Benzimidazole derivatives useful as histamine H3 antagonists

Abstract

Disclosed are novel compounds of the formula 1

Description

FIELD OF THE INVENTION

[0002] 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 H1 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 HI compounds.

BACKGROUND OF THE INVENTION

[0003] The histamine receptors, H1, H2 and H3 are well-identified forms. The H1 receptors are those that mediate the response antagonized by conventional antihistamines. H1 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.

[0004] 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.

[0005] 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 Oct. 15, 2001, and U.S. Provisional Application No. 60/275,417, filed Mar. 13, 2001.

[0006] U.S. Pat. No. 5,869,479 discloses compositions for the treatment of the symptoms of allergic rhinitis using a combination of at least one histamine H1 receptor antagonist and at least one histamine H3 receptor antagonist.

SUMMARY OF THE INVENTION

[0007] The present invention provides novel compounds of formula I: 2

[0008] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0009] the dotted line represents an optional double bond;

[0010] a is 0 to 2;

[0011] b is 0 to 2;

[0012] n is 1, 2 or 3;

[0013] p is 1, 2 or 3;

[0014] r is 0, 1, 2, or 3;

[0015] with the provisos that when 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;

[0016] M1 is C(R3) or N;

[0017] M2 is C(R3) or N;

[0018] X is a bond or C1-C6 alkylene;

[0019] Y is —C(O)—, —C(S)—, —(CH2)q—, —NR4C(O)—, —C(O)NR4—, —C(O)CH2—, —SO2—, —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);

[0020] q is 1 to 5, provided that when both M1 and M2 are N, q is 2 to 5;

[0021] Z is a bond, C1-C6 alkylene, C1-C6 alkenylene, —C(O)—, —CH(CN)—, —SO2— or —CH2C(O)NR4—; 3

[0022] Q is —N(R8)—, —S— or —O—;

[0023] k is 0, 1, 2, 3 or 4;

[0024] k1 is 0, 1, 2 or 3;

[0025] k2 is 0, 1 or 2;

[0026] R is H, C1-C6 alkyl, halo(C1-C6)alkyl-, C1-C6 alkoxy, (C1-C6)alkoxy-(C1-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)alkyl, (C3-C6)cycloalkyl-(C1-C6)alkoxy, (C3-C6)cycloalkyl-oxy-, R37-heterocycloalkyl, R37-heterocycloalkyl-oxy-, R37-heterocycloalkyl-(C1-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)0-2—, halo(C1-C6)alkyl-S(O)0-2—, N(R30)(R31)—(C1-C6)alkyl-S(O)0-2— or benzoyl;

[0027] R8 is H, C1-C6 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-;

[0028] 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; C1-C6 alkyl; hydrogen; thianaphthenyl; 4

[0029] wherein said six-membered heteroaryl ring or said five-membered heteroaryl ring is optionally substituted by R6;

[0030] R3 is H, halogen, C1-C6 alkyl, —OH, (C1-C6)alkoxy or —NHSO2—(C1-C6)alkyl;

[0031] R4 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6)cycloalkyl(C1-C6)alkyl, R33-aryl, R33-aryl(C1-C6)alkyl, and R32-heteroaryl;

[0032] R5 is hydrogen, C1-C6 alkyl, —C(O)R20, —C(O)2R2, —C(O)N(R20)2, (C1-C6)alkyl-SO2—, or (C1-C6)alkyl-SO2—NH—;

[0033] or R4 and R5, together with the nitrogen to which they are attached, form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring;

[0034] 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, 5

[0035] R7 is —N(R29)—, —O— or —S(O)0-2—;

[0036] R12 is independently selected from the group consisting of C1-C6 alkyl, hydroxyl, C1-C6 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;

[0037] R13 is independently selected from the group consisting of C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, or fluoro, provided that when R13 is hydroxy or fluoro then R13 is not bound to a carbon adjacent to a nitrogen; or two R13 substituents form a C1 to C2 alkyl bridge from one ring carbon to another non-adjacent ring carbon; or R13 is ═O;

[0038] R20 is independently selected from the group consisting of hydrogen, C1-C6 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;

[0039] R22 is C1-C6 alkyl, R34-aryl or heterocycloalkyl;

[0040] R24 is H, C1-C6 alkyl, —SO2R22 or R34-aryl;

[0041] R25 is independently selected from the group consisting of C1-C6 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-;

[0042] R29 is H, C1-C6 alkyl, C3-C6 cycloalkyl, R35-aryl or R35-aryl(C1-C6)alkyl-;

[0043] R30 is H, C1-C6 alkyl-, R35-aryl or R35-aryl(C1-C6)alkyl-;

[0044] R31 is H, C1-C6 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—;

[0045] or R30 and R31 together are —(CH2)4-5—, —(CH2)2—O—(CH2)2— or —(CH2)2—N(R38)—(CH2)2— and form a ring with the nitrogen to which they are attached;

[0046] R32 is 1 to 3 substituents independently selected from the group consisting of H, —OH, halogen, C1-C6 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)2O— group;

[0047] R33 is 1 to 3 substituents independently selected from the group consisting of C1-C6 alkyl, halogen, —CN, —NO2, —CF3, —OCF3, —OCHF2 and —O—(C1-C6)alkyl;

[0048] R34 is 1 to 3 substituents independently selected from the group consisting of H, halogen, —CF3, —OCF3, —OH and —OCH3;

[0049] R35 is 1 to 3 substituents independently selected from hydrogen, halo, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, phenoxy, —CF3, —N(R36)2, —COOR20 and —NO2;

[0050] R36 is independently selected form the group consisting of H and C1-C6 alkyl;

[0051] R37 is 1 to 3 substituents independently selected from hydrogen, halo, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, phenoxy, —CF3, —N(R36)2, —COOR20, —C(O)N(R29)2 and —NO2, or R37 is one or two ═O groups;

[0052] R33 is H, C1-C6 alkyl, R35-aryl, R35-aryl(C1-C6)alkyl-, (C1-C6)alkyl-SO2 or halo(C1-C6)alkyl-SO2—;

[0053] R39 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6)cycloalkyl(C1-C6)alkyl, R33-aryl, R33-aryl(C1-C6)alkyl, and R32-heteroaryl; and

[0054] R40 is hydrogen, C1-C6 alkyl, —C(O)R20, —C(O)2R20, —C(O)N(R20)2, (C1-C6)alkyl-SO2—, or (C1-C6)alkyl-SO2—NH—;

[0055] or R39 and R40, together with the nitrogen to which they are attached, form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring;

[0056] This invention also provides a pharmaceutical composition comprising an effective amount of compound of at least one compound of formula I and a pharmaceutically acceptable carrier.

[0057] This invention further provides a method of treating: allergy, allergy-induced airway (e.g., upper airway) responses, congestion (e.g., nasal congestion), hypotension, cardiovascular disease, diseases of the GI tract, hyper and hypo motility and acidic secretion of the gastro-intestinal tract, obesity, sleeping disorders (e.g., hypersomnia, somnolence, and narcolepsy), disturbances of the central nervous system, attention deficit hyperactivity disorder (ADHD), hypo and hyperactivity of the central nervous system (for example, agitation and depression), and/or other CNS disorders (such as Alzheimer's, schizophrenia, and migraine) comprising administering to a patient in need of such treatment (e.g., a mammal, such as a human being) an effective amount of at least one compound of formula I.

[0058] Compounds of this invention are particularly useful for treating allergy, allergy-induced airway responses and/or congestion.

[0059] This invention further provides a pharmaceutical composition comprising an effective amount of a combination of at least one compound of formula I and at least one H1 receptor antagonist in combination with a pharmaceutically acceptable carrier.

[0060] This invention further provides a method of treating allergy, allergy-induced airway (e.g., upper airway) responses, and/or congestion (e.g., nasal congestion) comprising administering to a patient in need of such treatment (e.g., a mammal, such as a human being) an effective amount of a combination of at least one compound of formula I and at least one HI receptor antagonist.

[0061] Kits comprising a compound of formula I in a pharmaceutical composition, and a separate H1 receptor antagonist in a pharmaceutical compositions in a single package are also contemplated.

DETAILED DESCRIPTION OF THE INVENTION

[0062] Preferred definitions of the variables in the structure of formula I are as follows:

[0063] R1 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.

[0064] R25 is preferably halogen or —CF3 and k is 0 or 1.

[0065] 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 R4 and R5 are independently selected from the group consisting of H and (C1-C6)alkyl, or R4 and R5 together with the nitrogen to which they are attached form a pyrrolidinyl, piperidinyl or morpholinyl ring. More preferably, R6 is —NH2.

[0066] X is preferably a bond.

[0067] Y is preferably —C(O)—.

[0068] Z is preferably straight or branched C1-C3 alkyl.

[0069] 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).

[0070] M2 is preferably C(R3) wherein R3 is hydrogen or fluorine; b is preferably 0; r is preferably 1; and p is preferably 2.

[0071] As used herein, the following terms have the following meanings, unless indicated otherwise:

[0072] alkyl (including, for example, the alkyl portions of arylalkyl and alkoxy) represents straight and branched carbon chains and contains from one to six carbon atoms;

[0073] alkylene represents a divalent straight or branched alkyl chain, e.g., ethylene (—CH2CH2—) or propylene (—CH2CH2CH2—);

[0074] 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;

[0075] aryl (including the aryl portion of arylalkyl) represents a carbocyclic group containing from 6 to 14 carbon atoms and having at least one aromatic ring (e.g., aryl is a phenyl or naphthyl ring), with all available substitutable carbon atoms of the carbocyclic group being intended as possible points of attachment;

[0076] arylalkyl represents an aryl group, as defined above, bound to an alkyl group, as defined above, wherein said alkyl group is bound to the compound;

[0077] cycloalkyl represents saturated carbocyclic rings of from 3 to 6 carbon atoms;

[0078] halogen (halo) represents fluoro, chloro, bromo and iodo;

[0079] heteroaryl represents cyclic groups, having 1 to 4 heteroatoms selected from O, S or N, said heteroatom interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, with the aromatic heterocyclic groups preferably containing from 2 to 14 carbon atoms; examples include but are not limited to isothiazolyl, isoxazolyl, oxazolyl, furazanyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, isothiadiazolyl, thienyl, furanyl (furyl), pyrrolyl, pyrazolyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridyl (e.g., 2-, 3-, or 4-pyridyl), pyridyl N-oxide (e.g., 2-, 3-, or 4-pyridyl N-oxide), triazinyl, pteridinyl, indolyl (benzopyrrolyl), pyridopyrazinyl, isoqinolinyl, quinolinyl, naphthyridinyl; the 5- and 6-membered heteroaryl groups included in the definition of R2 are exemplified by the heteroaryl groups listed above; all available substitutable carbon and nitrogen atoms can be substituted as defined;

[0080] heterocycloalkyl represents a saturated, carbocylic ring containing from 3 to 15 carbon atoms, preferably from 4 to 6 carbon atoms; examples include but are not limited to 2- or 3-tetrahydrofuranyl, 2- or 3-tetrahydrothienyl, 2-, 3- or 4-piperidinyl, 2- or 3-pyrrolidinyl, 2- or 3-piperazinyl, 2- or 4-dioxanyl, 1,3-dioxolanyl, 1,3,5-trithianyl, pentamethylene sulfide, perhydroisoquinolinyl, decahydroquinolinyl, trimethylene oxide, azetidinyl, 1-azacycloheptanyl, 1,3-dithianyl, 1,3,5-trioxanyl, morpholinyl, thiomorpholinyl, 1,4-thioxanyl, and 1,3,5-hexahydrotriazinyl, thiazolidinyl, tetrahydropyranyl.

[0081] In the definition of R32, when two R32 groups on adjacent carbon atoms of an aryl or heteroaryl ring are said to be taken together form a —OCH2O— or —O(CH2)2O— group, this means that the two R32 groups form a methylenedioxy or ethylenedioxy ring fused to the aryl or heteroaryl ring. When R12, 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.

[0082] {circle over (N)} for example in the structure 6

[0083] represents a nitrogen atom that is located at one of the 4 non-fused positions of the ring, i.e., positions 4, 5, 6 or 7 indicated below: 7

[0084] Similarly, {circle over (2N)} means that two nitrogens are located at any two of the 4 non-fused positions of the ring, e.g., the 4 and 6 positions, the 4 and 7 positions, or the 5 and 6 positions.

