Abstract:
Disclosed are novel compounds of the formula  
                         
 
     wherein R 1  is optionally substituted benzimidazolyl or a derivative thereof; R 2  is optionally substitutd aryl or heteroaryl; M 1  and M 2  are C(R 3 ) or N; Q is —N(R 8 )—, —S— or —O—; and the remaining variables are as defined in the specification.  
     Also disclosed are pharmaceutical compositions comprising the compounds of formula I and methods of treating various diseases or conditions, such as allergy, allergy-induced airway responses, and congestion (e.g., nasal congestion) using the compounds of formula I.  
     Also disclosed are methods of treating said diseases or conditions using the compounds of formula I in combination with an H 1  receptor antagonist.

Description:
CROSS REFERENCE TO RELATED APPLICATION  
       [0001]    This application claims the benefit of U.S. Provisional Application No. 60/373,731, filed Apr. 18, 2002. 
     
    
     
       FIELD OF THE INVENTION  
         [0002]    The present invention relates to novel substituted benzimidazoles and aza- and diaza-derivatives thereof useful as histamine H 3  antagonists. The invention also relates to pharmaceutical compositions comprising said compounds and their use in treating inflammatory diseases, allergic conditions and central nervous system disorders. The invention also relates to the use of a combination of novel histamine H 3  antagonists of this invention with histamine H 1  compounds for the treatment of inflammatory diseases and allergic conditions, as well as pharmaceutical compositions comprising a combination of one or more novel histamine H 3  antagonist compounds of the invention with one or more histamine HI compounds.  
         BACKGROUND OF THE INVENTION  
         [0003]    The histamine receptors, H 1 , H 2  and H 3  are well-identified forms. The H 1  receptors are those that mediate the response antagonized by conventional antihistamines. H 1  receptors are present, for example, in the ileum, the skin, and the bronchial smooth muscle of humans and other mammals. Through H 2  receptor-mediated responses, histamine stimulates gastric acid secretion in mammals and the chronotropic effect in isolated mammalian atria.  
           [0004]    H 3  receptor sites are found on sympathetic nerves, where they modulate sympathetic neurotransmission and attenuate a variety of end organ responses under control of the sympathetic nervous system. Specifically, H 3  receptor activation by histamine attenuates norepinephrine outflow to resistance and capacitance vessels, causing vasodilation.  
           [0005]    Imidazole H 3  receptor antagonists are well known in the art. More recently, non-imidazole H 3  receptor antagonists have been disclosed in PCT US01/32151, filed Oct. 15, 2001, and U.S. Provisional Application No. 60/275,417, filed Mar. 13, 2001.  
           [0006]    U.S. Pat. No. 5,869,479 discloses compositions for the treatment of the symptoms of allergic rhinitis using a combination of at least one histamine H 1  receptor antagonist and at least one histamine H 3  receptor antagonist.  
         SUMMARY OF THE INVENTION  
         [0007]    The present invention provides novel compounds of formula I:  
                         
 
           [0008]    or a pharmaceutically acceptable salt or solvate thereof, wherein:  
           [0009]    the dotted line represents an optional double bond;  
           [0010]    a is 0 to 2;  
           [0011]    b is 0 to 2;  
           [0012]    n is 1, 2 or 3;  
           [0013]    p is 1, 2 or 3;  
           [0014]    r is 0, 1, 2, or 3;  
           [0015]    with the provisos that when M 2  is N, p is not 1; and that when r is 0, M 2  is C(R 3 ); and that the sum of p and r is 1 to 4;  
           [0016]    M 1  is C(R 3 ) or N;  
           [0017]    M 2  is C(R 3 ) or N;  
           [0018]    X is a bond or C 1 -C 6  alkylene;  
           [0019]    Y is —C(O)—, —C(S)—, —(CH 2 ) q —, —NR 4 C(O)—, —C(O)NR 4 —, —C(O)CH 2 —, —SO 2 —, —N(R 4 )—, —NH—C(═N—CN)— or —C(═N—CN)—NH—; with the provisos that when M 1  is N, Y is not —NR 4 C(O)— or —NH—C(═N—CN)—; when M 2  is N, Y is not —C(O)NR 4 — or —C(═N—CN)—NH—; and when Y is —N(R 4 )—, M 1  is CH and M 2  is C(R 3 );  
           [0020]    q is 1 to 5, provided that when both M 1  and M 2  are N, q is 2 to 5;  
           [0021]    Z is a bond, C 1 -C 6  alkylene, C 1 -C 6  alkenylene, —C(O)—, —CH(CN)—, —SO 2 — or —CH 2 C(O)NR 4 —;  
                         
 
           [0022]    Q is —N(R 8 )—, —S— or —O—;  
           [0023]    k is 0, 1, 2, 3 or 4;  
           [0024]    k1 is 0, 1, 2 or 3;  
           [0025]    k2 is 0, 1 or 2;  
           [0026]    R is H, C 1 -C 6  alkyl, halo(C 1 -C 6 )alkyl-, C 1 -C 6  alkoxy, (C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl-, (C 1 -C 6 )-alkoxy-(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl-SO 0-2 , R 32 -aryl(C 1 -C 6 )alkoxy-, R 32 -aryl(C 1 -C 6 )alkyl-, R 32 -aryl, R 32 -aryloxy, R 32 -heteroaryl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl-(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl-(C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl-oxy-, R 37 -heterocycloalkyl, R 37 -heterocycloalkyl-oxy-, R 37 -heterocycloalkyl-(C 1 -C 6 )alkoxy, N(R 30 )(R 31 )—(C 1 -C 6 )alkyl-, —N(R 30 )(R 31 ), —NH—(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl, —NHC(O)NH(R 29 ); R 29 —S(O) 0-2 —, halo(C 1 -C 6 )alkyl-S(O) 0-2 —, N(R 30 )(R 31 )—(C 1 -C 6 )alkyl-S(O) 0-2 — or benzoyl;  
           [0027]    R 8  is H, C 1 -C 6  alkyl, halo(C 1 -C 6 )alkyl-, (C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl-, R 32 -aryl(C 1 -C 6 )alkyl-, R 32 -aryl, R 32 -heteroaryl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl-(C 1 -C 6 )alkyl, R 37 -heterocycloalkyl, N(R 30 )(R 31 )—(C 1 -C 6 )alkyl-, R 29 —S(O) 2 —, halo(C 1 -C 6 )alkyl-S(O) 2 —, R 29 —S(O) 0-1 —(C 2 -C 6 )alkyl-, halo(C 1 -C 6 )alkyl-S(O) 0-1 —(C 2 -C 6 )alkyl-;  
           [0028]    R 2  is a six-membered heteroaryl ring having 1 or 2 heteroatoms independently selected from N or N—O, with the remaining ring atoms being carbon; a five-membered heteroaryl ring having 1, 2, 3 or 4 heteroatoms independently selected from N, O or S, with the remaining ring atoms being carbon; R 32 -quinolyl; R 32 -aryl; heterocycloalkyl; (C 3 -C 6 )cycloalkyl; C 1 -C 6  alkyl; hydrogen; thianaphthenyl;  
                         
 
           [0029]    wherein said six-membered heteroaryl ring or said five-membered heteroaryl ring is optionally substituted by R 6 ;  
           [0030]    R 3  is H, halogen, C 1 -C 6  alkyl, —OH, (C 1 -C 6 )alkoxy or —NHSO 2 —(C 1 -C 6 )alkyl;  
           [0031]    R 4  is independently selected from the group consisting of hydrogen, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, R 33 -aryl, R 33 -aryl(C 1 -C 6 )alkyl, and R 32 -heteroaryl;  
           [0032]    R 5  is hydrogen, C 1 -C 6  alkyl, —C(O)R 20 , —C(O) 2 R 2 , —C(O)N(R 20 ) 2 , (C 1 -C 6 )alkyl-SO 2 —, or (C 1 -C 6 )alkyl-SO 2 —NH—;  
           [0033]    or R 4  and R 5 , together with the nitrogen to which they are attached, form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring;  
           [0034]    R 6  is 1 to 3 substituents independently selected from the group consisting of —OH, halogen, C 1 -C 6  alkyl-, C 1 -C 6  alkoxy, C 1 -C 6  alkylthio, —CF 3 , —NR 4 R 5 , —CH 2 —NR 4 R 5 , —NHSO 2 R 22 , —N(SO 2 R 22 ) 2 , phenyl, R 33 -phenyl, NO 2 , —CO 2 R 4 , —CON(R 4 ) 2 ,  
                         
 
           [0035]    R 7  is —N(R 29 )—, —O— or —S(O) 0-2 —;  
           [0036]    R 12  is independently selected from the group consisting of C 1 -C 6  alkyl, hydroxyl, C 1 -C 6  alkoxy, or fluoro, provided that when R 12  is hydroxy or fluoro, then R 12  is not bound to a carbon adjacent to a nitrogen; or two R 12  substituents form a C 1  to C 2  alkyl bridge from one ring carbon to another non-adjacent ring carbon; or R 12  is ═O;  
           [0037]    R 13  is independently selected from the group consisting of C 1 -C 6  alkyl, hydroxyl, C 1 -C 6  alkoxy, or fluoro, provided that when R 13  is hydroxy or fluoro then R 13  is not bound to a carbon adjacent to a nitrogen; or two R 13  substituents form a C 1  to C 2  alkyl bridge from one ring carbon to another non-adjacent ring carbon; or R 13  is ═O;  
           [0038]    R 20  is independently selected from the group consisting of hydrogen, C 1 -C 6  alkyl, or aryl, wherein said aryl group is optionally substituted with from 1 to 3 groups independently selected from halogen, —CF 3 , —OCF 3 , hydroxyl, or methoxy; or when two R 20  groups are present, said two R 20  groups taken together with the nitrogen to which they are bound can form a five or six membered heterocyclic ring;  
           [0039]    R 22  is C 1 -C 6  alkyl, R 34 -aryl or heterocycloalkyl;  
           [0040]    R 24  is H, C 1 -C 6  alkyl, —SO 2 R 22  or R 34 -aryl;  
           [0041]    R 25  is independently selected from the group consisting of C 1 -C 6  alkyl, halogen, —CN, —NO 2 , —CF 3 , —OH, C 1 -C 6  alkoxy, (C 1 -C 6 )alkyl-C(O)—, aryl-C(O)—, —C(O)OR 29 , —N(R 4 )(R 5 ), N(R 4 )(R 5 )—C(O)—, N(R 4 )(R 5 )—S(O) 1-2 —, R 22 —S(O) 0-2 —, halo-(C 1 -C 6 )alkyl- or halo-(C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl-;  
           [0042]    R 29  is H, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, R 35 -aryl or R 35 -aryl(C 1 -C 6 )alkyl-;  
           [0043]    R 30  is H, C 1 -C 6  alkyl-, R 35 -aryl or R 35 -aryl(C 1 -C 6 )alkyl-;  
           [0044]    R 31  is H, C 1 -C 6  alkyl-, R 35 -aryl, R 35 -aryl(C 1 -C 6 )alkyl-, R 35 -heteroaryl, (C 1 -C 6 )alkyl-C(O)—, R 35 -aryl-C(O)—, N(R 4 )(R 5 )—C(O)—, (C 1 -C 6 )alkyl-S(O) 2 — or R 35 -aryl-S(O) 2 —;  
           [0045]    or R 30  and R 31  together are —(CH 2 ) 4-5 —, —(CH 2 ) 2 —O—(CH 2 ) 2 — or —(CH 2 ) 2 —N(R 38 )—(CH 2 ) 2 — and form a ring with the nitrogen to which they are attached;  
           [0046]    R 32  is 1 to 3 substituents independently selected from the group consisting of H, —OH, halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, R 35 -aryl-O—, —SR 22 , —CF 3 , —OCF 3 , —OCHF 2 , —NR 39 R 40 , phenyl, R 33 -phenyl, NO 2 , —CO 2 R 39 , —CON(R 39 ) 2 , —S(O) 2 R 22 , —S(O) 2 N(R 20 ) 2 , —N(R 24 )S(O) 2 R 22 , —CN, hydroxy-(C 1 -C 6 )alkyl-, —OCH 2 CH 2 OR 22 , and R 35 -aryl(C 1 -C 6 )alkyl-O—, or two R 32  groups on adjacent carbon atoms together form a —OCH 2 O— or —O(CH 2 ) 2 O— group;  
           [0047]    R 33  is 1 to 3 substituents independently selected from the group consisting of C 1 -C 6  alkyl, halogen, —CN, —NO 2 , —CF 3 , —OCF 3 , —OCHF 2  and —O—(C 1 -C 6 )alkyl;  
           [0048]    R 34  is 1 to 3 substituents independently selected from the group consisting of H, halogen, —CF 3 , —OCF 3 , —OH and —OCH 3 ;  
           [0049]    R 35  is 1 to 3 substituents independently selected from hydrogen, halo, C 1 -C 6  alkyl, hydroxy, C 1 -C 6  alkoxy, phenoxy, —CF 3 , —N(R 36 ) 2 , —COOR 20  and —NO 2 ;  
           [0050]    R 36  is independently selected form the group consisting of H and C 1 -C 6  alkyl;  
           [0051]    R 37  is 1 to 3 substituents independently selected from hydrogen, halo, C 1 -C 6  alkyl, hydroxy, C 1 -C 6  alkoxy, phenoxy, —CF 3 , —N(R 36 ) 2 , —COOR 20 , —C(O)N(R 29 ) 2  and —NO 2 , or R 37  is one or two ═O groups;  
           [0052]    R 33  is H, C 1 -C 6  alkyl, R 35 -aryl, R 35 -aryl(C 1 -C 6 )alkyl-, (C 1 -C 6 )alkyl-SO 2  or halo(C 1 -C 6 )alkyl-SO 2 —;  
           [0053]    R 39  is independently selected from the group consisting of hydrogen, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, R 33 -aryl, R 33 -aryl(C 1 -C 6 )alkyl, and R 32 -heteroaryl; and  
           [0054]    R 40  is hydrogen, C 1 -C 6  alkyl, —C(O)R 20 , —C(O) 2 R 20 , —C(O)N(R 20 ) 2 , (C 1 -C 6 )alkyl-SO 2 —, or (C 1 -C 6 )alkyl-SO 2 —NH—;  
           [0055]    or R 39  and R 40 , together with the nitrogen to which they are attached, form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring;  
           [0056]    This invention also provides a pharmaceutical composition comprising an effective amount of compound of at least one compound of formula I and a pharmaceutically acceptable carrier.  
           [0057]    This invention further provides a method of treating: allergy, allergy-induced airway (e.g., upper airway) responses, congestion (e.g., nasal congestion), hypotension, cardiovascular disease, diseases of the GI tract, hyper and hypo motility and acidic secretion of the gastro-intestinal tract, obesity, sleeping disorders (e.g., hypersomnia, somnolence, and narcolepsy), disturbances of the central nervous system, attention deficit hyperactivity disorder (ADHD), hypo and hyperactivity of the central nervous system (for example, agitation and depression), and/or other CNS disorders (such as Alzheimer&#39;s, schizophrenia, and migraine) comprising administering to a patient in need of such treatment (e.g., a mammal, such as a human being) an effective amount of at least one compound of formula I.  
           [0058]    Compounds of this invention are particularly useful for treating allergy, allergy-induced airway responses and/or congestion.  
           [0059]    This invention further provides a pharmaceutical composition comprising an effective amount of a combination of at least one compound of formula I and at least one H 1  receptor antagonist in combination with a pharmaceutically acceptable carrier.  
           [0060]    This invention further provides a method of treating allergy, allergy-induced airway (e.g., upper airway) responses, and/or congestion (e.g., nasal congestion) comprising administering to a patient in need of such treatment (e.g., a mammal, such as a human being) an effective amount of a combination of at least one compound of formula I and at least one HI receptor antagonist.  
           [0061]    Kits comprising a compound of formula I in a pharmaceutical composition, and a separate H 1  receptor antagonist in a pharmaceutical compositions in a single package are also contemplated.  
         DETAILED DESCRIPTION OF THE INVENTION  
         [0062]    Preferred definitions of the variables in the structure of formula I are as follows:  
           [0063]    R 1  is preferably optionally substituted benzimidazolyl or 7-azabenzimidazolyl, wherein R is preferably alkyl, alkoxy, alkoxyalkoxy, alkylthio, heteroaryl or R 32 -aryl. More preferably, R is —CH 3 , —CH 2 CH 3 , —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 CH 3 , —OCH((CH 3 ) 2 , —SCH 3 , —SCH 2 CH 3 , pyridyl (especially 2-pyridyl), pyrimidyl, pyrazinyl, furanyl, oxazolyl or R 32 -phenyl.  
           [0064]    R 25  is preferably halogen or —CF 3  and k is 0 or 1.  
           [0065]    R 2  is preferably a six-membered heteroaryl ring, optionally substituted with one substituent. More preferably, R 2  is pyrimidyl, R 6 -pyrimidyl, pyridyl, R 6 -pyridyl or pyridazinyl, wherein R 6  is —NR 4 R 5 , wherein R 4  and R 5  are independently selected from the group consisting of H and (C 1 -C 6 )alkyl, or R 4  and R 5  together with the nitrogen to which they are attached form a pyrrolidinyl, piperidinyl or morpholinyl ring. More preferably, R 6  is —NH 2 .  
           [0066]    X is preferably a bond.  
           [0067]    Y is preferably —C(O)—.  
           [0068]    Z is preferably straight or branched C 1 -C 3  alkyl.  
           [0069]    M 1  is preferably N; a is preferably 0; and n is preferably 2; the optional double bond is preferably not present (i.e., a single bond is present).  
           [0070]    M 2  is preferably C(R 3 ) wherein R 3  is hydrogen or fluorine; b is preferably 0; r is preferably 1; and p is preferably 2.  
           [0071]    As used herein, the following terms have the following meanings, unless indicated otherwise:  
           [0072]    alkyl (including, for example, the alkyl portions of arylalkyl and alkoxy) represents straight and branched carbon chains and contains from one to six carbon atoms;  
           [0073]    alkylene represents a divalent straight or branched alkyl chain, e.g., ethylene (—CH 2 CH 2 —) or propylene (—CH 2 CH 2 CH 2 —);  
           [0074]    Haloalkyl and haloalkoxy represent alkyl or alkoxy chains wherein one or more hydrogen atoms are replaced by halogen atoms, e.g., —CF 3 , CF 3 CH 2 CH 2 —, CF 3 CF 2 — or CF 3 S;  
           [0075]    aryl (including the aryl portion of arylalkyl) represents a carbocyclic group containing from 6 to 14 carbon atoms and having at least one aromatic ring (e.g., aryl is a phenyl or naphthyl ring), with all available substitutable carbon atoms of the carbocyclic group being intended as possible points of attachment;  
           [0076]    arylalkyl represents an aryl group, as defined above, bound to an alkyl group, as defined above, wherein said alkyl group is bound to the compound;  
           [0077]    cycloalkyl represents saturated carbocyclic rings of from 3 to 6 carbon atoms;  
           [0078]    halogen (halo) represents fluoro, chloro, bromo and iodo;  
           [0079]    heteroaryl represents cyclic groups, having 1 to 4 heteroatoms selected from O, S or N, said heteroatom interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, with the aromatic heterocyclic groups preferably containing from 2 to 14 carbon atoms; examples include but are not limited to isothiazolyl, isoxazolyl, oxazolyl, furazanyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, isothiadiazolyl, thienyl, furanyl (furyl), pyrrolyl, pyrazolyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridyl (e.g., 2-, 3-, or 4-pyridyl), pyridyl N-oxide (e.g., 2-, 3-, or 4-pyridyl N-oxide), triazinyl, pteridinyl, indolyl (benzopyrrolyl), pyridopyrazinyl, isoqinolinyl, quinolinyl, naphthyridinyl; the 5- and 6-membered heteroaryl groups included in the definition of R 2  are exemplified by the heteroaryl groups listed above; all available substitutable carbon and nitrogen atoms can be substituted as defined;  
           [0080]    heterocycloalkyl represents a saturated, carbocylic ring containing from 3 to 15 carbon atoms, preferably from 4 to 6 carbon atoms; examples include but are not limited to 2- or 3-tetrahydrofuranyl, 2- or 3-tetrahydrothienyl, 2-, 3- or 4-piperidinyl, 2- or 3-pyrrolidinyl, 2- or 3-piperazinyl, 2- or 4-dioxanyl, 1,3-dioxolanyl, 1,3,5-trithianyl, pentamethylene sulfide, perhydroisoquinolinyl, decahydroquinolinyl, trimethylene oxide, azetidinyl, 1-azacycloheptanyl, 1,3-dithianyl, 1,3,5-trioxanyl, morpholinyl, thiomorpholinyl, 1,4-thioxanyl, and 1,3,5-hexahydrotriazinyl, thiazolidinyl, tetrahydropyranyl.  
           [0081]    In the definition of R 32 , when two R 32  groups on adjacent carbon atoms of an aryl or heteroaryl ring are said to be taken together form a —OCH 2 O— or —O(CH 2 ) 2 O— group, this means that the two R 32  groups form a methylenedioxy or ethylenedioxy ring fused to the aryl or heteroaryl ring. When R 12 , R 13  or R 37  is said to be one or two ═O groups, this means that two hydrogen atoms on the same carbon atom of the ring can be replaced by ═O; two such groups can be present on a ring.  
           [0082]    {circle over (N)} for example in the structure  
                         
