Urea compounds having substituents

Abstract

The present invention aims to provide a compound useful as an active ingredient for the prevention and treatment of inflammatory diseases, wherein the compound contains a specific chemical structure having a SIRT6 activation effect. The present invention relates to a compound of formula (1) or a pharmaceutically acceptable salt thereof. (The symbols in formula (1) are the same as those defined in the specification.)#imgabs0#

Description

Technical Field

[0001] The present invention provides a compound having a specific chemical structure that activates SIRT6, or a pharmaceutically acceptable salt thereof. Background Art

[0002] Sirtuins are nicotinamide adenine dinucleotide (NAD)-dependent deacylases that are highly conserved from prokaryotes to eukaryotes and play important roles in various life phenomena, including DNA repair, energy metabolism control, aging, and lifespan (Non-Patent Document 1).

[0003] Since ancient times, it has been known that calorie restriction can prolong life and inhibit various diseases known as aging-related diseases (metabolic diseases, cancer, cardiac and neurological diseases, inflammatory diseases, etc.). Once Sirtuin deficiency occurs in model organisms such as yeast and nematodes, the extension of life span caused by calorie restriction is not observed. Therefore, it is generally believed that Sirtuin plays a core role in the mechanism of calorie restriction (Non-patent Document 2).

[0004] In mammals, including humans, there are seven types of Sirtuins, SIRT1-7. SIRT1, SIRT6, and SIRT7 are mainly present in the nucleus, SIRT1 is mainly present in the nucleoplasm, SIRT6 is mainly present in the heterochromatin region, and SIRT7 is mainly present in the nucleolus. SIRT2 is present in the cytoplasm, and SIRT3-5 is present in the mitochondria (Non-Patent Document 3). SIRT6 has deacylation activity and mono-ADP ribosylation activity. The histone H3K9 deacetylation activity of SIRT6 is higher in substrate specificity than that of SIRT1, which also exists in the nucleus. In cells where SIRT6 is knocked out, H3K9 acetylation is hyperactive, so it is generally believed that SIRT6 acts as the main deacetylase (Non-Patent Documents 4, 5).

[0005] SIRT6 knockout mice develop normally about 2-3 weeks after birth, but thereafter rapidly develop premature aging symptoms such as decreased subcutaneous fat, decreased bone density, spinal curvature, and decreased lymphocytes (non-patent document 6). SIRT6 controls the transcription factor NF-κB, which is related to inflammation and immune response, through the deacetylation of H3K9. In SIRT6-deficient mice, the expression of inflammatory cytokines based on NF-κB is constantly activated, forming a chronic inflammatory state. The premature aging symptoms of SIRT6 knockout mice can be improved by inhibiting NF-κB (non-patent document 7). On the other hand, SIRT6 transgenic mice with high SIRT6 expression are tolerant to high-fat diet load (HFD) as well as when calorie restricted, and their lifespan is extended (non-patent document 8).

[0006] In recent years, research on Sirtuins has rapidly advanced, with SIRT6 being shown to play a variety of roles, including telomere stabilization, DNA repair, anti-aging, anti-fatty liver, anti-obesity, anti-diabetes, anti-atherosclerosis, anti-idiopathic pulmonary fibrosis (IPF), cardioprotection, and anti-inflammatory and anti-rheumatic effects (Non-Patent Documents 6-14). Therefore, it is expected that compounds that increase SIRT6 expression or enhance SIRT6 activity will become pharmaceuticals that are effective against diseases including those listed above.

[0007] Incidentally, the following compounds and the like are known as compounds having phosphatidylinositol 3-kinase inhibitory activity (Patent Documents 1 and 2).

[0008] [Chemical Formula 1]

[0009]

[0010] Prior art literature

[0011] Patent Literature

[0012] Patent Document 1: International Publication No. 2010 / 024258

[0013] Patent Document 2: International Publication No. 2010 / 125799

[0014] Non-patent literature

[0015] Non-patent literature 1: Imai Sand Guarente L. Ten years of NAD-dependent SIR2family deacetylases: implications for metabolic diseases. Trends PharmacolSci. 2010 31(5):212-220.

[0016] Non-patent document 2: Guarente L. Calorie restriction and sirtuins revisited. Genes Dev. 2013 27(19):2072-2085.

[0017] Non-patent document 3: Michishita E, Park JY, Burneskis JM, et al. Evolutionarilyconserved and nonconserved cellular localizations and functions of human SIRTproteins. Mol Biol Cell. 2005 16(10):4623-4635.

[0018] Non-patent document 4: Michishita E, McCord RA, Berber E, et al. SIRT6 is ahistone H3lysine 9 deacetylase that modulates telomeric chromatin. Nature. 2008 452(7186):492-496.

[0019] Non-patent document 5: Michishita E, McCord RA, Boxer LD, et al. Cell cycle-dependent deacetylation of telomeric histone H3 lysine K56 by human SIRT6. Cell Cycle. 2009 8(16): 2664-2666.

[0020] Non-patent document 6: Mostoslavsky R, Chua KF, Lombard DB, et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell. 2006 124(2): 315-329

[0021] Non-patent document 7: Kawahara TL, Michishita E, Adler AS, et al. SIRT6 linkstone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organismal life span. Cell. 2009 136(1): 62-74.

[0022] Non-patent document 8: Kanfi Y, Naiman S, Amir G, et al. The sirtuin SIRT6 regulates lifespan in male mice. Nature. 2012 483(7388):218-221

[0023] Non-patent document 9: McCord RA, Michishita E, Hong T, et al. SIRT6 stabilizes DNA-dependent protein kinase at chromatin for DNA double-strand break repair. Aging 2009 1(1):109-121

[0024] Non-patent literature 10: Kim HS, Xiao C, Wang RH, et al. Hepatic-specific disruption of SIRT6 in mice results in fatty liver formation due to enhanced glycolysis and triglyceride synthesis. Cell Metab. 2010 12(3):224-236

[0025] Non-patent literature 11: Kanfi Y, Peshti V, Gil R, et al. SIRT6 protects against pathological damage caused by diet-induced obesity. Aging Cell. 2010 9(2):162-173.

[0026] Non-Patent Literature 12: Stohr R, Mavilio M, Marino A, et al. ITCH modulates SIRT6 and SREBP2 to influence lipid metabolism and atherosclerosis in ApoE null mice. Sci Rep. 2015 Mar 17; 5: 9023.

[0027] Non-patent literature 13: Minagawa S, Araya J, Numata T, et al. Accelerated epithelialcell senescence in IPF and the inhibitory role of SIRT6 in TGF-β-inducedsenescence of human bronchial epithelial cells. Am J Physiol Lung Cell MolPhysiol. 2011 300(3):L391-401

[0028] Non-patent document 14: Sundaresan NR, Vasudevan P, Zhong L, et al. The sirtuin SIRT6 blocks IGF-Akt signaling and development of cardiac hypertrophy by targeting c-Jun. Nat Med. 2012 18(11):1643-1650 Summary of the Invention

[0029] Problems to be solved by the invention

[0030] The present invention provides compounds containing a specific chemical structure that activates SIRT6, pharmaceutically acceptable salts thereof, and novel methods and intermediates thereof, useful as active ingredients for preventing and treating inflammatory diseases. The compounds and pharmaceutically acceptable salts of the present invention possess properties that differ from existing anti-inflammatory agents in various aspects and are therefore expected to be useful as novel pharmaceuticals.

[0031] Means for solving problems

[0032] The inventors of the present application have conducted intensive research on compounds useful as active ingredients for preventing and treating inflammatory diseases, and pharmaceutically acceptable salts thereof, and have discovered the compounds of the present invention, and pharmaceutically acceptable salts thereof, etc. That is, the present invention is as described below. [1]

[0034] A compound of formula (1) or a pharmaceutically acceptable salt thereof.

[0035] [Chemical Formula 2]

[0036]

[0037] The symbols in formula (1) have the following meanings.

[0038] R 1 、R 2 :

[0039] are independently the same or different and represent a hydrogen atom or a C1-C6 alkyl group,

[0040] Or, R 1 With R 2 They are bonded to each other to form a substituent and represent any group selected from the following.

[0041] [Chemical Formula 3]

[0042]

[0043] R 12 : C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkylcarbonyl, or C1-C6 alkoxycarbonyl;

[0044] R 6 :

[0045] C1-C6 alkyl which may be substituted by 1 or 2 groups selected from Group G,

[0046] C3-C6 cycloalkyl which may be substituted by 1 or 2 groups selected from Group G, or

[0047] a 4-7 membered saturated heterocyclic group which may be substituted by 1 or 2 groups selected from Group G;

[0048] Group G:

[0049] Hydroxyl, halogen atom, amino, amino C1-C6 alkyl, C1-C6 alkylsulfonyl,

[0050] Carbamoyl which may be substituted by 1 or 2 groups selected from Group J,

[0051] C3-C6 cycloalkyl which may be substituted by 1 or 2 groups selected from Group J,

[0052] a 4-7 membered saturated heterocyclic group which may be substituted by 1 or 2 groups selected from Group J;

[0053] Group J:

[0054] aminoC1-C6 alkyl, amino, C1-C6 alkyl;

[0055] R 7 : Hydrogen atom

[0056] or

[0057] R 6 With R 7 They bond to each other to form a substituent and represent the groups shown below.

[0058] [Chemical Formula 4]

[0059]

[0060] The group can be oriented in any direction, left or right.

[0061] R 67-1 、R 67-2 :

[0062] are independently the same or different and are hydrogen, C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C4 alkylene, or

[0063] C1-C6 alkoxy C1-C6 alkyl;

[0064] Q:

[0065] Halogen atoms,

[0066] 1 to 3 selected from R Q3 C1-C6 alkyl substituted by any group in

[0067] 1 to 3 selected from R Q3 C3-C6 cycloalkyl substituted by any group in

[0068] 1 to 3 selected from R Q3 A 4-7 membered saturated heterocyclic group substituted by any group in

[0069] 1 to 3 selected from R Q3 An amino group substituted by any group in

[0070] Any group selected from the following.

[0071] [Chemical Formula 5]

[0072]

[0073] R Q1 :

[0074] a halogen atom, a cyano group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogenated C1-C6 alkyl group, a halogenated C1-C6 alkoxy group, a C3-C6 cycloalkylcarbonyl group, a C1-C6 alkylcarbamoyl group, a C1-C6 alkylsulfonyl group, or

[0075] Mono(C1-C6 alkyl)aminosulfonyl;

[0076] R Q2 :

[0077] Hydrogen atom, hydroxyl group, or halogen atom

[0078] or

[0079] R Q1 With R Q2 They bond to each other to form a substituent and represent the groups shown below.

[0080] [Chemical Formula 6]

[0081]

[0082] R Q3 :

[0083] a halogen atom, a C1-C6 alkoxy group, a halogenated C1-C6 alkyl group, a halogenated C1-C6 alkoxy group, a C3-C6 cycloalkoxy group, a phenoxy group, a benzyloxy group, a C1-C6 alkylcarbamoyl group, or

[0084] C1-C4 alkylene which may be substituted by a halogen group

[0085] Y:

[0086] Any group selected from the following, or a single bond

[0087] [Chemical Formula 7]

[0088]

[0089] The group can be oriented in any direction, left or right.

[0090] R Y1 : Hydrogen atom, or C1-C6 alkyl

[0091] The compound of formula (1) or its pharmaceutically acceptable salt does not include the following compounds or their pharmaceutically acceptable salts.

[0092] [Chemical Formula 8]

[0093] [2]

[0095] The compound according to [1] or a pharmaceutically acceptable salt thereof, wherein

[0096] R 1 、R 2 is a hydrogen atom, or

[0097] R 1 With R 2 are bonded to each other to form a substituent and are any group selected from the following:

[0098] [Chemical Formula 9]

[0099]

[0100] R 12: methyl, hydroxyethyl, acetyl, or methoxycarbonyl. [3]

[0102] The compound according to [1] or [2] or a pharmaceutically acceptable salt thereof, wherein R 6 is any group selected from the following:

[0103] C1-C6 alkyl,

[0104] Hydroxy C1-C6 alkyl,

[0105] Hydroxy C3-C6 cycloalkyl,

[0106] Tetrahydrofuranyl,

[0107] 2-oxopyrrolidin-3-yl. [4]

[0109] The compound according to [1] or [2] or a pharmaceutically acceptable salt thereof, wherein

[0110] R 6 is any group selected from the following:

[0111] methyl,

[0112] Hydroxypropyl,

[0113] 2-Hydroxy-2-methylpropyl,

[0114] Hydroxycyclobutyl,

[0115] Tetrahydrofuranyl. [5]

[0117] The compound according to [1] or [2] or a pharmaceutically acceptable salt thereof, wherein

[0118] R 6 With R 7 are bonded to each other to form a substituent and are any group selected from the following:

[0119] [Chemical Formula 10]

[0120]

[0121] The group can be oriented in any direction, left or right. [6]

[0123] The compound or pharmaceutically acceptable salt thereof according to any one of [1] to [5], wherein

[0124] Q is any group selected from the following.

[0125] [Chemical Formula 11]

[0126]

[0127] R Q1 is any group selected from the following:

[0128] Halogen atom, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy;

[0129] R Q2 is any group selected from the following:

[0130] Hydrogen atoms, hydroxyl groups, and fluorine atoms. [7]

[0132] The compound or pharmaceutically acceptable salt thereof according to any one of [1] to [5], wherein Q is any group selected from the following:

[0133] [Chemical Formula 12]

[0134]

[0135] R Q1 is any group selected from the following:

[0136] Fluorine atom, chlorine atom, methyl group, methoxy group, difluoromethyl group, trifluoromethyl group, difluoromethoxy group, trifluoromethoxy group;

[0137] R Q2 is any group selected from the following:

[0138] a hydrogen atom, a hydroxyl group, or a fluorine atom. [8]

[0140] The compound or pharmaceutically acceptable salt thereof according to any one of [1] to [5], wherein

[0141] Q is any group selected from the following:

[0142] 1 to 3 selected from R Q3 C3-C6 cycloalkyl substituted by any group in

[0143] 1 to 3 selected from R Q3 A 4-7 membered saturated heterocyclic group substituted by any group in;

[0144] R Q3 is any group selected from the following:

[0145] fluorine atom, chlorine atom, methoxy group, difluoromethyl group, trifluoromethyl group, difluoromethoxy group, trifluoromethoxy group, ethylene group. [9]

[0147] The compound or pharmaceutically acceptable salt thereof according to any one of [1] to [5], wherein

[0148] Q is any group selected from the following:

[0149] Halogen atom, halogenated C1-C6 alkyl group, halogenated C1-C6 alkoxy C1-C6 alkyl group, C1-C6 alkoxy C1-C6 alkyl group.

[10]

[0151] The compound or pharmaceutically acceptable salt thereof according to any one of [1] to [5], wherein Q is any group selected from the following:

[0152] fluorine atom, trifluoromethyl group, trifluoroethoxyethyl group, ethoxyethyl group.

[11]

[0154] The compound or pharmaceutically acceptable salt thereof according to any one of [1] to

[10] , wherein

[0155] Y is any group selected from the following:

[0156] [Chemical Formula 13]

[0157]

[0158] The group can take any orientation from left to right;

[0159] R Y1 is a hydrogen atom or a methyl group.

[12]

[0161] A compound according to [1] or a pharmaceutically acceptable salt thereof selected from the following compounds:

[0162] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-methylurea

[0163] N-Methyl-N'-{5-[5-(trifluoromethyl)-1,3,4-oxazol-2-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}urea

[0164] N-(5-{5-[(1R)-1-ethoxyethyl]-1,3,4-oxadiazol-2-yl}-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)-N'-methylurea

[0165] N-Methyl-N'-(5-{3-[1-(2,2,2-trifluoroethoxy)ethyl]-1,2,4-oxadiazol-5-yl}-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)urea

[0166] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-[(2R)-1-hydroxypropan-2-yl]urea

[0167] N-Methyl-N'-(10-{3-[cis-4-(trifluoromethyl)cyclohexyl]-1,2,4-oxadiazol-5-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl)urea

[0168] N-{(4S,8S)-10-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-methylurea

[0169] N-Methyl-N'-(5-{3-[3-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)urea

[0170] N-{5-[5-(4-Fluoro-3-methylphenyl)-1,3,4-oxazol-2-yl]-4,5,6,7-tetrahydro[[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-methylurea

[0171] N-{(5R * ,8S * )-9-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-5,6,7,8-tetrahydro-4H-5,8-cycloiminocyclohepta[d][1,3]thiazol-2-yl}-N'-methylurea

[0172] N-{9-[5-(4-Fluorophenyl)-1,2-oxazol-3-yl]-5,6,7,8-tetrahydro-4H-5,8-cycloiminocyclohepta[d][1,3]thiazol-2-yl}-N'-methylurea

[0173] N-{(5R * ,9S *)-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7,8,9-hexahydro-5,9-cycloiminocycloocta[d][1,3]thiazol-2-yl}-N'-methylurea

[0174] N-{(4S,8S)-10-[3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-methylurea

[0175] N-(10-{5-[3-(Difluoromethyl)phenyl]-1,3-oxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl)-N'-methylurea

[0176] N-{(4S,8S)-10-[5-(6-methoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-methylurea

[0177] N-{10-[5-(4-Fluorophenyl)-1,2-oxazol-3-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-methylurea

[0178] N-{(4S,8S)-10-[4-(4-Fluorophenyl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-methylurea

[0179] N-{10-[3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-[(2R)-1-hydroxypropan-2-yl]urea

[0180] N-{6-acetyl-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azoc-2-yl}-N'-methylurea

[0181] (5R)-3-{(4S,8S)-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-5-methylimidazoline-2,4-dione.

[13]

[0183] A SIRT6 activator comprising the compound described in any one of [1] to

[12] or a pharmaceutically acceptable salt thereof as an active ingredient.

[14]

[0185] A pharmaceutical composition comprising the compound described in any one of [1] to

[12] or a pharmaceutically acceptable salt thereof as an active ingredient.

[15]

[0187] The pharmaceutical composition according to

[14] , which is an oral preparation.

[16]

[0189] The pharmaceutical composition according to

[14] or

[15] is used for treating and / or preventing peripheral inflammatory diseases.

[17]

[0191] The compound according to any one of [1] to

[12] or a pharmaceutically acceptable salt thereof, for use in treating and / or preventing peripheral inflammatory diseases.

[18]

[0193] The pharmaceutical composition according to

[16] , wherein the peripheral inflammatory disease is any disease selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, scleroderma, bronchial asthma, asthmatic bronchitis, diffuse interstitial pneumonia, chronic obstructive pulmonary disease, ulcerative colitis, Crohn's disease, acute hepatitis, chronic hepatitis, fulminant hepatitis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, alcoholic hepatitis, non-alcoholic steatohepatitis, cirrhosis, peripheral neuritis, ankylosing spondylitis, acute eczema, subacute eczema, chronic eczema, contact dermatitis, sunlight and / or ultraviolet rays. Caused by photodermatitis, radiation dermatitis, atopic dermatitis, seborrheic dermatitis, psoriasis vulgaris, articular psoriasis, erythrodermic psoriasis, pustular psoriasis, lichen planus, erythema, rosacea, urticaria, alopecia areata, pityriasis syndrome, erythroderma, acne vulgaris, bedsores, trauma, burns, conjunctivitis, keratitis, scleritis, acute / chronic otitis media, perennial allergic rhinitis, hay fever, sinusitis, laryngitis, esophagitis, intractable stomatitis, glossitis, acute / chronic sialadenitis, angular cheilitis, cheilitis, Behcet's disease, multiple sclerosis, type 1 diabetes, type 2 diabetes, atherosclerosis, pancreatitis and chronic heart failure.

[19]

[0195] The pharmaceutical composition according to

[16] , wherein the peripheral inflammatory disease is any disease selected from the group consisting of: rheumatoid arthritis, systemic lupus erythematosus, scleroderma, bronchial asthma, acute hepatitis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, alcoholic hepatitis, non-alcoholic steatohepatitis, ankylosing spondylitis, contact dermatitis, photodermatitis caused by sunlight and / or ultraviolet rays, radiation dermatitis, atopic dermatitis, seborrheic dermatitis, psoriasis vulgaris, articular psoriasis, erythrodermic psoriasis, pustular psoriasis, lichen planus, erythema, rosacea, urticaria, alopecia areata, pityriasis syndrome, erythroderma, acne vulgaris, bedsores, trauma, burns, sinusitis, laryngitis, esophagitis, intractable stomatitis, glossitis, acute / chronic sialadenitis, angular cheilitis, cheilitis and Behcet's disease.

[20]

[0197] The pharmaceutical composition according to

[16] , wherein the peripheral inflammatory disease is any disease selected from the group consisting of: rheumatoid arthritis, systemic lupus erythematosus, alcoholic hepatitis, non-alcoholic steatohepatitis, contact dermatitis, photodermatitis caused by sunlight and / or ultraviolet rays, radiation dermatitis, atopic dermatitis, seborrheic dermatitis, psoriasis vulgaris, articular psoriasis, erythrodermic psoriasis, pustular psoriasis, lichen planus, erythema, rosacea, urticaria, alopecia areata, pityriasis septoria syndrome, erythroderma, acne vulgaris, bedsores, trauma, burns, intractable stomatitis, glossitis and Behcet's disease. [twenty one]

[0199] A method for treating and / or preventing peripheral inflammatory diseases, comprising administering an effective amount of the pharmaceutical composition described in

[14] or

[15] .

[0200] Other aspects of the present invention relate to the following [1A] to [32A].

[0201] [1A] A compound of formula (1) or a pharmaceutically acceptable salt thereof.

[0202] [Chemical Formula 14]

[0203]

[0204] The symbols in formula (1) have the following meanings.

[0205] R 1 、R 2 :

[0206] are independently the same or different and represent a hydrogen atom or a C1-C6 alkyl group,

[0207] Or, R 1 With R 2 They are bonded to each other to form a substituent and represent any group selected from the following.

[0208] [Chemical Formula 15]

[0209]

[0210] R 12 : C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, or C1-C6 alkylsulfonyl.

[0211] R 3 express:

[0212] a hydrogen atom or a C1-C6 alkyl group.

[0213] R 6 express:

[0214] C1-C6 alkyl which may be substituted by 1 to 3 groups selected from Group G,

[0215] C3-C6 cycloalkyl which may be substituted by 1 or 2 groups selected from Group G, or

[0216] A 4- to 7-membered heterocyclic group which may be substituted by 1 or 2 groups selected from Group G.

[0217] Group G:

[0218] Hydroxyl, halogen atom, amino, halogenated C1-C6 alkyl,

[0219] Hydroxy C1-C6 alkyl, amino C1-C6 alkyl, C1-C6 alkoxy,

[0220] C1-C6 alkylsulfonyl, hydroxy C1-C6 alkoxy,

[0221] C1-C6 alkylcarbonyl,

[0222] Carbamoyl which may be substituted by 1 or 2 groups selected from Group J,

[0223] C3-C6 cycloalkyl which may be substituted by 1 or 2 groups selected from Group J,

[0224] A 4-7 membered heterocyclic group which may be substituted by 1 or 2 groups selected from Group J, or

[0225] A 5- to 6-membered heteroaryl group which may be substituted by 1 or 2 groups selected from Group J.

[0226] Group J:

[0227] Hydroxyl, oxo, amino C1-C6 alkyl, amino, C1-C6 alkyl, or

[0228] C1-C6 alkylcarbonyl group.

[0229] R 7 express:

[0230] hydrogen atom

[0231] or

[0232] R 6 With R 7 They bond to each other to form a substituent and represent the groups shown below.

[0233] [Chemical Formula 16]

[0234]

[0235] The group can be oriented in any direction, left or right.

[0236] R67-1 、R 67-2 :

[0237] are independently the same or different and are hydrogen, C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C4 alkylene, or

[0238] C1-C6 alkoxy C1-C6 alkyl.

[0239] Q means:

[0240] Halogen atoms,

[0241] 1 to 3 selected from R Q3 C1-C6 alkyl substituted by any group in

[0242] 1 to 3 selected from R Q3 C3-C6 cycloalkyl substituted by any group in

[0243] 1 to 3 selected from R Q3 A 4-7 membered saturated heterocyclic group substituted by any group in

[0244] 1 or 2 selected from R Q3 An amino group substituted by any group in

[0245] Any group selected from the following.

[0246] [Chemical Formula 17]

[0247]

[0248] R Q1 :

[0249] a halogen atom, a cyano group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogenated C1-C6 alkyl group, a halogenated C1-C6 alkoxy group, a C3-C6 cycloalkylcarbonyl group, a C1-C6 alkylcarbamoyl group, a C1-C6 alkylsulfonyl group, a mono(C1-C6 alkyl)amino group, a di(C1-C6 alkyl)amino group, a mono(C1-C6 alkyl)aminosulfonyl group, or a tetrahydropyranyl group.

[0250] R Q2 express:

[0251] a hydrogen atom, a hydroxyl group, a C1-C6 alkyl group, or a halogen atom,

[0252] or

[0253] R Q1 With R Q2 They bond to each other to form a substituent and represent the groups shown below.

[0254] [Chemical Formula 18]

[0255]

[0256] R Q3 :

[0257] a halogen atom, a C1-C6 alkoxy group, a halogenated C1-C6 alkyl group, a halogenated C1-C6 alkoxy group, a C3-C6 cycloalkoxy group, a phenoxy group, a benzyloxy group, a C1-C6 alkylcarbamoyl group, or

[0258] C1-C4 alkylene which may be substituted with halogen.

[0259] Y means:

[0260] Any group or single bond selected from the following.

[0261] [Chemical Formula 19]

[0262]

[0263] The group can be oriented in any direction, left or right.

[0264] R Y1 : A hydrogen atom, or a C1-C6 alkyl group.

[0265] The compound of formula (1) or its pharmaceutically acceptable salt does not include the following compounds or their pharmaceutically acceptable salts.

[0266] [Chemical Formula 20]

[0267]

[0268] [2A] The compound according to [1A] or a pharmaceutically acceptable salt thereof, wherein

[0269] R 1 and R 2 are all hydrogen atoms, or

[0270] R 1 With R 2 are bonded to each other to form a substituent and represent any group selected from the following:

[0271] [Chemical Formula 21]

[0272]

[0273] R 12 : methyl, hydroxyethyl, acetyl, methoxycarbonyl, or

[0274] Methanesulfonyl,

[0275] R 3 represents a hydrogen atom or a methyl group.

[0276] [3A] The compound according to [1A] or a pharmaceutically acceptable salt thereof, wherein

[0277] R 1 and R 2 are all hydrogen atoms, or

[0278] R 1 With R 2 are bonded to each other to form a substituent and represent any group selected from the following:

[0279] [Chemical Formula 22]

[0280]

[0281] R 13 : acetyl or methoxycarbonyl;

[0282] R 3 Represents a hydrogen atom.

[0283] [4A] The compound according to [1A] or a pharmaceutically acceptable salt thereof, wherein R 1 and R 3 All represent methyl, R 2 Represents a hydrogen atom.

[0284] [5A] The compound according to any one of [1A] to [4A], or a pharmaceutically acceptable salt thereof, wherein

[0285] R 6 represents any group selected from the following:

[0286] C1-C6 alkyl,

[0287] Hydroxy C1-C6 alkyl,

[0288] Hydroxy C3-C6 cycloalkyl,

[0289] C1-C6 alkoxy C1-C6 alkyl,

[0290] Tetrahydrofuranyl,

[0291] tetrahydropyranyl, or

[0292] dioxanylmethyl;

[0293] R 7 Represents a hydrogen atom.

[0294] [6A] The compound according to any one of [1A] to [4A], or a pharmaceutically acceptable salt thereof, wherein

[0295] R 6 is any group selected from the following:

[0296] methyl,

[0297] Isobutyl,

[0298] 2-hydroxy-1-methylethyl,

[0299] 2-Hydroxy-2-methylpropyl,

[0300] 3-Hydroxybutyl,

[0301] 2-Hydroxycyclopentyl,

[0302] 4-Hydroxycyclohexyl,

[0303] 2-methoxypropyl,

[0304] 3-tetrahydrofuranyl,

[0305] 4-tetrahydropyranyl, or

[0306] 1,4-dioxan-2-ylmethyl;

[0307] R 7 A hydrogen atom.

[0308] [7A] The compound according to any one of [1A] to [6A], or a pharmaceutically acceptable salt thereof, wherein:

[0309] Q represents any group selected from the following:

[0310] 1 to 3 selected from R Q4 C3-C6 cycloalkyl substituted by any group in

[0311] 1 to 3 selected from R Q4 Phenyl substituted with any group in

[0312] 1 to 3 selected from R Q4 Pyridyl substituted by any group in

[0313] 1 to 3 selected from R Q4 1,3-benzoxazol-2-yl substituted by any group;

[0314] R Q4 :

[0315] a halogen atom, a cyano group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogenated C1-C6 alkyl group, a halogenated C1-C6 alkoxy group, a C1-C6 alkylsulfonyl group, a diC1-C6 alkylamino group, or a C3-C6 cycloalkylcarbonyl group.

[0316] [8A] The compound according to any one of [1A] to [6A], or a pharmaceutically acceptable salt thereof, wherein:

[0317] Q represents any group selected from the following:

[0318] Cyclohexyl substituted with 2 fluorine atoms,

[0319] Phenyl substituted by a fluorine atom or a cyclopropylcarbonyl group,

[0320] a pyridyl group substituted by one group selected from the group consisting of a methoxy group, an ethoxy group, and a difluoromethoxy group, or

[0321] A 1,3-benzoxazol-2-yl group substituted by one or two groups independently selected from the group consisting of a fluorine atom, a methyl group, a methoxy group, an ethoxy group, a dimethylamino group, and a methanesulfonyl group.

[0322] [9A] The compound according to any one of [1A] to [8A], or a pharmaceutically acceptable salt thereof, wherein Y represents a single bond or any group selected from the following:

[0323] [Chemical Formula 23]

[0324]

[0325] The group can be oriented in any direction, left or right.

[0326] [10A] The compound according to any one of [1A] to [6A], or a pharmaceutically acceptable salt thereof, wherein Q represents a 1,3-benzoxazol-2-yl group substituted by one or two groups independently selected from the group consisting of a fluorine atom, a methyl group, a methoxy group, an ethoxy group, a dimethylamino group, and a methanesulfonyl group,

[0327] Y is a single bond.

[0328] [11A] The compound according to any one of [1A] to [6A], or a pharmaceutically acceptable salt thereof, wherein:

[0329] Q means:

[0330] Cyclohexyl substituted with 2 fluorine atoms,

[0331] Phenyl substituted by a fluorine atom or a cyclopropylcarbonyl group, or

[0332] a pyridyl group substituted by one group selected from the group consisting of a methoxy group, an ethoxy group, and a difluoromethoxy group,

[0333] Y represents any group selected from the following.

[0334] [Chemical Formula 24]

[0335]

[0336] [12A] The compound according to [1A] or a pharmaceutically acceptable salt thereof, which is selected from the following compounds.

[0337] N-[(4S,8S)-10-{5-[3-(cyclopropanecarbonyl)phenyl]-1,3,4-oxadiazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]-N'-methylurea,

[0338] (-)-N-{(4R * ,8R * )-6-acetyl-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azoc-2-yl}-N'-methylurea,

[0339] (4R * ,8R * )-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-2-[(methylcarbamoyl)amino]-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylic acid (-)-methyl ester,

[0340] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-[(1R,2R)-2-hydroxycyclopentyl]urea,

[0341] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-[(1r,4r)-4-hydroxycyclohexyl]urea,

[0342] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-(3-methoxypropyl)urea,

[0343] N-{[(2S)-1,4-dioxane-2-yl]methyl}-N'-{(4S,8S)-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}urea,

[0344] N-[(2R)-1-hydroxypropane-2-yl]-N'-[(4S,8S)-10-(5-methoxy-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]urea,

[0345] N-[(4S,8S)-10-(5-fluoro-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl]-N'-[(2R)-1-hydroxypropane-2-yl]urea,

[0346] N-[(4S,8S)-10-(5-ethoxy-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]-N'-(2-hydroxy-2-methylpropyl)urea,

[0347] N-{(4S,8S)-10-[5-(dimethylamino)-1,3-benzoxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl}-N'-(2-hydroxy-2-methylpropyl)urea,

[0348] N-[(4S,8S)-10-(5,6-difluoro-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl]-N'-[(2R)-1-hydroxypropane-2-yl]urea,

[0349] N-{(4S,8S)-10-[5-(methanesulfonyl)-1,3-benzoxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-(2-methylpropyl)urea,

[0350] N-(2-hydroxy-2-methylpropyl)-N'-[(4S,8S)-10-(5-methoxy-6-methyl-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]urea,

[0351] N-[(4S,8S)-10-(5-methoxy-6-methyl-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]-N'-[(3R)-oxolan-3-yl]urea,

[0352] N-(2-hydroxy-2-methylpropyl)-N'-[(4S,8S)-10-(5-methoxy-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]urea,

[0353] N-[(4S,8S)-10-(5-methoxy-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]-N'-[(3R)-oxolan-3-yl]urea,

[0354] N-[(4S,8S)-10-(5-methoxy-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclotriene[5,4-d][1,3]thiazol-2-yl]-N'-methylurea,

[0355] N-methyl-N'-[(4S,8S)-10-(5-methyl-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]urea,

[0356] N-(2-Hydroxy-2-methylpropyl)-N'-[(4S,8S)-10-{5-[( 2 H3) methyloxy]-1,3-benzoxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]urea,

[0357] N-{(4S,8S)-10-[5-(4-fluorophenyl)-1,2-oxazol-3-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl}-N'-[(1s,4s)-4-hydroxycyclohexyl]urea,

[0358] N-{(4S,8S)-10-[5-(6-methoxypyridin-2-yl)-1,2-oxazol-3-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-oxan-4-ylurea,

[0359] N-[(4S,8S)-10-{5-[6-(difluoromethoxy)pyridin-2-yl]-1,3-oxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]-N'-[(2R)-1-hydroxypropane-2-yl]urea,

[0360] N-[(2R)-1-hydroxypropane-2-yl]-N'-{(4S,8S)-10-[5-(6-methoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}urea,

[0361] N-{(4S,8S)-10-[5-(6-ethoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-[(2R)-1-hydroxypropane-2-yl]urea,

[0362] N-[(2R)-1-hydroxypropane-2-yl]-N'-{5-[5-(methanesulfonyl)-1,3-benzoxazol-2-yl]-6,6-dimethyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}urea,

[0363] N-(2-hydroxy-2-methylpropyl)-N'-{5-[5-(methanesulfonyl)-1,3-benzoxazol-2-yl]-6,6-dimethyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}urea,

[0364] N-[(2R)-1-Hydroxypropan-2-yl]-N'-[(4S,8S)-10-{5-[( 2 H3) methyloxy]-1,3-benzoxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]urea,

[0365] N-[(4S,8S)-10-{5-[( 2H3) methyloxy]-1,3-benzoxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]-N'-[(3R)-oxolan-3-yl]urea,

[0366] N-[(1r,3S)-3-hydroxycyclobutyl]-N'-{(4S,8S)-10-[5-(6-methoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}urea,

[0367] N-{(4S,8S)-10-[5-(6-ethoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-(2-hydroxy-2-methylpropyl)urea,

[0368] N-{(4S,8S)-10-[5-(6-ethoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-[(1r,3S)-3-hydroxycyclobutyl]urea,

[0369] N-{(4S,8S)-10-[5-(6-methoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-oxan-4-ylurea.

