TW200402419A - Novel compounds - Google Patents

Abstract

Certain compounds of formula (I): wherein: R1 represents substituted or unsubstituted heteroaryl; Y represents -(CRnaRnb)n-; Rna and Rnb are each independently hydrogen or C1-6alkyl; n is an integer from 1 to 5; R2 represents unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl; R3 represents hydrogen or C1-6alkyl; and salts and solvates thereof are CCR-3 antagonists and are thus indicated to be useful in therapy.

Description

200402419 (1). Description of the invention: [Technical Field] The present invention relates to a novel compound, a method for preparing the same, a pharmaceutical composition containing the same, and its use in therapy. [Previous technique] Inflammation is the main response to tissue damage or microbial invasion, and is characterized by adhesion of white blood cells to the epidermis, exudation of blood cells, and activation of tissues. Leukocyte activation can lead to the production of toxic oxygen species (such as excess oxygen anions) and release of particulate products (such as peroxidases and proteases). Circulating white blood cells include neutrophils, eosinophils, basophils, and lymphocytes. Different types of inflammation include different types of immersed white blood cells. The specific contour is regulated by the contours of adhesion molecules, cytokines, and chemokines in the tissue. The main function of white blood cells is for the host to resist invading organisms such as bacteria and parasites. Once the tissue is damaged or infected, a series of events occur that cause leukocytes to be replenished from the circulatory system to the affected tissue. Leukocyte replenishment is controlled to cause sequential destruction of foreign matter or dead cells and phage, then repair the tissue and break down the inflammatory infiltrates. However, in chronic inflammatory conditions, supplementation is often inadequate, decomposition is not properly controlled, and tissue inflammation is caused by the inflammatory response. There is increasing evidence that bronchial inflammation with asthma characteristics represents a specialized form of cellular withering immunity, in which cell products such as the positive-doubling and positive-controlling particles released by T-helper 2 (Th2) lymphocytes The accumulation and activation of cells, especially 疋 θ fee leukocytes and to a lesser extent _ test leukocytes. Through the release of proteins that are mainly cytotoxic, inflammatory regulators, and oxygen free radicals, acidic white blood cells cause mucosal damage and initially constitute bronchial hyperactivity.

84384 200402419 mechanism. Therefore, blocking the supplementation and activation of Th2 cells and eosinophils seems to have anti-inflammatory activity in asthma. In addition, eosinophils are associated with other disease types' such as rhinitis, eczema, irritating bowel syndrome, and parasitic infections. Chemoactivins are a large group of small proteins involved in white blood cell communication and supplementation (see, for example, Luster, New England Journal of Medicine, 338, 436-445 (1998)). It attracts and activates various cell types by releasing and acting on a wide variety of cells, including eosinophils, basophils, neutrophils, giant bacteria, T and B lymphocytes. There are two main classes of chemical activins: CXC- (a) and CC- (p) chemical activins, which are classified based on the interval between two conserved cysteine residues near the amine end of the chemical activin protein. Chemoactivin binds to a specific cell surface receptor, which belongs to the G_protein-coupling family of 7 transmembrane domain proteins (see Luster, 1998). In these reactions, activation of chemostimulation / tonin receptors results in increased intracellular bowing, changes in cell shape, increased expression of cell adhesion molecules, degranulation, and promotion of cell migration (chemical activation). Several cc chemokine receptors have been identified and, particularly importantly, a CC-chemokine receptor-3 (CCR-3) of the present invention, which is predominantly expressed on acidic white blood cells and also on Alkaline white blood cells, mast cells and Th2 cells. Chemical activins such as CCR_3 and MCP-4 are known to replenish and activate eosinophils. Of particular interest are eotaxin and eotaxin-2 'which specifically bind to ccR-3. The localization and function of CCR-3 chemoactivin have shown that it plays a central role in the development of allergic diseases such as asthma. Therefore, CCR-3 is specifically manifested on all major cell types involved in inflammatory allergies 84384 200402419 response. Chemoactivin in CCR-3 is produced in response to inflammatory stimuli and acts to replenish these cell types to the inflammatory site, where it causes Its activation (eg, Griffiths et al., J. Exp. Med "179, 881-887 (1994), Lloyd et al .; J. Exp_ Med" 191, 265-273 (2000)). In addition, anti-CCR-3 monoclonal antibodies completely inhibit the interaction between eosin and eosinophils (Heath, H. et al., J. Clin. Invest. 99 (2), 178-184 (1997)) CCR-3 specific activin antibody, eosin, can simultaneously reduce bronchial overreaction and pulmonary eosinophilia in animal models of asthma (Gonzalo et al., J. Exp. Med., 188, 157 -167 (1998)). Therefore, multiple clues suggest that antagonists to the CCR-3 receptor appear to be extremely therapeutically useful in the treatment of various inflammatory conditions. In addition to its major role in inflammatory disorders, chemoactivin and its body-borne infections also play important roles. Mammalian cytomegalovirus, herpes virus, and poxviruses can express chemoactivin receptor homologs that can be activated by human CC chemoactivins such as RANTES and MCP-3 receptors (see, for example, Wells and Schwartz, Curr. Opin · Biotech ·, 8, 741-748, 1997). In addition, human chemical activin receptors such as CXCR-4, CCR-5 and CCR-3 can act as co-receptors for mammalian cells infected with microorganisms such as human immunodeficiency virus (HIV). Therefore, chemical activin receptor antagonists (including CCR-3 antagonists) can be used to block HIV infection of CCR-3 expressing cells or prevent immune cell responses from being manipulated by viruses such as cytomegalovirus. International Patent Application Publication No. wo 01/24786 (Shionogi & Co. Ltd.) discloses certain aryl and heteroaryl derivatives for the treatment of diabetes. WO 00/69830 (Torrey Pines Molecular Research Association) discloses a diaza heterocyclic compound for biological screening and a database containing the same. WO 00/18767 (Neurogen) discloses a piperidine derivative as 84384 200402419 dopamine D4 receptor antagonist. U.S. Patent No. 6,031,097 and WO 99/21848 (Neurogen) are both amine isoquinoline derivatives as dopamine receptor ligands. WO 99/06384 (Recordati Chemical Company) discloses piperin derivatives useful for treating lower urethral neuromuscular insufficiency. WO 98/56771 (Schering Aktiengesellschaft) discloses certain 12-endorphine derivatives as anti-inflammatory agents. WO 97/47601 (Yoshitomi Pharmaceutical Co., Ltd.) discloses a certain fused heterocyclic compound as a dopamine D-receptor blocker. WO 96/39386 (Schering) discloses a piperidine derivative as a neuron antagonist. WO 96/02534 (Byk Gulden Lomberg Chemische Fabrik GmbH) discloses a certain piperidine that can be used to control Spirulina. WO 95/32196 (Merck Sharp & Dohme Limited) discloses certain piperin, piperidine and tetrahydropyridine derivatives as 5-HTlD-oc antagonists. U.S. Patent No. 5,389,635 (E.L Du Pont de Nemours) discloses certain substituted imidazoles as angiotensin-II antagonists. European Patent Application Publication No. 0 306 440 (Schering Aktiengesellschaft) discloses a certain iminium derivative as a cardiovascular drug. A new class of compounds has now been discovered for CCR-3 antagonists. These compounds block the movement / chemotaxis of eosinophils and are therefore anti-inflammatory. These compounds therefore have potential therapeutic benefits, especially in cell-type diseases, especially allergic diseases (including but not limited to bronchial asthma, allergic rhinitis and atopic dermatitis), providing eosinophilic leukocytes, basophilic leukocyte hypertrophy Protective effects of cells and Th2-cells on tissue damage. SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide a compound of formula (I): 84384 -10- 200402419

Where = R1 represents a substituted or unsubstituted heteroaryl group; Y represents-(CR ^ RJn-; 1 and 1 are each independently hydrogen or Cm alkyl; η is an integer from 1 to 5; R2 represents unsubstituted Or substituted aryl or unsubstituted or substituted heteroaryl; R3 represents hydrogen or CV6 alkyl; and salts and solvates thereof, provided that: R1 is not oxazolyl; R1 is not substituted with phenyl , And the following compounds are excluded: N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -2- (5-methoxy-2-methyl-1H-ind Indol-3-yl) acetamide; N-{[4- (3,4 · dichlorobenzyl) morpholin-2-yl] methyl} -2-thien-3-ylacetamide; bucket { [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -2- (5-methyl-1-phenyl-111-pyrazol-4-yl) acetamide; 2- (4-Bromo-3,5-dimethyl-1Η-pyrazol-1-yl) -N- {[4- (3,4-dichlorofluorenyl) morpholine · 2-yl] methyl} Acetylamine; 84384 -11-200402419 Sense {[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -2- (2-pyracin-2-yl-1,3 -Pyrazol-4-yl) acetamidamine; N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methylb 2- (2-furyl) acetamidamine; 2- (3-Ethylfluorenyl benzopyrimin-4-yl) -N- {[4- (3 , 4-dichlorobenzyl) morpholin-2-yl] methyl} acetamidine trifluoroacetate; 2- (5-bromopyridin-3-yl) -N-{[4- (3,4- Dichlorobenzyl) morpholin-2-yl] methyl} acetamidine compound with formic acid (1: 1); N- {[((2S) -4- (3,4-diaminobenzyl) morpholine- 2-yl] methyl} -2- (2-furanyl) acetamidamine; 2- (4-bromo-1H-imidazol-1-yl) -N-{[4- (3,4-dichlorobenzyl ) Morpholine-2-yl] methyl} acetamidine; N-{[4- (3,4-difluorobenzyl) morpholin-2-yl] methyl} -2- (2-pyracine 2-yl-1,3-pyrazol-4-yl) acetamidamine; N-{[4- (4-fluorobenzyl) morpholin-2-yl] methyl} -2- (2-pyridine Fluoren-2-yl-1,3-thiazol-4-yl) amine; hydrazine {[4- (2,3-dichlorobenzyl) morpholin-2-yl] methyl} -2- (2- Pyridin-2-yl-1,3-thiazol-4-yl) acetamide; N-({4 · [(5-chloropyrimin-2-yl) methyl] morpholin-2-yl} formyl ) -2- (2-pyridin-2-yl-1,3-thiazol-4-yl) acetamidinium; N-{[4- (3-chlorofluorenyl) morpholin-2-yl] formyl } -2- (2-Pyridin-2-yl-1,3-pyrazol-4-yl) acetamidamine; N-{[4- (3,4-dichlorobenzyl) morpholine · 2 -Yl] methyl} -2- (5-methyl-2-pyridin-2-yl-1,3-pyrazol-4-yl) acetamide; 2- [2-({[4- ( 3,4-dichlorofluorenyl) morpholine-2- Methyl] methyl} amino) -2-oxoethyl] -84384 ^ -12-200402419 2H-1,2,3-benzotriazole-5 · carboxylic acid methyl ester; N- {[4_ (3 , 4-dichlorobenzyl) morpholinoyl] methylpyridine 2_ (mpyrrolo-pyridyl-1 -yl) ethoxyamine; N- {[4- (3,4-dichlorofluorenyl) Morpholine_2 · yl] methyl 丨 _2_ (5_pyridine · 2_yl_2h_tetrazol-2-yl) acetamidamine; N- {[4- (3,4, dichloromethyl) Morin-2_yl] methyl} _2_ (5_ bispyridyl. Tetramethyl-2-yl) acetamidamine; 1- [2-({[4- (3,4-dichlorofluorenyl) Morpholine jyl] methyl} amino) _2_oxoethyl] _1H-1,2,3-benzotriazole-5_carboxylic acid methyl ester compound with dichlorobenzyl) morpholine-2- Group] methyl} amino) _2_oxoethylbulfmlf, 2,3_benzotriazole · bucarboxylate (1: 1); N-{[(2S) -4- (3, 4-dichloroethenyl) morpholine 2-yl] methyl 2- (5-methyl_2_pyridin_2_yl-1,3-tetramethyl-4-yl) amine; and N- { [4- (3,4-Dichlorobenzyl) morpholine-2-yl] methylbutan-2- (2,3-dimethylquinoline each group) acetamidamine. [Embodiment] Examples of heteroaryl R1 include imidyl, triazolyl, dioxanyl, faryl, pyrimyl, isoxazolyl, isothiazyl, pyridyl, furyl, isopropyl Yin Junji, Four Gorges Foundation and outer bp sitting base. When R1 is a substituted heteroaryl group, suitable substituents include Ci 6 alkoxycarbonylamino groups; amine groups; carboxyl groups; hydrazinocarbonyl groups; (6-6 alkoxycarbonylhydrazinecarbonyl groups; (6-6 alkylsulfonyl) groups Amine group; CV6 alkylcarbonyl group; aminocarbonyl group; unsubstituted heterocyclic group; heterocyclic group substituted with CV6 alkyl, functional group, CV6 alkoxy or hydroxyl group; unsubstituted heteroaryl group; Radical, li radical, (^ 6 alkoxy or hydroxy is -13- 84384 200402419 instead of heteroaryl; perhalo c16 alkyl; (^ _6 alkyl; oxygen oxo; mono- and mono- (Ci_6 Arylamino; halo; CK6 alkoxy; nitro; (^ _6alkylsulfonyl; hydroxyl; Cl_6alkoxyCV6alkyl; &-6alkylthio; mono- and di- ( cv6 alkyl) amino group; cycloalkylaminocarbonyl group; formamyl group and CU6 alkylcarbonylamino group. When R1 is substituted with an unsubstituted or substituted heterocyclic group, examples of the heterocyclic group include alkyl When R1 is substituted with an unsubstituted or substituted heteroaryl, the examples of the heteroaryl include pyridinyl, dioxetyl, thiophenyl, imidyl, dioxidyl, isoxazolyl , Pyrazolyl and pyrenyl. Well, R1 is unsubstituted or substituted imidazolyl, unsubstituted or substituted triazolyl, unsubstituted or substituted oxadiazolyl, unsubstituted or substituted far fluorenyl, unsubstituted Substituted or substituted farphenyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted pyridyl, unsubstituted or substituted Substituted furanyl, unsubstituted or substituted isozazolyl, unsubstituted or substituted tetrasyl and unsubstituted or substituted bulk radical. When R1 is a substituted furanyl, it is suitable Substituents include carboxyl, 0-6 alkoxycarbonylhydrazinocarbonyl, hydrazinocarbonyl, substituted heteroaryl, mono- and di- (cv6 alkyl) aminocarbonyl, CU6 alkoxycarbonyl, and C3_8 cycloalkylamine When R1 is substituted imidazolyl, suitable substituents include CV6 alkoxycarbonyl and S groups. When R1 is substituted triazolyl, suitable substituents include alkyl and amine groups. When R1 is When substituted oxadiazolyl, suitable substituents include CU6 alkyl, CV6 84384 -14- 200402419 Group, amine group, and mono- and di- (6-6 alkyl) aminocarbonyl group. When R1 is a substituted oxazolyl group, suitable substituents include a Cw alkyl group and an unsubstituted or substituted heteroaryl group. When R1 is a substituted isordinodizolyl group, suitable substituents include an alkyl group. When R1 is a substituted pyrazolyl group, suitable substituents include an amine group, a C6 alkylcarbonylamino group, a CU6 alkyl group, Perd CV6 alkyl, C1-6 alkoxycarbonyl, methylamidyl and unsubstituted heteroaryl. When R1 is a substituted tetrazolyl, suitable substituents include unsubstituted heterocyclic groups, such as Piperidinyl and cv6 alkyl. When R1 is a substituted fluorenyl group, suitable substituents include CU6 alkoxy, amino, < 6 alkylcarbonylamino and alkyl. More preferably, R1 is 3- (third butoxycarboxyamino) eto-5-yl, 3- (amino) eto-5-yl, 3- (acetamido) eto-5-yl, 3- (propanoic acid amine) p than -5-yl, 3- (isopropylcarbonylamino) pyrazol-5-yl, furan-2-yl, 4- (ethoxycarbonyl) -5- Methyl imidazol-1-yl, 5- (bromo) imidazolide, 5-methyl-1,3,4-trifluoren-2-yl, 3-methyl-1,2,4-fluorenediamine Azol-5-yl, 3-ethoxycarbonyl-1,2,4-fluorenediazol-5-yl, 4- (carboxy) furan-2-yl, 2,4-dimethylpyrazol-5- Base, 3- (third butyl) isorazol-5-yl, p-phenen-2-yl, 3-methoxyiso-p-supranyl-5-yl, 4-methyl p-sept-5- Base, 3,5-dimethyl isoxazol-4-yl, isoxazolyl-3-yl, 3-methyl isoxazolyl-4-yl, isoxazolyl-5-yl, 3-methyl Isoxazolyl-5-yl, 2-methylthiazolyl, 5- (third-butoxycarbonylhydrazinocarbonyl) caran-2-yl, 5- (arylcarbonyl) caran-2-yl, 5 -(3-methyl-1,2,4 · indoxazol-5-yl) succin-2-yl, 5- (2-methyl-1,2,4-triazol-5-yl) furan -2-yl, 3-amino-2-methyl-1,2,4-triazol-5-yl, 3-amino-1,2,4-triazol-5-yl, 3-amino -l, 2,4_fluoradiazol-5-yl , 4- (third butoxycarbonyl) pyrazole 84384 -15-200402419, 2- (pyridin-2-yl) thiazol-4-yl, 2- (methylaminocarbonyl) furan-5-yl, 2- (ethoxycarbonyl) furan_5-yl, 2- (ethylaminocarbonyl) furan-5-yl, 2- (isopropylaminocarbonyl) furan-5-yl, 2- (cyclopropylaminocarbonyl) furan -5-yl, 2- (cyclopropylmethylaminocarbonyl) furan-5-yl, 2- (5-methyl-1,3,4-pyridadiazol-2-yl) furan-2-yl , 3- (methylaminocarbonyl) -1,2,4-pyridadiazol-5-yl, 3- (ethylaminocarbonyl) -1,2,4-indadiazol-5-yl, 3- ( Isopropylaminocarbonyl) -1,2,4-pyridadiazol-5-yl, 2-chloropyrimidin-4-yl, 3.aminoisopyrazol-5-yl, 3-ethylamidoaminoisoamidine Azol-5-yl, 3-propylamidoisoxazol-5-yl, 3- (isopropylcarbonylamino) isopurazol-5-yl, 4- (ethoxycarbonyl) furan-2-yl , 5- (methoxycarbonyl) furan-2-yl, 4- (isopropylaminocarbonyl) furan-2-yl, 4- (ethylaminocarbonyl) furan-2-yl, 4- (methylaminocarbonyl) ) Furan-2-yl, 5- (ethylaminocarbonyl) caran-2-yl, 5- (methylaminocarbonyl) caran-2-yl, 5- (isopropylaminocarbonyl) furan-2-yl, 4- (ethoxycarbonyl ) Furanyl, exo-3-yl, succin-2-yl, 2- (5-methylisotetra-3-yl) p-sec-4-yl, 2- (1-methylimidazole -5-yl) pyrazol-4-yl, 2- (4-methyl-1,2,3-pyrimidazol-5-yl) thiazolyl, 5-methyl-2- (5-methyl Iso-0 spit-3-yl) epiquat · 4-yl, 5-methyl-2- (1-methylimidazol-5-yl) pyrazol-4-yl, 2- (4-methyl-1 , 2,3-pyrimidazol-5-yl) -5-methylpyridin-4-yl, 2- (1-methylimid-5-yl) pyridin-4-yl, 4-formyl Methyl-2- (5-methylisoxazol · 3-yl) pyrazol-2-yl, 4-methyl-2- (5-methylisoxazol-5-yl), sedazole; 3 decathiophen-2-yl) -4- (methyl) pyrazole small group, 5- (isopropyl) tetrazole small group, 5-methyl (difluoromethyl) 17 smaller groups , 3 stoppers. Sit_2_yl) p is smaller than fluorene, 5 decadidin-1_yl) tetrazol-2-yl, 5- (piperidin-1-yl) tetrazolium, μ (methyl) tetrazole -5_ group, tetratyl-5-yl group, 5- (methyl) isoindazole group, 5- (isopropyl) tetrazol-2-yl group, 2- (methyl) tetrazol-5-yl group, 3- (methyl) isoxazol-5-yl, 3- (methylmethyl) pyrazolyl, 3- (methyl) pyrazol-1-yl, 3,5-dimethylpyrazole small Or 4- (ethoxycarbonyl 84384 -16- 200402419) p. Preferably, both L and I are hydrogen. Preferably, η is 1 or 2. Preferably, R3 is hydrogen. When R2 is aryl, examples thereof include phenyl. When R2 is a substituted aryl group, suitable substituents include cyano, all-i alkyl, amido, halo, CU6 alkyl, CV6 alkoxycarbonyl, mono- and di- (C ^ alkyl) amines Carbonyl, CV6 alkoxy, nitro, alkylsulfonyl, hydroxy, CU6 alkoxyalkyl, CV6 alkylthio, mono- and dialkyl) amino and Cu 6 alkylcarbonylamino. When R2 is heteroaryl, the examples include pyrimidinyl. When R2 is a substituted heteroaryl, suitable substituents include cyano, all 1¾ Cy alkyl, amido, i, cv6 alkyl, cU6 alkoxycarbonyl, mono- and di- (cv6 alkyl) Aminocarbonyl, cv6 alkoxy, nitro, alkylsulfonyl, hydroxyl, CV6 alkoxyalkyl, Cp6 alkylthio, mono- and di- (Cy alkyl) amino and CV 6 amidyl Amino group. Suitably, R2 is an unsubstituted or substituted phenyl or an unsubstituted or substituted pyrenyl. When R2 is substituted phenyl, suitable substituents include halo. When R2 is a substituted pyrenyl group, suitable substituents include a substituent. More suitably, R2 is phenyl substituted with chlorine or fluorine or pyrimidinyl substituted with gas. Preferably, R2 is 3-fluorophenyl, 3- (trifluoromethyl) phenyl, 2-chloropyrimidin-4-yl, 3-chlorophenyl, 3,4-difluorophenyl, or 3,4 -Dichlorophenyl. 84384 -17- 200402419 The compounds of formula (i) which can be mentioned are of formula (Γ):