 
           [0083]    represents a nitrogen atom that is located at one of the 4 non-fused positions of the ring, i.e., positions 4, 5, 6 or 7 indicated below:  
                         
 
           [0084]    Similarly, {circle over (2N)} means that two nitrogens are located at any two of the 4 non-fused positions of the ring, e.g., the 4 and 6 positions, the 4 and 7 positions, or the 5 and 6 positions.  
           [0085]    Also, as used herein, “upper airway” usually means the upper respiratory system—i.e., the nose, throat, and associated structures.  
           [0086]    Also, as used herein, “effective amount” generally means a therapeutically effective amount.  
           [0087]    “Patient” means a mammal, typically a human, although veterinary use is also contemplated.  
           [0088]    Lines drawn into the rings indicate that the indicated bond may be attached to any of the substitutable ring carbon atoms.  
           [0089]    Certain compounds of the invention may exist in different isomeric (e.g., enantiomeric, diastereoisomeric and geometric) forms. The invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures. Enol forms and tautomers are also included.  
           [0090]    The compounds of this invention are ligands for the histamine H 3  receptor. The compounds of this invention can also be described as antagonists of the H 3  receptor, or as H 3  antagonists.  
           [0091]    The compounds of the invention are basic and form pharmaceutically acceptable salts with organic and inorganic acids. Examples of suitable acids for such salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their corresponding salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to their corresponding free base forms for purposes of this invention.  
           [0092]    Depending upon the substituents on the inventive compounds, one may be able to form salts with bases. Thus, for example, if there are carboxylic acid substituents in the molecule, salts may be formed with inorganic as well as organic bases such as, for example, NaOH, KOH, NH 4 OH, tetraalkylammonium hydroxide, and the like.  
           [0093]    The compounds of formula I can exist in unsolvated as well as solvated forms, including hydrated forms, e.g., hemi-hydrate. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated forms for purposes of the invention.  
           [0094]    The compounds of this invention can be combined with an H 1  receptor antagonist (i.e., the compounds of this invention can be combined with an H 1  receptor antagonist in a pharmaceutical composition, or the compounds of this invention can be administered with H 1  receptor antagonist).  
           [0095]    Numerous chemical substances are known to have histamine H 1  receptor antagonist activity and can therefore be used in the methods of this invention. Many H 1  receptor antagonists useful in the methods of this invention can be classified as ethanolamines, ethylenediamines, alkylamines, phenothiazines or piperidines. Representative H 1  receptor antagonists include, without limitation: astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine, diphenhydramine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, meclizine, mizolastine, mequitazine, mianserin, noberastine, norastemizole, picumast, pyrilamine, promethazine, terfenadine, tripelennamine, temelastine, trimeprazine and triprolidine. Other compounds can readily be evaluated to determine activity at H 1  receptors by known methods, including specific blockade of the contractile response to histamine of isolated guinea pig ileum. See for example, WO98/06394 published Feb. 19, 1998.  
           [0096]    Those skilled in the art will appreciate that the H 1  receptor antagonist is used at its known therapeutically effective dose, or the H 1  receptor antagonist is used at its normally prescribed dosage.  
           [0097]    Preferably, said H 1  receptor antagonist is selected from: astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine, diphenhydramine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, meclizine, mizolastine, mequitazine, mianserin, noberastine, norastemizole, picumast, pyrilamine, promethazine, terfenadine, tripelennamine, temelastine, trimeprazine or triprolidine.  
           [0098]    More preferably, said H 1  receptor antagonist is selected from: astemizole, azatadine, azelastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, carebastine, descarboethoxyloratadine, diphenhydramine, doxylamine, ebastine, fexofenadine, loratadine, levocabastine, mizolastine, norastemizole, or terfenadine.  
           [0099]    Most preferably, said H 1  receptor antagonist is selected from: azatadine, brompheniramine, cetirizine, chlorpheniramine, carebastine, descarboethoxy-loratadine, diphenhydramine, ebastine, fexofenadine, loratadine, or norastemizole.  
           [0100]    Even more preferably, said H 1  antagonist is selected from loratadine, descarboethoxyloratadine, fexofenadine or cetirizine. Still even more preferably, said H 1  antagonist is loratadine or descarboethoxyloratadine.  
           [0101]    In one preferred embodiment, said H 1  receptor antagonist is loratadine.  
           [0102]    In another preferred embodiment, said H 1  receptor antagonist is descarboethoxyloratadine.  
           [0103]    In still another preferred embodiment, said H 1  receptor antagonist is fexofenadine.  
           [0104]    In yet another preferred embodiment, said H 1  receptor antagonist is cetirizine.  
           [0105]    Preferably, in the above methods, allergy-induced airway responses are treated.  
           [0106]    Also, preferably, in the above methods, allergy is treated.  
           [0107]    Also, preferably, in the above methods, nasal congestion is treated.  
           [0108]    In the methods of this invention wherein a combination of an H 3  antagonist of this invention (compound of formula I) is administered with a H 1  antagonist, the antagonists can be administered simultaneously or sequentially (first one and then the other over a period of time). In general, when the antagonists are administered sequentially, the H 3  antagonist of this invention (compound of formula 1) is administered first.  
           [0109]    Compounds of the present invention can be prepared by a number of ways evident to one skilled in the art. Preferred methods include, but are not limited to, the general synthetic procedures described herein. One skilled in the art will recognize that one route will be optimal depending on the choice of appendage substituents. Additionally, one skilled in the art will recognize that in some cases the order of steps has to be controlled to avoid functional group incompatibilities.  
           [0110]    The starting material and reagents used in preparing compounds described are either available from commercial suppliers such as Aldrich Chemical Co. (Wisconsin, USA) and Acros Organics Co. (New Jersey, USA) or were prepared by literature methods known to those skilled in the art.  
           [0111]    One skilled in the art will recognize that the synthesis of compounds of formula I may require the construction of carbon-nitrogen bond. Methods include but are not limited to the use of a substituted aromatic compound or heteroaromatic compound and amine at 0° C. to 200° C. The reaction may be carried out neat or in a solvent. Suitable solvents for the reaction are halogenated hydrocarbons, ethereal solvents, toluene, dimethylformamide and the like.  
           [0112]    One skilled in the art will recognize that the synthesis of compounds of formula I may require the construction of heterocycle. Methods include but are not limited to the use of a diamino compound and a carbonyl equivalent at 0° C. to 200° C. The reaction may be carried out in acidic, basic or neutral conditions. Suitable solvents for the reaction are water, halogenated hydrocarbons, ethereal solvents, alcoholic solvents, toluene, ketones, dimethylformamide and the like.  
           [0113]    One skilled in the art will recognize that the synthesis of compounds of formula I may require the need for the protection of certain functional groups (i.e. derivatization for the purpose of chemical compatibility with a particular reaction condition). See, for example, Green et al,  Protective Groups in Organic Synthesis . A suitable protecting group for an amine is methyl, benzyl, ethoxyethyl, t-butoxycarbonyl, phthaloyl and the like which can appended to and removed by literature methods known to those skilled in the art.  
           [0114]    One skilled in the art will recognize that the synthesis of compounds of formula I may require the construction of an amide bond. Methods include but are not limited to the use of a reactive carboxy derivative (e.g. acid halide) or the use of an acid with a coupling reagent (e.g. EDCI, DCC, HATU) with an amine at 0° C. to 100° C. Suitable solvents for the reaction are halogenated hydrocarbons, ethereal solvents, dimethylformamide and alike.  
           [0115]    One skilled in the art will recognize that the synthesis of compounds of formula I may require the reduction of a functional group. Suitable reducing reagents for the reaction include NaBH 4 , lithium aluminum hydride, diborane and the like at −20° C. to 100° C. Suitable solvents for the reaction are halogenated hydrocarbons, ethereal solvents, and the like.  
           [0116]    The starting materials and the intermediates of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and alike. Such materials can be characterized using conventional means, including physical constants and spectral data.  
           [0117]    One method shown in Scheme 1, below, is for the preparation of compounds of formula IA wherein R 1  is 1-benzimidazolyl or 2-benzamidazolyl and X is a bond or alkyl. Similar procedures can be used to prepare compounds wherein the benzene ring of the benzimidazolyl group is substituted, as well as the aza-benzimidazoles compounds (i.e., compounds wherein R 1  is other than benzimidazolyl as defined above) and the benzoxazolyl and benzothiazolyl derivatives.  
                         
 
           [0118]    Step a: A suitably monoprotected diamine of formula X, wherein X is a bond or alkyl, Prot is a protecting group, and the remaining variables are as defined above is alkylated or arylated with a halide. The intermediate diamine is then cyclized with an appropriate carbonyl or formyl equivalent to form a compound of formula XI. Suitable protecting groups are methyl, benzyl, butoxycarbonyl, or ethoxycarbonyl. A suitable halide for alkylation is a substituted aromatic compound or a substituted hetero-aromatic compound as described by Henning et al,  J. Med. Chem.  30, (1987), 814-819.  
           [0119]    Step b: The protected amine of formula XI is deprotected using methods known to those skilled in the art. A suitable method for methyl deprotection is reaction with a haloformate or the like. A suitable method for benzyl deprotection is cleavage with hydrogen at or above atmospheric pressure and a catalyst such as palladium. Suitable methods for carbamate deprotection are treatment with an acid, base or trimethylsilyl iodide.  
           [0120]    Step c: An amine of formula XII is reacted with an activated functional group Y of formula XIII to form the bond between the nitrogen and functional group Y in formula IA. When Y is a carbonyl group and M 2  is carbon, activation can be via a halide (i.e. acid chloride intermediate) or other coupling reagents (EDCI, DCC, HATU, or like). Suitable reaction conditions may require a base such as triethylamine or N,N-diisopropylethylamine.  
           [0121]    Another method for the preparation of compounds of formula IA wherein R 1  is 1-benzimidazolyl or 2-benzimidazolyl and X is a bond or alkyl is shown in Scheme 2, below. Similar procedures can be used to prepare compounds wherein the benzene ring of the benzimidazolyl group is substituted, as well as the aza-benzimidazoles compounds (i.e., compounds wherein R 1  is other than benzimidazolyl as defined above).  
                         