[0370] [12A-1] N-[(4S,8S)-10-{5-[3-(cyclopropanecarbonyl)phenyl]-1,3,4-oxadiazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]-N′-methylurea, or a pharmaceutically acceptable salt thereof.

[0371] [12A-2](-)-N-{(4R * ,8R * )-6-acetyl-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azoc-2-yl}-N′-methylurea, or a pharmaceutically acceptable salt thereof.

[0372] [12A-3](4R* ,8R * )-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-2-[(methylcarbamoyl)amino]-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylic acid (-)-methyl ester, or a pharmaceutically acceptable salt thereof.

[0373] [12A-4] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N′-[(1R,2R)-2-hydroxycyclopentyl]urea, or a pharmaceutically acceptable salt thereof.

[0374] [12A-5] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N′-[(1r,4r)-4-hydroxycyclohexyl]urea, or a pharmaceutically acceptable salt thereof.

[0375] [12A-6] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N′-(3-methoxypropyl)urea, or a pharmaceutically acceptable salt thereof.

[0376] [12A-7] N-{[(2S)-1,4-dioxan-2-yl]methyl}-N'-{(4S,8S)-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}urea, or a pharmaceutically acceptable salt thereof.

[0377] [12A-8] N-[(2R)-1-hydroxypropan-2-yl]-N'-[(4S,8S)-10-(5-methoxy-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]urea, or a pharmaceutically acceptable salt thereof.

[0378] [12A-9] N-[(4S,8S)-10-(5-fluoro-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]-N'-[(2R)-1-hydroxypropan-2-yl]urea, or a pharmaceutically acceptable salt thereof.

[0379] [12A-10] N-[(4S,8S)-10-(5-ethoxy-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]-N'-(2-hydroxy-2-methylpropyl)urea, or a pharmaceutically acceptable salt thereof.

[0380] [12A-11] N-{(4S,8S)-10-[5-(dimethylamino)-1,3-benzoxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-(2-hydroxy-2-methylpropyl)urea, or a pharmaceutically acceptable salt thereof.

[0381] [12A-12] N-[(4S,8S)-10-(5,6-difluoro-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]-N'-[(2R)-1-hydroxypropan-2-yl]urea, or a pharmaceutically acceptable salt thereof.

[0382] [12A-13] N-{(4S,8S)-10-[5-(methanesulfonyl)-1,3-benzoxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N′-(2-methylpropyl)urea, or a pharmaceutically acceptable salt thereof.

[0383] [12A-14] N-(2-hydroxy-2-methylpropyl)-N'-[(4S,8S)-10-(5-methoxy-6-methyl-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]urea, or a pharmaceutically acceptable salt thereof.

[0384] [12A-15] N-[(4S,8S)-10-(5-methoxy-6-methyl-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]-N'-[(3R)-oxolan-3-yl]urea, or a pharmaceutically acceptable salt thereof.

[0385] [12A-16] N-(2-hydroxy-2-methylpropyl)-N'-[(4S,8S)-10-(5-methoxy-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]urea, or a pharmaceutically acceptable salt thereof.

[0386] [12A-17] N-[(4S,8S)-10-(5-methoxy-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]-N'-[(3R)-oxolan-3-yl]urea, or a pharmaceutically acceptable salt thereof.

[0387] [12A-18] N-[(4S,8S)-10-(5-methoxy-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]-N′-methylurea, or a pharmaceutically acceptable salt thereof.

[0388] [12A-19] N-methyl-N'-[(4S,8S)-10-(5-methyl-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]urea, or a pharmaceutically acceptable salt thereof.

[0389] [12A-20]N-(2-Hydroxy-2-methylpropyl)-N'-[(4S,8S)-10-{5-[( 2 H3) methyloxy]-1,3-benzoxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]urea, or a pharmaceutically acceptable salt thereof.

[0390] [12A-21] N-{(4S,8S)-10-[5-(4-fluorophenyl)-1,2-oxazol-3-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-[(1s,4s)-4-hydroxycyclohexyl]urea, or a pharmaceutically acceptable salt thereof.

[0391] [12A-22] N-{(4S,8S)-10-[5-(6-methoxypyridin-2-yl)-1,2-oxazol-3-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N′-oxan-4-ylurea, or a pharmaceutically acceptable salt thereof.

[0392] [12A-23] N-[(4S,8S)-10-{5-[6-(difluoromethoxy)pyridin-2-yl]-1,3-oxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]-N'-[(2R)-1-hydroxypropan-2-yl]urea, or a pharmaceutically acceptable salt thereof.

[0393] [12A-24] N-[(2R)-1-hydroxypropan-2-yl]-N'-{(4S,8S)-10-[5-(6-methoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}urea, or a pharmaceutically acceptable salt thereof.

[0394] [12A-25] N-{(4S,8S)-10-[5-(6-ethoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-[(2R)-1-hydroxypropan-2-yl]urea, or a pharmaceutically acceptable salt thereof.

[0395] [12A-26] N-[(2R)-1-hydroxypropan-2-yl]-N′-{5-[5-(methanesulfonyl)-1,3-benzoxazol-2-yl]-6,6-dimethyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}urea, or a pharmaceutically acceptable salt thereof.

[0396] [12A-27] N-(2-hydroxy-2-methylpropyl)-N′-{5-[5-(methanesulfonyl)-1,3-benzoxazol-2-yl]-6,6-dimethyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}urea, or a pharmaceutically acceptable salt thereof.

[0397] [12A-28]N-[(2R)-1-Hydroxypropan-2-yl]-N'-[(4S,8S)-10-{5-[( 2H3) methyloxy]-1,3-benzoxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]urea, or a pharmaceutically acceptable salt thereof.

[0398] [12A-29]N-[(4S,8S)-10-{5-[( 2 H3) methyloxy]-1,3-benzoxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]-N'-[(3R)-oxolan-3-yl]urea, or a pharmaceutically acceptable salt thereof.

[0399] [12A-30] N-[(1r,3S)-3-hydroxycyclobutyl]-N'-{(4S,8S)-10-[5-(6-methoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}urea, or a pharmaceutically acceptable salt thereof.

[0400] [12A-31] N-{(4S,8S)-10-[5-(6-ethoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-(2-hydroxy-2-methylpropyl)urea, or a pharmaceutically acceptable salt thereof.

[0401] [12A-32] N-{(4S,8S)-10-[5-(6-ethoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-[(1r,3S)-3-hydroxycyclobutyl]urea, or a pharmaceutically acceptable salt thereof.

[0402] [12A-33] N-{(4S,8S)-10-[5-(6-methoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-oxan-4-ylurea, or a pharmaceutically acceptable salt thereof.

[0403] [13A] A SIRT6 activator comprising the compound according to any one of [1A] to [12A] or a pharmaceutically acceptable salt thereof as an active ingredient.

[0404] [14A] A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to any one of [1A] to [12A] as an active ingredient.

[0405] [15A] The pharmaceutical composition according to [14A], which is an oral preparation.

[0406] [16A] The pharmaceutical composition according to [14A], which is an external preparation.

[0407] [17A] The pharmaceutical composition according to any one of [14A] to [16A], which is used for treating and / or preventing peripheral inflammatory diseases.

[0408] [18A] The pharmaceutical composition according to [17A], wherein the peripheral inflammatory disease is any disease selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, scleroderma, bronchial asthma, asthmatic bronchitis, diffuse interstitial pneumonia, chronic obstructive pulmonary disease, ulcerative colitis, Crohn's disease, acute hepatitis, chronic hepatitis, fulminant hepatitis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, Angiotensin-converting enzymes (AES), inflammatory bowel disease (AEDs), hepatitis, cirrhosis, erythema, rosacea, urticaria, alopecia areata, rash, eczema, eczema, eczema, dermatitis ... Acne vulgaris, bedsores, trauma, burns, conjunctivitis, keratitis, scleritis, acute / chronic otitis media, perennial allergic rhinitis, hay fever, sinusitis, laryngitis, esophagitis, intractable stomatitis, glossitis, acute / chronic sialadenitis, angular cheilitis, cheilitis, Behcet's disease, multiple sclerosis, type I diabetes, type II diabetes, atherosclerosis, pancreatitis, chronic heart failure, vitiligo vulgaris, common warts, diabetic ulcers, leg ulcers, keloids, Hypertrophic scars, seborrheic keratosis, male pattern baldness, female pattern baldness, senile alopecia, acne scars, pigmentation disorders, solar keratosis, gray hair, chronic hand eczema, chronic pruritus, generalized pruritus, glaucoma, cataracts, age-related macular degeneration, idiopathic pulmonary fibrosis, acute glomerulonephritis, chronic glomerulonephritis, diabetic nephropathy, hypertrophic cardiomyopathy, osteoporosis, neurogenic muscular dystrophy, myogenic muscular dystrophy, and hypertension.

[0409] [19A] The pharmaceutical composition according to [17A], wherein the peripheral inflammatory disease is any disease selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, scleroderma, bronchial asthma, acute hepatitis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, alcoholic hepatitis, non-alcoholic steatohepatitis, ankylosing spondylitis, contact dermatitis, solar dermatitis caused by sunlight and / or ultraviolet rays, radiation dermatitis, atopic dermatitis, seborrheic dermatitis, psoriasis vulgaris, articular psoriasis, erythrodermic psoriasis, pustular psoriasis, and flatulence. Lichen, erythema, rosacea, urticaria, alopecia areata, pyometra, erythroderma, acne vulgaris, bedsores, trauma, burns, sinusitis, laryngitis, esophagitis, intractable stomatitis, glossitis, acute / chronic sialadenitis, angular cheilitis, cheilitis, Behçet's disease, vitiligo vulgaris, common warts, vitiligo vulgaris, common warts, diabetic ulcers, leg ulcers, keloids, hypertrophic scars, seborrheic keratosis, male pattern baldness, female pattern baldness, senile alopecia, acne scars, pigmentation disorders, solar keratosis, gray hair, chronic hand eczema, chronic pruritus, generalized pruritus, and idiopathic pulmonary fibrosis.

[0410] [20A] The pharmaceutical composition according to [17A], wherein the peripheral inflammatory disease is any disease selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, alcoholic hepatitis, nonalcoholic steatohepatitis, contact dermatitis, solar dermatitis caused by sunlight and / or ultraviolet rays, radiation dermatitis, atopic dermatitis, seborrheic dermatitis, psoriasis vulgaris, articular psoriasis, erythrodermic psoriasis, pustular psoriasis, lichen planus, erythema, Rosacea, urticaria, alopecia areata, pyroptosis, erythroderma, acne vulgaris, bedsores, trauma, burns, intractable stomatitis, glossitis, Behçet's disease, vitiligo vulgaris, common warts, diabetic ulcers, leg ulcers, keloids, hypertrophic scars, seborrheic keratosis, male pattern baldness, female pattern baldness, senile alopecia, acne scars, pigmentation disorders, solar keratosis, gray hair, chronic hand eczema, chronic pruritus, generalized pruritus, and idiopathic pulmonary fibrosis.

[0411] [21A] A method for treating and / or preventing a peripheral inflammatory disease, comprising administering an effective amount of the pharmaceutical composition according to any one of [14A] to [16A].

[0412] [22A] The method according to [21A], wherein the peripheral inflammatory disease is any disease selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, scleroderma, bronchial asthma, asthmatic bronchitis, diffuse interstitial pneumonia, chronic obstructive pulmonary disease, ulcerative colitis, Crohn's disease, acute hepatitis, chronic hepatitis, fulminant hepatitis, autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis. , alcoholic hepatitis, non-alcoholic steatohepatitis, cirrhosis, peripheral neuritis, ankylosing spondylitis, acute eczema, subacute eczema, chronic eczema, contact dermatitis, photodermatitis caused by sunlight and / or ultraviolet rays, radiation dermatitis, atopic dermatitis, seborrheic dermatitis, psoriasis vulgaris, psoriasis arthritis, erythrodermic psoriasis, pustular psoriasis, lichen planus, erythema, rosacea, urticaria, alopecia areata, pyrrhea syndrome, erythroderma, vulgaris Acne, bedsores, trauma, burns, conjunctivitis, keratitis, scleritis, acute / chronic otitis media, perennial allergic rhinitis, hay fever, sinusitis, laryngitis, esophagitis, intractable stomatitis, glossitis, acute / chronic sialadenitis, angular cheilitis, cheilitis, Behcet's disease, multiple sclerosis, type I diabetes, type II diabetes, atherosclerosis, pancreatitis, chronic heart failure, vitiligo vulgaris, common warts, diabetic ulcers, leg ulcers, keloids, Hypertrophic scars, seborrheic keratosis, male pattern baldness, female pattern baldness, senile alopecia, acne scars, pigmentation disorders, solar keratosis, gray hair, chronic hand eczema, chronic pruritus, generalized pruritus, glaucoma, cataracts, age-related macular degeneration, idiopathic pulmonary fibrosis, acute glomerulonephritis, chronic glomerulonephritis, diabetic nephropathy, hypertrophic cardiomyopathy, osteoporosis, neurogenic muscular dystrophy, myogenic muscular dystrophy, and hypertension.

[0413] [23A] The method according to [21A], wherein the peripheral inflammatory disease is any disease selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, scleroderma, bronchial asthma, acute hepatitis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, alcoholic hepatitis, non-alcoholic steatohepatitis, ankylosing spondylitis, contact dermatitis, solar dermatitis caused by sunlight and / or ultraviolet rays, radiation dermatitis, atopic dermatitis, seborrheic dermatitis, psoriasis vulgaris, articular psoriasis, erythrodermic psoriasis, and pustular psoriasis. Disease, lichen planus, erythema, rosacea, urticaria, alopecia areata, pyometra, erythroderma, acne vulgaris, bedsores, trauma, burns, sinusitis, laryngitis, esophagitis, intractable stomatitis, glossitis, acute / chronic sialadenitis, angular cheilitis, cheilitis, Behçet's disease, vitiligo vulgaris, common warts, diabetic ulcers, leg ulcers, keloids, hypertrophic scars, seborrheic keratosis, male pattern baldness, female pattern baldness, senile alopecia, acne scars, pigmentation disorders, solar keratosis, gray hair, chronic hand eczema, chronic pruritus, generalized pruritus, and idiopathic pulmonary fibrosis.

[0414] [24A] The method according to [21A], wherein the peripheral inflammatory disease is any disease selected from the group consisting of: rheumatoid arthritis, systemic lupus erythematosus, alcoholic hepatitis, non-alcoholic steatohepatitis, contact dermatitis, solar dermatitis caused by sunlight and / or ultraviolet rays, radiation dermatitis, atopic dermatitis, seborrheic dermatitis, psoriasis vulgaris, articular psoriasis, erythrodermic psoriasis, pustular psoriasis, lichen planus, erythema, alcoholic Rhinorrhoea, urticaria, alopecia areata, pyroptosis, erythroderma, acne vulgaris, bedsores, trauma, burns, intractable stomatitis, glossitis, Behçet's disease, vitiligo vulgaris, common warts, diabetic ulcers, leg ulcers, keloids, hypertrophic scars, seborrheic keratosis, male pattern baldness, female pattern baldness, senile alopecia, acne scars, pigmentation disorders, solar keratosis, grey hair, chronic hand eczema, chronic pruritus, generalised pruritus and idiopathic pulmonary fibrosis.

[0415] [25A] The compound or pharmaceutically acceptable salt thereof according to any one of [1A] to [12A], for use in the treatment and / or prevention of a peripheral inflammatory disease.

[0416] [26A] The compound according to [25A] or a pharmaceutically acceptable salt thereof, wherein the peripheral inflammatory disease is any disease selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, scleroderma, bronchial asthma, asthmatic bronchitis, diffuse interstitial pneumonia, chronic obstructive pulmonary disease, ulcerative colitis, Crohn's disease, acute hepatitis, chronic hepatitis, fulminant hepatitis, autoimmune hepatitis, primary biliary cirrhosis, primary Sclerosing cholangitis, alcoholic hepatitis, nonalcoholic steatohepatitis, cirrhosis, peripheral neuritis, ankylosing spondylitis, acute eczema, subacute eczema, chronic eczema, contact dermatitis, photodermatitis caused by sunlight and / or ultraviolet rays, radiation dermatitis, atopic dermatitis, seborrheic dermatitis, psoriasis vulgaris, articular psoriasis, erythrodermic psoriasis, pustular psoriasis, lichen planus, erythema, rosacea, urticaria, alopecia areata, pyrrhea syndrome, erythroderma Acne vulgaris, bedsores, trauma, burns, conjunctivitis, keratitis, scleritis, acute / chronic otitis media, perennial allergic rhinitis, hay fever, sinusitis, laryngitis, esophagitis, intractable stomatitis, glossitis, acute / chronic sialadenitis, angular cheilitis, cheilitis, Behçet's disease, multiple sclerosis, type I diabetes, type II diabetes, atherosclerosis, pancreatitis, chronic heart failure, vitiligo vulgaris, common warts, diabetic ulcers, leg ulcers, keloids Pimples, hypertrophic scars, seborrheic keratosis, male pattern baldness, female pattern baldness, senile alopecia, acne scars, pigmentation disorders, solar keratosis, gray hair, chronic hand eczema, chronic pruritus, generalized pruritus, glaucoma, cataracts, age-related macular degeneration, idiopathic pulmonary fibrosis, acute glomerulonephritis, chronic glomerulonephritis, diabetic nephropathy, hypertrophic cardiomyopathy, osteoporosis, neurogenic muscular dystrophy, myogenic muscular dystrophy, and hypertension.

[0417] [27A] The compound according to [25A] or a pharmaceutically acceptable salt thereof, wherein the peripheral inflammatory disease is any disease selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, scleroderma, bronchial asthma, acute hepatitis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, alcoholic hepatitis, non-alcoholic steatohepatitis, ankylosing spondylitis, contact dermatitis, solar dermatitis caused by sunlight and / or ultraviolet rays, radiation dermatitis, atopic dermatitis, seborrheic dermatitis, psoriasis vulgaris, arthritic psoriasis, and erythrodermic psoriasis. , pustular psoriasis, lichen planus, erythema, rosacea, urticaria, alopecia areata, pyometra syndrome, erythroderma, acne vulgaris, bedsores, trauma, burns, sinusitis, laryngitis, esophagitis, intractable stomatitis, glossitis, acute / chronic sialadenitis, angular cheilitis, cheilitis, Behçet's disease, vitiligo vulgaris, common warts, diabetic ulcers, leg ulcers, keloids, hypertrophic scars, seborrheic keratosis, male pattern baldness, female pattern baldness, senile alopecia, acne scars, pigmentation disorders, solar keratosis, gray hair, chronic hand eczema, chronic pruritus, generalized pruritus and idiopathic pulmonary fibrosis.

[0418] [28A] The compound according to [25A] or a pharmaceutically acceptable salt thereof, wherein the peripheral inflammatory disease is any disease selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, alcoholic hepatitis, nonalcoholic steatohepatitis, contact dermatitis, photodermatitis caused by sunlight and / or ultraviolet rays, radiation dermatitis, atopic dermatitis, seborrheic dermatitis, psoriasis vulgaris, articular psoriasis, erythrodermic psoriasis, pustular psoriasis, lichen planus , erythema, rosacea, urticaria, alopecia areata, pyroptosis syndrome, erythroderma, acne vulgaris, bedsores, trauma, burns, intractable stomatitis, glossitis, Behçet's disease, vitiligo vulgaris, common warts, diabetic ulcers, leg ulcers, keloids, hypertrophic scars, seborrheic keratosis, male pattern baldness, female pattern baldness, senile alopecia, acne scars, pigmentation disorder, solar keratosis, gray hair, chronic hand eczema, chronic pruritus, generalized pruritus and idiopathic pulmonary fibrosis.

[0419] [29A] Use of the compound or a pharmaceutically acceptable salt thereof according to any one of [1A] to [12A] in the manufacture of a pharmaceutical composition for the treatment and / or prevention of a peripheral inflammatory disease.

[0420] [30A] The use according to [29A], wherein the peripheral inflammatory disease is any disease selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, scleroderma, bronchial asthma, asthmatic bronchitis, diffuse interstitial pneumonia, chronic obstructive pulmonary disease, ulcerative colitis, Crohn's disease, acute hepatitis, chronic hepatitis, fulminant hepatitis, autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis. , alcoholic hepatitis, non-alcoholic steatohepatitis, cirrhosis, peripheral neuritis, ankylosing spondylitis, acute eczema, subacute eczema, chronic eczema, contact dermatitis, photodermatitis caused by sunlight and / or ultraviolet rays, radiation dermatitis, atopic dermatitis, seborrheic dermatitis, psoriasis vulgaris, psoriasis arthritis, erythrodermic psoriasis, pustular psoriasis, lichen planus, erythema, rosacea, urticaria, alopecia areata, pyrrhea syndrome, erythroderma, vulgaris Acne, bedsores, trauma, burns, conjunctivitis, keratitis, scleritis, acute / chronic otitis media, perennial allergic rhinitis, hay fever, sinusitis, laryngitis, esophagitis, intractable stomatitis, glossitis, acute / chronic sialadenitis, angular cheilitis, cheilitis, Behcet's disease, multiple sclerosis, type I diabetes, type II diabetes, atherosclerosis, pancreatitis, chronic heart failure, vitiligo vulgaris, common warts, diabetic ulcers, leg ulcers, keloids, Hypertrophic scars, seborrheic keratosis, male pattern baldness, female pattern baldness, senile alopecia, acne scars, pigmentation disorders, solar keratosis, gray hair, chronic hand eczema, chronic pruritus, generalized pruritus, glaucoma, cataracts, age-related macular degeneration, idiopathic pulmonary fibrosis, acute glomerulonephritis, chronic glomerulonephritis, diabetic nephropathy, hypertrophic cardiomyopathy, osteoporosis, neurogenic muscular dystrophy, myogenic muscular dystrophy, and hypertension.

[0421] [31A] The use according to [29A], wherein the peripheral inflammatory disease is any disease selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, scleroderma, bronchial asthma, acute hepatitis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, alcoholic hepatitis, non-alcoholic steatohepatitis, ankylosing spondylitis, contact dermatitis, solar dermatitis caused by sunlight and / or ultraviolet rays, radiation dermatitis, atopic dermatitis, seborrheic dermatitis, psoriasis vulgaris, articular psoriasis, erythrodermic psoriasis, and pustular psoriasis. Disease, lichen planus, erythema, rosacea, urticaria, alopecia areata, pyometra, erythroderma, acne vulgaris, bedsores, trauma, burns, sinusitis, laryngitis, esophagitis, intractable stomatitis, glossitis, acute / chronic sialadenitis, angular cheilitis, cheilitis, Behçet's disease, vitiligo vulgaris, common warts, diabetic ulcers, leg ulcers, keloids, hypertrophic scars, seborrheic keratosis, male pattern baldness, female pattern baldness, senile alopecia, acne scars, pigmentation disorders, solar keratosis, gray hair, chronic hand eczema, chronic pruritus, generalized pruritus, and idiopathic pulmonary fibrosis.

[0422] [32A] The use according to [29A], wherein the peripheral inflammatory disease is any disease selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, alcoholic hepatitis, non-alcoholic steatohepatitis, contact dermatitis, photodermatitis caused by sunlight and / or ultraviolet rays, radiation dermatitis, atopic dermatitis, seborrheic dermatitis, psoriasis vulgaris, articular psoriasis, erythrodermic psoriasis, pustular psoriasis, lichen planus, erythema, alcoholic dermatitis, Rhinorrhoea, urticaria, alopecia areata, pyroptosis, erythroderma, acne vulgaris, bedsores, trauma, burns, intractable stomatitis, glossitis, Behçet's disease, vitiligo vulgaris, common warts, diabetic ulcers, leg ulcers, keloids, hypertrophic scars, seborrheic keratosis, male pattern baldness, female pattern baldness, senile alopecia, acne scars, pigmentation disorders, solar keratosis, grey hair, chronic hand eczema, chronic pruritus, generalised pruritus and idiopathic pulmonary fibrosis.

[0423] Effects of the Invention

[0424] The compound having a specific chemical structure having an anti-inflammatory effect or a pharmaceutically acceptable salt thereof of the present invention is believed to have properties different from those of existing anti-inflammatory agents from various aspects and is therefore useful as a novel drug.

[0425] In addition, the compounds of the present invention and pharmaceutically acceptable salts thereof are believed to have excellent properties in terms of anti-inflammatory activity, bioavailability, solubility, cell membrane permeability, oral absorption, blood drug concentration, metabolic stability, tissue mobility, in vitro activity, in vivo activity, in vitro activity, speed of onset, duration of drug effect, physical stability, drug interactions, safety (e.g., cardiotoxicity or hepatotoxicity), etc., and are useful as drugs. DETAILED DESCRIPTION

[0426] The present invention is described in detail below.

[0427] (Explanation of substituents, terms, etc.)

[0428] One embodiment of the present invention is a compound of formula (1) or a pharmaceutically acceptable salt thereof.

[0429] [Chemical Formula 25]

[0430]

[0431] (The symbols representing the substituents in formula (1) have the same meanings as above.)

[0432] Preferred embodiments of the compound of formula (1) of the present invention include the following examples.

[0433] As R 1 and R 2 , preferably R 1 and R 2 Each of them is a hydrogen atom, or is bonded to each other to form a substituent and is any group selected from the following.

[0434] [Chemical Formula 26]

[0435]

[0436] R 12 : methyl, hydroxyethyl, acetyl, or methoxycarbonyl, or methanesulfonyl

[0437] As R 3 , preferably a hydrogen atom or a C1-C6 alkyl group.

[0438] As R 1 、R 2 and R 3 The preferred combination of R 1 、R 2 and R 3 All are hydrogen atoms.

[0439] As R 1 、R 2 and R 3Another preferred combination, R 1 and R 3 All are methyl, R 2 A hydrogen atom.

[0440] As R 1 、R 2 and R 3 Another preferred combination, R 1 and R 2 They are bonded to each other to form a substituent and are any group selected from the following.

[0441] [Chemical Formula 27]

[0442]

[0443] R 3 A hydrogen atom.

[0444] As R 6 , preferably a group represented by any one of the following (1)-(2).

[0445] (1) Any group selected from the following:

[0446] C1-C6 alkyl,

[0447] Hydroxy C1-C6 alkyl,

[0448] Hydroxy C3-C6 cycloalkyl,

[0449] Tetrahydrofuranyl,

[0450] Tetrahydropyranyl.

[0451] (2) Any group selected from the following:

[0452] methyl,

[0453] Hydroxypropyl,

[0454] 2-Hydroxy-2-methylpropyl,

[0455] Hydroxycyclobutyl,

[0456] Tetrahydrofuranyl,

[0457] Tetrahydropyranyl.

[0458] As R 7 , preferably a hydrogen atom.

[0459] As R 6 and R 7 Another way, preferably R 6 With R 7 They are bonded to each other to form any substituent selected from the following.

[0460] [Chemical Formula 28]

[0461]

[0462] The group can be oriented in any direction, left or right.

[0463] As R 6 and R 7 Another preferred combination, R 6 is methyl, R 7 A hydrogen atom.

[0464] As R 6 and R 7 Another preferred combination, R 6 is 2-hydroxy-2-methylpropyl, R 7 A hydrogen atom.

[0465] As R 6 and R 7 Another preferred combination, R 6 is 2-hydroxy-1-methylethyl, R 7 A hydrogen atom.

[0466] As R 6 and R 7 Another preferred combination, R 6 is 4-tetrahydropyranyl, R 7 A hydrogen atom.

[0467] Q is preferably a group represented by any one of the following (1) to (4).

[0468] (1) Any group selected from the following:

[0469] [Chemical Formula 29]

[0470]

[0471] R Q1 is any group selected from the following:

[0472] Halogen atom, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy;

[0473] R Q2 is any group selected from the following:

[0474] Hydrogen atoms, hydroxyl groups, and fluorine atoms.

[0475] (2) Any group selected from the following:

[0476] [Chemical formula 30]

[0477]

[0478] R Q1 is any group selected from the following:

[0479] Fluorine atom, chlorine atom, methyl group, methoxy group, difluoromethyl group, trifluoromethyl group, difluoromethoxy group, trifluoromethoxy group;

[0480] R Q2 is any group selected from the following:

[0481] a hydrogen atom, a hydroxyl group, or a fluorine atom.

[0482] (3) Any group selected from the following:

[0483] 1 to 3 selected from R Q3 C3-C6 cycloalkyl substituted by any group in

[0484] 1 to 3 selected from R Q3 A 4-7 membered saturated heterocyclic group substituted by any group in;

[0485] R Q3 is any group selected from the following:

[0486] fluorine atom, chlorine atom, methoxy group, difluoromethyl group, trifluoromethyl group, difluoromethoxy group, trifluoromethoxy group, ethylene group.

[0487] (4) Any group selected from the following:

[0488] Halogen atom, halogenated C1-C6 alkyl group, halogenated C1-C6 alkoxy C1-C6 alkyl group, C1-C6 alkoxy C1-C6 alkyl group.

[0489] Another preferred embodiment of Q is a group represented by any one of the following:

[0490] [Chemical Formula 31]

[0491]

[0492] Y is preferably any group selected from the following:

[0493] [Chemical Formula 32]

[0494]

[0495] The group can be oriented in any direction, left or right.

[0496] R Y1 is a hydrogen atom or a methyl group.

[0497] Another preferred embodiment of Y is a group represented by any of the following.

[0498] [Chemical Formula 33]

[0499]

[0500] A preferred combination of Q and Y is any one of the following groups.

[0501] [Chemical Formula 34]

[0502]

[0503] As another preferred combination of Q and Y, Y is a single bond, and Q is any one of the following groups.

[0504] [Chemical Formula 35]

[0505]

[0506] Another embodiment of the present invention is a compound selected from the following or a pharmaceutically acceptable salt thereof.

