TW200404000A - Novel compounds - Google Patents

Abstract

Certain compounds of formula (I): wherein: R1 represents substituted or unsubstituted aryl; X represents -O- or a bond; 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; R10 represents hydrogen or C1-6alkyl; and salts and solvates thereof are CCR3 antagonists and are therefore indicated to be useful in therapy.

Description

200404000 玖 玖, description of the invention (the description of the invention shall state: the technical field to which the invention belongs, the prior art, the content, the embodiment and the simple description of the drawings) TECHNICAL FIELD The present invention relates to a novel compound, a preparation method thereof, and a pharmaceutical formulation containing the same Substances and their use in therapy. Prior art 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 rotation of the tissues by the expression of adhesion molecules, cytokines and chemokines. 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 white blood cells to be locally replenished from the circulatory system to the affected tissue. Leukocyte supplementation is controlled to sequentially destroy foreign matter or dead cells and phage, then repair the tissue and break down the inflammatory infiltrates. However, in chronic inflammatory states, supplementation is often inadequate, breakdown is not properly controlled, and inflammatory responses cause tissue destruction. There is increasing evidence that bronchial inflammation with asthma characteristics represents a specialized form of cell-regulated immunity, in which cell products such as IL-4 and IL-5 released by T-helper cell 2 (Th2) lymphocytes can direct granules. The accumulation and activation of cells, especially eosinophils and to a lesser extent basophils. By releasing cytotoxic proteins, inflammatory regulators and oxygen free radicals, eosinophils cause mucosal damage and initiate bronchial formation. 84385 -10- 200404000

(2) Mechanism of excessive activity. Therefore, blocking supplementation and activation of T h 2 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 the communication and supplementation of white blood cells (see, for example, Luste r, New England Journal of Medicine '3 3 8, 4 3 6-4 4 5 (1 9 9 8)). It attracts and activates various cell types by releasing and acting on a wide variety of cells, including eosinophils, basophils, neutrophils, macrophages, T and B lymphocytes. There are two main types of chemical activins: CXC- (α) and CC- (dot) 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 specific cell surface receptors and belongs to the G-protein-coupling family of seven transmembrane domain proteins (see Luster, 1999). In these reactions, activation of the chemoactivin receptor results in increased intracellular calcium, 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 (CC R- 3) of the present invention, which is predominantly manifested on eosinophils and also in Basophils, mast cells and Th2 cells. CCR-3-containing chemical activins such as RANTES, MCP-3, and MCP-4 are known to replenish and activate eosinophils. Of particular interest are eotaxiη and eotaxin-2 ', which specifically bind to C C R-3. The localization and function of C C R-3 chemoactivin show that it plays a central role in the development of allergic diseases such as asthma. So ’CCR-3 specific 84385 -11-200404000

(3) The chemical activin carrying CC R-3 on all major cell types involved in inflammatory allergic reactions is produced in response to inflammatory stimuli and acts to replenish these cell types to the inflammatory site, which causes its activation (such as Griffiths et al. 'J. Exp. Med., 1 79, 8 8 1-8 87 (1 994) ^ Lloyd et al., J. Exp. Med., 191, 265-273 (2000)). In addition, the anti-CCR-3 monoclonal antibody completely inhibited the interaction between eosin and eosinophils (Heath, Η et al., J. Clin. Invest. 99 (2), 1 7 8- 1 84 (1 997)), and the antibody to CC R-3 specific activin, 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 useful in the treatment of various inflammatory conditions. In addition to its main role in inflammatory disorders, chemoactivins and their receptors also play important roles in infectious diseases. Mammalian cytomegalovirus, herpes virus, and poxviruses can express chemoactivin receptor homologs that can be activated by human C C chemoactivins such as RANTE S and MC P-3 receptors (see, for example,

Wells and Schwartz, Curr. Opin. Biotech., 8, 74 1-748, 1 997). In addition, 'human chemoactivin 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, chemoactivin receptor antagonists (including CCR-3 antagonists) can be used to block the infection of HCR to CCR-3 expressing cells or prevent immune cell responses due to manipulation of viruses such as cytomegalovirus. International Patent Application Publication No. wo 0 1/24786 (Shionogi & Co. Ltd.) discloses certain aryl and heteroaryl derivatives for the treatment of diabetes. w〇 -12- 84385 200404000

(4) 00/69830 (Torrey Pines Molecular Research Association) reveals a diazacyclic compound and its database for biological screening. WOOO / 18767 (N e r u g e η) discloses a certain type of peak-well derivative as a dopamine D 4 receptor antagonist. U.S. Patent 6,031,097 and WO 99/21848 (Neurogen Corporation) are both amine isoquinoline derivatives as dopamine receptor ligands. WO 99/063 84 (Recordati Chemical Company) discloses piperin derivatives useful for treating lower urethral neuromuscular insufficiency. WO 9 8/5 677 1 (Schering Aktiengesellschaft) discloses certain oral derivatives as anti-inflammatory agents. WO 97/4760 1 (Yoshitomi Pharmaceutical Co., Ltd.) discloses a fused heterocyclic compound as a dopamine D-receptor blocker. W Ο 9 6/3 9 3 8 6 (Scheherin Company) revealed a certain sigma sigma derivative as a neuron #antigen. W〇 96/02534 (Byk Gulden Lomberg Chemische Fabrik GmbH) reveals a certain p-well sulfur p ratio that can be used to control Helicobacter. WO 95/32196 (Merck Sharp & Dohme Limited) discloses certain bite, peak, and tetrahydropyridine derivatives as 5-Η T 1 D-a antagonists. U.S. Patent 5,389,635 (E.I. Du Pont de Nemours) discloses a substituted taste sigma as an angiotensin-II antagonist. European Patent Application Publication No. 0 306 440 (Schering Aktiengesellschaft) discloses a certain imidazole derivative as a cardiac tube 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 eosinophils, basophils 84385 -13 -200404000

(5) Protective effect of malignant leukocyte mast cells and T h 2 -cell-induced tissue damage. SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide a compound of formula (I):

R

(I) wherein: R1 represents a substituted or unsubstituted aryl group; X represents -0 or a chemical bond; Y represents-(CRnaRnb) n-,

Rna and Rnb are each independently hydrogen or Ci_6 alkyl; η is an integer from 1 to 5; R2 represents unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl; R3 represents hydrogen or Cu alkyl R1 () represents hydrogen or Cu alkyl; and its salts and solvates; except for the following compounds: 2- (4-Gaphenyl) -N-{[4- (3,4-dichlorofluorenyl) N-{[4- (3,4-dichlorofluorenyl) morpholin-2-yl] fluorenyl} -2-phenylacetamidine; N- {[4- (3,4-Diaminobenzyl) morpholin-2-yl] methyl} -2-phenoxyacetamidamine; 84385 -14- 200404000

N-{[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methylbutan-2- (4-methoxyphenyl) acetamidine; 2- (3-chlorophenyl) -N-{[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} acetamidine; N-{[4- (3,4-dichlorofluorenyl) morpholine- 2-yl] methyl} -2- [4- (methylthio) phenyl] ethanamine; N-{[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl Bu 2- [4- (dimethylamino) phenyl] acetamidine compound containing formic acid (1: 1); N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl ] Methyl} -2- {4-[(dimethylamino) sulfofluorenyl] phenyl} acetamidine compound containing fluorenic acid (1: 1); N-{[4- (3,4-di Chlorofluorenyl) morpholin-2-yl] methylbutan-2- [4- (methylsulfonyl) phenyl] acetamidine compound containing formic acid (1: 1); N-{[4- (3 , 4-dichlorofluorenyl) morpholin-2-yl] methyl} -2- (3-fluorophenyl) acetamidamine; 2- [3, 5-bis (trifluoromethyl) phenyl]- N-{[4_ (3,4-dichlorofluorenyl) morpholine-2-yl] methyl} ethanamine; 2- (2-chlorophenyl) -1 ^ {[4- (3,4- Dichlorofluorenyl) morpholin-2-yl] methyl} ethanamide; N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -2- (4 -Fluoro-2-methylphenyl) acetamidamine; N-{[4- (3,4-dichlorofluorenyl) morpholin-2-yl] } -2- (3,4-difluorophenyl) acetamidine; 4- [2-({[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} amine ) -2-oxoethyl] benzidine amine; 84385 -15-200404000 ⑺ Inventions are described on the next page ::: Fiberglass 遽 continued to refer to the media: end;丨: N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methylbu [2- (4- (trifluorofluorenyl) phenyl] ethyl] amine; N- { [4- (3,4-dichlorofluorenyl) morpholin-2-yl] methylbu 2- (4-methylbenzyl) acetamidamine; N-{[4- (3,4-dichloro Fluorenyl) morpholin-2-yl] fluorenyl} -2- (2,4-dichlorophenyl) ethanamine; N- {[4- (3,4-dichlorofluorenyl) morpholine-2 -Yl] methyl} -2- (4-fluorophenyl) acetamidamine; N-{[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} -2- ( 3,4-dichlorophenyl) acetamidine; N-{[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} -2- (2,5-dichlorobenzene Group) acetofluoramine; > ^-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -2- (2,6-dichlorophenyl) acetochlor ; 2- (4-chlorophenyl) -N- {[4- (2,3-dichlorofluorenyl) morpholin-2-yl] methyl} acetamidine trifluoroacetate; 2- [3- (Ethylamino) phenyl] -N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] } Ethylammonium amine; 2- (4-ethylammonylphenyl) -N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} acetamidine trifluoroacetic acid Salt; 2- (4-ethylammonylphenyl) -N- {[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} acetamidine; N-{[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} -2- (4-isobutylfluorenylphenyl) acetamidinium trifluoroacetate; 84385 -16- 200404000

⑻ 4- [2- ({[4- (3,4-dichlorofluorenyl) morpholin-2-yl] fluorenyl} amino) -2 -oxoethyl] benzoate trifluoroacetate ; 4- [2-({[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} amino) -2-oxoethyl] benzoic acid methyl ester; 2- ( 4-cyanophenyl) -N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} acetamidotrifluoroacetate; 2- (4-cyanobenzene )-≫ 1-{[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} acetamidine; 2- (4-chlorophenyl) -N- {[4 -(3,4-dichlorofluorenyl) morpholin-2-yl] methyl} propanamide; N-{[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl } -2- (3-fluoro-4-hydroxyphenyl) acetamidinium trifluoroacetate; N-{[(2R) -4- (3,4-dichlorobenzyl) morpholin-2-yl] Methyl} _2- [4- (methylsulfonyl) benzyl] acetamidine; & {[(2 3) -4- (3,4-dichlorobenzyl) morpholin-2-yl] Methyl} -2- [4- (methylsulfonyl) phenyl] ethanamine; N-{[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl}- 2- {4-[(4- -Pyridin-1 -yl) carbonyl] phenyl} ethanamine; 4- [2-({[4- (3,4-dichlorofluorenyl) morpholine- 2-yl] methyl} amino) -2-oxoethyl] -N- [2- (dimethylamino) ethyl] fluorenamine 4- [2-({[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} amino) -2-oxoethyl] -N, N-dimethylfluorene Fluorenamine; 4- [2-({[4- (3,4-difluorofluorenyl) morpholin-2-yl] methyl} amino) -2-oxoethyl] -N -ethylfluorene Stuffed amines; 84385 -17- 200404000

(9) 4- [2- ({[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} amino) -2-oxoethyl] -N- (2- Hydroxyethyl) benzamidine; N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -2 · [4- (morpholin-4-ylcarbonyl) benzene Yl] ethenylamine; N-{[((2S) -4- (3,4-diaminofluorenyl) morpholin-2-yl] methyl} -2- {3-[(dimethylamino) sulfonyl Ethyl] phenyl} ethylamine; N-{[((2R) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -2- {4-[(dimethylformate Amine) sulfofluorenyl] phenyl} acetamidine; N-{[(2S) -4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} -2- {4- [(Difluorenylamino) sulfofluorenyl] phenyl} ethylSSamine; 4- [2-({[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} amino ) -2-oxoethyl] -N-methylfluorenamine; 4- [2- ({[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} amino ) -2-oxoethyl] -N-isopropylsulfonylamine, N-cyclopropyl-4- [2-({[4- (3,4-dichlorobenzyl) morpholine-2- [Methyl] amino} -2 -oxoethyl] fluorenamine; 4- [2-({[4- (3,4-dichlorofluorenyl) morpholin-2-yl] fluorenyl} Amine) -2 -oxoethyl] -N- (2-methoxyethyl) fluorenamine; N-{[4- (3,4-Difluorofluorenyl) morpholin-2-yl] Methyl) -2- (4-nitro Phenyl) acetamide; N-{[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} -2- (3-nitrophenyl) acetamide; methyl · 3- [2-({[4- (3,4-Digas benzyl) morpholin-2-yl] methyl} amino) -2-oxoethyl] benzoic acid methyl ester; 84385 -18 -200404000 (ίο) Falun Yueming Ming Continued 2- [3- (Ethylamido) phenyl] -N-{[4- (3-fluorofluorenyl) morpholin-2-yl] methyl } Acetamidine; N-{[4- (3-fluorobenzyl) morpholin-2-yl] methyl} -2- {4-[(methylsulfonyl) amino] phenyl} acetamidine Amine; 2- [3- (ethylamidoamino) phenyl] -N-{[4- (3,4-difluorobenzyl) morpholin-2-yl] methyl} acetamidoamine; N- {[4- (3,4-difluorofluorenyl) morpholin-2-yl] methyl} -2- {4-[(methylsulfonyl) amino] phenyl} ethanamide; 2- [4- (Acetylamino) phenyl] -N-{[4- (3,4-Difluorofluorenyl)? 17-Lin-2-yl] methyl} acetamidine; N-{[4- (3,4-difluorobenzyl) morpholin-2-yl] fluorenyl} -2- {3-[(methylsulfonyl) amino] phenyl} ethanamide; N-{[4- (3,4-difluorofluorenyl) morpholin-2-yl] methyl} -2- [3- (methylsulfonyl) phenyl] ethanamine; N-{[4- (3-chloro Fluorenyl) morpholin-2-yl] methyl} -2- [4- (methylsulfonyl) phenyl] acetamidine ; N-{[4- (3-chloroamidino) morpholin-2-yl] methyl} -2- [3- (methylsulfonyl) phenyl] ethanamine; 2-[3- ( Ethylamido) phenyl] -N-{[4- (4-fluorofluorenyl) morpholin-2-yl] methyl} ethamidamine; > 1-{[4- (4-fluorofluorene ) Morpholine-2-yl] methyl} -2- {4-[(methylsulfonyl) amino] phenyl} ethanamide; 2- [4- (ethylamino) phenyl ] -N- {[4- (4-Fluorofluorenyl) morpholin-2-yl] methyl} acetamidine; 84385 -19- 200404000 00 Invention material continuation page 丨 N-{[4- (2,3 -Dichlorofluorenyl) morpholin-2-yl] methyl} -2- [4- (methylsulfonamido) phenyl] acetamidine; 2- [3- (ethylfluorenylamino) phenyl ] -N-{[4- (2,3-Diaminofluorenyl) morpholin-2-yl] methyl} acetamidine; N- {[4- (2,3-dichlorofluorenyl) morpholine -2-yl] fluorenyl} -2- {4-[(methylsulfonyl) amino] phenyl} amine; N-{[4- (2,3-dichlorofluorenyl) morpholine- 2-yl] methyl} -2- (4-{[(methylamino) carbonyl] amino} phenyl) acetamidamine; N-({4-[(5-chloropyrimidin-2-yl) Methyl] morpholin-2-yl} methyl) -2- [4- (methylsulfonyl) phenyl] ethylamine; 2- [3- (ethylamidinyl) phenyl] -N -({4-[(5-Chlorophen-2-yl) methyl]? Β-Lin-2-yl} methyl) Ethylamine, N-({4-[(5-chlorothien-2-yl) methyl] morpholin-2-yl} methyl) -2- {4-[(fluorenylsulfonyl SS) amino group ] Phenyl} acetamidine; > ^-({4-[(5-chloropyrimin-2-yl) methyl] morpholin-2-yl} fluorenyl) -2- {3-[(methyl Sulfofluorenyl) amino] phenyl] ethenylamine; 2- [3- (ethenylamino) phenyl] -N- {[4- (3-chlorofluorenyl) morpholin-2-yl ] Methyl} acetamidine; N-{[4- (3-chlorobenzyl) morpholin-2-yl] methyl} -2- {4-[(methylsulfonamido) amino] phenyl } Acetamidine; 2- [4- (ethamylamino) phenyl] _N-{[4- (3-airbenzyl) morpholin-2-yl] methyl} acetamidine; N- { [4- (3-Gabenzyl) morpholin-2-yl] methyl} -2- (4-{[((methylamino) carbonyl] amino} benzyl) acetamidamine; 84385 -20- 200404000

(12) 2- [4- (Ethylamino) phenyl] -N-{[4- (2,3-dichloroamidino) morpholin-2-yl] methyl} ethanamine; N -{[4- (2,3-dichlorofluorenyl) morpholin-2-yl] methyl} -2- [3- (methylsulfonyl) phenyl] ethanamine; 2- [4- (Aminosulfofluorenyl) phenyl] -N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} acetamidine; 2- [2- (ethylamyl) Amine) phenyl] -N-{[4- (3,4-difluorofluorenyl) morpholin-2-yl] methyl} ethanamide; 2- (3-cyanophenyl) -N- {[4- (3,4-Diaminobenzyl) morpholin-2-yl] methyl} acetamidine; N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl ] Methyl} -2- (2-fluorophenyl) acetamidine; N-{[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} -2- (2, 3-difluorophenyl) acetamidine; N-{[4- (3,4-dichloromethyl) morpholin-2-yl] methyl} -2- (2,4 · difluorophenyl) Acetylamine; N-{[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} -2- (2,5-difluorophenyl) acetamidamine; N- { [4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} -2- (2,6-difluorophenyl) acetamidine; N · cyclopropyl-3- [2 -({[4- (3,4-dichlorofluorenyl) morpholin-2-yl] fluorenyl} amino) -2-oxoethyl] fluorenamine; 3- [2-({[4 -(3,4 · two breaths ) Morpholine-2-yl] methyl} amino) -2-oxoethyl] -N- (2-methoxyethyl) fluorenamine; 84385 -21-200404000

(13) 3- [2-({[4- (3,4-Diaminofluorenyl) morpholin-2-yl] fluorenyl} amino) -2-oxoethyl] -N-ethylfluorene Fluorenamine; 3 42-(^ 4- (3,4-difluorofluorenyl) morpholin-2-yl] methyl} amino) -2-oxoethyl] -N, N-dimethylfluorene Fluorenamine; 3- [2-({[4- (3,4-difluorofluorenyl) morpholin-2-yl] methyl} amino) -2-oxoethyl] -N- [2- (Dimethylamino) ethyl] fluorenamine; N-{[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} -2- {3-[(4-methyl Piper-l-yl) jiki] phenyl} ethenylamine; 2- (3-aminophenyl) -N-{[4- (3,4-dichlorofluorenyl) morphin-2- [Methyl] methyl} ethenylamine; 2- (4-aminophenyl) -N _ {[4- (3,4-difluorofluorenyl) morphin-2-yl] fluorenyl} ethenylamine; 2 -[4- (ethylamidoamino) phenyl] -N- {[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} ethylamidoamine; N- {4- [2-({[4- (3,4-dichlorobenzyl) morpholine-2 · yl] methyl} amino) -2-oxoethyl] phenyl}-2-methylpropanamide ; N- {3- [2-({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) -2-oxoethyl] phenyl} -2 -Methylpropanamide; N-{[4- (3,4-dichlorofluorenyl) morpholin-2-yl] fluorenyl [(methylsulfonamido) amino] phenyl} ethanil N-{[4- (3,4-Diaminobenzyl) morpholin-2-yl] methylbutan-2- {4-[(methylsulfonyl) amino] phenyl} acetamidamine; N -{3- [2-({[4- (3,4-Diaminobenzyl) morpholin-2-yl] methyl} amino) -2-oxoethyl] phenyl} -2- ( Diamido) Ethylamine; 84385 -22- 200404000