 
           [0122]    Step d: A suitably monoprotected diamine of formula X, wherein X is a bond or alkyl, Prot is a protecting group, and the remaining variables are as defined above, is alkylated or arylated with a halide to form a compound of formula XIV. Suitable protecting groups are methyl, benzyl, butoxycarbonyl, and ethoxycarbonyl. A suitable halide for alkylation is a substituted aromatic compound or a substituted heteroaromatic compound as described by Henning et al.  
           [0123]    Step e:  
           [0124]    (1) The protected amine of formula XIV is deprotected using methods known to those skilled in the art. A suitable method for methyl deprotection is reaction with a haloformate or the like. A suitable method for benzyl deprotection is cleavage with hydrogen at or above atmospheric pressure and a catalyst such as palladium. Suitable methods for carbamate deprotection are treatment with an acid, base or trimethylsilyl iodide.  
           [0125]    (2) The resulting amine from Step e(1) is reacted with an activated functional group Y of formula XIII to form the bond between the nitrogen and functional group Y to obtain the compound of formula XV. When Y is a carbonyl group and M 2  is carbon, activation can be via a halide (i.e. acid chloride intermediate) or other coupling reagents (EDCI, DCC, HATU, or the like). Suitable reaction conditions may require a base such as triethylamine, N,N-diisopropylethylamine, pyridine, or the like.  
           [0126]    Step f: After reduction of formula XV, the resulting compound is reacted with a carbonyl equivalent to give the cyclized compound of formula IA. The reduction conditions can be hydrogen in the presence of catalyst, metal in the presence of an acid or a base, or other reduction reagent. The cyclization can be performed in acidic or basic conditions.  
           [0127]    More detailed methods for synthesis of compounds are shown in Scheme 3 below. The preparation of compounds of formula IB wherein R 1  is 1-benzimidazolyl (Methods A, B, C and F), Y is —C(O)— and R 2  is substituted pyridyl, and compounds of formulas IC and IC′ wherein R 1  is 2-benzimidazolyl (Methods D and E), Y is —C(O)— and R 2  is substituted pyridyl are shown, but those skilled in the art will recognize that similar procedures can be used to prepare compounds wherein the benzene ring of the benzimidazolyl group is substituted, R 2  is other than pyridyl, and azabenzimidazoles compounds (i.e., compounds wherein R 1  is other than benzimidazolyl as defined above).  
                         

                         

                         

                         

                         
 
           [0128]    Specifically exemplified compounds were prepared as described in the examples below, from starting materials known in the art or prepared as described below. These examples are being provided to further illustrate the present invention. They are for illustrative purposes only; the scope of the invention is not to be considered limited in any way thereby.  
           [0129]    Unless otherwise stated, the following abbreviations have the stated meanings in the Examples below:  
           [0130]    Me=methyl; Et=ethyl; Bu=butyl; Pr=propyl; Ph=phenyl; t-BOC=tert-butyloxycarbonyl;  
           [0131]    CBZ=carbobenzyloxy; and Ac=acetyl  
           [0132]    DCC=dicyclohexylcarbodiimide  
           [0133]    DMAP=4-dimethylaminopyridine  
           [0134]    DMF=dimethylformamide  
           [0135]    EDCI=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide  
           [0136]    ESMS=Electron spray mass spectroscopy  
           [0137]    FAB=Fast atom bombardment mass spectroscopy  
           [0138]    HATU=O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl uronium hexafluorophosphate  
           [0139]    HOBT=1-hydroxybenzotriazole  
           [0140]    LAH=lithium aluminum hydride  
           [0141]    LDA=lithium diisopropylamide  
           [0142]    NaBH(OAc) 3 =sodium triacetoxyborohydride  
           [0143]    NBS=N-bromosuccinimide  
           [0144]    PPA=polyphosphoric acid  
           [0145]    RT=room temperature  
           [0146]    TBAF=tetrabutylammonium fluoride  
           [0147]    TBDMS=t-butyldimethylsilyl  
           [0148]    TMEDA=N,N,N′,N′-tetramethylethylenediamine  
           [0149]    TEMPO=2,2,6,6-tetramethyl-1-piperidinyloxy, free radical  
           [0150]    TLC=thin layer chromatography  
           [0151]    HRMS=High Resolution Mass Spectrometry  
           [0152]    LRMS=Low Resolution Mass Spectrometry  
           [0153]    nM=nanomolar  
           [0154]    Ki=Dissociation Constant for substrate/receptor complex  
           [0155]    pA2=-logEC 50 , as defined by  J. Hey, Eur. J. Pharmacol., ( 1995), Vol. 294, 329-335.  
           [0156]    Ci/mmol=Curie/mmol (a measure of specific activity)  
         Preparation 1 
         [0157]    [0157]                           
           [0158]    Step 1:  
                         
 
           [0159]    To a solution of 2-amino-4-methylpyridine (10.81 g, 100 mmol) in tert-butanol (250 ml) was added t-BOC anhydride (26.19 g, 120 mmol). The reaction mixture was stirred at 23° C. overnight, and then concentrated to an oil. The crude product was dry loaded onto a silica gel column and flash chromatographed (eluant: 30% hexanes-CH 2 Cl 2  to 0-2% acetone-CH 2 Cl 2 ) to produce 15.25 g (73.32 mmol; 73%) of the desired product as a white solid.  
           [0160]    Step 2:  
                         
 
           [0161]    To a solution of the product of Step 1 (35.96 g, 173 mmol) in THF (1.4 l) at −78° C. was added a n-BuLi solution (1.4 M, 272 ml, 381 mmol) in hexanes portionwise over 30 min. The reaction mixture was then allowed to warm slowly and was stirred for 2 h at 23° C., which resulted in the formation of an orange precipitate. The mixture was then cooled back to −78° C., and pre-dried oxygen (passed through a Drierite column) was bubbled through the suspension for 6 h while the temperature was maintained at −78° C. The color of the reaction mixture changed from orange to yellow during this time. The reaction was quenched at −78° C. with (CH 3 ) 2 S (51.4 ml, 700 mmol) followed by AcOH (22 ml, 384 mmol) and allowed to warm with stirring to 23° C. After 48 h, water was added and the product extracted into EtOAc. Purification by silica gel flash chromatography (eluant: 0-15% acetone/CH 2 Cl 2 ) provided 20.15 g (90 mmol; 52%) of the alcohol as a pale yellow solid.  
           [0162]    Step 3:  
                         
 
           [0163]    To a solution of the product of Step 2 (19.15 g, 85.5 mmol) in CH 2 Cl 2  (640 ml) was added a saturated aqueous solution of NaHCO 3  (8.62 g, 103 mmol) and NaBr (444 mg, 4.3 mmol). The reaction mixture was cooled to 0° C., and TEMPO (140 mg, 0.90 mmol) was introduced. Upon vigorous stirring, commercial bleach solution (122 ml, 0.7 M, 85.4 mmol) (5.25% in NaOCl) was added portionwise over 40 min. After an additional 20 min at 0° C., the reaction mixture was quenched with saturated aqueous Na 2 S 2 O 3  and allowed to warm to 23° C. Dilution with water and extraction with CH 2 Cl 2 , followed by concentration and flash chromatography (eluant: 30% hexanes-CH 2 Cl 2  to 0-2% acetone-CH 2 Cl 2 ) afforded 15.97 g (71.9 mmol; 84% yield) of the aldehyde as an off-white solid.  
           [0164]    Step 4:  
                         
 
           [0165]    To a solution of the product of Step 3 (11.87 g, 53.5 mmol) in CH 2 Cl 2  (370 ml) was added ethyl isonipecotate (9.07 ml, 58.8 mmol) followed by four drops of AcOH. The reaction mixture was then stirred for 40 min at 23° C., after which NaB(OAc) 3 H (22.68 g, 107 mmol) was added. The reaction mixture was stirred overnight at 23° C., neutralized with saturated aqueous NaHCO 3 , diluted with water and extracted with CH 2 Cl 2 . Concentration of the organic extracts, followed by silica gel flash chromatography (eluant: 04% sat. NH 3  in CH 3 OH—CH 2 Cl 2 ) provided 19.09 g (52.6 mmol; 98%) of the ester as an off-white solid.  
           [0166]    Step 5:  
           [0167]    To a solution of the product of Step 4 (1.57 g, 4.33 mmol) in THF-water-CH 3 OH (10 ml of a 3:1:1 mixture) was added LiOH monohydrate (0.125 g, 5.21 mmol). The reaction mixture was stirred overnight at 23° C., concentrated and exposed to high vacuum to obtain 1.59 g of crude title compound as a yellowish solid which was used without purification.  
         Preparation 2 
         [0168]    [0168]                           
           [0169]    Step 1:  
                         
 
           [0170]    A solution of diamine 1B (see Method A, Step 1) (20 g, 71.1 mmol) and Et 3 N (30 ml, 213 mmol) in CH 2 Cl 2  (400 ml) was cooled to 0° C. in an ice-water bath. To the well-stirred solution was added triphosgene (14.2 g, 47.3 mmol) cautiously (exotherm!) and portionwise over a period of 30 min. When addition was complete, stirring was continued at 0° C. for 1 h, then at RT for 16 h. The mixture was washed with 0.5N NaOH (200 ml), the organic layer was dried over anhydrous MgSO 4  and concentrated under vacuum. Hot EtOAc (200 ml) was added to the semi-solid residue, and the resultant mixture was cooled to RT. Filtration yielded compound P2-1 as a white solid (16.5 g); and silica gel flash chromatography [CH 2 Cl 2 /CH 3 OH (2N NH 3 )=40:1] of the filtrate provided additional product as a white solid (2.7 g) [combined yield: 88%]. FABMS: 308 (MH + ; 100%).  
           [0171]    Step 2:  
                         
 
           [0172]    POCl 3  (100 ml) was added to P2-1 (17.2 g; 56 mmol) in a round-bottomed flask flushed with dry N 2 . The mixture was placed in an oil bath heated to 108° C. and was maintained at reflux for 6 h. POCl 3  was then removed in vacuo. The residue was adjusted to pH˜9-10 with 7N methanolic ammonia and was concentrated to dryness under vacuum. CH 2 Cl 2  was added to the residue, insoluble material was filtered off, and the filtrate was again concentrated in vacuo. The residue was crystallized from EtOH to obtain compound P2-2 as a white solid (12.6 g; 67%). ES-MS: 326.1 (MH + ; 100%).  
           [0173]    Varying amounts of compound P2-10 may be formed in this process and can be converted to desired product P2-2 by careful in situ treatment in CH 2 Cl 2  solution at 0° C. with one equivalent each of EtOH and NaH, followed by workup with ice-water and CH 2 Cl 2 . Low temperature is maintained in order to minimize reaction at the 2-position of the benzimidazole nucleus.  
           [0174]    Step 3:  
                         
 
           [0175]    Sodium thiomethoxide (1.05 g; 15.0 mmol) was added to DMF (15 ml) in a round-bottomed flask flushed with N 2 . After stirring at RT for 30 min, solid chloride P2-2 (3.25 g, 10 mmol) was added, and the resultant mixture was kept stirring at RT for 16 h. EtOAc (100 ml) and water (50 ml) were added to the reaction mixture. The aqueous layer was separated and further extracted with EtOAc (50 ml). The combined extracts were dried over anhydrous MgSO 4  and concentrated under vacuum. The residue was purified via flash chromatography on silica gel, eluting with EtOAc-hexanes (3:4), to obtain compound P2-3 as a white solid (2.12 g; 63%). FABMS: 338.3 (MH + ; 100%).  
           [0176]    Step 4:  
           [0177]    To a stirred solution of P2-3 (300 mg, 12.5 mmol) in EtOH (40 ml)-isopropyl alcohol (40 ml) was added 25% (w/w) aqueous NaOH solution (20 ml). The resultant mixture was stirred at 85° C. for 24 h, then at 100° C. for an additional 4 h. Alcohols were removed under vacuum, and the aqueous residue was extracted sequentially with CH 2 Cl 2  (2×40 ml), then EtOAc (30 ml). Combined extracts were dried over anhydrous MgSO 4 . Drying agent was removed by filtration, and the filtrate was concentrated under vacuum. The residue was purified by silica gel flash chromatography (CH 2 Cl 2 /2N methanolic ammonia=12:1) to obtain Preparation 2 as an off-white solid (2.85 g, 70%). ES-MS: 266 (MH + ; 100%).  
         Preparation 3 
         [0178]    [0178]                           
           [0179]    Step 1:  
                         
 
           [0180]    NaH (60 mg of a 60% dispersion; 1.48 mmol) was added to CH 3 OH (4 ml) in a flask charged with N 2 . After stirring at RT for 30 min, chloride P2-2 (400 mg, 1.23 mmol) was added, and the resultant mixture was stirred at RT for 16 h. CH 3 OH was removed in vacuo, and to the residue were added CH 2 Cl 2  (30 ml) and water (10 ml). The organic layer was dried over anhydrous MgSO 4 , filtered, and the filtrate concentrated under vacuum. The residue was purified via flash chromatography on silica gel, eluting with EtOAc-hexanes (3:2) to obtain P3-1 as a white foam (0.232 g; 59%). ES-MS: 322.1 (MH + ; 100%).  
           [0181]    Step 2:  
           [0182]    1 N aqueous KOH (4.82 mL; 4.82 mmol) was added to a solution of P3-1 in EtOH (15 ml), and the resultant mixture was stirred at 80° C. for 48 h. The mixture was concentrated under vacuum. Water (3 ml) and CH 2 Cl 2  (15 ml) were added to the residue, and the organic layer was separated and dried over anhydrous MgSO 4 . Drying agent was filtered, and the filtrate was concentrated in vacuo to obtain Preparation 3 as a colorless glass (160 mg; 95%). FABMS: 250.2 (MH + ; 100%).  
         Preparation 4 
         [0183]    [0183]                           
           [0184]    Step 1:  
                         
 
           [0185]    P2-2 (300 mg; 0.923 mmol) and morpholine (3 ml) were mixed in a round-bottomed flask under N 2 , and the resultant mixture was heated to 80° C. for 16 h. Morpholine was removed under vacuum, and the residue was dissolved in CH 2 Cl 2  (20 ml). An insoluble white precipitate was filtered off, and the filtrate was concentrated and purified by means of flash chromatography on silica gel, eluting with CH 2 Cl 2 /2N methanolic ammonia (45:1), to obtain P4-1 as a colorless glass (0.325 g; 94%). ES-MS: 377.1 (MH + ; 100%).  
           [0186]    Step 2:  
           [0187]    Trimethylsilyl iodide (240 microliters; 1.64 mmol) was added to a solution of P4-1 (316 mg; 0.843 mmol) in CHCl 3  (2 ml) under N 2 , and the resultant solution was stirred at 55° C. for 7 h. The reaction was quenched with EtOH (2 ml), and the mixture was concentrated to dryness under vacuum. The residue was basified with a 1:1 (v/v) mixture of concentrated NH 4 OH and water to pH 10 and extracted with CH 2 Cl 2  (2×5 ml). The combined extracts were dried over anhydrous MgSO 4 . Drying agent was filtered, and the filtrate was concentrated under vacuum. The residue was purified via flash chromatography on silica gel, eluting with CH 2 Cl 2 -2N methanolic ammonia (13:1), to obtain compound Preparation 4 as a colorless glass. (181 mg; 70%). ES-MS: 305.1 (MH + ; 100%).  
         Preparation 5 
         [0188]    [0188]                           
           [0189]    Step 1:  
                         
 
           [0190]    A solution of P5-1 (3.5 g, 21 mmol) and P5-2 (6.5 g, 38 mmol) in CH 2 Cl 2  (3 ml) was heated to 110° C. for 24 h and RT for 24 h. The reaction was diluted with CH 2 Cl 2 , washed with water and brine, and dried (Na 2 SO 4 ). Purification on a flash column (SiO 2 , 40% to 60% EtOAc in hexanes) gave P5-3 (1.3 g, 21%; M+H=295).  
           [0191]    Step 2:  
                         
 
           [0192]    To a solution of P5-3 (1.3 g, 4.4 mmol) in CH 3 OH (30 ml) was added Ra—Ni (0.5 g) and the mixture was hydrogenated under a H 2  atmosphere (50 psi) for 18 h. Filtration through a pad of celite gave P54 as a grey solid that was used without further purification (1.05 g, 90%; M+H=265).  
           [0193]    Step 3:  
                         
 
           [0194]    A solution of P54 (1.05 g, 3.97 mmol), P5-5 (0.49 g, 3.97 mmol), DEC (1.14 g, 5.96 mmol) and HOBT (0.8 g, 5.96 mmol) in CH 2 Cl 2  (10 ml) were stirred for 18 h at RT. The crude reaction mixture was diluted with additional CH 2 Cl 2  and washed with 5% aqueous NaOH and brine and dried (Na 2 SO 4 ). Purification using flash chromatography (SiO, 8% EtOAc in hexane to 10% CH 3 OH in EtOAc) gave P5-6 (0.35 g, 24%; M+H=370).  
           [0195]    Step 4:  
                         