[0507] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-methylurea,

[0508] N-methyl-N'-{5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}urea,

[0509] N-(5-{5-[(1R)-1-ethoxyethyl]-1,3,4-oxadiazol-2-yl}-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)-N'-methylurea,

[0510] N-methyl-N'-(5-{3-[1-(2,2,2-trifluoroethoxy)ethyl]-1,2,4-oxadiazol-5-yl}-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)urea,

[0511] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-[(2R)-1-hydroxypropane-2-yl]urea,

[0512] N-methyl-N'-(10-{3-[(1s,4s)-4-(trifluoromethyl)cyclohexyl]-1,2,4-oxadiazol-5-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl)urea,

[0513] N-{(4S,8S)-10-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl}-N'-methylurea,

[0514] N-methyl-N'-(5-{3-[3-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)urea,

[0515] N-{5-[5-(4-fluoro-3-methylphenyl)-1,3,4-oxadiazol-2-yl]-4,5,6,7-tetrahydro[[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-methylurea,

[0516] N-{(5R * ,8S * )-9-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-5,6,7,8-tetrahydro-4H-5,8-cycloiminocyclohepta[d][1,3]thiazol-2-yl}-N'-methylurea,

[0517] N-{9-[5-(4-fluorophenyl)-1,2-oxazol-3-yl]-5,6,7,8-tetrahydro-4H-5,8-cycloiminocyclohepta[d][1,3]thiazol-2-yl}-N'-methylurea,

[0518] N-{(5R * ,9S * )-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7,8,9-hexahydro-5,9-cycloiminocyclooctan[d][1,3]thiazol-2-yl}-N'-methylurea,

[0519] N-{(4S,8S)-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl}-N'-methylurea,

[0520] N-(10-{5-[3-(difluoromethyl)phenyl]-1,3-oxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl)-N'-methylurea,

[0521] N-{(4S,8S)-10-[5-(6-methoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl}-N'-methylurea,

[0522] N-{10-[5-(4-fluorophenyl)-1,2-oxazol-3-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl}-N'-methylurea,

[0523] N-{(4S,8S)-10-[4-(4-fluorophenyl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl}-N'-methylurea,

[0524] N-{10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacin-trieno[5,4-d][1,3]thiazol-2-yl}-N'-[(2R)-1-hydroxypropane-2-yl]urea, N-{6-acetyl-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azoc-2-yl}-N'-methylurea,

[0525] (5R)-3-{(4S,8S)-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl}-5-methylimidazoline-2,4-dione,

[0526] N-[(4S,8S)-10-{5-[3-(cyclopropanecarbonyl)phenyl]-1,3,4-oxadiazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]-N'-methylurea,

[0527] N-[(4S,8S)-10-{5-[3-(difluoromethoxy)phenyl]-1,3,4-oxadiazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]-N'-methylurea,

[0528] (-)-N-{(4R * ,8R * )-6-acetyl-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azoc-2-yl}-N'-methylurea,

[0529] (4R * ,8R * )-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-2-[(methylcarbamoyl)amino]-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylic acid (-)-methyl ester,

[0530] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-[(1R,2R)-2-hydroxycyclopentyl]urea,

[0531] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-[(1r,4r)-4-hydroxycyclohexyl]urea,

[0532] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-(3-methoxypropyl)urea,

[0533] N-{5-[3-(3,3-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-(2-hydroxy-2-methylpropyl)urea,

[0534] N-{[(2S)-1,4-dioxane-2-yl]methyl}-N'-{(4S,8S)-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}urea,

[0535] N-{10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-6-(methanesulfonyl)-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azoc-2-yl}-N'-oxan-4-yl urea, N-{10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-6-(methanesulfonyl)-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azoc-2-yl}-N'-methyl urea,

[0536] 10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-2-[(methylcarbamoyl)amino]-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylic acid propane-2-ester,

[0537] (4R * ,8R * )-2-{[(2-hydroxy-2-methylpropyl)carbamoyl]amino}-10-{3-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-5-yl}-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylic acid methyl ester,

[0538] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-[2-(2-hydroxyethoxy)ethyl]urea,

[0539] N-{5-[3-(3,3-difluorocyclopentyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-[(1r,3r)-3-hydroxycyclobutyl]urea,

[0540] N-{5-[3-(3,3-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-methylurea,

[0541] N-[(3R)-oxolan-3-yl]-N'-[(4S,8S)-10-{3-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-5-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl]urea,

[0542] N-[(2R)-1-hydroxypropane-2-yl]-N'-[(4S,8S)-10-(5-methoxy-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]urea,

[0543] N-[(4S,8S)-10-(5-fluoro-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl]-N'-[(2R)-1-hydroxypropane-2-yl]urea,

[0544] N-[(4S,8S)-10-(5-ethoxy-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]-N'-(2-hydroxy-2-methylpropyl)urea,

[0545] N-{(4S,8S)-10-[5-(dimethylamino)-1,3-benzoxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl}-N'-(2-hydroxy-2-methylpropyl)urea,

[0546] N-[(4S,8S)-10-(5,6-difluoro-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl]-N'-[(2R)-1-hydroxypropane-2-yl]urea,

[0547] N-{(4S,8S)-10-[5-(methanesulfonyl)-1,3-benzoxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-(2-methylpropyl)urea,

[0548] N-(2-hydroxy-2-methylpropyl)-N'-[(4S,8S)-10-(5-methoxy-6-methyl-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]urea,

[0549] N-[(4S,8S)-10-(5-methoxy-6-methyl-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]-N'-[(3R)-oxolan-3-yl]urea,

[0550] N-(2-hydroxy-2-methylpropyl)-N'-[(4S,8S)-10-(5-methoxy-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]urea,

[0551] N-[(4S,8S)-10-(5-methoxy-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]-N'-[(3R)-oxolan-3-yl]urea,

[0552] N-[(4S,8S)-10-(5-methoxy-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclotriene[5,4-d][1,3]thiazol-2-yl]-N'-methylurea,

[0553] N-methyl-N'-[(4S,8S)-10-(5-methyl-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]urea,

[0554] N-{(4S,8S)-10-[5-(methanesulfonyl)-1,3-benzoxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-propan-2-ylurea,

[0555] N-[(4S,8S)-10-(6-cyano-5-methyl-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]-N'-(2-hydroxy-2-methylpropyl)urea,

[0556] N-[(4S,8S)-10-(5-ethoxy-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]-N'-[(2R)-1-hydroxypropane-2-yl]urea,

[0557] N-{(4S,8S)-10-[5-(difluoromethyl)-1,3-benzoxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl}-N'-(2-hydroxy-2-methylpropyl)urea,

[0558] N-[(1r,3S)-3-hydroxycyclobutyl]-N'-[(4S,8S)-10-(5-trifluoromethoxy-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]urea,

[0559] N-{(4S,8S)-10-(5-cyano-6-fluoro-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]-N'-(2-hydroxy-2-methylpropyl)urea,

[0560] N-{(4S,8S)-10-[5-(difluoromethyl)-1,3-benzoxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-[(2R)-1-hydroxypropane-2-yl)urea,

[0561] N-{(4S,8S)-10-[5-(fluoromethoxy)-1,3-benzoxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-(2-hydroxy-2-methylpropyl)urea,

[0562] N-(1-hydroxy-2-methylpropane-2-yl)-N'-[(4S,8S)-10-(5-methoxy-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]urea,

[0563] N-[(4S,8S)-10-(5-chloro-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl]-N'-[(2R)-1-hydroxypropane-2-yl]urea, N-(2-hydroxy-2-methylpropyl)-N'-[(4S,8S)-10-{5-[( 2 H3) methyloxy]-1,3-benzoxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]urea,

[0564] N-{(4S,8S)-10-[5-(4-fluorophenyl)-1,2-oxazol-3-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl}-N'-[(1s,4s)-4-hydroxycyclohexyl]urea,

[0565] N-{(4S,8S)-10-[5-(6-methoxypyridin-2-yl)-1,2-oxazol-3-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-oxan-4-ylurea,

[0566] N-{(4S,8S)-10-[5-(4-fluorophenyl)-1,2-oxazol-3-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-(2-hydroxy-2-methylpropyl)urea,

[0567] 10-[5-(4-fluorophenyl)-1,2-oxazol-3-yl]-2-[(methylcarbamoyl)amino]-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylic acid methyl ester,

[0568] N-{(4S,8S)-10-[5-(4-fluorophenyl)-1,2-oxazol-3-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazolo-2-yl}-N'-[(2R)-2-hydroxypropyl]urea,

[0569] N-[(4S,8S)-10-{5-[6-(difluoromethoxy)pyridin-2-yl]-1,3-oxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]-N'-[(2R)-1-hydroxypropane-2-yl]urea,

[0570] N-[(2R)-1-hydroxypropane-2-yl]-N'-{(4S,8S)-10-[5-(6-methoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}urea,

[0571] N-{(4S,8S)-10-[5-(6-ethoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-[(2R)-1-hydroxypropane-2-yl]urea,

[0572] N-[(4S,8S)-10-{5-[3-(difluoromethyl)phenyl]-1,3-oxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]-N'-(1-hydroxy-2-methylpropane-2-yl)urea,

[0573] N-[(4S,8S)-10-{5-[3-(difluoromethoxy)phenyl]-1,3-oxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]-N'-[(2R)-1-hydroxypropane-2-yl]urea,

[0574] N-[(4S,8S)-10-{5-[3-(difluoromethyl)phenyl]-1,3-oxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]-N'-[(2R)-1-hydroxypropane-2-yl]urea,

[0575] N-[(4S,8S)-10-{5-[3-(difluoromethyl)phenyl]-1,3-oxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]-N'-[(2R)-2-hydroxypropyl]urea,

[0576] N-[(4S,8S)-10-{5-[3-(difluoromethoxy)phenyl]-1,3-oxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]-N'-[(3R)-oxolan-3-yl]urea,

[0577] N-[(2R)-1-hydroxypropane-2-yl]-N'-{5-[5-(methanesulfonyl)-1,3-benzoxazol-2-yl]-6,6-dimethyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}urea,

[0578] N-(2-hydroxy-2-methylpropyl)-N'-{5-[5-(methanesulfonyl)-1,3-benzoxazol-2-yl]-6,6-dimethyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}urea,

[0579] N-[(2R)-1-Hydroxypropan-2-yl]-N'-[(4S,8S)-10-{5-[( 2 H3) methyloxy]-1,3-benzoxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]urea,

[0580] N-[(4S,8S)-10-{5-[( 2 H3) methyloxy]-1,3-benzoxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]-N'-[(3R)-oxolan-3-yl]urea,

[0581] N-[(1r,3S)-3-hydroxycyclobutyl]-N'-{(4S,8S)-10-[5-(6-methoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}urea,

[0582] N-{(4S,8S)-10-[5-(6-ethoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-(2-hydroxy-2-methylpropyl)urea,

[0583] N-{(4S,8S)-10-[5-(6-ethoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-[(1r,3S)-3-hydroxycyclobutyl]urea,

[0584] N-{10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl}-N'-[(2S)-2-hydroxypropyl]urea,

[0585] N-{10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl}-N'-[(2R)-2-hydroxypropyl]urea,

[0586] N-{10-[3-(4-fluoro-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-[(2R)-1-hydroxypropane-2-yl]urea,

[0587] N-{10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl}-N'-[(1r,3r)-3-(hydroxymethyl)cyclobutyl]urea,

[0588] N-{10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl}-N'-[(1s,3s)-3-hydroxycyclobutyl]urea,

[0589] N-{(4S,8S)-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl}-N'-[(1r,3S)-3-hydroxycyclobutyl]urea,

[0590] N-{5-[3-(3,3-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-[(2R)-1-hydroxypropane-2-yl]urea,

[0591] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-(2-hydroxy-2-methylpropyl)urea,

[0592] N-[(2R)-1-hydroxypropan-2-yl]-N'-(5-{3-[1-(2,2,2-trifluoroethoxy)ethyl]-1,2,4-oxadiazol-5-yl}-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)urea,

[0593] N-{(4S,8S)-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-(1-hydroxy-2-methylpropane-2-yl)urea,

[0594] N-[(2R)-1-hydroxypropan-2-yl]-N'-(5-{3-[2-(2,2,2-trifluoroethoxy)propan-2-yl]-1,2,4-oxadiazol-5-yl}-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)urea,

[0595] N-(2-hydroxy-2-methylpropyl)-N'-(5-{3-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-5-yl}-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)urea,

[0596] N-{5-[3-(4-fluorobicyclo[2.2.1]heptane-1-yl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-methylurea,

[0597] N-{5-[3-(3,3-difluorocyclopentyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-(2-hydroxy-2-methylpropyl)urea,

[0598] N-{5-[3-(4,4-difluorooxan-2-yl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-[(3R)-oxolan-3-yl]urea,

[0599] N-(5-{3-[3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl]-1,2,4-oxadiazol-5-yl}-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)-N'-(2-hydroxy-2-methylpropyl)urea,

[0600] N-[(1r,3r)-3-hydroxycyclobutyl]-N'-(5-{3-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-5-yl}-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)urea,

[0601] N-{5-[3-(4,4-difluorooxan-2-yl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-(2-methoxyethyl)urea,

[0602] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-[(pyrimidin-5-yl)methyl]urea,

[0603] N-{5-[3-(4-fluoro-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-[(1-methyl-1H-imidazol-2-yl)methyl]urea,

[0604] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-[(2-oxo-1,2-dihydropyridin-4-yl)methyl]urea,

[0605] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-[(4H-1,2,4-triazol-3-yl)methyl]urea,

[0606] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-[(2-oxo-1,2-dihydropyridin-3-yl)methyl]urea,

[0607] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-[(1-hydroxycyclopropyl)methyl]urea,

[0608] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-[1-(hydroxymethyl)cyclopropyl]urea,

[0609] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]urea,

[0610] N-{5-[3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-oxan-4-ylurea,

[0611] N-{5-[3-(3-methoxyphenyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-oxan-4-ylurea,

[0612] N-(10-{5-[3-(difluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl)-N'-methylurea,

[0613] N-methyl-N'-(10-{5-[3-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl)urea,

[0614] N-{10-[5-(3-tert-butoxyphenyl)-1,3,4-oxadiazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl}-N'-methylurea,

[0615] N-(10-{3-[3-(cyclopropanecarbonyl)phenyl]-1,2,4-oxadiazol-5-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl)-N'-methylurea,

[0616] N-(10-{5-[3-(cyclobutylcarbonyl)phenyl]-1,3,4-oxadiazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl)-N'-methylurea,

[0617] N-(10-{5-[3-((cyclopropanecarbonyl)phenyl]-1,3,4-oxadiazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl)-N'-(2,2,2-trifluoroethyl)urea,

[0618] N-(10-{5-[3-(difluoromethoxy)phenyl]-1,3,4-oxadiazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl)-N'-[(3S)-oxolan-3-yl]urea,

[0619] N-(10-{5-[3-(cyclopropanecarbonyl)-2-fluorophenyl]-1,3-oxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl)-N'-methylurea,

[0620] N-[(4S,8S)-10-{5-[3-(cyclopropanecarbonyl)phenyl]-1,3,4-oxadiazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]-N'-propan-2-ylurea,

[0621] N-{(4S,8S)-10-[5-(3-ethylphenyl)-1,3,4-oxadiazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl}-N'-methylurea,

[0622] N-methyl-N'-[(4S,8S)-10-{5-[3-(propan-2-yl)phenyl]-1,3,4-oxadiazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]urea,

[0623] N-{(4S,8S)-10-[5-(3-methoxyphenyl)-1,3,4-oxadiazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl}-N'-methylurea,

[0624] N-{(4S,8S)-10-[5-(3-ethoxyphenyl)-1,3,4-oxadiazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl}-N'-methylurea,

[0625] N-methyl l-N'-[(4S,8S)-10-(5-{3-[(propane-2-yl)oxy]phenyl}-1,3,4-oxadiazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]urea,

[0626] 10-{5-[3-(cyclopropanecarbonyl)phenyl]-1,3,4-oxadiazol-2-yl}-2-[(methylcarbamoyl)amino]-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylic acid methyl ester,

[0627] N-(10-{3-[3-(difluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl)-N'-[(2R)-1-hydroxypropane-2-yl]urea,

[0628] N-[(4R,8R)-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-6-(2-methylpropionyl)-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azoc-2-yl]-N'-methylurea,

[0629] N-{6-acetyl-10-[5-(6-methoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocin-2-yl}-N'-methylurea,

[0630] N-[(4R,8R)-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-6-(2-hydroxyethyl)-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azoc-2-yl]-N'-methylurea,

[0631] N-(6-acetyl-10-{5-[6-(difluoromethoxy)pyridin-2-yl]-1,3-oxazol-2-yl}-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocin-2-yl)-N'-methylurea,

[0632] N-{6-acetyl-10-[5-(6-methoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocin-2-yl}-N'-methylurea,

[0633] N-[6-acetyl-10-(5-fluoro-1,3-benzoxazol-2-yl)-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azoc-2-yl]-N'-methylurea,

[0634] 10-[3-(3,3-difluorocyclopentyl)-1,2,4-oxadiazol-5-yl]-2-[(methylcarbamoyl)amino]-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylic acid methyl ester,

[0635] 10-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-2-[(methylcarbamoyl)amino]-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylic acid methyl ester,

[0636] 10-[3-(4-fluorobicyclo[2.2.1]heptane-1-yl)-1,2,4-oxadiazol-5-yl]-2-[(methylcarbamoyl)amino]-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylic acid methyl ester,

[0637] 2-[(Methylcarbamoyl)amino]-10-{3-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-5-yl}-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylic acid-ethyl ester,

[0638] 10-{3-[3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl]-1,2,4-oxadiazol-5-yl}-2-[(methylcarbamoyl)amino]-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylic acid methyl ester,

[0639] N-{6-acetyl-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azoc-2-yl}-N'-ethylurea,

[0640] N-{6-acetyl-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azoc-2-yl}-N'-propan-2-ylurea,

[0641] N-{6-acetyl-10-[3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azoc-2-yl}-N'-methylurea,

[0642] N-{6-acetyl-10-[5-(3-chlorophenyl)-1,3-oxazol-2-yl]-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azoc-2-yl}-N'-methylurea,

[0643] N-{6-acetyl-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azoc-2-yl}-N'-[(3R)-oxolan-3-yl]urea,

[0644] 10-(5-methoxy-1,3-benzoxazol-2-yl)-2-[(methylcarbamoyl)amino]-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylic acid methyl ester,

[0645] 10-[3-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol-5-yl]-2-[(methylcarbamoyl)amino]-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylic acid methyl ester,

[0646] 10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-2-{[(oxan-4-yl)carbamoyl]amino}-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylic acid propan-2-yl ester,

[0647] N-(2-hydroxy-2-methylpropyl)-N'-{(4S,8S)-10-[5-(trifluoromethyl)-1,3-benzoxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}urea,

[0648] N-(2-hydroxy-2-methylpropyl)-N'-[(4S,8S)-10-(5-methyl-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]urea,

[0649] N-[(4S,8S)-10-(5,6-difluoro-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl]-N'-(2-hydroxy-2-methylpropyl)urea,

[0650] N-[(4S,8S)-10-(5,7-difluoro-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl]-N'-[(2R)-1-hydroxypropane-2-yl]urea,

[0651] N-[(4S,8S)-10-(5,6-dimethyl-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl]-N'-[(2R)-1-hydroxypropane-2-yl]urea,

[0652] N-[(4S,8S)-10-(5-chloro-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]-N'-[(1r,4r)-4-hydroxycyclohexyl]urea,

[0653] N-[(4S,8S)-10-(5-chloro-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]-N'-[(4-hydroxyoxan-4-yl)methyl]urea,

[0654] N-[(4S,8S)-10-(5-methoxy-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]-N'-[(3S)-oxolan-3-yl]urea,

[0655] N-[(2R)-1-hydroxypropane-2-yl]-N'-{9-[5-(methanesulfonyl)-1,3-benzoxazol-2-yl]-5,6,7,8-tetrahydro-4H-5,8-cycloiminocyclohepta[d][1,3]thiazol-2-yl}urea,

[0656] N-{5-[5-(4,4-difluorocyclohexyl)-1,2-oxazol-3-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-[(2R)-2-hydroxypropyl]urea,

[0657] N-{(4S,8S)-10-[5-(4-fluorophenyl)-1,2-oxazol-3-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-[(2R)-1-hydroxypropane-2-yl]urea,

[0658] N-{(4S,8S)-10-[5-(4-fluorophenyl)-1,2-oxazol-3-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-[(2R)-1-hydroxypropane-2-yl]urea,

[0659] N-[(4S,8S)-10-{5-[3-(difluoromethyl)phenyl]-1,2-oxazol-3-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]-N'-[(2R)-1-hydroxypropane-2-yl]urea,

[0660] N-{(4S,8S)-10-[5-(4,4-difluorocyclohexyl)-1,2-oxazol-3-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-[(3R)-oxolan-3-yl]urea,

[0661] N-{(4S,8S)-10-[5-(4-fluorophenyl)-1,2-oxazol-3-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-[(1s,3R)-3-hydroxycyclobutyl]urea,

[0662] N-{(4S,8S)-10-[5-(4-fluorophenyl)-1,2-oxazol-3-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-[(1r,4r)-4-hydroxycyclohexyl]urea,

[0663] N-{(4S,8S)-10-[5-(4-fluorophenyl)-1,2-oxazol-3-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-(1-hydroxy-2-methylpropane-2-yl)urea,

[0664] N-{(4S,8S)-10-[5-(4-fluorophenyl)-1,2-oxazol-3-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-oxan-4-ylurea,

[0665] N-{(4S,8S)-10-[5-(6-methoxypyridin-2-yl)-1,2-oxazol-3-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-[(3S)-oxolan-3-yl]urea,

[0666] N-{(4S,8S)-10-[5-(6-methoxypyridin-2-yl)-1,2-oxazol-3-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-[(3R)-oxolan-3-yl]urea,

[0667] N-{(4S,8S)-10-[5-(3-methoxyphenyl)-1,2-oxazol-3-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-[(3R)-oxolan-3-yl]urea,

[0668] N-(1,1-dioxo-1λ 6 -tetrahydrothiopyran-4-yl)-N'-{(4S,8S)-10-[5-(4-fluorophenyl)-1,2-oxazol-3-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}urea,

[0669] N-(10-{5-[3-(difluoromethyl)phenyl]-1,3-oxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl)-N'-[(1r,3r)-3-hydroxycyclobutyl]urea,

[0670] N-[(4S,8S)-10-{5-[3-(difluoromethoxy)phenyl]-1,3-oxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]-N'-[(1r,3S)-3-hydroxycyclobutyl]urea,

[0671] N-[(4S,8S)-10-{5-[3-(difluoromethyl)phenyl]-1,3-oxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]-N'-[(2S)-1-hydroxypropane-2-yl]urea,

[0672] N-[(4S,8S)-10-{5-[6-(difluoromethoxy)pyridin-2-yl]-1,3-oxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl]-N'-[(2S)-1-hydroxypropane-2-yl]urea,

[0673] N-[(4S,8S)-10-{5-[3-(difluoromethoxy)phenyl]-1,3-oxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]-N'-(1-hydroxy-2-methylpropane-2-yl)urea,

[0674] N-[(4S,8S)-10-{5-[3-(difluoromethoxy)phenyl]-1,3-oxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]-N'-[(2R)-2-hydroxypropyl]urea,

[0675] N-[(4S,8S)-10-{5-[3-(difluoromethoxy)phenyl]-1,3-oxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]-N'-(2-hydroxy-2-methylpropyl)urea,

[0676] N-[(4S,8S)-10-{5-[3-(difluoromethoxy)phenyl]-1,3-oxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]-N'-[(2S)-1-hydroxypropane-2-yl]urea,

[0677] N-[(4S,8S)-10-{5-[6-(difluoromethoxy)pyridin-2-yl]-1,3-oxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]-N'-[(2S)-2-hydroxypropyl]urea,

[0678] N-[(4S,8S)-10-{5-[6-(difluoromethoxy)pyridin-2-yl]-1,3-oxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]-N'-[(3R,4S)-4-hydroxyoxolan-3-yl]urea,

[0679] N-[(4S,8S)-10-{5-[6-(difluoromethoxy)pyridin-2-yl]-1,3-oxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]-N'-[(1r,4r)-4-hydroxycyclohexyl]urea,

[0680] N-[(4S,8S)-10-{5-[6-(difluoromethoxy)pyridin-2-yl]-1,3-oxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]-N'-[(2-hydroxypyridin-4-yl)methyl]urea,

[0681] N-[(4S,8S)-10-{5-[6-(difluoromethoxy)pyridin-2-yl]-1,3-oxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]-N'-[(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methyl]urea,

[0682] N-[(4S,8S)-10-{5-[6-(difluoromethoxy)pyridin-2-yl]-1,3-oxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]-N'-[(1-hydroxycyclopropyl)methyl]urea,

[0683] N-[(4S,8S)-10-{5-[6-(difluoromethoxy)pyridin-2-yl]-1,3-oxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl]-N'-(1,1-dioxo-1λ 6 Tetrahydrothiopyran-4-yl)urea,

[0684] N-[(4S,8S)-10-{5-[6-(difluoromethoxy)pyridin-2-yl]-1,3-oxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]-N'-[1-(hydroxymethyl)cyclopropyl]urea,

[0685] N-[(3R)-1-acetylpyrrolidin-3-yl]-N'-[(4S,8S)-10-{5-[6-(difluoromethoxy)pyridin-2-yl]-1,3-oxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]urea,

[0686] N-(1-acetylazetidin-3-yl)-N'-[(4S,8S)-10-{5-[6-(difluoromethoxy)pyridin-2-yl]-1,3-oxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]urea,

[0687] N-(2-hydroxy-2-methylpropyl)-N'-{(4S,8S)-10-[5-(6-methoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}urea,

[0688] N-{(4S,8S)-10-[5-(6-methoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-[(3R)-oxolan-3-yl]urea,

[0689] N-{(4S,8S)-10-[5-(6-methoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-oxan-4-ylurea,

[0690] N-[(1s,4s)-4-hydroxycyclohexyl]-N'-{(4S,8S)-10-[5-(6-methoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}urea,

[0691] N-[(1r,4r)-4-hydroxycyclohexyl]-N'-{(4S,8S)-10-[5-(6-methoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}urea,

[0692] N-[(2R)-1-hydroxypropane-2-yl]-N'-[5-(5-methoxy-1,3-benzoxazol-2-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl]urea,

[0693] N-(2-hydroxy-2-methylpropyl)-N'-[5-(5-methoxy-1,3-benzoxazol-2-yl)-6,6-dimethyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl]urea,

[0694] N-[(2R)-1-hydroxypropane-2-yl]-N'-{5-[4-(oxan-3-yl)pyrimidin-2-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}urea,

[0695] N-[(1r,3r)-3-hydroxycyclobutyl]-N'-{5-[4-(oxan-3-yl)pyrimidin-2-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}urea,

[0696] N-[(2R)-1-hydroxypropane-2-yl]-N'-{(4S,8S)-10-[5-(6-methoxy-5-methylpyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}urea,

[0697] A preferred embodiment of the present invention is a compound selected from the following or a pharmaceutically acceptable salt thereof.

[0698] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-methylurea,

[0699] N-methyl-N'-{5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}urea,

[0700] N-(5-{5-[(1R)-1-ethoxyethyl]-1,3,4-oxadiazol-2-yl}-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)-N'-methylurea,

[0701] N-methyl-N'-(5-{3-[1-(2,2,2-trifluoroethoxy)ethyl]-1,2,4-oxadiazol-5-yl}-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)urea,

[0702] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-[(2R)-1-hydroxypropane-2-yl]urea,

[0703] N-methyl-N'-(10-{3-[(1s,4s)-4-(trifluoromethyl)cyclohexyl]-1,2,4-oxadiazol-5-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl)urea,

[0704] N-{(4S,8S)-10-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl}-N'-methylurea,

[0705] N-methyl-N'-(5-{3-[3-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)urea,

[0706] N-{5-[5-(4-fluoro-3-methylphenyl)-1,3,4-oxadiazol-2-yl]-4,5,6,7-tetrahydro[[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-methylurea,

[0707] N-{(5R * ,8S * )-9-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-5,6,7,8-tetrahydro-4H-5,8-cycloiminocyclohepta[d][1,3]thiazol-2-yl}-N'-methylurea,

[0708] N-{9-[5-(4-fluorophenyl)-1,2-oxazol-3-yl]-5,6,7,8-tetrahydro-4H-5,8-cycloiminocyclohepta[d][1,3]thiazol-2-yl}-N'-methylurea,

[0709] N-{(5R * ,9S * )-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7,8,9-hexahydro-5,9-cycloiminocyclooctan[d][1,3]thiazol-2-yl}-N'-methylurea,

[0710] N-{(4S,8S)-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl}-N'-methylurea,

[0711] N-(10-{5-[3-(difluoromethyl)phenyl]-1,3-oxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl)-N'-methylurea,

[0712] N-{(4S,8S)-10-[5-(6-methoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl}-N'-methylurea,

[0713] N-{10-[5-(4-fluorophenyl)-1,2-oxazol-3-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl}-N'-methylurea,

[0714] N-{(4S,8S)-10-[4-(4-fluorophenyl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl}-N'-methylurea,

[0715] N-{10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-[(2R)-1-hydroxypropane-2-yl]urea,

[0716] N-{6-acetyl-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azoc-2-yl}-N'-methylurea,

[0717] (5R)-3-{(4S,8S)-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl}-5-methylimidazoline-2,4-dione,

[0718] N-[(4S,8S)-10-{5-[3-(cyclopropanecarbonyl)phenyl]-1,3,4-oxadiazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]-N'-methylurea,

[0719] N-[(4S,8S)-10-{5-[3-(difluoromethoxy)phenyl]-1,3,4-oxadiazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]-N'-methylurea,

[0720] (-)-N-{(4R * ,8R * )-6-acetyl-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azoc-2-yl}-N'-methylurea,

[0721] (4R * ,8R * )-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-2-[(methylcarbamoyl)amino]-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylic acid (-)-methyl ester,

[0722] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-[(1R,2R)-2-hydroxycyclopentyl]urea,

[0723] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-[(1r,4r)-4-hydroxycyclohexyl]urea,

[0724] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-(3-methoxypropyl)urea,

[0725] N-{5-[3-(3,3-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-(2-hydroxy-2-methylpropyl)urea,

[0726] N-{[(2S)-1,4-dioxane-2-yl]methyl}-N'-{(4S,8S)-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}urea,

[0727] N-{10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-6-(methanesulfonyl)-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azoc-2-yl}-N'-oxan-4-ylurea,

[0728] N-{10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-6-(methanesulfonyl)-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azoc-2-yl}-N'-methylurea,

[0729] 10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-2-[(methylcarbamoyl)amino]-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylic acid propane-2-ester,

[0730] (4R * ,8R * )-2-{[(2-hydroxy-2-methylpropyl)carbamoyl]amino}-10-{3-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-5-yl}-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylic acid methyl ester,

[0731] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-[2-(2-hydroxyethoxy)ethyl]urea,

[0732] N-{5-[3-(3,3-difluorocyclopentyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-[(1r,3r)-3-hydroxycyclobutyl]urea,

[0733] N-{5-[3-(3,3-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-methylurea,

[0734] N-[(3R)-oxolan-3-yl]-N'-[(4S,8S)-10-{3-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-5-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl]urea,

[0735] N-[(2R)-1-hydroxypropane-2-yl]-N'-[(4S,8S)-10-(5-methoxy-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]urea,

[0736] N-[(4S,8S)-10-(5-fluoro-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl]-N'-[(2R)-1-hydroxypropane-2-yl]urea,

[0737] N-[(4S,8S)-10-(5-ethoxy-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]-N'-(2-hydroxy-2-methylpropyl)urea,

[0738] N-{(4S,8S)-10-[5-(dimethylamino)-1,3-benzoxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl}-N'-(2-hydroxy-2-methylpropyl)urea,

[0739] N-[(4S,8S)-10-(5,6-difluoro-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl]-N'-[(2R)-1-hydroxypropane-2-yl]urea,

[0740] N-{(4S,8S)-10-[5-(methanesulfonyl)-1,3-benzoxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-(2-methylpropyl)urea,

[0741] N-(2-hydroxy-2-methylpropyl)-N'-[(4S,8S)-10-(5-methoxy-6-methyl-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]urea,

[0742] N-[(4S,8S)-10-(5-methoxy-6-methyl-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]-N'-[(3R)-oxolan-3-yl]urea,

[0743] N-(2-hydroxy-2-methylpropyl)-N'-[(4S,8S)-10-(5-methoxy-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]urea,

[0744] N-[(4S,8S)-10-(5-methoxy-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]-N'-[(3R)-oxolan-3-yl]urea,

[0745] N-[(4S,8S)-10-(5-methoxy-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclotriene[5,4-d][1,3]thiazol-2-yl]-N'-methylurea,

[0746] N-methyl-N'-[(4S,8S)-10-(5-methyl-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]urea,

[0747] N-{(4S,8S)-10-[5-(methanesulfonyl)-1,3-benzoxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-propan-2-ylurea,

[0748] N-[(4S,8S)-10-(6-cyano-5-methyl-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]-N'-(2-hydroxy-2-methylpropyl)urea,

[0749] N-[(4S,8S)-10-(5-ethoxy-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]-N'-[(2R)-1-hydroxypropane-2-yl]urea,

[0750] N-{(4S,8S)-10-[5-(difluoromethyl)-1,3-benzoxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl}-N'-(2-hydroxy-2-methylpropyl)urea,

[0751] N-[(1r,3S)-3-hydroxycyclobutyl]-N'-[(4S,8S)-10-(5-trifluoromethoxy-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]urea,

[0752] N-{(4S,8S)-10-(5-cyano-6-fluoro-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]-N'-(2-hydroxy-2-methylpropyl)urea,

[0753] N-{(4S,8S)-10-[5-(difluoromethyl)-1,3-benzoxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-[(2R)-1-hydroxypropane-2-yl)urea,

[0754] N-{(4S,8S)-10-[5-(fluoromethoxy)-1,3-benzoxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-(2-hydroxy-2-methylpropyl)urea,

[0755] N-(1-hydroxy-2-methylpropane-2-yl)-N'-[(4S,8S)-10-(5-methoxy-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]urea,

[0756] N-[(4S,8S)-10-(5-chloro-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl]-N'-[(2R)-1-hydroxypropane-2-yl]urea,

[0757] N-(2-Hydroxy-2-methylpropyl)-N'-[(4S,8S)-10-{5-[( 2 H3) methyloxy]-1,3-benzoxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]urea,

[0758] N-{(4S,8S)-10-[5-(4-fluorophenyl)-1,2-oxazol-3-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl}-N'-[(1s,4s)-4-hydroxycyclohexyl]urea,

[0759] N-{(4S,8S)-10-[5-(6-methoxypyridin-2-yl)-1,2-oxazol-3-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-oxan-4-ylurea,

[0760] N-{(4S,8S)-10-[5-(4-fluorophenyl)-1,2-oxazol-3-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-(2-hydroxy-2-methylpropyl)urea,

[0761] 10-[5-(4-fluorophenyl)-1,2-oxazol-3-yl]-2-[(methylcarbamoyl)amino]-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylic acid methyl ester,

[0762] N-{(4S,8S)-10-[5-(4-fluorophenyl)-1,2-oxazol-3-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazolo-2-yl}-N'-[(2R)-2-hydroxypropyl]urea,

[0763] N-[(4S,8S)-10-{5-[6-(difluoromethoxy)pyridin-2-yl]-1,3-oxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]-N'-[(2R)-1-hydroxypropane-2-yl]urea,

[0764] N-[(2R)-1-hydroxypropane-2-yl]-N'-{(4S,8S)-10-[5-(6-methoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}urea,

[0765] N-{(4S,8S)-10-[5-(6-ethoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-[(2R)-1-hydroxypropane-2-yl]urea,

[0766] N-[(4S,8S)-10-{5-[3-(difluoromethyl)phenyl]-1,3-oxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]-N'-(1-hydroxy-2-methylpropane-2-yl)urea,

[0767] N-[(4S,8S)-10-{5-[3-(difluoromethoxy)phenyl]-1,3-oxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]-N'-[(2R)-1-hydroxypropane-2-yl]urea,

[0768] N-[(4S,8S)-10-{5-[3-(difluoromethyl)phenyl]-1,3-oxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]-N'-[(2R)-1-hydroxypropane-2-yl]urea,

[0769] N-[(4S,8S)-10-{5-[3-(difluoromethyl)phenyl]-1,3-oxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]-N'-[(2R)-2-hydroxypropyl]urea,

[0770] N-[(4S,8S)-10-{5-[3-(difluoromethoxy)phenyl]-1,3-oxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]-N'-[(3R)-oxolan-3-yl]urea,

[0771] N-[(2R)-1-hydroxypropane-2-yl]-N'-{5-[5-(methanesulfonyl)-1,3-benzoxazol-2-yl]-6,6-dimethyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}urea,

[0772] N-(2-hydroxy-2-methylpropyl)-N'-{5-[5-(methanesulfonyl)-1,3-benzoxazol-2-yl]-6,6-dimethyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}urea,

[0773] N-[(2R)-1-Hydroxypropan-2-yl]-N'-[(4S,8S)-10-{5-[( 2 H3) methyloxy]-1,3-benzoxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]urea,

[0774] N-[(4S,8S)-10-{5-[( 2 H3) methyloxy]-1,3-benzoxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]-N'-[(3R)-oxolan-3-yl]urea,

[0775] N-[(1r,3S)-3-hydroxycyclobutyl]-N'-{(4S,8S)-10-[5-(6-methoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}urea,

[0776] N-{(4S,8S)-10-[5-(6-ethoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-(2-hydroxy-2-methylpropyl)urea,

[0777] N-{(4S,8S)-10-[5-(6-ethoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-[(1r,3S)-3-hydroxycyclobutyl]urea,

[0778] A more preferred embodiment of the present invention is a compound selected from the following or a pharmaceutically acceptable salt thereof.