(14) 4- [bis (methylsulfodonyl) amino] phenylbenzene N-{[4- (3,4-difluorofluorenyl) morpholin-2-yl] methyl} acetamidinium; N-{[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} -2- [3- (methylsulfonyl) phenyl] ethanamine; N-{[ 4- (3,4-dichlorofluorenyl) morpholin-2-yl] fluorenyl} -2- [4- (methylsulfonyl) -2-nitrophenyl] ethanamine; N- { [4- (3,4-dichlorofluorenyl) morpholin-2-yl] fluorenyl} -2- (2-hydroxyphenyl) acetamidine; Ν-{[4- (3,4 · dichloro Fluorenyl) morpholin-2-yl] methyl} -2- {4- [methyl (methylsulfonyl) amino] phenyl} acetamidamine; Ν-{[4- (3,4- Dichlorobenzyl) morpholin-2-yl] methyl} -2- {3 · [methyl (methylsulfonyl) amino] phenyl} acetamidamine; 2- [2-amino-4 -(Methylsulfonyl) phenyl] -1 ^-{[4- (3,4-dichlorofluorenyl) morpholine-2 -yl] methyl} ethanamine; N-({(2S) -4-[(5-chloropyrimidin-2-yl) methyl] morpholin-2-yl} methyl ')-2- {3-[(methylsulfonyl) amino] phenyl} ethyl Fluorenamine; N-({(2R) -4-[(5-chloropyrimin-2-yl) fluorenyl] morpholin-2-yl} fluorenyl) -2- {3-[(fluorenylsulfonium (Amino) amino] phenyl] ethanamide; N-{[((2S) -4- (3,4-dichlorofluorenyl) morpholin-2-yl] methylphenyl 2- {4- [(Fluorenylamino) sulfofluorenyl] phenyl} ethanamine; N-{[(2S) -4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} -2 -{4-[(ethylamino) sulfofluorenyl] phenyl} ethanamine; 2- [3- (aminosulfofluorenyl) phenyl]-> ^-{[(23) -4- (3,4-Diaminofluorenyl) morpholine-2-yl] fluorenyl} ethenylamine; 84385 -23- 200404000 Sulfonyl] phenyl} -cardio {[(28) -4- (3,4-dichlorobenzyl) morpholine-2-yl] methyl} acetamidine; N-{[(2S) -4 -(3,4-dichlorofluorenyl) morpholin-2-yl] methyl} -2- {3-[(ethylamino) sulfofluorenyl] phenyl} ethanamine; N-{[( 2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] fluorenyl} -2- {3-[(methylamino) sulfofluorenyl] phenyl} ethanamide; N -{[(2S) -4- (4-fluorofluorenyl) morpholin-2-yl] methyl} -2- {4-[(methylsulfonyl) amino] phenyl} acetamidinium; N-{[(2R) -4- (4-fluoroamidino) morpholin-2-yl] methyl} -2- {4-[(methylsulfonyl) amino] phenyl} ethylamidine ; 2- [4- (Aminosulfofluorenyl) phenyl] -N-{[4- (3,4-dichlorofluorenyl) morpholine · 2-yl] methyl} acetamidine; 2- { 4-[(Cyclopropylamino) sulfofluorenyl] phenyl} -N-{[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl } Ethylamine; > ^-cyclopropyl-3_ [2-({[((2 8) -4- (2,3-dichlorofluorenyl) morpholin-2-yl] methyl]} amine ) -2-oxoethyl] fluorenamine; 3- {2-[({(28) -4-[(5-chloropyrimin-2-yl) methyl] morpholin-2-yl} (Methyl) amino] -2-oxoethylbenzene N-cyclopropylamidoamine; N-cyclopropyl-3- [2-({[(2S) -4- (4-fluorofluorenyl) Morpholin-2-yl] methyl} amino) -2-oxoethyl] fluorenamine; 3- [2-({[((2S) -4- (3-airino) morpholine-2 -Yl] methyl} amino) -2-oxoethyl] -N-cyclopropylbenzylamine; N-cyclopropyl-3- [2-({[((2S) -4- (3, 4-difluorofluorenyl) morpholin-2-yl] methyl} amino) -2-oxoethyl] fluorenamine; and 84385 -24- 200404000

(16) N-Cyclopropyl- 3- [2-({[((2S) -4- (3,4-difluorofluorenyl) morpholin-2-yl] methyl} amino) -2-oxo Ethyl] amidine. [Embodiment] Examples of aryl R 1 include phenyl. When R1 is a substituted aryl group, suitable substituents include an alkylsulfonyl group; a Cu alkylthio group; an unsubstituted or substituted heteroaryl group; a C3.8 cycloalkyl sulfanylamino group; C 1 _ 6-Alkylamino-Weiylamino; C 1 -6-amino-Arylaminyl, AlkylsulfonylaminoCualkyl; Amine; c3_8 cycloalkylaminocarbonyl; Ci_6-Alkylweilyl; ^ 3.8 Cycloalkynyl; Ci_6alkynylaminoamino; Ci.6alkylcarbonylamino; c3_8cycloalkylcarbonylamino; r4r5nc (o)-, where R4 and R5 can independently represent hydrogen or Cu alkyl , Or R4 and R5 may represent-(CH2) P- groups in which p is an integer of 3 to 7, so that together with the nitrogen atom to which it is bonded, a 4- to 8-membered heterocyclic ring is formed; Ci.6 alkoxycarbonyl ; Cyano group; amine group; amine group; halo group; halo group; Ci_6 alkynyl group, ^ yl group, stone group, Ci. 6 alkoxy group, early- and di- (Ci-6 group) Amine. When R1 is an aryl group substituted with an unsubstituted or substituted heteroaryl group, examples of the heteroaryl group include pyrazolyl, humidizolyl, and triazolyl. Suitable substituents for this heteroaryl group include Ci-6 alkyl. Preferably, R1 is unsubstituted or substituted phenyl. When R1 is a substituted phenyl group, the substituent includes a Cu alkylsulfonyl group; a Ch alkylthio group; an unsubstituted pyrazolyl group; an unsubstituted and substituted amidazolyl group; a substituted triazolyl group; a C3_8 ring Alkylsulfonylamino group; Alkylaminocarbonylamino group; C 1-6 alkylamino group; C 1.6 alkylamino group C1-6 alkyl group; cyano group; amine group; c3_8 cycloalkylaminocarbonyl; c3_8 cycloalkylcarbonyl; 84385 -25- 200404000 (17)

Cm alkylcarbonyl; Cu alkylsulfonamido; Cu; R4R5NC (0)-, where R4 and R5 can independently represent hydrogen or R4 and R5 can represent-(CH2) P- group where p is 3 to 7 The nitrogen atoms bonded to j together form a 4 to 8-membered heterocyclic ring carbon ring; an amino continuation group; an aminoweil group; a halogen group; or more preferably, R1 is unsubstituted Phenyl or ^ (methanesulfonyl), 4- (methylcarbonylamino), 2,4,6- (triyl), 2,5- (difluoro), 4- (pyrazole- 1-yl), 3- (methanesulfomethyl-1,3,4-. No. disialyl-5-yl), 3- (l, 3,4-Hydroxybis-α-methyl-l, 3 , 4-ditr-5-yl), 4- (ethyl >> carbonamino), carbonyl), 4- (carboxy), 3- (isopropylsulfonylamino), 3-ylamino ), 3- (ethanesulfonylamino), 4- (fluorenylamino 4 -methanesulfonyl-2 -methanesulfonylamino, 4- (ethanesulfonyl 3- (N, N-di Methylaminosulfonyl), 4- (methanesulfonylamine (methanesulfonylamino), 3- (cyclopropylcarbonyl), 3- (methyl (methoxycarbonyl), 3- (amino Sulfonyl), 4- (methanesulfonyl 3- (methylaminocarbonyl), 3- (dimethylaminocarbonyl), 3- (iso, 3- (iso Methylmethylaminocarbonyl), 4- (fluoro), 3- (amino) amino), 3- (cyclopropylaminocarbonyl), 3- (methylcarbonylaminoaminocarbonyl), 4- (piperidine 1-ylcarbonyl), 3- (ethoxywei, 4 · (aminocontinyl), 4- (amino), 4- (gas) or 3- (carboxyl is preferred, both Rna and Rnb are Hydrogen. Preferably, η is 1, 2 or 3. Preferably, R 10 is hydrogen or methyl.

L group of a few amino amines Ci-6 alkyl group, or: such that C 1 -6 alkoxy group. ^ Phenyl: 4-fluoro), 3- (methylthiofluorenyl), 3- (2-5-yl), 3- (2-4- (fluorenylamino Yl), phenylyl carbonyl), phenylmethyl), 3- ylamino), 3- (fluorenylamino), propylaminocarbonyl), 4- (methylcarbonyl), 3- (ethyl), 4 -Cyano). 84385 -26- 200404000 (18) Reconciliation is better, R 1G is hydrogen. Preferably, R3 is hydrogen. When R2 is aryl, examples thereof include phenyl. When R2 is a substituted aryl group, suitable substituents include cyano, perhalo Cm alkyl, amino amine, halo, Ci_6 alkyl, Ci_6 alkyloxy, mono- and di- (Cu alkyl) Aminocarbonyl, Cm alkoxy, nitro, Ci-6 alkylsulfonyl, hydroxy, Cu alkoxyCu alkyl, Cm alkylthio-, mono- and -di- (C ^ alkyl) amino and Cu alkylcarbonylamino. When R2 is heteroaryl, examples include thienyl and pyridyl. When R2 is a substituted heteroaryl group, suitable substituents include cyano, perhalo 1-6 alkynyl, aminoamine, alkynyl, fluorenyl 1.6 alkynyl, 0-1 alkoxyalkynyl, mono- and di- ( C ^ alkyl) aminocarbonyl, Ci.6alkoxy, nitro, Cualkylsulfonyl, hydroxyl, CualkoxyCualkyl, Cualkylthio-, mono- and -di_ (Ci_6 Alkyl) amino and Ci.6alkylamino. Preferably, R2 is an unsubstituted or substituted phenyl group, an unsubstituted or substituted thienyl group, or an unsubstituted or substituted pyridyl group. When R2 is substituted phenyl, suitable substituents include halo. More preferably, R2 is a phenyl group substituted with chlorine or fluorine, a 4-phenyl group substituted with chlorine, or an external alkyl group. Preferably, R2 is 3-fluorophenyl, 4-fluorophenyl, 2,5-dichlorophenyl, 3-chlorophenyl, 3- (trifluoromethyl) phenyl, 3-chlorobenzyl, 3 , 4-dichlorophenyl, 3,4-difluorophenyl, 3-gas-4-fluoro-phenyl, 2-chloroρethen-5-yl, or tri-3-yl. The compounds of formula (I) that can be mentioned are formula (Π): 84385 -27- 200404000 (19).

r2 (I〇 where: R1 represents a substituted or unsubstituted aryl group; X represents -0-or a chemical bond; Y represents-(CRnaRnb) n-;

Rna and Rnb are each independently hydrogen or Cu alkyl; η is an integer from 1 to 5; R 2 represents unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl; R 3 represents hydrogen or Cm alkyl ; And its salts and solvates; The limitation is that the following compounds are excluded: 2- (4-chlorophenyl)-~ {[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} Acetylamine; N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -2-phenylacetamidine; N-{[4- (3,4- Dichlorofluorenyl) morpholin-2-yl] methylbu 2-phenoxyacetamidamine; 1 {[4- (3,4-dichlorofluorenyl) morpholin-2-yl] fluorenyl}- 2- (4-methoxybenzyl) acetamidine; 2- (3-Gaphenyl) -N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl } Acetamidine; N-{[4- (3,4-diaminobenzyl) morpholin-2-yl] methyl} -2- [4- (methylthio) benzene 84385 -28- 200404000 (20 ) βιβίfluorenyl] acetamidine; Ν-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -2- [4- (dimethylamino) phenyl] ethyl Amidoamine compounds containing formic acid (1: 1); N-{[4- (3,4-dichloroamido) morpholin-2-yl] methyl} -2- {4-[(diamidoamine ) Sulfonyl] phenyl} acetamidine compound containing formic acid (1: 1); Ν-{[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} -2- [4- (fluorenylsulfonyl) phenyl] acetamidine compound containing formic acid (1: 1); Ν -{[4- (3,4-Difluorobenzyl) morpholin-2-yl] methyl} -2- (3-fluorophenyl) acetamidamine; 2- [3,5-bis (trifluoro Fluorenyl) phenyl] -cardio {[4- (3,4-difluorofluorenyl) morpholin-2-yl] methyl} ethanamide; 2- (2-chlorophenyl) -N-{[ 4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} acetamidine; Ν-{[4- (3,4-dichloro + yl) morpholin-2-yl] Methyl} -2- (4-Gas-2-fluorenyl basic group) acetamidine; Ν-{[4- (3,4-Digas benzyl) morpholin-2-yl] methyl} -2- (3,4-difluorophenyl) acetamidine; 4- [2-({[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} amino) -2- Oxoethyl] fluorenamine; N-{[4- (3,4-digas benzyl) morpholin-2-yl] methylb 2- [4- (trifluoromethyl) phenyl] ethyl Fluorenamine; N-{[4- (3,4-difluorofluorenyl) morpholin-2-yl] methyl} -2- (4-methylbenzyl) acetamidinium; N-{[4- (3,4-dichloro + yl) morphin-2-yl] methyl} -2- (2,4-difluorophenyl) 84385 -29- 200404000 (21) acetamide; N-{[4 -(3,4-dichloro + yl) morpholin-2-yl] methyl} -2- (4-fluorophenyl) ethylamine; N-{[4- (3, 4-diazinoyl) morpho-2-yl] fluorenyl} -2- (3,4-diazinobenzyl) acetamidine; N-{[4- (3,4-digas + yl) Morpho-2-yl] fluorenyl} -2- (2,5-difluorophenyl) acetamidine; N-{[4- (3,4-difluorofluorenyl) morpholin-2-yl] Methyl} -2- (2,6-difluorophenyl) acetamidine; 2- (4 · chlorophenyl) -N-{[4- (2,3-dichlorofluorenyl) morpholine-2 -Yl] methyl} amine acetate trifluoroacetate; 2- [3- (acetamido) phenyl] -N-{[4 · (3 · 4-diaziridinyl) morphin-2-yl ] Fluorenyl} ethenylamine; 2- (4-ethylethenylphenyl) -N-{[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} ethenylamine tri Fluoroacetate; 2- (4-Ethylfluorenylphenyl) -N-{[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} acetamidine; Ν-{[ 4- (3,4-dichlorofluorenyl) morphin-2-yl] methyl} -2- (4-isobutylimyl) acetamidine trifluoroacetate; 4- [2-({[ 4- (3,4-Difluorofluorenyl) morpholin-2-yl] fluorenyl} amino) -2-oxoethyl] benzoate methyl trifluoroacetate; 4- [2-({[ 4- (3,4-dichloroethenyl) morphin-2-yl] fluorenyl} amino) -2-oxoethyl] phenylbenzoate; 2- (4-cyanophenyl)- N- {[4- (3,4-Diaminobenzyl) morpholin-2-yl] methyl} ethyl 84 385 -30- 200404000

(22) Ammonium trifluoroacetate; 2- (4-cyanophenyl) -N-{[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} acetamidine ; 2- (4-chlorophenyl) -N-{[4- (3,4-dioxofluorenyl) morpholin-2-yl] methyl} propanamide; N-{[4- (3, 4-dichloroethenyl) morphin-2-yl] methyl} -2- (3-fluoro-4- ¾phenylphenyl) acetamidine trifluoroacetate; N-{[(2R) -4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} -2- [4- (fluorenylsulfonyl) phenyl] ethanamine; N-{[(2S) -4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} -2- [4- (fluorenylsulfonyl) phenyl] ethanamine; N-{[4- (3,4 -Dichlorohexyl) 17-17-2-yl] fluorenyl} -2- {4-[(4-methyl 17 melon 17 well-1 -yl) peptyl] phenyl} ethylamine, 4- [2-({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) -2-oxoethyl] -N- [2- (dimethylamino ) Ethyl] fluorenamine; 4- [2-({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) -2-oxoethyl]- N, N-dimethylphosphonium amine; 4- [2-({[4- (3,4-digas benzyl) morpholin-2-yl] methyl} amino) -2-oxoethyl Group] -N-ethylbenzylamine; 4- [2-({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) -2-oxoethyl Base) -N -(2-hydroxyethyl) fluorenamine; N-{[4- (3,4-dichloroethenyl) morphin-2-yl] fluorenyl} -2- [4-(? 17 Lin-4 -Yl · carbonyl) phenyl] ethenamide; N-{[((2S) -4- (3,4-dichloroethenyl) morphin-2-yl] methyl} -2- {3-[( MFA 84385 -31-200404000

(23) Amino) sulfofluorenyl] phenyl} acetamidinium; N-{[(2R) -4- (3,4-diaminobenzyl) morpholin-2-yl] fluorenyl 2- { 4-[(dimethylamino) sulfofluorenyl] phenyl} acetamidamine; N-{[((2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl] 2- {4-[(dimethylamino) ruthazinyl] phenyl} amine; 4- [2-({[4- (3,4-dichlorofluorenyl) morpholin-2-yl] Methyl} amino) -2-oxoethyl] -N-methylphosphonium amine; 4- [2-({[4- (3,4-dichlorobenzyl) morpholin-2-yl] Methyl} amino) -2-oxoethyl] -N-isopropylamidinoamine; N-cyclopropyl- 4- [2-({[4- (3,4-dichlorofluorenyl) Morpholin-2-yl] methyl} amino) -2-oxoethyl] benzylamidine; 4- [2-({[4- (3,4-dichlorobenzyl) morpholine-2- Group] fluorenyl} amino) -2-oxoethyl] -N- (2-methoxyethyl) fluorenamine; N-{[4- (3,4-dichlorobenzyl) morpholine -2-yl] methyl} -2- (4-nitrophenyl) acetamidamine; N-{[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl}- 2- (3-nitrophenyl) acetamidine; 3- [2-({[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} amino) -2- Oxoethyl] methyl benzoate; 2- [3- (ethylamidoamino) phenyl] -N-{[4- (3-fluorobenzyl) morpholine-2- ] Fluorenyl} ethenylamine; N-{[4- (3-fluorobenzyl) morpholin-2-yl] methyl} -2- {4-[(methylsulfonyl) amino] phenyl } Acetamidine; 2- [3- (ethylamidoamino) phenyl] -N- {[4- (3,4-difluorobenzyl) morpholin-2-yl] 84385 -32- 200404000 ( 24) β ·· 1 · methyl} acetamidine; Ν-{[4- (3,4-difluorobenzyl) morpholin-2-yl] methyl} -2- {4-[(methyl Sulfonyl) amino] phenyl} ethenylamine; 2- [4- (ethenylamino) phenyl] -N- {[4- (3,4-difluorofluorenyl) morpholine-2 -Yl] methyl} ethenylamine; N-{[4- (3,4-difluoromethyl) morpholin-2-yl] fluorenyl} -2- {3-[(methyl stone yellow alcohol ) Amino] phenyl} ethylamine, N-{[4- (3,4-difluoromethyl) morphin-2-yl] methyl} -2- [3- (fluorenylsulfuryl) Phenyl] ethyl Siamine; N-{[4- (3-chlorofluorenyl) morpholin-2-yl] methyl} -2- [4- (methylsulfonyl) phenyl] ethanamide; N-{[4- (3-chlorofluorenyl) morpholin-2-yl] methyl} -2- [3 · (methylsulfonyl) phenyl] ethanamine; 2-[3- (ethyl Fluorenylamino) phenyl] -N-{[4- (4-fluorofluorenyl) morpholin-2-yl] methyl} ethylfluorenamine; is N-{[4- (4-fluoromethyl)? 11 lin-2-yl] methyl} -2- {4-[(methyl azinyl) amino] phenyl} acetamidine ; 2- [4- (ethylamidoamino) phenyl] -N- {[4- (4-fluoroamido) morpholin-2-yl] amido} ethylamidoamine; N-{[4- (2,3-dichloroethenyl) morphin-2-yl] methyl} -2 · [4- (methylperazinyl) phenyl] acetamidamine; 2- [3- (ethylamyl Amine) phenyl] -N-{[4- (2,3-difluorofluorenyl) morpholin-2-yl] methyl} acetamidinium; Ν-{[4- (2,3-digas Hemyl) morphol-2-yl] fluorenyl} -2- {4-[(methyl stone yellow donkey 84385 -33- 200404000 (25) yl) amino] phenyl} ethanilamide; N- {[ 4- (2,3-dichlorofluorenyl) morpholin-2-yl] methylbutan-2- (4-{[(methylamino) carbonyl] amino} phenyl) acetamidamine; N-({ 4-[(5-Gathiophene-2-yl) methyl] morpholine-2-yl} methyl) -2- [4- (methylthiazyl) phenyl] ethyldonylamine; 2- [ 3- (ethylamidoamino) phenyl] ^-({4-[(5-chloroamido-2-yl) methyl] morpholine-2.yl} methyl) ethylamidoamine; N- ( {4-[(5-chlorothien-2-yl) methyl] morpholin-2-yl} methyl) -2- {4-[(methylsulfonamido) amino] phenyl} acetamidamine ; N-({4-[(5-Gathiophen-2-yl) methyl] morpholin-2-yl} methyl) -2- {3-[(methylsulfonyl) amino] phenyl } Acetylamine; 2- [3- (Ethylamido) phenyl] -N-{[4- (3-chloro ) Morpholin-2-yl] methyl} ethanamide; N-{[4- (3-chlorobenzyl) morpholin-2-yl] fluorenyl} -2- {4-[(methylsulfonyl Fluorenyl) amino] phenyl} ethenylamine; 2- [4- (ethenylamino) phenyl] -N _ {[4- (3-aminobenzyl) morpholin-2-yl] methyl } Acetamidine; N-{[4- (3-chlorobenzyl) morpholin-2-yl] methyl} -2- (4-{[((methylamino) carbonyl] amino} phenyl)) Acetylamine; 2- [4- (Ethylamino) phenyl] -N-{[4 · (2,3-dioxoyl) morpholin-2-yl] methyl} acetamidine; Ν-{[4- (2,3-dichlorofluorenyl) morpholin-2-yl] methyl} -2- [3- (methylsulfonyl) benzyl] acetamidamine; 2- [4 -(Aminosulfonyl) phenyl] -N-{[4- (3,4-dichlorofluorenyl) morpholin-2-yl] 84385 -34- 200404000

