MORPHOLINE COMPOUNDS FOR THE TREATMENT OF INFLAMMATIONS

Description

Technical Field

[0001] The present invention relates to a novel morpholine compounds having affinity for CCR3. The compound and a salt thereof are useful as a drug for the treatment and/or prophylaxis of a disease wherein a cell having CCR3 plays an important role in the onset, progress and retention of pathology, such as asthma, sinusitis, atopic dermatitis, allergic rhinitis, allergic conjunctivitis, allergic myelitis, ulcerative colitis, Crohn's disease and rheumatoid arthritis.

Background Art

[0002] As chemotactic substances that induce chemotaxis and topical infiltration of leukocytes such as neutrophil and monocyte, there are classical chemotactic factors such as complement catabolites C3a and C5a, arachidonate metabolites such as leukotriene B₄ and the like, platelet-activating factor and bacterium-derived formyl peptide. These are secondary products mainly associated with tissue lesions. On the other hand, the presence of a series of cytokines that are produced by new expression of gene and responsible for the induction and activation of particular leukocyte, namely, chemokines, was verified by interleukin (IL-8) (CXCL8) purified and gene cloned by Matsushima et al. in 1987 (see. e.g., Proc. Natl. Acad. Sci. USA, 84, 9223-9237 (1987) and J. Exp. Med., 167, 1883-1893 (1988)). There are 42 chemokines identified to the present, and chemokines are classified into four subgroups based on the characteristics of their amino acid sequences. That is, C chemokine, CC chemokine, CXC chemokine and CX₃C chemokine. XCL1 belonging to C chemokine shows chemotactic activity for T cells and NK cells.

[0003] CC chemokine shows chemotactic activity for monocytes other than neutrophils, lymphocytes, Langerhans cells, dendritic cells, eosinophils, mast cells and basophils. Furthermore, CXC chemokine mainly acts on chemotaxis of neutrophils as represented by the action of CXCL8, and CX₃C chemokine mainly acts on chemotaxis of NK cells. These chemokines exhibits their actions by binding to G-protein-coupled receptors (chemokine receptors) and 18 chemokine receptors have been identified to the present (see e.g., CELL TECHNOLOGY, 17, 1022-1029 (1998) and Immunity, 12, 121-127 (2000)).

[0004] Therefore, a substance that inhibits the binding between chemokine and its receptor suppresses selective chemotaxis and activation of leukocytes, and is considered to be useful as a pharmaceutical product for the prophylaxis or treatment of acute and chronic inflammatory diseases including allergic diseases.

[0005] Particularly, one of the pathological characteristics of asthma, sinusitis, atopic dermatitis, allergic rhinitis, allergic conjunctivitis, allergic myelitis, ulcerative colitis, Crohn's disease and rheumatoid arthritis is eosinophil infiltration into the inflammatory tissue. Therefore, eosinophils are considered to play a key role in the onset, progress and retention of these diseases. It is known that CCR3, one of the CC chemokine receptors, plays an important role in the chemotaxis to inflammatory lesion and activation of eosinophils, and CCR3 is expressed not only in eosinophils but also in inflammatory cells such as mast cells, basophils, dendritic cells and Th2 cells (J. Clin. Invest., 99(2), 178-184 (1997), J. Exp. Med., 190(2), 267-280 (1999), J. Clin. Invest., 100(5), 1137-1143 (1997), Science, 277, 5334, 2005-2007 (1997), and Pharmacol. Rev., 52(1), 145-176 (2000)). In asthma and atopic dermatitis models of CCR3 gene knockout mouse, eosinophils infiltration into the lung and skin, and airway hypersensitivity are suppressed as compared to wild-type mouse (J. Clin. Invest., 109(5), 621-628 (2002)). It is also known that infiltration of activated eosinophils is observed in nasal polyp tissue extract of sinusitis, and CCL11, CCL13 and CCL24, which are selective and strong ligands of CCR3, significantly increase therein (J. Immunol., 163(3), 1545-1551 (1999)). Moreover, CCR3 positive mononuclear cells significantly increase in peripheral blood and synovial fluid of rheumatoid arthritis patients as compared to healthy subjects (Arthritis Rheum., 44(5), 1022-1032 (2001)).

[0006] In consideration of the above, a compound having affinity for CCR3 is expected to be useful as a pharmaceutical product for the prophylaxis or treatment of immune and inflammatory diseases.

[0007] In addition, for example, the following patent references regarding therapeutic agents for immune and inflammatory diseases, which show affinity for chemokine receptors, have been published. WO97/24325 discloses diphenylmethane derivatives and WO98/25617 discloses arylpiperazine derivatives, as compounds having affinity for chemokine receptors, WO98/02151, WO98/04554 and WO00/34278 disclose tricyclic heteroaromatic derivatives having affinity for chemokine receptors, WO99/55324 and WO99/55330 disclose phenylalanine derivatives having affinity for chemokine receptors, WO00/58305 discloses piperazine derivatives having affinity for chemokine receptors, and WO00/31033, WO00/53600, WO01/14333, WO02/66460 and WO02/88111 disclose piperidine derivatives having affinity for chemokine receptors. In addition, WO02/18335 discloses cyclic amine derivatives having a CCR3 antagonistic action. In addition, WO02/26722, WO02/26723, WO03/82292, WO03/82294, WO03/82861, WO03/82862, WO03/82295, WO03/82863, WO03/99287 and WO03/99798 disclose morpholine derivatives having affinity for chemokine receptors. However, these compounds do not have the structural characteristics that the compound of the present invention to be mentioned below shows as a preferable embodiment (i.e., compounds having sulfur atom on alkylene chain having morpholine ring via methylene amide).

[0008] Since a clinically effective low-molecular-weight compound having CCR3 affinity has not bee reported to date, a CCR3 antagonist having a different structure is expected to be a pharmaceutical product for the treatment or prophylaxis of acute and chronic inflammatory diseases, including immune and allergic diseases.

[0009] EP243959A discloses a racemate, which is useful as a synthetic intermediate for the compound of the present invention.

Disclosure of the Invention

[0010] The present invention aims at provision of a pharmaceutical product having affinity for CCR3, which is used for the treatment and/or prophylaxis of immune and inflammatory diseases.

[0011] In view of the above-mentioned situation, the present inventors have conducted intensive studies in an attempt to find a nonpeptidic compound having a CCR3 antagonistic action and found that a morpholine compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof inhibits CCR3 ligand from binding to CCR3 and acts as an antagonist. Thus, they have found that the compound of the present invention can be a pharmaceutical product for the treatment or prophylaxis of acute and chronic inflammatory diseases including immune and allergic diseases, which resulted in the completion of the present invention.

[0012] Accordingly, the gist of the present invention is as follows.

[1] A compound represented by the formula (1)

wherein
ring A is a monocyclic to tricyclic C_6-14 aryl which may be partially hydrogenated and which may have substituent(s), or a 5- to 7-membered aromatic heterocyclic (monocyclic) group containing, as a ring atom besides carbon atom, 1 to 3 kinds of 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom or groups derived from an aromatic heterocycle (bicyclic or above) obtained by condensing a 5- to 7-membered aromatic heterocycle containing, as a ring atom besides carbon atom, 1 to 3 kinds of 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom and a benzene ring or the above-mentioned aromatic heterocyclic (monocyclic) group, each of which may be partially hydrogenated and which may have substituent(s),
ring B is a divalent 5- to 14-membered monocyclic to tricyclic heterocyclic group containing, as a ring atom besides carbon atom, 1 to 3 kinds of 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom which may have substituent(s), or a monocyclic to tricyclic cycloalkylene (including crosslinked cycloalkylene) having 3 to 8 carbon atoms and which may have substituent(s),
wherein said substituent(s) is/are selected from halogen atom, C_1-6 alkyl, C_3-8 cycloalkyl, C_3-8 cycloalkyloxy, C_1-6 haloalkyl, C_6-14 aryl, C_1-6 alkoxy, C_1-6 haloalkoxy, C_6-14 aryloxy, nitro, amino, mono- or di-C_1-6 alkylamino, mono-or di-(C_3-8 cycloalkyl)amino, mono- or di- (C_6-14 aryl)amino, C_1-11 acyl, mono- or di- (C_1-11 acyl) amino, mono- or di- (C_1-6 alkoxy-carbonyl)amino, sulfonylamino, amino-C_1-6 alkyl, mono- or di- (C_1-6 alkyl) amino-C_1-6 alkyl, C_3-8 cyclic amino, hydrazino, guanidino, amidino, hydroxyamidino, C_1-6 alkoxyamidino, aminomethyleneamino, imino, carboxy, C_1-6 alkoxy-carbonyl, carbamoyl, mono- or di-(C_1-6 alkyl)aminocarbonyl, mono- or di- (C_6-14 aryl)aminocarbonyl, cyano, C_7-13 aralkyl, mono- or di- (C_7-13 aralkyl) aminocarbonyl, heteroaryl, heteroaryl-C_1-3 alkyl, mono- or di- (heteroaryl-C_1-3 alkyl)-aminocarbonyl, hydroxy, mercapto, C_1-6 alkylthio, C_6-14 arylthio, -SO₃H, -SO₂NH₂, sulfonamide, oxo and thioxo,
m is an integer of 0 to 2,
n is an integer of 1 to 5,
X is a bond, -NH-, -NR¹- wherein R¹ is C_1-6 alkyl which may have substituent(s) as defined above, -CO-, -CO₂-, -OCO-, -CONR^a- wherein R^a, here and in the following, is hydrogen atom or C_1-6 alkyl which may have substituent(s) as defined above, -NR^aCO-, -NR²CONR³- wherein R² and R³ may be the same or different and each is hydrogen atom or C_1-6 alkyl which may have substituent(s) as defined above, or R² and R³ in combination optionally form, together with the atoms bonded thereto, a ring which may have substituent(s) as defined above, oxygen atom, sulfur atom, -SO-, -SO₂-, -NR^aSO₂-, -SO₂NR^a-, C_1-6 alkylene which may have substituent(s) as defined above, a straight chain or branched chain alkenylene having2 to 6 carbon atoms, which has double bond(s) at any position of the alkylene chain having 2 to 6 carbon atoms and which may have substituent(s) as defined above, a straight chain or branched chain alkynylene having 2 to 6 carbon atoms, which has triple bond(s) at any position of the alkylene chain having 2 to 6 carbon atoms and which may have substituent(s) as defined above, -O-X^a- wherein X^a, here and in the following, is C_1-6 alkylene which may have substituent(s) as defined above, -X^a-O-, -CO-X^a-, -X^a-CO-, -CONR^a-X^a-, -X^a-CONR^a-, -NR^aCO-X^a-, -X^a-NR^aCO-, -S-X^a-, -X^a-S-, -SO-X^a-, -X^a-SO-, -NR^a-X^a-, -X^a-NR^a-, -SO₂-X^a-, -X^a-SO₂-, -C(=N-CO₂-R¹)-, -C(=N-SO₂-R¹)-, -C(=N-SO₂NH₂)-, -C(=CH-NO₂)-, -C(=N-CN)- or a monocyclic to tricyclic cycloalkylidene (including crosslinked cycloalkylidene) having 3 to 8 carbon atoms which may have substituent(s) as defined above,
Y is a bond, -NH-, -NR⁴- wherein R⁴, here and in the following, is C_1-6 alkyl which may have substituent(s) as defined above, -CO-, -CO₂-, -OCO-, -CONR^b- wherein R^b, here and in the following, is hydrogen atom or C_1-6 alkyl which may have substituent(s) as defined above, -NR^bCO-, -NR⁵CONR⁶- wherein R⁵ and R⁶ may be the same or different and each is hydrogen atom or C_1-6 alkyl which may have substituent(s) as defined above, or R⁵ and R⁶ in combination optionally form, together with the atoms bonded thereto, a ring which may have substituent(s) as defined above, oxygen atom, sulfur atom, -SO-, -SO₂-, -NR^bSO₂-, -SO₂NR⁶-, C_1-6 alkylene which may have substituent(s) as defined above, a straight chain or branched chain alkenylene having 2 to 6 carbon atoms, which has double bond(s) at any position of the alkylene chain having 2 to 6 carbon atoms and which may have substituent(s) as defined above, a straight chain or branched chain alkynylene having 2 to 6 carbon atoms, which has triple bond(s) at any position of the alkylene chain having 2 to 6 carbon atoms and which may have substituent(s) as defined above, -O-X^b- wherein X^b, here and in the following, is C_1-6 alkylene which may have substituent(s) as defined above, -X^b-O-, -CO-X^b-, -X^b-CO-, -CONR^b-X^b-, -X^b-CONR^b-, -NR^bCOX^b-, -X^b-NR^bCO-, -S-X^b-, -X^b-S-, -SO-X^b-, -X^b-SO-, -NR^b-X^b-, -X^b-NR^b-, -SO₂-X^b-, -X^b-SO₂-, -C(=N-CO₂-R⁴)-, -C(=N-SO₂-R⁴)-, -C(=N-SO₂NH₂)-, -C(=CH-NO₂)-or -C(=N-CN)-, and
Z is hydrogen atom, halogen atom, C_1-6 alkyl which may have substituent(s) as defined above, a monocyclic to tricyclic cycloalkyl (including crosslinked cycloalkyl) having 3 to 8 carbon atoms which may have substituent(s) as defined above, a monocyclic to tricyclic C_6-14 aryl which may be partially hydrogenated which may have substituent(s) as defined above, a heterocyclic group which may have substituent(s) as defined above, hydroxy, nitro, amino, cyano, C_1-6 alkoxy which may have substituent(s) as defined above, mono- or di-C_1-6 alkylamino which may have substituent(s) as defined above, C_1-7 acylamino which may have substituent(s) as defined above, sulfonylamino which may have substituent(s) as defined above, hydrazino which may have substituent(s) as defined above, guanidino which may have substituent(s) as defined above or amidino which may have substituent(s) as defined above, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[2] The compound described in [1] above, wherein ring B is a divalent 5- to 14-membered monocyclic to tricyclic heterocyclic group containing, as a ring atom besides carbon atom, 1 to 3 kinds of 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom which may have substituent(s) as defined in [1] above, and X is a bond, -NH-, -NR¹- wherein R¹ is C_1-6 alkyl which may have substituent(s) as defined in [1] above, -CO-, -CO₂-, -OCO-, -CONR^a- wherein R^a, here and in the following, is hydrogen atom or C_1-6 alkyl which may have substituent(s) as defined in [1] above, -NR^aCO-, -NR²CONR³- wherein R² and R³ may be the same or different and each is hydrogen atom or C_1-6 alkyl which may have substituent(s) as defined in [1] above, or R² and R³ in combination optionally form, together with the atoms bonded thereto, a ring which may have substituent(s) as defined in [1] above, oxygen atom, sulfur atom, -SO-, -SO₂-,-NR^aSO₂-, -SO₂NR^a-, C_1-6 alkylene which may have substituent(s) as defined in [1] above, a straight chain or branched chain alkenylene having 2 to 6 carbon atoms, which has double bond(s) at any position of the alkylene chain having 2 to 6 carbon atoms and which may have substituent(s) as defined in [1] above, a straight chain or branched chain alkynylene having 2 to 6 carbon atoms, which has triple bond(s) at any position of alkylene chain having 2 to 6 carbon atoms and which may have substituent(s) as defined in [1] above, -O-X^a-wherein X^a, here and in the following, is C_1-6 alkylene which may have substituent(s) as defined in [1] above, -x^a-O-, -CO-X^a-, -X^a-CO-, -CONR^a-X^a-, -X^a-CONR^a-, -NR^aCO-X^a-, -X^a-NR^aCO-, -S-X^a-, -X^a-S-, -SO-X^a-, -X^a-SO-, -NR^a-X^a-, -X^a-NR^a-, -SO₂-X^a-, -X^a-SO₂-, -C(=N-CO₂-R¹)-, -C(=N- SO₂-R¹)-, -C(=N-SO₂NH₂)-, -C(=CH-NO₂)- or -C(=N-CN)-, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[3] The compound described in [1] or [2] above, wherein, in the formula (1), m is 0 or 2, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[4] The compound described in any one of [1] to [3] above, wherein, in the formula (1), m is 0, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[5] The compound described in any one of [1] to [4] above, wherein, in the formula (1), X is a bond, -NH-, -NR¹-wherein R¹ is C_1-6 alkyl which may have substituent(s) as defined in [1] above, -CO-, -CO₂-, -OCO-, -CONR^a- wherein R^a, here and in the following, is hydrogen atom or C_1-6 alkyl which may have substituent(s) as defined in [1] above, -NR^aCO-, -NR²CONR³- wherein R² and R³ may be the same or different and each is hydrogen atom or C_1-6 alkyl which may have substituent(s) as defined in [1] above, oxygen atom, sulfur atom, -SO-, -SO₂-, -NR^aSO₂-, -SO₂NR^a-,a straight chain or branched chain alkenylene having 2 to 6 carbon atoms, which has double bond(s) at any position of the alkylene chain having 2 to 6 carbon atoms which may have substituent(s) as defined in [1], -CO-X^a- wherein X^a here and in the following, is C_1-6 alkylene optionally having substituent(s) as defined in [1] above, -X^a-CO-, -CONR^a-X^a-, -X^a-CONR^a-, -NR^aCO-X^a-, -X^a-NR^aCO- or a monk-cyclic to tricyclic cycloalkylidene (including crosslinked cycloalkylidene) having 3 to 8 carbon atoms which may have substituent(s) as defined in [1] above, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[6] The compound described in any one of [1] to [5] above, wherein, in the formula (1), X is a bond, -CO-, -CONR^a-wherein R^a, here and in the following, is hydrogen atom or C_1-6 alkyl which may have substituent(s) as defined in [1] above, -NR^aCO-, -CO-X^a- wherein X^a, here and in the following, is C_1-6 alkylene which may have substituent(s) as defined in [1] above, -X^a-CO-, -CONR^a-X^a-, -X^a-CONR^a-, -NR^aCO-X^a- or -X^a-NR^aCO-, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[7] The compound described in any one of [1] to [6] above, wherein, in the formula (1), Y is a bond, -NH-, -NR⁴-wherein R⁴ is C_1-6 alkyl which may have substituent(s) as defined in [1] above, -CO-, -CO₂-, -OCO-, -CONR^b- wherein R^b, here and in the following, is hydrogen atom or C_1-6 alkyl which may have substituent(s) as defned in [1] above, -NR^bCO-, -NR⁵CONR⁶- wherein R⁵ and R⁶ may be the same or different and each is hydrogen atom or C_1-6 alkyl which may have substituent(s) as defined in [1] above, oxygen atom, sulfur atom, -SO-, -SO₂-, -NR^bSO₂-, -SO₂NR^b-, -CO-X^b-wherein X^b, here and in the following, is C_1-6 alkylene which may have substituent(s) as defined in [1] above, -X^b-CO-, -CONR^b-X^b-, -X^b-CONR^b-, -NR^bCO-X^b- or -X^b-NR^bCO-, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[8] The compound described in any one of [1] to [7] above, wherein, in the formula (1), Y is a bond, -CO-, -CONR^b-wherein R^b, here and in the following, is hydrogen atom or C_1-6 alkyl which may have substituent(s) as defined in [1] above, -NR^bCO-, -CO-X^b- wherein X^b, here and in the following, is C_1-6 alkylene which may have substituent(s) as defined in [1] above, -X^b-CO-, -CONR^b-X^b-,-X^b-CONR^b-, -NR^bCO-X^b- or -X^b-NR^bCO-, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[9] The compound described in any one of [1] to [8] above, wherein, in the formula (1), Z is hydrogen atom, halogen atom, C_1-6 alkyl which may have substituent(s) as defined in [1] above, monocyclic to tricyclic cycloalkyl (including crosslinked cycloalkyl) having 3 to 8 carbon atoms which may have substituent(s) as defined in [1] above, monocyclic to tricyclic C_6-14 aryl which may be partially hydrogenated which may have substituent(s) as defined in [1] above, heterocyclic group which may have substituent(s) as defined in [1] above, hydroxy, nitro, amino, cyano, C_1-6 alkoxy which may have substituent(s) as defined in [1] above, mono- or di-C_1-6 alkylamino which may have substituent(s) as defined in [1] above, C_1-7 acylamino which may have substituent(s) as defined in [1] above, sulfonylamino which may have substituent(s) as defined in [1] above, hydrazino which may have substituent(s) as defined in [1] above, guanidino which may have substituent(s) as defined in [1] above, or amidino which may have substituent(s) as defined in [1] above, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[10] The compound described in any one of [1] to [9] above, wherein, in the formula (1), Z is hydrogen atom, hydroxy, amino, C_1-6 alkyl which may have substituent(s) as defined in [1] above, C_1-6 alkoxy which may have substituent(s) as defined in [1] above, monocyclic to tricyclic C_6-14 aryl which may be partially hydrogenated which may have substituent(s) as defined in [1] above or heterocyclic group which may have substituent(s), or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[11] The compound described in [1] above, which is represented by the formula (1a)

wherein ring C is a monocyclic to tricyclic C_6-14 aryl which may be partially hydrogenated which may have substituent(s) as defined in [1] above, or a 5- to 7-membered aromatic heterocyclic (monocyclic) group containing, as a ring atom besides carbon atom, 1 to 3 kinds of 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom or groups derived from an aromatic heterocycle (bicyclic or above) obtained by condensing a 5- to 7-membered aromatic heterocycle containing, as a ring atom besides carbon atom, 1 to 3 kinds of 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom and a benzene ring or the above-mentioned aromatic heterocyclic (monocyclic) group, each of which may be partially hydrogenated and which may have substituent(s) as defined in [1] above, and the other symbols are as defined in [1] above, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[12] The compound described in any one of [1] to [11] above, wherein, in the formula (1), ring A is phenyl optionally having substituent(s) as defined in [1] above, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[13] The compound described in any one of [1] to [12] above, wherein, in the formula (1), n is 1 to 3, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[14] The compound described in any one of [1] to [13] above, wherein, in the formula (1), the absolute configuration at the 2-position of morpholine is S configuration, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[15] The compound described in [1] above, which is selected from the group consisting of (2S)-[4-(carboxymethyl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-[4-(3-aminophenyl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-[4-(3-carbamoyl-4-hydroxyphenyl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(pyridin-4-yl)thiazol-2-ylthio]acetamide, (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(3,4-dimethoxyphenyl)thiazol-2-ylthio]acetamide, (2S)-(4-carbamoylthiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-{4-[(2-amino-2-oxoethyl)aminocarbonyl]thiazol-2-ylthio}-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(5-methyl-1,2,4-oxadiazol-3-yl)thiazol-2-ylthio]acetamide, (2S)-(5-amino-8H-indeno[1,2-d]thiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-{4-[(2-amino-2-oxoethyl)aminocarbonyl]phenylthio}-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-{4-[(2-carboxyethyl)aminocarbonyl]thiazol-2-ylthio}-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-(5-acetamino-1,3,4-thiadiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-4-(4-carbamoylthiazol-2-ylthio)-N-{[4- (3, 4-dichlorobenzyl)morpholin-2-yl]methyl}butyramide, (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(1H-tetrazol-5-yl)thiazol-2-ylthio]acetamide, (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-([1,3]thiazolo[5,4-b]pyridin-2-ylthio)acetamide, (2S)-(E)-[4-(2-carbamoylethen-1-yl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-[4-(carbamoylmethyl)thiazol-2-ylthio]-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-[4-(carbamoylmethyl)thiazol-2-ylthio]-N-{[4-(4-fluorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-(4-carboxy-5-methylthiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-(4-carbamoyl-5-methylthiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-(4-carbamoylthiazol-2-ylthio)-N-{[4-(3-chloro-4-fluorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-[4-(2-amino-2-oxoethyl)aminocarbonylthiazol-2-ylthio]-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-(5-amino-1,3,4-thiadiazol-2-ylthio)-N-{[4-(3-chlorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-(5-amino-1,3,4-thiadiazol-2-ylthio)-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(pyrimidin-2-ylthio)acetamide, (2S)-(3-acetyl-2-oxo-2H-chromen-6-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}-(6-oxo-1,6-dihydropyridazin-3-ylthio)acetamide, (2S)-[6-(carbamoylmethyl)pyrazin-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide, and (2S)-4-(cyclopentanesulfonyl)-N-{[4-(3-chloro-4-fluorobenzyl)morpholin-2-yl]methyl}butyramide, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[16] A CCR3 antagonist comprising, as an active ingredient, the compound described in any one of [1] to [15] above, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[17] A pharmaceutical composition comprising the compound described in any one of [1] to [15] above, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, and a pharmaceutically acceptable carrier.

[18] The pharmaceutical composition described in [17] above, which is an agent for the prophylaxis and/or treatment of asthma, sinusitis, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, allergic myelitis, ulcerative colitis, Crohn's disease or rheumatoid arthritis.

[19] A compound as described in any one of [1] to [15] above, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof for use in the prophylaxis and/or treatment of a disease involving CCR3

[20] The compound for the use in the prophylaxis and/or treatment of a disease involving CCR3 as described in [19] above, wherein the disease involving CCR3 is asthma, sinusitis, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, allergic myelitis, ulcerative colitis, Crohn's disease or rheumatoid arthritis.

[21] Use of the compound described in any one of [1] to [15] above, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof for the production of an agent for the production of an agent for the prophylaxis and/or treatment of a disease involving CCR3.

[22] The use described in [21] above, wherein the disease involving CCR3 is asthma, sinusitis, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, allergic myelitis, ulcerative colitis, Crohn's disease or rheumatoid arthritis.

[23] A production method of a compound represented by the formula (1)

wherein ring A, ring B, m, n, X, Y and Z are as defined in [1] above, or a salt thereof, which comprises reacting a compound represented by the formula (6)

wherein each symbol is as defined in [1] above, or a salt thereof, with a compound represented by the formula (8)

wherein ring A is as defined above, or a salt thereof.

[24] (2S)-[4-(carboxymethyl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide.

[25] (2S)-[4-(2-carboxypropan-2-yl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide.

[26] (2S)-(5-amino-1,3,4-thiadiazol-2-ylthio)-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}acetamide.

[27] (2S)-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}-(6-oxo-1,6-dihydropyridazin-3-ylthio)acetamide.

[28] A pharmaceutical composition comprising the compound as described in any one of [24] to [27] above, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, and a pharmaceutically acceptable carrier.

[29] The pharmaceutical composition as described in [28] above, which is an agent for the prophylaxis and/or treatment of asthma, sinusitis, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, allergic myelitis, ulcerative colitis, Crohn's disease or rheumatoid arthritis.

[0013] According to the present invention, the diseases in which a cell having CCR3 plays an important role in the onset, progress and retention of pathology, such as asthma, sinusitis, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, allergic myelitis, ulcerative colitis, Crohn's disease and rheumatoid arthritis can be treated and/or prevented.

Best Mode for Embodying the Invention

[0014] The terms and symbols used in the present specification are defined as follows.

[0015] As the "halogen atom", for example, fluorine atom, chlorine atom, bromine atom and iodine atom can be mentioned.

[0016] The monocyclic to tricyclic C_6-14 aryl which may be partially hydrogenated and may have substituent(s)" means for example, phenyl, naphthyl, anthryl and indenyl. Preferable examples thereof include phenyl and naphthyl, and more preferable examples include phenyl.

[0017] The position of hydrogenation is not particularly limited. As the partially hydrogenated C_6-14aryl, for example, tetrahydronaphthyl and indanyl is mentioned. When the "C_6-14aryl" has a "substituent", the kind and number thereof are not particularly limited, and aryl has 1 to 4 substituents selected from the "substituents" defined below at substitutable position(s). Preferable examples of the substituents include halogen atom, cyano, nitro, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 alkoxy, hydroxy, amino, mono- or di- (C_1-11 acyl)amino, carboxy, C_1-6 alkoxy-carbonyl, carbamoyl and hydroxyamidino, more preferable examples thereof include chlorine atom, fluorine atom, cyano, nitro, methyl, trifluoromethyl, methoxy, hydroxy, amino, acetylamino, carboxy, methoxycarbonyl, carbamoyl and hydroxyamidino, still more preferable examples thereof include fluorine atom, chlorine atom, methyl and trifluoromethyl, and yet more preferable examples thereof include fluorine atom and chlorine atom.

[0018] The means a 5- to 7-membered aromatic heterocyclic (monocyclic) group containing, as a ring atom besides carbon atom, 1 to 3 kinds of 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom includes, for example, furyl, thienyl, pyrrolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, isothiazolyl, imidazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,3,5-triazinyl, azepinyl and diazepinyl. The groups derived from an aromatic heterocycle (bicyclic or above) obtained by condensing a 5- to 7-membered aromatic heterocycle containing, as a ring atom besides carbon atom, 1 to 3 kinds of 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom and a benzene ring or the above-mentioned aromatic heterocyclic (monocyclic) group includes, for example, indolyl, isoindolyl, benzo[b]furyl, benzo[b]thienyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, quinolyl and isoquinolyl.

[0019] The above heterocyclic group or groups derived there from may be partially hydrogenated. The position of hydrogenation is not particularly limited. As the partially hydrogenated heterocyclic group, for example, tetrahydrobenzimidazolyl, tetrahydroquinolyl and tetrahydroisoquinolyl are mentioned.

[0020] Preferable examples of the above heterocyclic group or groups derived there from include furyl, thienyl, thiazolyl, pyridyl, indolyl, benzo[b]furyl, benzo[b]thienyl, benzoxazolyl, benzothiazolyl, quinolyl and isoquinolyl, and more preferable examples include furyl, thienyl, thiazolyl and pyridyl.

[0021] When the above heterocyclic group or groups derived there from has "substituent(s)", the kind and number thereof are not particularly limited, and heteroaryl has 1 to 4 substituents selected from the "substituents" defined below at substitutable position(s). Preferable examples of the substituent include halogen atom, cyano and nitro, and more preferable examples include halogen atom.

[0022] The "heterocyclic group" of the 5- to 14-membered monocyclic to tricyclic heterocyclic group containing, as a ring atom besides carbon atom, 1 to 3 kinds of 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom which may have substituent(s)" for ring B encompasses a saturated ring, an aromatic ring (encompassing "heteroaryl" defined above), and a partially hydrogenated ring group thereof. As the partially hydrogenated ring group, for example, dihydrofuryl, dihydrothienyl, pyrrolinyl, thiazolinyl, pyrazolinyl, oxazolinyl, isoxazolinyl, isothiazolinyl, imidazolinyl, 1,2,4-oxadiazolinyl, 1,3,4-oxadiazolinyl, 1,2,3-triazolinyl, 1,2,4-triazolinyl, 1,2,4-thiadiazolinyl, 1,3,4-thiadiazolinyl, dihydropyridazinyl, tetrahydrobenzimidazolyl, tetrahydroquinolyl and tetrahydroisoquinolyl is mentioned.

[0023] As the "saturated ring group", for example, pyrrolidinyl, piperidyl, piperazinyl, tetrahydrofuranyl, morpholinyl, thiazolidinyl, thiomorpholinyl and homopiperazinyl are mentioned. In addition, the "heterocyclic group" encompasses a "crosslinked heterocyclic group" containing, as a ring atom besides carbon atom, 1 to 4 hetero atoms selected from oxygen atom, sulfur atom and nitrogen atom, and as the crosslinked ring group, for example, 3-aza-bicyclo[3.2.2]nonan-3-yl and 8-azabicyclo[3.2.1]octan-8-yl are mentioned.

[0024] When the "heterocyclic group" has "substituent(s)", the kind and number thereof are not particularly limited, and heterocyclic group has 1 to 4 substituents selected from the "substituents" defined below at substitutable position(s). Preferable examples of the substituent(s) that the heterocyclic group may have include C_1-6 alkyl, hydroxy, nitro, amino, cyano, carboxy, C_1-6 alkoxy-carbonyl, carbamoyl and oxo, and methyl, ethoxycarbonyl, carbamoyl and oxo are more preferable.

[0025] Preferable examples of the "heterocyclic group" include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrrolyl, pyrrolidinyl, morpholinyl, thienyl, furyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, quinolizinyl, quinazolyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,8-naphthyridinyl, acrydinyl, purinyl, pteridinyl, 1,2,4-oxadiazolyl, 1,2,4-oxadiazolinyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,5-triazinyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, piperidyl, piperazinyl, azepinyl, azepanyl, diazepanyl, diazepinyl, tetrahydrofuranyl, morpholinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, indazolyl, indolizinyl, carbazolyl, tetrahydrobenzimidazolyl, chromanyl, isochromanyl, chromenyl, isochromenyl, [1,3]thiazolo[5,4-b]pyridyl, 4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridyl, 1H-benzo[b]azepinyl, 2,3-dihydro-1H-benzo[b]azepinyl, thieno-[3,2-c]pyridyl, 3-azabicyclo[3.2.2]nonan-3-yl, 8-azabi-cyclo[3.2.1]octan-8-yl, benzo[b]furyl, benzo[b]thienyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, 8H-indeno[1,2-d]thiazolyland 4,5-dihydro-naphto[1,2-d]thiazolyl, and more preferable examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,5-triazinyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, benzo[b]furyl, benzo[b]-thienyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, 8H-indeno[1,2-d]thiazolyl, 4,5-dihydro-naphto[1,2-d]thiazolyl, more preferable examples thereof include thiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, and still more preferable examples thereof include thiazolyl, 1,3,4-thiadiazolyl, pyridazinyl and pyrazinyl.

[0026] The "divalent 5-14 membered heterocyclic group which may have substituent(s)" means a divalent group having a bond at any position of the above-mentioned "heterocyclic group". The position of the bond is not particularly limited and it can be appropriately determined depending on the kind of the group. Preferable examples of the "divalent 5-14 membered heterocyclic group" include pyrrolyl, thienyl, furyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl which may be partially hydrogenated, indenothiazolyl which may be partially hydrogenated, naphtothiazolyl which may be partially hydrogenated, quinazolyl, chromenyl, thiazolopyridyl which may be partially hydrogenated, benzoazepinyl, thienopyridyl, benzothiazolyl, imidazolyl and tetrazolyl, and more preferable examples include thienyl, thiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl, and more preferable examples thereof include thiazolyl, 1,3,4-thiadiazolyl, pyridazinyl and pyrazinyl. When the "divalent heterocyclic group" has "substituent(s)", the kind and number thereof are not particularly limited, and divalent heterocyclic group has 1 to 3 substituents selected from the "substituents" defined below at substitutable position(s). Preferable examples of the substituent(s) that the divalent heterocyclic group may have include C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 alkoxy, hydroxy, halogen atom, oxo and thioxo, more preferable examples thereof include methyl and oxo, wherein oxo is more preferable.

[0027] The "C_3-8 cycloalkylene" of the "C_3-8 cycloalkylene optionally having substituent(s)" means monocyclic to tricyclic cycloalkylene (including "crosslinked cycloalkylene") having 3 to 8 carbon atoms and, for example, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclooctylene, norbornylene, bicyclo[2.2.1]heptylene or bicyclo[2.2.2]octylene are mentioned, and preferably, cyclopropylene, cyclobutylene, cyclopentylene and cyclohexylene are mentioned.

[0028] When "C_3-8 cycloalkylene" has "substituent(s)", the kind and number thereof are not particularly limited, and C_3-8 cycloalkylene has 1 to 4 substituents selected from the "substituents" defined below at substitutable position(s). Preferable examples of the substituent(s) that the C_3-8 cycloalkylene may have include C_1-6 alkyl, C_1-6 alkoxy, hydroxy, amino, halogen atom, C_1-6 haloalkyl and C_1-6 haloalkoxy.

[0029] The "C_1-6 alkyl" of "C_1-6 alkyl optionally having substituent(s)" means straight chain or branched chain alkyl having 1 to 6 carbon atoms and, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tertiary pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyland 1-ethyl-1-methylpropyl are mentioned.

[0030] Preferable examples of "C_1-6 alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl, and more preferable examples thereof include methyl and ethyl.

[0031] When "C_1-6 alkyl" has substituent(s), the kind and number thereof are not particularly limited, and C_1-6 alkyl has 1 to 4 substituents selected from the "substituents" defined below at substitutable position(s) and the kind and number thereof are not particularly limited. Preferable examples of the substituent(s) that "C_1-6 alkyl" may have include C_1-6 alkoxy, hydroxy and halogen atom.

[0032] As the "ring" of the "ring optionally having substituent(s) formed by R² and R³ together with the atoms bond thereto" in -NR²CONR³- wherein R² and R³ may be the same or different and each is hydrogen atom or alkyl, or R² and R³ in combination optionally form a ring together with the atoms bonded thereto for X, "nitrogen-containing saturated heterocycle" (e.g., 1,3-imidazolidin-2-one and 3,4,5,6-tetrahydro-2(1H)-pyrimidinone) included in the "heterocyclic group" defined above are mentioned.

[0033] When the "ring" has "substituent(s)", the kind and number thereof are not particularly limited, and ring has 1 to 3 substituents selected from the "substituents" defined below at substitutable position(s). Preferable examples of the substituent(s) that the "ring" may have include C_1-6 alkyl, C_1-6 alkoxy, hydroxy and halogen atom.

[0034] The "C_1-6 alkylene" of the "C_1-6 alkylene optionally having substituent(s)" means an alkylene chain having 1 to 6 carbon atoms and, for example, methylene, ethylene, trimethylene, tetramethylene, pentamethylene and hexamethylene are mentioned. Preferable examples of "C_1-6 alkylene" include methylene, ethylene and trimethylene, and more preferable examples thereof include methylene and ethylene.

[0035] When "C_1-6 alkylene" has "substituent(s)", the kind and number thereof are not particularly limited, and C_1-6 alkylene has 1 to 3 substituents selected from the "substituents" defined below at substitutable position(s). Preferable examples of the substituent(s) that "C_1-6 alkylene" may have include C_1-6 alkyl, C_1-6 alkoxy, hydroxy, carboxy and carbamoyl, and methyl, isobutyl and carboxy are more preferable.

[0036] When "C_1-6 alkylene" is substituted by one or more C_1-6 alkyl mentioned above, it means a branched alkylene chain (e.g., methylmethylene, dimethylmethylene, 1-methylethylene, 2-methylethylene, 1,1-dimethylethylene, 2,2-dimethylethylene, ethylmethylene, diethylmethylene, 1-ethylethylene, 2-ethylethylene, 1-methyltrimethylene, 1,1-dimethyltrimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 3-methyltrimethylene, 3,3-dimethyltrimethylene, 1-ethyltrimethylene, 2-ethyltrimethylene and 3-ethyltrimethylene).

[0037] The "C_2-6 alkenylene" of "C_2-6 alkenylene optionally having substituent(s)" is straight chain or branched chain alkenylene having 2 to 6 carbon atoms, which has double bond(s) at any position of the above-mentioned "C_1-6 alkylene". The position and number of the double bond is not particularly limited. As "C_2-6 alkenylene", vinylene, 1-propenylene, 2-propenylene, 1-butenylene, 2-butenylene, 3-butenylene and 1-pentenylene are mentioned, and vinylene, 1-propenylene and 2-propenylene can be preferably mentioned. When "C_2-6 alkenylene" has "substituent(s)", the kind and number thereof are not particularly limited, and C_2-6 alkenylene has 1 to 3 substituents selected from the "substituents" defined below at substitutable position(s). Preferable examples of the substituent(s) that "C_2-6 alkenylene" may have include C_1-6 alkyl, C_1-6 alkoxy, hydroxy and halogen atom.

[0038] The "C_2-6 alkynylene" of the "C_2-6 alkynylene optionally having substituent(s)" is straight chain or branched chain alkynylene having 2 to 6 carbon atoms, which has triple bond(s) at any position of the above-mentioned "C_1-6 alkylene". The position and number of the triple bond are not particularly limited. As "C_2-6 alkynylene", ethynylene, 1-propynylene, 2-propynylene, 1-butynylene, 2-butynylene, 3-butynylene and 1-pentynylene are mentioned, and ethynylene, 1-propynylene and 2-propynylene are preferably mentioned. When "C_2-6 alkynylene" has "substituent(s)", the kind and number thereof are not particularly limited, and C_2-6 alkynylene has 1 to 3 substituents selected from the "substituents" defined below at substitutable position(s). Preferable examples of the substituent(s) that "C_2-6 alkynylene" may have include C_1-6 alkyl, C_1-6 alkoxy, hydroxy and halogen atom.

[0039] The "C_3-8 cycloalkylidene" of the "C_3-8 cycloalkylidene optionally having substituent(s)" means monocyclic to tricyclic cycloalkylidene (including "crosslinked cycloalkylidene") having 3 to 8 carbon atoms and, for example, cyclopropylidene, cyclobutylidene, cyclopentylidene, cyclohexylidene, cycloheptylidene, cyclooctylidene, norbornylidene, bicyclo[2.2.1]heptylidene and bicyclo[2.2.2]-octylidene are mentioned, and cyclopropylidene, cyclobutylidene, cyclopentylidene and cyclohexylidene are preferably mentioned.

[0040] When "C_3-8 cycloalkylidene" has "substituent(s)", the kind and number thereof are not particularly limited, and C_3-8 cycloalkylidene has 1 to 4 substituents selected from the "substituents" defined below at substitutable position(s). Preferable examples of the substituent(s) that C_3-8 cycloalkylidene may have include C_1-6 alkyl, C_1-6 alkoxy, hydroxy, amino, halogen atom, C_1-6 haloalkyl and C_1-6 haloalkoxy.

[0041] As the "ring" of the "ring optionally having substituent(s) formed by R⁵ and R⁶ together with the atoms bonded thereto" in -NR⁵CONR⁶- wherein R⁵ and R⁶ may be the same or different and each is hydrogen atom or alkyl, or R⁵ and R⁶ in combination optionally form a ring together with the atoms bonded thereto, for Y, "nitrogen-containing saturated heterocycle" (e.g., 1,3-imidazolidin-2-one and 3,4,5,6-tetrahydro-2(1H)-pyrimidinone) included in the "heterocyclic group" defined above are mentioned.

[0042] When the "ring" has "substituent(s)", the kind and number thereof are not particularly limited, and ring has 1 to 3 substituents selected from the "substituents" defined below at substitutable position(s). Preferable examples of the substituent(s) that the "ring" may have include C_1-6 alkyl, C_1-6 alkoxy, hydroxy and halogen atom.

[0043] "C_3-8 cycloalkyl" of the "C_3-8 cycloalkyl optionally having substituent(s)" means monocyclic to tricyclic cycloalkyl (including "crosslinked cycloalkyl") having 3 to 8 carbon atoms and, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, bicyclo[2.2.1]heptyl and bicyclo[2.2.2]octyl are mentioned, and cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are preferably mentioned.

[0044] When "C_3-8 cycloalkyl" has "substituent(s)", the kind and number thereof are not particularly limited, and C_3-8 cycloalkyl has 1 to 4 substituents selected from the "substituents" defined below at substitutable position(s). Preferable examples of the substituent(s) that the C_3-8 cycloalkyl may have include C_1-6 alkyl, C_1-6 alkoxy, hydroxy and halogen atom.

[0045] The "C_1-6 alkoxy" of the "C_1-6 alkoxy optionally having substituent(s)" means straight chain or branched chain alkoxy having 1 to 6 carbon atoms and, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, secondary butoxy, tertiary butoxy, pentoxy, isopentoxy, neopentoxy, tertiary pentoxy, 1-methylbutoxy, 2-methylbutoxy, 1,2-dimethylpropoxy, 1-ethylpropoxy, hexyloxy, isohexyloxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 2,2-dimethylbutoxy, 1-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-2-methylpropoxy and 1-ethyl-1-methylpropoxy are mentioned.

[0046] Preferable examples of "C_1-6 alkoxy" include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy, and more preferable examples include methoxy and ethoxy.

[0047] When "C_1-6 alkoxy" has substituent(s), the kind and number thereof are not particularly limited, and C_1-6 alkoxy has 1 to 4 substituents selected from the "substituents" defined below at substitutable position(s), and the kind and number of the substituent are not particularly limited. Preferable examples of the substituent(s) that the "C_1-6 alkoxy" may have include C_1-6 alkyl, C_1-6 alkoxy, hydroxy and halogen atom.

[0048] The "mono- or di-C_1-6 alkylamino" of the "mono- or di-C_1-6 alkylamino optionally having substituent(s)" is alkylamino mono- or di-substituted by linear or branched chain alkyl having 1 to 6 carbon atoms (total carbon number of di-alkylamino is 2 to 12), and shows methylamino, dimethylamino, ethylamino, diethylamino, methylethylamino, propylamino, dipropylamino, isopropylamino, diisopropylamino, butylamino, dibutylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamino and hexylamino.

[0049] Preferable examples of "mono- or di-C_1-6 alkylamino" include methylamino, dimethylamino, ethylamino, diethylamino, methylethylamino, propylamino, dipropylamino, isopropylamino and diisopropylamino, and more preferable examples include methylamino, dimethylamino, ethylamino, diethylamino, methylethylamino and propylamino.

[0050] When "mono- or di-C_1-6 alkylamino" has "substituent(s)", the kind and number thereof are not particularly limited, and mono- or di-C_1-6 alkylamino has 1 to 4 substituents selected from the "substituents" defined below at substitutable position(s). Preferable examples of the substituent(s) that the mono- or di-C_1-6 alkylamino may have include C_1-6 alkyl, C_1-6 alkoxy, hydroxy and halogen atom. The "C_1-7 acylamino" of the "C_1-7 acylamino optionally having substituent(s)" is acylamino wherein the acyl moiety is alkanoyl having 1 to 7 carbon atoms (e.g., formyl, acetyl, propionyl, butyryl, valeryl, pivaloyl), alkenoyl having 3 to 7 carbon atoms (e.g., acryloyl, methacryloyl, crotonoyl), alkynoyl having 3 to 7 carbon atoms (e.g., propioloyl) and benzoyl, and shows acetylamino, propionylamino, butyrylamino, valerylamino, pivaloylamino and benzoylamino.

[0051] Preferable examples of "C_1-7 acylamino" include acetylamino, propionylamino, butyrylamino, valerylamino, pivaloylamino and benzoylamino, and more preferable examples thereof include acetylamino, propionylamino and benzoylamino.

[0052] When "C_1-7 acylamino" has "substituent(s)", the kind and number thereof are not particularly limited, and C_1-7 acylamino has 1 to 4 substituents selected from the "substituents" defined below at substitutable position(s). Preferable examples of the substituent(s) that the C_1-7 acylamino may have include C_1-6 alkyl, C_1-6 alkoxy, hydroxy and halogen atom.

[0053] When "sulfonylamino optionally having substituent(s)" has "substituent(s)", the kind and number thereof are not particularly limited, and sulfonylamino has substituent(s) selected from the "substituents" defined below at the amino group. Preferable examples of the substituent(s) that the sulfonylamino may have include amino, C_1-6 alkyl, aryl and heteroaryl.

[0054] When "hydrazino optionally having substituent(s)" has "substituent(s)", the kind and number thereof are not particularly limited, and hydrazino has 1 to 3 substituents selected from the "substituents" defined below at substitutable position(s). Preferable examples of the substituent(s) that hydrazino may have include C_1-6 alkyl, aryl and heteroaryl. Examples of aryl and heteroaryl are as mentioned above.

[0055] When "guanidino optionally having substituent(s)" has "substituent(s)", the kind and number thereof are not particularly limited, and guanidino has 1 to 3 substituents selected from the "substituents" defined below at substitutable position(s). Preferable examples of the substituent(s) that guanidino may have include hydroxy, nitro and cyano.

[0056] When "amidino optionally having substituent(s)" has "substituent(s)", the kind and number thereof are not particularly limited, and amidino has 1 to 3 substituents selected from the "substituents" defined below at substitutable position(s). Preferable examples of the substituent(s) that amidino may have include hydroxy, nitro and cyano.

[0057] The "substituent" of each of the above-mentioned groups optionally having substituents is not particularly limited and, for example, halogen atom (e.g., fluorine atom, chlorine atom, bromine atom, iodine atom), C_1-6 alkyl (e.g., straight chain or branched chain alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tertiary pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl or 1-ethyl-1-methylpropyl), C_3-8 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, bi-cyclo[2.2.1]heptyl or bicyclo[2.2.2]octyl), C_3-8 cycloalkyloxy (e.g., cyclopropyloxy, cyclobutyloxy, cyclo-pentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, norbornyloxy, bicyclo[2.2.1]heptyloxy or bicyclo[2.2.2]-octyloxy), C_1-6 haloalkyl (e.g., the above-mentioned C_1-6 alkyl having at least one halogen atom mentioned above such as trifluoromethyl), C_1-6 alkoxy (e.g., straight chain or branched chain alkoxy having 1 to 6 carbon atoms such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, secondary butoxy, tertiary butoxy, pentoxy, isopentoxy, neopentoxy, tertiary pentoxy, 1-methylbutoxy, 2-methylbutoxy, 1,2-dimethylpropoxy, 1-ethylpropoxy, hexyloxy, isohexyloxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 2,2-dimethylbutoxy, 1-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-2-methylpropoxy, 1-ethyl-1-methylpropoxy), C_1-6 haloalkoxy (e.g., the above-mentioned C_1-6 alkoxy having at least one of the above-mentioned halogen atoms such as trifluoromethoxy), C_6-14 aryl (e.g., phenyl, naphthyl, anthryl), C_6-14 aryloxy (e.g., phenyloxy, naphthyloxy, anthryloxy), hydroxy, nitro, amino, mono- or di-C_1-6 alkylamino (e.g., methylamino, ethylamino, dimethylamino, diethylamino, propylamino, isopropylamino, butylamino, diisopropylamino), mono- or di-(C_3-8 cycloalkyl)amino (e.g., cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino, cyclooctylamino, norbornylamino, bicyclo[2.2.1]heptylamino, bicyclo[2.2.2]octylamino, dicyclopropylamino, dicyclobutylamino, dicyclopentylamino, dicyclohexylamino, di-cycloheptylamino, dicyclooctylamino, dinorbornylamino, di (bicyclo[2.2.1]heptyl)amino, di(bicyclo[2.2.2]octyl)amino), mono- or di-(C_6-14 aryl)amino (e.g., phenylamino, naphthylamino, anthrylamino, diphenylamino), C_1-11 acyl[for example, C_1-7 alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl), C_3-7 alkenoyl (e.g., acryloyl, methacryloyl, crotonoyl), C_3-7 alkynoyl (e.g., propioloyl), C_7-11 aroyl (e.g., benzoyl, 1-naphthoyl, 2-naphthoyl )], mono- or di-(C_1-11 acyl)amino (e.g., amino having the above-mentioned C_1-11 acyl such as acetylamino, benzoylamino), mono- or di-(C_1-6 alkoxy-carbonyl)amino (e.g., methoxycarbonylamino, ethoxycarbonylamino), sulfonylamino, amino-C_1-6 alkyl (e.g., aminomethyl, aminoethyl), mono- or di- (C₁-₆ alkyl)amino-C_1-6 alkyl (e.g., methylaminomethyl, ethylaminomethyl), C_3-8 cyclic amino (e.g., aziridino, azetidino, pyrrolidino, piperidino), hydrazino, guanidino, amidino, hydroxyamidino, C_1-6 alkoxyamidino (e.g., methoxyamidino, ethoxyamidino), aminomethyleneamino, imino, carboxy, C_1-6 alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tertiary butoxycarbonyl, pentyloxycarbonyl), carbamoyl, mono- or di-(C_1-6 alkyl)aminocarbonyl (e.g., methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, butylaminocarbonyl, sec-butylaminocarbonyl, tert-butylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, ethylmethylaminocarbonyl, dipropylaminocarbonyl, methylpropylaminocarbonyl, diisopropylaminocarbonyl), mono- or di-(C_6-14 aryl)aminocarbonyl (e.g., phenylaminocarbonyl, naphthylaminocarbonyl), cyano, C_7-13 aralkyl (e.g., C_1-3 alkyl having C_6-10 aryl such as benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl, 3-phenylpropyl, 1-phenylbutyl, 4-phenylbutyl, 1-naphthylmethyl, 2-naphthylmethyl, 1-(1-naphthyl)ethyl, 2-(1-naphthyl)ethyl, 1-(2-naphthyl)ethyl, 2-(2-naphthyl)ethyl), mono- or di-(C_7-13 aralkyl)aminocarbonyl (e.g., benzylaminocarbonyl, 2-phenylethylaminocarbonyl), heteroaryl (e.g., pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, azepinyl, diazepinyl), heteroaryl-C_1-3 alkyl (e.g., the above-mentioned C_1-3 alkyl having the above-mentioned heteroaryl such as 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 1-(2-pyridyl)ethyl, 1-(3-pyridyl)ethyl, 1-(4-pyridyl)ethyl, 2-(2-pyridyl)ethyl, 2-(3-pyridyl)ethyl, 2-(4-pyridyl)ethyl, 3-(2-pyridyl)propyl), mono- or di-(heteroaryl-C_1-3 alkyl)aminocarbonyl (e.g., 2-pyridylmethylaminocarbonyl, 3-pyridylmethylaminocarbonyl), hydroxy, mercapto, C_1-6 alkylthio (e.g., methylthio, ethylthio), C_6-14 arylthio (e.g., phenylthio, naphthylthio),-SO₃H, -SO₂NH₂, sulfonamide, oxo and thioxo are mentioned.

[0058] In the formula (1), ring A is aryl optionally having substituent(s), or heteroaryl optionally having substituent(s), and is preferably phenyl optionally having substituent(s).

[0059] As the substituent of ring A, halogen atom (e.g., fluorine atom, chlorine atom, particularly chlorine atom), C_1-6 alkyl optionally having substituent(s) (e.g., C_1-6 alkyl optionally substituted by halogen atom(s), particularly methyl, trifluoromethyl) or C_1-6 alkoxy optionally having substituent(s) (e.g., C_1-6 alkoxy optionally substituted by halogen atom(s), particularly methoxy) are preferable.

[0060] The ring A is particularly preferably phenyl substituted by 1 or 2 fluorine atoms or chlorine atoms, more preferably phenyl substituted by fluorine atom(s) or chlorine atom(s) at the 3-position and/or the 4-position, more preferably 3,4-dichlorophenyl or 3,4-difluorophenyl.

[0061] Ring B is divalent heterocyclic group optionally having substituent(s), C_3-8 cycloalkylene optionally having substituent(s), preferably heteroarylene optionally having substituent(s). Preferable examples of ring B include thienylene, pyridylene, thiazolylene optionally substituted by methyl, 1,3,4-thiadiazolylene, pyridazinylene which is optionally substituted by oxo, and optionally partially hydrogenated, indenothiazolylene, naphtothiazolylene, thiazolopyridylene and benzothiazolylene, thiazolopyridylene optionally partially hydrogenated, isoxazolylene, pyrimidinylene, chromenylene optionally substituted by oxo, quinazolinylene, benzoazepinylene, thienopyridylene, indanylene optionally substituted by oxo, furylene, imidazolylene, pyrazinylene, cyclopentylene and tetrazolylene, more preferable examples thereof include thienylene, thiazolylene, 1,3,4-thiadiazolylene, and pyridazinylene which is optionally substituted by oxo and optionally partially hydrogenated. As a more preferable embodiment, thiazolylene can be mentioned. As a still more preferable other embodiment, 1,3,4-thiadiazolylene can be mentioned. As a yet more preferable other embodiment, optionally partially hydrogenated pyridazinylene, which is optionally substituted by oxo, can be mentioned. As the substituent of ring B, C_1-6 alkyl and oxo are preferable, and methyl is more preferable.

[0062] m is an integer of 0 to 2, preferably 0 or 2, and more preferably 0.

[0063] n is an integer of 1 to 5, preferably 1 to 3, and more preferably 1.

