(1-4-PIPERIDINYL) BENZIMIDAZOLE DERIVATIVES USEFUL AS HISTAMINE H3 ANTAGONISTS FIELD OF THE INVENTION The present invention relates to novel substituted benzimidazoles and aza-and diaza-derivatives thereof useful as histamine H3 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 H3 antagonists of this invention with histamine Hn compounds for the treatment of inflammatory diseases and allergic conditions, as well as pharmaceutical compositions comprising a combination of one or more novel histamine H3 antagonist compounds of the invention with one or more histamine H compounds.

BACKGROUND OF THE INVENTION The histamine receptors, H,, H2 and H3 are well-identified forms. The H receptors are those that mediate the response antagonized by conventional antihistamines. Ha receptors are present, for example, in the ileum, the skin, and the bronchial smooth muscle of humans and other mammals. Through H2 receptor- mediated responses, histamine stimulates gastric acid secretion in mammals and the chronotropic effect in isolated mammalian atria.

H3 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, H3 receptor activation by histamine attenuates norepinephrine outflow to resistance and capacitance vessels, causing vasodilation.

Imidazole H3 receptor antagonists are well known in the art. More recently, non-imidazole H3 receptor antagonists have been disclosed in PCT US01/32151, filed October 15,2001, and US Provisional Application 60/275,417, filed March 13,2001.

US 5,869, 479 discloses compositions for the treatment of the symptoms of allergic rhinitis using a combination of at least one histamine H1 receptor antagonist and at least one histamine H3 receptor antagonist.

SUMMARY OF THE INVENTION The present invention provides novel compounds of formula I : or a pharmaceutical acceptable salt or solvate thereof, wherein: the dotted line represents an optional double bond; a isOto2 ; b is 0 to 2 ; n is 1, 2 or 3 ; p is 1, 2 or 3 ; r is 0, 1,2, or 3 ; with the provisos that when M2 is N, p is not 1; and that when r is 0, M2 is C (R3) ; and that the sum of p and r is 1 to 4; M'is C (R3) or N; M2 is C (R3) or N; X is a bond or C,-C6 alkylen ; Y is-C (O)-,-C (S)-,- (CH2) q-,-NR4C (O)-,-C (O) NR4-,-C (O) CH2-,-S02-, -N(R4)-, -NH-C(=N-CN)- or -C(=N-CN)-NH-; with the provisos that when M1 is N, Y is not -NR4C(O)- or -NH-C(=N-CN)-; when M2 is N, Y is not-C (O) NR4 - or -C(=N-CN)-NH-; and when Y is-N (R4)-, M1 is CH and M2 is C (R3) ; q is 1 to 5, provided that when both M'and M2 are N, q is 2 to 5; Z is a bond, Ci-Ce alkylene, C,-C6 alkenylene,-C (O)-,-CH (CN)-,-SO2-or - CH2C (O) NR4- ; Q is-N (R 8) _,-S-or-0- ; k is 0, 1,2, 3 or 4 ; k1 is 0, 1,2 or 3 ; k2 is 0, 1 or 2 ; R is H, Ci-Ce alkyl, halo (Cl-C6) alkyl-, Cl-C6 alkoxy, (CI-C6) alkoxy- (Ci-C6) alkyl-, (C1-C6)-alkoxy-(C1-C6)alkoxy, (C1-C6)alkoxy-(C1-C6)alkyl-SO0-2, R32-aryl(C1-C6)alkoxy-, R32-aryl(C1-C6)alkyl-, R32-aryl, R32-aryloxy, R32-heteroaryl, (C3-C6) cycloalkyl, (C3-C6) cycloalkyl-(C1-C6)alyl, (C3-C6) cycloalkyl-(C1-C6)alkoxy, (C3-C6) cycloalkyl-oxy-, R37-heterocycloalkyl, R37-heterocycloalkyl-oxy-, R37-heterocycloalkyl-(C,-C6) alkoxy, N (R30) (R31)-(C1-C6)alkyl-, -N(R30)(R31) -NH-(C1-C6)alkyl-O-(C1-C6)alkyl, -NHC(O)NH(R29) ; R29-S (O) o-2-, halo (C1-C6) alkyl-S(O)0-2-, N (R3°) (R3)-(C-C6) alkyl-S (O) 02-or benzoyl ; R8 is H, Ci-Ce alkyl, halo(C1-C6)alkyl-, (C1-C6)alkoxy-(C1-C6)alkyl-, r32-aryl(C1- C6) alkyl-, R32-aryl, R32-heteroaryl, (C3-C6) cycloalkyl, (C3-C6) cycloalkyl-(C1-C6)alkyl, R37-heterocycloalkyl, N (R30)(R31)-(C1-C6)alkyl-, R29-S(O)2-, halo(C1-C6)alkyl-S(O)2-, R29-S(O)0-1-(C2-C6)alkyl-, halo(C1-C6)alkyl-S(O)0-1-(C2-C6)alkyl-; R2 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; R32-quinolyl ; R32-aryl ; heterocycloalkyl ; (C3-C6) cycloalkyl ; C,-C6 alkyl ; hydrogen ; thianaphthenyl ; wherein said six-membered heteroaryl ring or said five-membered heteroaryl ring is optionally substituted by R6 ; R3 is H, halogen, Ci-Ce alkyl,-OH, (Ci-C6) alkoxy or -NHSO2-(C1-C6)alkyl ; R4 is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, C3-C6 cycloalkyl, (C3-C6) cycloalkyl(C1-C6)alkyl, R33-aryl, R33-aryl(C1-C6)alkyl, and R32-heteroaryl ; R5 is hydrogen, Ci-Ce alkyl,-C (O) R20,-C (O) 2R2°,-C (O) N (R20) 2, (Ci-C6) alkyl- SO2-, or (Ci-C6) alkyl-SO2-NH-; or R4 and R5, together with the nitrogen to which they are attached, form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring; R6 is 1 to 3 substituents independently selected from the group consisting of -OH, halogen, C1-C6 alkyl-, C1-C6 alkoxy, C1-C6 alkylthio, -CF3, -Nr4R5, -CH2-NR4R5, -NHSO2R22, -N(SO2R22) 2, phenyl, R33-phenyl, NO2, -CO2R4, -CON(R4) 2, R12 is independently selected from the group consisting of Cr-C6 alkyl, hydroxyl, Ci-Ce alkoxy, or fluoro, provided that when R12 is hydroxy or fluoro, then R12 is not bound to a carbon adjacent to a nitrogen; or two R12 substituents form a C1 to C2 alkyl bridge from one ring carbon to another non-adjacent ring carbon; or R12 is =O ; R'3 is independently selected from the group consisting of Ci-Ce alkyl, hydroxyl, C,-C6 alkoxy, or fluoro, provided that when R'3 is hydroxy or fluoro then R'3 is not bound to a carbon adjacent to a nitrogen; or two R'3 substituents form a C1 to C2 alkyl bridge from one ring carbon to another non-adjacent ring carbon; or R'3 is =O ; R20 is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, or aryl, wherein said aryl group is optionally substituted with from 1 to 3 groups independently selected from halogen,-CF3,-OCF3, hydroxyl, or methoxy; or when two

R20 groups are present, said two R20 groups taken together with the nitrogen to which they are bound can form a five or six membered heterocyclic ring; R22 is Ci-Ce alkyl, R34-aryl or heterocycloalkyl ; R24 is H, C-C6 alkyl, -SO2R22 or R34-aryl ; R25 is independently selected from the group consisting of Ci-Ce alkyl, halogen, -CN, -NO2, -CF3, -OH, C1-C6 alkoxy, (C1-C6)alkyl-C(O)-, aryl-C (O) -,-C (O) OR29, -N(R4)(R5), N (R4) (R5)-C (O)-, N (R4) (R5)-S(O)1-2-, R22-S(O)0-2-, halo-(C1-C6)alkyl- or halo-(C1-C6)alkoxy-(C1-C6)alkyl-; R29 is H, Ci-Ce alkyl, C3-C6 cycloalkyl, R35-aryl or R35-aryl(C1-C6)alkyl-; R30 is H, Ci-Ce alkyl-, R35-aryl or R35-aryl(C1-C6)alkyl-; R31 is H, Ci-Ce alkyl-, R35-aryl, R35-aryl(C1-C6)alkyl-, R35-heteroaryl, (C1- C6) alkyl-C (O)-, R35-aryl-C (O) -, N (R4) (R5)-C(O)-, (C1-C6)alkyl-S(O)2- or R35-aryl-S(O)2-; or R30 and R together are- (CH2) 4-5-,- (CH2) 2-0- (CH2) 2- or - (CH2) 2-N (R38)-(CH2)2- and form a ring with the nitrogen to which they are attached; R32 is 1 to 3 substituents independently selected from the group consisting of H, -OH, halogen, Ci-Ce alkyl, C1-C6 alkoxy, R35-aryl-O-, -SR22, -CF3, -OCF3, -OCHF2, -NR39R40, phenyl, R33-phenyl, NO2, -CO2R39, - CON(R39)2, -S(O)2R22, -S(O)2N(R20)2, -N(R24)S(O)2R22, -CN, hydroxy-(C1-C6)alkyl-, -OCH2CH2OR22, and R35-aryl(C1-C6)alkyl-O-, or two R32 groups on adjacent carbon atoms together form a -OCH2O- or -O (CH2) 20- group ; R33 is 1 to 3 substituents independently selected from the group consisting of Ci-Ce alkyl, halogen, -CN, -NO2, -CF3, -OCF3, -OCHF2 and -O-(C1-C6)alkyl ; R34 is 1 to 3 substituents independently selected from the group consisting of H, halogen,-CF3,-OCF3,-OH and-OCH3 ; R35 is 1 to 3 substituents independently selected from hydrogen, halo, Cl-C6 alkyl, hydroxy, Ci-Ce alkoy, phenoxy, -CF3, -N(R36)2, -COOR20 and -NO2 ; R36 is independently selected form the group consisting of H and Ci-Ce alkyl ; R37 is 1 to 3 substituents independently selected from hydrogen, halo, Cr-C6 alkyl, hydroxy, C1-C6 alkoxy, phenoxy,-CF3,-N (R36) 2,-COOR20,-C (O) N (R29) 2 and - N02, or R37 is one or two =0 groups; R38 is H, C1-C6 alkyl, R35-aryl, R35-aryl(C1-C6)alkyl-, (C1-C6)alkyl-SO2 or halo (Ci-C6) alkyl-SO2-;

R39 is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, C3-C6 cycloalkyl, (C3-C6) cycloalkyl (C,-C6) alkyl, R33-aryl, R33-aryl (Cr-C6) alkyl, and R32-heteroaryl ; and R40 is hydrogen, Ci-Ce alkyl,-C (O) R20,-C (O) 2R2°,-C (O) N (R2°) 2, (Ci-Ce) alkyl- S02-, or (Ci-C6) alkyl-SO2-NH-; or R39 and R, together with the nitrogen to which they are attached, form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring; 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.

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'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 1.

Compounds of this invention are particularly useful for treating allergy, allergy- induced airway responses and/or congestion.

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, receptor antagonist in combination with a pharmaceutically acceptable carrier.

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 H receptor antagonist.

Kits comprising a compound of formula I in a pharmaceutical composition, and a separate H, receptor antagonist in a pharmaceutical compositions in a single package are also contemplated.

DETAILED DESCRIPTION OF THE INVENTION Preferred definitions of the variables in the structure of formula I are as follows : R'is preferably optionally substituted benzimidazolyl or 7-azabenzimidazolyl, wherein R is preferably alkyl, alkoxy, alkoxyalkoxy, alkylthio, heteroaryl or R32-aryl.

More preferably, R is-CH3,-CH2CH3,-OCH3,-OCH2CH3,-OCH2CH2CH3, -OCH ((CH3) 2,-SCH3,-SCH2CH3, pyridyl (especially 2-pyridyl), pyrimidyl, pyrazinyl, furanyl, oxazolyl or R32-phenyl.