Among them: \ R1 represents a substituted or unsubstituted heteroaryl group; Υ represents Qiu Cong; t and Rnb are each independently hydrogen or alkyl; η is an integer from 1 to 5; R2 represents an unsubstituted or substituted aromatic Or unsubstituted or substituted heteroaryl; R3 represents hydrogen or C1-6 alkyl; and salts and solvates thereof, provided that R1 is not a pyrazolyl group; R1 is not substituted with a phenyl group, and Except the following compounds: N-{[4- (3,4-dichlorobenzyl) morphinyl] methyl 2-methyl 5- (5-methoxy-2-methyl · 1Η_indol-3 · yl) Acetylamine; Ν · {[4- (3,4-dichlorobenzyl) morphin} yl] methyl} -2-pyrimin-3-ylacetamidamine; & {[4- (3, 4-dichlorobenzyl) morpholin-2-yl] methyl} -2- (5-methyl small phenyl-11 ^ pyridin-4-yl) acetamidamine; 84384 -18-6463 200402419 2- (4-bromo-3,5-dimethyl-1H-pyrazolyl) -N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} acetamidine ; 1 ^ {[4- (3,4-Diaminobenzyl) morpholin-2-yl] methyl} -2- (2-pyridin-2-yl-1,3-oxazol-4-yl ) Acetic acid amine; N- {[4- (3,4-dimuridine) morpholin-2-yl] methyl} -2- (2-octyl) ethoxyamine; 2- (3-ethyl Fluorenyl-1-benzopyrimidin-4-yl) -N_ {[4- (3,4-Diaminobenzyl) morpholin-2-yl] methyl} acetamidine trifluoroacetate; 2- (5-bromopyridyl) -N- {[4- ( 3,4-dichlorofluorenyl) morpholin-2-yl] methyl} acetamidine compound with formic acid (1: 1); N- {[(2S) -4- (3,4-dimuridine ) Morin-2-yl] methyl} -2- (2-olanyl) acetamidine; 2- (4- > Smelt-1 H_taste mouth-1 -yl) -N_ {[4 -(3,4-dimurino) morphin-2-yl] methyl} ethanamide; meaning {[4- (3,4-difluorobenzyl) morpholin-2-yl] methyl} 2- (2-pyridin-2-yl-1,3-thiazol-4-yl) acetamidamine; N-{[4- (4-fluoroamidino) morpholin-2-yl] methyl} -2- (2-Pyridin-2-yl-1,3-thiazol-4-yl) acetamide;! ^ {[4- (2,3-dichlorobenzyl) morpholin-2-yl] Methyl} -2- (2-pyrimidin-2-yl-1,3-pyrazol-4-yl) acetamidinium; N-({4-[(5-chloropyrimin-2-yl) formyl Yl] morpholin-2-yl} methyl) -2- (2-pyridin-2-yl-1,3-pyrazol-4-yl) acetamidinium; N- {[4- (3-chloro Benzyl) morpholin-2-yl] methyl} -2- (2-pyracin-2-yl-1,3-pyrimazol-4-yl) acetamidamine; N- {[4- (3, 4-dichlorobenzyl) morpholin-2-yl] methylbutan-2- (5-methyl-2-pyridin-2-yl- 84384 -19- 200402419 1,3-pentan-4-yl) Ethylamine 2- [2- ({[4- (3,4-monomuryl + yl) morphin-2-yl] methyl} amino) -2-oxoethyl] 2H-1,2,3-benzene Methyl benzotriazol-5-carboxylate; N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methylb 2- (1Η _pyrrolo [2,37] Edo-1-yl) acetamidamine; N-{[4_ (3,4 · Dichlorobenzyl) morpholin-2-yl] methyl} -2- (5-pyridin-2-yl-2H- Tetramethyl-2-yl) acetamidamine; N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -2- (5-pyridin-3-yl-2H _Tetratyl 2-yl) acetamidamine; 1- [2-({[4- (3,4-dichlorobenzyl) morpholine-2-yl] methyl} amino) -2-oxo Ethyl] _ 1H-1,2,3_benzotriazole_5_carboxylic acid methyl ester compound with dichlorobenzyl) morpholin-2-yl] methyl} amino) -2 • oxoethyl ] -1H-1,2,3-benzotriazole methyl behenate (1: 1); N-{[(2S) -4- (3,4-dichlorobenzyl) morpholine-2- Propyl] methyl} -2- (5-methyl-2_ tonyl_2_yl-1,3-pyrazol-4-yl) acetamidinium; and N-{[4- (3,4-bis Chlorobenzyl) morpholin-2-yl] methyl} _2_ (2,3_dimethylsinolin-6_yl) acetamide. There are preferably a class of compounds of formula (I) that are compounds of formula (Γ):

R2 (丨 ·) where: 84384 20- 200402419

Rr represents an unsubstituted or substituted heteroaryl group; and Rr is a phenyl group substituted with a ¾ group. Preferably, R1 ′ is an ethyl group substituted with a phenyl group, a peak group, a carboenyl group, an alkoxycarbonyl group, a C1-6 alkyl group or a perhalo C ^ alkyl group; Tetrazolyl substituted with piperidinyl or Cl_6 alkyl; or isoxetyl substituted with Ci6 alkyl. It is preferred that R1 is 3 decathio-2-yl) etto-1-yl, 5- (1-piperidinyl) tetrazolyl, 5- (isopropyl) tetramethyl-2-yl, 2 -Methyltetrafluorenyl, 5, yl, 4-methyl · 3decathiophene · 2-yl) erim-1-yl, 5- (isopropyl) tetra-1-enyl, 1methyl_3_ (Trifluoromethyl) pyrazol-1-yl, 5- (piperidin-1-yl) tetrazol-1-yl, U methyltetrazol-5-yl, tetrazol-5-yl, pyrene Base) isosaki-5-yl, methylphenidyl) tonazole small group, 3- (methyl) pyrazol-1-yl, 3,5-dimethylpyrazole small group, 4- (ethoxycarbonyl) ) Pyrazole small groups or 5-methylisoxazole groups. Suitably, R2 'is phenyl substituted with chlorine or fluorine. Preferably, 'R2 is 3,4-dichlorophenyl or 3,4-difluorophenyl. Suitably, the stereochemistry at the position marked is (s). Accordingly, a compound of formula (Γ) or a salt or solvate thereof is provided. The suitable compounds of the present invention are Examples 1, 2, 3, 8, 12, M, 18, 19, 20, 2 and 23, 25, 27, 28, 30, 3 and 32, 34, 36, 40, 42. , 45, 46, 48, 49, 50, 52, 53, 54, 55, 56, 58, 60, 63, 64, 65, 67, 69, 70, 71, 72, 73, 74, 75, 76, 77 , 78, 80, 8 and 82, 83, 87, 88, 89, 90, 91, 93, 95, 97, 99, 100, 102, 104, 106, 108, 109, 11 and m. Preferred compounds of the present invention are Examples 1, 2, 3, 19, 23, 27, 32, 34, 84384 -21-1 200402419 36, 42, 45, 48, 50, 52, 54, 58, 63, 64, 65 , 67, 71, 75, 76, 78, 80, 89, 91, 93, 97, 102, 104, and 106. Preferred compounds of the present invention are Examples 1, 23, 32, 34, 36, 50, 71, 78 and 97. Suitable salts of the compound of formula (I) include bioacceptable salts and salts that are not physiologically acceptable but are useful in the preparation of compounds of formula (I) and their pharmaceutically acceptable salts. Where appropriate, acid addition salts may be derived from inorganic or organic acids, such as, for example, hydrochloric acid, hydrobromic acid, sulfate, phosphate, acetate, benzoate, citrate, succinate, lactate , Tartrate, fumarate, maleic acid, 1-hydroxy-2-fluorenic acid, dihydroxycarboxylic acid, methanesulfonate, formate or trifluoroacetate. Examples of solvates include hydrates. Certain compounds of formula (I) may contain palmatomic atoms and / or multiple bonds, and thus one or more stereoisomers may exist. The present invention includes all stereoisomers of the compound of formula (I), including geometric isomers and optical isomers, whether they are individual stereoisomers or mixtures containing racemic modification. Generally, it is preferred that the compound of formula (I) is a single enantiomer or a diastereomer. Certain compounds of formula (I) may exist in one of several tautomers. It is to be understood that the present invention includes all tautomers of a compound of formula (I), whether individual tautomers or mixtures thereof. The reference to '' aryl 'represents monocyclic and bicyclic carbocyclic aromatic rings such as fluorenyl and phenyl, especially phenyl. Suitable substituents for any aryl group include 1 to 5, preferably 1 to 3 selected from the following -22- 84384

OH / J 200402419 Substituents in the group: cyano, alliialkyl, amido, i, alkyl, alkoxycarbonyl, mono- and di- (alkyl) aminocarbonyl, alkyl Oxy, nitro, alkylsulfonyl, hydroxy, alkoxyalkyl, alkylthio, mono- and dialkyl) amino and alkylamino. The term "'heteroaryl'" represents a monocyclic heterocyclic aromatic ring containing 1-4 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heterocyclic aromatic rings include imidazolyl, triazolyl, stilbendyl, isodinyl, isodinyl, Pyridyl, Psedenyl, sulphanyl, fartyl, Spray base, tetrabenzyl, tri-alpha base, 4-di-base, saki 0-base, iso-17-base and ρ-bi-base, especially Weito-base, tri-alpha-base, Yinjijun base, 隹Phenyl, iso-4 difluorenyl, iso 17 far 17 base, Edo base, pbiolyl base, Si Jun base, Yuan Jun base and Isaki Jun base. Suitable substituents for any heteroaryl group include 1 to 5, preferably 1 to 3, groups selected from the group consisting of: alkoxycarbonylamino groups; amine groups; carboxyl groups; hydrazinocarbonyl groups; alkoxycarbonylhydrazinecarbonyl groups Alkylsulfonylamino; alkylcarbonyl; aminocarbonyl; unsubstituted heterocyclic groups; heterocyclic groups substituted with alkyl, S group, alkoxy or hydroxyl groups; unsubstituted heteroaryl groups; Heteroaryl substituted with alkyl, alkoxy, alkoxy or hydroxy; all-single alkyl; alkyl; alkoxycarbonyl; mono- and di- (alkyl) aminocarbonyl; i-based; alkoxy Nitro; Alkylsulfonyl; Methoxy; Alkoxyalkyl; Sulfuryl; Mono- and di- (alkyl) amino; Cycloalkylaminocarbonyl; Cyano; Alkylcarbonylamino And amido. "Related π alkyl" represents a linear and branched aliphatic isomer of a corresponding alkyl group which preferably contains up to 6 carbon atoms. Related "cycloalkyl π" represents a saturated alicyclic ring which preferably contains 3 to 8 carbon atoms. Suitable substituents for any cycloalkyl group include alkyl groups, functional groups, and hydroxyl groups. 84384 -23-200402419 Related "heterocyclyl" represents two to six, preferably three to five carbon atoms and one selected from nitrogen and oxygen. And sulfur heteroatoms are monocyclic heterocyclic aliphatic rings. Examples of heterocyclic rings include a radical. Halo, alkoxy, or hydroxy. Suitable substituents for any heterocyclyl include alkynyl. The related "dentin" or "letter" represents Qi, Macao, chlorine or gas, especially gas and chlorine. Compounds of formula (I), and phosphonium salts and solvates, are prepared by the method described later, and constitute another object of the present invention. Accordingly, a method of preparing a compound of formula (1) is provided, which method comprises combining a compound of formula (II) with a compound of formula (III);

Wherein: R, Y, R3 and R2 are as defined in formula ①, and react in the presence of an activator and a peptide coupling agent, and then, if necessary, perform one or more of the following steps as appropriate: ) Conversion of the compound into other compounds of formula (I); (ii) removal of any necessary protecting groups; (iii) preparation of salts or solvates of the compounds formed. Suitably the'activator is 1-hydroxybenzotriazole (HOBT). Examples of peptide coupling agents are 1,3-dicyclohexylcarbodiimide (DCC); 2-ethoxy-1-ethoxycarbonyl-1,2-dihydrophosphonium (EEDQ) and H3-dimethyl Aminopropyl) each 84384-24-24200402419 carbodiimide or its salt. Suitably, the peptide coupling agent is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride. Typically, the compound of formula (II) and compound of formula (III) are treated with a peptide coupling agent in a suitable solvent such as a polar organic solvent such as N, N-dimethylformamide at an ambient temperature such as about 18-25 ° C . The reaction mixture is stirred at ambient temperature for a suitable time such as about 12-20 hours. Compounds of formula (III) in which R3 is hydrogen can be prepared by reaction ⑻ or reaction (c). The S-enantiomer of the compound of formula (III) can be prepared by reaction (b). Reaction (a). A compound of formula (IV) reacts with a compound of formula (V):

Where R2 is as defined in formula (I) and A is a protected amine group, preferably a phthalimide group, and then the amine group is deprotected to obtain a compound of formula (III) in which R3 is hydrogen, that is, formula (IIIR) Compound

Wherein R2 is as defined above, and the obtained enantiomer of formula (IIIR) is resolved according to circumstances; or reaction (b). The compound of formula (IV) is reacted with a compound of formula (VA):

84384 -25- 200402419 where A is as defined in the above formula (V), and then the amine group is deprotected to obtain the relative enantiomer of the compound of formula (III) where R3 is hydrogen, that is, the compound of formula (IIIE)

Where R2 is as defined above. Reaction (c). Hydrolyzing a compound of formula (VI);