[0085] Also, as used herein, “upper airway” usually means the upper respiratory system—i.e., the nose, throat, and associated structures.

[0086] Also, as used herein, “effective amount” generally means a therapeutically effective amount.

[0087] “Patient” means a mammal, typically a human, although veterinary use is also contemplated.

[0088] Lines drawn into the rings indicate that the indicated bond may be attached to any of the substitutable ring carbon atoms.

[0089] Certain compounds of the invention may exist in different isomeric (e.g., enantiomeric, diastereoisomeric and geometric) forms. The invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures. Enol forms and tautomers are also included.

[0090] The compounds of this invention are ligands for the histamine H3 receptor. The compounds of this invention can also be described as antagonists of the H3 receptor, or as H3 antagonists.

[0091] The compounds of the invention are basic and form pharmaceutically acceptable salts with organic and inorganic acids. Examples of suitable acids for such salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their corresponding salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to their corresponding free base forms for purposes of this invention.

[0092] Depending upon the substituents on the inventive compounds, one may be able to form salts with bases. Thus, for example, if there are carboxylic acid substituents in the molecule, salts may be formed with inorganic as well as organic bases such as, for example, NaOH, KOH, NH4OH, tetraalkylammonium hydroxide, and the like.

[0093] The compounds of formula I can exist in unsolvated as well as solvated forms, including hydrated forms, e.g., hemi-hydrate. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated forms for purposes of the invention.

[0094] The compounds of this invention can be combined with an H1 receptor antagonist (i.e., the compounds of this invention can be combined with an H1 receptor antagonist in a pharmaceutical composition, or the compounds of this invention can be administered with H1 receptor antagonist).

[0095] Numerous chemical substances are known to have histamine H1 receptor antagonist activity and can therefore be used in the methods of this invention. Many H1 receptor antagonists useful in the methods of this invention can be classified as ethanolamines, ethylenediamines, alkylamines, phenothiazines or piperidines. Representative H1 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 H1 receptors by known methods, including specific blockade of the contractile response to histamine of isolated guinea pig ileum. See for example, WO98/06394 published Feb. 19, 1998.

[0096] Those skilled in the art will appreciate that the H1 receptor antagonist is used at its known therapeutically effective dose, or the H1 receptor antagonist is used at its normally prescribed dosage.

[0097] Preferably, said H1 receptor antagonist is selected from: astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine, diphenhydramine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, meclizine, mizolastine, mequitazine, mianserin, noberastine, norastemizole, picumast, pyrilamine, promethazine, terfenadine, tripelennamine, temelastine, trimeprazine or triprolidine.

[0098] More preferably, said H1 receptor antagonist is selected from: astemizole, azatadine, azelastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, carebastine, descarboethoxyloratadine, diphenhydramine, doxylamine, ebastine, fexofenadine, loratadine, levocabastine, mizolastine, norastemizole, or terfenadine.

[0099] Most preferably, said H1 receptor antagonist is selected from: azatadine, brompheniramine, cetirizine, chlorpheniramine, carebastine, descarboethoxy-loratadine, diphenhydramine, ebastine, fexofenadine, loratadine, or norastemizole.

[0100] Even more preferably, said H1 antagonist is selected from loratadine, descarboethoxyloratadine, fexofenadine or cetirizine. Still even more preferably, said H1 antagonist is loratadine or descarboethoxyloratadine.

[0101] In one preferred embodiment, said H1 receptor antagonist is loratadine.

[0102] In another preferred embodiment, said H1 receptor antagonist is descarboethoxyloratadine.

[0103] In still another preferred embodiment, said H1 receptor antagonist is fexofenadine.

[0104] In yet another preferred embodiment, said H1 receptor antagonist is cetirizine.

[0105] Preferably, in the above methods, allergy-induced airway responses are treated.

[0106] Also, preferably, in the above methods, allergy is treated.

[0107] Also, preferably, in the above methods, nasal congestion is treated.

[0108] In the methods of this invention wherein a combination of an H3 antagonist of this invention (compound of formula I) is administered with a H1 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.

[0109] Compounds of the present invention can be prepared by a number of ways evident to one skilled in the art. Preferred methods include, but are not limited to, the general synthetic procedures described herein. One skilled in the art will recognize that one route will be optimal depending on the choice of appendage substituents. Additionally, one skilled in the art will recognize that in some cases the order of steps has to be controlled to avoid functional group incompatibilities.

[0110] The starting material and reagents used in preparing compounds described are either available from commercial suppliers such as Aldrich Chemical Co. (Wisconsin, USA) and Acros Organics Co. (New Jersey, USA) or were prepared by literature methods known to those skilled in the art.

[0111] One skilled in the art will recognize that the synthesis of compounds of formula I may require the construction of carbon-nitrogen bond. Methods include but are not limited to the use of a substituted aromatic compound or heteroaromatic compound and amine at 0° C. to 200° C. The reaction may be carried out neat or in a solvent. Suitable solvents for the reaction are halogenated hydrocarbons, ethereal solvents, toluene, dimethylformamide and the like.

[0112] One skilled in the art will recognize that the synthesis of compounds of formula I may require the construction of heterocycle. Methods include but are not limited to the use of a diamino compound and a carbonyl equivalent at 0° C. to 200° C. The reaction may be carried out in acidic, basic or neutral conditions. Suitable solvents for the reaction are water, halogenated hydrocarbons, ethereal solvents, alcoholic solvents, toluene, ketones, dimethylformamide and the like.

[0113] One skilled in the art will recognize that the synthesis of compounds of formula I may require the need for the protection of certain functional groups (i.e. derivatization for the purpose of chemical compatibility with a particular reaction condition). See, for example, Green et al, Protective Groups in Organic Synthesis. A suitable protecting group for an amine is methyl, benzyl, ethoxyethyl, t-butoxycarbonyl, phthaloyl and the like which can appended to and removed by literature methods known to those skilled in the art.

[0114] One skilled in the art will recognize that the synthesis of compounds of formula I may require the construction of an amide bond. Methods include but are not limited to the use of a reactive carboxy derivative (e.g. acid halide) or the use of an acid with a coupling reagent (e.g. EDCI, DCC, HATU) with an amine at 0° C. to 100° C. Suitable solvents for the reaction are halogenated hydrocarbons, ethereal solvents, dimethylformamide and alike.

[0115] One skilled in the art will recognize that the synthesis of compounds of formula I may require the reduction of a functional group. Suitable reducing reagents for the reaction include 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.

[0116] The starting materials and the intermediates of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and alike. Such materials can be characterized using conventional means, including physical constants and spectral data.

[0117] One method shown in Scheme 1, below, is for the preparation of compounds of formula IA wherein R1 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 R1 is other than benzimidazolyl as defined above) and the benzoxazolyl and benzothiazolyl derivatives. 8

[0118] Step a: A suitably monoprotected diamine of formula X, wherein X is a bond or alkyl, Prot is a protecting group, and the remaining variables are as defined above is alkylated or arylated with a halide. The intermediate diamine is then cyclized with an appropriate carbonyl or formyl equivalent to form a compound of formula XI. Suitable protecting groups are methyl, benzyl, butoxycarbonyl, or ethoxycarbonyl. A suitable halide for alkylation is a substituted aromatic compound or a substituted hetero-aromatic compound as described by Henning et al, J. Med. Chem. 30, (1987), 814-819.

[0119] Step b: The protected amine of formula XI is deprotected using methods known to those skilled in the art. A suitable method for methyl deprotection is reaction with a haloformate or the like. A suitable method for benzyl deprotection is cleavage with hydrogen at or above atmospheric pressure and a catalyst such as palladium. Suitable methods for carbamate deprotection are treatment with an acid, base or trimethylsilyl iodide.

[0120] Step c: An amine of formula XII is reacted with an activated functional group Y of formula XIII to form the bond between the nitrogen and functional group Y in formula IA. When Y is a carbonyl group and 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.

[0121] Another method for the preparation of compounds of formula IA wherein R1 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). 9

[0122] Step d: A suitably monoprotected diamine of formula X, wherein X is a bond or alkyl, Prot is a protecting group, and the remaining variables are as defined above, is alkylated or arylated with a halide to form a compound of formula XIV. Suitable protecting groups are methyl, benzyl, butoxycarbonyl, and ethoxycarbonyl. A suitable halide for alkylation is a substituted aromatic compound or a substituted heteroaromatic compound as described by Henning et al.

[0123] Step e:

[0124] (1) The protected amine of formula XIV is deprotected using methods known to those skilled in the art. A suitable method for methyl deprotection is reaction with a haloformate or the like. A suitable method for benzyl deprotection is cleavage with hydrogen at or above atmospheric pressure and a catalyst such as palladium. Suitable methods for carbamate deprotection are treatment with an acid, base or trimethylsilyl iodide.

[0125] (2) The resulting amine from Step e(1) is reacted with an activated functional group Y of formula XIII to form the bond between the nitrogen and functional group Y to obtain the compound of formula XV. When Y is a carbonyl group and 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.

[0126] Step f: After reduction of formula XV, the resulting compound is reacted with a carbonyl equivalent to give the cyclized compound of formula IA. The reduction conditions can be hydrogen in the presence of catalyst, metal in the presence of an acid or a base, or other reduction reagent. The cyclization can be performed in acidic or basic conditions.

[0127] More detailed methods for synthesis of compounds are shown in Scheme 3 below. The preparation of compounds of formula IB wherein R1 is 1-benzimidazolyl (Methods A, B, C and F), Y is —C(O)— and R2 is substituted pyridyl, and compounds of formulas IC and IC′ wherein R1 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 azabenzimidazoles compounds (i.e., compounds wherein R1 is other than benzimidazolyl as defined above). 1011121314

[0128] Specifically exemplified compounds were prepared as described in the examples below, from starting materials known in the art or prepared as described below. These examples are being provided to further illustrate the present invention. They are for illustrative purposes only; the scope of the invention is not to be considered limited in any way thereby.

[0129] Unless otherwise stated, the following abbreviations have the stated meanings in the Examples below:

[0130] Me=methyl; Et=ethyl; Bu=butyl; Pr=propyl; Ph=phenyl; t-BOC=tert-butyloxycarbonyl;

[0131] CBZ=carbobenzyloxy; and Ac=acetyl

[0132] DCC=dicyclohexylcarbodiimide

[0133] DMAP=4-dimethylaminopyridine

[0134] DMF=dimethylformamide

[0135] EDCI=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide

[0136] ESMS=Electron spray mass spectroscopy

[0137] FAB=Fast atom bombardment mass spectroscopy

[0138] HATU=O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl uronium hexafluorophosphate

[0139] HOBT=1-hydroxybenzotriazole

[0140] LAH=lithium aluminum hydride

[0141] LDA=lithium diisopropylamide

[0142] NaBH(OAc)3=sodium triacetoxyborohydride

[0143] NBS=N-bromosuccinimide

[0144] PPA=polyphosphoric acid

[0145] RT=room temperature

[0146] TBAF=tetrabutylammonium fluoride

[0147] TBDMS=t-butyldimethylsilyl

[0148] TMEDA=N,N,N′,N′-tetramethylethylenediamine

[0149] TEMPO=2,2,6,6-tetramethyl-1-piperidinyloxy, free radical

[0150] TLC=thin layer chromatography

[0151] HRMS=High Resolution Mass Spectrometry

[0152] LRMS=Low Resolution Mass Spectrometry

[0153] nM=nanomolar

[0154] Ki=Dissociation Constant for substrate/receptor complex

[0155] pA2=-logEC50, as defined by J. Hey, Eur. J. Pharmacol., (1995), Vol. 294, 329-335.

[0156] Ci/mmol=Curie/mmol (a measure of specific activity)

Preparation 1

[0157] 15

[0158] Step 1: 16

[0159] To a solution of 2-amino-4-methylpyridine (10.81 g, 100 mmol) in tert-butanol (250 ml) was added t-BOC anhydride (26.19 g, 120 mmol). The reaction mixture was stirred at 23° C. overnight, and then concentrated to an oil. The crude product was dry loaded onto a silica gel column and flash chromatographed (eluant: 30% hexanes-CH2Cl2 to 0-2% acetone-CH2Cl2) to produce 15.25 g (73.32 mmol; 73%) of the desired product as a white solid.

