Title of Invention	NOVEL NON-IMIDAZOLE COMPOUNDS
Abstract	Disclosed are novel compounds of the formula: (I) Also disclosed are pharmaceutical compositions comprising the compounds of Formula (I). Also disclosed are methods of treating various diseases or conditions, such as, for example, allergy, allergy-induced airway responses, and congestion (e.g., nasal congestion) using the compounds of Formula (I). Also disclosed are methods of treating various diseases or conditions, such as, for example, allergy, allergy-induced airway responses, and congestion (e.g., nasal congestion) using the compounds of Formula (I) in combination with a H1 receptor antagonist.

Title of Invention

NOVEL NON-IMIDAZOLE COMPOUNDS

Abstract

Disclosed are novel compounds of the formula: (I) Also disclosed are pharmaceutical compositions comprising the compounds of Formula (I). Also disclosed are methods of treating various diseases or conditions, such as, for example, allergy, allergy-induced airway responses, and congestion (e.g., nasal congestion) using the compounds of Formula (I). Also disclosed are methods of treating various diseases or conditions, such as, for example, allergy, allergy-induced airway responses, and congestion (e.g., nasal congestion) using the compounds of Formula (I) in combination with a H1 receptor antagonist.

Full Text	NOVEL NON-IMIDAZOLE COMPOUNDS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application Serial No.' 60/240901 filed October 17, 2000. BACKGROUND OF THE INVENTION WO 95/14007 published May 26, 1995 discloses H3 receptor antagonists of the imidazole type. WO99/24405 published May 20. 1999 discloses H3 receptor ligands of the imidazole type. US 5,869,479 issued February 9, 1999 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 In view of the art's interest in compounds which affect H3 receptors, novel compounds that are antagonists of H3 receptors would be a welcome contribution to the art. This invention provides just such a contribution. (a) aryl; (b) heteroaryl; (c) heterocycloalkyi (d) alkyl; (e) cycloalkyi; or (f) alkylaryl; wherein said R1 groups are optionally substituted with 1 to 4 substituents independently selected from: (1) halogen (e.g., Br, F, or CI, preferably F or CI); (2) hydroxyl (i.e., -OH); (3) lower alkoxy (e.g., C1 to C6 alkoxy, preferably C1 to C4 aikoxy, most preferably C1 to C2 alkoxy, more preferably methoxy); (4) -CF3; (5) CF3O-; (6) -NR^R^; (7) phenyl; (8) -NO2, (9) -C02R4 (10) -C0N(R4)2 wherein each R4 is the same or different; (11) -S(0)mN(R20)2 wherein each R20 is the same or different H or alkyl group, preferably C1 to C4 alkyl, most preferably C1-C2 alkyl, and more preferably methyl; (12)-CN;or (13) alkyl; or (4) M1 is carbon; (5) M2 is selected from C or N; (6) M3 and M4 are independently selected from C or N; (7) Y is selected from: is -CHr, =C(0), =C(NOR20) (wherein R20 is as defined above), or =C(S); (8) Z is a C1 - C6 alkyl group; (9) R2 is a five or six-membered heteroaryl ring, said six-membered heteroaryl ring comprising 1 or 2 nitrogen atoms with the remaining ring atoms being carbon, and said five-membered heteroaryl ring containing 1 or 2 heteroatoms selected from: nitrogen, oxygen, or sulfur with the remaining ring atoms being carbon; said five or six membered heteroaryl rings being optionally substituted with 1 to 3 substituents independently selected from: halogen, hydroxyl, lower alkyl, lower alkoxy, -CF3. CF3O-, -NR4R5 phenyl, -NO2, -C02R4 -C0N(R4)2 wherein each R4 is the same or different, -CHaNR4R5 -(N)C(NR4R5)2, or-CN; (10) R3 is selected from: (a) hydrogen; (b) C1 - C6 alkyl; (c) aryl; (d) heteroaryl; (e) heterocycloalkyl; (f) arylalkyi (e.g., aryl{C1to C4)alkyi, e.g., -(CH2)waryl wherein w is 1 to 4, preferably 1 or 2, and most preferably 1, such as, for example -CH2phenyl or -CH2Substituted phenyl); (g) -(CH2)e-C(0)N(R')2 wherein each R" is the same or different, (h) -(CH2)e-C(0)0R4 (i) -(CH2)e-C(0)R30 wherein R30 is a heterocycloalkyl group, such as, for example, morpholinyl, piperidinyl, piperazinyl or pyrrolidinyl, including This invention also provides a pharmaceutical composition comprising an effective amount of compound of Formula I, and a pharmaceutically acceptable carrier. This invention further provides a method of treating: allergy, allergy-induced airway (e.g., upper airway) responses, congestion (e.g., nasal congestion). hypotension, cardiovascular disease, diseases of the Gl 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 other CNS disorders (such as Alzheimer's, schizophrenia, and migraine) comprising administering to a patient in need of such treatment (e.g., a mamma!, such as a human being) an effective amount of a compound of Formula I. This invention further provides a method of treating: allergy comprising administering to a patient in need of such treatment (e.g.. a mammal, such as a human being) an effective amount of a compound of Formula L This invention further provides a method of treating: allergy-induced airway (e.g., upper airway) responses comprising administering to a patient in need of such treatment (e.g., a mammal, such as a human being) an effective amount of a compound of Formula I. This invention further provides a method of treating: 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 compound of Formula I. This invention further provides a pharmaceutical composition comprising an effective amount of a compound of Formula I, and an effective amount of a Hi receptor antagonist in combination v/ith a pharmaceutically acceptable carrier. This invention further provides a method of treating: allergy, allergy-Induced airway (e.g.. upper airway) responses, and 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 compound of Formula I in combination with an effective amount of an H1 receptor antagonist. This invention further provides a method of treating: allergy comprising administering to a patient in need of such treatment (e.g., a mammal, such as a human being) an effective amount of a compound of Formula I in combination with an effective amount of an Hi receptor antagonist. This invention further provides a method of treating: allergy-induced airv^ay (e.g., upper airway) responses comprising administering to a patient in need of such treatment (e.g., a mammal, such as a human being) an effective amount of a compound of Formula I in combination with an effective amount of an Hi receptor antagonist. This invention further provides a method of treating: 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 compound of Formula I in combination with an effective amount of an H1 receptor antagonist. DETAILED DESCRIPTION OF THE INVENTION As used herein, the following terms have the following meanings, unless indicated otherwise: alkyi-(including the alkyl portions of alkoxy and alkylaryl)-represents straight and branched carbon chains and contains from one to twenty carbon atoms, preferably one to six carbon atoms; alkyiaryl-represents an alkyl group, as defined above, bound to an aryi group, as defined below, wherein said aryl group is bound to the rest of the molecule; aryl (including the aryl portion of alkylaryl)-represents a carbocyclic group containing from 6 to 15 carbon atoms and having at least one aromatic ring (e.g., aryl is a phenyl ring), with all available substitutable carbon atoms of the carbocyclic group being intended as possible points of attachment; arylalkyl-represents an aryl group, as defined above, bound to an alkyl group, as defined above, wherein said alkyl group is bound to the rest of the molecule; cycloalkyl-represents saturated carbocyclic rings of from 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms; halo (halogen)-represents fluoro, chloro, bromo and iodo; heteroaryl-represents cyclic groups, having at least one heteroatom selected from O, S or N, said heteroatom intermpting 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, furazanyl, triazolyl, thiazolyl, 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 (benzopyn-olyl), pyridopyrazinyl, isoqinolinyi, J heterocycloalkyl-represents a saturated, carbocylic ring containing from 3 to 15 carbon atoms, preferably from 4 to 6 carbon atoms, which carbocyclic ring is internjpted by 1 to 3 hetero groups selected from -0-, -S- or - NR40- wherein R40 represents Ci to Ce alkyl, arylalkyl, -C(0)R4 -C{0)OR4 or .C(0)N(R45)2 (wherein R45 is as defined above, and each R45 is independently selected); 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-piperi2inyl, 2- or 4-dioxanyl. 1,3-dioxolanyl, 1,3,5-trithianyl, pentamethyiene sulfide, perhydroisoquinolinyl, decahydroquinolinyl. trimethylene oxide, azetidinyl, l-azacycioheptanyl, 1,3-dithianyI. 1,3,5-trioxanyl, morpholinyi, thiomorpholinyl. 1,4-thioxanyl, and 1,3,5-hexahydrotria2inyI, thiazolidinyl, tetrahydropyranyi; lower alkyl-represents an alkyl group, as defined above, that comprises 1 to 6 carbon atoms, preferably 1-4 carbon atoms; lower alkoxy-represents an alkoxy group whose alkyl moiety comprises 1 to 6 carbon atoms, preferably 1-4 carbon atoms; AcOH-represents acetic acid; t-BOC-representst-butyioxycarbonyl; Ci/mmol-represents curie/mmol (a measure of specific activity); m-CPBA-represents m-chioroperbenzoic acid; CSA-represents camphorsulfonic acid; CBZ-represents carbonylbenzyloxy (-C(0)OCH2C6H5); DBU-represents 1,8-diazabicyclo[5.4.0]undec-7-ene; DBN-represents 1,5-dia2abicyclo[4.3.0]non-5-ene; DCC-representsdicyclohexylcarbodiimide; Dibal-H-represents diisobutylaiuminum hydride; DIPEA-represents N,N-diisopropylethylamine; DMAP-represents 4-(d}methylamino)pyridine; DEC-represents 2-diethyIaminoethyl chloride hydrochloride; DMF-represents dimethylformamide; EDCI-represents 1-{3-dimethylaminopropyl)-3-ethylcarbodiimide; EtOAc-represents ethyl acetate; EtOH-represents ethanol; FMOC-represents9-fluorenylmethoxycarbonyl; HOBT-represents 1 -hydroxybenzotriazole; HPLC-represents high performance liquid chromatography; HRMS-represents high resolution mass spectrometry; Ki-represents inhibition constant for substrate/receptor complex; LAH-lithium aluminum hydride; LDA-represents lithium diisopropylamide; LRMS-represents low resolution mass spectrometry; MeOH-represents methanol; NaBH{0Ac)3-represents sodium triacetoxyborohydride; NaBH4-represents sodium borohydride; NaBH3CN-represents sodium cyanoborohydride; NaHMDS-represents sodium hexamethyl disilyiazide; nM-represents nanomolar; pA2-represents -logECso, as defined by J. Hey, Eur. J. Pharmacol., (1995), Vol. 294, 329-335; PCC-represents pyridinium chlorochromate; PyBOP-represents benzotriazole-1-yl-oxy-trispyrrolidino-phosphonium hexaflurophosphate; TEMPO-represents 2,2,6,6-etramethyl-1-piperidinyloxy. free radical; TFA-represents trifluoroacetic acid; TMAD-represents N,N,N',N'4etramethylazodicarboxamide; TMEDA-represents tetramethylethylenediamine; Tr-represents triphenylmethyl; Tris-representstris(hydroxymethyl)aminomethane;and p-TsOH-represents p-toluenesulfonic acid. pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated forms for purposes of the invention. The compounds of this invention can be combined with an Hi receptor antagonist (i.e., the compounds of this invention can be combined with an Hi receptor antagonist in a phannaceutical composition, or the compounds of this invention can be administered with H1 receptor antagonist). Numerous chemical substances are known to have histamine H1 receptor antagonist activity. Many useful compounds can be classified as ethanolamines, ethylenediamines, alkylamines, phenothiazines or piperidines. Representative Hi receptor antagonists include, without limitation: astemizole, azatadine, azelastine. acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyioratadine (also known as SCH-34117), diphenhydramine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine. meclizine, mizolastine. mequrtazine, mianserin, noberastine, norastemizole, picumast, pyrilamine, promethazine, terfenadine. tripelennamine, temelastine, trimeprazine and triprolidine. Other compounds can readily be evaluated to determine activity at Hi receptors by known methods, including specific blockade of the contractile response to histamine of isolated guinea pig ileum. See for example, WO98/06394 published Febnjary19,1998. Thus, in the methods of this invention wherein a compound of Formula I is combined with an effective amount of an H1 receptor antagonist, said H1 receptor antagonist is selected from: astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine. cyproheptadine, carbinoxamine, descarboethoxyioratadine. 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. Also, in the methods of this invention wherein a compound of Formula I is combined with an effective amount of an H1 '•eceptor antagonist, said H1 receptor antagonist is selected from: astemizole, azatadine, azelastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, carebastine, descarboethoxyioratadine. diphenhydramine, doxylamine, ebastine. fexofenadine, loratadine. levocabastine, mizolastine, norastemizole. or terfenadine. Also, in the methods of this invention1 receptor antagonist, said H1 receptor antagonist is selected from: azatadine, brompheniramine, cetirizine, chlorpheniramine, carebastine, descarboethoxyioratadine (also known as SCH-34117), diphenhydramine, ebastine, fexofenadine, loratadine, or norastemizole. Also, in the methods of this invention wherein a compound of Formula I is combined with an effective amount of an H1 receptor antagonist, said H1 receptor antagonist is loratadine. Also, in the methods of this invention wherein a compound of Fomiula I is combined with an effective amount of an H1 receptor antagonist, said H1 receptor antagonist is descarboethoxyioratadine. Also, in the methods of this invention wherein a compound of Formula I is combined with an effective amount of an H1 receptor antagonist, said H1 receptor antagonist is fexofenadine. Also, in the methods of this invention wherein a compound of Formula I is combined with an effective amount of an Hi receptor antagonist, said Hi receptor antagonist is cetirizine. Preferably, in the above methods, allergy-induced airway responses are treated. Also, preferably, in the above methods, allergy is treated. Also, preferably, in the above methods, nasal congestion is treated. Preferably, in the above methods using a combination of a compound of Formula I (H3 antagonist) and an H1 antagonist, the H1 antagonist is selected from: loratadine, descarboethoxyioratadine, fexofenadine or cetirizine. Most preferably the H1 antagonist is loratadine or descarboethoxyioratadine. In the methods of this invention wherein a combination of an H3 antagonist of this invention (compound of Formula I) is administered with a Hi antagonist, the antagonists can be administered simultaneously, consecutively (one after the other within a relatively short period of time), or sequentially (first one and then the other over a period of time). In general, when the antagonists are administered consecutively or sequentially, the H3 antagonist of this invention (compound of Fomiula I) is administered first. Thus, one emodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of Compound 32 and a pharmaceutically acceptable carrier. Another emodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of Compound 54 and a pharmaceutically acceptable carrier. Another emodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of Compound 55 and a pharmaceutically acceptable carrier Another emodiment of this Invention is directed to a phanmaceutical composition comprising an effective amount of Compound 253A and a pharmaceutically acceptable carrier, Another emodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of Compound 287 and a pharmaceutically acceptable carrier. Another emodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of Compound 320 and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced airway responses, congestion, hypotension, cardiovascular disease, hypotension, 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 hyperactivrty 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 Compound 32. Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced airway responses, congestion, hypotension, cardiovascular disease, hypotension, diseases of the Gl 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 amourt of Compound 54. Another embodiment of this invention is directed to a method of treating; allergy, allergy-induced airway responses, congestion, hypotension, cardiovascular disease, hypotension, diseases of the Gl 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 Compound 55. Another embodiment of this invention Is directed to a method of treating: allergy, allergy-induced airway responses, congestion, hypotension, cardiovascular disease, hypotension, diseases of the Gl 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 Compound 253A. Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced airway responses, congestion, hypotension, cardiovascular disease, hypotension, diseases of the Gl 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 Compound 287. Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced airway responses, congestion, hypotension, cardiovascular disease, hypotension, diseases of the Gl 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 mioraine comprising administering to a patient in need of such treatment an effective amount of Compound 320. Another embodiment of this invention is directed to a method of treating allergy-induced airway responses comprising administering to a patient in need of such treatment an effective amount of Compound 32. Another embodiment of this invention is directed to a method of treating allergy-induced airway responses comprising administering to a patient in need of such treatment an effective amount of Compound 54. Another embodiment of this invention is directed to a method of treating allergy-induced airway responses comprising administering to a patient in need of such treatment an effective amount of Compound 55. Another embodiment of this invention is directed to a method of treating allergy-induced airway responses comprising administering to a patient in need of such treatment an effective amount of Compound 253A. Another embodiment of this invention is directed to a method of treating allergy-induced airway responses comprising administering to a patient in need of such treatment an effective amount of Compound 287. Another embodiment of this invention is directed to a method of treating allergy-induced airway responses comprising administering to a patient in need of such treatment an effective amount of Compound 320. Another embodiment of this invention is directed to a method of treating allergy or nasal congestion comprising administering to a patient in need of such treatment an effective amount of Compound 32. Another embodiment of this invention is directed to a method of treating allergy or nasal congestion comprising administering to a patient in need of such treatment an effective amount of Compound 54. Another embodiment of this invention is directed to a method of treating allergy or nasal congestion comprising administering to a patient in need of such treatment an effective amount of Compound 55. Another embodiment of this invention is directed to a method of treating allergy or nasal congestion comprising administering to a patient in need of such treatment an effective amount of Compound 253A. Another embodiment of this invention is directed to a method of treating allergy or nasal congestion comprising administering to a patient in need of such treatment an effective amount of Compound 287. Another embodiment of this invention is directed to a method of treating allergy or nasal congestion comprising administering to a patient in need of such treatment an effective amount of Compound 320. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of Compound 32, and an effective amount of H1 receptor antagonist, and a pharmaceutically effective carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of Compound 54, and an effective amount of H1 receptor antagonist, and a pharmaceutically effective carrier.Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of Compound 55, and an effective amount of H1 receptor antagonist, and a pharmaceutically effective carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of Compound 253A, and an effective amount of H1 receptor antagonist, and a phanmaceutically effective carrier. Another embodiment of this invention is directed to a phanmaceutical composition comprising an effective amount of Compound 287, and an effective amount of H1 receptor antagonist, and a pharmaceuticaiiy effective canier.Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of Compound 320. and an effective amount of Hi receptor antagonist, and a pharmaceutically effective carrier. Another embodiment of this invention is directed to 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 Compound 32 in combination with an effective amount of an H1 receptor antagonist. Another embodiment of this invention is directed to 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 Compound 54 in combination with an effective amount of an H1 receptor antagonist. Another embodiment of this invention is directed to 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 55 in combination with an effective amount of an Hi receptor antagonist.Another embodiment of this invention is directed to 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 Compound 253A in combination with an effective amount of an Hi receptor antagonist. Another embodiment of this invention is directed to 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 Compound 287 in combination with an effective amount of an H1 receptor antagonist. Another embodiment of this invention is directed to 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 Compound 320 in combination with an effective amount of an H1 receptor antagonist. Another embodiment of this invention is directed to 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 Compound 32 in combination with an effective amount of an 1 receptor antagonist 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. Another embodiment of this invention is directed to 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 Compound 54 in combination with an effective amount of an H1 receptor antagonist 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, teri'enadine, tripelennamine, temeiastine, trimeprazine or triprolidine. Another embodiment of this invention is directed to 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 Compound 55 in combination with an effective amount of an H1 receptor antagonist selected from: astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarix)ethoxyloratadine, diphenhydramine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, meclizine, mizolastine, mequitazine, mianserin, noberastine, norastemizole, picumast, pyrilamine. promethazine, terfenadine, tripelennamine, temeiastine, trimeprazine or triprolidine. Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced ainway responses, and congestion comprising administering to a patient in need of such treatment an effective amount of Compound 253A in combination with an effective amount of an H1 receptor antagonist selected from: astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descari3oethoxyloratadine, diphenhydramine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, meclizine, mizolastine, mequitazine, mianserin, noberastine, norastemizole, picumast, pyrilamine, promethazine, terfenadine, tripelennamine, temeiastine, trimeprazine or triprolidine. Another embodiment of this invention is directed to 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 Compound 287 in combination with an effective amount of an H1 receptor antagonist selected from: astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine. cyproheptadine, carbinoxamine, descarboethoxyloratadine, diphenhydramine, doxylamine, dinnethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, fevocabastine, meclizine, mizolastine, mequitazine, mianserin, noberastine, norastemizole, picumast, pyriiamine, promethazine, terfenadine, tripeiennamine, temelastine, trimeprazine or triprolidine. Another embodiment of this invention is directed to 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 Compound 320 in combination with an effective amount of an H1 receptor antagonist selected from: astemizole, azatadlne, azelastine, acrivastine. brompheniramine, cetirizine, chlorpheniramine, clemastine, cyciizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine, diphenhydramine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotrfen, loratadine, levocabastine, meclizine, mizolastine, mequitazine, mianserin, noberastine, norastemizole, picumast, pyriiamine, promethazine, terfenadine, tripeiennamine, temelastine, trimeprazine or triprolidine. Another embodiment of this invention is directed to 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 Compound 32 in combination with an effective amount of an Hi receptor antagonist selected from: loratadine, descariboethoxyloratadine, fexofenadine or cetirizine. Another embodiment of this invention is directed to 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 Compound 54 in combination with an effective amount of an H1 receptor antagonist selected from: loratadine, descariboethoxyloratadine, fexofenadine or cetirizine. Another embodiment of this invention is directed to 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 Compound 55 in combination with an effective amount of an Hi receptor antagonist selected from: loratadine. descarboethoxyloratadine, fexofenadine or cetirizine. Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced ain-vay responses, and congestion comprising administering to a patient in need of such treatment an effective amount of Compound 253A in combination with an effective amount of an Hi receptor antagonist selected from: loratadine. descarboethoxyloratadine, fexofenadine orcetirizine. Another embodiment of this invention is directed to 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 Compound 287 in combination with an effective amount of an H1 receptor antagonist selected from: loratadine, descarboethoxyloratadine, fexofenadine orcetirizine. Another embodiment of this invention is directed to 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 Compound 320 in combination with an effective amount of an H1 receptor antagonist selected from: loratadine, descarboethoxyloratadine, fexofenadine or cetirizine. Another embodiment of this invention is directed to 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 Compound 32 in combination with an effective amount of an Hi receptor antagonist selected from; loratadine or descarboethoxyloratadine. Another embodiment of this invention is directed to 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 Compound 54 in combination with an effective amount of an H1 receptor antagonist selected from; loratadine or descarboethoxyloratadine. Another embodiment of this invention is directed to 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 Compound 55 in combination with an effective amount of an Hi receptor antagonist selected from; loratadine or descarboethoxyloratadine. Another embodiment of this invention is directed to 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 Compound 253A in combination with an effective amount of an H1 receptor antagonist selected from; loratadine or descarboethoxyloratadine. Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced ainway responses, and congestion comprising administering to a patient in need of such treatment an effective amount of Compound 287 in combination with an effective amount of an H1 receptor antagonist selected from: loratadine or descarboethoxyloratadine. Another embodiment of this invention is directed to 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 Compound 320 in combination with an effective amount of an Hi receptor antagonist selected from: loratadine or descarboethoxyloratadine. R' is preferably selected from: (A) aryl (most preferably phenyl); (B) substituted aryl (e.g., substituted phenyl), wherein the substituents on said substitued aryl are most preferably selected from: (1) halo (e.g., monohalo ordihaio), more preferably chloro orfluoro, even more preferably monochloro, dichloro. monofluoro or difluoro; or (2) alkyl, more preferably unbranched (i.e., straight chain, e.g., methyl) alkyl, even more preferably substituted alkyl, still more preferably alkyl substituted with halo (e.g., 1, 2 or 3 halo atoms, such as CI or F), even still more preferably alkyl substituted with fluoro atoms, yet still more preferably trifluromethyl; (C) heteroaryl, most preferably a five or six membered heteroaryl ring, more preferably a six membered heteroaryl ring, and still more preferably pyridyl, examples of heteroaryl rings include pyridyl, thienyl, pyrimidinyl, thiazolyl or pyridyl N-Oxide, most preferred heteroaryl rings are exemplified by wherein c is most preferably 0 or 1. and when c is 1 then R6 is most preferably halo, and when c is 1 then R6 is more preferably fluoro. X is preferably =C{NOR3) wherein R3 is preferably selected from H, alkyl or halo substituted alkyl (e.g-. fluoro substituted alkyl, such as -CH2CF3), most preferably alkyl, more preferably methyl or ethyl, and still more preferably methyl. Preferably M2 is nitrogen. n is preferably 2. a is preferably 0 or 1, and most preferably 0. b is preferably 0 or 1, and most preferably 0. c is preferably 0 or 1, and most preferably 0, and when c is 1 then R6 is preferably halo, and when c is 1 R^ is most preferably fluoro. eis preferably 1-5, Y is preferably =C(0) (i.e.. =C=0). M^ and M"^ are preferably selected such that: (1) one is carbon and the other is nitrogen, or (2) both are nitrogen, with M3 most preferably being carbon. R3is preferably H or alkyl, most preferably H or methyl. R4 is preferably H or lower alkyl, most preferably H or methyl, and more preferably H. R5 is preferably H, C1 to C6alkyI or-C{0)R4, most preferably H or methyl, and more preferably H. R12 is preferably alkyl, hydroxy! or fluoro, and most preferably H. R13 is preferably alkyl, hydroxyl or fluoro, and most preferably H. Representative compounds of this invention include, but are not limited to: Compounds 23, 30, 31, 32, 33, 41. 44,45,49, 50. 52, 53, 54, 55, 56, 57A, 59, 65, 75, 76, 80, 82, 83. 88, 92, 99, 104, 105,110. 111, 117,121. 123, 127, 128,200-241, 244-273, 275, and 278-282, 287, 296, 301-439 and 446. Thus, representative compounds of this invention include, but are not limited to: Compounds 23, 30. 31, 32, 33, 44, 45,49, 50. 53, 54, 55, 59, 75,76, 83, 88, 92, 99, 104, 110, 117, 128, 200, 201. 203-215, 217-241, 244-246, 246A, 247-263, 253A, 254-273, 275, 278, and 280-282, 317, 334 and 403. Preferred compounds of this invention are selected from: Compound 23, 30. 31, 32, 33, 50, 53. 54, 55, 56, 57A, 59, 92, 212, 215, 218. 219, 220, 224, 225, 225, 227, 229, 233, 235, 237, 238. 246. 246A, 247. 248, 251, 253. 253A. 268-273. 275. 278-281. 287. 296. 301. 304-307, 309. 312. 314-318. 320-356, or 358-376. Most preferred compounds of this invention are selected from: Compound 30, 31. 32. 33. 54. 55, 56, 57A, 225. 237. 246A, 253A. 273, 280. 287. 296, 301, 304-307, 309, 312. 314-318. 320-348. 350-356, 359-372, and 374-376. Thus, one embodiment of this invention is directed to Compound 32. Another embodiment of this invention is directed to Compound 54. Another embodiment of this invention is directed to Compound 55. Another embodiment of this invention is directed to Compound 253A. Another embodiment of this invention is directed to Compound 287. Another embodiment of this invention is directed to Compound 320. Structures for the above compounds are found in the Examples below, and in Tables 1 to 3 below. One synthetic route involves a linear sequence of reactions to obtain the desired compounds, i.e., A + B->AB + C-> ABC + D -> ABCD This linear sequence of reactions to synthesize compounds of this invention is illustrated below. In the illustrated procedure R1 is aryl, heteroaryi, or alkyl; X = a ketone, oxime or substituted oxime; M1 = M3 = carbon; M2 = M4 = nitrogen; Y is C=0; Z = CHR; R2 is heteroaryi; and n and m = 2 (n and m being 1 can also be prepared by this procedure). In the above equations PG represents a protecting group, and M represents Li or MgX1 (wherein X1 represents CI, Br or I). In equation 1 and 2, a Grignard reagent 2 is reacted with an electrophile such as the aldehyde 1 or the nitrile 4 in a suitable aprotic solvent such as THf;or ether. PG represents a protecting group. Suitable protecting groups include, for example, methyl and benzyl, in the case of nitrile 4, acidic workup yields the ketone 8 directly. Alcohol 3 can be oxidized by a number of different reagents to give 8, Altematively, the amide 7 can be reacted with an organometallic reagent to directly give the ketone 8. Suitable protecting groups for this step include carbamates or amides or the like. Thus, examples of protecting groups in equation 3 include t-BOC, CBZ and FMOC. CH2CI2 in the presence of molecular sieves. After the reaction is complete (e.g.,i to 10 h), a reducing agent such as NaBH(0Ac)3 is added. Alternatively, when E is a halogen atom such as CI or Br, 12 and 13 are combined in a solvent, such as DMF, in the presence of a tertiary amine base to give the product 14. Suitable protecting groups include, for example t-Boc, phthaloyl. M represents Li. Na, or K. Compound 17 is saponified in a mixed solvent, such as, for example: (1) EtOH or MeOH and water, or (2) THF, water, and MeOH. using an alkali metal base such as LiOH or NaOH at a temperature of from 50 to 100°C to give the salt 18. Compound 18 can be combined with compound 9. as described above, to give 14. The remaining steps are the same. Compounds useful in this invention are exemplified by the following examples which should not be construed as limiting the scope of the disclosure. Alternative mechanistic pathways and analogous structures within the scope of the invention may be apparent to those skilled in the art. To a solution of 19.15 g (85.5 mmol) of alcohol 2A in 640 ml of CH2CI2 was added saturated aqueous solution of 8.62 g (103 mmol) of NaHCO3 and 444 mg (4.3 mmol) of NaBr. Reaction mixture was cooled to 0°C, and 140 mg (0.90 mmol) of TEMPO was introduced. Upon vigorous stirring 122 ml of 0.7 M (85.4 mmol) commercial bleach solution (5.25% in NaOCI) was added in portions over 40 min. After additional 20 min at 0°C reaction mixture was quenched with saturated aqueous NaaSaO3 and allowed to warm to room temperature. Dilution with water and extraction with CH2CI2 were followed by concentration and flash chromatography (from 30% hexanes/ CH2CI2 to 0 - 2% acetone/ CH2CI2) to afford 15.97 g (71.9 mmol; 84%) of aldehyde 3A as an off-white solid. To a solution of 1.57 g (4.33 mmol) of ester 4A in 10 ml of a 3 : 1 : 1 mixture of THF - water - methanol was added 0.125 g (5.21 mmol) of LiOH. Reaction mixture was stirred overnight at room temperature, concentrated and exposed to high vacuum to obtain 1.59 g of crude acid 5A as a yellowish solid which was used without purification. To a solution of 8A (10 g, 79.4 mmol) and DMAP (0.029 g, 0.24 mmol) in methylene chloride (150 mL) at 0°C was added phthaloyl dichloride (16,1 g, 79.4 mmol) dropwise. The reaction mixture was stirred at room temperature overnight. After stirring ovemight, the reaction was washed with saturated aqueous NaHCOs. water, dried and concentrated to give compound 9A as a yellow solid (20 g, 99.8%) which was used without further purification. Compound 10A (0.5 g, 1.5 mmol) and hydrazine (0.5 M in ethanol, 5 mL, 2.5 mmol) were combined and stirred at room temperature ovemight. The reaction was diluted with water and extracted with methylene chloride. The organic layer was dried, concentrated and the residue purified on a flash column (3% methanol in ethyl acetate) to give compound 11A (0.2 g, 66%). Compounds 12A (2 g, 18.o mmol) and 13A {3.5 g. 22 mmol) were dissolved in methylene chloride and stirred at room temperature for 1 h. NaB(0Ac)3H (5.4 g, 25.6 mmol) was added and the mixture stirred at room temperature for 5h. The reaction was washed with saturated aqueous NaHCO3, dried and concentrated, and the residue purified by flash column (2% methanol in ethyl acetate). Compound 14A was obtained (4.5g, 99%). To the solution of 2,4-diflorobenzylaldehyde (16A. 28.1mmoi) in THF (10ml) was added the Grignard reagent 17A (1.33M in THF. 30ml), and the mixture was stirred at room temperature overnight. The reaction was quenched with saturated NH4CI (150ml), extracted three times with EtOAc (100ml). dried, filtered and concentrated. Flash chromatography (20% MeOH/EtOAc) yielded the desired compound 18A (1.8g. 27%). To the suspension of NaH (0.41g, 10.2 mmol) in THF (10ml) was slowly added a solution of 19A (1.3 g, 5.11 mmol) in DMF (5 mL) dropwise and the reaction stirred at 70~75°C overnight. The mixture was extracted twice with EtOAc and three times with H2O (30 mL), dried over MgS04 and concentrated to give crude 20A which was used without further purification (1.04 g, 87%). To the solution of compound 20A (4.3 mmol) in dichloroethane (20 ml) at 0°C was added 2-chloroethyl chloroformate (6.2 mmol) and triethylamine (7.2 mmol) and the reaction was stirred at room temperature ovemight. The solvent was evaporated, Et20 was added to the residue, and the unreacted starting material was removed by filtration. The filtrate was concentrated and the residue redissolved in MeOH and refluxed for 30 min. Removal of the methanol gave the product 21 (0.3g) which was used without further purification. Compound 22 (0.2 g. 0.37 mmol) was dissolved in CF3CO2H (3 mL) and methylene chloride (3 mL)and stirred at room temperature ovemight. The solvent was removed by evaporation, saturated aqueous NaHCO3 was added and mixture A solution of 24 (50 g. 387 mmol) and triethylamine (110 mL) in dioxane (400 mL) and water (400 mL) at 4°C was treated with B0C2O (93 g. 426 mmol). The cooling bath was removed and the solution allowed to warm to room temperature. After 21 h. the volume was reduced by two-thirds under vacuum. The residue was poured into ethyl acetate (250 mL) and water (250 mL). Saturated aqueous NaHCOa (250 mL) was added and the organic phase was separated and discarded. The aqueous phase was acidified with 10% HCI and extracted with ethyl acetate. The combined organic phases were washed with water, brine, and dried (Na2S04), and concentrated to give 25 as a white powder (82 g. 94%), To a solution of 2-bromopyridine (17.6 mL. 0.184 mol) in THF (600 mL) at -78°C was added n-BuLi (115 mL of a 16M solution in hexanes. 