Where T is trifluoroacetamidine, and R3 and R2 are as defined in the aforementioned formula (I), and the enantiomers of the obtained compound of formula (III) are resolved as appropriate. For both reaction VII and (b), the cyclization of the intermediate diols (IIIBR) and (IIIBE) in the reaction between the compound of formula (IV) and the compound of formula (V) or (VA) is typically as follows Under Mitsunobu conditions: Typically, a mixture of a compound of formula (IV) with a compound of formula (V) or formula (VA) in a suitable solvent such as ) Stir for 20-24 hours. Then other solvents are added and the mixture is cooled (preferably 0-5 ° C). Add the appropriate phosphine (preferably triphenylphosphine) and stir the mixture until all solids are dissolved. Then the azo compound is preferably added in a better period of 10-15 minutes, preferably diisopropyl azodicarboxylate, while maintaining the temperature at < 7 ° C. Allow the mixture to stand for a period of time (preferably 2-3 hours), then warm to 20-25 ° C. 84384 -26- 200402419 After standing for a period of time (preferably 4-6 hours), phosphine and azo compounds are added. After standing for another period (preferably 20-24 hours), the reaction mixture is concentrated to almost dryness. Add the appropriate alcohol (preferably propan-2-ol) and repeat the concentration step; then repeat the alcohol addition and concentration steps. Additional alcohol was added and the mixture was heated to a temperature of preferably 65-75 ° C. After a suitable period (preferably 20-45 minutes), the resulting slurry is cooled (preferably 20-25 ° C), then allowed to stand (preferably 1.5-3 hours), and then the isolated product is filtered. The filter bed was washed with more alcohol and then dried under vacuum at 35-45 ° C to obtain protected compounds of formula (IIIR) or (IIIE), respectively. Protecting groups are typically removed from the product as described below. The slurry of the compound of formula (IIIR) or formula (IIIE) in a protected state in an appropriate polar solvent (preferably water) is heated to a temperature rise (preferably 70-75 ° C) and then dropwise with a concentrated inorganic acid (preferably concentrated sulfuric acid). deal with. The mixture is then heated at an elevated temperature (preferably the reflux temperature of the solvent) for a suitable time (preferably 20-24 hours), then the reaction mixture is cooled to 20-25 ° C and then washed with a suitable polar solvent (preferably methane). Then add alkali (preferably 0.880 ammonia solution) dropwise and maintain the temperature at 20-25 ° C. Then, a polar solvent was added, followed by separation of the aqueous phase and extraction with a polar solvent. The combined organic extracts were washed with water and evaporated to dryness. The residue is redissolved and the polar solvent is evaporated to obtain a compound of formula (IIIR) or formula (IIIE). The method for preparing the above-mentioned protected compound of formula (IIIR) or formula (IIIE) can also be performed in two steps, wherein the intermediate compound of formula (IIIBR) or formula (IIIBE) is isolated separately:

oh a / x ^ 〇h OH

(mBR)

(IIIBE) 84384 -27- DH / 0 200402419 where A is as defined in the aforementioned formulas (V) and (VA) and R2 is as defined in the aforementioned formula (I). Typically, a mixture of a compound of formula (IV) and a compound of formula (V) or formula (VA) in a suitable solvent such as tetrahydrofuran is stirred at a suitable temperature (preferably at the solvent reflux temperature) under an inert gas (preferably under nitrogen) for 20- 24 hours. The compound of formula (IV) is added and the mixture is stirred at a suitable temperature (preferably at the reflux temperature of the solvent) under an inert gas (preferably under nitrogen) for 3-6 hours. The reaction mixture is then cooled (preferably 20-25 ° C) and the compound is precipitated by adding a suitable co-solvent (preferably diisopropyl ether). Compounds of formula (IIIBR) or (IIIBE) are isolated by filtration, washed with co-solvent and dried in vacuo. Protected states of formula (IIIR) or formula (IIIE) can then be prepared from compounds of formula (IIIBR) or formula (IIIBE) under conditions similar to the reaction between compounds of formula (IV) and compounds of formula (V) or formula (VA) Compounds, but omitting the reflux period before adding phosphine and azo compounds. The reaction (c) is generally carried out by stirring a solution of the compound of the formula (VI) in an appropriate solvent (for example, a mixture of methanol and water) and adding an appropriate base such as potassium carbonate. The mixture is stirred at an appropriate temperature, such as 20-25 ° C, for an appropriate time, such as 16-20 hours, and then the organic solvent is removed in vacuo. Water is then added and the mixture is extracted with a suitable organic solvent such as ethyl acetate. The combined organic phases are washed with water and a saturated aqueous solution of sodium chloride, dried over a suitable desiccant, such as sodium sulfate, filtered and evaporated in vacuo. The crude product was then purified by flash chromatography. Using techniques known in the art, such as subjecting diastereoisomeric salts to preparative, high performance liquid chromatography (parallel HPLC) or by fractional crystallization, the racemic products, ie compounds of formula (IIIR), are resolved. Formula (IIIE). Compounds of formula (VI) can be prepared by reacting a compound of formula (VII) with a compound of formula (VIII) to 84384 -28- 200402419:

1 \ KI / eight Μ, 2 Η (VII) L R (VIII) where: T, R3 and R2 are as defined above and L2 is a leaving group. A suitable leaving group L2 is a halo group such as chlorine. The reaction between a compound of formula (VII) and a compound of formula (VIII) is typically carried out by placing the compound of formula (VII) in a suitable solvent (eg N, N-dimethylformamide) under an inert gas (eg under nitrogen). Stir; stir, add suitable test (such as 4 methyl carbonate) and suitable activator (such as sodium iodide) and mix. A solution of a compound of formula (VIII) in a suitable solvent, such as N, N-dimethylformamide, is added dropwise to the mixture. The mixture is then stirred at a suitable temperature (e.g. 20-25 ° C) for a suitable time (e.g. 16-20 hours) and the volatile components are removed in vacuo. The residue is partitioned between an organic solvent (such as dichloromethane) and a saturated aqueous solution (such as a saturated aqueous solution of carbon steel). The organic phase is then washed with additional saturated aqueous test solution and water, dried with a suitable desiccant (such as osmium sulfate), filtered and the solvent is evaporated in vacuo to obtain the crude product. The crude product was purified by rapid chromatography. A compound of formula (VII) can be prepared by reacting a compound of formula (IX) with a compound of formula (X):

84384 -29- (X) 200402419 wherein R3 and T are as defined above and \ is an alkyl group, preferably an ethyl group. The reaction between the compound of formula (IX) and the compound of formula (X) is typically performed by stirring the compound of formula (IX) in a suitable solvent (such as methanol) under an inert gas (such as nitrogen), and then adding the compound of formula (X) In a suitable solvent (such as ether). The mixture is then stirred at a suitable temperature (for example, 20-25 ° C) for a suitable time (for example, 20-40 hours), and then the volatile components are removed in vacuo. The residue is dissolved in a suitable organic solvent, such as methanol, and the volatile components are removed in vacuo. Furthermore, and in another object, wherein Y is -CH2- and R1 is an unsubstituted or substituted N-bonded heteroaryl compound of formula (I), that is, a compound of formula (XI):

Λ〇 3 N, R ^ (XI) can be prepared by reacting a compound of formula (XII) with a compound of formula (XIII):