[0779] N-[(4S,8S)-10-{5-[3-(cyclopropanecarbonyl)phenyl]-1,3,4-oxadiazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]-N'-methylurea,

[0780] (-)-N-{(4R * ,8R * )-6-acetyl-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azoc-2-yl}-N'-methylurea,

[0781] (4R * ,8R * )-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-2-[(methylcarbamoyl)amino]-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylic acid (-)-methyl ester,

[0782] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-[(1R,2R)-2-hydroxycyclopentyl]urea,

[0783] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-[(1r,4r)-4-hydroxycyclohexyl]urea,

[0784] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-(3-methoxypropyl)urea

[0785] N-{[(2S)-1,4-dioxane-2-yl]methyl}-N'-{(4S,8S)-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}urea,

[0786] N-[(2R)-1-hydroxypropane-2-yl]-N'-[(4S,8S)-10-(5-methoxy-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]urea,

[0787] N-[(4S,8S)-10-(5-fluoro-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl]-N'-[(2R)-1-hydroxypropane-2-yl]urea,

[0788] N-[(4S,8S)-10-(5-ethoxy-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]-N'-(2-hydroxy-2-methylpropyl)urea,

[0789] N-{(4S,8S)-10-[5-(dimethylamino)-1,3-benzoxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl}-N'-(2-hydroxy-2-methylpropyl)urea,

[0790] N-[(4S,8S)-10-(5,6-difluoro-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl]-N'-[(2R)-1-hydroxypropane-2-yl]urea,

[0791] N-{(4S,8S)-10-[5-(methanesulfonyl)-1,3-benzoxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-(2-methylpropyl)urea,

[0792] N-(2-hydroxy-2-methylpropyl)-N'-[(4S,8S)-10-(5-methoxy-6-methyl-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]urea,

[0793] N-[(4S,8S)-10-(5-methoxy-6-methyl-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]-N'-[(3R)-oxolan-3-yl]urea,

[0794] N-(2-hydroxy-2-methylpropyl)-N'-[(4S,8S)-10-(5-methoxy-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]urea,

[0795] N-[(4S,8S)-10-(5-methoxy-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]-N'-[(3R)-oxolan-3-yl]urea,

[0796] N-[(4S,8S)-10-(5-methoxy-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclotriene[5,4-d][1,3]thiazol-2-yl]-N'-methylurea,

[0797] N-methyl-N'-[(4S,8S)-10-(5-methyl-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]urea,

[0798] N-(2-Hydroxy-2-methylpropyl)-N'-[(4S,8S)-10-{5-[( 2 H3) methyloxy]-1,3-benzoxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]urea,

[0799] N-{(4S,8S)-10-[5-(4-fluorophenyl)-1,2-oxazol-3-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl}-N'-[(1s,4s)-4-hydroxycyclohexyl]urea,

[0800] N-{(4S,8S)-10-[5-(6-methoxypyridin-2-yl)-1,2-oxazol-3-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-oxan-4-ylurea,

[0801] N-[(4S,8S)-10-{5-[6-(difluoromethoxy)pyridin-2-yl]-1,3-oxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]-N'-[(2R)-1-hydroxypropane-2-yl]urea,

[0802] N-[(2R)-1-hydroxypropane-2-yl]-N'-{(4S,8S)-10-[5-(6-methoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}urea,

[0803] N-{(4S,8S)-10-[5-(6-ethoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-[(2R)-1-hydroxypropane-2-yl]urea,

[0804] N-[(2R)-1-hydroxypropane-2-yl]-N'-{5-[5-(methanesulfonyl)-1,3-benzoxazol-2-yl]-6,6-dimethyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}urea,

[0805] N-(2-hydroxy-2-methylpropyl)-N'-{5-[5-(methanesulfonyl)-1,3-benzoxazol-2-yl]-6,6-dimethyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}urea,

[0806] N-[(2R)-1-Hydroxypropan-2-yl]-N'-[(4S,8S)-10-{5-[( 2 H3) methyloxy]-1,3-benzoxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]urea,

[0807] N-[(4S,8S)-10-{5-[( 2 H3) methyloxy]-1,3-benzoxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]-N'-[(3R)-oxolan-3-yl]urea,

[0808] N-[(1r,3S)-3-hydroxycyclobutyl]-N'-{(4S,8S)-10-[5-(6-methoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}urea,

[0809] N-{(4S,8S)-10-[5-(6-ethoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-(2-hydroxy-2-methylpropyl)urea,

[0810] N-{(4S,8S)-10-[5-(6-ethoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-[(1r,3S)-3-hydroxycyclobutyl]urea.

[0811] The substituents and terms used to represent the compound of formula (1) or a pharmaceutically acceptable salt thereof are explained below.

[0812] The "C1-C6 alkyl group" in this specification refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, 1-propyl, isopropyl, 1-butyl, 2-butyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 2-ethyl-1-butyl, 2,2-dimethyl-1-butyl, and 2,3-dimethyl-1-butyl.

[0813] The "C1-C6 alkoxy group" in this specification refers to a group having a C1-C6 alkyl group bonded to an oxy group, and examples thereof include methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-butoxy, 2-methyl-1-propoxy, 2-methyl-2-propoxy, 1-pentoxy, 2-pentoxy, 3-pentoxy, 2-methyl-2-butoxy, 3-methyl-2-butoxy, 1-hexyloxy, 2-hexyloxy, 3-hexyloxy, 2-methyl-1-pentoxy, and 3-methyl-1-pentoxy.

[0814] As used herein, a "hydroxy C1-C6 alkyl group" refers to a group having any number of hydroxyl groups bonded to a C1-C6 alkyl group. A group having 1 to 3 hydroxyl groups bonded thereto is preferred, and a group having 1 hydroxyl group bonded thereto is more preferred. Specific examples include a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, a hydroxyisopropyl group, and a hydroxyisobutyl group.

[0815] In the present specification, the "C1-C6 alkylcarbonyl group" refers to a group in which a C1-C6 alkyl group is bonded to a carbonyl group, and examples thereof include an acetyl group, an ethylcarbonyl group, and a propylcarbonyl group.

[0816] In the present specification, the "C1-C6 alkylcarbamoyl group" means a group in which a C1-C6 alkyl group is bonded to a carbamoyl group, and examples thereof include a methylcarbamoyl group, an ethylcarbamoyl group, and a propylcarbamoyl group.

[0817] In the present specification, a "C1-C6 alkylsulfonyl group" means a group in which a C1-C6 alkyl group is bonded to a sulfonyl group, and examples thereof include a methanesulfonyl group, an ethanesulfonyl group, and a butanesulfonyl group.

[0818] In the present specification, a "C1-C6 alkoxycarbonyl group" means a group in which a C1-C6 alkoxy group is bonded to a carbonyl group, and examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, and a tert-butoxycarbonyl group.

[0819] As used herein, a "hydroxy C1-C6 alkoxy group" refers to a group having any number of hydroxyl groups bonded to a C1-C6 alkoxy group. A group having 1 to 3 hydroxyl groups bonded thereto is preferred, and a group having 1 hydroxyl group bonded thereto is more preferred. Specific examples include hydroxymethoxy, hydroxyethoxy, hydroxypropoxy, hydroxyisopropoxy, and hydroxyisobutoxy.

[0820] In the present specification, the "C3-C6 cycloalkyl group" refers to a cyclic alkyl group having 3 to 6 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0821] In the present specification, the "C3-C6 cycloalkoxy group" refers to a group in which a C3-C6 cycloalkyl group is bonded to an oxy group, and examples thereof include a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, and a cyclohexyloxy group.

[0822] The "C3-C6 cycloalkylcarbonyl group" in this specification refers to a group in which a cyclic alkyl group having 3 to 6 carbon atoms is bonded to a carbonyl group, and examples thereof include cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, and cyclohexylcarbonyl.

[0823] As used herein, a "hydroxy C3-C6 cycloalkyl group" refers to a group having any number of hydroxyl groups bonded to a C3-C6 cycloalkyl group. A group having 1 to 3 hydroxyl groups bonded thereto is preferred, and a group having 1 hydroxyl group bonded thereto is more preferred. Specific examples include hydroxycyclopropyl, hydroxycyclobutyl, hydroxycyclopentyl, and hydroxycyclohexyl groups.

[0824] In this specification, the term "4-7 membered heterocyclic group" refers to a group of a monocyclic 4-7 membered heterocyclic ring containing 1-3 atoms selected from the group consisting of nitrogen atoms, oxygen atoms and sulfur atoms, and the ring may contain 1 or 2 unsaturated bonds. Examples include azetidinyl, pyrrolidinyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, piperidinyl, azepanyl, piperazinyl, hexahydropyrimidinyl, morpholinyl, thiomorpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, thiacyclohexanyl, oxepanyl, and dihydropyridinyl. Preferred examples include the rings shown below.

[0825] [Chemical Formula 36]

[0826]

[0827] The "5- to 6-membered heterocyclic group" herein refers to a monocyclic 5- to 6-membered aromatic heterocyclic group containing 1 to 3 atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, and examples thereof include imidazolyl, triazolyl, pyridyl and pyrimidinyl.

[0828] Examples of the "halogen atom" in the present specification include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

[0829] As used herein, a "halogenated C1-C6 alkyl group" refers to a C1-C6 alkyl group substituted with any number of halogen atoms. Preferably, the group has 1 to 3 halogen atoms bonded thereto. Specific examples include difluoromethyl, trifluoromethyl, and difluoroethyl.

[0830] As used herein, a "halogenated C1-C6 alkoxy group" refers to a C1-C6 alkoxy group substituted with any number of halogen atoms. Preferably, the group has 1 to 3 halogen atoms bonded thereto. Specific examples include difluoromethoxy, trifluoromethoxy, and difluoroethoxy.

[0831] In the present specification, the "C1-C6 alkoxy C1-C6 alkyl group" refers to a group in which one C1-C6 alkoxy group is bonded to a C1-C6 alkyl group, and examples thereof include methoxymethyl, ethoxymethyl, and ethoxyethyl.

[0832] The "halogenated C1-C6 alkoxy C1-C6 alkyl" in this specification refers to a group in which one halogenated C1-C6 alkoxy group is bonded to a C1-C6 alkyl group, and examples thereof include difluoromethoxymethyl, trifluoromethoxymethyl, and difluoroethoxyethyl.

[0833] In the present specification, the "mono(C1-C6 alkyl)amino group" refers to a group in which one C1-C6 alkyl group is bonded to an amino group, and examples thereof include a methylamino group, an ethylamino group, and a propylamino group.

[0834] In the present specification, "di(C1-C6 alkyl)amino" refers to a group in which two identical or different C1-C6 alkyl groups are bonded to an amino group, and examples thereof include dimethylamino, diethylamino, and dipropylamino.

[0835] In the present specification, the "amino C1-C6 alkyl group" refers to a group in which one amino group is bonded to a C1-C6 alkyl group, and examples thereof include aminomethyl, aminoethyl, and aminopropyl groups.

[0836] In the present specification, a "mono(C1-C6 alkyl)aminosulfonyl group" means a group in which a mono(C1-C6 alkyl)amino group is bonded to a sulfonyl group, and examples thereof include a methylaminosulfonyl group and an ethylaminosulfonyl group.

[0837] In the present specification, the "C1-C4 alkylene group" refers to a saturated chain alkylene group having 1 to 4 carbon atoms and having two connecting bonds, and examples thereof include methylene, ethylene, propylene, and butylene.

[0838] The term "pharmaceutically acceptable salt thereof" refers to a salt that can be used as a pharmaceutical. When a compound has an acidic group or a basic group, it can form a basic salt or an acidic salt by reacting with a base or an acid, and thus refers to a salt thereof.

[0839] As the pharmacologically acceptable "basic salt" of the compound, preferably, an alkali metal salt such as sodium salt, potassium salt, lithium salt; an alkaline earth metal salt such as magnesium salt, calcium salt; an organic base salt such as N-methylmorpholine salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidinium salt, pyridine salt, 4-pyrrolidinylpyridine salt, methylpyridine salt; or an amino acid salt such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, aspartate, preferably an alkali metal salt.

[0840] As the pharmacologically acceptable "acid salt" of the compound, preferred are hydrohalide salts such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide, inorganic acid salts such as nitrate, perchlorate, sulfate, and phosphate; lower alkane sulfonates such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate, aryl sulfonates such as benzenesulfonate and p-toluenesulfonate, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, and maleate; or amino acid salts such as glycine, lysine, arginine, ornithine, glutamate, and aspartate, and hydrohalide salts (particularly hydrochloride) are most preferred.

[0841] The compounds of the present invention or pharmaceutically acceptable salts thereof may absorb moisture, adsorb water, or form hydrates due to exposure to the atmosphere or recrystallization. The present invention also includes such various hydrates, solvates, and polymorphic compounds.

[0842] The compounds of the present invention, their pharmaceutically acceptable salts, or solvates thereof may exist in various isomers, such as cis-isomers, trans-isomers, tautomers, rotational isomers, or optical isomers (including enantiomers and diastereomers), such as d-isomers and l-isomers, depending on the type and combination of substituents. Unless otherwise specified, the compounds of the present invention also include all of the above-mentioned isomers, stereoisomers, and mixtures of the above-mentioned isomers and stereoisomers in any ratio. The mixtures of the above-mentioned isomers can be separated by known resolution means.

[0843] The compounds of the present invention also include labeled compounds, that is, compounds in which one or more atoms of the compound are replaced with isotopes (eg, 2H, 3H, 13C, 14C, 35S, etc.).

[0844] The compounds of the present invention are generally named according to the nomenclature of the International Union of Pure and Applied Chemistry (IUPAC).

[0845] When a compound has an asymmetric center in its structure, the absolute configuration may be indicated by R and S (described together with position numbers) in the name of the compound of the present invention.

[0846] Regarding the relative configuration, when the configuration of the asymmetric center described first is R or S, an asterisk (*) may be added to the configuration symbol (R * and S * ), or add the prefix (symbol) rel- (meaning relative) before the name to indicate it.

[0847] For racemic mixtures, R and S are not usually used to indicate their absolute configuration. Sometimes the symbols RS and SR are used instead of R. * and S * , or by adding the prefix (symbol) rac- (meaning racemic) before the name.

[0848] In addition, the present invention also includes so-called prodrugs. Prodrugs are compounds having groups such as amino, hydroxyl, and carboxyl groups that can be converted into compounds by hydrolysis or under physiological conditions. Such prodrug-forming groups are described in Prog. Med., Vol. 5, pp. 2157-2161, 1985. More specifically, as such prodrugs,

[0849] (1) When an amino group is present in the compound, examples include:

[0850] Compounds in which the amino group is acylated, alkylated, or phosphorylated (for example, compounds in which the amino group is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonylated, tetrahydrofurylated, pyrrolidinylmethylated, pivaloyloxymethylated, or tert-butylated, etc.),

[0851] (2) When a hydroxyl group is present in the compound, examples include:

[0852] Compounds in which the hydroxyl group is acylated, alkylated, phosphorylated, or borated (for example, compounds in which the hydroxyl group is acetylated, palmitoylated, propionylated, pivaloylated, succinylated, fumarylated, alanylated, or dimethylaminomethylcarbonylated, etc.),

[0853] (3) In addition, when a carboxyl group is present in the compound, examples include:

[0854] Compounds in which the carboxyl group is esterified or amidated (for example, compounds in which the carboxyl group is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, amidated, or methylamidated).

[0855] (Manufacturing Method)

[0856] The production method is described below. However, the production method of the compound or its salt is not limited to the following method.

[0857] [Method A]

[0858] Method A is a method for producing compound (AV).

[0859] [Chemical Formula 37]

[0860]

[0861] [wherein, Bn represents benzyl, R 1 With R 2 They are bonded to each other to form a substituent, and represent any group selected from the following.

[0862] [Chemical Formula 38]

[0863]

[0864] R 12 : C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkylcarbonyl, or C1-C6 alkoxycarbonyl]

[0865] (A1 step) Oxidative cracking step

[0866] (When using ozone)

[0867] This is a step of obtaining compound (A-II) by reacting compound (AI) using ozone and a reducing agent.

[0868] Examples of the reducing agent include triphenylphosphine and dimethyl sulfide.

[0869] Examples of the solvent include methanol, dichloromethane, and mixtures thereof.

[0870] The reaction temperature is usually about -78°C to room temperature, and the reaction time is usually about 0.25 to 24 hours.

[0871] (When using oxidizing agents)

[0872] This is a step of reacting compound (AI) with an oxidizing agent to obtain compound (A-II).

[0873] Examples of the oxidizing agent include potassium permanganate, osmium tetroxide, sodium periodate, and mixtures thereof.

[0874] Examples of the solvent include tetrahydrofuran, acetonitrile, water, dichloromethane, and mixtures thereof.

[0875] The reaction temperature is usually about 0°C to room temperature, and the reaction time is usually about 0.5 to 24 hours.

[0876] (A2 step) epoxidation step

[0877] This is a step of obtaining compound (A-III) by reacting compound (AI) with an oxidizing agent in the presence or absence of a base.

[0878] Examples of the base include sodium hydrogen carbonate and pyridine.

[0879] Examples of the oxidizing agent include 3-chloroperoxybenzoic acid (mCPBA) and hydrogen peroxide.

[0880] Examples of the solvent include dichloromethane, acetonitrile, methanol, water, and mixtures thereof.

[0881] The reaction temperature is usually about 0°C to 60°C, and the reaction time is usually about 0.25 to 24 hours.

[0882] (Step A3) Step of performing epoxy ring opening

[0883] This is a step of obtaining compound (A-IV) by reacting compound (A-III) in the presence or absence of an acid or a base using an aqueous solvent.

[0884] Examples of the acid include sulfuric acid.

[0885] Examples of the base include sodium hydroxide and the like.

[0886] Examples of the solvent include tetrahydrofuran, methanol, water, and mixtures thereof.

[0887] The reaction temperature is usually room temperature to about 100°C, and the reaction time is usually about 0.25 to 24 hours.

[0888] (A4 step) Oxidative cracking step

[0889] This is a step of obtaining compound (A-II) by reacting compound (A-IV) with an oxidizing agent.

[0890] As the oxidizing agent, sodium periodate and the like can be mentioned.

[0891] Examples of the solvent include tetrahydrofuran, acetonitrile, methanol, water, and mixtures thereof.

[0892] The reaction temperature is usually about 0°C to room temperature, and the reaction time is usually about 0.5 to 24 hours.

[0893] (A5 step) looping step

[0894] This is a step of obtaining compound (AV) by reacting compound (A-II) with benzylamine and 1,3-acetonedicarboxylic acid in the presence of an acid.

[0895] Examples of the acid include hydrochloric acid.

[0896] Examples of the solvent include tetrahydrofuran, acetonitrile, methanol, water, and mixtures thereof.

[0897] The reaction temperature is usually about 0°C to 60°C, and the reaction time is usually about 0.5 to 24 hours.

[0898] [Method B]

[0899] Method B is a method for producing compound (B-III).

[0900] [Chemical Formula 39]

[0901]

[0902] [wherein, Bn represents benzyl, R 1 With R 2 They are bonded to each other to form a substituent, representing any group selected from the following.]

[0903] [Chemical Formula 40]

[0904]

[0905] R 12 : C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkylcarbonyl, or

[0906] C1-C6 alkoxycarbonyl;

[0907] P a1 represents a commonly used protecting group for an amino group.]

[0908] (Step B1) Deprotection

[0909] This is a step of obtaining compound (B-II) by reacting compound (BI) using a transition metal catalyst in the presence or absence of an acid under a hydrogen atmosphere.

[0910] Examples of the acid include hydrochloric acid, hydrogen chloride-1,4-dioxane, and hydrogen chloride-ethyl acetate.

[0911] Examples of the transition metal catalyst include palladium-carbon, palladium hydroxide-carbon, and Raney nickel.

[0912] Examples of the solvent include methanol, ethanol, ethyl acetate, chloroform, and mixtures thereof.

[0913] The reaction temperature is usually about 0 to 100°C, and the reaction time is usually about 0.5 to 24 hours.

[0914] (B2 process) Protection process

[0915] (In the case of carbamate group)

[0916] This is a step of obtaining compound (B-III) by reacting compound (B-II) with a carbamate-forming reagent in the presence of a base.

[0917] In this step, the carbamate group refers to a carbamate group generally used as a protecting group for an amino group in synthesis, such as tert-butoxycarbonyl (Boc), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), allyloxycarbonyl (Alloc), and benzyloxycarbonyl (Cbz).

[0918] Examples of the base include triethylamine, diisopropylethylamine, sodium hydrogen carbonate, and 4-dimethylaminopyridine.

[0919] Examples of the urethanizing agent include chloroformates, dicarbonic acid diesters, and succinimidyl carbonates.

[0920] Examples of the solvent include tetrahydrofuran, dichloromethane, N,N-dimethylformamide, water, and mixtures thereof.

[0921] The reaction temperature is usually about 0 to 80°C, and the reaction time is usually about 0.5 to 24 hours.

[0922] [Method C]

[0923] Method C is a method for producing compound (C-II).

[0924] [Chemical Formula 41]

[0925]

[0926] [Where R 1 and R 2 It has the same meaning as that of the compound of the above formula (1), and P a1 Means the same as above.]

[0927] (C1 step) Deprotection step

[0928] (In the case of tert-butoxycarbonyl (Boc))

[0929] This is a step of obtaining compound (C-II) by reacting compound (CI) containing an amino group protected by a tert-butoxycarbonyl group with an acid.

[0930] Examples of the acid include hydrochloric acid, hydrogen chloride-1,4-dioxane, hydrogen chloride-ethyl acetate, trifluoroacetic acid, and p-toluenesulfonic acid.

[0931] Examples of the solvent include methanol, ethanol, tetrahydrofuran, dichloromethane, water, and mixtures thereof.

[0932] The reaction temperature is usually about 0 to 100°C, and the reaction time is usually about 0.5 to 24 hours.

[0933] (In the case of benzyl (Bn))

[0934] This is a step of obtaining compound (C-II) by reacting compound (CI) containing an amino group protected by a benzyl group using a transition metal catalyst in the presence or absence of an acid under a hydrogen atmosphere.

[0935] This step can be performed in the same manner as in (Step B1).

[0936] [D Method]

[0937] Method D is a method for producing compound (D-III).

[0938] [Chemical Formula 42]

[0939]

[0940] [Where R 1 、R 2 and R 3 It has the same meaning as that of the compound of the above formula (1), and P a1 Means the same as above.]

[0941] (D1 step) step of forming a thiazole ring

[0942] (When using sulfur)

[0943] This is a step of obtaining compound (D-II) by reacting compound (DI) with a base, sulfur, cyanamide, and an acid.

[0944] Examples of the base include pyrrolidine, piperidine, diethylamine, and pyridine.

[0945] Examples of the acid include hydrochloric acid-1,4-dioxane and p-toluenesulfonic acid.

[0946] Examples of the solvent include methanol, ethanol, isopropanol, and toluene.

[0947] The reaction temperature is usually about 0 to 130° C., and the reaction time is usually about 0.5 to 24 hours.

[0948] (When using thiourea)

[0949] This is a step of obtaining compound (D-II) by reacting compound (DI) using a halogenating agent and thiourea in the presence or absence of a base.

[0950] Examples of the halogenating agent include N-bromosuccinimide, bromine, bromo-1,4-dioxane complex, pyridinium bromide perbromide, iodine, and N-iodosuccinimide.

[0951] Examples of the base include sodium hydrogen carbonate and the like.

[0952] Examples of the solvent include chloroform, ethanol, and mixtures thereof.

[0953] The reaction temperature is usually about 0 to 100°C, and the reaction time is usually about 0.5 to 24 hours.

[0954] (D2 step) Deprotection step

[0955] (In the case of tert-butoxycarbonyl (Boc))

[0956] This is a step of obtaining compound (D-III) by reacting compound (D-II) containing an amino group protected by a tert-butoxycarbonyl group with an acid.

[0957] Examples of the acid include hydrochloric acid, hydrogen chloride-1,4-dioxane, hydrogen chloride-ethyl acetate, trifluoroacetic acid, and p-toluenesulfonic acid.

[0958] Examples of the solvent include methanol, ethanol, tetrahydrofuran, dichloromethane, water, and mixtures thereof.

[0959] The reaction temperature is usually about 0 to 100°C, and the reaction time is usually about 0.5 to 24 hours.

[0960] [E-Law]

[0961] Method E is a method for producing compound (E-IV).

[0962] [Chemical Formula 43]

[0963]

[0964] [Where R 1 and R 2 It has the same meaning as that of the compound of the above formula (1), and P a1 Means the same as above, P a2 Indicates that P a1 independently selected commonly used amino protecting groups.]

[0965] (Step E1) Step of forming a thiazole ring

[0966] This is a step of obtaining compound (E-II) from compound (EI).

[0967] This step can be performed by the same method as (step D1).

[0968] (E2 process) Protection process

[0969] (In the case of carbamate group)

[0970] This is a step of reacting compound (E-II) with a base and a carbamate-forming agent to obtain compound (E-III).

[0971] This step can be performed by the same method as (Step B2).

[0972] In this step, the carbamate group refers to a carbamate group generally used as a protecting group for an amino group in synthesis, such as tert-butoxycarbonyl (Boc), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), allyloxycarbonyl (Alloc), and benzyloxycarbonyl (Cbz).

[0973] (In the case of acyl group)

[0974] This is a step of obtaining compound (E-III) by reacting compound (E-II) using a base and an acylating agent.

[0975] In this step, the acyl group refers to an acyl group generally used as a protecting group for an amino group in synthesis, such as an acetyl group, a trifluoroacetyl group, and a benzoyl group.

[0976] Examples of the base include triethylamine, diisopropylethylamine, pyridine, and 4-dimethylaminopyridine.

[0977] Examples of the acylating agent include acid chlorides and acid anhydrides.

[0978] Examples of the solvent include tetrahydrofuran, dichloromethane, and N,N-dimethylformamide.

[0979] The reaction temperature is usually about 0 to 80°C, and the reaction time is usually about 0.5 to 24 hours.

[0980] (E3 step) Deprotection step

[0981] (In the case of tert-butoxycarbonyl (Boc))

[0982] This is a step of obtaining compound (E-IV) by reacting compound (E-III) containing an amino group protected by a tert-butoxycarbonyl group with an acid.

[0983] This step can be performed by the same method as (Step C1).

[0984] (In the case of 2-(trimethylsilyl)ethoxycarbonyl (Teoc))

[0985] This is a step of obtaining compound (E-IV) by reacting compound (E-III) containing an amino group protected by a 2-(trimethylsilyl)ethoxycarbonyl group using a desilylation agent or an acid.

[0986] Examples of the desilylation agent include tetrabutylammonium fluoride (TBAF), hydrogen fluoride, and pyridine hydrogen fluoride.

[0987] Examples of the acid include hydrochloric acid, sulfuric acid, hydrochloric acid-methanol, hydrochloric acid-1,4-dioxane, hydrochloric acid-ethyl acetate, acetic acid, p-toluenesulfonic acid, and trifluoroacetic acid. In this case, the reaction can be carried out in a catalytic amount.

[0988] Examples of the solvent include methanol, ethanol, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile, water, and mixtures thereof.

[0989] The reaction temperature is usually about 0 to 60°C, and the reaction time is usually about 0.5 to 24 hours.

[0990] [F Method]

[0991] Method F is a method for producing compound (F-IV).

[0992] [Chemical Formula 44]

[0993]

[0994] [Where R 1 、R 2 、R 6 and R 7 It has the same meaning as that of the compound of the above formula (1), and P a1 Means the same as above.]

[0995] (F1 step) step of forming a thiazole ring

[0996] This is a step of obtaining compound (F-II) from compound (FI).

[0997] This step can be performed by the same method as (step D1).

[0998] (F2 step) urea-forming step

[0999] This is a step of obtaining compound (F-III) by reacting compound (F-II) with a ureidating reagent, a corresponding amine or its hydrochloride in the presence or absence of a base.

[1000] Examples of the ureidating agent include carbonyldiimidazole, triphosgene, phenyl chloroformate, and 4-nitrophenyl chloroformate.

[1001] Examples of the base include triethylamine and diisopropylethylamine.

[1002] Examples of the solvent include N,N-dimethylformamide, dichloromethane, and tetrahydrofuran.

[1003] The reaction temperature is usually about 0 to 60°C, and the reaction time is usually about 1 to 48 hours.

[1004] (F3 step) Deprotection step

[1005] This is a step of obtaining compound (F-IV) from compound (F-III).

[1006] This step can be performed by the same method as (Step E3).

[1007] [G Method]

[1008] Method G is a method for producing compound (G-VI).

[1009] [Chemical Formula 45]

[1010]

[1011] [Where R 6 and R 7 It has the same meaning as that of the compound of the above formula (1), and P a1 Means the same as above.

[1012] R 1’ With R 2’ They bond to each other to form a substituent, and represent the following groups.

[1013] [Chemical Formula 46]

[1014]

[1015] P a3 Indicates that P a1 、P a2 Commonly used amino protecting groups are independently selected.

[1016] R 1” With R 2” They bond to each other to form a substituent and represent the following groups.

[1017] [Chemical Formula 47]

[1018]

[1019] R 1”’ With R 2”’ They bond to each other to form a substituent, and represent the following groups.

[1020] [Chemical Formula 48]

[1021]

[1022] R12 represents a C1-C6 alkyl group, a hydroxy C1-C6 alkyl group, a C1-C6 alkylcarbonyl group, or a C1-C6 alkoxycarbonyl group.]

[1023] (Step G1) Step of forming a thiazole ring

[1024] This is a step of obtaining compound (G-II) from compound (GI).

[1025] This step can be performed by the same method as (step D1).

[1026] (G2 step) urea-forming step

[1027] This is a step of obtaining compound (G-III) from compound (G-II).

[1028] This step can be performed by the same method as (F2 step).

[1029] (Step G3) Deprotection

[1030] This is a step of obtaining compound (G-IV) from compound (G-III).

[1031] This step can be performed by the same method as (Step E3).

[1032] (Step G4) Amino-modification step

[1033] (In the case of urethane)

[1034] This is a step of obtaining compound (GV) by reacting compound (G-IV) using a base and a carbamate-forming agent.

[1035] Examples of the base include triethylamine, diisopropylethylamine, sodium hydrogen carbonate, and 4-dimethylaminopyridine.

[1036] Examples of the urethanizing agent include chloroformates and dicarbonic acid diesters.

[1037] Examples of the solvent include tetrahydrofuran, dichloromethane, and N,N-dimethylformamide.

[1038] The reaction temperature is usually about 0 to 80°C, and the reaction time is usually about 0.5 to 24 hours.

[1039] (In the case of acylation)

[1040] This is a step of obtaining compound (GV) by reacting compound (G-IV) with a base and an acylating agent.

[1041] Examples of the base include triethylamine, diisopropylethylamine, pyridine, and 4-dimethylaminopyridine.

[1042] Examples of the acylating agent include acid chlorides and acid anhydrides.

[1043] Examples of the solvent include tetrahydrofuran, dichloromethane, and N,N-dimethylformamide.

[1044] The reaction temperature is usually about 0 to 80°C, and the reaction time is usually about 0.5 to 24 hours.

[1045] (In the case of alkylation)

[1046] (When using a haloalkyl group)

[1047] This is a step of obtaining compound (GV) by reacting compound (G-IV) with a corresponding alkylating agent in the presence of a base.

[1048] Examples of the alkylating agent include alkyl halides such as alkyl iodide and alkyl bromide, and sulfonic acid esters such as alkyl tosylate and alkyl methanesulfonate.

[1049] Examples of the base include triethylamine, diisopropylethylamine, and potassium carbonate.

[1050] Examples of the solvent include tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, etc. The reaction temperature is usually about 0 to 100° C., and the reaction time is usually about 0.5 to 24 hours.

[1051] (In the case of using reductive amination reaction)

[1052] This is a step of obtaining compound (GV) by reacting compound (G-IV) with a corresponding aldehyde using a reducing agent in the presence or absence of an acid.

[1053] Examples of the reducing agent include sodium triacetoxyborohydride and sodium cyanoborohydride.

[1054] Examples of the acid include acetic acid, tetraisopropyl orthotitanate, and zinc chloride.

[1055] Examples of the solvent include methanol, acetonitrile, tetrahydrofuran, dichloromethane, and mixtures thereof.

[1056] The reaction temperature is usually about 0 to 80°C, and the reaction time is usually about 0.5 to 24 hours.

[1057] (G5 step) Deprotection step

[1058] This is a step of obtaining compound (G-VI) from compound (GV).

[1059] This step can be performed by the same method as (Step E3).

[1060] For convenience, the following production methods, such as Method H, Method I, Method J, Method K, Method L, Method M, Method N, Method X, Method Y, and Method Z, are described using the following compounds as starting materials.

[1061] [Chemical Formula 49]

[1062]

[1063] [Where R 1 、R 2 、R 6 and R 7 It has the same meaning as in the case of the compound of the above formula (1).]

[1064] However, in each of Method H, Method I, Method J, Method K, Method L, Method M, Method N, Method X, Method Y, and Method Z, the desired compound of the present invention can be obtained by appropriately using the following necessary compounds as starting materials.

[1065] [Chemical Formula 50]

[1066]

[1067] [Where R 1 、R 2 and R 3 It has the same meaning as that of the compound of the above formula (1), and P a2 Means the same as above.]

[1068] [H Method]

[1069] Method H is a method for producing compound (H-II) of the present invention.

[1070] [Chemical Formula 51]

[1071]

[1072] [Where R 1 、R 2 、R 6 、R 7 , Q and Y have the same meanings as in the compound of the above formula (1).]

[1073] (H1 step) coupling step with a heterocycle

[1074] This is a step of obtaining compound (H-II) by reacting compound (HI) using QY-Cl in the presence of a base.

[1075] Examples of the base include triethylamine, diisopropylethylamine, sodium hydrogen carbonate, and potassium carbonate.

[1076] Examples of the solvent include N,N-dimethylformamide and dimethyl sulfoxide.

[1077] The reaction temperature is usually about 0 to 140° C., and the reaction time is usually about 0.5 to 48 hours.

[1078] [I method]

[1079] Method I is a method for producing compound (I-II) of the present invention.

[1080] [Chemical Formula 52]

[1081]

[1082] [Where R 1 、R 2 、R 6 、R 7 and Q have the same meanings as in the case of the compound of formula (1).]

[1083] (Step I1) Step of coupling with a heterocycle

[1084] This is a step of obtaining compound (I-II) by reacting compound (II) with a condensing agent in the presence of a base.

[1085] Examples of the base include triethylamine and diisopropylethylamine.

[1086] Examples of the condensing agent include phosphazene chloride (trimer) and the like.

[1087] Examples of the solvent include N,N-dimethylformamide and dimethyl sulfoxide.

[1088] The reaction temperature is usually about 0 to 140° C., and the reaction time is usually about 0.5 to 48 hours.

[1089] [J Method]

[1090] Method J is a method for producing compound (J-III) of the present invention.

[1091] [Chemical Formula 53]

[1092]

[1093] [Where R 1 、R 2 、R 6 、R 7 and Q have the same meanings as in the case of the compound of formula (1).]

[1094] (J1 step) cyanamidation step

[1095] This is a step of obtaining compound (J-II) by reacting compound (JI) with a cyanogen halide in the presence or absence of a base.

[1096] Examples of the base include triethylamine, diisopropylethylamine, sodium hydrogen carbonate, and potassium carbonate.

[1097] Examples of the solvent include acetonitrile, acetone, dichloromethane, and tetrahydrofuran.

[1098] The reaction temperature is usually about 0°C to room temperature, and the reaction time is usually about 0.5 to 48 hours.

[1099] (J2 process) looping process

[1100] This is a step of obtaining compound (J-III) by reacting compound (J-II) using a metal halide, an acid, and the corresponding amide oxime.

[1101] Examples of the metal halide include zinc chloride and zinc bromide.

[1102] Examples of the acid include p-toluenesulfonic acid, sulfuric acid, and hydrochloric acid.

[1103] Examples of the solvent include diethyl ether, tetrahydrofuran, ethyl acetate, ethanol, water, and mixtures thereof.

[1104] The reaction temperature is usually about 0 to 100°C, and the reaction time is usually about 0.5 to 48 hours.

[1105] [K Method]

[1106] Method K is a method for producing the compound (KV) of the present invention.

[1107] [Chemical Formula 54]

[1108]

[1109] [Where R 1 、R 2 、R 6 、R 7 and Q have the same meanings as in the case of the compound of formula (1), R k1 represents a phenoxy group or an imidazolyl group which may have a substituent.]

[1110] (K1 step) a step of carbonylation

[1111] This is a step of obtaining compound (K-II) by reacting compound (KI) with a carbonylating agent in the presence of a base.

[1112] Examples of the base include triethylamine, diisopropylethylamine, and sodium hydrogen carbonate.

[1113] Examples of the carbonylating agent include carbonyldiimidazole, phenyl chloroformate, and 4-nitrophenyl chloroformate.

[1114] Examples of the solvent include tetrahydrofuran, dichloromethane, water, and mixtures thereof.