(26) Methyl} acetamidinium; 2- [2- (ethylamidoamino) phenyl] -N- {[4- (3,4-dichloroamido) morpholin-2-yl] } Ethanilamide; 2- (3 · cyanophenyl) -N-{[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} ethenylamine; N- { [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -2- (2-fluorophenyl) acetamide; N-{[4- (3,4-dichloro Fluorenyl) morpholin-2-yl] methylbutan-2- (2,3-difluorophenyl) acetamidine; [4- (3,4-diaminobenzyl) morpholin-2-yl] formyl } -2- (2,4-difluorophenyl) acetamidinium; N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -2- (2 , 5-difluorophenyl) acetamidine; N-{[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methylb 2- (2,6-difluorophenyl) Acetylamine; N-cyclopropyl- 3- [2-({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) -2 -oxoethyl ] Fluorenamine; 3- [2-({[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} amino) -2-oxoethyl] -N- ( 2-methoxyethyl) fluorenamine; 3- [2-({[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} amino) -2-oxo Ethyl] -N-ethyl benzamidine; 3- [2-({[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} amino) -2-oxo Ethyl] -N, N-dimethylfluorenamine; 3- [2-({[4- (3,4-Digas benzyl) morpholin-2-yl] fluorenyl} amino) -2 -Oxo 84385 -35- 200404000 (27) ethyl] -N- [2- (dimethylamino) ethyl] fluorenamine; N-{[4- (3,4-dichlorofluorenyl) Porphyrin-2-yl] methylbutan-2- {3-[(4-Amidinopipen · 1-yl) carbonyl] phenyl} ethanamine; 2- (3-aminophenyl) -N- { [4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} acetamidine; 2- (4-aminophenyl)-> ^ {[4- (3,4- Dichlorobenzyl) morpholin-2-yl] methyl} ethenylamine; 2- [4- (ethenylamino) phenyl] -N- {[4- (3,4-diaziridinyl ) Morpholin-2-yl] methyl} acetamidine; N- {4- [2-({[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} amino group ) -2-oxoethyl] phenyl} 2-methylpropanamide; N- {3- [2-({[4- (3,4-dichloroamidino) morpholin-2-yl] Fluorenyl} amino) -2-oxoethyl] phenyl} 2-methylpropylamidamine; N-{[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl } -2- {3-[(methylsulfonamido) amino] phenyl} ethanamide; N- {[4- (3,4-dichloroamido) morpholin-2-yl] methyl } -2- {4-[(methylsulfonamido) amino] phenyl} ethanamide; N- {3- [2-({[4- (3,4-dichlorohydrazone) ) Morpholine-2-yl] methyl} amino) -2-oxoethyl] phenyl} -2- (dimethylamino) acetamidamine; 2- {4- [bis (methylsulfonyl) Fluorenyl) amino] phenyl} -N-{[4- (3,4-diaminobenzyl) morpholine-2.yl] methyl} acetamidine; N-{[4- (3,4 -Dichlorobenzyl) morpholin-2-yl] methyl} -2- [3- (methylsulfonyl) phenyl] acetamidinium; N-{[4- (3,4-dichlorofluorene Base)? 17 lin-2-yl] fluorenyl} -2- [4- (methyl peperazinyl) 84385 -36- 200404000

(28) -2-Nitrophenyl] acetamidamine; N-{[4- (3,4-Difluorofluorenyl) morpholin-2-yl] methyl} -2- (2-hydroxyphenyl ) Ethylamine; N-{[4- (3,4-Difluorofluorenyl) morpholin-2-yl] methyl} -2- {4- [methyl (methylsulfonyl) amino] Phenyl} acetamidamine; N- {[4- (3,4-diaminobenzyl) morpholin-2-yl] methylb 2- {3- [methyl (methylsulfonyl) amino ] Phenyl} ethanesulfonylamine; 2- [2-amino-4- (methylsulfonyl) phenyl] -N- {[4- (3,4-dichlorofluorenyl) morpholine-2- [Methyl] methyl} acetamidine; N-({(2 S) -4-[(5-chlorofluoren-2-yl) methyl] morpholin-2-yl} methyl) -2- {3 -[(Methylsulfonamido) amino] phenyl} ethanamine; N-({(2R) -4-[(5-chlorofluoren-2-yl) methyl] morpholin-2-yl } Methyl) -2-{3-[(methylsulfonamido) amino] phenyl} ethanamide; N-{[((2S) -4- (3,4-dichlorofluorenyl) morpholine -2-yl] methyl} -2- {4-[(methylamino) sulfofluorenyl] phenyl} ethanamine; N-{[(2S) -4- (3,4 · dichlorofluorene ) Morpholine-2-yl] methyl} -2- {4-[(ethylamino) sulfofluorenyl] phenyl} ethylfluorenamine; 2- [3- (aminosulfofluorenyl) phenyl ] -N-{[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} acetamide; 2- {3-[(cyclo Ylamino) sulfofluorenyl] phenyl} -1 {[((2 3) -4- (3,4-dichloroethenyl)? [(2S) -4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} -2_ {3-[(ethylamino) sulfofluorenyl] phenyl} acetamidine; N-{[(2S) -4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} -2- {3-[(methyl 84385 -37- 200404000

(29) Amine) sulfofluorenyl] phenyl} acetamidine; N-{[((2S) -4- (4-Arylidene) morphin-2-yl] methyl} -2- {4- [(Methylpyrexyl) amino] phenyl} ethenylamine; N-{[((2R) -4- (4-fluorobenzyl) morpholin-2-yl] fluorenyl} -2- { 4-[(Methanesulfonyl) amino] phenyl} ethanamide; 2- [4- (aminosulfonyl) phenyl] -N-{[4- (3,4-dichlorobenzyl ) Morpholine-2-yl] methyl} acetamidine; 2- {4-[(cyclopropylamino) sulfonamido] phenyl} -N-{[4- (3,4-dichloro Benzyl) morpholine-2-yl] methyl} acetamidine; > ^-cyclopropyl-3- [2-({[(23) -4- (2,3-dichlorofluorenyl) Phenolin-2-yl] methyl} amino) -2-oxoethyl] fluorenamine; 3- {2-[({(2 (2S) -4-[(5-chlorothien-2-yl) methyl [Methyl] morpholine-2-yl} fluorenyl) amino] -2-oxoethyl} -N-cyclopropylbenzylamine; N-cyclopropyl-3- [2-({[(2S) -4- (4-fluorofluorenyl) morpholin-2-yl] methyl} amino) -2-oxoethyl] fluorenamine; 3- [2-({[((2 8) -4- (3-Chlorofluorenyl) morpholin-2-yl] methyl} amino) -2-oxoethyl] -N- $ Arylamidine, 1 cyclopropyl-3- [2- ( {[((23) -4- (3,4-difluorofluorenyl) morpholin-2-yl] methyl} amino) -2-oxoethyl] benzidine; and N-cyclopropyl- 3- [2-({[((2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) -2-oxoethyl] fluorenamine. There are sub-types of compounds of formula (I), with formula (IA): 84385 -38- 200404000

R

X Y

N-R N.

R

R

The basic formula of \) / Μ / IV is A, and R B-^ i§pi: ffs, reply

R

(M) where R6 represents Ch6 alkylthio, unsubstituted or substituted heteroaryl, C3_8 cycloalkylsulfonamidoamino; N, N-di ((^ _ 6alkyl) aminosulfoamido, R8R9NC (0)-wherein R8 and R9 each independently represent hydrogen or Ci_6 alkyl or R8 and R9 can represent-(CH2) q- radicals where q is an integer of 3 to 7 and thus forms 4 to 4 8-membered heterocyclyl ring; unsubstituted heteroaryl; heteroaryl substituted with Ch6 alkyl, ii, (^ .6 alkoxy or hydroxy; C3.8 cycloalkynylamino continuous group; C 3-8 ring alkyl group; amine group base; Wei group; mono- and di_ (Ci_6 group) amino group base group; Ci. 6 alkyl group base group; Ci_6 group base group ^ 3_8 cycloalkenylaminoweilyl; aminoweilyl; ^ 1_6alkyloxycarbonyl; Ci_6alkylsulfonyl; or Cualkylcarbonylamino; R7 represents cyano, perhalo Ci_6alkyl, hydrogen , Ci_6 alkyl, halo, Ci_6 alkoxy, or hydroxyl; Y, R2, R3, and R1G are as defined in the aforementioned formula (I); and the following compounds are excluded: 84385 -39- 200404000 (31) Fenchou description sheet: Fiber-fiber_Fiber-fiber condensed fiber N-{[4- (3,4-dichlorofluorenyl) morpholine-2- ] Methylbutan-2-phenoxyacetamidamine; 2- [3- (ethylamidoamino) phenyl] -N-{[4- (3,4-dichloroamido) morpholine-2- [Methyl] methyl} acetamidine; N-{[((2S) -4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} -2- {3-[(dimethylamine Group) sulfofluorenyl] phenyl} ethenylamine; 3- [2-({[4- (3,4-dichlorofluorenyl) morpholin-2-yl] fluorenyl} amino) -2-oxo Ethyl] methyl benzoate; 2- [3- (ethylamidoamino) phenyl] -N-{[4- (3-fluoroamido) morpholin-2-yl] methyl} acetamidine Amine; 2- [3- (Ethylamino) phenyl] -N-{[4- (3 · 4-difluorofluorenyl) morpholin-2-yl] methyl} acetamidine; Ν- {[4- (3,4-difluorofluorenyl) morpholin-2-yl] methyl} -2- {3-[(methylsulfonyl) amino] phenyl} amine acetate; N- { [4- (3,4-difluorobenzyl) morpholin-2-yl] methyl} -2- [3- (methylsulfonyl) phenyl] ethanamide; N-{[4- ( 3-chlorobenzyl) morpholin-2-yl] methyl} -2- [3- (methylsulfonamido) phenyl] acetamidoamine; 2- [3- (ethylamidoamino) phenyl ] -N- {[4- (4-Fluorofluorenyl) morpholin-2-yl] methyl} acetamidine; 2- [3- (ethylamylamino) phenyl] -N-{[4 -(2,3-dichlorobenzyl) morpholin-2-yl] fluorenyl} ethenylamine; 2- [3- (ethenylamino) benzene Group] -N-({4-[(5-chlorothiophen-2-yl) methyl] morphine-2 -yl} methyl) ethylamine, "({4-[(5-chlorothiophene-2 -Yl) methyl] morpholin-2-yl} methyl) -2- {3-[(methyl 84385 -40- 200404000

(32) Keystone yellow S & amino] phenyl} ethylamine; 2- [3- (ethylamidoamino) phenyl] -N-{[4- (3-benzyl) morpholine -2-yl] methyl} acetamidine; N- {[4- (2,3-digas benzyl) morpholin-2-yl] methyl} -2- [3- (methylsulfonyl ) Benzyl] acetamidine; N-cyclopropyl-3- [2-({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) -2- Oxoethyl] phosphonium amine, 3- [2-({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) -2-oxoethyl] -N -Ethylamine, 3- [2-({[4- (3,4-dichlorobenzyl) morpholin-2-yl] fluorenyl} amino) -2-oxoethyl] -N, N-dimethylbenzylamine; > ^ {3- [2-({[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} amino)- 2-oxoethyl] phenyl} -2-methylpropanamide; N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -2- {3 -[(Methylsulfonamido) amino] phenyl} ethanamine; N- {[4- (3,4-dichloroamido) morpholin-2-yl] methyl} -2- [3 -(Methylsulfonyl) phenyl] acetamidine; N-({(2S) _4-[(5-chlorothien-2-yl) methyl] morpholin-2-yl} methyl) -2 -{3-[(fluorenylsulfonyl) amino] phenyl} ethanamine; N-({(2R) -4-[(5-chloropyrimen-2-yl ) Fluorenyl] morpholin-2-yl} methyl) -2- {3-[(methylsulfonyl) amino] phenyl} ethanylamine; 2- [3- (aminosulfonyl) Phenyl]-[{[(2 8) -4- (3,4-dichlorobenzyl) morpholine-2 -yl] methyl} acetamidamine; 2- {3-[(cyclopropylamino ) Sulfonyl] phenyl} -N-{[(2S) -4- (3,4-digas 84385 -41-200404000

(33) Fluorenyl) morpho-2 -yl] methyl} ethyl amine, N-{[((2S) -4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl } -2- {3-[(ethylamino) sulfofluorenyl] phenyl} acetamidine; N-{[(2S) -4- (3,4-dichlorofluorenyl) morpholine-2- [Methyl] methyl} -2- {3-[(methylamino) sulfofluorenyl] phenyl} ethanamide; N-cyclopropyl-3- [2-({[(2 S) -4- (2,3-difluorofluorenyl) morpholin-2-yl] methyl} amino) -2-oxoethyl] fluorenamine; 3- {2-[({(2S) -4- [ (5-Chlorophen-2-yl) methyl] morpholin-2-yl} methyl) amino] -2-lactoethylpropylammonium amine, N-cyclopropyl-3- [ 2-({[((2S) -4- (4-fluorofluorenyl) morpholin-2-yl] methyl} amino) · 2-oxoethyl] fluorenamine; 3- [2-({ [(2S) -4- (3-chloroamidino) morpholin-2-yl] methyl} amino) -2-oxoethyl] · N-cyclopropylamidine; Ν-cyclopropyl -3- [2-({[((2S) -4- (3,4-difluorofluorenyl) morpholin-2-yl] methyl} amino) -2-oxoethyl] fluorenamine; And ~ cyclopropyl-3- [2-({[((23) -4- (3,4-difluorofluorenyl) morpholin-2-yl] methyl} amino) -2-oxoethyl ] Benzylamine. Preferably, 116 is Cm alkylsulfonylamino, C3.8 cycloalkylcarbonyl, Ci.6 alkylcarbonyl, (^ .6alkoxycarbonyl, aminosulfonyl, carboxyl, or mono- and Di- (Ci.6 alkyl) aminocarbonyl. Preferably, R7 is hydrogen. Preferably, R1 A contains phenyl substituted with: 3-methylthio, 3-methanesulfonyl, 3 · (2- Methyl-1, 3,4-. Diazol-5-yl), 3-(1, 3,4-oxadiazol-2-yl), 3- (2-methyl-1,3,4 -Triazole-5 · yl), 3- (methylaminocarbonyl), 3- 84385 -42- 200404000 (34) 面 _ 面 _ (isopropylsulfonylamino), 3-(cyclopropylsulfonyl Fluorenylamino), 3- (ethylsulfonylamino), 3- (isopropylaminosulfonyl), 3- (methylsulfonylamino), 3- (cyclopropylcarbonyl) ) V 3-(methylcarbonyl), 3-(fluorenyloxycarbonyl), 3-(aminosulfonyl), 4-(methylsulfonylaminomethyl), 3-(methylamino Carbonyl), 3- (dimethylaminocarbonyl), 3- (isopropylaminocarbonyl), 3- (isopropylmethylaminocarbonyl), 4- (fluoro), 3- (amino), 4- (methylcarbonylamino), 3- (cyclopropylaminocarbonyl), 3- (methylcarbonylamino) , 3- (ethylaminocarbonyl), 4- (piperidine-1-ylcarbonyl), 3- (ethoxycarbonyl), 4-cyano, 4- (aminosulfonyl), 4- ( Fluorenylamino), 4- (fluoro), and 3- (carboxy). More preferably, R1A contains a phenyl substituted with 3-methylthio, 3-fluorenylsulfonyl, 3- (2-methyl -1,3,4-pyridinediazol-5-yl), 3- (1,3,4-amidazol-2-yl), 3- (2-methyl-1,3,4-triazole -5-yl), 3- (methylaminocarbonyl), 3- (isopropylcontinuous amineamino), 3- (cyclopropylcontinuous amineamino), 3- (ethyl luteinylamino) , 3- (isopropylaminosulfonyl), 3- (cyclopropylcarbonyl), 3- (methylcarbonyl), 3- (methoxycarbonyl), 3- (aminosulfonyl), 3- (methylaminocarbonyl), 3- (dimethylaminocarbonyl), 3- (isopropylaminocarbonyl), 3- (isopropylmethylaminocarbonyl), 3- (ethylamine Carbonyl), 3- (methylsulfonamido) or 3- (carboxy). A second class of compounds of formula (Ii) that can be mentioned is formula (IAi):

Where 84385 -43-200404000 (35) R1 A is the base of formula (Μ):

Where R6 represents R8R9NC (〇)-where R8 and R9 each independently represent hydrogen or Cu alkyl or R8 and R9 can represent-(CH2) q- radicals where q is an integer from 3 to 7 and is therefore a nitrogen atom bonded to Together form a 4 to 8-membered heterocyclyl ring; unsubstituted heteroaryl; heteroaryl substituted with CU6 alkyl, halo, alkoxy, or hydroxyl; C3_8 cycloalkylaminosulfonyl; C3_8 cycloalkane Carbonyl group; amino acid group; weyl group; early- and di- (Ci_6 alkyl) amino group; Ci-6 alkylsulfonylamino group; Ci. 6 alkylcarbonyl group; C 3 _ 8-cycloalkylaminocarbonyl group; aminocarbonyl group; Cu alkoxycarbonyl group; Cu alkylsulfonyl group; or (^ .6 alkylcarbonylamino group; R7 represents cyano, perhalo Ci-6 alkyl, hydrogen, Cu Alkyl, halo, Cm alkoxy, or hydroxyl; Y, R2, and R3 are as defined in the foregoing formula (I); and the following compounds are excluded: N-{[4- (3,4-difluorofluorenyl) morpholine 2-yl] methyl} -2-phenoxyacetamidamine; 2- [3- (ethylamidoamino) phenyl] -N- {[4- (3,4-dichlorobenzyl) Morpholin-2-yl] methyl} acetamidamine; N-{[(2S) -4- (3,4-dichlorofluorenyl) morpholin-2-yl] fluorenyl} -2- {3- [(Dimethylamino) sulfofluorenyl] benzyl} ethane ; 3- [2-({[4- (3,4-Difluorofluorenyl) morpholin-2-yl] methyl} amino) -2-oxoethyl] benzoic acid ethyl ester; 2- [ 3- (ethylamidoamino) phenyl] -N-{[4- (3-fluorobenzyl) morpholin-2-yl] methyl 84385 -44- 200404000 (36) βιιιιιιιιειια-pentamine; 2 -[3- (ethylamidoamino) phenyl] -N-{[4- (3,4-difluorobenzyl) morpholin-2-yl] methyl} ethylamidoamine; N-{[4 -(3,4-difluorobenzyl) morpholin-2-yl] methyl} -2- {3-[(methylsulfonyl) amino] phenyl} acetamidamine; N-{[4 -(3,4-difluorofluorenyl) morpholin-2-yl] fluorenyl 2- [3- (methylsulfonyl) phenyl] ethanamide; N-{[4- (3-chloro Fluorenyl) morpholin-2-yl] methyl} -2- [3- (methylsulfonyl) phenyl] ethanamine; 2- [3- (ethylamidino) phenyl] -N -{[4- (4-fluorobenzyl) morpholin-2-yl] methyl} ethanamine; 2- [3- (ethylamido) phenyl] -N- {[4- (2 , 3-dichlorofluorenyl) morpholin-2-yl] methyl} acetamidine; 2- [3- (ethylamylamino) phenyl] -N-({4-[(5-chlorothiophene -2-yl) methyl] morpholin-2-yl} methyl) acetamidamine; * ({4-[(5-chlorothien-2-yl) methyl] morpholin-2-yl} methyl ) -2- {3-[(methylsulfonyl) amino] phenyl} ethanamide; 2-[3 -(Ethylamidoamino) phenyl] -N-{[4- (3-chloroamido) morpholin-2-yl] methyl} ethylamidoamine; N-{[4- (2,3- Dichlorobenzyl) morpholin-2-yl] fluorenyl} -2- [3- (methylsulfonyl) phenyl] acetamidine; N-cyclopropyl-3 [2-({[4 -(3,4-diaminobenzyl) morpholin-2-yl] methyl} amino) -2 -oxoethyl] benzylamidine; 3- [2-({[4- (3,4 -Dichlorofluorenyl) morpholin-2-yl] methyl} amino) -2-oxo 84385 -45-200404000 (37) Confirmation continued on the page Ethyl] -N -ethylammonium amine, 3 -[2-({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) -2-oxoethyl] -N, N-dimethylbenzidine Amine; N- {3- [2-({[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} amino) -2-oxoethyl] phenyl}- 2-methylpropylamidamine; N- {[4- (3,4-dichloroamidino) morpholin-2-yl] methylb 2- {3-[(methylsulfonyl) amino] Phenyl} acetamidine; N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -2- [3- (methylsulfonyl) phenyl] ethyl Sulfonamide; N-({(2S) -4-[(5-chlorofluoren-2-yl) methyl] morpholin-2-yl} methyl) -2- {3-[(methylsulfonate Fluorenyl) amino] phenyl} ethanilamide; N-({(2R) -4-[(5-chloropyrimin-2-yl) methyl] morpholine -2-yl} methyl) -2- {3-[(methylsulfonyl) amino] phenyl} ethanylamine; 2- [3- (aminosulfonyl) phenyl] -1 ^ -{[((28) -4- (3,4-dichlorobenzyl) morpholine-2-yl] methyl] ethanamidine; 2- {3-[(cyclopropylamino) sulfonyl)] Phenyl} -N-{[(2S) -4- (3,4-dichlorofluorenyl) morpholine-2-yl] methyl} acetamidine; N-{[(22) -4- (3 , 4-dichlorobenzyl) morpholin-2-yl] methyl} -2- {3-[(ethylamino) sulfofluorenyl] phenyl} ethanamide; N-{[(2S)- 4- (3,4-dichlorobenzyl) morpholine-2 · yl] methyl} -2- {3-[(fluorenylamino) sulfofluorenyl] phenyl} ethanamine; "cyclopropyl -3- [2-({[((23) -4- (2,3-diaminobenzyl) morpholin-2-yl] methyl} amino) -2-oxoethyl] benzylamine; 3- {2-[({(23) -4-[(5-chlorothien-2-yl) fluorenyl] morpholin-2-yl} methyl) amine 84385 -46- 200404000

