JP2006504625A - Morpholine derivatives having a substituted acetamide group at the 2-position used as CCR-3 antagonists for the treatment of inflammatory diseases - Google Patents

Abstract

［式中、R¹は、置換もしくは未置換アリールを表し；Xは、-O-または結合を表し；Yは、-(CR_naR_nb)_n-を表し；R_naおよびR_nbはそれぞれ独立に、水素またはC_1-6アルキルであり；ｎは１〜５の整数であり；R²は、未置換もしくは置換アリールまたは未置換もしくは置換ヘテロアリールを表し；R³は、水素またはC_1-6アルキルを表し；R¹⁰は、水素またはC_1-6アルキルを表す］はCCR3拮抗薬であることから、炎症状態の治療法において有用であることが示される。Certain compounds of formula (I) and their salts and solvates:

[Wherein R ¹ represents substituted or unsubstituted aryl; X represents —O— or a bond; Y represents — (CR _na R _nb ) _n —; R _na and R _nb are each independently a is hydrogen or C _1-6 alkyl; n is an integer from 1 to 5; R ² represents an unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl; R ³ is hydrogen or C _1- Represents ₆ alkyl; R ¹⁰ represents hydrogen or C _1-6 alkyl] is a CCR3 antagonist, indicating that it is useful in the treatment of inflammatory conditions.

Description

  The present invention relates to novel compounds, processes for their preparation, pharmaceutical formulations containing them and their use in therapy.

  Inflammation is the primary response to tissue damage or microbial invasion and is characterized by leukocyte adhesion to the endothelium, leakage, and activation within the tissue. When leukocytes are activated, toxic oxygen species (eg, superoxide anions) may be generated and granule products (eg, peroxidase and protease) may be released. Circulating leukocytes include neutrophils, eosinophils, basophils, monocytes, and lymphocytes. Different forms of inflammation involve different types of infiltrating leukocytes, the specific profile of which is controlled by the expression profile of adhesion molecules, cytokines, and chemotactic factors in the tissue.

  The primary function of white blood cells is to protect the host from invading organisms such as bacteria and parasites. When a tissue is damaged or infected, a series of events occur that cause local mobilization of leukocytes from the circulation to the affected tissue. Leukocyte recruitment is controlled such that ordered destruction and phagocytosis of foreign or dead cells, followed by tissue repair and degradation of inflammatory infiltrates. However, in chronic inflammatory conditions, mobilization is often not performed properly, degradation is not properly controlled, and inflammatory reactions cause tissue destruction.

  In bronchial inflammation unique to asthma, a special form of cellular immunity occurs, and cytokine products such as IL-4 and IL-5 released by T-helper cell 2 (Th2) lymphocytes become granulocytes, There is a lot of evidence, especially that it regulates basophil accumulation and activation to a lesser extent, especially eosinophils. With the release of cytotoxic basic proteins, pro-inflammatory mediators, and oxygen radicals, eosinophils cause mucosal damage and initiate the mechanism underlying bronchial hyperreactivity. Therefore, blocking mobilization and activation of Th2 cells and eosinophils will likely provide anti-inflammatory properties in asthma. In addition, eosinophils have been shown to be involved in other disease types such as rhinitis, eczema, irritable bowel syndrome, and parasitic infections.

  Chemokines are a large family of small proteins involved in leukocyte trafficking and mobilization (for a review, see Luster, New Eng. J. Med., 338, 436-445 (1998)). They are released by a wide variety of cells and act to attract and activate various cell types including eosinophils, basophils, neutrophils, macrophages, T and B lymphocytes. There are two main families of chemokines, CXC- (α) and CC- (β) chemokines, which are classified based on two conserved cysteine residues near the amino terminus of the chemokine protein. Chemokines bind to specific cell surface receptors belonging to the family of G protein-coupled seven transmembrane domain proteins (for a review, see Luster, 1998). Activation of the chemokine receptor, among other responses, increases intracellular calcium, changes in cell shape, increased expression of cell adhesion molecules, degranulation, and promotion of cell migration (chemotacticity). Occur.

  To date, many CC chemokine receptors have been identified and of particular importance in the present invention are CCs that are predominantly expressed on eosinophils and also on basophils, mast cells, and Th2 cells. -Chemokine receptor-3 (CCR-3). Chemokines that act on CCR-3, such as RANTES, MCP-3, and MCP-4, are known to recruit and activate eosinophils. Of particular interest are eotaxin and eotaxin-2, which specifically bind to CCR-3. The location and function of CCR-3 chemokines suggest that they play a central role in the development of allergic diseases such as asthma. In doing so, CCR-3 is specifically expressed on all major cell types involved in the inflammatory allergic response. Chemokines that act on CCR-3 are produced in response to inflammatory stimuli and mobilize these cell types to the site of inflammation to cause their activation (e.g., Griffiths et al., J. Exp. Med. , 179, 881-887 (1994), Lloyd et al., J. Exp. Med., 191, 265-273 (2000)). In addition, anti-CCR-3 monoclonal antibody completely inhibits the interaction between eotaxin and eosinophils (Heath, H. et al., (1997) J. Clin. Invest. 99 (2), 178 Meanwhile, antibodies against eotaxin, a CCR-3 specific chemokine, reduced both bronchial hyperreactivity and lung eosinophilia in animal models of asthma (Gonzalo et al., J Exp. Med., 188, 157-167 (1998)). Therefore, multifaceted evidence suggests that CCR-3 receptor antagonists are very likely to be available for therapeutic use to treat a range of inflammatory conditions.

  In addition to an important role in inflammatory disorders, chemokines and their receptors also play a role in infectious diseases. Mammalian cytomegaloviruses, herpesviruses, and poxviruses express chemokine receptor analogs that can be activated by human CC chemokines such as RANTES and MCP-3 receptors (for review, see Wells and Schwartz, Curr Opin. Biotech., 8, 741-748, 1997). In addition, human chemokine receptors such as CXCR-4, CCR-5, and CCR-3 may act as co-receptors for the infection of mammalian cells such as human immunodeficiency virus (HIV). is there. Thus, chemokine receptor antagonists, including CCR-3 antagonists, can block HIV infection of CCR-3 expressing cells or prevent manipulation of immune cell responses by viruses such as cytomegalovirus. It is considered useful.

  International Patent Application Publication No. WO01 / 24786 (Shionogi & Co. Ltd.) discloses certain aryl and heteroaryl derivatives for the treatment of diabetes. WO 00/69830 (Torrey Pines Institute for Molecular Studies) discloses certain diaza cyclic compounds for biological screening and libraries containing them. WO00 / 18767 (Neurogen Corporation) discloses certain piperazine derivatives as dopamine D4 receptor antagonists. US Pat. No. 6,031,097 and WO99 / 21848 (Neurogen Corporation) disclose certain aminoisoquinoline derivatives as dopamine receptor ligands. WO99 / 06384 (Recordati Industria Chimica) discloses piperazine derivatives useful for the treatment of neuromuscular dysfunction in the lower urinary tract. WO98 / 56771 (Schering Aktiengesellschaft) discloses piperazine derivatives as anti-inflammatory agents. WO 97/47601 (Yoshitomi Pharmaceutical Industries Ltd.) discloses certain fused heterocyclic compounds as dopamine D receptor blockers. WO96 / 39386 (Schering Corporation) discloses certain piperidine derivatives as neurokinin antagonists. WO96 / 02534 (Byk Gulden Lomberg Chemische Fabrik GmbH) discloses certain piperazine thiopyridines useful for controlling Helicobacter bacteria. WO95 / 32196 (Merck Sharp & Dohme Limited) discloses certain piperazine, piperidine and tetrahydropyridine derivatives as 5-HT1D-α antagonists. US Pat. No. 5,389,635 (E.I. Du Pont de Nemours and Company) discloses certain substituted imidazoles as angiotensin-II antagonists. European Patent Application Publication No. 0306440 (Schering Aktiengesellschaft) discloses certain imidazole derivatives as cardiovascular drugs.

  A new class of compounds has been found to be CCR-3 antagonists. These compounds have anti-inflammatory properties because they block eosinophil migration / chemotaxis. Thus, these compounds are particularly susceptible to tissue damage caused by eosinophils, basophils and Th2 cells, diseases involving such cell types, particularly allergic diseases such as, but not limited to It is considered therapeutically beneficial in terms of prevention in bronchial asthma, allergic rhinitis and atopic dermatitis.

Thus, according to one aspect of the present invention, there are provided compounds of the following formula (I) and salts and solvates of the compounds.

Where
R ¹ represents substituted or unsubstituted aryl;
X represents -O- or a bond;
Y represents-(CR _na R _nb ) _n- ;
R _na and R _nb are each independently hydrogen or C _1-6 alkyl;
n is an integer from 1 to 5;
R ² represents unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl;
R ³ represents hydrogen or C _1-6 alkyl;
R ¹⁰ represents hydrogen or C _1-6 alkyl;
However, the following compounds:
2- (4-chlorophenyl) -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-phenylacetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-phenoxyacetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (4-methoxyphenyl) acetamide;
2- (3-chlorophenyl) -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- [4- (methylthio) -phenyl] acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- [4- (dimethylamino) -phenyl] acetamide compound (1: 1) with formic acid;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-4-[(dimethylamino) -sulfonyl] phenylacetamide compound (1: 1) with formic acid;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- [4- (methylsulfonyl) -phenyl] acetamide compound (1: 1) with formic acid;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (3-fluorophenyl) acetamide;
2- [3,5-bis (trifluoromethyl) phenyl] -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] -methylacetamide;
2- (2-chlorophenyl) -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (4-fluoro-2-methylphenyl) -acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (3,4-difluorophenyl) -acetamide;
4- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -benzamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- [4- (trifluoromethyl) -phenyl] acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (4-methylphenyl) acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (2,4-dichlorophenyl) -acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (4-fluorophenyl) acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (3,4-dichlorophenyl) -acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (2,5-dichlorophenyl) -acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (2,6-dichlorophenyl) -acetamide;
2- (4-chlorophenyl) -N- [4- (2,3-dichlorobenzyl) morpholin-2-yl] methyl-acetamide trifluoroacetate;
2- [3- (acetylamino) phenyl] -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-acetamide;
2- (4-acetylphenyl) -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide trifluoroacetate;
2- (4-acetylphenyl) -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (4-isobutyrylphenyl) acetamide trifluoroacetate;
4- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -benzoic acid methyl trifluoroacetate;
4- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -methyl benzoate;
2- (4-cyanophenyl) -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide trifluoroacetate;
2- (4-cyanophenyl) -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
2- (4-chlorophenyl) -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylpropanamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (3-fluoro-4-hydroxyphenyl) -acetamide trifluoroacetate;
N-[(2R) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- [4- (methylsulfonyl) -phenyl] acetamide;
N-[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- [4- (methylsulfonyl) -phenyl] acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-4-[(4-methylpiperazin-1-yl) carbonyl] phenylacetamide;
4- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -N- [2- (dimethylamino) ethyl] benzamide;
4- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -N, N-dimethylbenzamide;
4- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -N-ethylbenzamide;
4- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -N- (2-hydroxyethyl) benzamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- [4- (morpholin-4-yl-carbonyl) phenyl] acetamide;
N-[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-3-[(dimethylamino) -sulfonyl] phenylacetamide;
N-[(2R) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-4-[(dimethylamino) -sulfonyl] phenylacetamide;
N-[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-4-[(dimethylamino) -sulfonyl] phenylacetamide;
4- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -N-methylbenzamide;
4- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -N-isopropylbenzamide;
N-cyclopropyl-4- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] benzamide;
4- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -N- (2-methoxyethyl) benzamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (4-nitrophenyl) acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (3-nitrophenyl) acetamide;
3- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -methyl benzoate;
2- [3- (acetylamino) phenyl] -N- [4- (3-fluorobenzyl) morpholin-2-yl] methyl-acetamide;
N- [4- (3-fluorobenzyl) morpholin-2-yl] methyl-2-4-[(methylsulfonyl) -amino] phenylacetamide;
2- [3- (acetylamino) phenyl] -N- [4- (3,4-difluorobenzyl) morpholin-2-yl] methyl-acetamide;
N- [4- (3,4-difluorobenzyl) morpholin-2-yl] methyl-2-4-[(methylsulfonyl) -amino] phenylacetamide;
2- [4- (acetylamino) phenyl] -N- [4- (3,4-difluorobenzyl) morpholin-2-yl] -methylacetamide;
N- [4- (3,4-difluorobenzyl) morpholin-2-yl] methyl-2-3-[(methylsulfonyl) -amino] phenylacetamide;
N- [4- (3,4-difluorobenzyl) morpholin-2-yl] methyl-2- [3- (methylsulfonyl) -phenyl] acetamide;
N- [4- (3-chlorobenzyl) morpholin-2-yl] methyl-2- [4- (methylsulfonyl) -phenyl] acetamide;
N- [4- (3-chlorobenzyl) morpholin-2-yl] methyl-2- [3- (methylsulfonyl) -phenyl] acetamide;
2- [3- (acetylamino) phenyl] -N- [4- (4-fluorobenzyl) morpholin-2-yl] methylacetamide;
N- [4- (4-fluorobenzyl) morpholin-2-yl] methyl-2-4-[(methylsulfonyl) amino] -phenylacetamide;
2- [4- (acetylamino) phenyl] -N- [4- (4-fluorobenzyl) morpholin-2-yl] methylacetamide;
N- [4- (2,3-dichlorobenzyl) morpholin-2-yl] methyl-2- [4- (methylsulfonyl) -phenyl] acetamide;
2- [3- (acetylamino) phenyl] -N- [4- (2,3-dichlorobenzyl) morpholin-2-yl] methyl-acetamide;
N- [4- (2,3-dichlorobenzyl) morpholin-2-yl] methyl-2-4-[(methylsulfonyl) -amino] phenylacetamide;
N- [4- (2,3-Dichlorobenzyl) morpholin-2-yl] methyl-2- (4-[(methylamino)-
-Carbonyl] aminophenyl) acetamide;
N- (4-[(5-chlorothien-2-yl) methyl] morpholin-2-ylmethyl) -2- [4- (methylsulfonyl) -phenyl] acetamide;
2- [3- (acetylamino) phenyl] -N- (4-[(5-chlorothien-2-yl) methyl] morpholin-2-ylmethyl) acetamide;
N- (4-[(5-chlorothien-2-yl) methyl] morpholin-2-ylmethyl) -2-4-[(methylsulfonyl) -amino] phenylacetamide;
N- (4-[(5-chlorothien-2-yl) methyl] morpholin-2-ylmethyl) -2-3-[(methylsulfonyl) -amino] phenylacetamide;
2- [3- (acetylamino) phenyl] -N- [4- (3-chlorobenzyl) morpholin-2-yl] methyl-acetamide;
N- [4- (3-Chlorobenzyl) morpholin-2-yl] methyl-2-4-[(methylsulfonyl)-
-Amino] phenylacetamide;
2- [4- (acetylamino) phenyl] -N- [4- (3-chlorobenzyl) morpholin-2-yl] methyl-acetamide;
N- [4- (3-chlorobenzyl) morpholin-2-yl] methyl-2- (4-[(methylamino) carbonyl] -aminophenyl) acetamide;
2- [4- (acetylamino) phenyl] -N- [4- (2,3-dichlorobenzyl) morpholin-2-yl] -methylacetamide;
N- [4- (2,3-dichlorobenzyl) morpholin-2-yl] methyl-2- [3- (methylsulfonyl) -phenyl] acetamide;
2- [4- (aminosulfonyl) phenyl] -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
2- [2- (acetylamino) phenyl] -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
2- (3-cyanophenyl) -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (2-fluorophenyl) acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (2,3-difluorophenyl) -acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (2,4-difluorophenyl) -acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (2,5-difluorophenyl) -acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (2,6-difluorophenyl) -acetamide;
N-cyclopropyl-3- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] benzamide;
3- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -N- (2-methoxyethyl) benzamide;
3- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -N-ethylbenzamide;
3- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -N, N-dimethylbenzamide;
3- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -N- [2- (dimethylamino) ethyl] benzamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-3-[(4-methylpiperazin-1-yl) carbonyl] phenylacetamide;
2- (3-aminophenyl) -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
2- (4-aminophenyl) -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
2- [4- (acetylamino) phenyl] -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-acetamide;
N-4- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -phenyl 2-methylpropanamide;
N-3- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -phenyl 2-methylpropanamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-3-[(methylsulfonyl) -amino] phenylacetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-4-[(methylsulfonyl) -amino] phenylacetamide;
N-3- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -phenyl-2- (dimethylamino) acetamide;
2-4- [bis (methylsulfonyl) amino] phenyl-N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- [3- (methylsulfonyl) -phenyl] acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- [4- (methylsulfonyl) -2-nitrophenyl] acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (2-hydroxyphenyl) acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-4- [methyl (methylsulfonyl) -amino] phenylacetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-3- [methyl (methylsulfonyl) -amino] phenylacetamide;
2- [2-amino-4- (methylsulfonyl) phenyl] -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
N-((2S) -4-[(5-chlorothien-2-yl) methyl] morpholin-2-ylmethyl) -2-3-[(methylsulfonyl) amino] phenylacetamide;
N-((2R) -4-[(5-chlorothien-2-yl) methyl] morpholin-2-ylmethyl) -2-3-[(methylsulfonyl) amino] phenylacetamide;
N-[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-4-[(methylamino) -sulfonyl] phenylacetamide;
N-[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-4-[(ethylamino) -sulfonyl] phenylacetamide;
2- [3- (aminosulfonyl) phenyl] -N-[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
2-3-[(cyclopropylamino) sulfonyl] phenyl-N-[(2S) -4- (3,4-dichlorobenzyl) -morpholin-2-yl] methylacetamide;
N-[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-3-[(ethylamino) -sulfonyl] phenylacetamide;
N-[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-3-[(methylamino) -sulfonyl] phenylacetamide;
N-[(2S) -4- (4-fluorobenzyl) morpholin-2-yl] methyl-2-4-[(methylsulfonyl) -amino] phenylacetamide;
N-[(2R) -4- (4-fluorobenzyl) morpholin-2-yl] methyl-2-4-[(methylsulfonyl) -amino] phenylacetamide;
2- [4- (aminosulfonyl) phenyl] -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
2-4-[(cyclopropylamino) sulfonyl] phenyl-N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
N-cyclopropyl-3- [2-([(2S) -4- (2,3-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] benzamide;
3-2-[((2S) -4-[(5-chlorothien-2-yl) methyl] morpholin-2-ylmethyl) amino] -2-oxoethyl-N-cyclopropylbenzamide;
N-cyclopropyl-3- [2-([(2S) -4- (4-fluorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] benzamide;
3- [2-([(2S) -4- (3-chlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -N-cyclopropylbenzamide;
N-cyclopropyl-3- [2-([(2S) -4- (3,4-difluorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] benzamide; and
N-cyclopropyl-3- [2-([(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] benzamide is excluded.