 
           [0196]    Compound P5-6 (0.7 g, 1.89 mmol) was dissolved in HOAc (10 ml) and heated to 120° C. for 3.5 h. The reaction was cooled to RT, concentrated in vacuo, neutralized by the addition of 10% aqueous NaOH and extracted with CH 2 Cl 2 . The combined organic layers were dried (Na 2 SO 4 ) and concentrated to give P5-7 (0.58 g, 87%; M+H=352) which was used in the next step without further purification.  
           [0197]    Step 5:  
           [0198]    A solution of P5-7 (0.58 g, 1.65 mmol) and NaOH (0.43 g, 13.2 mmol) in EtOH/H 2 O (9/1, 10 ml) was heated to 100° C. for 18 h. The reaction was cooled and concentrated and the residue purified on a flash column (SiO 2 , 10% CH 3 OH saturated with ammonia in CH 2 Cl 2 ) to give Preparation 5 (0.42 g, 91%; M+H=280).  
         Preparation 6 
         [0199]    [0199]                           
           [0200]    Step 1:  
                         
 
           [0201]    A solution of compound P6-1 (prepared by procedures analogous to P2-1) (10.5 g, 36.2 mmol) and 2,6-di-tert-butylpyridine (12.2 ml, 54.4 mmol) in CH 2 Cl 2  (400 ml) was treated with 1M sol. of Et 3 O+BF 4 — (in CH 2 Cl 2 , 55 ml, 55 mmol). The reaction mixture was stirred at RT for 2 h, quenched with 1 N NaOH (100 ml), extracted with CH 2 Cl 2  (3×), dried with Na 2 SO 4  and concentrated. Purification by silica gel chromatography (eluant: 5-10% acetone/CH 2 Cl 2 ) to give 6.37 g of P6-2 (20.0 mmol, 55%).  
           [0202]    Step 2:  
           [0203]    In a manner similar to that described in Preparation 3, Step 2, P6-2 was converted to Preparation 6.  
         Preparation 7 
         [0204]    [0204]                           
           [0205]    Step 1:  
                         
 
           [0206]    A mixture of P7-1 (40 g, 150 mmol), trimethyl orthoformate (66 ml, 64.0 g, 600 mmol) and a catalytic amount of p-toluenesulfonic acid monohydrate (300 mg, 1.58 mmol) was stirred under N 2  at 120° C. for 3 h. Excess orthoformate was removed under vacuum. The residue was partitioned between EtOAc (200 ml) and 1N NaOH (100 ml). The organic layer was washed with brine (100 ml) and dried over anhydrous MgSO 4 . Drying agent was removed by filtration, and the filtrate was concentrated under vacuum. The residue was purified by silica gel flash chromatography (CH 2 Cl 2 /CH 3 OH (2N NH 3 )=45:1) to obtain P7-2 as a dark purple syrup (27.2 g, 66%), which solidified upon standing. ES-MS: 275 (MH + ; 100%).  
           [0207]    Step 2:  
                         
 
           [0208]    NBS was added portionwise (exotherm) to a solution of P7-2 (27 g, 100 mmol) in CHCl 3  (300 ml), and the resultant solution was stirred at 60° C. for 16 h. Solvent was then removed under vacuum, and the residue was partitioned between EtOAc (200 ml) and 0.7N Na 2 S 2 O 4  (250 ml). The organic layer was washed with brine (150 ml) and dried over anhydrous MgSO 4 . Drying agent was removed by filtration, and the filtrate was concentrated under vacuum. The residue was purified by silica gel flash chromatography [CH 2 Cl 2 /acetone=45:1] to obtain P7-3 as a yellow solid (24.2 g, 69%). ES-MS: 353 (MH + ; 100%).  
           [0209]    Step 3:  
           [0210]    NaH (544 mg of a 60% dispersion, 13.6 mmol) was added to a solution of CH 3 OH (0.551 ml, 436 mg, 13.6 mmol) in DMF (5 ml). The resultant mixture was stirred at RT for 30 min before adding solid bromide P7-3 (3.99 g, 11.3 mmol). The reaction suspension was stirred at RT for 16 h. The mixture was then partitioned between EtOAc (800 ml) and water (40 ml). The aqueous layer was extracted with EtOAc (40 ml). Combined extracts were washed with brine (30 ml) and dried over anhydrous MgSO 4 . Drying agent was removed by filtration, and the filtrate was concentrated under vacuum to obtain Preparation 7 as a white syrup (2.81 g, 81%), which was used without further purification. ES-MS: 305 (MH + ; 100%).  
         Preparation 8 
         [0211]    [0211]                           
           [0212]    Step 1:  
                         
 
           [0213]    A solution of 1B (15 g, 52.8 mmol) and 1,1′-thiocarbonyldiimidazole (25 g, 140 mmol) in THF (300 ml) was stirred at 72° C. under N 2  for 16 h, during which time a precipitate formed. THF was removed under vacuum, and the residue was purified by silica gel flash chromatography (CH 2 Cl 2 /acetone=20:1) to obtain P8-1 as a light yellow solid (16.7 g, &gt;95%). ES-MS: 324 (MH + ; 100%).  
           [0214]    Step 2:  
           [0215]    To a stirred mixture of P8-1 (4.00 g, 12.5 mmol) and K 2 CO 3  (2.05 g, 13.6 mmol) in DMF (40 ml) under a N 2  atmosphere was added CH 31  (0.85 ml, 1.94 g, 13.6 mmol). The resultant mixture was stirred at RT for 16 h before partitioning between EtOAc (100 ml) and water (40 ml). The aqueous layer was extracted with EtOAc (40 ml). Combined extracts were washed with brine (30 ml) and dried over anhydrous MgSO 4 . Drying agent was removed by filtration, and the filtrate was concentrated under vacuum to obtain Preparation 8 as a foamy white solid (4.20 g, &gt;95%; contained a small amount of DMF), which was used without further purification. ES-MS: 338 (MH + ; 100%).  
         Preparation 9 
         [0216]    [0216]                           
           [0217]    Step 1:  
                         
 
           [0218]    (Modified published procedure: G. Heinisch, E. Luszczak, and M. Pailer:  Monatshefte für Chemie,  1973 (104), 1372.  
           [0219]    P9-1 (4.5 g, 47.8 mmoles), P9-2 (8.12 g, 76.5 mmoles), and anhydrous ZnCl 2  were heated, under N 2 , in a dry apparatus, at a bath temperature of 160° C. for 5 h. The resulting oil was purified by flash chromatography on silica gel using 30% Hexanes/EtOAc, yielding 5.92 grams (67%) of the product.  
           [0220]    Step 2:  
           [0221]    OsO 4  (5.0 ml in t-butanol, 2.5% w/w) was added to P9-3 (5.9 g, 32.38 mmoles) dissolved in p-dioxane (87 ml) and water (29 ml). NaIO 4  (14.1 g, 65.92 mmoles) was added, with good stirring, in small portions, over a period of 6 h. The mixture was then diluted with p-dioxane and filtered. After removing most of the solvent under reduced pressure, the residue was taken in CH 2 Cl 2  (600 ml) and dried over anhydrous Na 2 SO 4 . After removal of the solvent, the mixture was purified by flash chromatography on silica gel using 5% CH 3 OH/CH 2 Cl 2  as eluent to obtain Preparation 9. Yield: 2.89 g (82%).  
         Preparation 10 
         [0222]    [0222]                           
           [0223]    Step 1:  
                         
 
           [0224]    A solution of P10-1 (2 g, 15 mmol) in CH 2 Cl 2  (50 ml) was treated with Et 3 N (3 g, 30 mmol) and triphenylmethyl chloride (TrCl, 4.25 g, 15.3 mmol) and stirred at RT overnight. The solvent was removed in vacuo and the residue purified via flash column chromatography (SiO 2 , 20% EtOAc in hexane) to give P10-2 (5.2 g, 46%).  
           [0225]    Step 2:  
           [0226]    A solution of P10-2 (5.2 g, 14.6 mmol) in CCl 4  (80 ml) was treated with NBS (7.8 g, 43 mmol) and the reaction heated to 80° C. overnight. The reaction was cooled, filtered and concentrated, and the residue was purified via flash column chromatography (SiO 2 , 20% to 30% EtOAc in hexane) to give Preparation 10 (2.8 g, 42%, M+H=453, 455)  
         Preparation 11 
         [0227]    [0227]                           
           [0228]    Step 1:  
                         
 
           [0229]    To a stirred solution of P8-1 (6.5 g, 20.1 mmol) in EtOH (80 ml) was added 25% (w/w) aqueous NaOH solution (20 ml). The resultant mixture was stirred at 90° C. for 16 h. EtOH was removed under vacuum, and the residue was adsorbed directly onto silica gel and subjected to flash chromatography (CH 2 Cl 2 /2N methanolic ammonia=9:1) to obtain P11-1 as a white solid (4.46 g, 70%). ES-MS: 252 (MH + ; 100%).  
           [0230]    Step 2:  
                         
 
           [0231]    A mixture of P11-1 (3.95 g; 15.7 mmol), BOC-isonipecotic acid (3.60 g; 15.7 mmol), HOBT (3.19 g; 23.6 mmol), DIPEA (3 ml; 2.23 g; 17.2 mmol) and EDCI (4.50 g; 23.6 mmol) in DMF (30 ml) was stirred under N 2  at RT for 16 h. The reaction mixture was partitioned between EtOAc (60 ml) and water (40 ml). The aqueous phase was extracted with EtOAc (40 ml), and the combined extracts were washed with brine (40 ml) and dried over anhydrous MgSO 4 . Drying agent was removed by filtration, and the filtrate was concentrated under vacuum. The residue was purified by silica gel flash chromatography (CH 2 Cl 2 /CH 3 OH (2N NH 3 )=40:1) to obtain P11-2 as a white solid (˜7.3 g, 100%), containing a small amount of DMF, used without further purification in Step 3 below. ES-MS: 463 (MH + ; 70%); 407 (100%).  
           [0232]    Step 3.  
                         
 
           [0233]    To a stirred mixture of P11-2 (460 mg; 1 mmol) and K 2 CO 3  (165 mg; 1.20 mmol) in DMF (4 ml) under a N 2  atmosphere was added Etl (92 microliters; 179 mg; 1.15 mmol). The resultant mixture was stirred at RT for 16 h and was then partitioned between EtOAc (20 ml) and water (10 ml). The aqueous phase was extracted with EtOAc (10 ml), and the combined extracts were washed with brine (20 ml) and dried over anhydrous MgSO 4 . Drying agent was removed by filtration, and the filtrate was concentrated under vacuum to obtain P11-3 as a pale yellow foam (471 mg, 96%), containing a small amount of DMF, used without further purification in Step 4 below. ES-MS: 463 (MH + ; 85%); 435 (100%).  
           [0234]    Step 4:  
           [0235]    To a solution of P11-3 (465 mg; 0.949 mmol) in CH 2 Cl 2  (4 ml) was added TFA (1 ml; 1.54 g; 13.5 mmol). The resultant solution was stirred for 2 h at RT and was then partitioned between CH 2 Cl 2  (20 ml) and 1:1 (v/v) concentrated NH 4 OH:water (5 ml). The aqueous phase was extracted successively with 95:5 CH 2 CL 2 :EtOH (5 ml) and EtOAc (5 ml). The combined extracts were dried over anhydrous MgSO 4 . Drying agent was removed by filtration, and the filtrate was concentrated under vacuum to obtain Preparation 11 as a pale white foam (353 mg, 95%), used without further purification. ES-MS: 391 (MH + ; 100%). 
       
    
    
     EXAMPLE 1 
       [0236]    [0236]                           
         [0237]    Method A  
         [0238]    Step 1:  
                         
 
         [0239]    A mixture of a (25 g, 0.16 mol), b (27 g, 0.16 mol), K 2 CO 3  (26 g, 0.19 mol), and NaI (2.4 g, 0.016 mol) in dimethylacetamide (50 ml) was heated at 140° C. for 3.5 h. The reaction mixture was concentrated to one-third volume, poured onto saturated aqueous NaHCO 3 , and extracted with EtOAc (4×). The combined organic layers were washed with water (2×) and brine, dried over Na 2 SO 4 , and concentrated. Recrystallization with EtOH provided 1A (48 g, 98%).  
         [0240]    A suspension of 1A (20.00 g, 64.2 mmol,) and Raney® 2800 Nickel (5.0 g) in ethanol (70 ml) and THF (140 ml) was shaken under H 2  (40 psi) for 2 h. The mixture was filtered through a short pad of celite. The filtrate was concentrated and dried on vacuum to deliver a tan solid (18.20 g, 100%).  
         [0241]    Step 2:  
                         
 
         [0242]    A solution of 1B (5.00 g, 17.77 mmol) and picolinoyl chloride hydrochloride (3.16 g, 17.75 mmol) in CH 2 Cl 2  (400 ml) and Et 3 N (15 ml) was stirred at RT. After 15 h, the reaction was diluted with CH 2 Cl 2 , washed with water, dried over Na 2 SO 4 , concentrated, and dried on vacuum to provide a brown foam (6.47 g, 94%).  
         [0243]    Step 3:  
                         
 
         [0244]    A solution of 1C (1.77 g, 4.58 mmol) in ethanol (50 ml) and concentrated H 2 SO 4  (5.0 ml) was refluxed for 3 h, cooled to RT, and neutralized with 1.0 M NaOH until pH=10. The resulting mixture was extracted with CH 2 Cl 2 . The combined organic solutions were dried over Na 2 SO 4  and concentrated on reduced pressure. The residue was purified by flash chromatography (silica gel, 5% CH 3 OH in CH 2 Cl 2  as eluent) to provide a tan foam (1.58 g, 94%).  
         [0245]    Step 4:  
                         
 
         [0246]    Iodotrimethylsilane (6.30 g, 31.48 mmol) was added to a solution of 1D (3.88 g, 10.53 mmol) in anhydrous 1,2-dichloroethane (40 ml). The resulting solution was stirred at 75° C. for 4 hours, cooled to RT, and treated with 1.0 M NaOH solution. The mixture was then extracted with CH 2 Cl 2 . The combined extracts were washed with water, dried over Na 2 SO 4 , and the solvent evaporated. Purification of the residue by flash chromatography (silica gel, 10% CH 3 OH in CH 2 Cl 2  as eluent) delivered an off-white foam (2.10 g, 67%).  
         [0247]    Step 5:  
                         
 
         [0248]    Amine 1E (5.80 g, 19.6 mmol) and Preparation 1 (5.32 g, 23.4 mmol) were dissolved in DMF (60 ml) and CH 2 Cl 2  (60 ml). To the resulting solution, EDCI hydrochloride (5.70 g, 24.50 mmol), HOBT (1.30 g, 24.50 mmol), and diisopropylethylamine (5.08 g, 39.6 mmol) were added successively. The resulting reaction mixture was stirred at 70° C. for 4 hours, cooled to RT, diluted with CH 2 Cl 2 , washed with water, dried over Na 2 SO 4 , and concentrated. Flash chromatography (SiO 2 , 5% CH 3 OH in CH 2 Cl 2 →90:10:0.5 CH 2 Cl 2 :CH 3 OH:NH 4 OH) of the residue provided a tan foam (7.89 g, 65%).  
         [0249]    Step 6:  
         [0250]    A solution of 1F (7.89 g, 12.88 mmol) and TFA (29 g, 257 mmol) in CH 2 Cl 2  (65 ml) was stirred at RT for 12 h, neutralized with 1.0 M NaOH, and extracted with CH 2 Cl 2 . The combined organic layers were washed with water, dried over Na 2 SO 4  and concentrated. Purification of the crude product by flash chromatography (SiO 2 , 5% CH 3 OH in CH 2 Cl 2  to 90:10:0.5 CH 2 Cl 2 :CH 3 OH:NH 4 OH) provided the title compound as a white solid (5.80 g, 88%). MS: 514 (MH + ).  
       EXAMPLE 2 
       [0251]    [0251]                           
         [0252]    Method B  
                         
 
         [0253]    TFA (200 ml, 2.596 mol) was added to a solution of 2A (20 g, 51.36 mmol) in CH 2 Cl 2  (100 ml). The resulting reaction mixture was stirred at RT for 6 h, neutralized with 1.0 M NaOH, and extracted. The combined extracts were washed with water, dried over Na 2 SO 4 , and concentrated. Flash chromatography gave an orange solid (13.50 g, 91%).  
         [0254]    Step 2:  
                         
