JP2005526807A - Morpholine derivative substituted at the 2-position by an arylalkylurea group for use as a CCR-3 antagonist in the treatment of inflammatory conditions - Google Patents

Abstract

Formula (I) wherein R ¹ represents unsubstituted or substituted aryl; Y represents — (CR _na R _nb ) _n —; R _na and R _nb are each independently hydrogen or _{C 1} in There ₆ alkyl; n is an integer from 1 to 5; is R ^2, represents an unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl; R ³ and R ⁴ are each independently hydrogen or It is suggested that certain compounds represented by C _1-6 alkyl, and salts and solvates thereof, are CCR3 antagonists and are therefore of therapeutic use.

Description

  The present invention relates to novel compounds, methods 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, extravascular 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 tissue is damaged or infected, a series of events occur that cause local mobilization of leukocytes from the circulatory system 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.

  Asthma-specific bronchial inflammation is a special form of cell-mediated immunity in which cytokine products such as IL-4 and IL-5 released by T-helper 2 (Th2) lymphocytes There is increasing evidence that sphere accumulation and activation, particularly eosinophils and, to a lesser extent, regulate the accumulation and activation of basophils. 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 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 the spacing of two conserved cysteine residues near the amino terminus of the chemokine protein. Chemokines bind to specific cell surface receptors belonging to a family of G protein-coupled seven-transmembrane domain proteins (for a review, see Luster, 1998). Activation of chemokine receptors, among other responses, increases intracellular calcium, changes in cell shape, increases expression of cell adhesion molecules, degranulation, and promotes cell migration (chemotacticity). Occur.

  To date, several CC chemokine receptors have been identified and of particular importance to 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 serve to mobilize these cell types to inflammatory sites and cause their activation there (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 antibodies completely inhibit the interaction between eotaxin and eosinophils (Heath, H. et al., J. Clin. Invest. 99 (2), 178-184 ( In contrast, antibodies against eotaxin, a CCR-3 specific chemokine, reduced both bronchial hyperreactivity and lung eosinophilia in an animal model of asthma (Gonzalo et al., J Exp. Med., 188, 157-167 (1998) Therefore, multifaceted evidence suggests that antagonists of the CCR-3 receptor may be used for therapeutic use to treat a range of inflammatory conditions. It is considered very expensive.

  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 congeners 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 can act as co-receptors for the infection of mammalian cells such as human immunodeficiency virus (HIV). There is also sex. Thus, chemokine receptor antagonists, including CCR-3 antagonists, can prevent HIV infection of CCR-3 expressing cells or prevent the generation of immune cell responses by viruses such as cytomegalovirus. Will be useful.

  International Patent Application Publication No. WO 01/24786 (Shionogi & Co. Ltd.) discloses certain aryl and heteroaryl derivatives for treating diabetes. WO 00/69830 (Torrey Pines Institute for Molecular Studies) discloses specific diazacyclic compounds for biological screening and libraries containing them. WO 00/18767 (Neurogen Corporation) discloses certain piperazine derivatives as dopamine D4 receptor antagonists. US Pat. No. 6,031,097 and WO 99/21848 (Neurogen Corporation) disclose certain aminoisoquinoline derivatives as dopamine receptor ligands. WO 99/06384 (Recordati Industria Chimica) discloses piperazine derivatives useful for the treatment of neuromuscular dysfunction in the lower urinary tract. WO 98/56771 (Schering Aktiengesellschaft) discloses certain piperazine derivatives as anti-inflammatory agents. WO 97/47601 (Yoshitomi Pharmaceutical Industries Ltd.) discloses certain fused heterocyclic compounds as dopamine D receptor blockers. WO 96/39386 (Schering Corporation) discloses certain piperidine derivatives as neurokinin antagonists. WO 96/02534 (Byk Gulden Lomberg Chemische Fabrik GmbH) discloses certain piperazine thiopyridines useful for controlling Helicobacter bacteria. WO 95/32196 (Merck Sharp & Dohme Limited) discloses certain piperazine derivatives, piperidine derivatives, and tetrahydropyridine derivatives as 5-HT1D alpha antagonists. US Pat. No. 5,389,635 (E.I. Du Pont de Nemours and Company) discloses certain substituted imadazoles as angiotensin II antagonists. EP 0 306 440 (Schering Aktiengesellschaft) discloses certain imidazole derivatives as cardiovascular agents.

  We have now found a new group of compounds that are CCR-3 antagonists. These compounds have anti-inflammatory properties because they block eosinophil migration / chemotaxis. Thus, these compounds are particularly sensitive to tissue damage caused by eosinophils, basophils, mast cells, and Th2 cells, diseases involving such cell types, particularly allergic diseases such as Although not, 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, the formula (I):

[Where,
R ¹ represents unsubstituted or substituted aryl;
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 and R ⁴ each independently represent hydrogen or C _1-6 alkyl)
And the salts and solvates thereof are provided.

The following compounds are excluded:
N-benzyl-N ′-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-(2-phenylethyl) urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-(4-methoxybenzyl) urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-(2-methylbenzyl) urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-(3-methylbenzyl) urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-(4-methylbenzyl) urea;
N- (4-chlorobenzyl) -N ′-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} urea;
N- (3-chlorobenzyl) -N ′-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} urea;
N- (2-chlorobenzyl) -N ′-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} urea;
N- [3-({[({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) carbonyl] -amino} methyl) phenyl] acetamidoformate;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-[4- (methylsulfonyl) -benzyl] urea;
4-({[({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) carbonyl] amino} -methyl) benzenesulfonamide;
N-{[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N '-(4-methoxybenzyl) urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-(3,4-dimethoxybenzyl) urea;
N- (3-cyanobenzyl) -N ′-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-(3-methoxybenzyl) urea;
4-({[({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) carbonyl] amino} -methyl) benzamide;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-[3- (trifluoromethoxy) -benzyl] urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-[4- (trifluoromethyl) -benzyl] urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N '-[4- (1,2,3-thiadiazol-4-yl) benzyl] urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-[4- (trifluoromethoxy) -benzyl] urea;
N- (3,5-dichlorobenzyl) -N ′-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N '-[3- (trifluoromethyl) -benzyl] urea
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-(2,4-difluorobenzyl) urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-(3,4-difluorobenzyl) urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-(3-fluorobenzyl) urea;
N- (3,4-dichlorobenzyl) -N ′-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} urea;
3-({[({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) -carbonyl] amino} methyl) -N-methylbenzamide;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-[2- (trifluoromethoxy) benzyl] urea;
Methyl 3-({[({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) -carbonyl] amino} methyl) benzoate;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-[2- (trifluoromethyl) -benzyl] urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-(4-fluorobenzyl) urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-(2-fluorobenzyl) urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-(4-isopropoxybenzyl) urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-(2,4-dimethoxybenzyl) urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-[2- (4-methoxyphenyl) -ethyl] urea;
N- [2- (4-tert-butoxyphenyl) ethyl] -N ′-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-[3- (dimethylamino) benzyl] urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-[2- (methylthio) benzyl] urea;
N- (4-cyanobenzyl) -N ′-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} urea;
N ′-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N- (4-methoxybenzyl) -N-methylurea;
Methyl 4-({[({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) carbonyl] amino} methyl) benzoate;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-[1- (4-fluorophenyl) ethyl] urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-(1-methyl-1-phenylethyl) urea;
4-({[({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) carbonyl] amino} -methyl) -N- (1,3-thiazol-2-yl) benzene Sulfonamide;
4-({[({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) carbonyl] amino} -methyl) -benzoic acid and N, N, N-triethylamine (1 1) a compound;
4-({[({[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) carbonyl] -amino} methyl) benzamide hydrochloride;
4-({[({[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) carbonyl] -amino} methyl) benzamide;
4-({[({[(2R) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) carbonyl] -amino} methyl) benzamide;
3-({[({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) carbonyl] -amino} methyl) -N, N-dimethylbenzamide;
3-({[({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) carbonyl] -amino} methyl) -N-ethylbenzamide;
N-cyclopropyl-3-({[({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) -carbonyl] amino} methyl) benzamide;
4-({[({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) carbonyl] -amino} methyl) -N-methylbenzamide;
4-({[({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) carbonyl] -amino} methyl) -N, N-dimethylbenzamide;
4-({[({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) carbonyl] -amino} methyl) -N-ethylbenzamide;
N-cyclopropyl-4-({[({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) -carbonyl] amino} methyl) benzamide;
4- (2-{[({[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) -carbonyl] amino} ethyl) benzenesulfonamide;
3-({[({[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) -carbonyl] amino} methyl) -N-methylbenzamide;
N-cyclopropyl-3-({[({[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) -carbonyl] amino} methyl) benzenesulfonamide;
N-cyclopropyl-4-({[({[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) -carbonyl] amino} methyl) benzenesulfonamide;
4-({[({[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) -carbonyl] amino} methyl) -N-methylbenzamide, and;
N-cyclopropyl-4-({[({[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) carbonyl] amino} methyl) benzamide.

An example of an aryl group R ¹ includes phenyl.

Examples of substituents for R ¹ include perhaloalkyl, aminosulfonyl; carboxy; mono- and di- (alkyl) aminosulfonyl; alkylsulfonylamino; alkylcarbonyl; cycloalkylaminocarbonyl; aminocarbonyl; alkyl; alkoxycarbonyl; -And di- (alkyl) aminocarbonyl; unsubstituted heteroaryl; alkylsulfonylamino, alkylcarbonyl, alkyl, alkoxycarbonyl, mono- and di- (alkyl) aminocarbonyl, halo, alkoxy, nitro, alkylsulfonyl, hydroxy, alkoxy alkyl, C _{1 to 6} alkylthio -, mono - and di - (alkyl) amino or heteroaryl substituted with alkylcarbonylamino; halo; alkoxy; nitro; alkylsulfonyl; hydro Shea; alkoxyalkyl; alkylthio -; mono - and di - (alkyl) amino; and the like as well as alkylcarbonylamino is.