0.184 mol) dropwise over 15 min. After stirring for an additional 30 min at this temperature, a solution of 26 (25 g, 91.9 mmol) in THF (500 mL) was added dropwise over 15 min. The reaction was removed from the cold bath and placed in an oil bath and heated to 60°C for 1.5h, The reaction was then cooled to 4°C, diluted with ether (500 mL). and treated with saturated aqueous Na2S04 (~5 mL). The mixture was transfen-ed to an Erlenmeyer flask and diluted with additional ether (700 mL). Additional saturated aqueous Na2S04 was added followed by solid Na2S04. The mixture was filtered through a plug of solid Na2S04 and concentrated in vacuo. Flash column chromatography (0-20% ethyl acetate in hexanes) yielded compound 27 as a yellow oil (16.85 g, 63%). To a suspension of compound 5A (17.4 g, 50 mmol), compound 28 (11 g, 42 mmol), and dlisopropylethylamine (34.6 mL, 199 mmo!) in DMF (125 mL) was added HOBT (7.83 g, 58 mmol), EDC (18.54 g, 96.7 mmol). and 4A molecular sieves. The mixture was stirred for 40 h at room temperature, diluted with methylene chloride (60O mL) and 0.5 N NaOH (400 mL) and filtered. The precipitate was washed thoroughly with additional 0-5N NaOH and methylene chloride. The combined organic phases were concentrated and chromatographed twice on silica gel (1:1 hexane:methylene chloride to 6% saturated NH3 in methanol in methylene chloride) to produce 29 as a tan solid (22.3 g) which was used as is in the next step. Compound 30 (~17.9 g, 44 mmol) was dissolved in pyridine (420 mL). treated with HaNOCH3-HCI (21.78 g, 264 mmol) and heated to 90°C for 14h. The reaction was then concentrated and the residue taken up in a mixture of methylene chloride, (500 mL) and 2N NaOH (500 mL). The organic phase was separated and the aqueous phase extracted with additional methylene chloride (300 mL). The organic phases were dried and concentrated, and the residue chromatographed on SiOz (0-13% NH3/MeOH in CH2CI2) to produce a yellow solid (9.26 g). The mixed fractions from the column were rechromatographed to give an additional 3.23g of the desired material. Total yield 12.49 g (65% yield over the last two steps). Compound 31 (1 g) in ethanol (15 mL) was separated into the pure isomers using a Chiralcel AD column (20 mm x 500 mm) (eiuent: 75:25 hexane: isopropanol plus 0.5% N,N-diethylamine; flow rate: 50 mL/min; UV detection at 254 nM) to give compound 32 (0.6 g) and compound 33 (0.4 g). [M+H]+ 437 for 32 and 33. Alternatively, compound 32 can preferably be prepared from compound 5A in a manner similar to that described for compound 287 in Step 3 of Example 28, Compound 37 (0.98 g. 3.78 mmol), N-Boc isonipocotic acid (0.87 g. 3.78 mmol). DEC (1.11 g, 5.7 mmol), HOBT (0.68g, 4.91 mmol) and DIPEA (3 mL) were combined in CH2CI2 (40 mL) and stin-ed overnight at room temperature..The reaction was then diluted with CH2CI2 and washed with saturated aqueous NaHCOs. The organic layer was dried, concentrated and the residue chromatographed (10% hexane in EtOAc) to give 38 (1.61 g, 91 %). Compound 38 (1.61 g. 3.43 mmol) in CH2CI2 (15 mL) was treated with 1N HCl in dioxane (5.2 mL) and stirred overnight at room temperature. The solvent was removed in vacuo to give 39 (1.65 g) which was used without further purification. In a manner similar to that described in Example 7, Steps 3-4, compound 42 was converted to compound 43. To a solution of 43 (2.3 g. 6.3 mmol) in CH2CI2 (60 mL) was added 4A molecular sieves and 4-formylpyridine (0.68 mL, 6.9 mmol) and the mixture stirred for 3 h at room temperature. Na(0AG)3BH (2.7 g, 12.7 mmol) was then added and the reaction stirred for 1h. The reaction was quenched by the addition of NH4CI followed by the addition of saturated aqueous NaHCO3. The reaction mixture was then extracted with EtOAc, and the combined organic layers were dried and concentrated to give a residue which was chromatographed (20% MeOH in EtOAc). Compound 44 was obtained (2.3 g, 87%). A mixture of compound 48 (0.57 g, 2 mmol) and compound 42 (0.52 g, 2 mmol) in CH2CI (20 mL) was added EtaN (1.95 mL) and the reaction cooled to - 40°C. Triphosgene (0.2 g) was added and the reaction stirred at - 40°C for 2 h and room temperature for 48 h. The reaction was then washed with 1N NaOH, brine, and the organic layer dried. Concentration gave a residue that was purified by column chromatography (10% MeOH in EtOAc) to give 49 (0.14 g, 55%). In a manner similar to that described in Example 7, Step 6, compound 49 (0.09 g, 0.21 mmol) was converted to compound 50. A solution of n-BuLi (4.2 mL of a 1.6 M solution in hexane) in THF (25 mL) was treated at - 25°C with (i-Pr)2NH (0.69 g, 6.8 mmol). The reaction was stin-ed for 1 h at O'C and then cooled to - 70°C. Compound 4A (0.82 g, 2.26 mmol) in THF (5 mL) vvas added dropwise and the reaction stirred at - 70°C for 2 h and - 50°C for 2 h. The reaction was recooled to - 70°C and (1S)-(+)-(10-camphorsulfonyl)oxaziridine (1.04 g, 4.52 mmol) in THF (5 mL) was added. The reaction was stirred at - 70°C for 2 h and slowly warmed to room temperature overnight. The reaction was quenched by the addition of saturated aqueous NH4CI and extracted with EtOAc. The organic layer was dried and concentrated, and the residue purified by column chromatography (1:1 !iexane:EtOAc) to give 57 (0.44 g, 51%). A solution of compound 60 (10 g, 50.7 mmol) in ether (150 mL) at - 78°C was treated sequentially with TMEDA (11.8 g, 101.4 mmol) and s-BuLI ( 58.5 mL of a 1.3M solution in hexanes, 76 mmol) and the reaction stirred at this temperature for 6 h. Neat CH3SO4CH3 (12.8 g, 101.4 mmol) was then added and the reaction allowed to slowly warm to room temperature overnight. Saturated aqueous NaCI was added and the organic layer was separated. The aqueous layer was extracted three times with ether and the combined organic layers were dried, concentrated, and the residue chromatographed (5% EtOAc in hexane) to give 61 (8.0 g, 75%). reaction allowed to slowly warm to room temperature ovemight. The reaction v/as recooled to 0°C, EtOH (13 mL), pH = 7 buffer (25 mL) and H2O2 (25 mL) was added, and the reaction allowed to stir at room temperature overnight. The solvent was then removed in vacuo and the residue poured into water and CH2CI2. 10% aqueous NaOH (10 mL) was added and the organic layer separated. The aqueous layer was extracted with additional CH2CI2 and the combined organic layers were dried and concentrated. The residue was chromatographed (40% EtOAc in hexane) to give 62 {3g). A solution of 62 (2.8 g, 12.2 mmol) in EtOAc (30 mL) and NaBr (1,26 g. 0.12 mmol) in saturated aqueous NaHCOs (30 mL) was cooled to 0°C and treated with TEMPO (0.02 g, 0.12 mmol). After 15 min., NaOCl (17.44 mL) was added and the mixture stirred for 3 h. Saturated aqueous Na2S203 was added and the pH adjusted to 5 - 6 by the addition of 1N HCI. The mixture was extracted with EtOAc and the organic layers were dried and concentrated. The residue was chromatographed (10 -20% EtOAc in hexane) to give compound 63 (2.1 g. 76%). To a 0°C solution of Vilsmeier salt, prepared by the dropwise addition of phosphorus oxychloride (150.0 mL; 1.61 mol) to DMF (310.4 mL; 4.01 mol) over 15 min. and subsequent cooling in an ice bath, was added malonic acid (40.1 g; 0.39 mol) in portions over 45 min. The reaction mixture was then heated to 100°C, and the stining was continued for 48 h. The reaction mixture was then allowed to cool to room temperature and was quenched by slowly pouring it into a suspension of NaHCO3 (808 g; 9.62 mol) in water. The solution was decanted off the excess of NaHCO3 and concentrated to dryness under vacuum. After exposure to high vacuum for 2 days, the solid residue was washed repeatedly with CH2CI2 until TLC indicated complete removal of product. Combined organic extracts were concentrated under vacuum to produce 41.0 g of dark brown oil. which was used directly in the next step. To a mixture of 166 mg (1.35 mmol) of aminopyrimidine 67. 17 mg (0.14 mmol) of DMAP and 418 µL (3.00 mmol) of EtaN in 10 mL of THF was added 589 mg (2.7 mmol) of (B0C)20. The mixture was stirred at room temperature for 5 h, concentrated-dry loaded on silica gel and flash chromatographed (1-3% acetone/ CH2CI2) to produce 117 mg (0.36 mmol; 27%) of 68 as a clear oil. To a solution of 117 mg (0-36 mmol) of aldehyde 68 in 7 mL of CH2CI2 was added 67 µL (0.43 mmol) of ethyl isonipecotate and 5 µL of acetic acid. 30 min. later 153 mg (0,72 mmol) of NaBH(0Ac)3 was introduced. The mixture was stin-ed ovemight at room temperature, diluted with CH2CI2, washed with aqueous NaHCOs, dried and concentrated, and crude residue was flash chromatographed (0-4% sat. NH3 in MeOH/ CH2CI2 ) to produce 133 mg (0,29 mmol; 81%) of 69 as a white film. Reaction mixture was then allowed to want) up and was then stinred for 2 h at room temperature, which resulted in the formation of an orange precipiate. The mixture was cooled back to -78°C, and ethylene oxide was bubbled through the solution for 1 min. followed by stining for 5 min. This two-step sequence was repeated eight times. The mixture was then allowed to warm to -50°C, stin-ed at that temperature for 40 min,, quenched with 1,34 mL (23 mmol) of AcOH and allowed to warm to room temperature. Dilution with water was followed by extraction with EtOAc, concentration of the organic phase, and flash chromatography of the cmde residue (10-15% acetone/ CH2CI2) to produce 1.50 g (5.95 mmol; 53%) of 71 as a white solid. To a solution of 1.00 g (4.0 mmol) of aldehyde 72 in 25 mL of CH2CI2 was added 617 pL (4.8 mmol) of ethyl isonipecotate followed by one drop of AcOH, Reaction mixture was then stin-ed for 40 min at room temperature after which 1.70 g (8.0 mmol) of NaBH(OAc)3 was introduced. Reaction mixture was stin-ed overnight at room temperature, neutralized with saturated aqueous NaHCO3, diluted with water and extracted with CH2CI2. Concentration and flash chromatography (0 — 4% saturated NH3 in MeOH/ CH2CI2) provided 1.41 g (3.6 mmol; 90%) of 73 as a white solid. To a solution of 77 (0.73 g, 3.82 mmol) in CH2CI2 (10 mL) was added (C0CI)2 (0.41 mL, 4.58 nnmol) followed by DMF (0.1 mL) and the reaction was maintained at 40°C for 3 h. The reaction was then concentrated to give a brown solid which was dissolved in CH2CI2 (10 mL). N,0-dimethyihydroxylamine hydrochloride (0.56 g, 5.73 mmol) and DIPEA (1.33 mL) were added and the reaction was stirred at room temperature overnight. The reaction was quenched by the addition of saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic layers were dried and concentrated, and the residue purified by chromatography to give 78 (3.2 g, 84%). To a solution of 82 (0.115 g, 0.25 mmol) in DMF (4 mL) was added NaH (60% dispersion in mineral oil, 0.03g, 0.76 mmol). After 5 h at room temperature, CF3CH2OSO2CF3 (0.069 g. 0.3 mmol) was added and the reaction stirred at room temperature overnight. The reaction was diluted with EtOAc and extracted 3 times with water to remove the DMF. The organic layer was dried and concentrated to give a residue which was purified by chromatography (10% MeOH/NH3 in EtOAc) to give 83 (0.08 g. 30%). To the mixture of 85 (9.2 g) and MnO2 (42 g ) was added 200ml CH2CI2. and the mixture was stired at room temperature ovemight. Additional Mn02 (20g ) was added and the reaction was stirred another 24hrs. The Mn02 was filtered off and the reaction was concentrated and flashed over silica gel( 5% and 10% MeOH (NH3)/CH2Cl2) to give 86 (3,1g, yield: 33%). To the solution of 90 (0.65g) in CH2CI2 (6 ml) at -10°C was added TFA (6ml) and the reaction was stirred for 1 hr from -lO°C to O°C. Concentrated down and azeotroped twice with toluene (20ml), and concentrated to dryness to obtain 91 as a gummy oil which was used as is. To a solution of 93 (5.17 g, 22.7 mmol) in THF (100 mL) at -50°C was added s-BuLI (38.4 mL of a 1.3M solution in hexane, 49.9 mmol) dropwise. After 1.5h at -40°C, the reaction was recooled to -50°C and 95 (4.84 g, 22.7 mmol) in THF (20 mL) was added. After 2.75 h at -50°C, glacial acetic acid was added followed by saturated aqueous NH4CI. The mixture was warmed to room temperature and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were dried (MgS04) filtered and concentrated to give a residue that was purified by flash column chromatography (1% to 3% MeOH/NHa in CH2CI2) to give 95 (6.35 g, 63%). Compound 97 (0.7 g. 2.25 mmol), H2NOCH3-HCl (0.94 g, 11.23 mmo!) and NaOAc (1.47 g, 17.97 mmo!) were combined in 1-pentanol (20 mL) and water (2 mL) and heated to reflux for 2 days. The reaction was cooled to room temperature and 0.5 N NaOH was added. The EtOH was removed in vacuo, additional water (15 mL) was added, and the reaction extracted with 10% EtOH in CH2CI2 (180 ML total volume). The combined organic extracts were dried and concentrated to give 98 (0.55 g, 92%). A solution of 2.2 g (9.5 mmol) of 100 in 75 mL of glacial acetic acid was hydrogenated in the presence of 0.5 g of 10% w/w piatinum-on-charcoal for 5 h. The reaction mixture was filtered to remove the catalyst and the filtrate was concentrated by evaporation under reduced pressure to produce a solid residue which was basified with 0.5N NaOH and extracted with methylene chloride (CH2CI2). Methylene chloride extracts were dried over anhydrous MgS04 and concentrated. The residue was purified by flash chromatography eluted with 10 - 30% of 7N NHs-MeOH in CH2CI2 to give 0.82 9 of 101 (mp 158-163 OC). LCMS m/z 240 (MH+). A mixture of 0.12 g (0.52 mmol) of 101, 0.2 g (0.52 mmol) of 5A, 0.67 g (0.5 mmol) of 1-hydroxybenzotriazole hydrate (HOBt), and 0.11 g (0.57 mmol) of 1-(3-dimethylaminopropyl)-3-ethylGarbodiimide hydrochloride (DEC) in 7 mL of anhydrous dimethylformamide (DMF) was stin-ed at ambient temperature for 18 h. The mixture was diluted with water and the resulting precipitate was filtered to produce 0.26 g of 102 as a white solid (mp 110-115 °C). LCMS m/z 557 (MH+). To a stirred solution of 0.34 g (2.7 mmol) of oxalyl chloride in 3 mL of anhyrous CH2CI2 at -70° C was added 0.44 g (5.7 mmol) of anhyrous methylsulfoxide in 2 mL of CH2CI2. After being stirred at -70° C for 10 minutes, the reaction mixture was added 1.2 g (2.15 mmol) of 102 in 10 mL of CH2CI2. The stired mixture was kept at -70° C for 0.5 h, mixed with 1.8 mL (13 mmol) of triethylamine, and then allowed to warm up to ambient temperature by itself. The mixture was diluted with water and extracted with CH2CI2. Organic extracts were washed with brine, dried over anhydrous MgS04 and concentrated to produce 1.18 g of 103 as a glass. LCMS m/z 555 (MH+). A solution of 0.8g (1.44 mmol)of 103 and 0,6 g (7.2 mmol) of methoxylamine hydrochloride in 40 mL of ethanol and 40 mL of pyridine was heated under reflux for 18 h. The mixture was concentrated and the residue was taken up in ethyl acetate/ether and washed with water. The organic solution was dried over anhydrous MgS04 and concentrated to 0.65 g of viscous reidue which was dissolved in 8 mL of trifluoroacetic acid and 8 mL of CH2CI2 and stirred at ambient temperature for 18 h. The solution was concentrated and the residue was basified with IN NaHCO3 and extracted with ethyl acetate. Organic extracts were washed with brine, dried over anhydrous MgS04 and concentrated to a gummy residue. Purification of this residue by flash chromatography with 5-8% of 7N NH3-MeOH in CH2CI2 produced 0.151 g of 104 as a gum. LCMS m/z 484 (MH+) and 0.146 g of 105 as a glass, LCMS m/z 556 (mH+). Mixing a solution of 0.056 g of the free base of 104 in ethyl acetate v/ith a solution of 0,04 g of maleic acid in ethyl acetate produced a precipitate which was isolated by filtration to give 0.06 g of a dimaleate salt of 104 (mp 155-160 OC). 0.32 g (0.58 mmol) of 109 were reacted with 0.6 g (7.2 mmol) of methoxylamine hydrochloride in the same manner as that described in Example 22, step 4 to provide 0.065 g of 110 as a gum, LCMS m/z 484 (MH+) and 0.12 g of 111 as a glass, LCMS m/z 556 (MH+). A mixture of 18 g (74 mmol) of 112, 7.2 g ( 74 mmol) of N,0-dimethylhyroxylamine hydrochloride, 19.4 g (15 mmol) of N,N-diisopropylethyiamine, 1.1 g (8 mmol) of HOBt and 14.2 g ( 74 mmol) of DEC in 80 mL of anhydrous DMF was stirred at ambient temperature for 18 h. The mixture was diluted with water and extracted with ethyl acetate. Organic extracts were washed with 1% NaHCO3 and brine, dried over anhydrous MgS04 and concentrated to give 15.5 g of 113 as an oil. LCMS m/z 287 (MH+). A mixture of 0.466 g (2 mmol) of 116, 0.517 g (2.2 mmol) of 5A, 0.276 g (2 mmol) of HOBt and 0.46 g (2.4 mmol) of DEC in 20 mL of anhydrous DMF was stirred at ambient temperature for 18 h. The mixture was concentrated by evaporation under reduced pressure at bath temperature of 25-45°C and the residue was chromatographed with 4% (7N NH3/CH3OH) in CH2CI2 to produce 0.48 g of symp which was dissolved in 15 mL of EtAc-EtOH (3:1 v) and mixed with a solution of 0.26 9 of maleic acid in 10 mL of EtAc-EtOH (1:1). The resuting precipitate was filtered to produce 0.35 g of the maleate salt of 117 (mp 160-163 OC). LCMS m/z 451 (MH+). A solution of 3.71 g (8.8 mmol) of 118 and 3.7 g (44 mmol) of methoxylamine hydrochloride in 40 mL of pyridine and 40 mL of ethanol was heated under reflux for 2 days. The mixture was concentrated and the residue was taken up in CH2CI2 and washed with saturated aqeous NaCl. Organic solution was dried over anhydrous MgS04 and concentrated to give 2.6 g of 119 as a glass. LCMS m/z421 (MH+). In a similar manner to that described In Example 6, step 7, 122 (0.26 g, 0.41 mmol) was converted to 123 (0.08 g, 40%). To a suspension of LAH (0.83 g, 22 mmol) in ether (20 mL) at 0° C was added 124 (3.2 g, 17.5 mmol) in THF (15 mL) dropwise. The reaction was stirred at 0° C for 1.5 h, and quenched by the addition of water (0.8 mL), 20% aqueous NaOH (0.8 mL), and water (2.4 mL). The mixture was stirred for 15 min and filtered and the filter cake washed with CH2CL2. The filtrate was concentrated to give an oil which was dissolved in ether (30 mL) and washed with brine and dried (MgS04). Filtration and concentration in vacuo gave 125 (2.5 g) which was used without further purification. The compounds in Table 1 (first column) are prepared from the compounds in the last column of Table 1 by following essentially the same procedures as in the examples described above. In Table 1 "Cmpd. No." stands for "Compound Number", The isomers 246A and 253A. below, can be separated from 246 and 253, respectively, above, by techniques well known to those skilled in the art. MeOH/ CH2CI2) to produce 1.55 g (5.87 mmol; 72%) of amine 285 as a yellowish solid. Step 2 To a solution of 3.83 g (14.51 mmol) of ester 285 in 60 ml of 3 :1 : 1 mixture of THF - MeOH - H2O was added 1.22 g (29.02 mmol) of LiOH monohydrate. The reaction mixture was stirred at room temperature overnight, concentrated, and the residue was dried under high vacuum to produce 3.84 g of crude acid 286 lithium salt as a yellow solid. Material could be used directly or could be purified by passing through a silica gel plug eluting with ca. 3 N NH3 in MeOH. To a mixture of 3.32 g (14.05 mmol) of acid 286 and 4.07 g (14.05 mmol) of 4-[(E)-(methoxyimino)-2-pyridinylmethyl]piperidine dihydrochloride (see Compound 447 below) in 40 mL of DMF was added 8.94 mL (70.25 mmol) of 4-ethylmorpholine and 14.0 mL (23.52 mmol) of 50 wt. % solution of 1-propanephosphonic acid cyclic anhydride in ethyl acetate. The reaction mixture was stirred for 4.5 h at 50°C followed by 14 h at room temperature. Concentration of the mixture was followed by exposure to high vacuum for 24 h to remove remainlng DMF. The residue was partitioned between aqueous NaOH and CH2CI2, organic phase v;as separated, dried and concentrated, and the residue Was flash chromatographed (5-15% ca. 3 N NH3 in MeOH/ CH2CI2) to produce 4.60 g (10.51 mmol; 75 %) of amide 287 as a light tan foam. MS 438 (M+1). 