 
         [0255]    Amine 2B (1.50 g, 5.19 mmol) and Preparation 1 (1.75 g, 5.13 mmol) were dissolved in DMF (10 ml) and CH 2 Cl 2  (10 ml). To the resulting solution, EDCI hydrochloride (1.50 g, 7.83 mmol), HOBT (1.05 g, 7.82 mmol), and diisopropylethylamine (3.71 g, 28.70 mmol) were added successively. The resulting reaction mixture was stirred at 70° C. for 18 h, cooled to RT, diluted with CH 2 Cl 2 , washed with water, dried over Na 2 SO 4 , and concentrated. Flash chromatography of the residue provided an orange gel (2.31 g, 74%).  
         [0256]    Step 3:  
                         
 
         [0257]    A suspension of 2C (2.10 g, 3.46 mmol,) and Raney® 2800 Nickel (1.0 g) in CH 3 OH (100 ml) was shaken under H 2  (30 psi) for 6 h. The mixture was filtered through a short pad packed with celite. The filtrate was concentrated and dried on vacuum to deliver an orange solid (1.80 g, 90%).  
         [0258]    Step 4:  
                         
 
         [0259]    Amine 2D (200 mg, 0.347 mmol) and picolinoyl chloride hydrochloride (62 mg, 0.348 mmol) were dissolved in CH 2 Cl 2 . Et 3 N was then introduced via a syringe. The resulting solution was stirred at RT for 6 h, treated with 1.0 M NaOH solution, and extracted. The extracts were washed with water, dried over Na 2 SO 4 , and concentrated. Purification of the residue by flash chromatography gave a white foam (167 mg, 71% yield).  
         [0260]    Step 5:  
         [0261]    A solution of 2E (160 mg, 0.235 mmol) and H 2 SO 4  (concentrated, 0.50 ml) in ethanol (10 ml) was refluxed for 2.5 h, cooled to RT, and neutralized with 1.0 M NaOH. After extraction of the mixture, the combined organic layers were washed with water, dried over Na 2 SO 4 , and concentrated. Purification of the crude product using prep TLC (10% CH 3 OH in CH 2 Cl 2 ) provided the title compound as a white solid (88 mg, 66%). MS: 564 (MH + )  
       EXAMPLE 3 
       [0262]    [0262]                           
         [0263]    Method D  
         [0264]    Step 1:  
                         
 
         [0265]    Diamine 3A (1.43 g, 10 mmol) and isonipecotic acid 3B (1.29 g, 10 mmol) were mixed, and PPA (20 g) was added. The resulting mixture was heated at 180° C. for 3.5 h, cooled to RT and diluted with water to 100 ml. The solution was then basified with solid NaOH to pH 14. The resultant copious precipitate was filtered off. The precipitate was washed repeatedly with CH 3 OH, and combined CH 3 OH extracts were concentrated-dry loaded on silica gel and flash chromatographed (25-40% 5N NH 3  in CH 3 OH/CH 2 Cl 2 ) to provide 3C as a dark solid (1.90 g, 81%).  
         [0266]    Step 2:  
                         
 
         [0267]    To the mixture of acid 3D (181 mg, 0.54 mmol), HATU (247 mg, 0.65 mmol) and Et 3 N (84 μl, 0.6 mmol) in DMF (12 ml) was added amine 3C (126 mg, 0.54 mmol). The resulting mixture was stirred at RT for 24 h, concentrated, redissolved in CH 3 OH, concentrated-dry loaded on silica gel and flash chromatographed (5-10% 5N NH 3  in CH 3 OH/CH 2 Cl 2 ) to provide 3E as a yellow oil (210 mg, 70%).  
         [0268]    Step 3:  
         [0269]    A solution of 3E (96 mg, 0.174 mmol) in 15 ml of 1 M HCl in 25% CH 3 OH/dioxane was stirred at RT for 48 h. The mixture was concentrated, exposed to high vacuum, redissolved in CH 3 OH, concentrated-dry loaded on silica gel and flash chromatographed (10-15% 5N NH 3  in CH 3 OH/CH 2 Cl 2 ) to provide the title compound as a colorless oil (48 mg, 61%). MS: 453 (MH + )  
       EXAMPLE 4 
       [0270]    [0270]                           
         [0271]    Method E  
         [0272]    Step 1:  
                         
 
         [0273]    A mixture of neat 4A (1.75 g, 6.66 mmol) and 4B (2.93 g, 15.07 mmol) was stirred at 120° C. for 2 days, cooled to RT, treated with 1.0 M NaOH solution (30 ml), and extracted with EtOAc. The combined organic layers were washed with water and dried over Na 2 SO 4 . After evaporation to dryness, the crude residue was flash chromatographed (silica gel, 50% EtOAc in hexanes as eluent) to give 510 mg of 4C (18%).  
         [0274]    Step 2:  
                         
 
         [0275]    To a 500 ml pressure bottle was added 4C (490 mg, 1.18 mmol) in CH 3 OH (20 ml). Under N 2  stream, palladium hydroxide (300 mg, 20 wt. % on carbon) solid was added. The reaction mixture was shaken under 55 psi of hydrogen for 40 h and filtered. The filtrate was concentrated and dried on vacuum to deliver a yellow solid (340 mg, 88%).  
         [0276]    Step 3:  
                         
 
         [0277]    To a 50 ml round-bottomed flask were successively added 4D (287 mg, 0.88 mmol), Preparation 1 (300 mg, 0.88 mmol), EDCI hydrochloride (210 mg, 1.10 mmol), HOBT (149 mg, 1.10 mmol), and diisopropylethylamine (228 mg, 1.76 mmol). DMF (3 ml) and CH 2 Cl 2  (3 ml) were introduced via a syringe. The resulting reaction mixture was stirred at 70° C. for 15 h and cooled to RT. After addition of 1 N NaHCO 3  solution, the resulting mixture was extracted with CH 2 Cl 2 . The combined organic solutions were dried over Na 2 SO 4  and concentrated. Purification of the crude product by flash chromatography on silica gel with 10% CH 3 OH in CH 2 Cl 2  as the eluent provided 4E as a solid (231 mg, 41%).  
         [0278]    Step 4:  
         [0279]    To a 25 ml round-bottomed flask was added 4E (200 mg, 0.31 mmol) in CH 2 Cl 2  (2.5 ml). TFA was then introduced via a syringe. The resulting solution was stirred at RT for 15 h, diluted with CH 2 Cl 2 , neutralized with 1.0 M NaOH solution, and separated. The organic solution was washed with water and dried over Na 2 SO 4 . After evaporation of the solvent, the crude product was purified on a preparative TLC plate with 10% CH 3 OH in CH 2 Cl 2  as the eluent to provide the title compound as a white solid (85 mg, 50%). MS: 544 (MH + ).  
       EXAMPLE 5 
       [0280]    [0280]                           
         [0281]    Step 1:  
                         
 
         [0282]    A solution of compound 5A (100 g, 0.389 mol) in THF (400 ml) was added dropwise over 1.0 h to a solution of LDA (233 mL, 2.0 M in THF/heptane/ethyl-benzene, 0.466 mol) in THF (300 ml) at 0° C. The red-orange solution was stirred at 0° C. for 30 min, and then transferred by cannula to a pre-cooled (0° C.) solution of N-fluorobenzenesulfonimide (153 g, 0.485 mol) in dry THF (600 ml). The reaction mixture was stirred at 0° C. for 30 min, and then at 20° C. for 18 h. The total solvent volume was reduced to approximately one third, and EtOAc (1 l) was added. The solution was washed successively with water, 0.1 N aq. HCl, saturated aq. NaHCO 3 , and brine. The organic layer was dried over MgSO 4 , filtered, and concentrated under reduced pressure to yield a crude liquid. Separation by flash chromatography (6:1 hexanes-EtOAc) gave compound 5B (93.5 g, 87%).  
         [0283]    Step 2:  
                         
 
         [0284]    A solution of 5B (50 g, 0.181 mol) in THF (300 ml) and CH 3 OH (200 ml) was treated with a solution of LiOH—H 2 O (9.2 g, 0.218 mol) in water (100 ml) and then heated to 45° C. for 6 h. The mixture was then concentrated and dried in vacuo to provide 5C (45 g, 100%).  
         [0285]    Step 3:  
                         
 
         [0286]    Compound 5C (20.4 g, 0.081 mol) was added slowly to a stirred flask of CH 2 Cl 2  (250 ml) at 20° C. The resulting white slurry was cooled to 0° C. and treated slowly with oxalyl chloride (6.7 ml, 0.075 mol) and a drop of DMF. After stirring at 20° C. for 0.5 h, the mixture was concentrated and dried in vacuo to provide 5D.  
         [0287]    Step 4A:  
                         
 
         [0288]    A mixture of c (64 g, 0.40 mol), d (84 ml, 0.52 mol), and K 2 CO 3  (66 g, 0.48 mol) in anhydrous toluene (350 ml) was heated at reflux overnight. The reaction mixture was diluted with CH 2 Cl 2 , washed three times with 5% aqueous NaOH, dried over Na 2 SO 4 , and concentrated. Recrystallization with MeOH provided e (121 g, ˜100%) as a yellow solid.  
                         
 
         [0289]    A suspension of e (121 g, 0.41 mol) and Raney Nickel (10 g) in EtOH (400 ml) was shaken under H 2  (40 psi) for 4 h. The mixture was filtered through a short pad of Celite (washing with CH 3 OH). The filtrate was concentrated and dried in vacuo to provide f (109 g, ˜100%) as a dark brown solid.  
                         
 
         [0290]    A solution of f (109 g, 0.41 mol) in CH 2 Cl 2 -DMF (1:1, 500 ml) was treated with picolinic acid (61 g, 0.50 mol), EDCI (119 g, 0.62 mol), HOBt (84 g, 0.62 mol) and iPr 2 NEt (141 ml, 1.03 mol). The mixture was stirred at 70° C. for 6 h and then overnight at 20° C. The reaction mixture was diluted with EtOAc, washed 3 times with 5% aqueous NaOH, dried over Na 2 SO 4 , and concentrated. Flash chromatography (0-100% EtOAc/hexane) provided g (131 g, 86%).  
         [0291]    A solution of g (131 g, 0.36 mol) in AcOH (200 ml) was heated at 120° C. overnight. The reaction mixture was cooled, carefully basified with 5% aqueous NaOH and extracted with CH 2 Cl 2 . The combined organic extracts were dried over Na 2 SO 4  and concentrated. Flash chromatography (0-80% EtOAc/hexane) provided h (95 g, 76%) as a yellow solid.  
                         
 
         [0292]    A solution of h (95 g, 0.27 mol) in anhydrous CHCl 3  (300 ml) was treated with iodotrimethylsilane (272 g, 1.36 mol) and heated at 70° C. for 5 h. The reaction mixture was cooled, quenched with cold 10% aqueous NaOH, and extracted with CH 2 Cl 2 . The combined organic extracts were dried over Na 2 SO 4  and concentrated. Flash chromatography (2N NH 3 —CH 3 OH/EtOAc) provided 5E (43 g, 57%) as a pale yellow solid.  
         [0293]    Step 4B:  
                         
 
         [0294]    A mixture of 5D (0.075 mol) in CH 2 Cl 2  (250 ml) was treated with 5E (15 g, 0.054 mol) and iPr 2 NEt (25 ml, 0.135 mol) while maintaining a temperature of 20° C. After 1 h, the mixture was concentrated and then stirred in CH 3 OH (200 ml)/CH 2 Cl 2  (200 ml)/H 2 O (1 ml) for 1 h at 20° C. The solvent was then evaporated. Treatment with TFA (200 ml) in CH 2 Cl 2  (250 ml) at 20° C. followed by flash chromatography (0-7% 7N NH 3 —CH 3 OH/CH 2 Cl 2 ) provided 5F (80-90% from 5C).  
         [0295]    Step 5:  
         [0296]    Method A:  
                         
 
         [0297]    A solution of 5F (0.41 g, 1.0 mmol) in CH 2 Cl 2  (20 ml) was treated with 5G (0.31 g, 2.5 mmol, JP Patent 63227573, 1988), NaBH(OAc) 3  (0.53 g, 2.5 mmol) and few drops of AcOH and then stirred overnight at 20° C. The mixture was partitioned between 10% NaOH and CH 2 Cl 2 . The organic layer was dried with Na 2 SO 4  and concentrated. Flash chromatography (0-5% 7N NH 3 —CH 3 OH/CH 2 Cl 2 ) provided the title compound (0.45 g, 87%). MS: 516 (M+H).  
         [0298]    Method B:  
                         
 
         [0299]    A solution of 5G (50 g, 0.41 mol) in CH 3 OH (300 ml) was cooled to 0° C. and carefully treated with NaBH 4  (20 g, 0.53 mol in 6 batches) over 20 min. The reaction was then allowed to warm to 20° C. and was stirred for 4 h. The mixture was again cooled to 0° C., carefully quenched with saturated aqueous NH 4 Cl, and concentrated. Flash chromatography (5-10% 7N NH 3 —CH 3 OH/CH 2 Cl 2 ) provided 5H (31 g, 62%) as a light yellow solid.  
         [0300]    A slurry of 5H (31 g, 0.25 mol) in CH 2 Cl 2  (500 ml) was cooled to 0° C. and slowly treated with SOCl 2  (55 ml, 0.74 mol over 30 min). The reaction was then stirred overnight at 20° C. The material was concentrated, slurried in acetone, and then filtered. The resulting beige solid 5I was dried overnight in vacuo (38.4 g, 52%, HCl salt).  
         [0301]    A homogeneous solution of 5F (16.4 g, 40 mmol) in anhydrous DMF (200 ml) was cooled to 0° C., carefully treated with NaH (8 g, 200 mmol), and stirred at 20° C. for 20 min. The reaction mixture was then cooled to 0° C., treated with NaI (6 g, 40 mmol) and 5I (14.5 g, 80 mmol), and then stirred overnight at 20° C. The reaction was diluted with CH 2 Cl 2  (500 ml), washed with 1N aqueous NaOH, washed with brine, filtered through Celite, and concentrated. Flash chromatography (0-4% 7N NH 3 —CH 3 OH/CH 2 Cl 2 ) provided Ex. 5 (16.9 g, 82%) as a beige solid.  
       EXAMPLE 6 
       [0302]    [0302]                           
         [0303]    Step 1:  
                         
 
         [0304]    To a stirred solution of diamine 1B (1.0 g, 3.55 mmol) in C 2 H 5 OH (25 ml), at RT was added portionwise solid CNBr (564 mg; 5.33 mmol). The resultant solution was allowed to stir at RT for 5 days before removing solvent under vacuum. The residual oil was partitioned between EtOAc (30 ml) and 2M Na 2 CO 3  (10 ml). The aqueous layer was adjusted to pH˜10 by addition of a few drops of 6N NaOH and was then re-extracted with EtOAc (2×10 ml). Combined extracts were washed with brine (5 ml) and filtered through anhydrous MgSO 4 . The filtrate was stripped in vacuo to obtain compound 6A as brown powder (1.03 g; 94%) sufficiently pure for use without purification. FABMS: 307 (MH + ; 100%).  
         [0305]    Step 2.  
                         