R25 is preferably halogen or-CF3 and k is 0 or 1.

R2 is preferably a six-membered heteroaryl ring, optionally substituted with one substituent. More preferably, R2 is pyrimidyl, R6-pyrimidyl, pyridyl, R6-pyridyl or pyridazinyl, wherein R6 is-NR4R5, wherein R4and R5 are independently selected from the group consisting of H and (Ci-C6) alkyl, or R4and R5 together with the nitrogen to which they are attached form a pyrrolidinyl, piperidinyl or morpholinyl ring. More preferably, R6 is-NH2.

X is preferably a bond.

Y is preferably-C (O)-.

Z is preferably straight or branched Ci-C3 alkyl.

M1 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).

M2 is preferably C (R3) wherein R3 is hydrogen or fluorine ; b is preferably 0; r is preferably 1; and p is preferably 2.

As used herein, the following terms have the following meanings, unless indicated otherwise: 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; alkylen represents a divalent straight or branched alkyl chain, e. g., ethylene (-CH2CH2-) or propylene (-CH2CH2CH2-); Haloalkyl and haloalkoxy represent alkyl or alkoxy chains wherein one or more hydrogen atoms are replaced by halogen atoms, e. g.,-CF3, CF3CH2CH2-, CF3CF2-or CF3S ; 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; 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; cycloalkyl represents saturated carbocyclic rings of from 3 to 6 carbon atoms; halogen (halo) represents fluoro, chloro, bromo and iodo; 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 R2 are exemplified by the heteroaryl groups listed above; all available substitutable carbon and nitrogen atoms can be substituted as defined; 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.

In the definition of R32, when two R32 groups on adjacent carbon atoms of an aryl or heteroaryl ring are said to be taken together form a-OCH20-or-O (CH2) 20- group, this means that the two R32 groups form a methylenedioxy or ethylenedioxy ring fused to the aryl or heteroaryl ring. When R'2, R13 or R37 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.

(i), for example in the structure 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 : Similarly, 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.

Also, as used herein,"upper airway"usually means the upper respiratory system--i. e. , the nose, throat, and associated structures.

Also, as used herein,"effective amount"generally means a therapeutically effective amount.

"Patient"means a mammal, typically a human, although veterinary use is also contemplated.

Lines drawn into the rings indicate that the indicated bond may be attached to any of the substitutable ring carbon atoms.

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.

The compounds of this invention are ligands for the histamine H3 receptor. The compounds of this invention can also be described as antagonists of the H3 receptor, or as H3 antagonists.

The compounds of the invention are basic and form pharmaceutical 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.

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, NH40H, tetraalkylammonium hydroxide, and the like.

The compounds of formula I can exist in unsolvated as well as solvate forms, including hydrated forms, e. g. , hemi-hydrate. In general, the solvate forms, with pharmaceutical acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated forms for purposes of the invention.

The compounds of this invention can be combined with an H, receptor antagonist (i. e. , the compounds of this invention can be combined with an H, receptor antagonist in a pharmaceutical composition, or the compounds of this invention can be administered with Hn receptor antagonist).

Numerous chemical substances are known to have histamine H1 receptor antagonist activity and can therefore be used in the methods of this invention. Many H, receptor antagonists useful in the methods of this invention can be classified as ethanolamines, ethylenediamines, alkylamines, phenothiazines or piperidines.

Representative H, 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, receptors by known methods, including specific blockade of the contractile response

to histamine of isolated guinea pig ileum. See for example, W098/06394 published February 19,1998.

Those skilled in the art will appreciate that the H, receptor antagonist is used at its known therapeutical effective dose, or the H, receptor antagonist is used at its normally prescribed dosage.

Preferably, said H 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.

More preferably, said H, receptor antagonist is selected from: astemizole, azatadine, azelastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, carebastine, descarboethoxyloratadine, diphenhydramine, doxylamine, ebastine, fexofenadine, loratadine, levocabastine, mizolastine, norastemizole, or terfenadine.

Most preferably, said H, receptor antagonist is selected from: azatadine, brompheniramine, cetirizine, chlorpheniramine, carebastine, descarboethoxy- loratadine, diphenhydramine, ebastine, fexofenadine, loratadine, or norastemizole.

Even more preferably, said H, antagonist is selected from loratadine, descarboethoxyloratadine, fexofenadine or cetirizine. Still even more preferably, said Hr antagonist is loratadine or descarboethoxyloratadine.

In one preferred embodiment, said H, receptor antagonist is loratadine.

In another preferred embodiment, said H receptor antagonist is descarboethoxyloratadine.

In still another preferred embodiment, said H, receptor antagonist is fexofenadine.

In yet another preferred embodiment, said H, receptor antagonist is cetirizine.

Preferably, in the above methods, allergy-induced airway responses are treated.

Also, preferably, in the above methods, allergy is treated.

Also, preferably, in the above methods, nasal congestion is treated.

In the methods of this invention wherein a combination of an H3 antagonist of this invention (compound of formula 1) is administered with a H, 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 H3 antagonist of this invention (compound of formula 1) is administered first.

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.

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.

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.

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.

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.

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.

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 NaBH4, 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.

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.

One method shown in Scheme 1, below, is for the preparation of compounds of formula IA wherein R'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'is other than benzimidazolyl as defined above) and the benzoxazolyl and benzothiazolyl derivatives.

SCHEME 1. 12 (R 12) a (R 12) a H-x-NL -N. Pr. NNH 2 n J\i Q R3 b R 3 ) a ) b x I -2 2 2_ Step c N-N' Xu + Activation-Y--M. Z-NZ, R2-Prot-'n p xiii p 0 IA 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.

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.

Step c : An amine of formula XII is reacted with an activated functional group Y of formula Xlil to form the bond between the nitrogen and functional group Y in formula IA. When Y is a carbonyl group and M2 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.

Another method for the preparation of compounds of formula IA wherein R'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 R1 is other than benzimidazolyl as defined above).

Scheme 2. ) f X O N HN H2N XNProt Step d 2 HN N-Prot Step e (1) H2NI-X,--IQN-Prot n n X (R12) a (t) b (1 2 Step f IA XIVa + XIII Step e (2) 2N HN , N, Y, M . NZ, R XV xi 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 hetero- aromatic compound as described by Henning et al.

Step e : (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.

(2) The resulting amine from Step e (1) is reacted with an activated functional group Y of formula Xlil 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 M2 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.

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.

More detailed methods for synthesis of compounds are shown in Scheme 3 below. The preparation of compounds of formula IB wherein R'is 1-benzimidazolyl (Methods A, B, C and F), Y is-C (O)- and R 2is substituted pyridyl, and compounds of formulas IC and IC'wherein R'is 2-benzimidazolyl (Methods D and E), Y is-C (O)- and R2 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, R2 is other than pyridyl, and aza- benzimidazoles compounds (i. e. , compounds wherein R'is other than benzimidazolyl as defined above).

Scheme 3.

Method A: 0 0 N02 Step 1_ NH2 R H H 2 R R R ouzo 0 0 -'O \/3 \ \/4 5 Step NN-NH O O LiO) m2 N 6 m N R 4 Step 4o NlN {3NH Step 5 7 Step 5 5 tz2R (Prot) N> Z 0 R m 2 7 Step 6 SN VG tN-Z J2R6 nu in zu Method B : o 2 NH 6 NM2 N tH HN'v N-''R6 Prot 0' 0 9 o 9 StepNM2 'N s HN'v N-Z'R Prot H2N razz \ I O R N'M2 I i N Step 4 HN' N- R6 (Prot Step 6 HN i

Method C: 0 Step 1 2 Stee Cl ou 12 ce 12 Step 3 Ste b 13 \/13 Step 6 Step 6 Method D: NH2 N NHR H02C, . J : D"C + X 16 14 15 R 16 o 6-it, 2 St2p 3 Step 2 X N s Step Z R (Prot) R 17 Method E: /N N.-Prot N/N-Prot Step 1 % H N /'N N 18 19 R H 20 NH 20 Step 2 N"CH 21 aN N R H o 21 6 ON"Ulm 2 Step ic Step 3 LJLN-'6 (p N R H 22 Method F: 0 0 0 CIM2 I 5 Step 1 23 24 <, NfO< NgNtJ 4zNO< steP 2 NX tN N N N'u Step 2 ci N R ON, 24 Step 3 N6 1 B O /NYNH2 Step3 ==\ 1B 24 Step 3

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.

Unless otherwise stated, the following abbreviations have the stated meanings in the Examples below : Me=methyl ; Et=ethyl ; Bu=butyl ; Pr=propyl ; Ph=phenyl ; t-BOC=tert-butyloxycarbonyl ; CBZ=carbobenzyloxy ; and Ac=acetyl DCC= dicyclohexylcarbodiimide DMAP=4-dimethylaminopyridine <BR> <BR> <BR> <BR> DMF=dimethylformamide<BR> <BR> <BR> <BR> <BR> <BR> EDCI= 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide ESMS=Electron spray mass spectroscopy FAB=Fast atom bombardment mass spectroscopy HATU=0-(7-Azabenzotriazol-1-yl)-N, N, N', N'-tetramethyl uronium hexafluorophosphate HOBT= 1-hydroxybenzotriazole LAH= lithium aluminum hydride LDA= lithium diisopropylamide NaBH (OAc) 3= sodium triacetoxyborohyd ride NBS=N-bromosuccinimide PPA= polyphosphoric acid RT=room temperature TBAF=tetrabutylammonium fluoride TBDMS=t-butyidimethylsilyl TMEDA=N, N, N', N'-tetramethylethylenediamine TEMPO=2,2, 6, 6-tetramethyl-1-piperidinyloxy, free radical TLC=thin layer chromatography HRMS= High Resolution Mass Spectrometry LRMS= Low Resolution Mass Spectrometry nM= nanomolar Ki= Dissociation Constant for substrate/receptor complex pA2=-logEC50, as defined by J. Hey, Eur. J. Pharmacol., (1995), Vol. 294,329-335.

Ci/mmol= Curie/mmol (a measure of specific activity)

Preparation 1 Step 1 : 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- CH2CI2 to 0-2% acetone-CH2CI2) to produce 15.25 g (73.32 mmol ; 73%) of the desired product as a white solid.

Step 2: To a solution of the product of Step 1 (35.96 g, 173 mmol) in THF (1. 4 I) 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 (CH3) 2S (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/CH2CI2) provided 20.15 g (90 mmol ; 52%) of the alcohol as a pale yellow solid.

Step 3: To a solution of the product of Step 2 (19.15 g, 85.5 mmol) in CH2CI2 (640 mi) was added a saturated aqueous solution of NaHC03 (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 NaOCI) was added portionwise over 40 min.

After an additional 20 min at 0 °C, the reaction mixture was quenched with saturated aqueous Na2S203 and allowed to warm to 23 °C. Dilution with water and extraction with CH2CI2, followed by concentration and flash chromatography (eluant : 30% hexanes-CH2CI2 to 0-2% acetone-CH2CI2) afforded 15.97 g (71.9 mmol ; 84% yield) of the aldehyde as an off-white solid.

Step 4: To a solution of the product of Step 3 (11.87 g, 53.5 mmol) in CH2CI2 (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) 3H (22.68 g, 107 mmol) was added. The reaction mixture was stirred overnight at 23 °C, neutralized with saturated aqueous NaHC03, diluted with water and extracted with CH2CI2. Concentration of the organic extracts, followed by silica gel flash chromatography (eluant : 0-4% sat. NH3 in CH30H-CH2CI2) provided 19.09 g (52.6 mmol ; 98%) of the ester as an off-white solid.