[1115] The reaction temperature is usually about 0°C to room temperature, and the reaction time is usually about 0.5 to 24 hours.

[1116] (K2 step) Amidation step using hydrazine

[1117] This is a step of obtaining compound (K-III) by reacting compound (K-II) with hydrazine hydrate in the presence or absence of a base.

[1118] Examples of the base include triethylamine, diisopropylethylamine, and dimethylaminopyridine.

[1119] Examples of the solvent include ethanol, tetrahydrofuran, acetonitrile, and mixtures thereof.

[1120] The reaction temperature is usually room temperature to about 100°C, and the reaction time is usually about 1 to 24 hours.

[1121] (K3 step) a step of amidating hydrazide

[1122] (When using corresponding carboxylic acid and condensing agent)

[1123] This is a step of reacting compound (K-III) with a condensing agent and the corresponding carboxylic acid in the presence of a base to obtain compound (K-IV).

[1124] Examples of the condensing agent include O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholine (DMT-MM), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSC or EDCI), and 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent).

[1125] Examples of the base include triethylamine, diisopropylethylamine, and dimethylaminopyridine.

[1126] As additives, N-hydroxysuccinimide (HOSu), 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), etc. Additives may make the reaction proceed smoothly.

[1127] Examples of the solvent include tetrahydrofuran, N,N-dimethylformamide, dichloromethane, and mixed solvents thereof.

[1128] The reaction temperature is usually about 0°C to room temperature, and the reaction time is usually about 0.5 to 24 hours.

[1129] (From the corresponding carboxylic acid via the acid chloride)

[1130] This is a step of obtaining compound (K-IV) by reacting compound (K-III) with a carboxylic acid chloride (which is prepared from the corresponding carboxylic acid using a dehydrating chlorination agent) in the presence of a base.

[1131] Examples of the dehydrating chlorinating agent include oxalyl chloride, thionyl chloride, sulfuryl chloride, and phosphorus pentachloride.

[1132] Examples of the base include triethylamine, diisopropylethylamine, pyridine, and dimethylaminopyridine.

[1133] Examples of the solvent include tetrahydrofuran, dichloromethane, N,N-dimethylformamide, and mixed solvents thereof.

[1134] The reaction temperature is usually about 0 to 100°C, and the reaction time is usually about 0.5 to 24 hours.

[1135] (When using the corresponding acid chloride)

[1136] This is a step of obtaining compound (K-IV) by reacting compound (K-III) with the corresponding carboxylic acid chloride in the presence of a base.

[1137] Examples of the base include triethylamine, diisopropylethylamine, pyridine, and dimethylaminopyridine.

[1138] Examples of the solvent include tetrahydrofuran, dichloromethane, N,N-dimethylformamide, and mixed solvents thereof.

[1139] The reaction temperature is usually about 0 to 100°C, and the reaction time is usually about 0.5 to 24 hours.

[1140] (K4 process) Ring forming process

[1141] This is a step of obtaining compound (KV) by reacting compound (K-IV) using a dehydrating agent.

[1142] Examples of the dehydrating agent include (methoxycarbonylsulfamoyl)triethylammonium hydroxide intramolecular salt and p-toluenesulfonyl chloride.

[1143] Examples of the solvent include toluene, acetonitrile, and dichloromethane.

[1144] The reaction temperature is usually about 0 to 100°C, and the reaction time is usually about 0.5 to 24 hours.

[1145] [L method]

[1146] Method L is a method for producing compound (LV) of the present invention.

[1147] [Chemical Formula 55]

[1148]

[1149] [Where R 1 、R 2 、R 6 、R 7 and Q have the same meanings as in the case of the compound of formula (1).]

[1150] (L1 step) thiourea-forming step

[1151] This is a step of obtaining compound (L-II) by reacting compound (LI) with 1,1'-thiocarbonyldiimidazole in the presence or absence of a base.

[1152] Examples of the base include triethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene, and sodium carbonate.

[1153] Examples of the solvent include tetrahydrofuran, dichloromethane, N,N-dimethylformamide, acetonitrile, water, and mixtures thereof.

[1154] The reaction temperature is usually about 0°C to 80°C, and the reaction time is usually about 0.5 to 24 hours.

[1155] (L2 step) Amidation step using hydrazine

[1156] This is a step of obtaining compound (L-III) by reacting compound (L-II) with hydrazine hydrate in the presence or absence of a base.

[1157] Examples of the base include triethylamine, diisopropylethylamine, and dimethylaminopyridine.

[1158] Examples of the solvent include ethanol, tetrahydrofuran, acetonitrile, and mixtures thereof.

[1159] The reaction temperature is usually room temperature to about 100°C, and the reaction time is usually about 1 to 24 hours.

[1160] (Step L3) A step of amidating thiocarbohydrazide

[1161] This is a step of obtaining compound (L-IV) from compound (L-III).

[1162] This step can be performed by the same method as (K3 step).

[1163] (L4 process) Looping process

[1164] (When using a condensing agent)

[1165] This is a step of obtaining compound (LV) by reacting compound (L-IV) with a condensing agent in the presence or absence of a base.

[1166] Examples of the condensing agent include 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSC or EDCI) and 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent).

[1167] Examples of the base include triethylamine, diisopropylethylamine, and dimethylaminopyridine.

[1168] Examples of the solvent include dimethyl sulfoxide, tetrahydrofuran, N,N-dimethylformamide, and mixed solvents thereof.

[1169] The reaction temperature is usually room temperature to about 100°C, and the reaction time is usually about 0.5 to 24 hours.

[1170] (When using a dehydrating agent)

[1171] This is a step of obtaining compound (LV) by reacting compound (L-IV) using a dehydrating agent.

[1172] Examples of the dehydrating agent include (methoxycarbonylsulfamoyl)triethylammonium hydroxide intramolecular salt and p-toluenesulfonyl chloride.

[1173] Examples of the solvent include toluene, acetonitrile, and dichloromethane.

[1174] The reaction temperature is usually about 0 to 100°C, and the reaction time is usually about 0.5 to 24 hours.

[1175] [M Method]

[1176] Method M is a method for producing the compound (M-II) of the present invention.

[1177] [Chemical Formula 56]

[1178]

[1179] [Where R 1 、R 2 、R 6 、R 7 and Q have the same meanings as in the case of the compound of formula (1).]

[1180] (M1 process) looping process

[1181] This is a step of obtaining compound (M-II) by reacting compound (MI) with 1,1-dibromoformaldehyde oxime and the corresponding alkyne in the presence of a base.

[1182] Examples of the base include triethylamine and diisopropylethylamine.

[1183] Examples of the solvent include tetrahydrofuran, N,N-dimethylformamide, and mixtures thereof.

[1184] The reaction temperature is usually about 0°C to room temperature, and the reaction time is usually about 0.5 to 48 hours.

[1185] [X Law]

[1186] Method X is a method for producing compound (X-VI) of the present invention.

[1187] [Chemical Formula 57]

[1188]

[1189] [Where R 1 、R 2 、R 6 、R 7 , Q represents the same meaning as in the case of the compound of the above general formula (1), Ph represents a phenyl group, Imd represents an imidazolyl group, R x1 Indicates OPh or Imd.]

[1190] (X1 step) coupling step

[1191] This is a step of obtaining compound (X-II) by reacting compound (XI) with 1,1'-thiocarbonyldiimidazole or phenylchlorothioformate in the presence of a base.

[1192] Examples of the base include sodium tert-butoxide and lithium bis(trimethylsilyl)amide.

[1193] Examples of the solvent include tetrahydrofuran, N,N-dimethylformamide, and mixtures thereof.

[1194] The reaction temperature is usually about 0°C to 60°C, and the reaction time is usually about 0.5 to 24 hours.

[1195] (X2 step) coupling step

[1196] This is a step of obtaining compound (X-IV) by subjecting compound (X-II) to a coupling reaction using compound (X-III) in the presence or absence of a base.

[1197] Examples of the base include triethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene, and sodium carbonate.

[1198] Examples of the solvent include tetrahydrofuran, N,N-dimethylformamide, ethanol, and mixtures thereof.

[1199] The reaction temperature is usually about 0°C to 100°C, and the reaction time is usually about 0.5 to 24 hours.

[1200] (X3 step) methylation step

[1201] This is a step of obtaining compound (XV) by reacting compound (X-IV) with a methylating agent in the presence of a base.

[1202] Examples of the methylating agent include methyl iodide and dimethyl sulfate.

[1203] Examples of the base include triethylamine, diisopropylethylamine, and potassium carbonate.

[1204] Examples of the solvent include tetrahydrofuran, acetonitrile, N,N-dimethylformamide, and mixtures thereof.

[1205] The reaction temperature is usually about 0 to 100°C, and the reaction time is usually about 0.5 to 24 hours.

[1206] (X4 step) Cyclization step

[1207] This is a step of obtaining compound (X-VI) by reacting compound (XV) with hydroxylamine or its hydrochloride in the presence or absence of a base.

[1208] Examples of the base include triethylamine, sodium acetate, and sodium bicarbonate.

[1209] Examples of the solvent include methanol, ethanol, water, and mixed solvents thereof.

[1210] The reaction temperature is usually room temperature to about 100°C, and the reaction time is usually about 0.5 to 24 hours.

[1211] [N method]

[1212] Method N is a method for producing compound (N-III) of the present invention.

[1213] [Chemical Formula 58]

[1214]

[1215] [Where R 1 、R 2 、R 6 、R 7 and Q have the same meanings as in the case of the compound of formula (1).]

[1216] (N1 step) urea-forming step

[1217] A step of obtaining compound (N-II) from compound (NI).

[1218] This step can be performed by the same method as (F2 step).

[1219] (N2 process) Ring forming process

[1220] This is a step of obtaining compound (N-III) by reacting compound (N-II) with a dehydrating agent in the presence or absence of a base.

[1221] Examples of the dehydrating agent include trifluoroacetic anhydride and phosphorus oxychloride.

[1222] Examples of the base include triethylamine, diisopropylethylamine, and dimethylaminopyridine.

[1223] Examples of the solvent include dichloromethane, tetrahydrofuran, and the like, and no solvent may be used.

[1224] The reaction temperature is usually about 0 to 100°C, and the reaction time is usually about 0.5 to 24 hours.

[1225] [Y method]

[1226] Method Y is a method for producing compound (Y-II) of the present invention.

[1227] [Chemical Formula 59]

[1228]

[1229] [Where R 1 、R 2 、R 6 、R 7 , Q represents the same meaning as in the case of the compound of the above general formula (1), and Ph represents a phenyl group.]

[1230] (Y1 step) Step of forming a benzoxazole ring

[1231] This is a step of obtaining compound (Y-II) by reacting compound (YI) in the presence of an acid or a base and in the presence of tetramethoxymethane or dichlorodiphenoxymethane.

[1232] Examples of the acid include acetic acid and the like.

[1233] Examples of the base include triethylamine and the like.

[1234] Examples of the solvent include chloroform and toluene.

[1235] The reaction temperature is usually about 0 to 100°C, and the reaction time is usually about 0.5 to 48 hours.

[1236] [Z Method]

[1237] The Z method is a method for producing the compound (Z-II) of the present invention.

[1238] [Chemical Formula 60]

[1239]

[1240] [Where R 1 、R 2 、R 6 、R 7 , Q represents the same meaning as in the case of the compound of the above general formula (1), and LG represents a leaving group.]

[1241] (Step Z1) A step of carrying out a coupling reaction using a transition metal catalyst

[1242] This is a step of obtaining compound (Z-II) by reacting compound (ZI) using a copper or palladium catalyst in the presence or absence of a base and a ligand.

[1243] Examples of the copper catalyst include copper iodide, copper chloride, copper acetate, and copper sulfate.

[1244] Examples of the palladium catalyst include tetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium, palladium acetate, and bis(triphenylphosphine)palladium dichloride.

[1245] Examples of the base include triethylamine, diisopropylethylamine, potassium carbonate, and cesium carbonate.

[1246] Examples of the solvent include tetrahydrofuran, 1,4-dioxane, water, N,N-dimethylformamide, dimethyl sulfoxide, toluene, and mixtures thereof.

[1247] The reaction temperature is usually room temperature to about 150°C, and the reaction time is usually about 0.5 to 48 hours.

[1248] [O method]

[1249] Method O is a method for producing compound (O-III) of the present invention.

[1250] [Chemical Formula 61]

[1251]

[1252] [Where R 1 、R 2 、R 6 、R 7 , Q and Y have the same meanings as in the case of the compound of the above formula (1).]

[1253] (O1 step) step of forming a thiazole ring

[1254] This is a step of obtaining compound (O-II) from compound (OI).

[1255] This step can be performed by the same method as (step D1).

[1256] (O2 process) urea process

[1257] This is a step of obtaining compound (O-III) from compound (O-II).

[1258] This step can be performed by the same method as (F2 step).

[1259] [Q method]

[1260] Method Q is a method for producing compound (Q-III) of the present invention.

[1261] [Chemical Formula 62]

[1262]

[1263] [Where R 1 、R 2 、R 6 、R 7 , Q and Y have the same meanings as in the case of the compound of formula (1), P a2 Means the same as above.]

[1264] (Q1 step) Deprotection step

[1265] (In the case of tert-butoxycarbonyl (Boc))

[1266] This is a step of obtaining compound (Q-II) by reacting compound (QI) containing an amino group protected by a tert-butoxycarbonyl group with an acid.

[1267] This step can be performed by the same method as (Step C1).

[1268] (In the case of 2-(trimethylsilyl)ethoxycarbonyl (Teoc))

[1269] This is a step of obtaining compound (Q-II) by reacting compound (QI) containing an amino group protected by a 2-(trimethylsilyl)ethoxycarbonyl group with a desilylation agent or an acid.

[1270] This step can be performed by the same method as (Step E3).

[1271] (In the case of allyloxycarbonyl (Alloc))

[1272] This is a step of obtaining compound (Q-II) by reacting compound (QI) containing an amino group protected by an allyloxycarbonyl group (Alloc) with an amine in the presence of a palladium catalyst and a phosphine ligand.

[1273] Examples of the palladium catalyst include tetrakis(triphenylphosphine)palladium, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium, tris(dibenzylideneacetone)dipalladium, palladium acetate, palladium acetylacetonate, and bis(triphenylphosphine)palladium dichloride.

[1274] Examples of the phosphine ligand used together with the palladium catalyst include 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos), 1,1'-bis(diphenylphosphino)ferrocene (dppf), 2,2'-bis(diphenylphosphino)-1,1-binaphthyl (BINAP), bis(diphenylphosphino)methane (DPPM), triphenylphosphine, and 1,2-bis(diphenylphosphino)ethane (DPPE).

[1275] Examples of the base include diethylamine and morpholine.

[1276] Examples of the solvent include acetonitrile, tetrahydrofuran, dichloromethane, water, and mixtures thereof.

[1277] The reaction temperature is usually room temperature to about 60°C, and the reaction time is usually about 0.5 to 48 hours.

[1278] (In the case of benzyloxycarbonyl (Cbz))

[1279] This is a step of obtaining compound (Q-II) by reacting compound (QI) containing an amino group protected by a benzyloxycarbonyl (Cbz) group using a transition metal catalyst in the presence or absence of an acid under a hydrogen atmosphere.

[1280] Examples of the acid include hydrochloric acid, hydrogen chloride-1,4-dioxane, and hydrogen chloride-ethyl acetate.

[1281] Examples of the transition metal catalyst include palladium-carbon, palladium hydroxide-carbon, and Raney nickel.

[1282] Examples of the solvent include methanol, ethanol, ethyl acetate, chloroform, and mixtures thereof.

[1283] The reaction temperature is usually about 0 to 100°C, and the reaction time is usually about 0.5 to 24 hours.

[1284] (Q2 step) urea-forming step

[1285] This is a step of obtaining compound (Q-III) from compound (Q-II).

[1286] This step can be performed by the same method as (F2 step).

[1287] [R method]

[1288] Method R is a method for producing compound (R-II) of the present invention.

[1289] [Chemical Formula 63]

[1290]

[1291] [Where R 1 、R 2 、R 67-1 、R 67-2 , Q and Y have the same meanings as in the case of the compound of the above formula (1).]

[1292] (R1 step) step of forming a hydantoin ring

[1293] This is a process for obtaining compound (R-II) from compound (RI) by reacting with a ureidating reagent, a corresponding amine or its hydrochloride in the presence or absence of a base.

[1294] Examples of the ureidating agent include carbonyldiimidazole, triphosgene, phenyl chloroformate, and 4-nitrophenyl chloroformate.

[1295] Examples of the base include triethylamine and diisopropylethylamine.

[1296] Examples of the solvent include N,N-dimethylformamide, dichloromethane, and tetrahydrofuran.

[1297] The reaction temperature is usually about 0 to 100°C, and the reaction time is usually about 1 to 48 hours.

[1298] [S method]

[1299] Method S is a method for producing compound (S-III) of the present invention.

[1300] [Chemical Formula 64]

[1301]

[1302] [Where R 1 、R 2 、R 67-1 、R 67-2 , Q and Y have the same meanings as in the case of the compound of formula (1), R s1 represents a C1-C6 alkyl group.]

[1303] (S1 step) urea-forming step

[1304] This is a step of obtaining compound (S-II) from compound (SI).

[1305] This step can be performed by the same method as (F2 step).

[1306] (S2 step) looping step

[1307] This is a step of obtaining compound (S-III) from compound (S-II) using a condensing agent in the presence or absence of a base.

[1308] Examples of the condensing agent include 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSC or EDCI) and 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent).

[1309] Examples of the base include triethylamine, diisopropylethylamine, and dimethylaminopyridine.

[1310] Examples of the solvent include N,N-dimethylformamide, tetrahydrofuran, and mixed solvents thereof.

[1311] The reaction temperature is usually room temperature to about 100°C, and the reaction time is usually about 0.5 to 24 hours.

[1312] [T Method]

[1313] Method T is a method for producing the compound (T-IV) of the present invention.

[1314] [Chemical Formula 65]

[1315]

[1316] [Where R 1 、R 2 、R 67-1 、R 67-2, Q and Y have the same meanings as in the case of the compound of formula (1), P a4 represents a commonly used amino protecting group.]

[1317] (T1 step) Amidation step

[1318] This is a step of reacting compound (TI) with a condensing agent and a corresponding amino acid in the presence of a base to obtain compound (T-II).

[1319] Examples of the condensing agent include O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholine (DMT-MM), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSC or EDCI), and 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent).

[1320] Examples of the base include triethylamine, diisopropylethylamine, and dimethylaminopyridine.

[1321] As additives, N-hydroxysuccinimide (HOSu), 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), etc. Additives may make the reaction proceed smoothly.

[1322] Examples of the solvent include tetrahydrofuran, N,N-dimethylformamide, dichloromethane, and mixed solvents thereof.

[1323] The reaction temperature is usually about 0°C to room temperature, and the reaction time is usually about 0.5 to 24 hours.

[1324] (T2 step) Deprotection step

[1325] (In the case of tert-butoxycarbonyl (Boc))

[1326] This is a step of obtaining compound (T-III) by reacting compound (T-II) containing an amino group protected by a tert-butoxycarbonyl group with an acid.

[1327] This step can be performed by the same method as (Step C1).

[1328] (T3 step) looping step

[1329] This is a step of obtaining compound (T-IV) by reacting compound (T-III) with a ureidating reagent in the presence or absence of a base.

[1330] Examples of the ureidating agent include carbonyldiimidazole and triphosgene.

[1331] Examples of the base include triethylamine and diisopropylethylamine.

[1332] Examples of the solvent include N,N-dimethylformamide, dichloromethane, and tetrahydrofuran.

[1333] The reaction temperature is usually about 0 to 100°C, and the reaction time is usually about 1 to 48 hours.

[1334] The compound produced by the above method can be further isolated and purified by known methods such as extraction, precipitation, distillation, chromatography, fractional recrystallization, and recrystallization.

[1335] In addition, when a compound or an intermediate produced has a chiral carbon, optical isomers exist. These optical isomers can be separated and purified by conventional methods such as fractional recrystallization with an appropriate salt (salt resolution) and column chromatography. References for methods of resolving optical isomers from racemates include "Enantiomers, Racemates and Resolution, John Wiley and Sons, Inc." by J. Jacques et al.

[1336] (Giving method)

[1337] Administration can be any of the following forms: oral administration based on tablets, pills, capsules, granules, powders, liquids, etc., or non-oral administration based on injections for intra-articular, intravenous, intramuscular, etc., suppositories, eye drops, eye ointments, transdermal liquids, ointments, transdermal patches, transmucosal liquids, transmucosal patches, inhalants, etc.

[1338] As a solid composition for oral administration,

[1339] Tablets, powders, granules, etc. can be used. Such solid compositions contain one or more active ingredients and at least one inactive excipient, such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinyl pyrrolidone and / or magnesium aluminum metasilicate, etc. Inactive additives such as lubricants such as magnesium stearate, disintegrants such as sodium carboxymethyl starch, stabilizers, and solubilizers can be contained in the solid composition according to conventional methods. Tablets or pills can be coated with a film of a sugar coating, gastric soluble or enteric soluble material as needed.

[1340] As a liquid composition for oral administration,

[1341] Pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or elixirs can be used. Such liquid compositions may contain commonly used inactive diluents, such as purified water or ethanol. In addition to the inactive diluent, the liquid composition may also contain adjuvants such as solubilizers and wetting agents, sweeteners, flavoring agents, aromatics, and preservatives.

[1342] As an injection for parenteral administration,

[1343] Sterile aqueous or non-aqueous solutions, suspensions, or emulsions can be used. Examples of aqueous solvents include distilled water for injection or physiological saline. Examples of non-aqueous solvents include vegetable oils such as propylene glycol, polyethylene glycol, or olive oil, alcohols such as ethanol, or polysorbate 80. Such injection compositions may further include isotonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or cosolvents. These injection compositions can be sterilized, for example, by filtering through a bacteria-retaining filter, adding a bactericide, or irradiating. Alternatively, these injection compositions can be prepared as sterile solid compositions and dissolved or suspended in sterile water or a sterile injection solvent prior to use.

[1344] As an external use agent,

[1345] Ointments, plasters, creams, gels, pastes, sprays, lotions, eye drops, eye ointments, etc. can be used. These external preparations contain commonly used ointment bases, lotion bases, aqueous or non-aqueous liquids, suspensions, emulsions, etc. For example, polyethylene glycol, propylene glycol, white petrolatum, white beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, lauroyl alcohol, sorbitan sesquioleate, etc. can be used as ointment or lotion bases.

[1346] Transmucosal preparations such as inhalants and nasal preparations can be manufactured using solid, liquid, or semisolid preparations according to existing known methods. For example, known excipients, pH regulators, preservatives, surfactants, lubricants, stabilizers, thickeners, etc. can be appropriately added. As a method of administering these transmucosal preparations, suitable devices for inhalation or blowing can be used. For example, known devices such as metered-dose inhalation devices and nebulizers can be used to administer the compound alone or in combination as a powder of a mixture, or in combination with a pharmaceutically acceptable carrier in the form of a solution or suspension. Dry powder inhalers can be used for single or multiple administration, and dry powders or capsules containing powders can be used. Alternatively, suitable expellants can be used. For example, pressurized aerosol sprays using suitable gases such as chlorofluorocarbons, hydrofluorocarbons, or carbon dioxide can be used.

[1347] (Dosage)

[1348] Generally, when administered orally, a daily dose of about 0.001-100 mg / kg per body weight, preferably 0.1-30 mg / kg, more preferably 0.1-10 mg / kg is appropriate, and is administered once or divided into two or more doses. When administered intravenously, a daily dose of about 0.0001-10 mg / kg per body weight is appropriate, and is administered once a day or divided into multiple doses. Alternatively, as a transmucosal agent, about 0.001-100 mg / kg per body weight is administered once a day or divided into multiple doses. The dose can be appropriately determined based on individual circumstances, taking into account symptoms, age, sex, etc.

[1349] (Combination use)

[1350] In the present invention, the drug can be used in combination with therapeutic or preventive agents for various diseases that are believed to be effective. The combination can be administered simultaneously, or administered separately and continuously, or administered at desired intervals. The formulations administered simultaneously can be a combination formulation or a separate formulation.

[1351] (Preparation Example 1) Powder

[1352] 5 g of the compound of the present invention or a salt thereof, 895 g of lactose, and 100 g of corn starch are mixed in a mixer to obtain a powder.

[1353] (Preparation Example 2) Granules

[1354] 5 g of the compound of the present invention or a salt thereof, 865 g of lactose and 100 g of low-substituted hydroxypropyl cellulose were mixed, and then 300 g of a 10% aqueous solution of hydroxypropyl cellulose was added and kneaded. The mixture was granulated with an extrusion granulator and dried to obtain granules.

[1355] (Preparation Example 3) Tablet

[1356] 5 g of the compound of the present invention or a salt thereof, 90 g of lactose, 34 g of corn starch, 20 g of crystalline cellulose, and 1 g of magnesium stearate are mixed in a mixer and then tableted in a tableting machine to obtain tablets.

[1357] (Preparation Example 4) Ointment

[1358] 5 g of the compound of the present invention or its salt was dissolved in a mixture of 50 g of propylene glycol, 50 g of polyethylene glycol, and 50 g of glyceryl monooleate (Capmul GMO-50EP, NF) by heating at 60°C to 80°C. 350 g of white petrolatum was added, and the mixture was stirred at 60°C to 80°C for 15 minutes, followed by slow cooling while stirring to obtain a 1.0% ointment.

[1359] Example

[1360] The pharmacological activities of the compounds of the present invention or pharmaceutically acceptable salts thereof produced in the following examples were confirmed by the following tests.

[1361] (Test Example) Deacetylation Activity Measurement

[1362] Reactions were performed in duplicate using a white 384-well culture plate (Corning, 3824 or PerkinElmer, 6008350), with a final reaction volume of 20.1 μL. As controls for enzyme activity calculation, wells with enzyme added (DMSO(+)) and without enzyme added (DMSO(-)) were set at n = 8. A 100-fold concentration of the test substance (final concentrations, for example: 0.046, 0.14, 0.41, 1.2, 3.7, 11, 33, 100 μM) or 0.1 μL of DMSO was dispensed into the culture plate, followed by the addition of 5 μL of SIRT6 enzyme (manufactured by Daiichi Sankyo RD Novare Co., Ltd., final concentration: 25 ng / mL) diluted in assay buffer (10 mM Tris-HCl, pH 8.0, 0.1% BSA, 0.01% Tween 20, 1 mM DTT, 12.5% ​​glycerol). The enzyme reaction was initiated by adding 5 μL of a mixture of [Lys(Ac)9]-Histone H3(1-21)-NH2, H3K9(Ac), biotin-labeled, amide (AnaSpec, AS-64190, final concentration: 2 nM) and β-nicotinamide adenine dinucleotide (Sigma-Aldrich, N8285-15VL, final concentration: 10 μM) and incubating at room temperature for 30 minutes. A 10 μL mixture of nicotinamide (Sigma-Aldrich, 72340-100G, final concentration: 100 mM) prepared in AlphaLISA Epigenetics Buffer (PerkinElmer, AL008C), AlphaLISA Anti-unmodified Histone H3 Lysine 9 / Lysine 27 (H3K9 / K27) Acceptor Beads (PerkinElmer, AL138, final concentration: 10 μg / mL), and AlphaScreen Streptavidin Donor Beads (PerkinElmer, 6760002, final concentration: 5 μg / mL) was added. The cells were incubated at room temperature for 60 minutes. The reaction was stopped and acetylation was detected. Luminescence intensity was measured using EnVision (PerkinElmer).

[1363] The relative enzyme activity (%) of the test substance was calculated by the following mathematical formula.

[1364] Relative enzyme activity (%) = [(luminescence intensity of the well with test substance added - luminescence intensity of the DMSO(-) well) / (luminescence intensity of the DMSO(+) well - luminescence intensity of the DMSO(-) well)] × 100

[1365] The EC value of the test substance was calculated using the relative enzyme activity (%) value at each concentration and the Sigmoidal dose-response (variable slope) of GraphPad Prism (GraphPad Software). 150 (Indicates the concentration of the compound at which the relative enzyme activity reaches 150%), as shown in Tables 1-1 to 1-5.

[1366] [Table 1-1]

[1367] Example No. <![CDATA[EC 150 (μM)]]> 1 1.7 2 1.6 3 3.4 4 1.2 5 1.5 6 4.5 7 5.7 8 3.6 9 1.2 10 1.0 11 4.3 12 1.4 13 1.3 14 0.94 15 1.1 16 4.2 17 1.8 18 0.95 19 0.60 20 2.6 21 1.5 22 1.3 23 0.19 24 0.19 25 0.81 26 0.81 27 2.1 28 2.1 29 0.69 30 0.18 31 2.5 32 0.27 33 1.6 34 1.9 35 1 36 1.9 37 4.6 38 2 39 2.5 40 3.1

[1368] [Table 1-2]

[1369] 41 2.5 42 1.3 43 1.5 44 2.3 45 0.79 46 2.1 47 0.83 48 1.2 49 1.5 50 1.5 51 0.47 52 1.9 53 0.29 54 0.48 55 2.3 56 0.19 57 0.93 58 2.4 59 0.44 60 1.7 61 1.9 62 2.6 63 2.3 64 0.49 65 2.1 66 0.39 67 0.75 68 1 69 0.59 70 0.45 71 0.34 72 0.36 73 0.4 74 0.68 75 0.94 76 1.3 77 0.79 78 0.41 79 1.2 80 0.48

[1370] [Table 1-3]

[1371] 81 1.4 82 1.7 83 0.68 84 0.62 85 0.51 86 0.25 87 2.1 88 1.1 89 2.9 90 2.5 91 0.81 92 3.5 93 0.7 94 1.6 95 2.2 96 1.6 97 1.3 98 2.6 99 1.1 100 2.6 101 1.1 102 0.33 103 1.8 104 1.6 105 2 106 2.4 107 2.3 108 2.4 109 1.4 110 3.7 111 2.2 112 1.4 113 2.6 114 2.4 115 2 116 3.1 117 1 118 1.8 119 2.2 120 2.4

[1372] [Table 1-4]

[1373] 121 2.1 122 1.5 123 0.66 124 0.39 125 2.4 126 1 127 2.1 128 0.43 129 0.38 130 3.7 131 1.4 132 0.39 133 1.4 134 3.5 135 2.1 136 0.34 137 0.36 138 0.46 139 0.36 140 0.16 141 0.58 142 3.3 143 0.62 144 0.61 145 2.2 146 1.9 147 3.3 148 0.95 149 0.45 150 0.43 151 0.78 152 2.7 153 2.1 154 0.82 155 0.51 156 1 157 4.6 158 1.1 159 1.3 160 3.2

[1374] [Table 1-5]

[1375] 161 0.97 162 3.3 163 1.6 164 2.6 165 0.41 166 0.21 167 0.43 168 0.35 169 0.66 170 1.2 171 0.55 172 0.83 173 0.62 174 0.74 175 0.27 176 0.33 177 0.28 178 0.1 179 0.72 180 0.14 181 0.53 182 0.16 183 0.24 184 0.91 185 0.4 186 0.48 187 0.64 188 0.4 189 0.38 190 1.7 191 1.2 192 0.44 193 1.8

[1376] The present invention will be described in further detail below with reference to Examples and Test Examples, but the scope of the present invention is not limited to these Examples.

[1377] In the following examples, nuclear magnetic resonance (hereinafter referred to as 1 H NMR spectra are reported in δ values ​​(ppm) using tetramethylsilane as a standard substance or the chemical shift values ​​of the deuterated solvent used as a reference. The splitting pattern is represented by s for singlets, d for doublets, t for triplets, q for quadruplets, m for multiplets, and br for width.

[1378] (Example 1)

[1379] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-methylurea

[1380] (1a)

[1381] 4,4-Difluorocyclohexane-1-carbonitrile

[1382] 4,4-difluorocyclohexane-1-carbonitrile

[1383] 4-Oxocyclohexane-1-carbonitrile (CAS registration number: 34916-10-4) (1.0 g) was dissolved in dichloromethane (10 mL), and a dichloromethane solution (10 mL) of (diethylamino)sulfur trifluoride (1.6 g) was added at 0°C, followed by stirring at 0°C for 2 hours.

[1384] The reaction mixture was poured into aqueous sodium bicarbonate solution and extracted three times with dichloromethane. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: petroleum ether / ethyl acetate = 20 / 1 (v / v)] to obtain 0.70 g of the title compound as a yellow solid (yield: 50%).

[1385] (1b)

[1386] 4,4-Difluoro-N'-hydroxycyclohexane-1-carboxamidine

[1387] 4,4-difluoro-N'-hydroxycyclohexane-1-carboximidamide

[1388] 4,4-Difluorocyclohexane-1-carbonitrile (0.70 g) obtained in Example 1(1a) was dissolved in tetrahydrofuran (10 mL), and hydroxylamine hydrochloride (0.37 g) and triethylamine (1.24 g) were added, followed by stirring at 65°C for 12 hours.

[1389] The solvent was distilled off from the reaction mixture under reduced pressure, water was added to the resulting residue, and the reaction mixture was extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain 0.50 g of the title compound as a white solid (yield: 69%).

[1390] (1c)

[1391] N-(5-cyano-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)-N'-methylurea

[1392] N-(5-cyano-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)-N'-meth ylurea

[1393] N-Methyl-N'-(4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)urea (International Publication No. 2010 / 024258) (17 g) and sodium bicarbonate (13 g) were dissolved in dichloromethane (500 mL) and water (100 mL). A dichloromethane solution (100 mL) of cyanogen bromide (10 g) was added dropwise at 0°C. The mixture was stirred at 0°C for 2 hours and at room temperature for 13 hours.

[1394] The reaction mixture was poured into water and extracted three times with dichloromethane. The combined organic layers were washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 13.0 g of the title compound as a yellow solid (yield: 68%).

[1395] (1d)

[1396] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-methylurea

[1397] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahy dro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-methylurea

[1398] 4,4-Difluoro-N'-hydroxycyclohexane-1-carboximidamide (150 mg) of Example 1 (1b) was dissolved in N,N-dimethylformamide (5 mL), and N-(5-cyano-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)-N'-methylurea (222 mg) of Example 1 (1c), zinc chloride (34.4 mg), and p-toluenesulfonic acid monohydrate (48.0 mg) were added in sequence at room temperature, and the mixture was stirred at 80°C for 12 hours.

[1399] The reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine and then dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The resulting residue was purified by high-performance liquid chromatography (column: Phenomenex luna C18; mobile phase: acetonitrile / 0.225% formic acid aqueous solution = 30 / 70 to 60 / 40 (v / v)) to obtain 111 mg of the title compound as a white solid (yield: 32%).

[1400] (Example 2)

[1401] N-Methyl-N'-{5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}urea

[1402] (2a)

[1403] N-[5-(1H-imidazole-1-thiocarbonyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl]-N'-methylurea

[1404] N-[5-(1H-imidazole-1-carbothioyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl]-N'-methylurea

[1405] N-Methyl-N'-(4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)urea (International Publication No. 2010 / 024258) (5.0 g) was suspended in tetrahydrofuran (50 mL), 1,1'-thiocarbonyldiimidazole (4.6 g) was added, and the mixture was allowed to stand at room temperature for 2 days.