[0064] X is a bond, -NH-, -NR¹- wherein R¹ is C_1-6 alkyl optionally having substituent(s), hereinafter the same, -CO-, -CO₂-, -OCO-, -CONR^a- wherein R^a is hydrogen atom or C_1-6 alkyl optionally having substituent(s), hereinafter the same, -NR^aCO-, -NR²CONR³- wherein R² and R³ may be the same or different and each is hydrogen atom or C_1-6 alkyl optionally having substituent(s). Alternatively, R² and R³ in combination optionally form, together with the atoms bonded thereto, a ring optionally having substituent(s), hereinafter the same, oxygen atom, sulfur atom, -SO-, -SO₂-, -NR^aSO₂-, -SO₂NR^a-, C_1-6 alkylene optionally having substituent(s), C_2-6 alkenylene optionally having substituent(s), C_2-6 alkynylene optionally having substituent(s), -O-X^a-wherein X^a is C_1-6 alkylene optionally having substituent(s), hereinafter the same, -X^a-O-, -CO-X^a-, -X^a-CO-, -CONR^a-X^a-, -X^a-CONR^a-, -NR^aCO-X^a-, -X^a-N_R^aCO-, -S-X^a-, -X^a-S-, -SO-X^a-, -X^a-SO-, -NR^a-X^a-, -X^a-NR^a-, -SO₂-X^a-, -X^a-SO₂-, -C(=N-CO₂-R¹)-, -C(=N-SO₂-R¹)-, -C(=N-SO₂NH₂)-, -C(=CH-NO₂)-, -C(=N-CN)-, or C_3-8 cycloalkylidene optionally having substituent(s); preferably a bond, -NH-, -NR¹-, -CO-, -CO₂-, -OCO-, -CONR^a-, -NR^aCO-, -NR²CONR³-, oxygen atom, sulfur atom, -SO-, -SO₂-, -NR^aSO₂-, -SO₂NR^a-, C_2-6 alkenylene optionally having substituent(s), -CO-X^a-, -X^a-CO-, CONR^a-X^a-, -X^a-CONR^a-, - NR^aCO-X^a-, -X^a-NR^aCO- or C_3-8 cycloalkylidene optionally having substituent(s); more preferably a bond, -CO-, -CONR^a-, -NR^aCO-, -CO-X^a-, -X^a-CO-, -CONR^a-X^a-, -X^a-CONR^a-, -NR^aCO-X^a- or -X^a-NR^aCO-. Still more preferably, it is a bond, -CO-, -CO-X^a-, -X^a-CO-, -NR^aCO-X^a- or -X^a-NR^aCO-, yet more preferably a bond, -CO-, -CO-X^a-, and further more preferably -CO-X^a- or -X^a-CO-. R¹ is C_1-6 alkyl optionally having substituent(s), preferably C_1-3 alkyl; R²and R³ may be the same or different and each is hydrogen atom or C_1-6 alkyl optionally having substituent(s), preferably hydrogen atom or C_1-3 alkyl; R^a is hydrogen atom or C_1-6 alkyl optionally having substituent(s), preferably hydrogen atom or C_1-3 alkyl; X^a is C_1-6 alkylene optionally having substituent(s), preferably C_1-3 alkylene.

[0065] Y is a bond, -NH-, -NR⁴- wherein R⁴ is C_1-6 alkyl optionally having substituent(s), hereinafter the same, -CO-, -CO₂-, -OCO-, -CONR^b- wherein R^b is hydrogen atom or C_1-6 alkyl optionally having substituent(s), hereinafter the same, - NR^bCO-, -NR⁵CONR⁶- wherein R⁵ and R⁶ may be the same or different and each is hydrogen atom or C_1-6 alkyl optionally having substituent(s). Or, R⁵ and R⁶ in combination optionally form, together with the atoms bonded thereto, a ring optionally having substituent(s), hereinafter the same, oxygen atom, sulfur atom, -SO-, -SO₂-, -NR^bSO₂-, -SO₂NR^b-, C_1-6 alkylene optionally having substituent(s), C_2-6 alkenylene optionally having substituent(s), C_2-6 alkynylene optionally having substituent(s), -O-X^b- wherein X^b is C_1-6 alkylene optionally having substituent(s), hereinafter the same, -X^b-O-, -CO-X^b-, -X^b-CO-, -CONR^b-X^b-, -X^b-CONR^b-, -NR^bCO-X^b-, -X^b-NR^bCO-, -S-X^b-,-X^b-S-, -SO-X^b-, -X^b-SO-, -NR^b-X^b-, -X^b-NR^b-, -SO₂-X^b-,-X^b-SO₂-, -C(=N-CO₂-R⁴)-, -C (=N-SO₂-R⁴)-, -C(=N-SO₂NH₂)-, -C(=CH-NO₂)- or -C(=N-CN)-; preferably a bond, -NH-, -NR⁴-, -CO-, -CO₂-, -OCO-, -CONR^b-,-NR^bCO-, -NR⁵CONR⁶-, oxygen atom, sulfur atom, -SO-, -SO₂-, -NR^bSO₂-, -SO₂NR^b-, -CO-X^b-, -X^b-CO-, -CONR^b-X^b-, -X^b-CONR^b-, -NR^bCOX^b- or -X^b-NR^bCO-; more preferably, a bond, -CO-, -CONR^b-, -NR^bCO-, -CO-X^b-, -X^b-CO-, -CONR^b-X^b-, -X^b-CONR^b-, -NR^bCO-X^b-or -X^b-NR^bCO-, Y is more preferably a bond, -CO-, -CO-X^b-, -X^b-CO-,-NR^bCO-X^b- or -X^b-NR^bCO-, still more preferably a bond, -CO-, -CO-X^b- or -X^b-CO-, yet more preferably a bond, -CO-X^b- or -X^b-CO-, further more preferably a bond. R⁴ is C_1-6 alkyl optionally having substituent(s), preferably C_1-3 alkyl; R⁵ and R⁶ may be the same or different and each is hydrogen atom or C_1-6 alkyl optionally having substituent(s), preferably hydrogen atom or C_1-3 alkyl; R^b is hydrogen atom or C_1-6 alkyl optionally having substituent(s), preferably hydrogen atom or C_1-3 alkyl; X^b is C_1-6 alkylene optionally having substituent(s), preferably C_1-3 alkylene.

[0066] Z is hydrogen atom, halogen atom, C_1-6 alkyl optionally having substituent(s), C_3-8 cycloalkyl optionally having substituent(s), aryl optionally having substituent(s), heterocyclic group optionally having substituent(s), hydroxy, nitro, amino, cyano, C_1-6 alkoxy optionally having substituent(s), mono- or di-C_1-6 alkylamino optionally having substituent(s), C_1-7 acylamino optionally having substituent(s), sulfonylamino optionally having substituent(s), hydrazino optionally having substituent(s), guanidino optionally having substituent(s), or amidino optionally having substituent(s); preferably hydrogen atom, halogen atom, C_1-6 alkyl optionally having substituent(s), C_3-8 cycloalkyl optionally having substituent(s), aryl optionally having substituent(s), heterocyclic group optionally having substituent(s), hydroxy, nitro, amino, cyano, C₁-6 alkoxy optionally having substituent(s), mono-or di-C_1-6 alkylamino optionally having substituent(s), C_1-7 acylamino optionally having substituent(s), sulfonylamino optionally having substituent(s), hydrazino optionally having substituent(s), guanidino optionally having substituent(s), or amidino optionally having substituent(s); more preferably, hydrogen atom, hydroxy, amino, C_1-6 alkyl optionally having substituent(s), C_1-6 alkoxy optionally having substituent(s), aryl optionally having substituent(s) or a heterocyclic group optionally having substituent(s). More preferably, Z is hydrogen atom, hydroxy or amino, still more preferably hydroxy or amino. As a still more preferable embodiment, hydroxy can be mentioned. As a yet more preferable other embodiment, amino can be mentioned.

[0067] Preferable examples of the group represented by Z-Y-X-include hydrogen atom, carboxyl, carboxymethyl, amino, carbamoyl, carbamoylmethyl and (2-amino-2-oxoethyl)aminocarbonyl.

[0068] As the compound represented by the formula (1), a compound represented by the formula (la)

wherein ring C is aryl optionally having substituent(s) or heteroaryl, and other symbols are as defined above, is also preferable.

[0069] In the formula (la), ring C is preferably phenyl, pyridyl, 1,2,4-oxadiazolyl which may be partially hydrogenated, 1,2,4-triazolyl, tetrazolyl or isoxazolyl.

[0070] As the substituent of ring C, C_1-6 alkyl, C_1-6 alkoxy, hydroxy, nitro, amino, cyano, carboxy, C_1-6 alkoxy-carbonyl, carbamoyl and oxo are preferable, and methoxy, hydroxy, amino, carboxy, methyl, carbamoyl and oxo are more preferable.

[0071] More preferable specific compounds of the formula (1) include (2S)-[4-(carboxymethyl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-[4-(3-aminophenyl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-[4-(3-carbamoyl-4-hydroxyphenyl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(pyridin-4-yl)thiazol-2-ylthio]acetamide, (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(3,4-dimethoxyphenyl)thiazol-2-ylthio]acetamide, (2S)-(4-carbamoylthiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-{4-[(2-amino-2-oxoethyl)aminocarbonyl]thiazol-2-ylthio}-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(5-methyl-1,2,4-oxadiazol-3-yl)thiazol-2-ylthio]acetamide hydrochloride, (2S)-(5-amino-8H-indeno[1,2-d]thiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-{4-[(2-amino-2-oxoethyl)aminocarbonyl]phenylthio}-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-{4-[(2-carboxyethyl)aminocarbonyl]thiazol-2-ylthio}-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide hydrochloride, (2S)-(5-acetamino-1,3,4-thiadiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-4-(4-carbamoylthiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}butyramide hydrochloride, (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(1H-tetrazol-5-yl)thiazol-2-ylthio]acetamide, (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-([1,3]thiazolo[5,4-b]pyridin-2-ylthio)acetamide, (2S)-(E)-[4-(2-carbamoylethen-1-yl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-[4-(carbamoylmethyl)thiazol-2-ylthio]-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-[4-(carbamoylmethyl)thiazol-2-ylthio]-N-{[4-(4-fluorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-(4-carboxy-5-methylthiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-(4-carbamoyl-5-methylthiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-(4-carbamoylthiazol-2-ylthio)-N-{[4-(3-chloro-4-fluorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-[4-(2-amino-2-oxoethyl)aminocarbonylthiazol-2-ylthio]-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-(5-amino-1,3,4-thiadiazol-2-ylthio)-N-{[4-(3-chlorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-(5-amino-1,3,4-thiadiazol-2-ylthio)-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(pyrimidin-2-ylthio)acetamide, (2S)-(3-acetyl-2-oxo-2H-chromen-6-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}-(6-oxo-1,6-dihydropyridazin-3-ylthio)acetamide, (2S)-[6-(carbamoylmethyl)pyrazin-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide, and (2S)-4-(cyclopentanesulfonyl)-N-{[4-(3-chloro-4-fluorobenzyl)morpholin-2-yl]methyl}butyramide.

[0072] Since the compound of the formula (1) and a pharmaceutically acceptable salt thereof may be present in the form of a hydrate or a solvate (e.g., ethanol solvate), hydrates and solvates thereof are also encompassed in the present invention. In addition, since the compound of the formula (1) has an asymmetric atom, at least two kinds of optical isomers are present. The optical isomer and racemate thereof are encompassed in the present invention.

[0073] The compound of the formula (1) can be synthesized by the following methods (1) to (11), a method according to the method, a method known to those of ordinary skill in the art in the organic synthesis, and a method according to the method described in WO97/24325, WO98/25617, WO98/02151, WO98/04554, WO00/34278, WO99/55324, WO99/55330, WO00/58305, WO00/31033, WO00/53600, WO01/14333, WO02/66460, WO02/88111, WO02/18335, WO02/26722, WO02/26723, WO03/82292, WO03/82294, WO03/82861, WO03/82862, WO03/82295, WO03/82863, WO03/99287 and WO03/99798.

[0074] The following methods (1) to (11) show examples of the production method of the compound (the compound of the formula (1)) of the present invention, which are not to be construed as limitative.

[0075] The compounds of the formulas (2) to (26) to be used for the following methods (1) to (11) can be synthesized by a method known to those of ordinary skill in the art in the organic synthesis, and a method according to the methods described in the above-mentioned references.

[0076] The term "substituent necessary for construction of heteroaryl (including heteroarylene)" used for the explanation of the following synthetic methods means a substituent necessary for construction of heteroaryl, with an acidic or basic catalyst, light and heat and, in most cases, by an addition reaction or a condensation reaction accompanying elimination of water, alcohol, acid or halogenated hydrogen.

[0077] As specific "substituent necessary for construction of heteroaryl" mentioned above, any of the combinations of bromoacetyl and thioamide for the construction of thiazole, any of the combinations of hydroxyamidine and carboxylic acid for the construction of 1,2,4-oxadiazole, any of the combinations of hydrazide and carboxylic acid for the construction of 1,3,4-oxadiazole, any of the combinations of S-methylthioamide and hydrazide for the construction of 1,2,4-triazole, any of the combinations of imidate and hydrazide are mentioned.

[0078] The term "under ice-cooling or at room temperature" used for the explanation of the following synthetic methods means 0°C to 30°C.

Method (1)

[0079] By reacting a compound represented by the formula (2)

wherein each symbol is as defined above, or an acid addition salt thereof, with a compound represented by the formula (3)

wherein each symbol is as defined above, or an acid addition salt thereof, in a suitable solvent that does not inhibit the reaction (e.g., tetrahydrofuran (hereinafter to be abbreviated as THF), dichloromethane, N,N-dimethylformamide (hereinafter to be abbreviated as DMF) or a mixed solvent thereof), in the presence of a tertiary amine such as triethylamine and diisopropylethylamine, and using a condensation agent [for example, dicyclohexylcarbodiimide (hereinafter to be abbreviated as DCC), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (hereinafter to be abbreviated as EDC) or a hydrochloride thereof, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroxyquinoline (hereinafter to be abbreviated as EEDQ), carbodiimidazole (hereinafter to be abbreviated as CDI), diethylphosphoryl cyanide, benzotriazol-1-yloxy tripyrrolidinophosphonium hexafluorophosphate (hereinafter to be abbreviated as PyBOP), diphenylphosphoryl azide (hereinafter to be abbreviated as DPPA), isobutyl chloroformate, diethylacetyl chloride or trimethylacetyl chloride] alone, or in combination with an additive such as N-hydroxysuccinimide (hereinafter to be abbreviated as HONSu), hydroxybenzotriazole (hereinafter to be abbreviated as HOBT), or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (hereinafter to be abbreviated as HOOBT), or 4-dimethylaminopyridine (hereinafter to be abbreviated as DMAP), at a temperature of generally -30°C to 80°C, preferably -10°C to 25°C, for 1 - 24 h, a compound represented by the formula (1)

wherein each symbol is as defined above, can be obtained. In addition, by carrying out the similar reaction using a reactive derivative of a compound of the formula (2) (e.g., acid chloride, acylimidazole), a compound represented by the formula (1) can be obtained. Generally, this reaction is carried out in a suitable solvent that does not inhibit the reaction (e.g., THF, dichloromethane, chloroform, benzene or a mixed solvent thereof), in the presence of tertiary amine such as triethylamine or pyridine, under ice-cooling or at room temperature for 1 - 24 h.

Method (2)

[0080] By reacting a compound represented by the formula (2)

wherein each symbol is as defined above, or an acid addition salt thereof, with a compound represented by the formula (4)

wherein G¹ is a protecting group (e.g., tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), or an acid addition salt thereof, in a suitable solvent that does not inhibit the reaction (THF, dichloromethane, DMF or a mixed solvent thereof), in the presence of a tertiary amine such as triethylamine and diisopropylethylamine, and a condensation agent (same as the condensation agent described in method (1)) under ice-cooling or at room temperature for 1 - 24 h, a compound represented by the formula (5)

wherein each symbol is as defined above, can be obtained. The compound is deprotected, when the protecting group is a Boc group, for example, by reaction in an inert solvent such as acetonitrile, THF, 1,4-dioxane and ethyl acetate, using an acid such as hydrogen chloride or trifluoroacetic acid (hereinafter to be abbreviated as TFA), generally at -30°C to 60°C for 10 min - 24 h, and when the protecting group is a Cbz group, for example, by hydrogenation in an inert solvent such as methanol, ethanol or ethyl acetate, in the presence of a catalyst such as palladium carbon, or reaction using hydrogen bromide-acid (e.g., acetic acid) for generally -30°C to 60°C for 10 min to 24 h, whereby a compound represented by the formula (6)

wherein each symbol is as defined above, can be obtained. By reacting this compound with a compound represented by the formula (7)

wherein L¹ is a leaving group such as chlorine, bromine, iodine, methanesulfonyloxy, p-toluenesulfonyloxy or trifluoromethanesulfonyloxy, and other symbols are as defined above, in a suitable solvent that does not inhibit the reaction (THF, dichloromethane, DMF or a mixed solvent thereof), in the presence of a base such as triethylamine, pyridine, DMAP, potassium carbonate, sodium hydrogen carbonate and sodium hydroxide, under ice-cooling or at room temperature for 1 - 24 h, a compound represented by the formula (1)

wherein each symbol is as defined above, can be obtained. In addition, by reacting a compound of the formula (6) with an aldehyde compound represented by the formula (8)

wherein each symbol is as defined above, in the presence of sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, in a suitable solvent that does not inhibit the reaction (methanol, ethanol, dichloromethane, THF, acetonitrile, 1,4-dioxane), using, where necessary, an acidic catalyst such as acetic acid, p-toluenesulfonic acid, boron trifluoride - diethyl ether complex, generally at 0°C to 100°C for 10 min to 24 h, a compound represented by the formula (1)

wherein each symbol is as defined above, can be obtained.

Method (3)

[0081] A compound of the formula (1), wherein X is -CONH-(CH₂)_q-wherein q is an integer of 0 to 6, can also be synthesized by the following method. That is, by reacting a compound represented by the formula (9)

wherein each symbol is as defined above, or an acid addition salt thereof, with a compound represented by the formula (10)

wherein q is an integer of 0 to 6, and other symbols are as defined above, or an acid addition salt thereof, in a suitable solvent that does not inhibit the reaction (e.g., THF, dichloromethane, DMF or a mixed solvent thereof), in the presence of a tertiary amine such as triethylamine or diisopropylethylamine and a condensation agent (same as the condensation agent described in method (1)) under ice-cooling or at room temperature for 1 - 24 h, a compound represented by the formula (1)

wherein each symbol is as defined above and X is -CONH-(CH₂)_q- wherein q is an integer of 0 to 6, can be obtained. In addition, by carrying out the similar reaction using a reactive derivative of the compound of the formula (9) (acid chloride, acyl imidazole), a compound represented by the formula (1) can be obtained.

Method (4)

[0082] A compound of the formula (1), wherein X is -NHCO-(CH₂)_q-wherein q is an integer of 0 to 6, can also be synthesized by the following method. That is, by reacting a compound represented by the formula (11)

wherein each symbol is as defined above, or an acid addition salt thereof, with a compound represented by the formula (12)

wherein q is an integer of 0 to 6, and other symbols are as defined above, or an acid addition salt thereof, in a suitable solvent that does not inhibit the reaction (e.g., THF, dichloromethane, DMF or a mixed solvent thereof), in the presence of a tertiary amine such as triethylamine or diisopropylethylamine, and a condensation agent (same as the condensation agent described in method (2)) under ice-cooling or at room temperature for 1 - 24 h, a compound represented by the formula (1)

wherein each symbol is as defined above, and X is -NHCO-(CH₂)_q- wherein q is an integer of 0 to 6, can be obtained. In addition, by carrying out the similar reaction using a reactive derivative of a compound of the formula (12) (acid chloride, acyl imidazole), a compound represented by the formula (1) can be obtained.

Method (5)

[0083] A compound of the formula (1), wherein m=0 can also be synthesized by the following method. That is, by reacting a compound represented by the formula (13)

wherein each symbol is as defined above, or an acid addition salt thereof, in a suitable solvent that does not inhibit the reaction (e.g., dichloromethane, chloroform, dichloroethane, diethyl ether, dimethylformamide, water or a mixed solvent thereof), with a compound represented by the formula (14)

wherein L² is a leaving group such as chlorine, bromine, iodine, methanesulfonyloxy, p-toluenesulfonyloxy and trifluoromethanesulfonyloxy, and other symbols are as defined above, or an acid addition salt thereof, in the presence of a base such as triethylamine, pyridine, DMAP, potassium carbonate, sodium hydrogen carbonate or sodium hydroxide, under ice-cooling or at room temperature for 1 - 24 h, a compound represented by the formula (1)

wherein each symbol is as defined above and m=0, can be obtained. Of the compounds represented by the formula (14), a compound represented by the following formula, wherein n is 1, which is an optically active form

wherein each symbol is as defined above, or an acid addition salt thereof, can be obtained by reacting a compound represented by the formula (26)

wherein each symbol is as defined above, or an acid addition salt thereof, with a halogenated agent such as chlorine, bromine, pyridinium tribromide, trimethylphenyl-ammonium tribromide or iodine, in a suitable solvent that does not inhibit the reaction (e.g., dichloromethane, chloroform, dichloroethane, acetic acid or a mixed solvent thereof) at 0°C to 100°C for 10 min - 24 h. A compound represented by the formula (26) and an acid addition salt thereof are novel compounds, and can be produced by acetylating an optically active form of a compound represented by the above-mentioned formula (3) by a conventional method.

Method (6)

[0084] A compound of the formula (1), wherein m=0 can also be synthesized by the following method. That is, by reacting a compound represented by the formula (15)

wherein L³ is a leaving group such as chlorine, bromine, iodine, methanesulfonyloxy, p-toluenesulfonyloxy or trifluoromethanesulfonyloxy, and other symbols are as defined above, or an acid addition salt thereof, in a suitable solvent that does not inhibit the reaction (e.g., dichloromethane, chloroform, dichloroethane, diethyl ether, dimethylformamide, water or a mixed solvent thereof), with a compound represented by the formula (16)

wherein each symbol is as defined above, or an acid addition salt thereof, in the presence of a base such as triethylamine, pyridine, DMAP, potassium carbonate, sodium hydrogen carbonate or sodium hydroxide, under ice-cooling or at room temperature for 1 - 24 hrs, a compound represented by the formula (1)

wherein each symbol is as defined above and m=0, can be obtained.

Method (7)

[0085] A compound of the formula (1), wherein m=1 or 2 can also be synthesized by the following method. That is, by reacting a compound represented by the formula (17)

wherein each symbol is as defined above, or an acid addition salt thereof, using an oxidant such as m-chloroperbenzoic acid in a suitable solvent that does not inhibit the reaction (e.g., halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform or a mixed solvent thereof), or using an oxidant such as aqueous hydrogen peroxide in a carboxylic acid solvent such as acetic acid, trifluoroacetic acid or formic acid, at a temperature of generally -30°C to 80°C, preferably -10°C to 60°C for 0.5 - 24 h, a compound represented by the formula (1)

wherein each symbol is as defined above and m=1 or 2, can be obtained. When, in the above-mentioned reaction, an amino group irrelevant to the reaction are present in the reaction substances, the substituent may be protected with a suitable protecting group, followed by the reaction and the protecting group may be eliminated after the reaction. As the amino-protecting group used at that time, carbamates such as tertiary butoxycarbonyl and benzyloxycarbonyl, amides such as formyl, acetyl, trifluoroacetyl and benzoyl, arylalkyl such as benzyl, p-methoxybenzyl and tritylcan be mentioned. The protecting groups can be eliminated, for example, by solvolysis using an acid such as hydrochloric acid, formic acid and trifluoroacetic acid or a base such as sodium hydroxide and potassium hydroxide, reduction using metal hydride complex, hydrogenation using palladium-carbon catalyst or Raney-nickel and oxidization using 2,3-dichloro-5,6-dicyano-p-benzoquinone.

Method (8)

[0086] A compound of the formula (1), wherein ring B is heteroarylene optionally having substituent(s) can also be synthesized by the following method. That is, by reacting a compound represented by the formula (18)

wherein G² is a substituent necessary for the construction of heteroaryl, and other symbols are as defined above, or an acid addition salt thereof, with a compound represented by the formula (19)

wherein G³ is a substituent necessary for the construction of heteroaryl, and other symbols are as defined above, or an acid addition salt thereof, a compound represented by the formula (1)

wherein ring B is heteroarylene optionally having substituent(s), and other symbols are as defined above, can be obtained.

Method (9)

[0087] A compound of the formula (1), wherein Z is heteroaryl optionally having substituent(s), can also be synthesized by the following method. That is, by reacting a compound represented by the formula (20)

        G⁴     (20)

wherein G⁴ is a substituent necessary for construction of heteroaryl, or an acid addition salt thereof, with a compound represented by the formula (21)

wherein G⁵ is a substituent necessary for the construction of heteroaryl, and other symbols are as defined above, or an acid addition salt thereof, a compound represented by the formula (1)

wherein Z is heteroaryl optionally having substituent(s), and other symbols are as defined above, can be obtained.

Method (10)

[0088] A compound of the formula (1), wherein X is -Q₁-(CH₂)_q-wherein Q₁ is -NH-, -NR⁷- wherein R⁷ is C_1-6 alkyl optionally having substituent(s), oxygen atom or sulfur atom, and q is an integer of 0 to 6, can also be synthesized by the following method. That is, by reacting a compound represented by the formula (22)

wherein G⁶ is -NH₂, -NHR⁷ wherein R⁷ is C_1-6 alkyl optionally having substituent(s), -OH or -SH, and other symbols are as defined above, or an acid addition salt thereof, with a compound represented by the formula (23)

wherein L⁴ is a leaving group such as chlorine, bromine, iodine, methanesulfonyloxy, p-toluenesulfonyloxy or trifluoromethanesulfonyloxy, and other symbols are as defined above, or an acid addition salt thereof, in a suitable solvent that does not inhibit the reaction (e.g., dichloromethane, chloroform, dichloroethane, diethyl ether, water or a mixed solvent thereof), in the presence of a base (e.g., triethylamine, pyridine, DMAP, potassium carbonate, sodium hydrogen carbonate, sodium hydroxide) under ice-cooling or at room temperature for 1 - 24 h, a compound represented by the formula (1)

wherein X is -Q₁-(CH₂)_q- wherein Q₁ is -NH-, -NR⁷-wherein R⁷ is C_1-6 alkyl optionally having substituent(s), oxygen atom or sulfur atom, and q is an integer of 0 to 6, can be obtained.

Method (11)

[0089] A compound of the formula (1), wherein X is -Q₂-(CH₂)_q-wherein Q₂ is -NH-, -NR⁷- wherein R⁷ is C_1-6 alkyl optionally having substituent(s), oxygen atom or sulfur atom, and q is an integer of 0 to 6, can also be synthesized by the following method. That is, by reacting a compound represented by the formula (24)

wherein L⁵ is a leaving group such as chlorine, bromine, iodine, methanesulfonyloxy, p-toluenesulfonyloxy or trifluoromethanesulfonyloxy, and other symbols are as defined above, or an acid addition salt thereof, with a compound represented by the formula (25)

wherein G⁷ is -NH₂, -NHR⁷ wherein R⁷ is C_1-6 alkyl optionally having substituent(s), -OH or -SH, and other symbols are as defined above, or an acid addition salt thereof, in a suitable solvent that does not inhibit the reaction (e.g., dichloromethane, chloroform, dichloroethane, diethyl ether, water or a mixed solvent thereof) in the presence of a base such as triethylamine, pyridine, DMAP, potassium carbonate, sodium hydrogen carbonate or sodium hydroxide, under ice-cooling or at room temperature for 1 - 24 h, a compound represented by the formula (1)

wherein X is -Q₂-(CH₂)_q- wherein Q₂ is -NH-, -NR⁷- wherein R⁷ is C_1-6 alkyl optionally having substituent(s), oxygen atom or sulfur atom, and q is an integer of 0 to 6, can be obtained.

[0090] As a pharmaceutically acceptable salt of the compound of the formula (1), acid addition salts with inorganic acid and organic acid can be mentioned, and the compound of the formula (1) can be converted to salt by treating with an inorganic acid or an organic acid by a conventional method. In addition, hydrate and solvate of the compound of the formula (1) are also encompassed in the present invention, and can be produced by a well-known method.

[0091] The compound of the present invention thus obtained can be isolated and purified by a conventional method such as recrystallization and column chromatography. When the obtained resultant product is a racemate, for example, it can be resolved into a desired optically active form by fractional recrystallization of a salt with an optically active acid, or by passing through a column packed with an optically active carrier. Each of the diastereomers can be separated by fractional recrystallization and column chromatography. They can also be obtained by the use of an optically active starting material compound. In addition, the stereoisomer can be isolated by recrystallization and column chromatography.

[0092] When the morpholine compound of the present invention, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is used as a pharmaceutical agent, the compound of the present invention can be mixed with a pharmaceutically acceptable carrier (e.g., excipient, binder, disintegrant) and the obtained pharmaceutical composition or preparation (e.g., tablet, liquid) can be administered orally or parenterally. A pharmaceutical composition can be formed according to a conventional method.

[0093] The dose is determined in consideration of age, body weight, general health condition, sex, diet, administration time, administration method, clearance rate, combination of drugs, the severity of the disease state of patients under treatment at that time, and other factors. While the daily dose of the compound of the present invention varies depending on the condition and body weight of patients, the kind of compound and administration route, for example, oral dose is 0.01 - 1000 mg/kg body weight/day, which is administered in one to several portions a day, and parenteral dose is about 0.001 - 100 mg/kg body weight/day, which is administered in one to several portions a day.

[0094] As a disease to be the target of the treatment and/or prophylaxis, for example, diseases wherein a cell having CCR3 plays an important role in the onset, progress and retention of pathology, such as asthma, sinusitis, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, allergic myelitis, ulcerative colitis, Crohn's disease and rheumatoid arthritis can be mentioned. Here, the treatment in the present invention means administration of the compound of the present invention for the purpose of cure of disease, amelioration of disease, or prevention of aggravation of disease or prevention of fit in the individual already suffering from the disease (e.g., mammals including human), and the prophylaxis means administration of the compound of the present invention for the purpose of preventing the onset of a disease in a healthy individual free of a disease (e.g., mammals including human).

Examples

[0095] The present invention is explained in detail in the following by referring to Examples and Experimental Examples. ¹H-NMR spectrum of the compounds was measured at 300 MHz or 400 MHz. The chemical shift of ¹H-NMR is shown by parts per million (ppm) of relative delta (δ) value, using tetramethylsilane (TMS) as the internal standard. The coupling constant is shown in hertz (Hz), and the obvious multiplicity is shown by s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets) and brs (broad singlet). Column chromatography was performed using silica gel manufactured by Fuji-Silysia Chemical Ltd. Preparative isolation by HPLC was performed using a column manufactured by WATERS or Shiseido Co., Ltd., and a mixed solvent of 0.05% aqueous TFA solution and 0.05% TFA-acetonitrile solution as an eluent.

[0096] The term "room temperature" used in the explanation of the following Examples means 10°C to 30°C.

Example 1

Synthesis of (2S)-(4-carboxythiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0097] 

(1-1) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}chloroacetamide

[0098] (2S)-2-Aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (30.5 g) was added to chloroform (400 mL) and saturated aqueous sodium hydrogen carbonate solution (400 mL). After dropwise addition of chloroacetyl chloride (7.7 mL) under ice-cooling, and the mixture was stirred at room temperature for 3 h. After completion of the reaction, the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (31.6 g) as a colorless oil.

(1-2) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}chloroacetamide hydrochloride

[0099] The resultant product (31.0 g) of (1-1) was dissolved in ethyl acetate (100 mL), and a 4 mol/L hydrogen chloride-ethyl acetate solution (22.5 mL) was added dropwise under ice-cooling. Ethanol was further added for dissolution, and the mixture was left standing overnight and the resulting solid was collected by filtration, washed with ethyl acetate, and dried to give the title compound (29.8 g) as white crystals.

(1-3) Synthesis of 4-ethoxycarbonyl-2-mercaptothiazole

[0100] Ethyl bromopyruvate (90%, 100 g) was completely dissolved in ethanol (1000 mL), ammonium dithiocarbamate (55.9 g) was added, and the mixture was stirred at room temperature for 2.5 h and heated under reflux for 1 h. After completion of the reaction, the solvent was evaporated under reduced pressure, water was added to the obtained residue. The solid was collected by filtration, washed with water and isopropyl ether, and dried to give the title compound (63.3 g) as a yellow powder.

(1-4) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(ethoxycarbonyl)thiazol-2-ylthio]acetamide

[0101] The resultant product (776 mg) of (1-2) and the resultant product (379 mg) of (1-3) were dissolved in dimethylformamide (6 mL), potassium carbonate (829 mg) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (850 mg) as a pale-yellow oil.

(1-5) Synthesis of (2S)-(4-carboxythiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0102] The resultant product (850 mg) of (1-4) was dissolved in methanol (4 mL) and tetrahydrofuran (4 mL), 1 mol/L aqueous sodium hydroxide solution (4 mL) was added, and the mixture was stirred overnight at room temperature. 1 mol/L hydrochloric acid was added to the reaction mixture, and the organic solvent alone was evaporated under reduced pressure. Saturated brine was added to the obtained residue, and the mixture was extracted with a mixed solvent of chloroform-methanol. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (479 mg) as a white solid.
¹H-NMR(DMSO-d₆) δ 1.80(1H,t,J=10.5Hz), 1.99-2.10(1H, m), 2.55(1H, d, J=10.8Hz), 2.65(1H, d, J=10.8Hz), 3.13(2H, t, J=5.7Hz), 3.36-3.52(4H, m), 3.75(1H, d, J=10.8Hz), 3.99(2H, s), 7.29(1H, dd, J=1.2, 8.1Hz), 7.53-7.59(2H, m), 8.31-8.35(2H, m), 12.3(1H, brs).
MS (ESI) m/z:476 [M+H].

Example 2

Synthesis of (2S)-[4-(carboxymethyl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0103] 

(2-1) Synthesis of 4-ethoxycarbonylmethyl-2-mercaptothiazole

[0104] By a similar method as in (1-3), the title compound (40.1 g) was obtained as white crystals from ethyl 4-chloroacetoacetate (47.0 g) and ammonium dithiocarbamate (34.6 g).

(2-2) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(ethoxycarbonylmethyl)thiazol-2-ylthio]acetamide

[0105] By a similar method as in (1-4), the title compound (21.3 g) was obtained as a pale-yellow oil from the resultant product (15.5 g) of (1-2) and the resultant product (8.94 g) of (2-1).

(2-3) Synthesis of (2S)-[4-(carboxymethyl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0106] By a similar method as in (1-5), the title compound (18.0 g) was obtained as a white amorphous solid from the resultant product (21.3 g) of (2-2).
¹H-NMR(DMSO-d₆) δ 1.79(1H, t, J=10.8Hz), 2.00-2.11(1H, m), 2.56(1H, d, J=11.1Hz), 2.65(1H, d, J=11.1Hz), 3.13(2H, t, J=5.7Hz), 3.34-3.52(4H, m), 3.67(2H, s), 3.77(1H, d, J=11.1Hz), 3.92(2H, s), 7.29(1H, dd, J=1.8, 11.1Hz), 7.38(1H, s), 7.54-7.60(2H, m), 8.29-8.32(1H, m), 12.3(1H, brs).
MS(ESI)m/z:490[M+H].

Example 3

Synthesis of (2S)-[4-(3-cyanophenyl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0107] 

(3-1) Synthesis of 4-(3-cyanophenyl)-2-mercaptothiazole

[0108] By a similar method as in (1-3), the title compound (4.07 g) was obtained as a yellow pale solid from 3'-cyano-2-bromoacetophenone (8.96 g) and ammonium dithiocarbamate (4.41 g).

(3-2) Synthesis of (2S)-[4-(3-cyanophenyl)thiazol-2-yl-thio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-acetamide

[0109] By a similar method as in (1-4), the title compound (264 mg) was obtained as a brown amorphous solid from the resultant product (352 mg) of (1-1) and the resultant product (218 mg) of (3-1).
¹H-NMR(DMSO-d₆) δ 1.75(1H, t, J=10.8Hz), 1.91-1.99(1H, m), 2. 48 (1H, d, J=9.9Hz), 2.59(1H, d, J=9.9Hz), 3.15(2H, t, J=5.7Hz), 3.33-3.52(4H, m), 3.71(1H, d, J=10.5Hz), 4.05(2H, s), 7.20(1H, dd, J=1.8, 8.1Hz), 7.43(1H, d, J=1.8Hz), 7.55(1H, d, J=8.4Hz), 7.65(1H, t, J=7.8Hz), 7.81(1H, d, J=7.8Hz), 8.25-8.29(2H, m), 8.39-8.41(2H, m).
MS(ESI)m/z:533[M+H].

Example 4

Synthesis of (2S)-[4-(4-cyanophenyl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0110] 

(4-1) Synthesis of 4-(4-cyanophenyl)-2-mercaptothiazole

[0111] By a similar method as in (1-3), the title compound (4.24 g) was obtained as a yellow solid from 4'-cyano-2-bromoacetophenone (5.17 g) and ammonium dithiocarbamate (2.54 g).

(4-2) Synthesis of (2S)-[4-(4-cyanophenyl)thiazol-2-yl-thio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-acetamide

[0112] By a similar method as in (1-4), the title compound (469 mg) was obtained as a yellow amorphous solid from the resultant product (352 mg) of (1-1) and the resultant product (218 mg) of (4-1).
¹H-NMR(DMSO-d₆) δ 1.75(1H, t, J=10.8Hz), 1.91-2.00(1H, m), 2.50(1H, d, J=11.1Hz), 2.60(1H, d, J=11.1Hz), 3.15(2H, t, J=5.7Hz), 3.33-3.55(4H, m), 3.71(1H, d, J=11.7Hz), 4.05(2H, s), 7.22(1H, d, J=8.1Hz), 7.44(1H, s), 7. 56 (1H, d, J=8.1Hz), 7.91(2H, d, J=8.5Hz), 8.14(2H, d, J=8.5Hz), 8.32-8.40(2H, m).
MS (ESI) m/z:533 [M+H].

Example 5

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(4-methoxycarbonylphenyl)thiazol-2-ylthio]-acetamide

[0113] 

(5-1) Synthesis of 2-mercapto-4-(4-methoxycarbonyl-phenyl)thiazole

[0114] By a similar method as in (1-3), the title compound (4.81 g) was obtained as a pale-yellow solid from 4'-methoxycarbonyl-2-chloroacetophenone (7.64 g) and ammonium dithiocarbamate (3.96 g).

(5-2) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(4-methoxycarbonylphenyl)thiazol-2-ylthio]acetamide

[0115] By a similar method as in (1-4), the title compound (650 mg) was obtained as a pale-yellow amorphous solid from the resultant product (422 mg) of (1-1) and the resultant product (302 mg) of (5-1).
¹H-NMR(DMSO-d₆) δ 1.76(1H, t, J=10.8Hz), 1.91-2.01(1H, m), 2.50(1H, d, J=11.1Hz), 2.60(1H, d, J=11.1Hz), 3.15(2H, t, J=6.0Hz), 3.33-3.55(4H, m), 3.71 (1H, d, J=9.3Hz), 3.86(3H, s), 4.05(2H, s), 7.22 (1H, d, J=8.1Hz), 7.44 (1H, s), 7.55 (1H, d, J=8.1Hz), 8.01(2H, d, J=8.4Hz), 8.09(2H, d, J=8.4Hz), 8.25 (1H, s), 8.35-8.39(1H, m).
MS(ESI)m/z:566[M+H].

Example 6

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(3-nitrophenyl)thiazol-2-ylthio]acetamide

[0116] 

(6-1) Synthesis of 2-mercapto-4-(3-nitrophenyl)thiazole

[0117] By a similar method as in (1-3), the title compound 21.1 g) was obtained as a yellow solid from 3'-nitro-2-bromoacetophenone (25.0 g) and ammonium dithiocarbamate (11.3 g).

(6-2) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(3-nitrophenyl)thiazol-2-ylthio]acetamide

[0118] By a similar method as in (1-4), the title compound (4.94 g) was obtained as a yellow amorphous solid from the resultant product (3.52 g) of (1-1) and the resultant product (2.38 g) of (6-1).
¹H-NMR(DMSO-d₆) δ 1.76(1H, t, J=10.8Hz), 1.91-2.01(1H, m), 2.48(1H, d, J=9.9Hz), 2.61(1H, d, J=10.8Hz), 3.16(2H, t, J=5.7Hz), 3.33-3.52(4H, m), 3.71(1H, d, J=10.5Hz), 4.05(2H, s), 7.21(1H, d, J=8.1Hz), 7.44(1H, s), 7.55(1H, d, J=8.4Hz), 7.74(1H, t, J=7.8Hz), 8.19(1H, d, J=7.5Hz), 8.33-8.43(3H, m), 8.71(1H, s).
MS(ESI)m/z:553[M+H].

Example 7

Synthesis of (2S)-[4-(4-carboxyphenyl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0119] 

[0120] By a similar method as in (1-5), the title compound (388 mg) was obtained as a pale-yellow solid from the resultant product (580 mg) of (5-2).
¹H-NMR(DMSO-d₆) δ 1.76(1H, t, J=10.8Hz), 1.91-2.01(1H, m), 2.50(1H, d, J=11.1Hz), 2.61(1H, d, J=11.1Hz), 3.15(2H, t, J=5.7Hz), 3.33-3.55(4H, m), 3.71(1H, d, J=10.8Hz), 4.05(2H, s), 7.22(1H, dd, J=1.8, 8.1Hz), 7.45(1H, d, J=1.8Hz), 7.55(1H, d, J=8.1Hz), 7.99(2H, d, J=8.4Hz), 8.07(2H, d, J=8.4Hz), 8.22(1H, s), 8.36 (1H, t, J=5.7Hz), 13.0(1H, brs).
MS(ESI)m/z:552[M+H].

Example 8

Synthesis of (2S)-[4-(4-carbamoylphenyl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-acetamide

[0121] 

[0122] The resultant product (276 mg) of Example 7 was dissolved in tetrahydrofuran (2.5 mL), triethylamine (77 µL) and isobutyl chloroformate (72 µL) were added, and the mixture was stirred at room temperature for 2.5 h. A 7 mol/L ammonia-methanol solution (2 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 40 min. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and ethanol as an eluent. The solvent was evaporated from the eluent to give the title compound (202 mg) as a white amorphous solid.
¹H-NMR(DMSO-d₆) δ 1.76(1H, t, J=10.5Hz), 1.91-2.02(1H, m), 2.50(1H, d, J=11.1Hz), 2.61(1H, d, J=11.1Hz), 3.15(2H, t, J=5.6Hz), 3.33-3.55(4H, m), 3.72(1H, d, J=11.4Hz), 4.04(2H, s), 7.22(1H, dd, J=1.4, 8.2Hz), 7.40(1H, brs), 7.46(1H, d, J=1.4Hz), 7.55(1H, d, J=8.2Hz), 7.94(2H, d, J=8.3Hz), 8.02(3H, m), 8.17(1H, s), 8.36(1H, t, J=5.7Hz).
MS(ESI) m/z:551 [M+H].

Example 9

Synthesis of (2S)-[4-(3-aminophenyl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0123] 

[0124] A solution of the resultant product (4.65 g) of (6-2) in tetrahydrofuran (24 mL) and methanol (16 mL) was added dropwise to an aqueous (16 mL) suspension of ammonium chloride (2.25 g) and iron powder (1.41 g) at 60°C. The reaction mixture was heated under reflux for 3.5 h. After allowing to cool, the reaction mixture was filtered through celite. A 1 mol/L aqueous sodium hydroxide solution was added to the filtrate, and the organic solvent alone was evaporated under reduced pressure. The residue was extracted with ethyl acetate, the extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (3.87 g) as a pale-yellow amorphous solid.
¹H-NMR(DMSO-d₆) δ 1.77(1H, t, J=10.5Hz), 1.91-2.02(1H, m), 2.52(1H, d, J=11.1Hz), 2.62(1H, d, J=11.1Hz), 3.15(2H, t, J=5.7Hz), 3.37-3.53(4H, m), 3.73(1H, d, J=11.4Hz), 3.99(2H, s), 5.13(2H, s), 6.53(1H, m), 7.05(2H, m), 7.14(1H, s), 7.24(1H, dd, J=1.5, 8.4Hz), 7.49(1H, d, J=1.5Hz), 7.56(1H, d, J=8.4Hz), 7.79(1H, s), 8.31(1H, t, J=5.7Hz).
MS(ESI)m/z:523[M+H].

Example 10

Synthesis of (2S)-[4-(3-carbamoyl-4-hydroxyphenyl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]-methyl}acetamide

[0125] 

(10-1) Synthesis of 4-(3-carbamoyl-4-hydroxyphenyl)-2-mercaptothiazole

[0126] By a similar method as in (1-3), the title compound (24.0 g) was obtained as a white solid from 3'-carbamoyl-4'-hydroxy-2-bromoacetophenone (25.8 g) and ammonium dithiocarbamate (12.1 g).

(10-2) Synthesis of (2S)-[4-(3-carbamoyl-4-hydroxyphenyl)-thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0127] By a similar method as in (1-4), the title compound (10.0 g) was obtained as a white amorphous solid from the resultant product (7.03 g) of (1-1) and the resultant product (5.05 g) of (10-1).
¹H-NMR(DMSO-d₆) δ 1.74(1H, t, J=10.8Hz), 1.90-2.02(1H, m), 2.50 (1H, d, J=11.1Hz), 2 . 5 9 (1H, d, J=11.1Hz), 3.14(2H, m), 3.33-3.52(4H, m), 3. 70 (1H, d, J=11.1Hz), 4.03(2H, s), 6. 95 (1H, d, J=8.7Hz), 7.21(1H, d, J=8.1Hz), 7.45(1H, s), 7.55(1H, d, J=8.1Hz), 7.82(1H, s), 7.94-8.04(2H, m), 8.32-8.39(2H, m), 8.51(1H, brs), 13.2(1H, s).
MS(ESI) m/z:567 [M+H].

Example 11

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(pyridin-4-yl)thiazol-2-ylthio]acetamide

[0128] 

(11-1) Synthesis of 2-mercapto-4-(pyridine-4-yl)thiazole

[0129] By a similar method as in (1-3), the title compound (1.60 g) was obtained as a brown solid from 4-(bromoacetyl)pyridine hydrobromide (9.06 g) and ammonium dithiocarbamate (10.7 g).

(11-2) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(pyridin-4-yl)thiazol-2-ylthio]acetamide

[0130] By a similar method as in (1-4), the title compound (512 mg) was obtained as a white solid from the resultant product (535 mg) of (1-1) and the resultant product (295 mg) of (11-1).
¹H-NMR(DMSO-d₆) δ 1.76(1H, t, J=10.5Hz), 1.90-2.02(1H, m), 2.50(1H, d, J=11.1Hz), 2.61(1H, d, J=11.1Hz), 3.15(2H, t, J=5.7Hz), 3.33-3.51(4H, m), 3.72(1H, d, J=11.1Hz), 4.05(2H, s), 7.22(1H, d, J=8.4Hz), 7.47(1H, s), 7.56(1H, d, J=8.4Hz), 7.89(2H, d, J=5.7Hz), 8.34-8.40(2H, m), 8.63(2H, d, J=5.7Hz).
MS(ESI)m/z:509[M+H].

Example 12

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(pyridin-3-yl)thiazol-2-ylthio]acetamide

[0131] 

(12-1) Synthesis of 2-mercapto-4-(pyridin-3-yl)thiazole

[0132] By a similar method as in (1-3), the title compound (3.26 g) was obtained as pale-yellow crystals from 3-(dibromoacetyl)pyridine hydrobromide (10.8 g) and ammonium dithiocarbamate (13.2 g).

(12-2) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(pyridin-3-yl)thiazol-2-ylthio]acetamide

[0133] By a similar method as in (1-4), the title compound (283 mg) was obtained as a pale-yellow amorphous solid from the resultant product (352 mg) of (1-1) and the resultant product (194 mg) of (12-1).
¹H-NMR(DMSO-d₆) δ 1.75(1H, t, J=10.5Hz), 1.90-2.00(1H, m), 2.50(1H, d, J=11.1Hz), 2.61(1H, d, J=11.1Hz), 3.15(2H, t, J=5.7Hz), 3.33-3.52(4H, m), 3.71(1H, d, J=11.1Hz), 4.05(2H, s), 7.21-7.24(1H, m), 7.42-7.49(2H, m), 7.56(1H, d, J=8.1Hz), 8.21(1H, s), 8.26-8.28(1H, m), 8.31-8.39(1H, m), 8.53-8.56(1H, m), 9.16-9.18(1H, m).
MS(ESI) m/z:509 [M+H].

Example 13

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(3,4-dimethoxyphenyl)thiazol-2-ylthio]acetamide

[0134] 

(13-1) Synthesis of 4-(3,4-dimethoxyphenyl)-2-mercaptothiazole

[0135] By a similar method as in (1-3), the title compound (6.08 g) was obtained as a yellow solid from 3' ,4'-dimethoxy-2-bromoacetophenone (24.0 g) and ammonium dithiocarbamate (6.72 g).

(13-2) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(3,4-dimethoxyphenyl)thiazol-2-yl-thio] acetamide

[0136] By a similar method as in (1-4), the title compound (180 mg) was obtained as a pale-yellow solid from the resultant product (352 mg) of (1-1) and the resultant product (253 mg) of (13-1).
¹H-NMR(DMSO-d₆) δ 1.75(1H, t, J=10.5Hz), 1.90-2.02(1H, m), 2.50(1H, d, J=11.1Hz), 2.60(1H, d, J=11.1Hz), 3.15(2H, t, J=5.7Hz), 3.33-3.51(4H, m), 3.72(1H, d, J=11.1Hz), 3.78(3H, s), 3.82(3H, s), 4.00(2H, s), 6.99(1H, d, J=9.0Hz), 7.22(1H, d, J=8.1Hz), 7.44-7.50(3H, m), 7.55(1H, d, J=8.1Hz), 7.91(1H, s), 8.32(1H, t, J=5.7Hz).
MS(ESI)m/z:568[M+H].

Example 14

Synthesis of (2S)-[4-(3-acetaminophenyl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0137] 

[0138] To a solution of the resultant product (262 mg) of Example 9 in pyridine (2 mL) was added dropwise acetic anhydride (57 µL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (279 mg) as a white amorphous solid.
¹H-NMR(DMSO-d₆) δ 1.76(1H, t, J=10.5Hz), 1.90-2.02(1H, m), 2.05(3H, s), 2.50-2.62(2H, m), 3.15(2H, t, J=5.7Hz), 3.33-3.50(4H, m), 3.72(1H, m), 4.00(2H, s), 7.24(1H, dd, J=2.1, 8.4Hz), 7.34(1H, t, J=8.1Hz), 7.48(1H, d, J=2.1Hz), 7.54-7.61(3H, m), 7.92(1H, s), 8.09(1H, s), 8.30-8.34(1H, m), 10.0(1H, s).
MS (ESI) m/z:565 [M+H].

Example 15

Synthesis of (2S)-(4-carbamoylthiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0139] 

[0140] By a similar method as in Example 8, the title compound (4.07 g) was obtained as a white amorphous solid from the resultant product (4.76 g) of (1-5).
¹H-NMR(DMSO-d₆) δ 1.73(1H, t, J=10.6Hz), 1.92-2.07(1H, m), 2.52(1H, d, J=11.0Hz), 2.58(1H, d, J=11.0Hz), 3.13(2H, t, J=5.7Hz), 3.39-3.52(4H, m), 3.74(1H, d, J=11.4Hz), 3.96(1H, d, J=14.7Hz), 4.03(1H, d, J=14.7Hz), 7.28(1H, dd, J=1.5, 8.1Hz), 7.51-7.56(2H, m), 7.64(1H, brs), 7.75(1H, brs), 8.13(1H, s), 8.31(1H, t, J=6.5Hz).
MS (ESI) m/z:475 [M+H].

Example 16

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(ethylaminocarbonyl)thiazol-2-ylthio]-acetamide hydrochloride

[0141] 

[0142] The resultant product (476 mg) of (1-5) and ethylamine hydrochloride (98 mg) were dissolved in dimethylformamide (2 mL), then 1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (288 mg), hydroxybenzotriazole hydrate (230 mg) and triethylamine (167 µL) were added, and the mixture was stirred overnight at room temperature. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (free form, 441 mg) as a pale-yellow amorphous solid. By a similar method as in (1-2), the title compound (357 mg) was obtained as pale-yellow crystals from the obtained residue.
¹H-NMR (DMSO-d₆) δ 1.10(3H, t, J=7.2Hz), 2.60-2.79(1H, m), 2.89-3.06(1H, m), 3.08-3.31(6H, m), 3.70-4.04(5H, m), 4.31(2H, brs), 7.57(1H, d, J=8.1Hz), 7.74(1H, d, J=8.1Hz), 7.91(1H, brs), 8.13(1H, s), 8.37-8.42(1H, m), 8.56(1H, brs), 11.4(1H, brs).
MS(ESI)m/z:503[M+H].

Example 17

Synthesis of (2S)-{4-[(2-amino-2-oxoethyl)aminocarbonyl]thiazol-2-ylthio}-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0143] 

[0144] By a similar method as in Example 16, the title compound (286 mg) was obtained as a pale-yellow solid from the resultant product (476 mg) of (1-5) and glycinamide hydrochloride (133 mg).
¹H-NMR (DMSO-d₆) δ 1.75(1H, t, J=10.5Hz), 1.92-2.05(1H, m), 2.52(1H, d, J=11.1Hz), 2.61(1H, d, J=11.1Hz), 3.13(2H, t, J=5.7Hz), 3.36-3.50(4H, m), 3.70 (1H, d, J=11.4Hz), 3.83(2H, d, J=6.0Hz), 4.02(2H, s), 7.09(1H, brs), 7.28(1H, dd, J=1.8, 8.1Hz), 7.40(1H, brs), 7.53(1H, d, J=1.8Hz), 7.58(1H, d, J=8.1Hz), 8.18(1H, s), 8.34(1H, t, J=5.7Hz), 8.41(1H, t, J=6.0Hz).
MS (ESI)m/z:532 [M+H] .

Example 18

Synthesis of (2S)-[4-(carbamoylmethyl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0145] 

[0146] By a similar method as in Example 8, the title compound (318 mg) was obtained as a white amorphous solid from the resultant product (490 mg) of (2-3).
¹H-NMR (DMSO-d₆) δ 1.78(1H, t, J=10.5Hz), 1.94-2.09(1H, m), 2.55(1H, d, J=11.1Hz), 2.64(1H, d, J=11.1Hz), 3.13(2H, t, J=5.7Hz), 3.38-3.52(6H, m), 3.76(1H, d, J=11.4Hz), 3.91(1H, s), 6.97(1H, brs), 7.27-7.31(2H, m), 7.38(1H, brs), 7.53-7.60(2H, m), 8.28(1H, t, J=5.7Hz).
MS(ESI)m/z:489[M+H].

Example 19

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(ethylaminocarbonylmethyl)thiazol-2-ylthio]-acetamide hydrochloride

[0147] 

[0148] By a similar method as in Example 16, the title compound (425 mg) was obtained as white crystals from the resultant product (490 mg) of (2-3) and ethylamine hydrochloride (98 mg).
¹H-NMR(DMSO-d₆) δ 1.02(3H, t, J=7.5Hz), 2.60-2.80(1H, m), 2.86-3.28(7H, m), 3.51(2H, s), 3.63-4.01(5H, m), 4.32(2H, brs), 7.30(1H, s), 7.55(1H, d, J=8.1Hz), 7.74(1H, d, J=8.1Hz), 7.89(1H, s), 8.01 (1H, m), 8.46(1H, m), 11.1(1H, brs).
MS(ESI)m/z:517[M+H].

Example 20

Synthesis of (2S)-{4-[(2-amino-2-oxoethyl)aminocarbonyl-methyl]thiazol-2-ylthio}-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0149] 

[0150] By a similar method as in Example 16, the title compound (465 mg) was obtained as a white amorphous solid from the resultant product (490 mg) of (2-3) and glycinamide hydrochloride (133 mg).
¹H-NMR(DMSO-d₆) δ 1.78(1H, t, J=10.5Hz), 1.96-2.09(1H, m), 2.55(1H, d, J=10.8Hz), 2.64(1H, d, J=10.8Hz), 3.13(2H, t, J=5.7Hz), 3.39-3.50(4H, m), 3.60(2H, s), 3.66(2H, d, J=5.6Hz), 3.75(1H, d, J=11.4Hz), 3.92(2H, s), 7.07(1H, brs), 7.28-7.38(3H, m), 7.53-7.60(2H, m), 8.19(1H, t, J=5.6Hz), 8.28(1H, t, J=5.7Hz).
MS (ESI) m/z:546 [M+H].

Example 21

Synthesis of (2S)-{4-[(3-amino-3-oxopropyl)aminocarbonyl]-thiazol-2-ylthio}-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0151] 

[0152] By a similar method as in Example 16, the title compound (384 mg) was obtained as a white amorphous solid from the resultant product (476 mg) of (1-5) and β-alaninamide hydrochloride (149 mg).
¹H-NMR(DMSO-d₆) δ 1.74(1H, t, J=10.5Hz), 1.93-2.04(1H, m), 2.35(2H, t, J=7.2Hz), 2.52(1H, d, J=10.5Hz), 2.59(1H, d, J=10.5Hz), 3.14(2H, t, J=5.7Hz), 3.36-3.51(6H, m), 3.74(1H, d, J=10.8Hz), 3.98(1H, d, J=14.0Hz), 4.02(1H, d, J=14.0Hz), 6.85(1H, brs), 7.28(1H, dd, J=1.5, 8.4Hz), 7.37(1H, brs), 7.52(1H, d, J=1.5Hz), 7.57(1H, d, J=8.4Hz), 8.14(1H, s), 8.26-8.39(2H, m).
MS (ESI) m/z:546 [M+H].

Example 22

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(N²-hydroxyamidino)thiazol-2-ylthio]acetamide

[0153] 

(22-1) Synthesis of (2S)-(4-cyanothiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0154] The resultant product (3.45 g) of Example 15 was dissolved in tetrahydrofuran (15 mL), and pyridine (1.76 mL) was added. After dropwise addition of trifluoroacetic anhydride (2.05 mL) under ice-cooling, the reaction mixture was stirred overnight at room temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (2.85 g) as a colorless oil.