Examples of the aryl group R ¹ include phenyl.

When R ¹ is substituted aryl, suitable substituents include C _1-6 alkylsulfonyl; C _1-6 alkylthio; unsubstituted or substituted heteroaryl; C _3-8 cycloalkylsulfonylamino; C _1-6 alkyl C _1-6 alkylaminosulfonyl; C _1-6 alkylsulfonylamino C _1-6 alkyl; amino; C _3-8 cycloalkylaminocarbonyl; C _1-6 alkylcarbonyl; C _3-8 cycloalkylcarbonyl C _1-6 alkylsulfonylamino; C _1-6 alkylcarbonylamino; C _3-8 cycloalkylcarbonylamino; R ⁴ R ⁵ NC (O) — (R ⁴ and R ⁵ are each independently hydrogen or C _{1; -6} alkyl, or R ⁴ and R ⁵ represent a — (CH ₂ ) _p — group (p is an integer from 3 to 7), so that the nitrogen atom to which they are attached and Together, form a 4-8 membered heterocycle Rukoto can); C _1-6 alkoxycarbonyl, cyano, aminosulfonyl; aminocarbonyl; halo; carboxy; C _1-6 alkyl, hydroxy, nitro, C _1-6 alkoxy, mono- - and di - (C _1- and the like ₆ alkyl) amino.

When R ¹ is aryl substituted with unsubstituted or substituted heteroaryl, examples of such heteroaryl groups include pyrazolyl, oxadiazolyl and triazolyl.

Suitable substituents for such heteroaryl groups include C _1-6 alkyl.

Suitably R ¹ is unsubstituted or substituted phenyl.

When R ¹ is substituted phenyl, suitable substituents include C _1-6 alkylsulfonyl; C _1-6 alkylthio; unsubstituted pyrazolyl; unsubstituted and substituted oxadiazolyl; substituted triazolyl; C _3-8 cycloalkylsulfonylamino ; C _1-6 alkylaminocarbonyl amino, C _1-6 alkylaminosulfonyl; C _1-6 alkylsulfonylamino C _1-6 alkyl, cyano, amino, C _3-8 cycloalkyl amino carbonyl; C _3-8 cycloalkyl carbonyl; C _1-6 alkylcarbonyl; C _1-6 alkylsulfonylamino; C _1-6 ^{alkylcarbonylamino; R 4 R 5 NC (O} ) - (R 4 and R ⁵ are each independently hydrogen or C _{1- 6} alkyl can be represented, or R ⁴ and R ⁵ can represent a — (CH ₂ ) _p — group, where p is an integer from 3 to 7, so as to be integrated with the nitrogen atom to which they are attached. Become a complex of 4-8 members Ring can be formed); C _1-6 alkoxycarbonyl; aminosulfonyl; aminocarbonyl; halo; or carboxy.

More preferably R ¹ is unsubstituted phenyl or 4- (methanesulfonyl), 4- (methylcarbonylamino), 2,4,6- (trifluoro), 3- (methylthio), 2, 5- (difluoro), 4- (pyrazol-1-yl), 3- (methanesulfonyl), 3- (2-methyl-1,3,4-oxadiazol-5-yl), 3- (1, 3,4-oxadiazol-5-yl), 3- (2-methyl-1,3,4-triazol-5-yl), 4- (ethylcarbonylamino), 4- (methylaminocarbonyl), 4 -(Carboxy), 3- (iso-propanesulfonylamino), 3- (cyclopropanesulfonylamino), 3- (ethanesulfonylamino), 4- (methylaminocarbonylamino), 4-methanesulfonyl-2-methanesulfonyl Amino), 4- (ethylaminocarbonyl), 3- (N, N-dimethylaminosulfonyl), 4- (methanesulfonylaminomethyl), 3- (methanesulfonylamino), 3- (cyclopropyl) Rubonyl), 3- (methylcarbonyl), 3- (methoxycarbonyl), 3- (aminosulfonyl), 4- (methanesulfonylamino), 3- (methylaminocarbonyl), 3- (dimethylaminocarbonyl), 3- (Iso-propylaminocarbonyl), 3- (iso-propylmethylaminocarbonyl), 4- (fluoro), 3- (amino), 4- (methylcarbonylamino), 3- (cyclopropylaminocarbonyl), 3- (Methylcarbonylamino), 3- (ethylaminocarbonyl), 4- (piperidin-1-ylcarbonyl), 3- (ethoxycarbonyl), 4-cyano, 4- (aminosulfonyl), 4- (amide), 4 Phenyl substituted with-(chloro) or 3- (carboxy).

Suitably R _na and R _nb are both hydrogen.

  Preferably n is 1, 2 or 3.

Suitably R ¹⁰ is hydrogen or methyl.

More preferably, R ¹⁰ is hydrogen.

Suitably R ³ is hydrogen.

When R ² is aryl, examples include phenyl and the like.

When R ² is substituted aryl, suitable substituents include cyano, perhalo C _1-6 alkyl, amide, halo, C _1-6 alkyl, C _1-6 alkoxycarbonyl, mono- and di- (C _{1- 6} alkyl) aminocarbonyl, C _1-6 alkoxy, nitro, C _1-6 alkylsulfonyl, hydroxy, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkylthio-, mono- and di- (C _1- and the like ₆ alkyl) amino and C _1-6 alkylcarbonylamino.

When R ² is heteroaryl, examples include thiophenyl and pyridinyl.

When R ² is substituted heteroaryl, suitable substituents include cyano, perhalo C _1-6 alkyl, amide, halo, C _1-6 alkyl, C _1-6 alkoxycarbonyl, mono- and di- (C _{1 -6} alkyl) aminocarbonyl, C _1-6 alkoxy, nitro, C _1-6 alkylsulfonyl, hydroxy, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkylthio-, mono- and di- (C _{1 -6} alkyl) amino and C _1-6 alkylcarbonylamino.

Suitably R ² is unsubstituted or substituted phenyl, unsubstituted or substituted thiophenyl, or unsubstituted or substituted pyridinyl.

When R ² is substituted phenyl, suitable substituents include halo and the like.

More preferably R ² is phenyl substituted with chlorine or fluorine, thiophenyl substituted with chlorine, or pyridinyl.

Preferably R ² is 3-fluorophenyl, 4-fluorophenyl, 2,5-dichlorophenyl, 3-chlorophenyl, 3- (trifluoromethyl) phenyl, 3-chlorophenyl, 3,4-dichlorophenyl, 3,4-difluoro. Phenyl, 3-chloro-4-fluoro-phenyl, 2-chlorothiophen-5-yl, or pyridin-3-yl.

One group of compounds of formula (I) that may be mentioned are those of formula (Ii) below and their salts and solvates.

Where
R ¹ represents substituted or unsubstituted aryl;
X represents -O- or a bond;
Y represents-(CR _na R _nb ) _n- ;
R _na and R _nb are each independently hydrogen or C _1-6 alkyl;
n is an integer from 1 to 5;
R ² represents unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl;
R ³ represents hydrogen or C _1-6 alkyl;
However, the following compounds:
2- (4-chlorophenyl) -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-phenylacetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-phenoxyacetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (4-methoxyphenyl) acetamide;
2- (3-chlorophenyl) -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- [4- (methylthio) -phenyl] acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- [4- (dimethylamino) -phenyl] acetamide compound (1: 1) with formic acid;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-4-[(dimethylamino) -sulfonyl] phenylacetamide compound (1: 1) with formic acid;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- [4- (methylsulfonyl) -phenyl] acetamide compound (1: 1) with formic acid;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (3-fluorophenyl) acetamide;
2- [3,5-bis (trifluoromethyl) phenyl] -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] -methylacetamide;
2- (2-chlorophenyl) -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (4-fluoro-2-methylphenyl) -acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (3,4-difluorophenyl) -acetamide;
4- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -benzamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- [4- (trifluoromethyl) -phenyl] acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (4-methylphenyl) acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (2,4-dichlorophenyl) -acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (4-fluorophenyl) acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (3,4-dichlorophenyl) -acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (2,5-dichlorophenyl) -acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (2,6-dichlorophenyl) -acetamide;
2- (4-chlorophenyl) -N- [4- (2,3-dichlorobenzyl) morpholin-2-yl] methyl-acetamide trifluoroacetate;
2- [3- (acetylamino) phenyl] -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-acetamide;
2- (4-acetylphenyl) -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide trifluoroacetate;
2- (4-acetylphenyl) -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (4-isobutyrylphenyl) acetamide trifluoroacetate;
4- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -benzoic acid methyl trifluoroacetate;
4- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -methyl benzoate;
2- (4-cyanophenyl) -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide trifluoroacetate;
2- (4-cyanophenyl) -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
2- (4-chlorophenyl) -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylpropanamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (3-fluoro-4-hydroxyphenyl) -acetamide trifluoroacetate;
N-[(2R) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- [4- (methylsulfonyl) -phenyl] acetamide;
N-[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- [4- (methylsulfonyl) -phenyl] acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-4-[(4-methylpiperazin-1-yl) carbonyl] phenylacetamide;
4- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -N- [2- (dimethylamino) ethyl] benzamide;
4- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -N, N-dimethylbenzamide;
4- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -N-ethylbenzamide;
4- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -N- (2-hydroxyethyl) benzamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- [4- (morpholin-4-yl-carbonyl) phenyl] acetamide;
N-[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-3-[(dimethylamino) -sulfonyl] phenylacetamide;
N-[(2R) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-4-[(dimethylamino) -sulfonyl] phenylacetamide;
N-[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-4-[(dimethylamino) -sulfonyl] phenylacetamide;
4- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -N-methylbenzamide;
4- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -N-isopropylbenzamide;
N-cyclopropyl-4- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] benzamide;
4- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -N- (2-methoxyethyl) benzamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (4-nitrophenyl) acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (3-nitrophenyl) acetamide;
3- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -methyl benzoate;
2- [3- (acetylamino) phenyl] -N- [4- (3-fluorobenzyl) morpholin-2-yl] methyl-acetamide;
N- [4- (3-fluorobenzyl) morpholin-2-yl] methyl-2-4-[(methylsulfonyl) -amino] phenylacetamide;
2- [3- (acetylamino) phenyl] -N- [4- (3,4-difluorobenzyl) morpholin-2-yl] methyl-acetamide;
N- [4- (3,4-difluorobenzyl) morpholin-2-yl] methyl-2-4-[(methylsulfonyl) -amino] phenylacetamide;
2- [4- (acetylamino) phenyl] -N- [4- (3,4-difluorobenzyl) morpholin-2-yl] -methylacetamide;
N- [4- (3,4-difluorobenzyl) morpholin-2-yl] methyl-2-3-[(methylsulfonyl) -amino] phenylacetamide;
N- [4- (3,4-difluorobenzyl) morpholin-2-yl] methyl-2- [3- (methylsulfonyl) -phenyl] acetamide;
N- [4- (3-chlorobenzyl) morpholin-2-yl] methyl-2- [4- (methylsulfonyl) -phenyl] acetamide;
N- [4- (3-chlorobenzyl) morpholin-2-yl] methyl-2- [3- (methylsulfonyl) -phenyl] acetamide;
2- [3- (acetylamino) phenyl] -N- [4- (4-fluorobenzyl) morpholin-2-yl] methylacetamide;
N- [4- (4-fluorobenzyl) morpholin-2-yl] methyl-2-4-[(methylsulfonyl) amino] -phenylacetamide;
2- [4- (acetylamino) phenyl] -N- [4- (4-fluorobenzyl) morpholin-2-yl] methylacetamide;
N- [4- (2,3-dichlorobenzyl) morpholin-2-yl] methyl-2- [4- (methylsulfonyl) -phenyl] acetamide;
2- [3- (acetylamino) phenyl] -N- [4- (2,3-dichlorobenzyl) morpholin-2-yl] methyl-acetamide;
N- [4- (2,3-dichlorobenzyl) morpholin-2-yl] methyl-2-4-[(methylsulfonyl) -amino] phenylacetamide;
N- [4- (2,3-dichlorobenzyl) morpholin-2-yl] methyl-2- (4-[(methylamino) -carbonyl] aminophenyl) acetamide;
N- (4-[(5-chlorothien-2-yl) methyl] morpholin-2-ylmethyl) -2- [4- (methylsulfonyl) -phenyl] acetamide;
2- [3- (acetylamino) phenyl] -N- (4-[(5-chlorothien-2-yl) methyl] morpholin-2-ylmethyl) acetamide;
N- (4-[(5-chlorothien-2-yl) methyl] morpholin-2-ylmethyl) -2-4-[(methylsulfonyl) -amino] phenylacetamide;
N- (4-[(5-chlorothien-2-yl) methyl] morpholin-2-ylmethyl) -2-3-[(methylsulfonyl) -amino] phenylacetamide;
2- [3- (acetylamino) phenyl] -N- [4- (3-chlorobenzyl) morpholin-2-yl] methyl-acetamide;
N- [4- (3-chlorobenzyl) morpholin-2-yl] methyl-2-4-[(methylsulfonyl) -amino] phenylacetamide;
2- [4- (acetylamino) phenyl] -N- [4- (3-chlorobenzyl) morpholin-2-yl] methyl-acetamide;
N- [4- (3-chlorobenzyl) morpholin-2-yl] methyl-2- (4-[(methylamino) carbonyl] -aminophenyl) acetamide;
2- [4- (acetylamino) phenyl] -N- [4- (2,3-dichlorobenzyl) morpholin-2-yl] -methylacetamide;
N- [4- (2,3-dichlorobenzyl) morpholin-2-yl] methyl-2- [3- (methylsulfonyl) -phenyl] acetamide;
2- [4- (aminosulfonyl) phenyl] -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
2- [2- (acetylamino) phenyl] -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
2- (3-cyanophenyl) -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (2-fluorophenyl) acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (2,3-difluorophenyl) -acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (2,4-difluorophenyl) -acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (2,5-difluorophenyl) -acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (2,6-difluorophenyl) -acetamide;
N-cyclopropyl-3- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] benzamide;
3- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -N- (2-methoxyethyl) benzamide;
3- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -N-ethylbenzamide;
3- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -N, N-dimethylbenzamide;
3- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -N- [2- (dimethylamino) ethyl] benzamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-3-[(4-methylpiperazin-1-yl) carbonyl] phenylacetamide;
2- (3-aminophenyl) -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
2- (4-aminophenyl) -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
2- [4- (acetylamino) phenyl] -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-acetamide;
N-4- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -phenyl 2-methylpropanamide;
N-3- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -phenyl 2-methylpropanamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-3-[(methylsulfonyl) -amino] phenylacetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-4-[(methylsulfonyl) -amino] phenylacetamide;
N-3- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -phenyl-2- (dimethylamino) acetamide;
2-4- [bis (methylsulfonyl) amino] phenyl-N- [4- (3,4-dichlorobenzyl) morpholin-2-l] methylacetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- [3- (methylsulfonyl) -phenyl] acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- [4- (methylsulfonyl) -2-nitrophenyl] acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (2-hydroxyphenyl) acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-4- [methyl (methylsulfonyl) -amino] phenylacetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-3- [methyl (methylsulfonyl) -amino] phenylacetamide;
2- [2-amino-4- (methylsulfonyl) phenyl] -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
N-((2S) -4-[(5-chlorothien-2-yl) methyl] morpholin-2-ylmethyl) -2-3-[(methylsulfonyl) amino] phenylacetamide;
N-((2R) -4-[(5-chlorothien-2-yl) methyl] morpholin-2-ylmethyl) -2-3-[(methylsulfonyl) amino] phenylacetamide;
N-[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-4-[(methylamino) -sulfonyl] phenylacetamide;
N-[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-4-[(ethylamino) -sulfonyl] phenylacetamide;
2- [3- (aminosulfonyl) phenyl] -N-[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
2-3-[(cyclopropylamino) sulfonyl] phenyl-N-[(2S) -4- (3,4-dichlorobenzyl) -morpholin-2-yl] methylacetamide;
N-[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-3-[(ethylamino) -sulfonyl] phenylacetamide;
N-[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-3-[(methylamino) -sulfonyl] phenylacetamide;
N-[(2S) -4- (4-fluorobenzyl) morpholin-2-yl] methyl-2-4-[(methylsulfonyl) -amino] phenylacetamide;
N-[(2R) -4- (4-fluorobenzyl) morpholin-2-yl] methyl-2-4-[(methylsulfonyl) -amino] phenylacetamide;
2- [4- (aminosulfonyl) phenyl] -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
2-4-[(cyclopropylamino) sulfonyl] phenyl-N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
N-cyclopropyl-3- [2-([(2S) -4- (2,3-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] benzamide;
3-2-[((2S) -4-[(5-chlorothien-2-yl) methyl] morpholin-2-ylmethyl) amino] -2-oxoethyl-N-cyclopropylbenzamide;
N-cyclopropyl-3- [2-([(2S) -4- (4-fluorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] benzamide;
3- [2-([(2S) -4- (3-chlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -N-cyclopropylbenzamide;
N-cyclopropyl-3- [2-([(2S) -4- (3,4-difluorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] benzamide; and
N-cyclopropyl-3- [2-([(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] benzamide is excluded.