[0160] Step 2: 17

[0161] To a solution of the product of Step 1 (35.96 g, 173 mmol) in THF (1.4 l) at −78° C. was added a n-BuLi solution (1.4 M, 272 ml, 381 mmol) in hexanes portionwise over 30 min. The reaction mixture was then allowed to warm slowly and was stirred for 2 h at 23° C., which resulted in the formation of an orange precipitate. The mixture was then cooled back to −78° C., and pre-dried oxygen (passed through a Drierite column) was bubbled through the suspension for 6 h while the temperature was maintained at −78° C. The color of the reaction mixture changed from orange to yellow during this time. The reaction was quenched at −78° C. with (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/CH2Cl2) provided 20.15 g (90 mmol; 52%) of the alcohol as a pale yellow solid.

[0162] Step 3: 18

[0163] To a solution of the product of Step 2 (19.15 g, 85.5 mmol) in CH2Cl2 (640 ml) was added a saturated aqueous solution of NaHCO3 (8.62 g, 103 mmol) and NaBr (444 mg, 4.3 mmol). The reaction mixture was cooled to 0° C., and TEMPO (140 mg, 0.90 mmol) was introduced. Upon vigorous stirring, commercial bleach solution (122 ml, 0.7 M, 85.4 mmol) (5.25% in NaOCl) was added portionwise over 40 min. After an additional 20 min at 0° C., the reaction mixture was quenched with saturated aqueous Na2S2O3 and allowed to warm to 23° C. Dilution with water and extraction with CH2Cl2, followed by concentration and flash chromatography (eluant: 30% hexanes-CH2Cl2 to 0-2% acetone-CH2Cl2) afforded 15.97 g (71.9 mmol; 84% yield) of the aldehyde as an off-white solid.

[0164] Step 4: 19

[0165] To a solution of the product of Step 3 (11.87 g, 53.5 mmol) in CH2Cl2 (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 NaHCO3, diluted with water and extracted with CH2Cl2. Concentration of the organic extracts, followed by silica gel flash chromatography (eluant: 04% sat. NH3 in CH3OH—CH2Cl2) provided 19.09 g (52.6 mmol; 98%) of the ester as an off-white solid.

[0166] Step 5:

[0167] To a solution of the product of Step 4 (1.57 g, 4.33 mmol) in THF-water-CH3OH (10 ml of a 3:1:1 mixture) was added LiOH monohydrate (0.125 g, 5.21 mmol). The reaction mixture was stirred overnight at 23° C., concentrated and exposed to high vacuum to obtain 1.59 g of crude title compound as a yellowish solid which was used without purification.

Preparation 2

[0168] 20

[0169] Step 1: 21

[0170] A solution of diamine 1B (see Method A, Step 1) (20 g, 71.1 mmol) and Et3N (30 ml, 213 mmol) in CH2Cl2 (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 MgSO4 and concentrated under vacuum. Hot EtOAc (200 ml) was added to the semi-solid residue, and the resultant mixture was cooled to RT. Filtration yielded compound P2-1 as a white solid (16.5 g); and silica gel flash chromatography [CH2Cl2/CH3OH (2N NH3)=40:1] of the filtrate provided additional product as a white solid (2.7 g) [combined yield: 88%]. FABMS: 308 (MH+; 100%).

[0171] Step 2: 22

[0172] POCl3 (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. POCl3 was then removed in vacuo. The residue was adjusted to pH˜9-10 with 7N methanolic ammonia and was concentrated to dryness under vacuum. CH2Cl2 was added to the residue, insoluble material was filtered off, and the filtrate was again concentrated in vacuo. The residue was crystallized from EtOH to obtain compound P2-2 as a white solid (12.6 g; 67%). ES-MS: 326.1 (MH+; 100%).

[0173] Varying amounts of compound P2-10 may be formed in this process and can be converted to desired product P2-2 by careful in situ treatment in CH2Cl2 solution at 0° C. with one equivalent each of EtOH and NaH, followed by workup with ice-water and CH2Cl2. Low temperature is maintained in order to minimize reaction at the 2-position of the benzimidazole nucleus.

[0174] Step 3: 23

[0175] 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 MgSO4 and concentrated under vacuum. The residue was purified via flash chromatography on silica gel, eluting with EtOAc-hexanes (3:4), to obtain compound P2-3 as a white solid (2.12 g; 63%). FABMS: 338.3 (MH+; 100%).

[0176] Step 4:

[0177] To a stirred solution of P2-3 (300 mg, 12.5 mmol) in EtOH (40 ml)-isopropyl alcohol (40 ml) was added 25% (w/w) aqueous NaOH solution (20 ml). The resultant mixture was stirred at 85° C. for 24 h, then at 100° C. for an additional 4 h. Alcohols were removed under vacuum, and the aqueous residue was extracted sequentially with CH2Cl2 (2×40 ml), then EtOAc (30 ml). Combined extracts were dried over anhydrous MgSO4. Drying agent was removed by filtration, and the filtrate was concentrated under vacuum. The residue was purified by silica gel flash chromatography (CH2Cl2/2N methanolic ammonia=12:1) to obtain Preparation 2 as an off-white solid (2.85 g, 70%). ES-MS: 266 (MH+; 100%).

Preparation 3

[0178] 24

[0179] Step 1: 25

[0180] NaH (60 mg of a 60% dispersion; 1.48 mmol) was added to CH3OH (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. CH3OH was removed in vacuo, and to the residue were added CH2Cl2 (30 ml) and water (10 ml). The organic layer was dried over anhydrous MgSO4, filtered, and the filtrate concentrated under vacuum. The residue was purified via flash chromatography on silica gel, eluting with EtOAc-hexanes (3:2) to obtain P3-1 as a white foam (0.232 g; 59%). ES-MS: 322.1 (MH+; 100%).

[0181] Step 2:

[0182] 1 N aqueous KOH (4.82 mL; 4.82 mmol) was added to a solution of P3-1 in EtOH (15 ml), and the resultant mixture was stirred at 80° C. for 48 h. The mixture was concentrated under vacuum. Water (3 ml) and CH2Cl2 (15 ml) were added to the residue, and the organic layer was separated and dried over anhydrous MgSO4. Drying agent was filtered, and the filtrate was concentrated in vacuo to obtain Preparation 3 as a colorless glass (160 mg; 95%). FABMS: 250.2 (MH+; 100%).

Preparation 4

[0183] 26

[0184] Step 1: 27

[0185] 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 CH2Cl2 (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 CH2Cl2/2N methanolic ammonia (45:1), to obtain P4-1 as a colorless glass (0.325 g; 94%). ES-MS: 377.1 (MH+; 100%).

[0186] Step 2:

[0187] Trimethylsilyl iodide (240 microliters; 1.64 mmol) was added to a solution of P4-1 (316 mg; 0.843 mmol) in CHCl3 (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 NH4OH and water to pH 10 and extracted with CH2Cl2 (2×5 ml). The combined extracts were dried over anhydrous MgSO4. Drying agent was filtered, and the filtrate was concentrated under vacuum. The residue was purified via flash chromatography on silica gel, eluting with CH2Cl2-2N methanolic ammonia (13:1), to obtain compound Preparation 4 as a colorless glass. (181 mg; 70%). ES-MS: 305.1 (MH+; 100%).

Preparation 5

[0188] 28

[0189] Step 1: 29

[0190] A solution of P5-1 (3.5 g, 21 mmol) and P5-2 (6.5 g, 38 mmol) in CH2Cl2 (3 ml) was heated to 110° C. for 24 h and RT for 24 h. The reaction was diluted with CH2Cl2, washed with water and brine, and dried (Na2SO4). Purification on a flash column (SiO2, 40% to 60% EtOAc in hexanes) gave P5-3 (1.3 g, 21%; M+H=295).

[0191] Step 2: 30

[0192] To a solution of P5-3 (1.3 g, 4.4 mmol) in CH3OH (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 P54 as a grey solid that was used without further purification (1.05 g, 90%; M+H=265).

[0193] Step 3: 31

[0194] A solution of P54 (1.05 g, 3.97 mmol), P5-5 (0.49 g, 3.97 mmol), DEC (1.14 g, 5.96 mmol) and HOBT (0.8 g, 5.96 mmol) in CH2Cl2 (10 ml) were stirred for 18 h at RT. The crude reaction mixture was diluted with additional CH2Cl2 and washed with 5% aqueous NaOH and brine and dried (Na2SO4). Purification using flash chromatography (SiO, 8% EtOAc in hexane to 10% CH3OH in EtOAc) gave P5-6 (0.35 g, 24%; M+H=370).

[0195] Step 4: 32

[0196] Compound P5-6 (0.7 g, 1.89 mmol) was dissolved in HOAc (10 ml) and heated to 120° C. for 3.5 h. The reaction was cooled to RT, concentrated in vacuo, neutralized by the addition of 10% aqueous NaOH and extracted with CH2Cl2. The combined organic layers were dried (Na2SO4) and concentrated to give P5-7 (0.58 g, 87%; M+H=352) which was used in the next step without further purification.

[0197] Step 5:

[0198] A solution of P5-7 (0.58 g, 1.65 mmol) and NaOH (0.43 g, 13.2 mmol) in EtOH/H2O (9/1, 10 ml) was heated to 100° C. for 18 h. The reaction was cooled and concentrated and the residue purified on a flash column (SiO2, 10% CH3OH saturated with ammonia in CH2Cl2) to give Preparation 5 (0.42 g, 91%; M+H=280).

Preparation 6

[0199] 33

[0200] Step 1: 34

[0201] A solution of compound P6-1 (prepared by procedures analogous to P2-1) (10.5 g, 36.2 mmol) and 2,6-di-tert-butylpyridine (12.2 ml, 54.4 mmol) in CH2Cl2 (400 ml) was treated with 1M sol. of Et3O+BF4— (in CH2Cl2, 55 ml, 55 mmol). The reaction mixture was stirred at RT for 2 h, quenched with 1 N NaOH (100 ml), extracted with CH2Cl2 (3×), dried with Na2SO4 and concentrated. Purification by silica gel chromatography (eluant: 5-10% acetone/CH2Cl2) to give 6.37 g of P6-2 (20.0 mmol, 55%).

[0202] Step 2:

[0203] In a manner similar to that described in Preparation 3, Step 2, P6-2 was converted to Preparation 6.

Preparation 7

[0204] 35

[0205] Step 1: 36

[0206] A mixture of P7-1 (40 g, 150 mmol), trimethyl orthoformate (66 ml, 64.0 g, 600 mmol) and a catalytic amount of p-toluenesulfonic acid monohydrate (300 mg, 1.58 mmol) was stirred under N2 at 120° C. for 3 h. Excess orthoformate was removed under vacuum. The residue was partitioned between EtOAc (200 ml) and 1N NaOH (100 ml). The organic layer was washed with brine (100 ml) and dried over anhydrous MgSO4. Drying agent was removed by filtration, and the filtrate was concentrated under vacuum. The residue was purified by silica gel flash chromatography (CH2Cl2/CH3OH (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%).

[0207] Step 2: 37

[0208] NBS was added portionwise (exotherm) to a solution of P7-2 (27 g, 100 mmol) in CHCl3 (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 Na2S2O4 (250 ml). The organic layer was washed with brine (150 ml) and dried over anhydrous MgSO4. Drying agent was removed by filtration, and the filtrate was concentrated under vacuum. The residue was purified by silica gel flash chromatography [CH2Cl2/acetone=45:1] to obtain P7-3 as a yellow solid (24.2 g, 69%). ES-MS: 353 (MH+; 100%).

[0209] Step 3:

[0210] NaH (544 mg of a 60% dispersion, 13.6 mmol) was added to a solution of CH3OH (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 MgSO4. Drying agent was removed by filtration, and the filtrate was concentrated under vacuum to obtain Preparation 7 as a white syrup (2.81 g, 81%), which was used without further purification. ES-MS: 305 (MH+; 100%).

Preparation 8

[0211] 38

[0212] Step 1: 39

[0213] A solution of 1B (15 g, 52.8 mmol) and 1,1′-thiocarbonyldiimidazole (25 g, 140 mmol) in THF (300 ml) was stirred at 72° C. under 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 (CH2Cl2/acetone=20:1) to obtain P8-1 as a light yellow solid (16.7 g, >95%). ES-MS: 324 (MH+; 100%).