(22-2) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(N²-hydroxyamidino)thiazol-2-ylthio]-acetamide

[0155] The resultant product (2.85 g) of (22-1) was dissolved in ethanol (30 mL), potassium carbonate (2.58 g) and hydroxylamine hydrochloride (603 mg) were added, and the reaction mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the resultant solid was collected by filtration to give the title compound (2.32 g) as white crystals.
¹H-NMR(DMSO-d₆) δ 1.75(1H, t, J=10.5Hz), 1.92-2.08(1H, m), 2.52 (1H, d, J=11.7Hz), 2.61 (1H, d, J=11.7Hz), 3.12(2H, t, J=5.7Hz), 3.39-3.50(4H, m), 3.75 (1H, d, J=12.0Hz), 3.95 (1H, d, J=14.7Hz), 4.01 (1H, d, J=14.7Hz), 5.77(2H, s), 7.29 (1H, dd, J=1.8, 8.1Hz), 7.53 (1H, d, J=1.8Hz), 7.57 (1H, d, J=8.1Hz), 7.72(1H, s), 8.32(1H, t, J=5.7Hz), 9.54(1H, brs).
MS (ESI) m/z:490 [M+H].

Example 23

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(5-methyl-1,2,4-oxadiazol-3-yl)thiazol-2-ylthio]acetamide hydrochloride

[0156] 

[0157] The resultant product (490 mg) of (22-2) was dissolved in xylene (6 mL) and pyridine (1 mL). After dropwise addition of acetic anhydride (104 µL), the mixture was heated under reflux for 2 h. After allowing to cool, acetic anhydride (28 µL) was added dropwise, and the mixture was further heated under reflux for 4 h. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (free form, 457 mg) as a pale-yellow oil. By a similar method as in (1-2), the title compound (275 mg) was obtained as white crystals from the obtained residue.
¹H-NMR(DMSO-d₆) δ 2.65(3H, s), 2.67-2.89(1H, m), 2.90-3.09(1H, m), 3.10-3.41(4H, m), 3.72-4.04(3H, m), 4.09(2H, s), 4.32(2H, brs), 7.56(1H, d, J=8.1Hz), 7.74(1H, d, J=8.1Hz), 7.90(1H, brs), 8.34(1H, s), 8.51-8.58(1H, m), 11.3(1H, brs).
MS (ESI) m/z:514 [M+H].

Example 24

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(5-ethoxycarbonyl-1,2,4-oxadiazol-3-yl)-thiazol-2-ylthio]acetamide

[0158] 

[0159] By a similar method as in Example 23, the title compound (223 mg) was obtained as a pale-yellow amorphous solid from the resultant product (1.66 g) of (22-2) and ethyl chloroglyoxylate (451 µL).
¹H-NMR(DMSO-d₆) δ 1.37(3H, t, J=6.9Hz), 1.80(1H, t, J=10.6Hz), 1.97-2.09(1H, m), 2.53(1H, d, J=11.0Hz), 2.65(1H, d, J=11.0Hz), 3.15(2H, t, J=5.7Hz), 3.40-3.55(4H, m), 3.75(1H, d, J=11.3Hz), 4.08 (1H, s), 4.45 (1H, q, J=7.2Hz), 7.29 (1H, dd, J=1.7, 8.3Hz), 7.51(1H, d, J=1.7Hz), 7.57 (1H, d, J=8.3Hz), 8.40 (1H, t, J=5.6Hz), 8.52(1H, s).
MS(ESI)m/z:572[M+H].

Example 25

Synthesis of (2S)-[4-(5-carbamoyl-1,2,4-oxadiazol-3-yl)-thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0160] 

[0161] A 7 mol/L ammonia-methanol solution (2 mL) was added to the resultant product (175 mg) of Example 24, and the mixture was stirred at room temperature for 1.5 h. The resultant solid was collected by filtration to give the title compound (40 mg) as a white solid.
¹H-NMR(DMSO-d₆) δ 1.79(1H, t, J=10.6Hz), 1.98-2.09(1H, m), 2.54(1H, d, J=11.1Hz), 2.65(1H, d, J=11.1Hz), 3.15(2H, t, J=5.7Hz), 3.38-3.53(4H, m), 3.75(1H, d, J=11.2Hz), 4.07(1H, s), 7.27(1H, dd, J=1.4, 8.3Hz), 7.29(1H, d, J=1.4Hz), 7.57(1H, d, J=8.3Hz), 8.34-8.40(2H, m), 8.45(1H, brs), 8.80(1H, brs).
MS (ESI) m/z:543 [M+H].

Example 26

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(5-nitro-8H-indeno[1,2-d]thiazol-2-ylthio)acetamide

[0162] 

(26-1) Synthesis of 5-nitro-8H-2-mercapto-indeno[1,2-d]thiazole

[0163] By a similar method as in (1-3), the title compound (3.4 g) was obtained as a yellow powder from 2-bromo-6-nitro-l-indanone (7.4 g) and ammonium dithiocarbamate (6 g).

(26-2) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(5-nitro-8H-indeno[1,2-d]thiazol-2-ylthio)acetamide

[0164] By a similar method as in (1-4), the title compound (520 mg) was obtained as a pale-yellow powder from the resultant product (500 mg) of (26-1) and the resultant product (700 mg) of (1-1).
¹H-NMR(DMSO-d₆) δ 1.75-1.83(1H, m), 1.95-2.03(1H, m), 2.49-2.52(1H, m), 2.62-2.68(1H, m), 3.14-3.19(2H, m), 3.33(2H, s), 3.40-3.51(2H, m), 3.69-3.75(1H, m), 4.03(2H, s), 4.12(2H, s), 7.17-7.22(1H, m), 7.41(1H, d, J=2.4Hz), 7.52(1H, d, J=8.0Hz), 7.82(1H, d, J=8.0Hz), 8.13-8.18(1H, m), 8.31-8.36(2H, m).
MS (ESI)m/z: 565 [M+H] .

Example 27

Synthesis of (2S)-(5-amino-8H-indeno[1,2-d]thiazol-2-yl-thio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-acetamide

[0165] 

[0166] By a similar method as in Example 9, the title compound (180 mg) was obtained as a white powder from the resultant product (270 mg) of (26-2).
¹H-NMR(DMSO-d₆) δ 1.72-1.78(1H, m), 1.94-2.01(1H, m), 2.50-2.54(1H, m), 2.59-2.64(1H, m), 3.13-3.17(2H, m), 3.35(2H, s), 3.43-3.50(2H, m), 3.68-3.75(3H, m), 3.98(2H, s), 5.08(2H, s), 6.45-6.49(1H, m), 6.87-6.89(1H, m), 7.16(1H, d, J=8.0Hz), 7.20-7.23(1H, m), 7.45-7.47 (1H, m), 7.54 (1H, d, J=8.0Hz), 8.24-8.29(1H, m).
MS(ESI)m/z:535[M+H].

Example 28

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(4,5-dihydro-8-nitronaphto[1,2-d]thiazol-2-ylthio)acetamide

[0167] 

(28-1) Synthesis of 4,5--2-mercapto-8-nitronaphto[1,2-d]thiazole

[0168] By a similar method as in (1-3), the title compound (0.95 g) was obtained as a yellow powder from 2-bromo-7-nitro-1-tetralone (4.5 g) and ammonium dithiocarbamate (3.3 g).

(28-2) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(4,5-dihydro-8-nitronaphto[1,2-d]thiazol-2-ylthio)acetamide

[0169] By a similar method as in (1-4), the title compound (800 mg) was obtained as a white amorphous solid from the resultant product (500 mg) of (28-1) and the resultant product (670 mg) of (1-1).
¹H-NMR(DMSO-d₆) δ 1.70-1.81(1H, m), 1.95-2.02(1H, m), 2.49-2.52(1H, m), 2.61-2.66(1H, m), 3.03-3.19(6H, m), 3.35(2H, s), 3.41-3.52(2H, m), 3.69-3.73(1H, m), 4.02(2H, s), 7.21(1H, dd, J=1.6, 8.0Hz), 7.44(1H, d, J=1.6Hz), 7.52-7.60(2H, m), 8.07(1H, dd, J=2.4, 8.0Hz), 8.34-8.39(1H, m), 8.44(1H, d, J=2.4Hz).
MS(ESI)m/z:579[M+H].

Example 29

Synthesis of (2S)-(8-amino-4,5-dihydronaphto[1,2-d]thiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0170] 

[0171] By a similar method as in Example 9, the title compound (570 mg) was obtained as a white amorphous solid from the resultant product (600 mg) of (28-2).
¹H-NMR(DMSO-d₆) δ 1.74-1.81(1H, m), 1.96-2.04(1H, m), 2.51-2.54 (1H, m), 2.61-2.65 (1H, m), 2.79(2H, t, J=7.6Hz), 2.88(2H, t, J=7.6Hz), 3.12-3.17(2H, m), 3.38(2H, s), 3.40-3.52(2H, m), 3.71-3.74(1H, m), 3.94(2H, s), 4.96(2H, s), 6.42(1H, dd, J=1.6, 8.0Hz), 6.90(1H, d, J=8.0Hz), 7.06(1H, d, J=1.6Hz), 7.24(1H, dd, J=1.6, 8.0Hz), 7.48(1H, d, J=1.6Hz), 7.55(1H, d, J=8.0Hz), 8.24-8.27(1H, m).
MS(ESI)m/z:549[M+H].

Example 30

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(thiophen-2-ylthio)acetamide

[0172] 

[0173] By a similar method as in (1-4), the title compound (4.2 g) was obtained as a brown oil from 2-mercaptothiophene (1 mL) and the resultant product (3.7 g) of (1-1).
¹H-NMR(DMSO-d₆) δ 1.74-1.81(1H, m), 2.02-2.10(1H, m), 2.53-2.65(2H, m), 3.07-3.13(2H, m), 3.40-3.50(6H, m), 3.72-3.80(1H, m), 7.00-7.05(1H, m), 7.15-7.18(1H, m), 7.28-7.34(1H, m), 7.53-7.62(3H, m), 8.04-8.08(1H, m).
MS (ESI) m/z:431 [M+H].

Example 31

Synthesis of (2S)-(2-bromothiophen-5-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0174] 

[0175] The resultant product (2.0 g) of Example 30 was dissolved in acetic acid (40 mL), pyridinium tribromide (1.5 g) was added, and the mixture was stirred at 60°C for 1 h. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (2.0 g) as a white powder.
¹H-NMR(DMSO-d₆) δ 1.75-1.80(1H, m), 2.02-2.10(1H, m), 2.54-2.66(2H, m), 3.06-3.13(2H, m), 3.40-3.52(6H, m), 3.74-3.79(1H, m), 7.03(1H, d, J=4.0Hz), 7.15(1H, d, J=4.0Hz), 7.28-7.33(1H, m), 7.53-7.55(1H, m), 7.57(1H, d, J=8.0Hz), 8.07-8.13(1H, m).

Example 32

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[5-(pyridin-4-yl)thiophen-2-ylthio]acetamide

[0176] 

[0177] The resultant product (500 mg) of Example 31 and 4-pyridylboronic acid (250 mg) were dissolved in a mixed solvent of ethylene glycol dimethyl ether (25 mL) and water (5 mL), sodium hydrogen carbonate (500 mg) and tetrakistriphenylphosphine palladium (60 mg) were added, and the mixture was stirred overnight at 100°C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent, and the obtained residue was recrystallized from ethyl acetate to give the title compound (90 mg) as a pale-brown powder.
¹H-NMR (DMSO-d₆) δ 1.72-1.80(1H, m), 1.97-2.06(1H, m), 2.51-2.54 (1H, m), 2.60-2.64(1H, m), 3.08-3.13(2H, m), 3.37-3.47(4H, m), 3.59(2H, s), 3.71-3.76(1H, m), 7.21-7.27(2H, m), 7.47-7.49(1H, m), 7.52-7.59(3H, m), 7.71(1H, d, J=8.0Hz), 8.12-8.16(1H, m), 8.53-8.57(2H, m).
MS(ESI)m/z:508[M+H].

Example 33

Synthesis of (2S)-N-{[4-(3, 4-dichlorobenzyl)morpholin-2-yl]methyl}-[5-(3-nitrophenyl)thiophen-2-ylthio]acetamide

[0178] 

[0179] By a similar method as in Example 32, the title compound (350 mg) was obtained as a yellow powder from the resultant product (630 mg) of Example 31 and 3-nitrophenylboronic acid (210 mg).
¹H-NMR(DMSO-d₆) δ 1.74-1.81(1H, m), 1.96-2.05(1H, m), 2.50-2.55(1H, m), 2.59-2.64(1H, m), 3.08-3.14(2H, m), 3.36-3.47(4H, m), 3.58(2H, s), 3.71-3.76(1H, m), 7.20-7.25(2H, m), 7.43-7.45(1H, m), 7.52(1H, d, J=8.0Hz), 7.65-7.72(2H, m), 8.05(1H, d, J=8.0Hz), 8.11-8.17(2H, m), 8.32-8.35(1H, m).
MS (ESI) m/z:552 [M+H].

Example 34

Synthesis of (2S)-[5-(3-aminophenyl)thiophen-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0180] 

[0181] By a similar method as in Example 9, the title compound (190 mg) was obtained as a white powder from the resultant product (300 mg) of Example 33.
¹H-NMR(DMSO-d₆) δ 1.74-1.79(1H, m), 1.98-2.05(1H, m), 2.51-2.54(1H, m), 2.60-2.65(1H, m), 3.08-3.13(2H, m), 3.37-3.52(6H, m), 3.71-3.76(1H, m), 5.19(2H, brs), 6.51(1H, d, J=8.0Hz), 6.74(1H, d, J=8.0Hz), 6.78(1H, s), 7.02(1H, t, J=8.0Hz), 7.11(1H, d, J=4.0Hz), 7.22(1H, d, J=4.0Hz), 7.26(1H, s), 7.49(1H, s), 7.55(1H, d, J=8.0Hz), 8.05-8.10(1H, m).
MS (ESI) m/z:522 [M+H].

Example 35

Synthesis of (2S)-[5-(3-cyanophenyl)thiophen-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0182] 

[0183] By a similar method as in Example 32, the title compound (150 mg) was obtained as a white powder from the resultant product (560 mg) of Example 31 and 3-cyanophenylboronic acid (170 mg).
¹H-NMR (DMSO-d₆) δ 1.73-1.81(1H, m), 1.97-2.05(1H, m), 2.51-2.54(1H, m), 2.59-2.64(1H, m), 3.08-3.13(2H, m), 3.36-3.48(4H, m), 3.56(2H, s), 3.71-3.77(1H, m), 7.18-7.26(2H, m), 7.45(1H, s), 7.54(1H, d, J=8.0Hz), 7.57-7.64(2H, m), 7.74(1H, d, J=8.0Hz), 7.90(1H, d, J=8.0Hz), 8,12(2H, brs).
MS(ESI)m/z:532[M+H].

Example 36

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-{5-[3-(N²-hydroxyamidino)phenyl]thiophen-2-ylthio}acetamide

[0184] 

[0185] By a similar method as in (22-2), the title compound (210 mg) was obtained as a white powder from the resultant product (500 mg) of Example 35.
¹H-NMR(DMSO-d₆) δ 1.74-1.79(1H, m), 1.97-2.05(1H, m), 2.51-2.54(1H, m), 2.60-2.65(1H, m), 3.09-3.14(2H, m), 3.38-3.48(4H, m), 3.54(2H, s), 3.71-3.76(1H, m), 5.89(2H, s), 7.18(1H, d, J=3.6Hz), 7.23(1H, d, J=8.4Hz), 7.39 (1H, t, J=7.6Hz), 7.45(1H, d, J=3.6Hz), 7.48 (1H, s), 7.54(1H, d, J=8.4Hz), 7.59-7.64(2H, m), 7.90(1H, s), 8.08-8.13(1H, m), 9.69(1H, s).
MS(ESI)m/z:565[M+H].

Example 37 (Reference Example)

Synthesis of (2S)-(4-carboxyphenylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0186] 

By a similar method as in (1-4), the title compound (1.2 g) was obtained as a white amorphous solid from 4-mercaptobenzoic acid (500 mg) and the resultant product (1.1 g) of (1-1).
¹H-NMR(DMSO-d₆) δ 1.70-1.78(1H, m), 1.97-2.06(1H, m), 2.51-2.61(2H, m), 3.10-3.15(2H, m), 3.37-3.49(4H, m), 3.73-3.79(3H, m), 7.24-7.28(1H, m), 7.40(2H, d, J=8.4Hz), 7.50(1H, s), 7.56(1H, d, J=8.4Hz), 7.83(2H, d, J=8.4Hz), 8.22-8.26(1H, m), 12.85(1H, brs).
MS(ESI)m/z:469[M+H].

Example 38 (Reference Example)

Synthesis of (2S)-(4-carbamoylphenylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0187] 

[0188] By a similar method as in Example 8, the title compound (330 mg) was obtained as a white powder from the resultant product (520 mg) of Example 37.
¹H-NMR(DMSO-d₆) δ 1.70-1.76(1H, m), 1.96-2.04(1H, m), 2.51-2.61(2H, m), 3.09-3.14(2H, m), 3.37-3.48(4H, m), 3.70-3.79(3H, m), 7.25-7.33(2H, m), 7.36(2H, d, J=8.4Hz), 7.50-7.52(1H, m), 7.56(1H, d, J=8.4Hz), 7.80(2H, d, J=8.4Hz), 7.91(1H, brs), 8.17-8.22(1H, m).
MS(ESI)m/z:468[M+H].

Example 39 (Reference Example)

Synthesis of (2S)-(4-acetaminophenylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0189] 

(39-1) Synthesis of (2S)-(4-aminophenylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0190] By a similar method as in (1-4), the title compound (130 mg) was obtained as a white amorphous solid from 4-mercaptoaniline (300 mg) and the resultant product (850 mg) of (1-1).

(39-2) Synthesis of (2S)-(4-acetaminophenylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0191] By a similar method as in Example 14, the title compound (130 mg) was obtained as a white amorphous solid from the resultant product (120 mg) of (39-1).
¹H-NMR(DMSO-d₆) δ 1.68-1.75(1H, m), 1.96-2.05(4H, m), 2.51-2.60(2H, m), 3.06-3.12(2H, m), 3.37-3.47(4H, m), 3.53-3.56(2H, m), 3.71-3.78(1H, m), 7.25-7.32(3H, m), 7.50-7.58(4H, m), 8.04-8.09(1H, m), 9.93(1H, s).
MS(ESI)m/z:482[M+H].

Example 40 (Reference Example)

Synthesis of (2S)-{4-[(2-amino-2-oxoethyl)aminocarbonyl]-phenylthio}-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0192] 

[0193] By a similar method as in Example 16, the title compound (390 mg) was obtained as a white powder from the resultant product (400 mg) of Example 37 and glycinamide hydrochloride (100 mg).
¹H-NMR(DMSO-d₆) δ 1.71-1.77(1H, m), 1.98-2.06(1H, m), 2.51-2.63(2H, m), 3.09-3.15(2H, m), 3.38-3.50(4H, m), 3.71-3.83(5H, m), 7.00(1H, brs), 7.25-7.30(1H, m), 7.33(1H, brs), 7.38(2H, d, J=8.0Hz), 7.51(1H, s), 7.56(1H, d, J=8.0Hz), 7.81(2H, d, J=8.0Hz), 8.18-8.24(1H, m), 8.58-8.63(1H, m).
MS(ESI)m/z:525[M+H].

Example 41 (Reference Example)

Synthesis of (2S)-{3-[(2-amino-2-oxoethyl)aminocarbonyl]-phenylthio}-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0194] 

(41-1) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(3-methoxycarbonylphenylthio)acetamide

[0195] 3-mercaptobenzoic acid (840 mg) and the resultant product (2.1 g) of (1-2) were dissolved in dimethylformamide (50 mL), potassium carbonate (2.1 g) was added, and the mixture was stirred at room temperature for 4 h. Methyl iodide (0.34 mL) was added, and the mixture was further stirred for 1 h. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (2.0 g) as a white amorphous solid.

(41-2) Synthesis of (2S)-(3-carboxyphenylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0196] By a similar method as in (1-5), the title compound (800 mg) was obtained as a white amorphous solid from the resultant product (2.0 g) of (41-1).

(41-3) Synthesis of (2S)-{3-[(2-amino-2-oxoethyl)aminocarbonyl]phenylthio}-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0197] By a similar method as in Example 16, the title compound (210 mg) was obtained as a white powder from the resultant product (310 mg) of (41-2) and glycinamide hydrochloride (90 mg).
¹H-NMR(DMSO-d₆) δ 1.70-1.76(1H, m), 1.97-2.03(1H, m), 2.51-2.61(2H, m), 3.08-3.13(2H, m), 3.36-3.48(4H, m), 3.70-3.82(5H, m), 7.06(1H, s), 7.28(1H, d, J=8.0Hz), 7.38-7.43(2H, m), 7.47-7.59(3H, m), 7.66-7.70(1H, m), 7.83(1H, s), 8.19-8.24(1H, m), 8.67-8.74(1H, m).
MS (ESI) m/z:525 [M+H].

Example 42

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(hydrazinocarbonyl)thiazol-2-ylthio]acetamide

[0198] 

(42-1) Synthesis of (2S)-[4-(N'-tert-butoxycarbonyl-hydrazinocarbonyl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0199] By a similar method as in Example 16, the title compound (4.01 g) was obtained as white crystals from the resultant product (8.45 g) of (1-5) and tert-butoxycarbonyl hydrazide (2.81 g).

(42-2) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(hydrazinocarbonyl)thiazol-2-ylthio]-acetamide

[0200] The resultant product (4.01 g) of (42-1) was dissolved in methylene chloride (30 mL), trifluoroacetic acid (10 mL) was added, and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, a 1 mol/L aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from a mixed solvent of ethyl acetate and methanol to give the title compound (453 mg) as white crystals.
¹H-NMR(DMSO-d₆) δ 1.73(1H, t, J=10.5Hz), 1.92-2.07(1H, m), 2.52(1H, d, J=11.1Hz), 2.58(1H, d, J=11.1Hz), 3.13(2H, t, J=5.7Hz), 3.36-3.49(4H, m), 3.75 (1H, d, J=11.4Hz), 4.01(1H, d, J=14.7Hz), 4.06(1H, d, J=14.7Hz), 4.40-4.90(2H, brs), 7. 28 (1H, dd, J=1.8, 8.1Hz), 7.53 (1H, d, J=1.8Hz), 7.58 (1H, d, J=8.1Hz), 8.13 (1H, s), 8.34 (1H, t, J=5.7Hz), 9.62(1H, s).
MS (ESI) m/z:490 [M+H].

Example 43

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(5-methyl-1,2,4-triazol-3-yl)thiazol-2-ylthio]acetamide hydrochloride

[0201] 

[0202] The resultant product (490 mg) of (42-2) and ethyl imidoacetate hydrochloride (148 mg) were suspended in ethanol (5 mL), triethylamine (167 µL) was added, and the mixture was heated under reflux for 5 h. Ethyl imidoacetate hydrochloride (148 mg) and triethylamine (167 µL) were added to the reaction mixture, and the mixture was further heated under reflux for 6 h. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and ethanol as an eluent. The solvent was evaporated from the eluent to give a white amorphous solid. Purification by HPLC gave trifluoroacetic acid salt of the title compound as a colorless oil. By a similar method as in (1-2), the title compound (141 mg) was obtained as a white powder from the obtained residue.
¹H-NMR(DMSO-d₆) δ 2.43(3H, s), 2.72-2.82(1H, m), 2.90-3.07(1H, m), 3.10-3.36(4H, m), 3.72-4.08(6H, m), 4.31(2H, brs), 7.57(1H, d, J=8.1Hz), 7.73(1H, d, J=8.1Hz), 7.92(1H, s), 8.15(1H, s), 8.56-8.61(1H, m), 11.6(1H, brs).
MS(ESI)m/z:513[M+H].

Example 44

Synthesis of (2S)-{4-[((1S)-2-amino-1-hydroxymethyl-2-oxoethyl)aminocarbonyl]thiazol-2-ylthio}-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0203] 

[0204] By a similar method as in Example 16, the title compound (203 mg) was obtained as a white solid from the resultant product (476 mg) of (1-5) and L-serinamide hydrochloride (169 mg).
¹H-NMR (DMSO-d₆) δ 1.77(1H, t, J=10.8Hz), 1.95-2.07(1H, m), 2.54(1H, d, J=10.5Hz), 2.63(1H, d, J=10.5Hz), 3.15(2H, t, J=5.7Hz), 3.36-3.50(4H, m), 3.59-3.79(3H, m), 4.01(2H, s), 4.34-4.42(1H, m), 5.06(1H, t, J=5.7Hz), 7.21(1H, brs), 7.29(1H, dd, J=1.8, 8.4Hz), 7.49(1H, brs), 7.54(1H, d, J=1.8Hz), 7.58(1H, d, J=8.4Hz), 8.03(1H, d, J=8 . 1Hz), 8.21(1H, s), 8.37(1H, t, J=5.7Hz).
MS (ESI) m/z:562 [M+H].

Example 45

Synthesis of (2S)-[4-(carboxymethylaminocarbonyl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide hydrochloride

[0205] 

(45-1) Synthesis of (2S)-[4-(tert-butoxycarbonylmethyl-aminocarbonyl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0206] By a similar method as in Example 16, the title compound (592 mg) was obtained as a white amorphous solid from the resultant product (476 mg) of (1-5) and glycine-tert-butyl ester hydrochloride (201 mg).

(45-2) Synthesis of (2S)-[4-(carboxymethylaminocarbonyl)-thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide hydrochloride

[0207] By a similar method as in (42-2), trifluoroacetic acid salt of the title compound was obtained as a colorless oil from the resultant product (592 mg) of (45-1). By a similar method as in (1-2), the title compound (512 mg) was obtained as a white powder from the obtained residue.
¹H-NMR(DMSO-d₆) δ 2.62-2.80(1H, m), 2.88-3.07(1H, m), 3.10-3.30(4H, m), 3.64-4.08(7H, m), 4.29(2H, brs), 7.53 (1H, d, J=8.1Hz), 7.74(1H, d, J=8.1Hz), 7.86(1H, s), 8.20(1H, s), 8.51-8.55(1H, m), 8.60(1H, t, J=6.0Hz), 11.0(1H, brs), 12.6(1H, brs).
MS(ESI)m/z:533[M+H].

Example 46

Synthesis of (2S)-{4-[(2-carboxyethyl)aminocarbonyl]-thiazol-2-ylthio}-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide hydrochloride

[0208] 

(46-1) Synthesis of (2S)-{4-[(2-tert-butoxycarbonylethyl) aminocarbonyl]thiazol-2-ylthio}-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0209] By a similar method as in Example 16, the title compound (614 mg) was obtained as a colorless oil from the resultant product (476 mg) of (1-5) and β-alanine-tert-butyl ester hydrochloride (218 mg).

(46-2) Synthesis of (2S)-{4-[(2-carboxyethyl)aminocarbonyl]thiazol-2-ylthio}-N-{[4-(3,4-dichlorobenzyl)-morpholin-2-yl]methyl}acetamide hydrochloride

[0210] By a similar method as in (42-2), trifluoroacetic acid salt of the title compound was obtained as a colorless oil from the resultant product (592 mg) of (46-1). By a similar method as in (1-2), the title compound (531 mg) was obtained as a white powder from the obtained residue.
¹H-NMR(DMSO-d₆) δ 2.62-2.81(1H, m), 2.88-3.07(1H, m), 3.10-3.35(4H, m), 3.42-3.50(2H, m), 3.62-4.11(7H, m), 4.31(2H, brs), 7.57(1H, d, J=8.1Hz), 7.74(1H, d, J=8.1Hz), 7.92(1H, s), 8.16(1H, s), 8.39(1H, t, J=5.7Hz), 8.55(1H, t, J=5.7Hz), 11.5(1H, brs), 12.4(1H, brs).
MS(ESI)m/z:547[M+H].

Example 47

Synthesis of (2S)-{4-[((1S)-3-amino-1-(tert-butoxycarbonyl)-3-oxopropyl)aminocarbonyl]thiazol-2-ylthio}-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0211] 

By a similar method as in Example 16, the title compound (625 mg) was obtained as a white amorphous solid from the resultant product (476 mg) of (1-5) and L-asparagine-tert-butyl ester hydrochloride (270 mg).
¹H-NMR(DMSO-d₆) δ 1.39(9H, s), 1.78(1H, t, J=10.5Hz), 1.95-2.07(1H, m), 2.51-2.70(4H, d, J=10.5Hz), 3.14(2H, t, J=5.7Hz), 3.38-3.50(4H, m), 3.75(1H, d, J=10.8Hz), 4.00(2H, s), 4.60-4.67(1H, m), 6.97(1H, brs), 7.29(1H, d, J=8.4Hz), 7.46(1H, brs), 7.53-7.59(2H, m), 8.21(1H, s), 8.27-8.33(1H, m), 8.47(1H, d, J=8.1Hz).
MS (ESI) m/z:646 [M+H].

Example 48

Synthesis of (2S)-{4-[((1S)-3-amino-1-carboxy-3-oxopropyl)aminocarbonyl]thiazol-2-ylthio}-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide hydrochloride

[0212] 

[0213] By a similar method as in (42-2), trifluoroacetic acid salt of the title compound was obtained as a colorless oil from the resultant product (561 mg) of Example 47. By a similar method as in (1-2), the title compound (491 mg) was obtained as a white powder from the obtained residue.
¹H-NMR(DMSO-d₆) δ 2.60-2.82(3H, m), 2.88-3.07(1H, m), 3.09-3.35(4H, m), 3.72-4.12(5H, m), 4.32(2H, brs), 4.62-4.74(1H, m), 6.98(1H, brs), 7.51(1H, brs), 7.59(1H, dd, J=1.8, 8.1Hz), 7.73(1H, d, J=8.1Hz), 7.94(1H, d, J=1.8Hz), 8.21(1H, s), 8.42-8.58(2H, m), 11.6(1H, brs).
MS (ESI) m/z:590 [M+H].

Example 49

Synthesis of (2S)-{4-[(((1S)-1-carbamoyl-3-methyl)butyl)-aminocarbonyl]thiazol-2-ylthio}-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0214] 

[0215] By a similar method as in Example 16, the title compound (562 mg) was obtained as a white amorphous solid from the resultant product (476 mg) of (1-5) and L-leucinamide hydrochloride (200 mg).
¹H-NMR(DMSO-d₆) δ 0.82-0.92(6H, m), 1.49-1.69(3H, m), 1.74(1H, t, J=10.8Hz), 1.93-2.07(1H, m), 2.53(1H, d, J=10.5Hz), 2.60(1H, d, J=10.5Hz), 3.08-3.18(2H, m), 3.36-3.50(4H, m), 3.70-3.76(1H, m), 3.97-4.08(2H, m), 4.38-4.52(1H, m), 7.11(1H, brs), 7.28(1H, dd, J=1.8, 8.1Hz), 7.49-7.59(3H, m), 8.04(1H, d, J=9.0Hz), 8.19(1H, s), 8.35(1H, t, J=5.7Hz).
MS (ESI) m/z:588 [M+H].

Example 50

Synthesis of (2S)-{4-[(((1S)-1-carboxy-3-methyl)butyl)-aminocarbonyl]thiazol-2-ylthio}-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide hydrochloride

[0216] 

(50-1) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-{4-[((1S)-1-methoxycarbonyl-3-methyl)-butylaminocarbonyl]thiazol-2-ylthio}-acetamide

[0217] By a similar method as in Example 16, the title compound (559 mg) was obtained as a pale-yellow amorphous solid from the resultant product (476 mg) of (1-5) and L-leucine methyl ester hydrochloride (218 mg).

(50-2) Synthesis of (2S)-{4-[(((1S)-1-carboxy-3-methyl) butyl)aminocarbonyl]thiazol-2-ylthio}-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide hydrochloride

[0218] By a similar method as in (1-5), a free form of the title compound was obtained as a colorless oil form the resultant product (500 mg) of (50-1). By a similar method as in (1-2), the title compound (470 mg) was obtained as a white powder from the obtained residue.
¹H-NMR(DMSO-d₆) δ 0.80-0.99(6H, m), 1.51-1.70(2H, m), 1.71-1.87(1H, m), 2.62-2.80(1H, m), 2.88-3.07(1H, m), 3.10-3.30(4H, m), 3.74-4.13(5H, m), 4.32(2H, brs), 4.40-4.52(1H, m), 7.58(1H, d, J=8.4Hz), 7.74(1H, d, J=8.4Hz), 7.93(1H, s), 8.21(1H, s), 8.32(1H, d, J=8.7Hz), 8.57(1H, t, J=5.7Hz), 11.5(1H, brs), 12.7(1H, brs).
MS(ESI)m/z:589[M+H].

Example 51

Synthesis of (2S)-{4-[((1S)-1-carboxyethyl)aminocarbonyl]-thiazol-2-ylthio}-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide hydrochloride

[0219] 

(51-1) Synthesis of (2S)-{4-[((1S)-1-benzyloxycarbonylethyl)aminocarbonyl]thiazol-2-ylthio}-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0220] By a similar method as in Example 16, the title compound (677 mg) was obtained as a pale-yellow oil from the resultant product (476 mg) of (1-5) and L-alanine benzyl ester tosylate (422 mg).

(51-2) Synthesis of (2S)-{4-[((1S)-1-carboxyethyl)aminocarbonyl]thiazol-2-ylthio}-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0221] By a similar method as in (1-5), a free form of the title compound was obtained as a colorless oil from the resultant product (677 mg) of (51-1). By a similar method as in (1-2), the title compound (480 mg) was obtained as a white powder from the obtained residue.
¹H-NMR(DMSO-d₆) δ 1.40(3H, d, J=7.2Hz), 2.64-2.81(1H, m), 2.88-3.07(1H, m), 3.10-3.30(4H, m), 3.71-4.13(5H, m), 4.31(2H, brs), 4.39-4.51(1H, m), 7.57(1H, d, J=8.4Hz), 7.74(1H, d, J=8.4Hz), 7.91(1H, s), 8.20 (1H, s), 8.37(1H, d, J=7.8Hz), 8.55(1H, t, J=5.4Hz), 11.4(1H, brs), 12.7(1H, brs).
MS (ESI)m/z:547 [M+H].

Example 52

Synthesis of (2S)-(5-amino-1,3,4-thiadiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0222] 

[0223] By a similar method as in (1-4), the title compound (760 mg) was obtained as white crystals from the resultant product (776 mg) of (1-2) and 2-amino-5-mercapto-1,3,4-thiadiazole (266 mg).
¹H-NMR(DMSO-d₆) δ 1.79(1H, t, J=10.5Hz), 1.99-2.10(1H, m), 2.55(1H, d, J=11.1Hz), 2.65(1H, d, J=11.1Hz), 3.11(2H, t, J=5.7Hz), 3.41-3.52(4H, m), 3.70-3.81(3H, m), 7.21-7.33(3H, m), 7.53-7.59(2H, m), 8.20(1H, t, J=5.7Hz).
MS(ESI)m/z:448[M+H].

Example 53

Synthesis of (2S)-(5-acetamino-1,3,4-thiadiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0224] 

[0225] By a similar method as in Example 14, the title compound (447 mg) was obtained as white crystals from the resultant product (448 mg) of Example 52.
¹H-NMR(DMSO-d₆) δ 1.78(1H, t, J=10.5Hz), 1.96-2.09(1H, m), 2.16(3H, s), 2.54(1H, d, J=10.8Hz), 2.64(1H, d, J=10.8Hz), 3.13(2H, t, J=5.7Hz), 3.38-3.52(4H, m), 3.75(1H, d, J=11.1Hz), 3.94(2H, s), 7.29(1H, dd, J=1.5, 8.1Hz), 7.53(1H, d, J=1.5Hz), 7.58(1H, d, J=8.1Hz), 8.28(1H, t, J=5.7Hz), 12.6(1H, s).
MS (ESI) m/z:490 [M+H].

Example 54

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(4-methyl-5-carboxythiazol-2-ylthio)acetamide hydrochloride

[0226] 

(54-1) Synthesis of 4-methyl-5-ethoxycarbonyl-2-mercaptothiazole

[0227] By a similar method as in (1-3), the title compound (63.9 g) was obtained as a pale-yellow solid from ethyl 2-chloroacetoacetate (100 g) and ammonium dithiocarbamate (73.6 g).

(54-2) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(4-methyl-5-ethoxycarbonylthiazol-2-ylthio)acetamide

[0228] By a similar method as in (1-4), the title compound (975 mg) was obtained as a pale-yellow oil from the resultant product (776 mg) of (1-2) and the resultant product (407 mg) of (54-1).

(54-3) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(4-methyl-5-carboxythiazol-2-ylthio)acetamide

[0229] The resultant product (975 mg) of (54-2) was reacted by a similar method as in (1-5), and purified by HPLC to give trifluoroacetic acid salt of the title compound as a colorless oil. By a similar method as in (1-2), the title compound (120 mg) was obtained as a white solid from the obtained residue.
¹H-NMR(DMSO-d₆) δ 2.55(3H, s), 2.70-2.82(1H, m), 2.90-3.07(1H, m), 3.10-3.34(4H, m), 3.76-4.13(6H, m), 4.32(2H, brs), 7.57(1H, dd, J=1.5, 8.4Hz), 7.74(1H, d, J=8.4Hz), 7.93(1H, d, J=1.5Hz), 8.56(1H, d, J=5.7Hz), 11.5(1H, brs).
MS(ESI)m/z:490[M+H].

Example 55

Synthesis of (2S)-4-(4-carbamoylthiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}butyramide hydrochloride

[0230] 

(55-1) Synthesis of benzyl 4-[4-(ethoxycarbonyl)thiazol-2-ylthio]butyrate

[0231] By a similar method as in (1-4), the title compound (11.1 g) was obtained as a pale-yellow oil from the resultant product (8.33 g) of (1-3) and benzyl 4-bromobutyrate (10.3 g).

(55-2) Synthesis of 4-[4-(ethoxycarbonyl)thiazol-2-ylthio]butyric acid

[0232] The resultant product (10.7 g) of (55-1) was dissolved in trifluoroacetic acid (30 mL), thioanisole (10.3 mL) was added, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of hexane and ethyl acetate as an eluent. The solvent was evaporated from the eluent to give the title compound (5.81 g) as a white solid.

(55-3) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-4-[4-(ethoxycarbonyl)thiazol-2-ylthio]-butyramide

[0233] By a similar method as in Example 16, the title compound (2.61 g) was obtained as a colorless oil from the resultant product (3.03 g) of (55-2) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (3.48 g).

(55-4) Synthesis of (2S)-4-(4-carbamoylthiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}butyramide hydrochloride

[0234] By a similar method as in Example 25, a free form of the title compound was obtained as a colorless oil from the resultant product (533 mg) of (55-3). By a similar method as in (1-2), the title compound (397 mg) was obtained as a white solid from the obtained residue.
¹H-NMR(DMSO-d₆) δ 1.90-1.99(2H, m), 2.26(2H, t, J=7.2Hz), 2.60-2.89(1H, m), 2.90-3.07(1H, m), 3.08-3.31(6H, m), 3.70-4.01(3H, m), 4.33(2H, brs), 7.56-7.60(2H, m), 7.72-7.75(2H, m), 7.92(1H, brs), 8.10-8.15(2H, m), 11.4(1H, brs).
MS(ESI)m/z:503[M+H].

Example 56

Synthesis of (2S)-4-[4-(carbamoylmethyl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}butyramide hydrochloride

[0235] 

(56-1) Synthesis of benzyl 4-[4-(ethoxycarbonylmethyl)-thiazol-2-ylthio]butyrate

[0236] By a similar method as in (1-4), the title compound (2.17 g) was obtained as a pale-yellow oil from the resultant product (1.57 g) of (2-1) and benzyl 4-bromobutyrate (1.80 g).

(56-2) Synthesis of 4-[4-(ethoxycarbonylmethyl)thiazol-2-ylthio]butyric acid

[0237] By a similar method as in (55-2), the title compound (0.82 g) was obtained as a colorless oil from the resultant product (2.08 g) of (56-1).

(56-3) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-4-[4-(ethoxycarbonylmethyl)thiazol-2-ylthio]butyramide

[0238] By a similar method as in Example 16, the title compound (1.32 g) was obtained as a colorless oil from the resultant product (796 mg) of (56-2) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (870 mg).

(56-4) Synthesis of (2S)-4-[4-(carbamoylmethyl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-butyramide hydrochloride

[0239] By a similar method as in Example 25, trifluoroacetic acid salt of the title compound was obtained as a colorless oil from the resultant product (1.32 g) of (56-3). By a similar method as in (1-2), the title compound (181 mg) was obtained as a white solid from the obtained residue.
¹H-NMR(DMSO-d₆) δ 1.90-1.97(2H, m), 2.24(2H, t, J=7.2Hz), 2.63-2.82 (1H, m), 2.88-3.29(7H, m), 3.50(2H, s), 3.79-4.01(3H, m), 4.34(2H, brs), 6.98 (1H, brs), 7.32 (1H, s), 7.45(1H, brs), 7.62(1H, dd, J=1.5, 8.1Hz), 7.74(1H, d, J=8.1Hz), 7.97(1H, d, J=1.5Hz), 8.12(1H, d, J=5.7Hz), 11.8(1H, brs).
MS(ESI)m/z:517[M+H].

Example 57

Synthesis of (2S)-4-(4-carboxythiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}butyramide

[0240] 

[0241] By a similar method as in (1-5), the title compound (1.31 g) was obtained as a white amorphous solid from the resultant product (1.34 g) of (55-3).
¹H-NMR(DMSO-d₆) δ 1.70-1.99(3H, m), 2.00-2.11(1H, m), 2.23(2H, t, J=7.2Hz), 2.52(1H, d, J=11.1Hz), 2.61 (1H, d, J=11.1Hz), 3.05-3.11(2H, m), 3.20(2H, t, J=7.2Hz), 3.40-3.61(4H, m), 3.74 (1H, d, J=11.1H), 7.29 (1H, dd, J=1.8, 8.4Hz), 7.52-7.59(2H, m), 7.95 (1H, dd, J=6.0, 6.0z), 8.35(1H, s).
MS(ESI)m/z:504[M+H].

Example 58

Synthesis of (2S)-4-[4-(2-amino-2-oxoethyl)aminocarbonylthiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}butyramide

[0242] 

[0243] By a similar method as in Example 16, the title compound (1.12 g) was obtained as a white amorphous solid from the resultant product (1.01 g) of Example 57 and glycinamide hydrochloride (265 mg).
¹H-NMR(DMSO-d₆) δ 1.75-2.10(4H, m), 2.24(2H, t, J=7.2Hz), 2.54 (1H, d, J=11.1Hz), 2.64 (1H, d, J=11.1Hz), 3.06-3.12(2H, m), 3.23(2H, t, J=7.3Hz), 3.40-3.52(4H, m), 3.70-3.83(3H, m), 7.06(1H, brs), 7.28(1H, dd, J=1.7, 8.3Hz), 7.39 (1H, brs), 7.53(1H, d, J=1.7Hz), 7.57(1H, d, J=8.3Hz), 7.98(1H, dd, J=5.7, 5.7Hz), 8.18 (1H, s), 8.42 (1H, t, J=5.8Hz).
MS(ESI)m/z:560[M+H].

Example 59

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(1H-tetrazol-5-yl)thiazol-2-ylthio]acetamide

[0244] 

[0245] The resultant product (457 mg) of (22-1), sodium azide (78 mg) and ammonium chloride (525 mg) were suspended in dimethylformamide (3 mL), and the mixture was heated under reflux for 4 h. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (193 mg) as an orange powder.
¹H-NMR(DMSO-d₆) δ 1.82-1.96(1H, m), 2.02-2.18(1H, m), 2.66(1H, d, J=11.4Hz), 2.78(1H, d, J=11.4Hz), 3.12-3.18(2H, m), 3.39-3.57(4H, m), 3.72(1H, d, J=11.7Hz), 3.92(1H, d, J=15.0Hz), 4.00(1H, d, J=15.0Hz), 7.24(1H, d, J=8.1Hz), 7.49(1H, s), 7.54(1H, d, J=8.1Hz), 8.31(1H, dd, J=5.7, 5.7Hz), 8.34(1H, s).
MS(ESI)m/z:500[M+H].

Example 60

Synthesis of (2S)-(5-carboxymethyl-4-methylthiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-acetamide

[0246] 

[0247] By a similar method as in (1-4), the title compound (316 mg) was obtained as a pale-yellow amorphous solid from the resultant product (388 mg) of (1-2) and 5-carboxymethyl-4-methyl-2-mercaptothiazole (189 mg).
¹H-NMR(DMSO-d₆) δ 1.73-1.87(1H, m), 1.97-2.09(1H, m), 2.21(3H, s), 2.55(1H, d, J=11.1Hz), 2.66(1H, d, J=11.1Hz), 3.10-3.16(2H, m), 3.39-3.52(4H, m), 3.74(2H, s), 3.76(1H, d, J=11.1Hz), 3.88(2H, s), 7.29(1H, d, J=8.1Hz), 7.53-7.60(2H, m), 8.28(1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:504[M+H].

Example 61

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-methyl-5-(1-oxoethyl)thiazol-2-ylthio]acetamide hydrochloride

[0248] 

(61-1) Synthesis of 4-methyl-5-(1-oxoethyl)-2-mercaptothiazole

[0249] By a similar method as in (1-3), the title compound (25.0 g) was obtained as an orange solid from 3-chloroacetyl-acetone (23.7 g) and ammonium dithiocarbamate (21.4 g).

(61-2) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-methyl-5-(1-oxoethyl)thiazol-2-ylthio]acetamide hydrochloride

[0250] By a similar method as in (1-4), the title compound (free form, 455 mg) was obtained as a pale-yellow oil from the resultant product (388 mg) of (1-2) and the resultant product (173 mg) of (61-1). By a similar method as in (1-2), the title compound (420 mg) was obtained as a white solid from the obtained residue.
¹H-NMR(DMSO-d₆) δ 2.50(3H, s), 2.60(3H, s), 2.70-2.89(1H, m), 2.90-3.07(1H, m), 3.09-3.38(4H, m), 3.76-4.08(5H, m), 4.32(2H, brs), 7.56(1H, d, J=8.4Hz), 7.75(1H, d, J=8.4Hz), 7.91(1H, s), 8.56(1H, dd, J=5.4, 5.4Hz), 11.3(1H, brs).
MS(ESI)m/z:488[M+H].

Example 62

Synthesis of (2S)-(5-carbamoylmethyl-4-methylthiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-acetamide

[0251] 

[0252] By a similar method as in Example 16, the title compound (217 mg) was obtained as a white solid from the resultant product (409 mg) of Example 60 and ammonium chloride (321 mg).
¹H-NMR(DMSO-d₆) δ 1.72-1.86(1H, m), 1.97-2.09(1H, m), 2.22(3H, s), 2.55 (1H, d, J=10.5Hz), 2.66 (1H, d, J=10.5Hz), 3.10-3.16(2H, m), 3.39-3.52(6H, m), 3.76(1H, d, J=9.6Hz), 3.87(2H, s), 7.07(1H, brs), 7.29(1H, d, J=8.4Hz), 7.53-7.62(3H, m), 8.27(1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:503[M+H].

Example 63

Synthesis of (2S)-(5-carbamoyl-4-methylthiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0253] 

[0254] By a similar method as in Example 16, the title compound (245 mg) was obtained as a white solid from a free form (901 mg) of the resultant product of (54-3) and ammonium chloride (588 mg).
¹H-NMR(DMSO-d₆) δ 1.72-1.86(1H, m), 1.97-2.09(1H, m), 2.22(3H, s), 2.55(1H, d, J=10.5Hz), 2.65(1H, d, J=10.5Hz), 3.11-3.17(2H, m), 3.38-3.55(4H, m), 3.76(1H, d, J=11.1Hz), 3.96(2H, s), 7.29(1H, d, J=8.4Hz), 7.41-7.60(4H, m), 8.30(1H, dd, J=5.4, 5.4Hz).
MS(ESI)m/z:489[M+H].

Example 64

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-([1,3]thiazolo[5,4-b]pyridin-2-ylthio)acetamide

[0255] 

[0256] By a similar method as in (1-4), the title compound (405 mg) was obtained as a pale-yellow oil from the resultant product (388 mg) of (1-2) and 2-mercapto-[1,3]thiazolo-[5,4-b]pyridine (168 mg).
¹H-NMR(DMSO-d₆) δ 1.72-1.86(1H, m), 1.93-2.07(1H, m), 2.53 (1H, d, J=11.1Hz), 2.65 (1H, d, J=11.1Hz), 3.13-3.19(2H, m), 3.37-3.52(4H, m), 3.74 (1H, d, J=11.1Hz), 4.16(2H, s), 7.26 (1H, dd, J=1.8, 8.1Hz), 7.49-7.58(3H, m), 8.20 (1H, dd, J=1.2, 8.1Hz), 8.40 (1H, dd, J=5.7, 5.7Hz), 8.50 (1H, dd, J=1.5, 4.5Hz).
MS(ESI)m/z:483[M+H].

Example 65

Synthesis of (2S)-(6-aminobenzothiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0257] 

[0258] By a similar method as in (1-4), the title compound (371 mg) was obtained as a white amorphous solid from the resultant product (388 mg) of (1-2) and 6-amino-2-mercaptobenzothiazole (191 mg).
¹H-NMR(DMSO-d₆) δ 1.68-1.82(1H, m), 1.90-2.07(1H, m), 2.50-2.60(1H, m), 2.62(1H, d, J=10.3Hz), 3.05-3.19(2H, m), 3.35-3.52(4H, m), 3.74(1H, d, J=10.9Hz), 3.99(2H, s), 5.35(2H, s), 6.70(1H, d, J=8.5Hz), 7.00 (1H, s), 7.25(1H, d, J=7.8Hz), 7.43-7.58(3H, m), 8.21-8.35(1H, m).
MS(ESI)m/z:497[M+H].

Example 66

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-ylthio)acetamide

[0259] 

(66-1) Synthesis of 6-tertiary butoxycarbonyl-2-mercapto-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine

[0260] N-tertiary butoxycarbonyl-4-piperidone (996 mg) was dissolved in THF (15 mL), phenyltrimethylammonium tribromide (2.07 g) was added, and the mixture was stirred at room temperature for 30 min. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. By a similar method as in (1-3), the title compound (310 mg) was obtained as a colorless oil from obtained residue (1.33 g) and ammonium dithiocarbamate (551 mg).

(66-2) Synthesis of (2S)-(6-tertiary butoxycarbonyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0261] By a similar method as in (1-4), the title compound (558 mg) was obtained as a pale-yellow oil from the resultant product (442 mg) of (1-2) and the resultant product (310 mg) of (66-1).

(66-3) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-ylthio)acetamide

[0262] By a similar method as in (42-2), the title compound (286 mg) was obtained as a colorless oil from the resultant product (558 mg) of (66-2).
¹H-NMR(DMSO-d₆) δ 1.72-1.86(1H, m), 1.93-2.10(1H, m), 2.50-2.70(4H, m), 2.93(2H, d, J=5.7Hz), 3.09-3.15(2H, m), 3.32-3.52(4H, m), 3.74-3.80(3H, m), 3.88(2H, s), 7.29(1H, dd, J=1.7, 6.4Hz), 7.53-7.60(2H, m), 8.27(1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:487[M+H].

Example 67

Synthesis of (2S)-[4-(3-carbamoylisoxazol-5-yl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl} acetamide

[0263] 

(67-1) Synthesis of 4-(3-ethoxycarbonylisoxazol-5-yl)-2-mercaptothiazole

[0264] By a similar method as in (1-3), the title compound (1.12 g) was obtained as a yellow solid from 5-bromoacetyl-3-ethoxycarbonylisoxazole (2.00 g) and ammonium dithiocarbamate (841 mg).

(67-2) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(3-ethoxycarbonylisoxazol-5-yl)thiazol-2-ylthio]acetamide

[0265] By a similar method as in (1-4), the title compound (1.70 g) was obtained as an orange amorphous solid from the resultant product (1.16 g) of (1-2) and the resultant product (769 mg) of (67-1).

(67-3) Synthesis of (2S)-[4-(3-carbamoylisoxazol-5-yl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0266] By a similar method as in Example 25, the title compound (270 mg) was obtained as white crystals from the resultant product (572 mg) of (67-2).
¹H-NMR(DMSO-d₆) δ 1.69-1.83(1H, m), 1.96-2.07(1H, m), 2.52(1H, d, J=11.1Hz), 2.62(1H, d, J=11.1Hz), 3.11-3.17(2H, m), 3.34-3.53(4H, m), 3.72(1H, d, J=11.1Hz), 4.04(2H, s), 7.14(1H, s), 7.25(1H, dd, J=1.8, 8.1Hz), 7.50(1H, d, J=1.8Hz), 7.56(1H, d, J=8.1Hz), 7.90(1H, brs), 8.20(1H, brs), 8.33(1H, s), 8.37(1H, dd, J=5.7, 5.7Hz).
MS (ESI)m/z:542 [M+H] .

Example 68

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(2-methoxycarbonylpropan-2-yl)thiazol-2-ylthio]acetamide

[0267] 

(68-1) Synthesis of 4-(2-methoxycarbonylpropan-2-yl)-2-mercaptothiazole

[0268] By a similar method as in (66-1), the title compound (782 mg) was obtained as a pale-yellow oil from methyl 2,2-di-methylacetoacetate (1.44 g).

(68-2) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(2-methoxycarbonylpropan-2-yl)thiazol-2-ylthio]acetamide

[0269] By a similar method as in (1-4), the title compound (1.51 g) was obtained as a pale-yellow oil from the resultant product (1.33 g) of (1-2) and the resultant product (782 mg) of (68-1).
¹H-NMR(DMSO-d₆) δ 1.48(6H, s), 1.72-1.86(1H, m), 1.98-2.11(1H, m), 2.56(1H, d, J=11.1Hz), 2.65 (1H, d, J=11.1Hz), 3.09-3.15(2H, m), 3.38-3.52(4H, m), 3.58(3H, s), 3.76 (1H, d, J=11.1Hz), 3.90(2H, s), 7.29(1H, dd, J=1.5, 8.1Hz), 7.37(1H, s), 7.54(1H, d, J=1.5Hz), 7.58 (1H, d, J=8.1Hz), 8.29(1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:532[M+H].

Example 69

Synthesis of (2S)-[4-(2-carboxypropan-2-yl)thiazol-2-yl-thio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-acetamide

[0270] 

[0271] By a similar method as in (1-5), the title compound (183 mg) was obtained as a white amorphous solid from the resultant product (440 mg) of (68-2).
¹H-NMR(DMSO-d₆) δ 1.46(6H, s), 1.73-1.87 (1H, m), 2.00-2.11 (1H, m), 2.56 (1H, d, J=11.1Hz), 2.66 (1H, d, J=11.1Hz), 3.10-3.16(2H, m), 3.38-3.52(4H, m), 3.76 (1H, d, J=11.1Hz), 3.91(2H, s), 7.30 (1H, dd, J=1.5, 8.2Hz), 7.34 (1H, s), 7.54 (1H, d, J=1.5Hz), 7.58 (1H, d, J=8.2Hz), 8.29 (1H, dd, J=5.7Hz).
MS(ESI)m/z:518[M+H].

Example 70

Synthesis of (2S)-(E)-[4-(2-carboxyethen-1-yl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-acetamide

[0272] 

(70-1) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(hydroxymethyl)thiazol-2-ylthio]acetamide

[0273] The resultant product (2.09 g) of (1-4) was dissolved in ethanol (40 mL) and tetrahydrofuran (40 mL), sodium borohydride (454 mg) was added, lithium chloride (509 mg) was further added, and the mixture was stirred at room temperature for 4.5 h. Water was poured into the reaction mixture, the organic solvent alone was evaporated under reduced pressure, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (1.53 g) as a colorless oil.

(70-2) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(4-formylthiazol-2-ylthio)acetamide

[0274] The resultant product (1.53 g) of (70-1) was dissolved in chloroform (10 mL), magnesium sulfate (500 mg) was added, manganese dioxide (1.35 g) was further added, and the mixture was stirred overnight at room temperature. Magnesium sulfate (500 mg) and manganese dioxide (1.35 g) were further added and the mixture was stirred at room temperature for 7 h. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (643 mg) as a colorless oil.