Where (XII) is an unsubstituted or substituted heteroaryl group, L2 is a leaving group, and R3 and R2 are as defined in the aforementioned formula (I), and then if necessary, one or more of the following steps are performed as appropriate : (I) converting a compound of formula (I) into another compound of formula (I); 84384 -30- 200402419 (ii) removing any necessary protecting groups; (iii) preparing a salt or solvate of the compound formed. A suitable leaving group is a commercial group, preferably bromine. Typically, the reaction between a compound of formula (XII) and a compound of formula (XIII) is in a suitable organic solvent (such as methylene chloride, N, N-dimethylformamide, or a mixture thereof) at a suitable temperature (such as Temperature (eg 18-25 ° C) for a suitable period (eg 4-10 hours). Then add a suitable test or test metal carbonate such as potassium carbonate. A compound of formula (XIII) can be prepared by reacting a compound of formula (III) with a compound of formula (XIV): L2CH2COOH (XIV) wherein L2 is as defined in the aforementioned formula (XIII) and reacts in the presence of a peptide coupling agent. Examples of peptide coupling agents are 1,3-dicyclohexylcarbodiimide (DCC); 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) and 1- (3 -Dimethylaminopropyl) -3-ethylcarbodiimide or a salt thereof. Suitably, the peptide coupling agent is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride. Typically, the reaction between the compound of the formula (III) and the compound of the formula (XIV) is carried out at a low temperature, such as 0-5 ° C, in a suitable organic solvent, such as alkane, such as methylene chloride, for a suitable time, such as 20-60 minutes. . Compounds of formula (II), certain compounds of formula (III), certain compounds of formula (IV), (V), certain compounds of formula (VI), certain compounds of formula (VII), (VIII), (IX), ( X), (XII) and (XIV) compounds are known, commercially available compounds and / or can be prepared by known similar procedures, such as those described in standard reference books for synthetic methods, such as J. March, Advanced Organic Chemistry, Section 3rd edition (1985), Wiley Interscience. Compounds of formulae (IIIBR), (IIIBE) and (XIII) are considered novel. 84384 -31-200402419 Accordingly, compounds of formula (IIIBR) are provided. Compounds of formula (IIIBE) are also provided. Compounds of formula (XIII) are also provided. … The conversion of a compound of formula (I) into another compound of formula ① includes any transformation that can be performed using conventional methods, but in particular the transformation includes the conversion of the sequence of R n to the other. The above-mentioned transformations can be determined by any suitable method using a specific base. ^, Carried out under conditions. Due to a suitable method for the conversion of the U group into another R1 group, the unsubstituted heteroaryl α group is converted into the R1 group containing the calcined two; this conversion can be performed using appropriate conventional alkylation procedures, for example Manganese trialkylsilyl azide is properly protected by the compound of formula ①: (b) Converting a group representing a heteroaryl group substituted with an amine group to a group representing a heteroaryl group substituted with a carbamoyl group Ri group; this conversion can be carried out using a suitable :: soil donkey field &lt; self-aided hydration procedure, for example, treatment of a compound of formula (1) with appropriate protection by hydrazine chloride; ⑷ the R1 group representing an ester-substituted heteroaryl group Conversion to a R1 group representing a heteroaryl group substituted with several groups; this conversion can be performed using appropriate conventional hydrolysis procedures ^ such as treating the compound of formula (I) with appropriate protection with an aqueous test; (d) rendering an ester substituted The Ri group of the heteroaryl group is converted to the R1 group representing a heteroaryl group substituted with a carbazole ^ -azole; this conversion can be performed using a suitable procedure, such as treatment of an appropriately protected compound of formula (I) with acetamidooxime followed by Treated with caustic soda. (e) The R1 group representing a heteroaryl group substituted with a carboxyl group is converted into the R1 group representing a heteroaryl group substituted with a polyacrylic acid ester; this conversion can be performed using a suitable procedure, {listed as alkyl hydrazine formate Treatment in the presence of suitable activators and coupling agents such as; U hydroxyl $ # i 84384 -32- 200402419 azole and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride Appropriately protected compounds of formula (I). (f) Conversion of the R1 group representing a heteroaryl group substituted with a hydrazine carboxylic acid ester to the R1 group representing a heteroaryl group substituted with a hydrazine carboxylic acid; this conversion may be performed using a suitable hydrolysis procedure, such as treatment with fluorinated hydrochloric acid Appropriately protected compounds of formula (I). (g) Conversion of the R1 group representing a heteroaryl group substituted with a hydrazinecarboxylic acid to the R1 group representing a heteroaryl group substituted with an alkylsulfadiazole; this conversion may be performed using a suitable cyclization procedure, such as Ester treatment appropriately protects compounds of formula (I). (h) Conversion of the R1 group representing a heteroaryl group substituted with a hydrazinecarboxylic acid to the R1 group representing a heteroaryl group substituted with an alkyltriazole; this conversion may be performed using appropriate cyclization procedures, such as with alkylacetamidine The compound of formula (I) is appropriately protected by amine treatment. Such transformations can be performed on any intermediate compound described herein, if appropriate. Suitable protecting groups in any of the above reactions are those skilled in the art. Methods for forming and removing this protecting group are conventional methods suitable for the molecule to be protected, such as those described in standard reference methods for synthetic methods, such as PJ Kocienski, Protecting Group, (1994), Thieme. For any of the above reactions or methods, conventional heating and cooling methods can be used, such as an electric heating mantle and an ice / salt bath, respectively. If necessary, conventional purification methods such as crystallization and column chromatography can be used. Where appropriate, the individual isomers of the compound of formula (I) can be prepared as individual compounds using conventional procedures such as the fractional crystallization of diastereomeric derivatives or a high-performance liquid chromatography (palladium HPLC). Isomers. The absolute stereochemistry of a compound can be determined using conventional methods such as X-ray crystallography. 84384 -33-200402419 The salts and solvates of compounds of formula (i) can be prepared and isolated according to conventional procedures. The compounds of the present invention can be tested for in vitro biological activity according to the following analysis: (a) CCR-3 binding assay The CCR-3 competitive binding to SPA (flash proximity analysis) is used to assess the affinity of the novel compounds for CCR-3. Cell membrane (2.5 μg / hole) prepared from K562 cells stably expressing CCR-3 was mixed with 0.25 mg / hole of wheat germ agglutinin SPA beads (Amersham) and combined in binding buffer (HEPES 50 mM, CaCl2 1 mM, MgCl2 5 mM, 0.5% BSA) for 1.5 hours at 4 ° C. After the incubation, 20 pM [1251] eosin (Amersham) and increasing concentrations of the compound (1 pM to 30 μM) were added and incubated in a 96-well plate at 22 ° C. for 2 hours followed by counting on a Micrcbeta plate counter. The total analysis volume was 100 microliters. The data is fitted into a 4-parameter logarithmic equation to analyze competitively combined data. The data are reported as the average pIC50 value obtained from at least two experiments (negative logarithm of the concentration of the [1251] eosin-binding compound that inhibits 50%). Example compounds were tested in a CCR-3 binding assay. Example compounds tested in the CCR-3 binding assay carried pIC5 () values ranging from 5.5 to 8.6. (b) Eosinophil leukocyte chemotaxis analysis The compound evaluates its inhibitory effect on eosinophil leukocyte chemotaxis. By depletion of standard CD16 cells, Miltenyi cell separation columns and the aforementioned magnetic Super Macs magnet (Motegi &amp; Kita, 1998; Journal of Immunology, 161: 4340-6) were used to purify eosinophils from human peripheral blood. Cells were resuspended in RPMI 1640/10% FCS solution and incubated with calcitonin-AM (Molecular Carbon Needle) at 37 ° C for 30 minutes. After incubation, eosinophils were centrifuged at 400 g for 5 minutes and resuspended in RPMI / FCS at 2.2 84384 -34- 200402419 million / ml. Cells were then incubated at 37 ° C for 30 minutes in the presence of increasing concentrations of the compound (1 pM to 30 μM). For the control response, the cells were grown only with RPMI / FCS. The agonist eosin (EC8 () concentration) was added to the lower compartment of the 96-hole chemotaxis disc (5 micron filter paper: Receptor Technologies). Add eosinophils (50 microliters of 2 million cells / ml) to the end compartment above the filter paper plate and incubate at 37 ° C for 45 minutes. The cells held on the top of the chemotaxis filter paper were removed and the disc was read on a fluorescent disc reader to quantify the number of ammonium acidic leukocytes that had been moved. The data was fitted to a 4-parameter logarithmic equation to analyze the inhibition curve of the compound on the effect of acidic white blood cell chemotaxis. Use the following equation to generate the function pKi value (f ^ Ki) (Lazareno &amp; Birdsall, 1995, Br. J. Pharmacol 109: 1110-9) 0 fpKi: / C5〇ίΡ i [agonist] ec50 Example compounds in CCR- 3 Tested for binding and / or eosinophil leukocyte chemotaxis analysis (Analyze and (b)). Example compounds tested in the CCR-3 binding assay have pIC5Q values ranging from 6.6 to 9.1. The fpK values of the example compounds tested in the CCR-3 eosinophil chemotaxis assay are described in the following table: Example No. 34 10.3 32 9.4 78 9.3 Disease states where the compounds of the present invention have potential anti-inflammatory effects Examples include the respiratory tract Diseases such as bronchitis (including chronic bronchitis), bronchiectasis, asthma (including asthma reactions caused by allergens), chronic distress lung 84384 -35-200402419 disease (COPD), bladder fibrosis, sinusitis, and rhinitis. Gastrointestinal disorders are also included. For example, intestinal inflammatory diseases include inflammatory bowel diseases (such as Cologne's disease or colon ulcers ^) and secondary intestinal inflammatory diseases that are exposed to radiation or allergens. Furthermore, the compounds of the present invention can be used to treat nephritis; skin diseases such as psoriasis, eczema, allergic dermatitis, and overreactions; and central nervous system diseases (such as Alzheimer's disease, meningitis, and multiple diseases) with inflammatory components Sclerosis), HIV and AIDS dementia. The compounds of the invention are also useful in the treatment of nasal polyps, conjunctivitis or pruritus. Examples of disease states in which the compounds of the present invention have potential benefits include cardiovascular conditions such as arteriosclerosis, peripheral vascular disease, and the spontaneous eosinophilic syndrome. The compounds of the present invention are useful as immunosuppressants and have utility in the treatment of autoimmune diseases, such as allograft rejection after transplantation, rheumatoid arthritis and diabetes. The compounds of the invention can also be used to inhibit tumor migration. Wang Yao's related diseases include asthma, coPD and inflammatory diseases of the upper respiratory tract including seasonal and perennial rhinitis. It is well-known that this technique #predicts that the so-called treatment of delay in this article includes prevention and treatment of conditions that have already occurred. As mentioned above, the compound of the formula (I) can be used as a therapeutic agent. Therefore, another object of the present invention is to provide a compound of formula (1) or a physiologically acceptable salt or solvate thereof as an active therapeutic agent. Therefore, a formula compound or a physiologically acceptable compound thereof is also provided for use in treating an inflammatory condition such as asthma or rhinitis. 84384 200402419 According to another object of the present invention, there is provided a compound of formula (i) or a physiologically acceptable salt or solvate thereof for use in the manufacture of a medicament for treating an inflammatory condition such as asthma or rhinitis. Another object of the present invention is to provide a method for treating a human or mammalian subject suffering from or susceptible to an inflammatory condition such as asthma or rhinitis, which method comprises administering an effective amount of a compound of formula ① or a physiologically acceptable salt or solvent thereof Compound. The compounds according to the invention can be formulated for administration in any convenient manner. Therefore, a pharmaceutical composition is further provided, which comprises the compound of formula (1) or a physiologically acceptable amphoteric salt or solvate thereof, and optionally one or more physiologically acceptable diluents or carriers. A method for preparing the pharmaceutical composition is further provided, which comprises mixing the compound of formula (1) or a physiologically acceptable salt or solvate thereof with one or more physiologically acceptable diluents or carriers. The compound of the present invention can be formulated, for example, for oral, inhalation, nasal, buccal, parenteral or rectal administration, and is preferably for oral administration. Lozenges and capsules for oral administration may contain conventional excipients such as binders such as syrup, gum arabic, gelatin, sorbitol, tragacanth, starch gums, starch, quasiquinone, or acetofluoride P-bilofe Ketone 1; fillers such as lactose, microcrystalline cellulose, sugars, corn starch, calcium phosphate or sorbitol; lubricants such as magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants Examples include mochi starch, croscarmellose sodium or sodium starch glycolate; or wetting agents such as sodium lauryl sulfate. Lozenges can be coated according to techniques known in the art. Oral liquid preparations can be made into, for example, aqueous or oily suspensions, solutions, emulsions, 84384-37-200402419 :: or glycyrrhizin 'or can be made into dry products with water or enzymes before use. Suspensions such as sorbitan methyl cellulose, glucose / syrup, gelatin, methylol, carboxymethyl cellulose, stearic acid gel, or chlorinated edible fats = localizing agents such as lecithin, sorbid ip "such as fat, lactoflavin oleate or gum arabic .: carrier (may contain edible oil) such as almond oil, sub-nutrient oil: oil 5: = alcohol or ethanol, or preservatives such as Methyl benzoate or propyl ^ shanqin. The formulation may also contain buffer salts, flavoring agents, coloring and / or sweetening agents (e.g., mannitol) if appropriate. For buccal administration, the composition can be administered in a conventional manner. In 4 rounds, the compound can also be formulated as a suppository such as a conventional suppository base such as cocoa butter or other glycerin. The compounds of the invention can also be formulated for parenteral administration by pellet injection or continuous infusion and can be presented in unit dosage forms, such as ampoules, vials, small-volume irrigation masters or pre-filled syringes, or multiple doses added with a preservative container. The combination can be made into a solution, suppository or emulsion in an aqueous or non-aqueous carrier, and it can be prepared with a withering agent such as a hydrating oxidant, a buffer, an antimicrobial agent and / or a tonicity adjusting agent. Alternatively, the active ingredient may be a powder and reconstituted with a suitable carrier such as germicidal non-pyrogenic water before use. The dry solid can be prepared by filling the sterilization powder into individual sterilization containers under high pressure or by filling the sterilization solution with high pressure into each container and freeze-drying. The compound of the present invention and the medicinal composition can also be used in combination with other therapeutic agents, such as antihistamines, anticholinergics, anti-inflammatory agents such as corticosteroids such as 84384 -38-200402419 fluticasone propionate, Beclomethasone dipropionate, mometasone p-fumarate, triamcinolone propionate or budesonide; or nonsteroidal anti-inflammatory drugs (NSAIDs) such as Tryptophan, nedocromil sodium, PDE-4 inhibitors, leukotrimidine antagonists, iNOS inhibitors, trypsin and elastase inhibitors, β-2 integrin antagonists and adenine 2a agonists; Or beta adrenal agents such as salmeterol, salbutamol, formoterol, fenoterol or terbutaline and their salts; or anti-infective agents such as antibiotic agents And antiviral agents. It should be understood that when the compound of the present invention is administered in combination with other therapeutic agents that are normally administered by inhalation or intranasal route, the resulting pharmaceutical composition can be administered by inhalation or intranasal route. The compound of the present invention is preferably administered in an amount of, for example, 0.001 to 500 mg / kg body weight, preferably 0.01 to 500 mg / kg body weight, more preferably 0.01 to 100 mg / kg body weight, and administered at any appropriate number such as 1 to 4 times per day. Of course, the precise intake varies depending on, for example, the indication for treatment, the age of the patient, and the particular route of administration chosen. Throughout the specification and the scope of the following patent applications, unless otherwise stated, `` including '' and its variations need to be understood to mean the inclusion of the stated integer or step or group of integers, but do not exclude any other integer or step or integer Or step group. The invention will be illustrated with reference to the following non-limiting examples. It should be understood that for clarification purposes, the compounds of the illustrative examples and examples are indicated by numbers, such as `` Illustrative Example 3 '' and `` Example 5 ''. The compound structures represented are listed in Tables 1 and 2 for the examples and the description Examples are listed in Tables 3 to 4. 84384 -39- 200402419 General experimental details Quality-oriented automated preparative HPLC columns, conditions and eluent quality-oriented automated preparative high-performance liquid chromatography using LCABZ + 5 microns (5 cm xlO mm internal diameter) column, gradient dissolution using two solvent systems, (A) 0.1% formic acid water and (B) 95% acetonitrile and 0.5% formic acid water, flow rate 8 ml / min. Department of mass spectrometer The VG Platform mass spectrometer was used with HP1100 diode array detector and accurate flow splitter. The LC / MS system uses the following liquid chromatography mass spectrometer (LC / MS) system: This system uses a 3 micron ABZ + PLUS ( 3.3 cm x 4.6 mm ID) column, dissolved with solvent: A-0.1% v / v formic acid + 0.077% w / v ammonium acetate water and B-95: 5 acetonitrile: water + 0.05% v / v formic acid The flow rate is 3 ml / min. The following gradient method is used: 100% A for 0.7 minutes Clock; A + B mixture, gradient profile 0-100% B lasted 3.5 minutes; maintained at 100% B for 1 minute; returned to 100% A lasted 0.2 minutes. LC / MS system uses a micro mass spectrometer and electrospray ionization Mode, switch between positive and negative ions, mass range 80-1000 amu. Thermal spray mass spectrometry was measured on HP 5989A engine mass spectrometer, + ve thermal spray, heat source temperature 250 ° C, probe temperature 120 ° C (rod) , 190 ° C (tip), detection mass range 100-850 amu. Compounds were injected in 10 microliters of a solvent mixture including 65% methanol and 35% 0.05 M ammonium acetate in water at a flow rate of 0.7 ml / min. Solid phase extraction (Ion exchange) nSCXn stands for Isolute Flash SCX-2 Sulfuric Acid Solid Phase Extraction Cassette. 84384 -40- 200402419 Hydrophobic 彳 4_can separation of organic / water only hydrophobic solvent, which represents the pore size of 5.0 micron with PTFE solvent. Whatman polypropylene filter tube. All temperatures are in C. Exemplary examples MU_ 2 Li trifluoro? 4 methyl) Methanamine in morphine 1-ylmethylamine (3 ·! G) in methanol (7 〇mL) stirred solution under nitrogen, α, α, α-trifluoroethyl Ethyl ether solution (5 ml in 20 ml diethyl ether) was washed and dried with saturated aqueous sodium bicarbonate solution, water and brine. After stirring the mixture at 22 ° C for 30 minutes, all volatiles were removed in vacuo. The residue was dissolved in The volatiles were removed in methanol (10 mL) and again in vacuo to give the title compound (4.9 g) as white crushed ice bubbles. Thermal spray mass spectrum m / z 213 [MH + J. Wei Ming Example 2: Ν- {Γ4- (3 · 4 · Dichlorobenzyl) morpholin-2-yl 1methyl 丨 -2.2.2-trifluoroacetamidamine in Drum Jj—Example 1 (3.3 g) To a stirred solution of N-dimethylformamide (50 ml) was added carbon dioxide (2.46 g) and sodium hydroxide (2.12 g) under nitrogen. To the mixture was added dropwise a solution of 3,4-dichlorobenzyl chloride (2 ml) in N, N-dimethylformamide (10 ml). After the mixture was stirred at 22 ° C for 18 hours, the volatiles were removed in vacuo. The residue was partitioned between dichloromethane (100 ml) and a saturated aqueous sodium carbonate solution (50 ml). The organic phase was washed sequentially with additional saturated aqueous sodium carbonate (2 x 50 mL) and water (50 mL), dried over magnesium sulfate, filtered and the solvent was evaporated in vacuo to obtain a pale yellow oil. The oil was separated on a 90 g silicone cartridge by Biotage flash column chromatography at 25% ethyl acetate, and the title compound (2.97 g) was obtained as a colorless oil. 84384 -41-200402419 LC / MS &amp; 2.63 minutes, mass spectrum m / z 371 [MH +]. Illustrative Example 3 ·· "4-Π.4-Difluorofluorenyl) morpholin-2-yl 1 methylamine in a stirred solution of methanol (15 ml) and water (5 ml) in Illustrative Example 2 (2.97 g) Potassium carbonate (5.53 g) was added. After the mixture was stirred at 22 ° C for 18 hours, the methanol was removed in vacuo. Water (25 ml) was added and the mixture was extracted with ethyl acetate (3 x 30 ml). The combined organic phases were water (5 Ml) and a saturated aqueous solution of chlorinated steel (10 ml), dried over sulphuric acid steel, evaporated and the solvent evaporated in vacuo to obtain a pale yellow oil. This oil was chromatographed on a 90g silicone cartridge by Biotage flash column chromatography to 75 : 8: 1 Dichloromethane / ethanol / 0.880 ammonia solution was dissolved. The required fractions were combined and the solvent was evaporated in vacuo to obtain the title compound (1.85 g) as a colorless oil. LC / MS &amp; 1.77 minutes, mass spectrum m / z 275 [MH + ]. Example 4: "4- (3,4-dichlorofluorenyl) morpholin-2-yl 1 methylamine (another synthesis, 2-[(3,4-dichlorobenzyl) amino group ] Ethanol (Chem. Abstract No. 40172-06-3, 0.980 g) and 2- (Ethylene oxide · 2-ylmethyl) -1H-isoindole-1,3 (2H) -dione (1.10 g) Mixture at 80 ° C and nitrogen Stir for 3 hours. The solid obtained is treated with concentrated sulfuric acid (1.5 liters) and then stirred at 150 ° C for 24 hours. The mixture is treated with water (100 ml) and then washed with ethyl acetate (2 x 100 ml). Dark water The phases were basified with 5 μ sodium hydroxide aqueous solution to about pH 12, followed by extraction with ethyl acetate (2 × 100 mL). The combined organic extracts were washed with water and brine, dried (v% §〇4) and filtered. The product was concentrated to obtain the title compound (102 g) as a brown oil. Mass spectrum m / z 275 〇 复 iiAiJ_l-"(2S) -4- (3,4-dichlorosulfanyl 4-methyl [methylamine drum JiJLi (Racemic mixture '8 g) was separated into its single enantiomer by preparative para-palladium-HPLC. 2 "x22 cm Chiralpak AD 20 micron column 84384 -42- 200402419 (Merck self-packed DAC system) Separation was performed at 95: 5: 0.1 (v / v) heptane: absolute ethanol: diethylamine (flow rate: 55 ml / min for 40 minutes, UV detection at 225 nm); sample-loaded preparation: 400 mg sample in 20 ml of 3: 2 (v / v) absolute ethanol: system eluate. The title compound (2.49 g) was obtained as follows: Residual HPLC dwell time of 23.0 minutes. Example 5Γ Another procedure) The slurry of Example 7 (1.00 g) in water (8-5 ml) was heated to 75 ° C and then treated dropwise with concentrated sulfuric acid (2.5 ml). The mixture was then refluxed Heat. After 23 hours, cool the reaction mixture to 22 ° C and treat with dichloromethane (6 mL). Then, 880 ammonia solution (7 ml) was added dropwise under cooling. Add more dichloromethane (10 mL). The aqueous phase was separated and extracted with more dichloromethane (10 mL). The combined organic phases were washed with water (5 ml) and evaporated to dryness. The residue was redissolved in dichloromethane and the solvent was evaporated to obtain an oily product (662 mg). Illustrative example 6: l-"(2SV4- (3,4-dichlorofluorenyl) morpholin-2-yl 1 methylamine salt containing D-tartaric acid 1: 1 Illustrative example 3 (0.613 g) was dissolved in methanol ( 12.3 ml). D-tartaric acid (0.335 g) was added and the slurry was heated to reflux for 50 minutes. The mixture was cooled to 0.5 ° C and the precipitate was collected by filtration to obtain the title compound (0.4 g) as a white solid. Ee: 76% ee Analytical HPLC (Chiralpak AD column, 4.6x250 mm, eluent 50: 50: 0.1 MeOH: EtOH: butylamine, flow rate 0.5 ml / min, UV detection 220 nm) '8.9 minutes. Example 7: 2-f4_ (3,4-dichlorofluorenyl) morpholin-2-ylmethyl 1-isolamido-1.3-di 84384 -43- 200402419 2-[(3,4-dichlorobenzyl) amino ] Ethanol (2.038 g) and ⑶-2- (ethylene oxide-2-ylmethyl HH-isoindole-1,3 (2H) -dione (2.032 g) tetrahydrofuran (3.3 Ml) The mixture was stirred and heated under reflux under nitrogen. After 21.5 hours, more tetrachlorosulfan (12.5 ml) was added and the mixture was cooled to 3 ° C. Triphenylphosphine (2.793 g) was added and the mixture was stirred until all solids Dissolve. Then add azobisacid in 12 minutes Diisopropyl ester (2 · mL) was maintained at a temperature of <7 ° C. After 2.25 hours, the mixture was warmed to 22 ° C. After 5 · 3 hours, more triphenylphosphine (121 mg) and azobis were added Diisopropyl carboxylic acid (0.09 ml). After 22.5 hours, the reaction mixture was concentrated to near dryness. Propofol (12 ml) was added and concentrated repeatedly, and repeated again. More prop-2-ol was added. (12 ml) and the mixture was heated to 70. 05. After 5 hours, the slurry was cooled to 22 ° C and after another 2 hours, the product was collected. The bed was washed with propanol (2 × 4 ml) and dried under vacuum at 40 ° C The product (2.622 g) was obtained. Illustrative Example 8: f (2SV4- (3,4-difluorouryl)? 4-_2-yl-1 methylamine was similar to lean—Mingming Example 8 was prepared. Preparative The HPLC residence time was 28.3 minutes. The more conventional ... bromine-N-f (gS) _4_ (3,4-dioxoyl) morpholine · 2_some methyl [acetamidine

Description of Bin 11 (1.45 g) in dichloromethane (25 ml) solution with bromoacetic acid (3.65 g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (Ια1 g) at 84384 -44-200402419 and the mixture was stirred at room temperature for 3 hours. Then, the mixture was washed with an aqueous sodium hydrogen carbonate solution, and the aqueous phase was extracted with dichloromethane. The combined organic coherent division and vacuum thickening 'obtained black oil. Purification by casting chromatography and dissociation with 5% ethanol / dichloromethane gave the title compound (1.167 g) as a yellow oil. LC-MS: 2.30 minutes, mass spectrometer wall 397 [MH +].邈 —Suction example 10: (3-formamidine bispyrazole is small, α is similar to Example 12 on the first day and month, and the illustrative example 10 is prepared.

OHC

Β〇2% Ν, 〇2ίΒυ

A second potassium butoxide ((0.045 g) was added successively to 3- (ethoxycarbonyl) pyrazole [CAS 37622-90-5] (0.050 g) of N, N-dimethylformamidine (0 · 5 ml). The mixture was stirred for 5 minutes, and then bromoacetic acid tert-butyl (0.078 g) was added over 2 minutes. The mixture was stirred for 0.75 hours and then partitioned between ethyl acetate (30 ml) and 1.0 M carbonic acid. Between aqueous sodium hydrogen solution (20 ml). The organic phase was separated, washed with water (2 x 20 ml), dried (Na2S04) and concentrated in vacuo to give the title compound (0.073 g) as a colorless viscous oil. LC-MS: 1 ^ = 2.78 Min. Mass spectrum m / z 255 [MH +]. Illustrative Example 12 · 1_Aminomethyl-lH-p ratio Jun_4_ read acid

Et02C

Co2h 4.0 M hydrogen chloride in dioxane solution (0.5 ml) was added to a solution of 1,4-dihumane (3 ml) in Sauri (0.070484384-45-200402419 g). The mixture was stirred for 4 hours. Add more 4.0 M hydrogen chloride dioxane (0.5 ml). The mixture was stirred for another 3 hours and then left to stand over the weekend. The solvent and excess hydrogen chloride were removed in vacuo to give the title compound (0.056 g) as a pale yellow waxy solid. LC-MS: Rf L98 minutes. Mass spectra m / z 199 [ΜΗ +] and 197 [ΜΗ ·]. Illustrative Example 49: 5- (2-Methoxycarbonyl-ethyl VH.2.41 ethyldiazol-3-carboxylic acid ethyl ester

Add 4-dimethylamino leaf 1: monomethyl succinate (4.4 g) to anhydrous dimethoxyethane (50 ml). Esters (4.4 g) (see preparation of tetrahedron, 1992, 48 (30), 6335-60) and 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride Acid salt (7.7 g). The mixture was heated to 100 ° C for 30 hours, then cooled and partitioned between ethyl acetate and a 1 μ hydrogen acid aqueous solution. The phases were separated and the aqueous phase was extracted with more ethyl acetate. The combined organic liquids were washed with brine, dried (MgS04) and evaporated to give a red-brown solid. The solid was separated by column chromatography with 3: 1 cyclohexane / ethyl acetate to obtain the title compound (L2 g) as a colorless oil, which was found by NMR analysis to contain about 50 mole% of the starting half-ester. χϋ NMR (CDC13 400 MHz) δ 4.51 (2Η? q) 3.72 (3Η? s) 3.30 (2Η? t) 2.96 (2Η? t) 1.45 (3Η, t) 3-Π-methylaminomethyl -"1,2,41 oxadiazole_5-a) _ and methyl ester 84384 -46- 200402419

To a dry methanol (5 ml) mixture of ethyl carboxylic acid ethyl ester (0-5 g) of 5- (2-methoxycarbonyl · ethyl Hu〆] · oxadiazole as an impurity in Example 49 was added methylamine (2. m in tetrahydrofuran, 10.9 ml) and the mixture was stirred at room temperature. After 90 minutes, the solvent was removed in vacuo to give a nearly white solid. The solid was purified by column chromatography using 3: 2 cyclohexane / acetic acid The ethyl ester was dissolved to obtain the title compound (0.22 g) as an off-white solid. NMR (CDC13) δ 6.93 (1Η br s) 3.72 (3H? S) 3.27 (2H3 t) 3.03 (3H5 d) 2.94 (2H51). '1 · Illustrative Example 58: ^^ methylamino_ri · 2 · 4] humionyl group v propionic acid; compound containing triethylamine.