[0214] Step 2:

[0215] 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 MgSO4. 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

[0216] 40

[0217] Step 1: 41

[0218] (Modified published procedure: G. Heinisch, E. Luszczak, and M. Pailer: Monatshefte für Chemie, 1973 (104), 1372.

[0219] P9-1 (4.5 g, 47.8 mmoles), P9-2 (8.12 g, 76.5 mmoles), and anhydrous ZnCl2 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.

[0220] Step 2:

[0221] OsO4 (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). NaIO4 (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 CH2Cl2 (600 ml) and dried over anhydrous Na2SO4. After removal of the solvent, the mixture was purified by flash chromatography on silica gel using 5% CH3OH/CH2Cl2 as eluent to obtain Preparation 9. Yield: 2.89 g (82%).

Preparation 10

[0222] 42

[0223] Step 1: 43

[0224] A solution of P10-1 (2 g, 15 mmol) in CH2Cl2 (50 ml) was treated with Et3N (3 g, 30 mmol) and triphenylmethyl chloride (TrCl, 4.25 g, 15.3 mmol) and stirred at RT overnight. The solvent was removed in vacuo and the residue purified via flash column chromatography (SiO2, 20% EtOAc in hexane) to give P10-2 (5.2 g, 46%).

[0225] Step 2:

[0226] A solution of P10-2 (5.2 g, 14.6 mmol) in CCl4 (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

[0227] 44

[0228] Step 1: 45

[0229] To a stirred solution of P8-1 (6.5 g, 20.1 mmol) in EtOH (80 ml) was added 25% (w/w) aqueous NaOH solution (20 ml). The resultant mixture was stirred at 90° C. for 16 h. EtOH was removed under vacuum, and the residue was adsorbed directly onto silica gel and subjected to flash chromatography (CH2Cl2/2N methanolic ammonia=9:1) to obtain P11-1 as a white solid (4.46 g, 70%). ES-MS: 252 (MH+; 100%).

[0230] Step 2: 46

[0231] A mixture of P11-1 (3.95 g; 15.7 mmol), BOC-isonipecotic acid (3.60 g; 15.7 mmol), HOBT (3.19 g; 23.6 mmol), DIPEA (3 ml; 2.23 g; 17.2 mmol) and EDCI (4.50 g; 23.6 mmol) in DMF (30 ml) was stirred under 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 MgSO4. Drying agent was removed by filtration, and the filtrate was concentrated under vacuum. The residue was purified by silica gel flash chromatography (CH2Cl2/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%).

[0232] Step 3. 47

[0233] 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 MgSO4. Drying agent was removed by filtration, and the filtrate was concentrated under vacuum to obtain P11-3 as a pale yellow foam (471 mg, 96%), containing a small amount of DMF, used without further purification in Step 4 below. ES-MS: 463 (MH+; 85%); 435 (100%).

[0234] Step 4:

[0235] To a solution of P11-3 (465 mg; 0.949 mmol) in CH2Cl2 (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 CH2Cl2 (20 ml) and 1:1 (v/v) concentrated NH4OH: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 MgSO4. Drying agent was removed by filtration, and the filtrate was concentrated under vacuum to obtain Preparation 11 as a pale white foam (353 mg, 95%), used without further purification. ES-MS: 391 (MH+; 100%).

EXAMPLE 1

[0236] 48

[0237] Method A

[0238] Step 1: 49

[0239] A mixture of a (25 g, 0.16 mol), b (27 g, 0.16 mol), K2CO3 (26 g, 0.19 mol), and NaI (2.4 g, 0.016 mol) in dimethylacetamide (50 ml) was heated at 140° C. for 3.5 h. The reaction mixture was concentrated to one-third volume, poured onto saturated aqueous NaHCO3, and extracted with EtOAc (4×). The combined organic layers were washed with water (2×) and brine, dried over Na2SO4, and concentrated. Recrystallization with EtOH provided 1A (48 g, 98%).

[0240] A suspension of 1A (20.00 g, 64.2 mmol,) and Raney® 2800 Nickel (5.0 g) in ethanol (70 ml) and THF (140 ml) was shaken under 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%).

[0241] Step 2: 50

[0242] A solution of 1B (5.00 g, 17.77 mmol) and picolinoyl chloride hydrochloride (3.16 g, 17.75 mmol) in CH2Cl2 (400 ml) and Et3N (15 ml) was stirred at RT. After 15 h, the reaction was diluted with CH2Cl2, washed with water, dried over Na2SO4, concentrated, and dried on vacuum to provide a brown foam (6.47 g, 94%).

[0243] Step 3: 51

[0244] A solution of 1C (1.77 g, 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 CH2Cl2. The combined organic solutions were dried over Na2SO4 and concentrated on reduced pressure. The residue was purified by flash chromatography (silica gel, 5% CH3OH in CH2Cl2 as eluent) to provide a tan foam (1.58 g, 94%).

[0245] Step 4: 52

[0246] Iodotrimethylsilane (6.30 g, 31.48 mmol) was added to a solution of 1D (3.88 g, 10.53 mmol) in anhydrous 1,2-dichloroethane (40 ml). The resulting solution was stirred at 75° C. for 4 hours, cooled to RT, and treated with 1.0 M NaOH solution. The mixture was then extracted with CH2Cl2. The combined extracts were washed with water, dried over Na2SO4, and the solvent evaporated. Purification of the residue by flash chromatography (silica gel, 10% CH3OH in CH2Cl2 as eluent) delivered an off-white foam (2.10 g, 67%).

[0247] Step 5: 53

[0248] Amine 1E (5.80 g, 19.6 mmol) and Preparation 1 (5.32 g, 23.4 mmol) were dissolved in DMF (60 ml) and CH2Cl2 (60 ml). To the resulting solution, EDCI hydrochloride (5.70 g, 24.50 mmol), HOBT (1.30 g, 24.50 mmol), and diisopropylethylamine (5.08 g, 39.6 mmol) were added successively. The resulting reaction mixture was stirred at 70° C. for 4 hours, cooled to RT, diluted with CH2Cl2, washed with water, dried over Na2SO4, and concentrated. Flash chromatography (SiO2, 5% CH3OH in CH2Cl2→90:10:0.5 CH2Cl2:CH3OH:NH4OH) of the residue provided a tan foam (7.89 g, 65%).

[0249] Step 6:

[0250] A solution of 1F (7.89 g, 12.88 mmol) and TFA (29 g, 257 mmol) in CH2Cl2 (65 ml) was stirred at RT for 12 h, neutralized with 1.0 M NaOH, and extracted with CH2Cl2. The combined organic layers were washed with water, dried over Na2SO4 and concentrated. Purification of the crude product by flash chromatography (SiO2, 5% CH3OH in CH2Cl2 to 90:10:0.5 CH2Cl2:CH3OH:NH4OH) provided the title compound as a white solid (5.80 g, 88%). MS: 514 (MH+).

EXAMPLE 2

[0251] 54

[0252] Method B 55

[0253] TFA (200 ml, 2.596 mol) was added to a solution of 2A (20 g, 51.36 mmol) in CH2Cl2 (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 (13.50 g, 91%).

[0254] Step 2: 56

[0255] Amine 2B (1.50 g, 5.19 mmol) and Preparation 1 (1.75 g, 5.13 mmol) were dissolved in DMF (10 ml) and CH2Cl2 (10 ml). To the resulting solution, EDCI hydrochloride (1.50 g, 7.83 mmol), HOBT (1.05 g, 7.82 mmol), and diisopropylethylamine (3.71 g, 28.70 mmol) were added successively. The resulting reaction mixture was stirred at 70° C. for 18 h, cooled to RT, diluted with CH2Cl2, washed with water, dried over Na2SO4, and concentrated. Flash chromatography of the residue provided an orange gel (2.31 g, 74%).

[0256] Step 3: 57

[0257] A suspension of 2C (2.10 g, 3.46 mmol,) and Raney® 2800 Nickel (1.0 g) in CH3OH (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%).

[0258] Step 4: 58

[0259] Amine 2D (200 mg, 0.347 mmol) and picolinoyl chloride hydrochloride (62 mg, 0.348 mmol) were dissolved in CH2Cl2. 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).

[0260] Step 5:

[0261] 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% CH3OH in CH2Cl2) provided the title compound as a white solid (88 mg, 66%). MS: 564 (MH+)

EXAMPLE 3

[0262] 59

[0263] Method D

[0264] Step 1: 60

[0265] Diamine 3A (1.43 g, 10 mmol) and isonipecotic acid 3B (1.29 g, 10 mmol) were mixed, and PPA (20 g) was added. The resulting mixture was heated at 180° C. for 3.5 h, cooled to RT and diluted with water to 100 ml. The solution was then basified with solid NaOH to pH 14. The resultant copious precipitate was filtered off. The precipitate was washed repeatedly with CH3OH, and combined CH3OH extracts were concentrated-dry loaded on silica gel and flash chromatographed (25-40% 5N NH3 in CH3OH/CH2Cl2) to provide 3C as a dark solid (1.90 g, 81%).

[0266] Step 2: 61

[0267] To the mixture of acid 3D (181 mg, 0.54 mmol), HATU (247 mg, 0.65 mmol) and Et3N (84 μl, 0.6 mmol) in DMF (12 ml) was added amine 3C (126 mg, 0.54 mmol). The resulting mixture was stirred at RT for 24 h, concentrated, redissolved in CH3OH, concentrated-dry loaded on silica gel and flash chromatographed (5-10% 5N NH3 in CH3OH/CH2Cl2) to provide 3E as a yellow oil (210 mg, 70%).

[0268] Step 3:

[0269] A solution of 3E (96 mg, 0.174 mmol) in 15 ml of 1 M HCl in 25% CH3OH/dioxane was stirred at RT for 48 h. The mixture was concentrated, exposed to high vacuum, redissolved in CH3OH, concentrated-dry loaded on silica gel and flash chromatographed (10-15% 5N NH3 in CH3OH/CH2Cl2) to provide the title compound as a colorless oil (48 mg, 61%). MS: 453 (MH+)

EXAMPLE 4

[0270] 62

[0271] Method E

[0272] Step 1: 63

[0273] A mixture of neat 4A (1.75 g, 6.66 mmol) and 4B (2.93 g, 15.07 mmol) was stirred at 120° C. for 2 days, cooled to RT, treated with 1.0 M NaOH solution (30 ml), and extracted with EtOAc. The combined organic layers were washed with water and dried over 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%).

[0274] Step 2: 64

[0275] To a 500 ml pressure bottle was added 4C (490 mg, 1.18 mmol) in CH3OH (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%).

[0276] Step 3: 65

[0277] To a 50 ml round-bottomed flask were successively added 4D (287 mg, 0.88 mmol), Preparation 1 (300 mg, 0.88 mmol), EDCI hydrochloride (210 mg, 1.10 mmol), HOBT (149 mg, 1.10 mmol), and diisopropylethylamine (228 mg, 1.76 mmol). DMF (3 ml) and CH2Cl2 (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 NaHCO3 solution, the resulting mixture was extracted with CH2Cl2. The combined organic solutions were dried over Na2SO4 and concentrated. Purification of the crude product by flash chromatography on silica gel with 10% CH3OH in CH2Cl2 as the eluent provided 4E as a solid (231 mg, 41%).

[0278] Step 4:

[0279] To a 25 ml round-bottomed flask was added 4E (200 mg, 0.31 mmol) in CH2Cl2 (2.5 ml). TFA was then introduced via a syringe. The resulting solution was stirred at RT for 15 h, diluted with CH2Cl2, 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% CH3OH in CH2Cl2 as the eluent to provide the title compound as a white solid (85 mg, 50%). MS: 544 (MH+).

EXAMPLE 5

[0280] 66

[0281] Step 1: 67

[0282] A solution of compound 5A (100 g, 0.389 mol) in THF (400 ml) was added dropwise over 1.0 h to a solution of LDA (233 mL, 2.0 M in THF/heptane/ethyl-benzene, 0.466 mol) in THF (300 ml) at 0° C. The red-orange solution was stirred at 0° C. for 30 min, and then transferred by cannula to a pre-cooled (0° C.) solution of N-fluorobenzenesulfonimide (153 g, 0.485 mol) in dry THF (600 ml). The reaction mixture was stirred at 0° C. for 30 min, and then at 20° C. for 18 h. The total solvent volume was reduced to approximately one third, and EtOAc (1 l) was added. The solution was washed successively with water, 0.1 N aq. HCl, saturated aq. NaHCO3, and brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to yield a crude liquid. Separation by flash chromatography (6:1 hexanes-EtOAc) gave compound 5B (93.5 g, 87%).