There is a small group of compounds of formula (I) that are of formula (IA) below.

Where
R ^1A is a moiety of the following formula (M).

Where
R ⁶ is C _1-6 alkylthio, unsubstituted or substituted heteroaryl, C _3-8 cycloalkylsulfonylamino; N, N-di (C _1-6 alkyl) aminosulfonyl, R ⁸ R ⁹ NC (O) — (R ⁸ and R ⁹ each independently represent hydrogen or C _1-6 alkyl, or R ⁸ and R ⁹ are — (CH ₂ ) _q — groups (q is an integer of 3 to 7). ) May be combined with the nitrogen atom to which they are attached to form a 4- to 8-membered heterocycle); unsubstituted heteroaryl; C _1-6 alkyl, halo, C ₁ Heteroaryl substituted with _-6 alkoxy or hydroxy; C _3-8 cycloalkylaminosulfonyl; C _3-8 cycloalkylcarbonyl; aminosulfonyl; carboxy; mono- and di- (C _1-6 alkyl) aminosulfonyl; _1-6 alkylsulfonylamino; C _1-6 alkylcarbonyl; C _3-8 cycloalkyl Represent or C _1-6 alkylcarbonylamino; aminocarbonyl; aminocarbonyl; C _1-6 alkoxycarbonyl; C _1-6 alkylsulfonyl;
R ⁷ represents cyano, perhalo C _1-6 alkyl, hydrogen, C _1-6 alkyl, halo, C _1-6 alkoxy or hydroxy;
Y, R ² , R ³ and R ¹⁰ are as defined above for formula (I);
The following compounds:
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-phenoxyacetamide;
2- [3- (acetylamino) phenyl] -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] -methylacetamide;
N-[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-3-[(dimethylamino) -sulfonyl] phenylacetamide;
3- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] methyl benzoate;
2- [3- (acetylamino) phenyl] -N- [4- (3-fluorobenzyl) morpholin-2-yl] methylacetamide;
2- [3- (acetylamino) phenyl] -N- [4- (3,4-difluorobenzyl) morpholin-2-yl] methyl-acetamide;
N- [4- (3,4-difluorobenzyl) morpholin-2-yl] methyl-2-3-[(methylsulfonyl) -amino] phenylacetamide;
N- [4- (3,4-difluorobenzyl) morpholin-2-yl] methyl-2- [3- (methylsulfonyl) -phenyl] acetamide;
N- [4- (3-chlorobenzyl) morpholin-2-yl] methyl-2- [3- (methylsulfonyl) -phenyl] acetamide;
2- [3- (acetylamino) phenyl] -N- [4- (4-fluorobenzyl) morpholin-2-yl] methylacetamide;
2- [3- (acetylamino) phenyl] -N- [4- (2,3-dichlorobenzyl) morpholin-2-yl] -methylacetamide;
2- [3- (acetylamino) phenyl] -N- (4-[(5-chlorothien-2-yl) methyl] morpholin-2-yl-methyl) acetamide;
N- (4-[(5-chlorothien-2-yl) methyl] morpholin-2-ylmethyl) -2-3-[(methylsulfonyl) -amino] phenylacetamide;
2- [3- (acetylamino) phenyl] -N- [4- (3-chlorobenzyl) morpholin-2-yl] methyl-acetamide;
N- [4- (2,3-dichlorobenzyl) morpholin-2-yl] methyl-2- [3- (methylsulfonyl) -phenyl] acetamide;
N-cyclopropyl-3- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] benzamide;
3- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -N-ethylbenzamide;
3- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -N, N-dimethylbenzamide;
N-3- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] phenyl-2-methylpropanamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-3-[(methylsulfonyl) -amino] phenylacetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- [3- (methylsulfonyl) -phenyl] acetamide;
N-((2S) -4-[(5-chlorothien-2-yl) methyl] morpholin-2-ylmethyl) -2-3-[(methylsulfonyl) amino] phenylacetamide;
N-((2R) -4-[(5-chlorothien-2-yl) methyl] morpholin-2-ylmethyl) -2-3-[(methylsulfonyl) amino] phenylacetamide;
2- [3- (aminosulfonyl) phenyl] -N-[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] -methylacetamide;
2-3-[(cyclopropylamino) sulfonyl] phenyl-N-[(2S) -4- (3,4-dichlorobenzyl) -morpholin-2-yl] methylacetamide;
N-[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-3-[(ethylamino) -sulfonyl] phenylacetamide;
N-[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-3-[(methylamino) -sulfonyl] phenylacetamide;
N-cyclopropyl-3- [2-([(2S) -4- (2,3-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] benzamide;
3-2-[((2S) -4-[(5-chlorothien-2-yl) methyl] morpholin-2-ylmethyl) amino] -2-oxoethyl-N-cyclopropylbenzamide;
N-cyclopropyl-3- [2-([(2S) -4- (4-fluorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] benzamide;
3- [2-([(2S) -4- (3-chlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -N-cyclopropylbenzamide;
N-cyclopropyl-3- [2-([(2S) -4- (3,4-difluorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] benzamide; and
N-cyclopropyl-3- [2-([(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] benzamide is excluded.

Suitably R ⁶ is C _1-6 alkylsulfonylamino, C _3-8 cycloalkylcarbonyl, C _1-6 alkylcarbonyl, C _1-6 alkoxycarbonyl, aminosulfonyl, carboxy or mono- and di- (C _{1 -6} alkyl) aminocarbonyl.

Suitably R ⁷ is hydrogen.

Suitable groups R ^1A include 3-methylthio, 3-methanesulfonyl, 3- (2-methyl-1,3,4-oxadiazol-5-yl), 3- (1,3,4-oxadi (Azol-2-yl), 3- (2-methyl-1,3,4-triazol-5-yl), 3- (methylaminocarbonyl), 3- (iso-propylsulfonylamino), 3- (cyclopropyl) (Sulfonylamino), 3- (ethylsulfonylamino), 3- (iso-propylaminosulfonyl), 3- (methylsulfonylamino), 3- (cyclopropylcarbonyl), 3- (methylcarbonyl), 3- (methoxycarbonyl ), 3- (aminosulfonyl), 4- (methylsulfonylaminomethyl), 3- (methylaminocarbonyl), 3- (dimethylaminocarbonyl), 3- (iso-propylaminocarbonyl), 3- (iso-propyl) Methylaminocarbonyl), 4- (fluoro), 3- (amino), 4- (methylcarbonylamino), 3- (cyclopropylaminocarbo ), 3- (methylcarbonylamino), 3- (ethylaminocarbonyl), 4- (piperidin-1-ylcarbonyl), 3- (ethoxycarbonyl), 4-cyano, 4- (aminosulfonyl), 4- And phenyl substituted with (amide), 4- (chloro) and 3- (carboxy).

More preferably R ^1A is 3-methylthio, 3-methanesulfonyl, 3- (2-methyl-1,3,4-oxadiazol-5-yl), 3- (1,3,4-oxadi (Azol-2-yl), 3- (2-methyl-1,3,4-triazol-5-yl), 3- (methylaminocarbonyl), 3- (iso-propylsulfonylamino), 3- (cyclopropyl) (Sulfonylamino), 3- (ethylsulfonylamino), 3- (iso-propylaminosulfonyl), 3- (cyclopropylcarbonyl), 3- (methylcarbonyl), 3- (methoxycarbonyl), 3- (aminosulfonyl) 3- (methylaminocarbonyl), 3- (dimethylaminocarbonyl), 3- (iso-propylaminocarbonyl), 3- (iso-propylmethylaminocarbonyl), 3- (ethylaminocarbonyl), 3- (methyl Phenyl substituted with sulfonylamino or 3- (carboxy).

One subgroup of compounds of formula (Ii) that may be mentioned are those of formula (IAi) below.

Where
R ^1A is a part of the following formula (M)

Where
R ⁶ is R ⁸ R ⁹ NC (O)-(R ⁸ and R ⁹ can each independently represent hydrogen or C _1-6 alkyl, or R ⁸ and R ⁹ are — (CH ₂ ) _q -Represents a group (q is an integer from 3 to 7 and can form a 4 to 8 membered heterocycle together with the nitrogen atom to which they are attached); unsubstituted Heteroaryl; heteroaryl substituted with C _1-6 alkyl, halo, C _1-6 alkoxy or hydroxy; C _3-8 cycloalkylaminosulfonyl; C _3-8 cycloalkylcarbonyl; aminosulfonyl; carboxy; mono- and di - (C _1-6 alkyl) aminosulfonyl; C _1-6 alkylsulfonylamino; C _1-6 alkylcarbonyl; C _3-8 cycloalkyl aminocarbonyl; aminocarbonyl; C _1-6 alkoxycarbonyl; C _1-6 Alkylsulfonyl; or C _1-6 alkylcarbonylamino R ⁷ represents cyano, perhalo C _1-6 alkyl, hydrogen, C _1-6 alkyl, halo, C _1-6 alkoxy or hydroxy;
Y, R ² and R ³ are as defined above for formula (I);
The following compounds:
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-phenoxyacetamide;
2- [3- (acetylamino) phenyl] -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] -methylacetamide;
N-[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-3-[(dimethylamino) -sulfonyl] phenylacetamide;
3- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] methyl benzoate;
2- [3- (acetylamino) phenyl] -N- [4- (3-fluorobenzyl) morpholin-2-yl] methylacetamide;
2- [3- (acetylamino) phenyl] -N- [4- (3,4-difluorobenzyl) morpholin-2-yl] methyl-acetamide;
N- [4- (3,4-difluorobenzyl) morpholin-2-yl] methyl-2-3-[(methylsulfonyl) -amino] phenylacetamide;
N- [4- (3,4-difluorobenzyl) morpholin-2-yl] methyl-2- [3- (methylsulfonyl) -phenyl] acetamide;
N- [4- (3-chlorobenzyl) morpholin-2-yl] methyl-2- [3- (methylsulfonyl) -phenyl] acetamide;
2- [3- (acetylamino) phenyl] -N- [4- (4-fluorobenzyl) morpholin-2-yl] methylacetamide;
2- [3- (acetylamino) phenyl] -N- [4- (2,3-dichlorobenzyl) morpholin-2-yl] -methylacetamide;
2- [3- (acetylamino) phenyl] -N- (4-[(5-chlorothien-2-yl) methyl] morpholin-2-yl-methyl) acetamide;
N- (4-[(5-chlorothien-2-yl) methyl] morpholin-2-ylmethyl) -2-3-[(methylsulfonyl) -amino] phenylacetamide;
2- [3- (acetylamino) phenyl] -N- [4- (3-chlorobenzyl) morpholin-2-yl] methyl-acetamide;
N- [4- (2,3-dichlorobenzyl) morpholin-2-yl] methyl-2- [3- (methylsulfonyl) -phenyl] acetamide;
N-cyclopropyl-3- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] benzamide;
3- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -N-ethylbenzamide;
3- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -N, N-dimethylbenzamide;
N-3- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] phenyl-2-methylpropanamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-3-[(methylsulfonyl) -amino] phenylacetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- [3- (methylsulfonyl) -phenyl] acetamide;
N-((2S) -4-[(5-chlorothien-2-yl) methyl] morpholin-2-ylmethyl) -2-3-[(methylsulfonyl) amino] phenylacetamide;
N-((2R) -4-[(5-chlorothien-2-yl) methyl] morpholin-2-ylmethyl) -2-3-[(methylsulfonyl) amino] phenylacetamide;
2- [3- (aminosulfonyl) phenyl] -N-[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] -methylacetamide;
2-3-[(cyclopropylamino) sulfonyl] phenyl-N-[(2S) -4- (3,4-dichlorobenzyl) -morpholin-2-yl] methylacetamide;
N-[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-3-[(ethylamino) -sulfonyl] phenylacetamide;
N-[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-3-[(methylamino) -sulfonyl] phenylacetamide;
N-cyclopropyl-3- [2-([(2S) -4- (2,3-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] benzamide;
3-2-[((2S) -4-[(5-chlorothien-2-yl) methyl] morpholin-2-ylmethyl) amino] -2-oxoethyl-N-cyclopropylbenzamide;
N-cyclopropyl-3- [2-([(2S) -4- (4-fluorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] benzamide;
3- [2-([(2S) -4- (3-chlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -N-cyclopropylbenzamide;
N-cyclopropyl-3- [2-([(2S) -4- (3,4-difluorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] benzamide; and
N-cyclopropyl-3- [2-([(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] benzamide is excluded.

  Suitable compounds of the present invention are described in 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 compounds.

  Preferred compounds of the present invention are the same as in Examples 1, 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.

  More preferred compounds of the invention are those of Examples 13, 88, 14, 1, 4, 35, 29, 43, 45, 47, 49, 51, 55, 57, 59, 85 and 87.

  Suitable salts of the compound of formula (I) are physiologically acceptable salts, as well as useful for the preparation of compounds of formula (I) and physiologically acceptable salts thereof. The salt considered. Where appropriate, acid addition salts may be derived from inorganic or organic acids, such as hydrochloride, hydrobromide, sulfate, phosphate, acetate, benzoate, citrate, Examples include succinate, lactate, tartrate, fumarate, maleate, 1-hydroxy-2-naphthoate, palmate, methanesulfonate, formate, or trifluoroacetate.

  Examples of solvates include hydrates.

There is a preferred subgroup of compounds of formula (I) that are of the following formula (I ′):

Where
R ^{1 ′} is a moiety of the following formula (M ′);

Where
R ^{6 ′} is R ⁸ R ⁹ NC (O) — (R ⁸ and R ⁹ are as defined above); C _1-6 alkoxycarbonyl; C _1-6 alkylcarbonyl; C _3-8 cycloalkyl Represents carbonyl; C _1-6 alkylsulfonylamino; carboxy; or aminosulfonyl;
R ^{7 ′} is hydrogen or halo;
R ^{2 ′} is phenyl substituted by halo.

Suitably R ^{1 ′} is C _3-8 cycloalkylcarbonyl, C _1-6 alkylcarbonyl, C _1-6 alkoxycarbonyl, aminosulfonyl, C _1-6 alkylsulfonylamino, carboxy or mono- or di- (C _1-6 alkyl) phenyl substituted with aminocarbonyl.

Preferably R ^{1 ′} is 3- (cyclopropylcarbonyl) phenyl, 3- (methylcarbonyl) phenyl, 3- (methoxycarbonyl) phenyl, 3- (aminosulfonyl) phenyl, 3-carboxyphenyl, 3- (methylamino Carbonyl) phenyl, 3- (methylsulfonylamino) phenyl, 3- (dimethylaminocarbonyl) phenyl, 3- (ethylaminocarbonyl) phenyl), 3- (iso-propylaminocarbonyl) phenyl or 3- (iso-propyl ( Methyl) aminocarbonyl) phenyl.