〇 H3C eight V eight ch3

J Η〆 In the case (0.064 g) of methanol (2 ml), 2 M aqueous sodium hydroxide solution (0.30 ml) was added and the mixture was stirred at room temperature for 18 hours. 2M aqueous hydrochloric acid solution (0.30 ml) was added and the mixture was directly applied to sulfonic acid ion-exchange g (5 g, Isolute SCX, pre-washed with methanol) and the cartridge was dissolved with methanol ㈤) followed by 5% Ά 84384 -47- 200402419 Ethylamine was dissolved in methanol (x2). The solvent was removed from the combined major fractions in vacuo to obtain the title compound (0.051 g). LCMS m / z 200 [MH +]. Illustrative Example 55 ·· 3-Π-ethylaminomethylamido- "U.41" Dimethyl 1-5-ylpropanoate

A method similar to that described in Example 54 was prepared using ethylamine (2M in tetrahydrofuran). 'H NMR (CDC13 400MHz) δ 6.90 (1Η br s) 3.72 (3H? S) 3.52 (2H5 dq) 3.26 (2H, t) 2.93 (2H, t) 2.17 (3H, t) Illustration Example 56: 3- (3-ethylamine, a methylamidino- "1,2,41 oxadiazol-5-yl V propionic acid; a triethylamine-containing compound

Example 58 was prepared in a similar manner to that described in Example 55_. LCMS m / z214 [MH +]. Illustrative Example 50 ·· Isopropylamine fluorenyl group-"1,2,41 dijun-5-yl) · methyl propionate 84384 -48-200402419 CH.

Isopropylamine was prepared in a manner similar to that used in Example 54. Ή NMR (CDC13 400MΗζ) δ 6.72 (1Η, br s) 4.30 (1Η, m) 3.71 (3Η, s) 3.25 (2Η, t) 2.93 (2H, t) 1.27 (6H, d). Explanation Example 57: 3-Π-Isopropylaminomethylamididazol-5-ylν propionic acid

Q CH

A method similar to that used in Example 58 was prepared from Example 50. LCMS m / z 228 [MH +]. Illustrative Example 20: Γ5-Third-butoxycarbonylamino-2H-pyrazol-3-yl) acetic acid

In a stirred solution of (5-amino-1H-pyrazol-3-yl) acetic acid (1.0 g) (see WO 95/33724) in 10% triethylamine in methanol (10 ml), at room temperature under nitrogen Di-tert-butyl dicarbonate was added with vigorous stirring. The mixture was heated at 50 ° C for 1.5 84384 -49- 200402419 hours' and the solvent was evaporated in vacuo to obtain a light brown solid. Purify by flash chromatography on silica gel with Bi0tageTN, first dissolve with ethyl acetate: acetic acid 98: 2, then dissolve with ethyl acetate: methanol: acetic acid 88: 10: 2. After evaporating the solvent from the desired fraction, obtain The title compound (0.67 g). LCMSRt 2.21 minutes, m / z 242 [MH +]. JOLL4 ·· 〇-methylamidoamino group __ | ~ 1,2,41) Ethyl acetate §

Formic acid (16.4 ml) and acetic anhydride (38.2 ml) were heated at 5 ° C for 30 minutes followed by cooling the soil temperature. One addition (3_amino group &lt; 1,2,4] ^ No. 2 Junshiji) _ Ethyl acetate (5.55 g) (see Tetrahedron for its preparation; 1991; 47 (35); 7447_7458). The mixture was heated at 70 C for 45 minutes and the volatiles were evaporated in vacuo. The residue was dissolved in ethyl acetate and saturated with sodium bisulfate The solution was washed with water, a saturated saline solution, dried over sulphuric acid and filtered, and the solvent was evaporated to obtain the title compound (g) as a yellow oil, which crystallized after standing. Methyl) morpholin-2-yl 1 methylamine

Preparative preparative HPLC dwell time 25.2 minutes 84384 -50- 200402419 Instruction Example 19

V

CI character group)? 4-2-yl &quot; I methylamine Preparation example in a similar manner] 9 、 Residual preparative HPLC residence time 261 minutes Description example 16: Γ;-"ΐρ_ di '0,

νη2 F

F F and ιτ were prepared in a similar manner to nitrogen example 3_ to illustrate Example 16. 〇 Observed mass spectrum m / z 275 ρνΗ; | +. Stem J. Example 17: 〇 ^ 4- (3-fluoro ^ 〇morpholine · 2 · yl 1 methylamine

Illustrative Example 17 was prepared in a similar manner to Illustrative Example 3. Mass observed m / z 225 [ΜΗ] +. Example 25: 5- [2-Third-butoxycarbonylvinyl) furan wintercarboxylic acid methyl ester

-51-84384 w &gt; 4 200402419 methyl 5-bromo-2-furancarboxylate (3.6 g), triphenylphosphine (0.36 g), palladium acetate (0.4 g), third butyl acrylate (7 · 8 ml) and triethylamine (27.2 ml) in acetonitrile (45.4 ml) were divided into 13 equal portions. Each part was heated to 100 ° C in a sealed microwave tube for 40 minutes. Additional palladium acetate (0.02 g) was added to each container and the mixture was microwaved at 110 ° C for 15 minutes. The mixtures were combined, concentrated in vacuo and purified on a silicone SPE cartridge. The cartridge was dissolved with 10% ethyl acetate in cyclohexane. The product-containing fractions were combined and concentrated in vacuo to give the title compound (3.2 g). LCMS &amp; 3.26 minutes, m / z 270 [MNH /]. Note: The microwave oven is a 300-watt Smith generator.簠 明 例 26: 5- (2-Third-butoxycarbonylethyl) owan-2-# _ methyl ester

Prepared similarly to Example 29. LCMS &amp; 3.10 minutes, m / z 272 [MNH /] 0 Exemplary Example 27: 5- (2-Carboxyethyl) furan-2-carboxylic acid methyl ester

Prepared similarly to Example 28. LCMS 2.17 minutes, m / z 199 [MH +]. Example 30: 5 彳 2-Third butane, some carbonyl, some vinyl) furan-3 · # acid ethyl ester

(Diethylphosphinofluorenyl) tert-butyl acetate (1.65 g) in THF (5 ml) was added dropwise to 60% sodium trihalide (0-262 g) in THF (5 ml) at The suspension was stirred under nitrogen. The mixture was stirred at room temperature for 45 minutes and then re-cooled using an ice bath. To the mixture was added dropwise a solution of ethyl 5-formamylfuran 3-carboxylate (1.0 g) in THF (10 mL). The stirred mixture was heated to 60 ° C for 2 hours, and then left at room temperature overnight. The mixture was poured into 1: 1 ethyl acetate / 5% aqueous sodium bicarbonate solution (100 * L), and the layers were shaken and separated. The aqueous layer was extracted with ethyl acetate (50 mL) and the combined organic extracts were washed with a saturated aqueous saline solution (50 mL), dried over sodium sulfate, and concentrated in vacuo. The crude product was purified on a 50 g silicone SPE cartridge and dissolved in 50% ethyl acetate / cyclohexane. The product-containing fractions were combined and concentrated in vacuo 'to give the title compound (2.0 g). LCMS 3.58 minutes, m / z 284 [MNH4 + J. 5- (2-Third-butylethyl) furan_3 · carboxylic acid ethyl ester

Ethanol (60 ml) of Distinguished Example 30 (1.5 g) was added to a 10% palladium / carbon catalyst (0.0 g). The mixture was stirred under hydrogen. After 2 hours, the catalyst was filtered through celite, filtered and concentrated in vacuo. The residue was purified on a 50 g silicone SpE cartridge with 84384-53-200402419, and then dissolved using a solvent gradient, first with 100% cyclohexane and then sequentially with 100/0, 20%, 30%, 40% and 50 % Dichloromethane / cyclohexane. The product-containing fractions were combined and concentrated in vacuo to obtain the title compound (0.73 g). LCMS 1 ^ 2.41 minutes, m / z 269 [MH +]. Illustrative Example 28 · 5- (2-Multiethylethyl) anan-3-acetic acid ethyl ester η

Illustrative Example 29 (0.73 g) was dissolved in 1,4-diyin tiger (2 ml), treated with a 4 M HC1 in 1,4-diazine solution (10 ml) and stirred at room temperature for 6 hours. Dioxane was removed from the mixture in vacuo and the residue was dissolved in ethyl acetate and extracted with a 5% aqueous sodium bicarbonate solution (3x20 mL). The combined aqueous extracts were acidified to pH 3-4 with solid citric acid and extracted with dichloromethane (3 x 20 mL). The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was lyophilized from 1,4-dioxane under vacuum to obtain the title compound (0.374 g). LCMS 1 ^ 2.52 minutes, m / z213 [MH +]. Wei Mingshu 15: 3-methylimidazole-4-thiocarbamate

2 Η Ν In a solution of 3-methyl_3H-imidazole-4-carbonitrile (6.8 g) in ethanol (100 ml), add a freshly prepared ammonium polysulfide solution (102 ml) at room temperature (see organic Journal of Chemistry, 1993, 58 (22), 6103-8). The mixture was heated at 40 ° C for 6 hours and -54- 84384 200402419 was obtained. It was left at room temperature overnight.彳 军 #_ solid title compound was removed from the mixture under reduced pressure (7.1 g).

Mpt. 135-140 〇C 0 Description Example 13: 1H-pyrazole-4-carboxylic acid tert-butyl ^

A stirred suspension of 1H-pyrazole-4-carboxylic acid (U2 g) in anhydrous toluene (20 ml) was heated at 70 ° C for 15 minutes under nitrogen. To the hot suspension was added a solution of N, N-dimethylformamide-di-tert-butylacetal (8 ml) in anhydrous toluene (8 ml). Contents> Valley fluid was heated at 78 C for 21 hours. After cooling, the mixture was diluted with ethyl acetate (ml) and washed with saturated saline solution (5x25 ml). The organic phase was dried over magnesium sulfate, filtered and evaporated to dryness to obtain a gum. The gel was flash-chromatographed with silica gel (60 g Merck 9385) and dissolved in dichloromethane / methanol 50: 1. The desired fractions were combined and evaporated to dryness to give the title compound as a gum, which solidified upon standing (0481 g).

Mpt. 96-97 ° C.

84384 13 ^ 1 ^ _1 _ "(28) -4- (3,4-: fluorofluorenyl) morpholine_2-ylmethyl acridinium_2,5_ dione

-55- 200402419 Instruction Example 8 using a procedure similar to that described in f mz and succinate monoformate preparation. 9 LCMS m / z 325 [MH +].

Blue Example 24: N-K ^ g.) Dibenzyl) morpholine · 2-ylmethyl] butyl triethylamine-containing compound.

F Prepared using a procedure similar to that described in 歹 i: 77_ using instruction example 21. LCMS m / z 343 [MH +].惠 ^ 事 基) Moryl-2-ylmethyl 1 e Description Example 22: l-"(2SV4-n.4- ^ dione

A procedure similar to that described in JJ7 · Using Instruction Example 5 and Monomethyl Succinate was prepared. LCMS m / z 357 [ΜΗ +]. __ 明 例 _23 4-.. (3,4- ^ benzyl) morpholine _2_ylmethyl 1 butyl ^^^ Compound containing triethylamine 84384

-56- 200402419 ο

Prepared using Instruction Example 22 using a procedure similar to that described in Example 77. LCMS m / z 375 [MH +]. Qiming Example 43

Ethyl 5- (chloromethyl) -2-furancarboxylate (ι · 0 g), potassium moth (0.0442 g), and chloro (1,5-cyclooctyldi) germanium ① dimer (〇261 g ) The mixture was stirred in formic acid (25 ml). The mixture was stirred vigorously and heated at 75 C and carbon monoxide for 6 hours and then 'cooled to room temperature and left to stand overnight. The mixture was concentrated in vacuo to obtain a dark brown residue. The residue was diluted with ethyl acetate and washed with a 2M aqueous hydrogen acid solution (3x75 ml) and a saturated aqueous common salt solution (2x75 ml), dried over magnesium sulfate and filtered. The filtrate was evaporated to dryness to obtain a dark green gum, which was purified on a silica gel (90 g) by Biotage ™ flash chromatography and dissolved in 25% ethyl acetate and 2% acetic acid in cyclohexane. The desired fractions were combined and evaporated to dryness in vacuo to give the title compound (0.672 g) as a dark gum. LCMS \ 2.35 minutes; m / z 199 [MH +]. Exemplary Example 59: 5-Chloromethyl-1,3-Ethyl oleate 84384 -57- 200402419

Prepared from 5-chloromethyl-furan ethyl carboxylate (see Preparation of the Journal of Organic Chemistry; 41; 1976; 2835-2846) in a similar way to nm dream search. Ή NMR (CDC13 400 ΜΗζ) δ 7.95 (1H, s) 6.63 (1H s) 4.27 (2H, q) 3.74 (2H, s) 1.30 (3H, t). Say J Example 51: "5-Π" (2SV4- (3.4-diphenyl.fluorenyl) morpholin-2-ylmethyl 1aminomethylfluorenylmethyl) isoxazol-3-yl 1aminocarboxylic acid third butyl ester

Prepared in a manner similar to that of Example 27 using (3-third-butoxycarbamino-isohex-5-yl) acetic acid (for preparation, see Tetrahedron Newsletter; 1996, 37 (19), 3339-3342). . LCMS m / z 499 [MH +]. Let jg. Example 52: | · 5-({| · (28ν4- (3_amidobenzyl-2 • ylmethyl ~ 1 aminomethylagronon y methyl) isoxazole each base 1 aminocarboxylic acid third

Use similar! For example, use ^ 3 ^ 119 and (3-third butoxy carbon 84384 -58- 200402419) aminoamino-isoxazol-5-yl) acetic acid (for the preparation of tetrahedron communication; 1996, 37 (19), 3339-3342). LCMS m / z 465 [MH +]. Do all ... day and teach 5_3 "f 2_ (3-amino-isoxazole_5_some, ...-" Menbetsu (3 · chloroamidine, morpholin-2-ylmethyl 1 acetamidine

Prepared in a similar manner using Instruction Example 52. LCMS m / z 365 [ΜΗ +]. Mou m: di-stilbene group) morpholine _2_some methyl certain 1 amine group 5 j ethyl group 丨 ethyl) odor-^ 2_ carboxylic acid; + triethylamine compound

Prepared from Example 28 using a procedure similar to that described. LCMS m / z 441 [MH +] 〇 Rangming oblique_Li__: 5-(^ j ^ g) _4_i3.4_bis # fluorenyl) morpholine_2_ylmethyl 1 aminomethyl•H _) Sulfuric acid; compounds with ethylamine deficiency 84384 200402419

Prepared from Example 26 using a procedure similar to that described in Example 77. LCMS m / z 441 [MH +]. Explanation, Xun ^ 6: 5-({"(28) -4-_〇 ^^ 1 ^ _ ^ 1 ^ 1 wood_2-ylmethyl1aminomethyl} methyl) bitan-3- #acid

Prepared from Example 76 using a procedure similar to that described in Example 77. LCMS m / z 427 [MH +] 〇 Base 1 Propyl ^ containing 4. oxo-valeric acid ethyl ester

Di (5.55g) Partial solution of anhydrous chloroform (4ml) (5ml) was added dropwise to rc of ethyl levobanoate (5.0g) in rc of anhydrous chloroform (30ml) and stirred under nitrogen The mixture was then warmed to 20 ° C. . . in%. . After stirring for 18 hours, the remaining Chinese drop solution was added dropwise at about 15 knives and the reaction temperature was maintained at a pit with a water bath. 84384 DOi. -60- 200402419 The reaction was stirred at 20 ° C for 7 hours and then left at 20 ° C for 5 days. Subsequently, bromine was evaporated by passing nitrogen into the solution for 10 minutes, and the mixture was then evaporated in vacuo to obtain a transparent light brown liquid. A portion of this liquid (L34 g) was added to an &quot; reaction vial &quot; containing 5-methyl-isopyrazoledongamidothiocarbonate (0.426 g) and absolute ethanol (1.0 ml). The solution was stirred at 105 ° C for 3 hours and then cooled. The solvent was evaporated in a stream of nitrogen and the residue was dissolved in digas. The solution was applied to a silica solid phase extraction cartridge (10 g, Varian Bondelut) and sequentially cyclohexane, followed by 5 ° /. Then 100/0 ethyl acetate / cyclohexane was dissolved. The appropriate fractions were combined and evaporated in vacuo to obtain a brown solid in a 1: 1 ratio of the title compound (0.285 g) and ethyl levobate. LCMS &amp; 3.09 minutes, m / z 267 [MH +]. For Example 48: `` 4-methyl-2- (5-methyl-isoxazolyldongyl V pyrazole 4yl μ ethyl acetate

Bromine (5.55 g) in anhydrous chloroform (4 ml) and a partial solution (0.5 ml) was added dropwise to ethyl gluconate (5.0 g) in anhydrous chloroform (30 ml) at 5 ° C and the solution was stirred in nitrogen. The mixture was then warmed to 2 ° C. After stirring at 20 ° C for 18 hours, the remaining bromine solution was added dropwise over about 15 minutes, and the reaction temperature was maintained at 10-20 ° C by a water bath. The reaction was stirred at 20 ° C. 7 Hours were then allowed to stand at 20 ° C for another 5 days. Subsequently, bromine was evaporated by passing into nitrogen solution for 10 minutes, and the mixture was then evaporated in vacuo to obtain a transparent light brown liquid. Part of this liquid (1.34 g) was added with absolute ethanol (lo mL) in a π reaction vial of π in a π reaction vial of π_384_61-2004-2419 (0 · 426 g). The solution was stirred at 105 ° C. It was then cooled for 3 hours. The solvent was evaporated in a stream of nitrogen and the residue was dissolved in dichloromethane. The solution was applied to a solid phase extraction cartridge (10 g, Varian Bondelut) and successively cyclohexane followed by 10% acetic acid. Ethyl acetate / cyclohexane dissolve. Combine the appropriate fractions and evaporate in vacuo to obtain the title compound (0.114 g), and the amount of trace components is said to the sun and the moon {Column 47 is in a ratio of 2: 1. LCMS 1 ^ 3.06 minutes, m / z 267 _ +]. Explaining Example 31 ·· 「2- (5-methyl · · Isopurazolyl acetazol-4-ylacetate