When R ¹ is substituted aryl, suitable substituents, aminosulfonyl; carboxy; mono- - and di - (alkyl) aminosulfonyl; C _{1 to 6} alkylsulfonylamino; C _{1 to 6} alkyl carbonyl; _{C. 3 to 8} cycloalkylaminocarbonyl; aminocarbonyl; C _1-6 alkyl; C _1-6 alkoxycarbonyl; mono- and di- (C _1-6 alkyl) aminocarbonyl; unsubstituted heteroaryl; C _1-6 alkylsulfonylamino; C _1-6 alkylcarbonyl, C _1-6 alkyl, C _1-6 alkoxycarbonyl, mono- and di- (C _1-6 alkyl) aminocarbonyl, halo, C _1-6 alkoxy, nitro, C _1-6 alkyl sulfonyl, hydroxy, C _{1 to 6} alkoxy C _{1 to 6} alkyl, C _{1 to 6} alkylthio -, mono - and di - (C _{1 to 6} alkyl) amino or C _{1 to 6} alkyl carbonyl amino, In substituted heteroaryl; halo; C _{1 to 6} alkoxy; nitro; C _{1 to 6} alkylsulphonyl; hydroxy; C _{1 to 6} alkoxy C _{1 to 6} alkyl; C _{1 to 6} alkylthio -; mono - and di - ( C _1-6 alkyl) amino; as well as C _1-6 alkylcarbonylamino.

When R ¹ is unsubstituted or substituted with substituted heteroaryl, examples of the heteroaryl group include oxadiazolyl and triazolyl.

Suitably R ¹ is unsubstituted or substituted phenyl.

When R ¹ is substituted phenyl, suitable substituents include carboxy, halo, C _1-6 alkylsulfonyl, C _1-6 alkylsulfonylamino, mono- and di- (C _1-6 alkyl) aminosulfonyl, Aminosulfonyl, C _3-8 cycloalkylaminocarbonyl, mono- and di- (C _1-6 alkyl) aminocarbonyl; C _1-6 alkyl, C _1-6 alkylcarbonylamino, C _1-6 alkoxycarbonyl, and amino Heteroaryl substituted with carbonyl.

More preferably, R ¹ is 4- (3-methyl-1,2,4-oxadiazol-5yl), 4- (methanesulfonylamino), 4- (N, N-dimethylaminosulfonyl), 4- (aminosulfonyl), 3- (iso-propylaminocarbonyl), 3- (3-methyl-1,2,4-oxadiazol-5-yl), 3- (methylcarbonylamino), 4-fluoro- 3- (methoxycarbonyl), 3-amide, 4-fluoro-3- (ethylaminocarbonyl), 4-fluoro-3- (methylaminocarbonyl), 3- (methoxycarbonyl), 3-amido-4-fluoro, 3- (cyclopropylaminocarbonyl), 3- (ethylaminocarbonyl), 3- (methylaminocarbonyl), 3-carboxy 4-fluoro, 3-carboxy, 3- (methanesulfonyl), 3- (methanesulfonylamino) 4-amide, 3- (5-methyl-1,3,4-oxadiazol-2-yl), 3- (5-methyl-1,3,4-triazol-2-yl), or 3- (1,3,4-oxadia Is phenyl substituted with Lumpur 2-yl).

Suitably R _na and R _nb are both hydrogen.

  Preferably n is 1.

Suitably R ³ and R ⁴ are both hydrogen.

When R ² is aryl, an example includes phenyl.

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 to 6} alkoxy, nitro, C _{1 to 6} alkylsulphonyl, hydroxy, C _{1 to 6} alkoxy C _{1 to 6} alkyl, C _{1 to 6} alkylthio -, mono - and di - (C _{1 6} alkyl) amino, as well as C _{1 to 6} alkylcarbonylamino.

When R ² is heteroaryl, an example includes thiophenyl.

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, as well as C _1-6 alkylcarbonylamino.

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

When R ² is substituted phenyl or thiophenyl, suitable substituents include halo.

More preferably, R ² is phenyl or thiophenyl substituted with chloro or fluoro.

Preferably R ² is 3,4-dichlorophenyl, 3,4-difluorophenyl or 2-chloro-thiophen-5-yl.

The compound represented by formula (I) includes formula (IA)

[Where,
R ^1A is the formula (M)

{Wherein R ⁵ is C _3-8 cycloalkylaminosulfonyl, R ⁷ R ⁸ NC (O) — (where R ⁷ and R ⁸ are each independently hydrogen or C _1-6 alkyl R ⁷ and R ⁸ may be represented by the — (CH 2) _p — group, where p is 3 to 8 together with the nitrogen atom to which they are attached to form a 4-8 membered heterocyclyl ring. Aminosulfonyl; carboxy; mono- and di- (C _1-6 alkyl) aminosulfonyl; C _1-6 alkylsulfonylamino; C _1-6 alkylcarbonyl; C _3-8 Cycloalkylaminocarbonyl; aminocarbonyl; C _1-6 alkyl; C _1-6 alkoxycarbonyl; unsubstituted heteroaryl; C _1-6 alkyl, halo, C _1-6 alkoxy, or heteroaryl substituted with hydroxy; halo ; C _{1 to 6} alkoxy; nitro; C _{1 to 6} A Alkylsulfonyl; hydroxy; C _{1 to 6} alkoxy C _{1 to 6} alkyl; C _{1 to 6} alkylthio -; mono - and di - (C _{1 to 6} alkyl) amino; represents or C _{1 to 6} alkylcarbonylamino; R ⁶ Represents cyano, perhalo C _1-6 alkyl, hydrogen, C _1-6 alkyl, halo, C _1-6 alkoxy, or hydroxy}
And the part indicated by
R ² , R ³ , and R ⁴ are as defined above for formula (I).
And a salt and a solvate thereof exist.

However, the following compounds are excluded;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-(3-methylbenzyl) urea;
N- (3-chlorobenzyl) -N ′-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} urea;
N- [3-({[({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) carbonyl] -amino} methyl) phenyl] acetamidoformate;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-(3,4-dimethoxybenzyl) urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-(3-methoxybenzyl) urea;
N- (3,5-dichlorobenzyl) -N ′-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-(3,4-difluorobenzyl) urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-(3-fluorobenzyl) urea;
N- (3,4-dichlorobenzyl) -N ′-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} urea;
3-({[({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) carbonyl] -amino} methyl) -N-methylbenzamide;
Methyl 3-({[({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) carbonyl] -amino} methyl) benzoate;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-[3- (dimethylamino) -benzyl] urea;
3-({[({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) carbonyl] -amino} methyl) -N, N-dimethylbenzamide;
3-({[({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) carbonyl] -amino} methyl) -N-ethylbenzamide;
N-cyclopropyl-3-({[({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) -carbonyl] amino} methyl) benzamide, and;
3-({[({[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) carbonyl] -amino} methyl) -N-methylbenzamide.

When R ⁵ is unsubstituted or substituted heteroaryl, examples of the heteroaryl group include oxadiazolyl and triazolyl.

Suitably R ⁵ is carboxy, halo, C _1-6 alkylsulfonyl, C _1-6 alkylsulfonylamino, mono- and di- (C _1-6 alkyl) aminosulfonyl, aminosulfonyl, C _3-8 cyclo. alkylaminocarbonyl, mono - and di - (C _{1 to 6} alkyl) aminocarbonyl, unsubstituted heteroaryl, heteroaryl substituted with C _{1 to 6} alkyl, C _{1 to 6} alkylcarbonylamino, C _{1 to 6} alkoxy carbonyl Or aminocarbonyl.

Suitably R ⁶ is hydrogen or halo.

More preferably, R ^1A is 3- (5-methyl-1,3,4-triazol-2-yl), 3- (2-methyl-1,3,4-triazol-5-yl), 3 -(iso-propylaminocarbonyl), 3- (3-methyl-1,2,4-oxadiazol-5-yl), 3- (methylcarbonylamino), 4-fluoro-3- (methoxycarbonyl), 3 -Amide, 4-fluoro-3- (ethylaminocarbonyl), 4-fluoro-3- (methylaminocarbonyl), 3- (methoxycarbonyl), 3-amido-4-fluoro, 3- (cyclopropylaminocarbonyl), 3- (ethylaminocarbonyl), 3- (methylaminocarbonyl), 3-carboxy-4-fluoro, 3-carboxy, 3- (methanesulfonylamino), 3- (methanesulfonylamino), 3- (5-methyl- 1,3,4-oxadiazol-2-yl) or phenyl substituted with 3- (1,3,4-oxadiazol-2-yl).

The compound represented by the formula (I) includes the formula (I ′)

[Where,
R ^{1 ′} is the formula (M ′)

(This is the part indicated by
There are preferred subgroups indicated by

In the above formula, R ^{5 ′} is C _1-6 alkylaminocarbonyl, substituted heteroaryl, C _1-6 alkylcarbonylamino, halo, C _1-6 alkoxycarbonyl, amide, C _3-8 cycloalkylaminocarbonyl, carboxy. , C _1-6 alkylsulfonyl or C _1-6 alkylsulfonylamino;
R ^{6 ′} is H or halo; and R ^{2 ′} is phenyl substituted by halo.

  Preferably, M ′ is 3- (5-methyl-1,3,4-triazol-2-yl) phenyl, 3- (iso-propylaminocarbonyl) phenyl, 3- (3-methyl-1,2 , 4-oxadiazol-5-yl) phenyl, 3- (methylcarbonylamino) phenyl, 4-fluoro-3- (methoxycarbonyl) phenyl, 3-amidophenyl, 4-fluoro-3- (ethylaminocarbonyl) Phenyl, 4-fluoro-3- (methylaminocarbonyl) phenyl, 3- (methoxycarbonyl) phenyl, 3-amido-4-fluorophenyl, 3- (cyclopropylaminocarbonyl) phenyl, 3- (ethylaminocarbonyl) phenyl , 3- (methylaminocarbonyl) phenyl, 3-carboxy-4-fluorophenyl, 3-carboxyphenyl, 3- (methanesulfonyl) phenyl, 3- (methanesulfonylamino) phenyl, 3- (5-methyl-1, 3,4-oxadiazol-2-yl) phenyl, or 3- ( Represents 1,3,4-oxadiazol-2-yl) phenyl.