Preferably R ^{2 '} is phenyl substituted with chlorine or fluorine.

Preferably R ^{2 '} is 3,4-dichlorophenyl, 3,4-difluorophenyl or 3-chloro-4-fluorophenyl.

  Preferably, the stereochemistry at the positions marked with “*” is (S).

  Accordingly, provided is a compound of formula (I ′) or a salt or solvate thereof.

There is another preferred subgroup of compounds of formula (I) that are of formula (I ") below.

Where
R ^{1 ″} is substituted phenyl;
R ^{2 ″} is phenyl substituted with halo.

Suitably R ^{1 ″} is C _3-8 cycloalkylaminocarbonyl, C _1-6 alkylcarbonylamino, R ⁴ R ⁵ NCO (R ⁴ and R ⁵ are as defined above), C _1-6 Alkoxycarbonyl, carboxy, C _1-6 alkylsulfonylamino, cyano, aminosulfonyl, aminocarbonyl, halo or phenyl substituted with amino.

Preferably R ^{1 ″} is 3- (cyclopropylaminocarbonyl) phenyl, 3- (methylcarbonylamino) phenyl, 3- (ethylaminocarbonyl) phenyl, 3- (ethoxycarbonyl) phenyl, 3-carboxyphenyl, 3- (Methanesulfonylamino) phenyl, 3- (methylaminocarbonyl) phenyl, 4- (methylcarbonylamino) phenyl, 4- (piperidin-1-ylcarbonyl) phenyl or 3-aminophenyl.

Suitably R ^{2 ″} is phenyl substituted with chlorine.

Preferably R ^{2 ″} is 3,4-dichlorophenyl.

  Preferably, the stereochemistry at the position marked with “*” is (S).

  Accordingly, provided is a compound of formula (I ″) or a salt or solvate thereof.

There is another preferred subgroup of compounds of formula (I) that are of formula (I ′ ″) below.

Where
R ^{1 ″ ″} is 4-substituted phenyl;
R ^{2 ′ ″ ′} is phenyl substituted by halo.

Preferably R ^{1 '''} is phenyl substituted by C _1-6 alkylsulfonylaminoalkyl in the 4-position or para-position.

Preferably R ^{1 ′ ″ ′} is 4- (methanesulfonylaminomethyl) phenyl.

Preferably R ^{2 ′ ″ ′} is phenyl substituted with chlorine or fluorine.

Preferably R ^{2 ""} is 3,4-difluorophenyl.

  Preferably, the stereochemistry at the positions marked with “*” is (S).

  Accordingly, provided is a compound of formula (I ′ ″) or a salt or solvate thereof.

  Certain of the compounds of formula (I) may exist in one or more stereoisomers because they may have chiral atoms and / or multiple bonds. The present invention relates to all stereoisomers of compounds of formula (I) such as geometric isomers and optical isomers, whether as individual stereoisomers or as mixtures thereof including racemates. Is included.

  In general, the compounds of formula (I) are preferably in the form of a single enantiomer or diastereomer.

  Certain of the compounds of formula (I) may exist in any of several tautomeric forms. It will be clear that the present invention encompasses all tautomers of the compounds of formula (I), whether as individual tautomers or as mixtures thereof.

  Reference to “aryl” refers to monocyclic and bicyclic carbocyclic aromatic rings such as naphthyl and phenyl, especially phenyl.

  Suitable substituents for the aryl group include: alkylsulfonyl; alkylthio; unsubstituted or substituted heteroaryl; cycloalkylsulfonylamino; alkylaminocarbonylamino; alkylaminosulfonyl; perhaloalkyl; cycloalkylaminosulfonyl; Cycloalkyl; alkylcarbonyl; alkylsulfonylamino; cycloalkylaminocarbonyl; aminocarbonyl; halo; alkyl; alkoxycarbonyl; mono- and di- (alkyl) aminocarbonyl; alkoxy; nitro; Hydroxy; alkoxyalkyl; alkylthio; mono- and di- (alkyl) amino; 1-5 groups selected from, preferably, etc. 1-3 substituents.

  “Heteroaryl” refers to a heterocyclic aromatic ring containing from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heterocyclic aromatic rings include thiophenyl, pyrazolyl, oxadiazolyl and triazolyl.

  Suitable substituents for heteroaryl groups include cyano, perhaloalkyl, amide, halo, alkyl, alkoxycarbonyl, mono- and di- (alkyl) aminocarbonyl, alkoxy, nitro, alkylsulfonyl, hydroxy, alkoxyalkyl, alkylthio, These include mono- and di- (alkyl) amino and alkylcarbonylamino.

  References to “alkyl” preferably refer to both linear and branched aliphatic isomers of the corresponding alkyl having 6 or fewer carbon atoms.

  References to “cycloalkyl” preferably refer to saturated alicyclic rings having from 3 to 8 carbon atoms, such as cyclopropyl.

  When referring to "heterocycle" a monocyclic heterocycle having 2 to 6, preferably 3 to 5 carbon atoms and 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur Refers to the aliphatic ring. Examples of heterocycles include piperidinyl.

  Suitable substituents for the heterocyclic group include cycloalkylcarbonyl, aminocarbonyl, alkylsulfonylamino, alkylcarbonyl, cycloalkylaminocarbonyl, alkyl, alkoxycarbonyl, alkylaminocarbonyl, halo, alkoxy, nitro, alkylsulfonyl, hydroxy, Examples include alkoxyalkyl, alkylthio, mono- and di- (alkyl) amino and alkylcarbonylamino.

  Reference to “halogen” or “halo” refers to iodine, bromine, chlorine or fluorine, especially fluorine and chlorine.

  Compounds of formula (I) and salts and solvates thereof can be prepared by the following methods that constitute another aspect of the present invention.

Accordingly, in the process for producing the compound of formula (I), the compound of the following formula (II) is converted to the compound of the following formula (III) in the presence of a peptide coupling agent and optionally an activator.

Wherein R ¹ , X, Y, R ³ , R ¹⁰ and R ² are as defined above for formula (I); and then, if necessary, the following appropriate Stage of:
(i) converting a compound of formula (I) to another compound of formula (I);
(ii) removing the necessary protecting groups;
(iii) providing a method comprising performing one or more of the steps of preparing a salt or solvate of the compound so formed.

  Suitably the activator is 1-hydroxybenzotriazole (HOBT).

  Examples of peptide binders include 1,3-dicyclohexylcarbodiimide (DCC); 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) and 1- (3-dimethylaminopropyl) -3-ethyl There is carbodiimide or a salt thereof. Suitably the peptide binder is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride.

  Typically, the compound of formula (II) and the compound of formula (III) in a suitable solvent, such as a polar organic solvent such as N, N-dimethylformamide, at room temperature such as about 18-25 ° C. Treat with binder. The reaction mixture is stirred at room temperature for a suitable period of time, such as about 12-20 hours.

Compounds of formula (III) in which R ³ 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): Reaction between a compound of the following formula (IV) and a compound of the following formula (V)

[Wherein R ² and R ¹⁰ are as defined above for formula (I); A is a protected amino group, preferably phthalimide], followed by R ³ by deprotection of said amino group. A compound of formula (III) in which is hydrogen, ie a compound of formula (IIIR):

Obtaining (wherein R ² and R ¹⁰ are as defined above) and, optionally, resolution of the resulting enantiomer of the compound of formula (IIIR);
Or;
Reaction (b): Reaction of a compound of formula (IV) as defined above with a compound of formula (VA)

[Wherein A is as defined above for formula (V)] and the compound of formula (III) wherein R ³ is hydrogen by subsequent deprotection of the amino group, ie, of formula (IIIE) Compound:

Obtaining the corresponding enantiomer of (wherein R ² and R ¹⁰ are as defined above).

Reaction (c): Compound of the following formula (VI):

Hydrolysis of [wherein T is trifluoroacetyl; R ³ , R ¹⁰ and R ² are as defined above for formula (I)] and, optionally, yielding a compound of formula (III) Resolution of enantiomers.

  In both reactions (a) and (b), the reaction between the compound of formula (IV) and the compound of formula (V) or (VA) is typically carried out under Mitsunobu conditions as follows: .

  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 suitable under an inert atmosphere, preferably under a nitrogen atmosphere. Stir at temperature, preferably at the reflux temperature of the solvent, preferably for 20-24 hours. Then additional solvent is added and the mixture is cooled to preferably 0-5 ° C. A suitable phosphine, preferably triphenylphosphine, is added and the mixture is stirred until all solids are dissolved. The azo compound, preferably diisopropyl azodicarboxylate, is added over a period of time, preferably 10-15 minutes, while maintaining the temperature at <7 ° C. The mixture is allowed to elapse for a period of time, preferably 2-3 hours, and then allowed to warm to preferably 20-25 ° C. Further after a period of time, preferably 4-6 hours, additional phosphine and azo compounds are added. After a further period, preferably 20-24 hours, the reaction mixture is concentrated to near dryness. Add a suitable alcohol, preferably propan-2-ol, and repeat the concentration step. The alcohol addition and concentration steps are then repeated. Then more alcohol is added and the mixture is heated to a certain temperature, preferably 65-75 ° C. After a suitable period, preferably 20-45 minutes, the resulting slurry is cooled to preferably 20-25 ° C. and preferably allowed to stand for 1.5-3 hours before the product is simply filtered. Release. The filter bed is washed with additional alcohol and vacuum dried at 35-45 ° C. to obtain protectors of compounds of formula (IIIR) or formula (IIIE), respectively.

  The removal of the protecting group from the product is typically performed as follows. A slurry of a protector of a compound of formula (IIIR) or formula (IIIE) in a suitable polar solvent, preferably water, is heated to an elevated temperature, preferably 70-75 ° C., then concentrated mineral acid, preferably Add concentrated sulfuric acid dropwise. The mixture is then heated at an elevated temperature, preferably the reflux temperature of the solvent, for a suitable period, preferably 20-24 hours, after which the reaction mixture is cooled to 20-25 ° C. and a suitable nonpolar solvent Preferably with methylene chloride. A base, preferably 0.880 ammonia solution, is added dropwise while maintaining the temperature at 20-25 ° C. Additional non-polar solvent is added before the aqueous phase is separated and extracted with additional non-polar solvent. The combined organic phases are washed with water and evaporated to dryness. The residue is redissolved and the nonpolar solvent is distilled off to give the compound of formula (IIIR) or formula (IIIE).

The method for producing a protected form of the compound of the above formula (IIIR) or formula (IIIE) can also be carried out in two steps, in which case the intermediate compound of the following formula (IIIBR) or the following formula (IIIBE):

Wherein A is as defined above for formulas (V) and (VA); R ² and R ¹⁰ are as defined above for 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 suitable under an inert atmosphere, preferably under a nitrogen atmosphere. Stir at temperature, preferably at the reflux temperature of the solvent, preferably for 20-24 hours. Additional compound of formula (IV) is added and over a suitable period, preferably 3-6 hours, in an inert atmosphere, preferably under a nitrogen atmosphere, at a suitable temperature, preferably at the reflux temperature of the solvent, Heat the mixture. The reaction mixture is cooled, preferably to 20-25 ° C., and the compound is precipitated by adding a suitable cosolvent, preferably diisopropyl ether. The compound of formula (IIIBR) or formula (IIIBE), respectively, is isolated by filtration, washed with additional cosolvent and dried in vacuo.

  Next, except for omitting the reflux period before the addition of phosphine and azo compound, under the same conditions as in the reaction between the compounds of formula (IV) and formula (V) or (VA) described above, A protected compound of formula (IIIR) or formula (IIIE) can be prepared from a compound of formula (IIIBR) or formula (IIIBE).

  Reaction (c) is typically carried out by stirring a solution of the compound of formula (VI) in a suitable solvent such as a mixture of methanol and water and adding a suitable base such as potassium carbonate. The mixture is stirred at a suitable temperature, for example in the range of 20-25 ° C., for a suitable time, for example 16-20 hours, after which the organic solvent is removed under reduced pressure. Water is then added and the mixture is extracted with a suitable organic solvent, for example ethyl acetate. The combined organic phases are washed with water and saturated aqueous sodium chloride solution, then dried over a suitable desiccant such as sodium sulfate, filtered and the solvent is distilled off under reduced pressure. The crude product is then purified by flash chromatography.

  Resolution of racemic products, i.e. compounds of formula (IIIE) from compounds of formula (IIIR), using techniques known to those skilled in the art, e.g. preparative chiral high performance liquid chromatography (chiral HPLC) or diastereo This can be done by fractional crystallization of the mer salt.

The compound of the formula (VI) can be produced by reacting a compound of the following formula (VII) with a compound of the following formula (VIII).

Wherein T, R ³ , R ¹⁰ and R ² are as defined above for formula (VI); L ² is a leaving group. A suitable leaving group L ² is a halo group such as chlorine.

  The reaction between the compound of formula (VII) and the compound of formula (VIII) is typically carried out under an inert atmosphere, for example a nitrogen atmosphere, with a suitable base such as potassium carbonate and a suitable activity such as sodium iodide. This is done by adding the agent and stirring the solution of the compound of formula (VII) in a suitable solvent such as N, N-dimethylformamide. A solution of the compound of formula (VIII) in a suitable solvent such as N, N-dimethylformamide is added dropwise to the mixture. The mixture is then stirred at a suitable temperature, for example a temperature in the range 20-25 ° C., for a suitable period of time, for example 16-20 hours, after which the volatile components are removed under reduced pressure. The residue is partitioned between a suitable organic solvent such as methylene chloride and a saturated aqueous base such as saturated aqueous sodium carbonate. The organic phase is then washed with additional saturated aqueous base and water, then dried with a suitable dehydrating agent such as magnesium sulfate, filtered and the solvent is distilled off under reduced pressure to give the crude product. The crude product is purified by flash chromatography.

The compound of the formula (VII) can be produced by reacting the compound of the following formula (IX) with the compound of the following formula (X).

In which R ³ , R ¹⁰ and T are as defined above for formula (VI); R _x is an alkyl group, preferably ethyl.

  The reaction between the compound of formula (IX) and the compound of formula (X) typically involves a solution of the compound of formula (IX) in a suitable organic solvent, such as methanol, in an inert atmosphere, such as a nitrogen atmosphere. Stirring under and adding a solution of a compound of formula (X) in a suitable organic solvent, for example ether. The mixture is then stirred for a suitable period of time, for example 20-40 minutes, at a suitable temperature, for example in the range of 20-25 ° C., and the volatile constituents are removed under reduced pressure. The residue is then dissolved in a suitable organic solvent, such as methanol, and the volatile components are removed under reduced pressure.

In yet another embodiment, the compound of formula (I) is a compound of formula (XI):

[Wherein L ² is a leaving group; R ¹ , X and Y are as defined above for formula (I)] with a compound of formula (III) followed by The following appropriate steps:
(i) converting a compound of formula (I) to another compound of formula (I);
(ii) removing the necessary protecting groups;
(iii) It can be produced by carrying out one or more of the steps of producing a salt or solvate of the compound so formed.

  A suitable leaving group is a halo group, preferably bromine.

  Typically, the reaction between the compound of formula (III) and the compound of formula (XI) is carried out in an appropriate solvent such as a polar organic solvent such as acetonitrile in an alkali or alkaline earth metal such as potassium carbonate. It is carried out in the presence of a suitable base such as carbonate at a suitable temperature such as room temperature, for example 18-25 ° C., for a suitable period, for example 2-4 hours.

  Compounds of formula (II), certain compounds of formula (III), certain compounds of formula (IV), (V), certain compounds of formula (VI), formulas (VII), (VIII), Certain compounds of (IX), (X) and (XI) are either known or commercially available, or synthesized by, for example, J. March, Advanced Organic Chemistry, 3rd Edition (1985), Wiley Interscience, etc. It can be produced in the same manner as a known procedure such as a technique disclosed in a standard reference book on law.

  Compounds of formula (IIIBR) and (IIIBE) are considered novel.

  Accordingly, a compound of formula (IIIBE) is provided.

  Also provided is a compound of formula (IIIBR).

The above transformation of a compound of formula (I) into another compound of formula (I) includes any transformation that can be performed using conventional techniques, in particular the transformation comprises a group R ¹ Conversion to another group R ¹ is included.