[1406] The precipitated solid was collected by filtration and washed with tetrahydrofuran to obtain 7.5 g (yield: 99%) of the title compound as a white solid.

[1407] (2b)

[1408] N-[5-(Hydrazinothiocarbonyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl]-N'-methylurea

[1409] N-[5-(hydrazinecarbothioyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyrid in-2-yl]-N'-methylurea

[1410] N-[5-(1H-imidazole-1-thiocarbonyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl]-N'-methylurea (7.5 g) of Example 2(2a) was suspended in ethanol (100 mL), hydrazine monohydrate (3.4 mL) was added, and the mixture was allowed to stand at room temperature overnight.

[1411] The precipitated solid was collected by filtration and washed with ethanol to obtain 5.7 g (yield: 86%) of the title compound as a white solid.

[1412] (2c)

[1413] N-Methyl-N'-{5-[2-(trifluoroacetyl)hydrazinecarbonylthio]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}urea

[1414] N-methyl-N'-{5-[2-(trifluoroacetyl)hydrazinecarbothioyl]-4,5,6,7-tetrah ydro[1,3]thiazolo[5,4-c]pyridin-2-yl}urea

[1415] N-[5-(Hydrazinothiocarbonyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl]-N'-methylurea (6.54 g) of Example 2(2b) was suspended in dichloromethane (30 mL), and trifluoroacetic anhydride (4.80 mL) and trifluoroacetic acid (5.24 mL) were added, followed by stirring at room temperature for 3 hours.

[1416] The reaction solution was concentrated and azeotroped twice with toluene. The obtained solid was triturated with ethyl acetate / n-hexane and collected by filtration to obtain 8.8 g of the title compound as a light yellow solid (yield: quantitative).

[1417] (2d)

[1418] N-Methyl-N'-{5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}urea

[1419] N-methyl-N'-{5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]-4,5,6,7-tetra hydro[1,3]thiazolo[5,4-c]pyridin-2-yl}urea

[1420] N-Methyl-N'-{5-[2-(trifluoroacetyl)hydrazinethiocarbonyl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}urea (8.8 g) of Example 2 (2c) was dissolved in dimethyl sulfoxide (100 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.3 g) was added, and the mixture was stirred at 70°C for 2 hours.

[1421] Water was added to the reaction mixture, and the precipitated solid was filtered and washed with water and ethyl acetate. The resulting solid was suspended in ethyl acetate / ethanol and stirred briefly under heating. The precipitated solid was filtered and recovered while hot to obtain 4.1 g of the title compound as a light yellow solid (yield: 51%).

[1422] (Example 3)

[1423] N-(5-{5-[(1R)-1-ethoxyethyl]-1,3,4-oxadiazol-2-yl}-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)-N'-methylurea

[1424] (3a)

[1425] Methyl (2R)-2-ethoxypropionate

[1426] methyl(2R)-2-ethoxypropanoate

[1427] Methyl D-(+)-lactate (CAS Reg. No.: 17392-83-5) (2.0 g) and iodoethane (5.99 g) were dissolved in diethyl ether (20 mL). Silver oxide (8.90 g) was added at room temperature, and the mixture was stirred at room temperature for 12 hours. Iodoethane (3.00 g) and silver oxide (4.45 g) were further added, and the mixture was stirred at room temperature for 24 hours.

[1428] The reaction mixture was filtered, and the solvent was distilled off from the filtrate under reduced pressure to obtain 1.00 g (yield: 32%) of the title compound as a light yellow oil.

[1429] (3b)

[1430] (2R)-2-Ethoxypropionic acid

[1431] (2R)-2-ethoxypropanoic acid

[1432] Methyl (2R)-2-ethoxypropionate (1.0 g) obtained in Example 3(3a) was dissolved in tetrahydrofuran (6 mL), methanol (6 mL) and water (3 mL), and lithium hydroxide monohydrate (0.79 g) was added, followed by stirring at room temperature for 2 hours.

[1433] The solvent was distilled off from the reaction mixture under reduced pressure, water was added to the resulting residue, and the reaction mixture was washed with ethyl acetate. The pH of the aqueous layer was adjusted to 2 with 1M hydrochloric acid, and extracted five times with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was then distilled off under reduced pressure to obtain 0.60 g of the title compound as a light yellow oil (yield: 67%).

[1434] (3c)

[1435] N-(5-{2-[(2R)-2-ethoxypropionyl]hydrazinecarbonylthioyl}-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)-N'-methylurea

[1436] N-(5-{2-[(2R)-2-ethoxypropanoyl]hydrazinecarbothioyl}-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)-N'-methylurea

[1437] (2R)-2-Ethoxypropionic acid (112 mg) of Example 3 (3b) was dissolved in N,N-dimethylformamide (5 mL), and 4-methylmorpholine (0.208 mL), 1H-benzotriazol-1-yloxytripyrrolidinopyridinium phosphonium hexafluorophosphate (981 mg), and N-[5-(hydrazinethiocarbonyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl]-N'-methylurea (150 mg) of Example 2 (2b) were added at room temperature, and the mixture was stirred at 40°C for 12 hours.

[1438] The solvent was distilled off from the reaction mixture under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluting solvent: ethyl acetate / methanol = 1 / 0-30 / 1 (V / V)] to obtain 110 mg of the title compound as a yellow solid (yield: 60%).

[1439] (3d)

[1440] N-(5-{5-[(1R)-1-ethoxyethyl]-1,3,4-oxadiazol-2-yl}-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)-N'-methylurea

[1441] N-(5-{5-[(1R)-1-ethoxyethyl]-1,3,4-oxadiazol-2-yl}-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)-N'-methylurea

[1442] N-(5-{2-[(2R)-2-ethoxypropanoyl]hydrazinethiocarbonyl}-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)-N'-methylurea (90 mg) of Example 3(3c) was dissolved in dimethyl sulfoxide (3 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (112 mg) was added, and the mixture was stirred at 60°C for 15 minutes.

[1443] The filtrate obtained by filtering the reaction mixture was purified by high performance liquid chromatography [column: Phenomenex Gemini C18; mobile phase: acetonitrile / 0.05% aqueous ammonia = 18 / 82-42 / 58 (V / V)] to obtain 26 mg of the title compound as a light yellow solid (yield: 32%).

[1444] (Example 4)

[1445] N-Methyl-N'-(5-{3-[1-(2,2,2-trifluoroethoxy)ethyl]-1,2,4-oxadiazol-5-yl}-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)urea

[1446] (4a)

[1447] 2-(2,2,2-trifluoroethoxy)propionic acid

[1448] 2-(2,2,2-trifluoroethoxy)propanoic acid

[1449] 2,2,2-Trifluoroethanol (6.54 g) was dissolved in tetrahydrofuran (30 mL), and sodium (601 mg) was added at 0° C. After the sodium dissolved, 2-bromopropionic acid (CAS Reg. No.: 598-72-1) (2.00 g) was added, and the mixture was stirred at 50° C. for 12 hours.

[1450] Water was added to the reaction mixture, and the pH was adjusted to 9 with a 2M aqueous sodium hydroxide solution, followed by washing with ethyl acetate. The pH of the aqueous layer was adjusted to 2 with 2M hydrochloric acid, and extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain 2.20 g (yield: 98%) of the title compound as a colorless oil.

[1451] (4b)

[1452] 2-(2,2,2-trifluoroethoxy)propionamide

[1453] 2-(2,2,2-trifluoroethoxy)propanamide

[1454] Thionyl chloride (10 mL) was added to 2-(2,2,2-trifluoroethoxy)propionic acid (2.2 g) from Example 4(4a), and the mixture was stirred at room temperature for 12 hours. The solvent was distilled off from the reaction mixture under reduced pressure, and the resulting residue was dissolved in tetrahydrofuran (5 mL). Ammonia (4 mol / L tetrahydrofuran solution, 14.7 mL) was added at 0°C, and the mixture was stirred at room temperature for 12 hours.

[1455] The reaction solution was concentrated, and the obtained residue was triturated with ethyl acetate / petroleum ether and filtered to obtain 0.78 g (yield: 36%) of the title compound as a yellow solid.

[1456] (4c)

[1457] 2-(2,2,2-Trifluoroethoxy)propionitrile

[1458] 2-(2,2,2-trifluoroethoxy)propanenitrile

[1459] To 2-(2,2,2-trifluoroethoxy)propionamide (0.58 g) obtained in Example 4(4b) was added thionyl chloride (1.0 mL), and the mixture was stirred at 90°C for 12 hours.

[1460] The solvent was distilled off from the reaction mixture under reduced pressure to obtain 0.52 g (yield: quantitative) of the title compound as a yellow oil.

[1461] (4d)

[1462] N-Methyl-N'-(5-{3-[1-(2,2,2-trifluoroethoxy)ethyl]-1,2,4-oxadiazol-5-yl}-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)urea

[1463] N-methyl-N'-(5-{3-[1-(2,2,2-trifluoroethoxy)ethyl]-1,2,4-oxadiazol-5-yl}-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)urea

[1464] Using N'-hydroxy-2-(2,2,2-trifluoroethoxy)propionitrile of Example 4(4c) synthesized in the same manner as in Example 1(1b) and N-(5-cyano-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)-N'-methylurea (100 mg) of Example 1(1c), 52 mg (yield: 32%) of the title compound were obtained as a white solid by the same method as in Example 1(1d).

[1465] (Example 5)

[1466] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-[(2R)-1-hydroxypropan-2-yl]urea

[1467] (5a)

[1468] tert-Butyl 2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate

[1469] tert-butyl 2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate

[1470] Tert-butyl 2-amino-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate (CAS registration number: 365996-05-0) (10.0 g) and N,N-diisopropylethylamine (19.5 mL) were dissolved in tetrahydrofuran (100 mL), allyl chloroformate (5.90 mL) was added, and the mixture was stirred at room temperature for 12 hours.

[1471] Methanol was added to the reaction mixture, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluting solvent: petroleum ether / ethyl acetate = 3 / 1 (v / v)] to obtain 8.40 g (yield: 67%) of the title compound as a pale yellow solid.

[1472] (5b)

[1473] Propan-2-en-1-yl {5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}carbamate

[1474] prop-2-en-1-yl{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}carbamate

[1475] Using (5-cyano-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)carbamic acid prop-2-en-1-yl ester (282 mg) synthesized in the same manner as in Examples 6(6h) and 1(1c) from tert-butyl 2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate of Example 5(5a), and 4,4-difluoro-N'-hydroxycyclohexane-1-carboximidamide (190 mg) of Example 1(1b), 160 mg (yield: 35%) of the title compound were obtained as a light yellow solid by the same method as in Example 1(1d).

[1476] (5c)

[1477] 5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-amine

[1478] 5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-amine

[1479] Under a nitrogen atmosphere, propylene glycol {5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}carbamate (150 mg) and dimedone (240 mg) of Example 5 (5b) were dissolved in dichloromethane (5 mL), tetrakis(triphenylphosphine)palladium (45 mg) was added, and the mixture was stirred at room temperature for 12 hours.

[1480] The solvent was distilled off from the reaction mixture under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: petroleum ether / ethyl acetate / methanol = 1 / 1 / 0 - 0 / 100 / 1 (V / V / V)] to obtain 100 mg of the title compound as a yellow solid (yield: 66%).

[1481] (5d)

[1482] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-[(2R)-1-hydroxypropan-2-yl]urea

[1483] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahy dro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-[(2R)-1-hydroxypropan-2-yl]urea

[1484] 5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-amine (100 mg) from Example 5(5c) was dissolved in N,N-dimethylformamide (5 mL), and 1,1'-carbonyldiimidazole (95 mg) was added, followed by stirring at room temperature for 5.5 hours. (R)-(-)-2-amino-1-propanol (0.069 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 12 hours.

[1485] The reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by high-performance liquid chromatography (column: Phenomenex Synergi C18; mobile phase: acetonitrile / 0.225% formic acid aqueous solution = 28 / 72 to 58 / 42 (v / v)) to obtain 23 mg of the title compound as a yellow solid (yield: 17%).

[1486] (Example 6)

[1487] N-Methyl-N'-(10-{3-[(1s,4s)-4-(trifluoromethyl)cyclohexyl]-1,2,4-oxadiazol-5-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl)urea

[1488] (6a)

[1489] (1s,4s)-4-(Trifluoromethyl)cyclohexane-1-carboxamide

[1490] (1s,4s)-4-(trifluoromethyl)cyclohexane-1-carboxamide

[1491] (1s,4s)-4-(trifluoromethyl)cyclohexane-1-carboxylic acid (CAS Registry Number: 1202578-27-5) (1.00 g) and triethylamine (1.04 mL) were dissolved in dichloromethane (25 mL), and isobutyl chloroformate (0.87 mL) was added dropwise at 0°C, followed by stirring at 0°C for 1 hour. The reaction mixture was added dropwise to a 28% aqueous ammonia solution (19 mL) at 0°C, and stirred at room temperature for 2 hours.

[1492] The reaction mixture was poured into water and extracted three times with dichloromethane. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 1.04 g of the title compound as a white solid (yield: quantitative).

[1493] (6b)

[1494] (1s,4s)-4-(Trifluoromethyl)cyclohexane-1-carbonitrile

[1495] (1s,4s)-4-(trifluoromethyl)cyclohexane-1-carbonitrile

[1496] (1s,4s)-4-(trifluoromethyl)cyclohexane-1-carboxamide (1.04 g) of Example 6(6a) was suspended in dichloromethane (20 mL), triethylamine (1.41 mL) was added at 0°C, and trifluoroacetic anhydride (0.785 mL) was then added dropwise over 5 minutes, followed by stirring at 0°C for 2 hours.

[1497] The reaction mixture was diluted with water and extracted twice with dichloromethane. The combined organic layers were washed with water and saturated brine, then dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: ethyl acetate / n-hexane = 1 / 4-2 / 1 (v / v)] to obtain 804 mg of the title compound as a white solid (yield: 89%).

[1498] (6c)

[1499] (1s,4s)-N'-Hydroxy-4-(trifluoromethyl)cyclohexane-1-carboximidamide

[1500] (1s,4s)-N'-hydroxy-4-(trifluoromethyl)cyclohexane-1-carboximidamide

[1501] (1s,4s)-4-(trifluoromethyl)cyclohexane-1-carbonitrile (278 mg) obtained in Example 6(6b) was dissolved in ethanol (8 mL), and 50% aqueous hydroxylamine solution (0.15 mL) was added, followed by stirring at 50°C for 3.5 hours.

[1502] The solvent was distilled off from the reaction mixture under reduced pressure, and after azeotroping with ethanol, chloroform and water were added to the residue, stirred, and the organic layer was separated using a phase separator (Biotage Japan Ltd.), and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in ethanol (4 mL), and 50% aqueous hydroxylamine solution (2.0 mL) was added, followed by stirring at 60°C for 4 hours.

[1503] After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and the mixture was azeotroped with ethanol and then dried in vacuo at 50°C to obtain 187 mg of the title compound as a white solid (yield: 57%).

[1504] (6d)

[1505] 9-Benzyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-one

[1506] 9-benzyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-one

[1507] Dissolve 3,6-dioxabicyclo[3.1.0]hexane (CAS Registry Number: 285-69-8) (2.40 kg) in water (12 L), add concentrated sulfuric acid (25.2 g) at 15°C, and stir at 95°C for 16 hours. Cool the reaction mixture to 15°C, and add 3M aqueous sodium hydroxide solution (97 mL) to adjust the pH to 7-8.

[1508] Then, sodium periodate (5.33 kg) was added at 5-10°C over 3 hours, and the mixture was stirred at 10-15°C for 16 hours. Acetonitrile (12 L) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The precipitated solid was filtered off, and the filtrate was concentrated under reduced pressure to distill off most of the acetonitrile.

[1509] Next, 1,3-acetonedicarboxylic acid (4.47 kg), acetonitrile (8 L), and 12M hydrochloric acid (719 mL) were added, cooled to 10°C, and benzylamine (2.98 kg) was added dropwise at 10-30°C. After stirring at 10-20°C for 1 hour, the mixture was stirred at 50°C for 16 hours.

[1510] The precipitated solid was collected by filtration and washed with ethanol (300 mL) to obtain 2.70 kg (yield: 33%) of the title compound as a light yellow solid.

[1511] (6e)

[1512] tert-Butyl 7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate

[1513] tert-butyl 7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate

[1514] Example 6e-1

[1515] 9-Benzyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-one (150 g) from Example 6 (6d) was dissolved in 1 M hydrochloric acid (1.0 L) and ethanol (700 mL). 10% palladium on carbon (20 g) was added, and the mixture was stirred at 50° C. for 20 hours under a hydrogen atmosphere (50 psi). The insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure to distill off most of the ethanol, thereby obtaining a mixture containing 3-oxa-9-azabicyclo[3.3.1]nonan-7-one hydrochloride.

[1516] Example 6e-2

[1517] To the mixture obtained in Example 6e-1, tetrahydrofuran (1.2 L) and sodium bicarbonate (327 g) were added, and the mixture was stirred at room temperature for 1 hour. Then, di-tert-butyl dicarbonate (339 g) was added, and the mixture was stirred at 30-40°C for 16 hours.

[1518] The reaction mixture was filtered, and the filtrate was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was triturated with ethyl acetate / petroleum ether and filtered to obtain 190 g of the title compound as a yellow solid (yield: 61%).

[1519] (6f)

[1520] tert-Butyl 2-amino-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazole-10-carboxylate

[1521] tert-butyl 2-amino-4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4-d][1,3]thiazole-10-carboxylate

[1522] tert-Butyl 7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (300 g) of Example 6 (6e) was dissolved in toluene (1.4 L), and pyrrolidine (146 mL) and p-toluenesulfonic acid monohydrate (30.0 g) were added at room temperature, and the mixture was stirred at 135° C. for 4 hours using a Dean-Stark apparatus.

[1523] The solvent was distilled off from the reaction mixture under reduced pressure, and the obtained residue was dissolved in methanol (1.5 L). Sulfur (43.0 g) and cyanamide (68.0 g) were added, and the mixture was stirred at room temperature for 18 hours.

[1524] The reaction mixture was concentrated under reduced pressure to remove most of the methanol, and dichloromethane was added. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was triturated in ethyl acetate / petroleum ether and filtered to obtain 190 g of the title compound as a yellow solid (yield: 61%).

[1525] (6g)

[1526] tert-Butyl 2-[(Methylcarbamoyl)amino]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazole-10-carboxylate

[1527] tert-butyl 2-[(methylcarbamoyl)amino]-4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4-d][1,3]thiazole-10-carboxylate

[1528] tert-Butyl 2-amino-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazole-10-carboxylate (95 g) of Example 6 (6f) and N,N-diisopropylethylamine (133 mL) were dissolved in tetrahydrofuran (1 L), and N-methylcarbamoyl chloride (57 g) was added dropwise at 0°C, followed by stirring at 60°C for 12 hours.

[1529] The solvent was distilled off from the reaction mixture under reduced pressure, and the resulting residue was triturated in petroleum ether / ethyl acetate, and the precipitated solid was filtered. The resulting solid was dissolved in dichloromethane, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 100 g of the title compound as a yellow solid (yield: 84%).

[1530] (6h)

[1531] N-Methyl-N'-(4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl)urea monohydrochloride

[1532] N-methyl-N'-(4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4-d][1,3]thiazol-2-yl)urea--hydrogen chloride(1 / 1)

[1533] tert-Butyl 2-[(methylcarbamoyl)amino]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazole-10-carboxylate (100 g) from Example 6 (6 g) was dissolved in dichloromethane (1 L), and a 4 M hydrogen chloride-ethyl acetate solution (300 mL) was added, followed by stirring at room temperature for 12 hours.

[1534] The solvent was distilled off under reduced pressure to obtain 83 g of the title compound as a light yellow solid (yield: 95%).

[1535] (6i)

[1536] N-[10-cyano-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]-N'-methylurea

[1537] N-[10-cyano-4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4-d][1,3]thiazol-2-yl]-N'-methylurea

[1538] Using N-methyl-N'-(4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclotriene[5,4-d][1,3]thiazol-2-yl)urea monohydrochloride (2.19 g) from Example 6 (6h), 1.58 g (yield: 75%) of the title compound was obtained as a white solid by the same method as in Example 1 (1c).

[1539] (6j)

[1540] N-Methyl-N'-(10-{3-[(1s,4s)-4-(trifluoromethyl)cyclohexyl]-1,2,4-oxadiazol-5-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl)urea

[1541] N-methyl-N'-(10-{3-[(1s,4s)-4-(trifluoromethyl)cyclohexyl]-1,2,4-oxadiazol-5-yl}-4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4-d][1,3]thiazol-2-yl)urea

[1542] N-[10-cyano-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]-N'-methylurea (120 mg) from Example 6(6i), (1s,4s)-N'-hydroxy-4-(trifluoromethyl)cyclohexane-1-carboximidamide (101 mg) from Example 6(6c), and zinc chloride (77 mg) were suspended in N,N-dimethylformamide (5 mL) and stirred at 60°C for 2 hours under a nitrogen atmosphere. Concentrated sulfuric acid (0.1 mL) was added to the reaction mixture, and the mixture was further stirred at 80°C for 3 hours.

[1543] After cooling to room temperature, the reaction mixture was poured into water and extracted twice with ethyl acetate. The combined organic layers were washed twice with water and once with saturated brine, then dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: ethyl acetate / methanol = 1 / 0 to 9 / 1 (v / v)] to obtain 105 mg of the title compound as a white solid (yield: 52%).

[1544] (Example 7)

[1545] N-{(4S,8S)-10-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-methylurea

[1546] (7a)

[1547] tert-Butyl (4S,8S)-2-amino-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazole-10-carboxylate

[1548] tert-butyl(4S,8S)-2-amino-4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4-d][1,3]thiazole-10-carboxylate

[1549] (Optical resolution using chiral columns)

[1550] 2-Amino-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazole-10-carboxylic acid tert-butyl ester (160 g) of Example 6 (6f) was subjected to chiral SFC (column: CHIRALPAK AD (250mm*30mm, 10μm)) [mobile phase: 0.1% ammonia water / isopropanol / carbon dioxide], 67g (yield: 42%) of (4S,8S)-2-amino-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazole-10-carboxylic acid tert-butyl ester was obtained as a yellow solid (peak 1, retention time: 2.370min). In addition, 69g (yield: 43%) of (4R,8R)-2-[(methylcarbamoyl)amino]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazole-10-carboxylic acid tert-butyl ester was obtained as a yellow solid (peak 2, retention time: 2.573min).

[1551] It should be noted that the absolute configuration of tert-butyl (4S,8S)-2-amino-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazole-10-carboxylate was determined by X-ray crystallography of an intermediate synthesized using this compound (Example 20 (20a)).

[1552] (Optical resolution using diastereomeric salt method)

[1553] To tert-butyl 2-amino-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazole-10-carboxylate (1.0 kg) and (+)-di-p-toluoyl-D-tartaric acid (CAS Reg. No.: 32634-68-7) (580 g) from Example 6(6f) was added ethyl acetate (15 L), and the mixture was stirred at 70°C for 3 hours. The mixture was slowly cooled to room temperature, and the precipitated solid was collected by filtration and washed with ethyl acetate (1 L).

[1554] The obtained solid was added to a 1M aqueous sodium hydroxide solution and extracted three times with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in ethyl acetate (1 L) at 60°C and petroleum ether (1 L) was added. After stirring at 60°C for 0.5 hours, it was slowly cooled to room temperature, the precipitated solid was filtered out, and washed with ethyl acetate / petroleum ether (100 mL / 100 mL) to obtain 285 g of the title compound as a white solid (yield: 29%).

[1555] (7b)

[1556] N-Methyl-N'-[(4S,8S)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]urea hydrochloride

[1557] N-methyl-N'-[(4S,8S)-4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4-d][1,3]thiazol-2-yl]urea--hydrogen chloride(1 / 1)

[1558] Using (4S,8S)-2-[(methylcarbamoyl)amino]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazole-10-carboxylic acid tert-butyl ester (6.0 g) synthesized in the same manner as in Example 6 (6 g) from (4S,8S)-2-amino-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazole-10-carboxylate of Example 7 (7a), 6.0 g (yield: quantitative) of the title compound were obtained as a white solid by the same method as in Example 6 (6h).

[1559] (7c)

[1560] N-{(4S,8S)-10-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-methylurea

[1561] N-{(4S,8S)-10-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4-d][1,3]thiazol-2-yl}-N'-methylurea

[1562] Using N-[(4S,8S)-10-cyano-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]-N'-methylurea (80 mg) synthesized in the same manner as in Example 1(1c) from N-methyl-N'-[(4S,8S)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]urea monohydrochloride of Example 7(7b) and 4,4-difluoro-N'-hydroxycyclohexane-1-carboximidamide (50 mg) of Example 1(1b), 39 mg of the title compound (yield: 32%) was obtained as a white solid by the same method as in Example 1(1d).

[1563] (Example 8)

[1564] N-Methyl-N'-(5-{3-[3-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)urea

[1565] (8a)

[1566] N'-Hydroxy-3-(trifluoromethoxy)benzene-1-carboxamidine

[1567] N'-hydroxy-3-(trifluoromethoxy)benzene-1-carboximidamide

[1568] Using 3-(trifluoromethoxy)benzonitrile (CAS Registry No.: 52771-22-9) (500 mg), the title compound (300 mg, yield: 46%) was obtained as a white solid in the same manner as in Example 1(1b).

[1569] (8b)

[1570] N-Methyl-N'-(5-{3-[3-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)urea

[1571] N-methyl-N'-(5-{3-[3-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)urea

[1572] N-(5-cyano-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)-N'-methylurea (120 mg) from Example 1(1c) and N'-hydroxy-3-(trifluoromethoxy)benzene-1-carboximidamide (167 mg) from Example 8(8a) were dissolved in ethyl acetate (3 mL), and a tetrahydrofuran solution (3 mL) of zinc chloride (124 mg) was added, followed by stirring at 60°C for 15 hours. The solvent was evaporated from the reaction mixture under reduced pressure, and the resulting residue was dissolved in ethanol (3 mL). Concentrated hydrochloric acid (3 mL) was added, and the mixture was stirred at 80°C for 1 hour.

[1573] The solvent was distilled off from the reaction mixture under reduced pressure, methanol was added to the obtained residue, and the precipitated solid was collected by filtration and washed with methanol to obtain 46 mg of the title compound as a white solid (yield: 22%).

[1574] (Example 9)

[1575] N-{5-[5-(4-Fluoro-3-methylphenyl)-1,3,4-oxadiazol-2-yl]-4,5,6,7-tetrahydro[[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-methylurea

[1576] N-{5-[5-(4-fluoro-3-methylphenyl)-1,3,4-oxadiazol-2-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-methylurea

[1577] N-[5-(Hydrazinothiocarbonyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl]-N'-methylurea (0.40 g) of Example 2 (2b) was dissolved in dimethyl sulfoxide (6 mL), and 4-fluoro-3-methylbenzoic acid (0.24 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.80 g) were added, and the mixture was stirred at 60°C for 7 hours.

[1578] Water was added to the reaction mixture, and the precipitated solid was collected by filtration and washed with ethanol and ethyl acetate in that order to obtain 162 mg of the title compound as a brown solid (yield: 30%).

[1579] (Example 10)

[1580] N-{(5R * ,8S *)-9-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-5,6,7,8-tetrahydro-4H-5,8-cycloiminocyclohepta[d][1,3]thiazol-2-yl}-N'-methylurea

[1581] (10a)

[1582] tert-Butyl 2-amino-5,6,7,8-tetrahydro-4H-5,8-cycloiminocyclohepta[d][1,3]thiazole-9-carboxylate

[1583] tert-butyl 2-amino-5,6,7,8-tetrahydro-4H-5,8-epiminocyclohepta[d][1,3]thiazole-9-carboxylate

[1584] tert-Butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (CAS Registry No.: 185099-67-6) (110 g) was dissolved in toluene (500 mL). Pyrrolidine (49 mL) and p-toluenesulfonic acid monohydrate (8.4 g) were added at room temperature, and the mixture was stirred at 130°C for 18 hours using a Dean-Stark apparatus. The solvent was distilled off from the reaction mixture under reduced pressure, and the resulting residue was dissolved in methanol (500 mL) and cooled to 0°C. A methanol solution (100 mL) of sulfur (15.7 g) and cyanamide (22.6 g) was added at 0°C, and the mixture was stirred at room temperature for 16 hours.

[1585] The solvent was distilled off from the reaction mixture under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: petroleum ether / ethyl acetate / dichloromethane = 20 / 5 / 1 to 5 / 5 / 1 (V / V / V)] to obtain 91.8 g of the title compound as a yellow solid (yield: 67%).

[1586] (10b)

[1587] (5R * ,8S * )-tert-Butyl 2-amino-5,6,7,8-tetrahydro-4H-5,8-cycloiminocyclohepta[d][1,3]thiazole-9-carboxylate

[1588] tert-butyl(5R * ,8S * )-2-amino-5,6,7,8-tetrahydro-4H-5,8-epiminocyclohepta[d][1,3]thiazole-9-carboxylate

[1589] tert-Butyl 2-amino-5,6,7,8-tetrahydro-4H-5,8-cycloiminocyclohepta[d][1,3]thiazole-9-carboxylate (150 g) from Example 10 (10a) was subjected to chiral SFC (column: CHIRALPAKAD (150 mm*4.6 mm, 3 μm)) [mobile phase: 0.05% diethylamine / ethanol / carbon dioxide] to obtain 80 g of the enantiomer of Peak 1 (retention time: 1.962 min) and 78 g of the enantiomer of Peak 2 (retention time: 2.183 min). Petroleum ether / ethyl acetate / dichloromethane (100 mL / 10 mL / 5 mL) was added to the enantiomer of Peak 2, and the mixture was stirred at 50°C for 20 minutes. After cooling to room temperature, the precipitated solid was filtered to obtain 35 g of the title compound as a light yellow solid (yield: 24%).

[1590] (10c)

[1591] (5R * ,8S * tert-Butyl 2-[(methylcarbamoyl)amino]-5,6,7,8-tetrahydro-4H-5,8-cycloiminocyclohepta[d][1,3]thiazole-9-carboxylate

[1592] tert-butyl(5R * ,8S * )-2-[(methylcarbamoyl)amino]-5,6,7,8-tetrahydro-4H-5,8-epiminocyclohepta[d][1,3]thiazole-9-carboxylate

[1593] Using (5R * ,8S * )-tert-butyl 2-amino-5,6,7,8-tetrahydro-4H-5,8-cycloiminocyclohepta[d][1,3]thiazole-9-carboxylate (5.0 g) was added, and the title compound (5.4 g, yield: 95%) was obtained as a yellow solid by the same method as in Example 6 (6 g).

[1594] (10d)

[1595] N-methyl-N'-[(5R * ,8S * )-5,6,7,8-tetrahydro-4H-5,8-cycloiminocyclohepta[d][1,3]thiazol-2-yl]urea monohydrochloride

[1596] N-methyl-N'-[(5R * ,8S *)-5,6,7,8-tetrahydro-4H-5,8-epiminocyclohepta[d][1,3]thiazol-2-yl]urea--hydrogen chloride(1 / 1)

[1597] Using (5R * ,8S * )-tert-Butyl 2-[(methylcarbamoyl)amino]-5,6,7,8-tetrahydro-4H-5,8-cycloiminocyclohepta[d][1,3]thiazole-9-carboxylate (5.4 g) was added, and the title compound (4.2 g, yield: 96%) was obtained as a yellow solid by the same method as in Example 6 (6h).

[1598] (10e)

[1599] 3-(4-Fluorophenyl)-1,2,4-oxadiazol-5(4H)-one

[1600] 3-(4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one

[1601] 4-Fluoro-N'-hydroxybenzene-1-carboximidamide (CAS Registry No.: 22179-78-8) (24.0 g) was dissolved in tetrahydrofuran (300 mL), N,N-diisopropylethylamine (54.2 mL) was added, and then a solution of triphosgene (18.5 g) in tetrahydrofuran (50 mL) was added dropwise. The mixture was stirred at room temperature for 1 hour and then at 60°C for another 1 hour.

[1602] After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure. The resulting residue was dissolved in dichloromethane and extracted three times with a 1M aqueous sodium hydroxide solution. The combined aqueous layers were acidified with 1M hydrochloric acid, and the precipitated solid was filtered, washed with water, and dried under reduced pressure at 50°C to obtain 13.9 g of the title compound as a light yellow solid (yield: 50%).

[1603] (10f)

[1604] 5-Chloro-3-(4-fluorophenyl)-1,2,4-oxadiazole

[1605] 5-chloro-3-(4-fluorophenyl)-1,2,4-oxadiazole

[1606] Phosphorus oxychloride (148 g) and pyridine (7.5 mL) were added to 3-(4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (13.9 g) obtained in Example 10(10e) at room temperature, and the mixture was stirred at 130°C for 3 hours.

[1607] After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure. The resulting residue was dissolved in dichloromethane and washed with water and a saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 99 / 1 to 80 / 20 (v / v)] to obtain 11.2 g of the title compound as a light yellow solid (yield: 73%).

[1608] (10g)

[1609] N-{(5R * ,8S * )-9-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-5,6,7,8-tetrahydro-4H-5,8-cycloiminocyclohepta[d][1,3]thiazol-2-yl}-N'-methylurea

[1610] N-{(5R * ,8S * )-9-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-5,6,7,8-tetrahydro-4H-5,8-epiminocyclohepta[d][1,3]thiazol-2-yl}-N'-methylurea

[1611] The N-methyl-N'-[(5R * ,8S * )-5,6,7,8-tetrahydro-4H-5,8-cycloiminocyclohepta[d][1,3]thiazol-2-yl]urea monohydrochloride (800 mg) was dissolved in N,N-dimethylformamide (10 mL), and 5-chloro-3-(4-fluorophenyl)-1,2,4-oxadiazole (609 mg) prepared in Example 10(10f) and potassium carbonate (2.01 g) were added, followed by stirring at room temperature for 12 hours.

[1612] The reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: methanol / ethyl acetate = 1 / 99 to 20 / 80 (v / v)] to obtain 560 mg of the title compound as a yellow solid (yield: 48%).

[1613] (Example 11)

[1614] N-{9-[5-(4-Fluorophenyl)-1,2-oxazol-3-yl]-5,6,7,8-tetrahydro-4H-5,8-cycloiminocyclohepta[d][1,3]thiazol-2-yl}-N'-methylurea

[1615] (11a)

[1616] 8-Azabicyclo[3.2.1]octan-3-one monohydrochloride

[1617] 8-azabicyclo[3.2.1]octan-3-one--hydrogen chloride(1 / 1)

[1618] tert-Butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (CAS Reg. No.: 185099-67-6) (103 g) was dissolved in methanol (300 mL), 4 M hydrogen chloride-1,4-dioxane solution (320 mL) was added, and the mixture was stirred at room temperature for 20 hours.