3,4 Pyridine-dicarboximide 288 (10.0 g; 67.5 mmoles) was dissolved in 162 g. of 10% aqueous NaOH and the solution was cooled to an internal temperature of 7 °C in an ice-salt bath. Bromine (3.6 ml; 70 mmoles) was added dropwise. After the addition, the solution was heated for 45 minutes at a bath temperature of 80-85 °C. The yellow solution was then cooled to an internal temperature of 37 °C, then 17 ml of glacial acetic acid were added dropwise to a pH of 5.5. The resulting mixture was saved overnight in a refrigerator. The solid formed was filtered and washed with 5 ml of water and 5 ml of methanol. The reaction yielded 6.35 g. of product 289 melting at 280-285 °C (decomp.). NaOH, then by 30 ml of water. The resulting solid was filtered through a pad of Celite and washed several times with THF. The oil obtained after evaporation of the solvent, solidified on standing. The reaction mixture was purified by flash chromatography on silica gel using 5%MeOH(NH3)/EtOAc as eluent yielding 6.21 (72%) of Compound 290 . LC-MS: m/z = 125 (M+1), minutes with 100 ml of saturated aqueous sodium bicarbonate then separated from the aqueous layer. The organic layer was washed two more times with saturated aqueous sodium bicarbonate, then with brine and dried with anhydrous sodium sulfate. After evaporation of the solvent, the resulting oil was purified by flash chromatography on silica gel using EtOAc:Hexanes:MeOH(NH3) as eluent. The procedure yielded 6.8 gr.(94%) of Compound 292 . FAB-MS: m/z = 264 (M+1). quenched with 50 ml. of 0.5 N aqueous NaOH, then the solution was extracted with dichloromethane. The combined extracts were washed with brine and dried over anhydrous sodium sulfate. The product 295 was isolated by flash chromatography on silica gel using EtOAc:Hexanes:MeOH(NH3) (50:45:5) as eluent. Yields: 0.27 gr. (47%). FAB-MS: m/z = 408 (M+1). A mixture of 298 (1.8 g, 9 mmol), N,0-dimethyIhydroxylamine hydrochloride (2.6 g, 27 mmol), EDCI (5 g, 27 mmol), HOBt (0,1 g. 1 mmol). and DIPEA (12.5 mL, 72 mmol) in DMF (30 mL) was stin-ed at 20°C overnight. The reaction was then concentrated to half volume in vacuo, poured onto water, and extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous NH4CI, saturated aqueous NaHCO3. water and brine, dried (Na2S04), and concentrated to give 299 as a clear oil (2.1 g, 98%). Following procedures similar to those of Steps 4 to 7 of Example 6, compound 301 was obtained. MS 409 (M+1). Following procedures similar to those described in the examples above, the compounds in Table 2 were prepared. If one were to follow procedures similar to those described in the examples above, the compounds in the "Structure" column of Table 3 would be obtained using the starting material listed in Table 3. Each compound in Table 3 is a mixture of oxime isomers, as represented by the ~~ bond between the oxime nitrogen and the OH or OCH3 moiety. In Table 3 "CMPD" stands for "Compound". To a solution of LDA (233 mL, 2.0 M in THF/heptane/ethylbenzene, 0.466 mol) in THF (300mL) at 0 ""C was added, dropwise over 1.0 h, a solution of compound 440 (100g, 0.389 mol) in THF (~ 400 mL). The red-orange solution was stirred at 0 X for 30 min, and tlien 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 rt for 18 h. The total solvent volume was reduced to approximately one third, and EtOAc {- 1L) was added. The solution was washed successively with water, 0.1 N aq. HCI, saturated aq. NaHCOa, and brine. The organic layer was dried over MgS04, filtered, and concentrated under reduced pressure to yield a crude liquid. Separation by flash chromatography (6:1 hexanes-EtOAc) gave compound 441 (93.5 g, 87%). In a manner similar to that described in Example 1, Step 4, compound 442 vvas converted to compound 443. can be used to prepare the compounds of this invention, for example, see Examples 6 and 28. Preferably, Compound 447 Is prepared from a compound of formula: and from a compound of Formula 449: R50 is an alkyl or aryl group, f is 0 to 4, R51 is an alkyl group, and Q is a halo group, wherein said alkyl, aryl, and halo groups are as defined above. Compound 447 can be prepared from 448 and 449 by: (a) converting the compound of formula 449 into its Grignard form (c) reacting the compound of fonmula 450 with a suitable alkyl chloroformate of formula 451 to yield a compound of fonmula 452: (e) reacting the compound of formula 453 with an alkoxyamine (NHaOR51) or its hydrochloride to form an oxime of formula 454: (f) isomerizing the compound of formula 454 by treatment with a strong acid and simultaneously converting to the desired acid salt of Fonnula 454 with an enriched E isomer, wherein the E isomer predominates over the Z-isomer by at least a 90:10 ratio. When f=0, R51 is methyl, and the acid used for isomerization is HCi in the compound of fomriula 454, the final product is the compound of formula 447. The conversion of compound 461 to 447 predominantly yields the E-isomer of compound 447 in high stereochemical purity and high yields, Isomerization of a mixture of phenyl compounds by acid catalysis is discussed by T. Zsuzsanna et al, HungMagyKm.Foly., 74(3) (1968), 116-119. The above process starts with Compound 449. In step 1, a 4-halo-1-aikyipiperidine (or a 4-halo-l-arylpiperidine) is converted to its Grignard analog (449A) by reacting with magnesium. The reaction is performed generally at temperatures of about -10° C to reflux. Generally a hydrocarbon solvent such as. for example, toluene, xylene, chlorobenzene, dichlorobenzene and the like, or mixture of hydrocarbons listed above with an ether, such as, for example, a C5-C12 alkyl ether, 1,2-dimethoxyethane, 1.2-diethoxyethane, diglyme, 1,4-dioxane, tetrahydrofuran and the like are suitable for this reaction. The solution is cooled to around -10° C to about 10° C and then reacted with a suitable 2-cyanopyridine (448). for about 10-120 minutes. Examples of suitable 2-cyanopyridines are 2-cyanopyridine, 4-methyl-2- cyanopyridine, 4-ethyl-2-cyanopyridine, 4-phenyl-2-cyanopyridine, and the like. Preferred are 2-cyanopyridine and 4-methyl-2-cyanopyridine. The Grignard compound is used generally in about 1-4 molar equivalents with respect to the compound of formula 448, preferably in about 1-3 molar equivalents and typically in about 1.5-2.5 molar equivalents. The product of formula 450 may be isolated by procedures well known in the art, such as, for example, treatment with an acid (e.g. HCI),' preferably in a suitable solvent (e.g., tetrahydrofuran or ethyl acetate). The product of Fomiula 450 may then be reacted with an alkyl chloroformate in the next step. Suftable alkyl chloroformates are. for example, methyl chloroformate. ethyl chloroformate, propyl chloroformate, and the like, with the preferred being methyl chloroformate or ethyl chloroformate. Generally a hydrocarbon solvent such as, for example, toluene, xylene, chlorobenzene, dichlorobenzene and the like, or mixture of a hydrocarbons listed above with an ether such as, for example, a C5-C12 alkyl ether, 1,2-dimethoxyethane. 1.2-diethoxyethane, diglyme, 1,4-dioxane, tetrahydrofuran and the like Is suitable for this reaction. The reaction is generally performed at about 25-100°C, preferably about 40-90°C and typically about 50-80°C, for about 1-5 hours. After the reaction, generally the generated acid is washed off and the product of formula 452 may be isolated by organic solvent extraction. The compound of Formula 452 may then be converted into its acid salt by treatment with an acid such as, for example, sulfuric acid, hydrochloric acid, trifluoroacetic acid and the like, generally in a solvent at temperatures between ambient and reflux of the solvent. Suitable solvents include hydrocarbons such as. for example, toluene, xylene, chlorobenzene. dichlorobenzene and the like. There being two nitrogen atoms in the compound of Formula 452, the salt generally has 2 moles of acid to a mole of compound 452. The compound of formula 453 may then be converted to an alkyloxime of fomnula 454 by reacting it with an alkoxyamine (or its hydrochloride), usually in aqueous solution form. Suitable alkoxyamines are, for example, methoxyamine, ethoxyamine and the like. Methoxyamine is preferred. The alkoxyamine (or its hydrochloride) is employed generally in about 1 to about 4 molar equivalents, preferably in about 1 to about 3 molar equivalents, and typically in about 1 to about 2 molar equivalents. Generally, the reaction is catalyzed by a weak acid such as, for example, acetic acid, formic acid and the like, or mixtures thereof. A cosolvent such as, for example, methanol, ethanol, isopropanol, n-butanol and the like, or mixtures thereof may be added. The product of formula 454, after work-up, is a mixture of the Z- and the E-isomers, whose ratio may be analyzed for its stereochemical make-up, using techniques well known in the art such as, for example, HPLC. Treating the compound of formula 454 with a strong acid under the reaction conditions described below isomerizes the mixture of the Z and the E-isomers into predominantly the E-isomer. Generally, the compound of formula 454 may be dissolved in a solvent such as, for example, ethanol, methanol, isopropanol, n-butanol and the like, ether such as methyl tert-butyl ether, tetrahydrofuran and the like, hydrocarbon such as, for example, heptane, hexane, toluene and the like, nitrile such as, for example, acetonitrile, benzonitrile and the like, or mixtures of such solvents. The dissolved compound is then treated with a strong acid such as, for example, HCI, HBr, H2SO4 and the like, at temperatures in the range of 20 to 100°C for about 1-20 hours. The acid is employed generally in about 1 to about 8 molar equivalents, preferably in about 1 to about 6 molar equivalents, and typically in about 2 to about 4 molar equivalents. Work-up typically forms predominantly the acid salt of the E-isomerof the compound of formula 454, which is in fact the compound of formula 447 when R51 = methyl, n=0 and the acid salt is HCI in 454, The products of the various steps in the process described above may be isolated and purified by conventional techniques such as, for example, filtration, recrystallization, solvent extraction, distillation, precipitation, sublimation and the like, as is well known to those skilled in the art. The products may be analyzed and/or checked for purity by conventional methods such as, for example, thin layer chromatography, NMR. HPLC, melting point, mass spectral analysis, elemental analysis and the like, well known to those skilled in the art. H3-Receptor Binding Assay The source of the H3 receptors in this experiment was guinea pig brain. The animals weighed 400-600 g. The brain tissue was homogenized with a solution of 50 mM Tris, pH 7.5. The final concentration of tissue in the homogenization buffer was 10% w/v. The homogenates were centrifuged at 1,000 x g for 10 min. in order to remove clumps of tissue and debris. The resulting supernatants were then centrifuged at 50,000 x g for 20 min. in order to sediment the membranes, which were next washed three times in homogenization buffer (50,000 x g for 20 min, each). The membranes were frozen and stored at -70°C until needed. All compounds to be tested were dissolved in DMSO and then diluted into the binding buffer (50 mM Tris, pH 7.5) such that the final concentration was 2[jg/ml with 0.1% DMSO. Membranes were then added (400 \}g of protein) to the reaction tubes. The reaction was started by the addition of 3 nM [^HJR-a-methyl histamine (8.8 Ci/mmol) or 3 nM [3H]N"-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 en-or was always less than 10%. Compounds that inhibited more than 70% of the specific binding of radioactive ligand to the receptor were serially diluted to determine a Kj (nM). Compounds 23, 30, 31, 32. 33,44,45, 49, 50, 53, 54, 55. 56, 57A, 59, 75. 76, 83, 88, 92, 99,104,110, 117, 128, 200. 201, 203-215, 217-241, 244-246, 246A, 247-253, 253A. 254-273, 275. 278. 280-282, 287. 296. 301-310, and 312-379 had a Kj within the range of about 0.25 to about 370nM. Preferred Compounds 23. 30. 31. 32, 33, 50. 53,54, 55. 56, 57A, 59, 92, 212. 215, 218. 219.220.224. 225, 226. 227, 229, 233,235, 237, 238, 246. 246A, 247. 248. 251, 253, 253A. 268-273, 275. 278-281, 287, 296, 301, 304-307. 309, 312, 314-318, 320-356, and 358-376 had a K1 within the range of about 0.25 to about 33nM. Most preferred Compounds 30, 31, 32, 33. 54, 55, 56. 56A, 225,237. 246A, 253A, 273, 280. 287, 296, 301. 304-307. 309, 312. 314-318, 320-348, 350-356, 359-372, and 374-376 had a K1 within the range of about 0.25 to about 16nM. More preferred compound 32 had a Kj of 0.83nM. More preferred compounds 54, 55, 253A, 287, 320 had a Ki within the range of about 1.05 to about 9.75nM. 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 fonns suitable for oral administration. Examples of pharmaceutically acceptable earners and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, PA. Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration. Aerosol preparations suitable for inhalation may Include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable cam'er, such as an inert compressed gas, e.g. nitrogen. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions. The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdemial patch of the matrix or reservoir type as are conventional in the art for this purpose. Preferably the compound is administered orally. Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose. The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 150 mg, preferably from about 1 mg to about 75 mg, more preferably from about 1 mg to about 50 mg, according to the particular application. The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required. The amount and frequency of administration of the compounds of the invention. and/or the 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. The methods of this invention described above using a compound of Formula I also include the use of one or more compounds of Formula I, and the methods of this invention described above using a compound of Formula I in combination with an Hi receptor antagonist also include the use of one or more compounds of Formula I in combination with one or more H1 receptor antagonists. While the present 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. WE CLAIM: or a pharxnaceutically acceptable salt or solvate thereof, wherein: (1) R1 is selected from: (a) aryl; (b) heteroaryl; (c) heterocycloalkyl (d) alkyl; (e) cycloalkyl; or (f) alkylaryl; wherein said R1 groups are oplionally subsliluled with 1 to 4 substituenis independently selected from: (J) halogen; (2) hydroxy!; (3) lower alkoxy; (4) - CF3; (5) CF,0~-i (6) —NR-4R5; (7) phenyl; (8) —NO,, (9) —CO.R4 (10) ~CbN(R4)2 wherein each R4 is the same or different; (11) S(OX,N(R20)2, wherein each R20 is the same or diJDFerent H or alkyl group; (12) —CN; or (13) alkyl; or (2) R1 and X taken together form a group selected from: (4) M1 is carbon; (5) M2 IS N; (6) one of M3 and M4 is C and the other is N; (7) Y is selected from: is —CH.—. =C(0), =C(NOR20) (wherein R20 is as defined above), or «C(S); (8) Z is a C1-C6 alkyl group; (9) R2 is a live or six-membered heteroaryl ring, said six-membered heteroaryl ring comprising 1 or 2 nitro gen atoms with the remaining ring atoms being carbon, and said five-membered heteroaryl ring containing 1 or 2 beleroatoms selected from; nitrogen, oxygen, or (j) -CF3; or (k) —CH.CF3; wherein said aryl, heieroaryl, heierocycloalkyl, and the aryl portion of said arylalkyl are optionally substituted with I to 3 substiluents selected from: halogen, —OH, —OCF3, -CF3, —CN, —N(R45')., —CO.R45 or —C(0)N(R45').. wherein each R45 is independently selected from: H, alkyl, alkylaryL, or alkylaryl wherein .said aryl moiety is substituted with 1 to 3 substituents independently selected from —CF«, —OH, halogen, alkyl, —NO., or —CN; (B) substiluieci aryl, wherein the substituents on said substitucd aryl arc selected from: (1) halo; or (2) alkyl; or (3) substituted alkyl; (C) heieroaryl; (D) substituted heteroaryl; or (E) when R1 is taken together with X, then the moiety is 3. The compound as claimed in claim 2 wherein R1 is selected from; (A) phenyl; (B) substituted phenyl wherein the substituents on said substitued phenyl are selected from: (1) halo; (2) alkyl; (3) alkyl substituted with halo; (C) heteroaryl selected from; pyridyl, thienyl, pyrimidinyl, thiazolyl or pyridyl N-Oxide; (D) alkyl substituted thiazolyl; or (E) when R2 is taken together with X, then the moiety is wherein c is 0 or i, and when c is 1 then R6 is fluoro. 5. The compound as claimed in claim 1 wherein R1 is selected from: (A) phenyl; (B) substituted phenyl, wherein the substituents on said substitued phenyl are independently selected from chloro, fluoro or trifluoromethyl; (C) pyridyl; or (D) substituted heteroaryl of the formula: 16. The compound as claimed inclaim 1 wherein R2 is a six membered helcroaryl ring. 17. The compound as claimed in claim 16 wherein R2 is selected from pyridyl, pyridyl substituted with —NR4R5, pyrimidinyl, or pyrimidinyl substituled with —NR4R5. 18. The compound as claimed in claim 17 wherein R2 is pyridyl substituted with —NH^, or pyrimidinyl substituted with (2) X is =C(NOR3); (3) R3 is selected from H or alkyl; (4) M2 is nitrogen; (5) Y is =C(0); (6) M3 and M1 are selected such that; (1) one is carbon and the other is nitrogen; (7) Z is C1 to C3 alkyl; and (8) R2 is a six membered heteroaryl ring. 23. The compound as claimed in claim 22 wherein: (1) R1 is selected from: (A) phenyl; (B) substituted phenyl wherein the substituents on said substitued phenyl are selected from: (1) halo; (2) alkyl; (3) alkyl substituted with halo; (C) heteroaryl selected from: pyridyl, thieny), pyrimidinyi, thiazolyl or pyridyl N-Oxidc; or (D) alkyl substituted thiazolyl; or (E) when R1 is taken together with X, then the moiety is wherein c is 0 or 1, and when c is 1 then R6 is halo; (2) R3 is selected from H, methyl or ethyl; (3) n is 2, (4) a is 0 or 1, (5) b is 0 or 1. (6) c is 0 or I and when c is I then R0 is halo, (7) e is 1 to 5, (8) p is 2, (9) R1 is H or lower alkyl, (10) R5 is H, C1 to C6alkyl, or —C(0)R'; (11) R12 is alkyl, hydroxy or fluoro, and (12) R13 is alkyl, hydroxy or fluoro. 24. The compound as claimed in claim 23 wherein R2 is 7 6 HAY 2007