UN h3c Into a `` reaction vial '' containing 5-methyl-benzyl-3-thiocarbamoylamine (0.213 g) was added ethyl 4-chloroacetamidoacetate (0.305 ml) and absolute ethanol ( 0.5 ml) The mixture was stirred at 20 ° C for 16 hours, then at 105 ° C for 5 hours and then cooled. The solvent was evaporated under a stream of nitrogen and the residue was dissolved in dichloromethane. The solution was applied to emulsified solid phase extraction] (10 g, Varian Bondelut) and dissolved with cyclohexylamine followed by 5% ethyl acetate / cyclohexane. The appropriate fractions were combined and evaporated in vacuo 'to give the title compound (0.252 g) as a light brown solid. LCMS &amp; 2.92 minutes, m / z 253 [MH +]. : "2-Γ5 · methyl · isoxazol-3-yl vsetazol-4 · yl 1 acetic acid-84384

〇—N h3c -62- 200402419 In Example 31 (0.076 g), the reaction vial was added with ethanol (0.665 ml) and 2 M aqueous sodium hydroxide solution (0.478 ml) and the mixture was stirred at 70 ° C for 3.5 hour. After cooling, the mixture was neutralized by adding a 2M aqueous hydrochloric acid solution (approximately 0.375 ml) and then evaporated to dryness under a nitrogen stream to obtain a mixture of the title compound and an inorganic salt as a brown solid. LCMS &amp; 2.52 minutes, m / z 225 [ΜΗ +] 〇 Gas_ 明 例 34 ·· "5- 甲某 令 （5_methyl-isoxazole each hydrazone 1 ethyl acetate

A similar method was used using ethyl 4-bromooxo-valerate (for preparation, see Journal of Medicinal Chemistry, 1988, 31 (10), 1910-18). LCMS m / z 267 [MH +]. Doumou] acetic acid

A self-explanatory example is prepared in a similar manner to 1 Exemplar II. LCMS m / z 239 [ΜΗ +] 〇 Example 32 Ethyl acetate 84384 -63-200402419

Example 15 using a similar method using star, sun, and moon 31 is provided. LCMS m / z 252 [MH +] 〇 Exemplary Example 38

OH ° η3 was prepared from Illustrative Example 32 in a similar manner to Cap 37. LCMS m / z 224 [ΜΗ +] 〇 ΙΜΜϋΛ 5-pentyl-3H-imidazolyl V cetolide 1 ethyl

In a similar manner to Instruction Example 31, Instruction Example 15 and 4-bromo each oxo-valeric acid ethyl ester (for preparation, see Journal of Medicinal Chemistry, 1988, 31 (10), 1910-18) were prepared. LCMS m / z 266 [ΜΗ +] 0 Illustrative Example 41: "5-Methyl-2- (3-methyl_3H_weitant-4-yl Vsid-4--4- 1acetic acid_〆. _ · Ϊ́ V 'rv'!, 84384 -64- 200402419

Prepared from Illustrative Example 35 using a procedure similar to Illustrative Example 37. LCMS m / z 238 [MH +]. Illustrative Example 33: "2- (4-methyl-"

It was prepared in a similar manner to that of Example H using tolmethyl- [1,2,3] soranilide-5-thiophosphonium carbonate (see WO 00/06606 for preparation). LCMS m / z 270 [ΜΗ +]. 1 Exemplified Example 39: "2- (4-Methyl-" 1,2,31-thiadiazole-5: ^^ _ 4_yl] B_

An LCMS m / z 242 [MH +] was self-explanated using a similar method to that described in Example 37.

84384 -65- 200402419 In a similar manner to Instruction Example 31, 4-methyl- [1,2,3] farepine-5-thiophosphonium carbonate (for preparation, see wo 00/06606) and 4-bromo- 3-Oxo-valeric acid ethyl ester (for preparation, see Journal of Medicinal Chemistry, 1988, 31 (10), 1910-18). LCMS m / z 284 [MH +]. Stem JLM 42: "5-methyl-2_ (4-methyl-" 1,2,31-pyrimidin-2-sit_5_yl) imidazole_4-yl1 acetic acid

Prepared from Illustrative Example 36 in a similar manner to Illustrative Example 37. LCMS m / z 256 [MH +] 〇 Example Synthesis Method A Example 10

A solution of 1H-tetrazole-5-acetic acid (0.172 g) in N, N-dimethylformamide (2 ml) with 1-hydroxybenzotriazole (0.124 g), 1- (3-dimethylamino Propyl) -3-ethylcarbodiimide hydrochloride (0.200 g), N-N-dimethylformamidine (1 ml) and N, N- Diisopropylethylamine (0.112 ml) was treated with a solution of 84384 -66- 200402419 and the mixture was stirred at 1: j for 6 days. The solution was then diluted with dichloromethane (30 ml) and washed sequentially with a saturated aqueous sodium bicarbonate solution (30 ml) and a dilute aqueous sodium chloride solution (2 x 30 ml). Three hydrophobic melts (12 mL) were used to separate the organic phase and discharged directly to the SCX (10 g) ion exchange cartridge (pretreated with methanol) and dissolved with methanol and 10% 0.880 ammonia / methanol. Combine the main dissolving fractions and evaporate to obtain an ocher-colored film. Then, saccharine was purified by chromatography using Varian Bond Elut (5 g), followed by dichloromethane, ether, ethyl acetate, and acetone. , Acetonitrile and methanol. The methanol fractions were combined and evaporated in vacuo to give the title compound (0.042 g) as a colored gum. LC_MS: Rt = 2.11 minutes, mass spectrum m / z 385 [MH +]. Synthesis Method A (Another Example, Example 16

3-methyl-1H-pyrazole-1-acetic acid [CAS 180741-30_4] (0.017 g) and 0- (7-azabenzotriazole small group) _N, N, N ,, N, -tetramethyl A solution of carbamide urea hexafluorophosphate (0.042 g) in acetonitrile (2 ml) was stirred for 10 minutes, followed by the explanation of Example 5 (0.030 g) and Treatment with acetonitrile (1 mL). The mixture was stirred for 3.5 hours and then allowed to stand for a weekend. The solvent was removed in vacuo. The residue was partitioned between ethyl acetate (20 ml) and 0.5 M aqueous sodium bicarbonate solution (20 ml). The organic phase was separated, washed with water (20 ml), dried (Na2S04) and concentrated in vacuo to give 84384 -67- 200402419 as the title compound (0.033 g) as a light brown gum. LCMS: 1 ^ = 2.18 minutes, mass spectrum m / z 397 [MH +] 〇 Synthesis method A (Another library example 33 ··· N- "4- (3 · 4-dichlorofluorenyl 4-2-ylmethyl) 1-2-pyridine-3-ylamidamine; compounds containing formic acid

To pyridine-3-ylacetic acid (0.027 g) was added a partial solution (0.25 ml) of dichloromethane (3.72 ml) as illustrated in Example 3 (0.955 g) and the dichloromethane was evaporated. After adding N-methylpyrrolidone (1 drop) to the mixture, it was heated in a microwave oven (full power for 4 minutes) and then cooled. The sample was purified by mass-oriented preparative HPLC and the solvent was removed in vacuo to obtain the title compound (0.018 g).

LCMS \ 2.03 minutes, m / z 394 [MET]. i 成 方法 ΑΓ Another 裎 庠 U compound A84: N-"(2SV4_ (3.4-dioxanyl)? / Lindi 2_ylmethylmethyl-starch Z oxazole_3_yl V thiazole-4 -1-propanamide; containing compounds

To a reaction vial containing Instruction Example 47 (0.073 g), ethanol (0.665 mmol-68-ssia 84384 200402419 liter) and 2 M aqueous sodium hydroxide solution (0.478 ml) were added and the mixture was at 70%. ^ Stir for 35 hours. After cooling, the mixture was neutralized by the addition of 2 μ aqueous hydrochloric acid solution (about 0.375 ml) and the solvent was evaporated to dryness under a stream of nitrogen to obtain a beige solid. _Semi-solid was added to the stem JJ (κ.039g) of N, N-dimethylformamide (1ml), followed by 1-#-Benzotriazole (0 027g), i_ ( 3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride (0.044 g) and n, n-diisopropylethylamine (0.027 ml). The mixture was stirred at 20 ° C for 19 hours, and then diluted with dichloromethane (75 ml). The mixture was washed sequentially with a dilute aqueous solution of sodium bicarbonate (7.5 ml) and a dilute aqueous solution of sodium hydroxide (2 x 7.5 ml). The organic phase was separated using a hydrophobic melt and applied directly to the acid ion exchange cartridge (2 g, Isoiute SCX 'pre-washed with methanol). Dissolve in 4 column volumes of methanol and discard. Dissolve at 2% by volume of 10% ammonia / methanol, collect and evaporate to dryness under a nitrogen stream to obtain a brown gum. The gum was purified by mass-oriented preparative HPLC. After evaporation of the solvent under a nitrogen stream, the title compound (0.08 g) was obtained as a colorless film. LCMS 2.83 minutes, m / z 495 [MH +]. A Example 86 · N-"(2S) -4- (3,4-difluoromethyl) morphin-2-ylmethyl 1 · 3 ·" 2-f 5-methyl-didazol-3-yl V thiazol-4-yl 1-propanamide; compounds containing methyl formaldehyde

Use Example 8 in a manner similar to that described in Example 84. LCMS p 2.59 minutes, m / z 463 [MH +].

佥 A Method B 84384 -69- 200402419 Example 6 and Example 3

A solution of 5-isopropyltetramethylene (tetrahedron (1999), 55 (29), 8997_9006) (0.095 g) in N, N-dimethylformamide (10 ml) with bis (trimethylsilane) Base) lithium amidine (0.155 g) and stirred at room temperature for 25 minutes. Next, a solution of N, N-dimethylformamide (10 liters) in Example 9 (0.167 g) was added and the mixture was stirred at 60 for 6 hours. After cooling, the solvent was removed, the residue was dissolved in dichloromethane and the solution was washed with water. The aqueous phase was extracted with dichloromethane, then the combined organic phases were dried (Na2SO4) and the agent Z2 was reduced to obtain a residue, which was purified using mass-directed hplc. The appropriate fractions were combined and evaporated to give the title compound example 6 (0.021 g) as a colorless oil. LC-MS: 2.21 minutes, mass spectrum m / z [mh +] 427 Combine other suitable fractions and evaporate to give the title compound as a colorless oil, Ref. 1 (0.027 g). -LCMS &amp; = 2.35 minutes, mass spectrum m / z [MH +] 427. Synthetic method B (another procedure 1) 1 case of 37 ′ 1_ ((“4- (monochlorofluorenyl) morpholin-2-ylmethyl 1 methylmethyldonyl} methyl)-: 5-methyl- 1H_ 米 嗤 -4 · # Acid ethyl ester

SS2i 84384 200402419 3,5-dimethyl-4-methylphenoxyphenoxyethoxymethyl polystyrene aldehyde resin (1.0 g@0.9mmol/g load) in a small amount of 10 / 〇acetic acid N The N-dimethylformamide solution swells to form a slurry. A solution of N, N-dimethylformamidine (2 ml) in Instruction Example 3 (0.969 g) was added and the mixture was stirred at room temperature for 100 minutes. A 1% solution of N, N-dimethylformamide (10 ml) in acetic acid was added, followed by sodium triethylacetoxyborohydride (0.333 g). After the reaction was shaken for 20 minutes, sodium triethoxylate (0.30 g) was added and the reaction was shaken at room temperature for another 18 hours. The reaction solution was removed by filtration and the resin was washed with N, N-dimethylformamide (5x10 ml), methanol (5x10 ml), dichloromethane (5x10 ml) and ether (3x10 ml), and then dried under vacuum. A portion of the resin (0.10 g) was swollen with dichloromethane and then drained. Prepare a solution of diisopropylcarbodiimide (0.0705 ml) and bromoacetic acid (0.125 g) in 1: 1 dichloromethane / N, N-dimethylformamide (1 ml) and stir for 5 minutes. After that, it is added to the resin. The resin mixture was shaken at room temperature for 2 hours, the reaction mixture was removed over 漉 and the resin was washed with N, N-dimethylformamide (5 x 10 ml), methanol (5 x 100 ml) and dichloromethane (5 x 10 ml). A solution of potassium tertiary butoxide (50 mg) and 4-bromo-1H-imidazole (0.132 g) in N, N-dimethylformamide (0 ml) was prepared and stirred for 5 minutes before adding to the resin. The reaction mixture was heated to 60 and shaken for 18 hours. The reaction solution was removed by filtration and the resin was washed with n, N-dimethylformamide (5 x 1 ml), methanol (5 x 1 ml) and dichloromethane (5 x 1 ml). A 1: 1 solution of trifluoroacetic acid / dichloromethyl fe (1 liter) was added to the resin. After the mixture was shaken for 90 minutes, the reaction liquid was collected. This solution was combined with a washing solution for washing the resin with dichloromethane. Volatile residues were removed by evaporation and purified by mass-directed automated preparative chromatography to give the title compound (0.008 g). LCMS &amp; = 2.33 minutes, m / z 469 [MH +]. -71-6522 84384 200402419 Synthesis method B Another procedure 2 groups) morpholine_2_methylidylmethylmethylformyl} methyl V1H-pyrazole-4- # tributadiene

Ethyl dibutyl emulsified potassium (0.045 g) was added to a solution of iH-p Bijun-4 · tertiary butyl tertiary butyl ester (0.055 g) in N, N-dimethylmethanamine (1 ml). After the mixture was stirred at 20 for 0.75 hours', a solution of N, N-dimethylformamide (0.5 ml) of Example 9 (0.0QQ g) was added thereto. The mixture was stirred at 20 ° C for 2 hours and then allowed to stand overnight. The mixture was diluted with ethyl acetate (35 ml), washed with 1 M aqueous sodium bicarbonate solution (30 ml) and water (30 ml), dried over steel sulfate and concentrated in vacuo to obtain a gum. The gel was purified on a 20 g SPE cartridge and was first stripped with ethyl acetate followed by a ethyl acetate / methanol (100: 1) mixture. The product-containing fractions were evaporated in vacuo to give the title compound (0.032 g) as a light brown gum. LCMS 2.62 minutes, m / z 483 [ΜΗ +]. Synthesis method C (mutual Koreanization) Example 4 and Example 9 -72- ssis 84384 200402419

An example of a stirred solution of 10 (0.038 g) of dichloromethane (1.5 ml) and methanol (0.5 ml) was heated at room temperature with (trimethylsilyl) azide methane (0.22 ml of 10%). Solution). After stirring at room temperature for 2 hours, acetic acid (0.1 mL) was added and the solvent was evaporated to dryness under a stream of nitrogen. The residue was loaded onto an SCX (2 g) ion-exchange reactor (pretreated with methanol), and then dissolved with methanol and 10% 0.880 ammonia / methanol. The main fractions were combined and evaporated, and the residue was chromatographed on silica gel (Varian Bond Elut, 2 g) and eluted with 5% methanol / ethyl acetate followed by methanol. The mixed solvent was similarly purified on a silica gel (Varian Bond-Elut, 1 g) to obtain the title compound example 4 (0.0073 g) as a transparent colorless film. LCMS 2.14 minutes, mass spectrum m / z 399 [MH +]. Example 9 (0.0061 nm.) Of the title compound was combined with other suitable fractions and evaporated to obtain a clear, colorless film. 1 × -M8: 1 ^ = 2.14 minutes, mass spectrum m / z399 [MH +]. Gold method D (mutual conversion) Huang ^ ^ 5-({"(28) -4- (3,4-dichlorofluorenyl \ ^ _ 2_ylmethyl 1 aminomethyl phenyl group methyl V2H- Pyrazol-3-yl 1

200402419 To N, N-dimethylmethaneamine (1 ml) of Example 59 (0.036 g) was added ν, N-diisopropylethylamine (0,035 ml) and propionyl chloride ( 0.0086 liters) and the mixture was stirred at 20 ° C: stir for 5 hours. The mixture was applied directly to acid ion-exchange g (1 g, Isolute SCX) and dissolved in methanol followed by 10% 880 ammonia in methanol. The methanol / ammonia fraction was evaporated to obtain the crude product. Purification by mass-oriented preparative HPLC gave the title compound (0.0061 g). LCMS 2.16 minutes, m / z 454 [MH +] 〇 Synthesis method E (interconversion) Example 100: 2- (3-acetamido-isoxazol-5-yl VN-f (2SV4-i3.4 -Dihydroamidine, morpholin-2-ylmethyl 1 acetamide; compounds containing formic acid

To an example. (0.050 g) of anhydrous dichloromethane (3.5 ml) was added N, N-diisopropylethylamine (0.033 ml) and acetamidine chloride (0.0135 ml). After stirring at 20 ° C for 3 hours, ν, N-diisopropylethylamine (0.022 ml) and ethyl chloride (0.009 ml) were added. After the mixture was stirred at 20 ° C overnight, the solvent was removed under a stream of nitrogen. The residue was diluted with ethanol (4 ml), and 0.8880 ammonia (α1 耄 liter) was added thereto, and the mixture was then stirred at 20 ° C for 20 minutes. Part of the solvent was removed under a stream of nitrogen and the mixture was applied directly to a sulfonic acid ion exchange cartridge (2 g, Isolute SCX, pretreated with methanol) and the cartridge was dissolved with methanol followed by 5% triethylamine in methanol. The solvent was removed by vacuum and the residue was purified by mass-oriented preparative 84384 -74- 200402419 HPLC. After removing the solvent, the title compound (00197 g) was obtained. LCMS 1 ^ = 2.19 minutes, m / z 441 [MH +] 〇 Synthesis method F (mutual conversion) J1 case 77: 5 -_ ({_ 『(2S) -4- (3,4-dichlorodiamine)? Phenyl_2_ylmethyl 1 amine chromoyl} methyl) furan-2-carboxylic acid; compounds containing triethyl ether