(38) group] -2-oxoethyl} -N-cyclopropylbenzylamine; N-cyclopropyl-3- [2-({[(2S) -4- (4-fluorobenzyl) Morpholin-2-yl] methyl} amino) -2-oxoethyl] fluorenamine; 3- [2-({[((2 S) -4- (3-chlorobenzyl) morpholine- 2-yl] methyl} amino) -2-oxoethyl] -N-cyclopropylphosphonium amine; "cyclopropyl-3- [2-({[(2 3) -4- (3 , 4-difluorofluorenyl) morpholin-2-yl] methyl} amino) -2-oxoethyl] fluorenamine; and N-cyclopropyl-3- 3- [2-({[(2S ) -4- (3,4-dichloro + yl) morpholin-2-yl] methyl} amino) -2-oxoethyl] benzylamine. Suitable compounds of the invention are Examples 1, 2, 3, 4, 5, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 24, 25, 28 , 29, 30, 31, 35, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 77, 81, 82, 83, 85, 87, 88 , 89 and 90 ° The preferred compounds of the present invention are Examples 1, 3, 4, 5, 8, 10, 1 1, 12, 13, 14, 15, 16, 17, 29, 31, 35, 41, 43, 45, 47, 49, 51, 55, 57, 59, 61, 63, 65, 77, 85, 87, 88, 89, and 90 ° The better compounds of the present invention are examples 1 3, 8 8, 14, 1, 1, 4 , 3 5, 2 9, 43, 45, 47, 49, 51, 55, 57, 59, 85, and 87 ° Suitable salts of the compound of formula (I) include bioacceptable salts and non-physiologically acceptable but can be used for Salts of compounds of formula (I) and their pharmaceutically acceptable salts are prepared. Where appropriate, acid addition salts may be derived from inorganic or organic acids, such as, for example, hydrochloric acid, hydrobromic acid, sulfates, phosphates, acetates, benzoates, lemons 84385 -47- 200404000

(39) Citrate, succinate, lactate, tartrate, fumarate, maleate, 1-hydroxy-2 -pyranoate, pamoate, methane Luteinate, formate or triII acetate. Examples of solvates include hydrates. A preferred compound of formula (I) is of formula (Γ): R1

Η

(! ') Where is the base of formula (ΝΓ):

(M.) wherein RV represents R8R9NC (0)-wherein R8 and R9 are as defined above; Cu alkoxycarbonyl; Cu alkylcarbonyl; C3.8 cycloalkylcarbonyl; Cu alkylsulfonamido; carboxyl; Or aminosulfonyl; R7 represents murine or halo, and R2 is halo-substituted phenyl. Preferably, R 1 is C 3-8 bad radical Wei, C 1 -6 alkyl radical Wei, C 1 -6 alkyl radical Wei, amino amine, Ci_ 6 alkyl amine , Diphenyl, or mono- or di- (Ci.6 alkyl) aminocarbonyl substituted phenyl. Preferably, R1 ′ is 3- (cyclopropylcarbonyl) benzyl, 3- (fluorenylcarbonyl) phenyl, 84385 -48- 200404000 (40) I surface of 3- (methoxycarbonyl) phenyl, 3- (aminosulfonyl) phenyl, 3-carboxyphenyl, 3- (fluorenaminocarbonyl) phenyl, 3- (methylsulfonamido) phenyl, 3- (dimethylamino) Isopropyl) phenyl, 3- (ethylaminoweilyl) phenyl, 3- (isopropylaminocarbonyl) phenyl, or 3- (isopropyl (methyl) aminocarbonyl) benzyl. Preferably, R2 is phenyl substituted with chlorine or fluorine. Preferably, R2 is 3,4-difluorophenyl, 3,4-difluorophenyl or 3-chloro-4-fluorophenyl. Preferably, the stereochemistry of the position marked 'p is (S). Accordingly, a compound of formula (Γ) or a salt or solvate thereof is provided. There is a further preferred class of compounds of formula (I) as formula (Iπ):

Wherein: R 1 ”is a substituted phenyl group, and R 2” is a phenyl group substituted with a halogen group. Preferably, R 1 ”is a C3.8 cycloalkylaminocarbonyl group, (6-6 alkylcarbonylamino group, R4R5NCO (Wherein R4 and R5 are as defined above), Ci.6 alkoxycarbonyl group, benzyl group, Cl.6 alkyl group amino group, cyano group, amino group continuous group group, amino group group, amino group or amine group Preferably, R 1 π is 3- (cyclopropylaminocarbonyl) phenyl, 3- (fluorenylcarbonylamino) phenyl, 3- (ethylaminocarbonyl) benzyl, 3- (ethoxycarbonyl) phenyl, 3-carboxybenzyl, 3- (methanesulfonylamino) phenyl, 3- (methylaminocarbonyl) 84385 -49- 200404000 (41) phenyl, 4- (methylcarbonylamino) phenyl, 4- (piperidin-1-ylcarbonyl) phenyl or 3-aminophenyl. Preferably, R2 "is a phenyl substituted with a gas. Preferably, R2 "Is a 3,4-difluorophenyl group. Preferably, the stereochemistry at the position marked 1 ^ is (S). Accordingly, a compound of formula (Iπ) or a salt or solvate thereof is provided. There are further preferred times One type of compound of formula (I) is formula (Γ "): 〇

Wherein: R1 'is a 4-substituted phenyl group, and R2' "is a phenyl group substituted with a ii group. Preferably, R1 '' 'is a 4- or p-position alkyl (sulfonylamine) Alkyl substituted phenyl. Preferably, R1 " is a 4- (methanesulfonylaminofluorenyl) benzyl group. Preferably, R2 '"is a phenyl substituted with chlorine or fluorine. Preferably, R2 " 'Is 3,4-difluorophenyl. Preferably, the stereochemistry at the position marked f *' is (S). Accordingly, a compound of formula (factory) or a salt or solvate thereof is provided. Some formulas ( I) Compounds may contain opposite atoms and / or multiple bonds, and thus one or more stereoisomers may exist. The present invention includes all stereoisomers of compounds of formula (I), including geometric isomers and optical isomers Structure, whether 84385 -50- 200404000 (42) 1-i is an individual stereoisomer or a mixture containing racemic modification. Generally, it is preferred that the compound of formula (I) is a single enantiomer or a diastereomer Enantiomers. Certain compounds of formula (I) may exist in one of several tautomers. It is to be understood that the invention encompasses all tautomers of compounds of formula (I), whether individually Variations or mixtures thereof. "Related" arylπ represents monocyclic and bicyclic carbocyclic aromatic rings, such as fluorenyl and phenyl, especially phenyl. Suitable substituents for any aryl include 1 to 5, preferably 1 Up to 3 substituents selected from the group consisting of: alkylsulfonyl; alkylthio; unsubstituted or substituted heteroaryl; cycloalkenyl orthoamino; alkenylamino Alkyl; alkylaminosulfonyl; peralkyl; cycloalkylaminosulfonyl; heterocyclic carbonyl; alkylsulfonylaminoalkyl; cyano; amino; cycloalkylcarbonyl; Alkylweilyl; alkylalkynoamino; cycloalkylalkylamido; aminoamino; halo; alkyl; alkoxycarbonyl; mono- and di- (alkyl) aminocarbonyl; alkyl Oxy; nitro; alkylsulfonyl; hydroxyl; alkoxyalkyl; alkylthio: mono- and di- (alkyl) amino groups; and alkylcarbonylamino groups. About `` heteroarylπ Represents a heterocyclic aromatic ring containing 1-4 heteroatoms selected from nitrogen, oxygen, and sulfur. Examples of heterocyclic aromatic rings include thienyl, pyrazolyl, pyridisyl, and trisigma. Suitable substituents for heteroaryl Cyano, perhaloalkyl, amido, halo, alkyl, alkoxycarbonyl, mono- and di- (alkyl) aminocarbonyl, alkoxy, nitro, carbamoyl, Group, alkoxy group, thio group, mono- and -di- (alkyl) amino group, and alkylcarbonylamino group. 84385 -51-200404000 (43) ΙΒ_ΐβΡι 继 Follow i: ¾ 辑__________________, which refers to `` alkylπ '', represents linear and branched aliphatic isomers of corresponding alkyl groups which should preferably contain up to 6 carbon atoms. Π cycloalkylπ, which should preferably contain 3 to 8 carbon atoms A saturated alicyclic ring such as cyclopropyl. "Heterocyclyl" refers to a monocyclic heterocyclic ring containing 2 to 6, preferably 3 to 5 carbon atoms and 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Aliphatic ring. Examples of heterocycles include sigma-radicals. Suitable substituents for any heterocyclyl include cycloalkylcarbonyl, aminocarbonyl, alkylsulfonylamino, alkylcarbonyl, cycloalkylaminocarbonyl, alkyl, alkoxyalkyl, and alkylamino Alkyl, halo, alkoxy, alkynyl, alkynyl, yellow alkynyl, triphenyl, alkoxy, thio, thio-, di- (alkyl) amino, and alkylcarbonylamino . The "π halogen f 'or π halogen group" represents iodine, bromine, chlorine or fluorine, especially fluorine and chlorine. The compound of formula (I), its salt and solvate can be prepared by the method described later, and constitute another object of the present invention. Accordingly, a method for preparing a compound of formula (I) is provided, which method comprises combining a compound of formula (Π) with a compound of formula (III);

Among them: R1, X, Υ, R3, R1G and R2 are as defined in formula (I), and are reacted in the presence of a peptide coupling agent and 84385 -52- 200404000 (44) ill, if necessary, and then if necessary One or more of the following optional steps: (i) converting a compound of formula (I) into another compound of formula (I); (ii) removing any necessary protecting groups; (iii) preparing a salt or solvent of the compound formed Compound. Preferably, the activator is 1-hydroxybenzotriazole (HOB T). 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. Preferably, the peptide coupling agent is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride. Typically, the compound of formula (II) and the compound of formula (III) are peptide-coated in a suitable solvent such as a polar organic solvent such as N, N-dimethylformamide at ambient temperature, such as about 1 8-2 5 ° C. Mixture treatment. The reaction mixture is stirred at ambient temperature for a suitable time such as about 12-20 hours. Compounds of formula (III) where R3 is hydrogen can be prepared by reaction (a) 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):

Wherein R2 and R1G are as defined in formula (I) and A is a protected amine group, preferably a phthalimide imine group, and then the amine group is deprotected to obtain a compound of formula (III) in which R3 is hydrogen, namely IIIR) compounds. 84385 -53-200404000 (45)

R '(lllR) wherein R2 and R1G are as defined in formula (I), and the obtained enantiomers of formula (IIIR) are resolved as appropriate; or reaction (b). The aforementioned compound of formula (IV) and formula (VA ) Compound reaction: A, (VA) where A is as defined in the aforementioned formula (V), and then the amine group is deprotected to obtain the relative enantiomer of the compound of formula (III) in which R3 is hydrogen, that is, formula (III) E) Compounds.

(IIIE) wherein R2 and R1G are as defined above. Reaction (c): Hydrolyze the compound of formula (VI): Ν—Τ Ν 丨

The structure of the R compound is different (VIR mapping. And the combination of the compound R3 and TR of the TR \ _ ^ / 5 I 5 I group (I 醯 乙 得 所 所 三 为 况 in the case of the case and the meaning of the definition X) / η / _ \ The foregoing formula is as described in 84385 -54- 200404000 (46) For the reactions U) and (b), between the compound of formula (IV) and the compound of formula (v) or (VA) The reaction is typically carried out under the following Mitsuonobu conditions: Typically, a mixture of a compound of formula (IV) and a compound of formula (v) or formula (VA) in a suitable compound such as tetrahydrofuran at a suitable temperature (preferably at Solvent reflux temperature) should be stirred for hours in h sex lice (preferably under nitrogen). Then add other solvents and the mixture is cooled (preferably 0-5. 0. Add the appropriate phosphine (preferably two scales) and stir the mixture to dry until all solids are dissolved. Then add softened for 10--15 minutes The azo compound should be diisopropyl azodicarboxylate and the temperature should be maintained at <7 ° c. # Π Keep the composition to rest for a period of time (preferably 2-3 hours), and then warm to 20-25 ° C. * 趄 m Dan is left for a period of time (preferably 4-6 hours), and then phosphine and azo compounds are added. After being left for a period of time (preferably 20-24 hours), the reaction mixture Shrink to a few folds, ^ dry. Add the appropriate alcohol (preferably propan-2-ol) and repeat the concentration step;-, ^ then repeat the addition of alcohol and concentration steps. Add another alcohol and heat the mixture to a lower temperature.纡 6 5-7 5 C. After a suitable period (preferably 20-4 5 minutes), the resulting 喈 ^ water is cooled at night (preferably 2 0-2 5. (:), then left standing (more than Good 1 · 5-3 hours), follow the township. Σ drenches the isolated products. The filter bed is washed with more alcohol. The second step is to obtain the protected compound of formula (IIIR) or formula (III), respectively. Typically, the product is shifted from the product as follows: WTTT1 =? WL person f, 4 groups. Protected formula (IIIR) or Add the compound of formula (ΠΙΕ) in the appropriate polar solvent "(and water) to the temperature (temperature is preferably 70-75t), and then use a thick helmet. The mixture is mixed with # /", and then (better concentrated sulfuric acid) ) Drop by drop ... The material is heated at a suitable temperature (better solvent reflux temperature) for a suitable time (20-24 hours). Then the reaction mixture is cooled to M · ". Then with a suitable polar solvent (more Good digas pentane) wash bar ^ then add dropwise alkali (preferably 84385 -55- 200404000

(47) 0.8 8 0 ammonia solution), the temperature is maintained 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 above-mentioned method for preparing the 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:

Wherein A is as defined in the aforementioned formulas (V) and (VA) and R2 and R1G are 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) in 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). The compound of formula (niBR) or formula (IIIBE) is isolated by filtration, washed with a co-solvent and dried under vacuum. A protected state of formula (111R) or formula (111E) can then be prepared from a compound of formula (IIIBR) or formula (IIIBE) under conditions similar to the reaction between a compound of formula (IV) and a compound of formula (V) or formula (VA). Compounds, but omit the addition of phosphine and 84385 -56-200404000 giii :: the reflux period before the azo compound. 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 to 25 ° C, for an appropriate time, such as 16 to 20 hours, and then the organic solvent is removed in a vacuum. 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 sodium chloride solution, dried over a suitable desiccant such as sodium sulfate, filtered and the solvent is 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):

Wherein: T, R3, R1G and R2 are as defined in the aforementioned formula (VI) and L2 is a leaving group. Suitably the leaving group L2 is a halogen group such as gas. 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 and add a suitable base (such as potassium carbonate) and a suitable activator (such as sodium iodide). The compound of formula (V111) is suitable for 84385 -57- (49) 200404000

A solution of methyl methyl Si amine is added dropwise to the solvent of the mixture (for example, N, N-. The mixture is then stirred at a suitable temperature, W <Office 丨 Λ Λ, and / degree (for example, 20-25t) is suitable for stirring After a period of time (eg, female 16 2 J), the volatile components are removed after emptying. The residue is partitioned between an organic solvent (such as dichloromethane) and a saturated alkaline aqueous solution (such as a saturated sodium carbonate aqueous solution). After washing with saturated aqueous alkaline solution and water, drying with a suitable desiccant (such as magnesium sulfate), filtering and evaporating the solvent in vacuo, the crude product is obtained. The crude product is purified by flash chromatography. The compound of formula (νπ) can be obtained by the compound of formula (Ιχ) and Prepared by reacting a compound of formula (χ):

Among them, R3, R10 and T are as defined in the aforementioned formula (VI) and ^ is an alkyl group, preferably ethyl. The reaction between the compound of formula (IX) and the compound of formula (X) is typically performed by stirring the jUX) compound in a suitable solvent (such as methanol) under an inert gas (such as nitrogen), and then adding the compound of formula (x) as appropriate. Solvent (such as acetic acid) ^ This a substance is then stirred at an appropriate temperature (such as 20-50) for a suitable time (such as 20-40 minutes), and then the volatile components are removed in vacuo. The residue is dissolved in a suitable organic solvent (eg methanol) and the volatile components are removed in vacuo. In addition, and for another purpose, a compound of formula ⑴ can be prepared by reacting a compound of formula (χι) κ with a compound of formula (111):

R

84385 -58- (XI) 200404000 (50) Although the results are: page ,,, :: ,, \, where L2 is a leaving group, and R1, 乂, and ya are as defined in the above formula (1), and then If necessary, perform one or more of the following optional steps: (i) converting a compound of formula (I) into another compound of formula (1); (ii) removing any necessary protecting groups, (iii) preparing the formed compound Salt or bath. A suitable leaving group is a halo group, preferably odor. Typically, the reaction between a compound of formula (III) and a compound of formula (XI) is in a suitable solvent (such as a polar organic solvent such as acetonitrile) 'in the presence of a suitable test (such as a test or alkaline earth metal carbonate such as potassium carbonate)' in Suitable temperature (such as ambient temperature, such as 1 8-25 ° C) for a suitable period (such as 2.4 hours) ^ Compounds of formula (II), certain compounds of formula (II), certain compounds of formula (IV), (V) , Certain compounds of formula (VI), certain compounds of formula (VII), (VIII), (IX), (X) and (XI) are known, commercially available compounds or can be prepared by known similar procedures, such as synthesis The standard reference method for the method is' for example J. March, Advanced Organic Chemistry 3rd Edition (1985), Wiley Interscience. Compounds of the formulae (IIIBR) and (IIIBE) are considered novel. Accordingly, a compound of formula (IIIBBE) is provided. Compounds of formula (IIIBR) are also provided. Conversion of a compound of formula (I) into another compound of formula (I) includes any transformation that can be performed using conventional procedures, but in particular the transformation involves the conversion of one R1 group to another R1 group. The above transformations can be performed using any suitable method under conditions determined by the particular basis chosen. Therefore, a suitable method for converting one R1 group into another R1 group includes: 84385 -59- 200404000