 
         [0306]    In a dry flask, under an inert atmosphere, a mixture of compound 6A (369 mg; 1.20 mmol) and CH 2 Cl 2  (11 ml) was stirred and sonicated until the formation of a clear, amber solution to which was added via syringe 4-fluorophenyl isocyanate (158 microliters; 190 mg; 1.38 mmol). After 30.5 h at RT, a few drops of CH 3 OH were added to the reaction solution, and solvent was removed under vacuum. The residual solid was dissolved in boiling Et 2 O (˜30 ml). Insoluble matter was filtered, and the filtrate was diluted to a volume of ˜60 ml with hot hexanes. The solution was concentrated on a steam bath to a volume of ˜30 ml, by which point precipitation had begun. The mixture was allowed to stand at RT for ˜3 h. Filtration and washing with Et 2 O-hexanes (1 :1 v/v) yielded compound 6B as a reddish-brown powder (394 mg; 74%). FABMS: 444 (MH + ; 100%). Although TLC and NMR indicated the presence of minor impurities, the product was sufficiently pure for use in Step 3 below.  
         [0307]    Step 3:  
                         
 
         [0308]    To a stirred suspension of compound 6B (333 mg; 0.751 mmol) in CHCl 3  (2 ml), contained in a flask equipped for reflux under an inert atmosphere, was added via syringe (CH 3 ) 3 Sil (214 microliters; 301 mg; 1.51 mmol). Solids dissolved rapidly to produce a dark reddish-brown solution. Stirring was continued at RT for 20 min before placing the reaction mixture in an oil bath preheated to 50° C. After 5 h at 50° C., a second portion of (CH 3 ) 3 Sil (54 microliters; 75 mg; 0.378 mmol) was added and heating continued at 50° C. for another 2.5 h. The reaction mixture (consisting of solid and solution phases) was removed from the heating bath and was treated with CH 3 OH (2.5 ml) added in two portions. The reaction mixture was stirred and warmed to 50° C. for a few minutes, allowed to cool and was then filtered. Collected solids were washed with 1:1 (v/v) CH 3 OH-EtOAc to obtain the hydriodide salt form of 6C as a pale reddish-brown powder (356 mg) wich was used in the next step without further purification. FABMS: 372 (MH + ; 100%).  
         [0309]    Step 4:  
                         
 
         [0310]    To a stirred suspension of 6C (340 mg; 0.681 mmol), Prep. 1 (228 mg; 0.681 mmol), HOBT (9.2 mg; 0.0681 mmol) and NEt 3  (379 microliters; 275 mg; 2.72 mmol) in DMF (13 ml) was added solid EDCI (163 mg; 0.851 mmol). The cloudy reaction mixture was placed in a preheated oil bath and was stirred at 50° C. for 30 min, after which the resultant clear, amber solution was stirred for 23.5 h at RT. A few drops of water were added, and the reaction mixture was concentrated at 60° C. under vacuum. The concentrate was partitioned between EtOAc (20 ml) and water (5 ml)-brine (2.5 ml). The aqueous phase was extracted with EtOAc (2×5 ml). Combined extracts were washed with brine (2.5 ml) and filtered through anhydrous MgSO 4 . The filtrate was evaporated under vacuum, and the residue was purified by flash chromatography on silica gel, eluting with a gradient of CH 2 Cl 2 —CH 3 OH—NH 4 OH (97:3:0.5-&gt;96:4:0.5). Product 6D (222 mg; 47%) was obtained as pale yellow powder. FABMS: 689 (MH + ; ˜93%); 578 (˜58%); 478 (100%).  
         [0311]    Step 5:  
         [0312]    To a solution of 6D (208 mg; 0.302 mmol) in CH 2 Cl 2  (3 ml) was added TFA (928 microliters; 1.37 g; 12.1 mmol) with swirling of the flask, which was then flushed with dry N 2 , sealed and allowed to stand at RT for 6 h. The reaction solution was evaporated under vacuum, and the residue was partitioned between EtOAc (20 ml) and 2M Na 2 CO 3  (3 ml) plus sufficient water to produce two clear phases. The aqueous phase was extracted with EtOAc (3×5 ml). Combined extracts were washed with brine (3 ml) and filtered through anhydrous MgSO 4 . The filtrate was stripped of solvent in vacuo, and the residue was subjected to flash chromatography on silica gel, eluting with CH 2 Cl 2 —CH 3 OH—NH 4 OH (97:3:0.5). The title compound (130 mg; 72%) was obtained as pale yellow powder. FABMS: 589 (MH + ; ˜64%); 478 (100%).  
         [0313]    Using procedures similar to those described above, employing the appropriate starting materials, compounds in the following tables are prepared:  
                                                                                                                                                                                                                                                                                                                                                              Physical                                   Data       No.   R   R 25     R 3     R 13     Z   R 6     MS (MH + )               7   —CH 3     5-OCH 3     H   H   —CH 2 —   2-NH 2     463       8   —CH 3     6-Cl   H   H   —CH 2 —   2-NH 2     467       9   —CH 3     5-Cl   H   H   —CH 2 —   2-NH 2     467       10   —CH 3     5-Br   H   H   —CH 2 —   2-NH 2     512               11                                 5-Cl   H   H   —CH 2 —   2-NH 2     535               12   benzyl   5-F   H   H   —CH 2 —   2-NH 2     527       13   —CH(CH 3 ) 2     5-Br   H   H   —CH 2 —   2-NH 2     540       14   —CH 2 NH 2     H   H   H   —CH 2 —   2-NH 2     488       15   —CH 2 NHSO 2 CH 3     H   H   H   —CH 2 —   2-NH 2     526       16   —CH 2 NHC(O)CH 3     5-Cl   H   H   —CH 2 —   2-NH 2     524       17   —CH 2 OCH 3     5-F   H   H   —CH 2 —   2-NH 2     481       18   —CH 2 NH 2     5-Cl   H   H   —CH 2 —   2-NH 2     482       19   —CH 2 OCH 3     6,7-di-F   H   H   —CH 2 —   2-NH 2     499               20                                 6-F   H   H   —CH 2 —   2-NH 2     521               21                                 5-F   H   H   —CH 2 —   2-NH 2     521               22                                 6-F   H   H   —CH 2 —   2-NH 2     507               23                                 5-F   H   H   —CH 2 —   2-NH 2     520               24                                 5-F   H   H   —CH 2 —   2-NH 2     521               25                                 5-Br   H   H   —CH 2 —   2-NH 2     568               26                                 5-F   H   H   —CH 2 —   2-NH 2     507               27                                 5-F   H   H   —CH 2 —   2-NH 2     507               28                                 H   H   H   —CH 2 —   2-NH 2     531               29                                 5-F   H   H   —CH 2 —   2-NH 2     549               30                                 6-F   H   H   —CH 2 —   2-NH 2     531               31                                 6,7-di-F   H   H   —CH 2 —   2-NH 2     567               32                                 6-Cl   H   H   —CH 2 —   2-NH 2     547               33                                 5-F   H   H   —CH 2 —   2-NH 2     531               34                                 5-Cl   H   H   —CH 2 —   2-NH 2     565               35                                 H   H   H   —CH 2 —   2-NH 2     531               36                                 5-Cl   H   H   —CH 2 —   2-NH 2     547               37                                 5-Cl   H   H   —CH 2 —   2-NH 2     529               38                                 6-F   H   H   —CH 2 —   2-NH 2     557               39                                 5-Br   H   H   —CH 2 —   2-NH 2     592               40                                 5-Br   H   H   —CH 2 —   2-NH 2     610               41                                 5-F   H   H   —CH 2 —   2-NH 2     547               42                                 5-F   H   H   —CH 2 —   2-NH 2     529               43                                 6-F   H   H   —CH 2 —   2-NH 2     553               44                                 6-F   H   H   —CH 2 —   2-NH 2     564               45                                 H   H   H   —CH 2 —   2-NH 2     529               46                                 5-F   H   H   —CH 2 —   2-NH 2     581               47                                 5-Cl   H   H   —CH 2 —   2-NH 2     563               48                                 6-Cl   H   H   —CH 2 —   2-NH 2     563               49                                 5-F   H   H   —CH 2 —   2-NH 2     543               50                                 5-F   H   H   —CH 2 —   2-NH 2     581               51                                 5-Cl   H   H   —CH 2 —   2-NH 2     597               52                                 5-F   H   H   —CH 2 —   2-NH 2     597               53                                 5-Br   H   H   —CH 2 —   2-NH 2     604               54                                 6-Cl   H   H   —CH 2 —   2-NH 2     597               55                                 5-CH 3     H   H   —CH 2 —   2-NH 2     571               56                                 5-Cl   H   H   —CH 2 —   2-NH 2     665               57                                 5-Br   H   H   —CH 2 —   2-NH 2     710               58                                 6-ethoxy   H   H   —CH 2 —   2-NH 2     540               59                                 5-Cl   H   H   —CH 2 —   2-NH 2     546               60                                 H   H   H   —CH 2 —   2-NH 2     511               61                                 5-F   H   H   —CH 2 —   H   499               62                                 6-Cl   H   H   —CH 2 —   2-NH 2     530               63                                 5-F   H   H   —CH 2 —   2-NH 2     515               64                                 6-F   H   H   —CH 2 —   2-NH 2     514               65                                 6-F   H   H   —CH 2 —   2-NH 2     515               66                                 7-Cl   H   H   —CH 2 —   2-NH 2     531               67                                 H   H   H   —CH 2 —   2-NH 2     496               68                                 5-F   H   H   —CH 2 —   2-NH 2     515               69                                 5-Cl   H   H   —CH 2 —   2-NH 2     531               70                                 5-Cl   H   H   —CH 2 —   2-NH 2     531               71                                 5,6-di-F   H   H   —CH 2 —   2-NH 2     532               72                                 5-Br   H   H   —CH 2 —   2-NH 2     575               73                                 6-ethoxy   H   H   —CH 2 —   2-NH 2     541               74                                 5-F   H   H   —CH 2 —   2-NH 2     528               75                                 6-F   H   H   —CH 2 —   2-NH 2     515               76                                 5-Br   H   H   —CH 2 —   2-NH 2     591               77                                 5-Cl   H   H   —CH 2 —   2-NH 2     530               78                                 5-Cl   H   H   —CH 2 —   2-NH 2     530               79                                 5-F   H   H   —CH 2 —   2-NH 2     548               80                                 5-CF 3     H   H   —CH 2 —   2-NH 2     565               81                                 H   H   H   —CH 2 —   2-NH 2     497               82                                 6,7-di-F   H   H   —CH 2 —   2-NH 2     567               83                                 6,7-di-F   H   H   —CH 2 —   2-NH 2     532               84                                 5-F   H   H   —CH 2 —   2-NH 2     530               85                                 5-CF 3 , 7-F   H   H   —CH 2 —   2-NH 2     617               86                                 5-F   H   H   —CH 2 —   2-NH 2     529               87                                 H   H   H   —CH 2 —   2-NH 2     500               88                                 H   H   H   —CH 2 —   2-NH 2     485               89                                 H   H   H   —CH 2 —   2-NH 2     489               90                                 6-F   H   H   —CH 2 —   2-NH 2     514               91                                 6-F   H   H   —CH 2 —   2-NH 2     503               92                                 5-F   H   H   —CH 2 —   2-NH 2     503               93                                 H   H   H   —CH 2 —   2-NH 2     501               94                                 5-F   H   H   —CH 2 —   2-NH 2     518               95                                 5-Cl   H   H   —CH 2 —   2-NH 2     534               96                                 5-F   H   H   —CH 2 —   2-NH 2     519               97                                 6,7-di-F   H   H   —CH 2 —   2-NH 2     536               98                                 5-Br   H   H   —CH 2 —   2-NH 2     579               99                                 6-ethoxy   H   H   —CH 2 —   2-NH 2     544               100                                 5-F   H   H   —CH 2 —   2-NH 2     503               101                                 5-Br   H   H   —CH 2 —   2-NH 2     563               102                                 5-F   H   H   —CH 2 —   2-NH 2     502               103                                 5-CF 3     H   H   —CH 2 —   2-NH 2     568               104                                 5-CF 3 , 7-F   H   H   —CH 2 —   2-NH 2     586               105                                 5-F   H   H   —CH 2 —   2-NH 2     598               106                                 5-F   H   H   —CH 2 —   2-NH 2     517               107                                 5-F   H   H   —CH 2 —   2-NH 2     573               108                                 5-F   H   H   —CH 2 —   2-NH 2     517               109   CH 3 —S—   5-F   H   H   —CH 2 —   2-NH 2     483       110   CH 3 —CH 2 —S—   5-F   H   H   —CH 2 —   2-NH 2     497       111   CH 3 —SO 2 —   5-F   H   H   —CH 2 —   2-NH 2     515               112                                 5-F   H   H   —CH 2 —   2-NH 2     545               113                                 5-F   H   H   —CH 2 —   2-NH 2     511               114                                 5-F   H   H   —CH 2 —   2-NH 2     551               115                                 5-F   H   H   —CH 2 —   2-NH 2     540               116   HS—   5-F   H   H   —CH 2 —   2-NH 2     469       117   CH 3 —S—   5-F   H   2-   —CH 2 —   2-NH 2     497                       CH 3         118   CH 3 —S—   5-F   F   H   —CH 2 —   2-NH 2     501               119                                 5-F   H   H   —CH 2 —   2-NH 2     529               120                                 5-F   H   H   —CH 2 —   2-NH 2     522               121                                 5-F   H   H   —CH 2 —   2-NH 2     599               123                                 5-F   H   H   —CH 2 —   2-NH 2     528               124                                 5-F   H   H   —CH 2 —   2-NH 2     564               125                                 5-F   H   H   —CH 2 —   2-NH 2     578               126                                 5-F   H   H   —CH 2 —   2-NH 2     624               127                                 5-F   H   H   —CH 2 —   2-NH 2     546               128                                 5-F   H   H   —CH 2 —   2-NH 2     653               129   CH 3 —O—(CH 2 ) 2 —NH—   5-F   H   H   —CH 2 —   2-NH 2     510               130                                 5-F   H   H   —CH 2 —   2-NH 2     563               131                                 5-F   H   H   —CH 2 —   2-NH 2     480               132   CH 3 —O—   5-F   H   H   —CH 2 —   2-NH 2     467       133   CH 3 —CH 2 —O—   5-F   H   H   —CH 2 —   2-NH 2     481       134   CH 3 —O—(CH 2 ) 2 O—   5-F   H   H   —CH 2 —   2-NH 2     511       135   (CH 3 ) 2 —CH—O—   5-F   H   H   —CH 2 —   2-NH 2     495               136                                 5-F   H   H   —CH 2 —   2-NH 2     529               137                                 H   H   H   —CH 2 —   2-NH 2     511               138                                 5-CF 3 , 7-F   H   H   —CH 2 —   2-NH 2     582               139                                 5-F   H   H                                 2-NH 2     528               140                                 5-F   F   F   —CH 2 —   2-NH 2     532               141                                 5-F   OH   H   —CH 2 —   2-NH 2     530               142                                 5-F   H   H                                 2-NH 2     529               143                                 5-F   H   H                                 2-NH 2     529               144                                 5-F   —CH 3     H   —CH 2 —   2-NH 2     528               145                                 6-F   H   H                                 2-NH 2     528               146   H   5-F   H   H   —CH 2 —   2-NH 2     437               147                                 5-F   H   H   —CH 2 —   2-NH 2     531               148                                 5-F   H   H   —CH 2 —   2-NH 2     531               149                                 5-F   H   H   —CH 2 —   2-NH 2     585               150                                 5-F   H   H   —CH 2 —   2-NH 2     549               151                                 5-F   H   H   —CH 2 —   2-NH 2     571               152                                 H   F   H   —CH 2 —   2-NH 2     514               153   (CH 3 ) 2 N—(CH 2 ) 2 —NH—   5-F   H   H   —CH 2 —   2-NH 2     523               154   CH 3 —S—   5-F   H   H                                 2-NH 2     497               155                                 5-F   H   2- CH 3     —CH 2 —   2-NH 2     528               156                                 5-F   H   H   —CH 2 —   2-NH 2     514               157                                 5-F   H   H   —CH 2 —   3-NH 2     514               158                                 5-F   H   H   —CH 2 —   2-NH 2     589               159                                 5-F   H   H   —CH 2 —   2-NH 2     520               160   CH 3 CH 2 O—   5-F   F   H   —CH 2 —   2-NH 2     499               161                                 5-F   H   H   —CH 2 —   2-NH 2     537               162                                 5-F   H   H   —CH 2 —   2-NH 2     535               163                                 5-F   H   5-OH   —CH 2 —   2-NH 2     530               164                                 5-F   F   H   —CH 2 —   3-NH 2     532               165                                 5-F   F   H   —CH 2 —   2-NH 2     540               166                                 5-F   H   H   —CH 2 —   3-NH 2     515                                                                                                   Physical                               Data           No.   R   R 3     Z   R 6     MS (MH + )                       167                                  H   —CH 2 —   2-NH 2     502                       168   —CH 2 OCH 3     H   —CH 2 —   2-NH 2     464                       169                                 H   —CH 2 —   2-NH 2     504                       170                                 H   —CH 2 —   2-NH 2     460                       171   (CH 3 ) 2 —CH—   H   —CH 2 —   2-NH 2     462                       172                                 H   —CH 2 —   2-NH 2     477                       173                                 H   —CH 2 —   2-NH 2     514                       174                                 H   —CH 2 —   2-NH 2     532                       175                                 H   —CH 2 —   2-NH 2     530                       176                                 H   —CH 2 —   2-NH 2     532                       177                                 H   —CH 2 —   2-NH 2     540                       178                                 H   —CH 2 —   2-NH 2     564                       179                                 H   —CH 2 —   2-NH 2     526                       180                                 H   —CH 2 —   2-NH 2     558                       181                                 H   —CH 2 —   2-NH 2     497                       182                                 H   —CH 2 —   2-NH 2     512                       183                                 H   —CH 2 —   2-NH 2     531                       184                                  H   —CH 2 —   2-NH 2     498                       185                                 H   —CH 2 —   2-NH 2     497                       186                                 H   —CH 2 —   2-NH 2     511                       187                                 H   —CH 2 —   2-NH 2     501                       188                                 H   —CH 2 —   2-NH 2     486                       189                                 H   —CH 2 —   2-NH 2     486                       190                                 H   —CH 2 —   2-NH 2     501                       191                                 H   —CH 2 —   2-NH 2     536                       192                                 H   —CH 2 —   2-NH 2     547                       193                                 H   —CH 2 —   2-NH 2     547                       194                                 H   —CH 2 —   2-NH 2     543                       195                                 H   —CH 2 —   2-NH 2     581                       196                                 F   —CH 2 —   2-NH 2     519                       197                                 H                                 2-NH 2     515                       198                                 OH   —CH 2 —   2-NH 2     517                       199                                                               —CH 2 —   2-NH 2     577                       200                                 F   —CH 2 —   2-NH 2     515                       201                                 F   —CH 2 —   2-NH 2     504                       202                                 H   —CH 2 —   3-NH 2     497                       203                                 H   —CH 2 —   3-NH 2     532                       204                                 F   —CH 2 —   3-NH 2     515                       205                                 F   —CH 2 —   3-NH 2     550                                                                                           Physical                   Data           No.   R   MS (MH + )                       206   —CH 3     434                       207                                 497                       208                                 514                       209                                 530                                                                                                       Physical                               Data       No.   R   R 25     A   R 3     R 2     MS (MH + )               210                                 5-Cl   C   H                                 532               211                                 5-F   C   H                                 515               212                                 5-Cl   C   H                                 532               213                                 5-F   C   H                                 516               214                                 H   N   H                                 503               215                                 H   N   H                                 503               216   (CH 3 ) 2 CH—   H   N   H                                 463               217                                 5-F   C   H                                 550               218                                 5-F   C   H                                 515               219                                 5-Cl   C   H                                 532               220                                 6-Cl   C   H                                 548               221                                 5-F   C   H                                 516               222                                 6-Cl   C   H                                 600               223                                 5-Cl   C   H                                 532               224                                 6-F   C   H                                 515               225                                 H   N   H                                 499               226                                 H   N   H                                 502               227                                 H   N   H                                 487               228                                 H   N   H                                 548               229                                 H   N   H                                 548               230                                 H   N   H                                 499               231                                 H   N   H                                 502               232                                 H   N   H                                 537               233                                 H   N   H                                 548               234                                 H   N   H                                 541               235                                 H   N   H                                 559               236                                 N   C   H                                 498               237                                 5-F   C   F                                 533               238                                 5-F   C   H                                 550               239                                 5-F   C   H                                 550               240                                 5-F   C   H                                 515               241                                 5-F   C   H                                 516               242                                 H   C   H                                 497               243   (CH 3 ) 2 N—CH 2 —   H   N   H                                 478               244                                 5-F   C   H                                 519               245                                 H   C   H                                 501               246                                 5,6-di-F   C   H                                 537               247                                 5-F   C   H                                 500               248                                 5,6-di-F   C   H                                 534               249                                 5-F   C   F                                 537               250                                 5-F   C   F                                 534               251                                 5-F   C   F                                 534               252                                 5-F   C   F                                 533               253                                 5-F   C   F                                 568               254                                 5-F   C   F                                 568               255                                 H   N   H                                 487               256                                 H   C   F                                 515               257                                 H   C   F                                 519               258                                 H   N   F                                 516               259                                 H   N   H                                 505               260                                 H   N   F                                 516               261                                 H   N   F                                 520               262                                 5-F   C   H                                 504               263                                 5-F   C   H                                 522               264                                 5-F   C   H                                 504               265                                 H   N   H                                 537               266   (CH 3 ) 2 N—CH 2 —   H   N   F                                 496               267                                 H   N   F                                 505               268   CH 3 CH 2 —O—   5-F   C   H                                 482               269   CH 3 —S—   5-F   C   H                                 484               270   CH 3 CH 2 —O—   5-F   C   F                                 500               271                                 H   N   F                                 555               272                                 H   N   F                                 566               273                                 H   N   H                                 498               274                                 5,6-di-F   C   F                                 551               275                                 5-F   C   F                                 541               276                                 5-F   C   H                                 523               277                                 5-F   C   H                                 514               278                                 5-F   C   H                                 539               279                                 H   N   H                                 515               280                                 H   N   H                                 501               281                                 H   N   F                                 505               282                                 H   N   H                                 536               283                                 H   N   F                                 523               284                                 5-F   C   F                                 532               285                                 H   N   H                                 501               286                                 H   N   H                                 533               287                                 H   N   F                                 517               288                                 H   N   H                                 548               289                                 H   N   H                                 533               290   CH 3 S—   5-F   C   F                                 502               291                                 H   N   F                                 515               292                                 5-F   C   F                                 532               293                                 5-F   C   H                                 514               294                                 H   N   H                                 497               295   (CH 3 ) 2 N—   5-F   C   F                                 499               296   CH 3 CH 2 —S—   5-F   C   F                                 516               297   CH 3 —O—   5-F   C   F                                 486               298                                 H   N   H                                 512               299                                 H   N   F                                 530               300                                 5-F   C   F                                 547               301                                 5-F   C   H                                 529               302                                 5-F   C   H                                 517               303                                 5-F   C   F                                 535               304                                 H   N   H                                 551               305                                 H   N   F                                 551               306                                 5-F   C   H                                 500               307                                 5-F   C   H                                 500               308                                 5-F   C   F                                 547               309   (CH 3 CH 2 ) 2 N—   5-F   C   F                                 527               310                                 H   N   H                                 498               311                                 H   N   F                                 516               312                                 5-F   C   H                                 515               313                                 5-F   C   F                                 533               314                                 5-F   C   F                                 569               315   CH 3 —S—   H   N   F                                 485               316   CH 3 CH 2 —O—   H   N   F                                 483               317                                 H   N   F                                 566               318                                 H   N   F                                 489               319                                 H   N   F                                 489               320                                 H   N   F                                 505               321                                 H   N   F                                 505               322                                 5-F   C   F                                 533               323                                 H   N   F                                 516               325                                 H   N   F                                 540               325                                 H   N   F                                 524               326   (CH 3 ) 2 CH—O—   5-F   C   F                                 514               327                                 H   N   F                                 506               328                                 H   N   F                                 488               329                                 H   N   F                                 489               330                                 H   N   F                                 507               331                                 H   N   F                                 551               332                                 H   N   F                                 506               333                                 H   N   F                                 518               334                                 H   N   F                                 504               335   CH 3 —O—   H   N   F                                 464               336                                 H   N   F                                 491               337                                 H   N   F                                 563               338                                 5-F   C   H                                 545               339                                 5-F   C   F                                 533               340                                 H   N   F                                 518               341                                 5-F   C   H                                 535               342                                 H   N   F                                 520               343                                 6-Cl   C   H                                 548               345                                 H   N   H                                 503               346   (CH 3 ) 2 —CH—   H   N   H                                 463                                                                                           Physical                       Data           No.   R 3     R 2     MS (MH + )                       347   H                                 489                       348   F                                 506                       349   F                                 488                       350   F                                 507                       351   F                                 506                                                                                                   Physical                           Data       No.   R 1 —X—   Z   R 3     R 2     MS (MH + )               352                                 —CH 2 —   H                                 509               353                                 —CH 2 —   H                                 510               354                                 —CH 2 —   H                                 523               355                                 —CH 2 —   H                                 532               356                                 —CH 2 —   H                                 496               357                                 —CH 2 —   H                                 506               358                                 —CH 2 —   H                                 542               359                                 —CH 2 —   H                                 451               360                                 —CH 2 —   H                                 537               361                                 —CH 2 —   H                                 495               362                                 —CH 2 —   H                                 501               363                                 —CH 2 —   H                                 510               364                                 —CH 2 —   H                                 533               365                                 —CH 2 —   H                                 420               366                                 —CH 2 —   H                                 449               367                                 —CH 2 —   H                                 497               368                                 —CH 2 —   H                                 533               369                                 —CH 2 —   H                                 487               370                                 —CH 2 —   H                                 509               371                                 —CH 2 —   H                                 433               372                                 —CH 2 —   H                                 504               373                                 —CH 2 —   H                                 436               374                                 —CH 2 —   H                                 472               375                                 —(CH 2 ) 3 —   H                                 464               376                                 —CH 2 —   H                                 544               377                                 —CH 2 —   F                                 562                                                                                                   Physical                               Data           No.   R   M 1     Y   R 2     MS (MH + )                       378                                 CH   —CH 2 —                                 500                       379                                 N   —NH—                                 502                       380                                 N   —NH—                                 490                       381                                 N   —NH—                                 494                       382                                 N   —NH—                                 501                       383                                 N   —NH—                                 500                        384:                                         385:                                         386:                                         387:                                            
 