[0283] Step 2: 68

[0284] A solution of 5B (50 g, 0.181 mol) in THF (300 ml) and CH3OH (200 ml) was treated with a solution of LiOH—H2O (9.2 g, 0.218 mol) in water (100 ml) and then heated to 45° C. for 6 h. The mixture was then concentrated and dried in vacuo to provide 5C (45 g, 100%).

[0285] Step 3: 69

[0286] Compound 5C (20.4 g, 0.081 mol) was added slowly to a stirred flask of CH2Cl2 (250 ml) at 20° C. The resulting white slurry was cooled to 0° C. and treated slowly with oxalyl chloride (6.7 ml, 0.075 mol) and a drop of DMF. After stirring at 20° C. for 0.5 h, the mixture was concentrated and dried in vacuo to provide 5D.

[0287] Step 4A: 70

[0288] 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 ml) was heated at reflux overnight. The reaction mixture was diluted with CH2Cl2, washed three times with 5% aqueous NaOH, dried over Na2SO4, and concentrated. Recrystallization with MeOH provided e (121 g, ˜100%) as a yellow solid. 71

[0289] 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 CH3OH). The filtrate was concentrated and dried in vacuo to provide f (109 g, ˜100%) as a dark brown solid. 72

[0290] A solution of f (109 g, 0.41 mol) in CH2Cl2-DMF (1:1, 500 ml) was treated with picolinic acid (61 g, 0.50 mol), EDCI (119 g, 0.62 mol), HOBt (84 g, 0.62 mol) and 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%).

[0291] A solution of g (131 g, 0.36 mol) in AcOH (200 ml) was heated at 120° C. overnight. The reaction mixture was cooled, carefully basified with 5% aqueous NaOH and extracted with CH2Cl2. 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. 73

[0292] A solution of h (95 g, 0.27 mol) in anhydrous CHCl3 (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 CH2Cl2. The combined organic extracts were dried over Na2SO4 and concentrated. Flash chromatography (2N NH3—CH3OH/EtOAc) provided 5E (43 g, 57%) as a pale yellow solid.

[0293] Step 4B: 74

[0294] A mixture of 5D (0.075 mol) in CH2Cl2 (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 CH3OH (200 ml)/CH2Cl2 (200 ml)/H2O (1 ml) for 1 h at 20° C. The solvent was then evaporated. Treatment with TFA (200 ml) in CH2Cl2 (250 ml) at 20° C. followed by flash chromatography (0-7% 7N NH3—CH3OH/CH2Cl2) provided 5F (80-90% from 5C).

[0295] Step 5:

[0296] Method A: 75

[0297] A solution of 5F (0.41 g, 1.0 mmol) in CH2Cl2 (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 CH2Cl2. The organic layer was dried with Na2SO4 and concentrated. Flash chromatography (0-5% 7N NH3—CH3OH/CH2Cl2) provided the title compound (0.45 g, 87%). MS: 516 (M+H).

[0298] Method B: 76

[0299] A solution of 5G (50 g, 0.41 mol) in CH3OH (300 ml) was cooled to 0° C. and carefully treated with NaBH4 (20 g, 0.53 mol in 6 batches) over 20 min. The reaction was then allowed to warm to 20° C. and was stirred for 4 h. The mixture was again cooled to 0° C., carefully quenched with saturated aqueous NH4Cl, and concentrated. Flash chromatography (5-10% 7N NH3—CH3OH/CH2Cl2) provided 5H (31 g, 62%) as a light yellow solid.

[0300] A slurry of 5H (31 g, 0.25 mol) in CH2Cl2 (500 ml) was cooled to 0° C. and slowly treated with SOCl2 (55 ml, 0.74 mol over 30 min). The reaction was then stirred overnight at 20° C. The material was concentrated, slurried in acetone, and then filtered. The resulting beige solid 5I was dried overnight in vacuo (38.4 g, 52%, HCl salt).

[0301] A homogeneous solution of 5F (16.4 g, 40 mmol) in anhydrous DMF (200 ml) was cooled to 0° C., carefully treated with NaH (8 g, 200 mmol), and stirred at 20° C. for 20 min. The reaction mixture was then cooled to 0° C., treated with NaI (6 g, 40 mmol) and 5I (14.5 g, 80 mmol), and then stirred overnight at 20° C. The reaction was diluted with CH2Cl2 (500 ml), washed with 1N aqueous NaOH, washed with brine, filtered through Celite, and concentrated. Flash chromatography (0-4% 7N NH3—CH3OH/CH2Cl2) provided Ex. 5 (16.9 g, 82%) as a beige solid.

EXAMPLE 6

[0302] 77

[0303] Step 1: 78

[0304] To a stirred solution of diamine 1B (1.0 g, 3.55 mmol) in C2H5OH (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 (2×10 ml). Combined extracts were washed with brine (5 ml) and filtered through anhydrous MgSO4. The filtrate was stripped in vacuo to obtain compound 6A as brown powder (1.03 g; 94%) sufficiently pure for use without purification. FABMS: 307 (MH+; 100%).

[0305] Step 2. 79

[0306] In a dry flask, under an inert atmosphere, a mixture of compound 6A (369 mg; 1.20 mmol) and CH2Cl2 (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 CH3OH were added to the reaction solution, and solvent was removed under vacuum. The residual solid was dissolved in boiling Et2O (˜30 ml). Insoluble matter was filtered, and the filtrate was diluted to a volume of ˜60 ml with hot hexanes. The solution was concentrated on a steam bath to a volume of ˜30 ml, by which point precipitation had begun. The mixture was allowed to stand at RT for ˜3 h. Filtration and washing with Et2O-hexanes (1 :1 v/v) yielded compound 6B as a reddish-brown powder (394 mg; 74%). FABMS: 444 (MH+; 100%). Although TLC and NMR indicated the presence of minor impurities, the product was sufficiently pure for use in Step 3 below.

[0307] Step 3: 80

[0308] To a stirred suspension of compound 6B (333 mg; 0.751 mmol) in CHCl3 (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 CH3OH (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) CH3OH-EtOAc to obtain the hydriodide salt form of 6C as a pale reddish-brown powder (356 mg) wich was used in the next step without further purification. FABMS: 372 (MH+; 100%).

[0309] Step 4: 81

[0310] To a stirred suspension of 6C (340 mg; 0.681 mmol), Prep. 1 (228 mg; 0.681 mmol), HOBT (9.2 mg; 0.0681 mmol) and 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 (2×5 ml). Combined extracts were washed with brine (2.5 ml) and filtered through anhydrous MgSO4. The filtrate was evaporated under vacuum, and the residue was purified by flash chromatography on silica gel, eluting with a gradient of CH2Cl2—CH3OH—NH4OH (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%).

[0311] Step 5:

[0312] To a solution of 6D (208 mg; 0.302 mmol) in CH2Cl2 (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 ml) plus sufficient water to produce two clear phases. The aqueous phase was extracted with EtOAc (3×5 ml). Combined extracts were washed with brine (3 ml) and filtered through anhydrous MgSO4. The filtrate was stripped of solvent in vacuo, and the residue was subjected to flash chromatography on silica gel, eluting with CH2Cl2—CH3OH—NH4OH (97:3:0.5). The title compound (130 mg; 72%) was obtained as pale yellow powder. FABMS: 589 (MH+; ˜64%); 478 (100%).

[0313] Using procedures similar to those described above, employing the appropriate starting materials, compounds in the following tables are prepared:

82
							Physical
							Data
No.	R	R25	R3	R13	Z	R6	MS (MH+)
7	—CH3	5-OCH3	H	H	—CH2—	2-NH2	463
8	—CH3	6-Cl	H	H	—CH2—	2-NH2	467
9	—CH3	5-Cl	H	H	—CH2—	2-NH2	467
10	—CH3	5-Br	H	H	—CH2—	2-NH2	512
11	83	5-Cl	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	—CH2NHSO2CH3	H	H	H	—CH2—	2-NH2	526
16	—CH2NHC(O)CH3	5-Cl	H	H	—CH2—	2-NH2	524
17	—CH2OCH3	5-F	H	H	—CH2—	2-NH2	481
18	—CH2NH2	5-Cl	H	H	—CH2—	2-NH2	482
19	—CH2OCH3	6,7-di-F	H	H	—CH2—	2-NH2	499
20	84	6-F	H	H	—CH2—	2-NH2	521
21	85	5-F	H	H	—CH2—	2-NH2	521
22	86	6-F	H	H	—CH2—	2-NH2	507
23	87	5-F	H	H	—CH2—	2-NH2	520
24	88	5-F	H	H	—CH2—	2-NH2	521
25	89	5-Br	H	H	—CH2—	2-NH2	568
26	90	5-F	H	H	—CH2—	2-NH2	507
27	91	5-F	H	H	—CH2—	2-NH2	507
28	92	H	H	H	—CH2—	2-NH2	531
29	93	5-F	H	H	—CH2—	2-NH2	549
30	94	6-F	H	H	—CH2—	2-NH2	531
31	95	6,7-di-F	H	H	—CH2—	2-NH2	567
32	96	6-Cl	H	H	—CH2—	2-NH2	547
33	97	5-F	H	H	—CH2—	2-NH2	531
34	98	5-Cl	H	H	—CH2—	2-NH2	565
35	99	H	H	H	—CH2—	2-NH2	531
36	100	5-Cl	H	H	—CH2—	2-NH2	547
37	101	5-Cl	H	H	—CH2—	2-NH2	529
38	102	6-F	H	H	—CH2—	2-NH2	557
39	103	5-Br	H	H	—CH2—	2-NH2	592
40	104	5-Br	H	H	—CH2—	2-NH2	610
41	105	5-F	H	H	—CH2—	2-NH2	547
42	106	5-F	H	H	—CH2—	2-NH2	529
43	107	6-F	H	H	—CH2—	2-NH2	553
44	108	6-F	H	H	—CH2—	2-NH2	564
45	109	H	H	H	—CH2—	2-NH2	529
46	110	5-F	H	H	—CH2—	2-NH2	581
47	111	5-Cl	H	H	—CH2—	2-NH2	563
48	112	6-Cl	H	H	—CH2—	2-NH2	563
49	113	5-F	H	H	—CH2—	2-NH2	543
50	114	5-F	H	H	—CH2—	2-NH2	581
51	115	5-Cl	H	H	—CH2—	2-NH2	597
52	116	5-F	H	H	—CH2—	2-NH2	597
53	117	5-Br	H	H	—CH2—	2-NH2	604
54	118	6-Cl	H	H	—CH2—	2-NH2	597
55	119	5-CH3	H	H	—CH2—	2-NH2	571
56	120	5-Cl	H	H	—CH2—	2-NH2	665
57	121	5-Br	H	H	—CH2—	2-NH2	710
58	122	6-ethoxy	H	H	—CH2—	2-NH2	540
59	123	5-Cl	H	H	—CH2—	2-NH2	546
60	124	H	H	H	—CH2—	2-NH2	511
61	125	5-F	H	H	—CH2—	H	499
62	126	6-Cl	H	H	—CH2—	2-NH2	530
63	127	5-F	H	H	—CH2—	2-NH2	515
64	128	6-F	H	H	—CH2—	2-NH2	514
65	129	6-F	H	H	—CH2—	2-NH2	515
66	130	7-Cl	H	H	—CH2—	2-NH2	531
67	131	H	H	H	—CH2—	2-NH2	496
68	132	5-F	H	H	—CH2—	2-NH2	515
69	133	5-Cl	H	H	—CH2—	2-NH2	531
70	134	5-Cl	H	H	—CH2—	2-NH2	531
71	135	5,6-di-F	H	H	—CH2—	2-NH2	532
72	136	5-Br	H	H	—CH2—	2-NH2	575
73	137	6-ethoxy	H	H	—CH2—	2-NH2	541
74	138	5-F	H	H	—CH2—	2-NH2	528
75	139	6-F	H	H	—CH2—	2-NH2	515
76	140	5-Br	H	H	—CH2—	2-NH2	591
77	141	5-Cl	H	H	—CH2—	2-NH2	530
78	142	5-Cl	H	H	—CH2—	2-NH2	530
79	143	5-F	H	H	—CH2—	2-NH2	548
80	144	5-CF3	H	H	—CH2—	2-NH2	565
81	145	H	H	H	—CH2—	2-NH2	497
82	146	6,7-di-F	H	H	—CH2—	2-NH2	567
83	147	6,7-di-F	H	H	—CH2—	2-NH2	532
84	148	5-F	H	H	—CH2—	2-NH2	530
85	149	5-CF3, 7-F	H	H	—CH2—	2-NH2	617
86	150	5-F	H	H	—CH2—	2-NH2	529
87	151	H	H	H	—CH2—	2-NH2	500
88	152	H	H	H	—CH2—	2-NH2	485
89	153	H	H	H	—CH2—	2-NH2	489
90	154	6-F	H	H	—CH2—	2-NH2	514
91	155	6-F	H	H	—CH2—	2-NH2	503
92	156	5-F	H	H	—CH2—	2-NH2	503
93	157	H	H	H	—CH2—	2-NH2	501
94	158	5-F	H	H	—CH2—	2-NH2	518
95	159	5-Cl	H	H	—CH2—	2-NH2	534
96	160	5-F	H	H	—CH2—	2-NH2	519
97	161	6,7-di-F	H	H	—CH2—	2-NH2	536
98	162	5-Br	H	H	—CH2—	2-NH2	579
99	163	6-ethoxy	H	H	—CH2—	2-NH2	544
100	164	5-F	H	H	—CH2—	2-NH2	503
101	165	5-Br	H	H	—CH2—	2-NH2	563
102	166	5-F	H	H	—CH2—	2-NH2	502
103	167	5-CF3	H	H	—CH2—	2-NH2	568
104	168	5-CF3, 7-F	H	H	—CH2—	2-NH2	586
105	169	5-F	H	H	—CH2—	2-NH2	598
106	170	5-F	H	H	—CH2—	2-NH2	517
107	171	5-F	H	H	—CH2—	2-NH2	573
108	172	5-F	H	H	—CH2—	2-NH2	517
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—SO2—	5-F	H	H	—CH2—	2-NH2	515
112	173	5-F	H	H	—CH2—	2-NH2	545
113	174	5-F	H	H	—CH2—	2-NH2	511
114	175	5-F	H	H	—CH2—	2-NH2	551
115	176	5-F	H	H	—CH2—	2-NH2	540
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	177	5-F	H	H	—CH2—	2-NH2	529
120	178	5-F	H	H	—CH2—	2-NH2	522
121	179	5-F	H	H	—CH2—	2-NH2	599
123	180	5-F	H	H	—CH2—	2-NH2	528
124	181	5-F	H	H	—CH2—	2-NH2	564
125	182	5-F	H	H	—CH2—	2-NH2	578
126	183	5-F	H	H	—CH2—	2-NH2	624
127	184	5-F	H	H	—CH2—	2-NH2	546
128	185	5-F	H	H	—CH2—	2-NH2	653
129	CH3—O—(CH2)2—NH—	5-F	H	H	—CH2—	2-NH2	510
130	186	5-F	H	H	—CH2—	2-NH2	563
131	187	5-F	H	H	—CH2—	2-NH2	480
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—O—(CH2)2O—	5-F	H	H	—CH2—	2-NH2	511
135	(CH3)2—CH—O—	5-F	H	H	—CH2—	2-NH2	495
136	188	5-F	H	H	—CH2—	2-NH2	529
137	189	H	H	H	—CH2—	2-NH2	511
138	190	5-CF3, 7-F	H	H	—CH2—	2-NH2	582
139	191	5-F	H	H	192	2-NH2	528
140	193	5-F	F	F	—CH2—	2-NH2	532
141	194	5-F	OH	H	—CH2—	2-NH2	530
142	195	5-F	H	H	196	2-NH2	529
143	197	5-F	H	H	198	2-NH2	529
144	199	5-F	—CH3	H	—CH2—	2-NH2	528
145	200	6-F	H	H	201	2-NH2	528
146	H	5-F	H	H	—CH2—	2-NH2	437
147	202	5-F	H	H	—CH2—	2-NH2	531
148	203	5-F	H	H	—CH2—	2-NH2	531
149	204	5-F	H	H	—CH2—	2-NH2	585
150	205	5-F	H	H	—CH2—	2-NH2	549
151	206	5-F	H	H	—CH2—	2-NH2	571
152	207	H	F	H	—CH2—	2-NH2	514
153	(CH3)2N—(CH2)2—NH—	5-F	H	H	—CH2—	2-NH2	523
154	CH3—S—	5-F	H	H	208	2-NH2	497
155	209	5-F	H	2- CH3	—CH2—	2-NH2	528
156	210	5-F	H	H	—CH2—	2-NH2	514
157	211	5-F	H	H	—CH2—	3-NH2	514
158	212	5-F	H	H	—CH2—	2-NH2	589
159	213	5-F	H	H	—CH2—	2-NH2	520
160	CH3CH2O—	5-F	F	H	—CH2—	2-NH2	499
161	214	5-F	H	H	—CH2—	2-NH2	537
162	215	5-F	H	H	—CH2—	2-NH2	535
163	216	5-F	H	5-OH	—CH2—	2-NH2	530
164	217	5-F	F	H	—CH2—	3-NH2	532
165	218	5-F	F	H	—CH2—	2-NH2	540
166	219	5-F	H	H	—CH2—	3-NH2	515
220
						Physical
						Data
	No.	R	R3	Z	R6	MS (MH+)
	167	221	H	—CH2—	2-NH2	502
	168	—CH2OCH3	H	—CH2—	2-NH2	464
	169	222	H	—CH2—	2-NH2	504
	170	223	H	—CH2—	2-NH2	460
	171	(CH3)2—CH—	H	—CH2—	2-NH2	462
	172	224	H	—CH2—	2-NH2	477
	173	225	H	—CH2—	2-NH2	514
	174	226	H	—CH2—	2-NH2	532
	175	227	H	—CH2—	2-NH2	530
	176	228	H	—CH2—	2-NH2	532
	177	229	H	—CH2—	2-NH2	540
	178	230	H	—CH2—	2-NH2	564
	179	231	H	—CH2—	2-NH2	526
	180	232	H	—CH2—	2-NH2	558
	181	233	H	—CH2—	2-NH2	497
	182	234	H	—CH2—	2-NH2	512
	183	235	H	—CH2—	2-NH2	531
	184	236	H	—CH2—	2-NH2	498
	185	237	H	—CH2—	2-NH2	497
	186	238	H	—CH2—	2-NH2	511
	187	239	H	—CH2—	2-NH2	501
	188	240	H	—CH2—	2-NH2	486
	189	241	H	—CH2—	2-NH2	486
	190	242	H	—CH2—	2-NH2	501
	191	243	H	—CH2—	2-NH2	536
	192	244	H	—CH2—	2-NH2	547
	193	245	H	—CH2—	2-NH2	547
	194	246	H	—CH2—	2-NH2	543
	195	247	H	—CH2—	2-NH2	581
	196	248	F	—CH2—	2-NH2	519
	197	249	H	250	2-NH2	515
	198	251	OH	—CH2—	2-NH2	517
	199	252	253	—CH2—	2-NH2	577
	200	254	F	—CH2—	2-NH2	515
	201	255	F	—CH2—	2-NH2	504
	202	256	H	—CH2—	3-NH2	497
	203	257	H	—CH2—	3-NH2	532
	204	258	F	—CH2—	3-NH2	515
	205	259	F	—CH2—	3-NH2	550
260
			Physical
			Data
	No.	R	MS (MH+)
	206	—CH3	434
	207	261	497
	208	262	514
	209	263	530
264
						Physical
						Data
No.	R	R25	A	R3	R2	MS (MH+)
210	265	5-Cl	C	H	266	532
211	267	5-F	C	H	268	515
212	269	5-Cl	C	H	270	532
213	271	5-F	C	H	272	516
214	273	H	N	H	274	503
215	275	H	N	H	276	503
216	(CH3)2CH—	H	N	H	277	463
217	278	5-F	C	H	279	550
218	280	5-F	C	H	281	515
219	282	5-Cl	C	H	283	532
220	284	6-Cl	C	H	285	548
221	286	5-F	C	H	287	516
222	288	6-Cl	C	H	289	600
223	290	5-Cl	C	H	291	532
224	292	6-F	C	H	293	515
225	294	H	N	H	295	499
226	296	H	N	H	297	502
227	298	H	N	H	299	487
228	300	H	N	H	301	548
229	302	H	N	H	303	548
230	304	H	N	H	305	499
231	306	H	N	H	307	502
232	308	H	N	H	309	537
233	310	H	N	H	311	548
234	312	H	N	H	313	541
235	314	H	N	H	315	559
236	316	N	C	H	317	498
237	318	5-F	C	F	319	533
238	320	5-F	C	H	321	550
239	322	5-F	C	H	323	550
240	324	5-F	C	H	325	515
241	326	5-F	C	H	327	516
242	328	H	C	H	329	497
243	(CH3)2N—CH2—	H	N	H	330	478
244	331	5-F	C	H	332	519
245	333	H	C	H	334	501
246	335	5,6-di-F	C	H	336	537
247	337	5-F	C	H	338	500
248	339	5,6-di-F	C	H	340	534
249	341	5-F	C	F	342	537
250	343	5-F	C	F	344	534
251	345	5-F	C	F	346	534
252	347	5-F	C	F	348	533
253	349	5-F	C	F	350	568
254	351	5-F	C	F	352	568
255	353	H	N	H	354	487
256	355	H	C	F	356	515
257	357	H	C	F	358	519
258	359	H	N	F	360	516
259	361	H	N	H	362	505
260	363	H	N	F	364	516
261	365	H	N	F	366	520
262	367	5-F	C	H	368	504
263	369	5-F	C	H	370	522
264	371	5-F	C	H	372	504
265	373	H	N	H	374	537
266	(CH3)2N—CH2—	H	N	F	375	496
267	376	H	N	F	377	505
268	CH3CH2—O—	5-F	C	H	378	482
269	CH3—S—	5-F	C	H	379	484
270	CH3CH2—O—	5-F	C	F	380	500
271	381	H	N	F	382	555
272	383	H	N	F	384	566
273	385	H	N	H	386	498
274	387	5,6-di-F	C	F	388	551
275	389	5-F	C	F	390	541
276	391	5-F	C	H	392	523
277	393	5-F	C	H	394	514
278	395	5-F	C	H	396	539
279	397	H	N	H	398	515
280	399	H	N	H	400	501
281	401	H	N	F	402	505
282	403	H	N	H	404	536
283	405	H	N	F	406	523
284	407	5-F	C	F	408	532
285	409	H	N	H	410	501
286	411	H	N	H	412	533
287	413	H	N	F	414	517
288	415	H	N	H	416	548
289	417	H	N	H	418	533
290	CH3S—	5-F	C	F	419	502
291	420	H	N	F	421	515
292	422	5-F	C	F	423	532
293	424	5-F	C	H	425	514
294	426	H	N	H	427	497
295	(CH3)2N—	5-F	C	F	428	499
296	CH3CH2—S—	5-F	C	F	429	516
297	CH3—O—	5-F	C	F	430	486
298	431	H	N	H	432	512
299	433	H	N	F	434	530
300	435	5-F	C	F	436	547
301	437	5-F	C	H	438	529
302	439	5-F	C	H	440	517
303	441	5-F	C	F	442	535
304	443	H	N	H	444	551
305	445	H	N	F	446	551
306	447	5-F	C	H	448	500
307	449	5-F	C	H	450	500
308	451	5-F	C	F	452	547
309	(CH3CH2)2N—	5-F	C	F	453	527
310	454	H	N	H	455	498
311	456	H	N	F	457	516
312	458	5-F	C	H	459	515
313	460	5-F	C	F	461	533
314	462	5-F	C	F	463	569
315	CH3—S—	H	N	F	464	485
316	CH3CH2—O—	H	N	F	465	483
317	466	H	N	F	467	566
318	468	H	N	F	469	489
319	470	H	N	F	471	489
320	472	H	N	F	473	505
321	474	H	N	F	475	505
322	476	5-F	C	F	477	533
323	478	H	N	F	479	516
325	480	H	N	F	481	540
325	482	H	N	F	483	524
326	(CH3)2CH—O—	5-F	C	F	484	514
327	485	H	N	F	486	506
328	487	H	N	F	488	488
329	489	H	N	F	490	489
330	491	H	N	F	492	507
331	493	H	N	F	494	551
332	495	H	N	F	496	506
333	497	H	N	F	498	518
334	499	H	N	F	500	504
335	CH3—O—	H	N	F	501	464
336	502	H	N	F	503	491
337	504	H	N	F	505	563
338	506	5-F	C	H	507	545
339	508	5-F	C	F	509	533
340	510	H	N	F	511	518
341	512	5-F	C	H	513	535
342	514	H	N	F	515	520
343	516	6-Cl	C	H	517	548
345	518	H	N	H	519	503
346	(CH3)2—CH—	H	N	H	520	463
521
				Physical
				Data
	No.	R3	R2	MS (MH+)
	347	H	522	489
	348	F	523	506
	349	F	524	488
	350	F	525	507
	351	F	526	506
527
					Physical
					Data
No.	R1—X—	Z	R3	R2	MS (MH+)
352	528	—CH2—	H	529	509
353	530	—CH2—	H	531	510
354	532	—CH2—	H	533	523
355	534	—CH2—	H	535	532
356	536	—CH2—	H	537	496
357	538	—CH2—	H	539	506
358	540	—CH2—	H	541	542
359	542	—CH2—	H	543	451
360	544	—CH2—	H	545	537
361	546	—CH2—	H	547	495
362	548	—CH2—	H	549	501
363	550	—CH2—	H	551	510
364	552	—CH2—	H	553	533
365	554	—CH2—	H	555	420
366	556	—CH2—	H	557	449
367	558	—CH2—	H	559	497
368	560	—CH2—	H	561	533
369	562	—CH2—	H	563	487
370	564	—CH2—	H	565	509
371	566	—CH2—	H	567	433
372	568	—CH2—	H	569	504
373	570	—CH2—	H	571	436
374	572	—CH2—	H	573	472
375	574	—(CH2)3—	H	575	464
376	576	—CH2—	H	577	544
377	578	—CH2—	F	579	562
580
						Physical
						Data
	No.	R	M1	Y	R2	MS (MH+)
	378	581	CH	—CH2—	582	500
	379	583	N	—NH—	584	502
	380	585	N	—NH—	586	490
	381	587	N	—NH—	588	494
	382	589	N	—NH—	590	501
	383	591	N	—NH—	592	500
384:
593
385:
594
386:
595
387:
596