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

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

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

The compound represented by formula (I) includes formula (I '')

[Where,
R ^{1 ″} is substituted heteroaryl, C _1-6 alkylsulfonylamino, N, N-diC _1-6 alkylaminosulfonyl, aminosulfonyl, or phenyl substituted at the 4-position by an amide; and;
R ^{2 ''} is phenyl substituted by halo or thiophenyl substituted by halo.
There are additional subgroups indicated by

Suitably R ^{1 ''} is 4- (3-methyl-1,2,4-oxadiazol-5yl) phenyl, 4- (methanesulfonylamino) phenyl, 4- (N, N-dimethylamino) Sulfonyl) phenyl, 4- (aminosulfonyl) phenyl, or 4-amidophenyl.

Suitably R ^{2 ″} is 3,4-dichlorophenyl, 3,4-difluorophenyl, 3-chloro-4-fluorophenyl, or 2-chloro-thiophen-5-yl.

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

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

Formula (IB)

Wherein R ⁹ is mono- or di- (C _1-6 alkyl) aminocarbonyl or C _3-8 cycloalkylaminocarbonyl.
There is a further subgroup consisting of the compounds represented by

Suitably R ⁹ is ethylaminocarbonyl, cyclopropylaminocarbonyl, or dimethylaminocarbonyl.

Preferably R ⁹ is 4-ethylaminocarbonyl, 3-cyclopropylaminocarbonyl, or 3-dimethylaminocarbonyl.

  Accordingly, a compound represented by the formula (IB) or a salt or solvate thereof is provided.

  Suitable compounds of the invention are examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 31, 33, 34, and 35.

  Preferred compounds of the invention are examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 18, 20, 22, 28, 31, 33, 34, and 35.

  More preferred compounds of the invention are Examples 1, 2, 3, 4, 5, 6, 7, 12, 22, 28, 31, 33, and 34.

  Particularly preferred compounds of the invention are Examples 1, 2, 12, 22, 28, 31, 33, and 34.

  Suitable salts of the compound of formula (I) include physiologically acceptable salts and salts and physiology that may be physiologically unacceptable but may be useful for the preparation of compounds of formula (I) Pharmaceutically acceptable salts thereof are included. Where appropriate, acid addition salts can be derived from inorganic or organic acids (e.g., hydrochloride, hydrobromide, sulfate, phosphate, acetate, benzoate, citric acid) Salt, succinate, lactate, tartrate, fumarate, maleate, 1-hydroxy-2-naphthoate, palmate, methanesulfonate, formate, or trifluoroacetate).

  Examples of solvates include hydrates.

  Some of the compounds of formula (I) may contain chiral atoms and / or multiple bonds and thus exist in one or more stereoisomeric forms. The present invention includes compounds of formula (I), including geometric and optical isomers, whether present as individual stereoisomers or as mixtures thereof such as racemates. All stereoisomers are included.

  In general, the compound of formula (I) is preferably present in the form of a single enantiomer or diastereoisomer.

  Some of the compounds of formula (I) may exist as one of several tautomeric forms. Of course, the present invention encompasses all tautomers of the compounds of formula (I), whether present as individual tautomers or as mixtures thereof. .

  Where “aryl” is mentioned, mono- and bicyclic carbocyclic aromatic rings such as naphthyl and phenyl, especially phenyl, are of interest.

  Suitable substituents for any aryl group include heterocyclylcarbonyl; cycloalkylaminosulfonyl; aminosulfonyl; carboxy; mono- and di- (alkyl) aminosulfonyl; alkylsulfonylamino; alkylcarbonyl; cycloalkylaminocarbonyl; Alkyl; alkoxycarbonyl; mono- and di- (alkyl) aminocarbonyl; unsubstituted heteroaryl; heteroaryl substituted with alkyl, halo, alkoxy, hydroxy; halo; alkoxy; nitro; alkylsulfonyl; hydroxy; alkoxyalkyl; Alkylthio; mono- and di- (alkyl) amino; alkylcarbonylamino; hydrogen; cyano; perhaloalkyl; and 1-5 selected from the list consisting of amides, preferred It can be mentioned one to three substituents.

  When “heteroaryl” is mentioned, monocyclic heteroaromatic rings containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur are of interest. Examples of heterocyclic aromatic rings include thiophenyl and oxadiazolyl.

  Suitable substituents for any heteroaryl group include cyano, perhaloalkyl, amide, halo, alkyl, alkoxycarbonyl, mono- and di- (alkyl) aminocarbonyl, alkoxy, nitro, alkylsulfonyl, hydroxy, alkoxyalkyl, Examples include 1 to 5, preferably 1 to 3 substituents selected from the list consisting of alkylthio, mono- and di- (alkyl) amino, and alkylcarbonylamino.

  Where “alkyl” is mentioned, both the linear and branched aliphatic isomers of the corresponding alkyl, preferably containing up to 6 carbon atoms, are of interest.

  Where “cycloalkyl” is mentioned, it is preferably a saturated alicyclic ring containing from 3 to 8 carbon atoms.

  Suitable substituents for any cycloalkyl group include alkyl, halo, and hydroxy.

  When "heterocyclyl" is mentioned, it is a single atom containing 2 to 6, preferably 3 to 5 carbon atoms and 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Cyclic heterocyclic aliphatic rings are of interest. An example of a heterocyclic ring is piperidinyl.

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

  Where “halogen” or “halo” is mentioned, iodo, bromo, chloro or fluoro, in particular fluoro and chloro, are of interest.

  The compounds of formula (I) and their salts and solvates can be prepared by the methods described below that constitute a further aspect of the invention.

Accordingly, a method for preparing a compound of formula (I) is provided. This method comprises a compound represented by formula (II) and a compound represented by formula (III)

[Where,
R ¹ , Y, R ³ , R ⁴ , and R ² are as defined for formula (I) and U is a urea-forming group.
Reacting with
Then, if necessary, the following optional steps:
(i) converting the compound of formula (I) into a further compound of formula (I);
(ii) removing any required protecting groups;
(iii) preparing a salt or solvate of the compound so produced;
Including performing one or more of the following:

The urea-forming group is a group derived from a reagent that introduces a carbonyl group and a leaving group into an amino compound. Examples of urea-forming groups are imidazolylcarbonyl and chlorocarbonyl, R ⁴ is hydrogen, 4-nitrophenoxy carbonyl can be used. The reagents used for their derivation are 1,1′-carbonyldiimidazole, phosgene, and 4-nitrophenyl chloroformate, respectively. A preferred urea-forming group is 4-nitrophenoxycarbonyl.

  Typically, the compound of formula (II) and the compound of formula (III) in a suitable solvent (e.g. an organic solvent such as dichloromethane) are suitable at ambient temperature such as 18-25 ° C. With a simple base (eg, a tertiary amine such as triethylamine).

The compound represented by formula (III) is represented by formula (IV);

[Where,
R ⁴ and R ² are as defined above for formula (I).
Can be prepared by reacting with a compound of formula UL where U is a urea-forming group as defined above and L is a leaving group. Suitable leaving groups are halo groups such as chloro.

  The reaction of a compound of formula (IV) with compound UL in the presence of a suitable base (e.g. a tertiary amine such as triethylamine) is carried out in a suitable solvent (e.g. dichloromethane) at a suitable temperature (e.g. e.g. -5 ° C. to + 5 ° C.) over a suitable time (eg 3 to 5 hours).

Compounds of formula (IV) in which R ⁴ is hydrogen can be prepared by either reaction (a) or reaction (c). The S-enantiomer of the compound of formula (IV) can be prepared by reaction (b).

Reaction (a): a compound represented by formula (V) is reacted with a compound represented by formula (VI),

In which R ² is as defined above for formula (I) and A is a protected amino group, preferably phthalimide.
Subsequently, the amino group is deprotected to obtain a compound represented by the formula (IV) in which R ⁴ is hydrogen, that is, a compound represented by the formula (IVR),

[Wherein R ² is as defined above]
In some cases, the enantiomer of the compound represented by the formula (IVR) thus obtained is resolved.

Or;
Reaction (b): The compound represented by the formula (V) defined above is reacted with the compound represented by the formula (VIA),

[Wherein A is as defined above for formula (VI)]
Subsequently, the amino group is deprotected and the corresponding enantiomer of the compound of formula (IV) where R ⁴ is hydrogen, i.e. the formula (IVE)

[Wherein R ² is as defined above]
To obtain a compound represented by

Reaction (c): hydrolysis of a compound of formula (VII);

Wherein T is trifluoroacetyl and R ⁴ and R ² are as defined above for formula (I).
In some cases, the enantiomer of the compound represented by the formula (IV) thus obtained is resolved.

For both reactions (a) and (b), the ring of intermediate diols (IVBR) and (IVBE) in the reaction of the compound of formula (V) with the compound of formula (VI) or (VIA) Conversion is typically performed under Mitsunobu conditions as follows:
Typically, a mixture of a compound of formula (V) and a compound of formula (VI) or formula (VIA) in a suitable solvent such as tetrahydrofuran is preferably taken over a period of 20-24 hours. Stir at a suitable temperature, preferably at the reflux temperature of the solvent, under an inert atmosphere, preferably under an atmosphere of nitrogen. Then further solvent is added and the mixture is preferably cooled to 0-5 ° C. A suitable phosphine, preferably triphenylphosphine, is added and the mixture is stirred until all solids are dissolved. A suitable azo compound, preferably diisopropyl azodicarboxylate, is then added over a period of time, preferably over 10-15 minutes, while maintaining the temperature at <7 ° C. Allow the mixture to stand for a period of time, preferably 2-3 hours, and then warm to preferably 20-25 ° C. After standing for a further time, preferably 4-6 hours, further phosphine and azo compounds are added. After standing for a further time, preferably 20-24 hours, the reaction mixture is almost concentrated to dryness. A suitable alcohol, preferably propan-2-ol, is added and the concentration step is repeated; the alcohol addition and concentration steps are then repeated. Then further alcohol is added and the mixture is heated to a temperature preferably between 65 and 75 ° C. After a suitable time, preferably 20-45 minutes, the resulting slurry is preferably cooled to 20-25 ° C. and then preferably left for 1.5-3 hours, after which the product is Isolate by filtration. The filter bed is washed with more alcohol and then dried in vacuo at 35-45 ° C. to produce the protected form of the compound of formula (IVR) or formula (IVE), respectively.