       EXAMPLE 388 
       [0314]    [0314]                           
         [0315]    Step 1:  
                         
 
         [0316]    A solution of P7-1 (2.3 g, 8.9 mmol) in CH 2 Cl 2 -DMF (1:1, 50 ml) was treated with picolinic acid N-oxide (1.5 g, 10.6 mmol), EDCI (2.6 g, 13.3 mmol) and HOBT (1.8 g, 13.3 mmol). The mixture was stirred at 70° C. overnight. The reaction mixture was concentrated, diluted with EtOAc, washed three times with 5% aqueous NaOH, dried over Na 2 SO 4 , and concentrated. Flash chromatography (50% EtOAc/hexane) provided 388A (2.5 g, 74%).  
         [0317]    Step 2:  
                         
 
         [0318]    In a manner similar to that described in Preparation 5, Step 4, compound 388A was converted to compound 388B.  
         [0319]    Step 3:  
                         
 
         [0320]    A solution of 388B (0.66 g, 2.2 mmol) in DMF (15 ml) was treated with 5C (0.62 g, 2.5 mmol), 1-propanephosphonic acid cyclic anhydride (3.3 ml, 11.2 mmol, 50 wt. % in EtOAc) and N-ethylmorpholine (1.4 ml, 10.7 mmol). The mixture was stirred at 50° C. for 3 h. The reaction mixture was concentrated and diluted with EtOAc. The solution was washed three times with 5% aqueous NaOH, dried over Na 2 SO 4 , concentrated and subjected to flash chromatography (10% 2N NH 3 —CH 3 OH/EtOAc). The material was then taken up in CH 2 Cl 2  (20 ml) and treated with 4 M HCl-dioxane (4 ml). After stirring overnight at 20° C., the reaction was carefully basified with 10% aqueous NaOH and extracted with CH 2 Cl 2 . The combined organic layers were dried over Na 2 SO 4 , concentrated and subjected to flash chromatography (30% 2N NH 3 —CH 3 OH/EtOAc) to provide 388C as a white solid (0.08 g, 10%).  
         [0321]    Step 4:  
         [0322]    In a manner similar to that described in Example 5, Step 5, compound 388C was converted to Example 388.  
       EXAMPLE 389 
       [0323]    [0323]                           
         [0324]    Step 1:  
                         
 
         [0325]    To a stirred, cloudy solution of 389A (300 mg, 1.14 mmol) in THF (15 ml) were added a solution of 389B (292 mg, 1.37 mmol) in THF (1 ml), followed by NaBH(OAc) 3  (483 mg, 2.28 mmol). After stirring at RT for 39 h, TLC revealed the presence of unchanged starting materials in the cloudy white reaction suspension. Therefore, another quantity of NaBH(OAc) 3  (242 mg, 1.14 mmol) was added and stirring at RT continued for a total of 113 h. The reaction mixture was then filtered and collected solids washed thoroughly with CH 2 Cl 2 . The combined filtrate and washings were stripped of solvent under vacuum, and the residue was partitioned between EtOAc (60 ml) and a solution consisting of water (2.5 ml), 2M Na 2 CO 3  (6.5 ml) and 6N NaOH (5 ml). The aqueous layer was further extracted with EtOAc (3×15 ml). The combined extracts were washed with brine (5 ml) and dried over anhydrous MgSO 4 . Drying agent was removed by filtration, and the filtrate was concentrated under vacuum. The residue was purified by silica gel flash chromatography (EtOAc/hexanes 32  1:1) to obtain 389C as a mixture of colorless gum and white foam (368 mg, 70%), homogeneous to TLC, which solidified upon standing. ES-MS: 461 (MH + ; 100%).  
         [0326]    Step 2:  
                         