(70-3) Synthesis of (2S)-(E)-[4-(2-carboxyethen-1-yl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0275] The resultant product (643 mg) of (70-2) was dissolved in pyridine (5 mL), malonic acid (291 mg) and piperidine (14 µL) were added, and the mixture was stirred at 100°C for 3.5 h. The reaction mixture was poured into water, 1M hydrochloric acid was added to adjust to pH=4, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (618 mg) as a white amorphous solid.
¹H-NMR(DMSO-d₆) δ 1.70-1.84(1H, m), 1.98-2.10(1H, m), 2.53(1H, d, J=11.1Hz), 2.63(1H, d, J=11.1Hz), 3.11-3.17(2H, m), 3.38-3.52(4H, m), 3.75(1H, d, J=11.1Hz), 4.01(2H, s), 6.54(1H, d, J=15.3Hz), 7.28(1H, dd, J=1.5, 8.1Hz), 7.45-7.58(3H, m), 7.96(1H, s), 8.34(1H, dd, J=5.7, 5.7Hz), 12.4(1H, brs).
MS(ESI)m/z:502[M+H].

Example 71

Synthesis of (2S)-(E)-[4-(2-carbamoylethen-1-yl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl} acetamide

[0276] 

[0277] By a similar method as in Example 16, the title compound (173 mg) was obtained as a colorless oil from the resultant product (301 mg) of Example 70 and ammonium chloride (193 mg).
¹H-NMR(DMSO-d₆) δ 1.71-1.84(1H, m), 1.98-2.10(1H, m), 2.53(1H, d, J=11.7Hz), 2.63(1H, d, J=11.9Hz), 3.11-3.17(2H, m), 3.38-3.52(4H, m), 3.75(1H, d, J=11.7Hz), 3.98(2H, s), 6.74(1H, d, J=15.6Hz), 7.11(1H, brs), 7.27-7.33(2H, m), 7.52-7.60(3H, m), 7.82(1H, s), 8.31(1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:501[M+H] .

Example 72

Synthesis of (2S)-(E)-[5-(2-carboxyethen-1-yl)-4-methylthiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0278] 

(72-1) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[5-(hydroxymethyl)-4-methylthiazol-2-ylthio]acetamide

[0279] By a similar method as in (70-1), the title compound (450 mg) was obtained as a colorless oil from the resultant product (1.70 g) of (54-2).

(72-2) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(5-formyl-4-methyl-thiazol-2-ylthio)acetamide

[0280] By a similar method as in (70-2), the title compound (361 mg) was obtained as a white amorphous solid from the resultant product (450 mg) of (72-1).

(72-3) Synthesis of (2S)-(E)-[5-(2-carboxyethen-1-yl)-4-methylthiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0281] By a similar method as in (70-3), the title compound (140 mg) was obtained as a pale-yellow solid from the resultant product (361 mg) of (72-2).
¹H-NMR(DMSO-d₆) δ 1.72-1.86(1H, m), 1.98-2.10(1H, m), 2.41(3H, s), 2.55(1H, d, J=10.8Hz), 2.65(1H, d, J=10.8Hz), 3.11-3.17(2H, m), 3.38-3.52(4H, m), 3.77 (1H, d, J=10.8Hz), 4.00(2H, s), 5.91(1H, d, J=15.6Hz), 7.28(1H, d, J=8.1Hz), 7.51-7.66(3H, m), 8.37(1H, dd, J=5.7, 5.7Hz), 12.5(1H, brs).
MS(ESI)m/z:516[M+H] .

Example 73

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(1-ethoxycarbonylcyclopropan-1-yl)thiazol-2-ylthio]acetamide

[0282] 

(73-1) Synthesis of 4-(1-ethoxycarbonylcyclopropan-1-yl)-2-mercaptothiazole

[0283] By a similar method as in (1-3), the title compound (7.56 g) was obtained as a yellow oil from ethyl 1-bromoacetylcyclopropanecarboxylate (13.1 g) and ammonium dithiocarbamate (5.93 g).

(73-2) Synthesis of [4-(1-ethoxycarbonylcyclopropan-1-yl)thiazol-2-ylthio]methyl acetate

[0284] By a similar method as in (1-4), the title compound (1.61 g) was obtained as a yellow oil from the resultant product (7.56 g) of (73-1) and methyl bromoacetate (3.04 mL).

(73-3) Synthesis of [4-(1-ethoxycarbonylcyclopropan-1-yl)thiazol-2-ylthio]acetic acid

[0285] By a similar method as in (1-5), the title compound (1.06 g) was obtained as a pale-yellow oil from the resultant product (1.61 g) of (73-2).

(73-4) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(1-ethoxycarbonylcyclopropan-1-yl)thiazol-2-ylthio]acetamide

[0286] By a similar method as in Example 16, the title compound (675 mg) was obtained as a colorless oil from the resultant product (1.06 g) of (73-3) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (1.17 g).
¹H-NMR(DMSO-d₆) δ 1.15(3H, t, J=8.1Hz), 1.30-1.41(2H, m), 1.42-1.53(2H, m), 1.70-1.83(1H, m), 1.92-2.08(1H, m), 2.55(1H, d, J=10.5Hz), 2.63(1H, d, J=10.5Hz), 3.08-3.16(2H, m), 3.38-3.51(4H, m), 3.75(1H, d, J=10.5Hz), 3.90(2H, s), 3.98-4.10(2H, m), 7.29(1H, d, J=8.4Hz), 7.43-7.60(3H, m), 8.27(1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:544[M+H].

Example 74

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(1-carboxycyclopropan-1-yl)thiazol-2-ylthio]acetamide

[0287] 

[0288] By a similar method as in (1-5), the title compound (594 mg) was obtained as a white amorphous solid from the resultant product (615 mg) of (73-4).
¹H-NMR(DMSO-d₆) δ 1.34-1.38(2H, m), 1.47-1.52(2H, m), 1.70-1.84 (1H, m), 1.95-2.09 (1H, m), 2.52 (1H, d, J=10.5Hz), 2.63 (1H, d, J=10.5Hz), 3.09-3.15(2H, m), 3.38-3.52(4H, m), 3.76 (1H, d, J=10.5Hz), 3.90(2H, s), 7.29 (1H, dd, J=1.5, 8.4Hz), 7.53-7.60(3H, m), 8.27 (1H, dd, J=5.7, 5.7Hz), 12.5 (1H, s).
MS(ESI)m/z:516[M+H].

Example 75

Synthesis of (2S)-[4-(carboxymethyl)thiazol-2-ylthio]-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}acetamide

[0289] 

(75-1) Synthesis of (2S)-N-[(4-tertiary butoxycarbonyl-morpholin-2-yl)methyl]chloroacetamide

[0290] By a similar method as in (1-1), the title compound (6.15 g) was obtained as a colorless oil from 2-aminomethyl-4-tertiary butoxycarbonylmorpholine (4.65 g).

(75-2) Synthesis of (2S)-N-[(4-tertiary butoxycarbonylmorpholin-2-yl)methyl]-[4-(ethoxycarbonylmethyl)thiazol-2-ylthio]acetamide

[0291] By a similar method as in (1-4), the title compound (6.80 g) was obtained as a yellow oil from the resultant product (6.15 g) of (75-1) and the resultant product (4.48 g) of (2-1).

(75-3) Synthesis of (2S)-[4-(ethoxycarbonylmethyl)thiazol-2-ylthio]-N-[(morpholin-2-yl)methyl]acetamide

[0292] By a similar method as in (42-2), the title compound (3.96 g) was obtained as a pale-yellow oil from the resultant product (6.80 g) of (75-2).

(75-4) Synthesis of (2S)-[4-(ethoxycarbonylmethyl)thiazol-2-ylthio]-N-[(morpholin-2-yl)methyl]acetamide hydrochloride

[0293] By a similar method as in (1-2), the title compound (4.40 g) was obtained as a white amorphous solid from the resultant product (3.96 g) of (75-3).

(75-5) Synthesis of (2S)-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}-[4-(ethoxycarbonylmethyl)thiazol-2-ylthio]acetamide

[0294] Saturated aqueous sodium hydrogen carbonate was added to the resultant product (1.10 g) of (75-4), and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in methylene chloride (15 mL), 3,4-difluorobenzaldehyde (332 µL) and acetic acid (159 µL) were added and the mixture was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (1.18 g) was added to the reaction mixture, and the mixture was stirred overnight at room temperature. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and acetone as an eluent. The solvent was evaporated from the eluent to give the title compound (830 mg) as a colorless oil.

(75-6) Synthesis of (2S)-[4-(carboxymethyl)thiazol-2-ylthio]-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}acetamide

[0295] By a similar method as in (1-5), the title compound (260 mg) was obtained as a white amorphous solid from the resultant product (291 mg) of (75-5).
¹H-NMR(DMSO-d₆) δ 1.71-1.85(1H, m), 1.95-2.10(1H, m), 2.56(1H, d, J=11.1Hz), 2.65(1H, d, J=11.1Hz), 3.10-3.16(2H, m), 3.34-3.52(4H, m), 3.67(2H, s), 3.77(1H, d, J=11.1Hz), 3.92(2H, s), 7.13-7.16(1H, m), 7.29-7.42(3H, m), 8.29-8.33(1H, m).
MS(ESI)m/z:458[M+H] .

Example 76

Synthesis of (2S)-[4-(carboxymethyl)thiazol-2-ylthio]-N-{[4-(3-chloro-4-fluorobenzyl)morpholin-2-yl]methyl}acetamide

[0296] 

(76-1) Synthesis of (2S)-N-{[4-(3-chloro-4-fluorobenzyl) morpholin-2-yl]methyl}-[4-(ethoxycarbonylmethyl)thiazol-2-ylthio]acetamide

[0297] By a similar method as in (75-5), the title compound (719 mg) was obtained as a colorless oil from the resultant product (792 mg) of (75-4) and 3-chloro-4-fluorobenzaldehyde (349 mg).

(76-2) Synthesis of (2S)-[4-(carboxymethyl)thiazol-2-ylthio]-N-{[4-(3-chloro-4-fluorobenzyl)morpholin-2-yl]methyl}acetamide

[0298] By a similar method as in (1-5), the title compound (633 mg) was obtained as a white amorphous solid from the resultant product (719 mg) of (76-1).
¹H-NMR(DMSO-d₆) δ 1.73-1.89(1H, m), 1.92-2.11(1H, m), 2.50-2.69(2H, m), 3.10-3.16(2H, m), 3.34-3.52(4H, m), 3.67(2H, s), 3.77(1H, d, J=11.1Hz), 3.93(2H, s), 7.25-7.60(4H, m), 8.29-8.35(1H, m).
MS(ESI)m/z:474[M+H].

Example 77

Synthesis of (2S)-[4-(carboxymethyl)thiazol-2-ylthio]-N-{[4-(4-chloro-3-fluorobenzyl)morpholin-2-yl]methyl}acetamide

[0299] 

(77-1) Synthesis of (2S)-N-{[4-(4-chloro-3-fluorobenzyl) morpholin-2-yl]methyl}-[4-(ethoxycarbonylmethyl)thiazol-2-ylthio]acetamide

[0300] By a similar method as in (75-5), the title compound (735 mg) was obtained as a colorless oil from the resultant product (792 mg) of (75-4) and 4-chloro-3-fluorobenzaldehyde (349 mg).

(77-2) Synthesis of (2S)-[4-(carboxymethyl)thiazol-2-ylthio]-N-{[4-(4-chloro-3-fluorobenzyl)morpholin-2-yl]methyl}acetamide

[0301] By a similar method as in (1-5), the title compound (621 mg) was obtained as a white amorphous solid from the resultant product (735 mg) of (77-1).
¹H-NMR(DMSO-d₆) δ 1.70-1.88(1H, m), 1.95-2.11(1H, m), 2.56(1H, d, J=11.1Hz), 2.65(1H, d, J=11.1Hz), 3.10-3.16(2H, m), 3.34-3.52(4H, m), 3.67(2H, s), 3.77(1H, d, J=11.1Hz), 3.92(2H, s), 7.17(1H, d, J=8.1Hz), 7.33(1H, d, J=10.5Hz), 7.38(1H, s), 7.53(1H, t, J=8.1Hz), 8.29-8.32(1H, m).
MS(ESI)m/z:474[M+H] .

Example 78

Synthesis of (2S)-[4-(carboxymethyl)thiazol-2-ylthio]-N-{[4-(6-fluoronaphthyl-2-ylmethyl)morpholin-2-yl]methyl}-acetamide

[0302] 

(78-1) Synthesis of (2S)-[4-(ethoxycarbonylmethyl)thiazol-2-ylthio]-N-{[4-(6-fluoronaphthyl-2-ylmethyl)morpholin-2-yl]methyl}acetamide

[0303] By a similar method as in (75-5), the title compound (762 mg) was obtained as a colorless oil from the resultant product (792 mg) of (75-4) and 6-fluoro-2-naphtoaldehyde (383 mg).

(78-2) Synthesis of (2S)-[4-(carboxymethyl)thiazol-2-ylthio]-N-{[4-(6-fluoronaphthyl-2-ylmethyl)morpholin-2-yl]methyl}acetamide

[0304] By a similar method as in (1-5), the title compound (686 mg) was obtained as a white amorphous solid from the resultant product (762 mg) of (78-1).
¹H-NMR(DMSO-d₆) δ 1.73-1.89(1H, m), 1.92-2.11(1H, m), 2.52-2.76(2H, m), 3.10-3.16(2H, m), 3.34-3.52(4H, m), 3.67(2H, s), 3.77 (1H, d, J=11.1Hz), 3.91(2H, s), 7.36 (1H, s), 7.37-7.44 (1H, m), 7.53 (1H, d, J=8.4Hz), 7.68 (1H, d, J=8.4Hz), 7.83-7.90(2H, m), 7.95-8.01 (1H, m), 8.29-8.32 (1H, m). MS(ESI)m/z:490[M+H] .

Example 79

Synthesis of (2S)-[4-(carbamoylmethyl)thiazol-2-ylthio]-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}acetamide

[0305] 

[0306] By a similar method as in Example 16, the title compound (301 mg) was obtained as white crystals from the resultant product (458 mg) of (75-6) and ammonium chloride (321 mg).
¹H-NMR(DMSO-d₆) δ 1.71-1.84(1H, m), 1.94-2.09(1H, m), 2.55(1H, d, J=11.1Hz), 2.64(1H, d, J=11.1Hz), 3.10-3.17(2H, m), 3.38-3.52(6H, m), 3.76(1H, d, J=11.1Hz), 3.92(2H, s), 6.99(1H, brs), 7.10-7.16(1H, m), 7.31-7.42(4H, m), 8.30(1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:457[M+H].

Example 80

Synthesis of (2S)-[4-(carbamoylmethyl)thiazol-2-ylthio]-N-{[4-(3-chloro-4-fluorobenzyl)morpholin-2-yl]methyl}acetamide

[0307] 

[0308] By a similar method as in Example 16, the title compound (409 mg) was obtained as a colorless oil from the resultant product (443 mg) of (76-2) and ammonium chloride (300 mg).
¹H-NMR(DMSO-d₆) δ 1.71-1.85(1H, m), 1.94-2.09(1H, m), 2.55(1H, d, J=11.1Hz), 2.64(1H, d, J=11.1Hz), 3.09-3.17(2H, m), 3.38-3.52(6H, m), 3.76(1H, d, J=11.1Hz), 3.92(2H, s), 6.99(1H, brs), 7.27-7.41(4H, m), 7.48(1H, dd, J=1.8, 7.2Hz), 8.30(1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:473[M+H].

Example 81

Synthesis of (2S)-[4-(carbamoylmethyl)thiazol-2-ylthio]-N-{[4-(4-chloro-3-fluorobenzyl)morpholin-2-yl]methyl}acetamide

[0309] 

[0310] By a similar method as in Example 16, the title compound (403 mg) was obtained as a white solid from the resultant product (424 mg) of (77-2) and ammonium chloride (287 mg).
¹H-NMR (DMSO-d₆) δ 1.71-1.84(1H, m), 1.94-2.09(1H, m), 2.56(1H, d, J=11.1Hz), 2.64(1H, d, J=11.1Hz), 3.10-3.17(2H, m), 3.38-3.52(6H, m), 3.76(1H, d, J=11.1Hz), 3.92(2H, s), 6.99(1H, brs), 7.17(1H, dd, J=1.4, 8.2Hz), 7.31(1H, s), 7.34(1H, d, J=1.4Hz), 7.39(1H, brs), 7.53(1H, t, J=8.2Hz), 8.29(1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:473[M+H].

Example 82

Synthesis of (2S)-[4-(carbamoylmethyl)thiazol-2-ylthio]-N-{[4-(6-fluoronaphthyl-2-ylmethyl)morpholin-2-yl]methyl}-acetamide

[0311] 

[0312] By a similar method as in Example 16, the title compound (387 mg) was obtained as a white amorphous solid from the resultant product (462 mg) of (78-2) and ammonium chloride (303 mg).
¹H-NMR(DMSO-d₆) δ 1.76-1.90(1H, m), 1.99-2.13 (1H, m), 2.60(1H, d, J=11.2Hz), 2.70(1H, d, J=11.2Hz), 3.09-3.17(2H, m), 3.40-3.54(4H, m), 3.59(2H, s), 3.76(1H, d, J=11.2Hz), 3.91(2H, s), 6.98(1H, brs), 7.30(1H, s), 7.32-7.43(2H, m), 7.52(1H, d, J=8.5Hz), 7.68(1H, dd, J=2.6, 10.4Hz), 7.78-7.89(2H, m), 7.91-8.02(1H, m), 8.29(1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:489[M+H].

Example 83

Synthesis of (2S)-[4-(carboxymethyl)thiazol-2-ylthio]-N-{[4-(3-chlorobenzyl)morpholin-2-yl]methyl}acetamide

[0313] 

(83-1) Synthesis of (2S)-N-{[4-(3-chlorobenzyl)morpholin-2-yl]methyl}chloroacetamide

[0314] By a similar method as in (1-1), the title compound (13.4 g) was obtained as a yellow oil from (2S)-2-aminomethyl-4-(3-chlorobenzyl)morpholine dihydrochloride (12.5 g).

(83-2) Synthesis of (2S)-N-{[4-(3-chlorobenzyl)morpholin-2-yl]methyl}-[4-(ethoxycarbonylmethyl)thiazol-2-ylthio]acetamide

[0315] By a similar method as in (1-4), the title compound (1.01 g) was obtained as a pale-yellow oil from the resultant product (1.27 g) of (83-1) and the resultant product (813 mg) of (2-1).

(83-3) Synthesis of (2S)-[4-(carboxymethyl)thiazol-2-ylthio]-N-{[4-(3-chlorobenzyl)morpholin-2-yl]methyl}acetamide

[0316] By a similar method as in (1-5), the title compound (850 mg) was obtained as a white amorphous solid from the resultant product (1.01 g) of (83-2).
¹H-NMR(DMSO-d₆) δ 1.71-2.20(2H, m), 2.53-2.79(2H, m), 3.10-3.17(2H, m), 3.34-3.52(4H, m), 3.67(2H, s), 3.79(1H, d, J=10.7Hz), 3.93(2H, s), 7.20-7.42(5H, m), 8.25-8.36(1H, m).
MS(ESI)m/z:456[M+H].

Example 84

Synthesis of (2S)-[4-(carbamoylmethyl)thiazol-2-ylthio]-N-{[4-(3-chlorobenzyl)morpholin-2-yl]methyl}acetamide

[0317] 

[0318] By a similar method as in Example 16, the title compound (425 mg) was obtained as a colorless oil from the resultant product (456 mg) of (83-3) and ammonium chloride (321 1 mg).
H-NMR(DMSO-d₆) δ 1.71-1.85(1H, m), 1.94-2.09(1H, m), 2.55(1H, d, J=11.1Hz), 2.65(1H, d, J=11.1Hz), 3.09-3.17(2H, m), 3.38-3.52(6H, m), 3.76(1H, d, J=11.1Hz), 3.91(2H, s), 6.97(1H, brs), 7.20-7.41(6H, m), 8.28(1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:455[M+H] .

Example 85

Synthesis of (2S)-[4-(carboxymethyl)thiazol-2-ylthio]-N-{[4-(4-chlorobenzyl)morpholin-2-yl]methyl}acetamide

[0319] 

(85-1) Synthesis of (2S)-N-{[4-(4-chlorobenzyl)morpholin-2-yl]methyl}-[4-(ethoxycarbonylmethyl)thiazol-2-ylthio]-acetamide

[0320] The resultant product (899 mg) of (75-3) was dissolved in methylene chloride (12.5 mL), 4-chlorobenzaldehyde (387 mg) and acetic acid (143 µL) were added and the mixture was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (1.06 g) was added to the reaction mixture and the mixture was further stirred overnight at room temperature. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and acetone as an eluent. The solvent was evaporated from the eluent to give the title compound (1.16 g) as a pale-yellow oil.

(85-2) Synthesis of (2S)-[4-(carboxymethyl)thiazol-2-yl-thio]-N-{[4-(4-chlorobenzyl)morpholin-2-yl]methyl}acetamide

[0321] By a similar method as in (1-5), the title compound (904 mg) was obtained as a white amorphous solid from the resultant product (1.16 g) of (85-1).
¹H-NMR(DMSO-d₆) δ 1.68-1.88(1H, m), 1.95-2.10(1H, m), 2.50-2.70(2H, m), 3.09-3.17(2H, m), 3.34-3.52(4H, m), 3.67(2H, s), 3.77(1H, d, J=11.2Hz), 3.92(2H, s), 7.28-7.42(5H, m), 8.32(1H, dd, J=5.5, 5.5Hz).
MS(ESI)m/z:456[M+H].

Example 86

Synthesis of (2S)-[4-(carboxymethyl)thiazol-2-ylthio]-N-{[4-(2,3-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0322] 

(86-1) Synthesis of (2S)-N-{[4-(2,3-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(ethoxycarbonylmethyl)thiazol-2-ylthio]acetamide

[0323] By a similar method as in (85-1), the title compound (908 mg) was obtained as a colorless oil from the resultant product (899 mg) of (75-3) and 2,3-dichlorobenzaldehyde (481 mg).

(86-2) Synthesis of (2S)-[4-(carboxymethyl)thiazol-2-ylthio]-N-{[4-(2,3-dichlorobenzyl)morpholin-2-yl]methyl} acetamide

[0324] By a similar method as in (1-5), the title compound (650 mg) was obtained as a white amorphous solid from the resultant product (908 mg) of (86-1).
¹H-NMR(DMSO-d₆) δ 1.81-1.96(1H, m), 2.07-2.21(1H, m), 2.53-2.75(2H, m), 3.10-3.19(2H, m), 3.34-3.52(4H, m), 3.67(2H, s), 3.70-3.80(1H, m), 3.93(2H, s), 7.32-7.38(2H, m), 7.46(1H, dd, J=1.5, 7.8Hz), 7.56(1H, dd, J=1.5, 7.8Hz), 8.32(1H, dd, J=5.7, 5.7Hz), 12.3(1H, brs).
MS(ESI)m/z:490[M+H] .

Example 87

Synthesis of (2S)-[4-(carboxymethyl)thiazol-2-ylthio]-N-{[4-(2,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0325] 

(87-1) Synthesis of (2S)-N-{[4-(2,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(ethoxycarbonylmethyl)thiazol-2-ylthio]acetamide

[0326] By a similar method as in (85-1), the title compound (1.13 g) was obtained as a colorless oil from the resultant product (899 mg) of (75-3) and 2,4-dichlorobenzaldehyde (481 mg).

(87-2) Synthesis of (2S)-[4-(carboxymethyl)thiazol-2-ylthio]-N-{[4-(2,4-dichlorobenzyl)morpholin-2-yl]methyl} acetamide

[0327] By a similar method as in (1-5), the title compound (799 mg) was obtained as a white amorphous solid from the resultant product (1.13 g) of (87-1).
¹H-NMR(DMSO-d6) δ 1.80-1.93(1H, m), 2.07-2.21(1H, m), 2.59(1H, d, J=10.8Hz), 2.68(1H, d, J=10.8Hz), 3.09-3.19(2H, m), 3.34-3.52(4H, m), 3.67(2H, s), 3.78 (1H, d, J=10.8Hz), 3.93(2H, s), 7.36-7.44(2H, m), 7.49 (1H, d, J=8.4Hz), 7.59 (1H, d, J=2.1Hz), 8.31 (1H, dd, J=5.7, 5.7Hz), 12.4 (1H, brs).
MS(ESI)m/z:490[M+H].

Example 88

Synthesis of (2S)-[4-(carboxymethyl)thiazol-2-ylthio]-N-{[4-(3,5-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0328] 

(88-1) Synthesis of (2S)-N-{[4-(3,5-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(ethoxycarbonylmethyl)thiazol-2-ylthio]acetamide

[0329] By a similar method as in (85-1), the title compound (874 mg) was obtained as a colorless oil from the resultant product (899 mg) of (75-3) and 3,5-dichlorobenzaldehyde (481 mg).

(88-2) Synthesis of (2S)-[4-(carboxymethyl)thiazol-2-ylthio]-N-{[4-(3,5-dichlorobenzyl)morpholin-2-yl]methyl} acetamide

[0330] By a similar method as in (1-5), the title compound (615 mg) was obtained as a white amorphous solid from the resultant product (874 mg) of (88-1).
¹_H-NMR(DMSO-d₆) δ 1.71-1.89(1H, m), 1.96-2.11(1H, m), 2.55(1H, d, J=11.1Hz), 2.65(1H, d, J=11.1Hz), 3.09-3.17(2H, m), 3.34-3.52(4H, m), 3.67(2H, s), 3.77(1H, d, J=11.1Hz), 3.92(2H, s), 7.34-7.38(3H, m), 7.49(1H, dd, J=1.5, 1.5Hz), 8.30(1H, dd, J=5.7, 5.7Hz), 12.4(1H, brs).
MS(ESI)m/z:490[M+H].

Example 89

Synthesis of (2S)-[4-(carboxymethyl)thiazol-2-ylthio]-N-{[4-(3-chloro-2-fluorobenzyl)morpholin-2-yl]methyl}acetamide

[0331] 

(89-1) Synthesis of (2S)-N-{[4-(3-chloro-2-fluorobenzyl) morpholin-2-yl]methyl}-[4-(ethoxycarbonylmethyl)thiazol-2-ylthio]acetamide

[0332] By a similar method as in (85-1), the title compound (980 mg) was obtained as a colorless oil from the resultant product (899 mg) of (75-3) and 3-chloro-2-fluorobenzaldehyde (436 mg).

(89-2) Synthesis of (2S)-[4-(carboxymethyl)thiazol-2-ylthio]-N-{[4-(3-chloro-2-fluorobenzyl)morpholin-2-yl]methyl}acetamide

[0333] By a similar method as in (1-5), the title compound (823 mg) was obtained as a white amorphous solid from the resultant product (980 mg) of (89-1).
¹H-NMR(DMSO-d₆) δ 1.75-1.90(1H, m), 1.99-2.16(1H, m), 2.57(1H, d, J=11.1Hz), 2.68(1H, d, J=11.1Hz), 3.09-3.18(2H, m), 3.34-3.52(4H, m), 3.67(2H, s), 3.76(1H, d, J=11.1Hz), 3.92(2H, s), 7.16-7.24(1H, m), 7.33-7.40(2H, m), 7.45-7.53(1H, m), 8.30(1H, dd, J=5.7, 5.7Hz), 12.4 (1H, brs).
MS(ESI)m/z:474[M+H] .

Example 90

Synthesis of (2S)-[4-(carboxymethyl)thiazol-2-ylthio]-N-{[4-(3-chloro-4-methylbenzyl)morpholin-2-yl]methyl} acetamide

[0334] 

(90-1) Synthesis of (2S)-N-{[4-(3-chloro-4-methylbenzyl) morpholin-2-yl]methyl}-[4-(ethoxycarbonylmethyl)thiazol-2-ylthio]acetamide

[0335] By a similar method as in (85-1), the title compound (1.15 g) was obtained as a colorless oil from the resultant product (899 mg) of (75-3) and 3-chloro-4-methylbenzaldehyde (425 mg).

(90-2) Synthesis of (2S)-[4-(carboxymethyl)thiazol-2-ylthio]-N-{[4-(3-chloro-4-methylbenzyl)morpholin-2-yl]methyl}acetamide

[0336] By a similar method as in (1-5), the title compound (884 mg) was obtained as a white amorphous solid from the resultant product (1.15 g) of (90-1).
¹H-NMR(DMSO-d₆) δ 1.70-1.83(1H, m), 1.92-2.10(1H, m), 2.30(3H, s), 2.55(1H, d, J=11.1Hz), 2.65(1H, d, J=11.1Hz), 3.08-3.18(2H, m), 3.34-3.52(4H, m), 3.67(2H, s), 3.76(1H, d, J=11.1Hz), 3.92(2H, s), 7.12-7.18(1H, m), 7.26-7.32(2H, m), 7.37(1H, s), 8.30(1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:470[M+H] .

Example 91

Synthesis of (2S)-[4-(carboxymethyl)thiazol-2-ylthio]-N-{[4-(3-chloro-4-methoxybenzyl)morpholin-2-yl]methyl} acetamide

[0337] 

(91-1) Synthesis of (2S)-N-{[4-(3-chloro-4-methoxybenzyl) morpholin-2-yl]methyl}-[4-(ethoxycarbonylmethyl)thiazol-2-ylthio]acetamide

[0338] By a similar method as in (85-1), the title compound (1.28 g) was obtained as a colorless oil from the resultant product (899 mg) of (75-3) and 3-chloro-4-methoxybenzaldehyde (469 mg).

(91-2) Synthesis of (2S)-[4-(carboxymethyl)thiazol-2-ylthio]-N-{[4-(3-chloro-4-methoxybenzyl)morpholin-2-yl]-methyl}acetamide

[0339] By a similar method as in (1-5), the title compound (1.01 g) was obtained as a white amorphous solid from the resultant product (1.28 g) of (91-1).
¹H-NMR(DMSO-d₆) δ 1.67-1.80(1H, m), 1.92-2.10(1H, m), 2.50-2.65(2H, m), 3.09-3.17(2H, m), 3.34-3.52(4H, m), 3.67(2H, s), 3.73-3.77(1H, m), 3.83(3H, s), 3.92(2H, s), 7.09(1H, d, J=8.4Hz), 7.21 (1H, dd, J=1.8, 8.4Hz), 7.32(1H, d, J=1.8Hz), 7.37(1H, s), 8.30 (1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:486[M+H].

Example 92

Synthesis of (2S)-[4-(carboxymethyl)thiazol-2-ylthio]-N-{[4-(4-chloro-3-trifluoromethylbenzyl)morpholin-2-yl]methyl}acetamide

[0340] 

(92-1) Synthesis of (2S)-N-{[4-(4-chloro-3-trifluoromethylbenzyl)morpholin-2-yl]methyl}-[4-(ethoxycarbonylmethyl)thiazol-2-ylthio]acetamide

[0341] By a similar method as in (85-1), the title compound (663 mg) was obtained as a colorless oil from the resultant product (899 mg) of (75-3) and 4-chloro-3-trifluoromethyl-benzaldehyde (396 µL).

(92-2) Synthesis of (2S)-[4-(carboxymethyl)thiazol-2-yl-thio]-N-{[4-(4-chloro-3-trifluoromethylbenzyl)morpholin-2-yl]methyl}acetamide

[0342] By a similar method as in (1-5), the title compound (419 mg) was obtained as a white amorphous solid from the resultant product (663 mg) of (92-1).
¹H-NMR(DMSO-d₆) δ 1.72-1.88(1H, m), 1.99-2.14(1H, m), 2.50-2.66(2H, m), 3.09-3.17(2H, m), 3.34-3.52(4H, m), 3.67(2H, s), 3.73-3.77(1H, m), 3.92(2H, s), 7.37(1H, s), 7.62(1H, dd, J=1.5, 8.1Hz), 7.68(1H, d, J=8.1Hz), 7.75(1H, d, J=1.5Hz), 8.30(1H, dd, J=5.7, 5.7Hz), 12.3(1H, brs). MS(ESI)m/z:524[M+H].

Example 93

Synthesis of (2S)-[4-(carboxymethyl)thiazol-2-ylthio]-N-{[4-(2,4-difluorobenzyl)morpholin-2-yl]methyl}acetamide

[0343] 

(93-1) Synthesis of (2S)-N-{[4-(2,4-difluorobenzyl)morpholin-2-yl]methyl}-[4-(ethoxycarbonylmethyl)thiazol-2-ylthio]acetamide

[0344] By a similar method as in (85-1), the title compound (1.02 g) was obtained as a colorless oil from the resultant product (899 mg) of (75-3) and 2,4-difluorobenzaldehyde (301 µL).

(93-2) Synthesis of (2S)-[4-(carboxymethyl)thiazol-2-ylthio]-N-{[4-(2,4-difluorobenzyl)morpholin-2-yl]methyl}acetamide

[0345] By a similar method as in (1-5), the title compound (791 mg) was obtained as a white amorphous solid from the resultant product (1.02 g) of (93-1).
¹H-NMR(DMSO-d₆) δ 1.71-1.88(1H, m), 1.99-2.11(1H, m), 2.51-2.66(2H, m), 3.06-3.18(2H, m), 3.34-3.52(4H, m), 3.67(2H, s), 3.73-3.78(1H, m), 3.92(2H, s), 6.98-7.10(1H, m), 7.12-7.23(1H, m), 7.37(1H, s), 7.38-7.46(1H, m), 8.30(1H, dd, J=5.4, 5.4Hz), 12.4(1H, brs).
MS(ESI)m/z:458[M+H] .

Example 94

Synthesis of (2S)-[4-(carboxymethyl)thiazol-2-ylthio]-N-{[4-(3-fluorobenzyl)morpholin-2-yl]methyl}acetamide

[0346] 

(94-1) Synthesis of (2S)-[4-(ethoxycarbonylmethyl)thiazol-2-ylthio]-N-{[4-(3-fluorobenzyl)morpholin-2-yl]methyl} acetamide

[0347] By a similar method as in (85-1), the title compound (1.05 g) was obtained as a colorless oil from the resultant product (899 mg) of (75-3) and 3-fluorobenzaldehyde (292 µL).

(94-2) Synthesis of (2S)-[4-(carboxymethyl)thiazol-2-ylthio]-N-{[4-(3-fluorobenzyl)morpholin-2-yl]methyl}-acetamide

[0348] By a similar method as in (1-5), the title compound (768 mg) was obtained as a white amorphous solid from the resultant product (1.05 g) of (94-1).
¹H-NMR(DMSO-d₆) δ 1.70-1.91(1H, m), 1.92-2.10(1H, m), 2.50-2.78(2H, m), 3.07-3.19(2H, m), 3.34-3.52(4H, m), 3.67(2H, s), 3.77(1H, d, J=11.0Hz), 3.93(2H, s), 7.00-7.21(3H, m), 7.29-7.41(2H, m), 8.29-8.35 (1H, m).
MS (ESI)m/z:440 [M+H] .

Example 95

Synthesis of (2S)-[4-(carboxymethyl)thiazol-2-ylthio]-N-{[4-(4-fluorobenzyl)morpholin-2-yl]methyl}acetamide

[0349] 

(95-1) Synthesis of (2S)-[4-(ethoxycarbonylmethyl)thiazol-2-ylthio]-N-{[4-(4-fluorobenzyl)morpholin-2-yl]methyl}-acetamide

[0350] By a similar method as in (85-1), the title compound (999 mg) was obtained as a colorless oil from the resultant product (899 mg) of (75-3) and 4-fluorobenzaldehyde (294 [µL).

(95-2) Synthesis of (2S)-[4-(carboxymethyl)thiazol-2-yl-thio]-N-{[4-(4-fluorobenzyl)morpholin-2-yl]methyl}acetamide

[0351] By a similar method as in (1-5), the title compound (753 mg) was obtained as a white amorphous solid from the resultant product (999 mg) of (95-1).
¹H-NMR(DMSO-d₆) δ 1.70-1.89(1H, m), 1.92-2.11(1H, m), 2.56(1H, d, J=10.8Hz), 2.66(1H, d, J=10.8Hz), 3.08-3.16(2H, m), 3.34-3.52(4H, m), 3.67(2H, s), 3.76(1H, d, J=10.8Hz), 3.93(2H, s), 7.10-7.18(2H, m), 7.30-7.38(3H, m), 8.31(1H, dd, J=5.7, 5.7Hz).
MS (ESI)m/z: 440 [M+H] .

Example 96

Synthesis of (2S)-[4-(carboxymethyl)thiazol-2-ylthio]-N-{[4-(4-fluoro-3-trifluoromethylbenzyl)morpholin-2-yl]methyl}acetamide

[0352] 

(96-1) Synthesis of (2S)-N-{[4-(4-fluoro-3-trifluoromethylbenzyl)morpholin-2-yl]methyl}-[4-(ethoxycarbonylmethyl)thiazol-2-ylthio]acetamide

[0353] By a similar method as in (85-1), the title compound (690 mg) was obtained as a colorless oil from the resultant product (899 mg) of (75-3) and 4-fluoro-3-trifluoro-methylbenzaldehyde (528 mg).

(96-2) Synthesis of (2S)-[4-(carboxymethyl)thiazol-2-ylthio]-N-{[4-(4-fluoro-3-trifluoromethylbenzyl)morpholin-2-yl]methyl}acetamide

[0354] By a similar method as in (1-5), the title compound (616 mg) was obtained as a white amorphous solid from the resultant product (690 mg) of (96-1).
¹H-NMR(DMSO-d₆) δ 1.71-1.91(1H, m), 1.92-2.09(1H, m), 2.50-2.79(2H, m), 3.06-3.18(2H, m), 3.34-3.52(4H, m), 3.67(2H, s), 3.78(1H, d, J=10.8Hz), 3.93(2H, s), 7.37(1H, s), 7.43-7.52(1H, m), 7.58-7.77(2H, m), 8.23-8.35(1H, m).
MS(ESI)m/z:508[M+H].

Example 97

Synthesis of (2S)-[4-(carbamoylmethyl)thiazol-2-ylthio]-N-{[4-(4-chlorobenzyl)morpholin-2-yl]methyl}acetamide

[0355] 

[0356] By a similar method as in Example 16, the title compound (573 mg) was obtained as a white amorphous solid from the resultant product (751 mg) of (85-2) and ammonium chloride (528 mg).
¹H-NMR(DMSO-d6₎ δ 1.69-1.82(1H, m), 1.94-2.09(1H, m), 2.54(1H, d, J=11.1Hz), 2.64(1H, d, J=11.1Hz), 3.08-3.18(2H, m), 3.38-3.52(6H, m), 3.76(1H, d, J=11.1Hz), 3.91(2H, s), 6.97(1H, brs), 7.25-7.41(6H, m), 8.28(1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:455[M+H].

Example 98

Synthesis of (2S)-[4-(carbamoylmethyl)thiazol-2-ylthio]-N-{[4-(2,3-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0357] 

[0358] By a similar method as in Example 16, the title compound (402 mg) was obtained as a white amorphous solid from the resultant product (517 mg) of (86-2) and ammonium chloride (338 mg).
¹H-NMR(DMSO-d₆) δ 1.81-1.95 (1H, m), 2.06-2.20 (1H, m), 2.59 (1H, d, J=11.4Hz), 2.68 (1H, d, J=11.4Hz), 3.09-3.18(2H, m), 3.38-3.52(4H, m), 3.57(2H, s), 3.78 (1H, d, J=11.4Hz), 3.92(2H, s), 6.97 (1H, brs), 7.27-7.40(3H, m), 7.46 (1H, d, J=7.2Hz), 7.55 (1H, d, J=7.2Hz), 8.28 (1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:489[M+H].

Example 99

Synthesis of (2S)-[4-(carbamoylmethyl)thiazol-2-ylthio]-N-{[4-(2,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0359] 

[0360] By a similar method as in Example 16, the title compound (347 mg) was obtained as white crystals from the resultant product (440 mg) of (87-2) and ammonium chloride (288 mg).
¹H-NMR(DMSO-d₆) δ 1.80-1.91(1H, m), 2.04-2.19(1H, m), 2.58(1H, d, J=11.2Hz), 2.67(1H, d, J=11.2Hz), 3.09-3.18(2H, m), 3.38-3.55(6H, m), 3.77(1H, d, J=11.2Hz), 3.92(2H, s), 6.97(1H, brs), 7.30(1H,s), 7.32-7.42(2H, m), 7.49(1H, d, J=8.3Hz), 7.58(1H, d, J=2.0Hz), 8.28(1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:489[M+H].

Example 100

Synthesis of (2S)-[4-(carbamoylmethyl)thiazol-2-ylthio]-N-{[4-(3,5-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0361] 

[0362] By a similar method as in Example 16, the title compound (372 mg) was obtained as a colorless oil from the resultant product (615 mg) of (88-2) and ammonium chloride (402 mg).
¹H-N_MR(DMS_O-d₆) δ 1.74-1.85(1H, m), 1.97-2.10(1H, m), 2.55(1H, d, J=11.1Hz), 2.65(1H, d, J=11.1Hz), 3.10-3.18(2H, m), 3.38-3.56(6H, m), 3.76(1H, d, J=11.1Hz), 3.92(2H, s), 6.97(1H, brs), 7.30-7.41(4H, m), 7.48(1H, d, J=1.9Hz), 8.28(1H, dd, J=5.7, 5.7Hz).
MS (ESI)m/z: 489 [M+H] .

Example 101

Synthesis of (2S)-[4-(carbamoylmethyl)thiazol-2-ylthio]-N-{[4-(3-chloro-2-fluorobenzyl)morpholin-2-yl]methyl}acetamide

[0363] 

[0364] By a similar method as in Example 16, the title compound (470 mg) was obtained as a pale-yellow oil from the resultant product (547 mg) of (89-2) and ammonium chloride (370 mg).
¹H-NMR(DMSO-d₆) δ 1.77-1.89(1H, m), 1.99-2.10(1H, m), 2.57 (1H, d, J=11.1Hz), 2.67(1H, d, J=11.1Hz), 3.09-3.18(2H, m), 3.38-3.55(6H, m), 3.76(1H, d, J=11.1Hz), 3.92(2H, s), 6.97(1H, brs), 7.17-7.24(1H, m), 7.30(1H, s), 7.32-7.41(2H, m), 7.42-7.51(1H, m), 8.28(1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:473[M+H].

Example 102

Synthesis of (2S)-[4-(carbamoylmethyl)thiazol-2-ylthio]-N-{[4-(3-chloro-4-methylbenzyl)morpholin-2-yl]methyl}acetamide

[0365] 

[0366] By a similar method as in Example 16, the title compound (438 mg) was obtained as a colorless oil from the resultant product (589 mg) of (90-2) and ammonium chloride (402 mg).
¹H-NMR(DMSO-d₆) δ 1.69-1.81(1H, m), 1.94-2.08(1H, m), 2.30(3H, s), 2.55(1H, d, J=11.1Hz), 2.64(1H, d, J=11.1Hz), 3.08-3.16(2H, m), 3.38-3.52(6H, m), 3.75(1H, d, J=11.1Hz), 3.91(2H, s), 6.96 (1H, brs), 7.15 (1H, d, J=7.5Hz), 7.21-7.31(3H, m), 7.37 (1H, brs), 8.28 (1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:469[M+H] .

Example 103

Synthesis of (2S)-[4-(carbamoylmethyl)thiazol-2-ylthio]-N-{[4-(3-chloro-4-methoxybenzyl)morpholin-2-yl]methyl}-acetamide

[0367] 

[0368] By a similar method as in Example 16, the title compound (590 mg) was obtained as a colorless oil from the resultant product (587 mg) of (91-2) and ammonium chloride (388 mg).
¹H-NMR(DMSO-d₆) δ 1.69-1.80(1H, m), 1.94-2.06(1H, m), 2.54(1H, d, J=11.1Hz), 2.64(1H, d, J=11.1Hz), 3.08-3.15(2H, m), 3.38-3.52(6H, m), 3.75(1H, d, J=11.1Hz), 3.83(3H, s), 3.92(2H, s), 6.98(1H, brs), 7.09(1H, d, J=8.4Hz), 7.21(1H, dd, J=1.8, 8.4Hz), 7.30-7.33(2H, m), 7.38(1H, brs), 8.29(1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:485[M+H] .

Example 104

Synthesis of (2S)-[4-(carbamoylmethyl)thiazol-2-ylthio]-N-{[4-(4-chloro-3-trifluoromethylbenzyl)morpholin-2-yl]-methyl}acetamide

[0369] 

[0370] By a similar method as in Example 16, the title compound (207 mg) was obtained as a white amorphous solid from the resultant product (254 mg) of (92-2) and ammonium chloride (156 mg).
¹H-NMR(DMSO-d₆) δ 1.75-1.86(1H, m), 2.00-2.11(1H, m), 2.55(1H, d, J=11.1Hz), 2.65(1H, d, J=11.1Hz), 3.09-3.16(2H, m), 3.40-3.52(6H, m), 3.77(1H, d, J=11.1Hz), 3.91(2H, s), 6.98(1H, brs), 7.31(1H, s), 7.38(1H, brs), 7.62(1H, d, J=8.1Hz), 7.69 (1H, d, J=8.1Hz), 7.75(1H, s), 8.29(1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:523[M+H] .

Example 105

Synthesis of (2S)-[4-(carbamoylmethyl)thiazol-2-ylthio]-N-{[4-(2,4-difluorobenzyl)morpholin-2-yl]methyl}acetamide

[0371] 

[0372] By a similar method as in Example 16, the title compound (581 mg) was obtained as a pale-yellow oil from the resultant product (651 mg) of (93-2) and ammonium chloride (457 mg).
¹H-NMR(DMSO-d₆) δ 1.73-1.83(1H, m), 1.99-2.10(1H, m), 2.56(1H, d, J=11.4Hz), 2.66(1H, d, J=11.4Hz), 3.08-3.16(2H, m), 3.39-3.52(6H, m), 3.76(1H, d, J=11.4Hz), 3.92(2H, s), 6.98(1H, brs), 7.01-7.11(1H, m), 7.15-7.23(1H, m), 7.31(1H, s), 7.32-7.48(2H, m), 8.29(1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:457[M+H].

Example 106

Synthesis of (2S)-[4-(carbamoylmethyl)thiazol-2-ylthio]-N-{[4-(3-fluorobenzyl)morpholin-2-yl]methyl}acetamide

[0373] 

[0374] By a similar method as in Example 16, the title compound (379 mg) was obtained as a white amorphous solid from the resultant product (450 mg) of (94-2) and ammonium chloride (329 mg).
¹H-NMR(DMSO-d₆) δ 1.71-1.83(1H, m), 1.94-2.09(1H, m), 2.56(1H, d, J=10.8Hz), 2. 66 (1H, d, J=10.8Hz), 3.07-3.17(2H, m), 3.39-3.53(6H, m), 3.76(1H, d, J=10.8Hz), 3.92(2H, s), 6.98(1H, brs), 7.02-7.16(3H, m), 7.30-7.41(3H, m), 8.29(1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:439[M+H] .

Example 107

Synthesis of (2S)-[4-(carbamoylmethyl)thiazol-2-ylthio]-N-{[4-(4-fluorobenzyl)morpholin-2-yl]methyl}acetamide

[0375] 

[0376] By a similar method as in Example 16, the title compound (410 mg) was obtained as a pale-yellow oil from the resultant product (522 mg) of (95-2) and ammonium chloride (381 mg).
¹H-NMR(DMSO-d₆) δ 1.69-1.80(1H, m), 1.93-2.07(1H, m), 2.54(1H, d, J=11.1Hz), 2.64(1H, d, J=11.1Hz), 3.05-3.16(2H, m), 3.38-3.52(6H, m), 3.75(1H, d, J=11.1Hz), 3.92(2H, s), 6.98(1H, brs), 7.08-7.18(2H, m), 7.28-7.37(3H, m), 7.39(1H, brs), 8.29(1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:439[M+H].

Example 108

Synthesis of (2S)-[4-(carbamoylmethyl)thiazol-2-ylthio]-N-{[4-(4-fluoro-3-trifluoromethylbenzyl)morpholin-2-yl]methyl}acetamide

[0377] 

[0378] By a similar method as in Example 16, the title compound (389 mg) was obtained as a pale-yellow oil from the resultant product (489 mg) of (96-2) and ammonium chloride (309 mg).
¹H-NMR(DMSO-d₆) δ 1.72-1.84(1H, m), 2.00-2.09(1H, m), 2.54(1H, d, J=11.1Hz), 2.65(1H, d, J=11.1Hz), 3.07-3.17(2H, m), 3.40-3.54(6H, m), 3.76(1H, d, J=11.1Hz), 3.91(2H, s), 6.98(1H, brs), 7.31(1H, s), 7.38(1H, brs), 7.40-7.51(1H, m), 7.62-7.68(2H, m), 8.29(1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:507[M+H].

Example 109

Synthesis of (2S)-(4-carboxy-5-methylthiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0379] 

(109-1) Synthesis of 4-ethoxycarbonyl-5-methyl-2-mercaptothiazole

[0380] By a similar method as in (1-3), the title compound (2.10 g) was obtained as white crystals from ethyl 3-bromo-2-oxobutyrate (8.55 g) and ammonium dithiocarbamate (4.23 g).

(109-2) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl) morpholin-2-yl]methyl}-(4-ethoxycarbonyl-5-methylthiazol-2-ylthio)acetamide

[0381] By a similar method as in (1-4), the title compound (2.32 g) was obtained as a brown oil from the resultant product (1.55 g) of (1-2) and the resultant product (813 mg) of (109-1).

(109-3) Synthesis of (2S)-(4-carboxy-5-methylthiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0382] By a similar method as in (1-5), the title compound (1.94 g) was obtained as a white amorphous solid from the resultant product (2.32 g) of (109-2).
¹H-NMR(DMSO-d₆) δ 1.70-1.85(1H, m), 1.95-2.11(1H, m), 2.55(1H, d, J=11.4Hz), 2.64(3H, s), 2.65(1H, d, J=11.4Hz), 3.08-3.16(2H, m), 3.34-3.52(4H, m), 3.75(1H, d, J=11.4Hz), 3.92(2H, s), 7.28(1H, dd, J=1.5, 8.1Hz), 7.52-7.60(2H, m), 8.31(1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:490[M+H].

Example 110

Synthesis of (2S)-(4-carbamoyl-5-methylthiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0383] 

[0384] By a similar method as in Example 16, the title compound (250 mg) was obtained as white crystals from the resultant product (490 mg) of (109-3) and ammonium chloride (321 mg). ¹H-NMR(DMSO-d₆) δ 1.69-1.80(1H, m), 1.94-2.07(1H, m), 2.52(1H, d, J=12.0Hz), 2.59(1H, d, J=12.0Hz), 2.66(3H, s), 3.09-3.17(2H, m), 3.38-3.52(4H, m), 3.75(1H, d, J=12.0Hz), 3.92(2H, d, J=5.1Hz), 7.28(1H, dd, J=1.5, 8.1Hz), 7.49-7.59(3H, m), 7.65(1H, brs), 8.27(1H, dd, J=5.7, 5.7Hz). MS(ESI)m/z:489[M+H].

Example 111

Synthesis of (2S)-(4-carboxythiazol-2-ylthio)-N-{[4-(3-chloro-4-fluorobenzyl)morpholin-2-yl]methyl}acetamide

[0385] 

(111-1) Synthesis of (2S)-N-{[4-(3-chloro-4-fluorobenzyl)-morpholin-2-yl]methyl}chloroacetamide

[0386] By a similar method as in (1-1), the title compound (2.76 g) was obtained as a brown oil from (2S)-2-aminomethyl-4-(3-chloro-4-fluorobenzyl)morpholine dihydrochloride (2.32 g).

(111-2) Synthesis of (2S)-N-{[4-(3-chloro-4-fluorobenzyl) morpholin-2-yl]methyl}-(4-ethoxycarbonylthiazol-2-yl-thio)acetamide

[0387] By a similar method as in (1-4), the title compound (2.80 g) was obtained as a brown oil from the resultant product (2.76 g) of (111-1) and the resultant product (1.46 g) of (1-3).

(111-3) Synthesis of (2S)-(4-carboxythiazol-2-ylthio)-N-{[4-(3-chloro-4-fluorobenzyl)morpholin-2-yl]methyl} acetamide

[0388] By a similar method as in (1-5), the title compound (1.88 g) was obtained as a white amorphous solid from the resultant product (2.80 g) of (111-2).
¹H-NMR(DMSO-d₆) δ 1.70-1.89(1H, m), 1.95-2.15(1H, m), 2.57(1H, d, J=11.1Hz), 2.66(1H, d, J=11.1Hz), 3.08-3.19(2H, m), 3.34-3.52(4H, m), 3.76(1H, d, J=10.5Hz), 3.99(2H, s), 7.21-7.42(2H, m), 7.43-7.52(1H, m), 8.27-8.38(2H, m).
MS(ESI)m/z:460[M+H].

Example 112

Synthesis of (2S)-(4-carbamoylthiazol-2-ylthio)-N-{[4-(3-chloro-4-fluorobenzyl)morpholin-2-yl]methyl}acetamide

[0389] 

[0390] By a similar method as in Example 16, the title compound (1.47 g) was obtained as a white amorphous solid from the resultant product (1.65 g) of (111-3) and ammonium chloride (1.15 g).
¹H-NMR(DMSO-d₆) δ 1.66-1.78(1H, m), 1.91-2.08(1H, m), 2.51(1H, d, J=11.1Hz), 2.59(1H, d, J=11.1Hz), 3.09-3.17(2H, m), 3.36-3.52(4H, m), 3.74(1H, d, J=11.1Hz), 3.96(1H, d, J=11.7Hz), 4.04(1H, d, J=11.7Hz), 7.21-7.39(2H, m), 7.48(1H, dd, J=1.8, 7.2Hz), 7.65(1H, brs), 7.77(1H, brs), 8.14(1H, s), 8.26-8.39(1H, m).
MS(ESI)m/z:459[M+H] .

Example 113

Synthesis of (2S)-(4-carboxythiazol-2-ylthio)-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}acetamide

[0391] 

(113-1) Synthesis of (2S)-N-{[4-(3,4-difluorobenzyl)-morpholin-2-yl]methyl}chloroacetamide

[0392] By a similar method as in (1-1), the title compound (6.88 g) was obtained as a brown oil from (2S)-2-aminomethyl-4-(3,4-difluorobenzyl)morpholine dihydrochloride (6.30 g).

(113-2) Synthesis of (2S)-N-{[4-(3,4-difluorobenzyl)mor-pholin-2-yl]methyl}-(4-ethoxycarbonylthiazol-2-ylthio)-acetamide

[0393] By a similar method as in (1-4), the title compound (9.05 g) was obtained as a yellow oil from the resultant product (6.88 g) of (113-1) and the resultant product (4.16 g) of (1-3).

(113-3) Synthesis of (2S)-(4-carboxythiazol-2-ylthio)-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}acetamide

[0394] By a similar method as in (1-5), the title compound (3.53 g) was obtained as a white amorphous solid from the resultant product (9.05 g) of (113-2).
¹H-NMR(DMSO-d₆) δ 1.70-1.87(1H, m), 1.93-2.12(1H, m), 2.56(1H, d, J=11.1Hz), 2.66(1H, d, J=11.1Hz), 3.08-3.19(2H, m), 3.34-3.52(4H, m), 3.76(1H, d, J=11.1Hz), 4.00(2H, s), 7.03-7.19(1H, m), 7.22-7.43(2H, m), 8.24-8.37(2H, m).
MS(ESI)m/z:444[M+H].

Example 114

Synthesis of (2S)-(4-carbamoylthiazol-2-ylthio)-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}acetamide

[0395] 

[0396] By a similar method as in Example 16, the title compound (1.32 g) was obtained as a white amorphous solid from the resultant product (2.09 g) of (113-3) and ammonium chloride (1.51 g).
¹H-NMR(DMSO-d₆) δ 1.68-1.79(1H, m), 1.90-2.06(1H, m), 2.51(1H, d, J=11.1Hz), 2.58(1H, d, J=11.1Hz), 3.08-3.17(2H, m), 3.38-3.52(4H, m), 3. 74 (1H, d, J=11.1Hz), 3.92-4.09(2H, m), 7.04-7.17(1H, m), 7.23-7.42(2H, m), 7.66(1H, brs), 7.76(1H, brs), 8.14(1H, s), 8.27-8.39(1H, m).
MS(ESI)m/z:443[M+H].

Example 115

Synthesis of (2S)-[4-(2-amino-2-oxoethyl)aminocarbonyl-thiazol-2-ylthio]-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}acetamide

[0397] 

[0398] By a similar method as in Example 16, the title compound (133 mg) was obtained as a white solid from the resultant product (222 mg) of (113-3) and glycinamide hydrochloride (66 mg).
¹H-NMR(DMSO-d₆) δ 1.66-1.79(1H, m), 1.92-2.05(1H, m), 2.52(1H, d, J=11.1Hz), 2.60(1H, d, J=11.1Hz), 3.10-3.18(2H, m), 3.36-3.50(4H, m), 3.74(1H, d, J=11.1Hz), 3.83(2H, d, J=6.0Hz), 3.96-4.08(2H, m), 7.04-7.17(2H, m), 7.28-7.42(3H, m), 8.18(1H, s), 8.34(1H, dd, J=5.7, 5.7Hz), 8.41(1H, t, J=6.0Hz).
MS(ESI)m/z:500[M+H].