  Removal of the protecting group from the product is typically performed as follows. A slurry of the protected form of a compound of formula (IVR) or formula (IVE) in a suitable polar solvent, preferably in water, is heated to an elevated temperature, preferably 70-75 ° C., and then concentrated mineral The acid, preferably concentrated sulfuric acid, is treated dropwise. The mixture is then heated at an elevated temperature, preferably the reflux temperature of the solvent, for a suitable time, preferably 20-24 hours, after which the reaction mixture is allowed to cool to 20-25 ° C. and then Treat with a suitable non-polar solvent, preferably dichloromethane. Next, a base, preferably 0.880 ammonia solution, is added dropwise while maintaining the temperature between 20-25 ° C. Next, additional nonpolar solvent is added, then the aqueous phase is separated and extracted with additional nonpolar solvent. The combined organic phases are washed with water and then evaporated to dryness. The residue is redissolved and the nonpolar solvent is re-evaporated to give the compound of formula (IVR) or formula (IVE).

The method for preparing a protected form of the compound of formula (IVR) or formula (IVE) described above can also be carried out in two steps, in which case formula (IVBR) or formula (IVBE) respectively;

In which A is as defined above for formulas (VI) and (VIA) and R ² is as previously defined for formula (I).
The intermediate compound represented by is isolated.

  Typically, a mixture of a compound of formula (V) and a compound of formula (VI) or formula (VIA) in a suitable solvent such as tetrahydrofuran is preferably taken over a period of 20-24 hours. Stir at a suitable temperature, preferably at the reflux temperature of the solvent, under an inert atmosphere, preferably under an atmosphere of nitrogen. Additional compounds of formula (V) are added and the mixture is suitable for a suitable time at a suitable temperature, preferably at the reflux temperature of the solvent, under an inert atmosphere, preferably under an atmosphere of nitrogen. Heat for 3-6 hours. The reaction mixture is then preferably cooled at 20-25 ° C. and the compound is precipitated by adding a suitable cosolvent, preferably diisopropyl ether. The compound of formula (IVBR) or formula (IVBE), respectively, is isolated by filtration, washed with additional cosolvent and dried in vacuo.

  Next, under conditions similar to those described above for the reaction of the compound of formula (V) with the compound of formula (VI) or (VIA), but with the addition of phosphine and azo compounds It is possible to prepare a protected form of a compound of formula (IVR) or formula (IVE) from a compound of formula (IVBR) or formula (IVBE), omitting the previous reflux time.

Reaction (c) typically involves stirring a solution of a compound of formula (VII) in a suitable solvent such as a mixture of methanol and water and adding a suitable base such as potassium carbonate. Is done. 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, followed by removal of the organic solvent in vacuo. Next, water is added and the mixture is extracted with a suitable organic solvent, such as ethyl acetate. The combined organic phases are washed with water and saturated aqueous sodium chloride solution, then dried over a suitable dehydrating agent such as sodium sulfate, filtered and the solvent evaporated in vacuo . The crude product is then purified by flash chromatography.

  Resolution of a compound of formula (IVE) from a racemic product (i.e. a compound of formula (IVR)) can be accomplished using techniques well known to those skilled in the art, e.g., preparative chiral high performance liquid chromatography ( (Chiral HPLC) or by fractional crystallization of diastereomeric salts.

A compound of formula (VII) can be prepared by reacting a compound of formula (VIII) with a compound of formula (IX):

In the above formula, T, R ⁴ , and R ² are as defined above for formula (VII) and L ² is a leaving group. A suitable leaving group L ² is a halo group such as chloro.

The reaction of the compound of formula (VIII) with the compound of formula (IX) is typically carried out under an inert atmosphere, for example under an atmosphere of nitrogen, with a suitable base such as potassium carbonate and iodinated. This is done by adding a suitable activator such as sodium and stirring a solution of the compound of formula (VIII) in a suitable solvent, for example N, N-dimethylformamide. A solution of the compound of formula (IX) 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 in the range of 20-25 ° C., for a suitable time, for example 16-20 hours, after which the volatile components are removed in vacuo. The residue is partitioned between a suitable organic solvent such as dichloromethane and a saturated aqueous base solution such as a saturated aqueous sodium carbonate solution. 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 evaporated in vacuo to give the crude product. The crude product is purified by flash chromatography.

A compound of formula (VIII) can be prepared by reacting a compound of formula (X) with a compound of formula (XI);

In the above formula, R ⁴ and T are as defined above for formula (VII) and R _x is an alkyl group, preferably ethyl.

The reaction of a compound of formula (X) with a compound of formula (XI) is typically carried out in a suitable organic solvent, for example in methanol, under an inert atmosphere, for example under an atmosphere of nitrogen. Is carried out by stirring a solution of the compound of formula (X) and then adding a solution of the compound of formula (XI) in a suitable organic solvent, for example ether. The mixture is then stirred for a suitable time, eg, 20-40 minutes, at a suitable temperature, eg, in the range of 20-25 ° C., and the volatile components are removed in vacuo. Then, the residue is dissolved in a suitable organic solvent such as methanol, and the volatile constituents are removed in vacuo.

Compounds of formula (II) can be prepared from other compounds of formula (II) by procedures involving appropriate steps of protection, reaction, and deprotection. An example of such a procedure is the amino functionality of the compound of formula (II) wherein Y is —CH ₂ —, R ¹ is 3-carboxy-4-fluorophenyl and R ³ is hydrogen. It is protection. A preferred protecting group is tBoc. The carboxy function is then alkylated, for example with (trimethylsilyl) diazomethane, followed by removal of the tBoc group.

  A compound of formula (II), a specific compound of formula (IV), a specific compound of formula (V), (VI), a specific compound of formula (VII), formula (VIII) , (IX), (X), and (XI) are known commercially available compounds and / or known procedures, such as J. March, Advanced Organic Chemistry, 3rd Edition (1985). ), Can be prepared by analogy with procedures disclosed in standard reference books on synthetic methods such as Wiley Interscience.

  Compounds of formula (III), (IVBR), and (IVBE) are considered novel.

  Accordingly, a compound represented by the formula (III) is provided.

  A compound of formula (IVBR) is also provided.

  A compound of formula (IVBE) is also provided.

The above-described conversion from a compound of formula (I) to another compound of formula (I) includes any conversion that can be performed using conventional procedures, and in particular, the conversion includes , Conversion of one group R ¹ to another group R ¹ is included.

The transformations described above can be performed using any suitable method under conditions determined by the particular group selected. Thus, suitable transformations from one group R ¹ to another group R ¹ include the following transformations:
conversion of groups R ¹ representing an aryl group substituted with a (a) alkoxycarbonyl group, a group R ¹ which represents the aryl group substituted with 1, 2,4-oxadiazol-5-yl group; such Such a transformation can be performed using a suitable conventional ring-forming procedure, for example by treating a suitably protected compound of formula (I) with a suitable hydroxyamidine;
(b) the radicals R ¹ to which an alkoxycarbonyl-substituted aryl group with a group, the conversion to group R ¹ which represents the aryl group substituted with a carboxy group; such a conversion, a suitable conventional hydrolysis procedure Can be used, for example, by treating a suitably protected compound of formula (I) with a suitable aqueous base solution;
(c) from the base R ¹ representing the aryl group substituted with a carboxy group, conversion to group R ¹ which represents an aryl group substituted with an amide group; such a conversion using the appropriate conventional amination procedure For example, by treating a suitably protected compound of formula (I) with a suitable amine in the presence of a suitable peptide coupling agent and, if necessary, a suitable activator. Is possible;
(d) conversion of groups R ¹ representing an aryl group substituted with a carboxy group, the group R ¹ which represents an aryl group substituted with 2 alkyl-1,3,4-oxadiazol-5-yl group Such a transformation involves reacting a suitably protected compound of formula (I) with an alkyl carbazate to form a first intermediate and then hydrolyzing the first intermediate with a mineral acid. Can be accomplished by decomposition to form a second intermediate followed by cyclization with a suitable orthoester; and;
(e) conversion of groups R ¹ representing an aryl group substituted with a carboxy group, the group R ¹ which represents an aryl group substituted with 2 alkyl-1,3,4-triazol-5-yl group; the Such a conversion involves reacting a suitably protected compound of formula (I) with an alkyl carbazate to form a first intermediate and then hydrolyzing the first intermediate with a mineral acid. To form a second intermediate followed by cyclization with a suitable carboxymidate ester.

  The above-described conversion can be appropriately performed on any of the intermediate compounds listed in this specification.

  The above-described conversion can be appropriately performed on any of the intermediate compounds listed in this specification.

  In any of the reactions described above, suitable protecting groups are those commonly used in the art. Methods for the generation and removal of such protecting groups are discussed in standard references for conventional methods suitable for the molecule to be protected, e.g. PJ Kocienski, Protecting Groups, (1994), Thieme. Is the way.

  For any of the reactions or processes described above, conventional heating and cooling methods, such as electric mantle heaters and ice / salt baths, respectively, can be used. If necessary, conventional purification methods such as crystallization and column chromatography can be used.

  Where appropriate, the individual isomeric forms of the compounds of formula (I) can be individually isolated using conventional procedures such as fractional crystallization of diastereomeric derivatives or chiral high performance liquid chromatography (chiral HPLC). It can be prepared as an isomer.

  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 procedures.

The compounds of the invention can be tested for in vitro biological activity 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-30 μM) are added, incubated in a 96-well plate for 2 hours at 22 ° C., then counted in a Microbeta plate counter did. Total assay volume was 100 μl. Competitive binding data was analyzed by fitting the data to a 4-parameter logistic equation. Data are presented as mean pIC ₅₀ values obtained from at least two experiments (log of the concentration of compound that inhibits [ ¹²⁵ I] eotaxin binding by 50%).