Step 5: To a solution of the product of Step 4 (1.57 g, 4.33 mmol) in THF-water- CH30H (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

Step 1: A solution of diamine 1B (see Method A, Step 1) (20g, 71. 1mmol) and Et3N (30 ml, 213 mmol) in CH2CI2 (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 MgS04 and concentrated under vacuum. Hot EtOAc (200 mi) 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. 5g) ; and silica gel flash chromatography [CH2CI2/CH30H (2N NH3) = 40: 1] of the filtrate provided additional product as a white solid (2.7 g) [combined yield : 88%]. FABMS: 308 (MH+ ; 100%).

Step 2: POCI3 (100 ml) was added to P2-1 (17.2 g ; 56 mmol) in a round-bottomed flask flushed with dry N2. The mixture was placed in an oil bath heated to 108 °C and was maintained at reflux for 6 h. POC13 was then removed in vacuo. The residue was adjusted to pH-9-10 with 7N methanolic ammonia and was concentrated to dryness under vacuum. CH2CI2 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%).

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 CH2CI2 solution at 0 °C with one equivalent each of EtOH and NaH, followed by workup with ice-water and CH2CI2. Low temperature is maintained in order to minimize reaction at the 2- position of the benzimidazole nucleus.

Step 3: Sodium thiomethoxide (1.05 g ; 15.0 mmol) was added to DMF (15 ml) in a round-bottomed flask flushed with N2. 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 MgS04 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%).

Step 4: 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 CH2CI2 (2 x 40 ml), then EtOAc (30 ml). Combined extracts were dried over anhydrous MgS04. Drying agent was removed by filtration, and the filtrate was concentrated under vacuum. The residue was purified by silica gel flash chromatography (CH2CI2/2N methanolic ammonia = 12: 1) to obtain Preparation 2 as an off-white solid (2.85 g, 70%). ES-MS: 266 (MH+ ; 100%).

Preparation 3 Step 1 :

NaH (60 mg of a 60% dispersion; 1.48 mmol) was added to CH30H (4 ml) in a flask charged with N2. 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. CH30H was removed in vacuo, and to the residue were added CH2CI2 (30 ml) and water (10 ml).

The organic layer was dried over anhydrous MgS04, 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 (0.232g ; 59%). ES-MS: 322.1 (MH+ ; 100%).

Step 2: 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 CH2CI2 (15 ml) were added to the residue, and the organic layer was separated and dried over anhydrous MgS04.

Drying agent was filtered, and the filtrate was concentrated in vacuo to obtain Preparation 3 as a colorless glass (160mg ; 95%). FABMS: 250.2 (MH+ ; 100%).

Preparation 4 Step 1: P2-2 (300 mg; 0.923 mmol) and morpholine (3 ml) were mixed in a round- bottomed flask under N2, and the resultant mixture was heated to 80 °C for 16 h.

Morpholine was removed under vacuum, and the residue was dissolved in CH2CI2 (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 CH2CI2/2N methanolic ammonia (45: 1), to obtain P4-1 as a colorless glass (0.325g ; 94%). ES- MS: 377.1 (MH+ ; 100%).

Step 2: Trimethylsilyl iodide (240 microliters ; 1. 64mmol) was added to a solution of P4-1 (316 mg; 0.843 mmol) in CHCI3 (2 ml) under N2, 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 NH40H and water to pH-10 and extracted with CH2CI2 (2 x 5 ml). The combined extracts were dried over anhydrous MgS04. Drying agent was filtered, and the filtrate was concentrated under vacuum. The residue was purified via flash chromatography on silica gel, eluting with CH2CI2-2N methanolic ammonia (13: 1), to obtain compound Preparation 4 as a colorless glass. (181 mg; 70%). ES- MS: 305.1 (MH+ ; 100%).

Preparation 5 Step 1 : A solution of P5-1 (3.5 g, 21 mmol) and P5-2 (6.5 g, 38 mmol) in CH2CI2 (3 ml) was heated to 110° C for 24 h and RT for 24 h. The reaction was diluted with CH2CI2, washed with water and brine, and dried (Na2SO4). Purification on a flash column (Si02, 40% to 60% EtOAc in hexanes) gave P5-3 (1.3 g, 21% ; M+H = 295).

Step 2: To a solution of P5-3 (1.3 g, 4.4 mmol) in CH30H (30 ml) was added Ra-Ni (0.5 g) and the mixture was hydrogenated under a H2 atmosphere (50 psi) for 18 h.

Filtration through a pad of celite gave P5-4 as a grey solid that was used without further purification (1.05 g, 90% ; M+H = 265).

Step 3: A solution of P5-4 (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 CH2CI2 (10 ml) were stirred for 18 h at RT. The crude reaction mixture was diluted with additional CH2CI2 and washed with 5% aqueous NaOH and brine and dried (Na2S04). Purification using flash chromatography (SiO, 8% EtOAc in hexane to 10% CH30H in EtOAc) gave P5-6 (0.35 g, 24% ; M+H = 370).

Step 4: 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 CH2CI2. The combined organic layers were dried (Na2S04) and concentrated to give P5-7 (0.58 g, 87%; M+H = 352) which was used in the next step without further purification.

Step 5: A solution of P5-7 (0.58 g, 1.65 mmol) and NaOH (0.43 g, 13.2 mmol) in EtOH/H20 (9/1,10 mi) was heated to 100° C for 18 h. The reaction was cooled and concentrated and the residue purified on a flash column (Si02, 10% CH30H saturated with ammonia in CH2CI2) to give Preparation 5 (0.42 g, 91 % ; M+H = 280).

Preparation 6 Step 1: 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 CH2C12 (400 ml) was treated with 1 M sol. of Et30+BF4- (in CH2CI2, 55 ml, 55 mmol). The reaction mixture was stirred at RT for 2h, quenched with 1 N NaOH (100 ml), extracted with CH2CI2 (3x), dried with Na2SO4 and concentrated. Purification by silica gel chromatography (eluant : 5-10% acetone/CH2CI2) to give 6.37 g of P6-2 (20.0 mmol, 55%).

Step 2: In a manner similar to that described in Preparation 3, Step 2, P6-2 was converted to Preparation 6.

Preparation 7 Step 1: A mixture of P7-1 (40g, 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 N2 at 120 °C for 3 h. Excess orthoformate was removed under vacuum. The residue was partitioned between EtOAc (200 ml) and 1 N NaOH (100 ml). The organic layer was washed with brine (100 ml) and dried over anhydrous MgS04. Drying agent was removed by filtration, and the filtrate was concentrated

under vacuum. The residue was purified by silica gel flash chromatography (CH2CI2/CH30H (2N NH3) = 45: 1) to obtain P7-2 as a dark purple syrup (27.2 g, 66%), which solidified upon standing. ES-MS: 275 (MH+ ; 100%).

Step 2: NBS was added portionwise (exotherm) to a solution of P7-2 (27 g, 100 mmol) in CHCI3 (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 Na2S204 (250 ml). The organic layer was washed with brine (150 ml) and dried over anhydrous MgS04. Drying agent was removed by filtration, and the filtrate was concentrated under vacuum. The residue was purified by silica gel flash chromatography [CH2CI2/acetone = 45 : 1] to obtain P7-3 as a yellow solid (24.2 g, 69%). ES-MS: 353 (MH+ ; 100%).

Step 3: NaH (544 mg of a 60% dispersion, 13.6 mmol) was added to a solution of CH30H (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 MgS04. 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

Step 1 : 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 N2 for 16 h, during which time a precipitate formed. THF was removed under vacuum, and the residue was purified by silica gel flash chromatography (CH2CI2/acetone = 20: 1) to obtain P8-1 as a light yellow solid (16.7 g, >95%). ES-MS: 324 (MH+ ; 100%).

Step 2: To a stirred mixture of P8-1 (4.00 g, 12.5 mmol) and K2CO3 (2.05 g, 13.6 mmol) in DMF (40 ml) under a N2 atmosphere was added CH31 (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 MgS04.

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, >95%; contained a small amount of DMF), which was used without further purification. ES-MS: 338 (MH+ ; 100%).

Preparation 9 Step 1: (Modified published procedure: G. Heinisch, E. Luszczak, and M. Pailer : Monatshefte für Chemie, 1973 (104), 1372.

P9-1 (4.5 g, 47.8 mmoles), P9-2 (8.12g, 76.5 mmoles), and anhydrous Zinc12 were heated, under N2, 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.

Step 2: Os04 (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). Na104 (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 CH2CI2 (600 ml) and dried over anhydrous Na2SO4. After removal of the solvent, the mixture was purified by flash chromatography on silica gel using 5% CH30H/CH2CI2 as eluent to obtain Preparation 9. Yield : 2. 89 g (82%).

Preparation 10 Step 1 : A solution of P10-1 (2 g, 15 mmol) in CH2CI2 (50 ml) was treated with Et3N (3 g, 30 mmol) and triphenylmethyl chloride (TrCI, 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 (Si02, 20% EtOAc in hexane) to give P10-2 (5.2 g, 46%).

Step 2: A solution of P10-2 (5.2 g, 14.6 mmol) in CC14 (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 (SiO2, 20% to 30% EtOAc in hexane) to give Preparation 10 (2.8 g, 42%, M+H = 453,455)

Preparation 11 Step 1: 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 (CH2CI2/2N methanolic ammonia = 9: 1) to obtain P11-1 as a white solid (4.46 g, 70%). ES-MS: 252 (MH+ ; 100%).

Step 2: 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 (3ml ; 2.23g ; 17.2 mmol) and EDCI (4.50 g; 23.6 mmol) in DMF (30 ml) was stirred under N2 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 MgS04. Drying agent was removed by filtration, and the filtrate was concentrated under vacuum. The residue was purified by silica gel flash chromatography (CH2CI2/CH3OH (2N NH3) = 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%).

Step 3:

To a stirred mixture of P11-2 (460 mg; 1 mmol) and K2CO3 (165 mg; 1.20 mmol) in DMF (4 ml) under a N2 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 MgS04. 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%).

Step 4: To a solution of P11-3 (465 mg; 0.949 mmol) in CH2CI2 (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 CH2CI2 (20 ml) and 1: 1 (v/v) concentrated NH40H: water (5 ml). The aqueous phase was extracted successively with 95: 5 CH2CL2: EtOH (5 ml) and EtOAc (5 ml). The combined extracts were dried over anhydrous MgS04. 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 Method A Step 1 : A mixture of a (25 g, 0.16 mol), b (27 g, 0.16 mol), K2CO3 (26 g, 0.19 mol), and Nal (2.4g, 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 NaHC03, and extracted with EtOAc (4x). The combined organic layers were washed with water (2x) and brine, dried over Na2SO4, and concentrated.

Recrystallization with EtOH provided 1A (48 g, 98%).

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 H2 (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%).

Step 2: A solution of 1B (5.00 g, 17.77 mmol) and picolinoyl chloride hydrochloride (3.16g, 17.75 mmol) in CH2CI2 (400 mi) and Et3N (15 ml) was stirred at RT. After 15 h, the reaction was diluted with CH2CI2, washed with water, dried over Na2SO4, concentrated, and dried on vacuum to provide a brown foam (6. 47g, 94%).

Step 3: A solution of 1C (1.77g, 4.58 mmol) in ethanol (50 ml) and concentrated H2SO4 (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 CH2CI2. The combined organic solutions were dried over Na2SO4 and concentrated on reduced pressure. The residue was purified by flash chromatography (silica gel, 5% CH30H in CH2CI2 as eluent) to provide a tan foam (1.58g, 94%).

Step 4:

lodotrimethylsilane (6.30g, 31.48 mmol) was added to a solution of 1 D (3.88g, 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 CH2CI2. The combined extracts were washed with water, dried over Na2SO4, and the solvent evaporated. Purification of the residue by flash chromatography (silica gel, 10% CH30H in CH2CI2 as eluent) delivered an off- white foam (2. 10g, 67%).