(51) (a) The R 1 group representing an aryl group substituted with an alkoxycarbonyl group is converted to the R 1 group representing an aryl group substituted with a carboxyl group; this conversion may be performed using a suitable conventional hydrolysis procedure, for example, using a suitable Base treatment of a compound of formula (I) appropriately protected; (b) conversion of a R 1 group representing an aryl group substituted with a carboxyl group to an R 1 group representing an aryl group substituted with a fluorenyl group; this conversion may be performed using a suitable conventional amine The chemical procedure is carried out, for example, by treating an appropriately protected compound of formula (I) with an appropriate amine in the presence of a suitable peptide coupling agent and, if necessary, an appropriate activator; (c) rendering an aryl group substituted with an alkoxycarbonylamino group Conversion of the R1 group to an R1 group representing an amine-substituted aryl group; this conversion can be performed using appropriate conventional deprotection procedures, such as treating the appropriately protected compound of formula (I) with an appropriate inorganic acid; and (d) enabling the representative Conversion of the R1 group of an amine-substituted aryl group to the R1 group of an aryl group substituted with an alkylsulfonylamino group; this conversion can be performed using appropriate conventional sulfonation procedures, such as with an appropriate alkylsulfonyl group Tooths are treated in the presence of a suitable base with the appropriate protection of formula (I) Thereof. 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 P J 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 desired, conventional purification methods such as crystallization and column chromatography can be used. Where appropriate, individual isomers of compounds of formula (I) can be obtained using conventional procedures such as 84385 -60- 200404000

(52) Fractional crystallization of diastereoisomeric derivatives or the preparation of individual isomers by high performance liquid chromatography (parallel HPLC). The absolute stereochemistry of a compound allows clever conventional methods such as X-ray crystallography. 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 to Fenyan. CCR-3 competitive binding to SPA (Flash Proximity Analysis) is used to assess the affinity of novel compounds for CCR-3. Cell membranes (2.5 μg / hole) prepared from K562 cells stably expressing CCR-3 were mixed with 0.25 mg / hole wheat germ agglutinin SPA beads (Amersham) and combined in binding buffer (HEPES 50 mM, CaCl2 1 mM, MgCl25 mM, 0.5% BSA) and incubate at 4 ° C for 1.5 hours. After incubation, 20 pM [125I] euerythrin (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 MUrobeta plate counter. The total analysis volume is 100 liters. The data are incorporated into parametric logarithmic equations to analyze competitive binding data. The data is reported as the average p〗 C 値 from at least two experiments (negative logarithm of the concentration of the [1] eosin-binding compound that inhibits 50%). Example compounds were tested in a CCR-3 binding assay. The example compounds tested in the CCR-3 binding analysis carried p? C? In the range of 6.0 to 8.7. (b) Eosinophil leukocyte chemotactic analysis The compounds were evaluated for their inhibitory effect on eosinophil leukocyte chemotactic. To use the standard CD16 cell depletion effect, use Mihenyi cell separation columns and the aforementioned 84385 -61-200404000 (53) Super Macs magnet (Motegi &amp; Kita, 1 99 8; Journal of Immunology, 1 6 1: 4 3 4 0- 6) Purifying eosinophils from human peripheral blood. Cells were resuspended in RPMI 1 640/1 0% 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 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, cells were grown only with RPMI / FCS. The agonist eosin (EC8G concentration) was added to the lower compartment of the 96-hole chemotaxis disc (5 micron filter paper: Rector Technology). Add eosinophils (50 microliters of 2 million cells / ml) to the upper compartment of the filter paper plate and incubate at 37 ° C for 4 5 minutes. The cells held on top of the chemotaxis filter paper were removed and the disc was read on a fluorescent disc reader to quantify the number of eosinophils that had moved. The data were incorporated into the parametric logarithmic equation to analyze the inhibition curve of the compound's effect on eosinophil chemotaxis. The following equation was used to generate the function pKi value (Lazareno & Birdsall, 1995, Br J. Pharmacol 109: 1110-9). fpKi =, _ ^ 50 1 + [agonist]

~ ec5Q example compounds were tested in CCR-3 binding and / or eosinophil chemotaxis analysis (analysis (a) and (b)). Examples tested in the CCR-3 binding assay The compounds carry pIC5G values ranging from 6.6 to 9.1. The fp K values of the example compounds tested in the CCR-3 eosinophil leukocyte chemotaxis analysis are described in the table below: 84385 -62- 200404000 (54)

Example number fp K i 57 8.8 47 8.1 5 1 8.0 Examples of disease states in which the compounds of the present invention have potential anti-inflammatory effects include respiratory diseases such as bronchitis (including chronic bronchitis), bronchiectasis, asthma (including asthma induced by allergens) Response), chronic distress pulmonary disease (COPD), bladder fibrosis, sinusitis, and rhinitis. It also includes gastrointestinal disorders such as intestinal inflammatory diseases including 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 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. 84385 -63- 200404000 (55)

Invention 娆 Achievement I:: Difficult to discuss 1__ 议 | _ | Jiangmen medulla medulla I The main related diseases include asthma, COPD and inflammatory diseases of the upper respiratory tract including seasonal and perennial rhinitis. Those skilled in the art will understand the conditions referred to herein to extend to include prevention and treatment to produce conditions. As mentioned above, compounds of formula (I) are useful as therapeutic agents. Therefore, another object of the present invention is to provide a compound of formula (I) or a physiologically acceptable salt or solvate thereof as an active therapeutic agent. Accordingly, there is also provided the use of a compound of formula (I) or a physiologically acceptable salt or solvate thereof for the treatment of inflammatory conditions such as asthma or rhinitis. 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. Yet 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 (I) or a physiologically acceptable salt thereof Or solvate. The compounds according to the invention can be formulated for administration in any convenient manner. Accordingly, there is provided a pharmaceutical composition comprising a compound of formula (I) or a physiologically acceptable salt or solvate thereof, and optionally one or more physiologically acceptable diluents or carriers. There is also provided a method for preparing the pharmaceutical composition comprising mixing a compound of formula (I) or a physiologically acceptable salt or solvate thereof with one or more physiologically acceptable diluents or carriers. The compounds of the present invention can be formulated, for example, for oral, inhalation, nasal, intrabuccal 84385 -64- 200404000

(56), parenteral or rectal administration, preferably for oral administration. Lozenges and capsules for oral administration may contain conventional excipients such as binders such as syrup, acacia, gelatin, sorbitol, tragacanth, starch gums, cellulose or polyvinylpyrrolidone; 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; disintegrating agents such as potato starch, croscarmellose Sodium cellulose 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 formulated, for example, as aqueous or oily suspensions, solutions, emulsions, syrups or licorice preparations, or can be dried products which are reconstituted with water or other suitable vehicle before use. This liquid formulation may contain conventional additives such as suspending agents such as sorbitol syrup, methyl cellulose, glucose / syrup, gelatin, hydroxymethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, or hydrogenated food. Fats; emulsifiers such as lecithin, sorbitan monooleate or gum arabic; non-aqueous carriers (which may include edible oils) such as almond oil, crane oil, oleyl esters, propylene glycol, or ethanol; or preservatives such Methyl para-hydroxybenzoate or propionate or sorbic acid. The formulation may also contain buffer salts, bridging agents, coloring and / or sweetening agents (such as mannitol) if appropriate. For buccal administration, the composition can be made into tablets or flat preparations in a conventional manner. The compounds can also be formulated as suppositories such as those containing conventional suppository bases such as cocoa butter or other glycerol vinegar. The compounds of the present invention can also be formulated for injection by pellet injection or continuous infusion. 84385 -65-(57) (57) 200404000

Parenteral administration can be in unit dosage form, such as ampoules, vials, small volume infusion or pre-filled syringes, or multi-dose containers with preservatives. The composition may be prepared as a solution, suppository or emulsion in an aqueous or non-aqueous plant and may contain formulation agents such as antioxidants, buffers, antimicrobials and / or tension regulators. 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 with high pressure into individual sterilization containers or by filling the sterilization solution with high pressure into each container and freeze-drying. The compounds and pharmaceutical compositions of the present invention can also be used in combination with other therapeutic agents, such as antihistamines, anticholinergic agents, anti-inflammatory agents such as corticosteroids such as fluticasone propionate, belomethas dipropionate Beclomethasone, mometasone furanoate <mometasone, triamcinolone propionate 8 or budesonide; or nonsteroidal anti-inflammatory drugs (NSAIDs) such as Sodium tryptophan, Uedocromil) sodium, PDE-4 inhibitor, leukotriene antagonist, iNOs inhibitor, trypsin and elastase inhibitor, 3 integrin antagonist and adenosine 2 a agonist Agent 'or / 3 adrenal agents such as samet (sa 1 claw ete Γ 01), salbutamol, forinolol, fenoterol or terbutaline and Its 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 dosage of the compound of the present invention is, 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 / 84385 -66-200404000.

(58) kg of body weight and administered at any appropriate frequency, such as 1 to 4 times a 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 variants need to be understood to mean the inclusion of the stated integer or step or group of integers without excluding any other integer or step or group of integers or steps The present invention will be described with reference to the following non-limiting examples. To avoid misunderstanding, the free bond on the R1 group listed in the table represents the point at which the R1 group is bonded to the rest of the molecule. It is necessary to understand that 'for clarification, illustrative examples And the compounds of the examples are indicated by numbers, for example, π illustrates Example 3 "and, Example 5 π. The compound structures represented are shown in Tables 1 to 4 for the examples and 5 to 7 for the illustrative examples.

General experiment_detail LC / MS 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 and is dissolved in a solvent: A-0.1% v / v formic acid + 0. 077% w / v ammonium acetate in water; and β · 95 ·· 5 acetonitrile: water + 0.05% v / v acetic acid at a flow rate of 3 ml / min. The following gradient method was used: 100% A lasted 0.7 minutes; A + B mixture, gradient profile 0-1 00% B lasted 3.5 minutes; maintained at 100% B 1.1 minutes; returned to 100% A lasted 0.2 minutes. The LC / MS system uses a micro-mass spectrometer in electrospray ionization mode, switching between positive and negative ions, with a mass range of 80-1000a.m.U. 84385 -67- 200404000

(59) Thermal spray mass spectrometry was performed on an HP 5 9 89A engine mass spectrometer. The thermal spray mass spectrum was determined by spraying with a heat source temperature of 250 ° C and a probe temperature of 120 ° C (rod), ι9 (Γ (: (times, Detection mass range: 100- 8 5 0 a · m · U... The compound contains a solvent mixture of 65% methanol and 35% 0 · 0 5 M aqueous ammonium acetate solution in a spoon of 1 μl. The flow rate is 0.7 ml / min. Solid phase extraction (ion exchange) "SCX" stands for Isolute Flash SCX-2 sulfuric acid solid phase extraction. Separation of the organic / aqueous phase with a hydrophobic melt. Hydrophobic melt. Solvent pore size 5.0 microns &lt; Whatman polypropylene filter, tube. All temperatures are ° C. Explaining example -68-(60) (60) 200404000

Potassium carbonate (2.46 g) and sodium iodide (212 g) were added to the grain solution under nitrogen. ; α 5 was added dropwise a solution of 3,4-difluorofluorenyl chloride (2 ml) in ν, ν · dimethylfluorenamine (10 ml). After the mixture was stirred at 22 t for 18 hours, the volatiles were removed in vacuo. The residue was partitioned between dichloromethane (1 ml) and a saturated aqueous sodium carbonate solution (50 ml). The organic phase was washed sequentially with additional saturated aqueous sodium carbonate solution (2 X 50 mL) and water (50 mL), dried over magnesium sulfate, and the solvent was evaporated under vacuum to obtain a pale yellow oil. This oil was dissolved in 90 g of stone gelatin by Biotage flash column chromatography with 25% ethyl acetate in cyclohexane to obtain the title compound (2.97 g) as a colorless oil. B (: / 148 1112.63 minutes, mass spectrum 111/2 37 1 [] ^^ 1 +]. Illustrative Example 3: "4- (3.4-Difluorenyl) morpholine-2-some 1 is described in Illustrative Example 2 (2.97 g) of methanol (15 ml) and water (5 ml) were added to potassium carbonate (5.5 3 g). After the mixture was stirred at 22 ° C for 18 hours, the methanol was removed in vacuo. Water (2 5 Ml) and the mixture was extracted with ethyl acetate (3 x 30 ml). The combined organic phases were washed with water (5 ml) and saturated aqueous sodium gas solution (10 ml), filtered 'dried over sodium sulfate' and evaporated in vacuo. Solvent to obtain a pale yellow oil. This oil was dissolved in a 90 g silicone cartridge by Biotage flash column chromatography with 75: 8: 1 dichloromethane / ethanol / 0 · 880 ammonia solution. Combine the required dissolution fractions and Evaporate the solvent in vacuo to obtain a colorless oil (K 1 · 8 5 g). LC / MS Rt 1.77 minutes' mass spectrum m / z 275 [ΜΗ +]. Illustrative example 4: f 4-Π, 4 difluorenyl) Gu Di 2 · 棊 1 methyl amidamine-synthesis) 2-[(3,4-dichlorofluorenyl) amino] ethanol (Chemical Abstract 4172-〇6-3, 0.980 g) and 2- (epoxy Acetyl_2-ylmethyl) -1Η1 &quot; Noise -1,3 (2Η) -84385 -69- 200404000 (61) A mixture of dione (1.10 g) was stirred at 80 ° C under nitrogen for 3 hours. The obtained solid was treated with concentrated sulfuric acid (1.5 ml) and then Stir at 150 ° C for 2 4 hours. The mixture is treated with water (100 ml) and then washed with ethyl acetate (2 x 100 ml). The dark aqueous phase is basified with 5 M aqueous sodium hydroxide solution to about pH 1,2, It was then extracted with ethyl acetate (2 × 100 mL). The combined organic extracts were washed with water and brine, dried (Na 2 SO 4) and concentrated in vacuo to obtain the title compound as a brown oil (.02 g). Mass spectrum m / z 27 5 (MH +). Illustrative example 5: 1-"(2 S)-4-(3 · 4-dichlorofluorenyl) morpholin-2 -yl &quot; I methylamino group-Illustrative example 3 ( Racemic mixture, 8 g) Separated by preparative palmito-HPLC 84385 -70- 200404000 (62) Redissolved in methane and evaporated solvent to obtain an oily product (662 mg) ° OlX: l] ( 2S) -4-n, 4-Difluorofluorenyl) morpholin-2-ylamine containing a salt of 1D distillate 1: 1 (0.63 g) dissolved in methanol (12. 3 ml ). D-tartaric acid (0.35 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 standard compound (0.4 g) as a white solid. ee · 76% ee for palm HPLC (Chiralpak AD column, 4.6 X 250 cm, eluent 50: 50: 0.1 MeOH: EtOH: butylamine, flow rate 0.5 ml / min, UV detection 220 nm ), Rt 8.9 minutes. ^ J〇L7: 2-Γ4- (3.4-Diaza-fluorenylmorpholin-2-ylfluorenyl-1,3-diugium 2-[(3,4-dichlorobenzyl) amino] Ethanol (2.038 g) and (S) -2- (ethylene oxide-2-ylmethyl) -1 isoisoindole-1,3 (21 ^ -dione (2.032 g) tetrakifuran (3 · 3 ml) of the mixture was stirred and heated under reflux in nitrogen. After 2 1 · 5 Xiaori Temple, more tetrahydrofuran (1 2 · 5 ml) was added and the mixture was cooled to 3 t. Triphenylphosphine (2.793 g) was added and the mixture Stir until all the solids are dissolved. Then add chaotic dimetanoic acid monoisopropyl S (2.1 liters) for 12 minutes to maintain, w degree &lt; 7 it. After 2.25 hours, the mixture is warmed to 22. (: After 5.3 hours, more triphenylphosphine (121 mg) and diisopropyl azodicarboxylate (0.09 ml) were added. After 2 2 · 5 hours, the reaction mixture was concentrated to near dryness. Propylene was added -2 -alcohol (j 2 ml) and repeated concentration, repeated again. More propan-2-ol (2 ml) was added and the mixture was heated to 70 ° C. After 5 hours, the slurry was cooled to 2 2 After another 2 hours, the product was collected. The bed was treated with propan-2-ol (2 X 4 liters) Xilu 84385 -71-(63) (63) 200404000 and then dried under vacuum at 40C to obtain the product (2622 g). Description ^ Difluoroammonium) 4-2-yl 1 methylamine is similar to Suga tLl Illustrative Example 8 was prepared in this manner. Preparative HPLC dwell time 2 8.3 minutes. Explanation · _M—L_〇 · _diazamidyl) morpholine-2_ylmethyl-1 amine-methyl-ionyl 1 amine Tert-butyl formate

In (3-Second-butoxycarbonylamino-phenoxy) -acetic acid (0.100 g) (WO 9708 1 93), 1- (3-dimethylaminopropyl) · 3-ethylcarbodifluorene To a stirred solution of amine hydrochloride (0.143 g) and hydroxybenzotriazole (0.0597 g) of N, N-dimethylformamidine (3 ml), illustrative example 5 (0.093 6 coupons were added. ) Solution of N, N-dimethylmethylamine (1 ml). To the mixture was added N, N • diisopropylethylamine (0.119 ml), followed by stirring at 20 ° C for 19.5 hours. The mixture was diluted with methanol (approximately 2 ml) and applied to 10 g of a 30-well ion exchange cartridge (preconditioned with methanol). The cassette was dissolved in methanol with methanol and 〇〇 / 〇 〇 8.8 ammonia solution. The first ammonia-soluble fraction was evaporated in vacuo and the residue was flash-chromatographed on Shixijiao by BiotageTM and dissolved in a 300: 8: 1 two-gas methane / ethanol / 0.880 ammonia solution. The desired fractions were combined and the solvent was evaporated in vacuo to give the title compound as a colorless glass (0.126). LC / MS: Rt = 3.14 minutes, m / z 524, 526 [MH +]. -72- 200404000

(64)

Method G Example 27: 2-II-Amino-jasmonyl) -N- "4- (3,4-diaminofluorenyl) morpholino-2-ylfluorenyl-1acetamidine

To a stirred solution of methanol (3 ml) in Illustrative Example 10 (0.120 g) was added a 4.0 M solution of hydrogen chloride in 1,4-dihumane (1 ml). The mixture was stirred at 20 ° C for 6 hours and then left to stand for 16 hours. The solvent was evaporated in vacuo to obtain a residue, which was redissolved in methanol and evaporated to dryness under a stream of nitrogen to give the title compound (0.114 g) as a light brown gum. LC / MS: Rt = 2.30 minutes, m / z 424, 426 [MH +]. Illustrative Example 12: Is 0-"(28) -4- (3-Ga-4-Lanthino)? Lin-2-yl 1 methylamine

Illustrative Example 17 (0.36 g) of a digas methane (1 ml) solution was treated with trifluoroacetic acid (1 ml) and left to stand for 1 hour. The mixture was concentrated in vacuo and the residue was partitioned between dichloromethane and aqueous sodium bicarbonate solution; the phases were separated and the organic phase was dried (MgS04), filtered and the solvent was evaporated in vacuo to obtain the title compound (0.25 g) as a colorless gum. 84385 -73- 200404000

(65) LC-MS: Rt = 0.70 min, mass spectrum m / z 2 5 9 [MH +]. Illustrative Example 1 3: 3-a 1 ethyl amidinofluorenyl dicarboxylate

Stir the mixture of ethyl 3-hydroxybenzoate (1.66 g) and anhydrous sodium carbonate (1.38 g) in N, N-dimethylformamide (20 ml) at room temperature. Ethyl bromoacetate (1.67 g) was added. After the mixture was stirred overnight, the solvent was evaporated in vacuo and the resulting thick white paste was partitioned between water and ethyl acetate (two parts, a total of 50 ml). The combined organic extracts were washed with 2% aqueous sodium hydroxide (100 ml) and brine (2 x 50 ml), 'dried over sodium sulfate', filtered and the solvent was evaporated in vacuo. The residue was then subjected to flash column chromatography on silica gel, and dissolved in 4 ·· 1 cyclohexane / ethyl acetate. The desired fractions were combined and the solvent was evaporated in vacuo to give the title compound (2.18 g) as a colorless oil. nmr (25 0 MHz9 CDC13) 7.70δ (1_H? br.d, CH); 7.575 ΠΗ, br.d5 CH); 7.38δ ΠΗ, t? CH); 7.155 (1H, br · dd, CH), 4.68δ (2H.s, CH2); 4.40-4.205 (4H, 2xq, 2xCH2); 1.395 ΠΗ, t, CH3); 1.30δ (1H? T, CH3). Illustrative Example 1 4: 3 -Carboxymethanone-ethyl ceramate

〇 To a mixed solution of Example 1 i (0.397 g) in methanol (7 ml) and water (3 ml) was added potassium carbonate (0.217 g). The mixture confers 1 8 84385 -74- 200404000 at 2 0 t

After (66) hours, the methanol was evaporated in vacuo. The pH of the resulting solution was adjusted to about 1 by adding 2 M hydrogen. Acid water solution and the mixture was extracted with ethyl acetate (3 x 15 ml). The combined organic extracts were washed with brine (10 ml), dried over magnesium sulfate and the solvent was evaporated in vacuo to give the title compound (0.3 29 g) as a white solid. LC / MS: Rt = 2.81 minutes, m / z 225 [ΜΗ +]. 1 5 = X3 -methanefluorenylamino-benzyl) acetic acid