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NOVEL NON-IMIDAZOLE COMPOUNDS
REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application Serial No.' 60/240901 filed October 17, 2000.
BACKGROUND OF THE INVENTION
WO 95/14007 published May 26, 1995 discloses H3 receptor antagonists of the imidazole type.
WO99/24405 published May 20. 1999 discloses H3 receptor ligands of the imidazole type.
US 5,869,479 issued February 9, 1999 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
In view of the art's interest in compounds which affect H3 receptors, novel
compounds that are antagonists of H3 receptors would be a welcome contribution to the art. This invention provides just such a contribution.

(a) aryl;
(b) heteroaryl;
(c) heterocycloalkyi
(d) alkyl;
(e) cycloalkyi; or
(f) alkylaryl;
wherein said R1 groups are optionally substituted with 1 to 4 substituents independently selected from:
(1) halogen (e.g., Br, F, or CI, preferably F or CI);
(2) hydroxyl (i.e., -OH);
(3) lower alkoxy (e.g., C1 to C6 alkoxy, preferably C1 to C4 aikoxy,
most preferably C1 to C2 alkoxy, more preferably methoxy);
(4) -CF3;
(5) CF3O-;
(6) -NR^R^;
(7) phenyl;
(8) -NO2,

(9) -C02R4
(10) -C0N(R4)2 wherein each R4 is the same or different;
(11) -S(0)mN(R20)2 wherein each R20 is the same or different H or alkyl group, preferably C1 to C4 alkyl, most preferably C1-C2 alkyl, and more preferably methyl;
(12)-CN;or (13) alkyl; or

(4) M1 is carbon;
(5) M2 is selected from C or N;
(6) M3 and M4 are independently selected from C or N;
(7) Y is selected from: is -CHr, =C(0), =C(NOR20) (wherein R20 is as defined above), or =C(S);
(8) Z is a C1 - C6 alkyl group;
(9) R2 is a five or six-membered heteroaryl ring, said six-membered heteroaryl ring comprising 1 or 2 nitrogen atoms with the remaining ring atoms being carbon, and said five-membered heteroaryl ring containing 1 or 2 heteroatoms selected from: nitrogen, oxygen, or sulfur with the remaining ring atoms being carbon; said five or six membered heteroaryl rings being optionally substituted with 1 to 3 substituents independently selected from: halogen, hydroxyl, lower alkyl, lower alkoxy, -CF3. CF3O-, -NR4R5 phenyl, -NO2, -C02R4 -C0N(R4)2 wherein each R4 is the same or different, -CHaNR4R5 -(N)C(NR4R5)2, or-CN;
(10) R3 is selected from:

(a) hydrogen;
(b) C1 - C6 alkyl;
(c) aryl;
(d) heteroaryl;
(e) heterocycloalkyl;
(f) arylalkyi (e.g., aryl{C1to C4)alkyi, e.g., -(CH2)waryl wherein w is 1 to 4, preferably 1 or 2, and most preferably 1, such as, for example -CH2phenyl or -CH2Substituted phenyl);
(g) -(CH2)e-C(0)N(R'*)2 wherein each R"* is the same or different,
(h) -(CH2)e-C(0)0R4
(i) -(CH2)e-C(0)R30 wherein R30 is a heterocycloalkyl group, such as, for example, morpholinyl, piperidinyl, piperazinyl or pyrrolidinyl, including

This invention also provides a pharmaceutical composition comprising an effective amount of compound of Formula I, and a pharmaceutically acceptable carrier.
This invention further provides a method of treating: allergy, allergy-induced airway (e.g., upper airway) responses, congestion (e.g., nasal congestion).

hypotension, cardiovascular disease, diseases of the Gl 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 other CNS disorders (such as Alzheimer's, schizophrenia, and migraine) comprising administering to a patient in need of such treatment (e.g., a mamma!, such as a human being) an effective amount of a compound of Formula I.
This invention further provides a method of treating: allergy comprising administering to a patient in need of such treatment (e.g.. a mammal, such as a human being) an effective amount of a compound of Formula L
This invention further provides a method of treating: allergy-induced airway (e.g., upper airway) responses comprising administering to a patient in need of such treatment (e.g., a mammal, such as a human being) an effective amount of a compound of Formula I.
This invention further provides a method of treating: 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 compound of Formula I.
This invention further provides a pharmaceutical composition comprising an effective amount of a compound of Formula I, and an effective amount of a Hi receptor antagonist in combination v/ith a pharmaceutically acceptable carrier.
This invention further provides a method of treating: allergy, allergy-Induced airway (e.g.. upper airway) responses, and 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 compound of Formula I in combination with an effective amount of an H1 receptor antagonist.
This invention further provides a method of treating: allergy comprising administering to a patient in need of such treatment (e.g., a mammal, such as a human being) an effective amount of a compound of Formula I in combination with an effective amount of an Hi receptor antagonist.
This invention further provides a method of treating: allergy-induced airv^ay (e.g., upper airway) responses comprising administering to a patient in need of such treatment (e.g., a mammal, such as a human being) an effective amount of a

compound of Formula I in combination with an effective amount of an Hi receptor antagonist.
This invention further provides a method of treating: 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 compound of Formula I in combination with an effective amount of an H1 receptor antagonist.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the following terms have the following meanings, unless indicated otherwise:
alkyi-(including the alkyl portions of alkoxy and alkylaryl)-represents straight and branched carbon chains and contains from one to twenty carbon atoms, preferably one to six carbon atoms;
alkyiaryl-represents an alkyl group, as defined above, bound to an aryi group, as defined below, wherein said aryl group is bound to the rest of the molecule;
aryl (including the aryl portion of alkylaryl)-represents a carbocyclic group containing from 6 to 15 carbon atoms and having at least one aromatic ring (e.g., aryl is a phenyl ring), with all available substitutable carbon atoms of the carbocyclic group being intended as possible points of attachment;
arylalkyl-represents an aryl group, as defined above, bound to an alkyl group, as defined above, wherein said alkyl group is bound to the rest of the molecule;
cycloalkyl-represents saturated carbocyclic rings of from 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms;
halo (halogen)-represents fluoro, chloro, bromo and iodo;
heteroaryl-represents cyclic groups, having at least one heteroatom selected from O, S or N, said heteroatom intermpting 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, furazanyl, triazolyl, thiazolyl, 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 (benzopyn-olyl), pyridopyrazinyl, isoqinolinyi,

J
heterocycloalkyl-represents a saturated, carbocylic ring containing from 3 to 15 carbon atoms, preferably from 4 to 6 carbon atoms, which carbocyclic ring is internjpted by 1 to 3 hetero groups selected from -0-, -S- or - NR40- wherein R40 represents Ci to Ce alkyl, arylalkyl, -C(0)R4 -C{0)OR4 or .C(0)N(R45)2 (wherein R45 is as defined above, and each R45 is independently selected); 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-piperi2inyl, 2- or 4-dioxanyl. 1,3-dioxolanyl, 1,3,5-trithianyl, pentamethyiene sulfide, perhydroisoquinolinyl, decahydroquinolinyl. trimethylene oxide, azetidinyl, l-azacycioheptanyl, 1,3-dithianyI. 1,3,5-trioxanyl, morpholinyi, thiomorpholinyl. 1,4-thioxanyl, and 1,3,5-hexahydrotria2inyI, thiazolidinyl, tetrahydropyranyi;
lower alkyl-represents an alkyl group, as defined above, that comprises 1 to 6 carbon atoms, preferably 1-4 carbon atoms;
lower alkoxy-represents an alkoxy group whose alkyl moiety comprises 1 to 6 carbon atoms, preferably 1-4 carbon atoms;

AcOH-represents acetic acid;
t-BOC-representst-butyioxycarbonyl;
Ci/mmol-represents curie/mmol (a measure of specific activity);
m-CPBA-represents m-chioroperbenzoic acid;
CSA-represents camphorsulfonic acid;
CBZ-represents carbonylbenzyloxy (-C(0)OCH2C6H5);

DBU-represents 1,8-diazabicyclo[5.4.0]undec-7-ene; DBN-represents 1,5-dia2abicyclo[4.3.0]non-5-ene; DCC-representsdicyclohexylcarbodiimide; Dibal-H-represents diisobutylaiuminum hydride; DIPEA-represents N,N-diisopropylethylamine; DMAP-represents 4-(d}methylamino)pyridine; DEC-represents 2-diethyIaminoethyl chloride hydrochloride; DMF-represents dimethylformamide;
EDCI-represents 1-{3-dimethylaminopropyl)-3-ethylcarbodiimide; EtOAc-represents ethyl acetate; EtOH-represents ethanol; FMOC-represents9-fluorenylmethoxycarbonyl;
HOBT-represents 1 -hydroxybenzotriazole;
HPLC-represents high performance liquid chromatography;
HRMS-represents high resolution mass spectrometry;
Ki-represents inhibition constant for substrate/receptor complex;
LAH-lithium aluminum hydride;
LDA-represents lithium diisopropylamide;
LRMS-represents low resolution mass spectrometry;
MeOH-represents methanol;
NaBH{0Ac)3-represents sodium triacetoxyborohydride;
NaBH4-represents sodium borohydride;
NaBH3CN-represents sodium cyanoborohydride;
NaHMDS-represents sodium hexamethyl disilyiazide;
nM-represents nanomolar;
pA2-represents -logECso, as defined by J. Hey, Eur. J. Pharmacol., (1995),
Vol. 294, 329-335; PCC-represents pyridinium chlorochromate; PyBOP-represents benzotriazole-1-yl-oxy-trispyrrolidino-phosphonium
hexaflurophosphate; TEMPO-represents 2,2,6,6-etramethyl-1-piperidinyloxy. free radical; TFA-represents trifluoroacetic acid; TMAD-represents N,N,N',N'4etramethylazodicarboxamide;

TMEDA-represents tetramethylethylenediamine; Tr-represents triphenylmethyl; Tris-representstris(hydroxymethyl)aminomethane;and p-TsOH-represents p-toluenesulfonic acid.

pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated forms for purposes of the invention.
The compounds of this invention can be combined with an Hi receptor antagonist (i.e., the compounds of this invention can be combined with an Hi receptor antagonist in a phannaceutical composition, or the compounds of this invention can be administered with H1 receptor antagonist).
Numerous chemical substances are known to have histamine H1 receptor antagonist activity. Many useful compounds can be classified as ethanolamines, ethylenediamines, alkylamines, phenothiazines or piperidines. Representative Hi receptor antagonists include, without limitation: astemizole, azatadine, azelastine. acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyioratadine (also known as SCH-34117), diphenhydramine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine. meclizine, mizolastine. mequrtazine, mianserin, noberastine, norastemizole, picumast, pyrilamine, promethazine, terfenadine. tripelennamine, temelastine, trimeprazine and triprolidine. Other compounds can readily be evaluated to determine activity at Hi receptors by known methods, including specific blockade of the contractile response to histamine of isolated guinea pig ileum. See for example, WO98/06394 published Febnjary19,1998.
Thus, in the methods of this invention wherein a compound of Formula I is combined with an effective amount of an H1 receptor antagonist, said H1 receptor antagonist is selected from: astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine. cyproheptadine, carbinoxamine, descarboethoxyioratadine. 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.
Also, in the methods of this invention wherein a compound of Formula I is combined with an effective amount of an H1 '•eceptor antagonist, said H1 receptor antagonist is selected from: astemizole, azatadine, azelastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, carebastine, descarboethoxyioratadine.

diphenhydramine, doxylamine, ebastine. fexofenadine, loratadine. levocabastine, mizolastine, norastemizole. or terfenadine.
Also, in the methods of this invention1 receptor antagonist, said H1 receptor antagonist is selected from: azatadine, brompheniramine, cetirizine, chlorpheniramine, carebastine, descarboethoxyioratadine (also known as SCH-34117), diphenhydramine, ebastine, fexofenadine, loratadine, or norastemizole.
Also, in the methods of this invention wherein a compound of Formula I is combined with an effective amount of an H1 receptor antagonist, said H1 receptor antagonist is loratadine.
Also, in the methods of this invention wherein a compound of Fomiula I is combined with an effective amount of an H1 receptor antagonist, said H1 receptor antagonist is descarboethoxyioratadine.
Also, in the methods of this invention wherein a compound of Formula I is combined with an effective amount of an H1 receptor antagonist, said H1 receptor antagonist is fexofenadine.
Also, in the methods of this invention wherein a compound of Formula I is combined with an effective amount of an Hi receptor antagonist, said Hi receptor antagonist is cetirizine.
Preferably, in the above methods, allergy-induced airway responses are treated.
Also, preferably, in the above methods, allergy is treated.
Also, preferably, in the above methods, nasal congestion is treated.
Preferably, in the above methods using a combination of a compound of Formula I (H3 antagonist) and an H1 antagonist, the H1 antagonist is selected from: loratadine, descarboethoxyioratadine, fexofenadine or cetirizine. Most preferably the H1 antagonist is loratadine or descarboethoxyioratadine.
In the methods of this invention wherein a combination of an H3 antagonist of this invention (compound of Formula I) is administered with a Hi antagonist, the antagonists can be administered simultaneously, consecutively (one after the other within a relatively short period of time), or sequentially (first one and then the other over a period of time). In general, when the antagonists are administered

consecutively or sequentially, the H3 antagonist of this invention (compound of Fomiula I) is administered first.
Thus, one emodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of Compound 32 and a pharmaceutically acceptable carrier.
Another emodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of Compound 54 and a pharmaceutically acceptable carrier.
Another emodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of Compound 55 and a pharmaceutically acceptable carrier
Another emodiment of this Invention is directed to a phanmaceutical composition comprising an effective amount of Compound 253A and a pharmaceutically acceptable carrier,
Another emodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of Compound 287 and a pharmaceutically acceptable carrier.
Another emodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of Compound 320 and a pharmaceutically acceptable carrier.
Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced airway responses, congestion, hypotension, cardiovascular disease, hypotension, 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 hyperactivrty 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 Compound 32.
Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced airway responses, congestion, hypotension, cardiovascular disease, hypotension, diseases of the Gl 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 amourt of Compound 54.
Another embodiment of this invention is directed to a method of treating; allergy, allergy-induced airway responses, congestion, hypotension, cardiovascular disease, hypotension, diseases of the Gl 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 Compound 55.
Another embodiment of this invention Is directed to a method of treating: allergy, allergy-induced airway responses, congestion, hypotension, cardiovascular disease, hypotension, diseases of the Gl 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 Compound 253A.
Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced airway responses, congestion, hypotension, cardiovascular disease, hypotension, diseases of the Gl 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 Compound 287.
Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced airway responses, congestion, hypotension, cardiovascular disease, hypotension, diseases of the Gl 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 mioraine

comprising administering to a patient in need of such treatment an effective amount of Compound 320.
Another embodiment of this invention is directed to a method of treating allergy-induced airway responses comprising administering to a patient in need of such treatment an effective amount of Compound 32.
Another embodiment of this invention is directed to a method of treating allergy-induced airway responses comprising administering to a patient in need of such treatment an effective amount of Compound 54.
Another embodiment of this invention is directed to a method of treating allergy-induced airway responses comprising administering to a patient in need of such treatment an effective amount of Compound 55.
Another embodiment of this invention is directed to a method of treating allergy-induced airway responses comprising administering to a patient in need of such treatment an effective amount of Compound 253A.
Another embodiment of this invention is directed to a method of treating allergy-induced airway responses comprising administering to a patient in need of such treatment an effective amount of Compound 287.
Another embodiment of this invention is directed to a method of treating allergy-induced airway responses comprising administering to a patient in need of such treatment an effective amount of Compound 320.
Another embodiment of this invention is directed to a method of treating allergy or nasal congestion comprising administering to a patient in need of such treatment an effective amount of Compound 32.
Another embodiment of this invention is directed to a method of treating allergy or nasal congestion comprising administering to a patient in need of such treatment an effective amount of Compound 54.
Another embodiment of this invention is directed to a method of treating allergy or nasal congestion comprising administering to a patient in need of such treatment an effective amount of Compound 55.
Another embodiment of this invention is directed to a method of treating allergy or nasal congestion comprising administering to a patient in need of such treatment an effective amount of Compound 253A.

Another embodiment of this invention is directed to a method of treating allergy or nasal congestion comprising administering to a patient in need of such treatment an effective amount of Compound 287.
Another embodiment of this invention is directed to a method of treating allergy or nasal congestion comprising administering to a patient in need of such treatment an effective amount of Compound 320.
Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of Compound 32, and an effective amount of H1 receptor antagonist, and a pharmaceutically effective carrier.
Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of Compound 54, and an effective amount of H1 receptor antagonist, and a pharmaceutically effective carrier.Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of Compound 55, and an effective amount of H1 receptor antagonist, and a pharmaceutically effective carrier.
Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of Compound 253A, and an effective amount of H1 receptor antagonist, and a phanmaceutically effective carrier.
Another embodiment of this invention is directed to a phanmaceutical composition comprising an effective amount of Compound 287, and an effective amount of H1 receptor antagonist, and a pharmaceuticaiiy effective canier.Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of Compound 320. and an effective amount of Hi receptor antagonist, and a pharmaceutically effective carrier.
Another embodiment of this invention is directed to 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 Compound 32 in combination with an effective amount of an H1 receptor antagonist.
Another embodiment of this invention is directed to 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 Compound 54 in combination with an effective amount of an H1 receptor antagonist.

