10 mM MgCl 2 , 1 mM EDTA, 1 μM GDP, 0.1% BSA 
           
         
       
     
       Assay Volumes: 
       [0000]    
       
         
           
             25 μL of compound diluted in assay buffer 
             25 μL of assay buffer (agonist assay) or 0.6 μM motilin (0.1 μM final concentration) diluted in assay buffer (antagonist assay) 
             100 μL of [ 35 S]-GTPγS diluted in assay buffer 
           
         
       
     
       Final Test Concentrations (N=12) for Compounds: 
       [0000]    
       
         
           
             50, 20, 10, 5, 2, 1, 0.5, 0.2, 0.1, 0.05, 0.02, 0.01 μM. 
           
         
       
     
       Compound Handling: 
       [0226]    Compounds were provided frozen on dry ice at a stock concentration of 10 mM diluted in 100% DMSO and stored at −20° C. until the day of testing. On the test day, compounds were allowed to thaw at room temperature and than diluted in assay buffer according to the desired test concentrations. Under these conditions, the maximum final DMSO concentration in the assay was 0.5%. 
       Assay Protocol: 
       [0227]    CHO membranes were immobilized into 96-well FlashPlate® microplates. Test compound, GTPγS, motilin and [ 35 S]-GTPγS were combined in each well according to the Assay Volumes described above. 
         [0228]    For the assay to measure agonist activity, an additional 25 μl of buffer was added to each well in addition to 25 μL of either buffer (basal value, N=4), 1 μM (final conc.) motilin (E max  value, N=3), 25 μM (final conc.) GTPγS (non-specific value, N=4), or the appropriate concentration of test compound (N=3). 
         [0229]    For the assay to measure antagonist activity, an additional 25 μL of either buffer (unstimulated control) or motilin (0.1 μM final conc.) is added to each well, in addition to either 25 μL of buffer (basal value, N=3), 1 μM (final conc.) motilin (E max  value, N=3), 25 μM (final conc.) GTPγS (non-specific value, N=4), or the appropriate concentration of test compound (N=3). 
         [0230]    The reaction is initiated by addition of 100 mL of [ 35 S]-GTPγS to each well. Each plate is sealed (TopSeal-A™) and incubated in the dark at room temperature for 150 min. Then, plates are counted for 30 seconds per well on the TopCount® NXT. 
         [0231]    Data were analyzed by GraphPad™ Prism® 3.0 (GraphPad Software, San Diego, Calif.) using non-linear regression analysis (sigmoidal dose-response) for the calculation of IC 50 /EC 50  values. 
         [0000]    
       
         
           
             
               
                 
                   E 
                   max 
                 
                  
                 
                   ( 
                   agonist 
                   ) 
                 
               
                
               
                   
               
                
               or 
                
               
                   
               
                
               
                 
                   D 
                   max 
                 
                  
                 
                   ( 
                   antagonist 
                   ) 
                 
               
             
             = 
             
               
                 
                   Top 
                   - 
                   Bottom 
                 
                 Bottom 
               
               × 
               100 
             
           
         
       
     
         [0232]    Where Top and Bottom correspond to the top and bottom values of the dose-response curve calculated by GraphPad™ Prism®). 
       Example Method B4 
     Rabbit Duodenum Contractility Assay 
       [0233]    Duodenal segments were vertically suspended in organ chambers of 10 mL filled with Krebs buffer and connected to an isotonic force transducer, with a preload of 1 g. After a stabilization period, the muscle strips were challenged with 10 −4  M acetylcholine and washed. This was repeated until a stable maximal contraction was obtained (2-3 times), with an interval of at least 20 minutes. 
         [0234]    After a stable base line was reached, test compounds were added to the bath. After 15 min incubation, a dose response to motilin was recorded by adding logarithmically increasing concentrations of motilin to the bath (final concentration 10 −9  to 10 −6  M). A blank experiment (no test compound present) was also performed. At the end of the dose response curve, a supramaximal dose of acetylcholine (10 −4  M) was given and this response was used as a reference (100% contraction). 
         [0235]    The results of experiments at different concentrations of test compound were combined and analyzed to derive the pA 2  value from the Schild plot. 
         [0236]    It is appreciated that although specific experimental methods have been described herein for the purposes of illustration, various modifications to these experimental methods as well as alternate methods of experimentation may be used without departing from the scope of this invention. 
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
             
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 3 
               
               
                   
               
             
             
               
                 Binding activity of selected compounds 
               
             
          
           
               
                   
                 R 1   
                 R 3   
                 R 6   
               
               
                   
                   
               
             
          
           
               
                 1 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 3 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 4 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CH3 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 7 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 8 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 10 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 11 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 12 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 13 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 14 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 15 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 16 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 17 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 18 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 19 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 20 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 21 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 22 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 23 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 24 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 25 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 26 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 27 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 28 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 29 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 30 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 34 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 38 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CH 3   
               
               
                   
               
               