νΗϊΤΤ〇η was stirred in a solution of 3-aminobenzylacetic acid (3.2 g) and sodium carbonate (5.44 g) in deionized water (36 g per liter), and methanesulfonyl chloride (1.7 ml) was added. After mixing at 8 C and stirring for 4 hours, it was cooled to room temperature, acidified to pH with concentrated hydrochloric acid, and left in a refrigerator at 4 ° C overnight. The precipitated solid was filtered, and the combined filtrate and washings were evaporated to dryness with vacuum and water. The resulting residue was dissolved in heat, it, T, and it was left to recrystallize in a refrigerator at 4 ° C overnight. The crystals were filtered ′, washed with small | U 里 rinsing water and dried under vacuum to obtain the title compound (0.41 g) as colorless crystals. C / 1VIS · R 2. 00 minutes, m / z 228 [ΜΗ ·], m / z 247 [ΜΝΗ4 +]. Description—Propanyl-benzyl) acetic acid

Cyclobiyl 5802, 10; -M-pyridinone (Journal of Organic Chemistry (1 99 3), 58 (21), 16 · 0 g) and N-bromobutanediimide (1 7 · 8g) in four gasified carbon 84385 -75-200404000

(67) (100 ml) of the stirred suspension was slowly heated to reflux with an i 50 watt electric lamp. After refluxing for 2 hours, the solution was cooled in ice water to obtain a solid, which was filtered and washed with carbon tetracarbonate (10 ml). The filtrate and washings were combined and evaporated to obtain a yellow oil 'which was fractionated using a Vigreux column. The fractions distilled at 0.1 mmHg and 1 15-1 30 ° C were collected and dissolved in anhydrous N, N-dimethylformamide (20 ml). The solution was added dropwise to a stirred suspension of sodium cyanide (1.96 g) in anhydrous N, N-dimethylfamidamine (40 ml) for 10 hours. Stirring was maintained for an additional 1 hour, followed by stirring at room temperature for 2 hours. The mixture was poured into ice (140 g) and extracted with ethyl acetate (3 x 60 mL). The combined extracts were dried (MgS04) and evaporated to give a brown oil, which was then treated with 50% aqueous alcohol containing potassium hydroxide (3.66 g). The mixture was heated at reflux for 5 hours and then cooled, washed with aerobic (2 X 50 ml) and acidified to pH 1 with 5 M hydrogen acid (about 15 ml). The resulting yellow oil was extracted with ethyl acetate (2 X 75 ml) and the combined extracts were washed with water (3 X 15 liters) and dried (MgSCU) and the solvent was evaporated to obtain a yellow oil. This oil was extracted with hot petroleum ether (b.P. 60-80 ° C, 4x50 ml) and the combined extracts were evaporated to give a gelatinous oil. It was then combined with the residue remaining during extraction, filtered in 10% ethyl acetate / diethyl ether (200 mL), and the resulting solution was filtered, and extracted with water (3 x 20 mL); ) Get oil. This oil was dissolved by stone gum (1000 g), and the solution was isolated, and the appropriate dissolved fractions were combined and evaporated to obtain a light yellow oil, which was distilled in vacuum. The fractions were collected at 170 ° C and ^ mmHg to obtain the title of dark milky solid (15 g). Analyze the measured values. , 7. .44%: 11,60. % — (· Knife analysis &amp; ten different values C, 7 0 · 6%; Η, 5 · 9 2%. 84385 -76- 200404000

(68) 17: [f 2S) -4- (♦-2 -Amino group &quot; I amino group

OlJL tributyl ester

N / h ...

BocHN

A solution of Cl F (2-morpholinylmethyl) -carbamic acid dimethyl [[CAS 1 86202-57_3] (0.26 g) in dichloromethane (5 ml) with triethylamine (0.167 ml) and 3-Chloro-4-fluorofluorenyl bromide (0.27 g). After 18 hours of searching, the mixture was directly applied to SCX ion-exchange g (10 g) and purified by dissolving in methanol and then dissolving with 10% 0.888 ammonia / methanol. The main solution was evaporated in vacuo to obtain a colorless gum (37 g). LC-MS: Rt = 2.46 minutes, mass spectrum m / z 359 [ΜΗ +]. Illustrative Example 1 8 \ ΛΑΛ1Λζ ^ = ^^-^) morpho-2-ylmethyl 1 methylamine

29 (〇07 5 5g) of 5: 1 alcohol / water (7ml) and potassium carbonate, hydrazine, and eight substances were stirred at room temperature under nitrogen for 5 hours. 'Stand 6 5 (0.27g) mixed The paint was obtained and the residue was redissolved in water (6 ml). Water soluble / j, hour. Zhengenhe &quot; and / N also x 3 ml) extraction, using a hydrophobic melt box separation solution with dichloromethane (douqidan. Phase evaporates the solvent to obtain a dagger (0 · 0507 phase. Merged Zhishu 84385 -77- 200404000 (69) Description of the invention (cont. Gram). LCMS m / z 2 8 9 [ΜΗ +]. Illustrative example 20: 4- (2-{「(2S) -4- (3, 4-dichlorofluorenyl) morpholin-2-ylfluorenyl 1 amino fluorenyl 丨 ethyl) tert-butyl benzoate

Prepared in a manner similar to Example 18 using Illustrative Example 5 and tert-butyl 4- (2-carboxyethyl) benzoate. LCMS m / z 5 07 [MH +]. Illustrative Example 21: 4- (2-{((2S) -4- (3,4-diazamidino) morpholin-2-ylfluorenyl 1 aminomethylmethyl-1-ethyl) benzyl acid Salt

To Description Example 20 (0.29 g), a 4.0 M solution of HC1 in 1,4-dihumane (10 ml) was added. After the mixture was stirred at 20 ° C for 3 hours, the solvent was removed in vacuo to obtain the title compound as a brown solid. LCMS m / z 45 1 [MH +]. Illustrative example 22: 3- (4-Amino-benzyl) -Nf (2 S) -4- (3,4-dichlorofluorenyl) morpholin-2 -ylmethyl 1-propanol Yuean 84385- 78- 200404000

(70) 〇

h2n &quot; αΐ was prepared in a manner similar to that described in Example 18 using Illustrative Example 5 and 3- (4-aminophenyl) propionic acid. LCMS m / z 422 [ΜΗ +]. Illustrative Example 23: 3-II-Amino-benzyl) -N-"(2S) -4- (3,4-diazamidino) morpholine-2-ylmethyl1propanamide

Prepared in a similar manner as described in Example 18 using Illustrative Example 5 and 3- (3-aminophenyl) propionic acid. LCMS m / z 422 [MH +]. Illustrative Example 24: 4-({((2S) -4- (3,4-diazafluorenyl) morpholin-2-ylfluorenyl1aminofluorenyl group))

Prepared in a similar manner to that described in Example 18 using Illustrative Example 5 and 4- (methoxycarbonyl) phenylacetic acid. 84385 -79- 200404000 (71) Fibrils · LCMS m / z 45 1 [MH +]. Illustrative Example 25: Tertiary butyl azepine-co-carbonyl) phenyl 1-methyl acetate.

N, N-dimethylformamide in 3-methoxycarbonylfluorenyl-phenylarsinic acid (2.0 g) (for preparation see Journal of Chemical Research, Synopses (2000), (6), 282-283) ( 30 ml) of the stirring solution was added tert-butyl carbamic acid (1.338), 1 · (3-dimethylaminopropyl) -3 -ethylcarbodiimide hydrochloride Acid salt (3.19 g), hydroxybenzotriazole (1.96 g) and N, N-diisopropylethylamine (1.96 ml). After the mixture was stirred at 20 ° C under nitrogen for 42 hours, it was diluted with dichloromethane (250 ml). The mixture was washed with a dilute aqueous sodium bicarbonate solution (200 ml) and a common salt solution (2 x 200 ml), and the organic phase was passed through a box for incorporation into a hydrophobic melt. The organic solution was then applied in equal amounts to a 10 sulfonic acid ion exchange cartridge (10 X 10 g, Iso lute SCX, prewashed with methanol) and the cartridge was dissolved with methanol (X 3). The combined eluates were evaporated in vacuo to obtain the title compound as a colorless liquid. 0 LCMS m / z 3 09 [MH +] 0 m., Example 26: 3- (N, -tertiary) cage] acetic acid

2 M sodium hydroxide water was added for 75 hours. In the mixture Illustrative Example 2 5 (5.01 g) in methanol (9 ml) solution (9.1 ml) and the mixture was stirred at room temperature 5 84385 -80- 200404000 (72)

fJMM Add 2 M H C 1 aqueous solution (9.1 ml) and then add 2 μ sodium hydroxide aqueous solution (about 1 ml) to adjust the pH of the solution to 7. The solvent was evaporated in vacuo to give the title compound (4.766 g) as a colorless glassy substance in a mixture with an inorganic acid salt. LCMS m / z 295 [ΜΗ +].呑 儿 明 例 2 7 · _N "3-(_ {J (2.S)? £ ^ 3,4-difluorooctyl)? Methyl) benzoic acid

A solid-like method was prepared using 8 and Illustrative Examples 2-6. LCMS m / z 519 [MH +] 〇 Illustrative Example 2_8 difluorofluorenyl) morpholine-2 · ylsulfonium 1-2- (3-hydrazinocarbonyl-benzyl) ethyl

To OM11 (2.05 g) were added 4.0 M HC1 in 1,4-diuridine solution (35 ml) and anhydrous methanol (10 ml). After the mixture was stirred under nitrogen and room temperature for 17 hours, the vacuum strip was applied to> cereal. The residue was re-dissolved in methanol and the solution was applied to the 8 luteinate ions in equal amounts (10 × 丨 〇g, 〖s〇 丨 utesc X, prewashed with methanol) and the cartridge was dissolved with methanol (x3) Then it was dissolved in methanol (X 2) with 0% 08.8% ammonia. Evaporate the solvent from the main dissolve in vacuo to obtain orange 84385 -81-200404000

Foam of the title compound (1.24 grams). LCMS m / z 419 [ΜΗ +]. Illustrative Example 29: Dichlorofluorenyl) morpholin-2-ylmethyl 1,2,2,2-trifluoro-N-fluorenylacetamidamine

Instruction Example 2 (0.0755 g) of dichloromethane (5 ml) solution was sealed in eight 1116 (: 111 ^ tube (box with integrated solvent at the bottom). Add BEMP resin (Polymer Binding 2-3rd Butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphine) (0.65 g, @ 2.3mmole / g) followed by the addition of formazan Base iodine (0.1 6 8 ml). The mixture was stirred on a flat bed shaker at room temperature. The mixture was poured into a sulfonic acid ion exchange cassette (10 g, Isolute SCX, pre-washed with methanol) and the cassette was dissolved with methanol. Then it was dissolved in a methanol solution of 10% 0.88 0 ammonia. The solvent was removed in vacuo from the first main dissolution fraction. The residue was purified by dissolving in dichloromethane and the solution was applied to a silica solid phase extraction cartridge ( 10 g, VarianBondelut, pre-washed with dichloromethane), and sequentially dissolved with methane, chloroform, ether, ethyl acetate, acetone, acetonitrile, and methanol. The solvent was evaporated from the ether fraction to obtain the title compound ( 0.0755 g). LCMS m / z 3 8 5 [MH +]. Examples

Synthesis method A 84385 -82- 200404000 (74) Example 1 8

To a stirred solution of N, N-dimethylformamide (6 ml) in Instruction Example 1 4 (0.328 g) was added N, N-dimethylformamide (5 ml) in Instruction Example 5 (0.366 g) Solution. To the mixture was added N, N of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.408 g) and 1-hydroxybenzotriazole (0.234 g). -A solution of dimethylformamide (9 ml) followed by the addition of N, N-diisopropylethylamine (0.463 ml). After the mixture was stirred at 22 ° C for 18.5 hours, it was diluted with methanol (about 5 ml). The mixture was applied to a 4 X 10 g S C X ion-exchange cartridge (preconditioned with methanol). The cartridge was dissolved with methanol, followed by a methanol solution of 10% 0.88 0 ammonia. The first fractions of ammonia were combined and the solvent was evaporated in vacuo. The residue was again subjected to Biotag flash chromatography on silica gel, and was dissolved in 400: 8: 1 dichloromethane / ethanol / 0.88 0 ammonia solution. The desired fractions were combined and the solvent was evaporated in vacuo to give the title compound as a light brown gum (0.508 g). LC / MS: Rt = 2.9 (T minutes, m / z 481, 4 8 3 [MH +]. Method A Another procedure example 38: 3- (4-Azobenzyldiafluorofluorenyl) morpholine-2- Propyl amidinyl 1 propylamine; compounds containing trifluoroacetic acid 84385 -83-(75) (75) 200404000

To 3- (4-Gasyl) propionic acid g) was added a portion (0.25 mK) of a solution of dichloromethane (5.0 ml) in Example 3 (1.292 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 give the compound (0.0187 g). 1 ^ (3-] \ / 18: See 2.03 minutes, 111/2 394 [1 ^ 11 +].

Synthesis Method B Example 2 3 (Mutualization)

To a stirred solution of (0.50 38 g) in methanol (10 ml) was added 2M aqueous sodium hydroxide solution (105 ml) and water (10 ml). The mixture was allowed to fall at 22 ° C for 14 hours and left to stand for 18 hours. 2M aqueous hydrogen acid solution (1.05 ml) was added and the mixture was applied to a 2 X 10 g SCX ion-exchange cartridge (preconditioned with methanol). g Dissolve in methanol followed by 5% triethylamine in methanol. The first fractions of diethylamine were combined and the solvent was evaporated in vacuo to obtain a brown gum 84385 • 84-(76) 200404000 ___: page, the standard _. Title. Compound _ (0 · 4 5 3 g). LC / MS: Rt = 2.49 minutes, m / z 4 5 3, 4 5 5 [MH +]. Example 14 (Mutual

Η — &quot; αΐ 」" column 2 3 (0 · 148 g) of Ν, Ν-dimethylformamide (1 ml) solution was added to 1- (3-dimethylaminopropyl) -3 -ethyl Stirred solution of N, N • dimethylhydrazine (1 liter) of N-N-dimethylbenzylamine (0.081 g) and 1-hydroxybenzotriazole (0.047 g) at 20 ° C in. Cyclopropylamine (0.98 ml) was added followed by N, N-diisopropylethylamine (0.0923 ml) and the mixture was stirred at 20 ° C for 20 hours. The mixture was diluted with methanol (approximately 2 ml) and applied to a 10 · g § C X ion exchange cartridge (preconditioned with methanol). The cartridge was dissolved with methanol followed by 10% 0. 880 ammonia solution in methanol. The first eluent of ammonia was evaporated in vacuo and the residue was purified by flash chromatography on silica gel using Biotage ™, and then dissolved in 200 • 8 · 1 digasmethane / ethanol / 0.880 ammonia solution. The desired fractions were combined and the solvent was removed in vacuo to obtain a residue, which was purified on a silica gel by BiotageTM flash chromatography and eluted with 5% methanol / ethyl acetate. The desired fractions were combined and the solvent was vacuumed to obtain the title compound (f0 105). LC / MS: RP 2.53 minutes' m / z 492,494 [MH +].

Synthesis Method C Example 2 4 84385 200404000 (77)

To a stirred solution of Example 2 7 (0.0491 g) in dichloromethane (5 ml) and acetonitrile (1 ml) at 20 ° C was added N, N-diisopropylethylamine (0.05 16 ml) and pinane Sulfonium chloride (0.0 0 8 4 ml). The mixture was stirred at 20 ° C for 2 6 hours, during which time another part of sulfanesulfonyl chloride (0.003 1 ml) was added. The mixture was diluted with methanol (approximately 2 mL) and applied to a 5 g SCX ion exchange cartridge (preconditioned with methanol). The cartridge was lysed with methanol and then with 10% 0.888 ammonia solution in methanol. The first eluting fraction of ammonia was evaporated in vacuo and the residue was purified on a silica gel by BiotageTM flash chromatography and dissolved in 600: 8: 1 to 200: 8: 1 dichloromethane / ethanol / 0.8 8 0 ammonia solution. The desired fractions were combined and the solvent was removed in vacuo to give the title compound (0.0087 g) as pale brown glassy. LC / MS: Rt = 2.55 minutes, m / z 5 02,504 [MH +]. Synthesis Method D Example 5

Stir in N, N-dimethylformamide (5 ml) of 3-carboxymethyl-phenylbenzoic acid methyl ester (0.2 14 g) (Journal of Medical Chemistry, 1999, 42 (14), 2621-2632) To the mixture was added 1- (3-dimethylaminopropyl) -3 -ethylcarbodiazepine 84385 -86- (78) (78) 200404000 noodle_fresh: amine hydrochloride (0 · 2 8 8 g ) And 1-Benzyltriazole (0.162 g) followed by the addition of a solution of N, N-dimethylformamide (5 ml) in Example 8 (0.242 g). To the mixture was added N, N-diisopropylethylamine (0.348 ml), followed by stirring at 22 ° C for 18 hours. The mixture was also applied to a 2 X 10 g s C X ion exchange cassette (preconditioned with methanol). The box was dissolved with methanol and 10% 0.888 ammonia solution in methanol. The first fractions of ammonia were combined and the solvent was evaporated in vacuo. The residue was purified by flash chromatography on Shi Xijiao with B i 0 t ag e τ M, and was dissolved in 2000: 8: 1 two-gas methane / ethanol / 0.8 80 ammonia solution. The desired fractions were combined and the solvent was removed in vacuo to give the title compound as a cream-colored solid (0.31 g). LC / MS: Rt = 2.36 minutes, m / z 419 [ΜΗ +]. Synthesis Method E Example 7 (Mutualization)

To a stirred solution of methanol (5 ml) in Example 5 (0.2988 g) was added 2M aqueous sodium hydroxide solution (0.71 ml). After the mixture was stirred at 22 ° C for 6 6 hours, 2 M aqueous hydrogen acid solution (0.71 ml) was added. The mixture was applied to a 2 × 10 g SCX ion exchange cartridge (preconditioned with methanol). The cartridge was dissolved in methanol followed by 5% triethylamine in methanol. The first fractions of triethylamine were combined and the solvent was evaporated in vacuo to obtain the yellow compound (0.353 g). LC / MS: Rt = 2.15 minutes, m / z 405 [MH +]. 84385 -87- 200404000 (79) Example 1 ο

Example 7 (0.057 g) of a stirred solution of Ν, Ν-dimethylformamide (1 ml) was added with 1-(3-dimethylaminopropyl) -3 -ethylcarbodiimide hydrochloride Acid salt (0.0325 g) and 1-hydroxybenzotriazole (0.018 g). N, N-diisopropylethylamine (0.039 ml) was added followed by a 2 M solution of ethylamine in tetrahydrofuran (0.1 40 ml), and the mixture was stirred at 22 ° C for 18 hours. The mixture was applied to a 5 g SCX ion exchange cartridge (preconditioned with methanol). The cartridge was dissolved with methanol and then with 10% 0.888 ammonia solution in methanol. The first dissociated fraction of ammonia was evaporated under vacuum and the residue was purified on a silica gel using BiotageTM flash chromatography and dissolved in a 15: 8: 1 dichloromethane / ethanol / 0.88 ammonia solution. The required fractions were combined and the solvent was evaporated in vacuo to give the title compound (0.03 79 g) as a white solid. LC / MS: Rt = 2.14 minutes, m / z 432 [MH +]. Synthesis method F Example 2 2

84385 -88- 200404000

(80) To a stirred solution of lotus dJOL 丄 (0.05 0 g) in acetonitrile (1 ml) was added potassium carbonate (0.02 5 g). To the mixture was added (4-gas-phenoxy) _acetamidine (0.03 7 g) (Chem · Phairm · Bull. 1 9 8 8, 36 (11), 4426-34) and the mixture was at 20 ° C Stir for 3 hours. The solvent was evaporated in vacuo and the residue was partitioned between water (2 mL) and dichloromethane (2 mL). The phase was separated using a hydrophobic material and the organic phase was purified by flash chromatography on BiotageTMi with Shijiao, and dissolved in 300 × 8: 1 dichloromethane / ethanol / 0.88 ammonia solution. The desired fractions were combined and the solvent was evaporated in vacuo to give a white solid iron compound (0.02 86 1). LC / MS: Rt = 2.90 minutes, m / z 443, 445 [MH +]. Method Η Example 37-1: Fluorofluorenyl) morpholine-2 -ylmethyl 1 :: 1- 『3, _ (5: methyl-1—1_23,41) Amidine

Lan Ming Example 28 (0.20 g) was added with triethyl orthoacetate (1.5 ml) and heated in a reaction vial '' at 160 ° C for 18 hours. After cooling, after evaporation of the volatiles under a stream of nitrogen, the residue was redissolved in methanol and applied to sulfonic acid ion-exchange S (10 g IsoluteSCX, strip pre-washed with methanol). g Dissolved in methanol followed by dissolution in methanol with 10% 0.888 ammonia, and the main dissolving fraction was concentrated in vacuo to obtain the title compound 1 n) as a colorless gum. LCMS: Rt 2.12 minutes, m / z 443 [MH +]. 84385 -89-200404000 (81) 卺 Ming material continued

Method I Example 39 · N _ "(2S) -4-n, 4-difluorofluorene" morpholin-2-ylfluorenyl 1-2- (3- [1,3,41 Molybdenyl) acetamide, compounds containing acetic acid

Instruction Example 2 8 (0.20 g) was added with triethyl orthoacetate (1.5 ml) and heated in a "reaction vial" at 160 ° C for 18 hours. After cooling, the volatiles were evaporated under a nitrogen stream, and the residue was redissolved. In methanol and applied to a sulfonic acid ion exchange cartridge (10 g Isolute SCX, pre-washed with methanol). The cartridge was dissolved in methanol followed by 10% 0.8 8 0 ammonia in methanol, and the main dissolved fractions were concentrated in vacuo. The residue Further purification by mass-directed preparative HPLC gave the title compound (0-021 g) as a colorless gum after removing the solvent in vacuo. LCMS: Rt 2.05 min, m / z 429 [MH +].