(b) Eosinophil chemotaxis assay.
The 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) 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-30 μM). For the control response, cells were incubated with RPMI / FCS alone. 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 upper chamber of the filter plate and incubated at 37 ° C. for 45 minutes. Cells remaining on 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 four parameter logistic equation, an inhibition curve showing the effect of the compound on eosinophil chemotaxis was analyzed. Functional pK _i values (fpK _i ) were obtained using the following formula (Lazareno & Birdsall, 1995. Br. J. Pharmacol 109: 1110-9).

本発明の化合物が有益な抗炎症効果を示す可能性のある疾患状態の例としては、気管支炎(慢性気管支炎など)、気管支拡張症、喘息(アレルゲンにより惹起される喘息反応など)、慢性閉塞性肺疾患(COPD)、嚢胞性繊維症、静脈洞炎、および鼻炎のような気道の疾患が挙げられる。このほかに、胃腸管の疾患、たとえば、炎症性腸疾患(具体的には、クローン病または潰瘍性大腸炎)および放射線暴露またはアレルゲン暴露の後で生じる腸の炎症性疾患をはじめとする腸の炎症性疾患が挙げられる。 The compounds of the examples were tested in a CCR-3 binding assay and / or eosinophil chemotaxis assay (Assay (a) and Assay (b)). The example compounds tested in the CCR-3 binding assay had pIC ₅₀ values ranging from 6.6 to 9.1. The example compounds tested in the CCR-3 eosinophil chemotaxis assay had fpKi values as given in the following table:

Examples of disease states in which 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 copulmonary disease (COPD), cystic fibrosis, sinusitis, and rhinitis. In addition, diseases of the intestines, including gastrointestinal tract diseases such as inflammatory bowel disease (specifically Crohn's disease or ulcerative colitis) and intestinal inflammatory diseases that occur after radiation or allergen exposure. Inflammatory diseases are mentioned.

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

  The compounds of the invention are also believed to be useful in the treatment of nasal polyposis, conjunctivitis, or pruritus.

  Further examples of disease states in which the compounds of the present invention may have beneficial effects include cardiovascular conditions such as atherosclerosis, peripheral vascular disease, and idiopathic hypereosinophilia 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 appreciated by those skilled in the art that reference to treatment or therapy herein extends to prophylaxis as well as treatment of pre-determined symptoms.

  As described above, the compound represented by the formula (I) is useful as a therapeutic agent.

  Accordingly, as a further aspect of the invention there is provided a compound of formula (I) or a physiologically acceptable salt or solvate thereof for use as an active therapeutic agent.

  Accordingly, there is also provided a compound of formula (I) or a physiologically acceptable salt or solvate thereof for use in the treatment of inflammatory conditions (eg asthma or rhinitis).

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

  In further or alternative embodiments, methods of treating a human or animal subject suffering from or susceptible to inflammatory conditions (eg, asthma or rhinitis) are provided. This method comprises administering an effective amount of a compound of formula (I) or a physiologically acceptable salt or solvate thereof.

  The compounds according to the invention may be formulated for administration by any convenient method.

  Accordingly, 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 provided.

  Also provided are methods for preparing such pharmaceutical formulations. This method comprises mixing a compound of formula (I) or a physiologically acceptable salt or solvate thereof with one or more physiologically acceptable diluents or carriers.

  The compounds according to the invention may be formulated for oral administration, inhalation administration, intranasal administration, buccal administration, parenteral administration, or rectal administration, preferably oral administration.

  For tablets and capsules for oral administration, binders such as syrup, acacia, 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 Wetting agents may be included, for example, conventional excipients such as sodium lauryl sulfate. The tablets can be coated according to 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 provided as dry formulations that are combined with water or other suitable vehicle prior to use Is possible. 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 acacia; non-aqueous vehicles (which may include edible oils), such as tonsil oil, fractionated coconut oil, oily esters, propylene glycol, or ethyl alcohol; or preservatives, such as methyl or propyl p-hydroxybenzoate Or it may contain conventional additives such as sorbic acid. Formulations may optionally contain buffer salts, flavoring agents, coloring agents, and / or sweetening agents (eg, mannitol).

  When subjected to buccal administration, the composition can take the form of tablets or lozenges formulated in conventional manner.

  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, eg, in unit dosage forms as ampoules, vials, small volume infusions, or prefilled syringes. Or in multi-dose containers with additional preservatives. The composition can take the form of a solution, suspension, or emulsion in an aqueous or non-aqueous vehicle, with an antioxidant, buffer, antimicrobial, and / or tonicity agent. The following formulation may be contained. As another option, the active ingredient may take the form of a powder combined with a suitable vehicle (eg, sterile pyrogen-free water) prior to use. A dry solid donation can be prepared by aseptically filling individual sterile containers with sterile powder, or by filling each container with sterile solution aseptically and freeze-drying.

  The compounds and pharmaceutical compositions according to the present invention may also contain other therapeutic agents such as antihistamines, anticholinergics, anti-inflammatory agents (eg fluticasone propionate, beclomethasone dipropionate, mometasone furoate, triamcinolone acetonide. , Or corticosteroids such as budesonide); or non-steroidal anti-inflammatory drugs (NSAIDs) (eg, sodium cromoglycate, nedocromil sodium, PDE-4 inhibitors, leukotriene antagonists, iNOS inhibitors, tryptase and Elastase inhibitors, beta-2 integrin antagonists, and adenosine 2a agonists); or beta adrenergic agonists (eg, salmeterol, salbutamol, formoterol, fenoterol, or terbutaline, and salts thereof); Other anti-infective agents (e.g., antibiotics and antiviral agents) can be used in combination with. Of course, 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 compounds of the present invention may be administered in an amount of, for example, 0.001 to 500 mg / kg body weight, preferably 0.01 to 500 mg / kg body weight, more preferably 0.01 to 100 mg / kg body weight, and any suitable frequency, for example, 1 daily Can be conveniently administered up to 4 times. Of course, the exact dosing regimen will depend on such factors as the therapeutic indication, the age and health of the patient, and the particular route of administration chosen.

  Throughout the following description and claims, unless the context requires otherwise, the word "includes" and variations such as "included" and "include" are, of course, specified integers or It is meant to encompass steps or groups of integers, but does not exclude any other integers or steps or groups of integers or steps.

The present invention will be specifically described with reference to the following examples, but is not limited thereto.
To avoid doubt, the free bond on the R ¹ group presented in the table indicates the point of attachment of the R ¹ group to the residue of the molecule.
It should be noted that for clarity, the compounds of the illustrative examples and examples are referenced by numbers, eg, “Explanation Example 3” and “Example 26”. The structures of the compounds so referenced are given in Tables 1-3 for the examples and in Tables 4-5 for the illustrative examples.

Overall experimental details
Mass directed, automated preparative HPLC columns, conditions, and eluents
LCABZ + 5 μm (5 cm x 10 mm ID) using gradient elution with (A) 0.1% formic acid in water and (B) 95% acetonitrile and 0.5% formic acid in water at a flow rate of 8 ml per minute Mass directed automatic preparative high performance liquid chromatography was performed on the column. Mass spectrometry was performed using a VG Platform Mass Spectrometer equipped with an HP1100 Diode Array Detector and Accurate Flow Splitter.

LC / MS system The following liquid chromatography mass spectrometry (LC / MS) system was used:
This system uses a 3μm ABZ + PLUS (3.3cm x 4.6mm ID) column, solvent: A-0.1% v / v formic acid in water + 0.077% w / v ammonium acetate; and B-95: 5 acetonitrile: Elution was performed with water + 0.05% v / v formic acid at a flow rate of 3 ml / min. The following gradient protocol was used: 100% A for 0.7 min; A + B mixture (gradient profile 0-100% B) for 3.5 min; 100% B for 1.1 min; revert to 100% A over 0.2 min.
In the LC / MS system, a micro mass spectrometer was used in electrospray ionization mode, switching between positive and negative ions, mass range 80-1000 a.mu.

Thermospray mass spectrum
+ ve thermospray, source temperature 250 ° C, probe temperature 120 ° C (stem), 190 ° C (chip), detection mass range 100-850a.mu using HP 5989A engine mass spectrometer It was measured. The compound was injected as a 10 μl solvent mixture containing 65% methanol and 35% 0.05M aqueous ammonium acetate at a flow rate of 0.7 ml / min.

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

Organic layer / aqueous phase separation by hydrophobic frit “Hydrophobic frit” means Whatman polypropylene filter tube with PTFE frit with a pore size of 5.0 μm.

  All temperatures are in ° C.

Example
Illustrative example 1: 2,2,2-trifluoro-N- (morpholin-2-ylmethyl) acetamide A stirred solution of morpholin-2-ylmethylamine (3.1 g) in methanol (70 ml) under nitrogen was added Washed with aqueous sodium carbonate, water, and brine, dehydrated ether solution of ethyl-α, α, α-trifluoroacetate (5 ml in 20 ml ether) was added. The mixture was stirred at 22 ° C. for 30 minutes before removing all volatiles in vacuo . The residue was dissolved in methanol (10 ml) and volatiles were removed again in vacuo to give the title compound as a white brittle foam (4.9 g).
Thermospray mass spectrum m / z 213 [MH ⁺ ].

Illustrative example 2: N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -2,2,2-trifluoroacetamide in N, N-dimethylformamide (50 ml) under nitrogen Example 1 To a stirred solution of 3.3 g, potassium carbonate (2.46 g) and sodium iodide (2.12 g) were added. 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 removing volatiles in vacuo . The residue was partitioned between dichloromethane (100ml) and saturated aqueous sodium carbonate (50ml). Subsequently, after washing with the organic phase an additional saturated aqueous sodium carbonate solution (2 × 50 ml) and water (50 ml), dried over magnesium sulfate, filtered and the solvent was evaporated in vacuo, a pale yellow oil Obtained. The oil was purified by Biotage flash chromatography eluting with 25% ethyl acetate in cyclohexane using a 90 g silica cartridge 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 +].