The above transformations can be performed using appropriate methods under conditions that depend on the particular group selected. Therefore, the preferred conversion to another group R ¹ of a group R ¹ is,
(a) alkoxy groups R ¹ representing an aryl group substituted with a carbonyl group to convert the group R ¹ which represents the aryl group substituted with a carboxy group [such a transformation, for example suitably protected formula ( Can be performed using a suitable conventional hydrolysis method such as treating the compound of I) with a suitable base];
(b) converts the group R ¹ representing an aryl group substituted with a carboxy group to group R ¹ which represents an aryl group substituted with an amide group [such a transformation, for example a suitable peptide coupling agent and needs Can be carried out using a suitable conversion amination method, such as treatment of a suitably protected compound of formula (I) with a suitable amine, optionally in the presence of a suitable activator];
(c) alkoxy converts the group R ¹ which represents an aryl group substituted with a carbonyl amino group in group R ¹ which represents an aryl group substituted with an amino group [such a transformation, for example suitably protected formula Can be performed using any suitable conventional deprotection method such as treating the compound of (I) with a suitable mineral acid]; and
(d) converts the group R ¹ representing an aryl group substituted with an amino group to group R ¹ which represents the aryl group substituted with an alkylsulfonylamino group [such a transformation, for example suitably protected formula Appropriate conventional sulfonylation methods can be used, such as treating the compound of (I) with a suitable alkylsulfonyl halide in the presence of a suitable base]
and so on.

  The above transformations can be performed on intermediate compounds referred to herein as appropriate.

  The above transformations can be performed on intermediate compounds referred to herein as appropriate.

  Suitable protecting groups for the above reactions are those conventionally used in the art. The methods for the formation and elimination of such protecting groups are conventional methods suitable for the molecule to be protected, such as those described in standard reference books on synthetic methods such as PJ Kocienski, Protecting Groups, (1994), Thieme. Is the method.

  In the reactions or methods described above, conventional heating and cooling methods can be used, such as an electric heating mantle and an ice / salt bath, respectively. Conventional purification methods such as crystallization and column chromatography can be used as needed.

  Where appropriate, individual isomers of compounds of formula (I) are prepared as individual isomers using conventional techniques such as fractional crystallization of diastereomeric derivatives or chiral high performance liquid chromatography (chiral HPLC). can do.

  The absolute stereochemistry of the compound can be determined using conventional methods such as X-ray crystallography.

  Salts and solvates of the compounds of formula (I) can be prepared and isolated according to conventional methods.

  The compounds of the invention can be tested for in vitro bioactivity according to the following assay.

(a) CCR-3 binding assay
CCR-3 competitive binding SPA (scintillation proximity assay) was used to assess the affinity of the new compounds for CCR-3. Cell membranes (2.5 μg / well) prepared from K562 cells stably expressing CCR-3 were mixed with 0.25 mg / well wheat germ agglutinin SPA beads (Amersham) and binding buffer (HEPES 50 mM, CaC1) at 4 ° C. ₍₂ mM, MgCl ₂ 5 mM, 0.5% BSA) for 1.5 hours. Following incubation, 20 pM [ ¹²⁵ I] eotaxin (Amersham) and increasing concentrations of compound (1 pM to 30 μM) were added, incubated in a 96-well plate for 2 hours at 22 ° C. and counted in a Microbeta plate counter. Total assay volume was 100 μl. Competitive binding data was analyzed by fitting the data to a four parameter logistic equation. Data are presented as mean pIC ₅₀ values obtained from at least two experiments (log of compound concentration that inhibits [ ¹²⁵ I] eotaxin binding by 50%).

  The compounds of the examples were tested in a CCR-3 binding assay. The example compounds tested in the CCR-3 binding assay had pIC50 values in the range of 6.0 to 8.7.

(b) Eosinophil chemotaxis assay Compounds were evaluated for their inhibitory effect on eosinophil chemotaxis . As previously reported, eosinophils were purified from human peripheral blood by standard CD16 cell depletion using a Miltenyi cell separation column and a magnetic Super Macs magnet (Motegi & Kita, 1998; J. Immunology. 161 : 4340-6). Cells were resuspended in RPMI 1640/10% FCS solution and incubated with calcein-AM (Molecular Probes) for 30 minutes at 37 ° C. Cells were resuspended in RPMI 1640/10% FCS solution and incubated with calcein-AM (Molecular Probes) at 37 ° C. for 30 minutes. Following incubation, eosinophils were centrifuged at 400 g for 5 minutes and resuspended in RPMI / FCS at 2.2 million / ml. The cells were then incubated for 30 minutes at 37 ° C. in the presence of increasing concentrations of compound (1 pM to 30 μM). For the control response, cells were incubated with RPMI / FCS alone. The agonist eotaxin (EC ₈₀ concentration) was added to the lower chamber of a 96-well chemotaxis plate (5 μm filter: Receptor Technologies). Eosinophils (50 μl of 2 million / ml cells) were added to the top chamber of the filter plate and incubated at 37 ° C. for 45 minutes. Cells remaining at the top of the chemotaxis filter were removed, and the number of migrated eosinophils was quantified by reading the plate with a fluorescent plate reader. By fitting the data to a 4-parameter logistic equation, an inhibition curve showing the effect of the compound on eosinophil chemotaxis was analyzed. The functional pKi value (fpKi) was obtained using the following formula (Lazareno & Birdsall, 1995. Br. J. Pharmacol 109: 1110-9).

The compounds of the examples were tested in a CCR-3 binding assay and / or eosinophil chemotaxis assay (Assay (a) and (b)). The example compounds tested in the CCR-3 binding assay had pIC50 values ranging from 6.6 to 9.1. The compounds of the examples examined by CCR-3 eosinophil chemotaxis assay had fpKi values as shown in the table below.

  Examples of disease symptoms that the compounds of the present invention may exhibit beneficial anti-inflammatory effects include bronchitis (such as chronic bronchitis), bronchiectasis, asthma (such as allergen-induced asthmatic reactions), chronic obstruction Airway diseases such as pulmonary disease (COPD), cystic fibrosis, sinusitis and rhinitis. There are also gastrointestinal diseases such as intestinal inflammatory diseases, including inflammatory bowel diseases (eg, Crohn's disease or ulcerative colitis) and intestinal inflammatory diseases that occur after radiation or allergen exposure.

  In addition, the compounds of the present invention provide nephritis; skin diseases such as psoriasis, eczema, allergic dermatitis, and hypersensitivity reactions; and central nervous system diseases that have an inflammatory component (eg, Alzheimer's disease, meningitis, multiple Sclerosis), HIV and AIDS dementia can also be used.

  The compounds of the present invention are also considered useful for the treatment of nasal polyposis, conjunctivitis, or pruritus.

  Additional examples of disease conditions where the compounds of the present invention may have beneficial effects include cardiovascular conditions such as atherosclerosis, peripheral vascular disease, and idiopathic hypereosinophil syndrome.

  Since the compounds of the present invention are believed to be useful as immunosuppressants, they may also be used to treat autoimmune diseases such as allograft tissue rejection after transplantation, rheumatoid arthritis and diabetes.

  The compounds of the present invention are believed to be useful in inhibiting metastasis.

  Mainly targeted diseases include asthma, COPD, and inflammatory diseases of the upper respiratory tract associated with seasonal and perennial rhinitis.

  It will be apparent to those skilled in the art that when reference is made herein to treatment or therapy, it extends to cover not only the treatment of established conditions but also its prevention.

  As mentioned above, the compounds of formula (I) are useful as therapeutic agents.

  Thus, yet another aspect of the present invention provides a compound of formula (I) or a physiologically acceptable salt or solvate thereof, particularly for the treatment of inflammatory conditions such as asthma or rhinitis.

  According to another aspect of the present invention, there is provided a compound of formula (I) or a physiologically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of inflammatory conditions such as asthma or rhinitis. Use is provided.

  In further or alternative embodiments, methods of treating a human or animal subject suffering from or susceptible to an inflammatory condition such as asthma or rhinitis are provided. The method includes the step of administering an effective amount of a compound of formula (I), or a physiologically acceptable salt or solvate thereof.

  The compounds of the present invention can be formulated for administration by any convenient method.

  Accordingly, there is further 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.

  Further, the manufacture of such a pharmaceutical formulation comprising the step of mixing a compound of formula (I) or a physiologically acceptable salt or solvate thereof with one or more physiologically acceptable diluents or carriers. A method is also provided.

  The compounds of the invention can be formulated, for example, for oral administration, inhalation administration, intranasal administration, buccal administration, parenteral administration, or rectal administration, preferably oral administration.

  Tablets and capsules for oral administration include binders such as syrup, gum arabic, gelatin, sorbitol, tragacanth, starch starch, cellulose, or polyvinylpyrrolidone; fillers such as lactose, microcrystalline cellulose, sugar Corn starch, calcium phosphate, or sorbitol; lubricants such as magnesium stearate, stearic acid, talc, polyethylene glycol, or silica; disintegrants such as potato starch, croscarmellose sodium, or sodium starch glycolate; or Conventional excipients such as wetting agents such as sodium lauryl sulfate may be included. Tablets can be coated by methods well known in the art.

  Oral liquid formulations take the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or are dry formulations for constitution with water or other suitable vehicle prior to use. Can be provided as Such liquid formulations include suspending agents such as sorbitol syrup, methylcellulose, glucose / sugar syrup, gelatin, hydroxymethylcellulose, carboxymethylcellulose, aluminum stearate gel, or hydrogenated edible fat; emulsifiers such as lecithin, Sorbitan monooleate, or gum arabic; non-aqueous media (which may include edible oils) such as almond oil, fractionated coconut oil, oily esters, propylene glycol, or ethyl alcohol; or preservatives such as methyl or propyl p- Conventional additives such as hydroxybenzoate or sorbic acid may be included. The formulations may also optionally include buffer salts, flavoring agents, coloring agents, and / or sweetening agents (eg, mannitol).

  For buccal administration, the composition can take the form of tablets or lozenges formulated in conventional procedures.

  The compounds can also be formulated as suppositories, eg, containing conventional suppository bases such as cocoa butter or other glycerides.

  The compounds of the invention can also be formulated for parenteral administration by bolus injection or continuous infusion, for example in the form of a single dose or as an ampoule, vial, small volume infusion, or prefilled syringe Can be provided in multiple dose containers with a preservative. The composition can take the form of a solution, suspension, or emulsion in an aqueous or non-aqueous medium, antioxidant, buffer, antimicrobial, and / or isotonic. A prescription agent such as an agent may be included. Alternatively, the active ingredient may be in powder form configured with a suitable medium such as sterile water that does not contain pyrogens prior to use. It is also possible to produce a dry solid formulation by filling individual sterile containers with sterile powder aseptically or by filling each container with sterile solution and lyophilizing.

  Compounds and pharmaceutical compositions according to the present invention include antihistamines, anticholinergics, anti-inflammatory agents [such as corticosteroids such as fluticasone propionate, beclomethasone dipropionate, mometasone furoate, triamcinolone acetonide or budesonide] Or non-steroidal anti-inflammatory drugs (NSAIDs) (eg, cromoglycate sodium, nedocromil sodium, PDE-4 inhibitors, leukotriene antagonists, iNOS inhibitors, tryptase and elastase inhibitors, β-2 integrin antagonists, Or other drugs such as beta-adrenergic agents (eg salmeterol, salbutamol, formoterol, fenoterol or terbutaline and their salts); or other anti-infectives (eg antibiotics, antiviral agents); It is also possible to use in combination with agents. It will be appreciated that when the compounds of the invention are administered in combination with other therapeutic agents generally administered by inhalation or intranasal route, the resulting pharmaceutical composition may be administered by inhalation or intranasal route.

  The compound of the present invention may be administered in an appropriate number of times 1 to 4 times a day, for example, in an amount of 0.001 to 500 mg / kg, preferably 0.01 to 500 mg / kg, more preferably 0.01 to 100 mg / kg. Is possible. Of course, the exact method of administration will depend on the indication of treatment, the condition of the patient and the particular route of administration chosen.

  Throughout this specification and the appended claims, unless the context requires otherwise, the term “includes” and its derivatives, such as “included” and “included”, are designated integers. Or is understood to imply that a step or group of integers is included, but does not exclude other integers or steps or groups of integers or steps.

  EXAMPLES Hereinafter, although an Example demonstrates this invention, this invention is not limited by these.

To avoid questioning, the unbonded bond on the R ¹ group shown in the table indicates the point of attachment of the R ¹ group to the rest of the molecule.

  It should be noted that for clarity, the compounds of the illustrative examples and examples are represented by numbers such as “Explanation Example 3” and “Example 4”. The structures of the compounds so mentioned are shown in Tables 1-4 for the examples and in Tables 5-7 for the illustrative examples.

Details about the experiment in general
LC / MS system The following liquid chromatography mass spectrometry (LC / MS) system was used.

  This system uses a 3 μm ABZ + PLUS (3.3 cm × 4.6 mm ID) column, solvent A (0.1% v / v formic acid + 0.077% w / v aqueous ammonium acetate) and solvent B (95: 5 acetonitrile: water + 0.05). % V / v formic acid as eluent, flow rate was 3 ml / min 100% A for 0.7 minutes; A + B mixture, gradient profile from 0% to 100% B over 3.5 minutes; Was maintained for 1.1 minutes; a gradient protocol of returning to 100% A over 0.2 minutes was used.

  In this LC / MS system, an electrospray ionization mode, positive / negative ion switching, and a mass spectrometer with a mass range of 80 to 1000 a.m.u. was used.

The thermospray mass spectrum thermospray mass spectrum, HP5989A Engine Mass spectrometer, + ve thermospray, source temperature 250 ° C., the probe temperature 120 ° C. (shaft portion), 190 ° C. (tip), detection mass range 100~850a.mu It was measured. The compound was injected at a flow rate of 0.7 ml / min with a solution of 10 μl of a solvent mixture containing 65% methanol and 35% 0.05M aqueous ammonium acetate.

Solid phase extraction (ion exchange )
“SCX” refers to an Isolute Flash SCX-2 sulfonic acid solid phase extraction cartridge.

Organic / Aqueous Phase Separation by Hydrophobic Frit “Hydrophobic frit” refers to Whatman polypropylene filter tubes with PTFE frit attached and having a pore size of 5.0 μm.

  All temperatures are in ° C.

Example
Description Example 1: While stirring a solution of 2,2,2-trifluoro-N- (morpholin-2-ylmethyl) acetamide morpholin-2-ylmethylamine (3.1 g) in methanol (70 ml) under nitrogen, To it was added ether solution of α, α, α-trifluoroacetate ether (5 ml in 20 ml ether) which had been washed with saturated aqueous sodium bicarbonate, water and brine. The mixture was stirred at 22 ° C. for 30 minutes and then all volatiles were removed under reduced pressure. The residue was dissolved in methanol (10 ml) and the volatiles were removed again under reduced pressure to give the title compound as a crispy foam (4.9 g).

Thermospray mass spectrum m / z 213 [MH ⁺ ].

Example 2: N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2,2,2-trifluoroacetamide
Illustrative Example 1 While stirring a solution of (3.3 g) in N, N-dimethylformamide (50 ml) under nitrogen, potassium carbonate (2.46 g) and sodium iodide (2.12 g) were added thereto. A solution of 3,4-dichlorobenzyl chloride (2 ml) in N, N-dimethylformamide (10 ml) was added dropwise to the mixture. The mixture was stirred at 22 ° C. for 18 hours before the volatiles were removed under reduced pressure. The residue was partitioned between methylene chloride (100 ml) and saturated aqueous sodium carbonate (50 ml). The organic phase was washed with additional saturated aqueous sodium carbonate (2 x 50 ml) and water (50 ml), then dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure to give a pale yellow oil. I got a thing. The oil was purified by Biotage flash chromatography on a 90 g silica cartridge eluting with 25% ethyl acetate / cyclohexane to give the title compound as a colorless oil (2.97 g).

LC / MS: R _t 2.63 min, mass spectrum: m / z 371 [MH ⁺ ].

Example 3: [4- (3,4-Dichlorobenzyl) morpholin-2-yl] methylamine
Illustrative Example 2 While stirring a solution of 2.97 g in methanol (15 ml) and water (5 ml), potassium carbonate (5.53 g) was added thereto. The mixture was stirred at 22 ° C. for 18 hours before methanol was removed under reduced pressure. Water (25 ml) was added 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 chloride solution (10 ml), dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give a pale yellow oil. . The oil was purified by Biotage flash chromatography on a 90 g silica cartridge eluting with 75: 8: 1 methylene chloride / ethanol / 0.880 ammonia solution. The required fractions were combined and the solvent was removed under reduced pressure to give the title compound as a colorless oil (1.85g).

LC / MS: R _t 1.77 min, Mass ^{spectrum: m / z275 [MH +]} .

Example 4: [4- (3,4-Dichlorobenzyl) morpholin-2-yl] methylamine (another synthetic method)
2-[(3,4-dichlorobenzyl) amino] ethanol (Chemical Abstracts No. 40172-06-3, 0.980 g) and 2- (oxiran-2-ylmethyl) -1H-isoindole-1,3 (2H A mixture of) -dione (1.10 g) was heated at 80 ° C. under nitrogen for 3 hours. The resulting solid mass was treated with concentrated sulfuric acid (1.5 ml) and stirred at 150 ° C. for 24 hours. The mixture was treated with water (100 ml) and washed with ethyl acetate (2 x 100 ml). The dark aqueous phase was made basic at about pH 12 using 5M aqueous sodium hydroxide and extracted with ethyl acetate (2 x 100ml). The combined organic extracts were washed with water and brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give the title compound as a brown oil (1.02 g).