2] y [aqueous sodium hydroxide solution (0.488 ml) and water (3 ml) were added to 1 7j. (0.222 g) of methanol (3 ml). The mixture was stirred at 20t: 0.5 hours and allowed to stand overnight. The mixture was concentrated in vacuo, redissolved in water and the pH of the solution was adjusted to pH 7 by adding 2M aqueous hydrogen acid solution. The mixture was applied directly to a sulfonic acid ion exchange cassette (10 g, Isolute SCX, pretreated with methanol) and the cassette was washed with water (χ3) followed by diethylamine in methanol (χ2). The solvent was removed in vacuo from a major dissolving fraction. The residue was dissolved in acetonitrile and the solvent was evaporated under a stream of nitrogen to give the title compound (0.223 g) as a light brown gum. LCMSR2.21 minutes, m / z427 [ΜΗ +] 〇 Synthesis method Gi interconversion) Example 50: N-"(2SV4- (3,4-monochloro + yl) morpholin-2-ylmethyl &quot; [- 2- "5- (3-methyl_" 1,2,4,2,2,5,2,5,2,3,1,3,3,2,5,1,2,1,2,5,2,5]

6S2S 84384 -75- 200402419

To a solution of Example 75 (0.0642 g) in ethanol (2 ml) was added acetamidooxime (0.052 g) (according to the Journal of Medicinal Chemistry (1986), 29 (u), 2174-83). 2 ml). The suspension was treated with activated 4 angstrom powdered molecular sieve (0.240 g) and stirred for 5 minutes. To the suspension was added 21% sodium ethoxide in ethanol (0.104 ml) and the mixture was heated at reflux for 4.75 hours. The mixture was cooled and allowed to stand at room temperature overnight. The mixture was applied directly to a sulfonic acid ion exchange cartridge (5 g, Isolute scx, pretreated with methanol) and 11 was washed with methanol (x3) followed by washing with 10% 0.888 ammonia in methanol (x2). The solvent was removed in vacuo from the first major eluate. The residue was re-dissolved in acetonitrile / methanol and applied directly to a quaternary ammonium ion exchange cartridge (5 g, Isolute SAX, pretreated with acetonitrile) and the cartridge was acetonitrile (X3) followed by 10% citric acid. Acetonitrile (x2) was dissolved. The solvent was removed in vacuo from the first acetonitrile fraction. The residue was purified by mass-directed preparative HPLC. After removing the solvent in vacuo, the title compound (0.0032 g) was obtained as colorless glass. LCMS &amp; 2.46 minutes, m / z465 [MH +] Synthetic method _ Example _ · lH (2S) -4- (3,4-difluoromethyl)? 4-methylmethyl 1 each (3-methyl_ "1 , 2,41 humidazol-5-yl) propanamide

SS2 / 84384 200402419 itJL.M 24 (0.Q5 | g), 4- (N, N-dimethyl) aminopyridine (0.010 g), methylamido fatty acid (0.015 g), and 1- (3 -A mixture of dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.027 g) in 1,2-dimethoxyethane (2 ml) was heated at 100 ° C for 3 hours. After cooling, the mixture was applied directly to a sulfonic acid ion exchange cartridge (5 g, Isolute SCX, pretreated with methanol) and the cartridge was washed with methanol (x3) followed by strip washing with 10% 0.880 gas in methanol (x2). The solvent was removed in vacuo from the first major dissolving fraction. The residue was flash-chromatographed on a silica gel (8-gram cassette) using Biotage ™, and separated with chloroform / ethanol melon air-dropping solution. The desired eluates were combined and the solvent was removed in vacuo to give the title compound (0.0194 g) as a pale yellow gum. LCMS &amp; 1.86 minutes, m / z 381 [MH +]. Synthetic method U is converted into each other) Review 30: "5-({| &quot; (28 &gt; 4- (3,4-dichlorofluorenyl) morpholine_2-ylmethyl ~ | amine methylamido} Fluorenyl) furan-2-carbonyl-1hydrazinecarboxylic acid

To a solution of Example 77 (0.084 g) in N, N-methylformamide (3 ml) was added 1-hydroxybenzotriazole (0.030 g) and 1- (3-dimethylaminopropylpropane). Alkyl) -3-ethylcarbodiimide hydrochloride (0.0525 g). After the mixture was stirred at 20 ° C for 10 minutes, tert-butyl hydrazinecarboxylic acid (0.0226 g) and N, N-diisopropylethylamine (0.05% * liter) were added and the mixture was stirred at 20 ° C for 30 minutes. After a few minutes, let stand overnight. The mixture was diluted with methanol and applied directly to the acid ion exchange cartridge (5 g, Issolute SCx, 84384 -77- 200402419). Pretreated with methanol E Washed with methanol (x3) followed by 10% 〇_88〇 ammonia in methanol (x2) Wash. The solvent was removed in vacuo from the first major fraction. The residue was flash-chromatographed on a silica gel (8 g box) using Biotage ™ with 17: 8: 1 dichloromethane / ethanol / 0.88. The ammonia / valley solution was separated. The required eluents were combined and the solvent was removed in vacuo to obtain the title compound (0.0655 g) as a white solid. LCMS &amp; 2.47 minutes, m / z 541 [MH +]. You-. Method Uil Interconversion, Dichlorobenzyl) morpholine-2-a methylammonyl di-2-a) acetamidamine

To a solution of Column 30 (0.0655 g) in methanol (4 ml) was added 4.0 M HC1 1,4-dihydroalkane (1 ml) and the mixture was stirred at 20X for 3 hours. The volatiles were removed in vacuo and the residue was again dropped in methanol and applied directly to the acid ion exchange J £ (5 g, Isolute SCX, pretreated with methanol). The cartridge was washed with methanol (X3) followed by 10% 0.880 ammonia in methanol (x2). The solvent was removed from the first major fraction in vacuo to obtain the title compound (0.0532 g) as colorless glassy. LCMS &amp; 2.05 minutes, m / z 441 [MH +]. Method K (Interconversion) Example 48: Nr (2SV4-(_ 3,4-dichlorofluorenyl)? 4-2-ylmethylΓ1.3.41 fluorenazol-2-yl) furan_2-yl1acetamidine Amine 84384 -78- 200402419

f Example 46 (0.0312 g) of triethyl orthoacetate (0.22 ml) was heated in a "reaction vial" at 160 ° C for 21 hours. The mixture was diluted with methanol and applied directly to the sulfonic acid ion exchange cassette (5 G, Isolute SCX, pre-washed with methanol). Washed with methanol followed by 10% 0.880 ammonia in methanol and removed the solvent from the first major dissolving fraction, real Zhi. The residue was purified by mass-oriented preparative HPLC, vacuum After removal of the solvent, the title compound (00117 g) was obtained as a colorless gum. LCMS &amp; 2.41 min, m / z 465 [MH +]. Method Li interlocked with each other) Example 78: N _ "(2S) -4- (A methyl group of 3,4-dichlorofluorene, even 4H-fl, 2,41 three-port syl-3-yl) succin-2-yl 1 ethylamine

A solution of sodium hydroxide (0.10 g) in anhydrous methanol (3 ml) was prepared and a portion of the solution (2 ml) was added to the acetic acid ethyl hydrogen hydrochloride (00 bark. The mixture was stirred for 2 minutes and then it was still. Let it stand for 5 minutes, and the clear solution above the mixture is transferred to the "reaction vial" fed with t ± i ^ _32g by syringe. The mixture was pure to hong 84384 -79- 200402419. After 3 hours, it was cooled to room temperature and concentrated under a stream of nitrogen. The concentrated mixture was purified by mass-oriented preparative HPLC and the solvent was removed in vacuo to obtain a colorless gum. The gum was dissolved in dichloromethane and purified by chromatography on a silica solid-phase extraction cartridge (0.5 g, Varian Bondelut, pre-washed with dichloromethane), and then sequentially with dichloromethane, chloroform, ether, and ethyl acetate , Acetonitrile, acetone and methanol. The solvent was evaporated from the acetone and the residue was evaporated in vacuo and the residue was chromatographed on a silica gel (8 g box) using Biotage 1 ^^ and dissolved in 100: 8: 1 dichloromethane / ethanol / 0.880 ammonia solution. The solvent was removed from the combined desired eluates in vacuo to give the title compound (0.0051 g) as a colorless gum. LCMS 2_32 minutes, m / z 464 [MH +]. Example 35 · · N-"(2RV4- (3,4-Difluorofluorenyl) morpholin-2-ylmethyl 1_2_furan-2-yl acetamidamine

Female: The racemic mixture (0.018 g) (see WO 02/26722 for its preparation) was separated on a Chiralpak AD preparative HPLC column (25 x 2 cm) with 20% ethanol in n-heptane. The flow rate was 10 ml / min and the detection wavelength was 215 nm. The fractions (the first dissociated enantiomers) containing the desired product were combined and evaporated. The obtained residue was redissolved in 1,4-dioxane and lyophilized to obtain the title compound (0.013 g). LCMSR ^ 2.46 minutes, m / z 383 [MH +]. Example 27: 5- (2-{"(2SV4- (3,4-difluorofluorenyl) morpholin-2-ylmethyl 1 aminomethylhydrazone-80- 6531 84384 200402419 ethyl 1 ^ 1X2,41 唠Diazolium carboxylic acid; acetic acid-containing compounds

To a solution of ϋ !! (0.016 g) in anhydrous N, N-dimethylformamide (2 ml) was added illustrative example 56 (0.0275 g). To the solution were added 1-hydroxybenzotriazole (0.0107 g), N, N-diisopropylethylamine (0,024 ml), and 1- (3-dimethylaminopropyl) -3 · ethylcarbonate. Diamidine hydrochloride (0.05 g). The mixture was stirred at 20 ° C for 17 hours. The mixture was applied to an acid ion exchange cartridge (2 g, isoi SCX, pretreated with methanol) and the cartridge was dissolved with methanol followed by 10% 0.888 ammonia methanol. The solvent was removed in vacuo from the first major eluate. The residue was purified by mass-directed preparative HPLC. After removal of the solvent, the title compound (0.0063 g) was obtained. LCMS 2.02 minutes, m / z 438 [ΜΗ +]. Example 88: N-((2SV4-n, 4-dichlorofluorenyl) morpholine-2-somemethyl-1-2- "4-methyl_2_ (5-_methylisoxazole-3- V thiazolyl-5-yl 1 acetamide; compounds containing formic acid | 84384

In a π-reactive vial of Example 48 (0.071 g), ethanol (0.665 ml) and 2 M aqueous sodium hydroxide solution (0.478 ml) were added and the mixture was stirred at 70 ° C for 3 5 -81-

U ;. J Z 200402419 hours. After cooling: the compound was neutralized by adding a 2M aqueous hydrochloric acid solution (about 0.375 ml) and then evaporated under a stream of nitrogen to obtain a brown solid. Half of the solid was added to 1 N-N-dimethylformamidine (1 ml) in Example 5_ (0.039 g) followed by hydroxybenzotriazole (0.027 g), 1- (3-dimethylamine Propyl) -3-ethylcarbodiimide hydrochloride (0.044 g) and N, N-diisopropylethylamine (0.027 ml). The mixture was stirred at 20 C for 19 hours, and then diluted with dichloromethane (7.5 ml). The solution was washed with a dilute aqueous solution of sodium bicarbonate (1 x 7.5 ml) and a dilute aqueous solution of sodium hydroxide (2 x 7.5 ml) in this order. The organic phase was separated using a hydrophobic melt and applied directly to the sulfonic acid ion exchange cartridge (2 g, Isolute scx, pretreated with methanol). Dissolve in 4 column volumes of methanol and discard. Dissolve with 0.8% ammonia / methanol at 10% of the volume of the two columns, collect and evaporate to dryness under a nitrogen stream to obtain a brown gum. The gel was purified by mass-oriented preparative HpLC. After evaporating the solvent under a stream of nitrogen, the title compound (0.08 g) was obtained as a transparent brown film. The iiUi was a 3: 1 mixture with the minor components. LCMS 2.82 minutes, she 495 [ΜΗ +]. Infant example 90 · Ν · Fenonyl difluorobenzyl)? 4-2-ylmethylfluorenyl-2- "4-methyl-2_f-yl · isoπ-deficient · 5-yl-1acetamide; containing Formic acid compounds

Prepared in a similar manner using Example 8. LCMS 2.57 minutes, wall 463 [ΜΗ +]. 84384 -82-200402419 Table 1 ο

Example Number Synthesis Method R1 R2 Position (*) Calculated tillering amount in stereochemistry [M + Hf minimum · J Mass isomer 1 Observed molecular weight (LC / MS), unless otherwise stated; Wfc- 1 B / 7—N VN \ 3,4- ^ CIPh S 466.393 466 2 BN = NP person A, 3,4-:. CIPh s 468.39 468 3 BN = N ch3 3,4—-CIPh s 427.337 427 1 4 A + CN = N h, n, n, 3,4-DiClPh s 399.283 399 5 B α &gt; = N η3〇Α &gt; \ 3,4-^-FPh s 446.523 447 84384 -83- 200402419 Example number 'Synthesis method R1 Stereochemistry at the R2 position (*): calculated molecular weight [M + H] + observed molecular weight of the smallest mass isomer (LC / MS), unless otherwise stated 6 B h3c γCH3 N = N 3,4- : CIPh S 427.337 427 || 7 B ch3 3,4-Di CIPh s 465.306 465 ^ 8 BN = N \ ΝγΝ \ 0 3,4_ Di-ClPh s 468.39 468 9 A + CN—N n /, A ch3 3, Primary 2-CPh s 399.283 399 10 AN = NV person 3,4. 2 .ClPh s 385.256 385 11 A ch3 \ 3,4 · 2 -FPh s 365.383 366 12 A ch3v 3,4- 2CIPh s 398.292 398 84- 84384 200402419 Example number Synthesis method R1 R2 Stereochemistry of position (*) Amount [M + H; T Observed molecular weight (LC / MS) of the smallest mass isomer, unless otherwise stated 13 A ch3 \ 3,4 · di-FPh S 365.383 366 14 A ch3 \ 3,4 · di-CPh s 398.292 398 Λ 15 A 〇3, Primary II · ClPh s 411.291 411 16 A h3c ^ VN \ 3,4 ^ .CIPh s 397.308 397 17 A h3C \ &gt; N \ ch3 3,4 · Di-ClPh s 411.335 411 18 A 0 VN \ 3,4-:-CIPh s 455.345 455 ”85- 84384 200402419 Table 2 Observed value of the example structure [MH +] Observed value of the example structure [MH +] 19 0 0 丫 Ί CH3 N-0 ^ c, xy cr 456 20 Vxi 400 21 ο 0 y ^ y ^ V ,. h3c n j: xy 470 22 H, c:: x / 395 23 O 0 h3c / ^ ch3 i c, xV h〇 / 484 24, ^ Λτ, [. ] Vx: 414 25 o 0 A y ^ Ar.r〇 CH3 N-0 kN ^ j °; xy HO 424 26 τΛ ,, ·. cc, xy cr 469 27 0 0 H3C J; ^ N 438 28: xy 455 29 O 0 Λ-Τ ^ γΎ ° Ί CH3 N j; iy 452 30 V ^ V, n HfNH CX ^ CHj Cl 541 dS37 84384 _86_ 200402419

31 々Ό h3ct ^ n / n S 436 32 IX ^ 482 33 fly. 〕 Ι〇Η Vx: 394 34 ~. : x ^ N 468 35 From fly. ] ^ ΑαCl 383 36 ixr &quot; 454 37 r〇 ch3, evening chi ixy 469 38; A &gt; ^ v, [. 〕 ~. : x ^ N 468 39 / N, N \ Jl I X / 428 40 χ ^^ Λτ '. c, xy a, 454 84384 -87- 200402419 41) L &gt; Ϊ ds V N ~~~ N 478 42 454 43 Br Cl 462 44 r ^ rO 叩 人 κ 人. 482 45 0 rV Ah, 1) c ^ &gt; = 〇 S ^ C H3C 0 ch3 483 46 Ah. , H, NH c, xy cr 441 47 366 48 / ν &lt; ^ Λγ ^, Νγ ° U…: xy cr 465 49 N—N 〇 h3c ′ ,, [. 〔Αχ / cr 398 50 N &gt; Y ^ XV .... [. ] H3c n xy 465 51 from eight. [. 〕 Ν &quot;α; 351 52 ah] h3c, Xi χΛ 481 c't '84384 〇 V ^ Vs -88- 200402419

53 〇 〇 ^ v,. 〔. ] C, xy a, 397 54 ν〇 ^ Λτ,. [. ], Ch3 ^ Ιχ ^ 480 55 〇 365 56 free ^^ ν, [. ] 498 57 γ χΛ h3c gas η3 498 58 h3c 495 59 Η2N &gt; \ ΐ. ΗΝ, Λ ^ ν, Ό ι »αχ / α, 60 ch3 Ν〇Λ ^ ν, [. ], Ch3: X ^ 494 61, Αν ... [. 〕 440 62 ch3: points 512 84384 -89- 200402419

63 NN 〇HN people 乂) A ° j: xy 454 64 ah] h3c; xy 449 65 N-N 〇HN people owe people 0, ch3 468 66, ch3 l; xy 448 67 0 H3C I c, xy cr 413 68 pxV'〇466 69 h3c γ; iy 381 70 s _ / CH3 〇h3c 463 71 ci ^ y 471 72 .CH3 ν〇 ^ Λ '[. 〕, Ch3; Xj ^ 462 73 r ° y &quot; xy 423 74 ch3 ^ UsA〇 x / 480