Illustrative Example 3: [4- (3,4-Dichlorobenzyl) morpholin-2-yl] methylamine methanol (15 ml) and a stirred solution of Illustrative Example 2 (2.97 g) in potassium carbonate (5.53 g) was added. After the mixture was stirred at 22 ° C. for 18 hours , the methanol was removed in vacuo . Water (25 ml) was added and the mixture was extracted with ethyl acetate (3 × 30 ml). The combined organic phases were washed with water (5 ml) and saturated aqueous sodium chloride solution (10 ml), then dried over sodium sulfate, filtered and the solvent evaporated in vacuo to give a pale yellow oil. The oil was purified by Biotage flash chromatography using a 90 g silica cartridge eluting with 75: 8: 1 dichloromethane / ethanol / 0.880 ammonia solution. The required fractions were combined and the solvent evaporated in vacuo to give the title compound as a colorless oil (1.85g).
LC / MS / R _t 1.77 min, mass spectrum m / z 275 [MH ⁺ ].

Illustrative Example 4: [4- (3,4-Dichlorobenzyl) morpholin-2-yl] methylamine (alternative synthesis)
2-[(3,4-Dichlorobenzyl) amino] ethanol (Chem Abs No. 40172-06-3, 0.980 g) and 2- (oxiran-2-ylmethyl) -1H-isoindole-1,3 (2H) The mixture with 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 then stirred at 150 ° C. for 24 hours. The mixture was treated with water (100 ml) and then washed with ethyl acetate (2 × 100 ml). The dark aqueous phase was basified to about pH 12 using 5M aqueous sodium hydroxide and then extracted with ethyl acetate (2 × 100 ml). The combined organic extracts were washed with water and brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to 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. Separations were performed using a 2 "x 22 cm Chiralpak AD 20 μm column, Merck self-packed DAC system. 95: 5: 0.1 (v / v) heptane: absolute ethanol: diethylamine (flow rate: 55 ml / min over 40 min, UV Elution at 225 nm detection); sample loading preparation: 20 ml 3: 2 (v / v) absolute ethanol: 400 mg sample in system eluate.
The title compound (2.49 g) was obtained as follows: Preparative HPLC retention time 23.0 minutes.

Example 5 (alternative procedure)
A slurry of Illustrative Example 7 (1.00 g) in water (8.5 ml) was heated to 75 ° and then treated dropwise with concentrated sulfuric acid (2.5 ml). The mixture was then heated at reflux. After 23 hours, the reaction mixture was allowed to cool to 22 ° and then treated with dichloromethane (6 ml). Next, 880 ammonia solution (7 ml) was added dropwise while cooling. A larger amount of dichloromethane (10 ml) was added. The aqueous phase was separated and extracted with more dichloromethane (10 ml). The combined organic phases were washed with water (5 ml) and then evaporated to dryness. The residue was redissolved in dichloromethane and the solvent was re-evaporated 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 salt and 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 at 220 nm), Rt 8.9 min.

Illustrative example 7: 2-[(3,4-dichloro in 2- [4- (3,4-dichloro-benzyl) -morpholin-2-ylmethyl] -isoindole -1,3- dionetetrahydrofuran (3.3 ml) A mixture of (benzyl) amino] ethanol (2.038 g) and (S) -2- (oxiran-2-ylmethyl) -1H-isoindole-1,3 (2H) -dione (2.032 g) was refluxed under nitrogen. Stir and heat in the state. After 21.5 hours, more tetrahydrofuran (12.5 ml) was added and the mixture was allowed to cool to 3 °. Triphenylphosphine (2.793 g) was added and the mixture was stirred until all the solid dissolved. Next, diisopropyl azodicarboxylate (2.1 ml) was added over 12 minutes, keeping the temperature <7 °. After 2.25 hours, the mixture was warmed to 22 °. After 5.3 hours, more triphenylphosphine (121 mg) and diisopropyl azodicarboxylate (0.09 ml) were added. After 22.5 hours, the reaction mixture was nearly concentrated to dryness. Propan-2-ol (12 ml) was added, the concentration was repeated and this was repeated once more. A larger amount of propan-2-ol (12 ml) was added and the mixture was heated to 70 °. After 0.5 hours, the slurry was allowed to cool to 22 ° and then after another 2 hours the product was collected. The bed was washed with propan-2-ol (2 × 4 ml) and then dried in vacuo at 40 ° to give the product (2.622 g).

Description Example 8: 4-Nitrophenyl [4- (3,4-dichlorobenzyl) morpholin-2-yl] methylcarbamate with stirring under nitrogen at 20 ° C., triethylamine (0.09 ml) in dichloromethane (3 ml) Description To a solution of Example 3 (0.150 g, 0.545 mmol). The solution was allowed to cool to 0 ° C. and a solution of 4-nitrophenyl chloroformate (0.121 g) in dichloromethane (1 ml) was added dropwise. The resulting mixture was stirred at 0 ° C. for 4 hours. The solution was warmed to 20 ° C., washed with brine (4 ml), dried over (MgSO ₄ ) and concentrated in vacuo . Purification by Biotage flash chromatography using silica gel eluting with 35% ethyl acetate in cyclohexane gave the title compound (0.2 g).
LC-MS Rt 3.1 min. Mass spectrum m / z 441 [MH ⁺ ].

Example 9: 4-Nitrophenyl [(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methylcarbamate
Illustrative Example 9 was prepared from Illustrative Example 5 (0.225 g) and 4-nitrophenyl chloroformate (0.182 g) in a similar manner to Illustrative Example 8 to give the title compound (0.2 g).
LC-MS Rt 3.1 min mass spectrum m / z 441 [MH ⁺ ].

Example 10: [(2S) -4- (3,4-Difluorobenzyl) morpholin-2-yl] methylamine
An explanation example 10 was generated in the same manner as in the explanation example 5 .
Preparative HPLC retention time 28.3 minutes.

Example 11: 4-Nitrophenyl [(2S) -4- (3,4-difluorobenzyl) morpholin-2-yl] methylcarbamate
Illustrative Example 11 was prepared from Illustrative Example 10 and 4-nitrophenyl chloroformate in a manner similar to Illustrative Example 9 .
LC-MS Rt 2.52 min Mass spectrum m / z 408 [MH ⁺ ].

Description Example 12: 4-Nitrophenyl [(2S) -4- (3,4-difluorobenzyl) morpholin-2-yl] methylcarbamate
An explanatory example 12 was generated in the same manner as in the case of the fifth example .
Mass spectrum m / z 466 [MH ⁺ ].

Illustrative example 13: N '-(3- {3-[(2S) -4- (3,4-difluorobenzyl) morpholin-2-ylmethyl] ureidomethyl} benzoyl) hydrazinecarboxylic acid tert-butyl ester

A solution of Example 16 (0.626 g) in N, N-dimethylformamide (5.5 ml) was added to 1-hydroxybenzotriazole (0.174 g), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride ( 0.283 g), t-butyl carbazate (0.120 g), and N, N-diisopropylethylamine (0.174 ml)) and the mixture was stirred at room temperature for 17 hours. The solution was then diluted with dichloromethane (30 ml) and washed sequentially with saturated aqueous sodium bicarbonate (25 ml) and dilute aqueous sodium chloride (2 × 25 ml). The organic phase was separated using a hydrophobic frit (12 ml) and discharged directly onto a SCX (10 g) ion exchange cartridge pretreated with methanol, then eluted with methanol and 10% 0.880 ammonia / methanol. The basic fractions were combined and evaporated to give the title compound (0.480 g) as a yellow film.
LC-MS: Rt = 2.22min.

Illustrative example 14: 1-[(2S) -4- (3,4-difluorobenzyl) morpholin-2-ylmethyl] -3- (3-hydrazinocarbonyl-benzyl) urea

Illustrative Example 13 (0.480 g) was treated with 4M hydrogen chloride in dioxane (10 ml) at room temperature and 30 minutes later with methanol (3 ml). After another 2.5 hours at room temperature, the solution was concentrated to dryness and the residue was loaded directly and equally onto two SCX (10 g) ion exchange cartridges pretreated with methanol, then methanol and 10% 0.880 ammonia. Elute with / methanol. All basic fractions were combined and evaporated to give the title compound (0.374g) as a yellow glassy film.
LC-MS: Rt = 1.78 min.

Description Example 15: [(2S) -4- (3-Chloro-4-fluorobenzyl) morpholin-2-ylmethyl] carbamic acid 4-nitro-phenyl ester

To a solution of 4-nitrophenyl chloroformate (0.102 g) in anhydrous dichloromethane (5 ml) at 0 ° was added dropwise a solution of Example 17 (0.13 g) and triethylamine (0.070 ml) in anhydrous dichloromethane (2 ml). And processed. After stirring at room temperature for 18 hours, the mixture was concentrated in vacuo. Chromatographic purification using silica gel (Varian Bond-Elut cartridge, 5 g) eluting with a gradient of ethyl acetate / cyclohexane gave the title compound (0.19 g) as a colorless oil.
LC-MS: Rt = 2.66 min mass spectrum m / z 424 [MH ⁺ ].

Example 16: {(2S) -4-[(5-chlorothien-2-yl) methyl] morpholin-2-yl} methylamine
An explanation example 16 was generated by a method similar to that in the explanation example 5 .
Chiral preparative HPLC retention time 25.2 minutes.

Example 17: 4-Nitrophenyl [(2S) -4-[(5-chlorothien-2-yl) methyl] morpholin-2-yl] methylcarbamate
Illustrative Example 17 was prepared from Illustrative Example 16 and 4-nitrophenyl chloroformate in a manner similar to Illustrative Example 9 .
LC-MS Rt 2.58 min mass spectrum m / z 412 [MH ⁺ ].

Example 18: 5- (tert-Butoxycarbonylamino-methyl) -2-fluorobenzoic acid methyl ester

5-[[[[(1,1-dimethylethoxy) carbonyl] amino] methyl] -2-fluoro-benzoic acid (Tetrahedron Lett. (1993), 34 in a mixture of dichloromethane (4 ml) and methanol (4 ml). (39), prepared as described in 6263-4) was added (trimethylsilyl) diazomethane (0.9 M solution in hexane, 4.8 ml). The solution was stirred at room temperature for 1 hour. The solvent was removed in vacuo . Purify the residue by chromatography on silica gel (10 g Varian Bond-elut cartridge) eluting sequentially with 8: 1 to 6: 1 cyclohexane / ethyl acetate to give the title compound as a colorless oil (0.388 g). It was.
LC / MS R _t 2.91 min m / z 301 [MNH ₄ ⁺ ].