Another embodiment of this invention is directed to 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 55 in combination with an effective amount of an Hi receptor antagonist.Another embodiment of this invention is directed to 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 Compound 253A in combination with an effective amount of an Hi receptor antagonist.
Another embodiment of this invention is directed to 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 Compound 287 in combination with an effective amount of an H1 receptor antagonist.
Another embodiment of this invention is directed to 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 Compound 320 in combination with an effective amount of an H1 receptor antagonist.
Another embodiment of this invention is directed to 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 Compound 32 in combination with an effective amount of an 1 receptor antagonist 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.
Another embodiment of this invention is directed to 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 Compound 54 in combination with an effective amount of an H1 receptor antagonist 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, teri'enadine, tripelennamine, temeiastine, trimeprazine or triprolidine.
Another embodiment of this invention is directed to 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 Compound 55 in combination with an effective amount of an H1 receptor antagonist selected from: astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarix)ethoxyloratadine, diphenhydramine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, meclizine, mizolastine, mequitazine, mianserin, noberastine, norastemizole, picumast, pyrilamine. promethazine, terfenadine, tripelennamine, temeiastine, trimeprazine or triprolidine.
Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced ainway responses, and congestion comprising administering to a patient in need of such treatment an effective amount of Compound 253A in combination with an effective amount of an H1 receptor antagonist selected from: astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descari3oethoxyloratadine, diphenhydramine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, meclizine, mizolastine, mequitazine, mianserin, noberastine, norastemizole, picumast, pyrilamine, promethazine, terfenadine, tripelennamine, temeiastine, trimeprazine or triprolidine.
Another embodiment of this invention is directed to 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 Compound 287 in combination with an effective amount of an H1 receptor antagonist selected from: astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine. cyproheptadine, carbinoxamine,

descarboethoxyloratadine, diphenhydramine, doxylamine, dinnethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, fevocabastine, meclizine, mizolastine, mequitazine, mianserin, noberastine, norastemizole, picumast, pyriiamine, promethazine, terfenadine, tripeiennamine, temelastine, trimeprazine or triprolidine.
Another embodiment of this invention is directed to 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 Compound 320 in combination with an effective amount of an H1 receptor antagonist selected from: astemizole, azatadlne, azelastine, acrivastine. brompheniramine, cetirizine, chlorpheniramine, clemastine, cyciizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine, diphenhydramine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotrfen, loratadine, levocabastine, meclizine, mizolastine, mequitazine, mianserin, noberastine, norastemizole, picumast, pyriiamine, promethazine, terfenadine, tripeiennamine, temelastine, trimeprazine or triprolidine.
Another embodiment of this invention is directed to 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 Compound 32 in combination with an effective amount of an Hi receptor antagonist selected from: loratadine, descariboethoxyloratadine, fexofenadine or cetirizine.
Another embodiment of this invention is directed to 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 Compound 54 in combination with an effective amount of an H1 receptor antagonist selected from: loratadine, descariboethoxyloratadine, fexofenadine or cetirizine.
Another embodiment of this invention is directed to 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 Compound 55 in combination with an effective amount of an Hi receptor antagonist selected from: loratadine. descarboethoxyloratadine, fexofenadine or cetirizine.
Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced ain-vay responses, and congestion comprising administering

to a patient in need of such treatment an effective amount of Compound 253A in combination with an effective amount of an Hi receptor antagonist selected from: loratadine. descarboethoxyloratadine, fexofenadine orcetirizine.
Another embodiment of this invention is directed to 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 Compound 287 in combination with an effective amount of an H1 receptor antagonist selected from: loratadine, descarboethoxyloratadine, fexofenadine orcetirizine.
Another embodiment of this invention is directed to 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 Compound 320 in combination with an effective amount of an H1 receptor antagonist selected from: loratadine, descarboethoxyloratadine, fexofenadine or cetirizine.
Another embodiment of this invention is directed to 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 Compound 32 in combination with an effective amount of an Hi receptor antagonist selected from; loratadine or descarboethoxyloratadine.
Another embodiment of this invention is directed to 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 Compound 54 in combination with an effective amount of an H1 receptor antagonist selected from; loratadine or descarboethoxyloratadine.
Another embodiment of this invention is directed to 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 Compound 55 in combination with an effective amount of an Hi receptor antagonist selected from; loratadine or descarboethoxyloratadine.
Another embodiment of this invention is directed to 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 Compound 253A in combination with an effective amount of an H1 receptor antagonist selected from; loratadine or descarboethoxyloratadine.

Another embodiment of this invention is directed to a method of treating: allergy, allergy-induced ainway responses, and congestion comprising administering to a patient in need of such treatment an effective amount of Compound 287 in combination with an effective amount of an H1 receptor antagonist selected from: loratadine or descarboethoxyloratadine.
Another embodiment of this invention is directed to 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 Compound 320 in combination with an effective amount of an Hi receptor antagonist selected from: loratadine or descarboethoxyloratadine.
R' is preferably selected from:
(A) aryl (most preferably phenyl);
(B) substituted aryl (e.g., substituted phenyl), wherein the substituents on said substitued aryl are most preferably selected from: (1) halo (e.g., monohalo ordihaio), more preferably chloro orfluoro, even more preferably monochloro, dichloro. monofluoro or difluoro; or (2) alkyl, more preferably unbranched (i.e., straight chain, e.g., methyl) alkyl, even more preferably substituted alkyl, still more preferably alkyl substituted with halo (e.g., 1, 2 or 3 halo atoms, such as CI or F), even still more preferably alkyl substituted with fluoro atoms, yet still more preferably trifluromethyl;
(C) heteroaryl, most preferably a five or six membered heteroaryl ring, more preferably a six membered heteroaryl ring, and still more preferably pyridyl, examples of heteroaryl rings include pyridyl, thienyl, pyrimidinyl, thiazolyl or pyridyl N-Oxide, most preferred heteroaryl rings are exemplified by

wherein c is most preferably 0 or 1. and when c is 1 then R6 is most preferably halo, and when c is 1 then R6 is more preferably fluoro.
X is preferably =C{NOR3) wherein R3 is preferably selected from H, alkyl or halo substituted alkyl (e.g-. fluoro substituted alkyl, such as -CH2CF3), most preferably alkyl, more preferably methyl or ethyl, and still more preferably methyl.
Preferably M2 is nitrogen.
n is preferably 2.
a is preferably 0 or 1, and most preferably 0.
b is preferably 0 or 1, and most preferably 0.
c is preferably 0 or 1, and most preferably 0, and when c is 1 then R6 is preferably halo, and when c is 1 R^ is most preferably fluoro.
eis preferably 1-5,
Y is preferably =C(0) (i.e.. =C=0).
M^ and M"^ are preferably selected such that: (1) one is carbon and the other is nitrogen, or (2) both are nitrogen, with M3 most preferably being carbon.

R3is preferably H or alkyl, most preferably H or methyl.
R4 is preferably H or lower alkyl, most preferably H or methyl, and more preferably H.
R5 is preferably H, C1 to C6alkyI or-C{0)R4, most preferably H or methyl, and more preferably H.
R12 is preferably alkyl, hydroxy! or fluoro, and most preferably H.
R13 is preferably alkyl, hydroxyl or fluoro, and most preferably H.
Representative compounds of this invention include, but are not limited to: Compounds 23, 30, 31, 32, 33, 41. 44,45,49, 50. 52, 53, 54, 55, 56, 57A, 59, 65, 75, 76, 80, 82, 83. 88, 92, 99, 104, 105,110. 111, 117,121. 123, 127, 128,200-241, 244-273, 275, and 278-282, 287, 296, 301-439 and 446.
Thus, representative compounds of this invention include, but are not limited to: Compounds 23, 30. 31, 32, 33, 44, 45,49, 50. 53, 54, 55, 59, 75,76, 83, 88, 92,

99, 104, 110, 117, 128, 200, 201. 203-215, 217-241, 244-246, 246A, 247-263, 253A, 254-273, 275, 278, and 280-282, 317, 334 and 403.
Preferred compounds of this invention are selected from: Compound 23, 30. 31, 32, 33, 50, 53. 54, 55, 56, 57A, 59, 92, 212, 215, 218. 219, 220, 224, 225, 225, 227, 229, 233, 235, 237, 238. 246. 246A, 247. 248, 251, 253. 253A. 268-273. 275. 278-281. 287. 296. 301. 304-307, 309. 312. 314-318. 320-356, or 358-376.
Most preferred compounds of this invention are selected from: Compound 30, 31. 32. 33. 54. 55, 56, 57A, 225. 237. 246A, 253A. 273, 280. 287. 296, 301, 304-307, 309, 312. 314-318. 320-348. 350-356, 359-372, and 374-376.
Thus, one embodiment of this invention is directed to Compound 32.
Another embodiment of this invention is directed to Compound 54.
Another embodiment of this invention is directed to Compound 55.
Another embodiment of this invention is directed to Compound 253A.
Another embodiment of this invention is directed to Compound 287.
Another embodiment of this invention is directed to Compound 320.
Structures for the above compounds are found in the Examples below, and in Tables 1 to 3 below.

One synthetic route involves a linear sequence of reactions to obtain the desired compounds, i.e.,
A + B->AB + C-> ABC + D -> ABCD
This linear sequence of reactions to synthesize compounds of this invention is illustrated below. In the illustrated procedure R1 is aryl, heteroaryi, or alkyl; X = a ketone, oxime or substituted oxime; M1 = M3 = carbon; M2 = M4 = nitrogen; Y is C=0; Z = CHR; R2 is heteroaryi; and n and m = 2 (n and m being 1 can also be prepared by this procedure).

In the above equations PG represents a protecting group, and M represents Li or MgX1 (wherein X1 represents CI, Br or I).
In equation 1 and 2, a Grignard reagent 2 is reacted with an electrophile such as the aldehyde 1 or the nitrile 4 in a suitable aprotic solvent such as THf;or ether. PG represents a protecting group. Suitable protecting groups include, for example, methyl and benzyl, in the case of nitrile 4, acidic workup yields the ketone 8 directly. Alcohol 3 can be oxidized by a number of different reagents to give 8, Altematively, the amide 7 can be reacted with an organometallic reagent to directly give the ketone 8. Suitable protecting groups for this step include carbamates or amides or the like. Thus, examples of protecting groups in equation 3 include t-BOC, CBZ and FMOC.

CH2CI2 in the presence of molecular sieves. After the reaction is complete (e.g.,i to 10 h), a reducing agent such as NaBH(0Ac)3 is added. Alternatively, when E is a halogen atom such as CI or Br, 12 and 13 are combined in a solvent, such as DMF, in the presence of a tertiary amine base to give the product 14. Suitable protecting groups include, for example t-Boc, phthaloyl.

M represents Li. Na, or K.
Compound 17 is saponified in a mixed solvent, such as, for example: (1) EtOH or MeOH and water, or (2) THF, water, and MeOH. using an alkali metal base such as LiOH or NaOH at a temperature of from 50 to 100°C to give the salt 18.
Compound 18 can be combined with compound 9. as described above, to give 14. The remaining steps are the same.
Compounds useful in this invention are exemplified by the following examples which should not be construed as limiting the scope of the disclosure. Alternative mechanistic pathways and analogous structures within the scope of the invention may be apparent to those skilled in the art.

To a solution of 19.15 g (85.5 mmol) of alcohol 2A in 640 ml of CH2CI2 was added saturated aqueous solution of 8.62 g (103 mmol) of NaHCO3 and 444 mg (4.3 mmol) of NaBr. Reaction mixture was cooled to 0°C, and 140 mg (0.90 mmol) of TEMPO was introduced. Upon vigorous stirring 122 ml of 0.7 M (85.4 mmol) commercial bleach solution (5.25% in NaOCI) was added in portions over 40 min. After additional 20 min at 0°C reaction mixture was quenched with saturated aqueous NaaSaO3 and allowed to warm to room temperature. Dilution with water and

extraction with CH2CI2 were followed by concentration and flash chromatography (from 30% hexanes/ CH2CI2 to 0 - 2% acetone/ CH2CI2) to afford 15.97 g (71.9 mmol; 84%) of aldehyde 3A as an off-white solid.

To a solution of 1.57 g (4.33 mmol) of ester 4A in 10 ml of a 3 : 1 : 1 mixture of THF - water - methanol was added 0.125 g (5.21 mmol) of LiOH. Reaction mixture was stirred overnight at room temperature, concentrated and exposed to high vacuum to obtain 1.59 g of crude acid 5A as a yellowish solid which was used without purification.

To a solution of 8A (10 g, 79.4 mmol) and DMAP (0.029 g, 0.24 mmol) in methylene chloride (150 mL) at 0°C was added phthaloyl dichloride (16,1 g, 79.4 mmol) dropwise. The reaction mixture was stirred at room temperature overnight. After stirring ovemight, the reaction was washed with saturated aqueous NaHCOs. water, dried and concentrated to give compound 9A as a yellow solid (20 g, 99.8%) which was used without further purification.

Compound 10A (0.5 g, 1.5 mmol) and hydrazine (0.5 M in ethanol, 5 mL, 2.5 mmol) were combined and stirred at room temperature ovemight. The reaction was diluted with water and extracted with methylene chloride. The organic layer was dried, concentrated and the residue purified on a flash column (3% methanol in ethyl acetate) to give compound 11A (0.2 g, 66%).

Compounds 12A (2 g, 18.o mmol) and 13A {3.5 g. 22 mmol) were dissolved in methylene chloride and stirred at room temperature for 1 h. NaB(0Ac)3H (5.4 g, 25.6 mmol) was added and the mixture stirred at room temperature for 5h. The reaction was washed with saturated aqueous NaHCO3, dried and concentrated, and the residue purified by flash column (2% methanol in ethyl acetate). Compound 14A was obtained (4.5g, 99%).

To the solution of 2,4-diflorobenzylaldehyde (16A. 28.1mmoi) in THF (10ml) was added the Grignard reagent 17A (1.33M in THF. 30ml), and the mixture was stirred at room temperature overnight. The reaction was quenched with saturated NH4CI (150ml), extracted three times with EtOAc (100ml). dried, filtered and concentrated. Flash chromatography (20% MeOH/EtOAc) yielded the desired compound 18A (1.8g. 27%).

To the suspension of NaH (0.41g, 10.2 mmol) in THF (10ml) was slowly added a solution of 19A (1.3 g, 5.11 mmol) in DMF (5 mL) dropwise and the reaction stirred at 70~75°C overnight. The mixture was extracted twice with EtOAc and three times with H2O (30 mL), dried over MgS04 and concentrated to give crude 20A which was used without further purification (1.04 g, 87%).

To the solution of compound 20A (4.3 mmol) in dichloroethane (20 ml) at 0°C was added 2-chloroethyl chloroformate (6.2 mmol) and triethylamine (7.2 mmol) and the reaction was stirred at room temperature ovemight. The solvent was evaporated, Et20 was added to the residue, and the unreacted starting material was removed by filtration. The filtrate was concentrated and the residue redissolved in MeOH and refluxed for 30 min. Removal of the methanol gave the product 21 (0.3g) which was used without further purification.

Compound 22 (0.2 g. 0.37 mmol) was dissolved in CF3CO2H (3 mL) and methylene chloride (3 mL)and stirred at room temperature ovemight. The solvent was removed by evaporation, saturated aqueous NaHCO3 was added and mixture

A solution of 24 (50 g. 387 mmol) and triethylamine (110 mL) in dioxane (400 mL) and water (400 mL) at 4°C was treated with B0C2O (93 g. 426 mmol). The cooling bath was removed and the solution allowed to warm to room temperature. After 21 h. the volume was reduced by two-thirds under vacuum. The residue was poured into ethyl acetate (250 mL) and water (250 mL). Saturated aqueous NaHCOa (250 mL) was added and the organic phase was separated and discarded. The aqueous phase was acidified with 10% HCI and extracted with ethyl acetate. The combined organic phases were washed with water, brine, and dried (Na2S04), and concentrated to give 25 as a white powder (82 g. 94%),

To a solution of 2-bromopyridine (17.6 mL. 0.184 mol) in THF (600 mL) at -78°C was added n-BuLi (115 mL of a 16M solution in hexanes. 0.184 mol) dropwise over 15 min. After stirring for an additional 30 min at this temperature, a solution of 26 (25 g, 91.9 mmol) in THF (500 mL) was added dropwise over 15 min. The reaction was removed from the cold bath and placed in an oil bath and heated to 60°C for 1.5h, The reaction was then cooled to 4°C, diluted with ether (500 mL). and treated with saturated aqueous Na2S04 (~5 mL). The mixture was transfen-ed to an Erlenmeyer flask and diluted with additional ether (700 mL). Additional saturated aqueous Na2S04 was added followed by solid Na2S04. The mixture was filtered through a plug of solid Na2S04 and concentrated in vacuo. Flash column chromatography (0-20% ethyl acetate in hexanes) yielded compound 27 as a yellow oil (16.85 g, 63%).

To a suspension of compound 5A (17.4 g, 50 mmol), compound 28 (11 g, 42 mmol), and dlisopropylethylamine (34.6 mL, 199 mmo!) in DMF (125 mL) was added HOBT (7.83 g, 58 mmol), EDC (18.54 g, 96.7 mmol). and 4A molecular sieves. The mixture was stirred for 40 h at room temperature, diluted with methylene chloride (60O mL) and 0.5 N NaOH (400 mL) and filtered. The precipitate was washed thoroughly with additional 0-5N NaOH and methylene chloride. The combined organic phases were concentrated and chromatographed twice on silica gel (1:1 hexane:methylene chloride to 6% saturated NH3 in methanol in methylene chloride) to produce 29 as a tan solid (22.3 g) which was used as is in the next step.

Compound 30 (~17.9 g, 44 mmol) was dissolved in pyridine (420 mL). treated with HaNOCH3-HCI (21.78 g, 264 mmol) and heated to 90°C for 14h. The reaction was then concentrated and the residue taken up in a mixture of methylene chloride, (500 mL) and 2N NaOH (500 mL). The organic phase was separated and the aqueous phase extracted with additional methylene chloride (300 mL). The organic phases were dried and concentrated, and the residue chromatographed on SiOz (0-13% NH3/MeOH in CH2CI2) to produce a yellow solid (9.26 g). The mixed fractions from the column were rechromatographed to give an additional 3.23g of the desired material. Total yield 12.49 g (65% yield over the last two steps).

Compound 31 (1 g) in ethanol (15 mL) was separated into the pure isomers using a Chiralcel AD column (20 mm x 500 mm) (eiuent: 75:25 hexane: isopropanol plus 0.5% N,N-diethylamine; flow rate: 50 mL/min; UV detection at 254 nM) to give compound 32 (0.6 g) and compound 33 (0.4 g). [M+H]+ 437 for 32 and 33.
Alternatively, compound 32 can preferably be prepared from compound 5A in a manner similar to that described for compound 287 in Step 3 of Example 28,

Compound 37 (0.98 g. 3.78 mmol), N-Boc isonipocotic acid (0.87 g. 3.78 mmol). DEC (1.11 g, 5.7 mmol), HOBT (0.68g, 4.91 mmol) and DIPEA (3 mL) were combined in CH2CI2 (40 mL) and stin-ed overnight at room temperature..The reaction was then diluted with CH2CI2 and washed with saturated aqueous NaHCOs. The organic layer was dried, concentrated and the residue chromatographed (10% hexane in EtOAc) to give 38 (1.61 g, 91 %).

Compound 38 (1.61 g. 3.43 mmol) in CH2CI2 (15 mL) was treated with 1N HCl in dioxane (5.2 mL) and stirred overnight at room temperature. The solvent was removed in vacuo to give 39 (1.65 g) which was used without further purification.

In a manner similar to that described in Example 7, Steps 3-4, compound 42 was converted to compound 43.

To a solution of 43 (2.3 g. 6.3 mmol) in CH2CI2 (60 mL) was added 4A molecular sieves and 4-formylpyridine (0.68 mL, 6.9 mmol) and the mixture stirred for 3 h at room temperature. Na(0AG)3BH (2.7 g, 12.7 mmol) was then added and the reaction stirred for 1h. The reaction was quenched by the addition of NH4CI followed by the addition of saturated aqueous NaHCO3. The reaction mixture was then extracted with EtOAc, and the combined organic layers were dried and concentrated to give a residue which was chromatographed (20% MeOH in EtOAc). Compound 44 was obtained (2.3 g, 87%).