Mass spectrum: m / z 275 (MH ⁺ ).

Example 5: 1-[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamine
Example 3 (Racemic mixture, 8 g) was separated into its single enantiomers by preparative chiral HPLC. Separation: 2 "x 22 cm Chiralpak AD 20 μm column, Merck self pack DAC system, 95: 5: 0.1 (v / v) heptane: pure ethanol: diethylamine (flow rate: 55 ml / min over 40 min, UV Detection 225 nm); sample input preparation: 3: 2 (v / v) pure ethanol: 400 mg sample in 20 mL system eluent.

  The title compound (2.49 g) was obtained with a preparative HPLC retention time of 23.0 minutes.

Example 5 (alternative method)
Description Example 7 A slurry of (1.00 g) in water (8.5 ml) was heated to 75 ° C. and concentrated sulfuric acid (2.5 ml) was added dropwise. The mixture was heated to reflux. After 23 hours, the reaction mixture was cooled to 22 ° C. and treated with methylene chloride (6 ml). 880 ammonia solution (7 ml) was added dropwise with cooling. Additional methylene chloride (10 ml) was added. The aqueous phase was separated and extracted with additional methylene chloride (10 ml). The combined organic phases were washed with water (5 ml) and evaporated to dryness. The residue was redissolved in methylene chloride and the solvent was removed again to give the product as an oil (662 mg).

Example 6: 1: 1 salt of 1-[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methanamine with D-tartaric acid
Example 3 (0.613 g) was dissolved in methanol (12.3 ml). D-tartaric acid (0.335 g) was added and the slurry was heated to reflux for 50 minutes. The mixture was allowed to cool to 0-5 ° C. and the precipitate was isolated by filtration to give the title compound as a white solid (0.4 g).

  ee: 76% ee.

  Chiral analytical HPLC (Chiralpak AD column, 4.6 × 250 mm, eluent 50: 50: 0.1 MeOH: EtOH: butylamine, flow rate: 0.5 ml / min, UV detection: 220 nm): Rt 8.9 min.

Example 7: 2- [4- (3,4-Dichloro-benzyl) -morpholin-2-ylmethyl] -isoindole-1,3-dione
2-[(3,4-Dichlorobenzyl) amino] ethanol (2.038 g) and (S) -2- (oxiran-2-ylmethyl) -1H-isoindole-1,3 (2H) -dione (2.032 g) Of tetrahydrofuran in 3.3 ml was stirred and heated to reflux under nitrogen. After 21.5 hours, additional tetrahydrofuran (12.5 ml) was added and the mixture was cooled to 3 ° C. Triphenylphosphine (2.793 g) was added and the mixture was stirred until all solids were dissolved. Diisopropyl azodicarboxylate (2.1 ml) was added over 12 minutes while maintaining the temperature <7 ° C. After 2.25 hours, the mixture was warmed to 22 ° C. After 5.3 hours, additional triphenylphosphine (121 mg) and diisopropyl azodicarboxylate (0.09 ml) were added. After 22.5 hours, the reaction mixture was concentrated to near dryness. Propan-2-ol (12 ml) was added and concentration was repeated, which was repeated again. Additional propan-2-ol (12 ml) was added and the mixture was heated to 70 ° C. After 0.5 hours, the slurry was cooled to 22 ° C., and after another 2 hours the product was recovered. The bed was washed with propan-2-ol (2 x 4ml) and dried in vacuo at 40 ° C to give the product (2.622g).

Example 8: [(2S) -4- (3,4-difluorobenzyl) morpholin-2-yl] methylamine
Description Example 8 was produced in the same manner as in Description Example 5 .

  Preparative HPLC: retention time 28.3 minutes.

Explanation Example 10: [3-([(2S) -4- (3,4-dichlorobenzyl) morpholin-2-ylmethyl] carbamoylmethoxy) phenyl] carbamic acid tert-butyl ester

(3-tert-Butoxycarbonylamino-phenoxy) -acetic acid (0.100 g) (WO9708193), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.1043 g) and 1-hydroxybenzotriazole (0.0597 g ) In N, N-dimethylformamide (3 ml) was added with stirring to the solution of Illustrative Example 5 (0.0936 g) in N, N-dimethylformamide (1 ml). N, N-diisopropylethylamine (0.119 ml) was added to the mixture, which was then stirred at 20 ° C. for 19.5 hours. The mixture was diluted with methanol (ca. 2 ml) and loaded onto a 10 g SCX ion exchange cartridge (preconditioned with methanol). The cartridge was eluted with methanol and 10% 0.880 ammonia in methanol. The first ammonia fraction was evaporated under reduced pressure and the residue was further purified by Biotage ™ flash chromatography on silica gel eluting with 300: 8: 1 methylene chloride / ethanol / 0.880 ammonia solution. . The required fractions were combined and the solvent was removed under reduced pressure to give the title compound (0.1256 g) as a clear glass.

LC / MS: R _t = 3.14 min, m / z 524,526 [MH ⁺ ].

Method G
Example 27: 2- (3-Amino-phenoxy) -N- [4- (3,4-dichlorobenzyl) morpholin-2-ylmethyl] acetamide

Description Example 10 While stirring a solution of 0.120 g in methanol (3 ml), 4.0 M hydrogen chloride in 1,4-dioxane (1 ml) was added thereto. The mixture was stirred at 20 ° C. for 6 hours and left for 16 hours. The solvent was removed under reduced pressure to give 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. Obtained.

LC / MS: R _t = 2.30 min, m / z 424,426 [MH ⁺ ].

Description Example 12: C-[(2S) -4- (3-chloro-4-fluorobenzyl) morpholin-2-yl] methylamine

Illustrative Example 17 A solution of (0.36 g) in methylene chloride (1 ml) was treated with trifluoroacetic acid (1 ml) and left for 1 hour. The mixture was concentrated under reduced pressure and the residue was partitioned between methylene chloride and aqueous sodium bicarbonate. The phases were separated, the organic phase was dried (MgSO ₄ ), filtered and the solvent was removed under reduced pressure to give the title compound (0.25 g) as a colorless gum.

LC-MS: Rt = 0.70 min. Mass spectrum: m / z 259 [MH ⁺ ].

Example 13: 3-Ethoxycarbonylmethoxy-benzoic acid ethyl ester

  While stirring a mixture of ethyl 3-hydroxybenzoate (1.66 g) and anhydrous potassium carbonate (1.38 g) in N, N-dimethylformamide (20 ml) at room temperature, ethyl bromoacetate (1.67 g) was added thereto. The mixture was stirred overnight, then the solvent was removed under reduced pressure, and the resulting thick white paste was partitioned between water and ethyl acetate (2 portions, total 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 removed under reduced pressure. The residue was further purified by flash column chromatography on silica gel eluting with 4: 1 cyclohexane / ethyl acetate. The necessary fractions were combined and the solvent was removed under reduced pressure to give the title compound (2.18 g) as a colorless oil.

¹ Hnmr (250 MHz, CDCl ₃ ) 7.70 δ (1 H , br. D, CH); 7.57 δ (1 H , br. D, CH); 7.38 δ (1 H , t, CH); 7.15 δ (1 H , br. Dd) , CH); 4.68δ (2H, s, CH 2); 4.40~4.20δ (4H, 2 × q, 2xCH 2); 1.39δ (3H, t, CH 3); 1.30δ (3H, t, CH 3 ).

Example 14: 3-Carboxymethoxy-benzoic acid ethyl ester

Example 13 Potassium carbonate (0.217 g) was added to a stirred solution of 0.397 g in methanol (7 ml) and water (3 ml). The mixture was stirred at 20 ° C. for 18 hours and then the methanol was distilled off under reduced pressure. The pH of the resulting solution was adjusted to about 1 by adding 2M aqueous hydrochloric acid 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, filtered and the solvent was removed under reduced pressure to give the title compound (0.329 g) as a white solid.

LC / MS: R _t = 2.81 min, m / z 225 [MH ⁺ ].

Example 15: (3-Methanesulfonylamino-phenyl) acetic acid

  To a stirred solution of 3-aminophenylacetic acid (3.2 g) and sodium carbonate (5.44 g) in deionized water (36 ml) was added methanesulfonyl chloride (1.7 ml). The mixture was heated and stirred at 85 ° C. for 4 hours, then allowed to cool to room temperature, acidified to pH 2 with concentrated hydrochloric acid, and left in the refrigerator at 4 ° C. overnight. The precipitated solid was filtered and washed with water and ether, and the combined filtrate and washings were evaporated to dryness under reduced pressure. The resulting residue was dissolved in hot water and recrystallized overnight at 4 ° C. in a refrigerator. The crystals were collected by filtration, washed with a small amount of cold water, and dried in vacuo to give the title compound (0.417 g) as colorless crystals.

LC / MS: R _t = 2.00 min, m / z228 [MH ⁻ ], m / z247 [MNH ₄ ⁺ ].

Example 16: (3-Cyclopropanecarbonyl-phenyl) acetic acid

While stirring, a suspension of cyclopropyl-m-tolylketone (J Org Chem (1993), 58 (21), 5802-10; 16.0 g) and N-bromosuccinimide (17.8 g) in carbon tetrachloride (100 ml) was stirred. The mixture was slowly heated to reflux using a 150W electric lamp. After refluxing for 2 hours, the solution was cooled with ice water to give a solid, which was filtered off and washed with carbon tetrachloride (10 ml). The filtrate and washings were combined and evaporated to give a yellow oil. It was fractionally distilled using a Vigreux column. The fraction distilled at 115 to 130 ° C./0.1 mm mercury was collected and dissolved in dehydrated N, N-dimethylformamide (20 ml). The solution was added dropwise over 1 hour to a stirred suspension of sodium cyanide (1.96 g) in dehydrated N, N-dimethylformamide (40 ml) at <10 ° C. Stirring was maintained at 10 ° C. for an additional hour and then at room temperature for 2 hours before the mixture was poured onto ice (140 g) and extracted with ethyl acetate (3 × 60 ml). The combined extracts were dried (MgSO ₄ ) and evaporated to give a brown oil. It was treated with 50% aqueous alcohol containing potassium hydroxide (3.36 g). The mixture was heated to reflux for 5 hours, allowed to cool, washed with chloroform (2 × 50 ml) and acidified to pH 1 by adding 5M hydrochloric 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 ml), dried (MgSO ₄ ) and evaporated to a yellow oil. Got. The oil was extracted with warm petroleum ether (boiling point: 60-80 ° C., 4 × 50 ml) and the combined extracts were evaporated to give a gummy oil. It is recombined with the residue remaining from the extraction, dissolved in 10% ethyl acetate / ether (200 ml), the resulting solution is filtered, washed with water (3 × 20 ml), dried (MgSO ₄ ), The solvent was distilled off to obtain an oily substance. The oil was purified by chromatography on silica gel (100 g) eluting with ethyl acetate, the appropriate fractions combined and evaporated to give a pale yellow oil. It was then distilled under high vacuum. The distillate at 170 ° C./0.1 mm mercury was collected to give the title compound (1.5 g) as a dark cream solid.

Elemental analysis measured values: C, 70.44%; H, 6.00%;
Calculated elemental analysis: C, 70.6%; H, 5.92%.

Description Example 17: [(2S) -4- (3-chloro-4-fluorobenzyl) morpholin-2-ylmethyl] carbamic acid tert-butyl ester

  A solution of (2-morpholinylmethyl) -carbamic acid 1,1-dimethyl ester [CAS186202-57-3] (0.26 g) in methylene chloride (5 ml) was added triethylamine (0.167 ml) and 3-chloro-4- Treated with fluorobenzyl bromide (0.27 g). After stirring for 18 hours, the mixture was purified by direct loading onto an SCX ion exchange cartridge (10 g) eluting with methanol and then 10% 0.880 ammonia / methanol. The basic fraction was evaporated under reduced pressure to give the title compound (0.37 g) as a colorless gum.

LC-MS: Rt = 2.46 min. Mass spectrum: m / z 359 [MH ⁺ ].

Explanation Example 18: [4- (3,4-dichlorobenzyl) morpholin-2-ylmethyl] methylamine

Example 29 (0.0755 g) in 5: 1 methanol / water (7 ml) and potassium carbonate (0.27 g) were stirred at room temperature for 5 hours under nitrogen and then allowed to stand for 65 hours. The solvent was removed under reduced pressure and the residue was redissolved in water (6 ml). The aqueous solution was extracted with methylene chloride using a hydrophobic frit cartridge (4 × 3 ml) and the phases separated. The title compound (0.0507 g) was obtained from the combined organic extracts after evaporation of the solvent.

LCMS: m / z 289 [MH ⁺ ].

Example 20: 4- (2-[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-ylmethyl] carbamoylethyl) benzoic acid tert-butyl ester

Prepared in a similar manner to that used for Example 18 using Example 5 and 4- (2-carboxy-ethyl) benzoic acid tert-butyl ester.

LCMS: m / z 507 [MH ⁺ ].

Explanation Example 21: 4- (2-[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-ylmethyl] carbamoylethyl) benzoic acid hydrochloride

To Example 20 (0.29 g) was added 4.0 M HCl / 1,4-dioxane solution (10 ml). The mixture was stirred at 20 ° C. for 3 hours before the solvent was removed under reduced pressure to give the title compound as a brown solid.

LCMS: m / z 451 [MH ⁺ ].

Illustrative example 22: 3- (4-amino-phenyl) -N-[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-ylmethyl] propionamide

Prepared in a manner similar to that used for Example 18 using Example 5 and 3- (4-aminophenyl) propionic acid.

LCMS: m / z422 [MH ⁺ ]
Illustrative example 23: 3- (3-amino-phenyl) -N-[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-ylmethyl] propionamide

Prepared in a manner similar to that used for Example 18 using Example 5 and 3- (3-aminophenyl) propionic acid.

LCMS: m / z 422 [MH ⁺ ].

Explanation Example 24: 4-([(2S) -4- (3,4-dichlorobenzyl) morpholin-2-ylmethyl] carbamoylmethyl) benzoic acid methyl ester

Prepared in a similar manner to that used for example 18 using illustration 5 and 4- (methoxycarbonyl) phenylacetic acid.

LCMS: m / z 451 [MH ⁺ ].

Example 25: [3- (N′-tert-butoxycarbonyl-hydrazinocarbonyl) phenyl] acetic acid methyl ester

  A solution of 3-methoxycarbonylmethyl-benzoic acid (2.0 g) (see Journal of Chemical Research, Synopses (2000), (6), 282-283 for production) in N, N-dimethylformamide (30 ml). While stirring, tert-butylcarbazide (1.358 g), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (3.19 g), 1-hydroxybenzotriazole (1.96 g) and N, N-diisopropylethylamine (1.96 ml) was added. The mixture was stirred at 20 ° C. for 42 hours under nitrogen and then diluted with methylene chloride (250 ml). The mixture was washed with dilute aqueous sodium bicarbonate (200 ml) and brine (2 x 200 ml) before passing the organic phase through a cartridge incorporating a hydrophobic frit. Next, an equal amount of the organic solution was poured directly into 10 sulfonic acid ion exchange cartridges (10 by 10 g, Isolute SCX, pre-washed with methanol), and the cartridge was eluted with methanol (3 times). The combined eluates were evaporated under reduced pressure to give the title compound as a colorless liquid.

LCMS: m / z 309 [MH ⁺ ].

Illustrative example 26: [3- (N′-tert-butoxycarbonyl-hydrazinocarbonyl) phenyl] acetic acid

Example 25 To a solution of 5.01 g in methanol (9 ml) was added 2M aqueous sodium hydroxide (9.1 ml) and the mixture was stirred at room temperature for 5.75 hours. 2M aqueous HCl (9.1 ml) was added to the mixture followed by 2M aqueous sodium hydroxide (about 1 ml) to adjust the pH of the solution to 7. The solvent was removed under reduced pressure to give the title compound (4.766 g) as a colorless glass as a mixture with inorganic salts.

LCMS: m / z 295 [MH ⁺ ].

Example 27: N ′-[3-([(2S) -4- (3,4-difluorobenzyl) morpholin-2-ylmethyl] carbamoylmethyl) benzoyl] hydrazinecarboxylic acid tert-butyl ester

Using Description Example 8 and Description Example 26 , the same production method as in Example 5 was used.

LCMS: m / z 519 [MH ⁺ ].