Example 116

Synthesis of (2S)-[4-(4-carboxyphenyl)thiazol-2-ylthio]-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}acetamide

[0399] 

(116-1) Synthesis of (2S)-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}-[4-(4-methoxycarbonylphenyl)thiazol-2-ylthio]acetamide

[0400] By a similar method as in (1-4), the title compound (1.46 g) was obtained as a yellow oil from the resultant product (1.02 g) of (113-1) and the resultant product (1.61 g) of (5-1).

(116-2) Synthesis of (2S)-[4-(4-carboxyphenyl)thiazol-2-ylthio]-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl} acetamide

[0401] By a similar method as in (1-5), the title compound (1.10 g) was obtained as a white amorphous solid from the resultant product (1.46 g) of (116-1).
¹H-NMR(DMSO-d₆) δ 1.69-1.80(1H, m), 1.91-2.03(1H, m), 2.50(1H, d, J=11.1Hz), 2.61(1H, d, J=11.1Hz), 3.10-3.20(2H, m), 3.33-3.55(4H, m), 3.71(1H, d, J=11.1Hz), 4.04(2H, s), 7.04-7.10(1H, m), 7.18-7.39(2H, m), 7.99 (2H, d, J=8.4Hz), 8.06 (2H, d, J=8.4Hz), 8.21(1H, s), 8.34(1H, dd, J=5.7, 5.7Hz), 12.9(1H, brs).
MS(ESI)m/z:520[M+H].

Example 117

Synthesis of (2S)-[4-(4-carbamoylphenyl)thiazol-2-ylthio]-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}acetamide

[0402] 

[0403] By a similar method as in Example 16, the title compound (152 mg) was obtained as a white solid from the resultant product (260 mg) of (116-2) and ammonium chloride (160 mg).
¹H-NMR(DMSO-d₆) δ 1.70-1.81(1H, m), 1.91-2.02(1H, m), 2.50(1H, d, J=11.1Hz), 2.61(1H, d, J=11.1Hz), 3.10-3.19(2H, m), 3.34-3.52(4H, m), 3.72(1H, d, J=11.1Hz), 4.04(2H, s), 7.02-7.10(1H, m), 7.18-7.41(3H, m), 7.91-8.04(5H, m), 8.17(1H, s), 8.34(1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:519[M+H].

Example 118

Synthesis of (2S)-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}-[4-(5-methyl-4H-1,2,4-triazol-3-yl)thiazol-2-ylthio]acetamide hydrochloride

[0404] 

(118-1) Synthesis of (2S)-[4-(N'-tertiary butoxycarbonyl-hydrazinocarbonyl)thiazol-2-ylthio]-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}acetamide

[0405] By a similar method as in Example 16, the title compound (1.10 g) was obtained as a white solid from the resultant product (1.11 g) of (113-3) and tertiary butoxycarbonyl hydrazide (396 mg).

(118-2) Synthesis of (2S)-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}-[4-(hydrazinocarbonyl)thiazol-2-ylthio]acetamide

[0406] By a similar method as in (42-2), the title compound (565 mg) was obtained as a white amorphous solid from the resultant product (1.10 g) of (118-1).

(118-3) Synthesis of (2S)-N-{[4-(3,4-difluorobenzyl)morpholin-2-yllmethyll-[4-(5-methyl-4H-1,2,4-triazol-3-yl)-thiazol-2-ylthio]acetamide hydrochloride

[0407] By a similar method as in Example 43, trifluoroacetic acid salt of the title compound was obtained as a colorless oil from the resultant product (565 mg) of (118-2) and ethyl imidoacetate hydrochloride (229 mg). By a similar method as in (1-2), the title compound (53 mg) was obtained as a white powder from the obtained residue.
¹H-NMR(DMSO-d₆) δ 2.42(3H, s), 2.68-2.80(1H, m), 2.88-3.05(1H, m), 3.10-3.30(4H, m), 3.72-4.10(6H, m), 4.29(2H, brs), 7.36-7.59(2H, m), 7.75(1H, t, J=8.7Hz), 8.13(1H, s), 8.58(1H, m), 11.5(1H, brs).
MS (ESI)m/z:481[M+H].

Example 119

Synthesis of (2S)-N-{[4-(3-chloro-4-fluorobenzyl)morpholin-2-yl]methyl}-[4-(1H-tetrazol-5-yl)thiazol-2-ylthio]acetamide

[0408] 

(119-1) Synthesis of (2S)-N-{[4-(3-chloro-4-fluorobenzyl)-morpholin-2-yl]methyl}-(4-cyanothiazol-2-ylthio)acetamide

[0409] By a similar method as in (22-1), the title compound (995 mg) was obtained as a colorless oil from the resultant product (1.32 g) of Example 112.

(119-2) Synthesis of (2S)-N-{[4-(3-chloro-4-fluorobenzyl) morpholin-2-yl]methyl}-[4-(1H-tetrazol-5-yl)thiazol-2-yl-thio]acetamide

[0410] By a similar method as in Example 59, the title compound (195 mg) was obtained as a pale-yellow amorphous solid from the resultant product (995 mg) of (119-1).
¹H-NMR(DMSO-d₆) δ 1.80-1.95(1H, m), 2.02-2.19(1H, m), 2.66(1H, d, J=11.4Hz), 2.78(1H, d, J=11.4Hz), 3.09-3.19(2H, m), 3.39-3.57(4H, m), 3.74(1H, d, J=11.7Hz), 3.92(1H, d, J=14.6Hz), 4.00(1H, d, J=14.6Hz), 7.18-7.39(2H, m), 7.44(1H, dd, J=1.9, 7.3Hz), 8.22(1H, s), 8.36(1H, dd, J=5.8, 5.8Hz).
MS(ESI)m/z:484 [M+H].

Example 120

Synthesis of (2S)-N-{[4-(3, 4-difluorobenzyl)morpholin-2-yl]methyl}-[4-(1H-tetrazol-5-yl)thiazol-2-ylthio]acetamide

[0411] 

(120-1) Synthesis of (2S)-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}-(4-cyanothiazol-2-ylthio)acetamide

[0412] By a similar method as in (22-1), the title compound (796 mg) was obtained as a colorless oil from the resultant product (1.14 g) of Example 114.

(120-2) Synthesis of (2S)-N-{[4-(3,4-difluorobenzyl) morpholin-2-yl]methyl}-[4-(1H-tetrazol-5-yl)thiazol-2-ylthio]acetamide

[0413] By a similar method as in Example 59, the title compound (305 mg) was obtained as a yellow amorphous solid from the resultant product (796 mg) of (120-1).
¹H-NMR(DMSO-d₆) δ 1.80-1.95 (1H, m), 2.04-2.18 (1H, m), 2.66 (1H, d, J=12.3Hz), 2.78 (1H, d, J=11.4Hz), 3.10-3.19 (2H, m), 3.37-3.59 (4H, m), 3.73 (1H, d, J=12.3Hz), 3.93 (1H, d, J=14.6Hz), 4.00 (1H, d, J=14.6Hz), 7.01-7.16 (1H, m), 7.22-7.40 (2H, m), 8.28 (1H, s), 8.35(1H, dd, J=5.7, 5.7Hz).
MS (ESI)m/z: 468 [M+H] .

Example 121

Synthesis of (2S)-(5-amino-1,3,4-thiadiazol-2-ylthio)-N-{[4-(3-chloro-4-fluorobenzyl)morpholin-2-yl]methyl}acetamide

[0414] 

(121-1) Synthesis of (2S)-N-{[4-(3-chloro-4-fluorobenzyl) morpholin-2-yl]methyl}chloroacetamide hydrochloride

[0415] By a similar method as in (1-2), the title compound (3.50 g) was obtained as a pale-yellow amorphous solid from the resultant product (3.37 g) of (111-1).

(121-2) Synthesis of (2S)-(5-amino-1,3,4-thiadiazol-2-yl-thio)-N-{[4-(3-chloro-4-fluorobenzyl)morpholin-2-yl]-methyl}acetamide

[0416] By a similar method as in (1-4), the title compound (435 mg) was obtained as a white solid from the resultant product (743 mg) of (121-1) and 2-amino-5-mercapto-1,3,4-thiadiazole (266 mg).
¹H-NMR(DMSO-d₆) δ 1.71-1.83(1H, m), 1.98-2.09(1H, m), 2.54(1H, d, J=11.1Hz), 2.65(1H, d, J=11.1Hz), 3.08-3.18(2H, m), 3.41-3.51(4H, m), 3.70-3.82(3H, m), 7.23-7.39(4H, m), 7.49(1H, dd, J=1.8, 7.2Hz), 8.23(1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:432[M+H].

Example 122

Synthesis of (2S)-(5-acetamino-1,3,4-thiadiazol-2-ylthio)-N-{[4-(3-chloro-4-fluorobenzyl)morpholin-2-yl]methyl}acetamide

[0417] 

[0418] By a similar method as in Example 14, the title compound (125 mg) was obtained as white crystals from the resultant product (130 mg) of (121-2).
1H-NMR(DMSO-d6) 8 1.73-1.81(1H, m), 1.96-2.09(1H, m), 2.16(3H, s), 2.54(1H, d, J=11.1Hz), 2.64(1H, d, J=11.1Hz), 3.08-3.18(2H, m), 3.38-3.54(4H, m), 3.75(1H, d, J=11.1Hz), 3.94(2H, s), 7.27-7.40(2H, m), 7.48(1H, d, J=7.2Hz), 8.31(1H, dd, J=5.7, 5.7Hz), 12.6(1H, s).
MS(ESI)m/z:474[M+H].

Example 123

Synthesis of (2S)-(5-amino-1,3,4-thiadiazol-2-ylthio)-N-{[4-(3-chlorobenzyl)morpholin-2-yl]methyl}acetamide

[0419] 

[0420] By a similar method as in (1-4), the title compound (723 mg) was obtained as white crystals from the resultant product (1.27 g) of (83-1) and 2-amino-5-mercapto-1,3,4-thiadiazole (533 mg).
¹H-NMR(DMSO-d₆) δ 1.71-1.83(1H, m), 1.98-2.10(1H, m), 2.55(1H, d, J=11.4Hz), 2.66(1H, d, J=11.4Hz), 3.07-3.17(2H, m), 3.38-3.54(4H, m), 3.70-3.81(3H, m), 7.21-7.39(6H, m), 8.21(1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:414[M+H].

Example 124

Synthesis of (2S)-(5-acetamino-1,3,4-thiadiazol-2-ylthio)-N-{[4-(3-chlorobenzyl)morpholin-2-yl]methyl}acetamide

[0421] 

[0422] By a similar method as in Example 14, the title compound (405 mg) was obtained as white crystals from the resultant product (414 mg) of Example 123.
¹H-NMR(DMSO-d₆) δ 1.71-1.80 (1H, m), 1.96-2.09 (1H, m), 2.16(3H, s), 2.54 (1H, d, J=10.8Hz), 2.64 (1H, d, J=10.8Hz), 3.08-3.13(2H, m), 3.38-3.51(4H, m), 3.75 (1H, d, J=10.8Hz), 3.94(2H, s), 7.23-7.38(4H, m), 8.31 (1H, dd, J=5.7, 5.7Hz), 12.6 (1H, s).
MS (ESI)m/z: 456 [M+H] .

Example 125

Synthesis of (2S)-(5-amino-1,3,4-thiadiazol-2-ylthio)-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}acetamide

[0423] 

[0424] By a similar method as in (1-4), the title compound (333 mg) was obtained as white crystals from the resultant product (638 mg) of (113-1) and 2-amino-5-mercapto-1,3,4-thiadiazole (266 mg).
¹H-NMR(DMSO-d₆) δ 1.71-1.82(1H, m), 1.98-2.08(1H, m), 2.55(1H, d, J=11.1Hz), 2.65(1H, d, J=11.1Hz), 3.07-3.16(2H, m), 3.39-3.52(4H, m), 3.70-3.91(3H, m), 7.11-7.18(1H, m), 7.21-7.40(4H, m), 8.23(1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:416[M+H] .

Example 126

Synthesis of (2S)-(5-acetamino-1,3,4-thiadiazol-2-ylthio)-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}acetamide

[0425] 

[0426] By a similar method as in Example 14, the title compound (220 mg) was obtained as white crystals from the resultant product (208 mg) of Example 125.
¹H-NMR(DMSO-d₆) δ 1.70-1.82(1H, m), 1.96-2.08(1H, m), 2.16(3H, s), 2.54(1H, d, J=10.8Hz), 2.64(1H, d, J=10.8Hz), 3.07-3.16(2H, m), 3.38-3.52(4H, m), 3.75(1H, d, J=11.1Hz), 3.94(2H, s), 7.10-7.16(1H, m), 7.27-7.42(2H, m), 8.30(1H, dd, J=5.7, 5.7Hz), 12.6(1H, s).
MS(ESI)m/z:458[M+H].

Example 127

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(5-methyl-1,3,4-thiadiazol-2-ylthio)acetamide

[0427] 

By a similar method as in (1-4), the title compound (3.38 g) was obtained as a pale-yellow solid from the resultant product (3.49 g) of (1-2) and 2-mercapto-5-methyl-1,3,4-thiadiazole (1.19 g).
¹H-NMR(DMSO-d₆) δ 1.72-1.87 (1H, m), 1.99-2.10(1H, m), 2.54 (1H, d, J=11.1Hz), 2.65-2.68(4H, m), 3.09-3.18(2H, m), 3.41-3.52(4H, m), 3.75 (1H, d, J=11.1Hz), 4.00(2H, s), 7.30 (1H, dd, J=1.9, 8.3Hz), 7.53-7.60(2H, m), 8.32 (1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:447[M+H] .

Example 128

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-{2-[(3-ethoxy-1,3-dioxopropyl)amino]-1,3,4-thiadiazol-5-ylthio}acetamide

[0428] 

[0429] The resultant product (902 mg) of Example 52 was dissolved in dimethylformamide (5 mL) and, under ice-cooling, ethyl malonyl chloride (255 µL) was added, and the mixture was stirred for 40 min. Triethylamine (280 µL) and ethyl malonyl chloride (255 µL) were added to the reaction mixture, and the mixture was further stirred for 30 min. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried, and the solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate to give the title compound (773 mg) as a white solid.
¹H-NMR(DMSO-d₆) δ 1.19(3H, t, J=7.2Hz), 1.74-1.86(1H, m), 1.96-2.09(1H, m), 2.53(1H, d, J=10.8Hz), 2.63(1H, d, J=10.8Hz), 3.10-3.16(2H, m), 3.38-3.52(4H, m), 3.63(2H, s), 3.75(1H, d, J=10.8Hz), 3.95(2H, s), 4.11(2H, q, J=7.2Hz), 7.29(1H, dd, J=1.5, 8.1Hz), 7.53-7.59(2H, m), 8.29 (1H, dd, J=5.7, 5.7Hz), 12.8(1H, s).
MS(ESI)m/z:562[M+H].

Example 129

Synthesis of (2S)-{[2-(3-amino-1,3-dioxopropyl)amino]-1,3,4-thiadiazol-5-ylthio}-N-{[4-(3,4-dichlorobenzyl) morpholin-2-yl]methyl}acetamide

[0430] 

[0431] By a similar method as in Example 25, the title compound (112 mg) was obtained as a white solid from the resultant product (562 mg) of Example 128.
¹H-NMR(DMSO-d₆) δ 1.74-1.83(1H, m), 1.94-2.09(1H, m), 2.54(1H, d, J=10.5Hz), 2.65(1H, d, J=10.5Hz), 3.08-3.18(2H, m), 3.38(2H, s), 3.39-3.52(4H, m), 3.75(1H, d, J=10.5Hz), 3.94(2H, s), 7.18(1H, brs), 7.29(1H, d, J=8.4Hz), 7.53-7.59(3H, m), 8.28(1H, dd, J=5.7, 5.7Hz), 12.7(1H, s).
MS(ESI)m/z:533[M+H].

Example 130

Synthesis of (2S)-{[2-(4-amino-1,4-dioxobutyl)amino]-1,3,4-thiadiazol-5-ylthio}-N-{[4-(3,4-dichlorobenzyl) morpholin-2-yl]methyl}acetamide

[0432] 

[0433] By a similar method as in Example 16, the title compound (123 mg) was obtained as a white solid from the resultant product (448 mg) of Example 52 and succinamic acid (141 mg).
¹H-NMR(DMSO-d₆) δ 1.73-1.85(1H, m), 1.95-2.09(1H, m), 2.42(2H, t, J=6.9Hz), 2.54(1H, d, J=11.1Hz), 2.60-2.70(3H, m), 3.10-3.17(2H, m), 3.38-3.52(4H, m), 3.75 (1H, d, J=11.1Hz), 3.93(2H, s), 6.79 (1H, brs), 7.28-7.38(2H, m), 7.53-7.60(2H, m), 8.28(1H, dd, J=5.7, 5.7Hz), 12.6 (1H, s).
MS(ESI)m/z:547[M+H] .

Example 131

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-{2-[((5S)-2-oxopyrrolidin-5-yl)carbonylamino]-1,3,4-thiadiazol-5-ylthio}acetamide

[0434] 

[0435] By a similar method as in Example 16, the title compound (252 mg) was obtained as a white amorphous solid from the resultant product (448 mg) of Example 52 and L-pyroglutamic acid (155 mg).
¹H-NMR(DMSO-d₆) δ 1.74-1.85(1H, m), 1.90-2.10(2H, m), 2.11-2.21(2H, m), 2.29-2.43(1H, m), 2.54(1H, d, J=10.8Hz), 2.64 (1H, d, J=10.8Hz), 3.08-3.18(2H, m), 3.38-3.52(4H, m), 3.74-3.76 (1H, m), 3.95(2H, s), 4.29-4.38(1H, m), 7.29 (1H, dd, J=1.2, 8.1Hz), 7.53 (1H, d, J=1.2Hz), 7.58 (1H, d, J=8.1Hz), 7.89(1H, s), 8.29(1H, dd, J=5.7, 5.7Hz), 12.8 (1H, s).
MS(ESI)m/z:559[M+H].

Example 132

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-{2-[((5R)-2-oxopyrrolidin-5-yl)carbonylamino]-1,3,4-thiadiazol-5-ylthio}acetamide

[0436] 

[0437] By a similar method as in Example 16, the title compound (297 mg) was obtained as a white amorphous solid from the resultant product (448 mg) of Example 52 and D-pyroglutamic acid (155 mg).
¹H-NMR(DMSO-d₆) δ 1.74-1.85(1H, m), 1.90-2.10(2H, m), 2.11-2.21(2H, m), 2.29-2.43(1H, m), 2.54(1H, d, J=10.8Hz), 2.64(1H, d, J=10.8Hz), 3.09-3.19(2H, m), 3.40-3.55(4H, m), 3.74-3.76(1H, m), 3.95(2H, s), 4.30-4.40(1H, m), 7.29(1H, dd, J=1.5, 8.4Hz), 7.53(1H, d, J=1.5Hz), 7.58(1H, d, J=8.4Hz), 7.89(1H, s), 8.29(1H, dd, J=5.7, 5.7Hz), 12.8(1H, s).
MS(ESI)m/z:559[M+H].

Example 133

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(1,3,4-thiadiazol-2-ylthio)acetamide

[0438] 

[0439] By a similar method as in (1-4), the title compound (240 mg) was obtained as white crystals from the resultant product (300 mg) of (1-2) and 2-mercapto-1,3,4-thiadiazole (100 mg).
¹H-NMR(DMSO-d₆) δ 1.74-1.80(1H, m), 1.98-2.06(1H, m), 2.53(1H, d, J=11.1Hz), 2.64(1H, d, J=11.1Hz), 3.10-3.14(2H, m), 3.41-3.48(4H, m), 3.74(1H, d, J=11.1Hz), 4.05(2H, s), 7.28(1H, dd, J=8.4, 1.5Hz), 7.52(1H, d, J=1.5Hz), 7.57(1H, d, J=8.4Hz), 8.36(1H, dd, J=5.7, 5.7Hz), 9.50(1H, s).
MS(ESI)m/z:433[M+H].

Example 134

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[2-(3-ethylureido)-1,3,4-thiadiazol-5-ylthio]-acetamide

[0440] 

[0441] The resultant product (250 mg) of Example 52 was dissolved in tetrahydrofuran (1.8 mL), ethyl isocyanate (50 µL) was added, and the mixture was stirred at room temperature for 4.5 h. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with ethyl acetate to give the title compound (200 mg) as white crystals.
¹H-NMR(DMSO-d₆) δ 1.01(3H, t, J=7.2Hz), 1.72-1.79(1H, m), 1.95-2.04(1H, m), 2.50(1H, d, J=11.1Hz), 2.62(1H, d, J=11.1Hz), 3.08-3.12(4H, m), 3.32-3.48(4H, m), 3.72(1H, d, J=11.1Hz), 3.85(2H, s), 6.57(1H, brs), 7.26(1H, dd, J=8.4, 1.5Hz), 7.50(1H, d, J=1.5Hz), 7.55(1H, d, J=8.4Hz), 8.24(1H, dd, J=5.7, 5.7Hz), 10.92(1H s).
MS(ESI)m/z:519[M+H].

Example 135

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[2-(2-hydroxyacetamino)-1,3,4-thiadiazol-5-ylthio]acetamide

[0442] 

(135-1) Synthesis of (2S)-[2-(2-acetoxyacetamino)-1,3,4-thiadiazol-5-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0443] The resultant product (250 mg) of Example 52 dissolved in dimethylformamide (1.6 mL), acetoxyacetyl chloride (60 µL) and triethylamine (80 µL) were added, and the mixture was stirred at room temperature for 1.5 h. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with ethyl acetate to give the title compound (270 mg) as a white solid.

(135-2) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[2-(2-hydroxyacetylamino)-1,3,4-thiadiazol-5-ylthio]acetamide

[0444] The resultant product (170 mg) of (135-1) was dissolved in methanol (3.0 mL), potassium carbonate (45 mg) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was poured into ice water, the mixture was neutralized with a 4N hydrochloric acid, and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained crystal was washed with ethyl acetate to give the title compound (125 mg) as white crystals.
¹H-NMR(DMSO-d₆) δ 1.72-1.79(1H, m), 1.96-2.04(1H, m), 2.52(1H, d, J=11.1Hz), 2.62(1H, d, J=11.1Hz), 3.08-3. 12 (2H, m), 3.3-3.5(4H, m), 3.73 (1H, d, J=11.1Hz), 3.92(2H, s), 4.14(2H, d, J=4.5Hz), 5.51(1H, brs), 7.27 (1H, d, J=8.1Hz), 7. 51 (1H, s), 7.55 (1H, d, J=8.1Hz), 8.28 (1H, dd, J=5.7, 5.7Hz), 12.34 (1H, brs).
MS(ESI)m/z:506[M+H].

Example 136

Synthesis of (2S)-(5-carboxymethylthio-1,3,4-thiadiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl} acetamide

[0445] 

[0446] By a similar method as in (1-4), the title compound (970 mg) was obtained as a white amorphous solid from the resultant product (1.0 g) of (1-2) and (5-mercapto-1,3,4-thiadiazol-2-yl)thioacetic acid (600 mg).
¹H-NMR(DMSO-d₆) δ 1.77-1.84(1H, m), 2.01-2.09(1H, m), 2.55(1H, d, J=11.1Hz), 2.66(1H, d, J=11.1Hz), 3.09-3.13(2H, m), 3.41-3.51(4H, m), 3.75(1H, d, J=11.1Hz), 3.97(2H, s), 4.09(2H, s), 7.28(1H, dd, J=8.1, 1.5Hz), 7.53 (1H, d, J=1.5Hz), 7.56 (1H, d, J=8.1Hz), 8.33 (1H, dd, J=5.7, 5.7Hz).
MS (ESI)m/z:523 [M+H] .

Example 137

Synthesis of (2S)-[5-(2-amino-2-oxoethylthio)-1,3,4-thiadiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0447] 

[0448] By a similar method as in Example 16, the title compound (100 mg) was obtained as white crystals from the resultant product (300 mg) of Example 136 and ammonium chloride (185 mg).
¹H-NMR(DMSO-d₆) δ 1.74-1.81(1H, m), 1.99-2.06(1H, m), 2.54(1H, d, J=11.1Hz), 2.64(1H, d, J=11.1Hz), 3.09-3.13(2H, m), 3.27-3.49(4H, m), 3.75(1H, d, J=11.1Hz), 3.98(4H, s), 7.27-7.30(2H, m), 7.53(1H, s), 7.56(1H, d, J=8.1Hz), 7.69(1H, brs)8.34(1H, dd, J=5.4, 5.4Hz).
MS(ESI)m/z:522[M+H].

Example 138

Synthesis of (2S)-[5-(2-methylamino-2-oxoethylthio)-1,3,4-thiadiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0449] 

[0450] By a similar method as in Example 16, the title compound (240 mg) was obtained as white crystals from the resultant product (250 mg) of Example 136 and methylamine hydrochloride (120 mg) .
¹H-NMR(DMSO-d₆) δ 1.74-1.81(1H, m), 1.98-2.06(1H, m), 2.53(1H, d, J=11.1Hz), 2.59(3H, d, J=4.8Hz), 2.64(1H, d, J=11.1Hz), 3.09-3.13(2H, m), 3.42-3.48(4H, m), 3.74(1H, d, J=11.1Hz), 3.96(2H, s), 3.97(2H, s), 7.28(1H, dd, J=8.4, 1.8Hz), 7.52(1H, d, J=1.8Hz), 7.56 (1H, d, J=8.4Hz), 8.16(1H, brs)8.32(1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:536[M+H].

Example 139

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl)methyl}-(5-mercapto-1,3,4-thiadiazol-2-ylthio)acetamide

[0451] 

[0452] By a similar method as in Example 16, the title compound (550 mg) was obtained as a yellow amorphous solid from (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (1.0 g) and (5-mercapto-1,3,4-thiadiazol-2-yl)thioacetic acid (600 mg).
¹H-NMR(DMSO-d₆) δ 1.79-1.86(1H, m), 2.05-2.12(1H, m), 2.57(1H, d, J=11.1Hz), 2.67(1H, d, J=11.1Hz), 3.10-3.13(2H, m), 3.42-3.50(4H, m), 3.76(1H, d, J=11.1Hz), 3.86(2H, s), 7.29(1H, d, J=8.4Hz), 7.54(1H, s), 7. 57 (1H, d, J=8.4Hz), 8.30(1H, dd, J-5.4, 5.4Hz).
MS(ESI)m/z:465[M+H].

Example 140

Synthesis of (2S)-[5-(2-carboxypropan-2-ylthio)-1,3,4-thiadiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0453] 

[0454] The resultant product (150 mg) of Example 139 and potassium carbonate (130 mg) were dissolved in dimethylformamide (1.0 mL), bromoisobutyric acid (65 mg) was added, and the mixture was stirred at room temperature for 4.5 h. Thereafter, bromoisobutyric acid (65 mg) was further added, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water, and the mixture was neutralized with a 1N hydrochloric acid and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (50 mg) as a white solid.
¹H-NMR(DMSO-d₆) δ 1.52(6H, s), 1.83-1.89(1H, m), 2.06-2.13(1H, m), 2.58(1H, d, J=11.1Hz), 2.71(1H, d, J=11.1Hz), 3.10-3.14(2H, m), 3.44-3.51(4H, m), 3.75(1H, d, J=11.1Hz), 4.02(2H, s), 7.29(1H, d, J=8.4Hz), 7.54(1H, s), 7.57(1H, dd, J=8.1, 2.7Hz), 8.38(1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:551[M+H].

Example 141 (Reference Example)

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(1-oxoethyl)phenylthio]acetamide

[0455] 

[0456] By a similar method as in Example 16, the title compound (477 mg) was obtained as a colorless oil from (4-acetylphenyl)thioacetic acid (252 mg) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (348 mg).
¹H-NMR(DMSO-d₆) δ 1.70-1.80(1H, m), 1.94-2.08(1H, m), 2.52(3H, s), 2.52-2.62(2H, m), 3.08-3.17(2H, m), 3.38-3.52(4H, m), 3.72-3.80(3H, m), 7.26(1H, dd, J=1.8, 8.1Hz), 7.42(2H, dd, J=1.8, 6.9Hz), 7.51(1H, d, J=1.8Hz), 7.58 (1H, d, J=8.1Hz), 7.87(2H, dd, J=1.8, 6.9Hz), 8.28 (1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:467[M+H].

Example 142 (Reference Example)

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(4-methoxycarbonylphenylthio)acetamide

[0457] 

[0458] The resultant product (220 mg) of Example 37 was dissolved in dimethylformamide (3 mL), potassium carbonate (130 mg) and methyl iodide (22 µL) were added, and the mixture was stirred at room temperature for 4 h. The reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (150 mg) as a white amorphous solid.
¹H-NMR(DMSO-d₆) δ 1.76-1.71 (1H, m), 1.97-2.03 (1H, m), 2.52-2.59(2H, m), 3.11-3.14(2H, m), 3.38(2H, s), 3.40-3.47(2H, m), 3.73-3.77(3H, m), 3.81(3H, s), 7.26(1H, dd, J=1.6, 8.0Hz), 7.42(2H, d, J=8.4Hz), 7.49(1H, d, J=1.6Hz), 7.56(1H, d, J=8.0Hz), 7.85(2H, d, J=8.4Hz), 8.24(1H, dd, J=5.8, 5.8Hz).
MS(ESI)m/z:483[M+H].

Example 143

Synthesis of (2S)-(5-carboxypyridin-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0459] 

[0460] By a similar method as in (1-4), the title compound (580 mg) was obtained as a white amorphous solid from the resultant product (990 mg) of (1-2) and 6-mercaptonicotinic acid (440 mg).
¹H-NMR(DMSO-d₆) δ 1.73-1.79 (1H, m), 1.95-2.02 (1H, m), 2.52-2.54 (1H, m), 2.59-2.63 (1H, m), 3.06-3.17(2H, m), 3.43-3.47(4H, m), 3.72-3.76 (1H, m), 3.83-3.92(2H, m), 7.28 (1H, dd, J=1.6, 8.4Hz), 7.38 (1H, d, J=8.4Hz), 7.51 (1H, d, J=1.6Hz), 7.57 (1H, d, J=8.4Hz), 8.05 (1H, dd, J=1.9, 8.4Hz), 8.18 (1H, dd, J=5.7, 5.7Hz), 8.86 (1H, d, J=1.9Hz).
MS (ESI)m/z: 470 [M+H] .

Example 144 (Reference Example)

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(morpholin-4-ylsulfonyl)phenylthio]acetamide

[0461] 

(144-1) Synthesis of methyl 4-(morpholin-4-ylsulfonyl)-phenylthioacetate

[0462] Dichloromethane (15 mL) and potassium carbonate (1.3 g) dissolved in water (15 mL) were added to 4-fluorobenzenesulfonyl chloride (1 g). Then, morpholine (530 µL) was added, and the mixture was stirred at room temperature for 1.5 h. After completion of the reaction, the mixture was extracted with chloroform, then the extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a white solid (1.3 g). By a similar method as in (1-4), the title compound (0.93 g) was obtained as a white solid from the obtained white solid (1.3 g) and methyl thioglycolate (0.6 mL).

(144-2) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)-morpholin-2-yl]methyl}-[4-(morpholin-4-ylsulfonyl)phenylthio]acetamide

[0463] The resultant product (400 mg) of (144-1) was dissolved in methanol (10 mL) and tetrahydrofuran (10 mL), a 1 mol/L aqueous sodium hydroxide solution (2 mL) was added, and the mixture was stirred overnight at room temperature. 1 mol/L hydrochloric acid (2 mL) was added to the reaction mixture, and the solvent was evaporated under reduced pressure. By a similar method as in Example 16, the title compound (400 mg) was obtained as a white amorphous solid from the obtained residue and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (280 mg).
¹H-NMR(DMSO-d₆) δ 1.73-1.79 (1H, m), 2.00-2.06 (1H, m), 2.52-2.57 (1H, m), 2.59-2.64 (1H, m), 2.86(4H, t, J=4.6Hz), 3.11-3.15(2H, m), 3.40-3.49(4H, m), 3.61(4H, t, J=4.6Hz), 3.74-3.78(1H, m), 3.79(2H, s), 7.28(1H, dd, J=1.6, 8.3Hz), 7.51-7.58(4H, m), 7.60-7.64(2H, m), 8.27(1H, dd, J=, 5.6, 5.6Hz) .
MS(ESI)m/z:574[M+H].

Example 145 (Reference Example)

[0464] Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(4-sulfamoylphenylthio)acetamide

(145-1) Synthesis of methyl 4-sulfamoylphenylthioacetate

[0465] By a similar method as in (1-4), the title compound (150 mg) was obtained as a white solid from 4-fluorobenzenesulfonamide (1 g) and methyl thioglycolate (0.62 mL).

(145-2) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)-morpholin-2-yl]methyl}-(4-sulfamoylphenylthio)acetamide

[0466] By a similar method as in (144-2), the title compound (260 mg) was obtained as a white amorphous solid from the resultant product (190 mg) of (145-1) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (220 mg).
¹H-NMR(DMSO-d₆) δ 1.73-1.79(1H, m), 1.99-2.07(1H, m), 2.53-2.57(1H, m), 2.60-2.63(1H, m), 3.10-3.14(2H, m), 3.41-3.49(4H, m), 3.74-3.78(3H, m), 7.26-7.31(3H, m), 7.44-7.49(2H, m), 7.53(1H, d, J=1.5Hz), 7.57(1H, d, J=8.4Hz), 7.68-7.73(2H, m), 8.24(1H, dd, J=5.6, 5.6Hz).
MS (ESI)m/z: 504 [M+H].

Example 146

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(pyrimidin-2-ylthio)acetamide

[0467] 

[0468] By a similar method as in (1-4), the title compound (240 mg) was obtained as a white amorphous solid from the resultant product (200 mg) of (1-2) and 2-mercaptopyrimidine (70 mg).
¹H-NMR(DMSO-d₆) δ 1.74-1.81(1H, m), 1.97-2.05(1H, m), 2.52-2.56(1H, m), 2.61-2.66(1H, m), 3.09-3.14(2H, m), 3.41-3.49(4H, m), 3.72-3.77(1H, m), 3.83(2H, s), 7.21(1H, t, J=4.9Hz), 7.29(1H, dd, J=1.8, 8.3Hz), 7.53(1H, d, J=1.8Hz), 7.57(1H, d, J=8.3Hz), 8.14(1H, dd, J=5.7, 5.7Hz), 8.60(2H, d, J=4.9Hz).
MS (ESI)m/z:427[M+H].

Example 147

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(4-methoxypyrimidin-2-ylthio)acetamide

[0469] 

(147-1) Synthesis of methyl 4-methoxypyrimidin-2-ylthio-acetate

[0470] By a similar method as in (1-4), the title compound (310 mg) was obtained as a colorless oil from 2-chloro-4-methoxypyrimidine (0.5 g) and methyl thioglycolate (320µL.

(147-2) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(4-methoxypyrimidin-2-ylthio)acetamide

[0471] By a similar method as in (144-2), the title compound (400 mg) was obtained as a yellow amorphous solid from the resultant product (310 mg) of (147-1) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (450 mg).
¹H-NMR(DMSO-d₆) δ 1.73-1.80 (1H, m), 1.96-2.04 (1H, m), 2.51-2.56 (1H, m), 2.59-2.64 (1H, m), 3.09-3.14(2H, m), 3.41-3.48(4H, m), 3.71-3.76 (1H, m), 3.82(2H, s), 3.90(3H, s), 6.62 (1H, d, J=5.5Hz), 7.28 (1H, dd, J=1.5, 8.1Hz), 7.52 (1H, d, J=1.5Hz), 7.57 (1H, d, J=8.1Hz), 8.11(1H, dd, J=5.7, 5.7Hz), 8.29(1H, d, J=5.5Hz).
MS(ESI)m/z:457[M+H].

Example 148

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(4,6-dimethoxypyrimidin-2-ylthio)acetamide

[0472] 

(148-1) Synthesis of methyl 4,6-dimethoxypyrimidin-2-ylthioacetate

[0473] By a similar method as in (1-4), the title compound (370 mg) was obtained as a white powder from 2-chloro-4,6-di-methoxypyrimidine (0.6 g) and methyl thioglycolate (320 µL).

(148-2) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(4,6-dimethoxypyrimidin-2-ylthio)acetamide

[0474] By a similar method as in (144-2), the title compound (300 mg) was obtained as a white powder from the resultant product (370 mg) of (148-1) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (450 mg).
¹H-NMR(DMSO-d₆) δ 1.72-1.78(1H, m), 1.95-2.04(1H, m), 2.52-2.56(1H, m), 2.58-2.63(1H, m), 3.09-3.14(2H, m), 3.40-3.47(4H, m), 3.71-3.76(1H, m), 3.81(2H, s), 3.85(6H, s), 5. 92 (1H, s), 7.28(1H, dd, J=1.6, 8.0Hz), 7.52(1H, d, J=1.6Hz), 7.57(1H, d, J=8.0Hz), 8.09(1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:487[M+H].

Example 149

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(2,4-dimethoxypyrimidin-6-ylthio)acetamide

[0475] 

(149-1) Synthesis of methyl 2,4-dimethoxypyrimidin-6-ylthioacetate

[0476] By a similar method as in (1-4), the title compound (600 mg) was obtained as a colorless oil from 4-chloro-2,6-di-methoxypyrimidine (550 mg) and methyl thioglycolate (300 µL).

(149-2) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl) morpholin-2-yl]methyl}-(2,4-dimethoxypyrimidin-6-ylthio)acetamide

[0477] By a similar method as in (144-2), the title compound (510 mg) was obtained as a white amorphous solid from the resultant product (300 mg) of (149-1) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (380 mg).
¹H-NMR(DMSO-d₆) δ 1.73-1.80(1H, m), 1.96-2.04(1H, m), 2.51-2.56(1H, m), 2.58-2.63(1H, m), 3.09-3.15(2H, m), 3.40-3.48(4H, m), 3.72-3.76(1H, m), 3.83(2H, s), 3.84(3H, s), 3.87(3H, s), 6.49(1H, s), 7.28(1H, dd, J=1.7, 8.1Hz), 7.52(1H, d, J=1.7Hz), 7.57(1H, d, J=8.1Hz), 8.15(1H, dd, J=5.8, 5.8Hz).
MS (ESI)m/z:487[M+H].

Example 150

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(pyrimidin-5-ylthio)acetamide

[0478] 

(150-1) Synthesis of methyl pyrimidin-5-ylthioacetate

[0479] By a similar method as in (1-4), the title compound (50 mg) was obtained as a colorless oil from 5-bromopyrimidine (1 g) and methyl thioglycolate (600 µL).

(150-2) Synthesis of ((2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(pyrimidin-5-ylthio)acetamide

[0480] By a similar method as in (144-2), the title compound (90 mg) was obtained as a white amorphous solid from the resultant product (50 mg) of (150-1) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (97 mg).
¹H-NMR(DMSO-d₆) δ 1.71-1.78(1H, m), 2.00-2.08(1H, m), 2.52-2.62(2H, m), 3.08-3.12(2H, m), 3.36-3.49(4H, m), 3.72-3.78(3H, m), 7.27-7.31(1H, m), 7.52-7.59(2H, m), 8.22(1H, dd, J=5.4, 5.4Hz), 8.79(2H, s), 9.01(1H, s).
MS (ESI)m/z: 427 [M+H].

Example 151

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(4-methylpyrimidin-2-ylthio)acetamide

[0481] 

[0482] By a similar method as in (1-4), the title compound (210 mg) was obtained as a white amorphous solid from the resultant product (230 mg) of (1-2) and 2-mercapto-4-methylpyrimidine monohydrochloride (100 mg).
¹H-NMR(DMSO-d₆) δ 1.73-1.80(1H, m), 1.96-2.03(1H, m), 2.39(3H, s), 2.51-2.56 (1H, m), 2.61-2.65 (1H, m), 3.09-3.14(2H, m), 3.42-3.48(4H, m), 3.72-3.77 (1H, m), 3.79-3.82(2H, m), 7.09 (1H, d, J=5.0Hz), 7.29 (1H, dd, J=1.4, 8.2Hz), 7.53 (1H, d, J=1.4Hz), 7.58 (1H, d, J=8.2Hz), 8.15(1H, dd, J=5.7, 5.7Hz), 8.44(1H, d, J=5.0Hz).
MS(ESI)m/z:441[M+H].

Example 152

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(4-trifluoromethylpyrimidin-2-ylthio)acetamide

[0483] 

[0484] By a similar method as in (1-4), the title compound (180 mg) was obtained as a white amorphous solid from the resultant product (230 mg) of (1-2) and 2-mercapto-4-trifluoromethylpyrimidine (110 mg).
¹H-NMR(DMSO-d₆) δ 1.76-1.82(1H, m), 1.98-2.07(1H, m), 2.52-2.56(1H, m), 2.63-2.67(1H, m), 3.09-3.14(2H, m), 3.42-3.50(4H, m), 3.73-3.77(1H, m), 3.92(2H, s), 7.29(1H, dd, J=1.5, 8.1Hz), 7.54(1H, d, J=1.5Hz), 7.58(1H, d, J=8.1Hz), 7.71 (1H, d, J=5.0Hz), 8.26(1H, dd, J=5.7, 5.7Hz), 8.96(1H, d, J=5.0Hz).
MS(ESI)m/z:495[M+H].

Example 153

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(5-ethoxycarbonyl-4-trifluoromethylpyrimidin-2-ylthio)acetamide

[0485] 

(153-1) Synthesis of 5-ethoxycarbonyl-4-trifluoromethyl-pyrimidin-2-ylthioacetic acid

[0486] By a similar method as in (1-4), the title compound (1.1 g) was obtained as an orange oil from 2-chloro-5-ethoxycarbonyl-4-trifluoromethylpyrimidine (1 g) and thioglycol acid (300 µL).

(153-2) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(5-ethoxycarbonyl-4-trifluoromethyl-pyrimidin-2-ylthio)acetamide

[0487] By a similar method as in Example 16, the title compound (240 mg) was obtained as a white amorphous solid from the resultant product (1 g) of (153-1) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (1.3 g).
¹H-NMR(DMSO-d₆) δ 1.29(3H, t, J=7.1Hz), 1.75-1.82(1H, m), 1.98-2.07(1H, m), 2.51-2.57(1H, m), 2.63-2.68(1H, m), 3.09-3.17(2H, m), 3.43-3.50(4H, m), 3.73-3.78(1H, m), 3.98(2H, s), 4.34(2H, q, J=7.1Hz), 7.29(1H, dd, J=1.6, 8.4Hz), 7.53(1H, d, J=1.6Hz), 7.57(1H, d, J=8.4Hz), 8.29(1H, dd, J=5.7, 5.7Hz), 9.16(1H, s).
MS(ESI)m/z:567[M+H].

Example 154

Synthesis of (2S)-(3-carbamoylpyridin-6-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0488] 

[0489] By a similar method as in Example 8, the title compound (270 mg) was obtained as a white powder from the resultant product (450 mg) of Example 143.
¹H-NMR(DMSO-d₆) δ 1.71-1.78(1H, m), 1.94-2.01(1H, m), 2.51-2.55(1H, m), 2.59-2.63(1H, m), 3.09-3.14(2H, m), 3.40-3.48(4H, m), 3.72-3.76(1H, m), 3.86-3.90(2H, m), 7.28(1H, dd, J=1.6, 8.2Hz), 7.42(1H, d, J=8.4Hz), 7.52(1H, d, J=1.6Hz), 7.53(1H, brs), 7.57(1H, d, J=8.2Hz), 8.06(1H, dd, J=2.0, 8.4Hz), 8.09(1H, brs), 8.20(1H, dd, J=5.8, 5.8Hz), 8.86(1H, d, J=2.0Hz).
MS(ESI)m/z:469[M+H].

Example 155

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(4-hydroxy-6-trifluoromethylpyrimidin-2-yl-thio)acetamide

[0490] 

[0491] By a similar method as in (1-4), the title compound (390 mg) was obtained as a white powder from the resultant product (380 mg) of (1-2) and 4-hydroxy-2-mercapto-6-tri-fluoromethylpyrimidine (200 mg).
¹H-NMR(DMSO-d₆) δ 1.85-1.91(1H, m), 2.08-2.15(1H, m), 2.58-2.62(1H, m), 2.70-2.74(1H, m), 3.10-3.14(2H, m), 3.43-3.52(4H, m), 3.75-3.79(1H, m), 3.89(2H, s), 6.60(1H, s), 7.31(1H, dd, J=1.4, 8.3Hz), 7.55(1H, d, J=1.4Hz), 7.59(1H, d, J=8.3Hz), 8.26(1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:511[M+H].

Example 156

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(5-methoxycarbonylpyrimidin-2-ylthio)acetamide

[0492] 

(156-1) Synthesis of 5-methoxycarbonylpyrimidin-2-ylthioacetic acid

[0493] 2-Benzylthio-5-methoxycarbonylpyrimidine (400 mg) was dissolved in dichloromethane (10 mL). Then, m-chloroperbenzoic acid (350 mg) was added, and the mixture was stirred at room temperature for 2 h. After evaporation of the solvent under reduced pressure, by a similar method as in (1-4), the title compound (200 mg) was obtained as a white solid from the obtained residue and thioglycol acid (105 µL).

(156-2) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(5-methoxycarbonylpyrimidin-2-ylthio)-acetamide

[0494] By a similar method as in Example 16, the title compound (220 mg) was obtained as a white solid from the resultant product (240 mg) of (156-1) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (440 mg).
¹H-NMR(DMSO-d₆) δ 1.77-1.82(1H, m), 2.00-2.05(1H, m), 2.53-2.56(1H, m), 2.65-2.67(1H, m), 3.10-3.15(2H, m), 3.42-3.49(4H, m), 3.73-3.77(1H, m), 3.86(3H, s), 3.93(2H, s), 7.29(1H, dd, J=1.6, 8.1Hz), 7.52(1H, d, J=1.6Hz), 7.57(1H, d, J=8.1Hz), 8.22(1H, dd, J=5.8, 5.8Hz), 9.00(2H, s).
MS(ESI)m/z:485[M+H].

Example 157

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(5-ethoxycarbonyl-4-methylpyrimidin-2-ylthio) acetamide

[0495] 

(157-1) Synthesis of 5-ethoxycarbonyl-4-methylpyrimidin-2-ylthioacetic acid

[0496] By a similar method as in (156-1), the title compound (200 mg) was obtained as a white solid from 2-benzylthio-5-methoxycarbonyl-4-methylpyrimidine (400 mg) and thioglycol acid (100 µL).

(157-2) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl) morpholin-2-yl]methyl}-[(5-ethoxycarbonyl-4-methyl) pyrimidin-2-ylthio]acetamide

[0497] By a similar method as in Example 16, the title compound (420 mg) was obtained as a white amorphous solid from the resultant product (200 mg) of (157-1) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (330 mg).
¹H-NMR(DMSO-d₆) δ 1.29(3H, t, J=7.1Hz), 1.76-1.81(1H, m), 1.97-2.04(1H, m), 2.52-2.55(1H, m), 2.61-2.65(1H, m), 2.66(3H, s), 3.11-3.15(2H, m), 3.41-3.49(4H, m), 3.72-3.77(1H, m), 3.89(2H, s), 4.29(2H, q, J=7.1Hz), 7.28(1H, dd, J=1.4, 8.3Hz), 7.52(1H, d, J=1.4Hz), 7.56(1H, d, J=8.3Hz), 8.19(1H, dd, J=5.8, 5.8Hz), 8.88(1H s).
MS(ESI)m/z:513[M+H].

Example 158 (Reference Example)

Synthesis of (2S)-[4-(2-carboxyethyl)phenylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0498] 

[0499] By a similar method as in (1-4), the title compound (350 mg) was obtained as a white amorphous solid from 3-(4-mercaptophenyl)propionic acid (200 mg) and the resultant product (400 mg) of (1-2).
¹H-NMR(DMSO-d₆) δ 1.73-1.78(1H, m), 1.98-2.06(1H, m), 2.47-2.67(4H, m), 2.77(2H, t, J=7.6Hz), 3.08-3.12(2H, m), 3.38-3.48(4H, m), 3.58(2H, s), 3.74-3.78(1H, m), 7.14-7.18(2H, m), 7.22-7.30(3H, m), 7.51-7.53(1H, m), 7.56(1H, d, J=8.0Hz), 8.12(1H, dd, J=5.8, 5.8Hz), 12.08(1H, brs).
MS(ESI)m/z:497[M+H].

Example 159 (Reference Example)

Synthesis of (2S)-[4-(2-carbamoylethyl)phenylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0500] 

[0501] By a similar method as in Example 8, the title compound (220 mg) was obtained as a white solid from the resultant product (230 mg) of Example 158.
¹H-NMR(DMSO-d₆) δ 1.72-1.78(1H, m), 2.00-2.05(1H, m), 2.31(2H, t, J=7.8Hz), 2.52-2.62(2H, m), 2.75(2H, t, J=7.8Hz), 3.08-3.12(2H, m), 3.38-3.48(4H, m), 3.58(2H, s), 3.73-3.78(1H, m), 6.72(1H, brs), 7.12-7.17(2H, m), 7.23-7.30(4H, m), 7.52(1H, d, J=1.5Hz), 7.57(1H, d, J=8.4Hz), 8.11(1H, dd, J=5.9, 5.9Hz).
MS (ESI)m/z:496[M+H].

Example 160

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(4-methyl-2-oxo-2H-chromen-7-ylthio)acetamide

[0502] 

[0503] By a similar method as in (1-4), the title compound (450 mg) was obtained as a white amorphous solid from 7-mercapto-4-methyl-2H-chromen-2-one (200 mg) and the resultant product (380 mg) of (1-2).
¹H-NMR(DMSO-d₆) δ 1.72-1.77(1H, m), 1.95-2.02(1H, m), 2.39(3H, s), 2.50-2.52(1H, m), 2.56-2.59(1H, m), 3.12-3.15(2H, m), 3.36(2H, s), 3.40-3.47(2H, m), 3.72-3.84(3H, m), 6.30(1H, s), 7.21-7.29(2H, m), 7.35(1H, d, J=1.5Hz), 7.46-7.47(1H, m), 7.55(1H, d, J=8.1Hz), 7.66(1H, d, J=8.4Hz), 8.29(1H, dd, J=5.8, 5.8Hz).
MS(ESI)m/z:507[M+H].

Example 161 (Reference Example)

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(4-ethoxycarbonylmethylphenylthio)acetamide

[0504] 

(161-1) Synthesis of 4-ethoxycarbonylmethylphenylthio-acetic acid

[0505] Ethyl 4-bromophenylacetate (500 mg), diisopropylethylamine (700 µL), tris(dibenzylidenacetone)dipalladium(0) (46 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xant-phos) (58 mg) were dissolved in dioxane (5 mL). Then, thioglycol acid (140 µL) was added, and the mixture was heated under reflux for 4 h. The reaction mixture was poured into water, the aqueous phase was washed with ethyl acetate and acidified with 1 mol/L hydrochloric acid. Then, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (260 mg) as a colorless oil.

(161-2) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(4-ethoxycarbonylmethylphenylthio)-acetamide

[0506] By a similar method as in Example 16, the title compound (220 mg) was obtained as a white amorphous solid from the resultant product (260 mg) of (161-1) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (350 mg).
¹H-NMR(DMSO-d₆) δ 1.16(3H, t, J=7.1Hz), 1.73-1.80(1H, m), 1.98-2.07 (1H, m), 2.52-2.63(2H, m), 3.08-3.15(2H, m), 3.40-3.49(4H, m), 3.61(2H, s), 3.62(2H, s), 3.73-3.78 (1H, m), 4.05(2H, q, J=7.1Hz), 7.19(2H, d, J=8.3Hz), 7.26-7.30(3H, m), 7.53(1H, d, J=1.9Hz), 7.57(1H, d, J=8.5Hz), 8.15(1H, dd, J=5.8, 5.8Hz). MS (ESI)m/z: 511[M+H].

Example 162 (Reference Example)

Synthesis of (2S)-(4-carboxymethylphenylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0507] 

[0508] By a similar method as in (1-5), the title compound (130 mg) was obtained as a white amorphous solid from the resultant product (180 mg) of (161-2).
¹H-NMR(DMSO-d₆) δ 1.73-1.79(1H, m), 2.00-2.06(1H, m), 2.52-2.68(2H, m), 3.08-3.12(2H, m), 3.40-3.49(4H, m), 3.52(2H, s), 3.61(2H, s), 3.74-3.78(1H, m), 7.17-7.21(2H, m), 7.26-7.31(3H, m), 7.53(1H, d, J=1.2Hz), 7.57 (1H, d, J=8.3Hz), 8.15(1H, dd, J=5.8, 5.8Hz).
MS (ESI)m/z:483[M+H].

Example 163

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(4-hydroxy-5-methyl-pyrimidin-2-ylthio)acetamide

[0509] 

[0510] By a similar method as in (1-4), the title compound (270 mg) was obtained as a white solid from 4-hydroxy-2-mercapto-5-methylpyrimidine (150 mg) and the resultant product (380 mg) of (1-2).
¹H-NMR(DMSO-d₆) δ 1.76-1.82(1H, m), 1.85(3H, s), 1.97-2.06(1H, m), 2.51-2.56(1H, m), 2.63-2.67(1H, m), 3.08-3.12(2H, m), 3.42-3.49(4H, m), 3.72-3.78(1H, m), 3.80-3.83(2H, m), 7.29(1H, dd, J=1.5, 8.0Hz), 7.53(1H, d, J=1.5Hz), 7.58(1H, d, J=8.0Hz), 7.69(1H, brs), 8.17(1H, dd, J=5.8, 5.8Hz), 12.71(1H, brs).
MS(ESI)m/z:457[M+H].

Example 164

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(4-hydroxypyrimidin-2-ylthio)acetamide

[0511] 

[0512] By a similar method as in (1-4), the title compound (130 mg) was obtained as a white solid from 2-thiouracil (130 mg) and the resultant product (380 mg) of (1-2).
¹H-NMR(DMSO-d₆) δ 1.76-1.83(1H, m), 2.00-2.07(1H, m), 2.51-2.57(1H, m), 2.63-2.67(1H, m), 3.09-3.13(2H, m), 3.42-3.49(4H, m), 3.73-3.85(3H, m), 6.13(1H, brs), 7.29(1H, dd, J=1.6, 8.0Hz), 7.53(1H, d, J=1.6Hz), 7.58(1H, d, J=8.0Hz), 7.81(1H, brs), 8.15-8.21(1H, m), 12.74(1H, brs).
MS (ESI)m/z:443[M+H].

Example 165

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(4-hydroxy-5-ethoxycarbonylpyrimidin-2-ylthio)-acetamide

[0513] 

[0514] By a similar method as in (1-4), the title compound (380 mg) was obtained as a yellow solid from 5-ethoxycarbonyl-2-thiouracil (210 mg) and the resultant product (400 mg) of (1-2).
¹H-NMR(DMSO-d₆) δ 1.21(3H, t, J=7.0Hz), 1.76-1.82(1H, m), 1.97-2.03(1H, m), 2.51-2.53(1H, m), 2.63-2.66(1H, m), 3.05-3.16(2H, m), 3.37-3.47(4H, m), 3.67-3.77(3H, m), 4.15(2H, q, J=7.0Hz), 7. 28 (1H, dd, J=1.3, 8.4Hz), 7.52(1H, d, J=1.3Hz), 7.56(1H, d, J=8.4Hz), 8.24-8.29(1H, m), 8.32(1H, s).
MS (ESI)m/z:515 [M+H] .

Example 166

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(4-ethoxycarbonylmethyl-6,7-dimethoxyquinazolin-2-ylthio)acetamide

[0515] 

(166-1) Synthesis of 2-chloro-4-[bis(ethoxycarbonyl) methyl]-6,7-dimethoxyquinazoline

[0516] Diethyl malonate (0.76 mL) was dissolved in dioxane (25 mL), sodium hydride (200 mg) was added, and the mixture was stirred at room temperature for 30 min. Then, 2,4-dichloro-6,7-dimethoxyquinazoline (1.3 g) was added, and the mixture was heated under reflux for 3.5 h. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from a mixed solvent of ethyl acetate and hexane to give the title compound (840 mg) as a white solid.

(166-2) Synthesis of 4-[bis(ethoxycarbonyl)methyl]-2-mercapto-6,7-dimethoxyquinazoline

[0517] The resultant product (600 mg) of (166-1) and thiourea (250 mg) were dissolved in ethanol (100 mL), and the mixture was heated under reflux for 48 h. The yellow solid precipitated in the reaction mixture was collected by filtration and washed with water and ethyl acetate to give the title compound (500 mg) as a yellow solid.

(166-3) Synthesis of 4-ethoxycarbonylmethyl-2-mercapto-6,7-dimethoxyquinazoline

[0518] By a similar method as in (1-5), the title compound (71 mg) was obtained as a white amorphous solid from the resultant product (180 mg) of (166-2).