A mixture of compound 48 (0.57 g, 2 mmol) and compound 42 (0.52 g, 2 mmol) in CH2CI (20 mL) was added EtaN (1.95 mL) and the reaction cooled to - 40°C. Triphosgene (0.2 g) was added and the reaction stirred at - 40°C for 2 h and room temperature for 48 h. The reaction was then washed with 1N NaOH, brine, and the organic layer dried. Concentration gave a residue that was purified by column chromatography (10% MeOH in EtOAc) to give 49 (0.14 g, 55%).

In a manner similar to that described in Example 7, Step 6, compound 49 (0.09 g, 0.21 mmol) was converted to compound 50.

A solution of n-BuLi (4.2 mL of a 1.6 M solution in hexane) in THF (25 mL) was treated at - 25°C with (i-Pr)2NH (0.69 g, 6.8 mmol). The reaction was stin-ed for 1 h at O'C and then cooled to - 70°C. Compound 4A (0.82 g, 2.26 mmol) in THF (5 mL) vvas added dropwise and the reaction stirred at - 70°C for 2 h and - 50°C for 2 h. The reaction was recooled to - 70°C and (1S)-(+)-(10-camphorsulfonyl)oxaziridine (1.04 g, 4.52 mmol) in THF (5 mL) was added. The reaction was stirred at - 70°C for 2 h and slowly warmed to room temperature overnight. The reaction was quenched by the addition of saturated aqueous NH4CI and extracted with EtOAc. The organic layer was dried and concentrated, and the residue purified by column chromatography (1:1 !iexane:EtOAc) to give 57 (0.44 g, 51%).

A solution of compound 60 (10 g, 50.7 mmol) in ether (150 mL) at - 78°C was treated sequentially with TMEDA (11.8 g, 101.4 mmol) and s-BuLI ( 58.5 mL of a 1.3M solution in hexanes, 76 mmol) and the reaction stirred at this temperature for 6 h. Neat CH3SO4CH3 (12.8 g, 101.4 mmol) was then added and the reaction allowed to slowly warm to room temperature overnight. Saturated aqueous NaCI was added and the organic layer was separated. The aqueous layer was extracted three times with ether and the combined organic layers were dried, concentrated, and the residue chromatographed (5% EtOAc in hexane) to give 61 (8.0 g, 75%).

reaction allowed to slowly warm to room temperature ovemight. The reaction v/as recooled to 0°C, EtOH (13 mL), pH = 7 buffer (25 mL) and H2O2 (25 mL) was added, and the reaction allowed to stir at room temperature overnight. The solvent was then removed in vacuo and the residue poured into water and CH2CI2. 10% aqueous NaOH (10 mL) was added and the organic layer separated. The aqueous layer was extracted with additional CH2CI2 and the combined organic layers were dried and concentrated. The residue was chromatographed (40% EtOAc in hexane) to give 62
{3g).

A solution of 62 (2.8 g, 12.2 mmol) in EtOAc (30 mL) and NaBr (1,26 g. 0.12 mmol) in saturated aqueous NaHCOs (30 mL) was cooled to 0°C and treated with TEMPO (0.02 g, 0.12 mmol). After 15 min., NaOCl (17.44 mL) was added and the mixture stirred for 3 h. Saturated aqueous Na2S203 was added and the pH adjusted to 5 - 6 by the addition of 1N HCI. The mixture was extracted with EtOAc and the organic layers were dried and concentrated. The residue was chromatographed (10 -20% EtOAc in hexane) to give compound 63 (2.1 g. 76%).

To a 0°C solution of Vilsmeier salt, prepared by the dropwise addition of phosphorus oxychloride (150.0 mL; 1.61 mol) to DMF (310.4 mL; 4.01 mol) over 15 min. and subsequent cooling in an ice bath, was added malonic acid (40.1 g; 0.39 mol) in portions over 45 min. The reaction mixture was then heated to 100°C, and the stining was continued for 48 h. The reaction mixture was then allowed to cool to room temperature and was quenched by slowly pouring it into a suspension of NaHCO3 (808 g; 9.62 mol) in water. The solution was decanted off the excess of NaHCO3 and concentrated to dryness under vacuum. After exposure to high vacuum for 2 days, the solid residue was washed repeatedly with CH2CI2 until TLC indicated complete removal of product. Combined organic extracts were concentrated under vacuum to produce 41.0 g of dark brown oil. which was used directly in the next step.

To a mixture of 166 mg (1.35 mmol) of aminopyrimidine 67. 17 mg (0.14 mmol) of DMAP and 418 µL (3.00 mmol) of EtaN in 10 mL of THF was added 589 mg (2.7 mmol) of (B0C)20. The mixture was stirred at room temperature for 5 h, concentrated-dry loaded on silica gel and flash chromatographed (1-3% acetone/ CH2CI2) to produce 117 mg (0.36 mmol; 27%) of 68 as a clear oil.

To a solution of 117 mg (0-36 mmol) of aldehyde 68 in 7 mL of CH2CI2 was added 67 µL (0.43 mmol) of ethyl isonipecotate and 5 µL of acetic acid. 30 min. later 153 mg (0,72 mmol) of NaBH(0Ac)3 was introduced. The mixture was stin-ed ovemight at room temperature, diluted with CH2CI2, washed with aqueous NaHCOs, dried and concentrated, and crude residue was flash chromatographed (0-4% sat. NH3 in MeOH/ CH2CI2 ) to produce 133 mg (0,29 mmol; 81%) of 69 as a white film.

Reaction mixture was then allowed to want) up and was then stinred for 2 h at room temperature, which resulted in the formation of an orange precipiate. The mixture was cooled back to -78°C, and ethylene oxide was bubbled through the solution for 1 min. followed by stining for 5 min. This two-step sequence was repeated eight times. The mixture was then allowed to warm to -50°C, stin-ed at that temperature for 40 min,, quenched with 1,34 mL (23 mmol) of AcOH and allowed to warm to room temperature. Dilution with water was followed by extraction with EtOAc, concentration of the organic phase, and flash chromatography of the cmde residue (10-15% acetone/ CH2CI2) to produce 1.50 g (5.95 mmol; 53%) of 71 as a white solid.

To a solution of 1.00 g (4.0 mmol) of aldehyde 72 in 25 mL of CH2CI2 was added 617 pL (4.8 mmol) of ethyl isonipecotate followed by one drop of AcOH, Reaction mixture was then stin-ed for 40 min at room temperature after which 1.70 g (8.0 mmol) of NaBH(OAc)3 was introduced. Reaction mixture was stin-ed overnight at room temperature, neutralized with saturated aqueous NaHCO3, diluted with water and extracted with CH2CI2. Concentration and flash chromatography (0 — 4% saturated NH3 in MeOH/ CH2CI2) provided 1.41 g (3.6 mmol; 90%) of 73 as a white solid.

To a solution of 77 (0.73 g, 3.82 mmol) in CH2CI2 (10 mL) was added (C0CI)2 (0.41 mL, 4.58 nnmol) followed by DMF (0.1 mL) and the reaction was maintained at 40°C for 3 h. The reaction was then concentrated to give a brown solid which was dissolved in CH2CI2 (10 mL). N,0-dimethyihydroxylamine hydrochloride (0.56 g, 5.73

mmol) and DIPEA (1.33 mL) were added and the reaction was stirred at room temperature overnight. The reaction was quenched by the addition of saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic layers were dried and concentrated, and the residue purified by chromatography to give 78 (3.2 g, 84%).

To a solution of 82 (0.115 g, 0.25 mmol) in DMF (4 mL) was added NaH (60% dispersion in mineral oil, 0.03g, 0.76 mmol). After 5 h at room temperature, CF3CH2OSO2CF3 (0.069 g. 0.3 mmol) was added and the reaction stirred at room temperature overnight. The reaction was diluted with EtOAc and extracted 3 times with water to remove the DMF. The organic layer was dried and concentrated to give a residue which was purified by chromatography (10% MeOH/NH3 in EtOAc) to give 83 (0.08 g. 30%).

To the mixture of 85 (9.2 g) and MnO2 (42 g ) was added 200ml CH2CI2. and the mixture was stired at room temperature ovemight. Additional Mn02 (20g ) was added and the reaction was stirred another 24hrs. The Mn02 was filtered off and the reaction was concentrated and flashed over silica gel( 5% and 10% MeOH (NH3)/CH2Cl2) to give 86 (3,1g, yield: 33%).

To the solution of 90 (0.65g) in CH2CI2 (6 ml) at -10°C was added TFA (6ml) and the reaction was stirred for 1 hr from -lO°C to O°C. Concentrated down and azeotroped twice with toluene (20ml), and concentrated to dryness to obtain 91 as a gummy oil which was used as is.

To a solution of 93 (5.17 g, 22.7 mmol) in THF (100 mL) at -50°C was added s-BuLI (38.4 mL of a 1.3M solution in hexane, 49.9 mmol) dropwise. After 1.5h at -40°C, the reaction was recooled to -50°C and 95 (4.84 g, 22.7 mmol) in THF (20 mL) was added. After 2.75 h at -50°C, glacial acetic acid was added followed by saturated aqueous NH4CI. The mixture was warmed to room temperature and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were dried (MgS04) filtered and concentrated to give a residue that was purified by flash column chromatography (1% to 3% MeOH/NHa in CH2CI2) to give 95 (6.35 g, 63%).

Compound 97 (0.7 g. 2.25 mmol), H2NOCH3-HCl (0.94 g, 11.23 mmo!) and NaOAc (1.47 g, 17.97 mmo!) were combined in 1-pentanol (20 mL) and water (2 mL) and heated to reflux for 2 days. The reaction was cooled to room temperature and 0.5 N NaOH was added. The EtOH was removed in vacuo, additional water (15 mL) was added, and the reaction extracted with 10% EtOH in CH2CI2 (180 ML total volume). The combined organic extracts were dried and concentrated to give 98 (0.55 g, 92%).

A solution of 2.2 g (9.5 mmol) of 100 in 75 mL of glacial acetic acid was hydrogenated in the presence of 0.5 g of 10% w/w piatinum-on-charcoal for 5 h. The reaction mixture was filtered to remove the catalyst and the filtrate was concentrated by evaporation under reduced pressure to produce a solid residue which was basified with 0.5N NaOH and extracted with methylene chloride (CH2CI2). Methylene chloride extracts were dried over anhydrous MgS04 and concentrated. The residue was purified by flash chromatography eluted with 10 - 30% of 7N NHs-MeOH in CH2CI2 to give 0.82 9 of 101 (mp 158-163 OC). LCMS m/z 240 (MH+).

A mixture of 0.12 g (0.52 mmol) of 101, 0.2 g (0.52 mmol) of 5A, 0.67 g (0.5 mmol) of 1-hydroxybenzotriazole hydrate (HOBt), and 0.11 g (0.57 mmol) of 1-(3-dimethylaminopropyl)-3-ethylGarbodiimide hydrochloride (DEC) in 7 mL of anhydrous dimethylformamide (DMF) was stin-ed at ambient temperature for 18 h. The mixture was diluted with water and the resulting precipitate was filtered to produce 0.26 g of 102 as a white solid (mp 110-115 °C). LCMS m/z 557 (MH+).

To a stirred solution of 0.34 g (2.7 mmol) of oxalyl chloride in 3 mL of anhyrous CH2CI2 at -70° C was added 0.44 g (5.7 mmol) of anhyrous methylsulfoxide in 2 mL of CH2CI2. After being stirred at -70° C for 10 minutes, the reaction mixture was added 1.2 g (2.15 mmol) of 102 in 10 mL of CH2CI2. The stired mixture was kept at -70° C for 0.5 h, mixed with 1.8 mL (13 mmol) of triethylamine, and then allowed to warm up to ambient temperature by itself. The mixture was diluted with water and extracted with CH2CI2. Organic extracts were washed with brine, dried over anhydrous MgS04 and concentrated to produce 1.18 g of 103 as a glass. LCMS m/z 555 (MH+).

A solution of 0.8g (1.44 mmol)of 103 and 0,6 g (7.2 mmol) of methoxylamine hydrochloride in 40 mL of ethanol and 40 mL of pyridine was heated under reflux for 18 h. The mixture was concentrated and the residue was taken up in ethyl acetate/ether and washed with water. The organic solution was dried over anhydrous MgS04 and concentrated to 0.65 g of viscous reidue which was dissolved in 8 mL of trifluoroacetic acid and 8 mL of CH2CI2 and stirred at ambient temperature for 18 h. The solution was concentrated and the residue was basified with IN NaHCO3 and extracted with ethyl acetate. Organic extracts were washed with brine, dried over anhydrous MgS04 and concentrated to a gummy residue. Purification of this residue by flash chromatography with 5-8% of 7N NH3-MeOH in CH2CI2 produced 0.151 g of 104 as a gum. LCMS m/z 484 (MH+) and 0.146 g of 105 as a glass, LCMS m/z 556 (mH+).

Mixing a solution of 0.056 g of the free base of 104 in ethyl acetate v/ith a solution of 0,04 g of maleic acid in ethyl acetate produced a precipitate which was isolated by filtration to give 0.06 g of a dimaleate salt of 104 (mp 155-160 OC).

0.32 g (0.58 mmol) of 109 were reacted with 0.6 g (7.2 mmol) of methoxylamine hydrochloride in the same manner as that described in Example 22, step 4 to provide 0.065 g of 110 as a gum, LCMS m/z 484 (MH+) and 0.12 g of 111 as a glass, LCMS m/z 556 (MH+).

A mixture of 18 g (74 mmol) of 112, 7.2 g ( 74 mmol) of N,0-dimethylhyroxylamine hydrochloride, 19.4 g (15 mmol) of N,N-diisopropylethyiamine, 1.1 g (8 mmol) of HOBt and 14.2 g ( 74 mmol) of DEC in 80 mL of anhydrous DMF was stirred at ambient temperature for 18 h. The mixture was diluted with water and extracted with ethyl acetate. Organic extracts were washed with 1% NaHCO3 and brine, dried over anhydrous MgS04 and concentrated to give 15.5 g of 113 as an oil. LCMS m/z 287 (MH+).

A mixture of 0.466 g (2 mmol) of 116, 0.517 g (2.2 mmol) of 5A, 0.276 g (2 mmol) of HOBt and 0.46 g (2.4 mmol) of DEC in 20 mL of anhydrous DMF was stirred at ambient temperature for 18 h. The mixture was concentrated by evaporation under reduced pressure at bath temperature of 25-45°C and the residue was chromatographed with 4% (7N NH3/CH3OH) in CH2CI2 to produce 0.48 g of symp which was dissolved in 15 mL of EtAc-EtOH (3:1 v) and mixed with a solution of 0.26 9 of maleic acid in 10 mL of EtAc-EtOH (1:1). The resuting precipitate was filtered to produce 0.35 g of the maleate salt of 117 (mp 160-163 OC). LCMS m/z 451 (MH+).

A solution of 3.71 g (8.8 mmol) of 118 and 3.7 g (44 mmol) of methoxylamine hydrochloride in 40 mL of pyridine and 40 mL of ethanol was heated under reflux for 2 days. The mixture was concentrated and the residue was taken up in CH2CI2 and washed with saturated aqeous NaCl. Organic solution was dried over anhydrous MgS04 and concentrated to give 2.6 g of 119 as a glass. LCMS m/z421 (MH+).

In a similar manner to that described In Example 6, step 7, 122 (0.26 g, 0.41 mmol) was converted to 123 (0.08 g, 40%).

To a suspension of LAH (0.83 g, 22 mmol) in ether (20 mL) at 0° C was added 124 (3.2 g, 17.5 mmol) in THF (15 mL) dropwise. The reaction was stirred at 0° C for 1.5 h, and quenched by the addition of water (0.8 mL), 20% aqueous NaOH (0.8 mL), and water (2.4 mL). The mixture was stirred for 15 min and filtered and the filter cake washed with CH2CL2. The filtrate was concentrated to give an oil which was dissolved in ether (30 mL) and washed with brine and dried (MgS04). Filtration and concentration in vacuo gave 125 (2.5 g) which was used without further purification.

The compounds in Table 1 (first column) are prepared from the compounds in the last column of Table 1 by following essentially the same procedures as in the examples described above. In Table 1 "Cmpd. No." stands for "Compound Number",

The isomers 246A and 253A. below, can be separated from 246 and 253, respectively, above, by techniques well known to those skilled in the art.

MeOH/ CH2CI2) to produce 1.55 g (5.87 mmol; 72%) of amine 285 as a yellowish solid.
Step 2
To a solution of 3.83 g (14.51 mmol) of ester 285 in 60 ml of 3 :1 : 1 mixture of THF - MeOH - H2O was added 1.22 g (29.02 mmol) of LiOH monohydrate. The reaction mixture was stirred at room temperature overnight, concentrated, and the residue was dried under high vacuum to produce 3.84 g of crude acid 286 lithium salt as a yellow solid. Material could be used directly or could be purified by passing through a silica gel plug eluting with ca. 3 N NH3 in MeOH.

To a mixture of 3.32 g (14.05 mmol) of acid 286 and 4.07 g (14.05 mmol) of 4-[(E)-(methoxyimino)-2-pyridinylmethyl]piperidine dihydrochloride (see Compound 447 below) in 40 mL of DMF was added 8.94 mL (70.25 mmol) of 4-ethylmorpholine and 14.0 mL (23.52 mmol) of 50 wt. % solution of 1-propanephosphonic acid cyclic anhydride in ethyl acetate. The reaction mixture was stirred for 4.5 h at 50°C followed by 14 h at room temperature. Concentration of the mixture was followed by exposure to high vacuum for 24 h to remove remainlng DMF. The residue was partitioned between aqueous NaOH and CH2CI2, organic phase v;as separated, dried and

concentrated, and the residue Was flash chromatographed (5-15% ca. 3 N NH3 in MeOH/ CH2CI2) to produce 4.60 g (10.51 mmol; 75 %) of amide 287 as a light tan foam. MS 438 (M+1).

3,4 Pyridine-dicarboximide 288 (10.0 g; 67.5 mmoles) was dissolved in 162 g. of 10% aqueous NaOH and the solution was cooled to an internal temperature of 7 °C in an ice-salt bath. Bromine (3.6 ml; 70 mmoles) was added dropwise. After the addition, the solution was heated for 45 minutes at a bath temperature of 80-85 °C. The yellow solution was then cooled to an internal temperature of 37 °C, then 17 ml of glacial acetic acid were added dropwise to a pH of 5.5. The resulting mixture was saved overnight in a refrigerator. The solid formed was filtered and washed with 5 ml of water and 5 ml of methanol. The reaction yielded 6.35 g. of product 289 melting at 280-285 °C (decomp.).