Step 5: Amine 1 E (5.80g, 19.6 mmol) and Preparation 1 (5.32g, 23.4 mmol) were dissolved in DMF (60 ml) and CH2CI2 (60 ml). To the resulting solution, EDCI hydrochloride (5.70g, 24.50 mmol), HOBT (1.30g, 24.50 mmol), and diisopropylethylamine (5.08g, 39.6 mmol) were added successively. The resulting reaction mixture was stirred at 70°C for 4 hours, cooled to RT, diluted with CH2CI2, washed with water, dried over Na2SO4, and concentrated. Flash chromatography (Si02, 5% CH30H in CH2CI2 o 90: 10: 0.5 CH2CI2 : CH30H: NH40H) of the residue provided a tan foam (7.89g, 65%).

Step 6: A solution of 1 F (7.89g, 12.88 mmol) and TFA (29g, 257 mmol) in CH2CI2 (65 ml) was stirred at RT for 12 h, neutralized with 1.0 M NaOH, and extracted with CH2CI2. The combined organic layers were washed with water, dried over Na2SO4 and concentrated. Purification of the crude product by flash chromatography (Si02, 5% CH30H in CH2CI2 to 90: 10: 0.5 CH2CI2 : CH30H : NH40H) provided the title compound as a white solid (5.80g, 88%). MS: 514 (MH+).

Example 2

Method B Step 1: TFA (200 ml, 2.596 mol) was added to a solution of 2A (20g, 51.36 mmol) in CH2CI2 (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 Na2SO4, and concentrated. Flash chromatography gave an orange solid (13.50g, 91%).

Step 2: Amine 2B (1. 50g, 5.19 mmol) and Preparation 1 (1. 75g, 5.13 mmol) were dissolved in DMF (10 ml) and CH2CI2 (10 ml). To the resulting solution, EDCI hydrochloride (1.50g, 7.83 mmol), HOBT (1. 05g, 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 CH2CI2, washed with water, dried over Na2SO4, and concentrated. Flash chromatography of the residue provided an orange gel (2. 31 g, 74%).

Step 3: A suspension of 2C (2. 10 g, 3.46 mmol,) and Raney@ 2800 Nickel (1. 0 g) in CH30H (100 ml) was shaken under H2 (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%).

Step 4:

Amine 2D (200 mg, 0.347 mmol) and picolinoyl chloride hydrochloride (62 mg, 0.348 mmol) were dissolved in CH2CI2. Et3N 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 Na2SO4, and concentrated. Purification of the residue by flash chromatography gave a white foam (167 mg, 71% yield).

Step 5: A solution of 2E (160 mg, 0.235 mmol) and H2SO4 (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 Na2SO4, and concentrated. Purification of the crude product using prep TLC (10% CH30H in CH2CI2) provided the title compound as a white solid (88 mg, 66%). MS: 564 (MH+) Example 3 Method D Step 1 : 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 CH30H, and combined CH30H extracts were concentrated-dry loaded on silica gel and flash chromatographed (25-40% 5N NH3 in CH30H/CH2CI2) to provide 3C as a dark solid (1.90 g, 81 %).

Step 2:

To the mixture of acid 3D (181mg, 0.54 mmol), HATU (247 mg, 0.65 mmol) and Et3N (84 111, 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 CH30H, concentrated-dry loaded on silica gel and flash chromatographed (5-10% 5N NH3 in CH30H/CH2CI2) to provide 3E as a yellow oil (210mg, 70%).

Step 3: A solution of 3E (96 mg, 0.174 mmol) in 15 mi of 1 M HCI in 25% CH30H/ dioxane was stirred at RT for 48 h. The mixture was concentrated, exposed to high vacuum, redissolved in CH30H, concentrated-dry loaded on silica gel and flash chromatographed (10-15% 5N NH3 in CH30H/CH2CI2) to provide the title compound as a colorless oil (48 mg, 61 %). MS: 453 (MH+) Example 4 Method E Step 1: A mixture of neat 4A (1.75g, 6.66 mmol) and 4B (2.93g, 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 Na2SO4. 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%).

Step 2: To a 500 ml pressure bottle was added 4C (490 mg, 1.18 mmol) in CH30H (20 ml). Under N2 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%).

Step 3: 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 CH2CI2 (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 NaHC03 solution, the resulting mixture was extracted with CH2CI2. The combined organic solutions were dried over Na2SO4 and concentrated. Purification of the crude product by flash chromatography on silica gel with 10% CH30H in CH2CI2 as the eluent provided 4E as a solid (231 mg, 41%).

Step 4: To a 25 ml round-bottomed flask was added 4E (200 mg, 0.31 mmol) in CH2CI2 (2.5 ml). TFA was then introduced via a syringe. The resulting solution was stirred at RT for 15 h, diluted with CH2CI2, neutralized with 1.0 M NaOH solution, and separated. The organic solution was washed with water and dried over Na2SO4. After evaporation of the solvent, the crude product was purified on a preparative TLC plate with 10% CH30H in CH2CI2 as the eluent to provide the title compound as a white solid (85 mg, 50%). MS: 544 (MH+).

Example 5 Step 1 : A solution of compound 5A (100g, 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 (300ml) 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 (11) was added. The solution was washed successively with water, 0.1 N aq. HCI, saturated aq. NaHC03, and brine. The organic layer was dried over MgS04, 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%).

Step 2 : A solution of 5B (50g, 0.181 mol) in THF (300 ml) and CH30H (200 ml) was treated with a solution of LiOH-H20 (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%).

Step 3: Compound 5C (20.4 g, 0.081 mol) was added slowly to a stirred flask of CH2CI2 (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.

Step 4A: A mixture of c (64 g, 0.40 mol), d (84 ml, 0.52 mol), and K2CO3 (66 g, 0.48 mol) in anhydrous toluene (350 mi) was heated at reflux overnight. The reaction mixture was diluted with CH2CI2, washed three times with 5% aqueous NaOH, dried over Na2SO4, and concentrated. Recrystallization with MeOH provided e (121 g,-100%) as a yellow solid.

A suspension of e (121 g, 0.41 mol) and Raney Nickel (10 g) in EtOH (400 ml) was shaken under H2 (40 psi) for 4 h. The mixture was filtered through a short pad of Celite (washing with CH30H). The filtrate was concentrated and dried in vacuo to provide f (109 g,-100%) as a dark brown solid.

A solution of f (109 g, 0.41 mol) in CH2CI2-DMF (1: 1,500 mi) was treated with picolinic acid (61 g, 0.50 mol), EDCI (119 g, 0.62 mol), HOBt (84 g, 0.62 mol) and iPr2NEt (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 Na2SO4, and concentrated. Flash chromatography (0- 100% EtOAc/hexane) provided g (131 g, 86%).

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 CH2CI2. The combined organic extracts were dried over Na2SO4 and concentrated. Flash chromatography (0-80% EtOAc/hexane) provided h (95 g, 76%) as a yellow solid.

A solution of h (95 g, 0.27 mol) in anhydrous CHC13 (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 CH2CI2. The combined organic extracts were dried over Na2SO4 and concentrated. Flash chromatography (2N NHs-CHsOH/EtOAc) provided 5E (43 g, 57%) as a pale yellow solid.

Step 4B: A mixture of 5D (0.075 mol) in CH2CI2 (250 ml) was treated with 5E (15 g, 0.054 mol) and iPr2NEt (25 ml, 0.135 mol) while maintaining a temperature of 20 °C.

After 1 h, the mixture was concentrated and then stirred in CH30H (200 ml)/CH2CI2 (200 ml)/H20 (1 ml) for 1 h at 20 °C. The solvent was then evaporated. Treatment with TFA (200 ml) in CH2CI2 (250 ml) at 20 °C followed by flash chromatography (0- 7% 7N NH3-CH30H/CH2CI2) provided 5F (80-90% from 5C).

Step 5: Method A: A solution of 5F (0.41 g, 1.0 mmol) in CH2CI2 (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 CH2CI2. The organic layer was dried with Na2SO4 and concentrated. Flash chromatography (0-5% 7N NH3-CH30H/CH2CI2) provided the title compound (0. 45g, 87%). MS: 516 (M+H).

Method B: A solution of 5G (50 g, 0.41 mol) in CH30H (300 ml) was cooled to 0 °C and carefully treated with NaBH4 (20g, 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 NH4CI, and concentrated.

Flash chromatography (5-10% 7N NH3-CH30H/CH2CI2) provided 5H (31g, 62%) as a light yellow solid.

A slurry of 5H (31 g, 0.25 mol) in CH2CI2 (500 ml) was cooled to 0 °C and slowly treated with SOC12 (55ml, 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 51 was dried overnight in vacuo (38.4g, 52%, HCI salt).

A homogeneous solution of 5F (16.4 g, 40 mmol) in anhydrous DMF (200 ml) was cooled to 0 °C, carefully treated with NaH (8g, 200 mmol), and stirred at 20 °C for 20 min. The reaction mixture was then cooled to 0 °C, treated with Nal (6g, 40 mmol) and 51 (14. 5g, 80 mmol), and then stirred overnight at 20 °C. The reaction was diluted with CH2CI2 (500 ml), washed with 1 N aqueous NaOH, washed with brine, filtered through Celite, and concentrated. Flash chromatography (0-4% 7N NH3- CH30H/CH2CI2) provided Ex. 5 (16. 9g, 82%) as a beige solid.

Example 6 Step 1: To a stirred solution of diamine 1 B (1. 0g, 3.55 mmol) in C2H50H (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 Na2CO3 (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 x 10 ml). Combined extracts were washed with brine (5 ml) and filtered through anhydrous MgS04. 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%).

Step 2: In a dry flask, under an inert atmosphere, a mixture of compound 6A (369 mg; 1.20 mmol) and CH2CI2 (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 CH30H were added to the reaction solution, and solvent was removed under vacuum. The residual solid was dissolved in boiling Et20 (-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 mi, by which point precipitation had begun. The mixture was allowed to stand at RT for-3 h. Filtration and washing with Et20-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.

Step 3: To a stirred suspension of compound 6B (333 mg; 0.751 mmol) in CHCI3 (2 ml), contained in a flask equipped for reflux under an inert atmosphere, was added via syringe (CH3) 3Sil (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 (CH3) 3Sil (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 CH30H (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) CH30H-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%).

Step 4 : 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 NEt3 (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 x 5 ml). Combined extracts were washed with brine (2.5 ml) and filtered through anhydrous MgS04. The filtrate was evaporated under vacuum, and the residue was purified by flash chromatography on silica gel, eluting with a gradient of CH2CI2-CH30H-NH40H (97: 3: 0.5-> 96: 4: 0.5).

Product 6D (222 mg; 47%) was obtained as pale yellow powder. FABMS: 689 (MH+ ; #93%) ; 578 (-58%) ; 478 (100%).

Step 5: To a solution of 6D (208 mg; 0.302 mmol) in CH2CI2 (3 ml) was added TFA (928 microliters ; 1.37 g ; 12.1 mmol) with swirling of the flask, which was then flushed with dry N2, 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 Na2CO3 (3 mi) plus sufficient water to produce two clear phases. The aqueous phase was extracted with EtOAc (3 x 5 ml). Combined extracts were washed with brine (3 ml) and filtered through anhydrous MgS04. The filtrate was stripped of solvent in vacuo, and the residue was subjected to flash chromatography on silica gel, eluting with CH2CI2-CH30H-NH40H (97: 3: 0.5). The title compound (130 mg; 72%) was obtained as pale yellow powder. FABMS: 589 (MH+ ;-64%) ; 478 (100%).