 
         [0327]    To a stirred, ice-cold solution of 389C (358 mg, 0.777 ml) in CH 2 Cl 2  (7 ml) was added via syringe cold, neat TFA (576 microliters, 886 mg, 7.77 mmol). The resultant solution was stirred in an ice-water bath for 30 min, then at RT for 29.5 h. Volatiles were removed under vacuum, and the gummy residue was triturated (magnetic stirrer) with Et 2 O (35 ml) for 16 h. Filtration and washing with Et 2 O yielded the bis-trifluoroacetate salt of 389D as a white powder (449 mg, 98%).  
         [0328]    Step 3:  
         [0329]    To a stirred suspension of 389D (100 mg, 0.170 mmol) in CH 2 Cl 2  (5 ml) was added Et 3 N (47.4 microliters, 34.4 mg, 0.340 mmol), whereupon all solids dissolved. To the stirred solution were then added 5G (25.1 mg, 0.204 mmol), followed by NaBH(OAc) 3  (72.1 mg, 0.340 mmol). After stirring at RT for 66 h, TLC revealed the presence of unchanged starting materials in the light yellow reaction suspension. Therefore, another quantity of NaBH(OAc) 3  (72.1 mg, 0.340 mmol) was added and stirring at RT continued for a total of 90 h. The reaction mixture was then filtered and collected solids washed thoroughly with CH 2 Cl 2 . The combined filtrate and washings were stripped of solvent under vacuum, and the residue was partitioned between EtOAc (20 ml) and a solution consisting of water (0.6 ml), 2M Na 2 CO 3  (1.5 ml) and 6N NaOH (1.2 ml). The aqueous layer was further extracted with EtOAc (3×5 ml). The combined extracts were washed with brine (2 ml) and dried over anhydrous MgSO 4 . Drying agent was removed by filtration, and the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (silica gel; CH 2 Cl 2 /CH 3 OH/conc. NH 4 OH=90:9:1) to obtain the title compound as a light beige foam (36 mg, 45%). FABMS: 468 (MH + ; 100%).  
         [0330]    Using procedures similar to those described above in Examples 1-6 and 388-389, following compounds were prepared:  
                                               Mass Spec       Ex.   Structure   (M + H)                                   390                                 533 (ESMS)               391                                 518 (ESMS)               392                                 535 (ESMS)               393                                 520 (ESMS)               394                                 592 (FAB)               395                                 670 (FAB)               396                                 528 (ESMS)               397                                 491 (ESMS)               398                                 470 (ESMS)               399                                 488 (ESMS)               400                                 487 (ESMS)               401                                 471 (ESMS)               402                                 487 (ESMS)               403                                 471 (ESMS)               404                                 489 (ESMS)               405                                 506 (ESMS)               406                                 505 (ESMS)               407                                 522 (ESMS)               408                                 522 (ESMS)               409                                 506 (ESMS)               410                                 523 (ESMS)               411                                 524 (ESMS)               412                                 501 (ESMS)               413                                 490 (ESMS)               414                                 473 (ESMS)               415                                 488 (ESMS)               416                                 487 (ESMS)               417                                 504 (ESMS)               418                                 504 (ESMS)               419                                 488 (ESMS)               420                                 505 (ESMS)               421                                 506 (ESMS)               422                                 526 (FAB)               423                                 518 (ESMS)               424                                 585 (FAB)               425                                 591 (ESMS)               426                                 499 (ESMS)               427                                 516 (ESMS)               428                                 546 (ESMS)               429                                 498 (ESMS)               430                                 514 (ESMS)               431                                 571 (ESMS)               432                                 589 (ESMS)               433                                 573 (ESMS)               434                                 591 (ESMS)               435                                 512 (ESMS)               436                                 530 (ESMS)               437                                 483 (ESMS)               438                                 484 (ESMS)               439                                 502 (ESMS)               440                                 499 (FAB)               441                                 471 (ESMS)               442                                 488 (ESMS)               443                                 506 (ESMS)               444                                 470 (ESMS)               445                                 488 (ESMS)               446                                 531 (ESMS)               447                                 497 (ESMS)               448                                 513 (ESMS)               449                                 548 (ESMS)               450                                 563 (ESMS)               451                                 514 (ESMS)               452                                 532 (ESMS)               453                                 502 (ESMS)               454                                 550 (ESMS)               455                                 520 (ESMS)               456                                 451 (ESMS)               457                                 545 (ESMS)               458                                 513 (ESMS)               459                                 514 (FAB)               460                                 496 (FAB)               461                                 442 (ESMS)               462                                 458 (ESMS)               463                                 503 (ESMS)               464                                 407 (ESMS)               465                                 534 (ESMS)               466                                 516 (ESMS)               467                                 514 (ESMS)               468                                 484 (ESMS)               469                                 458 (ESMS)               470                                 474 (ESMS)               471                                 467 (ESMA)               472                                 440 (ESMS)               473                                 465 (ESMS)               474                                 487 (ESMS)               475                                 472 (ESMS)               476                                 466 (ESMS)               477                                 505 (ESMS)               478                                 456 (ESMS)               479                                 456 (ESMS)               480                                 504 (ESMS)               481                                 514 (ESMS)               482                                 531 (FAB)               483                                 472 (ESMS)               484                                 438 (ESMS)               485                                 438 (ESMS)               486                                 454 (ESMS)               487                                 470 (ESMS)               488                                 502 (ESMS)               489                                 554 (FAB)               490                                 556 (FAB)               491                                 470 (ESMS)               492                                 487 (ESMS)               493                                 469 (ESMS)                44                                 555 (ESMS)               495                                 452 (ESMS)               496                                 487 (ESMS)               497                                 440 (ESMS)               498                                 424 (ESMS)               499                                 470 (ESMS)               500                                 486 (ESMS)               501                                 556 (ESMS)               502                                 500 (ESMS)               503                                 566 (ESMS)               504                                 577 (ESMS)               505                                 550 (ESMS)               506                                 506 (ESMS)               507                                 522 (ESMS)               508                                 533 (ESMS)               509                                 504 (ESMS)               510                                 520 (ESMS)               511                                 456 (ESMS)               512                                 467 (ESMS)               513                                 482 (ESMS)               514                                 482 (ESMS)               515                                 500 (ESMS)               516                                 500 (ESMS)               517                                 500 (ESMS)               518                                 482 (ESMS)               519                                 498 (ESMS)               520                                 481 (ESMS)               521                                 516 (ESMS)               522                                 512 (FAB)               523                                 495 (FAB)               524                                 499 (FAB)               525                                 499 (ESMS)               526                                 560 (ESMS)               527                                 499 (ESMS)               528                                 501 (ESMS)               529                                 483 (ESMS)               530                                 526 (ESMS)               531                                 509 (ESMS)               532                                 449 (ESMS)               533                                 500 (ESMS)               534                                 512 (ESMS)               535                                 495 (ESMS)               536                                 546 (ESMS)               537                                 530 (ESMS)               538                                 531 (ESMS)               539                                 545 (ESMS)               540                                 468 (ESMS)               541                                 540 (ESMS)               542                                 481 (ESMS)               543                                 482 (ESMS)               544                                 515 (ESMS)               545                                 517 (ESMS)               546                                 526 (ESMS)               547                                 5560 (ESMS)               548                                 526 (ESMS)               549                                 550 (ESMS)               550                                 517 (ESMS)               551                                 532 (ESMS)               552                                 464 (ESMS)               553                                 516 (ESMS)               554                                 486 (ESMS)               555                                 502 (ESMS)               556                                 526 (ESMS)               557                                 516 (ESMS)               558                                 487 (ESMS)               559                                 496 (ESMS)               560                                 481 (FAB)               561                                 534 (ESMS)               562                                 501 (ESMS)               563                                 517 (ESMS)               564                                 517 (ESMS)               565                                 517 (ESMS)               566                                 577 (ESMS)               567                                 592 (ESMS)               568                                 519 (ESMS)               569                                 552 (ESMS)               570                                 537 (ESMS)               571                                 453 (ESMS)               572                                 505 (ESMS)               573                                 504 (ESMS)               574                                 519 (ESMS)               575                                 533 (ESMS)               576                                 549 (ESMS)               577                                 548 (ESMS)               578                                 533 (ESMS)               579                                 566 (ESMS)               580                                 551 (ESMS)               581                                 559 (ESMS)               582                                 560 (ESMS)               583                                 592 (ESMS)               584                                 579 (ESMS)               585                                 466 (ESMS)               586                                 479 (FAB)               587                                 505 (ESMS)               588                                 480 (ESMS)               589                                 535 (ESMS)               590                                 536 (ESMS)               591                                 498 (ESMS)               592                                 483 (ESMS)               593                                 575 (ESMS)               594                                 550 (ESMS)               595                                 529 (ESMS)               596                                 517 (ESMS)               597                                 533 (ESMS)               598                                 466 (ESMS)               599                                 438 (ESMS)               600                                 421 (ESMS)               601                                 423 (ESMS)               602                                 406 (ESMS)               603                                 456 (ESMS)               604                                 441 (ESMS)               605                                 439 (ESMS)               606                                 516 (ESMS)               607                                 498 (ESMS)               608                                 525 (ESMS)               609                                 516 (ESMS)               610                                 501 (ESMS)               611                                 547 (ESMS)               612                                 531 (ESMS)               613                                 543 (ESMS)               614                                 558 (ESMS)               615                                 544 (ESMS)               616                                 452 (FAB)               617                                 424 (ESMS)               618                                 480 (ESMS)               619                                 465 (ESMS)               620                                 560 (ESMS)               621                                 511 (ESMS)               622                                 496 (ESMS)               623                                 510 (ESMS)               624                                 503 (ESMS)               625                                 518 (ESMS)               626                                 505 (ESMS)               627                                 498 (ESMS)               628                                 485 (ESMS)               629                                 481 (ESMS)               630                                 499 (ESMS)               631                                 499 (ESMS)               632                                 514 (ESMS)               633                                 517 (ESMS)               634                                 532 (ESMS)               635                                 488 (ESMS)               636                                 518 (ESMS)               637                                 451 (ESMS)               638                                 537 (MH+)               639                                 472 (MH+)               640                                 519 (MH+)               641                                 487 (MH+)               642                                 516 (MH+)               643                                 503 (MH+)               644                                 484 (ESMS)               645                                 503 (ESMS)               646                                 498 (ESMS)               647                                 516 (ESMS)               648                                 468 (ESMS)               649                                 486 (ESMS)               650                                 469 (ESMS)               651                                 487 (ESMS)               652                                 483 (ESMS)               653                                 501 (ESMS)               654                                 453 (ESMS)               655                                 471 (ESMS)               656                                 468 (ESMS)               657                                 450 (ESMS)               658                                 530 (ESMS)               659                                             660                                 453 (FAB)               661                                 470 (FAB)               662                                 455 (FAB)               663                                 497 (ESMS)               664                                 481 (FAB)                    664A                                 499 (FAB)                  
 
       EXAMPLE 665 
       [0331]    [0331]                           
         [0332]    4-[[4-[2-(5-methyl-3-isoxazolyl)-3H-imidazo[4,5-b]pyridine-3-yl]-1-(4-piperidinylcarbonyl)piperidine (0.99 g, 2.51 mmoles) and pyridazine 4-carboxaldehyde (0.35 g, 3.26 mmoles) were stirred at RT in dry CH 2 Cl 2  (25 ml) containing activated 3 Å molecular sieves (6.5 g). After 5 h, triacetoxy borohydride (3.2 g, 15 mmoles) was added and the mixture was stirred for 70 h. The mixture was diluted with CH 2 Cl 2  and the solid filtered through a pad of Celite. The filtrate was stirred for 20 min. with saturated aqueous NaHCO 3 , then separated, washed with brine, and dried over anahydrous Na 2 SO 4 . The reaction mixture was purified by preparative TLC. The plates were eluted with EtOAc:Hexanes:CH 3 OH(NH 3 ) (75:20:5). Extraction of the bands with 13% CH 3 OH(NH 3 )/EtOAc gave a mixture of Example 665 and Example 496. Example 658: MS (M+H): 423.  
         [0333]    In a similar manner, using 4-[[4-[2-(methylthio)-3H-imidazo[4,5-b]pyridine-3-yl]-1-(4-piperidinylcarbonyl)piperidine (0.88 gr.;2.44 mmoles), pyridazine 4-carboxaldehyde (0.34 g, 3.18 mmoles), and triacetoxy borohydride, a mixture of Example 666 and Example 495 was prepared:  
                         
 
       EXAMPLE 666  
     MS (M+H): 388  
       [0334]    General Procedure for H 13 Receptor Binding Assay  
         [0335]    The source of the H 3  receptors in this experiment was guinea pig brain. The animals weighed 400-600 g. The brain tissue was homogenized with a solution of 50 mM Tris, pH 7.5. The final concentration of tissue in the homogenization buffer was 10% w/v. The homogenates were centrifuged at 1,000×g for 10 min. in order to remove clumps of tissue and debris. The resulting supernatants were then centrifuged at 50,000×g for 20 min. in order to sediment the membranes, which were next washed three times in homogenization buffer (50,000×g for 20 min. each). The membranes were frozen and stored at −70° C. until needed.  
         [0336]    All compounds to be tested were dissolved in DMSO and then diluted into the binding buffer (50 mM Tris, pH 7.5) such that the final concentration was 2 μg/ml with 0.1% DMSO. Membranes were then added (400 μg of protein) to the reaction tubes. The reaction was started by the addition of 3 nM [ 3 H]R-α-methyl histamine (8.8 Ci/mmol) or 3 nM [ 3 H]N α -methyl histamine (80 Ci/mmol) and continued under incubation at 30° C. for 30 min. Bound ligand was separated from unbound ligand by filtration, and the amount of radioactive ligand bound to the membranes was quantitated by liquid scintillation spectrometry. All incubations were performed in duplicate and the standard error was always less than 10%. Compounds that inhibited more than 70% of the specific binding of radioactive ligand to the receptor were serially diluted to determine a K i  (nM).  
         [0337]    General Procedure for rHu H 3 Binding Assay  
         [0338]    [ 3 H]N ∝ -methylhistamine (82 Ci/mmole) was obtained from Dupont NEN. Thioperamide was obtained from the Chemical Research Department, Schering-Plough Research Institute.  
         [0339]    HEK-293 human embryonic kidney cells stably expressing the human histamine H 3  receptor were cultured in Dulbecco&#39;s modified Eagle&#39;s medium/10% fetal calf serum/penicillin (100 U/ml)/streptomycin (100 μg/ml)/Geneticin (0.5 mg/ml) at 37° C. in a humidified 5% CO 2  atmosphere. Cells were harvested between passages five and twenty at 37° C. in 5 mM EDTA/Hank&#39;s balanced salt solution and processed for membrane preparation. After low-speed centrifugation, ten min at 1000×g, they were put into ten volumes of ice-cold buffer and disrupted with a Polytron (PTA 35/2 tip, 30 sec at setting 6). After subsequent low-speed centrifugation, supernatant was centrifuged ten min at 50,000×g. The high-speed pellet was resuspended in the original volume of buffer, a sample was taken for protein assay (bicinchoninic acid, Pierce) and the suspension was centrifuged again at 50,000×g. Membranes were resuspended at 1 mg of protein/ml of buffer and frozen at −80° C. until use.  
         [0340]    Membrane (15 μg of protein) was incubated with 1.2 nM [ 3 H]N ∝ -methyl-histamine, without or with inhibitor compounds, in a total volume of 200 μl of buffer. Nonspecific binding was determined in the presence of 10 −5  M thioperamide. Assay mixtures were incubated for 30 min at 30° C. in polypropylene, 96-well, deep-well plates, then filtered through 0.3% polyethylenimine-soaked GF/B filters. These were washed three times with 1.2 ml of 4° C. buffer, dried in a microwave oven, impregnated with Meltilex wax scintillant and counted at 40% efficiency in a Betaplate scintillation counter (Wallac).  
         [0341]    IC 50  values were interpolated from the data or were determined from curves fit to the data with Prism nonlinear least squares curve-fitting program (GraphPad Software, San Diego, Calif.). K i  values were determined from IC 50  values according to the Cheng and Prusoff equation.  
         [0342]    In these assays, compounds of formula I have a K i  within the range of about 0.1 to about 600 nM. Preferred compounds of formula I have a K i  within the range of about 0.1 to about 100 nM. More preferred compounds of formula I have a K i  within the range of about 0.1 to about 20 nM.  
         [0343]    Representative compounds of the present invention tested according to the above procedures have the following Ki values:  
                                                         Receptor           Ex.   Source   K 1                                  1   rHu   1       3   Guinea pig   13       5   rHu   9       13   Guinea Pig   27       54   Guinea Pig   30       71   Guinea Pig   1       94   Guinea Pig   1       109   rHu   1       120   Guinea Pig   0.3       165   rHu   2       170   Guinea Pig   0.5       173   Guinea Pig   0.4       195   Guinea Pig   10       211   Guinea Pig   7       254   Guinea Pig   13       269   rHu   4       270   rHu   4       281   rHu   4       290   rHu   3       290   rHu   3       297   rHu   4       297   rHu   4       315   rHu   5       316   rHu   5       316   rHu   5       326   rHu   2       335   rHu   12       388   rHu   30       423   rHu   5       442   rHu   1       449   rHu   1       459   rHu   4       460   rHu   4       468   rHu   10       493   rHu   1       502   rHu   7       512   rHu   2       547   rHu   14       552   rHu   4       557   rHu   19       571   rHu   2       574   rHu   2       577   rHu   44       588   rHu   6       592   rHu   9       595   rHu   41       598   rHu   17       608   rHu   1       618   rHu   9       619   rHu   2       625   rHu   10       628   rHu   4                  
 
         [0344]    In this specification, the term “at least one compound of formula I” means that one to three different compounds of formula I may be used in a pharmaceutical composition or method of treatment. Preferably one compound of formula I is used. Similarly, “at least one H 1  receptor antagonist” means that one to three different H 1  antagonists may be used in a pharmaceutical composition or method of treatment. Preferably, one H 1  antagonist is used.  
         [0345]    For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.),  The Science and Practice of Pharmacy,  20 th  Edition, (2000), Lippincott Williams &amp; Wilkins, Baltimore, Md.  
         [0346]    Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.  
         [0347]    Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.  
         [0348]    Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.  
         [0349]    The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.  
         [0350]    Preferably the compound is administered orally.  
         [0351]    Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.  
         [0352]    The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 350 mg, preferably from about 1 mg to about 150 mg, more preferably from about 1 mg to about 50 mg, according to the particular application.  
         [0353]    The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.  
         [0354]    The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 300 mg/day, preferably 1 mg/day to 75 mg/day, in two to four divided doses.  
         [0355]    When the invention comprises a combination of H 3  antagonist and H, antagonist compounds, the two active components may be co-administered simultaneously or sequentially, or a single pharmaceutical composition comprising a H 3  antagonist and an H 1  antagonist in a pharmaceutically acceptable carrier can be administered. The components of the combination can be administered individually or together in any conventional dosage form such as capsule, tablet, powder, cachet, suspension, solution, suppository, nasal spray, etc. The dosage of the H 1  antagonist can be determined from published material, and may range from 1 to 1000 mg per dose.  
         [0356]    When separate H 3  and H 1  antagonist pharmaceutical compositions are to be administered, they can be provided in a kit comprising in a single package, one container comprising an H 3  antagonist in a pharmaceutically acceptable carrier, and a separate container comprising an H 1  antagonist in a pharmaceutically acceptable carrier, with the H 3  and H 1  antagonists being present in amounts such that the combination is therapeutically effective. A kit is advantageous for administering a combination when, for example, the components must be administered at different time intervals or when they are in different dosage forms.  
         [0357]    While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.