Example 19: 5-aminomethyl-2-fluoro-benzoic acid methyl ester hydrochloride

Illustrative Example 18 (0.60 g) was dissolved in 4M hydrogen chloride in dioxane (8 ml) and the solution was stirred at 20 ° for 40 minutes. The solvent was removed in vacuo to give the title compound as a white solid (0.435g).
LC / MS R _t 1.18 min m / z 184 [MH ⁺ ].

Example 20: (3-Ethylcarbamoyl-benzyl) carbamic acid tert-butyl ester

To a solution of 3-[[[[(1,1-dimethylethoxy) carbonyl] amino] methyl] benzoic acid (0.980 g) in tetrahydrofuran (25 ml) with stirring under nitrogen, 1- (3-dimethylaminopropyl ) -3-Ethylcarbodiimide hydrochloride (0.750 g) was added followed by triethylamine (0.543 ml) and the mixture was stirred at 22 ° for 1.5 hours. A 2M solution of ethylamine in tetrahydrofuran (6.0 ml) was added and the mixture was stirred at 20 ° for 18 hours. The mixture was evaporated to dryness and the residue was partitioned between water and ethyl acetate. The organic layer was separated, dried (MgSO ₄ ) and evaporated in vacuo. The residue was purified by chromatography on silica gel eluting with ethyl acetate containing 0.5% triethylamine to give the title compound (0.345 g).
LC / MS Rt = 2.62 min Mass spectrum m / z 296 [MNH ₄ ⁺ ].

Explanation Example 21: 3-Aminomethyl-N-ethyl-benzamide trifluoroacetate

Trifluoroacetic acid (1 ml) was added to a solution of Example 20 in dichloromethane (1 ml) and the mixture was stirred at 22 ° until all starting material was consumed (LC / MS check). The mixture was evaporated to dryness, toluene was added and re-evaporated to dryness twice. The residue was triturated with ether to produce a white solid and the ether was evaporated in vacuo to give the title compound as the trifluoroacetate salt.
NMR (D ₆ DMSO) 8.55 (1 H , t, NH); 8.25 (3 H , bs, NH ₃ ⁺ ); 8.0 (1 H , bs, CH), 7.85 (1 H , bd, CH); 7.6 ( 1 H, bd, CH); 7.53 (1 H, dd, CH); 4.1 (2 H, bs, CH 2); 3.3 (2 H, m, CH 2); 1.15 (3 H, t, CH 3) .

Illustrative example 22: [(2S) -4- (3-chloro-4-fluoro-benzyl) -morpholin-2-ylmethyl] carbamic acid tert-butyl ester

A solution of 2-morpholinylmethyl) -carbamic acid 1,1-dimethyl ester [CAS 186202-57-3] (0.26 g) in dichloromethane (5 ml) was added to 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 application to an SCX ion exchange cartridge (10 g) and eluting with methanol followed by 10% 0.880 ammonia / methanol. The basic fraction was evaporated in vacuo 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 23: C-[(2S) -4- (3-Chloro-4-fluorobenzyl) morpholin-2-yl] methylamine

A solution of Illustrative Example 22 (0.36 g) in dichloromethane (1 ml) was treated with trifluoroacetic acid (1 ml) and left for 1 hour. The mixture was concentrated in vacuo and the residue was partitioned between dichloromethane and aqueous sodium bicarbonate; the phases were separated, the organic phase was dried (MgSO ₄ ), filtered and dried and the solvent was removed in vacuo. Evaporated 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 24: 3- {3-[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-ylmethyl] ureidomethyl} benzoic acid; compound with triethylamine

Prepared in an analogous manner to that used for Example 15 using Example 12 and 4- (methoxycarbonyl) phenylacetic acid.
LCMS m / z 452 [MH ⁺ ].

Example 25: (4-Ethylcarbamoyl-benzyl) carbamic acid tert-butyl ester

Prepared in a similar manner to that used for Example 20 .
LCMS m / z 279 [MH ⁺ ].

Example 26: 4-Aminomethyl-N-ethylbenzamide hydrochloride

Prepared in a similar manner to that used for Illustrative Example 21, but using 4.0M HCl in 1,4-dioxane instead of trifluoroacetic acid and dichloromethane.
LCMS m / z 179 [MH ⁺ ].

Example
Synthesis method A
Example 5

To a solution of Illustrative Example 9 (0.408 g) in N, N-dimethylformamide (5 ml) was added Illustrative Example 19 (0.2 g) and N, N-diisopropylethylamine (0.346 ml). The solution was stirred at 20 ° for 18 hours. The mixture was applied to a sulfonate ion exchange cartridge (10 g, Isolute SCX, pretreated with methanol). Elution from the cartridge with methanol followed by 10% 0.880 ammonia in methanol; the basic fraction was evaporated in vacuo to give a yellow gum. The residue was dissolved in ethyl acetate (50 ml) and the solution was washed with 2N sodium hydroxide (30 ml and 15 ml × 2). The combined aqueous washes were extracted with ethyl acetate (30 ml). The combined organic extracts were washed with water (20 ml), dried (MgSO ₄ ) and concentrated in vacuo to give the title compound as an oil (0.377 g).
LC / MS R _t 2.61 min m / z 484 [MH ⁺ ].

Synthesis method B
Example 2

To a solution of Illustrative Example 12 (0.047 g) and N-hydroxy-ethaneimidoamide (0.037 g) in absolute ethanol (1 ml) was added sodium ethoxide (21 wt% solution in ethanol, 0.1 ml). Pre-dried 4A powdered molecular sieve (0.230 g) was added to the solution. The suspension was heated under reflux for 5 hours. The suspension was filtered and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (10 g Varian Bond-elut cartridge) eluting sequentially with 5% methanol in cyclohexane / ethyl acetate / chloroform to give the title compound as a white solid.
LC / MS R _t 2.65 min m / z 490 [MH ⁺ ].

Synthesis method C
Example 15

To a solution of Example 5 (0.210 g) in methanol (5 ml) was added 2N sodium hydroxide (1 ml). The solution was stirred at 20 ° for 2 hours. The solvent was removed in vacuo . The residue was dissolved in water (5 ml) and acidified to pH 1 using 2H hydrochloric acid. The suspension was applied to a sulfonate ion exchange cartridge (2 × 10 g, Isolute SCX, pretreated with methanol). Elution from the cartridge with water followed by 5% triethylamine in methanol; the basic fraction was evaporated in vacuo to give the title compound as a colorless oil (0.246g).
LC / MS R _t 2.42 min m / z 470 [MH ⁺ ].

Synthesis method D
Example 7

To a solution of Example 15 (0.043 g) in N, N-dimethylformamide (2 ml) was added N, N-diisopropylethylamine (0.026 ml), 1-hydroxybenzotriazole (0.013 g), and 1- (3-dimethyl Aminopropyl) -3-ethylcarbodiimide hydrochloride (0.017 g) was added. The solution was stirred at 20 ° for 5 minutes and then treated with ethylamine hydrochloride (0.036 g). After 0.75 hours, the solution was treated with additional N, N-diisopropylethylamine (0.026 ml) and stirred in a sealed vial for 18 hours. The mixture was applied onto a sulfonate ion exchange cartridge (5 g Isolute SCX, pretreated with methanol). Elution from the cartridge with methanol followed by 10% 0.880 ammonia in methanol; the basic fraction was evaporated in vacuo to give an oil. The residue was purified by chromatography on silica gel (10 g Varian Bond-elut cartridge) eluting sequentially with 5% methanol in cyclohexane / ethyl acetate / dichloromethane to give the title compound (0.020 g).
LC / MS R _t 2.45 min m / z 497 [MH ⁺ ].

Synthesis method E
Example 21

Triethylorthoacetate (0.54 ml) was added to Illustrative Example 14 (0.047 g) and the mixture was heated to 160 ° for 18 hours. After cooling, the mixture was diluted with methanol (2 ml) and loaded directly onto an SCX (2 g) ion exchange cartridge pretreated with methanol, then eluted with methanol followed by 10% 0.880 ammonia / methanol. It was. Combine the basic fractions and evaporate to obtain a pale yellow film and purify by chromatography using silica gel (Varian Bond-Elut cartidge, 1 g) eluting with 0%, 5%, and 10% methanol / ethyl acetate. Two impure colorless and transparent films were produced. These were recombined and purified using mass directed HPLC. Appropriate fractions were combined and evaporated to give the title compound (0.0021 g) as a clear colorless film.
LC-MS: Rt = 2.07 min mass spectrum m / z [MH ⁺ ] 458.

Synthesis method F
Example 22

Ethyl acetimidate hydrochloride (0.011 g) was treated with sodium hydroxide (0.112 ml of a 0.0915 g solution in methanol (2.86 ml)) and the mixture was shaken for 10 minutes and then allowed to stand for 2 minutes. The supernatant was then transferred by syringe into a thick sealed vial (Reactivial ^™ ) containing Illustrative Example 14 (0.039 g); the mixture was heated at reflux for 1 hour 15 minutes and allowed to cool to give an orange gum . The gum was dissolved in methanol (1 ml) and loaded directly onto an SCX (2 g) ion exchange cartridge pretreated with methanol, then eluted with methanol followed by 10% 0.880 ammonia / methanol. The basic fractions were combined and evaporated to obtain a clear and colorless film that was further purified using mass directed HPLC. Appropriate fractions were combined and evaporated to give the title compound (0.0035 g) as a clear colorless film.
LC-MS: Rt = 2.02 min mass spectrum m / z [MH ⁺ ] 457.