Description Example 28: N-[(2S) -4- (3,4-difluorobenzyl) morpholin-2-ylmethyl] -2- (3-hydrazinocarbonyl-phenyl) acetamide

To Example 27 (2.05 g) was added 4.0 M HCl / 1,4-dioxane solution (35 ml) and dehydrated methanol (10 ml). The mixture was stirred at room temperature under nitrogen for 17 hours before the solvent was removed under reduced pressure. The residue was redissolved in methanol, and the solution was poured directly into 8 sulfonic acid ion exchange cartridges (10 per 10 g, Isolute SCX, prewashed with methanol). ) And then 10% 0.880 ammonia / methanol (twice). The solvent was removed from the basic fractions under reduced pressure to give the title compound as an orange-red foam (1.246 g).

LCMS: m / z 419 [MH ⁺ ].

Example 29: N- [4- (3,4-dichlorobenzyl) morpholin-2-ylmethyl] -2,2,2-trifluoro-N-methylacetamide

Description Example 2 (0.0755 g) in methylene chloride (5 ml) was sealed in an Alltech ™ tube (cartridge with an integrated frit on the bottom). BEMP resin (polymer conjugated to 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorin) (0.65 g at 2.3 mmol / g) was added followed by methyl iodide (0.168 ml) was added. The mixture was stirred on a flat bottom shaker at room temperature. The mixture was loaded onto a sulfonate ion exchange cartridge (10 g, Isolute SCX, prewashed with methanol) and the cartridge was eluted with methanol and then 10% 0.880 ammonia / methanol. The solvent was distilled off from the first basic fraction under reduced pressure. Dissolve the residue in methylene chloride and place the solution in a silica solid phase extraction cartridge (10 g, Varian Bondelut, pre-washed with methylene chloride) and methylene chloride, chloroform, ether, ethyl acetate, acetone, acetonitrile and methanol. Further elution was performed by elution in this order. The solvent was distilled off from the ether fraction under reduced pressure to obtain the title compound (0.0755 g).

LCMS: m / z 385 [MH ⁺ ].

Example
Synthesis method A
Example 18

While stirring a solution of Illustrative Example 14 (0.328 g) in N, N-dimethylformamide (6 ml), a solution of Illustrative Example 5 (0.366 g) in N, N-dimethylformamide (5 ml) was added thereto. A solution of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.408 g) and 1-hydroxybenzotriazole (0.234 g) in N, N-dimethylformamide (9 ml) was added to the mixture, followed by To this was added N, N-diisopropylethylamine (0.463 ml). The mixture was stirred at 22 ° C. for 18.5 hours and then diluted with methanol (ca. 5 ml). The mixture was loaded into four 10 g SCX ion exchange cartridges (preconditioned with methanol). The cartridge was eluted with methanol followed by 10% 0.880 ammonia solution / methanol. The first ammonia fractions were combined and the solvent was removed under reduced pressure. The residue was further purified by Biotage ™ flash chromatography on silica gel eluting with 400: 8: 1 methylene chloride / ethanol / 0.880 ammonia solution. The required fractions were combined and the solvent was removed under reduced pressure to give the title compound (0.508 g) as a light brown gum.

LC / MS: R _t = 2.90 min, m / z 481,483 [MH ⁺ ].

Method A Alternative
Example 38: 3- (4-Chlorophenyl) -N- [4- (3,4-dichlorobenzyl) morpholin-2-ylmethyl] propionamide; compound with trifluoroacetic acid

To 3- (4-chlorophenyl) propionic acid (0.037 g) was added a portion (0.25 ml) of a solution of Description Example 3 (1.292 g) in methylene chloride (5.0 ml) and the methylene chloride was evaporated. N-methylpyrrolidinone (1 drop) was added to the mixture, which was then heated in a microwave (4 minutes at full power) and allowed to cool. The sample was purified by preparative HPLC by mass and the solvent was removed under reduced pressure to give the title compound (0.0187g).

LCMS: R _t 2.03 ^{min, m / z394 [MH +]} .

Synthesis method B
Example 23 (mutual conversion)

To a stirred solution of Example 18 (0.5038 g) in methanol (10 ml) was added 2M aqueous sodium hydroxide (1.05 ml) and water (10 ml). The mixture was stirred at 22 ° C. for 14 hours and left for an additional 18 hours. 2M aqueous hydrochloric acid (1.05 ml) was added and the mixture was loaded into two 10 g SCX ion exchange cartridges (preconditioned with methanol). The cartridge was eluted with methanol and then 5% triethylamine / methanol. The first triethylamine fractions were combined and the solvent was removed under reduced pressure to give the title compound (0.453 g) as a brown gum.

LC / MS: R _t = 2.49 min, m / z 453,455 [MH ⁺ ].

Example 14 (mutual conversion)

A solution of Example 23 (0.148 g) in N, N-dimethylformamide (1 ml) was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.081 g) and 1-hydroxybenzotriazole (0.047 g). A solution of g) in N, N-dimethylformamide (1 ml) was added to what was stirred at 20 ° C. Cyclopropylamine (0.0918 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 (ca. 2 ml) and loaded onto a 10 g SCX ion exchange cartridge (preconditioned with methanol). The cartridge was eluted with methanol and then with 10% 0.880 ammonia solution / methanol. The first ammonia fraction was evaporated under reduced pressure and the residue further purified by Biotage ™ flash chromatography on silica gel eluting with 200: 8: 1 methylene chloride / ethanol / 0.880 ammonia solution. did. The necessary fractions were combined and the solvent was distilled off under reduced pressure to give a residue. It was further purified by Biotage ™ flash chromatography on silica gel eluting with 5% methanol / ethyl acetate. The necessary fractions were combined, and the solvent was evaporated under reduced pressure to give the title compound (0.105 g) as a colorless glass.

LC / MS: R _t = 2.53 min, m / z 492,494 [MH ⁺ ].

Synthesis method C
Example 24

While stirring a solution of Example 27 (0.0491 g) in methylene chloride (5 ml) and acetonitrile (1 ml) at 20 ° C., N, N-diisopropylethylamine (0.0516 ml) and methanesulfonyl chloride (0.0084 ml) were added to it. added. The mixture was stirred at 20 ° C. for 26 hours, during which time additional methanesulfonyl chloride (0.0031 ml) was added. The mixture was diluted with methanol (ca. 2 ml) and loaded onto a 5 g SCX ion exchange cartridge (preconditioned with methanol). The cartridge was eluted with methanol and 10% 0.880 ammonia solution / methanol. The first ammonia fraction was evaporated under reduced pressure and the residue was Biotage ™ on silica gel eluting with a gradient of 600: 8: 1 to 200: 8: 1 methylene chloride / ethanol / 0.880 ammonia solution. ) Further purification by flash chromatography. The required fractions were combined and the solvent was removed under reduced pressure to give the title compound (0.0087g) as a light brown glass.

LC / MS: R _t = 2.55 min, m / z 502,504 [MH ⁺ ].

Synthesis method D
Example 5

While stirring a solution of 3-carboxymethyl-benzoic acid methyl ester (0.214 g) (J. Med. Chem. 1999, 42 (14), 2621-2632) in N, N-dimethylformamide (5 ml), 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.288 g) and 1-hydroxybenzotriazole (0.162 g) were added, followed by N, N-dimethylformamide of Example 8 (0.242 g) ( In 5 ml) was added. N, N-diisopropylethylamine (0.348 ml) was added to the mixture, which was then stirred at 22 ° C. for 18 hours. Equal amounts of the mixture were loaded onto two 10 g SCX ion exchange cartridges (preconditioned with methanol). The cartridge was eluted with methanol and 10% 0.880 ammonia solution / methanol. The first ammonia fractions were combined and the solvent was removed under reduced pressure. The residue was further purified by Biotage ™ flash chromatography on silica gel eluting with 200: 8: 1 methylene chloride / ethanol / 0.880 ammonia solution. The required fractions were combined and the solvent was removed under reduced pressure to give the title compound (0.301 g) as a cream solid.

LC / MS: R _t = 2.36 min, m / z 419 [MH ⁺ ].

Synthesis method E
Example 7 (mutual conversion)

To a stirred solution of Example 5 (0.2988 g) in methanol (5 ml) was added 2M aqueous sodium hydroxide (0.71 ml). The mixture was stirred at 22 ° C. for 66 hours before 2M aqueous hydrochloric acid (0.71 ml) was added. Equal amounts of the mixture were loaded onto two 10 g SCX ion exchange cartridges (preconditioned with methanol). The cartridge was eluted with methanol and 5% triethylamine / methanol. The first triethylamine fractions were combined and the solvent was removed under reduced pressure to give the title compound (0.353 g) as a yellow gum.

LC / MS: R _t = 2.15 min, m / z 405 [MH ⁺ ].

Example 10

While stirring a solution of Example 7 (0.057 g) in N, N-dimethylformamide (1 ml), it was mixed with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.0325 g) and 1-hydroxy Benzotriazole (0.018 g) was added. N, N-diisopropylethylamine (0.039 ml) was added, followed by 2M ethylamine in tetrahydrofuran (0.140 ml) and the mixture was stirred at 22 ° C. for 18 hours. The mixture was loaded onto a 5 g SCX ion exchange cartridge (preconditioned with methanol). The cartridge was eluted with methanol and 10% 0.880 ammonia solution / methanol. The first ammonia fraction was evaporated under reduced pressure and the residue was further purified by Biotage ™ flash chromatography on silica gel eluting with 150: 8: 1 methylene chloride / ethanol / 0.880 ammonia solution. . The necessary fractions were combined, and the solvent was evaporated under reduced pressure to give the title compound (0.0379 g) as a solid.

LC / MS: R _t = 2.14 min, m / z 432 [MH ⁺ ].

Synthesis method F
Example 22

Illustrative Example 5 While stirring a solution of (0.050 g) in acetonitrile (1 ml), potassium carbonate (0.025 g) was added thereto. To the mixture was added (4-chloro-phenoxy) -acetyl chloride (0.037 g) (Chem. Pharm. Bull. 1988, 36 (11), 4426-34) and the mixture was stirred at 20 ° C. for 3 hours. The solvent was removed under reduced pressure and the residue was partitioned between water (2 ml) and methylene chloride (2 ml). The phases were separated on a hydrophobic frit and the organic phase was purified directly by Biotage ™ flash chromatography on silica gel eluting with 300: 8: 1 methylene chloride / ethanol / 0.880 ammonia solution. The required fractions were combined and the solvent was removed under reduced pressure to give the title compound (0.0286 g) as a white solid.

LC / MS: R _t = 2.90 min, m / z 443,445 [MH ⁺ ].

Method H
Example 37: N-[(2S) -4- (3,4-difluorobenzyl) morpholin-2-ylmethyl] -2- [3- (5-methyl- [1,3,4] oxadiazole-2 -Yl) phenyl] acetamide

To Example 28 (0.20 g), triethyl orthoacetate (1.5 ml) was added and heated in “Reacti-vial” at 160 ° C. for 18 hours. After cooling, the volatiles were distilled off under a stream of nitrogen, and the residue was redissolved in methanol and charged directly into a sulfonate ion exchange cartridge (10 g Isolute SCX, preconditioned with methanol). The cartridge was eluted with methanol and then 10% 0.880 ammonia / methanol and the basic fraction was concentrated under reduced pressure to give the title compound as a colorless gum (0.17 g).

LCMS: R _t 2.12 ^{min, m / z443 [MH +]} .

Method I
Example 39: N-[(2S) -4- (3,4-difluorobenzyl) morpholin-2-ylmethyl] -2- (3- [1,3,4] oxadiazol-2-yl-phenyl) Acetamide; compound with formic acid

To Description Example 28 (0.20 g), triethyl orthoformate (1.5 ml) was added and heated in “Reacti-vial” at 160 ° C. for 18 hours. After cooling, the volatiles were distilled off under a nitrogen stream, and the residue was redissolved in methanol and charged directly into a sulfonate ion exchange cartridge (10 g Isolute SCX, preconditioned with methanol). The cartridge was eluted with methanol and then 10% 0.880 ammonia / methanol, and the basic fraction was concentrated under reduced pressure. The residue was further purified by preparative HPLC by mass to give the title compound as a colorless gum (0.021 g) after removal of the solvent under reduced pressure.

LCMS: R _t 2.05 min, m / z 429 [MH ⁺ ].

Method J
Example 41: N-[(2S) -4- (3,4-difluorobenzyl) morpholin-2-ylmethyl] -2- [3- (5-methyl-4H- [1,2,4] triazole-3 -Yl) phenyl] acetamide; compound with formic acid

A solution of sodium hydroxide (0.0933 g) in dehydrated methanol (2.91 ml) was prepared and a portion of the solution (0.596 ml) was added to ethylacetimidate hydrochloride (0.059 g). The mixture was shaken for 2 minutes and allowed to stand for another 5 minutes, after which the supernatant of the mixture was transferred by syringe to “Reacti-vial” containing Description 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 a mixture of 5% methanol / chloroform and methylene chloride, loaded onto a silica solid phase extraction cartridge (10 g, Varian Bondelut, prewashed with methylene chloride) and eluted with 5% methanol / chloroform. The solvent was removed from the required fractions under reduced pressure, the residue was further purified by preparative HPLC by mass, and the solvent was removed under reduced pressure to give the title compound as a colorless gum (0.020 g). .

LCMS: R _t 2.01 min, m / z 442 [MH ⁺ ].

Example 42: N-[(2R) -4- (3,4-dichlorobenzyl) morpholin-2-ylmethyl] -2- (3-dimethylsulfamoyl-phenyl) acetamide

(4-Dimethylsulfamoyl-phenyl) acetic acid (0.049 g) (containing a small amount of the isomer 3-dimethylsulfamoyl-phenyl) acetic acid in Example 3 (1.1 g) in methylene chloride (4.0 ml). A portion of the solution (0.25 ml) was added and the methylene chloride was evaporated. N-methylpyrrolidinone (1 drop) was added to the mixture, which was then heated in a microwave oven (4 minutes at full power) and allowed to cool. The sample was purified by preparative HPLC by mass and the solvent was distilled off under a stream of nitrogen. The residue, which is a racemic mixture of isomers, was separated on a Chiralpak AD preparative HPLC column (25 × 2 cm) eluting with 40% ethanol / n-heptane. The flow rate was 15 ml / min and the detection wavelength was 215 nm. Fractions containing the required product (first eluted product) were combined and evaporated to give the title compound (0.0017g).

LCMS: R _t 2.70 ^{min, m / z500 [MH +]} .

Example 51: N-[(2S) -4- (3,4-dichloro-benzyl) morpholin-2-ylmethyl] -3- (4-propionylamino-phenyl) propionamide

Illustrative Example 22 To a solution of (0.10 g) in dehydrated methylene chloride (8 ml) was added N, N-diisopropylethylamine (0.062 ml) followed by propionyl chloride (0.0329 g). The mixture was stirred at room temperature for 22 hours. The mixture was loaded onto a sulfonate ion exchange cartridge (10 g, Isolute SCX, prewashed with methanol) and the cartridge was eluted with methanol and then 10% 0.880 ammonia / methanol. The solvent was distilled off from the basic fraction under reduced pressure to obtain the title compound (0.0936 g).

LCMS: R _t 2.45 ^{min, m / z478 [MH +]} .

Example 82: N- [4- (3,4-dichlorobenzyl) morpholin-2-ylmethyl] -2- (3-methylsulfanyl-phenyl) acetamide

Example 3 (0.312 g), 1-hydroxybenzotriazole (0.199 g), N, N-diisopropylethylamine (0.387 ml) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.346 g) The mixture was stirred in N, N-dimethylformamide (5 ml) at 20 ° C. for 7 hours and left for 18 hours. Volatiles were removed under reduced pressure and the residue was redissolved in methanol. The mixture was aliquoted into two sulfonate ion exchange cartridges (2 × 10 g, Isolute SCX, prewashed with methanol) and the cartridge was eluted with methanol and then 10% 0.880 ammonia / methanol. From the first basic fractions combined, the solvent was distilled off under reduced pressure. The residue was dissolved in methylene chloride, and the solution was put into two silica solid phase extraction cartridges (2 × 10 g, Varian Bondelut, pre-washed with methylene chloride), and methylene chloride, chloroform, ether, ethyl acetate, Further purification was performed by eluting with acetone, acetonitrile and methanol in that order. From the combined acetone fractions, the solvent was distilled off under reduced pressure to obtain the title compound (0.122 g).

LCMS: R _t 2.84 ^{min, m / z439 [MH +]} .

  Examples 35, 44, 46, 48, 52, 54, 56, 58, 62, 67, 68, 70, 75, 77, 81, 85, 86, 87, 88, 88, 89, 78, 80, 60, Synthesis method A was used for the production of 66 and 82.

  In the production of Examples 30, 32, 34, 36, 72, 74, 76, 38 and 42, Synthesis Method A (another method) was used.

  Synthesis method B was used for the production of Examples 65, 79, 73, 69 and 71.

  Synthesis method C was used for the production of Examples 45, 63, 59, 61, 47, 84 and 43.

  Synthesis method D was used for the production of Examples 50, 64, 31, 33, 83 and 90.