Using procedures similar to those described above, employing the appropriate starting materials, compounds in the following tables are prepared: No. R R25 R3 R13 Z R6 Physical Data S (MH+ 7-CH3 5-OCH3 H H-CH2-2-NH2 463 8-CH3 6-CI H H-CH2-2-NH2 467 9-CH3 5-CI H H-CH2-2-NH2 467 10-CH3 5-Br H H-CH2-2-NH2 512 11 0- 5-CI H H-CH2-2-NH2 535 12 benzyl 5-F H H-CH2-2-NH2 527 13-CH CH3 2 5-Br H H-CH2-2-NH2 540 14-CH2NH2 H H H-CH2-2-NH2 488 15-CH2NHS02CH3 H H H-CH2-2-NH2 526 1 6-CH2NHC (O) CH3 5-CI H H-CH2-2-NH2 524 17-CH20CH3 5-F H H-CH2-2-NH2 481 18-CH2NH2 5-CI H H-CH2-2-NH2 482 19-CH20CH3 6, 7-di-F H H-CH2-2-NH2 499 20 OD-6-F H H-CH2-2-NH2 521 21 5-F H H-CH2-2-NH2 521 22 rO 6-F H H-CH2-2-NH2 507 k 23 9Tf 5-F H H-CH2-2-NH2 520 L 24 0 5-F H H-CH2-2-NH2 521 N- 25 qu 5-Br H H-CH2-2-NH2 568 0 26 5-F H H-CH2-2-NH2 507 27 5-F H H-CH2-2-NH2 507 - 0 0 28 922 H H H-CH2-2-NH2 531 F 29 FF 5-F H H-CH2-2-NH2 549 zu JF 30 F45 6-F H H-CH2-2-NH2 531 2 31 6, 7-di-F H H-CH2-2-NH2 567 2 F 32 6-cul H H-CH2-2-NH2 547 2 33 F435 5-F H H-CH2-2-NH2 531 34 5-cul H H-CH2-2-NH2 565 F 35 H H H-CH2-2-NH2 531 p 36 5-cul H H-CH2-2-NH2 547 2 37 8Z 5-CI H H-CH2-2-NH2 529 2 6-F H H-CH2-2-NH2 557 o 39 5-Br H H-CH2-2-NH2 592 F F 40 F 5-Br H H-CH2-2-NH2 610 F F 41 Cl45 5-F H H-CH2-2-NH2 547 42 5-F H H-CH2-2-NH2 529 OH OH z 6-F H H-CH2-2-NH2 553 44 6-F H H-CH2-2-NH2 564 MON- 45 Cl <2 H H H-CH2-2-NH2 529 Z 46 5-F H H-CHZ-2-NH2 58 cl CI 47 Cl<82 5-CI H H-CH2-2-NH2 563 46 Cl < 22 6-CI H H-CH2-2-NH2 563 49 O CH3 F H H-CH2-2-NH2 543 OCH3 OCH3 50 CF2 S F H H-CH2-2-NH2 581 CF3 51 ci 5-Cl H H-CH2-2-NH2 597 Cl 52 Q- 5-F H H-CH2-2-NH2 597 OCH OCF3 53 Q- 5-Br H H-CH2-2-NH2 604 OCH3 54 Ci 6-CI H H-CH2-2-NH2 597 ci 55 F 5-CH3 H H-CH2-2-NH2 571 H3CH2CO 56 F3Ca=N 5-CI H H-CH2-2-NH2 665 F3C 57 F3C) 5-Br H H-CH2-2-NH2 710 F3C 56 8 6-ethoxy H H-CH2-2-NH2 540 2 59 $-5-CI H H-CH2-2-NH2 546 N+ N+ 80 NH2 11 H H-CH2-2-NH2 511 Nu/ NH2 61 N 5-F H H-CH2-H 499 2 62 N 6-Cl H H-CH2-2-NH2 530 Z 63 sN § 5-F H H-CH2-2-NH2 515 Z 64 N 6-F H H-CH2-2-NH2 514 Z 65 CN § 6-F H H-CH2-2-NH2 515 N-'c 66 t ; 7-CI H H-CH2-2-NH2 531 NU 67 N H H H-CH2-2-NH2 496 2 68 N 5-F H H-CH2-2-NH2 515 N 69 =N 5-Cl H H-CH2-2-NH2 531 N 70 aN 5 5-CI H H-CH2-2-NH2 531 N,, 71 N 5, 6-di-F H H-CH2-2-NH2 532 2 72 =N 5-Br H H-CH2-2-NH2 575 73 m N 2 6-ethoxy H H-CH2-2-NH2 2 74 C 5-F H H-CH2-2-NHz 528 # 75 N 6-F H H-CH2-2-NH2 515 N\, 76 5-Br H H-CH2-2-NH2 591 N+ 0' 77 5-Cl H H-CH2-2-NH2 530 NU 78 ND/5-Cl H H-CH2-2-NH2 530 2 79 Cl iF H H-CH2-2-NH2 548 Cl 80 N N 5-CF3 H H-CH2-2-NH2 565 N,, 81 N-*7 H H H-CH2-2-NH2 497 zon 82 N 6, 7-di-F H H-CH2-2-NH2 567 cl C 83 N 6, 7-di-F H H-CH2-2-NH2 532 Z 84 5-F H H-CH2-2-NH2 530 Nu OH 85 cl 5-CF3, 7-F H H-CH2-2-NH2 617 nu N 88 H2N iF H H-CH2-2-NH2 529 H N H2N 87 0 CH3 H H H-CH2-2-NH2 500 N 88 o H H H-CH2-2-NH2 485 \° w 89- H H H-CH2-2-NH2 489 N ru 90 's e-F H H-CH2-2-NH2 514 Y '-LTU-U 91 90 6-F H H-CH2-2-NH2 503 Y 92 ro 5-F H H-CH2-2-NH2 503 0 W 93 \ H H H-CH2-2-NH2 501 s 94 t N F H H-CH2-2-NH2 518 / \N 95 H3 0 5-CI H H-CH2-2-NH2 534 zon 98 9\ FF H H-CH2-2-NH2 519 S w 97 $ 6, 7 F H H-CH2-2-NH2 536 Nu' n 98 H3 0 5-Br H H-CH2-2-NH2 579 / \N 99 ti 6 sthoxy H H-CH2-2-NH2 544 /y \N 100 5-F H H-CH2-2-NH2 503 Y 101 5-ber H H-CH2-2-NH2 563 N 102 5-F H H-CH2-2-NH2 502 N 103 H3 0 5-CF3 H H-CH2-2-NH2 568 / \N 104 H3 5-CF3, 7-F H H-CH2-2-NH2 586 / "YN 'ru 105 t b F H H-CH2-2-NH2 598 . jazz 106 on 5-F H H-CH2-2-NH2 517 H3C-91 w 107 (CH3) 3 5-F H H-CH2-2-NH2 573 HsC- H3c-q\ C 108 5-F H H-CH2-2-NH2 517 HC" wu 109 CH3-S-5-F H H-CH2-2-NH2 483 110 CH3-CH2-S-5-F H H-CH2-2-NH2 497 111 CH3-S02-5-F H H-CH2-2-NH2 515 112 0-s- 5-F H H-CH2-2-NH2 545 113 H3C 0 5-F H H-CH2-2-NH2 511 H3C 114 F3CS- 5-F H H-CH2-2-NH2 551 115 H3C 4 5-F H H-CH2-2-NH2 540 Hue 116 HS-5-F H H-CH2-2-NH2 469 117 CH3-S-5-F H 2--CH2-2-NH2 497 CH3 118 CH3-S-5-F F H-CH2-2-NH2 501 119 S Ng 5-F H H-CH2-2-NH2 529 120 5-F H H-CH2-2-NH2 522 0 N 121 5-F H H-CH2-2-NH2 599 123 @ Ng 5-F H H-CH2 528 124 F H 5-F H H-CH2-2-NH2 564 F + N-g 125 F CHg 5. F H H-CH2-2-NH2 578 1- 126 S02CH3 5-F H H-CH2-2-NH2 624 F N- 127 4 Ng 5-F H H-CH2-2-NH2 546 128 F3CO2S-NN $ 5-F H H-CH2-2-NH2 653 U 129 CH3-0- (CH2) 2- 5-F H H-CH2-2-NH2 510 NH- 130 O 5-F H H-2-NH 563 H21VN 131 H3Cs _ 2 5-F H H-CH2-2-NH2 480 Q H3C 132 CH3-O-5-F H H-CH2-2-NH2 467 133 CH3-CH2-O-5-F H H-CH2-2-NH2 481 134 CH3-0- (CH2) 2-0- 5-F H H-CH2-2-NH2 511 (CH3) 2-CH-0- 5-F H H-CH2-2-NH2 495 35E 136 0- 5-F H H-CH2-2-NH2 529 137 H, N H H H-CH2-2-NH2 511 N 138 5-CF3, 7-F H H-CH2-2-NH2 582 N 139 $ 5-F H H ICH3 2-NH2 528 N 140 >$ 5-F F H-CH2-2-NH2 532 N 141 5-F OH H-CH2-2-NH2 530 N 142 § 5-F H H-CH 2-NH2 529 -CH- 143 NN 2. 5-F H H-CH 2-NH2 529 N-CH- 144 5-F-CH3 H-CH2-2-NH2 528 zon 145 6-F H H P 2-NH2 528 ZON 146 H 5-F H H-CH2-2-NH2 437 147 vCH3 5-F H H-CH2-2-NH2 531 H3C HsC- 148 H3 CH3 5-F H H-CH2-2-NH2 531 O 149 ich3 5-F H H-CH2-2-NH2 585 F3c_4 150 5-F H H-CH2-2-NH2 549 H3C CH3 151 CF3 5-F H H-CH2-2-NH2 571 yo 152 N H F H-CH2-2-NH2 514 153 (CH3) 2N- (CH2) 2- 5-F H H-CH2-2-NH2 523 NH- 154 CH3-S-5-F H H-CH 2-NH2 497 - CH- 155 t 5-F H 2--CH2-2-NH2 528 CH3 156 5-F H H-CH2-2-NH2 514 N 157 G8 5-F H H-CH2-3-NH2 514 158 S N_ 5-F H H-CH2-2-NH2 589 U 159 CN$ 5-F H H-CH2-2-NH2 520 160 CH3CH20-5-F F H-CH2-2-NH2 499 161 H3C CH3 5-F H H-CH2-2-NH2 537 N- (CH2) 2-N HgC 162 5-F H H-CH2-2-NH2 535 163 N 5-F H 5-OH-CH2-2-NH2 530 164 N 5-F F H-CH2-3-NH2 532 165 5-F F H-CH2-2-NH2 540 0 N 166 N 5-F H H-CH2-3-NH2 515 2 No. R R3 z R6 Physical Data MS (MH) 167 H-CH2-2-NH2 502 U 168-CH20CH3 H-CH2-2-NH2 464 169 AtS H-CH2-2-NH2 504 170 >oS H-CH2-2-NH2 460 171 (CH3) 2-CH-H-CH2-2-NH2 462 172 H3Cs ws H-CH2-2-NH2 477 HIC 1 73 F45 H-CH2-2-NH2 514 2 174 H-CH2-2-NH2 532 F 175 H-CH2-2-NH2 530 176 H-CH2-2-NH2 532 F F 177 0 H-CH2-2-NH2 540 . 178 H-CH2-2-NH2 564 Cl95 179 P- H-CH2-2-NH2 526 OCH3 180 H3CH2CO H-CH2-2-NH2 558 F F 181 N H-CH2-2-NH2 497 182 H-CH2-2-NH2 512 N/ NH2 183 N-2-NH2 Ct 184 S82 H-CH2-2-NH2 498 N,, 185 N H-CH2-2-NH2 497 Z 186 H3C H-CH2-2-NH2 511 zu 187 3C H-CH2-3-NH2 501 \N 188 0 \ H-CH2-2-NH2 486 0 189 P H-CH2-2-NH2486 Y 190 H3 N H-CHz-Z NHz 501 //' ? \N 191 1-1 H-CH2-2-NH2 536 o 192 H-CH2-2-NH2 547 N 193 XSS H-CH2-2-NH2 547 N 194 CH33 H-CH2-2-NH2 543 \N 195 F i \ o. N H-CH2-2-NH2 581 0. 1 196 r. F-CH2-2-NH2519 N CH 197 H3C nn H CH 2-N H2 515 fN-cH- 198 H3C) ga OH-CH2-2-NH 517 199 H3 N -CH2-2-NH2 577 200 F-CH2-2-NH2515 2 201 0 F-CH2-2-NH2 504 uvlt., 202 8 H-CH2-3-NH2 497 Z 203 F H-CH2-3-NH2 532 F 204 N F-CH2-3-NH2 515 2 205 F- F-CH2-3-NH2 550 F No. Physical Data MS (MH+) 206-CH3 434 207 N 497 208 F 514 209 Cl 4$ 530 No. R R25 A R3 R2 Physical Data MS MH+ 210 N S 8 5-CI C H ß NH2 532 \ z N 211 H 22 5-F C H N 515 -nu z 212 N 5-Cl C H N 532 In 2 213 N 5-F C H tX NF N H2 516 2'-NH2 N 214 gap H N H N 503 .. 1 N 215 ? H N N 503 0-/>-NH2 N 216 (CH3) 2CH- H N H N 463 -NH2 N 217 F w$ 5-F C H g/NH2 550 />-NH2 N 218 N 5-F C H g/NH2 515 />-NH2 N 219 N'* 5-Cl C H N 532 /I,-2 N 220 6-Cl C H N 548 Z \ i ILS 221 N 5-F C H N 516 Z-NH2 N 222 6-cul C H N 600 W N cri 223 m N 22 5-CI C H N 532 N\,/>-NH2 N 224 N 6-F C H N 515 z N 225 N S 2z H N H t {NFNH2 499 \ zon 226 hic H N H N 502 nu2 OZON 227 H N H N 487 />-NH2 0 ? N 228 H N H N 548 NH2 N N 229 N H N H N 548 2 , SS N 230 ? S\ y/NH 2 N\,. 231 H3C H N H N 502 />-NH2 O N 232 H N H N 537 />-NH2 N 233 N H N H N 548 />-NH2 N 234 H N H N 541 \ 2 0-y-N 235 CH3CH20 H N H N 559 \/ N F 236 G§ H N H t NH2 498 />-NH2 N 237 N 5-F C F N 533 2 FUN 238 F 2. 5-F C H /_ N H 550 Zizi F N 239 5-F C H N 550 />-NH2 F N 240 <T))-'Sip'C"'H/=N'5i5 240 N 2. 5-F C H NH2 515 '-N N N 241 N t5 5-F C H N 516 TON N N N 242 N H C H N 497 243 (CH3) 2N-CH2- H N H N 478 N N 244 ti 5-F C H N 519 2 N N 245 H3C H C H N 501 /z OZON - ru 246 ti 5, 6-di-F C H N> 537 NH2 247 N 2. 5-F C H NN 500 / 248 N N 5, 6-di-F C H NH 534 jazz N 249 3-5-F C F t NH2 53/ _CN 537 \/_nu2 O N 250 N 5-F C F N 534 J 2H2 N 251 NS2 5-F C F t<NPNH2 534 2 z zon 252 5-F C F N 533 / N 253 F 5-F C F t NH2 /2 F N 254 95 5-F C F N 568 zu F N 255 Ç H N H N 487 >_ NH2 N 256 8Z H C F N 515 \C/>-NH2 N 257 H3C H C F 'N 519 O- (-NH2 ozon 258 N H N F N 516 2-NH2 N 259 H N H N 505 0 NH2 N 260 N H N F/=N 516 2 2 261 H3C H N F t NH2 520 2 N N 262 5-F C H N 504 xc/>-NH2 N 263 5-F C H N 522 '-N . J /NH2 N 264 5-F C H 2/=\ 504 0 ? N N 265 H N H N 537 />-NH2 O v, N 266 (CH3) 2N-CH2- H N F N 496 />-NH2 N 267 H N F N 505 />-NH2 0 ? N 268 CH3CH2-O-5-F C H N 482 />-NH2 N 269 CH3-S-5-F C H N 484 />-NH2 N 270 CH3CH2-0-5-F C F N 500 />-NH2 N 271 H N F N 555 2 N 272 N H N F P/=\ 566 2 I N 273 N H N H N 498 '*-N N 274 : N 5, 6- C F N 551 d i-F 275 ON$ 5-F C F N 541 N 277' 5-F C H H2N 514 /-N HAN 277 N 2. 5-F C I-I 514 Z H2N 278 22 5-F C H t<NN 5 NON NN 279 H3 H N H N 515 />-NH2 H3C N 280 H N H N 501 Hic 3C N 261 9 H N F it 505 />-NH2 N 282 H N H N 536 />-NH2 N 283 °Si H N F t NH2 523 / N H2N don HAN H2N 285 H3C H N H N 501 - NH2 DZ N 286 H N H __CN 533 2 \ i 2 F N 287'=LpH') \r"FP/='517 287 N H N F N 517 2 N 288 H N H N H t NH2 4 -nu2 289 F H N H __CN 533 />-NH2 N 290 CH3S-5-F C F N 502 zon N 291 N H N F 515 2H2 ZON 292 22 5-F C F teNH2 532 N IN 293 t 5-F C H nu 514 2 zon IN 2 NU2 295 (CH3) 2N- 5-F C F N 499 />-NH2 N 296 CH3CH2-S-5-F C F N 516 />-NH2 N 297 CH3-O-5-F C F N 486 />-NH2 N 298 2 H N H N H N 512 2 OCH3 299 N H N F N OCH 530 3 300 N 5-F C F AoOCH3 547 3 301 N 5-F C H AoOCH3 529 2 3 302 8 5-F C H F 517 F 303 t 5-F C F N 535 F 304 22 H N H RCN 551 Cl Cl 30s 922 H N F N 551 2/ F N 306 N 5-F C H 500 N-N 307 N 5-F C H N 500 N 308/=P 5-F C F 2/"\ 547 Z 2 N HgC 309 (CH3CH2) 2N- 5-F C F N 527 />-NH2 N 310 N H N H NH 498 Z 311 N . H N F NU 516 Z 312 N 5-F C H rl-NH 515 313 N 5-F C F NH 533 314 H3C 5-F C F N 569 O N- 0 N- N H3C 315 CH3-S-H N F N 485 NH2 N 316 CH3CH2-0-H N F N 483 \ N 317 X H N F t-NH2 566 "_NH2 w I 318 N H N F 0 489 321 G5 H N F \< s 505 Z 319 N 2. H N F 2., 489 zozo 320 N Z. H N F S/505 2 321 N H N F 2, 505 s 322 5-F C F , /N nu2 323 N H N F NH2 516 /N NH2 325 H N F 2, 540 S F 325 O\JN$ H N F t NH2 524 . __C N 326 (CH3) 2CH-0- 5-F C F > 514 /_NH2 N 327 N 2. H N F S1 5os N 326 N 2. H N F 328 N H N F N 488 1 \ a/-I -U/ Z > N-N 330 N H N F N-N 507 s ' such3 Z 332 H N F 506 vs 333/P H N F C g zon Y 0 H3C 334 N H N F CH3 504 2 Z, -o N 335 CH3-O-H N F N 464 />-NH2 N 336 N H N F \dNt 491 zozo N N S 337 2. H N F N ?-NC (O) CH3 563 Z 338/= 5-F C H H3C,, CH3 545 - 0 J 339 N 5-F C F N 533 NU2 340 8 H N F < NH2 518 Z 341 N 5-F C H 0 NH2 535 : Kj s 342 H N F 520 2 J 3 JAN 343 6-Cl C H \ N 548 N- NH N N NHz 346 (CH3) 2-CH- H N H , N 463 \nec NH2 No. R3 R2 Physical Data MS (MH+) 347 H N 489 -NH2 N 348 F NH2 s06 NH2 349 F NH2 488 NH2 350 F N> 507 . _C zon 351 F N 506 NH2 No. R'-X-Z R3 R2 Physical Data M S (M H) 352 N'-CH2-H / N 509 N-H N H2 353 N 510 N N N H2 "rr''"" nu2 f L NH 2 N 355 F-CH2-H N 532 FI zon F NH2 t-l 356 N-CH2-H 496 zon N ,-61 nu2 'N"=< ) nu2 I NH2 I NH2 (CH2) 2ocH2cH3 2 358 H H 542 N NH2 F F 359 F \ f N-CH2-H / N 451 N H NH2 360 0-CH2-H N 537 N i L NH2 N, NH2 361 N-CH2-H 495 N NU2 6 NH2 362 \ N, Z-CH2-H / N 501 N S CH2CF3 NH2 363 N-CH2-H N 510 NU2 N H2 I 364 F-CH2-H N 533 N N NH2 F N Nt 365 N N-CH2-H 420 N H NEZ 366 N-CH2-H 449 zu N 2 3 H NH2 367 N CH2-H N 497 N S\ N I 368 F \ (N-CH2-H / N 533 N CH2CF3 NH2 CHCPg2 369 CI) o-H 487 CL H NH2 370 4/-CH, H NH, 509 R5 6 NH2 371 (NNk tJ-CH2-H Nlt 433 N N H2 372 F3C--a N-CH2-H 504 S NH 373 t0 S t-CH2-H NH2 43S S NH 374 Cl N CH2-H 472 N NEZ nu2 375 (aN- (CH2) 3- H 464 \>--N NH 376-CH2-H N 544 N N'N- NHZ cri a CI 377 9 N-CH2-F < 562 N N'N- NH2 cil No. R ml y R2 Physical Data MS (MH") 378 : N CH-CH2-\N 500 nu2 NH 379 N N-NH-N 502 /-nu2 Zon 380 N-NH-N 490 />-NH2 N 381 N-NH-N 494 /NH2 w, \ N 382/=3 N-NH-P/= 501 />-NH2 N 383 N N-NH-N 500 nu2 NH