Synthesis method G
Example 23: 1-[(2S) -4- (3,4-difluorobenzyl) morpholin-2-ylmethyl] -3- (3- [1,3,4] oxadiazol-2-ylbenzyl) urea

Illustrative Example 14 (0.114 g) to which triethylorthoformate (1.3 ml) was added was heated at reflux under nitrogen for 18 hours. After cooling, the mixture was diluted with methanol and applied directly onto a sulfonate ion exchange cartridge (5 g Isolute SCX, prewashed with methanol). The basic fraction was concentrated in vacuo by eluting from the cartridge with methanol followed by 5% triethylamine in methanol. Use silica gel (8 g cartridge) to elute with 400: 8: 1, then 300: 8: 1, then 200: 8: 1, and then 100: 8: 1 dichloromethane / ethanol / 0.880 ammonia solution. The residue was further purified by Biotage flash chromatography. The required fractions were combined and the solvent was evaporated in vacuo to give the title compound as a colorless gum (0.0025g).
LCMS R _t 2.12 min, m / z 444 [MH ⁺ ].

Additional examples described in the following table were prepared according to or by analogy with the methods described above.

Claims (26)

Formula (I):

[Where,
R ¹ represents unsubstituted or substituted aryl;
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 and R ⁴ each independently represent hydrogen or C _1-6 alkyl)
And the salts and solvates thereof;
The following compounds are excluded:
N-benzyl-N ′-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-(2-phenylethyl) urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-(4-methoxybenzyl) urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-(2-methylbenzyl) urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-(3-methylbenzyl) urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-(4-methylbenzyl) urea;
N- (4-chlorobenzyl) -N ′-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} urea;
N- (3-chlorobenzyl) -N ′-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} urea;
N- (2-chlorobenzyl) -N ′-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} urea;
N- [3-({[({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) carbonyl] -amino} methyl) phenyl] acetamidoformate;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-[4- (methylsulfonyl) -benzyl] urea;
4-({[({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) carbonyl] amino} -methyl) benzenesulfonamide;
N-{[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N '-(4-methoxybenzyl) urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-(3,4-dimethoxybenzyl) urea;
N- (3-cyanobenzyl) -N ′-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-(3-methoxybenzyl) urea;
4-({[({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) carbonyl] amino} -methyl) benzamide;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-[3- (trifluoromethoxy) -benzyl] urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-[4- (trifluoromethyl) -benzyl] urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N '-[4- (1,2,3-thiadiazol-4-yl) benzyl] urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-[4- (trifluoromethoxy) -benzyl] urea;
N- (3,5-dichlorobenzyl) -N ′-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N '-[3- (trifluoromethyl) -benzyl] urea
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-(2,4-difluorobenzyl) urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-(3,4-difluorobenzyl) urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-(3-fluorobenzyl) urea;
N- (3,4-dichlorobenzyl) -N ′-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} urea;
3-({[({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) -carbonyl] amino} methyl) -N-methylbenzamide;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-[2- (trifluoromethoxy) benzyl] urea;
Methyl 3-({[({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) -carbonyl] amino} methyl) benzoate;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-[2- (trifluoromethyl) -benzyl] urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-(4-fluorobenzyl) urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-(2-fluorobenzyl) urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-(4-isopropoxybenzyl) urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-(2,4-dimethoxybenzyl) urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-[2- (4-methoxyphenyl) -ethyl] urea;
N- [2- (4-tert-butoxyphenyl) ethyl] -N ′-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-[3- (dimethylamino) benzyl] urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-[2- (methylthio) benzyl] urea;
N- (4-cyanobenzyl) -N ′-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} urea;
N ′-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N- (4-methoxybenzyl) -N-methylurea;
Methyl 4-({[({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) carbonyl] amino} methyl) benzoate;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-[1- (4-fluorophenyl) ethyl] urea;
N-{[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} -N ′-(1-methyl-1-phenylethyl) urea;
4-({[({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) carbonyl] amino} -methyl) -N- (1,3-thiazol-2-yl) benzene Sulfonamide;
4-({[({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) carbonyl] amino} -methyl) -benzoic acid and N, N, N-triethylamine (1 1) a compound;
4-({[({[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) carbonyl] -amino} methyl) benzamide hydrochloride;
4-({[({[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) carbonyl] -amino} methyl) benzamide;
4-({[({[(2R) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) carbonyl] -amino} methyl) benzamide;
3-({[({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) carbonyl] -amino} methyl) -N, N-dimethylbenzamide;
3-({[({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) carbonyl] -amino} methyl) -N-ethylbenzamide;
N-cyclopropyl-3-({[({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) -carbonyl] amino} methyl) benzamide;
4-({[({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) carbonyl] -amino} methyl) -N-methylbenzamide;
4-({[({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) carbonyl] -amino} methyl) -N, N-dimethylbenzamide;
4-({[({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) carbonyl] -amino} methyl) -N-ethylbenzamide;
N-cyclopropyl-4-({[({[4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) -carbonyl] amino} methyl) benzamide;
4- (2-{[({[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) -carbonyl] amino} ethyl) benzenesulfonamide;
3-({[({[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) -carbonyl] amino} methyl) -N-methylbenzamide;
N-cyclopropyl-3-({[({[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) -carbonyl] amino} methyl) benzenesulfonamide;
N-cyclopropyl-4-({[({[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) -carbonyl] amino} methyl) benzenesulfonamide;
4-({[({[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) -carbonyl] amino} methyl) -N-methylbenzamide, and;
N-cyclopropyl-4-({[({[(2S) -4- (3,4-dichlorobenzyl) morpholin-2-yl] methyl} amino) carbonyl] amino} methyl) benzamide. The compound of formula (I) according to claim 1, wherein R ¹ is unsubstituted or substituted phenyl. R ¹ is 4- (3-methyl-1,2,4-oxadiazol-5yl), 4- (methanesulfonylamino), 4- (N, N-dimethylaminosulfonyl), 4- (aminosulfonyl ), 3- (iso-propylaminocarbonyl), 3- (3-methyl-1,2,4-oxadiazol-5-yl), 3- (methylcarbonylamino), 4-fluoro-3- (methoxy Carbonyl), 3-amide, 4-fluoro-3- (ethylaminocarbonyl), 4-fluoro-3- (methylaminocarbonyl), 3- (methoxycarbonyl), 3-amido-4-fluoro, 3- (cyclo Propylaminocarbonyl), 3- (ethylaminocarbonyl), 3- (methylaminocarbonyl), 3-carboxy-4-fluoro, 3-carboxy, 3- (methanesulfonylamino), 3- (methanesulfonylamino), 4- Amido, 3- (5-methyl-1,3,4-oxadiazol-2-yl), 3- (5-methyl-1,3,4-triazol-2-yl), or 3- (1, 3,4-oxadiazol-2-yl) Is phenyl substituted, the compounds of formula (I) according to claim 1 or claim 2. The compound represented by formula (I) according to any one of claims 1 to 3, wherein R _na and R _nb are both hydrogen.   The compound represented by the formula (I) according to any one of claims 1 to 4, wherein n is 1. R ³ and R ⁴ are both hydrogen, the compounds of formula (I) according to any one of claims 1 to 5. The compound represented by the formula (I) according to any one of claims 1 to 6, wherein R ² is unsubstituted or substituted phenyl or unsubstituted or substituted thiophenyl. R ² is substituted with chloro or fluoro, phenyl or thiophenyl, the compound represented by formula (I) according to any one of claims 1-7. R ² is 3,4-dichlorophenyl, 3,4-difluorophenyl or 2-chloro-thiophen-5-yl represented by formula (I) according to any one of claims 1-8. Compound. Formula (IB)

[Where,
R ⁹ is mono- or di- (C _1-6 alkyl) aminocarbonyl or C _3-8 cycloalkylaminocarbonyl)
Or a salt or solvate thereof. The compound represented by the formula (IB) according to claim 10, wherein R ⁹ is ethylaminocarbonyl, cyclopropylaminocarbonyl, or dimethylaminocarbonyl. The compound represented by the formula (IB) according to claim 10 or 11, wherein R ⁹ is 4-ethylaminocarbonyl, 3-cyclopropylaminocarbonyl, or 3-dimethylaminocarbonyl.   11. A compound according to claim 1 or claim 10 selected from the examples.   Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 11. A compound according to claim 1 or claim 10 selected from 26, 27, 28, 29, 31, 33, 34 and 35.   Claims selected from Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 18, 20, 22, 28, 31, 33, 34, and 35. The compound of Claim 1 or Claim 10.   11. A compound according to claim 1 or claim 10 selected from examples 1, 2, 3, 4, 5, 6, 7, 12, 22, 28, 31, 33, and 34.   11. A compound according to claim 1 or claim 10 selected from examples 1, 2, 12, 22, 28, 31, 33, and 34. A method for preparing a compound of formula (I) according to claim 1 comprising a compound of formula (II) and a compound of formula (III)

[Where,
R ¹ , Y, R ³ , R ⁴ , and R ² are as previously defined for formula (I) in claim 1 and U is a urea-forming group.
Reacting with
Then, if necessary, the following optional steps:
(i) converting the compound of formula (I) into a further compound of formula (I);
(ii) removing any required protecting groups;
(iii) preparing a salt or solvate of the compound so produced;
Performing the one or more of the above. Formula (III)

In which U is a urea-forming group and R ² and R ⁴ are as defined for formula (I) in claim 1
The compound shown by. Formula (IVBR)

Wherein A is a protected amino group and R ² is as defined for formula (I) in claim 1.
The compound shown by. Formula (IVBE)

Wherein A is a protected amino group and R ² is as defined for formula (I) in claim 1.
The compound shown by.   A compound of formula (I) as defined in claim 1 or a physiologically acceptable salt or solvate thereof for use as an active therapeutic agent.   A compound of formula (I) as defined in claim 1 or a physiologically acceptable salt or solvate thereof for use in the treatment of inflammatory conditions (eg asthma or rhinitis).   Use of a compound of formula (I) according to claim 1 or a physiologically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of inflammatory conditions (eg asthma or rhinitis).   A method of treating a human or animal subject suffering from or susceptible to inflammatory symptoms (eg asthma or rhinitis), comprising an effective amount of a compound of formula (I) according to claim 1 or physiological Or a pharmaceutically acceptable salt or solvate thereof.   Comprising a compound of formula (I) according to claim 1 or a physiologically acceptable salt or solvate thereof, and optionally one or more physiologically acceptable diluents or carriers. Pharmaceutical composition.