(166-4) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl) morpholin-2-yl]methyl}-[(4-ethoxycarbonylmethyl-6,7-dimethoxyquinazoline)-2-ylthio]acetamide

[0519] By a similar method as in (1-4), the title compound (18 mg) was obtained as a white solid from the resultant product (71 mg) of (166-3) and the resultant product (77 mg) of (1-2).
¹H-NMR(DMSO-d₆) δ 1.17(3H, t, J=7.1Hz), 1.68-1.76(1H, m), 1.85-1.89(1H, m), 2.42-2.46(1H, m), 2.54-2.56(1H, m), 3.11-3.16(2H, m), 3.24(2H, s), 3.35-3.50(2H, m), 3.63-3.68(1H, m), 3.86-3.91(5H, m), 3.97(3H, s), 4.12(2H, q, J=7.1Hz), 4.30(2H, s), 7.16-7.22(2H, m), 7.38(1H, s), 7.43(1H, s), 7.54(1H, d, J=8.0Hz), 8.11-8.17(1H, m).
MS(ESI)m/z:623[M+H].

Example 167

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(4-methoxycarbonyl-1-methyl-2,3-dihydro-1H-benzo[b]azepin-7-ylthio)acetamide

[0520] 

(167-1) Synthesis of 4-methoxycarbonyl-1-methyl-2,3-di-hydro-1H-benzo[b]azepin-7-ylthioacetic acid

[0521] By a similar method as in (161-1), the title compound (430 mg) was obtained as a yellow oil from 7-bromo-4-methoxycarbonyl-1-methyl-2,3-dihydro-1H-benzo[b]azepine (600 mg) and thioglycol acid (140 µL).

(167-2) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl) morpholin-2-yl]methyl}-(4-methoxycarbonyl-1-methyl-2,3-dihydro-1H-benzo[b]azepin-7-ylthio)acetamide

[0522] By a similar method as in Example 16, the title compound (350 mg) was obtained as a yellow amorphous solid from the resultant product (420 mg) of (167-1) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (480 mg).
¹H-NMR(DMSO-d₆) δ 1.69-1.76(1H, m), 1.95-2.03(1H, m), 2.51-2.59(2H, m), 2.68-2.72(2H, m), 2.96(3H, s), 3.05-3.10(2H, m), 3.16-3.21(2H, m)3.36-3.49(6H, m), 3.69-3.76(4H, m), 6.78(1H, d, J=8.7Hz), 7.23-7.27(2H, m), 7.40(1H, d, J=2.0Hz), 7.48-7.57(3H, m), 8.01(1H, dd, J=5.6, 5.6Hz).
MS(ESI)m/z:564[M+H].

Example 168

Synthesis of (2S)-(4-carboxy-1-methyl-2,3-dihydro-1H-benzo[b]azepin-7-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0523] 

[0524] By a similar method as in (1-5), the title compound (170 mg) was obtained as a white amorphous solid from the resultant product (330 mg) of (167-2).
¹H-NMR(DMSO-d₆) δ 1.70-1.77(1H, m), 1.95-2.03(1H, m), 2.53-2.59(2H, m), 2.65-2.69(2H, m), 2.95(3H, s), 3.05-3.10(2H, m), 3.14-3.20(2H, m)3.39-3.49(6H, m), 3.71-3.76(1H, m), 6.76(1H, d, J=8.6Hz), 7.20-7.28(2H, m), 7.37(1H, d, J=1.1Hz), 7.48-7.57(3H, m), 8.01(1H, dd, J=5.3, 5.3Hz), 12.43(1H, brs).
MS (ESI)m/z:550[M+H] .

Example 169

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yllmethyll-(pyridin-4-ylthio)acetamide

[0525] 

[0526] By a similar method as in Example 16, the title compound (290 mg) was obtained as a white amorphous solid from pyridin-4-ylthioacetic acid (0.3 g) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (0.6 g).
¹H-NMR(DMSO-d₆) δ 1.72-1.79(1H, m), 1.98-2.06(1H, m), 2.52-2.62(2H, m), 3.10-3.15(2H, m), 3.40-3.49(4H, m), 3.74-3.80(3H, m), 7.25-7.29(3H, m), 7.52 (1H, d, J=1.3Hz), 7.57 (1H, d, J=8.4Hz), 8.27-8.32 (1H, m), 8.36(2H, d, J=6.1Hz).
MS(ESI)m/z:426[M+H].

Example 170

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(thieno[3,2-c]pyridin-4-ylthio)acetamide

[0527] 

(170-1) Synthesis of 4-mercaptothieno[3,2-c]pyridine

[0528] By a similar method as in (166-2), the title compound (240 mg) was obtained as a brown solid from 4-chlorothieno[3,2-c]pyridine (0.5 g) and thiourea (350 mg).

(170-1) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(thieno[3,2-c]pyridin-4-ylthio)acetamide

[0529] By a similar method as in (1-4), the title compound (250 mg) was obtained as a white amorphous solid from the resultant product (230 mg) of (170-1) and the resultant product (500 mg) of (1-2).
¹H-NMR(DMSO-d₆) δ 1.70-1.77(1H, m), 1.90-1.98(1H, m), 2.49-2.55(1H, m), 2.58-2.63(1H, m), 3.07-3.16(2H, m), 3.36-3.46(4H, m), 3.69-3.74(1H, m), 3.98-4.02(2H, m), 7.24-7.29(1H, m), 7.49-7.53(2H, m), 7.56(1H, d, J=8.1Hz), 7.84(1H, d, J=5.5Hz), 7.93(1H, d, J=5.5Hz), 8.18(1H, dd, J=5.6, 5.6Hz), 8.23(1H, d, J=5.7Hz).
MS (ESI)m/z:482 [M+H].

Example 171 (Reference Example)

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(1-oxoindan-5-ylthio)acetamide

[0530] 

(171-1) Synthesis of 1-oxoindan-5-ylthioacetic acid

[0531] By a similar method as in (161-1), the title compound (100 mg) was obtained as a yellow solid from 5-bromo-1-indanone (450 mg) and thioglycol acid (140 µL).

(171-2) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)-morpholin-2-yl]methyl}-(1-oxoindan-5-ylthio)acetamide

[0532] By a similar method as in Example 16, the title compound (90 mg) was obtained as a white amorphous solid from the resultant product (100 mg) of (171-1) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (160 mg).
¹H-NMR(DMSO-d₆) δ 1.72-1.79(1H, m), 1.98-2.04(1H, m), 2.51-2.63(4H, m), 3.04(2H, t, J=5.4Hz), 3.11-3.15(2H, m), 3.38-3.49(4H, m), 3.72-3.80(3H, m), 7.24-7.33(2H, m), 7.46-7.59(4H, m), 8.25-8.30(1H, m).
MS(ESI)m/z:479[M+H].

Example 172

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(2-methoxycarbonylfuran-5-ylthio)acetamide

[0533] 

(172-1) Synthesis of 2-methoxycarbonylfuran-5-ylthioacetic acid

[0534] By a similar method as in (161-1), the title compound (750 mg) was obtained as a white solid from 5-bromo-2-methoxycarbonylfuran (820 mg) and thioglycol acid (300 µL).

(172-2) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(2-methoxycarbonylfuran-5-ylthio)acetamide

[0535] By a similar method as in Example 16, the title compound (1.6 g) was obtained as a white amorphous solid from the resultant product (750 mg) of (172-1) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (1.2 g).
¹H-NMR(DMSO-d₆) δ 1.72-1.79(1H, m), 1.99-2.06(1H, m), 2.53-2.58(1H, m), 2.59-2.64(1H, m), 3.05-3.13(2H, m), 3.39-3.49(4H, m), 3.63(2H, s), 3.73-3.80(4H, m), 6.69(1H, d, J=3.6H), 7.30(1H, dd, J=1.3, 8.4Hz), 7.32(1H, d, J=3.6Hz), 7.53-7.56(1H, m), 7.58(1H, d, J=8.4Hz), 8.21(1H, dd, J=5.7, 5.7Hz).
MS (ESI)m/z:473[M+H].

Example 173 (Reference Example)

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(1-oxoindan-6-ylthio)acetamide

[0536] 

(173-1) Synthesis of 1-oxoindan-6-ylthioacetic acid

[0537] By a similar method as in (161-1), the title compound (90 mg) was obtained as a white solid from 6-bromo-1-indanone (420 mg) and thioglycol acid (140 µL).

(173-2) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(1-oxoindan-6-ylthio)acetamide

[0538] By a similar method as in Example 16, the title compound (180 mg) was obtained as a white amorphous solid from the resultant product (90 mg) of (173-1) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (140 mg).
¹H-NMR(DMSO-d₆) δ 1.71-1.78(1H, m), 1.97-2.05(1H, m), 2.51-2.61(2H, m), 2.62(2H, t, J=5.8Hz), 3.04(2H, t, J=5.8Hz), 3.07-3.12(2H, m), 3.38-3.47(4H, m), 3.69(2H, s), 3.72-3.76(1H, m), 7.27(1H, dd, J=1.5, 8.3Hz), 7.50-7.53(2H, m), 7.54-7.58(2H, m), 7.60-7.64(1H, m), 8.18(1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:479[M+H].

Example 174

Synthesis of (2S)-(3-acetyl-2-oxo-2H-chromen-6-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0539] 

(174-1) Synthesis of 3-acetyl-2-oxo-2H-chromen-6-ylthio-acetic acid

[0540] By a similar method as in (161-1), the title compound (300 mg) was obtained as a yellow solid from 6-bromo-3-acetyl-2H-chromen-2-one (520 mg) and thioglycol acid (140 µL).

(174-2) Synthesis of (2S)-(3-acetyl-2-oxo-2H-chromen-6-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl} acetamide

[0541] By a similar method as in Example 16, the title compound (100 mg) was obtained as a yellow solid from the resultant product (300 mg) of (174-1) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (340 mg).
¹H-NMR(DMSO-d₆) δ 1.68-1.76(1H, m), 1.94-2.02 (1H, m), 2.51-2.58(5H, m), 3.08-3.12(2H, m), 3.35-3.45(4H, m), 3.68(2H, s), 3.71-3.75(1H, m), 7.25(1H, dd, J=1.6, 8.3Hz), 7.43(1H, d, J=8.6Hz), 7.49(1H, d, J=1.6Hz), 7.55(1H, d, J=8.3Hz), 7.72(1H, dd, J=2.2, 8.6Hz), 7.94(1H, d, J=2.2Hz), 8.18(1H, dd, J=5.7, 5.7Hz), 8.55(1H, s).
MS(ESI)m/z:535[M+H].

Example 175

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-{4-[bis(ethoxycarbonyl)methyl]pyrimidin-2-ylthio}acetamide

[0542] 

(175-1) Synthesis of 2-chloro-4-[bis(ethoxycarbonyl) methyl]pyrimidine

[0543] By a similar method as in (166-1), the title compound (1.3 g) was obtained as a yellow solid from 2,4-dichloropyrimidine (2 g) and diethyl malonate (480 mg).

(175-2) Synthesis of 4-[bis(ethoxycarbonyl)methyl]-2-mercaptopyrimidine

[0544] By a similar method as in (166-2), the title compound (510 mg) was obtained as a yellow solid from the resultant product (530 mg) of (175-1) and thiourea (150 mg).

(175-3) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-{4-[bis(ethoxycarbonyl)methyl]pyrimidin-2-ylthio}acetamide

[0545] By a similar method as in (1-4), the title compound (370 mg) was obtained as a white amorphous solid from the resultant product (210 mg) of (175-2) and the resultant product (300 mg) of (1-2).
¹H-NMR(DMSO-d₆) δ 1.14-1.24(6H, m), 1.75-1.81(1H, m), 1.97-2.06(1H, m), 2.51-2.56(1H, m), 2.62-2.67(1H, m), 3.08-3.13(2H, m), 3.40-3.49(4H, m), 3.72-3.76(1H, m), 3.81(2H, s), 4.13-4.20(4H, m), 5.14(1H, s), 7.25-7.31(2H, m), 7.53(1H, d, J=1.8Hz), 7.57(1H, d, J=8.4Hz), 8.11(1H, dd, J=5.7, 5.7Hz), 8.63(1H, d, J=5.3Hz).
MS (ESI)m/z:585[M+H].

Example 176

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(3-methoxycarbonyl-2-oxo-2H-chromen-6-ylthio)acetamide

[0546] 

(176-1) Synthesis of 3-methoxycarbonyl-2-oxo-2H-chromen-6-ylthioacetic acid

[0547] By a similar method as in (161-1), the title compound (830 mg) was obtained as a yellow solid from 6-bromo-3-methoxycarbonyl-2H-chromen-2-one (1 g) and thioglycol acid (700 µL).

(176-2) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(3-methoxycarbonyl-2-oxo-2H-chromen-6-ylthio)acetamide

[0548] By a similar method as in Example 16, the title compound (1.1 g) was obtained as a yellow solid from the resultant product (820 mg) of (176-1) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (970 mg).
¹H-NMR(DMSO-d₆) δ 1.68-1.73(1H, m), 1.93-2.01(1H, m), 2.51-2.58(2H, m), 3.07-3.12(2H, m), 3.35-3.45(4H, m), 3.68(2H, s), 3.71-3.75(1H, m), 3.82(3H, s), 7.25(1H, dd, J=1.7, 8.0Hz), 7.42(1H, d, J=8.7Hz), 7.49(1H, d, J=1.7Hz), 7.56(1H, d, J=8.0Hz), 7.73(1H, dd, J=2.2, 8.7Hz), 7.92(1H, d, J=2.2Hz), 8.22(1H, dd, J=5.8, 5.8Hz), 8.70(1H, s).
MS (ESI)m/z:551[M+H].

Example 177 (Reference Example)

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(4-methoxycarbonylphenylsulfinyl)acetamide

[0549] 

(177-1) Synthesis of 4-methoxycarbonylphenylthioacetic acid

[0550] By a similar method as in (161-1), the title compound (2.1 g) was obtained as a white solid from methyl 4-bromobenzoate (3 g) and thioglycol acid (1 mL).

(177-2) Synthesis of 4-methoxycarbonylphenylsulfinylacetic acid

[0551] The resultant product (300 mg) of (177-1) was dissolved in dichloromethane (10 mL), and m-chloroperbenzoic acid (290 mg) was added. The mixture was stirred at room temperature 2 h, and the solid precipitated in the reaction mixture was collected by filtration to give the title compound (230 mg) as a white solid.

(177-3) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl) morpholin-2-yl]methyl}-(4-methoxycarbonylphenylsulfinyl)-acetamide

[0552] By a similar method as in Example 16, the title compound (410 mg) was obtained as a white amorphous solid from the resultant product (230 mg) of (177-2) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (330 mg).
¹H-NMR(DMSO-d₆) δ 1.72-1.82(1H, m), 1.98-2.08(1H, m), 2.52-2.58(1H, m), 2.61-2.66(1H, m), 3.02-3.17(2H, m), 3.30-3.50(4H, m), 3.72-3.83(2H, m), 3.86-3.93(4H, m), 7.27-7.33 (1H, m), 7.53-7.57 (1H, m), 7.59 (1H, d, J=8.3Hz), 7.81(2H, d, J=8.4Hz), 8.13(2H, d, J=8.4Hz), 8.24-8.29(1H, m).
MS(ESI)m/z:499[M+H].

Example 178 (Reference Example)

Synthesis of (2S)-(4-carboxyphenylsulfinyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0553] 

[0554] By a similar method as in (1-5), the title compound (95 mg) was obtained as a white solid from the resultant product (400 mg) of (177-3).
¹H-NMR(DMSO-d₆) δ 1.73-1.84(1H, m), 2.02-2.10(1H, m), 2.53-2.58(1H, m), 2.62-2.67(1H, m), 3.01-3.19(2H, m), 3.42-3.49(4H, m), 3.73-3.91(3H, m), 7.31(1H, d, J=8.1Hz), 7.54(1H, s), 7.58(1H, d, J=8.1Hz), 7.78(2H, d, J=8.2Hz), 8.10(2H, d, J=8.2Hz), 8.20-8.25(1H, m), 13.21(1H, brs).
MS(ESI)m/z:485[M+H].

Example 179 (Reference Example)

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(2-methoxycarbonylnaphthalen-6-ylthio)acetamide

[0555] 

(179-1) Synthesis of 2-methoxycarbonylnaphthalen-6-ylthioacetic acid

[0556] By a similar method as in (161-1), the title compound (460 mg) was obtained as a white solid from methyl 6-bromo-2-naphtoate (1 g) and thioglycol acid (300 µL).

(179-2) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(2-methoxycarbonylnaphthalen-6-ylthio)acetamide

[0557] By a similar method as in Example 16, the title compound (870 mg) was obtained as a white amorphous solid from the resultant product (460 mg) of (179-1) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (570 mg).
¹H-NMR(DMSO-d₆) δ 1.62-1.69(1H, m), 1.83-1.92(1H, m), 2.41-2.49(2H, m), 3.09-3.20(4H, m), 3.36-3.44(2H, m), 3.68-3.73(1H, m), 3.83-3.86(2H, m), 3.89(3H, s), 7.15(1H, dd, J=1.1, 8.4Hz), 7.37(1H, d, J=1.1Hz), 7.52(1H, d, J=8.4Hz), 7.53-7.57(1H, m), 7.87-7.91(2H, m), 7.93-7.98(1H, m), 8.07(1H, d, J=8.7Hz), 8.32(1H, dd, J=5.7, 5.7Hz), 8.56(1H, s).
MS(ESI)m/z:533[M+H].

Example 180 (Reference Example)

Synthesis of (2S)-(2-carboxynaphthalen-6-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0558] 

[0559] By a similar method as in (1-5), the title compound (430 mg) was obtained as a white solid from the resultant product (750 mg) of (179-2).
¹H-NMR(DMSO-d₆) δ 1.64-1.72(1H, m), 1.86-1.95(1H, m), 2.43-2.54(2H, m), 3.10-3.16(2H, m), 3.23(2H, s), 3.36-3.45(2H, m), 3.69-3.74(1H, m), 3.78-3.85(2H, m), 7.17(1H, dd, J=1.3, 8.3Hz), 7.41(1H, d, J=1.3Hz), 7.50-7.55(2H, m), 7.84-7.88(2H, m), 7.96(1H, d, J=8.6Hz), 8.03(1H, d, J=8.7Hz), 8.26(1H, dd, J=5.8, 5.8Hz), 8.54(1H, s), 12.99(1H, brs).
MS(ESI)m/z:519[M+H].

Example 181

Synthesis of (2S)-(2-carboxyfuran-5-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0560] 

[0561] By a similar method as in (1-5), the title compound (210 mg) was obtained as a white solid from the resultant product (1.6 g) of (172-2).
¹H-NMR(DMSO-d₆) δ 1.77-1.84(1H, m), 2.04-2.11(1H, m), 2.55-2.60(1H, m), 2.63-2.68(1H, m), 3.08-3.12(2H, m), 3.43-3.51(4H, m), 3.60(2H, s), 3.74-3.79(1H, m), 6.65(1H, d, J=3.2H), 7.19(1H, d, J=3.2Hz), 7.28-7.32(1H, m), 7.53-7.59(2H, m), 8.14-8.20(1H, m).
MS (ESI)m/z:459[M+H].

Example 182

Synthesis of (2S)-(3-carboxy-2-oxo-2H-chromen-6-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0562] 

[0563] By a similar method as in (1-5), the title compound (270 mg) was obtained as a yellow amorphous solid from the resultant product (780 mg) of (176-2).
¹H-NMR(DMSO-d₆) δ 1.69-1.76(1H, m), 1.95-2.04(1H, m), 2.51-2.60(2H, m), 3.07-3.12(2H, m), 3.37-3.46(4H, m), 3.66-3.76(3H, m), 7.26(1H, dd, J=1.4, 8.4Hz), 7.40(1H, d, J=8.7Hz), 7. 50 (1H, d, J=1.4Hz), 7. 55 (1H, d, J=8.4Hz), 7.71(1H, dd, J=2.2, 8.7Hz), 7.90(1H, d, J=2.2Hz), 8.18(1H, dd, J=5.7, 5.7Hz), 8.64(1H, s).
MS(ESI)m/z:537[M+H]

Example 183 (Reference Example)

Synthesis of (2S)-(3-carboxyphenylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0564] 

[0565] By a similar method as in (1-4), the title compound (3 g) was obtained as a white amorphous solid from 3-mercaptobenzoic acid (1.26 g) and the resultant product (3.2 g) of (1-2).
¹H-NMR(DMSO-d6) δ 1.69-1.77(1H, m), 1.98-2.04(1H, m), 2.52-2.59(2H, m), 3.08-3.13(2H, m), 3.39-3.47(4H, m), 3.68-3.76(3H, m), 7.27(1H, dd, J=1.2, 8.3Hz), 7.42(1H, t, J=7.8Hz), 7.51(1H, d, J=1.2Hz), 7.55-7.60(2H, m), 7.74(1H, d, J=7.8Hz), 7.86(1H, s), 8.24(1H, dd, J=5.8, 5.8Hz).
MS(ESI)m/z:469[M+H].

Example 184 (Reference Example)

Synthesis of (2S)-(3-carbamoylphenylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0566] 

[0567] By a similar method as in Example 8, the title compound (200 mg) was obtained as a white amorphous solid from the resultant product (250 mg) of Example 183.
¹H-NMR(DMSO-d₆) δ 1.69-1.76(1H, m), 1.96-2.04(1H, m), 2.51-2.60(2H, m), 3.08-3.13(2H, m), 3.38-3.47(4H, m), 3.69-3.76(3H, m), 7.27(1H, dd, J=1.5, 8.0Hz), 7.34-7.42(2H, m), 7.45-7.50(1H, m), 7.52(1H, d, J=1.5Hz), 7.56(1H, d, J=8.0Hz), 7.64-7.70(1H, m), 7.81(1H, s), 7.96(1H, brs), 8.15(1H, dd, J=5.8, 5.8Hz).
MS (ESI)m/z:468[M+H].

Example 185 (Reference Example)

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(3-methoxycarbonylmethylphenylthio)acetamide

[0568] 

(185-1) Synthesis of 3-methoxycarbonylmethylphenylthioacetic acid

[0569] By a similar method as in (161-1), the title compound (450 mg) was obtained as a colorless oil from methyl 3-bromophenylacetate (1 g) and thioglycol acid (900 µL).

(185-2) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)-morpholin-2-yl]methyl}-(3-methoxycarbonylmethylphenylthio)acetamide

[0570] By a similar method as in Example 16, the title compound (170 mg) was obtained as a white amorphous solid from the resultant product (450 mg) of (185-1) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (600 mg).
¹H-NMR(DMSO-d₆) δ 1.72-1.79(1H, m), 1.98-2.06(1H, m), 2.52-2.62(2H, m), 3.08-3.13(2H, m), 3.40-3.48(4H, m), 3. 60 (3H, s), 3.63(2H, s), 3.64(2H, s), 3.73-3.78(1H, m), 7.05-7.10(1H, m), 7.19-7.30(4H, m), 7.52(1H, d, J=1.6Hz), 7.57(1H, d, J=8.0Hz), 8.15(1H, dd, J=5.7, 5.7Hz).
MS (ESI)m/z:497 [M+H].

Example 186 (Reference Example)

Synthesis of (2S)-(3-carboxymethylphenylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0571] 

[0572] By a similar method as in (1-5), the title compound (140 mg) was obtained as a white amorphous solid from the resultant product (160 mg) of (185-2).
¹H-NMR(DMSO-d₆) δ 1.73-1.79(1H, m), 1.99-2.06(1H, m), 2.52-2.62(2H, m), 3.09-3.13(2H, m), 3.41-3.49(4H, m), 3.53(2H, s), 3.63(2H, s), 3.74-3.78(1H, m), 7.05-7.09(1H, m), 7.19-7.30(4H, m), 7.52(1H, d, J=1.2Hz), 7.57(1H, d, J=8.3Hz), 8.15(1H, dd, J=5.6, 5.6Hz).
MS(ESI)m/z:483[M+H].

Example 187

Synthesis of (2S)-N-{[4-(3-chloro-4-fluorobenzyl)morpholin-2-yl]methyl}-(4-hydroxypyrimidin-2-ylthio)acetamide

[0573] 

[0574] By a similar method as in (1-4), the title compound (80 mg) was obtained as a white solid from 2-mercaptouracil (135 mg) and the resultant product (400 mg) of (111-1).
¹H-NMR(DMSO-d₆) δ 1.75-1.82(1H, m), 1.97-2.06(1H, m), 2.51-2.57(1H, m), 2.63-2.68(1H, m), 3.09-3.14(2H, m), 3.39-3.50(4H, m), 3.73-3.77(1H, m), 3.79-3.87(2H, m), 6.12(1H, brs), 7.27-7.41(2H, m), 7.46-7.50(1H, m), 7.82(1H, brs), 8.15-8.22(1H, m), 12.74(1H, brs).
MS(ESI)m/z:427[M+H].

Example 188 (Reference Example)

Synthesis of (2S)-N-{[4-(3-chloro-4-fluorobenzyl)morpholin-2-yl]methyl}-(4-methoxycarbonylphenylthio)acetamide

[0575] 

[0576] By a similar method as in Example 16, the title compound (640 mg) was obtained as a white amorphous solid from the resultant product (330 mg) of (177-1) and (2S)-2-aminomethyl-4-(3-chloro-4-fluorobenzyl)morpholine dihydrochloride (490 mg).
¹H-NMR(DMSO-d₆) δ 1.69-1.76(1H, m), 1.95-2.03(1H, m), 2.51-2.59(2H, m), 3.09-3.14(2H, m), 3.36(2H, s), 3.39-3.48(2H, m), 3.72-3.77(3H, m), 3.83(3H, s), 7.23-7.29 (1H, m), 7.34 (1H, dd, J=8.7, 9.1Hz), 7.40-7.46(3H, m), 7.83-7.87(2H, m), 8.24 (1H, dd, J=5.8, 5.8Hz).
MS (ESI) m/z:467 [M+H].

Example 189 (Reference Example)

Synthesis of (2S)-(4-carboxyphenylthio)-N-{[4-(3-chloro-4-fluorobenzyl)morpholin-2-yl]methyl}acetamide

[0577] 

[0578] By a similar method as in (1-5), the title compound (340 mg) was obtained as a white amorphous solid from the resultant product (420 mg) of Example 188.
¹H-NMR(DMSO-d₆) δ 1.70-1.75(1H, m), 1.96-2.02(1H, m), 2.51-2.59(2H, m), 3.10-3.14(2H, m), 3.37(2H, s), 3.43-3.47(2H, m), 3.71-3.79(3H, m), 7.24-7.29(1H, m), 7.33(1H, dd, J=8.7, 9.1Hz), 7.40(2H, d, J=8.5Hz), 7.43-7.46(1H, m), 7.83(2H, d, J=8.5Hz), 8.23(1H, dd, J=5.7, 5.7Hz), 12.85(1H, brs).
MS(ESI)m/z:453[M+H].

Example 190 (Reference Example)

Synthesis of (2S)-(4-carbamoylphenylthio)-N-{[4-(3-chloro-4-fluorobenzyl)morpholin-2-yl]methyl}acetamide

[0579] 

[0580] By a similar method as in Example 8, the title compound (130 mg) was obtained as a white solid from the resultant product (220 mg) of Example 189.
¹H-NMR(DMSO-d₆) δ 1.69-1.75(1H, m), 1.96-2.03(1H, m), 2.51-2.60(2H, m), 3.10-3.14(2H, m), 3.37(2H, s), 3.40-3.47(2H, m), 3.71-3.78(3H, m), 7.24-7.38(5H, m), 7.44-7.47(1H, m), 7.80(2H, d, J=8.2Hz), 7.91(1H, brs), 8.20(1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:452[M+H].

Example 191 (Reference Example)

Synthesis of (2S)-(4-carboxyphenylsulfonyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0581] 

(191-1) Synthesis of 4-methoxycarbonylphenylsulfonylacetic acid

[0582] By a similar method as in (177-2), the title compound (310 mg) was obtained as a white amorphous solid from the resultant product (450 mg) of (177-1).

(191-2) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)-morpholin-2-yl]methyl}-(4-methoxycarbonylphenyl-sulfonyl)acetamide

[0583] By a similar method as in Example 16, the title compound (140 mg) was obtained as a white amorphous solid from the resultant product (310 mg) of (191-1) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (420 mg).

(191-3) Synthesis of (2S)-(4-carboxyphenylsulfonyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0584] By a similar method as in (1-5), the title compound (70 mg) was obtained as a white solid from the resultant product (140 mg) of (191-2).
¹H-NMR(DMSO-d₆) δ 1.73-1.78(1H, m), 2.00-2.07(1H, m), 2.54-2.62(2H, m), 2.99-3.11(2H, m), 3.40-3.50(4H, m), 3.73-3.77(1H, m), 4.36(2H, s), 7.28-7.32(1H, m), 7.53-7.59(2H, m), 7.96(2H, d, J=8.1Hz), 8.15(2H, d, J=8.1Hz), 8.29(1H, dd, J=5.4, 5.4Hz).
MS(ESI)m/z:501[M+H].

Example 192

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(1-methyl-1H-imidazol-2-ylthio)acetamide

[0585] 

[0586] By a similar method as in (1-4), the title compound (250 mg) was obtained as a white amorphous solid from 2-mercapto-1-methyl-1H-imidazole (180 mg) and the resultant product (610 mg) of (1-2).
¹H-NMR(DMSO-d₆) δ 1.74-1.79(1H, m), 2.00-2.07(1H, m), 2.50-2.56(1H, m), 2.62-2.65(1H, m), 3.07-3.10(2H, m), 3.40-3.49(4H, m), 3.57(3H, s), 3.62(2H, s), 3.74-3.77(1H, m), 6.90(1H, s), 7.22(1H, s), 7.30(1H, dd, J=1.8, 8.2Hz), 7.54(1H, d, J=1.8Hz), 7.57(1H, d, J=8.2Hz), 8.23(1H, dd, J=5.6, 5.6Hz).
MS (ESI)m/z:429[M+H].

Example 193 (Reference Example)

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(2-methoxycarbonyl-2-propoxy)phenylthio]-acetamide

[0587] 

(193-1) Synthesis of methyl 2-(4-bromophenoxy)-2-methyl-propionate

[0588] 2-(4-Bromophenoxy)-2-methylpropionic acid (1 g) was dissolved in methanol (5 mL), a catalytic amount of thionyl chloride was added, and the mixture was stirred at room temperature for 7 h. Saturated brine was added to the reaction mixture, and the mixture was extracted with a mixed solvent of chloroform-methanol. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (920 mg) as a colorless oil.

(193-2) Synthesis of 4-(2-methoxycarbonyl-2-propoxy)-phenylthioacetic acid

[0589] By a similar method as in (161-1), the title compound (430 mg) was obtained as a colorless oil from the resultant product (440 mg) of (193-1) and thioglycol acid (120 µL).

(193-3) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)-morpholin-2-yl]methyl}-[4-(2-methoxycarbonyl-2-propoxy)-phenylthio]acetamide

[0590] By a similar method as in Example 16, the title compound (630 mg) was obtained as a white amorphous solid from the resultant product (420 mg) of (193-2) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (510 mg).
¹H-NMR(DMSO-d₆) δ 1.49(6H, s), 1.72-1.78(1H, m), 1.98-2.07(1H, m), 2.52-2.62(2H, m), 3.07-3.11(2H, m), 3.38-3.48(4H, m), 3.52(2H, s), 3.68(3H, s), 3.73-3.77(1H, m), 6.73(2H, d, J=8.6Hz), 7.25-7.31(3H, m), 7.53(1H, d, J=1.3Hz), 7.57(1H, d, J=8.1Hz), 8.05-8.09(1H, m).
MS(ESI)m/z:541[M+H].

Example 194 (Reference Example)

Synthesis of (2S)-[4-(2-carboxy-2-propoxy)phenylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0591] 

[0592] By a similar method as in (1-5), the title compound (360 mg) was obtained as a white amorphous solid from the resultant product (500 mg) of (193-3).
¹H-NMR(DMSO-d₆) δ 1.48(6H, s), 1.74-1.79(1H, m), 2.00-2.07(1H, m), 2.54-2.57(1H, m), 2.60-2.62(1H, m), 3.07-3.10(2H, m), 3.38-3.49(4H, m), 3.51(2H, s), 3.74-3.77 (1H, m), 6.77(2H, d, J=8.9Hz), 7.25-7.31(3H, m), 7.53-7.58(2H, m), 8.06(1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:527[M+H].

Example 195 (Reference Example)

Synthesis of (2S)-[4-(2-carbamoyl-2-propoxy)phenylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0593] 

[0594] By a similar method as in Example 8, the title compound (180 mg) was obtained as a white amorphous solid from the resultant product (240 mg) of Example 194.
¹H-NMR(DMSO-d₆) δ 1.40(6H, s), 1.75-1.80(1H, m), 2.01-2.07(1H, m), 2.54-2.57(1H, m), 2.61-2.64(1H, m), 3.07-3.13(2H, m), 3.40-3.50(4H, m), 3.53(2H, s), 3.74-3.78(1H, m), 6.82-6.86(2H, m), 7.22-7.32(4H, m), 7.47(1H, brs), 7.52-7.59(2H, m), 8.06-8.12(1H, m).
MS(ESI)m/z:526[M+H].

Example 196

Synthesis of (2S)-N-{[4-(3-chloro-4-fluorobenzyl)morpholin-2-yl]methyl}-(6-oxo-1,6-dihydropyridazin-3-ylthio)-acetamide

[0595] 

(196-1) Synthesis of 3-mercapto-6-methoxypyridazine By a similar method as in (166-2), the title compound (1.4 g) was obtained as a yellow solid from 3-chloro-6-methoxypyridazine (2.1 g) and thiourea (1.7 g).

(196-2) Synthesis of ethyl 6-oxo-1,6-dihydropyridazin-3-ylthioacetate

[0596] By a similar method as in (1-4), a white powder was obtained from the resultant product (1.4 g) of (196-1) and ethyl bromoacetate (1.3 mL), and the powder was dissolved in a 1 mol/L hydrogen chloride-ethanol solution (20 mL), and the mixture was heated under reflux for 5 h. The solid precipitated in the reaction mixture was collected by filtration to give the title compound (950 mg) as a white solid.

(196-3) Synthesis of 6-oxo-1,6-dihydropyridazin-3-ylthioacetic acid

[0597] By a similar method as in (1-5), the title compound (280 mg) was obtained as a white solid from the resultant product (790 mg) of (196-2).

(196-4) Synthesis of (2S)-N-{[4-(3-chloro-4-fluorobenzyl) morpholin-2-yllmethyll-(6-oxo-1,6-dihydropyridazin-3-ylthio)acetamide

[0598] By a similar method as in Example 16, the title compound (260 mg) was obtained as a white solid from the resultant product (280 mg) of (196-3) and (2S)-2-aminomethyl-4-(3-chloro-4-fluorobenzyl)morpholine dihydrochloride (520 mg).
¹H-NMR(DMSO-d₆) δ 1.73-1.79(1H, m), 1.97-2.04(1H, m), 2.51-2.55(1H, m), 2.61-2.64(1H, m), 3.09-3.12(2H, m), 3.40-3.48(4H, m), 3.72-3.76(3H, m), 6.81-6.84(1H, m), 7.27-7.40(3H, m), 7.47-7.50(1H, m), 8.13(1H, dd, J=5.8, 5.8Hz), 12.97(1H, s).
MS (ESI)m/z:427[M+H].

Example 197

Synthesis of (2S)-N-{[4-(3-chlorobenzyl)morpholin-2-yl]methyll-(6-oxo-1,6-dihydropyridazin-3-ylthio)acetamide

[0599] 

[0600] By a similar method as in (144-2), the title compound (150 mg) was obtained as a white solid from the resultant product (300 mg) of (196-2) and (2S)-2-aminomethyl-4-(3-chlorobenzyl)morpholine dihydrochloride (400 mg).
¹H-NMR(DMSO-d₆) δ 1.74-1.79(1H, m), 1.98-2.04(1H, m), 2.52-2.55(1H, m), 2.62-2.65(1H, m), 3.09-3.12(2H, m), 3.40-3.49(4H, m), 3.72-3.76(3H, m), 6.82(1H, d, J=9.8Hz), 7.24-7.36(4H, m), 7.39(1H, d, J=9.8Hz), 8.13(1H, dd, J=5.7, 5.7Hz), 12.96(1H, s).
MS(ESI)m/z:409[M+H].

Example 198

Synthesis of (2S)-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}-(6-oxo-1,6-dihydropyridazin-3-ylthio)acetamide

[0601] 

[0602] By a similar method as in (144-2), the title compound (110 mg) was obtained as a white solid from the resultant product (300 mg) of (196-2) and (2S)-2-aminomethyl-4-(3,4-difluorobenzyl)morpholine dihydrochloride (400 mg).
¹H-NMR(DMSO-d₆) δ 1.73-1.79(1H, m), 1.98-2.04(1H, m), 2.51-2.55(1H, m), 2.61-2.64(1H, m), 3.09-3.12(2H, m), 3.41-3.49(4H, m), 3.71-3.77(3H, m), 6.82(1H, d, J=9.8Hz), 7.12-7.16(1H, m), 7.29-7.41(3H, m), 8.13(1H, dd, J=5.5, 5.5Hz), 12.97(1H, s).
MS(ESI)m/z:411[M+H].

Example 199 (Reference Example)

Synthesis of (2S)-4-(4-carboxyphenylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}butyramide

[0603] 

(199-1) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl) morpholin-2-yl]methyl}-4-chlorobutyramide

[0604] By a similar method as in (1-1), the title compound (1.4 g) was obtained as a colorless oil from (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (2 g) and 4-chlorobutyryl chloride (680 µL).

(199-2) Synthesis of (2S)-4-(4-carboxyphenylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}butyramide

[0605] By a similar method as in (1-4), the title compound (190 mg) was obtained as a white amorphous solid from 4-mercaptobenzoic acid (160 mg) and the resultant product (410 mg) of (199-1).
¹H-NMR(DMSO-d₆) δ 1.75-1.84(3H, m), 2.02-2.09(1H, m), 2.23(2H, t, J=7.1Hz), 2.54-2.58(1H, m), 2.64-2.68(1H, m), 3.01(2H, t, J=7.1Hz), 3.08-3.11(2H, m), 3.44-3.51(4H, m), 3.74-3.78(1H, m), 7.28(1H, dd, J=1.5, 8.1Hz), 7.37(2H, d, J=8.4Hz), 7.52(1H, d, J=1.5Hz), 7.57(1H, d, J=8.1Hz), 7.85(2H, d, J=8.4Hz), 7.93(1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:497[M+H].

Example 200 (Reference Example)

Synthesis of (2S)-3-(4-carboxyphenylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}propionamide

[0606] 

(200-1) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl) morpholin-2-yl]methyl}-3-chloropropionamide

[0607] By a similar method as in (1-1), the title compound (600 mg) was obtained as a colorless oil from (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (500 mg) and 3-chloropropionyl chloride (160 µL). (200-2) Synthesis of (2S)-3-(4-carboxyphenylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}propionamide By a similar method as in (1-4), the title compound (240 mg) was obtained as a white amorphous solid from 4-mercaptobenzoic acid (200 mg) and the resultant product (600 mg) of (200-1).
¹H-NMR(DMSO-d₆) δ 1.77-1.83(1H, m), 2.02-2.09(1H, m), 2.45(2H, t, J=6.9Hz), 2.55-2.58 (1H, m), 2.66-2.69 (1H, m), 3.08-3.11(2H, m), 3.20(2H, t, J=6.9Hz), 3.42-3.52(4H, m), 3.74-3.78(1H, m), 7.28-7.31(1H, m), 7.35(2H, d, J=8.2Hz), 7.53-7.58(2H, m), 7.84(2H, d, J=8.2Hz), 8.01(1H, dd, J=5.4, 5.4Hz), 12.85(1H, m).
MS(ESI)m/z:483[M+H].

Example 201

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-4-(6-oxo-1,6-dihydropyridazin-3-ylthio)butyramide

[0608] 

(201-1) Synthesis of methyl 4-(6-oxo-1,6-dihydropyridazin-3-ylthio)butyrate

[0609] By a similar method as in (196-2), the title compound (350 mg) was obtained as a yellow solid from the resultant product (300 mg) of (196-1) and methyl 4-chlorobutyrate.

(201-2) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-4-(6-oxo-1,6-dihydropyridazin-3-ylthio)butyramide

[0610] By a similar method as in (144-2), the title compound (460 mg) was obtained as a white amorphous solid from the resultant product (350 mg) of (201-1) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (340 mg).
¹H-NMR(DMSO-d₆) δ 1.74-1.83(3H, m), 2.02-2.08(1H, m), 2.18(2H, t, J=7.2Hz), 2.55-2.58 (1H, m), 2.63-2.66 (1H, m), 2.95(2H, t, J=7.2Hz), 3.05-3.09(2H, m), 3.39-3.51(4H, m), 3.74-3.78(1H, m), 6.80(1H, d, J=9.8Hz), 7.28-7.33(2H, m), 7.53(1H, d, J=1.7Hz), 7.57(1H, d, J=8.1Hz), 7.93(1H, dd, J=5.8, 5.8Hz), 12.95(1H, s).
MS(ESI)m/z:471[M+H].

Example 202

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(2-ethoxycarbonylpyridin-5-ylthio)acetamide

[0611] 

(202-1) Synthesis of 2-ethoxycarbonylpyridin-5-ylthioacetic acid

[0612] By a similar method as in (161-1), the title compound (600 mg) was obtained as a colorless oil from 5-bromo-2-ethoxycarbonylpyridine (970 mg) and thioglycol acid (350 µL).

(202-2) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(2-ethoxycarbonylpyridin-5-ylthio)-acetamide

[0613] By a similar method as in Example 16, the title compound (730 mg) was obtained as a white amorphous solid from the resultant product (600 mg) of (202-1) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (550 mg).
¹H-NMR(DMSO-d₆) δ 1.29(3H, t, J=7.1Hz), 1.70-1.75(1H, m), 1.97-2.03(1H, m), 2.52-2.59(2H, m), 3.10-3.14(2H, m), 3.39-3.48(4H, m), 3.73-3.77(1H, m), 3.83(2H, s), 4.00(2H, q, J=7.1Hz), 7.27(1H, dd, J=1.5, 8.4Hz), 7.51(1H, d, J=1.5Hz), 7.57(1H, d, J=8.4Hz), 7.91(1H, dd, J=2.2, 8.4Hz), 7.96(1H, d, J=8.4Hz), 8.31 (1H, dd, J=5.7, 5.7Hz), 8.62(1H, d, J=2.2Hz).
MS (ESI)m/z:498 [M+H] .

Example 203

Synthesis of (2S)-(2-carboxypyridin-5-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0614] 

[0615] By a similar method as in (1-5), the title compound (460 mg) was obtained as a white solid from the resultant product (620 mg) of (202-2).
¹H-NMR(DMSO-d₆) δ 1.69-1.84(1H, m), 1.95-2.10(1H, m), 2.51-2.69(2H, m), 3.10-3.15(2H, m), 3.40-3.51(4H, m), 3.75-3.86(3H, m), 7.28-7.31(1H, m), 7.53-7.60(2H, m), 7.90(1H, dd, J=2.2, 8.1Hz), 7.94(1H, d, J=8.1Hz), 8.30-8.34(1H, m), 8.60(1H, d, J=2.2Hz).
MS(ESI)m/z:470[M+H].

Example 204

Synthesis of (2S)-(2-carbamoylpyridin-5-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0616] 

[0617] By a similar method as in Example 8, the title compound (230 mg) was obtained as a white amorphous solid from the resultant product (270 mg) of Example 203.
¹H-NMR(DMSO-d₆) δ 1.69-1.74(1H, m), 1.97-2.04(1H, m), 2.52-2.60(2H, m), 3.10-3.13(2H, m), 3.39-3.47(4H, m), 3.74-3.83(3H, m), 7.27(1H, dd, J=1.6, 8.4Hz), 7.52(1H, d, J=1.6Hz), 7.57(1H, d, J=8.4Hz), 7.61(1H, brs), 7.91-7.96(2H, m), 8.04(1H, brs), 8.27(1H, dd, J=5.7, 5.7Hz), 8.54(1H, s).
MS(ESI)m/z:469[M+H].

Example 205

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(3-ethoxycarbonylpyridin-5-ylthio)acetamide

[0618] 

(205-1) Synthesis of 3-ethoxycarbonylpyridin-5-ylthioacetic acid

[0619] By a similar method as in (161-1), the title compound (580 mg) was obtained as a colorless oil from 5-bromo-3-ethoxycarbonylpyridine (670 mg) and thioglycol acid (300 µL).

(205-2) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(3-ethoxycarbonylpyridin-5-ylthio)-acetamide

[0620] By a similar method as in Example 16, the title compound (480 mg) was obtained as a white amorphous solid from the resultant product (260 mg) of (205-1) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (350 mg).
¹H-NMR(DMSO-d₆) δ 1.32(3H, t, J=7.1Hz), 1.70-1.75(1H, m), 1.97-2.04(1H, m), 2.52-2.59(2H, m), 3.08-3.11(2H, m), 3.39-3.47(4H, m), 3.72-3.77(3H, m), 4.34(2H, q, J=7.1Hz), 7.27(1H, dd, J=1.5, 8.3Hz), 7.51 (1H, d, J=1.5Hz), 7.56 (1H, d, J=8.3Hz), 8.22-8.28(2H, m), 8.77 (1H, d, J=2.3Hz), 8.88(1H, d, J=1.8Hz).
MS (ESI)m/z:498[M+H].

Example 206

Synthesis of (2S)-(3-carboxypyridin-5-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0621] 

[0622] By a similar method as in (1-5), the title compound (240 mg) was obtained as a white amorphous solid from the resultant product (410 mg) of (205-2).
¹H-NMR(DMSO-d₆) δ 1.70-1.76(1H, m), 1.98-2.05(1H, m), 2.52-2.60(2H, m), 3.08-3.12(2H, m), 3.38-3.47(4H, m), 3.72-3.77(3H, m), 7.28(1H, dd, J=1.8, 8.4Hz), 7.52 (1H, d, J=1.8Hz), 7.56(1H, d, J=8.4Hz), 8.21-8.22(1H, m), 8.25(1H, dd, J=5.8, 5.8Hz), 8.73(1H, d, J=2.2Hz), 8.86(1H, d, J=1.6Hz).
MS(ESI)m/z:470[M+H].

Example 207

Synthesis of (2S)-(3-carbamoylpyridin-5-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0623] 

[0624] By a similar method as in Example 8, the title compound (150 mg) was obtained as a white amorphous solid from the resultant product (180 mg) of Example 206.
¹H-NMR(DMSO-d₆) δ 1.69-1.75(1H, m), 1.97-2.04(1H, m), 2.51-2.60(2H, m), 3.08-3.12(2H, m), 3.37-3.47(4H, m), 3.71-3.79(3H, m), 7.28(1H, dd, J=1.5, 8.2Hz), 7.53(1H, d, J=1.5Hz), 7.57(1H, d, J=8.2Hz), 7.66(1H, brs), 8.16(1H, brs), 8.18-8.20(1H, m), 8.22(1H, dd, J=5.7, 5.7Hz), 8.65(1H, d, J=2.2Hz), 8.33(1H, d, J=1.5Hz).
MS(ESI)m/z:469[M+H].

Example 208

Synthesis of (2S)-(E)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[5-(2-carboxyethen-1-yl)pyridin-2-ylthio]-acetamide

[0625] 

(208-1) Synthesis of methyl (E)-5-(2-tertiary butoxycarbonylethen-1-yl)pyridin-2-ylthioacetate

[0626] By a similar method as in (1-4), the title compound (600 mg) was obtained as a white amorphous solid from (E)-2-chloro-5-(2- tertiary butoxycarbonylethen-1-yl)pyridine (800 mg) and methyl thioglycolate (290 µL).

(208-2) Synthesis of (2S)-(E)-N-{[4-(3,4-dichlorobenzyl) morpholin-2-yl]methyl}-[5-(2-carboxyethen-1-yl)pyridin-2-ylthio]acetamide

[0627] By a similar method as in (144-2), a white amorphous solid was obtained from the resultant product (440 mg) of (208-1) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (420 mg). The solid was dissolved in trifluoroacetic acid (3 mL) and the mixture was stirred for 1 h. The solvent was evaporated, and the obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (310 mg) as a white amorphous solid.
¹H-NMR(DMSO-d₆) δ 1.70-1.82(1H, m), 1.93-2.10(1H, m), 2.51-2.70(2H, m), 3.10-3.20(2H, m), 3.40-3.60(4H, m), 3.75-3.92(3H, m), 6.60(1H, d, J=16.2Hz), 7.30-7.36(1H, m), 7.38(1H, d, J=8.4Hz), 7.58(1H, d, J=16.2Hz), 7.59-7.63(2H, m), 8.03(1H, dd, J=2.0, 8.4Hz), 8.17-8.26(1H, m), 8.64(1H, d, J=2.0Hz), 12.44(1H, brs).
MS(ESI)m/z:496[M+H].

Example 209

Synthesis of (2S)-(3-chloropyridazin-6-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0628] 

[0629] By a similar method as in (144-2), the title compound (220 mg) was obtained as a white solid from methyl 3-chloropyridazin-6-ylthioacetate (219 mg).
¹H-NMR(DMSO-d₆) δ 1.77-1.82(1H, m), 1.99-2.06(1H, m), 2.52-2.55(1H, m), 2.65-2.68(1H, m), 3.11-3.14(2H, m), 3.45-3.50(4H, m), 3.73-3.76(1H, m), 3.98(2H, s), 7.28-7.30(1H, m), 7.53(1H, s), 7.56(1H, d, J=8.0Hz), 7.74(1H, d, J=9.3Hz), 7.80(1H, d, J=9.3Hz), 8.26(1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:461[M+H].

Example 210

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[3-(methoxycarbonyl)methylthiopyridazin-6-ylthio]acetamide

[0630] 

[0631] By a similar method as in (1-4), the title compound (54 mg) was obtained as a yellow oil from the resultant product (462 mg) of Example 209 and methyl thioglycolate (91 µL).
¹H-NMR(DMSO-d₆) δ 1.75-1.80(1H, m), 1.99-2.04(1H, m), 2.53-2.55(1H, m), 2.62-2.65(1H, m), 3.10-3.13(2H, m), 3.43-3.48(4H, m), 3.64(3H, s), 3.73-3.76(1H, m), 3.96(2H, s), 4.15(2H, s), 7.28-7.30(1H, m), 7.53-7.59(4H, m), 8.24-8.27(1H, m).
MS(ESI)m/z:531[M+H].

Example 211

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(3-methoxypyridazin-6-ylthio)acetamide

[0632] 

[0633] By a similar method as in (144-2), the title compound (109 mg) was obtained as a brown oil from methyl 3-methoxypyridazin-6-ylthioacetate (214 mg) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (348 mg).
¹H-NMR(DMSO-d₆) δ 1.75-1.81(1H, m), 1.99-2.04(1H, m), 2.52-2.55(1H, m), 2.62-2.65(1H, m), 3.11-3.14(2H, m), 3.44-3.48(4H, m), 3.73-3.76(1H, m), 3.91(2H, s), 3.95(3H, s), 7.13(1H, d, J=9.0Hz), 7.27-7.29(1H, m), 7.52(1H, d, J-=1.6Hz), 7.59(2H, t, J=9.4Hz), 8.19(1H, dd, J=5.8, 5.8Hz).
MS(ESI)m/z:457[M+H].

Example 212

Synthesis of (2S)-(3-acetaminopyridazin-6-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0634] 

[0635] By a similar method as in (144-2), the title compound (55 mg) was obtained as a brown solid from methyl 3-acetamino-pyridazin-6-ylthioacetate (483 mg) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (696 mg).
¹H-NMR(DMSO-d₆) δ 1.73-1.78(1H, m), 2.00-2.02(1H, m), 2.11(3H, s), 2.50-2.63(2H, m), 3.12(2H, brs), 3.37-3.43(4H, m), 3.72-3.75(1H, m), 3.94(2H, s), 7.27-7.29(1H, m), 7.52-7.66(3H, m), 8.15-8.20(2H, m), 10.99(1H, s).
MS(ESI)m/z:484[M+H].

Example 213

Synthesis of (2S)-(2-chloropyrazin-3-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0636] 

[0637] By a similar method as in (144-2), the title compound (170 mg) was obtained as a pale-yellow amorphous solid from methyl 2-chloropyrazin-3-ylthioacetate (981 mg) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (1.57 g).
¹H-NMR (DMSO-d₆) δ 1.76-1.81(1H, m), 2.00-2.07(1H, m), 2.50-2.57(1H, m), 2.63-2.66(1H, m), 3.09-3.13(2H, m), 3.31-49(4H, m), 3.74-3.77(1H, m), 3.91(2H, s), 7.28-7.31(1H, m), 7.54-7.59(2H, m), 8.20-8.23(2H, m), 8.45(1H, d, J=2.4Hz).
MS(ESI)m/z:461[M+H].

Example 214

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(6-oxo-1,6-dihydropyridazin-3-ylthio)acetamide

[0638] 

[0639] By a similar method as in (144-2), the title compound (108 mg) was obtained as a brown solid from methyl 6-oxo-1,6-dihydropyridazin-3-ylthioacetate (203 mg) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (348 mg).
¹H-NMR(DMSO-d₆) δ 1.75-1.80(1H, m), 2.00-2.05(1H, m), 2.50-2.65(2H, m), 3.11(2H, brs), 3.45(4H, brs), 3.72(3H, brs), 6.81-6.83(1H, m), 7.29-7.31(1H, m), 7.37-7.40(1H, m), 7.54-7.59(2H, m), 8.13(1H, brs), 12.97(1H, brs).
MS(ESI)m/z:443[M+H].

Example 215

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(pyrazin-2-ylthio)acetamide

[0640] 

[0641] By a similar method as in (144-2), the title compound (1.0 g) was obtained as a white solid from methyl pyrazin-2-yl-thioacetate (829 mg) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (1.57 g).
¹H-NMR(DMSO-d₆) δ 1.74-1.80(1H, m), 2.02-2.03(1H, m), 2.54-2.56(1H, m), 2.61-2.64(1H, m), 3.10-3.13(2H, m), 3.45-3.48(4H, m), 3.74-3.76(1H, m), 3.88(2H, s), 7.28-7.30(1H, m), 7.53(1H, s), 7.58(1H, d, J=8.0Hz), 8.20(1H, brs), 8.33(1H, s), 8.42(1H, s), 8.62(1H, s).
MS(ESI)m/z:427[M+H].

Example 216

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(3,6-dimethylpyrazin-2-ylthio)acetamide

[0642] 

[0643] By a similar method as in (144-2), the title compound (330 mg) was obtained as a white solid from methyl 3,6-di-methylpyrazin-2-ylthioacetate (488 mg) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (800 mg).
¹H-NMR(DMSO-d₆) δ 1.73-1.78(1H, m), 1.95-2.02(1H, m), 2.38(3H, s), 2.40(3H, s), 2.49-2.55(1H, m), 2.60-2.63(1H, m), 3.10-3.13(2H, m), 3.41-3.48(4H, m), 3.72-3.75(1H, m), 3.85-3.90(2H, m), 7.27-7.29(1H, m), 7.52(1H, d, J=1.7Hz), 7.57(1H, d, J=8.4Hz), 8.09(1H, s), 8.12(1H, dd, J=5.8,5.8Hz).
MS (ESI)m/z:455[M+H].

Example 217

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(6-methylpyridazin-3-ylthio)acetamide

[0644] 

(217-1) Synthesis of 3-chloro-6-di-(tertiary butoxycarbonyl)methylpyridazine

[0645] Sodium hydride (60%, 333 mg) was suspended in dioxane (20 mL), di(tert-butyl)malonate (1.13 mL) was added, and the mixture was stirred at room temperature for 30 min. 3,6-Dichloropyridazine (0.75 g) was added to the reaction mixture and the mixture was heated under reflux for 1 h. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of ethyl acetate and hexane as an eluent. The solvent was evaporated from the eluent to give the title compound (1.44 g) as a yellow solid.

(217-2) Synthesis of methyl 6-di-(tertiary butoxycarbonyl)methylpyridazin-3-ylthioacetate

[0646] By a similar method as in (1-4), the title compound (1.64 g) was obtained as a yellow oil from the resultant product (1.82 g) of (217-1) and methyl thioglycolate (499 µL).

(217-3) Synthesis of (2S)-[6-di-(tertiary butoxycarbonyl) methylpyridazin-3-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0647] By a similar method as in (144-2), the title compound (940 mg) was obtained as a red-brown oil from the resultant product (1.21 g) of (217-2) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (1.04 g).