Example 388 Step 1 : A solution of P7-1 (2.3 g, 8.9 mmol) in CH2CI2-DMF (1: 1,50 mi) 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 Na2SO4, and concentrated. Flash chromatography (50% EtOAc/hexane) provided 388A (2.5 g, 74%).

Step 2: In a manner similar to that described in Preparation 5, Step 4, compound 388A was converted to compound 388B.

Step 3:

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 3h. The reaction mixture was concentrated and diluted with EtOAc. The solution was washed three times with 5% aqueous NaOH, dried over Na2SO4, concentrated and subjected to flash chromatography (10% 2N NH3-CH30H/EtOAc).

The material was then taken up in CH2CI2 (20 ml) and treated with 4 M HCI-dioxane (4 ml). After stirring overnight at 20 °C, the reaction was carefully basified with 10% aqueous NaOH and extracted with CH2CI2. The combined organic layers were dried over Na2SO4, concentrated and subjected to flash chromatography (30% 2N NH3- CH30H/EtOAc) to provide 388C as a white solid (0.08g, 10%).

Step 4: In a manner similar to that described in Example 5, Step 5, compound 388C was converted to Example 388.

Example 389 Step 1 : 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 CH2CI2. 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 Na2CO3 (6.5 ml) and 6N NaOH (5

ml). The aqueous layer was further extracted with EtOAc (3 x 15 ml). The combined extracts were washed with brine (5 ml) and dried over anhydrous MgS04. Drying agent was removed by filtration, and the filtrate was concentrated under vacuum. The residue was purified by silica gel flash chromatography (EtOAc/hexanes = 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%).

Step 2: To a stirred, ice-cold solution of 389C (358 mg, 0.777 ml) in CH2CI2 (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 Et20 (35 ml) for 16 h. Filtration and washing with Et20 yielded the bis- trifluoroacetate salt of 389D as a white powder (449 mg, 98%).

Step 3: To a stirred suspension of 389D (100 mg, 0.170 mmol) in CH2CI2 (5 ml) was added Et3N (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 CH2CI2. 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 Na2CO3 (1.5 ml) and 6N NaOH (1.2 ml). The aqueous layer was further extracted with EtOAc (3 x 5 ml). The combined extracts were washed with brine (2 ml) and dried over anhydrous MgS04.