NaOH, then by 30 ml of water. The resulting solid was filtered through a pad of Celite and washed several times with THF. The oil obtained after evaporation of the solvent, solidified on standing. The reaction mixture was purified by flash chromatography on silica gel using 5%MeOH(NH3)/EtOAc as eluent yielding 6.21 (72%) of Compound 290 . LC-MS: m/z = 125 (M+1),

minutes with 100 ml of saturated aqueous sodium bicarbonate then separated from the aqueous layer. The organic layer was washed two more times with saturated aqueous sodium bicarbonate, then with brine and dried with anhydrous sodium sulfate. After evaporation of the solvent, the resulting oil was purified by flash chromatography on silica gel using EtOAc:Hexanes:MeOH(NH3) as eluent. The procedure yielded 6.8 gr.(94%) of Compound 292 . FAB-MS: m/z = 264 (M+1).

quenched with 50 ml. of 0.5 N aqueous NaOH, then the solution was extracted with dichloromethane. The combined extracts were washed with brine and dried over anhydrous sodium sulfate. The product 295 was isolated by flash chromatography on silica gel using EtOAc:Hexanes:MeOH(NH3) (50:45:5) as eluent. Yields: 0.27 gr. (47%). FAB-MS: m/z = 408 (M+1).

A mixture of 298 (1.8 g, 9 mmol), N,0-dimethyIhydroxylamine hydrochloride (2.6 g, 27 mmol), EDCI (5 g, 27 mmol), HOBt (0,1 g. 1 mmol). and DIPEA (12.5 mL, 72 mmol) in DMF (30 mL) was stin-ed at 20°C overnight. The reaction was then concentrated to half volume in vacuo, poured onto water, and extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous NH4CI, saturated aqueous NaHCO3. water and brine, dried (Na2S04), and concentrated to give 299 as a clear oil (2.1 g, 98%).

Following procedures similar to those of Steps 4 to 7 of Example 6, compound 301 was obtained. MS 409 (M+1).
Following procedures similar to those described in the examples above, the compounds in Table 2 were prepared.

If one were to follow procedures similar to those described in the examples above, the compounds in the "Structure" column of Table 3 would be obtained using the starting material listed in Table 3. Each compound in Table 3 is a mixture of oxime isomers, as represented by the ~~ bond between the oxime nitrogen and the OH or OCH3 moiety. In Table 3 "CMPD" stands for "Compound".

To a solution of LDA (233 mL, 2.0 M in THF/heptane/ethylbenzene, 0.466 mol) in THF (300mL) at 0 ""C was added, dropwise over 1.0 h, a solution of compound 440 (100g, 0.389 mol) in THF (~ 400 mL). The red-orange solution was stirred at 0 X for 30 min, and tlien 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 rt for 18 h. The total solvent volume was reduced to approximately one third, and EtOAc {- 1L) was added. The solution was washed successively with water, 0.1 N aq. HCI, saturated aq. NaHCOa, and brine. The organic layer was dried over MgS04, filtered, and concentrated under reduced pressure to yield a crude liquid. Separation by flash chromatography (6:1 hexanes-EtOAc) gave compound 441 (93.5 g, 87%).

In a manner similar to that described in Example 1, Step 4, compound 442 vvas converted to compound 443.

can be used to prepare the compounds of this invention, for example, see Examples 6 and 28. Preferably, Compound 447 Is prepared from a compound of formula:

and from a compound of Formula 449:

R50 is an alkyl or aryl group, f is 0 to 4, R51 is an alkyl group, and Q is a halo group, wherein said alkyl, aryl, and halo groups are as defined above. Compound 447 can be prepared from 448 and 449 by:
(a) converting the compound of formula 449 into its Grignard form

(c) reacting the compound of fonmula 450 with a suitable alkyl chloroformate of formula 451

to yield a compound of fonmula 452:

(e) reacting the compound of formula 453 with an alkoxyamine
(NHaOR51) or its hydrochloride to form an oxime of formula 454:

(f) isomerizing the compound of formula 454 by treatment with a
strong acid and simultaneously converting to the desired acid salt of Fonnula 454 with
an enriched E isomer, wherein the E isomer predominates over the Z-isomer by at

least a 90:10 ratio. When f=0, R51 is methyl, and the acid used for isomerization is HCi in the compound of fomriula 454, the final product is the compound of formula 447.

The conversion of compound 461 to 447 predominantly yields the E-isomer of compound 447 in high stereochemical purity and high yields, Isomerization of a mixture of phenyl compounds by acid catalysis is discussed by T. Zsuzsanna et al, HungMagyKm.Foly., 74(3) (1968), 116-119.
The above process starts with Compound 449. In step 1, a 4-halo-1-aikyipiperidine (or a 4-halo-l-arylpiperidine) is converted to its Grignard analog (449A) by reacting with magnesium. The reaction is performed generally at temperatures of about -10° C to reflux. Generally a hydrocarbon solvent such as. for example, toluene, xylene, chlorobenzene, dichlorobenzene and the like, or mixture of hydrocarbons listed above with an ether, such as, for example, a C5-C12 alkyl ether, 1,2-dimethoxyethane, 1.2-diethoxyethane, diglyme, 1,4-dioxane, tetrahydrofuran and the like are suitable for this reaction. The solution is cooled to around -10° C to about 10° C and then reacted with a suitable 2-cyanopyridine (448). for about 10-120 minutes. Examples of suitable 2-cyanopyridines are 2-cyanopyridine, 4-methyl-2-

cyanopyridine, 4-ethyl-2-cyanopyridine, 4-phenyl-2-cyanopyridine, and the like. Preferred are 2-cyanopyridine and 4-methyl-2-cyanopyridine. The Grignard compound is used generally in about 1-4 molar equivalents with respect to the compound of formula 448, preferably in about 1-3 molar equivalents and typically in about 1.5-2.5 molar equivalents. The product of formula 450 may be isolated by procedures well known in the art, such as, for example, treatment with an acid (e.g. HCI),' preferably in a suitable solvent (e.g., tetrahydrofuran or ethyl acetate).
The product of Fomiula 450 may then be reacted with an alkyl chloroformate in the next step. Suftable alkyl chloroformates are. for example, methyl chloroformate. ethyl chloroformate, propyl chloroformate, and the like, with the preferred being methyl chloroformate or ethyl chloroformate. Generally a hydrocarbon solvent such as, for example, toluene, xylene, chlorobenzene, dichlorobenzene and the like, or mixture of a hydrocarbons listed above with an ether such as, for example, a C5-C12 alkyl ether, 1,2-dimethoxyethane. 1.2-diethoxyethane, diglyme, 1,4-dioxane, tetrahydrofuran and the like Is suitable for this reaction. The reaction is generally performed at about 25-100°C, preferably about 40-90°C and typically about 50-80°C, for about 1-5 hours. After the reaction, generally the generated acid is washed off and the product of formula 452 may be isolated by organic solvent extraction.
The compound of Formula 452 may then be converted into its acid salt by treatment with an acid such as, for example, sulfuric acid, hydrochloric acid, trifluoroacetic acid and the like, generally in a solvent at temperatures between ambient and reflux of the solvent. Suitable solvents include hydrocarbons such as. for example, toluene, xylene, chlorobenzene. dichlorobenzene and the like. There being two nitrogen atoms in the compound of Formula 452, the salt generally has 2 moles of acid to a mole of compound 452.
The compound of formula 453 may then be converted to an alkyloxime of fomnula 454 by reacting it with an alkoxyamine (or its hydrochloride), usually in aqueous solution form. Suitable alkoxyamines are, for example, methoxyamine, ethoxyamine and the like. Methoxyamine is preferred. The alkoxyamine (or its hydrochloride) is employed generally in about 1 to about 4 molar equivalents, preferably in about 1 to about 3 molar equivalents, and typically in about 1 to about 2 molar equivalents. Generally, the reaction is catalyzed by a weak acid such as, for example, acetic acid, formic acid and the like, or mixtures thereof. A cosolvent such

as, for example, methanol, ethanol, isopropanol, n-butanol and the like, or mixtures thereof may be added. The product of formula 454, after work-up, is a mixture of the Z- and the E-isomers, whose ratio may be analyzed for its stereochemical make-up, using techniques well known in the art such as, for example, HPLC.
Treating the compound of formula 454 with a strong acid under the reaction conditions described below isomerizes the mixture of the Z and the E-isomers into predominantly the E-isomer. Generally, the compound of formula 454 may be dissolved in a solvent such as, for example, ethanol, methanol, isopropanol, n-butanol and the like, ether such as methyl tert-butyl ether, tetrahydrofuran and the like, hydrocarbon such as, for example, heptane, hexane, toluene and the like, nitrile such as, for example, acetonitrile, benzonitrile and the like, or mixtures of such solvents. The dissolved compound is then treated with a strong acid such as, for example, HCI, HBr, H2SO4 and the like, at temperatures in the range of 20 to 100°C for about 1-20 hours. The acid is employed generally in about 1 to about 8 molar equivalents, preferably in about 1 to about 6 molar equivalents, and typically in about 2 to about 4 molar equivalents. Work-up typically forms predominantly the acid salt of the E-isomerof the compound of formula 454, which is in fact the compound of formula 447 when R51 = methyl, n=0 and the acid salt is HCI in 454,
The products of the various steps in the process described above may be isolated and purified by conventional techniques such as, for example, filtration, recrystallization, solvent extraction, distillation, precipitation, sublimation and the like, as is well known to those skilled in the art. The products may be analyzed and/or checked for purity by conventional methods such as, for example, thin layer chromatography, NMR. HPLC, melting point, mass spectral analysis, elemental analysis and the like, well known to those skilled in the art.
H3-Receptor Binding Assay
The source of the H3 receptors in this experiment was guinea pig brain. The animals weighed 400-600 g. The brain tissue was homogenized with a solution of 50 mM Tris, pH 7.5. The final concentration of tissue in the homogenization buffer was 10% w/v. The homogenates were centrifuged at 1,000 x g for 10 min. in order to remove clumps of tissue and debris. The resulting supernatants were then centrifuged at 50,000 x g for 20 min. in order to sediment the membranes, which were

next washed three times in homogenization buffer (50,000 x g for 20 min, each). The membranes were frozen and stored at -70°C until needed.
All compounds to be tested were dissolved in DMSO and then diluted into the binding buffer (50 mM Tris, pH 7.5) such that the final concentration was 2[jg/ml with 0.1% DMSO. Membranes were then added (400 \}g of protein) to the reaction tubes.
The reaction was started by the addition of 3 nM [^HJR-a-methyl histamine (8.8
Ci/mmol) or 3 nM [3H]N"-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 en-or was always less than 10%. Compounds that inhibited more than 70% of the specific binding of radioactive ligand to the receptor were serially diluted to determine a Kj (nM).
Compounds 23, 30, 31, 32. 33,44,45, 49, 50, 53, 54, 55. 56, 57A, 59, 75. 76, 83, 88, 92, 99,104,110, 117, 128, 200. 201, 203-215, 217-241, 244-246, 246A, 247-253, 253A. 254-273, 275. 278. 280-282, 287. 296. 301-310, and 312-379 had a Kj within the range of about 0.25 to about 370nM.
Preferred Compounds 23. 30. 31. 32, 33, 50. 53,54, 55. 56, 57A, 59, 92, 212. 215, 218. 219.220.224. 225, 226. 227, 229, 233,235, 237, 238, 246. 246A, 247. 248. 251, 253, 253A. 268-273, 275. 278-281, 287, 296, 301, 304-307. 309, 312, 314-318, 320-356, and 358-376 had a K1 within the range of about 0.25 to about 33nM.
Most preferred Compounds 30, 31, 32, 33. 54, 55, 56. 56A, 225,237. 246A, 253A, 273, 280. 287, 296, 301. 304-307. 309, 312. 314-318, 320-348, 350-356, 359-372, and 374-376 had a K1 within the range of about 0.25 to about 16nM.
More preferred compound 32 had a Kj of 0.83nM.
More preferred compounds 54, 55, 253A, 287, 320 had a Ki within the range of about 1.05 to about 9.75nM.
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 fonns suitable for oral administration. Examples of pharmaceutically acceptable earners and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, PA.
Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
Aerosol preparations suitable for inhalation may Include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable cam'er, such as an inert compressed gas, e.g. nitrogen.
Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.
The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdemial patch of the matrix or reservoir type as are conventional in the art for this purpose.
Preferably the compound is administered orally.
Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 150 mg, preferably from about 1 mg to about 75 mg, more preferably from about 1 mg to about 50 mg, according to the particular application.
The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For

convenience, the total daily dosage may be divided and administered in portions during the day as required.
The amount and frequency of administration of the compounds of the invention. and/or the 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.
The methods of this invention described above using a compound of Formula I also include the use of one or more compounds of Formula I, and the methods of this invention described above using a compound of Formula I in combination with an Hi receptor antagonist also include the use of one or more compounds of Formula I in combination with one or more H1 receptor antagonists.
While the present 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.

WE CLAIM:

or a pharxnaceutically acceptable salt or solvate thereof, wherein:
(1) R1 is selected from:
(a) aryl;
(b) heteroaryl;
(c) heterocycloalkyl
(d) alkyl;
(e) cycloalkyl; or
(f) alkylaryl;
wherein said R1 groups are oplionally subsliluled with 1 to 4 substituenis independently selected from: (J) halogen;
(2) hydroxy!;
(3) lower alkoxy;
(4) - CF3;
(5) CF,0~-i
(6) —NR-4R5;
(7) phenyl;
(8) —NO,,
(9) —CO.R4
(10) ~CbN(R4)2 wherein each R4 is the same or
different;
(11) S(OX,N(R20)2, wherein each R20 is the same or diJDFerent H or alkyl group;
(12) —CN; or
(13) alkyl; or
(2) R1 and X taken together form a group selected from:

(4) M1 is carbon;
(5) M2 IS N;
(6) one of M3 and M4 is C and the other is N;
(7) Y is selected from: is —CH.—. =C(0), =C(NOR20) (wherein R20 is as defined above), or «C(S);
(8) Z is a C1-C6 alkyl group;
(9) R2 is a live or six-membered heteroaryl ring, said
six-membered heteroaryl ring comprising 1 or 2 nitro
gen atoms with the remaining ring atoms being carbon,
and said five-membered heteroaryl ring containing 1 or
2 beleroatoms selected from; nitrogen, oxygen, or

(j) -CF3; or
(k) —CH.CF3; wherein said aryl, heieroaryl, heierocycloalkyl, and the aryl portion of said arylalkyl are optionally substituted with I to 3 substiluents selected from: halogen, —OH, —OCF3, -CF3, —CN, —N(R45')., —CO.R45 or —C(0)N(R45').. wherein each R45 is independently selected from: H, alkyl, alkylaryL, or alkylaryl wherein .said aryl moiety is substituted with 1 to 3 substituents independently selected from —CF«, —OH, halogen, alkyl, —NO., or —CN;

(B) substiluieci aryl, wherein the substituents on said
substitucd aryl arc selected from: (1) halo; or (2) alkyl;
or (3) substituted alkyl;
(C) heieroaryl;
(D) substituted heteroaryl; or
(E) when R1 is taken together with X, then the moiety is

3. The compound as claimed in claim 2 wherein R1 is selected from;
(A) phenyl;
(B) substituted phenyl wherein the substituents on said substitued phenyl are selected from: (1) halo; (2) alkyl; (3) alkyl substituted with halo;
(C) heteroaryl selected from; pyridyl, thienyl,
pyrimidinyl, thiazolyl or pyridyl N-Oxide;
(D) alkyl substituted thiazolyl; or
(E) when R2 is taken together with X, then the moiety is

wherein c is 0 or i, and when c is 1 then R6 is fluoro.
5. The compound as claimed in claim 1 wherein R1 is selected from:
(A) phenyl;
(B) substituted phenyl, wherein the substituents on said
substitued phenyl are independently selected from
chloro, fluoro or trifluoromethyl;
(C) pyridyl; or
(D) substituted heteroaryl of the formula:

16. The compound as claimed inclaim 1 wherein R2 is a six
membered helcroaryl ring.
17. The compound as claimed in claim 16 wherein R2 is selected
from pyridyl, pyridyl substituted with —NR4R5, pyrimidinyl, or pyrimidinyl substituled with —NR4R5.
18. The compound as claimed in claim 17 wherein R2 is pyridyl
substituted with —NH^, or pyrimidinyl substituted with

(2) X is =C(NOR3);
(3) R3 is selected from H or alkyl;
(4) M2 is nitrogen;
(5) Y is =C(0);
(6) M3 and M1 are selected such that; (1) one is carbon and the other is nitrogen;
(7) Z is C1 to C3 alkyl; and
(8) R2 is a six membered heteroaryl ring.
23. The compound as claimed in claim 22 wherein:
(1) R1 is selected from:
(A) phenyl;
(B) substituted phenyl wherein the substituents on said substitued phenyl are selected from: (1) halo; (2) alkyl; (3) alkyl substituted with halo;
(C) heteroaryl selected from: pyridyl, thieny),
pyrimidinyi, thiazolyl or pyridyl N-Oxidc; or
(D) alkyl substituted thiazolyl; or
(E) when R1 is taken together with X, then the moiety
is

wherein c is 0 or 1, and when c is 1 then R6 is halo;
(2) R3 is selected from H, methyl or ethyl;
(3) n is 2,
(4) a is 0 or 1,

(5) b is 0 or 1.
(6) c is 0 or I and when c is I then R0 is halo,
(7) e is 1 to 5,
(8) p is 2,
(9) R1 is H or lower alkyl,
(10) R5 is H, C1 to C6alkyl, or —C(0)R';
(11) R12 is alkyl, hydroxy or fluoro, and
(12) R13 is alkyl, hydroxy or fluoro.
24. The compound as claimed in claim 23 wherein R2 is

7 6 HAY 2007

Documents:

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528-chenp-2003-description(complete)filed.pdf

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528-chenp-2003-form 26.pdf

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Patent Number

211772

Indian Patent Application Number

528/CHENP/2003

PG Journal Number

52/2007

Publication Date

28-Dec-2007

Grant Date

09-Nov-2007

Date of Filing

11-Apr-2003

Name of Patentee

M/S. SCHERING CORPORATION

Applicant Address

Patent Department K-6-1 1990 2000 Galloping Hill Road, Kenilworth, NEW JERSEY 07033-0530

Inventors:

#	Inventor's Name	Inventor's Address
1	ASLANIAN, Robert, G	144 Philip Drive Rockaway, NJ 07866

PCT International Classification Number

C07D 213/73

PCT International Application Number

PCT/US2001/032151

PCT International Filing date

2001-10-15

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	60/240,901	2000-10-17	U.S.A.