(217-4) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(6-methylpyridazin-3-ylthio)acetamide

[0648] The resultant product (940 mg) of (217-3) was dissolved in trifluoroacetic acid (6 mL), and the mixture was stirred at room temperature for 1 h. The reaction mixture was adjusted to pH=4 with a 1 mol/L aqueous sodium hydroxide solution. Saturated brine was added to the obtained solution, and the mixture was extracted with a mixed solvent of chloroform-methanol. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (265 mg) as a white solid.
¹H-NMR(DMSO-d₆) δ 1.79-1.82(1H, m), 1.99-2.03(1H, m), 2.52-2.56(4H, m), 2.68-2.70(1H, m), 3.12-3.15(2H, m), 3.41-3.48(4H, m), 3.73-3.76(1H, m), 3.95(2H, s), 7.28(1H, d, J=7.9Hz), 7.41(1H, d, J=8.8Hz), 7.52-7.58(3H, m), 8.23(1H, dd, J=5.6, 5.6Hz).
MS(ESI)m/z:441[M+H].

Example 218

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(3-methoxycarbonylpyridazin-6-ylthio)acetamide

[0649] 

[0650] By a similar method as in Example 16, the title compound (388 mg) was obtained as a white solid from 3-methoxycarbonylpyridazin-6-ylthioacetic acid (799 mg) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (1.22 g).
¹H-NMR(DMSO-d₆) δ 1.77-1.82(1H, m), 1.98-2.05(1H, m), 2.49-2.54(1H, m), 2.66-2.69(1H, m), 3.12-3.15(2H, m), 3.45-3.51(4H, m), 3.73-3.76(1H, m), 3.88(3H, s), 4.07(2H, s), 7.27-7.29(1H, m), 7.51(1H, s), 7.57(1H, d, J=8.0Hz), 7.87(1H, d, J=9.0Hz), 8.00(1H, d, J=9.0Hz), 8.30(1H, dd, J=5.7, 5.7Hz).
MS (ESI)m/z:485[M+H].

Example 219

Synthesis of (2S)-(3-carboxypyridazin-6-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0651] 

[0652] By a similar method as in (1-5), the title compound (164 mg) was obtained as a white solid from the resultant product (270 mg) of Example 218.
¹H-NMR(DMSO-d₆) δ 1.81-1.87(1H, m), 2.04-2.10(1H, m), 2.55-2.58(1H, m), 2.70-2.73(1H, m), 3.10-3.18(2H, m), 3.43-3.55(4H, m), 3.74-3.77(1H, m), 4.06(2H, s), 7.28-7.30(1H, m), 7.53(1H, d, J=1.3Hz), 7.57(1H, d, J=8.2Hz), 7.83(1H, d, J=9.0Hz), 7.97(1H, d, J=9.0Hz), 8.29(1H, dd, J=5.6, 5.6Hz).
MS(ESI)m/z:471[M+H].

Example 220

Synthesis of (2S)-(3-carbamoylpyridazin-6-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0653] 

[0654] By a similar method as in Example 16, the title compound (46 mg) was obtained as a pale-yellow solid from the resultant product (67 mg) of Example 219 and ammonium chloride (46 mg).
¹H-NMR (DMSO-_d6) δ 1.74-1.80(1H, m), 1.98-2.04(1H, m), 2.50-2.55(1H, m), 2.62-2.65(1H, m), 3.12-3.14(2H, m), 3.42-3.48(4H, m), 3.73-3.76(1H, m), 4.06(2H, s), 7.27-7.29(1H, m), 7.52(1H, d, J=1.2Hz), 7.57(1H, d, J=8.4Hz), 7.85(2H, d, J=9.0Hz), 7.99(1H, d, J=9.0Hz), 8.24(1H, dd, J=5.6, 5.6Hz), 8.40(1H, brs).
MS(ESI)m/z:470[M+H].

Example 221

Synthesis of (2S)-[6-(carboxymethyl)pyrazin-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0655] 

(221-1) Synthesis of 2-chloro-6-di-(tertiary butoxycarbonyl)methylpyrazine

[0656] By a similar method as in (217-1), the title compound (2.11 g) was obtained as a white solid from di-(tertiary butoxycarbonyl)malonic acid (2.26 mL) and 2,6-dichloropyrazine (1.49 g).

(221-2) Synthesis of methyl 6-di-(tertiary butoxycarbonyl)methylpyrazin-2-ylthioacetate

[0657] By a similar method as in (1-4), the title compound (1.92 g) was obtained as a yellow oil from the resultant product (2,11 g) of (221-1) and methyl thioglycolate (581 µL).

(221-3) Synthesis of (2S)-[6-di-(tertiary butoxycarbonyl) methylpyrazin-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0658] By a similar method as in (144-2), the title compound (1.57 g) was obtained as a white solid from the resultant product (1.20 g) of (221-2) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (1.04 g).

(221-4) Synthesis of (2S)-[6-(carboxymethyl)pyrazin-2-yl-thio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-acetamide

[0659] By a similar method as in (217-4), the title compound (707 mg) was obtained as a white solid from the resultant product (1.57 g) of (221-3).
¹H-NMR(DMSO-d₆) δ 1.91(1H, brs), 1.99(1H, brs), 2.49-2.51(1H, m), 2.67(1H, brs), 3.11-3.14(2H, m), 3.49-3.57(4H, m), 3.79-3.82(3H, m), 3.86(2H, s), 7.31-7.33(1H, m), 7.59-7.61(2H, m), 8.21(1H, brs), 8.31(1H, s), 8.49(1H, s)11.43(1H brs).
MS(ESI)m/z:485[M+H].

Example 222

Synthesis of (2S)-(3-aminopyridazin-6-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0660] 

[0661] The resultant product (270 mg) of Example 212 was dissolved in a 1 mol/L hydrochloric acid, and the mixture was heated under reflux for 1 h. The reaction mixture was adjusted to pH=9 with a 1 mol/L aqueous sodium hydroxide solution. The obtained solution was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (58 mg) as a white solid.
¹H-NMR(DMSO-d₆) δ 1.79-1.84(1H, m), 2.06-2.08(1H, m), 2.55-2.58(1H, m), 2.64-2.67(1H, m), 3.09-3.12(2H, m), 3.43-3.52(4H, m), 3.74-3.82(3H, m), 6.32(2H, s), 6.74(1H, d, J=9.4Hz), 7.25-7.31(2H, m), 7.54-7.59(2H, m), 8.13(1H, dd, J=5.8, 5.8Hz).
MS(ESI)m/z:442[M+H].

Example 223

Synthesis of (2S)-[6-(carbamoylmethyl)pyrazin-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0662] 

[0663] By a similar method as in Example 16, the title compound (200 mg) was obtained as a white solid from the resultant product (700 mg) of Example 221 and ammonium chloride (430 mg).
¹H-NMR(DMSO-d₆) δ 1.72-1.78(1H, m), 1.99-2.03(1H, m), 2.50-2.54(1H, m), 2.58-2.61(1H, m), 3.10-3.13(2H, m), 3.42-3.47(4H, m), 3.61(2H, s), 3.72-3.75(1H, m), 3.85(2H, s), 7.07(1H, brs), 7.28(1H, d, J=7.9Hz), 7.52-7.58(3H, m), 8.15-8.16(1H, m), 8.27(1H, s), 8.46(1H, s).
MS(ESI)m/z:484[M+H].

Example 224

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[6-(methoxycarbonyl)methylpyridazin-3-ylthio]-acetamide

[0664] 

[0665] By a similar method as in (1-4), the title compound (88 mg) was obtained as a white solid from the resultant product (388 mg) of (1-2) and 3-mercapto-6-methoxy-carbonylmethylpyridazine (190 mg).
¹H-NMR(DMSO-d₆) δ 1.77-1.82(1H, m), 1.99-2.02(1H, m), 2.51-2.54(1H, m), 2.67-2.69(1H, m), 3.11-3.14(2H, m), 3.42-3.49(4H, m), 3.62(3H, s), 3.73-3.75(1H, m), 3.97(2H, s), 4.06(2H, s), 7.28-7.30(1H, m), 7.51-7.54(2H, m), 7.58(1H, d, J=8.4Hz), 7.67(1H, d, J=8.4Hz), 8.24(1H, brs).
MS(ESI)m/z:499[M+H].

Example 225

Synthesis of (2S)-(E)-[6-(2-carboxyethen-1-yl)pyridazin-3-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-acetamide

[0666] 

(225-1) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)-morpholin-2-yl]methyl}-[6-(hydroxymethyl)pyridazin-3-ylthio]acetamide

[0667] By a similar method as in (70-1), the title compound (310 mg) was obtained as a colorless oil from the resultant product (815 mg) of Example 218.

(225-2) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(3-formylpyridazin-6-ylthio)acetamide

[0668] By a similar method as in (70-2), the title compound (134 mg) was obtained as a colorless oil from the resultant product (310 mg) of (225-1).

(225-3) Synthesis of (2S)-(E)-[6-(2-carboxyethen-1-yl)pyridazin-3-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0669] By a similar method as in (70-3), the title compound (16 mg) was obtained as a white amorphous solid from the resultant product (134 mg) of (225-2) and malonic acid (61 mg).
¹H-NMR(DMSO-d₆) δ 1.76-1.82(1H, m), 1.98-2.03(1H, m), 2.50-2.54(1H, m), 2.64-2.67(1H, m), 3.12-3.15(2H, m), 3.37-3.48(4H, m), 3.73-3.76(1H, m), 4.00(2H, s), 6.91(1H, d, J=16.2Hz), 7.27(1H, d, J=7.7Hz), 7.50-7.57(2H, m), 7.65(1H, d, J=16.2Hz), 7.75(1H, d, J=9.0Hz), 7.99(1H, d, J=9.0Hz), 8.26(1H, dd, J=5.5, 5.5Hz), 12.74(1H, brs).
MS (ESI)m/z: 497 [M+H].

Example 226

Synthesis of (2S)-[6-(carbamoylmethyl)pyridazin-3-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0670] 

[0671] By a similar method as in Example 25, the title compound (415 mg) was obtained as a white solid from the resultant product (720 mg) of Example 224.
¹H-NMR(400MHz, DMSO-d₆) δ :1.76-1.82(1H, m), 1.99-2.02(1H, m), 2.52-2.55(1H, m), 2.65-2.67(1H, m), 3.11-3.14(2H, m), 3.43-3.49(4H, m), 3.72-3.76(3H, m), 3.96(2H, s), 7.04(1H, brs), 7.28-7.30(1H, m), 7.47(1H, d, J=8.8Hz), 7.53(1H, d, J=1.9Hz), 7.56-7.62(3H, m), 8.23(1H, brs)
MS(ESI)m/z:484[M+H].

Example 227

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(6-thioxo-1,6-dihydropyridazin-3-ylthio)acetamide

[0672] 

[0673] By a similar method as in (144-2), the title compound (157 mg) was obtained as a yellow solid from methyl 6-thioxo-1,6-dihydropyridazin-3-ylthioacetate (432 mg) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (696 mg).
¹H-NMR(DMSO-d₆) δ 1.74-1.79(1H, m), 1.99-2.02(1H, m), 2.05-2.56(1H, m), 2.63-2.66(1H, m), 3.10-3.13(2H, m), 3.44-3.49(4H, m), 3.74-3.80(3H, m), 7.28-7.32(2H, m), 7.47(1H, d, J=9.5Hz), 7.55-7.60(2H, m), 8.22-8.25(1H, m), 14.68(1H, brs).
MS(ESI)m/z:459[M+H].

Example 228

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(6-oxo-1-methyl-1,6-dihydropyridazin-3-ylthio)-acetamide

[0674] 

[0675] By a similar method as in (144-2), the title compound (143 mg) was obtained as a white solid from methyl 6-oxo-1-methyl-1,6-dihydropyridazin-3-ylthioacetate (100 mg) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (163 mg).
¹H-NMR(DMSO-d₆) δ 1.75-1.80(1H, m), 2.00-2.05(1H, m), 2.50-2.56(1H, m), 2.62-2.65(1H, m), 3.11-3.14(2H, m), 3.43-3.47(4H, m), 3.59(3H, s), 3.72-3.77(3H, m), 6.87-6.89(1H, m), 7.28-7.32(1H, m), 7.40-7.42(1H, m), 7.53-7.59(2H, m), 8.15-8.18(1H, m).
MS(ESI)m/z:457[M+H].

Example 229

Synthesis of (2S)-(cyclopentylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0676] 

[0677] By a similar method as in (1-4), the title compound (150 mg) was obtained as white crystals from the resultant product (388 mg) of (1-2) and cyclopentylmercaptan (118 µL).
¹H-NMR(DMSO-d₆) δ 1.30-1.71(6H, m), 1.71-1.95(3H, m), 2.02-2.13(1H, m), 2.53-2.69(2H, m), 3.01-3.14(5H, m), 3.39-3.54(4H, m), 3.78(1H, d, J=11.4Hz), 7.30(1H, dd, J=1.8, 8.4Hz), 7.55(1H, d, J=1.8Hz), 7.58(1H, d, J=8.4Hz), 8.04(1H, t, J=5.8Hz).
MS(ESI)m/z:417[M+H].

Example 230

Synthesis of (2S)-4-(cyclopentylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}butyramide

[0678] 

[0679] By a similar method as in Example 16, the title compound (325 mg) was obtained as white crystals from 4-cyclo-pentylthiobutyric acid (244 mg) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (348 mg).
¹H-NMR(DMSO-d₆) δ 1.30-1.82(9H, m), 1.84-2.10(5H, m), 2.45(2H, t, J=7.2Hz), 2.52-2.69(2H, m), 2.98-3.12(3H, m), 3.38-3.52(4H, m), 3.72-3.80(1H, m), 7.30(1H, dd, J=1.9, 8.3Hz), 7.54(1H, d, J=1.9Hz), 7.59(1H, d, J=8.3Hz), 7.91(1H, t, J=5.8Hz).
MS(ESI)m/z:445[M+H].

Example 231

Synthesis of (2S)-4-(cyclopentanesulfonyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}butyramide

[0680] 

[0681] By a similar method as in Example 16, the title compound (39 mg) was obtained as white crystals from 4-cyclopentanesulfonylbutyric acid (264 mg) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (348 mg).
¹H-NMR(DMSO-d₆) δ 1.50-1.72(4H, m), 1.73-1.99(7H, m), 2.00-2.10(1H, m), 2.23(2H, t, J=7.2Hz), 2.52-2.70(2H, m), 2.95-3.12(4H, m), 3.38-3.62(5H, m), 3.72-3.80(1H, m), 7.30(1H, dd, J=1.2, 8.4Hz), 7.55(1H, d, J=1.2Hz), 7.59(1H, d, J=8.4Hz), 7.96(1H, t, J=5.7Hz).
MS(ESI)m/z:477[M+H].

Example 232

Synthesis of (2S)-4-(cyclopentanesulfonyl)-N-{[4-(3-chloro-4-fluorobenzyl)morpholin-2-yl]methyl}butyramide

[0682] 

[0683] By a similar method as in Example 16, the title compound (317 mg) was obtained as white crystals from 4-cyclopentanesulfonylbutyric acid (264 mg) and (2S)-2-aminomethyl-4-(3-chloro-4-fluorobenzyl)morpholine dihydrochloride (332 mg).
¹H-NMR(DMSO-d₆) δ 1.50-1.72(4H, m), 1.73-1.99(7H, m), 2.00-2.10 (1H, m), 2.23(2H, t, J=7.2Hz), 2.52-2.70(2H, m), 2.95-3.12(4H, m), 3.38-3.62(5H, m), 3.70-3.80 (1H, m), 7.27-7.39(2H, m), 7.49 (1H, dd, J=1.8, 7.2Hz), 7.96 (1H, t, J=5.7Hz).
MS(ESI)m/z:461[M+H].

Example 233

Synthesis of (2S)-4-(cyclopentanesulfonyl)-N-{[4-(3-chlorobenzyl)morpholin-2-yl]methyl}butyramide

[0684] 

[0685] By a similar method as in Example 16, the title compound (290 mg) was obtained as white crystals from 4-cyclopentanesulfonylbutyric acid (264 mg) and (2S)-2-aminomethyl-4-(3-chlorobenzyl)morpholine dihydrochloride (314 mg).
¹H-NMR(DMSO-d₆) δ 1.50-1.72(4H, m), 1.73-1.99(7H, m), 2.00-2.10 (1H, m), 2.23(2H, t, J=7.2Hz), 2.52-2.70(2H, m), 2.95-3.12(4H, m), 3.39-3.62(5H, m), 3.70-3.80(1H, m), 7.21-7.39(4H, m), 7.96(1H, t, J=5.7Hz).
MS(ESI)m/z:443[M+H].

Example 234

Synthesis of (2S)-4-(cyclopentanesulfonyl)-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}butyramide

[0686] 

[0687] By a similar method as in Example 16, the title compound (336 mg) was obtained as white crystals from 4-cyclopentanesulfonylbutyric acid (264 mg) and (2S)-2-aminomethyl-4-(3,4-difluorobenzyl)morpholine dihydrochloride (315 mg).
¹H-NMR(DMSO-d₆) δ 1.50-1.72(4H, m), 1.73-1.99(7H, m), 2.00-2.10(1H, m), 2.23(2H, t, J=7.2Hz), 2.52-2.69(2H, m), 2.95-3.12(4H, m), 3.38-3.62(5H, m), 3.70-3.80(1H, m), 7.07-7.18(1H, m), 7.28-7.44(2H, m), 7.96(1H, t, J=5.7Hz).
MS(ESI)m/z:445[M+H] .

Example 235

Synthesis of (2S)-4-(cyclopentylthio)-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}butyramide

[0688] 

[0689] By a similar method as in Example 16, the title compound (351 mg) was obtained as a colorless oil from 4-cyclopentylthiobutyric acid (244 mg) and (2S)-2-aminomethyl-4-(3,4-difluorobenzyl)morpholine dihydrochloride (315 mg).
¹H-NMR(DMSO-d₆) δ 1.30-1.80(9H, m), 1.83-2.09(5H, m), 2.44(2H, t, J=7.2Hz), 2.52-2.69(2H, m), 2.98-3.12(3H, m), 3.38-3.52(4H, m), 3.72-3.80(1H, m), 7.09-7.18(1H, m), 7.28-7.41(2H, m), 7.89(1H, t, J=5.7Hz).
MS(ESI)m/z:413[M+H] .

Example 236

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(1-methyl-1H-tetrazol-5-ylthio)acetamide

[0690] 

[0691] By a similar method as in (1-4), the title compound (367 mg) was obtained as a colorless oil from the resultant product (388 mg) of (1-2) and 5-mercapto-1-methyl-1H-tetrazole (122 mg).
¹H-NMR(DMSO-d₆) δ 1.71-1.87(1H, m), 1.96-2.10(1H, m), 2.51-2.69(2H, m), 3.08-3.14(2H, m), 3.39-3.52(4H, m), 3.70-3.81(1H, m), 3.96(3H, s), 4.02(2H, s), 7.30(1H, dd, J=1.8, 8.4Hz), 7.54(1H, d, J=1.8Hz), 7.59 (1H, d, J=8.4Hz), 8.37(1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:431[M+H].

Example 237

Synthesis of (2S)-(2-carboxythiophen-5-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0692] 

(237-1) Synthesis of 2-bromo-5-ethoxycarbonylthiophene

[0693] 2-Bromo-5-thiophenecarboxylic acid (500 mg) was dissolved in ethanol (5 mL), conc. sulfuric acid (50 µL) was added and the mixture was heated under reflux for 4 h. Conc. sulfuric acid (50 µL) was further added and the mixture was heated under reflux for 5 h. Then, the mixture was allowed to return to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using a mixed solvent of ethyl acetate and hexane as an eluent. The solvent was evaporated from the eluent to give the title compound (500 mg) as a yellow oil.

(237-2) Synthesis of 2-ethoxycarbonylthiophen-5-ylthioacetic acid

[0694] By a similar method as in (161-1), the title compound (390 mg) was obtained as a colorless oil from the resultant product (500 mg) of (237-1) and thioglycol acid (150 µL).

(237-3) Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(2-ethoxycarbonylthiophen-5-ylthio)-acetamide

[0695] By a similar method as in Example 16, the title compound was obtained as a white solid from the resultant product (390 mg) of (237-2) and (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (550 mg).

(237-4) Synthesis of (2S)-(2-carboxythiophen-5-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0696] The total amount of the resultant product of (237-3) was dissolved in ethanol (5 mL), a 1 mol/L aqueous sodium hydroxide solution (5 mL) was added, and the mixture was stirred overnight at room temperature. 1 mol/L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (485 mg) as a white solid.
¹H-NMR(DMSO-d₆) δ 1.74-1.79(1H, m), 2.00-2.06(1H, m), 2.54(1H, d, J=11.4Hz), 2.62(1H, d, J=11.4Hz), 3.10-3.13(2H, m), 3.40-3.49(4H, m), 3.65(2H, d, J=1.8Hz), 3.74-3.77(1H, m), 7.15(1H, d, J=3.9Hz), 7.29(1H, dd, J=2.0, 8.4Hz), 7.53(1H, d, J=2.0Hz)7.56-7.60(2H, m), 8.17(1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:475[M+H].

Example 238

Synthesis of (2S)-[5-(4-carboxyphenyl)thiophen-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0697] 

[0698] The resultant product (200 mg) of Example 31, tetrakistriphenylphosphinepalladium (25 mg), sodium carbonate (200 mg) and 4-methoxycarbonylphenylboronic acid (105 mg) were dissolved in a mixed solution of ethylene glycol dimethylether (4 mL) and water (250 µL), and the mixture was heated under reflux at 130°C for 6 h. Then, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was evaporated under reduced pressure, and the residue was purified by column chromatography using chloroform as an eluent. The eluent was evaporated and the obtained yellow oil was dissolved in ethanol (2 mL). A 1N aqueous sodium hydroxide solution (50 µL) was added and the mixture was stirred overnight at room temperature. The reaction mixture was adjusted to pH=5 with 1N hydrochloric acid, and the mixture was extracted with chloroform. The extract was dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (90 mg) as a pale-yellow solid.
¹H-NMR(DMSO-d₆) δ 1.74-1.79(1H, m), 1.96-2.03(1H, m), 2.5(1H, m), 2.62(1H, d, J=11.0Hz), 3.10-3.13(2H, m), 3.3-3.4(4H, m), 3.57(2H, s), 3.73(1H, d, J=11.0Hz), 7.20-7.24(2H, m), 7.45(1H, s), 7.53(1H, d, J=8.1Hz), 7.57 (1H, d, J=3.4Hz), 7.72(2H, d, J=8.1Hz), 7.94(2H, d, J=8.1Hz), 8.13(1H, brs).
MS(ESI)m/z:551[M+H].

Example 239

Synthesis of (2S)-[5-(3-carboxyphenyl)thiophen-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0699] 

[0700] By a similar method as in Example 238, the title compound (45 mg) was obtained as a pale-yellow solid from the resultant product (200 mg) of Example 31 and 3-methoxycarbonylphenylboronic acid (105 mg).
¹H-NMR (DMSO-d₆) δ 1.74-1.79(1H, m), 1.97-2.03(1H, m), 2.5 (1H, m), 2.62 (1H, d, J=11.1Hz), 3.10-3.13(2H, m), 3.30-3.47(4H, m), 3.55(2H, s), 3.73(1H, d, J=11.1Hz), 7.19(1H, d, J=3.7Hz), 7.22 (1H, dd, J=1.4, 8.0Hz), 7.45 (1H, d, J=1.4Hz), 7.50-7.54(3H, m), 7.86(2H, dd, J=1.4, 8.0Hz), 8.00-8.14(2H, m).
MS(ESI)m/z:551[M+H].

Example 240

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) thiazol-2-ylthio]acetamide hydrochloride

[0701] 

[0702] The resultant product (245 mg) of (22-2) was dissolved in 1,4-dioxane (5 mL), carbonyldiimidazole (122 mg) was added, and the mixture was heated under reflux for 2 h. After allowing to cool, carbonyldiimidazole (122 mg) was added, and the mixture was further heated under reflux for 2 h. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (87 mg) as a white solid.
¹H-NMR(DMSO-d₆) δ 1.71-1.84(1H, m), 1.98-2.10(1H, m), 2.53-2.69(2H, m), 3.07-3.18(2H, m), 3.39-3.53(4H, m), 3.69-3.78(1H, m), 3.92-4.04(2H, m), 7.28(1H, dd, J=2.1, 8.1Hz), 7.52(1H, d, J=2.1Hz), 7.57(1H, d, J=8.1Hz), 8.17(1H, s), 8.33(1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:516[M+H].

Example 241(Reference Example)

Synthesis of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

[0703] 

[0704] By a similar method as in Example 135, the title compound (530 mg) was obtained as a white amorphous solid from (2S)-2-aminomethyl-4-(3,4-dichlorobenzyl)morpholine (0.6 g) and acetyl chloride (370 µL).
¹H-NMR(DMSO-d₆) δ 1.75-1.81(4H, m), 2.01-2.08(1H, m), 2.54-2.58(1H, m), 2.65-2.68(1H, m), 3.03-3.08(2H, m), 3.41-3.50(4H, m), 3.74-3.78(1H, m), 7.30(1H, dd, J=1.6, 8.3Hz), 7.55(1H, d, J=1.6Hz), 7.59(1H, d, J=8.3Hz), 7.93(1H, dd, J=5.7, 5.7Hz).
MS(ESI)m/z:317[M+H].

Experimental Example 1: Binding inhibitory test of chemokine to human eosinophils

[0705] Human eosinophils were separated by the CD16 negative selection method from anticoagulation-treated peripheral blood of healthy subject (e.g., J. Immunol. Methods, vol. 145, pages 105-110, 1991). The separated eosinophils (2×10⁵ cells), 50 pmol/L[¹²⁵I]-eotaxin (2000 Ci/mmoL, manufactured by Amersham Pharmacia Biotech) and a test compounds were mixed in 0.1 mL of binding buffer (50 mmol/L HEPES, 1 mmol/L CaCl₂, 5 mmol/L MgCl₂, 0.5% bovine serum albumin (BSA), 0.1 % sodium azide, pH 7.4), and the mixture was incubated in a multiscreen plate (manufactured by MILLIPORE) at 25°C for 1 h. After incubation, the reaction mixture in the multiscreen plate was filtered by vacuum manifold, and washed with 0.6 mL of a cold washing buffer (50 mmol/L HEPES, 1 mmol/L CaCl₂, 5 mmol/L MgCl₂, 0.5 mol/L NaCl, 0.1% sodium azide, pH 7.4), and the radioactivity maintained on the filter was measured. The compounds of the present invention showed a binding inhibitory activity against chemokine in this assay. The IC₅₀ values (concentration of test compound necessary for decreasing binding of [¹²⁵I]-eotaxin to human eosinophils by 50 %) of some of the compounds of the present invention were as follows.

Table 1

compounds	IC50(nmol/L)
Example 2	2.4
Example 9	12.7
Example 10	2.4
Example 11	0.8
Example 13	0.4
Example 15	0.4
Example 17	0.9
Example 23	1.0
Example 27	2.3

Experimental Example 2: Effect on intracellular calcium concentration

[0706] The effect of the compound of the present invention on intracellular calcium mobilization in peripheral blood eosinophils of healthy subject upon CCL11 stimulation was examined by the following method.

[0707] Eosinophils separated from peripheral blood of healthy subject were suspended in 0.5% bovine serum albumin-containing phosphate buffered saline, and incubated at 37°C for 45 min in the presence of 5 µmol/L of Fura-2 AM (manufactured by DOJINDO LABORATORIES).

[0708] After incubation, the cells were washed 3 times with a measurement buffer (10 mmol/L HEPES, and 0.5% bovine serum albumin-containing hanks' balanced salt solution) to remove Fura-2 AM that was not incorporated into the cells. Finally, the cells were adjusted to 1×10⁶ cells/mL with the measurement buffer and preserved in a dark place until measurement. The intracellular calcium was measured using FDSS3000 manufactured by Hamamatsu Photonics K.K. In other words, the cell suspension (0.1 mL) loaded with Fura-2 AM was placed in a 96 well plate for measurement, the fluorescence intensity to the excitation light at wavelengths 340 nm and 380 nm was measured by FDSS3000, the ratio of the fluorescence intensity to the excitation light at these two wavelengths was determined, based on which the intracellular calcium concentration was calculated. As the agonist, used was CCL11 (1.0 nmol/L), which is a CCR3 selective ligand, and the antagonistic activity was determined as 50% suppression rate (IC₅₀ value) of the increase in the intracellular calcium concentration, when eosinophils were treated with various concentrations of the compound of the present invention at 3 min before agonist stimulation.

Table 2

compounds	IC50(nmol/L)
Example 2	1.8
Example 15	1.6
Example 17	2.5
Example 23	0.8
Example 46	3.1
Example 53	5.3
Example 55	1.1
Example 59	2.1
Example 64	0.3
Example 71	0.5
Example 79	0.9
Example 107	2.5
Example 109	22.3
Example 110	1.5
Example 112	0.9
Example 115	2.6
Example 123	2.6
Example 125	3.6
Example 146	2.5
Example 174	16.2
Example 198	3.9
Example 207	2.4
Example 223	0.1
Example 232	38.5

Experimental Example 3: Effect on antigen induced allergic and biphasic ear edema model

[0709] The in vivo effect of the compound of the present invention was examined using a mouse ovalbumin (OVA) induced allergic and biphasic ear edema model. The model was prepared according to the method of Sugawara et al. (Allergy & Clinical Immunology International, Supplement No. 2, P 785, 2000). In other words, male BALB/c mice were immunized by intraperitoneal injection with 10 µg of OVA and 1 mg of aluminum hydroxide gel (Alum). At 14 days after immunization, OVA (5 µg) were subcutaneously injected to the both ears of the mouse, whereby ear edema was induced. The thickness of the ears was measured using a dial sickness gauge immediately before subcutaneous injection and 1 and 24 h after subcutaneous injection of OVA. The compound of the present invention was suspended in a vehicle, 0.5% hydroxypropylmethyl cellulose solution, and orally administered at 3 mg/kg or 10 mg/kg once a day using an orally gavage needle from 2 days before ear edema induction. The doses of some of the compounds of the present invention that showed a significant suppressive action as compared to a vehicle administration group are shown in the following Table.

Table 3

compounds	Immediate phase (mg/kg)	Late phase (mg/kg)
Example 2	3	3
Example 17	3	3
Example 46	10	10
Example 53	3	3
Example 64	10	3
Example 123	10	10
Example 125	10	3
Example 146	3	3
Example 198	10	10

Industrial Applicability

[0710] The compound of the present invention is an antagonist that inhibits binding of human eosinophils and CCL11, which is a CCR3 selective chemokine, and also inhibits an increase in the intracellular calcium mobilization, which is induced by CCL11. Therefore, the compound is considered to be useful as a pharmaceutical agent for the treatment and/or prevention of immune and inflammatory diseases.

Claims

1. A compound represented by the formula (1)

wherein
ring A is a monocyclic to tricyclic C_6-14 aryl which may be partially hydrogenated and which may have substituent(s), or a 5- to 7-membered aromatic heterocyclic (monocyclic) group containing, as a ring atom besides carbon atom, 1 to 3 kinds of 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom or groups derived from an aromatic heterocycle (bicyclic or above) obtained by condensing a 5- to 7-membered aromatic heterocycle containing, as a ring atom besides carbon atom, 1 to 3 kinds of 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom and a benzene ring or the above-mentioned aromatic heterocyclic (monocyclic) group, each of which may be partially hydrogenated and which may have substituent(s),
ring B is a divalent 5- to 14-membered monocyclic to tricyclic heterocyclic group containing, as a ring atom besides carbon atom, 1 to 3 kinds of 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom which may have substituent(s), or a monocyclic to tricyclic cycloalkylene (including crosslinked cycloalkylene) having 3 to 8 carbon atoms and which may have substituent(s), wherein said substituent(s) is/are selected from halogen atom, C_1-6 alkyl, C_3-8 cycloalkyl, C_3-8 cycloalkyloxy, C_1-6 haloalkyl,C_6-14 aryl, C_1-6 alkoxy, C_1-6 haloalkoxy, C_6-14 aryloxy, nitro, amino, mono- or di-C_1-6 alkylamino, mono- or di-(C_3-8 cycloalkyl)amino, mono- or di-(C_6-14 aryl)amino, C_1-11 acyl, mono- or di-(C_1-11 acyl)amino, mono- or di-(C_1-6 alkoxy-carbonyl)amino, sulfonylamino, amino-C_1-6 alkyl, mono- or di-(C_1-6 alkyl)amino-C_1-6 alkyl, C_3-8 cyclic amino, hydrazino, guanidino, amidino, hydroxyamidino, C_1-6 alkoxyamidino, aminomethyleneamino, imino, carboxy, C_1-6 alkoxy-carbonyl, carbamoyl, mono- or di-(C_1-6 alkyl)aminocarbonyl, mono- or di- (C_6-14 aryl)aminocarbonyl, cyano, C_7-13 aralkyl, mono- or di- (C_7-13 aralkyl)aminocarbonyl, heteroaryl, heteroaryl-C_1-3 alkyl, mono- or di- (heteroaryl-C_1-3 alkyl)aminocarbonyl, hydroxy, mercapto, C_1-6 alkylthio, C_6-14 arylthio, -SO₃H, -SO₂NH₂, sulfonamide, oxo and thioxo,
m is an integer of 0 to 2,
n is an integer of 1 to 5,
X is a bond, -NH-, -NR¹- wherein R¹ is C_1-6 alkyl which may have substituent(s) as defined above, -CO-, -CO₂-, -OCO-, -CONR^a-wherein R^a, here and in the following, is hydrogen atom or C_1-6 alkyl which may have substituent(s) as defined above, -NR^aCO-, -NR²CONR³- wherein R² and R³ may be the same or different and each is hydrogen atom or C_1-6 alkyl which may have substituent(s) as defined above, or R² and R³ in combination optionally form, together with the atoms bonded thereto, a ring which may have substituent(s) as defined above, oxygen atom, sulfur atom, -SO-, -SO₂-, -NR^aSO₂-, -SO₂NR^a-, C_1-6 alkylene which may have substituent(s) as defined above, a straight chain or branched chain alkenylene having 2 to 6 carbon atoms, which has double bond(s) at any position of the alkylene chain having 2 to 6 carbon atoms and which may have substituent(s) as defined above, a straight chain or branched chain alkynylene having 2 to 6 carbon atoms, which has triple bond(s) at any position of the alkylene chain having 2 to 6 carbon atoms and which may have substituent(s) as defined above, -O-X^a- wherein X^a, here and in the following, is C_1-6 alkylene which may have substituent(s) as defined above, -X^a-O-, -CO-X^a-, -X^a-CO-, -CONR^a-X^a-, -X^a-CONR^a-, -NR^aCO-X^a-, -X^a-NR^aCO-, -S-X^a-, -X^a-S-, -SO-X^a-, -X^a-SO-, -NR^a-X^a-, -X^a-NR^a-, -SO₂-X^a-, -X^a-SO₂-, -C(=N-CO₂-R¹)-, -C(=N-SO₂-R¹)-, -C(=N-SO₂NH₂)-, -C(=CH-NO₂)-, -C(=N-CN)- or a monocyclic to tricyclic cycloalkylidene (including crosslinked cycloalkylidene) having 3 to 8 carbon atoms which may have substituent(s) as defined above, Y is a bond, -NH-, -NR⁴- wherein R⁴, here and in the following, is C_1-6 alkyl which may have substituent(s) as defined above, -CO-, -CO₂-, -OCO-, -CONR^b- wherein R^b, here and in the following, is hydrogen atom or C_1-6 alkyl which may have substituent(s) as defined above, -NR^bCO-, -NR⁵CONR⁶- wherein R⁵ and R⁶ may be the same or different and each is hydrogen atom or C_1-6 alkyl which may have substituent(s) as defined above, or R⁵ and R⁶ in combination optionally form, together with the atoms bonded thereto, a ring which may have substituent(s) as defined above, oxygen atom, sulfur atom, -SO-, -SO₂-, -NR^bSO₂-, -SO₂NR^b-, C_1-6 alkylene which may have substituent(s) as defined above, a straight chain or branched chain alkenylene having 2 to 6 carbon atoms, which has double bond(s) at any position of the alkylene chain having 2 to 6 carbon atoms and which may have substituent(s) as defined above, a straight chain or branched chain alkynylene having 2 to 6 carbon atoms, which has triple bond(s) at any position of the alkylene chain having 2 to 6 carbon atoms and which may have substituent(s) as defined above, -O-X^b- wherein X^b, here and in the following, is C_1-6 alkylene which may have substituent(s) as defined above, -X^b-O-, -CO-X^b-, -X^b-CO-, -CONR^b-X^b-, -X^b-CONR^b-, -NR^bCO-X^b-, -X^b-NR^bCO-, -S-X^b-, -X^b-S-, -SO-X^b-, -X^b-SO-, -NR^b-X^b-, -X^b-NR^b-, -SO₂-X^b-, -X^b-SO₂-, -C(=N-CO₂-R⁴)-, -C(=N-SO₂-R⁴)-, -C(=N-SO₂NH₂)-, -C(=CH-NO₂)- or -C(=N-CN)-, and
Z is hydrogen atom, halogen atom, C_1-6 alkyl which may have substituent(s) as defined above, a monocyclic to tricyclic cycloalkyl (including crosslinked cycloalkyl) having 3 to 8 carbon atoms which may have substituent(s) as defined above, a monocyclic to tricyclic C_6-14 aryl which may be partially hydrogenated which may have substituent(s) as defined above, a heterocyclic group which may have substituent(s) as defined above, hydroxy, nitro, amino, cyano, C_1-6 alkoxy which may have substituent(s) as defined above, mono- or di-C_1-6 alkylamino which may have substituent(s) as defined above, C_1-7 acylamino which may have substituent(s) as defined above, sulfonylamino which may have substituent(s) as defined above, hydrazino which may have substituent(s) as defined above, guanidino which may have substituent(s) as defined above or amidino which may have substituent(s) as defined above,
or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

2. The compound of claim 1, wherein ring B is a divalent 5- to 14-membered monocyclic to tricyclic heterocyclic group containing, as a ring atom besides carbon atom, 1 to 3 kinds of 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom which may have substituent(s) as defined in claim 1, and X is a bond, -NH-, -NR¹- wherein R¹ is C_1-6 alkyl which may have substituent(s) as defined in claim 1, -CO-, -CO₂-, -OCO-, -CONR^a- wherein R^a, here and in the following, is hydrogen atom or C_1-6 alkyl which may have substituent(s) as defined in claim 1, -NR^aCO-, -NR²CONR³- wherein R² and R³ may be the same or different and each is hydrogen atom or C_1-6 alkyl which may have substituent(s) as defined in claim 1, or R² and R³ in combination optionally form, together with the atoms bonded thereto, a ring which may have substituent(s) as defined in claim 1, oxygen atom, sulfur atom, -SO-, -SO₂-, -NR^aSO₂-, -SO₂NR^a-, C_1-6 alkylene which may have substituent(s) as defined in claim 1, a straight chain or branched chain alkenylene having 2 to 6 carbon atoms, which has double bond(s) at any position of the alkylene chain having 2 to 6 carbon atoms and which may have substituent(s) as defined in claim 1, a straight chain or branched chain alkynylene having 2 to 6 carbon atoms, which has triple bond(s) at any position of alkylene chain having 2 to 6 carbon atoms and which may have substituent(s) as defined in claim 1, -O-X^a- wherein X^a, here and in the following, is C_1-6 alkylene which may have substituent(s) as defined in claim 1, -X^a-O-, -CO-X^a-, -X^a-CO-, -CONR^a-X^a-, -X^a-CONR^a-, -NR^aCOX^a-, -X^a-NR^aCO-, -S-X^a-, -X^a-S-, -SO-X^a-, -X^a-SO-, -NR^a-X^a-, -X^a-NR^a-, -SO₂-X^a-, -X^a-SO₂-, -C(=N-CO₂-R¹)-, -C(=N-SO₂-R¹)-, -C(=N-SO₂NH₂)-, -C(=CH-NO₂)- or -C(=N-CN)-, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

3. The compound of claim 1 or 2, wherein, in the formula (1), m is 0 or 2, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

4. The compound of any one of claims 1 to 3, wherein, in the formula (1), m is 0, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

5. The compound of any one of claims 1 to 4, wherein, in the formula (1), X is a bond, -NH-, -NR¹- wherein R¹ is C_1-6 alkyl which may have substituent(s) as defined in claim 1, -CO-, -CO₂-, -OCO-, -CONR^a-wherein R^a, here and in the following, is hydrogen atom or C_1-6 alkyl which may have substituent(s) as defined in claim 1, -NR^aCO-, -NR²CONR^3- wherein R² and R³ may be the same or different and each is hydrogen atom or C_1-6 alkyl which may have substituent(s) as defined in claim 1, oxygen atom, sulfur atom, -SO-, -SO₂-, -NR^aSO₂-, -SO₂NR^a-, a straight chain or branched chain alkenylene having 2 to 6 carbon atoms, which has double bond(s) at any position of the alkylene chain having 2 to 6 carbon atoms which may have substituent(s) as defined in claim 1, -CO-X^a- wherein X^a, here and in the following, is C_1-6 alkylene optionally having substituent(s) as defined in claim 1, -X^a-CO-, -CONR^a-X^a-, -X^a-CONR^a-, -NR^aCO-X^a-, -X^a-NR^aCO-or a monocyclic to tricyclic cycloalkylidene (including crosslinked cycloalkylidene) having 3 to 8 carbon atoms which may have substituent(s) as defined in claim 1, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

6. The compound of any one of claims 1 to 5, wherein, in the formula (1), X is a bond, -CO-, -CONR^a- wherein R^a, here and in the following, is hydrogen atom or C_1-6 alkyl which may have substituent(s) as defined in claim 1, -NR^aCO-, -CO-X^a- wherein X^a, here and in the following, is C_1-6 alkylene which may have substituent(s) as defined in claim 1, -X^a-CO-, -CONR^a-X^a-, -X^a-CONR^a-, -NR^aCO-X^a- or -X^a-NR^aCO-, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

7. The compound of any one of claims 1 to 6, wherein, in the formula (1), Y is a bond, -NH-, -NR⁴- wherein R⁴ is C_1-6 alkyl which may have substituent(s) as defined in claim 1, -CO-, -CO₂-, -OCO-, -CONR^b-wherein R^b, here and in the following, is hydrogen atom or C_1-6 alkyl which may have substituent(s) as defned in claim 1, -NR^bCO-, -NR⁵CONR⁶- wherein R⁵ and R⁶ may be the same or different and each is hydrogen atom or C_1-6 alkyl which may have substituent(s) as defined in claim 1, oxygen atom, sulfur atom, -SO-, -SO₂-, -NR^bSO₂-, -SO₂NR^b-, -CO-X^b- wherein X^b, here and in the following, is C_1-6 alkylene which may have substituent(s) as defined in claim 1, -X^b-CO-, -CONR^b-X^b-, -X^b-CONR^b-, -NR^bCO-X^b- or -X^b-NR^bCO-, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

8. The compound of any one of claims 1 to 7, wherein, in the formula (1), Y is a bond, -CO-, -CONR^b- wherein R^b, here and in the following, is hydrogen atom or C_1-6 alkyl which may have substituent(s) as defined in claim 1, -NR^bCO-, -CO-X^b- wherein X^b, here and in the following, is C_1-6 alkylene which may have substituent(s) as defined in claim 1, -X^b-CO-, -CONR^b-X^b-, -X^b-CONR^b-, -NR^bCO-X^b- or -X^b-NR^bCO-, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

9. The compound of any one of claims 1 to 8, wherein, in the formula (1), Z is hydrogen atom, halogen atom, C_1-6 alkyl which may have substituent(s) as defined in claim 1, monocyclic to tricyclic cycloalkyl (including crosslinked cycloalkyl) having 3 to 8 carbon atoms which may have substituent(s) as defined in claim 1, monocyclic to tricyclic C_6-14 aryl which may be partially hydrogenated which may have substituent(s) as defined in claim 1, heterocyclic group which may have substituent(s) as defined in claim 1, hydroxy, nitro, amino, cyano, C_1-6 alkoxy which may have substituent(s) as defined in claim 1, mono- or di-C_1-6 alkylamino which may have substituent(s) as defined in claim 1, C_1-7 acylamino which may have substituent(s) as defined in claim 1, sulfonylamino which may have substituent(s) as defined in claim 1, hydrazino which may have substituent(s) as defined in claim 1, guanidino which may have substituent(s) as defined in claim 1, or amidino which may have substituent(s) as defined in claim 1, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

10. The compound of any one of claims 1 to 9, wherein, in the formula (1), Z is hydrogen atom, hydroxy, amino, C_1-6 alkyl which may have substituent(s) as defined in claim 1, C_1-6 alkoxy which may have substituent(s) as defined in claim 1, monocyclic to tricyclic C_6-14 aryl which may be partially hydrogenated which may have substituent(s) as defined in claim 1 or heterocyclic group which may have substituent(s), or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

11. The compound of claim 1, which is represented by the formula (1a)

wherein ring C is a monocyclic to tricyclic C_6-14 aryl which may be partially hydrogenated which may have substituent(s) as defined in claim 1, or a 5- to 7-membered aromatic heterocyclic (monocyclic) group containing, as a ring atom besides carbon atom, 1 to 3 kinds of 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom or groups derived from an aromatic heterocycle (bicyclic or above) obtained by condensing a 5- to 7-membered aromatic heterocycle containing, as a ring atom besides carbon atom, 1 to 3 kinds of 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom and a benzene ring or the above-mentioned aromatic heterocyclic (monocyclic) group, each of which may be partially hydrogenated and which may have substituent(s) as defined in claim 1, and the other symbols are as defined in claim 1, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

12. The compound of any one of claims 1 to 11, wherein, in the formula (1), ring A is phenyl optionally having substituent(s) as defined in claim 1, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

13. The compound of any one of claims 1 to 12, wherein, in the formula (1), n is 1 to 3, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

14. The compound of any one of claims 1 to 13, wherein, in the formula (1), the absolute configuration at the 2-position of morpholine is S configuration, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

15. The compound of claim 1, which is selected from (2S)-[4-(carboxymethyl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-[4-(3-aminophenyl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-[4-(3-carbamoyl-4-hydroxyphenyl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(pyridin-4-yl)thiazol-2-ylthio]acetamide, (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(3,4-dimethoxyphenyl)thiazol-2-ylthio]acetamide, (2S)-(4-carbamoylthiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-{4-[(2-amino-2-oxoethyl)aminocarbonyl]thiazol-2-ylthio}-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(5-methyl-1,2,4-oxadiazol-3-yl)thiazol-2-ylthio]acetamide, (2S)-(5-amino-8H-indeno[1,2-d]thiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-{4-[(2-amino-2-oxoethyl)aminocarbonyl]phenylthio}-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-{4-[(2-carboxyethyl)aminocarbonyl]thiazol-2-ylthio}-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-(5-acetamino-1,3,4-thiadiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-4-(4-carbamoylthiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}butyramide, (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(1H-tetrazol-5-yl)thiazol-2-ylthio]acetamide, (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-([1,3]thiazolo[5,4-b]pyridin-2-ylthio)acetamide, (2S)-(E)-[4-(2-carbamoylethen-1-yl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-[4-(carbamoylmethyl)thiazol-2-ylthio]-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-[4-(carbamoylmethyl)thiazol-2-ylthio]-N-{[4-(4-fluorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-(4-carboxy-5-methylthiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-(4-carbamoyl-5-methylthiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-(4-carbamoylthiazol-2-ylthio)-N-{[4-(3-chloro-4-fluorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-[4-(2-amino-2-oxoethyl)aminocarbonylthiazol-2-ylthio]-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-(5-amino-1,3,4-thiadiazol-2-ylthio)-N-{[4-(3-chlorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-(5-amino-1,3,4-thiadiazol-2-ylthio)-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(pyrimidin-2-ylthio)acetamide, (2S)-(3-acetyl-2-oxo-2H-chromen-6-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide, (2S)-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}-(6-oxo-1,6-dihydropyridazin-3-ylthio)acetamide, (2S)-[6-(carbamoylmethyl)pyrazin-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide, and (2S)-4-(cyclopentanesulfonyl)-N-{[4-(3-chloro-4-fluorobenzyl)morpholin-2-yl]methyl}butyramide, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

16. A CCR3 antagonist comprising, as an active ingredient, the compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

17. A pharmaceutical composition comprising the compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, and a pharmaceutically acceptable carrier.

18. The pharmaceutical composition of claim 17, which is an agent for the prophylaxis and/or treatment of asthma, sinusitis, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, allergic myelitis, ulcerative colitis, Crohn's disease or rheumatoid arthritis.

19. A compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof for use in the prophylaxis and/or treatment of a disease involving CCR3.

20. The compound for the use in the prophylaxis and/or treatment of a disease involving CCR3 of claim 19, wherein the disease involving CCR3 is asthma, sinusitis, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, allergic myelitis, ulcerative colitis, Crohn's disease or rheumatoid arthritis.

21. The use of the compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof for the production of an agent for the prophylaxis and/or treatment of a disease involving CCR3.

22. Use of claim 21, wherein the disease involving CCR3 is asthma, sinusitis, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, allergic myelitis, ulcerative colitis, Crohn's disease or rheumatoid arthritis.

23. A production method of a compound represented by the formula (1)

wherein ring A, ring B, m, n, X, Y and Z are as defined in claim 1, or a salt thereof, which comprises reacting a compound represented by the formula (6)

wherein each symbol is as defined above, or a salt thereof, with a compound represented by the formula (8)

wherein ring A is as defined above, or a salt thereof.

24. (2S)-[4-(carboxymethyl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide.

25. (2S)-[4-(2-carboxypropan-2-yl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide.

26. (2S)-(5-amino-1,3,4-thiadiazol-2-ylthio)-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}acetamide.

27. (2S)-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}-(6-oxo-1,6-dihydropyridazin-3-ylthio)acetamide.

28. A pharmaceutical composition comprising the compound of any one of claims 24 to 27, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, and a pharmaceutically acceptable carrier.

29. The pharmaceutical composition of claim 28, which is an agent for the prophylaxis and/or treatment of asthma, sinusitis, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, allergic myelitis, ulcerative colitis, Crohn's disease or rheumatoid arthritis.

Ansprüche

1. Verbindung, die durch die Formel (1)

dargestellt wird, wobei
Ring A Folgendes ist: ein monocyclisches bis tricyclisches C_6-14-Aryl, das partiell hydriert sein kann und das einen oder mehrere Substituenten aufweisen kann, oder eine fünf- bis siebengliedrige aromatische heterocyclische (monocyclische) Gruppe, die als Ringatom neben Kohlenstoffatomen 1 bis 3 Arten von 1 bis 4 Heteroatomen enthält, welche aus einem Stickstoffatom, einem Schwefelatom und einem Sauerstoffatom ausgewählt sind, oder Gruppen, die von einem aromatischen Heterocyclus (bicyclisch oder oben) abgeleitet sind und durch Kondensation eines fünf- bis siebengliedrigen aromatischen Heterocyclus, der als Ringatom neben Kohlenstoffatomen 1 bis 3 Arten von 1 bis 4 Heteroatomen enthält, welche aus einem Stickstoffatom, einem Schwefelatom und einem Sauerstoffatom ausgewählt sind, und einem Benzolring oder der oben genannten aromatischen heterocyclischen (monocyclischen) Gruppe erhalten werden, die jeweils partiell hydriert sein können und einen oder mehrere Substituenten aufweisen können;
Ring B Folgendes ist: eine zweiwertige fünf- bis vierzehngliedrige monocyclische bis tricyclische heterocyclische Gruppe, die als Ringatom neben Kohlenstoffatomen 1 bis 3 Arten von 1 bis 4 Heteroatomen, welche aus einem Stickstoffatom, einem Schwefelatom und einem Sauerstoffatom ausgewählt sind, enthält und die einen oder mehrere Substituenten aufweisen kann, oder ein monocyclisches bis tricyclisches Cycloalkylen (einschließlich vernetztes Cycloalkylen), das 3 bis 8 Kohlenstoffatome aufweist und das einen oder mehrere Substituenten aufweisen kann, wobei die Substituenten ausgewählt sind aus einem Halogenatom, C_1-6-Alkyl, C_3-8-Cycloalkyl, C_3-8-Cycloalkyloxy, C_1-6-Halogenalkyl, C_6-14-Aryl, C_1-6-Alkoxy, C_1-6-Halogenalkoxy, C_6-14-Aryloxy, Nitro, Amino, Mono- oder Di-C_1-6-alkylamino, Mono- oder Di(C_3-8-cycloalkyl)amino, Mono- oder Di(C_6-14-aryl)-amino, C_1-11-Acyl, Mono- oder Di(C_1-11-aryl)amino, Mono- oder Di(C_1-6-alkoxycarbonyl)amino, Sulfonylamino, Amino-C_1-6-alkyl, Mono- oder Di-(C_1-6-alkyl)amino-C_1-5-alkyl, cyclisches C_3-8-Amino, Hydrazino, Guanidino, Amidino, Hydroxyamidino, C_1-6-Alkoxyamidino, Aminomethylenamino, Imino, Carboxy, C_1-6-Alkoxycarbonyl, Carbamoyl, Mono- oder Di(C_1-6-alkyl)aminocarbonyl, Mono- oder Di(C_6-14-aryl)aminocarbonyl, Cyano, C_7-13-Aralkyl, Mono- oder Di(C_7-13-aralkyl)aminocarbonyl, Heteroaryl, Heteroaryl-C_1-3-alkyl, Mono- oder Di(heteroaryl-C_1-3-alkyl)aminocarbonyl, Hydroxy, Mercapto, C_2-6-Alkylthio, C_6-14-Arylthio, -SO₃H, -SO₂NH₂, Sulfonamid, Oxo und Thioxo;
m eine ganze Zahl von 0 bis 2 ist;
n eine ganze Zahl von 1 bis 5 ist;
X Folgendes ist: eine Bindung, -NH-, -NR¹-, wobei R¹ = C_1-6-Alkyl ist, das einen oder mehrere Substituenten, wie sie oben definiert sind, aufweisen kann, -CO-, -CO₂-, -OCO-, -CONR^a-, wobei R^a hier und im Folgenden ein Wasserstoffatom oder C_1-6-Alkyl, das einen oder mehrere Substituenten, wie sie oben definiert sind, aufweisen kann, ist, -NR^aCO-, -NR²CONR³-, wobei R² und R³ gleich oder verschieden sein können und jeweils ein Wasserstoffatom oder C_1-6-Alkyl, das einen oder mehrere Substituenten, wie sie oben definiert sind, aufweisen kann, sind oder R² und R³ gegebenenfalls in Kombination zusammen mit den daran gebundenen Atomen einen Ring bilden, der einen oder mehrere Substituenten, wie sie oben definiert sind, aufweisen kann, ein Sauerstoffatom, ein Schwefelatom, -SO-, -SO₂-, -NR^aSO₂-, -SO₂NR^a-, C_1-6-Alkylen, das einen oder mehrere Substituenten, wie sie oben definiert sind, aufweisen kann, ein geradkettiges oder verzweigtes Alkenylen mit 2 bis 6 Kohlenstoffatomen, das an einer beliebigen Position der Alkylenkette mit 2 bis 6 Kohlenstoffatomen, die einen oder mehrere Substituenten aufweisen kann, wie sie oben definiert ist, eine oder mehrere Doppelbindungen aufweist, ein geradkettiges oder verzweigtes Alkinylen mit 2 bis 6 Kohlenstoffatomen, das an einer beliebigen Position der Alkylenkette mit 2 bis 6 Kohlenstoffatomen, die einen oder mehrere Substituenten aufweisen kann, wie sie oben definiert ist, eine oder mehrere Dreifachbindungen aufweist, -O-X^a-, wobei X^a hier und im Folgenden ein C_1-6-Alkylen, das einen oder mehrere Substituenten, wie sie oben definiert sind, aufweisen kann, ist, -X^a-O-, -Co-X^a-, -X^a-CO-, -CONR^a-X^a-, -X^a-CONR^a-, -NR^aCO-X^a-, -X^a-NR^aCO-, -S-X^a-, -X^a-S-, -SO-X^a-, -X^a-SO-, -NR^a-X^a-, -X^a-NR^a-, -SO₂-X^a-, -X^a-SO²-, -C(=N-CO₂-R¹)-, -C(=N-SO₂-R¹)-, -C(=N-SO₂NH₂)-, -C(=CH-NO₂)-, -C(=N-CN)- oder ein monocyclisches bis tricyclisches Cycloalkyliden (einschließlich vernetztes Cycloalkyliden) mit 3 bis 8 Kohlenstoffatomen, das einen oder mehrere Substituenten, wie sie oben definiert sind, aufweisen kann;
Y Folgendes ist: eine Bindung, -NH-, -NR⁴-, wobei R⁴ hier und im Folgenden C_1-6-Alkyl ist, das einen oder mehrere Substituenten, wie sie oben definiert sind, aufweisen kann, -CO-, -CO₂-, -OCO-, -CONR^b-, wobei R^b hier und im Folgenden ein Wasserstoffatom oder C_1-6-Alkyl, das einen oder mehrere Substituenten, wie sie oben definiert sind, aufweisen kann, ist, -NR^bCO-, -NR⁵CONR⁶-, wobei R⁵ und R⁶ gleich oder verschieden sein können und jeweils ein Wasserstoffatom oder C_1-6-Alkyl, das einen oder mehrere Substituenten, wie sie oben definiert sind, aufweisen kann, sind oder R⁵ und R⁶ gegebenenfalls in Kombination zusammen mit den daran gebundenen Atomen einen Ring bilden, der einen oder mehrere Substituenten, wie sie oben definiert sind, aufweisen kann, ein Sauerstoffatom, ein Schwefelatom, -SO-, -SO₂-, -NR^bSO₂-, -SO₂NR^b-, C_1-6-Alkylen, das einen oder mehrere Substituenten, wie sie oben definiert sind, aufweisen kann, ein geradkettiges oder verzweigtes Alkenylen mit 2 bis 6 Kohlenstoffatomen, das an einer beliebigen Position der Alkylenkette mit 2 bis 6 Kohlenstoffatomen, die einen oder mehrere Substituenten aufweisen kann, wie sie oben definiert ist, eine oder mehrere Doppelbindungen aufweist, ein geradkettiges oder verzweigtes Alkinylen mit 2 bis 6 Kohlenstoffatomen, das an einer beliebigen Position der Alkylenkette mit 2 bis 6 Kohlenstoffatomen, die einen oder mehrere Substituenten aufweisen kann, wie sie oben definiert ist, eine oder mehrere Dreifachbindungen aufweist, -O-X^b-, wobei X^b hier und im Folgenden ein C_1-6-Alkylen, das einen oder mehrere Substituenten, wie sie oben definiert sind, aufweisen kann, ist, -X^b-O-, -CO-X^b-, -X^b-CO-, -CONR^b-X^b-, -X^b-CONR^b-, -NR^bCO-X^b-, -X^b-NR^bCO-, -S-X^b-, -X^b-S-, -SO-X^b-, -X^b-SO-, -NR^b-X^b-, -X^b-NR^b-, -SO₂-X^b-, -X^b-SO₂-, -C(=N-CO₂-R⁴)-, -C(=N-SO₂-R⁴)-, -C(=N-SO₂NH₂)-, -C(=CH-NO₂)- oder -C(=N-CN)-; und
Z Folgendes ist: ein Wasserstoffatom, ein Halogenatom, C_1-6-Alkyl, das einen oder mehrere Substituenten, wie sie oben definiert sind, aufweisen kann, ein monocyclisches bis tricyclisches Cycloalkyl (einschließlich vernetztes Cycloalkyl), das 3 bis 8 Kohlenstoffatome aufweist und das einen oder mehrere Substituenten, wie sie oben definiert sind, aufweisen kann, ein monocyclisches bis tricyclisches C_6-14-Aryl, das partiell hydriert sein kann und das einen oder mehrere Substituenten, wie sie oben definiert sind, aufweisen kann, eine heterocyclische Gruppe, die einen oder mehrere Substituenten, wie sie oben definiert sind, aufweisen kann, Hydroxy, Nitro, Amino, Cyano, C_1-6-Alkoxy, das einen oder mehrere Substituenten, wie sie oben definiert sind, aufweisen kann, Mono- oder Di-C_1-6-alkylamino, das einen oder mehrere Substituenten, wie sie oben definiert sind, aufweisen kann, C_1-7-Acylamino, das einen oder mehrere Substituenten, wie sie oben definiert sind, aufweisen kann, Sulfonylamino, das einen oder mehrere Substituenten, wie sie oben definiert sind, aufweisen kann, Hydrazino, das einen oder mehrere Substituenten, wie sie oben definiert sind, aufweisen kann, Guanidino, das einen oder mehrere Substituenten, wie sie oben definiert sind, aufweisen kann, oder Amidino, das einen oder mehrere Substituenten, wie sie oben definiert sind, aufweisen kann;
oder ein pharmazeutisch annehmbares Salz davon oder ein Hydrat oder Solvat davon.