Drying agent was removed by filtration, and the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (silica gel ; CH2CI2/CH3OH/conc. NH40H = 90: 9: 1) to obtain the title compound as a light beige foam (36 mg, 45%). FABMS: 468 (MH+ ; 100%).

Using procedures similar to those described above in Examples 1-6 and 388- 389, the following compounds were prepared: Ex. Structure Mass Spec (M+H) 390/t o 533 (ESMS) N,-, r F \/ F N N J N o \\ h' N \ i 392 o F 535 N \1 NH2 (ESMS) N /N/ p Ki N 0 \/ F N s (ESMS) N (ESMS) -ton \ 1 l N 394 0 592 -'-ON IN (FAB) N o ; H3 NU 0 395 S CH3 N F 395 O 670 I N N (FAB) N i N N CH3 /'CH3 0 F 0 1 396 0 H3C 528 N N (ESMS) -cl3 N'o 0 -ton \/ 397 0, 491 N'N=N, (ESMS) 1, nu -tu nu \/ -ton nez Ni N NH N 399 0 488 N N (ESMS) Nr N S N 400 m ° 487 0, gN (ESMS) -tN Nui N N 401 0 471 N (ESMS) N N 0 N N 402/ o 487 N (ESM) N w N 403 0 (ESMS) 404 489 Nu N 405 506 - N (ESMS) N--o N 0 \N N''N Q 405/\ 506 N $N (ESMS) N- N --o N I F 406/\ 505 - N (ESMS) nu F \ N A 407 522 (ESMS) N--o N F-& N SPI I F 408 522 N--N (ESMS) N- F N Spi I S 0F 409 506 (ESMS) N F I F L m i I Nx Fp 410 523 (ESMS) N- S 0 F IF 411 524 (ESMS) N N N s 0 F 412 0 501 N NON (ESMS) % N I Ni N -ton /N 413 0, 490 N NH (ESMS) N Ni N N w N 414 $ 473 N'N=N, (ESMS) N N'\/w/ N w N 415 0 488 N N (ESMS) Ni N O 416 0 487 N (ESMS) F i N NH F 417 0 504 F N (ESMS) '0 F 418/\ 0 504 In N kN/S F 419/ 0 488 N LNjO (ESMS) N \ [, O '0 420 0 505 I, N (ESMS) Ni N N N 421 0 506 S) (ESMS) /N S nui N 0 F 526 0-0 Nly NH2 (FAB) Nl-N N Nui N 423 0 F 518 I (ESMS) IN NUI N F 424 4 o 585 k (FAB) N W -w NH NH CH3 W F 425 591 - N (ESMS) N=< N N N NH2 NH CH3 CHg lr 426 0 499 N N NH2 (ESMS) Nui N Nt N 427 0 516 N ON, Nly NH2 (ESMS) N F nui _N 428 I 546 N (ESMS) If t N NX O N-CH3 HC 429 N 498 (ESMS) //N N I w N N NH2 Q 1/ N (ESMS) '-\ N CL N-NH2 431 fri o 431 I i N p 571 431 N 9 N ZCJ J<N AS>NXS (E5S7MS) (ESMS) N N--C tN 'I 432 t o 589 N (ESMS) N N S C 433 0 573 ZON 433 I 1 0 573 (ESMS) i /N N /\/ N N N S O 434 0 591 N (ESMS) C N N/N N/N N N tel N zon 435 0 512 CH3 N N IY (ESMS) NON ZON N \tri 436 \- 0 530 N N NH2 (ESMS) N N zon N w N Nt 437 0 483 N NON (ESMS) N Ni N w N tN zozo 484 N-N_ (ESMS) -tu nui N ZON \/ N N, _,, CN-CH3 (ESMS) (ESMS) \ 1 Ni N N 440 H3C'F N 499 s NON Ni N Nl-N -ton \/ 441 0 471 N (ESMS) j\, NH Zon N 442 0 488 ZON (ESMS) , NH N N 442 9 N X < N < N' (E4S8M8 F 443 0 F 506 N N < W F \) NH Nui N N F 444 0 470 W N wC J< N 4 (ESMS) (ESMS) N ['NH N U 445 0 F 488 N - (ESMS) w N 446 , a U I O N N NH2 (FAB) N S N N N (FAB) ZON non -ton \/ 447 H3C 0 F N NH2 497 \ r ? f'Y" 0 1 (FAB) N 7 Zon N 448 H3 U F 513 s Y (FAB) N-N N N N 449 0 548 (FAB) il NON Ni N 450 0 563 3 N-CH3 (ESMS) E F 451/\ 0 514 (ESM N'bN I S) T -N 0 nu 452/o. 532 (ESM) N N w S Nui N zon N '453'Y0NH, 502 N- (ESMS) -tu je N \/ 454 < ° F BN+ O-550 ION N"OybN (ESMS) -TON zon N / -ton N-S (ESMS) Ni N w N 456 0 451 ur \ N., NH2 NNH2 ESMA) N y Ni N zon \ I 457 0 F 545 N NON Ni N ou CL 458 H3C Pp 513 H3C-s ly (ESMS) 3 % NN Nui N N 459 WGNJX 0 F 514 ly (FAB) NON Ni N 460 H3C 0 496 N NH2 (FAB) NON Nu E 461 Op 442 (ESM) O -ton /N 462 tN 458 zozo (ESMS) /N NS -ton N 463 H3C 0F 503 (ESM) Nit 464 X 407 N C, r ly (ESMS) N N N N 465 0F 534 ion ( (ESMS) N'x--N+ nô N N 0 \/ 466 0 516 . WC/G J<N >, sN (e5M S > N o- (ESMS) N ,/'N, own 467/\ 0 514 0 (ESMS) Non Ni N N N 468 0 484 1, , N NON Ni N F 469 0 458 H3C-S (ESMS) Ni N N O -ton 470 0 474 (ESM) S ZON X 1 4710467 NNH2 (ESMA) Non nui N "1 N 472 0 440 (ESMS) Ni N -ton \/ 473 H3C ° 465 N vNzC)) < N Xt N (ESMS) 474 (ESMS) NON nui N , 1 \/ 474 O 487 TON (ESMS) Nez nui N w N \/ N 475 H3C 0F 472 (ESM) NEZ Nui N , 1 N 476 H3 F 466 0 (ESMS) Nl-No Nui N -fizz 477/ 0 505 N (ESMS) N Ni N N 478 H3C F 456 o T ) (ESMS) Zozo N N -tN 479 H3 F 456 (ESMS) Ni N N O Non 0 tu 480 n ° F 504 WON X tN<NH2 (ESMS) b Zon N 481 0 OH 514 N N NH2 (ESMS) Non Nu N -ton \/ 482 N < N N NH2 (FAB) NON N N N OH 483 HsC 9p 472 > N jS) t N s/4 (ESMS) (ESMS) Nez nui N \ I N 484 H3C 9 438 -0 (ESMS) eN N ; N /N N N 485 H3C P 438 (ESMS) Nl-N N) N N 486 H3C'1° 454 (ESMS) N kNxS N S N /N -tN 487 F 470 H3C-S N (ESMS) nui N N N 488 O 502 tY 488 > O 502 9 ßNJ S3 (ESMS) N Ni N NH2 N 489 X 0 554 O N N NH2 FAB % N \ N i N Non 490 Om ° F 556 0 FAB) N N i N ly 491 0 470 (ESMS) NU2 N N NU2 N \/ 493 0 469 H3C-S N F N 493 469 tyN NH2 1 i N N \ I N S 44/ 0 555 (ESMS) Ni N S -ton N > 4950452 H3C-S N (ESMS) l /N N ./ N N N 496 H3C+o ° 487 N 496"sC. Q 487 (ESMS) N N nui N w N 497 HgC0440 NNN (ESMS) N t N 4 498 H3C, 0 0 424 t (ESMS) Nez ru N 499 3 470 (ESMS) N N \ zozo I 500 486 (ESMS) N S Q I 501 556 ? F (ESMS) O N N NH2 1 N\==, N N 0 F 502 0 500 H3C, S Nly NH2 (ESMS) NON 0 N N 503 CS W 566 N 4N (ESMS) N N \ O Q 504 577 N <N (ESMS) N Bu X N NH2 505 550 N_-N' (ESMS) N N I \ Br-\ Q 506 506 N_N (ESMS) F 0 F 0 FQ 507 522 N 'N (ESMS) N F 0 FQ 508 533 N _-PN (ESMS) N F "N NH2 NAH2 F 0 509 d $ 504 (ESMS) N"o 0 N N \ Q I 510 520 N_N (ESMS) N- N N \ CI \ N S Q 511 sCH3 0 456 il (ESMS) N 1 S - w zon 512 JCH3 467 \Nt (ESMS) N NN' N I 513 <\ O 482 N N (ESMS) S Nui N N 514 0 482 N (ESMS) tN Ni N N , 1 515 0 F 500 N I (ESMS) N Ni N N N /N 516 0 F 500 (ESMS) N : D N, N < N X 517 0 F 500 nu N (ESMS) b N 518 482 N \/ -ton N (ESMS) N kNN N 519 CH3 O 498 N NH2 (ESMS) N k N N v 520 CH3 0 481 S N NYNH2 (ESMS) N N N N w N 521 0 516 O SCH3 N N NH2 IY (ESMS) N N 522 H3C o 512 N NHz (FAB) N N N N F 523 H3CA 0 495 N NH2 (FAB) !) !) ! t, N z zon N N N FAB N\N IV N w N 525 0 499 N ON (ESMS) N N Ni N N 526 H3C 9 560 NNH2 (ESMS) : Ni N 527 Br 499 "FEZ : : (ESMS) e F F 528 0 501 (ESM N S) N-CH3 Nui N 529 0 483 ozz. S"CH3 N NH2 (ESMS) N',' N 530 hic526 N t N NHZ (ESMS) r"VT f v NA Nui N 531 H3C 509 O NNH2 (ESMS) zon nui N N N 532 0 449 H3C GN, NQ, NH2 (ESMS) 1, N N N ,", 1 /N N 533 0 500 . S"CH (ESMS) /N N N 534 H3C 0 512 H3C) N l NYNH2 (ESMS) N o N A W N 535 H3C 0 495 H3C N NYNHZ (ESMS) /N \ N H 3 w N ,,-tN 5360546 H3C-S sly NH2 (ESMS) N N ber N 537 0 530 X N (ESMS) I N Br 538 0 531 N (ESMS) i N N ,. N Ber \ 539 0 545 H3C-S N (ESMS) N NH2 3 540 0 468 H3C-0 NIY NH2 (ESMS) 1 N I-N N 541 F 540 (ESMS) N i N N F 542 0 481 IN (ESMS) Nez N 543 O 482 N (ESMS) _,, CN Ni N 544 0 515 (ESMS) N Ni N ci 545 0 517 N IN (ESMS) N Nu N F 546 H3C dCH3 526 3 NIY NH2 (ESMS) Nf k N/< N i N F 547 1 5560 9 o (ESMS) S N N NH2 1 N zu N Ni N W 548 CH3 O 526 N NH2 (ESMS) 1 N) k N N Nui N F 549 H3C F O N N NH2 550 1 W (ESMS) F F F 550 H3C 0 517 N (ESMS) f F Ni N F 551 H3C 0 532 Nb N N (ESMS) ru N F F 552 H3CA 0 464 O N NN (ESMS) N Ni N nit N N 553 H3C 0 516 N NH2 (ESMS) ZON zu N y ouf F H3C-S j3N N (ESMS) ZIZI r N N .-/ N OF 555 O 502 H3C-S N IY NH2 (ESMS) F F OF F 556 Chus ? 526 | N N 557 X NJT N (ESMS) NA N N N N E 557 0 516 N I N (ESMS) _,, CN' nui N r 558 487 (ESMS) N N F F F 559 H3C 0 496 H3C0 N NYNH2 (ESMS) N N'O N E nui N 560 H3C 481 H C N NN (FAB) N N N E N 561 534 l/NNH2 (ESMS) N i N. NN N F 561 H3C-S, C JN < Xt (N H2 (E5S3M4S) X N N N 562 0 501 N (ESMS) Nu2 ouf F 563 1 F 517 N (ESMS) 'LU nui N N (ESMS) N (w (ESMS) N , N N 565 1 o F 517 N (ESMS) N ION N 566 0 F 577 N I N (ESMS) Nj : : y Nu N 567 O 592 N N NH2 (ESMS) N ION Br N 568 519 NON (ESMS) N FUZZ F 569 0 552 F F 569 F 552 NNH2 (ESMS) 1 i N NN F F \ F Fez FLA i NJ N/ N \ F 571 453 NN (ESMS) i NJ N/ N 572 o 505 (ESMS) Nl-N-"bN OUF F F 573 Op 504 H3C-S IN (ESMS) OF zu F 574 Ñ S N (00 ; J X NN FENH (e5M S) ß F H3C-s (ESMS) Nl-N NH2 OF N NH2 l F 575 O F 533 N N (ESMS) > r N N 576 1 o F 549 N NYNH2 (ESMS) N r : ! 577 H3C 0 548 NNH2 (ESTS) NON F F 578 H3C 0 533 s-"-ON N (ESMS) F f F F F 579 H3C F O F 566 s N NH2 (ESMS) IY N N NUI N F F 580 NH2 Op 551 (ESMS) zon FEZ F F F 581.. 0 559 N N (ESMS) N W N N .. 582 \ ° 560 N N (ESMS) /N W N i N Br 583 0F 592 Br N J---aN (ESMS) NA N N W N N NHZ 584 1 o F 579 N N N (ESMS) in BER 585 CH3 466 0 (ESTS) N N-0 'on"" zon N 586 H3C'O 479 N NH2 (FAB) NON Nui N N l 587 0 505 N (ESMS) /N w N Nui N F s (ESMS) '-N Zon N N 589, o F 535 bN N N (ESMS) t Ouf 590 0 536 A it F 1/F N N (ESMS) 11 r N NN OUF F F 591 H3C 0 498 (ESMS) 1 N Ni N \ ci 592 H3C 9 483 N N (ESMS) N i N N CI W N X XN X N NH2 (ESMS) oNcS N N N ou Hic 594 0 550 N N (ESMS) OF N N NH2 F 595 0 529 H3C-S N r N N HIC O ; S ; HC 596 0 517 (ESMS) N N O ; S HC H3C HgC 597 O-533 Ñ > N XJ Jt N/4 > (ESMS) (ESMS) Nez z O ; SO H03-CS-° 598 0 466 H3C N NYNH2 (ESMS) N-"ON N Ni N 599 0 438 599 438 NNH2 (ESMS) N < N N nui N \ 600 421 NNH2 (ESMS) N ion Nu N N 601 0 423 N (ESMS) N t N N JE 602 0 406 (ESMS) N : : /N 603 F 456 N N i NH2 (ESMS) JE 0 j 604 F 441 ,."CN (ESMS) NeNo ; J N +N 0 605 ou 439 N ir NyNH2 (ESMS) N//'N'j N Nui N N \/ 606 k 0 516 N N NH2 I (ESMS) NJ : :) Ni N Nez 607 0 N NH2 498 N IY (ESMS) N Ni N N) <t NU1 608 0 525 N NwN NH2 /N N i N N NH2 w N C 609 H3C Op 516 N N NH2 (ESMS) N CI 610 H3C 501 o, NN'N'N (ESMS) I' bN N ci 611 HIC 0 547 (ESM) N neu Hic 0 HsC 612 H3C 0 531 (EMS) N N ozszo Hic H3C 613 H3C 0 543 (ESMS) N N \/ H3C hic 614"HC0558 N y N NH2 ESMS) HIC r Han 615 0 544 Hic Nl-N N " asc hic o=s ; p H3C 616 0 452 H. C N j ) 616 rNIY NH2 (FAB) F F F 617 424 (ESMS) -ton N N 618 H3C o 480 WNz N CN (ESMS) N F 619 H3C 0 465 (ESMS) N NN NON F 620 1S\ ° 560 N-0---N (ESMS) N NO"N,, C N N H3C-rO 0 621 0 511 N NIY NH2 (ESMS) N N ON N N H3C t 622 m ° 496 IN (ESMS) N H3C \ 623 0 510 (ESM) N "-NH, H-CH H3C \/ 624 o F 503 (ESMS) ci N. C ! 625 0 518 624, H3C-S N NH2 518 U N N nez CI 626 0 505 v \N (ESMS) TU N F 627 0 498 (ESMS) NN N F \/ F 628 0 485 N (ESMS) Nl-N N C ! cl 629 0 481 (ESMS) Zon 630 H3C 0 499 Nl-N (ESMS) N N. ci 631 \sX ° F 499 (ESMS) \-ton 1 632 NX 0 514 (ESMS) t4 N 0 ci CI 633 H3C 517 (ESMS) W N \ CI 634 H3C F 532 s N NH2 (ESMS) N N N, CI 635 0 488 Nf Nz N X (ESMS) N Ct N 636 0 518 -pu (ESMS) N_ 636518 N N I N F \ N N F 0 F0 637 H3C'° F 451 I (ESMS) N 0 F 638, 0 537 \N ?/ O N 639 0 472 N 640 CNC t N < N (MH+) -tN o' \ 1 640, o F 519 fL 7 NA (MH+) F 640 519 F 641, 0 487 N N- (MH+) N N N-CH3 F 642 0 516 NA N (MH+) W r H3C-S\ O v 0 643, 0 503 (MH+) N N N 4NU 0 ci 644 0 484 H/N N W N NH2 ESMS) N N ON N F 645 ou 503 N W N NH2 ESMS) N N Fuzz 646 0 498 H3C NO N ly NH2 (ESMS) N F-\ 647 ou 516 H N ly NH2 (ESMS) N w N F \ 648 0 468 N y N NH2 ESMS) ZON Fuzz 649 486 N w N NH2 ESMS) 647 N} N S t N < N 0 S M S| '-N BON N Fuzz 650 0 469 H3C'S NI NN (ESMS) N/N w I Nl-N F-0 651 Op 487 bN (ESMS) 650 469 9 < N < (E S M S) 651 ° F 487 Ñ g No C J Jt N JO (ESMS) FEZ Fro 652 0 483 HIC N IN (ESMS) ., N" kNJ N. F 653 ou 501 H3C N (ESMS) N F \ 654 0 453 H3C'o N (ESMS) A F < 655 Ñ2sN S t N < (E4S7M S) N F < 655 Op 471 I (ESMS) Fez N F.) 656 Op 468 H, C'O N (ESMS) N N, 657 0 450 H3C g N JS (ESMS) > r 658 0 530 t O C N < ¢ N r NH2 N A4 N < N N H3Co 659 CH3 L-N NH2 O N'NNHZ N/N N 0 \/ F 660 CH3 453 I (FAB) N /N N N F 661 H3C'S N ly NH2 470 Nl-N N (FAB) F F 662 H3 N N. N 455 FAB F \/ F 663 H3C 0 497 s N (ESMS) # N F 664 H3C 0 481 0 N (FAB) N Y 664 H3CA ° 481 N>Nv N t (FAB) F 664A H3C'F N 499 (FAB) (FAB) N N N \/