[1619] The solvent was distilled off from the reaction mixture under reduced pressure to obtain 81 g of the title compound as a light yellow solid (yield: quantitative).

[1620] (11b)

[1621] 8-[5-(4-Fluorophenyl)-1,2-oxazol-3-yl]-8-azabicyclo[3.2.1]octan-3-one

[1622] 8-[5-(4-fluorophenyl)-1,2-oxazol-3-yl]-8-azabicyclo[3.2.1]octan-3-one

[1623] 8-Azabicyclo[3.2.1]octan-3-one monohydrochloride (2.0 g) from Example 11(11a) and N,N-diisopropylethylamine (5.4 mL) were dissolved in tetrahydrofuran (15 mL) and added dropwise to a tetrahydrofuran solution (15 mL) of 1,1-dibromoformaldehyde oxime (3.7 g) cooled to -20°C under a nitrogen atmosphere. The mixture was stirred at 0°C for 30 minutes. Subsequently, a toluene solution (30 mL) of triethylamine (5.2 mL) and 1-ethynyl-4-fluorobenzene (CAS Registry No.: 766-98-3) (1.8 g) was added, and the mixture was stirred at 80°C for 9.5 hours.

[1624] The reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluting solvent: petroleum ether / ethyl acetate = 1 / 0 to 3 / 1 (v / v)] to obtain 350 mg of the title compound as a yellow solid (yield: 8.4%).

[1625] (11c)

[1626] 9-[5-(4-Fluorophenyl)-1,2-oxazol-3-yl]-5,6,7,8-tetrahydro-4H-5,8-cycloiminocyclohepta[d][1,3]thiazol-2-amine

[1627] 9-[5-(4-fluorophenyl)-1,2-oxazol-3-yl]-5,6,7,8-tetrahydro-4H-5,8-epiminocyclohepta[d][1,3]thiazol-2-amine

[1628] 8-[5-(4-Fluorophenyl)-1,2-oxazol-3-yl]-8-azabicyclo[3.2.1]octan-3-one (0.15 g) of Example 11(11b) was dissolved in pyridine (15 mL), sulfur (29 mg) and cyanamide (340 mg) were added, and the mixture was stirred at 130°C for 1.5 hours.

[1629] The solvent was distilled off from the reaction mixture under reduced pressure, and the resulting residue was purified by thin-layer silica gel chromatography [developing solvent: petroleum ether / ethyl acetate = 1 / 1 (V / V)] to obtain 20 mg of the title compound as a yellow solid (yield: 12%).

[1630] (11d)

[1631] N-{9-[5-(4-Fluorophenyl)-1,2-oxazol-3-yl]-5,6,7,8-tetrahydro-4H-5,8-cycloiminocyclohepta[d][1,3]thiazol-2-yl}-N'-methylurea

[1632] N-{9-[5-(4-fluorophenyl)-1,2-oxazol-3-yl]-5,6,7,8-tetrahydro-4H-5,8-epiminocyclohepta[d][1,3]thiazol-2-yl}-N'-methylurea

[1633] Using 9-[5-(4-fluorophenyl)-1,2-oxazol-3-yl]-5,6,7,8-tetrahydro-4H-5,8-cycloiminocycloheptano[d][1,3]thiazol-2-amine (50 mg) from Example 11 (11c), the title compound (4.5 mg, yield: 7.9%) was obtained as a light yellow solid by the same method as Example 6 (6 g).

[1634] (Example 12)

[1635] N-{(5R * ,9S * )-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7,8,9-hexahydro-5,9-cycloiminocycloocta[d][1,3]thiazol-2-yl}-N'-methylurea

[1636] (12a)

[1637] N-{10-[3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7,8,9-hexahydro-5,9-cycloiminocycloocta[d][1,3]thiazol-2-yl}-N'-methylurea

[1638] N-{10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7,8,9-hexahydro-5,9-epiminocycloocta[d][1,3]thiazol-2-yl}-N'-methylurea

[1639] Using N-(4,5,6,7,8,9-hexahydro-5,9-cycloiminocycloocta[d][1,3]thiazol-2-yl)-N'-methylurea monohydrochloride (2.5 g) synthesized in the same manner as Examples 6(6f), 6(6g), and 6(6h) from tert-butyl 3-oxo-9-azabicyclo[3.3.1]nonane-9-carboxylate (CAS Registry No.: 512822-27-4), and 5-chloro-3-(4-fluorophenyl)-1,2,4-oxadiazole (1.5 g) from Example 10(10f), 2.8 g (yield: 95%) of the title compound were obtained as a yellow solid by the same method as Example 10(10g).

[1640] (12b)

[1641] N-{(5R * ,9S * )-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7,8,9-hexahydro-5,9-cycloiminocycloocta[d][1,3]thiazol-2-yl}-N'-methylurea

[1642] N-{(5R * ,9S * )-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7,8,9-hexahydro-5,9-epiminocycloocta[d][1,3]thiazol-2-yl}-N'-methylurea

[1643] N-{10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7,8,9-hexahydro-5,9-cycloiminocycloocta[d][1,3]thiazol-2-yl}-N'-methylurea (3.8 g) from Example 12(12a) was subjected to chiral SFC (column: CHIRALPAK AD (100 mm*4.6 mm, 3 μm)) [mobile phase: 0.05% diethylamine / isopropanol / carbon dioxide], and the enantiomers of Peak 1 (retention time: 1.827 min) and Peak 2 (retention time: 4.412 min) were separated. 1.5 g of the title compound was obtained as the enantiomer of Peak 1 (yield: 41%), as a light yellow solid.

[1644] (Example 13)

[1645] N-{(4S,8S)-10-[3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-methylurea

[1646] (13a)

[1647] N-{10-[3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-methylurea

[1648] N-{10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4-d][1,3]thiazol-2-yl}-N'-methylurea

[1649] Using N-methyl-N'-(4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl)urea monohydrochloride (40 g) of Example 6 (6h) and 5-chloro-3-(4-fluorophenyl)-1,2,4-oxadiazole (32 g) of Example 10 (10f), the title compound 25 g (yield: 51%) was obtained as a white solid by the same method as Example 10 (10 g).

[1650] (13b)

[1651] N-{(4S,8S)-10-[3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-methylurea

[1652] N-{(4S,8S)-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4-d][1,3]thiazol-2-yl}-N'-methylurea

[1653] N-{10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl}-N'-methylurea (50 g) of Example 13 (13a) was subjected to chiral SFC (column: CHIRALCELOD (100 mm*4.6 mm, 3 μm)) [mobile phase: 0.05% diethylamine / methanol / carbon dioxide] to obtain N-{(4R,8R)-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl}-N'-methylurea as a white solid. ,8,9-tetrahydro-5H-4,8-cycloiminooxacyclotriene[5,4-d][1,3]thiazol-2-yl}-N'-methylurea 22g (yield: 45%) (peak 1, retention time: 1.054min), and in addition, N-{(4S,8S)-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclotriene[5,4-d][1,3]thiazol-2-yl}-N'-methylurea 20g (yield: 43%) (peak 2, retention time: 1.599min) was obtained in the form of a white solid.

[1654] In addition, since the title compound was produced from the compound of Example 7 (7a), an intermediate whose absolute configuration had been determined, it was confirmed that the enantiomer of Peak 2 had the absolute configuration of the title compound.

[1655] (Example 14)

[1656] N-(10-{5-[3-(Difluoromethyl)phenyl]-1,3-oxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl)-N'-methylurea

[1657] (14a)

[1658] 3-(Difluoromethyl)benzaldehyde

[1659] 3-(difluoromethyl)benzaldehyde

[1660] Under a nitrogen atmosphere, 1-bromo-3-(difluoromethyl)benzene (CAS Registry No.: 29848-59-7) (2.0 g) was dissolved in tetrahydrofuran (40 mL), and n-butyllithium (2.5 M n-hexane solution, 4.1 mL) was slowly added at -78°C. After stirring at -78°C for 30 minutes, N,N-dimethylformamide (2 mL) was added, and the mixture was stirred at room temperature for 12 hours.

[1661] The reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: petroleum ether / ethyl acetate = 1 / 0-10 / 1 (v / v)] to obtain 0.30 g of the title compound as a yellow oil (yield: 20%).

[1662] (14b)

[1663] 5-[3-(Difluoromethyl)phenyl]-1,3-oxazole

[1664] 5-[3-(difluoromethyl)phenyl]-1,3-oxazole

[1665] 3-(Difluoromethyl)benzaldehyde (0.30 g) obtained in Example 14(14a) was dissolved in methanol (10 mL), p-toluenesulfonylmethyl isocyanide (0.38 g) and potassium carbonate (0.38 g) were added, and the mixture was stirred at 70°C for 1 hour.

[1666] The solvent was distilled off from the reaction mixture under reduced pressure, water was added to the resulting residue, and the reaction mixture was extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain 0.29 g (yield: 77%) of the title compound as a yellow oil.

[1667] (14c)

[1668] 2-Chloro-5-[3-(difluoromethyl)phenyl]-1,3-oxazole

[1669] 2-chloro-5-[3-(difluoromethyl)phenyl]-1,3-oxazole

[1670] Under a nitrogen atmosphere, 5-[3-(difluoromethyl)phenyl]-1,3-oxazole (0.29 g) from Example 14(14b) was dissolved in tetrahydrofuran (10 mL), and lithium bis(trimethylsilyl)amide (1 M tetrahydrofuran solution, 1.8 mL) was slowly added at -78°C. After stirring at -78°C for 30 minutes, hexachloroethane (0.42 g) was added, and the mixture was stirred at -78°C for 30 minutes and then at room temperature for 12 hours.

[1671] The reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The resulting residue was purified by thin-layer chromatography [developing solvent: petroleum ether / ethyl acetate = 10 / 1 (v / v)] to obtain 0.16 g of the title compound as a white solid (yield: 47%).

[1672] (14d)

[1673] N-(10-{5-[3-(Difluoromethyl)phenyl]-1,3-oxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl)-N'-methylurea

[1674] N-(10-{5-[3-(difluoromethyl)phenyl]-1,3-oxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4-d][1,3]thiazol-2-yl)-N'-methylurea

[1675] N-Methyl-N'-(4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl)urea monohydrochloride (0.24 g) from Example 6 (6h) was dissolved in dimethyl sulfoxide (2 mL), and 2-chloro-5-[3-(difluoromethyl)phenyl]-1,3-oxazole (0.16 g) from Example 14 (14c) and N,N-diisopropylethylamine (0.61 mL) were added, and the mixture was stirred at 100°C for 12 hours.

[1676] The reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The resulting residue was purified by high-performance liquid chromatography (column: Waters Xbridge; mobile phase: acetonitrile / 0.05% aqueous ammonia = 25 / 75 to 55 / 45 (v / v)) to obtain 97 mg of the title compound as a white solid (yield: 31%).

[1677] (Example 15)

[1678] N-{(4S,8S)-10-[5-(6-methoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-methylurea

[1679] N-{(4S,8S)-10-[5-(6-methoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4-d][1,3]thiazol-2-yl}-N'-methylurea

[1680] Using 2-(2-chloro-1,3-oxazol-5-yl)-6-methoxypyridine (0.10 g) synthesized from 6-methoxypyridine-2-carboxaldehyde (CAS Registry No.: 54221-96-4) in the same manner as in Examples 14(14b) and 14(14c), and N-methyl-N'-[(4S,8S)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]urea monohydrochloride (0.13 g) of Example 7(7b), 67 mg (yield: 35%) of the title compound were obtained as a pink solid by the same method as in Example 14(14d).

[1681] (Example 16)

[1682] N-{10-[5-(4-Fluorophenyl)-1,2-oxazol-3-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-methylurea

[1683] N-{10-[5-(4-fluorophenyl)-1,2-oxazol-3-yl]-4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4-d][1,3]thiazol-2-yl}-N'-methylurea

[1684] The synthesis was carried out in the same manner as in Example 11 (11b) using N-methyl-N'-(4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclotriene[5,4-d][1,3]thiazol-2-yl)urea monohydrochloride (0.65 g) of Example 6 (6h) to obtain 58 mg of the title compound as a yellow oil (yield: 6.3%).

[1685] (Example 17)

[1686] N-{(4S,8S)-10-[4-(4-Fluorophenyl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-methylurea

[1687] (17a)

[1688] 4-(4-Fluorophenyl)-1,3-oxazole

[1689] 4-(4-fluorophenyl)-1,3-oxazole

[1690] 2-Bromo-1-(4-fluorophenyl)ethan-1-one (CAS registration number: 403-29-2) (5.0 g) was dissolved in formic acid (10 mL), and ammonium formate (14.5 g) was added, followed by stirring at 130° C. for 8 hours.

[1691] Water was added to the reaction mixture, and the reaction mixture was extracted three times with ethyl acetate. The combined organic layers were washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 10 / 0 to 7 / 3 (v / v)] to obtain 1.2 g of the title compound as a yellow solid (yield: 32%).

[1692] (17b)

[1693] 2-Chloro-4-(4-fluorophenyl)-1,3-oxazole

[1694] 2-chloro-4-(4-fluorophenyl)-1,3-oxazole

[1695] The same synthesis as in Example 14(14c) was carried out using 4-(4-fluorophenyl)-1,3-oxazole (1.2 g) from Example 17(17a) to obtain 1.4 g (yield: 96%) of the title compound as a light yellow solid.

[1696] (17c)

[1697] (4S,8S)-4,7,8,9-Tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-amine dihydrochloride

[1698] (4S,8S)-4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4-d][1,3]thiazol-2-amine--hydrogen chloride(1 / 2)

[1699] Tert-butyl (4S,8S)-2-amino-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazole-10-carboxylate (15 g) of Example 7 (7a) was dissolved in ethanol (100 mL), and a 4 M hydrogen chloride-1,4-dioxane solution (100 mL) was added, followed by stirring at room temperature for 5 hours.

[1700] The solvent was distilled off from the reaction mixture under reduced pressure, and the mixture was azeotroped twice with toluene. The precipitated solid was washed with ethyl acetate / n-hexane to obtain 13.4 g (yield: 98%) of the title compound as a light yellow solid.

[1701] (17d)

[1702] (4S,8S)-10-[4-(4-Fluorophenyl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-amine

[1703] (4S,8S)-10-[4-(4-fluorophenyl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4-d][1,3]thiazol-2-amine

[1704] (4S,8S)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-amine dihydrochloride (2.0 g) from Example 17 (17c) was dissolved in dimethyl sulfoxide (20 mL), and 2-chloro-4-(4-fluorophenyl)-1,3-oxazole (1.4 g) and N,N-diisopropylethylamine (6.4 mL) from Example 17 (17b) were added. The mixture was stirred at 100°C for 12 hours and allowed to stand at room temperature overnight. The mixture was then stirred at 100°C for 11 hours and allowed to stand at room temperature overnight. The mixture was further stirred at 100°C for 12 hours, poured into water, and extracted three times with ethyl acetate. The combined organic layers were washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the resulting residue was purified by NH silica gel column chromatography [eluting solvent: methanol / ethyl acetate = 0 / 10-1 / 9 (V / V)] to obtain 0.64 g (yield: 24%) of the title compound as a yellow solid.

[1705] (17e)

[1706] N-{(4S,8S)-10-[4-(4-Fluorophenyl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-methylurea

[1707] N-{(4S,8S)-10-[4-(4-fluorophenyl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4-d][1,3]thiazol-2-yl}-N'-methylurea

[1708] (4S,8S)-10-[4-(4-fluorophenyl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxa[5,4-d][1,3]thiazol-2-amine (0.20 g) from Example 17(17d) was dissolved in tetrahydrofuran (4 mL), and 1,1'-carbonyldiimidazole (0.14 g) was added. The mixture was allowed to stand at room temperature overnight. Methylamine (2 mol / L tetrahydrofuran solution, 0.84 mL) was added, and the mixture was stirred at room temperature for 8 hours.

[1709] The solvent was distilled off from the reaction mixture under reduced pressure, and ethyl acetate was added to the resulting residue. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: methanol / ethyl acetate = 0 / 10-1 / 19 (v / v)] to obtain 0.13 g of the title compound as a light yellow solid (yield: 57%).

[1710] (Example 18)

[1711] N-{10-[3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-[(2R)-1-hydroxypropan-2-yl]urea

[1712] (18a)

[1713] 2-(Trimethylsilyl)ethyl 7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate

[1714] 2-(trimethylsilyl)ethyl 7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate

[1715] 2-(Trimethylsilyl)ethanol (199 g) and triethylamine (240 mL) were dissolved in tetrahydrofuran (800 mL). A tetrahydrofuran solution (400 mL) of triphosgene (173 g) was added dropwise at -10°C to -5°C over 40 minutes. The mixture was stirred at the same temperature for 20 minutes and then at room temperature for 2.5 hours. The precipitated white solid was filtered off, and the solvent was distilled off from the filtrate under reduced pressure to obtain a residue.

[1716] To an aqueous solution (700 mL) of 3-oxa-9-azabicyclo[3.3.1]nonan-7-one hydrochloride (99 g) obtained in Example 6 (6e-1) were added tetrahydrofuran (600 mL) and sodium bicarbonate (234 g). A tetrahydrofuran solution (450 mL) of the residue obtained above was added over 30 minutes, and the mixture was stirred at room temperature for 16 hours.

[1717] The reaction mixture was extracted three times with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was triturated with ethyl acetate / petroleum ether and collected by filtration to obtain 93 g of the title compound as a light yellow solid (yield: 58%).

[1718] (18b)

[1719] 2-(Trimethylsilyl)ethyl 2-amino-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazole-10-carboxylate

[1720] 2-(trimethylsilyl)ethyl 2-amino-4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4-d][1,3]thiazole-10-carboxylate

[1721] Using 2-(trimethylsilyl)ethyl 7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (90 g) from Example 18 (18a), synthesis was carried out in the same manner as in Example 6 (6f) to obtain 90 g of the title compound as a light yellow solid (yield: 61%).

[1722] (18c)

[1723] 2-(Trimethylsilyl)ethyl 2-[(tert-Butoxycarbonyl)amino]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazole-10-carboxylate

[1724] 2-(trimethylsilyl)ethyl 2-[(tert-butoxycarbonyl)amino]-4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4-d][1,3]thiazole-10-carboxylate

[1725] 2-(Trimethylsilyl)ethyl 2-amino-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazole-10-carboxylate (180 g) from Example 18 (18b) was dissolved in tetrahydrofuran (1 L), and triethylamine (102 g) and dimethylaminopyridine (1.5 g) were added. Subsequently, di-tert-butyl dicarbonate (152 g) was slowly added at 35°C to 40°C over 5 hours, and the mixture was stirred at 40°C for 16 hours.

[1726] Saturated brine was added to the reaction mixture, and after stirring at room temperature for 30 minutes, the reaction mixture was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluting solvent: petroleum ether / ethyl acetate = 5 / 1-2 / 1 (v / v)] to obtain 180 g of the title compound as a white solid (yield: 77%).

[1727] (18d)

[1728] tert-Butyl 4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-ylcarbamate

[1729] tert-butyl 4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4-d][1,3]thiazol-2-ylcarbamate

[1730] 2-[(tert-Butoxycarbonyl)amino]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazole-10-carboxylic acid-2-(trimethylsilyl)ethyl ester (183 g) of Example 18 (18c) was dissolved in tetrahydrofuran (600 mL), and tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution, 580 mL) was added, and the mixture was stirred at 40°C to 45°C for 16 hours.

[1731] The solvent was distilled off from the reaction mixture under reduced pressure, water was added to the resulting residue, and the reaction mixture was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and most of the solvent was distilled off under reduced pressure. The precipitated solid was filtered and washed with ethyl acetate (30 mL) to obtain 98 g of the title compound as a white solid (yield: 78%).

[1732] (18e)

[1733] 10-[3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-amine monohydrochloride

[1734] 10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4-d][1,3]thiazol-2-amine--hydrogen chloride(1 / 1)

[1735] Using tert-butyl {10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}carbamate (1.6 g) synthesized in the same manner as in Example 10 (10 g) from tert-butyl 4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-ylcarbamate of Example 18 (18d), 1.5 g (yield: quantitative) of the title compound was obtained as a white solid by the same method as in Example 6 (6h).

[1736] (18f)

[1737] Phenyl {10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}carbamate

[1738] phenyl {10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4-d][1,3]thiazol-2-yl}carbamate

[1739] 10-[3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-amine monohydrochloride (1.4 g) from Example 18(18e) was suspended in dichloromethane (50 mL), and triethylamine (2.0 mL) and phenyl chloroformate (1.1 g) were added, followed by stirring at 40°C for 3 hours. Phenyl chloroformate (1.1 g) was further added, and the mixture was stirred at 40°C for 12 hours.

[1740] The solvent was distilled off from the reaction mixture under reduced pressure, water was added to the resulting residue, and the reaction mixture was extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 3.0 g of the title compound as a brown oil (yield: quantitative).

[1741] (18g)

[1742] N-{10-[3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-N'-[(2R)-1-hydroxypropan-2-yl]urea

[1743] N-{10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4-d][1,3]thiazol-2-yl}-N'-[(2R)-1-hydroxypropan-2-yl]urea

[1744] Phenyl {10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl}carbamate (192 mg) of Example 18 (18f) was dissolved in 1,4-dioxane (2 mL), and pyridine (0.128 mL) and (2R)-2-aminopropan-1-ol (90 mg) were added, and the mixture was stirred at 80°C for 2 hours.

[1745] The solvent was distilled off from the reaction mixture under reduced pressure, and the resulting residue was purified by silica gel column chromatography [elution solvent: petroleum ether / ethyl acetate = 5 / 1-1 / 1 (V / V)]. The solvent was distilled off under reduced pressure, and the resulting residue was purified by high-performance liquid chromatography [chromatographic column: Phenomenex luna C18; mobile phase: acetonitrile / 0.225% formic acid aqueous solution = 36 / 64-56 / 44 (V / V)] to obtain 84 mg of the title compound as a white solid (yield: 45%).

[1746] (Example 19)

[1747] N-{6-acetyl-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azoc-2-yl}-N'-methylurea

[1748] (19a)

[1749] 2,5-Dihydro-1H-pyrrole monohydrochloride

[1750] 2,5-dihydro-1H-pyrrole--hydrogen chloride(1 / 1)

[1751] The same synthesis as in Example 6 (6h) was carried out using tert-butyl 2,5-dihydro-1H-pyrrole-1-carboxylate (CAS Registry No.: 73286-70-1) (10 g) to obtain 6.8 g (yield: 98%) of the title compound as a gray solid.

[1752] (19b)

[1753] 1-(2,5-Dihydro-1H-pyrrol-1-yl)ethan-1-one

[1754] 1-(2,5-dihydro-1H-pyrrol-1-yl)ethan-1-one

[1755] 2,5-Dihydro-1H-pyrrole monohydrochloride (8.9 g) of Example 19(19a) and triethylamine (23.5 mL) were dissolved in dichloromethane (150 mL), and acetyl chloride (7.3 mL) was added dropwise at 0°C, followed by stirring at 15°C for 2 hours.

[1756] The reaction mixture was diluted with dichloromethane, and the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The resulting residue was triturated with petroleum ether / ethyl acetate and filtered to obtain 8.3 g of the title compound as a yellow solid (yield: 80%).

[1757] (19c)

[1758] 3-Acetyl-9-benzyl-3,9-diazabicyclo[3.3.1]nonan-7-one

[1759] 3-acetyl-9-benzyl-3,9-diazabicyclo[3.3.1]nonan-7-one

[1760] 1-(2,5-dihydro-1H-pyrrol-1-yl)ethane-1-one (7.0 g) from Example 19 (19b) was dissolved in dichloromethane / methanol (100 mL / 10 mL), and sodium bicarbonate (4.8 g) was added. While stirring the reaction mixture at -78°C, ozone gas was blown into the mixture for 15 minutes. Then, nitrogen gas was blown into the mixture at -78°C for 15 minutes. Next, triphenylphosphine (7.4 g) was added, the temperature was slowly raised, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered, and about half of the solvent was distilled off from the filtrate under reduced pressure. 1,3-acetonedicarboxylic acid (5.6 g), 12M hydrochloric acid (1.6 mL), and benzylamine (4.2 mL) were added to the resulting residue, and the mixture was stirred at 15°C for 1 hour and at 50°C for 12 hours. The solvent was distilled off from the reaction mixture under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: petroleum ether / ethyl acetate = 3 / 1 - 0 / 1 (V / V)] to obtain 2.0 g (yield: 12%) of the title compound as a yellow solid.

[1761] (19d)

[1762] tert-Butyl 3-acetyl-7-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate

[1763] tert-butyl 3-acetyl-7-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate

[1764] 3-Acetyl-9-benzyl-3,9-diazabicyclo[3.3.1]nonan-7-one (1.4 g) of Example 19 (19c) was dissolved in ethanol (8 mL), and 1 M hydrochloric acid (7.1 mL) and 10% palladium on carbon (200 mg) were added, and the mixture was stirred at 20° C. under a hydrogen (30 psi) atmosphere for 16 hours.

[1765] The reaction mixture was filtered, and sodium bicarbonate (333 mg) and di-tert-butyl dicarbonate (317 mg) were added to the obtained filtrate, followed by stirring at 15°C for 16 hours.

[1766] The solvent was distilled off from the reaction mixture under reduced pressure, water was added to the resulting residue, and the reaction mixture was extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: petroleum ether / ethyl acetate = 3 / 1 to 2 / 1 (v / v)] to obtain 270 mg of the title compound as a colorless oil (yield: 72%).

[1767] (19e)

[1768] N-{6-acetyl-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azoc-2-yl}-N'-methylurea

[1769] N-{6-acetyl-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7,8,9-hexahydro-4,8-epimino[1,3]thiazolo[5,4-d]azocin-2-yl}-N'-methylurea

[1770] Using N-(6-acetyl-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azoc-2-yl)-N'-methylurea monohydrochloride (50 mg) synthesized in the same manner as in Example 10(10f) from tert-butyl 3-acetyl-7-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate of Example 19(19d) and Examples 6(6f), 6(6g) and 6(6h), and 5-chloro-3-(4-fluorophenyl)-1,2,4-oxadiazole (30 mg) of Example 10(10f), 21 mg (yield: 30%) of the title compound were obtained as a white solid.

[1771] (Example 20)

[1772] (5R)-3-{(4S,8S)-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-5-methylimidazoline-2,4-dione

[1773] (20a)

[1774] (4S,8S)-10-[3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-amine

[1775] (4S,8S)-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4-d][1,3]thiazol-2-amine

[1776] (4S,8S)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-amine dihydrochloride (4.59 g) of Example 17 (17c) was dissolved in N,N-dimethylformamide (100 mL), and 5-chloro-3-(4-fluorophenyl)-1,2,4-oxadiazole (4.04 g) of Example 10 (10f) and potassium carbonate (7.04 g) were added, and the mixture was stirred at room temperature for 24 hours.

[1777] The reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the resulting residue was triturated in ethyl acetate. The precipitated solid was filtered to obtain 4.08 g of the title compound as a light yellow solid (yield: 67%).

[1778] (20b)

[1779] N-({(4S,8S)-10-[3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}carbamoyl)-D-alanine

[1780] N-({(4S,8S)-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4-d][1,3]thiazol-2-yl}carbamoyl)-D-alanine

[1781] (4S,8S)-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-amine (0.30 g) from Example 20(20a) was dissolved in N,N-dimethylformamide (6 mL), 1,1'-carbonyldiimidazole (0.20 g) was added, and the mixture was allowed to stand at room temperature overnight. D-alanine (0.22 g) and triethylamine (0.58 mL) were added to the reaction mixture, and the mixture was stirred at 50°C for 3 hours. Ethyl acetate was added to the reaction mixture, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 0.46 g of the title compound as a yellow solid (yield: quantitative).

[1782] (20c)

[1783] (5R)-3-{(4S,8S)-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}-5-methylimidazoline-2,4-dione

[1784] (5R)-3-{(4S,8S)-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4-d][1,3]thiazol-2-yl}-5-methylimidazolidine-2,4-dione

[1785] N-({(4S,8S)-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclotriene[5,4-d][1,3]thiazol-2-yl}carbamoyl)-D-alanine (0.46 g) of Example 20 (20b) was dissolved in N,N-dimethylformamide (8 mL), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.28 g) and 4-dimethylaminopyridine (0.024 g) were added, and the mixture was allowed to stand at room temperature overnight.

[1786] Water was added to the reaction mixture, and the reaction mixture was extracted three times with ethyl acetate. The combined organic layers were washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: methanol / ethyl acetate = 0 / 10-1 / 9 (v / v)]. The resulting solid was washed with ethyl acetate / n-hexane to obtain 0.21 g of the title compound as a light yellow solid (yield: 48%).

[1787] (Example 21)

[1788] N-[(4S,8S)-10-{5-[3-(Cyclopropanecarbonyl)phenyl]-1,3,4-oxadiazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]-N'-methylurea

[1789] (21a)

[1790] 4-Nitrophenyl (4S,8S)-2-[(Methylcarbamoyl)amino]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazole-10-carboxylate

[1791] 4-nitrophenyl(4S,8S)-2-[(methylcarbamoyl)amino]-4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4-d][1,3]thiazole-10-carboxylate

[1792] N-Methyl-N'-[(4S,8S)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl]-N'-methylurea monohydrochloride (70 g) from Example 7(7b) was suspended in tetrahydrofuran (600 mL), and triethylamine (107 mL) was added. The reaction mixture was stirred for 10 minutes, and then 4-nitrophenyl chloroformate (46 g) was added, and the mixture was stirred at room temperature for 12 hours.

[1793] The reaction mixture was filtered and washed with tetrahydrofuran (200 mL). The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [elution solvent: petroleum ether / ethyl acetate = 1 / 1-0 / 1 (V / V)] to obtain 60 g of the title compound as a yellow solid (yield: 60%).

[1794] (21b)

[1795] N-[(4S,8S)-10-(hydrazinecarbonyl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]-N'-methylurea

[1796] N-[(4S,8S)-10-(hydrazinecarbonyl)-4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4-d][1,3]thiazol-2-yl]-N'-methylurea

[1797] 4-Nitrophenyl (4S,8S)-2-[(methylcarbamoyl)amino]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazole-10-carboxylate (60 g) from Example 21(21a) was dissolved in tetrahydrofuran (600 mL), hydrazine monohydrate (55.6 mL) was added, and the mixture was stirred at 70°C for 16 hours. The reaction mixture was cooled to room temperature, and the precipitated solid was collected by filtration and washed with tetrahydrofuran (150 mL). The resulting solid was triturated in ethyl acetate (150 mL) / methanol (45 mL) and collected by filtration to obtain 36 g of the title compound as a yellow solid (yield: 81%).

[1798] (21c)

[1799] N-[(4S,8S)-10-{2-[3-(cyclopropanecarbonyl)benzoyl]hydrazinecarbonyl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]-N'-methylurea

[1800] N-[(4S,8S)-10-{2-[3-(cyclopropanecarbonyl)benzoyl]hydrazinecarbonyl}-4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4-d][1,3]thiazol-2-yl]-N'-methylurea

[1801] N-[(4S,8S)-10-(hydrazinecarbonyl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl]-N'-methylurea (7.4 g) from Example 21 (21b) was dissolved in N,N-dimethylformamide (150 mL). 3-(Cyclopropanecarbonyl)benzoic acid (CAS Reg. No.: 34916-10-4) (5 g), 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (11.5 g), and triethylamine (10 mL) were added and allowed to stand at room temperature overnight. The reaction mixture was poured into water, acidified with 1N hydrochloric acid, and neutralized with saturated aqueous sodium bicarbonate. The reaction mixture was extracted twice with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: methanol / ethyl acetate = 0 / 10-1 / 9 (V / V)] to obtain 12.4 g of the title compound as a yellow solid (yield: quantitative).

[1802] (21d)

[1803] N-[(4S,8S)-10-{5-[3-(Cyclopropanecarbonyl)phenyl]-1,3,4-oxadiazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]-N'-methylurea

[1804] N-[(4S,8S)-10-{5-[3-(cyclopropanecarbonyl)phenyl]-1,3,4-oxadiazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4-d][1,3]thiazol-2-yl]-N'-methylurea

[1805] N-[(4S,8S)-10-{2-[3-(cyclopropanecarbonyl)benzoyl]hydrazinecarbonyl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl]-N'-methylurea (12.4 g) from Example 21 (21c) was suspended in dichloromethane (130 mL), p-toluenesulfonyl chloride (7.3 g) and triethylamine (10.7 mL) were added, and the mixture was allowed to stand at room temperature overnight. Water was added to the reaction mixture, and the reaction mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [elution solvent: methanol / ethyl acetate = 0 / 10-1 / 9 (V / V)] to obtain 7.5 g of the title compound as a light yellow solid (yield: 63%).

[1806] (Example 22)

[1807] N-[(4S,8S)-10-{5-[3-(Difluoromethoxy)phenyl]-1,3,4-oxadiazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]-N'-methylurea

[1808] N-[(4S,8S)-10-{5-[3-(difluoromethoxy)phenyl]-1,3,4-oxadiazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4-d][1,3]thiazol-2-yl]-N'-methylurea

[1809] Using N-methyl-N'-[(4S,8S)-10-{2-[3-(difluoromethoxy)benzoyl]hydrazinethiocarbonyl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]-N'-methylurea (3.8 g) synthesized in the same manner as in Examples 2(2a), 2(2b) and 3(3c) from N-methyl-N'-[(4S,8S)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatriene[5,4-d][1,3]thiazol-2-yl]urea monohydrochloride of Example 7(7b), the title compound (970 mg, yield: 27%) was obtained as a white solid by the same method as in Example 2(2d).

[1810] (Example 23)

[1811] (-)-N-{(4R * ,8R *)-6-acetyl-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azoc-2-yl}-N'-methylurea

[1812] (23a)

[1813] 2-(Trimethylsilyl)ethyl 2,5-dihydro-1H-pyrrole-1-carboxylate

[1814] 2-(trimethylsilyl)ethyl 2,5-dihydro-1H-pyrrole-1-carboxylate

[1815] 2-(Trimethylsilyl)ethanol (269 g) and triethylamine (330 mL) were dissolved in tetrahydrofuran (1.5 L). A tetrahydrofuran solution (400 mL) of triphosgene (225 g) was added dropwise at -10°C to -5°C over 60 minutes. The mixture was stirred at the same temperature for 30 minutes and then at room temperature for 1.5 hours. The precipitated white solid was filtered off, and the solvent was distilled off from the filtrate under reduced pressure to obtain a residue.

[1816] The 2,5-dihydro-1H-pyrrole monohydrochloride obtained in Example 19 (19a) was dissolved in tetrahydrofuran / water (500 mL / 700 mL), and sodium bicarbonate (250 g) was added. A tetrahydrofuran solution (400 mL) of the residue obtained previously was added over 60 minutes, and the mixture was stirred at room temperature for 16 hours. The organic layer was separated from the aqueous layer, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluting solvent: petroleum ether] to obtain 730 g of the title compound as a yellow oil (yield: quantitative).