84384 -90- 200402419 75 C αγΛ ο, ΧΧ 455 76 H3A ^ v, [. 〕: XyN 455 77 -γ ^ Λ / 丫] € H3 427 78 〇 / r, .O See: H3C 464 79 〇Y ^ KAho H3c'H; X) ^ 408 80 0 m ^ y: ~ Λ 〇j \ ^ Eight .. [. ]: ^ Y 454 81 0γ ^^ ν, [. ] &Quot; χ / 422 82 、 Vv.t:] k〇H c, xy cr 440 83 〇 ^ ζ ^ Α 广 ， Ά h3c NH IJ &quot; χ ^ 436 84 1 ^ r ^ X] h3c 0 495- 91-84384 200402419 85 V j; x / 434 86 〆〇i fx / h3c 463 87 〇γζΚΛκ ,, [. ] 448 88 H ^ HXXr ... [. 〕 1. Into. 1xy cr 495 89 ...... [. 〕. : Minutes 440 90 sounds: A ,. 〔〕, H: χ / 463 91 Ah. 'rijH k J cC c, _j ο, Χ ^ 454 92 ^' .. O Eight &quot; a: 413 93 〇 丫 ^ 八 ά VJ c,) 〇 &quot; cr 466 94 々Ό, Ν = (NHz XXCI 399 95, CH3 h3c or 428 96 JMa. [...] cr 400 84384 -92- 200402419 97 .c &gt; p ^ r'0 One: Iy 454 98 N—O 0 399 99 (&gt; ^ Λτ '〔.〕 Vx: 413 100 HiWr .._ [.] L. ': Xi 441 101 ch3 428 102 N—O 〇HN Into Ag Ag r ^ ° j 455 103 ch3 I cxy cr 428 104 hnXXAd HQ CH &gt; IX ^ 469 105 _ / CH3. '. 〔.〕, Nka: 412 106 N—O 0 407 -93- 84384 D.D㈣ 200402419

Synthesis method A was used to prepare Examples 19, 20, 21, 23, 24, 26, 28, 75, 76, 92, 94, 95, 97, 99, 1 (Π, 49, 52, 53, 54, 56, 57 , 58, 60, 62, 29, 47, 51, 55, 64, 66, 68, 70, 72, 73, 74, 27, 96, 33, 35, 86, 90, 103, 105, 107, 109, 11 Bu 4 Bu 39, 25, 84, and 88. Synthesis method A + F + I + J + L was used to prepare Example 31. Synthesis method A + J was used to prepare Example 98. Synthesis method B (another procedure 1) was used to Preparation examples 43 and 37. Synthesis method B (another procedure 2) was used to prepare example 45. Synthesis method D was used to prepare examples 61, 65, and 63. Synthesis method E was used to prepare examples 102, 104, 106, 108, 110. And 100. Synthesis method F is used to prepare Examples 22 and 77. Synthesis method G is used to prepare Example 50. 84384 -94- 200402419 Synthesis method is used to prepare Examples 67, 71, and 69. Synthesis method I is used to prepare Examples 32, 34, 36, 38, 40, 42, 44, 79, 80, 8 and 82, 83, 85, 87, 89, 91, 93, and 30. Synthesis method J is used to prepare examples 59 and 46. Synthesis method KK is used to Preparation Example 48. Synthesis method L was used to prepare Example 78. ** 实NMR data of Example 59 1Η NMR (D4-MeOH 400MHz) 8.14 (1Η, s) 7.53 (1Η, s) 7.48 (1Η, d) 7.27 (1Η, d) 3.86 (1H, m) 3.62 (2H , M) 3.53 (2H, s) 3.42 (2H, s) 3.24 (2H, m) 2.76 (1H, d) 2.68 (1H, d) 2 · 23 (1H, m) 1.96 (1H, t ) -95- 84384

D -D 200402419 Table 3 Η

Lr2

Describe the stereochemistry of position number R1 R2 (*) 9 B CH2C〇-3,4-di-CIPh S Table 4

Description example number Structure 10 〇HC &quot; OJoh 11 Et〇2〇 ^ / N ^ v = N 2 12 13 n〇H3 N H 14 X h3c Eight o ^ / VN 15 ch3 S

84384 -96- 200402419

84384 -97- 200402419 84384

-98- 200402419 84384

-99- 200402419 84384 45 46 H〇V ^ rr, palindrome, &quot; αι 47 0-Ν plex 48 h3c ch3 49 fVws H3C ^ N ~ 〇 called 50 Ν, (Λ ^ Υ〇, οη3 0 51: &gt; C ^ XAr, [...] Na &quot; a: 52 WM '. [...] palmity w 53 N-0 0 〆〇, palmity H 9 54 0' ^ Vn H IK ^ O, 0 y ch3 0 -100- 200402419 84384

-101-

Claims (1)

200402419 Patent application park: 1. A compound of formula (I): 〇 r2 (I) where: R1 represents a substituted or unsubstituted heteroaryl group; γ represents-(cm; Rna and Rnb are each independently hydrogen or alkyl; η is an integer from 1 to 5; R2 represents an unsubstituted or Substituted aryl or unsubstituted or substituted heteroaryl; R3 represents hydrogen or (6 alkyl); and salts and solvates thereof, provided that: R1 is not a phenyl group; R1 is not phenyl Substitutions, except for the following compounds: Ν-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -2- (5-methoxy-2-methyl-1fluorene- Razol-3-yl) acetamide; Ν-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -2-thien-3-ylacetamide; Ν -{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -2- (5-methyl small phenyl-1Η- 84384 200402419 pyrazol-4-yl) ethyl · Amidoamine; 2- (4-bromo-3,5-dimethyl-111-pyrazolyl) -sense {[4- (3,4-dichloroamidino) morpholin-2-yl] methyl } Acetamidine; meaning {[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -2- (2-pyracin-2-yl-1,3-thiazole-4 -Yl) acetamidinium; N-{[4- (3,4-dichlorobenzyl) morpholin_2_yl] methyl} -2- (2-furyl) acetamidinium; 2- (3-Ethylfluorenyl benzopyrimin-4-yl) -N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} acetamidine trifluoro Acetate; 2- (5-bromopyridin-3-yl) -N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} acetamide compound with formic acid (1 : 1); N- {[((2S) -4- (3,4 · dichlorobenzyl) morpholin-2-yl] methylb 2- (2-furanyl) acetamidamine; 2- (4 -Bromo-1H-imidazol-1-yl) -N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} acetamidine; N- {[4- (3,4-difluorobenzyl) morpholin-2-yl] methyl} -2- (2-pyridine · 2-yl_1,3_pyrazol-4-yl) Acetylamine; Ν-{[4- (4-fluorobenzyl) morpholin-2-yl] methyl} -2- (2-pyridin-2-yl-1,3-oxazol-4-yl ) Acetylamine; Ν-{[4- (2,3-dichlorobenzyl) morpholin-2-yl] methyl} -2- (2-pyracin-2-yl-1,3-pyrazole -4-yl) acetamidamine; Ν-({4-[(5-chloropyrimin-2-yl) methyl] morpholin-2-yl} methyl) -2- (2-beden-2 -Yl-1,3-pyrazol-4-yl) acetamidinium; N-{[4- (3-chlorofluorenyl) morpholin-2-yl] methyl} -2- (2-pyracyl- 2-yl-1,3-pyrazole- 84384 -2- 200402419 4-yl) acetamidamine; di-N-{[4- (3,4-dichlorobenzyl) morpholinyl 1methyl] methylbut 2 -(5 • methyl_2-pyracyl-1,3-thiazol-4-yl) acetamidamine; 2- [2- ({[4_ (3,4_dichlorobenzyl) morpholinoyl ] Methyl} amino) _2 · oxoethyl] -1H-1,2,3-benzotri. Z--5-chinoic acid formaldehyde; N- {[4- (3,4-dichlorobenzyl) morpholin_2yl] methylbu 2 _ (. Pyrrolo [2,3hepta] pyridyl) Acetamide N- {[4- (3,4-dichlorofluorenyl) morpholine_2_yl] methylbutan-2- (5_pyridoyl_2h_tetrazol-2-yl) acetamidinium; N- {[4- (3,4-Dichlorobenzyl) morpholin-2 · yl] methylbu 2 · (5-pyridyldongyl · 2H_tetra-2-enyl) amine; 1- [2_ ( {[4- (3,4-Dichlorobenzyl) morpholinyl] methyl} aminooxoethyl] -1H-1,2,3-benzotriazole-5-carboxylic acid methyl ester compound with 1- [2-({[4j3, 'dichlorobenzyl)? 4 wood_2_yl] methyl} amino) 4oxoethyl]] Η], 2,3_benzotriazole-6 -Methyl carboxylate (1: 1); Ν-{[(2S) -4- (3,4-dichloromethyl) morphin-2-yl] methyl} -2- (5-methyl-2-ρ , 3-pyrimazol-4-yl) acetamidinium; and N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methylbull 2- (2,3-dimethyl Quinazolin-6-yl) acetamide. 2. The compound of formula (I) according to item 1 of the scope of patent application, wherein R1 is an unsubstituted or substituted midoyl group, an unsubstituted or substituted trisyl group, an unsubstituted or substituted second group Oxazolyl, unsubstituted or substituted saphenyl, unsubstituted or substituted phenenyl, unsubstituted or substituted isozadiazole, unsubstituted or substituted isoxazolyl , Unsubstituted or 84384 200402419 substituted pyridyl, unsubstituted or substituted sulfanyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted tetramethyl and unsubstituted Or substituted Eye. 3. The compound of formula (I) as in item 1 or 2 of the scope of the patent application, wherein R1 is 3_ (third butoxycarbonylamino) erazol-5-yl, 3- (amino) exocyclic group, 3 -(Acetamido) pyrazol-5-yl, 3- (propylamido) pyrazole groups, 3- (isopropylcarbonylamino) erazol-5-yl, furan-2-yl, 4- (ethoxycarbonyl) -5-methylimidazol-1-yl, 5- (bromo) imidazolyl, 5-methyl-1,3,4-triazol-2-yl, 3-methyl ], 2,4-triazol-5-yl, 3-ethoxycarbonyl · 1,2,4-oxadiazol-5-yl, 4- (carboxy) sulfan-2-yl, 2,4-di Methylthiazol-5-yl, 3- (third butyl) isozazol-5-yl, pyrimiphen-2-yl, 3-methoxyisoxazol-5-yl, 4-methyloxazole -5-yl, 3,5-dimethylisoxazolidyl, isoxazol-3-yl, 3-methylisoxazol-4-yl, isoxazol-5-yl, 3- Methylisoxazol-5-yl, 2-methylthiazolidine, hydrazone (third butoxycarbonylhydrazinocarbonyl) furan-2-yl, 5- (hydrazinocarbonyl) furan-2-yl, 5- ( 3-methyl-1,2,4-fluorenediazol-5-yl) furan-2-yl, 5- (2-methyl-1,2,4-triazol-5-yl) furan-2-yl Amino, 3-amino-2-methyl-1,2,4-triazol-5-yl, 3-amino-1,2 , 4-triazol-5-yl, 3-amino-1,2,4-pyridazol-5-yl, 4- (third butoxybenzyl) p ratio, small group, 20% ratio 2-yl) ρ-sec-tetra-4-yl, 2- (methylaminocarbonyl) furan-5-yl, 2- (ethoxycarbonyl) furan-5-yl, 2- (ethylaminocarbonyl) furan_ 5 -Yl, 2- (isopropylaminocarbonyl) furanyl, 2-cyclopropylaminocarbonyl) furan-5-yl, 2- (cyclopropylmethylaminocarbonyl) furanyl, 2_ (5_methyl_ 1 , 3,4-fluorenediazole_2_yl) anan_2_yl, 3- (methylaminocarbonylsulfonyl-5-yl, 3- (ethylaminocarbonyl) -fluorene, 2, φ ^ No. 2π seat group, 3- (isopropylaminofluorenyl) · 1,2,4-indino-5-yl, 2-chlorop-phenphen-4-yl, 3-aminoiso, _5 _Base, -4- .. 84384 200402419 3-Ethylisoxazol-5-yl, 3-propylamidoisoxazol-5-yl, 3- (isopropylcarbonylamino) isoxazol-5-yl, 4 -(Ethoxycarbonyl) furan-2-yl, 5- (methoxycarbonyl) furandol, 4- (isopropylaminocarbonyl) furan-2-yl, 4- (ethylaminocarbonyl) furan-2- 4- (methylaminocarbonyl) furan-2-yl, 5- (ethylaminocarboxy) furan-2-yl, 5- (methylaminocarbonyl) furan-2-yl, 5- (isopropylamino) Carbonyl) furan_2-yl, 4- (ethoxycarbonyl) furan-2-yl, pyridyl, succin-2-yl, 2- (5-methyliso-p-jun-3-yl) Ethyl-4-yl, 2- (1-f-methylimid-5-yl) pyrazol-4-yl, 2- (4-methyl-1,2,3-pyrimidazol-5-yl) pyrimidin Azol-4-yl, 5-methyl-2- (5 • methylisoxazol_3_yl) thiazol-4-yl, 5-methyl-2_ (1-methylimid-5-yl) Pyrimazol-4-yl, 2- (4-methyl-1,2,3 · pyrimidazol-5-yl) -5-methyllacido-4-yl, 2_ (1-methylimidazolyl) Thiazol-4-yl, 4-methyl-2- (5-methyloxane, 0 ton each radical) Group) Telemet-5-yl, 3-othiophen-2-yl) -4- (methyl) pyrazol-1-yl, 5- (Isopropyl) tetrazol-1-yl, 5-methyl-3- (trifluoromethyl) pyrazol-1-yl, 3- (thiazol-2-yl) Small group) tetrazol-2-yl, 5- (piperidin-1-yl) tetrazol-1-yl, 1- (methyl) tetrazol-5-yl, tetrazol-5-yl, 5- (formyl) Radicals) isoxazolyl radicals, 5- (isopropyl) tetrazol-2-yl radicals, 2-aminomethyl) tetrazol-5-yl radicals, 3- (methyl) isoxazol-5-yl radicals, 3- ( Formamyl) pyrazole 4 • yl, 3′methyl) pyrazole + yl, 3,5-dimethylexyl I: thio-1-yl or 4- (ethoxycarbonyl) pyrazole small group. 4. If the compound of formula (!) In item 1 or 2 of the declared patent scope, its center and u sentence are hydrogen. 5. The compound of formula (I) according to item 1 or 2 of the scope of patent application, wherein 丨 or 2. 6. The compound of formula ① according to item 1 or 2 of the scope of patent application, wherein RS is hydrogen. 7. The compound of formula (I) according to item 1 or 2 of the scope of patent application, wherein R2 is a phenyl substituted with chlorine ^ f. DO.) / 84384 200402419 or a fluorine-substituted P phenenyl substituted with chlorine. 8. The compound of formula (I) according to item 丨 or 2 of the scope of the patent application, wherein R2 is 3-fluorophenyl, 3- (trifluoromethyl) phenyl, 2-chloropyrim-4-yl, 3- Chlorophenyl, 3,4-dichlorophenyl. 9. The compound of formula (I) according to item 丨 of the scope of patent application is a compound selected from the examples. 10. The compound of formula (I) as claimed in item 9 of the scope of patent application, is selected from Examples 1, 2, 3, 8, 12, 14, 16, 18, 19, 20, 21, 23, 25, 27, 28, 30, 3, 32, 34, 36, 40, 42, 45, 46, 48, 49, 50, 52, 53, 54, 55, 56, 58, 60 '63, 64, 65, 67, 69, 70, 7 Bu 72, 73, 74, 75, 76, 77, 78, 80, 8 Bu 82, 83, 87, 88, 89, 90, 9 Bu 93, 95, 97, 99, 100, 102 104, 106, 108, 109, 110 and m. 11. The compound of formula (I) as claimed in item 9 of the scope of patent application, is selected from Examples 1, 2, 3, 19, 23, 27, 32, 34, 36, 42, 45, 48, 50, 52, 54, 58, 63, 64, 65, 67, 7 and 75, 76, 78, 80, 89, 9 and 93, 97, 102, 104 and 106. 12. The compound of formula (I) according to item 9 of the scope of patent application, which is selected from Examples 1, 23, 32, 34, 36, 50, 71, 78 and 97. 13. A method for preparing a compound of formula (1) as described in claim 1 in the scope of patent application, which method comprises combining a compound of formula (II) with a compound of formula (m); 84384 -6 200402419 Among them: R1, Y, R3 and R2 are as defined in the formula ① of the scope of the patent application, and react in the presence of an activator and a peptide coupling agent, and then, if necessary, perform one of the following steps or Multiple steps: (I) converting a compound of formula (I) into another compound of formula ①; (II) removing any necessary protecting groups; (III) preparing a salt or solvate of the compound formed. 14. A method for preparing a compound of formula (I) as in item 1 of the scope of the patent application, wherein γ is -CIV and R1 is an unsubstituted or substituted heteroaryl group, that is, a compound of formula (χι) Method ... The salt method includes reacting a compound of formula (XΠ) with a compound of formula (XIII): Where (XII) is an unsubstituted or substituted heteroaryl group, L2 is a leaving group, and R and R2 are as defined in Formula (I) of the first item of the scope of the patent application, and then, if necessary, perform the following steps One or more steps: 84384 200402419 (i) converting the amidine of formula (I) to another compound of formula ①; (ii) removing any necessary protecting groups; (iii) preparing a salt or solvate of the compound formed. 15 · The compound of formula (1), or a physiologically acceptable salt or solvate thereof according to item 1 of the scope of patent application, is used as an active therapeutic agent. 16. The compound of formula (1), or a physiologically acceptable salt or solvate thereof according to item 1 of the scope of patent application, is for use in treating an inflammatory condition such as asthma or rhinitis. 17. The use of a compound of formula (1) or a physiologically acceptable salt or solvate thereof according to item 1 of the scope of patent application for the manufacture of a medicine for treating an inflammatory condition such as asthma or rhinitis. 18.-A pharmaceutical composition for treating a human or mammalian subject suffering from or susceptible to an inflammatory condition such as asthma or rhinitis, the composition comprising an effective amount of a compound of formula (I) as claimed in item 1 of the scope of patent application or its physiology Acceptable salts or solvates. 19. A pharmaceutical composition comprising a compound or a physiologically acceptable salt or solvate thereof according to formula (i) of the scope of application for a patent, and optionally one or more physiologically acceptable diluents or carriers. 20. — Compounds of formula (IIIBR), • Α / ν ^ 0Η &lt; 0Η V R (IIIBR) where A is a protected amine group and R2 is as defined in formula ① in the scope of the patent application. 84384 200402419 21.-a compound of formula (IIIIIBE), A / OH OH (III ΒΕ) where A is a protected amine group and R2 is as defined in the formula (I) in the first item of the patent application scope. 22. a compound of formula (XIII), Where L2 is a leaving group and R3 and R4 are as defined in the formula (I) in the first item of the patent application scope. 84384 9- 200402419 Chai, designated representative map: (1) The designated representative map in this case is the () map. (2) A brief description of the component symbols in this representative map: 捌 If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention: 84384