EXAMPLE 388

[0314] 597

[0315] Step 1: 598

[0316] A solution of P7-1 (2.3 g, 8.9 mmol) in CH2Cl2-DMF (1:1, 50 ml) was treated with picolinic acid N-oxide (1.5 g, 10.6 mmol), EDCI (2.6 g, 13.3 mmol) and HOBT (1.8 g, 13.3 mmol). The mixture was stirred at 70° C. overnight. The reaction mixture was concentrated, diluted with EtOAc, washed three times with 5% aqueous NaOH, dried over Na2SO4, and concentrated. Flash chromatography (50% EtOAc/hexane) provided 388A (2.5 g, 74%).

[0317] Step 2: 599

[0318] In a manner similar to that described in Preparation 5, Step 4, compound 388A was converted to compound 388B.

[0319] Step 3: 600

[0320] A solution of 388B (0.66 g, 2.2 mmol) in DMF (15 ml) was treated with 5C (0.62 g, 2.5 mmol), 1-propanephosphonic acid cyclic anhydride (3.3 ml, 11.2 mmol, 50 wt. % in EtOAc) and N-ethylmorpholine (1.4 ml, 10.7 mmol). The mixture was stirred at 50° C. for 3 h. The reaction mixture was concentrated and diluted with EtOAc. The solution was washed three times with 5% aqueous NaOH, dried over Na2SO4, concentrated and subjected to flash chromatography (10% 2N NH3—CH3OH/EtOAc). The material was then taken up in CH2Cl2 (20 ml) and treated with 4 M HCl-dioxane (4 ml). After stirring overnight at 20° C., the reaction was carefully basified with 10% aqueous NaOH and extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, concentrated and subjected to flash chromatography (30% 2N NH3—CH3OH/EtOAc) to provide 388C as a white solid (0.08 g, 10%).

[0321] Step 4:

[0322] In a manner similar to that described in Example 5, Step 5, compound 388C was converted to Example 388.

EXAMPLE 389

[0323] 601

[0324] Step 1: 602

[0325] To a stirred, cloudy solution of 389A (300 mg, 1.14 mmol) in THF (15 ml) were added a solution of 389B (292 mg, 1.37 mmol) in THF (1 ml), followed by NaBH(OAc)3 (483 mg, 2.28 mmol). After stirring at RT for 39 h, TLC revealed the presence of unchanged starting materials in the cloudy white reaction suspension. Therefore, another quantity of NaBH(OAc)3 (242 mg, 1.14 mmol) was added and stirring at RT continued for a total of 113 h. The reaction mixture was then filtered and collected solids washed thoroughly with CH2Cl2. 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 (3×15 ml). The combined extracts were washed with brine (5 ml) and dried over anhydrous MgSO4. Drying agent was removed by filtration, and the filtrate was concentrated under vacuum. The residue was purified by silica gel flash chromatography (EtOAc/hexanes32 1:1) to obtain 389C as a mixture of colorless gum and white foam (368 mg, 70%), homogeneous to TLC, which solidified upon standing. ES-MS: 461 (MH+; 100%).

[0326] Step 2: 603

[0327] To a stirred, ice-cold solution of 389C (358 mg, 0.777 ml) in CH2Cl2 (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 Et2O (35 ml) for 16 h. Filtration and washing with Et2O yielded the bis-trifluoroacetate salt of 389D as a white powder (449 mg, 98%).

[0328] Step 3:

[0329] To a stirred suspension of 389D (100 mg, 0.170 mmol) in CH2Cl2 (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 CH2Cl2. 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 (3×5 ml). The combined extracts were washed with brine (2 ml) and dried over anhydrous MgSO4. Drying agent was removed by filtration, and the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (silica gel; CH2Cl2/CH3OH/conc. NH4OH=90:9:1) to obtain the title compound as a light beige foam (36 mg, 45%). FABMS: 468 (MH+; 100%).

[0330] Using procedures similar to those described above in Examples 1-6 and 388-389, following compounds were prepared:

		Mass Spec
Ex.	Structure	(M + H)
390	604	533 (ESMS)
391	605	518 (ESMS)
392	606	535 (ESMS)
393	607	520 (ESMS)
394	608	592 (FAB)
395	609	670 (FAB)
396	610	528 (ESMS)
397	611	491 (ESMS)
398	612	470 (ESMS)
399	613	488 (ESMS)
400	614	487 (ESMS)
401	615	471 (ESMS)
402	616	487 (ESMS)
403	617	471 (ESMS)
404	618	489 (ESMS)
405	619	506 (ESMS)
406	620	505 (ESMS)
407	621	522 (ESMS)
408	622	522 (ESMS)
409	623	506 (ESMS)
410	624	523 (ESMS)
411	625	524 (ESMS)
412	626	501 (ESMS)
413	627	490 (ESMS)
414	628	473 (ESMS)
415	629	488 (ESMS)
416	630	487 (ESMS)
417	631	504 (ESMS)
418	632	504 (ESMS)
419	633	488 (ESMS)
420	634	505 (ESMS)
421	635	506 (ESMS)
422	636	526 (FAB)
423	637	518 (ESMS)
424	638	585 (FAB)
425	639	591 (ESMS)
426	640	499 (ESMS)
427	641	516 (ESMS)
428	642	546 (ESMS)
429	643	498 (ESMS)
430	644	514 (ESMS)
431	645	571 (ESMS)
432	646	589 (ESMS)
433	647	573 (ESMS)
434	648	591 (ESMS)
435	649	512 (ESMS)
436	650	530 (ESMS)
437	651	483 (ESMS)
438	652	484 (ESMS)
439	653	502 (ESMS)
440	654	499 (FAB)
441	655	471 (ESMS)
442	656	488 (ESMS)
443	657	506 (ESMS)
444	658	470 (ESMS)
445	659	488 (ESMS)
446	660	531 (ESMS)
447	661	497 (ESMS)
448	662	513 (ESMS)
449	663	548 (ESMS)
450	664	563 (ESMS)
451	665	514 (ESMS)
452	666	532 (ESMS)
453	667	502 (ESMS)
454	668	550 (ESMS)
455	669	520 (ESMS)
456	670	451 (ESMS)
457	671	545 (ESMS)
458	672	513 (ESMS)
459	673	514 (FAB)
460	674	496 (FAB)
461	675	442 (ESMS)
462	676	458 (ESMS)
463	677	503 (ESMS)
464	678	407 (ESMS)
465	679	534 (ESMS)
466	680	516 (ESMS)
467	681	514 (ESMS)
468	682	484 (ESMS)
469	683	458 (ESMS)
470	684	474 (ESMS)
471	685	467 (ESMA)
472	686	440 (ESMS)
473	687	465 (ESMS)
474	688	487 (ESMS)
475	689	472 (ESMS)
476	690	466 (ESMS)
477	691	505 (ESMS)
478	692	456 (ESMS)
479	693	456 (ESMS)
480	694	504 (ESMS)
481	695	514 (ESMS)
482	696	531 (FAB)
483	697	472 (ESMS)
484	698	438 (ESMS)
485	699	438 (ESMS)
486	700	454 (ESMS)
487	701	470 (ESMS)
488	702	502 (ESMS)
489	703	554 (FAB)
490	704	556 (FAB)
491	705	470 (ESMS)
492	706	487 (ESMS)
493	707	469 (ESMS)
44	708	555 (ESMS)
495	709	452 (ESMS)
496	710	487 (ESMS)
497	711	440 (ESMS)
498	712	424 (ESMS)
499	713	470 (ESMS)
500	714	486 (ESMS)
501	715	556 (ESMS)
502	716	500 (ESMS)
503	717	566 (ESMS)
504	718	577 (ESMS)
505	719	550 (ESMS)
506	720	506 (ESMS)
507	721	522 (ESMS)
508	722	533 (ESMS)
509	723	504 (ESMS)
510	724	520 (ESMS)
511	725	456 (ESMS)
512	726	467 (ESMS)
513	727	482 (ESMS)
514	728	482 (ESMS)
515	729	500 (ESMS)
516	730	500 (ESMS)
517	731	500 (ESMS)
518	732	482 (ESMS)
519	733	498 (ESMS)
520	734	481 (ESMS)
521	735	516 (ESMS)
522	736	512 (FAB)
523	737	495 (FAB)
524	738	499 (FAB)
525	739	499 (ESMS)
526	740	560 (ESMS)
527	741	499 (ESMS)
528	742	501 (ESMS)
529	743	483 (ESMS)
530	744	526 (ESMS)
531	745	509 (ESMS)
532	746	449 (ESMS)
533	747	500 (ESMS)
534	748	512 (ESMS)
535	749	495 (ESMS)
536	750	546 (ESMS)
537	751	530 (ESMS)
538	752	531 (ESMS)
539	753	545 (ESMS)
540	754	468 (ESMS)
541	755	540 (ESMS)
542	756	481 (ESMS)
543	757	482 (ESMS)
544	758	515 (ESMS)
545	759	517 (ESMS)
546	760	526 (ESMS)
547	761	5560 (ESMS)
548	762	526 (ESMS)
549	763	550 (ESMS)
550	764	517 (ESMS)
551	765	532 (ESMS)
552	766	464 (ESMS)
553	767	516 (ESMS)
554	768	486 (ESMS)
555	769	502 (ESMS)
556	770	526 (ESMS)
557	771	516 (ESMS)
558	772	487 (ESMS)
559	773	496 (ESMS)
560	774	481 (FAB)
561	775	534 (ESMS)
562	776	501 (ESMS)
563	777	517 (ESMS)
564	778	517 (ESMS)
565	779	517 (ESMS)
566	780	577 (ESMS)
567	781	592 (ESMS)
568	782	519 (ESMS)
569	783	552 (ESMS)
570	784	537 (ESMS)
571	785	453 (ESMS)
572	786	505 (ESMS)
573	787	504 (ESMS)
574	788	519 (ESMS)
575	789	533 (ESMS)
576	790	549 (ESMS)
577	791	548 (ESMS)
578	792	533 (ESMS)
579	793	566 (ESMS)
580	794	551 (ESMS)
581	795	559 (ESMS)
582	796	560 (ESMS)
583	797	592 (ESMS)
584	798	579 (ESMS)
585	799	466 (ESMS)
586	800	479 (FAB)
587	801	505 (ESMS)
588	802	480 (ESMS)
589	803	535 (ESMS)
590	804	536 (ESMS)
591	805	498 (ESMS)
592	806	483 (ESMS)
593	807	575 (ESMS)
594	808	550 (ESMS)
595	809	529 (ESMS)
596	810	517 (ESMS)
597	811	533 (ESMS)
598	812	466 (ESMS)
599	813	438 (ESMS)
600	814	421 (ESMS)
601	815	423 (ESMS)
602	816	406 (ESMS)
603	817	456 (ESMS)
604	818	441 (ESMS)
605	819	439 (ESMS)
606	820	516 (ESMS)
607	821	498 (ESMS)
608	822	525 (ESMS)
609	823	516 (ESMS)
610	824	501 (ESMS)
611	825	547 (ESMS)
612	826	531 (ESMS)
613	827	543 (ESMS)
614	828	558 (ESMS)
615	829	544 (ESMS)
616	830	452 (FAB)
617	831	424 (ESMS)
618	832	480 (ESMS)
619	833	465 (ESMS)
620	834	560 (ESMS)
621	835	511 (ESMS)
622	836	496 (ESMS)
623	837	510 (ESMS)
624	838	503 (ESMS)
625	839	518 (ESMS)
626	840	505 (ESMS)
627	841	498 (ESMS)
628	842	485 (ESMS)
629	843	481 (ESMS)
630	844	499 (ESMS)
631	845	499 (ESMS)
632	846	514 (ESMS)
633	847	517 (ESMS)
634	848	532 (ESMS)
635	849	488 (ESMS)
636	850	518 (ESMS)
637	851	451 (ESMS)
638	852	537 (MH+)
639	853	472 (MH+)
640	854	519 (MH+)
641	855	487 (MH+)
642	856	516 (MH+)
643	857	503 (MH+)
644	858	484 (ESMS)
645	859	503 (ESMS)
646	860	498 (ESMS)
647	861	516 (ESMS)
648	862	468 (ESMS)
649	863	486 (ESMS)
650	864	469 (ESMS)
651	865	487 (ESMS)
652	866	483 (ESMS)
653	867	501 (ESMS)
654	868	453 (ESMS)
655	869	471 (ESMS)
656	870	468 (ESMS)
657	871	450 (ESMS)
658	872	530 (ESMS)
659	873
660	874	453 (FAB)
661	875	470 (FAB)
662	876	455 (FAB)
663	877	497 (ESMS)
664	878	481 (FAB)
664A	879	499 (FAB)