Example 665 4- [ [4- [2- (5-methyl-3-isoxazolyl)-3H-imidazo [4,5-b] pyridine-3-yi]-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 CH2CI2 (25 ml) containing activated 3A 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 CH2CI2 and the solid filtered through a pad of Celite. The filtrate was stirred for 20 min. with saturated aqueous NaHCO3, then separated, washed with brine, and dried over anahydrous Na2SO4. The reaction mixture was purified by preparative TLC. The plates were eluted with EtOAc: Hexanes: CH30H (NH3) (75: 20: 5). Extraction of the bands with 13% CH30H (NH3)/EtOAc gave a mixture of Example 665 and Example 496. Example 658: MS (M+H): 423.

In a similar manner, using 4-[[4-[2-(metnhylthio)-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 General Procedure for Hg-Receptor Binding Assay The source of the H3 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 x g for 10 min. in order to remove clumps of tissue and debris. The resulting supernatants were then centrifuged at 50,000 x g for 20 min. in order to sediment the membranes, which were next

washed three times in homogenization buffer (50,000 x g for 20 min. each). The membranes were frozen and stored at-70°C until needed.

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 pg/ml with 0. 1 % DMSO. Membranes were then added (400 gug of protein) to the reaction tubes.

The reaction was started by the addition of 3 nM [3H] R-a-methyl histamine (8.8 Ci/mmol) or 3 nM [3H] Na-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 Kj (nM).

General Procedure for rHu H3 Binding Assay [3H] N «-methylhistamine (82 Ci/mmole) was obtained from Dupont NEN.

Thioperamide was obtained from the Chemical Research Department, Schering- Plough Research Institute.

HEK-293 human embryonic kidney cells stably expressing the human histamine H3 receptor were cultured in Dulbecco's modified Eagle's medium/10% fetal calf serum/penicillin (100 U/ml)/streptomycin (100 pg/ml)/Geneticin (0.5 mg/ml) at 37° C in a humidified 5% C02 atmosphere. Cells were harvested between passages five and twenty at 37° C in 5 mM EDTA/Hank's balanced salt solution and processed for membrane preparation. After low-speed centrifugation, ten min at 1000 xg, they were put into ten volumes of ice-cold buffer and disrupted with a Poltron (PTA 35/2 tip, 30 sec at setting 6). After subsequent low-speed centrifugation, supernatant was centrifuged ten min at 50,000 xg. 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 xg. Membranes were resuspended at 1 mg of protein/ml of buffer and frozen at-80° C until use.

Membrane (15 ug of protein) was incubated with 1. 2 nM [3 H] Nx-methyl- histamine, without or with inhibitor compounds, in a total volume of 200 ul 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).

IC50 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, CA). Ki values were determined from IC50 values according to the Cheng and Prusoff equation.

In these assays, compounds of formula I have a Ki within the range of about 0.1 to about 600 nM. Preferred compounds of formula I have a Ki within the range of about 0.1 to about 100 nM. More preferred compounds of formula I have a Ki within the range of about 0.1 to about 20 nM.

Representative compounds of the present invention tested according to the above procedures have the following Ki values: Ex. Receptor Ki Source 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 Ex. Receptor Ki Source 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

In this specification, the term"at least one compound of formula 1"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 Hr receptor antagonist"means that one to three different H antagonists may be used in a pharmaceutical composition or method of treatment.

Preferably, one H, antagonist is used.

For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutical 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 pharmaceutical acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), The Science and Practice of Pharmacy, 20th Edition, (2000), Lippincott Williams & Wilkins, Baltimore, MD.

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.

Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutical acceptable carrier, such as an inert compressed gas, e. g. nitrogen.

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.

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.

Preferably the compound is administered orally.

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.

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.

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.

The amount and frequency of administration of the compounds of the invention and/or the pharmaceutical 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.

When the invention comprises a combination of H3 antagonist and H, antagonist compounds, the two active components may be co-administered simultaneously or sequentially, or a single pharmaceutical composition comprising a H3 antagonist and an Hr antagonist in a pharmaceutical 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 Hr antagonist can be determined from published material, and may range from 1 to 1000 mg per dose.

When separate H3 and H, antagonist pharmaceutical compositions are to be administered, they can be provided in a kit comprising in a single package, one container comprising an H3 antagonist in a pharmaceutically acceptable carrier, and a separate container comprising an H1 antagonist in a pharmaceutical acceptable carrier, with the H3 and H1 antagonists being present in amounts such that the

combination is therapeutical 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.

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.