[1817] (23b)

[1818] 2-(Trimethylsilyl)ethyl 9-benzyl-7-oxo-3,9-diazabicyclo[3.3.1]nonane-3-carboxylate

[1819] 2-(trimethylsilyl)ethyl 9-benzyl-7-oxo-3,9-diazabicyclo[3.3.1]nonane-3-carboxylate

[1820] Example 23b-1

[1821] 2-(Trimethylsilyl)ethyl 2,5-dihydro-1H-pyrrole-1-carboxylate (180 g) from Example 23 (23a) was dissolved in dichloromethane / methanol (1.5 L / 300 mL), and sodium bicarbonate (56.7 g) was added. Ozone gas was introduced while stirring the reaction mixture at -70°C for 8 hours. Then, nitrogen was introduced to replace the atmosphere. Triphenylphosphine (155 g) was added over 10 minutes at -60 to -20°C, the temperature was slowly increased, and the mixture was stirred at room temperature for 16 hours. The mixture was filtered to obtain a filtrate (0.84 mol, 1.8 L).

[1822] Example 23b-2

[1823] Example 23b-1 was carried out in two batches, and the filtrates were combined and used in the following reaction.

[1824] 1,3-Propanedicarboxylic acid (244 g) and 12M hydrochloric acid (40 mL) were added to the filtrate, and the mixture was cooled to 0° C. Benzylamine (200 mL) was added to the reaction mixture, and the mixture was stirred at 10-20° C. for 1 hour and at 50° C. for 16 hours.

[1825] The solvent was distilled off from the reaction mixture under reduced pressure, petroleum ether / ethyl acetate (3 L / 600 mL) was added to the residue, the precipitate was filtered, and the solvent was then distilled off from the filtrate under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluting solvent: petroleum ether / ethyl acetate = 50 / 1-5 / 1 (V / V)] to obtain 340 g of the title compound as a white solid (yield: 54%).

[1826] (23c)

[1827] 3-Acetyl-9-benzyl-3,9-diazabicyclo[3.3.1]nonan-7-one

[1828] 3-acetyl-9-benzyl-3,9-diazabicyclo[3.3.1]nonan-7-one

[1829] 2-(Trimethylsilyl)ethyl 9-benzyl-7-oxo-3,9-diazabicyclo[3.3.1]nonane-3-carboxylate (296 g) from Example 23 (23b) was dissolved in tetrahydrofuran (100 mL). Tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution, 1.39 L) was added, and the mixture was stirred at 50°C to 55°C for 16 hours under a nitrogen atmosphere. N,N-diisopropylethylamine (280 mL) was added to the reaction mixture, and after cooling to 5°C, acetyl chloride (100 mL) was slowly added over 30 minutes at 5°C to 10°C, followed by stirring at 15°C for 16 hours. The solvent was distilled off from the reaction mixture under reduced pressure, and ethyl acetate and water were added to the resulting residue, followed by extraction three times with ethyl acetate. The solvent was distilled off from the combined organic layers under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: petroleum ether / ethyl acetate = 5 / 1-0 / 1 (V / V); dichloromethane / ethyl acetate = 1 / 20 (V / V)] to obtain 298 g of the title compound as a yellow oil (yield: quantitative).

[1830] (23d)

[1831] tert-Butyl 3-acetyl-7-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate

[1832] tert-butyl 3-acetyl-7-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate

[1833] 3-Acetyl-9-benzyl-3,9-diazabicyclo[3.3.1]nonan-7-one (217 g) of Example 23 (23c) was dissolved in ethanol (700 mL), and 1 M hydrochloric acid (700 mL) and 10% palladium on carbon (20 g) were added, and the mixture was stirred at 40° C. for 16 hours under a hydrogen atmosphere (50 psi).

[1834] The reaction mixture was filtered, and sodium bicarbonate (134 g) was added to the resulting filtrate, followed by stirring for 30 minutes. Then, di-tert-butyl dicarbonate (240 g) was added, and the mixture was stirred at 25°C for 16 hours. Ethanol was distilled off from the reaction mixture under reduced pressure, and the residue was extracted five times with ethyl acetate. The combined organic layers were washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: petroleum ether / ethyl acetate = 3 / 1 - 1 / 1 (V / V); petroleum ether / ethyl acetate / dichloromethane = 1 / 1 / 1 (V / V / V)] to obtain 180 g of the title compound as a white solid (yield: 80%).

[1835] (23e)

[1836] tert-Butyl 6-acetyl-2-amino-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-10-carboxylate

[1837] tert-butyl 6-acetyl-2-amino-4,5,6,7,8,9-hexahydro-4,8-epimino[1,3]thiazolo[5,4-d]azocine-10-carboxylate

[1838] Using tert-butyl 3-acetyl-7-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate (180 g) from Example 23 (23d), the title compound (115 g, yield: 51%) was obtained as a light yellow solid in the same manner as in Example 6 (6f).

[1839] (23f)

[1840] (4R * ,8R * )-tert-Butyl 6-acetyl-2-amino-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-10-carboxylate

[1841] tert-butyl(4R * ,8R * )-6-acetyl-2-amino-4,5,6,7,8,9-hexahydro-4,8-epimino[1,3]thiazolo[5,4-d]azocine-10-carboxylate

[1842] (Optical resolution using chiral columns)

[1843] tert-Butyl 6-acetyl-2-amino-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-10-carboxylate (115 g) from Example 23 (23e) was subjected to chiral SFC (column: CHIRALPAK OD (250 mm*50 mm, 10 μm)) [mobile phase: 0.1% aqueous ammonia / isopropanol / carbon dioxide]. The enantiomers of Peak 1 (retention time: 1.414 min) and Peak 2 (retention time: 1.676 min) were separated. 55 g of the title compound was obtained as the enantiomer of Peak 2 (yield: 49%) as a light yellow solid.

[1844] (Optical resolution using diastereomeric salt method)

[1845] 6-Acetyl-2-amino-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-10-carboxylic acid tert-butyl ester (80 g) from Example 23 (23e) was dissolved in acetonitrile (800 mL). Ethyl acetate (15 L) was added to (+)-di-p-anisyl-L-tartaric acid (CAS Reg. No. 50583-51-2) (94 g). The mixture was stirred at 30°C for 1 hour and then at 70°C for 2 hours. The mixture was stirred for 16 hours while slowly cooling to room temperature. The precipitated solid was collected by filtration and washed with acetonitrile (50 mL). The resulting solid (87 g) was dissolved in acetonitrile (500 mL), stirred at 70°C for 2 hours, and then stirred for 10 hours while slowly cooling to room temperature. The precipitated solid was collected by filtration and washed with acetonitrile (50 mL). To the resulting solid (80 g) was added water (250 mL), and a 2M aqueous lithium hydroxide solution was added to adjust the pH to 7. The aqueous layer was extracted 10 times with ethyl acetate (400 mL). The combined organic layers were washed with a 1M aqueous lithium hydroxide solution (500 mL), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 31.5 g (yield: 41%) of the title compound as a white solid.

[1846] (23g)

[1847] (4R * ,8R * )-tert-Butyl-6-acetyl-2-[(methylcarbamoyl)amino]-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-10-carboxylate

[1848] tert-butyl(4R * ,8R * )-6-acetyl-2-[(methylcarbamoyl)amino]-4,5,6,7,8,9-hexahydro-4,8-epimino[1,3]thiazolo[5,4-d]azocine-10-carboxylate

[1849] Using (4R * ,8R * )-tert-Butyl 6-acetyl-2-amino-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-10-carboxylate (20.0 g) was added, and the title compound (30 g, quantitative yield) was obtained as a yellow solid by the same method as in Example 6 (6 g).

[1850] (23h)

[1851] N-[(4R * ,8R * )-6-acetyl-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azoc-2-yl]-N'-methylurea monohydrochloride

[1852] N-[(4R * ,8R * )-6-acetyl-4,5,6,7,8,9-hexahydro-4,8-epimino[1,3]thiazolo[5,4-d]azocin-2-yl]-N'-methylurea--hydrogen chloride(1 / 1)

[1853] Using (4R * ,8R * )-tert-Butyl 6-acetyl-2-[(methylcarbamoyl)amino]-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-10-carboxylate (30.0 g) was added and the title compound (31 g, quantitative yield) was obtained as a yellow solid by the same method as in Example 6 (6h).

[1854] (23i)

[1855] (-)-N-{(4R * ,8R * )-6-acetyl-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azoc-2-yl}-N'-methylurea

[1856] (-)-N-{(4R * ,8R * )-6-acetyl-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7,8,9-hexahydro-4,8-epimino[1,3]thiazolo[5,4-d]azocin-2-yl}-N'-methylurea

[1857] Using N-[(4R * ,8R *)-6-acetyl-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azoc-2-yl]-N′-methylurea monohydrochloride (31 g) was added and the title compound (19 g, yield: 47%) was obtained as a yellow solid by the same method as in Example 10 (10 g).

[1858] (Example 24)

[1859] (4R * ,8R * )-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-2-[(methylcarbamoyl)amino]-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylic acid (-)-methyl ester

[1860] (24a)

[1861] 9-tert-Butyl 3-[2-(Trimethylsilyl)ethyl]7-oxo-3,9-diazabicyclo[3.3.1]nonane-3,9-dicarboxylate

[1862] 9-tert-butyl 3-[2-(trimethylsilyl)ethyl]7-oxo-3,9-diazabicyclo[3.3.1]nonane-3,9-dicarboxylate

[1863] 2-(Trimethylsilyl)ethyl 9-benzyl-7-oxo-3,9-diazabicyclo[3.3.1]nonane-3-carboxylate (190 g) of Example 23 (23b) was dissolved in ethanol (700 mL), and 1 M hydrochloric acid (665 mL) and 10% palladium on carbon (10 g) were added, and the mixture was stirred at 40° C. under a hydrogen atmosphere (50 psi) for 16 hours.

[1864] The reaction mixture was filtered, and sodium bicarbonate (70 g) was added to the filtrate, followed by stirring for 30 minutes. Di-tert-butyl dicarbonate (152 g) was then added, and the mixture was stirred at 15° C. for 16 hours. Ethanol was distilled off from the reaction mixture under reduced pressure, and the precipitated solid was collected by filtration to obtain 190 g of the title compound as a white solid (yield: 98%).

[1865] (24b)

[1866] 10-tert-Butyl 6-[2-(Trimethylsilyl)ethyl]-2-amino-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6,10(5H)-dicarboxylate

[1867] 10-tert-butyl 6-[2-(trimethylsilyl)ethyl]2-amino-4,7,8,9-tetrahydro-4,8-epimino[1,3]thiazolo[5,4-d]azocine-6,10(5H)-dicarboxylate

[1868] Using 9-tert-butyl 3-[2-(trimethylsilyl)ethyl]-7-oxo-3,9-diazabicyclo[3.3.1]nonane-3,9-dicarboxylate (190 g) from Example 24 (24a), the title compound (150 g, yield: 69%) was obtained as a white solid by the same method as Example 6 (6f).

[1869] (24c)

[1870] 2-Amino-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6(5H)-10-carboxylic acid methyl ester dihydrochloride

[1871] methyl 2-amino-4,7,8,9-tetrahydro-4,8-epimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylate--hydrogen chloride(1 / 2)

[1872] 10-tert-Butyl 6-[2-(Trimethylsilyl)ethyl]-2-amino-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6,10(5H)-dicarboxylate (50 g) from Example 24(24b) was dissolved in tetrahydrofuran (50 mL). Tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution) (200 mL) was added, and the mixture was stirred at 50°C to 55°C for 16 hours under a nitrogen atmosphere. N,N-diisopropylethylamine (30 mL) was added to the reaction mixture, and after cooling to 5°C, methyl chloroformate (9.4 mL) was slowly added at 5°C to 10°C over 30 minutes, and the mixture was stirred at 15°C for 16 hours. The solvent was distilled off from the reaction mixture under reduced pressure, and ethyl acetate was added to the resulting residue. The mixture was washed three times with water, and then a 4M hydrogen chloride-ethyl acetate solution (120 mL) was added, followed by stirring at 15°C for 16 hours. The precipitated solid was collected by filtration and washed with ethyl acetate to obtain 38 g of the title compound as a white solid (yield: quantitative).

[1873] (24d)

[1874] 2-Amino-10-cyano-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6(5H)-10-carboxylic acid methyl ester

[1875] methyl 2-amino-10-cyano-4,7,8,9-tetrahydro-4,8-epimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylate

[1876] Methyl 2-amino-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6(5H)-10-carboxylate dihydrochloride (36 g) and sodium bicarbonate (37 g) from Example 24(24c) were dissolved in dichloromethane (300 mL) and water (50 mL). Cyanogen bromide (18 g) was added and stirred at 15°C for 16 hours. The reaction mixture was filtered and washed with dichloromethane / methanol (100 mL / 10 mL). The aqueous layer was extracted four times with dichloromethane, and the combined organic layers were dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: dichloromethane / methanol = 1 / 0 to 20 / 1 (V / V)] to obtain 17 g of the title compound as a white solid (yield: 60%).

[1877] (24e)

[1878] (4R * ,8R * )-2-amino-10-cyano-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylic acid methyl ester

[1879] methyl(4R * ,8R * )-2-amino-10-cyano-4,7,8,9-tetrahydro-4,8-epimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylate

[1880] Methyl 2-amino-10-cyano-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6(5H)-10-carboxylate (32 g) from Example 24 (24d) was subjected to chiral SFC (column: CHIRALPAK IC (250 mm*30 mm, 10 μm)) [mobile phase: 0.1% aqueous ammonia / ethanol / carbon dioxide]. The enantiomers of Peak 1 (retention time: 0.591 min) and Peak 2 (retention time: 0.964 min) were separated. As the enantiomer of Peak 2, 13.3 g of the title compound was obtained (yield: 43%) as a light yellow solid.

[1881] (24f)

[1882] (4R * ,8R * )-10-cyano-2-[(methylcarbamoyl)amino]-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylic acid methyl ester

[1883] methyl(4R * ,8R * )-10-cyano-2-[(methylcarbamoyl)amino]-4,7,8,9-tetrahydro-4,8-epimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylate

[1884] The (4R * ,8R * Methyl 2-amino-10-cyano-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylate (500 mg) and N,N-diisopropylethylamine (0.312 mL) were dissolved in tetrahydrofuran (5 mL). N-methylcarbamoyl chloride (251 mg) was added, and the mixture was stirred at 60°C for 12 hours. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the resulting residue was purified by high-performance liquid chromatography (column: Phenomenexlina C18; mobile phase: acetonitrile / 0.225% aqueous ammonium hydroxide solution = 3 / 97 to 33 / 67 (V / V)) to obtain 321 mg of the title compound as a white solid (yield: 53%).

[1885] (24g)

[1886] (4R *,8R * )-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-2-[(methylcarbamoyl)amino]-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylic acid (-)-methyl ester

[1887] (-)-methyl(4R * ,8R * )-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-2-[(methylcarbamoyl)amino]-4,7,8,9-tetrahydro-4,8-epimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylate

[1888] The (4R * ,8R * Methyl 10-cyano-2-[(methylcarbamoyl)amino]-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylate (150 mg) was dissolved in N,N-dimethylformamide (2 mL). 4-Fluoro-N'-hydroxybenzene-1-carboximidamide (CAS Registry Number: 22179-78-8) (89.4 mg), zinc chloride (12.2 mg), and p-toluenesulfonic acid monohydrate (15.4 mg) were added sequentially at room temperature, and the mixture was stirred at 80°C for 12 hours. The reaction mixture was filtered, and the filtrate was purified by high-performance liquid chromatography (column: Waters Xbridge; mobile phase: acetonitrile / 10 mM aqueous ammonium bicarbonate = 21 / 79 to 51 / 49 (V / V)) to obtain 31.4 mg of the title compound as a white solid (yield: 15%).

[1889] (Example 25)

[1890] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-[(1R,2R)-2-hydroxycyclopentyl]urea

[1891] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-[(1R,2R)-2-hydroxycyclopentyl]urea

[1892] Using 5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-amine (150 mg) and (1R,2R)-2-aminocyclopentane-1-ol hydrochloride (CAS Reg. No.: 68327-11-7) (242 mg) from Example 5 (5c), 66.6 mg (yield: 32%) of the title compound were obtained as a light yellow solid by the same method as in Example 5 (5d).

[1893] (Example 26)

[1894] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-[(1r,4r)-4-hydroxycyclohexyl]urea

[1895] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-[(1r,4r)-4-hydroxycyclohexyl]urea

[1896] Using 5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-amine (150 mg) and trans-4-aminocyclohexan-1-ol (CAS Reg. No.: 27489-62-9) (202 mg) from Example 5 (5c), 119 mg (yield: 56%) of the title compound were obtained as an orange solid by the same method as in Example 5 (5d).

[1897] (Example 27)

[1898] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-(3-methoxypropyl)urea

[1899] N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-(3-methoxypropyl)urea

[1900] Using 5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-amine (150 mg) and 3-methoxypropane-1-amine (CAS Reg. No.: 5332-73-0) (0.179 mL) from Example 5(5c), the title compound (99.5 mg, yield: 50%) was obtained as a light yellow solid by the same method as in Example 5(5d).

[1901] (Example 28)

[1902] N-{5-[3-(3,3-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-(2-hydroxy-2-methylpropyl)urea

[1903] N-{5-[3-(3,3-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-(2-hydroxy-2-methylpropyl)urea

[1904] Using tert-butyl 4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-ylcarbamate (International Publication No. 2013 / 134226) and 3-oxocyclohexanecarbonitrile (CAS Registry No. 17983-30-1) synthesized in the same manner as in Examples 1(1a), 1(1b), 1(1c), 1(1d), and 29(29b), and 1-amino-2-methylpropane-2-ol (0.146 mL), 84.6 mg of the title compound (yield: 48%) was obtained as a white solid by the same method as in Example 5(5d).

[1905] (Example 29)

[1906] N-{[(2S)-1,4-dioxan-2-yl]methyl}-N'-{(4S,8S)-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}urea

[1907] (29a)

[1908] tert-Butyl (4S,8S)-2-[({[(2S)-1,4-dioxan-2-yl]methyl}carbamoyl)amino]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazole-10-carboxylate

[1909] tert-butyl(4S,8S)-2-[({[(2S)-1,4-dioxan-2-yl]methyl}carbamoyl)amino]-4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4-d][1,3]thiazole-10-carboxylate

[1910] tert-Butyl (4S,8S)-2-amino-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazole-10-carboxylate (2 g) from Example 7(7a) was dissolved in N,N-dimethylformamide (40 mL), 1,1'-carbonyldiimidazole (1.64 g) was added, and the mixture was allowed to stand at room temperature overnight. (S)-(1,4-dioxan-2-yl)methanamine hydrochloride (2.07 g) and triethylamine (4.69 mL) were added, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, and the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 1 / 1 - 0 / 1 (V / V)] to obtain 2.9 g (yield: 98%) of the title compound as a pale yellow solid.

[1911] (29b)

[1912] N-{[(2S)-1,4-Dioxan-2-yl]methyl}-N'-[(4S,8S)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]urea

[1913] N-{[(2S)-1,4-dioxan-2-yl]methyl}-N'-[(4S,8S)-4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4-d][1,3]thiazol-2-yl]urea

[1914] tert-Butyl (4S,8S)-2-[({[(2S)-1,4-dioxan-2-yl]methyl}carbamoyl)amino]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazole-10-carboxylate (2.9 g) from Example 29(29a) was dissolved in dichloromethane (24 mL), trifluoroacetic acid (6 mL) was added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated and azeotroped twice with toluene. The resulting residue was purified by NH silica gel column chromatography [elution solvent: methanol / ethyl acetate = 0 / 10 to 25 / 75 (V / V)] to obtain 1.75 g of the title compound as a yellow solid (yield: 78%).

[1915] (29c)

[1916] N-{[(2S)-1,4-dioxan-2-yl]methyl}-N'-{(4S,8S)-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl}urea

[1917] N-{[(2S)-1,4-dioxan-2-yl]methyl}-N'-{(4S,8S)-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4-d][1,3]thiazol-2-yl}urea

[1918] N-{[(2S)-1,4-dioxan-2-yl]methyl}-N'-[(4S,8S)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxatrieno[5,4-d][1,3]thiazol-2-yl]urea (300 mg) from Example 29 (29b) was dissolved in N,N-dimethylformamide (5 mL), and 5-chloro-3-(4-fluorophenyl)-1,2,4-oxadiazole (210 mg) from Example 10 (10f) and potassium carbonate (365 mg) were added, followed by stirring at room temperature for 6 hours. Water was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: methanol / ethyl acetate = 0 / 10-15 / 85 (V / V)] to obtain 386 mg of the title compound as a pale yellow solid (yield: 87%).

[1919] (Example 30)

[1920] N-{10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-6-(methanesulfonyl)-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azoc-2-yl}-N'-oxan-4-ylurea

[1921] N-{10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-6-(methanesulfonyl)-4,5,6,7,8,9-hexahydro-4,8-epimino[1,3]thiazolo[5,4-d]azocin-2-yl}-N'-oxan-4-ylurea

[1922] Using 2-amino-10-cyano-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylic acid-2-(trimethylsilyl)ethyl ester and tetrahydro-2H-pyran-4-amine of Example 31(31b), N-{10-[3-( The title compound (12.9 mg, yield: 13%) was obtained as a white solid by the same method as in Example 31 (31d) to prepare 4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azoctan-2-yl]-N'-oxan-4-ylurea (85 mg).

[1923] (Example 31)

[1924] N-{10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-6-(methanesulfonyl)-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azoc-2-yl}-N'-methylurea

[1925] (31a)

[1926] 2-(Trimethylsilyl)ethyl 2-amino-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylate

[1927] 2-(trimethylsilyl)ethyl 2-amino-4,7,8,9-tetrahydro-4,8-epimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylate

[1928] 10-tert-Butyl 6-[2-(Trimethylsilyl)ethyl]-2-amino-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6,10(5H)-dicarboxylate (2.5 g) from Example 24(24b) was dissolved in ethanol (11 mL), p-toluenesulfonic acid monohydrate (2.37 g) was added, and the mixture was stirred at 65°C for 7 hours. Water was added to the reaction mixture, and the reaction mixture was extracted three times with chloroform. The combined organic layers were washed with saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 1.45 g of the title compound as a light yellow solid (yield: 74%).

[1929] (31b)

[1930] 2-(Trimethylsilyl)ethyl 2-amino-10-cyano-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylate

[1931] 2-(trimethylsilyl)ethyl 2-amino-10-cyano-4,7,8,9-tetrahydro-4,8-epimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylate

[1932] Using 2-amino-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylic acid-2-(trimethylsilyl)ethyl ester (1.45 g) of Example 31 (31a), 1.55 g (yield: quantitative) of the title compound was obtained as a light orange solid by the same method as Example 1 (1c).

[1933] (31c)

[1934] 2-(Trimethylsilyl)ethyl 10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-2-[(methylcarbamoyl)amino]-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylate

[1935] 2-(trimethylsilyl)ethyl 10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-2-[(methylcarbamoyl)amino]-4,7,8,9-tetrahydro-4,8-epimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylate

[1936] 10-Cyano-2-[(methylcarbamoyl)amino]-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylic acid-2-(trimethylsilyl)ethyl ester (600 mg) and 4-fluoro-N'-hydroxybenzene-1-carboxamidine (CAS Registry No. 55760-0006) were prepared in the same manner as in Example 5(5d) using 2-amino-10-cyano-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylic acid-2-(trimethylsilyl)ethyl ester and methylamine monohydrochloride of Example 31(31b). Number: 22179-78-8) (219 mg), and by the same method as in Example 1 (1d), 207 mg (yield: 26%) of the title compound were obtained as a light yellow solid.

[1937] (31d)

[1938] N-{10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-6-(methanesulfonyl)-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azoc-2-yl}-N'-methylurea

[1939] N-{10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-6-(methanesulfonyl)-4,5,6,7,8,9-hexahydro-4,8-epimino[1,3]thiazolo[5,4-d]azocin-2-yl}-N'-methylurea

[1940] N-{10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-2-[(methylcarbamoyl)amino]-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylic acid-2-(trimethylsilyl)ethyl ester prepared in Example 31(31c) was synthesized in the same manner as in Example 18(18d). -[3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azoc-2-yl}-N'-methylurea (51.1 mg) was dissolved in dichloromethane (1 mL), and triethylamine (0.051 mL) and methanesulfonyl chloride (0.014 mL) were added at 0°C, followed by stirring at 0°C for 1.5 hours. Triethylamine (0.111 mL) and methanesulfonyl chloride (0.048 mL) were added to the reaction mixture, and the mixture was stirred at 0°C for 3.5 hours. Triethylamine (0.111 mL) and methanesulfonyl chloride (0.048 mL) were then added, and the mixture was stirred at 0°C for 2 hours.

[1941] Water was added to the reaction mixture, and the mixture was extracted three times with chloroform using a phase separator (Biotage Japan Ltd.). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography [eluting solvent: hexane / ethyl acetate = 88 / 12 to 0 / 100 (v / v); ethyl acetate / methanol = 100 / 0 to 80 / 20 (v / v)] to obtain 7.1 mg of the title compound as a white solid (yield: 12%).

[1942] (Example 32)

[1943] 10-[3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl]-2-[(methylcarbamoyl)amino]-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylic acid propan-2-yl ester

[1944] propan-2-yl 10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-2-[(methylcarbamoyl)amino]-4,7,8,9-tetrahydro-4,8-epimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylate

[1945] N-{10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-2-[(methylcarbamoyl)amino]-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylic acid-2-(trimethylsilyl)ethyl ester prepared in Example 31(31c) was synthesized in the same manner as in Example 18(18d). -[3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azoctan-2-yl}-N'-methylurea (51.1 mg) was dissolved in dichloromethane (1 mL), and triethylamine (0.051 mL) and isopropyl chloroformate (0.021 mL) were added at 0°C, followed by stirring at 0°C for 16 hours. Triethylamine (0.111 mL) and isopropyl chloroformate (0.070 mL) were added to the reaction mixture, and the mixture was stirred ...

Claims

1. A compound of formula (1) or a pharmaceutically acceptable salt thereof, The symbols in formula (1) have the following meanings: R 1 、R 2 : are independently the same or different and represent a hydrogen atom or a C1-C6 alkyl group, Or, R 1 With R 2 are bonded to each other to form a substituent and represent any group selected from the following: R 12 : C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, or C1-C6 alkylsulfonyl; R 3 : represents a hydrogen atom or a C1-C6 alkyl group; R 6 :express C1-C6 alkyl which may be substituted by 1 to 3 groups selected from Group G, C3-C6 cycloalkyl which may be substituted by 1 or 2 groups selected from Group G, or A 4-7 membered heterocyclic group which may be substituted by 1 or 2 groups selected from Group G; Group G: Hydroxyl, halogen atom, amino, halogenated C1-C6 alkyl, Hydroxy C1-C6 alkyl, amino C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylsulfonyl, hydroxy C1-C6 alkoxy, C1-C6 alkylcarbonyl, Carbamoyl which may be substituted by 1 or 2 groups selected from Group J, C3-C6 cycloalkyl which may be substituted by 1 or 2 groups selected from Group J, A 4-7 membered heterocyclic group which may be substituted by 1 or 2 groups selected from Group J, or A 5-6 membered heteroaryl group which may be substituted by 1 or 2 groups selected from Group J; Group J: Hydroxyl, oxo, amino, C1-C6 alkyl, amino, C1-C6 alkyl, or C1-C6 alkylcarbonyl; R 7 : represents a hydrogen atom; or R 6 With R 7 They are bonded to each other to form a substituent and represent the following groups: The group can take any orientation from left to right; R 67-1 、R 67-2 : are independently the same or different and are a hydrogen atom, a C1-C6 alkyl group, Hydroxy C1-C6 alkyl, C1-C4 alkylene, or C1-C6 alkoxy C1-C6 alkyl; Q represents a 1,3-benzoxazol-2-yl group substituted by 1 or 2 groups independently selected from the group consisting of a fluorine atom, a methyl group, a methoxy group, an ethoxy group, a dimethylamino group and a methanesulfonyl group, and Y is a single bond; or Q means: Cyclohexyl substituted with 2 fluorine atoms, Phenyl substituted by fluorine atom or cyclopropylcarbonyl, or a pyridyl group substituted by one group selected from the group consisting of a methoxy group, an ethoxy group and a difluoromethoxy group, Y represents any group selected from the following:

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are hydrogen atoms, or R 1 With R 2 are bonded to each other to form a substituent and represent any group selected from the following: R 12 : methyl, hydroxyethyl, acetyl, methoxycarbonyl, or methanesulfonyl; R 3 represents a hydrogen atom or a methyl group.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are hydrogen atoms, or R 1 With R 2 are bonded to each other to form a substituent and represent any group selected from the following: R 13 : acetyl, or methoxycarbonyl; R 3 Represents a hydrogen atom.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 3 All represent methyl, R 2 Represents a hydrogen atom.

5. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R 6 represents any group selected from the following: C1-C6 alkyl, Hydroxy C1-C6 alkyl, Hydroxyl C3-C6 cycloalkyl, C1-C6 alkoxy C1-C6 alkyl, Tetrahydrofuranyl, Tetrahydropyranyl, or Dioxanylmethyl; R 7 Represents a hydrogen atom.

6. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R 6 is any group selected from the following: methyl, Isobutyl, 2-Hydroxy-1-methylethyl, 2-Hydroxy-2-methylpropyl, 3-Hydroxybutyl, 2-Hydroxycyclopentyl, 4-Hydroxycyclohexyl, 2-methoxypropyl, 3-tetrahydrofuranyl, 4-tetrahydropyranyl, or 1,4-dioxane-2-ylmethyl; R 7 A hydrogen atom.

7. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein: Q represents a 1,3-benzoxazol-2-yl group substituted by 1 or 2 groups independently selected from the group consisting of a fluorine atom, a methyl group, a methoxy group, an ethoxy group, a dimethylamino group and a methanesulfonyl group, Y is a single bond.

8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein Q means: Cyclohexyl substituted with 2 fluorine atoms, Phenyl substituted by fluorine atom or cyclopropylcarbonyl, or a pyridyl group substituted by one group selected from the group consisting of a methoxy group, an ethoxy group and a difluoromethoxy group, Y represents any group selected from the following:

9. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the following compounds: N-[(4S,8S)-10-{5-[3-(cyclopropanecarbonyl)phenyl]-1,3,4-oxadiazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl]-N'-methylurea, (-)-N-{(4R * ,8R * )-6-acetyl-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7,8,9-hexahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocin-2-yl}-N'-methylurea, (4R * ,8R * )-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-2-[(methylcarbamoyl)amino]-4,7,8,9-tetrahydro-4,8-cycloimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylic acid (-)-methyl ester, N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-[(1R,2R)-2-hydroxycyclopentyl]urea, N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-[(1r,4r)-4-hydroxycyclohexyl]urea, N-{5-[3-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}-N'-(3-methoxypropyl)urea, N-{[(2S)-1,4-dioxane-2-yl]methyl}-N'-{(4S,8S)-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl}urea, N-[(2R)-1-hydroxypropane-2-yl]-N'-[(4S,8S)-10-(5-methoxy-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl]urea, N-[(4S,8S)-10-(5-fluoro-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl]-N'-[(2R)-1-hydroxypropane-2-yl]urea, N-[(4S,8S)-10-(5-ethoxy-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl]-N'-(2-hydroxy-2-methylpropyl)urea, N-{(4S,8S)-10-[5-(dimethylamino)-1,3-benzoxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl}-N'-(2-hydroxy-2-methylpropyl)urea, N-[(4S,8S)-10-(5,6-difluoro-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl]-N'-[(2R)-1-hydroxypropane-2-yl]urea, N-{(4S,8S)-10-[5-(methanesulfonyl)-1,3-benzoxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl}-N'-(2-methylpropyl)urea, N-(2-hydroxy-2-methylpropyl)-N'-[(4S,8S)-10-(5-methoxy-6-methyl-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl]urea, N-[(4S,8S)-10-(5-methoxy-6-methyl-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl]-N'-[(3R)-oxolan-3-yl]urea, N-(2-hydroxy-2-methylpropyl)-N'-[(4S,8S)-10-(5-methoxy-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl]urea, N-[(4S,8S)-10-(5-methoxy-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl]-N'-[(3R)-oxolan-3-yl]urea, N-[(4S,8S)-10-(5-methoxy-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl]-N'-methylurea, N-methyl-N'-[(4S,8S)-10-(5-methyl-1,3-benzoxazol-2-yl)-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl]urea, N-(2-Hydroxy-2-methylpropyl)-N'-[(4S,8S)-10-{5-[( 2 H3) methyloxy]-1,3-benzoxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl]urea, N-{(4S,8S)-10-[5-(4-fluorophenyl)-1,2-oxazol-3-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl}-N'-[(1s,4s)-4-hydroxycyclohexyl]urea, N-{(4S,8S)-10-[5-(6-methoxypyridin-2-yl)-1,2-oxazol-3-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl}-N'-oxacyclohexane-4-ylurea, N-[(4S,8S)-10-{5-[6-(difluoromethoxy)pyridin-2-yl]-1,3-oxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl]-N'-[(2R)-1-hydroxypropane-2-yl]urea, N-[(2R)-1-hydroxypropane-2-yl]-N'-{(4S,8S)-10-[5-(6-methoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl}urea, N-{(4S,8S)-10-[5-(6-ethoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl}-N'-[(2R)-1-hydroxypropane-2-yl]urea, N-[(2R)-1-hydroxypropane-2-yl]-N'-{5-[5-(methanesulfonyl)-1,3-benzoxazol-2-yl]-6,6-dimethyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}urea, N-(2-hydroxy-2-methylpropyl)-N'-{5-[5-(methanesulfonyl)-1,3-benzoxazol-2-yl]-6,6-dimethyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl}urea, N-[(2R)-1-Hydroxypropan-2-yl]-N'-[(4S,8S)-10-{5-[( 2 H3) methyloxy]-1,3-benzoxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl]urea, N-[(4S,8S)-10-{5-[( 2 H3) methyloxy]-1,3-benzoxazol-2-yl}-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl]-N'-[(3R)-oxolan-3-yl]urea, N-[(1r,3S)-3-hydroxycyclobutyl]-N'-{(4S,8S)-10-[5-(6-methoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl}urea, N-{(4S,8S)-10-[5-(6-ethoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl}-N'-(2-hydroxy-2-methylpropyl)urea, N-{(4S,8S)-10-[5-(6-ethoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl}-N'-[(1r,3S)-3-hydroxycyclobutyl]urea, N-{(4S,8S)-10-[5-(6-methoxypyridin-2-yl)-1,3-oxazol-2-yl]-4,7,8,9-tetrahydro-5H-4,8-cycloiminooxacyclo[5,4-d][1,3]thiazol-2-yl}-N'-oxan-4-ylurea. 10 . A SIRT6 activator comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

11. A pharmaceutical composition comprising the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition according to claim 11 , which is an oral preparation. The pharmaceutical composition according to claim 11 , which is an external preparation.

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