Method J Example 41: N-"(2S) -4- (3,4-difluorofluorenyl) morpholin-2-ylfluorenyl 2-" 3- (5-fluorenyl-4H- "1,2 , 41triazol-3-yl) benzyl 1acetamide, compounds containing acetic acid

84385 -90- 200404000 (82) Prepare a solution of sodium hydroxide (0 _ 0 9 3 3) in anhydrous methanol (2.9 1 ml) and add a part of the solution (0.5 9 6 ml) to acetimidate hydrogen acid In salt (0.0 5 9 g). After the mixture was shaken for 2 minutes and allowed to stand for another 5 minutes, the clear solution on the mixture was moved by a syringe into a "reaction vial" fed with Instruction Example 28 (0.20 g). The mixture was heated at 90 ° C for 1 hour, then cooled to room temperature and concentrated under a stream of nitrogen. The residue was dissolved in 5% methanol / chloroform and dichloromethane and applied to a solid phase extraction cartridge (10 g, Varian Bondelut, pre-washed with dichloromethane) and dissolved in 5% methanol / dichloromethane. . The solvent was evaporated in vacuo from the desired fractions and the residue was purified by mass-directed preparative HPLC and the solvent was removed in vacuo to give the title compound (0.020 g) as a colorless gum. 1 ^^ 43: 1 ^ 2.01 minutes, 111/2 442 [1 ^ 11 +]. Example 42: N-K2S) -4- (3,4-difluorofluorenyl) morpholin-2-ylmethylb- 2- (3-dimethylaminesulfonyl-benzyl) acetamidamine

N &quot; αΐ added to (4-dimethylaminesulfonyl-phenyl) acetic acid (0.049 g) (containing a certain amount of 3-dimethylaminesulfonylphenylacetic acid isomer) 3 (1.1 g) of a solution (0.25 ml) of dioxane (4.0 ml) and dichloromethane was evaporated. After adding N-fluorenylpyrrolidone (1 drop) to the mixture, it was heated in a microwave oven (full power for 4 minutes) and then cooled. The samples were purified by mass-oriented preparative HPLC and the solvent was removed under a stream of nitrogen. Isomeric and racemic mixture 84385 -91-200404000 (83) Description of the invention The residue of the continuation was separated on a Chiralpak AD preparative HPLC column (25 x 2 cm) and dissolved in 40% ethanol in n-heptane. The flow rate is 15 ml / min and the detection wavelength is 2 1 5 nm. Fractions containing the desired product (the first eluate) were combined and evaporated to give the title compound (0.0017 g). 1 ^ "8: Play 2.70 minutes, 111 / ^ 5 00 [" 1 * 1 +]. Example 5 1: N-"(2 S) -4- (3,4-Digas-fluorenyl) morpholin-2-ylmethylb 3- (4-propanamido-benzyl) propanil 〇

To a solution of 2 (0.10 g) in anhydrous digas methane (8 ml) was added N, N · diisopropylethylamine (0.062 ml), followed by propane gas (0.0 3 2 9 g). ). The mixture was stirred at room temperature for 2 2 hours. The mixture was poured into a sulfonic acid ion exchange cartridge (1 g, Isolute SCX, pre-washed with methanol) and the cartridge was dissolved with methanol and then with 10% 0.88 ammonium alcohol. The solvent was evaporated from the main fraction in vacuo to obtain the title compound (0.093 6 g). LCMS: Rt 2.45 minutes, m / z 478 [MH +]. Example 8 2: N-"4-(3,4-Diarginofluorenyl) morpholine-2 -ylfluorenyl 1-2-(3-fluorenylthio-benzyl) acetamidine 84385 -92- 200404000 (84)

(0.312 g), 1-hydroxybenzotriazole (0.199 g), N, N-diisopropylethylamine (0.387 ml), and 1- (3-dimethylaminopropyl) -3- A mixture of ethyl monoimide hydrochloride (0.346 g) was stirred in N, N-dimethylformamide (5 liters) at 20 ° C for 7 hours and then left to stand for 18 hours. The volatiles were removed in vacuo and the residue was redissolved in methanol. The mixture was likewise applied directly to two% acid ion exchange cartridges (2 x 10 g, IsoluteScx, pre-washed with methanol) and E was dissolved in methanol followed by 〇0 / 〇〇 8 〇 ammonia The methanol was dissolved. The combined major fractions were evaporated in vacuo. The residue was again dissolved in chloroform and the solution was applied to two silica solid-phase extraction cartridges (2 x g, Varian BondeUt, prewashed with digas methane) in the same manner, with digas methane, chloroform, ether, and ethyl acetate. , Acetone, acetonitrile and methanol are dissolved in sequence. The solvent was removed from the combined fractions of C-steel in vacuo to obtain the title hydrazone (η 122 g), LCMS: Rt 2.84 minutes, m / z 439 [ΜΗ +].

R

84385 '93-200404000 (85) «ill Example number Synthesis method R1 R2 Position (*) Stereochemical calculation of molecular weight minimum mass § Observed molecular weight of the structure (LC / MS) [M + Hf, unless otherwise stated. 1 D 〇EL 3,4-bis-CIPh S 461.392 461 ^ II 2 D HV 〇0 3,4-bis-FPli s 402.445 403 3 D 〇c L 3,4-bis-FPh s 428.483 429 4 D 〇0 \ 3,4-di-CIPh s 435.354 435 5 D 〇3,4-di-FPh s 418.444 419 _ 6 D H2N, 〆, 0) \ 3,4-di-FPh s 439.485 440, 7 * D + EV 〇3,4-bis-FPh s 404.41 405 8 D + E 〇3,4-bis-FPh s 417.46 418 -94- 84385 200404000 (86) Example number Synthesis method R1 R2 Position (*) calculation Observed molecular weight (LC / MS) [M + Hf, unless otherwise specified 9 D + E 〇3,4_ di-FPh S 431.487 432 10 D + E 〇3,4-di-FPh s 431.487 432 I 11 D + EH CH3 0 3,4-di-FPh 445.514 446 12 D + E? Ha ch3 0 3,4_ di-FPh s 459.541 460 29 D &quot; vCXX 0 H 3-CI, 4- FPh s 469.966 470 7 cases of ammonium salt of ammonium 3 Table 2

R 〇

N——Η 〇 N,

R 84385 -95-200404000 87) r \ The case number is the formula R1 R2 The stereochemistry at position (*) m The observed molecular weight of the smallest mass foreign matter (LC / MS) [M + H] +, unless otherwise specified Description 3 1

A

NH X

3,4-bis-CIPh

S 466.368 466 4 1

B

3,4-bis-CIPh

S 492.406 492 5 1

A HN Yo

3,4-bis-CIPh

S 466.368 466 6 1

B o: C3

NH

3,4-bis-CIPh

S 480.395 480 7 1

A

〇 3,4-Di-CIPh

S 520.46 520 8 1

A

〇 3,4-Di-CIPh

S 481.38 481 9 1

A

3,4-bis-CIPh

S 434.326 434 20

N 〇 2 H

3,4-bis-CIPh

S 488.393 488 21

A σ 3,4-bis-CIPh

S 452.341 452: 〇 22

F cl

3,4-bis-CIPh

S 443.761 443 84385 -96- 200404000 (88) Example number Synthesis method R1 R2 Stereochemistry of position (*) Calculated molecular weight Observed molecular weight of the smallest mass isomer (LC / MS) [M + Hf, unless otherwise specified Instructions • 23 * Β HO ^ /) 3,4-bis-CIPh S 453.32 453 24 C 3,4-bis-CIPh S 502.42 502 25 Β 3,4-bis-CIPh s 466.368 466 26 A 3 / 3,4 -Di-CIPh s 427.306 427 27 ** G α 3,4-Di-CIPh s 424.33 424 * Example 2 3 is triethylammonium salt, * * Example 2 7 is Table 3 〇1 ΗDihydrochloride • * Example number Synthesis method R1 R2 Observed molecular weight (LC / MS) of the smallest molecular weight isomers calculated by Richtek chemical properties at position (*) ^ [M + Hf, unless otherwise specified 28 D 3,4-Di-FPh S 467.539 468 84385 -97- 200404000 (89) Table 4 Description of the invention Continuation page Example structure observation only [mfT] • Example structure observation [Mtr] 30 0: χ ^ 459 31 Η Q; xy 454 32 〇ό 421 33 ΗίχΛΐΝ ., 〇HF. H C] w 454 34 CXAr ... [. 〔Ya ′ ″ ′ ch3 C 丨 407 35 c, xyN Cr 471 36 〇Λ,. H s ^ Hi Vx 407 37 ^ XXAr ya.] R SJ 443 38 x ^ x] Ten: xy 441 39 〇 ^ V .. .〇429 84385 -98-(90) 200404000 84385 Description of the Invention Continued 1 _Ji Yi Qian: Zhong Shi Qie No .; ΐ 辕 §_ 释 :: Examination) Qi 40 〇Η0 ^ τΓ ^ ι 〇H υ hicx : 3 ;; xy 437 41 / s &lt; CLv ah.] VNH chi ° ^; xy 442 42 c, xy cr 500 43 'Again, ah, ah, 〇 = S = 0 ”person x / 482 44 0 ^ // 0 kXAq. 〔Sp F 421 45 〇 = S = 0 480 46 HTX) a ^ h again〕 400 47 H = o H H W 468 48 Sr 421 49 A L: xy 478 -99- 200404000 (91)

50 Sa; 439 51 JX ^ 'O IXj ^ 478 52 η3〇ανχΧλν ^^ H, again] 450 53 p ^ V, 〇 1 1 xr &quot; \ 〇H Cl, 464 54 486 55 464 56:} sbuq. &quot; a 421 57, 〆, .. '〇H IX ^ 464 58 &quot; a 421 59 ςτν..〇M &gt; ci〇H &quot; a: 500 60 ^ Vxu ^ o, H XJ ° ^ y 437 61 〇 rV .... [:] ch3! &gt;. W Cl 500 84385 -100- 200404000

84385 -101-200404000 (93) ^ βΙΙΗΙΙ 74 441 75 H) s, ^ A, '[. ] Y 452 76 CI 447 77 H, /, XXAr .... [. ] V 452 78 ^^^ 1 X Ν &quot; α: 485 79 0 464 80 Φλ? 〇 CI 443 81 hAh ^^ V '. [. ] 400 82 h3c, s ^ C ^ An ^^ 'Η υ c, xy Cl 439 83 hA ^^ v .....' 〔. ] Xr1 418 84 H3C // 0 564 85 JAV 〔. 〕 450 84385 -102- 200404000 (94) Fa said I said 啕 Weng: buy, 86 σ ° 々 .. '〇 &quot; αΐ 409 87 H, KXXV.' [. 〔416 88〕〕: xyN 486 89 Dagger 'χχν'. [. ] C, ^ y 422 90 439 Synthesis Method A was used to prepare Example 3 5, 4 4, 4 6, 4, 8, 5, 2, 5, 4, 5, 6, 58, 62, 67, 68, 70, 75, 77, 81, 85, 86, 87, 88, 89, 78, 80, 60, 66, and 82 ° Synthesis method A (another procedure) was used to prepare Example 3 0, 3 2, 3 4, 3 6, 11, 74, 76, 38 and 42 ° Synthesis Method B was used to prepare Examples 6 5, 7 9, 7 3, 6 9 and 71. Synthesis method C was used to prepare Examples 4, 5, 6, 3, 5, 9, 6, 1, 7, 7, 4 and 43. Synthesis Method D was used to prepare Examples 50, 64, 31, 33, 83, and 90. Synthesis method E was used to prepare Example 40. 84385 -103- 200404000

(95) Synthesis method G was used to prepare Examples 49, 55, 57, 51, and 53. Synthesis method Η was used to prepare Examples 37. Synthesis method I was used to prepare Example 39. Synthesis method J was used to prepare Example 41. R1 \ Η Table 5

R2 Description example number R1 R2 Position (*) Stereochemistry 10 tBuOCONHv ^^^ OCh ^ CO- 3,4-di-CIPh S 12 Η 3-CI, 4-F-Ph s 17 tBuOCO- 3-CI, 4-F-Ph s Table 6 Description example number structure 13 Et02C \ ^^ / 0CH2C02Et 14 Et〇2C \ ^^ CH2C〇2H u 15 h ^ nXW0H 0 H 16 84385 -104- 200404000 (96) Table 7

Description Example No. Structure 18 H3C, N ^ V〇, CI 20 J ^ α: 21 η ° ° ι χχ 22 Chiral 23 f νΌ NH? Chiral 24 ~ ^ ΛΤ] 25 26 25Λχτ 27 M :: M.义 〆 丫 ChtiM (XX Description of the Invention, Continued 84385 -105 200404000 (97) The post of the aunt moth: Explanation example number structure 28 H, SyCLV,. [.] _ Sa: 29 &gt; Λγ〇 &quot; αΐ 84385 106-

Claims (1)