2. Verbindung gemäß Anspruch 1, wobei Ring B eine zweiwertige fünf- bis vierzehngliedrige monocyclische bis tricyclische heterocyclische Gruppe ist, die als Ringatom neben Kohlenstoffatomen 1 bis 3 Arten von 1 bis 4 Heteroatomen, welche aus einem Stickstoffatom, einem Schwefelatom und einem Sauerstoffatom ausgewählt sind, enthält und die einen oder mehrere Substituenten, wie sie in Anspruch 1 definiert sind, aufweisen kann, und X Folgendes ist: eine Bindung, -NH-, -NR¹-, wobei R¹ = C_1-6-Alkyl ist, das einen oder mehrere Substituenten, wie sie in Anspruch 1 definiert sind, aufweisen kann, -CO-, -CO₂-, -OCO-, -CONR^a-, wobei R^a hier und im Folgenden ein Wasserstoffatom oder C_1-6-Alkyl, das einen oder mehrere Substituenten, wie sie in Anspruch 1 definiert sind, aufweisen kann, ist, -NR^aCO-, -NR²CONR³-, wobei R² und R³ gleich oder verschieden sein können und jeweils ein Wasserstoffatom oder C_1-6-Alkyl, das einen oder mehrere Substituenten, wie sie in Anspruch 1 definiert sind, aufweisen kann, sind oder R² und R³ gegebenenfalls in Kombination zusammen mit den daran gebundenen Atomen einen Ring bilden, der einen oder mehrere Substituenten, wie sie in Anspruch 1 definiert sind, aufweisen kann, ein Sauerstoffatom, ein Schwefelatom, -SO-, -SO₂-, -NR^aSO₂-, - SO₂NR^a-, C_1-6-Alkylen, das einen oder mehrere Substituenten, wie sie in Anspruch 1 definiert sind, aufweisen kann, ein geradkettiges oder verzweigtes Alkenylen mit 2 bis 6 Kohlenstoffatomen, das an einer beliebigen Position der Alkylenkette mit 2 bis 6 Kohlenstoffatomen, die einen oder mehrere Substituenten aufweisen kann, wie sie in Anspruch 1 definiert ist, eine oder mehrere Doppelbindungen aufweist, ein geradkettiges oder verzweigtes Alkinylen mit 2 bis 6 Kohlenstoffatomen, das an einer beliebigen Position der Alkylenkette mit 2 bis 6 Kohlenstoffatomen, die einen oder mehrere Substituenten aufweisen kann, wie sie in Anspruch 1 definiert ist, eine oder mehrere Dreifachbindungen aufweist, -O-X^a-, wobei X^a hier und im Folgenden ein C_1-6-Alkylen, das einen oder mehrere Substituenten, wie sie in Anspruch 1 definiert sind, aufweisen kann, ist, -X^a-O-, -Co-X^a-, -X^a-CO-, -CONR^a-X^a-, -X^a-CONR^a-, -NR^aCO-X^a-, -X^a-NR^aCO-, -S-X^a-, -X^a-S-, - SO-X^a-, -X^a-SO-, -NR^a-X^a-, -X^a-NR^a-, -SO₂-X^a-, -X^a-SO₂-, -C(=N-CO₂-R¹)-, -C(=N-SO₂-R¹)-, -C(=N-SO₂NH₂)- -C(=CH-NO₂)- oder -C(=N-CN)-; oder ein pharmazeutisch annehmbares Salz davon oder ein Hydrat oder Solvat davon.

3. Verbindung gemäß Anspruch 1 oder 2, wobei in der Formel (1) m = 0 oder 2 ist, oder ein pharmazeutisch annehmbares Salz davon oder ein Hydrat oder Solvat davon.

4. Verbindung gemäß einem der Ansprüche 1 bis 3, wobei in der Formel (1) m = 0 ist, oder ein pharmazeutisch annehmbares Salz davon oder ein Hydrat oder Solvat davon.

5. Verbindung gemäß einem der Ansprüche 1 bis 4, wobei in der Formel (1) X Folgendes ist: eine Bindung, -NH-, -NR¹-, wobei R¹ = C_1-6-Alkyl ist, das einen oder mehrere Substituenten, wie sie in Anspruch 1 definiert sind, aufweisen kann, -CO-, -CO₂-, -OCO-, -CONR^a-, wobei R^a hier und im Folgenden ein Wasserstoffatom oder C_1-6-Alkyl, das einen oder mehrere Substituenten, wie sie in Anspruch 1 definiert sind, aufweisen kann, ist, -NR^aCO-, -NR²CONR³-, wobei R² und R³ gleich oder verschieden sein können und jeweils ein Wasserstoffatom oder C_1-6-Alkyl, das einen oder mehrere Substituenten, wie sie in Anspruch 1 definiert sind, aufweisen kann, sind, ein Sauerstoffatom, ein Schwefelatom, -SO-, -SO₂-, -NR^aSO₂-, -SO₂NR^a-, ein geradkettiges oder verzweigtes Alkenylen mit 2 bis 6 Kohlenstoffatomen, das an einer beliebigen Position der Alkylenkette mit 2 bis 6 Kohlenstoffatomen, die einen oder mehrere Substituenten aufweisen kann, wie sie in Anspruch 1 definiert ist, eine oder mehrere Doppelbindungen aufweist, -Co-X^a-, wobei X^a hier und im Folgenden ein C_1-6-Alkylen, das einen oder mehrere Substituenten, wie sie in Anspruch 1 definiert sind, aufweisen kann, ist, -X^a-CO-, -CONR^a-X^a-, -X^a-CONR^a-, -NR^aCO-X^a-, -X^a-NR^aCO- oder ein monocyclisches bis tricyclisches Cycloalkyliden (einschließlich vernetztes Cycloalkyliden) mit 3 bis 8 Kohlenstoffatomen, das einen oder mehrere Substituenten, wie sie in Anspruch 1 definiert sind, aufweisen kann; oder ein pharmazeutisch annehmbares Salz davon oder ein Hydrat oder Solvat davon.

6. Verbindung gemäß einem der Ansprüche 1 bis 5, wobei in der Formel (1) X Folgendes ist: eine Bindung, -CO-, -CONR^a-, wobei R^a hier und im Folgenden ein Wasserstoffatom oder C_1-6-Alkyl, das einen oder mehrere Substituenten, wie sie in Anspruch 1 definiert sind, aufweisen kann, ist, -NR^aCO-, -CO-X^a-, wobei X^a hier und im Folgenden ein C_1-6-Alkylen, das einen oder mehrere Substituenten, wie sie in Anspruch 1 definiert sind, aufweisen kann, ist, -X^a-CO-, -CONR^a-X^a-, -X^a-CONR^a-, -NR^aCO-X^a- oder -X^a-NR^aCO-; oder ein pharmazeutisch annehmbares Salz davon oder ein Hydrat oder Solvat davon.

7. Verbindung gemäß einem der Ansprüche 1 bis 6, wobei in der Formel (1) Y Folgendes ist: eine Bindung, -NH-, -NR⁴-, wobei R⁴ C_1-6-Alkyl ist, das einen oder mehrere Substituenten, wie sie in Anspruch 1 definiert sind, aufweisen kann, -CO-, -CO₂-, -OCO-, -CONR^b-, wobei R^b hier und im Folgenden ein Wasserstoffatom oder C_1-6-Alkyl, das einen oder mehrere Substituenten, wie sie in Anspruch 1 definiert sind, aufweisen kann, ist, -NR^bCO-, -NR⁵CONR⁶-, wobei R⁵ und R⁶ gleich oder verschieden sein können und jeweils ein Wasserstoffatom oder C_1-6-Alkyl, das einen oder mehrere Substituenten, wie sie in Anspruch 1 definiert sind, aufweisen kann, sind, ein Sauerstoffatom, ein Schwefelatom, -SO-, -SO₂-, -NR^bSO₂-, -SO₂NR^b-, -CO-X^b-, wobei X^b hier und im Folgenden ein C_1-6-Alkylen, das einen oder mehrere Substituenten, wie sie in Anspruch 1 definiert sind, aufweisen kann, ist, -X^b-CO-, -CONR^b-X^b-, -X^b-CONR^b-, -NR^bCO-X^b- oder -X^b-NR^bCO-; oder ein pharmazeutisch annehmbares Salz davon oder ein Hydrat oder Solvat davon.

8. Verbindung gemäß einem der Ansprüche 1 bis 7, wobei in der Formel (1) Y Folgendes ist: eine Bindung, -CO-, -CONR^b-, wobei R^b hier und im Folgenden ein Wasserstoffatom oder C_1-6-Alkyl, das einen oder mehrere Substituenten, wie sie in Anspruch 1 definiert sind, aufweisen kann, ist, -NR^bCO-, -CO-X^b-, wobei X^b hier und im Folgenden ein C_1-6-Alkylen, das einen oder mehrere Substituenten, wie sie in Anspruch 1 definiert sind, aufweisen kann, ist, -X^b-CO-, -CONR^b-X^b-, -X^b-CONR^b-, -NR^bCO-X^b- oder -X^b-NR^bCO-; oder ein pharmazeutisch annehmbares Salz davon oder ein Hydrat oder Solvat davon.

9. Verbindung gemäß einem der Ansprüche 1 bis 8, wobei in der Formel (1) Z Folgendes ist: ein Wasserstoffatom, ein Halogenatom, C_1-6-Alkyl, das einen oder mehrere Substituenten, wie sie in Anspruch 1 definiert sind, aufweisen kann, ein monocyclisches bis tricyclisches Cycloalkyl (einschließlich vernetztes Cycloalkyl), das 3 bis 8 Kohlenstoffatome aufweist und das einen oder mehrere Substituenten, wie sie in Anspruch 1 definiert sind, aufweisen kann, ein monocyclisches bis tricyclisches C_6-14-Aryl, das partiell hydriert sein kann und das einen oder mehrere Substituenten, wie sie in Anspruch 1 definiert sind, aufweisen kann, eine heterocyclische Gruppe, die einen oder mehrere Substituenten, wie sie in Anspruch 1 definiert sind, aufweisen kann, Hydroxy, Nitro, Amino, Cyano, C_1-6-Alkoxy, das einen oder mehrere Substituenten, wie sie in Anspruch 1 definiert sind, aufweisen kann, Mono- oder Di-C_1-6-alkylamino, das einen oder mehrere Substituenten, wie sie in Anspruch 1 definiert sind, aufweisen kann, C_1-7-Acylamino, das einen oder mehrere Substituenten, wie sie in Anspruch 1 definiert sind, aufweisen kann, Sulfonylamino, das einen oder mehrere Substituenten, wie sie in Anspruch 1 definiert sind, aufweisen kann, Hydrazino, das einen oder mehrere Substituenten, wie sie in Anspruch 1 definiert sind, aufweisen kann, Guanidino, das einen oder mehrere Substituenten, wie sie in Anspruch 1 definiert sind, aufweisen kann, oder Amidino, das einen oder mehrere Substituenten, wie sie in Anspruch 1 definiert sind, aufweisen kann; oder ein pharmazeutisch annehmbares Salz davon oder ein Hydrat oder Solvat davon.

10. Verbindung gemäß einem der Ansprüche 1 bis 9, wobei in der Formel (1) Z Folgendes ist: ein Wasserstoffatom, Hydroxy, Amino, C_1-6-Alkyl, das einen oder mehrere Substituenten, wie sie in Anspruch 1 definiert sind, aufweisen kann, C_1-6-Alkoxy, das einen oder mehrere Substituenten, wie sie in Anspruch 1 definiert sind, aufweisen kann, monocyclisches bis tricyclisches C_6-14-Aryl, das partiell hydriert sein kann und das einen oder mehrere Substituenten, wie sie in Anspruch 1 definiert sind, aufweisen kann, oder eine heterocyclische Gruppe, die einen oder mehrere Substituenten aufweisen kann; oder ein pharmazeutisch annehmbares Salz davon oder ein Hydrat oder Solvat davon.

11. Verbindung gemäß Anspruch 1, die durch die Formel (1a)

dargestellt wird, wobei Ring C Folgendes ist: ein monocyclisches bis tricyclisches C_6-14-Aryl, das partiell hydriert sein kann und das einen oder mehrere Substituenten, wie sie in Anspruch 1 definiert sind, aufweisen kann, oder eine fünf- bis siebengliedrige aromatische heterocyclische (monocyclische) Gruppe, die als Ringatom neben Kohlenstoffatomen 1 bis 3 Arten von 1 bis 4 Heteroatomen enthält, welche aus einem Stickstoffatom, einem Schwefelatom und einem Sauerstoffatom ausgewählt sind, oder Gruppen, die von einem aromatischen Heterocyclus (bicyclisch oder oben) abgeleitet sind und durch Kondensation eines fünf- bis siebengliedrigen aromatischen Heterocyclus, der als Ringatom neben Kohlenstoffatomen 1 bis 3 Arten von 1 bis 4 Heteroatomen enthält, welche aus einem Stickstoffatom, einem Schwefelatom und einem Sauerstoffatom ausgewählt sind, und einem Benzolring oder der oben genannten aromatischen heterocyclischen (monocyclischen) Gruppe erhalten werden, die jeweils partiell hydriert sein können und einen oder mehrere Substituenten, wie sie in Anspruch 1 definiert sind, aufweisen können, und die anderen Symbole wie in Anspruch 1 definiert sind; oder ein pharmazeutisch annehmbares Salz davon oder ein Hydrat oder Solvat davon.

12. Verbindung gemäß einem der Ansprüche 1 bis 11, wobei in der Formel (1) Ring A ein Phenyl ist, das gegebenenfalls einen oder mehrere Substituenten, wie sie in Anspruch 1 definiert sind, aufweisen kann; oder ein pharmazeutisch annehmbares Salz davon oder ein Hydrat oder Solvat davon.

13. Verbindung gemäß einem der Ansprüche 1 bis 12, wobei in der Formel (1) n = 1 bis 3 ist; oder ein pharmazeutisch annehmbares Salz davon oder ein Hydrat oder Solvat davon.

14. Verbindung gemäß einem der Ansprüche 1 bis 13, wobei in der Formel (1) die absolute Konfiguration an der 2-Position des Morpholins eine S-Konfiguration ist; oder ein pharmazeutisch annehmbares Salz davon oder ein Hydrat oder Solvat davon.

15. Verbindung gemäß Anspruch 1, die ausgewählt ist aus:

(2S)-[4-(Carboxymethyl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorbenzyl)morpholin-2-yl]methyl}acetamid,

(2S)-[4-(3-Aminophenyl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorbenzyl)morpholin-2-yl]methyl}acetamid,

(2S)-[4-(3-Carbamoyl-4-hydroxyphenyl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorbenzyl)morpholin-2-yl]methyl}acetamid,

(2S)-N-{[4-(3,4-Dichlorbenzyl)morpholin-2-yl]methyl}-[4-(pyridin-4-yl)-thiazol-2-ylthio]acetamid,

(2S)-N-{[4-(3,4-Dichlorbenzyl)morpholin-2-yl]methyl}-[4-(3,4-dimethoxyphenyl)thiazol-2-ylthio]acetamid,

(2S)-(4-Carbamoylthiazol-2-ylthio)-N-{[4-(3,4-dichlorbenzyl)morpholin-2-yl]methyl}acetamid,

(2S)-{4-[(2-Amino-2-oxoethyl)aminocarbonyl]thiazol-2-ylthio}-N-{[4-(3,4-dichlorbenzyl)morpholin-2-yl]methyl}acetamid,

(2S)-N-{[4-(3,4-Dichlorbenzyl)morpholin-2-yl]methyl}-[4-(5-methyl-1,2,4-oxadiazol-3-yl)thiazol-2-ylthio]acetamid,

(2S)-(5-Amino-8H-indeno[1,2-d]thiazol-2-ylthio)-N-{[4-(3,4-dichlorbenzyl)morpholin-2-yl]methyl}acetamid,

(2S)-{4-[(2-Amino-2-oxoethyl)aminocarbonyl]phenylthio}-N-([4-(3,4-dichlorbenzyl)morpholin-2-yl]methyl}acetamid,

(2S)-{4-[(2-Carboxyethyl)aminocarbonyl]thiazol-2-ylthio}-N-{[4-(3,4-dichlorbenzyl)morpholin-2-yl]methyl}acetamid,

(2S)-(5-Acetamino-1,3,4-thiadiazol-2-ylthio)-N-{[4-(3,4-dichlorbenzyl)-morpholin-2-yl]methyl}acetamid,

(2S)-4-(4-Carbamoylthiazol-2-ylthio)-N-{(4-(3,4-dichlorbenzyl)morpholin-2-yl]methyl}butyramid,

(2S)-N-{[4-(3,4-Dichlorbenzyl)morpholin-2-yl]methyl}-[4-(1H-tetrazol-5-yl)thiazol-2-ylthio]acetamid,

(2S)-N-{[4-(3,4-Dichlorbenzyl)morpholin-2-yl]methyl}-([1,3]thiazolo[5,4-b]pyridin-2-ylthio)acetamid,

(2S)-(E)-[4-(2-Carbamoylethen-1-yl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorbenzyl)morpholin-2-yl]methyl}acetamid,

(2S)-[4-(Carbamoylmethyl)thiazol-2-ylthio]-N-{[4-(3,4-difluorbenzyl)-morpholin-2-yl]methyl}acetamid,

(2S)-[4-(Carbamoylmethyl)thiazol-2-ylthio]-N-{[4-(4-fluorbenzyl)morpholin-2-yl]methyl}acetamid,

(2S)-(4-Carboxy-5-methylthiazol-2-ylthio)-N-{[4-(3,4-dichlorbenzyl)morpholin-2-yl]methyl}acetamid,

(2S)-(4-Carbamoyl-5-methylthiazol-2-ylthio)-N-{[4-(3,4-dichlorbenzyl)-morpholin-2-yl]methyl}acetamid,

(2S)-(4-Carbamoylthiazol-2-ylthio)-N-{[4-(3-chlor-4-fluorbenzyl)morpholin-2-yl]methyl}acetamid,

(2S)-[4-(2-Amino-2-oxoethyl)aminocarbonylthiazol-2-ylthio]-N-{[4-(3,4-difluorbenzyl)morpholin-2-yl]methyl}acetamid,

(2S)-(5-Amino-1,3,4-thiadiazol-2-ylthio)-N-{[4-(3-chlorbenzyl)morpholin-2-yl]methyl}acetamid,

(2S)-(5-Amino-1,3,4-thiadiazol-2-ylthio)-N-{[4-(3,4-difluorbenzyl)morpholin-2-yl]methyl}acetamid,

(2S)-N-{[4-(3,4-Dichlorbenzyl)morpholin-2-yl]methyl}-(pyrimidin-2-yl-thio)acetamid,

(2S)-(3-Acetyl-2-oxo-2H-chromen-6-ylthio)-N-{[4-(3,4-dichlorbenzyl)-morpholin-2-yl]methyl}acetamid,

(2S)-N-{[4-(3,4-Difluorbenzyl)morpholin-2-yl]methyl}-(6-oxo-1,6-di-hydropyridazin-3-ylthio)acetamid,

(2S)-[6-(Carbamoylmethyl)pyrazin-2-ylthio]-N-{[4-(3,4-dichlorbenzyl)-morpholin-2-yl]methyl}acetamid und

(2S)-4-(Cyclopentansulfonyl)-N-{[4-(3-chlor-4-fluorbenzyl)morpholin-2-yl]methyl}butyramid;

oder ein pharmazeutisch annehmbares Salz davon oder ein Hydrat oder Solvat davon.

16. CCR3-Antagonist, der als Wirkstoff die Verbindung gemäß einem der Ansprüche 1 bis 15 oder ein pharmazeutisch annehmbares Salz davon oder ein Hydrat oder Solvat davon umfasst.

17. Pharmazeutische Zusammensetzung, die die Verbindung gemäß einem der Ansprüche 1 bis 15 oder ein pharmazeutisch annehmbares Salz davon oder ein Hydrat oder Solvat davon sowie einen pharmazeutisch annehmbaren Träger umfasst.

18. Pharmazeutische Zusammensetzung gemäß Anspruch 17, bei der es sich um ein Mittel zur Prophylaxe und/oder Behandlung von Asthma, Sinusitis, allergischer Rhinitis, atopischer Dermatitis, allergischer Konjunktivitis, allergischer Myelitis, ulzerativer Kolitis, Morbus Crohn oder rheumatoider Arthritis handelt.

19. Verbindung gemäß einem der Ansprüche 1 bis 15 oder ein pharmazeutisch annehmbares Salz davon oder ein Hydrat oder Solvat davon zur Verwendung bei der Prophylaxe und/oder Behandlung einer Krankheit, an der CCR3 beteiligt ist.

20. Verbindung zur Verwendung bei der Prophylaxe und/oder Behandlung einer Krankheit, an der CCR3 beteiligt ist, gemäß Anspruch 19, wobei es sich bei der Krankheit, an der CCR3 beteiligt ist, um Asthma, Sinusitis, allergische Rhinitis, atopische Dermatitis, allergische Konjunktivitis, allergische Myelitis, ulzerative Kolitis, Morbus Crohn oder rheumatoide Arthritis handelt.

21. Verwendung der Verbindung gemäß einem der Ansprüche 1 bis 15 oder eines pharmazeutisch annehmbaren Salzes davon oder eines Hydrats oder Solvats davon zur Herstellung eines Mittels zur Prophylaxe und/oder Behandlung einer Krankheit, an der CCR3 beteiligt ist.

22. Verwendung gemäß Anspruch 21, wobei es sich bei der Krankheit, an der CCR3 beteiligt ist, um Asthma, Sinusitis, allergische Rhinitis, atopische Dermatitis, allergische Konjunktivitis, allergische Myelitis, ulzerative Kolitis, Morbus Crohn oder rheumatoide Arthritis handelt.

23. Herstellungsverfahren für eine Verbindung, die durch die Formel (1)

dargestellt wird, wobei Ring A, Ring B, m, n, X, Y und Z wie in Anspruch 1 definiert sind, oder ein Salz davon, umfassend das Umsetzen einer Verbindung, die durch die Formel (6)

dargestellt wird, wobei jedes Symbol wie oben definiert ist, oder eines Salzes davon mit einer Verbindung, die durch die Formel (8)

dargestellt wird, wobei Ring A wie oben definiert ist, oder einem Salz davon.

24. (2S)-[4-(Carboxymethyl)thiazol-2-ylthio]-N-{[4(3,4-dichlorbenzyl)morpholin-2-yl]methyl}acetamid.

25. (2S)-[4-(2-Carboxypropan-2-yl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorbenzyl)morpholin-2-yl]methyl}acetamid.

26. (2S)-(5-Amino-1,3,4-thiadiazol-2-ylthio)-N-{[4-(3,4-difluorbenzyl)morpholin-2-yl]methyl}acetamid.

27. (2S)-N-{[4-(3,4-Difluorbenzyl)morpholin-2-yl]methyl}-(6-oxo-1,6-di-hydropyridazin-3-ylthio)acetamid.

28. Pharmazeutische Zusammensetzung, die die Verbindung gemäß einem der Ansprüche 24 bis 27 oder ein pharmazeutisch annehmbares Salz davon oder ein Hydrat oder Solvat davon sowie einen pharmazeutisch annehmbaren Träger umfasst.

29. Pharmazeutische Zusammensetzung gemäß Anspruch 28, bei der es sich um ein Mittel zur Prophylaxe und/oder Behandlung von Asthma, Sinusitis, allergischer Rhinitis, atopischer Dermatitis, allergischer Konjunktivitis, allergischer Myelitis, ulzerativer Kolitis, Morbus Crohn oder rheumatoider Arthritis handelt.

Revendications

1. Composé représenté par la formule (1)

dans laquelle
le cycle A est un groupe aryle en C₆ à C₁₄ monocyclique ou tricyclique qui peut être partiellement hydrogéné et qui peut avoir un/des substituant(s), ou un groupe hétérocyclique (monocyclique) aromatique, de 5 à 7 chaînons, contenant comme atome cyclique, outre l'atome de carbone, 1 à 3 sortes de 1 à 4 hétéro-atomes choisis parmi un atome d'azote, un atome de soufre et un atome d'oxygène ou des groupes dérivés d'un hétérocycle aromatique (bicyclique ou supérieur) obtenu par condensation d'un hétérocycle aromatique de 5 à 7 chaînons, contenant comme atome cyclique, outre l'atome de carbone, 1 à 3 sortes de 1 à 4 hétéro-atomes choisis parmi un atome d'azote, un atome de soufre et un atome d'oxygène et un cycle benzène ou le groupe hétérocyclique (monocyclique) aromatique mentionné ci-dessus, chacun d'eux pouvant être partiellement hydrogéné et pouvant avoir un/des substituant(s),
le cycle B est un groupe hétérocyclique monocyclique à tricyclique de 5 à 14 chaînons contenant, comme atome cyclique, outre l'atome de carbone, 1 à 3 sortes de 1 à 4 hétéro-atomes choisis parmi un atome d'azote, un atome de soufre et un atome d'oxygène qui peut avoir un/des substituant(s) ou un groupe cycloalkylène monocyclique à tricyclique (comprenant un groupe cycloalkylène réticulé) ayant 3 à 8 atomes de carbone et qui peut avoir un/des substituant(s),
ledit/lesdits substituant(s) étant choisi(s) parmi un atome d'halogène, un groupe alkyle en C₁ à C₆, cycloalkyle en C₃ à C₈, cycloalkyloxy en C₃ à C₈, halogénoalkyle en C₁ à C₆, aryle en C₆ à C₁₉, alcoxy en C₁ à C₆, halogénoalcoxy en C₁ à C₆, aryloxy en C₆ à C₁₄, nitro, amino, mono- ou di-alkylamino en C₁ à C₆, mono-ou di-(cycloalkyle en C₃ à C₈)amino, mono- ou di-(aryle en C₆ à C₁₄)amin.o, acyle en C₁ à C₁₁, mono- ou di (acyle en C₁ à C₁₁) amino, mono- ou di- (alcoxy en C₁ à C₆-carbonyl)amino, sulfonylamino, amino-alkyle en C₁ à C₆, mono- ou di- (alkyle en C₁ à C₆) amino-alkyle en C₁ à C₆, amino cyclique en C₃ à C₈, hydrazino, guanidino, amidino, hydroxyamidino, alcoxyamidino en C₁ à C₆, aminométhylène-amino, imino, carboxy, alcoxy en C₁ à C₆-carbonyle, carbamoyle, mono- ou di-(alkyle en C₁ à C₆)aminocarbonyle, mono- ou di-(aryle en C₆ à C₁₉) aminocarbonyle, cyano, aralkyle en C₇ à C₁₃, mono-ou di-(aralkyle en C₇ à C₁₃)aminocarbonyle, hétéroaryle, hétéroaryl-alkyle en C₁ à C₃, mono- ou di-(hétéroaryl-alkyle en C₁ à C₃)amino-carbonyle, hydroxy, mercapto, alkylthio en C₁ à C₆, arylthio en C₆ à C₁₉, -SO₃H, - SO₂NH₂, sulfonamide, oxo et thioxo,
m est un nombre entier de 0 à 2,
n est un nombre entier de 1 à 5,
X est une liaison, -NH-, -NR¹-, où R¹ est un groupe alkyle en C₁ à C₆ qui peut avoir un/des substituant(s) tels que définis ci-dessus, -CO-, -CO₂-, -OCO-, -CONR^a, R^a étant, ici et dans ce qui suit, un atome d'hydrogène ou un groupe alkyle en C₁ à C₆ qui peut avoir un/des substituant(s) tels que définis ci-dessus, -NR^aCO-, -NR²CONR³-, R et R³ pouvant être identiques ou différents et chacun étant un atome d'hydrogène ou un groupe alkyle en C₁ à C₆ qui peut avoir un/des substituant(s) tels que définis ci-dessus, ou R² et R³ en combinaison forment éventuellement, conjointement avec les atomes liés à ceux-ci, un cycle qui peut avoir un/des substituant(s) tels que définis ci-dessus, un atome d'oxygène, un atome de soufre, -SO-, -SO₂--NR^aSO₂-, -SO₂NR^a-, alkylène en C₁ à C₆ qui peut avoir un/des substituant(s) tels que définis ci-dessus, un groupe alcénylène à chaîne linéaire ou ramifiée ayant 2 à 6 atomes de carbone qui a une/des double(s) liaison(s) sur une position quelconque de la chaîne alkylène ayant 2 à 6 atomes de carbone et qui peut avoir un/des substituant(s) tels que définis ci-dessus, un groupe alcynylène à chaîne linéaire ou ramifiée ayant 2 à 6 atomes de carbone qui a une/des triple(s) liaison(s) sur une position quelconque de la chaîne alkylène ayant 2 à 6 atomes de carbone et qui peut avoir un/des substituant(s) tels que définis ci-dessus, -O-X^a, où X^a ici, et dans ce qui suit, est un groupe alkylène en C₁ à C₆ qui peut avoir un/des substituant(s) tels que définis ci-dessus, -X^a-O-, -CO-X^a-, -X^a-CO-, -CONR^a-X^a-, -X^a-CONR^a-, -NR^aCO-X^a-, -X^a-NR^aCO-, -S-X^a-, -X^a-S-, -SO-X^a-, -X^a-SO-, -NR^a-X^a, -X^a-NR^a-, -SO₂-X^a-, -X^a-SO₂-, -C(=N-CO₂-R¹) -, -C (=N-SO₂-R¹) -, -C(=N-SO₂NH₂) -, -C(=CH-NO₂)-, -C(=N-CN)- ou un groupe cycloalkylidène monocyclique à tricyclique (comprenant un groupe cycloalkylidène réticulé) ayant 3 à 8 atomes de carbone qui peut avoir un/des substituant(s) tels que définis ci-dessus, Y est une liaison, -NH-, -NR⁴- où R⁴, ici et dans ce qui suit, est un groupe alkyle en C₁ à C₆ qui peut avoir un/des substituant(s) tels que définis ci-dessus, -CO-, -CO₂-, -OCO-, -CONR^b, où R^b, ici et dans ce qui suit, est un atome d'hydrogène ou un groupe alkyle en C₁ à C₆ qui peut avoir un/des substituant(s) tels que définis ci-dessus, -NR^bCO-, -NR⁵CONR⁶-, où R⁵ et R⁶ peuvent être identiques ou différents et chacun est un atome d'hydrogène ou un groupe alkyle en C₁ à C₆ qui peut avoir un/des substituant(s) tels que définis ci-dessus, ou R⁵ et R⁶ en combinaison forment éventuellement, conjointement avec les atomes qui y sont liés, un cycle qui peut avoir un/des substituant(s) tels que définis ci-dessus, un atome d'oxygène, un atome de soufre, -SO-, -SO₂-, -NR^bSO₂-, -SO₂NR^b, un groupe alkylène en C₁ à C₆ qui peut avoir un/des substituant(s) tels que définis ci-dessus, un groupe alcénylène à chaîne linéaire ou ramifiée ayant 2 à 6 atomes de carbone qui a une/des doubles liaison(s) sur une position quelconque de la chaîne alkylène ayant 2 à 6 atomes de carbone et qui peut avoir un/des substituant(s) tels que définis ci-dessus, un groupe alcynylène à chaîne linéaire ou ramifiée ayant 2 à 6 atomes de carbone qui a une/des triple(s) liaison(s) sur une position quelconque de la chaîne alkylène ayant 2 à 6 atomes de carbone et qui peut avoir un/des substituants tels que définis ci-dessus, -O-X^b, où X^b, ici et dans ce qui suit, est un groupe alkylène en C₁ à C₆ qui peut avoir un/des substituants tels que définis ci-dessus, -X^b-O-, -CO-X^b-, -X^b-CO-, -CONR^b-X^b-, -X^b-CONR^b-, -NR^bCO-X^b-, -X^b-NR^bCO-, -S-X^b-, -X^b-S-, -SO-X^b-, -X^b-SO-, -NR^b-X^b, -X^b-NR^b-, -SO₂-X^b-, -X^b-SO₂-, -C(=N-CO₂-R⁴)-, -C (=N-SO₂-R⁴) -, -C(=N-SO₂NH₂)-, -C(=CH-NO₂)- ou -C(=N-CN)- et
Z est un atome d'hydrogène, un atome d'halogène, un groupe alkyle en C₁ à C₆ qui peut avoir un/des substituant(s) tels que définis ci-dessus, un groupe cycloalkyle monocyclique à tricyclique (comprenant un groupe cycloalkyle réticulé) ayant 3 à 8 atomes de carbone qui peut avoir un/des substituant(s) tels que définis ci-dessus, un groupe aryle en C₆ à C₁₄ monocyclique à tricyclique qui peut être partiellement hydrogéné, qui peut avoir un/des substituants tels que définis ci-dessus, un groupe hétérocyclique qui peut avoir un/des substituant(s) tels que définis ci-dessus, un groupe hydroxy, nitro, amino, cyano, alcoxy en C₁ à C₆ qui peut avoir un/des substituant(s) tels que définis ci-dessus, mono- ou di-alkylamino en C₁ à C₆ qui peut avoir un/des substituant(s) tels que défini(s) ci-dessus, acylamino en C₁ à C₇ qui peut avoir un/des substituant(s) tels que définis ci-dessus, sulfonylamino qui peut avoir un/des substituant(s) tels que définis ci-dessus, hydrazino qui peut avoir un/des substituant(s) tels que définis ci-dessus, guanidino qui peut avoir un/des substituant(s) tels que défini(s) ci-dessus, ou amidino qui peut avoir un/des substituant(s) tels que défini(s) ci-dessus,
ou un sel pharmaceutiquement acceptable de ceux-ci ou un hydrate ou solvate de ceux-ci.

2. Composé selon la revendication 1, dans lequel le cycle B est un groupe hétérocyclique monocyclique à tricyclique de 5 à 14 chaînons contenant comme atome cyclique, outre l'atome de carbone, 1 à 3 sortes de 1 à 4 hétéro-atomes choisis parmi un atome d'azote, un atome de soufre et un atome d'oxygène qui peut avoir un/des substituant(s) tels que définis dans la revendication 1 et X est une liaison, -NH-, -NR¹-, R¹ étant un groupe alkyle en C₁ à C₆ qui peut avoir un/des substituant(s) tels que définis dans la revendication 1, -CO-, -CO₂-, -OCO-, -CONR^a, où R^a, ici et dans ce qui suit, est un atome d'hydrogène ou un groupe alkyle en C₁ à C₆ qui peut avoir un/des substituant(s) tels que définis dans la revendication 1, -NR^aCO-, -NR²CONR³, R² et R³ pouvant être identiques ou différents et chacun étant un atome d'hydrogène ou un groupe alkyle en C₁ à C₆ qui peut avoir un/des substituant(s) tels que définis dans la revendication 1, ou R² et R³, en combinaison, forment éventuellement, conjointement avec les atomes qui y sont liés, un cycle qui peut avoir un/des substituant(s) tels que définis dans la revendication 1, un atome d'oxygène, un atome de soufre, -SO-, -SO₂-, -NR^aSO₂-, -SO₂NR^a, un groupe alkylène en C₁ à C₆ qui peut avoir un/des substituant(s) tels que définis dans la revendication 1, un groupe alcénylène à chaîne linéaire ou ramifiée ayant 2 à 6 atomes de carbone qui a une/des double(s) liaison(s) sur une position quelconque de la chaîne alkylène ayant 2 à 6 atomes de carbone et qui peut avoir un/des substituant(s) tels que définis dans la revendication 1, un groupe alcynylène à chaîne linéaire ou ramifiée ayant 2 à 6 atomes de carbone qui a une/des triple (s) liaison(s) sur une position quelconque de la chaîne alkylène ayant 2 à 6 atomes de carbone et qui peut avoir un/des substituant(s) tels que définis dans la revendication 1, -O-X^a, où X^a ici, et dans ce qui suit, est un groupe alkylène en C₁ à C₆ qui peut avoir un/des substituant(s) tels que définis dans la revendication 1, -X^a-O-, -CO-X^a-, -X^a-CO-, -CONR^a-X^a-, -X^a-CONR^a-, -NR^aCO-X^a-, -X^a-NR^aCO-, -S-X^a-, -X^a-S-, -SO-X^a-, -X^a-SO-, -NR^a-X^a, -X^a-NR^a-, -SO₂-X^a-, -X^a-SO₂-, -C(=N-CO₂-R¹)-, -C(=N-SO₂-R¹) -, -C(=N-SO₂NH₂)-, -C(=CH-NO₂)-, -C (=N-CN) - ou un sel pharmaceutiquement acceptable de celui-ci, ou un hydrate ou un solvate de celui-ci.

3. Composé selon la revendication 1 ou 2, dans lequel, dans la formule (1), m est 0 ou 2, ou un sel pharmaceutiquement acceptable de celui-ci, ou un hydrate ou un solvate de celui-ci.

4. Composé selon l'une quelconque des revendications 1 à 3, dans lequel, dans la formule (1), m est 0, ou un sel pharmaceutiquement acceptable de celui-ci, ou un hydrate ou un solvate de celui-ci.

5. Composé selon l'une quelconque des revendications 1 à 4, dans lequel, dans la formule (1), X est une liaison, -NH-, -NR¹-, où R¹ est un groupe alkyle en C₁ à C₆ qui peut avoir un/des substituant(s) tels que définis dans la revendication 1, -CO-, -CO₂-, -OCO-, -CONR^a, R^a étant, ici et dans ce qui suit, un atome d'hydrogène ou un groupe alkyle en C₁ à C₆ qui peut avoir un/des substituant(s) tels que définis dans la revendication 1, -NR^aCO-, -NR²CONR³, R² et R³ pouvant être identiques ou différents et chacun étant un atome d'hydrogène ou un groupe alkyle en C₁ à C₆ qui peut avoir un/des substituant(s) tels que définis dans la revendication 1, un atome d'oxygène, un atome de soufre, -SO-, -SO₂- -NR^aSO₂-, -SO₂NR^a, un groupe alcénylène à chaîne linéaire ou ramifiée ayant 2 à 6 atomes de carbone qui a une/des double(s) liaison(s) sur une position quelconque de la chaîne alkylène ayant 2 à 6 atomes de carbone qui peuvent avoir un/des substituant(s) tels que définis dans la revendication 1, -CO-X^a-, X^a étant, ici et dans ce qui suit, un groupe alkylène en C₁ à C₆ ayant éventuellement un/des substituant(s) tels que définis dans la revendication 1, -X^a-CO-, -CONR^a-X^a-, -X^a-CONR^a-, -NR^aCO-X^a-, -X^a-NR^aCO- ou un groupe cycloalkylidène monocyclique à tricyclique (comprenant un groupe cycloalkylidène réticulé) ayant 3 à 8 atomes de carbone qui peut avoir un/des substituant(s) tels que définis dans la revendication 1, ou un sel pharmaceutiquement acceptable de celui-ci ou un hydrate ou un solvate de celui-ci.

6. Composé selon l'une quelconque des revendications 1 à 5, dans lequel, dans la formule (1), X est une liaison, -CO-, -CONR^a, R^a étant, ici et dans ce qui suit, un atome d'hydrogène ou un groupe alkyle en C₁ à C₆ qui peut avoir un/des substituant(s) tels que définis dans la revendication 1, -NR^aCO-, -CO-X^a, X^a étant, ici et dans ce qui suit, un groupe alkylène en C₁ à C₆ qui peut avoir un/des substituant(s) tels que définis dans la revendication 1, -X^a-CO-, -CONR^a-X^a-, -X^a-CONR^a-, -NR^aCO-X^a- ou -X^a-NR^aCO-, ou un sel pharmaceutiquement acceptable de celui-ci ou un hydrate ou un solvate de celui-ci.

7. Composé selon l'une quelconque des revendications 1 à 6, dans lequel, dans la formule (1), Y est une liaison, -NH-, -NR⁴- où R⁴ est un groupe alkyle en C₁ à C₆ qui peut avoir un/des substituant(s) tels que définis dans la revendication 1, -CO-, -CO₂-, -OCO-, -CONR^b, où R^b, ici et dans ce qui suit, est un atome d'hydrogène ou un groupe alkyle en C₁ à C₆ qui peut avoir un/des substituant(s) tels que défini(s) dans la revendication 1, -NR^bCO-, -NR⁵CONR⁶-, où R⁵ et R⁶ peuvent être identiques ou différents et chacun est un atome d'hydrogène ou un groupe alkyle en C₁ à C₆ qui peut avoir un/des substituant(s) tels que définis dans la revendication 1, un atome d'oxygène, un atome de soufre, -SO-, -SO₂-, -NR^bSO₂-, -SO₂NR^b, -CO-X^b, X^b étant, ici et dans ce qui suit, un groupe alkylène en C₁ à C₆ qui peut avoir un/des substituant(s) tels que définis dans la revendication 1, -X^b-CO-, -CONR^b-X^b-, -X^b-CONR^b-, -NR^bCO-X^b- ou -X^b-NR^bCO-, ou un sel pharmaceutiquement acceptable de celui-ci ou un hydrate ou un solvate de celui-ci.

8. Composé selon l'une quelconque des revendications 1 à 7, dans lequel, dans la formule (1), Y est une liaison, -CO-, -CONR^b, où R^b, ici et dans ce qui suit, est un atome d'hydrogène ou un groupe alkyle en C₁ à C₆ qui peut avoir un/des substituant(s) tels que défini(s) dans la revendication 1, -NR^bCO-, -CO-X^b, X^b étant, ici et dans ce qui suit, un groupe alkylène en C₁ à C₆ qui peut avoir un/des substituant(s) tels que définis dans la revendication 1, -X^b-CO-, -CONR^b-X^b-, -X^b-CONR^b-, -NR^bCO-X^b- ou -X^b-NR^bCO-, ou un sel pharmaceutiquement acceptable de celui-ci ou un hydrate ou un solvate de celui-ci.

9. Composé selon l'une quelconque des revendications 1 à 8, dans la formule (1), Z est un atome d'hydrogène, un atome d'halogène, un groupe alkyle en C₁ à C₆ qui peut avoir un/des substituant(s) tels que définis dans la revendication 1, un groupe cycloalkyle monocyclique à tricyclique (comprenant un groupe cycloalkyle réticulé) ayant 3 à 8 atomes de carbone qui peut avoir un/des substituant(s) tels que définis dans la revendication 1, un groupe aryle en C₆ à C₁₄ monocyclique à tricyclique qui peut être partiellement hydrogéné, qui peut avoir un/des substituants tels que définis dans la revendication 1, un groupe hétérocyclique qui peut avoir un/des substituant(s) tels que définis dans la revendication 1, un groupe hydroxy, nitro, amino, cyano, alcoxy en C₁ à C₆ qui peut avoir un/des substituant(s) tels que définis dans la revendication 1, mono- ou di-alkylamino en C₁ à C₆ qui peut avoir un/des substituant(s) tels que défini(s) dans la revendication 1, acylamino en C₁ à C₇ qui peut avoir un/des substituant(s) tels que définis dans la revendication 1, sulfonylamino qui peut avoir un/des substituant(s) tels que définis dans la revendication 1, hydrazino qui peut avoir un/des substituant(s) tels que définis dans la revendication 1, guanidino qui peut avoir un/des substituant(s) tels que définis dans la revendication 1 ou amidino qui peut avoir un/des substituant(s) tels que définis dans la revendication 1, ou un sel pharmaceutiquement acceptable de celui-ci ou un hydrate ou solvate de celui-ci.

10. Composé selon l'une quelconque des revendications 1 à 9, dans lequel, dans la formule (1), Z est un atome d'hydrogène, un groupe hydroxy, amino, alkyle en C₁ à C₆ qui peut avoir un/des substituant(s) tels que définis dans la revendication 1, alcoxy en C₁ à C₆ qui peut avoir un/des substituant(s) tels que définis dans la revendication 1, aryle en C₆ à C₁₄ monocyclique à tricyclique qui peut être partiellement hydrogéné, qui peut avoir un/des substituants tels que définis dans la revendication 1 ou un groupe hétérocyclique qui peut avoir un/des substituant(s), ou un sel pharmaceutiquement acceptable de celui-ci ou un hydrate ou solvate de celui-ci.

11. Composé selon la revendication 1, qui est représenté par la formule (la)

dans laquelle le cycle C est un groupe aryle en C₆ à C₁₄ monocyclique à tricyclique qui peut être partiellement hydrogéné, qui peut avoir un/des substituant(s) tels que définis dans la revendication 1, ou un groupe hétérocyclique (monocyclique) aromatique de 5 à 7 chaînons contenant, comme atome cyclique, outre l'atome de carbone, 1 à 3 sortes de 1 à 4 hétéro-atomes choisis parmi un atome d'azote, un atome de soufre et un atome d'oxygène ou des groupes dérivés d'un hétérocycle aromatique (bicyclique ou supérieur) obtenu par condensation d'un hétérocycle aromatique de 5 à 7 chaînons contenant, comme atome cyclique, outre l'atome de carbone, 1 à 3 sortes de 1 à 4 hétéro-atomes choisis parmi un atome d'azote, un atome de soufre et un atome d'oxygène et un cycle benzène ou le groupe hétérocyclique (monocyclique) aromatique mentionné ci-dessus, chacun d'eux pouvant être partiellement hydrogéné et pouvant avoir un/des substituant(s) tels que définis dans la revendication 1, et les autres symboles sont tels que définis dans la revendication 1, ou un sel pharmaceutiquement acceptable de celui-ci, ou un hydrate ou un solvate de celui-ci.

12. Composé selon l'une quelconque des revendications 1 à 11, dans lequel, dans la formule (1), le cycle A est un groupe phényle ayant éventuellement un/des substituant(s) tels que définis dans la revendication 1, ou un sel pharmaceutiquement acceptable de celui-ci, ou un hydrate ou un solvate de celui-ci.

13. Composé selon l'une quelconque des revendications 1 à 12, dans lequel, dans la formule (1), n est 1 à 3, ou un sel pharmaceutiquement acceptable de celui-ci, ou un hydrate ou un solvate de celui-ci.

14. Composé selon l'une quelconque des revendications 1 à 13, dans lequel, dans la formule (1), la configuration absolue de la position 2 de la morpholine est une configuration S, ou un sel pharmaceutiquement acceptable de celui-ci, ou un hydrate ou un solvate de celui-ci.

15. Composé selon la revendication 1, qui est choisi parmi
le (2S)-[4-(carboxyméthyl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]méthyl}acétamide,
le (2S)-[4-(3-aminophényl)thiazol-2-ylthio]-N-([4-(3,4-dichlorobenzyl)morpholin-2-yl]méthyl}acétamide,
le (2S)-[4-(3-carbamoyl-4-hydroxyphényl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]méthyl}acétamide,
le (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]méthyl}-[4-(pyridin-4-yl)thiazol-2-ylthio]acétamide,
le (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]méthyl}-[4-(3,4-diméthoxyphényl)thiazol-2-ylthio]acétamide,
le (2S)-(4-carbamoylthiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]méthyl}-acétamide,
le (2S)-{4-[(2-amino-2-oxoéthyl)aminocarbonyl] thiazol-2-ylthio}-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]méthyl}-acétamide
le (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]méthyl}-[4-(5-méthyl-1,2,4-oxadiazol-3-yl)thiazol-2-ylthio]acétamide
le (2S)-(5-amino-8H-indéno[1,2-d]thiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]méthyl}acétamide,
le (2S)-{4-[(2-amino-2-oxoéthyl)aminocarbonyl] phénylthio}-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]méthyl}acétamide,
le (2S)-{4-[(2-carboxyéthyl)aminocarbonyl]thiazol-2-ylthio}-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]méthyl}acétamide,
le (2S)-(5-acétamino-1,3,4-thiadiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]méthyl}acétamide,
le (2S)-4-(4-carbamoylthiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]méthyl}butyramide,
le (2S)-N-{4-(3,4-dichlorobenzyl)morpholin-2-yl]méthyl}-[4-(1H-tétrazol-5-yl)thiazol-2-ylthio]acétamide,
le (2S)-N-{4-(3,4-dichlorobenzyl)morpholin-2-yl]méthyl}-([1,3]thiazolo[5,4-b]pyridin-2-ylthio)acétamide,
le (2S)-(E)-[4-(2-carbamoyléthén-1-yl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]méthyl}-acétamide,
le (2S)-[4-(carbamoylméthyl)thiazol-2-ylthio]-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]méthyl}-acétamide,
le (2S)-[4-(carbamoylméthyl)thiazol-2-ylthio]-N-{[4-(4-fluorobenzyl)morpholin-2-yl]méthyl}-acétamide,
le (2S)-(4-carboxy-5-méthylthiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]méthyl}-acétamide,
le (2S)-(4-(carbamoyl-5-méthylthiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]méthyl}-acétamide,
le (2S)-[4-(carbamoylméthyl)thiazol-2-ylthio]-N-{[4-(3-chloro-4-fluorobenzyl)morpholin-2-yl]méthyl}-acétamide
le (2S)-[4-(2-amino-2-oxoéthyl)aminocarbonyl thiazol-2-ylthio]-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]méthyl}-acétamide,
le (2S)-(5-amino-1,3,4-thiadiazol-2-ylthio]-N-{[4-(3-chlorobenzyl)morpholin-2-yl]méthyl}-acétamide
le (2S)-(5-amino-1,3,4-thiadiazol-2-ylthio]-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]méthyl}-acétamide,
le (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]méthyl}-(pyrimidin-2-ylthio)acétamide,
le (2S)-(3-acétyl-2-oxo-2H-chromén-6-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]méthyl}-acétamide,
le (2S)-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]méthyl}-(6-oxo-1,6-dihydropyridazin-3-ylthio)acétamide
le (2S)-[6-(carbamoylméthyl)pyrazin-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]méthyl}-acétamide et
le (2S)-4-(cyclopentanesulfonyl)-N-{[4-(3-chloro-4-fluorobenzyl)morpholin-2-yl]méthyl}-butyramide, ou un sel pharmaceutiquement acceptable de ceux-ci, ou un hydrate ou un solvate de ceux-ci.

16. Antagoniste de CCR3 comprenant, comme ingrédient actif, le composé selon l'une quelconque des revendications 1 à 15, ou un sel pharmaceutiquement acceptable de celui-ci, ou un hydrate ou un solvate de celui-ci.

17. Composition pharmaceutique comprenant le composé selon l'une quelconque des revendications 1 à 15, ou un sel pharmaceutiquement acceptable de celui-ci, ou un hydrate ou un solvate de celui-ci.

18. Composition pharmaceutique selon la revendication 17, qui est un agent pour la prophylaxie et/ou le traitement de l'asthme, de la sinusite, de la rhinite allergique, de la dermatite atopique, de la conjonctivite allergique, de la myélite allergique, de la rectocolite hémorragique, de la maladie de Crohn ou de la polyarthrite rhumatoïde.

19. Composé selon l'une quelconque des revendications 1 à 15, ou un sel pharmaceutiquement acceptable de celui-ci, ou un hydrate ou un solvate de celui-ci pour son utilisation dans la prophylaxie et/ou le traitement d'une maladie impliquant CCR3.

20. Composé pour son utilisation dans la prophylaxie et/ou le traitement d'une maladie impliquant CCR3 de la revendication 19, la maladie impliquant CCR3 étant l'asthme, la sinusite, la rhinite allergique, la dermatite atopique, la conjonctivite allergique, la myélite allergique, la rectocolite hémorragique, la maladie de Crohn ou la polyarthrite rhumatoïde.

21. Utilisation du composé selon l'une quelconque des revendications 1 à 15, ou un sel pharmaceutiquement acceptable de celui-ci, ou un hydrate ou un solvate de celui-ci pour la production d'un agent pour la prophylaxie et/ou le traitement d'une maladie impliquant CCR3.

22. Utilisation selon la revendication 21, dans laquelle la maladie impliquant CCR3 est l'asthme, la sinusite, la rhinite allergique, la dermatite atopique, la conjonctivite allergique, la myélite allergique, la rectocolite hémorragique, la maladie de Crohn ou la polyarthrite rhumatoïde.

23. Procédé de synthèse d'un composé représenté par la formule (1)

dans laquelle le cycle A, le cycle B, m, n, X, Y et Z sont tels que définis dans la revendication 1, ou un sel de celui-ci, qui comprend la réaction d'un composé représenté par la formule (6)

dans laquelle chaque symbole est tel que défini ci-dessus, ou un sel de celui-ci, avec un composé représenté par la formule (8)

dans laquelle le cycle A est tel que défini ci-dessus, ou un sel de celui-ci.

24. (2S)-[4-(carboxyméthyl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]méthyl}-acétamide.

25. (2S)-[4-(2-carboxypropan-2-yl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]méthyl}-acétamide.

26. (2S)-(5-amino-1,3,4-thiadiazol-2-ylthio)-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]méthyl}-acétamide

27. (2S)-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]méthyl}-(6-oxo-1,6-dihydropyridazin-3-ylthio)acétamide.

28. Composition pharmaceutique comprenant le composé selon l'une quelconque des revendications 24 à 27, ou un sel pharmaceutiquement acceptable de celui-ci, ou un hydrate ou un solvate de celui-ci, et un véhicule pharmaceutiquement acceptable.

29. Composition pharmaceutique selon la revendication 28, qui est un agent pour la prophylaxie et/ou le traitement de l'asthme, de la sinusite, de la rhinite allergique, de la dermatite atopique, de la conjonctivite allergique, de la myélite allergique, de la rectocolite hémorragique, de la maladie de Crohn ou de la polyarthrite rhumatoïde.