  For the production of Example 40, synthesis method E was used.

  Synthesis method G was used for the production of Examples 49, 55, 57, 51 and 53.

  Synthesis method H was used for the production of Example 37.

  For the production of Example 39, Synthesis Method I was used.

For the production of Example 41, Synthesis Method J was used.

Claims (24)

Compounds of formula (I) below and salts and solvates of said compounds.

[Where:
R ¹ represents substituted or unsubstituted aryl;
X represents -O- or a bond;
Y represents-(CR _na R _nb ) _n- ;
R _na and R _nb are each independently hydrogen or C _1-6 alkyl;
n is an integer from 1 to 5;
R ² represents unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl;
R ³ represents hydrogen or C _1-6 alkyl;
R ¹⁰ represents hydrogen or C _1-6 alkyl;
However, the following compounds:
2- (4-chlorophenyl) -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-phenylacetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-phenoxyacetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (4-methoxyphenyl) acetamide;
2- (3-chlorophenyl) -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- [4- (methylthio) -phenyl] acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- [4- (dimethylamino) -phenyl] acetamide compound (1: 1) with formic acid;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-4-[(dimethylamino) -sulfonyl] phenylacetamide compound (1: 1) with formic acid;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- [4- (methylsulfonyl) -phenyl] acetamide compound (1: 1) with formic acid;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (3-fluorophenyl) acetamide;
2- [3,5-bis (trifluoromethyl) phenyl] -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] -methylacetamide;
2- (2-chlorophenyl) -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (4-fluoro-2-methylphenyl) -acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (3,4-difluorophenyl) -acetamide;
4- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -benzamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- [4- (trifluoromethyl) -phenyl] acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (4-methylphenyl) acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (2,4-dichlorophenyl) -acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (4-fluorophenyl) acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (3,4-dichlorophenyl) -acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (2,5-dichlorophenyl) -acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (2,6-dichlorophenyl) -acetamide;
2- (4-chlorophenyl) -N- [4- (2,3-dichlorobenzyl) morpholin-2-yl] methyl-acetamide trifluoroacetate;
2- [3- (acetylamino) phenyl] -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-acetamide;
2- (4-acetylphenyl) -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide trifluoroacetate;
2- (4-acetylphenyl) -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (4-isobutyrylphenyl) acetamide trifluoroacetate;
4- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -benzoic acid methyl trifluoroacetate;
4- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -methyl benzoate;
2- (4-cyanophenyl) -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide trifluoroacetate;
2- (4-cyanophenyl) -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
2- (4-chlorophenyl) -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylpropanamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (3-fluoro-4-hydroxyphenyl) -acetamide trifluoroacetate;
N-[(2R) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- [4- (methylsulfonyl) -phenyl] acetamide;
N-[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- [4- (methylsulfonyl) -phenyl] acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-4-[(4-methylpiperazin-1-yl) carbonyl] phenylacetamide;
4- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -N- [2- (dimethylamino) ethyl] benzamide;
4- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -N, N-dimethylbenzamide;
4- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -N-ethylbenzamide;
4- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -N- (2-hydroxyethyl) benzamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- [4- (morpholin-4-yl-carbonyl) phenyl] acetamide;
N-[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-3-[(dimethylamino) -sulfonyl] phenylacetamide;
N-[(2R) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-4-[(dimethylamino) -sulfonyl] phenylacetamide;
N-[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-4-[(dimethylamino) -sulfonyl] phenylacetamide;
4- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -N-methylbenzamide;
4- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -N-isopropylbenzamide;
N-cyclopropyl-4- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] benzamide;
4- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -N- (2-methoxyethyl) benzamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (4-nitrophenyl) acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (3-nitrophenyl) acetamide;
3- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -methyl benzoate;
2- [3- (acetylamino) phenyl] -N- [4- (3-fluorobenzyl) morpholin-2-yl] methyl-acetamide;
N- [4- (3-fluorobenzyl) morpholin-2-yl] methyl-2-4-[(methylsulfonyl) -amino] phenylacetamide;
2- [3- (acetylamino) phenyl] -N- [4- (3,4-difluorobenzyl) morpholin-2-yl] methyl-acetamide;
N- [4- (3,4-difluorobenzyl) morpholin-2-yl] methyl-2-4-[(methylsulfonyl) -amino] phenylacetamide;
2- [4- (acetylamino) phenyl] -N- [4- (3,4-difluorobenzyl) morpholin-2-yl] -methylacetamide;
N- [4- (3,4-difluorobenzyl) morpholin-2-yl] methyl-2-3-[(methylsulfonyl) -amino] phenylacetamide;
N- [4- (3,4-difluorobenzyl) morpholin-2-yl] methyl-2- [3- (methylsulfonyl) -phenyl] acetamide;
N- [4- (3-chlorobenzyl) morpholin-2-yl] methyl-2- [4- (methylsulfonyl) -phenyl] acetamide;
N- [4- (3-chlorobenzyl) morpholin-2-yl] methyl-2- [3- (methylsulfonyl) -phenyl] acetamide;
2- [3- (acetylamino) phenyl] -N- [4- (4-fluorobenzyl) morpholin-2-yl] methylacetamide;
N- [4- (4-fluorobenzyl) morpholin-2-yl] methyl-2-4-[(methylsulfonyl) amino] -phenylacetamide;
2- [4- (acetylamino) phenyl] -N- [4- (4-fluorobenzyl) morpholin-2-yl] methylacetamide;
N- [4- (2,3-dichlorobenzyl) morpholin-2-yl] methyl-2- [4- (methylsulfonyl) -phenyl] acetamide;
2- [3- (acetylamino) phenyl] -N- [4- (2,3-dichlorobenzyl) morpholin-2-yl] methyl-acetamide;
N- [4- (2,3-dichlorobenzyl) morpholin-2-yl] methyl-2-4-[(methylsulfonyl) -amino] phenylacetamide;
N- [4- (2,3-Dichlorobenzyl) morpholin-2-yl] methyl-2- (4-[(methylamino)-
-Carbonyl] aminophenyl) acetamide;
N- (4-[(5-chlorothien-2-yl) methyl] morpholin-2-ylmethyl) -2- [4- (methylsulfonyl) -phenyl] acetamide;
2- [3- (acetylamino) phenyl] -N- (4-[(5-chlorothien-2-yl) methyl] morpholin-2-ylmethyl) acetamide;
N- (4-[(5-chlorothien-2-yl) methyl] morpholin-2-ylmethyl) -2-4-[(methylsulfonyl) -amino] phenylacetamide;
N- (4-[(5-chlorothien-2-yl) methyl] morpholin-2-ylmethyl) -2-3-[(methylsulfonyl) -amino] phenylacetamide;
2- [3- (acetylamino) phenyl] -N- [4- (3-chlorobenzyl) morpholin-2-yl] methyl-acetamide;
N- [4- (3-Chlorobenzyl) morpholin-2-yl] methyl-2-4-[(methylsulfonyl)-
-Amino] phenylacetamide;
2- [4- (acetylamino) phenyl] -N- [4- (3-chlorobenzyl) morpholin-2-yl] methyl-acetamide;
N- [4- (3-chlorobenzyl) morpholin-2-yl] methyl-2- (4-[(methylamino) carbonyl] -aminophenyl) acetamide;
2- [4- (acetylamino) phenyl] -N- [4- (2,3-dichlorobenzyl) morpholin-2-yl] -methylacetamide;
N- [4- (2,3-dichlorobenzyl) morpholin-2-yl] methyl-2- [3- (methylsulfonyl) -phenyl] acetamide;
2- [4- (aminosulfonyl) phenyl] -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
2- [2- (acetylamino) phenyl] -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
2- (3-cyanophenyl) -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (2-fluorophenyl) acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (2,3-difluorophenyl) -acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (2,4-difluorophenyl) -acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (2,5-difluorophenyl) -acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (2,6-difluorophenyl) -acetamide;
N-cyclopropyl-3- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] benzamide;
3- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -N- (2-methoxyethyl) benzamide;
3- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -N-ethylbenzamide;
3- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -N, N-dimethylbenzamide;
3- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -N- [2- (dimethylamino) ethyl] benzamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-3-[(4-methylpiperazin-1-yl) carbonyl] phenylacetamide;
2- (3-aminophenyl) -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
2- (4-aminophenyl) -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
2- [4- (acetylamino) phenyl] -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-acetamide;
N-4- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -phenyl 2-methylpropanamide;
N-3- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -phenyl 2-methylpropanamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-3-[(methylsulfonyl) -amino] phenylacetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-4-[(methylsulfonyl) -amino] phenylacetamide;
N-3- [2-([4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -phenyl-2- (dimethylamino) acetamide;
2-4- [bis (methylsulfonyl) amino] phenyl-N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- [3- (methylsulfonyl) -phenyl] acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- [4- (methylsulfonyl) -2-nitrophenyl] acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2- (2-hydroxyphenyl) acetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-4- [methyl (methylsulfonyl) -amino] phenylacetamide;
N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-3- [methyl (methylsulfonyl) -amino] phenylacetamide;
2- [2-amino-4- (methylsulfonyl) phenyl] -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
N-((2S) -4-[(5-chlorothien-2-yl) methyl] morpholin-2-ylmethyl) -2-3-[(methylsulfonyl) amino] phenylacetamide;
N-((2R) -4-[(5-chlorothien-2-yl) methyl] morpholin-2-ylmethyl) -2-3-[(methylsulfonyl) amino] phenylacetamide;
N-[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-4-[(methylamino) -sulfonyl] phenylacetamide;
N-[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-4-[(ethylamino) -sulfonyl] phenylacetamide;
2- [3- (aminosulfonyl) phenyl] -N-[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
2-3-[(cyclopropylamino) sulfonyl] phenyl-N-[(2S) -4- (3,4-dichlorobenzyl) -morpholin-2-yl] methylacetamide;
N-[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-3-[(ethylamino) -sulfonyl] phenylacetamide;
N-[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl-2-3-[(methylamino) -sulfonyl] phenylacetamide;
N-[(2S) -4- (4-fluorobenzyl) morpholin-2-yl] methyl-2-4-[(methylsulfonyl) -amino] phenylacetamide;
N-[(2R) -4- (4-fluorobenzyl) morpholin-2-yl] methyl-2-4-[(methylsulfonyl) -amino] phenylacetamide;
2- [4- (aminosulfonyl) phenyl] -N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
2-4-[(cyclopropylamino) sulfonyl] phenyl-N- [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylacetamide;
N-cyclopropyl-3- [2-([(2S) -4- (2,3-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] benzamide;
3-2-[((2S) -4-[(5-chlorothien-2-yl) methyl] morpholin-2-ylmethyl) amino] -2-oxoethyl-N-cyclopropylbenzamide;
N-cyclopropyl-3- [2-([(2S) -4- (4-fluorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] benzamide;
3- [2-([(2S) -4- (3-chlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] -N-cyclopropylbenzamide;
N-cyclopropyl-3- [2-([(2S) -4- (3,4-difluorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] benzamide; and
N-cyclopropyl-3- [2-([(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methylamino) -2-oxoethyl] benzamide is excluded. ] The compound of formula (I) according to claim 1, wherein R ¹ is unsubstituted or substituted phenyl. R ¹ is unsubstituted phenyl or 4- (methanesulfonyl), 4- (methylcarbonylamino), 2,4,6- (trifluoro), 3- (methylthio), 2,5- (difluoro), 4- (pyrazol-1-yl), 3- (methanesulfonyl), 3- (2-methyl-1,3,4-oxadiazol-5-yl), 3- (1,3,4-oxadi (Azol-5-yl), 3- (2-methyl-1,3,4-triazol-5-yl), 4- (ethylcarbonylamino), 4- (methylaminocarbonyl), 4- (carboxy), 3 -(Iso-propanesulfonylamino), 3- (cyclopropanesulfonylamino), 3- (ethanesulfonylamino), 4- (methylaminocarbonylamino), 4-methanesulfonyl-2-methanesulfonylamino), 4- ( Ethylaminocarbonyl), 3- (N, N-dimethylaminosulfonyl), 4- (methanesulfonylaminomethyl), 3- (methanesulfonylamino), 3- (cyclopropylcarbonyl), 3- (methylcarbonyl) Bonyl), 3- (methoxycarbonyl), 3- (aminosulfonyl), 4- (methanesulfonylamino), 3- (methylaminocarbonyl), 3- (dimethylaminocarbonyl), 3- (iso-propylaminocarbonyl) 3- (iso-propylmethylaminocarbonyl), 4- (fluoro), 3- (amino), 4- (methylcarbonylamino), 3- (cyclopropylaminocarbonyl), 3- (methylcarbonylamino), 3 -(Ethylaminocarbonyl), 4- (piperidin-1-ylcarbonyl), 3- (ethoxycarbonyl), 4-cyano, 4- (aminosulfonyl), 4- (amido), 4- (chloro) or 3- 3. A compound of formula (I) according to claim 1 or 2 which is phenyl substituted with (carboxy). A compound of formula (I) according to any one of claims 1 to 3, wherein R _na and R _nb are both hydrogen.   n is 1, 2 or 3 The compound of formula (I) according to any one of claims 1 to 4. A compound of formula (I) according to any of claims 1 to 5, wherein R ¹⁰ is hydrogen or methyl. A compound of formula (I) according to any of claims 1 to 6, wherein R ¹⁰ is hydrogen. Compounds of formula (I) according to any one of claims 1 to 7 R ³ is hydrogen. R ² is an unsubstituted or substituted phenyl, the compound of formula (I) according to claim 1 which is unsubstituted or substituted thiophenyl or unsubstituted or substituted pyridinyl. Compounds of formula (I) according to claim 1 which is or pyridinyl; which thiophenyl substituted by chlorine; R ² is phenyl which substituted by chlorine or fluorine. R ² is 3-fluorophenyl, 4-fluorophenyl, 2,5-dichlorophenyl, 3-chlorophenyl, 3- (trifluoromethyl) phenyl, 3-chlorophenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3 11. A compound of formula (I) according to any of claims 1 to 10, which is -chloro-4-fluoro-phenyl, 2-chlorothiophen-5-yl or pyridin-3-yl.   2. A compound of formula (I) according to claim 1 selected from the examples.   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, From 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 13. A compound of formula (I) according to claim 12, which is selected.   Examples 1, 3, 4, 5, 8, 10, 11, 12, 13, 14, 15, 16, 17, 29, 31, 35, 41, 43, 45, 47, 49, 51, 55, 57, 13. A compound of formula (I) according to claim 12, selected from 59, 61, 63, 65, 77, 85, 87, 88, 89 and 90.   Example 13, 88, 14, 1, 4, 35, 29, 43, 45, 47, 49, 51, 55, 57, 59, 85 and 87 of formula (I) according to claim 12 Compound. A process for the preparation of a compound of formula (I) according to claim 1, wherein the compound of formula (II) below is converted to a compound of formula (III) below in the presence of a peptide coupling agent and optionally an activator. Compound

Wherein R ¹ , X, Y, R ³ , R ¹⁰ and R ² are as defined above for formula (I) in claim 1; and thereafter if necessary The following appropriate steps:
(i) converting a compound of formula (I) to another compound of formula (I);
(ii) removing the necessary protecting groups;
(iii) performing one or more of the steps of producing a salt or solvate of the compound so formed. A process for producing a compound of formula (I), comprising a compound of formula (XI)

Wherein L ² is a leaving group; R ¹ , X and Y are as defined above for formula (I) in claim 1 with a compound of formula (III) and then If necessary, the following appropriate steps:
(i) converting a compound of formula (I) to another compound of formula (I);
(ii) removing the necessary protecting groups;
(iii) performing one or more of the steps of producing a salt or solvate of the compound so formed. Compound of the following formula (IIIBE).

Wherein R ² and R ¹⁰ are as defined for formula (I) in claim 1; A is a protected amino group. ] A compound of the following formula (IIIBR):

Wherein R ² and R ¹⁰ are as defined for formula (I) in claim 1; A is a protected amino group. ]   A compound of formula (I) or a physiologically acceptable salt or solvate of said compound according to claim 1 for use as an active therapeutic agent.   2. A compound of formula (I) or a physiologically acceptable salt or solvate of said compound according to claim 1 for use in the treatment of inflammatory conditions such as asthma or rhinitis.   Use of a compound of formula (I) or a physiologically acceptable salt or solvate of said compound according to claim 1 in the manufacture of a medicament for the treatment of inflammatory conditions such as asthma or rhinitis.   A method of treating a human or animal subject suffering from or susceptible to an inflammatory condition such as asthma or rhinitis, comprising an effective amount of a compound of formula (I) according to claim 1 or a physiologically active compound thereof. Administering an acceptable salt or solvate.   A pharmaceutical composition comprising a compound of formula (I) according to claim 1 or a physiologically acceptable salt or solvate of said compound, and optionally one or more physiologically acceptable diluents or carriers. .