200404000 Scope of patent application 1. A compound of formula (I), R (1) wherein: R1 represents a substituted or unsubstituted aryl group; X represents -0- or a chemical bond; Y represents-(CRnaRnb) n-; Rna and Rnb are each independently hydrogen or Ci-6 alkyl; η is An integer of 1 to 5; R2 represents an unsubstituted or substituted aryl group or an unsubstituted or substituted heteroaryl group; R3 represents hydrogen or a Cu alkyl group; R1G represents hydrogen or a Ci.6 alkyl group; and a salt thereof And solvates; the limitation is that the following compounds are excluded: 2- (4-chlorobenzyl) -N- {[4- (3,4-difluorofluorenyl) morpholin-2-yl] methyl} acetamidine ; N-{[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} -2-phenylacetamidamine; N-{[4-(3,4-dichlorobenzyl ) Morpholine-2 -yl] fluorenyl}-2 -phenoxyacetamidamine; 84385 200404000 N-{[4- (3,4-dioxofluorenyl) morpholin-2-yl] methyl} -2- (4-methoxyphenyl) acetamidamine; 2- (3-chlorophenyl) -N-{[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl } Ethylamine; N- {[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methylb 2- [4- (methylthio) phenyl] ethanamine; N -{[4- (3,4-dichlorofluorenyl) morpholin-2-yl] fluorenyl 2- [4- (difluorenylamino) phenyl] acetamidinium compound, containing Acid (1: 1); N-{[4- (3,4-diaminofluorenyl) morpholin-2-yl] methyl} -2- {4-[(dimethylamino) sulfofluorenyl] Phenyl} acetamide compound containing formic acid (1: 1); N-{[4- (3,4-dichloroethenyl) morphin-2-yl] methyl} -2- [4- (form Keystone stilbene) phenyl] acetamidine compound containing formic acid (1: 1); N-{[4- (3,4-dichloro + yl) morpholin-2-yl] methyl} -2- ( 3-fluorophenyl) acetoamine; 2- [3,5-bis (trifluorofluorenyl) phenyl]-&gt; ^-{"4- (3,4-difluorofluorenyl) morpholine-2 -Yl] fluorenyl} ethenylamine; 2- (2-chlorophenyl) · N-{[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} ethenamide; N-{[4- (3,4-dichloroethenyl) morpholin-2-yl] fluorenyl} -2- (4-fluoro-2-methylphenyl) acetamidine; Ν · {[4 -(3,4-dichloromethyl) morphin-2-yl] fluorenyl} -2- (3,4-difluorophenyl) acetamidamine; 4- [2-({[4- (3 , 4-Difluorofluorenyl) morphin-2-yl] methyl} amino) -2 -oxoethyl] fluorenamine; 84385 -2-200404000: round ___ page N-{[4- (3,4-Difluorofluorenyl) morpholin-2-yl] methyl} -2- [4- (trifluoromethyl) phenyl] acetamidamine; N-{[4- (3,4- Diaminofluorenyl) morpholin-2-yl] methyl} -2- (4-methylphenylacetamidine ; N-{[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} -2- (2,4-dichlorophenyl) acetamidine; N- {[4- (3,4-dichlorofluorenyl) morpholin-2-yl] fluorenyl} -2- (4-fluorobenzyl) acetamidine; N-{[4- (3,4-dichlorofluorenyl) Morpholin-2-yl] methyl} -2- (3,4-dichlorophenyl) acetamidamine; N-{[4- (3,4-dichlorofluorenyl) morpholin-2-yl] Methyl} -2- (2,5-dichlorophenyl) ethenamide; N-{[4- (3,4-dichlorofluorenyl) morphin-2-yl] fluorenyl} -2- ( 2,6-difluorobenzyl) acetamidamine; 2- (4-Gaphenyl) -N-{[4- (2,3-dichlorofluorenyl) morpholin-2-yl] methyl} ethyl Amidotrifluoroacetate; 2- [3- (ethylamidoamino) phenyl] -N-{[4- (3,4-difluoroamido) morpholine-2-yl] methyl} ethyl Fluorenamine; 2- (4-ethylammonylphenyl) -N-{[4- (3,4-dichlorofluorenyl) morpholin-2-yl] fluorenyl} acetamidine trifluoroacetate; 2 -(4 -Ethylfluorenylbenzyl) -N-{[4- (3,4-diazinofluorenyl) morpholin-2-yl] fluorenyl} acetamidine; N-{[4- (3, 4-dichlorobenzyl) morpholin-2-yl] fluorenyl} -2- (4-isobutylfluorenylphenyl) acetamidamine trifluoroacetate; 84385 200404000 4- [2- ({[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} amino) -2-oxoethyl] benzoate methyl trifluoroacetate ; 4- [2-({[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} amino) -2-oxoethyl] benzoic acid methyl ester; 2- (4-cyanophenyl)-^ {[4- (3,4-difluorofluorenyl) morpholin-2-yl] methyl} acetamidine trifluoroacetate; 2- (4-cyanobenzene ) -N- {[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} acetamidine; 2- (4-chlorophenyl) -N- {[4- ( 3,4-dichlorofluorenyl) morpholin-2-yl] fluorenyl} propanamidinium; N-{[4- (3,4-difluorofluorenyl) morpholin-2-yl] fluorenyl}- 2- (3-fluoro-4-hydroxyphenyl) acetamidinium trifluoroacetate; ~ [[(211) -4- (3,4-difluorofluorenyl) morpholin-2-yl] fluorenyl} -2- [4- (fluorenylsulfonyl) phenyl] ethenylamine; ~ {[(23) -4- (3,4-difluorofluorenyl) morpholin-2-yl] fluorenyl}- 2- [4- (methylsulfonyl) phenyl] ethanamine; N-{[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} -2- {4 -[(4-methylpiperin-1 -yl) carbonyl] phenyl} ethanamidin; 4- [2-({[4- (3,4-difluoroamidino) morpholin-2-yl] Fluorenyl} amino) -2-oxoethyl] -N- [2- (dimethylamino) ethyl] Amidoamine; 4- [2- ({[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} amino) -2-oxoethyl] -N, N- Dimethylphosphonium amine; 4- [2-({[4- (3,4-Difluoroamido) morpholin-2-yl] methyl} amino) -2-oxoethyl] -N -Ethylphosphoniumamine; 84385 -4- 200404000 4- [2- ({[4- (3,4-digas benzyl) morpholin-2-yl] methyl} amino) -2-oxo Ethyl] -N-(2-hydroxyethyl) fluorenamine; N-{[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} -2- [4- ( Morpholin-4-ylcarbonyl) phenyl] ethenylamine; N-{[((2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] fluorenyl [(dimethylamino ) Sulfofluorenyl] phenyl} acetamidine; &amp; {[(211) -4- (3,4-dichlorofluorenyl) morpholin-2-yl] fluorenyl} -2- {4-[( Dimethylamino) sulfofluorenyl] phenyl} ethanamide; N-{[(2S) -4- (3,4-dichlorofluorenyl) morpholin-2-yl] fluorenyl} -2- { 4-[(Difluorenylamino) sulfofluorenyl] phenyl} ethanamine; 4- [2-({[4- (3,4-dichloro + yl) morphin-2-yl] methyl} Amine) -2-oxoethyl] -N-methylfluorenamine; 4- [2-({[4- (3,4-dichlorofluorenyl) morpholin-2-yl] fluorenyl} Amine) -2-oxoethyl] -N-isopropylamidamine; N-cyclopropyl-4- [2-({[4- (3,4- Chlorofluorenyl) morpholin-2-yl] methyl} amino) -2-oxoethyl] fluorenamine; 4- [2-({[4- (3,4-dichlorofluorenyl)? Porphyrin-2-yl] methyl} amino) -2-oxoethyl] -N- (2-methoxyethyl) fluorenamine; N-{[4- (3,4-diazinium ) Morpholin-2-yl] fluorenyl} -2- (4-stilsylphenyl) acetofluorenyl; N-{[4- (3,4-difluorofluorenyl) morpholin-2-yl] fluorenyl } -2- (3-nitrophenyl) acetamidine; 3- [2-({[4- (3,4-difluorofluorenyl) morpholin-2-yl] methyl} amino) 2-Oxoethyl] fluorenyl benzoate; 84385 200404000 Yuanwei ___ 丨 2- [3- (ethylamidoamino) phenyl] -N-{[4- (3-fluorofluorenyl) Morpholin-2-yl] methyl} ethylfluorenamine; N-{[4- (3- (fluorobenzyl) morpholin-2-yl] methyl} -2- {4-[(fluorenylsulfonyl) ) Amine] phenyl} acetamidine; 2- [3- (ethylamylamino) phenyl] -N-{[4 · (3,4-difluorobenzyl) morpholine-2-yl] Methyl} acetamidine; Ν-{[4- (3,4-difluorobenzyl) morpholin-2-yl] fluorenyl 2- {4-[(fluorenylsulfonyl) amino] benzene } Ethanylamine; 2- [4- (ethenylamino) phenyl] -N-{[4- (3,4-difluorofluorenyl) morpholin-2-yl] fluorenyl} ethanyl Amine; N-{[4- (3,4-difluorofluorenyl) morpholine-2- ] Fluorenyl} -2- {3-[(fluorenylsulfonyl) amino] phenyl} ethenylamine; N-{[4- (3,4-difluoromethyl) morphin-2-yl ] Fluorenyl} -2- [3- (fluorenylsaflavinyl) phenyl] ethanamidine; N-{[4- (3- (chlorobenzyl) morpholin-2-yl] methylpyridine 2- [4- (Methylsulfonyl) phenyl] ethanamide; N-{[4- (3-chlorofluorenyl) morpholin-2-yl] fluorenyl 2- [3- (methylsulfonyl) benzene Yl] ethenylamine; 2- [3- (ethenylamino) phenyl] -N-{[4- (4-fluorofluorenyl) morpholin-2-yl] fluorenyl} ethenylamine; N -{[4- (4-fluorobenzyl) morpholin-2-yl] methyl} -2- {4-[(methylsulfonyl) amino] benzyl} acetamidamine; 2- [4 -(Ethenylamino) phenyl] -N-{[4- (4-fluorofluorenyl) morpholin-2-yl] fluorenyl} ethenylamine; 84385 200404000 N-{[4- (2,3-dichlorofluorenyl) morpholin-2-yl] fluorenyl} -2- [4- (methylsulfonyl) phenyl] ethanamide; 2- [3 -(Ethylamidoamino) phenyl] -N-{[4- (2,3-dichloroamido) morpholine-2-yl] methyl} acetamidoamine; N-{[4- (2 , 3-dichlorofluorenyl) morpholin-2-yl] fluorenyl} -2- {4-[(methylsulfonyl) amino] phenyl} ethanamide; N-{[4- (2 , 3-dichlorofluorenyl) morpholin-2-yl] methyl} -2- (4-{[((methylamino) carbonyl] amino} phenyl) ethanilamide; N-({4- [ (5-chlorothien-2-yl) methyl] morpholin-2-yl} methyl) -2- [4- (methylsulfonyl) phenyl] acetamidamine; 2- [3- (ethyl Fluorenylamino) phenyl] -N-({4-[(5-chloro4phen-2-yl) methyl] morpholin-2-yl} fluorenyl) ethenylamine; N-({4- [(5-chloropyrimidin-2 -yl) methyl] morpholine-2 -yl} methyl) · 2-{4-[(methylsulfonyl) amino] phenyl} acetamidamine; N -({4-[(5 -Gathiophene-2-yl) fluorenyl] morpholine-2 -yl} methyl) -2-{3-[(methylsulfonyl) amino] phenyl} ethyl Fluorenylamine; 2- [3- (ethylfluorenylamino) phenyl] -N-{[4- (3-chlorobenzyl) morpholin-2-yl] fluorenyl} acetamide; N-{[ 4- (3-chlorofluorenyl) morpholin-2-yl] fluorenyl} -2- {4-[(fluorenylsulfonyl Yl) amino] phenyl} as acetamide; 2- [4- (ethyl stuffed yl) phenyl] -N - {[4- (3- Bian gas-yl) morpholine? Lin-2-yl] methyl} acetamidamine; N-{[4- (3--Arylidene) morpholin-2-yl] methyl} -2- (4-{[(methylamino) Carbonyl] amino} phenyl) acetamidamine; 84385 200404000 ΙΙΙΒΙΙΗ * ...! 2- [4- (ethylamidoamino) phenyl] -N-{[4- (2,3-dichloroamido) ) Morpholine-2-yl] methyl} acetamidamine; N- {[4- (2,3-dioxofluorenyl) morpholin-2-yl] methylbull 2- [3- (methylsulfonate Fluorenyl) phenyl] ethenylamine; 2- [4- (aminosulfonyl) phenyl] -N-{[4- (3,4-dichlorofluorenyl) morpholin-2-yl] fluorene Methyl} ethylamine; 2- [2- (ethylamidoamino) phenyl] -N-{[4- (3,4-dichloroamido) morpholine-2-yl] fluorenyl} ethane Amine; 2- (3-aminophenyl) -N-{[4- (3,4-difluorofluorenyl) morphin-2-yl] fluorenyl} acetamidine; Ν-{[4- ( 3,4-dichlorofluorenyl) morpholin-2-yl] fluorenyl} -2- (2-fluorophenyl) acetamidamine; Ν-{[4- (3,4-difluorofluorenyl) Phenolin-2-yl] methyl} -2- (2,3-difluorophenyl) acetamidine; Ν-{[4- (3,4-dichlorofluorenyl) morpholin-2-yl] formyl } -2- (2,4-difluorophenyl) acetamidine; Ν-{[4- (3,4-difluorofluorenyl) morpholin-2-yl] methyl} -2- (2 , 5-difluorophenyl) acetamidine; Ν-{[4- (3,4-difluorofluorenyl) Morpholin-2-yl] methylbutan-2- (2,6-difluorophenyl) acetamide; N-cyclopropyl-3- [2-({[4- (3,4-dichlorohydrazone) ) Morpholine-2-yl] methyl} amino) -2-oxoethyl] fluorenamine; 3- [2-({[4- (3,4-difluorofluorenyl) morpholine- 2-yl] methyl} amino) -2-oxoethyl] -N- (2-fluorenylethyl) fluorenamine; 84385 200404000 Application for a patent in Puyuan Garden Page 3- [2-({ [4- (3,4-Diaminofluorenyl) morpholin-2-yl] methyl} amino) -2-oxoethyl] -N-ethylbenzylamine; 3- [2-({ [4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} amino) -2-oxoethyl] -N, N-difluorenylfluorenamine; 3- [2 -({[4- (3,4-Dichloromethyl) morpholin-2-yl] methyl} amino) -2-oxoethyl] [2- (diamido) ethyl] 乙基Fluorenamine; N-{[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} -2- {3-[(4-methylpiperin-1 -yl) carbonyl] Phenyl} acetamide; 2- (3-aminophenyl) -N-{[4- (3,4-diamyl) morphin-2-yl] methyl} acetamide; 2 -(4-aminophenyl) -N- {[4- (3,4-dichlorofluorenyl) morpholin-2-yl] fluorenyl} acetamidine; 2- [4- (ethylamylamine ) Phenyl] -N-{[4- (3,4-dioxofluorenyl) morpholine-2-yl] methyl} Acetylamine; N- {4- [2-({[4- (3,4-dichlorobenzyl) morpholin-2-yl] fluorenyl} amino) -2-oxoethyl] phenyl } 2-Amidinopropanamide; N- {3- [2-({[4- (3,4-dichloroamidino) morpholin-2-yl] amido} amino) -2-oxo Ethyl] phenyl} 2-methylpropanamide; N-{[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} -2- {3-[(fluorenyl Sulfonyl) amino] phenyl} ethanamide; N-{[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} -2- {4-[(methyl Sulfonyl) amino] phenyl} ethenylamine; N- {3- [2-({[4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} amino) 2-oxoethyl] phenyl} -2- (dimethylamino) ethenamide; 84385 -9- 200404000 2- {4- [bis (fluorenylsulfonyl) amino] phenyl}- N-{[4- (3,4-Difluorofluorenyl) morpholine-2 -yl] methyl} acetamidoamine; N-{[4- (3,4-Diaminofluorenyl) morpholine-2 -Yl] methyl} -2- [3- (methylsulfonamido) phenyl] ethanamine; N-{[4- (3,4-difluorofluorenyl) morpholin-2-yl] methyl Yl} -2- [4- (methylsulfonyl) -2-nitrophenyl] ethanamine; N-{[4- (3,4-dichlorofluorenyl) morpholin-2-yl] Methyl} -2- (2-hydroxyphenyl) acetamidine; N-{[4- (3,4-difluorofluorenyl) morpholin-2-yl] methyl Benzyl 2- {4- [methyl (fluorenylsulfonyl) amino] phenyl} ethanamine; &gt; ^-{[4- (3,4-dichlorofluorenyl) morpholine-2- Group] methyl} -2- {3- [fluorenyl (methylsulfonyl) amino] phenyl} ethanesulfonylamine; 2- [2-amino-4- (fluorenylsulfonyl) phenyl ] -N-{[4- (3,4-dichlorobenzyl) morpholine-2 -yl] methyl} acetamidine; N-({(2S) -4-[(5-Gathiophene-2 -Yl) methyl] morpholine-2 -yl} fluorenyl) -2- {3-[(methylsulfonyl) amino] phenyl} ethanylamine; N-({(2R) -4- [(5-chlorothiophene-2-yl) methyl] morpholin-2-yl} methyl) -2- {3-[(methylsulfonyl) amino] phenyl) acetamidamine; N- {[((2S) -4- (3,4 · Difluorofluorenyl) morpholin-2-yl] methyl} -2- {4-[(methylamino) sulfofluorenyl] phenyl} ethyl} Amine; N-{[(2S) -4- (3,4-dichlorofluorenyl) morpholin-2-yl] fluorenyl [(ethylamino) sulfofluorenyl] phenyl} acetamidine; 2 -[3- (Aminosulfofluorenyl) phenyl] -N-{[(2S) -4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} acetamidine; 84385 -10- 200404000 Scope of patent application reading page 2- {3-[(Cyclopropylamino) sulfofluorenyl] phenyl} -N-{[(2S) -4- (3,4-difluorofluorenyl) Morin-2-yl] methyl} ethylamine, N-{[(2S) -4- (3 , 4-dichlorofluorenyl) morpholin-2-yl] methyl} -2- {3-[(ethylamino) sulfofluorenyl] phenyl} ethanamide; N- {[(2 S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -2- {3-[(methylamino) sulfofluorenyl] phenyl} ethanamine; N- { [(2S) -4- (4-fluorofluorenyl) morpholin-2-yl] fluorenyl} -2- {4-[(fluorenylsulfonyl) amino] phenyl} ethanylamine; N- {[(2R) -4- (4-fluoroamidino) morpholin-2-yl] fluorenyl} -2- {4-[(methylsulfonyl) amino] phenyl} ethylamidine; 2 -[4- (aminocontinyl) phenyl] -N-{[4- (3,4-dichloroethenyl) morphin-2-yl] methyl} acetamidine; 2- {4- [(Cyclopropylamino) sulfofluorenyl] phenyl} -N-{[4- (3,4-dichlorofluorenyl) morpholine-2.yl] methyl} acetamidine; N-cyclopropyl 3--3- [2-({[((2 S) -4- (2,3-dichlorofluorenyl) morpholin-2-yl] methyl} amino) -2-oxoethyl] fluorene Amine; 3- {2-[({(2S) -4-[(5-chlorothien-2-yl) methyl] morpholin-2-yl} methyl) amino] -2-oxoethyl } -Ν-ί ^ propylpyridamine; Ν-cyclopropyl-3- [2-({[((2 S) -4- (4-fluorofluorenyl) morpholin-2-yl] methyl} Amine) -2-oxoethyl] benzylamidine; 3- [2-({[((2 3) -4- (3-chlorofluorenyl) morpholin-2-yl] fluorenyl} amino) -2 -Oxoethyl] -N-cyclopropylamidine; N-cyclopropyl-3- [2-({[((2S) -4- (3,4-difluoroamidino) morpholine-2 -Yl] fluorenyl} amino) -2 -oxoethyl] fluorenamine; and 84385 -11-200404000 Scope of Patent Application Continued N-Cyclopropyl-3- [2-({[(2S)- 4- (3,4-dichlorofluorenyl) morpholin-2-yl] methyl} amino) -2-oxoethyl] fluorenamine. 2. The compound of formula (I), such as item 1 of the patent application scope, wherein R1 is an unsubstituted or substituted phenyl group. 3. For the compound of formula (I) in item 1 or 2 of the scope of patent application, wherein R1 is an unsubstituted phenyl group or a substituted phenyl group: 4- (methanesulfonyl), 4- (methylcarbonyl) Amine group), 2,4,6- (trifluoro), 3- (methylthio), 2,5- (difluoro), 4- (pyrazol-1-yl), 3- (methanesulfonyl) ), 3- (2-methyl-1,3,4-slogan diazol-5-yl), 3- (1,3,4-fluorenediazol-5-yl), 3- (2-fluorenyl -1,3,4-triazol-5-yl), 4- (ethylcarbonylamino), 4- (methylaminocarbonyl), 4- (carboxy), 3- (isopropylsulfonamidoamine) Group), 3- (Cyclopropane yellow alcohol amine group), 3- (Ethyl sulfan yellow alcohol group amine group), 4- (methylamino sulfonylamino group), 4- (methanesulfonylamino)- 2-methanesulfonylamino, 4- (ethylaminocarbonyl), 3- (N, N-diamidinosulfonyl), 4- (methanesulfonylaminomethyl), 3- ( Methanesulfonylamino), 3- (cyclopropylcarbonyl), 3- (fluorenylcarbonyl), 3- (fluorenyloxycarbonyl), 3- (aminosulfonyl), 4- (methanesulfonyl) Methylamino), 3- (methylaminocarbonyl), 3- (dimethylaminocarbonyl), 3- (isopropylaminocarbonyl), 3- (isopropylmethylamino) Group), 4- (fluoro), 3- (amino), 4- (methylcarbonylamino), 3- (cyclopropylaminocarbonyl), 3- (methylcarbonylamino), 3- (ethyl Aminocarbonyl), 4- (piperidin-1-ylcarbonyl), 3- (ethoxycarbonyl), 4-cyano, 4- (aminosulfonyl), 4- (amino), 4- (Chloro) or 3- (carboxy). 4. For a compound of formula (I) as claimed in item 1 or 2 of the patent application, wherein both Rna and Rnb are hydrogen. 84385 -12- 200404000 5. If the compound of formula (I) in the scope of patent application item 1 or 2, wherein η is 1, 2 or 3 〇6. In the compound of formula (I) in the scope of patent application application 1 or 2, wherein R1G is hydrogen or methyl. 7. The compound of formula (I) as claimed in item 1 or 2, wherein R1G is hydrogen. 8. The compound of formula (I) as claimed in item 1 or 2, wherein R3 is hydrogen. 9. The compound of formula (I) as claimed in claim 1 or 2, wherein R2 is an unsubstituted or substituted phenyl group, an unsubstituted or substituted thienyl group, or an unsubstituted or substituted pyridyl group. 10. The compound of formula (I) according to item 1 or 2 of the scope of patent application, wherein R2 is phenyl substituted by chlorine or fluorine, 4-phenyl or pyridyl substituted by chlorine. 11. The compound of formula (I) according to item 1 or 2 of the scope of patent application, wherein R2 is 3-fluorophenyl, 4-fluorophenyl, 2,5-dichlorophenyl, 3-aminophenyl, 3- (Trifluoromethyl) phenyl, 3-gasphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3-gas-4-gas-phenyl, 2-gas p-phene -5-base or p than bite -3-base. 12. The compound of formula (I) as claimed in item 1 of the patent application scope is a compound selected from the examples. 13. The compound of formula (I) as claimed in claim 12 is selected from Examples 1, 2, 3, 4, 5, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 24, 25, 28, 29, 30, 31, 35, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65 , 77, 81, 82, 83, 85, 87, 88, 8 9 &amp; 90 〇14. The compound of formula (I) according to item 12 of the scope of patent application, which is selected from Examples 1 84385 -13-200404000 , 3, 4, 5, 8, 10, 11, 12, 13, 14, 15, 16, 17, 29, 31, 35, 41, 43, 45, 47, 49, 51, 55, 57, 59, 61 , 63, 65, 77, 85, 87, 88, 89, and 90 ° 15. The compound of formula (I) according to item 12 of the scope of patent application, which is selected from Examples 13, 88, 14, 1, 4, 35, 29, 43, 45, 47, 49, 51, 55, 57, 59, 85 and 87. 16. A method for preparing a compound of formula (I) as claimed in item 1 of the patent application scope, which method comprises combining a compound of formula (II) with a compound of formula (III); 〇 R1 (ill) where: R1, X, Y, R3, R10, and R2 are as defined in Formula (I) of the first patent application range, and are reacted in the presence of a peptide coupling agent and an activator if necessary, and then, if necessary, performed One or more of the following optional steps: (i) converting a compound of formula (I) into another compound of formula (I); (ii) removing any necessary protecting groups; (iii) preparing a salt or solvent of the compound formed Compound. 17. · A method of preparing a compound of formula (I), the method comprising reacting a compound of formula (XI) with a compound of formula (III): R (XI) 84385 -14- 200404000 where L2 is a leaving group, and R1, X, and Y are defined as formula (I) in item 1 of the scope of patent application, and then, if necessary, perform one or more of the following steps as appropriate (I) converting a compound of formula (I) into another compound of formula (I); (ii) removing any necessary protecting groups; (iii) preparing a salt or solvate of the compound formed. 18. A compound of formula (IIIBE), A〆, OH OH ^ N ^ R1 ° Lr2 R (ΝΙΒΕ) wherein R2 and R1G are as defined by formula (I) in item 1 of the patent application scope and A is a protected amine group. 19. A compound of formula (IIIBR), A OH Among them, R2 and R1G are defined as the formula (I) in item 1 of the patent application scope and A is a protected amine group. 20. A compound of formula (I) or a physiologically acceptable salt or solvate thereof according to item 1 of the scope of patent application, which is used as an active therapeutic agent. 21. —A compound of formula (I) such as item 1 of the scope of patent application or its physiological properties 84385 -15-200404000 Receptive salts or solvates are used to treat inflammatory conditions such as asthma or rhinitis. 22.-Use of a compound of formula (I), or a physiologically acceptable salt or solvate thereof, as defined in item 1 of the scope of patent application, for the manufacture of a medicament for treating an inflammatory condition such as asthma or rhinitis. 23.-A pharmaceutical composition for treating a human or mammalian subject suffering from or susceptible to an inflammatory condition such as asthma or rhinitis, comprising an effective amount of a compound of formula (I) as claimed in item 1 of the patent application scope or a physiologically acceptable Salts or solvates, and optionally one or more physiologically acceptable diluents or carriers. 24. A pharmaceutical composition comprising a compound of formula (I) or a physiologically acceptable salt or solvate thereof as in item 1 of the scope of the patent application, and optionally one or more physiologically acceptable diluents or carriers. 84385 16- 200404000 Lu, (1), the designated representative of this case is ... Figure _ (b), the representative symbol of this representative diagram is briefly explained: 柒, if there is a chemical formula in this case, please disclose the one that can best show the characteristics of the invention Chemical formula 84385