                 39 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 40 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 41 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 52 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 55 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 56 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 57 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 58 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 59 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 60 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 65 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 71 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 72 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 76 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 77 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 80 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 85 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 87 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 88 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 89 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 90 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 91 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 92 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 96 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 97 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 98 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 99 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 109 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 110 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 111 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 112 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 122 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 123 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 124 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 125 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 126 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 127 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 128 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 129 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 130 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 131 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 132 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 133 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 134 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 135 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 136 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 137 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 138 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 139 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 140 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 141 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 142 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 143 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 144 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 145 
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 146 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 147 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 148 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 149 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 150 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 151 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 152 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 153 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 154 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 155 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 156 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 157 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 158 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 159 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 160 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 161 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 162 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 163 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 164 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 165 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 166 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 167 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 168 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 169 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 170 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 171 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 172 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 173 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 174 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 175 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 176 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 177 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 178 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 179 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 180 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 181 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 182 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 183 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 184 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 185 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 186 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 187 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 188 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 189 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 190 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 191 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 192 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 193 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 194 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 195 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 196 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 197 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 198 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 199 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 200 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 201 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 202 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 203 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 204 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 205 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 206 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 207 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 208 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 209 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 210 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 211 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 212 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 213 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 214 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 215 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 216 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 217 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 218 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 219 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 220 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 221 
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 222 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 223 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 224 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 225 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 226 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 227 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                 T 
                 K i   1,2   
               
               
                   
                   
               
             
          
           
               
                   
                 1 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 3 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 4 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 7 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 8 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 10 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 11 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 12 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 13 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 14 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 15 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 16 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 17 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 18 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 19 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 20 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 21 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 22 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 23 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 24 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 25 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 26 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 27 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 28 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 29 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 30 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 34 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 38 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 C 
               
               
                   
                   
               
               
                   
                 39 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 40 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 C 
               
               
                   
                   
               
               
                   
                 41 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 C 
               
               
                   
                   
               
               
                   
                 52 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 55 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 56 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 57 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 58 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 59 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 60 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 C 
               
               
                   
                   
               
               
                   
                 65 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 71 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 72 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 76 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 C 
               
               
                   
                   
               
               
                   
                 77 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 C 
               
               
                   
                   
               
               
                   
                 80 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 85 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 87 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 88 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 C 
               
               
                   
                   
               
               
                   
                 89 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 C 
               
               
                   
                   
               
               
                   
                 90 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 C 
               
               
                   
                   
               
               
                   
                 91 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 C 
               
               
                   
                   
               
               
                   
                 92 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 96 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 C 
               
               
                   
                   
               
               
                   
                 97 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 C 
               
               
                   
                   
               
               
                   
                 98 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 C 
               
               
                   
                   
               
               
                   
                 99 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 C 
               
               
                   
                   
               
               
                   
                 109 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 110 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 111 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 112 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 122 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 123 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 124 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 125 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 126 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 127 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 128 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 129 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 130 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 131 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 132 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 133 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 134 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 C 
               
               
                   
                   
               
               
                   
                 135 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 136 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 137 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 138 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 139 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 140 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 141 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 142 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 143 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 144 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 145 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 146 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 147 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 148 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 149 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 150 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 151 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 152 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 153 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 154 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 155 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 156 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 157 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 158 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 159 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 160 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 161 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 162 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 163 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 164 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 165 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 166 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 167 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 168 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 169 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 170 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 171 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 172 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 173 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 174 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 175 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 176 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 177 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 178 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 179 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 180 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 181 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 182 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 183 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 184 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 185 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 186 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 187 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 188 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 189 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 190 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 191 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 192 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 193 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 194 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 195 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 196 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 197 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 198 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 199 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 200 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 201 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 202 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 203 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 204 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 205 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 206 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 207 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 208 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 209 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 C 
               
               
                   
                   
               
               
                   
                 210 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 211 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 212 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 213 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 214 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 215 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 216 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 217 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 218 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 219 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 220 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 221 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 222 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
                   
               
               
                   
                 223 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 C 
               
               
                   
                   
               
               
                   
                 224 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 225 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 226 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 C 
               
               
                   
                   
               
               
                   
                 227 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B 
               
               
                   
                   
               
               
                   
                 Notes 
               
               
                   
                 Radioligand competitive binding assays performed using Method B1 
               
               
                   
                 Values reported as ranges: A = 0.001-0.100 μM; B = 0.100-1.0 μM; C = 1.0-10.0 μM 
               
             
          
         
       
     
         [0237]    X is NH except for: 
         [0238]    Compound 223 and 225, X is: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0239]    Compound 224, X is NMe 
         [0240]    Compound 226, X is: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0241]    Compound 227, X is 
         [0000]    
       
                 
         
             
             
         
       
     
         [0242]    Z 1 , Z 2  and Z 3  are NH except for compounds 30, 173 and 174 and where Z1 is O and compound 111 where Z 2  is O. 
         [0243]    R 2 , R 4  and R 5  are hydrogen except for compound 85 where it is: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    m, n 1  and p are zero.