EXAMPLE 665

[0331] 880

[0332] 4-[[4-[2-(5-methyl-3-isoxazolyl)-3H-imidazo[4,5-b]pyridine-3-yl]-1-(4-piperidinylcarbonyl)piperidine (0.99 g, 2.51 mmoles) and pyridazine 4-carboxaldehyde (0.35 g, 3.26 mmoles) were stirred at RT in dry CH2Cl2 (25 ml) containing activated 3 Å molecular sieves (6.5 g). After 5 h, triacetoxy borohydride (3.2 g, 15 mmoles) was added and the mixture was stirred for 70 h. The mixture was diluted with CH2Cl2 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:CH3OH(NH3) (75:20:5). Extraction of the bands with 13% CH3OH(NH3)/EtOAc gave a mixture of Example 665 and Example 496. Example 658: MS (M+H): 423.

[0333] In a similar manner, using 4-[[4-[2-(methylthio)-3H-imidazo[4,5-b]pyridine-3-yl]-1-(4-piperidinylcarbonyl)piperidine (0.88 gr.;2.44 mmoles), pyridazine 4-carboxaldehyde (0.34 g, 3.18 mmoles), and triacetoxy borohydride, a mixture of Example 666 and Example 495 was prepared: 881

EXAMPLE 666

MS (M+H): 388

[0334] General Procedure for H13Receptor Binding Assay

[0335] 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×g for 10 min. in order to remove clumps of tissue and debris. The resulting supernatants were then centrifuged at 50,000×g for 20 min. in order to sediment the membranes, which were next washed three times in homogenization buffer (50,000×g for 20 min. each). The membranes were frozen and stored at −70° C. until needed.

[0336] All compounds to be tested were dissolved in DMSO and then diluted into the binding buffer (50 mM Tris, pH 7.5) such that the final concentration was 2 μg/ml with 0.1% DMSO. Membranes were then added (400 μg of protein) to the reaction tubes. The reaction was started by the addition of 3 nM [3H]R-α-methyl histamine (8.8 Ci/mmol) or 3 nM [3H]Nα-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 Ki (nM).

[0337] General Procedure for rHu H3Binding Assay

[0338] [3H]N∝-methylhistamine (82 Ci/mmole) was obtained from Dupont NEN. Thioperamide was obtained from the Chemical Research Department, Schering-Plough Research Institute.

[0339] HEK-293 human embryonic kidney cells stably expressing the human histamine H3 receptor were cultured in Dulbecco's modified Eagle's medium/10% fetal calf serum/penicillin (100 U/ml)/streptomycin (100 μg/ml)/Geneticin (0.5 mg/ml) at 37° C. in a humidified 5% CO2 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×g, they were put into ten volumes of ice-cold buffer and disrupted with a Polytron (PTA 35/2 tip, 30 sec at setting 6). After subsequent low-speed centrifugation, supernatant was centrifuged ten min at 50,000×g. The high-speed pellet was resuspended in the original volume of buffer, a sample was taken for protein assay (bicinchoninic acid, Pierce) and the suspension was centrifuged again at 50,000×g. Membranes were resuspended at 1 mg of protein/ml of buffer and frozen at −80° C. until use.

[0340] Membrane (15 μg of protein) was incubated with 1.2 nM [3H]N∝-methyl-histamine, without or with inhibitor compounds, in a total volume of 200 μl of buffer. Nonspecific binding was determined in the presence of 10−5 M thioperamide. Assay mixtures were incubated for 30 min at 30° C. in polypropylene, 96-well, deep-well plates, then filtered through 0.3% polyethylenimine-soaked GF/B filters. These were washed three times with 1.2 ml of 4° C. buffer, dried in a microwave oven, impregnated with Meltilex wax scintillant and counted at 40% efficiency in a Betaplate scintillation counter (Wallac).

[0341] 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, Calif.). Ki values were determined from IC50 values according to the Cheng and Prusoff equation.

[0342] 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.

[0343] Representative compounds of the present invention tested according to the above procedures have the following Ki values:

	Receptor
Ex.	Source	K1
1	rHu	1
3	Guinea pig	13
5	rHu	9
13	Guinea Pig	27
54	Guinea Pig	30
71	Guinea Pig	1
94	Guinea Pig	1
109	rHu	1
120	Guinea Pig	0.3
165	rHu	2
170	Guinea Pig	0.5
173	Guinea Pig	0.4
195	Guinea Pig	10
211	Guinea Pig	7
254	Guinea Pig	13
269	rHu	4
270	rHu	4
281	rHu	4
290	rHu	3
290	rHu	3
297	rHu	4
297	rHu	4
315	rHu	5
316	rHu	5
316	rHu	5
326	rHu	2
335	rHu	12
388	rHu	30
423	rHu	5
442	rHu	1
449	rHu	1
459	rHu	4
460	rHu	4
468	rHu	10
493	rHu	1
502	rHu	7
512	rHu	2
547	rHu	14
552	rHu	4
557	rHu	19
571	rHu	2
574	rHu	2
577	rHu	44
588	rHu	6
592	rHu	9
595	rHu	41
598	rHu	17
608	rHu	1
618	rHu	9
619	rHu	2
625	rHu	10
628	rHu	4

[0344] In this specification, the term “at least one compound of formula I” means that one to three different compounds of formula I may be used in a pharmaceutical composition or method of treatment. Preferably one compound of formula I is used. Similarly, “at least one H1 receptor antagonist” means that one to three different H1 antagonists may be used in a pharmaceutical composition or method of treatment. Preferably, one H1 antagonist is used.

[0345] For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), The Science and Practice of Pharmacy, 20th Edition, (2000), Lippincott Williams & Wilkins, Baltimore, Md.

[0346] Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.

[0347] Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.

[0348] Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

[0349] The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.

[0350] Preferably the compound is administered orally.

[0351] Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.

[0352] The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 350 mg, preferably from about 1 mg to about 150 mg, more preferably from about 1 mg to about 50 mg, according to the particular application.

[0353] The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.

[0354] The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 300 mg/day, preferably 1 mg/day to 75 mg/day, in two to four divided doses.

[0355] When the invention comprises a combination of 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 H1 antagonist in a pharmaceutically acceptable carrier can be administered. The components of the combination can be administered individually or together in any conventional dosage form such as capsule, tablet, powder, cachet, suspension, solution, suppository, nasal spray, etc. The dosage of the H1 antagonist can be determined from published material, and may range from 1 to 1000 mg per dose.

[0356] When separate H3 and H1 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 pharmaceutically acceptable carrier, with the H3 and H1 antagonists being present in amounts such that the combination is therapeutically effective. A kit is advantageous for administering a combination when, for example, the components must be administered at different time intervals or when they are in different dosage forms.

[0357] While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.

Claims

1. A compound represented by the structural formula

2. A compound of claim 1 wherein M1 is N, a is 0, and n is 2, and the optional double bond is not present.

3. A compound of claim 2 wherein M2 is C(R3) wherein R3 is hydrogen or fluorine, b is 0, r is 1, and p is 2.

4. A compound of claim 3 wherein X is a bond.

5. A compound of claim 4 wherein Y is —C(O)—.

6. A compound of claim 5 wherein Z is straight or branched C1-C3 alkyl.

7. A compound of claim 6 wherein R is a six-membered heteroaryl ring, optionally substituted with one R6 substituent.

8. A compound of claim 7 wherein R2 is pyrimidy, R6-pyrimidyl, pyridyl, R6-pyridyl or pyridazinyl and R6 is —NH2.

9. A compound of claim 8 wherein R2 is

10. A compound of claim 2 wherein R1 is

11. A compound of claim 10 wherein R is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkoxy, (C1-C6)alkylthio, heteroaryl or R32-aryl; R25 is halogen or —CF3; and k and k1 are 0 or 1.

12. A compound of claim 11 wherein R is —CH3, —CH2CH3, —OCH3, —OCH2CH3, —OCH2CH2CH3, —OCH((CH3)2, —CH2CH3, —SCH3, —SCH2CH3, pyridyl, pyrimidyl, pyrazinyl, furanyl, oxazolyl or R32-phenyl.

13. A compound of claim 12 wherein R2 is

14. A compound of claim 1 selected from the group consisting of

15. A pharmaceutical composition comprising an effective amount of a compound of claim 1 and a pharmaceutically effective carrier.

16. A method of treating allergy, allergy-induced airway responses, congestion, hypotension, cardiovascular disease, diseases of the GI tract, hyper and hypo motility and acidic secretion of the gastro-intestinal tract, obesity, sleeping disorders, disturbances of the central nervous system, attention deficit hyperactivity disorder, hypo and hyperactivity of the central nervous system, Alzheimer's disease, schizophrenia, and migraine comprising administering to a patient in need of such treatment an effective amount of a compound of claim 1.

17. The method of claim 14 wherein allergy-induced airway responses are treated.

18. The method of claim 14 wherein allergy or nasal congestion is treated.

19. A pharmaceutical composition comprising an effective amount of a compound of claim 1, and an effective amount of H1 receptor antagonist, and a pharmaceutically effective carrier.

20. A method of treating allergy, allergy-induced airway responses, and congestion comprising administering to a patient in need of such treatment an effective amount of a compound of claim 1 in combination with an effective amount of an H1 receptor antagonist.

21. The method of claim 20 wherein said H1 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.

22. The method of claim 21 wherein said H1 receptor antagonist is selected from: loratadine, descarboethoxyloratadine, fexofenadine or cetirizine.

23. The method of claim 22 wherein said H1 receptor antagonist is selected from: loratadine or descarboethoxyloratadine.